Metal-free sequential dual oxidative amination of C(sp3)–H bonds: A direct approach to benzothiadiazine 1,1-dioxide derivatives

Article abstract of DOI:10.1080/00397911.2016.1265128

An efficient and metal-free Di-tert-butyl peroxide (DTBP)-promoted dual oxidative amination annulation of 2-amino arylsulfonamide with methylarene has been developed. This protocol provides straightforward access to benzothiadiazine 1,1-dioxide derivatives without using prefunctionalized substrates in good to excellent yields with good functional group tolerance.

Full text of DOI:10.1080/00397911.2016.1265128

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Metal-free sequential dual oxidative amination
of C(sp3)–H bonds: A direct approach to
benzothiadiazine 1,1-dioxide derivatives
Dongyin Wang, Xiaokang Li, Yongli Zhao & Junmin Chen
To cite this article: Dongyin Wang, Xiaokang Li, Yongli Zhao & Junmin Chen (2016): Metal-free
sequential dual oxidative amination of C(sp3)–H bonds: A direct approach to benzothiadiazine
1,1-dioxide derivatives, Synthetic Communications, DOI: 10.1080/00397911.2016.1265128
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1265128
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Date: 30 January 2017, At: 23:33

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1265128
Metal-free sequential dual oxidative amination of C(sp3)–H
bonds: A direct approach to benzothiadiazine 1,1-dioxide
derivatives
Dongyin Wanga, Xiaokang Lia,b, Yongli Zhaoa, and Junmin Chena
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry and
Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi, China; bKey Laboratory of
Organo-pharmaceutical Chemistry, Gannan Normal University, Ganzhou, Jiangxi, China
ABSTRACT
ARTICLE HISTORY
Received 22 June 2016
An efficient and metal-free Di-tert-butyl peroxide (DTBP)-promoted
dual oxidative amination annulation of 2-amino arylsulfonamide with
methylarene has been developed. This protocol provides straight-
forward access to benzothiadiazine 1,1-dioxide derivatives without
using prefunctionalized substrates in good to excellent yields with
good functional group tolerance.
KEYWORDS
2-Amino arylsulfonamide;
benzothiadiazine
1,1-dioxide; metal free;
oxidative amination
GRAPHICAL ABSTRACT
Introduction
Benzothidiazine-1,1-dioxides are a class of important fused heterocyclic scaffolds that
exhibit a wide range of biological and pharmacological activities, including diuretic,[1]
antihypertensive,[2] KATP channel activators,[3] and anticancer activities.[4] In connection
with this, numerous methods have been developed for the synthesis of benzothidiazine-1,1-
dioxide ring system. The typical procedures are the reactions of o-aminobenzene sulfona-
mide with either carboxylic acid derivatives under harsh conditions[5] or aldehydes[6] with
subsequent oxidation using strong oxidants. An alternative approach to the 1,2,4-
benzothiadiazine-1,1-dioxide ring is based on transition metal catalyzed reactions,
for example, Yang et al.[7] developed an efficient method for the synthesis of
1,2,4-benzothiadiazine through iron-catalyzed cascade coupling reactions of
o-bromobenzenesulfonamide with amidine hydrochlorides. Cherepakha et al.[8a] reported
a
facile approach to 1,2,4-benzothiadiazine-1,1-dioxides through Cu(I)-catalyzed
intramolecular cyclization of o-bromoarylsulfonylated amidines, in addition, the same
CONTACT Junmin Chen
jxnuchenjm@163.com
Key Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
Supplemental data (detailed experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for
all of the products 3a–n) can be accessed on the publisher’s website.
© 2017 Taylor & Francis

