Synthesis of imidazo-and pyrazolothiadiazoles from dithiobiureas and dimethyl ethynedicarboxylate

Article abstract of DOI:10.3184/030823409X12510192920270

Microwave irradiation of 1-substituted-2, 5-dithiobiureas and 1, 6-disubstituted-2, 5-dithiobiureas with dimethyl ethynedicarboxylate gave methyl 2-{6-oxo-2-(substituted amino)imidazo-[2, 1-b][1, 3, 5]thiadiazol-5(6H)- ylidene} acetate and methyl 7-oxo-1,

Full text of DOI:10.3184/030823409X12510192920270

602 RESEARCH PAPER
OCTOBER, 602–606
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis of imidazo- and pyrazolothiadiazoles from dithiobiureas and
dimethyl ethynedicarboxylate
Yusria R. Ibrahim*
Chemistry Department, Faculty of Science, Minia University, 61519 Minia, A. R. Egypt
Microwave irradiation of 1-substituted-2, 5-dithiobiureas and 1, 6-disubstituted-2, 5-dithiobiureas with dimethyl
ethynedicarboxylate gave methyl 2-{6-oxo-2-(substituted amino)imidazo-[2, 1-b][1, 3, 5]thiadiazol-5(6H)-ylidene}
acetate and methyl 7-oxo-1, 3-bis(substituted imino)-3, 7-dihydro-1H-pyrazolo[1, 2-c][1, 3, 4]thiadiazole-5-carboxylate.
Rationales for these transformations are presented.
Keywords: 2, 5-dithiobiurea, dimethyl ethynedicarboxylate, (imidazo[2, 1-b][1, 3, 5]thiadiazolylidene)acetate
Acetylenecarboxylic acid derivatives are classified as
electrophilic reagents whose reactions with thioamides were
used for the synthesis of various heterocyclic systems over
the last century.1-5 The reactions of acetylenecarboxylic
acid derivatives with unsubstituted thioureas,6,7 N-mono-
substituted thioureas,8-10 N, N-disubstituted thioureas,11
N, N'-disubstituted thioureas,12 as well as substituted
thiosemicarbazides were reported.13-18 Unlike thioureas, the
molecule of thiosemicarbazide contains four nucleophilic
centres; therefore hydrazinothiazolidinone was obtained
by heating unsubstituted thiosemicarbazide with dimethyl
ethynedicarboxylate in methanol.19 On the other hand,
microwave (MW) irradiation or refluxing in acetic acid
equimolar amounts of 4-substituted-thiosemicarbazides 1a–c
and dimethyl ethynedicarboxylate (2) in DMF afforded the
formation of 5-oxo-3-thioxo-1, 2, 4-triazepine-7-carboxylic
acid methyl ester derivatives 3a–c and 4a–c (Scheme 1).20
In addition, microwave (MW) heating has been employed
for the rapid synthesis of a wide variety of organic
substances,21 where chemical reactions are accelerated because
of selective absorption of MW energy by polar molecules.
The application of MW irradiation provides enhanced
reaction rates, higher yields, greater selectivity, and the ease
of manipulation.
Compound 2 offers the C/C triple bond and the elecrtophilic
carbonyl carbon atoms for attack by nucleophiles, and
compounds 5a–f may react at least with their sulfur atom,
N-3, N-4 and N-6 as nucleophilic sites. Thus several options
for interactions between 5a–f and 2 may be envisaged as will
be outlined later. In the light of the abovementioned findings,
we undertook to investigate the reaction of dithiobiureas
5a–f with dimethyl ethynedicarboxylate (2) (Scheme 2).
Results and discussion
In methanol at reflux temperature or by using microwave
irradiation, the dithiobiureas 5a–f reacted with dimethyl
ethynedicarboxylate to give methyl 2-{6-oxo-2-(substituted
amino)imidazo[2,1-b][1,3,4]thiadiazol-5(6H)-ylidene}acetate
6a–c and methyl 7-oxo-1, 3-bis(substituted imino)-3, 7-
dihydro-1H-pyrazolo[1, 2-c][1, 3, 4]thiadiazol-5-carboxylate
7a–c (Scheme 2).
