A one-pot, non-catalytic approach to 1,2,4-benzothiadiazine-1,1-dioxides

Article abstract of DOI:10.1016/j.tet.2011.06.063

Condensations of o-halo-substituted benzenesulfonyl chlorides with 2-aminopyridines and amidines may give the corresponding 1,2,4-benzothiadiazine- 1,1-dioxides under mild, non-catalytic conditions in nearly quantitative yields. The successful one-pot cyclization depends on three factors: (i) the nature of the o-halogen, (ii) the electronic character of the benzene ring substituent, and (iii) the steric load around the amidine unit. O-Fluorobenzenesulfonyl chlorides bearing methylcarboxyl- or nitro-group and o-chloro- and o-bromobenzenesulfonyl chlorides bearing nitro-group are reactive enough to give the desired 1,2,4-benzothiadiazine-1,1-dioxides in a one-pot base-promoted reaction. In all other cases, open-chain sulfonylated amidine intermediates are isolated. The latter are converted to the title compounds either in the presence of potassium carbonate or upon the addition of a copper(I) catalyst.

Full text of DOI:10.1016/j.tet.2011.06.063

Tetrahedron 67 (2011) 6233e6239
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A one-pot, non-catalytic approach to 1,2,4-benzothiadiazine-1,1-dioxides
,
,b,
Artem Cherepakha a, Vladimir O. Kovtunenko a, Andrey Tolmachev a b, Oleg Lukin a
*
a National Taras Shevchenko University, ChemBioCenter, Volodymyrska St. 62, 01033 Kiev, Ukraine
b Enamine Ltd., A. Matrosova St. 23, 01103 Kiev, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Condensations of o-halo-substituted benzenesulfonyl chlorides with 2-aminopyridines and amidines
may give the corresponding 1,2,4-benzothiadiazine-1,1-dioxides under mild, non-catalytic conditions in
nearly quantitative yields. The successful one-pot cyclization depends on three factors: (i) the nature of
the o-halogen, (ii) the electronic character of the benzene ring substituent, and (iii) the steric load around
the amidine unit. O-Fluorobenzenesulfonyl chlorides bearing methylcarboxyl- or nitro-group and
o-chloro- and o-bromobenzenesulfonyl chlorides bearing nitro-group are reactive enough to give the
desired 1,2,4-benzothiadiazine-1,1-dioxides in a one-pot base-promoted reaction. In all other cases,
open-chain sulfonylated amidine intermediates are isolated. The latter are converted to the title com-
pounds either in the presence of potassium carbonate or upon the addition of a copper(I) catalyst.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 February 2011
Received in revised form 31 May 2011
Accepted 20 June 2011
Available online 25 June 2011
Keywords:
1,2,4-Benzothiadiazine-1,1-dioxide
Sulfonyl chlorides
Amidines
One-pot synthesis
1. Introduction
environmental toxicity. In addition, their separation from polar
reaction products, which is of particular importance for the syn-
Benzothidiazine-1,1-dioxides are a remarkably important class
of heterocycles in the pharmacological area because of their broad
range of biological activities, such as antihypertensive,1,2 antimi-
crobial,3 and antiviral4 ones. In this connection several synthetic
routes to the benzothiadiazine ring system have been developed.
These synthetic routes can roughly be divided into two common
approaches. In the first, non-catalytic, approach the ring is con-
structed through reactions of o-aminoaryl-sulfonamides with
orthoesters5,6 or acylating reagents7e9 and o-haloaryl-sulfon-
amides with lactim ethers.10 Main disadvantages of this approach
are considerably harsh reaction conditions (e.g., pyrolytic condi-
tions in the case of acylating reagents7) causing the formation of
byproducts and a somewhat limited availability of o-amino-
sulfonamides narrowing the chemical space for drug design. An
alternative approach to the 1,2,4-benzothiadiazine-1,1-dioxide ring
is based on metal catalyzed reactions, such as: FriedeleCrafts ring
closure of Michael adducts of chlorosulfonyl isocyanate and aniline
derivatives,11 a Cu(I)-catalyzed coupling of o-bromobenzylsulfonyl
azide with functionalized terminal acetylene and ammonium
chloride,12 a cyclization of o-haloarylsulfonyl amidines in the
presence of a copper bronze powder,13 and a Fe(III)-mediated cy-
clization of o-bromobenzenesulfonamide with amidines.14 How-
ever, transition metal-based protocols, although successful, have
some inherent limitations, such as moisture sensitivity and
thesis of pharmaceutical fine chemicals because of their residual
toxicity in the target compounds, is a central issue to consider.
Given the limitations of the mentioned above synthetic approaches
the development of efficient non-catalytic synthetic routes to the
benzothiadiazine-1,1-dioxide ring system is necessary. In this
contribution an efficient base-promoted synthesis of 4H-1,2,4-
benzothiadiazine-1,1-dioxides from o-halobenzenesulfonyl chlo-
rides and amidines or 2-aminopyridines is described.
2. Results and discussion
The 1,2,4-benzothiadiazine-1,1-dioxide is converted retro-
synthetically into an o-halobenzenesulfonyl chloride and an ami-
dine. These two components can be combined to give rise to the
desired benzothiadiazine-1,1-dioxide ring by a two-step procedure
involving the sulfonylation of the amidine and the aromatic nu-
cleophilic substitution of the ortho-halogen atom. As noted above
the latter step was carried out via Fe(III)14 or copper bronze pow-
der13 mediated reaction. However, there are examples in which the
intermolecular nucleophilic substitution of a halogen atom in ac-
tivated o-halobenzenesulfonamides with nitrogen nucleophiles,
such as aliphatic and aromatic amines, takes place under ambient
non-catalytic conditions.15 Consequently, a combination of en-
hanced reactivity of the ortho-halogen under the sufonylation
conditions with sufficient nucleophilicity of the remaining amidine
amine moiety should afford target benzothiadiazine dioxides via
a one-pot procedure that would not require metal catalyst.
* Corresponding author. E-mail address: oleg.lukin@univ.kiev.ua (O. Lukin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.063

6234
A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
X
S
A systematic study of reactions of o-halobenzenesulfonyl chlo-
rides 1 with amidines 2 and aminopyridines 5 (Schemes 1 and 2)
revealed clear structural requirements to reagents to allow their
clean and high-yielding one-pot conversion to the title compounds
under non-catalytic conditions. Thus, reactions of sulfonyl chlo-
rides 1aef, 1h, and 1i with amidines 2 (Scheme 1) resulted in open-
chain sulfonylated products 3 in high yields. Isolated adducts 3a,
3b, 3e, 3gej, 3n, and 3l are then nearly quantitatively converted to
corresponding benzothiadiazine-1,1-dioxides 4 via nucleophilic
substitution of the halogen in the presence of potassium carbonate
in DMF. Bromine-substituted adducts 3c, 3f, 3k, and 3m require the
addition of copper(I) iodide and N,N-dimethylethylenediamine
(DMEDA) to complete the thiadiazine ring closure. It is interesting
to note that the use of DMEDA instead of 1,10-phenanthroline as
reported by Chang et al.12 allowed us to achieve generally better
conversions and a clean workup.
HN
N
R1
i
R2
O
O
6
ii or iii
R2
R2
1
+
H2N
N
i
5
N
S
N
O
R1
O
7
5a: R2 = H
5b:
2 = 3-Me
5c: R2 = 4-Me
6g: X = Br CO2Me, R2 = 4-Me
6h: X = Cl R1 = CO2Me, R2 = 5-Me
R
6i: X = Br
6j: X = Cl
R
R
1 = CO2Me, R2 = 5-Me
1 = CO2Me, R2 = 6-Me
X
5d:
5e:
R
R
2 = 5-Me
2 = 6-Me
HN
NH
R1
S
R2
6k: X = Br R1 = CO2Me, R2 = 6-Me
O
O
X
S
3
H2N
NH
i
i
ii or iii
R2
Cl
O
+
6a: X = F R1 = R2 = H
6b: X = Cl R1 = R2 = H
6c:
R1
R2
O
7a: R1 = R2 = H
H
N
1
2
7b: R1 = CO2Me, R2 = H
X = Br
R
1 = R2 = H
N
O
R1
S
O
1 = CO2Me, R2 = H
7c:
R
1 = NO2, R2 = H
6d:
6e:
X = Cl
R
4
7d: R1 = CO2Me, R2 = 4-Me
X = Br R1 = CO2Me, R2 = H
1 = CO2Me, R2 = 4-Me
1 = H
1 = H
1 = H
3f:
X = Br R1 = CO2Me, R2 = Me
7e:
R
1 = CO2Me, R2 = 5-Me
1a:
1b:
X = F
R
R
R
R
R
6f: X = Cl
R
1 = NO2, R2 = Me
1 = NO2, R2 = Me
1 = H, R2 = Ph
Scheme 2. Preparation of 1,2,4-benzothiadiazine-1,1-dioxides through the reaction of
different o-halobenzenesulfonyl chlorides with 2-methylpyridine. Reagents and con-
ditions: (i) pyridine, reflux, (ii) K2CO3, DMF, 80 ꢀC, (iii) K2CO3, CuI, DMEDA, DMF, 80 ꢀC.
