Anticancer activities of bis(pyrazol-1-ylthiocarbonyl)disulfides against HeLa cells

Journal of Chemical Research www.scilet.com Contents

Issue No. 5 JRPSDC

Research Papers 269

Ferric hydrogensulfate as a recyclable catalyst for the synthesis of some new bis(indolyl)methane derivatives Mohammad Rahimizadeh, Hossein Eshghi, Zahra Bakhtiarpoor and Mehdi Pordel

271

Four-component reaction of isocyanides, acetylenic esters, and carboxylic acids for the synthesis of functionalised 2,5-diaminofurans Mohammad Anary-Abbasinejad, Maryam Rasekh and Hossein Anaraki-Ardakani

274

Synthesis, crystal structures and spectra properties of two new Cu(II) complexes containing thiocyanato anions as ancillary ligand Xiuqing Zhang, Hedong Bian, Wen Gu, Jingyuan Xu, Shiping Yan and Hong Liang

277

Chemistry of phosphorus ylides. Part 27. Metal complexes of4-hydroxyquinaldine, its Mannich base and phosphonium ylide Fouad Soliman, Ibrahim Abd-Ellah, Soher Maigali and Gamal Abd-El-Naim

283

EPR studies on carboxylic esters. Part 20. EPR spectra and spin densities in radical anions of isocoumarin, benzocoumarin and their sulfur analogues Jürgen Voss, Gabriele Kupczik and Heidi Stahncke

287

Solid-phase synthesis of aryl vinyl ethers based on polystyrene-supported β-phenylselenoethanol Jia-Li Zhang, Shou-Ri Sheng, Xue Liu and Shu-Ying Lin

290

Synthesis and anti-bacterial screening of ethyl 6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole-2-carboxylate and 7-phenyl-5H-pyran o[3’,2’:4,5]indolo[1,2-a]quinoxaline-6,10-dione Abid Ali Mir and Vinata V. Mulwad

293

Synthesis of 8-methyl[2.2]metacyclophanes and their charge-transfer complexes with tetracyanoethylene Tomoe Shimizu, Katsuhiro Hita, Shofiur Rahman and Takehiko Yamato

298

ipso-Acylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]metacyclophane with acid anhydrides: through-space electronic interaction among the two benzene rings Tomoe Shimizu, Arjun Paudel and Takehiko Yamato

302

Regio-controlled Michaelis–Arbuzov reactions of 3-(halomethyl)-coumarins Thompo J. Rashamuse, Musiliyu A. Musa, Rosalyn Klein and Perry T. Kaye

306

A new norditerpenoid alkaloid from Delphinium densiflorum Jian-Yun Sun and Tian-Cheng Li

308

Stereochemistry of products of reactions between 3-diazo-naphthalene-1,2,4-trione and β-dicarbonyl compounds. Structure of ethyl 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hydrazono]-3-phenyl-3-oxo-propionate Fernando de C. da Silva, Vitor F. Ferreira, Patrícia de O. Lopes, James L. Wardell and Solange M. S. V. Wardell

312

Synthesis of perialkynylated tetrapyrazinoporphyrazines and its optical properties Chun Keun Jang and Jae Yun Jaung

317

Synthesis of novel Schiff bases from the reaction of 3-O-methyl-4, 6-O-benzylidene-β-D-glucopyranosylamine with substituted aldehydes Chao Shen, Qing Zhao, Hui Zheng and Pengfei Zhang

319

Stereoselective synthesis of 3-[2-(dialkoxyphosphoryl)-1,2-dialkoxy-carbonyl-ethyl]-4-hydroxycoumarins by reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and 4-hydroxycoumarin Mohammad Anary-Abbasinejad, Khadijeh Charkhati and Alireza Hassanabadi

322

Anticancer activities of bis(pyrazol-1-ylthiocarbonyl)disulfides against HeLa cells Frankline K. Keter, Margo J. Nell, Ilia A. Guzei, Bernard Omondi and James Darkwa

326

Vicinal benzo[b]thiophene-5,6-dicarboxaldehyde in heterocyclic synthesis: a reagent for fluorescence determination of amino acids Mohamed A. El-Borai and Hala F. Rizk

329

Synthesis of functionalised phosphonates or phosphoranes by reaction between trialkyl phosphites or triphenylphosphine, dimethyl acetylenedicarboxylate and aldehyde ethyl carbazones Mohammad Anary-Abbasinejad, Mohammad H. Mosslemin, Alireza Hassanabadi and Alimohammad Dehghan

333

The synthesis of benzimidazole derivatives in the absence of solvent and catalyst Chuanming Yu, Peng Guo, Can Jin and Weike Su

Journal of Chemical Research 2009

Issue 5

May Pages 269-336

Reviews and Research Papers from all branches of Chemistry

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0308-2342(2009)2009:5;1-J

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Journal of Chemical Research 2009     Issue 5     May     Pages 269–336

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ISSN 0308-2342

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Journal of Chemical Research 2009 ISSN 0308-2342

Issue No. 5 JRPSDC

This journal is covered by the following secondary information sources: Chemical Abstracts, Current Contents, Current Abstracts of Chemistry/Index Chemicus, Current Chemical Reactions, Current Bibliography on Science and Technology, Science Citation Index, Bulletin Signalétique, Referativnyi Zhurnal and ChemInform

Contents Research Papers 269

Ferric hydrogensulfate as a recyclable catalyst for the synthesis of some new bis(indolyl)methane derivatives

R

R2

R2

H N H

Mohammad Rahimizadeh, Hossein Eshghi, Zahra Bakhtiarpoor and Mehdi Pordel 271

Four-component reaction of isocyanides, acetylenic esters, and carboxylic acids for the synthesis of functionalised 2,5-diaminofurans

R'O2C _ + 2R N C +

1

R R1

N H

R'O2C

CO2R'

R O R"

Mohammad Anary-Abbasinejad, Maryam Rasekh and Hossein Anaraki-Ardakani 274

N

O

OH

CO2R' O

R"

N

H

R

Synthesis, crystal structures and spectra properties of two new Cu(II) complexes containing thiocyanato anions as ancillary ligand

Xiuqing Zhang, Hedong Bian, Wen Gu, Jingyuan Xu, Shiping Yan and Hong Liang 277

Chemistry of phosphorus ylides. Part 27. Metal complexes of4-hydroxyquinaldine, its Mannich base and phosphonium ylide

OH

N

Fouad Soliman, Ibrahim Abd-Ellah, Soher Maigali and Gamal Abd-El-Naim 283

M X

EPR studies on carboxylic esters. Part 20. EPR spectra and spin densities in radical anions of isocoumarin, benzocoumarin and their sulfur analogues

JCR_05_2009 Book.indb 1

X

– – X Y

Jürgen Voss, Gabriele Kupczik and Heidi Stahncke

CH3

X

X, Y = O, S

Y

28/5/09 11:54:01

CONTENTS

287

Solid-phase synthesis of aryl vinyl ethers based on polystyrene-supported β-phenylselenoethanol

R

Synthesis and anti-bacterial screening of ethyl 6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole2-carboxylate and 7-phenyl-5H-pyrano [3',2':4,5]indolo[1,2-a]quinoxaline-6,10-dione

R

OCH=CH2

Ph3P/DEAD

Jia-Li Zhang, Shou-Ri Sheng, Xue Liu and Shu-Ying Lin 290

OH

THF/NMM, rt

O

R1

O

O

R1 O

NaNo2 HCl

+ N

NH2

Abid Ali Mir and Vinata V. Mulwad 293

R2

NCl

R2

NC

Synthesis of 8-methyl[2.2]metacyclophane s and their charge-transfer complexes with tetracyanoethylene

CN C

C CN

NC Me Me

Me Me

Tomoe Shimizu, Katsuhiro Hita, Shofiur Rahman and Takehiko Yamato 298

ipso-Acylation of 5,13-di-tert-butyl-8,16-dimet hyl[2.2]metacyclophane with acid anhydrides: through-space electronic interaction among the two benzene rings Tomoe Shimizu, Arjun Paudel and Takehiko Yamato

302

R

Me

(RCO)2O Lewis acid CH2Cl2 0°C for 2h

Me

O Me +

O

Me

Thompo J. Rashamuse, Musiliyu A. Musa, Rosalyn Klein and Perry T. Kaye A new norditerpenoid alkaloid from Delphinium densiflorum Jian-Yun Sun and Tian-Cheng Li

JCR_05_2009 Book.indb 2

Me

Me

R

Regio-controlled Michaelis–Arbuzov reactions of 3-(halomethyl)-coumarins 3

d+ :Nu

1' X 2 O d+ O

4

308

+

O

Me

R

d+

306

Me

R

R X = I o r Cl

OCH3 OH

OAc

N

OCH3 OH

OH

Stereochemistry of products of reactions between 3-diazo-naphthalene-1,2,4-trione and β-dicarbonyl compounds. Structure of ethyl 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen2-yl)-hydrazono]-3-phenyl-3-oxo-propionate Fernando de C. da Silva, Vitor F. Ferreira, Patrícia de O. Lopes, James L. Wardell and Solange M. S. V. Wardell

28/5/09 11:54:07

contents

312

R1

Synthesis of perialkynylated tetrapyrazinoporphyrazines and its optical properties

R2

N R2

N

N

N

N

N

N N

317

322

N

N

R2

N M= Mg, 2H

R2

Synthesis of novel Schiff bases from the reaction of 3-O-methyl-4, 6-O-benzylideneβ-D-glucopyranosylamine with substituted aldehydes

Ph

R1

O O

O

H 3CO

Chao Shen, Qing Zhao, Hui Zheng and Pengfei Zhang 319

N

N M N

R1

Chun Keun Jang and Jae Yun Jaung

R1

N

N

Stereoselective synthesis of 3-[2-(dialkoxyphosphoryl)-1,2-dialkoxycarbonyl-ethyl]-4-hydroxycoumarins by reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and 4-hydroxycoumarin Mohammad Anary-Abbasinejad, Khadijeh Charkhati and Alireza Hassanabadi

N

OH

H

P(OR)3

OH

CO2R' O P

OH

+ O

Ar

CH3CN, r.t.

O

O

O

OR OR CO2R'

R'O2C C C CO2R'

Anticancer activities of bis(pyrazol1-ylthiocarbonyl)disulfides against HeLa cells

Frankline K. Keter, Margo J. Nell, Ilia A. Guzei, Bernard Omondi and James Darkwa 326

Vicinal benzo[b]thiophene-5,6-dicarboxaldehyde in heterocyclic synthesis: a reagent for fluorescence determination of amino acids

SCH2CH2OH N

Mohamed A. El-Borai and Hala F. Rizk 329

333

Synthesis of functionalised phosphonates or phosphoranes by reaction between trialkyl phosphites or triphenylphosphine, dimethyl acetylenedicarboxylate and aldehyde ethyl carbazones Mohammad Anary-Abbasinejad, Mohammad H. Mosslemin, Alireza Hassanabadi and Alimohammad Dehghan The synthesis of benzimidazole derivatives in the absence of solvent and catalyst

S

P(OR)3 Ar

N

H N

OEt O

NH2 NH2

Chuanming Yu, Peng Guo, Can Jin and Weike Su

JCR_05_2009 Book.indb 3

CH3

+

CH3CN, r.t.

CH3O2C C C CO2CH3

+

NC R

R = Aryl, heteroary

O

OR P OR

N

OEt

H3CO2C Ar

N

CO2CH3

O

CN

N

H

N H

R

86-95%

28/5/09 11:54:13

CONTENTS

Reviews Short reviews are published in Journal of Chemical Research. These are normally commissioned, but authors who are interested in contributing such a review should make contact with one of the Editors. Reviews should be between 2,000 and 5,000 words in length, and authors will be remunerated at a rate of £40 ($60) per printed page. The previous topics were: J. Eames and N. Weerasooriya, Recent Studies on the regioselective C-protonation of enol derivatives using carbonyl-containing proton donors. J. Chem. Research (S), 2001, 2-8. J.R. Hanson, A.J.M. Sanchez and C. Uyanik, Applications of tetracyanoethylene as a p-acid catalyst. J. Chem. Research (S), 2001, 121-123. K. Hemming, Recent developments in the synthesis, chemistry, and applications of the fully unsaturated 1,2,4-oxadiazoles. J. Chem. Research (S), 2001, 209-216. A.G. Davies, The generation of organic radical cations: a guide to current practice for EPR spectroscopic studies. J. Chem. Research (S), 2001, 253-261. D.J. Evans, Metal-sulfur chemistry with a view to modelling the active sites of some enzymes of environmental importance. J. Chem. Research (S), 2001, 297-303. L.J. Twyman and A.S.H. King, Catalysis using peripherally functionalized dendrimers J. Chem. Research (S), 2002, 43-59. R.L. Richards and M.C. Durrant, Copper complexes with N-donor ligands as models of the active centres of nitrite reductase and related enzymes. J. Chem. Research (S), 2002, 95-98. T. Thiemann and K.G. Dongol, Thiophene S-oxides. J. Chem. Research (S), 2002, 303-308. R.A. Henderson, Protonation mechanisms of nickel complexes relevant to industrial and biological catalysis. J. Chem. Research (S), 407-411. W. Levason and G. Reid, Early transition metal complexes of polydentate and marcrocyclic thio- and seleno-ethers. J. Chem. Research (S), 2002, 1-5. J.R. Hanson, Directing effects in the hydroboration of steroidal alkenes. J. Chem. Research, 2004, 1-5. Z.V. Todres, Recent advances in the study of mechanochromic transitions of organic compounds. J. Chem. Research, 2004, 89-93. S. Ghosh, Recent research and development in synthetic polymer-based drug delivery systems. J. Chem. Research, 2004, 241-246. A.G. Davies, Difunctional distannoxanes. J. Chem. Research, 2004, 241-246 J.A.R. Salvador and J.R. Hanson, Solid phase oxidation of steroidal alkenes with potassium permanganate and metal salts. J. Chem. Research, 2004, 513-516 K. Hemming and C. Loukou, Synthetic approaches to 1,2,5-benzothiadiazepine 1,1-dioxides: sulphonamide analogues of 1,4-benzodiazepines. J. Chem. Research, 2005, 1-12. J.R. Hanson, General dienol:benzene rearrangement of ring A of the steroids. J. Chem. Research, 2005, 141-146. N.L. Lancaster, Organic reactivity in ionic liquids: some mechanistic insights into nucleophiloic substitution reactions. J. Chem. Research, 2005, 413-417. A.G. Davies, Recent advances in the chemistry of the organotin hydrides. J. Chem. Research, 2006, 141-148. Goreti Ribeiro Morais, Masataka Watanabe, Masao Imai, Naho Yoshioka, Tomohiro Matsumoto, Shuntaro Mataka and Thies Thiemann, Ring D 16,17–heteroannelated estranes. J.Chem. Research, 2006, 617-622. Simón E. López, Jelem Restrepo and José Salazar, Polyphosphoric acid trimethylsilylester: a useful reagent for organic synthesis. J.Chem. Research, 2007, 497-502. Dennis N. Kevill and Malcolm J. D’Souza, Sixty years of the Grunwald–Winstein equation: development and recent applications. J.Chem. Research, 2008, 61-66. Po S. Poon, Ajoy K. Banerjee, William J. Vera, Henry D. Mora, Manuel S. Laya, Liadis Bedoya, Elvia V. Cabrera and Carlos E. Melean, Use of 5-methoxy, 6-methoxy and 7-methoxy-a-tetralones in the synthesis of diterpenes, sesquiterpenes and other natural products. J.Chem. Research, 2008, 181-187. Alwyn G. Davies, Autoxidation of organoboranes and related organometallics: radicals and their ramifi cations. J.Chem. Research, 2008, 361-375. Kieran C. Molloy, Precursors for the formation of tin(IV) oxide and related materials. J.Chem. Research, 2008, 549–554

JCR_05_2009 Book.indb 4

28/5/09 11:54:19

JOURNAL OF CHEMICAL RESEARCH 2009

RESEARCH PAPER  269

May, 269–270

Ferric hydrogensulfate as a recyclable catalyst for the synthesis of some new bis(indolyl)methane derivatives Mohammad Rahimizadeh*, Hossein Eshghi, Zahra Bakhtiarpoor and Mehdi Pordel Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 91375-1436, Iran

New bis(indolyl)methanes were synthesised in excellent yields by the reaction of indole derivatives with aromatic and aliphatic aldehydes in the presence of ferric hydrogensulfate as an efficient, inexpensive, heterogeneous, reusable and non-toxic catalyst.

Keywords: aldehydes, bis(indolyl)methanes, catalysis, indoles, ferric hydrogensulfate Indoles and their derivatives are an important class of heterocyclic compounds in medicinal chemistry. Bis(indolyl)methanes (BIMs) have been found to have anticancer,1 antihyperglycemic, antiviral, antimicrobial, and tranquiliser activity.2 The development of a high throughputmethod for the synthesis of bis(indolyl)methanes is a topic of current interest. Numerous methods have been reported for the synthesis of bis (indolyl)methanes based on the reaction of indoles and carbonyl compounds using different catalysts such as protic acids,3 Lewis acids,4,5 heterogeneous acidic catalysts,6,7 and reagents such as iodine,8 NBS,9 CAN,10 and the hexamethylenetetramine bromine adduct.11 However, there are still some drawbacks to these catalytic systems including the requirement for large amounts of catalyst,5,12-14 long reaction times,12,15 low yields of product,16 drastic reaction conditions for catalyst preparation,17 and tedious workup leading to the generation of large amount of toxic waste. Recently, metal triflate in ionic liquid,18 Fe(III) salts in ionic liquid19 and other ionic liquids,8 have been reported to be efficient systems for this transformation, but they are highly expensive. For these reasons, a superior catalyst which is cheap, less toxic, easily available and air stable is desirable. To the best of our knowledge there are no reports on the use of Fe(HSO4)3 as a catalyst for this conversion. We now report ferric hydrogensulfate as an efficient, mild, inexpensive and recyclable catalyst for the electrophilic condensation of indoles with aldehydes.

and the reaction was completed in 30 minutes. The work-up procedure which was very simple, was performed by filtration of the precipitated product and washing with n-hexanedichloromethane (50 : 50) and water, respectively. To prove the generality of the protocol, the reaction was then extended with a variety of aldehydes and different indoles (Scheme 1). The results are summarised in Table 1. This method is effective for aldehydes bearing both electron-withdrawing and electron-donating substituents on the aromatic ring. Aliphatic aldehydes also react satisfactorily under these conditions. The products 3p–t are new derivatives of bis(indolyl)methanes and are synthesised from the reaction of 2-methyl-5-nitroindole with different aldehydes. The re-use of Fe(HSO4)3 was investigated in the reaction between 4-chlorobenzaldehyde and 2-methylindole. After completion of the reaction, the products together with the catalyst precipitate out. The catalyst was separated from the precipitate by adding acetone which dissolved the organic compound. The catalyst was found to be reusable four times without significant loss of activity. Comparing of catalytic efficiency of Fe(HSO4)3 with Lewis acid like FeCl3 and Bronsted acid like HCl showed that ferric hydrogensulfate was acting as a bifunctional catalyst. In summary, we have developed a new method for the synthesis of bis(indolyl)methanes from aldehydes and indoles using Fe(HSO4)3 as an efficient, mild, practical and recyclable catalyst. Experimental

Results and discussion

Ferric hydrogensulfate was prepared by the reaction of anhydrous ferric chloride and concentrated sulfuric acid. The IR spectrum of the solid showed similar absorption to that of NaHSO4 and differed from that of Na2SO4 and Fe2(SO4)3 thus supporting the formulation of ferric hydrogensulfate as Fe(HSO4)3 rather than as a double salt of Fe2(SO4)3 and H2SO4. In order to determine the best molar ratio of catalyst, we studied the reaction of 2-methylindole with naphthaldehyde in dichloromethane in the presence of different amount of Fe(HSO4)3 at room temperature (rt). The best result was obtained with 5 mole% of Fe(HSO4)3 in which after 10 minutes, the product started to precipitate out R2

O R

Fe(HSO4)3

H 1

N H

R1

Melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu spectrometer and only noteworthy absorptions are listed. The 1H NMR (100 MHz) spectra were recorded on a Bruker AC 100 spectrometer. Chemical shifts are reported in ppm downfield from TMS as internal standard; coupling constants (J) are given in Hz. The mass spectra were obtained on a Varian. Mat CH-7 at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyser. 2-Methyl-5-nitro-indole22 was prepared according to the published method. Other reagents which were commercially available, were obtained from the Merck and Aldrich companies. Preparation of ferric hydrogensulfate A 500 mL suction flask was equipped with a constant-pressure dropping funnel. A gas outlet was connected to a vacuum system R

R2

DCM, rt

R2

H N H

R1 R1

N H

3a-t

2a : R1, R2 = H 2b : R1 = Me, R2 = H 2c : R1 = H, R2 = CN 2d : R1 = Me, R2 = NO2

Scheme1

* Correspondent. E-mail: [email protected]

PAPER: 08/0291

JCR_05_2009 Book.indb 269

28/5/09 11:54:24

270  JOURNAL OF CHEMICAL RESEARCH 2009 Table 1  Synthesis of bis indolylmethanes by the reaction of indoles and aldehydes in the presence of Fe(HSO4)3 in dichloromethane at room temperature Entry

Aldehyde/R

Indole

Product

1 C6H5 2a 2 4-OMeC6H4 2a 3 4-ClC6H4 2a 4 4-MeC6H4 2a 5 4-NO2C6H4 2a 6 4-OHC6H4 2a 7 2-OMeC6H4 2a 8 3-NO2C6H4 2a 9 C6H5 2b 10 CH3(CH2)6 2b 11 4-MeC6H4 2b 12 4-NO2C6H4 2b 13 C6H5 2c 14 4-OMeC6H4 2c 15 4-NO2C6H4 2c 16 4-NO2C6H4 2d 17 1-C10H7 2d 18 3-OHC6H4 2d 19 4-ClC6H4 2d 20 2-OHC6H4 2d aThe products were characterised by comparison of their the procedure given in the references.

Time/min

Yield/%

M.p °C/Lit.a

3a 40 90 124–127 (124–126)20 3b 35 90 192–194 (195)20 3c 30 80 79–81 (76–78)21 3d 40 85 95–97 (96–98)20 3e 25 97 241–243 (245–246)20 3f 25 91 120–123 (119–121)20 3g 35 93 129–132 (131–133)20 3h 25 91 267–269 (261–263)20 3i 45 93 247–248 (244–246)21 3j 35 70 Oily liquid 3k 30 85 175–177 (175–177)21 3l 30 95 239–241 (241–243)21 3m 45 94 241–243 (240–242)20 3n 40 87 245–248 (245)20 3o 45 82 157–159 (158–159)20 3p 40 85 170–172 3q 50 83 156–159 3r 60 80 138–140 3s 60 75 145–147 3t 60 79 135–137 spectroscopic and physical data with authentic samples synthesised by

through an absorbing solution (water) and an alkali trap. Anhydrous FeCl3 (250 mmol) was charged into the flask and concentrated sulfuric acid (98%, 73.5 g, 750 mmol) was added dropwise over a period of 30 min at r.t. HCl gas was evolved immediately. After completion of the addition of the H2SO4, the mixture was shaken for 30 min; meanwhile, the residual HCl was exhausted by suction. A pale brown solid material was thus obtained.23,24 In order to eliminate of any H2SO4 contamination, this solid washed with absolute ethanol to give an almost white solid. The atomic absorption analysis shows the expected percentage of Fe and the titration of an aqueous solution of Fe(HSO4)3 with NaOH solution did not show any contamination of the catalyst with H2SO4. The structure of the catalyst was further confirmed by comparison of its IR spectrum (KBr disk) with the IR spectra of the NaHSO4, Na2SO4 and Fe2(SO4)3.

crystals (EtOH), yield (75%), m.p. 145–147 °C; 1H NMR (100 MHz, CD3CN) d = 2.13 (s, 6H), 6.21 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.24–7.43 (m, 4H), 7.77 (d, J = 2.1 Hz, 2H), 7.89 (dd, J = 8.6 Hz, J' = 2.1 Hz, 2H), 9.73 (br s, 2H) ppm; IR (KBr): 3425 cm-1 (NH). MS (70 eV): m/z = 474 (M+). Anal. Calcd for C25H19ClN4O4 (474.90): C, 63.23; H, 4.03; N, 11.80. Found: C, 63.15; H, 4.29; N, 11.73%. 2-[Di(2-methyl-5-nitro-1H-3-indolyl)methyl]phenol (3t): Compound 3t was obtained as yellow crystals (EtOH), yield (79%), m.p. 135–137 °C; 1H NMR (100 MHz, CD3CN) d = 2.12 (s, 6H), 6.20 (s, 1H), 7.33–7.46 (m, 6H), 7.50 (br s, 1H), 7.77 (d, J = 2.0 Hz, 2H), 7.89 (dd, J = 8.6 Hz, J' = 2.0 Hz, 2H), 9.75 (br s, 2H) ppm; IR (KBr): 3435 cm-1 (NH), 3480 cm-1 (OH). MS (70 eV): m/z = 456 (M+). Anal. Calcd for C24H18N4O5 (456.46): C, 65.78; H, 4.42; N, 12.27. Found: C, 65.68; H, 4.38; N, 12.33%.

General procedure for BIMs 3a–t A mixture of benzaldehyde (0.11 g 1 mmol) and indole (0.26 g, 2 mmol) in dichloromethane (5 mL) was stirred at rt in the presence of a catalytic amount of Fe(HSO4)3 (0.2 mmol) for an appropriate time (Table 1). After completion of the reaction, as indicated by TLC, the precipitated was filtered and washed with n-hexane-dichloromethane (4 mL) (50:50) and then water (10 mL). After drying the product in the air, practically pure product was obtained. More purification was achieved by crystallisation from suitable solvent such as n-hexaneethyl-acetate or EtOH–water. 2-Methyl-3-[(2-methyl-5-nitro-1H-3-indolyl)(4-nitrophenyl)methyl]5-nitro-1H-indole (3p): Compound 3p was obtained as yellow crystals (EtOH), yield (85%), m.p. 170–172 °C; 1H NMR (100 MHz, CD3CN) d = 2.14 (s, 6H), 6.27 (s, 1H), 7.37–7.49 (m, 4H), 7.77 (d, J = 2.1 Hz, 2H), 7.90 (dd, J = 8.8 Hz, J = 2.1 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H), 9.78 (br s, 2H) ppm; IR (KBr): 3435 cm-1 (NH). MS (70 eV): m/z = 485 (M+). Anal. Calcd for C25H19N5O6 (485.43): C, 61.85; H, 3.94; N, 14.43. Found: C, 61.77; H, 3.84; N, 14.29%. 2-Methyl-3-[(2-methyl-5-nitro-1H-3-indolyl)(1-naphthyl)methyl]-5nitro-1H-indole (3q): Compound 3q was obtained as yellow crystals (EtOH), yield (83%), m.p. 156–159 °C; 1H NMR (100 MHz, CD3CN) d = 2.14 (s, 6H), 6.21 (s, 1H), 7.25–7.70 (m, 7H), 7.75 (d, J = 2.1 Hz, 2H), 7.87–8.09 (m, 4H), 9.71 (br s, 2H) ppm; IR (KBr): 3425 cm-1 (NH). MS (70 eV): m/z = 540 (M+). Anal. Calcd for C33H24N4O4 (540.56): C, 73.32; H, 4.47; N, 10.36. Found: C, 72.98; H, 4.37; N, 10.55%. 3-[(2-Methyl-5-nitro-1H-3-indolyl)(5-nitro-1H-3-indolyl)methyl] phenol (3r): Compound 3r was obtained as yellow crystals (EtOH), yield (80%), m.p. 138–140 °C; 1H NMR (100 MHz, CD3CN) d = 2.13 (s, 6H), 6.17 (s, 1H), 7.24–7.43 (m, 6H), 7.69 (br s, 1H), 7.78 (d, J = 2.0 Hz, 2H), 7.88 (dd, J = 8.6 Hz, J' = 2.0 Hz, 2H), 9.75 (br s, 2H) ppm; IR (KBr): 3435 cm-1 (NH), 3480 cm-1 (OH). MS (70 eV): m/z = 456 (M+). Anal. Calcd for C24H18N4O5 (456.46): C, 65.78; H, 4.42; N, 12.27. Found: C, 65.68; H, 4.38; N, 12.33%. 3-[(4-Chlorophenyl)(2-methyl-5-nitro-1H-3-indolyl)methyl]-2methyl-5-nitro-1H-indole (3s): Compound 3s was obtained as yellow

Received 11 November 2008; accepted 17 February 2009 Paper 08/0291  doi: 10.3184/030823409X430194 Published online: 19 May 2009 References 1 C. Hong, G.L. Firestone and L.F. Bjeldance, Biochem. Pharmacol., 2002, 63, 1085. 2 L. Povszsz, G.P. Katakin, S. Foleat and B. Malkovics, Acta Phys. Acad. Sci. Hung, 1996, 29, 299. 3 A. Kamal and A.A. Qureshi, Tetrahedron, 1963, 19, 513. 4 P.K. Prandhan, S. Dey, V.S. Giri and P. Jaisankar, Synthesis, 2005, 1779. 5 Z.H. Zhang, L. Yin and Y.M. Wang, Synthesis, 2005, 1949. 6 V.T. Kamble, K.R. Kadam, N.S. Joshi and D.B. Muley, Catal. Commun., 2007, 8, 498. 7 M.A. Zolfigol, P. Salehi, M. Shiri and Z. Tanbakouchian, Catal. Commun., 2007, 8, 173. 8 S.J. Ji, S.Y. Wang, Y. Zhang and T.P. Loh, Tetrahedron, 2004, 60, 2051. 9 H. Koshima and W Matsuaka, J. Heterocycl. Chem., 2002, 39, 1089. 10 C. Ramesh, N. Ravindranath and B. Das, J. Chem. Res., 2003, (S) 72. 11 B.P. Bandgar, S.V. Bettigeri and N.S. Joshi, Monatsh Chem., 2004, 135, 1265. 12 J.S. Yadav, B.V.S. Reddy, V.S.R. Murthy, G. Mahesh Kumar and C. Madan, Synthesis, 2001, 783. 13 R. Nagrajan and P.T. Perumal, Chem. Lett., 2004, 288. 14 C. Ramesh, J. Banerjee, R. Pal and B. Das, Adv. Synth. Catal., 2003, 345, 557. 15 D. Chen, L. Yu and P.G. Wang, Tetrahedron Lett., 1996, 37, 4467. 16 A.V. Reddy, K. Ravinder, V.L.N. Reddy, T.V. Goud, V. Ravikant and Y. Venkateswarlu, Synth. Commun., 2003, 33, 3687. 17 L. Wang, J. Han, H. Tian, J. Sheng, Z. Fan and X. Tang, Synlett, 2005, 337. 18 X. Mi, S. Luo, J. He and J.P. Cheng, Tetrahedron Lett., 2004, 45, 4567. 19 S.J. Ji, M.F. Zhou, D.G. Gu, Z.Q. Jiang and T.P. Loh, Eur. J. Chem., 2004, 1584. 20 M.M. Heravi, K. Bakhtiari, A. Fatehi and F.F. Bamoharram, Cat. Commun., 2008, 9, 289. 21 A. Hasaninejad, A. Zare, H. Sharghi, K. Niknam and M. Shekouhy, Arkivoc, 2007, 14, 39. 22 K. Brown and A.R. Katritzky, Tetrahedron Lett., 1964, 5, 803. 23 H. Eshghi, J. Chin. Chem. Soc., 2006, 53, 987. 24 P. Salehi, M.M. Khodaei, M.A. Zolfigol and S. Zeinoldini, Synth. Commun., 2003, 33, 1367.

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RESEARCH PAPER  271

May, 271–273

Four-component reaction of isocyanides, acetylenic esters, and carboxylic acids for the synthesis of functionalised 2,5-diaminofurans Mohammad Anary-Abbasinejad*, Maryam Rasekh and Hossein Anaraki-Ardakani Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran

An improved four-component reaction of isocyanides is described. The reaction between two equivalents of an isocyanide, dialkyl acetylenedicarboxylates and aliphatic carboxylic acids at room temperature leads to 2,5diaminofuran derivatives in good yields.

Keywords: isocyanide, four-component reaction, dialkyl acetylenedicarboxylates, carboxylic acids, diaminofurans An important subject that has gained a great deal of attention from organic and bioorganic chemists during the last few decades has been the developing of new strategies for the synthesis of complex molecular structures from easily available substrates by short and effective routes. The most important of these strategies has been the developing of multi-component reactions (MCRs), a reaction in which three or more compounds connect together by covalent bonds to produce a complex molecule contains the main structure of all the starting materials. As MCRs are one-pot reactions, they are easier to carry out than multistep syntheses. Coupled with high-throughput library screening, this strategy was an important development in the drug discovery in the context of rapid identification and optimisation of biologically active lead compounds.1-9 Among the MCRs, isocyanide based multi-component reactions (IMCRs) have gained the most attention by the organic chemists. Ugi four component reaction(U-4CR)6-8 and Passerini three component reaction (P-3CR)10 are among the most important IMCRs. U-4CR and P-3CR describe the reaction of isocyanides with carboxylic acids in the presence of imines or aldehydes, respectively. Recently, another kind of IMCRs has been developed and extensively investigated. Isocyanides react easily with electron-deficient acetylene diesters such as dimethyl acetylenedicarboxylate (DMAD) to produce a reactive zwitterionic intermediate (Scheme 1), which can be trapped by an electrophile. In recent years, a wide variety of electrophiles have been applied to trap isocyanide–DMAD intermediate, among them are carbon electrophiles such as aldehydes, imines, quinonids,11 1,2-diketones,12 1,2,3-tricarbonyl compounds,13 isocyanates,14 and hydrogen electrophiles such as pyrrole,15 amides,16 hydroxy coumarine,17 phenoles,18 phthalic anhydride,19 and isatoic anhydride.20 Treatment of isocyanide–DMAD zwitterion with aromatic carboxylic acids has been reported to produce unsaturated amides.21 Reaction of isocyanide-DMAD adduct with aromatic-substituted acetic acids has been reported to afford 2,5-diaminofuran derivatives in the presence of two equivalents of an isocyanide.22 In the context of our previous work on IMCRs,15-17, 23 we now report the results of our investigations on the reaction of isocyanides and dialkyl acetylenedicarboxylates (DAADs) in the presence of aliphatic carboxylic acids such as acetic acid, propionic acid, trifluoroacetic acid, formic acid and succinic acid.

2

_ + N C + 1

R _ + R N C + R'O2C

R'O2C

CO2Me + Me 2

_ CO2R'

Scheme 1  Isocyanide–acetylene diester zwitterion.

Treatment of tert-butyl isocyanide (2 equiv.) with DMAD (1 equiv.) and acetic acid (1 equiv) in dichloromethane for 24 h at room temperature, after silica gel column chromatography afforded dimethyl 2-(acetyl-tert-butylamino)5-(tert-butylamino)-furan-3,4-dicarboxylate (4a) in 97% yield (Scheme 2). The structure of compound 4a was deduced form its elemental and spectral data. The 1H NMR spectrum of compound 4a was completely simple and exhibited six sharp single lines, which are respectively due to two tertbutyl groups (d = 1.17 and 1.22 ppm), one methyl group (d = 1.76), two methoxy groups (d = 3.61 and 3.68 ppm) and one NH group (d = 6.70 ppm, disappeared with addition of D2O). The 13C NMR spectrum of compound 4a showed 14 distinct resonances in agreement with the proposed structure. The signals at 114.5, 139.5, 159.9, 163.4, 161.3 and 172.9 ppm are related to furan ring carbons and two carbonyl groups. The IR spectrum showed an absorption band at 3410 cm-1 for NH group. The carbonyl stretching vibrations observed as strong absorption bands at 1734, 1685 and 1676 cm-1. The molecular ion peak at 368 in the mass spectrum of compound 4a supported the 2:1:1 adduct of tert-butyl isocyanide, acetic acid and DMAD. Similar reactivity was observed with other acetylene diesters, such as diethyl acetylenedicarboxylate (DEAD) and di(tert-butyl) acetylenedicarboxylate (DTAD), which underwent facile reaction with tert-butyl isocyanide and acetic acid yielding the 2,5-diaminofuran derivatives 4b–c in good yields (enties 2–3, Table 1). The reaction was also compatible with cyclohexyl isocyanide, instead of tertbutyl isocyanide affording 2,5-diaminofuran derivative 4d. Propionic acid was also found to be as reactive as acetic acid and 2,5-diaminofuran derivatives 4e–h were obtained from its reaction with DAADs and isocyanides. The reaction was also examined with trifluoroacetic acid under similar conditions. MeO2C

O MeO2C

CO2R'

N+ C

OH

N

CH2Cl2, rt, 24 h

3

O

CO2Me O

N

H

Me 4a

Scheme 2  Reaction of tert-butyl isocyanide, DMAD and acetic acid.

* Correspondent. E-mail: [email protected]

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272  JOURNAL OF CHEMICAL RESEARCH 2009 Clean reactions took place with DMAD, trifluoroacetic and tert-butyl or cyclohexyl isocyanide and after silica gel column chromatography 2,5-diaminofuran derivatives 4i and 4j were obtained in good yields, respectively. From the reaction between tert-butyl isocyanide-DMAD zwitterion and formic acid a complex mixture was obtained and our efforts for separation of a pure product were unsuccessful. We also could not isolate any pure product from the complex mixture of the reaction between tert-butyl isocyanide-DMAD intermediate and succinic acid. On the basis of the well established chemistry of isocyanides6-8,22 it is reasonable to assume that compound 4 is produced by initial protonation of isocyanide–DAAD zwitterion intermediate by carboxylic acid followed by the addition of carboxylate anion 6 on nitrilium cation 5 to afford intermediate 7 which then rearranges to unsaturated imide 8. Cycloaddition of another molecule of isocyanide to imide 8 leads to dihydrofuran intermediate 9 that tautomerises to furan derivative 4. In conclusion, the four-component reaction between isocyanides, aliphatic carboxylic acids and dialkyl acetylenedicarboxylates is a simple and efficient route for the synthesis of functionalised 2,5-diaminofuran derivatives. The advantages of the reported method are inexpensive and easily available starting materials, simple and neutral reaction conditions, high yields, single-product reaction and simple work-up processes.

Table 1  Four-component reaction of isocyanides, dialkyl acetylenedicarboxylates and aliphatic carboxylic acids R'O2C _ + 2R N C +

O

R

1 tert-Bu 2 tert-Bu 3 tert-Bu 4 tert-Bu 5 tert-Bu 6 tert-Bu 7 tert-Bu 8 Cy 9 Cy 10 Cy aIsolated yields.

General procedure To a magnetically stirred solution of isocyanide (2 mmol) and carboxylic acid (1 mmol) in 10 mL dichloromethane was added a mixture of dialkyl acetylenedicarboxylate (1 mmol) in 1 mL dichloromethane at room temperature. The reaction mixture was then stirred for 24 h. The solvent was removed and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (6 : 1) as eluent. The solvent was removed under reduced pressure to afford the product. Dimethyl 2-[acetyl(tert-butyl)amino]-5-(tert-butylamino)furan-3,4dicarboxylate (4a): Yellow oil, yield 0.36 g (97%); IR (KBr) (nmax, cm-1): 3410 (NH), 1734, 1685, 1676 (carbonyl groups). Anal. Calcd

R"

H

R'O2C

R"

Product

Yield/%a

Me Et t-Bu Me Me Et t-Bu Me Me Me

Me Me Me Me Et Et Et Et CF3 CF3

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j

95 95 90 94 90 93 95 90 85 88

O R R'O2C

6

5 R" O

O N R R'O2C

N H

9

R

C _

R"

N

O

CO2R'

R

R N+

O R"

H

N

R'

R" _ O

O

for C18H28N2O6: C, 58.68; H, 7.66; N, 7.60%. Found: C, 58.47; H, 7.50; N, 7.71%. MS (m/z,%): 368 (M+, 10). 1H NMR (500.1 MHz, CDCl3): d = 1.17 and 1.22 (18 H, 2 s, 2 tert-butyl), 1.76 (3 H, s, CH3), 3.61 and 3.68 (6 H, 2 s, 2 OCH3), 6.70 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 24.3 (CH3), 28.5, 30.1 (methyl groups of 2 tert-butyl), 53.0 and 60.6 (2 NC), 52.7 and 55.8 (2 OCH3), 86.6, 114.5, 139.5, 159.9, 163.4, 165.1 and 172.9 (Furan ring and carbonyl carbons). Diethyl 2-[acetyl(tert-butyl)amino]-5-(tert-butylamino)furan-3,4dicarboxylate (4b): Yellow oil, yield 0.38 g (95%); IR (KBr) (nmax, cm-1): 3350 (NH), 1729, 1688, 1665 (carbonyl groups). Anal. Calcd for C20H32N2O6: C, 60.59; H, 8.14; N, 7.07%. Found: C, 60.77; H, 8.33; N, 6.78%. MS (m/z,%): 396 (M+, 15). 1H NMR (500.1 MHz, CDCl3): d = 1.29 and 1.35 (6 H, 2 t, J = 7 Hz, 2 CH3), 1.39 and 1.45 (18 H, 2 s, 2 tert-butyl), 2.00 (3 H, s, CH3), 4.28 (4 H, m, 2 CH2), 6.88 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 14.5 and 14.7 (2 CH3), 24.9 (CH3), 28.5, 30.1 (methyl groups of 2 tert-butyl), 53.0 and 60.6 (2 NC), 60.2 and 61.8 (2 OCH2), 86.6, 114.5, 139.5, 159.9, 163.4, 165.1 and 172.9 (Furan ring and carbonyl carbons). Di-tert-butyl 2-[acetyl(tert-butyl)amino]-5-(tert-butylamino)furan3,4-dicarboxylate (4c): Yellow oil, yield 0.41 g (90%); IR (KBr) (nmax, cm-1): 3400 (NH), 1725, 1689, 1663 (carbonyl groups). Anal. Calcd for C24H40N2O6: C, 63.69; H, 8.91; N, 6.19%. Found: C, 63.71; H, 8.80; N, 6.44%. MS (m/z,%): 452 (M+, 12). 1H NMR (500.1 MHz, CDCl3): d = 1.30, 1.32, 1.43 and 1.45 (36 H, 4 s, 4 tert-butyl), 1.90 (3 H, s, CH3), 6.66 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 24.9 (CH3), 28.5, 28.6, 28.9, 30.1 (methyl groups of 4 tert-butyl), 52.7 and 60.3 (2 NC), 80.7 and 82.3 (2 OC), 88.0, 115.9, 138.6, 159.5, 162.1, 164.7 and 173.0 (Furan ring and carbonyl carbons).

Elemental analyses were performed using a Heraeus CHN-ORapid analyser. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H and 13C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer at solution in CDCl3 using TMS as internal standard. The chemicals used in this work purchased from Fluka (Buchs, Switzerland) and were used without further purification.

