Reactions of 5-dialkylamino-1,2,3-thiadiazole-4-carbaldehydes with amines as a method for the synthesis of 1,2,3-triazole-4-carbothioamides

Article abstract of DOI:10.1023/B:RUCB.0000042292.19119.3d

A method for the synthesis of previously inaccessible 5-dialkylamino- substituted 1,2,3-thiadiazole-4-carbaldehydes was developed. Ring transformation in these compounds induced by primary aliphatic and aromatic amines, hydroxylamines, and N-substituted hydrazines resulted in the synthesis of a broad range of 1,2,3-triazole-4-carbothioamide.

Full text of DOI:10.1023/B:RUCB.0000042292.19119.3d

Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1311—1317, June, 2004
1311
Reactions of 5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehydes with amines
as a method for the synthesis of 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides ✾
a
a
b
T. V. Glukhareva,a Yu. Yu. Morzherin,a L. V. Dyudya, K. V. Malysheva, A. V. Tkachev,
ꢀ
A. Padva,c and V. A. Bakuleva
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation,
Eꢀmail: morjerine@htf.ustu.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation
Eꢀmail: atkachev@nioch.nsc.ru
cEmory University, Department of Chemistry, 1515, Pierce Drive, Atlanta GA 30322, USA.
Eꢀmail: chemap@emory.edu
A method for the synthesis of previously inaccessible 5ꢀdialkylaminoꢀsubstituted 1,2,3ꢀthiaꢀ
diazoleꢀ4ꢀcarbaldehydes was developed. Ring transformation in these compounds induced by
primary aliphatic and aromatic amines, hydroxylamines, and Nꢀsubstituted hydrazines reꢀ
sulted in the synthesis of a broad range of 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamide.
Key words: 1,2,3ꢀtriazole, 1,2,3ꢀthiadiazole, thioamides, Cornfort rearrangement, nucleoꢀ
philic substitution, reduction, oxidation.
Thioamides are highly reactive compounds, which find
extensive use in organic synthesis,1 medicine,2 and engiꢀ
neering.3 However, the most popular methods for their
synthesis such as thionation4 or sulfhydration of nitriles5
are inapplicable, in some cases, to heterocyclic thioꢀ
amides, because under the reaction conditions, heteroꢀ
cycles can undergo various transformations.6 The rearꢀ
rangements of some heterocycles into other ones repreꢀ
sent a convenient route to compounds that are difficult or
impossible to prepare by other methods;7 however, rearꢀ
rangements are seldom used for targeted synthesis of
heterocyclic systems.8 As a continuation of our studies
dealing with rearrangements of 1,2,3ꢀthiadiazoles,9 in this
work, we present a method for the synthesis of 1,2,3ꢀtriꢀ
azoleꢀ4ꢀcarbothioamides 1.
We developed a synthetic route to 1,2,3ꢀtriazoleꢀ4ꢀ
carbothioamides 1 whose key step was the rearrangement
of imines 2, which are produced in the reaction of
1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehydes 3 with primary amines
(Cornfort rearrangement). In a reported example where
this method was used for the synthesis of 1,2,3ꢀtriazoleꢀ
4ꢀcarbothioamide derivatives, 5ꢀchloroꢀ or 5ꢀtertꢀbutylꢀ
thioꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehyde was taken as the
starting compound.10,11 However, this approach restricts
the scope of the method to the triazoles with identical
substituents in position 1 of the ring and the thioamide
function, because the substitution occurs simultaneously
at the two reaction centers. We used aldehydes 3 for the
synthesis of triazoles with various substituents in position
1 and the thioamide group in position 4 of the ring. It
should be noted that aldehydes 3 have not been reported.
They can be prepared by oxidation of the CH2OH group
in 5ꢀaminoꢀ4ꢀhydroxymethylꢀ1,2,3ꢀthiadiazoles 4. This
method has been used to synthesize ethyl 5ꢀformylꢀ1,2,3ꢀ
thiadiazoleꢀ4ꢀcarboxylate.12 The existing methods for the
preparation of 4ꢀhydroxymethylꢀ1,2,3ꢀthiadiazoles inꢀ
clude nucleophilic substitution of an OH group for the
halogen atom in the reaction of 4ꢀbromomethylꢀ1,2,3ꢀ
thiadiazole with NaOH and the reaction of 4ꢀlithioꢀ1,2,3ꢀ
thiadiazole with formaldehyde.13 The scope of both reꢀ
actions is markedly limited as regards the structure of
the starting compounds, and they have not found wide
use for the synthesis of aldehydes of the 1,2,3ꢀtriadiazole
series.
We synthesized compounds 4 in two steps from availꢀ
able14 ethyl 5ꢀchloroꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarboxylate (5).
The nucleophilic replacement of the chlorine atom in
compound 5 in reactions with secondary amines gave
5ꢀaminoꢀ1,2,3ꢀthiadiazoles 6a—e (Scheme 1). It is known
that these reactions can be accompanied by side proꢀ
cesses;15—16 therefore, the reaction was carried out in ethaꢀ
nol with cooling. Under these conditions, the ester groups
in compounds 6a—e were not amidated, and these comꢀ
pounds were obtained in 50—85% yields.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1258—1264, June, 2004.
