Oxidative cyclization of N-alkyl-o-methyl-arenesulfonamides to biologically important saccharin derivatives

Article abstract of DOI:10.1016/j.tet.2006.05.038

Various biologically important saccharin skeletons and their N-alkyl derivatives have been efficiently prepared by chromium(VI) oxide catalyzed H₅IO₆ oxidation of N-alkyl-o-methyl-arenesulfonamides in acetonitrile. N-tert-Butyl saccharin skeletons were easily prepared by H₅IO₆-CrO₃ oxidation of N-tert-butyl-o-methyl arenesulfonamides in the presence of acetic anhydride. The method that furnished the novel fluoro and trifluoromethyl substituted saccharin skeletons is characterized by two steps, a simple work-up procedure, a single purification and good overall yields from substituted toluene derivatives.

Full text of DOI:10.1016/j.tet.2006.05.038

Tetrahedron 62 (2006) 7902–7910
Oxidative cyclization of N-alkyl-o-methyl-arenesulfonamides to
biologically important saccharin derivatives
*
Liang Xu, Hong Shu, Ying Liu, Suhong Zhang and Mark L. Trudell
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 13 March 2006; revised 11 May 2006; accepted 15 May 2006
Available online 19 June 2006
Abstract—Various biologically important saccharin skeletons and their N-alkyl derivatives have been efficiently prepared by chromium(VI)
oxide catalyzed H5IO6 oxidation of N-alkyl-o-methyl-arenesulfonamides in acetonitrile. N-tert-Butyl saccharin skeletons were easily
prepared by H5IO6–CrO3 oxidation of N-tert-butyl-o-methyl arenesulfonamides in the presence of acetic anhydride. The method that
furnished the novel fluoro and trifluoromethyl substituted saccharin skeletons is characterized by two steps, a simple work-up procedure,
a single purification and good overall yields from substituted toluene derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
only one method has been reported in the literature for the
transformation of N-alkyl-o-methyl-arenesulfonamides to
N-alkyl saccharin derivatives.14 However, this method is
limited to N-methyl derivatives with electron-withdrawing
aryl ring substituents and the yields are fairly low. During
our recent study of chromium catalyzed periodic acid oxida-
tions,5–7,15 we found that N-alkyl-o-methyl-arenesulfon-
amides could be efficiently oxidized to saccharin and
saccharin N-alkyl derivatives with H5IO6–CrO3 in aceto-
nitrile. Herein we report this novel and efficient method
for the preparation of various saccharin skeletons.
The H5IO6–CrO3 oxidation system has been used for various
C–H oxidations, such as tertiary C–H,1 benzylic C–H,2 alco-
holic C–H,3 aromatic C–H.4 In recent years, our group has
been studying the H5IO6–CrO3 oxidation system and
reported several novel C–H oxidations by using H5IO6–
CrO3 to oxidize N-alkylamides to imides,5 N-alkylsulfon-
amides to sulfonimides,6 benzylic silyl ethers to aldehydes
or ketones.7 Although the chromium(VI) catalyzed H5IO6
oxidation of toluenes to benzoic acids has been described
by Yamazaki,2 the application of this oxidation system to
oxidize N-alkyl-o-methyl-arenesulfonamides to saccharin
skeletons has not been reported.
2. Results
2.1. Direct oxidation of N-alkyl-o-toluenesulfonamides
to saccharin derivatives
O
O
O
O
7
4
H5IO6 /CrO3
Ac2O
6
5
S
S
X
N
R
N
R
X
MeCN
H
The results of oxidation of N-alkyl-o-methyl-toluenesulfon-
amides 1 to afford saccharin derivatives 2 are summarized in
Table 1. The oxidation of o-toluenesulfonamide (1a) was
incomplete with only 4 equiv of H5IO6 either at rt or 85 ꢀC
(Table 1, entries 1–3). At least 6 equiv of H5IO6 and
10 mol % of CrO3 were required for complete reaction at
85 ꢀC (Table 1, entry 5). The oxidation was also completed
in 1 h by refluxing 1a with 8 equiv of H5IO6 and 5% of CrO3
in acetonitrile (Table 1, entry 7). Similar results were
obtained at rt with 8 equiv of H5IO6 but longer reaction
time (16 h) or higher catalyst loading (10 mol %) was
required.
Me
O
1,2-Benzisothiazole-3-one-1,1-dioxide (saccharin) has been
widely incorporated into a variety of biologically active
compounds. The saccharin moiety has been identified as
an important molecular component in various classes of
5-HT1a antagonists,7 human leukocyte elastase inhibitors,8
analgesics,9 human mast cell tryptase inhibitors,10 a1a and
a1c adrenergic receptor antagonists,11 aldehyde dehydro-
genase inhibitors,12 and bactericides.13 To our knowledge,
Keywords: Saccharin; Sulfonamides; Periodic acid; Chromium trioxide;
Oxidation; Oxidative cyclization
* Corresponding author. Tel.: +1 504 280 7337; fax: +1 504 280 6860;
e-mail: mtrudell@uno.edu
A competitive oxidation of the a-C–H of the N-alkyl group
was observed in the oxidation of several N-alkyl-o-toluene-
sulfonamides. Oxidation of N-methyl-o-toluenesulfonamide
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.038

L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
7903
Table 1. Direct oxidation of N-alkyl-o-toluenesulfonamides to saccharin
derivatives
toluenesulfonamide were unsuccessful and only an intracta-
ble mixture was obtained.
O
O
O
S
H5IO6
CrO3
O
N
R
S
2.2. Oxidation of various substituted o-toluenesulfon-
amides to saccharin skeletons
N
R
H
CH3CN
CH3
O
2
1
To date a number of methods have been reported for the
construction of the saccharin ring system.16–21 However,
currently available methods either employ sophisticated
reagents or give only moderate yields of saccharin deriva-
tives. A practical and general method for the preparation
of saccharin-based compounds is still desirable. The direct
oxidation of o-methyl arenesulfonamides is the simplest
and most straightforward method for the preparation of sac-
charin skeletons. However, most of the reported oxidations
are generally conducted in aqueous acidic or basic solutions
affording the product in fairly low yields (40–50%).16 Some
oxidations even use excess CrO3 as the oxidant but these
conditions can lead to the environmental problem of waste
metal disposal. Based on our initial results from the direct
oxidation of N-alkyl-o-toluenesulfonamides (Table 1), we
developed a practical and general method for the preparation
of N-unsubstituted saccharin derivatives. As summarized in
Table 2, various substituted o-toluenesulfonamides 3 were
easily oxidized to the corresponding substituted saccharin
derivatives 4 by refluxing with 8 equiv of H5IO6 and a cata-
lytic amount of CrO3 in acetonitrile. Higher catalyst loading
(10 mol %) of CrO3 was required for complete oxidation of
substrates with strong electron-withdrawing groups. It is
noteworthy that p-xylenesulfonamide (3i) was efficiently
oxidized to the 6-CO2H saccharin derivative 4i with
10 equiv of H5IO6 and 10 mol % of CrO3 (Table 2, entry 9).
Entry
1
R
2
H5IO6 CrO3
(equiv) (mol %) (ꢀC)
Temperature Time Yield
(h)
(%)a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b Me
1c Et
1d i-Pr
1e c-Pr
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
4
4
4
6
6
8
8
8
8
8
8
8
8
6
6
8
8
8
8
8
10
20
20
5
10
5
5
5
5
5
5
5
10
5
5
5
5
10
10
5
22
22
85
85
85
22
85
22
22
22
22
85
22
22
22
22
22
22
22
22
16
16
1
32
48
60
68
75
75
75
35b
12
20
46
94
94
76
84c
80
86d
86
88d
0e
1
1
16
1
8
9
8
8
10
11
12
13
14
15
16
17
18
19
20
16
1
8
1f CF3CH2 2f
1f CF3CH2 2f
1g t-Bu
1g t-Bu
1g t-Bu
1g t-Bu
1g t-Bu
1g t-Bu
1h MeO
2g
2g
2g
2g
2g
2g
16
16
16
10
8
8
3
a
Isolated yields.