N+ C

CO2R'

N

O

OH

Experimental

R

R

R"

Entry

R'O2C

CO2R'

O H

7

CO2R'

O N R R'O2C

H

8

CO2R'

4

CO2R'

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JOURNAL OF CHEMICAL RESEARCH 2009  273 Dimethyl 2-[acetyl(cyclohexyl)amino]-5-(cyclohexylamino)furan3,4-dicarboxylate (4d): Yellow oil, yield 0.39 g (94%); IR (KBr) (nmax, cm-1): 3340 (NH), 1732, 1690, 1675 (carbonyl groups). Anal. Calcd for C22H32N2O6: C, 62.84; H, 7.67; N, 6.66%. Found: C, 62.74; H, 7.33; N, 6.60%. MS (m/z,%): 420 (M+, 9). 1H NMR (500.1 MHz, CDCl3): d = 0.96–1.96 (10 H, 5 CH2 of cyclohexyl), 1.99 (3 H, m, CH3), 3.75 and 3.79 (6 H, 2 s, 2 OCH3), 4.29 (1 H, m, CH of cyclohexyl), 6.68 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 22.97 (CH3), 24.8, 25.7, 25.8, 26.1, 32.9, 33.9 (10 CH2 of cyclohexyl groups), 51.51 and 51.85 (2 NCH), 52.71 and 55.74 (2 OCH3), 85.7, 114.9, 137.9, 160.1, 163.5, 165.3 and 172.2 (Furan ring and carbonyl carbons). Dimethyl 2-[tert-butyl(propanoyl)amino]-5-(tert-butylamino)furan-3, 4-dicarboxylate (4e): Yellow oil, yield 0.34 g (90%); IR (KBr) (nmax, cm-1): 3335 (NH), 1733, 1685, 1675 (carbonyl groups). Anal. Calcd for C19H30N2O6: C, 59.67; H, 7.91; N, 7.32%. Found: C, 59.44; H, 7.99; N, 7.10%. MS (m/z,%): 382 (M+, 15). 1H NMR (500.1 MHz, CDCl3): d = 0.89 (3 H, t, J = 7 Hz, CH3), 1.22 and 1.28 (18 H, 2 s, 2 t-butyl), 1.84 and 2.25 (2 H, 2 dq, J = 7 Hz, J = 16 Hz, CH2), 3.62 and 3.68 (6 H, 2 s, 2 OCH3), 6.76 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 9.4 (CH3), 29.1 (CH2), 28.4, 30.0 (methyl groups of 2 tert-butyl), 52.9 and 60.5 (2 NC), 51.3 and 52.5 (2 OCH3), 86.3, 114.1, 139.5, 159.9, 163.6, 165.3 and 175.8 (Furan ring and carbonyl carbons). Diethyl 2-[tert-butyl(propionyl)amino]-5-(tert-butylamino)furan3,4-dicarboxylate (4f): Yellow oil, yield 0.38 g (93%); IR (KBr) (nmax, cm-1): 3330 (NH), 1729, 1691, 1665 (carbonyl groups). Anal. Calcd for C21H34N2O6: C, 61.44; H, 8.35; N, 6.82%. Found: C, 61.65; H, 8.50; N, 6.68%. MS (m/z,%): 410 (M+, 14). 1H NMR (500.1 MHz, CDCl3): d = 0.96 (3 H, t, J = 7 Hz, CH3), 1.21 and 1.55 (6 H, 2 t, J = 7 Hz, 2 CH3), 1.31 and 1.34 (18 H, 2 s, 2 tert-butyl), 1.93 and 2.36 (2 H, 2 dq, J = 7 Hz, J = 16 Hz, CH2), 4.22 (4 H, m, 2 CH2), 6.81 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 9.4 (CH3), 14.3 and 14.6 (2 CH3), 29.3 (CH2), 28.5, 30.7 (methyl groups of 2 tert-butyl), 52.9 and 60.5 (2 NC), 60.0 and 61.6 (2 OCH2), 86.6, 114.4, 139.0, 159.8, 163.3, 165.0 and 175.9 (Furan ring and carbonyl carbons). Ditert-butyl 2-[tert-butyl(propionyl)amino]-5-(tert-butylamino) furan-3,4-dicarboxylate (4g): Yellow oil, yield 0.44 g (95%); -1 IR (KBr) (nmax, cm ): 3400 (NH), 1717, 1694, 1663 (carbonyl groups). Anal. Calcd for C25H42N2O6: C, 64.35; H, 9.07; N, 6.00%. Found: C, 64.23; H, 9.26; N, 6.24%. MS (m/z,%): 466 (M+, 12). 1H NMR (500.1 MHz, CDCl3): d = 0.95 (3 H, t, J = 7 Hz, CH3), 1.31, 1.33, 1.43 and 1.45 (36 H, 4 s, 4 tert-butyl), 1.93 and 2.41 (2 H, 2 dq, J = 7 Hz, J = 17 Hz, CH2), 6.75 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 9.3 (CH3), 28.3 (CH2), 28.5, 28.7, 28.9, 30.2 (methyl groups of 4 tertbutyl), 52.7 and 60.3 (2 NC), 80.7 and 82.2 (2 OC), 88.0, 116.0, 138.2, 159.5, 162.2, 164.8 and 176.3 (Furan ring and carbonyl carbons). Dimethyl 2-[cyclohexyl(propionyl)amino]-5-(cyclohexylamino) furan-3,4-dicarboxylate (4h): Yellow oil, yield 0.39 g (90%); IR (KBr) (nmax, cm-1): 3340 (NH), 1732, 1691, 1675 (carbonyl groups). Anal. Calcd for C23H34N2O6: C, 63.57; H, 7.89; N, 6.45%. Found: C, 63.22; H, 7.91; N, 6.29%. MS (m/z,%): 434 (M+, 17). 1H NMR (500.1 MHz, CDCl3): d = 0.96-1.96 (13 H, 5 CH2 of cyclohexyl and CH3), 1.95 and 2.39 (2 H, 2 dq, J = 7 Hz, J = 16 Hz, CH2), 3.70 and 3.78 (6 H, 2 s, 2 OCH3), 4.26 (1 H, m, CH of cyclohexyl), 6.65 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 9.3 (CH3), 28.3 (CH2), 24.8, 25.6, 25.8, 26.4, 32.9, 33.9 (10 CH2 of cyclohexyl groups), 51.6 and 51.8 (2 NCH), 52.6 and 55.8 (2 OCH3), 85.7, 114.7, 137.7, 160.1, 163.5, 165.5 and 172.2 (Furan ring and carbonyl carbons).

Dimethyl 2-[tert-butyl(trifluoroacetyl)amino]-5-(tert-butylamino) furan-3,4-dicarboxylate (4i):Yellow oil, yield 0.36 g (85%); IR (KBr) (nmax, cm-1): 3335 (NH), 1735, 1685, (carbonyl groups). Anal. Calcd for C18H25F3N2O6: C, 51.18; H, 5.97; N, 6.63%. Found: C, 51.39; H, 5.66; N, 6.73%. MS (m/z,%): 422 (M+, 10). 1H NMR (500.1 MHz, CDCl3): d = 1.44 and 1.48 (18 H, 2 s, 2 tert-butyl), 3.80 and 3.84 (6 H, 2 s, 2 OCH3), 7.00 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 27.6, 30.6 (methyl groups of 2 tert-butyl), 53.2 and 64.4 (2 NC), 51.6 and 52.5 (2 OCH3), 86.5, 114.8, 135.2, 157.8, 162.6 and 165.5 (Furan ring and two ester carbonyl carbons), 117.2 (d, J = 281 Hz, CF3), 157.7 (q, J = 36 Hz, COCF3). Dimethyl 2-[cyclohexyl(trifluoroacetyl)amino]-5-(cyclohexylamino) furan-3,4-dicarboxylate (4j): Yellow oil, yield 0.42 g (88%); IR (KBr) (nmax, cm-1): 3335 (NH), 1735, 1685, (carbonyl groups). Anal. Calcd for C22H29F3N2O6: C, 55.69; H, 6.16; N, 5.90%. Found: C, 55.48; H, 6.12; N, 5.76%. MS (m/z,%): 474 (M+, 9). 1H NMR (500.1 MHz, CDCl3): d = 0.93-1.96 (10 H, 5 CH2 of cyclohexyl), 3.82 and 3.85 (6 H, 2 s, 2 OCH3), 4.21 (1 H, m, CH of cyclohexyl), 7.12 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): d = 24.8, 25.3, 25.4, 26.7, 32.6, 33.9 (10 CH2 of cyclohexyl groups), 51.5 and 51.8 (2 NCH), 51.7 and 52.4 (2 OCH3), 86.3, 114.2, 135.6, 157.9, 162.8 and 165.3 (Furan ring and two ester carbonyl carbons), 117.5 (d, J = 280 Hz, CF3), 157.0 (q, J = 36 Hz, COCF3).

Received 28 January 2009; accepted 2 March 2009 Paper 09/0415  doi: 10.3184/030823409X439735 Published online: 20 May 2009 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

P. Eibracht and A. Schimdt, Chem. Rev., 1999, 99, 3329. I. Ugi, Pure Appl. Chem., 2001, 77, 187. M.C. Bagley, J.W. Cale and J. Bower, Chem. Commun., 2002, 1682. U. Bora, A. Saikia and R.C. Boruah, Org. Lett., 2003, 5, 435. L. Weber, Curr. Med. Chem., 2002, 9, 1241. I. Ugi, B. Werner and A. Domling, Molecules, 2003, 8, 53. A. Domling, Curr. Opin. Chem. Biol., 2000, 4, 318. A. Domling, Chem. Rev., 2006, 106, 17. L. Weber, Drug Discovery today, 2002, 7, 143. M. Passerini, Gazz. Chim. Ital., 1921, 51 II, 126. V. Nair, R.S. Menon and V. Sreekumar, Pure Appl. Chem., 2005, 77, 1191. V. Nair, R.S. Menon, A. Deepthi, B.R. Devi and A.T. Biju, Tetrahedron Lett., 2005, 46, 1337. V. Nair and A. Deepthi, Tetrahedron Lett., 2006, 47, 2037. A. Alizadeh, S. Rostamnia, N. Zohreh and H.R. Bijanzadeh, Chem. Month., 2008, 139, 49. M. Anary-Abbasinejad, M.H. Mosslemin, H. Anaraki-Ardakani and S. Tahan, J. Chem. Res., 2006, 306. M. Anary-Abbasinejad, M.H. Mosslemin, S. Tahan and H. AnarakiArdakani, J. Chem. Res., 2006, 170. M. Anary-Abbasinejad, H. Anaraky-Ardakani, F. Rastegari and A. Hassanabadi, J. Chem. Res., 2007, 602. I. Yavari, H. Djahaniani and F. Nasiri, Tetrahedron, 2003, 59, 9409. A. Shaabani, M.B. Teimouri and H.R. Bijanzadeh, J. Chem. Res., 2002, 381. A. Shaabani, M.B. Teimouri, P. Mirzaei and H.R. Bijanzadeh, J. Chem. Res., 2003, 82. A. Alizadeh, S. Rostamnia and L.G. Zho, Tetrahedron, 2006, 62, 5641. A. Alizadeh, S. Rostamnia and M.L. Hu, Synlett, 2006, 1592. M. Anary-Abbasinejad and M. Kamali-Gharamaleki, J. Chem. Res., 2008, 383.

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274  RESEARCH PAPER

May, 274–276

JOURNAL OF CHEMICAL RESEARCH 2009

Synthesis, crystal structures and spectra properties of two new Cu(II) complexes containing thiocyanato anions as ancillary ligand Xiuqing Zhanga,b, Hedong Biana,b, Wen Gua, Jingyuan Xua, Shiping Yana* and Hong Lianga,b aDepartment bCollege

of Chemistry, Nankai University, Tianjin, 300071, P. R. China

of Chemistry and Chemical Engineering, Guangxi Normal University, Guilin, Guangxi, 541004, P. R. China

As the result of different ratio of reactants, two novel mixed–ligand complexes with different structures have been synthesised and characterised by IR and electronic spectra. In [Cu(L)(NCS)]2∙0.5H2O, (L = N,N–dimethyl–N'– (pyrid–2–ylmethyl)ethylenediamine), there are two crystallographically independent mononuclear units which are enantiomers. The thiocyanato anions act as terminal ligands. In [Cu2(L)2(μ2–NCS)2]2(ClO4)2, two thiocyanato anions bridge two Cu(II) ions in the end–to–end mode.

Keywords: crystal structures, N, N-dimethyl-N'-(pyrid–2–ylmethyl)–ethylenediamine, copper complexes Schiff bases and their complexes containing different central metal atoms have been studied in great detail for their various crystallographic features, enzymatic reactions, steric effects,1–4 structure–redox relationships,5 catalysis and magnetic properties,6,7 and their important role in living beings.8–10 They also act as models for biologically important species.11–13 The chemistry of copper complexes with multidentate Schiff base and reduced Schiff base ligands has attracted particular attention because copper ions have an important role in many metalloproteins and biomimetical analogues, and have been shown to be very important in the elucidation of the active site of these natural compounds.14 Furthermore, the thiocyanatoanion is a versatile inorganic ligand in the synthesis of coordination complexes with end–to–end or end–on coordination modes.15,16 It is used to bridge metal centres to afford a number of discrete, one-, two- or three-dimensional structural assemblies.17 In this paper, we report the synthesis, IR, UV-vis spectra, and crystal structures of two mixed–ligand Cu(II) complexes with N,N-dimethyl-N'-(pyrid-2-ylmethyl)– ethylenediamine (L) and thiocyanato anion. Experimental Materials and instruments: The ligand L was synthesised according to the published procedure.18 All starting materials were of analytical grade. IR spectra were recorded as KBr discs on a Shimadzu IR – 408 infrared spectrophotometer in the 4000–400 cm–1 region.

The ultraviolet and visible spectra were measured on a Shimadzu UV – 2101 PC spectrophotometer. Caution: Perchlorate salts may be explosive when heated. Synthesis of [Cu(L)(NCS)]2∙0.5H2O 1: The ligand L (0.5 mmol) in methanol (5 mL) was added to a solution of Cu(CH3COO)2∙H2O or Cu(ClO4)2∙6H2O (0.5 mmol) in methanol (5 mL). The solution was stirred for 10 min and NH4SCN 1.0 mmol in methanol (5 mL) was added. The solution was evaporated to dryness and the resultimg powder was dissolved in acetonitrile. Blue single crystals, suitable for X–ray analysis, separated after several weeks. Anal. Calcd for C24H35Cu2N10O0.50S4: C, 39.65, H, 4.85, N, 19.27; Found: C, 39.71, H, 4.78, N, 19.32%. UV–vis (lmax, nm) (e, dm3·mol–1·cm–1) (methanol): 628 (222). Synthesis of [Cu2(L)2(μ2–NCS)2]2(ClO4)2 2: The ligand L (0.5 mmol) and Cu(ClO4)2·6H2O (0.5 mmol) were dissolved in methanol (10 mL). The solution was stirred for 1 h, and NH4SCN (0.25 mmol) in methanol (5 mL) was added. The mixture was stirred for 4 h, and then filtered. The resulting powder was washed with methanol and ethyl ether, then dissolved in 1:1 (v:v) ethanol–water solution. Blue single crystals, suitable for X–ray analysis, separated after several weeks. Anal. Calcd for C11H17ClCuN4O4S: C, 33.00, H, 4.2, N, 13.99; Found: C, 33.07, H, 4.18, N, 13.93(%). UV–vis (lmax, nm) (e, dm3·mol–1·cm–1) (methanol): 630 (180). X-ray structures Crystal data for the two compounds are shown in Table 1. CCDC: 603161 1, 603163 2. Single crystal X–ray diffraction studies were performed on a Bruker Smart 1000 CCD diffractometer with Mo Ka radiation (l = 0.71073 Å).

Table 1  Data collection and processing parameters for the complexes Complex

1

2

Empirical formula Formula weight Temperature/K Wavelength/nm Crystal system space group a (Å) b (Å) c (Å) b (°) V (Å3) Z Dcalc ( Mg•m–3) Absorption coefficient (mm–1) F(000) q range for data collection (°) Index ranges Reflections collected Independent reflection (Rint) Final R indices [I > 2s(I)] R indices (all data)

C24H35Cu2N10O0.50S4 726.94 293(2) 0.071073 Monoclinic C2/c 27.845(10) 7.302(3) 32.241(12) 97.423(8) 6500(4) 8 1.481 1.600 3000 2.89 – 25.03 –30 ≤ h ≤ 29, –5 ≤ k ≤ 8, –6 ≤ l ≤ 38 6783 4879 (0.0608) R1 = 0.0623, wR2 = 0.1436 R1 = 0.1442, wR2 = 0.1691

C11H17ClCuN4O4S 400.34 293(2) 0.071073 Monoclinic P2(1)/c 6.663(5) 24.429(19) 10.289(8) 101.120(15) 1643(2) 4 1.618 1.640 820 2.18 – 25.35 –8 ≤ h ≤ 4, –29 ≤ k ≤ 25, –12 ≤ l ≤ 11 5645 2782 (0.1592) R1 = 0.0747, wR2 = 0.1485 R1 = 0.2057, wR2 = 0.2022

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  275 The structures were solved by direct methods and semi–empirical absorption corrections were applied. The non–hydrogen atoms were located by direct phase determination and full-matrix least-squares refinement on F2, while the hydrogen atoms for non–water protons were treated using the riding mode. All calculations were carried out using SHELXS–97,19 and SHELXL–9720 programs. Further details of the structural analyses are summarised in Table 1. The selected bond distances and angles are listed in Table 2.

Result and discussion Crystal structure of the complexes The crystal structure of 1 consists of two crystallographically independent neutral units which are noted as I and II (Fig. 1). The two molecules coexisting in the crystal are enantiomers to form a racemic complex. The copper centres have distorted square pyramidal geometry by the τ parameters of 0.033 for Cu1 and 0.001 for Cu2,21 respectively. In the structures, the base plane is comprised of three nitrogen atoms of the tridentate ligand and a nitrogen atom of NCS-, and the nitrogen atom of another NCS- completes the coordination sphere in the apical sites. In the two molecules, the Cu–N distances are in the range of 1.955 to 2.116 Å in which the distances of Cu–N involving the NCS- of apical sites is the longest, and the distances involving tertiary nitrogen atoms are longer than those of the other nitrogen atoms of L. The Cu(II) ion

lies over 0.3082 Å (molecule I) and 0.2867 Å (molecule II) above the base plane, respectively. The NCS- groups in the molecules of the complex are linear and also exhibits close to a linear coordination mode (N4–C11–S1/Cu1–N4–C11 = 178.1(10)°/171.1(9)° and N5– C12–S2/Cu1–N5 –C12 = 179.5(10)°/170.7(9)° (molecule I), N9– C23–S3/Cu2–N9–C23 = 178.8(10)°/165.0(7)°, N10–C(24)–S(4)/ Cu2–N10–C24 = 178.6(10)°/163.2(8)° (molecule II). The structure of 2 contains one dimmer [Cu2L2(μ2–SCN)]2+ together with two ClO4– anions. In the dimeric unit, two Cu(II) ions are bridged by two thiocyanate ligands in an end–to–end fashion with the Cu···Cu separation of 5.535 Å, which is similar to other Cu(II) complexes with double end-to-end thiocyanate bridges.22 One S atom and one N atom from two different bridging thiocyanate ligands, and three N atoms from one tridentate ligand L coordinate to the Cu(II) ion to complete a distorted square pyramidal geometry by the τ parameter of 0.073.21 In the basal plane, the Cu–N bond lengths are in the range of 1.946(10) to 2.041(11) Å. The bond length of Cu1–N4 (tertiary amine) is the longest, and the distance of Cu1–N1 involving NCS- is the shortest. The S of SCN- occupies the apical position with the Cu–S distance of 2.878 Å, which is similar to that reported for thiocyanate bridging nickel complexes.15,22,23 The SCN- group is linear with an S–C–N angle of 178.4°. The Cu–S–C and Cu–N–C angles for bridging SCN- groups are 94.9 and 162.8°, respectively.

I

II

Fig.1  Perspective view of the crystallographically independent units of 1 with the atom numbering. Thermal ellipsoids are drawn at the 30% probability level and the hydrogen atoms are omitted for simplicity. Table 2  Selected bond lengths (Å) and bond angles (°) of the complexes Complex 1: Bond lengths Cu1–N5 Cu1–N3 Cu2–N6 Cu2–N10

1.962(9) 2.039(6) 2.000(6) 2.112(9)

Cu1–N2 Cu1–N4 Cu2–N7

1.995(6) 2.116(10) 2.013(6)

Cu1–N1 Cu2–N9 Cu2–N8

2.027(6) 1.955(8) 2.055(6)

Bond angles N5–Cu1–N2 N5–Cu1–N3 N5–Cu1–N4 N3–Cu1–N4 N6–Cu2–N7 N7–Cu2–N8 N7–Cu2–N10

163.4(3) 93.8(3) 98.3(4) 98.0(3) 80.9(3) 85.6(3) 100.4(3)

N5–Cu1–N1 N2–Cu1–N3 N2–Cu1–N4 N9–Cu2–N6 N9–Cu2–N8 N9–Cu2–N10 N8–Cu2–N10

95.0(3) 85.0(3) 99.3(3) 95.2(3) 93.4(3) 98.1(3) 100.6(3)

N2–Cu1–N1 N1–Cu1–N3 N1–Cu1–N4 N9–Cu2–N7 N6–Cu2–N8 N6–Cu2–N10

80.6(3) 158.0(3) 100.6(3) 161.4(3) 161.2(3) 94.7(3)

Complex 2:

Cu1–N1

2.041(11)

N2–Cu1–N1 N3–Cu1–N1

85.2(4) 161.6(5)

Bond lengths Cu1–N4 1.946(10) Cu1–N3 1.973(11) Cu1–N2 1.968(10) Cu1–S1A 2.878(11) Bond angles N4–Cu1–N2 174.4(5) N2–Cu1–N(3) 82.9(5) N4–Cu1–N3 96.4(5) N4–Cu1–N(1) 94.0(5) Symmetry transformations used to generate equivalent atoms: A: 1–x, 1–y, 1–z.

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276  JOURNAL OF CHEMICAL RESEARCH 2009 Received 22 December 2008; accepted 9 February 2009 Paper 08/0353  doi: 10.3184/030823409X440300 Published online: 28 May 2009 References

Fig. 2  A perspective view of 2 with the atom numbering. Thermal ellipsoids are drawn at the 30% probability level and the hydrogen atoms are omitted for simplicity.

Spectroscopic properties IR spectra Both of the complexes 1 and 2 showed weak bands in the range of 3100–3400 cm–1, which can be assigned to v(NH). The bands in the range 2800–3000 cm–1 are assigned to aliphatic C–H stretching vibrations. The v(C≡N) absorption at 2100 cm–1 is consistent with N– coordinated NCS groups. The v(C–N) absorptions of 1 and 2 appear at 1565 and 1560 cm–1, respectively. The IR spectra show strong absorption at 1100, 1121 cm-1, which correspond to the vibration of dissociated ClO4- ions. UV–Vis spectra Complex 1 in acetonitrile and 2 in methanol show a broad band centred at about 628 and 630 nm, respectively, which is due to the electronic transitions 2B1→2E and 2B1→2B2.24,25 The spectra are typical d–d bands in the square–pyramidal Cu(II) surrounding.

This work was supported by the National Natural Science Foundation of China (No. 20171026) and Tianjin Natural Science Foundation (No. 013605811)

1 S.C. Bhatia, J.M. Bindlish, A.R. Saini and P.C. Jain, J. Chem. Soc., Dalton Trans., 1981, 9, 1773. 2 J.M. Bindlish, S.C. Bhatia and P.C. Jain, Indian J. Chem., 1975, 13, 81. 3 R.P. Kashyap, J.M. Bindlish and P.C. Jain, Indian J. Chem., 1973, 11, 388. 4 J.M. Bindlish, S.C. Bhatia and P. Gautam, Indian J. Chem., Sect. A, 1978, 16, 279. 5 I. Bernal, Stereochemical Control, Bonding and Steric Rearrangements. Amsterdam: Elsevier, 1990, Bernal I, Chapter 3. 6 R.K. Rath, M. Nethaji and A.R. Chakravarty, Polyhedron, 2001, 20, 2735. 7 M. Masahiro, K. Yoshihisa and N. Ryoji, Bull. Chem. Soc. Jpn., 2001, 74, 1425. 8 P.Z. Neuman and A.J. Sass-Kortsak, Clin. Invest., 1967, 46, 646. 9 D.R. Williams, An Introduction to Bio–Inorganic Chemistry, Thomas Springfield, 1975, 120-125. 10 R.S. Himmelwright, N.C. Eichmann and E.I. Solomon, J. Am. Chem. Soc., 1979, 101, 1576. 11 S. Gourbatsis, S.P. Perlepes and N. Hadjiliadis, Trans. Met. Chem., 1990, 15, 300. 12 C.M. Perkins, N.J. Rose and R.E. Stenkamp, Inorg. Chim. Acta, 1990, 172, 119. 13 R.G. Bhirud and T.S. Srinivasan, Inorg. Chim. Acta, 1990, 173, 121. 14 T. Sorrel, Tetrahedron, 1989, 45, 3. 15 G.Y. Liu, H.N. Chen and F.Q. Liu, J. Chem. Crystallogr., 2008, 38, 631. 16 H.D. Bian, W. Gu, Q. Yu, S.P. Yan, D.Z. Liao, Z.H. Jiang and P. Cheng, Polyhedron, 2005, 24, 2002. 17 O.V. Nesterova, S.R. Petrusenko, V.N. Kokozay, B.W. Skelton, J. Jezierska, W. Linert and A. Ozarowski, Dalton Trans., 2008, 1431. 18 H.D. Bian, J.Y. Xu, W. Gu and S.P. Yan, Inorg. Chem. Commun., 2003, 6, 573. 19 G.M. Sheldrick, SHELXS-97, A Program for the Solution of Crystal Structures, University of Göttingen, Germany, 1997. 20 G.M. Sheldrick, SHELXL-97, A Program for the Refinement of Crystal Structures, University of Göttingen, Germany, 1997. 21 A.W. Addison, T.N. Rao, J. Reedijk, J. Van Rijn and G.C. Verschoor, J. Chem. Soc. Dalton Trans., 1984, 1349. 22 Z. Hong, Transition Met. Chem., 2008, 33, 797. 23 C.Y. Wang, Acta Cryst., 2007, E63, m832. 24 B.J. Hathaway, Struct. Bonding, Berlin, 1984, 57, 55-118. 25 B.J. Hathaway, Comprehensive coordination chemistry, the synthesis, reactions, properties and applications of coordination compounds, Oxford: Pergamon Press, 1987, 5, 533-774.

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JOURNAL OF CHEMICAL RESEARCH 2009

RESEARCH PAPER  277

May, 277–282

Chemistry of phosphorus ylides. Part 27. Metal complexes of 4-hydroxyquinaldine, its Mannich base and phosphonium ylide Fouad Solimana*, Ibrahim Abd-Ellahb, Soher Maigalia and Gamal Abd-El-Naima aDepartment

of Organometallic and Organometalloid Chemistry, National Research Centre, Dokki, Cairo, Egypt

bDepartment

of Inorganic Chemistry, Faculty of Science, Al-Azhar University, Egypt

The reaction of Hg2+, Cd2+, Co2+, and Ni2+ ions with 1 mol of the ligands 2-methylquinoline-4-ol, 3[(diethylamino)methyl]2-methylquinoline-4-ol, and methyl-3-(4-hyrdoxy-2-methylquinoline-3-yl)-2-(triphenylphosphoranylidene)propanoate, has been investigated to give the corresponding 1 : 1 metal:ligand complexes. Reaction of 2 mol of the ligand gave the corresponding 1 : 2 metal:ligand complexes. The coordination takes place only through the quinoline nitrogen atom. The spectroscopic and the physicochemical data of the new metal complexes are discussed.

Keywords: quinaldine complexes, phosphoranes Quinaldine and its derivatives constitute an important class of organic compounds with industrial and medicinal applications.1-4 The have uses as dyes,5 catalysis,6 antioxidant precursors,7 and corrosion inhibitors,8 and are used as antitumor,9 anti-HIV,10 antimalarial,11 antileishmanial,12 antimicrobial,13 antihistamine, anticholinergic, cardiovascular effects,14 and also as molluscicides for the aquatic snails, e.g. Biomphalaria glabrata and Biomphalaria alexandrina.15 On the other hand, phosphonium ylide complexes attract interest from both the synthetic,16,17 and biological

viewpoints.18 However, known methods for their preparation are difficult and lengthy.19,20 A simple route for the preparation of alkylated phosphonium ylide 3 derived from 2-methylquinoline-4-ol (1) has been reported.21 This was achieved via transylidation of 3-[(diethylamino)methyl]-2-methylquinoline-4-ol (2) by stabilised phosphonium ylide 4 (see Scheme 1). We now report a study of the reaction of some metal salts with 2-methylquinoline-4-ol (1), 3[(diethylamino)methyl]2-methylquinoline-4-ol (2), and/or methyl-3-(4-hyrdoxyOH

OH

N

diethylamine

X

X

5a–e

C2H5 OH

C2 H5 OH

C2H5 N CH2

C2 H5 N CH2

HgCl2,CdCl2 Co(SCN)2 CoCl2,NiCl2

N

CH3

CH3

3

N

(C6H5)3P=CH-COOCH

2

CH3

M

paraformaldehyde

1

N

CH3

M X

X

6a–e

Stable ylide

4

C6 H 5 C6 H5

C6 H5 P

C6 H5 C6 H 5

C6 H5

OH

P OH

C

C

COOCH3

CH2

COOCH3

CH2

N

3

CH3

a, M=Hg; X=Cl b, M=Cd; X=Cl c, M=Co; X=SCN d, M=Co; X=Cl e, M= Ni; X=Cl

N

CH3

7a–e

M X

X

Scheme 1

* Correspondent. E-mail: [email protected]

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278  JOURNAL OF CHEMICAL RESEARCH 2009 2-methylquinoline-3-yl)-2-(triphenylphosphoranylidene) propanoate (3), to prepare new metallic complexes of potential biological interest. The metal cations selected in the current study were Hg2+, Cd2+, Co2+, and Ni2+. The product obtained in each case was isolated and identified by elemental microanalysis, and by physicochemical and spectroscopic methods (IR, 1H NMR, MS). The reaction of one mol of the ligand 2-methylquinoline4-ol (1) with one mol of the previously mentioned transition metal cations in ethanol, afforded the complexes 5a–e. The assignments of the proposed structures were based on the following points. The IR and Far IR spectra for the isolated metal complexes 5a–e were determined and compared with the IR spectrum of the ligand 1. The OH stretching vibrations absorb around n = 3500–3560 cm-1, while the other stretching vibration modes in the ligand are much less affected by adduct formation. The Far IR spectra in the range 200–600 cm-1 were examined and observed bands in the region 200–300 cm-1 for complexes 5a,b,d,e were attributed to the metal chloride (M-Cl) bands.22,23 The 1H NMR spectra for the complexes 5a–e showed the phenolic OH proton at d = 11.2–11.9 ppm which disappeared upon the addition of D2O, and the CH3 protons at d = 3.3–4.0 ppm. The presence of the OH proton in transition metal complexes suggested that the coordination takes place through the N atom while the OH proton is not affected. The 1H NMR spectra of Co and Ni complexes are broad and less sharp than those of Hg and Cd compounds. The magnetic susceptibility data showed the values of μ = 3.2, 3.5 B.M. for

Co complexes 5c,d and μ = 2.5 B.M. for Ni complex 5e, which indicate their paramagnetic and tetrahedral properties.24,25 In the mass spectrum of 2-methylquinoline-4-ol mercuric chloride complex (5a), taken as an example, the molecular ion M+, which would appear at 430, was not recorded. The spectrum showed peaks at m/z 393 (6%) (M+ – Cl), and at m/z 365 (1.7%) (M+– Cl, CO), which undergo fragmentation to a cation with the most abundant peak at m/z 130, (2-methyl3H-indole-3-ylium). On the other hand, compound 5a showed also peaks at m/z 159 (59.3%) (M+– HgCl), which undergo fragmentation to the same cation with the most abundant peak at m/z 130 (100%), and a mercuric chloride peak at m/z 272 (17.7%), which on further fragmentation gave a mercury peak at m/z 202 (14%). When the ligand 1 was allowed to react with (HgCl2) in molar ratio (2 : 1), a white product was isolated, which gave physical data suggesting the general formula 8 (Scheme 2). The IR spectrum of the complex 8 showed the OH group at n = 3521 cm-1 and the C–H (aliphatic) at n = 2912 cm-1, the C–N stretching mode at n = 1632 cm-1. The 1H NMR spectrum for compound 8 showed the OH peak at d = 11.5 (exchangeable with D2O), the aromatic protons at d = 7.2–8.1 (m), CH proton at d = 5.6 (s), and CH3 protons at d = 2.2 (s). The reactions of 3-[(diethylamino)methyl]-2-methylquinoline-4-ol, (2) with the metal cations Hg2+, Cd2+, Co2+ and Ni2+ were also studied, (Scheme 1). The IR spectra for the isolated products 6a–e showed the OH stretching vibrations around n = 3393–3530 cm-1, CH3 around n = 2900–2976 cm-1, OH

N OH

Hg

Cl

Cl

N

HgCl2 N

CH 3

CH 3

CH 3

1

OH

8

C 2H 5 OH

C2H5 N CH 2

C2H 5 OH

C 2H5 N CH 2

N

Cl N

CH 3

HgCl2 ,CdCl2 CoCl2 ,NiCl2

CH 3

M N

Cl CH 3

2 CH 2

9 a,

M b,M c, M d, M

OH C2H 5

N C 2H5

= Hg = Cd = Co = Ni

Scheme 2

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JOURNAL OF CHEMICAL RESEARCH 2009  279 while the other stretching vibration modes in the ligand are much less affected by adduct formation. Moreover, the (SCN) group appeared at n = 2065 cm-1 in the complex 6c. The far IR spectra of the complexes 6a,b,d,e were observed in the region 216–307 cm-1 and were assigned to the appropriate metal halogen bands. The 1H NMR spectra for the complexes 6a–e showed the phenolic OH proton at d = 9.2–11.9 ppm, which disappeared upon the addition of D2O and the CH3 protons were found at d = 2.5–3.4 ppm, The presence of the OH proton in transition metal complexes suggested that the coordination takes place also through the N atom while the OH proton is not affected. In the mass spectrum of 6b for example, the cleavage of the molecular ion of 3-[(diethylamino)methyl]2-methylquinoline-4-ol cadmium chloride complex showed the appearance of the Mannich quinaldine ligand 2 peak at

m/z 244 (1.2%) (M+– CdCl2) and the most abundant peak at m/z 171 (98.1%) [M+– CdCl2, NH(C2H5)2], which loses CO to give a peak at m/z 143 (38.3%), then undergoes further fragmentation to the phenyl cation peak at m/z 77 (12.9%). The magnetic susceptibility data for complexes 6c,d showed the values of μ = 3.1, 3.2 B.M, for Co2+ complexes and for Ni2+ complex 6e μ = 2.3 B.M. When two mols of the ligand 2 were reacted with one mol of the metal chloride salts of Hg2+, Cd2+, Co2+, and Ni2+ in ethanol, the isolated solid products obtained had the suggested formula 9a–d (Scheme 2). In the mass spectroscopy, the molecular ion of the compound 9c, as an example, undergoes the following fragmentation. Its cleavage is shown by the appearance of a peak at m/z 475 (2.98%) [M+-2N(C2H5)2], characteristic to the 2 mol addition, and also the 1 mol addition peak at m/z 372 (5.75%) [M+– mol

Table 1  Physical and microanalytical data for metal complexes 5a–e, 6a–e, 7a–e, 8 and 9a–d Comp. No.

M.p./ °Ca

Colour

Yield/%













Anal. Calcd/ Found%

C

H

N

Cl

M

S

5a

230

White Yellow

95

C10H9NO.HgCl2 (430.5)

27.87 27.83

2.09 2.06

3.25 3.14

16.46 16.25

46.58 46.36

— —

5b

>300

White

88

C10H9NO.CdCl2 (342.3)

35.05 35.00

2.62 2.58

4.09 3.97

20.70 20.08

32.82 31.86

— —

5c

285

Blue

76

C10H9NO.Co(SCN)2 (334)

43.11 43.00

2.69 2.63

12.57 11.95

—

17.66 16.92

19.18 18.89

5d

>300

Blue

84

C10H9NO.CoCl2.H20 (306.8)

39.11 39.01

3.59 3.88

4.56 4.16

23.14 22.97

19.23 19.08

— —

5e

>300

Green

66

C10H9NO.NiCl2 (288.6)

41.58 41.55

3.11 3.01

4.85 3.92

24.55 23.82

20.32 19.97

— —

6a

>300

Pale Yellow

90

C15H20N2O.HgCl2 (515)

34.95 34.90

3.88 3.83

5.43 4.83

13.75 12.91

38.89 38.03

— —

6b

265

White

85

C15H20N2O.CdCl2 (427.3)

42.12 42.01

4.68 4.56

6.55 6.36

16.58 15.79

26.29 25.97

— —

6c

>300

Green

75

C15H20N2O.Co(SCN)2 (419)

48.69 48.81

4.77 4.68

13.36 12.96

— —

14.05 13.66

15.29 14.86

6d

260

Blue

88

C15H20N2O.CoCl2.H20 (391.8)

45.94 45.83

5.62 5.00

7.14 6.87

18.08 17.78

15.03 14.95

— —

6e

>300

Green

60

C15H20N2O.NiCl2 (373.6)

48.17 48.03

5.35 5.26

7.49 6.97

18.96 17.57

15.70 15.22

— —

7a

185

White

92

C32H28NO3P.HgCl2 (776.5)

49.45 49.40

3.60 3.58

1.80 1.37

9.13 8.51

25.81 25.33

— —

3.99 3.59

7b

230

White

87

C32H28NO3P.CdCl2 (688.3)

55.78 55.71

4.06 4.01

2.03 1.91

10.29 09.57

16.32 16.22

— —

4.50 3.88

7c

150

Violet

74

C32H28NO3P.Co(SCN)2 (680)

60.00 60.29

4.11 4.00

6.17 6.30

— —

8.67 8.15

9.41 8.90

4.55 4.24

7d

185

Blue

65

C32H28NO3P.CoCl2.H20 (652.8)

58.82 58.75

4.59 4.95

2.20 1.93

11.16 11.07

9.28 8.59

— —

4.87 3.97

7e

>300

Blue

77

C32H28NO3P. NiCl2 634.6

60.51 60.30

4.41 4.20

2.21 2.10

11.16 10.66

9.24 8.64

— —

4.88 4.24

8

250

White

88

(C10H9NO)2.HgCl2 589

40.74 40.65

3.05 3.00

4.75 3.95

12.02 11.88

34.01 33.90

— —

— —

9a

228

Yellow

90

(C15H20N2O)2.HgCl2 759

47.43 47.21

5.27 5.02

7.37 6.86

9.33 9.01

26.39 25.91

— —

— —

9b

260

White

85

(C15H20N2O)2.CdCl2 671

53.65 53.50

5.96 5.87

8.34 7.96

10.55 10.01

16.73 16.06

— —

— —

9c

260

Blue

66

(C15H20N2O)2.CoCl2.H20 56.62 635.8 56.50

6.29 6.19

8.80 8.86

11.16 10.91

9.27 8.96

— —

— —

230 Green 69 (C15H20N2O)2.NiCl2 58.29 9d 617.6 58.09 aAll the new metal complexes were crystallised from absolute ethanol.

6.48 6.34

9.50 8.96

11.49 10.81

9.49 9.06

— —

— —



Mol. Formula (MWt)

P

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280  JOURNAL OF CHEMICAL RESEARCH 2009 of ligand 2], which undergoes further fragmentation to give the most abundant peak at m/z 171 (100%) [quinonemethylene], and a peak at m/z 144 [quinonemethylene – CO] (32.94%). The magnetic susceptibility data for compound 9c showed the value of μ = 3.1 B.M. for the Co2+ complex and μ = 2.6 B.M. for the Ni complex 9d. Finally, the reaction of quinaldine phosphonium ylide, namely methyl-3-(4-hyrdoxy-2-methylquinoline-3-yl)-2(triphenylphosphoranylidene) propanoate, ligand 3, with the same metal cations was performed to give 7a–e. In their IR spectra, the OH stretching vibrations absorbed around n = 3443–3600 cm-1, and P-C stretching modes around n = 1366–1439 cm-1, while the other stretching vibration modes in the ligand are much less affected by adduct formation. Moreover, the (SCN) group appears at n = 2070 cm-1 in the complex 7c. Far IR spectra were observed in the region 200– 300 cm-1 for complexes 7a,b,d,e and are attributed to the metal halogen bands. The 1H NMR spectra for the complexes 7a–e showed the phenolic OH proton at d = 11.1–11.8 ppm which disappeared upon the addition of D2O, the CH3 protons at d = 2.1–2.5 ppm and the ester CH3 protons at d = 3.4–3.7 ppm. Generally, the Co2+ and Ni2+ complexes which are paramagnetic gave broad NMR spectra. In the mass spectrum of the isolated complex 7a, the cleavage of the molecular ion of the quinaldine phosphonium mercuric chloride complex moiety, was indicated by the appearance of the quinaldine ylide peak at m/z 505 (0.18%) (M+– HgCl2), and at m/z 272 (12.33%) for HgCl2 which undergo fragmentation to the mercuric peak at m/z 199 (7.61%). Moreover, cleavage of M+ 7a also, gave a peak at m/z 444 (0.13%) [M+– phosphonium ylide], and the ylide peaks at m/z = 333 (35%), which fragmented to the most abundant peak at m/z = 262 (100%) for triphenylphosphine. The magnetic susceptibility data for compounds 7c,d showed the values of μ = 3.2, 3.5 B.M. for Co complexes and 7e showed the value of μ = 2.1 B.M. for Ni complex, which indicates tetrahedral structures. From the magnetic susceptibility data, it could be concluded that the paramagnetic Co2+ and Ni2+ are tetrahedral. The Hg2+ and Cd2+ complexes are diamagnetic and also tetrahedral.24,25 Conductometric titration for the complexes Further insight concerning the products of reactions of 1, 2, and 3, with metal cations was gleaned from a consideration

of conductometric measurements. Conductometric titrations were performed by titrating the metal cation solution against the ligand solution of 1, 2, and/or 3. The titration curves are smooth straight lines for all the points and the well-defined breaks are coincident with the stoichometric ratio of the complexes formed in solution. The obtained data are in a good agreement with the 1 : 1 and 2 : 1 (L : M) molar ratio suggested for the previously mentioned complexes. In conclusion, from our experimental results it is evident that ligands 1, 2, and 3 reacted with the metal salt cations (Hg2+, Cd2+, Co2+, Ni2+) and the coordination takes place only through the quinoline nitrogen atom, since the OH group is not a true phenolic hydroxyl group, due to the resonance structure of quinoline, and also due to the steric hindrance of the diethyl amine group in Mannich ligand 2, and of the triphenyl phosphonium group in the phosphonium ylide ligand 3. This is in contrast to the coordination of 8-hydroxyquinoline as the two functional groups in 4-hydroxyquinoline are located at opposite sides of the aromatic ring.26 The data obtained from the conductance titration curves showed that the ligands reacted with the metal salts in 1:1 and 2:1 molar ratio (L : M). The paramagnetic Co(II) and Ni(II) complexes 5–9 appear to have tetrahedral geometry, as do the diamagnetic Hg and Cd complexes. Experimental All melting points were measured on a Gallenkamp electrothermal melting point apparatus and are uncorrected. The IR spectra were recorded in KBr pellets on a Pye-Unicam SP 3300 and FTIR 8101PC Shimadzu IR spectrometers. NMR spectra were obtained in DMSO on a Varian MERCURY (1H: 300 MHz) spectrometer using (TMS) as an internal reference. 31P NMR spectra were run on the same spectrometer using, H3PO4 (85%) as external reference. Mass spectra were recorded on a Shimadzu GC-MS QP 1000 Ex spectrometer at (E I, 70 eV). All the new compounds were crystallised from absolute ethanol. Elemental analyses were carried out at the microanalytical centre of National Research Centre, Cairo. Their results were in agreement with the calculated values. Physical, microanalytical data and spectroscopic data (IR, NMR and MS) of the collected complexes are reported in Tables 1 and 2. Reaction of metal salts with 2-methylquinoline-4-ol (1) in (1/1 molar ratio). Preparation of 2-methylquinoline-4-ol transition metal complexes 5a–e A solution of the metal salts (HgCl2, CdCl2, CoCl2, Co(SCN)2, or NiCl2) (0.01 mol) in 50 mL absolute ethanol was added dropwise

Table 2  IR, 1H NMR, and 31P NMR data for metal complexes 5a–e , 6a–e , 7a–e and 9a–d

(3H,CH3-, s)

1

OH

(1H,CH, s)

C–N

NMR(d)/ppm

(4H, aromatics, m)

CH3

M(SCN)

Compd

OH

1H

Aromatic

IR (v)/cm-1

No.

10.6

7.0–8.2

5.4

3.2

5a

3550

2915

1630

1580–1490 –1464

—

11.5

7.2–8.0

5.9

3.3

5b

3500

2987

1635

1594–1513 –1446

—

11.5

7.2–8.1

5.7

3.6

5c

3556

2965

1631

1599–1558 –1549

2076

11.4

7.2–8.0

5.8

3.3

5d

3521

3321

1631

1599–1496 –1466

—

11.2

7.2–8.3

4.8

4

5e

3560

3392

1632

1548–1470 –1409

—

11.9

7.0–8.2

5.8

3.3

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JOURNAL OF CHEMICAL RESEARCH 2009  281 Table 2  (cont.)