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D. WANG ET AL.
author developed a facile approach to hetaryl-annulated 1,2,4-thiadiazine-1,1-dioxides
through a reaction of hetaryl-sulfonyl chlorides with amidines under mild noncatalytic
conditions.[8b] Recently, benzyl alcohols as acylating reagents were also used for prep-
aration of 1,2,4-benzothiadiazine-1,1-dioxide through ruthenium-catalyzed hydrogen
transfer reaction.[9] Very recently, a transition-metal-free, K2S2O8-mediated intramolecular
oxidative nitrogenation of C(sp3)–H in N-aryl benzylic amines followed by oxidation at the
benzylic center has been developed for the synthesis of benzothidiazine-1,1-dioxide
ring.[10] It was worth to mention that all synthetic routes mentioned above depended on
the use of functional groups in the substrates.
In recent years, direct oxidative C(sp2)–H/N–H coupling reaction has received
tremendous attraction, and great progress was made in the synthesis of N-heterocycles.[11]
However, C(sp3)–H, which are naturally more abundant, still face great challenges in C–N
bond formation. Recently, the C–N bond formation through C(sp3)–H activation has been
the focus of recent interest,[12] and various methodologies were developed, including
transition metal catalyzed,[13] iodide salt catalyzed,[14] and hypervalent iodine-mediated[15]
benzylic C(sp3)–H amination. Very recently, Li reported an elegant metal-free approach for
the synthesis of o-aryl quinazolinones through dual benzylic C(sp3)–H bond amination,
using o-amino benzamides and methylarenes as the accessible starting materials.[16]
Encouraged by the above results, and in the continuation of our research in C–H
Table 1. Optimization of the reaction conditions.a
Entry
Oxidantb
Additive
Solvent
DMSO
Yield (%)c
1
Benzoquinone
H2O2
BPO
TBHP
KIO3
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
TsOH
0
Trace
Trace
23
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
CH3CN
1,4-Dioxane
H2O
3
4
5
26
6
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
93
7
76
8
H3PO4
KH2PO4
65
9
52
10
11d
12e
13
14
15
16
17f
18g
19
CH3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
\
85
37
51
15
19
17
Trace
56
DMSO
DMSO
DMSO
78
32
aReaction conditions: 1a (0.2 mmol), 2a (8 mmol), oxidant (2 mmol), additive (0.2 mmol), DMSO (1 mL), 110 °C, 24 h.
bH2O2: 30% H2O2 in water, TBHP: 70% t-BuOOH in water, BPO: (PhCOO)2, TBPB: PhCOOOt-Bu.
cIsolated yield.
d5 equiv. of DTBP relative to 1a.
e2 equiv. of CF3COOH relative to 1a.
f30 equiv. of toluene relative to 1a.
g50 equiv. of toluene relative to 1a.

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activation,[17] we envisaged whether o-aminobenzene sulfonamide and methylarenes were
used as substrates for the synthesis of 1,2,4-benzothiadiazine-1,1-dioxides. To certify our
purpose, herein, we would like to report our recent efforts toward the synthesis of
benzothiadiazine-1,1-dioxide derivatives through metal-free sequential dual oxidative
amination of C(sp3)–H bonds.
Results and discussion
To verify our hypothesis, our study began with a model reaction of o-aminobenzene
sulfonamide (1a), 40 equiv. of toluene 2a and 1 equiv. of CF3COOH as the additive in
the presence of 10 equiv. of various oxidants (Table 1). We first examined benzoquinone
as oxidant; in DMSO at 110 °C for 24 h, none of the desired 3a was detected (Table 1,
entry 1). When using H2O2 and BPO: (PhCOO)2, only trace amount of product 3a was
obtained (Table 1, entries 2, 3). Other oxidants such as TBHP and KIO3 afforded the
desired product in moderate yield (Table 1, entries 4, 5). To our delight, 3a was obtained
in excellent yield when using di-tert-butyl peroxide (DTBP) as an oxidant (93%, Table 1,
Table 2. Substrate scope for the reaction of 1 with methylarenes 2.a,b
aReaction conditions: 1 (0.2 mmol), 2 (8 mmol), DTBP (2 mmol), CH3COOH (0.2 mmol), DMSO (1 mL), 110 °C, 24 h.
bIsolated yield.

