Synthesis of benzosultams via an intramolecular sp² C–H bond amination reaction of o-arylbenzenesulfonamides under metal-free conditions

Abstract

A practical synthetic method for the generation of benzosultams via an intramolecular sp² C–H bond amination reaction of o-arylbenzenesulfonamides with PhI(OAc)₂–I₂ under metal-free conditions is developed. A broad range of substrates are tolerated under mild reaction conditions, affording bioactive benzosultams in good to excellent yields. The resulting benzothiazines could be conveniently transformed into their corresponding iodinated derivatives via electrophilic substitution reactions.

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Introduction

Benzosultams are important privileged structures ubiquitously found in drug discovery. Compounds with the core structure usually exhibit versatile inhibitory properties. For instance, benzothiazine dioxide derivatives have been found to show active inhibitory properties against a variety of enzymes such as 11β-HSD2,¹ Calpain I,² HIV integrand,³ and cyclooxygenase-2 (COX-2)⁴ (Fig. 1). Additionally, it was reported that members of the family also show powerful anti-inflammatory properties; some of the medicines like Meloxicam⁵ and Piroxicam⁶ have already been marketed widely.

Fig. 1 Structures of biologically active benzosultams.

Consequently, there have been several routes successfully developed for the synthesis of benzothiazine derivatives, including the transition-metal or Lewis acid-catalyzed intramolecular cyclization,⁷ metal-free cyclization,⁸ as well as the intermolecular synthetic strategy.⁹ In 2007, Pal and co-workers^7e reported a facile single-step Ag- or Cu-catalyzed intramolecular cyclization of o-(1-alkynyl)benzenesulfonamides to afford 3-substituted benzothiazines with high regioselectivity. Thibaudeau and co-workers^8a described a novel method to access benzofused sultams starting from N-allylic sulfonamides through superelectrophilic activation by superacid HF–SbF₅. Kanai and co-workers^9a reported the synthesis of sultams via Cu-catalyzed intermolecular carboamination of alkenes with N-fluorobenzenesulfonimide. Recently, we have developed an efficient synthesis of 6H-benzo[f]cyclopean[d][1,2]thiazinepine 5,5-dioxides via a palladium-catalyzed tandem reaction of 2-(2-alkyl)benzene sulfonamides.¹⁰ Inspired by these results, and the recent advancement in C–H bond direct functionalizations,¹¹ we are aware that it is of high urgency to develop a general catalytic system for the synthesis of benzothiazines based on the oxidative sp² C–H amination strategy under mild and metal-free conditions. Herein we would like to report our recent success in the generation of 6H-dibenzo[c,e][1,2]thiazine 5,5-dioxides 2 from 1,1′-biphenyl-2-sulfonamides 1 with the PhI(OAc)₂–I₂ system¹²via an intramolecular sp² C–H bond amination reaction. In addition, the resulting benzothiazines could be conveniently transformed into the corresponding iodinated derivatives 3via an electrophilic substitution reaction.

