Microwave-assisted direct synthesis of 4H-1,2,4-benzothiadiazine 1,1-dioxide derivatives

Article abstract of DOI:10.1080/10426507.2011.590171

We describe a rapid and convenient methodology for the preparation of diverse 3-aryl and 3-trifluoromethyl 4H-1,2,4-benzothiadiazine-1,1-dioxides in a one-pot microwavepromoted reaction between 2-aminobenzenesulfonamides and benzaldehydes, trifluoroacetic acid or benzoic acids. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2011.590171

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Phosphorus, Sulfur, and Silicon and the
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Microwave-Assisted Direct Synthesis of
4H-1,2,4-Benzothiadiazine 1,1-Dioxide
Derivatives
Jelem Restrepo a , José Salazar a & Simón E. López a
a Laboratory of Heterocycles and Medicinal Chemistry, Department
of Chemistry, Universidad Simón Bolívar, Apartado, 89000, Venezuela
Version of record first published: 31 Oct 2011.
To cite this article: Jelem Restrepo , José Salazar & Simón E. López (2011): Microwave-Assisted
Direct Synthesis of 4H-1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 186:12, 2311-2320
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Phosphorus, Sulfur, and Silicon, 186:2311–2320, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.590171
MICROWAVE-ASSISTED DIRECT SYNTHESIS
OF 4H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE
DERIVATIVES
Jelem Restrepo, Jose´ Salazar, and Simo´n E. Lo´pez*
Laboratory of Heterocycles and Medicinal Chemistry, Department of Chemistry,
Universidad Simo´n Bol´ıvar, Apartado 89000, Venezuela
GRAPHICAL ABSTRACT
Abstract We describe a rapid and convenient methodology for the preparation of diverse
3-aryl and 3-trifluoromethyl 4H-1,2,4-benzothiadiazine-1,1-dioxides in a one-pot microwave-
promoted reaction between 2-aminobenzenesulfonamides and benzaldehydes, trifluoroacetic
acid or benzoic acids.
Keywords 1,2,4-Benzothiadiazines; sodium hydrogen sulfite; microwave irradiation; 2-
aminobenzenesulfonamides; trifluoroacetic acid; benzoic acids
Received 19 April 2011; accepted 16 May 2011.
The authors would like to thank Decanato de Investigacio´n y Desarrollo (Universidad Simo´n Bol´ıvar,
Caracas, Venezuela) and Fonacit (Project S1-99000020, Caracas-Venezuela) for its financial support, as well as
to TSU Noelani Cigu¨ela at Laboratorio de Resonancia Magne´tica Nuclear (Laboratorio B, Universidad Simo´n
Bol´ıvar, Caracas) for the NMR spectra. We also thank MSc Sara Pekerar (Laboratorio de RMN, IVIC, Venezuela)
for the NOESY spectra. J. Restrepo thanks Departamento de Qu´ımica (Universidad Simo´n Bol´ıvar, Caracas) and
Fonacit (Caracas, Venezuela) for a doctoral fellowship.
Address correspondence to Simo´n E. Lo´pez, Laboratory of Heterocycles and Medicinal Chemistry, Depart-
ment of Chemistry, Universidad Simo´n Bol´ıvar, Valle de Sartenejas, Baruta. Caracas 1080-A, Apartado 89000,
Venezuela. E-mail: slopez@usb.ve
2311

