Conversion of enamines, enamides and triazoles by trithiazyl trichloride into 1,2,5-thiadiazoles

Article abstract of DOI:10.1039/b010140k

Trithiazyl trichloride 1 converts primary and secondary enamines, enamides and 1,2,3-triazoles into 1,2,5-thiadiazoles. These mild reactions provide one-pot routes to various alkyl, aryl, functional and quaternary 1,2,5-thiadiazoles, in moderate to good yields. The trimer 1 reacts as a 1,2-bis-electrophile adding an N-S unit across C=C-N. For primary enamines ¹⁵N-labelling reveals an additional, minor pathway in which N-S-N is added across C=C, with elimination of the enamine nitrogen. With N-alkylated enamines the alkyl group is retained in a quaternised thiadiazole, but this can be dealkylated in situ. Enamides react similarly but with spontaneous N-deacylation. 1,2,3-Triazoles with electron withdrawing groups to stabilise their acyclic diazoimine tautomers also give 1,2,5-thiadiazoles, with loss of dinitrogen. Mechanisms are proposed for these new reactions.

Full text of DOI:10.1039/b010140k

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Conversion of enamines, enamides and triazoles by trithiazyl
trichloride into 1,2,5-thiadiazoles
Charles W. Rees and Tai-Yuen Yue
1
Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY
Received (in Cambridge, UK) 13th December 2000, Accepted 16th February 2001
First published as an Advance Article on the web 7th March 2001
Trithiazyl trichloride 1 converts primary and secondary enamines, enamides and 1,2,3-triazoles into 1,2,5-
thiadiazoles. These mild reactions provide one-pot routes to various alkyl, aryl, functional and quaternary
1,2,5-thiadiazoles, in moderate to good yields. The trimer 1 reacts as a 1,2-bis-electrophile adding an N–S unit
across C᎐C–N. For primary enamines 15N-labelling reveals an additional, minor pathway in which N–S–N is
᎐
added across C᎐C, with elimination of the enamine nitrogen. With N-alkylated enamines the alkyl group is
᎐
retained in a quaternised thiadiazole, but this can be dealkylated in situ. Enamides react similarly but with
spontaneous N-deacylation. 1,2,3-Triazoles with electron withdrawing groups to stabilise their acyclic
diazoimine tautomers also give 1,2,5-thiadiazoles, with loss of dinitrogen. Mechanisms are proposed for
these new reactions.
We have shown that trithiazyl trichloride, (NSCl)3, “the trimer”
1 reacts readily with nucleophilic unsaturated substrates, by
electrophilic attack or by cycloaddition, to give a useful range
of sulfur–nitrogen heterocylic compounds.1 Thus pyrroles, for
example, are converted into isothiazoles or fused 1,2,5-
thiadiazoles.2 It seemed that enamines might undergo some-
what analogous reactions, with addition of the trimer across the
bisnucleophilic enamine group or across the carbon–carbon
double bond, and we now describe these and related reactions.
latter with the amino group, being eliminated, presumably as
ammonia, as in 5. We have distinguished between these possi-
bilities by 15N-labelling experiments. 15N-Labelled primary
enamine 2b was made by treatment of methyl acetoacetate in
aqueous ethanol with labelled ammonia gas which was gener-
ated from 15N-labelled ammonium sulfate (98% enriched).
The mass spectrum of the enamine 2b showed 97% 15N
incorporation.
