Acid-Catalyzed Hydrolysis and Intramolecular Cyclization of N-Cyano Sulfoximines for the Synthesis of Thiadiazine 1-Oxides

Abstract

Herein, we describe a novel approach for the practical synthesis of thiadiazine 1-oxides 10. The first example of an intramolecular cyclization with 2-N-cyano-sulfonimidoyl amides 9 to form the desired thiadiazine 1-oxides 10 was developed. One-pot acid-induced hydrolysis of the cyano group and the intramolecular cyclocondensation protocol readily provided various heterocyclic frameworks in good to moderate yields. Notably, the crystal structures of N-urea sulfoximine 11 and thiadiazine 1-oxide 10i have been determined using X-ray crystallography.

Introduction

Thiadiazine 1-oxide―a benzene-fused sulfoximine moiety―was first reported in 1964.¹ With regard to drug discovery, thiadiazine 1-oxide derivatives displayed interesting biological properties.^2,3 For representative examples, thiadiazine 1-oxide A displayed blood-pressure-lowering activity as an analogue of Prazosin which is the commercial antihypertensive drug,^2a and compound B was found to be a useful inhibitor in treating or preventing a hepatitis C virus infection^3l (Figure 1a). Due to the interesting biological properties of this fused heterocycle, several synthetic strategies have been investigated to further develop these derivatives.⁴ In general, thiadiazine 1-oxides are prepared by the cyclization of 2-NH-sulfonimidoyl anilines 2. To overcome difficulties for the preparation of the desired NH sulfoximines 2 starting from 2-thiomethyl-anilines,⁵N-protected 2-thio-substituted anilines or ortho-nitroaryl thioethers 1 are commonly used as the starting materials. However, demanding reaction conditions such as multistep, elevated reaction temperatures, and long reaction times often limit the practicability or the scope of substrates (Figure 1b).^{2a,3l,4b,4e,6} In particular, the NH-sulfoximine moiety of compound 2 often behaves as a challenging class of N-nucleophiles for N-alkyl and N-acyl substitutions.⁷

Figure 1.

(a) Representative examples of bioactive thiadiazine 1-oxides A,^2a and B,^3l (b) common synthetic approach.²⁻⁶

For the recent alternative synthetic strategy, ortho-C–H amination of the NH-sulfoximines 6 has generally been applied as the key transformation step (Figure 2a). For example, Bolm and co-workers developed the method, the directed C–H bond amidation of sulfoximines 6 under rhodium catalysis.⁸ For one-pot approaches, transition metal-catalyzed approaches to afford thiadiazine 1-oxide derivatives 10, including Rh(III)-, Co(III)-, Ir(III)-, and Cu-catalyzed reaction, were reported (Figure 2a).⁹ Although these approaches seem to be quite applicable, these procedures have several drawbacks such as expensive transition-metal catalysts and noncommercial amination reagents.^9c Consequently, a practical method of synthesizing biologically active thiadiazine 1-oxide 10 is strongly required.

Figure 2.

(a) Recently reported strategies to benzothiadiazine 1-oxide structures^8,9 and (b) our method.^10,11

With a goal of enhanced simplicity and synthetic efficiency for the synthesis of thiadiazine 1-oxides 10, we envisaged the one-pot acid-induced intramolecular cyclocondensation approach. Our previous finding of the thionium ion-mediated N-cyano sulfilimine 8 synthesis¹⁰ and the subsequent oxidation¹¹ successfully provided the desired 2-N-cyano-sulfonimidoyl amides 9 (Figure 2b). It should be highlighted that the recent success in the imination of reactive functional group-substituted thioanisoles 7(10) has been used as the key step in the practical synthesis of thiadiazine 1-oxides 10. Mechanistically, this reaction is assumed to proceed via the intramolecular cyclization of NH sulfoximines, which is formed in situ by the acid-catalyzed hydrolysis of the N-cyano group.¹²

Results and Discussion

To determine whether acid could catalyze both hydrolysis of N-cyano group and cyclization step, the one-pot process was performed using an aqueous acid solution.^12,13 For the preparation of the starting material 9a, the sulfoximination of sulfide 7a proceeded with excellent yield.^9,14 Using the aqueous acid solution as reagent and solvent, the optimization study was performed (Table 1). Based on the reported method for the cleavage of the N–CN bond, aqueous H₂SO₄ and HCl solution was used.^12,13 As shown in entries 1–3 in Table 1, changing the amount and concentration of aqueous sulfuric acid solutions affected the yield. Increasing the reaction time (entry 2 vs 4) did not increase the yield of the desired product. Replacing H₂SO₄ with HCl did not lead to improved yield (entries 5–8). Thus, this reaction was substantially influenced by the choice of the acid. Interestingly, when 1.6 mL of 1 N aqueous HCl solution was added, urea compound 11―synthetic intermediate of NH sulfoximine―was obtained (entry 5).^13b The attempt to improve the yield of this one-pot process by changing the reaction time and acid concentration of HCl solution was unsuccessful (entries 6 and 8). No product was observed with dioxane as a solvent (entry 7), implying that the aqueous solution was necessary for the reaction. Finally, the condition from entry 2 was selected to continue our study. The scope for this transformation was explored with these optimized conditions (Scheme 1).

