Transition metal-catalyzed C–H functionalization of arylacetic acids for the synthesis of benzothiadiazine 1,1-dioxides

Article abstract of DOI:10.1016/j.tetlet.2019.02.031

Copper-catalyzed practical route for the synthesis of benzothiadiazine 1,1-dioxides has been developed. The method involves C–H functionalization of arylacetic acids to form aromatic aldehydes and their subsequent condensation with 2-aminobenzenesulfonami

Full text of DOI:10.1016/j.tetlet.2019.02.031

Accepted Manuscript
Transition Metal-Catalyzed C-H Functionalization of Arylacetic Acids for the
Synthesis of Benzothiadiazine 1,1-dioxides
Bhausaheb N. Patil, Jatin J. Lade, Aniket S. Karpe, B.B. Pownthurai, Kamlesh
S. Vadagaonkar, V. Mohanasrinivasan, Atul C. Chaskar
PII:
S0040-4039(19)30163-7
https://doi.org/10.1016/j.tetlet.2019.02.031
TETL 50625
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 January 2019
15 February 2019
17 February 2019
Please cite this article as: Patil, B.N., Lade, J.J., Karpe, A.S., Pownthurai, B.B., Vadagaonkar, K.S.,
Mohanasrinivasan, V., Chaskar, A.C., Transition Metal-Catalyzed C-H Functionalization of Arylacetic Acids for
the Synthesis of Benzothiadiazine 1,1-dioxides, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.02.031
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Graphical Abstract
Transition Metal-Catalyzed C-H Functionalization of
Arylacetic Acids for the Synthesis of Benzothiadiazine
1,1-dioxides
Leave this area blank for abstract info.
Bhausaheb N. Patil,a† Jatin J. Lade,a† Aniket S. Karpe,a B. Pownthurai B,a Kamlesh S. Vadagaonkar, b* V.
Mohanasrinivasan,c and Atul C. Chaskar a*

1
Tetrahedron Letters
Transition Metal-Catalyzed C-H Functionalization of Arylacetic Acids for the
Synthesis of Benzothiadiazine 1,1-dioxides.
Bhausaheb N. Patila†, Jatin J. Ladea†, Aniket S. Karpea, B. Pownthurai Ba, Kamlesh S. Vadagaonkarb,* V.
Mohanasrinivasanc, and Atul C. Chaskar a,*
aNational Centre for Nanosciences and Nanotechnology, University of Mumbai, Vidyanagari, Mumbai-400098, Maharashtra, India.
bDepartment of Dyestuff Technology, Institute of Chemical Technology, Mumbai-400019, Maharashtra, India.
cDepartment of Biomedical Sciences, Vellore Institute of Technology, 632014, Tamil Nadu, India.
Tel.: +91-7507375261; E-mail: achaskar25@gmail.com, vadgaonkarks@gmail.com,
†Authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper-catalyzed practical route for the synthesis of benzothiadiazine 1,1-dioxides has been
developed. The method involves C-H functionalization of arylacetic acids to form aromatic
aldehydes and their subsequent condensation with 2-aminobenzenesulfonamide. This functional
group tolerant approach furnished benzothiadiazine 1,1-dioxide derivatives in good to excellent
yields. Broad substrate scope, inexpensive catalyst and high product yields are notable features
of this protocol.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Arylacetic acids
Benzothiadiazine 1,1-dioxides
C-H Functionalization
Transition metal-catalyzed
Introduction
report for their synthesis was published in 1979 by M. Okano et
al.
using
aryl
carboxylic
acids
and
2-
aminobenzenesulfonamide.13 Thereafter, various reports were
published for the synthesis of benzothiadiazine 1,1-dioxides
using aryl carboxylic acids,14 aldehydes,15 methylarenes16 and
benzyl alcohols.17 Su and co-workers synthesized
benzothiadiazine 1,1-dioxides via reductive cyclization of N,N-
diethyl o-nitro benzenesulfonamide with nitriles using SmI2 as
a reducing agent.18 Another method involving condensation of
o-halosubstituted benzenesulfonyl chloride with amidines was
reported by Lukin et al.19 In 2015, Laha and co-workers
developed potassium persulfate-mediated cyclization of N-aryl
benzylamines followed by their oxidation to give
benzothiadiazine 1,1-dioxides.20
Transition metal-catalyzed C-H functionalization has been
highly explored field over the last decade.1 Construction of
various heterocyclic moieties with ubiquitous biological and
pharmaceutical applications has always been an attractive
research area for the biochemists. Benzothiadiazine 1,1-dioxide
and its analogues are found to be key structural scaffolds in
many medicinally important compounds.2 They have shown
many biological activities such as antiviral,3 antimicrobial,4
antihypertensive5 and diuretic.6 They have been used as KATP
channel activators[7] and are known to display anticancer8
properties. Amongst them, cyclothiazide (I) is one of the most
potent compounds in vitro that by removal of AMPA receptors
desensitization enhances synaptic transmission.9 Prime
analogues of cyclothiazide can manage to reach the central
nervous system without any peripheral effects. IDRA-21 (II)
has shown an inhibitory effect on AMPA (α-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid) receptor desensitization
and improves cognition in animals.10 3,4-Dihydro-2H-1,2,4-
benzothiadiazine 1,1-dioxides constitute the most investigated
chemical class. BPAM 321 (III) is a very interesting scaffold as
AMPA receptor potentiators.11 BPDZ 73 (IV) (7-chloro-3-
isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) has
been identified as one of the most potent pancreatic KATP
channel activator reported to date, whereas compound V is a
potent anti-tubercular agent.12
Figure 1. Examples of benzothiadiazine 1,1-dioxide drugs.
In last few decades, many methods have been developed
for the synthesis of benzothiadiazine 1,1-dioxides. The first

