Reactions of 5-mercaptoazoles and pyridine-2-thiones with acetylenic esters. Selectivity of the formation of novel fused thiazin-4-ones and thiazolidin-4-ones

Article abstract of DOI:10.1039/b207854f

A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate with 5-mercaptoazoles and pyridine-2-thiones has been carried out and as a result, a number of novel imidazo[1,5-b]-thiazin-4-ones 6a,b, pyrazolo[1,5-b] thiazin-4-ones 15a-f, imidazo[1,5-b]thiazol-4-ones 7a,b and thiazolo[3,2-a]-pyridines 21a-c have been prepared. The influence of the size of the ring of the starting "cyclic" thioamides on the size of the fused ring in the reaction products has been established. The preferred formation of a six-membered thiazine ring took place in the reactions of 5-mercaptoazoles. In contrast, the five membered thiazolidine ring is formed in reactions of pyridine-2-thiones. In both cases the product is a five-membered ring fused to a six-membered heterocycle.

Full text of DOI:10.1039/b207854f

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Reactions of 5-mercaptoazoles and pyridine-2-thiones with
acetylenic esters. Selectivity of the formation of novel fused
thiazin-4-ones and thiazolidin-4-ones
Vasiliy A. Bakulev,*a Vera S. Berseneva,a Natalia P. Belskaia,a Yury Yu. Morzherin,a
Andreiy Zaitsev,a Wim Dehaen,*b Ingrid Luytenb and Suzanne Toppetb
a Department of Technology and Organic Synthesis, The Urals State Technical University,
620002, Ekaterinburg, Russia. E-mail: primavera@ural.org; Fax: ϩ7 3432 420086
b Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
E-mail: wim.dehaen@chem.kuleuven.ac.be; Fax: ϩ32 16 32 79 90
Received 12th August 2002, Accepted 15th October 2002
First published as an Advance Article on the web 5th December 2002
A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate with
5-mercaptoazoles and pyridine-2-thiones has been carried out and as a result, a number of novel imidazo[1,5-b]-
thiazin-4-ones 6a,b, pyrazolo[1,5-b] thiazin-4-ones 15a–f, imidazo[1,5-b]thiazol-4-ones 7a,b and thiazolo[3,2-a]-
pyridines 21a–c have been prepared. The influence of the size of the ring of the starting “cyclic” thioamides on the
size of the fused ring in the reaction products has been established. The preferred formation of a six-membered
thiazine ring took place in the reactions of 5-mercaptoazoles. In contrast, the five membered thiazolidine ring is
formed in reactions of pyridine-2-thiones. In both cases the product is a five-membered ring fused to a six-membered
heterocycle.
reactions of 5-mercaptoimidazoles, -pyrazoles, -1,2,3-triazoles
and tetrahydropyridine-2-thiones with DMAD and methyl
Introduction
The reactions of thioureas, thiosemicarbazides and thioamides
propynoate.
with electron poor acetylenes are known as convenient and
effective methods to prepare thiazolidin-4-ones and thiazin-4-
ones.1–12 The most probable mechanism of these reactions
involves the addition of the sulfur atom of the thiocarbamoyl
moiety onto the triple bond of the acetylenes, followed by
cyclocondensation of the intermediate vinylthioimidates of
type 2 via elimination of a molecule of methanol. Reactions of
thioamides of various natures with DMAD have been shown to
occur via one of two possible mechanisms where generally the
α-situated ester group participates in the cyclization leading to a
five-membered thiazolidine ring 3.3,4,6,10–12 An alternative possi-
Results and discussion
Reaction of 5-mercaptoimidazole-4-carboxamide 5a with
DMAD in principle could give both thiazine 6a and thiazol-
idine 7a rings. We have found that this reaction in methanol at
room temperature results in the exclusive formation of fused
thiazine 6a in 66% yield. However, a mixture of thiazine 6a and
thiazolidine 7a in a ratio of 7 to 3 was obtained when sodium
methoxide was used as a catalyst. It should be noted that com-
pound 5a did not react with methyl propynoate in either
circumstances.
