Synthesis of 1,3,4-thiadiazole oligomers

Article abstract of DOI:10.1039/b203705j

A range of hydrazono chlorides 8, readily prepared from 5-substituted tetrazoles 7 and Appel salt 1, are rapidly converted by triphenylphosphine into 5-cyano-1,3,4-thiadiazoles 9 in high yield. These cyanides are converted by azide into the corresponding tetrazoles 10 which with Appel salt give the hydrazono chlorides 11 which are similarly converted by triphenylphosphine into the bi-1,3,4-thiadiazolyls 12a,c,g, all in high yield. Repetition of the 3-step sequence (12 → 13 → 14 → 15) gives the ter-1,3,4-thiadiazolyls 15a,g.

Full text of DOI:10.1039/b203705j

View Online / Journal Homepage / Table of Contents for this issue
Synthesis of 1,3,4-thiadiazole oligomers
Van-Duc Le, Charles W. Rees and Sivaprasad Sivadasan
Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY. E-mail: c.rees@ic.ac.uk
1
Received (in Cambridge, UK) 16th April 2002, Accepted 10th May 2002
First published as an Advance Article on the web 30th May 2002
A range of hydrazono chlorides 8, readily prepared from 5-substituted tetrazoles 7 and Appel salt 1, are rapidly
converted by triphenylphosphine into 5-cyano-1,3,4-thiadiazoles 9 in high yield. These cyanides are converted by
azide into the corresponding tetrazoles 10 which with Appel salt give the hydrazono chlorides 11 which are similarly
converted by triphenylphosphine into the bi-1,3,4-thiadiazolyls 12a,c,g, all in high yield. Repetition of the 3-step
sequence (12
13
14
15) gives the ter-1,3,4-thiadiazolyls 15a,g.
We have shown that 4,5-dichloro-1,2,3-dithiazolium chloride
(Appel salt) 1 reacts with 5-aminotetrazole 2 at both the pri-
mary amino group and the heterocyclic ring, to give a modest
yield of the red crystalline bis(imino-1,2,3-dithiazole) 3.1
Although simple mono(imino-1,2,3-dithiazoles) are usually
very stable thermally, the red solution of 3 in warm DMSO
(35 ЊC) slowly faded to yellow over one or two days. This
change was complete in 4 h at 50 ЊC and a new yellow product 5
was isolated; similar results were obtained in DMF (Scheme 1).
been confirmed by X-ray crystallography.1 It is interesting to
note that the central “imidoyl” chloride in 3 is inert to inter-
molecular displacement1 and therefore considered not to be the
first site for nucleophilic attack on 3; however the correspond-
ing chlorine in intermediate 4 is reactive enough to be displaced
intramolecularly as shown (Scheme 1).
We have shown that triphenylphosphine rapidly converts
N-arylimino-1,2,3-dithiazoles into cyanothioformanilides
under mild conditions,3 and this stronger thiophile should be
more effective for the conversion of 3 into 5 by the mechanism
of Scheme 1. The red compound 3 was therefore treated with
triphenylphosphine in undried DCM; it rapidly gave (30 min,
RT) the same yellow product 5 (25%) together with the orange
cyanothioformamide 6 (20%). This latter has arisen by the
usual opening of the second dithiazole ring in 3 by triphenyl-
phosphine; treatment of 3 with an excess of the phosphine
gave 6 (85%) as the sole product. Triphenylphosphine oxide
and sulfide were also isolated in almost quantitative yields in
agreement with a previously proposed mechanism.3
We have also shown the conversion of 5-substituted tetra-
zoles 7, where the 5-substituent is inert towards Appel salt 1,
into the hydrazono chlorides 8 by reaction with one equivalent
of this salt.1 On the basis of the mechanism of Scheme 1, these
products would be expected to react similarly with triphenyl-
phosphine to give the 1,3,4-thiadiazoles 9, analogous to 5 but
with the second dithiazole imine replaced by the substituent R
(Scheme 2). With 2 equiv. of triphenylphosphine in undried
Scheme 1
Evaporation of the solvent, flash chromatography on silica and
crystallisation from DCM–light petroleum (60–80 ЊC) gave fine
yellow cubic crystals (25%).
Analysis, spectroscopy and mass spectrometry of the yellow
product showed the absence of hydrogen, the presence of
a conjugated cyano group and the molecular formula to be
C5ClN5S3, representing the loss of the elements of SCl2 from 3.