2312
J. RESTREPO ET AL.
INTRODUCTION
Microwave-assisted organic synthesis is a highly useful tool and a continuously
growing area over the last years, with a wide application to the synthesis of hetero-
cyclic compounds.1 Its use provides diminished reaction times, usually increased yields,
as well as reproducible results facilitating the rapid development of new reactions.2 1,2,4-
Benzothiadiazines have attracted the scientific community for over 50 years, mainly be-
cause of their interesting biological activities, which include diuretic,3 antihypertensive,4
α1-adrenoceptor antagonists,5 KATP channel activators,6 and anticancer;7 however, their
preparation through microwave-assisted synthesis has not been well explored8 a remarkable
difference when compared with their isoster analogs 4-quinazolinones.9 Classical synthesis
of 3-substituted alkyl and aryl 1,2,4-benzothiadiazine-1,1-dioxides includes their prepara-
tion by condensation of a 2-aminobenzenesulfonamide with an alkyl-orthoformate10,11 and
a two-step procedure that involves the preparation of a 2-acylaminobenzenesulfonamide
intermediate with reactive carboxylic acid derivatives followed by a cyclodehydration pro-
moted by heating with base.11,12 Other much less common procedures are the direct cyclo-
condensation with amidines at elevated temperatures,13 and the cyclodehydrogenation with
some aldehydes in the presence of sodium hydrogen sulfite.14 Recently, an iron-catalyzed
(FeCl3) method for the cascade synthesis of 1,2,4-benzothiadiazine-1,1-dioxides has been
reported.15 We have described the preparation and biological evaluation of novel 3,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide derivatives16 and explored the preparation
of 3-trifluoromethyl-4H-1,2,4-benzothiadiazines by the promoted direct condensation of
2-aminobenzenesulfonamides with trifluoroacetic acid (TFA) using polyphosphoric acid
trimethylsilyl ester (PPSE).17
RESULTS AND DISCUSSION
Intrigued by our previously obtained results concerning to the lacking of the 3,4
double-bond direct generation for desired 2H-1,2,4-benzothiadiazines by the attempted cy-
clodehydrogenation reaction of 2-aminobenzenesulfonamides with substituted benzalde-
hydes using sodium hydrogen sulfite,16 we now decided to explore such reactions un-
der microwave irradiation as well as the direct condensation–cyclodehydration between
2-aminobenzenesulfonamides and carboxylic acids (Figure 1). Initially, we started to op-
timize the conditions for the direct preparation of the 3-aryl-4H-1,2,4-benzothiadiazine-
1,1-dioxide 2a using a microwave-promoted cyclodehydrogenation reaction between 2-
aminobenzenesulfonamide 1a and benzaldehyde (Table 1). As seen, it was necessary to use
an irradiation time of 17 min and 2.5 equivalents of sodium hydrogen sulfite to complete
the full conversion to desired 4H-1,2,4-benzothiadiazine 2a in 85% yield (entry 5), instead
of the 3,4-dihydro analog 3c (entries 1–4). Once optimized, we proceed to prepare a set of
seven 4H-1,2,4-benzothiadiazines (2a–g) in good to excellent yields (80%–92%, Table 2,
Method A). Different electron-donating and electron-withdrawing groups located at meta
and para positions of the 3-aryl ring were employed giving good results; even with an
ortho–chloro substituent (2g), the reaction worked satisfactorily. Knowing the reaction is
thought to pass through the 3,4-dihydro intermediate before oxidation to the 4H-1,2,4-
benzothiadiazine,14 we proceeded to test the microwave-promoted direct conversion of the
isolated dihydro analog 3a into the 4H-1,2,4-benzothiadiazine 2c (Tables 3 and 4), finding
the required conditions to fulfill the conversion in almost quantitative yield to be 1.2 equiv-
alents of sodium hydrogen sulfite and an irradiation time of 7 min. A possible mechanism

MW-ASSISTED DIRECT SYNTHESIS OF 4H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE 2313
Figure 1 Preparation of 4H-1,2,4-benzothiadiazine 1,1-dioxide derivatives from 2-aminobenzenesulfonamides
by microwave irradiation.
Figure 2 A proposed mechanism for the dehydrogenation step to form desired 4H-1,2,4-benzothiadiazines.