bility for the cyclization of intermediate 2 (R2 ᎐ H) involves the
᎐
reaction of the β-ester group to afford a thiazin-4-one ring.4,6,10
The respective thiazin-4-one and thiazolin-4-one structures
of products 6a and 7a are confirmed by their 1H and 13C NMR
1
spectral data (Experimental section, Table 1). The H NMR
spectra for both products are very similar but all signals of
thiazine 6a are shifted 0.14–0.18 ppm downfield in comparison
with those of 7a. The signals in the 13C NMR spectra are also
1
very similar for both isomeric products 6a and 7a. The H
coupled 13C NMR spectra of 6a and 7a show doublet signals at
1
119.0 and 118.8 ppm, respectively, with similar JCH coupling
constants of 175 Hz, which is typical for CC units. The final
decision in favor of the thiazolidine structure for 7a and thia-
zine for 6a can be made after considering the magnitudes of
the 13C–1H coupling constants in the 13C NMR spectra.2,11,12
The C6 and C4 signals of 7a are found in the coupled spectrum
2
as doublets with JC6–H5 coupling constants of 1.4 Hz and
In previous work, we have shown that novel 2,5-di-
methylenethiazolidin-4-one derivatives can be prepared by reac-
tion of malonthioamide derivatives with DMAD11 and a new
synthetic approach to conjugated bicyclic heterocycles has been
elaborated based on a similar reaction of heterocyclic thio-
amides.12 Reactions of heterocyclic compounds where an endo-
cyclic thioamide group is present with DMAD and methyl
propynoate have only been reported once.4 In order to find
a general synthetic method to thiazin-4-ones and thiazolin-
4-ones fused to azole and azine rings we have studied the
3JC4–H5 of 4.8 Hz. This shows the presence of an exocyclic double
bond in the structure of thiazolidine 7a. In contrast to this, the
coupled spectrum of 6a contains a doublet signal for C4 with a
2JC4–H5 coupling constant of 1.4 Hz, which confirms the structure
of 6a as thiazin-4-ones.
In contrast to 5a, 5-mercapto-1,2,3-triazole-4-carboxamide
does not react with DMAD and methyl propynoate. All our
attempts to involve this compound in these reactions failed. We
have shown that 5-mercapto substituted imidazole-4-thio-
carboxamides can react with DMAD to form 2-imidazolyl-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
134

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thiazolidines.12 Therefore, we expected from the reaction of
thioamide 5b with DMAD the formation of the products of
type 6–9 from the condensation with both the exocyclic and
endocyclic thioamide groups.
We have found that reaction of 5b with DMAD in methanol,
either with or without sodium methoxide, affords a mixture of
thiazine 6b and thiazolidine 7b in a ratio of 9 to 1 in 50% yield.
The 1H and 13C NMR spectra of products 6b, 7b are very simi-
lar to those of 7a and 7b (See Table 1). The downfield shift
(0.5– 0.6 ppm) of the signals of C8–H of 6b, 7b in comparison
with the conjugated imidazolylthiazolidines12 also confirmed the
formation of fused imidazoles in this reaction. The 13C NMR
spectra of 7a and 7b contain signals at 186.8 and 187.3 ppm
corresponding to signals of the unchanged thioamide groups.
We have found that 5-mercapto-1,2,3-triazole-4-thiocarb-
oxamides 10 are less active in the reaction with DMAD in
comparison with 5-mercaptoimidazoles. Triazoles, that are
unsubstituted at the ring nitrogen did not react either with
DMAD or methyl propynoate. On the other hand 1-R-5-
mercapto-1,2,3-triazoles reacted with both DMAD and methyl
propynoate to form vinyl sulfide derivatives 11. The presence of
two ester groups and a vinyl moiety in compounds 11 was con-
firmed by the presence of two signals in their 1H NMR spectra
at 3.45–3.76 ppm, signals at 6.69 and 6.70 in spectra of 11a,b
respectively and of doublet signals at 6.10 and 7.25 with vicinal
coupling constant of 8.6 Hz in spectra of 11c. We did not man-
age to react compounds 11a–c with a further equivalent of
DMAD, although 11c smoothly reacted with o-nitrophenacyl
bromide to give 2-triazolylthiazole 12 in 74% yield.
Indeed, reaction of DMAD with 5-mercaptoazole-4-thio-
carboxamides 5b,10a,b preferably occurs with participation of
the endocyclic thioamide group, similar to the reaction of these
compounds with alkylating agents.13,14 This can be rationalized
by the existence of 5b,10 in a zwitterionic tautomeric form
where the negative charge is located at the 5-sulfur atom which
should enhance an electrophilic attack to this center.
In the reaction of 4-arylhydrazonopyrazole-5-thiones 13
with esters of acetylenecarboxylic acids one can theoretically
expect the formation at least 4 products 15–18 because both
thioamide and hydrazono groups of 13 are known to react with
DMAD.10–12,15 If we suppose that the most nucleophilic sulfur
atom reacts first with the acetylene to form an intermediate
vinylthioimidate of type 14 then the direction of its cyclization
will govern the composition of the products 15–18.