Saccharin was also obtained (20%).
The reaction was performed in the presence of 6 equiv of Ac2O.
The reaction was performed in the presence of 8 equiv of Ac2O.
Intractable mixture.
b
c
d
e
(1b) (Table 1, entry 8) afforded N-methyl saccharin (2b) in
35% yield and saccharin (2a) was also obtained in 20%
yield. Only a 12% yield of N-ethyl saccharin (2c) was
obtained in oxidation of N-ethyl-o-toluenesulfonamide (1c,
Table 1, entry 9). The competitive a-C–H oxidation was
more significant in oxidation of N-isopropyl-o-toluenesulfon-
amide (1d) than that of N-cyclopropyl-o-toluenesulfon-
amide (1e) (Table 1, entries 10 and 11). However, the 2, 2,
2-trifluoroethyl group and tert-butyl group were tolerant of
the oxidation conditions. Oxidation of N-2, 2, 2-trifluoro-
ethyl-o-toluenesulfonamide (1f) afforded the corresponding
saccharin derivative 2f in 94% either at rt or at reflux (Table
1, entries 12 and 13). The oxidation of N-tert-butyl-o-
toluenesulfonamide (1g) also gave high yields of the cor-
responding N-tert-butyl saccharin (2g) at rt (Table 1, entry
14). In addition, the yields of the 2g were slightly
improved when acetic anhydride was added to the reaction
mixture to maintain anhydrous conditions (Table 1, entries
15, 17, and 19). Acetic anhydride was selected as a desiccant
over molecular sieves or other inorganic reagents because of
the heterogeneous character of the reaction mixture. Iodic
acid (HIO3) is formed as a by-product of the oxidation and
precipitates from the reaction mixture. The addition of solid
desiccant reagents was not desirable since adequate mixing
could become difficult. To this end, optimal conditions were
realized with 8 equiv of acetic anhydride to yield the N-tert-
butyl saccharin (2g) in 88% yield. The presence of acetic
anhydride also significantly shortened the reaction time
(Table 1, entry 19). In addition, no acetylated products
were identified. Attempts to oxidize the N-methoxy-o-
Table 2. Oxidation of substituted o-toluenesulfonamides to saccharin
skeletons
O
O
O
S
H5IO6 (8 equiv.)
CrO3 (cat.)
O
N
7
4
S
NH2
CH3
H
X
X
CH3CN
reflux
O
4
3
Entry
3
4
Saccharin X CrO3 (mol %) Time (h) Yield (%)a
1
2
3
4
5
6
7
8
3a 4a 6-Cl
3b 4b 5-Cl
3c 4c 4-Cl
3d 4d 7-Cl
3e 4e 6-Br
3f 4f 5-Br
3g 4g 6-F
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
10.0
10.0
10.0
10.0
1
1
1
1
1
1
1.5
1.5
2
76
76
74
75
76
76
74
74
75b
70
68
65
3h 4h 5-F
9
3i 4i 6-CO2H
3j 4j 6-SO2Me
3k 4k 6-SONH2
3l 4l 6-NO2
10
11
12
2
3
3
a
Isolated yield.
Starting material was p-xylenesulfonamide and H5IO6 (10 equiv).
b
2.3. Oxidation of N-tert-butyl-o-methyl arenesulfon-
amides to saccharin derivatives
From the study of N-alkyl substituted toluenesulfonamides
described above, it was evident the N-tert-butyl group could
be utilized as a protecting group in this system for the prep-
aration of N-protected saccharin derivatives. As summarized

7904
L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
Table 3. Oxidation of N-tert-butyl-o-methyl arenesulfonamides to saccharin
derivatives
such as chromium(III) acetylacetonate, chromium(III) ace-
tate hydroxide or chromium(III) trichloride, while effective
for the oxidation of sulfide to sulfones and alcohols and silyl
ethers to carbonyl compounds, were inferior as catalysts for
the a-C–H oxidation of the N-alkyl-o-methyl-arenesulfon-
amides.7,15
H5IO6 (8 equiv.)
O
O
S
O
Ac2O (8 equiv.)
CrO3 (10 mol%)
O
N
7
4
S
N
X
X
H
CH3CN
r.t.
CH3
O
6
5
The N-tert-butyl group proved to be a suitable nitrogen-pro-
tecting group for the preparation of N-tert-butyl saccharin
derivatives from o-methyl arenesulfonamides. It was found
that the tert-butyl group could be more easily removed
than protective groups (methyl or a p-methoxy benzyl) typi-
cally used for the preparation of saccharin derivatives.22,23 In
addition, the purification of the substituted saccharin
derivatives either by column chromatography or by recrys-
tallization from ethanol was greatly facilitated by the
N-tert-butyl group. Based upon these results, it was of inter-
est to develop a direct method for the preparation of
substituted saccharin derivatives from substituted toluene
derivatives that employ the N-tert-butyl group as a protecting
group for the saccharin nitrogen atom. To this end, the
required N-tert-butyl-o-methyl arenesulfonamides were
easily prepared by chlorosulfonation of substituted toluene
derivatives 7 with chlorosulfonic acid.24 The resulting sulfo-
nyl chlorides were treated with tert-butyl amine to furnish
the N-tert-butyl-o-toluenesulfonamide derivatives. For tolu-
ene and some substituted toluene derivatives (F, Cl, Br, CF3,
t-Bu) a mixture of isomers was observed (NMR, TLC)
derived from the chlorosulfonation step. The other re-
gioisomers present in small amounts (10–20%) were very
difficult to separate from the N-tert-butyl-o-toluene-
sulfonamide isomers either by distillation or column chro-
matography. However, typically the isomeric mixture of
N-tert-butyl-toluenesulfonamides was carried forward
without purification to the oxidation step. Upon H5IO6
–CrO3 oxidation of the mixture, the N-tert-butyl-o-toluene-
sulfonamide isomer was converted into the desired saccharin
derivative 6 while other N-tert-butyl-toluenesulfonamide re-
gioisomers present in the mixture were converted into
substituted benzoic acids. The acid derivatives could then
be easily removed by washing with saturated sodium bicar-
bonate solution affording the clean N-tert-butyl protected
saccharin derivatives in moderate to good yields. As summa-
rized in Table 4, a series of 6- and 5-substituted saccharin
Entry
5
6
Saccharin X
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
6a
6-t-Bu
6-Cl
5-Cl
4-Cl
7-Cl
6-Br
5-Br
6-F
5-F
6-MeSO2
6-SO2NHt-Bu
6-NO2
5-NO2
7-NO2
5-Cl-6-Me
5
8
10
14
10
8
10
10
10
14
16
20
20
20
4
90
88
86
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
88b(64)c
92b(65)c
90
88
86
86
80
76
72
72
9
10
11
12
13
14
15
88b(62)c
42
a
Isolated yield.
Crude yield, >90% purity by 1H NMR.
The product was inseparable by chromatography, the yield was deter-
mined after recrystallization from ethanol.
b
c
in Table 3, a variety of N-tert-butyl-o-methyl arenesulfon-
amides (5) were smoothly oxidized to the corresponding
N-protected saccharin derivatives (6) in good to excellent
yields by using 8 equiv of H5IO6 and 10 mol % of CrO3 in
the presence of acetic anhydride at rt. The oxidation of
N-tert-butyl-5-tert-butyl-o-toluenesulfonamides furnished
the corresponding N-tert-butyl-6-tert-butyl saccharin 6a in
90% yield (Table 3, entry 1). Longer reaction times were
required for substrates with halogen or electron-withdrawing
substituents.
