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Article

Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety

by
Nadia Abdelhamed Abdelriheem
1,
Sayed Abdel-Kader Ahmad
2 and
Abdou Osman Abdelhamid
1,*
1
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
2
Department of Chemistry, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2015, 20(1), 822-838; https://doi.org/10.3390/molecules20010822
Submission received: 6 December 2014 / Accepted: 29 December 2014 / Published: 7 January 2015
(This article belongs to the Section Organic Chemistry)
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Abstract

:
2-Sulfanyl-6-(2-thienyl)pyridine-3-carbonitrile, 1-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile, thieno[2,3-b]pyridins, pyrimidino[4',5':4,5]thieno[2,3-b]pyridine, quinazoline and carbamate derivatives were synthesized from sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate with. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthesis whenever possible and chemical transportation.

Graphical Abstract

1. Introduction

The thieno[2,3-b]pyridine derivatives occupy special place and have attracted considerable attention because of their broad pharmacological activities, including anticancer [1,2,3,4,5,6,7,8,9], antiviral [10,11,12,13], anti-inflammatory [14,15,16,17], antimicrobial [18,19], antidiabetic [20,21,22,23], antihypertensive [24,25,26] and osteogenic [27,28] activities, in addition to treatment of CNS disorders [29,30,31]. Also, pyridine derivatives of different heterocyclic nucleus have shown potent pharmacological properties like antifungal [32,33], antitubercular [34], antibacterial [35], antimicrobial [36], insecticida [37]. In view of these findings and in continuation to our previous work [38,39,40,41,42,43], we report here the convenient synthesis of some new thieno[2,3-b]pyridines, pyrimidino[4',5':4,5]thieno[2,3-b]pyridines and pyridines incorporating 5-bromobenzofuran-2-yl moiety.

2. Results and Discussion

Treatment of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) [44] with each of cyanothioacetamide or 2-cyanoacetohydrazide in piperidinium acetate under refluxed to give 6-(5-bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) and 1-amino-6-(5-bromobenzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (3), respectively in a good yield (Scheme 1). Structure 2 was elucidated by elemental analysis, spectra, and chemical transformation. 6-(5-bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) was reacted with chloroacetone in N,N-dimethylformamide containing potassium hydroxide to afford the product corresponding to addition and dehydrochlorination reactions. The IR spectrum of this product showed bands at 2218 and 1700 cm−1 corresponding to CN and CO groups. Its 1H-NMR spectrum revealed the signals at δ 2.39 (s, 3H, CH3), 4.38 (s, 2H, SCH2) and 7.23–7.97 (m, 6H, ArH’s). Based on these data, these reaction products could be formulated as 2-(2-oxopropylthio)-6-(5-bromobenzofuran-2-yl)pyridine-3-carbonitrile (5a). Further confirmation of the structure of 5a arose from their cyclization in boiling ethanol containing a catalytic amount of piperidine to give the corresponding 1-(3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethanone (6a) (Scheme 1). The IR spectrum of 6a showed no band of the CN function but the bands at 3274, 3174 (NH2 group). 1H-NMR spectrum of 6a revealed an absence of signals of the -SCH2- group and the presence of the NH2 protons. These findings proved that the CN and the -SCH2- groups were both involved in the cyclization step leading to 6a.
Also, 2 was reacted with each ω-bromoacetophenone and idomethane in N,N-dimethylformamide containing potassium hydroxide to afford 6-(5-bromo-benzofuran-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-nicotinonitrile (5b) and 6-(5-bromobenzofuran-2-yl)-2-(methylthio)nicotinonitrile. Compound 5b was converted to (3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (6b) by its boiling in ethanolic piperidine solution. 1H-NMR of 6b showed signals at δ 4.05 (s, 2H, NH2), and 7.14–7.78 (m, 11H, ArH’s) (Scheme 1).
In contrast, compound 2 was reacted with each of chloroacetonitrile and ethyl chloroacetate afforded 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carbonitrile (6c) and ethyl 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d), in a good yield. Structure of 6c was confirmed by elemental analysis, spectral data and chemical transportation. Thus, compound 6c was reacted with each of formic acid or formamide to give the corresponding 7-(2-thienyl)-3-hydropyrimidino[4',5':4,5]thieno[2,3-b]pyridine-4-one (7) and 7-(2-thienyl)pyrimidine[4',5':4,5]thieno[2,3-b]pyridine-4-ylamine (8), respectively (Scheme 1). Structures 7 and 8 were established on the basis of spectral data and elemental analysis. Thus, IR spectrum of 7 revealed a band at 1666 (CO). IR spectrum of 8 revealed bands at 3320, 3151 (NH2). Meanwhile, 6c reacted with triethyl ortho-formate to give ethyl N-[6-(5-bromo-benzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9). The latter compound was reacted with ammonia or formamide gave a product identical in all aspects (mp., mixed mp., and spectra) with compound 8.
Molecules 20 00822 g001 550
Scheme 1. Synthesis of pyridenes 2, 3, thieno[2,3-b]pyridenes 6a–d and pyrimidine[4',5':4,5]thieno[2,3-b]pyridines 7 and 8.
Scheme 1. Synthesis of pyridenes 2, 3, thieno[2,3-b]pyridenes 6a–d and pyrimidine[4',5':4,5]thieno[2,3-b]pyridines 7 and 8.
Molecules 20 00822 g001
Treatment of 2 with 2,4-pentanedione, ethyl 3-oxobutanoate, ethyl cyanoactate, malononitrile or benzoylacetonitrile in boiling acetic acid and ammonium acetate under refluxed gave 1-(6-(5-bromobenzofuran-2-yl)-2-methylpyridin-3-yl)ethanone (10) and ethyl 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carboxylate (11), ethyl 2-amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carboxylate (12), 2-amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carbonitrile (13) and 2-amino-6-(5-bromobenzofuran-2-yl)-3-benzoylpyridine (14), respectively (Scheme 2).
Molecules 20 00822 g002 550
Scheme 2. Synthesis of pyridines 10–14.
Scheme 2. Synthesis of pyridines 10–14.
Molecules 20 00822 g002
Next, Compounds 11 was reacted with hydrazine hydrate afforded 2-methyl-6-(2-oxo-2H-chromen-3-yl)pyridine-3-carbohydrazide (15). The structure of 15 was elucidated by elemental analyses, spectra and chemical transformations. Thus, compounds 15 was reacted with each of ethyl acetoacetate, acetylacetone and nitrous acid, gave 2-[6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridine-3-carbonyl]-5-methyl-2,4-dihydropyrazol-3-one (16a), [6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-(3,5-dimethyl-pyrazol-1-yl)-methanone (16b) and 6-(5-bromobenzofuran-2-yl)-2-methylnicotinoyl azide (20), respectively (Scheme 3).
Molecules 20 00822 g003 550
Scheme 3. Synthesis of pyridines 15–18, 20–22, quinazoline 22 and carbamates 23.
Scheme 3. Synthesis of pyridines 15–18, 20–22, quinazoline 22 and carbamates 23.
Molecules 20 00822 g003
Structures 16a, 16b and 20 were confirmed by elemental analyses, spectral data and chemical transformations. Thus, treatment of 16a and 16b with benzenediazonium chloride in ethanolic sodium acetate gave 17 and 18, respectively. Structures 17 and 18 were confirmed by elemental analyses, spectral data and alternative synthetic route (reaction of the appropriate ethyl 3-oxo-2-(2-phenylhydrazono)butanoate (19a) [45] or 3-(2-phenylhydrazono)pentane-2,4-dione (19b) [46] with 15 in boiling acetic acid under refluxed gave identical product in aspects (mp., mixed mp. and spectra) with corresponding compounds 17 and 18). structure 20 was established by elemental analyses, spectral and chemical transformation. Thus, treatment of 20 with each of the appropriate aromatic amine (aniline, p-toluidine, p-anisidine, 3-amino-5-phenylpyrazole or anthranilic acid (or methyl anthranilate) in boiling dioxane and phenol in boiling benzene gave 1-[6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-3-substituted urea 21a–d, 3-[6-(5-bromo-benzofuran-2-yl)-2-methylpyridin-3-yl]-1H-quinazoline-2,4-dione (22) and phenyl [6-(5-bromo-benzofuran-2-yl)-2-methyl-pyridin-3-yl]-carbamoate (23) (Scheme 3). Structures 21–23 were elucidated by elemental analyses and spectral data.