We have found that compounds 13a–f readily react with
DMAD and methyl propynoate to form 15a–f as the only
products in good yields. The assignments of the structures of
compounds 15 as pyrazolo[1,5-b]thiazin-4-ones follows from
1
the analysis of their H and 13C NMR spectra and from the
reaction of 15d with sodium dithionite. Mass spectra, and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
135

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decoupled 1H and 13C NMR spectra did not allow one to make
a difference between structures 15–18. At the same time, the
similarity of the NMR spectra for the products obtained in
the reaction of DMAD and methyl propynoate allowed us to
assume that the same type of product was formed in both types
of reactions. The spectrum of 15f shows two doublets as an AB
system with a coupling constant of 10.6 Hz which is typical for
a CH᎐CH moiety. The C and C7 signals in the coupled
᎐
4
spectrum of 15d are found at δ = 154.9 ppm as doublets with a
2JC4–H5 coupling constant of 0.6 Hz and at 161.9 ppm with
3JC7–H5 of 3.8 Hz, respectively. These data allowed us to rule the
structures 16 and 17 out of consideration, since one should
observe an AB system in their spectra with a geminal constant of
18–22 Hz and a higher magnitude (2–5 Hz) for the coupling
constant JC4–H5
.
An additional argument in favor of structure 15 was made
from reduction of compound 15d by sodium dithionite. The
arylhydrazino derivative 19 was obtained, and hydrazines are
typical reduction products of arylazo compounds. This finally
eliminates structures 17 and 18.
Thus, the novel imidazo[1,5-b]thiazin-4-ones 6a,b, pyrazolo-
[1,5-b]thiazin-4-ones 15a-f and imidazo[1,5-b]thiazole-4-ones
7a,b have been prepared by reactions of 5-mercaptoazoles with
DMAD and methyl propynoate.
To study whether the size of the ring formed in the reaction
of endocyclic thioamides with acetylene carboxylic esters
depends on the type of ring in the starting compounds, we have
carried out the reaction of 3,4-dihydropyridine-2(1H)-thiones
20a–c with DMAD.
Reaction of 2(1H )-pyridinethiones with DMAD is known to
give thiazolo[3,2-a]pyridinium salts. At the same time, the reac-
tion of 2(1H )-pyridinethiones with methyl propynoate results
in the acyclic condensation products.16–18 3,4-Dihydropyridin-
2(1H )-ones have not been reacted with acetylene carboxylic
acids so far.
constant of 5.6 Hz with the vinyl proton, and of C7 with a 2JCH
By analogy with the reactions of malonthioamides and with
the chemistry of the 5-mercaptoazoles mentioned above, one
can expect the formation of both pyridothiazoles of type 21
and pyridothiazines 22 from the reaction of compounds 20
with DMAD. We have found that the reaction of pyrid-
inethiones 20a–c with DMAD in chloroform in the presence of
triethylamine selectively affords thiazolo[3,2-a]pyridines 21a–c
in good yields. The structure assignment of the compounds
prepared follows from their NMR spectra. 1H NMR spectra of
21a–c show signals at 6.65–6.78 ppm and the coupled 13C NMR
coupling constant of less than 1.0 Hz with the same vinyl pro-
ton. This is in accordance with the presence of an exocyclic
double bond in the structures of compounds 21a–c. Further-
3
more, the magnitude of the constant JC4–H5 confirms the
(Z)-configuration of this bond.
Conclusion
The data obtained allows us to make some conclusions. The
size of the rings formed in the reactions of cyclic thioamides
3
spectrum of 21c contains doublets of C4 with a JCH coupling
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
136

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methanol (10 mL) or chloroform (10 mL) with triethylamine
(0.001 mol). The reaction mixture was stirred at room temper-
ature for 1–3 h until, according to TLC, all the starting material
had disappeared. On cooling, a precipitate was formed, which
was filtered off and crystallized from methanol to afford the
pure product.
8-Carbamoyl-2-methoxycarbonyl-4-oxo-4H-imidazo[5,1-b]-
[1,3]thiazine (6a). From 5-mercaptoimidazole-4-carboxamide
5a19 and DMAD. Yield 66% (method A), 43%. (method B).
Yellow crystals, mp 218–221 ЊC. Mass spectrum, m/z (%): 253
(50) Mϩ . Found, %: C 42.55; H 2.90; N 16.93; S 12.21.
ؒ
C9H7N3O4S. Calcd, %: C 42.69; H 2.79; N 16.60; S 12.65;
δH (DMSO-d ) 3.97 (3H, s, OCH ), 7.24 (1H, s, ᎐ C H), 7.63
᎐
6
3
(5)
(1H, s, NH), 7.83 (1H, s, NH), 8.80 (1H, s, ᎐ C H).
