Regioselective cyclization of chloroacylaminobenzenesulfonamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.04.009

Chloroacylaminobenzensulfonamides regioselectively thermally cyclize under solvent free conditions to 1,2,4-benzothiadiazines with five- and six-membered rings fused on face b.

Full text of DOI:10.1016/j.tetlet.2012.04.009

Tetrahedron Letters 53 (2012) 3023–3026
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective cyclization of chloroacylaminobenzenesulfonamide derivatives
Marina M. Carrozzo a, Umberto M. Battisti b, Giuseppe Cannazza b, , Cinzia Citti a, Carlo Parenti b,
⇑
Luigino Troisi a,
⇑
a Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
b Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Chloroacylaminobenzensulfonamides regioselectively thermally cyclize under solvent free conditions to
1,2,4-benzothiadiazines with five- and six-membered rings fused on face b.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 February 2012
Revised 30 March 2012
Accepted 2 April 2012
Available online 9 April 2012
Keywords:
1,2,4-Benzothiadiazine
Chloroacylaminobenzenesulfonamides
Thermal cyclization
Benzothiadiazines represent an important scaffold in pharma-
ceutical field due to their biological properties such as diuretics,
antitumor, and antiviral agents, ATP-sensitive potassium channel
activators and positive allosteric modulators of AMPA receptors
(AMPApams).1–4
O
O
S
NH
In particular, benzothiadiazines with a pyrrolo ring fused
on face c as ( )-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-ben-
zothiadiazine 5,5-dioxide (1) (Fig. 1) have attracted particular
attention since in vivo animal experiments demonstrated their
cognition enhancing properties, suggesting a potential applicabil-
ity of this drug as a nootropic agent.5–14 Moreover 1,2,4-benzothi-
adiazines with the ring fused on face b are important scaffold of
biological interests such as antitumor and antiviral agents.15,16
Since only few publications reported the synthesis of this
important class of heterocycles,15–21 it becomes important to de-
velop a simple and versatile synthetic pathway to obtain 1,2,4-ben-
zothiadiazine 1,1-dioxide with a ring condensed on face b and/or
on face c.
A common strategy for the synthesis of 1,2,4-benzothiadia-
zines with the ring fused on face c involves the annulations of
chloroacylaminobenzenesulfonamides (3,4) as reported in Scheme
1.17–21 It was possible to obtain 2,3-dihydro-1H-pyrrolo[2,1-
c][1,2,4]benzothiadiazine 5,5-dioxide (6) and 3-chloro-7,8,9,10-
tetrahydropyrido[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide (7) in
N
Figure 1. ( )-2,3,3a,4-Tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,
5-dioxide (1).
aminobenzenesulfonamide (4) in NaOH at 2% for 15 min,
respectively. 2-(6-Chlorohexanoyl)-5-chloroaminobenzenesulfona-
mide (5) refluxed in NaOH gave quantitatively the corresponding
7-chloro-3-(5-chloropenthyl)-2H-1,2,4-benzothiadiazine 1,1-diox-
ide (10) and not the expected 3-chloro-8,9,10,11-tetrahydro-7H-
azepino[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide (11) (Scheme
2).
The subsequent reduction with lithium aluminium hydride fur-
nished the corresponding 1,2,4-dihydrobenzothiadiazine deriva-
tives with five- and six-membered rings fused on face c (8,9).
Due to the biological importance of benzothiadiazine with the
ring fused on face b, we have tentatively varied the reaction condi-
tions in order to cyclize chloroacylaminobenzensolfonamides
regioselectively on face b. Since 1,2,4-benzothiadiazines with the
ring fused on face c were obtained in basic media, in a first attempt
the cyclization reaction was performed in neutral and acidic media.
Anyway only starting material was isolated when the pH was
excellent yields (98%) by refluxing 2-(c-chlorobutyryl)-5-chloro-
aminobenzenesulfonamide (3) and 2-(d-chlorovaleryl)-5-chloro-
⇑
Corresponding authors. Tel.: +39 059 2055136; fax: +39 059 2055750.
E-mail addresses: giuseppe.cannazza@unimore.it (G. Cannazza), luigino.troisi@
unisalento.it (L. Troisi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.009