1066ꢀ5285/04/5306ꢀ1311 © 2004 Plenum Publishing Corporation

1312
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Glukhareva et al.
Scheme 1
carbonyl group in compounds 6a—e with sodium boroꢀ
hydride.17 According to our data, unlike those published
previously,18 the reduction involves only the ethoxyꢀ
carbonyl group and does not affect the thiadiazole ring.
The oxidation of the hydroxymethylene group of comꢀ
pounds 4a—e to an aldehyde group was performed by
active manganese dioxide in chloroform at ~20 °C. Note
that aldehydes 3a—e are thermally labile compounds and
are easily deformylated: on heating in solvents such as
benzene, toluene, or ethanol, 4Hꢀ1,2,3ꢀthiadiazoles 7a—c
are formed.
The reactions of 1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehydes
3a—h with amines and hydrazines were carried out at
~20 °C in ethanol. However, imines 2 have not been
isolated, as under these conditions, they underwent the
Cornfort rearrangement through intermediate diazo comꢀ
pounds 8a—z (Scheme 2). Thus, two successive condenꢀ
sations and ring transformation provided the target
1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides 1a—z.
The structure of the compounds obtained was conꢀ
firmed by IR, 1H NMR, and 13C NMR spectroscopy,
mass spectrometry, and elemental analysis data. The main
clues pointing to the triazole structure are the chemical
shifts of the 13C NMR signals of the thioamide carbon
atom in the region of 184.8 ppm and the C(4) and C(5)
atoms of the triazole ring at 147 and 122.8 ppm, respecꢀ
tively. The signal of the proton of the triazole ring occurs
at 8.15 ppm as a singlet. The proton and carbon chemical
shifts are consistent with published data for 1,2,3ꢀtriazoleꢀ
4ꢀcarbothioamides.19 In the case of 1,2,3ꢀthiadiazole 2,
the signals for the C(4) and C(5) atoms of the thiadiꢀ
azole ring should have been observed at 138—141 and
165—166 ppm, that for the carbon atom of the CH=N
group would be at 140—142 ppm, and the proton signal
for the CH=N group would be at 9.1—9.5 ppm.19
3, 4, 6, 7
a
b
c
d
e
R
X
H
O
Me
O
H
—
H
NMe
H
CHCH2Ph
4ꢀHydroxymethylꢀ1,2,3ꢀthiadiazoles 4a—e were preꢀ
pared in 44—80% yields by the reduction of the ethoxyꢀ
Scheme 2
R1
=
,
,
,
,
R2 = OH (a), OMe (b), NHC6H3(NO2)2ꢀ2,4 (c), C6H4OMeꢀ2 (d, q, v, t), C6H4Fꢀ4 (e, r), Me (f), C6H4CF3ꢀ2 (g),
C6H4OMeꢀ3 (h), C6H4OMeꢀ4 (i), C6H11 (j), C6H4Fꢀ2 (k), C6H4OHꢀ2 (l, s), C6H4Brꢀ4 (m), CH2Ph (n, t, w, y),
NHSO2C6H4Meꢀ4 (o), C6H4Meꢀ4 (p, u, z), C6H4Meꢀ3 (x)

Reaction of 1,2,3ꢀthiadiazole with amines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1313
UVꢀ254 plates in chloroform and in the chloroform—ethanol
(9 : 1, 15 : 1, 20 : 1) and ethyl acetate—hexane (1.5 : 2, 1 : 2)
solvent systems. IR spectra were measured on a URꢀ20 spectroꢀ
photometer in KBr pellets; and NMR spectra were recorded on
Вruker WMꢀ250 (250 MHz for 1H) and Вruker DRXꢀ400
(400 MHz for 1H and 100 MHz for 13C) instruments with Me4Si
as the internal standard; and mass spectra were run on Varian
MAT 311A and Finnigan MAT 8200 spectrometers with an
ionizing voltage of 70 eV and with direct sample injection into
the ion source. The solvents were purified by standard proceꢀ
dures. Ethyl 5ꢀaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarboxylate14 and
Thus, by using a new approach to the synthesis of
5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehydes, we
have developed a convenient method for the synthesis of
a broad range of 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamide deꢀ
rivatives.
