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

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.

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

References

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<A NAME="RG37904ST-33">33</A>

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).

<A NAME="RG37904ST-34">34</A>

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): t_R(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).