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Synthesis, Reactions and Biological Evaluation of Some Novel 5-Bromobenzofuran-Based Heterocycles

Ahmed Hamdy Halawa

Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt

Abstract: Condensation of 2-acetyl-5-bromobenzofuran with hydrazine derivatives 2a,b afforded hydrazone derivatives 3a,b, which reacted with alkyl halides4a,b to yield ethylidene derivatives 5a,b. Also, 3a reacted with hydrazonyl halides6a,b to give 1,3,4-thiadiazole derivatives 9a,b. Thiosemicarbazone3b was reacted with acetic anhydride and halogenated compounds to afford the corresponding heterocyclic derivatives 10, 11a,b, 12-17 and 18a,b.Moreover, interaction of 16 with tetracyanoethylene and salicyldehyde derivatives furnished 24 and 26a,b, respectively. Finally, reaction of 16 with DMF-DMA afforded enaminone29, which on treatment with different heterocyclic amines yielded 31 and 33 respectively. Some of the newly synthesized compounds showed promising antimicrobial activity.

Keywords: benzofuran, 1,3,4-thiadiazole, thiazolidinone, thiazole, antimicrobial

Received May 15, 2014; Revised May 26, 2014; Accepted May 26, 2014

Citation: Ahmed Hamdy Halawa, Synthesis, Reactions and Biological Evaluation of Some Novel 5-Bromobenzofuran-Based Heterocycles. World Journal of Organic Chemistry, 2 (1). 9-17. January 2014. doi:10.12691/wjoc-2-1-2

1. Introduction

Benzofuran derivatives are a class of fused ring heterocycles, that occur in a large number of natural products and have shown a high importance in medicinal chemistry [1,2]. Many natural products with benzofuran moiety exhibit interesting biological and pharmacological activities. They are antitumor [3], anti-inflammatory [4], antifungal [5], pesticidal and insecticidal [6], nematocidal [7], and anthelmintic [7]. On the other hand, thiosemicarbazones have been recently used as synthetic intermediates for heterocyclic compounds which have attracted much attention because of their widespread applications in the biological field [8,9,10,11,12]. In addition, thiazoles and their derivatives exhibit various biological activities such as antiviral, antimicrobial, antituberculosis and cytotoxic activities [13-22]. In continuation of my research on the synthesis of new heterocyclic compounds [23,24], this work deals with synthesis, characterization and biological evaluation of new compounds containing a benzofuran nucleus combined with thiosemicarbazide, thiazole and thiazolidinone moieties, which are expected to possess high biological activity.

2. Materials and Methods

All melting points are uncorrected. IR spectra (KBr) were recorded on FT-IR 5300 spectrometer and Perkin Elmer spectrum RXIFT-IR system (ν, cm⁻¹). The ¹H NMR spectra were recorded in (DMSO-d₆) at (300) MHz on a Varian Mercury VX-300 NMR spectrometer (δ, ppm) using TMS as an internal standard. ¹³C NMR spectra were recorded on Varian Mercury VX 300 NMR using DMSO-d6 as solvent and TMS as an internal standard. Mass spectra were obtained on GC Ms-QP 1000 EX mass spectrometer at 70 eV. The Microanalytical Research Center, Faculty of Science, Cairo University carried out elemental analyses.

General procedure for preparation of 3a,b.

A mixture of (1; 0.01mol) and methyl hydrazine carbodithioate(2a) or thiosemicarbazide(2b) (0.01 mol) in ethanol (30 ml) was refluxed for 2 h. The separated solid on heating was filtered off and recrystallized from dioxane to give compounds 3a,b respectively.

[(E)-methyl2-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazinecarbodithioate] (3a).

Brown crystals; Yield: 92%; mp: 155-157°C; IR (vcm⁻¹): 3176 (NH) and 1274 (C=S); ¹H-NMR (δ ppm): 2.40 (s, 3H, CH₃C=N), 2.48 (s, 3H, SCH₃), 7.44-7.92 (m, 4H, Ar-H and CH-furan) and 12.52 (s, 1H, NH); MS m/z (%): 342 (48); Anal. calcd. for C₁₂H₁₁BrN₂OS₂: C 41.99, H 3.23, N 8.16. Found: C 41.89, H 3.20, N 8.08.

[(E)-2-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazinecarbothioamide] (3b).

Yellow crystals; Yield: 88%; mp: 190-192°C; IR (vcm⁻¹): 3422, 3336, 3176 (NH₂/NH) and 1258 (C=S); ¹H-NMR (δ ppm): 2.33 (s, 3H, CH₃C=N), 7.36-7.87 (m, 4H, Ar-H and CH-furan), 8.43 (s, 2H, NH₂) and 10.53 (s, 1H, NH); MS m/z (%): 311 (73); Anal. calcd. for C₁₁H₁₀BrN₃OS: C 42.32, H 3.23, N 13.46. Found: C 42.26, H 3.17, N 13.39.

