DESIGN AND SYNTHESIS OF 1, 2, 4 – TRIAZOLE SUBSTITUTED THIOPHENESHTML Full Text
DESIGN AND SYNTHESIS OF 1, 2, 4 - TRIAZOLE SUBSTITUTED THIOPHENES
Nishu Singla*1, 2, Jitender Bariwal 3 and Satvinder Kaur 4
Department of Pharmaceutical Chemistry 1, ISF College of Pharmacy, Moga - 142001, Punjab, India.
I. K. G. Punjab Technical University 2, Jalandhar - 144603, Punjab, India.
Department of Pharmaceutical Chemistry 3, Shiva College of Pharmacy, Bilaspur - 174004, Himachal Pradesh, India.
Department of Pharmaceutical Chemistry 4, GHG Khalsa College of Pharmacy, Gurusar Sudhar - 141104, Punjab, India.
ABSTRACT: Highly substituted thiophene derivatives first synthesized by Gewald synthesis in 1965, are important heterocyclic compounds present in numerous biologically active compounds. The synthesis of title compounds was carried out by preparing derivatives of Gewald product. In the present study, a series of 2-aminothiophene derivatives were first prepared by Gewald reaction and further converted into 2-aminothiophene-1, 2, 4-triazole derivatives. Knoevenagel condensation of aryl ketones (1a-1d) with ethylcyanoacetate and subsequent treatment of the α-β-unsaturated nitriles (2) with sulfur and amine resulted in the corresponding 2-aminothiophenes (3a-3d), which were used as a starting material for the synthesis of substituted Gewald products. In the subsequent steps (3a-3d) were converted into carbohydrazides (4a-4d). Substituted carbohydrazides were then converted into potassium aryl carbonyl hydrazine carbodithionate (5a-5d) which were further converted into final compound 2-amino thiophene-1, 2, 4-triazole derivatives (6a-6d). The structures of all the synthesized compounds were confirmed by their spectral data (IR and 1H NMR spectroscopy).
2-aminothiophene, Gewald synthesis, 1, 2, 4-triazole, Heterocyclic, Aryl ketones, Derivatives
INTRODUCTION: Heterocyclic chemistry has currently become popular and emerged as distinct field of chemistry with extensive historical background and widespread future prospective. The most primitive compounds known to mankind are of heterocyclic origin and their considerable biological importance has stimulated much work on them 1 - 4.
Traditionally, small heterocyclic molecules have been a reliable source for discovering novel biologically active molecules. Our interest in the Sulfur and nitrogen heterocycles prompted us to take up the present study.
Of all the heterocyclic compounds, thiophene derivatives have attracted considerable attention. The highly substituted thiophene derivatives are found in numerous biologically active and natural compounds 5 - 9. Further, many biologically active molecules 10 like antibacterial 11, antifungal 12, antiamoebic 13, antioxidant 14, antitumor 15, anticoagulants and antithrombotics 16 contains this S-heterocyclic core which has broadened interest in this kind of heterocycle.
The multi-substituted 2-aminothiophenes are privileged structures in the designing of biologically active molecule, synthesized by the most popular approach known as Gewald reaction. Gewald reaction was initially reported in 1965 by Gewald. 2-aminothiophenes are polysubstituted containing electron withdrawing groups like cyano, ethoxycarbonyl or aminocarbonyl in the 3-position and alkyl, aryl or hetaryl groups in the 4- and 5-position and are prepared by utilizing Gewald reaction 17. Gewald reaction is the traditional route for synthesizing 2-aminothiophenes with diverse pharmaceutical, agrochemical and dye properties, involving one-pot cyclocondensation of ketones or aldehydes and β-substituted acetonitrile derivatives with elemental sulfur in the presence of a suitable base 18-20.
