|Basma S Baaue, Khalid M Darwish* and Hussniya Al-Difar|
|Corresponding Author: Khalid M Darwish, Department of Chemistry, Faculty of Science, University of Benghazi, Libya, Tel: 00218945693580; E-mail: email@example.com|
|Received: January 10, 2019; Accepted: January 21, 2019; Published: May 09, 2019;|
|Citation: Baaue BS, Darwish KM & Al-Difar H. (2019) Synthesis of Novel Heterocyclic Compounds Containing Benzofuran Moiety. J Pharm Drug Res, 2(3): 120-123.|
|Copyrights: ©2019 Baaue BS, Darwish KM & Al-Difar H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
1. Abdel‐Aziem A (2015) An efficient and simple synthesis of 2,3-dihydro-1,3,4-thiadiazoles, pyazoles and coumarins containing benzofuran moiety using both conventional and grinding methods. Int J Pharm Sci 7: 32.
2. Abdel‐Aziem A, AbdelhamidA O (2013) One pot synthesis of pyridine, thiazolidine, pyrazole and 2, 3-dihydro-1, 3, 4-thiadiazole derivatives under solvent-free condition. Int J Adv Res 9: 717-728.
3. Halawa AH (2014) Synthesis, reactions and biological evaluation of some novel 5-bromobenzofuran-based heterocycles. World J Org Chem 2: 9-17.
4. Santana L, Teijeira M, Uriarte E, Teran C, Linares B, et al. (1998) AM1 theoretical study, synthesis and biological evaluation of some benzofuran analogues of anti-inflammatory aryl alkanoic acids. Eur J Pharm Sci 7: 161-166.
5. Findlay JA, Buthelezi S, Li G, Seveck M (1997). Insect toxin from an endophytic fungus from wintergreen. J Nat Prod 60: 1214-1215.
6. Dawood KM, Abdel-Gawad H, Rageb EA, Ellithey M, Mohamad HA (2006) Synthesis, anti-convulsant and anti-inflammatory evaluation of some new benzotriazole and benzofuran based heterocycles. Bioorg Med Chem 14: 3672-3680.
7. Rida SM, EI-Hawash SAM, Fahmy HTY, Hazzaa AA, EIMeligy MMM (2006) Synthesis of novel benzofuran and related benzimidazole derivative for evaluation of in vitro anti-HIV-1, anticancer and antimicrobial activites. Arch Pham Res 29: 826-833.
8. Raj PA, Suddendra G, Shakeeland AS, Girish M (2012) Synthesis of new benzofuran derivatives and their in vitro evaluation for antimicrobial activity. Inter J Drug Formulation Res 3: 135-147.
9. Eweiss NE, Osman A (1979) Synthesis of heterocycles. One step synthesis of acetyl thiadiazolines. Tetrahedron Lett 13: 1169-1170.
10. Shawali AS, Abdelhamid AO (1976) Reaction of dimethylphenacylsulfonium bromide with N-nitrosoacetarylamides and reactions of the products with nucleophiles. Bull Soc Chim Jpn 49: 321-324.
11. Shawali AS, Osman A (1971) Synthesis and reactions of phenylcarbamoyl-arylhydrazidic chlorides. Tetrahedron 27: 2517-2528.
12. Abdelhamid AO, Attaby FA, Zaki MY (1990) Reactions with 2-(thiocyanatoacetyl) and 2-(selenacyanoacetyl)-2-benzofuran. Synthesis of some new thiadiazoline, selenadiazoline, thiadiazolo[2,3-b] quinazopline and arylazothiazole derivatives. Phosphorous, Sulfur, Silicon and Related Element 53: 403-410.
13. Yilmaz M, Uzunalioglu N, Pekel AT (2005) Manganese (III) acetate based oxidative cyclizations of 3-oxopropanenitriles with conjugated alkenes and synthesis of 4,5-dihydrofuran-3-carbonitriles containing heterocycles. Tetrahedron 61: 8860.
14. Yılmaz EVB, Yılmaz M, Oktemer A (2011) Radical cyclizations of conjugated esters and amides with 3-oxopropanenitriles mediated by manganese (III) acetate. Arkivoc 2: 363-376.