Green approach toward one pot cascade synthesis of 3-aryl-3,4-dihydro-1,2,4 benzothiadiazine-1,1-dioxides

Article abstract of DOI:10.1080/10426507.2013.769986

A silica-gel-supported ceric ammonium nitrate (CAN-SiO2) was found to be an effective catalyst for the cascade synthesis of functionalized 3-aryl-3,4-dihydro-1,2,4-benzo- thiadiazine-1,1-dioxides using 2-aminobenzenesulfonamide and benzaldehydes at room temperature. The reaction allows rapid cyclization (10-70 min) with 5 mol% CAN impregnated on silica gel to give the desired products in excellent yield without further column purification. The protocol uses inexpensive and environmentally friendly CAN-SiO2as the catalyst, and no ligand or additive was required. [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional figures]

Full text of DOI:10.1080/10426507.2013.769986

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Green Approach Toward One Pot Cascade
Synthesis of 3-Aryl-3,4-Dihydro-1,2,4
Benzothiadiazine-1,1-Dioxides
Someshwar Dagduappa Dindulkar a b , Kwon Taek Lim a , Byung Kwon
Cho a & Yeon Tae Jeong a
a Department of Image Science and Engineering , Pukyong National
University , Busan , Korea
b Mahatma Gandhi Missions Jawaharlal Nehru Engineering College ,
Aurangabad , 431003 , Maharashtra , India
Accepted author version posted online: 02 Aug 2013.Published
online: 03 Dec 2013.
To cite this article: Someshwar Dagduappa Dindulkar , Kwon Taek Lim , Byung Kwon Cho & Yeon
Tae Jeong (2014) Green Approach Toward One Pot Cascade Synthesis of 3-Aryl-3,4-Dihydro-1,2,4
Benzothiadiazine-1,1-Dioxides, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:1,
40-51, DOI: 10.1080/10426507.2013.769986
To link to this article: http://dx.doi.org/10.1080/10426507.2013.769986
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Phosphorus, Sulfur, and Silicon, 189:40–51, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.769986
GREEN APPROACH TOWARD ONE POT CASCADE
SYNTHESIS OF 3-ARYL-3,4-DIHYDRO-1,2,4
BENZOTHIADIAZINE-1,1-DIOXIDES
Someshwar Dagduappa Dindulkar,1,2 Kwon Taek Lim,1
Byung Kwon Cho,1 and Yeon Tae Jeong1
1Department of Image Science and Engineering, Pukyong National University,
Busan, Korea
2Mahatma Gandhi Missions Jawaharlal Nehru Engineering College, Aurangabad,
431003, Maharashtra, India
GRAPHICAL ABSTRACT
Abstract A silica-gel-supported ceric ammonium nitrate (CAN-SiO2) was found to be an
effective catalyst for the cascade synthesis of functionalized 3-aryl-3,4-dihydro-1,2,4-benzo-
thiadiazine-1,1-dioxides using 2-aminobenzenesulfonamide and benzaldehydes at room tem-
perature. The reaction allows rapid cyclization (10−70 min) with 5 mol% CAN impregnated
on silica gel to give the desired products in excellent yield without further column purification.
The protocol uses inexpensive and environmentally friendly CAN-SiO2 as the catalyst, and no
ligand or additive was required.
[Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
files: Additional figures]
Keywords: Supported ceric ammonium nitrate; heterogeneous catalyst; benzothiadiazine-1,
1-dioxides; cascade synthesis
Received 22 October 2012; accepted 13 January 2013.
This research work was supported by Second Phase of Brain Korea (BK21) Program.
