Synthesis of 1,3-benzothiazol-2(3H)-ones with a carbamate function at the C-6 atom

Article abstract of DOI:10.1007/s10593-013-1194-4

A new method has been developed for the synthesis of 1,3-benzothiazol-2(3H) -ones with carbamate function based on the adducts of the 1,4-addition of thioacetic acid to 2-R-N,N'-dimethoxycarbonyl-1,4-benzoquinone diimines. Refluxing the 2-thioacetyl-substituted dicarbamates in ethanol in the presence of hydrochloric acid gave 1,3-benzothiazol-2(3H)-ones with methoxycarbonylamine group at the C-6 atom. Modifications of the obtained compounds were performed.

Full text of DOI:10.1007/s10593-013-1194-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS OF 1,3-BENZOTHIAZOL-2(3H)-ONES
WITH A CARBAMATE FUNCTION AT THE C-6 ATOM
A. V. Velikorodov1*, A. K. Kuanchalieva1, and V. A. Ionova1
A new method has been developed for the synthesis of 1,3-benzothiazol-2(3H)-ones with carbamate
function based on the adducts of the 1,4-addition of thioacetic acid to 2-R-N,N'-dimethoxycarbonyl-
1,4-benzoquinone diimines. Refluxing the 2-thioacetyl-substituted dicarbamates in ethanol in the
presence of hydrochloric acid gave 1,3-benzothiazol-2(3H)-ones with methoxycarbonylamine group at
the C-6 atom. Modifications of the obtained compounds were performed.
Keywords: 2-(3H)-benzothiazolone, N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine, thioacetic acid,
alkylation, 1,4-addition, cyclization.
A number of methods are known for the preparation of 1,3-benzothiazol-2(3H)-ones: 1) cyclization of
2-aminothiophenols with phosgene, chloroformates, and urea [1]; 2) reductive carbonylation of substituted
nitrobenzenes using sulfur, carbon monoxide, and water in the presence of bases [1]; 3) cyclization of
thiocarbamates followed by decomposition of the 2-alkoxybenzothiazoles prepared [2]; 4) oxidation of
2-mercaptobenzothiazoles or benzothiazolylalkyl thioethers with the formation of 2-sulfonyl- or 2-alkyl-
sulfonylbenzothiazoles with their subsequent hydrolysis; 5) reaction of o-nitrochlorobenzenes with thioglycolic
acid and subsequent cyclocondensation of the o-nitrophenylthioacetic acid with acetic anhydride, followed by
deacylation [1]; 6) reaction of 2-aminobenzothiazoles with alkali metal hydroxides in anhydrous medium and
cyclization of the o-mercaptophenylureas formed [1, 3]; 7) reaction of thiosalicylic acid with ammonium azide
and three equivalents of DMF–POCl3 complex [4].
We have shown previously that 1,3-benzothiazol-2(3H)-one is formed on heating bis(2,2'-dimethoxy-
carboxamido)phenyl disulfide in glacial acetic acid in the presence of zinc dust [5].
Various 2- and 3-substituted derivatives of 1,3-benzothiazol-2(3H)-ones possess a wide spectrum of
biological activity. Compounds have been found among them with high herbicidal, antimicrobial, analgesic,
antioxidant, anticonvulsive, antifungal, and other types of activity [1, 4, 6, 7]. They also serve as valuable
precursors in the synthesis of new functionally substituted compounds [8]. In this connection the preparation of
new derivatives of 2(3H)-benzothiazolones and their subsequent screening are of considerable interest.
It is known that reactions of quinones [9] and aroyl(sulfonyl) derivatives of benzoquinone diimines [10,
11] with mercaptans occur differently depending on the nature of the quinoid compound and mercaptan, and
the reaction conditions. The products of these reactions are mercapto derivatives of diamides with aromatic
_______
*To whom correspondence should be addressed, e-mail: avelikorodov@mail.ru.
1 Astrakhan State University, 1 Shaumyan Sq., Astrakhan 414000, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1808-1812, November, 2012.
Original article submitted January 22, 2012.
0009-3122/13/4811-1691©2013 Springer Science+Business Media New York
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structures. However, in many cases the preferred direction of reaction is quinone imide reduction into the
corresponding diamides unsubstituted in the benzene ring, while the mercaptans are oxidized to disulfides [10].
We note that the reaction of N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine (1) with thioacetic acid
had not been investigated previously.
We have established that the reaction of N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine (1) and
2-chloro-N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine (2) with thioacetic acid in methylene chloride at
room temperature occurs as 1,4-addition at the N=C–C=N conjugated bond system of the quinone diimine with
1
formation of the aromatic products 3, 4, the structures of which were confirmed by IR, H NMR, and mass
spectroscopy.
