Three-Component Reaction between Isocyanides, Aliphatic Amines and Elemental Sulfur: Preparation of Thioureas under Mild Conditions with Complete­ Atom Economy

Abstract

The reaction of isocyanides with aliphatic amines in the presence of elemental sulfur was found to proceed efficiently at, or near, room temperature to produce thioureas in excellent yields and with complete atom economy.

Key words

multicomponent reactions - elemental sulfur - isocyanides - thioureas - atom economy - sulfur–amine interaction

• References


For selected examples, see:
• 1a Anzini M, Chelini A, Mancini A, Cappelli A, Frosini M, Ricci L, Valoti M, Magistretti J, Castelli L, Giordani A, Makovec F, Vomero S. J. Med. Chem. 2010; 53: 734
• 1b Lee J, Lee J, Kang M, Shin M, Kim J, Kang S, Lim J, Choi H, Suh Y, Park H, Oh U, Kim H, Park Y, Ha H, Kim Y, Toth A, Wang Y, Tran R, Pearce LV, Lundberg DJ, Blumberg PM. J. Med. Chem. 2003; 46: 3116
• 1c Touati-Jallabe Y, Bojnik E, Legrand B, Mauchauffée E, Chung NN, Schiller PW, Benyhe S, Averlant-Petit M.-C, Martinez J, Hernandez J.-F. J. Med. Chem. 2013; 56: 5964
• 1d Van Daele I, Munier-Lehmann H, Froeyen M, Balzarini J, Van Calenbergh S. J. Med. Chem. 2007; 50: 5281
• 1e Verlinden BK, Niemand J, Snyman J, Sharma SK, Beattie RJ, Woster PM, Birkholtz L.-M. J. Med. Chem. 2011; 54: 6624
• 1f Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS, Casero RA. Jr, Woster PM. J. Med. Chem. 2010; 53: 5197
• 1g Kim HS, Jin M, Kang S, Lim J, Tran P, Hoang V, Ann J, Ha T, Pearce LV, Pavlyukovets VA, Blumberg PM, Lee J. Bioorg. Med. Chem. Lett. 2014; 24: 2685

For recent examples, see:
• 2a For amidines: Biswas K, Greaney MF. Org. Lett. 2011; 13: 4946
• 2b For benzothiazoles: Zhao J, Huang H, Wu W, Chen H, Jiang H. Org. Lett. 2013; 15: 2604
• 2c For thiazoles: Kim SK, Kim JH, Park YC, Kim JW, Yum EK. Tetrahedron 2013; 69: 10990
• 2d For pyrimidines: Dotsenko F, Krivokolysko P. Chem. Heterocycl. Compd. 2013; 49: 440
• 2e For aminotetrazoles: Batey RA, Powell DA. Org. Lett. 2000; 2: 3237
• 2f For 2-amino-4H-1,3-thiazines: Huang S, Pan Y, Zhu Y, Wu A. Org. Lett. 2005; 7: 3797

For representative examples, see:
• 3a Jordan BJ, Pollier MA, Miller LA, Tiernan C, Clavier G, Audebert P, Rotello VM. Org. Lett. 2007; 9: 2835
• 3b Osorio-Planes L, Rodríguez-Escrich C, Pericàs MA. Org. Lett. 2014; 16: 1704
• 3c Vonlanthen M, Finney NS. J. Org. Chem. 2013; 78: 3980
• 3d Wu Z, An Z, Chen X, Chen P. Org. Lett. 2013; 15: 1456
• 3e Boyle EM, Comby S, Molloy JK, Gunnlaugsson T. J. Org. Chem. 2013; 78: 8312
• 3f Vachal P, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 10012
• 4 Schroeder DC. Chem. Rev. 1955; 55: 181
• 5 Kumamoto K, Misawa Y, Tokita S, Kubo Y, Kotsuki H. Tetrahedron Lett. 2002; 43: 1035
• 6 Matsumura T, Nakada M. Tetrahedron Lett. 2014; 55: 1412
• 7a Vazquez J, Bernes S, Reyes Y, Moya M, Sharma P, Alvarez C, Gutierrez R. Synthesis 2004; 1955
• 7b Maddani MR, Prabhu KR. J. Org. Chem. 2010; 75: 2327
• 8 Yin BL, Liu ZG, Zhang JC, Li ZR. Synthesis 2010; 991
• 9 At the time of preparing this manuscript, elemental sulfur (99.5–100.5% chemical purity) was commercially available from Sigma-Aldrich for US$38.80/kg or US$1.24/mol (13803-1KG-R).
• 10a Davis RE, Nakshbendi HF. J. Am. Chem. Soc. 1962; 84: 2085
• 10b Hodgson WG, Buckler SA, Peters G. J. Am. Chem. Soc. 1963; 85: 543
• 10c Thomson JW, Nagashima K, Macdonald PM, Ozin GA. J. Am. Chem. Soc. 2011; 133: 5036
• 10d McMillan FH. J. Am. Chem. Soc. 1948; 70: 868