Table 1 Optimization conditions for the microwave-promoted synthesis of 4H-1,2,4-benzothiadiazine-1,1-
dioxides from 2-aminobenzenesulfonamides and benzaldehydes using sodium hydrogen sulfite
1a (equivalent): NaHSO3
Entry
(equivalent)
Time (min)
Yield (%)a
1
2
3
4
5
1:1
1:1.5
1:2
1:2
1:2.5
8
8
8
12
17
3c (30)
3c (43)
3c (65)
3c (80)
2a (85)
aYields of isolated products. Compound 2a was only detected in entry 5.

2314
J. RESTREPO ET AL.
Table 2 One-pot microwave-promoted synthesis of 4H-1,2,4-benzothiadiazine-1,1-dioxides from 2-
aminobenzenesulfonamides and benzaldehydes using sodium hydrogen sulfite (Method A) or benzoic acids
(Method B)
Method A
yield (%)
Method B
yield (%)a
Mp (◦C)
(Lit. mp)
Compounds
X
Y
R
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
Cl
H
85
80
85
90
92
82
85
90
93
87
93
–
300–302 (302–303)19
337–339 (334–336)20
335–337
4ꢀ-Me
4ꢀ-Me
4ꢀ-Cl
3ꢀ-F
Cl
Cl
Cl
Br
Cl
285–287
339–340
190–192
271–272
3ꢀ-Me
2ꢀ-Cl
86
80
2g
a10N hydrochloric acid (5% mol) was added to the irradiated reaction mixture.
Table 3 Optimization conditions for the microwave-promoted dehydrogenation of 3-aryl-3,4-dihydro-1,2,4-
benzothiadiazine-1,1-dioxides to 3-aryl-4H-1,2,4-benzothiadiazine-1,1-dioxides using sodium hydrogen sulfite
3b (equivalent):
NaHSO3 (equivalent)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
1:0.5
1:0.5
1:1
1:1.2
1:1.2
2
4
3
3
7
b
b
b
3a (60):2c (38)c
2c (99)
aYields of isolated products.bOnly compound 3a could be detected (1H NMR).cFollowing separation using
column chromatography.

MW-ASSISTED DIRECT SYNTHESIS OF 4H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE 2315
Table 4 Direct-microwave-promoted dehydrogenation of 3-aryl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-
dioxides to 3-aryl-4H-1,2,4-benzothiadiazine-1,1-dioxides using sodium hydrogen sulfite
Compounds
R
Yield (%)
Mp (◦C)
2c
2d
4ꢀ-Me
4ꢀ-Cl
99
98
335–337
285–287
for this reaction is given (Figure 2), where the decomposition of sodium hydrogen sulfite
under heating generates sulfur dioxide,18 which forms an adduct with the nitrogen atom
of the sulfonamide on the dihydro intermediate, and then eliminates hyposulfurous acid to
produce the 3,4 double bond of desired 4H-1,2,4-benzothiadiazines.
Turning our attention to a direct condensation–cyclodehydration reaction between 2-
aminobenzenesulfonamides with carboxylic acids, we tried to avoid the classical synthesis
that includes the isolation of a 2-acylaminobenzenesulfonamide key intermediate before al-
kaline cyclization,11,12 doing a microwave irradiation of 2-aminobenzenesulfonamides with
benzoic acid (Table 2, Method B) and TFA (Table 7). Optimization experiments gave inter-
esting results when a 10N hydrochloric acid solution (5% mol) was added as a catalyst to rise
up the yields to 90% with an irradiation time of 18 min and 2 equivalents of the benzoic acid
(entry 6, Table 5); thus, a series of 4H-1,2,4-benzothiadiazine-1,1-dioxides (2a–d, 2f–g)
were prepared by using these conditions in good yields (Table 2, Method B). Finally, guided
Table 5 Optimization conditions for the microwave-promoted synthesis of 3-aryl-4H-1,2,4-benzothiadiazine-
1,1-dioxides from 2-aminobenzenesulfonamides and benzoic acids
Entry
1a: benzoic acid
Time (min)
Yield (%)a
1
2
3
4
5
6
1:1
1:1.2
1:1.3
1:1.5
1:1.5b
1:2b
6
6
9
9
18
18
4a (65)
4a (70)
4a (60)20: 2a (30)
4a (40): 2a (50)
2a (80)
2a (90)
aYields of isolated products.b10N hydrochloric acid (5% mol) was added to the irradiated reaction mixture.