Results and discussion

We began the intramolecular sp² C–H bond amination reaction using N-ethyl-4′,5-dimethyl-[1,1′-biphenyl]-2-sulfonamide 1a as a model substrate. As shown in Table 1, the reaction conditions were initially screened with a combination of PhI(OAc)₂ (1.1 equiv.) and I₂ (1.1 equiv.) in different solvents at 60 °C. The cyclization reaction did not proceed at all in DMSO (Table 1, entry 1). However, we were pleased to isolate the corresponding product 3a in 39% yield when the reaction was performed in CH₃CN (Table 1, entry 2), while the other solvents such as acetone, ethyl acetate, 1,2-dichloroethane, and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) gave unsatisfactory results (Table 1, entries 3–6). An interesting solvent effect was observed on further screening. Under the same conditions, compound 2a was isolated as a major product in isopropanol, DMF, THF, dioxane, and CH₂Cl₂ (Table 1, entries 7–11), and the best results 2a and 3a were obtained in 64% and 15% yields in CH₂Cl₂, respectively (Table 1, entry 11). Further studies revealed that the yield of 2a could be improved when the reaction was carried out at 35 °C (71% yield, Table 1, entry 12). Lowering the amount of iodine to 10 mol% resulted in a drastic decrease of yield (24% yield of 2a, Table 1, entry 13). No product was detected when the reaction was carried out in the absence of PhI(OAc)₂ or I₂ (Table 1, entries 14 and 15), which indicates the important role of PhI(OAc)₂ and I₂ in the oxidative transformation. The structures of 2a and 3a were verified by ¹H and ¹³C NMR, HRMS, as well as X-ray diffraction analysis (Fig. 2, also see ESI†). It was reported that potassium carbonate was used as an efficient promoter in the Hofmann–Fleer–Freytag reaction.^8f Prompted by this result, we then optimized the reaction conditions using different bases [Na₂CO₃, KOH, KHCO₃, and K₂CO₃] as additives (Table 1, entries 16–19). K₂CO₃ was found to be the most efficient one to yield a single product 2a in 94% yield (Table 1, entry 19). On the other hand, the desirable product 3a could be improved to 79% yield when 2.0 equivalents of PhI(OAc)₂ were employed (Table 1, entry 20). While increasing the amount of PhI(OAc)₂ did not facilitate the transformation, we could improve the yield of 3a to 95% by optimization of the reaction temperature (60 °C) and the amount of I₂ (2.0 equivalents) (Table 1, entries 21–23).

Fig. 2 X-ray crystallographic structure of compounds 2a and 3a.

Table 1 Optimization of the reaction conditions^a

Entry	PhI(OAc)2/I2 (equiv.)	Solvent	T (°C)	Yield^b (%)
				2a	3a
a 1a (0.2 mmol), additive (1.5 equiv.), solvent (2.0 mL), 4 h. HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol. b Yield of isolated product; n.d. = not detected. c 1.5 Equivalents of Na2CO3 were added. d 1.5 Equivalents of KOH were added. e 1.5 Equivalents of KHCO3 were added. f 1.5 Equivalents of K2CO3 were added.
1	1.1/1.1	DMSO	60	Trace	n.d.
2	1.1/1.1	CH3CN	60	n.d.	39
3	1.1/1.1	Acetone	60	n.d.	12
4	1.1/1.1	AcOEt	60	n.d.	23
5	1.1/1.1	DCE	60	n.d.	28
6	1.1/1.1	HFIP	60	n.d.	37
7	1.1/1.1	^iPrOH	60	40	Trace
8	1.1/1.1	DMF	60	31	n.d.
9	1.1/1.1	THF	60	51	9
10	1.1/1.1	Dioxane	60	48	Trace
11	1.1/1.1	CH2Cl2	60	64	15
12	1.1/1.1	CH2Cl2	35	71	14
13	1.1/0.1	CH2Cl2	35	24	Trace
14	1.1/–	CH2Cl2	35	n.d.	n.d.
15	–/1.1	CH2Cl2	35	n.d.	n.d.
16^c	1.1/1.1	CH2Cl2	35	78	n.d.
17^d	1.1/1.1	CH2Cl2	35	10	n.d.
18^e	1.1/1.1	CH2Cl2	35	52	n.d.
19^f	1.1/1.1	CH2Cl2	35	94	n.d.
20	2.0/1.1	CH2Cl2	35	Trace	79
21	3.0/1.1	CH2Cl2	35	Trace	80
22	2.0/1.1	CH2Cl2	60	n.d.	84
23	2.0/2.0	CH2Cl2	60	n.d.	95

