American Journal of Organic Chemistry

p-ISSN: 2163-1271    e-ISSN: 2163-1301

2015;  5(2): 73-77

doi:10.5923/j.ajoc.20150502.02

A Convenient access to Functionalized 1,3,4-Thiadiazole, Thiazole, Thiophene, Thieno[2,3-d]pyrimidine, Pyrimidine, and Thiazolo[3,2-a]pyrimidine Derivatives

Ahmad M. Farag1, Nabila A. Kheder1, 2, Kamal M. Dawood1, 3

1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt

2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Khalid University, Abha, Saudi Arabia

3Department of Chemistry, Faculty of Science, Kuwait University, Safat, Kuwait

Correspondence to: Nabila A. Kheder, Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.

Email:

Copyright © 2015 Scientific & Academic Publishing. All Rights Reserved.

Abstract

Novel thiophene, pyrimidine, 1,3-thiazole, 1,3,4-thiadiazole,thieno[2,3-d]pyrimidine, and thiazolo[3,2-a]pyrimidine derivatives bearing pyridine moiety were synthesized starting from the readily accessible 3-oxo-N-(pyridin-2-yl)butanamide.

Keywords: Hydrazonoyl halides, Pyrimidine, 1,3,4-Thiadiazole, Thieno[2,3-d]pyrimidine, Thiazolo[3,2-a]pyrimidine

Cite this paper: Ahmad M. Farag, Nabila A. Kheder, Kamal M. Dawood, A Convenient access to Functionalized 1,3,4-Thiadiazole, Thiazole, Thiophene, Thieno[2,3-d]pyrimidine, Pyrimidine, and Thiazolo[3,2-a]pyrimidine Derivatives, American Journal of Organic Chemistry, Vol. 5 No. 2, 2015, pp. 73-77. doi: 10.5923/j.ajoc.20150502.02.

Article Outline

1. Introduction
2. Results and Discussion
3. Experimental
4. Conclusions

1. Introduction

The pyridine ring is present in numerous pharmacologically important compounds and natural products [1, 2]. These include the anti-inflammatory Piroxicam (A), anti-anginal Nifedipine (B), anti-hypertensive Pinacidil (C) and Picloram (D) which is highly active against broad leaved plants. In addition, pyridine derivatives show insecticidal activities [3]. Furthermore, 3-oxo-N-(pyrid-2-yl) butanamide (1) has been used as a key synthon in synthesis of biologically active heterocycles [4-7]. Encouraged by all these findings and in continuation of our previous work aimed at the synthesis of a variety of heterocyclic systems for biological and pharmacological evalution [8-27], we report herein a convenient route to several new pyridine-based heterocyclic compounds, via the readily accessible 3-oxo-N-(pyrid-2-yl) butanamide (1) [28] as a versatile building block for the title compounds which are expected to have interesting biological activity.
Figure 1. Example of pharmacologically important pyridines

