Heteropolyacid as an efficient catalyst for synthesis of 3,4-dihydro-1H-2,3-benzothiazine-2,2-dioxides

Article abstract of DOI:10.1080/00397910802219585

A facile and efficient method for the formation of 3,4-dihydro-1H-2,3- benzothiazine 2,2-dioxides 2, compounds from benzylsulfonamides and formaldehyde is described using heteropolyacids H3PW12O40 and H3PMo12O40 supported on silica as catalysts. Copyright

Full text of DOI:10.1080/00397910802219585

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Heteropolyacid as an Efficient
Catalyst for Synthesis
of 3,4-Dihydro-1H-2,3-
benzothiazine-2,2-dioxides
Alicia S. Cánepa a , Leandro D. Sasiambarrena a
Rodolfo D. Bravo a
&
a Laboratorio de Estudio de Compuestos Orgánicos,
Departamento de Química , Facultad de Ciencias
Exactas, Universidad Nacional de La Plata , La Plata,
Argentina
Published online: 09 Sep 2008.
To cite this article: Alicia S. Cánepa , Leandro D. Sasiambarrena & Rodolfo D. Bravo
(2008) Heteropolyacid as an Efficient Catalyst for Synthesis of 3,4-Dihydro-1H-2,3-
benzothiazine-2,2-dioxides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:15, 2655-2661, DOI:
10.1080/00397910802219585
To link to this article: http://dx.doi.org/10.1080/00397910802219585
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Synthetic Communications1, 38: 2655–2661, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219585
Heteropolyacid as an Efficient Catalyst for
Synthesis of 3,4-Dihydro-1H-2,3-benzothiazine
2,2-dioxides
ꢀ
Alicia S. Canepa, Leandro D. Sasiambarrena, and Rodolfo D. Bravo
ꢀ
´
Laboratorio de Estudio de Compuestos Organicos, Departamento de Quımica,
Facultad de Ciencias Exactas, Universidad Nacional de La Plata,
La Plata, Argentina
Abstract: A facile and efficient method for the formation of 3,4-dihydro-1H-2,3-
benzothiazine 2,2-dioxides 2, compounds from benzylsulfonamides and formalde-
hyde is described using heteropolyacids H3PW12O40 and H3PMo12O40 supported
on silica as catalysts.
Keywords: Benzothiazines, catalyst, intramolecular cyclization, keggin heteropo-
lyacid, sulfonylamidomethylation
The sulfonylamidomethylation of aromatic sulfonamides is an example
of electrophilic aromatic substitution and has been studied in the prep-
aration of 3,4-dihydro-1H-2,3-benzothiazine-2,2-dioxides, 2, compounds
with unexplored potential biological activity.
The reaction occurs by interaction of benzylsulfonamide 1 and
formaldehyde in the presence of an acid catalyst followed by intra-
molecular cyclization of imine intermediate via electrophilic aromatic
substitution.[1]
For this procedure, homogeneous and heterogeneous catalysts are
used. By using homogeneous catalysts, such as methanesulfonic acid
(MSA), trifluoromethanesulfonic anhydride (TFMSA), and trifluoro-
acetic acid (TFA), the final products are obtained in good yield.[1]
Received in the USA April 25, 2008
Address correspondence to Rodolfo D. Bravo, Laboratorio de Estudio de
ꢀ
´
Compuestos Organicos, Departamento de Quımica, Facultad de Ciencias Exac-
tas, Universidad Nacional de La Plata, Calle 47 y 115, 1900 La Plata, Argentina.
E-mail: rdb@exactas.unlp.edu.ar
2655

