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

<A NAME="RD03504ST-1A">1a</A> Umemura K. Watanabe K. Ono K. Yamamura M. Yoshimura J. Tetrahedron Lett.  1997,  38:  4811 

<A NAME="RD03504ST-1B">1b</A> Southan GI. Zingarelli B. O’Connor M. Salzman AL. Szabo C. J. Pharmacol.  1996,  117:  619 

<A NAME="RD03504ST-1C">1c</A> Tanaka A. Sakai H. Motoyama Y. Ishikawa T. Takasugi H. J. Med. Chem.  1994,  37:  1189 

<A NAME="RD03504ST-2A">2a</A> Gürsoy A. Karali N. Turk. J. Chem.  2003,  27:  545 

<A NAME="RD03504ST-2B">2b</A> Hiremath SP. Swamy KMK. Mruthyujayaswamy BHM. J. Indian Chem. Soc.  1992,  69:  87 

<A NAME="RD03504ST-2C">2c</A> Habib NS. Khalil MA. J. Pharm. Sci.  1984,  73:  982 

<A NAME="RD03504ST-3A">3a</A> Boga C. Forlani L. Silvestroni C. Bonamartini Corradi A. Sgarabotto P. J. Chem. Soc., Perkin Trans. 1  1999,  1363 

<A NAME="RD03504ST-3B">3b</A> Schantl JG. Lagoja IM. Synth. Commun.  1998,  28:  1451 

<A NAME="RD03504ST-4A">4a</A> Liebscher J. In Houben-Weyl   Vol E8b:  Georg Thieme Verlag; Stuttgart: 1994.  p.1-399  

<A NAME="RD03504ST-4B">4b</A> Bauer W. Kühlein K. In Houben-Weyl   Vol. E5:  Georg Thieme Verlag; Stuttgart, New York: 1985.  p.1218-1279  

<A NAME="RD03504ST-5A">5a</A> Attanasi OA. Filippone P. Foresti E. Guidi B. Santeusanio S. Tetrahedron  1999,  55:  13423 

<A NAME="RD03504ST-5B">5b</A> Arcadi A. Attanasi OA. Guidi B. Rossi E. Santeusanio S. Chem. Lett.  1999,  59 

<A NAME="RD03504ST-5C">5c</A> Arcadi A. Attanasi OA. De Crescentini L. Guidi B. Rossi E. Santeusanio S. Gazz. Chim. Ital.  1997,  127:  609 

<A NAME="RD03504ST-5D">5d</A> Attanasi OA. De Crescentini L. Foresti E. Galarini R. Santeusanio S. Serra-Zanetti F. Synthesis  1995,  11:  1397 

<A NAME="RD03504ST-6A">6a</A> Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. Arkivoc  2002,  274 ; and references cited therein

<A NAME="RD03504ST-6B">6b</A> Attanasi OA. De Crescentini L. Filippone P. Mantellini F. New J. Chem.  2001,  25:  534 

<A NAME="RD03504ST-7">7</A>

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

<A NAME="RD03504ST-8">8</A>

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.

<A NAME="RD03504ST-9">9</A> Arcadi A. Attanasi OA. Filippone P. Giorgi G. Rossi E. Santeusanio S. Tetrahedron Lett.  2003,  44:  8391 

<A NAME="RD03504ST-10">10</A> Lagodzi ski TS. Chem. Rev.  2003,  103:  197 

<A NAME="RD03504ST-11A">11a</A> Bulka E. Pfeiffer WD. Troeltsch C. Dilk E. Gaertner H. Daniel D. Collect. Czech. Chem. Commun.  1978,  43:  1227 

<A NAME="RD03504ST-11B">11b</A> Bulka E. Rohde GH. Beyer H. Chem. Ber.  1965,  98:  259