Address correspondence to Professor Yeon Tae Jeong, Pukyong National University, Image Science and
Engg, Gaon Building room 801, Daeon-Dong-3 Nam Gu, Busan 608739 Korea. E-mail: ytjeong@pknu.ac.kr
40

SYNTHESIS OF BENZOTHIADIAZINE-1,1-DIOXIDE
41
INTRODUCTION
Sulfur-nitrogen heterocyclic compounds have retained the interest of organic re-
searchers for several decades. Organosulfur compounds constitute an important class of
organic compounds with diverse biological activities, and valuable building blocks for a
variety of sulfur containing heterocyclic molecule synthesis.1 Owing to their biological and
physical properties as well as their utility as synthetic intermediates.2 Organosulfur com-
pounds also have applications in the field of Electron Probe Microanalysis.3 Specifically,
benzothiadiazine-1,1-dioxides are known to show various useful biological and medicinal
activities.4,5 In particular, benzo or pyridothiadiazine dioxides, as well as dihydrobenzopy-
rans, represent interesting targets to develop in the field of potassium channel openers,
potent AMPA receptors, and also the benzothiadiazine groups were found to be a potent
selective aldose reductase inhibitors in vitro (Figure 1).6–14 Due to broad application in
the field of medicinal chemistry, the benzothiadiazine molecules have raised great interest
among chemists, biologists, and pharmacologists. Due to their wide therapeutic use in
medicinal chemistry, these adventitious heterocycles encourage us to develop an efficient
route for their synthesis.
Although many methods have been developed for the synthesis of different aromatic
sulfur heterocyclic compounds, the synthesis of a benzothiadiazine-1,1-dioxide heterocycle,
typically involves conventional methods for example H2SO4 or HCl and NaHSO3 have
frequently been used.15–17 Overall studies indicate that the reported methods possess long
reaction times, low yields, costly reagent conditions, and toxic acidic wastes after reaction
work up procedure.
Owing to their environmental restrictions on disposal of hazardous toxic acidic waste
due to the water-quenching step for neutralization of acidic reagents used in reaction
condition, developmental efforts are needed to overcome these drawbacks. Chemists are
focusing more on the uses of heterogeneous metal Lewis catalysts instead of traditional
homogeneous metal Lewis and Brønsted acid catalysts. This can avoid difficult acidic waste-
disposal problems because of easy separation of the heterogeneous catalyst and minimal
leaching of catalyst in the solvent. Over the last few years, the number of reports dealing
with the preparation, characterization and use of supported catalysts has increased.18 Many
outstanding reviews on supported catalysts have also been reported.19 Inorganic material-
supported catalysts are more efficient due to an increased effective area for the reaction, due
Figure 1 Chemical structures of some reported biologically active molecule (1–6) and a general formula of the
newly synthesized benzothiadiazine-1,1-dioxides (7).

42
S. D. DINDULKAR ET AL.
to the presence of pores which force both substrate and catalyst towards a particular course
of reaction and thus lower the entropy activation of reaction and accelerate the reaction by
constraining both substrate and reagent into proximity.20–22
Recently ceric ammonium nitrate (CAN) (Ce(NH4)2(NO3)6) has been used in or-
ganic synthesis not only based on its electron-transfer capacity but also with its Lewis
acidic property. Due to a dual role as both as oxidant and a Lewis acid,23–25 it able to
catalyze various organic transformations, such as functional-group conversion and pro-
motion of bond-forming reactions.26,27 It has been reported that silica-gel-supported CAN
reagent is an efficient catalyst for selective removal of trityl and silyl groups from pro-
tected nucleosides and nucleotides.28 It is also used in oxidation of aromatic compounds to
quinines.29 Silica-gel-supported CAN proximate the reactant, leading to a faster electron-
transfer process between reactants and thus may catalyzes the reaction in shorter time. As
a part of our interest on the development of newer environmentally benign methodology
for diverse heterocyclic compounds of biological significance, industry and key interme-
diate for the multistep synthesis, we have implemented a number of green strategies in
organic transformations using environmentally friendly catalytic reaction conditions.30–34
We decided to investigate an efficient catalytic system for the synthesis of biologically
active benzothiadiazine-1,1-dioxides. So, herein, we intend to report the tandem synthesis
of 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides, from aromatic aldehydes and
2-aminobenzenesulfonamide using CAN-SiO2 as an expeditious catalyst at room temper-
ature. (Scheme 1).
Scheme 1
RESULT AND DISCUSSION
In the present study, we have developed a highly practical and very simple method for
synthesis of 3,4-dihydro-1,2,4-benzothiadiazines from 2-aminobenzenesulfonamide and
aromatic aldehydes using CAN-SiO2 catalyst at room temperature. After a series of stud-
ies, we achieved excellent yields in a very short duration at room temperature. Knowing
the reaction is thought to give 2 products,17 one of which is 3,4-dihydro and another
one is 4H-1,2,4-benzothiadiazine-oxidized product, our studies indicated that this reaction
proceed selectively with the formation of only 3,4-dihydro-1,2,4-benzothiadiazine using
catalytic amount of CAN-SiO2 (containing 0.05 equiv. of CAN) with short reaction time,
at ambient temperature. On the other hand, the use of a heterogeneous catalyst makes this
methodology more advantageous, because of the easy work-up procedure and recovery of
catalyst.
