A challenging synthesis of new 1,3,4-thiadiazole derivatives starting from 2-acylamino-3,3-dichloroacrylonitriles

Article abstract of DOI:10.1002/hc.20041

Available 2-acylamino-3,3-dichloro-acrylonitriles, when treated with hydrazine hydrate, provide 2-alkyl- or 2-aryl-5-hydrazino-1,3-oxazole-4- carbonitriles that readily add alkyl or aryl isothio-cyanates and the adducts formed recyclize on heating. Finally, the synthesis results in 5-alkyl(aryl)amino-1,3,4-thiadiazol-2-yl(acylamino)acetonitriles or the products of their further cyclization, 2-(5-amino-1,3-oxazol-2-yl)-1,3,4-thiadiazole derivatives. The structures of the novel substituted 1,3,4-thiadiazoles are corroborated spectroscopically as well as by X-ray diffraction method.

Full text of DOI:10.1002/hc.20041

Heteroatom Chemistry
Volume 15, Number 6, 2004
A Challenging Synthesis of New
1,3,4-Thiadiazole Derivatives Starting from
2-Acylamino-3,3-dichloroacrylonitriles
Oleksandr V. Golovchenko,1 Stepan G. Pilyo,1 Vladimir S. Brovarets,1
Alexander N. Chernega,2 and Boris S. Drach1
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
Received 3 June 2004
of 1,3-oxazole [1–7,10,11], 4H-imidazole [8], and
ABSTRACT: Available 2-acylamino-3,3-dichloro-
1,3,4-oxadiazole [9]. The present work addresses
acrylonitriles, when treated with hydrazine hydrate,
a new line in harnessing of 2-acylamino-3,3-
provide 2-alkyl- or 2-aryl-5-hydrazino-1,3-oxazole-4-
dichloroacrylonitriles for the preparation of interest-
carbonitriles that readily add alkyl or aryl isothio-
ing 1,3,4-thiadiazole derivatives.
cyanates and the adducts formed recyclize on heating.
Finally, the synthesis results in 5-alkyl(aryl)amino-
1,3,4-thiadiazol-2-yl(acylamino)acetonitriles or the
products of their further cyclization, 2-(5-amino-1,3-
RESULTS AND DISCUSSION
oxazol-2-yl)-1,3,4-thiadiazole derivatives. The struc-
tures of the novel substituted 1,3,4-thiadiazoles are
corroborated spectroscopically as well as by X-ray
To obtain novel 1,3,4-thiadiazole derivatives, 1a–e
were first treated with an excess of hydrazine hy-
drate and then heated with alkyl or aryl isothio-
cyanates in dioxane. In doing so, the conver-
sions 1→2→3→4→5→6 successively proceeded as
shown in Scheme 1.
The cyclocondensation 1→2 was studied before
[4,9]. It represents a particular case of a quite general
synthetic route to 5-hydrazino-1,3-oxazole deriva-
tives containing various electron acceptor groups,
such as CN, C(O)OAlk, P(O)(OAlk)2, PPh+3 , etc., at
the position 4 [4,9,12].
ꢀ
C
diffraction method.
2004 Wiley Periodicals, Inc.
Heteroatom Chem 15:454–458, 2004; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20041
INTRODUCTION
It is more than 30 years since two research teams,
in Japan and Ukraine, started systematic stud-
ies on the conversions of 2-acylamino-3,3-dichloro-
acrylonitriles demonstrating unique properties as
reagents for heterocyclizations [1–11]. Starting from
these reagents, the preparative syntheses were elab-
orated for a number of functional derivatives
In the reaction with alkyl and aryl isothio-
cyanates, compounds 2a–e first produce substituted
thiosemicarbazidooxazoles 3a–j that can occasion-
ally be isolated in the individual state (Table 1) and
1
studied by IR and H NMR spectroscopy to verify
the presence of the nitrile group and the C(S)-NH-
NH-Het moiety (Table 2). If heated in dioxane, com-
pounds 3d,e containing alkyl substituents at the po-
sition 2 of the oxazole ring recyclize to give products
c
ꢀ
2004 Wiley Periodicals, Inc.
454

Synthesis of New 1,3,4-Thiadiazole Derivatives 455
SCHEME 1
5d,e. The IR spectra of these compounds exhibit the
signals from the C O and C N bonds, whereas the
1H NMR spectra point to the presence of the CHNH
fragment giving rise to doublets in the regions 6.4–
6.5 and 9.4–9.5 ppm (Table 2).