General procedure for preparation of 5a,b.

To a solution of 3a (0.01mol) and alkylating agent namely (methyl iodide, ethyl bromoacetate) (0.01 mol) in ethanol (30 ml) triethylamine (0.01 mol) was added. The resulting mixture was heated under reflux for 3h and left to cool. The precipitate product was collected and recrystallized from glacial acetic acid to give compounds 5a,b respectively.

[(E)-dimethyl(1-(5-bromobenzofuran-2-yl)ethylidene)carbonohydrazonodithioate] (5a).

Brown crystals; Yield: 85%; mp: 110-112°C; IR (vcm⁻¹): 2950 (CH-aliph.); ¹H-NMR (δ ppm): 2.34 (s, 3H, CH₃C=N), 2.37 (s, 3H, SCH₃), 2.49 (s, 3H, SCH₃) and 7.43-7.92 (m, 4H, Ar-H and CH-furan); Anal. calcd. for C₁₃H₁₃BrN₂OS₂: C 43.70, H 3.67, N 7.84. Found: C 43.62, H 3.60, N 7.78.

[Ethyl2-(((Z)-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)(methylthio)methyl)thio)acetate] (5b).

Yellow crystals; Yield: 83%; mp: 103-105°C; IR (vcm⁻¹): 1710 (C=O); ¹H-NMR (δ ppm): 1.21 (t, 3H, CH₃), 2.30 (s, 3H, CH₃C=N), 2.39 (s, 3H, SCH₃), 4.01 (s, 2H, CH₂), 4.16 (q, 2H, CH₂) and 7.44-7.93 (m, 4H, Ar-H and CH-furan); Anal. calcd. for C₁₆H₁₇BrN₂O₃S₂: C 44.76, H 3.99;, N 6.52. Found: C 44.69, H 3.90, N 6.46.

General procedure for preparation of 9a,b.

A mixture of 3a(0.01mol) and appropriate hydrazonyl halide 6a,b (0.01 mol) and triethylamine (1 ml) in ethanol (30 ml) was heated under reflux for 5 hrs. During the reflux period crystalline solids were separated. The resulting products were filtered off, washed with ethanol and recrystallized from dioxane to afford compounds 9a,b respectively.

[1-(5-{[1-(5-Bromo-benzofuran-2-yl)-ethylidene]-hydrazono}-4-phenyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl)ethanone] (9a).

Orange crystals; Yield: 80%; mp: 206-208°C; IR (vcm⁻¹): 2920 (CH-aliph.) and 1680 (C=O); ¹H-NMR (δ ppm): 2.33 (s, 3H, CH₃C=N), 2.38 (s, 3H, CH₃) and 7.34-8.03 (m, 9H, Ar-H and CH-furan); MS m/z (%): 454 (28); Anal. calcd. for C₂₀H₁₅BrN₄O₂S: C 52.76, H 3.32, N 12.30. Found: C 52.71, H 3.26, N 12.22.

[(5-{[1-(5-Bromo-benzofuran-2-yl)-ethylidene]-hydrazono}-4-phenyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-phenylmethanone] (9b).

Red crystals; Yield: 82%; mp: 150-152°C; IR (vcm⁻¹): 2924 (CH-aliph.) and 1640 (C=O); ¹H-NMR (δ ppm): 2.33 (s, 3H, CH₃C=N) and 7.36-8.25 (m, 14H, Ar-H and CH-furan); MS m/z (%): 516 (68); Anal. calcd. for C₂₅H₁₇BrN₄O₂S: C 58.03, H 3.31, N 10.83. Found: C 57.93, H 3.24, N 10.77.

Synthesis of [N-(4-acetyl-5-(5-bromobenzofuran-2-yl)-4,5-dihydro-5-methyl-1,3,4-thiadiazol-2-yl)acetamide] (10).

A solution of 3b (0.01 mol) and acetic anhydride (5 ml) was heated under reflux for 3h. After the reaction mixture was attained room temperature, excess acetic anhydride was decomposed by water (10 ml) and the mixture was stirred for 30 min. The separated product was filtered and recrystallized from glacial acetic acid to give compound 10.

White crystals; Yield: 62%; mp: 200-202°C; IR (vcm⁻¹): 3308 (NH), 2938 (CH-aliph.) and 1704, 1660 (2C=O); ¹H-NMR (δ ppm): 2.05 (s, 3H, CH₃), 2.16 (s, 3H, CH₃), 2.25 (s, 3H, CH₃), 6.89-7.83 (m, 4H, Ar-H and CH-furan) and 11.74 (s, 1H, NH); Anal. calcd. for C₁₅H₁₄BrN₃O₃S: C 45.47, H 3.56, N 10.60;. Found: C 45.38, H 3.50, N 10.49.

