Synthesis of novel dihydronaphthothiazine S,S-dioxides by intramolecular sulfonylamidomethylation of 2-naphthylmethanesulfonamides using Amberlyst XN-1010

Article abstract of DOI:10.1016/j.tetlet.2015.11.042

We describe herein an efficient synthetic method for novel dihydronaphthothiazines S,S-dioxides by aromatic intramolecular sulfonylamidomethylation of 2-naphthylmethanesulfonamides with s-trioxane using Amberlyst XN-1010 as acid heterogeneous catalyst. Cyclization of the formed sulfonyliminium ion occurred with high regioselectivity and in excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.11.042

Tetrahedron Letters 56 (2015) 7184–7189
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel dihydronaphthothiazine S,S-dioxides
by intramolecular sulfonylamidomethylation
of 2-naphthylmethanesulfonamides using Amberlyst XN-1010
⇑
⇑
Leandro D. Sasiambarrena , Alicia S. Cánepa, Rodolfo D. Bravo
Laboratorio de Estudio de Compuestos Orgánicos LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, La Plata
1900, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein an efficient synthetic method for novel dihydronaphthothiazines S,S-dioxides by aro-
matic intramolecular sulfonylamidomethylation of 2-naphthylmethanesulfonamides with s-trioxane
using Amberlyst XN-1010 as acid heterogeneous catalyst. Cyclization of the formed sulfonyliminium
ion occurred with high regioselectivity and in excellent yields.
Received 13 October 2015
Revised 10 November 2015
Accepted 12 November 2015
Available online 14 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Naphthothiazines
Heterogeneous catalysis
Cyclization reactions
Amberlyst XN-1010
Sultams
Introduction
Gabriel–Colman type rearrangement of N-substituted saccharin
derivatives,20 aminosulfonyl chlorides cyclizations,21 intramolecu-
Compounds containing the sulfonamide group are well known
to possess diverse biological properties.1,2 They have extensive
use in a variety of applications including its use as peptidomimet-
ics, antibacterials, thyroid inhibitors, antitumor agents, HIV-1 inte-
grase and HIV-1 protease inhibitors, diuretics, carbonic anhydrase
inhibitors, and hypoglycemic agents.3–6 Sultams, their cyclic ana-
logues, have also been investigated because of their diverse phar-
macological activities7 (Fig. 1). These compounds exhibit a broad
spectrum of medicinal uses such as anticancer,1 hypoglycemic,8
diuretics,9 antimicrobial,10 antiviral,11 antileukemic,7g,h 5-HT2 and
5-HT7 antagonists,12 and inhibitors of a variety of enzymes includ-
ing COX-2,13 calpain I14, and HIV-1.15 In particular, a number of
benzofused sultams have shown promising bioactivity for treating
disorders of the brain.16
Furthermore, these compounds are also useful structural motifs
in heterocyclic chemistry17 and applied as chiral auxiliaries in
asymmetric synthesis.18
Several synthetic routes have been described in the literature to
obtain benzo and naphthofused cyclic sulfonamides. These
include Friedel–Crafts19 and Pictet–Spengler7g type reactions,
lar Heck reactions,22 oxa-Michael and Baylis–Hillman reactions,23
ring closing metathesis,24 and radical cyclization.25 Some reviews
describe more examples of the synthesis of fused sultams.26
In our laboratory we have studied the synthesis of novel 3,4-
dihydro-1H-2,3-benzothiazine 2,2-dioxides and 1,2,4,5-tetra-
hydro-3,2-benzothiazepine
3,3-dioxides
by
intramolecular
aromatic sulfonylamidomethylation of phenylmethane and
2-phenylethanesulfonamides with s-trioxane in the presence of
an homogeneous or heterogeneous acid catalyst.27 This cyclization
has been interpreted as an intramolecular Friedel–Crafts reaction of
a sulfonyliminium intermediate ion. We have also studied the
scope of this reaction using various substituents in the substrates
and catalysts used (Scheme 1, reaction a).