For a mechanistic study of the room temperature reaction of sulfur with benzylamine, see:
• 10e Sasaki Y, Olsen FP. Can. J. Chem. 1971; 49: 283
• 10f Nguyen TB, Ermolenko L, Al-Mourabit A. Org. Lett. 2012; 14: 4274
• 11 Nguyen TB, Tran MQ, Ermolenko L, Al-Mourabit A. Org. Lett. 2014; 16: 310
• 12 Lipp M, Dallacker F, Meier zu Köcker I. Monatsh. Chem. 1959; 90: 41

Isothiocyanates have been reported to be formed by refluxing a benzene solution of elemental sulfur and the parent isocyanides; see:
• 13a Tanaka S, Uemura S, Okano M. Bull. Chem. Soc. Jpn. 1977; 50: 2785
• 13b Boyer JH, Ramakrishnan VT. J. Org. Chem. 1972; 37: 1360
• 14 Zhu T, Xu X, Cao J, Wei T, Wang S, Ji S. Adv. Synth. Catal. 2014; 356: 509
• 15 Zajdlik A, Wang Z, Hickey JL, Aman A, Schimmer AD, Yudin AK. Angew. Chem. Int. Ed. 2013; 52: 8411

Isocyanides have been found to react with S₈ in the presence of catalysts on heating to provide isothiocyanates; with selenium, see:
• 16a Fujiwara S.-i, Shin-Ike T, Sonoda N, Aoki M, Okada K, Miyoshi N, Kambe N. Tetrahedron Lett. 1991; 32: 3503

With molybdenum catalysts, see:
• 16b Adam W, Bargon RM, Bosio SG, Schenk WA, Stalke D. J. Org. Chem. 2002; 67: 7037
• 16c Byrne JJ, Vallee YA. Tetrahedron Lett. 1999; 40: 489

With rhodium complexes, see:
• 16d Arisawa M, Ashikawa M, Suwa A, Yamaguchi M. Tetrahedron Lett. 2005; 46: 1727
• 17 We thank the reviewer for suggesting this alternative mechanism.
• 18a Scheuer PJ. Acc. Chem. Res. 1992; 25: 433
• 18b Garson MJ, Simpson JS. Nat. Prod. Rep. 2004; 21: 164
• 19 De Esch IJ. P, Mills JE. J, Perkins TD. J, Romeo G, Hoffmann M, Wieland K, Leurs R, Menge WM. P. B, Nederkoorn PH. J, Dean PM, Timmerman H. J. Med. Chem. 2001; 44: 1666
• 20 Bourdais J, Omar AM. M. E. J. Heterocycl. Chem. 1980; 17: 555
• 21 Novak L, Hanania M, Kovacs P, Kovacs CE, Kolonits P, Szantay C. Synth. Commun. 1999; 29: 1757
• 22 Lange JH. M, Verhoog S, Sanders HJ, Van Loevezijn A, Kruse CG. Tetrahedron Lett. 2011; 52: 3198
• 23 Omar AM. M. E, Eshba NH. J. Pharm. Sci. 1984; 73: 1166
• 24 Mohanta PK, Dhar S, Samal SK, Ila H, Junjappa H. Tetrahedron 2000; 56: 629