Facile and High-Yielding Direct Synthesis of 2-Alkyliminothiazolines

Abstract

1,2-Diaza-1,3-butadienes readily react with O-alkyl­thiocarbamate derivatives via a hetero-Michael addition/cyclization reaction affording directly 2-alkyliminothiazolines in high yields under mild conditions.

1,2-diaza-1,3-butadienes - Michael additions - annulation - thiocarbamate - thiazolines

References

1a Umemura K. Watanabe K. Ono K. Yamamura M. Yoshimura J. Tetrahedron Lett.  1997,  38:  4811 

1b Southan GI. Zingarelli B. O’Connor M. Salzman AL. Szabo C. J. Pharmacol.  1996,  117:  619 

1c Tanaka A. Sakai H. Motoyama Y. Ishikawa T. Takasugi H. J. Med. Chem.  1994,  37:  1189 

2a Gürsoy A. Karali N. Turk. J. Chem.  2003,  27:  545 

2b Hiremath SP. Swamy KMK. Mruthyujayaswamy BHM. J. Indian Chem. Soc.  1992,  69:  87 

2c Habib NS. Khalil MA. J. Pharm. Sci.  1984,  73:  982 

3a Boga C. Forlani L. Silvestroni C. Bonamartini Corradi A. Sgarabotto P. J. Chem. Soc., Perkin Trans. 1  1999,  1363 

3b Schantl JG. Lagoja IM. Synth. Commun.  1998,  28:  1451 

4a Liebscher J. In Houben-Weyl   Vol E8b:  Georg Thieme Verlag; Stuttgart: 1994.  p.1-399  

4b Bauer W. Kühlein K. In Houben-Weyl   Vol. E5:  Georg Thieme Verlag; Stuttgart, New York: 1985.  p.1218-1279  

5a Attanasi OA. Filippone P. Foresti E. Guidi B. Santeusanio S. Tetrahedron  1999,  55:  13423 

5b Arcadi A. Attanasi OA. Guidi B. Rossi E. Santeusanio S. Chem. Lett.  1999,  59 

5c Arcadi A. Attanasi OA. De Crescentini L. Guidi B. Rossi E. Santeusanio S. Gazz. Chim. Ital.  1997,  127:  609 

5d Attanasi OA. De Crescentini L. Foresti E. Galarini R. Santeusanio S. Serra-Zanetti F. Synthesis  1995,  11:  1397 

6a Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. Arkivoc  2002,  274 ; and references cited therein

6b Attanasi OA. De Crescentini L. Filippone P. Mantellini F. New J. Chem.  2001,  25:  534 

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The reagent was kindly supplied by Oxon Italia S.p.A.

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Representative procedure for the preparation of 2-alkyliminothiazoline derivatives 5:
Preparation of 5a. O-Methyl ethylthiocarbamate (2a; 119 mg, 1 mmol) was dissolved in MeOH (6 mL) and 1,2-diaza-1,3-butadiene (1a; 247 mg, 1 mmol) was added portionwise to the solution with magnetic stirring at r.t. After 2 h the red color of the solution disappeared and TLC analysis indicated completion of the reaction. The desired product 5a was purified by flash chromatography on silica gel (cyclohexane-EtOAc) and crystallized from EtOAc-light petroleum ether mixture as a white powder. Analytical data of 5a: mp 156-158 °C. IR (nujol): 3302, 3258, 1706, 1645, 1599, 1563 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.14 (t, 3 H, J = 7.2 Hz, NCH₂CH ₃), 2.37 (s, 3 H, CH₃), 2.98-3.15 (m, 2 H, NCH ₂CH₃), 3.74 (s, 3 H, OCH₃), 6.99 (t, 1 H, J = 7.6 Hz, Ar), 7.27 (t, 2 H, J = 7.6 Hz, Ar), 7.44 (d, 2 H, J = 7.6 Hz, Ar), 8.89 (s, 1 H, NH, D₂O exchange), 9.32 (s, 1 H, NH, D₂O exchange). ¹³C NMR (100.65 MHz, DMSO-d ₆): δ = 12.57, 15.53, 47.91, 51.80, 94.58, 118.34, 122.23, 128.57, 138.80, 149.30, 152.55, 153.75, 161.44. MS: m/z (%) = 334 (6) [ M⁺], 242 (100), 200 (70), 172 (23). Anal. Calcd for C₁₅H₁₈N₄O₃S: C, 53.88; H, 5.43; N, 16.75. Found: C, 53.84; H, 5.47; N, 16.71.
Preparation of 5h. The reaction procedure, starting from 1b and 2b, is analogous to that of 5a and completion of the reaction occurs within 7 h. The product crystallizes from the reaction medium as a white powder. Analytical data of 5h: mp 168-170 °C (dec.). IR (nujol): 3393, 3345, 3291, 1719, 1674, 1649, 1631, 1612 cm^-1. ¹H NMR (400 MHz,
DMSO-d ₆): δ = 0.87 (t, J = 7.7 Hz, 3 H, CH₃), 1.33 (sext, J = 7.7 Hz, 2 H, NCH₂CH₂CH ₂CH₃), 1.48-1.58 (m, 2 H, NCH₂CH ₂CH₂CH₃), 2.31 (s, 3 H, CH₃), 3.00 (t, J = 6.4 Hz, 2 H, NCH ₂CH₂CH₂CH₃), 3.71 (s, 3 H, OCH₃), 6.36 (s, 2 H, NH₂, D₂O exchange), 8.68 (s, 1 H, NH, D₂O exchange). ¹³C NMR (100.65 MHz, DMSO-d ₆): δ = 12.52, 13.80, 19.95, 32.21, 51.65, 53.19, 94.15, 149.45, 152.60, 156.98, 161.46. MS: m/z (%) = 286 (25) [M⁺], 243 (53), 227 (70), 212 (60), 185 (37). Anal. Calcd for C₁₁H₁₈N₄O₃S: C, 46.14; H, 6.34; N, 19.57. Found: C, 46.18; H, 6.31; N, 19.53.

9 Arcadi A. Attanasi OA. Filippone P. Giorgi G. Rossi E. Santeusanio S. Tetrahedron Lett.  2003,  44:  8391 

10 Lagodziski TS. Chem. Rev.  2003,  103:  197 

11a Bulka E. Pfeiffer WD. Troeltsch C. Dilk E. Gaertner H. Daniel D. Collect. Czech. Chem. Commun.  1978,  43:  1227 

11b Bulka E. Rohde GH. Beyer H. Chem. Ber.  1965,  98:  259