Synthesis of aryloxy-substituted 1,2,5-thiadiazoles by the Ullmann reaction

Article abstract of DOI:10.1023/A:1013148125019

3-Aryloxy-1,2,5-thiadiazoles were synthesized by the Ullmann reaction either from 3-chloro-1,2,5-thiadiazoles and phenols having donor substituents or from 3-hydroxy-1,2,5-thiadiazoles and chlorobenzenes containing acceptor substituents.

Full text of DOI:10.1023/A:1013148125019

Russian Journal of Organic Chemistry, Vol. 37, No. 9, 2001, pp. 1330 1334. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 9, 2001,
pp. 1395 1399.
Original Russian Text Copyright
2001 by Strunskaya, Bredikhina, Azancheev, Bredikhin.
Synthesis of Aryloxy-Substituted 1,2,5-Thiadiazoles
by the Ullmann Reaction
E. I. Strunskaya, Z. A. Bredikhina, N. M. Azancheev, and A. A. Bredikhin
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
Received July 19, 2000
Abstract 3-Aryloxy-1,2,5-thiadiazoles were synthesized by the Ullmann reaction either from 3-chloro-1,2,5-
thiadiazoles and phenols having donor substituents or from 3-hydroxy-1,2,5-thiadiazoles and chlorobenzenes
containing acceptor substituents.
Substituted 1,2,5-thiadiazoles are known to exhibit
a wide spectrum of biological activity [1]. In addition
to pronounced herbicide activity, 1,2,5-thiadiazole
derivatives were found to be efficient muscarine
receptor agonists [2], as well as inhibitors of HIV-1
replication [3]. For example, 1-(1,1-dimethylethyl-
amino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-
propanol (Timolol) is one of the most important
medicines for treatment of glaucoma [4, 5]. The
review articles on the chemistry of 1,2,5-thiadiazole
Our attempts to obtain aryloxy-substituted 1,2,5-
thiadiazoles from phenols and 3-chloro-4-morpholino-
1,2,5-thiadiazole (III) under the conditions reported
in [5] for the synthesis of analogous alkyloxy deriva-
tives (t-BuOK/t-BuOH, 100 C) were unsuccessful.
In all cases 3-hydroxy-4-morpholino-1,2,5-thiadiazole
(IV) was isolated. A general method for preparation
of diaryl ethers is based on the Ullmann reaction
of phenoxides with aryl halides in the presence of
a catalyst [8]. By reaction of chlorothiadiazoles I and
II with potassium phenoxide under severe conditions
[6] dealt mainly with the methods of building up the
1
,2,5-thiadiazole ring, whereas its chemical modifica- (130 190 C, 2 10 h, no solvent) we succeeded in
tions were covered to a lesser extent. However, this
obtaining 3-phenoxy- and 3,4-diphenoxy-1,2,5-thiadi-
problem often arises while creating screening data- azoles V and VI in satisfactory yields (Scheme 2).
bases and libraries.
Scheme 2.
The present communication reports on the synthesis
of a series of 3-aryloxy-1,2,5-thiadiazoles most of
which contain a morpholino group in the 4-position of
the heteroring. The starting compounds were 3-chloro-
and 3,4-dichloro-1,2,5-thiadiazoles I and II. They
were obtained by chlorination of a mixture of sulfur(I)
chloride and ethylenediamine dihydrochloride with
I, X = H; II, X = Cl; V, Y = H; VI, Y = OPh.
chlorine in the presence of FeCl as catalyst [7]
3
(
Scheme 1). 3-Chloro-4-morpholino-1,2,5-thiadiazole
With 3-chloro-4-morpholino-1,2,5-thiadiazole (III)
as an example, we performed the Ullmann reaction
with a series of substituted phenols and isolated a set
of 3-aryloxy-4-morpholino-1,2,5-thiadiazoles VII XV
(
III) was prepared from dichloro derivative II by
the procedure described in [5].
Scheme 1.