General procedure for preparation of 11a,b and 12-15.

A mixture of 3b(0.01mol) and α-halo derivatives namely (methyl α-bromobutyrate, ethyl α-bromobutyrate, chloroacetyl chloride, chloroacetonitrile, chloroacetaldehyde and ethyl-4-chloroacetoacetate) (0.01 mol) in ethanol (30 ml) containing fused sodium acetate (0.02 mol) was refluxed for 3h, the obtained products were collected by filtration, washed with water and recrystallized from dioxane to give compounds 11a,b and 12-15 respectively.

[(E)-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-5-methyl- thiazolidin-4-one] (11a).

White crystals; Yield: 92%; mp: 205-207°C; IR (vcm⁻¹): 3255 (NH) and 1722 (C=O); ¹H-NMR (δ ppm): 2.35 (s, 3H, CH₃), 2.36 (s, 3H, CH₃), 7.40-7.92 (m, 5H, Ar-H, CH-furan and CH-thiazolidinone) and 12.03 (s, 1H, NH); MS m/z (%): 365 (90); Anal. calcd. for C₁₄H₁₂BrN₃O₂S: C 45.91, H 3.30, N 11.47. Found: C 45.85, H 3.22, N 11.40.

[(E)-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-5-ethyl -thiazolidin-4-one] (11b).

White crystals; Yield: 90%; mp: 210-212°C; IR (vcm⁻¹): 3140 (NH), 2958 (CH-aliph.) and 1698 (C=O); ¹H-NMR (δ ppm): 0.99 (t, 3H, CH₃), 2.36 (s, 3H, CH₃), 4.24 (q, 2H, CH₂), 7.36-7.92 (m, 5H, Ar-H, CH-furan and CH-thiazolidinone) and 12.05 (s, 1H, NH); Anal. calcd. for C₁₅H₁₄BrN₃O₂S: C 47.38, H 3.71, N 11.05. Found: C 47.32, H 3.66, N 11.00.

[(E)-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)thiazoli-din-5-one] (12).

Orange crystals; Yield: 68%; mp: 214-216°C; IR (vcm⁻¹): 3180 (NH), 2924 (CH-aliph.) and 1700 (C=O); ¹H-NMR (δ ppm): 2.34 (s, 3H, CH₃), 3.90 (s, 2H, CH₂), 7.36-7.95 (m, 4H, Ar-H and CH-furan) and 12.05 (s, 1H, NH); Anal. calcd. for C₁₃H₁₀BrN₃O₂S: C 44.33, H 2.86, N 11.93. Found: C 44.27, H 2.80, N 11.86.

[(E)-2-(2-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazinyl)thiazol-4(5H)-imine] (13).

Red crystals; Yield: 79%; mp: 166-168°C; IR (vcm⁻¹): 3154 (NH) and 2922 (CH-aliph.); ¹H-NMR (δ ppm): 2.33 (s, 3H, CH₃), 4.01 (s, 2H, CH₂), 7.29-8.34 (m, 4H, Ar-H and CH-furan) and 8.78, 10.55 (2s, 2H, 2NH); Anal. calcd. for C₁₃H₁₁BrN₄OS: C 44.46, H 3.16, N 15.95. Found: C 44.40, H 3.10, N 15.88.

[(E)-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-2,3-dihydro- thiazole] (14).

Gray crystals; Yield: 81%; mp: 180-182°C; IR (vcm⁻¹): 3190 (NH); ¹H-NMR (δ ppm): 2.31 (s, 3H, CH₃), 6.84, 7.24 (dd, 2H, 2CH), 7.19-7.87 (m, 4H, Ar-H and CH-furan) and 11.36 (s, 1H, NH); Anal. calcd. for C₁₃H₁₀BrN₃OS: C 46.44, H 3.00, N 12.50. Found: C 46.37, H 2.92, N 12.41.

[Ethyl 2-((E)-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-2,3-di-hydrothiazol-4-yl)acetate] (15).

Orange crystals; Yield: 68%; mp: 208-210°C; IR (vcm⁻¹): 3160 (NH) and 1722 (C=O); ¹H-NMR (δ ppm): 1.20 (t, 3H, CH₃), 3.71 (s, 2H, CH₂), 4.14 (q, 2H, CH₂), 6.79 (s, 1H, CH), 7.24-7.88 (m, 4H, Ar-H and CH-furan) and 10.12 (s, 1H, NH); Anal. calcd. for C₁₇H₁₆BrN₃O₃S: C 48.35, H 3.82, N 9.95. Found: C 48.28, H 3.75, N 9.90.

Synthesis of [2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)thiazolidin-4-one] (16).

