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Synlett 2005(1): 79-82  
DOI: 10.1055/s-2004-836035
LETTER
© Georg Thieme Verlag Stuttgart · New York

2,4,5-Trisubstituted Thiazole Building Blocks by a Novel Multi-Component Reaction

Michael Umkehrer*a,b, Jürgen Kolba, Christoph Burdacka, Wolfgang Hillerb
a Priaton GmbH, Bahnhofstr. 9-15, 82327 Tutzing, Germany
b Technical University Munich, Lichtenbergstr.4, 85747 Garching, Germany
Fax: +49(8158)904022; e-Mail: Umkehrer@priaton.de;
Further Information

Publication History

Received 5 October 2004
Publication Date:
29 November 2004 (online)

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Abstract

A novel multi-component reaction (MCR) of oxo-components, primary amines, thiocarboxylic acids and 3-bromo-2-isocyanoacrylates yielding 2,4,5-trisubstituted thiazole building blocks is described.

Key words

combinatorial chemistry - multicomponent reaction - one-pot synthesis - 3-substituted 3-bromo-2-isocyanoacrylates - 2,4,5-trisubstituted thiazoles

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Typical Procedure:
Aldehyde or ketone (1 mmol), amine and MgSO4 are stirred under inert and water-free conditions in 2 mL dry MeOH at 0 °C. The imine is precondensed for 2 h and the solution is cooled to -10 °C: 1 mmol of the thiocarboxylic acid and isocyanide are added and the reaction volume is increased to 4 mL. The reaction mixture is allowed to warm up to r.t. and stirred for 24 h until the reaction is completed (indication by TLC). Then the reaction mixture is diluted with 25 mL CH2Cl2. The organic layer is washed with sat. NaHCO3 solution, 3% HCl and sat. NaCl solution, dried over MgSO4 and concentrated in vacuo. The resulting oil is purified by column chromatography on silica gel (hexane-EtOAc).

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Compound 7b was isolated in 43% yield as a yellow oil. HPLC-MS spectra (Varian 1200); RP OmniSpher C18 column, 3 mm × 150 mm, 5 µm; ProStar 320 (254 nm); 0.3 mL/min, 10 min, MeCN-H2O = 70:30 coupled with a Quadrupol MS/MS mass spectrometer using electrospray ionisation (ESI): tR(254nm) = 5.37 min; m/z = 361.1 [M + H]+, 383.1 [M + Na]+. 1H NMR (270.17 MHz, CDCl3): δ = 1.30 [d, 6 H, J = 7.01 Hz, CH(CH3)2], 1.61 (d, 3 H, J = 7.01 Hz, H3C-CH), 2.12 (s, 3 H, H3C-CO), 3.91 (s, 3 H, CH3OOC), 4.07 [h, 1 H, J = 7.01 Hz, CH(CH3)2], 4.57 (s, 1 H, CH2-C6H5), 4.60 (s, 1 H, CH2-C6H5), 6.18 (q, 1 H, J = 7.01 Hz, CH-CH3), 7.14-7.31 (m, 5 H, C6H5). 13C NMR (100.53 MHz, CDCl3): δ = 17.13 (H3C-CH), 22.26 (H3C-CO), 24.96 [(CH(CH3)2], 24.99 [CH(CH3)2], 27.89 [CH(CH3)2], 48.85 (CH2-C6H5), 51.56 (CH-CH3), 51.94 (CH3OOC-), 125.79, 127.17, 128.58, 137.30 (Cq), 138.60 (Cq), 159.71 (Cq), 162.71 (Cq), 166.35 (CON), 171.85 (COOMe).
Compound 7d was isolated in 41% yield as a yellow oil. HPLC-MS spectra (Varian 1200); RP OmniSpher C18 column, 3 mm × 150 mm, 5 µm; ProStar 320 (254 nm); 0.3 mL/min, 10 min, MeCN-H2O = 80:20 coupled with a Quadrupol MS/MS mass spectrometer using electrospray ionisation (ESI): t R (254 nm) = 5.08 min; m/z = 395.4 [M + H]+, 417.2 [M + Na]+. 1H NMR (399.78 MHz, CDCl3): δ = 1.66 (d, 3 H, J = 7.26 Hz, H3C-CH), 2.13 (s, 3 H, H3C-CO), 3.79 (s, 3 H, CH3O-), 4.67 (s, 2 H, CH2-C6H5), 6.04 (q, 1 H, J = 7.26 Hz, CH-CH3), 7.19-7.41 (m, 10 H, C6H5). 13C NMR (100.53 MHz, CDCl3): δ = 17.23 (H3C-CH), 22.34 (H3C-CO), 49.19 (CH2-C6H5), 51.85 (CH-CH3), 52.07 (CH3OOC-), 125.94, 127.31, 128.11, 128.70, 129.09, 129.73, 130.27, 137.34 (Cq), 139.27 (Cq), 147.29 (Cq), 162.53 (Cq), 168.86 (CON), 171.83 (COOMe).