᎐
(8)
Methyl 2-(7-carbamoyl-3-oxoimidazo[5,1-b]thiazol-2-ylidene)
acetate (7a). From 5-mercaptoimidazole-4-carboxamide 5a and
DMAD, method B. The precipitate, that was insoluble in hot
methanol, was washed by methanol and dried. Yellow crystals,
yield 60%. Mp 252–262 ЊC (decomp.). Mass spectrum, m/z (%):
with acetylenecarboxylic esters depends on the size of the
starting heterocycle. Thus, a five-membered thiazolidine ring
condenses onto the pyridine ring and a six-membered thiazine
ring is fused onto a five-membered azole ring. In contrast to
all reactions of thioamides of various structures,9–12 includ-
ing reactions of pyridinethiones with DMAD where the
thiazolidin-4-ones are formed exclusively, the reactions of
5-mercaptoazoles with acetylenecarboxylic esters lead to the
preferred formation of a six-membered thiazine ring. This
exception to the general rule can be explained by the increased
ring strain for two fused five-membered rings compared to a
situation where a six-and five-membered ring are fused. This
also implies that the reactions are under thermodynamic rather
than kinetic control.
253 (100) Mϩ .Found, %: C 42.60; H 2.70; N 16.04; S 12.23.
ؒ
C9H7N3O4S. Calcd, %: C 42.69; H 2.79; N 16.60; S 12.65;
δH (DMSO-d ) 3.79 (3H, s, OCH ), 7.07 (1H, s, ᎐ C H), 7.45
᎐
6
3
(5)
(1H, s, NH), 7.65 (1H, s, NH), 8.63 (1H, s, ᎐ C H).
᎐
(8)
2-Methoxycarbonyl-4-oxo-8-thiocarbamoyl-4H-imidazo-
[5,1-b][1,3]thiazine (6b) and methyl (3-oxo-7-thiocarbamoyl-
imidazo[5,1-b]thiazol-2-ylidene) acetate (7b). Obtained as a
mixture from 5-mercaptoimidazole-4-thiocarboxamide 5b19
and DMAD, yield 48% (method B). Yellow crystals, mp 268–
270 ЊC (decomp.). Mass spectrum, m/z (%): 269 (100) Mϩ
.
ؒ
Found, %: C 40.40; H 2.69; N 15.29; S 23.88. C9H7N3O3S2.
Calcd, %: C 40.14; H 2.62; N 15.60; S 23.81; 6b δH (DMSO-d6)
Experimental
General
3.97 (3H, s, OCH ), 7.27 (1H, s, ᎐ C H), 8.86 (1H, s, ᎐ C H),
9.41 (1H, s, NH), 9.70 (1H, s, NH); 7b δH (DMSO-d6) 3.76 (3H,
᎐
᎐
3
(5)
(8)
1H and 13C spectra were recorded at 400 and 100 MHz,
respectively on a Bruker AMX 400 with SiMe4 as an internal
reference in ether DMSO-d6 ϩ CCl4 or CDCl3 solutions.
Mass spectra were obtained on a Varian MAT 311A instrument
using the electron impact ionization technique (40–200 ЊC,
70 eV). Reactions were monitored by TLC (Silufol®) on
aluminium foil plates) in CHCl3–EtOH (9 : 1), CHCl3–EtOH–
NH4OH (15 : 8 : 1), acetone–hexane (3 : 5) visualized under UV
light. All solvents were distilled prior to use.
s, OCH ), 6.93 (1H, s, ᎐ C H), 8.70 (1H, s, ᎐ C H), 9.42 (1H, s,
᎐
᎐
3
(5)
(8)
NH), 9.70 (1H, s, NH).
Dimethyl 2-(3-methyl-5-thiocarbamoyl-3H-[1,2,3]triazol-4-yl-
thio)but-2-enedioate (11a). From 1-methyl-5-mercapto-1,2,3-
triazole-4-thiocarboxamide 10a20 and DMAD, yield 43%
(method A). Yellow crystals, mp 175–178 ЊC. Mass spectrum,
m/z (%): 316 (60) Mϩ . Found, %: C 37.70; H 3.91; N 17.72;
ؒ
S 20.65. C10H12N4O4S2. Calcd, %: C 37.97; H 3.82; N 16.70;
S 20.27; δH (DMSO-d6) 3.48 (3H, s, OCH3), 3.76 (1H, s, OCH3),
General procedure. For reaction of 5-mercaptoazoles and
pyridine-2-thiones with esters of acetylenecarboxylic and
propiolic acids.
