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DOI: 10.1055/s-0043-1763751
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Yaroslav O. Chuchvera a Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, UkraineURL: www.enamine.net b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine , Valentyna Tararina a Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, UkraineURL: www.enamine.net b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine , Inna Chuchvera a Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, UkraineURL: www.enamine.net b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine , Eugeniy N. Ostapchuk a Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, UkraineURL: www.enamine.net b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine , Maria V. Popova b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine c Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany , Svitlana V. Shishkina d SSI ‘Institute for Single Crystals’ National Academy of Science of Ukraine, Nauky Avenue 60, Kharkiv 61001, Ukraine , Yulian M. Volovenko b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine , a Enamine Ltd., Winston Churchill Street 78, Kyiv 02094, UkraineURL: www.enamine.net b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01033, Ukraine
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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
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- Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1763751.
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Publication History
Received: 14 February 2024
Accepted after revision: 18 March 2024
Article published online:
15 April 2024
© 2024. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References and Notes
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- 14 Benzyl Sulfinyl Chloride (3)The solution of 1,2-dibenzyldisulfane (4, 24.6 g, 100 mmol) and AcOH (12.6 g, 12 mL, 210 mmol) in CH2Cl2 (250 mL) was cooled to –40 °C followed by dropwise addition of freshly distilled SO2Cl2 (43.2 g, 25.9 mL, 320 mmol) maintaining the above temperature. The resulting mixture was stirred at –40 °C for 30 min, then warmed to rt, and stirred at this temperature for another 30 min. Then the reaction mixture was carefully heated to 35–40 °C (Caution! Violent gas release). After gas evolution had ceased, the reaction mixture was evaporated at reduced pressure maintaining the internal temperature below 35 °C, and then dried in a vacuum (0.5 mmHg) with stirring at rt for 2 h. Thus obtained sulfinyl chloride 3 (ca. 33 g, 95% crude yield) was used in the sulfinylation step without additional purification, and the rest was stored at 4 °C.
- 15 General Procedure for the Synthesis of Sulfinamides 2a–cPhCH2SOCl (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–eThe 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).
- 18 4-Amino-2,3,3-trimethyl-5-phenyl-2,3-dihydroisothiazole 1-oxide (1a)From 2a (4.73 g); yield 3.78 g (16 mmol, 80%); white solid; mp 92–94 °C. 1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.5 Hz, 2 H), 7.22 (t, J = 7.5 Hz, 1 H), 4.36 (s, 2 H), 2.85 (s, 3 H), 1.54 (s, 3 H), 1.31 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ= 155.2, 131.8, 129.2, 128.0, 127.0, 111.8, 69.9, 28.0, 27.0, 24.1. MS (APCI): m/z = 237 [М + Н]+.
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