Vicarious nucleophilic substitution of hydrogen in nitroarenes with in situ generated carbanions of 1-methyl-3-chloro-1,3-dihydro-2,1-benzisothiazole 2,2-dioxides

Article abstract of DOI:10.1055/s-2003-40530

Base-induced transformation of an equimolar mixture of 1-alkyl-1,3-dihydro-2,1-benzisothiazole 2,2-dioxides (benzosultams) and their 3,3-dichloro derivatives furnishes 1-alkyl-3-chloro-1,3-dihydro-2,1-benzisothiazole 2,2-dioxides which react with nitroare

Full text of DOI:10.1055/s-2003-40530

SHORT PAPER
1503
Vicarious Nucleophilic Substitution of Hydrogen in Nitroarenes with in situ
Generated Carbanions of 1-Methyl-3-chloro-1,3-dihydro-2,1-benzisothiazole
2,2-Dioxides
VNS
Arylation of
r
Benzosu
z
ltam
s
ysztof Wojciechowski,* Helena Modrzejewska
Institute of Organic Chemistry Polish Academy of Sciences, ul. Kasprzaka 44/52, P.O.Box 58, 01-224 Warszawa, Poland
Fax +48(22)6326681; E-mail: kris@icho.edu.pl
Received 1 April 2003
(hexachloroethane or carbon tetrachloride) under these
Abstract: Base-induced transformation of an equimolar mixture of
conditions were unsuccessful; the reactions led to an in-
1-alkyl-1,3-dihydro-2,1-benzisothiazole 2,2-dioxides (benzosul-
separable mixture of mono- and dichloro derivatives with
unreacted benzosultam. A similar result was obtained
tams) and their 3,3-dichloro derivatives furnishes 1-alkyl-3-chloro-
1,3-dihydro-2,1-benzisothiazole 2,2-dioxides which react with ni-
troarenes according to the vicarious nucleophilic substiution of hy- when an equimolar mixture of sultam 1a and its dichloro
drogen (VNS) mechanism giving 3-(nitroaryl)benzosultams.
derivative 2a was equilibrated under PTC conditions. The
1H NMR spectrum of such a crude reaction mixture re-
Key words: benzosultams, halogenation, nitro compounds, carban-
ions, nucleophilic aromatic substitution
vealed the presence of about 70% of the desired
monochloro derivative (based on the presence of three
signals corresponding to N–Me groups and one signal at
5.6 ppm assigned to CHCl). Following this observation
we decided to generate the monochlorosultam in situ and
introduce it into vicarious nucleophilic substitution of hy-
drogen in nitroarenes.
Thermal extrusion of sulfur dioxide from 1-alkyl-1,3-di-
hydro-2,1-benzisothiazole 2,2-dioxides (benzosultams)1
leads to reactive cyclohexadiene methylene imines (aza-
ortho-xylylenes)2 being potential building blocks for the
construction of heterocycles. In our studies directed to-
wards the reactions of these reactive intermediates we
were interested in reactions of derivatives substituted at
the exocyclic C=C bond with an aryl substituent, which
could be generated from 3-arylbenzosultams. Previously
we synthesized 3-arylbenzosultams via an arylation of
carbanions derived from benzosultams with 1-fluoro-4-
nitrobenzene,3 intramolecular SNAr reaction in a-toluene-
sulfon-(3-nitro)anilides,4 or intramolecular oxidative nu-
cleophilic substitution of hydrogen.3
Now we present the synthesis of 3-arylbenzosultams by
the vicarious nucleophilic substitution of hydrogen
(VNS)5 in nitroarenes by carbanions of 3-chlorobenzosul-
tams. VNS is a general reaction between carbanions bear-
ing leaving groups at the carbanionic center and
nitroarenes which result in a replacement of hydrogen at
ortho or para position to the nitro group.