Table 1. Optimization of the Intramolecular Cyclization with Aqueous Acid Solution.

			yield (%)
entry	reaction conditionsa,b	time (h)	10a	11
1	aq H2SO4 (10 N), 3 mL	0.5	40	d
2	aq H2SO4 (10 N), 1.5 mL	0.5	58	d
3	aq H2SO4 (10 N), 1.5 mL	0.5	16	d
4	aq H2SO4 (10 N), 1.5 mL	3.5	40	d
5	aq HCl (1 N), 1.6 mL	16	18	29
6	aq HCl (1 N), 1.6 mL	26	35	d
7	aq HCl (1 N), 0.8 mLc	18	d	d
8	aq HCl (3 N), 1.6 mL	16	21	d

^a0.17 mmol of starting material 9a was used.

^bReaction temperature was 110 °C.

^cIn dioxane 0.8 mL.

^dNot obtained.

Scheme 1. Scope of One-Pot Synthesis of Benzothiadiazine 1-Oxides 10.

As following our previous study, imination of thioanisol derivatives 7(10) produced the corresponding N-cyano sulfilimines 8 in excellent yield. The subsequent oxidation of sulfilimines with m-CPBA¹¹ provided the target N-cyano sulfoximine 9b–9i.¹⁴ For heterocycle-substituted 2-N-cyano-S-methyl sulfonimidoyl amides, the desired benzothiadiazine 1-oxides 10b, 10c, and 10d were obtained in good yield. The electron-donating methoxy group in the N-benzamide position diminished the yield, giving 10e in 29% yield.¹⁵ In N-2-naphthamide and 2-N-cyanophenylsulfonimidoyl phenyl compounds 9f and 9g, the cyclized products 10f and 10g were obtained in good yield (63 and 60%). Both 4-chloro-6-methylphenyl 9h and pyridin-4-yl benzamide 9i afforded the desired product 10h and 10i in excellent yield (79 and 71%). Notably, we report the first X-ray crystal structures of N-urea sulfoximine 11 and thiadiazine 1-oxide 10i, as illustrated in Figure 3.¹⁶

Figure 3.

X-ray crystal structures of 11 and 10i.¹⁶

To obtain insights into the reaction mechanism, we performed control experiments (Table 2). For the one-pot reaction of N-acetamide 9j, 2-NH-sulfonimidoyl aniline 12 was obtained under the standard condition (Table 2, entry 1). Interestingly, the base-catalyzed approach using aqueous 1 N NaOH provided 2-NH-sulfonimidoyl aniline 12. These results clearly demonstrated that the intramolecular cyclization proceeded via the formation of NH-sulfoximine.

Table 2. Control Experiments.

entry	starting materials	R	reaction conditionsa	12, yield (%)d
1	9j	CH3	aq H2SO4 (10 N), 1.5 mLb	29
2	9a	Ph	aq NaOH (1 N), 1.5 mLc	64

^a0.17 mmol of starting material 9 was used.

^b110 °C for 0.5 h.

^c110 °C for 16 h.

^dAfter column chromatography.

On the basis of our studies and the reported literature,^9a we propose a plausible mechanism in Scheme 2. The hydrolysis of N-cyano sulfoximine with aqueous H₂SO₄ generates an N-urea sulfoximine 11, which then undergoes hydrolysis to give NH-sulfoximine. Intramolecular cyclocondensation of NH-sulfoximine provides the desired thiadiazine 1-oxide 10.

Scheme 2. Proposed Mechanism^9a.

Conclusions

In summary, we have developed a new one-pot process for the synthesis of thiadiazine 1-oxides 10 using H₂SO₄, a key substance in the chemical industry. The N-cyano sulfoximine is an excellent moiety for the acid-catalyzed intramolecular cyclization. Various functional groups on benzamides proved to be compatible with this transformation. Further application of these attractive molecules to drug discovery is currently under investigation in our group.

Experimental Section

General Information

Analytical thin-layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates precoated with a 0.2 mm thickness of silica gel. The TLC plates were visualized by UV (254 nm), potassium permanganate or ceric ammonium molybdate stain. Flash chromatography was carried out with Kieselgel 60 (230–400 mesh) on a silica gel. Melting points: Barnstead/Electrothermal 9300, measurements were performed in open glass capillaries. IR spectra: Bruker ALPHA-P. NMR spectra: Bruker AV 300 MHz (¹H NMR: 300 MHz, ¹³C NMR: 75 MHz), AV 400 MHz (¹H NMR: 400 MHz, ¹³C NMR: 100 MHz), AV 500 MHz (¹H NMR: 500 MHz, ¹³C NMR: 125 MHz), and AV2 500 MHz (¹⁹F NMR: 470 MHz), and the spectra were recorded in CDCl₃, MeOD, and DMSO-d₆ using TMS as internal standard and are reported in ppm. ¹H NMR data are reported as follows: [s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, td = doublet of triplet, and m = multiplet; coupling constant(s) J is given in Hz; integration, proton assignment]. High-resolution mass spectra (HRMS): JEOL JMS-700. X-ray crystallography: Bruker SMART APEX II X-ray diffractometer. All solvents were purified using the column filter solvent purification system before use unless otherwise indicated. Reagents were purchased and used without further purification (Schemes 3–6).

Scheme 3. For the Preparation of Thioanisols (7a–7j).

Scheme 6. General Cyclization Method.

Scheme 4. General Imination Method.

Scheme 5. General Oxidation Method.

