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Article

Sulfoximines-Assisted Rh(III)-Catalyzed C–H Activation and Intramolecular Annulation for the Synthesis of Fused Isochromeno-1,2-Benzothiazines Scaffolds under Room Temperature

by
Bao Wang
1,2,3,
Xu Han
1,2,
Jian Li
1,
Chunpu Li
1,2,* and
Hong Liu
1,2,3,*
1
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
2
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
3
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(11), 2515; https://doi.org/10.3390/molecules25112515
Submission received: 14 May 2020 / Revised: 22 May 2020 / Accepted: 25 May 2020 / Published: 28 May 2020
(This article belongs to the Special Issue Organic Synthesis via Transition Metal-Catalysis)
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Versions Notes

Abstract

:
A mild and facile Cp*Rh(III)-catalyzed C–H activation and intramolecular cascade annulation protocol has been proposed for the furnishing of highly fused isochromeno-1,2-benzothiazines scaffolds using S-phenylsulfoximides and 4-diazoisochroman-3-imine as substrates under room temperature. This method features diverse substituents and functional groups tolerance and relatively mild reaction conditions with moderate to excellent yields. Additionally, retentive configuration of sulfoximides in the conversion has been verified.

Graphical Abstract

1. Introduction

Over the past decade, sulfoximines moiety has gained an increasing attention in organic chemistry [1,2,3,4,5,6,7,8,9] and pharmaceutical industries for their interesting properties such as multiple hydrogen-bond acceptor/donor functionalities, structural diversity, and favorable physicochemical properties [10,11,12,13]. For instances, sulfoximines along with benzothiazines scaffold-containing compounds possess diversified biologically active molecules such as antihypertensive activity α-adrenergic receptor blocker [14], anti-HIV nonnucleoside reverse transcriptase inhibitors [15], and hepatocytes protective mitogen-activated protein kinase kinase 4 (MKK4) inhibitor (Figure 1).
Considering the significance of the sulfoximines motif as a pharmacophore in medicinal chemistry, synthetic methods accessing to this moiety have been increasingly studied. The typical route approach to the sulfoximines starting from commercially available sulfides requires two steps include oxidation and successively imination [6,16,17]. Sometimes, in order to produce the N-free sulfoximines, an additional step should be involved to dissociate the protecting group. Thus, these traditional methods have drawbacks such as requiring relatively harsh reaction conditions and poor step-economy for constructing cyclic sulfoximines. In recent years, transition-metal-catalyzed direct C–H functionalization has been broadly investigated, and these strategies have been proven to be an efficient tool for the rapid construction of C–C, C–O, C–N, or C–S bonds [18,19,20,21,22,23,24,25,26,27,28,29,30]. Additionally, owing to the high efficiency and easy accessibility of Rh(III) catalysis, the construction of 1,2-benzothiazines through Rh(III)-catalyzed C–H bond activation has attracted attention and been extensively studied [31,32,33]. For instance, in 2013, Bolm and coworkers developed a Rh(III)-catalyzed C–H functionalization for the synthesis of 1,2-benzothiazines starting from N-H-sulfoximines and alkynes (Scheme 1a) [34]. This process had been accomplished under 1 atm O2 at 100 °C, and the desired products could be yielded in good to excellent yields but with limited structural diversity. Later in 2015, Bolm et al. has disclosed another strategy approaching the 1,2-benzothiazines via sulfoximines-assisted Rh(III)-catalyzed C–H functionalization and coupling reaction with diazo compounds (Scheme 1b) [35]. It is noteworthy that the dizao coupling partners should be electro-withdrawing groups-incorporated moieties, which lead to a limited versatility, and the process was carried out under argon at 100 °C. Recently, in Lee’s group, an Rh(III)-catalyzed domino C–H activation/cyclization strategy has been reported by mixing sulfoximine and pyridotriazole compounds to build the 1,2-benzothiazines skeleton (Scheme 1c) [36]. In the methodology, the target products were 1,2-benzothiazines bearing pyridyl motifs as well as carbonyl groups and the process was conducted at a high reaction temperature. However, it is of note that most of these strategies have to be conducted at harsh reaction conditions with a limited reaction versatility and structural diversity. Only in 2019, Wu et al. reported a mild protocol to synthesize 1,2-benzothiazines derivatives [37]. Moreover, the constructed 1,2-benzothiazines scaffolds were bicyclic moieties, and to the best of our knowledge, only limited examples have been disclosed for the synthesis of fused 1,2-benzothiazines motif under harsh reaction conditions [38].
In continuation of our studies on the establishment of fused ring heterocyclic compounds via Rh(III)-catalyzed C-H functionalization [39,40,41], we envisioned that a fused 1,2-benzothiazines scaffold could be achieved via an Rh(III)-catalyzed C–H functionalization/annulation between sulfoximines and 4-diazoisochroman-3-imines. To our delight, the fused isochromeno-1,2-benzothiazines were successfully accomplished in good to excellent yields through a redox-neutral process, and our strategy could be carried out in the air under room temperature with broad generality and versatility. We herein described our results in detail.