(2H,CH2-CH3,q)

(3H,CH2-CH3,t)

3.4

2.5

2.3

1.0

6a

3447

2972

1612

1579–1521– 1440

9.2

7.2–8.2

3.3

2.9

2.5

1.0

6b

3530

2976

1614

1581–1498

11.4

7.2–8.0

3.3

2.6

2.4

1.0

6c

3743

2970

1631

1557–1510– 1469

11.4

7.2–8.0

3.5

3.4

2.4

1.0

6d

3433

2950

1629

1586–1553– 1529

11.9

7.2–8.2

3.5

2.7

2.5

1.0

6e

3393

2900

1627

1523–1475

11.5

7.0–8.0

3.3

2.5

2.3

1.1

OH

CH3

C=O

Aromatic

OH

(3H,CH3, s)

(3H,CH3-,s)

7.1–8.1

(3HCOOCH3,s)

9.8

(2H,CH2,2d)

OH

(19H, armatic,m)

2

NMR(d)/ppm.

(2H,CH2-N,s)

1H

(4H,aromatic,m)

IR (v)/cm-1

No.

31P

10.3

7.6–8.3

2.8,3.2

3.6

2.1

2065

P–C

1436

11.7

7.3–8.3

2.5,3.3

3.6

2.2

25.7

7b

3457

2974

1622

1579–1501

1366

11.1

7.1–8.1

2.5,3.3

3.7

2.1

25.9

7c

3443

2924

1627

1523–1471

1433

11.3

7.1–8.1

2.4,3.5

3.5

2.2

25.7

7d

3588

2975

1750

1583–1499

1439

11.7

7.9

2.4,3.5

3.5

2.4

25.4

7e

3600

3100

1739

1523–1474

1437

11.8

7.2–8.0

2.7,2.9

3.4

2.5

25.4

OH

CH3

C-N

9a

3424

2927

1632

9b

3522

2974

9c

3552

9d

3422

OH

(3H,CH2-CH3,t)

1549–1527

(3H,CH2-CH3,q)

1611

(3H,CH3-,s)

2934

(2H,CH2-N,s)

3572

(4H,aromatic,m)

7a

Aromatic

3

1579–1548– 1497

11.5

7.3–8.1

3.6

2.9

2.5

1.0

1622

1579–1501– 1367

11.4

7.2–8.1

3.5

2.7

2.4

1.0

3059

1630

1580–1541– 607

11.4

7.2–8.0

3.6

2.7

2.5

1.0

2986

1629

1527–1475

11.2

7.3–8.1

3.3

2.5

2.3

1.0

to a well-stirred solution of 1 (0.16 g, 0.01 mol) in absolute ethanol (50 mL). After complete addition of the metal salt the reaction mixture was heated under reflux for two hours, and then the solvent was evaporated under reduced pressure to give the metal complexes 5a–e. Reaction of mercuric chloride with 2-methylquinoline-4-ol (1) in (1/2 molar ratio) A solution of the mercuric chloride (0.27 g, 0.01 mol) in absolute ethanol (50 mL) was added dropwise to a well-stirred solution of 1 (0.32 g, 0.02 mol) in absolute ethanol (50 mL). After complete

addition of the metal salt the reaction mixture was heated under reflux for two hours, and then the solvent was evaporated under vacuum to give white crystals of 8. Reaction of metal salts with 3-[(diethylamino) methyl]-2methylquinoline-4-ol (2) in (1/1 molar ratio) Preparation of 3-[(diethylamino) methyl]-2-methylquinoline-4-ol transition metal complexes 6a–e A solution of the metal salts (HgCl2, CdCl2, CoCl2, Co(SCN)2, or NiCl2) (0.01 mol) in absolute ethanol (50 mL) was added dropwise

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282  JOURNAL OF CHEMICAL RESEARCH 2009 to a well-stirred solution of 2 (0.16 g, 0.01 mol) in absolute ethanol (50 mL). After complete addition of the metal salt the reaction mixture was heated under reflux for two hours, then the solvent was evaporated under reduced pressure to give the metal complexes 6a–e. Reaction of metal salts with 3-[(diethylamino) methyl]-2-methylquinoline-4-ol (2) in (1/2 molar ratio) A solution of the metal salts (HgCl2, CdCl2, CoCl2, or NiCl2) (0.01 mol) in absolute ethanol (50 mL) was added dropwise to a wellstirred solution of two mols of the Mannich base 2 (0.5 g, 0.02 mol) in absolute ethanol (50 mL). After complete addition of the metal salt the reaction mixture was heated under reflux for two hours, then the solvent was evaporated under reduced pressure to give the metal complexes 9a–d. Reaction of metal salts with methyl-3-(4-hyrdoxy-2-methylquinoline3-yl)-2-(triphenylphosphoranyli-dene) propanoate (3) in (1/1 molar ratio). A solution of the metal salts (HgCl2, CdCl2, CoCl2, Co(SCN)2, or NiCl2) (0.01 mol) in absolute ethanol (50 mL) was added dropwise to a well-stirred solution of 3 (0.5 g, 0.01 mol) in absolute ethanol (50 mL). After complete addition of the metal salt, the reaction mixture was heated under reflux for two hours; the solvent was evaporated under vacuum to give the metal complexes 7a–e.

Received 4 June 2008; accepted 28 January 2009 Paper 08/5313  doi: 10.3184/030823409X440841 Published online: 20 May 2009 References 1 S.S. Maigali, M.M. Said, M.A. Abd-El-Maksoud and F.M. Soliman, Monatsh. Chem., 2008, 139, 495. 2 R. Shabana, S.S. Maigali, S.A. Essawy, M.El-Hussieny and F.M. Soliman, Egypt. J. Chem., 2007, 59. 3 M.M. Said, S.S. Maigali, M.A. Abd-El Maksoud and F.M. Soliman, Monatsh. Chem., 2008, in press. 4 S.S. Maigali, R. Shabana, M. El- Hussieny and F.M. Soliman, Phosphorus, Sulfur, Silicon, 2008 in press.

5 R.M. Abd El-Aal and M. Younis, Bioorganic Chem., 2004, 32, 193-210. 6 D.I. Nebahat and Ö Beytiye, Monatsh. Chem., 2003, 134, 1565. 7 L.P.H. Clarke and M.C. Otto ARKIVOC (online computer file), 2000, 1, 364. 8 S.M. Li, H.R. Zhang and J.h. Liu, Trans. Nonferrous Met. Soc. China, 2007, 17, 318. 9 B.K. Sinha, R.M. Philen, R. Sato and R.L. Cysyk, J. Med. Chem., 1977, 20, 1528. 10 J. Polanski, F. Zouhiri, L. Jeanson, D. Desmaële, J. d'Angelo, J.F. Mouscadet, R. Gieleciak, J. Gasteiger and M. Le Bret, J. Med. Chem., 2002, 45, 4647. 11 B.M. Kotecka, G.B. Barlin, M.D. Edstein and K.H. Rieckmann, Antimicrob. Agents Chemother, 1997, 41, 1369. 12 A.G. Tempone, A.C.M.P. da Silva, C.A. Brandt, F.S. Martinez, M.A.B. Borborema SET,da Silveira and Jr. H.F. de Andrade, Antimicrob. Agents Chemother., 2005, 49, 1076. 13 K.R. Nandha, S. Thangaraj and M.P. Subraminiam, Acta Pharm., 2003, 53, 1. 14 A.A. Alhaider, Life Sciences, 1986, 38, 601. 15 P.C. Vieira and I. Kubo, Phytochemistry, 1990, 29, 813. 16 A.A. Esmaili, M. Ghereghloo, M.R. Islami and H.R. Bijanzadeh, Tetrahedron, 2003, 59, 4785. 17 L. Saghatforoush, M.T. Maghsoodlou, A. Aminkhani, Gh. Marandi and R. Kabiri, J. Sulfur Chem., 2006, 27, 583. 18 K.C. Fylaktakidou, D.R. Gautam, D. Hadjipavlou-Litina, C.A. Kontogiorgis, K.E. Litinas and L.N. Nicolaides, J. Chem Soc Perkin Trans., 2001, 1, 3073. 19 F.R. Hartley, The Chemistry of organophosphorus compounds: phosphonium salts, ylides and phosphoranes, John Wiley & Sons Inc. (2006). 20 J.J. Kiddle, Tetrahedron Lett., 2000, 41, 1339. 21 F.M. Soliman, K.M. Khalil, A.A. Elkateb, R. Shabana and G. AbdelNaim, Chem. Indust., 1985, 16, 554. 22 Y. Xie, Y. Ni, H. Jiang, and Q. Liu, J. Mol. Struct., 2004, 687, 73. 23 F. Neese, T. Petrenko, D. Ganyushin and G. Olbrich, Coord. Chem. Rev., 2007, 251, 288. 24 I.M. Abd-Ellah, B.A. El-Sayed, M.A. El-Nawawy and A.M.A. Alaghaz, Phosphorus, Sulfur Silicon, 2002, 177, 2895. 25 F.A. Cotton, G. Wilkinson, C.A. Murillo and M. Bochmann, Adv. Inorg. Chem., 1999, 6th edn, Wiley: New York. 26 E.J. Alvarez, V.H. Vartanian and J.S. Brodbelt, Anal. Chem., 1997, 69, 1147.

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RESEARCH PAPER  283

EPR studies on carboxylic esters. Part 20. EPR spectra and spin densities in radical anions of isocoumarin, benzocoumarin and their sulfur analogues Jürgen Voss*, Gabriele Kupczik and Heidi Stahncke University of Hamburg, Department of Chemistry – Organic Chemistry, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany

The radical anions of isocoumarin, benzocoumarin and the six corresponding sulfur analogues have been generated by internal electroreduction and studied by EPR spectrosopy. The spin density distributions have been evaluated from the proton hyperfine structure coupling constants and by MO calculations. They are discussed with respect to the spin density distributions in related radical anions.

Keywords: isocoumarin, benzocoumarin, thio-isocoumarins, thio-benzocoumarins, EPR spectroscopy, spin densities Recently we have reported on the radical anions of coumarins and their sulfur analogues,1,2 which may be thought of as cyclic cinnamate esters and thioesters. Their isomeric counterparts, the isocoumarins, on the other hand, represent cyclo-conjugated benzoate esters and thioesters, whereas the corresponding benzoanellated derivatives exhibit a combination of both these features. Accordingly, this should be reflected in the spin density distributions. We have therefore prepared these compounds and studied the EPR spectra of their radical anions in order to corroborate these considerations by experimental evidence. Results and discussion

The compounds to study, 1–8, were prepared according to literature procedures (see Experimental).

X Y 1: X = Y = O 2: X = S, Y = O 3: X = O, Y = S 4: X = Y = S

X Y 5: X = Y = O 6: X = S, Y = O 7: X = O, Y = S 8: X = Y = S

Their polarographic half-wave reduction potentials E½ corresponding to the formation of radical anions by single electron transfer (SET) of 1–8, which we have determined as described earlier,2–4 are compiled in Table 1. A continuous shift of E½ into the positive direction is observed in the two series 1 → 2 → 3 → 4 and 5 → 6 → 7 → 8 of the compounds. This shift can be explained by the enhanced polarisability of sulfur as compared with oxygen and, in particular, of the thiocarbonyl group versus the carbonyl group, which facilitates the uptake of an electron into the molecule. We have observed this effect also in the coumarin series2 and in open-chain esters and their sulfur analogues.5–9 Furthermore, a significant shift in the same direction occurs between the isocoumarins 1–4 and the corresponding benzocoumarins 5–8. This effect should be due to the more extended p-electron system of the latter with a smaller HOMO–LUMO difference. Remarkably, the reduction potentials E½ of the benzocoumarins are similar to E½ of the corresponding coumarin derivatives2 whereas the E½-values of the isocoumarins deviate significantly. Thus, in terms of the SET step, the benzocoumarin system is obviously more closely related to the coumarin than to the isocoumarin system, each of which formally represents a constituent of the benzocoumarin system. * Correspondent. E-mail: [email protected]

Table 1  Polarographic reduction potentials E½/V a and peak current ratios iap/icpb Compound

E½/Va

iap/icpb

1 –1.41 0.43 2 –1.27 0.43 3 –1.07 0.47 4 –0.72 0.77 5 –1.32 0.90 6 –1.16 1.04 7 –0.68 0.72 c 8 –0.58 avs the internal Ag/Ag+/AgBr/Br– reference electrode in dry DMF, the potential of which is shifted by –520 mV vs the SCE according to ref. 3; baccording to refs 10,11 measured at a sweep rate of 500 mVs–1; cno anodic peak observed.

With the exception of 8, the ratios iap/icp of the anodic and the cathodic peaks10,11 (Table 1) are well above 0.4. This is, in general, indicative of the formation of radical anions which are sufficiently persistent for EPR measurements at ambient temperature. Accordinglyly, we could record well-resolved EPR spectra with high signal-to-noise ratios as exemplarily illustrated for the radical anions of isocoumarin 1 (Fig. 1), thioloisocoumarin 2 (Fig. 2), thionobenzocoumarin 7 (Fig. 3) and dithiobenzocoumarin 8 (Fig. 4). Fortunately, this even holds for the dithiobenzocoumarin 8 (see Fig. 4) although 8 does not exhibit an anodic counter peak in its cyclovoltamogram (Table 1). This unexpected result may be due to the different geometries of the cells and different time-scales of the cyclovoltammetric and the EPR measurements and is observed occasionally. The isocoumarin radical anions and their sulfur analogues 1¯ • – 4¯ • exhibit g-factors close to the values of the respective benzocoumarin radical anions 5¯ • – 8¯ •. They are similar to those found in the coumarin series.2 Due to the heavyatom effect of the thiocarbonyl sulfur, i.e. its high spin-orbit coupling constant x = –382 cm–1, the g-factors of 3¯ •, 4¯ •, 7¯ • and 8¯ • are markedly higher than these of 1¯ •, 2¯ •, 5¯ • and 6¯ •. The data are, in a semi-quantitative sense, indicative of significant spin densities in the thiocarbonyl groups of the thiono and dithio derivatives, although a precise and conclusive calculation of rp(C=S) from the g-factors is not possible. The proton hyperfine structure (hfs) coupling constants aHμ could be determined exactly by use of the autocorrelation function2,12 and simulation of the spectra in spite of the fact that due to the low symmetry of the molecules the number of different hfs splittings and consequently the number of lines is rather large. The coupling constants and g-factors of 1¯ • – 8¯ • are compiled in Table 2. In the case of 6¯ •, 7¯ • and 8¯ • several protons appear as accidentally equivalent. The assignment of the coupling constants aHμ to distinct protons was achieved through

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Fig. 1  Experimental (top) and simulated (bottom) EPR spectrum of the isocoumarin radical anion (1¯ •).

Fig. 2  Experimental (top) and simulated (bottom) EPR spectrum of the thioloisocoumarin radical anion (2¯ •).

Fig. 3  Experimental (top) and simulated (bottom) EPR spectrum of the thionobenzocoumarin radical anion (7¯ •).

Fig. 4  Experimental (top) and simulated (bottom) EPR spectrum of the dithiobenzocoumarin radical anion (8¯ •).

comparison of the experimental data with values calculated from McLachlan type HMO spin densities rpμ by application of the McConnell equation aHμ = –2.7rpμ (cf. Table 3). On the whole, the agreement between the theoretical and experimental spin densities is quite satisfactory. The assignment of the very low values close to zero is of course, somewhat arbitrary but this fact does not affect the discussion of the spin density distributions significantly. There are however some more significant deviations. In particular, rp8 is overestimated for the carbonyl derivatives 1 and 2. This may be due to a reduced resonance interaction between the carbonyl groups of 1 and 2 and the adjacent benzene rings

as compared with open-chain benzoic esters from which the parameters k and h of the Coulomb and resonance integrals are taken (see Experimental). In fact, an improved agreement for rp8 was achieved by use of a lower resonance integral kC1-C8a = 1.1 instead of 1.2. On the other hand, rp6 results as too large for the thiocarbonyl derivatives 3 and 4, which could also be adjusted by choice of lower resonance parameters kC1-C8a = 0.9 (3) and 1.1 (4) and a higher resonance parameter kC=S = 1.23 instead of 0.77 for 3 (cf. Table 4). The highest spin densities are found in the 6- and 8-positions with rp6 > rp8, which positions are equivalent to the para- and ortho-positions in open-chain benzoate esters and thioesters.5–9 Considerable spin densities

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JOURNAL OF CHEMICAL RESEARCH 2009  285 Table 2  Proton hfs coupling constants aHμ/mT and g-factors of the radical anions of 2 4

5

10

6

3 X

7 8





X

8 7

Y



3 4

9

1–4 Compound

1

Y

5–8 aHμ /mT











a(3-H) a(4-H) a(5-H) a(6-H) a(7-H) a(8-H) 1 0.214 0.067 0.063 0.780 0.110 0.467 2 0.304 0.105 0.084 0.652 0.125 0.364 3 0.148 0.087 0.020 0.636 0.150 0.465 4 0.138 0.098 0.044 0.518 0.159 0.414 a(1-H) a(2-H) a(3-H) a(4-H) a(7-H) a(8-H) a(9-H) a(10-H) 5 0.299 0.045 0.171 0.124 0.171 0.015 0.535 0.149 6 0.297 0.047 0.147 0.047 0.171 0.027 0.589 0.123 a a 7 0.128 0.074 0.415 0.047 0.572 0.128 a a 8 0.122 0.061 0.359 0.061 0.482 0.122 aNot resolved.

g-factor

2.00335 2.00435 2.00457 2.00644

2.00389 2.00413 2.00476 2.00637

Table 3  Experimental (rpμ = aHµ/–2.7) and theoreticala (HMO) spin densities rpμ in the iso- and benzocoumarin radical anions 2 4

5

10

6

3 X

7 8 •

Compound





X

8 7

•

exist, however, also in the 7-position, which may be regarded as a meta-position in a benzoate ester. Furthermore, rp3 is significantly non-zero too. This is not unexpected because the 3-position in an isocoumarin corresponds with the 6-position in a 2H-thiopyrane-2-thione, and we have found aH6 = 0.69 mT and rp6 = 0.256 for the radical anion of 5-tert-butyl-2Hthiopyrane-2-thione.13 Thus, the general order of the spin densities in the radical anions of the isocoumarins 1–4 is rp6 > rp8 > rp3 ª rp7. This spin density distribution is different from the situation in the coumarin radical anions, which obviously

Y •

5¯ – 8¯

•

rpμ at centre µ



3 4 5 1 0.079 0.025 0.023 0.097 –0.037 –0.010 2 0.113 0.039 0.031 0.115 –0.046 –0.027 3 0.055 0.032 0.007 0.056 –0.026 –0.008 4 0.051 0.036 0.016 0.057 –0.032 –0.016 1 2 3 5 0.111 0.017 0.064 0.124 –0.023 0.080 6 0.110 0.017 0.054 0.110 –0.024 0.078 b 7 0.047 0.027 0.064 –0.012 0.040 b 8 0.045 0.023 0.060 –0.013 0.038 aShown in Italics. bNo couplings observed, see Table 2.

3 4

9

Y

1¯ – 4¯

1

6 0.289 0.297 0.241 0.243 0.235 0.247 0.192 0.184

7 0.041 –0.053 0.046 –0.041 0.056 –0.057 0.059 –0.057

8 0.173 0.185 0.135 0.137 0.172 0.178 0.153 0.154

4 0.046 0.046 0.017 0.034 b 0.017

7 0.067 0.082 0.064 0.086 0.154 0.157 0.133 0.134

8 0.006 0.006 0.010 –0.006 0.027 –0.050 0.023 –0.045

b

0.014





9 0.198 0.198 0.218 0.190 0.212 0.183 0.178 0.164

10 0.055 –0.062 0.046 –0.058 0.047 –0.053 0.045 –0.051

can be considered as cyclic cinnamic acid derivatives and exhibit thus the highest spin densities in the 7- and the 5-positions.2 In the benzocoumarin series, the calculated spin density rp1 comes out too high for 5 and the calculated rp9 values are too low for 6–8 as compared with the experimental values although we used Coulomb integrals for the exocyclic heteroatoms [hO(5) = 1.65; hO(6) = 0.6; hS(8) = 0.25] which were slightly different from the parameters given in the literature (cf. Table 4). More spin density is located in the rings adjacent

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286  JOURNAL OF CHEMICAL RESEARCH 2009 Table 4  Coulomb (k) and resonance parameters (h) used for the McLachlan type MO calculations Parametera

1

2

3

4

5

6

1.6 1.1 1.23 0.7 1.6 1.2 k(C ═ X) k(C–Y) 1.2 0.8 0.68 0.8 1.1 0.9 k(C–C)b 1.1 1.1 0.90 1.1 1.2 1.2 hX(C ═ X) 1.5 0.2 0.62 0.0 1.65 0.6 hY(C–Y) 2.1 1.8 1.54 2.0 2.0 2.0 aX = O for 1, 2, 5, 6; X = S for 3, 4, 7, 8; Y = O for 1, 3, 5, 7; Y = S for 2, 4, 6, 8. bC1–C8a for 1–4; C6–C6a for 5–8.

to the carbonyl or thiocarbonyl double bond as compared with the other annelated benzene ring. Thus, the spin density distributions in the benzocoumarin radical anions with rp9 > rp1 > rp3 ª rp7 for 5¯ • and 6¯ •, and rp9 > rp7 > rp1 for 7¯ • and 8¯ • resemble those in the isocoumarin radical anions if one considers that the 6- and 8-positions in 1–4 correspond with the 9- and 7-positions in 5–8. This is to be expected because the benzocoumarins can be regarded as intramolecular phenyl benzoates and thiobenzoates. Considerable spin density is, however, also found in the second ring since the benzo- coumarins may also be regarded as biphenyl derivatives with an observed hfs coupling constant of e.g. 0.32 mT for the 4'proton in the tert-butyl biphenyl-4-carboxylate radical anion.14 Experimental Isocoumarin (isochromen-1-one, 1) was prepared from homophthalic acid [(2-carboxyphenyl)ethanoic acid] and ethyl formate. White needles, m.p. 44–46 °C (petroleum ether), lit.15: 45–46 °C. Thioloisocoumarine (thioisochromen-1-one, 2) was obtained from 2formylbenzoic acid. Light-yellow needles, m.p. 78–80 °C (petroleum ether), lit.16: 78–79 °C. Thiono-isocoumarin (isochromene-1-thione, 3) was prepared by thionation of 1 with Lawesson's reagent17,18 in toluene instead of P4S10.19,20 Yellow needles, m.p. 106–107 °C (EtOH), lit.19,20: 106 °C. Dithio-isocoumarin (thioisochromene1-thione, 4) was prepared by thionation of 2 with Lawesson's reagent17,18 in toluene instead of P4S10.21 Red needles (68% yield), m.p. 88–89 °C (EtOH). Found: C, 60.66; H, 3.33; S, 36.10. Calcd for C9H6S2 (178.28), C, 60.63; H, 3.39; S, 35.97%. 1H and 13C NMR in agreement with lit.21 Benzocoumarin (6H-benzo[c]chromen-6one, 5) was prepared by oxidation of biphenyl-2-carboxylic acid with CrO3. Colourless crystals, m.p. 92 °C (MeOH), lit.22,23: 92.5– 93.5 °C. Thiolo-benzocumarin (6H-benzo[c]thiochromen-6-one, 6) was obtained by oxidation of 8 with Hg(OAc)2. Yellow needles, m.p. 125–127 °C (petroleum ether), lit.24,25: 130–131 °C. Thionobenzocoumarin (6H-benzo[c]chromene-6-thione, 7) was prepared by thionation of 5 with Lawesson's reagent17,18,23 in toluene. Yellow crystals, m.p. 148–149 °C (EtOH), lit.23: 150–151 °C, lit.26: 148–150 °C. Dithio-benzocoumarin (6H-benzo[c]thiochromene6-thione, 8) was prepared by reaction of biphenyl-2-thiol27 with CSCl2, and subsequent intramolecular Friedel–Crafts-acylation of the intermediate biphenyl-2-yl chlorodithioformate [94%, orange oil, C13H9ClS2 (264.80), Calcd C 58.97, H 3.43, Cl 13.39 S 24.22; found C 59.05, H 3.35, Cl 13.31, S 24.19] with AlCl3. Red needles, m.p. 106 °C (petroleum ether), lit.25: 113–114 °C, lit.28: 106 °C. The polarographic and cyclovoltammetric measurements, the generation of the radical anions by in situ electroreduction in DMF at room temperature, and the recording of the EPR spectra were performed as described previously.2 The g-factors were determined by direct measurement of the field Ho and the microwave frequency no according to g = 7.14484·10–11 no·Ho–1 and corrected by using the perylene radical cation (g = 2.002569) as internal standard. Spectra simulations were carried out by using the Simfonia program (Bruker). Simple HMO calculations were performed by use of the online program Shmo.29 An unpublished Fortran-77 program Hueckel30,31 was used for the McLachlan type calculations. The applied Coulomb and resonance parameters are compiled in Table 4. They differ slightly from the literature data for open-chain benzoates (1 and 5),32 thiolobenzoates (2 and 6),6 thionobenzoates (3 and 7)5 and dithiobenzoates (4 and 8);5 see above.

7

8

0.77 0.54 1.2 0.5 1.5

0.66 0.65 1.2 0.25 1.9

The University of Hamburg, the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie are gratefully acknowledged for financial support. G. K. thanks the Fonds der Chemischen Industrie for a graduate scholarship. We thank Karin Grünewald, Hamburg, for the preparation of 5 and 7. Received 10 January 2009; accepted 2 March 2009 Paper 09/0384  doi: 10.3184/030823409X449428 Published online: 22 May 2009 References 1 Part 19. J. Voss, K. Strey, T. Maibom, M. Krasmann and G. Adiwidjaja, Phosphorus, Sulfur, Silicon, 2009, 184, (accepted). 2 J. Voss and R. Edler, J. Chem. Res., 2007, 226. 3 H. Günther and J. Voss, J. Chem. Res., 1987 (S) 68, (M) 775. 4 J. Voss and F.-R. Bruhn, Liebigs Ann. Chem., 1979, 1938. 5 J. Voss and K. Schlapkohl, Tetrahedron, 1975, 31, 2982. 6 U. Debacher, W. Schmüser and J. Voss, J. Chem. Res., 1982 (S) 74, (M) 876. 7 L. Prangova, T. Strelow and J. Voss, J. Chem. Res., 1985 (S) 118, (M) 1401. 8 L.S. Prangova, A. Böge, B. Wollny and J. Voss, J. Chem. Res., 1987 (S) 182, (M) 1601. 9 L. Prangova, K. Osternack and J. Voss, J. Chem. Res., 1995 (S) 234, (M) 1551. 10 R. Nicholson and I. Shain, Anal. Chem., 1964, 36, 706. 11 R. Nicholson, Anal. Chem., 1966, 38, 1406. 12 F. Schneider and M. Plato, Elektronenspinresonanz, Thiemig, München, 1972, p. 182f. 13 R. Röske and J. Voss, Phosphorus, Sulfur and Silicon, 1986, 26, 257. 14 S. Bruns, Dichtefunktional-theoretische Berechnungen der Strukturen und der EPR-Hyperfeinstrukturen von Biarylen, PhD thesis, University of Hamburg, Germany, 2002. 15 H.W. Johnston, C.E. Kaslow, A. Langsjoen and R.L. Shriner, J. Org. Chem., 1948, 13, 477. 16 J. Dijksman and G.T. Newbold, J. Chem. Soc., 1951, 1213. 17 J. Voss, Encyclopedia of reagents for organic synthesis, L.A. Paquette and S.D. Burke (eds), Vol. 1, John Wiley & Sons Ltd., Chichester, 1995, 534. 18 J. Voss, Electronic Encyclopedia of reagents for organic synthesis, “EROS” L.A. Paquette and D. Crich (eds), 2nd edn., Vol. 1, John Wiley & Sons Ltd., Chichester, 2006. Online: http://www.mrw.interscience. wiley.com/eros/articles/rb170/sect0.html. 19 V. Prey, B. Kerres and H. Berbalk, Monatsh. Chem., 1960, 91, 774. 20 L. Legrand and N. Lozac'h, Bull. Soc. Chim. Fr., 1964, 31, 1787. 21 H. Duddeck and M. Kaiser, Spectrochim. Acta, 1985, 41A, 913. 22 G.W. Kenner, M.A. Murray and C.M.B. Tylor, Tetrahedron, 1957, 1, 259. 23 F.M. Dean, J. Goodchild and A.W. Hill, J. Chem. Soc., C, 1969, 2192. 24 I.W.J. Still, N. Plavac, D.M. McKinon and M.S. Chauhan, Can. J. Chem., 1976, 54, 280. 25 J.L. Charlton, S.M. Loosmore and D.M. McKinnon, Can. J. Chem., 1974, 52, 3021. 26 I. Jabre, M. Saquet and A. Thuillier, J. Chem., Res., 1990, (S) 106, (M) 756. 27 D.D. Emrick and W.E. Truce, J. Org. Chem., 1960, 25, 1103. 28 L. Benati and P.C. Montevecchi, J. Org. Chem., 1976, 41, 2639. 29 R. Cannings, Simple Huckel molecular orbital, SHMO, iterative online program (http://www.chem.ucalgary.ca/SHMO/). 30 D. Buddensiek, Semiempirische MO-Rechnungen und experimentelle Untersuchungen an Thioketonen und ihren Radikal-Anionen, PhD thesis, University of Hamburg, Germany, pp. 64, 200, 1985. 31 D. Buddensiek, B. Köpke and J. Voß, Chem. Ber., 1987, 120, 575. 32 M. Hirayama, Bull. Chem. Soc. Jpn, 1967, 40, 1822.

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RESEARCH PAPER  287

May, 287–289

Solid-phase synthesis of aryl vinyl ethers based on polystyrenesupported β-phenylselenoethanol Jia-Li Zhanga, Shou-Ri Shengb*, Xue Liub and Shu-Ying Linb aDepartment bCollege

of Chemistry and Chemical Engineering, East China Jiaotong University, Nanchang 330013, P. R. China of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, P. R. China

A novel facile solid-phase organic synthesis of aryl vinyl ethers by reaction of polystyrene-supported b-phenylselenoethanol with phenols under Mitsunobu conditions and subsequent oxidation-elimination with 30% hydrogen peroxide has been developed. The advantages of this method include straightforward operation, lack of odour, good yield and high purity of the products.

Keywords: solid-phase organic synthesis, polystyrene-supported b-phenylselenoethanol, aryl vinyl ether Vinyl ethers are valuable intermediates that can be used in a wide array of chemical transformations.1 More specifically, aryl vinyl ethers with unsubstituted vinyl moiety, have wide synthetic applications and are employed as key intermediates for the generation of new polymeric materials,2 as dienophiles for cycloaddition reactions such as [2 + 2],3 [2 + 4]4 and 1,3-dipolar cycloadditons,5 in cyclopropanations,6 in hydroformylations,7 and in natural product analogue synthesis.8 Aryl vinyl ethers are usually prepared according to the following procedures: the dehydrohalogenation of aryl 2-haloethyl ethers,9 the addition of phenols to acetylene10 and the copper (II)-promoted coupling of arylboronic acids with phenols.11 Recently, the use of vinyl acetate in an iridiumcatalysed reaction with phenols,12 and the transformations with copper (II) acetate mediated coupling of 2, 4, 6-trivinylcyclotriboroxane as a vinylboronic acid equivalent,13 and tributy(vinyl)tin14 with phenols have also been reported. However, most of these methods involved difficulties such as harsh reactions, laborious manipulation and low overall yields, or in some cases, reactions are unsuitable for sensitive substrates, vigorous toxic compounds are used or some reagents are not readily available. It is well known that phenylseleno group is readily converted to a leaving group giving access to carbon–carbon double bond via oxidation followed by b-elimination under extremely mild conditions.15 Moreover, the polymeric selenium reagents16 have been now developed for solid-phase organic synthesis (SPOS) with a combined advantage of decrease volatility and simplification of product work-up. In continuation of our interest in solidphase organoselenium chemistry,17 describe here a new simple and efficient SPOS approach to aryl vinyl ethers based on a novel polystyrene-supported b-phenylselenoethanol reagent (Scheme 1). SeBr

LiBH4 THF, rt

1 R

SeLi

Polymer-supported b-phenylselenoethanol (3) was readily prepared by treatment of a THF-swollen suspension of crosslinked (1%) polystyrene-bound selenium bromide (1)16 with LiBH4, followed by treatment with 2-chloroethanol. The IR spectrum of resin 3 showed a large hydroxyl absorption at 3400 cm-1, and band at 1060 cm-1 (C–O). Resin 3 can be stored at room temperature for a long time without diminution of capacity or the liberation of disagreeable odors. With the resin 3 in hand, the etherification reaction was investigated from resin 3 with phenol (4a) under Mitsunobu reaction conditions [triphenylphosphine/diethyl azodicarboxylate] in 4-methylmorpholine to afford polystyrene-supported 2phenoxyethyl selenide(5a) efficiently, which could not be reliably analysed with FT-IR. Hence we carried out next cleavage reaction directly after washing the resin 5a using solvents. Treatment of resin 5a with 30% hydrogen peroxide at 0 °C and then at room temperature afforded the corresponding phenyl vinyl ether (6a) in good yields (90%) and with good purities of crude material (95%). The residual resin, polystyrene-supported phenylseleninic acid, was obtained as a by-product, whose IR data were identical to the previously reported data.18 The polystyrene-supported phenylseleninic acid could be converted to polymer-supported selenium lithium for recycle by treatment of it with KI/Na2S2O319,20 followed by bromine.16 For example, phenyl vinyl ether (6a) was obtained in 88% yield under the same reaction condition using the recovered selenium lithium resin (second run), and in 85% yield after second recycle (i.e. third run). It was shown that recycling 2–3 times led to a gradual deterioration of the resin. After successfully preparation of 6a, extension of this method to the synthesis of other analogues in good yields and good purities was investigated (Table 1). As seen from the Table 1, for substrates phenols, with substitution of an ClCH2CH2OH

SeCH2CH2OH

rt

2

3

OH (4) Ph3P/DEAD THF/NMM, rt

R SeCH2CH2O

5

H2O2 THF

R

OCH=CH2

6

Scheme 1

* Correspondent. E-mail: [email protected]

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288  JOURNAL OF CHEMICAL RESEARCH 2009 Table 1  The yields and purities of aryl vinyl ethers (6a–6m) Entry R (Phenol)

Product

Yielda/%

Purityb/%

6a 90 95 1 H (4a) 2 3-CH3 (4b) 6b 89 94 3 4-CH3O (4c) 6c 90 97 4 4-t-C4H9 (4d) 6d 88 95 5 4-C6H5 (4e) 6e 86 96 6 4-Cl(4f) 6f 83 95 7 4-Br (4g) 6g 88 95 8 2-Br (4h) 6h 86 94 9 4-NO2 (4i) 6i 90 96 10 4-CN (4j) 6j 88 95 11 4-CO2CH3 (4k) 6k 86 94 12 4-NHCOCH3 (4l) 6l 88 96 13 1-Naphthol (4m) 6m 84 95 aOverall yields based on polystyrene-supported selenium bromide 1 (1.18 mmol Br/g). bDetermined by HPLC of crude cleavage product (l = 254 nm).

electron-withdrawing group or an electron-donating group on the aromatic ring resulted in no obvious effect on the reaction yields. In summary, we have developed a novel, efficient and convenient method for the SPOS of aryl vinyl ethers employing polymer-supported b-phenylselenoethanol. The advantages of this method include straightforward operation, lack of odour, good yield and high purity of the products. Experimental Melting points were uncorrected.1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker Avance (400 MHz) spectrometer, using CDCl3 as the solvent and TMS as internal standard. FT-IR spectra were taken on a Perkin–Elmer SP One FT-IR spectrophotometer. HPLC analysis was performed on Agilent 1100 automated system having a PDA detector using a gradient with CH3CN/H2O (1 mL min-1) on a RP-18e column (150 ¥ 4.6 mm). Polystyrene (H 1000, 100–200 mesh, cross-linked with 1% divinylbenzene) for preparation of selenium bromide resin16 was purchased from Nankai University, and the other starting materials were purchased from commercial suppliers and used without further purification. THF was stilled from sodium benzophenone immediately prior to use. Preparation of polystyrene-supported b-phenylselenoethanol (3) Under a nitrogen atmosphere, to deep red coloured polystyrenesupported selenium bromide 1 (1.0 g, 1.18 mmol Br/g, the loading of functional Br was analysed by elementary analysis) swollen in THF (10 mL) for 30 min was added LiBH4 (3.0 mmol). After 1 h with shaking at room temperature, 2-chloroethanol (3.0 mmol) in 2 mL of THF was added slowly and the mixture was shaken for 6 h. The resin was collected on a filter and washed successively with H2O (2 ¥ 20 mL), THF (3 ¥ 5 mL) and CH2Cl2 (3 ¥ 5 mL), and then dried under vacuum overnight to afford 950 mg of resin 3, which was calculated to have a loading of 1.20 mmol g-1, assuming the etherification reaction went to completion. IR (KBr): n = 3400, 3052, 2925, 1595, 1475, 1060, 940, 732, 688 cm-1. Preparation of aryl vinyl ethers(6a–m); general procedure The resin 3 (1.0 g, 1.20 mmol) was swollen in THF (10 mL) at room temperature for 30 min and then a solution of triphenylphosphine (1.57 g, 6.0 mmol) and phenols (4a–m) (5.0 mmol) in 4-methylmorpholine (5 mL) was added. Neat diethyl azodicarboxylate (790 μL, 5.0 mmol) was added in small portions over a period of 20 min at room temperture After the suspension was shaken for 12 h at room temperture, the resin (5a–m) was filtered and subsequently washed with THF (3 ¥ 5 mL), DMSO (2 ¥ 10 mL), THF (3 ¥ 5 mL), water (2 ¥ 10 mL), MeOH (2 ¥ 10 mL) and CH2Cl2 (3 ¥ 5 mL). To a suspension of the swollen resin 5a–m in CH2Cl2 (10 mL) and 0.5 mL of 30% H2O2 (5.8 mmol) was added at 0 °C. The suspension was shaken at 0 °C for 0.5 h and then at room temperature for 1.0 h, the residual resin was collected by filtration and washed with CH2Cl2 (2 ¥ 10 mL). The filtrate was treated with saturated NaHCO3 (20 mL) and washed with water, dried over magnesium sulfate and evaporated to give crude products 6a–m with 94–97% purity determined by HPLC, which were further purified by column chromatography on

silica gel using chloroform/hexane (10:90) as eluent to give pure products 6a–m for1H NMR and IR analyses. Phenyl vinyl ether (6a): Colourless oil. (lit.14 oil); 1H NMR: d = 7.15– 7.02 (m, 5 H), 6.58 (dd, J = 14.0, 6.0 Hz, 1 H), 4.70 (dd, J = 14.0, 1.5 Hz, 1 H), 4.34 (dd, J = 6.0, 1.5 Hz, 1 H); 13C NMR: d = 154.0, 144.4, 133.1, 120.5, 115.3, 95.3; IR (neat): n = 3045, 1640, 1623, 1600, 1495, 1230, 1212, 1165, 1155, 1145, 956, 942 cm-1. 3-Methylphenyl vinyl ether (6b): Colourless oil (lit.10 oil); 1H NMR: d = 6.83–7.20 (m, 4 H), 6.50 (dd, J = 14.2, 6.5 Hz, 1 H), 4.32 (dd, J = 14.2, 1.8 Hz, 1 H), 4.04 (dd, J = 6.5, 1.8 Hz, 1 H), 2.30 (s, 3 H); 13C NMR: d = 154.6, 140.4, 132.1, 123.7, 122.6, 119.5, 115.3, 95.6, 21.5; IR (neat): n = 3050, 1640, 1622, 1600, 1500, 1380, 1230, 1160, 1149, 960, 822 cm-1. 4-Methoxyphenyl vinyl ether (6c): Colourless oil (lit.21 oil); 1H NMR: d = 6.95 (d, J = 8.2 Hz, 2 H), 6.86 (d, J = 8.2 Hz, 2 H), 6.58 (dd, J = 14.1, 6.3 Hz, 1 H), 4.65 (dd, J = 14.1, 2.0 Hz, 1 H), 4.35 (dd, J = 6.3, 2.0 Hz, 1 H), 3.78 (s, 3 H); 13C NMR: d = 155.4, 145.8, 134.1, 120.5, 118.0, 115.5, 95.5, 55.2; IR (neat): n = 3045, 1638, 1620, 1600, 1495, 1379, 1230, 1162, 1145, 958, 825 cm-1. 4-t-Butylphenyl vinyl ether (6d): Colourless oil (lit.9 oil); 1H NMR: d = 6.80 (d, J = 8.2 Hz, 2 H), 7.18 (d, J = 8.2 Hz, 2 H), 6.51 (dd, J = 14.0, 6.2 Hz, 1 H), 4.28 (dd, J = 14.0, 1.6 Hz, 1 H), 4.24 (dd, J = 6.2, 1.6 Hz, 1 H), 1.31 (s, 9 H); 13C NMR: d = 157.1, 145.5, 133.7, 120.0, 117.3, 95.8, 38.0, 28.5; IR (neat): n = 3045, 2940, 1640, 1600, 1600, 1500, 1378, 1240, 1180, 1149, 825 cm-1. 4-Phenylphenyl vinyl ether (6e): White solid, m.p. 72–73 °C. (lit.14 m.p. 71–72 °C); 1H NMR: d = 7.66–7.34 (m, 7 H), 7.12–7.06 (m, 2 H), 6.80 (dd, J = 13.5, 6.0 Hz, 1 H), 4.72 (dd, J = 13.5, 1.5 Hz, 1 H), 4.47 (dd, J = 6.0, 1.5 Hz, 1 H); 13C NMR: d = 156.6, 148.2, 140.6, 136.3, 129.0, 128.5, 127.2, 126.8, 117.5, 95.5; IR (KBr): n = 3050, 3021, 1636, 1595, 1509, 1476, 1240, 1136, 826, 755 cm-1. 4-Chlorophenyl vinyl ether (6f): Colourless oil (lit.22 oil); 1H NMR: d = 7.43 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 6.63 (dd, J = 13.7, 6.1 Hz, 1 H), 4.80 (dd, J = 13.7, 1.8 Hz, 1 H), 4.51 (dd, J = 6.1, 1.8 Hz, 1 H); 13C NMR: d = 156.2, 148.1, 132.8, 119.1, 116.1, 95.8; IR (neat): n = 3048, 1635, 1595, 1475, 1232, 1165, 1142, 1058, 1002, 955, 834 cm-1. 4-Bromophenyl vinyl ether (6g): Colourless oil (lit.14 oil); 1H NMR: d = 7.40 (d, J = 8.5 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 2 H), 6.60 (dd, J = 13.8, 6.1 Hz, 1 H), 4.78 (dd, J = 13.8, 1.8 Hz, 1 H), 4.48 (dd, J = 6.1, 1.8 Hz, 1 H); 13C NMR: d = 155.9, 147.7, 132.6, 118.5, 115.7, 96.0; IR (neat): n = 3050, 1636, 1578, 1475, 1230, 1160, 1140, 1060, 1000, 950, 820 cm-1. 2-Bromophenyl vinyl ether (6h): Colourless oil (lit.13 oil); 1H NMR: d = 7.67–7.65 (m, 1 H), 7.42–7.36 (m, 1 H), 7.21–7.18 (m, 1 H), 7.10–7.06 (m, 1 H), 6.80 (dd, J = 6.3, 13.5 Hz, 1 H), 4.68 (dd, J = 1.8, 13.5 Hz, 1 H), 4.53 (dd, J = 1.8, 6.3 Hz, 1 H); 13C NMR: d = 153.5, 148.7, 133.7, 129.7, 125.3, 118.5, 113.6, 96.2; IR (neat): n = 3043, 1640, 1595, 1472, 1232, 1164, 1142, 1063, 1005, 953, 765 cm-1. 4-Nitrophenyl vinyl ether (6i): Colourless oil (lit.14 oil); 1H NMR: d = 8.25 (d, J = 8.9 Hz, 2 H), 7.10 (d, J = 8.9 Hz, 2 H), 6.68 (dd, J = 13.6, 6.0 Hz, 1 H), 5.01 (dd, J = 13.6, 1.9 Hz, 1 H), 4.70 (dd, J = 6.0, 1.9 Hz, 1 H); 13C NMR: d = 161.3, 145.5, 142.8, 125.7, 116.3, 99.1; IR (neat): n = 3060, 1638, 1600, 1580, 1498, 1481, 1330, 1230, 1160, 1120, 1100, 945, 840 cm-1. 4-Cyanophenyl vinyl ether (6j): Colourless oil (lit.14 oil); 1H NMR: d = 7.70 (d, J = 8.6 Hz, 2 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.66 (dd, J = 13.7, 6.1 Hz, 1 H), 4.98 (dd, J = 13.7, 2.0 Hz, 1 H), 4.68 (dd, J = 6.1, 2.0 Hz, 1 H); 13C NMR: d = 159.8, 145.8, 134.1, 118.6, 117.1, 106.1, 98.6; IR (neat): n = 3050, 2200, 1635, 1595, 1492, 1300, 1235, 1160, 1125, 950, 824 cm-1. 4-Methoxycarbonylphenyl vinyl ether (6k): Colourless oil (lit.14 oil); 1H NMR: d = 8.00 (d, J = 8.3 Hz, 2 H), 7.15 (d, J = 8.3 Hz, 2 H), 6.88 (dd, J = 13.6, 6.0 Hz, 1 H), 4.85 (dd, J = 13.6, 1.6 Hz, 1 H), 4.55 (dd, J = 6.0, 1.6 Hz, 1 H), 3.84 (s, 3 H); 13C NMR: d = 166.5, 160.2, 146.6, 131.5, 124.5, 116.1, 97.3, 51.8; IR (neat): n = 3050, 2985, 2940, 1710, 1635, 1596, 1498, 1425, 1300, 1272, 1235, 1156, 1132, 1100, 840 cm-1. 4-Acetaminophenyl vinyl ether (6l): White solid, m.p. 102–103 °C. (lit.14 m.p. 103–103.5 °C); 1H NMR: d = 7.40–7.50 (m, 2 H), 7.26 (br s, 1 H), 6.95–7.05 (m, 2 H), 6.63 (dd, J = 13.7, 6.1 Hz, 1 H), 4.75 (dd, J = 13.7, 1.7 Hz, 1 H), 4.55 (dd, J = 6.1, 1.7 Hz, 1 H), 2.18 (s, 3 H); 13C NMR: d = 169.2, 153.2, 148.5, 133.4, 122.1, 117.3, 94.6, 24.1; IR (KBr): n = 3258, 3188, 3130, 3055, 1650, 1600, 1495, 1300, 1235, 1210, 1162, 1145, 940, 830 cm-1. 1-Naphthyl vinyl ether (6m): White solid, m.p. 31–32 °C. (lit.23 m.p. 32 °C); 1H NMR: d = 7.00–7.50 (m, 7 H), 6.71 (dd, J = 14.1, 6.0 Hz, 1 H), 4.81 (dd, J = 14.1, 1.6 Hz, 1 H), 4.45 (dd, J = 6.0, 1.6 Hz,

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JOURNAL OF CHEMICAL RESEARCH 2009  289 1 H); 13C NMR: d = 152.7, 144.9, 133.9, 132.6, 128.9, 128.7, 128.3, 126.7, 125.9, 123.5, 115.8, 95.7; IR (KBr): n = 3050, 1630, 1600, 1495, 1255, 1226, 1172, 1152, 1142, 942 cm-1.