A mixture of 3b(0.01mol), ethyl bromoacetate (0.01 mol) and fused sodium acetate (0.02 mol) in ethanol (30 ml) was refluxed for 2h, the obtained product was collected by filtration, washed with water and recrystallized from glacial acetic acid to give compound 16.

Yellow crystals; Yield: 94%; mp: 225-227°C; IR (vcm⁻¹): 3272 (NH), 2932 (CH-aliph.) and 1702 (C=O); ¹H-NMR (δ ppm): 2.35 (s, 3H, CH₃), 3.89 (s, 2H, CH₂), 7.36-7.92 (m, 4H, Ar-H and CH-furan) and 12.15 (s, 1H, NH); MS m/z (%): 351 (43); Anal. calcd. for C₁₃H₁₀BrN₃O₂S: C 44.33, H 2.86, N 11.93. Found: C 44.27, H 2.80, N 11.86.

Synthesis of [ethyl 2-(2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-oxothiazolidin-3-yl)acetate] (17).

Method A

A mixture of 16(0.01mol), fused sodium acetate (0.02 mol) and ethyl bromoacetate (0.01 mol) in ethanol (30 ml) was refluxed for 3h, after cooling the solid which formed was collected and recrystallized from dioxane to give compound 17.

Method B

A mixture of 3b(0.01mol), ethyl bromoacetate (0.02 mol) and fused sodium acetate (0.02 mol) in ethanol (40 ml) was refluxed for 3h, after cooling the obtained product was collected and recrystallized from dioxane to give compound 17.

M.p, mixed m.p with product from procedure (A) gave no depression.

Yellow crystals; Yield: 74%; mp: 170-172°C; IR (vcm⁻¹): 2980 (CH-aliph.) and 1730 (C=O); ¹H-NMR (δ ppm): 1.19 (t, 3H, CH₃), 2.33 (s, 3H, CH₃), 4.14 (q, 2H, CH₂), 4.52 (s, 2H, CH₂), 4.63 (s, 2H, CH₂) and 7.35-7.92 (m, 4H, Ar-H and CH-furan); Anal. calcd. for C₁₇H₁₆BrN₃O₄S: C 46.59, H 3.68, N 9.59. Found: C 46.50, H 3.60, N 9.53.

General procedure for preparation of 18a,b.

A mixture of 3b(0.01mol) and chloroacetone and/or phenacyl bromide (0.01 mol) and fused sodium acetate (0.02 mol) in ethanol (30 ml) was refluxed for 2h. The solid product that formed was collected by filtration and recrystallized from dioxane to give compound 18a,b.

[2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-methyl-2,3-dihydro- thiazole] (18a).

Black crystals; Yield: 61%; mp: 180-182°C; IR (vcm⁻¹): 3184 (NH) and 2924 (CH-aliph.); ¹H-NMR (δ ppm): 2.16 (s, 3H, CH₃), 2.33 (s, 3H, CH₃), 6.33 (s, 1H, CH-thiazole), 7.18-7.89 (m, 4H, Ar-H and CH-furan) and 11.35 (s, 1H, NH); Anal. calcd. for C₁₄H₁₂BrN₃OS: C 48.01, H 3.45, N 12.00. Found: C 47.93, H 3.39, N 11.94.

[2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-phenyl-2,3-dihydro- thiazole] (18b).

Orange crystals; Yield: 66%; mp: 258-260°C; IR (vcm⁻¹): 3172 (NH) and 2924 (CH-aliph.); ¹H-NMR (δ ppm): 2.35 (s, 3H, CH₃), 7.26-8.30 (m, 10H, Ar-H, CH-furan and CH-thiazole) and 11.65 (s, 1H, NH); Anal. calcd. for C₁₉H₁₄BrN₃OS: C 55.35, H 3.42, N 10.19. Found: C 55.28, H 3.36, N 10.00.

Synthesis of [2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-phenyl-5-(phenyldiazenyl)-2,3-dihydrothiazole] (19).

Method A

To a cold solution of 18b (0.01 mol) in ethanol containing sodium acetate (3g), benzene diazonium chloride (0.01 mol) was added, [prepared by diazotization of aniline (0.012 mol) in conc. HCl (6 ml) with sodium nitrite (0.97 g in 5 ml H₂O) at 0° c] portion wise over (30 min) with constant stirring. After complete addition, the reaction mixture was stirred for a further 1h at 0°c. The solid product was filtered off, washed with water and recrystallized from glacial acetic acid to give compound 19.

Method B

To a mixture of 3b(0.01mol) and appropriate hydrazonyl halide 6b (0.01 mol) in ethanol (30 ml), triethylamine (0.5 ml) was added and the reaction mixture was refluxed for 2h. The isolated product was collected by filtration and recrystallized to give a product that was identical in m.p, mixed m.p and spectral data with 19, which was obtained from method A.