analogs synthesized recently by a similar recycliza-
tion and containing, instead of a nitrile group,
other electron acceptor residues, C(O)OAlk and
P(O)(OAlk)2 [12]. Prototropic tautomers 4 are likely
to play a significant part in the conversion 3→→5,
since their nonaromatic structure favors the recy-
clization 4→5. By structural features, this reaction
For a reliable identification of compounds 5a–e,
we have made use of the spectral data for their
TABLE 1 Physical and Analytical Data of Compounds 2,3,5,6
Analysis (%) Found (Calcd.)
mp (◦C)
Yield (%) Mol. Formula (Mol. Wt.)
C
H
N
S
2e
3b
3g
5d
5e
6a
6b
6c
6f
85–87a
182–184
176–177
209–211b
222–223b
210–212c
236–238c
207–208c
205–207c
183–185d
198–200d
205–207c
201–202c
75
89
85
55
60
61
66
58
63
69
64
54
57
C6H8N4O (152.2)
47.53 (47.36)
62.09 (61.87)
54.51 (54.34)
52.98 (52.73)
56.28 (56.00)
61.09 (60.88)
62.11 (61.87)
59.41 (59.17)
61.99 (61.87)
54.51 (54.34)
58.61 (58.34)
63.09 (62.79)
60.02 (60.14)
5.42 (5.30)
4.27 (4.33)
4.83 (4.56)
4.21 (4.06)
5.16 (5.02)
4.15 (3.91)
4.12 (4.33)
4.38 (4.14)
4.69 (4.33)
4.79 (4.56)
6.16 (5.81)
4.96 (4.71)
4.78 (4.52)
36.50 (36.82)
20.23 (20.04)
24.49 (24.37)
25.75 (25.62)
23.07 (23.23)
20.73 (20.88)
20.28 (20.04)
19.01 (19.17)
20.17 (20.04)
24.35 (24.37)
21.11 (21.26)
23.39 (19.27)
18.59 (18.46)
–
C
C
18H15N5OS (349.4)
13H13N5OS (287.4)
8.93 (9.18)
11.08 (11.16)
11.59 (11.73)
10.43 (10.64)
9.69 (9.56)
9.33 (9.18)
8.92 (8.77)
9.28 (9.18)
11.38 (11.17)
9.95 (9.73)
9.56 (8.82)
8.61 (8.45)
C12H11N5OS (273.3)
C14H15N5OS (301.4)
C17H13N5OS (335.4)
C18H15N5OS (349.4)
C18H15N5O S (365.4)
C18 15
H
N5O2S (349.4)
6g
6h
6i
C13H13N5OS (287.4)
C16H19N5OS (329.5)
C19 17
H
N5OS (363.4)
6j
C19H17N5O2S (349.4)
aRecrystallization from hexane.
bRecrystallization from MeOH.
cRecrystallization from the mixture MeCN-DMF.
dRecrystallization from MeCN.