X = Cl
X = Br
X = F
3g:
X = Cl
X = Br
X = F
R
R
R
R
1c:
1d:
1e:
1f:
3h:
3i:
1 = CO2Me
1 = CO2Me
Interestingly, the reaction of 4-fluoro-3-chlorosulfonyl-methyl-
benzoate 1d with methylamidine 2a readily gives open-chain sul-
famoyl-4-fluoro-benzoic acid 3d. A similar result was obtained in
the case of the reaction of 4-chloro-3-chlorosulfonyl-methyl-
benzoate 1e with phenylamidine 2b giving rise to sulfamoyl-4-
chlorobenzoic acid 3l. Presumably this occurs on account of the
good solubility of the intermediate sulfonylated amidines in
aqueous NaOH in which the hydrolysis of the ester group takes
place. All attempts to carry out cyclization reactions of acids 3d and
3l to yield the corresponding thiadiazine-1,1-dioxide rings were
unsuccessful.
X = Cl
3j:
X = Cl
1 = H, R2 = Ph
X = Br R1 = CO2Me
X = F
1 = NO2
3k:
3l:
X = Br R1 = H, R2 = Ph
1g:
1h:
1i:
R
X = Cl R1 = CO2H, R2 = Ph
X = Cl R1 = NO2
X = Br R1 = NO2
3m: X = Br
R
R
R
1 = CO2Me, R2 = Ph
1 = NO2, R2 = Ph
1 = NO2, R2 = Ph
3n:
3o:
X = Cl
X = Br
2a: R2 = Me
On the contrary, the reaction of 1d with phenylamidine 2b
readily gives benzothiadiazine-1,1-dioxide carboxylic acid 4g. This
indicates that in the latter case the rate of aromatic nucleophilic
substitution is faster than that of the hydrolysis. Finally, both the
sulfonylation and cyclization steps proceed in one-pot in case of
the reaction of fluoronitrobenzenesulfonyl chloride 1g with 2a
and 2b giving rise to benzothiadiazine-1,1-dioxides 4c and 4f,
respectively. To our knowledge this constitutes the first example
of a one-pot non-catalytic construction of the thiadiazine-1,1-
dioxide ring. Additionally, this is a straightforward method for
preparation of nitrobenzothiadiazine dioxides. The latter were
formerly prepared by nitration of the parent benzothiadiazine
dioxides.16
2b:
R
2 = Ph
4a:
4b:
4c:
4d:
4e:
4f:
R1 = H, R2 = Me
R1 = CO2Me, R2 = Me
3a:
3b:
3c:
X = F
R
1 = H, R2 = Me
R
R
1 = NO2, R2 = Me
1 = H, R2 = Ph
X = Cl R1 = H, R2 = Me
X = Br
X = F
R
R
1 = H, R2 = Me
1 = CO2H, R2 = Me
R1 = CO2Me, R2 = Ph
3d:
3e:
X = Cl R1 = CO2Me, R2 = Me
R
R
1 = NO2, R2 = Ph
1 = CO2H, R2 = Ph
4g:
The versatility of the one-pot approach to the benzothiadiazine-
1,1-dioxides could be possibly expanded by the use of stronger
intramolecular nucleophiles, such as sulfonylated 2-aminopyridine
derivatives. Indeed, the reactions of parent 2-aminopyridine
Scheme 1. Preparation of 1,2,4-benzothiadiazine-1,1-dioxides through the reaction of
different o-halobenzenesulfonyl chlorides with amidines. Reagents and conditions: (i)
CH2Cl2, aq NaOH, 0e10 ꢀC; (ii) K2CO3, DMF,100 ꢀC; (iii) K2CO3, CuI, DMEDA, DMF,100 ꢀC.

A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
6235
5a with halonitrobenzenesulfonyl chlorides 1gei (Scheme 2)
readily afford the corresponding benzothiadiazine-1,1-dioxide 7c.
Moreover, the reaction of 4-fluoro-3-chlorosulfonyl-methyl-
benzoate 1d with 5a also proceeds in one-pot resulting in the
benzothiadiazine-1,1-dioxide 7b. Similar reactions of other hal-
obenzenesulfonyl chlorides with aminopyridine 5a yield open-
chain sulfonamides 6aee (Scheme 2) of which compounds 6a, 6b,
and 6d undergo base-promoted cyclization to give corresponding
benzothiadiazine-1,1-dioxides 7a and 7b.
the high-yielding one-pot procedure allowing the multigram
scale preparation of nitro-functionalized benzothiadiazine
dioxides with the variety of functional group transformations
the nitro-group can undergo opens a range of possibilities for
the design and synthesis of biologically potent benzothiadiazine
derivatives.
4. Experimental details
4.1. General
To investigate the influence of the steric load around the
amidine unit on the reaction outcome a series of isomeric meth-
ylpyridin-2-ylamines 5bee were reacted with methylcarboxyl-
substituted o-halobenzenesulfonyl chlorides 1def (Scheme 2).
Reactions of the three sulfonyl chlorides with 4- and 5-
methylpyridin-2-ylamines 5c and 5d proceed identically to
those with parent 2-aminopyridine 5a. Thus, the reaction of 1d
with either 5c or 5d is a one-pot process giving rise to benzo-
thiadiazine-1,1-dioxides 7d and 7e, respectively. Similar reactions
of 1e and 1f with 5c or 5d result in open-chain adducts 6fei.
Chlorinated adducts 6f and 6h are easily cyclized in the presence
of potassium carbonate to give thiadiazine-1,1-dioxides 7d and 7e,
respectively. Brominated derivatives 6g and 6i undergo the cy-
clization step under copper(I) catalyzed conditions (Scheme 2). In
the case of 3-methylpyridin-2-ylamine 5b no reaction occurs
irrespective of the o-halobenzenesulfonyl chloride used. Sulfonyl
chlorides 1e and 1f react with 6-methylpyridin-2-ylamine 5e to
give open-chain sulfonylated amidines 6j and 6k, respectively. The
latter, however, are not cyclized to the benzothiadiazine-1,1-
dioxides under both base-promoted and copper(I) catalyzed
conditions.
Interestingly, although the methyl group of 5b situated next
to the amino group sterically precludes the sulfonylation step
there is no steric obstacle for aromatic nucleophilic substitution
of the halogen. In the case of 5e the aromatic nucleophilic sub-
stitution step is apparently prevented sterically. Therefore, only
the sulfonylated amidine is capable of the nucleophilic dis-
placement of the halogen under given conditions. A reasonable
explanation for this fact shown in Scheme 3 is that in the pres-
ence of a base sulfonylated amidines tautomerize into a more
favorable form in which the imine unit is conjugated with the
sulfo-group.17
1H (500 MHz) and 13C (125 MHz) NMR spectra were recorded
on Bruker Avance DRX 500 spectrometer with TMS as an internal
standard. High-performance (HP) LCeMS analyses were done on
an Agilent 1100 LCMSD SL instrument (APCI mode). Elemental
analyses were carried out on a LECO CHN-900 analyzer. The
values of elemental analyses reported herein are averages of
three independent measurements. Melting points were mea-
€
sured with a Buchi melting point apparatus and are uncorrec-
ted. IR spectra were recorded on Perkin Elmer Spectrum BX II
(FT-IR).
Sulfonyl chlorides 1aec and 1dei were purchased from Acros
and Enamine Ltd, respectively.
4.2. General procedure for preparation of sulfonylated
amidines 3
To a stirred solution of equimolar amounts of o-halogenoar-
ylsulfonyl chloride 1 (0.02 mol) and amidine hydrochloride 2
(0.02 mol) in dichloromethane (50 mL) a concentrated water so-
lution of potassium hydroxide (5.6 g, 0.1 mol) was slowly added at
0 ꢀC. The reaction mixture was allowed to stir overnight at room
temperature and acidified to pH 1. The precipitated sulfonylated
amidine was filtered, washed with water and dichloromethane and
dried at ambient conditions. If necessary the product is recrystal-
lized from ethanol/water mixture.
4.2.1. N0-((2-Fluorophenyl)sulfonyl)ethanimidate (3a). Colorless solid;
yield 3.6 g (83%); mp 138e140 ꢀC; [found: C, 44.48; H, 4.19; N, 12.95.
C8H9FN2O2S requires C, 44.44; H, 4.20; N, 12.96%]; dH (500 MHz,
DMSO-d6) 1.98 (3H, s, CH3), 7.40e7.53 (2H, m, ArH), 7.79 (1H, dd,
J 14.0, 7.0 Hz, ArH), 7.94 (1H, t, J 7.0 Hz, ArH), 12.5 (1H, br s, NH); dC
(125 MHz, DMSO-d6) 23.6,117.7 (d, J 20.0 Hz),125.3 (d, J 2.5 Hz),127.5
(d, J 13.8 Hz), 131.7, 137.0 (d, J 8.8 Hz), 158.7 (d, J 253.8 Hz), 169.4; dF
(470 MHz, DMSO-d6) ꢁ110.3.
base
R1
R1
O
O
O
O
R2
R2
S
S
Ar
N
N
H
Ar
HN
N
4.2.2. N0-[(2-Chlorophenyl)sulfonyl]ethanimidamide (3b). Colorless
solid; yield 3.94 g (85%); mp 156e158 ꢀC; [found: C, 41.31; H, 3.89;
Cl, 15.20; N, 12.06. C8H9ClN2O2S requires C, 41.29; H, 3.90; Cl, 15.24;
N, 12.04%]; dH (500 MHz, DMSO-d6) 2.13 (3H, s, CH3), 7.52 (1H, t,
J 7.0 Hz, ArH), 7.55e7.68 (2H, m, ArH), 8.05 (1H, d, J 7.0 Hz, ArH), 8.17
(1H, br s, NH), 8.56 (1H, br s, NH); dC (125 MHz, DMSO-d6) 22.1,
127.5, 129.5, 131.6, 132.0, 133.7, 140.9, 168.8.