The structure of compounds 6a–c and 7a–c is in accord
1
with their IR, H NMR, 13C NMR and mass spectral data in
addition to elemental analyses.
Compounds 6a–c
From elemental analyses and the mass spectra a net release of
H2S and MeOH (M.Wt 66) has occurred; the weak noticeable
M•+ peak in the mass spectra which also showed the
following three fragments common to all products [M+-31],
[M+-RNCS] and [M+-28]. In the IR spectra (see also table 1)
two carbonyl bands were seen in the ranges 1720–1715 cm-1
and 1695–1690 cm-1, and a band between 1615 and 1630 cm-1
Unfortunately, no reactions between diester 2 and 1-
substituted-2, 5-dithiobiureas 5a–c or 1, 6-disubstituted-2,
5-dithiobiureas 5d–f have been published so far. The
heterocyclisation of dithiobiureas 5a–f using ethenetetra-
carbonitrile (TCNE) gave pyrazole,22 thiadiazepine,22
thiadiazole22 and imidazothiadiazole derivatives.23
S
H
N
H
N
+
R
C
NH2
MeO2C
C
C
CO2Me
1a-c
2
AcOH, reflux
8-10 h
DMF, MW
COMe
N
H
N
H
N
S
NH
S
R
CO2Me
CO2Me
N
N
R
O
O
4a-c
3a-c
1,3,4: a
, R = phenyl
, R = benzyl
, R = allyl
b
c
Scheme 1
* Correspondent. E-mail: dryusria2009@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2009 603
S
C
S
C
H
N
H
N
H
N
H
N
+
R'
MeO2C
R = R'
C
C CO2Me
R
2
5a-f
R' = H
H
CO2Me
O
CO2Me
O
N
S
N
N
N
R
N
H
N
NR
RN
S
6a-c
7a-c
5: a, R = phenyl, R' = H
b, R = benzyl, R' = H
c, R = allyl, R' = H
d, R = R' = phenyl
e, R = R' = benzyl
f
, R = R' = allyl
6,7: a
, R = phenyl
, R = benzyl
, R = allyl
b
c
Scheme 2
was assigned to C=N vibration, in addition to another band
between 3310 and 3295 due to NH group.
The H NMR of 6c did reveal a vinylic-CH at 6.51 ppm;
Nucleophilic attack on the triple bond of 2 by exocyclic or
endocyclic NH of thiadiazole 8 or its tautomer on either the
a- or b-ester group followed by elimination a molecule of
MeOH giving rise to structures 6 or the isomeric products 9
and 10 (Scheme 4).
1
while a low field NH attached to allyl group resonated at
7.89 ppm,24 the expected signals for the allyl group at 4.27
(allyl-CH2N), 5.26–5.34 (allyl-CH2=) and 6.03–6.12 (allyl-
CH=) were observed. The 13C NMR spectrum of 6c showing
signals at 165.83 (ring-C=O), 170.00 (ester-C=O), 154.96
(C-2), 154.72 (C-7a), 139.12 (C-5), 110.02 (vinyl-CH)
ppm. One ester group was converted into a ring carbonyl,
and the hydrazinecarbothioamide groups had taken part in
heterocyclisation.
Since 2 can offer only electrophilic sites for attack, N-3, N-4,
N-6, C-2 and C-5 of 5a–c have to act as a nucleophile. Taking
all the restrictions from above into account, a total of four
alternative products structures (Scheme 4) may be expected
from the following reactions which involving cyclisation of
compounds 5a–c via intermolecular nucleophilic attacks on
either of the thiocarbonyl groups.