2316
J. RESTREPO ET AL.
Table 6 Optimization conditions for the microwave-promoted synthesis of 3-trifluoromethyl-4H-1,2,4-
benzothiadiazine-1,1-dioxides from 2-aminobenzenesulfonamides and TFA
1b (equivalent):
CF3CO2H (equivalent)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
1:1
1:1
1:2
1:2
1:2.5
2
4
6
9
13
5a (40)
5a (39)
5a (45)
5a (34)17: 2i (43)
2i (56)
aYields of isolated products.
by our previous experience in the synthesis of 3-trifluomethyl-1,2,4-benzohiadiazine-1,1-
dioxide derivatives by a PPSE-promoted trifluoroacetylation–cyclodehydration reaction
of anilines with TFA,16 we extended the above methodology to the preparation of 3-
trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxides 2h–j, requiring an irradiation time of
13 min (13 irradiation sets of 1 min each) and 2.5 equivalents of TFA to perform this
reaction (Table 6), giving the desired heterocyclic compounds only in moderate yields
(Table 7). Assigned 4H-isomeric form of prepared 1,2,4-benzothiadiazines was confirmed
by NOESY NMR experiments, by the observation of an spatial correlation between the
nitrogen H-4 and the ring H-5 hydrogen atoms of these compounds in hexadeuterated
dimethylsulfoxide solutions. Due to the importance of trifluoromethyl-substituted hetero-
cyclic compounds,21,22 an extension of this reaction using other trifluoroacetyl intermediates
will also be explored for the preparation of new trifluoromethyl heterocycles.
Table 7 One-pot microwave-promoted synthesis of 3-trifluoromethyl-4H-1,2,4-benzothiadiazine-1,1-dioxides
from 2-aminobenzenesulfonamides and TFA
Yield
(%)
Mp (◦C)
(Lit. mp)
Compounds
X
Y
2h
2i
2j
Cl
Br
Cl
H
H
Cl
53
56
60
245–246
230–232 (230–232)17
270–272

MW-ASSISTED DIRECT SYNTHESIS OF 4H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE 2317
CONCLUSION
We have developed a rapid and convenient methodology for the preparation
of different 3-aryl and 3-trifluoromethyl 4H-1,2,4-benzothiadiazine-1,1-dioxides
in a one-pot microwave-promoted reaction from readily available starting mate-
rials, such as 2-aminobenzenesulfonamides, benzoic acids, and TFA. High yields
of desired 2-aryl 4H-1,2,4-benzothiadiazines were obtained for their preparation
from 2-aminobenzenesulfonamides and benzaldehydes or benzoic acids under the
developed protocols, but moderate yields were obtained for 3-trifluoromethyl-4H-1,2,4-
benzothiadiazines.