Methanesulfonic acid,27a,b was used as a homogeneous catalyst
and among the heterogeneous ones, we can mention tungsten and
molybdenum heteropolyacids (H3PWO40 and H3PMoO40
)
supported on silica,27c Amberlyst 15 and Amberlyst XN-1010
resins27d,e and sulfated zirconia.27f In almost all cases, yields
were increased when heterogeneous catalysts were used.
In a recent publication, we have reported the synthesis of novel
1,2,4,5-tetrahydronaphtho[1,2-d]3,2-thiazepine 3,3-dioxides and
1,2,4,5-tetrahydronaphtho[2,1-d]3,4-thiazepine 3,3-dioxides by
sulfonylamidomethylation of 2-(2-naphthyl)ethanesulfonamides
and 2-(1-naphthyl)ethanesulfonamideswiths-trioxane, respectively,
⇑
Corresponding authors. Tel.: +54 221 424 3104.
E-mail addresses: sasiamba@quimica.unlp.edu.ar (L.D. Sasiambarrena), rdb@
exactas.unlp.edu.ar (R.D. Bravo).
http://dx.doi.org/10.1016/j.tetlet.2015.11.042
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

L. D. Sasiambarrena et al. / Tetrahedron Letters 56 (2015) 7184–7189
7185
CH3
O
O
NBS, light
Br
N
NH2
O
O
N
H
O
S
Br
CCl4 reflux
4 h
S
Na2SO3
O
NH
O
2
OH
1
S
water/acetone
reflux 12 h
70 %
N
S
O
O
H2N
S
OH
O
O
POCl3
platelet stickiness and aggregation
inhibitor
carbonic anhydrase inhibitor
11β-hydroxysteroid
dehydrogenase 1 inhibitor
acetonitrile-sulfolane
SO2Cl
SO3Na
O
O
S
55°C 6 h
68 %
4
O
O
3
OH
O
S
N
S
NH
RNH2
N
N
H
toluene/CHCl3
40°C
N
SO2NHR
OH
F
S
O
O
O
glucokinase activator
COX-2 inhibitor (meloxicam)
HIV-1 protease inhibitor
5
Figure 1. Representative biologically active sultams.
Scheme 3. Synthetic route for 2-naphthylmethanesulfonamides (5).
O
n
n
reusability with very little loss in activity.29m Numerous articles
have been reported in the literature about the use and properties
of these resins as heterogeneous acid catalysts.29n–q In particular
resins Amberlyst XN-1010, that have been used in this work,
were less studied as catalysts to date.
H+
S
O
SO2NHR
O
R
a.
+
N
O
O
n=1,2
R=H, alkyl, aryl
O
R
O
N
S
Amberlyst
XN-1010
SO2 NHR
O
+
b.
c.
O
O
Results and discussion
O
S
R=alkyl, aryl
O
R
Synthesis of 2-naphthylmethanesulfonamides
SO2 NHR
N
Amberlyst
XN-1010
O
+
2-Naphthylmethanesulfonamides (5) used as substrates are
novel compounds and were obtained by a synthetic route illus-
trated in Scheme 3.
O
O
R=H, alkyl, aryl
The starting material, 2-methylnaphthalene (1) underwent rad-
ical bromination of the side chain using NBS in CCl4 in the presence
of light to afford 2-bromomethylnaphthalene (2) that was con-
verted to the sodium sulfonate (3) using sodium sulfite in an
acetone–water mixture in 70% yield. 2-Naphthylmethanesulfonyl
chloride (4) was prepared in good yield using POCl3 in an acetoni-
trile–sulfolane mixture at 55 °C. The preparation of 2-naphthyl-
methanesulfonamides (5) was performed by reaction of (4) with
primary amines in a toluene-chloroform mixture at 40 °C.