Results and discussion
Reactions with primary enamines
We first treated the stable primary enamines 3-aminocrotono-
nitrile 2a and methyl, ethyl and p-nitrobenzyl 3-aminocroton-
ates 2b–d with the trimer 1 (1 equiv.) in tetrachloromethane
at RT for 16 h (Scheme 1). Moderate yields of the 1,2,5-
The labelled enamine 2b and trimer 1 under the same condi-
tions as before gave the thiadiazole 3b (60%) which showed the
same Rf, mp and H NMR spectrum as the unlabelled com-
1
pound. Analysis of the mass spectrum of labelled 3b using an
isotopic abundance calculation program showed 87% incorpor-
ation of a single 15N label, 13% of unlabelled thiadiazole
and a negligibly small amount of doubly labelled material. The
fragment peak at m/z 74, which corresponds to 15N-aceto-
nitrile sulfide, was observed in the mass spectrum of labelled
thiadiazole 3b; the same fragment in unlabelled 3b was
observed at m/z 73. This strongly suggested that the 15N label is
at N-5 rather than N-2 (Scheme 2), indicating retention of the
nitrogen of the enamine in the thiadiazole with no scrambling
of the label during reaction. This assignment was further sup-
ported by the 15N NMR spectrum which showed one singlet at
341 ppm with nitromethane as external reference.
Scheme 1
thiadiazoles 3 (28, 62, 40 and 56% respectively) were obtained
after chromatographic purification, and their structures fol-
lowed from their mass spectra, infrared, 1H and 13C NMR
spectra. This reaction provides a new, simple one-pot prepar-
ation for 1,2,5-thiadiazoles with electron withdrawing groups in
the 3-position.
Since the trimer 1 is known to contribute either an S–N or an
N–S–N unit in its ring-forming reactions,1 formation of the
1,2,5-thiadiazoles could involve the former with incorporation
of the primary amino group into the product, as in 4, or the
In solution trithiazyl trichloride 1 exists in equilibrium with
᎐
the dissociated monomer, thiazyl chloride, N᎐S–Cl, the pos-
᎐
ition of equilibrium depending on the solvent, the temperature
and the purity of the sample.3 The reactive species could there-
fore be the trimer, the monomer or both. We have argued that
the monomer is the reactive species in many reactions of the
trimer in hot solutions where an N–S unit is transferred and
where only one-third of an equivalent of trimer is required for
complete conversion, as in the almost quantitative rearrange-
662
J. Chem. Soc., Perkin Trans. 1, 2001, 662–667
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b010140k

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Table 1 Effect of temperature on yield and 15N incorporation in the
conversion of enamine 2b (1 mmol) and trithiazyl trichloride
(1 mmol) into the thiadiazole 3b
1
Temperature/
ЊC
Yield of
3b (%)
15N-label
incorporation (%)
Solvent
Ϫ78
20
77
DCM
CCl4
CCl4
37
60
55
25
93
87
87
92
111
PhMe
Scheme 3
Scheme 2
Scheme 4
ment of 2,5-diphenylfuran into 5-benzoyl-3-phenylisothiazole.4
Treatment of the enamine 2b with trimer was therefore
repeated, in boiling tetrachloromethane, with 0.33 and 1.0
equiv. of trimer; thiadiazole 3b was obtained in 19 and 55% of
yield respectively, making it less likely that the reaction occurs
via the monomer. Furthermore, 3b was obtained in 37% yield
from 2b and trimer (1 equiv.) in DCM at Ϫ78ЊC at which tem-
perature the monomer would be formed extremely slowly from
pure trimer.3
thermally unstable and dimerises very readily to S4N4 and
polymerises to poly(sulfur nitride).5 Variable amounts of S4N4
were isolated in these experiments. A control experiment
showed that S4N4 did not convert enamine 2b into thiadiazole
3b, even on prolonged boiling in tetrachloromethane.
In the minor pathway (Scheme 4) protonation of the same
intermediate enamine 6, on carbon or on nitrogen, would make
it vulnerable to intramolecular nucleophilic attack by the
neighbouring trimer nitrogen, shown in dipolar form in 8. Fur-
ther protonation by the HCl generated could lead to loss of
ammonia to give a sulfur-bridged intermediate 9 which could
fragment to thiadiazole 3b and the known bis(chlorothio)-
nitronium {IUPAC name: chloro[(chlorothio)imino]sulfonium}
The effect of temperature on the 15N-incorporation as well as
on the yield was studied, and the results are shown in Table 1.