2. Results and Discussion

Based on our previous work and relevant reports, we initially focused the studies on the Rh(III)-catalyzed coupling of sulfoximide (1a) and 4-diazoisochroman-3-imine (2a) (Table 1). In the presence of 10 mol% [Cp*RhCl2]2 and 40 mol% AgSbF6 in dichloroethane (DCE) at 80 °C, the desired product 3aa was produced in 16% yield, and its structure was further confirmed by 1H NMR spectroscopy (Table 1, Entry 2). We further assessed the reaction temperature in different solvents (Table 1, Entries 1–5), and the results demonstrated that when applying hexafluoro-isopropanol (HFIP) as the solvent, the reaction could be preceded by producing the 3aa in 47% yield under room temperature. This result leads us to realize that the polar alcohols would more facilitate the reaction at mild conditions rather than alkane such as DCE, which might retarded the process (Table 1, Entries 4 and 5). Inspired by this result, the other reaction solvents were screened under room temperature (Table 1, Entries 6–9). After a series of solvents was examined, the trifluoroethanol (TFE) was found to be the optimal in which 3aa was obtained in 75% yield (Table 1, Entry 6), and the structure of the desired product was further verified by X-ray crystallography (CCDC 1988905). We next investigated the effect of additives and gratifyingly, AgOPiv emerged to be the most effective additive among all those examined ones (Table 1, entries 10–13) to afford the desired product in an excellent isolated yield of 92%. Afterward, the ratio of the catalyst and additive was subsequently conducted (Table 1, Entries 14–16). The results disclosed that the 1:4 ratio of catalyst and additive was necessary for the full conversion of the starting material 1a and 2a (Table 1, Entries 13–17). In addition, further exploration proved that there was no obvious discrepancy of the yield of 3aa when the reaction was moved to an argon atmosphere (Table 1, Entry 18). However, when the reaction time was shortened to 12 h, the yield of 3aa was slightly reduced (Table 1, Entry 19). Moreover, we also tested different transition-metal catalysts such as the cost-effective ruthenium (II) or iridium (III) complex, and 3aa could be only detected in 85% yield when treated with 10 mol% [Cp*lrCl2]2 as catalyst (Table 1, entries 20–21). Notably, 3aa could not be detected when in the absence of [Cp*RhCl2]2, which indicated the [Cp*RhCl2]2 catalyst is indispensable for this transformation (Table 1, Entry 22). Therefore, the standard conditions for this Rh(III)-catalyzed coupling reaction is 5 mol %[Cp*RhCl2]2 and 20 mol %AgOPiv in TFE at room temperature for 18 h in the air.
After establishing the optimal reaction conditions, we next turned to investigate the scope of sulfoximide derivatives. As illustrated in Table 2, this Rh-catalyzed coupling reaction could proceed smoothly with substituted S-aryl sulfoximine substrates bearing electron-donating or electron-withdrawing substituents, and the corresponding products could be yielded in moderate to good yields. Sulfoximines with substituents including methyl, methoxyl, halogen, nitro, etc. installed at the para-position of the benzene ring coupled with 2a smoothly to afford the isochromeno-benzothiazines products in good yields (3ca–3ha), albeit methyl substituted product (3ba) was obtained in only 47% yield. It should be mentioned that functional groups such as carbonyl, ester, or carbamate were all viable under the standard reaction conditions to give the desired products in 66% (3ia), 82% (3ja), and 89% (3ka) yields, respectively. This result indicated that the strategy could be broadly extended for further transformation. The ortho-methyl-incorporated sulfoximines also gave a relatively low yield of the desired product (3la, 58% yield). Notably, the substituents of sulfoximine substrates at different positions of its benzene ring did not alter the reaction efficiency, as for the halogenated substrates (compare 3ga, 3ma, and 3na) provided the desired products in similar yields (72% to 74%). Interestingly, when an electron-withdrawing group such as bromo was installed at the meta-position of the benene ring in 1a, only the o-C-H bond of sulfoximine located on the less hindered site was activated, which led to a production of 3na as a single isomer in 72% yield. On the contrary, if an electron-donating group was incorporated on the meta-position, the products were isolated as a regioisomer (3oa and 3oa’) in a total yield of 50%. In addition, naphthalene-fused sulfoximide was also coupled with 2a smoothly, and the desired product 3pa was obtained as a single isomer through activation/annulation on the less hindered site of sulfoximine in 73% yield.
We also evaluated a variety of S-substituted phenylsulfoximine substrates (3qa–3va), and the results revealed that alkyl, halogen, hydroxyl, and aryl substituents on sulfur substrates were also compatible under the standard conditions and generated the corresponding product in moderate to good yields varying from 40% to 90%. In particularly, the cyclopropyl with huge steric hindrance effect exhibited no impact on the reaction efficiency and showed the best reactivity with 90% yield. Additionally, pyridine sulfoximine substrate could not generate the desired product (3wa), which might be caused by the strong coordination effect of the nitrogen atom in pyridine, which ceased the reaction process.
Subsequently, we investigated the scope of 4-diazoisochroman-3-imine coupling partner (Table 3). The introduction of both electron-donating or electron-withdrawing substituents including methyl, methoxy, Cl, F, and trifluoromethyl at the 6- or 7- positions of isochroman were all tolerated in this coupling reaction (3ab–3aj) and the yields were varying from 53% to 76%. Among all the substituents, the electron-deficient trifluoromethyl isochroman substrates exhibited good reactivity and independently furnished the products 3aj and 3ai in 76% and 74% yields. Besides, the nitro group-substituted substrate was not compatible for this coupling reaction, and no desired product (3ak) was achieved. Substituents at different positions has no obvious influence on the reaction efficiency, as the yields of the 6- and 7- substituted substrates are basically the same.
The chirality of the sufoximine group is important [42,43,44,45,46]. In order to verify the stereospecificity in the whole reaction process, optically pure R- and S-configured 1a were parallelly coupled with 2a under the standard condition (Scheme 2). The results demonstrated that the corresponding products were obtained with a retention of configuration with no erosion of the enantiopurity of the sulfoximine occurred, which indicated that the current coupling protocol possesses a potential utility on asymmetric synthesis.
Next, we conducted a series of control experiments to explore the preliminary reaction mechanism (Scheme 3). First, the kinetic isotope effect (KIE) experiment in intramolecular between d1-1a and 2a were performed and a small KIE value (kH/kD) was measured as 0.47, which indicated that the aryl Csp2-H bond cleavage was not the rate-limiting step (Scheme 3a) [47]. Next, in the H/D exchange study, phenylsulfoximine 1a was conducted under the standard conditions in deuterium TFE in the absence of 2a, and the deuterated d2-1a recovered in 91% deuterium at the ortho-position of benzene, which suggested that the C–H bond activation process was reversible (Scheme 3b). Finally, an intermolecular competitive experiment between electron-rich and electron-deficient substrates (1c/1i = 1:1) lead to the products 3ca/3ia with a ratio of 1.46, implying that an electrophilic rhodation of C–H bond activation probably involved in the catalytic cycle (Scheme 3c).
A plausible mechanism has been proposed based on the preliminary mechanistic experiments and previous reports [33,38,41,48]. As shown in Scheme 4, initially the five-membered rhodacycle intermediate A was formed via coordination of the activated rhodium catalyst with the nitrogen of the sulfoximine moiety and undergoes electrophilic C–H bond cleavage at the benzene ortho-position of substrate 1a. Then, intermediate A coordinated with 2a generates rhodium carbenoid intermediate B, followed by intramolecular carbene migratory insertion and produced a six-membered rhodacycle intermediate C. Finally, the intermediate C protonation to yield compound D and regenerated the active cationic Cp*Rh(III) species for the next catalytic cycle. Compound D could easily undergo intramolecular nucleophilic attack of imine and elimination of the p-toluenesulfonamide (TsNH2) process to produce the desired isochromeno-1,2-benzothiazines product 3aa.