3. Experimental Section

All melting points were determined on an Electrothermal melting point apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer (Kyoto, Japan). 1H-NMR and 13C-NMR spectra were recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini 300 MHz (Varian Inc., Palo Alto, CA, USA) and JNM-LA 400 FT-NMR system spectrometer (Japan Electronic Optics Laboratory Co. Ltd., Tokyo, Japan) and chemical shifts are expressed in δ units using TMS as internal reference. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (70 eV, Shimadzu, Kyoto, Japan). Elemental analyses were carried out at Micro analytical Center of the University of Cairo, Giza, Egypt.

3.1. General Procedure for the Synthesis of 6-(5-Bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2) and 1-Amino-6-(5-bromobenzofuran-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (3)

Method A: A mixture of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) (1.43 g, 5 mmol), the appropriate cyanothioacetamide or 2-cyanoacetohydrazide (5 mmol), and few catalytic drops of acetic acid was thoroughly ground with a pestle in an open mortar at room temperature for 3–5 min until the mixture turned into a melt. Grinding of the initial syrup was continued for 5–10 min, and the reaction was monitored by TLC. The solid was washed with water and recrystallized from the appropriate solvent gave the corresponding fused pyridines 2 and 3, respectively.
Method B: A mixture of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate (1) (1.43 g, 5 mmol) and the appropriate cyanothioacetamide or 2-cyanoacetohydrazide (5 mmol) in a solution of piperidinum acetate (piperidine (2.5 mL), water (5 mL), and acetic acid (2 mL)) was heated under reflux for about 10 min; acetic acid (1.5 mL) was added to the reaction mixture while boiling. Then the mixture was cooled, and the resulting solid was collected and recrystallized from the appropriate solvent gave 2 and 3, respectively.
Method C: A mixture of 1-(5-bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one (4) (1.47 g, 5 mmol) and the appropriate cyanothioacetamide or 2- cyanoacetohydrazide (5 mmol) in a solution of ethanol containing catalytical amount of piperdine (20 mL) was refluxed for 4–5 h. The resulting solid was collected and recrystallized to give identical in all aspects (mp., mixed mp. and spectra) with 2 and 3, respectively.
6-(5-Bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2). Deep red crystals. Yield: 65%, melting point: 172–174 °C (acetic acid). IR (KBr, cm−1): 3380 (NH), 3082 (CH), 2218 (CN), 1635 (C=N), 1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.97 (s, 1H, furan H-3), 7.28–7.66 (m, 4H, ArH’s), 7.89–7.61 (d, 1H, J = 8.0 Hz, ArH’s), 14.42 (s, br., 1H, NH); 13C-NMR (400 MHz, DMSO-d6): δ = 101.5 (C18), 102.9 (C9), 114.1 (C1), 115.9 (C14), 116.5 (C16), 117.4 (C5), 122.3 (C2), 129.3 (C13), 129.5 (C15), 144.2 (C6), 148.7 (C8), 154.6 (C11), 159.1 (C8), 182.1 (C4); (CMS, m/z, (%); Calcd. for C14H7BrN2OS (331.19) C, 50.77; H, 2.13; Br, 24.13; N, 8.46; S, 9.68 Found: C, 50.66; H, 2.18; Br, 24.07; N, 8.41; S, 9.75.
l-Amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (3). Yellow crystals. Yield: 62%, melting point: > 300 °C (acetic acid). IR (KBr, cm−1): 3380,3260 (NH2), 3082 (CH), 2218 (CN), 1635 (C=N), 1570(C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.12 (s, br., 2H, NH2), 7.01 (s, 1H, benzofuran H-3), 7.32–8.17 (m, 5H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 102.5 (C2), 104.7 (C9), 109.8 (C19), 114.1 (C16), 115.5 (C1), 116.5 (C14), 124.3 (C2), 125.4 (C13), 129.3 (C10), 129.57 (C1), 144.8 (C8), 152.1 (C6), 154.0 (C11), 164.4 (C4); Calcd. for C14H8BrN3O2 (330.14) C, 50.93; H, 2.44; Br, 24.20; N, 12.73 Found: C, 50.88; H, 2.51; Br, 24.11; N, 12.65%.