Red crystals; Yield: 68%; mp: 196-198°C; IR (vcm⁻¹): 3184 (NH); MS m/z (%): 515 (26); Anal. calcd. for C₂₅H₁₈BrN₅OS: C 58.14, H 3.51, N 13.56. Found: C 58.08, H 3.45, N 13.50.

Synthesis of [(5E)-2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-5-(4-methoxybenzylidene)thiazolidin-4-one] (20).

Method A

A mixture of 16 (0.01 mol) and p-methoxybenzaldehyde (0.01 mol) in ethanol (30 ml) in the presence of piperidine (1 ml) was refluxed for 1h, the resulting solid on heating was collected by filtration and recrystallized from dioxane to give compound 20.

Method B

A mixture of 16 (0.01 mol) and α-cyano-4-methoxyphenyl cinnamonitrile(0.01 mol) in ethanol (30 ml) in the presence of piperidine (1 ml) was refluxed for 1h. The resulting solid on heating was collected by filtration and recrystallized from dioxane to give compounds 20.

M.p. and mixed m.p. determined with authentic sample gave no depression.

Yellow crystals; Yield: 88%; mp: 230-232°C; IR (vcm⁻¹): 3252 (NH) and 1700 (C=O); ¹H-NMR (δ ppm): 2.43 (s, 3H, CH₃), 3.84 (s, 3H, OCH₃), 7.11-7.94 (m, 9H, Ar-H, CH-furan and CH=C) and 12.58 (s, 1H, NH); Anal. calcd. for C₂₁H₁₆BrN₃O₃S: C 53.63, H 3.43, N 8.93. Found: C 53.57, H 3.38, N 8.86.

Synthesis of [2-(2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-oxothiazolidin-5-ylidene)malononitrile ] (24).

A mixture of 16 (0.01 mol) and tetracyanoethylene (0.01 mol) in ethanol (30 ml) and a catalytic amount of piperidine was refluxed for 2 h. The precipitate formed was filtered off hot, washed with ethanol several times, dried and recrystallized from dioxane to give compound 24.

Black crystals; Yield: 58%; mp: 300-302°C; IR (vcm⁻¹): 3318 (NH), 2218 (CN) and 1708 (C=O); MS m/z (%): 413 (76); Anal. calcd. for C₁₆H₈BrN₅O₂S: C 46.39, H 1.95, N 16.91. Found: C 46.30, H 1.89, N 16.82.

General procedure for preparation of 26a,b.

A mixture of 16 (0.01 mol) and o-hydroxycarboxaldehyde derivatives namely (5-bromosalicylaldehyde and 2-hydroxy-1-naphthaldehyde) (0.01 mol) and piperidine (0.01) in ethanol (40 ml) was heated under reflux for 3 h, the solid products which produced on heating was collected and recrystallized from dioxane to give compounds 26a,b.

[7-bromo-2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-2H-chromeno- [2,3-d]thiazole ] (26a).

Brown crystals; Yield: 60%; mp: 252-254°C; MS m/z (%): 515 (24); Anal. calcd. for C₂₀H₁₁Br₂N₃O₂S: C 46.45, H 2.14, N 8.12. Found: C 46.39, H 2.08, N 8.05.

[9-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-9H-benzo[5,6]chromeno- [2,3-d]thiazole] (26b).

Brown crystals; Yield: 77%; mp: 266-268°C; MS m/z (%): 487 (30); Anal. calcd. for C₂₄H₁₄BrN₃O₂S: C 59.03, H 2.89, N 8.60. Found: C 58.96, H 2.82, N 8.53.

Synthesis of [(5Z)-5-(4-amino-3-phenylthiazol-2(3H)-ylidene)-2-((1-(5-bromo- benzofuran-2-yl)ethylidene)hydrazono)thiazolidin-4-one] (28).

To a cold suspension of finely grounded KOH (0.01 mol) in dry DMF (30 ml), thiazolidinone derivative 16 (0.01 mol) and subsequently phenyl isothiocyante (0.01 mol) were added, the reaction was stirred overnight at room temperature, then treated with chloroacetonitrile (0.01 mol) and left at room temperature for an additional 24 hr. The reaction mixture was then treated with cold H₂O (50 ml) and neutralized with 1N HCl. The resulting precipitate was collected by filtration, washed with water, dried and recrystallized from dioxane to give compound 28.

Gray crystals; Yield: 50%; mp: 204-206°C; IR (vcm⁻¹): 3340, 3212, 3124 (NH₂/NH) and 1702 (C=O); ¹H-NMR (δ ppm): 2.33 (s, 3H, CH₃), 4.90 (s, 1H, CH-thiazole), 7.33-7.94 (m, 11H, Ar-H, CH-furan and NH₂) and 12.04 (s, 1H, NH); MS m/z (%): 525 (38); Anal. calcd. for C₂₂H₁₆BrN₅O₂S₂: C 50.19, H 3.06, N 13.30. Found: C 50.10, H 3.00, N 13.23

Synthesis of [(5E)-2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-5-((dimethylamino)methylene)thiazolidin-4-one ] (29).