Scheme 3. A possible tautomerization of sulfonylated amidines.
3. Conclusions
The presented approach allows the straightforward preparation
of 1,2,4-benzothiadiazine-1,1-dioxides from readily available o-
halo-substituted benzenesulfonyl chlorides and 2-aminopyridines
or amidines in the presence of a base in high yields. The presence
of electron withdrawing groups in the benzene ring of the o-hal-
obenzenesulfonyl chlorides is a prerequisite for the successful
one-pot preparation of benzothiadiazine-1,1-dioxides. In the case
of fluorine containing sulfonyl chlorides the presence of a rela-
tively weak electron acceptor, such as methylcarboxyl-group, is
sufficient for activating the halogen toward aromatic nucleophilic
substitution under mild conditions. This is, however, not the case
for the chlorine and bromine containing sulfonyl chlorides re-
quiring the presence of the much stronger electron withdrawing
nitro-group to react under given conditions. The combination of
4.2.3. N0-[(2-Bromophenyl)sulfonyl]ethanimidamide (3c). Colorless
solid; yield 5.28 g (95%); mp 177e179 ꢀC; [found: C, 34.62; H, 3.21;
Br, 23.75; N, 10.19. C8H9BrN2O2S requires C, 34.67; H, 3.27; Br,
23.83; N, 10.11%]; nmax (ATP) 3409, 3324, 3242 (NH), 1637 (NH2),
1541 (C]N), 1288, 1146 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.12
(3H, s, CH3), 7.48 (1H, t, J 7.0 Hz, ArH), 7.55 (1H, t, J 7.0 Hz, ArH), 7.81
(1H, d, J 7.0 Hz, ArH), 8.06 (1H, d, J 7.0 Hz, ArH), 8.13 (1H, br s, NH),
8.56 (1H, br s, NH); dC (125 MHz, DMSO-d6) 22.2, 120.2, 128.2, 129.6,
133.6, 135.5, 142.5, 168.8.
4.2.4. 3-((1-Aminoethylidene)sulfamoyl)-4-fluoro-benzoic
acid
(3d). Colorless solid; yield 4.36 g (84%); mp 232e234 ꢀC; [found:

6236
A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
C, 41.52; H, 3.48; N, 10.78. C9H9FN2O4S requires C, 41.54; H, 3.49;
N, 10.76%]; dH (500 MHz, DMSO-d6) 1.99 (3H, s, CH3), 7.62 (1H, t, J
9.0 Hz, ArH), 8.30 (1H, br s, ArH), 8.43 (1H, d, J 2.0 Hz, ArH), 12.66
(1H, br s, CO2H); dC (125 MHz, DMSO-d6) 23.7, 118.5 (d, J 21.3 Hz),
127.7 (d, J 13.8), 128.1, 132.9, 137.9 (d, J 11.3), 162.2 (d, J 261.3),
165.6, 169.6; dF (470 MHz, DMSO-d6) ꢁ105.38.
(125 MHz, DMSO-d6) 120.4, 128.3, 129.0, 133.0, 133.8, 134.1, 135.6,
141.8, 163.8.
4.2.12. 3-((Amino(phenyl)methylidene)sulfamoyl)-4-chlorobenzoic
acid (3l). Colorless solid; yield 5.55 g (82%); mp 229e231 ꢀC;
[found: C, 49.51; H, 3.29; Cl, 10.48; N, 8.27. C14H11ClN2O4S requires
C, 49.64; H, 3.27; Cl, 10.47; N, 8.27%]; dC (500 MHz, DMSO-d6) 7.50
(2H, t, J 7.0 Hz, ArH), 7.61 (1H, t, J 7.0 Hz, ArH), 7.71 (2H, s, ArH), 7.88
(2H, d, J 7.0 Hz, ArH), 8.15 (1H, s, ArH), 8.85 (2H, br s, NH2); dC
(125 MHz, DMSO-d6) 128.6, 129.0, 129.4, 130.5, 132.4, 133.1, 133.6,
133.8, 133.9, 141.7, 164.2.
4.2.5. Methyl-3-((1-aminoethylidene)sulfamoyl)-4-chlorobenzoate
(3e). Colorless solid; yield 5.34 g (92%); mp 178e180 ꢀC; [found: C,
41.35; H, 3.80; Cl, 12.23; N, 9.64. C10H11ClN2O4S requires C, 41.31; H,
3.81; Cl, 12.19; N, 9.64%]; dH (500 MHz, DMSO-d6) 2.14 (3H, s, CH3),
3.91 (3H, s, CO2CH3), 7.78 (1H, d, J 8.0 Hz, ArH), 8.09 (1H, d, J 8.0 Hz,
ArH), 8.29 (1H, br s, NH), 8.53 (1H, s, ArH), 8.71 (1H, br s, NH); dC
(125 MHz, DMSO-d6) 22.0, 53.2, 129.1, 129.8, 132.9, 133.8, 136.5,
141.2, 165.1, 169.2.
4.2.13. Methyl-3-((amino(phenyl)methylidene)sulfamoyl)-4-
bromobenzoate (3m). Colorless solid; yield 7.3 g (92%); mp
191e193 ꢀC; [found: C, 45.02; H, 3.37; Br 19.89; N, 6.92.
C15H13BrN2O4S requires C, 45.35; H, 3.30; Br, 20.11; N, 7.05%]; nmax
(ATP) 3335, 3177 (NH), 1586 (NH2), 1482(C]N), 1297, 1174 (SO2)
4.2.6. Methyl-3-((1-aminoethylidene)sulfamoyl)-4-bromobenzoate
(3f). Colorless solid; yield 5.7 g (85%); mp 193e195 ꢀC; [found: C,
35.75; H, 3.22; Br, 23.67; N, 8.15. C10H11BrN2O4S requires C, 35.84;
H, 3.31; Br, 23.84; N, 8.36%]; nmax (ATP) 3331, 3131 (NH),1590 (NH2),
cmꢁ1
; dH (500 MHz, DMSO-d6) 3.90 (3H, s, CO2CH3), 7.49 (2H, t, J
8.0 Hz, ArH), 7.60 (1H, t, J 8.0 Hz, ArH), 7.91 (2H, t, J 8.0 Hz, ArH),
8.00 (2H, s, ArH), 8.41 (1H, br s, NH), 8.54 (1H, s, ArH), 9.33 (1H, br s,
NH); dC (125 MHz, DMSO-d6) 52.8, 125.8, 128.6, 128.6, 128.7, 129.5,
130.0, 130.9, 134.3, 135.1, 147.7, 166.0, 166.1.
1537 (C]N), 1292, 1130 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.15
(3H, s, CH3), 3.90 (3H, s, CO2CH3), 7.97 (2H, s, ArH), 8.54 (1H, s, ArH),
9.12 (2H, br s, NH); dC (125 MHz, DMSO-d6) 22.1, 53.2, 125.8, 129.5,
129.7, 133.6, 136.4, 143.2, 165.3, 169.2.
4.2.14. N0-[(2-Chloro-5-nitrophenyl)sulfonyl]benzenecarbox-
imidamide (3n). Yellow solid; yield 6.38 g (94%); mp 162e164 ꢀC;
[found: C, 45.94; H, 2.98; Cl, 10.49; N, 12.35. C13H10ClN3O4S requires
C, 45.96; H, 2.97; Cl, 10.43; N, 12.37%]; dH (500 MHz, DMSO-d6) 7.51
(2H, t, J 7.0 Hz, ArH), 7.62 (1H, t, J 7.0 Hz, ArH), 7.90 (2H, d, J 7.0 Hz,
ArH), 7.96 (1H, d, J 8.0 Hz, ArH), 8.42 (1H, d, J 8.0 Hz, ArH), 8.47 (1H,
br s, NH), 8.83 (1H, s, ArH), 9.31 (1H, br s, NH); dC (125 MHz, DMSO-
d6) 124.6, 128.4, 128.6, 129.0, 133.2, 133.4, 133.9, 138.4, 141.5, 146.5,
164.3.
