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.

Being a relatively novel class of compounds sulfoximines have already been recognized by medicinal chemists and drug developers as prospective templates,[1] and are unofficially referred to as a rising star in modern drug discovery.[1d] Owing to its unique structural and electronic features,[2] the sulfoximine functional group has been utilized in multiple drug discovery programs and has been embedded into the structures of various lead compounds and drug candidates. One such example is the experimental drug methionine sulfoximine,[3] which increases the life span of mice with Lou Gehrig’s disease. The investigational anticancer drugs ceralasertib[4] and enitociclib[5] show promising results in the treatment of hematological malignancies and solid tumors, respectively. These two drugs are currently undergoing Phase II studies (Figure [1]).

Considering the pivotal role of heterocyclic compounds in drug discovery projects,[6] cyclic sulfoximines have unsurprisingly been the subject of significant new interest in medicinal chemistry, and the development of appropriate lead compounds and experimental drugs is expected shortly. Notwithstanding the recent advances in the chemistry of cyclic sulfoximines,[7] their chemical space remains rather scarce.

Within the scope of the present paper we focused on C5-functionalized 1-(hetero)aryl-1,2-thiazine 1-oxides. Several synthetic strategies for constructing this framework have been reported to date. An early example is the thermo-induced vinylation of NH-sulfoximines with functionalized (thio)alkoxyethenes and subsequent base-mediated cyclization of the intermediate vinylimino-λ⁶-sulfanones (Scheme [1]A).[8] Another method involves the Lewis acid mediated intermolecular cyclization of N-arylsulfonimidoyl chloride with monofunctionalized alkenes (Scheme [1]B).[9] The Pd-catalyzed N-arylation of an NH-sulfoximine with C2-functionalized bromobenzenes followed by KH-promoted cyclization of the obtained C2-functionalized phenylimino-λ⁶-sulfanones successfully gives the desired products. This strategy is also known as the Harmata benzothiazine synthesis (Scheme [1]C).[10] Finally, a more recent report described a stereoselective version of a modified Harmata synthesis: Pd-catalyzed N-arylation of an NH-sulfoximine with aromatic N-protected bromoaldimines followed by LiHMDS-promoted cyclization and acidic deprotection of the obtained N-(tert-butylsulfinyl)-4-aminobenzothiazine sulfinimines gave the target 1,2-thiazine 1-oxides (Scheme [1]D).[11]

As can be seen, base-mediated cyclization of β-functionalized imino(methyl)-λ⁶-sulfanones has become a strategy of increasing importance for the synthesis of C5-functionalized endocyclic sulfoximines possessing other attractive functional groups and substituents (Schemes 1A, C and D). However, to the best of our knowledge, spirocyclic representatives of C5-functionalized 1,2-thiazine 1-oxides, as well as their S-heteroaryl-substituted counterparts have not been reported to date.

As an extension to the given literature methods and in continuation of our interest in carbanion-mediated sulfonate (or sulfonamide) intermolecular coupling and intramolecular cyclization (CSIC) reactions,[12] we have developed a convenient strategy for the synthesis of C5-functionalized 6-membered endocyclic sulfoximines bearing 4,4-spirocyclic and S-(hetero)aryl substituents (Scheme [1]E).

We assumed that the target endocyclic enamino sulfoximines 1 could be accessed via base-mediated cyclization of sulfaneylidene amino propanenitriles 2. The latter are expected to be easily prepared through alkylation of the corresponding imino sulfanones 4 with 3-bromopropanenitriles 3 (Scheme [2]).

Based on the above retrosynthetic strategy, we chose readily available 2,2-disubstituted 3-bromopropanenitriles 3a–d and the corresponding imino(methyl)(hetero/aryl)-λ⁶-sulfanones 4a–c as starting materials for the present research (Figure [2]).