3. Materials and Methods

3.1. General Information

All reagents and solvents were purchased from commercial sources (J&K Scientific Co., Ltd., Beijing, China; TCI Development Co., Ltd., Shanghai, China; Adamas Reagent, Co., Ltd., Shanghai, China.) and used without further purification. The analytical thin layer chromatography (TLC) was HSGF 254 (0.15–0.2 mm thickness). All products were characterized by their NMR and MS spectra. 1H and 13C nuclear magnetic resonance spectra (NMR) were acquired on a Bruker 400 MHz or 500 MHz or 600 MHz NMR spectrometer (Billerica, MA, USA). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane, and the coupling constants (J) were indicated in Hz. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd), and broad (br). Low-resolution mass spectra (LRMS) data were measured on Agilent 1260 Infinity II (Palo Alto, CA, USA) with Electrospray Ionization (ESI). High-resolution mass spectra (HRMS) data were measured on an Agilent G6520 Q-TOF (Palo Alto, CA, USA) with Electrospray Ionization (ESI). AgOPiv was prepared according to the reported literature method [49].

3.2. Experimental Part Method

3.2.1. General Procedure A for the Synthesis of Substrates 1a–1w

To a stirred solution of sulfide (1 mmol) in MeOH (10 mL) was added (NH4)2CO3 (1.5 equiv.). Subsequently, PhI(OAc)2 (2.3 equiv.) was added, and the solution was stirred at rt for 10 min. The solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography eluted with dichloromethane (DCM)/MeOH from 30:1 to 10:1 to give the desired product 1. Compounds 1e, 1f, 1q, R-1a, and S-1a were purchased from commercial sources and used without further purification. Compounds 1a–1c, 1g-1i, 1l–1p, 1r–1w are known compounds.
[4-(S-Methylsulfonimidoyl)phenyl]methanol (1d): white solid; m.p.: 108–109 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.88 (d, J = 8.3 Hz, 2H), 7.55–7.49 (m, 2H), 5.41 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.15 (s, 1H), 3.04 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 147.5, 142.3, 127.2, 126.6, 62.2, 46.0; LRMS (ESI): m/z 186.0 [M + H]+; HRMS (ESI): calculated for C8H12NO2S [M + H]+: 186.0583, found: 186.0584.
Ethyl [4-(S-methylsulfonimidoyl)phenyl]acetate (1j): colorless oil (207.5 mg, 86% yield); 1H NMR (600 MHz, DMSO-d6): δ 7.88 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.18 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.05 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 170.6, 142.5, 139.8, 130.4, 128.1, 61.4, 46.3, 41.2, 14.3; LRMS (ESI): m/z 242.1 [M + H]+; HRMS (ESI): calculated for C11H16NO3S [M + H]+: 242.0845, found: 242.0841.
tert-Butyl (4-(S-methylsulfonimidoyl)phenyl)carbamate (1k): white solid; m.p.: 155–156 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.78 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 4.01 (s, 1H), 3.00 (s, 3H), 1.49 (s, 9H); 13C NMR (126 MHz, DMSO-d6): δ 152.5, 143.3, 136.7, 128.4, 117.5, 79.8, 46.2, 28.0; LRMS (ESI) m/z: 271.1 [M + H]+; HRMS (ESI) m/z: calculated for C12H18N2O3S [M + H]+: 271.1111, found: 271.1115.

3.2.2. General Procedure for the Synthesis of Substrates 2a–2k

To a two-neck round bottom flask was successively added (2-ethynylphenyl)methanols (5.0 mmol, 1.0 equiv.), CuBr (0.5 mmol, 0.1 equiv.), and Et3N (10.0 mmol, 2.0 equiv.) in anhydrous MeCN (50 mL, 0.1 M). The mixture was evacuated and refilled with Ar 3 times. To the resulting mixture was slowly added p-toluenesulfonyl azide (75% in EA solution, 11.0 mmol, 2.2 equiv.) over 10 min under Ar, and the reaction was processed under room temperature for 4–6 h. Then, the mixture was filtered through a pad of celite and washed with DCM (30 mL × 3). The combined organic layer was washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography eluted with hexane/EA/DCM = 5:1:2 to give the desired product 2 as a yellow solid. Compounds 2a–2k are known compounds.

3.2.3. General Procedure for the Synthesis of Compounds 3

To a 15 mL vial was added sulfoximines 1 (0.15 mmol), 4-diazoisochroman-3-imines 2 (0.165 mmol), [Cp*RhCl2]2 (5 mol%), and AgOPiv (20 mol%) under air. Trifluoroethanol (TFE, 2.5 mL) was added subsequently. The resulting mixture was stirred at ambient temperature for 18 h. Upon completion of the reaction, the mixture was filtered through a celite pad and washed with DCM (10 mL × 3). The combined organic layer was concentrated under vacuo, and the residue was purified by silica gel chromatography eluting with DCM/MeOH from 50:1 to 10:1 to give the desired isochromeno-1,2-benzothiazines product 3.