4.2.7. N0-[(2-Chloro-5-nitrophenyl)sulfonyl]ethanimidamide
(3g). Yellowish solid; yield 4.72 g (85%); mp 203e204 ꢀC (dec);
[found: C, 34.55; H, 2.90; N, 15.15. C8H8ClN3O2S requires C, 34.60;
H, 2.90; N, 15.13%]; dH (500 MHz, DMSO-d6) 2.18 (3H, s, CH3), 7.94
(1H, s, ArH), 8.40 (2H, br s, NH2), 8.72 (2H, d, J 7.0 Hz, ArH); dC
(125 MHz, DMSO-d6) 22.1, 124.2, 128.1, 133.8, 138.3, 142.1, 146.4,
169.6.
4.2.8. N0-[(2-Bromo-5-nitrophenyl)sulfonyl]ethanimidamide
(3h). Yellowish solid; yield 5.86 g (91%); mp 235e237 ꢀC (dec);
[found: C, 29.80; H, 2.51; Br, 25.00; N, 12.99. C8H8BrN3O4S requires
C, 29.83; H, 2.50; Br, 24.80; N, 13.04%]; dH (500 MHz, DMSO-d6)
2.19 (3H, s, CH3), 8.12 (1H, s, ArH), 8.31(2H, br s, NH2), 8.73 (2H, s,
ArH); dC (125 MHz, DMSO-d6) 22.2, 124.1, 127.8, 137.3, 144.0, 147.0,
169.6.
4.2.15. N0-[(2-Bromo-5-nitrophenyl)sulfonyl]benzenecarbox-
imidamide (3o). Yellowish solid; yield 7.3 g (95%); mp 186e188 ꢀC;
[found: C, 40.61; H, 2.63; Br, 20.83; N, 10.94. C13H10BrN3O4S re-
quires C, 40.64; H, 2.62; Br, 20.80; N, 10.94%]; dH (500 MHz, DMSO-
d6) 7.50 (2H, t, J 7.0 Hz, ArH), 7.62 (1H, t, J 7.0 Hz, ArH), 7.90 (2H, d, J
7.0 Hz, ArH), 8.14 (1H, d, J 8.5 Hz, ArH), 8.31 (1H, d, J 8.5 Hz, ArH),
8.49 (1H, br s, NH), 8.3 (1H, s, ArH), 9.34 (1H, br s, NH); dC (125 MHz,
DMSO-d6) 124.5, 127.8, 128.1, 128.6, 129.0, 133.2, 133.4, 137.4, 143.3,
147.0, 164.3.
4.2.9. N0-((2-Fluorophenyl)sulfonyl)benzenecarboximidamide
(3i). Colorless solid; yield 5.06 g (91%); mp 105e106 ꢀC; [found: C,
56.08; H, 4.00; N, 10.05. C13H11FN2O2S requires C, 56.11; H, 3.98; N,
10.07%]; dH (500 MHz, DMSO-d6) 7.34e7.46 (2H, m, ArH), 7.50 (1H,
t, J 8.0 Hz, ArH), 7.61 (1H, t, J 8.0 Hz, ArH), 7.65e7.75 (1H, m, ArH),
7.88 (2H, d, J 8.0 Hz, ArH), 7.99 (1H, t, J 8.0 Hz, ArH), 8.77 (2H, br s,
ArH); dC (125 MHz, DMSO-d6) 117.6 (d, J 21.3 Hz), 125.0 (d, J 3.8 Hz),
128.4, 129.0, 129.2, 130.6 (d, J 13.8 Hz), 133.1, 133.6, 135.3 (d, J
8.8 Hz), 159.0 (d, J 252.5 Hz), 163.7; dF (470 MHz, DMSO-d6) ꢁ110.6,
ꢁ75.8.
4.3. General non-catalytic procedure for the preparation of
4H-1,2,4-benzothiadiazine-1,1-dioxides 4 from sulfonylated
amidines 3
A stirred solution of sulfonylated amidine (0.015 mol) and po-
tassium carbonate (4.5 g, 0.035 mol) in dry DMF (100 mL) was
heated at 80 ꢀC for 8 h. Then the solvent was removed under re-
duced pressure. The residue was triturated with water (200 mL)
and acidified with hydrochloric acid to pH 1. The solid precipitate
was filtered, washed with water, and dried under vacuum.
4.2.10. N0-((2-Chlorophenyl)sulfonyl)benzenecarboximidamide
(3j). Colorless solid; yield 5.3 g (90%); mp 125e127 ꢀC; [found: C,
53.01; H, 3.74; Cl,12.00; N, 9.49. C13H11ClN2O2S requires C, 52.97; H,
3.76; Cl, 12.03; N, 9.50%]; dH (500 MHz, DMSO-d6) 7.39e7.78 (5H, m,
ArH), 7.90 (2H, d, J 7.0 Hz, ArH), 8.17 (1H, d, J 7.0 Hz, ArH), 8.81 (2H,
br s, NH); dC (125 MHz, DMSO-d6) 127.4, 128.5, 129.0, 129.8, 131.8,
132.2, 133.0, 133.7, 134.1, 140.2, 163.8.
4.4. One-pot procedure for the preparation of 4H-1,2,4-
benzothiadiazine-1,1-dioxides 4c, 4f, and 4g from o-
fluoronitrobenzenesulfonyl chlorides 1d, 1g and amidines 2
To a stirred solution of equimolar amounts of o-halogenoar-
ylsulfonyl chloride 1 (0.015 mol) and amidine 2 hydrochloride
(0.015 mol) in dichloromethane (37 mL) a concentrated water so-
lution of potassium hydroxide (4.2 g, 0.075 mol) was slowly added
at 0 ꢀC. The reaction mixture was allowed to stir overnight at room
temperature and then acidified with hydrochloric acid to pH 1. The
precipitated 4H-1,2,4-benzothiadiazine-1,1-dioxide was filtered,
4.2.11. N0-((2-Bromophenyl)sulfonyl)benzenecarboximidamide
(3k). Colorless solid; yield 6.5 g (96%); mp132e134 ꢀC; [found: C,
45.99; H, 3.28; N 8.23. C13H11BrN2O2S requires C, 46.03; H, 3.27;
N, 8.26%]; dH (500 MHz, DMSO-d6) 7.43e7.58 (3H, m, ArH),
7.58e7.66 (2H, m, ArH), 7.83 (1H, d, J 7.0 Hz, ArH), 7.90 (2H, d, J
7.0 Hz, ArH), 8.18 (1H, d, J 7.0 Hz, ArH), 8.62 (2H, br s, NH); dC

A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
6237
washed with water and dichloromethane, and dried under ambient
conditions.
51.50; H, 2.98; N, 13.87. C13H9N3O4S requires C, 51.48; H, 2.99; N,
13.85%]; dH (500 MHz, DMSO-d6) 7.67 (2H, t, J 7.0 Hz, ArH), 7.75 (1H,
t, J 7.0 Hz, ArH), 7.90 (1H, d, J 9.0 Hz, ArH), 8.11 (2H, d, J 7.0 Hz, ArH),
8.53 (1H, d, J 9.0 Hz, ArH), 8.58 (1H, s, ArH), 12.58 (1H, br s, NH); dC
(125 MHz, DMSO-d6) 120.4, 120.9, 121.6, 128.3, 129.0, 129.4, 131.7,
133.9, 140.8, 145.0, 156.0.
4.5. General catalytic procedure for the preparation of 4H-
1,2,4-benzothiadiazine-1,1-dioxides 4 from o-
bromoarylsulfonyl amidines 3
Potassium carbonate (4.08 g, 0.03 mol), copper(I) iodide (0.14 g,
0.75 mmol, 5 mol %), and 0.13 g (0.0015 mol, 10 mol %) of DMEDA
were added to a solution of sulfonylated amidine 2 (0.015 mol) in
DMF (100 mL) under argon. The reaction mixture was stirred under
argon at 80 ꢀC for 8 h. Then the solvent was removed under re-
duced pressure. The residue was dissolved in water and acidified
with hydrochloric acid to pH 1. Solid precipitate was filtered,
washed with water, and dried under ambient condition.
4.5.7. 3-Phenyl-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-
dioxide (4g). Colorless solid; yield 3.85 g (85%) (from 1d); mp
340e343 ꢀC; [found: C, 55.60; H, 3.32; N, 9.29. C14H10N2O4S
requires C, 55.62; H, 3.33; N, 9.27]; dH (500 MHz, DMSO-d6)
7.66 (2H, t, J 7.0 Hz, ArH), 7.70e7.83 (2H, m, ArH), 8.09 (2H, d, J
7.0 Hz, ArH), 8.26 (1H, d, J 8.0 Hz, ArH), 8.34 (1H, s, ArH), 12.50
(1H, br s, NH), 13.47 (1H, br s, CO2H); dC (125 MHz, DMSO-d6)
119.6, 121.7, 125.4, 128.9, 129.2, 129.4, 132.1, 133.6, 134.0, 139.2,
155.8, 165.9.
4.5.1. 3-Methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (4a). Colorless
solid; yield 2.76 g (96%) (from 3a), 2.73 g (93%) (from 3b), 2.88 g
(98%) (from 3c); mp 253e255 ꢀC (lit. 254e255 ꢀC12); [found: C,
48.75; H, 4.05; N, 14.53. C8H8N2O2S requires C, 48.97; H, 4.11; N
14.28%]; dH (500 MHz, DMSO-d6) 2.31 (3H, s, CH3), 7.30 (1H, d, J
8.0 Hz, ArH), 7.43 (1H, t, J 8.0 Hz, ArH), 7.67 (1H, t, J 8.0 Hz, ArH), 7.79
(1H, d, J 8.0 Hz, ArH), 12.03 (1H, br s, NH); dC (125 MHz, DMSO-d6)
23.2, 120.1, 120.5, 126.2, 126.3, 129.6, 137.0, 158.0.
