Regioselective reduction of 3-substituted 2,3-dihydrobenzothiadiazines with borohydrides

Article abstract of DOI:10.1016/j.tetlet.2010.06.081

A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides was developed based on regioselective reduction with NaBH₃CN in different solvents.

Full text of DOI:10.1016/j.tetlet.2010.06.081

Tetrahedron Letters 51 (2010) 4433–4436
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective reduction of 3-substituted 2,3-dihydrobenzothiadiazines
with borohydrides
a
a
a
Umberto M. Battisti a, Giuseppe Cannazza a, , Marina M. Carrozzo , Daniela Braghiroli , Carlo Parenti ,
*
Francesca Rosato b, Luigino Troisi b
a Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 4100 Modena, Italy
b Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides was
developed based on regioselective reduction with NaBH3CN in different solvents.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 May 2010
Revised 14 June 2010
Accepted 16 June 2010
Available online 20 June 2010
Keywords:
2-Aminobenzenesulfonamide
3-Chiral 2,3-dihydrobenzothiadiazines
Reduction
Sodium cyanoborohydride
The chemistry of 2-aminobenzenesulfonamide is extensively
studied because it represents an important scaffold in pharmaceu-
tical chemistry.1–5 Recently 5-chloro-2-(methylamino)benzene sul-
fonamide and 5-chloro-2-(ethylamino)benzenesulfonamide have
been proposed as positive allosteric modulators of AMPA receptor
suggesting a possible use as nootropic drugs.6 In this work a possi-
ble synthetic route is proposed to obtain different substituted 2-
aminobenzenesulfonamides at the sulfonamidic or anilinic nitro-
gen atom. Recently, we demonstrated that some derivatives of chi-
ral C-3 2,3-dihydrobenzothiadiazines undergo a rapid racemization
in protic solvents.7–9 It was hypothesized that the racemization in-
volves the formation of an imine intermediate with the double
bond at N-2 C-3 or C-3 N-4 depending on the nature of the substit-
uents and on the pH of the racemization solvent (Scheme 1).10
Starting from the proposed mechanism, the selected chiral 2,3-
dihydrobenzothiadiazine, ( )-7-chloro-3-methyl-3,4-dihydro-2H-
1,2,4-benzothiadiazine 1,1-dioxide (IDRA21, 1), was subjected to
the action of imine-reducing agents. As previously reported by
Biressi et al. we tested on 1 the action of sodium borohydride
(NaBH4) in methanol and of triethylamino borane in acetic acid
obtaining, respectively, 2-amino-5-chloro-N-ethylbenzenesulfona-
mide (1b) and 5-chloro-2-(ethylamino)benzenesulfonamide
(1a).11 In the attempt to explain if the results of the reduction
depend on reductive agents or solvent conditions, sodium cyano-
borohydride (NaBH3CN) was selected because it is presently the
most successful and often used reductive agent for imine reduc-
tions and it is effective with different solvent conditions. When
compound 1 was treated with NaBH3CN in glacial acetic acid at
room temperature, 1a was obtained in 93% yield (Table 1, entry
1).12 Differently, when compound 1 was treated with NaBH3CN un-
der water/alcoholic conditions 1b was isolated in 86% yield (Table
1, entry 2).13 The results could be explained with the formation of
two different imine intermediates depending on the pH of the reac-
tion mixture. Using glacial acetic acid as the solvent the protonation
of N-2 led to the C-3 N-4 imine intermediate that was subsequently
reduced by NaBH3CN giving 1a (Scheme 2). Using water/ethanol
(1:3 (v/v)) as the solvent, the dissociation of the more acidic sulfo-
namidic nitrogen promoted by the electron-withdrawing effect of
the sulfone moiety led to N-2 C-3 imine intermediate giving 1b in
good yields (89%) by the action of NaBH3CN (Scheme 2). Interest-
ingly in the latter conditions 2-amino-5-chlorobenzenesulfona-
mide was isolated in 10% yield. Its formation could be explained
by the hydrolysis of the imine intermediate as reported in Scheme
1. In our opinion the rate of the reductive reaction is lowered
because NaBH3CN is a less effective reducing agent under neutral/
basic than under acidic conditions allowing hydrolysis process.
Subsequently different substituted 2,3-dihydrobenzothiadiazines
were subjected to the reductive action of NaBH3CN. The results
are reported in Table 1. Reduction of compound 2 under acidic con-
ditions led to 2a (Table 1, entry 3) while in water/ethanol solvent
only 2-amino-5-chloro-N-ethylbenzenesulfonamide (1b) was
obtained (Table 1, entry 4). Previously it was reported that no race-
mization occurred under neutral conditions for 2-alkyl-substituted
* Corresponding author. Tel.: +39 059 2055136; fax: +39 059 2055750.
E-mail address: giuseppe.cannazza@unimore.it (G. Cannazza).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.081