These data suggested that one of the dithiazole rings had
opened, probably under nucleophilic attack by DMSO or DMF
since 5 was stable above 50 ЊC in acetone, DCM, chloroform or
ethanol. Attack on sulfur in the appropriate dithiazole ring
(arrows in 3) will generate a cyano group, as usual,2 and further
attack will generate nucleophilic sulfur suitably placed (4) to
cyclise to a cyano-1,3,4-thiadiazole. This sequence suggested
the thiadiazole structure 5 for the yellow product, and this has
Scheme 2
DCM at RT for 15 min, compounds 8 all gave the correspond-
ing 5-substituted-2-cyano-1,3,4-thiadiazoles 9a–h (Table 1),
together with triphenylphosphine oxide and sulfide in high
yields, as expected.3 This transformation provides good support
DOI: 10.1039/b203705j
J. Chem. Soc., Perkin Trans. 1, 2002, 1543–1547
This journal is © The Royal Society of Chemistry 2002
1543

View Online
Table 1 Conversion of hydrazono chlorides 8 into 1,3,4-thiadiazoles 9
with triphenylphosphine
and Bruker AM500 (at 125 MHz) machines. Deuterated
solvents were used for homonuclear lock and the signals are
referenced to the deuterated solvent peaks. Mass spectra were
recorded on a VG micromass 7070E or a VG Autospec “Q”
mass spectrometer.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-(4-cyano-
phenyl)-1,2-diazaprop-2-ene 8d
R
9
Yield (%)
5-(4-Cyanophenyl)tetrazole [7, R = –C6H4–CN(4)]11 (1.71 g,
10 mmol) and Appel salt 1 (2.29 g, 11 mmol) in dichloro-
methane (40 ml) were stirred at room temperature for 4 h. After
removal of solvent under reduced pressure the crude product
was purified by flash chromatography on silica gel, eluting with
dichloromethane–hexane to give the title compound 8d (2.4 g,
70%) as yellow crystals (Found: C, 37.9; H, 1.1; N, 17.4.
C10H4Cl2N4S2 requires C, 38.1; H, 1.3; N, 17.8%); δH (500 MHz,
CDCl3) 8.21–8.24 (2H, dd, Ar–H), 7.75–7.78 (2H, dd,
Ar–H); δC (100 MHz, CDCl3) 167.0, 148.2, 144.3, 137.3, 132.4,
129.1, 118.0, 115.4; m/z 315 (Mϩ, 65%), 280 (Mϩ Ϫ Cl, 46), 212
(Mϩ Ϫ SCl2, 90), 135, 103, 77.
C6H5
9a
9b
9c
9d
9e
9f
82
92
99
72
75
90
73
76
4-O2N–C6H4
4-MeO–C6H4
4-NC–C6H4
C6H5O
ClCH2CH2
MeS
9g
9h
2-Thienyl
for the structures assigned to 8, and the sequence of reactions
shown in Scheme 2 provides a very mild, high-yielding synthesis
of 1,3,4-thiadiazoles 9 from nitriles, R–CN, via the tetrazoles 7
and dithiazoles 8.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-
This new route to 1,3,4-thiadiazoles has the useful feature of
directly giving the reactive 2-cyano derivatives 9 which are rare
1,3,4-thiadiazoles, previously made only by multi-step pro-
cesses.4 Since the starting cyanide, RCN, is converted into the
new cyanide 9 the sequence of Scheme 2 could be repeated to
give a series of unsymmetrical thiadiazole oligomers of pre-
cisely known structure, with a cyano group at one end and
various groups, including strong electron donors, at the other.
This sequence of reactions would be somewhat similar to that
used by Huisgen et al. to convert acyltetrazoles into oligo-
meric 1,3,4-oxadiazoles.5 So far we have shown (Table 2) that
this route gives high yields of the highly fluorescent dimers 12
(R = Ph, 4-MeOC6H4 and MeS) and trimers 15 (R = Ph and
MeS). A few such trimers have been made before by classical
1,3,4-thiadiazole ring forming reactions.6 The structure of
15g was confirmed by X-ray diffraction;7 in the crystal the
thiadiazole rings are nearly coplanar with the all-anti
orientation. Well-defined conjugated oligomers related to
polythiophenes are important as active compounds in field
effect transistors and light-modulating and light-emitting
devices with properties that can surpass those of the
corresponding polymers.8
sulfanyl-1,2-diazaprop-2-ene 8g
5-Methylsulfanyltetrazole (2.0 g, 17.2 mmol) and Appel salt 1
(3.95 g, 19.0 mmol) in dichloromethane (80 ml) were stirred
at room temperature for 12 h to give the title compound 8g
(3.50 g, 78%) as yellow crystals (Found: C, 18.2; H, 1.1; N, 16.0.
C4H3Cl2N3S3 requires C, 18.5; H, 1.2; N, 16.15%); δH (500 MHz,
CDCl3) 2.60 (3H, s, SMe); δC (100 MHz, CDCl3) 164.2,
152.7, 143.9, 17.0; m/z 260 (Mϩ, 42%), 224 (Mϩ Ϫ Cl, 53), 157
(Mϩ Ϫ SCl2, 62), 151, 135, 103, 77.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-(2-thienyl)-
1,2-diazaprop-2-ene 8h
5-(2-Thienyl)tetrazole (7, R = 2-thienyl)12 (1.87 g, 12.3 mmol)
and Appel salt 1 (2.82 g, 13.5 mmol) in dichloromethane (20 ml)
were stirred at room temperature for 4 h. Work-up as before
gave the title compound 8h (3.12 g, 86%) as red crystals, mp
122–123 ЊC (Found: C, 28.1; H, 0.9; N, 13.9. C7H3Cl2N3S3
requires C, 28.4; H, 1.0; 14.2%); δH (500 MHz, CDCl3) 7.79
(1H, dd, J 3.7, 1.4 Hz, Ar–H), 7.56 (1H, dd, J 5.1, 1.3 Hz,
Ar–H), 7.12 (1H, dd, J 5.1, 3.8 Hz, Ar–H); δC (100 MHz,
CDCl3) 165.5, 144.3, 144.2, 137.7, 132.9, 132.5, 127.9; m/z 296
(Mϩ, 30%), 64 (S2ϩ, 25).