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We then explored the substrate scope and generality of the method under the optimized reaction conditions A [o-arylbenzenesulfonamide 1 (0.2 mmol), PhI(OAc)₂ (1.1 equiv.), I₂ (1.1 equiv.), CH₂Cl₂ (2 mL), K₂CO₃ (1.5 equiv.), 35 °C, for 2 h], and the results are presented in Table 2. We first examined the substitution effect on the aryl moiety of compound 1. In general, the oxidative cyclization proceeded smoothly with substrates bearing electron-donating substituents (R²) at the nucleophilic phenyl part (Table 2, entries 3–5 and 7). Substrates with 4-methyl, 3,5-dimethyl, and 4-methoxyl groups were tolerated, providing the corresponding products 2 in yields ranging from 65 to 96%. For instance, when N-ethyl-3′,5,5′-trimethyl-[1,1′-biphenyl]-2-sulfonamide 1e was employed, product 2e was obtained in an excellent yield (96%, Table 2, entry 5). Except for the ortho-position substituted substrate 1f, the corresponding desired product 2f was obtained in poor yield (Table 2, entry 6), which indicated that the steric hindrance effect of the substrate was very obvious. In contrast, substrates with weak electron-withdrawing substituents (e.g. chloro, fluoro, and acetyl) exhibited good reactivity, giving the corresponding products in moderate to excellent yields (62–92%, Table 2, entries 8–10). 4′-Acetyl-N-ethyl-5-methyl-[1,1′-biphenyl]-2-sulfonamide 1j could be converted into the corresponding product 2j in 92% yield (Table 2, entry 10), whereas the reaction of substrates with strong electron-withdrawing substituents displayed lower reactivity. For instance, N-ethyl-5-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-sulfonamide 1l under the standard reactions resulted in poor conversion (38% yield, Table 2, entry 12). For changing R¹ from methyl to strong electron-withdrawing substituents (CF₃), the reaction proceeded smoothly to furnish the desired product 2m in almost quantitative yield (99%, Table 2, entry 13). Subsequently, the effect of the nitrogen substituent was investigated. Under the standard reaction conditions A, substrates with R³ bearing alkyl or aryl substituents were studied next. Compounds 1n and 1o (R³ = ⁿBu) exhibited good reactivity affording the expected products 2n and 2o in 85% and 93% yield, respectively (Table 2, entries 14 and 15). For comparison, the aryl-substituted substrates exhibited lower reactivity.

Table 2 Scope of sp² C–H bond amination^a

Entry	Substrate 1	Product 2	Yield^b (%)
a Reaction conditions A: 1 (0.2 mmol), PhI(OAc)2 (1.1 equiv.), I2 (1.1 equiv.), CH2Cl2 (2.0 mL), K2CO3 (1.5 equiv.), 35 °C, for 2 h. b Yield of isolated product based on 1.
1			94
2			75
3			65
4			80
5			96
6			17
7			83
8			62
9			63
10			92
11			30
12			38
13			99
14			85
15			93
16			76

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After refining the oxidative intramolecular sp² C–H bond amination for the synthesis of benzosultams 2 under the reaction conditions A, we next switched our attention to the cascade electrophilic substitution reaction for the synthesis of iodinated benzosultams 3 under the optimized reaction conditions B [o-arylbenzenesulfonamide 1 (0.2 mmol), PhI(OAc)₂ (2.0 equiv.), I₂ (2.0 equiv.), CH₂Cl₂ (2 mL), 60 °C, for 2 h] and the results are summarized in Table 3. In general, the reactivity of the cascade reaction under conditions B is similar to the former C–H amination reaction under conditions A, which tolerates a wide range of substituents such as methyl, methoxy, halogen (F and Cl), and trifluoromethyl groups. When substrates 1d and 1e (R² = 3,5-dimethyl) were subjected to conditions B, 2d and 2e were obtained in high yields (86% and 94%, respectively) (data not shown in Table 2). This might be the reason that the active site of the electrophilic substitution reaction was occupied by the methyl group. The same treatment with substrates 1j–1l (containing 4-acetyl, 3,5-difluoro, and 4-trifluoromethyl groups) afforded amination products 2j–2l only, instead of the electrophilic substituted products 3 (data not shown in Table 2), which was due to the reduction of electron density by electron-withdrawing substituents (R²) on the aromatic ring toward the iodonium species. Substrates 1m–1p were also examined in this reaction; the corresponding expected products 3m–3p were obtained in good to excellent yields ranging from 75 to 95%.

Table 3 Scope of amination and electrophilic substitution reaction^a,b

a Reaction conditions B: 1 (0.2 mmol), PhI(OAc)₂ (2.0 equiv.), I₂ (2.0 equiv.), CH₂Cl₂ (2 mL), 60 °C, for 2 h. b Yield of isolated product based on 1.