In the beginning, the optimization of the reaction conditions was undertaken by in-
vestigating the effect of the various reaction parameters like different catalysts and solvents
was carried out (Table 1). In order to establish the real effectiveness of the catalyst for

SYNTHESIS OF BENZOTHIADIAZINE-1,1-DIOXIDE
43
Table 1 Optimization of reaction conditions using various solvents and catalysts
Entrya
Catalyst (10 mol%)
Solvent
Ethanol
Time (h)
Yieldb (%)
1
2
3
4
5c
6
7
8
9
10
11
12
13
14
15d
16e
Conc. HCl
Conc. H2SO4
PTSA
Amberlyst-15
CAN-SiO2
Cu(OTf)2·SiO2
CAN
12
12
7
5
0.16
1
1
2
24
1
1
1
1
2
0.16
0.16
68
75
74
62
95
90
87
56
≤20
87
76
89
78
84
94
95
Ethanol
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Acetonitrile
Ethanol
DCM
SiO2
—
CAN-SiO2
CAN-SiO2
CAN-SiO2
CAN-SiO2
CAN-SiO2
CAN-SiO2
CAN-SiO2
THF
Water
Toluene
Toluene
aReactions and conditions: all reactions were carried out at room temperature using 2-aminobenzene-
sulfonamide (0.6 mmol), benzaldehyde (0.6 mmol), and 10%w/v or w/w acid catalyst.
bIsolated yields.
cCAN-SiO2 containing 10 mol% CAN.
dCAN-SiO2 containing 5 mol% CAN.
eCAN-SiO2 containing 20 mol% CAN.
the synthesis of 3-phenyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides, a test reaction
was performed without catalyst using equimolar, amounts of 2-aminobenzenesulfonamide
(1) and benzaldehyde (2), at room temperature in air. It was found that less than 20%
yield product was obtained in the absence of catalyst even after 24 h (Table 1, entry 9). In
order to find a more efficient and eco-friendly catalytic system for this reaction, the same
test reaction was performed with different acid catalysts such as PTSA, Amberlyst-15,
CAN, CAN-SiO2, and Cu(OTf)2·SiO2 (Table 1),which were further compared with tradi-
tional reported acid catalysts such as conc. HCl and conc. H2SO4 (Table 1, entry 1 and 2).
The overall study shows that use of traditional acids (mineral acids) reaction takes a long
time with lower yield as compared to other acid catalysts; moreover, the work-up of this
concentrated acid-catalyzed reaction is tedious and creates a large amount of acid waste.
Among all screened catalysts, CAN-SiO2 gave the best yield in least reaction time (Ta-
ble 1, entry 5). It noteworthy that when the test reaction was performed using Cu(OTf)2·SiO2
catalyst, the reaction was completed with good yield in 1 h. But from the view point of
cost, ease of availability, and reaction time, CAN-SiO2 is the best catalyst as compared
to Cu(OTf)2·SiO2. To study the role of SiO2, the test reaction was also performed with
SiO2, and we observed a good yield was obtained as compared to catalyst free reactions
(Table 1, entry 8). Also the same test reaction was performed using a CAN, and was found
to be less efficient as compared to supported CAN and also provided impurities to the
products. Supported CAN is more efficient because of its weak surface Brønsted acidity of
OH sites of silica gels. Silica supports improved the performance of heterogeneous metal-
containing catalysts, though the mechanism through which it works is not well understood.
In additionally, our literature survey on the usage of supported CAN as a catalyst for

44
S. D. DINDULKAR ET AL.
the synthesis of 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides are unprecedented
and more efficient than conventional methods.