The maximum yield of thiadiazole 3b was obtained at room
temperature. In boiling toluene the yield was much reduced,
possibly because of the faster decomposition of trimer to sulfur
and S4N4 at this temperature; the resulting complex reaction
mixture was also more difficult to separate in this experiment.
The percentage of 15N incorporated remained essentially
constant over the temperature range studied.
cation [Cl–S–N᎐S–Cl]+.6 In this minor pathway the trimer has
acted as an N(1)electrophile–N(3)nucleophile, and it should be
noted that for this transfer of N–S–N the trimer is a much more
reasonable reagent than the monomer.
᎐
Reaction mechanism
Reactions with secondary enamines
The evidence available supports, but does not prove, that the
trimer is the reactive species in the conversion of 2b into 3b, and
we offer a mechanistic explanation for the extensive, but
incomplete, incorporation of the isotopic label on this basis.
Mechanisms are proposed for a major pathway (Scheme 3)
which involves incorporation of the enamine nitrogen into the
product and a minor pathway (Scheme 4) in which this nitrogen
is eliminated. Both mechanisms start by electrophilic attack of
the enamine carbon by the trimer, through nitrogen, with loss
of chlorine from the adjacent sulfur atom, to give intermediate
6; this process would be favoured by the SIV to SII transform-
ation. In the major pathway the 1,3-bisnucleophilic enamine
cyclises onto the heterocyclic ring to give the bicyclic inter-
mediate 7, the trimer having acted as a 1,2-bis-electrophile. The
final elimination of HCl, as shown in 7, is accompanied by
fragmentation to the aromatic thiadiazole and S2N2; the latter is
Evidence for the minor pathway mechanism (Scheme 4) could
be provided by detection of the eliminated ammonia. We con-
sidered that support for this elimination would be more feasible,
and more interesting, if the eliminated amino group remained
attached to the thiadiazole produced, by starting with a cyclic
enamine. The enamino-ester 10 (Scheme 5) was therefore pre-
pared from 2-methoxy-1-pyrroline and Meldrum’s acid and
ethanolysis of the product.7 If 10 reacted with the trimer 1 by
the “minor” pathway, the aminopropylthiadiazole 11 would be
produced as its hydrochloride. However, no formation of 11
was observed in this reaction at RT. The only product isolated
was the chloropropylthiadiazole 13, in very low yield (6%). This
had a molecular ion peak at m/z 234 with the characteristic
isotopic cluster for one chlorine atom, a loss of ethanol from
the molecular ion by
a McLafferty-type rearrangement
(cf. Scheme 2), and the formula C8H11ClN2O2S from HRMS;
J. Chem. Soc., Perkin Trans. 1, 2001, 662–667
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Scheme 5
1H and 13C NMR indicated the presence of a chloropropyl
group.
Scheme 6
In contrast with the primary enamine reactions, an increase
in temperature for the reaction of trimer with 10, in boiling
tetrachloromethane, gave a substantial increase in the yield of
13 (50%). Clearly the major pathway (Scheme 3) has predomin-
ated since this mechanism would lead to the thiadiazolium salt
12 as the primary product which would be susceptible to
“dealkylation” by chloride ion, slowly at RT and more rapidly
in boiling tetrachloromethane. In the light of this reaction, an
acyclic secondary enamine, methyl 3-N-methylaminocrotonate
14, was treated with trimer in tetrachloromethane. At RT,
traces of a product with an Rf value identical to that of thiadi-
azole 3b were observed; from a reaction in the boiling solvent,
3b was isolated in 19%. This was presumably formed via the
corresponding N-methylthiadiazolium chloride 15a.
obtained in 53 and 38% respectively (Scheme 6). Presumably
these reactions proceed through the N-acylthiadiazolium salts
but these were too sensitive to be readily isolated. This simple
reaction provides a new route to aryl-1,2,5-thiadiazoles.
