Reaction of 2-aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles with aryl Isothiocyanates

Article abstract of DOI:10.1134/S1070363207050209

Accessible 2-aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles add to aryl isothiocyanates. The resulting products undergo recyclization to form new 1,3,4-thiadiazole derivatives bearing an acylamino group on C² and an (acylamino)(cyano)methyl grou

Full text of DOI:10.1134/S1070363207050209

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 5, pp. 932 935.
Pleiades Publishing, Ltd., 2007.
Original Russian Text
No. 5, pp. 837 841.
O.V. Shablykin, A.V. Golovchenko, V.S. Brovarets, B.S. Drach, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77,
Reaction of 2-Aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles
with Aryl Isothiocyanates
O. V. Shablykin, A. V. Golovchenko, V. S. Brovarets, and B. S. Drach
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received October 9, 2006
Abstract Accessible 2-aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles add to aryl isothiocyanates. The
resulting products undergo recyclization to form new 1,3,4-thiadiazole derivatives bearing an acylamino group
on C2 and an (acylamino)(cyano)methyl group on C5. The structure of the new compounds was proved by
their IR and 1H NMR spectra, as well as by conversion in other 1,3,4-thiadiazole derivatives.
DOI: 10.1134/S1070363207050209
Proceeding with the research on transformations of
substituted 5-hydrazino-1,3-oxazoles (I) [1 3] we
have studied reaction of accessible bases I with aryl
isothiocyanates. As shown in the scheme, the reaction
produces initially expected adducts II that are capable
of prototropism. Prototropic tautomers III lack the
aromatic oxazole ring, and, therefore, they can un-
dergo recyclization under fairly mild conditions
(heating in dioxane) to form new 1,3,4-thiadiazole
derivatives IV (Table 1). Analogous recyclization also
occurs in the reactions of bases I with alkyl and aryl
isothiocyanates [3]. However, in spite of this analogy,
the structure of compounds IV, because of their in-
tricate formation route, had to be reliably confirmed
by spectral and chemical methods. The presence of the
RCONHCHC N fragment in the recyclization pro-
three types of relative compounds IV VI in rigid
conditions is accompanied by deacylation and decar-
boxylation to form, presumably, one and the same
compound,
2-amino-5-(methylamino)-1,3,4-thiadi-
azole hydrochloride (VII). The latter, while not iso-
lated individual, was converted into diacetyl deri-
vative VIII which was previously obtained by in-
dependent synthesis [5]. Thus, the assignment of
compounds IV VI to 1,3,4-thiadiazoe derivatives is
beyond doubt.
In summary we can conclude that attempted syn-
thesis of one more type of related compounds IX
containing, along with the thiadiazole ring, an
-
amino acid moiety failed. Treatment of amide VI with
nitrous acid even under very mild conditions gave a
complex mixture of compounds, that contained no
acid IX. At the same time, compounds IV and VI in
the scheme may well be considered as derivatives of
not only 1,3,4-thiadiazole, but also of glycine, which
is of no low importance for their assessment as
potential bioregulators.
1
ducts follows no only from the IR and H NMR spec-
tra (Table 2), but also was proved by the IV
V
transformation. This transformation readily occurs in
trifluoroacetic acid already at 20 25 C, which is
characteristic of many simpler -acylaminonitriles
[4]. The involvement of the acylamino fragment and
the C N bond in the cyclization is consistent the
1
EXPERIMENTAL
absence from the H NMR spectra of compounds V of
two doublet signals at 6.54 6.81 and 9.52 10.10 ppm,
characteristic of the CHNH fragment in compounds
IV. Furthermore, the presence of the unstable 5-amino-
1,3-oxazole fragment in compounds V is evidenced
by the fact that the latter are cleaved by aqueous acetic
acid to give new-type 1,3,4-thiadiazole derivatives VI.
The IR spectra were recorded on a Specord M-80
spectrometer in KBr. The 1H NMR spectra were ob-
tained on a VXR-300 instrument in DMSO-d6, in-
ternal reference TMS.