Experimental
2-Phenyl-1,3,4-thiadiazole-5-carbonitrile 9a
General details
To a solution of 3-chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-phenyl-1,2-diazaprop-2-ene 8a1 (6.46 g, 22 mmol)
in dichloromethane (250 ml), triphenylphosphine (12.88 g,
49 mmol) was added portionwise. The reaction mixture was
stirred at room temperature for 10 min and evaporated to dry-
ness. The product was purified by flash chromatography on
silica gel eluting with dichloromethane to give the title
compound 9a (3.43 g, 82%), mp 116–117 ЊC (Found: C, 58.0; H,
2.6; N, 22.2. C9H5N3S requires C, 57.75; H, 2.7; N, 22.5%);
νmax (Nujol)/cmϪ1 2236 (CN), 1568, 1108, 774 and 733;
δH (270 MHz, CDCl3) 7.45 (5H, m, Ar–H); δC (68 MHz, CDCl3)
172.3, 138.4, 133.0, 129, 128.1, 110.1 (CN); m/z 187 (Mϩ,
100%), 135 (61, PhCNSϩ), 121 (23, PhCSϩ), 103 (35, PhCNϩ),
84 (5, C2N2Sϩ), 77 (26, C6H5ϩ).
Except where noted, all reactions were protected from moisture
by calcium chloride drying tubes, unless carried out under a dry
nitrogen atmosphere. Anhydrous magnesium sulfate was used
for drying organic extracts, and volatiles were removed under
reduced pressure. Ether refers to diethyl ether and light petrol-
eum had bp 60–80 ЊC. All reactions and chromatography
column eluents were monitored by TLC using commercial
aluminium-backed thin-layer chromatography (TLC) plates
(Merck Kieselgel 60 F254). The plates were observed under UV
light at 254 and 350 nm. Flash column chromatography refers
to the technique9 using medium pressure generated by hand
bellows or a small air compressor and was used throughout.
Dry flash chromatography was carried out with suction using a
water pump as described by Harwood.10 Melting points were
determined using a Reichert Kofler hot-stage apparatus. IR
spectra were recorded on a Perkin–Elmer 1710FT spectrometer.
1H NMR spectra were recorded on JEOL GSX 270 (at 270
MHz), Bruker AM300WB (at 300 MHz), Bruker RX-400 (at
400 MHz) and Bruker AM500 (at 500 MHz) machines. 13C
NMR spectra were recorded on JOEL GSX 270 (at 68 MHz),
Bruker AM300WB (at 76 MHz), Bruker RX-400(at 100 MHz)
2-(4-Nitrophenyl)-1,3,4-thiadiazole-5-carbonitrile 9b
To a solution of 3-chloro-l-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-(4-nitrophenyl)-1,2-diazaprop-2-ene 8b1 (100 mg,
0.30 mmol) in dichloromethane (15 ml), triphenylphosphine
(173 mg, 0.66 mmol) was added portionwise. The reaction mix-
ture was stirred at room temperature for 10 min and evaporated
1544
J. Chem. Soc., Perkin Trans. 1, 2002, 1543–1547

View Online
Table 2 Repeated sequence of cyanide
tetrazole
R
iminodithiazole
Yield (%)
cyanide
C6H5
4-MeOؒC6H4
Yield (%)
100
MeS
Yield (%)
97
10
a
86
c
g
a
11
12
a
a
71
83
—
g
g
84
85
c
59b
13
14
15
a
a
a
92
90
64
—
g
g
g
89
87
79
—
—
a Not isolated. b Yield from 10c.
to dryness. The product was purified by flash chromatography
on silica gel, eluting with dichloromethane–light petroleum
(1 : 1) to give the title compound 9b (64 mg, 92%), mp 185 ЊC
(Found: C, 46.2; H, 1.5; N, 24.0. C9H4N4O2S requires C, 46.55;
H, 1.7; N, 24.1%); νmax (Nujol)/cmϪ1 2246 (CN), 1603, 1522,
1431, 1407, 1352, 1319, 1303, 1239, 1192, 1162, 1100, 990, 872,
854, 757 and 691; δH (270 MHz, CDCl3) 8.41 (2H, dd, J 1, 5 Hz,
Ar–H), 8.22 (2H, dd, J 1, 5 Hz, Ar–H); δC (68 MHz, CDCl3)
172.2, 138.3, 132.9, 129.6, 128.6, 128.1, 110.1 (CN); m/z 232
(Mϩ, 15%), 202 (58, Mϩ Ϫ NO), 160 (9), 148 (7), 136 (28), 118
(100, OC6H4CNϩ), 91 (8).