As seen in Table 1 the products 5 were obtained in moderate to
good yields for reactions in which R is alkyl or aralkyl while for
R = aryl the yield was lower due to nitrogen atoms less
nucleophilicity.
Scheme 1. Synthetic method for the preparation of cyclic sulfonamides.
R
N
O
S
O
X=H
X
Amberlyst
XN-1010
O
SO2NHR
+
O
O
Br
O
O
R
S
N
X=Br
Similarly (1-bromonaphthalen-2-yl)methanesulfonamides (12)
were synthesized from 2-methylnaphthalene by a synthetic route
illustrated in Scheme 4. 2-Methylnaphthalene was subjected to
bromination in the 1-position of the naphthalene ring and without
isolation, the side chain was brominated affording 1-bromo-2-
bromomethylnaphtalene (9) in 67% yield. Treatment of 9 with
sodium sulfite in an ethyleneglycol–water mixture produced
sodium (1-bromonaphthalen-2-yl)methanesulfonate (10) which
reacts with POCl3 in an acetonitrile–sulfolane mixture to afford
(1-bromonaphthalen-2-yl)methanesulfonyl chloride (11) in 81%
yield. (1-Bromonaphthalen-2-yl)methanesulfonamides (12) were
prepared from 11 by reaction with primary amines in toluene at
80 °C in good yields (Table 2).
Scheme 2. Synthesis of dihydronaphthothiazines S,S-dioxides.
using Amberlyst XN-1010 in excellent yields and with high
regioselectivity.28 (Scheme 1, reactions b and c).
As continuation of our work on the development of this useful
synthetic methodology, we studied the aromatic intramolecular
sulfonylamidomethylation of 2-naphthylmethanesulfonamides
with s-trioxane, as a source of formaldehyde, for the synthesis of
novel 1,4-dihydro-2H-naphtho[1,2-d]3,2-thiazine 3,3-dioxides
and 10-bromo-3,4-dihydro-1H-naphtho[2,3-d]2,3-thiazine 2,2-
dioxides.
Due to the excellent results obtained by the use of Amberlyst
XN-1010 in similar cyclization reactions, we decided to use it as
catalyst in these reactions (Scheme 2).
Cyclization of the 2-naphthylmethanesulfonamides
Ion exchange resins Amberlyst were widely used in the esterifi-
cation of carboxylic acids,29a Michael addition reactions,29b
condensation reactions,29c acylation of Friedel–Crafts,29d
synthesis of substituted phosphonates,29e Prins reactions,29f
protection and deprotection of functional groups,29g and
synthesis of nitrogen and oxygen heterocycles.29h–l These resins
have been used by its mildness, simplicity in its use, easy
removal from the reaction mixture, good selectivity, and
The sulfonamides 5 and 12 reacted with s-trioxane in 1,2-
dichloroethane in the presence of Amberlyst XN-1010 to generate
the corresponding naphthothiazines 6 and 13. Yields obtained for
these reactions are presented in Tables 3 and 4. This intramolecular
sulfonylamidomethylation has been interpreted as a ring-closing
process via 6-endo-trig of
a sulfonyliminium intermediate
ion27a,b,28 in an intramolecular electrophilic aromatic substitution.

7186
L. D. Sasiambarrena et al. / Tetrahedron Letters 56 (2015) 7184–7189
Table 1
Br
Br
CH3
Synthesis of 2-naphthylmethanesulfonamides (5)
CH3
Br2/CCl4
NBS/CCl
4
Br
light
Br
SO2Cl
SO2NHR
RNH2
9
Na2SO3
1
toluene-CHCl3
40°C
H2O/(CH2)2(OH)2
120°C 2 h
Br
4
5
POCl3
SO3Na
SO2Cl
78 %
CH3CN-sulfolane
.
