A. Cherepakha et al. / Tetrahedron Letters 54 (2013) 986–988
987
O
O
O
O
O
O
H
N
6
9
5
R
S
F
R
S
N
S
R
i
H2N
4
Cl
NH
N
NH
5a
9a
N
7
8
+
3a
Y
X
R1
R1
Y
X
3
N
N
X
Y
5
6
1
1
2
1a: R=R1=H
Figure 1. Atom numbering scheme for compounds 3 and 6.
1b: R=CO2CH3 R1=H
1c: R=NO2 R1=H
1i: R=H R1=NO2
IR spectra of compounds 3 and 6 at 1110–1135 cmÀ1 and 1289–
1318 cmÀ1, respectively.
As shown in Figure 2, the reaction of methyl 3-(chlorosulfonyl)-
4-fluorobenzoate (1b) with 4H-1,2,3-triazol-3-amine (5b) could
give two cyclization products 6c (structures A and B).
5a: X=CH, Y=C-CN
5b: X=CH, Y=N
5c: X=Y=N
In structure A, C-2 is connected to two sp2 nitrogen atoms, N-1
and N-3, whereas in structure B, C-1 is bound to an sp3 nitrogen N-
1a and sp2 nitrogen N-2. Analysis of the literature shows that C-2
of [1,2,4]triazolo[1,5-a]pyridine (structure C in Fig. 2), which is
analogous with structure A, appears at 154 ppm in the 13C NMR
spectrum.8 The 13C NMR spectrum of compound 6c reveals the
signal for C-2 at 153.7 ppm. Notably, C-1 of structure D (Fig. 2),
which is analogous to structure B, appears at 136 ppm in the 13C
NMR spectrum.8 Therefore, on the basis of its 13C NMR spectrum,
compound 6c is ascribed to structure A.
5d: X=C-CO2CH3 Y=N
6a: R=R1=H, X=C-CO2CH3 Y=N
6b: R=CO2CH3, R1=H, X=CH, Y=C-CN
6c: R=CO2CH3, R1=H, X=CH, Y=N
6d: R=CO2CH3, R1=H, X=Y=N
6e: R=NO2, R1=H, X=CH, Y=N
6f: R=H, R1=NO2, X=CH, Y=N
Additional synthetic evidence for structure A for 6c is derived
from its N-methylation reaction. Scheme 3 shows that three iso-
meric products 7a–7c might be expected as a result of the
methylation.
Scheme 2. Preparation of annulated 2H-1,2,4-benzothiadiazine S,S-dioxides 6.
Reagents and conditions: (i) DMF, K2CO3, 20–90 °C.
The 1H NMR spectrum of compound 7 showed two closely lying
singlets at 3.85 and 3.93 ppm corresponding to two methyl groups.
Nuclear Overhauser effect (NOE) analysis (Fig. 3) revealed that the
methyl group appearing as a singlet at 3.93 ppm had NOEs with
protons H-6 and H-8, while the remaining methyl group singlet
at 3.85 ppm demonstrated NOEs with protons H-9 and H-2. This
means that the former methyl signal corresponds to a carboxy-
methyl group, while the latter corresponds to the N-Me group.
Therefore, compound 7 exists in form 7b. This provides additional
confirmation of structure A ascribed above to compound 6c.
As shown in Scheme 4, the azolo[c][1,2,4]benzothiadiazine unit
is considerably stable under basic and acidic conditions allowing
for flexible functional group transformations. For example, hydro-
lysis of the ester groups in 6a and 6c gives rise to carboxylic acids 8
and 9, respectively. Reduction of the nitro-group in 6e and 6f read-
ily yields amines 10 and 11.
sulfonamides 4c,d did not undergo the intramolecular nucleo-
philic displacement under either catalytic or non-catalytic
conditions.
Variation of the azole part was studied by reacting methyl
3-(chlorosulfonyl)-4-fluorobenzoate (1b) with 3-aminoazoles
5a–c (Scheme 2). The reactions proceeded in one pot under
non-catalytic conditions resulting in the corresponding annulated
2H-1,2,4-benzothiadiazine S,S-dioxides 6 (Scheme 2).
The 1H NMR spectra of compounds 3 and 6 recorded in DMSO-
d6 revealed broad singlets due to NH protons in the range of 12–
13 ppm. The 3-CH protons (Fig. 1) of compounds 3 manifested
themselves as characteristic singlets at 5.9–6.0 ppm. The 13C
NMR spectra of compounds 3 and 6 showed characteristic signals
due to C-3a in the range of 135–140 ppm. Characteristic symmetric
and asymmetric vibrations of the sulfo-group were observed in the
In summary, we have described a new and efficient approach to
a variety of azolo[c][1,2,4]benzothiadiazine S,S-dioxides. The title
compounds were prepared through one- or two-step reactions of
o-haloarylsulfonyl chlorides and aminoazoles. The reported ap-
proach broadens considerably the scope of the available methods
for the preparation of azolo[c][1,2,4]benzothiadiazine S,S-dioxides.
This method allows variation of the number of substituents on
both the benzene and azole rings, as well as the azole fragment
itself.
CH3
CH3
O
O
O
O
1a
1a
O
O
O
O
1
2
1
2
N
S
NH
N
N
S
NH
Typical procedure for the preparation of annulated azol-
o[c][1,2,4]benzothiadiazine S,S-dioxides 3 from sulfonyl chlorides
1a–1c and 2.
N
N
3
N
3
B
6c
A
To a stirred solution of a 3-aminoazole 2 (0.005 mol) and K2CO3
(1.38 g, 0.01 mol) in DMF (50 mL) was added dropwise a solution
of sulfonyl chloride 1 (0.005 mol) in DMF (50 mL). The mixture
was stirred for 2 h at room temperature and then for 8 h at 80 °C.
The solvent was removed under reduced pressure and the residue
was dissolved in deionized H2O (200 mL). The pH of the solution
was adjusted to 1 with concentrated HCl causing precipitation of
a colorless solid. The precipitate was filtered and washed with
H2O (3 Â 75 mL) and with i-PrOH (2 Â 10 mL).
1a
1a
1
N
N
3
N
1 N
N
3
N
2
2
D
C
Figure 2. Structural considerations for compound 6c.
Cherepakha, Artem
