Phase Transfer Catalysis Assisted Thorpe Reaction for the Synthesis of 3-Aminothiophene-2-carboxylates

ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry 2011, 8(1), 368-372 http://www.e-journals.net Phase Transfer Catalysis Assisted Thorpe Reaction for the Synthesis of 3-Aminothiophene-2-carboxylates R D SHAH Chemistry Department, M. G. Science Institute Navrangpura, Ahmedabad – 380009, Gujarat, India Received 30 March 2010; Accepted 24 May 2010 Abstract : Thorpe cyclization constructing synthetically important methyl or ethyl 3-amino-4-arylthiophene-2-carboxylates has been studied using eco friendly phase transfer catalysis technique. 3-Amino-4-arylthiophene-2carboxylates have been synthesized from 3-hydroxy-2-arylacrylonitriles and thioglycolates under different solid-liquid phase-transfer conditions. Keywords: Thorpe reaction, 3-Aminothiophenes-2-carboxylates, Thioglycolate, 3-Hydroxy-2arylacrylonitriles, Phase-transfer catalyst. Introduction In the chemistry of five member amino heterocycles the intermolecular Thorpe1-3 reaction and its intramolecular version Thorpe-Zeigler4-6 reactions are one of the most promising lines. They are base catalyzed and sodium or potassium alkoxide7,8, sodium hydride9, potassium hydroxide10, lithium hydroxide11 and potassium carbonate1,2 were employed frequently. Radical alternatives12, solvent free13 strategies as well as iridium hydride complexes14 also have been applied to intramolecular as well as intermolecular Thorpe reaction. Yet, a little to our surprise, no much attention was given to employ comprehensive strategies for Thorpe reaction involving different PT conditions. Thorpe cyclization is well known for the formation of synthetically important five membered heterocycles such as furan, thiophene, pyrrazole and many more having adjacent amino and carbethoxy or nitrile functionalities1,7,15-17. It is very well understood that such functionalities are constructive moieties when treated with varieties of condensing agents resulting into various fused heterocycles of almost all kinds of promising biological interests7,17-19. Strategy to incorporate Thorpe reaction with eco friendly15,20 phase-transfer catalysis (PTC) technique is always been of great interest to study. Our earlier work presented Thorpe cyclization for 3-aminopyrazole-2-carboxylates15. Herein, we report synthesis of important building blocks such as 4-substituted methyl or ethyl 3-amino-4arylthiophene-2-carboxylates involving Thorpe reaction from 3-hydroxy-2-aryl acrylonitriles19 and thioglycolates under different solid-liquid PTC. Phase Transfer Catalysis Assisted Thorpe Reaction 369 Conventional method for the synthesis of methyl or ethyl 3-amino-4-arylthiophenes-2carboxylates involved the treatment of 3-hydroxy-2-arylacrylonitriles and methyl or ethyl thioglycolate with hydrochloric acid followed by sodium methoxide or ethoxide under heating condition where reaction time was 30 min and yield16,19 was 35-60%. To set improved protocol the same reaction was assisted by PTC, where compounds methyl or ethyl 3-amino-4-arylthiophenes-2-carboxylates were synthesized from 3-hydroxy-2arylacrylonitriles, thioglycolates and HCl using different solid-liquid phase-transfer conditions. All reactions were carried out at RT, potassium hydroxide along with 18-crown6 was choice of catalyst, where as acetonitrile was used as solvent (Scheme 1). R CN H 1. HSCH2COOR1,HCl 2.KOH, AcCN,18-C-6, 60-70 0C OH R CN H S R NH 2 COOR1 S COOR 1 1a-f 3a-f Scheme 1 To