Once we found CAN-SiO2 as the best catalyst for this reaction, solvent and appro-
priate catalyst-loading optimization was performed. We screened various solvents, such as
toluene, EtOH, CH3CN, water, and THF at room temperature. Among the different tested
organic solvents, only toluene and acetonitrile were found to give good yields. When we
performed reaction in aqueous media, the reaction was completed with moderate yield
(Table 1, entry 14). Furthermore, in an attempt to optimize the catalyst, a model reaction
was carried out using 5 and 20 mol% of CAN supported on silica at room temperature in
toluene (Table 1, entries 15 and 16). It was found that 5 mol% of CAN supported with
silica showed the maximum yield in the minimum amount time. A larger amount of the
catalyst loading (20 mol%) neither increases the yield nor shortens the conversion time. It
was found that, instead of using 1.0 equivalent aldehyde, use of 1.2 equivalent of aldehyde
provides a better yield in a short time. Furthermore, CAN-SiO2 was recovered simply by
dissolving the reaction mixture in acetone and filtering it to obtain the solid heterogeneous
catalyst in excellent yields (about 93%). The crude product was obtained by evaporating
the acetone. The crude product was further purified by recrystallization from ethanol or just
by giving few washings of chloroform/ethyl acetate (4:1). The recovered catalyst could be
further reused in two more consecutive reactions between (1) and (2a).
Although our aim is to find the best alternative methodology to avoid the forma-
tion hazardous acidic waste by a conventional acid mediated method and not toward the
reusability of catalyst, we were interested to find determine the reusability of catalyst for
two more cycles. Accordingly, after the first fresh run with 94% yield, the recovered cat-
alyst was washed, dried, and used for a second and third time. Yields of 91% and 72%,
respectively, were obtained, thus proving the catalyst’s reusability (Table 2).
Once the effective catalytic amount of the CAN-SiO2 catalyst (containing 0.05 equiv.
of CAN) was proven, to further generalize this, we extended the synthesis to a variety
of novel 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides using 2-aminobenzene-
sulfonamide and various electron-donating, (methoxy, ethoxy, and isopropyl) as well as
electron-withdrawing (nitro, bromo-, and chloro-substituted) aromatic aldehydes (Table 3).
Various aromatic aldehydes with different substituents at ortho, meta, or para-
positions show equal ease toward product formation in high yields. In contrast, aromatic
aldehydes having groups such as Cl, F, Br, MeO, EtO, and nitro showed better reactiv-
ity and the reactions were completed in a shorter time. In the of diflurobenzaldehyde
and heteroaryl aldehydes such as, nicotinaldehyde, thiophene-2-carbaldehyde the desired
product was formed in moderate yields. The overall study concluded that the CAN-SiO2
is best catalytic system for this cascade synthesis, which gives excellent yields in very
short duration at room temperature. A possible mechanism for this one pot reaction has
Table 2 The reusability of CAN-SiO2 in the synthesis of 3-phenyl-3,4-dihydro-1,2,4-benzothiadiazine-1,
1-dioxides
Entry
Reaction cycle
Yield (%)a
1
2
3
Ist (Fresh run)
IInd cycle
IIIrd cycle
94
91
72
aIsolated yield.

SYNTHESIS OF BENZOTHIADIAZINE-1,1-DIOXIDE
45
Table 3 Synthesis of diversified 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides via scheme 1a
Entrya
Ar = Aldehydes
C6H5
4-iPr-C6H5
4-MeO-C6H5
2-F-C6H5
3-MeO-C6H5
2,3-diF-C6H4
4-Cl-C6H5
3,4-diF-C6H4
2,4-diF-C6H4
4-F-3-NO2-C6H4
2-F-4-MeO-C6H4
4-F–C6H5
3-F–C6H5
4-EtO–C6H5
4-Br–C6H5
3,5-diF-C6H4
Thiophene-2-carbaldehyde
Picolinaldehyde
4-NO2−C6H4
Time (min)
Yield (%)b
Referencec
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
10
35
50
70
50
20
10
40
10
50
60
30
15
15
30
40
30
60
20
94
92
90
87
84
95
93
89
93
87
90
92
85
92
93
94
81
78
96
37
—
37
—
—
—
37
—
—
—
—
37
—
—
—
—
—
—
37
3s
aReactions and condition: 2-aminobenzenesulfonamide (0.6 mmol), aldehyde (0.72 mmol), and CAN-SiO2
(containing 5 mol% CAN) in toluene at room temperature.
bIsolated yields.
cReported compounds.