We gratefully acknowledge financial support from the Natural Science Foundation of Jiangxi Province of P. R. China  (No. 2007GZH839 and No. 2008GZH0029) and the Research Program of Jiangxi Province Department of Education (GJJ08165). Received 26 December 2008; accepted 6 March 2009 Paper 08/0352  doi: 10.3184/030823409X447682 Published online: 20 May 2009 References 1 B.M. Trost and I. Fleming, (eds.), Comprehensive organic synthesis, Pergamon: Oxford, Vol. 9, 1991. 2 K. Kojima, M. Sawamoto and T. Higashimura, Macromolecules, 1989, 22, 1552. 3 H.A.A. El-Nabi, Tetrahedron, 1997, 53, 1813. 4 I.E. Markó, G.R. Evans and J.-P. Declercq, Tetrahedron, 1994, 50, 4557.

5 S.N. Savinov and D.J. Austin, J. Chem. Soc., Chem. Commun., 1999, 1813. 6 P.E. Maligres, M.M. Waters, J. Lee, R.A. Reamer, D. Askin,  M.S. Ashwood and M. Cameron, J. Org. Chem., 2002, 67, 1093. 7 A. Nait Ajjou and H. Alper, J. Am. Chem. Soc., 1998, 120, 1466. 8 K.A. Ahrendt, R.G. Bergman and J.A. Ellman, Org. Lett., 2003, 5, 1301. 9 K. Mizuno, Y. Kimura and Y. Otsuji, Synthesis, 1979, 688. 10 W. Reppe, Liebigs Ann. Chem., 1956, 601, 8. 11 D.A. Evans, J.L. Katz and T.R. West, Tetrahedron Lett., 1998, 39, 2937. 12 Y. Okimoto, S. Sakaguchi and Y. Ishii, J. Am. Chem. Soc., 2002, 124, 1590. 13 N.F. Mckinley and D.F. O'Shea, J. Org. Chem., 2004, 69, 5087. 14 M. Blouin and R. Frenette, J. Org. Chem., 2001, 66, 9043. 15 H.J. Reich, Acc. Chem. Res., 1979, 12, 22. 16 K.C. Nicolaou, J. Pastor, S. Barluenga and N. Winssinger, Chem. Commun., 1998, 1947. 17 Q.-S. Hu, S.-R. Sheng, S.-Y. Lin, M.-H. Wei, Q. Xin and X.-L. Liu,  J. Chem. Res(S)., 2007, 74. 18 G. Zundel, Angew. Chem., Int. Ed. Engl., 1969, 8, 499. 19 X. Huang and W.-M. Xu, Tetrahedron Lett., 2002, 43, 5495. 20 F. Ferranti and D. De Filippo, J. Chem. Soc (B)., 1971, 1925. 21 S. Matysiak, H.-P. Fitznar, R. Schnell and W. Pfleiderer, Helv. Chim. Acta,. 1998, 81, 1545. 22 S. Kuwata, Y. Shigemitsu and Y. Odaira, J. Org. Chem., 1973, 38, 3803. 23 H. Christol, H.-J. Cristau and M. Soleiman, Synthesis, 1975, 736.

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290  RESEARCH PAPER

May, 290–292

JOURNAL OF CHEMICAL RESEARCH 2009

Synthesis and anti-bacterial screening of ethyl 6-oxo-3-phenyl1,6-dihydropyrano[3,2-e]indole-2-carboxylate and 7-phenyl-5H-pyrano [3',2':4,5]indolo[1,2-a]quinoxaline-6,10-dione Abid Ali Mir and Vinata V. Mulwad* Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400 032, India

Ethyl 6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole-2-carboxylate 3a–c were synthesised from ethyl 2-[(2-oxo2H-1-benzopyran-6-yl)-hydrazono]-3-phenylpropanoate 2a–c. Compounds 2a–c was in turn prepared by reacting diasotised solution of 6-aminocoumarin and ethyl-2-benzylacetoacetate. N-nitroarylation of ethyl 6-oxo-3-phenyl1,6-dihydropyrano[3,2-e]indole-2-carboxylate 3a–c was carried out with 2-chloronitrobenzene to give ethyl 1-(2-nitrophenyl)-6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole-2-carboxylate 4a–c, which on catalytic reductive cyclisation with H2/Ni affords 7-phenyl-5H-pyrano[3',2':4,5]indolo[1,2-a]quinoxaline-6,10-dione 5a–c. The structures of all these compounds have been established on the basis of analytical and spectral data. All the compounds show significant antibacterial activity.

Keywords: 6-amino-coumarin, indole-2-carboxylate, N-nitroarylation, quinoxaline, antibacterial activity Coumarins constitute an important class of naturally occurring compounds with useful pharmacological activity1-6 as antibacterial7-12 and antifungal agents.13-17 The result of the variety of the physiological activity of pyrroloindole derivatives18-19 and also the possibility of their use in the synthesis of alkaloids and alkaloid related substances. We report here the synthesis of quinoxalin-6,10-dione 5a–c from ethyl 1-(2-nitrophenyl)-6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e] indole-2-carboxylate 4a–c. Compound 4a–c was obtained from successive steps using 6-aminocoumarin as starting material. Diasotised solution of 6-aminocoumarin was treated with ethyl-2-benzylacetoacetate to yield ethyl 2-[(2-oxo-2H-1benzopyran-6-yl)-hydrazono]-3-phenylpropanoate 2a–c. In its 1H NMR it showed singlet at d 4.11 for two protons of CH – 2 Ph along with the other signals. Compounds 2a–c on refluxing with thionyl chloride underwent Fischer-indole cyclisation to yield ethyl 6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole2-carboxylate 3a–c. In the 1H NMR of compound 3c, it shows signals as triplet for CH3 protons at d 1.08 and as a quartet at d 4.16 for methylene protons and a signal at d 9.45 for –NH group which is D2O exchangeable. It also shows absence of CH2–Ph protons which were observed in compound 2c as a singlet at d 4.11. The mass spectra of 3c exhibit peaks at m/z 361(50%) corresponding to molecular ion peak of the compound, other significant peaks were observed at m/z 347 (40%), 315 (100%). N-Nitroarylation of carboxylates 3a–c was achieved via Ullamann reaction20-21 by refluxing pyranoindole-2O

R1

carboxylate 3a–c with 2-choronitrobenzene using anhydrous K2CO3 and cupric oxide in dry pyridine to afford ethyl 1-(2-nitrophenyl)-6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e] indole-2-carboxylate 4a–c. Its IR spectra did not show any peak beyond 3050 cm-1, indicating the absence of –NH stretching. Compounds 4a–c on catalytic reductive cyclisation with H2/Ni gave 7-phenyl-5H-pyrano[3',2':4,5]indolo[1,2-a] quinoxaline-6,10 5a–c. IR spectra of 5c showed a peak at 3432 cm-1 for –NH stretching and a peak at 1655 cm-1 for –NH–C=O in addition to carbonyl stretch of coumarin. The 1H NMR of 5c exhibited a signal at d 8.85 for –NH proton which is D2O exchangeable. Antibacterial activity All the synthesised compounds 3a–c, 4a–c and 5a–c, were screened for their antibacterial activity against Staphylococcus aureus, S. typhi and Escherichia coli (Table 1), by disc diffusion method.22 The zone of inhibition was measured in mm and was compared with standard drug. DMSO was used as a blank and Streptomycin was used as antibacterial standard. All the compounds were tested at 50 and 100 mgm mL-1 concentration. From the antibacterial screening of the compounds amongst 3a–c to 5a–c, it could be concluded that 3b, 4b, and 5b were less active as compared to 3a, 3c, 4a, 4c and 5a, 5c. It was observed that presence of methyl group in benzopyran moiety possess moderate activity, indicating the importance of methyl substitution.23 O

R1

Ph

Ph

O

O COOEt N R

H2/Ni N

NO2

2

O

4a-c

NH

R2

5a-c

4a : R1 = H, R2 = CH3 4b : R1 = H, R2 = H 4c : R1 = CH3, R2 = CH3

5a : R1 = H, R2 = CH3 5b : R1 = H, R2 = H 5c : R1 = CH3, R2 = CH3

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  291 Table 1  Antibacterial activity of compounds (3a–c), (4a–c) and (5a–c) Antibacterial activity/mg mL-1

Compound

S. aureus



50

3a 3b 3c 4a 4b 4c 5a 5b 5c Sm Disc size: 6.25 mm Duration: 24 h.

12 10 13 12 11 13 13 12 14 16

S. typhi 100

50

14 12 15 13 14 15 14 13 17 23 Sm: Streptomycin resistant (11 mm/less) sensitive(15 mm/more)

O

100

50

100

14 13 16 14 13 16 13 14 17 24

13 12 17 13 11 15 13 13 16 17

14 12 18 13 14 17 13 15 20 25

10 11 13 12 10 14 12 11 13 15 Control: DMSO intermediate (12–14 mm)

R1

O

O

R1 O

NaNo2 HCl

+ N

NH2 R2

NCl

R2

1a-c

CH3COONa, rt, 6hr

O

E. coli

Ethyl 2-benzylacetoacetate

O

R1

R1

Ph O

O COOEt N H R2

N H

reflux

N

R2 2a-c

3a-c

1a : R1 = H, R2 = CH3 1b : R1 = H, R2 = H 1c : R1 = CH3, R2 = CH3 1

O

SOCl2 / EtOH C

COOEt

Ph

3a : R1 = H, R2 = CH3 3b : R1 = H, R2 = H 3c : R1 = CH3, R2 = CH3

2

2a : R = H, R = CH3 2b : R1 = H, R2 = H 2c : R1 = CH3, R2 = CH3

Scheme 1

Experimental Melting points were taken in open capillaries and are uncorrected. IR spectra (vmax in cm-1) were recorded on a Perkin Elmer FTIR, 1H NMR on 300 MHz JEOL NMR AL300 using TMS as standard and CDCl3 as a solvent. Mass spectra (GC–MS) were recorded on Shimadzu GC–MS QP-2010. Elemental analyses were carried out at IIT, Mumbai. All products are purified by recrystallisation. The reaction are followed up and purity of the products is carried out on pre-coated TLC plates (Silica gel 60 F254, Merck), visualising the spots in UV light. Synthesis of ethyl 2-[(2-oxo-2H-1-benzopyran-6-yl)hydrazono]3-phenylpropanoate (2a–c): A solution of 6-aminocoumarin 1a–c (9.45 g, 0.05 mol) in a mixture of 25 mL of hydrochloric acid and 50 mL of glacial acetic acid was diasotised at 0 °C with sodium nitrite solution (4 g. (0.055 mol) dissolved in 10 mL of water). The mixture is kept at this temperature for 1 h. The resulting solution of diazonium salt was filtered and added into mixture of 60 mL of glacial acetic acid, 0.051 mol of ethyl 2-benzylacetoacetate (97%) and 50 g. (0.37 mol) of sodium acetate (AcONa 3H2O) at 0 to 5 °C at pH = 5.5.The mixture was left for 6 h. After that an equal volume of water was added into the mixture. The crude product was collected, washed with ethanol, then water and recrystallised from ethanol to give compound as red product 2a–c.

2a: M.p. 130 °C, Yield 65%; IR: (KBr) 3438 (NH), 3054, 2950 (–CH), 1730, 1710 (>C=O), 805 cm-1, etc. 1H NMR (CDCl3) 1.43(t, 3H, J = 6.0 Hz, CH2-CH3), 2.20(s, 3H, CH3), 4.15(s, 2H, CH2–Ph), 4.42(q, 2H, J = 6.0 Hz, CH2–CH3), 6.24(d, 1H, J = 9.3 Hz, C3–H), 6.98(s, 1H, C8–H), 7.27–7.36(m, 5H, Arom-H), 7.60(s, 1H, C5–H), 7.65(d, 1H, J = 9.3 Hz, C4–H), 8.01(s, 1H, NH, D2O-exchangable). Anal. Calcd for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 69.40; H, 5.50; N, 7.74%. 2b: M.p. 124 °C, Yield 60%; IR: (KBr) 3430 (NH), 3050, 2952 (–CH), 1735, 1715 (>C=O), 810 cm-1, etc. 1H NMR (CDCl3) 1.39(t, 3H, J = 6.0 Hz, CH2–CH3), 4.12(s, 2H, CH2–Ph), 4.40(q, 2H, J = 6.0 Hz, CH2–CH3), 6.21(d, 1H, J = 9.3 Hz, C3–H), 6.98(d, 1H, J = 9.0 Hz, C8–H), 7.27–7.36(m, 5H, Arom-H), 7.38(d, 1H, J = 9 Hz, C7–H), 7.60(s, 1H, C5–H), 7.65(d, 1H, J = 9.3 Hz, C4–H), 8.01(s, 1H, NH, D2O-exchangable). Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.72; H, 5.29; N, 8.06%. 2c: M.p. 134 °C, Yield 62%; IR: (KBr) 3420 (NH), 3050, 2950 (–CH), 1732, 1712 (>C=O), 805 cm-1, etc. 1H NMR (CDCl3) 1.42(t, 3H, J = 6.0 Hz, CH2–CH3), 2.18(s, 3H, CH3), 2.38 (s, 3H, CH3), 4.11(s, 2H, CH2–Ph), 4.40(q, 2H, J = 6.0 Hz, CH2–CH3), 6.23 (s, 1H, C3–H), 6.98(s, 1H, C8–H), 7.27–7.35(m, 5H, Arom-H), 7.60 (s, 1H, C5–H), 8.01(s, 1H, NH, D2O-exchangable). MS, m/z (%): (M + ) 378(75), 188(100), 160(40). Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C, 70.02; H, 5.91; N, 7.45%.

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292  JOURNAL OF CHEMICAL RESEARCH 2009 Synthesis of ethyl 6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole-2carboxylate (3a–c) Compound 2a–c (0.028 mol) was added to a mixture of 35 mL ethanol and 12 mL SOCl2. The reaction mixture was refluxed for 8 h, cooled and precipitate was filtered off, washed with ethanol, then water. The compound 3a–c was recrystallised from ethanol. 3a: M.p. 200 °C, Yield 62%; IR: (KBr) 3368 (NH), 3058, 2981 (–CH), 1736, 1712 (>C=O), 811 cm-1, etc. 1H NMR (CDCl3) 1.12 (t, 3H, J = 6.8 Hz, CH2–CH3), 2.50(s, 3H, CH3), 4.18(q, 2H, J = 6.8 Hz CH2–CH3), 6.10(d, 1H, J = 9.3 Hz, C3–H), 6.90(s, 1H, C8–H), 7.19– 7.37(m, 5H, Arom-H), 7.68(d, 1H, J = 9.0 Hz, C4–H), 9.40(s, 1H, NH, D2O-exchangable). Anal. Calcd for C21H17N1O4: C, 72.61; H, 4.93; N, 4.03. Found: C, 72.73; H, 4.96; N, 4.09%. 3b: M.p.192 °C, Yield 60%; IR: (KBr) 3376 (NH), 3052, 2981 (–CH), 1735, 1715 (>C=O), 812 cm-1, etc. 1H NMR (CDCl3) 1.15(t, 3H, J = 6.8 Hz, CH2–CH3), 4.25(q, 2H, J = 6.8 Hz CH2–CH3), 6.18(d, 1H, J = 9.3 Hz, C3–H), 6.95(d, 1H, J = 9 Hz, C8–H), 7.19– 7.37(m, 5H, Arom-H), 7.50(d, 1H, J = 9 Hz, C7–H), 7.68(d, 1H, J = 9.0 Hz, C4–H), 9.35(s, 1H, NH, D2O-exchangable). Anal. Calcd for C20H15N1O4: C, 72.06; H, 4.54; N, 4.20. Found: C, 72.20; H, 4.58; N, 4.14%. 3c: M.p. 205 °C, Yield 65%; IR: (KBr) 3370 (NH), 3050, 2950 (–CH), 1730, 1718 (>C=O), 806 cm-1, etc. 1H NMR (CDCl3) 1.08(t, 3H, J = 6.8 Hz, CH2–CH3), 2.25(s, 3H, CH3), 2.65(s, 3H, CH3), 4.16(q, 2H, J = 6.8 Hz, CH2–CH3), 6.07(s, 1H, C3–H), 7.19(s, 1H, C8– H), 7.27–7.35(m, 5H, Arom-H), 9.45(s, 1H, NH, D2O-exchangable). MS, m/z (%): (M + ) 361(50), 347(40), 315(100), 287(60). 13C NMR (CDCl3): 14.8(CH3–COOEt), 17.70(CH3), 18.08(CH3), 60.20(CH2– COOEt), 113.10(–CH=C), 111.50–138.23(13-Arom-C), 152.50, 153.54, 159.51(C=O), 160.2(C=O). Anal. Calcd for C22H19N1O4: C, 73.11; H, 5.30; N, 3.88. Found: C, 73.25; H, 5.32; N, 3.93%. Synthesis of ethyl 1-(2-nitrophenyl)-6-oxo-3-phenyl-1,6-dihydropyrano[3,2-e]indole-2-carboxylate (4a–c) A mixture of pyranoindole-2-carboxylate 3a–c (50 mmol), appropriate 2-chloronitrobenzene (50 mmol), anhydrous potassium carbonate (5 g) and cupric oxide (0.20 g) were taken in dry pyridine and the mixture was refluxed for 26 h. It was then cooled and filtered, the residue was washed with hot pyridine and the combined filtrate was poured in ice/cold dilute HCl to get the solid product which was washed with water. The product was crystallised from ethanol to give yellow crystals. 4a: M.p. 238 °C, Yield 52%; IR: (KBr) 3045, 2930 (–CH-arom), 1732, 1718 (>C=O), 1550, 1330 (NO2), 701 cm-1, etc. 1H NMR (CDCl3) 1.33(t, 3H, J = 6.8 Hz, CH2–CH3), 2.45(s, 3H, CH3), 4.20(q, 2H, J = 6.8 Hz, CH2–CH3), 6.21(d, 1H, J = 9.0 Hz, C3–H), 6.98(s, 1H, C8–H), 7.17–7.85(m, 9.0H, Arom-H), 7.68(d, 1H, J = 9.0 Hz, C4–H). Anal. Calcd for C27H20N2O6: C, 62.22; H, 4.30; N; 5.98. Found: C, 62.44; H, 4.35; N, 6.03%. 4b: M.p. 220 °C, Yield 50%; IR: (KBr) 3040, 2935 (–CH), 1738, 1721(>C=O), 1548, 1335 (NO2), 982 cm-1, etc. 1H NMR (CDCl3) 1.38(t, 3H, J = 6.8 Hz, CH2–CH3), 4.15(q, 2H, J = 6.8 Hz, CH2– CH3), 6.23(d, 1H, J = 9.0 Hz, C3–H), 7.10(d, 1H, J = 9.3 Hz, C8–H), 7.15(d, 1H, J = 9.0 Hz, C7–H), 7.20–7.58(m, 9H, Arom-H), 7.73(d, 1H, J = 9.0 Hz, C4–H). Anal. Calcd for C26H18N2O6: C, 68.71; H, 3.99; N, 6.16. Found: C, 68.92; H, 3.89; N, 6.18%. 4c: M.p. 232 °C, Yield 48%; IR: (KBr) 3042, 2930 (–CH), 1730, 1723(>C=O), 1552, 1330, (NO2), 980 cm-1, etc. 1H NMR (CDCl3) 1.33(t, 3H, J = 6.8 Hz, CH2–CH3), 2.30(s, 3H, CH3), 2.50(s, 3H, CH3), 4.20(q, 2H, J = 6.8 Hz, CH2–CH3), 6.25(s, 1H, C3–H), 6.98(s, 1H, C8–H), 7.17–7.85(m, 9H, Arom-H). Anal. Calcd for C28H22N2O6: C, 69.70; H, 4.59; N, 5.80. Found: C, 69.43; H, 4.65; N, 5.86%. Synthesis of 7-phenyl-5H-pyrano[3',2':4,5]indolo[1,2-a]quinoxaline6,10-dione (5a–c) Compound 4a–c was subjected to reductive cyclisation in DMF (50 mL) with freshly prepared Ranay nickel (2 g) and hydrogen in paar low hydrogenator. The catalyst was removed by filtration and repeatedly washed with dimethylformamide. The solvent was removed under reduced pressure and product was obtained as light yellow solid. 5a: M.p. 260 °C, Yield 55%; IR: (KBr) 3389(–NH), 2978(–CHarom), 1723, 1655(–CONH), 978 cm-1, etc. 1H NMR (CDCl3) 2.32(s,

3H, CH3), 6.20(d, 1H, J = 9.0 Hz, C3–H), 6.85(s, 1H, C8–H), 7.20– 7.80(m, 9H, Arom-H), 7.73(d, 1H, J = 9.0 Hz, C4–H), 8.85 (s, 1H, NH, D2O-exchangable). Anal. Calcd for C25H16N2O3: C, 76.53; H, 4.08; N, 7.14. Found: C, 76.73; H, 4.15; N, 7.17%. 5b: M.p. 258 °C, Yield 50%; IR: (KBr) 3382(–NH), 2970 (–CHarom), 1723, 1660(–CONH), 1050 cm-1, etc. 1H NMR (CDCl3) 6.23(d, 1H, J = 9.0 Hz, C3–H), 6.85(d, 1H, J = 9.0 Hz, C8–H), 7.20–7.80(m, 9H, Arom-H), 7.85(d, 1H, J = 9.0 Hz, C7–H), 7.70(d, 1H, J = 9.3 Hz, C4–H), 8.80 (s, 1H, NH, D2O-exchangable). Anal. Calcd for C24H14N2O3: C, 76.18; H, 3.73; N, 7.40. Found: C, 76.34; H, 3.75; N, 7.18%. 5c: M.p. 262 °C, Yield 58%; IR: (KBr) 3432(–NH), 2955(–CHarom), 1719, 1655(–CONH), 1060 cm-1, etc. 1H NMR (CDCl3) 2.15(s, 3H, CH3), 2.56(s, 3H, CH3), 6.20(s, 1H, C3–H), 6.95(s, 1H, C8–H), 7.20–7.80(m, 9H, Arom-H), 8.85 (s, 1H, NH, D2Oexchangable). 13C NMR (CDCl3): 16.80(CH3), 17.90(CH3), 111.50– 136.80(18-aromatic-C), 150.21, 151.80, 156.30(C=O), 160.0(C=O). Anal. Calcd for C26H18N2O3: C, 76.83; H, 4.44; N, 6.89. Found: C, 76.71; H, 4.50; N, 6.92%. Antibacterial activity The newly prepared compounds were screened for their antibacterial activity against Staphylococcus aureus, S. typhi and Escherichia coli bacterial strains by disc diffusion method.22 A standard inoculum was introduced on to the surface of sterile agar plates, and a sterile glass spreader was used for even distribution of the inoculum. The discs measuring 6.25 mm in diameter were prepared from Whatman no. 1 filter paper and sterilised by dry heat at 140 °C for 1 h. The sterile discs previously soaked in a known concentration of the test compounds were placed in nutrient agar medium. Solvent and growth controls were also kept. The plates were inverted and incubated for 24 h at 37 °C. Streptomycin was used as a standard drug. Inhibition zones were measured and compared with the standard. The bacterial zones of inhibition values are given in Table 1.

Received 29 December 2008; accepted 6 March 2009 Paper 08/0365  doi: 10.3184/030823409X447691 Published online: 28 May 2009 References 1 C.M. Chiliro, S. Katsuno, M. Omura, H. Tokuda, H. Nishino and H. Furukawa, J. Nat. Prod., 2000, 63, 1218. 2 A.Z. Abyshev, G.I. D'Yachuk, E.V. Semenov and M.P. Pukhov, Pharm. Chem J., 1993, 27, 66. 3 C.A. Kontogiorgis and D.J. Hadjipavlou, Bioorg. Med. Chem. Lett., 2004, 14, 611. 4 A.Z. Abyshev, A.T. Alekseev, V.G. Platonov and I.A. Byrkin, Pharm. Chem. J., 1996, 30, 441. 5 C. Teran, L. Santana, E. Uriarte, Y. Fall, L. Lena and B.R. Tolf, Bioorg. Med. Chem. Lett., 1998, 8, 3570. 6 T.C. Wang, Y.L. Chen, C.C. Cherng and C.M. Teng, Helv. Chim. Acta, 1996, 79, 1620. 7 A.M. El-Syed, A.G. Ghattas, M.T. El-Wassimy and O.A. Abd Allah, Farmaco, 1999, 54, 56. 8 S.A. Mayekar and V.V. Mulwad, Ind. J. Chem., 2008, 47B, 1254. 9 V.V. Mulwad and A.C. Chaskar, Ind. J. Chem., 2006, 45B, 1710. 10 V.V. Mulwad and R.B. Pawar, Ind. J. Chem., 2003, 42B, 2091. 11 V.V. Mulwad and M.V. Lohar, Ind. J. Chem., 2003, 42B, 1937. 12 V.V. Mulwad and J.M. Shirodkar, J. Het. Chem., 2003, 40, 377. 13 V.V. Mulwad, R.B. Pawar and A.C. Chaskar, J. Kor. Chem. Soc., 2008, 52, 3, 249. 14 V.V. Mulwad and D.S. Satwe, Ind. J. Chem., 2006, 45B, 1210. 15 B.P. Choudhari and V.V. Mulwad, Ind. J. Chem., 2006, 45B, 309. 16 V.V. Mulwad, A.C. Chaskar and J.M. Shirodkar, Ind. J. Chem., 2005, 44B, 1465. 17 B.P. Choudhari and V.V. Mulwad, Ind. J. Chem., 2006, 45B, 314. 18 S. Chikvaidze, S.A. Samsoniya and Z.E. Saliya, Chem. Het. Compounds., 2000, 36, 12. 19 A. Guiotto, A. Chilin, P. Manzini and P. Rodighiero, Farmaco., 1995, 50, 479. 20 M.A. Khan and J.B. Polya, J. Chem. Soc. (C)., 1970, 85. 21 P.E. Fanta, Synthesis, 1974, 1, 9. 22 R. Cruickshank, J.P. Duguid, B.P. Marmion and R.H.A. Swain, Medicinal microbiology, 12 edn, Vol. II, Churchill Livingstone, London, 1975, pp. 196–202. 23 V.V. Mulwad and D.S. Satwe, Ind. J. Chem., 2004, 43B, 2727.

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RESEARCH PAPER  293

May, 293–297

Synthesis of 8-methyl[2.2]metacyclophanes and their charge-transfer complexes with tetracyanoethylene Tomoe Shimizu, Katsuhiro Hita, Shofiur Rahman and Takehiko Yamato* Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga-shi, Saga 840-8502, Japan

The regioselective 1:1 charge-transfer band of 13-substituted 8-methyl[2.2]metacyclophanes with tetracyanoethylene in CH2Cl2, attributable to the 8-methyl substituted benzene-site complex, are observed in the field of 556–605 nm, which is strongly affected by p-electron density of the opposite aromatic ring.

Keywords: cyclophanes, through-space electronic interaction, charge-transfer complex, substituent effect [2.2]Metacyclophanes ([2.2]MCP) are distinguished by abnormal physical and chemical properties. Several qualitative explanations have been given for the origin of the abnormality: p-electron repulsion between the benzene rings,1–7 hyperconjugation with the bridging C–C bonds,8 nonplanarity of the benzene rings,9 and transannular p–p interaction between the benzene rings.10 Boschi and Schmidt10 suggested from the ionisation energies and transannular p–p resonance integrals of [2.2]MCP that transannular p–p interaction may take place between C-8 and C-16. Later on, Sato and Takemura11 comfirmed the transannular p–p interaction of [2.2]MCPs by comparison of the charge-transfer bands of cyclophane molecule with those of the corresponding acyclic models. [2.2]MCP showed only a moderate increase reflecting decreased overlap between the two aryl groups, compared with the large enhancement in the p-basicity in the lower membered paracyclophanes. However, only the charge transfer bands of 8,16-unsubstituted [2.2]MCP and its alkyl derivatives were investigated. We have reported12,13 the iodine-induced transannular cyclisation of 8-methoxy[2.2]MCPs to give 4,5,9,10tetrahydropyrenes with remarkable ease and with high selectivity. The cycloisomerisation was found to be strongly

affected by the substituents at C-13 and proceeded involvement of the iodine molecule, possibly via p complexation. These reactions are quite different from those of 8,16-unsubstituted [2.2]MCPs, which give 1,2,3,3a,4,5-hexahydropyrene14,15 and might be attributed to the presense of the methoxy group at a position 8, which would increase the difference of the p-electron densities among the two benzene rings. Thus there is substantial interest in investigating the effects of substituents at positions 8 and 13 on the charge transfer complexes with tetracyanoethylene (TCNE). We report here on the synthesis and charge trans­fer complexation of a series of 8-methyl[2.2]MCPs with tetracyanoethylene. Results and discussion

The preparative route of 13-substituted 8-methyl[2.2]MCPs 5a–d is shown in Scheme 1. 1,3-Bis(bromomethyl)benzenes 1a–d were prepared by bromination of the corresponding methylbenzenes with N-bromosuccinimide (NBS) in the presence of 2,2'-azobis(2,4-dimethylpentanenitrile) in a methylene dichloride solution. 1,3-Bis(sulfanylmethyl)-2,4,5,6-tetramethylbenzene 2 was prepared by chloromethylation of 1,3,4,5-tetramethylbenzene with chloromethyl methyl ether in the presence of ZnCl2 followed Me

CH2X

XCH2

+

HSCH2

CH2SH

Me Me

R 1 a; R= H, X= Br b; R= Me, X= Br c; R= tBu, X= Br d; R= Br, X= Br

S

2

Me

Me

Me

EtOH high dilution

Me

Me Me

Me

KOH/NaBH4

S

R 3 a; R= H b; R= Me c; R= tBu d; R= Br

m-CPBA CH2Cl2

(70%) (58%) (57%) (74%)

O2S

Me

Me

Me

R 4 a; R= H b; R= Me c; R= tBu d; R= Br

SO2

(100%) ( 98%) ( 92%) (100%)

Me 500°C 1 Torr

Me

Me

R 5 a; R= H b; R= Me c; R= tBu d; R= Br

(74%) (63%) (70%) (73%)

Scheme 1

* Correspondent. E-mail: [email protected]

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294  JOURNAL OF CHEMICAL RESEARCH 2009 substutuents effect of the 13-substituents by the chemical shift differences Dd16-H and Dd8-Me in comparison of the internal aromatic protons at 16 position and the methyl protons at 8-position of 5b–f with those of 5a. The introduction of the electron-donating group such as methyl, tert-butyl and methoxy group, caused the increase of the ring-current shielding of the internal aromatic protons at 16-position by Dd8-Me + 0.23–0.41 ppm attributable to the increased pelectrons density of the opposing benzene ring by the throughspace electronic interaction. Interestingly, in the case of 13cyano-8-methyl[2.2]MCP 5f the large reduction of shielding of 8-methyl protons by Dd8-Me –0.60 ppm, whereas the large increase of shielding of the internal aromatic protons at 16position by Dd16-H + 0.48 ppm. This can be interpreted as a reduction of the ring-current shielding caused by the opposite benzene ring by the introduction of the electron-withdrawing group such as cyano group. The through-space interaction between the 8-methyl group and the opposite benzene pelectrons arising from the C–H–p interaction may not shorten the distance between the 8-methyl group and the opposite benzene ring, whereas the 16–H–p interaction could make the distance between the 16-H proton and the opposite benzene ring shorter in the case of the cyano derivative 5f. The different structures might be possible in the 8-methyl[2.2]MCPs 5 depending on the substituents at 13 position. Charge-transfer (CT) complexes of cyclophanes with tetracyanoethylene (TCNE) have been studied in order to evaluate the p-basicity of the cyclophane rings and to demonstrate transannular interactions in such systems.23,24 To this effect, the complexes of para- and metacyclophanes have been extensively studied. Thus, Cram and Bauer25 established the order of the p base strength for [m.n]paracyclophanes and compared them to those of open chain arenes. Additionally, Singer and Cram26 investigated transannular substituent effects in [2.2] and [3.3]paracyclophane–TCNE complexes. Furthermore, Misumi et al.27 reported that the absorption maxima of CT complexes of multilayered paracyclophanes with a TCNE shift to longer wavelengths with increasing

by the treatment with thiourea as following to the reported procedure.16 The cyclisation of bis(bromomethyl)benzenes 1a–d and bis(sulfanylmethyl)benzene 2 was carried out under highly diluted conditions in 10% ethanolic KOH in the presence of a small amount of NaBH4,17–21 giving the desired 2,11-dithia[3.3]MCPs 3a–d in good yield. The assignment of structures for 3a–d was readily apparent from its 1H NMR spectrum. Thus the internal proton, methyl protons should show an upfield shift due to the ring current of the opposite aromatic ring.1,2 For example, the 1H NMR spectra of the dithia[3.3]MCP 3a prepared in the present paper showed the internal proton and methyl protons at  d 5.58 and 1.82 ppm. The bridged CH2SCH2 bridge showed a pair of doublets at d 3.27, 3.59 ppm (J = 16.0 Hz) and d 3.80, 4.04 ppm (J = 12.0 Hz) at room temperature. With increasing temperature in DMSO-d6, the doublets do not coalesce below 150 °C, respectively, and the energy barriers of flipping are both above 25 kcal mol-1. These observations strongly suggest that compound 3a adopts rigid anti-conformation. The similar findings were observed in 3b–d. These data strongly support the rigid anti-[3.3]MCP structures 3b–d. Oxidation of 3a–d with m-chloroperbenzoic acid in chloroform afforded the corresponding bis-sulfone 4a–d in almost quantitative yield. Pyrolysis of 4a–d under reduced pressure (1 torr) at 500 °C was carried out according to the reported method17–21 to afford the corresponding desired 13-substituted 8-methyl[2.2]MCPs 5a–d in good yields, respectively. Compound 5e was obtained in 85% yield by the reaction of 5d with MeONa in the presence of CuI in DMF–MeOH. Compound 5f was obtained in 95% yield by the reaction of 5d with CuCN in N-methylpyrrolidone. The structures of 5a–f were established on the basis of the base peak molecular ions in their mass spectra, and they were assigned the anti-stereochemistry on the basis of their 1H NMR, since the 16-proton of 5a–f appears at around d 3.42–  3.90 ppm, attributable to be shielded by the opposite ring. The similar upper field shifts of the internal methyl protons at 5-position were observed at around d 0.48–1.09 ppm.  These observations strongly suggest that compounds 5a–f all adopt anti-conformations. The chemical shifts (d) of the internal methyl protons and the aromatic internal protons at the 16-position of anti-8-methyl[2.2]MCPs 5a–f are compiled  in Table 1. The ring current effect of the opposite aromatic  ring on the internal protons and methyl protons at the  8-position can be judged by the values of the chemical shift differences (Dd). In the 1H NMR spectra of 5a–f, the signals of the internal aromatic protons at 16 position and the methyl protons at  8-position are shifted to higher magnetic field by 3.10–  3.58 ppm (d2-ArH 7.00 ppm for 1,3-dimethyl-5-tertbutylbenzene) and 1.19–1.80 ppm (d5-Me 2.28 ppm for 1,2,3,5tetramethylbenzene), respectively.22 We have evaluated the

Table 1  Chemical shifts of the internal proton and methyl protons of 8-methyl[2.2]MCPs 5a d Internal H (Dd16-H)b

Substrate R

5a R= H 3.90 ( – ) 0.49 ( – ) 5b R=Me 3.62 (+0.28) 0.51 (–0.02) 5c R= tBu 3.67 (+0.23) 0.48 (+0.01) 5d R= Br 3.68 (+0.22) 0.59 (–0.10) 5e R= OMe 3.49 (+0.41) 0.63 (–0.14) 5f R= CN 3.42 (+0.48) 1.09 (–0.60) aDetermined in CDCl using SiMe as a reference. bDd 3 4 16-H = d16– H – d16–HR, Dd8–Me = d8–Me – d8–MeR; – denotes the down field shift and + denotes the upfield shift due to ring current.

Me

Me Me

Me

Me

Me

d Internal Me (Dd8-Me)b

NaOMe/ CuI/DMF reflux for 24h (85%)

5d

CuCN/ N-methylpyrrolidone 180°C for 21h (95%)

OMe 5e

Me

Me

CN 5f Scheme 2

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JOURNAL OF CHEMICAL RESEARCH 2009  295 Table 2  Charge-transfer bands of p–p salts of 8-methyl [2.2]MCPs 5 and tetracyanoethylene in CH2Cl2a Substrate

lmax (nm)



log e

R=H 584 5a 5b R=Me 592 5c R=tBu 596 5d R=Br 571 5e R=OMe 605 5f R=CN 556 aThe complexes were prepared in dichloromethane equimolar quantities of substrate and TCNE at 25 °C.

2.297 1.996 1.881 1.797 2.136 1.723 using

number of layers. In the field of MCPs, Hayashi and Sato28 showed that [2.2]MCP 6 affords a 1 : 1 complex with TCNE, which is stabilised due to a p–p interaction. Likewise, the work of Langer and Lehner29 showed the formation of only 1 : 1 complexes with substituted and unsubstituted [2.2]MCPs. A solution of 8-methyl[2.2]MCP (5a) and TCNE in CH2Cl2 present a reddish brown colour and the charge-transfer band at 584 nm (log e 2.297) was observed in its UV spectrum. This absorption is due to the formation of 1 : 1 charge-transfer complex among the electron donor, [2.2]MCP and the electron acceptor, TCNE. No spectral changes occurred when a 4–12fold excess of TCNE was added. The charge transfer band positions of other 8-methyl[2.2]MCPs 5a–f–TCNE complexes are summarised in Table 2. The stoichiometry of the 8-methyl[2.2]MCPs 5a–f complexes with TCNE in dichloromethane was also determined by using the continuous variation method. Typical Job plots31 for 13-methoxy derivative 5e is shown in Fig. 1. The absorbances for charge-transfer band reach maximum at 0.5 mole fraction when the 13-methoxy derivative 5e and TCNE were changed systematically, indicating the formation of 1:1 complex. Also the 8-methyl[2.2]MCPs 5a–d and 5f form exclusively 1:1 charge transfer complexes with TCNE in dichloromethane, as can be similarly deduced from Job plots. TCNE complexes have often been used in studies on the relative p-base strength of various methyl-substituted benzenes.23 The p-basicity of the donor molecules increases with an increase in the number of substituted methyl groups and/or stacking benzene rings and an increase in the face-toface overlapping between aromatic nuclei. In contrast to the cyclophanes having symmmetric donor-sites, unsymmetric cyclophanes containing non-equivalent donor-sites such as 4acetyl- and 4-methoxy[2.2]paracyclophanes26 can be expected 0.25

Abs

0.20 0.15

to form two isomeric one-to-one complexes with TCNE, i.e., pseudo-configurational isomers.31 An important factor for determining which isomeric compex is more predominant. Similarly, two possible pseudo-configurational isomers A and B are also expected for the one-to-one complex of 8-methyl[2.2]MCPs 5 as shown in Fig 2. In studying the electronic spectra of 5-TCNE complexes, it is advantageous to examine those of TCNE complexes of [2.2]MCP 6. In contrast to [2.2]MCP 6, which exhibits the charge-transfer absorption band with TCNE at 486 nm (log e = 2.415),16 a mixture of TCNE and 8-methyl[2.2]MCP 5a exhibits CT-band at 584 nm (log e 2.297). Thus, introduction of the electron-donating group to [2.2]MCP 6 such as methyl groups at 4,5,6 and 8-positions causes a larger red shift (98 nm) for CT-band of 5a. Complexing with TCNE is considered to be attributable to the increased p-basicity of the benzene ring by the methyl groups introduced. Thus the observed CT-bands of 5-TCNE complexes should be due to the 8-methyl substituted benzene-site complex (A), but not to the unsubstituted benzene-site one (B). Although the charge-transfer of [2.2]MCP 5a-TCNE complex exhibits an absorption peak at 584 nm (log e = 2.297), that of 5b is shifted to 592 nm. Such a red shift could be due to the benzene ring at the other side of the molecule which tends to work as a p-electron donor. Introduction of the electron-donating group to [2.2]MCP 5a such as methyl group at 13-position causes a larger red shift (8 nm) for CT-band of 5a. Similar red shifts are observed for the CT-band of 13tert-butyl- (5c) and 13-methoxy[2.2]MCP (5e) as indicated by the 12 and 21 nm shifts, respectively. Interestingly, the bulky group such as tert-butyl group at 13 position in 5c did not inhibit the formation of the charge transfer complex. In contrast, introduc­tion of electron-withdrawing groups such as bromine or cyano at 13-position causes a larger blue shift by 13 and 28 nm the CT-band for CT-band of 13-bromo(5d) and 13-cyano respectively. These finding also strongly supports the observed CT-bands of 8-methyl[2.2]MCPs 5-TCNE complexes should be attributed to the 8-methyl substituted benzene-site complex. Conclusions

We have developed synthesis of a series of 8-methyl[2.2]MCPs 5 by the cyclisation of 1,3-bis(bromomethyl)benzenes 1 and 1,3-bis(sulfanylmethyl)-2,4,5,6-tetramethylbenzene 2 carried out under highly diluted conditions in 10% ethanolic KOH to afford 2,11-dithia[3.3]MPCPs 3, follwed by oxidation and pyrolysis at 500 °C under reduced pressure. The present study indicates that the substituents effect at 8-position does exist in the complexation of 8-methyl[2.2]MCPs 5 with TCNE and through space electronic interaction of the opposite uncomplexed benzene ring must be considered. The further studies on the iodine-induced transannular cyclisation of 5 are now in progress. NC C

0.10

C

CN

Me

Me

Me

0.05

Me

Me

CN

NC Me

Me

R

Me

0 0

20

40

60

80

R

100

TCNE ratio (mol %)

A

Fig. 1  Job plots of charge-transfer complexes of 13-methoxy4,5,6,8-tetramethyl[2.2]MCP 5e with TCNE in dichloromethane (1 ¥ 10-2 M).