optimize PT condition the same reaction was carried out using different PT catalysts in solid-liquid and liquid-liquid PTC (Table 1). Table 1. Comparison of PTC assisted synthesis of 3-amino-4-arylthiophene-2-carboxylates (3a-f) Entry R R1 3a* 3b 3c 3d 3e 3f C6H5 4-OCH3CH4 benzo[b]furyl-2 Thienyl-2 dimethyl-2,5-thienyl C6H5 COOCH3 COOCH3 COOCH3 COOCH3 COOCH3 COOC2H5 Liquid-liquid PTC a TBHSO4 Yield % 58 56 55 60 59 51 Solid-liquid PTC c 18-Crown-6 Yield % M.P, 0 C 80 75 73 80 77 70 69 111 115 90 137 73 *PTC = Phase-transfer catalyst, a = CH2Cl2 / KOH (aq. 50 % w/v), TBHSO4= Tetrabutylammoniumhydrogensulfate; c = 18-crown-6, KOH (solid), CH3CN Scheme 2 shows probable mechanism for Thorpe cyclization for the synthesis of 3-amino-4arylthiophene-2-carboxylates 3, in which 3-hydroxy-2-arylacrylonitriles 1 were believed to undergo reaction with thioglycolates 2 in presence of HCl resulting in situ generation of uncyclized thioglycolates, followed by addition of active methylene to nitrile forming compound 3. R C R CN C OH H C HCl, HSCH 2COOR 1 R CN S H C N Base H C C Base C COOR 1 H S COOR 1 1 R NH 2 S 3 COOR 1 Scheme 2 R NH H S COOR 1 370 R D SHAH The IR spectra of 3 showed bands at 3500-3140 cm-1 for amino and 1680-1670 cm-1 for C=O of ester functionality. Table 2 shows physical constants and 1H NMR spectral data. Table 2. Physical constants of 3-amino-4-arylthiophene-2-carboxylates (3a-f) Entry Mol. Formula (MW) %C 3a* C12H11NO2S (233.39) Calcd (Found) 61.80 (61.35) 3b** C13H13NO2S (263.31) 59.31 (59.59) 3c* C14H11NO3S (273.31) 61.56 (61.94) 3d* C10H9NO2S2 (239.32) C12H13NO2S2 (267.37) 50.21 (49.81) 53.93 (53.66) C13H13NO2S (247.07) 63.13 (63.01) 3e* 3f* %H %N 1 H NMR (δ ppm) Calcd Calcd (Found) (Found) 4.75 6.01 (s, 5H, 7.0) Ar-H; (s, 1H, 6.75); (4.59) (5.86) Ar-H at C4, (m, 2H, 5.3) NH2; (s, 3H, 3.6) CH3 4.98 5.32 (d, 2H, 7.3) Ar-H; (d, 2H, 6.9) (4.81) (5.19) Ar-H; (s, 1H, 7.05) Ar-H at C4; (m, 2H, 5.5) NH2; (s, 3H, 3.95) OCH3; (s, 3H, 3.8) CH3 4.06 5.13 (m, 5H, 7.1-7.6) Ar-H; (s, 1H, (3.91) (4.85) 6.7) Ar-H at C4;(m, 2H, 6.1) NH2, (s, 3H, 3.75) CH3 3.79 5.86 (m, 4H, 6.9-7.3) Ar-H; (m, 2H, (3.67) (5.69) 5.7) NH2; (s, 3H, 3.75) CH3 4.90 5.24 (s, 1H, 6.95) Ar-H at C4, (s, 1H, (4.85) (5.11) 6.5) Ar-H; (m, 2H, 5.5) NH2; (s, 3H, 3.75), CH3 of ester; (s, 3H, 2.45) CH3 at C2’; (s, 3H, 2.35) CH3 at C5’ 5.30 5.66 (s, 5H, 7.1) Ar-H; (s, 1H,6.8) Ar(5.34) (5.53) H at C4; (m, 2H, 5.3) NH2; (q, 2H, 4.3) CH2; (s, 3H, 3.6) CH3; (t, 3H, 1.29) CH3 of ester Solvent used for crystallization *ethanol and **benzene:ether mixture (5:5) Experimental Melting points were determined by electro thermal method in open capillary tube and are uncorrected. The IR spectra were recorded (in cm-1 for KBr pellets) on Buck-500 spectrophotometer. The 1H NMR spectra were recorded on Bruker 300 MHz spectrophotometer in CDCl3 using TMS as internal standard and the chemical shifts are expressed in δ ppm. MS spectra were recorded on JEOL/ SX-102 mass spectrophotometer under electron-impact (EI) ionization. Elemental analyses were performed on a Carlo Erba 1108 microanalyzer or Elementar’s Vario EL III microanalyzer. The purity of the compounds was routinely checked by TLC using silica gel G and spots were exposed in iodine vapour. General method for Synthesis of methyl or ethyl 3-amino-4-arylthiophene-2carboxylates (3a-f) Method 1 Solid-liquid PTC: A well stirred solution of toluene or MeCN (20 mL), powdered KOH (840 mg, 15 mmol) and 18-crown-6 (0.132 g, 0.5 mmol) was added with (...truncated)