been postulated on the basis of similar reaction product 2,3-dihydro-quinazolin-4(1H)-ones
from anthranilamide with aldehydes or ketones in the presence of cerium(IV) ammonium
nitrate.35,36 On the basis of the reported literature, the reaction begins with the formation of
imine, with an amine of 2-aminobenzenesulfonamide and benzaldehydes and followed by
nucleophilic attack of an amide nitrogen to an imine carbon intermediate to give the cor-
responding benzothiadiazine-1,1-dioxides (Scheme 2). All the new, as well as previously
reported compounds, were completely characterized by their spectral properties such as 1H,
13C NMR, and HRMS. Spectral data and melting point of reported compounds coincides
with the reported data in literature.37 Sample 1H and 13C NMR spectra are provided in the
Supplemental Materials (Figures S1–S38)
Scheme 2

46
S. D. DINDULKAR ET AL.
CONCLUSION
In conclusion, we have proposed a mild, easy, and efficient method for the synthesis
of 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides using silica supported CAN as
green and expeditious catalyst at ambient temperature. The advantages of performing this
cascade synthesis in the presence of CAN-SiO2 catalyst can be summarized as follows: (1)
use of a safe, nonvolatile, noncorrosive bifunctional metal-acid catalysts; (2) high yields of
recovering of catalyst at the end of the reactions easily; and (3) no base or any additional
activator required and the residue was crystallized from ethanol to give the pure product with
excellent yield without further column purification. We believe that this novel protocol may
useful for the easy generation of new bioactive benzothiadiazine-1,1-dioxides for future
medicinal chemistry research.
EXPERIMENTAL
Chemicals were purchased from Aldrich and Alfa aesar Chemical Companies. NMR
spectra were recorded in ppm in DMSO-d6 on a JEOL JNM ECP 400 NMR instrument
using TMS as internal standard. HR-MS were recorded on JEOL JMS-700 mass spec-
trometer, respectively. Melting points are taken in open capillaries and are uncorrected;
Electrothermal-9100 (Japan) instrument was used to determine the melting point of the
compounds.
General Procedure for the Synthesis of Silica-Supported Ceric
Ammonium Nitrate Catalyst
A supported CAN catalyst was prepared by adopting the literature procedure.28
Neutral silica gel (9.01 g, Merck Kieselgel 60, particle size 0.063–0.200 mm, 70–230
mesh) was mixed with a solution of CAN (1.02 g) in water (2.0 mL). Evaporation of water
under reduced pressure gave a dry yellowish powder, which contained 10% (by weight) of
CAN. According to Hwu et al., this reagent was found active for at least six months by
storage in a well-capped bottle.28
Typical Procedure for the Synthesis of 3-Aryl-3,4-Dihydro-1,2,4-
Benzothiadiazine-1,1-Dioxides (3a–3s)
The standard procedure was followed by use of 1 (1.0 equiv.), 2 (1.2 equiv.), CAN-
SiO2 0.127 mg (containing 31.0 mg of CAN, 0.058 mmol, 0.05 equiv.), and toluene
(5.0 mL). After the reaction mixture was stirred for certain period as indicated in Table 3.
After completion of the reaction indicated by TLC, the reaction mixture was dissolved in
acetone and the catalyst was recovered by filtration. The solvent was then evaporated under
vacuum to afford the crude product. This further recrystallised from ethanol or just by
giving chloroform: ethyl acetate (4:1). All new compounds were completely characterized
by 1H/13C NMR and HRMS of few selected compounds is given below. Previously known
products (3a. 3c. 3g and 3l) are identical to those reported.37

SYNTHESIS OF BENZOTHIADIAZINE-1,1-DIOXIDE
47
3-Phenyl-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Ddioxide (3a)37
1
Pale white solid; Mp. 129–131◦C; Yield 94%. H NMR (400 MHz, DMSO-d6) δ:
7.93 (d, J = 12.0 Hz, 1H), 7.70 (d, J = 6.0 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.48–7.42
(m, 4H), 7.33 (t, J = 7.6 Hz, 1H) 6.95 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.3 Hz, 1H), 5.82
(d, J = 12.0 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO- d6) δC: 143.9, 137.3, 132.8,
129.1, 128.5, 127.5, 123.7, 121.6, 116.5 (d, J = 34.1 Hz), and 68.4 ppm; and HRMS: m/z
calculated: 360.0619, found: 360.0619.