(Scheme 3). The reaction conditions and the yields
and properties of compounds V XV are collected in
Table 1. It should be emphasized that the conditions
given therein were not optimized (all products were
synthesized under standard conditions). Moreover, the
yields refer to the isolated products, i.e., they also
reflect the efficiency of purification procedure (e.g.,
1
070-4280/01/3709-1330$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS OF ARYLOXY-SUBSTITUTED 1,2,5-THIADIAZOLES
1331
1
Table 1. Reaction conditions and yields, physical properties, and H NMR spectral parameters of thiadiazoles V XVII
Reaction conditions
Comp.
no.
Yield, bp,
C
mp,
(solvent)
C
1H NMR spectrum,a
2
0
n
D
%
(p, mm)
, ppm (J, Hz)
temp., C time, h
V
130
10
2
54
55
53
56
128 130 1.5915
10)
7.34 br.s (5H, Harom), 7.95 s (1H, 4-H
in Ht)
7.18 br.s (10H, Harom)
(
VI
170
106 107
80% EtOH)
(
VII
VIII
180 190
180 190
2
132 134 1.5944
0.005)
128 129 1.5870
0.005)
3.32 3.50 m (4H, CH NCH ), 3.59 3.75 m
2 2
(
(4H, CH OCH ), 7.06 br.s (5H, Harom)
2 2
2
2.16 s (3H, CH ), 3.40 3.60 m (4H,
3
(
CH NCH ), 3.69 3.83 m (4H, CH O-
2
2
2
CH ), 7.06 br.s (4H, Harom)
2
IX
X
180 190
170 180
2
2
53
56
150 152
0.005)
107 108
(80% EtOH)
2.12 s (6H, 2CH ), 3.51 3.63 m (4H,
3
(
CH NCH ), 3.69 3.82 m (4H, CH O-
2
2
2
CH ), 6.91 br.s (3H, Harom)
2
140 142 1.5862
0.003)
3.29 d (2H, CH , allyl, 7.0), 3.45 3.56 m
2
(
(4H, CH NCH ), 3.63 3.76 m (4H,
2
2
CH OCH ), 4.75 5.05 m (2H, CH ,
2
2
2
allyl), 5.50 6.30 m (1H, CH, allyl),
.10 br.s (4H, Harom
3.35 3.49 m (4H, CH NCH ), 3.60 3.73 m
7
)
XI
170 180
180 190
180 190
170 180
180 190
150
2
2
53
50
80
63
53
52
53
155 160 1.5920
0.008)
2
2
(
(4H, CH OCH ), 3.70 s (3H, OCH ),
2 2 3
6
.46 7.16 m (4H, Harom
)
XII
83 84
90% EtOH)
3.43 3.56 m (4H, CH NCH ), 3.70 3.83 m
2
2
(
(4H, CH OCH ), 6.83 7.52 m (4H,
2 2
Harom
)
XIII
XIV
XV
2
67 68
80% EtOH)
2.36 s (3H, CH ), 3.42 3.60 m (4H, CH N-
3
2
(
CH), 3.67 3.85 m (4H, CH OCH ),
2 2
7
.01 s (4H, Harom
)
2
155 160
0.015)
52 53
(100% EtOH)
3.40 3.56 m (4H, CH NCH ), 3.66 3.83 m
2
2
(
(4H, CH OCH ), 3.83 s (3H, OCH ),
2 2 3
6
.62 7.07 m (4H, Harom
)
2
140 143
0.02)
69 70
(100% EtOH)
3.38 3.52 m (4H, CH NCH ), 3.65 3.80 m
2
2
(
(4H, CH OCH ), 6.92 7.38 m (4H,
2 2
Harom
)
XVI
XVII
20
20
145 146
80% EtOH)
3.50 3.65 m (4H, CH NCH ), 3.76 3.92 m
2
2
(
(4H, CH OCH ), 7.35 8.38 m (4H,
2 2
Harom
)
150
145 150
0.004)
87 88
(80% EtOH)
3.50 3.65 m (4H, CH NCH ), 3.76 3.92 m
2
2
(
(4H, CH OCH ), 7.42 8.26 m (3H,
2 2
Harom
)
a
1
The H NMR spectra of compounds VII XV were recorded in CCl , and of V, VI, XVI, and XVII, in CDCl .