EXPERIMENTAL
Melting points were determined in a Fischer–Johns micro hot-stage apparatus and
were uncorrected. Microwave irradiation was made using a GoldStar microwave domestic
oven, model MA-690M (600-W power, 2450-MHz, and cycled irradiation multimode
employs a time-slicing method, where the maximum power is applied for time intervals
that are proportional to the power which the user sets on the controller); the reactions were
performed in a 10-mL-capped conical flask that was put into a teflon cylinder container (5
cm diameter × 15 cm height). NMR spectra were obtained on a JEOL Eclipse Plus (1H
NMR spectra were recorded at 400 MHz, 13C NMR at 100 MHz, and 19F NMR spectra
at 376 MHz) and Bruker Avance-500 (500 MHz, NOESY experiments) spectrometers
in hexadeuterated dimethylsulfoxide (DMSO-d6). Chemical shifts (δ) are given in ppm
versus tetramethylsilane (TMS) (1H NMR, 13C NMR) or CFCl3 (19F NMR) used as internal
references. Coupling constants are given in hertz. The IR spectra were recorded as KBr
discs using an FTIR Nicolet Magna Spectrometer. Elemental analyses of new synthesized
compounds were performed on a Perkin Elmer 2400 CHN analyzer; results fell in the range
ꢁR
of 0.4% of the required theoretical values. Silica gel plates ALUGRAM SIL G/UV254
(Macherey-Nagel GmbH & Co., Germany) were used for TLC testing. Reagents were
obtained from Aldrich (Milwaukee, MI, USA) or Merck (Darmstadt, Germany) and used
without further purification. 2-Aminobenzenesulfonamides 1a–d were easily obtained from
substituted anilines as reported.23 All products were obtained in high purity as indicated by
TLC, 1H NMR, and elemental analysis.
General Procedure for the Preparation of 3-Aryl-4H-1,2,4-
Benzothiadiazine-1,1-Dioxides 2a–g from 2-Aminobenzenesulfonamides and
Benzaldehydes Using Sodium Hydrogen Sulfite (Method A)
A mixture of the corresponding 2-aminobenzenesulfonamide 1a–d (16 mg; 0.062
mmol), appropriate substituted benzaldehyde (0.093 mmol), sodium hydrogen sulfite (29
mg; 0.155 mmol), and dimethylacetamide (0.5 mL) was microwave-irradiated at several
stages (2–3 min each) to complete the indicated time. An initial microwave-promoted
preheating of 30 s (70% power) was needed in all cases, followed by seven irradiation
steps of 2–3 min each (90% power). The reaction was followed by TLC until the starting 5-
bromo-aminobenzenesulfonamide was consumed. After being cooled to room temperature,
an amount of ice water was added to the resulting mixture to precipitate the products that
were then filtered and washed three times with cool water and dried in vacuo to give
compounds 2a–g.

2318
J. RESTREPO ET AL.
7-Chloro-3-(4-methylphenyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide (2c): Beige
solid, mp 335 ◦C–337 ◦C. 1H NMR: δ 11.68 (s, 1H, NH), 7.77 (d, 2H, ArH, J = 8.1 Hz,
H3ꢀ, H5ꢀ), 7.62 (d, 1H, ArH, J = 2.2 Hz, H8), 7.40 (d, 1H, ArH, J = 8.8 Hz, H6), 7.29
(dd, 1H, ArH, J = 2.2 Hz, J = 8.8 Hz, H5), 7.11 (d, 2H, ArH, J = 8.1 Hz, H2ꢀ, H6ꢀ),
2.22 (s, 3H, CH3); 13C NMR: δ 143.7, 134.5, 132.8, 130.9, 129.3, 128.9, 128.5, 123.3,
120.2, 118.6, 21.5; IR (KBr, cm−1) υ: 3310 (NH), 1360 (SO2), 1156 (SO2); Anal. Calcd.
for C14H11ClN2O2S; C, 54.81; H, 3.61; N, 9.13. Found: C, 54.58; H, 3.74; N, 9.25.
7-Chloro-3-(4-c◦hloroph◦enyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide
(2d):
1
Brown solid, mp 285 C–287 C. H NMR: δ 11.71 (s, 1H, NH), 7.46 (d, 1H, ArH, J =
8.1 Hz, H3ꢀ, H5ꢀ), 7.18 (d, 1H, ArH, J = 2.0 Hz, H8), 7.00 (m, 2H, ArH), 6.95 (d, 2H,
ArH, J = 8.1 Hz, H2ꢀ,6ꢀ); 13C NMR: δ 153.7, 138.5, 134.1, 132.8, 130.7, 129.9, 129.7,
128.6, 122.6, 122.3, 120.3; IR (KBr, cm−1) υ: 3315 (NH), 1360 (SO2), 1158 (SO2); Anal.
