Synthesis of 3-methoxy-5-oxo-6-phenyl-5,6-dihydro-4H-isothiazolo[5,4-b]-1,4-thiazine 7,7-dioxide, the first representative of a new heterocyclic system

Article abstract of DOI:10.1023/A:1015002922937

When treated with an excess of MeONa in DMF, 5-benzylsulfonyl-3-chloro-4-methoxy-carbonylaminoisothiazole undergoes cyclization into 3-methoxy-5-oxo-6-phenyl-5,6-dihydro-4H-isothiazolo[5,4-6]-1,4-thiazine 7,7-dioxide, the first representative of a new het

Full text of DOI:10.1023/A:1015002922937

Russian Chemical Bulletin, International Edition, Vol. 51, No. 1, pp. 187—188, January, 2002
187
Synthesis of 3ꢀmethoxyꢀ5ꢀoxoꢀ6ꢀphenylꢀ5,6ꢀdihydroꢀ
4Hꢀisothiazolo[5,4ꢀb]ꢀ1,4ꢀthiazine 7,7ꢀdioxide,
the first representative of a new heterocyclic system

N. V. Voskoboev, A. I. Gerasyuto, and S. G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: zlotin@cacr.ioc.ac.ru
When treated with an excess of MeONa in DMF, 5ꢀbenzylsulfonylꢀ3ꢀchloroꢀ4ꢀmethoxyꢀ
carbonylaminoisothiazole undergoes cyclization into 3ꢀmethoxyꢀ5ꢀoxoꢀ6ꢀphenylꢀ5,6ꢀdihydroꢀ
4Hꢀisothiazolo[5,4ꢀb]ꢀ1,4ꢀthiazine 7,7ꢀdioxide, the first representative of a new heterocyclic
system. The starting 5ꢀbenzylsulfonylꢀ3ꢀchloroꢀ4ꢀmethoxycarbonylaminoisothiazole was preꢀ
pared by the reaction of 5ꢀbenzylsulfonylꢀ4ꢀcarbamoylꢀ3ꢀchloroisothiazole with PhI(OAc)2 in
methanol.
Key words: 2,3ꢀdihydroꢀ1,4ꢀthiazinꢀ3ꢀones, isothiazolo[5,4ꢀb]ꢀ1,4ꢀthiazinꢀ5ꢀones, inꢀ
tramolecular cyclization, phenyl iodosoacetate.
Scheme 1
Derivatives of annelated 2,3ꢀdihydroꢀ1,4ꢀthiazinꢀ3ꢀ
ones attract attention because of a broad spectrum of their
biological activity.1—5
Recently, we have developed a method for the syntheꢀ
sis of 2,3ꢀdihydrobenzothiazinꢀ3ꢀone derivatives. The key
stage in this method is a baseꢀinduced intramolecular
cyclization of Nꢀ(methoxycarbonyl)anilines containing
orthoꢀsulfide or sulfonyl groups with an active methylene
fragment adjacent to the S atom.6 This reaction underlies
a new strategy of the synthesis of annelated 2,3ꢀdihydroꢀ
thiazinꢀ3ꢀones with the formation of a C(2)—C(3) bond
of the thiazine ring at the stage of cyclization.
We demonstrated that the cyclization of this type is of
general character and can be used to obtain 2,3ꢀdihydroꢀ
thiazinꢀ3ꢀones annelated with heterocycles, particularly
with the isothiazole ring.
An isothiazole derivative required for cyclization was
prepared from available 4ꢀcarbamoylꢀ3,5ꢀdichloroisoꢀ
thiazole7,8 (1) in several steps. First, the chlorine atom in
position 5 was replaced by a benzylthio group to give
5ꢀbenzylthioꢀ4ꢀcarbamoylꢀ3ꢀchloroisothiazole (2). Comꢀ
pound 2 was oxidized into 5ꢀbenzylsulfonylꢀ4ꢀcarbamꢀ
oylꢀ3ꢀchloroisothiazole (3), which was converted to
5ꢀbenzylsulfonylꢀ3ꢀchloroꢀ4ꢀmethoxycarbonylaminoꢀ
isothiazole (4) under the action of PhI(OAc)2 in methaꢀ
nol (Scheme 1).
Reagents and conditions: i. PhCH2SH, K2CO3, DMF, yield 46%.
ii. H2O2, AcOH, yield 90%. iii. PhI(OAc)2, MeOH, yield 81%.
atom with a methoxy group in position 3 of the heteroꢀ
cycle (Scheme 2).
Scheme 2
It turned out that the reaction of compound 4 with an
excess of MeONa in DMF gives 3ꢀmethoxyꢀ5ꢀoxoꢀ6ꢀ
phenylꢀ5,6ꢀdihydroꢀ4Hꢀisothiazolo[5,4ꢀb]ꢀ1,4ꢀthiazine
7,7ꢀdioxide (5) in 81% yield. The heterocyclization is
accompanied by the nucleophilic replacement of the Cl
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 175—177, January, 2002.
1066ꢀ5285/02/5101ꢀ187 $27.00 © 2002 Plenum Publishing Corporation

