Novel method for the synthesis of 3-monosubstituted six-membered benzosultams

Article abstract of DOI:10.3987/com-07-11120

3-Monosubstituted six-membered benzosultams with a wide range of functional groups were prepared by simple and convenient two-step procedures. o-Lithiation of N-Boc-o-toluenesulfonamide followed by reaction with aldehydes gave carbinol sulfonamides, which were converted to 3-monosubstituted six-membered benzosultams via TMSCI/NaI/MeCN reagent mediated cyclization. The mechanism and the scope of this novel transformation are studied.

Full text of DOI:10.3987/com-07-11120

HETEROCYCLES, Vol. 71, No. 11, 2007
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HETEROCYCLES, Vol. 71, No. 11, 2007, pp. 2377 - 2388. © The Japan Institute of Heterocyclic Chemistry
Received, 25th May, 2007, Accepted, 25th July, 2007, Published online, 3rd August, 2007. COM-07-11120
NOVEL METHOD FOR THE SYNTHESIS OF 3-MONOSUBSTITUTED
SIX-MEMBERED BENZOSULTAMS
Fang Fang, Rui Wang, Zhao-Peng Liu,* and Ai-Guo Ji
Department of Organic Chemistry, School of Pharmaceutical Sciences, Shandong
University, Jinan 250012, P.R. China. E-mail: liuzhaop@sdu.edu.cn
Abstract – 3-Monosubstituted six-membered benzosultams with a wide range of
functional groups were prepared by simple and convenient two-step procedures.
o-Lithiation of N-Boc-o-toluenesulfonamide followed by reaction with aldehydes
gave carbinol sulfonamides, which were converted to 3-monosubstituted
six-membered benzosultams via TMSCl/NaI/MeCN reagent mediated cyclization.
The mechanism and the scope of this novel transformation are studied.
INTRODUCTION
The importance of the sulfonamide unit in medicinal chemistry cannot be overstated.1 Sulfonamides have
been shown to exhibit a wide spectrum of biological activities and constitute an important class of drugs,
with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic,
hypoglycemic, antithyroid, antiviral and anticancer activity among others.2 In addition to being a carboxyl
isostere, the introduction of the SO2-N moiety induces an increase of stability, for example, towards
protease-catalyzed degradation in the case of sulfonamide-containing peptidomimetics.3 Recently,
conformationally constrained sulfonamides (sultams) have served as key functional groups in the
development of: nonsteroidal antiinflammatory agents, agonists of 5-HT1A receptors, novel serine
inhibitors, zinc enzyme carbonic anhydrase inhibitors, etc.4 Beyond their significance in the treatment of
diseases, sultams have also been employed with considerable success as chiral auxiliaries in asymmetric
versions of several reactions, including alkylations, acylations, aldol reactions, Diels-Alder reactions and
azidations.5 Synthesis of N-fluorobenzosultam templates has become one of the important strategies for
the development of novel electrophilic fluorinating agents.6
As part of a program to study the biological activities of highly functionalized cyclic sulfonamides, we
are interested in the development of an efficient method for the construction of 3-monosubstituted
six-membered benzosultams, especially for the synthesis of 3-arylated analogues. Takeuchi’s group
reported a simple way to prepare such benzosultams from N-acyl-o-toluenesulfonamide in two steps via
ortho-methyl lithiation/cyclization processes followed by Pd/C catalyzed hydrogenation.7 The yields for

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HETEROCYCLES, Vol. 71, No. 11, 2007
the cyclization were highly dependent on the bulkiness of the acyl substituents (RCO-, R = t-Bu, 74%;
c-Hex, 54%; i-Pr, 46%; i-Bu, 20%; Ph, 25%; Me, 0%), the bulky t-butyl worked best with a moderate
yield, whereas the small methyl group failed to be introduced into the 3-position. The low yields and
substrate limitations make this method not very useful. There are other ways to prepare N-methyl or
phenyl substituted six-membered benzosultams,8 however, the difficulty in removing the methyl or
phenyl protective group at the nitrogen atom limited their applications. Thus, a simple and general
procedure to generate 3-monosubstituted six-membered benzosultams, which can tolerate a wide variety
of functional groups, remains elusive. In our previous researches, we demonstrated that both
3,3-disubstituted five- and six-membered benzosultams can be constructed very efficiently via the
TMSCl/NaI/MeCN reagent mediated novel cyclization.9 To study the mechanism, scope and limitations
of this novel methodology, we hereby report the application of TMSCl/NaI/MeCN reagent in the
synthesis of 3-monosubstituted six-membered benzosultams.
RESULTS AND DISCUSSION
The first step takes advantage of the powerful sulfonamide directed ortho metalation (DoM)10 effect.
N-Boc-o-toluenesulfonamide 1 underwent ortho-methyl metalation, as well as N-metalation, with two
equivalents of BuLi in anhydrous THF under nitrogen atmosphere at –78°C for 30 min to form
dilithiosulfonamide, which was reacted with an aldehyde to form a carbinol (Scheme 1).