Calcd. for C13H8Cl2N2O2S; C, 47.72; H, 2.46; N, 8.56. Found: C, 47.93; H, 2.52; N, 8.45.
7-Chloro-3-(3-fluorophenyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide (2e): Brown
solid, mp 339 ◦C–340 ◦C. 1H NMR: δ 11.76 (s, 1H, NH), 7.64 (m, 3H, ArH), 7.28 (m, 3H,
ArH), 7.08 (m, 1H, ArH); 13C NMR: δ 154.6, 134.2, 133.0, 131.4, 130.5 (d, J = 8.4 Hz),
124.4, 123.5, 122.9, 120.2, 119.9 (d, J = 20.6 Hz), 116.1, 115.5. 19F NMR: δ −111.5; IR
(KBr, cm−1) υ: 3316 (NH), 1368 (SO2), 1167 (SO2); Anal. Calcd. for C13H8ClFN2O2S; C,
50.25; H, 2.60; N, 9.02. Found: C, 50.08; H, 2.73; N, 8.89.
7-Bromo-3-(3-methylphenyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide (2f): Beige
solid, mp 190 ◦C–192 ◦C. 1H NMR: δ 12.29 (s, 1H, NH), 8.01 (d, 1H, ArH, J = 2.0 Hz),
7.93 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz), 7.86 (s, 1H, ArH), 7.60 (d, 1H, ArH, J = 8.8
Hz), 7.51 (d, 2H, ArH, J = 8.8 Hz, H2ꢀ, H6ꢀ), 7.53 (bs, 2H, ArH), 2.44 (s, 3H, CH3).;13C
NMR: δ 155.6, 139.0, 136.6, 135.4, 134.2, 132.2, 129.4, 129.2, 126.1, 125.9, 123.4, 121.6,
118.3, 21.5; IR (KBr, cm−1) υ: 3314 (NH), 1354 (SO2), 1165 (SO2); Anal. Calcd. for
C14H11BrN2O2S; C, 47.88; H, 3.16; N, 7.98. Found: C, 47.99; H, 3.25; N, 7.86.
6,7-Dichloro-3-(2-chlorophenyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide
(2g):
Brown solid, mp 271 ◦C–272 ◦C. 1H NMR: δ 11.84 (s, 1H, NH), 8.29 (s, 1H, ArH), 8.60
(s, 1H, ArH), 8.50 (d, 1H, ArH, J = 8.1 Hz), 8.25 (dd, 1H, ArH, J = 8.1 Hz, J = 7.8 Hz),
7.86 (d, 1H, ArH, J = 8.1 Hz), 7,78 (t, 1H, ArH, J = 7.7 Hz, J = 7.7 Hz); IR (KBr, cm−1
)
υ: 3312 (NH), 1366 (SO2), 1162 (SO2); Anal. Calcd. for C13H7Cl3N2O2S; C, 43.18; H,
1.95; N, 7.75. Found: C, 43.09; H, 1.90; N, 7.71.
General Procedure for the Preparation of 3-Aryl-4H-1,2,4-
Benzothiadiazine-1,1-Dioxides 2a–d and f–g from
2-Aminobenzenesulfonamides and Benzoic Acid (Method B)
A mixture of the corresponding 2-aminobenzenesulfonamide 1a–d (16 mg;
0.062 mmol), appropriate substituted benzoic acid (0.124 mmol), 5% mol of hydrochloric
acid (10N solution), and dimethylacetamide (1 mL) was microwave-irradiated at several
stages (3 min each) to complete the indicated time. An initial microwave-promoted
preheating of 30 s (50% power) was needed in all cases, followed by six irradiation
steps of 3 min each (90% power). The reaction was followed by TLC until the starting
5-bromo-2-aminobenzenesulfonamide was consumed. After being cooled to room
temperature, an amount of ice water was added to the resulting mixture to precipitate the
products that were then filtered and washed three times with cool water and dried in vacuo
to give compounds 2a–d and f–g.

