Synthesis of 1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxides using Amberlyst-15

Article abstract of DOI:10.1080/00397910903533983

A convenient method for the synthesis of 1,2,4,5-tetrahydro-3,2- benzothiazepine 3,3-dioxides from 2-phenylethanesulfonamides and formaldehyde using Amberlyst resin as catalyst is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903533983

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Synthesis of 1,2,4,5-Tetrahydro-3,2-
benzothiazepine 3,3-Dioxides Using
Amberlyst-15
Leandro D. Sasiambarrena a , Alicia S. Cánepa 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: 15 Dec 2010.
To cite this article: Leandro D. Sasiambarrena , Alicia S. Cánepa & Rodolfo D. Bravo (2010)
Synthesis of 1,2,4,5-Tetrahydro-3,2-benzothiazepine 3,3-Dioxides Using Amberlyst-15, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:2, 200-205, DOI: 10.1080/00397910903533983
To link to this article: http://dx.doi.org/10.1080/00397910903533983
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Synthetic Communications1, 41: 200–205, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903533983
SYNTHESIS OF 1,2,4,5-TETRAHYDRO-3,2-
BENZOTHIAZEPINE 3,3-DIOXIDES USING
AMBERLYST-15
´
Leandro D. Sasiambarrena, Alicia S. Canepa, 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
A convenient method for the synthesis of 1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-
dioxides from 2-phenylethanesulfonamides and formaldehyde using Amberlyst resin as
catalyst is described.
Keywords: Amberlyst-15; 3,2-benzothiazepine 3,3-dioxides; 2-phenylethanesulfonamides; sulfonylamido-
methylation
Benzothiazepines are an important class of compounds because of their diverse
therapeutic and pharmacological applications. For example, 1,2-, 1,4-, and 1,5-
benzothiazepines have shown activity as endogenous natriuretic factors, enzyme
inhibitors, anticonvulsants, sedatives, and hypnotics.[1–3]
The biological activity of 1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxides 2
has not been investigated yet.
Until now, only one method for the synthesis of 1,2,4,5-tetrahydro-3,2-
benzothiazepine 3,3-dioxides is known. These compounds were obtained by sulfony-
lamidomethylation of 2-phenylethanesulfonamides 1 with formaldehyde in the pres-
ence of an acid catalyst followed by intramolecular cyclization of the imine
intermediate by means of electrophilic aromatic substitution.[4] For this procedure,
homogeneous catalysts have been used such as methanesulfonic acid (MSA) and
trifluoroacetic acid (TFA) with good yield of products (Scheme 1).
A series of N-mono-substituted 2-phenylethanesulfonamides was employed in
this work where R1 consists of mainly alkyl groups. The cyclization was also studied
when functional groups were employed in R1 such as ester (R1 ¼ EtO2C), ketone
(R1 ¼ PhCOCH2), or alcohol (R1 ¼ HOCH2CH2), although with minor yield of
products. Besides, one example with
a
nuclear substituent (R2 ¼ 3-MeO;
Received May 19, 2009.
´
Address correspondence to Rodolfo D. Bravo or Alicia S. Canepa, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata, 47 y 115 La Plata (1900), Argentina. E-mail: rdb@exactas.unlp.edu.ar;
ascanepa@quimica.unlp.edu.ar
200