2
Although these methods offer benzothiadiazine 1,1-dioxides
in moderate to good yields, they suffer from drawbacks such as
use of toxic reagents, stoichiometric quantity of catalysts, low
product yields etc. Thus, development of novel route which
offers advantages such as use of inexpensive catalyst, easy
availability of starting materials and operational simplicity etc.
is still desirable.
65% yields, respectively (Table 1, entry 2). Encouraged with
this result, we increased the amount of Cs2CO3 (1.0 equiv.)
which interestingly afforded 4a in 78% yield (Table 1, entry 3).
Further elevation in temperature did not show any improvement
in the reaction yields of 3a and 4a (Table 1, entry 4). Use of
K2CO3 and Na2CO3 as bases for this reaction afforded lower
yields of 4a (Table 1, entries 5 and 6). We also employed
different solvents such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA) and 1,4-dioxane but none of
these solvents could enhance the yield of 3a and 4a (Table 1,
entries 7-9). We also screened different copper catalysts such as
CuCl2, CuSO4 and CuI but surprisingly all of them could afford
3a and 4a in moderate yields (Table 1, entries 10, 11 and 12),
whereas the use of Cu(OAc)2 (20 mol%) did not improve the
yield of 3a as well as 4a respectively (Table 1, entry 13). The
reaction by using 2.0 equiv. of Cs2CO3 could furnish 4a in
moderate yield (69%) (Table 1, entry 14), while the reaction
without Cu(OAc)2 failed to give product 4a (Table 1, entry 15).
Thus, the optimization studies concluded that Cu(OAc)2 (10
In continuation with our interest in the development of
bioactive heterocycles,21 we herein report synthesis of
benzothiadiazine 1,1-dioxides using copper-catalyzed C-H
functionalization of arylacetic acids to form aromatic aldehydes
followed
by
their
condensation
with
2-
aminobenzenesulfonamide.
We initiated our optimization studies by the reaction of 2-
aminobenzenesulfonamide 1a (1.0 equiv.) with phenylacetic
acid 2a (1.0 equiv.) using Cu(OAc)2 (10 mol%) as a catalyst
and DMSO as a solvent at 100 oC for 12 h under oxygen
atmosphere which gave the product 3a in 62% yield. The same
reaction was repeated with addition of Cs2CO3 (0.5 equiv.) as a
base which resulted in formation of 4a in 60% yield (Table 1,
entry 1). To improve the yield of 3a and 4a, we carried out both
o
mol%) in DMSO at 110 C and Cu(OAc)2 (10 mol%), Cs2CO3
(1.0 equiv.) in DMSO at 110 oC for 12h are the suitable
reaction conditions for the synthesis of 3a and 4a, respectively.
o
the reactions at 110 C which offered 3a and 4a in 80% and
Table 1. Optimization of reaction conditions[a]
Yield (%)
Entry
Catalyst (mol%)
Base (equiv.)[b]
Solvent
Temp. (°C)
3a[c]
62
80
81
80
65
49
67
71
31
63
69
68
80
63
nr
4a[d]
60
65
78
77
62
45
53
56
15
57
64
62
77
69
nr
1
2
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OAc)2 (10)
CuCl2 (10)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
K2CO3 (1.0)
Na2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
110
110
120
110
110
110
110
110
110
110
110
110
110
110
3
4
5
6
7
8
DMA
9
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
11
12
13
14
15
CuSO4 (10)
CuI (10)
Cu(OAc)2 (20)
Cu(OAc)2 (10)
-
[a]Reaction conditions: 2-aminobenzenesulphonamide 1a (1.0 equiv.), phenylacetic acid 2a (1.0 equiv.), catalyst (10-20 mol%) and base (0.5-1.0
equiv.) for 12 h at 100-120 oC.
[b]Base screening for the synthesis of 4a.
[c]Isolated yields of 3a in the absence of a base.
[d]Isolated yields of 4a.
nr = No reaction.