1
Structure 9 could be ruled out on the basis of H NMR
and the absence of an exocyclic-NH group, whereas the
presence of NH attached to phenyl (dH = 9.96 ppm), benzyl
(dH = 8.75 ppm) and allyl (dH = 7.89 ppm). There is no way so
far to experimentally discriminate between compounds 6 and
10. As can be seen easily, structure 6, however, accommodates
all spectral data listed above, especially the 13C chemical
shifts for the ring carbonyl C-atom (C-5), see Table 1 for
comparison with all relevant spectral data with literature data
of suitable model substances for 6 and its alternative 10. For
the latter alternative structural type in every case expected
ring carbonyl 13C resonances are considerably upfield to
these which have been observed, and the IR frequencies
(1695–1690 cm-1) to be expected are typical for such a,
b-unsaturated esters (1750–1725).25 The ring C=O frequencies
H
N
H
N
R
C
S
NH
or MW
- H2S
or MW
- H2S
R' = H
N
R = R'
HS
NR'
5
NH
HN NH
R
N
RN
NR'
NR'
S
8
S
H
2
+
- MeOH
+ 2
- MeOH
H
CO2Me
O
CO2Me
O
N
N
N
S
N
NR'
RN
S
R
N
H
N
7
6
Scheme 3

604 JOURNAL OF CHEMICAL RESEARCH 2009
H
CO2Me
NH
O
CO2Me
O
N
N
N
N
Ph
N
H
PhN
S
9
N
H
S
6a
O
N
CO2Me
O
N
N
H
PhHN
N
N
S
CO2Me
PhN
10
N
S
Scheme 4
(1720–1715 cm-1)26 observed rule out structures 10a–c
(1667-1648 cm-1)27-29 while they are agreeable for structures
6a–c. The values found for ester C=O 13C resonances do not
allow an assignment beyond doubt (see Table 1). A rationale
for the formation of 6a–c is given in Scheme 3.
The 13C chemical shifts for the ring carbons resonated
at 164.21–164.08 ppm, due to lactam-C=O33 (Table 1).
Also, the IR absorption for pyrazol-3-ones comparable to
7a–c resonate at (1710–1735 cm-1).34 Pyrazolone-proton
4-H showed in DMSO-d6 a strong singlet between 6.95 and
6.92 ppm, for all compounds.
As shown in Table 2 the application of MW irradiation
provided higher yields in comparison with yields obtained by
application of a direct heating process.
Finally, the question whether the products 6a–c has an E- or
Z-configuration, has to be left unanswered at present.
Compounds 7a–c
The molecular ions in their EI-mass spectra confirm the
molecular masses and the gross compositions. Further, the
following common features of fragmentation patterns lend
support to the assigned structures: Loss of 31 amu (representing
methoxy group). The resulting acylium fragment ions undergo
loss of RNCS followed by loss of 28 amu (may be dinitrogen
or CO). The spectroscopic data found for isolated products fit
best for structure 7.
Conclusion
The reactions and products presented here provide insight into
the spontaneous reactions between mono- and disubstituted
dithiobiureas 5a–f and dimethyl ethynedicarboxylate
(2), followed by heterocyclisation. Although, we have
thiaheterocycles neither the S–C–N + C–2 nor N–C(S)–N
+ C-2 mode of cyclisation is found in this study, a novel
Table 1 13C NMR data for C=O groups (ring and ester)a in products 6a–c and 7a–c and literature data26-34 of compounds comparable
to 6,7 and structural alternatives.
