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

Yaroslav O. Chuchvera; Oleksandr P. Korobka; Yurii O. Horbatochkin; Eugeniy N. Ostapchuk; Maria V. Popova; Svitlana V. Shishkina; Yulian M. Volovenko; Alexey V. Dobrydnev

doi:10.1055/a-2602-6899

Synlett, Table of Contents

Synlett
DOI: 10.1055/a-2602-6899

letter

Small Molecules in Medicinal Chemistry

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

Yaroslav O. Chuchvera

^aEnamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine

^bTaras Shevchenko National University of Kyiv, Volodymyrska Steet 60, Kyiv 01033, Ukraine

,

Oleksandr P. Korobka

^aEnamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine

^cV.N. Karazin Kharkiv National University, Svobody Square 4, Kharkiv 61022, Ukraine

,

Yurii O. Horbatochkin

^aEnamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine

^cV.N. Karazin Kharkiv National University, Svobody Square 4, Kharkiv 61022, Ukraine

,

Eugeniy N. Ostapchuk

^aEnamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine

^bTaras Shevchenko National University of Kyiv, Volodymyrska Steet 60, Kyiv 01033, Ukraine

,

Maria V. Popova

^bTaras Shevchenko National University of Kyiv, Volodymyrska Steet 60, Kyiv 01033, Ukraine

^dMax Planck Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany

,

Svitlana V. Shishkina

^eInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine

^fSSI ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, Nauky Avenue 60, Kharkiv 61001, Ukraine

,

Yulian M. Volovenko

^bTaras Shevchenko National University of Kyiv, Volodymyrska Steet 60, Kyiv 01033, Ukraine

,

Alexey V. Dobrydnev ∗

^aEnamine Ltd., Winston Churchill Street 78, Kyiv 02094, Ukraine

^bTaras Shevchenko National University of Kyiv, Volodymyrska Steet 60, Kyiv 01033, Ukraine

› Author Affiliations

Abstract

All articles of this category

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

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References

References and Notes

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13 2,2-Disubstituted-3-((methyl(hetero/aryl)(oxo)-λ⁶-sulfaneylidene)amino)propanenitriles 2c–e; General Procedure Imino(methyl)(hetero/aryl)-λ⁶-sulfanone 4a,b (2.5 mmol, 1 equiv) was dissolved in DMF (3 mL) followed by the addition of t-BuOK (421 mg, 3.75 mmol, 1.5 equiv) in one portion. The obtained mixture was then stirred at ambient temperature for 1 h. Next, 2,2-disubstituted 3-bromopropanenitrile 3a,c,d (3.75 mmol, 1.5 equiv) was added dropwise and the resulting mixture was stirred at 40 °C overnight (the progress of the reaction was monitored by TLC). The mixture was poured into ice-cold saturated aq. NH₄Cl (15 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was dried (Na₂SO₄) and evaporated under reduced pressure to give the crude product, which was purified by HPLC (using gradient elution with acetonitrile–water).
14 1-(((Methyl(oxo)(phenyl)-λ⁶-sulfaneylidene)amino)methyl)cyclobutane-1-carbonitrile (2с) The product was obtained from 3с (653 mg) and 4a (388 mg). Yield: 484 mg (1.95 mmol, 78%); yellowish amorphous solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 7.9 Hz, 2 H), 7.60–7.50 (m, 3 H), 3.16 (d, J = 12.2 Hz, 1 H), 3.07 (s, 3 H), 2.96 (d, J = 12.2 Hz, 1 H), 2.46–2.35 (m, 2 H), 2.28–2.24 (m, 1 H), 2.04–1.88 (m, 3 H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 139.0, 133.2, 129.6, 128.7, 49.3, 45.1, 37.4, 29.6, 29.5, 16.6. MS (APCI): m/z = 249 [М + Н]⁺.
15 5-Enamino 1-(Hetero)aryl-1,2-thiazine 1-Oxides 1c,e (Two-Step Method); General Procedure 2,2-Disubstituted-3-((methyl(hetero/aryl)(oxo)-λ⁶-sulfaneylidene)amino)propanenitrile 2c,e (1.5 mmol, 1 equiv) was dissolved in DMF (2 mL) followed by the addition of t-BuOK (252 mg, 2.25 mmol, 1.5 equiv). The obtained mixture was then stirred at 60 °C overnight. Next, the mixture was poured into ice-cold saturated aq. NH₄Cl (8 mL) and extracted with EtOAc (3 × 4 mL). The organic layer was dried (Na₂SO₄) and evaporated under reduced pressure to give the crude product, which was purified by HPLC (using gradient elution with acetonitrile–water).
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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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