NC NC

CN C

C B

CN

Fig. 2  Two possible charge transfer complexes of 8-methyl[2.2] MCPs 5 with TCNE.

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296  JOURNAL OF CHEMICAL RESEARCH 2009 Experimental All melting points are uncorrected. 1H NMR spectra were recorded at 300 MHz on a Nippon Denshi JEOL FT-300 NMR spectrometer in deuteriochloroform with Me4Si as an internal reference. IR spectra were measured as KBr pellets on a Nippon Denshi JIR-AQ2OM spectrometer. Mass spectra were obtained on a Nippon Denshi JMS-HX110A Ultrahigh Performance Mass Spectrometer at 75 eV using a direct-inlet system. Elemental analyses were performed by Yanaco MT-5. The visible and UV spectra were obtained by means of a Shimadzu spectrophotometer. The TCNE was recrystallised twice from chlorobenzene and sublimed twice at 125 °C (4 mmHg). Materials 1,3-Bis(bromomethyl)benzenes 1a–d were prepared by bromination of the corresponding methylbenzenes with N-bromosuccinimide (NBS) in the presence of 2,2'-azobis(2,4-dimethylpentanenitrile) in a methylene dichloride solution as following to the reported procedure.17,19 Preparation of 2,6-bis(chloromethyl)-1,3,4,5-tetramethylbenzene: Zinc chloride (40 g, 0.29 mol) at room temperature was added to a solution of 1,2,3,5-tetramethylbenzene (67.1 g, 0.5 mol) and chloromethyl methyl ether (150 mL). After the reaction mixture was stirred for 10 min, it was poured into ice-water (300 mL) and extracted with CH2Cl2 (200 mL ¥ 3). The CH2Cl2 extract was washed with saturated aqueous NaCl (100 mL ¥ 2), water (200 mL) and dried (Na2SO4) and evaporated in vacuo to leave a colourless solid. Recrystallisation from hexane gave the title compound as a colourless prism (88.0 g, 76.1%), m.p. 110–111 °C (lit.15 114 °C). Preparation of 2,6-bis(sulfanylmethyl)-1,3,4,5-tetramethylbenzene (2): A solution of 2,6-bis(chloromethyl)-1,3,4,5-tetramethylbenzene (9.25 g, 0.40 mmol) and thiourea (6.7 g, 88 mmol) in DMSO (50 mL) was stirred at room temperature under atmosphere of nitrogen for 14 h. After the reaction mixture was poured into a solution of NaOH (20 g) in water (200 mL), the solution was stirred for 1 h, acidified with aqueous 10% HCl and extracted with CH2Cl2 (100 mL ¥ 2). The CH2Cl2 extract was washed with water (100 mL) and saturated aqueous NaCl (100 mL), and dried (Na2SO4) and evaporated in vacuo to leave a colourless solid. Recrystallisation from hexane gave 2 as a colourless prism (6.5 g, 71.8%), m.p. 81–82 °C; nmax/cm-1 (KBr) 3040, 2960, 2900, 2550, 1430, 1370, 1225, 1010, 790 and 675; dH (CDCl3) 1.56 (2H, t, J = 6.6 Hz, SH), 2.28 (12H, s, Me) and 3.80 (4H, d, J = 6.6 Hz, CH2); m/z 226 (M+) (Found: C, 63.61; H, 8.13. C12H18S2 (226.4) requires C, 63.66; H, 8.01%). Preparation of 9-methyl-2,11-dithia[3.3]metacyclophanes (3); typical procedure A solution of a,a'-dibromo-m-xylene (1a) (5.27 g, 20 mmol) and 2 (4.52 g, 20 mmol) in benzene (100 mL) was added dropwise over a period of 12 h from a Hershberg funnel with stirring under nitrogen to a solution of potassium hydroxide (4.0 g, 71 mmol) and sodium borohydride (1 g) in ethanol (4 l). After the addition, the reaction mixture was concentrated and the residue was extracted with CH2Cl2 (200 mL ¥ 2). The CH2Cl2 extract was concentrated and the residue was chromatographed on silica gel (Wako C-300, 400 g) (hexanebenzene, 1:1 v/v, as eluent) to give a colourless solid. Recrystallisation from hexane/benzene 1:1 (v/v) gave 5,6,7,9-tetramethyl-2,11-dithia [3.3]metacyclophane (3a) as colourless prisms (4.59 g, 70%), m.p. 152–154 °C; nmax/cm-1 (KBr) 3010, 2900, 1580, 1440, 1400, 1375, 1215, 1160, 1080, 910, 780, 760 and 700; dH (CDCl3) 1.82 (3H, s, Me), 2.14 (3H, s, Me), 2.30 (6H, s, Me), 3.27 (2H, d, J = 16.0 Hz, CH2), 3.59 (2H, d, J = 16.0 Hz, CH2), 3.80 (2H, d, J = 12.0 Hz, CH2), 4.04 (2H, d, J = 12.0 Hz, CH2), 5.58 (1H, broad s, ArH) and 6.84– 7.01 (3H, broad s, ArH); m/z 328 (M+) (Found: C, 73.05; H, 7.28. C20H24S2 (328.53) requires C, 73.12; H, 7.36%). Cyclisation reaction of 1b–d and 2 was carried out using the same procedure as described above to afford 3b, 3c and 3d in 58, 57 and 74% yields, respectively. 5,6,7,9,15-Pentamethyl-2,11-dithia[3.3]metacyclophane (3b): Colourless prisms, m.p. 175–176 °C (from methanol); nmax/cm-1 (KBr) 3010, 2900, 1590, 1440, 1400, 1370, 1220, 910, 860, 835, 720 and 700; dH (CDCl3) 1.83 (3H, s, Me), 2.16 (3H, s, Me), 2.21 (3H, s, Me), 2.31 (6H, s, Me), 3.25 (2H, d, J = 16.0 Hz, CH2), 3.56 (2H, d, J = 16.0 Hz, CH2), 3.80 (2H, d, J = 14.0 Hz, CH2), 4.02 (2H, d, J = 14.0 Hz, CH2), 5.39 (1H, broad s, ArH) and 6.76 (2H, broad s, ArH); m/z 342 (M+) (Found: C, 73.86; H, 7.63. C21H26S2 (342.56) requires C, 73.63; H, 7.65%). 15-tert-Butyl-5,6,7,9-tetramethyl-2,11-dithia[3.3]metacyclophane (3c): Colourless prisms, m.p. 158–160 °C (from hexane); nmax/cm-1 (KBr) 3020, 2950, 2900, 1590, 1430, 1400, 1355, 1220, 910, 875, 720

and 700; dH (CDCl3) 1.26 (9H, s, tBu), 1.80 (3H, s, Me), 2.15 (3H, s, Me), 2.32 (6H, s, Me), 3.30 (2H, d, J = 16.0 Hz, CH2), 3.62 (2H, d, J = 16.0 Hz, CH2), 3.82 (2H, d, J = 12.0 Hz, CH2), 4.00 (2H, d, J = 12.0 Hz, CH2), 5.55 (1H, broad s, ArH) and 6.99 (2H, J = 1.5 Hz, ArH); m/z 384 (M+) (Found: C, 75.09; H, 8.28. C24H32S2 (384.64) requires C, 74.94; H, 8.39%). 15-Bromo-5,6,7,9-tetramethyl-2,11-dithia[3.3]metacyclophane (3d): Colourless prisms, m.p. 154–155 °C [(from hexane-benzene 2 : 1 (v/v)); nmax/cm-1 (KBr) 3020, 2950, 2900, 1590, 1560, 1420, 1400, 1370, 1245, 1240, 1215, 920, 860, 850, 810, 715 and 680; dH (CDCl3) 2.06 (3H, s, Me), 2.11 (3H, s, Me), 2.25 (6H, s, Me), 3.33 (2H, d, J = 16.0 Hz, CH2), 3.58 (2H, d, J = 16.0 Hz, CH2), 3.82 (2H, d, J = 14.0 Hz, CH2), 4.06 (2H, d, J = 14.0 Hz, CH2), 5.94 (1H, broad s, ArH) and 7.02 (2H, J = 2.0 Hz, ArH); m/z 406 and 408 (M+) (Found: C, 59.54; H, 5.67. C20H23BrS2 (407.43) requires C, 58.96; H, 5.69%). Preparation of 9-methyl-2,11-dithia[3.3]metacyclophane-2,2,11,11tetraoxide (4); typical procedure To a solution of 3a (2.72 g, 8.3 mmol) in CHCl3 (150 mL) was added m-chloroperbenzoic acid (3.96 g, 19.5 mmol, 85% purity) at 0 °C while stirring with a magnetic stirrer. After the solution was stirred for 24 h at room temperature, the solvent was evaporated in vacuo to leave the residue which was washed with 10% NaHCO3 (100 mL), water (50 mL) and ethanol to afford 5,6,7,9-tetramethylas 2,11-dithia[3.3]metacyclophane-2,2,11,11-tetraoxide (4a) colourless prisms (3.26 g, 100%), m.p. >300 °C; nmax/cm-1 (KBr) 3020, 2930, 1490, 1450, 1420, 1390, 1310, 1140, 1100, 920, 860, 810, 710 and 700; dH (CDCl3) 1.49 (3H, s, Me), 2.40 (3H, s, Me), 2.57 (6H, s, Me), 3.99 (4H, s, CH2), 4.50 (2H, d, J = 16.0 Hz, CH2), 4.72 (2H, d, J = 16.0 Hz, CH2), 5.00 (1H, broad s, ArH) and 7.16–7.53 (3H, m, ArH); m/z 264 (M+–2SO2) (Found: C, 60.99; H, 6.08. C20H24O4S2 (392.53) requires C, 61.19; H, 6.16%). Oxidation of 3b–d with m-CPBA was carried out using the same procedure as described above to afford 4b, 4c and 4d in 98, 92 and 100% yields, respectively. 5,6,7,9,15-Pentamethyl-2,11-dithia[3.3]metacyclophane-2,2,11, 11-tetraoxide (4b): Colourless prisms, m.p. >300 °C; nmax/cm-1 (KBr) 3000, 2910, 1600, 1455, 1385, 1295, 1245, 1140, 1100, 920, 860 and 710; dH (CDCl3) 1.52 (3H, s, Me), 2.33 (3H, s, Me), 2.40 (3H, s, Me), 2.57 (6H, s, Me), 3.96 (4H, s, CH2), 4.50 (2H, d, J = 16.0 Hz, CH2), 4.72 (2H, d, J = 16.0 Hz, CH2), 4.80 (1H, broad s, ArH) and 7.27 (2H, broad s, ArH); m/z 278 (M+–2SO2) (Found: C, 62.01; H, 6.24. C21H26O4S2 (406.56) requires C, 62.04; H, 6.45%). 15-tert-Butyl-5,6,7,9-tetramethyl-2,11-dithia[3.3]metacyclophane2,2,11,11-tetraoxide (4c): Colourless prisms, m.p. >300 °C; nmax/cm-1 (KBr) 3040, 2950, 1600, 1450, 1390, 1300, 1240, 1140, 1100, 910, 890, 800, 730 and 710; dH (CDCl3) 1.31 (9H, s, tBu), 1.45 (3H, s, Me), 2.40 (3H, s, Me), 2.56 (6H, s, Me), 4.00 (4H, s, CH2), 4.48 (2H, d, J = 16.0 Hz, CH2), 4.48 (1H, broad s, ArH), 4.71 (2H, d, J = 16.0 Hz, CH2) and 7.51 (2H, J = 2.0 Hz, ArH); m/z 320 (M+–2SO2) (Found: C, 64.00; H, 7.10. C24H32O4S2 (448.64) requires C, 64.25; H, 7.19%). 5,6,7,9-Tetramethyl-15-bromo-2,11-dithia[3.3]metacyclophane2,2,11,11-tetraoxide (4d): Colourless prisms, m.p. >300 °C; nmax/cm-1 (KBr) 3010, 2970, 2930, 1565, 1440, 1390, 1300, 1275, 1260, 1145, 1105, 880 and 705; dH (CDCl3) 1.62 (3H, s, Me), 2.39 (3H, s, Me), 2.56 (6H, s, Me), 3.95 (4H, s, CH2), 4.54 (2H, d, J = 16.0 Hz, CH2), 4.75 (2 H, d, J = 16.0 Hz, CH2), 5.00 (1H, broad s, ArH) and 7.60 (2H, J 2.0 Hz, ArH); m/z 342 and 344 (M+–2SO2) (Found: C, 50.50; H, 4.92. C20H23BrO4S2 (471.43) requires C, 50.96; H, 4.92%). Pyrolysis of disulfone 4 to give 5-methyly[2.2]metacyclophanes (5); typical procedure Pyrolysis of disulfones 4a was carried out in an apparatus consisting of a horizontal tube (15 mm in diameter) passing through two adjacent tube furnace, each of which 20 cm long. The first furnace provided a temperature that would induce sublimation of the sulfone; the second was used at a higher temperature (500 °C) that would assure pyrolysis. A vacuum pump was connected at the exit from the second furnace. Disulfone 4a (1 g, 2.55 mmol) was pyrolysed at 500 °C under reduced pressure (1 Torr) in the above apparatus as follows. The sample of disulfone was placed in the first furnace and small glass beads were packed into the second furnace. The product which sublimed was collected and chromatographed on silica gel (Wako C-300, 100 g) (hexane as eluent) to give a colourless solid. Recrystallisation from methanol gave 4,5,6,8-tetramethyl[2.2]meta- cyclophane (3a) as colourless prisms (498 mg, 74%), m.p. 129–130 °C;

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JOURNAL OF CHEMICAL RESEARCH 2009  297 nmax/cm-1 (KBr) 3040, 2950, 2910, 1470, 1420, 1360, 1180, 1160, 1020, 940, 780 and 720; dH (CDCl3) 0.49 (3H, s, Me), 1.96–2.54 (4H,

m, CH2), 2.26 (3H, s, Me), 2.31 (6H, s, Me), 2.80–3.34 (4H, m, CH2), 3.80 (1H, s, ArH) and 6.98–7.13 (3H, m, ArH); m/z 264 (M+) (Found: C, 90.95; H, 9.27. C20H24 (264.41) requires C, 90.85; H, 9.15%). Pyrolysis of 4b–d was carried out using the same procedure as described above to afford 5b, 5c and 5d in 63, 70 and 73% yields, respectively. 4,5,6,8,13-Pentamethyl[2.2]metacyclophane (5b): Colourless prisms (from hexane), m.p. 169–170 °C; nmax/cm-1 (KBr) 3000, 2900, 1580, 1470, 1435, 1410, 1365, 1325, 1180, 1135, 870, 840 and 720; dH (CDCl3) 0.51 (3H, s, Me), 1.94–2.53 (4H, m, CH2), 2.23 (6H, s, Me), 2.28 (6H, s, Me), 2.74–2.91 (2H, m, CH2), 3.12–3.31 (2H, m, CH2), 3.62 (1H, broad s, ArH) and 6.85 (2H, broad s, ArH); m/z 278 (M+) (Found: C, 90.56; H, 9.70. C21H26 (278.44) requires C, 90.59; H, 9.41%). 13-tert-Butyl-4,5,6,8-tetramethyl[2.2]metacyclophane (5c): Colourless prisms (from methanol), m.p. 176–177 °C; nmax/cm-1 (KBr) 3040, 2950, 1580, 1470, 1440, 1430, 1355, 1275, 1180, 880, 850 and 720; dH (CDCl3) 0.48 (3H, s, Me), 1.28 (9H, s, tBu), 1.97– 2.36 (4H, s, CH2), 2.26 (3H, s, Me), 2.32 (6H, s, Me), 2.80–3.33 (4H, s, CH2), 3.67 (1H, broad s, ArH) and 7.08 (2H, J = 2.0 Hz, ArH); m/z 320 (M+) (Found: C, 89.97; H, 10.09. C24H32 (320.52) requires C, 89.94; H, 10.06%). 13-Bromo-4,5,6,8-tetramethyl[2.2]metacyclophane (5d): Colourless prisms [(from hexane–benzene 1 : 1 (v/v)), m.p. 220– 221 °C; nmax/cm-1 (KBr) 3010, 2970, 1460, 1440, 1410, 1370, 1325, 1180, 1160, 1020, 930, 880 and 745; dH (CDCl3) 0.59 (3H, s, Me), 1.92–2.54 (4H, m, CH2), 2.24 (3H, s, Me), 2.28 (6H, s, Me), 2.75– 2.92 (2H, m, CH2), 3.14–3.34 (2H, m, CH2), 3.68 (1H, broad s, ArH) and 7.19 (2H, d, J = 2.0 Hz, ArH); m/z 342 and 344 (M+) (Found: C, 69.92; H, 6.79. C20H23Br (343.31) requires C, 69.97; H, 6.75%). 13-Methoxy-4,5,6,8-tetramethyl[2.2]metacyclophane (5e): Sodium (2.18 g, 95 mmol) and then a mixture of CuI (0.7 g) and 5d (1.7 g, 5.64 mmol) in DMF (22 mL) was added to methanol (72 mL). After the reaction mixture was refluxed for 24 h, it was poured into a large amount of ice-water and extracted with CH2Cl2. The CH2Cl2 extract was washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed on SiO2 by using hexane as eluent. Recrystallisation from hexane gave 5e as colourless prisms (1.41 g, 84%), m.p. 143–144 °C; nmax/ cm-1 (KBr) 2918, 1587, 1458, 1431, 1333, 1278, 1137, 1026, 846 and 838; dH (CDCl3) 0.63 (3H, s, Me), 2.10–2.20 (2H, m, CH2), 2.27 (3H, s, Me), 2.33 (6H, s, Me), 2.42–2.54 (2H, m, CH2), 2.80–2.92 (2H, m, CH2), 3.20–3.32 (2H, m, CH2), 3.49 (1H, broad s, ArH), 3.78 (3H, s, OMe) and 6.67 (2H, d, J = 1.2 Hz, ArH); m/z 294 (M+) (Found: C, 85.56; H, 8.79. C21H26O (294.44) requires C, 85.67; H, 8.90%). 13-Cyano-4,5,6,8-tetramethyl[2.2]metacyclophane (5f): After a mixture of 5d (686 mg, 2.0 mmol) and cuprous cyanide (4.0 g) in N-methylpyrrolidone (30 mL) was heated at 180–185 °C for 21 h, it was then poured into a mixture of water and concentrated aqueous ammonia [400 mL, 1 : 1 (v/v)]. After the resulting mixture had been stirred under cooling for 3 h, it was extracted with CH2Cl2. The CH2Cl2 extract was washed with water, dried (Na2SO4) and the

solvent was evaporated under reduced pressure. The residue was chromatographed on SiO2 by using CH2Cl2 as eluent. Recrystallisation from hexane–benzene 1 : 1 (v/v) gave 5f as colourless prisms (550 mg, 95%), m.p. 229–230 °C; nmax/cm-1 (KBr) 3050, 2950, 2920, 2220, 1580, 1430, 1365, 1270, 1180, 1160, 1040, 895, 875, 860 and 720; dH (CDCl3) 1.09 (3H, s, Me), 1.47–2.08 (4H, m, CH2), 1.77 (3H, s, Me), 1.81 (6H, s, Me), 2.35–2.96 (4H, m, CH2), 3.42 (1H, broad s, ArH) and 6.89 (2H, d, J = 2.0 Hz, ArH); m/z 289 (M+) (Found: C, 87.01; H, 8.11; N, 4.74. C21H23N (289.42) requires C, 87.15; H, 8.01; N, 4.84%).

Received 20 January 2009; accepted 6 March 2009 Paper 09/0401  doi: 10.3184/030823409X447718 Published online: 22 May 2009 References 1 P.M. Keehn and S.M. Rosenfield (eds), Cyclophanes, Academic Press, New York, Vol. 1&2, 1983. 2 F. Vögtle, Cyclophane chemistry, Wiley, Chichester, 1993. 3 L.L. Ingraham, J. Chem. Phys., 1957, 27, 1228. 4 N.L. Allinger, M.A. Da Rooge and R.B. Hermann, J. Am. Chem. Soc., 1961, 83, 1974. 5 T. Sato, T. Takemura and M. Kainosho, J. Chem. Soc., Chem. Commun., 1974, 97. 6 T. Sato, H. Matsui and R. Komaki, J. Chem. Soc., Perkin Trans. 1, 1976, 2053. 7 T. Takemura and T. Sato, Can. J. Chem., 1976, 54, 3412. 8 R. Gleiter, Tetrahedron Lett., 1969, 4453. 9 D.J. Cram, N.L. Allinger and H. Steinberg, J. Am. Chem. Soc., 1954, 76, 6132. 10 R. Boschi and W. Schmidt, Angew. Chem., Int. Ed. Engl., 1973, 12, 402. 11 T. Sato and T. Takemura, J. Chem. Soc., Perkin Trans. 2, 1976, 1195. 12 M. Tashiro, T. Yamato, K. Kobayashi and T. Arimura, J. Org. Chem., 1987, 52, 3196. 13 T. Yamato, J. Matsumoto, N. Shinoda, S. Ide, M. Shigekuni and M. Tashiro, J. Chem. Res. (S), 1994, 178. 14 T. Sato and K. Nishiyama, J. Chem. Soc., Chem. Commun., 1973, 220. 15 T. Sato and K. Nishiyama, J. Org. Chem., 1972, 37, 3254. 16 T. Sato and T. Takemura, J. Chem. Soc., Perkin 2, 1976, 1195. 17 M. Tashiro and T. Yamato, J. Org. Chem., 1981, 46, 1543. 18 M. Tashiro, K. Koya and T. Yamato, J. Am. Chem. Soc., 1982, 104, 3707. 19 M. Tashiro and T. Yamato, J. Org. Chem., 1985, 50, 2939. 20 T. Yamato, T. Arimura and M. Tashiro, J. Chem. Soc., Perkin Trans. 1, 1987, 1. 21 M. Tashiro, A. Tsuge, T. Sawada, T. Makishima, S. Horie, T. Arimura, S. Mataka and T. Yamato, J. Org. Chem., 1990, 55, 2404. 22 A. Paudel, T. Shimizu, J. Hu and T. Yamato, J. Chem. Res., 2008, 731. 23 R.E. Merrifield and W.D. Phillips, J. Am. Chem. Soc., 1958, 80, 2778. 24 H.A. Staab, G. Voit, J. Weisener and M. Futscher, Chem. Ber., 1992, 125, 2303. 25 D.J. Cram and R.H. Bauer, J. Am. Chem. Soc., 1959, 81, 5971. 26 L.A. Singer and D.J. Cram, J. Am. Chem. Soc., 1963, 85, 1080. 27 T. Otsubo, S. Mizogami, I. Otsubo, Z. Tozuka, A. Sakagami, Y. Sakata and S. Misumi, Bull. Chem. Soc. Jpn., 1973, 46, 3519. 28 S. Hayashi and T. Sato, Nippon Kagaku Zasshi, 1970, 91, 950. 29 E. Langer and H. Lehner, Tetrahedron, 1973, 29, 375. 30 P. Job, Ann. Chem., 1928, 9, 113. 31 T. Kaneda and S. Misumi, Bull. Chem. Soc. Jap., 1977, 50, 3310.

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298  RESEARCH PAPER

May, 298–301

JOURNAL OF CHEMICAL RESEARCH 2009

ipso-Acylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]metacyclophane with acid anhydrides: through-space electronic interaction among the two benzene rings Tomoe Shimizu, Arjun Paudel and Takehiko Yamato* Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-machi 1, Saga 840-8502, Japan

Acylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]metacyclophane with acid anhydrides led to mono-ipso-acylation at the tert-butyl group to give 5-acyl-13-tert-butyl-8,16-dimethyl[2.2]metacyclophanes, from which the second electrophilic substitition with acid anhydrides can be strongly suppressed because of deactivation of the second aromatic ring by acyl group introduced by the through-space electronic interaction.

Keywords: cyclophanes, [2.2]metacyclophanes, ipso-acylation, Clemmensen reduction For many years various research groups have been attracted by the chemistry and spectral properties of the [2.2]MCP ([2.2]MCP = [2.2]metacyclophane) skeleton.1-3 Its conformation, which was elucidated by X-ray measurements,4 is apparently frozen into a chair-like non-planar form. The two halves of the molecule form a stepped system. The benzene rings are not planar, but have a boat conformation, with the result that the molecule avoids the steric interaction of the central carbon atoms C-8 and C-16 and of the attached hydrogen atoms. The C(8)–C(16) distance is 2.689 Å. The increased strain in the molecule 8,16-dimethyl[2.2]MCP as compared with that in the parent hydrocarbon can be seen, in particular, in the distance between C-1 and C-2 (1.573 Å).5 Previously, we reported that6–8 nitration of 5,13-di-tertbutyl-8,16-dimethyl[2.2]MCP 1 with fuming HNO3 afforded 13-tert-butyl-5-nitro-8,16-dimethyl[2.2]MCP 2 along with the transannular reaction product, 2,7-di-tert-butyl-4,9-dinitrotrans-10b,10c-dimethyl-10b,10c-dihydropyrene 3. Although the replacement of a tert-butyl group by a nitro group in electrophilic aromatic substitutions has frequently been described,9–16 generally the yields are modest because of the accompanying side reactions.17 Only in activated compounds are better yields obtained. However, the mechanistic aspects for ipso-attack in electrophilic aromatic substitutions having more than two aromatic rings are still not clear in spite of the possibility of through space electronic interactions among the other benzene rings.18 Thus there is substantial interest in investigating the acylation of the internally substituted [2.2]MCPs, which might afford single mono- and di-acylated products. We report here on the through-space electronic interaction among the two benzene rings during Me

the acylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]MCP 1 with various acid anhydrides. Further Clemmensen reduction of the acylation products to prepare 8,16-dimethyl[2.2]benzonapthaleno- and benzoanthracenoMCPs by Friedel–Crafts intramolecular cyclisation was also described. Results and discussion

When acetylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]MCP (1)19 with acetic anhydride in the presence of TiCl4 as a catalyst was carried out at 0 °C for 2 h, 5-acetyl-13-tert-butyl8,16-dimethyl[2.2]MCP (5a) and 2,7-di-tert-butyl-trans10b,10-dimethyl-10b,10c-dihydropyrene (7)20 were obtained in 83% and 17% yield, respectively. Interestingly, acetylation of 1 with acetic anhydride in the presence of AlCl3–MeNO2 as a catalyst was carried out at 0 °C for 2 h led to the two-fold ipso-acetylation to give 5,13-diacetyl-8,16-dimethyl[2.2]MCP (6a) in 90% yield along with the monoacylation product 5a in 10% yield. TiCl4 catalysed acylation of 1 with benzoic anhydride carried out at 0 °C for 2 h afforded 5-benzoyl-13-tert-butyl8,16-dimethyl[2.2]MCP (5b) in 95% yield along with a small amount of 7. A similar reaction was carried out in the presence of AlCl3–MeNO2 that led to ipso-acylation at just one tert-butyl group to give 5b in quantitative yield. However, attempted further acylation of 1 with benzoic anhydride failed. In spite of increasing the amount of benzoic anhydride and AlCl3–MeNO2 or increasing the reaction temperature to 50 °C and prolonging the reaction time, no formation of two-fold ipso-acylation product 6b was observed. Only the mono-ipso-acylation product 5b was obtained in good yields.

HNO3 CH2Cl2

Me 1

Me + Me

NO2

O2N

Me

Me

NO2

2 3 Scheme 1

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  299 (RCO)2O (4)

1

Lewis acid CH2Cl2 0°C for 2h O Me +

O

Me

Me

R

+

O

Me

R

R

6 a; R= CH3 b; R= C6H5 c; R= (CH2)2COOH d; R= C6H4(o-COOH)

5 a; R= CH3 b; R= C6H5 c; R= (CH2)2COOH d; R= C6H4(o-COOH)

Me

Me

7

Scheme 2

Similar treatment of 1 with 3.0 equiv. of succinic anhydride or phthalic anhydride in the presence of AlCl3–MeNO2 under the same conditions afforded the corresponding mono-acylation product 5c and 5d in 90 and 95% yields, respectively. Thus, the number of ipso-acylation of 1 was strongly affected by the acid anhydrides and the reaction conditions used. The present acylation behaviour of [2.2]MCP 1 can be explained by the stability of the cationic intermediates, which could arise from the through-space electronic interaction with the benzene ring located on the opposite side. Thus, a first scomplex intermediate (A) would be stabilised by the throughspace electronic intraannular interaction through 8,16-positions with the opposing benzene ring, thus accelerating the reaction. However, the second electrophilic substitition with acyl group can be strongly suppressed in the intermediate (B) because of deactivation of the second aromatic ring by acyl group like nitration of 8,16-dimethyl[2.2]MCP, which only afforded mono-nitration product even in the drastic nitration conditions.8 This effect seems to be increased for benzoyl, 3-(carboxyl)propionyl and (2-carboxyl)benzoyl group in comparison with that of acetyl group. Me

O R

+

Me

A

+

O R

Similarly, 5-tert-butyl-1,2,3-trimethylbenzene (8)21 with excess succinic anhydride in the presence of AlCl3-MeNO2 at room temperature only gave a quantitative recovery of the starting compound. Raising the reaction temperature to 50 °C and prolonging the reaction time resulted only the recovery of the starting compound. No formation of the ipso-acylation at the tert-butyl group was observed. In contrast with 8, acylation of [2.2]MCP 1 with excess succinic anhydride in the presence of AlCl3–MeNO2 led to ipso-acylation only at one of the tert-butyl groups to give 5c in good yield. This result seems to indicate that the metacyclophane structure in 1 plays an important role in the present ipso-acylation reaction. The ipsoacylation of 1 is attributed to the highly activated character of the aryl ring and the increased stabilisation of s-complex intermediate A arising from the through-space electronic. Recently, Cacace et al. reported22 that the intramolecular proton shift, namely, ring-to-ring proton migration in (b-phenylethyl)arenium ions from the higher cationic alkylation rate of 1,2-diphenylethane than that of toluene in the gas-phase. Thus in the present system, s-complex intermediate A would be stabilised by a through-space electronic interaction through intraannular 8,16-positions O

Me

Me

O

Me

Me

Me

R B

8

Fig. 1  The through-space electronic interaction of s-complex intermediates

O O

(4c)

Me

AlCl3-MeNO2 CH2Cl2 room temp. for 2 h

Me

Me

CO(CH2)2COOH 9

Scheme 3

Table 1 Lewis acid catalysed acylation of 5,13-di-tert-butyl-8,16-dimethyl[2.2]MCP (1) with acid anhydrides (4) Run

Reagent (4)

Lewis acida

4/1 (mol mol-1)

Product/%b,c

1 Acetic anhydride (4a) A 3.0 5a (83) [70]d 6a (0) 2 Acetic anhydride (4a) B 3.0 5a (10) [ 5] 6a (90) [85] 3 Benzoic anhydride (4b) A 3.0 5b (95) [90]d 6b (0) 4 Benzoic anhydride (4b) B 3.0 5b (100) [95] 6b (0) 5 Succinic anhydride (4b) A 1.5 5c (0) 6c (0) 6 Succinic anhydride (4b) B 1.5 5c (85) [73] 6c (0) 7 Succinic anhydride (4b) B 3.0 5c (90) [80] 6c (0) 8 Phthalic anhydride (4c) A 1.5 5d (0) 6d (0) 9 Phthalic anhydride (4c) B 3.0 5d (95) [89] 6d (0) aA: TiCl , Catalyst/reagent (4) = 7.0 (mol/mol); B: AlCl –MeNO , Catalyst/reagent (4) = 3.0 (mol/mol). bYields were determined by 4 3 2 G.L.C. analyses. cIsolated yields are shown in square brackets. d2,7-Di-tert-butyl-trans-10b,10-dimethyl-10b,10c-dihydropyrene (7) was also obtained in 17 and 3% yields, respectively.

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300  JOURNAL OF CHEMICAL RESEARCH 2009 Me 5c

Zn(Hg), HCl toluene-H2O reflux for 24 h

Me 10c (60%)

5d

HOOC

Zn(Hg), HCl toluene-H2O reflux for 24 h Me

Me +

Me

O Me

10d (17%)

HOOC

O 11d (38%)

Scheme 4

with the opposing benzene ring, therefore accelerating the reaction like the formylation of tert-butyl[n.2]MCPs.23,24 However, only one tert-butyl group is ipso-acylated because of deactivation of the second aromatic ring by the acyl group introduced (intermediate B). Clemmensen reduction of 5c with Zn–Hg afforded the desired 10c in 60% yield. In contrast, in the case of 5d the desired product 10d was obtained only in 17% yield along with 5-tert-butyl-13-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-8,16dimethyl[2.2]metacyclophane 11d was obtained in 38% yield. The structure of 11d was assigned on the basis of elemental analyses and spectral data. The 1H NMR spectrum of 11d shows two kinds of methyl protons, each as a singlet and the methyl protons shifted strongly up-field at d –0.26 and 0.35 ppm in comparison with those of 10d (d 0.54 and 0.58 ppm). In contrast, the cyclophane aromatic protons of 11d are observed as four sets of doublet (J = 1.8 Hz) at much lower fields (d 7.00, 7.02, 7.24 and 7.45 ppm) than those of 10d at d 6.85 and 7.08 ppm as a singlet. The methine proton was also observed at d 7.32 ppm as a singlet. The above data show that the structure of 11d is the 8,16-dimethyl[2.2.MCP having the isobenzofuran group at the 13-position in which benzene ring cause one of the methyl protons to the upper field shift at d –0.26 ppm due to the ring current effect. We conclude that the ipso-acylation reactions of 1 lead to the first-reported direct introduction of one acyl group. The selective ipso-acylation of 1 is attributed to the highly activated character of the aryl ring and the increased stabilisation of s-complex intermediate. Also we have deduced that a first s-complex intermediate, (b-phenylethyl)arenium ion is stabilised by the through-space electronic interaction with the other benzene ring in acylation like the electrophilic aromatic substitution of MCPs. Further studies on ipsoacylation and Friedel–Crafts intramolecular cyclisation of 10c and 10d to prepare 8,16-dimethyl[2.2]benzonapthalenoand benzoanthracenoMCPs are currently in progress in our laboratory. Experiment All melting points are uncorrected. 1H NMR spectra were recorded at 300 MHz on a Nippon Denshi JEOL FT-300 NMR spectrometer in deuteriochloroform with Me4Si as an internal reference. IR spectra were measured as KBr pellets on a Nippon Denshi JIR-AQ2OM spectrometer. Mass spectra were obtained on a Nippon Denshi JMS-HX110A ultrahigh performance mass spectrometer at 75 eV using a direct-inlet system. Elemental analyses were performed by Yanaco MT-5.

Materials The preparations of 5,13-di-tert-butyl-8,16-dimethyl[2.2]metacyclophane 119, and 5-tert-butyl-1,2,3-trimethylbenzene 821 have been previously described. Titanium tetrachloride catalysed acylation of 5,13-di-tert-butyl-8,16dimethyl [2.2]metacyclophane (1); typical procedure A solution of TiCl4 (1.2 ml, 10.92 mmol) in CH2Cl2 (1 mL) at 0 °C was added to a solution of 5,13-di-tert-butyl-8,16-dimethyl[2.2]metacyclophane (1) (181 mg, 0.52 mmol) and acetic anhydride (0.16 mL, 1.56 mmol) in CH2Cl2 (4 mL). After the reaction mixture was stirred at 0 °C for 2 h, it was poured into ice-water (10 mL). The organic layer was extracted with CH2Cl2 (10 mL ¥ 2). The extract was washed with water (5 mL), dried (Na2SO4), and concentrated. The residue was column chromatographed over silica gel with hexane, hexane: benzene 1:1, and benzene as eluent to give 30 mg (17%) of 7 and 144 mg (70%) of 5a, respectively. 5-Acetyl-13-tert-butyl-8,16-dimethyl[2.2]metacyclophane (5a): Colourless prisms (hexane), m.p. 157–161 °C; nmax/cm-1 (KBr) 1665 (C=O); dH (CDCl3) 0.50 (3H, s, Me), 0.63 (3H, s, Me), 1.30 (9H, s, tBu), 2.55 (3H, s, Me), 2.73–3.04 (8H, m, CH2), 7.13 (2H, s, ArH) and 7.73 (2H, s, ArH); m/z 334 (M+) (Found: C, 86.65; H, 8.98. C24H30O (334.51) requires C, 86.18; H, 9.04%). 2,7-Di-tert-butyl-trans-10b,10c-dimethyl-10b,10c-dihydropyrene (7): Deep green prisms (hexane), m.p. 203–204 °C (lit.20 m.p. 203– 204 °C). Compound 5b was obtained by the acylation of 1 with benzoic anhydride in the same manner described above. The yields are compiled in Table 1. 5-Benzoyl-13-tert-butyl-8,16-dimethyl[2.2]metacyclophane (5b): Colourless prisms (hexane), m.p. 179–182 °C; nmax/cm-1 (KBr) 1648 (C=O); dH (CDCl3) 0.58 (3H, s, Me), 0.67 (3H, s, Me), 1.30 (9H, s, tBu), 2.74–3.03 (8H, m, CH2), 7.14 (2H, s, ArH), 7.45–7.78 (5H, m, ArH) and 7.65 (2H, s, ArH); m/z 396 (M+) (Found: C, 87.74; H, 8.22. C29H32O (396.58) requires C, 87.83; H, 8.13%). Acylation of 1 with acid anhydrides in the presence of AlCl3-MeNO2; typical procedure To a solution of 1 (1.0 g, 2.87 mmol) and succinic anhydride (432 mg, 4.31 mmol) in CH2Cl2 (17 mL) was added a solution of aluminum chloride (1.73 g, 12.9 mmol) in nitromethane (3 mL) at 0 °C. After the reaction mixture was stirred at room temperature for 2 h, it was poured into a large amount of water. The organic layer was extracted with diethyl ether (20 mL ¥ 3). The extract was washed with 10% hydrochloric acid (10 mL ¥ 2) and water (10 mL ¥ 2), dried with Na2SO4, and evaporated in vacuo. The residue was recrystallised from benzene to afford 13-tert-butyl-5-(3-carboxylpropionyl)-8,16- dimethyl[2.2]metacyclophane (5c) (821 mg, 73%) as colourless prisms, m.p. 176–178 °C; nmax/cm-1 (KBr) 1712, 1676 (C=O); dH (CDCl3) 0.50 (3H, s, Me), 0.63 (3H, s, Me), 1.30 (9 H, s, tBu), 2.69–2.86 (6H, m, CH2), 2.90–3.07 (4H, m, CH2), 3.27–3.33 (2H, m, CH2), 7.13 (2H, s, ArH) and 7.69 (2H, s, ArH); m/z 392 (M+) (Found: C, 79.89; H, 8.13. C26H32O3 (392.56) requires C, 79.56; H, 8.22%).

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JOURNAL OF CHEMICAL RESEARCH 2009  301 Acylation of 1 with acetic anhydride carried out as described above afforded 5,13-diacetyl-8,16-dimethyl[2.2]metacyclophane 6a in 85% yield as colourless prisms (hexane), m.p. 284–285 °C; nmax/cm-1 (KBr) 1666 (C=O); dH (CDCl3) 0.59 (6H, s, Me), 2.58 (6H, s, Me), 2.79–3.10 (8H, m, CH2), 7.76 (4H, s, ArH); m/z 320 (M+) (Found: C, 82.56; H, 7.56. C22H24O2 (320.44) requires C, 82.46; H, 7.55%). Acylation of 1 with phthalic anhydride carried out as described above afforded 13-tert-butyl-5-[(2-carboxyl)benzoyl]-8,16-dimethyl [2.2]metacyclophane 5d in 89% yield as colourless prisms, m.p. 257 °C; nmax/cm-1 (KBr) 1690, 1649 (C=O); dH (CDCl3) 0.49 (3H, s, Me), 0.57 (3H, s, Me), 1.29 (9H, s, tBu), 2.65–2.78 (4H, m, CH2), 2.83–2.93 (4H, m, CH2), 7.10 (2H, s, ArH), 7.27–7.30 (1H, m, ArH), 7.46 (2H, s, ArH), 7.50–7.57 (1H, m, ArH), 7.60–7.68 (1H, m, ArH) and 8.06–8.10 (1 H, m, ArH); m/z 440 (M+) (Found: C, 81.67; H, 7.26. C30H32O3 (440.57) requires C, 81.78; H, 7.32%).

Compound 10d was obtained as prisms [hexane–benzene (1 : 2)]; m.p. 215 °C; nmax/cm-1 (KBr) 1695 (C=O); dH (CDCl3) 0.54 (3H, s, Me), 0.58 (3H, s, Me), 1.27 (9H, s, tBu), 2.69–2.88 (8H, m, CH2), 4.33 (2H, s, CH2), 6.85 (2H, s, ArH), 7.08 (2H, s, ArH), 7.22 (1H, d, J = 7.3 Hz, ArH), 7.31 (1H, t, J = 7.3 Hz, ArH), 7.46 (1H, t, J = 7.3 Hz, ArH) and 8.05 (1H, d, J = 7.3 Hz, ArH); m/z 426 (M+) (Found: C, 84.33; H, 8.05. C30H34O2 (426.6) requires C, 84.47; H, 8.03%). Compound 11d was obtained as prisms [hexane–benzene (1 : 2)]; m.p. 235–237 °C; nmax/cm-1 1775 (C=O); dH (CDCl3) –0.26 (3H, s, Me), 0.35 (3H, s, Me), 1.23 (9H, s, tBu), 2.59–2.85 (8H, m, CH2), 7.00 (1H, d, J = 1.8 Hz, ArH), 7.02 (1H, d, J = 1.8 Hz, ArH), 7.24 (1H, d, J = 1.8 Hz, ArH), 7.32 (1H, s, CH), 7.35 (1H, t, J = 7.9 Hz, ArH), 7.45 (1H, d, J = 1.8 Hz, ArH), 7.56 (1H, d, J = 7.9 Hz, ArH), 7.74 (1H, t, J = 7.9 Hz, ArH) and 8.41 (1H, d, J = 7.9 Hz, ArH); m/z 424 (M+) (Found: C, 84.63; H, 7.75. C30H32O2 (424.59) requires C, 84.87; H, 7.6%).

Reduction of 5c with Zn-Hg To a solution of HgCl2 (206 mg, 0.76 mmol) in conc. HCl (0.1 mL) and water (3.44 mL) was added zinc powder (2.06 g, 31.5 mmol) and a mixture was stirred for 5 min. at room temperature. A suspension was decantated to leave the residue to which conc. HCl (3.1 mL), water (1.3 mL) was added. To the reaction mixture was added a solution of 5c (500 mg, 1.28 mmol) in toluene (1.7 mL) and refluxed for 6 h. After the fresh conc. HCl (2 mL) was added three times every 6 h, the reaction mixture was cooled to room temperature. The organic layer was extracted with ether (10 mL ¥ 3). The extract was washed with water (10 mL ¥ 2), dried with Na2SO4, and evaporated in vacuo. The residue was recrystallised from hexane– benzene (1 : 2) to afford 10c (290 mg, 60%) as colourless prisms, m.p. 150–156 °C; nmax/cm-1 (KBr) 1700 (C=O); dH (CDCl3) 0.56 (3H, s, Me), 0.59 (3H, s, Me), 1.29 (9H, s, tBu), 1.90–1.99 (2H, m, CH2), 2.35–2.41 (2H, m, CH2), 2.52–2.58 (2H, m, CH2), 2.74–2.93 (8H, m, CH2), 6.92 (2H, s, ArH) and 7.11 (2H, s, ArH); m/z 378 (M+) (Found: C, 82.22; H, 9.05. C26H34O2 (378.56) requires C, 82.49; H, 9.05%).