ꢀ
A. S. Canepa, L. D. Sasiambarrena, and R. D. Bravo
2656
Scheme 1. 1a, R ¼ H; R0 ¼ H; 1b, R ¼ 3-Me; R0 ¼ H; 1c, R ¼ 3-AcNH; R0 ¼ H;
1d, R ¼ 3-Cl; R0 ¼ H; 1e, R ¼ H; R0 ¼ Me; 1f, R ¼ H; R0 ¼ Et; 1g, R ¼ H,
R0 ¼ i-Pr; 1h, R ¼ H; R0 ¼ p-ClC6H4; and 1i, R ¼ H; R0 ¼ p-NO2C6H4.
As reported, short reaction times or low acid strength led to
1,3,5-tris-(benzylsulfonyl)-hexahydro-1,3,5-triazines
3
(R0 ¼ H) and
N,N0-methylene-bis-benzylsulfonamides 4 (R ¼ H, R0 ¼ H) as kinetic
products, whereas under strong acid catalysis, the thermodynamic
products were obtained in good yield.[1] (Scheme 1).
Similar compounds are obtained, alternatively, in good yield by
another route, the intramolecular vicarious nucleophilic substitution of
hydrogen of m-nitrochloromethylsulfonamides.[2–4]
The problems associated with the handling and disposal of strong
acids, and their environmental and potential hazards, have directed our
attention to the development of alternative procedures using solid acid
catalysts, which are safer and more environmentally friendly. Hetero-
geneous catalysts are used in a great number of developed processes,
and in view of the increasingly strict environmental legislation, the appli-
cation of these catalysts has become attractive.[5–8] In addition, solid acid
catalysts can be regenerated and reused after the reactions.
More recently, we used ion exchange resins Amberlyst 15 and
Amberlyst XN 1010 in the synthesis of 3,4-dihydro-1H-2,3-benzothiazine
2,2-dioxide, which had important advantages over the previously
reported method. The workup is an easy process, and highly pure
products are obtained, in most cases with excellent yield.[9,10]
Heteropolyacids (HPAs) are another type of promising acid catalysts
used in electrophilic substitutions. They are typical strong Brønsted acids
such as perchloric and sulfuric acids, and they have attracted much atten-
tion, particularly in the past two decades. Until now, most of fundamen-
tal investigations and all practical applications employed Keggin-type
HPAs, with the general formula H3M12O40P.[11,12]
The HPAs have been supported on different materials possessing
high surface area in order to increase their activity in the heterogeneous
reactions. The equilibrium impregnation of tungstophosphoric acid

3,4-Dihydro-1H-2,3-benzothiazine 2,2-dioxides
2657
(TPA) or molybdophosphoric acid (MPA) on silica, among other
supports, was studied and showed higher catalytic activity in different
reactions.[13,14] Many typical acid-catalyzed reactions such as alkene
hydratation, ether cleavage, esterification, hydrolysis, transesterification,
and acetalization are effective in the presence of these catalysts.[15–17]
In continuation of our program to develop reactions with ecofriendly
conditions, and given our interest in the synthesis of 3,4-dihydro-1H-2,3-
benzothiazine 2,2-dioxides 2, in the present work we report an efficient
and convenient procedure for the cyclization of benzylsulfonamides
using Keggin-type HPAs H3PW12O40 (TPA) and H3PMO12O40 (MPA)
supported on silica as catalysts.
The reaction was performed by stirring a solution of benzylsulfona-
mide 1 (1.0 mmol) and trioxane (0.33 mmol) in 1,2-dichloroethane or
toluene under reflux (80 ꢀC or 110 ꢀC, respectively) with the catalyst
for the specified time. The catalyst was then removed by filtration,
and the solvent was evaporated. The crude products were purified by
crystallization or column chromatography on silica gel. All products
are known compounds and were characterized by melting points and
1H NMR spectra.
Cyclization experiments were conducted using different TPA and
MPA ratios (5–50 wt%). By-product formation increased as the catalyst
quantity increased. The yield of the final product has been invariable
when either TPA or MPA were used.
The best results were obtained with 25% of catalyst. The reactions
were completed in 4.5 h, with the exception of substrate 1i with an
electron-withdrawing group on the aromatic ring. In this case, greater
reaction time (8 h) and catalyst quantity (50%) were used.
The effect of temperature on the yield and rate of the reaction was
studied in the range of 80–110 ꢀC. With an increase in the temperature
from 80 ꢀC to 110 ꢀC, the rate of the reaction increased significantly.
However, there was almost no change in the yield of final products.
Good yields with high selectivity of final products 2 were obtained
under the reaction conditions used. Compounds 3 (R ¼ R0 ¼ H) were
obtained when either lower catalyst quantities or shorter reaction times
are used. The yields of 2 are comparable with the reported method using
homogeneous catalyst (Table 1).
In summary, a simple and attractive catalytic process for the
synthesis of 3,4-dihydro-1H-2,3-benzothiazine 2,2-dioxides 2 has been
demonstrated. The mild conditions, good yields, high selectivity,
operational simplicity, and easy availability make this process a useful
and practical alternative to the existing methods for the preparation of
these compounds. The waste disposal of the process is greatly diminished
compared with the use of homogeneous catalysts.