2-(4-Cyanophenyl)-1,3,4-thiadiazole-5-carbonitrile 9d
The hydrazono chloride 8d (1.2 g, 3.81 mmol) and triphenyl-
phosphine (2.20 g, 8.38 mmol) in dichloromethane (14 ml) were
stirred at room temperature for 1 h. After evaporation under
reduced pressure the reaction mixture was separated by flash
chromatography on silica, with hexanes–ethyl acetate as eluent
to give the title compound 9d (0.58 g, 72%) as crystals (Found:
C, 56.2; H, 1.7; N, 26.2. C10H4N4S requires C, 56.6; H, 1.9; N,
26.4%); δH (500 MHz, CDCl3) 8.17–8.19 (2H, dd, Ar–H), 7.87–
7.89 (1H, dd, Ar–H); δC (100 MHz, CDCl3) 170.0, 139.5, 133.3,
131.7, 129.0, 117.4, 116.2 (CN), 109.7 (CN); m/z 212 (Mϩ,
100%), 135, 121.
2-(4-Methoxyphenyl)-1,3,4-thiadiazole-5-carbonitrile 9c
To a solution of 3-chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-(4-methoxyphenyl)-1,2-diazaprop-2-ene 8c1 (2.22 g,
7.00 mmol) in dichloromethane (150 ml), triphenylphosphine
(4.01 g, 15.3 mmol) was added portionwise. The reaction mix-
ture was stirred at room temperature for 10 min and evaporated
to dryness. The product was purified by flash chromatography
on silica gel, eluting with dichloromethane to give the title com-
pound 9c (1.50 g, 99%) as fluorescent needles, mp 132–133 ЊC
(Found: C, 55.4; H, 3.0; N, 19.3. C10H7N3OS requires C, 55.3;
H, 3.2; N, 19.35%); νmax (Nujol)/cmϪ1 2240 (CN), 1598, 1515,
1433, 1401, 1318, 1265, 1261, 1176, 1105, 1034, 983, 837, 722
and 625; δH (270 MHz, CDCl3) 7.79 (2H, d, J 9 Hz, Ar–H), 7.03
(2H, d, J 9 Hz, Ar–H), 3.91 (3H, s, Ar–OCH3); δC (68 MHz,
CDCl3) 172.0, 163.4, 137.3, 130.4, 120.7, 115.1, 110.3 (CN),
55.6; m/z 217 (Mϩ, 90%), 202 (3, Mϩ Ϫ CH3), 174 (4), 165 (3),
151 (23), 146 (4), 133 (100, CH3OC6H4CNϩ), 122 (6), 118 (8),
108 (6), 103 (18), 90 (23), 75 (11).
2-Phenoxy-1,3,4-thiadiazole-5-carbonitrile 9e
To a solution of 3-chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-phenoxy-1,2-diazaprop-2-ene 8e1 (200 mg, 0.66
mmol) in dichloromethane (20 ml), triphenylphosphine
(359 mg, 1.39 mmol) was added portionwise. The reaction mix-
ture was purified by flash chromatography on silica gel, eluting
with dichloromethane–light petroleum (bp 60–80 ЊC) to give the
title compound 9e (100 mg, 75%) as a colourless oil; νmax
(Nujol)/cmϪ1 2238 (CN), 1567, 1525, 1445, 1398, 1358, 1281,
1248, 1198, 1123, 1008, 965, 845 and 637; δH (270 MHz, CDCl3)
7.45 (2H, m, Ar–H), 7.29 (3H, m, Ar–H); m/z 203 (Mϩ, 2%),
201 (100), 157 (91), 77 (100, C6H5ϩ).
2-Chloroethyl-1,3,4-thiadiazole-5-carbonitrile 9f
To a solution of 3,5-dichloro-1-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-1,2-diazapent-2-ene 8f1 (100 mg, 0.36 mmol) in
J. Chem. Soc., Perkin Trans. 1, 2002, 1543–1547
1545

View Online
dichloromethane (15 ml), triphenylphosphine (199 mg, 0.76
mmol) was added portionwise. The reaction mixture was stirred
at room temperature for 10 min and evaporated to an oil. The
product was purified by flash chromatography on silica gel,
eluting with dichloromethane–light petroleum (bp 60–80 ЊC)
(1 : 1) to give the title compound 9f (57 mg, 90%) as an unstable
colourless oil; νmax (Nujol)/cmϪ1 2243 (CN), 1702, 1607, 1447,
1397, 1296, 1171, 1120, 1086, 1017, 946 and 656; δH (270 MHz,
CDCl3) 3.95 (2H, t, J, 6 Hz, CH2–CH2Cl), 3.70 (2H, t, J 6 Hz,
–CH2–CH2–Cl); m/z 174 (Mϩ, 86%), 138 (Mϩ Ϫ HCl, 100), 70
(SCCNϩ, 67), 52 (NCCNϩ, 23).