A mixture of thiazolidinone derivative 16 (0.01 mol) and DMF-DMA (0.01 mol) in dry benzene (40 ml) was heated under reflux for 5 hrs. The separated solid was filtered off, washed with ethanol and recrystallized from dioxane to give compound 29.

Brown crystals; Yield: 88%; mp: 188-190°C; IR (vcm⁻¹): 3290 (NH) and 1718 (C=O); ¹H-NMR (δ ppm): 2.34 (s, 3H, CH₃), 2.46, 3.15 (2s, 6H, N(CH₃)₂), 6.81-7.93 (m, 5H, Ar-H, CH-furan and CH=C) and 10.62 (s, 1H, NH); Anal. calcd. for C₁₆H₁₅BrN₄O₂S: C 47.18, H 3.71, N 13.76. Found: C 47.12, H 3.66, N 13.68.

Synthesis of [2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-9-thioxo-8,9-dihydro-1H-pyrimido[1,6-a]thiazolo[5,4-e]pyrimidin-7(2H)-one] (31).

A mixture of enaminone29 (0.01 mol) and 6-amino-2-thiouracil (0.01 mol) in glacial acetic acid (40 ml) was refluxed for 3 h. The solvent was removed by distillation under reduced pressure and the resulting solution was left to cool. The solid precipitate was collected by filtration and recrystallized from dioxane to give compound 31.

Red crystals; Yield: 55%; mp: 290-292°C; IR (vcm⁻¹): 3327, 3200 (2NH) and 1688 (C=O); MS m/z (%): 486 (25); Anal. calcd. for C₁₈H₁₁BrN₆O₂S₂: C 44.36, H 2.28, N 17.24. Found: C 44.29, H 2.22, N 17.18.

Synthesis of [2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-7-(methylthio)-1,2-dihydropyrazolo[1,5-a]thiazolo[5,4-e]pyrimidine-6-carbonitrile] (33).

A solution of enaminone29 (0.01 mol) and 5-amino-3-methylthiopyrazole-4-carbonitrile (0.01 mol) in glacial acetic acid (30 ml) was heated under reflux for 7 hrs. During the reflux period, a crystalline solid was separated. The obtained solid was filtered off, washed with ethanol and recrystallized from dioxane to give compound 33.

Brown crystals; Yield: 58%; mp: 268-270°C; IR (vcm⁻¹): 3210 (NH) and 2220 (CN); MS m/z (%): 469 (48); Anal. calcd. for C₁₉H₁₂BrN₇OS₂: C 45.79, H 2.43, N 19.67. Found: C 45.70, H 2.37, N 19.60.

3. Results and Discussion

In the interest of the above suggestion, condensation of 2-acetyl-5-bromobenzofuran (1) [25] with methyl hydrazinecarbodithioate and thiosemicarbazide(2a,b) in ethanol at reflux temperature afforded (methyl-2-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazinecarbodithioate) (3a) and (2-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazinecarbothioamide) (3b), respectively. The ¹H NMR spectrum for 3a exhibited two singlet signals at δ 2.40 and 2.48 ppm due to 2CH₃ groups, while the ¹H NMR spectrum for 3b showed the presence of downfield two singlet signals at 8.43 and 10.53 ppm assigned to NH₂ and NH respectively, (Scheme 1).

Treatment of 3a with methyl iodide (4a) gave the corresponding bis alkyl thio derivative 5a. Also alkylation of 3a with ethyl bromoacetate (4b) afforded the corresponding methylthio ethoxycarbonyl thiomethylene derivative 5b. The structures of the reaction products were ascertained on the basis of their elemental analysis and spectral data, where showed no evidences for the presence of an (NH) group in both IR and ¹H NMR spectra, (Scheme 2).

Interaction of alkyl dithioester 3a with hydrazonyl halides 6a,b [26,27] in ethanol containing triethylamine at reflux temperature furnished 1,3,4-thiadiazole derivatives 9a,b respectively, which established based on elemental analysis and spectroscopic data. The formation of compounds 9a,b could be interpreted through the elimination of alkyl mercaptan from the corresponding cyclo adduct 8a.b, which are assumed to be formed from the 1,3-dipolar cycloaddition of nitrile imines 7a,b [formed from 6a,b and triethylamine in situ] to the (C=S) group in 3a, (Scheme 3).

