Stereoselective Metal-Free Reaction of Imidazoles with Isothiocyanates Involving Cyanophenylacetylene: A Shortcut to N-(Z-Alkenyl)imidazole-2-carbothioamides

Abstract

N-(Z)-(2-Cyano-1-phenylethenyl)imidazole-2-carbothioamides have been synthesized in up to 91% yield by the new reaction between 1-substituted imidazoles and isothiocyanates in the presence of cyanophenylacetylene under catalyst- and solvent-free conditions at room temperature. The reaction proceeds via zwitterion–carbene intermediates which are trapped by isothiocyanates to form the zwitterion with ambident N–S anionic site, which then undergoes stereo- and regioselective migration of the alkenyl moiety.

Key words

alkynes - carbenes - multicomponent reaction - nucleophilic addition - stereoselectivity

• References

• 1 Grimmett MR In Comprehensive Heterocyclic Chemistry II . Vol. 3. Katritzky AR, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996: 77-220
• 2 Bellina F, Cauteruccio S, Rossi R. Tetrahedron 2007; 63: 4571
• 3 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. Delgado JN, Remers WA. Lippincott-Raven; Philadelphia: 1998
• 4 Coura JR. S, de Castro L. Mem. Inst. Oswaldo Cruz 2002; 97: 3
• 5 Chandra T, Brown KL. Tetrahedron Lett. 2005; 46: 8617
• 6 VanVliet DS, Gillespie P, Scicinski JJ. Tetrahedron Lett. 2005; 46: 6741
• 7a Legros J, Dehli JR, Bolm C. Adv. Synth. Catal. 2005; 347: 19
• 7b Bhatnagar A, Sharma PK, Kumar N. Int. J. Pharm. Tech. Res. 2011; 3: 268
• 8a Kleeman A, Engel J In Pharmaceutical Substances (Syntheses, Patents, Applications) . Vol. 2. Kutscher B, Reicher D. Thieme; Stuttgart: 2001: 1742
• 8b Chauhan A, Sharma PK, Kaushik N, Kumar N. Int. J. Pharm. Pharm. Sci. 2011; 3: 166; Suppl. 5
• 8c Jin C.-H, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Mohan AV. N, Park C.-Y, Son J.-Y, Sheen YY, Kim D.-K. Bioorg. Med. Chem. Lett. 2011; 21: 6049
• 9a Ofitserov VI, Mokrushin VS, Nifontov VI, Pushkareva ZV, Nikiforova NV, Lych LN. Khim. Geterotsikl. Soedin. 1975; 1550
• 9b Berseneva VS, Bakulev VA, Mokrushin VS. Khim. Geterotsikl. Soedin. 2000; 269 ; Chem. Heterocycl. Comp. 2000, 36, 229
• 9c Berseneva VS, Morzherin YY, Dehaen W, Luyten I, Bakulev VA. Tetrahedron 2001; 57: 2179
• 9d Guernon JM, Wu Y.-J. Tetrahedron Lett. 2011; 52: 3633
• 10 Trofimov BA, Andriyankova LV, Belyaeva KV. Khim. Geterocycl. Soedin. 2012; 153 ; Chem. Heterocycl. Comp. 2012, 48, 147
• 11a Trofimov BA, Andriyankova LV, Belyaeva KV, Mal’kina AG, Nikitina LP, Afonin AV, Ushakov IA. Eur. J. Org. Chem. 2010; 1772
• 11b Trofimov BA, Andriyankova LV, Belyaeva KV, Mal’kina AG, Nikitina LP, Dyachenko OA, Kazheva ON, Alexandrov GG, Shilov GV, Afonin AV, Ushakov IA. Tetrahedron 2011; 67: 1288
• 11c Belyaeva KV, Andriyankova LV, Nikitina LP, Ivanov AV, Afonin AV, Ushakov IA, Mal’kina AG, Mikhaleva AI, Trofimov BA. Synthesis 2011; 2843
• 12a Liu M.-F, Wang B, Cheng Y. Chem. Commun. 2006; 1215