4.6. General procedure for preparation of sulfonamides 6
To
a stirred solution of 2-aminopyridine derivative 5
(0.025 mol) in dry pyridine (25 mL) 2-halobenzenesulfonyl
chloride 1 (0.025 mol) was added. The reaction mixture was
stirred at reflux for 4 h. Then the solvent was removed under
reduced pressure and the residue triturated with deionized water
(50 mL). The resulting solid precipitate was filtered, washed with
water (2ꢂ15 mL), methanol (3ꢂ10 mL), and dried in vacuum. The
product can additionally be purified by recrystallization from
methanol.
4.5.2. Methyl-1,1-dioxo-3-methyl-4H-1,2,4-benzothiadiazine-7-
carboxylate (4b). Colorless solid; yield 3.54 g (93%) (from 3e),
3.71 g (95%) (from 3f); mp 263e265 ꢀC; [found: C, 47.02; H, 3.92; N,
11.15. C10H10N2O4S requires C, 47.24; H, 3.96; N, 11.02%]; nmax (ATP)
1244, 1133 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.34 (3H, s, CH3),
4.6.1. 2-Fluoro-N-(pyridin-2-yl)benzenesulfonamide (6a). Colorless
solid; yield 5.77 g (92%); mp 202e205 ꢀC; [found: C, 52.35; H, 3.61;
N, 11.05. C11H9FN2O2S requires C, 52.37; H, 3.60; N, 11.10%]; nmax
3.90 (3H, s, CO2CH3), 7.43 (1H, d, J 9.0 Hz, ArH), 8.18 (1H, dd, J 9.0,
2.0 Hz, ArH), 8.25 (1H, d, J 2.0 Hz, ArH), 12.43 (1H, br s, NH); dC
(125 MHz, DMSO-d6) 23.2, 53.0, 118.5, 121.2, 125.5, 127.4, 133.7,
139.1, 158.5, 164.9.
(ATP) 3215 (NH), 1600 (C]N), 1294, 1146 (SO2) cmꢁ1
; dH (500 MHz,
DMSO-d6) 6.83e6.89 (1H, m, ArH), 7.26 (1H, d, J 9.0 Hz, ArH),
7.30e7.37 (2H, m, ArH), 7.59e7.65 ( 1H, m, ArH), 7.79 (1H, t, J 7.0 Hz,
ArH), 7.92e7.95 (2H, m, ArH), 12.62 (1H, br s, NH); dH (500 MHz,
CF3CO2D) 7.34 (1H, t, J 10.0 Hz, ArH), 7.49 (1H, t, J 6.5 Hz, ArH),
7.67e7.74 (2H, m, ArH), 7.84 (1H, d, J 4.5 Hz, ArH), 8.10 (1H, t, J
6.0 Hz, ArH), 8.48 (1H, t, J 8.5 Hz, ArH), 8.52 (1H, d, J 5.0 Hz, ArH); dC
(125 MHz, DMSO-d6) 114.5, 115.5, 117.5 (d, J 21.3 Hz), 124.9, 130.1,
130.9 (d, J 7.5 Hz), 134.8 (d, J 7.5 Hz), 140.9, 142.2, 154.6, 158.8 (d, J
251.3 Hz); dC (125 MHz, CF3CO2D) 116.6, 176.0 (d, J 18.8 Hz), 120.9,
125.0 (d, J 12.5 Hz), 125.3, 129.8, 138.1, 138.2 (d, J 8.8 Hz), 146.5,
148.5 (d, J 253.8 Hz); dF (470 MHz, DMSO-d6) ꢁ111.5; dF (470 MHz,
CF3CO2D) ꢁ79.5.
4.5.3. 3-Methyl-7-nitro-4H-1,2,4-benzothiadiazine-1,1-dioxide
(4c). Yellow solid; yield 3.4 g (94%) (one-pot from 4g), 3.4 g (94%)
(from 3g), 3.33 g (92%) (from 3h); mp 264e266 ꢀC (lit.
264e265 ꢀC16); [found: C, 39.85; H, 2.90; N, 17.43. C8H7N3O4S re-
quires C, 39.83; H, 2.92; N, 17.42%]; dC (500 MHz, DMSO-d6) 2.38
(3H, s, CH3), 7.51 (1H, d, J 9.0 Hz, ArH), 8.45 (1H, dd, J 9.0, 2.0 Hz,
ArH), 8.50 (1H, d, J 2.0 Hz, ArH); dC (125 MHz, DMSO-d6) 23.3, 119.6,
120.5, 121.1, 128.3, 140.5, 144.6, 159.0.
4.5.4. 3-Phenyl-4H-1,2,4-benzothiadiazine-1,1-dioxide
(4d). Colorless solid; yield 3.68 g (95%) (from 3i), 3.75 g (97%) (from
3j), 3.72 g (96%) (from 3k); mp 307e309 ꢀC (lit. 307e308 ꢀC1);
[found: C, 60.43; H, 3.91; N, 10.81. C13H10N2O2S requires C, 60.45; H,
3.90; N, 10.85%]; dH (500 MHz, DMSO-d6) 7.53 (1H, t, J 8.0 Hz, ArH),
7.60e7.69 (3H, m, ArH), 7.69e7.80 (2H, m, ArH), 7.88 (1H, d, J 8.0 Hz,
ArH), 8.07 (2H, d, J 8.0 Hz, ArH); dC (125 MHz, DMSO-d6) 119.0,
122.0, 123.8, 127.2, 128.8, 129.3, 132.4, 133.3, 133.6, 136.1, 155.3.
4.6.2. 2-Chloro-N-(pyridin-2-yl)benzenesulfonamide (6b). Colorless
solid; yield 6.04 g (90%); mp 215e217 ꢀC; [found: C, 49.23; H,
3.35; Cl, 13.21; N, 10.40. C11H9ClN2O2S requires C, 49.17; H, 3.38;
Cl, 13.19; N, 10.42%]; nmax (ATP) 1600 (C]N), 1292, 1145 (SO2)
cmꢁ1
; dH (500 MHz, DMSO-d6) 6.84 (1H, t, J 6.0 Hz, ArH),
7.20 (1H, d, J 8.5 Hz, ArH), 7.50e7.55 (1H, m, ArH), 7.55e7.59
(2H, m, ArH), 7.77 (1H, t, J 8.0 Hz, ArH), 7.92 (1H, d, J 4.5 Hz,
ArH), 8.13 (1H, d, J 7.5 Hz, ArH), 12.71 (1H, br s, NH); dH
(500 MHz, CF3CO2D) 7.68e7.74 (3H, m, ArH), 7.74e7.81 (2H,
m, ArH), 8.34 (1H, d, J 8.0 Hz, ArH), 8.49 (1H, t, J 8.0 Hz, ArH),
8.54 (1H, d, J 5.5 Hz, ArH); dC (125 MHz, DMSO-d6) 115.6, 127.7,
130.8, 131.3, 132.0, 133.7, 140.6, 142.0, 154.5; dC (125 MHz,
CF3CO2D) 116.5, 120.8, 127.8, 131.5, 132.4, 134.3, 136.6, 138.2,
146.7, 148.5.
4.5.5. Methyl-1,1-dioxo-3-phenyl-4H-1,2,4-benzothiadiazine-7-
carboxylate (4e). Colorless solid; yield 4.6 g (97%) (from 3m); mp
302e304 ꢀC; [found: C, 56.72; H, 3.85; N, 8.78. C15H12N2O4S re-
quires C, 56.95; H, 3.82; N, 8.86%]; nmax (ATP) 1246, 1123 (SO2)
cmꢁ1
; dH (500 MHz, DMSO-d6) 3.90 (3H, s, CO2CH3), 7.6e7.68 (2H,
m, ArH), 7.69e7.82 (2H, m, ArH), 8.0e8.1 (2H, m, ArH), 8.25 (1H, d, J
7.5 Hz, ArH), 8.32 (1H, s, ArH), 12.55 (1H, br s, NH); dC (125 MHz,
DMSO-d6) 53.1, 119.7, 121.6, 125.3, 128.0, 128.9, 129.5, 131.9, 133.8,
133.8, 139.4, 156.0, 165.0.
