Reaction of heterocyclic thioamides with dimethyl acetylenedicarboxylate. Synthesis of novel 2-azolyl-5-methoxycarbonylmethylene thiazolin-4-ones

Article abstract of DOI:10.1016/S0040-4020(01)00049-7

A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) with heterocyclic thioamides has been carried out and a number of new 2-isoxazolyl-(8), imidazolyl-(13a,b and 17a), 1,2,3-triazolyl-(13d,e) and 1,2,3-thiadiazolyl (17b) thiazolines have been prepared. The higher reactivity of the thioamide group in comparison with the amino group in these reactions has been established.

Full text of DOI:10.1016/S0040-4020(01)00049-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2179±2184
Reaction of heterocyclic thioamides with dimethyl
acetylenedicarboxylate. Synthesis of novel
2-azolyl-5-methoxycarbonylmethylene thiazolin-4-ones
Vera S. Berseneva,a Yury Yu. Morzherin,a Wim Dehaen,b,p Ingrid Luytenb
and Vasiliy A. Bakuleva,p
aDepartment of Technology and Organic Synthesis, The Urals State Technical University, 620002 Ekaterinburg, Russian Federation
bDepartment of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Received 16 November 2000; revised 3 January 2001; accepted 10 January 2001
AbstractÐA systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) with heterocyclic thioamides has been carried
out and a number of new 2-isoxazolyl-(8), imidazolyl-(13a,b and 17a), 1,2,3-triazolyl-(13d,e) and 1,2,3-thiadiazolyl (17b) thiazolines have
been prepared. The higher reactivity of the thioamide group in comparison with the amino group in these reactions has been established.
q 2001 Elsevier Science Ltd. All rights reserved.
The reaction of thioureas and thiosemicarbazide derivatives
with dimethyl acetylene dicarboxylate (DMAD) is known as
a convenient and effective method to prepare 2-imino-5-
methoxycarbonylthiazolidin-4-ones.1±4 The reactions of
thioamides with DMAD are studied to a lesser extent,2,5,6
and a general strategy to prepare thiazoline derivatives
based on this reaction was not developed before our work
on the subject.7 Earlier we have shown that the reaction of
thiocarbamoyl pyridinium and isoquinolinium ylides 1 with
esters of acetylenecarboxylic acids, depending on the nature
of the acetylene, leads to formation of ®ve- or six-membered
rings to give ylides containing thiazolinone 3 and thiazinone
moieties 4.6 The proof that the ®rst step of the overall
process includes addition of the sulfur atom onto the
Scheme 1.
Keywords: dimethyl acetylene dicarboxylate; thioamides; thiazoline.
Corresponding authors. Fax: 132-16-32-79-90; e-mail: wim.dehaen@chem.kuleuven.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00049-7

2180
V. S. Berseneva et al. / Tetrahedron 57 (2001) 2179±2184
Table 1. 1H Chemical shifts, d (ppm)
No.
