Synthesis of 5-Functionalized 1-(Hetero)Aryl-1,2-thiazine 1-Oxides through a CSIC Reaction Strategy

Dedicated to Prof. José Marco-Contelles for his invaluable contribution to the CSIC reaction.

Abstract

Herein, we report an efficient strategy for the synthesis of C5-functionalized 1-(hetero)aryl-1,2-thiazine 1-oxides (i.e., C5-functionalized six-membered endocyclic sulfoximines) based on the carbanion-mediated sulfonate (or sulfonamide) intermolecular coupling and intramolecular cyclization (CSIC) reaction. The starting compounds are readily available 2,2-disubstituted 3-bromopropanenitriles and imino(methyl)(hetero/aryl)-λ⁶-sulfanones, and the reaction is performed in a one-pot fashion. The method works well and provides previously unreported spirocyclic and S-heteroaryl-substituted 1,2-thiazine 1-oxides. These compounds are designed as multi-target small molecules and a preliminary in silico study indicates their good binding affinity to CLK4 and MAO B – the receptors associated with cancer and neurodegenerative diseases.

Key words

sulfoximines - CSIC reaction - cyclization - alkylation - enamines

Publication History

Received: 28 February 2025

Accepted after revision: 07 May 2025

Accepted Manuscript online:
07 May 2025

Article published online:
18 June 2025

• References and Notes

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• 17 9-Amino-7-phenyl-7-thia-6-azaspiro[3.5]nona-6,8-diene 7-Oxide (1c) The product was obtained from 2c (373 mg) following the two-step method; yield: 175 mg (0.71 mmol, 47%). The same product was also obtained from 3c (653 mg) and 4a (388 mg) following the one-pot procedure; yield 236 mg (0.95 mmol, 38%); beige powder. ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 7.2 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.35 (t, J = 7.2 Hz, 2 H), 5.08 (s, 1 H), 4.99 (s, 2 H), 3.59 (s, 2 H), 2.44–2.36 (m, 1 H), 2.29–2.21 (m, 1 H), 2.12–2.01 (m, 2 H), 1.92–1.85 (m, 1 H), 1.73–1.64 (m, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 163.5, 143.8, 131.7, 128.6, 127.9, 88.9, 51.2, 39.0, 29.6, 25.6, 15.9. MS (APCI): m/z = 249 [М + Н]⁺.
• 18 CCDC 2416330 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
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• 20 1-(((Methyl(oxo)(phenyl)-λ⁶-sulfaneylidene)amino)methyl)cyclobutane-1-carboxylic Acid (6c) The product was obtained from 1c (50 mg). Yield: 47 mg (0.176 mmol, 88%); white solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 7.2 Hz, 2 H), 7.66 (t, J = 7.2 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 2 H), 3.25 (d, J = 11.9 Hz, 1 H), 3.21 (s, 3 H), 3.05 (d, J = 11.9 Hz, 1 H), 2.43 (dt, J = 19.9, 9.7 Hz, 2 H), 2.02–1.97 (m, 1 H), 1.88 (dt, J = 19.9, 9.7 Hz, 2 H), 1.79–1.69 (m, 1 H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 176.6, 138.0, 133.6, 129.8, 128.6, 48.7, 44.7, 28.2, 27.7, 21.1, 15.2. MS (APCI): m/z = 266 [М – Н]^–.
• 21 (E)-N,N-Dimethyl-N′-(7-(1-methyl-1H-1,2,3-triazol-5-yl)-7-oxido-7λ⁶-thia-6-azaspiro[3.5]nona-6,8-dien-9-yl)formimidamide (7f) An excess of DMF–DMA (894 mg, 1 mL, 7.5 mmol) was added to a solution of enamino sulfoximine 1f (63 mg, 0.25 mmol) in toluene (5 mL) and the obtained mixture was refluxed overnight. The mixture was then evaporated under reduced pressure and triturated with hexane (5 mL). The obtained precipitate was filtered and washed with hexane (5 mL) to give the title compound. Yield: 66 mg (0.21 mmol, 85%); beige solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.03 (d, J = 3.2 Hz, 1 H), 7.85 (s, 1 H), 5.76 (d, J = 3.2 Hz, 1 H), 4.11 (s, 3 H), 3.55 (d, J = 13.0 Hz, 1 H), 3.43 (d, J = 13.0 Hz, 1 H), 3.07 (s, 3 H), 3.00 (s, 3 H), 2.65–2.57 (m, 1 H), 2.14–2.05 (m, 1 H), 2.01–1.91 (m, 2 H), 1.86–1.75 (m, 1 H), 1.67–1.57 (m, 1 H). ¹³C{¹H} NMR (126 MHz, DMSO-d ₆): δ = 173.2, 154.3, 139.4, 136.4, 96.2, 51.5, 40.3, 36.0, 34.3, 27.8, 26.5, 15.2. MS (APCI): m/z = 309 [М + Н]⁺.
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