4434
U. M. Battisti et al. / Tetrahedron Letters 51 (2010) 4433–4436
O
O
Cl
S
N
R
NH2
O
O
Cl
S
N-
H2O
R
N
H
b)
H
H
O
O
O
O
O
NH2
Cl
O
S
Cl
S
Cl
S
NH
NH
R
O
+
R
R
H
NH2
N
H
N
H
O
O
H
H
Cl
S
N+
H
R
a)
H2O
N
H
H
O
O
Cl
S
N
NH2
R
Scheme 1. Possible racemization and hydrolysis mechanism for C-3 chiral 2,3-dihydrobenzothiadiazines. (a) Acid conditions (b) neutral/basic conditions.
Table 1
Reduction of 2,3-dihydrobenzothiadiazines with NaBH3CN
Entry
Compound
Conditions
Product
Yielda (%)
O
O
O
O
Cl
S
Cl
S
NH2
CH3
NH
NH
N
1
a
93
NH
N
H
CH3
1a
1
O
O
O
O
O
Cl
Cl
S
Cl
S
NH
2
b
86
NH2
CH3
N
H
CH3
1b
1
O
O
O
S
S
Cl
Cl
Cl
CH3
CH3
NH
CH3
CH3
3
4
a
96
95
N
H
NH
2a
2
O
O
O
O
O
Cl
Cl
S
S
N
CH3
CH3
NH
b
N
H
NH2
CH3
2
1b
O
O
O
S
O
O
S
Cl
S
NH
NH
CH3
CH3
NH2
CH3
CH3
*
5
a
—
N
CH3
CH3
NH
N
3
3a
2a

U. M. Battisti et al. / Tetrahedron Letters 51 (2010) 4433–4436
4435
Table 1 (continued)
Entry
Compound
Conditions
Product
Yielda (%)
O
O
O
O
O
Cl
S
N
Cl
S
NH
NH
CH3
CH3
6
7
8
9
b
89
65
90
CH3
NH
2a
CH3
3
O
O
O
Cl
S
Cl
S
NH
NH2
CH3
a
b
a
N
H
CH3
NH
H3C
Cl
H3C
Cl
4
O
4a
O
O
O
S
S
NH
NH
N
H
CH3
NH2
CH3
H3C
Cl
H3C
Cl
4
4b
O
O
O
O
O
O
S
S
N
Cl
S
NH
NH
NH
NH2
**
—
CH3
NH
CH3
N
CH3
5
O
5a
O
5b
O
O
Cl
S
Cl
S
N
NH
10
11
12
b
a
b
91
98
—
NH
CH3
CH3
5
O
5b
O
O
O
S
S
N
NH
NH
NH2
N
6
O
6a
O
S
N
—
6
Reaction conditions a: NaBH3CN (6.0 equiv) in glacial AcOH at room temperature for 3 h.
Reaction conditions b: NaBH3CN (6.0 equiv) in water/ethanol 1:3 (v/v) at 70 °C for 6 h.
a
Isolated yield.
*
Isolated in a molar ratio of 1:3, respectively.
Isolated in a molar ratio of 4:1, respectively.
**
benzothiadiazines while a rapid racemization under acidic condi-
tions was observed.8 Probably in water/ethanol the absence of the
acid hydrogen on N-2 of 2 prevents the formation of the N-2 C-3
imine intermediate, leading to a rapid thermally induced hydroly-
sis. Compound 3 in glacial acetic acid reacts with NaBH3CN giving
2a and 3a in a ratio of 3:1, respectively (Table 1, entry 5). The alkyl
substituent on N-4 could favor the N-2 C-3 imine intermediate over
the C-3 N-4 iminium intermediate. Interestingly when the reduc-
tion was performed at lower temperature (10 °C), a mixture of 2a
and 3a in a 1:1 ratio was obtained suggesting that the C-3 N-4 imin-
ium intermediate is kinetically favored while the N-2 C-3 imine
intermediate is thermodynamically more stable. Reduction of 3 in
water/ethanol shows, as expected, a complete regioselectivity giv-
ing 2a (Table 1, entry 6). Similar to IDRA21 compound 4 provides
a good regioselective reduction giving 4a (Table 1, entry 7) under
acidic conditions and 4b in water/ethanol (Table 1, entry 8). How-