Entry
1
R
Product (5)
Yield (%)
10
11
70°C 8 h
81 %
2 RNH2
toluene
SO2NHCH2CH3
5a
SO2NHCH2CH2CH3
5b
SO2NHCH(CH3)2
5c
SO2NH(CH2)3CH3
5d
SO2NH2
5e
SO2NH CH2
5f
Br
Et
64
51
77
64
58
SO2NHR
12
2
3
4
5
n-Pr
i-Pr
n-Bu
H
Scheme 4. Synthetic route for (1-bromonaphthalen-2-yl)methanesulfonamides
(12).
Table 2
Synthesis of (1-bromonaphthalen-2-yl)methanesulfonamides (12)
Br
Br
SO2Cl
SO2NHR
RNH2
6
7
62
65
toluene 80°C
11
12
SO2NH CH2
5g
F
.
Entry
1
R
Product (12)
Yield (%)
72
F
Br
SO2NH
5h
SO2NH
5i
SO2NHCH2CH2
5j
8
42
36
75
SO2NHCH2CH3
12a
Et
Cl
Br
Br
Br
9
Cl
SO2NHCH2
12b
2
3
4
56
57
65
10
SO2NH2
12c
H
The cyclizing proposed pathway is shown in Scheme 5 according to
the literature.
SO2 NH
Cl
Cl
12d
In the cyclization step of sulfonamides 5, there are two possible
positions of ring closure, on C-1 or C-3. The ring closure onto C-1
would provide 1,4-dihydro-2H-naphtho[1,2-d]3,2-thiazine 3,3-
dioxides (6) while the substitution at C-3 would afford 3,4-dihy-
dronaphtho[2,3-d]2,3-thiazine 2,2-dioxides (7) (Fig. 2). In all cases
the products obtained were 6 due to higher reactivity of the C-1 of
the naphthalene ring toward electrophilic aromatic substitution
(Table 3). Substrate 5j (R = 2-phenylethyl, Table 3 entry 10) under-
goes cyclization on the phenyl ring substituent providing N-(2-
naphthylmethanesulfonyl)-1,2,3,4-tetrahydroisoquinoline (8) in a
6-endo-trig cyclization (Scheme 6). Presumably the preference of
ring closure in a process 6-endo-trig with exo-cyclic SO2 group
instead to a closure process 6-endo-trig with SO2 endo-cyclic group
is due to steric effects in the same manner as we described for
cyclization of N-(2-phenylethyl)-2-(2-naphthyl)ethanesulfon-
amide in a previous work.28
The best results were achieved using 1.5 meq of Amberlyst XN-
1010 as catalyst in 1,2-dichloroethane at reflux. Reactions per-
formed using lower temperatures or lower catalyst ratio gave
lower yields.30 In cyclization reactions of sulfonamides 5 with sub-
stituent R = alkyl or aralkyl, yields were excellent while sulfon-
amides with R = aryl provides the naphthosultam 6h (R = phenyl)
in 60% yield and 6i (R = p-chlorophenyl) in 95% yield and in longer
reaction times. The stabilizing effect of the electron donor groups
(R = alkyl or aralkyl) to the iminium ion produced higher yields
and especially shorter reaction times compared with the substrates
5h and 5i (R = aryl). The lower reactivity of 5h and 5i is due to the
less nucleophilic nitrogen of the sulfonamide to form the interme-
diate cation. When unsubstituted sulfonamide was used (5e), good
yield was obtained (88%) in an average reaction time.
(1-Bromonaphthalen-2-yl)methanesulfonamides (12) reacted
with s-trioxane in the same conditions to form the corresponding
10-bromo-3,4-dihydro-1H-naphtho[2,3-d]2,3-thiazine 2,2-dioxide
(13) and the proposed cyclizing mechanism toward position 3 is
the same. These sulfonamides were employed in order to study
the cyclization reaction to the 3-position of the naphthalene ring
by being hindered at position 1. Additionally, our aim was also to
synthesize naphthosultams with an analogous anthracene skele-
ton. The yields ranged from good to low. When an ethyl group
was used as a N-substituent, naphthosultam was obtained in 90%
yield and after a 12-h reaction time. When the other group was
used, the products were obtained after a higher reaction time
(24 h, probably due to steric effects) and in variable yield (Table 4).
