Novel synthesis of 3-arylated 5,6-dimethoxybenzo[d]isothiazole 1,1- dioxides

Article abstract of DOI:10.2174/157017810791130568

A novel simple three-step synthesis of 3-arylated 5,6-dimethoxybenzo[d] isothiazole 1,1-dioxide is reported. ortho-Lithiation of N-tert-butyl-3,4- dimethoxybenzenesulfonamide followed by reaction with aryl aldehydes gave carbinol sulfonamides, which were

Full text of DOI:10.2174/157017810791130568

332
Letters in Organic Chemistry, 2010, 7, 332-334
Novel Synthesis of 3-Arylated 5,6-Dimethoxybenzo[d]isothiazole 1,1-
Dioxides
Fei Xiea,b, Bing-Lei Gaob, De-Feng Wangb and Zhao-Peng Liu*,b
aMarine College, Shandong University at Weihai, Weihai 264209, Shandong, P. R., China
bDepartment of Organic Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, P. R.,
China
Received February 08, 2010: Revised March 12, 2010: Accepted March 12, 2010
Abstract: A novel simple three-step synthesis of 3-arylated 5,6-dimethoxybenzo[d]isothiazole 1,1-dioxide is reported.
ortho-Lithiation of N-tert-butyl-3,4-dimethoxybenzenesulfonamide followed by reaction with aryl aldehydes gave
carbinol sulfonamides, which were oxidized into ketosulfonamides and converted to the ketimines via TMSCl/NaI/MeCN
reagent mediated novel cyclization.
Keywords: Ketimines, TMSCl/NaI/MeCN, cyclization, benzo[d]isothiazoles, sulfonamides.
3-Substituted benzo[d]isothiazole 1,1-dioxides, the cyclic
ketimines derived from saccharins, are versatile synthetic
intermediates for the construction of both five- and six-
membered benzosultams [1]. They are also the privileged
structures in drug discovery due to wide range of biological
activities [2]. The most direct method for the preparation of
3-substituted benzo[d]isothiazole 1,1-dioxides involves the
reaction of saccharin or its derivatives with organolithium or
Grignard reagents [3]. However, this method has limitations
owning to the unavailability of some of the functionalized
organometallic species, or the poor reactivities of some
hindered organometallic reagents with saccharin. In addition,
saccharins with substituents on the aromatic ring are not
readily available and usually take several steps to prepare
[4]. Another elegant approach for the preparation of
benzo[d]isothiazoles utilizes the aromatic heteroannulation
strategy [3a,5]. Many other transformations have also been
used for the construction of saccharin-related cyclic
ketimines [6]. However, a simple method for the preparation
of cyclic ketimines with substituents on the benzene ring of
saccharin remains valuable. Since the methoxybenzene
moiety is a common structure in many natural tubulin
inhibitors like podophyllotoxin, colchicine, steganacine,
combretastatin A4 [7], and sulfonamides are the privileged
structures in many drugs [8], we are interested in the
synthesis of the title compounds, that have the structural
features to combine the two important pharmacophores into
one molecule.
benzosultams [9]. This methodology is also suitable for the
preparation of benzo[d]isothiazole 1,1-dioxides having a
secondary alkyl substituent at the 3-position in a simple two-
step via the ortho-lithiation of N-tert-butylbenzenesul-
fonamide and reaction with 2-arylpropionic acid methyl ester
to form an ortho-ketosulfonamide followed by the
TMSCl/NaI/MeCN reagent mediated cyclization [10].
However, when a benzoic or substituted benzoic acid methyl
ester is used, we find, the ketosulfonamide is not available.
In fact, the aryl ketone thus formed is rather active to react
with another molecule of the lithiated benzenesulfonamide to
form a tertiary carbinol sulfonamide, even when the reaction
is run at –78°C. Therefore, this approach can not be directly
applied for the preparation of 3-arylated 5,6-dimethoxybenzo
[d]isothiazole 1,1-dioxides. By adopting a similar strategy,
we hereby report an alternative route to the synthesis of 3-
substituted benzo[d]isothiazole 1,1-dioxides (Scheme 1).
The ortho-lithiation of N-substituted benzenesul-
fonamides is a well-documented method for the preparation
of their ortho-functionalized derivatives and heterocycles
[11]. When N-tert-butyl-3,4-dimethoxybenzenesulfonamide
1 was treated with an excess of n-BuLi (2.5 eq) in THF
solution under nitrogen atmosphere at 0°C for 30 min, the
ortho-lithiation of 1 occurred smoothly to yield an anion,
which reacted with 4-methoxybenzaldehyde to form a
carbinol 2a in 81% yield. When 3,4-dimethoxy-, 3,4,5-
trimethoxy-, 4-chloro- and 4-methyl-substituted benzaldehy-
des were applied, the corresponding carbinol sulfonamides
2b-e were obtained in general good yields, ranging from
67% to 81% (Scheme 1). In next step, the alcohol 2a was
In the course of synthesizing functinalized benzosultams,
we have developed a novel cyclization method mediated by
iodotrimethylsilane (Me3SiI, TMSI), generated in situ by
mixing chlorotrimethylsilane (TMSCl) with sodium iodide
(NaI) in acetonitrile (MeCN) solution, for the efficient
construction of both 3-substituted five- and six-membered
converted completely to
a ketsulfonamide by PDC
(pyridinium dichromate) oxidization in anhydrous
dichloromethane at room temperature for 6 h. After filtration
of the reaction mixture through a short pad of celite, the
filtrate was evaporated and the crude arylketone was used
directly for the cyclization promoted by TMSCl/NaI/MeCN
reagent. As expected, when the ketosulfonamide was treated
with two equivalents of TMSCl and NaI in acetonitrile under
reflux conditions for 1.5 h, the cyclization occurred to
*Address correspondence to this author at the Department of Organic
Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan
250012, P. R., China; Tel: +86-531-88382006; Fax: +86-531-88382548; E-
mail: liuzhaop@sdu.edu.cn
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© 2010 Bentham Science Publishers Ltd.