3. Discussion
For benzylic oxidation of substituted toluenes to benzoic
acids, Yamazaki reported that only 3.5 equiv of H5IO6 was
necessary for complete oxidation but 20 mol % CrO3 was
required for a complete oxidation of toluene derivatives
with electron-withdrawing groups. Our investigation found
that for the oxidation of o-toluenesulfonamides lower cata-
lyst loading of only 5–10 mol % could be achieved with
8 equiv of H5IO6 in acetonitrile at reflux (Table 2). In addi-
tion, the oxidation reaction was significantly accelerated
after addition of acetic anhydride. The oxidation of a-C–H
of the N-alkyl group was identified as a competitive side re-
action in oxidation of N-alkyl-o-methyl-arenesulfonamides,
thus limiting the scope of utility of the process. The reactivity
of N–a-CH bonds in this side reaction decreased in the
following order: secondary>tertiary>primary. Only 12%
of N-ethyl saccharin was obtained in oxidation of N-ethyl-
o-toluenesulfonamide. For N-2, 2, 2-trifluoroethyl and
N-tert-butyl substituted o-toluenesulfonamide, the a-C–H
of N-alkyl group was not oxidized and high yields of products
were obtained.
Table 4. Direct preparation of saccharin derivatives from substituted toluene
derivatives
O
S
O
N
1) ClSO3H (10 equiv.),
7
4
-20 °C, 1 h then 0-25 °C, 4h
X
X
CH3
2) t-BuNH2/Et3N
0 °C, 2h, then r.t., 6h
3) H5IO6 (7 equiv.)
CrO3 (10 mol%)
Ac2O (7 equiv.)
CH3CN, r.t., 5-10h
O
7
6
Entry
6
X
H
Yield (%)a Entry
6
X
Yield (%)a
1
2
3
4
5
2g
45
6
7
6g 5-Br
6h 6-F
6i 5-F
6p 6-CF3 58
6q 5-CF3 38
52
79
66
6a 6-t-Bu 56
6b 6-Cl
6c 5-Cl
6f 6-Br
65
58
61
8
9
10
Chromium(VI) oxide was found to be the most effective cat-
alyst in this oxidative cyclization. Other chromium species
a
Isolated yield.

L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
7905
skeletons were easily prepared by this direct method. This
one-pot procedure was amenable to the preparation of a vari-
ety of substituted saccharin derivatives, some not readily
available by other methods. In addition, to our knowledge,
this is the first report of the preparation of trifluoromethyl
substituted saccharin derivatives 6p and 6q.
intermediates were never observed during the oxidation of
N-alkyl-o-methyl-arenesulfonamides.
4. Conclusion
In conclusion, we have developed a novel and practical
method for the preparation of saccharin and saccharin deriv-
atives from substituted toluene derivatives by oxidation with
the H5IO6–CrO3 system. This oxidative-cyclization proce-
dure is superior to other methods in both yield and waste
metal production for the construction of the saccharin ring
system. In addition, this method is tolerant of a variety of
functional groups and has allowed the facile preparation of
substituted saccharin derivatives that were previously diffi-
cult to synthesize.
The mechanism of this novel oxidative cyclization has not
been clearly established. Based upon observation in this
study and related studies, we believe that this oxidative
cyclization is likely to occur through the mechanism illus-
trated in Scheme 1. Chromium oxo or peroxo species are
believed to abstract a benzylic hydrogen atom from the
N-alkyl-o-toluenesulfonamide 1 and form benzylic radical
A. It is well known that Cr(VI) oxo and peroxo species
can abstract activated hydrogen atoms from organic com-
pounds to form alkylradical intermediates.25 Although the
initial catalyst is Cr(VI) other oxidation states of chromium
[e.g., Cr(V) and Cr(IV)] may be involved in the oxidative
cyclization. The presence of N-dealkylation by-products
suggests the possibility of a N-centered radical intermediate
formed by intramolecular hydrogen transfer to form radical
B. The radical B could then be easily oxidized to carbonyl
diradical C that could cyclize quickly to afford the saccharin
skeleton 2. Alternatively, B could undergo a second H atom
abstraction to give an alkyl diradical species D. The intra-
molecular coupling of the N-centered radical and benzylic
radical of D would then afford intermediate E. Once formed,
intermediate E could be easily and quickly oxidized to the
saccharin skeleton. This reaction pathway is supported by
recent studies in our laboratories that have shown that
N-alkylamides and N-alkylsulfonamides are easily oxidized
by H5IO6–CrO3 system to give high yields of imide deriva-
tives.5 In addition, it is not likely that the oxidative cycli-
zation reaction takes place through the dehydration of a
benzoic acid intermediate. We have found that 2-carboxy-
N-alkyl benzenesulfonamides do not cyclize to generate
the saccharin skeleton under acidic conditions (aqueous
HCl). Therefore, it is believed that the excess H5IO6 used
in this oxidation is necessary to force the reaction to comple-
tion but not for the dehydration. Moreover, benzoic acid
5. Experimental
5.1. General
All known compounds were identified by comparison of
NMR spectral and physical data with the data reported in
the literature and with the authentic samples when available.
All new compounds were characterized by IR, 1H NMR, 13
C
NMR and elemental analysis. NMR spectra were recorded
on a Varian-400 MHz spectrometer at ambient temperature
in CDCl3/DMSO-d6 with TMS as an internal standard. Infra
red spectra were recorded with BOMEM Infrared Spectro-
meter, MB Series. Elemental analyses (C, H, N) were deter-
mined by Atlantic Microlabs, Inc., Norcross, GA. Melting
points were recorded on a Hoover Mel-Temp apparatus
and are uncorrected.
5.2. General procedure for the preparation of
N-unsubstituted saccharin skeletons (2a and 4a–l)
A mixture of H5IO6 (18 g, 80 mmol), CrO3 (50 mg,
0.5 mmol, 5 mol %) and o-methyl arenesulfonamide
(10 mmol) in acetonitrile (100 mL) was heated to reflux
until the oxidation was complete (monitored by TLC).
O
O
O O
S
O
O
H-atom
transfer
-H+, -e-
R
S
R
R
S
N
N
N
H
H
n = 4,5,6
CH3
CH2
CH3
B
1
Cr(n)
HIO3
Cr(n-1)
H5IO6
A
-H+, -e-
[Ox]
O O
S
O O
S
R
R
N
N
H
C
CH2
O
C
D
O
S
O
S
O
O
[Ox]
N R
N R
E
2
O
Scheme 1.

7906
L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
Isopropyl alcohol (10 mL) was added dropwise. After the
addition was complete, the mixture was heated to reflux
for an additional 10 min, cooled to rt, filtered and the solids
were washed with acetone (2ꢁ60 mL). The filtrates were
combined and concentrated under reduced pressure. The
residue was triturated with 2 N H2SO4 solution (30 mL)
and the crude product was collected by vacuum filtration.
Most products were quite pure based on 1H NMR and
melting points. If necessary, further purification was
performed by dissolving the crude product in satd Na2CO3
solution (40 mL). Any solids were filtered and the filtrate
was extracted with EtOAc (40 mL). The aqueous layer
was separated and acidified with concentrated HCl solution
to pH 1. The resulting precipitate was collected by vacuum
filtration to give pure products.
2873, 1540, 1394, 1311, 1137, 1000 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 7.78 (d, J¼8.4, 1H), 7.35 (d,
J¼7.6, 1H), 7.36 (s, 1H), 2.57 (s, 3H), 1.26 (s, 9H), 1.08
(s, 9H). 13C NMR (75 MHz, DMSO-d6) d 155.3, 139.5,
136.4, 129.6, 128.6, 123.2, 53.6, 34.9, 31.2, 30.1, 20.3.
Anal. Calcd for C15H25NO2S: C, 63.60; H, 8.83; N, 4.94.
Found: C, 63.56; H, 8.90; N, 4.86.