Scheme 1
One of the general methods to introduce halogens into a-
position to the electron withdrawing group deals with
chlorination of the corresponding carbanions with per-
haloalkanes (tetrachloromethane or hexachloroethane).6
In one of our previous papers7 we have shown that benzo-
sultams can be chlorinated with hexachloroethane in a cat-
alytic two-phase system [50% aqueous NaOH,
tetrabutylammonium bromide (TBAB)] to form corre-
sponding 3,3-dichlorobenzosultams in good yields. At-
tempts to obtain mono halogeno derivatives from
equimolar amounts of benzosultam and chlorinating agent
One example of such a reaction was presented earlier
when a mixture of neopentyl phenylmethanesulfonate and
its dichloro derivative reacted with nitrobenzene to
form neopentyl (4-nitrophenyl)phenylmethanesulfonate.8
Thus, when we treated a 1:1 molar mixture of sultams 1a
and 2a with nitrobenzene in DMSO with powdered NaOH
the reaction mixture turned deep-violet and after 30 min-
utes TLC analysis revealed complete disappearance of the
starting materials. After quenching with diluted aqueous
hydrochloric acid and standard work-up the expected 1-
methyl-3-(4-nitrophenyl)-2,1-benzisothiazoline 2,2-diox-
ide (4a) was isolated in 62% yield (Scheme 1).
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1503,1505,ftx,en;Z04703SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1504
K. Wojciechowski, H. Modrzejewska
SHORT PAPER
Benzosultams were obtained from the corresponding N-alkyl-2-
chloro-N-(methanesulfonyl)anilines following the procedure de-
scribed by Bunnett.10
Table 1 Synthesis of 3-(Nitroaryl)benzosultams
Com-
pounds
1–4
R
Q
X
Y
Yield (%)
3,3-Dichlorobenzosultams were obtained by chlorination of benzo-
sultams with hexachloroethane in a catalytic two-phase system.7
a
b
c
d
e
f
H
C-H
C-H
C-H
C-H
N
H
H
H
H
H
Cl
Cl
H
62
63
71
65
64
62
60
Arylation of Benzosultams; General Procedure
Me
Me
H
H
To a solution of benzosultam (1, 1 mmol), dichlorobenzosultam (2,
1 mmol) and nitroarene (3, 2.2 mmol) in DMSO (5 mL) solid pow-
dered NaOH (1.5 g) was added in one portion. The reaction mixture
was stirred at r.t. for 30 min and then poured into 5% diluted HCl
with ice. The precipitate was separated, dissolved in CH2Cl2 (50
mL) and dried with Na2SO4. After evaporation of the solvent the
product was chromatographed (cyclohexane–EtOAc, 4:1) and re-
crystallized from EtOH–EtOAc (10:1).
Cl
Cl
H
H
MeO
H
N
H
g
N
EtO
1-Methyl-3-(4-nitrophenyl)-1,3-dihydro-2,1-benzisothiazole
2,2-Dioxide (4a)
Mp 144–145 °C (decomp).
Other nitrobenzene and nitropyridine derivatives reacted
similarly (Table 1). In all investigated instances, due to
steric reasons, the replacement of hydrogen occurred at
the para position to the nitro group, similarly as in the
case of other tertiary a-chloro-a-sulfonyl carbanions.9 A
plausible reaction pathway is shown in the Scheme 2.
IR (KBr): 2917, 1606, 1520, 1481, 1466, 1349, 1320, 1298, 1180,
1150, 1116, 1057, 853, 759, 732 cm–1.
1H NMR (200 MHz): d = 3.22 (s, 3 H), 5.54 (s, 1 H), 6.87 (d, J = 8.0
Hz, 1 H), 7.03–7.15 (m, 2 H), 7.30–7.40 (m, 3 H), 8.25–8.34 (m, 2
H).
13C NMR (50 MHz): d = 27.0, 65.8, 109.5, 122.6, 124.1, 125.7,
130.5, 131.3, 137.3.
MS (EI 70 eV): m/z (%) = 304 (21, M+), 240 (22), 239 (47), 223
(33), 194 (27), 193 (100), 179 (9), 165 (10), 152 (12), 139 (3), 118
(13).
