Efficient Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives by a One-Pot Asinger-Type Reaction

Abstract

A one-pot, three-component reaction has been developed and successfully employed for the synthesis of biologically relevant, highly functionalized spirooxindole-fused 3-thiazoline derivatives. Starting from ammonia, three mercapto carbonyl components and a series of substituted isatins, products were obtained in good yields (24 examples), by following a simple and rapid protocol. The obtained thiazolines proved to be optimal substrates for further transformations, including the three-component Ugi–Joullié reaction.

Key words

thiazoline - oxindole - spiro compounds - Asinger - multicomponent reactions - Ugi–Joullié reaction

• References and Notes

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• 22 Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives 3a–x; General Procedure A (GP-A): To a solution of isatin 1a–r (1 mmol) in anhydrous toluene (1 mL, 1.0 M), MgSO₄ (3 mmol) and NH₃ (2 M in methanol, 2 mmol) were added. The solution was stirred for 8 h at r.t., then mercapto-derivative 2a–c was added (1.1 mmol). The resulting mixture was stirred for 30 min at the same temperature then diluted with CH₂Cl₂ (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (FC). Representative Analytical Data for 1-Benzyl-4′-methyl-5′H-spiro[indoline-3,2′-thiazol]-2-one (3a): Prepared according to GP-A using isatin 1a and mercaptoacetone 2a and purified by column chromatography (CH₂Cl₂–EtOAc, 19:1). Yield: 271 mg (88%); pale-orange foam. ¹H NMR (300 MHz, CDCl₃): δ = 7.36–7.24 (m, 6 H), 7.19 (br t, J = 7.7 Hz, 1 H), 7.04 (br t, J = 7.7 Hz, 1 H), 6.69 (br d, J = 7.8 Hz, 1 H), 4.94 (d, J = 15.7 Hz, 1 H), 4.84 (d, J = 15.7 Hz, 1 H), 4.43 (d, J = 15.8 Hz, 1 H), 4.27 (d, J = 15.8 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 175.3, 174.9, 142.4, 135.4, 130.2, 129.6, 128.9 (2C), 127.7, 127.3 (2C), 125.5, 123.5, 109.5, 88.2, 48.7, 44.2, 19.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₆N₂NaOS⁺: 331.0876; found: 331.0884.