SYNTHESIS OF 3,2-BENZOTHIAZEPINES
201
Scheme 1.
R1 ¼ PhCH2CH2) was used with a moderate yield. This substituent at the para
position to ring closure is necessary to avoid the formation of N-(2-phenylethanesul-
fonil)1,2,3,4-tetrahydroisoquinoline as a result of favorable 6-endo-trig process.
Until now, only the 1-ethoxy-2,4,5-trihydro-3,2-benzothiazepine 3,3-dioxide,
which was obtained in poor yield (17%) with several steps by an alternative synthetic
route, was reported.[5]
The use of strong acids has several disadvantages, such as tedious workup pro-
cedure, environmental pollution by their disposal, and their corrosive nature.
The intramolecular sulfonylamidomethylation reaction has been previously
applied to benzylsulfonamides 3 to obtain the homologous cyclic compounds,
3,4-dihydro-1H-2,3-benzothiazine 2,2-dioxides 4. First, we studied the cyclization
using a homogeneous catalyst, such as MSA, TFA, and trifluoromethanesulfonic
acid (TFMSA), with good yield for various substituents R1 and R2[6] (Scheme 2).
The heterogeneous catalysts offer ideal alternatives to convert polluting pro-
cesses into greener processes with advantages over homogeneous catalysts, such as
ease of isolation, waste minimization, and mild reaction conditions.
More recently, macroporous Amberlyst resin and heteropolyacids H3PWO40
and H3PMoO40 supported on silica as heterogeneous catalysts in the synthesis of
3,4-dihydro-1H-2,3-benzothiazine 2,2-dioxides 4 have been employed with very good
yields to obtain these products and have advantages compared to homogeneous acid
catalysts.[7,8]
Continuing with our work on the use of heterogeneous catalysts for develop-
ment of useful synthetic methodologies, the cyclization of 2-phenylethanesulfona-
mides 1 with aldehydes using a macroporous resin, Amberlyst-15, for the synthesis
of 1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxides 2 was examined.
The resin Amberlyst-15 was chosen because it presents several advantages. It
catalyzes a wide variety of reactions in a heterogeneous phase, offering a strong option
for efficient and cleaner processing compared to conventional mineral acids.[9–12]
The reaction was performed by heating a solution of 2-phenylethanesulfona-
mide 1 (1.0 mmol) and trioxane (0.33 mmol) in 1,2-dichloroethane under reflux
Scheme 2.

´
L. D. SASIAMBARRENA, A. S. CANEPA, AND R. D. BRAVO
202
Table 1. Cyclization of 2-phenylthanesulfonamides 1 catalyzed with Amberlyst-15
Compound
R1
Time (h) Yield (%) 2 Yield (%) of 2 (lit.)[4] Mp (ꢀC) found=lit.[4]
1a
1b
1c
1d
1e
1f
H
Et
18
20
20
18
72
12
12
24
12
92
92
42
84
––
85
60
39
58
89
––
––
––
82
73
––
79
––
163–164=163–164
95–96 (cyclohexane)
91–92 (hex=EtOAc)
78–79 (cyclohexane)
159–160
i-Pr
n-Bu
C6H11
CH2C6H4
4-BrC6H4
p-CH3C6H4SO2
4-ClC6H4
136–137=138–139
153–154 (hex=EtOAc)
196–197=195–196
141–142 (hex=EtOAc)
1g
1h
1i
(82 ꢀC) with the resin for the specified time, followed by filtration and evaporation of
the solvent.
Thus,
a
series of N-substituted 1,2,4,5-tetrahydro-3,2-benzothiazepine
3,3-dioxides 2 (R2 ¼ H) were prepared by this method. The results are summarized
in Table 1.
The best yield of the final product was obtained when N-alkyl derivatives were
used, with the exception of N-cyclohexyl-2-phenylethanesulfonamide 1e, probably
because of its steric hindrance. In this case, the reaction was unsuccessful, providing
the reactive majority after 72 h.
The best results were obtained with 6 meq. of Amberlyst-15 (calculated with
exchange capacity, 4.7 meq=g; Sigma Chemical Company catalog). The crude
product was purified by crystallization or preparative column chromatography.
1
The new compounds 2b, 2c, 2d, 2g, and 2i were identified by mp, H NMR and
13C NMR spectra and elemental analysis. Well-known compounds 2a, 2f, and 2h
1
were characterized by mp and H NMR spectra.[4]
The recovered catalyst, after activation, was consecutively reused three times
with minimum variation in the yield. For example, with fresh catalyst, 92% yield
of 2b compound was obtained; subsequently, with the recovered catalyst in two
cycles, the yields of 2b were 89 and 90%.
In conclusion, the use of Amberlyst-15 provides a simple and attractive cata-
lytic process for the synthesis of 1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxides
2. The advantages of the present procedure are convenient manipulation, mild
conditions, good yields, reusability, and readly availability. The waste disposal of
the process was greatly diminished compared with the use of homogeneous catalysts.
EXPERIMENTAL
1
Melting points were determined with a Buchi apparatus. H NMR and 13C
NMR spectra were obtained on a Varian-Mercury (200-MHz) spectrometer.
Thin-layer chromatography (TLC) was performed on silica-gel 60 F254 sheets
(Merck). Reagent-grade s-trioxane was used. Reagent-grade solvents were used;
1,2-dichloroethane was distilled over phosphorous pentoxide and stored over 4-Aꢀ
molecular sieves. The resin was dried prior to use for 2 h under vacuum at 45 ꢀC.

