Synthesis of 1,3,4-thiadiazoles from aldehyde hydrazones

Article abstract of DOI:10.1055/s-2004-829156

Reaction of p-tolualdehyde hydrazone with disulfur dichloride in the presence of DBU gave 2,5-di (p-tolyl)-1,3,4-thiadiazole (1a) in 54% yield. Phenyldiazomethane also reacted with disulfur dichloride to afford 2,5-diphenyl-1,3,4-thiadiazole (1b) in 80% y

Full text of DOI:10.1055/s-2004-829156

SHORT PAPER
1929
Synthesis of 1,3,4-Thiadiazoles from Aldehyde Hydrazones
S
K
ynthesis of 1,3,4-
e
Thiadiazole
n
s from Alde
t
hyde
H
a
ydrazones ro Okuma,* Kazuko Nagakura, Yasutaka Nakajima, Kento Kubo, Kosei Shioji
Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
Fax +81(92)8656030; E-mail: kokuma@fukuoka-u.ac.jp
Received 18 March 2004; revised 10 May 2004
Dedicated to Professor Teruaki Mukaiyama on the occasion of his 77th birthday.
p-Tol
Abstract: Reaction of p-tolualdehyde hydrazone with disulfur
C
NNH2
S
p-Tol
p-Tol
p-Tol
dichloride in the presence of DBU gave 2,5-di (p-tolyl)-1,3,4-thia-
diazole (1a) in 54% yield. Phenyldiazomethane also reacted with
disulfur dichloride to afford 2,5-diphenyl-1,3,4-thiadiazole (1b) in
H
C N
2
a
H
+
CH2Cl2
Base
N
N
H
N C
+
S2Cl2
p-Tol
1a
3a
8
0% yield.
Key words: hydrazone, disulfur dichloride, 1,3,4-thiadiazole, phe-
nyldiazomethane
Scheme 1
Table 1 Reaction of p-Tolualdehyde Hydrazone with S Cl
2
2
Reagents
S2Cl2
Products
Successful use of 1,3,4-thiadiazoles 1 in biology and in-
dustry stimulated various authors to investigate their syn-
Entry
Base
Temp
(°C)
1a
3a
1
thetic methods, including the reaction of dithioformate
(
Equiv)
Yield (%) Yield (%)
2
3
with hydrazine, tetrazoles with thiobenzoyl chloride, tet-
4
1
2
3
4
5
6
7
1
2
2
2
3
2
2
Et N
0
18
15
28
22
28
54
48
38
65
55
45
59
21
33
razoles with Appel salts, N,N-diacylhydrazines with
Lawesson reagent, and the reaction of 1,3,4-oxadiazoles
3
5
Et N
reflux
3
6
with thiourea.
Et N
r.t.
0
3
However, there is no report on the synthesis of 1 from
simple aldehyde hydrazones 2. It is well known that the
reaction of sterically crowded ketone hydrazones with
disulfur dichloride in the presence of bases afforded
Et N
3
Et N
0
3
7
thiones in good yields. Recently, we have reported the
DBU
DBU
0
synthesis of 1,3,4-selenadiazolines by the reaction of ke-
tone hydrazones with diselenium dibromide, suggesting
that the intermediates were not only selenoketones but
r.t.
8
also diazoalkanes. These results prompted us to investi-
We next applied the condition used in entry 6 to other sub-
strates. Treatment of benzaldehyde hydrazone 2b with
disulfur dichloride in the presence of DBU at 0 °C resulted
in the formation of 2,5-diphenyl-1,3,4-dithiazole (1b) in
gate the reaction of aromatic aldehyde hydrazones with
disulfur dichloride in the hope of producing 1,3,4-thiadia-
zolines. In this paper, we would like to show a simple syn-
thesis of 2,5-diaryl-1,3,4-thiadiazoles from benzaldehyde
hydrazones.
2
8% yield along with diphenylazine 3b (45%) (Scheme 2,
Table 2).
We first tried the reaction of p-tolualdehyde hydrazone 2a
with disulfur dichloride in the presence of bases, a condi-
tion similar to those used in the synthesis of thioketones
7
(
Scheme 1). When one equivalent of disulfur dichloride
was used, unreacted 2a (30%) was recovered (Table 1, en-
try 1). When the reaction was carried out in refluxing
dichloromethane, mainly p-tolualdehyde azine 3a was ob- Scheme 2
tained (Table 1, entry 2). Best result was obtained by us-
ing 2 molar amounts of disulfur dichloride and 1,8-
diazibicyclo[5.4.0]undec-7-ene (DBU) as a base, at 0 °C
The mechanism for the reaction is intriguing. The follow-
ing mechanism is suggested. Nucleophilic attack of ben-
zaldehyde hydrazone on disulfur dichloride gives the
corresponding unstable N-thionitrosoimine, which ex-
trudes nitrogen to afford the thione. The thione further re-
acts with diazoalkane, which is produced independently
from hydrazone and disulfur dichloride by oxidation, to
give the corresponding 1,3,4-thiadiazoline. The interme-
(
entry 6).
SYNTHESIS 2004, No. 12, pp 1929–1931
x
x.
x
x
.
2
0
0
4
Advanced online publication: 21.07.2004
DOI: 10.1055/s-2004-829156; Art ID: F03804SS
Georg Thieme Verlag Stuttgart · New York
©