Refluxing the ring-substituted dicarbamates (3, 4) in ethanol in the presence of concentrated
hydrochloric acid for 5 h was accompanied by heterocyclization with the formation of methyl N-(4-R-2-oxo-
2,3-dihydro-1,3-benzothiazol-6-yl)carbamates 5 and 6. The structures of compounds 5 and 6 were confirmed by
IR, as well as 1H and 13C NMR spectroscopy, and compound 5 also by mass spectroscopy.
NHCO2Me
NCO2Me
H
HCl, EtOH
MeO2CN
S
AcSH
O

O
CH2Cl2
–AcOH
–MeOH
N
H
R
S
Me
R
NHCO2Me
NCO2Me
R
1, 2
3, 4
5, 6
1, 3, 5 R = H, 2, 4, 6 R = Cl
In the case of the unsymmetrical quinone diimine 2, the 1,4-addition occurred regioselectively
according the thin layer chromatography to give a single product, ascribed with the structure 4 on the basis of
considering the 1H NMR, 1H–1H COSY and NOESY spectra of its cyclization product.
In the 1H-1H COSY spectrum of 4-chloro-substituted 1,3-benzthiazol-2(3H)-one 6 there are nondiagonal
cross peaks between the benzene ring protons (4J = 3.0 Hz), which should be absent in the 5-chloro derivative.
At the same time, in the NOESY spectrum of this compound there are two cross peaks between protons at the
ortho position relative to the carbamate group and the NH proton of the carbamate group. In the case of the
alternative product, two cross peaks would also be expected, but between protons at the ortho position to two
different NH-groups.
The observed direction of nucleophile addition to the unsymmetrical quinone diimine 2 is probably
explained by the preferred protonation of the more basic nitrogen atom [12], which is decreased by the presence
of chlorine at the ortho position to the N-methoxycarbonylimino group.
It is probable that the heterocyclization of compounds 3 and 4 occurs via formation of the thiol
intermediate A.
NHCO2Me
R
SH
NHCO2Me
A
Alkylation of two equivalents of 1,3-benzothiazol-2(3H)-one 5 with 1,2-dibromoethane in acetone in
the presence of potassium carbonate led to the formation of dimethyl [ethan-1,2-diylbis(2-oxo-1,3-benzo-
thiazol-3,6-(2H)-diyl)]biscarbamate (7).
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O
S
NHCO2Me
BrCH2CH2Br
N
5
N
K2CO3, Me2CO
MeO2CN

H
S
O
7
Alkylation of compound 5 with ethyl bromoacetate under analogous conditions gave ethyl 2-{6-[(meth-
oxycarbonyl)amino]-2-oxo-1,3-benzothiazol-3(2H)-yl}-acetate (8), which was further converted into the
corresponding hydrazide 9. The synthesis of compound 9 was carried out by maintaining equimolar amounts of
the reagents in absolute ethanol for 8 h at 50°C.
H
H
BrCH2CO2Et
K2CO3
N2H4
EtOH
MeO2CN
MeO2CN
S
S
O
O
5
50°C
8 h
Me2CO
N
N

CONHNH2
CO2Et
9
8
The structures of the new compounds 7-9 were confirmed by IR and 1H NMR spectroscopy.
So we have studied for the first time the interaction of N,N'-dimethoxycarbonyl-1,4-benzoquinone
diimine with thioacetic acid and proposed a new method for the synthesis of 1,3-benzothiazol-2(3H)-ones with
methoxycarbonylamino group at the C-6 atom by heterocyclization of the obtained 1,4-addition adducts.
EXPERIMENTAL
IR spectra were recorded with a Specord M-80 instrument. The 1H, 1H1H COSY, NOESY, and 13C NMR
1
spectra were recorded on a Bruker DRX-500 instrument (500 MHz for H nuclei, 126 MHz for 13C nuclei) in
DMSO-d6, with TMS as internal standard. Mass spectra were recorded with a Finnigan MAT INCOS 50
quadrupole mass spectrometer (ionization energy 70 eV). Elemental analyses were carried out on an EuroVector
EA-3000 CHNS analyzer. Melting points were determined with a Boetius hot stage apparatus. TLC was carried
out on Silufol UV-254 plates with 1:1 dioxane–Et2O as eluent.