2-(Acylamino)-2-(2-acylamino-1,3,4-thiadiazol-5-
yl)acetonitriles IVa IVf. Acyl isothiocyanate,
0.01 mol, was added to a stirred solution of 0.01 mol
of compound Ia Ic [1 3] in 20 ml of anhydrous
dioxane. The mixture was refluxed for 15 min, cooled
However, from the preparative viewpoint, instead
of the V VI transformation, one can take better
advantage of the acid hydrolysis IV VI that occurs
already at 20 25 C. The acid hydrolysis of all the
932

REACTION OF 2-ARYL(METHYL)-4-CYANO-5-HYDRAZINO-1,3-OXAZOLES
933
C
N
C
N
N
C
O
N
N
N
N=C=S
R
NH
R
R
NH
NH
N
O
S
O
O
NH2
NH
S
Ia Ic
HN
HN
R
R
O
O
IIa IIf
IIIa IIIf
dioxane,
H2SO4/H2O, 20 25 C
H
N
O
N
N
H
N
O
O
N
N N
S
N
CF3C(O)OH
MeC(O)OH/H2O
R
R
R
N
N
H
R
R
N
H
N
H
S
S
R
O
O
O
C
R
NH2
NH2
VIa VId
N
IVa IVf
Va Vf
HNO2, 5 C
HCl/H2O,
H
N
H
N
O
O
N
N
N
N
N
S
N
+
(MeCO)2O
R
Me
H3N
Me
R
N
H
NH2
N
H
S
S
Cl
O
O
O
OH
VII
VIII
IXa IXd
R = Mf (Ia, IIa IIc Va Vc), Ph (Ib, IId IIf Vd Vf, VIa, VIb; IXa, IXb), 4-MeC6H4 (Ic, IIg, IIh Vg, Vh; VIc, Vd;
IXc, IXd); R = Me (IIa, IId Va, Vd), EtO (IIb, IIe, IIg Vb, Ve, Vg; VIb, VIc; IXb, IXc), Ph (IIc, IIf, IIh Vc, Vf, Vh;
VId, IXd).
Table 1. Yields, constants, and elemental analyses of compounds IV VI and VIII
Found, %
Calculated, %
Comp. Yield,
mp, C (solvent for crystallization)
Formula
no.
%
N
S
N
S
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
Va
66
71
90
82
70
92
75
87
85
95
93
247 248 (EtOH)
246 246 (dioxane)
290 292 (dioxane)
29.11 13.52
25.85 12.33
23.03 10.72
23.01 10.75
C8H9N5O2S
C9H11N5O3S
C13H11N5O2S
C13H11N5O2S
C14H13N5O3S
C18H13N5O2S
C15H15N5O3S
C19H15N5O2S
C8H9N5O2S
29.27 13.40
26.01 11.91
23.24 10.64
23.24 10.64
>300 decomp. (EtOH)
>300 decomp. (dioxane)
260 262 (dioxane)
>300 decomp. (dioxane)
255 257 (dioxane)
245 246 decomp. (dioxane)
197 198 (CF3COOH MeOH, 1:10)
195 196 (CF3COOH MeOH, 1:10)
21.01
19.10
20.08
18.42
9.53
8.68
9.14
8.30
21.14
19.27
20.28
18.56
9.68
8.82
9.28
8.49
29.05 13.35
25.80 11.73
23.15 10.75
29.27 13.40
26.01 11.91
23.24 10.64
Vb
Vc
C9H11N5O3S
C13H11N5O2S
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

934
SHABLYKIN et al.
Table 1. (Contd.)
Found, %
Calculated, %
Comp. Yield,
mp, C (solvent dor crystallization)
Formula
no.