3-(4-Isopropyl-Phenyl)-3,4-Dihydro-2H Benzo[1,2,4]thiadiazine
1,1-Dioxide (3b)
1
Pale white solid; Mp. 159–161◦C; Yield 81%. H NMR (400 MHz, DMSO- d6) δ:
7.84 (d, J = 12.1 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.53–7.51 (m, 1H), 7.36–7.29 (m, 4H),
6.80 (d, J = 8.0 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 5.74 (d, J = 12.0 Hz, 1H), 2.98–2.88 (m,
1H), 1.22 (d, J = 6.9 Hz, 6H) ppm; 13C NMR (100.5 MHz, DMSO- d6) δC: 149.4, 143.8,
134.8, 132.7, 127.5, 126.3, 123.6, 121.5, 116.5 (d, J = 28.6 Hz), 68.2, and 33.2 ppm; and
HRMS: m/z calculated: 302.1089, found: 302.1087.
3-(4-Methoxy-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3c)37
Faint brown solid; Mp. 135–137◦C; Yield 87%.1H NMR (400 MHz, DMSO-d6) δ:
7.81 (d, J = 11.7 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.32–7.22 (m, 4H), 7.01 (d, J =
7.6 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 9.2 Hz, 1H), 6.66–6.59 (m, 1H), 5.73
(d, J = 11.7 Hz, 1H), 3.78 (s, 3H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 159.8,
145.5, 143.9, 132.8, 129.5, 128.8, 127.8, 123.7, 121.5, 116.4 (d, J = 29.4 Hz), 67.9, and
55.2 ppm; and HRMS: m/z calculated: 290.0725, found: 290.0727.
3-(2-Fluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3d)
Pink solid; Mp. 102–104◦C; Yield 88%. 1H NMR (400 MHz, DMSO-d6) δ: 8.01 (d,
J = 11.7 Hz, 1H), 7.83 (br s, 1H), 7.53–7.29 (m, 6H), 6.88 (d, J = 7.6 Hz, 1H), 6.77 (br s,
1H), 6.07 (d, J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.8, 132.9,
131.2, 128.9, 124.6, 122.7, 121.6, 117.0, 116.4, 115.5 (d, J = 21.4 Hz), and 61.4 ppm; and
HRMS: m/z calculated: 278.0525, found: 278.0526.
3-(3-Mthoxy-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3e)
1
Pale white solid; Mp. 172–174◦C; Yield 84%. H NMR (400 MHz, DMSO-d6) δ:
7.88 (d, J = 12.0 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.39–7.30 (m, 4H), 7.23 (d, J = 7.3 Hz,
1H), 7.01 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H) 5.77 (d,
J = 12.0 Hz, 1H), 3.80 (s, 3H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 159.3, 143.8,
138.7, 132.8, 129.5, 123.7, 121.6, 119.7, 116.5 (d, J = 34.1 Hz), 114.9, 112.8, 68.3, and
55.2 ppm; and HRMS: m/z calculated: 290.0725, found: 290.0728.

48
S. D. DINDULKAR ET AL.
3-(2,3-Difluoro-Phenyl)-3,4-Dihydro-2H-benzo[1,2,4]thiadiazine
1,1-Dioxide (3f)
1
Pale white solid; Mp. 180–182◦C; Yield 95%. H NMR (400 MHz, DMSO-d6) δ:
8.14 (d, J = 12.0 Hz, 1H), 7.62–7.51 (m, 4H), 7.37–7.34 (m, 2H), 6.91 (d, J = 8.0 Hz,
1H), 6.81 (t, J = 7.5 Hz, 1H), 6.12 (d, J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz,
DMSO-d6) δC: 143.6, 133.0, 126.7, 125.0, 123.9, 123.7, 121.7, 118.1 (d, J = 16.6), 117.2,
116.4, and 61.3 ppm; and HRMS: m/z calculated: 296.0431, found: 296.0432.
3-(4-Chloro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3g)37
1
Pale white solid; Mp. 186–188◦C; Yield 93%. H NMR (400 MHz, DMSO-d6) δ:
7.94 (d, J = 12.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 3H), 7.40 (br
s, 1H), 7.34–7.30 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 5.81 (d,
J = 12.1 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.7, 136.2, 133.6, 132..8,
129.4, 128.4, 123.7, 121.6, 116.6 (d, J = 49.2 Hz), and 67.5 ppm.