5.3.5. N-tert-Butyl-2-methyl-5-chlorobenzenesulfon-
amide (5b). Mp 140–142 ꢀC. IR (CHCl3) 3285, 2969,
1
1540, 1467, 1320, 1142, 1009 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 7.83 (s, 1H), 7.69 (s, 1H), 7.58 (d, J¼8.4,
1H), 7.42 (d, J¼8.4, 1H), 2.56 (s, 3H), 1.11 (s, 9H). 13C
NMR (75 MHz, DMSO-d6) d 144.0, 135.8, 134.7, 132.2,
130.8, 127.9, 53.9, 30.1, 19.4. Anal. Calcd for
C11H16ClNO2S: C, 50.47; H, 6.12; N, 5.35. Found: C,
50.18; H, 6.21; N, 5.38.
5.3. General procedure for the preparation of N-alkyl-
o-methyl-arenesulfonamide derivatives
5.3.6. N-tert-Butyl-2-methyl-4-chlorobenzenesulfon-
amide (5c). Mp 142–144 ꢀC. IR (CHCl3) 3294, 2965,
A solution of o-methylarenesulfonyl chloride (20 mmol) in
CH2Cl2 (40 mL) was added dropwise to a solution of alkyl-
amine (21 mmol) and triethylamine (21 mmol) in CH2Cl2
(80 mL) at 0 ꢀC. The reaction mixture was stirred at 0 ꢀC
for 2 h and then rt for 6 h. The mixture was washed, respec-
tively, with 0.1 N HCl solution (50 mL) and satd NaHCO3
solution (50 mL) and dried over MgSO4. Removal of the
solvent under reduced pressure afforded the N-alkyl-o-
methyl-arenesulfonamides in sufficient purity for further
use. If necessary, further purification by flash column
chromatography (hexanes/EtOAc, 4:1) furnished the pure
N-alkyl-o-methyl-arenesulfonamide derivatives.
1
2878, 1559, 1464, 1312, 1151 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 7.87 (d, J¼8.8, 1H), 7.61 (s, 1H), 7.50
(s 1H), 7.44 (d, J¼8.8, 1H), 2.59 (s, 3H), 1.11 (s, 9H). 13C
NMR (75 MHz, DMSO-d6) d 140.9, 138.9, 136.5, 131.8,
130.2, 126.1, 53.4, 29.7, 19.5. Anal. Calcd for
C11H16ClNO2S: C, 50.47; H, 6.12; N, 5.35. Found: C,
50.49; H, 6.15; N, 5.25.
5.3.7. N-tert-Butyl-2-methyl-3-chlorobenzenesulfon-
amide (5d). Mp 146–148 ꢀC. IR (CHCl3) 3280, 2965,
1
1430, 1311, 1202, 1142, 1000 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 7.91 (d, J¼8.4, 1H), 7.71 (s, 1H), 7.69 (d,
J¼8.8, 1H), 7.40 (t, J¼8.0, 1H), 2.64 (s, 3H), 1.12 (s, 9H).
13C NMR (75 MHz, DMSO-d6) d 144.2, 135.6, 134.1,
132.8, 127.4, 127.3, 53.6, 29.7, 16.5. Anal. Calcd for
C11H16ClNO2S: C, 50.47; H, 6.12; N, 5.35. Found: C,
50.64; H, 6.19; N, 5.32.
5.3.1. N-Cyclopropyl-o-toluenesulfonamide (1e). Yellow
oil. IR (liquid film) 3285, 3019, 1453, 1312, 1160, 1069,
1
881 cmꢂ1. H NMR (400 MHz, DMSO-d6) d 7.98 (s, 1H),
7.87 (d, J¼7.6, 1H), 7.53 (t, J¼7.6, 1H), 7.38–7.42 (m,
2H), 2.56 (s, 3H), 2.10–2.14 (m, 1H), 0.30–0.45 (m, 4H).
13C NMR (75 MHz, DMSO-d6) d 138.3, 136.5, 132.4,
132.3, 128.9, 126.1, 23.4, 19.7, 5.0. Anal. Calcd for
C10H13NO2S: C, 56.87; H, 6.16; N, 6.63. Found: C, 57.06;
H, 6.33; N, 6.62.
5.3.8. N-tert-Butyl-2-methyl-6-chlorobenzenesulfon-
amide (5e). Mp 162–168 ꢀC. IR (CHCl3) 3308, 2969,
1
1536, 1449, 1320, 1151, 1005 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 7.58 (s 1H), 7.47 (d, J¼7.6, 1H), 7.42 (d,
J¼7.6, 1H), 7.34 (d, J¼7.2, 1H), 2.63 (s, 3H), 1.11 (s,
9H). 13C NMR (75 MHz, DMSO-d6) d 140.3, 139.9,
132.8, 132.7, 132.6, 130.7, 54.0, 29.8, 23.6. Anal. Calcd
for C11H16ClNO2S: C, 50.47; H, 6.12; N, 5.35. Found: C,
50.47; H, 6.16; N, 5.29.
5.3.2. N-(2,2,2-Trifluoroethyl)-o-toluenesulfonamide (1f).
Mp 78–80 ꢀC. IR (CHCl3) 3285, 3061, 1540, 1453, 1330,
1270, 1168 cmꢂ1. 1H NMR (400 MHz, DMSO-d6) d 8.7 (t,
J¼6.8, 1H), 7.84 (d, J¼8.0, 1H), 7.53 (t, J¼7.2, 1H),
7.36–7.42 (m, 2H), 3.69–3.78 (m, 2H), 2.58 (s, 3H). 13C
NMR (75 MHz, DMSO-d6) d 138.9, 136.5, 132.7, 132.5,
128.1, 126.3, 122.6, 43.4, 19.7. Anal. Calcd for
C9H10F3NO2S: C, 42.68; H, 3.95; N, 5.53. Found: C,
42.75; H, 4.04; N, 5.49.
5.3.9. N-tert-Butyl-2-methyl-5-bromobenzenesulfon-
amide (5f). Mp 160–162 ꢀC. IR (CHCl3) 3276, 2974,
1
1540, 1472, 1316, 1137, 1009 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 7.96 (s, 1H), 7.71 (d, J¼8.4, 1H), 7.70
(s, 1H), 7.36 (d, J¼8.4, 1H), 2.55 (s, 3H), 1.12 (s, 9H).
13C NMR (75 MHz, DMSO-d6) d 144.2, 136.2, 135.1,
135.0, 130.7, 118.8, 53.9, 30.1, 19.5. Anal. Calcd for
C11H16BrNO2S: C, 43.13; H, 5.22; N, 4.57. Found: C,
43.20; H, 5.31; N, 4.56.
5.3.3. N-Methoxy-o-toluenesulfonamide (1h). Yellow oil.
IR (liquid film) 3283, 3011, 1456, 1318, 1149, 1066,
1
883 cmꢂ1. H NMR (400 MHz, DMSO-d6) d 10.5 (s, 1H),
7.85 (d, J¼8.4, 1H), 7.58 (t, J¼7.6, 1H), 7.48–7.37 (m
2H), 3.62 (s, 3H), 2.60 (s, 3H). 13C NMR (75 MHz,
DMSO-d6) d 138.1, 135.6, 133.4, 132.5, 130.0, 126.3,
64.2, 20.1. Anal. Calcd for C8H11NO3S: C, 47.76; H, 5.47;
N, 6.96. Found: C, 47.48; H, 7.02; N, 6.74.
5.3.10. N-tert-Butyl-2-methyl-4-bromobenzenesulfon-
amide (5g). Mp 146–148 ꢀC. IR (CHCl3) 3285, 2969,
1540, 1316, 1151, 1009 cmꢂ1
.
1H NMR (400 MHz,
5.3.4. N-tert-Butyl-2-methyl-5-tert-butylbenzenesulfon-
amide (5a). Mp 140–142 ꢀC. IR (CHCl3) 3280, 2965,
DMSO-d6) d 7.78 (d, J¼8.4, 1H), 7.64 (s, 1H), 7.57–7.60
(m, 2H), 2.57 (s, 3H), 1.09 (s, 9H). 13C NMR (75 MHz,

L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
7907
DMSO-d6) d 141.7, 139.5, 135.1, 130.6, 129.5, 125.9, 53.8,
30.0, 19.8. Anal. Calcd for C11H16BrNO2S: C, 43.13; H,
5.22; N, 4.57. Found: C, 43.11; H, 5.27; N, 4.48.