2. Results and Discussion

The nucleophilic addition of the butanamide 1 to phenyl isothiocyanate in DMF, in the presence of potassium hydroxide, afforded the corresponding potassium salt 2. Heterocyclisation of the intermediate 2 with hydrazonoyl chloride 3 [29] furnished one isolable product. Which was identified as thiadiazole derivative 6 (Scheme 1). The 1H NMR spectrum of compound 6 showed signals at δ 2.20 due to CH3, two D2O-exchangeable signals at δ 10.23 and 11.74 due to two NH protons, in addition to aromatic multiplet at δ 7.00-8.24. Its mass spectrum revealed molecular ion peak at m/z 458. The formentioned results indicate that the reaction of the non-isolable intermediate 2 with the hydrazonoyl chloride 3 proceeded via loss of potassium chloride and aniline molecules, respectively.
Scheme 1. Synthesis of 1,3,4-thiadiazole derivative 6
Treatment of potassium salt 2 with 1-phenyl-2- bromoethanone (7) [30] gave 2-(3,4-diphenyl thiazol-2(3H)-ylidene) -3-oxo-N-(pyridin-2-yl)butanamide (10) in good yield (Scheme 2). The reaction proceeds via nucleophilic displacement of bromide to give S-alkylated intermediate 8, followed by nucleophilic addition of NH group to the carbonyl group of benzoyl moiety to give the respective intermediate 9. The latter intermediate was converted into the thiazole derivative 10 via loss of a water molecule (Scheme 2).
Scheme 2. Synthesis of thiazole derivative 10
2-Amino-3-functionally substituted thiophene derivatives are useful precursors in azo dye production in industry and as intermediates for the pharmaceutically important thieno[2,3-d]pyrimidines [31, 32]. It was worthwhile to investigate the reaction of the butanamide 1 with elemental sulfur and malononitrile, which led to the formation of 5-amino-4-cyano-3-methyl-N-(pyridin-2-yl)thiophene-2-carboxamide (14) (Scheme 3).
Scheme 3. Synthesis of thiophene 14 and thieno[2,3-d]pyrimidine 15
The structure of the latter was established from its elemental analysis and spectral data. For example, its IR spectrum revealed absorption bands at 1638, 2206, 3165-3346, 3439 cm-1 due to amide carbonyl, nitrile, amino and NH Functions, respectively. Its 1H NMR showed signals at δ 2.41 due to CH3 and D2O-exchangeable signals at δ 7.80, 9.85 due to NH2 and NH protons, respectively, in addition to an aromatic multiplet at δ 7.09-8.35. Its mass spectrum revealed a molecular ion peak at m/z 258. When compound 14 was refluxed with formamide, it afforded the thieno[2,3-d]pyrimidine 15 (Scheme 3).
Compound 14 reacts also with triethyl orthoformat under reflux to give the corresponding thiophene 16, in excellent yield (Scheme 4). Compound 16 reacts with hydrazine hydrate to afford the corresponding thieno[2,3-d]pyrimidine 18 (Scheme 4). The structures of the isolated products 14, 16, and 18 were established from their elemental analyses and spectral data (see experimental part).
Scheme 4. Synthesis of thieno[2,3-d]pyrimidine 18
4-(4-Chlorophenyl)-6-methyl-N-(pyridin-2-yl)-2-thioxo- 1,2,3,4-tetrahydro-pyrimidine-5-carboxamide (19) was prepared by the acid-catalysed condensation of a ternary mixture of the butanamide 1, thiourea and 4-chlorobenzaldehyde (Scheme 5). Both the elemental analysis and spectral data of 19 are consistent with the assigned structure [33, 34]. The 1H NMR spectrum of 19 showed signals at δ 2.09, 5.41, 7.02-8.27, 9.40, 10.01 and 10.2 due to methyl, pyrimidine-4H, aromatic multiplet and three D2O-exchangeable signals due to three NH protons, respectively. Heating compound 19 with chloroacetyl chloride in dry dioxane under reflux afforded 5-(4-chloro phenyl)-7-methyl-3-oxo-N-(pyridin-2-yl)-3,5-dihydro-2H- thiazolo-[3,2-a]pyrimidine-6-carboxamide (20) (Scheme 5). The 1H NMR spectrum of compound 20 showed signals at δ 2.13, 4.15, 6.12, 7.20-8.32 and D2O exchangeable at δ 11.15 due to methyl, CH2, pyrimidine-4H, aromatic multiplet and NH protons, respectively. Its IR spectrum displayed absorption bands at 1684, 1765 and 3377 cm-1 due two carbonyl and NH groups, respectively. The 1H NMR spectra of compound 20 is in favor of its structure. The chemical shift of the pyrimidine-4H proton in 19 appeared at δ 5.41 while the corresponding pyrimidine proton in 20 appeared at δ 6.12. The low-field shift of pyrimidine protons is in support of structure 20. Also, the chemical shifts of the methyl group in 19 and 20 appeared at almost the same δ value. If structure 21 was present, one would expect low-field shift of methyl group due to deshielding by the neighbouring carbonyl group.
Scheme 5. Synthesis of pyrimidine 19 and thiazolo[3,2-a]pyrimidine 20