3.2.4. Characterization of the Products

5-Methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3aa): yellow-green solid; m.p.: 182–184 °C; 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 9.6 Hz, 1H), 7.78 (dd, J = 8.0, 1.3 Hz, 1H), 7.62–7.54 (m, 2H), 7.38–7.26 (m, 2H), 7.21–7.11 (m, 2H), 5.20–4.99 (m, 2H), 3.49 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 157.3, 135.0, 132.9, 131.3, 128.8, 128.2, 125.0, 124.8, 124.5, 124.4, 123.2, 122.2, 120.0, 91.9, 70.3, 43.0; LRMS (ESI): m/z 284.1 [M + H]+; HRMS (ESI): calculated for C16H14NO2S [M + H]+: 284.0740, found: 284.0745.
2,5-Dimethyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ba): yellow solid; m.p.: 101–103 °C; 1H NMR (600 MHz, CDCl3): δ 7.87 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.18–7.13 (m, 2H), 5.14–5.00 (m, 2H), 3.46 (s, 3H), 2.44 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.3, 143.7, 135.2, 131.4, 128.8, 128.2, 125.7, 125.0, 124.7, 124.2, 123.2, 122.2, 117.6, 91.6, 70.2, 43.1, 22.2; LRMS (ESI): m/z 298.0 [M + H]+; HRMS (ESI): calculated for C17H16NO2S [M + H]+: 298.0896, found: 298.0900.
2-Methoxy-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ca): pale yellow solid; m.p.: 105–106 °C; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.35–7.27 (m, 1H), 7.20 (d, J = 5.9 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.88 (dd, J = 8.9, 2.4 Hz, 1H), 5.07 (q, J = 12.2 Hz, 2H), 3.86 (s, 3H), 3.42 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 163.3, 157.9, 137.5, 131.5, 128.9, 128.2, 125.5, 125.1, 124.6, 121.8, 112.9, 112.8, 106.7, 91.5, 70.1, 55.7, 43.7; LRMS (ESI): m/z 314.0 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0844.
(5-Methyl-5-oxido-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazin-2-yl)methanol (3da): orange solid; m.p.: 65–67 °C; 1H NMR (600 MHz, CDCl3): δ 7.99 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.29–7.23 (m, 2H), 7.13 (d, J = 6.8 Hz, 2H), 5.01–4.93 (m, 2H), 4.73 (s, 2H), 3.40 (s, 3H), 2.97 (s, 1H); 13C NMR (126 MHz, CDCl3): δ 157.2, 146.6, 135.0, 131.1, 128.7, 128.3, 125.0, 124.8, 123.4, 122.8, 122.1, 121.7, 118.6, 92.0, 70.1, 64.5, 42.9; LRMS (ESI): m/z 314.0 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0846.
2-Fluoro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ea): yellow solid; m.p.: 149–151 °C; 1H NMR (600 MHz, CDCl3): δ 7.79 (dd, J = 8.9, 5.5 Hz, 1H), 7.70 (dd, J = 11.3, 2.5 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.5, 1.7 Hz, 1H), 7.22–7.13 (m, 2H), 7.07–6.99 (m, 1H), 5.15–5.02 (m, 2H), 3.47 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.8, 134.5, 133.5, 132.2, 131.9, 131.1–130.2 (m), 125.5, 125.0, 124.0, 123.4, 121.5–121.3 (m), 120.2, 118.6 (q, J = 3.8 Hz), 91.3, 69.7, 43.0; LRMS (ESI): m/z 302.0 [M + H]+; HRMS (ESI): calculated for C16H13FNO2S [M + H]+: 302.0646, found: 302.0650.
2-Chloro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3fa): yellow-green solid; m.p.: 210–211 °C; 1H NMR (600 MHz, CDCl3): δ 8.04 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.39–7.30 (m, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.22–7.15 (m, 2H), 5.15–5.02 (m, 2H), 3.48 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.6, 139.2, 136.0, 130.2, 128.2, 127.9, 124.6, 124.6, 124.3, 124.0, 123.2, 121.5, 117.3, 91.1, 69.8, 42.6; LRMS (ESI): m/z 318.0 [M + H]+; HRMS (ESI): calculated for C16H13ClNO2S [M + H]+: 318.0350, found: 318.0350.
2-Bromo-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ga): yellow-green solid; m.p.: 93–94 °C; 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.5, 1.8 Hz, 1H), 7.37–7.33 (m, 1H), 7.22 – 7.15 (m, 2H), 5.16–5.02 (m, 2H), 3.48 (s, 3H).; 13C NMR (126 MHz, CDCl3): δ 157.6, 136.1, 130.1, 128.2, 128.0, 127.8, 126.8, 126.3, 124.6, 124.6, 124.2, 121.5, 117.7, 91.0, 69.8, 42.5; LRMS (ESI): m/z 361.0 [M + H]+; HRMS (ESI): calculated for C16H13BrNO2S [M + H]+: 361.9845, found: 361.9850.
5-Methyl-2-nitro-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ha): brown solid; m.p.: 179–181 °C; 1H NMR (600 MHz, CDCl3): δ 8.92 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.7, 2.1 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.39 (dt, J = 8.2, 4.4 Hz, 1H), 7.23 (d, J = 4.1 Hz, 2H), 5.21 – 5.03 (m, 2H), 3.61 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 158.1, 150.0, 135.5, 129.6, 128.3, 128.1, 125.3, 124.8, 124.3, 121.8, 121.4, 119.5, 117.3, 92.6, 70.0, 42.2; LRMS (ESI): m/z 329.2 [M + H]+; HRMS (ESI): calculated for C16H13N2O4S [M + H]+: 329.0591, found: 329.0603.
1-(5-Methyl-5-oxido-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazin-2-yl)ethanone (3ia): orange-yellow solid; m.p.: 112–114 °C; 1H NMR (600 MHz, CDCl3): δ 8.63 (s, 1H), 7.86–7.80 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.35 (td, J = 7.5, 1.7 Hz, 1H), 7.24–7.16 (m, 2H), 5.21–5.02 (m, 2H), 3.57 (s, 3H), 2.63 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 197.4, 157.8, 140.1, 135.1, 130.8, 128.7, 128.6, 125.3, 125.2, 123.6, 123.0, 122.0, 122.0, 92.7, 70.4, 42.7, 27.1; LRMS (ESI): m/z 326.0 [M + H]+; HRMS (ESI): calculated for C18H16NO3S [M + H]+: 326.0845, found: 326.0850.
Ethyl (5-methyl-5-oxido-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazin-2-yl)acetate (3ja): yellow solid; m.p.: 70–72 °C; 1H NMR (600 MHz, CDCl3): δ 7.96 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.31 (td, J = 7.5, 1.6 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 7.6, 1.5 Hz, 1H), 7.15 (td, J = 7.4, 1.1 Hz, 1H), 5.17–4.97 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 3.48 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 170.7, 157.5, 139.4, 135.2, 131.2, 128.8, 128.2, 125.5, 125.0, 125.0, 124.8, 123.5, 122.1, 118.7, 91.8, 70.2, 61.3, 43.0, 41.7, 14.3; LRMS (ESI): m/z 370.0 [M + H]+; HRMS (ESI): calculated for C20H20NO4S [M + H]+: 370.1108, found: 370.1116.
tert-Butyl (5-methyl-5-oxido-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazin-2-yl)carbamate (3ka): yellow-green solid; m.p.: 77–79 °C; 1H NMR (600 MHz, CDCl3): δ 7.90 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.98 (s, 1H), 5.08 – 4.95 (m, 2H), 3.39 (s, 3H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3): δ 157.5, 152.3, 143.0, 136.3, 131.2, 128.6, 128.2, 124.9, 124.7, 124.6, 122.0, 115.1, 114.2, 111.9, 91.5, 81.4, 70.1, 43.4, 28.3; LRMS (ESI): m/z 399.0 [M + H]+; HRMS (ESI): calculated for C21H23N2O4S [M + H]+: 399.1373, found: 399.1383.