5.3.17. N-tert-Butyl-2-methyl-6-nitrobenzenesulfon-
amide (5n). Mp 181–183 ꢀC. IR (CHCl3) 3290, 2976,
1
1545, 1330, 1156 cmꢂ1. H NMR (400 MHz, DMSO-d6)
d 8.09 (s, 1H), 7.68–7.62 (m, 3H), 2.68 (s, 3H), 1.10 (s,
9H). 13C NMR (75 MHz, DMSO-d6) d 150.0, 140.0,
135.2, 133.4, 132.9, 122.0, 54.6, 29.7, 20.6. Anal. Calcd
for C11H16N2O4S: C, 48.52; H, 5.88; N, 10.29. Found: C,
48.77; H, 5.94; N, 10.35.
5.3.11. N-tert-Butyl-2-methyl-5-fluorobenzenesulfon-
amide (5h). Mp 118–120 ꢀC. IR (CHCl3) 3299, 2976,
2868, 1490, 1316, 1229, 1142, 1005 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 7.67 (s, 1H), 7.60–7.63 (m, 1H),
7.42–7.45 (m, 1H), 7.33–7.39 (m, 1H), 2.56 (s, 3H), 1.12
(s, 9H). 13C NMR (75 MHz, DMSO-d6) d 158.9, 144.0,
134.8, 133.0, 119.4, 115.5, 53.9, 30.0, 19.2. Anal. Calcd
for C11H16FNO2S: C, 53.87; H, 6.53; N, 5.71. Found: C,
53.67; H, 6.60; N, 5.71.
5.3.18. N-tert-Butyl-2, 5-dimethyl-4-chlorobenzenesul-
fonamide (5o). Mp 170–172 ꢀC. IR (CHCl3) 3294, 2974,
1545, 1316, 1142, 1005 cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6) d 7.82 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 2.53
(s, 3H), 2.34 (s, 3H), 1.1 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 141.1, 137.0, 136.3, 133.7, 132.6, 131.1,
53.7, 30.1, 19.4, 19.3. Anal. Calcd for C12H18ClNO2S: C,
52.26; H, 6.53; N, 5.08. Found: C, 52.51; H, 6.63; N, 5.01.
5.3.12. N-tert-Butyl-2-methyl-4-fluorobenzenesulfon-
amide (5i). Mp 140–142 ꢀC. IR (CHCl3) 3294, 2978,
2878, 1582, 1476, 1311, 1147, 1005 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 7.90–7.93 (m, 1H), 7.53 (s, 1H),
7.25–7.28 (m, 1H), 7.17–7.21 (m, 1H), 2.59 (s, 3H), 1.09
(s, 9H). 13C NMR (75 MHz, DMSO-d6) d 162.7, 140.6,
138.8, 131.6, 119.3, 113.3, 53.7, 30.1, 20.1. Anal. Calcd
for C11H16FNO2S: C, 53.87; H, 6.53; N, 5.71. Found: C,
53.71; H, 6.63; N, 5.69.
5.4. General procedure for the preparation of N-alkyl
saccharin derivatives
A mixture of H5IO6 (18 g, 80 mmol) in acetonitrile
(140 mL) was stirred vigorously at rt for 1 h, then CrO3
(100 mg, 1 mmol, 10 mol %) was added followed by acetic
anhydride (8.2 g, 80 mmol). The resulting orange solution
was cooled to 0 ꢀC. The N-alkyl-o-methyl-arenesulfon-
amide (10 mmol) was then added in one portion. After
stirring at 0 ꢀC for 15 min, the reaction mixture was allowed
to warm to rt and stirred until the oxidation was complete
(monitored by TLC). The solvent was removed at rt under
reduced pressure and the residue was extracted with EtOAc
(2ꢁ80 mL). The combined organic portions were washed
with satd NaHCO3 solution (80 mL), satd Na2S2O3 solution
(60 mL), brine (60 mL) and dried over MgSO4. The solvent
was removed under reduced pressure to afford the crude
product. Some of the crude saccharin derivatives were quite
pure by 1H NMR. If necessary, further purification by flash
column chromatography (hexanes/EtOAc, 4:1) furnished
the pure N-alkyl saccharin derivatives.
5.3.13. N-tert-Butyl-2-methyl-5-methylsulfonylbenzene-
sulfonamide (5j). Mp 182–184 ꢀC. IR (CHCl3) 3285,
1
2976, 1545, 1316, 1147, 1005 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 8.34 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.69
(d, J¼7.6, 1H), 3.26 (s, 3H), 2.69 (s, 3H), 1.12 (s, 9H). 13C
NMR (75 MHz, DMSO-d6) d 143.3, 143.2, 139.3, 134.2,
130.8, 127.0, 54.2, 43.9, 30.1, 20.2. Anal. Calcd for
C12H19NO4S2: C, 47.21; H, 6.22; N, 4.59. Found: C,
47.35; H, 6.22; N, 4.49.
5.3.14. N-tert-Butyl-2-methyl-5-(N-tert-butylaminosulfo-
nyl)benzenesulfonamide (5k). Mp 224–226 ꢀC. IR
(CHCl3) 3280, 2978, 2878, 1540, 1394, 1325, 1147,
1
995 cmꢂ1. H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H),
7.92 (d, J¼8.0, 1H), 7.76 (d, J¼5.6, 1H), 7.58 (d, J¼8.4,
1H), 2.65 (s, 3H), 1.109 (s, 9H), 1.107 (s, 9H). 13C NMR
(75 MHz, DMSO-d6) d 142.6, 142.4, 140.6, 133.3, 129.5,
126.4, 53.6, 53.4, 29.79, 29.69, 19.70. Anal. Calcd for
C15H26N2O4S2: C, 49.72; H, 7.18; N, 7.73. Found: C,
49.71; H, 7.35; N, 7.68.
5.4.1. N-Cyclopropyl-1,2-benzisothiazole-3-one-1,1-di-
oxide (2e). Mp 144–146 ꢀC. IR (CHCl3) 3010, 1737,
1540, 1458, 1320,1183 cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6) d 8.27 (d, J¼7.2, 1H), 7.99–8.10 (m, 3H),
2.80–2.81 (m, 1H), 1.02–1.03 (m, 4H). 13C NMR
(75 MHz, DMSO-d6) d 159.5, 136.6, 135.8, 135.1, 126.1,
124.9, 121.4, 20.2, 3.74. Anal. Calcd for C10H9NO3S: C,
53.81; H, 4.04; N, 6.27. Found: C, 53.73; H, 4.07; N, 6.31.
5.3.15. N-tert-Butyl-2-methyl-5-nitrobenzenesulfon-
amide (5l). Mp 127–129 ꢀC. IR (CHCl3) 3294, 2974,
1522, 1353, 1156, 995 cmꢂ1. 1H NMR (400 MHz, DMSO-
d6) d 8.61 (s, 1H), 8.34 (d, J¼8.4, 1H), 7.92 (s, 1H), 7.71
(d, J¼8.0, 1H), 2.73 (s, 3H), 1.13 (s, 9H). 13C NMR
(75 MHz, DMSO-d6) d 145.4, 144.3, 143.1, 134.0, 126.3,
122.7, 53.7, 29.6, 19.7. Anal. Calcd for C11H16N2O4S: C,
48.52; H, 5.88; N, 10.29. Found: C, 48.66; H, 5.94; N, 10.22.
5.4.2. N-(2,2,2-Trifluoroethyl)-1,2-benzisothiazole-3-one-
1,1-dioxide (2f). Mp 132–134 ꢀC. IR (CHCl3) 3093, 3024,
1
1756, 1540, 1348, 1247, 1174 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 8.40 (d, J¼8.0, 1H), 8.19 (d, J¼7.2, 1H),
8.13 (t, J¼7.6, 1H), 8.06 (t, J¼8.0, 1H), 4.62–4.69 (q,
J¼9.2, 2H). 13C NMR (75 MHz, DMSO-d6) d 158.7,
136.7, 136.5, 135.6, 125.7, 125.60, 124.7, 121.9, 40.2.