3-(3,4-Difluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3h)
Pink solid; Mp. 178–180◦C; Yield 89%. 1H NMR (400 MHz, DMSO-d6) δ: 7.97 (d,
J = 12.0 Hz, 1H), 7.81 (t, J = 9.7 Hz, 1H), 7.57–7.32 (m, 5H), 6.91 (d, J = 8.4 Hz, 1H),
6.80 (t, J = 7.4 Hz, 1H), 5.86 (d, J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6)
δC: 143.6, 134.9, 132.9, 124.8, 123.7, 121.7, 117.6, 117.5, 117.0, 116.4 (d, J = 39.7 Hz,
1H), and 67.2 ppm; and HRMS: m/z calculated: 296.0431, found: 296.0432.
3-(2,4-Difluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3i)
1
Pale white solid; Mp. 175–177◦C; Yield 93%. H NMR (400 MHz, DMSO-d6) δ:
8.07 (d, J = 11.7 Hz, 1H), 7.92–7.86 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.45 (br s, 1H),
7.41–7.24 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.07 (d, J = 12.0 Hz,
1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.7, 133.0, 130.4, 123.7, 121.7, 117.1,
116.4, 112.0, and 61.1 ppm; and HRMS: m/z calculated: 296.0431, found: 296.0442.
3-(4-Fluoro-3-Nitro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3j)
Pale white solid; Mp. 165–167◦C; Yield 87%.1H NMR (400 MHz, DMSO-d6) δ:
8.56 (d, J = 6.9 Hz, 1H), 8.14 (d, J = 11.7 Hz, 2H), 7.72 (t, J = 9.9 Hz, 1H), 7.58–7.53
(m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.01
(d, J = 12.0 Hz, 1H); 13C NMR (100.5 MHz, DMSO-d6) δC: 156.1, 153.4, 143.6, 136.6,
135.8, 134.8 133.0, 125.4, 123.8, 121.8, 118.7 (d, J = 21.4 Hz), 117.2, and 116.5 ppm; and
HRMS: m/z calculated: 323.0376, found: 323.0379.

SYNTHESIS OF BENZOTHIADIAZINE-1,1-DIOXIDE
49
3-(3-Fluoro-4-Methoxy-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3k)
1
Pale white solid; Mp. 187–189◦C; Yield 79%. H NMR (400 MHz, DMSO-d6) δ:
7.95 (d, J = 12.0 Hz, 1H), 7.75 (t, J = 8.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.38–7.31
(m, 2H), 6.95–6.89 (m, 3H), 6.78 (t, J = 7.5 Hz, 1H), 6.00 (d, J = 12.0 Hz, 1H), 3.81 (s,
3H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 161.3, 143.8, 132.9, 129.5, 123.7, 121.5,
116.6 (d, J = 53.2 Hz), 110.6, 101.2 (d, J = 24.6 Hz), 61.2, and 55.8 ppm; and HRMS:
m/z calculated: 308.0631, found: 308.0632.
3-(4-Fluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3l).37
Pink solid; Mp. 180–182◦C; Yield 92%. 1H NMR (400 MHz, DMSO-d6) δ: 7.92 (d,
J = 12.1 Hz, 1H), 7.75–7.72 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (br s, 1H), 7.39–7.28
(m, 3H), 6.91 (d, J = 8.4 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 5.82 (d, J = 12.0 Hz, 1H) ppm;
13C NMR (100.5 MHz, DMSO-d6) δC: 1143.8, 133.6, 132.8, 129.8, 129.7, 123.7, 121.6,
116.6 (d, J = 46.1 Hz), 115.3 (d, J = 21.4 Hz), and 67.6 ppm.
3-(3-Fluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3m)
Brown solid, Mp; 154–156◦C, Yield 85%. 1H NMR (400 MHz, DMSO-d6) δ: 7.96
(d, J = 12.0 Hz, 1H), 7.58–7.27 (m, 7H), 6.93 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.5 Hz,
1H), 5.86 (d, J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.7, 139.8
(d, J = 7.1 Hz), 132.9, 130.5 (d, J = 8.7 Hz), 123.8, 121.7, 116.9, 115.9 (d, J = 20.6 Hz),
114.4 (d, J = 22.5 Hz), 67.67, 26.1, and 24.2 ppm; and HRMS: m/z calculated: 278.0525,
found: 278.0527.
