Synthesis of α-Phenyl β-Enamino γ-Sultims: the New Horizon of the CSIC Reaction

Abstract

Herein, we report the novel strategy for the synthesis of 4-enamino-5-phenyl-2,3-dihydroisothiazole 1-oxides (in other words α-phenyl β-enamino γ-sultims) based on the CSIC reaction. Particularly, readily available α-amino nitriles (the Strecker products) reacted with benzyl sulfinyl chloride to give the corresponding sulfinamides, which upon treatment with excess of LiHMDS converted into the target α-phenyl β-enamino γ-sultims. The method works well and tolerates strained 3- and 4-membered spirocyclic substituents. A preliminary in silico study indicated that the γ-sultim scaffold can be considered a promising pharmacophore template.

Key words

sulfinamides - enamines - sultims - CSIC reaction - cyclization

Publikationsverlauf

Eingereicht: 14. Februar 2024

Angenommen nach Revision: 18. März 2024

Artikel online veröffentlicht:
15. April 2024

• References and Notes

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• 15 General Procedure for the Synthesis of Sulfinamides 2a–c PhCH₂SOCl (3, 9.6 g, 55 mmol, 1.1 equiv) was added dropwise to the stirred cold (–20 °C) solution of α-amino nitrile 5a–e (50 mmol, 1 equiv) and DIPEA (14.2 g, 19.2 mml, 110 mmol, 2.2 equiv) in anhydrous CH₂Cl₂ (100 mL). After the reagent had been added the reaction mixture was stirred at –20 °C for 30 min whereupon was left to react overnight allowing to equilibrate to rt. The resulting reaction mixture was filtered, the filtrate was evaporated at reduced pressure and redissolved in EtOAc (100 mL). The organic layer was sequentially washed with saturated aq. NaHCO₃ (1 × 10 mL) and brine (1 × 10 mL), dried (Na₂SO₄), and evaporated at reduced pressure to give the title product 2a–e. Thus obtained sulfinamides were pure enough to be used in subsequent cyclization step without additional purification. If necessary, sulfinamides 2a–e can be purified by silica gel flash chromatography (gradient elution from hexanes–t-BuOMe (1:1) to t-BuOMe).
• 16 N-(2-Cyanopropan-2-yl)-N-methyl-1-phenylmethanesulfinamide (2a) From 5a (4.9 g); yield 8.27 g (35 mmol, 70%); yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.23 (m, 3 H), 7.18 (d, J = 7.6 Hz, 2 H), 3.94 (dd, J = 13.0, 9.6 Hz, 2 H), 2.81 (s, 3 H), 1.40 (s, 3 H), 1.32 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 130.1, 130.0, 128.9, 128.3, 120.5, 60.2, 55.8, 27.1, 26.5, 25.5. MS (APCI): m/z = 237 [М + Н]⁺.
• 17 General Procedure for the Synthesis of β-Enamino γ-Sultims 1a–e The solution of LiHMDS (15 g, 90 mmol, 4.5 equiv) in THF (85 mL) was added dropwise to the stirred cold (–60 °C) solution of sulfinamide 2a–e (20 mmol) in THF (40 mL) under Ar atmosphere. After the reagent had been added the reaction mixture was stirred at –60 °C for 30 min whereupon was heated to 0 °C within 90 min. After this time the reaction mixture was quenched by pouring it into cold (0 °C) saturated aq. NH₄Cl (100 mL) followed by extraction with t-BuOMe (3 × 50 mL). The combined organic layer was dried (Na₂SO₄) and evaporated at reduced pressure to give the target product 1a–e. Thus obtained β-enamino γ-sultims were pure enough and if necessary were further purified by silica gel flash chromatography (gradient elution from hexanes–t-BuOMe (1:1) to t-BuOMe).
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