Anal. Calcd for C9H6F3NO3S: C, 40.75; H, 2.26; N, 5.28.
Found: C, 40.68; H, 2.29; N, 5.18.
5.3.16. N-tert-Butyl-2-methyl-4-nitrobenzenesulfon-
amide (5m). Mp 157–159 ꢀC. IR (CHCl3) 3290, 2978,
1
2868, 1531, 1320, 1156, 1005 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 8.25 (s, 1H), 8.20 (d, J¼8.8, 1H), 8.13 (d,
J¼8.8, 1H), 7.92 (s, 1H), 2.71 (s, 3H), 1.11 (s, 9H). 13C
NMR (75 MHz, DMSO-d6) d 149.0, 147.5, 138.8, 129.8,
126.9, 121.3, 53.8, 29.7, 19.7. Anal. Calcd for
C11H16N2O4S: C, 48.52; H, 5.88; N, 10.29. Found: C,
48.76; H, 5.89; N, 10.33.
5.4.3. N-tert-Butyl-6-tert-butyl-1,2-benzisothiazole-3-
one-1,1-dioxide (6a). Mp 120–122 ꢀC. IR (CHCl3) 2965,
2873, 1719, 1536, 1334, 1252, 1192 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 8.12 (d, J¼7.6, 1H), 8.05 (d,

7908
L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
J¼8.4, 1H), 7.97 (s, 1H), 1.69 (s, 9H), 1.35 (s, 9H). 13C NMR
(75 MHz, DMSO-d6) d 159.7, 158.6, 134.4, 132.8, 126.3,
120.8, 120.5, 60.2, 35.4, 30.4, 27.2. Anal. Calcd for
C15H21NO3S: C, 61.01; H, 7.12; N, 4.74. Found: C, 60.89;
H, 7.20; N, 4.72.
(400 MHz, DMSO-d6) d 8.32 (dd, J¼7.2, J¼2.0, 1H), 8.1
(dd, J¼8.4, J¼4.4, 1H), 7.82 (dt, J¼8.8, J¼2.0, 1H), 1.69
(s, 9H). 13C NMR (75 MHz, DMSO-d6) d 158.6, 139.1,
127.7, 122.7, 122.51, 109.1, 60.6, 27.2. Anal. Calcd for
C11H12FNO3S: C, 51.36; H, 4.67; N, 5.44. Found: C,
51.27; H, 4.74; N, 5.59.
5.4.4. N-tert-Butyl-6-chloro-1,2-benzisothiazole-3-one-
1,1-dioxide (6b). Mp 162–164 ꢀC. IR (CHCl3) 3079, 2974,
5.4.11. N-tert-Butyl-5-fluoro-1,2-benzisothiazole-3-one-
1,1-dioxide (6i). Mp 88–90 ꢀC. IR (CHCl3) 3102, 2983,
1
1714, 1540, 1330, 1266, 1151 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 8.51 (s, 1H), 8.02 (s, 2H), 1.69 (s, 9H). 13C
NMR (75 MHz, DMSO-d6) d 158.6, 140.5, 138.3, 135.2,
126.3, 124.7, 121.1, 60.6, 27.2. Anal. Calcd for
C11H12ClNO3S: C, 48.26; H, 4.38; N, 5.11. Found: C,
48.25; H, 4.40; N, 5.06.
1724, 1472, 1279, 1174 cmꢂ1 1H NMR (400 MHz,
.
DMSO-d6) d 8.31–8.35 (m, 1H), 7.80–7.91 (m, 2H), 1.69
(s, 9H). 13C NMR (75 MHz, DMSO-d6) d 158.3, 133.05,
129.49, 123.9, 123.2, 122.9, 112.1, 60.7, 27.1. Anal. Calcd
for C11H12FNO3S: C, 51.36; H, 4.67; N, 5.44. Found: C,
51.53; H, 4.71; N, 5.36.
5.4.5. N-tert-Butyl-5-chloro-1,2-benzisothiazole-3-one-
1,1-dioxide (6c). Mp 141–143 ꢀC. IR (CHCl3) 3088, 2987,
5.4.12. N-tert-Butyl-6-methylsulfonyl-1,2-benzisothia-
zole-3-one-1,1-dioxide (6j). Mp 194–196 ꢀC. IR (CHCl3)
1
1714, 1540, 1417, 1330, 1174 cmꢂ1. H NMR (400 MHz,
1
DMSO-d6) d 8.26 (d, J¼9.2, 1H), 8.08 (d, J¼7.2, 1H),
8.07 (s, 1H), 1.69 (s, 9H). 13C NMR (75 MHz, DMSO-d6)
d 158.2, 139.9, 135.5, 135.4, 128.2, 124.5, 122.6, 60.7,
27.1. Anal. Calcd for C11H12ClNO3S: C, 48.26; H, 4.38;
N, 5.11. Found: C, 48.16; H, 4.38; N, 5.09.
3102, 2992, 2919, 1714, 1545, 1339, 1183 cmꢂ1. H NMR
(400 MHz, DMSO-d6) d 8.82 (s, 1H), 8.45 (d, J¼7.6, 1H),
8.28 (d, J¼8.4, 1H), 3.45 (s, 3H), 1.71 (s, 9H). 13C NMR
(75 MHz, DMSO-d6) d 158.2, 147.0, 137.4, 133.3, 130.0,
126.1, 120.0, 61.0, 42.6, 27.1. Anal. Calcd for
C12H15NO5S2: C, 45.42; H, 4.73; N, 4.41. Found: C,
45.42; H, 4.77; N, 4.27.
5.4.6. N-tert-Butyl-4-chloro-1,2-benzisothiazole-3-one-
1,1-dioxide (6d). Mp 162–164 ꢀC. IR (CHCl3) 3079, 2974,
1719, 1458, 1330, 1151 cmꢂ1
.
1H NMR (400 MHz,
5.4.13. N-tert-Butyl-6-(N-tert-butylaminosulfonyl)-1,2-
benzisothiazole-3-one-1,1-dioxide (6k). Mp 166–168 ꢀC.
IR (CHCl3) 3285, 2978, 1728, 1545, 1398, 1339,
DMSO-d6) d 8.17 (dd, J¼6.0, 2.4, 1H), 7.95–8.00 (m, 2H),
1.69 (s, 9H). 13C NMR (75 MHz, DMSO-d6) d 157.2,
139.2, 136.7, 136.6, 131.5, 122.0, 119.7, 60.7, 27.1. Anal.
Calcd for C11H12ClNO3S: C, 48.26; H, 4.38; N, 5.11. Found:
C, 48.12; H, 4.42; N, 5.10.
1151 cmꢂ1 1H NMR (400 MHz, DMSO-d6) d 8.54 (s,
.
1H), 8.35 (d, J¼8.4, 1H), 8.23 (d, J¼7.6, 1H), 7.99 (s,
1H), 1.70 (s, 9H), 1.13 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 158.3, 150.7, 137.4, 132.4, 128.6, 126.1,
118.4, 60.9, 54.0, 29.6, 27.1. Anal. Calcd for
C15H22N2O5S2: C, 48.12; H, 5.88; N, 7.48. Found: C,
48.33; H, 6.20; N, 7.36.
5.4.7. N-tert-Butyl-7-chloro-1,2-benzisothiazole-3-one-
1,1-dioxide (6e). Mp 72–74 ꢀC. IR (CHCl3) 2987, 1728,
1545, 1453, 1343, 1158 cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6) d 8.10 (d, J¼8.8, 1H), 7.9–8.0 (m, 2H), 1.69 (s,
9H). 13C NMR (75 MHz, DMSO-d6) d 158.2, 136.7,
135.9, 133.9, 128.8, 126.2, 123.4, 60.9, 27.1. Anal. Calcd
for C11H12ClNO3S: C, 48.26; H, 4.38; N, 5.11. Found: C,
48.31; H, 4.31; N, 5.00.