Experimental
The course of the reactions was monitored and the purity of
the synthesized compounds was checked by TLC on Silufol
Table 1. Physicochemical characteristics of the synthesized compounds
Comꢀ Yield M.p. Found
Molecular
formula
Mass
spectrum, m/z poꢀ
(Irel (%))
Comꢀ Yield M.p. Found
Molecular
formula
Mass
spectrum, m/z
(Irel (%))
(%)
(%)
poꢀ
(%)
/°C Calculated
(%)
/°C Calculated
und
und
N
S
N
S
1a
1b
1c
1d
1e
1f
89
88
76
53
38
40
85
92
91
62
62
73
85
76
57
86
92
67
52
60
112 26.03 14.42
26.15 14.97
112 24.55 14.42
24.54 14.05
C7H10N4O2S
C8H12N4O2S
214
(27)
228
1u
1v
1w
1x
1y
1z
4a
4b
4c
4d
4e
6a
6b
6c
6d
6e
7a
7b
7c
60
75
66
95
82
28
73
44
80
76
69
85
61
130 17.79 10.45 C15H18N4O2S
17.60 10.07
104 20.90 11.80 C14H16N4S
20.57 11.77
106 19.78 11.17 C14H16N4OS
19.43 11.12
102 23.08 10.55 C15H19N5S
23.23 10.64
272
(10)
288
(12)
301
(13)
376
(5)
376
(33)
201
(87)
299
(36)
185
(30)
—
(59)
182 25.5
8.50
C13H13N7O5S 379
25.85 8.45
160 18.66 10.59
18.40 10.54
146 18.82 11.30
19.17 10.97
114 26.11 14.93
26.39 15.11
89 16.03 9.39
16.37 9.37
128 19.03 10.39
18.41 10.53
92 18.39 10.89
18.41 10.53
92 19.79 11.99
19.98 11.44
92 18.79 11.15
19.17 10.97
164 19.17 11.01
19.30 11.04
180 16.03 9.25
15.86 9.08
140 20.00 10.81
19.43 11.12
112 19.55 17.42
19.06 17.45
150 19.32 11.28
19.43 11.12
112 17.58 10.22
17.71 10.13
130 17.63 10.18
17.71 10.13
114 16.72 9.43
16.85 9.65
(3)
C14H16N4O2S 304
(12)
C13H13FN3OS 292
(47)
110 14.65
14.88
8.73 C12H24N4S
8.52
C8H12N4OS
212
(42)
342
130 14.35
14.88
8.46 C22H24N4S
8.52
1g
1h
1i
C14H16N4OS
120 21.10 15.80 C7H11N3O2S
20.88 15.93
(70)
C14H16N4O2S 304
88
90
90
18.30 13.87 C9H15N3O2S
18.33 13.98
22.58 17.47 C7H11N3OS
22.68 17.31
26.03 15.07 C8H14N4OS
26.15 14.96
(33)
C14H16N4O2S 304
(76)
1j
C13H20N4OS
280
(85)
1k
1l
C13H13FN4OS 292
105 15.05 10.78 C15H19N3OS
14.52 11.08
289
(20)
—
(35)
C13H14N4O2S 290
(12)
92
17.50 12.70 C9H13N3O3S
17.27 13.18
1m
1n
1o
1p
1q
1r
1s
1t
C13H13BrN4OS
C14H16N4OS
C14H17N5O3S2
C14H16N4OS
C16H20N4OS
C16H20N4OS
—
82* 15.97 12.06 C11H17N3O3S
15.49 11.82
—
—
—
—
288
(16)
—
47 76—78 18.53 14.09 C9H13N3O2S
18.49 14.11
67 62—65 21.53 12.49 C10H16N4O2S
21.86 12.51
64
72
77
68
288
(25)
316
(12)
316
(25)
84
12.78
12.68
9.44 C17H21N3O2S
9.67
90
24.90 18.78 C6H9N3OS
24.54 18.73
171
(65)
199
(20)
155
(67)
136 21.39 16.12 C8H13N3OS
21.09 16.09
C16H20N4O2S 332
80
26.79 20.51 C6H9N3S
27.07 20.66
(13)
C15H17FN4OS 320
(8)
130 17.33 10.13
17.49 10.01
* cf. Ref. 19: 82 °C.

1314
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Glukhareva et al.
1
Table 2. H NMR spectra (DMSOꢀd6) of 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides 1a—z
Comꢀ
pound
δ (J/Hz)
C(5)H
R2
R1
NCH2
Other signals
1a
1b
8.40
8.77
13.94 (br.s, 1 H, ОH)
4.25 (s, 3 H, OCH3)
3.76 (t, 2 H, NCH2, J = 4.6);
3.68 (t, 2 H, NCH2, J = 4.6)
3.77 (t, 2 H, NCH2, J = 4.9);
3.67 (t, 2 H, NCH2, J = 4.9)
4.30 (t, 2 H, ОCH2, J = 4.6);
4.07 (t, 2 H, ОCH2 J = 4.6)
4.20—4.35 (m, 2 H, OCH2);
4.03 (t, 2 H, OCH2, J = 4.9)
1c
1d
8.83
8.77