SYNTHESIS OF 3,2-BENZOTHIAZEPINES
203
The purity of the isolated compounds was checked by comparison with authentic
samples prepared according to known procedures (1H NMR spectra, mp, TLC).[4]
The 2-phenylethanesulfonamides 1 were prepared from the corresponding
2-phenylethyl halides following the general method.[2]
The catalyst could be recycled. After the reaction, the catalyst was filtered and
then refluxed with 1,2-dichloroethane to remove any adsorbed material from the
catalyst surface and pores and then dried at 80 ꢀC.
General Procedure for Cyclization of 2-Phenylethanesulfonamides 1 to
1,2,4,5-Tetrahydro-3,2-benzothiazepine 3,3-Dioxides 2
A flask equipped with a reflux condenser and magnetic bar was charged with
2-phenylethanesulfonamides 1 (1.0 mmol), s-trioxane (0.33 mmol) in 1,2-dichlor-
oethane (4 mL), and the catalyst (6 meq.). Stirring continued at 82 ꢀC for the speci-
fied 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 evapo-
rated at reduced pressure to give the crude benzothiazepines 2. 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.
Characterization Data of 1,2,4,5-Tetrahydro-3,2-benzothiazepine
3,3-Dioxides 2
1,2,4,5-Tetrahydro-3,2-benzothiazepine 3,3-dioxide 2a. 13C NMR (62.9
MHz): d 30.0 (C-5), 47.8 (C-4), 53.8 (C-1), 128.0, 129.1, 129.4; 130.7 (C-6, C-7,
C-8, C-9), 138.9 (C-10), 139.2 (C-11).
1
N-Ethyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide 2b. H NMR
(200 MHz): d 1.15 (t, 3H, J ¼ 7.3 Hz, CH2-CH3), 3.17 (brs, 6H, N-CH2 exo,
CH2CH2S), 4.39 (brs, 2H, NCH2 endo), 7.20–7.35 (m, 4H, Ph); 13C NMR
(62.9 MHz): d 13.6 (NCH2CH3), 30.4 (C-5), 41.1 (C-1), 49.9 (CH2 exo), 50.4 (C-4),
127.6, 129.1, 130.5, 130.8 (C-6, C-7, C-8, C-9), 136.6 (C-10), 139.0 (C-11). Anal.
calcd. for C11H15NO2S (255.08): C, 58.64; H, 6.71; N, 6.22; O, 14.20; S, 14.23.
Found: C, 58.56; H, 6.71; N, 6.16; O, 14.24; S, 14.33.
N-i-Propyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide 2c. 1H
NMR (200 MHz): d 1.01 (d, 6H, J ¼ 6.8 Hz, (CH3)2CH), 3.21 (s, 4H, CH2CH2S),
4.07 (sep, 1H, J ¼ 6.8 Hz, (CH3)2CH), 4.40 (s, 2H, NCH2 endo), 7.25 (s, 4H, Ph);
13C NMR (62.9 MHz): d 21.5 (NCH(CH3)2), 30.8 (C-5), 48.0 (C-1), 51.0 (CH
exo), 54.5 (C-4), 127.6, 128.7, 129.4, 130.7 (C-6, C-7, C-8, C-9), 138.9 (C-10),
139.9 (C-11). Anal. calcd. for C12H17NO2S (239.10): C, 60.22; H, 7.16; N, 5.85; O,
13.37; S, 13.40. Found: C, 60.22; H, 7.27; N, 5.71; O, 13.37; S, 13.41.
N-Butyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide 2d. 1H
NMR (200 MHz): d 0.87 (t, 3H, J ¼ 7.3 Hz, (N(CH2)3CH3), 1.35 (sex, 2H, J ¼ 7.6 Hz,
N(CH2)2CH2CH3), 1.48 (m, 2H, NCH2CH2CH2CH3), 3.17 (brs, 6H, N-CH2 exo,
CH2CH2S), 4.45 (brs, 2H, NCH2 endo), 7.26 (m, 4H, Ph); 13C NMR (62.9 MHz):
d 13.9 (N(CH2)3CH3), 19.8 (N(CH2)2CH2CH3), 29.7 (NCH2CH2CH2CH3), 30.5