gave, after recrystallisation (from ethanol), the title compound
10c (1.12 g, 100%) as a pale yellow solid, mp 234 ЊC (Found:
260.0480. C10H8N6OS requires 260.0480); νmax (Nujol)/cmϪ1
1603, 1402, 1378, 1313, 1263, 1170, 1103, 1084, 1029, 995, 975,
841, 811 and 723; δH (270 MHz, (CD3)2SO) 8.04 (2H, d, J 9 Hz,
Ar–H), 7.14 (2H, d, J 9 Hz, Ar–H) and 3.87 (3H, s, Ar–OCH3);
δC (68 MHz, (CD3)2SO) 169.9, 162.3, 153.1, 149.9, 130.0, 121.2,
115.0, 55.8 (Ar–OCH3); m/z 260 (Mϩ, 8%), 232 (8, Mϩ Ϫ N2),
217 (36, Mϩ Ϫ HN3), 151 (3), 108 (100, CH3OPhϩ), 103 (31),
102 (10), 76 (13, C6H4ϩ), 70 (11).
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-(2-phenyl-
2-Methylsulfanyl-1,3,4-thiadiazole-5-carbonitrile 9g
1,3,4-thiadiazol-5-yl)-1,2-diazaprop-2-ene 11a
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-
sulfanyl-1,2-diazaprop-2-ene 8g (2.44 g, 9.38 mmol) and tri-
phenylphosphine (5.42 g, 20.6 mmol) in dichloromethane
(160 ml) were stirred at room temperature for 30 min to give the
title compound (1.08 g, 73%) as a crystalline solid, mp 116–
117 ЊC (Found: C, 30.3; H, 2.3; N, 27.1. C4H3N3S2 requires C,
30.6; H, 1.9; N, 26.7%); δH (500 MHz, CDCl3) 2.90 (3H, s,
SCH3); δC (100 MHz, CDCl3) 173.0, 137.9, 109.8 (CN), 16.6
(SCH3); m/z 157 (Mϩ, 100%), 135, 103, 84.
To a suspension of 2-phenyl-5-(5-tetrazolyl)-1,3,4-thiadiazole
10a (1.5 g, 6.5 mmol) in dichloromethane (200 ml) was added
4,5-dichloro-1,2,3-dithiazolium chloride 1 (1.5 g, 7.19 mmol).
The mixture was stirred at room temperature for 15 h. Pyridine
(0.5 ml, 6.5 mmol) was slowly added and stirred for a further
10 min. A yellow–brown solid was filtered off and washed with
dichloromethane to give the title compound 11a. The filtrate
was concentrated in vacuo and the product was purified by flash
chromatography on silica gel eluting with dichloromethane to
give more of the title compound 11a (1.73 g, 71%) as red cubes,
mp 158–159 ЊC (Found: C, 35.9; H, 1.0; N, 18.3. C11H5Cl2N5S3
requires C, 35.3; H, 1.3; N, 18.7%); νmax (Nujol)/cmϪ1 1553,
1157, 886, 733 and 723; δH (500 MHz, DMSO-d6) 8.09–8.11
(2H, m, Ar–H), 7.57–7.65 (3H, m, Ar–H); δC (100 MHz,
DMSO-d6) 169.6, 162.6, 154.6, 142.9, 139.6, 132.4, 129.7,
128.8, 128.3; m/z 374 (Mϩ, 10%), 310 (24, Mϩ Ϫ S2), 271
(100, Mϩ Ϫ C6H5CN), 187 (73, Mϩ Ϫ C6H5C3N3S), 135 (59,
C6H5CNSϩ), 121 (42, C6H5CSϩ), 103 (35, PhCNϩ), 77 (34,
C6H5ϩ), 64 (25, Sϩ2).