4.08 (3H, s, NCH ), 6.69 (1H, s, ᎐CH), 9.50 (1H, s, NH), 9.72
᎐
3
(1H, s, NH).
Dimethyl 2-(5-thiocarbamoyl-3-phenyl-3H-[1,2,3]triazol-4-yl-
thio)but-2-enedioate (11b). From 1-phenyl-5-mercapto-1,2,3-
triazole-4-thiocarboxamide 10b20 and DMAD, yield 44%
(method A). Yellow crystals, mp 100–105 ЊC (ethanol). Found,
%: C 47.85; H 3.91; N 14.44; S 17.32. C15H14N4O4S2. Calcd, %:
C 47.61; H 3.73; N 14.81; S 16.93; δH (DMSO-d6) 3.45 (3H, s,
Method A. The acetylenecarboxylic ester (0.0015 mol) was
added to a suspension of mercaptoheterocycle (0.001 mol) in
methanol (10 mL). The reaction mixture was stirred at room
temperature for 2–20 h until, according to TLC, all the starting
materials had disappeared. On cooling, a precipitate was
formed, that was filtered off and crystallized from methanol to
afford the pure product.
OCH ), 3.74 (3H, s, OCH ), 6.70 (1H, s, ᎐CH), 7.20–7.45 (5H,
᎐
3
3
m, Ph), 9.53 (1H, s, NH), 9.79 (1H, s, NH).
Method B. The acetylenecarboxylic ester (0.0015 mol) was
added to a solution of mercaptoheterocycle (0.001 mol) and
sodium methoxide in methanol, which was prepared from Na
(23 mg, 0.001 mol) and methanol (5 mL). The reaction mixture
was stirred at room temperature for 8–10 h until, according to
TLC, all the starting materials had disappeared. On cooling, a
precipitate was formed, which was filtered off and the product
was extracted with hot methanol. After cooling, the precipitate
was collected.
Methyl 2-(3-methyl-5-thiocarbamoyl-3H-[1,2,3]triazol-4-yl-
thio)acrylate (11c). From 1-methyl-5-mercapto-1,2,3-triazole-4-
thiocarboxamide 10a and methyl propynoate, yield 43%
(method A). Yellow crystals, mp 167–170oC (from ethanol).
Mass spectrum, m/z (%): 258 (71) Mϩ . Found, %: C 36.78; H
ؒ
4.0; N 22.14. C8H10N4O2S2. Calcd, %: C 37.2; H 3.88; N 21.71;
δH (DMSO-d6) 3.78 (3H, s, OCH3), 4.04 (3H, s, NCH3),
6.10(1H, d, J = 8.6 Hz, ᎐CH), 7,25 (1H, d, 8.6, ᎐CH), 9.56 (1H,
᎐
᎐
s, NH), 9.80 (1H, s, NH).
Method C. The acetylenecarboxylic ester (0.0015 mol) was
added to a suspension of mercaptoheterocycle (0.001 mol) in
Methyl
2-{3-methyl-5-[4-(2-nitrophenyl)thiazol-2-yl]-3H-
(0.001 mol)
[1,2,3]triazol-4-ylthio}acrylate (12). 0.245
g
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
137

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o-nitrophenacyl bromide was added to a suspension of 0.316 g
(0.001 mol) triazole 11c in 10 mL ethanol. The reaction mixture
was refluxed for 1 h. After cooling, the precipitate was filtered
off. The product was crystallized from ethanol. Yield 74%, mp
180–183 ЊC. Found, %: C 47.62; H 3.50; N 17.74; S 16.32.
C16H15N5O4S2. Calcd, %: C 47.63; H 3.25; N 17.36; S 15.88;
δH (DMSO-d6) 3.79 (3H, s, OCH3), 4.14 (3H, s, NCH3),
2.34 (3H, s, Me), 3.88 (3H, s, COOMe), 6.82 (1H, dd, J = 7.5,
J = 7.3 Hz, H17), 6.84 (2H, d, J = 7.5 Hz, H13, H14), 7.01(1H, s,
C(5)H), 7.14 (2H, dd, J = 7.5, J = 7.3 Hz, H15H16), 7.44 (1H, s,
NH), 7.80 (1H, s, NH).