´
L. D. SASIAMBARRENA, A. S. CANEPA, AND R. D. BRAVO
204
(C-5), 45.6 (C-1), 50.2 (NCH2 exo), 50.3 (C-4), 127.6, 129.1, 130.7, 130.8 (C-6, C-7,
C-8, C-9), 136.5 (C-10), 139.0 (C-11). Anal. calcd. for C13H19NO2S (253.11): C,
61.63; H, 7.56; N, 5.53; O, 12.63; S, 12.66. Found: C, 61.60; H, 7.62; N, 5.47; O,
12.63; S, 12.65.
N-Benzyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide 2f. 13C
NMR (62.9 MHz): d 30.5 (C-5), 49.5 (C-1), 49.7 (CH2Ph), 50.9 (C-4), 127.5, 128.1,
128.7, 128.9, 129.2, 130.9, 131.1, 135.5, 136.1, 139.1 (C-6, 7, 8, 9, 10, 11, and Ph).
N-p-Bromophenyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide
2g. 1H NMR (200 MHz): d 3.11 (brs, 2H, CH2CH2S), 3.63–3.79 (m, 4H, NCH2;
CH2CH2S), 6.82 (t, 2H, J ¼ 6.8 Hz, Ph), 7.05–7.21 (m, 6H, Ph); 13C NMR
(62.9 MHz): d 29.4 (C-5), 46.3 (C-1), 56.9 (C-4), 125.2, 127.5, 128.7, 128.9, 129.0,
129.4, 129.6, 132.8, 133.1, 136.9 (C-6, 7, 8, 9, 10, 11, and Ph). Anal. calcd. for
C15H14BrNO2S (350.99): C, 51.15; H, 4.01; Br, 22.68; N, 3.98; O, 9.08; S, 9.10.
Found: C, 51.05; H, 4.00; Br, 22.60; N, 3.96; O, 9.08; S, 9.23.
N-4-Methylbencensulfonil-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-
dioxide 2h. 13C NMR (62.9 MHz): d 21.8 (CH3Ph), 30.0 (C-5), 43.7 (C-1), 53.1
(C-4), 128.0, 129.4, 129.04, 129.5, 130.4, 131.8, 136.3, 136.7, 138.0, 145.1 (C-6, 7,
8, 9, 10, 11, and Ph).
N-p-Chlorophenyl-1,2,4,5-tetrahydro-3,2-benzothiazepine 3,3-dioxide
2i. 1H NMR (200MHz): d 2.99 (brs, 2H, CH2CH2S), 3.18–3.32 (m, 4H, NCH2;
CH2CH2S), 6.59 (t, 2H, J ¼ 6.8 Hz, Ph); 6.90 (t, 2H, J ¼ 6.9 Hz, Ph), 7.05–7.29 (m,
6H, Ph); 13C NMR (62.9 MHz): d 30.68 (C-5), 52.62 (C-1), 55.46 (C-4), 127.9,
128.3, 129.5, 130.3, 130.4, 130.9, 134.3, 138.2, 138.4, 138.6 (C-6, 7, 8, 9, 10, 11, and
Ph). Anal. calcd. for C15H14ClNO2S (307.04): C, 58.53; H, 4.58; Cl, 11.52; N, 4.55;
O, 10.40; S, 10.42. Found: C, 58.50; H, 4.55; Cl, 11.42; N, 4.60; O, 10.45; S, 10.42.
ACKNOWLEDGMENTS
´
The authors thank UNLP and CICBA for financial support and Drs. Agustın
Ponzinibbio and Ruben Rimada for NMR measurements.
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