1, 2, 4-triazole is another important heterocyclic compound with respect to their wide range of biological activities. Over the past few decades, the biological and pharmaceutical applications of 1, 2, 4-triazoles have fashioned substantial interest in their synthesis and characterization. 1, 2, 4-triazoles and their derivatives possess differing activities which range from antiasthmatic 21, antiviral (ribavirin) 22, antifungal (ﬂuconazole) 23, antibacterial 24, hypnotics 25 (triazolam) to anti-cancer. In this regard, we come up with the hypothesis that incorporation of 1H-1, 2, 4-triazole into the multi-substituted 2-amino thiophene unit may enhance their biological activity. This type of diheterocyclic compounds encompassing the properties of both the rings in the one structure may enhance the interaction of these molecules with the biological targets and can be exploited for their use in pharmaceutical industry. To achieve this aim, various 4-aryl substituted 2-amino thiophene derivatives were prepared by well known Gewald method as shown in Scheme 1 and then linked with 1H-1, 2, 4 -triazole as shown in Scheme 2.
RESULT AND DISCUSSION: In the present study, several aryl ketones (1a-e) were reacted with ethylcyanoacetae in benzene under a constant water separator in the presence of glacial acetic acid and catalytic amount of ammonium acetate through knoevengel condensation 26, 27. The condensation products (2a-2e) were subsequently cyclized with sulfur and diethylamine in methanol to yield 2-amino-4-arylthiophene-3-carboxylate (3a-e) as shown in Scheme 1. 2-amino-4-arylthiophene-3-carboxylate was used as a precursor to synthesize many useful compounds as shown in Scheme 2.
SCHEME 1: SYNTHESIS OF SUBSTITUTED 2-AMINO-THIOPHENES BY GEWALD REACTION
After refluxing (3a-3e) with hydrazine hydrate in ethanol, hydrazides (4a-4e) were formed. 1H NMR spectrum of (4a-4e) showed the absence of the two signals of ester moiety along with other protons at their expected locations. (5a-5e) were achieved by reacting hydrazide with carbon disulfide in ethanolic Potassium hydroxide. Signal at δ 6.7ppm for NH2 and δ 8.1ppm for NH protons were observed in 1H NMR spectrum. Moreover, hydrazine cyclizes the compounds (5a-5e) to afford 2-amino thiophene linked with 1, 2, 4-triazole (6a-6e) as shown in Scheme 2. Signal at δ 2.0ppm characteristic of NH2 at 1, 2, 4-triazole moiety was observed in 1H NMR spectra. The structure of various triazole substituted thiophenes is shown in Table 1.
SCHEME 2: SYNTHESIS OF 2-AMINO THIOPHENE LINKED WITH 1, 2, 4-TRIAZOLE
TABLE 1: VARIOUS 1, 2, 4-TRIAZOLE SUBSTITUTED THIOPHENES
|Entry||Ketone||Triazole linked Thiophene||Isolated Yield|
Experimental: All the chemicals used in the synthesis were of laboratory grade. The melting points were determined in open capillary method on Veego (VMP-D) electronic apparatus and are uncorrected. The IR spectra of synthesized compounds were recorded on Shimadzu 8400-S FT-IR, as well as, Perkin Elmer BX2 FT-IR Spectrophotometer in potassium bromide discs. 1H NMR spectra were recorded on a Bruker AC 400 MHz FT-NMR spectrometer using TMS (Tetramethylsilane) as an internal standard and DMSO-d6 as a solvent at SAIF, Punjab University, Chandigarh. To monitor the reactions, as well as, to establish the identity and purity of reactants and products, thin layer chromatography was performed on pre-coated silica plates (Merck Silicagel F254) using hexane-ethyl acetate-glacial acetic acid as the solvent systems and the spots were visualized by exposure to iodine vapours or under Ultraviolet (UV) light at 254nm and 360nm.