Structures
13C of ring C=O
13C of ester C=O
Products 6a–c
165.64–165.87a
164.08–164.21
158.627, 16028
164.6–166.126
165.2–165.730
16831, 163.6–165.532
160.3–163.433
169.74–170.0
169.75–169.83
164.7–16527
170.126
Products 7a–c
Pyrimidin-4-ones comparable to 6a–c
Imidazol-5-ones comparable to 6a–c
Pyrazol-3-ones comparable to 7a–c
164.9,166.04,166.534
Table 2 Conventional heating under reflux (A) and MW irradiation (B) of dithiobiureas 5a–f and dimethyl ethynedicarboxylate (2)
Starting materials (Conditions)
Products
Yield/%
A
B
5a + 2
(A: Reflux in MeOH, 3 h)
(B: MW, 3 min, power 70%)
6a
6a
51
78
5b + 2
(A: Reflux in MeOH, 5 h)
(B: MW, 5 min, power 100 %)
6b
6b
47
43
58
53
51
75
71
79
79
76
5c + 2
(A: Reflux in MeOH, 6 h)
(B: MW, 6 min, power 100 %)
6c
6c
5d + 2
(A: Reflux in MeOH, 5 h)
(B: MW, 4 min, power 100 %)
7a
7a
5e + 2
(A: Reflux in MeOH, 7 h)
(B: MW, 6 min, power 100 %)
7b
7b
5f + 2
(A: Reflux in MeOH, 8 h)
(B: MW, 7 min, power 100 %)
7c
7c

JOURNAL OF CHEMICAL RESEARCH 2009 605
CH2N), 53.59 (OCH3), 110.12 (methylene-CH), 116.06 (allyl-CH2=),
153.14 (allyl-CH=), 139.12 (C-5), 154.72 (C-7a), 154.96 (C-2),
165.83 (C-6), 170.00 ppm (ester-CO). MS (m/z,%): 266 [M+] (21),
235 (12), 136 (41), 108 (42), 99 (23), 66 (36), 41 (100). Anal. Calcd
for C10H10N4O3S (266.28): C, 45.11; H, 3.79; N, 21.04; S, 12.04.
Found: C, 44.89; H, 3.92; N, 20.88; S, 11.94%.
N–C–N + C-2 mode is observed due to dibithiourea reactivity.
The results reported here supplement the rich chemistry of
dimethyl ethynedicarboxylate and dithiobiureas.
Experimental
Methyl7-oxo-1,3-bis(phenylimino)-3,7-dihydro-1H-pyrazolo[1,2-c]
[1, 3, 4]thiadiazol-5-carboxylate (7a): Yellow crystals, m.p. 282–
284°C (acetonitrile). IR (KBr): 1720 (CO), 1697 (COO), 1625
(C=N), 1605 (Ar-C=C) cm-1. 1H NMR (DMSO-d6): d = 3.76 (s, 3H,
All the melting points were determined in open glass capillaries
on a Gallenkamp melting point apparatus and are uncorected. The
IR spectra were recorded with a Shimadzu 408 using potassium
1
bromide pellets. 500 MHz H and 125 MHz 13C NMR spectra were
CH3), 6.95 (s, 1H, pyrazole-H), 7.11–7.51 ppm (m, 10H, Ph-H). 13
C
recorded from DMSO-d6 solution on a Bruker Avance DRX 500
spectrometer. Chemical shifts are expressed as d [ppm] with reference
to tetramethylsilane as an internal standard, s = singlet, d = doublet,
dd = doublet of doublet and b = broad. 13C assignments were made
with the aid of distortionless enhancement by polarisation transfer
(DEPT) 135/90 spectra. Mass spectra were recorded on a Varian MAT
CH-7 instrument in EI mode at 70 eV ionisation energy. A Somsung
MX 45 microwave oven was used at its full power 1400 W, 100%
and 700% power level for the experiments recorded for this study.
Preparative layer chromatography (PLC) used air dried 1.0 mm thick
layers of slurry applied silica gel Merck Pf254 on 48 cm wide and
20 cm high glass plates using the solvents listed. Zones were detected
by quenching of indicator fluorescence upon exposure to 254 nm
light and were extracted with acetone.
Starting materials: 1-Substituted-2, 5-dithiobiureas 5a–c and 1,
6-disubstituted-2, 5-dithiobiureas 5d–f were prepared according
to published procedures as were 1-phenyl-2, 5-dithiobiurea (5a),35
1-benzyl-2, 5-dithiobiurea (5b),35,36 1-allyl-2, 5-dithiobiurea (5c),35
1, 6-diphenyl-2, 5-dithiobiurea (5d),37 1, 6-dibenzyl-2, 5-dithiobiurea
(5e),38 1, 6-diallyl-2, 5-dithiobiurea (5f).39 Dimethyl ethynedi-
carboxylate (2) was bought from Fluka.