%
N
S
N
S
Vd
Ve
Vf
Vg
91
96
94
97
285 286 decomp. (dioxane)
22.90 10.82
C13H11N5O2S
C14H13N5O3S
C18H13N5O2S
C15H15N5O3S
C19H15N5O2S
C13H13N5O3S
C14H15N5O4S
C15H17N5O4S
C19H17N5O3S
C7H10N4O2S
23.24 10.64
>300 decomp. (CF3COOH MeOH, 1:10)
268 269 (CF3COOH MeOH ,1: 10)
>300 decomp. (CF3COOH MeOH, 1:10)
260 261 (CF3COOH MeOH, 1:10)
290 291 (DMSO H2O, 1:10)
21.03
19.13
20.11
18.44
21.87
9.79
8.70
9.09
8.32
9.98
9.34
8.95
8.23
21.14
19.27
20.28
18.56
9.68
8.82
9.28
8.49
Vh
92
VIa
VIb
VIc
VId
VIII
55a
90a
87a
85a
51
21.93 10.04
233 235 decomp. (CH3COOH H2O, 10: 1) 19.89
203 205 decomp. (CH3COOH H2O, 10: 1) 19.07
266 267 decomp. (CH3COOH H2O, 10: 1) 17.51
20.01
19.27
17.71
9.17
8.82
8.11
290 292b (EtOH H2O, 2: 1)
26.31 15.01
26.15 14.97
a
b
Yield by procedure a.
Published data [5]: mp 292 C.
Table 2. Spectral data of compounds IV VI and VIII
Comp.
no.
1
IR spectrum (KBr), , cm
1H NMR spectrum (DMSO-d6), , ppm
3
IVa
IVb
IVc
IVd
IVf
1675 (NC=O), 1705 (NC=O), 3100 3450 1.95 s (3H, CH3), 2.20 s (3H, CH3), 6.61 d (1H, CH, JHH 7.8 Hz),
(NH as.)
3
9.55 d (1H, NH, JHH 7.8 Hz), 12.70 br.s (1H, NH)
1660 (NC=O), 1725 (OC=O), 3150 3400 1.29 t (3H, CH3), 1.94 s (3H, CH3), 4.25 q (2H, OCH2), 6.54 d (1H,
(NH as.)
CH, 3JHH 8.1 Hz), 9.52 d (1H, NH, 3JHH 8.1 Hz), 12.28 br.s (1H, NH)
1675a (NC=O), 3100 3380 (NH as.)
1.98 s (3H, CH3), 6.58 d (1H, CH, JHH 7.5 Hz), 7.56 m (3Harom),
8.14 d (2Harom), 9.55 d (1H, NH, JHH 7.5 Hz), 13.19 s (1H, NH)
3
3
1670a (NC=O), 3000 3300 (NH as.)
2.19 s (3H, CH3), 6.81 d (1H, CH, JHH 7.5 Hz), 7.50 m (3Harom),
3
7.92 d (2Harom), 10.07 d (1H, NH, 3JHH 7.5 Hz), 12.69 br.s (1H, NH)
3
1650 (NC=O), 1730 (NC=O), 3100 3300 6.81 d (1H, CH, JHH 8.1 Hz), 7.56 m (6Harom), 7.95 d (2Harom),
(NH as.)
8.12 d (2Harom), 10.10 d (1H, NH, 3JHH 8.1 Hz), 13.20 br.s (1H, NH)
IVg
1655 (NC=O), 1730 (C=O), 3100 3400 1.32 t (3H, CH3), 2.37 s (3H, CH3), 4.24 † (2H, OCH2), 6.69 d (1H,
3
(NH as.)
CH, JHH 7.8 Hz), 7.27 d (2Harom), 7.82 d (2Harom), 9.93 d (1H,
3
NH, JHH 7.8 Hz), 12.25 br.s (1H, NH)
3
IVh
1650 (NC=O), 1680 (NC=O), 3100 3350 2.40 s (1H, CH3), 6.79 d (1H, CH, JHH 7.8 Hz), 7.31 d (2Harom),
(NH as.)