N-[2-(Methylthio)phenyl]benzamide (7a) lit.¹⁷

N-[2-(Methylthio)phenyl]furan-2-carboxamide (7b) lit.¹⁸

N-[2-(Methylthio)phenyl]thiophene-2-carboxamide(7c) lit.¹⁸

6-Chloro-N-[2-(methylthio)phenyl]nicotinamide (7d)

To a solution of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluorophosphate (983.4 mg, 2.59 mmol) and 6-chloronicotinic acid (455.1 mg, 2.59 mmol) in dimethylformamide (DMF) (4 mL) were added dropwise 2-(methylthio)aniline (300 mg, 2.16 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.31 mmol) in DMF (6 mL) at 0 °C. The reaction mixture was stirred at rt for 16 h and quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc: hexane = 1:10) to give the desired sulfide 7d as a white solid (482 mg, 80% yield). mp 107–108 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.20 (br, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.22 (dd, J = 8.3, J = 2.5 Hz, 1H), 7.56 (dd, J = 1.1, J = 7.8 Hz, 1H), 7.49 (d, J = 8.3 Hz. 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.15 (td, J = 7.7, J = 1.3 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 162.4, 154.9, 148.3, 138.1, 137.9, 133.4, 129.6, 129.4, 126.0, 125.3, 124.8, 120.7, 19.4; HRMS (EI): calcd for C₁₃H₁₁ClN₂OS, 278.0281; found, 278.0291.

4-Methoxy-N-[2-(methylthio)phenyl]benzamide (7e) lit.¹⁷

N-[2-(Methylthio)phenyl]-2-naphthamide (7f) lit.¹⁷

N-[2-(Phenylthio)phenyl]benzamide (7g)

To a solution of 2-(phenylthio)aniline (1 g, 4.97 mmol) and trimethylamine (1 g, 9.94 mmol) in CH₂Cl₂ (5 mL) was added benzoyl chloride(768.1 mg, 5.46 mmol) in CH₂Cl₂ (5 mL) at 0 °C. The reaction mixture was stirred at rt for 16 h and quenched with water. The reaction mixture was extracted with CH₂Cl_2. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:10) to give the desired sulfide 7g as a white solid (1.51 g, quantitative yield). mp 67–68 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.08 (br, 1H), 8.71 (dd, J = 2.7, J = 1.4 Hz, 1H), 7.66–7.62 (m, 3H), 7.54–7.48 (m, 2H), 7.27–7.23 (m, 2H), 7.19–7.11 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 165.4, 140.2, 136.8, 135.6, 134.9, 132.0, 131.4, 129.5, 128.9, 127.2, 127.1, 126.5, 124.6, 120.7, 120.2; HRMS (EI) calcd for C₁₃H₁₁ClN₂OS, 305.0874; found, 305.0858.

N-[4-Chloro-2-methyl-6-(methylthio)phenyl]benzamide (7h)

To a solution of 4-chloro-2-methyl-6-(methylthio)aniline (1 g, 5.33 mmol) and trimethylamine (1.08 g, 10.65 mmol) in CH₂Cl₂ (2 mL) was added benzoyl chloride(748 mg, 5.33 mmol) in CH₂Cl₂ (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h and quenched with water. The reaction mixture was extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired sulfide 7h as a brown solid (300 mg, 19% yield). mp 164–165 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J = 7.2 Hz), 7.58 (t, J = 7.3 Hz, 1H), 7.52–7.47 (m, 3H), 7.09 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 166.0, 138.6, 138.6, 134.1, 133.5, 132.2, 131.3, 129.0, 127.5, 127.5, 123.3, 18.7, 15.6; HRMS (EI): calcd for C₁₅H₁₄ClNOS, 291.0485; found, 291.0475.

N-[3-(Methylthio)pyridin-4-yl]benzamide (7i)

To a solution of 3-(methylthio)pyridin-4-amine (400 mg, 2.85 mmol) and trimethylamine (433.1 mg, 4.28 mmol) in CH₂Cl₂ (6 mL) was added benzoyl chloride(748 mg, 5.33 mmol) in CH₂Cl₂ (6 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h and quenched with water. The reaction mixture was extracted with CH₂Cl_2. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired sulfide 7i as a white solid (647.0 mg, 93% yield). mp 100–101 °C; ¹H NMR (300 MHz, CDCl₃): δ 9.46 (br, 1H), 8.71 (s, 1H), 8.53–8.49 (m, 2H), 7.94 (m, 2H), 7.64–7.51 (m, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 165.5, 154.9, 151.1, 146.0, 133.9, 132.7, 129.1, 127.2, 120.8, 113.3, 19.8; HRMS (EI): calcd for C₁₃H₁₂N₂OS, 244.0670; found, 244.0664.

N-[2-(Methylthio)phenyl]acetamide (7j) lit.¹⁹

To a solution of sulfide 7 (1 equiv) and PhI(OAc)₂ (1 equiv) in DMF (0.4 M) was added H₂NCN (3 equiv) in DMF (1 mL) at 0 °C. The reaction mixture was stirred at rt overnight and quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired product 8.

(E)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]benzamide (8a) lit.¹⁰

(E)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]furan-2-carboxamide (8b) lit.¹⁰

(E)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]thiophene-2-carboxamide (8c)

Following the general imination method, the reaction of sulfide 7c (300 mg, 1.20 mmol) with PhI(OAc)₂ (387.6 mg, 1.20 mmol) and H₂NCN (151.7 mg, 3.61 mmol) in DMF (3 mL) gives the desired sulfilimine 8c as a yellow solid (36.3 mg, 63% yield). mp 140–141 °C; IR (KBr): ν 2136 (CN) cm^–1; ¹H NMR (400 MHz, DMSO): δ 10.90 (br, 1H), 8.16 (dd, J = 8.0, J = 1.0 Hz, 1H), 8.08 (d, J = 3.7 Hz, 1H), 7.96 (dd, J = 5.0, J = 1.2 Hz, 1H), 7.74 (td, J = 7.7, J = 1.5 Hz, 1H), 7.65 (td, J = 7.8, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.0, J = 1.3 Hz, 1H), 7.30–7.28 (m, 1H), 3.17 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 161.5, 137.6, 135.3, 134.1, 133.6, 133.0, 130.6, 128.4, 128.3, 126.6, 126.2, 120.7, 35.4; HRMS (EI): calcd for C₁₃H₁₁N₃OS₂, 289.0344; found, 289.0350.