Thiosemicarbazone derivative 3b was considered as a good starting material for the synthesis of many heterocyclic compounds. (N-(4-acetyl-5-(5-bromo- benzofuran-2-yl)-4,5-dihydro-5-methyl-1,3,4-thiadiazol-2-yl)acetamide) (10)was prepared by refluxing 3b with acetic anhydride. Its IR spectrum showed new bands at 1704, 1660 cm⁻¹ attributed to carbonyl groups, while ¹H NMR spectrum indicated three signals due to methyl groups at 2.05, 2.16 and 2.25 ppm.

The behavior of the thiocarbamoyl functional group in compound 3b towards some α-halo compounds was investigated. Thus, the reaction of 3b with alkyl α-bromo butyrate in refluxing ethanol in the presence of fused sodium acetate produced thiazolidin-4-one derivatives 11a,b. The reaction pathway is assumed to proceed via S-alkylation followed by intramolecular cyclization with concomitant loss of an alcohol molecule (Scheme 4). The infrared spectrum of compounds 11a,b showed absorption bands at 1722 and 1698 cm⁻¹ (2C=O) respectively, while the mass spectrum of compound 11a indicated a molecular ion peak at m/z 365 (90). The ¹H NMR spectrum of compound 11b revealed a triplet and quartet at δ 0.99, 4.24 ppm for the methyl and methylene protons. Also, treatment of thiosemicarbazone derivative 3b with chloroacetyl chloride in boiling ethanol containing a catalytic amount of anhydrous sodium acetate afforded thiazolidin-5-one derivative 12. Its ¹H NMR spectrum showed a new singlet at 3.90 ppm attributed to CH₂ thiazolidinone. The novel iminothiazole derivative 13 was obtained by the reaction of compound 3b with chloroacetonitrile in ethanol containing anhydrous sodium acetate. Moreover, interaction of compound 3b with chloroacetaldehyde in refluxing ethanol containing fused sodium acetate furnished a single product which identified as: (2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-2,3-dihydrothiazole) (14). Its ¹H NMR spectrum exhibited signal characteristic for NH proton and two new signals at 6.84, 7.24 ppm attributed to 2CH thiazole. Furthermore, thiosemicarbazone derivative 3b was reacted with ethyl-4-chloroacetoacetate under the same reaction conditions to produce (ethyl-2-(-2-((E)-(1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono )-2,3-dihydrothiazol-4-yl)acetate) (15). The ¹H NMR spectrum of 15 in DMSO-d₆ exhibited a triplet at δ 1.20 ppm characteristic for CH₃ protons and a quartet at δ 4.14 ppm for CH₂ protons, (Scheme 4).

On the same manner, when thiosemicarbazone derivative 3b treated with one equivalent of ethyl bromoacetate in refluxing ethanol containing a catalytic amount of anhydrous sodium acetate underwent a cyclization thus giving the thiazolidinone derivative 16. However, 3b reacted with two moles of ethyl bromoacetate to give N-ethoxycarbonylthiazolidinone derivative 17, which was obtained from treatment of 16 with ethyl bromoacetate, (Scheme 5). The ¹H NMR spectrum of 17 lacked signal characteristic of NH proton and showed a new two signals at 4.52, 4.63 ppm attributed to 2CH₂ groups. Interaction of 3b with haloketones under the same reaction conditions afforded thiazole derivatives 18a,b. When 18b subjected to coupling reaction with benzene diazonium chloride in ethanol/sodium acetate, gave phenyl azothiazole derivative 19. The latter compound was prepared directly from the cyclocondensation reaction of 3b with hydrazonyl halide 6b in ethanol containing triethylamine under reflux, (Scheme 5).

The reactivity of (2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)thiazolidin-4-one) (16) toward some electrophilic reagents was investigated. Thus, condensation of compound 16 with p-methoxybenzaldehyde in boiling ethanol containing a catalytic amount of piperidine afforded the corresponding benzylidine thiazolidinone derivative 20, (Scheme 6).

In contrast to the anticipated formation of pyrano[2,3-d]thiazole derivative 21, the reaction of 16 with α-cyano-4-methoxyphenylcinnamonitrile in boiling ethanol/piperidine afforded a product identical in all aspects (mp, mixed mp and spectral data) with compound 20. The formation of this compound was assumed to proceed via retro Michael addition through the elimination of malononitrile from the non-isolable adduct 22. Moreover, the reaction of 16 with tetracyanoethylene in ethanol-piperidine under reflux furnished the product which identified as: (2-(2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-4-oxo-thiazolidin-5-ylidene)malononitrile) (24). The formation of compound 24 could be interpreted through addition of 16 to the activated double bond to form intermediate 23 followed by intramolecular cyclization through elimination of malononitrile molecule to afford the final product. Cyclization of compound 16 with salicylaldehyde derivatives in ethanol under reflux in the presence of piperidine yielded the corresponding chromeno[2,3-d]thiazole derivatives 26a,b. Formation of these compounds may be explained by condensation of 16 with salicylaldehyde derivatives afforded acyclic intermediate 25a,b which undergoes intramolecular cyclization and tautomerization through nucleophilic addition of the (OH) group to the carbonyl site followed by elimination of water molecule yielded the expected compounds 26a,b respectively, (Scheme 6).