3.2. General Procedure for the Synthesis of 6-(5-bromobenzofuran-2-yl)-2-((2-oxopropyl)thio)-nicotinonitrile (5a), 6-(5-bromobenzofuran-2-yl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-nicotinonitrile (5b) and 6-(5-bromobenzofuran-2-yl)-2-(methylthio)nicotinonitrile (5c)

Grinding Method: Equimolar amounts of 2 (1.66 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) was ground with a pestle in an open mortar followed by the appropriate chloroacetone, ω-bromoacetophenone, or iodomethane (5 mmol) at room temperature for 2–3 min. until the mixture turned into a melt. The initial syrupy reaction mixture solidified within 3–5 min. Grinding was continued for 5–10 min. while the reaction was monitored by TLC. The solid was washed with water and recrystallized from N,N-dimethylformamide afforded the corresponding 5a–c, respectively.
Traditional Method: A mixture of 6-(5-bromobenzofuran-2-yl)-2-mercaptonicotinonitrile (2) (1.66 g, 5 mmol) and potassium hydroxide (0.56 g, 5 mmol) in N,N-dimethylformamide (20 mL) was stirred for 2 h. The appropriate chloroacetone, ω-bromoacetophenone or iodomethane (5 mmol) was added to the above mixture. Then, the reaction was stirred for 2 h. The resulting solid was formed after dilution of water was collected and recrystallized from the proper solvent gave pyridine derivatives 5a–c, respectively.
6-(5-Bromobenzofuran-2-yl)-2-((2-oxopropyl)thio)nicotinonitrile (5a). Brown crystals. Yield: 84%, melting point: 264–266 °C (dioxane). IR (KBr, cm−1): 3082 (CH), 2233 (CN), 1700 (CO), 1605 (C=N), 1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.39 (s, 3H, CH3), 4.38 (s, 2H, CH2), 7.23–7.97 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 19.3 (C 12), 39.8 (C9), 102.8 (C13), 103.1 (C5), 114.1 (C20), 116.2 (C22), 116.5 (C18), 119.1 (C1), 125.3 (17), 129.3 (C14), 129.5 (C19), 136.1 (C6), 150.2 (C2), 154.0 (C15), 159.2 (C4), 159.6 (C8), 201.8 (C1); Calcd. for C17H11BrN2O2S (387.25) C, 52.73; H, 2.86; Br, 20.63; N, 7.23; S, 8.28 Found: C, 52.67; H, 2.91; Br, 20.52; N, 7.15; S, 8.10%.
6-(5-Bromobenzofuran-2-yl)-2-((2-oxo-2-phenylethyl)thio)nicotinonitrile (5b). Deep red crystals. Yield: 80%, melting point: 184–186 °C (acetic acid). IR (KBr, cm−1): 3058 (CH), 2221 (CN), 1697 (CO), 1655 (C=N), 1527 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 4.58 (s, 2H, CH2), 7.23–8.00 (m, 11H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): 37.1 (C18), 102.5 (C8), 103.1 (C5), 114.1 (C15), 116.2 (C19), 116.6 (C13), 119.0 (C1), 125.3 (C12), 128.5 (C24 & C28), 128.7 (C25 & C27), 129.3 (C9), 129.5 (C14), 133.1 (C26), 123.3 (C23), 136.0 (C6), 150.5 (C2), 154.0 (C10), 159.2 (C4), 159.6 (C7), 193.8 (C21), Calcd. For C22H13BrN2O2S (449.32) C, 58.81; H, 2.92; Br, 17.78; N, 6.23; S, 7.14 Found: C, 58.92; H, 2.87; Br, 17.84; N, 6.31; S, 7.00%.
6-(5-Bromobenzofuran-2-yl)-2-(methylthio)pyridine-3-carbonitrile (5c). Brown crystals. Yield: 73%, melting point: 228–230 °C (dioxane). IR (KBr, cm−1): 3008 (CH), 2118 (CN), 1642 (C=O), 1566 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.65 (s, 2H, CH2), 7.21–7.89 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 13.3 (C18), 102.1 (C8), 104.7 (C5), 114.1 (C15), 114.6 (C13), 116.5 (C13), 118.7 (C1), 125.3 (C12), 129.3 (C9), 129.5 (C14), 135.6 (C6), 150.1 (C2), 154.0 (C10), 159.6 (C7), 161.2 (C4); Calcd. for C15H9BrN2OS (345.21) C, 52.19; H, 2.63; Br, 23.15; N, 8.11; S, 9.29 Found: C, 52.00; H, 2.57; Br, 23.08; N, 8.00; 8,9.35%.

3.3. General Procedure for the Synthesis of 1-(3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethan-1-one (6a), (3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)methanone (6b), 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carbonitrile (6c) and ethyl 3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d)