Methyl (5-amino-8-carbamoyl-3-oxo-7-phenyl-6-cyano-7H-
thiazolo[3,2-a]pyridin-2-ylidene)acetate (21a). From pyridin-
ethione 20a21 and DMAD in chloroform, yield 42% (method
C). Yellow crystals, mp 305–307 ЊC. Found, %: C 56.56; H 3.75;
N 14.60; S 8.95. C18H14N4O4S. Calcd, %: C 56.54; H 3.69; N
14.69; S 8.41; δH (DMSO-d6) 3.81 (3H, s,OCH3), 4.76 (1H, s,
CH), 6.66 (1H, s, C(5)H), 7.25–7.35 (5H, m, ArH), 7.27 (2H, s
NH2).
6.19(1H, d, J = 9.6, ᎐CH), 7.40 (1H,d, J = 9.6 Hz, ᎐CH), 7.73
᎐
᎐
(1H, t, ArH), 8.15–8.22 (1H, m, ArH), 8.35–8.41 (1H, m, ArH),
8.50 (1H, s, Hthiazole), 8.77 (1H, t, ArH).
5-Methoxycarbonyl-3-(4-methoxyphenylazo)-2-methyl-7-oxo-
7H-pyrazolo[5,1-b][1,3]thiazine (15a). From pyrazole 13a and
DMAD in methanol by method C, yield 73%, mp 218–220 ЊC.
Found, %: C, 53.81; H, 4.01; N, 15.71; S, 9.00. C16H14N4O4S.
Calcd, %: C, 53.63; H, 3.91; N, 15.64; S, 8.94; δH (DMSO-d6)
2,59 (3H, s, Me), 3.89 (3H, s, OMe), 4.0 (3H, s, COOMe),
7.33 (1H, s, C(5)H), 7.81 and 7.04 (4H, AAЈXXЈ, J = 9.3 Hz,
ArH).
Methyl (5-amino-8-carbamoyl-3-oxo-7-thienyl-6-cyano-7H-
thiazolo[3,2-a]pyridin-2-ylidene)acetate (21b). From pyridin-
ethione 20b21 and DMAD in chloroform, yield 71% (method
C). Yellow crystals, mp 292–295 ЊC. Found, %: C 49.55; H 3.02;
N 14.93; S 16.00. C16H12N4O4S2. Calcd, %: C 49.48; H 3.11; N
14.42; S 16.51; δH (DMSO-d6) 3.80 (3H, s, OCH3), 5.18 (1H, s,
5-Methoxycarbonyl-2-methyl-7-oxo-3-p-tolylazo-7H-pyra-
zolo[5,1-b][1,3]thiazine (15b). From pyrazole 13b and DMAD
in methanol by method C, yield 80%, mp 183–185 ЊC. Found,
%: C, 56.25; H, 4.12; N, 16.52; S, 9.50. C16H14N4O3S. Calcd, %:
C, 56.14; H, 4.09; N, 16.37; S, 9.36; δH (DMSO-d6) 2,44 (3H, s,
Me), 2.70 (3H, s, Me), 3.99 (3H, s, COOMe), 7.36 (1H, s, C(5)H),
7.74 and 7.33 (4H, AAЈXXЈ, J = 8.0 Hz, ArH).
CH), 6.67 (1H, s, ᎐C H), 6.92–6.94 (1H, m, Hthienyl), 7.03–7.04
᎐
(5)
(1H, m, NH), 7.28–7.31 (2H, m, Hthienyl), 7.33 (1H, s, NH), 7.43
(2H, s, NH2).
Methyl (5-amino-8-ethoxycarbonyl-3-oxo-7-thienyl-6-cyano-
7H-thiazolo[3,2-a]pyridin-2-ylidene)acetate (21c). From pyrid-
inethione 20c22 and DMAD in chloroform, yield 48% (method
C). Yellow crystals, mp 249–252 ЊC. Found, %: C 51.98; H 3.55;
N 10.51; S 14.95. C18H15N3O5S. Calcd, %: C 51.79; H 3.62; N
10.06; S 15.36; δH (DMSO-d6) 1.21 (3H, t, CH3), 3.83 (3H, s,
OCH3), 4.18 (2H, q, CH2), 4.86 (1H, s, CH), 6.77 (1H, s,
5-Methoxycarbonyl-2-methyl-7-oxo-3-phenylazo-7H-pyra-
zolo[5,1-b][1,3]thiazine (15c). From pyrazole 13c and DMAD
by method C, yield 69%, mp 198–200 ЊC. Found, %: C, 55.01;
H, 3.71; N, 17.07; S, 9.81. C15H12N4O3S. Calcd, %: C, 54.85; H,
3.66; N, 17.15; S, 9.76; δH (DMSO-d6) 2,71 (3H, s, Me), 3.99
(3H, s, COOMe), 7.52 (1H, s, C(5)H), 7.3–7.26 (3H, m, ArH),
7.84 (2H, dd, J = 8.3, J = 2.3 Hz, ArH).