The active methylene group in thiazolidinone derivative 16 was allowed to react with phenyl isothiocyante in dimethylformamide in the presence of potassium hydroxide at room temperature yielded the non-isolable intermediate potassium sulfide salt 27, which treated with chloroacetonitrile at room temperature afforded the corresponding thiazole derivative 28. The formation of 28 was assumed to proceed through the initial alkyla-tion by loss of potassium chloride followed by in situ heterocyclization via Dieckmann type [28]. Treatment of equimolar quantities of thiazolidinone derivative 16 with dimethylformamide dimethylacetal (DMF-DMA) in refluxing benzene afforded the corresponding enaminone as ((5E)-2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-5-((dimethylamino)-methylene)thiazolidin-4-one) (29), (Scheme 7).

Finally, this investigation was extended to include the reactivity of enaminone 29 towards heterocyclic amine namely; (6-amino-2-thiouracil [29] and 5-amino-3-methylthiopyrazole-4-carbonitrile [30]) in glacial acetic acid under reflux to yield a product which identified as: (2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-9-thioxo-8,9-dihydro-1H-pyrimido[1,6-a]thiazolo[5,4-e]pyrimidin-7(2H)-one) (31) and (2-((1-(5-bromobenzofuran-2-yl)ethylidene)hydrazono)-7-(methylthio)-1,2-dihydropyrazolo[1,5-a]thiazolo[5,4-e]pyrimidine-6-carbonitrile) (33) respectively. The formation of 31 and 33 were explained by the addition of exoamino group of heterocyclic amines to unsaturated moiety of enaminone 29 to yield the corresponding acyclic non-isolable intermediates 30,32 which undergoes intramolecular cyclization through nucleophilic addition of imino (NH) to the carbonyl group followed by elimination of dimethylamine and water molecules to afford the final products, (Scheme 7).

Antimicrobial Activity:The synthesized compounds were tested for their antimicrobial activities in vitro by agar diffusion method using "Mueller–Hinton" agar medium for bacteria and "Sabouraud’s" agar medium for yeasts.

Theassayed collection included two Gram-positive bacteria: Bacillus subtilis (NCIB 3610) and Staphylococcus aureus (NCTC7447); two Gram-negative bacteria: Escherichia coli (NCTC10416) and Pseudomonas aeruginosa (NCIB 9016); Unicellularfungi: Candida albicans (IMRU 3669) and Filamentous fungi:Aspergillus niger (ATCC 16404) using Ampicillin 25 µg/ml as areference compound. The inhibition zone diameters were recordedand rounded up to the nearest whole number (mm) for analysis. The inhibitory effects of the synthesized compounds againstthese organisms are given in Table 1.

The results of antimicrobial screening show that; compounds 13, 19, 20 were the most active compounds againstBacillus subtilis (NCIB 3610) and the compounds 28, 29, 31gave good results againstStaphylococcus aureus (NCTC7447). Also the results indicated that compounds3a, 15, 18bexhibited highest activity againstEscherichia coli (NCTC10416) and the compounds 5a, 13, 29showed well results against Pseudomonas aeruginosa (NCIB 9016).While11b, 12, 13 were the most active compounds againstCandida albicans (IMRU 3669) and the remaining compounds showed moderate activity. The results of antimicrobial activity illustrate that the presence of benzofuran compounds incorporated with SCH₃ group and/orthiazole moiety substitutedwith electron donating groups like CH₃, C₂H₅, NH, NH₂ increases the antibacterial as well as antifungal activities.

Table 1. Biological activity of the newly synthesized compounds

Antimicrobial Assay:

In the agar diffusion method [31,32] compounds dissolved indimethylformamide (DMF) at a concentration of 100 mg/mL were used. Agar media seeded with the tested microorganisms were poured in Petri dishes and were allowed to solidify, and then holes of about 7 mm were punched in the agar using a sterile cork porrer. A 50-μl volume of the dissolved compounds were added to the pores and DMF was included as solvent control. Plates were allowed to stand in a refrigerator for two hours before incubation to allow the tested compounds to diffuse through the agar. The plates containing bacterial cultures were incubated at 37°C for 24 h and those containing yeasts were incubated at 30°C for 48h. After incubation, the growth inhibition zones around the holes were observed, indicating that the examined compoundinhibits thegrowth of microorganism. The tested microorganisms were obtained from the Regional Center for Mycology & Biotechnology (RCMP), Al-Azhar University.

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