Method A: A mixture of 2 (1.66 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) in N,Ndimethylformamide (10 mL) was stirred for 2 h at room temperature. The appropriate of chloroacetone, ω-bromoacetophenone, chloroacetonitrile or ethyl chloroacetate (10 mmol) was refluxed while stirring for 2 h. The resulting solid formed after cooling and dilution with water was collected and crystallized from N, N-dimethylformamide afforded 6a–d, respectively.
Method B: A mixture of the appropriate 5a or 5b (5 mmol) in ethanol (15 mL) and piperidine (5 drops) was heated under refluxed for 2 h. The solid formed was collected and recrystallized gave products identical in all aspects (mp., mixed mp. and spectra) with 6a and 6b which were obtained from method A.
1-(3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)ethanone (6a). Brown crystals. Yield: 84%, melting point: 279–281 °C (dioxane). IR (KBr, cm−1): 3274, 3174 (NH2), 3074 (CH), 1670 (CO), 1604 (C=N), 1570 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.36 (s, 2H, CH3), 6.90 (s, br., 2H, NH2), 7.52–8.70 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 28.5 (C23), 102.8 (C13), 114.1 (C20), 116.5 (C18), 118.3 (C1), 122.3 (C5), 123.8 (C9), 125.3 (C17), 126.5 (C6), 129.3 (C14), 129.5 (C19), 136.0 (C10), 149.5 (C2), 153.8 (C15), 159.4 (C7), 160.0 (C4), 193.2 (C12). Calcd. for C17H11BrN2O2S (387.25) C, 52.73; H, 2.86; Br, 20.63; N, 7.23; S, 8.28 Found: C, 52.67; H, 2.78; Br, 20.58; N, 7.11; S, 8.348%.
[3-Amino-6-(5-bromobenzofuran-2-yl)-thieno[2,3-b]pyridin-2-yl]-phenyl-methanone (6b). Brown crystals. Yield: 84%, melting point: 260–262 °C (dioxane). IR (KBr, cm−1): 3425, 3294, 3132 (NH2), 3070 (CH), 1672 (CO), 1593 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.80 (s, br., 2H, NH2), 7.44–8.28 (m, 11H, ArH’s); Calcd. for C22H13BrN2O2S (449.32) C, 58.81; H, 2.92; Br, 17.78; N, 6.23; S, 7.14 Found: C, 58.75; H, 3.01; Br, 17.84; N, 6.32; S, 7.00%.
2-(3-Amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridin-2-yl)-2-carbonitrile (6c). Brown crystals. Yield: 90%, melting point: 280–282 °C (dioxane). IR (KBr, cm−1): 3425, 3348, 3247 (NH2), 3070 (CH), 2194 (CN), 1658 (C=N), 1569 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 7.39–8.62 (m, 8H, ArH’s and NH2); Calcd. for C16H8BrN3OS (370.22) C, 51.91; H, 2.18; Br, 21.58; N, 11.35; S, 8.66 Found: C, 52.01; H, 2.22; Br, 21.51; N, 11.39; 8,8.59%.
Ethyl 3-amino-6-(5-bromobenzofuran-2-yl)thieno[2,3-b]pyridine-2-carboxylate (6d). Yellow crystals. Yield: 87%, melting point: 290–292 °C (dioxan). IR (KBr, cm−1): 3293, 3197 (NH2), 2979 (CH), 1670 (CO), 1611 (C=N), 1556 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 1.30 (t, 3H, J = 7.5 Hz, CH2CH3), 4.27 (q, 2H, J = 7.5 Hz, CH2CH3), 7.34–8.64 (m, 8H, ArH’s and NH2); 13C-NMR (400 MHz, DMSO-d6): δ = 8.3 (C24), 33.7 (C23), 102.7 (C13), 114.2 (C20), 116.5 ( C18), 118.6 (C1), 121.5 (C5), 125.0 (C17), 126.3 (C9), 126.7 (C6), 129.3 (C14), 129.6 (C19), 135.4 (C10), 149.5 (C2), 154.0 (C15), 159.6 (C7), 160.0 (C4), 198.5 (C12). Calcd. for C18H13BrN2O3S (417.28) C, 51.81; H, 3.14; Br, 19.15; N, 6.71; S, 7.68 Found: C, 51.92; H, 3.24; Br, 19.00; N, 6.61; 8,7.72%.

3.4. Synthesis of 7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7), 7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (8) and ethyl (E)-N-(6-(5-Bromobenzofuran-2-yl)-2-cyanothieno[2,3-b]pyridin-3-yl)formimidate (9)

7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one (7). A mixture of 6c (1.85 g, 5 mmol) and formic acid (7 mL, 99%) in N,N,-dimethylformamide (5 mL) was boiled under reflux for 7 h. The reaction mixture was poured onto ice (30 g). The solid so formed was collected and recrystallized from DMF gave 7 as brown crystals. Yield: 72%, melting point: > 300 °C (DMF). IR (KBr, cm−1): 3320 (NH), 3001 (CH), 1666 (CO), 1569 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 7.01–8.21 (m, 7H, ArH’s), 12.85 (s, br., 1H, NH); MS, m/z, (%): 399 (M+1, 29%), 398 (M+, 100%), 397 (M−1,12%), 371 (17%), 370 (67%), 200 (7%), 199 (7%), 105 (10%), 77 (27%); Calcd. for C17H8BrN3O2S (398.23) C, 51.27; H, 2.02; Br, 20.06; N, 10.55; S, 8.05 Found: C, 51.15; H, 1.95; Br, 20.00; N, 10.42; S, 7.87%.
7-(5-bromobenzofuran-2-yl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (8). Method A: A mixture of 6c (1.85 g, 5 mmol) and formamide (5 mL, 99%) in N,N,-dimethylformarnide (5 mL) was boiled under reflux for 7 h. The reaction mixture was poured onto ice (30 g). recrystallized from DMF to give 8 as brown crystals. Yield: 78%, melting point: > 300 °C. The solid so formed was collected and (DMF). IR (KBr, cm−1): 3320, 3151 (NH2), 3001 (CH), 1648 (C=N), 1573 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.88 (s, br., 2H, NH2), 7.31–8.11 (m, 7H, ArH’s); MS, m/z (%): 399 (M+2, 29%), 398 (M+1, 100%), 397 (M+,12%), 371 (17%), 370 (67%), 200 (7%), 199 (7%), 105 (10%), 77 (27%); Calcd. for C17H9BrN4OS (397.25) C, 51.40; H, 2.28; Br, 20.11; N, 14.10; S, 8.07 Found: C, 51.31; H, 2.32; Br, 20.00; N, 14.23; S, 7.88%. Method B: A mixture of ethyl N-[6-(5-bromo-benzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9) (0.5 g) and formamide (0.5 mL) in N,N,-dimethylformamide (5 mL) was boiled for 2 h. The solid so formed was collected and recrystallized from DMF gave a product identical in all aspects (mp., mixed mp. and spectra) with product 8.
Ethyl N-[6-(5-bromobenzofuran-2-yl)-2-cyano-thieno[2,3-b]pyridin-3-yl]-formimidoate (9). A mixture of 2d (1.85 g, 5 mmol) and triethyl ortho-formate (1.48 g, 10 mmol) in acetic anhydride (20 mL) was heated under reflux for 6 h. The reaction mixture was poured onto ice (30 g). The resulting solid was collected and recrystallized from dioxane gave 9 as brown crystals. Yield: 71%, melting point: 250–252 °C (dioxane). IR (KBr, cm−1): 3070 (CH), 2194 (CN), 1648 (C=N), 1573 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 1.37 (t, 3H, J = 8.0 Hz, CH2CH3), 4.32 (q, 2H, J = 8.0 Hz, CH2CH3), 7.31–8.22 (m, 7H, ArH’s and CH=); 13C-NMR (400 MHz, DMSO-d6): δ = 15.3 (C25), 62.6 (C24), 101.7 (C9), 102.2 (C13), 113.7 (C12), 113.0 (C12), 114.2 (C20), 116.6 (C18), 118.4 (C1), 125.3 (C16), 125.5 (C5), 127.6 (C6), 129.3 (C13), 129.6 (C18), 133.2 (C10), 149.1 (C2), 153.8 (C14), 157.1 (C21), 159.7 (C7), 161.1 (C4). Calcd. for C19H12BrN3O2S (426.29) C, 53.53; H, 2.84; N, 9.86; S, 7.52 Found: C, 53.39; H, 2.75; Br, 18.68; N, 10.00; S, 7.41%.