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A plausible reaction mechanism based on the PhI(OAc)₂–I₂ system¹² is illustrated in Scheme 1. Firstly, a reaction of PhI(OAc)₂ and iodine would occur to produce a reactive electrophile IOAc,^12d which reacts with substrate 1 to form the N-iodinated compound I. The homolytic cleavage of N–I bonds in compound I would occur to give a reactive radical species II. Intramolecular radical recombination of intermediate II followed by oxidative aromatization generated the amination product 2. The iodinated product 3 would be formed via an electrophilic substitution reaction of compound 2. To verify the possible pathway of the proposed mechanism, 2.0 equivalents of TEMPO serving as a radical-trapping agent were added to the model reaction; only a trace of the desired product 2a was observed. This result suggested that free radical intermediates were possibly involved in the reaction. In addition, when compound 2a was employed as a test substrate, the electrophilic substitution reaction took place smoothly under the standard conditions B to generate product 3a in 95% yield (Scheme 2).

Scheme 1 Plausible reaction mechanism.

Scheme 2 The reaction of 2a under conditions B.

Conclusion

In summary, we have demonstrated an efficient intramolecular sp² C–H bond amination reaction of aryl sulfonamides with PhI(OAc)₂–I₂ to give benzosultams in good to excellent yields. The cyclization was proposed to proceed via a radical mechanism under metal-free conditions with a good functional group tolerance. The resulting benzothiazines could be conveniently transformed into the corresponding iodinated derivatives in high yields. Further screening of biological activities of these molecules is under investigation in our laboratory.

Experimental

General procedure for the synthesis of 6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives

Conditions A: a solution of o-arylbenzenesulfonamide 1 (0.2 mmol), PhI(OAc)₂ (70.8 mg, 0.22 mmol), I₂ (55.9 mg, 0.22 mmol), and K₂CO₃ (41.4 mg, 0.3 mmol) in DCM (2.0 mL) was stirred at 35 °C.

Conditions B: a solution of o-arylbenzenesulfonamide 1 (0.2 mmol), PhI(OAc)₂ (128.8 mg, 0.4 mmol), and I₂ (101.6 mg, 0.4 mmol) in DCM (2.0 mL) was stirred at 60 °C.

After completion of the reaction as detected by TLC, the reaction mixture was cooled to room temperature, and purified directly by silica gel chromatography (EtOAc–hexane, 1 : 20 v/v) to provide the title compound 2 or 3 as an amorphous solid.

6-Ethyl-2,8-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2a). ¹H NMR (400 MHz, CDCl₃) δ 1.13 (t, J = 6.8 Hz, 3H), 2.44 (s, 3H), 2.50 (s, 3H), 3.92 (q, J = 6.7 Hz, 2H), 7.13–7.17 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.83–7.87 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.5, 21.9, 44.3, 122.3, 122.4, 123.1, 125.4, 125.6, 126.3, 128.6, 132.5, 132.7, 138.5, 140.6, 142.7; m.p.: 146–148 °C; HRMS (ESI) calcd for C₁₆H₁₈NO₂S [M + H]⁺ 288.1058; found, 288.1044.

6-Ethyl-9-iodo-2,8-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3a). ¹H NMR (400 MHz, CDCl₃) δ 1.13 (t, J = 6.8 Hz, 3H), 2.51 (s, 6H), 3.91 (q, J = 6.7 Hz, 2H), 7.23 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.8, 20.9, 27.3, 43.1, 95.4, 121.2, 121.5, 124.0, 124.6, 128.2, 129.8, 131.5, 134.5, 137.4, 142.0, 142.5; m.p.: 172–174 °C; HRMS (ESI) calcd for C₁₆H₁₇INO₂S [M + H]⁺ 414.0025; found, 414.0019.

6-Ethyl-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide^8e (2b). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.95 (q, J = 7.2 Hz, 2H), 7.33–7.38 (m, 3H), 7.45–7.49 (m, 1H), 7.74 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 22.0, 44.3, 121.8, 122.3, 125.2, 125.6, 125.7, 126.0, 129.1, 130.1, 132.4, 133.0, 138.5, 142.9; m.p.: 112–114 °C; HRMS (ESI) calcd for C₁₅H₁₆NO₂S [M + H]⁺ 274.0902; found, 274.0905.

