Facile Synthesis of 4,5-Dihydro-1,3,4-Thiadiazoles by 1,3-Dipolar Cycloaddition of Thioisomünchnones

B.S. thanks the Spanish Ministerio de Educación y Ciencia for a Ph.D. scholarship. Financial support from the same Ministry (Grants CTQ2005–07676 and CTQ2007–66641) is gratefully acknowledged. We are thankful to Professors J. L. Jiménez and P. Cintas (Universidad de Extremadura) for valuable comments on this work.

[1]   Kornis G., in Comprehensive Heterocyclic Chemistry (Eds A. R. Katritzky, C. W. Rees) 1984, Vol. 6, Part 4B, pp. 575–577 (Pergamon Press: Oxford).

[2]   N. S. A. M. Khalil, Eur. J. Med. Chem. 2007, 42,  1193.
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[20]   Typical Procedure (3): To a solution of 1 (1.0 mmol) in CH₂Cl₂ (3 mL) was added the corresponding azodicarboxylate (2, 1.0 mmol) and the reaction mixture was stirred at room temperature for 60 min. After removal of the solvent under vacuum, the product crystallized from diethyl ether in moderate to good yields (40–65%, not optimized). Spectrocopic data: (3a) Mp 179°C (dec.). ¹H-NMR (400 MHz, CDCl₃) δ 8.35–7.26 (14H, m, ar), 4.45 (2H, s, CH₂), 3.65 (3H, s, COOCH₃), 3.37 (3H, s, COOCH₃), 2.96 (3H, s, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ 168.08 (C=O(C-5)), 153.70 (C=O(OCH₃)), 152.43 (C=O(OCH₃)), 151.00 (C-2), 147.45, 143.51, 136.69, 136.41, 129.35, 128.92, 128.77, 128.56, 127.98, 127.86, 127.74, 127.68, 127.53, 125.89, 125.04, 124.68, 119.70 (ar), 88.83 (C-5), 56.95 (CH₂), 54.44 (CH₃OOC), 53.34 (CH₃OOC), 37.15 (NCH₃). IR ν_max/cm^–1 1743, 1688, 1528, 1353, 1254. HRMS (CI) C₂₇H₂₅N₅O₇S requires [M+Na]⁺ 586.1372; Found 586.1405. (3b) ¹H-NMR (400 MHz, CDCl₃) δ 8.37–7.12 (14H, m, ar), 4.47 (2H, s, CH₂), 2.91 (3H, s, NCH₃), 1.52 (9H, s, C(CH₃)₃), 1.28 (9H, s, C(CH₃)₃). (3c) Mp 154°C. Elemental analysis found: C 58.88, H 4.92, N 11.83, S 5.24. C₂₉H₂₉N₅O₇S requires C 58.88, H 4.94, N 11.84, S 5.41%. ¹H-NMR (400 MHz, CDCl₃) δ 8.34–7.26 (14H, m, ar), 4.44 (2H, s, CH₂), 4.04 (2H, bm, CH₂), 3.89 (1H, m, J_H,H′ 11.2, J_CH2,CH3 7.1, CH₂), 3.78 (1H, m, J_H,H′ 11.1, J_CH2,CH3 7.2, CH₂), 2.96 (3H, s, NCH₃), 1.17 (3H, bs, CH₃), 0.91 (3H, t, J 7.0, CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ 168.21 (C=O(C-5)), 153.22 (C=O(OCH₂CH₃)), 151.97 (C=O(OCH₂CH₃)), 150.77 (C-2), 147.32, 143.71, 137.02, 136.50, 129.30, 128.72, 127.81, 127.65, 127.59, 124.59 (ar), 88.74 (C-5), 64.22 (OCH₂), 62.16 (OCH₂), 56.86 (NCH₂), 37.12 (NCH₃), 14.33 (CH₃), 13.64 (CH₃). IR ν_max/cm^–1 1740, 1720, 1690, 1620, 1520, 1250, 740, 730, 700.

[21]   The authors have deposited the atomic coordinates for this structure with the Cambridge Crystallographic Data Centre. The coordinates can be obtained, upon request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. Crystal data for 3c (CCDC-146112), C₂₉H₂₉N₅O₇S, Mr = 590.63, monoclinic, P2₁/c, a = 12.127(6), b = 19.843(10), c = 12.262(3) Å, V = 2931(2) ų, Z = 4, D_calcd = 1.341 g cm^–3, λ(MoKα) = 0.71073 Å, μ = 0.165 mm^–1, F(000) = 1240, T = 150(2) K, GooF² = 0.985, independent reflections = 5179 [R_int = 0.0471] of a total of 9415 collected reflections, R(F) obeying F² > 2σ(F²) = 0.0445, wR(F²) = 0.0931, R(all data) = 0.0822, wR(F²) = 0.1074.

[22]   To a solution of (2S,3R,4S,5S)-N-(2,3,4,5,6-pentaacetoxy)hexyl-N-methyl-N′-(4-nitrophenyl)thiourea (1.0 g, 1.7 mmol) in dry chloroform (20 mL) was added α-clorophenylacetyl chloride (0.8 mL, 5.0 mmol) and was refluxed for 1 h. After, the reaction mixture was concentrated under vacuum and washed with dry diethyl ether. Chloroform (40 mL) and triethylamine (0.5 mL, 3.6 mmol) were then added to the residue obtained and the mixture was refluxed for 10 min. The crude product was then washed with distilled water, dried over magnesium sulfate, and concentrated under reduced pressure to afford a viscous oil. This product was dissolved in dry chloroform (10 mL), treated with diethylazodicarboxylate (0.3 mL, 2.0 mmol), and left to react at room temperature for 1 h. Subsequent purification by column chromatography (ethyl acetate/petroleum ether, 2:3) afforded a nearly 1:1 diastereomeric mixture of 8a and 8b (38% yield). ¹H-NMR (400 MHz, CDCl₃) δ 8.33–7.30 (9H, m, ar), 5.44–5.34 (6H, m, H-2′, H-3′, H-4′), 5.03 (2H, m, H-5′), 4.32–3.78 (12H, m, H-6′, H-6″, CH₂), 3.52 (4H, m, H-1′, H-1″), 3.00 (3H, CH₃), 2.13 (3H, CH₃), 2.12 (3H, CH₃), 2.11 (3H, CH₃), 2.08 (3H, CH₃), 2.06 (3H, CH₃), 2.04 (3H, CH₃), 2.03 (3H, CH₃), 2.01 (3H, CH₃), 1.26–083 (12H, CH₃). ¹³C-NMR (100 MHz, CDCl₃) δ 170.48, 170.18, 170.11, 169.81, 169.76, 168.06 (C=O(C-5)), 167.90 (C=O(C-5)), 153.20, 152.94, 150.47 (C-2), 150.37 (C-2), 143.69, 137.10, 129.39, 129.28, 128.36, 127.82, 127.71, 127.56, 124.57 (ar), 88.81 (C-5), 88.70 (C-5), 69.11 (2C, C-4′), 68.97 (2C, C-5′), 68.74 (2C, C-3′), 68.25 (2C, C-2′), 64.17 (2C, C-6′), 62.00 (C-1′), 61.40 (C-1′), 52.47 (CH₂), 52.18 (CH₂), 38.31 (NCH₃), 38.18 (NCH₃), 20.71, 20.63, 20.47 (10C, CH₃(OAc)), 14.30 (CH₃), 13.64 (CH₃). IR ν_max/cm^–1 1750, 1720, 1700, 1610, 1390, 1350, 1220, 1150, 1025, 950, 810, 690, 620.