SO2NHBoc
SO2NHBoc
OH
1) BuLi, THF, -78¡ãC
2) RCHO
Me
1
2
R
O2
S
TMSCl/NaI/MeCN
reflux
NH
3
R
Scheme 1
Keen to test the generality of our strategy, a wide range of aldehydes, including aliphatic and functionally
substituted aromatic aldehydes, were used, and the corresponding carbinol sulfonamides 2a-l were
obtained in high yields, the results are outlined in Table 1.
With the carbinol sulfonamides readily available, we next tested the cyclization promoted by
TMSCl/NaI/MeCN reagent. As is expected, when substrate 2a was subjected to two equivalents of
TMSCl and NaI in acetonitrile under reflux conditions for 1.5 h, the cyclization went smoothly to produce
the benzosultam 3a in 84% yield. Sultams 3b-l were obtained in the same way (Table 1). As can be seen

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2379
from Table 1, this procedure is especially effective for the preparation of 3-monoarylated benzosultams, a
number of important functional groups that include both electron donating, withdrawing ones, such as
chloro-, fluoro-, dimethylamino-, methoxy-, cyano-, are tolerant to the reaction conditions. For the less
bulky aliphatic substituents at the 3-position, the yields are moderate (entries i and j), but for the bulky
aliphatic substituents like cyclohexyl and tert-butyl (entries k and l), the yields are less than satisfactory
even for an extended reaction time (10 h). It is also of note that 3-methylated bezosultam (3i) which was
unavailable by Takeuchi’s method are readily obtained by TMSCl/NaI/MeCN reagent mediated novel
transformation.
Table 1. Synthesis of 3-monosubstituted benzosultams
Yields (%)
Yield (%)
3a-l
84
Entry
R
2a-l
92
87
79
88
86
82
77
81
78
80
86
78
a
b
c
d
e
f
phenyl
4-chlorophenyl
4-fluorophenyl
4-dimethylaminophenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
3,4,5-trimethoxyphenyl
4-cyanophenyl
methyl
81
86
82
82
90
g
h
i
86
78
75
j
ethyl
72
k
l
cyclohexyl
46a
25a
t-butyl
a refluxed for 10 h
The TMSCl/NaI/MeCN system is well-known as a versatile reagent for reaction with many functional
groups.11 We assumed that the novel cyclization mediated by the TMSCl/NaI/MeCN reagent may
proceed through a sequence of consecutive processes, involving in removing the Boc- protective group in
the carbinol sulfonamide 2, conversion of the hydroxy group to iodide, and an intramolecular nucleophilic
substitution for the cyclization. In fact, when substrate 2l was treated with two equivalents of TMSCl and
NaI in acetonitrile at room temperature for 2 hours, the N-Boc protective group was cleared thoroughly to
form the carbinol sulfonamide 4, which was turned into the iodide 5 rather slowly at room temperature
and only 25% iodide 5 was formed after 16 hours. When heated, substrate 2l was converted to the iodide

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5 much quickly (about 30 min). After heating for 10 hours, we isolated the cyclization product 3l (25%),
the elimination product 6 (42%), along with the unreacted iodide 5 (20%) (Scheme 2). It is apparent that
the intramolecular nucleophilc substitution (cyclization) and elimination reactions are competitive, and
the sterically hindered iodide 5 with a benzylic hydrogen favors the elimination, so the olefin 6 thus
formed is predominant. Since a benzenesulfonamide is a weak nucleophile, the cyclization step may
highly depend on the nature of the iodide. The bulky alkyl iodides (entries k and l) are less reactive than
the less bulky ones (entries i and j) and the benzyl iodides in the bimolecular nucleophilic substitution,
so the corresponding 3-monoalkylated benzosultams with a bulky substituents like cyclohexyl and
tert-butyl are obtained in much lower yields.
SO2NH2
OH
SO2NHBoc
OH
SO2NH2
I
But
But
But
4
2l
5
O2
S
SO2NH2
But
NH
+
But
6
3l
Scheme 2
Numerous natural products, such as flavanoids, phenolic acids, tannins, stilbenes and lignans, have the
key polyphenolic or polymethoxyphenolic units. These polyphenolic substances have a wide range of
biological activities and are on the hot topics as nutritious antioxidants, in the prevention and treatment of
cardiovascular diseases, cancers, osteoporosis, diabetes and neurodegenerative diseases.12 By our novel
method, the methoxyphenolic and polymethoxyphenolic benzosultams are available for the first time.
In conclusion, we have developed a new synthetic approach for the facile preparation of the
3-monosubstituted six-membered benzosultams via the novel cyclization mediated by TMSCl/NaI/MeCN
reagent. The mechanism, scope and limitations of this novel transformation is also elucidated. Our
method is superior and complementary to Tacheuchi’s method in the synthesis of 3-monosubstituted
six-membered benzosultams. Application of this reaction towards the synthesis of benzosultam libraries
is now underway.
EXPERIMENTAL
Melting points were determined on an X-6 micro-melting point apparatus (Beijing Tech. Co., Ltd) and are

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1
uncorrected. IR spectra (cm–1) were recorded on a Perkin-Elmer 1600 spectrometer. H NMR (600
MHz) spectra were recorded at room temperature for CDCl3 solutions. All chemical shifts were reported
as δ values (ppm) relative to Me4Si (0.00 ppm) as internal standards for 1H spectra.