4,5-Dimethyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3la): yellow solid; m.p.: 109–111 °C; 1H NMR (600 MHz, CDCl3): δ 7.90 (d, J = 6.5 Hz, 1H), 7.53 (d, J = 6.7 Hz, 1H), 7.44 (dd, J = 8.3, 7.3 Hz, 1H), 7.28 (td, J = 7.7, 1.6 Hz, 1H), 7.18 (dd, J = 7.4, 0.8 Hz, 1H), 7.13 (td, J = 7.4, 1.1 Hz, 1H), 7.10 (dt, J = 7.3, 1.0 Hz, 1H), 5.12–5.02 (m, 2H), 3.43 (s, 3H), 2.76 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 156.2, 136.6, 135.4, 132.5, 131.7, 128.9, 128.1, 127.6, 125.0, 124.6, 123.0, 122.2, 120.0, 91.2, 70.2, 46.6, 21.1; LRMS (ESI): m/z 298.1 [M + H]+; HRMS (ESI): calculated for C17H16NO2S [M + H]+: 298.0896, found: 298.0900.
4-Bromo-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ma): yellow solid; m.p.: 101–103 °C; 1H NMR (500 MHz, CDCl3): δ 8.07 (dd, J = 8.4, 1.1 Hz, 1H), 7.53–7.42 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.31–7.25 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 5.19–5.02 (m, 2H), 3.89 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.5, 138.5, 132.8, 131.1, 129.7, 128.9, 128.2, 125.2, 125.0, 124.6, 122.3, 120.9, 118.2, 91.2, 70.3, 49.2; LRMS (ESI): m/z 360.9 [M + H]+; HRMS (ESI): calculated for C16H13BrNO2S [M + H]+: 361.9845, found: 361.9854.
3-Bromo-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3na): yellow solid; m.p.: 120–122 °C; 1H NMR (600 MHz, CDCl3): δ 7.95 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.31 (td, J = 7.5, 1.7 Hz, 1H), 7.21–7.12 (m, 2H), 5.15–5.01 (m, 2H), 3.52 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.3, 135.9, 133.7, 130.7, 128.7, 128.3, 126.2, 125.5, 125.1, 125.1, 122.1, 120.9, 116.2, 91.9, 70.3, 42.9; LRMS (ESI): m/z 361.2 [M + H]+; HRMS (ESI): calculated for C16H13BrNO2S [M + H]+: 361.9845, found: 361.9843.
3-Methoxy-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3oa) and 1-Methoxy-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3oa’): pale yellow solid; 1H NMR (500 MHz, CDCl3) for the mixtures: δ 8.00 (d, J = 9.7 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 5.8 Hz, 1H), 7.41–7.33 (m, 5H), 7.30 (t, J = 7.4 Hz, 1H), 7.23–7.16 (m, 6H), 7.13 (d, J = 6.2 Hz, 7H), 7.08 (t, J = 7.2 Hz, 3H), 6.90 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 3H), 5.16–4.96 (m, 7H), 3.89 (s, 3H), 3.77 (s, 8H), 3.64 (s, 8H), 3.45 (s, 3H); 13C NMR (126 MHz, CDCl3) for the mixtures: δ 157.5, 154.8, 132.2, 132.0, 130.8, 128.2, 128.0, 127.6, 126.3, 125.8, 124.9, 124.5, 124.3, 124.1, 123.8, 123.2, 123.1, 123.1, 122.0, 121.4, 121.3, 120.0, 115.7, 115.1, 113.6, 113.5, 104.8, 89.4, 69.8, 69.6, 55.5, 54.8, 42.4, 42.0; LRMS (ESI): m/z 314.2 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0837.
8-Methyl-5H-8λ4-isochromeno[3,4-c]naphtho[2,3-e][1,2]thiazine 8-oxide (3pa): yellow solid; m.p.: 98–100 °C; 1H NMR (600 MHz, CDCl3): δ 8.40 (s, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.61–7.55 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.19 (t, J = 6.5 Hz, 1H), 5.11 (s, 2H), 3.41 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 156.4, 135.8, 131.7, 130.2, 130.0, 129.3, 128.9, 128.8, 128.2, 127.8, 126.0, 125.1, 124.8, 124.6, 123.3, 121.9, 121.8, 91.8, 70.2, 42.5; LRMS (ESI): m/z 334.0 [M + H]+; HRMS (ESI): calculated for C20H16NO2S [M + H]+: 334.0896, found: 334.0894.
5-Ethyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3qa): yellow-green solid; m.p.: 77–79 °C; 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.59–7.55 (m, 1H), 7.34–7.27 (m, 2H), 7.19 (d, J = 5.9 Hz, 1H), 7.14 (td, J = 7.4, 1.2 Hz, 1H), 5.09 (q, J = 12.2 Hz, 2H), 3.60 (ddt, J = 32.6, 14.5, 7.3 Hz, 2H), 1.36 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 157.7, 136.0, 133.0, 131.4, 128.8, 128.2, 125.0, 124.7, 124.6, 124.2, 123.8, 122.0, 117.2, 91.3, 70.2, 49.3, 7.9; LRMS (ESI): m/z 298.1 [M + H]+; HRMS (ESI): calculated for C17H16NO2S [M + H]+: 298.0896, found: 298.0904.
5-Cyclopropyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ra): yellow oil; 1H NMR (600 MHz, CDCl3): δ 8.09 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.33–7.28 (m, 2H), 7.19 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 5.17–4.99 (m, 2H), 2.88 (tt, J = 8.0, 4.7 Hz, 1H), 1.78 – 1.70 (m, 1H), 1.57–1.49 (m, 1H), 1.42 (dt, J = 14.9, 7.8 Hz, 1H), 1.31–1.26 (m, 1H); 13C NMR (151 MHz, CDCl3): δ 157.4, 135.2, 132.5, 131.3, 128.8, 128.1, 125.0, 124.7, 124.4, 124.1, 123.3, 122.3, 120.5, 91.8, 70.2, 30.7, 7.0, 4.6; LRMS (ESI): m/z 310.1 [M + H]+; HRMS (ESI): calculated for C18H16NO2S [M + H]+: 310.0896, found: 310.0904.
5-(Chloromethyl)-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3sa): yellow-green solid; m.p.: 194–196 °C; 1H NMR (600 MHz, CDCl3): δ 8.06 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.1, 1.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.38–7.34 (m, 1H), 7.32 (td, J = 7.5, 1.7 Hz, 1H), 7.21 (dd, J = 7.6, 1.6 Hz, 1H), 7.17 (td, J = 7.3, 1.1 Hz, 1H), 5.09 (q, J = 12.3 Hz, 2H), 4.89–4.75 (m, 2H); 13C NMR (126 MHz, CDCl3): δ 157.3, 137.3, 134.3, 130.8, 128.9, 128.3, 125.8, 125.1, 125.1, 124.7, 124.4, 122.1, 114.6, 91.7, 70.4, 58.6; LRMS (ESI): m/z 317.9 [M + H]+; HRMS (ESI): calculated for C16H13ClNO2S [M + H]+: 318.0350, found: 318.0345.
2-(5-Oxido-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazin-5-yl)ethanol (3ta): yellow-green solid; m.p.: 143–145 °C; 1H NMR (600 MHz, CDCl3): δ 8.08 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 8.1, 1.3 Hz, 1H), 7.64–7.56 (m, 2H), 7.36–7.29 (m, 2H), 7.21–7.14 (m, 2H), 5.19–5.03 (m, 2H), 4.18–4.07 (m, 2H), 3.95 – 3.83 (m, 2H), 3.26 (s, 1H); 13C NMR (151 MHz, CDCl3): δ 156.5, 135.1, 132.9, 130.9, 129.7, 128.6, 128.1, 126.4, 125.0, 124.4, 123.4, 122.2, 118.8, 92.2, 70.2, 56.3, 56.2; LRMS (ESI): m/z 314.1 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0842.
5-Phenyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ua): yellow solid; m.p.: 102–103 °C; 1H NMR (600 MHz, CDCl3): δ 8.13 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.19–7.13 (m, 2H), 5.24–5.10 (m, 2H); 13C NMR (151 MHz, CDCl3): δ 157.4, 136.8, 134.6, 134.3, 132.2, 131.3, 129.8, 129.3, 128.9, 128.2, 125.0, 124.9, 124.7, 124.2, 124.1, 122.5, 121.2, 92.1, 70.4; LRMS (ESI): m/z 346.0 [M + H]+; HRMS (ESI): calculated for C21H16NO2S [M + H]+: 346.0896, found: 346.0899.