᎐C H), 6.90–6.95 (2H, m, Hthienyl), 7.25–7.30 (1H, m, Hthienyl),
᎐
(5)
7.35 (2H, s, NH2).
General method for the synthesis of arylazopyrazolethiones 13a-e
Arylazopyrazolones23 (0.004 mol) were refluxed about 30 min
in toluene (50 mL) with Lawesson’s reagent (0.0022 mol). The
solution was cooled and the solid filtered off. The product was
crystallized from ethanol.
3-(4-Chlorophenylazo)-2-methyl-7-oxo-7H-pyrazolo[5,1-b]-
[1,3]thiazine-5-carboxylic acid methyl ester (15d). From
pyrazole 13d and DMAD by method C, yield 85%, mp 224–
226 ЊC. Found, %: C, 49.83; H, 3.10; N, 15.37; S, 8.75.
C15H11ClN4O3S. Calcd, %: C, 49.66; H, 3.03; N, 15.45; S,
8.83; δH (DMSO-d6) 2.71 (3H, s, Me), 3.99 (3H, s, COOMe),
7.39 (1H, s, C(5)H), 7.85 and 7.54 (4H, AAЈXXЈ, J = 8.8 Hz,
ArH).
4-(4-Methoxyphenylazo)-5-methyl-2,4-dihydropyrazole-3-
thione (13a). Yield 81%, mp 201–202 ЊC. Mass spectrum, m/z
(%): 248 (78) Mϩ .Found, %: C 53.45; H 4.77; N, 22.58; S,
ؒ
12.90. C11H12N4OS. Calcd, %: C 53.21; H 4.87; N, 22.67; S,
13.00; δH (DMSO-d6) 2.26 (3H, s, Me), 3.89 (3H, s, OMe), 7.52
and 7.01 (4H, AAЈBBЈ, J = 8.8 Hz, ArH), 12.99 (1H, s, NH),
16.78 (1H, s, NH).
3-(4-Ethoxycarbonylphenylazo)-5-methoxycarbonyl-2-methyl-
7-oxo-7H-pyrazolo[5,1-b][1,3]thiazine (15e). From pyrazole 13e
and DMAD by method C, yield 71%, mp 195–197 ЊC. Found,
%: C, 53.82; H, 3.93; N, 14.10; S, 7.93. C18H16N4O5S. Calcd, %:
C, 54.00; H, 4.00; N, 14.00; S, 8.00; δH (DMSO-d6) 1.41 (3H, t,
7.0, CH2CH3), 2.72 (3H, s, Me), 4.00 (3H, s, COOMe), 4.37
(2H, q, J = 7.0 Hz, OCH2), 7.39 (1H, s, C(5)H), 8.09 and 7.88
(4H, AAЈXXЈ, J = 8.5 Hz, ArH).
4-(4-Methylphenylazo)-5-methyl-2,4-dihydropyrazole-3-
thione (13b). Yield 85%, mp 190–193 ЊC. Mass spectrum, m/z
(%): 232 (50) Mϩ .Found, %: C 56.69; H 5.37; N, 24.14; S,
ؒ
13.79. C11H12N4S. Calcd, %: C 56.87; H 5.21; N, 24.03; S, 13.86;
δH (DMSO-d6) 2.38 (3H, s, Me), 2.53 (3H, s, Me), 7.59 and 7.27
(4H, AAЈBBЈ, J = 8.8 Hz, ArH), 13.00 (1H, s, NH), 16.70 (1H,
s, NH).
3-(4-Chlorophenylazo)-2-methyl-7H-pyrazolo[5,1-b][1,3]thi-
azin-7-one (15 f). From pyrazole 13d and methyl propynoate in
ethanol by method C, yield 73%, mp 248–249 ЊC. Found, %: C,
51.40; H, 3.11; N, 18.10; S, 10.71. C18H16N4O5S. Calcd, %: C,
51.23; H, 2.96; N, 18.39; S, 10.51; δH (CDCl3) 2.81 (3H, s, Me),
7.73 and 6.85 (2H, AAЈXXЈ, J = 10.6 Hz, C(5)H ϩC(6)H), 7.84
and 7.49 (4H, AAЈXXЈ, J = 8.4 Hz, ArH).
4-Phenylazo-5-methyl-2,4-dihydropyrazole-3-thione
(13c).
Yield 83%, mp 171–172 ЊC. Mass spectrum, m/z (%): 218 (75)
Mϩ . Found, %: C 55.15; H 4.80; N, 25.69; S, 14.68. C10H10N4S.