4
3
the ease of crystallization). Nevertheless we can speak
about a weak effect of the steric factor on the reaction
course. ortho-Substituted phenols do not fall out of
the general series, and even 2,6-dimethylphenol turned
out to be an effective reagent. By contrast, electronic
effect of the substituent in the benzene ring was
essential. Phenols with strongly acceptor substituents,
such as NO and CF groups, failed to react with
compound III despite wide variation of the reaction
conditions. Therefore, the corresponding 1,2,5-thiadi-
azolyl ethers were synthesized by the reverse mode of
the Ullmann reaction, i.e., 3-hydroxy-4-morpholino-
2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
332
STRUNSKAYA et al.
The IR spectra of compounds V XVII contained
Scheme 3.
1
the following absorption bands, , cm : 1050 1130
C O), 1450 1500 (Ht), 1450 1600 (Ar).
-Chloro- and 3,4-dichloro-1,2,5-thiadiazoles I
(
3
and II. Sulfur(I) chloride, 165 ml (1.8 mol), was
added to 450 ml of DMF and 1 g of iron powder, and
the mixture was saturated with chlorine at 20 C.
Ethylenediamine dihydrochloride, 134 g (1 mol),
was added to the mixture at 30 40 C, and 830 g
(
11.7 mol) of chlorine was passed through the mixture
at 57 59 C. The mixture was cooled to 20 C and
00 ml of water was added. The products were
separated by azeotropic distillation with water at
5 110 C, the distillate was treated with methylene
6
7
VII, R = H; VIII, R = 2-Me; IX, R = 2,6-Me ; X, R =
2
chloride, and the extract was washed with water, dried
over Na SO , and evaporated. The residue was
separated by fractional distillation through a column
2
-allyl; XI, R = 3-OMe; XII, R = 3-Br; XIII, R = 4-Me;
XIV, R = 4-OMe; XV, R = 4-Br.
2
4
to isolate 5 g of 3-chloro-1,2,5-thiadiazole (I),
1
,2,5-thiadiazole sodium salt (IV) was used as nucleo-
20
bp 123 124 C, n 1.5379 (published data: bp 124 C
D
phile while the substrate was an appropriately substi-
tuted phenyl chloride (Scheme 4).
20
[
9], nD 1.5379 [10]), and 115.7 g (74%) of 3,4-di-
20
chloro-1,2,5-thiadiazole (II), bp 156 158 C, nD
.5620 (published data [9]: bp 155 C).
-Morpholino-3-phenoxy-1,2,5-thiadiazole (VII).
Potassium phenoxide was prepared from 1.18 g
12.6 mmol) of phenol and 0.65 g (11.6 mmol) of
1
Scheme 4.
4
(
powdered KOH in 25 ml of toluene with removal of
water by azeotropic distillation through a Dean Stark
trap. Copper powder, 0.02 g (0.3 mmol), and thiadi-
azole III, 2 g (9.7 mmol), were added to the resulting
potassium phenoxide, and the mixture was heated
for 2 h at 180 190 C. The mixture was diluted with
2
0 ml of water and extracted with ether. The extract
was washed with 10% solutions of NaOH and
NaHCO and with water to neutral reaction, dried
3
over Na SO , and evaporated. The viscous residue
2
4
was distilled under reduced pressure.
XVI, R = 4-NO ; XVII, R = 4-CF -2-NO .
2
3
2
3
-Aryloxy-4-morpholino-1,2,5-thiadiazoles V,
VI, and VIII XV were synthesized by a similar
procedure. In the synthesis of compound VII a double
amount of potassium phenoxide was used. The reac-
tion conditions and yields, physical constants, and
H and C NMR spectra of the products are given
in Tables 1 and 2.