5-Benzyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3va): yellow-green solid; m.p.: 66–68 °C; 1H NMR (600 MHz, CDCl3): δ 7.99 (dd, J = 8.1, 1.1 Hz, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.38 (td, J = 7.5, 1.1 Hz, 1H), 7.32 (t, J = 6.9 Hz, 1H), 7.30–7.26 (m, 2H), 7.25–7.22 (m, 1H), 7.18 (td, J = 7.4, 1.1 Hz, 1H), 7.16–7.12 (m, 3H), 5.33 (d, J = 15.5 Hz, 1H), 5.08 (d, J = 12.1 Hz, 1H), 4.98 (d, J = 15.5 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ 147.2, 137.0, 133.9, 131.4, 130.6, 129.0, 128.8, 128.5, 128.3, 127.8, 127.4, 126.5, 125.8, 125.4, 125.3, 124.9, 123.5, 97.0, 70.4, 54.2; LRMS (ESI): m/z 360.0 [M + H]+; HRMS (ESI): calculated for C22H18NO2S [M + H]+: 360.1053, found: 360.1053.
5,10-Dimethyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ab): yellow-green solid; m.p.: 152–154 °C; 1H NMR (600 MHz, CDCl3): δ 8.05 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.59–7.54 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.12 (dd, J = 8.0, 1.8 Hz, 1H), 7.01 (s, 1H), 5.12–5.00 (m, 2H), 3.49 (s, 3H), 2.36 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.8, 135.1, 134.6, 132.8, 129.0, 128.8, 128.4, 125.7, 124.5, 124.3, 123.2, 122.2, 119.9, 91.9, 70.3, 43.0, 21.1.; LRMS (ESI): m/z 298.1 [M + H]+; HRMS (ESI): calculated for C17H16NO2S [M + H]+: 298.0896, found: 298.0902.
10-Methoxy-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ac): yellow-green solid; m.p.: 108–110 °C; 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 5.05 (q, J = 12.3 Hz, 2H), 3.82 (s, 3H), 3.50 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.2, 156.2, 135.0, 132.8, 130.5, 124.4, 124.2, 123.9, 123.5, 123.1, 119.8, 113.5, 110.9, 91.7, 70.2, 55.6, 42.9; LRMS (ESI): m/z 314.1 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0847.
11-Methoxy-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ad): yellow solid; m.p.: 209–211 °C; 1H NMR (600 MHz, CDCl3): δ 8.06 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 6.7 Hz, 1H), 7.60–7.51 (m, 1H), 7.32–7.27 (m, 1H), 7.12 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.2, 2.5 Hz, 1H), 5.07–4.95 (m, 2H), 3.78 (s, 3H), 3.46 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 159.7, 157.5, 135.0, 133.0, 132.6, 125.9, 124.5, 124.4, 123.2, 121.4, 120.0, 109.4, 108.7, 91.9, 69.9, 55.5, 42.9; LRMS (ESI): m/z 314.0 [M + H]+; HRMS (ESI): calculated for C17H16NO3S [M + H]+: 314.0845, found: 314.0842.
10-Chloro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ae): yellow solid; m.p.: 180–182 °C; 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 7.3 Hz, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 1H), 7.60–7.56 (m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.37–7.31 (m, 1H), 7.28–7.24 (m, 1H), 7.17 (d, J = 2.2 Hz, 1H), 5.11–4.95 (m, 2H), 3.51 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 157.3, 134.7, 133.0, 130.4, 129.9, 129.8, 128.2, 125.1, 124.6, 124.3, 123.3, 123.3, 120.1, 91.3, 69.6, 43.0; LRMS (ESI): m/z 318.1 [M + H]+; HRMS (ESI): calculated for C16H13ClNO2S [M + H]+: 318.0350, found: 318.0359.
11-Chloro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3af): yellow-green solid; m.p.: 66–68 °C; 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 1H), 7.65–7.60 (m, 1H), 7.56 (s, 1H), 7.38–7.33 (m, 1H), 7.11 (d, J = 1.3 Hz, 2H), 5.13–4.95 (m, 2H), 3.50 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.7, 134.6, 134.2, 133.3, 133.2, 126.9, 126.2, 124.8, 124.5, 124.2, 123.3, 121.9, 120.1, 91.2, 69.7, 43.0; LRMS (ESI): m/z 318.1 [M + H]+; HRMS (ESI): calculated for C16H13ClNO2S [M + H]+: 318.0350, found: 318.0349.
10-Fluoro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ag): yellow-green solid; m.p.: 77–79 °C; 1H NMR (600 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 1H), 7.60–7.55 (m, 1H), 7.53 (dd, J = 8.6, 5.2 Hz, 1H), 7.40–7.30 (m, 1H), 7.00 (td, J = 8.6, 2.8 Hz, 1H), 6.91 (dd, J = 8.4, 2.7 Hz, 1H), 5.12–4.97 (m, 2H), 3.52 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 161.1, 159.5, 156.8, 134.7, 132.9, 130.7 (d, J = 7.0 Hz), 127.3 (d, J = 3.2 Hz), 124.4 (d, J = 42.3 Hz), 123.6 (d, J = 7.7 Hz), 123.2, 120.1, 114.9 (d, J = 21.4 Hz), 112.3 (d, J = 22.3 Hz), 91.4, 69.6 (d, J = 2.1 Hz), 42.9; LRMS (ESI): m/z 302.1 [M + H]+; HRMS (ESI): calculated for C16H13FNO2S [M + H]+: 302.0646, found: 302.0649.
11-Fluoro-5-methyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ah): pale yellow solid; m.p.: 91–93 °C; 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 1H), 7.67–7.57 (m, 1H), 7.38–7.32 (m, 1H), 7.28 (dd, J = 10.6, 2.5 Hz, 1H), 7.14 (dd, J = 8.3, 5.7 Hz, 1H), 6.82 (td, J = 8.4, 2.5 Hz, 1H), 5.12–4.97 (m, 2H), 3.51 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 163.7, 162.1, 157.6, 134.5, 133.3 (d, J = 9.2 Hz), 133.1, 126.3 (d, J = 9.3 Hz), 124.6, 124.1 (d, J = 3.6 Hz), 123.2, 120.0, 111.0 (d, J = 22.3 Hz), 109.0 (d, J = 24.1 Hz), 91.3 (d, J = 2.2 Hz), 69.6, 42.9; LRMS (ESI): m/z 302.0 [M + H]+; HRMS (ESI): calculated for C16H13FNO2S [M + H]+: 302.0646, found: 302.0645.
5-Methyl-10-(trifluoromethyl)-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ai): yellow solid; m.p.: 191–193 °C; 1H NMR (600 MHz, CDCl3): δ 8.01 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 8.0, 1.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.63–7.58 (m, 1H), 7.56–7.52 (m, 1H), 7.44 (s, 1H), 7.42–7.35 (m, 1H), 5.21–5.02 (m, 2H), 3.53 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 158.3, 135.0, 134.5, 133.2, 128.7, 126.4 (q, J = 32.6 Hz), 125.3 (d, J = 3.6 Hz), 124.9, 124.3, 123.3, 122.0 (d, J = 3.9 Hz), 121.9, 120.2, 91.4, 69.7, 43.0; LRMS (ESI): m/z 352.0 [M + H]+; HRMS (ESI): calculated for C17H13F3NO2S [M + H]+: 352.0614, found: 352.0617.
5-Methyl-11-(trifluoromethyl)-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3aj): yellow solid; m.p.: 150–152 °C; 1H NMR (600 MHz, CDCl3): δ 8.00 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.81 (dd, J = 8.1, 1.3 Hz, 1H), 7.67–7.61 (m, 1H), 7.42–7.36 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 5.20–5.04 (m, 2H), 3.52 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.8, 134.5, 133.5, 132.2, 131.9, 131.0–130.3 (m), 125.5, 125.0, 124.0, 123.4, 121.5–121.4 (m), 120.2, 118.6 (q, J = 3.9 Hz), 91.3, 69.7, 43.0; LRMS (ESI): m/z 352.0 [M + H]+; HRMS (ESI): calculated for C17H13F3NO2S [M + H]+: 352.0614, found: 352.0618.