Reactions with 1,2,3-triazoles
1,2,3-Triazoles were also considered as a potential source of an
enamine-like unit for condensation with the trimer. 1,2,3-
Triazoles with an electron-withdrawing group on N(1), such as
18, are in equilibrium with acyclic diazoimines9 e.g. 19↔20
which are 1,3-electrophile–nucleophiles activated by the loss of
dinitrogen and hence potentially able to condense with the
trimer to form 1,2,5-thiadiazoles 21 (Scheme 7). We therefore
Attempts were made to isolate the dithiazolium salt inter-
mediates. Upon dropwise addition of a tetrachloromethane
solution of trimer 1 to stirred solutions of the enamines 10 and
14 in the same solvent at RT, brown precipitates were formed.
These were filtered, washed with dry tetrachloromethane under
nitrogen, dissolved in water and extracted thoroughly with
DCM to remove organic impurities. The resulting aqueous
solutions were treated with activated charcoal, filtered and
evaporated under high vacuum. The crude chloride salts, 12
and 15a, which have appropriate infra red spectra, were purified
by anion exchange; a saturated aqueous solution of ammonium
hexafluorophosphate was slowly added to their concentrated
aqueous solutions to give the hexafluorophosphate salts in low
overall yields (8 and 15% respectively). The structures of these
Scheme 7
prepared the 5-(p-nitrophenyl) derivative, 18a, Ar = C6H4NO2-
p,10 since the nitro group was expected to facilitate triazole ring
opening and to confer crystallinity on reaction products.
The reaction between triazole 18a and trimer 1 in boiling
tetrachloromethane for 16 h gave the detosylated thiadiazole
21a, Ar = C6H4NO2-p, in high yield (90%). If the triazole 18a
were first detosylated in boiling aqueous ethanol the product
gave the same thiadiazole with trimer, at a comparable rate
but in a lower yield (67%). The N-tosyl group is therefore not
crucial to the reaction, and indeed it was probably removed
under the acidic conditions generated; we found that 18a was
detosylated by dry hydrogen chloride gas.
However, the p-nitro group is crucial to the reaction since
4-phenyl-1,2,3-triazole10 did not give 3-phenyl-1,2,5-thiadi-
azole on treatment with trimer under the same conditions; only
starting triazole, S4N4 and S8 were isolated. This could indicate
that the trimer does not react with the intact triazole but
requires a very small amount (at least) of the diazoimine
tautomer, the formation of which will be strongly favoured by
delocalisation of charge onto the nitro group 22. An alternative
and perhaps more likely explanation is that the trimer does
react with the triazole, through sulfur, to give a species like 23 in
which the triazole is activated to ring opening (arrows in 23)
just as it is in the N-tosyl derivative. It is possible that this ring
opening could occur with the extra activation provided by the
p-nitro group, but not its absence.
1
salts followed from their FAB-MS, IR and H NMR spectra.
The FAB-MS showed the expected molecular ion peaks and the
1
IR spectra showed strong ester carbonyl absorption. In the H
NMR spectra of cations 12 and 15 the N-5 and C-4 substituent
signals were at substantially lower field than for those of
the neutral thiadiazoles 13 and 3b; these latter were formed
from the PF6Ϫ salts on treatment with benzyltriethylammonium
chloride in suspension in boiling tetrachloromethane. All
these results support the mechanisms proposed above. It is
worth noting that, in contrast with the alkylation of 1,2,5-
thiadiazoles, these trimer reactions provide a regiospecific syn-
thesis of the thiadiazolium salts like 12 and 15 although the
reactions have yet to be optimised.
Reactions with enamides
We next considered treatment of enamides with the trimer since
although enamides are less nucleophilic than enamines, the
deacylation of analogous intermediate N-acylthiadiazolium
salts should proceed more readily than the N-dealkylations.