We initiated the synthetic aspects of our study with preliminary experiments to find optimal conditions for the alkylation of NH-sulfoximines 4. Several solvents and bases were tested at different reaction temperatures, and the best result was obtained when 1.5 equivalents of t-BuOK in DMF were utilized under moderate heating (see Table S1 in the Supporting Information). In this way we prepared the three alkylated products 2c–e in good yields (Scheme [3]).[13] [14]

Cyclization of linear sulfoximines 2c,e to give endocyclic products was also effected by treatment with excess t-BuOK (2 equiv) in the same solvent (DMF). A temperature of 60 °C was the optimal for efficient conversion (see Table S2 in the Supporting Information). This allowed us to prepare enamino sulfoximines 1c,e in moderate yields (Scheme [4]).[15]

Considering that both steps proceeded in the same solvent with the same base we envisaged a one-pot protocol to develop a more efficient procedure. Thus, after the formation of alkylated sulfoximine 2 was deemed complete, as determined by TLC, another 1.5 equivalents of t-BuOK were added to the reaction mixture before final heating at 60 °C.[16] Pleasingly, the one-pot procedure resulted in better yields and surpassed the overall yields obtained via the two-step procedure. Specifically, endocyclic sulfoximines 1с,e were isolated in 37% and 38% overall yields, respectively, following the two-step procedure (Scheme [4]). At the same time, 38% and 41% yields, respectively, were obtained using the one-pot method (Table [1], entries 3 and 5).[17]

Table 1 Synthesis of C5-Functionalized 1-(Hetero)aryl-1,2-thiazine 1-Oxides 1a–c,e–g, 5d,h (One-Pot Method)

Entry	Bromo nitrile	Sulfoximine	Product	Yield (%)a
1				34
2				39
3				38
4				19
5				41
6				48
7				40
8				21

^a Yield over two steps after HPLC purification.

With optimal reaction condition in hands, the substrate scope was next investigated using the starting materials depicted in Figure [2]. Overall, the one-pot method proved itself to be effective, such that the corresponding enamino sulfoximines 1a–c,e–g were obtained in moderate yields (Table [1], entries 1–3 and 5–7). The only concern we faced was associated with the pairs of substrates 3d + 4a and 3c + 4c. Instead of the expected enamino sulfoximines, the corresponding keto sulfoximines 5d and 5h were isolated in significantly lower yields (Table [1], entries 4 and 8).

The structure of enamino sulfoximine 1g was established unambiguously by X-ray crystal structure analysis (Figure [3]).[18]

Assuming that hydrolysis of the enamine fragment of the resulting keto sulfoximines 5d and 5h occurred during HPLC purification, we performed acid hydrolysis of the other enamino sulfoximines 1. To our disappointment, the acid-mediated hydrolysis of enamino sulfoximines 1c,e–g, even under mild conditions, could not be stopped at the formation of the corresponding keto sulfoximines 5, but accompanied by a retro-Claisen reaction, resulted in ring opening and the formation of acids 6c,e–g (Scheme [5]A).[19] [20] This was supported by the acid hydrolysis of keto sulfoximines 5h under similar reaction conditions, which also resulted in the corresponding carboxylic acid 6h (Scheme [5]B). Subsequently, we found that keto sulfoximines 5d,h were present in the reaction mixture after quenching the excess base and prior to the HPLC purification procedure. Currently we do not have a clear explanation for this phenomenon.

On the other hand, the NH₂ group of model 1f participated in the reaction with DMF–DMA to give the corresponding (dimethylaminomethylene)enamino sulfoximine 7f in a good yield of 75% (Scheme [6]).[21] [22]

Next, to demonstrate the potential utility of C5-functionalized 1-heteroaryl-1,2-thiazine 1-oxides as a promising pharmacological template, a molecular docking study was conducted. Among the biggest global health problems in 2024 were cancer[22] and neurodegenerative diseases.[23] Therefore, we focused on in silico targeting CDK-like kinase 4 (CDK4),[24] associated with tumor progression and metastasis, and monoamine oxidase B (MAO B),[25] related to Alzheimer’s and Parkinson’s diseases. On the other hand, the structure of 1g, with defined geometric parameters, acted as a model ligand. The presence of a stereogenic center at the sulfur atom endows endocyclic sulfoximines with chirality, therefore both enantiomers of 1g (i.e., R and S) were docked to predict the most biologically active form. Additionally, the known drugs silmitasertib[26] and selegiline[27] (Figure [4]) were used as references for a comparative assessment of predicted affinity to CDK4 and MAO B, respectively.