Synthesis of Compounds (3a-3e):
Step-I: Acetophenone (0.1mol), ethyl cyanoacetate (0.1mol), glacial acetic acid (0.08mol), anhydrous ammonium acetate (0.02mol) and dry benzene (50mL) were refluxed in a round bottomed flask, fitted with a Dean-Stark condenser until the total water removed in the side arm was slightly excess than the calculated value. Benzene was distilled out thereafter and reaction mixture was dissolved in dichloromethane (50mL) and given washings of aq. NaHCO3 (20ml; 10% w/v solution), aq. NaCl (20mL; 10% w/v solution) and water (20mL). The organic layer was separated, dried (Na2SO4) and dichloromethane was distilled out. The solid product alkylidene ethyl cyanoacetate (2) obtained was used as such for the second step, without purification.
Step-II: The alkylidene ethyl cyanoacetate (2) was thereafter dissolved in methanol (50ml) and sulfur (0.08mole) was added, the reaction mixture was then stirred and maintained at 50-60 °C. Then, diethylamine (0.1mol) was added dropwise over 30 min at a temperature around 60 °C. The reaction mixture was stirred further at 50 °C for 6-8 hrs and cooled overnight. The crystalline product separated was filtered, washed with 50% aq. ethanol and dried. The product, (75% yield) melting at 95-97 °C, (97-99 °C) 5, was characterized as ethyl 2-amino-4-phenylthiophene-3-carboxylate.
Ethyl 2-amino-4-phenylthiophene-3-carboxylate (3a): Yield 80%; m.p 110-112 °C; 1H NMR (DMSO-d6) δ (ppm): 7.5 (m, 1H, CH); 6.9 (br, NH2, D2O Exchangable); 6.3 (s, 1H, CH); 4.29 (q, 2H, CH2); 1.29 (t, 3H, CH3); FT-IR (n cm-1): 3408 (γ NH2); 2988 (γ C-H); 1722 (γ COOEt)cm-1
Ethyl-2-amino-4-(4-chloro phenyl)thiophene-3-carboxylate (3b): Yield 78%; m.p 114-116° 1C; 1H NMR (DMSO-d6) δ (ppm): 7.7 (m, 1H, CH); 6.8 (br, NH2, D2O Exchangable); 6.1 (s, 1H, CH); 4.1 (q, 2H, CH2); 1.3 (t, 3H, CH3); FT-IR (n cm-1): 3408 (γ NH2); 2988 (γ C-H); 1722 (γ COOEt) cm-1
Ethyl 2- amino- 4- (p-tolyl) thiophene- 3-carboxylate (3c): Yield 79%; m.p 112-116º 1C; 1H NMR (DMSO-d6) δ (ppm): 7.2 (m, 1H, CH); 6.7 (br, NH2, D2O Exchangable); 6.2 (s, 1H, CH); 4.3 (q, 2H, CH2); 2.3 (s, 3H, CH3); 1.27 (t, 3H, CH3); FT-IR (n cm-1): 3408 (γ NH2); 2988 (γ C-H); 1722 (γ COOEt) cm-1
Ethyl-2-amino-4-(4-methoxyphenyl)thiophene-3-carboxylate (3d): Yield 75%; m.p 113-115º 1C; 1H NMR (DMSO-d6) δ (ppm): 7.5 (m, 1H, CH); 6.99 (br, NH2, D2O Exchangable); 6.0 (s, 1H, CH); 4.27 (q, 2H, CH2); 3.83 (s, 3H, CH3); 1.27 (t, 3H, CH3); FT-IR (n cm-1): 3408 (γ NH2); 2988 (γ C-H); 1722 (γ COOEt) cm-1
Synthesis of Compounds (4a-4e):
General Procedure: A suspension of dry compounds (3a-3e) (0.01mol), hydrazine hydrate (5mL) and absolute ethanol (30mL) was stirred under gentle reflux. The solid dissolved within 10 min with copious evolution of hydrogen sulphide to form a clear solution. After 30 min, the solid product started separating out; heating was continued for 8 hr. The reaction mixture was then allowed to cool to room temperature. The solid was filtered off, washed with ethanol, dried and crystallized from dioxane.