11.88 (br.s, 1 H, NH); 8.92 (d, 1 H,
ArH, J = 2.8); 8.35 (dd, 1 H, ArH, J =
9.5, J = 2.8); 6.46 (d, 1 H, ArH, J = 9.5)
7.67 (dd, 1 H, ArH, J = 6.7, J = 1.8);
7.55 (ddd, 1 H, ArH, J = 7.6, J = 7.9,
J = 1.5); 7.33 (ddd, 1 H, ArH, J = 7.6,
J = 7.8, J = 1.6); 7.16 (dd, 1 H, ArH,
J = 7.6, J = 1.2); 3.87 (s, 3 H, OMe)
7.77—7.72 (m, 2 H, 2 ArH); 7.29—7.81
(m, 2 H, 2 ArН)
3.81 (t, 2 H, NCH2, J = 4.6);
3.75 (t, 2 H, NCH2, J = 4.6)
4.35 (t, 2 H, ОCH2, J = 4.6);
4.12 (t, 2 H, ОCH2, J = 4.6)
3.79 (t, 2 H, NCH2, J = 4.6);
3.71 (t, 2 H, NCH2, J = 4.6)
4.35 (t, 2 H, OCH2, J = 4.6);
4.12 (t, 2 H, OCH2, J = 4.6)
1e
1f
8.55
8.14
8.86
8.58
3.94—3.82 (m, 4 H, N(СH2)2)
4.48—4.38 (m, 4 H, O(СH2)2)
4.09 (s, 3 H, Me)
3.89 (t, 2 H, NCH2, J = 4.6);
3.82 (t, 2 H, NCH2, J = 4.6)
3.82 (t, 2 H, N(СH)2 J = 4.5);
3.75 (t, 2 H, N(СH)2, J = 4.5)
4.42 (t, 2 H, OCH2 J = 4.6);
4.35 (t, 2 H, OCH2, J = 4.6)
4.37 ( t, 2 H, О(CH)2, J = 4.5);
4.10 (t, 2 H, О(СH)2, J = 4.5)
4.46 (t, 2 H, O(CH)2, J = 4.8);
4.40 (t, 2 H, O(CH)2, J = 4.8);
3.93—3.84 (m, 7 H,
1g
1h
8.05—7.78 (m, 4 H, ArH)
7.43 (dd, 1 H, ArH, J = 8.1, J = 8.1); 7.26—7.34
(m, 2 H, 2 ArH); 7.0 (dd, H, ArH, J = 6.3, J = 1.5);
3.93—3.84 (m, 7 H, OCH3 and N(СН2)2)
Me and N(СН2)2)
1i
8.50
8.52
8.91
7.65 (d, 2 H, 2 ArH, J = 9.2); 7.03 (d,
2 H, 2 ArH, J = 9.2); 3.85 (s, 3 H, OCH3) 3.72 (t, 2 H, N(СH)2, J = 4.4)
4.40—4.55 (m, 1 H, СH); 2.00—2.20 (m, 3.76 (t, 2 H, N(СH)2, J = 4.9); 4.31 (t, 2 H, О(CH)2, J = 4.9);
2 Н, СН2); 1.20—2.00 (m, 8 Н, 4 (СН2)) 3.68 (t, 2 H, N(СH)2, J = 4.9)
3.80 (t, 2 H, N(СH)2, J = 4.4); 3.75—3.88 (m, 4 Н, О(CН2)2)
1j
4.10 (t, 2 H, О(СH)2, J = 4.9)
3.81 (t, 2 Н, N(СН)2, J = 4.8); 4.36 (t, 2 H, O(СН)2, J = 4.8);
3.72 (t, 2 Н, N(СН)2, J = 4.8) 4.08 (t, 2 Н, O(СН)2, J = 4.8)
1k
7.88 (ddd, 1 H, ArH, J = 6.4, J = 6.0,
J = 1.6); 7.56—7.66 (m, 2 H, 2 ArH);
7.10 (dd, 1 H, ArH, J = 7.6, J = 7.6)
10.53 (уш.s, 1 H, ОH); 7.69 (dd, 1 H,
ArH, J = 8.0, J = 1.2); 7.29 (ddd, ArH,
J = 8.0, J = 8.0, J = 1.6); 7.12 (dd,
1 H, ArН, J = 7.2, J = 1.2); 6.97 (ddd,
1 Н, ArН, J = 7.2, J = 8.0, J = 1.2)
7.96 (d, 2 H, 2 ArH, J = 8.8); 7.72 (d,
2 H, 2 ArH, J = 8.8)
7.39—7.35 (m, 5 H, Ph); 5.62 (s, 2 H,
СН2)
12.00 (br.s, 1 H, NH); 7.62 (d, 2 H,
2 ArH, J = 8.5); 7.44 (d, 2 H, 2 ArH,
J = 8.5); 2.42 (s, 3 Н, Me)
1l
8.74
3.83 (t, 2 Н, N(СН)2, J = 4.4); 4.36 (t, 2 Н, O(СН)2, J = 4.8);
3.77 (t, N(СН)2, J = 4.8) 4.26 (t, 2 Н, O(СН)2, J = 4.4)
1m
1n
1o
8.55
8.59
8.42
3.83 (t, 2 Н, N(СН)2, J = 4.8); 4.36 (t, 2 H, O(CH)2, J = 4.8);
3.75 (t, 2 Н, NСН2, J = 4.7) 4.15 (t, 2 H, O(CH)2, J = 4.6)
3.76 (t, 2 H, N(CH)2, J = 4.8); 4.31 (t, 2 H, O(СH)2, J = 4.9);
3.67 (t, 2 H, N(CH)2, J = 4.9) 4.11 (t, 2 H, О(СH)2, J = 4.8)
3.76 (t, 2 H, N(CH)2, J = 4.9); 4.28 (t, 2 H, О(CH)2, J = 4.9);
3.67 (t, 2 Н, N(СН)2, J = 4.9)
3.91 (t, 2 H, О(CH)2, J = 4.9)
1p
1q
8.55
8.08
7.65 (d, 2 H, 2 ArH, J = 8.0); 7.61 (d,
2 H, 2 ArH, J = 8.0); 2.43 (s, 3 H, Me)
3.83—3.93 (m, 4 H, N(CH2)2)
4.38—4.47 (m, 4 H, O(СН2)2)
7.33—7.41 (m, 5 H, Ph); 5.45—5.43 (m, 3 H, СH2 and NCH);