5.4.14. N-tert-Butyl-6-nitro-1,2-benzisothiazole-3-one-
1,1-dioxide (6l). Mp 182–184 ꢀC. IR (CHCl3) 3111, 2996,
1
1733, 1545, 1334, 1270, 1188 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 9.12 (s, 1H), 8.68 (dd, J¼8.4, 1H), 8.26 (d,
J¼8.0, 1H), 1.71 (s, 9H). 13C NMR (75 MHz, DMSO-d6)
d 157.9, 151.7, 137.7, 130.6, 130.0, 126.4, 117.1, 61.2,
27.1. Anal. Calcd for C11H12N2O5S: C, 46.47; H, 4.23; N,
9.85. Found: C, 46.65; H, 4.26; N, 9.79.
5.4.8. N-tert-Butyl-6-bromo-1,2-benzisothiazole-3-one-
1,1-dioxide (6f). Mp 168–170 ꢀC. IR (CHCl3) 3083, 2965,
1714, 1540, 1334, 1151 cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6) d 8.63 (s, 1H), 8.16 (dd, J¼8.4, J¼1.6, 1H),
7.94 (d, J¼7.6, 1H), 1.69 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 158.8, 138.3, 138.0, 129.2, 126.3, 125.3,
123.7, 60.6, 27.1. Anal. Calcd for C11H12BrNO3S: C,
41.50; H, 3.77; N, 4.40. Found: C, 41.57; H, 3.84; N, 4.38.
5.4.15. N-tert-Butyl-5-nitro-1,2-benzisothiazole-3-one-
1,1-dioxide (6m). Mp 151–153 ꢀC. IR (CHCl3) 3102,
2983, 1728, 1540, 1339, 1266, 1156 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 8.76 (d, J¼8.4, 1H), 8.58 (s, 1H),
8.52 (d, J¼8.4, 1H), 1.71 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 157.6, 151.5, 140.7, 130.6, 128.0, 122.8,
119.7, 61.2, 27.1. Anal. Calcd for C11H12N2O5S: C, 46.47;
H, 4.23; N, 9.85. Found: C, 46.59; H, 4.28; N, 9.87.
5.4.9. N-tert-Butyl-5-bromo-1,2-benzisothiazole-3-one-
1,1-dioxide (6g). Mp 146–148 ꢀC. IR (CHCl3) 3092, 2992,
1714, 1540, 1417, 1330, 1256, 1169 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d 8.16–8.24 (m, 3H), 1.69 (s, 9H).
13C NMR (75 MHz, DMSO-d6) d 158.2, 138.3, 135.7,
128.6, 128.1, 127.3, 122.6, 60.7, 27.1. Anal. Calcd for
C11H12BrNO3S: C, 41.50; H, 3.77; N, 4.40. Found: C,
41.33; H, 3.73; N, 4.33.
5.4.16. N-tert-Butyl-7-nitro-1,2-benzisothiazole-3-one-
1,1-dioxide (6n). Mp 152–154 ꢀC. IR (CHCl3) 3102, 2992,
1719, 1545, 1348, 1197 cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6) d 8.74 (d, J¼8.4, 1H), 8.44 (d, J¼7.6, 1H),
8.23 (t, J¼8.0, 1H), 1.72 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 157.5, 141.1, 136.9, 130.7, 130.5, 130.3,
129.2, 61.2, 27.2. Anal. Calcd for C11H12N2O5S: C, 46.47;
H, 4.23; N, 9.85. Found: C, 46.55; H, 4.25; N, 9.76.
5.4.10. N-tert-Butyl-6-fluoro-1,2-benzisothiazole-3-one-
1,1-dioxide (6h). Mp 134–136 ꢀC. IR (CHCl3) 3070, 2978,
1728, 1600, 1485, 1330, 12656, 1151 cmꢂ1 1H NMR
.

L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
7909
5.4.17. N-tert-Butyl-5-chloro-6-methyl-1,2-benziso-
thiazole-3-one-1,1-dioxide (6o). Mp 205–207 ꢀC. IR
DMSO-d6) d 8.50 (d, J¼8.4, 1H), 8.42 (d, J¼8.4, 1H),
8.32 (s, 1H), 1.71 (s, 9H). 13C NMR (75 MHz, DMSO-d6)
d 158.3, 140.1, 135.0, 134.7, 132.8, 127.7, 122.4, 121.9,
60.9, 27.1. Anal. Calcd for C12H12NF3O3S: C, 46.90; H,
3.90; N, 4.56. Found: C, 46.90; H, 3.87; N, 4.58.
(CHCl3) 3001, 2960, 1714, 1545, 1325, 1261, 1165 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6) d 8.28 (s, 1H), 8.03 (s,
1H), 2.52 (s, 3H), 1.69 (s, 9H). 13C NMR (75 MHz,
DMSO-d6) d 158.4, 144.7, 140.1, 135.4, 125.6, 124.6,
122.8, 60.6, 27.1, 20.2. Anal. Calcd for C12H14ClNO3S: C,
50.08; H, 4.87; N, 4.87. Found: C, 50.06; H, 4.85; N, 4.86.
Acknowledgements
5.5. General procedure for direct preparation of
saccharin skeletons from toluenes
We wish to thank Professor Gregory Fu and the Department
of Chemistry at MIT for all of the assistance provided H.S.
during the evacuation of New Orleans due to Hurricane
Katrina.
Toluene or a substituted toluene derivative (20 mmol) was
added portionwise over a period of 30 min to pre-cooled
chlorosulfonic acid (0.2 mol) at ꢂ20 ꢀC. After addition,
the reaction mixture was stirred at ꢂ20 ꢀC for 1 h, then grad-
ually allowed warm to rt over 1 h and stirred at rt for addi-
tional 4 h. The mixture was poured onto ice (500 g),
extracted with Et2O or CH2Cl2 (120ꢁ2 mL). The extracts
were combined and washed with satd NaHCO3 solution
and dried over MgSO4. The solvent was removed under
reduced pressure and the residue was dissolved in dry
CH2Cl2 (40 mL). The solution was then added dropwise to
a solution of tert-butyl amine (21 mmol) and triethylamine
(21 mmol) in CH2Cl2 (80 mL) at 0 ꢀC. After addition, the
reaction mixture was stirred at 0 ꢀC for 2 h and then rt
for 6 h, washed, respectively, with 0.1 N HCl solution and
satd NaHCO3 solution, dried over MgSO4. Removal of the
solvent afforded the isomers N-tert-butyl-o-methyl arene-
sulfonamides.
References and notes
1. Lee, S.; Fuchs, P. J. Am. Chem. Soc. 2002, 124, 13978.
2. Yamazaki, S. Org. Lett. 1999, 1, 2129.
3. Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39,
5323.
4. Yamazaki, S. Tetrahedron Lett. 2001, 42, 3355.
5. Xu, L.; Zhang, S.; Trudell, M. L. Chem. Commun. 2004, 1668.
6. Xu, L.; Zhang, S.; Trudell, M. L. Synlett 2004, 1901.
7. Zhang, S.; Xu, L.; Trudell, M. L. Synthesis 2005, 1757.
8. (a) Hibert, M. F.; Mir, A. K.; Fozard, J. R. Serotonin (5-HT)
receptors. Comprehensive Medicinal Chemistry; Sammes,
P. G., Taylor, J. B., Eds.; Pergamon: Oxford, 1990; Vol. 3,
pp 578–580; (b) Romero, A. G.; Darlington, W. H.; Piercey,
M. F.; Lahti, R. A. Bioorg. Med. Chem. Lett. 1992, 2, 1703.
9. Gonzalez-Martin, G.; Lyndon, C.; Sunkel, C. Eur. J. Pharm.
Biopharm. 1998, 46, 293.