2-amino- 4- phenylthiophene- 3- carbohydrazide (4a): Yield 82%; mp 142 °C - 145 °C; 1H NMR (DMSO-d6) δ (ppm): 8.16 (s, 1H, NH, D2O exchangeable); 7.5 (m, 1H, CH); 6.9 (Br, s, 2H, NH2, D2O exchangable); 6.7 (s, 1H, CH); 2.0 (Br, s, 2H, NH2, D2O exchangeable); FT-IR (n cm-1): 3425 (γ NH2); 3355 (γ NH-NH); 1690 (γ CO).
2- amino- 4- (4-chlorophenyl) thiophene- 3-carboxyhydrazide (4b): Yield 75%; mp 140 °C -145 °C; 1H NMR (DMSO-d6) δ (ppm): 8.0 (s, 1H, 2NH); 7.7 (m, 1H, CH); 6.7 (Br, s, 2H, NH2, D2O exchangable); 6.6 (s, 1H, CH); 2.2 (Br, s, 2H, NH2, D2O exchangeable); FT-IR (n cm-1): 3455 (γ NH2); 3310 (γ NHNH); 1700 (γ CO).
2-amino-4-(p-tolyl)thiophene- 3- carbohydrazide (4c): Yield 70%; mp 145 °C – 147 °C; 1H NMR (DMSO-d6) δ (ppm): 8.2 (Br, t, H, NH, D2O exchangable); 7.6 (m, 1H, CH); 6.7 (Br, s, 2H, NH2, D2O exchangable); 6.5 (s, 1H, CH); 2.3 (s, 3H, CH3); 2.0 (Br, d, 2H, NH2, D2O exchangeable); FT-IR (n cm-1): 3400 (γ NH2); 3325 (γ NHNH); 1710 (γ CO).
2- amino- 4- (4-methoxyphenyl)thiophene- 3-carbohydrazide (4d): Yield 75%; mp 146-148 °C; 1H NMR (DMSO-d6) δ (ppm): 7.9 (Br, t, H, NH, D2O exchangable); 6.9 (Br, s, 2H, NH2, D2O exchangable); 6.4 (s, 1H, CH); 3.8 (s, 3H, CH3); 2.1 (Br, d, 2H, NH2, D2O exchangable); FT-IR (n cm-1): 3440 (γ NH2); 3324 (γ NHNH); 1705 (γ CO).
Synthesis of Compounds (5a-5e):
General Procedure: To a solution of 0.023 molcarbohydrazides (4a-4e) and 0.027 mol of potassium hydroxide, 20mL absolute ethanol and 0.034mol of carbon disulfide was added and stirred for 8-10 hours until the solution became orange colored. The obtained precipitates were filtered.
(2- (2- amino- 4- phenylthiophene- 3- carbonyl) hydrazine carbonyl) potassium (III) Sulphide (5a): Yield 70%; mp 256 °C – 258 °C; 1H NMR (DMSO-d6) δ (ppm): 8.1 (Br, d, 1H, 2NH, D2O exchangable); 7.5 (m, 1H, CH); 6.9 (Br, s, 2H, NH2, D2O exchangeable); 6.9 (s, 1H, CH); FT-IR (n cm-1):3445 (γNH2); 3360 (γ NHNH); 1700 (CO); 710 (γ C-S).
(2- (2- amino- 4- (4-chlorophenyl)thiophene-3-carbonyl)hydrazine carbonyl) potassium (III) Sulphide (5b): Yield 79%; mp 255 °C-257 °C; 1H NMR (DMSO-d6) δ (ppm): 8.0 (Br, d, 1H, 2NH, D2O exchangable); 7.5 (s, 1H, CH); 6.8 (Br, s, 2H, NH2, D2O exchangable); 6.1 (s, 1H, CH); FT-IR (n cm-1): 3415 (γ NH2); 3350 (γ NHNH); 1710 (γ CO); 690 (γ C-S).