3.2.5. Mechanistic Investigations

KIE Experiment. To a 15 mL vial was added d1-1a (23.43 mg, 0.15 mmol), 2a (54.01 mg, 0.165 mmol), [Cp*RhCl2]2 (4.64 mg, 5 mol%), AgOPiv (6.27 mg, 20 mol%) under air. Trifluoroethanol (TFE, 2.5 mL) was added subsequently. The resulting mixture was stirred at ambient temperature for 6 h. Then, the mixture was filtered through a celite pad and washed with DCM (10 mL × 3). The combined organic layer was concentrated under vacuo, and the residue was purified by silica gel chromatography eluting with DCM/MeOH from 50:1 to 30:1 to give the mixture of 3aa and d1-3aa. The ratio of two products was determined by 1H NMR to give an intramolecular kinetic isotopic effect (KIE) kH/kD = 0.47. (see Supporting Information).
H/D Exchange Experiment. A mixture of 1a (23.43 mg, 0.15 mmol), [Cp*RhCl2]2 (4.64 mg, 5 mol%), AgOPiv (6.27 mg, 20 mol%) and d3-TFE was added into a vial under air. The resulting mixture was stirred at room temperature for 18 h. Then, the mixture was filtered through a celite pad and washed with DCM (10 mL × 3). The combined organic layer was concentrated under vacuo, and the residue was purified by silica gel chromatography eluting with DCM/MeOH 10:1 to give the product d2-1a. H/D exchange occurred at the o-position of S-phenylsulfoximine (91% D). (see Supporting Information).
Competition Experiment. To a mixture of 1c (27.79 mg, 0.15 mmol), 1i (29.59 mg, 0.15 mmol), 2a (54.01 mg, 0.165 mmol), [Cp*RhCl2]2 (4.64 mg, 5 mol%), and AgOPiv (6.27 mg, 20 mol%) was added TFE (2.5 mL) under air. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the mixture was filtered through a celite pad and washed with DCM (10 mL × 3). The combined organic layer was concentrated under vacuo and the residue was purified by silica gel chromatography eluting with DCM/MeOH from 100:1 to 30:1 to give the isolated products 3ca and 3ia. The ratio was calculated according to the moles of products.

4. Conclusions

In summary, we have developed a sulfoximie-assisted Rh(III)-catalyzed C–H activation and intramolecular annulation. In this strategy, fused isochromeno-1,2-benzothiazines was unprecedentedly synthesized, and the desired products could be yields in good to excellent yields. Most importantly, it is a redox-neutral process that can be conducted under room temperature and the strategy features broad generality and versatility.