3.5. Pyridine Derivatives 10–14

l-(5-Bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-l-one (3). (1.86 g, 5 mmol), the appropriate acetylacetone, ethyl acetoacetate, ethyl cyanoacetate, malononitrile, benzoylacetonitrile, (5 mmol) and ammonium acetate (0.38 g, 5 mmol), was heated in acetic acid (10 mL) under reflux for 3 h. on cooling, the separated solid was filtered, washed with water and crystallized from the proper solvent afforded 10–14, respectively.
l-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)ethanone (10). Beige crystals, Yield: 84%, melting point: 160–162 °C (acetic acid). IR (KBr, cm−1): 3001 (CH), 1710 (CO), 1648 (C=N), 1573 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.51 (s, 3H, CH3), 2.57 (s, 3H, CH3), 7.31–7.89 (m, 6H, ArH’s); 13C-NMR (400 MHz, DMSO-d6): δ = 24.6 (C7), 28.5 (C9), 102.2 (C12), 114.1 (C19), 116.7 (C16), 118.8 (C1), 124.9 (C16), 129.0 (C13), 129.5 (C18), 131.2 (C6), 133.1 (C5), 152.2 (C1), 153.7 (C14), 158.0 (C4), 160.2 (C11), 201.1 (C8). MS, m/z, (%): 331 (M+1, 78%), 329 (M−1, 83%), 316 (100%), 314 (94%), 288 (16%), 286 (16%), 207 (48%), 204 (48%), 152 (18%), 150 (13%), 89 (25%), 77 (16%), 63 (36%); Calcd. for C16H12BrNO2 (330.18) C, 58.20; H, 3.66; Br, 24.20; N, 4.24 Found: C, 58.12; H, 3.58; Br, 24.00; N, 4.18%.
Ethyl 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carboxylate (11). Yellow crystals, Yield: 85%, melting point: 176–178 °C (dioxane). IR (KBr, cm−1): 3058 (CH), 1708 (CO), 1639 (C=N), 1585 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 8.0 Hz, CH2CH3), 2.62 (s, 3H, CH3), 4.22 (q, 2H, J = 8.0 Hz, CH2CH3), 7.28–7.98 (m, 6H, ArH’s); MS, m/z, (%)): 361 (M+1, 64%), 359 (M−1, 100%), 317 (46%), 315 (63%), 259 (45%), 247 (63%), 89 (45%), 97 (45%), 62 (64%); 13C-NMR (400 MHz, DMSO-d6): δ = 14.2 (C22), 24.3 (C7), 61.8 (C22), 102.8 (C12), 114.0 (C19), 116.5 (C17), 120.1 (C1), 124.8 (C16), 125.0 (C5), 129.2 (C13), 129.7 (C18), 130.2 (C6), 148.8 (C2), 153.9 (C14), 157.0 (C4), 160.0 (C11), 166.8 (C8). Calcd. for C17H14BrNO3 (360.2) C, 56.69; H, 3.92; Br, 22.18; N, 3.89 Found: C, 56.58; H, 4.11; Br, 22.07; N, 3.96%.
Ethyl 2-Amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carboxylate (12). Yellow crystals, Yield: 90%, melting point: 220–222 °C (dioxane). IR (KBr, cm−1): 3078 (CH), 1701 (CO), 1643 (C=N), 1550 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 1.35 (t, 3H, J = 8.0 Hz, CH2CH3), 4.23 (q, 2H, J = 8.0 Hz, CH2CH3), 7.30–8.10 (m, 8H, NH2 and ArH’s); MS, m/z, (%): 362 (M+1, 53%), 360 (M−1, 50%), 290 (53%), 149 (53%), 90 (100%), 89 (53%), 81 (70%), 75 (47%); Calcd. for C16H13BrN2O3 (361.19) C, 53.21; H, 3.63; Br, 22.12; N, 7.76 Found: C, 53.27; H, 3.69; Br, 22.00; N, 7.68%.
2-Amino-6-(5-bromobenzofuran-2-yl)pyridine-3-carbonitrile (13). Brown crystals, Yield: 80%, melting point: 270–272 °C (dioxane). IR (KBr, cm−1): 3344, 3105 (NH2), 3078 (CH), 2218 (CN), 1653 (C=N), 1585 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 6.21 (s, br., 2H, NH2), 7.30–8.22 (m, 6H, ArH’s); MS, m/z, (%): 315 (M+1, 94%), 313 (M−1, 100%), 289 (11%), 287 (12%), 164 (11%), 129 (11%), 127 (16%), 75 (25%); Calcd. for C14H8BrN3O (314.14) C, 53.53; H, 2.57; Br, 25.44; N, 13.38 Found: C, 53.48; H, 2.61; Br, 25.33; N, 13.29%.
(2-Amino-6-(5-bromobenzofuran-2-yl)pyridin-3yl)(phenyl)methanone (14). Brown crystals, Yield: 90%, melting point: 240–242 °C (acetic acid). IR (KBr, cm−1): 3344, 3105 (NH2), 3078 (CH), 1680 (CO), 1624 (C=N), 1577 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 7.30–7.79 (m, 11H, ArH’s), 10.21 (s, br., 2H, NH2); MS, m/z, (%): 394 (M+1, 77%), 393 (M+, 54%), 392 (17%), 290 (33), 288 (35%), 224 (68%), 222 (67%), 168 (17%), 166 (52%), 146 (15%), 144 (17%), 109 (56%), 88 (97%), 75 (31%); Calcd. for C20H13BrN2O2 (393.23) C, 61.09; H, 3.33; Br, 20.32; N, 7.12 Found: C, 61.15; H, 3.42; Br, 20.12; N, 7.00%.
6-(5-Bromobenzofuran-2-yl)-2-methylpyridine-3-carbohydrazide (15). A mixture of 12 (1.85 g, 5 mmol) and hydrazine hydrate (1 g, 20 mmol) in ethanol (20 mL) was heated under refluxed for 3 h. The resulting solid was collected and recrystallized from acetic acid gave a beige crystals. Yield: 96%, melting point: 250–252 °C. IR (KBr, cm−1): 3388, 3337, 3217 (NH, NH2), 3062 (CH), 2920, 2851 (CH), 1680 (CO), 1640 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.62 (s, 3H, CH3), 6.24 (s, br., 3H, NH and NH2), 7.23–7.89 (m, 6H, ArH’s); MS, m/z, (%): 347 (M+1, 15%), 345 (M−1, 13%), 315 (79%), 314 (100%), 313 (86%), 207 (43%), 205 (40%), 152 (20%), 151 (23%), 150 (0%), 103 (18%), 77 (25%), 63 (43%); Calcd. for C15H12BrN3O2 (346.18) C, 52.04; H, 3.49; Br, 23.08; N, 12.14 Found: C, 52.04; H, 3.49; Br, 23.08; N, 12.14%