ؒ
Calcd, %: C 55.03; H 4.62; N, 25.71; S, 14.90; δH (DMSO-d6)
2.26 (3H, s, Me), 7.27 (1H, dd, J-7.5, J = 7.3 Hz, ArH), 7.44
(2H, dd, J = 7.5, J = 7.3 Hz, ArH), 7.56 (2H, d, J = 7.7 Hz,
ArH), 13.03 (1H, s, NH), 16.58 (1H, s, NH).
5-Methoxycarbonyl-2-methyl-7-oxo-3-(2-phenylhydrazino)-
7H-pyrazolo[5,1-b][1,3]thiazine (19). A mixture of sodium
dithionite (0.4 g, 0.0023 mol) and azo compound 15c (0.3 g,
0.0009 mol) in acetone (40 mL) and water (10 mL) was refluxed
for 3 hours. The solvents were evaporated and the residue was
crystallized from MeOH–DMF. Yield 30%, mp 175–176 ЊC.
Found, %: C, 54.55; H, 4.24; N, 16.97; S, 9.70. C15H14N4O3S.
Calcd, %: C, 54.40; H, 4.11; N, 17.14; S, 9.91; δH (DMSO-d6)
4-(4-Chlorophenylazo)-5-methyl-2,4-dihydropyrazole-3-thione
(13d). Yield 93%, mp 205–208 ЊC. Mass spectrum, m/z (%): 252
(85) Mϩ . Found, %: C 47.33; H 3.88; N, 22.18; S, 12.67.
ؒ
C10H9ClN4S. Calcd, %: C 47.53; H 3.59; N, 22.11; S, 12.80;
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
138

View Article Online
6 S. Coen, B. Ragonnet, C. Vieillescares and J. P. Roggero,
Heterocycles, 1985, 23, 1225.
7 N. D. Abramova and B. V. Trzhtsinskaya, Khim. Geterotsikl.
Soedin., 1988, 12, 1587.
8 V. Ya. Kauss, E. E. Liepinsh, I. Ya. Kalvinsh and E. Lukevits,
Khim. Geterotsikl. Soedin., 1990, 120.
9 G. Giammona, M. Neri, A. Pazzo and C. La Rosa, J. Heterocycl.
Chem., 1991, 28, 325.
10 V. S. Berseneva, N. Yu. Biryucheva and V. A. Bakulev,
Khim. Geterotsikl. Soedin., 1993, 1688.
11 V. S. Berseneva, A. V. Tkachev, Yu. Yu. Morzherin, W. Dehaen,
I. Luyten and V. A. Bakulev, J. Chem. Soc., Perkin Trans. 1, 1998,
2133.
δH (DMSO-d6) 2.30 (3H, s, Me), 7.75 and 7.56 (4H, AAЈBBЈ,
J = 8.8 Hz, ArH), 13.10 (1H, s, NH), 16.55 (1H, s, NH).
4-(4-Ethoxycarbonylphenylazo)-5-methyl-2,4-dihydropyrazole-
3-thione (13e). Yield 85%, mp 195–197 ЊC. Mass spectrum, m/z
(%): 290 (89) Mϩ .Found, %: C 54.01; H 4.98; N, 19.31; S,
ؒ
11.09. C13H14N4O2S. Calcd, %: C 53.78; H 4.86; N, 19.54; S,
11.35; δH (DMSO-d6) 1.38 (3H, q, J = 7.0 Hz, CH2CH3), 2.26
(3H, s, Me), 4.32 (2H, q, J = 7.0 Hz, CH2CH3), 8.02 and 7.60
(4H, AAЈBBЈ, J = 9.0 Hz, ArH), 13.21 (1H, s, NH), 16.43 (1H,
s, NH).
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14 E. D. Shtephan and V. Yu. Vvedenskii, Uspekhi Khimii, 1996, 65,
326.
15 A. Reliquet, R. Besbes, F. Reliquet and J. C. Meslin, Synthesis, 1991,
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16 J. Becher and C. C. Stidsen, Sulfur Reports, 1988, 8, 105.
17 R. Lie and K. Undheim, Acta Chem. Scand., 1973, 27, 1756.
18 K. Undheim and L. A. Riege, J. Chem. Soc., Perkin Trans. 1, 1975,
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Acknowledgements
W. D. thanks the F. W. O.-Vlaanderen, the Ministerie voor
Wetenschapsbeleid and the University of Leuven for financial
support. V. S. B. and V. A. B. thank the Russian Foundation
for Basic Research (grant 01-03-33173) and CRDF (grant
Rec 005).
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 – 1 3 9
139