(E)-6-Chloro-N-[2-(N-cyano-S-methylsulfinimidoyl)phenyl]nicotinamide (8d)

Following the general imination method, the reaction of sulfide 7d (300 mg, 1.08 mmol) with PhI(OAc)₂ (346.7 mg, 1.08 mmol) and H₂NCN (136 mg, 3.23 mmol) in DMF (3 mL) gives the desired sulfilimine 8d as a white solid (228.0 mg, 66% yield). mp 165–166 °C; IR (KBr): ν 2134 (CN) cm^–1; ¹H NMR (400 MHz, DMSO): δ 11.10 (br, 1H), 9.02 (s, 1H), 8.42 (dd, J = 8.4, J = 2.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.79–7.74 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 3.18 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 164.6, 153.6, 149.6, 139.2, 135.2, 134.1, 133.7, 128.6, 128.1, 126.5, 126.5, 124.4, 120.6, 35.5; HRMS (EI): calcd for C₁₄H₁₁ClN₄OS, 318.0342; found, 318.0354.

(E)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]-4-methoxybenzamide (8e)

Following the general imination method, the reaction of sulfide 7e (400 mg, 1.46 mmol) with PhI(OAc)₂ (471 mg, 1.46 mmol) and H₂NCN (184.4 mg, 4.39 mmol) in DMF (2 mL) gives the desired sulfilimine 8e as a white solid (320.1 mg, 70% yield). mp 154–155 °C; IR (KBr): ν 2130 (CN) cm^–1; ¹H NMR (500 MHz, DMSO): δ 10.75 (br, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.19 (s, 3H); ¹³C NMR (125 MHz, DMSO): δ 166.4, 162.6, 136.1, 134.1, 133.5, 130.0, 128.0, 126.5, 126.1, 124.7, 120.8, 113.9, 55.6, 35.4.; HRMS (EI): calcd for C₁₆H₁₅N₃O₂S, 313.0885; found, 313.0901.

(E)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]-2-naphthamide (8f)

Following the general imination method, the reaction of sulfide 7f (500 mg, 1.70 mmol) with PhI(OAc)₂ (549 mg, 1.70 mmol) and H₂NCN (215 mg, 5.11 mmol) in DMF (5 mL) gives the desired sulfilimine 8f as a white solid (429 mg, 87% yield). mp 155–156 °C; IR (KBr): ν 2140 (CN) cm^–1; ¹H NMR (300 MHz, DMSO): δ 11.09 (s, 1H), 8.70 (s, 1H), 8.21–8.04 (m, 5H), 7.76 (td, J = 3.8, J = 0.6 Hz, 1H), 7.69–7.63 (m, 3H), 7.52 (d, J = 3.9 Hz, 1H), 3.23 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 166.4, 137.6, 136.3, 134.6, 132.1, 131.1, 130.6, 129.5, 129.1, 128.4, 128.4, 128.2, 127.8, 127.1, 124.1, 112.0, 42.2; HRMS (EI): calcd for C₁₉H₁₅N₃OS, 333.0936; found, 333.0915.

(E)-N-[2-(N-Cyano-S-phenylsulfinimidoyl)phenyl]benzamide (8g)

Following the general imination method, the reaction of sulfide 7g (1.0 g, 3.27 mmol) with PhI(OAc)₂ (1.05 g, 3.27 mmol) and H₂NCN (413 mg, 9.82 mmol) in DMF (8 mL) gives the desired sulfilimine 8g as a white solid (756.0 mg, 67% yield). mp 161–162 °C; IR (KBr): ν 2141 (CN) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 10.23 (br, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.82–7.68 (m, 4H), 7.58–7.31 (m, 9H);¹³C NMR (100 MHz, CDCl₃): δ 165.4, 134.0, 135.4, 133.9, 133.0, 132.6, 132.3, 131.2, 130.0, 128.9, 127.4, 126.0, 125.8, 124.9, 122.8, 120.8; HRMS (EI): calcd for C₂₀H₁₅N₃OS, 345.0936; found, 345.0923.

(E)-N-[4-Chloro-2-(N-cyano-S-methylsulfinimidoyl)-6-methylphenyl]benzamide (8h)

Following the general imination method, the reaction of sulfide 7h (100 mg, 0.34 mmol) with PhI(OAc)₂ (110.4 mg, 0.34 mmol) and H₂NCN (43.2 mg, 1.03 mmol) in DMF (2 mL) gives the desired sulfilimine 8h as a white solid (48 mg, 42% yield). mp 184–185 °C; IR (KBr): ν 2161 (CN) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 9.80 (br, 1H), 8.05–8.02 (m, 2H), 7.78 (d, J = 2.3 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.53–7.47 (m, 3H), 3.25 (s, 3H), 2.32 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 139.6, 136.7, 135.3, 134.6, 133.1, 132.9, 132.3, 128.9, 128.2, 123.1, 121.5, 38.0, 18.3; HRMS (FAB): calcd for C₁₆H₁₅ClN₃OS, 332.0624; found, 332.0608.