3024
M. M. Carrozzo et al. / Tetrahedron Letters 53 (2012) 3023–3026
O
O
O
O
Cl
S
Cl
S
Cl
SO2NH2
(i)
Cl
SO2NH2
NH
N
(ii)
(CH2)n
Cl
(CH2)n
Cl
N
N
H
NH2
NHCOCH2(CH2)nCH2Cl
3: n = 1
4: n = 2
5: n = 3
2
O
O
O
O
Cl
S
Cl
S
N
(iii)
NH
N
N
(CH2)n
(CH2)n
6: n = 1
7: n = 2
8: n = 1
9
: n = 2
Scheme 1. Reagents and conditions: (i) chloroacyl chloride (2 equiv), N,N-DMA, 0 °C; (ii) NaOH (2%) (3 equiv), 100 °C, 15 min; (iii) LiAlH4 (2 equiv), diethylether, À10 °C.
O
O
O
O
Cl
SO2NH2
Cl
S
Cl
S
(i)
N
N
NHCO(CH2)5Cl
N
N
H
(CH2)5Cl
5
11
10
Scheme 2. Reagent and conditions: (i) NaOH refluxed; 250 °C 15 min.
10000000
8000000
6000000
4000000
2000000
0
4
6
8
10 12 14 16 18 20 22 24 26 28 30
Time (min)
Figure 2. GC–MS chromatogram of 3.

M. M. Carrozzo et al. / Tetrahedron Letters 53 (2012) 3023–3026
3025
O
O
O
O
Cl
S
Cl
S
NH
Cl
SO2NH2
NH2
Cl
SO2NH2
N
(ii)
(i)
(CH2)n
Cl
(CH2)n
Cl
N
N
H
NHCOCH2(CH2)nCH2Cl
3: n = 1
4: n = 2
2
5
: n = 3
O
O
O
O
N
Cl
S
Cl
S
N
(iii)
(CH2)n
(CH2)n
N
N
H
12: n = 1 (yield 86 %)
13: n = 2 (yield 82 %)
14
: n = 1 (yield 50 %)
15
: n = 2 (yield 42 %)
Scheme 3. Reagents and conditions: (i) chloroacylchloride (2 equiv), N,N-DMA, 0 °C; (ii) 250 °C, 15 min; (iii) LiAlH4 (2 equiv), diethylether, À10 °C.
lower than 7. Moreover no cyclization occurred when the reaction
was performed in different solvents such as 2-propanol, acetoni-
trile, and ethyl acetate at their refluxed temperatures.
the corresponding 3-chloro-8,9,10,11-tetrahydro-7H-azepino[2,
1-c][1,2,4]benzothiadiazine 5,5-dioxide but to 7-chloro-3-(5-chlor-
openthyl)-2H-1,2,4-benzothiadiazine 1,1-dioxide (10) without fur-
ther cyclization (Scheme 2). The same result was obtained when
the cyclization of 5 was performed in refluxed NaOH (Scheme 2).
The last step was the saturation of the double bond of thiadiaz-
ide ring (Scheme 3).17–21 This was achieved by the action of lithium
aluminium hydride leading to final dihydrobenzothiadiazines with
the five- and six-membered ring fused on face b (14 and 15)
In conclusion, the results obtained have suggested a simple and
versatile synthetic strategy for the preparation of two different
pharmacological relevant scaffolds. Starting from chloroacylben-
zenesulfonamides, it was possible to obtain selectively 1,2,4-ben-
zothiadiazines with five- and six-membered rings fused on face c
and on face b in one pot.
An important indication to prepare 1,2,4-benzothiadiazine with
the ring fused on face b was obtained by injection of chloroacyla-
minobenzensulfonamides (3,4) in GC–MS. Injection of 3 furnished
a chromatogram with two peaks with the same molecular ion cor-
responding to the cyclized 1,2,4-benzothiadiazine 6 (Fig. 2). As a
consequence authentic 6 was injected into GC–MS and the reten-
tion time and fragmentation spectrum were superimposable to
those of second eluted peak obtained by injection of 3. This result
indicated that the second eluted peak corresponded to the cycliza-
tion product of 3 with the ring fused on face c (6).
We hypothesized that the first eluted peak (with the same
molecular ion of the second peak eluted corresponding to 6) was
the isomer of 6 with the ring fused on face b (Fig. 2). In order to
confirm the identity of the first eluted peak, 7-chloro-2,3-dihy-
dro-1H-pyrrolo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide (12)
was prepared as reported in the literature and injected into GC–
MS.16Authentic 12 eluted with the same retention time with a
fragmentation spectrum superimposable to that of the first eluted
peak obtained by injection of 3.
Supplementary data
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.009.
References and notes
The results obtained indicated that 3, when injected into GC–
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ring fused on face b and on face c (Fig. 2).
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