Methyl 2-acetamidoacrylate 16a was attractive since it is com-
mercially available and a range of 3-aryl groups can be readily
introduced by palladium coupling reactions.8
Methyl 2-acetamidoacrylate 16a and methyl 2-acetamido-3-
phenylacrylate 16b, prepared by palladium catalysed coupling
with iodobenzene,8 were treated with trimer in refluxing tetra-
chloromethane, and the expected thiadiazoles 17a and b were
A triazole with an intermediate electron withdrawing
substituent gave intermediate results. Methyl 5-methyl-3H-
1,2,3-triazole-4-carboxylate 24, prepared by cycloaddition of
trimethylsilyl azide and methyl tetrolate,11 was treated with
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J. Chem. Soc., Perkin Trans. 1, 2001, 662–667

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Reactions of trithiazyl trichloride with primary enamines
General procedure. The primary enamine (1 mmol) was dis-
solved in CCl4 (10 ml), and trithiazyl trichloride (245 mg,
1 mmol) in CCl4 (10 ml) was added dropwise. The reaction mix-
ture was stirred at room temperature for 16 h. The reaction
mixture was then filtered through a short pad of silica. The
filtrate was concentrated under reduced pressure. The residue
was then subjected to column chromatography on silica with
DCM–light petroleum (1 : 1) mixture as eluent.
3-Cyano-4-methyl-1,2,5-thiadiazole 3a. 3-Aminocrotono-
nitrile 2a was treated with trithiazyl trichloride and the title
compound (35 mg, 28%) was obtained as a light yellow oil
(Found: M+ 125.0041. C4H3N3S requires M 125.0048); νmax
(neat)/cmϪ1 2241vs (nitrile), 1483s, 1439s, 1405s, 1388s, 1292s,
and 1150s; δH (250 MHz; CDCl3) 2.76 (3H, s, Me); δC (63 MHz;
CDCl3) 163.5. 134.0, 111.9 (nitrile C) and 15.25 (Me); m/z 125
(M+, 43%), 84 (32, M Ϫ MeCN), 73 (100, M Ϫ NCCN) and 46
(26, NS).
trimer under the standard conditions in boiling tetrachloro-
methane; the reaction was slow giving only 9% of thiadiazole
3b and recovered 24 (54%) after 16 h. Presumably a higher tem-
perature is required for triazole ring opening; the reaction was
still slow in boiling toluene, giving a 17% yield and 49% of 24.
Further improvement of the isolated yield to 34% was obtained
by portionwise addition of the trimer, to minimise its decom-
position at this higher temperature; starting triazole (46%) was
recovered so the corrected yield of 3b was 65%.
Methyl 4-methyl-1,2,5-thiadiazole-3-carboxylate 3b. Methyl
3-aminocrotonate 2b was treated with trithiazyl trichloride and
the title compound (98 mg, 62%) was obtained as colourless
needles, mp 25–26ЊC (Found: M+ 158.0157. C5H6N2O2S
Although the scope of this 1,2,3-triazole to 1,2,5-thiadiazole
transformation is limited, it does provide an attractive route to
thiadiazoles with electron withdrawing substituents.
requires M 158.0150); νmax (neat)/cmϪ1 1728vs (C᎐O), 1590s
᎐
(C᎐N), 1444vs, 1263vs and 1103vs; δ (250 MHz; CDCl3) 4.00
᎐
H
(3H, s, ester Me), and 2.83 (3H, s, 4-Me); δC (63 MHz; CDCl3)
Experimental
For general information, see references 1, 2 and 4
163.0 (C᎐O, ester), 160.75, 150.0, 52.8 (ester Me) and 17.3
᎐
(4-Me); m/z 158 (M+, 31%), 127 (55, M Ϫ MeO), 126 (100,
M Ϫ MeOH), 86 (24, SNCCO), 73 (14, CH3CNS) and 72 (7,
CH2CNS).