Electrospray-ionization mass spectrometry (ESI-MS) was performed on an API 4000 instrument. HRMS
was measured on a Finnigan LC QDECA mass spectrometer. Microanalyses were performed with a
YANAKO CHN-coder MT-5. Column chromatography was performed on silica gel (200-300 mesh). All
reactions involving oxygen- or moisture-sensitive compounds were carried out under a dry N2 atmosphere.
Unless otherwise noted, reagents were added by syringe. THF was distilled from sodium/benzophenone
immediately prior to use.
N-Boc-2-(2-hydroxy-2-phenylethyl)benzenesulfonamide (2a). 2.20 M solution of BuLi (3.70 mL, 8
mmol) in hexane was added cautiously dropwise over 5 min to a stirred solution of
N-Boc-o-toluenesulfonamide (1.09 g, 4 mmol) in THF (18 mL) under nitrogen at -78°C. After 15 min,
another solution of benzaldehyde (0.43 g, 4 mmol) in THF (5 mL) was added. The mixture was stirred for
1 h and quenched by careful addition of saturated aqueous NH4Cl. The mixture was then extracted with
EtOAc (4 × 15 mL) and the combined extracts were dried and evaporated under reduced pressure to leave
a yellow oil, which was purified by column chromatography on silica using hexane-EtOAc (8:1) as eluent
to give compound 2a (1.3 g, 92%) as colorless oil: IR (neat) cm-1 3480, 3220, 1740, 1341, 1148, 757; 1H
NMR δ 1.34 (s, 9H), 3.15 (s, 1H), 3.36 (dd, J = 14.0, 4.4 Hz, 1H), 3.51 (dd, J = 14.0, 8.8 Hz, 1H), 5.04
(dd, J = 8.8, 4.4 Hz, 1H), 7.28—7.33 (m, 2H), 7.36—7.39 (m, 2H), 7.41—7.44 (m, 3H), 7.54 (td, J = 7.5,
1.4 Hz, 1H), 7.94 (s, 1H), 8.19 (dd, J = 7.5, 1.4 Hz, 1H); MS m/z 376 [M–H]–; HRMS calcd for
C19H22NO5S: 376.1218; found: 376.1214.
N-Boc-2-[2-(4-chlorophenyl)-2-hydroxyethyl]benzenesulfonamide (2b). From N-Boc-o-toluene-
sulfonamide (1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and 4-chlorobenzaldehyde (0.56 g, 4
mmol), compound 2b (1.42 g, 87%) was obtained as a white solid after purification by silica gel column
chromatography (20% EtOAc in hexane). mp 124–126 °C; IR (KBr) cm-1 3525, 3218, 1748, 1345, 1216,
758; 1H NMRδ1.36 (s, 9H), 2.91 (s, 1H), 3.41 (dd, J = 14.0, 4.4 Hz, 1H), 3.53 (dd, J = 14.0, 8.6 Hz, 1H),
4.69 (dd, J = 8.6, 4.4 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H),
7.34 (m, 1H), 7.44 (m, 2H), 7.99 (d, J = 7.7 Hz, 1H); MS m/z 410 [M–H]–; Anal. Calcd for
C19H22ClNO5S: C, 55.40; H, 5.38; N, 3.40. Found: C, 55.32; H, 5.47; N, 3.58.
N-Boc-2-[2-(4-fluorophenyl)-2-hydroxyethyl]benzenesulfonamide (2c). From N-Boc-o-toluene-
sulfonamide (1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and 4-fluorobenzaldehyde (0.50 g, 4
mmol), compound 2c (1.25 g, 79%) was obtained as a white solid after purification by silica gel column
chromatography (15% EtOAc in hexane). mp 114–116 °C; IR (KBr) cm-1 3528, 3225, 1740, 1350, 1216,
758; 1H NMR δ 1.38 (s, 9H), 2.48 (s, 1H), 3.44 (dd, J = 14.6, 4.4 Hz, 1H), 3.57 (dd, J = 14.6, 8.6 Hz, 1H),

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4.65 (dd, J = 8.6, 4.4 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H),
7.51—7.62 (m, 4H), 7.89 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H); MS m/z 394 [M–H]–; Anal. Calcd for
C19H22FNO5S: C, 57.71; H, 5.61; N, 3.54. Found: C, 57.66; H, 5.42; N, 3.79.