(E)-N-[3-(N-Cyano-S-methylsulfinimidoyl)pyridin-4-yl]benzamide (8i)

Following the general imination method, the reaction of sulfide 7i (50 mg, 0.21 mmol) with PhI(OAc)₂ (65.9 mg, 0.21 mmol) and H₂NCN (25.8 mg, 0.61 mmol) in DMF (1 mL) gives the desired sulfilimine 8i as an ivory color solid (42 mg, 84% yield). mp 143–144 °C; IR (KBr): ν 2145 (CN) cm^–1; ¹H NMR (300 MHz, DMSO): δ 11.26 (br, 1H), 9.27 (s, 1H), 8.81 (d, J = 5.4 Hz, 1H), 8.05–8.02 (m, 2H), 7.70 (t, J = 7.3 Hz, 1H), 7.63–7.58 (m, 3H), 3.38 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 167.1, 153.7, 148.9, 143.6, 133.1, 132.3, 128.8, 128.2, 128.1, 120.5, 118.4, 35.1.; HRMS (EI): calcd for C₁₄H₁₂N₄OS, 284.0732; found, 284.0709.

(Z)-N-[2-(N-Cyano-S-methylsulfinimidoyl)phenyl]acetamide (8j) lit.¹⁰

To a solution of sulfilimine (1 eq) 8 and K₂CO₃ (1.1 equiv) in MeOH was added m-CPBA (70%, 1.1 equiv) in MeOH at 0 °C. The reaction mixture was stirred at 0 °C overnight and quenched with water. The reaction mixture was extracted with EtOAc. The organic layer was dried over MgSO_4, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:1) to give the desired product 9.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]benzamide (9a)

Following the general oxidation method, the reaction of sulfilimine 8a (92.6 mg, 0.33 mmol) with m-CPBA (91.9 mg, 0.37 mmol) and K₂CO₃ (49.7, 1.1 mmol) in MeOH (3.3 mL) gives 9a as a white solid (60.9 mg, 66% yield). mp 157–158 °C; IR (KBr): ν 2196 (CN) cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 10.13 (s, 1H), 8.70 (dd, J = 8.4, J = 0.9 Hz, 1H), 8.02 (dd, J = 8.1, J = 1.5 Hz, 1H), 7.97–7.95 (m, 2H), 7.83 (t, J = 7.9 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.58–7.55 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 3.38 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 166.2, 137.6, 136.3, 133.8, 132.3, 130.5, 129.3, 128.7, 128.3, 127.7, 127.0, 111.9, 42.3; HRMS (EI): calcd for C₁₅H₁₃N₃O₂S, 299.0728; found, 299.0753.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]furan-2-carboxamide (9b)

Following the general oxidation method, the reaction of sulfilimine 8b (300 mg, 1.10 mmol) with m-CPBA (297.6 mg, 1.21 mmol) and K₂CO₃ (167.0 mg, 1.21 mmol) in MeOH (11 mL) gives the desired sulfoximine 9b as an ivory color solid (211.4 mg, 67% yield). mp 163–164 °C; IR (KBr): ν 2161 (CN) cm^–1; ¹H NMR (500 MHz, DMSO): δ 10.43 (br, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.05 (dd, J = 8.2, J = 1.3 Hz, 1H), 8.00 (s, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 6.76–76.75 (m, 1H), 3.80 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 156.3, 146.8, 146.4, 137.0, 136.4, 130.3, 126.8, 126.2, 126.2, 116.0, 112.7, 111.7, 42.7; HRMS (EI): calcd for C₁₃H₁₁N₃O₃S, 289.0521; found, 289.0518.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]thiophene-2-carboxamide (9c)

Following the general oxidation method, the reaction of sulfilimine 8c (200 mg, 0.69 mmol) with m-CPBA (187.4 mg, 0.76 mmol) and K₂CO₃ (105 mg, 0.76 mmol) in MeOH (6.9 mL) gives the desired sulfoximine 9c as a white solid (149.9 mg, 71% yield). mp 160–161 °C; IR (KBr): ν 2198 (CN) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 10.06 (br, 1H), 8.65 (d, J = 8.4 Hz 1H), 8.00 (dd, J = 8.2, J = 1.6 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.70 (dd, J = 3.8, J = 1.1 Hz, 1H), 7.66 (dd, J = 5.0, J = 1.1 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.21–7.18 (m, 1H), 3.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 159.8, 138.4, 138.0, 137.3, 132.8, 129.7, 129.5, 128.6, 125.1, 124.2, 122.6, 110.7, 44.5; HRMS (EI): calcd for C₁₃H₁₁N₃O₂S₂, 305.0293; found, 305.0301.

6-Chloro-N-[2-(N-cyano-S-methylsulfonimidoyl)phenyl]nicotinamide (9d)

Following the general oxidation method, the reaction of sulfilimine 8d (200 mg, 0.63 mmol) with m-CPBA(170.1 mg, 0.69 mmol) and K₂CO₃ (95.4 mg, 0.69 mmol) in MeOH (6.3 mL) gives the desired sulfoximine 9d as a white solid (83.2 mg, 40% yield). mp 146–147 °C; IR (KBr): ν 2197 (CN) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 10.26 (br, 1H), 8.97 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.17 (dd, J = 8.4, J = 2.6 Hz, 1H), 7.99 (dd, J = 8.2, J = 1.6 Hz, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 3.40 (s, 3H), 1.24 (s, grease); ¹³C NMR (100 MHz, CDCl₃): δ 162.7, 155.8, 149.2, 137.9, 137.5, 137.4, 130.0, 128.1, 125.9, 124.9, 124.5, 123.2, 110.6, 44.9, 29.8 (grease); HRMS (FAB): calcd for C₁₄H₁₂ClN₄O₂S, 335.0369; found, 335.0387.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]-4-methoxybenzamide (9e)