4.6.3. 2-Bromo-N-(pyridin-2-yl)benzenesulfonamide (6c). Colorless
solid; yield 7.35 g (94%); mp 217e219 ꢀC; [found: C, 42.07; H,
2.87; Br, 25.57; N, 8.93. C11H9BrN2O2S requires C, 42.19; H, 2.90;
Br, 25.51; N, 8.94%]; nmax (ATP) 1601 (C]N), 1294, 1146 (SO2)
4.5.6. 7-Nitro-3-phenyl-4H-1,2,4-benzothiadiazine-1,1-dioxide
(4f). Yellowish solid; yield 4.41 g (97%) (one-pot from 1g), 4.18 g
(92%) (from 3n), 4.1 g (90%) (from 3o); mp 310e312 ꢀC; [found: C,

6238
A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
cmꢁ1
;
dH (500 MHz, DMSO-d6) 6.83 (1H, t, J 8.0 Hz, ArH), 7.19 (1H,
m, ArH), 7.67e7.76 (1H, m, ArH), 8.22 (1H, d, J 8.0 Hz, ArH),
8.47e8.52 (2H, m, ArH), 9.20 (1H, s, ArH); dC (125 MHz, DMSO-
d6) 22.0, 53.2, 115.2, 115.9, 124.8, 125.6, 129.4, 130.4, 133.2, 136.3,
138.0, 143.8, 149.1, 154.9, 155.1, 165.4; dC (125 MHz, CF3CO2D)
21.2, 53.5, 116.5, 122.7, 126.3, 129.9, 133.1, 136.6, 137.0, 137.4, 137.7,
145.5, 164.7, 167.6.
d, J 9.0 Hz, ArH), 7.47 (1H, t, J 8.0 Hz, ArH), 7.56 (1H, t, J 7.5 Hz,
ArH), 7.77 (2H, d, J 8.0 Hz, ArH), 7.92 (1H, d, J 4.5 Hz, ArH), 8.15
(1H, d, J 7.5 Hz, ArH), 12.82 (1H, br s, NH); dH (500 MHz, CF3CO2D)
7.71e7.73 (3H, m, ArH), 7.76 (1H, d, J 9.0 Hz, ArH), 7.94 (1H, d, J
9.0 Hz, ArH), 8.39 (1H, d, J 9.0 Hz, ArH), 8.49 (1H, t, J 8.0 Hz, ArH),
8.55 (1H, d, J 6.0 Hz, ArH); dC (125 MHz, DMSO-d6) 114.2, 115.8,
119.9, 128.3, 130.9, 133.6, 135.5, 140.5, 142.3, 154.7; dC (125 MHz,
CF3CO2D) 116.4, 120.0, 120.8, 128.3, 132.0, 135.9, 136.1, 136.4,
138.2, 146.7, 148.4.
4.6.8. Methyl-4-chloro-3-{[(5-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6h). Colorless solid; yield 7.91 g (93%); mp 216e218 ꢀC;
[found: C, 49.37; H, 3.83; Cl, 10.46; N, 8.20. C14H13ClN2O4S requires
C, 49.34; H, 3.85; Cl, 10.40; N, 8.22%]; nmax (ATP) 1593 (C]N), 1281,
4.6.4. Methyl-4-chloro-3-[(pyridine-2-ylamino)sulfonyl]benzoate
(6d). Colorless solid; yield 7.51 g (92%); mp 226e228 ꢀC; [found: C,
47.75; H, 3.39; Cl, 10.87; N, 8.52. C13H11ClN2O4S requires C, 47.79; H,
3.39; Cl, 10.85; N, 8.57%]; nmax (ATP) 1604 (C]N), 1287, 1167 (SO2)
1133 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.13 (3H, s, CH3), 3.91
(3H, s, CO2CH3), 7.16 (1H, d, J 8.0 Hz, ArH), 7.67 (1H, d, J 8.0 Hz,
ArH), 7.72 (1H, d, J 4.0 Hz, ArH), 7.76 (1H, s, ArH), 8.06 (1H, d, J
8.0 Hz, ArH), 8.62 (1H, s, ArH), 12.89 (1H, br s, NH); dH (500 MHz,
CF3CO2D) 2.66 (3H, s, CH3), 4.30 (3H, s, CO2CH3), 7.80 (1H, d, J
6.0 Hz, ArH), 7.95 (1H, s, J 5.0 Hz, ArH), 8.39e8.50 (2H, m, ArH),
8.55 (1H, d, J 5.0 Hz, ArH), 9.12 (1H, s, ArH); dC (125 MHz, DMSO-
d6) 17.0, 53.2, 115.5, 124.0, 129.0, 130.9, 132.8, 133.6, 136.3, 138.9,
141.6, 144.1, 152.9, 165.2; dC (125 MHz, CF3CO2D) 15.9, 53.5, 116.6,
129.3, 132.8, 133.2, 133.9, 135.7, 136.8, 137.2, 138.0, 143.9, 150.1,
167.4.
cmꢁ1
; dH (500 MHz, DMSO-d6) 3.98 (3H, s, CO2CH3), 6.83e6.88 (1H,
m, ArH), 7.25 (1H, d, J 8.5 Hz, ArH), 7.74 (1H, d, J 8.0 Hz, ArH), 7.82
(1H, t, J 7.5 Hz, ArH), 7.92 (1H, d, J 2.0 Hz, ArH), 8.07 (1H, d, J 8.0 Hz,
ArH), 8.64 (1H, s, ArH), 13.03 (1H, br s, NH); dH (500 MHz, CF3CO2D)
4.32 (3H, s, CO2CH3), 7.76e7.88 (1H, m, ArH), 7.88e8.03 (2H, m,
ArH), 8.56 (1H, t, J 8.5 Hz, ArH), 8.60e8.67 (2H, m, ArH), 9.16 (1H, s,
ArH); dC (125 MHz, DMSO-d6) 53.2, 116.0, 125.4, 129.0, 130.8, 132.8,
133.7, 136.3, 141.6, 143.0, 154.9, 165.2; dC (125 MHz, CF3CO2D) 53.5,
116.7, 121.2,129.4, 132.9, 133.2, 135.7, 136.9, 138.1, 138.5, 146.4, 148.7,
167.4.
4.6.9. Methyl-4-bromo-3-{[(5-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6i). Colorless solid; yield 8.76 g (91%); mp 111e113 ꢀC;
[found: C, 43.68; H, 3.38; Br, 20.64; N, 7.31. C14H13BrN2O4S requires
C, 43.65; H, 3.40; Br, 20.74; N, 7.27%]; nmax (ATP) 1602 (C]N),
4.6.5. Methyl-4-bromo-3-[(pyridine-2-ylamino)sulfonyl]benzoate
(6e). Colorless solid; yield 8.63 g (93%); mp 243e245 ꢀC; [found:
C, 42.00; H, 3.01; Br, 21.57; N, 7.68. C13H11BrN2O4S requires C,
42.06; H, 2.99; Br, 21.53; N, 7.55%]; nmax (ATP) 1605 (C]N), 1280,
1296, 1130 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.14 (3H, s, CH3),
3.91 (3H, s, CO2CH3), 7.15 (1H, d, J 8.5 Hz, ArH), 7.67 (1H, d, J 8.5 Hz,
ArH), 7.76 (1H, s, ArH), 7.90e8.00 (2H, m, ArH), 8.64 (1H, s, ArH),
12.83 (1H, br s, NH); dH (500 MHz, CF3CO2D) 2.78 (3H, s, CH3), 4.42
(3H, s, CO2CH3), 7.94 (1H, d, J 7.5 Hz, ArH), 8.30 (1H, d, J 7.5 Hz,
ArH), 8.51e8.64 (2H, m, ArH), 9.27 (1H, s, ArH); dC (125 MHz,
DMSO-d6) 17.0, 53.2, 115.7, 123.7, 125.4, 129.6, 130.9, 133.4, 136.3,
1147 (SO2)cmꢁ1
; dH (500 MHz, DMSO-d6) 3.91 (3H, s, CO2CH3), 6,84
(1H, t, J 7.0 Hz, ArH), 7.21 (1H, d, J 8.0 Hz, ArH), 7.82 (1H, t, J 8.0 Hz,
ArH), 7.90e7.95 (3H, m, ArH), 8.63 (1H, s, ArH), 13.30 (1H, br s,
NH); dH (500 MHz, CF3CO2D) 4.31 (3H, s, CO2CH3), 7.81 (1H, t, J
6.0 Hz, ArH), 7.92 (1H, d, J 8.5 Hz, ArH), 8.18 (1H, d, J 8.5 Hz, ArH),
8.45 (1H, d, J 6.0 Hz, ArH), 8.59e8.67 (2H, m, ArH), 9.18 (1H, s,
ArH); dC (125 MHz, DMSO-d6) 53.2, 113.5, 116.3, 125.5, 129.5, 130.7,
133.4, 136.4, 143.3, 154.9, 165.4; dC (125 MHz, CF3CO2H) 53.5, 116.7,
121.2, 126.4, 129.9, 133.1, 136.6, 136.9, 137.5, 138.5, 146.4, 148.7,
167.6.
138.6, 143.4, 144.2, 153.0, 165.4;
d (125 MHz, CF3CO2D) 16.0, 53.6,
116.7, 126.4, 129.9, 133.2, 134.0, 136.6, 137.0, 137.3, 137.6, 144.0,
150.1, 167.7.