N-Boc-2-[2-(4-dimethylaminophenyl)-2-hydroxyethyl]benzenesulfonamide (2d). From N-Boc-o-
toluenesulfonamide (1.09 g,
4
mmol), BuLi (2.20 M, 3.70 mL,
8
mmol) and
4-dimethylaminobenzaldehyde (0.60 g, 4 mmol), compound 2d (1.46 g, 88%) was obtained as a yellow
solid after purification by silica gel column chromatography (20% EtOAc in hexane). mp 123–125 °C; IR
(KBr) cm-1 3210, 1738, 1340, 1150, 758; 1H NMR δ 1.32 (s, 9H), 2.66—2.69 (m, 6H), 2.98 (s, 1H), 3.45
(dd, J = 14.4, 4.4 Hz, 1H), 3.57 (dd, J = 14.4, 8.9 Hz, 1H), 4.77 (dd, J = 8.9, 4.4 Hz, 1H), 6.89 (d, J = 7.6
Hz, 2H), 7.04—7.24 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H),
8.07(s, 1H); MS m/z 419 [M–H]–; Anal. Calcd for C21H28N2O5S: C, 59.98; H, 6.71; N, 6.66. Found: C,
59.82; H, 6.56; N, 6.74.
N-Boc-2-[2-hydroxy-2-(4-methoxyphenyl)ethyl]benzenesulfonamide (2e). From N-Boc-o-toluene-
sulfonamide (1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and 4-methoxybenzaldehyde (0.54 g, 4
mmol), compound 2e (1.41 g, 86%) was obtained as a white solid after purification by silica gel column
chromatography (25% EtOAc in hexane). mp 119–121 °C; IR (KBr) cm-1 3480, 3221, 1742, 1340, 1150,
756; 1H NMR δ 1.36 (s, 9H), 2.68 (s, 1H), 3.11 (dd, J = 14.0, 4.6 Hz, 1H), 3.29 (dd, J = 14.0, 8.8 Hz, 1H),
3.78 (s, 3H), 4.88 (dd, J = 8.8, 4.6 Hz, 1H), 6.91 (d, J = 7.7 Hz, 2H), 7.27 (td, J = 7.6, 1.1 Hz, 1H), 7.31
(d, J = 7.7 Hz, 2H), 7.46 (m, 1H), 7.56 (td, J = 7.6, 1.1 Hz, 1H), 7.92 (s, 1H), 8.09 (dd, J = 7.6, 1.1 Hz,
1H); MS m/z 406 [M–H]–; Anal. Calcd for C20H25NO6S: C, 58.95; H, 6.18; N, 3.44. Found: C, 58.99; H,
6.21; N, 3.41.
N-Boc-2-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]benzenesulfonamide (2f). From N-Boc-o-toluene-
sulfonamide (1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and 3,4-dimethoxybenzaldehyde (0.67 g,
4 mmol), compound 2f (1.43 g, 82%) was obtained as a white solid after purification by silica gel column
chromatography (25% EtOAc in hexane). mp 141–143 °C; IR (KBr) cm-1 3520, 3220, 1744, 1328, 1148,
758; 1H NMR δ 1.35 (s, 9H), 2.48 (s, 1H), 3.27 (dd, J = 14.6, 4.4 Hz, 1H), 3.44 (dd, J = 14.6, 8.6 Hz, 1H),
3.71—3.75 (m, 6H), 4.82 (dd, J = 8.6, 4.4 Hz, 1H), 6.86—6.95 (m, 3H), 7.05 (m, 1H), 7.12 (t, J = 7.7 Hz,
1H), 7.48 (t, J = 7.7 Hz, 1H), 7.62 (s, 1H), 8.07 (dd, J = 7.7, 1.2 Hz, 1H); MS m/z 436 [M–H]–; Anal.
Calcd for C21H27NO7S: C, 57.65; H, 6.22; N, 3.20. Found: C, 57.69; H, 6.40; N, 3.24.
N-Boc-2-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]benzenesulfonamide (2g). From N-Boc-o-
toluenesulfonamide (1.09 g,
4
mmol), BuLi (2.20 M, 3.70 mL,
8
mmol) and
3,4,5-trimethoxybenzaldehyde (0.79 g, 4 mmol), compound 2g (1.44 g, 77%) was obtained as a white
solid after purification by silica gel column chromatography (25% EtOAc in hexane). mp 131–133 °C; IR
(KBr) cm-1 3518, 3224, 1740, 1310, 1145, 757; 1H NMR δ 1.36 (s, 9H), 2.36 (s, 1H), 3.37 (dd, J = 14.0,

HETEROCYCLES, Vol. 71, No. 11, 2007
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8.6 Hz, 1H), 3.64 (dd, J = 14.0, 4.4 Hz, 1H), 3.68—3.71 (m, 9H), 4.82 (dd, J = 8.6, 4.4 Hz, 1H), 6.81 (d,
J = 1.2 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.50 (td, J = 7.6, 1.2 Hz, 1H),
7.82 (dd, J = 7.6, 1.2 Hz, 1H), 8.32 (s, 1H); MS m/z 466 [M–H]–; Anal. Calcd for C22H29NO8S: C, 56.52;
H, 6.25; N, 3.00. Found: C, 56.48; H, 6.19; N, 3.05.