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D. WANG ET AL.
entry 6). In addition, various additives were also examined using DTBP as oxidant; we
found that organic acid such as p-toluenesulfonic acid (TsOH) as additive can afford
76% yield (Table 1, entry 7) and inorganic acids such as H3PO4 and NaH2PO4 offer the
desired product in 65 and 52%, respectively (Table 1, entry 8, 9). Significantly, CH3COOH
was also able to work in this transformation, affording the desired product in 85% yield
(Table 1, entry 10). Furthermore, the amount of DTBP was also optimized, reducing the
amount of DTBP to 5 equiv. obviously decreased the yield of 3a (Table 1, entry 11). Inter-
estingly, only 51% yield was obtained when the amount of CF3COOH was increased to 2
equiv. (Table 1, entry 12). Various solvents were also examined, and DMSO was turned out
to be the best choice still (Table 1, entries 13–16). The yields dropped after varying the
amount of toluene 2a (Table 1, entries 17, 18). Finally, we found that only 32% yield of
3a was obtained in the absence of CF3COOH, (Table 1, entry 19). Therefore, the optimal
conditions are those described in entry 6.
Under the optimal reaction conditions, we investigated the substrate scope of
intermolecular annulation of 1 with methylarenes 2. First, we performed the generality
of this methodology with different methylarenes (Table 2). Most of the toluenes 2 with
electron-donating and -withdrawing substituents were found to be suitable reaction
partners with 1 to provide the corresponding benzothidiazine-1,1-dioxide derivatives in
good to excellent yields. For example, p-methyl- and p-methoxy-substituted toluenes were
successfully converted and gave the corresponding products in 82, 78% yields, respectively
(3b, 3c). Halogen-substituted toluenes such as p-chloro, p-bromo, and p-iodo can be
reacted as well the desired products were isolated in 73–85% yields (3d–f). Furthermore,
m-substituted methylarenes 2 can also generate the corresponding products in good yields.
For example, m-methyl, m-methoxyl, m-chloro, and m-bromo gave the corresponding
products 3g–j in 63–72% yields. Remarkably, halogen groups substituted at the aromatic
ring of 1, such as bromo and even iodo, were all well tolerated and afforded the desired
products in high to excellent yields (3k–n), which provided the possibility for further
functionalization. However the steric hindrance played a key role in the present reaction,
an attempt to use o-substituted methylarenes 2 failed to afford the desired products.
Conclusion
In summary, we have developed an efficient and practical methodology for the synthesis
of o-aryl benzothidiazine-1,1-dioxides derivatives. The present protocol is based on a
metal-free sequential oxidative animation of benzylic C(sp3)–H bonds in the present of
DTBP/TFA, using 2-aminobenzene sulfonamide and methylarenes as the accessible
starting materials, this novel protocol shows some distinguished characteristics, such as
the lack of any expensive transition metals, excellent functional group tolerance, and a
broad substrate scope. Further applications of the oxidative C–H aminations for the
synthesis of other heterocycles are going on in our laboratory.
Experimental
All reactions were performed in air. Chemicals were purchased from Aldrich, Acros, or
Alfa Asar, and, unless otherwise noted, were used without further purification. Flash
1
chromatography was performed on silica gel (silica gel, 200–300 mesh). H NMR and
13C NMR spectra were recorded on Bruker 400 MHz and Bruker 100 MHz spectrometers

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with DMSO as the solvent. High-resolution mass spectral data were recorded on Bruker
APEX IV Fourier transform ion cyclotron resonance mass spectrometer using ESI. 1b–c
was prepared according to the literature.[18]
Typical experimental procedure
A flask equipped a magnetic stirring bar was charged with o-amino arylsulfonamide 1
(0.2 mmol), methylarenes 2 (8 mmol), DTBP (2 mmol), and DMSO (1 mL). The reaction
mixture was stirred under a nitrogen atmosphere at 110 °C for 24 h. The reaction mixture
was cooled to room temperature; the reaction mixture was extracted with diethyl ether
(5 � 3 mL). The combined extracts were washed with brine and dried over MgSO4, and
the crude product was purified by flash column chromatography on silica gel with
petroleum ether/EtOAc as the eluent to give the desired product 3.
Funding
We are grateful for the financial support from the National Natural Science Foundation of China
(51463002), the Science and Technology Planning Project of Jiangxi Province, China
(20142BAB203007).
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