Received 14 January 2009; accepted 6 March 2009 Paper 09/0391  doi: 10.3184/030823409X447727 Published online: 20 May 2009

Reduction of 5d with Zn-Hg Zinc powder (1.84 g, 28.2 mmol) was added to a solution of HgCl2 (184 mg, 0.68 mmol) in conc. HCl (0.1 mL) and water (3.1 mL) and the mixture was stirred for 5 min. at room temperature. The suspension was decantated to leave the residue to which conc. HCl (2.8 mL), water (1.2 mL) was added. A solution of 5d (500 mg, 1.14 mmol) in toluene (1.5 mL) was added to the reaction mixture and refluxed for 6 h. After the fresh conc. HCl (2 mL) was added three times every 6 h, the reaction mixture was cooled to room temperature. The organic layer was extracted with ether (10 cm3 ¥ 3). The extract was washed with water (10 mL ¥ 2), dried with Na2SO4, and evaporated in vacuo. The residue was recrystallised from hexane– benzene (1 : 2) to afford 10d (83 mg, 17%) as colourless prisms. Chromatography on silica gel (Wako, C-300; 100 g) eluting with hexane–benzene (1 : 3) afforded 11d (178 mg, 38%) as colourless solid.

References 1 Medium-sized Cyclophanes. part 82: T. Shimizu, K. Hita, A. Paudel, J. Tanaka and T. Yamato, J. Chem. Res., 2009, 246. 2 R.W. Griffin, Jr., Chem. Rev., 1963, 63, 45. 3 D.J. Cram, Acc. Chem. Res., 1971, 4, 204. 4 C.J. Brown, J. Chem. Soc., 1953, 3278. 5 P.M. Keehn and S.M. Rosenfield (eds), Cyclophanes, Academic Press, New York, 1983, Vol. 1, Chap. 6, p. 428. 6 M. Tashiro, T. Yamato and K. Kobayashi, J. Org. Chem., 1984, 49, 3380. 7 T. Yamato, J. Matsumoto, T. Ando, K. Tokuhisa and M. Tashiro, J. Chem. Res., 1991, (S) 276. 8 T. Yamato, H. Kamimura and T. Furukawa, J. Org. Chem., 1997, 62, 7560. 9 R.B. Moodie and K. Schofield, Acc. Chem. Res., 1976, 9, 297. 10 A. Fischer and R. Röderer, Can. J. Chem., 1976, 54, 3978. 11 A. Fischer and K.C. Teo, Can. J. Chem., 1978, 56, 258. 12 A. Fischer and K.C. Teo, Can. J. Chem., 1978, 56, 1758. 13 H. Suzuki, Synthesis, 1977, 217. 14 P.C. Myhre and M. Beug, J. Am. Chem. Soc., 1966, 88, 1568. 15 P.C. Myhre and M. Beug and L.L. James, J. Am. Chem. Soc., 1968, 90, 2105. 16 P.C. Myhre, M. Beug, K.S. Brown and B. Östman, J. Am. Chem. Soc., 1971, 93, 3452. 17 W. Verboom, A. Durie, R.J. Egberink, M.Z. Asfari and D.N. Reinhoudt, J. Org. Chem., 1992, 57, 1313. 18 T. Yamato, H. Kamimura, K. Noda and M. Tashiro, J. Chem. Res. (S), 1994, 424, (M) 2401. 19 M. Tashiro and T. Yamato, J. Org. Chem., 1981, 46, 1543. 20 M. Tashiro and T. Yamato, J. Am. Chem. Soc., 1982, 104, 3701. 21 M. Tashiro and T. Yamato, J. Chem. Soc., Perkin Trans. 1, 1979, 176. 22 F. Cacace, M.E. Crestoni, S. Fornarini and D. Kuck, J. Am. Chem. Soc., 1993, 115, 1024. 23 T. Yamato, J. Matsumoto, S. Kabu, Y. Takezaki and M. Tashiro, J. Chem. Res. (S) 1993, 44. 24 T. Yamato, K. Maeda, H. Kamimura, K. Noda and M. Tashiro, J. Chem. Res. (S) 1995, 310; (M) 1865.

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Regio-controlled Michaelis–Arbuzov reactions of 3-(halomethyl)coumarins Thompo J. Rashamuse, Musiliyu A. Musa, Rosalyn Klein and Perry T. Kaye* Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, 6140, South Africa

3-(Iodomethyl)coumarins and 3-(chloromethyl)coumarins, obtained chemoselectively via Baylis–Hillman reactions of salicylaldehyde derivatives with t-butyl acrylate, can be reacted with triethyl phosphite to afford regioisomeric Michaelis–Arbuzov products. Under nitrogen, the 3-(iodomethyl)coumarins undergo direct displacement of iodide to afford the expected 1'-phosphonated derivatives. The reactions with 3-(chloromethyl)coumarins in air, however, proceed with overall allylic rearrangement to afford the regioisomeric 3-methyl-4-phosphonated derivatives.

Keywords: 3-(chloromethyl)coumarins, 3-(iodomethyl)coumarins, Michaelis–Arbuzov reaction, allylic rearrangement Many compounds containing the coumarin moiety (2H-1benzopyran-2-one), both naturally-occurring and synthetic, have been shown to exhibit interesting medicinal properties, including anti-inflammatory,1,2 antifungal3 and anti-HIV properties.4 Warfarin 1, for example, is used as an anticoagulant and has been shown to be weakly active against HIV-1 protease enzyme.5 Another 4-hydroxycoumarin derivative, phenprocoumon 2, acts as a competitive HIV1 protease inhibitor and was identified as a lead structure in the design of non-peptidic inhibitors.6 The hydroxycoumarin, umbelliferone 3, is found in a variety of plants, and has been used as a sunscreen and as a fluorescence indicator.7-9

OH

O

R O

O

R

R=H

O

iii

i,ii O

OH

O

1

O

O

2

HO

O

O

OH

OH

R

5 a–d

* Correspondent. E-mail: [email protected]

R a b c d

H 3-OE t 5-Cl 5 -Br

iv

O

3

Numerous methods have been developed for the the synthesis of coumarins, including the Pechmann condensation,10,11 the Perkin reaction,11 the Knoevenagel condensation12 and the Wittig reaction.13 In our own group, particular attention has been given to applications of the Baylis–Hillman reaction in the construction of benzannulated heterocyclic systems,14,15 including coumarins.16-18 We have found that reaction of salicylaldehyde derivatives 4 with t-butyl acrylate using 1,4diazabicyclo[2.2.2]octane (DABCO) as catalyst affords the isolable Baylis–Hillman adducts 5 (Scheme 1), which cyclise on treatment with HCl to form the 3-(chloromethyl)coumarin derivatives 6 in good yields (86–90%).18 This approach obviated the need to protect the nucleophilic phenolic group (via benzylation, as in 7) and thus prevent the formation of complex mixtures of chromene and coumarin deivatives (Scheme 1).16,17 As part of an ongoing programme directed at the development of novel HIV-1 protease inhibitors,19 we have begun to explore the synthesis of various coumarin derivatives as potential inhibitors. In this paper, we discuss the formation of phosphonated coumarin derivatives via Arbuzov reactions of series of specially prepared 3-(chloromethyl)- and 3(iodomethyl)coumarins. Following our earlier procedure,18 the Baylis–Hillman adducts 5a–d were reacted with hydrochloric acid in a mixture of acetic acid and acetic anhydride, under reflux for 2 hours, to give the 3-(chloromethyl)coumarin derivatives 6a–d in yields of up to 94%. The Baylis–Hillman adducts 5a–d were similarly reacted with hydriodic acid to give 3-(iodomethyl)coumarins 8a–d, previously obtained

O

ii

4a– d O

O

H 8-O Et 6-Cl 6-Br

6a–d

R

OH

O

R

7

H OH

Cl

ii i

a b c d

reflux, 1h

reflu x, 8h

r eflux, 2h

I

I R

R

O 8a–d

O 9c,d

O +

O

R

O

O

9c,d

R

R a b c d

O

O

8c,d

H 8-O Et 6-Cl 6-Br

Scheme 1  Reagents and conditions: (i) PhCH2Br, K2CO3, NaI, acetone; (ii) Methyl acrylate or t-butyl acrylate, DABCO, CHCl3; (iii) HCl, Ac2O, AcOH, reflux; (iv) HI, Ac2O, AcOH, reflux.

using protection strategies.16,17 However, in the cases of the 5-chloro- and 5-bromo substrates (5c,d), the 3-methyl analogues 9c,d were isolated together with the corresponding 3-(iodomethyl)coumarins 8c,d. When the reaction mixtures containing the adducts 5c and 5d were refluxed for 8 hours, the 3-methyl analogues 9c,d were obtained as the sole products − a result attributed to HI-mediated reduction of the initially formed 3-(iodomethyl)coumarins 8c,d. In view of this complication, the reaction time for these two substrates (9c,d) was reduced to 1 h and the required 3-(iodomethyl)coumarins 8c and 8d were obtained as the sole products (see Table 1). The 3-(halomethyl)coumarins (6a–d and 8a–d) may be expected, in principle, to be susceptible to nucleophilic attack at one or more of three electrophilic centres (C-2, C-4 or C-1'; Fig. 1).

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JOURNAL OF CHEMICAL RESEARCH 2009  303 Table 1  Yields obtained for the synthesis of the coumarin derivatives 8a–d and 9c,d using HI (Scheme 1) O

R

O

R

8 a–d

Substrate

R

5a 5b 5c 5d

H 8-OEt 6-Cl 6-Br

O

O

O

R

OEt

O

Reflux period/h

Yield of 8/%

Yield of 9/%

2 2 1 2 8 1 2 8

60 62 61 52 – 58 52 –

– – – 45 91 – 43 80

OEt

O

R

11a–d

9c,d

P

OEt

P

I O

O

O Et

O

12a–d

R a b c d

H 8-OEt 6-Cl 6-Br

Path II

ii

X = Cl

O

P

OEt

i

X R

O

OEt

X = Cl

O

Path I

O

R

6a–d; X = Cl 8a–d; X = I

O

12a–d

ii Path III d+

R

3

d+

1' X 2 O d+ O

4

X= I

:Nu

O P O

R

X = I o r Cl

O

OEt

OEt

11a–d

Fig. 1  Possible modes of nucleophilic attack on the 3-(halomethyl)coumarin derivatives 8 and 9.

The Michaelis–Arbuzov reaction, which involves heating alkyl halides with triethyl phosphite, provides convenient access to alkylphosphonate derivatives, the mechanism typically involving direct (SN) displacement of halide.20 However, when the 3-(chloromethyl)coumarin derivatives 6a–d were boiled under reflux with two equivalents of triethyl phosphite under solvent-free conditions in air (pathway I, Scheme 2), the 4phosphonated (SN') products 12a–d were obtained in yields of up to 68% (Table 2), but none of the expected 1'-phosphonated products 11a–d. [Interestingly, reactions of 3-substituted coumarins with nitrogen and carbon nucleophiles, examined in an earlier study,21 appeared to proceed with exclusive, direct (SN) substitution at the exocyclic C-1' electrophilic centre!] The 3-(chloromethyl)coumarin derivatives 6a–d were then treated with 2 equivalents of triethylphosphite under the same conditions, except that the reaction was conducted under nitrogen (pathway II;). Flash chromatography of the isolated material afforded both the 1'-phosphonated (SN) products 11a–d (in yields of up to 67%) together with the 4-phosphonated (SN') products 12a–d (in yields of up to 16%). Remarkably, when the 3-(iodomethyl)coumarins 8a–d were treated with 2 equivalents of triethyl phosphite under nitrogen, the 1'-phosphonated (SN) products 11a–d were isolated with no trace of the 4-phosphorylated analogues 12a–d (pathway III, Scheme 2)! The role of nitrogen in these reactions, however, is not, as yet, understood. Formation of the 1'-phosphonated products 11a–d presumably proceeds by direct (SN) displacement of the halide anion (chloride or iodide), whereas displacement of chloride in formation of the 4-phosphonated analogues 12a–d could involve either an SN' pathway or a conjugate addition-elimination sequence. The observed halide-specific regioselectivities may be tentatively rationalised in terms of the relative electronegativities of the halogen atoms and the leaving-group potential of the corresponding halide anions. Since iodide is a very good leaving group, the Michaelis–

Scheme 2  Reagents and conditions: (i) 2 equiv. P(OEt)3, reflux, 4 h; (ii) 2 equiv. P(OEt)3, N2, reflux, 4 h. Table 2  Yields obtained for the synthesis of 1'-phosphorylated products 11a–d and 4-phosphorylated products 12a–d (Scheme 2) OEt O P O

R

O

Substrate

X

R

P

OEt

OE t

OE t

11a–d

O

R

Methoda

O

O

12a–d

Yield of Yield of 11/% 12/%

Cl H A – 60 6a 6b Cl 8-OEt A – 52 6c Cl 6-Cl A – 68 6d Cl 6-Br A – 65 6a Cl H B 43 16 6b Cl 8-OEt B 67 14 6c Cl 6-Cl B 53 10 6d Cl 6-Br B 53 8 I H B 61 – 8a 8b I 8-OEt B 40 – 8c I 6-Cl B 54 – 8d I 6-Br B 40 – aMethod A: Reflux in air. Method B: reflux under nitrogen.

Arbuzov reaction may well favour attack of phosphorus at the less hindered 1'-centre of an intermediate, delocalised allylic carbocation via a direct (SN1) pathway. Chloride, on the other hand, is a somewhat poorer leaving group, and its bimolecular displacement by phosphorus could occur at either the sp3 allylic centre (C-1') via an SN2 pathway or, preferentially, at the less-hindered sp2 vinylic centre (C-4) via an SN2' pathway, the electrophilicity of the latter centre being enhanced by the electron-withdrawing inductive effect of the more

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304  JOURNAL OF CHEMICAL RESEARCH 2009

O

:P(OE t)3

O

+P

O

O

Cl O

R

O

O P+

O Cl

Cl

-

O

R

O:

13a–d

6a–d

-

O:

O

R

13a–d

P ath I

P ath II :Cl-

O

R

O P

O

12a–d

O

O

O

O P

O

R

O

O

H

O

R

O

+P

O

O

O

14a–d

15a–d

Scheme 3  Mechanistic possibilities for the conjugate addition–elimination pathway.

electronegative chlorine. Alternatively, the mechanism for the formation of the 4-phosphonated analogues 12a–d from the 3-(chloromethyl)coumarins derivatives 6a–d could involve initial conjugate addition of P(OEt)3 to the a,b-unsaturated carbonyl system to afford the intermediates 13a–d. Concerted (Path I; Scheme 3) or step-wise (via intermediates 14; Path II) routes, involving halide displacement and attack at one of the O-ethyl groups would both be expected to afford the common intermediates 15. Rearrangement of the double bond would then afford the aromatic 4-phosphonated derivatives 12a–d. Whatever the mechanism, the net result is, effectively, a Michaelis–Arbuzov reaction with allylic rearrangement – a process, which to our knowledge, is unprecedented! All new products were fully characterised by elemental (HRMS) and spectroscopic (IR and 1- and 2-D NMR) analysis. In the 1H NMR spectra of the 1'-phosphonate derivatives 11a– d, the P-O-methylene protons typically resonate as a quartet at ca. 4.1 ppm, while the 13C NMR data are consistent with magnetic equivalence of both O-methylene carbons. The P-O-methylene protons in the 4-phosphonate derivatives 12a–d, on the other hand, resonate as a pair of discrete or overlapping multiplets in the region 4.1–4.3 ppm. The DEPT135, HSQC and proton noise decoupled 13C NMR spectra of each of the 4-phosphonate derivatives 12a–d, however, indicate the presence of a single, P-O-methylene carbon doublet [e.g., for 12c: dC = 63.0 (d, 3JP,C = 5.6 Hz)] corresponding to the pair of methylene proton multiplets at ca 4.2 and 4.3 ppm. These observations are attributed to the diastereotopicity and, hence, magnetic non-equivalence of the geminal O-methylene protons on the magnetically equivalent O-methylene carbons. Experimental NMR spectra were recorded on Bruker AMX 400 and Biospin 600 spectrometers at 303K in DMSO-d6 or CDCl3 and calibrated using solvent signals [7.25 (CHCl3) and 2.50 ppm (DMSO-d6) for 1H NMR; 77.0 (CDCl3) and 34.5 (DMSO-d6) for 13C NMR]. 31P NMR spectra were recorded using phosphoric acid (H3PO4) as an internal reference. Melting points were measured using a Kofler hot stage apparatus and are uncorrected. Flash column chromatography was performed using Merck Silica gel 60 [particle size 0.040–0.063 mm (230–400 mesh)] and MN Kieselgel 60 (particle size 0.063–0.200 mm). IR spectra were obtained on a Perkin Elmer FT-IR Spectrum 2000 spectrometer using nujol mulls. Low-resolution (EI) mass spectra were obtained on a Finnigan-Mat GCQ mass spectrometer and high-resolution (EI) mass spectra on a VG70-SEQ Micromass double-focusing magnetic sector spectrometer (Potchefstroom University Mass Spectrometry Unit). The reagents used in the present study were supplied by Aldrich and used without further purification.

Compounds 5a–d, 6a–d, 7 and 9c,d are known.16,17 The 3-(iodomethyl)coumarins 8a–d are also known,16,17 but their synthesis via the tert-butyl acrylate esters 5a–d has not been published previously. The procedures used in this study are illustrated by the following examples. 3-(Iodomethyl)coumarin (8a): Conc. HI (10 mL) was added to a solution of tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)-2methylenepropanoate 5a (0.50 g, 2.0 mmol) in a mixture of AcOH (5 mL) and Ac2O (5 mL). The mixture was boiled under reflux for 2 h, allowed to cool to room temperature and then poured into ice-cooled water (10 mL). Stirring for ca 30 min gave a precipitate, which was filtered off and washed with hexane to afford 3-(iodomethyl)coumarin 8a as a grey solid (0.35 g, 60%), m.p. 148–151 °C (lit.,16 150–152 °C). 6-Chloro-3-(iodomethyl)coumarin 8c and 6-chloro-3-methylcoumarin (9c): The procedure described for the synthesis of 3(iodomethyl)coumarin 8a was followed, using conc. HI (10 mL) and tert-butyl 3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-2-methylenepropanoate 5c (0.52 g, 2 mmol) in a mixture of AcOH (5 mL) and Ac2O (5 mL). Work-up and chromatography [on silica gel; elution with ethyl acetate-chloroform-hexane (1 : 1 : 3)] afforded two fractions. Fraction 1: 6-Chloro-3-(iodomethyl)coumarin 8c as a yellow solid (0.308 g, 52%), m.p. 186–189 °C (lit.,16 188–190 °C). Fraction 2: 6-Chloro-3-methylcoumarin 9c as pale yellow solid (0.162 g, 45%), m.p. 128–132 °C (lit.,22 158–160 °C). Michaelis-Arbuzov phosphonation: Method A Diethyl (3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12a): To 3-(chloromethyl)coumarin 6a (0.35 g, 1.3 mmol) was added triethyl phosphite (0.42 mL) and the mixture was boiled under reflux for 4 h. Upon completion of the reaction, as monitored by TLC, the mixture was separated by flash column chromatography [on silica gel; elution with ethyl acetate–hexane (3 : 1)] to afford diethyl (3-methyl2-oxo-2H-chromen-4-yl)phosphonate 12a as a yellow solid (0.318 g, 60%), m.p. 47–49 °C; (Found M+: 296.082484. C14H17O5P requires M: 296.081362); nmax (nujol)/cm-1 1734 (C=O) and 1240 (P = O); dH (400 MHz; CDCl3) 1.34 (6H, t, J = 7 Hz, 2 ¥ CH2CH3), 2.61 (3H, d, J = 3.2 Hz, 3-CH3), 4.16 and 4.26 (4H, 2 ¥ m, 2 ¥ CH2OP), 7.25-7.30 (2H, m, ArH), 7.46 (1H, m, ArH) and 8.49 (1H, dd, J = 8.2 and 1 Hz, ArH); dC (100 MHz; CDCl3) 16.26 (d, JP,C = 6.1 Hz, 2 ¥ CH2CH3), 16.3 (3-CH3), 62.8 (d, JP,C = 5.5 Hz, 2 ¥ CH2OP), 116.7 (d, JP,C = 2.6 Hz), 118.1 (d, JP,C = 11.2 Hz), 124.2, 128.0 (d, JP,C = 1.5 Hz), 130.6, 135.5 (d, JP,C = 23 Hz), 137.4 and 152.0 (d, JP,C = 13.2 Hz) (ArC), and 161.1 (d, JP,C = 13.2 Hz, C=O); m/z 296 (M+, 100%). Michaelis-Arbuzov phosphonation: Method B Diethyl [(2-oxo-2H-chromen-3-yl)methyl]phosphonate 11a and diethyl (3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12a): To 3-(chloromethyl)coumarin 6a (0.823 g, 4.3 mmol) was added triethyl phosphite (1.4 mL) and the mixture was refluxed under nitrogen for 4 h. Upon completion of the reaction, as monitored by TLC, the mixture was separated by flash column chromatography [on silica gel; elution with ethyl acetate-hexane (3:1)] to afford two fractions.

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JOURNAL OF CHEMICAL RESEARCH 2009  305 Fraction 1: Diethyl (3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12a): Pale yellow solid (0.236 g, 16%). Fraction 2: Diethyl [(2-oxo-2H-chromen-3-yl)methyl]phosphonate (11a): Pale brown oil (0.401 g, 43%); (Found M+: 296.079819. C14H17O5P requires M: 296.081362); nmax (nujol)/cm-1 1734 (C=O) and 1240 (P = O); dH (400 MHz; CDCl3) 1.31 (6H, t, J = 7 Hz, 2 ¥ OCH2CH3), 3.18 (2H, d, JP,H = 22 Hz, CH2P), 4.14 (4H, m, 2 ¥ CH2OP), 7.25–7.52 (4H, series of multiplets, ArH) and 7.83 (1H, d, JP,C = 4.4 Hz, 4-H); dC (100 MHz; CDCl3) 16.3 (d, JP,C = 6.1 Hz, 2 ¥ OCH2CH3), 26.7 (d, JP,C = 139 Hz, CH2P), 62.4 (d, JP,C = 6.6 Hz, 2 ¥ CH2OP), 116.4, 119.1 (d, JP,C = 3.5 Hz), 120.5 (d, JP,C = 9.4 Hz), 124.4, 127.6 (d, JP,C = 1.3 Hz), 131.3, 141.7 (d, JP,C = 7.9 Hz) and 153.2 (d, JP,C = 1.8 Hz) (ArC) and 161.2 (d, JP,C = 6.6 Hz, C=O); m/z 296 (M+, 90%) and 160 (100%). Analytical data for other new compounds isolated in this study are as follows. Diethyl [(8-ethoxy-2-oxo-2H-chromen-3-yl)methyl]phosphonate (11b): Yellow solid (0.83 g, 67%), m.p. 53–56 °C; (Found M+: 340.107526. C16H21O6P requires M: 340.107577); nmax (nujol)/cm-1 1724 (C=O) and 1258 (P = O); dH (400 MHz; CDCl3) 1.26 (6H, m, 2 ¥ POCH2CH3), 1.45 (3H, t, J = 6.8 Hz, Ar-OCH2CH3), 3.14 (2H, d, JP,H = 22 Hz, CH2P), 4.11 (6H, m, 2 ¥ CH2OP and Ar-OCH2CH3), 7.00 (2H, dd, J = 7.8 and 4.6 Hz, ArH), 7.13 (1H, t, J = 7.8 Hz, ArH) and 7.77 (1H, d, JP,C = 4.4 Hz, 4-H); dC (100 MHz; CDCl3) 14.6 (ArOCH2CH3), 16.3 (d, JP,C = 6.1 Hz, 2 ¥ OCH2CH3), 26.6 (d, JP,C = 139 Hz, CH2P), 62.4 (d, JP,C = 6.5 Hz, 2 ¥ CH2OP), 64.9 (Ar-OCH2CH3), 114.5, 119.0, 119.9, 120.3, 124.3, 142.0 (d, JP,C = 7.8 Hz), 143.1, 146.3 and 147..0 (ArC) and 160.8 (d, JP,C = 6.6 Hz, C=O); m/z 340 (M+, 100%). Diethyl [(6-chloro-2-oxo-2H-chromen-3-yl)methyl]phosphonate (11c): Yellow solid (0.61 g, 53%), m.p. 72–74 °C; (Found M+: 330.042081. C14H1635ClO5P requires M: 330.042389); nmax (nujol)/cm-1 1725 (C=O) and 1260 (P = O); dH (400 MHz; CDCl3) 1.31 (6H, t, J = 7.2 Hz, 2 ¥ OCH2CH3), 3.18 (2H, d, JP,H = 22 Hz, CH2P), 4.13 (4H, m, 2 ¥ CH2OP), 7.27 (1H, s, ArH), 7.44–7.46 (2H, s and overlapping d, ArH) and 7.75 (1H, d, JP,C = 4 Hz, 4-H); dC (100 MHz; CDCl3) 16.4 (d, JP,C = 6.1 Hz, 2 ¥ CH2CH3), 26.8 (d, JP,C = 139 Hz, CH2P), 62.5 (d, JP,C = 6.4 Hz, 2 ¥ CH2OP), 117.9, 120.1 (d, JP,C = 3.6 Hz), 121.6 (d, JP,C = 6.6 Hz), 126.8, 129.7, 131.2, 140.4 (d, JP,C = 7.9 Hz) and 151.5 (d, JP,C = 1.9 Hz) (ArC) and 161.3 (d, JP,C = 6.4 Hz, C=O); m/z 330 [M+ (35Cl), 80%] and 109 (100%). Diethyl [(6-bromo-2-oxo-2H-chromen-3-yl)methyl]phosphonate (11d): Pale brown oil (0.761 g, 53%); (Found M+: 375.849564. C14H1681BrO5P requires M: 375.850947); nmax (nujol)/cm-1 1725 (C=O) and 1260 (P = O); dH (400 MHz; CDCl3) 1.28 (6H, t, J = 7.2 Hz, 2 ¥ CH2CH3), 3.15 (2H, d, JP,H = 22 Hz, CH2P), 4.10 (4H, q, J = 6.8 Hz, 2x CH2OP), 7.27–7.45 (3H, series of multiplets, ArH) and 7.74 (1H, d, JP,C = 6.1 Hz, 4-H); m/z 376 [M + 1 (81Br), 70%] and 109 (100%). Diethyl (8-ethoxy-3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12b): Pale Yellow solid (0.186 g, 52%), m.p. 42–45 °C; (Found M+: 340.106262. C16H21O6P requires M: 340.107577); nmax (nujol)/cm-1 1709 (C=O) and 1260 (P = O); dH (400 MHz; CDCl3) 1.32 (6H, t, J = 7.2 Hz, 2 ¥ POCH2CH3), 1.46 (3H, t, J = 7 Hz, Ar-OCH2CH3), 2.60 (3H, d, JP,H = 3.2 Hz, 3-CH3), 4.10–4.27 (6H, m, 2 ¥ CH2OP and 1 ¥ Ar-OCH2CH3), 7.01 (1H, d, J = 8 Hz, ArH), 7.15 (1H, t, J = 8.2 Hz, ArH) and 8.03 (1H, d, J = 8.4 Hz, ArH); dC (100 MHz; CDCl3) 14.7 (Ar-OCH2CH3), 16.2 (3-CH3), 16.3 (d, JP,C = 6.2 Hz, 2 ¥ POCH2CH3), 62.7 (d, JP,C = 5.5 Hz, 2 ¥ CH2OP), 65.0 (ArOCH2CH3), 114.0, 118.8 (d, JP,C = 11.7 Hz), 119.3 (d, JP,C = 1.7 Hz), 123.7, 135.7, 135.8 (d, JP,C = 1.6 Hz), 137.5, 142.2 (d, JP,C = 1.9 Hz) and 146.3 (d, JP,C = 3.7 Hz) (ArC) and 160.6 (d, JP,C = 24 Hz, C=O). Diethyl (6-chloro-3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12c): Pale yellow solid (0.26 g, 68%), m.p. 76–78 °C; (Found M+: 330.042192. C14H1635Cl O5P requires M: 330.042390); nmax (nujol)/ cm-1 1730 (C=O) and 1255 (P = O); dH (400 MHz; CDCl3) 1.34 (6H, t, J = 7 Hz, 2 ¥ CH2CH3), 2.57 (3H, d, JP,H = 3.2 Hz, 3-CH3), 4.16 and 4.26 (4H, 2 ¥ m, 2 ¥ CH2OP), 7.19 (1H, d, J = 8.8 Hz, ArH), 7.40 (1H, dd, J = 8.8 and 2.4 Hz, ArH) and 8.52 (1H, d, J = 2.4 Hz, ArH); dC (100 MHz; CDCl3) 16.3 (d, JP,C = 6.2 Hz, 2 ¥ OCH2CH3),

16.5 (JP,C = 4.1 Hz, 3-CH3), 63.0 (d, JP,C = 5.6 Hz, 2 ¥ CH2OP), 117.9 (d, JP,C = 2.4 Hz), 119.1 (d, JP,C = 11 Hz), 127.5, 129.7, 130.7, 134.8, 136.5 (d, JP,C = 9 Hz) and 150.4 (d, JP,C = 13 Hz) (ArC) and 160.4 (d, JP,C = 23 Hz, C=O); m/z 330 [M+ (35Cl), 100%]. Diethyl (6-bromo-3-methyl-2-oxo-2H-chromen-4-yl)phosphonate (12d): Yellow solid (0.31 g, 65%), m.p. 77–79 °C; (Found M+: 373.989683. C14H1679BrO5P requires M: 373.991873); nmax (nujol)/ cm-1 1734 (C=O) and 1240 (P = O); dH (400 MHz; CDCl3) 1.36 (6H, t, J = 7.2 Hz, 2 ¥ CH2CH3), 2.59 (3H, d, JP,H = 3.2 Hz, 3-CH3), 4.18 and 4.27 (4H, 2 ¥ m, 2 ¥ CH2OP), 7.16 (1H, d, J = 8.8 Hz, ArH), 7.55 (1H, dd, J = 8.8 and 1.8 Hz, ArH) and 8.69 (1H, d, JP,H = 2 Hz, ArH); dC (100 MHz; CDCl3) 16.3 (d, JP,C = 6.1 Hz, 2 ¥ OCH2CH3), 16.5 (d, JP,C = 4.1 Hz, 3-CH3), 63.0 (d, JP,C = 5.6 Hz, 2 ¥ CH2OP), 117.2, 118.3 (d, JP,C = 2.4 Hz), 119.6, 130.6, 133.5, 134.8, 136.6 (d, JP,C = 9 Hz) and 150.8 (d, JP,C = 13 Hz) (ArC), and 160.3 (d, JP,C = 23 Hz, C=O).

The authors thank the Medical Research Council of South Africa (MRC), the Innovation Fund Programme of the South African Department of Science and Technology, and the National Research Foundation (NRF: GUN 2069255) and Rhodes University for generous bursary and financial support. Received 19 December 2008; accepted 2 March 2009 Paper 08/0350  doi: 10.3184/030823409X439708 Published online: 26 May 2009 References 1 M. Ghate, D. Manohar, V. Kulkarni, R. Shobha and S.Y. Kattimani, Eur. J. Med. Chem., 2003, 38, 297. 2 C. Kontogiorgis and D. Hadjipavlou-Litina, J. Enzyme Inhib. Med. Chem., 2003, 18, 63. 3 T. Mouri, T. Yano, S. Kochi, T. Ando and M. Hori, J. Pestic. Sci., 2005, 30, 209. 4 C. Spino, M. Dodier and S. Sotheeswaran, Bioorg. Med. Chem., 1998, 8, 3475. 5 P.J. Tummino, D. Ferguson and D. Hupe, Biochem. Biophys. Res. Commun., 1994, 201, 290. (Chem. Abstr. 1994,121:73068.) 6 S. Thaisrivongs, P.K. Tomich, K.D.Watenpaugh, K.H.W. Chong, K. Howe, C. Yang, J. Strohbach, S. Tureer, J. McGrath, M. Bohanon, J. Lynn, A. Mulichak, P. Spinelli, R. Hinshaw, P. Pagano, J. Moon, M. Ruwart, K. Wilkinson, B. Rush, G. Zipp, R. Dalga, F. Schwende, G.P.G. Howard, L. Toth, Z. Zhao, K. Koeplinger, T. Kakuk, S. Cole, R.Zaya, R. Piper and P. Jeffrey, J. Med. Chem., 1994, 37, 3200. 7 I.P. Singh, S.B. Bharate and K.K. Bhutani, Curr. Sci., 2005, 89, 2. 8 O.A. Lima and J. Polonskwi, Phytochemistry, 1973, 12, 913. 9 F.M. Dean, Naturally occurring oxygen ring compounds, Butterworths, London, 1963, p. 337. 10 M. Maheswar, S. Vidavalur, L. Guri, D. Vasantha, K.R. Yerra and C.V. Rao, J. Mol. Catal., 2006, 255, 49. 11 S. Vilar, E. Quezada, L. Santana, E. Uriarte, Y.N. Fraiz, C. Alcaide, E. Cano, and F. Orallo, Bioorg. Med. Chem. Lett., 2006, 16, 257. 12 M.M. Heravi, R. Hekmatshoar and M. Emamgholizadeh, Phosphorus, Sulfur Silicon Relat. Elem., 2004, 179, 1893. 13 D. Bogdal, J. Chem. Res (S)., 1998, 468. 14 O.B. Familoni, P.J. Klaas, K.A. Lobb, V.E. Pakade and P.T. Kaye, Org. Biomol. Chem., 2006, 4, 3960. 15 P.T. Kaye, S. Afr. J. Sci., 2004, 100, 545. 16 P.T. Kaye and M.A. Musa, Synth. Commun., 2003, 33(10), 1755 17 P.T. Kaye and M.A. Musa, Synthesis, 2002, 2701. 18 P.T. Kaye, M.A. Musa and X.W. Nocanda, Synthesis, 2003, 531. 19 P.T. Kaye, M.A. Musa, A.T. Nchinda and X.W. Nocanda, Synth. Commun., 2004, 34, 2575. 20 J. March, Advanced organic chemistry: reactions, mechanisms and structure, 4th edn, Wiley Interscience, New York, 1992, p. 959. 21 P.T. Kaye and M.A. Musa, Synth.Commun., 2004, 34, 3409. 22 G.A. Cartwright and H.J. McNab, J. Chem. Res. (S), 1997, 296.

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306  RESEARCH PAPER

May, 306–307

JOURNAL OF CHEMICAL RESEARCH 2009

A new norditerpenoid alkaloid from Delphinium densiflorum Jian-Yun Suna* and Tian-Cheng Lib aGansu

Centre for Disease Control and Prevention, Lanzhou, 730000, P.R. China

bDepartment

of Cardiovascular Surgery, the First Hospital of Lanzhou University, Lanzhou, 730000, P.R. China

A new norditerpenoid alkaloid delphidenine was isolated from the EtOH extract of the whole plants of Delphinium densiflorum. Its structure was established by extensive application of spectroscopic methods, including IR, HR-ESIMS, 1D and 2D NMR spectroscopy.

Keywords: Delphinium densiflorum, Ranunculaceae, norditerpenoid alkaloid The alkaloids from Aconitum and Delphinium species are interesting because of their structural diversity and significant bioactivities.1,2 Delphinium densiflorum has been used in traditional Chinese medicine over a long period for the treatment of ringworm, scabies and other skin diseases and inflammations.3 However the chemical constituents and their biological activities have not been reported previously. In the course of our investigation on the alkaloids from the whole plant, a new norditerpenoid alkaloid was isolated. We now report on its isolation and structural elucidation. Compound 1 was obtained as a colourless soild. The HRESI-MS gave a protonated molecular ion peak ([M + H]+, m/z 464.2649, Calcd: 464.2643), suggesting a molecular formula of C25H37NO7 with eight degrees of unsaturation. The IR spectrum indicated the presence of hydroxyl (3478 and 3453 cm-1) and carbonyl (1745 cm-1) groups. The 1H NMR spectrum (Table 1) displayed a characteristic methyl signal at dH 2.06 (s) which, conjunction with 13C NMR data (dC 170.0 (C) and 21.4 (Me)), indicated that an AcO group was present in 1. In addition, the 1H NMR spectrum displayed a signal for an N-ethyl group at dH 1.10 (3H, q, 6.8 Hz) and 2.89 (2H, m) and two methoxy groups at dH 3.35 and 3.48 (each 3H, s). This characteristic data suggested that 1 was a C19-norditerpenoid alkaloid, most of which have a hydroxy or a methoxy group at C-1, C-14 and C-16.4 Four fragments: C(1)–C(2)– C(3), C(5)–C(6)–C(7), C(9)–C(14)–C(13)–C(12)–C(10) and C(15)–C(16) were identified from the 1H–1H COSY and HSQC spectra. The HMBC experiments showed the following correlations: H-15/C-16, C-7, C-8, C-9 and C-13; H-5/C-18, C-7, C-19, C-11, C-3 and C-4; and H-1/C11, C-17 and C-5; H-10/C-5 and C-11, which linked the above four fragments. Thus the planar structure of 1 was established as a C19-norditerpenoid alkaloid. In the HMBC experiments correlations between dH 3.35, 3.48 and C-16 and C-8, respectively, indicated that the methoxy groups were located at C-16 and C-8. The correlation of H-14 with Table 1  No.

1H

OCH3 OH

OAc

N

OCH3 OH

OH

Scheme 1

dC 170.0, indicated that the AcO group was located at C-14.

The stereochemistry of 1 was established from the NOESY experiments which showed correlations between H-6, Ha-15 and H-21; between H-14 and H-13; between H-13, H-10 and Hb-12; between H-1 and H-10; between Ha-12, H-16 and H19, and between Ha-15 and H-16. Considering a molecular model of 1, if H-19 were arbitrarily assigned to a-orientation, the relative configation of H-1, H-6, H-14 and H-16 were then b, a, b, and a, respectively. Consequently the structure of 1 was established and named as delphidenine. Experimental Optical rotations were measured on a Perkin–Elmer Model 341 polarimeter. IR spectra were recorded on a Nicolet Avatar 360 FTIR instrument using KBr discs over the range of 400–4000 cm-1. 1D and 2D NMR spectra were obtained on a Varian Mercury-400bb NMR spectrometer with TMS as standard. HRESIMS determinations were run on a Bruker APEX P FT-MS spectrometer. Analytical and preparative TLC were performed on silica gel plates (GF254 10–40 mm, Qingdao Marine Chemical Factory). Analytical TLC was used to follow the separation and check the purity of isolated compounds. Spots on the plates were observed under UV light and visualised by spraying them with 5% H2SO4 in C2H5OH (v/v), followed by heating. Column chromatography (CC) was performed on silica gel (200–300 mesh, Qingdao Marine Chemical Factory).

(400 MHz) and 13C (100 MHz) NMR spectroscopic data for compound 1 (CDC13, d in ppm, J in Hz) dH

dC

No.

dH

1 3.73 (d, J = 4.4) 71.1 (d) 14 4.81 (t, 4.8) 2 5.79 (dd, 9.6, 4.4) 130.1 (d) 15 2.52 (m)/1.86 (m) 3 5.66 (d, 9.6) 137.6 (d) 16 3.35 (d, J = 4.8) 4 – 33.3 (s) 17 2.78 (s) 5 1.69 (br s) 57.8 (d) 18 1.09 (s) 6 4.31 (br s) 82.0 (d) 19 2.42 (m) 7 – 89.2 (s) 21 2.89 (m) 8 – 85.0 (s) 22 1.10 (q, J = 6.8) 9 2.16 (m) 44.5 (d) OMe-(8) 3.48 (s) 10 2.58 (m) 37.2 (d) OMe-(16) 3.35 (s) 11 – 49.6 (s) OAc 2.06 (s) 12 2.28 (m)/2.23 (m) 27.7 (t) 13 3.25 (m) 42.5 (d)

dC 75.0 (d) 26.3 (t) 82.8 (d) 65.5 (d) 23.6 (q) 56.6 (t) 50.4 (t) 13.5 (q) 57.5 (q) 56.4 (q) 21.4 (q) 170.0 (s)

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  307 Plant material Delphinium densiflorum was collected in Tianzhu county (Gansu Province, China) in September 2007 and was identified by Prof. YinFe Wang (College of Life Science, Northwest Normal University, Lanzhou, P.R. China). A voucher specimen (No. 200709DD) is deposited in Gansu Centre for Disease Control and Prevention, Lanzhou, China. Extraction and isolation The air-dried and powdered herb (4.5 kg) was extracted with 95% EtOH (15 L) three times (each time for 7 days) at room temperature to give a syrup 520g, which was dissolved in water and defatted with petroleum ether. The defatted aqueous extract was then extracted with EtOAc at two pH levels: pH 4–5 and 9–10, which was adjested by the addition of H2SO4 (2%) and NaOH (2%) solution, respectively. The fraction (pH 9–10, 39.0 g) was subjected to column chromatography (6 ¥ 100 cm) on silica gel eluting with CHCl3CH3OH (99 : 1, 50:1, 30 : 1, 10 : 1, 5 : 1) to afford five fractions (1–5). Fraction 2 (5.2 g) was further chromatographed on silica gel CC (2 ¥ 50 cm) and eluted with petroleum ether-EtOAc (16 : 1, 8 : 1, 2 : 1) gradient to give 1 (5 mg).

Delphidenine (1); Colourless solid; [a]20D: +68 (c 0.4 CHCl3); IR (KBr) nmax = 3478, 3453 and 1745 cm-1; 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz) see Table 1; HR-ESI-MS: m/z = 464.2649 (Calcd for [M + H]+: 464.2643).

We thank the Health Bureau of Gansu Province for financial support. Received 5 February 2009; accepted 2 March 2009 Paper 09/0432  doi: 10.3184/030823409X439681 Published online: 28 May 2009 References 1 Atta-ur-Rahman and M.I Choudhary, Nat. Prod. Rep., 1997, 14, 191. 2 Atta-ur-Rahman and M.I. Choudhary, Nat. Prod. Rep., 1999, 16, 619. 3 The Flora Committee of Chinese Academy of Sciences, The Chinese flora, Vol. 27 Science Press, Beijing, 1979, p.365. 4 D.R. Gardner, G.D. Manners, K.E. Panter, S.T. Lee and J.A. Pfister, J. Nat. Prod., 2000, 63, 1127.

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308  RESEARCH PAPER

May, 308–311

JOURNAL OF CHEMICAL RESEARCH 2009

Stereochemistry of products of reactions between 3-diazo-naphthalene1,2,4-trione and β-dicarbonyl compounds. Structure of ethyl 2-[(3-hydroxy1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hydrazono]-3-phenyl-3-oxopropionate Fernando de C. da Silvaa, Vitor F. Ferreiraa, Patrícia de O. Lopesa, James L. Wardellb,c and Solange M. S. V. Wardelld aUniversidade

Federal Fluminense, Instituto de Química, Departamento de Química Orgânica-PQO, 24020-150 Niterói, Rio de Janeiro, Brazil bCentro

de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (Fiocruz), Casa Amarela, Campus de Manguinhos, Av. Brazil 4365, 21040-900, Rio de Janeiro, RJ, Brazil cDepartment

of Chemistry, University of Aberdeen, Old Aberdeen AB24 3UE, UK

dDepartamento

de Síntese, Farmanguinhos – Fiocruz, Instituto de Tecnologia em Fármacos, R. Sizenando Nabuco 100, 21041-250 Manguinhos, Rio de Janeiro, RJ Brazil

3-Hydroxy-2-[(R1CO)(R2CO)]C=NNH-1,4-naphthoquinones, obtained from reactions of 3-diazonaphthalene-1,2,4trione with b-diketones, R1C(O)CH2COR2, have been previously found to have high antibacterial activity. However, confirmation of the stereochemistry about the C=N bond could not be achieved by spectroscopic means for products having different R1 and R2 groups, thereby limiting the utility of the reaction. Full characterisation of the product isolated from reaction of 3-diazonaphthalene-1,2,4-trione with PhC(O)CH2CO2Et is now reported, from a single crystal X-ray structure determination: the product, 3-hydroxy-2-[(PhCO)(EtCO2)]C=NNH-1,4-naphthoquinone has a (Z)-stereochemistry. The Z-isomer is obtained rather than the E form due to the preferred formation of the stronger intramolecular N–H---O hydrogen-bond with the ester carbonyl oxygen rather than a weaker one with the ketone oxygen. Weaker C–H---O hydrogen bonds link the molecules into columns. It is suggested that similar Z geometries will arise from other RC(O)CH2CO2Ri reactants.