(2- (2- amino- 4- (p-tolyl) thiophene- 3- carbonyl hydrazine carbonyl) potassium (III) sulphide (5c): Yield 60-62%; mp 265-267 °C; 1H NMR (DMSO-d6) δ (ppm): 7.9 (Br, d, H, 2NH, D2O exchangable); 7.4 (s, 1H, CH); 6.8 (Br, s, 2H, NH2, D2O exchangable); 6.1 (s, 1H, CH); 2.3 (s, 3H, CH3); FT-IR (n cm-1): 3465 (γ NH2); 3340 (γ NHNH); 1715 (γ CO); 715 (γ C-S).
(2- (2-amino- 4- (4- methoxyphenyl) thiophene-3-carbonyl) hydrazine carbonyl) potassium (III) Sulphide (5d): Yield 75%; mp 267 °C -269 °C; 1H NMR (DMSO-d6) δ (ppm): 7.8 (Br, d, 1H, 2NH, D2O exchangable); 7.6 (s, 1H, CH); 6.7 (Br, s, 2H, NH2, D2O exchangable); 6.2 (s, 1H, CH); 3.83 (s, 3H, CH3); FT-IR (n cm-1): 3415 (γ NH2); 3370 (γ NHNH); 1725 (γ CO); 730 (γ C-S).
Synthesis of Compounds (6a-6e):
General Procedure: To a solution of 0.012 mol of potassium hydrazine carbodithionate (3a-3d) in 3mL of water, 0.024 mol hydrazine hydrate was added and the mixture was gently heated on steam bath for 1 h. After cooling the solution was quenched with 10mL water and acidified with acetic acid. The obtained solid was filtered and re-crystallized with water.
4-amino-3-(2-amino-4-pheylthiophene-3-yl)- 1H-1,2,4-triazole-5-(4H)-thione (6a): Yield 76%; mp 177 °C - 180 °C; 1H NMR (DMSO-d6) δ(ppm): 7.5 (s, 1H, CH), 7.0 (Br, s, 1H, NH, D2O exchange), 6.9 (Br, s, 2H, NH2, D2O exchange), 6.8 (s, 1H, CH), 2.0 (Br, s, 2H, NH2); FT-IR (n cm-1): 3410 (γ NH2); 2940 (γ CH); 1250 (γ C=S).
4-amino- 3- (2-amino-4-chloropheylthiophene-3-yl)-1H-1,2,4-triazole-5-(4H)-thione (6a): Yield 70%; mp 190 °C -195 °C; 1H NMR (DMSO-d6) δ(ppm): 7.3 (s, 1H, CH), 7.1 (Br, s, 1H, NH, D2O exchange), 6.8 (Br, s, 2H, NH2, D2O exchange), 6.6 (s, 1H, CH), 2.1 (Br, s, 2H, NH2); FT-IR (n cm-1): 3390 (γ NH2); 2860 (γ CH); 1236 (γ C=S).
4-amino- 3- (2-amino- 4- p-tolyl)thiophene-3-yl)-1H-1,2,4-triazole-5-(4H)-thione (6a): Yield 80%; mp 180 °C-186 °C; 1H NMR δ (ppm): 7.5 (s, 1H, CH), 7.2 (Br, s, 1H, NH, D2O exchange), 6.7 (Br, s, 2H, NH2, D2O exchange), 6.4 (s, 1H, CH), 2.3 (s, 3H, CH3), 2.2 (Br, s, 2H, NH2); FT-IR (n cm-1): 3410 (γ NH2); 2895 (γ CH); 1290 (γ C=S).
4-amino-3- (2-amino- 4-methoxypheylthiophene-3-yl)-1H-1,2,4-triazole-5-(4H)-thione (6a): Yield 84%; mp 176 °C -178 °C; 1H NMR δ (ppm): 7.4 (s, 1H, CH), 7.1 (Br, s, 1H, NH, D2O exchange), 6.5 (Br, s, 2H, NH2, D2O exchange), 6.4 (s, 1H, CH), 3.8 (s, 3H, CH3), 2.1 (Br, s, 2H, NH2); FT-IR (n cm-1): 3370 (γ NH2); 2905 (γ CH); 1210 (γ C=S).