In comparison with 2-naphthylmethanesulfonamides cyclization,
(1-bromonaphthalen-2-yl)methanesulfonamides were less reac-
tive due to lower reactivity of 3-position of naphthalene ring to
electrophilic attack with longer reaction times and lower yields.

L. D. Sasiambarrena et al. / Tetrahedron Letters 56 (2015) 7184–7189
7187
Table 3
Table 4
Cyclization of 2-naphthylmethanesulfonamides (5)
Cyclization of (1-bromonaphthalen-2-yl)methanesulfonamides
R
N
O
Br
O
S
O
Br
O
O
O
O
S
N
SO2NHR
O
SO2NHR
O
O
Amberlyst XN-1010
1,2-dicloroethane 80°C
R
13
12
Amberlyst XN-1010
5
1,2-dicloroethane 80°C
6
Entry
1
R
Product (13)
Time (h)
Yield (%)
90
Entry
1
R
Product (6)
CH2CH3
Time (h)
Yield (%)
95
Br
O
S
N
O
Et
12
24
N
O
S
CH2CH3
O
Et
3
13a
Br
O
6a
CH2CH2CH3
S
N
O
CH2
N
O
2
71
S
O
13b
2
3
4
5
n-Pr
i-Pr
n-Bu
H
3
98
97
96
88
6b
CH(CH3)2
Br
O
S
N
N
O
O
H
3
4
H
24
24
55
28
S
O
3
13c
Br
6c
(CH2)3CH3
O
S
N
O
N
O
S
Cl
O
13d
3
Cl
H
6d
H
N
O
S
O
O
R
O
R
12
N
N
S
S
O
O
HO
H2O
O
6e
S
OH
O
+
NHR
H
H
5
CH2
+ H2O
R
- H2O
N
O
O
S
6
7
8
3
94
74
60
R
N
R
N
O
O
O
O
O
N
S
O
S
S
H
6f
- H+
F
6
CH2
N
O
O
7
S
F
Scheme 5. Cyclizing proposed pathway.
6g
R
N
O
S
O
O
N
O
O
S
S
24
O
R
N
6
7
favoured
disfavoured
6h
Cl
N
Figure 2. Favoured and disfavoured cyclization products of 5.
9
24
24
95
78
O
O
S
Cl
O
H
N
N
S
O
O
S
O
O
O
O
6i
Amberlyst XN-1010
1,2-dicloroethane
80°C 24 h 78 %
8
5j
O
O
N
S
10
Scheme 6. Synthesis of N-(2-naphthylmethanesulfonyl)-1,2,3,4-tetrahydroiso-
quinoline (8) from 5j.
8

7188
L. D. Sasiambarrena et al. / Tetrahedron Letters 56 (2015) 7184–7189
11. Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Marongiu, M. E.; Loi, A. G.; De
Conclusion
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LópezRodríguez, M. L.; Porras, E.; Morcillo, M. J.; Benhamú, B.; Soto, L. J.;
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In conclusion we have developed a useful method for the prepa-
ration of dihydronaphthothiazine S,S-dioxides by an intramolecular
sulfonylamidomethylation of 2-naphthylmethanesulfonamides
with s-trioxane and synthesized in this way 14 novel naphthosul-
tams. Amberlyst XN-1010 resins were used as heterogeneous acid
catalysts with very good results. When sulfonamides 5 were
reacted with s-trioxane, naphthothiazines 6 were obtained in good
to excellent yields and in high regioselectivity of cyclization toward
position 1 of the naphthalene ring while cyclization of (1-bromo-
naphthalen-2-yl)methanesulfonamides (12) occurred toward
position 3 due to hindered position 1 in good to low yields of
naphthothiazines 13. An N-aralkylsulfonyltetrahydroisoquinoline
was obtained in good yield when 2-phenylethyl moiety attached
to nitrogen was used; the cyclization toward the phenyl ring of
the 2-phenylethyl moiety is due probably to steric effects. We have
also prepared new 2-naphthylmethanesulfonamides that have
been used as substrates in the cyclization reactions. Amberlyst
XN 1010 resins used as acid catalysts showed great advantages;
they are mild, they can be recovered by simple filtration, they no
generate acid residues, and provide high reaction yields.