6-Ethyl-9-iodo-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3b). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (t, J = 7.2 Hz, 3H), 2.52 (s, 3H), 3.93 (q, J = 7.2 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 22.0, 44.0, 89.1, 122.4, 123.3, 126.0, 127.6, 129.7, 130.9, 132.9, 134.4, 138.2, 138.7, 143.2; m.p.: 188–190 °C; HRMS (ESI) calcd for C₁₅H₁₅INO₂S [M + H]⁺ 399.9868; found, 399.9852.

6-Ethyl-8-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2c). ¹H NMR (400 MHz, CDCl₃) δ 1.15 (t, J = 7.0 Hz, 3H), 2.45 (s, 3H), 3.95 (q, J = 7.0 Hz, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.6, 44.4, 122.2, 122.3, 123.0, 125.3, 125.4, 126.4, 127.8, 132.2, 132.6, 135.1, 138.2, 140.8; m.p.: 125–127 °C; HRMS (ESI) calcd for C₁₅H₁₆NO₂S [M + H]⁺ 274.0902; found, 274.0905.

6-Ethyl-9-iodo-8-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3c). ¹H NMR (400 MHz, CDCl₃) δ 1.15 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.94 (q, J = 7.2 Hz, 2H), 7.24 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 28.4, 44.3, 96.5, 122.4, 122.5, 125.1, 125.4, 128.5, 131.0, 132.4, 135.2, 135.7, 138.4, 143.8; m.p.: 122–124 °C; HRMS (ESI) calcd for C₁₅H₁₅INO₂S [M + H]⁺ 399.9868; found, 399.9852.

6-Ethyl-7,9-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2d). ¹H NMR (400 MHz, CDCl₃) δ 0.72 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.44 (br, 1H), 3.69 (br, 1H), 7.15 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.66 (dt, J = 1.2, 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.94 (dt, J = 0.8, 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 11.8, 18.0, 21.3, 47.1, 123.6, 124.0, 125.8, 128.4, 128.6, 132.5, 133.3, 133.8, 135.3, 135.7, 136.1, 137.2; m.p.: 140–142 °C; HRMS (ESI) calcd for C₁₆H₁₈NO₂S [M + H]⁺ 288.1058, found, 288.1059.

6-Ethyl-2,7,9-trimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2e). ¹H NMR (400 MHz, CDCl₃) δ 0.72 (t, J = 7.0 Hz, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 2.50 (s, 3H), 3.42 (br, 1H), 3.67 (br, 1H), 7.13 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.69 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 11.8, 18.0, 21.3, 22.0, 47.1, 123.6, 124.0, 126.3, 128.7, 129.1, 133.1, 133.5, 133.7, 135.5, 135.7, 137.1, 143.1; m.p.: 166–168 °C; HRMS (ESI) calcd for C₁₇H₁₉NO₂S [M + H]⁺ 302.1215, found, 302.1198.

6-Ethyl-2,10-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2f). ¹H NMR (400 MHz, CDCl₃) δ 1.00 (t, J = 7.0 Hz, 3H), 2.50 (s, 3H), 2.72 (s, 3H), 3.82 (q, J = 7.0 Hz, 2H), 7.23–7.26 (m, 2H), 7.33–7.37 (m, 2H), 7.63 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 22.0, 23.2, 45.0, 120.5, 122.6, 126.8, 128.4, 128.9, 129.4, 129.9, 132.5, 134.8, 136.4, 139.1, 141.4; m.p.: 139–141 °C; HRMS (ESI) calcd for C₁₆H₁₈NO₂S [M + H]⁺ 288.1058, found, 288.1044.