1
930
K. Okuma et al.
SHORT PAPER
Table 2 Reaction of Aldehyde Hydrazones with S Cl
2
2
2
Products, Yields (%)
Ar
Ph
1
3
2
2
2
2
2
2
b
c
d
e
f
1b
1c
1d
1e
1f
28
48
53
55
57
73
3b
3c
3d
3e
3f
3g
45
35
20
26
28
21
p-MeOC H
6
4
Scheme 4
p-FC H4
6
have developed a two-step method for the formation of
,3,4-thiadiazoles from benzaldehydes.
p-ClC H4
6
1
p-BrC H4
6
Flash chromatography was carried out with Merck Kieselgel 60
230–400 mesh). TLC was carried out on commercially available
g
p-CF C H
4
1g
3
6
(
precoated aluminum plates (Merck Kieselgel 60F254). All solvents
were distilled before use, and no further treatment was done. NMR
1
diate thiadiazoline is then oxidized by sulfur to give 1,3,4- spectra were measured on a Varian Innova-400 (400 MHz for H,
1
3
thiadiazole (Scheme 3).
100 MHz for C). The melting points are uncorrected.
2
,5-Di(p-tolyl)-1,3,4-thiadiazole (1a); Typical Procedure
To a solution of p-tolualdehyde hydrazone (0.27 g, 2.0 mmol) and
DBU (0.61 g, 4 mmol) in CH Cl (10 mL) was added a solution of
Ph
Ph
H
2
b
C
N
C
S
CH2Cl2
base
2
2
+
S2Cl2
H
N
Sn
S Cl (0.54 g, 4 mmol) in CH Cl (10 mL) at 0 °C. After stirring for
2
2
2
2
2
h, the reaction mixture was poured into H O and extracted with
2
CH Cl (3 × 10 mL). The combined organic extracts were dried
2
2
Ph
H
(
MgSO ) and filtered, which was evaporated to give a pale yellow
4
C
N2
oil. The oil was chromatographed over silica gel using hexane–
H
4
H
S
1b
CH Cl (2:1) as eluent to give 1a (0.14 g, 54%) and p-tolualdehyde
2
2
Ph
Ph
azine 3a (0.050 g, 21%).
N
N
Scheme 3
1a
1
3
Mp 159–160 °C (Lit. mp 162–163 °C).
As can be seen from Table 1, azines 3 were obtained as
side products. Their formation might be explained by di-
3
a
14
Mp 158–159 °C (Lit. mp 159–160 °C).
sulfur dichloride assisted decomposition of hydrazone 2
9
via diazoalkanes. A similar formation of 3c by air oxida- 2,5-Diphenyl-1,3,4-thiadiazole (1b)
5
tion of p-anisaldehyde hydrazone 2c has also been report- Mp 143–144 °C (Lit. mp 142–143 °C).
1
0
ed by Hinman.
Benzaldehyde Azine 3b
Mp 93–94 °C (Lit. mp 93–94 °C).
The synthesis of 1,3,4-thiadiazolines generally involve
15
1
1
the reaction of thiones with diazoalkanes. 5-Unsubstitut-
ed 1,3,4-thiadiazoline is rather unstable and is generated 2,5-Di(p-anisyl)-1,3,4-thiadiazole (1c)
1
3
Mp 170–171 °C (Lit. mp 171–172 °C).
as a transient intermediate in the formation of thiocarbon-
yl ylides, which in absence of dipolarophile are further
converted to episulfides or 1,3-dithiolanes. The synthe-
sis of sterically congested thioketones by the reaction of
p-Anisaldehyde Azine 3c
1
2
1
6
Mp 169–170 °C (Lit. mp 169–170 °C).
ketone hydrazones with disulfur dichloride has also been
reported. In the report, the possibility of the formation of Mp 210–211 °C.
2
,5-Bis(p-fluorophenyl)-1,3,4-thiadiazole (1d)
7
diazomethane intermediates was rejected by the fact that
the reaction of diphenyldiazomethane with sulfur in the
presence of triethylamine did not give thiobenzophenone.
We reasoned that if diazoalkanes were formed as the in-
1
H NMR (CDCl ): d = 7.21 (4 H, m, Ar), 7.99 (4 H, m, Ar).
3
Anal. Calcd for C H F N S: C, 61.31; H, 2.91; N, 10.21. Found: C,
6
1
4
8
2
2
0.97; H, 3.07; N, 9.94.
termediates, then the reaction of phenyldiazomethane (4) p-Fluorobenzaldehyde Azine 3d
1
6
with disulfur dichloride should afford 1b. Indeed, it was Mp 210–212 °C (Lit. mp 212 °C).