5.15 (d, 1 H, NCH, J = 6.5); 3.04 (dd, 1 H, NCH, J = 13.1,
J = 10.7); 2.83 (dd, 1 H, NCH, J = 13.1, J = 10.7)
3.73—3.81 (m, 2 H, O(CH)2);
1.21 (d, 3 H, Me, J = 6.1)
1r
9.11
7.84 (d, 2 H, 2 ArH, J = 8.2); 7.41 (d,
2 H, 2 ArH, J = 8.2); 2.39 (s, 3 Н, Me)
5.36 (dd, 1 H, NCH, J = 13.2,
J = 0.6); 4.54 (d, 1 H, NCH,
3.63—3.72 (m, 2 H, О(CH)2);
1.22 (d, 3 H, Me, J = 6.4);
J = 13.2); 3.13 (dd, 1 Н, NCH, 1.19 (d, 3 H, Me, J = 6.1)
J = 12.8, J = 10.7); 2.93 (dd,
1 Н,NCH, J = 12.8, J = 10.7)
(to be continued)

Reaction of 1,2,3ꢀthiadiazole with amines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1315
Table 2 (continued)
Comꢀ
pound
δ (J/Hz)
C(5)H
8.63
R2
R1
NCH2
Other signals
1s
1t
1u
7.73 (dd, 1 H, ArH, J = 7.6, J = 1.6);
7.49 (ddd, 1 H, ArH, J = 8.5, J = 8.9,
J = 1.6); 7.27 (dd, 1 H, ArH, J = 8.5,
J = 0.8); 7.13 (ddd, 1 H, ArH, J = 7.7,
J = 8.7, J = 0.9); 3.95 (s, 3 Н, OMe)
7.72—7.77 (m, 2 H, 2 ArH); 7.28—7.21
(m, 2 H, 2 ArH)
5.40 (d, 1 H, NCH, J = 13.0);
4.91 (d, 1 Н, NСН, J = 13.2);
3.10 (dd, 1 Н, NСН, J = 13.0,
J = 10.6); 2.84 (dd, 1 H, NCH,
J = 13.0, J = 10.8)
5.52 (d, 1 H, NСH, J = 13.2);
5.08 (dd, 1 H, NСH, J = 13.2,
J = 2.2); 3.11 (dd, 1 H, NCH,
J = 12.9, J = 11.0); 2.89 (dd,
1 Н, NСН, J = 13.2, J = 11.0)
5.36 (d, 1 H, NCH, J = 13.1);
4.66 (d, 1 Н, NСН, J = 13.1);
3.70—3.76 (m, 2 Н, О(СН)2);
1.27 (d, 3 Н, Me, J = 6.2);
1.18 (d, 3 Н, Me, J = 6.2)
8.54
8.76
3.76—3.87 (m, 2 H, О(СН)2);
1.32 (d, 3 Н, Me, J = 5.9);
1.24 (d, 3 Н, Me, J = 6.3)
10.63 (br.s, 1 H, ОH); 7.66 (dd, 1 H,
ArH, J = 7.9, J = 1.5); 7.36 (ddd, 1 H,
3.66—3.72 (m, 2 Н, О(СН)2);
1.22 (d, 3 H, Me, J = 6.1);
1.11 (d, 3 H, Me, J = 6.1)
ArH, J = 9.2, J = 8.2, J = 1.7); 7.13 (dd, 3.15 (dd, 1 H, NCH, J = 12.5,
1 H, ArH, J = 8.2, J = 0.9); 7.00 (ddd,
1 H, ArH, J = 7.9, J = 8.6, J = 1.2)
J = 10.7); 2.92 (dd, 1 H, NCH,
J = 13.1, J = 11.0)
1v
8.53
8.69
7.20—7.50 (m, 5 H, 5 ArH); 5.59 (s, 2 H, 4.12 (t, 2 H, N(СH)2, J = 6.4); 1.90—2.10 (m, 4 H, 2 СH2)
СH2) 3.86 (t, 2 H, N(СH)2, J = 6.4)
1w
7.69 (d, 1 H, ArH, J = 7.3); 7.50 (dd, 1 H, ArH, J = 7.0, J = 7.3);
7.28 (d, 1 H, ArH, J = 8.2); 7.13 (dd, 1 H, ArH, J = 7.6, J = 7.6);
4.19 (t, 2 H, N(CH)2, J = 6.4); 3.81—4.10 (m, 5 Н, OMe and N(CH)2)
1.90—2.25 (m, 4 Н, 2 СН2)
1x
1y
8.83
8.52
7.40—7.54 (m, 4 H, ArH); 2.18 (s, 3 H,
Me)
7.16—7.42* (m, 10 H, 2 Ph);
5.60 (s, 2 H, СH2)
4.34 (t, 2 H, NCH2, J = 4.9);
4.04 (t, 2 H, NCH2, J = 4.9)
5.33 (dd, NCH, J = 6.7, J =
4.9); 4.58 (dd, 1 H, NCH,
J = 14.3, J = 4.0); 3.12—3.67
(m, 2 H, N(CH)2)
5.35 (d, 1 H, NCH, J = 12.5);
4.46 (d, 1 Н, NСН, J = 12.5);
3.20—3.42 (m, 2 Н, N(CH)2)
2.45—2.54 (m, 4 H, 2 N(CH)2);
2.25 (s, 3 H, NMe)
2.56 (d, 2 Н, СН2, J = 7.0);
1.80—2.02 (m, 1 Н, СН);
1.65—1.75 (m, 2 Н, 2 СН);
1.24—1.39 (m, 2 Н, 2 СН);**
7.18—7.32 (m, 5 H, Ph);
2.57 (d, 2 Н, СН2, J = 7.3);
1.90—2.10 (m, 1 Н, СН);
1.60—1.90 (m, 2 Н, 2 СН);
1.20—1.50 (m, 2 Н, 2 СН)
1z
9.03
7.82 (m, 2 H, 2 ArH); 7.40 (m, 2 H,
2 ArH); 2.39 (s, 3 Н, Me)
* The signals of the Ph groups occur together with the signals of the Ph group of R1.