CONCLUSION: In summary, we have described a facile and practical method for the synthesis of 2-aminothiophene - 1, 2, 4-triazole analogues. The synthesized compounds are characterized by suitable analytical techniques such as IR, 1H NMR. Hence, these compounds are suitable candidates for further exploration.
ACKNOWLEDGEMENT: Authors are thankful to Shri Praveen Garg (Chairman), I.S.F. College of Pharmacy, Moga 142001, India for providing necessary facilities during the conduct of study.
CONFLICT OF INTEREST: Authors do not have any conflict of interest.
- Gupta RR, Kumar M and Gupta V: Heterocyclic Chemistry. Five-Membered Heterocycles. Springer Science and Business Media 2013; 2.
- Katritzky, Alan R and Jeanne ML: The principles of heterocyclic chemistry. Elsevier 2013.
- Foye WO: Principles of Medicinal Chemistry. Lea and amp Febiger London, 3rd ed, 1989.
- Fitton AO and Smalley RK: Practical heterocyclic chemistry. Elsevier 2013.
- Ma S, Zhang H, Zhao N, Cheng Y, Wang M, Shen Y and Tu G: Spiro-thiophene derivatives as hole-transport materials for perovskite solar cells.Journal of Materials Chemistry A 2015; 3: 12139-12144.
- Huynh TP, Pietrzyk-Le A, KC CB, Noworyta KR, Sobczak JW, Sharma PS and Kutner W: Electrochemically synthesized molecularly imprinted polymer of thiophene derivatives for flow-injection analysis determination of adenosine-5′-triphosphate (ATP).Biosensors and Bioelectronics 2013; 41: 634-641.
- Dumur F, Thirion D, Fagour S, Vacher A, Sallenave X, Morlet-Savary F, Graff B, Fouassier JP, Gigmes D and Lalevee J: Multicolorphotoinitiators for radical and cationic polymerization: monofunctional vs polyfunctional thiophene derivatives.Macromolecules 2013; 46: 6786-6793.
- Wang X, Wang K and Wang M: Synthesis of conjugated polymers via an exclusive direct-arylation coupling reaction: a facile and straightforward way to synthesize thiophene-flanked benzothiadiazole derivatives and their copolymers.Polymer Chemistry 2015; 6: 1846-1855.
- Tkach V and Yagodynets P: The mathematical description for the electropolymerization of furan, pyrrole and thiophene derivatives in alkaline media.Mediterranean Journal of Chemistry 2015; 3: 1122-1128.
- Koike K, Jia Z, Nikaido T, Liu Y, Zhao Y and Guo D: Echinothiophene, a novel benzothiophene glycoside from the roots of Echinops grijissii. Organic Letters 1999; 1: 197-8.
- Foroumadi A, Mansouri S, Kiani Z and Rahmani A: Synthesis and in vitro antibacterial evaluation of N-[5-(5-nitro-2-thienyl)-1, 3, 4-thiadiazole-2-yl] piperazinyl quinolones. European journal of medicinal chemistry 2003; 38: 851-4.
- Al‐Omran F, El‐Khair AA and Mohareb RM: Synthesis and biological effects of new derivatives of benzotriazole as antimicrobial and antifungal agents. Journal of heterocyclic chemistry 2002; 39: 877-83.
- Bharti, N: Synthesis, characterization and in vitro anti-amoebic activity of new palladium (II) complexes with 5-nitrothiophene-2-carboxaldehyde N (4)-substituted thiosemicarbazones. Bioorganic and medicinal chemistry 2004; 12: 4679-4684.
- Meotti FC, Silva DO, dos Santos AR, Zeni G, Rocha JB and Nogueira CW: Thiophenes and furans derivatives: a new class of potential pharmacological agents. Environmental toxicology and pharmacology 2003; 15: 37-44.