2-(2-Thienyl)-1,3,4-thiadiazole-5-carbonitrile 9h
The hydrazono chloride 8h (1.61 g, 5.44 mmol) and triphenyl-
phosphine (3.00 g, 11.4 mmol) in dichloromethane (14 ml) were
stirred at room temperature for 1 h and chromatographed as
before to give the title compound 9h (0.8 g, 76%) as crystals, mp
129–130 ЊC (Found: C, 43.3; H, 1.3; N, 21.6. C7H3N3S2 requires
C, 43.5; H, 1.6; N, 21.7%); δH (500 MHz, CDCl3) 7.72 (1H, dd,
J 3.7, 1.1 Hz, Ar–H), 7.67 (1H, dd, J 5.1, 1.1 Hz, Ar–H), 7.21
(1H, dd, J 5.0, 3.8 Hz, Ar–H); δC (100 MHz, CDCl3) 165.7,
137.2, 132.3, 131.9, 130.0, 128.7, 110.0 (CN); m/z 193 (Mϩ,
100%), 168 (35), 135, 121.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-(2-methyl-
sulfanyl-1,3,4-thiadiazol-5-yl)-1,2-diazaprop-2-ene 11g
2-Phenyl-5-(tetrazol-5-yl)-1,3,4-thiadiazole 10a
2-Methylsulfanyl-5-(tetrazol-5-yl)-1,3,4-thiadiazole 10g was
prepared (97%) from the cyanide 9g, aluminium chloride
and sodium azide exactly as for the other tetrazoles 10, and
was converted directly into 11g. Compound 10g (400 mg,
2.00 mmol) and Appel salt 1 (417 mg, 2.00 mmol) in dichloro-
methane (6 ml) were stirred at room temperature for 6 h to give
the title compound 11g (580 mg, 84%) as a red crystalline solid,
mp 193–194 ЊC (Found: C, 20.8; H, 1.4; N, 20.5. C6H3Cl2N5S4
requires C, 20.9; H, 0.9; N, 20.3%); δH (500 MHz, DMSO-d6)
2.84 (3H, s, SMe); δC (100 MHz, DMSO-d6) 172.7, 169.5, 162.0,
142.8, 139.1, 16.7; m/z 344 (Mϩ, 18%), 280 (Mϩ Ϫ S2, 30), 271,
187, 64 (Sϩ2, 25).
A
mixture of 5-phenyl-1,3,4-thiadiazole-2-carbonitrile 9a
(2.00 g, 11.0 mmol), anhydrous aluminium chloride (1.43 g,
11.0 mmol) and pulverised sodium azide (2.16 g, 33.0 mmol)
suspended in tetrahydrofuran (80 ml) was refluxed under
nitrogen for 24 h. The reaction mixture was cooled to room
temperature and neutralised by the slow addition of 2 M hydro-
chloric acid (20 ml) (CAUTION! HN3 was generated, and was
removed by the use of a water pump). The tetrahydrofuran
layer was separated from the aqueous layer, extraction of
the aqueous layer with ethyl acetate (3 × 300 ml) recovered the
remaining product. The ethyl acetate extracts were combined
with the tetrahydrofuran layer and dried. Evaporation of the
solvents gave, after recrystallisation (from ethanol), the title
compound 10a (2.11 g, 86%) as a pale yellow solid, mp 243–
245 ЊC; νmax (Nujol)/cmϪ1 1570, 1169, 1095, 734 and 689;
δH (270 MHz, (CD3)2SO) 8.13 (2H, d, J 1 Hz, Ar–H), 7.63 (3H,
m, Ar–H); m/z 230 (Mϩ, 100%), 202 (30, Mϩ Ϫ N2), 188 (34,
Mϩ Ϫ N3), 135 (18, PhCNSϩ), 121 (62, PhCSϩ), 103 (64,
PhCNϩ), 77 (47, C6H5ϩ).
5-Cyano-5Ј-phenyl-2,2Ј-bi(1,3,4-thiadiazolyl) 12a
To a suspension of 3-chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-(2-phenyl-1,3,4-thiadiazol-5-yl)-1,2-diazaprop-2-ene
11a (1.44 g, 3.85 mmol) in dichloromethane (120 ml), tri-
phenylphosphine (2.22 g, 8.47 mmol) was added portionwise.
The reaction mixture was stirred at room temperature for 30
min and evaporated to dryness. The product was purified by
flash chromatography on silica gel, eluting with dichlorometh-
ane to give the title compound 12a (0.84 g, 83%), mp 245–246 ЊC
(Found: C, 48.6; H, 1.8; N, 25.9. C11H5N5S2 requires C, 48.7; H,
1.85; N, 25.8%); νmax (Nujol)/cmϪ1 2242 (CN), 1568, 1092, 949,
772, 687 and 606; δH (500 MHz, DMSO-d6) 8.10–8.13 (2H, m,
Ar–H), 7.60–7.67 (3H, m, Ar–H); δC (100 MHz, DMSO-d6)
170.7, 157.1, 141.1, 132.0, 129.2, 128.2, 127.9, 110.0 (CN);
m/z 271 (Mϩ, 100%), 187 (5, C6H5C3N3Sϩ), 168 (6), 135 (32,
C6H5CNSϩ), 121 (20, C6H5CSϩ), 103 (15, PhCNϩ), 77 (16,
C6H5ϩ).