7.60 m (3Harom), 7.84 d (2Harom), 8.11 d (2Harom), 10.01 d (1H,
NH, JHH 7.8 Hz), 13.19 br.s (1H, NH)
), 2800 3200 (NH as.), 2.16 s (3H, CH3), 2.31 s (3H, CH3), 6.53 br.s (2H, NH2), 12.14 br.s
(1H, NH)
), 1725 (OC=O), 2800 1.30 t (3H, CH3), 2.32 s (3H, CH3), 4.22 q (2H, OCH2), 6.61 br.s
3
Va
Vb
Vc
Vd
Ve
Vf
1670a (NC=O,
NH2
3280, 3420 (NH2)
1670a (NC=O,
NH2
3200 (NH as.), 3350, 3425 (NH2)
(2H, NH2), 11.79 br.s (1H, NH)
1650a (NC=O,
), 3000 3300 (NH as.), 2.31 s (3H, CH3), 6.69 br.s (2H, NH2), 7.52 m (3Harom), 8.11 d
(2Harom), 12.78 br.s (1H, NH)
), 2700 3250 (NH as.), 2.20 s (3H, CH3), 7.27 br.s (2H, NH2), 7.50 m (3Harom), 7.83 d
(2Harom), 12.41 br.s (1H, NH)
NH2
3350, 3420 (NH2)
1650 (NC=O,
NH2
3270, 3380 (NH2)
1650a (NC=O,
), 1740 (OC=O), 2800 1.32 t (3H, CH3), 4.27 q (2H, OCH2), 7.07 br.s (2H, NH2), 7.47 m
NH2
3250 (NH as.), 3300, 3430 (NH2)
(3Harom), 7.83 d (2Harom), 11.88 br.s (1H, NH)
1650a (NC=O,
), 2800 3100 (NH as.), 7.18 br.s (2H, NH2), 7.51 m (6Harom), 7.87 d (2Harom), 8.15
(2Harom), 12.60 br.s (1H, NH)
), 1720 (O=OC), 2800 1.31 t (3H, CH3), 2.37 s (3H, CH3), 4.24 q (2H, OCH2), 7.00 br.s
NH2
3320, 3450 (NH2)
Vg
1655a (NC=O,
NH2
3200 (NH as.), 3325, 3420 (NH2) (2H, NH2), 7.35 d (2Harom), 7.60 d (2Harom), 11.87 br.s (1H, NH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

REACTION OF 2-ARYL(METHYL)-4-CYANO-5-HYDRAZINO-1,3-OXAZOLES
Table 2. (Contd.)
935
Comp.
no.
1
IR spectrum (KBr), , cm
1H NMR spectrum (DMSO-d6), , ppm
Vh
1650a (NC=O,
), 2800 3180 (NH as.), 2.38 s (3H, CH3), 7.12 br.s (2H, NH2), 7.27 d (2Harom), 7.61 m
NH2
3340,
3460
(NH2)
(3Harom), 7.75 d (2Harom), 8.14 d (2Harom), 12.87 br.s (1H, NH)
1635 (NC=O), 1700a (NC=O), 2800 3400 2.18 s (3H, CH3), 5.95 d (1H, CH, JHH 7.7 Hz), 7.51 m (3Harom),
3
VIa
(NH as.)
7.55 br.s, 7.83 br.s (2H, NH2), 7.93 d (2Harom), 9.23 d (1H, NH,
3JHH 7.7 Hz), 12.48 br.s (1H, NH)
VIb
VIc
VId
1645a (NC=O), 1730a (OC=O), 2800 3400 1.28 t (3H, CH3), 4.22 q (2H, OCH2), 5.80 d (1H, CH, 3JHH 8.1 Hz),
(NH as.)
3
7.51 m (5H, 3Harom, NH2), 7.93 d (2Harom), 9.08 d (1H, NH, JHH
8.1 Hz), 12.02 br.s (1H, NH)
1645 (NC=O), 1705, 1740 (NC=O, OC=O), 1.28 t (3H, CH3), 2.38 s (3H, CH3), 5.91 d (1H, CH, JHH 7.8 Hz),
a
3
2800 3500 (NH as.)
7.27 d (2Harom), 7.47 br.s, 7.74 br.s (2H, NH2), 7.81 d (2Harom),
3
8.97 d (1H, NH, JHH 7.8 Hz), 12.00 br.s (1H, NH)
1645a (NC=O), 1665, 1680 (NC=O), 2800 2.39 s (3H, CH3), 5.97 d (1H, CH, JHH 7.5 Hz), 7.27 d (2Harom),
3
3400 (NH as.)