2658

3,4-Dihydro-1H-2,3-benzothiazine 2,2-dioxides
2659
It is noteworthy to mention that the catalyst is reusable. The catalyst
was reused up to three times without affecting the yield.
EXPERIMENTAL
Melting points were determined with a Buchi apparatus. 1H NMR
spectra were obtained on a Brucker AC-F (250-MHz) spectrometer.
Thin-layer chromatography (TLC) was performed on silica-gel sheets
60 F254 (Merck). Reagent-grade s-trioxane was used. Reagent grade
solvents were used; 1,2-dichloroethane was distilled over phosphorous
˚
pentoxide and stored over 4 A molecular sieves. Toluene was dried with
CaSO4, filtered, and distilled over sodium. The purity of the isolated
compounds was checked by comparison with authentic samples prepared
according to known procedures (1H NMR spectra, mp, TLC).[1]
The benzylsulfonamides 1 were prepared from the corresponding
benzyl halides via sodium benzylsulfonates and benzylsulfonyl chlorides.
The silica-supported catalysts were prepared by impregnation techni-
ques according to a well-established procedure with solutions of MPA
(H3PMO12O40 ꢁ nH2O, Merck) or TPA (H3PW12O40 ꢁ nH2O, Fluka) in
H2O–EtOH (1:1) and were physically and chemically characterized.[18]
The support was SiO2 (Grace) with a surface area of 311 m2=g and a
mean pore diameter of 3.4 nm. These catalysts were washed with the
reaction solvent, dried, and calcined at 200 ꢀC. The catalyst was dried
at 150 ꢀC for 1 h prior to use for the reactions.
The catalyst could be recycled after removing the reaction product by
filtration, washing with solvent, and drying at 200 ꢀC for 2 h. The results
of the first experiment and subsequent experiment were almost consistent
in yields.
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 benzylsulfonamide 1 (1.0 mmol) and s-trioxane (0.33 mmol) in
1,2-dichloroethane or toluene (4 mL) and the catalyst. Stirring was con-
tinued at 80 ꢀC (using 1,2-dichloroethane) or 110 ꢀC (using toluene) for
the specified time (Table 1). The progress of the reaction was monitored
by TLC. The catalyst was filtered off and washed with fresh solvent, and
the organic solution was evaporated at reduced pressure to give the crude
benzothiazines. They were purified by crystallization or by column
chromatography on silica gel 60 (70–230 mesh, Merck) with hexane–ethyl
acetate (90:10 or 70:30) as eluent in most cases.

ꢀ
A. S. Canepa, L. D. Sasiambarrena, and R. D. Bravo
2660
Procedure for Preparation of 1,3,5-Tris-(benzylsulfonyl)-hexahydro-1,3,5-
triazine (3a)
A mixture of 0.171 g (1 mmol) of benzylsulfonamide (1a), s-trioxane
(0.33 mmol) in 1,2-dichloroethane (4 mL), and the catalyst (25% p=p)
was stirred at 80 ꢀC for 2 h with formation of a white precipitate. The
solid was dissolved with dimethylsulfoxide, and the catalyst was filtered
off. The solvent was evaporated at reduced pressure. The crude product
was purified by crystallization from nitromethane to give 1,3,5-tris-
(benzylsulfonyl)-hexahydro-1,3,5-triazine (3a) (yield 51%), mp 277–278 ꢀC
(lit.[19] 276–278 ꢀC).
ACKNOWLEDGMENT
ꢀ
The authors thank Comision de Investigaciones Cientıficas de Buenos
Aires (CICBA) for financial support and Carmen Caceres and Mirta
´
ꢀ
ꢀ
Blanco (Centro de Investigacion y Desarrollo de Ciencias Aplicadas
(CINDECA)) for the catalysts and valuable discussions.
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