An efficient synthesis of 3,4-dihydro-1H-2,3-benzothiazine 2,2-dioxides using amberlyst 15 and amberlyst XN 1010

Article abstract of DOI:10.1081/SCC-120014987

Resins Amberlyst 15 and Amberlyst XN 1010 are used in the synthesis of 3,4-dihydro-1H-2,3-benzothiazines 2,2-dioxide. Advantages of this new procedure are simple work-up, high yield and selectivity, easy recovery of the catalyst and no waste problems.

Full text of DOI:10.1081/SCC-120014987

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AN EFFICIENT SYNTHESIS OF 3,4-DIHYDRO-1H-2,3-
BENZOTHIAZINE 2,2-DIOXIDES USING AMBERLYST 15
AND AMBERLYST XN 1010
Rodolfo D. Bravo a & Alicia S. Cánepa a
a Laboratorio de Estudio de Compuestos Orgánicos , Departamento de Química , Facultad
de Ciencias Exactas , Universidad Nacional de La Plata , Calle 47 y 115, 1900-La Plata,
Argentina
Published online: 16 Aug 2006.
To cite this article: Rodolfo D. Bravo & Alicia S. Cánepa (2002) AN EFFICIENT SYNTHESIS OF 3,4-DIHYDRO-1H-2,3-
BENZOTHIAZINE 2,2-DIOXIDES USING AMBERLYST 15 AND AMBERLYST XN 1010, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:23, 3675-3680, DOI: 10.1081/SCC-120014987
To link to this article: http://dx.doi.org/10.1081/SCC-120014987
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 23, pp. 3675–3680, 2002
AN EFFICIENT SYNTHESIS OF
3,4-DIHYDRO-1H-2,3-BENZOTHIAZINE
2,2-DIOXIDES USING AMBERLYST 15
AND AMBERLYST XN 1010
*
Rodolfo D. Bravo and Alicia S. Canepa
Laboratorio de Estudio de Compuestos Organicos,
Departamento de Quımica, Facultad de Ciencias
Exactas, Universidad Nacional de La Plata,
Calle 47 y 115, 1900-La Plata, Argentina
ABSTRACT
Resins Amberlyst 15 and Amberlyst XN 1010 are used in the
synthesis of 3,4-dihydro-1H-2,3-benzothiazines 2,2-dioxide.
Advantages of this new procedure are simple work-up, high
yield and selectivity, easy recovery of the catalyst and no
waste problems.
Although acylaminomethylation is a widely employed and important
electrophilic aromatic substitution,[1–3] the related sulphonylamido-
methylation is less known. A previous paper described the intramolecular
sulphonylamidomethylation of benzylsulphonamides 1 to give 3,4-dihydro-
1H-2,3-benzothiazine 2,2-dioxides 2.[4] As reported, short reaction times or
*Corresponding author. E-mail: rdb@nahuel.biol.unlp.edu.ar
3675
DOI: 10.1081/SCC-120014987
Copyright & 2002 by Marcel Dekker, Inc.
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3676
BRAVO AND CANEPA
1a R1 ¼ H; R2 ¼ H
1d R1 ¼ Cl; R2 ¼ H
1e R1 ¼ H; R2 ¼ Me
1f R1 ¼ H; R2 ¼ Et
1g R1 ¼ H; R2 ¼ i-Pr
1b R1 ¼ Me; R2 ¼ H
1h R1 ¼ H; R2 ¼ p-ClC6H4
1i R1 ¼ H; R2 ¼ p-NO2C6H4
1c R1 ¼ AcNH; R2 ¼ H
Scheme 1.
low acid strength led to the 1,3,5-tris-(benzylsulphonyl)-hexahydro-1,3,5-
triazines and N,N0-methylene-bis-benzylsulphonamides as kinetic products,[4]
while under strong acid catalysis, the thermodynamic products 2 were
obtained.
Another route to obtain 2 is the intramolecular vicarious nucleophilic
substitution of hydrogen(VNS), which is however, limited to chloromethyl-
sulphonamides of m-nitrobenzylamines.[5–7]
In the previously reported method,[4] the large excess of acid which
had to be used presented some difficulties in the work up of the reaction
mixture. Therefore, we have searched for a modification of the reaction.
The use of ion exchange resins in organic synthesis received great
attention during the last years. The resins are commercially available in a
wide variety of shapes and with different chemical features.[8] Amberlyst 15
and Amberlyst XN 1010 have been used in various catalyzed reactions, e.g.,
esterification,[9–11] etherification,[12] oxidation,[13] hydration of olefins,[14]
condensation,[15] cyclization[16] and electrophilic aromatic substitution.[17]
We now report that ion exchange resins Amberlyst 15 and Amberlyst XN
1010 are excellent catalyst for sulphonylamidomethylation.
In the presence of either Amberlyst 15 or Amberlyst XN 1010 benzyl-
sulphonamides 1 and formaldehyde, generated in situ from s-trioxane,
reacted in 1,2-dichloroethane (Tables 1 and 2). Temperatures of 35 or 80ꢀC
and reaction times from 3 to 6 h were usually required. In some cases filtration
from the exchange resin, and evaporation gave the products in high purity
(>97% by GLC). In other cases the crude product was purified by cristalliza-
tion or preparative column chromatography.
In regard to the choice as Amberlyst 15 vs. Amberlyst XN 1010 Table 1
indicates that the first one gave better results with benzylsulphonamides 1
with a nuclear substituent (R1 ¼ H, R2 ¼ H).
On the other hand, when N-monosubstituted derivates (R1 ¼ H,
R2 ¼ H) with a bulky substituted were used (Table 2) Amberlyst XN 1010