** The signals of the Ph groups occur together with the signals of the benzene groups of R2.
1
Table 3. H NMR spectra of 1,2,3ꢀthiadiazoles 4a—e
Comꢀ
pound
Solvent
δ (J/Hz)
OH
CH2O
Other signals
4a
4b
CDCl3
CDCl3
5.00 (d, J = 5.5)
5.00 (d, J = 6.1)
2.48 (t, J = 5.5)
2.34 (t, J = 6.1)
3.34—3.39 (m, N(CH2)2); 3.35—3.88 (m, 4 H, О(CH2)2)
3.51 (dd, 2 H, 2NCH, J =11.9, J =1.5); 2.75 (dd, 2 H, 2 NCH,
J = 11.9, J = 10.7); 33.77—3.89 (m, 2 H, О(CH)2); 1.24 (d, 6 H,
2 Me, J = 6.4)
4c
4d
DMSOꢀd6 4.80 (d, J = 4.9)
DMSOꢀd6 4.79 (s)
5.24 (t, J = 4.9)
5.24 (br.s)
3.48—3.53 (m, 4 H, N(CH2)2); 1.98—2.03 (m, 4 H, 2 CH2)
3.51 (t, 4 H, N(CH2)2, J = 5.2); 2.50 (t, 4 H, N(CH2)2, J = 5.2);
2.24 (s, 3 H, Me)
4e
CDCl3
4.82 (br.s)
5.73 (br.s)
7.10—7.35 (m, 5 H, Ph); 5.30 (dd, 1 H, NCH, J = 12.2); 4.82
(br.s, 2 H, CH2);
4.48 (dd, 1 Н, NСН, J = 12.2); 3.20—3.43 (m, 2 Н, CH2)

1316
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Glukhareva et al.
Table 4. 1H NMR spectra (DMSOꢀd6) of 1,2,3ꢀthiadiazoles 6a—e
Comꢀ
pound
δ (J/Hz)
OCH2
Me
Other signals
6a
6b
4.35 (q, J = 7.0) 1.32 (t, J =7.0)
4.32 (q, J = 7.0) 1.32 (t, J =7.0)
3.76 (t, 4 H, O(CH2)2, J = 4.8); 3.43 (t, 4 H, N(CH2)2, J = 4.8)
3.70—3.82 (m, 2 H, 2 СH); 3.67 (dd, 2 H, 2 СH, J = 12.2, J = 2.7);
2.81 (dd, 2 Н, 2 СH, J = 12.2, J = 11.0); 1.32 (t, 3 H, OCH2CH3, J = 7.0);
1.12 (d, 6 H, 2 Me, J = 6.4)
6c
6d
4.33 (q, J = 7.0) 1.31 (t, J =7.0)
4.34 (q, J = 7.0) 1.32 (t, J =7.0)
3.27—3.45 (t, 4 H, N(CH2)2, J = 6.7); 1.97—3.03 (pentete, 4 H, 2 СH2, J = 6.7)
3.43 (t, 4 H, О(CH2)2, J = 5.0); 2.49 (t, 4 H, N(CH2)2, J = 5.0);
2.23 (s, 3 H, NCH3)
6e
4.33 (q, J = 7.1) 1.32 (t, J =7.1)
7.26—7.23 (m, 2 H, ArH); 7.13—7.17 (m, 3 H, ArH); 3.70 (d, 2 H,N(CH)2,
J = 12.5); 3.13—3.05 (m, 2 Н, (СН)2); 2.57 (d, 2 Н, СН2, J = 7.1); 1.85—1.79
(m, 1 Н, СН); 1.73 (dd, 2 Н, N(СН)2, J = 13.0); 1.48—1.50 (m, 2 Н, (СН)2)
Table 5. 13C NMR spectra (CDCl3) of 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides 1b—d
Comꢀ
pound
δ
C=S
C(4)
C(5)
NCH2
OCH2
Other signals
1b
1c
184.8
185.6
147.0
146.4
122.8 52.9, 50.7
115.8 52.6, 51.1
66.8, 66.3
67.2, 66.7
67.8 (OMe)
140.4 (ArNO2); 135.9 (ArNO2); 132.8 (ArNH); 132.1 (ArH),
130.5 (ArH); 123.2 (ArH)
1d
185.1
147.7
130.3 52.8, 50.1
66.4, 65.8
151.6 (ArO); 131.1 (Ar); 125.7 (ArH); 125.0 (Ar); 120.8 (ArH);
113.0 (ArH); 56.20 (Me)