Solvent
1H Chemical shifts
8
12g
13a
CDCl3
DMSO-d6
DMSO-d6
2.97 (3H, s, CH3), 3.80 (3H, s, OCH3), 7.04 (1H ,s, vCH), 7.5±7.6 (5H, m)
2.52 (3H, s, CH3), 7.85 (1H, s, v CH)
1.32 (3H, t, CH3); 3.25 (2H, q, CH2); 3.80 (3H, s, OCH3); 6.85 (1H, s, v CH);
8.15 (1H, s, v CH)
13b
DMSO-d6
3.8 (3H, s, OCH3), 4.53 (2H, q, CH2); 6.87 (1H, s, v CH), 7.2±7.5(5H, m, ArH),
8.2 (1H, s, vCH)
13e
13f
CDCl3
DMSO-d6
2.7 (3H, s, SCH3), 3.9 (3H, s, OCH3), 4.2 (3H, s, NCH3), 7.2 (1H, s, v CH)
2.58 (3H, s, SCH3), 3.84 (3H, s, OCH3), 5.83 (2H, s, CH2), 7.04 (1H, s, vCH),
7.25±7.45 (5H, m, ArH)
15
16d
DMSO-d6
DMSO-d6
3.97 (3H, s, OCH3), 6.66 (1H, s, vCH), 8.6 (1H, s, vCH), 7.40 (2H, d br, NH)
3.78 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.06 (3H, s, OCH3),
5.40 (1H, s, NH), 5.65 (1H, s, vCH), 6.89 (1H, s, NH), 14.84 (1H, s, NH)
2.80 (3H, d br, NCH3), 3.71 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.91 (3H, s, OCH3),
3.96 (3H, s, OCH3), 5.57 (1H, s, vCH), 7.80 (1H, s br, NH)
3.78 (3H, s, OCH3); 6.68 (1H, s, vCH); 7.56 (1H, s, vCH); 7.78 (2H, s, NH2)
3.84 (3H, s, OCH3); 6.97 (1H, s, vCH); 9.15 (2H, s, NH2)
16e
DMSO-d6
17a
17b
DMSO-d6
DMSO-d6
acetylene triple bond comes from the study of this type of
ylides with ethyl propiolate. The intermediate product of
type 2, generated in the reaction of isoquinoline ylide and
ethyl propiolate undergoes 1,5-electrocyclization to give,
after oxidation, vinyl sul®de of type 5 (Scheme 1).
value of 7.04 ppm in the 1H NMR spectrum.7 The 1H
coupled 13C spectrum of 8 shows a doublet signal at
122.6 ppm with a coupling constant of 173.0 Hz, which is
typical for a CvCH fragment. Moreover, the signals of C4
and C7 at 180.8 and 165.7 ppm are more in agreement with
the thiazoline rather than with the thiazinone structure.7 In
the case of the thiazinone structure one could expect the
doublet signal at 108±112 ppm and the signals for C4 and
C7 should be up®eld at 165±160 and 158±161 ppm, respec-
tively.1,2 A ®nal decision in favor of the thiazolinone struc-
ture can be made after considering the magnitudes of the
13C±1H coupling constants in the 13C NMR spectrum.7 The
C7 signal in the coupled spectrum of 8 is found as a doublet
with a 2JCH coupling constant of 1.0 Hz, caused by the vinyl
proton. This shows the presence of the exocyclic double
bond in the structures of thiazoline. Furthermore, the
The formation of 2-substituted thiazolin-4-ones was also
observed in the reaction of both benzothioamide2 and conju-
gated enaminothioamides5 with DMAD. In previous work,
we have shown that novel 2,5-dimethylenethiazolidin-4-one
derivatives can be prepared by the reaction of malonthio-
amide derivatives with DMAD.7 The thioamides of hetero-
aromatic carboxylic acids have not been studied in the
reaction with DMAD so far. In order to ®nd a general
approach to bis-heterocyclic compounds containing the
thiazoline moiety, we have studied the reactions of azole-
carbothioamides with DMAD, using isoxazoles 6, imida-
zoles 12a,b and 14a, 1,2,3-triazoles 12d±g, and 1,2,3-
thiadiazole 14b.
3
constant JC(4)H(6) of 4.0 Hz clearly demonstrates the
Z-con®guration of the double bond C5vC6. In conclusion,
the NMR spectra are in full agreement with the thiazoline
structure for 8 and reject the thiazinone structure 7 (Scheme
2).
5-Methyl-3-phenylisoxazol-4-carbothioamide 6 was pre-
pared in 50% yield by the treatment of the corresponding
nitrile derivative with hydrogen sul®de. Reaction of
3-phenyl derivative 6 with DMAD in principle could give
either thiazinone 7 or thiazoline 8 derivatives. We have
found that this reaction in ethanol at room temperature
results in the exclusive formation of bis-heterocycle 8,
containing a thiazolin-4-one ring.
The 5(4)-mercaptoimidazol-4(5)-carbothioamide 9 contains
two sulfur atoms which each may react with the triple bond
of DMAD. To avoid the formation of the addition product of
the acetylene function with the mercapto group, we ®rst
alkylated compound 9, leading to sul®des 12a±c.