2-(4-Methoxyphenyl)-5-(tetrazol-5-yl)-1,3,4-thiadiazole 10c
A mixture of 2-(4-methoxyphenyl)-1,3,4-thiadiazole-5-carbo-
nitrile 9c (1.00 g, 4.6 mmol), anhydrous aluminium chloride
(0.61 g, 4.6 mmol) and pulverised sodium azide (1.70 g,
21 mmol) suspended in tetrahydrofuran (50 ml) was refluxed
under nitrogen for 24 h. The reaction mixture was cooled to
room temperature and neutralised by the slow addition of 2 M
hydrochloric acid (7 ml) (CAUTION! HN3 was generated, and
was removed by the use of a water pump). The tetrahydrofuran
layer was separated from the aqueous layer, extraction of the
aqueous layer with ethyl acetate (3 × 150 ml) gave the remaining
product. The ethyl acetate extracts were combined with the
tetrahydrofuran layer and dried. Evaporation of the solvents
5-Cyano-5Ј-(4-methoxyphenyl)-2,2Ј-bi(1,3,4-thiadiazolyl) 12c
To a suspension of 2-(4-methoxyphenyl)-5-(tetrazol-5-yl)-1,3,4-
thiadiazole 10c (100 mg, 0.38 mmol) in dichloromethane
1546
J. Chem. Soc., Perkin Trans. 1, 2002, 1543–1547

View Online
(30 ml) was added 4,5-dichloro-1,2,3-dithiazolium chloride 1
(96 mg, 0.46 mmol). The mixture was stirred at room temper-
ature for 16 h. Pyridine (0.03 ml, 0.38 mmol) was added and
stirred for a further 4 h, and then triphenylphosphine (352 mg,
1.3 mmol) was added and this mixture was stirred for 30 min.
The product was purified by flash chromatography on silica
eluting with ethyl acetate–dichloromethane (1 : 9) to give the
title compound 12c (68 mg, 59%) as yellow–green needles, mp
258–260 ЊC (Found: C, 47.8; H, 2.1; N, 23.2. C12H7N5OS2
requires C, 47.8; H, 2.3; N, 23.3%); νmax (Nujol)/cmϪ1 2243
(CN), 1598, 1514, 1397, 1316, 1305, 1255, 1175, 1118, 1091,
1024, 981, 949, 843 and 799; δH (270 MHz, CDCl3) 8.07 (2H, d,
J 8 Hz, Ar–H), 7.16 (2H, d, J 8 Hz, Ar–H), 3.88 (3H, s,
ArOCH3); m/z 301 (Mϩ, 65%), 217 (19, Mϩ Ϫ C2N2S), 165
(6, Mϩ Ϫ C4N4S), 151 (32), 133 (100, MeOC6H4CNϩ), 122 (10),
108 (12), 103 (15), 90 (22), 88 (10), 70 (24), 63 (13), 52 (16,
C2N2).
H, 1.1; N, 22.7. C8H3Cl2N7S5 requires C, 22.4; H, 0.7; N,
22.9%); δH (500 MHz, DMSO-d6) 2.88 (3H, s, SMe); δC (100
MHz, DMSO-d6), 172.2, 170.7, 164.1, 161.3, 157.6, 142.9,
138.7, 16.9 (SMe); m/z 428 (Mϩ, 30%), 64 (S2ϩ, 25).
5-Cyano-5Љ-phenyl-2,2Ј:5Ј,2Љ-ter(1,3,4-thiadiazolyl) 15a
The hydrazono chloride 14a (217 mg, 0.47 mmol) and tri-
phenylphosphine (273 mg, 1.04 mmol) in dichloromethane
(10 ml) were stirred at room temperature for 30 min to give the
title compound 15a (108 mg, 64%), mp 308–310 ЊC (Found: C,
43.5; H, 1.9; N, 27.1. C13H5N7S3 requires C, 43.9; H, 1.4; N,
27.6%); δH (500 MHz, DMSO-d6) 8.10–8.13 (2H, m, Ar–H),
7.60–7.67 (3H, m, Ar–H); δC (100 MHz, DMSO-d6) 170.7,
163.0, 157.1, 141.1, 132.0, 129.2, 128.2, 127.9, 110.0 (CN); m/z
355 (Mϩ, 100%), 187 (Mϩ Ϫ C6H5C3N3Sϩ, 2), 135 (C6H5CNSϩ,
40), 121 (C6H5CSϩ, 27), 103 (PhCNϩ, 10), 77 (C6H5ϩ, 20).
5-Cyano-5Љ-methylsulfanyl-2,2Ј:5Ј,2Љ-ter(1,3,4-thiadiazolyl) 15g
5-Cyano-5Ј-methylsulfanyl-2,2Ј-bi(1,3,4-thiadiazolyl) 12g
The hydrazono chloride 14g (100 mg, 0.23 mmol) and tri-
phenylphosphine (135 mg, 0.51 mmol) in dichloromethane
(6 ml) were stirred at room temperature for 30 min to give the
title compound 15g (60 mg, 79%) as crystalline solid, mp 264–
265 ЊC (Found: C, 29.7; H, 0.8; N, 30.3. C8H3N7S4 requires C,
29.5; H, 0.9; N, 30.1%); δH (500 MHz, DMSO-d6) 2.89 (s, SMe);
δC (100 MHz, DMSO-d6) 172.5, 162.9, 161.4, 159.1, 157.3,
142.4, 110.6 (CN), 16.9 (SMe); m/z 325 (Mϩ, 100%), 168 (6),
135, 121.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-(2-methyl-
sulfanyl-1,3,4-thiadiazol-5-yl)-1,2-diazaprop-2-ene 11g (300
mg, 0.87 mmol) and triphenylphosphine (530 mg, 1.92 mmol)
in dichloromethane (10 ml) was stirred at room temperature for
30 min to give the title compound 12g (178 mg, 85%), mp 168–
169 ЊC (Found: C, 29.9; H, 1.5; N, 29.1. C6H3N5S3 requires C,
29.9; H, 1.25; N, 29.0%); δH (500 MHz, CDCl3) 2.91 (3H, s,
SMe); δC (100 MHz, CDCl3) 172.5, 162.4, 156.4, 140.2, 109.5
(CN), 16.7 (SMe); m/z 241 (Mϩ, 19%), 177 (M Ϫ S2, 32).