456 Golovchenko et al.
TABLE 2 Spectroscopic Data of Compounds 3,5,6
IR (KBr) (cm−1
)
1H NMR (DMSO-d6/TMS) δ, J (Hz)
MS: m/z (M +H)+
3b
3g
5d
5e
2220 (C N)
3120–3200 (NH)
2230 (C N)
3150–3300 (NH)
2320 (C N) 1670 (NC O)
3200–3300 (NH)
1650 (NC O)
2.38 (s, 3H, CH ), 7.16–7.73 (m, 9H, C H5, C6H4), 10.02
(br s, 2H, NH,3NH), 10.37 (s, 1H, NH)6
350
1.09 (t, 3H, CH3), 3.50 (q, 2H, CH ), 7.50–7.80 (m, 5H, C6H5),
8.50 (br s, 1H, NH), 9.70 (s, 1H,2NH),10.37 (s, 1H, NH)
1.95 (s, 3H, CH3), 6.45 (d, 1H, J = 7.5, CH), 7.00–7.59 (m, 5H,
C6H5), 9.49 (d, 1H, J = 7.5, NH), 10.45 (br s, 1H, NH)
1.06 (t, 3H, CH3), 2.19 (q, 2H, CH2), 2.28 (s, 3H, CH3),
6.42 (d, 1H, J = 7.5, CH), 7.13–7.43 (m, 4H, C6H4),
9.41 (d, 1H, J = 7.5, NH), 10.30 (s, 1H, NH)
–
274
302
3200–3420 (NH)
5ha
–
0.94 (t, 3H, CH3), 1.41 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.36
(s, 3H, CH3), 3.27 (m, 2H, NCH2), 6.48 (d, 1H, J = 7.5, CH),
7.27–7.80 (m, 4H, C6H4), 7.78 (t, 1H, NH), 9.81 (d, 1H,
J = 7.5, NH)
–
6a
6b
6c
6f
1645b (δ, NH2),
6.95–7.82 (m, 10H, 2 × C6H5), 7.07 (br s, 2H, NH2), 10.19
336
350
366
350
288
330
3200–3440 (NH, NH2)
(s, 1H, NH)
1630b (δ, NH2)
2.36 (s, 3H, CH ), 6.99–7.73 (m, 9H, C6H4, C6H5), 7.11
(br s, 2H, NH23), 10.26 (s, 1H, NH)
3.82 (s, 3H, CH3), 6.92 (br s, 2H, NH2), 6.94–7.78 (m, 9H,
C6H4, C6H5), 10.14 (s, 1H, NH)
2.28 (s, 3H, CH3), 7.03 (br s, 2H, NH2), 7.09–7.84 (m, 9H,
C6H5, C6H4), 10.06 (s, 1H, NH)
1.23 (t, 3H, CH3), 3.31 (q, 2H, CH2), 6.86 (br s, 2H, NH2),
7.38–7.80 (m, 6H, C6H5, NH)
0.94 (t, 3H, CH3), 1.41 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.36
(s, 3H, CH3), 3.29 (m, 2H, CH2), 6.77 (br s, 2H, NH2),
7.24–7.69 (m, 4H, C6H4), 7.49 (t, 1H, NH)
2.28 (s, 3H, CH3), 2.37 (s, 3H, CH3), 6.97 (br s, 2H, NH2),
7.08–7.73 (m, 8H, 2 × C6H4), 10.05 (s, 1H, NH)
2.28 (s, 3H, CH3), 3.82 (s, 3H, CH3), 6.83 (br s, 2H, NH2),
6.98–7.77 (m, 8H, 2 × C6H4), 9.97 (s, 1H, NH)
3200–3370 (NH, NH2)
1630b (δ, NH2)
3200–3450 (NH, NH2)
1640b (δ, NH2)
3200–3440 (NH, NH2)
1635b (δ, NH2)
6g
6h
3180–3400 (NH, NH2)
1640b (δ, NH2)
3200–3400 (NH, NH2)
6i
6j
1640b (δ, NH2)
364
380
3180–3400 (NH, NH2)
1640b (δ, NH2)
3140–3450 (NH, NH2)
aThe data refer to the ca. 1:1 mixture of compounds 5h and 6h.
bAn unidentified absorption band is also present in this region.
belongs to a particular rearrangement type studied
by Boulton et al. [13] that involves azole side chains.
As regards compounds 3a–c,f–j bearing aryl sub-
stituents at the position 2 of the oxazole ring, it is
notable that on long heating them in dioxane, re-
action products 5a–c,f–j are as a rule inseparable
as they undergo further cyclization 5→6. Cycliza-
tions of this kind affording substituted 5-amino-1,3-
oxazoles are well known for ꢀ-acylaminonitriles of
a simpler structure [14]. At the same time, heating
compound 3h in dioxane for a short time results in a
mixture of products 5h and 6h, which is confirmed
method has been performed for one compound of
this family, 2-(5-amino-2-phenyl-1,3-oxazol-4-yl)-5-
ethylamino-1,3,4-thiadiazole 6g (Fig. 1 and Table 3).