Compound 12c was also obtained by thionation of 5(4)-
methylthioimidazol-4(5)-carboxamide 11 with P4S10 in
boiling dioxane. This alternative synthesis proved the
structure of compounds 12a±c as 5-alkylmercaptoimida-
zole-5-carbothioamides (Scheme 3).
The structure of product 8 was identi®ed as a thiazolin-4-
one by 1H and 13C NMR spectroscopy (Tables 1 and 2). The
signal of the methine group resonates at a characteristic
Table 2. 13C Chemical shifts d (ppm, solvent) and JC±H (Hz)
No.
Solvent
13C Chemical shifts d
C2
C4
C5
C6
C7
1JC6±H6
2JC5±H6
2JC7±H6
,1.0
3JC4ÐH6
4.0
8
CDCl3
DMSO-d6
CDCl3
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
183.2 (s)
182.2
180.8 (d)
180.7
181.8
142.2 (d)
144.6
142.9
122.6
119.3
123.0 (d)
165.7
165.8
165.8
1.0
13b
13e
15
13f
17a
17b
167.0
,1.0
5.0
181.8
173.2
168.8
182.3
179.6
180.2 (d)
142.8
146.5
143.4 (d)
123.0
114.9 (d)
120.0
165.7
166.3
165.6
170.0
172.0
2.0
4.5

V. S. Berseneva et al. / Tetrahedron 57 (2001) 2179±2184
2181
Scheme 2.
We have found that 5(4)-mercaptosubstituted imidazol-
5(4)-carbothioamides 12a,b also react smoothly with
DMAD in chloroform to form 2-imidazolylthiazinones
1
13a,b in good yield. The H and 13C NMR spectral data
are, again in accordance with their structures as thiazolin-
4-ones (Tables 1 and 2, Scheme 4).
In contrast to imidazoles 12a,b, 1,2,3-triazole-4-carbothio-
amides 12d,e are unreactive towards DMAD. Only in the
case of N-alkylated triazole 12f,g we could obtain the
thiazolin-4-ones 13f,g in moderate yield. The lesser reac-
tivity of the triazolecarbothioamides 12d±g in comparison
with the imidazolyl derivatives 12a,b may be due to the
inductive effect of the extra nitrogen atom on the thioamide
functionality.
In the reaction of the 5-aminoimidazole-4-carbo(thio)-
amides 14a±e with DMAD one could expect the formation
of various compounds, because both the (thio)amide group
and the 5-amino group are able to react with DMAD.8 It was
found that the thioamides 14a,b react exclusively with the
Scheme 3.
Scheme 4.

2182
V. S. Berseneva et al. / Tetrahedron 57 (2001) 2179±2184
Scheme 5.
thioamide function to afford thiazolines 17a,b. On the
contrary, the reaction of 5-aminoimidazole-4-carboxamide
14c with DMAD involves both the amino group and NH
moiety of imidazole ring to give imidazo[1,5-a]pyri-
midinone 15 in good yield.
pation of the thioamide group to form novel conjugated
bisheterocycles incorporating a thiazolinone ring.
1. Experimental
1.1. General
On the other hand, reaction of 5-amino-1,2,3-thiadiazoles
14d,e with DMAD took place to the amino group only, to
furnish adducts with two moles of DMAD of type 16d,e.
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, on a Bruker AMX 400 with TMS
as internal reference in DMSO-d6 and CDCl3 solutions. The
products were analyzed by TLC on DC-Plastikfolen
Kieselgel 60 F 254. The melting points were uncorrected.
The mass spectra were recorded in a Varian-311A mass
spectrometer under standard conditions.
1
The H NMR spectra of these compounds contain four
signals for the methoxycarbonyl groups at 3.70±3.96 ppm
and a single methine signal at 5.6 ppm. In the 13C NMR
spectra of compounds 16d,e four signals, due to the meth-
oxycarbonyl groups at 51.5±53.4 ppm and ®ve signals due
to carbonyl atoms at 160.4±166.4 ppm were observed. The
mass spectral data also con®rm the structure of compounds
16d,e as bearing a substituted butadiene moiety (Scheme 5).
