A novel series of benzofuran derivatives were synthesized via treatment of 3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 1 with diazonium salts of heterocyclic amines 2a-e and with aryl diazonium chlorides to give the new 3a-e and 5a,b derivatives, respectively . In addition, compound 1 was reacted with hydrazonoyl halides 6a-c to give pyrazoles 8a-c. On the other hand, 3-(benzofuran-2-yl)-3-oxopropanenitrile 9 was reacted with phenyl isothiocyanate and each of ethyl chloroacetate, chloroacetone and chloroacetonitrile to give compounds 10-12, respectively. The structures of the newly synthesized compounds were elucidated based on their spectral data and elemental analysis, whenever possible.

Keywords: Benzofuran derivatives, 3-oxopropanenitrile, Aryldiazonium chloride, Hydrazonoyl halides

EXPERIMENTAL

All melting points were determined on an electrothermal apparatus and were uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer. ¹H and ¹³C NMR spectra were recorded in CDCl₃ and (CD₃)₂SO solutions on a Varian Gemini 300 MHz and JNM-LA 400 FT-NMR system spectrometer and chemical shifts are expressed in ppm units using TMS as an internal reference. Mass spectra were recorded on a GC-MS QP1000 EX Shimadzu. Elemental analyses were carried out at the Microanalytical Center of Cairo University.

Synthesis of 3a-e, 5a,b, 11 and 12a-c

A solution of the appropriate diazonium salt of amines (5 mmol) was added to a mixture of 3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile or 4-(5-bromobenzofuran-2-yl)-thiazole-2-amine 10 (5 mmol) and sodium acetate (0.65 g, 5 mmol) in ethanol (30 mL) at 0-5°C while stirring. The resulting solid which formed after 2 h was collected, washed with water and recrystallized from a proper solvent to give 3a-e, 5a,b, 11 and 12a-c, respectively.

(E)-2-(2-(5-phenyl-1H-pyrazol-5-yl)hydrazono)-3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 3a

Brown crystals from dioxane, yield (75%), mp: 256-259°C; IR (KBr): 3334, 3166 (2NH), 3065 (CH, aromatic), 2224 (CN), 1640 (C=O); 1H NMR δ=6.46 (s, 1H, pyrazole), 7.21-7.79 (m, 9H, ArH's); 8.81,9.24 (s, 2H, 2NH). Anal. Calcd. for C₂₀H₁₂BrN₅O₂ (434.25): C, 55.32; H, 2.79; Br, 18.40; N, 16.13. Found: C, 55.36; H, 2.75; Br, 18.44; N, 16.17.

(E)-2-(2-(4-phenyl-1H-pyrazol-5-yl)hydrazono)-3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 3b

Yellow crystals from AcOH, yield (75%), mp: 260-263°C; IR (KBr): 3051 (CH, aromatic), 2230 (CN), 1658 (C=O); 1H NMR δ=6.43 (s, 1H, pyrazole), 7.21-7.72 (m, 9H, ArH's); 8.80, 9.0 (s, 2H, 2NH). Anal. Calcd. For C₂₀H₁₂BrN₅O₂ (434.25): C, 55.32; H, 2.79; Br, 18.40; N, 16.13. Found: C, 55.36; H, 2.75; Br, 18.44; N, 16.17. 

(E)-2-(2-(4-cyano-1H-pyrazol-5-yl)hydrazono)-3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 3c

Brown crystals from dioxane, yield (84%), mp: >300°C; IR (KBr): 3340 (NH), 2220 (CN); ¹H NMR δ=7.20-7.71 (m, 7H, ArH's and 2NH). Anal. Calcd. for C₁₅H₇BrN₆O₂ (383.16): C, 47.02; H, 1.84; Br, 20.85; N, 21.93. Found: C, 47.06; H, 1.80; Br, 20.81; N, 21.97.

(E)-2-(2-(1H-1,2,3-triazol-1-yl)hydrazono)-3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 3d

Brown crystals from AcOH, yield (84%), mp: 284-86°C; IR (KBr): 3300 (NH), 2215 (CN), 1675 (CO); 1H NMR δ=7.10-7.95 (m, 8H, ArH’s+NH). Anal. Calcd. for C₁₃H₇BrN₆O₂ (359.14): C, 43.48; H, 1.96; Br, 22.25; N, 23.40. Found: C, 43.44; H, 1.92; Br, 22.21; N, 23.44.

(E)-2-(2-(1H-benzo[d]imidazol-2-yl)hydrazono)-3-(5-bromobenzofuran-2-yl)-3-oxopropanenitrile 3e

Brown powder from AcOH, yield (72%), mp: >300°C; IR (KBr): 3320, 3183 (2NH), 2224 (CN), 1668 (CO); 1H NMR δ=7.07-8.11 (m, 10H, ArH's). Anal. Calcd. For C₁₈H₁₀BrN₅O₂ (408.21): C, 52.96; H, 2.47; Br, 19.57; N, 17.16. Found: C, 52.92; H, 2.43; Br, 19.53; N, 17.14.