Following the general oxidation method, the reaction of sulfilimine 8e (300 mg, 0.96 mmol) with m-CPBA (259.6 mg, 1.05 mmol) and K₂CO₃ (145.5 mg, 1.05 mmol) in MeOH (9.6 mL) gives the desired sulfoximine 9e as a white solid (190 mg, 60% yield). mp 151–152 °C; IR (KBr): ν 2194 (CN) cm^–1; ¹H NMR (300 MHz, DMSO): δ 10.36 (br, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.00–7.87 (m, 4H), 7.61 (t, J = 7.7 Hz,f 1H), 7.14–7.09 (m, 2H), 3.85 (s, 3H), 3.76 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 165.5, 162.4, 137.9, 136.2, 130.4, 129.6, 128.8, 127.9, 126.6, 125.8, 114.0, 111.9, 55.5, 42.3; HRMS (EI): calcd for C₁₆H₁₅N₃O₃S, 329.0834; found, 329.0850.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]-2-naphthamide (9f)

Following the general oxidation method, the reaction of sulfilimine 8f (300 mg, 0.90 mmol) with m-CPBA (244 mg, 0.99 mmol) and K₂CO₃ (136.8 mg, 0.99 mmol) in MeOH (9 mL) gives 9f as a white solid (196 mg, 62% yield). mp 169–170 °C; IR (KBr): ν 2192 (CN) cm^–1; ¹H NMR (300 MHz, DMSO): δ 10.69 (s, 1H), 8.59 (s, 1H), 8.11 (d, J = 4.33 Hz, 3H), 8.12–7.90 (m, 4H), 7.71–7.62 (m, 3H), 3.80 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 167.1, 135.9, 134.7, 134.1, 133.6, 132.1, 130.1, 129.1, 128.8, 128.4, 128.3, 128.2, 127.8, 127.1, 126.6, 126.2, 124.2, 120.8, 40.2; HRMS (EI): calcd for C₁₉H₁₅N₃O₂S, 349.0885; found, 349.0912.

N-[2-(N-Cyanophenylsulfonimidoyl)phenyl]benzamide (9g)

Following the general oxidation method, the reaction of sulfilimine 8g (500 mg, 1.45 mmol) with m-CPBA (392.5 mg, 1.59 mmol) and K₂CO₃ (220.1 mg, 1.59 mmol) in MeOH (14.5 mL) gives the desired sulfoximine 9g as a white solid (416.8 mg, 80% yield). mp 129–130 °C; IR (KBr): ν 2204 (CN) cm^–1; ¹H NMR (300 MHz, DMSO): δ 10.17 (br, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.95–7.81 (m, 6H), 7.77–7.62 (m, 3H), 7.58–7.53 (m, 4H); ¹³C NMR (100 MHz, DMSO): δ 165.4, 137.7, 136.6, 135.9, 135.3, 133.2, 132.2, 130.4, 130.2, 130.0, 128.6, 127.6, 127.6, 111.4; HRMS (EI): calcd for C₂₀H₁₅N₃O₂S, 361.0885; found, 361.0908.

N-[4-Chloro-2-(N-cyano-S-methylsulfonimidoyl)-6-methylphenyl] Benzamide (9h)

Following the general oxidation method, the reaction of sulfilimine 8h (150 mg, 0.45 mmol) with m-CPBA(122.6 mg, 0.5 mmol) and K₂CO₃ (68.7 mg, 0.5 mmol) in MeOH (4.5 mL) gives the desired sulfoximine 9h as a white solid (37.7 mg, 21% yield). mp 167–168 °C; IR (KBr): ν 2208 (CN) cm^–1; ¹H NMR (300 MHz, CDCl₃): δ 8.76 (br, 1H), 8.00–7.95 (m, 3H), 7.10–7.05 (m, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.56–7.51 (m, 1H), 3.29 (s, 3H), 2.33 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 166.3, 142.9, 138.2, 134.3, 134.2, 133.2, 133.1, 132.3, 129.3, 127.8, 127.7, 111.3, 43.6, 18.8; HRMS (EI): calcd for C₁₆H₁₄ClN₃O₂S, 347.0495; found, 347.0477.

N-[3-(N-Cyano-S-methylsulfonimidoyl)pyridin-4-yl]benzamide (9i)

Following the general oxidation method, the reaction of sulfilimine 8i (150 mg, 0.53 mmol) with m-CPBA (143.1 mg, 0.58 mmol) and K₂CO₃ (80.2 mg, 0.58 mmol) in MeOH (5.3 mL) gives the desired sulfoximine 9i as a white solid (103.4 mg, 65% yield). mp 153–154 °C; IR (KBr): ν 2204 (CN) cm^–1; ¹H NMR (400 MHz, DMSO): δ 10.71 (br, 1H), 9.09 (s, 1H), 8.91 (s, 1H), 8.40 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.71 (t, J = 7.0 Hz, 1H) 7.64–7.60 (m, 2H), 3.98 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 165.6, 157.5, 150.9, 145.9, 133.8, 132.6, 129.5, 127.6, 117.8, 115.6, 110.0, 45.6, 29.8 (grease); HRMS (EI): calcd for C₁₄H₁₂N₄O₂S, 300.0681; found, 300.0671.