HRMS: m/z calcd for C14H12N2O4S: 304.0518; found: 304.0528.
1,5-Dimethyl-3-(4-nitrophenyl)-1,3-dihydro-2,1-benzisothia-
zole 2,2-Dioxide (4b)
Mp 156–158 °C (decomp).
IR (KBr): 2919, 1605, 1521, 1494, 1353, 1314, 1266, 1178, 1151,
1130, 1056, 865, 827, 818, 741 cm–1.
1H NMR (200 MHz): d = 2.31 (s, 3 H), 3.18 (s, 3 H), 5.50 (s, 1 H),
6.77 (d, J = 8.2 Hz, 1 H), 6.86 (br s, 1 H), 7.25 (d, J = 8.2 Hz, 1 H),
7.46–7.57 (m, 2 H), 8.25–8.36 (m, 2 H).
MS (EI 70 eV): m/z (%) = 318 (21, M+), 254 (30), 253 (49), 237
(36), 208 33), 207 (100), 193 (16), 180 (6), 178 (6), 165 (14), 152
(8), 148 (14), 132 (14).
Scheme 2
HRMS: m/z calcd for C15H14N2O4S: 318.0674, found: 318.0691.
Another possibility for the formation of nitroarylated
products was an oxidative nucleophilic substitution of hy-
drogen by the carbanion of the starting sultam. However,
when we reacted the 1,5-dimethylbenzosultam 1b with 2-
nitrochlorobenzene under employed conditions a complex
mixture of products was formed from which the expected
sultam 4b was isolated in less than 10% yield. This con-
firms that the initial step of the investigated reaction was
chlorination of the sultam by dichlorosultam.
3-(3-Chloro-4-nitrophenyl)-1,5-dimethyl-1,3-dihydro-2,1-
benzisothiazole 2,2-Dioxide (4c)
Mp 139–141 °C (decomp).
IR (KBr): 2937, 2913, 1597, 1583, 1529, 1494, 1357, 1318, 1270,
1176, 1148, 1131, 1052, 843, 828, 818 cm–1.
1H NMR (400 MHz): d = 2.31 (s, 3 H), 3.17 (s, 3 H), 5.40 (s, 1 H),
6.76 (d, J = 8.0 Hz, 1 H), 6.86 (br s, 1 H), 7.24 (d, J = 8.0, 1 H), 7.38
(dd, J = 8.4, 1.8 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H), 7.92 (d, J = 8.4
Hz, 1 H).
Melting points are uncorrected. 1H and 13C NMR spectra were ob-
tained with Varian Mercury 400 BB (400 MHz) and Varian Gemini
(200 MHz) instruments in CDCl3 with TMS as internal standard. IR
spectra were recorded using a Perkin-Elmer 2000 FTIR instrument.
Mass spectra (electron impact, 70 eV) were obtained on an AMD
604 (AMD Intectra GmbH, Germany) instrument. HRMS were
measured in the presence of perfluorokerosene as the reference
compound. Column chromatography was performed using silica gel
240–400 mesh (Merck).
13C NMR (100 MHz): d = 20.9, 27.2, 65.3, 109.7, 121.2, 126.0,
126.2, 127.8, 129.4, 131.1, 133.4, 136.7, 139.2, 148.3.
MS (EI 70 eV): m/z (%) = 352, (11, M+), 288 (26), 287 (34), 273
(10), 271 (13), 244 (21), 243 (41), 242 (60), 241 (100), 229 (12),
227 (15), 207 (29), 206 (44), 192 (22), 191 (24), 178 (13), 165 (21),
148 (22), 132 (23).
HRMS: m/z calcd for C15H13N2O4SCl: 352.0285, found: 352.0295.
Synthesis 2003, No. 10, 1503–1505 © Thieme Stuttgart · New York

SHORT PAPER
VNS Arylation of Benzosultams
1505
Anal. Calcd for C15H13N2O4SCl: C, 51.07; H, 3.71; N, 7.94. Found:
C, 51.70; H, 3.97; N, 8.04.