2-(benzofuran-2-yl)-2-oxo-N'-phenylacetohydrazonoyl cyanide 5a

Brown powder from AcOH, yield 85%, mp: 210-12°C; IR (KBr): 3190 (NH), 3076 (CH, aromatic), 2223 (CN), 1710 (CO): 1H NMR δ=7.20-7.96 (m, 9H, ArH's),12.46 (s,1H, NH). Anal. Calcd. for C₁₇H₁₀BrN₃O₂ (368.18): C, 55.46; H, 2.74; Br, 21.70; N, 11.41.

2-(benzofuran-2-yl)-2-oxo-N'-(p-tolyl)phenylacetohydrazonoyl cyanide 5b

Brown powder from EtOH, yield (83%), mp: 195-97°C; IR (KBr): 3205 (NH), 3040 (CH, aromatic), 2209 (CN), 1634 (CO); 1H NMR δ=2.40 (s, 3H, CH₃) 7.23-8.22 (m, 8H, ArH's), 15.44 (s, 1H, NH). Anal. Calcd. for C₁₈H₁₂BrN₃O₂ (382.21): C, 56.56; H, 3.16; Br, 20.91; N, 10.99. Found: C, 56.52; H, 3.12; Br, 20.95; N, 10.95.

Synthesis of 3-substituted 5-(benzofuran-2-yl)4-cyano-1-phenyl-1H-pyrazole 8a-c

Compound 1 (5 mmol) was added to a stirred ethanolic sodium ethoxide solution (0.12 g sodium metal in absolute ethanol 20 mL). After 20 min., the appropriate hydrazonoyl halide 6a-c (5 mmol) was added and the reaction mixture was stirred for 4 h. The resulting solid was collected by filtration, dried and recrystallized from a proper solvent to give 8a-c, respectively.

Ethyl-5-(bromobenzofuran-2-yl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylate 8a

Yellow crystals from ethanol. yield (83%), mp.: 193°C. FT-IR (KBr, cm^-1): 3066v (CH-aroma.), 2995, 2915v (CH-aliph), 2232v (CN), 1727v (CO), 1585v (C=C). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 1.20 (t, 3H, J=7 Hz, CH2CH3), 4.33 (q, 2H, J=7 Hz, CH₂CH₃), 6.90 (s, 1H, CH-furan), 7.39-7.60 (m, 8H, ArH's). Anal. Calcd. for C₂₁H₁₄BrN₃O₃ (436.26): C, 57.82; H, 3.23; Br, 18.32; N, 9.63. Found: C, 57.86; H, 3.27; Br, 18.36; N, 9.67.

3-Acetyl-5-(bromobenzofuran-2-yl)-1-phenyl-1H-pyrazole-4-carbonitrile 8b

Yellow crystals from acetic acid; yield (79%), m.p. 244-246°C. FT-IR (KBr, cm^-1): 3060 v (CH-arom.), 2229 v (CN), 1697 v (CO), 1600 v (C=N). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 2.60 (s, 3H, CH3), 7.00 (s, 1H, CH-furan), 7.20-7.65 (m, 8H, ArH's). Anal. Calcd. for C₂₀H₁₂BrN₃O (390.23): C, 61.56; H, 3.10; Br, 20.48; N, 10.77. Found: C, 61.52; H, 3.14; Br, 20.44; N, 10.73.

3-(Bromobenzofuran-2-yl-carbonyl)-5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-4-carbonitrile 8c

Red crystals from ethanol. Yield: 80%, m.p. 227-230°C. 1H NMR (300 MHz, DMSO-d6, δ, ppm): 7.23-7.55 (m, 14H, ArH's). Anal. Calcd. for C₂₇H₁₄BrN₃O₃ (508.32): C, 63.80; H, 2.78; Br, 15.72; N, 8.27. Found: C, 63.84; H, 2.74; Br, 15.68; N, 8.31.

Synthesis of 10, 11a and 11b

A mixture of compound 9 (10 mmol), phenyl isothiocyanate (10 mmol) and potassium hydroxide (10 mmol) in N, N-dimethylformamide (10 mL) was stirred for 2 h at room temperature. The appropriate of ethyl chloroacetate, chloro acetyl chloride, chloroacetone or chloroacetonitrile (10 mmol) was added while stirring. Stirring was continued for 2 h. The resulting solid was collected and crystallized from a proper solvent affording 10, 11a and 11b, respectively.