found that the reaction of 4 prepared from benzaldehyde
9
2,5-Bis(p-chlorophenyl)-1,3,4-thiadiazole (1e)
Mp 225–226 °C (Lit. mp 224–225 °C).
p-tosylhydrazone and sodium methoxide with disulfur
1
3
dichloride in the presence of triethylamine at 0 °C gave 1b
in 80% yield (Scheme 4).
p-Chlorobenzaldehyde Azine 3e
Mp 209–211 °C (Lit. mp 209–211 °C).
1
7
In summary, the reaction of aldehyde hydrazones or phe-
nyldiazomethane with disulfur dichloride gave 2,5-diaryl-
2
,5-Bis(p-bromophenyl)-1,3,4-thiadiazole (1f)
1
,3,4-thiadiazoles in good to moderate yields. Thus, we
1
3
Mp 235–236 °C (Lit. mp 240–241 °C).
Synthesis 2004, No. 12, 1929–1931 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 1,3,4-Thiadiazoles from Aldehyde Hydrazones
1931
p-Bromobenzaldehyde Azine 3f
(2) Jensen, K. A.; Pederson, C. Acta Chem. Scand. 1961, 15,
Mp 229–231 °C (Lit.1 mp 231–232 °C).
8
1124.
(
3) Huisgen, R.; Strurumu, H. J.; Seidel, M. Chem. Ber. 1961,
94, 1555.
2
,5-Bis(p-trifluoromethyl)-1,3,4-thiadiazole (1g)
Mp 224–226 °C.
(4) Le, V.-D.; Rees, C. W.; Sivadasan, S. J. Chem. Soc., Perkin
Trans. 1 2002, 1543.
1
H NMR (CDCl ): d = 7.78 (4 H, d, J = 8.0 Hz, Ar), 8.15 (4 H, d,
3
(5) Rusmussen, P. B.; Pedersen, U.; Thompson, I.; Yde, B. S.;
J = 8.0 Hz, Ar).
Lawesson, O. Bull. Soc. Chim. Fr. 1985, 62.
1
3
C NMR (CDCl ): d = 123.78 (q, JC,F = 270 Hz, CF ), 126.49 (Ar),
3
3
(6) Linganna, N.; Lokanatha, K. M. Synth. Commun. 1998, 28,
611.
7) (a) Okazaki, R.; Inoue, K.; Inamoto, N. Tetrahedron Lett.
979, 3673. (b) Okazaki, R.; Inoue, K.; Inamoto, N. Bull.
1
28.49 (Ar), 133.18, 133.20, 167.39 (SC=N).
4
(
Anal. Calcd for C H F N S: C, 51.34; H, 2.15; N, 7.48. Found: C,
16
8
3
2
1
5
1.56; H, 2.31; N, 7.61.
Chem. Soc. Jpn. 1981, 54, 3541.
(
8) Okuma, K.; Kubo, K.; Yokomori, Y. Heterocycles 2003, 60,
p-Trifluoromethylbenzaldehyde Azine 3g
Mp 145–146 °C.
IR (KBr): 1631 cm–1 (C=N) (Lit.19 1631 cm–1).
299.
(9) Creary, X. Org. Synth. 1986, 64, 207.
(
(
10) Hinman, R. L. J. Org. Chem. 1960, 26, 1775.
11) Barton, D. H. R.; Guziec, F. S. Jr.; Shahak, I. J. Chem. Soc.
974, 1794.
12) (a) Staudinger, H.; Siegert, J. Helv. Chim. Acta 1920, 3, 833.
b) Schönberg, A.; Vargha, L. Liebigs Ann. Chem. 1930,
83, 176. (c) Kalwinski, I.; Li, X.; Gottstein, J.; Huisgen, R.
Reaction of Phenyldiazomethane with Disulfur Dichloride
To a solution of freshly prepared phenyldiazomethane (0.12 g, 1
1
9
(
mmol) and Et N (0.20 g, 2 mmol) in CH Cl (10 mL) was added a
3
2
2
(
4
solution of S Cl (0.27 g, 2 mmol) in CH Cl (5 mL) at 0 °C. After
2
2
2
2
stirring for 2 h, the reaction mixture was poured into H O and ex-
2
J. Am. Chem. Soc. 1981, 103, 7032.
tracted with CH Cl (3 × 5 mL). The combined organic extracts
2
2
(
(
13) Mazzonne, G.; Puglisi, G.; Bonina, F.; Corsaro, A. J.
Heterocycl. Chem. 1983, 20, 1399.
14) Tsuge, O.; Kanemasa, S. Bull. Chem. Soc. Jpn. 1972, 45,
were dried (MgSO ), filtered and evaporated to give pale yellow
4
oily crystals, which was chromatographed over silica gel using
CH Cl –hexane (1:2) as eluent to afford 1b; yield: 0.095 g (80%).
2
2
3591.
(
(
15) Rosini, G.; Soverini, M.; Ballini, R. Synthesis 1983, 909.
16) Flowers, W. T.; Robinson, J. F.; Taylor, D. R.; Tipping, A.
E. J. Chem. Soc., Perkin Trans. 1 1981, 349.
References
(
1) For reviews, see: (a) Wilkins, D. J.; Bradley, P. A. In
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Synthesis 2004, No. 12, 1929–1931 © Thieme Stuttgart · New York