J = 8.8, 2.7 Hz, 1 H), 7.32 (d, J = 8.2 Hz, 1 H), 8.21 (d, J = 8.2 Hz,
1 H).
13C NMR (100 MHz): d = 28.1, 55.8, 67.5, 111.4, 112.2, 116.0,
3-(3-Chloro-4-nitrophenyl)-1-methyl-1,3-dihydro-2,1-benz-
isothiazole 2,2-Dioxide (4d)
Mp 143–144 °C.
122.0, 123.4, 135.27, 135.33, 135.36, 143.4, 155.66, 155.70.
MS (EI 70 eV): m/z (%) = 369 (4, M+), 304 (8), 288 (4), 259 (6), 258
(12), 244 (4), 223 93), 216 (2), 181 (3), 170 (20), 64 (100).
IR (KBr): 3101, 2936, 1606, 1595, 1584, 1537, 1479, 1464, 1414,
1366, 1326, 1309, 1276, 1171, 1144, 1112, 1055, 837, 826, 753
cm–1.
1H NMR (400 MHz): d = 3.21 (s, 3 H), 5.46 (s, 1 H), 6.86 (d, J = 8.0
Hz, 1 H), 7.04–7.12 (m, 2 H), 7.38 (dd, J = 8.4, 2.0 Hz, 1 H), 7.46
(ddd, J = 8.0, 7.1, 1.8 Hz, 1 H), 7.50 (d, J = 2.0 Hz, 1 H), 7.92 (d,
J = 8.4 Hz, 1 H).
13C NMR (100 MHz): d = 27.0, 65.2, 109.7, 121.2, 122.7, 125.7,
126.1, 127.8, 129.4, 130.8, 133.4, 136.4, 141.4, 148.4.
MS (EI 70 eV): m/z (%) = 338 (14, M+), 275 (24), 274 931), 273
(62), 257 (17), 239 919), 229 (41), 228 (60), 227 (100), 193 (25),
192 (39), 191 (15), 165 (13), 151 (12), 118 (24).
HRMS: m/z calcd for C14H12N3O5SCl: 369.0186, found: 369.0187.
Anal. Calcd for C14H12N3O5SCl: C, 45.47; H, 3.27; N, 11.36.
Found: C, 45.16; H, 3.79; N, 11.17.
3-(4-Ethoxy-5-nitropyridin-2-yl)-1-methyl-1,3-dihydro-2,1-
benzisothiazole 2,2-Dioxide (4g)
Mp 161–163 °C (decomp).
IR (KBr): 3106, 2985, 1604, 1564, 1506, 1486, 1471, 1358, 1320,
1289, 1198, 1170, 1123, 1024, 988, 856, 835, 757 cm–1.
1H NMR (200 MHz): d = 1.45 (t, J = 7.0 Hz, 3 H), 3.21 (s, 3 H),
4.16 (q, J = 7.0 Hz, 2 H), 5.70 (s, 1 H), 6.86 (d, J = 7.8 Hz, 1 H),
6.96 (s, 1 H), 7.00–7.18 (m, 2 H), 7.38–7.52 (m, 1 H), 9.00 (s, 1 H).
13C NMR (50 MHz): d = 14.0, 27.2, 66.1, 67.9, 109.7, 110.0, 121.0,
122.6, 125.8, 130.6, 136.6, 141.5, 147.0, 156.9, 158.9.
MS (EI 70 eV): m/z (%) = 349 (43, M+), 285 (100), 284 (87), 270
(59), 257 (41), 256 (95), 242 (51), 240 (35), 239 (82), 229 (31), 212
(24), 211 (81), 210 (34), 209 (30), 196 (42), 183 (61), 182 (73), 168
(54), 154 (48), 140 (54), 128 (26), 118 (59).
HRMS: m/z calcd for C14H11N2O4ClS: 338.0128, found: 338.0135.
Anal. Calcd for C14H11N2O4ClS: C, 49.64; H, 3.27; N, 8.27. Found:
C, 49.71; H, 3.33; N, 8.23.