3-(benzofuran-2-yl)-3-oxo-2-(4-oxo-3-phenylthiazolidin-2-yl)propanenitrile 10

Brown crystals from ethanol. Yield: 81% mp: 283-285°C; FT-IR (KBr, cm^-1): 3062 v (CH-aroma.), 2931, 2873 v (CH-aliph.), 2182 v (CN), 1664 v (CO), 1600 v (C=N). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 4.10 (s, 2H, CH₂), 6.90 (s, 1H, CH-furan) and 7.41-7.63 (m, 9H, ArH's). Anal. Calcd. for C₂₀H₁₂N₂O₃S (360.39): C, 66.65; H, 3.36; N, 7.77. Found: C, 66.61; H, 3.32; N, 7.72.

3-Amino-4-(benzofuran-2-yl-carbonyl)-5-phenylamino-thiophen-2-yl)ethanone 11

Brown crystals from ethanol. Yield 75% m.p. 280°C; FT-IR (KBr, cm^-1): 3240 v (NH), 3031 v (CH-arom.), 1670 (C=O), 1606 v (C=N). 1H NMR (300 MHz, DMSO-d6, δ, ppm): 4.20 (s, 2H, CH₂), 2.40 (s, 3H, CH₃), 4.20 (s, 1H, NH), 4.71 (s, 2H, NH₂), 6.90 (s, 1H, CH-furan), 7.41-7.63 (m, 9H, ArH's). Anal. Calcd. for C₂₁H₁₆N₂O₃S (376.43): C, 67.00; H, 4.28; N, 7.44; S, 8.52. Found: C, 67.13; H, 4.15; N, 7.37; S, 8.67.

2-(benzofuran-2-yl-carbonyl)-3-phenylamino-3(cyanomethylthio)acrylonitrile 12

Brown crystals from ethanol. Yield 75% mp. 160°C; FT-IR (KBr, cm^-1): 3128 v (NH), 3058 v (CH-aroma.), 2175 v (CN) 1H NMR (300 MHz, DMSO-d6, δ, ppm): 4.20 (s, 2H, CH2), 4.20 (s, 1H, NH), 6.81 (s, 1H, CH-furan) , 7.40-7.59 (m, 9H, ArH's). Anal. Calcd. for C₂₀H₁₃N₃O₂S (359.4): C, 66.84; H, 3.65; N, 11.69. Found: C, 66.70; H, 3.55; N, 11.59.

RESULTS AND DISCUSSION

Treatment of 3-(5-bromobenzofuran-2-yl)-3-oxo propanenitrile 1 with diazonium salt of heterocyclic amines 2a-e in ethanol containing sodium acetate solution under stirring afforded 3a-e, respectively (Scheme 1). The structures of the products were confirmed on the basis of elemental analysis, spectral data. Thus, 1HNMR of 3a revealed signals at δ=6.48 (s, 1H, pyrazole), 7.21-7.79 (m, 9H, ArH's); 8.81, 9.24 (s, 2H, 2NH).

In a similar manner, compound 1 reacted with each of benzenediazonium chloride and 4-methyl benzenediazonium chloride in ethanol containing sodium acetate to afford 5a and 5b, respectively (Scheme 1). The structure of 5a,b were confirmed based on elemental analysis and spectral data.

Furthermore, treatment of compound 1 with three different hydrazonoyl halides [9-12] 6a-c gave products generally assigned as 3-substituted 5-(5-bromobenzofuran-2-yl)-4-cyano-1-phenyl-1H-pyrazole derivatives 8a-c on the basis of their analytical and spectral data (Scheme 2).

On the other hand, 3-(benzofuran-2-yl)-3-oxopropanenitrile [13,14] 9 reacted with phenyl isothiocyanate and ethyl chloroacetate in N,N-dimethylformamide under stirring at room temperature affording 3-(benzofuran-2-yl)-3-oxo-2(4-oxo-3-phenylthiazolidin-2-ylidene)propanenitrile 10 (Scheme 3). The IR spectra of 10 displayed an absorption band at 2931, 2873 v (CH-aliph.), 2171 v (CN) and 1660 v (C=O). It’s ¹H NMR in (DMSO-d₆) revealed signals at δ 4.10 (s, 2H, CH²), 6.90 (s, 1H, CH-furan), 7.41-7.63 (m, 9H, ArH's). In a similar manner, compound 9 reacted with phenyl isothiocyanate and each of chloroacetone and chloroacetonitrile yielding 2-(benzofuran-2-yl-carbonyl)-3-phenylamino-3-(acetylmethylthio)propanenitrile 11 and 2-(benzofuran-2-yl-carbonyl)-3-phenyl amino-3(cyanomethylthio) propanenitrile 12, respectively (Scheme 3).

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