4-Morpholino-3-(4-nitrophenoxy)-1,2,5-thiadi-
azole (XVI). A solution of 1.12 g (6 mmol) of thiadi-
azole IV in 4 ml of DMF was added dropwise to
a suspension of 0.15 g (6 mmol) of sodium hydride
in 2 ml of DMF, stirred in an inert atmosphere. The
mixture was heated for 0.5 h at 70 80 C, 0.04 g
(0.6 mmol) of copper powder and 0.95 g (6 mmol)
of 4-nitrochlorobenzene were added, and the mixture
was stirred for 20 h at 150 C. The solvent was dis-
tilled off under reduced pressure, 50 ml of water was
Thus the Ullmann reaction provides an efficient
procedure for preparation of aryloxy-substituted
1
,2,5-thiadiazoles. Here, the heterocyclic component
should be used as the corresponding halogen deriva-
tive in reactions with phenols or as hydroxy derivative
in reactions with aryl halides having electron-acceptor
groups.
1
13
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer in mineral oil (or in film for liquid samples).
The NMR spectra were obtained on Varian T-60
1
(
(
H, 60 MHz) and Bruker MSL-400 spectrometers
1
3
C, 100.6 MHz) using CDCl and CCl as solvents
3
4
and TMS as internal reference.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

SYNTHESIS OF ARYLOXY-SUBSTITUTED 1,2,5-THIADIAZOLES
Table 2. 13C NMR spectra of thiadiazoles V XVIIa
1333
Ar
Comp.
no.
H CN
H CO
C3, C4
C(R)
2
2
HC
RC
OC
V
164.07, 139.46
151.08
152.21, 151.11
152.31, 150.45
152.05, 149.86
152.53, 150.70
119.91, 125.47, 129.77
120.10, 125.74, 129.87
120.51, 125.63, 129.96
154.56
154.53
154.90
153.27
152.11
153.10
VI
VII
VIII
IX
X
48.61
48.46
48.61
48.67
66.68
66.54
66.66
66.75
16.60 121.10, 125.87, 127.34, 131.55
16.94 126.17, 129.25
34.99, 121.58, 126.16, 128.02, 131.08
16.65,
129.55
130.30
131.61
1
1
36.30
XI
48.62
66.62
151.93, 151.14
55.54 106.67, 111.40, 112.49, 130.18
155.84,
1
61.25
XII
XIII
XIV
48.69
48.62
48.62
66.67
66.72
66.66
151.46, 151.02
152.55, 150.96
152.86, 150.75
119.12, 124.00, 128.86, 130.92
21.26 120.38, 130.42
55.66 114.92, 121.64
123.17
135.03
155.34
152.77
148.43,
1
57.47
XV
XVI
XVII
48.67
48.30
48.34
66.65
66.50
66.53
151.66, 150.96
151.06, 150.32
150.34, 150.13
122.24, 133.04
120.24, 125.74
124.08 123.76, 124.80, 131.45
118.68
145.02
128.97,
153.84
158.90
149.56
1
41.53
a
13
The C NMR spectra of compounds VII XV were recorded in CCl , and of V, VI, XVI, and XVII, in CDCl .
4
3
Table 3. Elemental analyses of thiadiazoles V XVII
Found, %
Comp.
Calculated, %
H
Formula
no.