S-{2,5-Bis[(methoxycarbonyl)amino]phenyl}ethanethioate (3). Thioacetic acid (0.36 ml, 5 mmol)
was added to a solution of N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine (1) [13] (1.10 g, 5 mmol) in
CH2Cl2 (10 ml), and the mixture was maintained at room temperature for 3 h. The precipitated crystalline
product was filtered off, washed on the filter with Et2O (5 ml), and recrystallized from CHCl3. Yield 1.39 g
(94%). Colorless crystals; mp 189-190°C. IR spectrum, ν, cm-1: 3340 (NH), 1725, 1710 (C=O), 1610, 1575,
1545 (CCAr). 1H NMR spectrum, δ, ppm (J, Hz): 2.38 (3H, s, COCH3); 3.65 (3H, s, NHCO2CH3); 3.68 (3H, s,
NHCO2CH3); 7.33 (1H, d, 3J = 8.6, H Ar); 7.47 (1H, d, J = 8.6, H Ar); 7.55 (1H, s, H Ar); 8.77 (1H, br. s, NH);
9.74 (1H, br. s, NH). Mass spectrum, m/z (Irel, %), 300 [M+2H]+ (1), 299 (2) [M+H]+, 298 [M]+ (17), 256 (68),
238 (17), 224 (26), 197 (31), 192 (20), 180 (12), 165 (20), 137 (9),121 (9), 109 (6), 93 (4), 79 (10), 59 (49), 52
(12). Found, %: C 48.12; H 4.55; N 9.21. C12H14N2O5S. Calculated, %: C 48.32; H 4.73; N 9.39.
S-{3-Chloro-2,5-bis[(methoxycarbonyl)amino]phenyl}ethanethioate (4) was obtained analogously
from 2-chloro-N,N'-dimethoxycarbonyl-1,4-benzoquinone diimine (2) [14] (1.30 g, 5 mmol) and thioacetic acid
(0.36 ml, 5 mmol). Yield 1.47 g (87%). Colorless crystals; mp 138-140°C. Rf 0.64. IR spectrum, ν, cm-1: 3340
1
(NH), 1725, 1715 (C=O), 1610, 1580, 1555 (CCAr). H NMR spectrum, δ, ppm: 2.24 (3H, s, COCH3); 3.65
(3H, s, NHCO2CH3); 3.73 (3H, s, NHCO2CH3); 7.75 (1H, s HAr); 7.90 (1H, s, HAr); 8.75 (1H, br. s, NH); 9.54
(1H, br. s, NH). Found, %: C 43.27; H 3.94; N 8.32. C12H13ClN2O5S. Calculated, %: C 43.31; H 3.94; N 8.42.
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Methyl N-(2-Oxo-2,3-dihydro-1,3-benzothiazol-6-yl)carbamate (5). A mixture of compound 3
(0.80 g, 2.7 mmol) and conc. HCl (1 ml) in ethanol (10 ml) was refluxed for 5 h, poured into ice water (50 ml),
the precipitate was filtered off, washed with water, dried in air, and recrystallized from dioxane. Yield 0.54 g
(90%). Colorless crystals; mp 256-258°C. IR spectrum, ν, cm-1: 3300-3340 (NH), 1725, 1710 (C=O), 1615,
1565, 1535 (CCAr). 1H NMR spectrum, δ, ppm (J, Hz): 3.68 (3H, s, NHCO2CH3); 7.03 (1H, d, 3J = 8.7, H Ar);
7.27 (1H, d, 3J =8.7, H Ar); 7.68 (1H, s, H Ar); 9.65 (1H, br. s, NHCOOMe); 11.73 (1H, br. s, 1-NH). 13C NMR
spectrum, δ, ppm: 52.3 (OCH3); 109.7 (C-7); 118.7 (C-4); 120.1 (C-5); 128.4 (C-8); 135.2 (C-6); 138.6 (C-9);
155.3 (NHCO2Me); 170.4 (2C=O). Mass spectrum, m/z (Irel,%): 226 [M+2H]+ (5), 225 [M+H]+ (10), 224 [M]+
(100), 192 (74), 164 (40), 137 (93), 125 (20), 119 (13), 110 (24), 93 (15), 83 (21), 79 (48), 69 (24), 59 (86), 52
(79). Found, %: C 47.98; H 3.55; N 12.28. C9H8N2O3S. Calculated, %: C 48.21; H 3.60; N 12.49.
Methyl N-(4-chloro-2-oxo-2,3-dihydro-1,3-dibenzothiazol-6-yl)carbamate (6) was prepared
analogously by cyclization of adduct 4 (0.90 g, 2.7 mmol). Yield 0.60 g, (87%). Colorless crystals; mp 242-
245°C (dioxane). Rf 0.81. IR spectrum, ν, cm-1: 3320-3340 (NH), 1720, 1710 (C=O), 1615, 1575, 1535 (CCAr).