6-Ethyl-9-iodo-2,10-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3f). ¹H NMR (400 MHz, CDCl₃) δ 0.98 (t, J = 7.0 Hz, 3H), 2.49 (s, 3H), 2.78 (s, 3H), 3.82 (q, J = 7.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 22.0, 30.2, 44.7, 100.3, 121.1, 122.4, 129.0, 130.6, 132.5, 134.8, 139.1, 139.7, 141.5; m.p.: 217–219 °C; HRMS (ESI) calcd for C₁₆H₁₇INO₂S [M + H]⁺ 414.0025, found, 413.9979.

6-Ethyl-8-methoxy-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2g). ¹H NMR (400 MHz, CDCl₃) δ 1.16 (t, J = 7.0 Hz, 3H), 2.49 (s, 3H), 3.96 (s, 3H), 3.93 (q, J = 7.0 Hz, 2H), 6.86–6.89 (m, 2H), 7.26–7.30 (m, 1H), 7.64 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.9, 44.0, 55.6, 106.9, 111.4, 118.7, 122.3, 125.3, 126.8, 128.1, 131.9, 132.5, 139.4, 142.8, 161.1; m.p.: 120–122 °C; HRMS (ESI) calcd for C₁₆H₁₈NO₃S [M + H]⁺ 304.1007, found, 304.0998.

9-Iodo-8-methoxy-2,6-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3g). ¹H NMR (400 MHz, CDCl₃) δ 1.12 (t, J = 7.0 Hz, 3H), 2.51 (s, 3H), 3.92 (q, J = 7.0 Hz, 2H), 3.96 (s, 3H), 6.77 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.7, 21.9, 44.5, 56.7, 82.3, 104.3, 120.8, 122.5, 125.3, 128.7, 131.2, 131.9, 136.2, 140.3, 143.1, 159.3; m.p.: 159–161 °C; HRMS (ESI) calcd for C₁₆H₁₇INO₃S [M + H]⁺ 429.9974, found, 429.9966.

6-Ethyl-8-fluoro-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2h). ¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J = 7.0 Hz, 3H), 2.50 (s, 3H), 3.97 (q, J = 7.0 Hz, 2H), 7.01–7.07 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.96 (t, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.0, 22.0, 43.4, 108.0 (²J_C–F = 25 Hz), 112.3 (²J_C–F = 22 Hz), 121.5, 122.2, 125.8, 127.4, 129.0, 131.7, 132.2, 140.0, 143.1, 163.4 (¹J_C–F = 249 Hz); m.p.: 127–129 °C; HRMS (ESI) calcd for C₁₅H₁₅FNO₂S [M + H]⁺ 292.0808, found, 292.0788.

6-Ethyl-8-fluoro-9-iodo-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3h). ¹H NMR (400 MHz, CDCl₃) δ 1.22 (t, J = 7.0 Hz, 3H), 2.53 (s, 3H), 3.96 (q, J = 7.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 6.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.0, 22.0, 43.3, 107.9 (²J_C–F = 27 Hz), 122.3, 123.4, 125.8, 129.5, 130.5, 132.2, 136.2, 140.2 (d, ³J_C–F = 9 Hz), 143.3, 162.2 (d, ¹J_C–F = 248 Hz); m.p.: 190–192 °C; HRMS (ESI) calcd for C₁₅H₁₄FINO₂S [M + H]⁺ 417.9774, found, 417.9768.

8-Chloro-6-ethyl-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2i). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (t, J = 7.0 Hz, 3H), 2.51 (s, 3H), 3.96 (q, J = 7.0 Hz, 2H), 7.29 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.0, 21.9, 43.8, 121.3, 122.3, 123.9, 125.3, 125.9, 126.7, 129.4, 131.6, 132.7, 135.7, 139.5, 143.1; m.p.: 160–162 °C; HRMS (ESI) calcd for C₁₅H₁₅ClNO₂S [M + H]⁺ 308.0512, found 308.0484.

8-Chloro-6-ethyl-9-iodo-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3i). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (t, J = 7.0 Hz, 3H), 2.54 (s, 3H), 3.95 (q, J = 7.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.66 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.9, 43.6, 92.8, 121.5, 122.4, 125.5, 125.8, 129.8, 130.2, 132.8, 136.7, 139.8, 143.3; m.p.: 138–140 °C; HRMS (ESI) calcd for C₁₅H₁₄ClINO₂S [M + H]⁺ 433.9478, found, 433.9485.