N-[2-(N-Cyano-S-methylsulfonimidoyl)phenyl]acetamide (9j)

Following the general oxidation method, the reaction of sulfilimine 8j (150 mg, 0.68 mmol) with m-CPBA (183.8 mg, 0.75 mmol) and K₂CO₃ (102.6 mg, 0.75 mmol) in MeOH (4.5 mL) gives the desired sulfoximine 9j as a white solid (56 mg, 35% yield). mp 140–141 °C; IR (KBr): ν 2191 (CN) cm^–1; ¹H NMR (400 MHz, DMSO): δ 9.82 (br, 1H), 8.01 (dd, J = 8.1, J = 1.1 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 3.71 (s, 3H), 2.10 (s, 3H); ¹³C NMR (100 MHz, DMSO): δ 169.6, 137.1, 136.1, 130.1, 129.6, 128.8, 126.8, 112.0, 42.2, 23.5; HRMS (EI): calcd for C₁₀H₁₁N₃O₂S, 237.0572; found, 237.0588.

A solution of sulfoximine 9 (0.17 mmol) in aqueous H₂SO₄ (10 N, 1.5 mL) was stirred at 110 °C for 0.5 h and quenched with saturated NaHCO₃. The reaction mixture was basified with saturated NaHCO₃ solution until pH 8 and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired product 10.

1-Methyl-3-phenyl-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10a)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10a as a white solid (25.0 mg, 58% yield). mp 135–136 °C; ¹H NMR (300 MHz, CDCl₃): δ 8.39–8.36 (m, 2H), 7.83 (dd, J = 7.9, J = 1.4 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.63 (dd, J = 8.4, J = 1.3 Hz, 1H), 7.48–7.39 (m, 4H), 3.56 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 158.0, 147.6, 137.5, 135.1, 131.2, 129.1, 128.6, 128.3, 126.3, 123.7, 113.1, 47.3; HRMS (EI): calcd for C₁₄H₁₂N₂OS, 256.0670; found, 256.0665.

3-(Furan-2-yl)-1-methyl-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10b)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10b as a white solid (23.3 mg, 55% yield). mp 198–199 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.80 (dd, J = 7.9, J = 1.3 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.65 (dd, J = 8.4, J = 1.0 Hz, 1H), 7.62–7.61 (m, 1H), 7.41 (t, J = 7.5 Hz, 1H), 6.55–6.54 (m, 1H), 3.56 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 151.4, 150.4, 147.2, 145.5, 135.3, 128.9, 126.4, 123.7, 115.0, 113.6, 112.2, 47.2; HRMS (EI): calcd for C₁₂H₁₀N₂O₂S, 246.0463; found, 246.0468.

1-Methyl-3-(thiophen-2-yl)-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10c)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10c as a yellow solid (19.1 mg, 44% yield). mp 157–158 °C; ¹H NMR (300 MHz, CDCl₃): δ 7.92 (dd, J = 3.7, J = 1.2 Hz, 1H), 7.79 (dd, J = 8.0, J = 1.1 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 5.0, J = 1.2 Hz, 1H), 7.38 (t, J = 7.6 Hz 1H), 7.11 (m, 1H), 3.54 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 154.3, 147.5, 143.3, 135.2, 130.5, 130.1, 128.7, 128.0, 126.1, 123.7, 113.2, 47.2; HRMS (EI): calcd for C₁₂H₁₀N₂OS₂, 262.0235; found, 262.0229.

3-(6-Chloropyridin-3-yl)-1-methyl-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10d)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10d as a white solid (27.8 mg, 57% yield). mp 187–188 °C; ¹H NMR (300 MHz, CDCl₃): δ 9.30 (d, J = 2.4 Hz, 1H), 8.57 (dd, J = 8.4, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.0, J = 1.5 Hz, 1H), 7.73 (t, J = 7.7 Hz 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 155.0, 153.6, 150.4, 146.9, 138.6, 135.4, 132.1, 129.1, 127.0, 123.7, 123.7, 113.4, 47.2; HRMS (EI): calcd for C₁₃H₁₀ClN₃OS, 291.0233; found, 291.0225.

3-(4-Methoxyphenyl)-1-methyl-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10e)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10e as a white solid (14.1 mg, 29% yield). mp 153–154 °C; ¹H NMR (300 MHz, CDCl₃): δ 8.37–8.32 (m, 2H), 7.81 (dd, J = 8.0, J = 1.5 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.5, 1H), 6.98–6.93 (m, 2H), 3.87 (s, 3H), 3.54 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 162.3, 157.8, 147.8, 135.1, 130.5, 130.0, 128.8, 125.9, 123.7, 113.6, 112.9, 55.5, 47.3; HRMS (EI): calcd for C₁₅H₁₄N₂O₂S, 286.0776; found, 286.0758.

1-Methyl-3-(naphthalen-2-yl)-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10f)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10f as a white solid (32.2 mg, 63% yield). mp 177–178 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.91 (s, 1H), 8.50 (dd, J = 8.6, J = 0.8 Hz, 1H), 8.01–8.98 (m, 1H), 7.92–7.84 (m, 3H), 7.76–7.68 (m, 2H), 7.56–7.49 (m, 2H), 7.43 (t, J = 7.4 Hz, 1H), 3.60 (s, 3H); ¹³C NMR (100 MHz, CDCl3): δ 157.9, 147.6, 135.2, 135.0, 134.8, 133.1, 129.4, 129.3, 129.1, 127.9, 127.8, 127.4, 126.4, 126.3, 125.3, 123.7, 113.2, 47.3; HRMS (EI): calcd for C₁₈H₁₄N₂OS, 306.0827; found, 306.0817.