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This work was generously supported by funds provided by
Universidad Nacional de La Plata, Argentina (11X/509) and CONI-
CET, Argentina. The authors thank Dr. Agustín Ponzinibbio and
Dr. Rubén Rimada for assistance with NMR measurements also to
Dr. Sergio Laurella for assistance with GC–MS measurements and
analysis. L.D.S. is a holder of a CONICET fellowship.
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Supplementary data associated with this article can be found, in
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13, respectively) in all cases as
a white solid which was purified by
recrystallization or column chromatography (CH2Cl2). Representative
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(6a). Yield 95%, mp: 87-88 °C (hexane/EtOAc 1:1).
C14H15NO2S; found C,
64.32; H, 5.84; N, 5.36; S, 12.28%; requires C, 64.34; H, 5.79; N, 5.36; O, 12.24;
S, 12.27%. 1H NMR (200 MHz, CDCl3, ppm): d 7.92–7.81 (m, 2H, H-7, H-10), 7.78
(d, J = 8.5 Hz, 1H, H-6), 7.68–7.45 (m, 2H, H-8, H-9), 7.09 (d, J = 8.5 Hz, 1H, H-5),
4.99 (s, 2H, ArCH2N), 4.41 (s, 2H, CH2SO2N), 3.37 (q, J = 7.2 Hz, 2H, NCH2CH3),

L. D. Sasiambarrena et al. / Tetrahedron Letters 56 (2015) 7184–7189
7189
1.31 (t, J = 7.2 Hz, 3H, NCH2CH3). 13C NMR (50 MHz, CDCl3, ppm): d 133.08,
130.49, 129.16, 128.62, 127.44, 127.21, 126.71, 125.91, 125.47, 122.16, 50.38,
50.01, 43.62, 13.91. MS (m/z): 261 (M+Å), 196 (BP), 182, 167, 153, 155, 142, 140,
115, 56. (b) 10-bromo-3-ethyl-3,4-dihydro-1H-naphtho[2,3-d]2,3-thiazine 2,2-
dioxide (13a). Yield 90%, mp: 163–164 °C (EtOAc). C14H14BrNO2S; found C,
49.49; H, 4.19; N, 4.11; S, 9.51%; requires C, 49.42; H, 4.15; Br, 23.48; N, 4.12;
O, 9.40; S, 9.42%. 1H NMR (200 MHz, CDCl3, ppm): d 8.34–8.18 (m, 1H, H-9),
7.77 (m, 1H, H-6), 7.65 (s, 1H, H-5), 7.62–7.49 (m, 2H, H-7, H-8), 4.76 (s, 2H,
ArCH2N), 4.51 (s, 2H, CH2SO2), 3.26 (q, J = 7.2 Hz, 2H, NCH2CH3), 1.26 (t,
J = 7.2 Hz, 3H, NCH2CH3). 13C NMR (50 MHz, CDCl3, ppm): d 133.52, 131.60,
128.55, 128.20, 128.00, 127.86, 127.34, 127.00, 126.35, 126.27, 51.98, 51.19,
43.26, 13.84. MS (m/z): 341 (M+Å), 339 (M+Å), 276 (BP), 274, 262, 260, 235, 233,
196, 167, 153, 152, 139, 76.