188
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 1, January, 2002
Voskoboev et al.
1H NMR (DMSOꢀd6), δ: 3.82 (s, 3 H, Me); 4.91 (s, 2 H, CH2);
7.32—7.45 (m, 5 H, Ph); 8.69 (br.s, 1 H, NH). Found (%):
C, 41.46; H, 3.11; Cl, 9.98; N, 8.03; S, 18.05. C12H11ClN2O4S2.
Calculated (%): C, 41.56; H, 3.20; Cl, 10.22; N, 8.08; S, 18.49.
3ꢀMethoxyꢀ5ꢀoxoꢀ6ꢀphenylꢀ5,6ꢀdihydroꢀ4Hꢀisothiazoloꢀ
[5,4ꢀb]ꢀ1,4ꢀthiazine 7,7ꢀdioxide (5). Isothiazole 4 (0.15 g,
0.43 mmol) was added to a suspension of MeONa (0.05 g,
0.91 mmol) in 2 mL of anhydrous DMF. The reaction mixture
was stirred at ∼20 °C for 1 h (monitoring by TLC) and poured
into 10 mL of 2 M HCl. The precipitate that formed was filtered
off, washed with water (2×5 mL), and dried in air to give
S,Sꢀdioxide 5 (0.11 g, 81%), m.p. 115—117.5 °C, Rf 0.61 (benꢀ
zene—acetone, 4 : 1). 1H NMR (DMSOꢀd6), δ: 3.77 (s, 3 H,
Me); 7.08 (s, 1 H, CH); 7.51—7.76 (m, 5 H, Ph); 9.22 (br.s,
1 H, NH). 13C NMR (DMSOꢀd6), δ: 53.7 (OMe); 85.5 (CH);
105.5; 112.8; 129.5; 129.9; 130.0; 131.1; 131.8, 154.4 (C=O).
Found (%): C, 46.70; H, 3.19; N, 8.75; S, 20.19. C12H10N2O4S2.
Calculated (%): C, 46.44; H, 3.25; N, 9.03; S, 20.66. MS,
m/z (Irel (%)): 310 [M]+ (0.6), 278 [M – S]+ (0.5), 246
[M – SO2]+ (1.3), 214 [M – SO2MeOH]+ (4.9), 156 (10.3), 128
(3.3), 106 [PhCOH]+ (91.4), 105 [PhCO]+ (95.7), 91 [PhCH2]+
(16.7), 78 [PhH]+ (66), 77 [Ph]+ (100.0), 64 [SO2]+ (69.9).
The structure of compound 5 was determined from 1H
and 13C NMR spectra and mass spectra and confirmed by
elemental analysis data.
Thus, compound 5 was synthesized, which is, as
far as we know, the first representative of the isoꢀ
thiazolo[5,4ꢀb]ꢀ1,4ꢀthiazine heterocyclic system.
Experimental
Solvents were purified according to the standard procedures.9
1H and 13C NMR spectra were recorded on Bruker AMꢀ250 and
Bruker AMꢀ300 spectrometers (250 and 300 MHz, respectively)
in DMSOꢀd6. Mass spectra (EI, 70 eV) were recorded on a
Kratos MSꢀ30 instrument. TLC was performed on Silufol
UVꢀ254 silica gel with benzene—acetone as an eluent.
5ꢀBenzylthioꢀ4ꢀcarbamoylꢀ3ꢀchloroisothiazole (2). Benzylꢀ
thiol (0.70 mL, 5.86 mmol) and Na2CO3 (0.62 g, 5.86 mmol)
were successively added with stirring to a solution of 4ꢀcarbamꢀ
oylꢀ3,5ꢀdichloroisothiazole (1) (1.10 g, 5.33 mmol) in 6 mL of
DMF. The reaction mixture was kept at 40 °C for 120 h (moniꢀ
toring by TLC) and mixed with water (45 mL). The precipitate
that formed was filtered off and washed with water (3×15 mL).
The product obtained was recrystallized from PriOH—acetone
to give isothiazole 2 (0.69 g, 46%), m.p. 181.5—183 °C, Rf 0.58
(benzene—acetone, 5 : 1). 1H NMR (DMSOꢀd6), δ: 4.38 (s,
2 H, CH2); 7.28—7.48 (m, 5 H, Ph); 7.77 (br.s, 2 H, NH2).
5ꢀBenzylsulfonylꢀ4ꢀcarbamoylꢀ3ꢀchloroisothiazole (3). A 50%
solution of H2O2 (0.48 mL, 11.3 mmol) was added dropwise to a
solution of isothiazole 2 (0.30 g, 1.05 mmol) in 4 mL of glacial
AcOH. The reaction mixture was heated at 90 °C for 6 h (moniꢀ
toring by TLC), cooled, and mixed with water (30 mL). The
precipitate that formed was filtered off, washed with water
(2×5 mL), and dried in air to give isothiazole 3 (0.30 g, 90%),
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1
m.p. 176—178 °C, Rf 0.51 (benzene—acetone, 4 : 1). H NMR
(DMSOꢀd6), δ: 5.01 (s, 2 H, CH2); 7.22—7.44 (m, 5 H, Ph);
8.31, 8.47 (both br.s, each 1 H, NH). Found (%): C, 42.23;
H, 3.03; Cl, 10.78; N, 8.59; S, 19.49. C11H9ClN2O3S2. Calcuꢀ
lated (%): C, 41.71; H, 2.86; Cl, 11.19; N, 8.84; S, 20.24.
5ꢀBenzylsulfonylꢀ3ꢀchloroꢀ4ꢀmethoxycarbonylaminoisothiꢀ
azole (4). PhI(OAc)2 (0.36 g, 1.11 mmol) was added to a suspenꢀ
sion of isothiazole 3 (0.30 g, 0.95 mmol) in 4 mL of MeOH. The
reaction mixture was stirred at 15 °C for 12 h (monitoring by
TLC) and poured into water (30 mL). The crystalline product
that formed was filtered off and washed with water (2×5 mL)
and hexane (7 mL), and dried in air to give isothiazole 4 (0.30 g,
91%), m.p. 116—119.5 °C, Rf 0.73 (benzene—acetone, 4 : 1).
Received July 18, 2001;
in revised form October 29, 2001