It turned out that compound S-1g showed a greater affinity to CLK4, but both enantiomers were inferior to silmitasertib (Table [2] and Figure [5], see also Figures S2–S4 in the Supporting Information). Both enantiomers R-1g and S-1g showed almost equal and superior binding affinity to MAO B compared to selegeline (Table [2] and Figure [6], see also Figures S5–S7 in the Supporting Information). Thus, the predicted values for the binding energy and the inhibition constant indicate that 1g can be considered as a promising inhibitor of both CLK4 and MAO B.

In conclusion, we have developed a simple and efficient method for the synthesis of C5-functionalized 1-(hetero)aryl-1,2-thiazine 1-oxides starting from readily available reagents. The reaction can be either performed by isolating the linear sulfoximine precursor (two-step protocol) or in a one-pot fashion. The latter approach demonstrates advantages in terms of simplicity and the obtained yields of the target products.

These compounds were designed as multi-target small molecules,[28] which are of significant interest to medicinal chemistry. Preliminary in silico studies showed that enamino sulfoximines are able to inhibit simultaneously CLK4 and MAO B – the targets for the most pressing diseases of modern society. We hope that our findings will provide medicinal chemists with a novel platform for the construction of next-generation lead compounds and drug candidates, thus contributing to global health.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank Dr. Yuliia Satska (Enamine Ltd.) for the chromatographic purification of the discussed compounds, Anton O. Poliudov (National Technical University of Ukraine ‘Igor Sikorsky Kyiv Polytechnic Institute’) for the molecular docking study, and Prof. Andrey A. Tolmachev (Enamine Ltd. and Taras Shevchenko National University of Kyiv) for his encouragement and support.

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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).
• 16 C5-Functionalized 1-(Hetero)aryl-1,2-thiazine 1-Oxides 1a–c,e–g and 5d,h (One-Pot Method); General Procedure Imino(methyl)(hetero/aryl)-λ⁶-sulfanone 4a–c (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–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). After the starting compounds had been consumed, the reaction mixture was cooled to room temperature followed by the addition of another portion of t-BuOK (421 mg, 3.75 mmol, 1.5 equiv), and the obtained mixture was then stirred at 60 °C overnight. Next, 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).
• 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
• 19 2,2-Disubstituted-3-((methyl(hetero/aryl)(oxo)-λ⁶-sulfaneylidene)amino)propanoic Acids 6c,e–h; General Procedure A solution of C5-functionalized 1-(hetero)aryl-1,2-thiazine 1-oxide 1c,e–g or 5h (0.2 mmol) in a mixture of HOAc (1 mL) and water (1 mL) was heated at 60 °C overnight. The mixture was then evaporated under reduced pressure, triturated with hexane (5 mL), filtered and washed twice with a few drops of water to give the product 6c,e–h.
• 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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Corresponding Author

Publication History

Received: 28 February 2025

Accepted after revision: 07 May 2025

Accepted Manuscript online:
07 May 2025

Article published online:
18 June 2025

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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).
• 16 C5-Functionalized 1-(Hetero)aryl-1,2-thiazine 1-Oxides 1a–c,e–g and 5d,h (One-Pot Method); General Procedure Imino(methyl)(hetero/aryl)-λ⁶-sulfanone 4a–c (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–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). After the starting compounds had been consumed, the reaction mixture was cooled to room temperature followed by the addition of another portion of t-BuOK (421 mg, 3.75 mmol, 1.5 equiv), and the obtained mixture was then stirred at 60 °C overnight. Next, 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).
• 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
• 19 2,2-Disubstituted-3-((methyl(hetero/aryl)(oxo)-λ⁶-sulfaneylidene)amino)propanoic Acids 6c,e–h; General Procedure A solution of C5-functionalized 1-(hetero)aryl-1,2-thiazine 1-oxide 1c,e–g or 5h (0.2 mmol) in a mixture of HOAc (1 mL) and water (1 mL) was heated at 60 °C overnight. The mixture was then evaporated under reduced pressure, triturated with hexane (5 mL), filtered and washed twice with a few drops of water to give the product 6c,e–h.
• 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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