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3,4-DIHYDRO-1H-2,3-BENZOTHIAZINE 2,2-DIOXIDES
3677
Table 1. Cyclization of Benzylsulphonamides
benzothiazine 2,2-Dioxides 2 with s-Trioxane (R1
1
to 3,4-Dihydro-1H-2,3-
6
¼H, R2 ¼ H)
M.P. (ꢀC)
Yield 2
(%)
Lit. Yield[4]
(%)
Temp. (ꢀC)/
Time (h)
Resin
(meq.)a
Entry
R1
Found
Lit.[4]
1a
1a
1b
1b
1c
1c
1d
1d
H
H
100
100
78
68
68
44
44
62
62
49
49
142–143
142–143
119–120d
119–120d
201–202d
201–202d
119–120d
118–119d
142–143
142–143
118–119
118–119
201–202
201–202
118–119
118–119
80/3
80/6
80/3
80/6
80/3
80/3
80/3
80/3
3b
3c
1b
3c
1b
3c
3b
3c
Me
Me
68
70
AcNH
AcNH
Cl
50
90
Cl
77
aCalculated with exchange capacity (4.7 meq./g for Amberlyst 15, 3.3 meq./g for
Amberlyst XN 1010);[18] bRefer to Amberlyst 15; cRefer to Amberlyst XN1010;
dPurified by crystallization: EtOH for 1b; MeOH for 1c; CHCl3 for 1d.
Table 2. Cyclization of Benzylsulphonamides
1
to 3,4-Dihydro-1H-2,3-
¼H)
benzothiazine 2,2-Dioxides 2 with s-Trioxane (R1 ¼ H, R2
6
Mp (ꢀC)
Yield 2 Lit. Yield[4]
Temp. (ꢀC)/
Time (h)
Resin
(meq.)a
Entry
R2
(%)
(%)
Found
Lit.[4]
1e
1e
1f
1f
1g
1g
1h
1h
1i
Me
Me
Et
100
100
100
100
100
100
54
78
78
88
88
90
90
70
70
48
48
75–76
75–76
70–71
70–71
90–91
90–91
143–144d 142–143
143–144d 142–143
154–155e 154–155
154–155e 154–155
74–75
74–75
71–72
71–72
90–91
90–91
35/3
35/6
35/3
35/6
35/3
35/6
80/3
80/3
80/6
80/3
3b
3c
3b
3c
3b
3c
3b
3c
3b
3c
Et
i-Pr
i-Pr
p-ClC6H4
p-ClC6H4
75
45
p-NO2C6H4
p-NO2C6H4
1i
52
aCalculated with exchange capacity (4.7 meq./g for Amberlyst 15, 3.3 meq./g for
Amberlyst XN 1010);[18] bRefer to Amberlyst 15; cRefer to Amberlyst XN1010;
dPurified by crystallization of EtOH; ePurified by column chromatography with
CHCl3/EtOAc (90 : 10) as eluent.

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3678
BRAVO AND CANEPA
gave better results in accordance with its larger porosity volume (47%,
compared to 32% for Amberlyst 15).[18]
Both Amberlyst resins gave good selectivity to ring substituted benzyl-
sulphonamides (R1 ¼ H, R2 ¼ H) with high preference of the para position
(yields of 70% and 90% for 2b and 2d, respectively, Table 1). Using strong
acids as catalysts, however, the product obtained by substitution on the ortho
position gave lower yields of benzothiazines 2b and 2d (44 and 49%, respec-
tively, Table 1).[4] This selectivity on the orientation in electrophilic aromatic
substitution using Amberlyst resins had been previously observed.[18]
In conclusion, the use of both Amberlyst 15 and Amberlyst XN 1010
presents important advantages over the previously reported method[4] using
strong and not easily handled acids such as MSA, TFMSA and TFA.
The work up is very easy, highly pure products are obtained and, in most
cases, yields are excellent.
EXPERIMENTAL
The benzylsulphonamides 1 were prepared from the corresponding
benzyl halides via sodium benzylsulphonates and benzylsulphonyl
chlorides.[4]
General Procedure for Cyclization of Benzylsulphonamides
1 to 3,4-Dihydro-1H-2,3-benzothiazine 2,2-Dioxides 2
A flask equipped with a reflux condenser and magnetic bar, was
charged with benzylsulphonamide 1 (1.0 mmol) and s-trioxane (30.0 mg,
0.33 mmol) in 1,2-dichloroethane (4 mL) and the resin (1.0 or 3.0 meq.).
The mixture was shaked at 35 or 80ꢀC for the specified time (after the
reaction was completed, Tables 1 and 2). The progress of the reaction was
monitored by TLC and GLC. The resin was filtered off, washed with fresh
1,2-dichloroethane and the organic solution evaporated (10 torr) to give, in
some cases, pure crude benzothiazines 2. Otherwise, they were purified by
crystallization or by column chromatography on silica gel 60 (70–230 mesh,
Merck) (Tables 1 and 2). The purity of the isolated compounds was checked
by comparison (IR and 1H-NMR spectra, m.p., TLC, GLC) with authentic
samples prepared according to known procedures. Resins could be used
repeatedly (2 and 3 times) with different benzylsulphonamides without
noticeable loss in activity.

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3,4-DIHYDRO-1H-2,3-BENZOTHIAZINE 2,2-DIOXIDES
ACKNOWLEDGMENTS
3679
The authors thank CONICET and CICBA for financial support and
Dr. A. Lieberknecht for valuable discussions.
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BRAVO AND CANEPA
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Received in the USA November 25, 2001