4.6.10. Methyl-4-chloro-3-{[(6-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6j). Colorless solid; yield 7.58 g (89%); mp 233e235 ꢀC;
[found: C, 49.39; H, 3.82; Cl, 10.43; N, 8.21. C14H13ClN2O4S requires
C, 49.34; H, 3.85; Cl, 10.40; N, 8.22%]; nmax (ATP) 1590 (C]N),
4.6.6. Methyl-4-chloro-3-{[(4-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6f). Colorless solid; yield 7.75 g (91%); mp 236e237 ꢀC;
[found: C, 49.36; H, 3.79; Cl, 10.45; N, 8.21. C14H13ClN2O4S requires
C, 49.34; H, 3.85; Cl, 10.40; N, 8.22%]; nmax (ATP) 1612 (C]N), 1287,
1280, 1118 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.33 (3H, s, CH3),
3.92 (3H, s, CO2CH3), 6.68 (1H, d, J 7.0 Hz, ArH), 7.04 (1H, d, J
7.5 Hz, ArH), 7.68e7.76 (2H, m, ArH), 8.06 (1H, dd, J 8.0, 1.5 Hz,
ArH), 8.64 (1H, s, ArH), 13.20 (1H, br s, NH); dH (500 MHz,
CF3CO2D) 3.19 (3H, s, CH3), 4.52 (3H, s, CO2CH3), 7.84 (1H, d, J
7.0 Hz, ArH), 8.01 (1H, d, J 8.0 Hz, ArH), 8.17 (1H, d, J 8.0 Hz, ArH),
8.67 (1H, t, J 8.0 Hz, ArH), 8.77 (1H, d, J 7.0 Hz, ArH), 9.32 (1H, s,
ArH); dC (125 MHz, DMSO-d6) 19.5, 53.2, 112.5, 126.6, 128.9, 130.9,
132.8, 133.5, 136.4, 143.5, 165.3; dC (125 MHz, DMSO-d6) 18.6, 53.6,
113.8, 121.9, 129.5, 133.0, 133.4, 135.9, 137.0, 138.2, 146.1, 148.7,
152.6, 167.6.
1128 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.82 (3H, s, CH3), 3.92
(3H, s, CO2CH3), 6.71 (1H, d, J 7.0 Hz, ArH), 7.08 (1H, s, ArH), 7.74
(1H, d, J 8.0 Hz, ArH), 7.78 (1H, d, J 7.0 Hz, ArH), 8.07 (1H, dd, J 8.0,
2.0 Hz, ArH), 8.62 (1H, d, J 2.0 Hz, ArH), 12.98 (1H, br s, NH); dH
(500 MHz, CF3CO2D) 2.84 (3H, s, CH3), 4.34 (3H, s, CO2CH3),
7.66e7.73 (1H, m, ArH), 7.73e7.76 (1H, m, ArH), 7.98 (1H, d, J
8.0 Hz, ArH), 8.49 (1H, m, ArH), 8.58 (1H, m, ArH), 9.17 (1H, s,
ArH); dC (125 MHz, DMSO-d6) 22.0, 53.2, 115.8, 126.8, 127.0, 130.5,
132.8, 133.4, 136.3, 165.3; dC (125 MHz, CF3CO2D) 21.3, 53.5, 116.6,
122.8, 129.5, 132.9, 133.3, 135.9, 137.0, 137.5, 138.1, 145.5, 164.8,
167.5.
4.6.11. Methyl-4-bromo-3-{[(6-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6k). Colorless solid; yield 8.37 g (87%); mp 228e230 ꢀC;
[found: C, 43.69; H, 3.38; Br, 20.69; N, 7.29. C14H13BrN2O4S re-
quires C, 43.65; H, 3.40; Br, 20.74; N, 7.27%]; nmax (ATP) 3228 (NH),
4.6.7. Methyl-4-bromo-3-{[(4-methylpyridine-2-yl)amino]sulfonyl}
benzoate (6g). Colorless solid; yield 8.95 g (93%); mp
227e229 ꢀC; [found: C, 43.62; H, 3.43; Br, 20.81; N, 7.25.
C14H13BrN2O4S requires C, 43.65; H, 3.40; Br, 20.74; N, 7.27%];
1609 (C]N), 1283, 1119 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.34
(3H, s, CH3), 3.92 (3H, s, CO2CH3), 6.67 (1H, d, J 7.0 Hz, ArH), 7.05
(1H, s, ArH), 7.70 (1H, t, J 7.0 Hz, ArH), 7.86e8.00 (2H, m, ArH), 8.66
(1H, s, ArH), 13.37 (1H, br s, NH); dH (500 MHz, CF3CO2D) 3.06 (3H,
s, CH3), 4.39 (3H, s, CO2CH3), 7.70 (1H, d, J 7.0 Hz, ArH), 7.87 (1H, d, J
8.0 Hz, ArH), 8.26 (1H, d, J 8.0 Hz, ArH), 8.50e8.56 (2H, m, ArH),
9.21 (1H, s, ArH); dC (125 MHz, DMSO-d6) 19.2, 53.2, 112.9, 125.6,
129.4, 130.7, 133.2, 136.3, 143.7, 165.4; dC (125 MHz, CF3CO2D) 18.5,
nmax (ATP) 1628 (C]N), 1296, 1149 (SO2) cmꢁ1
; dH (500 MHz,
DMSO-d6) 2.29 (3H, s, CH3), 3.92 (3H, s, CO2CH3), 6.70 (1H, d, J
6.0 Hz, ArH), 7.09 (1H, s, ArH), 7.76 (1H, d, J 6.0 Hz, ArH), 7.9e7.97
(2H, m, ArH), 8.66 (1H, s, ArH), 12.73 (1H, br s, NH); dH (500 MHz,
CF3CO2D) 2.85 (3H, s, CH3), 4.35 (3H, s, CO2CH3), 7.59e7.67 (1H,

A. Cherepakha et al. / Tetrahedron 67 (2011) 6233e6239
6239
53.5, 113.7, 121.8, 126.4, 130.0, 133.1, 136.5, 137.0, 137.6, 146.0, 148.5,
152.5, 167.7.
CF3CO2D) 53.8, 120.3, 121.5, 122.5, 125.6, 129.7, 133.0, 135.4, 136.1,
138.4, 146.8, 150.5, 166.6.
4.9.3. 3-Nitro[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide (7c). Yellow
solid; yield 6.5 g (94%) (from 1g), 6.37 g (92%) (from 1h), 6.37 g (92%)
(from 1i); mp 317e319 ꢀC; [found: C, 47.59; H, 2.53; N, 15.18.
C11H7N3O4S requires C, 47.65; H, 2.54; N,15.16%];nmax (ATP) 1646 (C]
4.7. One-pot procedure for the preparation of pyrido[2,1-c]
[1,2,4]benzothiazine-5,5-dioxides 7 from selected sulfonyl
chlorides 1 and 2-aminopyridines 5
N), 1508, 1348 (NO2), 1295, 1126 (SO2)cmꢁ1
; dH (500 MHz, DMSO-
The procedure is identical to the General procedure for the
preparation of sulfonamides 6 above.
d6)¼ 7.12 (1H, t, J 7.0 Hz, ArH), 7.20 (1H, d, J 9.0 Hz, ArH), 7.92 (1H, t, J
8.0 Hz, ArH), 8.45 (1H, d, J 9.5 Hz, ArH), 8.61 (1H, s, ArH), 8.67 (1H, d, J
9.0 Hz, ArH), 8.93 (1H, d, J 7.0 Hz, ArH); dC (125 MHz, DMSO-d6) 114.2,
119.5, 123.3, 124.2, 127.5, 127.8, 133.6, 139.9, 141.8, 147.4, 153.0.
4.8. General non-catalytic procedure for the preparation of
pyrido[2,1-c][1,2,4]benzothiazine-5,5-dioxides 7 from 2-
halobenzenesulfonamides 6
4.9.4. Methyl-8-methylpyrido[2,1-c][1,2,4]benzothiadiazine-3-
carboxylate 5,5-dioxide (7d). Colorless solid; yield 7.07 g (93%)
(one-pot from 1d), 4.15 g (91%) (from 6f), 4.24 g (93%) (from 6g);
mp 240e242 ꢀC; [found: C, 55.24; H, 3.98; N, 9.24. C14H12N2O4S
requires C, 55.26; H, 3.97; N, 9.21%]; nmax (ATP) 1645 (C]N), 1290,
A stirred solution of 2-halo-N-(pyridine-2yl)benzenesulfona-
mide (0.015 mol) and potassium carbonate (4.5 g, 0.0326 mol) in
dry DMF (100 mL) was heated at 80e90 ꢀC for 8 h. Then the
solvent was removed under reduced pressure and the residue
triturated with deionized water (250 mL). The precipitated crude
product was filtered, washed with water, and dried under
vacuum.
1124 (SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.40 (3H, s, CH3), 3.96
(3H, s, CO2CH3), 6.97e7.15 (2H, m, ArH), 8.30 (1H, d, J 8.5 Hz, ArH),
8.36e8.39 (2H, m, ArH), 8.81 (1H, d, J 6.5 Hz, ArH); dH (500 MHz,
CF3CO2D) 3.00 (3H, s, CH3), 4.43 (3H, s, CO2CH3), 7.78e8.00 (2H, m,
ArH), 8.52 (1H, d, J 8.5 Hz, ArH), 9.00 (1H, d, J 8.5 Hz, ArH), 9.14 (1H,
s, ArH), 9.25 (1H, d, J 6.0 Hz, ArH); dC (125 MHz, DMSO-d6) 21.4,
53.3, 116.4, 121.4, 122.0, 124.7, 127.5, 130.6, 132.4, 133.3, 138.7, 152.6,
153.8, 164.8; dC (125 MHz, CF3CO2D) 21.2, 53.8, 119.6, 122.6, 123.5,
125.7, 130.5, 133.0, 135.4, 136.4, 137.9, 148.1, 164.8, 166.4.