Acknowledgements
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-[2-
(2-phenyl-1,3,4-thiadiazol-5-yl)-1,3,4-thiadiazol-5-yl]-1,2-
diazaprop-2-ene 14a
We thank the SERC and MDL Information Systems UK Ltd
for financial support and the Wolfson Foundation for establish-
ing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College.
5-Phenyl-5Ј-tetrazolyl-2,2Ј-bi(1,3,4-thiadiazolyl) 13a was pre-
pared (92%) from the cyanide 12a, aluminium chloride and
sodium azide, as before, and was converted directly into 14a.
Compound 13a (300 mg, 0.96 mmol) and Appel salt 1 (200 mg,
0.96 mmol) in dichloromethane (6 ml) were stirred at room
temperature for 6 h to give the title compound 14a (396 mg,
90%) as a red crystalline solid, mp 266–267 ЊC (Found: C, 33.8;
H, 1.0; N, 21.3. C13H5Cl2N7S4 requires C, 34.1; H, 1.1; N,
21.4%); δH (500 MHz, DMSO-d6) 8.09–8.11 (2H, m, Ar–H),
7.57–7.65 (3H, m, Ar–H); δC (100 MHz, DMSO-d6) 169.6,
162.6, 154.6, 142.9, 139.6, 132.4, 129.7, 128.8, 128.3; m/z 458
(Mϩ, 20%), 310 (Mϩ Ϫ S2, 48), 271 (Mϩ Ϫ C6H5CN, 100), 135
(C6H5CNSϩ, 45), 103 (PhCNϩ, 34), 77 (C6H5ϩ, 20).
References
1 C. W. Rees, S. Sivadasan, A. J. P. White and D. J. Williams, J. Chem.
Soc., Perkin Trans. 1, DOI: 10.1039/b202211g.
2 T. Besson, M.-J. Dozias, J. Guillard, P. Jacquault, M.-D. Legoy and
C. W. Rees, Tetrahedron, 1998, 54, 6475.
3 T. Besson, K. Emayan and C. W. Ress, J. Chem. Soc., Perkin Trans.
1, 1995, 2097.
4 W. A. Remers, G. J. Gibs and M. J. Weiss, J. Heterocycl. Chem., 1969,
6, 835; H. Kristinsson, Synthesis, 1979, 102; C. B. Chapleo,
P. L. Myers, A. C. B. Smith, M. R. Stillings, I. F. Tulloch and
D. S. Walter, J. Med. Chem., 1988, 31, 7.
5 R. Huisgen, C. Axen and H. Seidl, Chem. Ber., 1965, 98, 2966.
6 W. Thiel and R. Mayer, J. Prakt. Chem., 1989, 331, 243; W. Thiel and
R. Mayer, J. Prakt. Chem., 1989, 331, 649; W. Thiel and R. Mayer,
J. Prakt. Chem., 1990, 332, 55.
7 V.-D. Le, C. W. Rees and S. Sivadasan, Tetrahedron Lett., 2000, 41,
9407–9411.
3-Chloro-1-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-[2-
(2-methylsulfanyl-1,3,4-thiadiazol-5-yl)-1,3,4-thiadiazol-
5-yl]-1,2-diazaprop-2-ene 14g
5-Methylsulfanyl-5Ј-tetrazolyl-2,2Ј-bi(1,3,4-thiadiazolyl) 13g
was prepared (89%) from cyanide 12g, aluminium chloride and
sodium azide, as before, and was converted directly into 14g.
Compound 13g (120 mg, 0.42 mmol) and Appel salt 1 (97 mg,
0.46 mmol) in dichloromethane (6 ml) were stirred at room
temperature for 6 h to give the title compound 14g (158 mg,
87%) as a red crystalline solid, mp 224–224 ЊC (Found: C, 22.5;
8 U. Mitschke, E. M. Osteritz, T. Debaerdemaeker, M. Sokolowski
and P. Bäuerle, Chem. Eur. J., 1998, 4, 221.
9 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
10 L. M. Harwood, Aldrichimica Acta, 1985, 18, 25.
11 M. Koyama, N. Ohtani, F. Kai, I. Moriguchi and S. Inouye, J. Med.
Chem., 1987, 30, 552.
12 B. Elpern and F. C. Nachod, J. Am. Chem. Soc., 1950, 72, 3379.
J. Chem. Soc., Perkin Trans. 1, 2002, 1543–1547
1547