3.6. 1-(6-(5-Bromobenzofuran-2-yl)-2-methylnicotinoyl)-3-methyl-1H-pyrazol-5(4H)-one (16a) and (6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (16b)

A mixture of 6-(5-bromobenzofuran-2-yl)-2-methylpyridine-3-carbohydrazide (15) (1.73 g, 5 mmol), ethyl acetoacetate or acetylacetone in ethanol (20 mL) and acetic acid (5 drops) was heated under reflux for 3 h. on cooling, the separated yellow solid was filtered, washed with water and crystallized gave 16a and 16b, respectively.
1-(6-(5-Bromobenzofuran-2-yl)-2-methylnicotinoyl)-3-methyl-1H-pyrazol-5(4H)-one (16a). Yellow crystals, Yield: 87%, melting point: 260–262 °C (DMF). IR (KBr, cm−1): 2920 (CH), 1687 (CO), 1639 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.42 (q, 1H, CH2), 3.62 (q, 1H, CH2), 7.30–7.95 (m, 6H, ArH’s); MS, m/z, (%): 413 (M+1, 19%), 411 (M−1, 18%), 98 (48%), 91 (22%), 88 (44%), 86 (30%), 80 (85%), 64 (44%); Calcd. for C19H14BrN3O3 (412.24) C, 55.36; H, 3.42; Br, 19.38; N, 10.19 Found: C, 55.41; H, 3.38; Br, 19.28; N, 10.00%.
(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (16b). Yellow crystals, Yield: 91%, melting point: 272–274 °C (dioxan). IR (KBr, cm−1): 2977 (CH), 1681 (CO), 1585 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 2.30 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.66 (s, 3H, CH3), 5.78 (s, 1H, pyrazole H-4), 7.30–7.99 (m, 6H, ArH’s); MS, m/z, (%): 410 (M+, 100%), 331 (48%), 316 (5%), 314 (8%), 289 (10%), 206 (16%), 179 (49%), 167 (16%), 165 (11%), 139 (11%), 137 (11%), 113 (15%), 111 (19%), 91 (35%), 77 (34%), 65 (12%); Calcd. for C20H16BrN3O2 (410.26) C, 58.55; H, 3.93; Br, 19.48; N, 10.24 Found: C, 58.48; H, 4.12; Br, 19.52; N, 10.00%.

3.7. 2-[6-(5-Bromobenzofuran-2-yl)-2-methyl-pyridine-3-carbonyl]-5-methyl-4-(phenyl-hydrazono)-2,4-dihydro-pyrazol-3-one (17) and (6-(5-bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-4-(2-phenylhydrazinyl)-1H-pyrazol-1-yl)methanone (18)