N-Boc-2-[2-(4-cyanophenyl)-2-hydroxyethyl]benzenesulfonamide (2h). From N-Boc-o-toluene-
sulfonamide (1.09 g, 4 mmol), BuLi (2.50 M, 3.20 mL, 8 mmol) and 4-cyanobenzaldehyde (0.53 g, 4
mmol), compound 2h (1.30 g, 81%) was obtained as a yellow solid after purification by silica gel column
chromatography (20% EtOAc in hexane). mp 125–126 °C; IR (KBr) cm-1 3210, 2238, 1595, 1482, 757;
1H NMR δ 1.35 (s, 9H), 2.42 (s, 1H), 3.26 (dd, J = 14.2, 8.4 Hz, 1H), 3.58 (dd, J = 14.2, 4.4 Hz, 1H), 4.77
(dd, J = 8.4, 4.4 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.38—7.41 (m, 3H), 7.54 (d, J
= 7.6 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H); MS m/z 401 [M–H]–; Anal. Calcd for C20H22N2O5S:
C, 59.69; H, 5.51; N, 6.96. Found: C, 59.58; H, 5.60; N, 6.84.
N-Boc-2-(2-hydroxypropyl)benzenesulfonamide (2i). From N-Boc-o-toluenesulfonamide (1.09 g, 4
mmol), BuLi (2.50 M, 3.20 mL, 8 mmol) and acetaldehyde (0.18 g, 4 mmol), compound 2i (0.96 g, 78%)
was obtained as a colorless oil after purification by silica gel column chromatography (30% EtOAc in
hexane). IR (neat) cm-1 3411, 1615, 1160, 750; 1H NMR δ 1.30 (d, J = 6.2 Hz, 3H), 1.36 (s, 9H), 3.09 (dd,
J = 14.4, 2.8 Hz, 1H), 3.31 (dd, J = 14.4, 10.2 Hz, 1H), 3.47 (m, 1H), 7.31 (m, 2H), 7.48 (t, J = 7.8 Hz,
1H), 7.92 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H); MS m/z 314 [M–H]–; HRMS calcd for C14H20NO5S: 314.1061;
found: 314.1070.
N-Boc-2-(2-hydroxybutyl)benzenesulfonamide (2j). From N-Boc-o-toluenesulfonamide (1.09 g, 4
mmol), BuLi (2.50 M, 3.20 mL, 8 mmol) and propionaldehyde (0.24 g, 4 mmol), compound 2j (1.06 g,
80%) was obtained as a colorless oil after purification by silica gel column chromatography (30% EtOAc
in hexane). IR (neat) cm-1 3420, 1605, 1440, 1165, 757; 1H NMR δ 0.95 (t, J = 5.8 Hz, 3H), 1.28 (m, 2H),
1.34 (s, 9H), 2.92 (s, 1H), 3.11 (dd, J = 14.0, 2.8 Hz, 1H), 3.26 (dd, J = 14.0, 10.2 Hz, 1H), 3.55 (m, 1H),
7.38 (t, J = 7.6 Hz, 2H ), 7.50 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 8.42 (s, 1H); MS m/z 328
[M–H]–; HRMS calcd for C15H22NO5S: 328.1218; found: 328.1227.
N-Boc-2-(2-cyclohexyl-2-hydroxyethyl)benzenesulfonamide (2k). From N-Boc-o-toluenesulfonamide
(1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and cyclohexanecarboxaldehyde (0.45 g, 4 mmol),
compound 2k (1.32 g, 86%) was obtained as a colorless oil after purification by silica gel column
1
chromatography (20% EtOAc in hexane). IR (neat) cm-1 3420, 1738, 1338, 1160, 758; H NMR δ
1.06—2.01 (m, 11H), 1.38 (s, 9H), 2.28 (s, 1H), 3.12 (dd, J = 14.1, 2.8 Hz, 1H), 3.34 (dd, J = 14.1, 10.7
Hz, 1H), 3.58 (m, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 8.12 (m,
2H); MS m/z 382 [M–H]–; HRMS calcd for C19H28NO5S: 382.1687; found: 382.1689.
N-Boc-2-(2-hydroxy-3,3-dimethylbutyl)benzenesulfonamide (2l). From N-Boc-o-toluenesulfonamide

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HETEROCYCLES, Vol. 71, No. 11, 2007
(1.09 g, 4 mmol), BuLi (2.20 M, 3.70 mL, 8 mmol) and 2,2-dimethylpropionaldehyde (0.35 g, 4 mmol),
compound 2l (1.10 g, 78%) was obtained as a colorless oil after purification by silica gel column
chromatography (20% EtOAc in hexane). IR (neat) cm-1 3410, 1740, 1335, 1161, 759; 1H NMR δ 1.02 (s,
9H), 1.38 (s, 9H), 2.45 (s, 1H), 3.09 (dd, J = 14.1, 2.5 Hz, 1H), 3.28 (dd, J = 14.1, 10.8 Hz, 1H), 3.53 (dd,
J = 10.8, 2.5 Hz, 1H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.44 (m, 1H), 7.58 (td, J = 7.6, 1.3 Hz, 1H), 7.89 (s,
1H), 8.13 (dd, J = 7.6, 1.3 Hz, 1H); MS m/z 356 [M–H]–; HRMS calcd for C17H26NO5S: 356.1531; found:
356.1528.