5ꢀmorpholinoꢀ1,2,3ꢀthiadiazolecarbaldehydes 3a,b were syntheꢀ
sized by known procedures.9,20
(DMSOꢀd6+CCl4), δ: 10.27 (s, 1 H, CH); 7.25—7.28 (m, 2 H,
ArH); 7.12—7.17 (m, 3 H, ArH); 3.72 (t, 2 H, N(CH)2, J =
12.5 Hz); 3.13—3.05 (m, 2 H, (CH)2); 2.57 (d, 2 H, CH2, J =
7.1 Hz); 1.80—1.85 (m, 1 H, CH); 1.70 (t, 2 H, N(CH)2, J =
13.0 Hz); 1.49—1.50 (m, 2 H, (CH)2). IR, ν/cm–1: 1735 (C=O).
MS, m/z (Irel (%)): 287 [M]+ (15). Found (%): N, 15.08; S, 11.44.
C15H17N3OS. Calculated (%): N, 14.62; S, 11.16.
Synthesis of 5ꢀdialkylaminoꢀ4ꢀhydroxymethylꢀ1,2,3ꢀthiaꢀ
diazoles (4a—e) (general procedure). NaBH4 (0.53 g, 14 mmol)
was added to a solution of ethyl 5ꢀdialkylaminoꢀ1,2,3ꢀthiaꢀ
diazoleꢀ4ꢀcarboxylate 6 (3.5 mmol) in 50 mL of anhydrous ethaꢀ
nol. The mixture was refluxed for 1 h and cooled. Water (100 mL)
was added. The product was extracted with CHCl3 (3×50 mL),
the combined organic extract was dried with Na2SO4, and the
solvent was evaporated in vacuo. The product was recrystallized
from benzene.
Synthesis of 1ꢀsubstituted 1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides
(1) (general procedure). Amine (1 mmol) was added to a soluꢀ
tion of 5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehyde 3
(1 mmol) in 2 mL of ethanol. The mixture was kept for 1 h at
~20 °C and cooled. The precipitate was filtered off and recrysꢀ
tallized from ethanol. The data of elemental analysis and physiꢀ
cochemical characteristics are given in Tables 1—5.
Synthesis of 5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldeꢀ
hydes (3a—e) (general procedure). Freshly prepared active MnO2
(10.5 g, 0.12 mmol) was added to a solution of 5ꢀdialkylaminoꢀ
4ꢀhydroxymethylꢀ1,2,3ꢀthiadiazole (4) (5 mmol) in 50 mL of
CH2Cl2. The reaction mixture was stirred for 2 h at ~20 °C and
filtered to remove the inorganic compounds. The solvent was
evaporated in vacuo and the residue was triturated with hexane.
5ꢀPyrrolidinoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldehyde (3c). Yield
Synthesis of ethyl 5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbꢀ
oxylates (6a—e) (general procedure). Dialkylamine (20 mmol)
was added to a solution of ethyl 5ꢀchloroꢀ1,2,3ꢀthiadiazoleꢀ4ꢀ
carboxylate (1.97 g, 10 mmol) in 10 mL of ethanol. The mixture
was stirred at ~20 °C for 30 min and cooled. The precipitate was
filtered off.
1
0.47 g (47%), m.p. 46—47 °C. H NMR (DMSOꢀd6+CCl4), δ:
10.33 (s, 1 H, CH); 3.33—3.45 (m, 4 H, N(CH2)2); 1.97—3.03
(m, 4 H, 2 CH2). IR, ν/cm–1: 1730 (C=O). MS, m/z (Irel (%)):
199 [M]+ (15). Found (%): N, 18.53; S, 14.09. C9H13N3O2S.
Calculated (%): N, 18.49; S, 14.11.
5ꢀ(4ꢀMethylpiperazino)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldeꢀ
hyde (3d). Yield 1.75 g (75%), m.p. 554 °C. 1H NMR
(DMSOꢀd6+CCl4), δ: 10.34 (s, 1 H, CH); 3.44 (t, 4 H, O(CH2)2,
J = 5.0 Hz); 2.54 (t, 4 H, N(CH2)2, J = 5.0 Hz); 2.23 (s, 3 H,
NCH3). IR, ν/cm–1: 1735 (C=O). MS, m/z (Irel (%)): 212 [M]+
(15). Found (%): N, 26.38; S, 14.94. C8H12N4OS. Calcuꢀ
lated (%): N, 26.39; S, 15.10.
Synthesis of 5ꢀdialkylaminoꢀ1,2,3ꢀthiadiazoles (7a—c) (genꢀ
eral procedure). Aldehyde 3 (1.5 mmol) was dissolved in DMF
(0.5 mL). The mixture was heated on a water bath for 2.5 h and
cooled. The product was precipitated with water and filtered off.