Method A: benzenediazonium chloride (5 mmol), which was prepared via reaction of aniline (0.46 g. 5 mmol), hydrochloric acid (3 mL, 6 M) and sodium nitrite (0.37 gm, 5 mniole) at 0–5 °C, was added to a mixture of the appropriate 16a or 16b (5 mmole) and sodium acetate (0.41 gm, 5 mmole) in ethanol (30 mL) at 0–5 °C, while stirring. The reaction mixture was stilted for 3 h. The resulting solid, was collected, washed with water and recrystallized from acetic acid gave 17 and 18, respectively.
Method B: A mixture of 15 (1.73 g, 5 mmol) and the appropriate of ethyl 2-(2-phenylhydrazono)-3-oxobutanoate (19a) or 3-(2-phenyl-hydrazono)pentane-2,4-dione (19b) (5 mmol) in ethanol (20 mL) and catalytic amount of acetic acid (2 drops) was refluxed for 2 h. The resulting solid, so formed, was collected and recrystallized from acetic acid gave products identical in all aspects to those obtained from method A.
2-[6-(5-Bromobenzofuran-2-yl)-2-methyl-pyridine-3-carbonyl]-5-methyl-4-(pheny1-hydrazono)-2,4-dihydro-pyrazoI-3-one (17). Brown crystals, Yield: 82%, melting point: 276–278 °C (DMF). IR (KBr, cm−1): 3345 (NH), 2989 (CH), 1712 (CO), 1639 (C=N), 1581 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.12 (s, 3H, CH3), 2.68 (s, 3H, CH3), 7.11–7.99 (m, 11H, ArH’s), 10.88 (s, br., 1H, NH); MS, m/z, (%): 516 (M+, 13%), 423 (39%), 420 (13%), 394 (10%), 392 (75%), 362 (25%), 346 (17%), 318 (9%), 316 (15%), 290 (11%), 288 (9%), 195 (19%), 193 (19%), 167 (17%), 165 (11%), 139 (100%), 114 (22%), 112 (35%), 100 (37%), 87 (41%), 75 (57%), 62 (31%); Calcd. for C25H18BrN5O3 (516.35) C, 58.15; H, 3.51; Br, 15.47; N, 13.56 Found: C, 58.08; H, 3.64; Br, 15.52; N, 13.61%.
(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)(3,5-dimethyl-4-(2-phenylhydrazinyl)-1H-pyrazol-1-yl)methanone (18). Brown crystals, Yield: 82%, melting point: 230–232 °C (DMF). IR (KBr, cm−1): 2916 (CH), 1652 (CO), 1616 (C=N), 1546 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.18 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.68 (s, 3H, CH3), 7.31–8.35 (m, 11H, ArH’s); MS, m/z, (%): 515 (M+1, 0.98%), 513 (M−1, 75%), 223 (13%), 252 (13%), 251 (11%), 213 (15%), 211 (14%), 169 (6%), 167 (7%), 116 (35%), 114 (28%), 102 (27%), 87 (85%), 77 (50%), 62 (100%); Calcd. for C26H20BrN5O2 (514.37) C, 60.71; H, 3.92; Br, 15.53; N, 13.62 Found: C, 60.64; H, 4.10; Br, 15.39; N, 13.52%.
6-(5-Bromobenzofuran-2-yl)-2-methylnicotinoyl azide (20). A stirred solution of 15 (1.78 g, 5 mmol) in hydrochloric acid (15 mL, 6M) at 0-5 °C, sodium nitrite was added portion-wise tell effervescence ended. The reaction mixture was stirred for 1 h. The resulting solid, was collected, filtered, washed with water and recrystallized from DMF gave a beige crystals. Yield: 78%, melting point: >300 °C. IR (KBr, cm−1): 3070(CH), 2989, 2927 (CH), 2124 (Azide), 1712 (CO), 1639 (C=N), 1581 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 2.61 (s, 3H, CH3), 7.12–7.95 (m, 6H, ArH’s); MS, m/z, (%): 359 (M+2, 5%), 357 (M+, 6%), 330 (89%), 328 (87%), 304 (92%), 302 (100%), 223 (16%), 221 (15%), 194 (14%), 192 (14%), 180 (15%), 178 (13%), 152 (33%), 150 (27%), 126 (23%), 124 (13%), 113 (16%), 97 (32%), 77 (42%), 62 (55%); Calcd. for C15H9BrN4O2 (357.16) C, 50.44; H, 2.54; Br, 22.37; N, 15.69 Found: C, 50.38; H, 2.47; Br, 22.42; N, 15.75%.