3-(4-Ethoxy-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3n)
Yellow solid; Mp. 143–145◦C; Yield 92%. 1H NMR (400 MHz, DMSO-d6) δ: 7.81
(d, J = 12.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.32–7.29 (m,
2H), 7.01 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.76 (t, J = 7.3 Hz, 1H), 5.73 (d,
J = 12.1 Hz, 1H), 4.09–4.04 (m, 2H), 1.34 (t, J = 6.7 Hz, 3H) ppm; 13C NMR (100.5 MHz,
DMSO-d6) δC: 159.0, 143.9, 132.7, 129.3, 128.8, 123.7, 121.5, 116.4 (d, J = 27.0 Hz),
114.25, 68.0, 63.1, and 14.5 ppm; and HRMS: m/z calculated: 360.0619, found: 360.0619.
3-(4-Bromo-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3o)
Pink solid; Mp. 186–188◦C, Yield 93%. 1H NMR (400 MHz, DMSO-d6) δ: 8.16 (d,
J = 12.1 Hz, 1H), 7.88–7.83 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H), 7.60 (br s, 1H), 7.52 (t,
J = 7.3 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.02 (d, J = 12.0 Hz,
1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.7, 136.6, 132.8, 131.4, 129.7, 123.7,
122.3, 121.7, 116.6 (d, J = 49.27 Hz), and 67.7 ppm; and HRMS: m/z calculated: 337.9725,
found: 337.9727.

50
S. D. DINDULKAR ET AL.
3-(3,5-Difluoro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine
1,1-Dioxide (3p)
Pink solid; Mp. 154–156◦C; Yield 94%. 1H NMR (400 MHz, DMSO-d6) δ: 7.98 (d,
J = 12.0 Hz, 1H), 7.55–7.32 (m, 6H), 6.90 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.3 Hz, 1H),
5.87 (d, J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.5, 132.9, 123.7,
121.7, 117.1, 116.4, 111.0 (d, J = 26.2 Hz), and 67.1 ppm; and HRMS: m/z calculated:
296.0431, found: 296.0442.
3-Thiophen-2yl-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide (3q)
Yellow solid; Mp. 128–130◦C; Yield 81%. 1H NMR (400 MHz, DMSO-d6) δ: 8.13
(d, J = 11.7 Hz, 1H), 7.13 (d, J = 5.1 Hz, 1H), 7.57–7.51 (m, 2H), 7.45 (d, J = 3.2 Hz,
1H), 7.37–7.33 (m, 1H), 7.13–7.11 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.81 (t, J = 7.6 Hz,
1H) 6.10 (d, J = 11.3 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 143.5, 140.0,
132.9, 126.9, 126.6, 123.6, 121.8, 117.1, 116.5, and 64.1 ppm; and HRMS: m/z calculated:
266.0184, found: 266.0186.
3-Pyridin-2yl-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide (3r)
Brown solid; Mp. 158–160◦C; Yield 78%. 1H NMR (400 MHz, DMSO-d6) δ: 8.66
(d, J = 4.4 Hz, 1H), 8.04–7.94 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.56–7.47 (m, 3H),
7.34 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 5.88 (d, J =
12.0 Hz, 1H) ppm; 13C NMR (100.5 MHz, CDCl3) δC: 155.1, 148.7, 143.4, 137.4, 132.9,
124.2, 123.7, 121.7, 116.2 (d, J = 18.2 Hz), and 68.59 ppm; and HRMS: m/z calculated:
261.0572, found: 261.0574.
3-(4-Nitro-Phenyl)-3,4-Dihydro-2H-Benzo[1,2,4]thiadiazine 1,1-Dioxide
(3s)
1
Pale white solid; Mp. 230–232◦C; Yield 96%. H NMR (400 MHz, DMSO-d6) δ:
8.33 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 11.7 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.56–7.53
(m, 2H), 7.37–7.33 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 7.3 Hz, 1H), 5.99 (d,
J = 11.7 Hz, 1H) ppm; 13C NMR (100.5 MHz, DMSO-d6) δC: 147.8, 144.1, 143.6, 132.9,
129.0, 123.7, 121.8, 117.1, 116.5, and 67.3 ppm.
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