1-(6-Ethyl-2-methyl-5,5-dioxido-6H-dibenzo[c,e][1,2]thiazin-8-yl)ethanone (2j). ¹H NMR (400 MHz, CDCl₃) δ 1.17 (t, J = 7.0 Hz, 3H), 2.53 (s, 3H), 2.66 (s, 3H), 4.02 (q, J = 6.7 Hz, 2H), 7.43 (d, J = 8.0 Hz 1H), 7.77 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.9, 26.7, 44.1, 121.2, 122.4, 124.8, 125.9, 126.5, 129.6, 130.2, 131.4, 133.5, 138.0, 138.8, 143.2, 196.8; m.p.: 174–176 °C; HRMS (ESI) calcd for C₁₇H₁₈NO₃S [M + H]⁺ 316.1007, found, 316.0990.

6-Ethyl-7,9-difluoro-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2k). ¹H NMR (400 MHz, CDCl₃) δ 0.83 (t, J = 7.0 Hz, 3H), 2.53 (s, 3H), 3.74 (q, J = 7.0 Hz, 2H), 6.97–7.02 (m, 1H), 7.42–7.47 (m, 2H), 7.64 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.46, 21.9, 47.3, 105.4 (d, ²J_CF = 26 Hz), 105.5 (dd, ²J_CF = 26, 26 Hz), 107.8 (dd, ²J_CF = 24, 24 Hz), 123.3, 123.8 (d, ³J_CF = 9 Hz), 126.5, 130.6, 131.0, 131.3, 133.9, 143.4, 157.5 (dd, J_CF = 12, 252 Hz), 160.6 (dd, J_CF = 12, 247 Hz); m.p.: 126–128 °C; HRMS (ESI) calcd for C₁₅H₁₄F₂NO₂S [M + H]⁺ 310.0713, found, 310.0697.

6-Ethyl-2-methyl-8-(trifluoromethyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2l). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (t, J = 7.0 Hz, 3H), 2.54 (s, 3H), 4.01 (q, J = 7.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.76 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 21.9, 44.0, 118.4, 121.5, 122.4, 123.5 (q, ¹J_CF = 275 Hz), 126.2, 126.4, 128.5, 130.2, 131.1, 131.9 (d, ²J_CF = 34 Hz), 133.4, 138.9, 143.3; m.p.: 132–134 °C; HRMS (ESI) calcd for C₁₆H₁₅F₃NO₂S [M + H]⁺ 342.0776, found, 342.0756.

6,8-Dimethyl-2-(trifluoromethyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2m). ¹H NMR (400 MHz, CDCl₃) δ 2.47 (s, 3H), 3.45 (s, 3H), 7.15 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H),7.92 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.7, 33.0, 120.1, 120.5, 122.4 (d, ³J_C–F = 3 Hz), 123.3 (q, ¹J_C–F = 273 Hz), 123.4, 124.4 (d, ³J_C–F = 3 Hz), 125.5, 126.1, 133.4, 134.3 (q, ²J_C–F = 33 Hz), 136.4, 139.5, 142.2; m.p.: 176–178 °C; HRMS (ESI) calcd for C₁₅H₁₃F₃NO₂S [M + H]⁺ 328.0619, found, 328.0613.

9-Iodo-6,8-dimethyl-2-(trifluoromethyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3m). ¹H NMR (400 MHz, CDCl₃) δ 2.53 (s, 3H), 3.44 (s, 3H), 7.20 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.39 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 28.6, 32.8, 95.9, 120.4, 122.4 (d, ³J_C–F = 3 Hz), 123.2 (q, ¹J_C–F = 273 Hz), 123.6, 125.1 (d, ³J_C–F = 3 Hz), 131.9, 134.5 (q, ²J_C–F = 34 Hz), 135.6, 136.6, 139.5, 145.2; m.p.: 211–213 °C; HRMS (ESI) calcd for C₁₅H₁₂F₃INO₂S [M + H]⁺ 453.9586, found, 453.9581.