Keywords: 1,4-naphthoquinones, lapachol derivatives, hydazones, antibacterial activity Quinones have been the subject of considerable interest for many years as a result of their biological activities. It has been over 60 years since Wendel initially showed that certain 2-hydroxy-3-alkyl-naphthoquinones inhibited the growth of Plasmodium.1 Further studies have proven that the toxicity of naphthoquinones to Plasmodium sp. is due to interaction with the mitochondrial respiratory chain.2,3 Among the family of naphthoquinones, lapachol, 1, (a naturally occurring compound), and its derivatives have been particularly well investigated over the past decades for their antibacterial,4-6 antifungal7 and anticancer 8-12 activities. The anti-cancer activity of b-lapachone, 2, an isomer of lapachol 1, has also been intensely investigated.13-16 Studies with substituted lapachol derivatives have indicated certain correlations between structure and biological activity. For example, a relationship was established between the length of the side chain at site 3 in 2-hydroxy-3-alkyl-substituted1,4-naphthoquinones and the toxic effects on several microorganisms.17,18 Fieser and Richardson showed that, as the alkyl side chain in hydrolapachol, 3, is lengthened by the insertion of methylene units, the activity against P. lophurae in duck increases up to a C9-side chain, but then falls away.19 Ferreira and co-workers20 have reported the synthesis and antibacterial activity of the 2-hydroxy-3-hydrazino-1,4naphthoquinones, 4a–e, obtained from 3-diazo-naphthaleneO

O O

O

N2

R

O

O

H

O

O

1

2 O

O O

H

O

O

3

O N H

H

O

N O

R1 R2

4: (a) R 1 = R 2 = Me (b) R 1 = Me, R 2 = OEt (c) R 1 = Me, R 2 = OBu t (d) R 1 = R 2 = OCMe 2O (e) R 1 = R 2 = OEt (f) R 1 = Ph, R 2 = OEt

Fig. 1  Selected 1,4-naphthoquinones.

1,2,4-trione following a procedure published by Reid et al.,21 see Scheme 1 and Fig. 1. Compounds 4 can be considered as analogues of the 2-hydroxy-3-alkyl-substituted-1,4-

O

1

O

O

O O

R2

K2CO 3 ,Me 2CO

N O

H N C

COR

1

COR 2

1

H

Scheme 1

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  309 naphthoquinones. The most active of these compounds, 4b, in preliminary susceptibility testing in discs, exhibited a higher level of antibacterial activity than lapachol, 1. Additional studies on the minimal inhibitory concentration (MIC) for Staphylococcus aureus showed that 4b has shown an activity twice that of lapachol. The stereochemistry about the hydrazone C=N bond for compounds, 4, having different R1 and R2 groups, could not be established by spectroscopic means. Without confirmation of the stereochemistry, the scope of this reaction is somewhat limited to symmetrical compounds. Thus we have turned to X-ray crystallography to help solve the stereochemical problem. The unsymmetrical hydrazono compound, ethyl 2-[(3-hydroxy-1,4-dioxo1,4-dihydro-naphthalen-2-yl)hydrazono]-3-phenyl-3-oxopropionate (4f), containing an ester and a ketone groups produced suitable crystals for the X-ray study. Results and discussion

The isolated yields of 4a–4e, as pure single-component solids, were reported to be in the range 55–68%,20 while that for the new derivative, purple 2-[(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-hydrazono]-3-phenyl-3-oxo-propinoate (4f), obtained from ethyl benzoylacetate, was found to be lower at 27%, after two recrystallisations. While no product balance was carried out, there were no indications of other isomeric products: starting materials had been totally consumed. No other products were isolated or identified in the reaction residue despite attempts to do so. Spectral and other data were consistent with the formula for 4f, but could not distinguish between the possible geometric isomers. The sample of 4f used in the crystallographic study was recrystallised from EtOH. The atom arrangement and numbering scheme are

shown in Fig. 2a, while selected bond lengths and angles are listed in Table 1. There are several possible combined stereochemical and conformational forms for 4f, some of which are drawn in Fig. 3. The form actually determined was the [(Z)-4f-I] form, i.e. with a (Z) stereochemistry at C(9)) = N(2), see Figs 2a and 3. This geometry is cemented by the N1–H1---O6 (involving the ester group) and the O–H---N intramolecular hydrogen bonds. The corresponding (E)-4f-I form would have the ketone carbonyl oxygen atom, O3, H-bonded to NH- a less favourable situation due to the reduced H-bond ability of keto compared to ester carbonyl groups. It is noticeable that the Z-form adopted in the solid state is the [(Z)-4f-I] form rather than the [(Z)-4f-II] form. The (Z)-form, [(Z)-4f-II], would also allow the strong N1–H1---O6 intramolecular hydrogen-bonding and additionally an O2–H2---O3 intramolecular H-bond. However this is not favoured in the solid state. Instead of being involved in an intramolecular H–bond, the PhCO oxygen, O3, takes part preferentially in intermolecular hydrogen bonding. This C5–H5---O3i intermolecular hydrogen bond, as well as C18–H18b---O2ii, link the molecules into columns: symmetry codes: i: –1/2–x, –1/2 + y, –3/2 + z, ii: –1/2–x, 1/2 + y, 1/2 + z, see Fig. 2b and Table 1. Geometric parameters for the hydrogen bonds, recognised by PLATON,22 are listed in Table 1. The intramolecular hydrogen bonds, O2–H2---N2 and O2–H2---N1, would occur irrespective of the nature of the stereochemistry at the C=N bond. In addition to the intermolecular H-bonds, there are also π–π stacking intermolecular interactions linking molecules, see Table 1. The most significant of these are shown in Fig. 2c. The stereochemistry about the C=N bond is significant while the conformation found in the solid state really has relevance only for the solid state as thermal motions and solvation effects

a

b b

c a

Fig. 2  (a) Atom arrangements and numbering scheme for 4f, probability ellipsoids of atoms are drawn at the 50% level, hydrogen atoms are drawn as spheres of arbitrary radius; intramolecular H-bonds drawn as dashed lines; (b) molecules linked by intermolecular H-bonds, C5–H5---O33 and C183–H18b3---O2; (c) molecules indicating the p–p stacking interactions involving the quinone ring [C(5)–C(8), C(8A), C(4A)] and the terminal aryl ring [C(1)–C(4), C(4A), C(8A)]: symmetry codes are listed in Table 2.

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310  JOURNAL OF CHEMICAL RESEARCH 2009 Table 1  Geometric parameters for 4f (a) Selected bond lengths and angles [Å,°] O(4)–C(4) O(2)–C(3) O(5)–C(18)

1.211(8) 1.355(8) 1.443(8)

O(1)–C(1) O(5)–C(17) O(6)–C(17)

1.210(8) 1.321(9) 1.221(9)

N(1)–N(2) N(2)–C(9) C(10)–C(11)

1.341(7) 1.300(9) 1.472(10)

N(1)–C(2) C(9)–C(10) O(3)–C(10)

1.395(9) 1.481(10) 1.239(8)

C(4)–C(4A) C(1)–C(8A) C(3)–C(2)

1.509(10) 1.495(10) 1.361(9)

C(8A)–C(4A) C(2)–C(1) C(4)–C(3)

1.405(10) 1.481(10) 1.469(10)

N(2)–N(1)–C(2) N(2)–C(9)–C(10)

119.2(6) 113.1(7)

C(9)–N(2)–N(1) C(11)–C(10)–C(9)

122.5(6) 119.0(5)

C(3)–C(4)–C(4A) C1–C(8A)–C(4A) C(3)–C(2)–C(1)

116.1(7) 120.3(7) 122.1(7)

C(8A)–C(4A)–C(4) C(2)–C(1)–C(8A) C(2)–C(3)–C(4)

121.4(7) 117.0(7) 122.9(7)

(a) Hydrogen bonds (Å,°) D–H---A

D–H

H---A

N1–H1---O6 1.05 1.88 O2–H2---N1 0.82 2.45 O2–H2---N2 0.82 1.91 i C5–H5---O3 0.95 2.39 C18–H18B---O2ii 0.99 2.56 Symmetry codes: i = –1/2–x, –1/2 + y, –3/2 + z; ii = –1/2–x, 1/2 + y, 1/2 + z

D---A

–D–H---A

2.632(6) 2.923(6) 2.647(7) 3.207(8) 3.183(8)

125 117 150 144 121

(b) p–p- stacking interactions (Å,°)a Cg(I)---Cg(J)

a

Cg··Cg

b

g

Cgperp

Slippage

Cg(1)---Cg(2)iii 4.282(5) 1.3(4) 38.57 39.65 3.297(3) 3.348(3) Cg(2)---Cg(1)iv 4.281(5) 1.3(4) 39.65 38.57 3.347(3) 3.297(3) aCg(1) is the centroid of the ring defined by C(1)–C(4), C(4A), C(8A) and Cg(2) is the centroid of the ring defined by C(5)–C(8), C(8A), C(4A); a is the dihedral angle between the overlapping rings; b is the angle at either Cg between the vectors Cg··Cg and Cgperp; Cg··Cg is the distance between the ring centroids; Cgperp is the perpendicular between the ring planes and slippage, or lateral displacement, is the distance between Cg(I) and perpendicular projection of Cg(J) on ring I. [Symmetry codes: (iii) x,y,1 + z (iv) z, y,–1 + z]

O

O

O O N H

O

H N O

O

N H

O

OE t

(Z)-4f-I O

O

O N H

N O

OE t

(Z)-4f-II O

H

O

H

OE t

N

O

O

O

(E)-4f-I

O N H

H N

O OE t

O

(E)-4f-II

Fig. 3  Selected stereoisomers and conformers of 4f.

are significant in solution and can affect the conformational equilibrium. The atoms, O2, C3, C2, C1, O1, C8A, C8, C7, C6, C5, C4A, C4, O4, N1, N2, C10 are essentially co-planar, with atoms O1 and O4, being the furthest out of the best plane by 0.096(4) and 0.098(4) Å, respectively. The angles between this best plane and that of the C11-C16 phenyl plane is 59.02 (12)°. It has to be stated that (Z)-4f-I was isolated in a low yield. While no product balance was undertaken, no indication of an

(E)-4f product was obtained. However, it remains a possibility that a (E)-4f stereoisomer had been formed, but had escaped detection and isolation. No indication of a tautomer of 4f either was found. The crystallographic findings, with respect to the stereochemistry for 4f, are clear, and suggest that similar Z-configurations will apply to other keto-ester compounds, such as 4b and 4c, shown in Fig. 1.

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JOURNAL OF CHEMICAL RESEARCH 2009  311 Experimental NMR spectra were run in CDCl3 solutions on a Varian Unity 300 MHz Plus Spectrometer, infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrum One spectrophotometer calibrated relative to the 1601.8 cm-1 absorbance of polystyrene, thin layer chromatography on silicagel 60F-254 (5554 MERCK), 0.2 mm thick, and with spraying with aqueous ammonium sulfate (25% m/v), column chromatography on silicagel 60 (0.063–0.200 mm ref. Merck. 1.05554). Melting points were measured on Reichert micro hot stage and are uncorrected. Solvents were dried by standard methods. Preparation of 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2yl)-hydrazono]-3-phenyl-3-oxo-propionate (4f) A mixture of ethyl benzoylacetate (0.38 mmol) and anhydrous K2CO3 (57 mg, 0.4 mmol) in dry acetone (15 mL) was stirred for 15 min under a nitrogen atmosphere. To this mixture was added slowly through a syringe, a solution of 3-diazo-naphthalene-1,2,4trione (5, 77 mg, 0.38 mmol) in dry acetone (5 mL) during 15 min. After stirring for 2 h the reaction was acidified with 5% (v/v) HCl (40 mL), the solid material was collected by filtration gave (Z) 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hydrazono]3-phenyl-3-oxo-propinoate (4f) as a purple solid (m.p. 178–179 °C) in 27% yield. 6 7

O 5 4a 4 8

3

O

8a 1 2 N H O

H N O

The authors thank the EPSRC X-Ray Crystallography Service, based at the University of Southampton, England for the data collection. Received 28 December 2008; accepted 1 Fenruary 2009 Paper 08/0363  doi: 10.3184/030823409X440850 Published online: 20 May 2009

O O

IR nmax:1736, 1676, 1668, 1651, 1618, 1595, 1530, 1466, 1447, 1370, 1335, 1293, 1272, 1258, 1214, 1202, 1149, 959, 713 cm-1. 1H NMR (300.00 MHz, CDCl ) d 1.35 (3H, t, J = 7.1 Hz, OCH CH ), 3 2 3 4,43 (2H, q, J = 7.1 Hz, OCH2CH3), 7.53–7.48 (2H, m, meta-Ph), 7.53–7.48 (1H, m, H-6); 7.69–7.75 (1H, m, para-Ph); 7.69–7.75 (1H, m, H-7), 7.86 (1H, d, J = 9.0 Hz, H-8); 7.93–7.97 (1H, m, ortho-Ph), 8.09 (1H, d, J = 9.0 Hz, H-5) ppm; 13C NMR (75.0 MHz, CDCl3) d 13.7 (OCH2CH3), 62.3 (OCH2CH3), 122.4 (C-2), 126.0 (C-5), 126.4 (C-8), 128.3 (Cmeta-Ph), 128.7 (Cortho-Ph), 129.3 (Cpara-Ph), 129.5 (C=N), 130.6 (C-4a), 133.6 (C-7), 134.1 (C-6), 135.8 (C-8a), 142.5 (Ph), 144.6 (C-3), 162.4 (CO2Et), 168.7 (C-4), 174.4 (C-1), 178.9 (PhC=O) ppm. Found: C, 64.1; H, 4.3; N, 7.2. C21H16N2O6 requires: C, 64.28; H, 4.11; N, 7.14% Table 2  Crystal data and structure refinement for 4f C21H16N2O6 392.36 120(2) K 0.71073 Å Orthorhombic, Pna21 a = 20.5630(9)Å b = 14.633(2) Å c = 6.011(3) Å 1808.7(9) Å 3 4 1.441 Mg m-3 0.107 mm–1 816 0.60 ¥ 0.05 ¥ 0.03 mm 2.96 to 25.00 deg. –17< = h< = 24; –17< = k< = 17; –7< = l< = 7 Reflections collected 9888 Independent reflections 1719 [R(int) = 0.1350] Reflections observed (>2 sigma) 1050 Data Completeness 0.976 Absorption correction None Refinement method Full–matrix least–squares on F2 Data/restraints/parameters 1719/1/266 Goodness–of–fit on F@2 1.099 Final R indices [I>2 sigma(I)] R1 = 0.0911 wR2 = 0.1385 R indices (all data) R1 = 0.1599 wR2 = 0.1631 Absolute structure parameter 0.00 (10) Largest diff. peak and hole 0.259 and –0.265 e Å 3 CCDC deposit number 676187

Empirical formula Formula weight Temperature Wavelength Crystal system, space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges

Crystallography The sample was recrystallised from EtOH. Data were obtained at 120 K with Mo-K– radiation by means of the Enraf Nonius KappaCCD area detector diffractometer of the EPSRC crystallographic service, based at the University of Southampton. Data collection was carried out under the control of the program COLLECT23 and data reduction and unit cell refinement were achieved with the COLLECT23 and DENZO programs.24 Correction for absorption, by comparison of the intensities of equivalent reflections, was applied using the program SADABS.25 The program ORTEP3 for Windows26 was used in the preparation of the figures and SHELXL-9727 and PLATON22 in the calculation of molecular geometry. The structure was solved by direct methods using SHELXS-9728 and fully refined by means of the program SHELXL-97.27 In the final stages of refinement hydrogen atoms were introduced in calculated positions and refined with a riding model. Crystal data and structure refinement details are listed in Table 2. CCDC 676187 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif”.

References

1 2 3 4

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

W.B. Wendel, Fed Proc., 1946, 5, 406. E.G. Ball, C.B. Anfinsen and O. Cooper, J Biol Chem., 1947, 168, 257. T.H. Porter and K. Folkers, Angew Chem Int Ed., 1974, 13, 559. W. Kurylowicz, in: W. Kurylowicz, Antibióticos: Uma Revisão Crítica, Guanabara Koogan, Brasil, Recife, 1981, p 226. I.L. D'Albuquerque, M.C.N. Maciel, R.P. Schuler, M.C.N. Araújo, G.M. Maciel, M.S.B. Cavalcanti, D.G. Martins and A.L. Lacerda, Rev Inst Antibiot. (Recife), 1971, 11, 21. M. Cortes, J. Katalinic and J. Valderrama, An Quím., 1983, 79c, 202. P. Guiraud, R. Steiman, G.-M. Campos-Takaki, F. Seigle-Murandi and M.S. De Buochberg, Planta Med., 1994, 60, 73. K.V. Rao, T.J. McBride and J.J. Oleson, Cancer Res., 1968, 28, 952. C.Y. Lui, A.A. Ayeni, C. Gylenhall and M.J. Grover, Drug Dev Ind Pharm., 1985, 11, 1763. M.D. Consolação, F. Linardi, M.M.D. Oliveira and M.R.P. Sampaio, J Med Chem., 1975, 18, 1159. J.B. Block, A.A. Serpick, W. Miller and H. Wiernik, Cancer Chemother Res., 1974, 4, 27. S. Subramanian, M.M.C. Ferreira and M. Trsic, Struct Chem., 1998, 9, 47. J.J. Pink, S.M. Planchon and D.A. Boothman, J Biol Chem., 2000, 275, 5416. J.J. Pink, S.M. Planchon and S. Wuerzberger-Davis, Exp Cell Res., 2000, 255, 144. C.J. Li, Y.-Z. Li, A.V. Pinto and A.B. Pardee, Proc Natl Acad Sci., 1999, 96, 13369. C.J. Li, Y.-Z. Li Y-Z, A.V. Pinto and A.B. Pardee, Mol Med., 2000, 5, 232. A. Mazunder, S. Wang, N. Neamati, M. Nicklaus, S. Sunder, J. Chen, G. Milne, W. Rice, R.T. Burke and Y. Pommer, J Med Chem., 1996, 39, 2472. R.J.Weaver, M. Dickins and M.D. Burke, Biochem Pharmacol., 1993, 46, 1183. L.F.Fieser and A.P. Richardson, J Am Chem Soc., 1948, 70, 3156. G.T. Oliveira, F.F. Miranda, V.F. Ferreira, C.C. Freitas, R.F. Rabello, J.M. Carballido and L.C.D. Correa, (2001) J Braz Chem Soc., 2001, 12, 339. W. Reid and E. Kahr, Liebigs Ann Chem., 1969, 725, 228. A.L. Spek, J. Appl. Cryst., 2003, 36, 7. R.W.W. Hooft, COLLECT. Nonius BV, Delft, The Netherlands. 1998. Z. Otwinowski and W. Minor, Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, eds C.W. Carter Jr and R.M. Sweet, pp. 307-326. New York: Academic Press. 1997. G.M. Sheldrick, SADABS. Version 2.10. Bruker AXS Inc., Madison, Wisconsin, USA. (2003). L.J. Farrugia, J. Appl. Cryst., 1999, 32, 837. G.M. Sheldrick, SHELXL-97. Program for Crystal Structure Refinement. University of Göttingen, Germany, 1997. G.M. Sheldrick, SHELXS-97. Program for the Solution of Crystal Structures. University of Göttingen, Germany, 1997.

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312  RESEARCH PAPER

May, 312–316

JOURNAL OF CHEMICAL RESEARCH 2009

Synthesis of perialkynylated tetrapyrazinoporphyrazines and its optical properties Chun Keun Jang and Jae Yun Jaung* Department of Fiber and Polymer Engineering, Hanyang University 17 Haengdang-dong, Seongdong-gu, Seoul, 133791, Korea

Some phthalocyanines soluble in organic solvents have been developed by peripheral introduction of substituent groups. We report a new method for preparation of the polyphenyl-substituted dicyanopyrazines based on the [2 + 4] Diels–Alder cycloaddition of the tetraphenylcyclopentadienone to an ethynyl compound. The synthesised tetrapyrazinoporphyrazinato metal complexes were characterised by UV-visible spectroscopy, MALDI-TOF-Ms (matrix-assisted laser desorption ionisation time-of-flight mass) spectroscopy, and 1H NMR spectroscopy.

Keywords: porphyrazine, spectral change, aggregation, fluorescence, perialkynyl substituent Phthalocyanine derivatives have found wide applications as traditional dyes1 in liquid crystallinity,2 chemical sensors,3 and non-linear optical materials.4 In addition, they can be applied to the electronics industry. For instance, they may be used for optical data storage, colour display technology, and biological technology (e.g. photodynamic tumour therapy (PDT)).5-6 The properties of phthalocyanines are influenced by the nature of the peripheral substituents and the central metal ion. Unsubstituted phthalocyanine has poor solubility. However, alkyl chain substituents can increase the solubility in common organic solvents and facilitate the formation of discotic mesophases. It promises high potential for high charge mobilities in sufficiently ordered rod-like structures. The phthalocyanine transferred films or patterning have been actively researched. Zangmeister et al. transferred peripherally ethylene oxide substituted copper phthalocyanines to bilayer films by Langmuir–Blodgett (LB) films.7,8 Faust et al. researched phthalocyanines or tetrapyrazinoporphyrazines that contained acetylene groups as their peripheral substituents. Peripheral alkynyl substitution of strongly absorbent chromophores, such as porphyrins and phthalocyanines, is becoming an increasingly popular strategy for the design of functional dyes. We now report a general synthesis of 2,3-dicyanopyrazines and their conversion to tetrapyrazinoporphyrazines equipped with polyphenyl dendrons. The perialkynyl substituent can modify the chromophores in two different ways. First, it can cause bathochromic shifts in the electron absorption and emission spectra, due to the expansion of the p-electron systems of the chromophores. Second, it can act as a monomer Br

O(CH2)7CH3

and can be linked to form delocalised multichromophore chains or two-dimensional polymer networks.9,10 Result and discussion

Synthesis The preparation method of 1-bromo-4-(4-(octyloxy)styryl) benzene (1) has been described in previous literature.11,12 1-(4-Bromophenyl)-2-[4-(octyloxy)phenyl]ethane-1,2-dione (2) was prepared by refluxing 1 in dimethyl sulfoxide (DMSO) and 0.4 equiv. of iodine with a 69% yield. 1-[4-(Octyloxy) phenyl]-2-[4-((trimethylsilyl)ethynyl)phenyl]ethane-1,2dione (3) was synthesised by palladium-catalysed ethynylation in triethylamine. Scheme 1 shows these steps for preparing an acetylene group containing an a-diketone. Compound 3 can be a precursor of various compounds, which are used for preparing peripheral substituents of phthalocyanines, as shown in Scheme 2. The reaction of 3 with 2,3-diaminomaleonitrile (DAMN) in ethanol, in the presence of p-toluenesulfonic acid produced the 2,3-dicyanopyrazine derivative 4. Treatment of 4 with tetrabutylammonium fluoride in THF, under mild conditions, with subsequent removal of the triisopropyl silyl group resulted in a high conversion to 5-(4-ethynylphenyl)-6-(4-(octyloxy)phenyl)pyrazine-2,3dicarbonitrile (5). The compounds 6 were prepared by the condensation between dibenzyl ketone and a-diketones, in the presence of potassium hydroxide in ethanol.13 However, the reaction conditions were highly basic and this meant that the reaction rate was too fast. A low yield, with various by-products, Br

I2 / DMSO

O O

1

H3C(H2C)7O

O

Si

N(Et) 3 O

1) Pd(OAc) 2 / PPH3 2)

H3C(H2C)7O

2

Si

3

Scheme 1  Synthesis method of acetylene-containing a-diketone.

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  313 NC

O

Si

O

NC

NH2 NH2

MeOH H3C(H2C)7O

H

Si NC

N

NC

N

N

NC

N

THF Bu 4NFO(CH2)7CH3

4

3

NC

O(CH2)7CH3

5

O

O

Benzyltrimethylammonium hydroxide tert-butyl alcohl Si

O(CH2)7CH3

6

SO2(CH2)2CH(CH3)2 H O

NC

N

NC

N O(CH2)7CH3

SO2(CH2)2CH(CH3)2

H3CO

NC

N

NC

N

OCH3

5

7

O(CH2)7CH3

Scheme 2  Preparation of 2,3-dicyanopyrazines.

resulted. But in an improvement the base and solvent used were benzyltrimethyl ammonium hydroxide and tert-butyl alcohol respectively and as a result even though the reaction rate was slightly slower a more favourable yield (72%) resulted. A [2 + 4] Diels–Alder cycloaddition reaction between tetraphenylcyclopentadienone 6 and the acetylene-groupcontaining compound 5 was used, and the polyphenylene substituent-containing 2,3-dicyanopyrazine 7 was created by refluxing in degassed p-xylene, followed by the elimination of carbon monoxide. The advantage of this cycloaddition is that it is practically free of side reactions, and the equilibrium is shifted toward the products due to the irreversible loss of CO and the formation of a benzene ring. Therefore, a retro Diels–Alder reaction cannot occur.14 The synthesised 2,3-dicyanopyrazine compounds 4 and 7 are precursors of tetrapyrazinoporphyrazines. 2,3Dicyanopyrazines undergo cyclotetramerisation with a magnesium metal ion, which was prepared from a magnesium

butoxide emulsion to afford magnesium complexes 8 and 10. The magnesium derivatives were demetallised by stirring them with excess p-toluenesulfonic acid in THF at room temperature for 30 min to produce 9 and 11, as shown in Scheme 3. UV-visible spectra The maximum absorption wavelength and molar absorptivity (e) values for compounds 8–11 are shown in Table 1. The typical B-band (Soret band, around 400nm), and Q-band (in 600–700nm region) of phthalocyanines were identified in this study. The metal-free tetrapyrazinoporphyrazine generally have two narrow splitting Qx/Qy bands. These are not related to their peripheral substituents. The compound 8 shows the highest molar absorptivity of all of the products. Even if compounds 8 and 9 have only TIPS groups attached, the wavelengths of the Q-bands are almost the same as those for 10 and 11, which have polyphenylene SO2(CH2)2CH(CH3)2

H3C(H2C)7O

Si OCH3

N Si N N H3C(H2C)7O

N C N C N

C

N

Si

N

C

M C

(H3C)2HC(H2C)2O2S

N

N

N

C C

C

N

N

O(CH2)7CH3

N

N

N

N

N

OCH3

H3C(H2C)7O

H3C(H2C)7O Si

N

C C N N N C C N M N C C N N N C C N

O(CH2)7CH3 N N

N

N

SO2(CH2)2CH(CH3)2

O(CH2)7CH3

8 : M = Mg 9 : M = 2H

H3CO

(H3C)2HC(H2C)2O2S

O(CH2)7CH3

OCH3

10 : M = Mg 11 : M = 2H

Scheme 3  Structure of tetrapyrazinoporphyrazines.

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314  JOURNAL OF CHEMICAL RESEARCH 2009 Table 1  Absorption and molar absorptivity of tetrapyrazinoporphyrazines Compd.

Solvent





lmax(nm) Soret band (B-band)

e( l/mol·cm)a

Q-band

8 CHCl3 383 667 THF 385 661 CCl4 380 666 9 CHCl3 379 650, 679 THF 373 650, 673 CCl4 374 681 10 CHCl3 384 662 THF 380 660 CCl4 381 661 11 CHCl3 377 650,679 THF 371 679,673 CCl4 374 649, 679 aMolar absorptivity of Q-band or Q band. y

3.68 ¥ 105 3.77 ¥ 105 2.79 ¥ 105 8.98 ¥ 104 7.55 ¥ 104 4.45 ¥ 104 7.20 ¥ 104 9.16 ¥ 104 4.53 ¥ 104 1.55 ¥ 105 1.49 ¥ 105 1.24 ¥ 105

groups attached as their peripheral substituents. The aggregation behaviour of phthalocyanines is a specific property due to the intermolecular stacking of the planar and rigid core structures of the molecules. Sometimes this can become a significant problem for their various applications. The synthesised products aggregated in solution, and this tendency was varied by controlling the products' environments, such as the solvents, their concentration and the basicity. Figure 1 shows spectra of compounds 8 and 9 in CCl4, chloroform, and THF all at the same concentration. Spectra of 10 and 11 show almost the same behaviour. The absorbance of the spectra was significantly decreased in CCl4. Especially comparing with 9 and 11, spectral peaks of compound 10 were severely broadened. However, spectral peaks of compound 11 remain as narrow peaks, although the absorptivity is decreased. It is assumed that the rigidity of the phthalocyanine structure is decreased because of the out-oftwisted peripheral phenyl components. The aggregation behaviour of 8 was investigated at different concentrations in CHCl3. In CHCl3, as the concentration was decreased, the intensity of absorption of the Q-band increased as shown in Fig. 2, because of reduction of aggregation. There has been a great deal of research focusing on the optical sensitivity of phthalocyanines due to their acidic or basic properties. In this paper, the synthesised products also experience an anion effect, especially with the F- anion,

Fig.1  Absorption spectra of 8 (A, 4.4 ¥ 10-6 M) and 9 (B, 1.78 ¥ 10-5 M) in CCl4 (dot line), tetrahydrofuran (dashed line), and chloroform (solid line).

Fig 2  Effect of concentration on the absorption spectra of compound 8 (solid line: 2.8 ¥ 10-5 M, dashed line: 2.8 ¥ 10-6 M, dotted line: 0.7 ¥ 10-6 M).

which was added to the nonaqueous solvents in the form of tetra-n-butylammonium salts. The spectra were found to rapidly change. Previous researchers showed that the fluoride anion can bind within the cores of metallophthalocyanines. Strictly speaking, it forms F- coordinated complexes15 or causes deprotonation of the proton on the pyrrole group of metal-free phthalocyanines.16 In our case, Figure 3 shows the UV-visible spectral changes of 10 and 11 upon adding tetrabutylammonium fluoride monohydrate (TBAF). The spectra showed a sharp peak in the Q-band and the molar absorptivity was higher than that for the initial solution. Fluorescence property Tetrapyrazinoporphyrazine derivatives show fluorescence properties which vary according to different environments around the molecule. The excitation wavelengths used in the experiments were the lmax of B and Q-bands.

Fig.3  UV-vis absorption spectral change upon adding a base to 10 (1.74x10-5 M) and 11 (1.75x10-5 M).

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Fig. 4  Fluorescence spectra in chloroform (solid line) and THF (dashed line) at the same concentration (8: 2.6 ¥ 10-7 M, 9 : 2.6 ¥ 10-7 M, 10 : 1.74 ¥ 10-7M, 11 : 1.75 ¥ 10-7 M).

Fig. 5  Fluorescence change upon adding a base to 8 (8 : TBAF = 1:0 (solid line), 8 : TBAF = 1 : 108 (dashed line) mol ratio), and 9 (9 : TBAF = 1 : 0 (solid line), 9:TBAF = 1 : 150 (dashed line) mol ratio).

Figure 4 shows fluorescence spectra of the synthesised products in chloroform and THF, from the emission peak in the B-band. Generally, the emission peak around 450–550 nm was more intense in chloroform. However, the emission peak around 650–750 nm which shows a red fluorescence, was significantly more intense in THF than in chloroform. The appearance of the long wavelength region can be examined by the fluorescence quenching effect, due to the intermolecular p-p interaction relatively decreasing in solution. Figure 5 displays the emission spectra of compounds 8 and 9 when tetra-n-butylammonium fluoride (TBAF) was added in chloroform. The Fmax was significantly changed and Fig. 5 also shows the strong fluorescence in the 650–750nm region. Conclusion

In this study, the peripheral acetylene group was successfully attached in the pyrazine unit, and it could be used as a precursor of various compounds by using condensation and cycloaddition reactions. We also designed and synthesised metal and metal-free tetrapyrazinoporphyrazines, which show that the polyphenylene dendrimers increase the solubility of porphyrazines in common organic solvents. The aggregation behaviour in solution was investigated through their absorption and emission spectra. Experimental General Compounds were identified and their properties were measured using the following techniques. Flash chromatography was performed with Merck-EM type 60 (230–400 mesh) silica gel (flash). Melting

points were obtained with a capillary melting point apparatus and are uncorrected. 1H NMR spectra were recorded on a VARIAN UnityInova 300 MHz FT-NMR Spectrometer. UV-visible and fluorescence spectra were measured using a SCINCO S-4100 and a SHIMADZU RF-5301PC spectrophotometer. MALDI-TOF-Ms (matrix-assisted laser desorption ionisation time-of–flight mass) spectra were obtained on a Waters Limited MALDI-TOF spectrometer with dithranol as a matrix. All chemicals were used of reagent grade without further purification unless otherwise specified. Tetrapyrazinoporphyrazinato magnesium complex (8) A suspension of Mg turning (200 mg, 8.4 mmol), one small crystal of iodine and n-butanol 20 mL were heated under reflux for 4 h. The reaction mixture was then cooled to room temperature, and dicyanopyrazine 4 (1.2 g, 2.1 mmol) was added in one portion. The reaction mixture was quickly reheated to reflux for 1 h. After approximately 10 min, the reaction mixture had become dark green. The mixture was cooled and the solvent was removed in vacuo, yielding crude product as a dark green solid. The crude product was purified using chloroform/methanol (30/1) as an eluent. 8 (dark green solid, 48%): m.p >300 °C; 1H NMR (300 MHz, CDCl3) d : 0.40– 1.85 (m, –CH3, 12H), 1.08–1.55 (m, –Si–C–CH3, 72H; methylene, 40H; –Si–CH, 12H), 1.90–2.21 (m, –O–C–CH2, 8H,), 3.90–4.38 (m, O–CH2, 8H,), 6.6–8.3 (m, aryl protons, 32H); MALDI-TOF mass-spectra: m/z 2387.1 (Calcd 2387.8) Demetallised tetrapyrazinoporphyrazine (9) p-Toluenesulfonic acid (0.81 g, 4.23 mmol) was added to a solution of Mg tetrapyrazinoporphyrazine 8 (200 mg, 0.08 mmol) in tetrahydrofuran (THF, 10 mL) and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo, yielding the crude product as a dark green solid. The crude product was purified by column chromatography on silica gel using chloroform/methanol (30/1) as an eluent. 9 (dark green solid, 58%): m.p >300 °C; 1H NMR (300 MHz, CDCl3) d : –0.80 (s, N–H, 2H), 0.98–1.08 (m, CH3, 12H), 1.20 (s, –Si–C–CH3, 72H), 1.36–1.58 (m,

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316  JOURNAL OF CHEMICAL RESEARCH 2009 methylene, 40H), 1.59–1.68(m, –Si–CH, 12H), 1.83–2.13 (m, –O– C–CH2, 8H), 3.90–4.20 (m, O–CH2, 8H), 6.92–7.05 (m, ArH, 8H), 7.62–7.80 (m, ArH, 16H), 7.87–8.10(m, ArH, 8H); MALDI-TOF mass-spectra: m/z 2364.9 (Calcd 2365.51) Tetrapyrazinoporphyrazinato magnesium complex (10) This compound was prepared by the procedure described for 8 but from magnesium (0.11 g, 4.5 mmol), 10 mL of n-butanol and 7 (0.72 g, 0.75 mmol). The mixture was cooled and the solvent was removed in vacuo, yielding crude product as a dark green solid. The crude product was purified using chloroform/methanol (30/1) as an eluent. 10 (dark green solid, 59%): m.p >300 °C; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) d : 0.80–1.08 (m, –CH3, 36 protons), 1.22–1.53 (m, methylene, 40H), 1.53–1.75 (m, O–C–CH2, 8H), 1.80–2.20 (m, –S–C–CH2–CH, 12H), 2.90–3.10 (m, –S–CH2, 8H), 3.62–3.80 (m, –O–CH3, 12 protons), 4.00–4.24 (m, –O–CH2, 8H), 6.2–8.2 (m, Aryl protons, 108H); MALDI-TOF mass-spectra: m/z 3841.4 (Calcd 3845.16) Demetallised tetrapyrazinoporphyrazine (11) This compound was prepared by the procedure described for 9 but from compound 10 (100 mg, 0.04 mmol), p-toluenesulfonic acid (0.4 g, 2.12 mmol). The solvent was removed in vacuo, yielding the crude product as a dark green solid. The crude product was purified by column chromatography on silica gel using chloroform/methanol (30/1) as an eluent. 11 (dark green solid, 70%): m.p >300 °C; 1H NMR (300 MHz, CDCl ) d : –0.64 (s, N–H, 2H), 0.90–1.00 (m, 3 CH3, 36H), 1.25–1.50 (m, methylene, 40H), 1.53–1.65 (m, O–C–CH2, 8H), 1.80–2.00 (m, –S–C–CH2–CH, 12H), 2.90–3.02 (m, –S–CH2, 8H), 3.62 (s, –O–CH3, 12 protons), 4.08–4.15 (m, –O–CH2, 8H), 6.46 (d, J = 9.0 Hz, ArH, 8H), 6.53 (d, J = 9.0 Hz, ArH, 8H), 6.71 (d, J = 9.0 Hz, ArH, 8H), 6.77 (d, J = 9.0 Hz, ArH, 8H), 6.90–7.05 6.46(m, ArH, 30H), 7.09 (d, J = 9.0 Hz, ArH, 8H), 7.20 (s, ArH, 4H), 7.35 (d, J = 9.0 Hz, ArH, 8H), 7.47 (d, J = 9.0 Hz, ArH, 8H), 7.53 (d, J = 9.0 Hz, ArH, 8H), 7.77(d, J = 12.0 Hz, ArH, 4H), 7.95–8.03 (m, ArH, 6H); MALDI-TOF mass-spectra: m/z 3822.7 (Calcd 3822.87)

This study was supported by a grant from the Fundamental R&D Program (M200701004) for Core Technology of Materials funded by the Ministry of Commerce, Industry and Energy, and a grant No. R01-2006-000-10489-0 from the Basic Research Program of the Korea Science and Engineering Foundation and BK21 project in Republic of Korea. Received 1 July 2008; accepted 28 July 2008 Paper 08/5298A doi: 10.3184/030823409X449473 Published online: 20 May 2009 References 1 C.C. Lenzoff and A.P.F. Lever, Phthalocyanine-properties and applications, VCH, New York, 1996, Vol. IV. 2 C. Piechoki, J. Simon, A. Skoulious, D. Gullion and P. Weber, J. Am. Chem. Soc., 1982, 104, 5245. 3 A.W. Snow, W.R. Barger, M. Klusty, H. Wohltjen and N.L. Jarvis, Langmuir, 1986, 2, 513. 4 A. Grund, A. Kaltbeitzel, A. Mathy, R. Schwarz, C. Bubeck, P. Vernmehren and M. Hanack, J. Phys. Chem., 1992, 96, 7450-4. 5 I. Okura. Photosensitisation of porphyrins and phthalocyanines, Taylor & Francis, 2001. 6 H. Ali and J.E. van Lier, Chem. Rev., 1999, 99, 2379-2450. 7 P. Smolenyak, R. Peterson, K. Nebesny, M. Toerker, D. O'Brien and N.R. Armstrong, J. Am. Chem. Soc., 1999, 12, 8628. 8 R.A.P. Zangmeister, D.F. O'Brien and N.R. Armstrong, Adv. Funct. Mater., 2002, 12, 179-186. 9 R. Faust and C. Weber, J. Org. Chem., 1999, 64, 2571. 10 R. Faust, Eur. J. Org. Chem., 2001, 15, 2797-2803. 11 W. Pisula, F. Dierschke and K. Müllen, J. Mater. Chem., 2006, 16, 40684064. 12 B.H. Lee and J.Y. Jaung, Dyes Pigments, 2003, 59, 135-142. 13 M. Wehmeier, M. Wagner and K. Müllen, Chem. Eur. J., 2001, 7, 21972205. 14 U.M. Wiesler, A.J. Berresheim, F. Morgenroth, G. Leser and K. Müllen, Macromolecules 2001, 34,187-199. 15 Z. Ou, J. Shen and K.M. Kadish, Inorg. Chem., 2006, 45, 9569-79. 16 H. Weitman, S. Schatz, H.E. Gottlieb, N. Kobayashi and B. Ehrenberg, Photochem. Photobiol., 2001, 73, 473-481.

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RESEARCH PAPER  317

May, 317–318

Synthesis of novel Schiff bases from the reaction of 3-O-methyl4, 6-O-benzylidene-β-D-glucopyranosylamine with substituted aldehydes Chao Shen, Qing Zhao, Hui Zheng and Pengfei Zhang* College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, P.R. China

The synthesis of novel sugar derived Schiff base derivatives from reaction of 3-O-methyl-4, 6-O-benzylidene-b-Dglucopyranosylamine with several substituted aldehydes is described.

Keywords: sugar derived Schiff base, 3-O-methyl-4, 6-O-benzylidene-b-D-glucopyranosylamine, substituted aldehydes Owing to the remarkable biological relevance of carbohydrate, the synthesis of oligosaccharides or carbohydrate derivatives has attracted much attention.1 The sugar derived Schiff base are important intermediates in the synthesis of N-nucleosides and glycosylamino heterocycles.2 The active site on carbohydrate structure directed reversible inhibitors of glycosidases and played important roles in various biological processes.3 Carbohydrates are widespread chiral natural products, generally cheap and easily obtainable and stereogenic centres allows the regional and stereoselective introduction of different functionalities. These features are well-suited for developing catalysis in non-conventional conditions with a reduced environmental impact. Carbohydrates have recently received much attention as sources of chiral ligands for asymmetric catalysis.4 A variety of iminic chiral ligands constituted by a chiral amino part and an aldehydic or acidic part can be found in literature.5 However the complexity and diversity of carbohydrates found in nature makes the synthesis of carbohydrates a challenging task despite the numerous efforts documented.6 One reason is that different carbohydrate scaffolds often manifest moderate to drastic different reactivity in various reactions.7 Several glycosylamines are known, but as far as the glycosylamine derived Schiff base molecules are concerned, the literature is scarce.8 Recently, we have demonstrated that carbohydrates have emerged as versatile auxiliaries and reagents in regio- and stereoselective chemical reactions, and which can be straightforwardly prepared by suitable modification of common and inexpensive sugars such as Dglucose.10 In connection with a program directed to broaden the application of carbohydrates in organic chemistry, we have focussed our attention on the development of new chiral OH O

HO H3 CO

Schiff bases for biological products and asymmetric catalysis. Here, we describe the efficient synthesis of chiral Schiff base from glucosamine and a series of substituted aldehydes. Results and discussion

In this paper, we shall report multiple chemical modifications that were carried out on D-glucose to produce the corresponding Schiff bases. Such modifications performed on D-glucose not only helped in increasing the solubility of the products in nonaqueous solvents, but also restricted the anomerisation of the saccharide moiety in solution. We first prepared 3-O-methyl-4, 6-O-benzylidene-b-D-gluco- pyranosylamine from D-glucose by several steps, followed by treatment with a series of substituted aldehydes to afford the corresponding Schiff base (4a–e) (Scheme 1). The results are reported in Table 1. It is well known that under mild conditions aldoses react with primary or secondary amines to form glycosylamines where the hydroxyl group on C1 is replaced by the amine in order to produce C-1-NRR by condensation. The peak corresponding to C-1-NH2 observed Table 1  Synthesis of sugar derived Schiff basea Entry

Product

Ph

O O H 3CO

OH 1

Yield/%b

O

OH

OH

2 OH

NH 3 , CH 3OH

Time/h

1 Ph 4a 2.0 82.9 2 o-OH-C6H4 4b 2.0 72.7 3 p-OCH3-C6H4 4c 2.5 75.7 4 p-NO2-C6H4 4d 2.5 86.9 5 p-Cl-C6H4 4e 2.0 80.6 aReagent and conditions: amine (1.0 mmol), substituted aldehydes (1.1 mmol) reflux in MeOH; bIsolated yields.