3-(6-Chloro-5-nitropyridin-2-yl)-1-methyl-1,3-dihydro-2,1-
benzisothiazole 2,2-Dioxide (4e)
Mp 147–148 °C (decomp).
HRMS: m/z calcd for C15H15N3O5S: 349.0732, found: 349.0726.
IR (KBr): 3085, 2936, 1576, 1528, 1487, 1469, 1430, 1379, 1340,
1307, 1271, 1203, 1169, 1124, 1050, 838, 747 cm–1.
1H NMR (400 MHz): d = 3.22 (s, 3 H), 5.72 (s, 1 H), 6.82 (d, J = 8.0
Hz, 1 H), 7.00–7.08 (m, 2 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.40 (dd,
J = 8.2, 8.2 Hz, 1 H), 8.15 (d, J = 8.2 Hz, 1 H).
13C NMR (100 MHz): d = 27.3, 67.2, 109.8, 120.6, 122.8, 123.4,
126.0, 131.0, 135.3, 141.4, 143.4, 144.6, 155.7.
MS (EI 70 eV): m/z (%) = 339 (40, M+), 275 (27), 274 (61), 258
(11), 240 (16), 230 (18), 229 (53), 228 (100), 214 (8), 209 (9), 201
(14), 194 (36), 193 (68), 181 (11), 179 (15), 167 (26), 166 (21), 153
(22), 140 (13), 118 (61).
References
(1) For a review on benzosultams, see: Wojciechowski, K.
Heterocycles 2002, 57, 1717.
(2) For a review on aza-ortho-xylylenes, see: Wojciechowski,
K. Eur. J. Org. Chem. 2001, 3587.
(3) Wojciechowski, K. Synth. Commun. 1997, 26, 135.
(4) Wojciechowski, K. Pol. J. Chem. 1992, 66, 1121.
(5) For recent reviews on vicarious nucleophilic substitution of
hydrogen, see: (a) Mąkosza, M.; Wojciechowski, K. Liebigs
Ann./Recueil 1997, 1805. (b) Mąkosza, M.; Kwast, A. J.
Phys. Org. Chem. 1998, 11, 341. (c) Mąkosza, M.;
Wojciechowski, K. Heterocycles 2001, 54, 445.
(6) (a) Kattenberg, J.; de Waard, E. R.; Huisman, H. O.
Tetrahedron 1973, 29, 4149. (b) For a review on
chlorination of carbanions, see: Abele, E.; Lukevics, E. Org.
Prep. Proc. Int. 1999, 31, 359.
(7) Wojciechowski, K.; Siedlecka, U.; Modrzejewska, H.;
Kosiński, S. Tetrahedron 2002, 58, 7583.
(8) Mąkosza, M.; Goliński, J. Synthesis 1983, 1023.
(9) Mąkosza, M.; Goliński, J.; Baran, J. J. Org. Chem. 1984, 49,
1488.
HRMS: m/z calcd for C13H10N3O4SCl: 339.0081, found: 339.0067.
Anal. Calcd for C13H10N3O4SCl: C, 45.96; H, 2.96; N, 12.37.
Found: C, 45.62; H, 3.33; N, 12.43.
3-(6-Chloro-5-nitropyridin-2-yl)-5-methoxy-1-methyl-1,3-dihy-
dro-2,1-benzisothiazole 2,2-Dioxide (4f)
Mp 126–128 °C.
IR (KBr): 3084, 2935, 1577, 1533, 1496, 1470, 1334, 1309, 1287,
1241, 1196, 1120, 1055, 1027, 836 cm–1.
1H NMR (400 MHz): d = 3.18 (s, 3 H), 3.76 (s, 3 H), 5.67 (s, 1 H),
6.70 (d, J = 2.7 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 6.99 (dd,
(10) Bunnett, J. F.; Kato, T.; Flynn, R. R.; Skorcz, J. A. J. Org.
Chem. 1963, 28, 1.
Synthesis 2003, No. 10, 1503–1505 © Thieme Stuttgart · New York