NMR (DMSO-d6): d = 52.86 (OCH3), 87.12 (pyrazole-CH), 126.28,
127.56, 129.47 (Ph-CH), 147.76 (Ph-C), 153.37 (C-5), 157.55 (C-1,
3), 164.12 (pyrazole-CO), 169.75 ppm (ester-CO). MS (m/z,%): 378
[M+] (14), 347 (26), 212 (41), 184 (22), 135 (36), 103 (16), 91 (56),
77 (100), 65 (68). Anal. Calcd for C19H14N4O3S (378.40): C, 60.31;
H, 3.73; N, 14.81; S, 8.47. Found: C, 60.47; H, 3.61; N, 15.02; S,
8.32%.
Methyl7-oxo-1,3-bis(benzylimino)-3,7-dihydro-1H-pyrazolo[1,2-c]
[1, 3, 4]thiadiazol-5-carboxylate (7b): This compound was obtained
as pale yellow crystals, m.p. 303–305°C (acetonitrile). IR (KBr):
1715 (CO), 1695 (COO), 1630 (C=N), 1595 (Ar-C=C) cm-1. 1H NMR
(DMSO-d6): d = 3.78 (s, 3H, CH3), 4.56 (s, 2H, Ph-CH2), 6.92 (s, 1H,
pyrazole-H), 7.18–7.56 ppm (m, 10H, Ph-H). 13C NMR (DMSO-d6):
d = 47.18 (CH2Ph), 52.82 (OCH3), 87.98 (pyrazole-CH), 126.19,
127.45, 129.45 (Ph-CH), 137.67 (Ph-C), 153.24 (C-5), 157.49 (C-1,
3), 164.21 (pyrazole-CO), 169.83 ppm (ester-CO). MS (m/z,%): 406
[M+] (19), 375 (38), 226 (32), 198 (45), 127 (18), 91 (100), 77 (55).
C21H18N4O3S (406.46): Anal. Calcd for C, 62.05; H, 4.46; N, 13.78;
S, 7.89. Found: C, 61.88; H, 4.32; N, 13.93; S, 8.03%.
Methyl 7-oxo-1, 3-bis(allylimino)-3, 7-dihydro-1H-pyrazolo[1, 2-c]
[1, 3, 4]thiadiazol-5-carboxylate (7c): Pale yellow crystals, m.p.
246–248°C (acetonitrile). IR (KBr): 2995 (Ali-H), 1715 (CO), 1700
(COO), 1625 (C=N) cm-1. 1H NMR (DMSO-d6): d = 3.75 (s, 3H,
CH3), 4.19 (br, 2H, allyl-CH2N), 5.28–5.33 (m, –2H, allyl-CH2=),
5.96–6.05 (m, 1H, allyl-CH=), 6.95 ppm (s, 1H, pyrazole-H). 13C
NMR (DMSO-d6): d = 43.56 (allyl-CH2N), 52.90 (OCH3), 87.05
(pyrazole-CH), 115.94 (allyl-CH2=), 135.21 (allyl-CH=), 153.28
(C-5), 157.62 (C-1, 3), 164.08 (pyrazole-CO), 169.80 ppm (ester-
CO). MS (m/z,%): 306 [M+] (16), 275 (29), 176 (37), 148 (7), 99
(27), 55 (17), 41 (100). Anal. Calcd for C13H14N4O3S (306.34):
C, 50.97; H, 4.61; N, 18.29; S, 10.47. Found: C, 51.14; H, 4.49;
N, 18.11; S, 10.61%.
Reactions of 5a–f with dimethyl ethynedicarboxylate (2)
Method (A): Conventional heating under refluxing in methanol:
Into a 250 cm3 two-necked flask containing 2 (284 mg, 2.0 mmol) in
methanol (10 mL), a solution of 2 mmol of 5a–f in methanol (50 mL)
was added dropwise with stirring. The mixture was gently refluxed
with stirring for 3–8 h. The resulting yellow precipitate was filtered
off, washed with methanol, and recrystallised from a suitable solvent
to give pure crystals of 6a–c and 7a–c.