MW-ASSISTED DIRECT SYNTHESIS OF 4H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE 2319
General Procedure for the Preparation of 3-Aryl-4H-1,2,4-
Benzothiadiazine-1,1-Dioxides 2c–d from
3,4-Dihidro-2H-1,2,4-Benzotiadiazine-1,1-Dioxides
A solution of substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dio´xide 3a,b
(20 mg, 0.062 mmol) and sodium hydrogen sulfite (10 mg, 0.093 mmol) in dimethylac-
etamide (0.5 mL) was microwave-irradiated at several stages (2–3 min each) to complete
the indicated time (7 min). An initial microwave-promoted preheating of 30 s (70% power)
was needed in all cases, followed by several irradiation steps of 2–3 min (90% power).
The reaction was followed by TLC until the starting 3,4-dihydro-2H-benzothiadiazine-1,1-
dioxide was consumed. After being cooled to room temperature, an amount of ice water
was added to the resulting mixture to precipitate the products that were then filtered and
washed three times with cool water and dried in vacuo to give title pure compounds 2c–d
in almost quantitative yield.
General Procedure for the Preparation of 3-Trifluoromethyl-4H-1,2,4-
Benzothiadiazine-1,1-Dioxides 2h–j from 2-Aminobenzenesulfonamides and
TFA
A mixture of the corresponding 2-aminobenzenesulfonamide 1b–d (16 mg; 0.062
mmol), TFA (0.124 mmol), and dimethylacetamide (1 mL) was microwave-irradiated at
several stages (3 min each) to complete the indicated time. An initial microwave-promoted
preheating of 30 s (40% power) was needed in all cases, followed by 13 irradiation steps
of 1 min each (80% power). The reaction was followed by TLC until the starting 2-
aminobenzenesulfonamide was consumed. After being cooled to room temperature, an
amount of ice water was added to the resulting mixture to precipitate the products that were
then filtered and washed three times with cool water and dried in vacuo to give compounds
2h–j.
7-Chloro-3-trifluoromethyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (2h): Brown
solid, mp 245 ◦C–246 ◦C. 1H NMR: δ 11.81 (bs, 1H, NH), 7.88 (d, 1H, ArH, J = 2.5 Hz,
H8), 7.77 (dd, 1H, ArH, J = 2.5 Hz, J = 8.9 Hz, H6), 7.36 (d, 1H, ArH, J = 8.9 Hz,
H5); 13C NMR: δ 148.5 (d, J = 36.7 Hz), 139.8, 136.3, 125.7, 125.5, 124.6, 118.4. 19F
NMR: δ −77.0; IR (KBr, cm−1) υ: 3278 (NH), 1369 (SO2), 1168 (SO2); Anal. Calcd. for
C8H4ClF3N2O2S; C, 33.76; H, 1.42; N, 9.84. Found: C, 33.68; H, 1.39; N, 9.89.
6,7-Dichloro-3-trifluoromethyl-4H-1,2,4-benzothiadiazine-1,1-dioxide
(2j):
Brown solid, mp 270 ◦C–272 ◦C. 1H NMR: δ 13.26 (s, 1H, NH), 7.76 (s, 1H, ArH), 7.59
(s,1H, ArH); 13C NMR: δ 175.1, 147.8 (d, J = 36.7 Hz), 137.8, 133.5, 131.6, 125.6,
121.6, 120.9; 19F NMR: δ −71.2; IR (KBr, cm−1) υ: 3263 (NH), 1363 (SO2), 1160 (SO2);
Anal. Calcd. for C8H3Cl2F3N2O2S; C, 30.11; H, 0.95; N, 8.78. Found: C, 30.09; H, 0.92;
N, 8.71.
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