3-Phenyl-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3a). Chlorotrimethylsilane (0.52 mL, 4 mmol) was
added cautiously dropwise to a stirred solution of 2a (0.76 g, 2 mmol) and sodium iodide (0.60 g, 4
mmol) in MeCN (10 mL) under nitrogen at rt. The mixture was heated under reflux for 1.5 h, after which
it was cooled and 10% aqueous sodium thiosulfate was added. The mixture was extracted with EtOAc,
and the combined organic layers was washed with 10% aqueous sodium thiosulfate, brine, dried (Na2SO4),
concentrated in vacuo and chromatographed using hexane-EtOAc (7:1) as eluent to give compound 3a
(0.44 g, 84%) as a white solid: Mp and spectral data (1H NMR, IR, MS) were in agreement with literature
values.7
3-(4-Chlorophenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3b). From 2b (1.03 g, 2.5 mmol),
chlorotrimethylsilane (0.65 mL, 5 mmol) and sodium iodide (0.75 g, 5 mmol), compound 3b (0.61 g,
84%) was obtained as a white solid after purification by silica gel column chromatography (20% EtOAc
in hexane). mp 169–171 °C; IR (KBr) cm-1 3260, 1320, 1169, 754; 1H NMR δ 3.21 (dd, J = 16.6, 11.5 Hz,
1H), 3.28 (dd, J = 16.6, 5.1 Hz, 1H), 4.72 (td, J = 11.5, 5.1 Hz, 1H), 4.96 (d, J = 11.5 Hz, 1H), 7.12 (d, J
= 7.7 Hz, 1H), 7.21—7.25 (m, 4H), 7.34 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.81 (d, J = 7.7 Hz,
1H); MS m/z 292 [M–H]–; Anal. Calcd for C14H12ClNO2S: C, 57.24; H, 4.12; N, 4.77. Found: C, 57.20; H,
4.22; N, 4.81.
3-(4-Fluorophenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3c). From 2c (0.80 g, 2 mmol),
chlorotrimethylsilane (0.52 mL, 4 mmol) and sodium iodide (0.60 g, 4 mmol), compound 3c (0.45 g, 81%)
was obtained as a white solid after purification by silica gel column chromatography (20% EtOAc in
hexane). mp 157–158 °C; IR (KBr) cm-1 3257, 1334, 1160, 759; 1H NMR δ 3.32 (dd, J = 16.6, 11.5 Hz,
1H), 3.45 (dd, J = 16.6, 5.1 Hz, 1H), 4.65 (td, J = 11.5, 5.1 Hz, 1H), 4.92 (d, J = 11.5 Hz, 1H), 7.28 (d, J
= 7.6 Hz, 1H), 7.32—7.50 (m, 5H), 7.55 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); MS m/z 276
[M–H]–; Anal. Calcd for C14H12FNO2S: C, 60.64; H, 4.36; N, 5.05. Found: C, 60.57; H, 4.31; N, 5.01.
3-(4-Dimethylaminophenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3d). From 2d (0.72 g, 1.7 mmol),
chlorotrimethylsilane (0.45 mL, 3.4 mmol) and sodium iodide (0.51 g, 3.4 mmol), compound 3d (0.42 g,
82%) was obtained as a white solid after purification by silica gel column chromatography (10% EtOAc
in hexane). mp 172–174 °C; IR (KBr) cm-1 3260, 1320, 1210, 757; 1H NMR δ 2.86—2.88 (m, 6H), 3.47

HETEROCYCLES, Vol. 71, No. 11, 2007
2385
(dd, J = 16.1, 11.4 Hz, 1H), 3.52 (dd, J = 16.1, 5.4 Hz, 1H), 4.02 (td, J = 11.4, 5.4 Hz, 1H), 4.61 (d, J =
11.4 Hz, 1H), 6.87—7.01(m, 5H), 7.47—7.52 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H); MS m/z 301 [M–H]–;
Anal. Calcd for C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26. Found: C, 63.61; H, 6.26; N, 9.03.
3-(4-Methoxyphenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3e). From 2e (0.77 g, 1.9 mmol),
chlorotrimethylsilane (0.50 mL, 3.8 mmol) and sodium iodide (0.57 g, 3.8 mmol), compound 3e (0.45 g,
82%) was obtained as a white solid after purification by silica gel column chromatography (20% EtOAc
in hexane). mp 147–149 °C; IR (KBr) cm-1 3260, 1322, 1240, 757; 1H NMR δ 3.20 (dd, J = 16.6, 11.5 Hz,
1H), 3.25 (dd, J = 16.6, 5.1 Hz, 1H), 3.72 (s, 3H), 4.42 (td, J = 11.5, 5.1 Hz, 1H), 4.82 (d, J = 11.5 Hz,
1H), 6.92 (d, J = 7.7 Hz, 2H), 7.08—7.16 (m, 3H), 7.41 (d, J = 7.7 Hz, 1H), 7.52 (td, J = 7.7, 1.2 Hz, 1H),
7.71 (d, J = 7.7 Hz, 1H); MS m/z 288 [M–H]–; Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84.
Found: C, 62.14; H, 5.39; N, 4.78.