A molecule of 6g contains a practically planar
system consisting of two five-membered heterocycles
1
by the H NMR spectra. On further long heating in
dioxane, this mixture turns into the only compound,
6h.
The structures of the final products yielded by
the complex conversions 3→4→5→6 are corrob-
orated by a combined spectroscopic study. Thus
it is found that the last cyclization involves the
C N bond and causes formation of the primary
amino group (Table 2). In addition, an unequivo-
cal structural determination using X-ray diffraction
FIGURE 1 Perspective view and labeling scheme for the
molecule 6g.

Synthesis of New 1,3,4-Thiadiazole Derivatives 457
TABLE 3 Selected Bond Lengths and Bond Angles of 6g
measured on a Surveyor MSQ instrument (Thermo
Finnigan) using the APCI ionization method, and
0.1% aqueous solution of formic acid and acetoni-
trile as solvents.
S(1) C(1)
S(1) C(2)
O(1) C(4)
O(1) C(5)
N(1) N(2)
N(1) C(1)
N(2) C(2)
N(3) C(3)
N(3) C(5)
N(4) C(1)
N(4) C(6)
N(5) C(4)
C(2) C(3)
C(3) C(4)
1.747(2)
1.739(2)
1.363(2)
1.380(3)
1.385(3)
1.304(3)
1.299(3)
1.402(3)
1.293(3)
1.348(3)
1.434(3)
1.349(3)
1.440(3)
1.357(3)
C(1) S(1) C(2)
C(4) O(1) C(5)
N(2) N(1) C(1)
N(1) N(2) C(2)
C(3) N(3) C(5)
C(1) N(4) C(6)
S(1) C(1) N(1)
S(1) C(2) N(2)
N(3) C(3) C(4)
O(1) C(4) C(3)
O(1) C(5) N(3)
86.42(12)
105.28(16)
112.08(18)
113.17(19)
104.56(17)
122.6(2)
114.24(17)
114.09(17)
109.47(19)
107.42(18)
113.26(18)
2-Alkyl(aryl)-5-hydrazino-1,3-oxazole-4-
carbonitriles 2a–e
To a solution of 1a–e (10 mmol) obtained by the
known procedure [2,3] in EtOH (30 mL) was added
hydrazine hydrate (35 mmol). The mixture was al-
lowed to stand at r.t. for 24 h. After filtering off hy-
drazine hydrochloride, the solvent was evaporated
in vacuo, and the residue was treated with H2O,
filtered off, dried, and purified by recrystallization
from EtOH or hexane to give 2a–e (Table 1). Com-
pounds 2a–d were described before [4,9].
and the benzene ring. The dihedral angle between
the five-membered rings S(1)C(1)N(1)N(2)C(2)
and O(1)C(4)C(3)N(3)C(5) amounts to only 0.9◦,
whereas the benzene ring C(8–13) makes with the
plane O(1)C(4)C(3)N(3)C(5) a dihedral angle of
7.1◦. An efficient ꢁ-conjugation in the moieties
nN(4) ꢁC(1) N(1) and nN(5) ꢁC(4) C(3) leads
to a notable shortening of the bonds N(4) C(1)
2-Alkyl(aryl)-5-[4-alkyl(aryl)thiosemicarbazido]-
1,3-oxazole-4-carbonitriles 3a–j
To a solution of 2a–e (10 mmol) in anhydrous diox-
ane (60 mL) was added the corresponding alkyl or
aryl isothiocyanate (11 mmol). The mixture was al-
lowed to stand at r.t. for 72 h. The resulting precipi-
tate was filtered off, washed with dioxane, and dried
in vacuo. Analytical and spectral data were obtained
for 3b,g (Table 1) whereas their analogs 3a,c–f,h–j
were immediately used in the preparation of 5d,e
and 6a,c–f,h–j without isolation.
˚
and N(5) C(4) down to 1.348(3) and 1.349(3) A,
respectively (a standard length of a single bond
2
2
˚
N(sp ) C(sp ) amounts to 1.43–1.45 A [15,16]).