C
H
N
C
N
V
VI
VII
VIII
IX
53.64
62.02
54.61
56.39
58.16
59.55
53.18
42.27
56.42
53.18
42.18
76.82
41.57
3.28
3.54
4.83
5.34
5.82
5.72
5.21
3.41
5.14
5.29
3.48
3.62
3.08
15.82
10.30
16.01
14.99
14.38
13.90
14.23
12.12
15.50
15.08
12.24
18.23
14.63
C H N OS
53.93
62.22
54.75
65.31
57.73
59.40
53.24
42.11
56.31
53.24
42.11
76.75
41.49
3.37
3.70
4.94
5.41
5.84
5.61
5.12
3.51
5.41
5.12
3.51
3.89
2.92
15.73
10.37
15.97
15.16
14.43
13.86
14.33
12.28
16.16
14.33
12.28
18.18
14.89
8
6 2
C H N O S
14 10 2 2
C H N O S
12 13 3 2
C H N O S
1
3 15 3 2
C H N O S
1
4 17 3 2
X
XI
C H N O S
15 17 3 2
C H N O S
13 15 3 2
XII
XIII
XIV
XV
XVI
XVII
C H BrN O S
12 12 3 2
C H N O S
1
3 15 3 2
C H N O S
1
3 15 3 3
C H BrN O S
1
2
12
3 2
C H N O S
1
2 12 4 4
C H F N O S
1
3 11 3 4 4
added to the residue, and the mixture was treated with
methylene chloride. The combined organic extracts
were washed with 10% solutions of NaOH and
4-Morpholino-3-(2-nitro-4-trifluoromethylphen-
oxy)-1,2,5-thiadiazole (XVII) was synthesized by
a similar procedure. The reaction conditions and the
properties of compound XVII are given in Tables 1
and 2. Table 3 contains the analytical data for the
newly synthesized compounds.
NaHCO and with water to neutral reaction, dried over
3
Na SO , and evaporated. The residue was purified
2
4
by recrystallization from EtOH H O (4:1).
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
334
STRUNSKAYA et al.
REFERENCES
4. Sorensen, S.J. and Abel, S.R., Ann. Pharmacother.,
996, vol. 30, pp. 43 54; Chem. Abstr., 1996,
1
vol. 124, no. 219106b.
Weinstock, L.M., Mulvey, D.M., and Tull, R.,
J. Org. Chem., 1976, vol. 41, no. 19, pp. 3121 3123.
Weinstock, L.M. and Pollak, P.I., Adv. Heterocycl.
Chem., 1968, vol. 9, pp. 107 163; Weinstock, L.M.
and Shinkai, I., Comprehensive Heterocyclic Chem-
istry, Katritzky, A.R. and Rees, C.W., Eds., Oxford:
Pergamon, 1996, vol. 6, pp. 513 528; Carmack, M.,
Sulfur Rep., 1995, vol. 16, no. 2, pp. 299 342.
GDR Patent no. 271425, 1989; Chem. Abstr., 1990,
vol. 112, no. 158259g.
Weingarten, H., J. Org. Chem., 1964, vol. 29, no. 4,
pp. 977 978.
1
2
.
.
Yoon, S., Cho, J., and Kim, K., J. Chem. Soc., Perkin
Trans. 1, 1998, no. 1, pp. 109 116.
5
6
.
.
Mitch, S.H., Brown, T.J., Bumaster, F.P., Calli-
garo, D.O., Dieckman, D., Merrit, L., Peters, S.C.,
Quimby, S.J., Shannon, H.E., Shipley, L.A.,
Ward, J.S., Hansen, K., Olesen, P.H., Sauerberg, P.,
Seardown, M.J., Swedberg, M.J.V., Suzdak, P., and
Greenwood, B., J. Med. Chem., 1997, vol. 40, no. 4,
pp. 538 546; Periyasamy, S., Messer, W.S., Rok-
nich, S., Sauerberg, P., and Hoss, W., Brain Res.,
7
8
.
.
1
1
995, vol. 693, nos. 1 2, pp. 118 123; Chem. Abstr.,
995, vol. 123, no. 275207b.
3
.
Hanasaki, Y., Watanabe, H., Katsuura, K., Takaya-
ma, H., Shirakawa, S., Yamaguchi, K., Sakai, S.,
Ijichi, K., Fujiwara, M., Konno, K., Yokota, T.,
Shigeta, S., and Baba, M., J. Med. Chem., 1995,
vol. 38, no. 12, pp. 2038 2040.
9. Weinstock, L.M., Davis, P., Handelsman, V., and
Tull, R., J. Org. Chem., 1967, vol. 32, no. 9,
pp. 2823 2829.
10. Appel, R., Lundehn, J.-R., and Labnann, E., Chem.
Ber., 1976, vol. 107, no. 7, pp. 2442 2455.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001