Methyl 3-aminocrotonate 2b,12 methyl 3-N-methylamino-
crotonate 14,12 ethyl α-(pyrrolidin-2-ylidene)acetate 10,7 methyl
2-acetamido-3-phenylacrylate 16b,8 5-p-nitrophenyl-1,2,3-tri-
azole10 and its 1-p-tolylsulfonyl derivative 18a10 and methyl
5-methyl-3H-1,2,3-triazole-4-carboxylate (24)11 were prepared
by literature methods. Methyl 3-15N-aminocrotonate was pre-
pared by treatment of a solution of methyl acetoacetate
(900 mg, 7.8 mmol) in water (1 ml) and ethanol (1 ml) with
15N-enriched ammonia gas which was generated from
15N-enriched ammonium sulfate (500 mg, 3.9 mmol) (98%
enriched) with sodium hydroxide solution. The labelled com-
pound (319 mg, 26%) separated to give colourless crystals, mp
82–83ЊC, m/z 116 (M+, 38%), 85 (100, M Ϫ OMe) and 84 (26,
M Ϫ MeOH).
15N Labelled methyl 3-aminocrotonate 2b was treated with
trithiazyl trichloride in different solvents and at different tem-
peratures. Yields and isotopic incorporation are given in Table
1. The labelled title compound has identical mp, 1H NMR and
IR spectra to the unlabelled compound. For the labelled com-
pound obtained from room temperature reaction, δN-15 341.0
(external reference MeNO2); m/z 159 (M+, 31%), 158 (4), 128
(53, M Ϫ MeO), 127 (100, M Ϫ MeOH), 86 (27, S14NCCO), 74
(15, CH3C15NS) and 73 (8, CH2C15NS).
Ethyl 4-methyl-1,2,5-thiadiazole-3-carboxylate 3c. Ethyl
3-aminocrotonate 2c was treated with trithiazyl trichloride to
give the title compound (69 mg, 40%) as a light yellow oil
(Found: M+ 172.0304. C6H8N2O2S requires M 172.0306);
p-Nitrobenzyl 3-aminocrotonate 2d
νmax (neat)/cmϪ1 1723vs (C᎐O), 1422s, 1172vs and 1100vs;
᎐
Ethyl acetoacetate (4.0 g, 26 mmol) and p-nitrobenzyl alcohol
(4.1 g, 31 mmol) were mixed and heated until ethanol was
evolved. The ethanol was distilled off and excess of ethyl
acetoacetate was distilled off in vacuo. The crude oil of
p-nitrobenzyl acetoacetate (5.1 g) was used in the next step
without further purification.
Crude p-nitrobenzyl acetoacetate (1.2 g, 5 mmol) and con-
centrated ammonia solution (d = 0.88) (3 ml) were dissolved
in ethanol (3 ml). The reaction mixture was stirred at room
temperature for 30 min. The yellow precipitate which separ-
ated was filtered off and dried. Recrystallization of the crude
product from ethanol–water (1 : 1) afforded the title com-
pound (380 mg, 32%) as pale yellow needles, mp 133–134ЊC
(ethanol–water) (Found: C, 55.9; H, 5.1; N, 11.6. C11H12N2O4
requires C, 55.9; H, 5.1; N, 11.9%); νmax (Nujol mull)/cmϪ1
δH (250 MHz; CDCl3) 4.47 (2H, q, J 7.2, ester CH2) and 2.84
(3H, s, 4-Me) and 1.46 (3H, t, J 7.2, ester Me); δC (63 MHz;
CDCl ) 162.9 (C᎐O ester), 160.3, 150.3, 62.05 (ester CH ), 17.4
᎐
3
2
(4-Me) and 14.1 (ester Me); m/z 172 (M+, 27%), 144 (25), 127
(84, M Ϫ EtO), 126 (100, M Ϫ EtOH), 86 (27, SNCCO) and 73
(20, MeCNS).