5ꢀMorpholinoꢀ1,2,3ꢀthiadiazole (7a). Yield 0.18 g (72%),
m.p. 90 °C. 1H NMR (DMSOꢀd6), δ: 8.17 (s, 1 H, CH);
3.71—3.76 (m, 4 H, O(CH2)2); 3.28—3.32 (m, 4 H, N(CH2)2).
MS, m/z (Irel (%)): 171 [M]+ (65). Found (%): N, 24.90; S, 18.78.
C6H9N3OS. Calculated (%): N, 24.54; S, 18.73.
5ꢀ(4ꢀBenzylpiperidino)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbaldeꢀ
hyde (3e). Yield 0.98
g
(64%), m.p. 78 °C. 1H NMR

Reaction of 1,2,3ꢀthiadiazole with amines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
1317
5ꢀ(2,6ꢀDimethylmorpholino)ꢀ1,2,3ꢀthiadiazole (7b). Yield
0.23 g (77%), m.p. 136 °C. 1H NMR (DMSOꢀd6), δ: 8.16 (s,
1 H, CH); 3.66—3.79 (m, 2 H, O(CH)2); 3.43 (dd, 2 H, N(CH)2,
J = 10.3 Hz, J = 2.4 Hz); 275 (dd, 2 H, N(CH)2, J = 11.9 Hz,
J = 10.7 Hz); 1.14 (d, 6 H, 2 CH3, J = 6.1 Hz). MS,
m/z (Irel (%)): 199 [M]+ (20). Found (%): N, 22.39; S, 17.12.
C8H13N3OS. Calculated (%): N, 22.21; S, 16.95.
6. Yu. Yu. Morzherin, V. A. Bakulev, E. F. Dankova, and
V. S. Mokrushin, Khim. Geterotsikl. Soedinen., 1994, 548
[Chem. Heterocycl. Compd., 1994, 30, 483 (Engl.Transl.)].
7. G. L´abbé, B. D´hooge, and W. Dehaen, Molecules,
1996, 190.
8. T. Rosenau, A. Potthast, G. Ebner, A. Hofinger, and
P. Kosma, Org. Lett., 2002, 4, 1257.
5ꢀPyrrolidinoꢀ1,2,3ꢀthiadiazole (7c). Yield 0.16 g (68%), m.p.
80 °C. H NMR (DMSOꢀd6), δ: 7.75 (s, 1 H, CH); 3.29—3.35
(m, 4 H, N(CH2)2); 2.01—2.06 (m, 4 H, 2 CH2). MS,
m/z (Irel (%)): 155 [M]+ (67). Found (%): N, 26.79; S, 20.51.
C6H9N3S. Calculated (%): N, 27.07; S, 20.66.
9. T. V. Glukhareva, Yu. Yu. Morzherin, V. S. Mokrushin,
A. V. Tkachev, and V. A. Bakulev, Khim. Geterotsikl.
Soedinen., 2000, 707 [Chem. Heterocycl. Compd., 2000, 36,
626 (Engl. Transl.)].
10. G. L´abbé, E. Vanderstede, W. Dehaen, P. Delbeke, and
S. Toppert, J. Chem. Soc., Perkin Trans. 1, 1991, 607.
11. G. L´abbé, M. Verbeke, W. Dehaen, and S. Toppet, J. Chem.
Soc., Perkin Trans. 1, 1993, 1719.
12. A. Shafiee, J. Heterocycl. Chem., 1976, 13, 301.
13. W. Dehaen, M. Voets, and V. A. Bakulev, in Adventure in
Nitrogen Heterocycles, 4, JAI Press Inc.Stamford, Connectiꢀ
cut, 2000, p. 37.
14. J. Goerdeler and G. Gnad, Chem. Ber., 1966, 99, 1618.
15. G. L´Abbé and E. Vanderstede, J. Heterocycl. Chem., 1989,
26, 1811.
1
This work was supported by the American Civil Reꢀ
search and Development Foundation (CRDF, grants
RC1ꢀ2393ꢀEKꢀ02 and RECꢀ005), the Russian Foundaꢀ
tion for Basic Research (Project No. 04ꢀ03ꢀ96104ꢀ
р2004ural_a), and the Ministry of Education of the Rusꢀ
sian Federation (Program for the Support of the Research
of PostꢀGraduates of Higher Education Institutes, grant
A03ꢀ2.11ꢀ739).
16. Yu. Yu. Morzherin, E. V. Tarasov, and V. A. Bakulev, Khim.
Geterotsikl. Soedinen., 1994, 554 [Chem. Heterocycl. Compd.,
1994 (Engl. Transl.)].
17. K. Soai, H. Oyamada, and A. Ookawa, Synth.Commun., 1982,
12, 463.
18. D. L. Pain and R. Slack, J. Chem. Soc., 1965. 5166.
19. A. R. Katritzky, S. Sobiak, and C. M. Marson, Magn. Reson.
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20. T. V. Glukhareva, Yu. Yu. Morzherin, E. A. Savel´eva, Yu.
A. Rozin, A. V. Tkachev, and V. A. Bakulev, Izv. Akad.
Nauk. Ser. Khim., 2001, 258 [Russ. Chem. Bull., Int. Ed.,
2001, 50, 268].
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Received November 4, 2003;
in revised form February 27, 2004