- Gobbi S, Rampa A, Bisi A, Belluti F, Piazzi L, Valenti P, Caputo A, Zampiron A and Carrara M: Synthesis and Biological Evaluation of 3-Alkoxy Analogues of Flavone-8-acetic Acid §. Journal of medicinal chemistry 2003; 46: 3662-9.
- Lee K, Park CW, Jung WH, Park HD, Lee SH, Chung KH, Park SK, Kwon OH, Kang M, Park DH and Lee SK: Efficacious and orally bioavailable thrombin inhibitors based on a 2, 5-thienylamidine at the P1 position: discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl [(5-amidino-2-thienyl) methyl] amide. Journal of medicinal chemistry 2003; 46: 3612-22.
- Forero SB, Jones J and da Silva FM: The Synthetic Potential and Chemical Aspects of the Gewald Reaction: Application in the Preparation of 2-Aminothiophenes and Related Heterocycles.Current Organic Synthesis 2013; 10: 347-365.
- Ma L, Yuan L, Xu C, Li G, Tao M and Zhang W: An efficient synthesis of 2-aminothiophenes via the Gewald reaction catalyzed by an N-methylpiperazine-function-alized polyacrylonitrile fiber.Synthesis 2013; 45: 45-52.
- Han Y, Tang WQ and Yan CG: Gewald-type reaction of double activated 2, 3-diarylcyclopropanes with elemental sulfur for synthesis of polysubstituted 2-aminothio-phenes.Tetrahedron Letters 2014; 55: 1441-1443.
- Shearouse WC, Shumba MZ and Mack J: A Solvent-Free, One-Step, One-Pot Gewald Reaction for Alkyl-aryl Ketones via Mechano chemistry.Applied Sciences 2014; 4: 171-179.
- Maddila S, Pagadala R and Jonnalagadda, BS: 1, 2, 4-Triazoles: A review of synthetic approaches and the biological activity.Letters in Organic Chemistry 2013; 10: 693-714.
- De Clercq E: Antiviral drugs in current clinical use. Journal of Clinical Virology 2004; 30: 115-33.
- Chen C, Dagnino R, Huang CQ, McCarthy JR and Grigoriadis DE: 1-Alkyl-3-amino-5-aryl-1H-[1, 2, 4] triazoles: novel synthesis via cyclization of N-Acyl-S-methylisothioureas with alkylhydrazines and their potent corticotropin-Releasing factor-1 (CRF 1) receptor antagonist activities. Bioorganic and medicinal chemistry letters 2001; 11: 3165-8.
- Wadsworth HJ, Jenkins SM, Orlek BS, Cassidy F, Clark MS, Brown F, Riley GJ, Graves D, Hawkins J and Naylor CB: Synthesis and muscarinic activities of quinuclidin-3-yltriazole and-tetrazole derivatives. Journal of medicinal chemistry 1992; 35: 1280-90.
- Jenkins SM, Wadsworth HJ, Bromidge S, Orlek BS, Wyman PA, Riley GJ and Hawkins J: Substituent variation in azabicyclic triazole-and tetrazole-based muscarinic receptor ligands. Journal of medicinal chemistry 1992; 35: 2392-406.
- Voskressensky LG, Festa AA and Varlamov AV: Domino reactions based on Knoevenagel condensation in the synthesis of heterocyclic compounds. Recent advances.Tetrahedron 2014; 70: 551-572.
- Kaki VR, Akkinepalli RR, Deb PK and Pichika MR: Basic ionic liquid [bmIm] OH–mediated Gewald reaction as green protocol for the synthesis of 2-aminothio phenes.Synthetic Communications 2015; 45: 119-126.
How to cite this article:
Singla N, Bariwal J and Kaur S: Design and synthesis of 1, 2, 4 - triazole substituted thiophenes. Int J Pharm Sci Res 2018; 9(1): 158-64. doi: 10.13040/IJPSR.0975-8232.9(1).158-64.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
N. Singla*, J. Bariwal and S. Kaur
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
28 April, 2017
14 June, 2017
07 July, 2017
01 January, 2018