3. Experimental

All melting points were measured on a Gallenkamp melting point apparatus. The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP 3300 and Shimadzu FT IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer. 1H spectra were run at 300 MHz and 13C spectra were run at 75.46 MHz in deuterated chloroform (CDCl3) or dimethyl sulphoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 e.V. Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. 3-Oxo-N-(pyrid-2-yl)butanamide (1)[28], hydrazonoyl chlorides 3[29], 1-phenyl-2-bromoethanone (7)[30], and pyrimidine derivative 19[33,34] were prepared according to the reported literature.
Rections of 3-oxo-N-(pyrid-2-yl)butanamide (1) with phenyl isothiocyanate, hydrazonoyl halide and α-heloketones.
General Procedure: To a stirred solution of potassium hydroxide (0.11 g, 2 mmol) in DMF (20 mL) was added the butanamide 1 (0.36 g, 2 mmol). After stirring for 30 min., phenyl isothiocyanate (0.27 g, 0.24 mL, 2 mmol) was added to the resulting mixture. Stirring was continued for 6 h, then the hydrazonoyl chloride 3 or 1-phenyl-2-bromoethanone (7) was added portionwise over a period of 30 min. After the addition was complete, the reaction mixture was stirred for additional 12 h, during which a solid product was precipitated. The solid product was filtered off, washed with water and dried. Recrystallization from the suitable solvent afforded the corresponding products 6 or 10, respectively.
5-(1,3-Dioxo-1-(pyridin-2-ylamino)butan-2-ylidene)-N,4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (6).
Yield (86%), mp 226-7℃ (EtOH); IR (KBr) νmax /cm-1: 3385 (NH), 3283 (NH), 1645 (C=O); 1H NMR (DMSO-d6) δ 2.20 (s, 3H, CH3), 7.00-8.24 (m, 14H, ArH), 10.23 (s, 1H, D2O-exchangeable, NH), 11.74 (s,1H, D2O-exchangeable, NH); MS (m/z, %): 458 (M+, 3.7). Anal. Calcd for C24H19N5O3S: C, 63.01; H, 4.19; N, 15.31. Found: C, 63.10; H, 4.25; N, 15.21%.
2-(3,4-Diphenylthiazol-2(3H)-ylidene)-3-oxo-N-(pyridin-2-yl)butanamide (10).
Yield (80%), mp 168-170 oC (EtOH); IR (KBr) νmax /cm-1: 3258 (NH), 1676 (C=O), 1618 (C=O); 1H NMR (CDCl3) δ 2.17 (s, 3H, CH3), 5.96 (s, 1H, CH), 7.01-7.81 (m, 14H, ArH), 10.7 (s, 1H, D2O- exchangeable, NH); MS (m/z, %): 415 (3.4), 414 (15.2), 413 (M+, 54.8), 336 (0.3), 78 (33.1), 77 (100.0). Anal. Calcd for C24H19N3O2S: C, 69.71; H, 4.63; N, 10.16. Found: C, 69.78; H, 4.72; N, 10.25%.
5-Amino-4-cyano-3-methyl-N-(pyridin-2-yl)thiophene-2-carboxamide (14).
To a solution of the butanamide 1 (3.56 g, 20 mmol) in EtOH (20 mL), elemental sulfur (0.64 g) was added malononitrile (1.32 g, 20 mmol) and a catalytic amount of triethylamine. The reaction mixture was heated at 60-65℃ for 30 min, then allowed to cool to room temperature. The precipitated solid was filtered off, washed with EtOH, dried and finally recrystallized from DMF/water to afford 14 in 90%, mp 270-1℃; IR (KBr) νmax /cm-1: 3439 (NH), 3165 and 3346 (NH2), 2206 (C≡N), 1638 (C=O); 1H NMR (CDCl3) δ 2.41 (s, 3H, CH3), 7.09-8.35 (m, 4H, ArH), 7.8 (br., 2H, D2O-exchangeable, NH2), 9.85 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 15.01, 88.53, 112.95, 114.19, 115.29, 119.36, 137.93, 141.34, 147.77, 151.88, 160.72, 165.70; MS (m/z, %): 260 (9.5), 259 (50.9), 258 (M+, 38.7), 121 (3.7), 93 (9.5), 78.(13.0). Anal. Calcd for C12H10N4OS: C, 55.80; H, 3.90; N, 21.69. Found: C, 55.91; H, 3.96; N, 21.78%.