3.8. Urea Derivatives 21a–e

A mixture of appropriate aniline, p-toluidine, p-anisidine, 3-amino-5-phenylpyrazole or 3-amino-l,2,4-triazole (5 mmol) and azido compound 20 (1.78 g, 5 mmol) in dry dioxane (20 mL) was refluxed for 4 h. The resulting solid, so formed, was collected and recrystallized gave 21a–d, respectively.
1-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)-3-phenylurea (21a). Yellow crystals. Yield: 94%, melting point: 268–270 °C (DMF). IR (KBr, cm−1): 3103 (NH), 3055 (CH), 2920, 2850 (CH), 1700 (CO), 1639 (C=N), 1589 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 2.15 (s, 3H, CH3), 7.00–7.95 (m, 11H, ArH’s), 8.67 (s, br., 2H, 2NH); MS, m/z, (%): 422 (M+,5%), 420 (5%), 213 (8%), 151 (9%), 119 (13%), 116 (29%), 1–14 (14%), 90 (18%), 87 (60%), 77 (72%), 62 (100%); Calcd. for C21H16BrN3O2 (422.27) C, 59.73; H, 3.82; Br, 18.92; N, 9.95 Found: C, 59.69; H, 3.88; Br, 19.12; N, 10.00%.
l-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)-3-p-tolylurea (21b). White crystals. Yield: 93%, melting point: 290–292 °C (DMF). IR (KBr, cm−1) 255 (NH), 3070 (CH), 2916, 2850 (CH), 1690 (CO), 1639 (C=N), 1593 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3H, CH3), 2.24 (s, 3H, CH3), 7.00–7.66 (m, 10H, ArH’s), 8.75 (s, br., 2H, 2NH); MS, m/z, (%): 438 (M+2, 5%), 436 (M+, 5%), 304 (13%), 169 (12%), 167 (11%), 106 (27%), 88 (17%), 87 (31%), 86 (28%), 77 (26%), 62 (100%); Calcd. for C22H18BrN3O2 (436.3) C, 60.56; H, 4.16; Br, 18.31; N, 9.63 Found: C, 60.56; H, 4.16; Br, 18.31; N, 9.63%.
l-(6-(5-Bromobenzofuran-2-y1)-2-methylpyridin-3-yl)-3-(4-methoxyphenyl) urea (21c). Beige crystals. Yield: 92%, melting point: 280–252 °C (DMF). IR (KBr, cm−1): 3255 (NH), 3070 (CH), 2916, 2850 (CH), 1690 (CO), 1639 (C=N),1593 (C=C); 1H-NMR(400 MHz, DMSO-d6): δ = 2.10 (s, 3H, CH3), 3.71 (s, 3H, CH3), 6.87–8.52 (m, 10H, ArH’s), 9.25 (s, br., 2H, 2NH); MS, m/z, (%): 452 (M+, 1.3%), 451 (4%), 333 (7%), 332 (20%), 331 (100%), 238 (54%), 175 (12%), 160 (64%), 155 (62%), 93 (35%), 91 (54%), 84 (17%); Calcd. for C22H18BrN3O3 (452.3) C, 58.42; H, 4.01; Br, 17.67; N, 9.29 Found: C, 58.48; H, 4.11; Br, 17.71; N, 9.34%.
1-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)-3-(3-phenyl-1H-pyrazol-5-yl)urea (21d). Yellow crystals. Yield: 92%, melting point: 262–264 °C (DMF). IR (KBr, cm−1): 3101 (NH), 3058 (CH), 2916, 2850 (CH), 1690 (CO), 1639 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSC-d6): δ = 2.11 (s, 3H, CH3), 5.34 (s, 1H, pyrazole H-4), 7.22–7.79 (m, 11H, ArH’s), 9.88 (s, br., 3H, 3NH); Calcd. for C24H18BrN5O2 (488.34) C, 59.03; H, 3.72; Br, 16.36; N, 14.34 Found: C, 59.03; H, 3.72; Br, 16.36; N, 14.34%.
1-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)-3-(4H-1,2,4-triazol-3-yl)urea (21e). Yellow crystals. Yield: 93%, melting point: 274–276 °C (DMF). IR (KBr, cm−1): 3101 (NH), 3058 (CH), 2916, 2850 (CH), 1690 (CO), 1639 (C=N), 1589 (OC); 1H-NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3H, CH3), 7.22–7.79 (m, 10H, ArH’s), 9.897 (s, br., 3H, 3NH); Calcd. for C17H13BrN6O2(413.23) C, 49.41; H, 3.17; Br, 19.34; N, 20.34 Found: C, 49.38; H, 3.21; Br, 19.29; N, 20.41%.
3-(6-(5-Bromobenzofuran-2-yl)-2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (22). A mixture of appropriate methyl anthranilate or anthranilic acid (5 mmol) and azido compound 20 (1.78 g, 5 mmol) in dry dioxane (20 mL) was refluxed for 4 h. The resulting solid, so formed, was collected and recrystallized from DMF gave 22 as beige crystals Yield: 87.6%, melting point: >300 °C. IR (KBr, cm−1): 3255 (NH), 3062 (CH), 2923 (CH), 1681 (CO), 1639 (C=N), 1589 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.48 (s, 3H, CH3), 7.14–8.22 (m, 10H, ArH’s), 10.55 (s, br., 1H, NH); 13C-NMR (400 MHz, DMSO-d6): δ = 21.2 (C8), 102.4 (C21), 114.1 (C13), 114.2 (C28), 115.1 (C17), 126.4 (C26), 122.2 (C1), 123.2 (C19), 125.0 (C25), 127.0 (C20), 129.3 (C22), 129.7 (C27), 131.0 (C6), 135.0 (C18), 138.1 (C5), 148.1 (C2), 149.0 (C10), 154.0 (C13), 158.0 (C4), 159.6 (C7), 163.1 (C14). Calcd. for C22H14BrN3O3 (448.27) C, 58.95; H, 3.15; Br, 17.83; N, 9.37 Found: C, 59.12; H, 3.04; Br, 17.75; N, 9.3742%.
Phenyl 6-(5-bromobenzofuran-2-yl)-2-methylpyridin-3-ylcarbamate (23). A mixture of 20 (1.78 g, 5 mmol) and phenol (5 mmol) in dry benzene (20 mL) was refluxed for 4 h. The resulting solid, so formed, was collected and recrystallized from dioxane to give 23 as beige crystals Yield: 87.6%, melting point: >300 °C. IR (KBr, cm−1): 3255 (NH), 3062 (CH), 2923 (CH), 1670 (CO), 1620 (C=N), 1566 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ = 2.48 (s, 3H, CH3), 7.14–8.22 (m, 11H, ArH’s), 10.55 (s, br., 1H, NH); Calcd. for C21H15BrN2O3(423.26) C, 59.59; H, 3.57; Br, 18.88; N, 6.62 Found C, 59.64; H, 3.59; Br, 18.75; N, 6.57%.

4. Conclusions

Compound 1 proved to be a useful precursor for synthesis of various pyridines and thieno[2,3-b]pyridines via its reactions with the appropriate cyanothioacetamide, 2-cyanoacetohydrazidem, pentane-2,4-dione, ethyl 3-oxobutanoate, ethyl cyanoacetate or benzoylacetonitrile. Moreover, compound 15 proved a useful precursor in the synthesis of various urea and carbomate derivatives. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses.

Author Contributions

AOA designed research. NAA, SAA, and AOA performed experiments and analyzed the data. All authors contributed to the paper and approved the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 5a–c, 6a–d, 7–9, 10–18, 20–23 are available from the authors.

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Abdelriheem, N.A.; Ahmad, S.A.-K.; Abdelhamid, A.O. Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety. Molecules 2015, 20, 822-838. https://doi.org/10.3390/molecules20010822

AMA Style

Abdelriheem NA, Ahmad SA-K, Abdelhamid AO. Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety. Molecules. 2015; 20(1):822-838. https://doi.org/10.3390/molecules20010822

Chicago/Turabian Style

Abdelriheem, Nadia Abdelhamed, Sayed Abdel-Kader Ahmad, and Abdou Osman Abdelhamid. 2015. "Synthesis of some new Thieno[2,3-b]pyridines, Pyrimidino[4',5':4,5]thieno[2,3-b]pyridine and Pyridines Incorporating 5-Bromobenzofuran-2-yl Moiety" Molecules 20, no. 1: 822-838. https://doi.org/10.3390/molecules20010822

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