Novel Synthesis of 3-Arylated 5,6-Dimethoxybenzo[d]isothiazole
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
333
MeO
MeO
SO2NHBut
OH
O2
MeO
S
MeO
MeO
SO2NHBut
N
1) PDC, CH2Cl2
MeO
1) n-BuLi, THF, 0 ˚C
2) ArCHO
2) TMSCl, NaI, MeCN
R
R
2a: R = 4-OMe, 81%
3a: R = 4-OMe, 75%
2b: R = 3,4-(OMe)2, 76%
2c: R = 3,4,5-(OMe)3, 72%
2d: R = 4-Cl, 67%
3b: R = 3,4-(OMe)2, 82%
3c: R = 3,4,5-(OMe)3, 71%
3d: R = 4-Cl, 70%
2e: R = 4-Me, 78%
3e: R = 4-Me, 68%
Scheme 1. Synthetic route to 3-arylated 5,6-dimethoxybenzo[d]isothiazole 1,1-dioxides.
produce the benzo[d]isothiazole in an overall of 75% yield
(two steps). In similar manner, other 3-arylated
benzo[d]isothiazole 1,1-dioxides 3b-e were easily obtained
in high yields (Scheme 1).
mixture through a short pad of celite, the filtrate was
evaporated in vacuo. The residue was dissolved in MeCN
(15 mL), sodium iodide (0.93 g, 6.20 mmol) was added and
stirred. Chlorotrimethylsilane (0.81 mL, 6.2 mmol) was
added dropwise under nitrogen at room temperature. The
mixture was refluxed for 1.5 h, after which it was cooled and
10% sodium thiosulfate solution was added. The mixture
was extracted with EtOAc, and the combined organic layers
was washed with 10% sodium thiosulfate solution, brine,
dried (Na2SO4), concentrated in vacuo. Crystallizion from
EtOAc/hexane gave give 3a (0.78 g, 75%) as a white solid:
mp 223–225 °C; IR (KBr) 3010, 2938, 1604, 1506, 1332,
1316, 1255, 1163, 1144, 849, 770 cm-1; 1H NMR (600 MHz,
CDCl3) ꢀ 3.93 (s, 3H), 3.97 (s, 3H), 4.04 (s, 3H), 7.09 (d, J =
9.0 Hz, 2H), 7.25 (s, 1H), 7.45 (s, 1H), 7.96 (d, J = 9.0 Hz,
2H); MS (ESI) m/z 334.1 [M+H]+. Anal. Calcd for
C16H15NO5S: C, 57.65; H, 4.54; N, 4.20. Found: C, 57.60; H,
4.56; N, 4.17.
a
In conclusion, we have developed a simple method for
the facile preparation of the 3-arylated benzo[d]isothiazole
1,1-dioxides. These novel benzo[d]isothiazoles can be
regarded as the sulfonamide-bridged and conformationally
restricted analogues of combretastatin A4 family [7] and
may have interesting biological activities. Application of this
novel method towards the synthesis of the cyclic ketimine
libraries and the studies of the antiproliferative activity of
these novel compounds against a panel of human tumor cell
lines are currently in progress.
TYPICAL SYNTHETIC PROCEDURES
Carbinol Sulfonamide 2a
A 2.5 M solution of n-BuLi (4.0 mL, 10 mmol) in hexane
was added dropwise to a stirred solution of sulfonamide 1
(1.10 g, 4 mmol) in THF (15 mL) under nitrogen at 0°C.
After stirring for 30 min, another solution of 4-
methoxybenzaldehyde (0.55 g, 4 mmol) in THF (5 mL) was
added. The mixture was stirred for 1 h and quenched by
aturated aqueous NH4Cl. The mixture was then extracted
with EtOAc, and the combined organic layers were dried
(Na2SO4), concentrated in vacuo. Purification by column
chromatography on silica gel using hexane-EtOAc (10:1) as
an eluent gave 2a as a white solid (1.32 g, 81%), mp 116–
118 °C; IR (KBr) 3485, 3286, 2972, 1610, 1510, 1267, 1249,
ACKNOWLEDGEMENTS
This work was supported by the Natural Science
Foundation of China (30873134) and Natural Science
Foundation of Shandong Province (Y2007C125).
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