3
The scope of current protocol with optimized reaction conditions
is shown in Table 2. Various arylacetic acids 2 were investigated
in the reaction with 2-aminobenzenesulfonamide 1a; the
corresponding products were obtained in good yields.
71-74%. 4-Methyl phenylacetic acid 2h formed the
corresponding product 3h in 69% yield, while 3-phenoxy
phenylacetic acid 2j on reaction with 1a gave product 3j in 67%
yield. 4-Nitro phenylacetic acid 2l furnished product 3f in 77%
yield.
Table.2. Substrate scope study with various arylacetic acids.a
Furthermore, oxidation of 3a into 4a (78% yield) took place
smoothly when 2-aminobenzenesulfonamide 1a was treated with
phenylacetic acid in the presence of Cs2CO3 (1.0 equiv.) which is
described in Table 3. Halogen substituted arylacetic acids
furnished corresponding oxidized products 4b-4g in good yields
(63-76%). Arylacetic acids bearing electron donating groups such
as 4-methyl, 4-methoxy and 3-phenoxy afforded respective
products 4h-4j in good yields (67-79%). Arylacetic acids bearing
electron withdrawing groups such as 4-CF3 and 4-NO2 offered
corresponding products 4k and 4l in 85% and 83% yields,
respectively. We also carried out this reaction using different
heteroarylacetic acids. 2-aminobenzenesulfonamide reacted
easily with thiophene-2-acetic acid and furan-2-acetic acid to
give corresponding benzothiadiazine 1,1-dioxides 4m and 4n in
64% and 69% yields, respectively.
aReaction conditions: 1a (1.0 equiv.), 2 (1.0 equiv.), Cu(OAc)2 (10 mol%)
To get insight into the reaction mechanism, we carried out some
control experiments. Initially, the reaction of phenylacetic acid
(2a) was performed using Cu(OAc)2 and DMSO which led to the
formation of benzaldehyde [Scheme 3(a)] (92%), while same
reaction in the presence 2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) failed to give benzaldehyde [Scheme 3(b)]. The
reaction of 2-aminobenzenesulfonamide (1a) with phenylacetic
acid 2a was also carried out using Cu(OAc)2 and DMSO as well
as Cs2CO3 with and without TEMPO.
and DMSO (2.0 mL) at 110 oC under O2 atm. for 12 h.
The reaction of 2-aminobenzenesulfonamide 1a with
phenylacetic acid 2a occurred smoothly to give corresponding
product 3a in 81% yield, whereas halo-substituted arylacetic
acids 2c, 2f and 2g offered yields of 3c, 3f and 3g ranging from
Table 3. Substrate scope study with various arylacetic acids.a
Scheme 3. Control experiments.
aReaction conditions: 1a (1.0 equiv.), 2 (1.0 equiv.), Cu(OAc)2 (10 mol%),
Cs2CO3 (1.0 equiv.) and DMSO (2.0 mL) at 110 oC under O2 atm. for 12 h.