10. Combrink, K. D.; Gulgeze, H. B.; Meanwell, N. A.; Pearce,
B. C.; Zulan, P.; Bisacchi, G. S.; Roberts, D. G. M.; Stanley,
P.; Seiler, S. M. J. Med. Chem. 1998, 41, 4854.
11. Patane, M. A.; Dipardo, R. M.; Price, R. P.; Chang, R. S. L.;
Ransom, R. W.; O’Malley, S. S.; Di Salvo, J.; Bock, M. G.
Bioorg. Med. Chem. Lett. 1998, 8, 2495.
12. Nagasawa, H. T.; Kawle, S. P.; Elberling, J. A.; DeMaster,
E. G.; Fukuto, J. M. J. Med. Chem. 1995, 38, 1865.
13. Subramanayam, C.; Bell, M. R.; Carabates, P.; Court, J. J.;
Dority, J. A., Jr.; Ferguson, E.; Gordon, R.; Hlasta, D. J.;
Kumar, V. J. Med. Chem. 1994, 37, 2623.
14. (a) Togo, H.; Katohgi, M.; Yokoyama, M. Synlett 1998, 131; (b)
Katohgi, M.; Togo, H.; Yamaguchi, K.; Yokoyama, M.
Tetrahedron 1999, 55, 14885.
A mixture of H5IO6 (0.14 mol) in acetonitrile (200 mL) was
stirred vigorously at rt for 1 h, then CrO3 (200 mg, 2 mmol,
10 mol %) was added followed by acetic anhydride
(0.14 mol). The resulting orange solution was cooled to
0 ꢀC. To this solution was added the isomers of N-tert-
butyl-o-methyl arenesulfonamides in one portion. After stir-
ring at 0 ꢀC for 30 min, the reaction mixture was allowed to
warm to rt and stirred until the oxidation was complete
(monitored by TLC). The solvent was removed at rt under
reduced pressure and the residue was extracted with EtOAc
(2ꢁ100 mL). The extracts were collected and washed,
respectively, with satd NaHCO3 solution (160 mL), satd
Na2S2O3 solution (120 mL) and brine, dried over MgSO4.
The solvent was removed under reduced pressure to afford
the crude product. Some of the crude saccharin derivatives
1
were quite pure by H NMR. If necessary, further purifica-
tion by flash column chromatography (hexanes/EtOAc,
4:1) or recrystallization from ethanol furnished the pure
N-tert-butyl saccharin derivatives.
15. (a) Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68,
5388; (b)Xu, L.;Trudell, M. L. Tetrahedron Lett. 2003, 44, 2553.
16. For method via oxidation of o-methyl arenesulfonamides, see:
(a) Gadanyi, S.; Kalai, T.; Jeko, J.; Berente, Z.; Hideg, K.
Synthesis 2000, 2039; (b) Reap, J. J. U.S. Patent 4,566,898;
Chem. Abstr. 1986, 105, 42848z; (c) Kamogawa, H.;
Yamamoto, S.; Nanasawa, M. Bull. Chem. Soc. Jpn. 1982,
55, 3824; (d) Rose, N. C. J. Heterocycl. Chem. 1969, 6, 745;
(e) Hamor, G. H. J. Pharm. Sci. 1963, 52, 603.
17. For method via chlorosulfonation of diazonium salt, see:
(a) Dunlap, R. P.; Boaz, N. W.; Mura, A. J.; Kumar, V.;
Subramanyam, C.; Desai, R. C.; Hlasta, D. J.; Saindane,
M. T.; Bell, M. R. U.S. Patent 5,512,589; Chem. Abstr.
1996, 125, 58504h; (b) Hillemann, C. L. U.S. Patent
4,849,010; Chem. Abstr. 1990, 112, 179033u; (c) Saari,
W. S.; Schwering, J. E. J. Heterocycl. Chem. 1986, 23,
5.5.1. N-tert-Butyl-6-trifluoromethyl-1,2-benzisothia-
zole-3-one-1,1-dioxide (6p). Mp 156–158 ꢀC. IR (CHCl3)
1
2982, 1732, 1419, 1252, 1152 cmꢂ1. H NMR (400 MHz,
DMSO-d6) d 8.57 (s, 1H), 8.34 (d, J¼8.0, 1H), 8.23 (d,
J¼8.0, 1H), 1.71 (s, 9H). 13C NMR (75 MHz, DMSO-d6)
d 158.3, 137.7, 135.1, 134.8, 132.1, 129.7, 125.9, 118.9,
60.9, 27.1. Anal. Calcd for C12H12NF3O3S: C, 46.90; H,
3.90; N, 4.56. Found: C, 46.82; H, 3.85; N, 4.53.
5.5.2. N-tert-Butyl-5-trifluoromethyl-1,2-benzisothia-
zole-3-one-1,1-dioxide (6q). Mp 132–134 ꢀC. IR (CHCl3)
1
2989, 1723, 1430, 1263, 1130 cmꢂ1. H NMR (400 MHz,

7910
L. Xu et al. / Tetrahedron 62 (2006) 7902–7910
1253; (d) Tonne, P.; Jaedicke, H. Eur. Patent 52,750 A1;
Chem. Abstr. 1982, 97, 182396s.
1991, 1, 733; (d) Koike, W.; Kimoto, T.; Matsui, S. Japanese
Patent 52,071,464; Chem. Abstr. 1977, 87, 168016e.
21. For other methods, see: (a) Siegrist, U.; Rapold, T.; Blaser,
H. U. Org. Process Res. Dev. 2003, 7, 429; (b) Milstein, D.
U.S. Patent 5,034,534, 1991; Chem. Abstr. 1992, 116, 6544r;
(c) Engel, W.; Mihm, G.; Trummlitz, G.; Eberlein, W. Ger.
Offen. DE 3,607,343; Chem. Abstr. 1987, 106, 50193t.
22. Ahn, K. H.; Baek, H. H.; Lee, S. J.; Cho, C. W. J. Org. Chem.
2000, 65, 7690.
23. Yeung, K. S.; Meanwell, N. A.; Li, Y.; Gao, Q. Tetrahedron
Lett. 1998, 39, 1483.
24. Cremlyn, R. J. Chlorosulfonic Acid. A Versatile Reagent; The
Royal Society of Chemistry: Cambridge, 2002.
18. For method via direct ortho-lithiation: (a) Proudfoot, J. R.;
Patel, U. R.; Dyatkin, A. B. J. Org. Chem. 1997, 62, 1851;
(b) Desai, R. C.; Hlasta, D. J.; Monsour, G.; Saindane, M. T.
J. Org. Chem. 1994, 59, 7161; (c) Hlasta, D. J.; Court, J. J.;
Desai, R. C. Tetrahedron Lett. 1991, 32, 7179; (d) Lombardino,
J. G. J. Org. Chem. 1971, 36, 1843.
19. For method via Diels–Alder cycloaddition, see: (a) Yeung,
K. S.; Meanwell, N. A.; Li, Y.; Gao, Q. Tetrahedron Lett.
1998, 39, 1483; (b) Burri, K. F. Helv. Chim. Acta 1990, 73, 69.
20. For methods via oxidation of sulfides or thiols, see: (a)
Serebryakov, E. A.; Kislitsin, P. G.; Semenov, V. V.; Zlotin,
S. G. Synthesis 2001, 1659; (b) Berryman, K. A.; Edmunds,
J. J.; Bunker, A. M.; Haleen, S.; Bryant, J.; Welch, K. M.;
Doherty, A. M. Bioorg. Med. Chem. 1998, 6, 1447; (c)
Subramanyam, C.; Bell, M. R. Bioorg. Med. Chem. Lett.
25. (a) Wistuba, T.; Limberg, C.; Kircher, P. Angew. Chem., Int. Ed.
1999, 38, 3037; (b) Mayer, L. M. Acc. Chem. Res. 1998, 31,
441; (c) Shilov, A. E.; Shulpin, G. B. Chem. Rev. 1997, 97,
2879.