Compounds 7, 9, 10, 12c±f, 14a,b,d,e have been synthe-
sized according to the literature.9±11
On the other hand, we have found that the reactions of
thioamides 14a,b with DMAD occur selectively with the
participation of the thioamide groups. Amino groups at
position 5 do not take part in the process and these reac-
tions lead to thiazolin-4-ones 17a,b as single products.
This experiment con®rms the higher reactivity of the
thioamide group in these reactions in comparison with
the amino functionalities. The structures of these
compounds are in a good agreement with their NMR spectra
(Tables 1 and 2).
1.1.1. 5-Methyl-3-phenylisoxazol-4-carbothioamide (6).
5-Methyl-3-phenylisoxazol-4-carbonitrile 7 (0.01 mol) was
added to a solution of sodium (0.005 mol) in ethanol
(150 ml). The mixture was saturated by H2S at 08C. Then
the mixture was heated at 758C in a closed ampoule for 5 h.
The precipitate formed after cooling was ®ltered off and
recrystallized from ethanol, mp 173±1758C. Yield 50%.
Found: N 13.0; S 14.97. Calcd for C11H10N2OS. N 12.83;
S 14.7%.
In conclusion, we have shown that reactions of heterocyclic
thioamides with DMAD take place selectively with partici-
1.1.2. 3-Phenyl-4-(4-oxo-5-methoxycarbonylmethylene-
thiazolin-2-yl)-5-methylisoxazole (8). DMAD (0.001 mol)

V. S. Berseneva et al. / Tetrahedron 57 (2001) 2179±2184
2183
was added to a solution of carbothioamide 6 (0.001 mol) in
ethanol. The mixture was stirred at room temperature for
2 h. Filtration gave compound 8 as yellow crystals, mp 228±
2318C (from acetone). Yield 36%. Found: N 8.76; S 10.20.
Calcd for C16H12O4N2S; N 8.54; S 9.76%.
The compound was obtained by analogy with 8 in ethanol
as yellow crystals, mp 159±1618C (from ethanol). Yield
37%. Found: N 15.32, S 17.46. Calcd for C16H14N4O3S2;
N 14.96, S 17.09%.
1.1.11. 8-Carbamoyl-4-oxo-1,4-dihydroimidazo[1,5-a]-
pyrimidine-2-carboxylic acid methyl ester (15). To a
solution of 5-amino-4-imidazolecarboxamide hydrochloride
14c (0.001 mol) in ethanol (50 ml), DMAD (0.0015 mol)
was added. The reaction mixture was re¯uxed for 3 h. Fil-
tration gave compound 15 as yellow crystals, mp 172±
1758C (decomp., ethanol). Yield 45%. Found: N 23,67, C
46.12%, H 3.67. Calcd for C9H8N4O4; N 23.72, C 45.77, H
3.41%. 13C NMR (DMSO): 165.0 (COOEt), 160.7 (CO),
158.2 (CO), 135.0 (C2 imidaz.), 134.4 (C4 imidaz.), 135.0
(C6 pyrim.), 113.0 (C5 pyrim.)
1.1.3. 5(4)-Methylmercaptoimidazole-4(5)carboxamide
(11). 5(4)-Mercaptoimidazol-4(5)-carboxamide 10 (0.01 mol)
was added to a sodium methylate solution made of sodium
(0.01 mol) and methanol (5 ml). After 30 min methyl iodide
(0.012 mol) was added. The mixture was stirred at room
temperature for 2 h. Filtration gave compound 11 as yellow
crystals, mp 193±1968C (from ethanol). Yield 49%. Found:
N 20.22; S 26.33. Calcd for C5H7N3OS; N 20.40; S 26.73%.
1.1.4. 5(4)-Ethylmercaptoimidazole-4(5)carbothioamide
(12a). The compound was obtained by analogy with 11
in ethanol as colourless crystals, mp 165±1678C (from
ethanol). Yield 57%. Found: N 22.36; S 34.07. Calcd for
C6H9N3S2; N 22.46; S 34.27%.