3-(3,4-Dimethoxyphenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3f). From 2f (0.96 g, 2.2 mmol),
chlorotrimethylsilane (0.57 mL, 4.4 mmol) and sodium iodide (0.66 g, 4.4 mmol), compound 3f (0.63 g,
90%) was obtained as a white solid after purification by silica gel column chromatography (20% EtOAc
in hexane). mp 181–183 °C; IR (KBr) cm-1 3240, 1323, 1220, 759; 1H NMR δ 3.22 (dd, J = 16.6, 11.5 Hz,
1H), 3.29 (dd, J = 16.6, 5.2 Hz, 1H), 3.74—3.77 (m, 6H), 4.81 (td, J = 11.5, 5.2 Hz, 1H), 4.93 (d, J = 11.5
Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 7.08—7.38 (m, 3H), 7.46 (td, J = 7.7, 1.0 Hz,
1H), 7.54 (d, J = 7.7 Hz, 1H); MS m/z 318 [M–H]–; Anal. Calcd for C16H17NO4S: C, 60.17; H, 5.37; N,
4.39. Found: C, 60.22; H, 5.32; N, 4.41.
3-(3,4,5-Trimethoxyphenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3g). From 2g (0.93 g, 2 mmol),
chlorotrimethylsilane (0.52 mL, 4 mmol) and sodium iodide (0.60 g, 4 mmol), compound 3g (0.60 g, 86%)
was obtained as a white solid after purification by silica gel column chromatography (15% EtOAc in
hexane). mp 212–213 °C; IR (KBr) cm-1 3249, 1316, 1220, 757; 1H NMR δ 3.15 (dd, J = 16.6, 11.5 Hz,
1H), 3.26 (dd, J = 16.6, 5.4 Hz, 1H), 3.71—3.73 (m, 9H), 4.07 (td, J = 11.5, 5.4 Hz, 1H), 4.82 (d, J = 11.5
Hz, 1H), 6.25 (d, J = 1.2 Hz, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.7, 1.2 Hz, 1H), 7.44 (td, J = 7.7,
1.2 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H); MS m/z 350 [M+H]+, 367 [M+NH4]+; Anal. Calcd for C17H19NO5S:
C, 58.44; H, 5.48; N, 4.01. Found: C, 58.41; H, 5.32; N, 4.07.
3-(4-Cyanophenyl)-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3h). From 2h (0.61 g, 1.5 mmol),
chlorotrimethylsilane (0.40 mL, 3 mmol) and sodium iodide (0.45 g, 3 mmol), compound 3h (0.33 g,
78%) was obtained as a white solid after purification by silica gel column chromatography (15% EtOAc
in hexane). mp 154–156 °C; IR (KBr) cm-1 3310, 2230, 1590, 756; 1H NMR δ 3.18 (dd, J = 16.1, 11.0 Hz,
1H), 3.22 (dd, J = 16.1, 5.4 Hz, 1H), 3.95 (td, J = 11.0, 5.4 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 7.32 (d, J
= 7.6 Hz, 1H), 7.40—7.51 (m, 3H), 7.62—7.76 (m, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H);
MS m/z 283 [M–H]–; Anal. Calcd for C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.29; H, 4.33;

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HETEROCYCLES, Vol. 71, No. 11, 2007
N, 9.76.
3-Methyl-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3i). From 2i (0.57 g, 1.8 mmol),
chlorotrimethylsilane (0.47 mL, 3.6 mmol) and sodium iodide (0.54 g, 3.6 mmol), compound 3i (0.27 g,
75%) was obtained as a white solid after purification by silica gel column chromatography (20% EtOAc
1
in hexane). mp 129–130 °C; IR (KBr) cm-1 3250, 1326, 1178, 758; H NMR δ 1.33 (d, J = 6.0 Hz, 3H),
2.95 (dd, J = 17.1, 11.0 Hz, 1H), 3.02 (dd, J = 17.1, 5.4 Hz, 1H), 3.78 (m, 1H), 4.28 (d, J = 12.4 Hz, 1H),
7.20 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.41 (td, J = 7.7, 1.2 Hz, 1H), 7.85 (dd, J = 7.7, 1.2 Hz,
1H); MS m/z 196 [M–H]–; Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found: C, 54.71; H,
5.73; N, 7.18.
3-Ethyl-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3j). From 2j (0.66 g, 2 mmol), chlorotrimethylsilane
(0.52 mL, 4 mmol) and sodium iodide (0.60 g, 4 mmol), compound 3j (0.31 g, 72%) was obtained as a
white solid after purification by silica gel column chromatography (25% EtOAc in hexane). mp
134–136 °C; IR (KBr) cm-1 3241, 1328, 1160, 758; 1H NMR δ 0.95 (t, J = 6.1 Hz, 3H), 1.31 (m, 2H), 2.81
(dd, J = 16.4, 11.0 Hz, 1H), 2.96 (dd, J = 16.4, 5.4 Hz, 1H), 3.82 (m, 1H), 4.31 (d, J = 12.4 Hz, 1H), 7.28
(d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.39 (td, J = 7.7, 1.2 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H); MS
m/z 210 [M–H]–; Anal. Calcd for C10H13NO2S: C, 56.85; H, 6.20; N, 6.63. Found: C, 56.72; H, 6.27; N,
6.54.