4436
U. M. Battisti et al. / Tetrahedron Letters 51 (2010) 4433–4436
O
O
Cl
S
NH2
CH3
AcOH
O
O
NH
Cl
S
NH
NaBH3CN
1a
N
H
CH3
O
O
H2O/EtOH
Cl
S
1
NH
NH2
CH3
1b
Scheme 2. Reduction of compound 1 with NaBH3CN in AcOH and in water/ethanol.
2. Shaw, A. N.; Tedesco, R.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M. G.;
Dhanak, D.; Duffy, K.; Fitch, D. M.; Gates, A. Bioorg. Med. Chem. Lett. 2009, 19,
4350–4353.
3. Lachenicht, S.; Fischer, S.; Schimdt, C.; Winkler, M.; Rood, A.; Lemoine, H.;
Braun, M. ChemMedChem 2009, 4, 1850–1858.
4. Francotte, P.; Goffin, E.; Fraikin, P.; Lestage, P.; Van Heugen, J.; Gillotin, F.;
Caignard, D.; Danobèr, L.; Thomas, J.; Chiap, P.; Caignard, D. J. Med. Chem. 2010,
53, 1700–1711.
5. Phillips, D.; Sonnenberg, J.; Arai, A. C.; Vaswani, R.; Krutzik, P. O.; Kleisli, T.;
Kessler, M.; Granger, R.; Lynch, G.; Chamberlain, A. R. Bioorg. Med. Chem. 2002,
10, 1229–1248.
6. Cannazza, G.; Jozwiak, K.; Parenti, C.; Braghiroli, D.; Carrozzo, M. M.; Puia, G.;
Losi, G.; Baraldi, M.; Lindner, W.; Wainer, I. Bioorg. Med. Chem. Lett. 2009, 19,
1254–1257.
7. Cannazza, G.; Carrozzo, M. M.; Braghiroli, D.; Parenti, C. J. Chromatogr., A 2008,
1212, 41–47.
8. Carrozzo, M. M.; Cannazza, G.; Battisti, U.; Braghiroli, D.; Parenti, C. Chirality
2010, 22, 389–397.
9. Cannazza, G.; Braghiroli, D.; Tait, A.; Baraldi, M.; Parenti, C.; Lindner, W.
Chirality 2001, 13, 94–101.
ever, it was observed that under acidic conditions the yield of
reduction was lower than the one obtained for IDRA21 (65% yield).
A longer reaction time (12 h) was required to obtain a 95% yield
suggesting that the inductive effect of the ethyl substituent in 5 po-
sition could affect reduction timescale. These data are in accordance
with the previously observed decreased racemization rate at low
pH for chiral 5-alkyl-substituted 2,3-dihydrobenzothiadiazines.
Reduction with NaBH3CN of compound 5 has shown a behavior
similar to that observed for 3: in water/ethanol only 5b was isolated
(Table 1, entry 10), while under acidic conditions 5a and 5b were
obtained (Table 1, entry 9). Compound 6 was reduced by NaBH3CN
only under acidic conditions to give 6a (Table 1, entry 11) while in
water/ethanol only unchanged starting material was obtained. Pre-
viously no racemization was observed for compound 6 under neu-
tral/basic conditions, while it racemizes at low pH indicating that
strong acid conditions are required for the iminium intermediate
formation.8 In summary, a new synthetic path for N-1 or N-2 al-
kyl-substituted 2-aminobenzenesulfonamides was developed
based on regioselective reduction with NaBH3CN in different sol-
vents. This simple method could be adapted for the synthesis of
more advanced intermediates.
10. Cannazza, G.; Carrozzo, M. M.; Battisti, U.; Braghiroli, D.; Parenti, C.; Troisi, A.;
Troisi, L. Chirality 2010. doi:10.1002/chir.20838.
11. Biressi, M. G.; Carissimi, M.; Ravenna, F. Tetrahedron Lett. 1966, 33, 3949–3952.
12. General procedure
NaBH3CN: To
a
for the reduction of 2,3-dihydrobenzothiadiazines with
solution of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4
a
benzothiadiazine-1,1-dioxide (1.0 mmol) in glacial acetic acid (20 ml)
NaBH3CN (6.0 mmol) was added. The resulting mixture was stirred at room
temperature for 3 h. The mixture was then neutralized with NaOH 10 M and
extracted with ethyl acetate (2 Â 20 ml). The organic layer was washed with
deionized water and dried over anhydrous sodium sulfate. The solvent was
removed under vacuum and the residue was purified by chromatography,
eluting with diethyl ether/petroleum ether 1:1, to give the pure product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.081.
13. General procedure
b
for the reduction of 2,3-dihydrobenzothiadiazines with
solution of 7-chloro-3-
NaBH3CN: NaBH3CN (6.0 mmol) was added to
a
methyl-3,4-dihydro-2H-1,2,4 benzothiadiazine-1,1-dioxide (1.0 mmol) in 30%
aqueous ethanol (20 ml). The mixture was stirred at 70 °C for 6 h. The mixture
was neutralized with dil HCl and extracted with ethyl acetate (2 Â 20). The
organic layer was dried over anhydrous sodium sulfate and the solvent was
removed under vacuum. The residue was purified by column chromatography
using diethyl ether/petroleum ether 1:1, to give the pure product.
References and notes
1. Yoshikawa, K.; Kobayashi, S.; Nakamoto, Y.; Haginoya, N.; Komoriya, S.;
Yoshino, T.; Nagata, T.; Mochizuki, A.; Watanabe, K.; Suzuki, M.; Kanno, H.;
Ohta, T. Bioorg. Med. Chem. 2009, 17, 8221–8233.