4
Tetrahedron
The reaction in the absence of TEMPO resulted in the
References and notes
formation of oxidized product 4a in 78% yield [Scheme 3 (c)],
while the reaction in the presence of TEMPO did not form the
product 4a [Scheme 3 (d)]. We also carried out the reactions of
2-aminobenzenesulfonamide (1) with benzaldehyde (A) as well
as oxo-2-phenylacetic acid (B) which provided product 4a in
80% and 83% respectively. These control experiments suggested
that reaction proceeds through the formation of oxo-2-
phenylacetic acid as an intermediate which upon decarboxylation
gives benzaldehyde.
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mechanism is depicted in Scheme 4. Initially, the conversion of
phenylacetic acid (2a) into benzaldehyde (A) occurs through
aerobic
oxidative
decarboxylation.22
Then,
2-
aminobenzenesulfonamide (1a) on condensation with
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to give compound 3a. Further oxidation of 3a takes place in the
presence of a base to afford corresponding benzothiadiazine 1,1-
dioxide 4a.
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Scheme 4. Plausible reaction mechanism.
In summary, we have developed a novel and efficient route for
the synthesis of benzothiadiazine 1,1-dioxides via transition
metal-catalysed C-H functionalization of arylacetic acids to form
aromatic aldehydes followed by their condensation with 2-
aminobenzenesulfonamide. Use of readily available starting
materials, cheap catalyst, wide substrate scope and good to
excellent yields of the products are prominent features of this
method. A wide range of functional possibilities are open for the
design and development of biologically potent benzothiadiazine
1,1-dioxide derivatives.
Acknowledgments
13. Tanimoto, S.; Yoshida, N.; Sugimoto, T.; Okano, M. Bull. Inst.
Chem. 1979, 57, 381.
B.N.P. and J.J.L. thank University Grants Commission
(UGC), New Delhi, India for providing fellowships. K.S.V. and
A.C.C. thank DST-SERB, India (sanction no. SB/FT/CS-
147/2013) for financial support. A.C.C. thanks DRDO, India
(sanction no. ERIP/ER/1503212/M/01/1666) for financial
support.
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Supporting information for this article is available online at
http://dx.doi.org/.

5
20. Laha, J. K.; Tummalapalli, K. S. S.; Nair, A.; Patel, N. J. Org.
Chem. 2015, 80, 11351.
12 h under O2 atmosphere. After completion of reaction
(monitored by TLC), the reaction mass was cooled to room
temperature. To this reaction mixture was added water (10 mL)
and it was extracted with ethylacetate (2×10 mL). The organic
layer after separation was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue obtained was
purified by column chromatography on 60:120 mesh silica gel
using 5% ethyl acetate:n-hexane as the eluent to afford the pure
product 3a (yield 81%, white solid).
21. a) Vadagaonkar, K. S.; Murugan, K.; Chaskar, A. C.; Bhate, P. M.
RSC Adv. 2014, 4, 34056. b) Vadagaonkar, K. S.; Kalmode, H. P.;
Prakash, S.; Chaskar, A. C. New J. Chem. 2015, 39, 3639. c)
Kalmode, H. P.; Vadagaonkar, K. S.; Murugan, K.; Chaskar, A. C.
New J. Chem. 2015, 39, 4631. d) Vadagaonkar, K. S.; Kalmode,
H. P.; Murugan, K.; Chaskar, A. C. RSC Adv. 2015, 5, 5580. e)
Kalmode, H. P.; Vadagaonkar, K. S.; Murugan, K.; Prakash, S.;
Chaskar, A. C. RSC Adv. 2015, 5, 35166. f) Lade, J. J.; Patil, B.
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24. Experimental procedure for the synthesis of 4a:
A clean and dry round bottom flask with magnetic needle is
charged with phenylacetic acid 2a (1 equiv.) and Cu(OAc)2 (10
mol%) in DMSO (2.0 mL). The resulting mixture was purged by
O2 with subsequent addition of 2-aminobenzenesulfonamide 1a
(1.0 equiv.) and Cs2CO3 (1.0 equiv.) The resulting mixture was
then heated at 110 oC for 12 h under O2 atmosphere. After
completion of reaction (monitored by TLC), the reaction mass was
cooled to room temperature. To this reaction mixture was added
water (10 mL) and it was extracted with ethylacetate (2×10 mL).
The organic layer after separation was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue
obtained was purified by column chromatography on 60:120 mesh
silica gel using 20% ethyl acetate:n-hexane as the eluent to afford
the pure product 4a (yield 78%, white solid).
22. a) Feng, Q.; Song, Q. J. Org. Chem. 2014, 79, 1867 b) Song, Q.;
Feng, Q.; Zhou, M. Org. Lett. 2013, 15, 5990.
23. Experimental procedure for the synthesis of 3a:
A clean and dry round bottom flask with magnetic needle is
charged with phenylacetic acid 2a (1.0 equiv.) and Cu(OAc)2 (10
mol%) in DMSO (2.0 mL). The resulting mixture was purged by
O2 with subsequent addition of 2-aminobenzenesulfonamide 1a
o
(1.0 equiv.). The resulting mixture was then heated at 110 C for

6
Tetrahedron
Highlights of the work
 Domino protocol for the synthesis of
benzothiadiazine 1,1-dioxides.
 Transition Metal Catalyzed C-H Activation
of Arylacetic Acids.
 Good to excellent yields of the products
with operational simplicity.
 Readily available and inexpensive starting
materials.
 Wide range of functional possibilities.