4.9. General catalytic procedure for the preparation of pyrido
[2,1-c][1,2,4]benzothiazine-5,5-dioxides 7 from 2-
halobenzenesulfonamides
To a degassed stirred solution of 2-halo-N-(pyridin-2-yl)ben-
zenesulfonamide (0.015 mol) in DMF (100 mL) potassium car-
bonate (4.5 g, 0.0326 mol), copper(I) iodide (0.14 g, 0.75 mmol),
and DMEDA (0.13 g, 0.015 mol) were added under argon flow.
The stirred reaction mixture was heated at 80e90 ꢀC for 8 h
under argon. Then the reaction mixture was filtered through
a Celite pad. The solvent was removed under reduced pressure
and the residue was triturated with deionized water (250 mL).
The solid precipitate was filtered, washed with water, and dried
in vacuum.
4.9.5. Methyl-9-methylpyrido[2,1-c][1,2,4]benzothiadiazine-3-
carboxylate 5,5-dioxide (7e). Colorless solid; yield 6.92 g (91%)
(one-pot from 1d), 4.2 g (92%) (from 6h), 4.2 g (92%) (from 6i); mp
158e160 ꢀC; [found: C, 55.30; H, 3.95; N, 9.24. C14H12N2O4S re-
quires C, 55.26; H, 3.97; N, 9.21%] nmax (ATP) 1653 (C]N),1291,1129
(SO2) cmꢁ1
; dH (500 MHz, DMSO-d6) 2.30 (3H, s, CH3), 3.95 (3H, s,
CO2CH3), 7.10 (1H, d, J 8.0 Hz, ArH), 7.78 (1H, d, J 8.0 Hz, ArH),
8.26e8.43 (2H, m, ArH), 8.69 (1H, s, ArH); dH (500 MHz, CF3CO2D)
2.95 (3H, s, CH3), 4.49 (3H, s, CO2CH3), 8.09 (1H, d, J 8.0 Hz, ArH),
8.62e8.75 (2H, m, ArH), 9.09 (1H, d, J 7.0 Hz, ArH), 9.22(1H, s, ArH),
9.26 (1H, s, ArH); dC (125 MHz, DMSO-d6) 17.4, 53.3, 121.7, 123.7,
124.7, 127.3, 130.3, 130.7, 133.3, 138.8, 144.0, 151.9, 164.7; dC
(125 MHz, CF3CO2D) 16.5, 53.9, 120.3, 123.2, 125.8, 130.6, 132.6,
133.2, 134.6, 134.7, 136.7, 138.5, 150.0, 168.3.
4.9.1. Pyrido[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide (7a). Colorless
solid; yield 3.41 g (98%) (from 6a), 1.84 g (53%) (from 6b), 2.96 g
(85%) (from 6c); mp 235e237 ꢀC; [found: C, 55.82; H, 3.49; N,
12.02. C11H8N2O2S requires C, 56.89; H, 3.47; N, 12.06%]; nmax (ATP)
1641 (C]N), 1297, 1116 (SO2)cmꢁ1
; dH (500 MHz, DMSO-d6)
7.00e7.06 (1H, m, ArH), 7.12 (1H, d, J 8.0 Hz, ArH), 7.75e7.90 (2H,
m, ArH), 7.92 (1H, t, J 8.0 Hz, ArH), 8.01 (1H, d, J 5.0 Hz, ArH), 8.16
(1H, d, J 6.5 Hz, ArH), 8.83 (1H, s, ArH); dH (500 MHz, CF3CO2D)
7.89e7.93 (2H, m, ArH), 8.09 (1H, t, J 6.5 Hz, ArH), 8.14e8.25 (2H,
m, ArH), 8.31 (1H, d, J 7.0 Hz, ArH), 8.56 (1H, t, J 6.5 Hz, ArH), 9.22
(1H, d, J 5.0 Hz, ArH); dC (125 MHz, DMSO-d6) 113.5, 120.7, 123.9,
124.0, 127.7, 130.3, 133.1, 133.6, 135.7, 140.7, 152.7; dC (125 MHz,
CF3CO2D) 120.2, 121.7, 122.1, 123.6, 130.1, 132.6, 134.6, 135.9, 136.4,
147.4.
References and notes
1. Topiliss, J. G.; Yudis, M. D. J. Med. Chem. 1972, 15, 394e400.
2. Tait, A.; Luppi, A.; Franchini, S.; Preziosi, E.; Parenti, C.; Buccioni, M.; Marucci, G.;
Leonardi, A.; Poggessi, E.; Brasili, L. Bioorg. Med. Chem. Lett. 2005, 15, 1185e1188.
3. Dibella, M.; Rinaldi, M.; Fabio, U.; Manicard, G. Farmaco 1973, 28, 777e783.
4. Zhan, P.; Liu, X. Y.; De Clercq, E. Curr. Med. Chem. 2008, 15, 1529e1540.
5. Francotte, P.; de Tullio, P.; Goffin, E.; Dinitilhac, G.; Graindorge, E.; Fraikin, P.;
Lestage, P.; Danober, L.; Thomas, J.-Y.; Caignard, D.-H.; Pirotte, B. J. Med. Chem.
2007, 50, 3153e3157.
6. Pirotte, B.; Podona, T.; Diouf, O.; de Tulio, P.; Lebrun, P.; Dupont, L.; Somers, F.;
Delarge, J.; Morain, P.; Lestage, P.; Lepagnol, J.; Spedding, M. J. Med. Chem. 1998,
41, 2946e2959.
7. Yale, H. L.; Losee, K.; Bernstein, J. J. Am. Chem. Soc. 1960, 82, 2042e2046.
8. Girad, Y.; Atkinson, J. J. Med. Chem. 1982, 25, 113e116.
9. Makino, S.; Okuzumi, T.; Nakanishi, T.; Tsuji, T. Tetrahedron Lett. 2002, 43,
8401e8403.
10. Nazarenko, K. G.; Shirokaya, T. I.; Tolmachev, A. Khim. Geterotsikl. Soedin. 2005,
225e229.
11. Girad, Y.; Atkinson, J. G.; Rokach, J. J. Chem. Soc., Perkin Trans. 1 1979, 1043e1047.
12. Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454e9457.
13. Nielsen, F. E.; Ebdrup, S.; Jensen, A. F.; Ynddal, L.; Bodvarsdottir, T. B.; Stidsen, C.;
Worsaae, A.; Boonen, H. C. M.; Arkhammar, P. O. G.; Fremming, T.; Wahl, P.;
Kornø, H. T.; Hansen, J. B. J. Med. Chem. 2006, 49, 4127e4139.
14. Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Comb. Chem. 2009, 11, 653e657.
15. Moelehr, H.; Niefenthaler, H. Arch. Pharmacol. 1990, 323, 47e52.
16. Khelili, S.; Faury, G.; Nicolle, E.; Verdetti, J.; Leclerc, G. Med. Chem. Res. 2003, 12,
457e470.
4.9.2. Methyl-pyrido[2,1-c][1,2,4]benzothiadiazine-3-carboxylate
5,5-dioxide (7b). Colorless solid; yield 6.3 g (87%) (one-pot from 1a
and 5a), 3.91 g (90%) (from 6d), 4 g (92%) (from 6e); mp
237e239 ꢀC; [found: C, 53.70; H, 3.48; N, 9.61. C13H10N2O4S re-
quires C, 53.79; H, 3.47; N, 9.65%]; nmax (ATP) 1655 (C]N), 1290,
1126 (SO2)cmꢁ1
; dH (500 MHz, DMSO-d6) 3.96 (3H, s, CO2CH3), 7.08
(1H, t, J 7.0 Hz, ArH), 7.16 (1H, d, J 8.0 Hz, ArH), 7.89 (1H, t, J 7.0 Hz,
ArH), 8.24e8.47 (3H, m, ArH), 8.89 (1H, d, J 7.0 Hz, ArH); dH
(500 MHz, CF3CO2D) 4.37 (3H, s, CO2CH3), 7.89 (1H, t, J 7.0 Hz, ArH),
7.96 (1H, d, J 8.0 Hz, ArH), 8.45 (1H, d, J 8.0 Hz, ArH), 8.59 (1H, t, J
8.0 Hz, ArH), 8.93 (1H, d, J 8.0 Hz, ArH), 9.10 (1H, s, ArH), 9.22 (1H, d,
J 7.0 Hz, ArH); dC (125 MHz, DMSO-d6) 53.3, 113.8,121.7,124.2, 124.7,
127.4, 130.8, 132.2, 133.4, 138.8, 141.3, 152.8, 164.7; dC (125 MHz,
17. Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038e2039.