PhCH(OMe)2, Pyridiniump-TsOH, DMF

OH

Ar

O

HO H3 CO

NH 2

ArCHO

OH

Ph

O O

H3 CO

O OH

Ar N H

4a Ar = Ph b Ar = o-OH-C6 H4 c Ar = p-OCH3 -C 6H 4 d Ar = p-NO2 -C 6H 4 e Ar = p-Cl-C6 H4

3

Scheme 1

* Correspondent. E-mail: [email protected]

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318  JOURNAL OF CHEMICAL RESEARCH 2009 in 3 at 2.32 ppm disappears in 4 and a new peak appears at around 8.432 ppm arising from –CH=N indicating that the –NH2 group present in the former was converted to its Schiff base in 4. Conclusions

In conclusion, D-glucose was successfully modified into the corresponding Schiff base through partial protection and glycosyl amination, followed by condensation with substituted aldehydes. All the compounds were characterised by analytical and spectral methods. Such modifications facilitate the solubility of the resulting Schiff base products in nonaqueous solvents and lock the saccharide in the anomeric form. Futher research of other Schiff base is taking place in our laboratory and the results will be reported later. Experimental All chemicals were reagent-grade quality. All reactions were carried out under an nitrogen atmosphere in oven-dried glassware with magnetic stirring. Column chromatography was performed on silical gel, Merck grade 60 (230–400 mesh). Reactions were monitored by TLC performed on a Merck precoated TLC (silica gel 60 F254) plate. Melting points were determined on an X4-Data microscopic melting point apparatus; IR spectra were determined on a Nicolet NEXUS470FT-IR spectrometer as KBr pellets. The 1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker AVANCE DRX400 NMR spectrometer, using TMS as the internal standard. General procedure for preparation of 1 3-O-Methyl-D-glucose11-12 (10.0 g, 52 mmol) was dissolved in dry dimethylformamide (50 mL, 90 °C) and pyridinium p-toluenesulfonate (100 mg) added. a,a-Dimethoxytoluene (9.0 g, 60 mmol) in dimethylformamide (50 mL) was then added dropwiseunder a stream of dry nitrogen (2 h, 90 °C). Evaporation and recrystallisation of the residue gave 3-O-methyl-4, 6-O-benzylidene-D-glucose as needles (12.65 g, 86.3%). M.p.129–131 °C. MS: m/z (EI): 282 (M+). 1H NMR (CDCl3, 400 MHz) d: 7.52–7.27 (m, 5 H, ArH), 5.62 (d, 1 H, J = 5.7 Hz, SacOH), 5.54 (s, 1 H, CHPh), 4.81 (d, 1 H, J = 3.9 Hz), 4.30 (dd, 1 H, J = 4.2 Hz, 9.7 Hz), 3.92 (d, 1 H, J = 5.7 Hz, SacOH), 3.37 (s, 3 H), 3.18–3.80 (m, 5 H, Sac). 13C NMR (CDCl3, 100 MHz) d–129.0, 128.2, 126.0, 125.9, 101.2, 92.9, 81.9, 80.1, 77.3, 77.2, 76.9, 72.3, 68.9, 66.6, 61.0. General procedure for preparation of 3 3-O-methyl-4, 6-O-benzylidene-D-glucose (10.0 g., 35 mmol) was added to a chilled (ice-salt) solution of ammonia (35–40 g.) in methanol (120 mL), contained in a steel bomb. The bomb was closed, and with shaking the temperature was raised gradually and maintained at 60 °C for 3 h. At the end of this period, the bomb was allowed to reach room temperature and then cooled to 0 °C. Upon careful removal of the excess of ammonia by means of a water-pump, compound 3, which had already begun to crystallise, separated out in a mass. It was kept at 0 °C overnight, filtered off, washed with small portions of methanol and dried over calcium chloride and potassium hydroxide; yield (6.5 g. 66.3%), M.p. 129–131 °C. IR (KBr, cm‑1): 1627 (NH2). MS: m/z (EI): 281 (M+). 1H NMR (CDCl3, 400 MHz) d: 7.54–7.26 (m, 5 H, ArH), 5.55 (d, 1 H, J = 5.7 Hz, SacOH), 5.31 (s, 1 H, CHPh), 4.81 (d, 1 H, J = 3.9 Hz), 4.30 (d, 1 H, J = 4.2 Hz), 3.37 (s, 3 H), 3.18–3.80 (m, 5 H, Sac), 2.32 (br., 2H); 13C NMR (CDCl3, 100 MHz) d: 137.9, 128.9, 128.2, 126.3, 100.2, 87.7, 83.4, 81.4, 79.3, 79.2, 73.7, 68.6, 67.2, 60.3. Anal. Calcd for C14H19NO5: C, 59.77; H, 6.80; N, 4.95. Found: C, 59.80; H, 6.90; N, 4.98%. General procedure for preparation of 4 To a suspension of 3-O-methyl-4, 6-O-benzylidene-b-D-gluco- pyranosylamine (0.281 g, 1.0 mmol) in MeOH (15 mL) was added substituted aldehyde (1.1 mmol), and the reaction mixture was refluxed for 2.0 h to produce a clear orange solution. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 5 mL diethyl ether and excess hexane was added to the solution while stirring to afford the light yellow solid product which was isolated through filtration and dried under vacuum. The crude product was recrystallised from ethanol–water to give a pure sample. The physical and spectra data of the compounds (4a–e) are as follows. N-benzylidene-3-O-methyl-4, 6-O-benzyliden -b-D-glucopyranosylamine (4a): Yield: 0.306 g, 82.9% M.p. 152–154 °C. IR (KBr, cm‑1):

1634 (CH=N). MS: m/z (EI): 369 (M+). 1H NMR (DMSO-d6, 400 MHz) d: 8.56 (s, 1 H, HC=N), 7.30–7.62 (m, 8 H, ArH), 6.78–6.94 (m, 2 H, ArH), 5.62 (d, 1 H, J = 3.2 Hz, SacOH), 5.51 (s, 1 H, CHPh), 4.71 (1 H, J = 4.4 Hz), 4.24 (1 H, J = 12.2 Hz), 3.37 (s, 3 H), 3.18–3.80 (m, 5 H, Sac). 13C NMR (DMSO-d6, 100 MHz) d: 159.6, 138.2, 136.5, 135.6, 130.4, 129.1, 129.1, 128.2, 126.8, 101.1, 97.0, 81.1, 75.0, 74.2, 68.7, 57.9, 20.2. Anal. Calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.41; H, 6.20; N, 3.82%. N-(2-hydroxybenzylidene)-3-O-methyl-4, 6-O-benzylidene-b-D-glucopyranosylamine (4b): Yield: 0.280 g, 72.7%. M.p. 172–174 °C. IR (KBr, cm‑1): 1624 (CH=N). MS: m/z (EI): 385 (M+). 1H NMR (DMSO-d6, 400 MHz) d: 12.95 (s, 1 H, ArOH), 8.62 (s, 1 H, HC=N), 7.22–7.62 (m, 7 H, ArH), 6.80–7.1 (m, 2 H, ArH), 5.62 (d, 1 H, J = 3.2 Hz, SacOH), 5.51 (s, 1 H, CHPh), 4.56 (1 H, J = 6.2 Hz), 4.10 (1 H, J = 4.8 Hz), 3.37 (s, 3 H), 3.70–3.52 (m, 5 H, Sac). 13C NMR (DMSO-d6, 100 MHz) d: 165.7, 160.7, 138.2, 133.4, 132.8, 129.3, 128.5, 126.8, 119.3, 118.8, 116.9, 101.1, 95.9, 81.0, 75.1, 73.7, 68.3. 20.1. Anal. Calcd for C21H23NO6: C, 65.41; H, 6.01; N, 3.60. Found: C, 65.15; H, 6.22; N, 3.71%. N- (4-methoxybenzylidene)-3-O-methyl-4, 6-O-benzylidene-b-D-glucopyranosylamine (4c): Yield: 0.302 g, 75.7%. M.p. 162–164 °C. IR (KBr, cm‑1):1612 (CH=N). MS: m/z (EI): 399 (M+). 1H NMR (DMSO-d , 400 MHz d: 8.56 (s, 1 H, HC=N), 7.58–7.62 6 ) (m, 7 H, ArH), 6.85–6.96 (m, 2 H, ArH), 5.52 (d, 1 H, J = 5.2 Hz, SacOH), 5.30 (s, 1 H, CHPh), 4.70 (1 H, J = 6.4 Hz), 4.24 (1 H, J = 6.5 Hz), 3.79 (s, 3 H, ArCH3), 3.37 (s, 3 H), 3.11–3.75 (m, 5 H, Sac).13C NMR (DMSO-d6, 100 MHz) d: 161.8, 159.2, 135.1, 134.5, 132.5, 131.8, 128.3, 126.9, 125.9, 101.6, 85.2, 78.6, 77.2, 70.4, 67.1, 50.6,39.5, 20.2. Anal. Calcd for C22H25NO6: C, 66.20; H, 6.32; N, 3.64. Found: C, 66.35; H, 6.43; N, 3.70%. N-(4-nitrobenzylidene)-3-O-methyl-4, 6-O-benzylidene -b-D-glucopyranosylamine (4d): Yield: 0.356 g, 86.9%. M.p.142–144 °C. IR (KBr, cm‑1): 1646 (CH=N). MS:m/z (EI): 414 (M+). 1H NMR (DMSO-d6, 400 MHz) d: 8.82 (s, 1 H, HC=N), 8.54–7.85 (m, 7 H, ArH), 7.21–7.03 (m, 2 H, ArH), 5.66 (d, 1 H, J = 5.5 Hz, SacOH), 5.51 (s, 1 H, CHPh), 4.71 (1 H, J = 5.1 Hz), 4.24 (1 H, J = 8.4 Hz), 3.37 (s, 3 H), 3.18–3.80 (m, 5 H, Sac). 13C NMR (DMSO-d6, 100 MHz) d: 166.8, 162.5, 137.5, 128.3, 118.6, 129.0, 128.2, 126.8, 101.7, 96.6, 81.8, 75.6, 71.5, 68.7. 20.1. Anal. Calcd for C21H22N2O7: C, 60.91; H, 5.35; N, 6.78. Found: C, 60.72; H, 5.47; N, 6.83%. N- (4-Chlorobenzylidene)-3-O-methyl-4, 6-O-benzylidene-b-D-glucopyranosylamine (4e): Yield: 0.325 g, 80.6%. M.p.170–172 °C. IR (KBr, cm‑1): 1645 (CH=N). MS m/z (EI): 403 (M+); 1H NMR (DMSO-d6, 400 MHz) d: 8.43 (s, 1 H, HC=N), 7.83–7.75 (m, 7 H, ArH), 7.37–7.26 (m, 2 H, ArH), 5.56 (d, 1 H, J = 5.7 Hz, SacOH), 5.16 (s, 1 H, CHPh), 4.70 (1 H, J = 8.6 Hz), 4.19 (1 H, J = 12.3 Hz), 3.37 (s, 3 H), 3.17–3.80 (m, 5 H, Sac). 13C NMR (DMSO-d6, 100 MHz) d: 160.5, 13.6, 137.1, 133.6, 130.8, 129.9, 128.9, 128.2, 125.9, 101.2, 95.4, 87.7, 82.8, 77.3, 73.8, 68.3, 60.9. Anal. Calcd for C21H22ClNO5: C,62.40; H, 5.61; N, 3.52.86 Found: C,62.52; H, 5.74; N, 3.62%.

This work was supported by the Natural Science Foundation of Zhejiang Province (No. R406378) Received 10 January 2009; accepted 2 March 2009 Paper 09/0379 doi: 10.3184/030823409X449851 Published online: 28 May 2009 References 1 J.D. Onofrio, M. Champdor, L. Napoli, D. Montesarchio and G. Fabio, Bioconjugate Chem., 2005, 16, 1299. 2 H. Paulsen and K.W. Pflughaupt, The carbohydrates: chemistry and biochemistry, W. Pigman and D. Horton, eds, 2nd edn; Academic: New York, 1980; Vol. 1B, pp. 881–892. 3 A.K. Sah, C.P. Rao and P.K Saarenketo, J. Chem. Soc. Dalton Trans., 2000, 3681. 4 C. Borriello, R.D. Litto, A. Panunzi and F. Ruffo, Tetrahedron: Asymmetry, 2004, 15, 681. 5 M.S. Sigman, P. Vachal and E.N. Jacobsen, Angew. Chem. Int. Ed., 2000, 39, 1279. 6 W. Zhang, T. Jiang, S. Ren, Z. Zhang, H. Guan and J. Yu, Carbohydr. Res., 2004, 339, 2139. 7 A.K. Sah, C.P. Rao, P.K. Saarenketo, E.K. Wegelius, E. Kolehmainen and K. Rissanen, Eur. J. Inorg. Chem., 2001, 2773. 8 A. Fragoso, M.L. Kahn, A. Castin, J.P. Sutter, O. Kahn and R. Cao, Chem. Commun., 2000, 1547. 9 G.B. Zhou, W.X. Zheng, D. Wang, P.F. Zhang and Y.J. Pan, Helv. Chim. Acta., 2006, 89, 520. 10 W.L. Glen, G.S. Myers and G.A. Grant, J. Chem. Soc., 1951, 2568. 11 J.J. Patroni, V. Robert, W.S. Brian, A. Skelton and A.H. White, Aust. J. Chem., 1988, 41, 91.

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RESEARCH PAPER  319

May, 319–321

Stereoselective synthesis of 3-[2-(dialkoxyphosphoryl)-1,2-dialkoxycarbonyl-ethyl]-4-hydroxycoumarins by reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and 4-hydroxycoumarin Mohammad Anary-Abbasinejad*, Khadijeh Charkhati and Alireza Hassanabadi Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran

A three-component reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and 4-hydroxycoumarin is described as a simple and efficient route for the synthesis of 3-[2-(dialkoxyphosphoryl)-1,2-dialkoxycarbonyl-ethyl]4-hydroxycoumarins in high yields.

Keywords: dialkyl acetylenedicarboxylates, trialkyl phosphites, 4-hydroxycoumarin, phosphonates, stereoselective synthesis The synthesis of coumarin and its derivatives has attracted considerable attention from organic and medicinal chemists for many years as a large number of natural products contain this heterocyclic nucleus. They are widely used as additives in food, perfumes, cosmetics, pharmaceuticals1 and optical brighteners2 and dispersed fluorescent and laser dyes.3 Among the various substituted coumarins, 4-hydroxycoumarins substituted on their C-3 position represents a significant class of compounds as biologically active compounds4,5 and useful scaffolds, which can be used for the synthesis of 3,4-substituted compounds.6–9 The existing methods for the synthesis of 3-substituted 4-hydroxycoumarins include direct synthesis of the target compound10–13 or C3-alkylation/ substitution of 4-hydroxycoumarin.14 The reaction of trimethyl phosphite and dimethyl acetylenedicarboxylate (DMAD) in the presence of alcohols is reported to produce phosphite ylide derivatives which are stable at low temperatures, but are converted to phosphonate derivatives by warming or by treatment with water.15 There are some other recent reports on the reaction between phosphites and acetylenic esters in the presence of an acidic organic compound, all of them proceeding through a phosphite ylide intermediate.16-22 In continuation of our works on the reaction between trivalent phosphorus nucleophiles and acetylenic esters in the presence of organic NH, OH, or CH-acids,17-23 here we report the results of our study on the reaction between dialkyl acetylenedicarboxylates (DAADs) and trialkyl phosphites in the presence of 4-hydroxycoumarin.

Results and discussion

The reaction of DAAD 2 with trialkyl phosphite 3 in the presence of 4-hydroxycoumarin 1 leads to 3-[2-(dialkoxyphosphoryl)-1,2-dialkoxycarbonyl-ethyl]-4-hydroxycoumarins 4 in high yields (Scheme 1). Products 4a–f were all new compounds and their structures were deduced from their elemental analyses and spectral data. The mass spectrum of compound 4a showed the molecular ion peak at 414. The 1H NMR spectrum of compound 4a displayed two doublets (JHP = 11 Hz) at 3.41 and 3.47 ppm for two POCH3 groups and two singlets at 3.54 and 3.67 ppm for two methoxycarbonyl groups. Two signals were observed at 3.99 (dd, 3JHH = 11 Hz, 2JHP = 21 Hz) and 4.89 ppm (dd, 3J 3 HH = 11 Hz, JHP = 5 Hz) for two vicinal methine protons. Aromatic protons resonated between 7.35 and 7.69 ppm. A broad signal was observed at 12.62 ppm for the OH proton and disappeared by addition of D2O to d6-DMSO solution of 4a. The 13C NMR spectrum of compound 4a showed 17 distinct resonances in agreement with the proposed structure. The structural assignments made on the basis of the NMR spectra of compound 4a were supported by its IR spectrum, the ester carbonyl groups exhibited strong absorption bands at 1731 and 1690 cm-1. Observation of 3JHH = 11 Hz for the vicinal protons in compound 4a indicates an anti arrangement for these protons.24,25 Since compound 4a possesses two stereogenic centres, two diastereoisomers with anti HCCH arrangements

P(OR)3

OH

CO2R' O P

OH

3 + O 1

O

CH3CN, r.t.

4

2 4

R'

Yield* (%)

a

R Me

Me

89

b

Et

Me

90

c

n-Bu

Me

91

d

Me

Et

90

e

Et

Et

91

f

n-Bu

Et

88

*

O

O

R'O2C C C CO2R'

OR OR CO2R'

Isolated yields

Scheme 1  Three-component reaction between trialkyl phosphites, DAADs and 4-hydroxycoumarin.

* Correspondent. E-mail: [email protected]

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O

O O Me2O3P H

OH H CO2Me CO2Me

OH

O H Me2O3P

H CO2Me

CO2Me

(2S,3R) - 4a

(2R,3S) - 4a

Scheme 2  Two enantiomers of phosphonate 4a.

are possible (Scheme 2). The three-bond carbon–phosphorus coupling, 3JCP, depends on configuration, as expected, transoid couplings being larger than cisoid ones. The observation of 3J 3 CP of 21 Hz for the ester C=O group and JCP of 0 Hz for the C-3 of coumarin ring is in agreement with the (2R,3S)4a and its mirror image (2S,3R)-4a geometries.26 The same diasteromers were observed for compounds 4b–f. Any traces of the other diastereomer were not detected by the NMR spectra of compounds 4a–f. A reasonable mechanism for the formation of compound 4a is presented in Scheme 3. The initial addition of trimethyl phosphite on DMAD leads to a diionic intermediate that is protonated by 4-hydroxycoumarin to produce the vinyl phosphonium 5. The conjugate addition of anion 6 to cation 5 afforded the phosphite ylide 7 which then hydrolyses to product 4a. In summary, we report here that three-component reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and 4-hydroxycoumarin provides a simple and efficient onepot route for the synthesis of 3-[2-(dialkoxyphosphoryl)-1,2dialkoxycarbonyl-ethyl]-4-hydroxycoumarins in good yields. Experimental Melting points were determined with an electrothermal 9100 apparatus. Elemental analyses were performed using a Costech ECS 4010 CHNS–O analyser. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.1H, 13C and 31P NMR spectra were recorded on Bruker DRX-500 AVANCE spectrometer in d6-DMSO using TMS as internal standard or 85% H3PO4 as external standard. The chemicals used in this work purchased from Fluka (Buchs, Switzerland) and were used without further purification. General procedure for preparation of compounds 4a–g by reaction between dialkyl acetylenedicarboxylates, trialkyl phosphites and 4-hydroxycoumarin To a magnetically stirred solution of trialkyl phosphite (2 mmol) and 4-hydroxycoumarin (2 mmol) in acetonitrile (15 mL) was added dropwise a mixture of dialkyl acetylenedicarboxylate (2 mmol) in acetonitrile (3 mL) at room temperature over 2 min. The reaction mixture was then stirred for 24 h. The solvent was removed under

reduced pressure and diethyl ether (20 mL) was added. The solid was filtered off and washed with diethyl ether (20 mL) to afford the pure product. 3-[2-(Dimethoxyphosphoryl)-1,2-dimethoxycarbonyl-ethyl]-4hydroxycoumarin (4a): Yield: 89%; White powder, m.p. 194–196 °C, IR (KBr)(nmax, cm-1): 3150 (OH), 1731, 1690 (C=O, ester). Anal. Calcd for C17H19O10P: C, 49.28; H, 4.62. Found: C, 49.04; H, 4.43%. MS (m/z,%): 414 (M+, 1). 1H NMR (500 MHz, CDCl3): d 3.41 and 3.47 (6 H, 2 d, 3JHP = 11 Hz, 2 POCH3), 3.54 and 3.67 (6 H, 2 s, 2 OCH3), 3.99 (1 H, dd, 3JHH = 11 Hz, 2JHP = 21 Hz, CH), 4.89 (1 H, dd, 3JHH = 11 Hz, 3JHP = 5 Hz, CH), 7.35 (2 H, m, aromatic), 7.61 (1 H, t, 3JHH = 8 Hz, aromatic), 7.69 (1 H, d, 3JHH = 8 Hz, aromatic), 12,62 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 40.7 (d, 2JCP = 1 Hz, CH), 43.6 (d, 1JCP = 131 Hz, CP), 52.2 and 52.3 (2 OCH3), 52.5 and 52.7 (2 d, 2JCP = 11 Hz, 2 POCH3), 101.9, 116.9, 117.2, 124.6, 125.0, 133.4, 153.0, 162.3, 162.9 (coumarin moiety), 169.5 (d, 2JCP = 5 Hz, C=O), 172.2 (d, 3JCP = 21 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.8. 3-[2-(Diethoxyphosphoryl)-1,2-dimethoxycarbonyl-ethyl]-4hydroxycoumarin (4b): Yield: 90%; White powder, m.p. 207–210 °C, IR (KBr)(nmax, cm-1): 3130 (OH), 1733, 1702 (C=O, ester). Anal. Calcd for C19H23O10P: C, 51.59; H, 5.24%. Found: C, 51.74; H, 5.38%. MS (m/z,%): 442 (M+, 1). 1H NMR (500 MHz, CDCl3): d 0.95 (6 H, m, 2 CH3), 3.32 and 3.49 (6 H, 2 s, 2 OCH3), 3.60 (4 H, m, 2 OCH2), 3.80 (1 H, dd, 3JHH = 11 Hz, 2JHP = 21 Hz, CH), 4.72 (1 H, dd, 3JHH = 11 Hz, 3JHP = 5 Hz, CH), 7.20 (2 H, m, aromatic), 7.44 (1 H, t, 3JHH = 8 Hz, aromatic), 7.77 (1 H, d, 3JHH = 8 Hz, aromatic), 12,60 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 16.19 and 16.27 (2 d, 3JCP = 2 Hz, 2 CH3), 40.7 (d, 2JCP = 1 Hz, CH), 43.7 (d, 1J 2 CP = 130 Hz, CP), 52.7 and 52.9 (2 OCH3), 62.5 and 62.7 (2 d, JCP = 6 Hz, 2 POCH2), 101.6, 116.6, 116.7, 124.1, 124.6, 132.9, 152.5, 162.2, 162.6 (coumarin moiety), 169.3 (d, 2JCP = 5 Hz, C=O), 172.4 (d, 3JCP = 21 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.6. 3-[2-(Dibutoxyphosphoryl)-1,2-dimethoxycarbonyl-ethyl]-4hydroxycoumarin (4c): Yield: 91%; White powder, m.p. 190–192 °C, IR (KBr)(nmax, cm-1): 3110 (OH), 1732, 1691 (C=O, ester). Anal. Calcd. for C23H31O10P: C, 55.42; H, 6.27%. Found: C, 55.54; H, 6.11%. MS (m/z,%): 498 (M+, 1). 1H NMR (500 MHz, CDCl3): d 0.95 (6 H, m, 2 CH3), 1.08 (4 H, m, 2 CH2), 1.32 (4 H, m, 2 CH2), 3.50 and 3.65 (6 H, 2 s, 2 OCH3), 3.77 (4 H, m, 2 OCH2), 3.97 (1 H, dd, 3JHH = 9 Hz, 2JHP = 19 Hz, CH), 4.88 (1 H, dd, 3JHH = 9 Hz, 3J 3 HP = 4 Hz, CH), 7.35 (2 H, m, aromatic), 7.61 (1 H, t, JHH = 8 Hz, aromatic), 7.95 (1 H, d, 3JHH = 8 Hz, aromatic), 12,63 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 14.1 and 14.2 (2 CH3), 18.8 and 18.9 (2 CH2), 32.5 and 32.6 (2 CH2), 40.6 (d, 2JCP = 1 Hz, CH), 44.3 (d, 1JCP = 131 Hz, CP), 53.1 and 53.3 (2 OCH3), 66.5

O O

+ (MeO)3P

H

H3CO2C

CO2CH3 5

O

O (MeO)3P H MeO2C

O _ 6

O

H2O, - ROH

4a

H CO2Me 7

Scheme 3  Suggested mechanism for formation of compound 4a.

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JOURNAL OF CHEMICAL RESEARCH 2009  321 and 66.6 (2 d, 2JCP = 7 Hz, 2 POCH2), 102.2, 117.0, 117.1, 124.5, 125.0, 133.3, 152.9, 162.6, 162.9 (coumarin moiety), 169.6 (d, 2JCP = 5 Hz, C=O), 172.4 (d, 3JCP = 21 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.8. 3-[2-(Dimethoxyphosphoryl)-1,2-diethoxycarbonyl-ethyl]-4hydroxycoumarin (4d): Yield: 90%; White powder, m.p. 182–184 °C, IR (KBr)(nmax, cm-1): 3110 (OH), 1725, 1684 (C=O, ester). Anal. Calcd for C19H23O10P: C, 51.59; H, 5.24. Found: C, 51.31; H, 5.43%. MS (m/z,%): 442 (M+, 1). 1H NMR (500 MHz, CDCl3): d 1.01 and 1.20 (6 H, 2 t 3JHH = 7 Hz, 2 CH3), 3.42 and 3.98 and 4.13 (5 H, 2 m, 2 OCH2 and CH), 4.85 (1 H, dd, 3JHH = 11 Hz, 3JHP = 4 Hz, CH), 7.35 (2 H, m, aromatic), 7.61 (1 H, t, 3JHH = 8 Hz, aromatic), 7.96 (1 H, d, 3JHH = 8 Hz, aromatic), 12,62 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 14.7 and 14.8 (2 CH3), 40.7 (CH), 43.8 (d, 1J 2 CP = 130 Hz, CP), 53.6 and 53.8 (2 d, JCP = 11 Hz, 2 POCH3), 61.8 and 61.9 (2 OCH2), 102.3, 116.9, 117.2, 124.6, 125.0, 133.3, 153.0, 162.5, 162.9 (coumarin moiety), 169.1 (d, 2JCP = 5 Hz, C=O), 171.7 (d, 3JCP = 21 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.9. 3-[2-(Diethoxyphosphoryl)-1,2-diethoxycarbonyl-ethyl]-4hydroxycoumarin (4e): Yield: 91%; White powder, m.p. 157–159 °C, IR (KBr)(nmax, cm-1): 3100 (OH), 1729, 1691 (C=O, ester). Anal. Calcd for C21H27O10P: C, 53.62; H, 5.79. Found: C, 53.84; H, 5.90%. MS (m/z,%): 470 (M+, 1). 1H NMR (500 MHz, CDCl3): d 0.95 (6 H, m, 2 CH3), 1.11 and 1.27 (6 H, 2 t 3JHH = 7 Hz, 2 CH3), 3.55–4.22 (9 H, m, 4 OCH2 and CH), 4.70 (1 H, dd, 3JHH = 10 Hz, 3JHP = 5 Hz, CH), 7.21 (2 H, m, aromatic), 7.44 (1 H, t, 3JHH = 8 Hz, aromatic), 7.71 (1 H, d, 3JHH = 8 Hz, aromatic), 12,63 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 14.7 and 14.8 (2 CH3), 16.1 and 16.3 (2 d, 3J = 1 Hz, 2 CH ), 40.7 (d, 2J = 1 Hz, CH), 43.6 (d, 1J = 130 Hz, CP 3 CP CP CP), 61.7 and 61.9 (2 OCH2), 62.5 and 62.7 (2 d, 2JCP = 7 Hz, 2 POCH2), 101.5, 116.6, 116.8, 124.0, 124.6, 132.9, 152.5, 162.1, 162.6 (coumarin moiety), 169.4 (d, 2JCP = 5 Hz, C=O), 172.1 (d, 3JCP = 20 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.7. 3-[2-(Dibutoxyphosphoryl)-1,2-dimethoxycarbonyl-ethyl]-4hydroxycoumarin (4f): Yield: 88%; White powder, m.p. 148–150 °C, IR (KBr)(nmax, cm-1): 3110 (OH), 1729, 1691 (C=O, ester). Anal. Calcd. for C19H23O10P: C, 57.03; H, 6.70%. Found: C, 56.79; H, 6.51%. MS (m/z,%): 526 (M+, 1). 1H NMR (500 MHz, CDCl3): d 0.53 (6 H, m, 2 CH3), 0.83 (3 H, t, 3JHH = 7 Hz, CH3), 0.92 (4 H, m, 2 CH2), 1.03 (3 H, t, 3JHH = 7 Hz, CH3), 1.17 (4 H, m, 2 CH2), 3.50–4.29 (9 H, m, 4 OCH2 and CH), 4.68 (1 H, dd, 3JHH = 10 Hz, 3J 3 HP = 5 Hz, CH), 7.35 (2 H, m, aromatic), 7.63 (1 H, t, JHH = 8 Hz, aromatic), 7.96 (1 H, d, 3JHH = 8 Hz, aromatic), 12,62 (1 H, broad s, OH). 13C NMR (125.8 MHz, CDCl3): d 14.1, 14.2 and 14.4 (4 CH3), 18.4 and 18.5 (2 CH2), 32.1 and 32.2 (2 CH2), 40.6 (d, 2JCP = 1 Hz, CH), 44.0 (d, 1JCP = 131 Hz, CP), 61.3 and 61.4 (2 OCH2), 66.0 and 66.2 (2 d, 2JCP = 7 Hz, 2 POCH2), 101.9, 116.6, 116.8, 124.1, 124.5, 132.8, 152.6, 162.1, 162.5 (coumarin moiety), 169.4 (d, 2JCP = 5 Hz, C=O), 172.8 (d, 3JCP = 21 Hz, C=O). 31P NMR (202.5 MHz, CDCl3): d 21.9.

Received 14 January 2009; accepted 10 March 2009 Paper 09/0390 doi: 10.3184/030823409X450435 Published online: 20 May 2009 References 1 R. O'Kennedy and R.D. Thornes, Coumarins: biology, applications and mode of action, John Wiley & Sons, Chichester, 1997. 2 M. Zabradnik, The production and application of fluorescent brightening agents; John Wiley & Sons: New York, 1992. 3 R.D. Murray, J. Mendez and S.A. Brown, The natural coumarins: occurrence, chemistry and biochemistry, John Wiley & Sons, New York, 1982. 4 G. Raj, R. Kumar and W.P. McKinney, Am. J. Med. Sci., 1994, 307, 128. 5 M.R. Hadler and R.S. Shadbolt, Nature, 1975, 253, 275. 6 A. Estevez-Braun and A.G. Gonzalez, Nat. Prod. Rep., 1997, 14, 465. 7 A. Clerici and O. Porta, Synthesis, 1993, 99. 8 T. Mizuno, I. Nishiguchi, T. Hirashima, A. Ogawa, N. Kambe and N. Sonoda, Synthesis, 1988, 257. 9 S. Milne, G.W.A. Yan, X. Posey, I.J. Nicklaus, M.C. Graham, L. Wang and W.G. Rice, J. Med. Chem., 1996, 39, 2047. 10 D.C. Dittmer, Q. Li and D.V. Avilov, J. Org. Chem., 2005, 70, 4682. 11 A.V. Kalinin and V. Snieckus, Tetrahedron Lett., 1998, 39, 4999. 12 A.V. Da Silva, A.J.M. Lopes, C.C. Lopes, R.S.C. Snieckus and V. Kalinin, Tetrahedron Lett., 1998, 39, 4995. 13 S.E. Church, A.C. Tummns, R.C. Beam and C.F. Heterocycl, J. Chem. Davis, 1997, 34, 1159. 14 C.R. Reddy, B. Srikanth, N.N. Rao and D.S. Shin, Tetrahedron, 2008, 64, 11666. 15 A.W. Johnson, W.C. Kaska, A.O. Starzewski and K.D.A. Dixon, Ylides and imines of phosphorus, John Wiley & Sons, 1993, pp. 386-387. 16 I. Yavari, M. Anary-Abbasinejad and Z. Hossaini, Org. Biomol. Chem., 2003, 3, 560. 17 M. Anary-abbasinejad and N. Ascarrian, J. Chem. Res., 2007, 11. 18 M. Anary-Abbasinejad, N. Rostami, A. Parhami and A. Hassanabadi, J. Chem. Res., 2007, 257. 19 M. Anary-Abbasinejad, A. Hassanabadi and H. Anaraki-Ardakani, J. Chem. Res., 2007, 455. 20 M. Anary-Abbasinejad and A. Hassanabadi, J. Chem. Res., 2007, 475. 21 M. Anary-Abbasinejad, H. Anaraki-Ardakani, A. Dehghan, A. Hassanabadi and M.R. Seyedmir, J. Chem. Res., 2007, 574. 22 M. Anary-Abbasinejad, A. Hassanabadi and M. Mazraeh-Seffid, J. Chem. Res., 2007, 708. 23 M. Anary-Abbasinejad, K. Charkhati and A. Hassanabadi, J. Chem. Res. (in press). 24 M. Karplus, J. Am. Chem. Soc. 1966, 85, 2870. 25 C.A.G. Haasnot, F.A.A.M. De Leeuww and C. Altona, Tetrahedron, 1980, 36, 2783. 26 E. Breitmaier and W. Voelter, Carbon-13 NMR spectroscopy 3rd edn, VCH, New York, 1990, p. 250.

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322  RESEARCH PAPER

May, 322–325

JOURNAL OF CHEMICAL RESEARCH 2009

Anticancer activities of bis(pyrazol-1-ylthiocarbonyl)disulfides against HeLa cells Frankline K. Ketera, Margo J. Nellb, Ilia A. Guzeic, Bernard Omondia and James Darkwaa* aDepartment

of Chemistry, University of Johannesburg, PO Box 524 Auckland Park 2006, South Africa

bDepartment

of Pharmacology, University of Pretoria, Pretoria 0002, South Africa

cDepartment

of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA

Oxidation of the pyrazol-1-yldithiocarbamate compounds {[3,5-R2C3HN2CS2]- (R = H, Me} and indazol-1lydithiocarbamate by iodine produces the sulfur–sulfur coupling compounds {R'C(S)S-S(S)CR'} (R' = pyrazolyl, 3,5-dimethylpyrazolyl, indazolyl). All compounds were spectroscopically characterised, and, in some cases, structurally characterised. The X-ray structures reveal that these compounds contain a disulfide bridging the pyrazolylthiocarbonyl units. Two of the three disulfide compounds showed very good anticancer activities against HeLa cells at micromolar concentrations, with the most active compound active being 9.6 times more selective in its activity towards tumour cells than normal cells.

Keywords: dithiocarbamates, pyrazolyl, indazolyl, disulfide, anticancer, HeLa cells Dithiocarbamates (dtcs) are of interest as therapeutic agents.1 For instance, the well known chelating agent diethyldithiocarbamate ([Et2NCS2]-), is a good anticancer agent,2 and the sulfur–sulfur dimer of [Et2NCS2], tetraethylthiuram disulfide (disulfram), has profound anticancer activity3 where extensive pharmacokinetics studies have proved that it has an excellent safety record as well.4 Several mechanisms of action of disulfram as anticancer agent have been proposed. These include DNA topoisomerase inhibition 5 angiogenesis reduction6 and proteasome pathways inhibition.7 These facts suggest induction of apoptosis, even though the actual mechanisms have not yet been fully established.8-10 These mechanistic studies suggest that the potency of disulfide compounds is associated with the interactions of the S-S moiety with sulfhydryl groups of enzymes.11,12 Two examples of disulfide closely related to disulfram, are diallyl disulfide13 and 1-methyl-1-propyl-2imidazolyl disulfide.14 The former is found in garlic and has been shown to effectively inhibit the growth of human breast cancer cells in vitro and in vivo by apoptosis through inducing caspase-3.13 The diallyl disulfide antitumor action shows no side effects. Experiments involving HeLa cells treated with 1-methyl-1-propyl-2-imidazolyl disulfide have shown thioredoxin reductase as a target for disulfide anticancer activity.14 Therefore, there is no doubt that the extensive work

on disulfram and related sulfur–sulfur containing compounds clearly point to some therapeutic properties associated with disulfide compounds. This current study reports the potential of pyrazolyl-based disulfide compounds as anticancer agents. Interestingly their dithiocarbamate precursors exhibit no anticancer activity. Iodine oxidation of the appropriate dithiocarbamate salts {pyrazol-1-yldithiocarbamate (1), 3,5-dimethylpyrazol-1yldithiocarbamate (2)15,16 or indazol-1-yldithiocarbamate (3)} produced one known (5)17 and two new (4 and 6) bis (dithiocarbonyl)disulfides as yellow powders in moderate yields (Scheme 1). Except for 6, compounds 4 and 5 were readily soluble in chlorinated solvents. NMR data are consistent with the formulations in Scheme 1 and the 13C{1H} NMR data showed typical C(C=S) peaks around 193 ppm compared to C(C=S) peaks of the starting dithiocarbamates which appeared between 218.6 and 222.2 ppm. IR spectra of compounds 4–6 showed bands assignable to the υ(C=S) and υ(C–S) vibrational modes in the region of 1334–1254 cm-1 and 869–901 cm-1, respectively. The structures of 4 and 5 were confirmed by single crystal X-ray crystallography, and have structures similar to the closely related bis [(3,5-dimethylpyrazol-1-yl)ethyl]disulfide reported by Mills et al.18 and bis[(3-hydroxymethyl-5-methylpyrazol-1-yl) thiocarbonyl]disulfide reported by El ldrissi et al.19 R

R R

N

N

R

(a)

NH

R = H, Me

N

R

N

S

N

C

(b)

R

(a) N

C

C

S

R N N R

R = H (4), Me (5)

S

(b)

N

S S

S

S-K+

R = H (1), Me (2)

N H

N

S C S-K+

3

N N

C

S

S

C

N

N

S

6

Scheme 1  Reagents and conditions: (a) KOH, CS2, THF, rt, 20 min, 71–79%; (b) I2, MeOH, rt, 15 min, 56–75%.

* Correspondent. E-mail: [email protected]

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JOURNAL OF CHEMICAL RESEARCH 2009  323 Table 1  Crystal data and structure refinement for 4 and 5 Parameter

4

5

Empirical formula Formula weight Temperature (K) Wavelength (Å) Crystal system Space group Unit cell dimensions a(Å) b(Å) c(Å) a b g Volume (Å3) Z Density (calculated) ( Mg/m3) Absorption coefficient (mm-1) F(000) Final R indices (R1) Reflections collected Completeness to theta Goodness of fit on F2 Largest diff. peak and hole (e Å-3)

C8H6N4S4 286.41 293(2) 0.71073 Triclinic P1- 5.43340(10) 31.3556(7) 7.2893(2) 90° 107.9860(10)° 90° 1181.17(5) 4 1.611 0.780 584 0.0416 20623 100.0% 1.116 0.664 and –0.617

C12H14N4S4 342.51 100(2) 0.71073 Monoclinic I2/a

Orange crystals suitable for single crystal X-ray analysis were obtained from slow evaporation of THF solutions of 4 and 5. The crystal data are presented in Table 1, while molecular structures and selected bond distances and angles are shown in Figs 1 and 2. All the bond distances and angles of 4 and 5 are normal. In 4 and 5, the two planar fragments – C( = S)- pyrazolyl ring are connected by a disulfide bridge. The C–S–S–C torsion angle is 83.67(6)° in 4 and is substantially larger at 101.70(7)° in 5. In both compounds the S–C–N–N chains are in the E configuration. Compounds 4 and 5 are structurally similar to other disulfide compounds, e.g. bis[(3, 5-dimethylpyrazol-1-yl)ethyl]disulfide {(S–S = 2.0396(6) Å, S–C = 1.8097(15)/1.8156(16) Å, C–S–S = 103.95(1)/

Fig. 1  A molecular drawing of 4 shown with 50% probability ellipsoids. The hydrogen atoms omitted for clarity. Selected bond distances [Å] and angles [o]: S(1)–C(4), 1.621(2); S(2)–C(4), 1.778(3); S(2)–S(3), 2.0194(10); N(1)–N(2), 1.370(3); N(2)–C(4), 1.386(3); C(4)–S(2)–S(3), 102.49(9); C(1)–N(1)–N(2); C(4)–N(2)– N(1), 104.1(2).

10.6094(16) 9.4667(14) 15.156(2) 90° 101.760(2)° 90° 1490.2(4) 4 1.527 0.632 712 0.0262 13011 98.5% 1.062 0.483 and –0.251

105.73(6)o},18 bis(2,4-imidazolidinedione-5-ethyl)disulfide {(S–S = 2.022(4) Å, S–S = 2.022(4) Å, S–C = 1.801(7)/1.817(7) Å, C–S–S = 103.1(3)/103.9(3)o}20 and didenzoyldisulfide {(S–S = 2.020(1) Å, S–C = 1.805(2)/1.823(2) Å, C–S–S = 100.2(1)/101.7(1)o}.21 Compounds 1–6 (Scheme 1) were screened for their antitumour activities against human cervix epithelial carcinoma (HeLa) cells and human lymphocytes (PBMCs). All data were acquired in triplicate and the final values recorded as averages. Table 2 lists the dose values that caused 50% inhibition of cell growth (IC50). In order to establish the activities of the disulfide compounds, it was important to investigate the activities of the primary dtcs (1, 2 and 3) from which the disulfides were prepared. These experiments helped in determining whether the observed activities of the disulfides are due to the involvement of the S-S moiety in compounds 4–6. Compounds 1–3 were found to be inactive against HeLa cells (Table 2). The disulfides 4 and 5 on the other hand showed moderate to very good antitumour activities against HeLa cells. Compound 4 had an IC50 value of 3.7 μM (Table 2) compared to cisplatin (1.1 μM), while that of 5 (17.8 μM) was ca 16 times less active than cisplatin. Compound 6 could not be tested due to its low solubility in DMSO. Compound 4 was further tested against PBMCs, allowing us to establish its antitumour specificity against cancerous HeLa. The IC50 values registered for resting and stimulated lymphocytes were 34.0 μM and 36.4 μM, respectively (Table 3), as compared to its activity of 3.7 μM against HeLa cells. TS =

Mean IC50 of the normal cells (stimulated + resting lymphocytes)

(1)

Mean IC50 of the cancer cells Table 2  Growth inhibition values of compounds 1-6 tested against HeLa cells Compound Fig. 2  A molecular drawing of 5 shown with 50% probability ellipsoids. The hydrogen atoms omitted for clarity. Selected bond distances [Å] and angles [o]: S(1)–C(6), 1.6294(11); S(2)– C(6), 1.7958(11); S(2)–S(2)#1, 2.0309(6); N(1)–N(2), 1.3884(12); N(2)–C(6), 1.3825(13); C(6)–S(2)–S(2)#1, 102.78(4); C(2)–N(1)– N(2); 105.28(9); C(6)–N(2)–N(1), 91.07(12).

IC50 (μM)

Compound

IC50 (mM)

1 >50 4 3.7 ± 0.2 2 >50 5 17.8 ± 4.2 3 >50 6 ND Cisplatin 1.1 ± 0.2 IC50 is the concentration of drug required to inhibit cell growth by 50%. ND, Not done.

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324  JOURNAL OF CHEMICAL RESEARCH 2009 Table 3  Tumour specificity of 4 Compound

HeLa IC50 (mM)

Lymph (resting) IC50 (mM)

Lymph (stimulated) IC50 (mM)

4 3.7 34.0 36.4 IC50 is the concentration of drug required to inhibit cell growth by 50%. Lymph, lymphocytes

These results were used to calculate the tumour specificity factor (TS) as shown in equation (1). The TS for 4 was found to be 9.6 (Table 3) indicating that that cancerous HeLa cells were approximately ten times more sensitive to the cytotoxic action of 4 compared to normal cells. Certainly this selectivity is superior to that of disulfram, which is reported to be 2.9 by Wickström and coworkers using the same cell-lines.3 Compound 4 is structurally similar to disulfram which has anticancer activity against many cell lines, such as melanoma CRL1585 (IC50 = 2.5 µM), prostate adenocarcinoma CRL1435 (IC50 = 2.5 µM),22 and cervical adenocarcinoma HeLa (~ 45 µM, p