Sulfoximines-assisted Rh(III)-catalyzed C-H activation and intramolecular annulation for the synthesis of fused isochromeno-1,2-benzothiazines scaffolds under room temperature

Article abstract of DOI:10.3390/molecules25112515

Amild and facile Cp?Rh(III)-catalyzed C-Hactivation 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.

Full text of DOI:10.3390/molecules25112515

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
Bao Wang 1,2,3, Xu Han1,2, 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;
wangbao@shanghaitech.edu.cn (B.W.); 201718012342004@simm.ac.cn (X.H.); jianl@simm.ac.cn (J.L.);
lichunpu@simm.ac.cn (C.L.); hliu@simm.ac.cn (H.L.)
2
3
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
* Correspondence: lichunpu@simm.ac.cn (C.L.); hliu@simm.ac.cn (H.L.); Tel.: +86-50807042(H.L.)
Academic Editor: Gianfranco Favi
Received: 14 May 2020; Accepted: 25 May 2020; Published: 28 May 2020
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.
Keywords: sulfoximide; C–H activation; benzothiazine; rhodium.
1. Introduction
Over the past decade, sulfoximines moiety has gained an increasing attention in organic
chemistry [1–9] and pharmaceutical industries for their interesting properties such as multiple
hydrogen-bond acceptor/donor functionalities, structural diversity, and favorable physicochemical
properties [10–13]. 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).
Me
O
F
Me
O
S
O
O
Cl
S
O
N
N
O
O
O
S
N
S
N
N
O
N
F
H
N
N
Cl
N
H
S
N
O
H
antihypertensive agent
anti-HIV agent
MKK4 inhibitor
Figure 1. Representatives of biologically active compounds containing sulfoximines moiety.
Molecules 2020, 25, 2515; doi:10.3390/molecules25112515
www.mdpi.com/journal/molecules

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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 [18–30]. 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 [31–33]. 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].
Scheme 1. Synthetic methods access to sulfoximines. (a) Bolm's work; (b) Bolm's work; (c) Lee's
work; (d) This work.

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In continuation of our studies on the establishment of fused ring heterocyclic compounds via
Rh(III)-catalyzed C-H functionalization [39–41], 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
1
product 3aa was produced in 16% yield, and its structure was further confirmed by H 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.
Table 1. Optimization of reaction conditions.a TFE: trifluoroethanol
Additive
(mol%)
Temp
(°C)
100
80
Yield of 3aa
(%)b
Entry
Catalyst (mol%)
Solvent
1
2
3
4
5
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
AgSbF6 (40)
AgSbF6 (40)
AgSbF6 (40)
AgSbF6 (40)
AgSbF6 (40)
DCE
DCE
HFIP
DCE
HFIP
ND
16
80
trace
trace
47
rt
rt

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6
7
[Cp*RhCl2]2 (10)
AgSbF6 (40)
AgSbF6 (40)
AgSbF6 (40)
AgSbF6 (40)
AgOAc (40)
AgNTf2 (40)
AgBF4 (40)
TFE
EtOH
THF
DME
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
75
57
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (20)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (10)
[Cp*RhCl2]2 (10)
[Cp*RuCl2]2 (10)
[Cp*lrCl2]2 (10)
-
8
ND
trace
69
9
10
11
12
13
14
15
16
17
18d
19e
20
21
22
27
ND
99 (92)c
47
AgOPiv (40)
AgOPiv (40)
AgOPiv (40)
AgOPiv (20)
AgOPiv (10)
AgOPiv (40)
AgOPiv (40)
AgOPiv (40)
AgOPiv (40)
AgOPiv (40)
77
97 (93)c
87
90 (89)c
82
trace
85
ND
aReaction conditions: 1a (0.15 mmol), 2a (0.165 mmol), catalyst and additive in solvent (2.5 mL) under
b
1
air. Determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
cIsolated yield in parentheses. dUnder an Argon atmosphere. eThe reaction time was shortened to 12
h.
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.

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Table 2. Substrate scope of sulfoximinesa.
aReaction 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. bDetermined
by 1H NMR spectroscopy. cNR means No Reaction.
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.

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Table 3. Substrate scope of 4-diazoisochroman-3-imines.a
aReaction conditions: 1a (0.15 mmol), 2 (0.165 mmol), [Cp*RhCl2]2 (5 mol%) and AgOPiv (20 mol%) in
b
TFE (2.5 mL) under air at room temperature for 18 h. All listed yields are isolated ones. NR means
No Reaction.
The chirality of the sufoximine group is important [42–46]. 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.
Scheme 2. Conversion of stereoisomer substrates.

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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).
68% D
(a) KIE experiment
H/D
O
96% D
S
[Cp*RhCl2]2 (5 mol%)
AgOPiv (20 mol%)
N
N2
D
O
S
NTs
O
NH
TFE, rt, 6h, air
KIE = 0.47
O
H
1
1a
2a
d -
1
3aa
3aa
/d -
(b) H/D exchange experiment
H
91% D
H/D
O
[Cp*RhCl2]2 (5 mol%)
AgOPiv (20 mol%)
O
S
S
NH
NH
CF3CD2OD
rt, 18h, air
H
H/D
1a
91% D
2
d -
1a
(c) Competitive experiment
O
O
S
N
N2
3ca
NTs
R = OMe,
3ia
standard condition
S
R
O
R = Ac,
NH
O
R
1c/1i
2a
= 1:1
3ca/3ia
= 1.46
Scheme 3. Preliminary mechanistic experiments. (a) KIE experiment; (b) H/D exchange experiment;
(c) Competitive experiment.
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.

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Scheme 4. Proposed mechanism.
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.
1
[4-(S-Methylsulfonimidoyl)phenyl]methanol (1d): white solid; m.p.: 108–109 °C; H 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;

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LRMS (ESI): m/z 186.0 [M + H]+; HRMS (ESI): calculated for C8H12NO2S [M + H]+: 186.0583, found:
186.0584.
1
Ethyl [4-(S-methylsulfonimidoyl)phenyl]acetate (1j): colorless oil (207.5 mg, 86% yield); H
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.
1
tert-Butyl (4-(S-methylsulfonimidoyl)phenyl)carbamate (1k): white solid; m.p.: 155–156 °C; H
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 =
13
8.9, 2.4 Hz, 1H), 5.07 (q, J = 12.2 Hz, 2H), 3.86 (s, 3H), 3.42 (s, 3H); C NMR (126 MHz, CDCl3): δ

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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,

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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 oC; 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.
1
5-Cyclopropyl-8H-5λ4-isochromeno[3,4-c][1,2]benzothiazine 5-oxide (3ra): yellow oil; H 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.

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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),
13
7.22 (t, J = 8.0 Hz, 2H), 7.19–7.13 (m, 2H), 5.24–5.10 (m, 2H); C 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,

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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),
13
6.91 (dd, J = 8.4, 2.7 Hz, 1H), 5.12–4.97 (m, 2H), 3.52 (s, 3H); C 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):
1
yellow solid; m.p.: 150–152 °C; H 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.
1
The ratio of two products was determined by H 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

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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 Materials can be found online.
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.
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