Supplementary Materials

Supplementary File 1

Author Contributions

Experiments and investigation, B.W., X.H. and J.L.; formal analysis and data curation, B.W.; writing—original draft preparation, B.W. and X.H.; writing—review and editing, C.L. and H.L. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the National Natural Science Foundation of China (No. 21672232, 21977106, 81620108027), National S&T Major Projects (2018ZX09711002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040217) for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 25 02515 g001 550
Figure 1. Representatives of biologically active compounds containing sulfoximines moiety.
Figure 1. Representatives of biologically active compounds containing sulfoximines moiety.
Molecules 25 02515 g001
Molecules 25 02515 sch001 550
Scheme 1. Synthetic methods access to sulfoximines. (a) Bolm’s work; (b) Bolm’s work; (c) Lee’s work; (d) This work.
Scheme 1. Synthetic methods access to sulfoximines. (a) Bolm’s work; (b) Bolm’s work; (c) Lee’s work; (d) This work.
Molecules 25 02515 sch001
Molecules 25 02515 sch002 550
Scheme 2. Conversion of stereoisomer substrates.
Scheme 2. Conversion of stereoisomer substrates.
Molecules 25 02515 sch002
Molecules 25 02515 sch003 550
Scheme 3. Preliminary mechanistic experiments. (a) KIE experiment; (b) H/D exchange experiment; (c) Competitive experiment.
Scheme 3. Preliminary mechanistic experiments. (a) KIE experiment; (b) H/D exchange experiment; (c) Competitive experiment.
Molecules 25 02515 sch003
Molecules 25 02515 sch004 550
Scheme 4. Proposed mechanism.
Scheme 4. Proposed mechanism.
Molecules 25 02515 sch004
Table
Table 1. Optimization of reaction conditions a. TFE: trifluoroethanol.
Table 1. Optimization of reaction conditions a. TFE: trifluoroethanol.
Molecules 25 02515 i001
EntryCatalyst (mol%)Additive (mol%)SolventTemp (°C)Yield of 3aa (%) b
1[Cp*RhCl2]2 (10)AgSbF6 (40)DCE100ND
2[Cp*RhCl2]2 (10)AgSbF6 (40)DCE8016
3[Cp*RhCl2]2 (10)AgSbF6 (40)HFIP80trace
4[Cp*RhCl2]2 (10)AgSbF6 (40)DCErttrace
5[Cp*RhCl2]2 (10)AgSbF6 (40)HFIPrt47
6[Cp*RhCl2]2 (10)AgSbF6 (40)TFErt75
7[Cp*RhCl2]2 (10)AgSbF6 (40)EtOHrt57
8[Cp*RhCl2]2 (10)AgSbF6 (40)THFrtND
9[Cp*RhCl2]2 (10)AgSbF6 (40)DMErttrace
10[Cp*RhCl2]2 (10)AgOAc (40)TFErt69
11[Cp*RhCl2]2 (10)AgNTf2 (40)TFErt27
12[Cp*RhCl2]2 (10)AgBF4 (40)TFErtND
13[Cp*RhCl2]2 (10)AgOPiv (40)TFErt99 (92) c
14[Cp*RhCl2]2 (20)AgOPiv (40)TFErt47
15[Cp*RhCl2]2 (5)AgOPiv (40)TFErt77
16[Cp*RhCl2]2 (5)AgOPiv (20)TFErt97 (93) c
17[Cp*RhCl2]2 (2.5)AgOPiv (10)TFErt87
18 d[Cp*RhCl2]2 (10)AgOPiv (40)TFErt90 (89) c
19 e[Cp*RhCl2]2 (10)AgOPiv (40)TFErt82
20[Cp*RuCl2]2 (10)AgOPiv (40)TFErttrace
21[Cp*lrCl2]2 (10)AgOPiv (40)TFErt85
22-AgOPiv (40)TFErtND
a Reaction conditions: 1a (0.15 mmol), 2a (0.165 mmol), catalyst and additive in solvent (2.5 mL) under air. b Determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. c Isolated yield in parentheses. d Under an Argon atmosphere. e The reaction time was shortened to 12 h.
Table
Table 2. Substrate scope of sulfoximines a.
Table 2. Substrate scope of sulfoximines a.
Molecules 25 02515 i002
Molecules 25 02515 i003
a Reaction conditions: 1 (0.15 mmol), 2a (0.165 mmol), [Cp*RhCl2]2 (5 mol%) and AgOPiv (20 mol%) in TFE (2.5 mL) under air at room temperature for 18 h. All listed yields are isolated ones. b Determined by 1H NMR spectroscopy. c NR means No Reaction.
Table
Table 3. Substrate scope of 4-diazoisochroman-3-imines a.
Table 3. Substrate scope of 4-diazoisochroman-3-imines a.
Molecules 25 02515 i004
Molecules 25 02515 i005
a Reaction conditions: 1a (0.15 mmol), 2 (0.165 mmol), [Cp*RhCl2]2 (5 mol%) and AgOPiv (20 mol%) in TFE (2.5 mL) under air at room temperature for 18 h. All listed yields are isolated ones. b NR means No Reaction.

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Wang, B.; Han, X.; Li, J.; Li, C.; Liu, H. Sulfoximines-Assisted Rh(III)-Catalyzed C–H Activation and Intramolecular Annulation for the Synthesis of Fused Isochromeno-1,2-Benzothiazines Scaffolds under Room Temperature. Molecules 2020, 25, 2515. https://doi.org/10.3390/molecules25112515

AMA Style

Wang B, Han X, Li J, Li C, Liu H. Sulfoximines-Assisted Rh(III)-Catalyzed C–H Activation and Intramolecular Annulation for the Synthesis of Fused Isochromeno-1,2-Benzothiazines Scaffolds under Room Temperature. Molecules. 2020; 25(11):2515. https://doi.org/10.3390/molecules25112515

Chicago/Turabian Style

Wang, Bao, Xu Han, Jian Li, Chunpu Li, and Hong Liu. 2020. "Sulfoximines-Assisted Rh(III)-Catalyzed C–H Activation and Intramolecular Annulation for the Synthesis of Fused Isochromeno-1,2-Benzothiazines Scaffolds under Room Temperature" Molecules 25, no. 11: 2515. https://doi.org/10.3390/molecules25112515

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