Among the structural peculiarities of compound
6g is the intramolecular hydrogen bond [17]
N(5) H(51). . . N(2) with the relevant bond lengths
˚
˚
and angles as follows: N(5). . . N(2) 2.973(3) A,
˚
Acylamino[5-alkyl(aryl)amino-1,3,4-thiadiazol-
2-yl]acetonitriles 5a–j
H(51). . . N(2) 2.36(3) A, N(5) H(51) 0.81(3) A,
N(5)H(51)N(2) 132(3)◦, which closes the six-
membered ring N(2)C(2)C(3)C(4)N(5)H(51).
To a solution of 2a–e (10 mmol) in anhydrous diox-
ane (60 mL) was added the corresponding alkyl or
aryl isothiocyanate (11 mmol). The mixture was re-
fluxed for 8 h, and dioxane was removed in vacuo.
For crystallization, the residue was treated with H2O;
then it was filtered off and recrystallized from an ap-
propriate solvent (Table 1). Analytical and spectral
data were obtained for 5d,e whereas their analogs
5a–c,f–j were not isolated, since they cyclize rapidly
to give 6a–c,f–j.
Thus, the conversion of reagents 2a–e into hith-
erto unknown 1,3,4-thiadiazole derivatives 5d,e and
6a–c,f–j is supported by solid evidence. The ap-
proach developed is of undeniable preparative sig-
nificance, since the starting reagents are easy to
obtain from the available adducts formed by car-
boxamides with chloral [2,18]. Moreover, the con-
versions 2→→5 and 2→→6 are quite straightfor-
ward and furnish the 1,3,4-thiadiazole derivatives
unobtainable by the previously described methods
[19]. Finally, compounds 5d,e and 6a–c,f–j can
in turn be converted with ease into other novel
1,3,4-thiadiazole derivatives that will be considered
elsewhere.
2-[5-Amino-2-aryl-1,3-oxazol-4-yl]-5-
alkyl(aryl)amino-1,3,4-thiadiazoles 6a–c,f–j
To a solution of 2a–c (10 mmol) in anhydrous diox-
ane (60 mL) was added the corresponding alkyl or
aryl isothiocyanate (11 mmol). The mixture was re-
fluxed for 8 h, and dioxane was removed in vacuo.
The product was purified by recrystallization from
an appropriate solvent (Table 1).
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Gemini
300 spectrometer at 300 MHz using TMS as an inter-
nal standard. IR spectra were measured on a Specord
M-80 spectrometer for KBr disks. Mass spectra were
Compound 6b was also obtained from 3b
(10 mmol) by boiling in dioxane (60 mL) for 8 h.

458 Golovchenko et al.
[2] Drach, B. S.; Sviridov, E. P.; Kisilenko A. A.; Kirsanov,
A. V. Zh Org Khim 1973, 9, 1818–1824.
[3] Drach, B. S.; Sviridov, E. P.; Lavrenyuk, T. Ya. Zh Org
Khim 1974, 10, 1271–1274.
[4] Matsumura, K.; Saraie, T.; Hashimoto, N. Chem
Pharm Bull 1976, 24, 924–940.
The product was isolated as described in the general
procedure, yield 71%, mp 236–238◦C. The IR spectra
for the samples of compound 6b obtained from 2b
and 3b were identical.
[5] Matsumura, K.; Miyashita, O.; Shimadzu, H.;
Hashimoto, N. Chem Pharm Bull 1976, 24, 948–
959.
[6] Drach, B. S.; Mis’kevich, G. N. Zh Org Khim 1977, 13,
1398–1404.
[7] Drach, B. S.; Mis’kevich, G. N. Zh Org Khim 1978, 14,
501–507.
[8] Vinogradova, T. K.; Mis’kevich, G. N.; Drach, B. S. Zh
Org Khim 1980, 16, 1869–1874.
X-ray Structure Determination for 6g
Crystal Data. C13H13N5OS, M = 287.35, mono-
˚
−3
clinic, a = 15.394(9), b = 7.839(3), c = 11.431(6) A,
◦
3
˚
ꢂ = 90.31(5) , V = 1379(1) A , Z = 4, d = 1.38 g cm ,
space group P21/c, ꢃ = 20.74 cm−1, F(000) = 602.8,
crystal size ca. 0.31 × 0.46 × 0.48 mm.