4-Amino-5-methyl-N-(pyridin-2-yl)thieno[2,3-d]pyrimidine-6-carboxamide (15).
A mixture of 14 (0.52 g, 2 mmol) and freshly distilled formamide (8 mL) was heated under reflux for 7h., then left to cool. The formed solid product was filtered off, washed with water and dried. Recrystallization from DMF afford 15 in 77% yield; mp >300℃; IR (KBr) νmax /cm-1: 3442- 3167 (NH and NH2), 1692 (C=O); 1H NMR (DMSO-d6) δ 2.73 (s, 3H, CH3), 7.1-7.2 (m, 1H), 7.3 (br., 2H, D2O-exchangeable, NH2), 7.6-8.39 (m, 3H), 10.61 (s, 1H) 12.57 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 15.25, 114.49, 116.30, 119.99, 138.18, 139.12, 147.38, 147.93, 155.0, 155.54, 159.96, 164.16, 166.75. Anal. Calcd for C13H11N5OS: C, 54.72; H, 3.89; N, 24.55. Found: C, 54.79; H, 3.81; N, 24.48%.
Ethyl N-3-cyano-4-methyl-5-(pyridin-2-ylcarbamoyl) thiophen-2-ylformimidate (16).
A mixture of compound 14 (5.16 g, 20 mmol) and triethyl orthoformate (5 mL) was refluxed for 4h, then left to cool to room temperature. The precipitated product was filtered off, washed with EtOH and dried. Recrystallization from EtOH afforded 16 in 90% yield, mp 130-2℃ (EtOH); IR (KBr) νmax /cm-1: 3437 (NH), 2224 (C≡N), 1653 (C=O); MS (m/z, %): 318 (1.0 ), 317 (4.3), 316 (11.4), 315 (61.6), 314 (M+, 68.7), 299 (13.3), 288 (0.5), 193 (28.2), 121 (17.8), 93 (16.1), 78 (39.6). Anal. Calcd for C15H14N4O2S: C, 57.31; H, 4.49; N, 17.82. Found: C, 57.38; H, 4.41; N, 17.89%.
3-Amino-4-imino-5-methyl-N-(pyridin-2-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide (18).
To a solution of 16 (0.63g, 2 mmol) in EtOH (20 mL), hydrazine hydrate (80%, 0.2 mL) was added and the reaction mixture was refluxed for 4 h, then allowed to cool. The formed solid product so was filtered off, washed with EtOH and dried. Recrystallization from EtOH/DMF afforded 18 in 88% yield, mp 255-6℃; IR (KBr) νmax /cm-1: 3312 (NH), 3206-3250 (NH2 and 2NH), 1660 (C=O); 1H NMR (DMSO-d6) δ 2.8 (s, 3H, CH3), 5.6 (s, 2H, D2O- exchangeable, NH2), 7.6 (br.,1H, D2O-exchangeable, NH), 7.15-8.35 (m, 5H, ArH), 10.35 (s, 1H, D2O-exchangeable, NH); MS (m/z, %): 301 (0.8), 300 (M+, 59.12), 121 (1.7), 93 (3.1), 78 (4.4). Anal. Calcd for C13H12N6OS: C, 51.99; H, 4.03; N, 27.98. Found: C, 52.06; H, 4.18; N, 27.85%.
5-(4-Chlorophenyl)-7-methyl-3-oxo-N-(pyridin-2-yl)-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine- 6-carboxamide (20).
To a solution of pyrimidine derivative 19 (1.79 g, 5 mmol) in dioxane (20 mL) was added chloroacetyl chloride (0.57 g, 0.40 mL, 5 mmol) and the reaction mixture was heated under reflux, where the reactants went into solution and a yellow precipitate was formed. The obtained solid product was collected by filtration, washed with EtOH, dried and then crystallized from DMF/H2O to afford 20 in 70% yield, mp 217-8℃; IR (KBr) νmax /cm-1: 3377 (NH), 1765 (C=O), 1684 (C=O); 1H NMR (DMSO-d6) δ 2.13 (s, 3H, CH3), 4.15 (s, 2H, CH2), 6.12 (s, 1H, pyrimidine CH), 7.20-8.32 (m, 8H, ArH), 11.15 (s, 1H, D2O-exchangeable, NH). Anal. Calcd for C19H15N4O2SCl: C, 57.21; H, 3.79; N, 14.05. Found: C, 57.29; H, 3.70; N, 14.11%.

4. Conclusions

A new simple approach to novel thiophene, pyrimidine, 1,3-thiazole, 1,3,4-thiadiazole, thieno[2,3-d]pyrimidine, and thiazolo[3,2-a]pyrimidine derivatives bearing pyridine moiety have been achieved starting from the readily accessible 3-oxo-N-(pyridin-2-yl)butanamide (1).

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