1H NMR spectrum, δ, ppm: 3.73 (3H, s, NHCО2CH3); 7.51 (1H, s, H Ar); 7.62 (1H, s, H Ar); 9.13 (1H, s,
NHCO2Me); 12.01 (1H, s, NH). 13C NMR spectrum, δ, ppm: 52.3 (OCH3); 112.1 (C-7); 122.1 (C-5); 123.0
(C-4); 127.5 (C-8); 130.1 (C-9); 135.2 (C-6); 155.3 (NHCO2Me); 170.5 (2C=O). Found, %: C 41.55; H 2.57;
N 10.67. C9H7ClN2O3S. Calculated, %: C 41.79; H 2.73; N 10.83.
Dimethyl [Ethan-1,2-diylbis(2-oxo-1,3-benzothiazol-3,6(2H)-diyl)]biscarbamate (7). A mixture of
carbamate 5 (1.12 g, 5.0 mmol) and anhydrous K2CO3 (0.69 g, 5.0 mmol) in acetone (7 ml) was refluxed for 10
min; freshly distilled 1,2-dibromoethane (0.22 ml, 2.5 mmol) was added, and the mixture was heated at 70°C for
6 h, cooled, poured onto ice, the crystalline precipitate was filtered off, dried in air, and recrystallized from
MeOH. Yield 0.85 g (72%). Colorless crystals; mp 284-286°C. IR spectrum, ν, cm-1: 3335 (NH), 1710, 1680
1
(C=O), 1610, 1555, 1530 (CCAr). H NMR spectrum, δ, ppm (J, Hz): 3.71 (6H, s, 2NHCO2CH3); 5.50 (4H, s,
2CH2); 6.89 (2H, d, 3J = 8.7, H Ar); 7.02 (2H, d, 3J = 8.7, H Ar); 7.36 (2H, s, H Ar); 11.53 (2H, s, 2NH). Found,
%: C 50.55; H 3.92; N 11.65. C20H18N4O6S2. Calculated, %: C 50.62; H 3.82; N 11.81.
Ethyl 2-{6-[(methoxycarbonyl)amino]-2-oxo-1,3-benzothiazol-3(2H)-yl)}acetate (8) was obtained
analogously using ethyl bromoacetate (0.57 ml, 5.1 mmol) as an alkylating agent. The product was
recrystallized from CHCl3. Yield 1.24 g (80%). Colorless crystals; mp 276-278°C. IR spectrum, ν, cm-1: 3340
1
(NH), 1715, 1670 (C=O), 1595, 1580, 1565 (CCAr). H NMR spectrum, δ, ppm (J, Hz): 1.27 (3H, t, J = 6.8,
CH2CH3); 3.71 (3H, s, NHCO2CH3); 4.20 (2H, q, J = 6.8, CH2CH3); 5.10 (2H, s, CH2COOEt); 6.95 (1H, d,
3J = 8.5, H Ar); 7.14 (1H, d, 3J = 8.5, H Ar); 7.45 (1H, s, H Ar); 11.62 (1H, s, NHCO2Me). Found, %: C 50.04;
H 4.20; N 8.92. C13H14N2O5S. Calculated, %: C 50.32; H 4.55; N 9.03.
Methyl N-[3-(2-Hydrazino-2-oxoethyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl]carbamate (9). A
mixture of compound 8 (0.78 g, 2.5 mmol) and 99% hydrazine hydrate (0.18 g, 3.5 mmol) in EtOH (7 ml) was
kept at 50°C for 8 h, cooled, the crystalline precipitate was filtered off, washed on the filter with cold EtOH,
dried in air, and recrystallized from dioxane. Yield 0.70 g (94%). Colorless crystals; mp 260-262°C. IR
spectrum, ν, cm-1: 3340, 3400 (NH), 1715, 1680 (C=O), 1615, 1565, 1530 (CCAr). 1H NMR spectrum, δ, ppm
3
3
(J, Hz): 3.71 (3H, s, NHCO2CH3); 5.25 (2H, s, CH2CO); 6.95 (1H, d, J = 8.5, H Ar); 7.25 (1H, d, J = 8.5,
H Ar); 7.48-7.52 (1H, m, NHNH2); 7.69 (1H, s, H Ar ); 8.23-8.27 (2H, m, NHNH2); 11.54 (1H, s, NHCO2Me).
Found, %: C 44.57; H 4.00; N 18.77. C11H12N4O4S. Calculated, %: C 44.59; H 4.08; N 18.91.
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