[9] Pilyo, S. G.; Brovarets, V. S.; Vinogradova, T. K.;
Chernega, A. N.; Drach, B. S. Zh Obshch Khim 2001,
71, 310–315.
[10] Pilyo, S. G.; Brovarets, V. S.; Vinogradova, T. K.;
Golovchenko, A. V.; Drach, B. S. Zh Obshch Khim
2002, 72, 1818–1827.
[11] Pilyo, S. G.; Brovarets, V. S.; Romanenko, Ye. A.;
Drach, B. S. Zh Obshch Khim 2002, 72, 1828–
1833.
[12] Golovchenko, A. V.; Pilyo, S. G.; Brovarets, V. S.;
Chernega, A. N.; Drach, B. S. Synthesis 2003, 18,
2851–2857.
[13] Boulton, A. J.; Katritzky, A. R.; Hamid, A. M. J Chem
Soc C 1967; 2005–2007.
[14] The Chemistry of Heterocyclic Compounds, Vol. 45:
Oxazoles; Turchi, I. J. (Ed). Wiley: New York, 1986,
pp 102, 322.
[15] Allen, F. H.; Kennard, O; Watson, D. G.; Brammer, L.;
Orpen, A. G.; Tailor, R J Chem Soc, Perkin Trans 2
1987, No. 12, S1–19.
[16] Burke-Laing, M.; Laing, M. Acta Crystallogr Sect B
1976, 32, 3216–3224.
[17] Kuleshova, L. N.; Zorkii, P. M. Acta Crystallogr Sect
B 1981, 37, 1363–1366.
[18] Drach, B. S.; Mis’kevich, G. N. Zh Org Khim 1974, 10,
2315–2319.
[19] Sandstro¨m, Adv Hetorocycl Chem 1968, 9, 165–
209.
[20] North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr Sect A 1968, 24, 351–359.
[21] Watkin, D. J.; Prout, C. K.; Carruthers, J. R.;
Betteridge, P. W. CRYSTALS, Issue 10; Chemical Crys-
tallography Laboratory, University of Oxford: Oxford,
1996.
[22] Carruthers, J. R.; Watkin, D. J. Acta Crystallogr Sect
A 1979, 35, 698–699.
Data Collection. All crystallographic measure-
ments were performed at 20◦C on a CAD-4 Enraf-
Nonius diffractometer operation in the ꢄ–2ꢅ scan
mode (the ratio of the scanning rates ꢄ/2ꢅ = 1.2).
Intensity data were collected within the range 2 <
ꢅ < 70◦ (0 ≤ h ≤ 18, 0 ≤ k ≤ 9, −13 ≤ l ≤ 13) us-
ing graphite-monochromated Cu Kꢀ radiation (ꢆ =
˚
1.54178 A). Intensities of 2794 reflections (2491
unique reflections, R = 0.013) were measured.
int
Data were corrected for Lorentz and polarization ef-
fects, and an empirical absorption correction based
on azimuthal scan data was applied [20].
Structure Solution and Refinement. The struc-
ture was solved by direct methods and refined by
full-matrix least-squares technique in the anisotropic
approximation using the CRYSTALS program pack-
age [21]. In the refinement, 1939 reflections with I >
3ꢇ(I) were used. All hydrogen atoms were located
in the difference Fourier maps and included in the
final refinements with fixed positional and thermal
parameters (only H(4), H(51), and H(52) atoms par-
ticipating in hydrogen bonding were refined isotrop-
ically). Convergence was obtained at R = 0.041 and
Rw = 0.044, GOF = 1.108 (193 refined parameters;
obs/variabl. = 10.0; the largest and minimal peaks in
−3
˚
the final difference map, 0.27 and −0.31 e/A ). The
Chebyshev weighting scheme [22] with the parame-
ters 1.23, −0.38, 0.55, and 0.44 was used [23].
[23] Full crystallographic details have been deposited at
Cambridge Crystallographic Data Center (CCDC).
Any request to the CCDC for this material should
quote the full literature citation and reference
number CCDC 224128.
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