6-Butyl-2,8-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2n). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.2 Hz, 3H), 1.15–1.25 (m, 2H), 1.44–1.56 (m, 2H), 2.43 (s, 3H), 2.49 (s, 3H), 3.85 (t, J = 7.2 Hz, 2H), 7.12–7.15 (m, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H), 7.82–7.86 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 19.8, 21.6, 21.9, 30.3, 48.15, 121.9, 122.3, 122.8, 125.4, 125.6, 126.1, 128.6, 132.5, 138.5, 140.5, 142.7; m.p.: 104–105 °C; HRMS (ESI) calcd for C₁₈H₂₂NO₂S [M + H]⁺ 316.1371, found, 316.1345.

6-Butyl-9-iodo-2,8-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3n). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.2 Hz, 3H), 1.14–1.21 (m, 2H), 1.49–1.54 (m, 2H), 2.50 (s, 3H), 2.51 (s, 3H), 3.85 (t, J = 7.4 Hz, 2H), 7.20 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 19.8, 21.9, 28.4, 30.2, 47.9, 96.1, 122.3, 122.4, 125.0, 125.6, 129.3, 130.9, 132.5, 135.7, 138.6, 143.0, 143.5; m.p.: 123–124 °C; HRMS (ESI) calcd for C₁₈H₂₁INO₂S [M + H]⁺ 442.0338, found, 442.0326.

6-Butyl-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2o). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.4 Hz, 3H), 1.15–1.23 (m, 2H), 1.50–1.57 (m, 2H), 2.48 (s, 3H), 3.88 (t, J = 7.4 Hz, 2H), 7.28–7.35 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.97 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 19.8, 21.9, 30.3, 48.0, 121.4, 122.3, 125.0, 125.4, 125.6, 126.0, 129.0, 130.1, 132.3, 132.8, 138.6, 142.8; m.p.: 76–78 °C; HRMS (ESI) calcd for C₁₇H₂₀NO₂S [M + H]⁺ 302.1215, found, 302.1221.

6-Butyl-9-iodo-2-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3o). ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.4 Hz, 3H), 1.14–1.23 (m, 2H), 1.48–1.55 (m, 2H), 2.51 (s, 3H), 3.86 (t, J = 7.4 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 19.8, 21.9, 30.2, 47.7, 88.7, 122.3, 123.0, 126.0, 127.4, 129.7, 130.9, 132.8, 134.4, 138.3, 138.6, 143.1; m.p.: 118–120 °C; HRMS (ESI) calcd for C₁₇H₁₉INO₂S [M + H]⁺ 428.0181, found, 428.0171.

1,3,6,8-Tetramethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (2p). ¹H NMR (400 MHz, CDCl₃) δ 2.43 (s, 3H), 2.44 (s, 3H), 2.63 (s, 3H), 3.33 (s, 3H), 7.12 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.34 (s, 1H), 7.67 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.0, 21.6, 23.0, 32.9, 120.5, 121.0, 125.0, 128.6, 129.3, 135.9, 136.8, 137.7, 139.4, 139.8; m.p.: 236–238 °C; HRMS (ESI) calcd for C₁₆H₁₈NO₂S [M + H]⁺: 288.1058, found, 288.1062.

9-Iodo-1,3,6,8-tetramethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3p). ¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H), 2.50 (s, 3H), 2.63 (s, 2H), 3.32 (s, 3H), 7.18 (s, 1H), 7.36 (s, 1H), 7.67 (s, 1H), 8.26 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.1, 22.7, 28.3, 32.7, 94.9, 120.6, 121.1, 124.3, 127.0, 136.0, 136.1, 138.5, 139.3, 139.5, 142.8; m.p.: 238–240 °C; HRMS (ESI) calcd for C₁₆H₁₇INO₂S [M + H]⁺: 414.0025, found, 414.0029.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21002042), the Project of Jiangxi Youth Scientist (20122BCB23012), Jiangxi Educational Committee (GJJ12169), and Open Project Program of Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University (no. KLFS-KF-201203 and 201217) is gratefully acknowledged.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all new compounds. CCDC 951230 and 951231. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41810c

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