3-Cyclohexyl-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3k). From 2k (0.81 g, 2.1 mmol),
chlorotrimethylsilane (0.55 mL, 4.2 mmol) and sodium iodide (0.63 g, 4.2 mmol), compound 3k (0.26 g,
46%) was obtained as a white solid after purification by silica gel column chromatography (10% EtOAc
in hexane). Mp and Spectral data (1H NMR, IR, MS) were in agreement with literature values.7
3-t-Butyl-2H,4H-benzo[e][1,2]thiazine 1,1-dione (3l). From 2l (0.40 g, 1.1 mmol),
chlorotrimethylsilane (0.30 mL, 2.2 mmol) and sodium iodide (0.33 g, 2.2 mmol), compound 3l (0.066 g,
25%) was obtained as a white solid after purification by silica gel column chromatography (10% EtOAc
in hexane). Mp and Spectral data (1H NMR, IR, MS) were in agreement with literature values.7
Chlorotrimethylsilane (0.30 mL, 2.2 mmol) was added cautiously dropwise at rt to a stirred solution of 2l
(0.40 g, 1.1 mmol) and sodium iodide (0.33 g, 2.2 mmol) in MeCN (10 mL) under nitrogen. The reaction
mixture was stirred at rt and the process was monitored by TLC. After 2 h, compound 2l was disappeared.
The solution was divided into two equal portions. One portion was added 10% aqueous sodium
thiosulfate immediately. The mixture was extracted with EtOAc and the combined organic layers was
washed with 10% aqueous sodium thiosulfate, brine, dried (Na2SO4), concentrated in vacuo and
chromatographed using hexane-EtOAc (6:1) as eluent to give compound 4 (0.11g, 78%). The other
portion was continued to react at rt for overnight. After the usual work up, the residue was
chromatographed using hexane-EtOAc (10:1) as eluent to give production 4 (0.092g, 65%) and 5 (0.051,

HETEROCYCLES, Vol. 71, No. 11, 2007
2387
25%).
2-(2-Hydroxy-3,3-dimethylbutyl)benzenesulfonamide (4). White solid; mp 102–104 °C; IR (KBr)
3310, 3218, 1502, 769 cm-1; 1H NMR δ 1.06 (s, 9H), 2.47 (s, 1H,), 3.11 (dd, J = 14.4, 8.1 Hz, 1H), 3.69
(dd, J = 14.4, 4.4 Hz, 1H), 3.88 (dd, J = 8.1, 4.4 Hz, 1H), 7.25—7.36 (m, 2H), 7.41 (s, 2H), 7.68 (t, J =
7.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H); MS m/z 256 [M–H]–. Anal. Calcd for C12H19NO3S: C, 56.01; H,
7.44; N, 5.44. Found: C, 56.07; H, 7.49; N, 5.40.
2-(2-Iodo-3,3-dimethylbutyl)benzenesulfonamide (5). Colorless oil; IR (neat) 3455, 3022, 1735, 1540,
1
757 cm-1. H NMR δ 1.11 (s, 9H), 3.01 (dd, J = 14.4, 4.1 Hz, 1H), 3.64 (dd, J = 14.4, 8.6 Hz, 1H), 3.78
(dd, J = 8.6, 4.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.44 (td, J = 7.8, 1.2 Hz, 1H), 7.55 (s, 2H), 7.60 (t, J =
7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H); MS m/z 366 [M–H]–; HRMS calcd for C12H17INO2S: 366.0024;
found: 366.0027.
Chlorotrimethylsilane (0.30 mL, 2.2 mmol) was added cautiously dropwise to a stirred solution of 2l
(0.40 g, 1.1 mmol) and sodium iodide (0.33 g, 2.2 mmol) in MeCN (10 mL) under nitrogen at rt. The
reaction mixture was refluxed for 10 h and was monitored by TLC. The solution was cooled and 10%
aqueous sodium thiosulfate was added. The mixture was extracted with EtOAc, and the combined organic
layer was washed with 10% aqueous sodium thiosulfate, brine, dried (Na2SO4), concentrated in vacuo and
chromatographed using hexane-EtOAc (10:1) as eluent to give compound 5 (0.079g, 20%), 6 (0.11g,
42%), and 3l (0.066g, 25%).
(E)-2-(3,3-dimethylbut-1-enyl)benzenesulfonamide (6). Yellow oil; IR (neat) 3320, 3055, 1740, 1638,
1528, 975 cm-1; 1H NMR δ 1.07 (s, 9H), 4.90 (s, 2H), 6.24 (d, J = 16.0 Hz, 1H), 7.12 (d, J = 16.0 Hz, 1H),
7.28—7.36 (m, 2H), 7.50 (td, J = 7.7, 1.2 Hz, 1H), 7.96 (t, J = 7.7 Hz, 1H); MS m/z 238 [M–H]–; HRMS
calcd for C12H16NO2S: 238.0901; found: 238.0899.
ACKNOWLEDGEMENTS
This work was supported by the Scientific Research Foundation for the Returned Oversea Chinese
Scholars of Shandong University and National Science Foundation of China.
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