• 12b Delaude L. Eur. J. Inorg. Chem. 2009; 1681
• 13 Typical Experimental Procedure for the Synthesis of N-[(Z)-2-Cyano-1-phenylethenyl]-N,1-dimethyl-1H-imidazole-2-carbothioamide (4a) To a mixture of acetylene 3 (0.127 g, 1 mmol) and methylisothiocyanate (2a; 0.073 g, 1 mmol) was added 1-methylimidazole (1a; 0.082 g, 1 mmol). The mixture was stirred at 20–25 °C for 24 h. The reaction mixture was washed with Et₂O (1 × 3 mL) to give imidazole-2-carbothioamide 4a (0.257 g, 91%) as a yellow powder; mp 162–164 °C (EtOH). IR (KBr): ν = 2217 (CN), 1612 (C=C), 1351 (C=S) cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 7.50–7.40 [m, 5 H, C(8)Ph], 6.85 (s, 1 H, 4-H), 6.80 (s, 1 H, 5-H), 5.37 (s, 1 H, 9-H), 3.84 [s, 3 H, N(1)CH₃], 3.61 [s, 3 H, N(7)CH₃] ppm. ¹³C NMR (100.62 MHz, CDCl₃): δ = 189.7 (C-6), 164.0 (C-8), 144.7 (C-2), 134.1 [C _i , C(8)Ph], 131.6 [C _p , C(8)Ph], 129.1 [C _m , C(8)Ph], 127.9 [C _o , C(8)Ph], 127.3 (C-4), 124.9 (C-5), 115.7 (C-10, CN), 91.1 (C-9), 42.7 [N(7)CH₃], 36.0 [N(1)CH₃] ppm. ¹⁵N NMR (40.55 MHz, CDCl₃): δ = –114.2 (N-3), –116.2 (CN-10), –214.3 (N-7), –218.3 (N-1) ppm. Anal. Calcd for C₁₅H₁₄N₄S (282.37): C, 63.81; H, 5.00; N, 19.84; S, 11.35. Found: C, 63.74; H, 5.07; N, 19.87; S, 10.95. N-Allyl-N-[(Z)-2-cyano-1-phenylethenyl]-1-methyl-1H-imidazole-2-carbothioamide (4b) To a mixture of acetylene 3 (0.127 g, 1 mmol) and allylisothiocyanate (2b; 0.099 g, 1 mmol) was added 1-methylimidazole (1a; 0.082 g, 1 mmol). The mixture was stirred at 20–25 °C for 24 h. Column chromatography afforded imidazole-2-carbothioamide (4b; 0.250 g, 81%) as a dark-yellow oil. IR (microlayer): ν = 2216 (CN), 1607 (C=C), 1382 (C=S) cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 7.60–7.40 [m, 5 H, C(8)Ph], 6.83 (s, 2 H, 4-H, 5-H), 6.06 [m, 1 H, H_X, N(7)All]), 5.35 (s, 1 H, 9-H), 5.21 [d, ³ J _HA,HX = 9.2 Hz, 1 H, H_A, N(7)All], 5.09 [d, ³ J _HB,HX = 16.8 Hz, 1 H, H_B, N(7)All], 4.05 [m, 2 H, –CH₂–, N(7)All], 3.88 [s, 3 H, N(1)CH₃] ppm. ¹³C NMR (100.62 MHz, CDCl₃): δ = 189.3 (C-6), 161.9 (C-8), 144.6 (C-2), 137.6 (CH_X, All), 133.5 [C _i , C(8)Ph], 131.4 [C _p , C(8)Ph], 129.0 [C _m , C(8)Ph], 127.6 [C-4, C _o , C(8)Ph], 125.1 (C-5), 120.7 (CH_A,B, All), 115.8 (C-10, CN), 92.7 (C-9), 55.3 [(N(7)CH₂, All], 35.9 [N(1)CH₃] ppm. Anal. Calcd for C₁₇H₁₆N₄S (308.40): C, 66.21; H, 5.23; N, 18.17; S, 10.40. Found: C, 66.59; H, 5.09; N, 18.55; S, 10.01.
• 14a Miller SI, Tanaka R In Selective Organic Transformation . Vol. 1. Thyagarajan BS. Wiley-Interscience; New York: 1970: 143
• 14b Dickstein JI, Miller SI In The Chemistry of the Carbon–Carbon Triple Bond . Vol. 2. Patai S. Wiley; New York: 1978: 814
• 15 Trofimov BA, Andriyankova LV, Belyaeva KV, Mal’kina AG, Nikitina LP, Afonin AV, Ushakov IA. J. Org. Chem. 2008; 73: 9155
• 16 Wei D, Tang M. J. Phys. Chem. 2009; 113: 11035
• 17a Dallas G, Lown JW, Ma JC. N. J. Chem. Soc. C 1968; 20: 2510
• 17b Trofimov BA, Vavilova AN. Sulfur Lett. 1985; 3: 189