1,3-Diphenylbenzo[e][1,2,4]thiadiazine 1-Oxide (10g)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10g as a white solid (31.6 mg, 59% yield). mp 157–158 °C; ¹H NMR (400 MHz, DMSO): δ 8.36–8.33 (m, 2H), 7.97–7.93 (m, 2H), 7.84–7.70 (m, 4H), 7.66–7.61 (m, 2H), 7.58–7.48 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H); ¹³C NMR (100 MHz, DMSO): δ 156.6, 146.1, 139.5, 137.0, 135.1, 134.6, 131.3, 129.9, 128.5, 128.4, 128.2, 128.1, 127.1, 125.0, 113.6.; HRMS (EI): calcd for C₁₉H₁₄N₂OS, 318.0827; found, 318.0824.

7-Chloro-1,5-dimethyl-3-phenyl-1λ⁴-benzo[e][1,2,4]thiadiazine 1-Oxide (10h)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:2) to give the desired thiadiazine 10h as a white solid (40.3 mg, 79% yield). mp 209–210 °C; ¹H NMR (300 MHz, CDCl₃): δ 8.43–8.39 (m, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 2.3, J = 0.8 Hz, 1H), 7.49–7.42 (m, 3H), 3.55 (s, 3H), 2.64 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 156.9, 144.5, 140.0, 137.5, 135.7, 131.3, 130.1, 128.7, 128.3, 120.4, 113.2, 47.3, 18.0; HRMS (EI): calcd for C₁₅H₁₃ClN₂OS, 304.0437; found, 304.0463.

1-Methyl-3-phenyl-1λ⁴-pyrido[4,3-e][1,2,4]thiadiazine 1-Oxide (10i)

This follows the general cyclization method. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:1) to give the desired thiadiazine 10i as a white solid (30.7 mg, 71% yield). mp 154–155 °C; ¹H NMR (300 MHz, CDCl₃): δ 9.09 (s, 1H), 8.73 (d, J = 5.8 Hz, 1H), 8.42–8.38 (m, 2H), 7.56–7.44 (m, 4H), 3.64 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 161.9, 154.0, 153.1, 146.9, 136.6, 132.3, 129.2, 128.5, 122.0, 110.4, 47.8; HRMS (EI): calcd for C₁₃H₁₁N₃OS, 257.0623; found, 257.0610.

N-[2-(N-Carbamoyl-S-methylsulfonimidoyl)phenyl]benzamide (11)

A solution of sulfoximine 9a (0.17 mmol) added aqueous 1 N HCl (1.6 mL) was stirred at 110 °C for 16 h and quenched with saturated NaHCO₃. The reaction mixture was basified with saturated NaHCO₃ solution until pH 8 and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:1) to give the undesired thiadiazine 10a as white solid (9 mg, 18%) and the desired sulfoximine 11 as a yellow solid (15.6 mg, 29% yield). mp 181–182 °C; ¹H NMR (400 MHz, CDCl₃): δ 10.80 (br, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.00–7.98 (m, 3H), 7.70 (t, J = 7.9 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.53–7.49 (m, 2H), 7.32 (t, J = 7.7 Hz, 1H), 5.01 (br, 2H), 3.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 165.3, 160.9, 137.6, 135.5, 134.0, 132.7, 129.2, 128.9, 127.5, 125.5, 124.5, 123.5, 43.9; HRMS (EI): calcd for C₁₅H₁₅N₃O₃S, 317.0834; found, 317.0834.

Synthesis of (2-Aminophenyl) (imino) (methyl)-λ⁶-sulfanone (12)

A: Following the general cyclization method, the reaction of sulfoximine 9j (39.6 mg, 0.17 mmol) with aqueous 10 N H₂SO₄ (1.5 mL) gives the desired sulfoximine 12 as a yellow gum (8.2 mg, 29% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.79 (dd, J = 8.0, J = 1.5 Hz, 1H), 7.33 (td, J = 7.7, J = 1.6 Hz, 1H), 6.81 (td, J = 7.6, J = 1.0 Hz, 1H), 6.73 (dd, J = 8.1, J = 0.9 Hz, 1H), 5.35 (br, 2H), 3.12 (s, 3H);¹³C NMR (100 MHz, CDCl₃): δ 146.5, 134.8, 129.8, 124.1, 117.9, 117.6, 43.1; HRMS (EI): calcd for C₇H₁₀N₂OS, 170.0514; found, 170.0522.

B: A solution of sulfoximine 9a (0.17 mmol) in aqueous 1 N NaOH (1.5 mL) was stirred at 110 °C for 16 h, The reaction mixture was quenched with saturated NH₄Cl. The reaction mixture was acidified with saturated NH₄Cl solution until pH 6 and extraction with EtOAc. The organic layer was dried over MgSO₄, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc/hexane = 1:1) to give the desired sulfoximine 12 as a yellow gum (18.2 mg, 64% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.79 (dd, J = 8.0, J = 1.5 Hz, 1H), 7.33 (td, J = 7.7, J = 1.6 Hz, 1H), 6.81 (td, J = 7.6, J = 1.0 Hz, 1H), 6.73 (dd, J = 8.1, J = 0.9 Hz, 1H), 5.35 (br, 2H), 3.12 (s, 3H);¹³C NMR (100 MHz, CDCl₃): δ 146.5, 134.8, 129.8, 124.1, 117.9, 117.6, 43.1; HRMS (EI): calcd for C₇H₁₀N₂OS, 170.0514; found, 170.0522.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c05570.

• Crystallographic data of compound 10h (CIF)

• Crystallographic data of compound 11 (CIF)

• Copies of ¹H and ¹³C spectra and X-ray data of 10i and 11 (PDF)

The authors declare no competing financial interest.