Method (B): Heterocyclisation by microwave irradiation:
Equimolar amounts of 5a–f (2 mmol) and 2 (284 mg, 1 mmol) were
well-mixed in methanol (10 mL). The mixture was irradiated in
a microwave oven in an open glass tube (the time of irradiation as
monitored in Table 2. After completion of the reaction as monitored
by TLC, the residue was separated as reported above. Comparison of
the yields from compounds 2 and 5a–f is given in Table 2.
Methyl2-{6-oxo-2-(phenylamino)imidazo[2,1-b][1,3,4]thiadiazol-5
(6H)-ylidene}acetate (6a): Yellow crystals, m.p. 261–263°C
(acetonitrile). IR (KBr): 3310 (NH), 1720 (CO), 1695 (COO), 1620
(C=N), 1600 (Ar-C=C) cm-1. 1H NMR (DMSO-d6): d = 3.81 (s, 3H,
CH3), 6.48 (s, 1H, methylene-H), 7.28–7.40 (m, 5H, phenyl-H), 9.96
ppm (br, 1H, Ph-NH). 13C NMR (DMSO-d6): d = 53.63 (OCH3),
109.93 (methylene-CH), 127.57, 127.98, 128.44 (Ph-CH), 137.73
(Ph-C), 138.96 (C-5), 154.67 (C-7a), 155.11 (C-2), 165.87 (C-6),
169.74 ppm (ester-CO). MS (m/z,%): 302 [M+] (17), 271 (41), 167
(38), 139 (51), 135 (64), 91 (62), 77 (100), 66 (69). Anal. Calcd for
C13H10N4O3S (302.31): C, 51.65; H, 3.33; N, 18.53; S, 10.61. Found:
C, 51.79; H, 3.41; N, 18.37; S, 10.75%.
Methyl2-{6-oxo-2-(benzylamino)imidazo[2,1-b][1,3,4]thiadiazol-5
(6H)-ylidene}acetate (6b): Yellow crystals, m.p. 276–278°C
(methanol). IR (KBr): 3295 (NH), 1715 (CO), 1690 (COO), 1630
(C=N), 1595 (Ar-C=C) cm-1. 1H NMR (DMSO-d6): d = 3.79 (s,
3H, CH3), 4.59 (s, 2H, Ph-CH2), 6.45 (s, 1H, methylene-H), 7.26–
7.37 (m, 5H, phenyl-H), 8.75 ppm (br, 1H, PhCH2-NH). 13C NMR
(DMSO-d6): d = 46.91 (CH2Ph), 53.47 (OCH3), 109.74 (methylene-
CH), 127.42, 127.93, 128.36 (Ph-CH), 137.84 (Ph-C), 138.73 (C-5),
154.56 (C-7a), 155.31 (C-2), 165.64 (C-6), 169.83 ppm (ester-CO).
MS (m/z,%): 316 [M+] (11), 285 (26), 167 (37), 149 (76), 91 (100),
77 (62), 66 (51). Anal. Calcd for C14H12N4O3S (316.34): C, 53.16;
H, 3.82; N, 17.71; S, 10.14. Found: C, 52.93; H, 3.91; N, 17.58;
S, 9.97%.
Received 14 June; accepted 17 August 2009
Paper 09/0640 doi: 10.3184/030823409X12510192920270
Published online: 8 October 2009
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Methyl 2-{6-oxo-2-(allylamino)imidazo[2, 1-b][1, 3, 4]thiadiazol-
5(6H)-ylidene}acetate (6c): Yellow crystals, m.p. 218–220°C
(ethanol). IR (KBr): 3305 (NH), 2990 (Ali-H), 1715 (CO), 1695
(COO), 1620 (C=N) cm-1. 1H NMR (DMSO-d6): d = 3.80 (s, 3H,
CH3), 4.27 (br, 2H, allyl-CH2N), 5.26–5.34 (m, 2H, allyl-CH2 = ),
6.03–6.12 (m, 1H, allyl-CH=), 6.51 (s, 1H, methylene-H), 7.89
ppm (br, 1H, allyl-NH). 13C NMR (DMSO-d6): d = 43.67 (allyl-

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