7.52 (3Harom), 7.60 br.s, 7.79 br.s (2H, NH2), 7.84 d (2Harom),
8.11 d (2Harom), 9.02 d (1H, NH, 3JHH 7.5 Hz), 12.97 br.s (1H, NH)
VIII
1655 (NC=O), 1700 (NC=O), 2900 3280 1.88 s (3H, CH3), 2.16 s (3H, CH3), 4.48 d (2H, CH2, 3JHH 5.7 Hz),
(NH as.)
8.63 t (1H, NH), 12.34 br.s (1H, NH)
a
Band with a shoulder.
to 20 25 C, the precipitate was filtered off, and
compounds IVa IVf were purified by crystallization
from dioxane.
2-(Acetylamino)-5-(acetylaminomethyl)-1,3,4-
thiadiazole (VIII). A suspension of 0.01 mol of com-
pound IV VI in 20 ml of 30% HCl was refluxed for
6 h, the precipitate was filtered off, the mother liquor
was evaporated in a vacuum to dryness, the residue
was treated with acetone, filtered off, dried, and dis-
solved in 20 ml of pyridine. Acetic anhydride,
0.06 mol, was then added, the mixture was stirred for
4 h at 50 C, the solvent was removed in a vacuum,
the residue was treated with water, filtered, and
compound VIII was purified by crystallization. A
mixture of this sample of compound VIII and a
sample of the same compound obtained by the known
procedure [5] gave no melting point depression.
2-(Acylamino)-5-[2-aryl(methyl)-5-amino-1,3-
oxazol-4-yl]-1,3,4-thiadiazoles Va Vf. A solution
of 0.01 mol of compound IVa IVf in 20 ml of tri-
fluoroacetic acid was left to stand for 10 min at 20
25 C, poured into 200 ml of ice water, the solution
was neutralized to pH 7 with aqueous sodium car-
bonate, the precipitate was filtered off, and compounds
Va Vf were purified by crystallization.
2-(Acylamino)-2-(2-acylamino-1,3,4-thiadiazol-5-
yl)acetamides VIa IVd. a. A solution of 0.002 mol
of compound Vd, Ve, Vg, or Vh in 10 ml of 70%
acetic acid was refluxed for 2 3 h, the solvent was
removed in a vacuum, the residue was treated with a
5% solution of sodium hydrocarbonate, the precipitate
was filtered off, washed with water, and compounds
VIa VId were purified by crystallization.
REFERENCES
1. Pil’o, S.G., Brovarets, V.S., Vinogradova, T.K., Cher-
nega, A.N., and Drach, B.S., Zh. Obshch. Khim., 2001,
vol. 71, no. 2, p. 310.
2. Golovchenko, A.V., Pil’o, S.G., Brovarets, V.S., Cher-
nega, A.N., and Drach, B.S., Zh. Obshch. Khim., 2005,
vol. 75, no. 3, p. 461.
3. Golovchenko, O.V., Pilyo, S.G., Brovarets, V.S., Cher-
nega, A.N., and Drach, B.S., Heteroatom. Chem., 2004,
vol. 15, no. 6, p. 454.
4. Turchi, I.J., Oxazoles. The Chemistry of Heterocyclic
Compounds, Turchi, I.J., Ed., New York: Wiley, 1986,
vol. 45.
b. A solution of 0.004 mol of compound Vd, Ve,
Vg, or Vh in 2 ml of conc. H2SO4 was left to stand
for 6 h at 20 25 C, poured into 100 ml of ice water,
neutralized with 10% sodium carbonate, the precipi-
tate was filtered off, and compounds VIa VId were
purified by reprecipitation from acetic acid with water
(10:1). The yields of compounds VIa VId were 60
70%. Mixed samples of samples of compounds VIa
VId prepared by procedures a and b gave no melting
point depression.
5. Ohta, M. and Koyata, H., J. Pharm. Soc. Jpn., 1952,
vol. 72, p. 1636, Chem. Abstr., 1953, vol. 47, 9324a.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007