1.1.12. 2-(4-Carbamoyl-[1,2,3]thiadiazol-5-yl)-amino-3,4-
bis(methoxycarbonyl)hexa-2,4-dienedioic acid dimethyl
ester (16d). To a solution of 5-amino-1,2,3-thiadiazol-4-
carboxamide 14d (0.001 mol) in ethanol (50 ml), DMAD
(0.002 mol) was added. The reaction mixture was re¯uxed
for 4 h. Filtration gave compound 16d as red crystals (from
ethanol), mp 205±2088C, Yield 32%.C15H16N4O9S. M1
428.
1.1.5. 5(4)-Benzylmercaptoimidazole-4(5)carbothioamide
(12b). The compound was obtained by analogy with 11
in ethanol as colourless crystals, mp 155±1578C (from
ethanol). Yield 46%. Found: N 16.63; S 26.16. Calcd for
C11H11N3S2; N 16.87; S 25.70%.
1.1.13.
2-(4-Methylcarbamoyl-[1,2,3]thiadiazol-5-yl)-
amino-3,4-bis-methoxycarbonyl-hexa-2,4-dienedioic acid
dimethyl ester (16e). The compound was obtained by
analogy with 16d as red crystals, mp 172±1758C (from
ethanol). Yield 35%. C16H18N4O9S. M1 442.
1.1.6. 5(4)-Methylmercaptoimidazole-4(5)carbothioamide
(12c). Procedure 1. The compound was obtained from
carbothioamide 9 by analogy with 11 as yellow crystals,
mp 200±2038C (from ethanol). Yield 85%. Found: N
24.23; S 36.96. Calcd for C5H7N3S2; N 24.7; S 37.0%.
Procedure 2. P4S10 (0.015 mol) was added to carboxamide
10 (0.01 mol) in dry dioxane (50 ml) at 608C with stirring.
The mixture was boiled for 4 h and, after cooling, ®ltered
off. The precipitate was dissolved in 100 ml of boiling water
and treated with charcoal. The water phase was concen-
trated in vacuum. Yellow crystals, mp 200±2028C (from
water). Yield 40%.
1.1.14. 2-(5-Aminoimidazol-4-yl)-5-methoxycarbonyl-
methylenethiazolin-4-on (17a). The compound was
obtained by analogy with 8 as brown crystals, mp 2258C
(decomp., ethanol). Yield 47%. Found: N 21.95, S 12.69.
Calcd for C9H8N4O3S; N 22.21, S 12.70%.
1.1.15. 4-(4-Oxo-5-methoxycarbonylmethylenethiazolin-
2-yl)-1,2,3-thiadiazol-5-amine (17b). The compound was
obtained by analogy with 8 as yellow crystals, mp 213±
2168C (from ethanol). Yield 41%. Found: N 20.63, S
24.12. Calcd for C8H6N4O3S2; N 20.73, S 23.72%.
1.1.7.
2-(5-Ethylmercaptoimidazol-4-yl)-5-methoxy-
carbonylmethylenethiazolin-4-on (13a). The compound
was obtained by analogy with 8 in chloroform as yellow
crystals, mp 250±2528C (from ethanol). Yield 50%.
Found: N 14.32; S 22.0. Calcd for C11H11N3O3S2; N
14.13; S 21.56%.
Acknowledgements
We thank the Russian Foundation for Basic Research, the
C.R.D.F., the F.W.O., the University of Leuven and the
Ministerie voor Wetenschapsbeleid for their ®nancial
support. I. L. is a postdoctoral fellow of the F.W.O.
1.1.8.
2-(5-Benzylmercaptoimidazol-4-yl)-5-methoxy-
carbonylmethylenethiazolin-4-on (13b). The compound
was obtained by analogy with 8 in chloroform as yellow
crystals, mp 2328C (decomp., ethanol). Yield 71%. Found:
N 11.46; S 18.10. Calcd for C16H14N3O3S2; N 11.67, S
17.78%.
References
1.1.9. 5-Methylmercapto-1-methyl-4-(4-oxo-5-methoxy-
carbonylmethylenethiazolin-2-yl)-1,2,3-triazole
The compound was obtained by analogy with 8 in ethanol
as yellow crystals, mp 169±1728C (from ethanol). Yield
45%. Found: N 19.18, S 21.12. Calcd for C10H10N4O3S2;
N 18.78, S 21.0%.
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