p-Nitrobenzyl 4-methyl-1,2,5-thiadiazole-3-carboxylate 3d. p-
Nitrobenzyl 3-aminocrotonate 2d was treated with trithiazyl
trichloride and the title compound (143 mg, 56%) was obtained
as pale yellow prisms, mp 100–102ЊC (ethanol) (Found: C, 47.0;
H, 2.9; N, 14.9. C11H9N3O4S requires C, 47.3; H, 3.25; N,
15.0%); νmax (Nujol)/cmϪ1 1749vs (C᎐O), 1604vs, 1516vs,
᎐
1342vs, 1258s and 1112s; δH (400 MHz; CDCl3) 8.25 (2H, dt,
J 8.8, 2.1), 7.64 (2H, dt, J 8.8, 2.1), 5.51 (2H, s, CH2) and 2.83
1667vs (C᎐O), 1640s, 1567s, 1504s, 1289s and 1171s; δ (400
᎐
H
(3H, s, Me); δC (101 MHz; CDCl ) 163.3 (C᎐O ester), 159.9,
᎐
3
MHz; CDCl3) 8.18 (2H, d, J 8.8), 7.90 (1H, br, N-H hydro-
gen bonded), 7.49 (2H, d, J 8.8), 5.18 (2H, s, CH2), 4.76 (1H,
br, N-H free), 4.61 (1H, s, alkene-H) and 1.92 (3H, s, CH3);
149.3, 147.9, 142.1, 128.8, 123.95, 66.0 (CH2) and 17.4 (Me);
m/z 279 (M+, 2%) and 233 (2, M Ϫ NO2)
δC (101 MHz; CDCl ) 169.3 (C᎐O ester), 161.0 (C-4Ј),
᎐
3
Ethyl 4-(3-chloropropyl)-1,2,5-thiadiazole-3-carboxylate 13
147.3 (C-1Ј), 145.0, 127.7, 123.6, 83.0, 62.9 (CH2) and 22.3
(Me); m/z 236 (M+, 12%), 136 (6, O2NC6H4CH2), 106 (11,
O2NC6H4CH2 Ϫ NO) and 84 (86, M Ϫ O2NC6H4CH2O) and
57 (100, H2NC(CH3)CH2).
To a refluxing solution of ethyl α-(pyrrolidin-2-ylidene)acetate
10 (200 mg, 1.3 mmol) in CCl4 (10 ml), trithiazyl trichloride
(380 mg, 1.55 mmol) in CCl4 (10 ml) was added dropwise. The
J. Chem. Soc., Perkin Trans. 1, 2001, 662–667
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reaction mixture was heated under reflux for 18 h. The reaction
mixture was cooled and filtered through a short pad of
silica and the filtrate was concentrated under reduced pressure.
Column chromatography of the residue on silica with DCM–
light petroleum (1 : 1) afforded the title compound (150 mg,
50%) as a light brown oil (Found: M+ 234.0231. C8H11ClN2O2S
solution was removed through a filter cannula, and the resulting
brown solid was washed repeatedly with CCl4 under nitrogen to
remove excess of trithiazyl trichloride. The brown solid was
then dissolved in water (20 ml) and extracted with DCM
(3 × 30 ml). The aqueous solution was treated with activated
charcoal and filtered. The resulting clear solution was evapor-
ated to dryness under high vacuum to give a pale yellow solid.
The yellow solid was dissolved in water (10 ml) and a saturated
solution of ammonium hexafluorophosphate was added
dropwise until a white precipitate started to appear. The title
compound (93 mg, 15%) was filtered off, dried under vacuum
and obtained as colourless microcrystalline needles, mp
155–157ЊC (Found: M+ 173.0378. C6H9N2O2S+ requires M
requires M 234.0230); νmax (neat)/cmϪ1 1723vs (C᎐O), 1424s,
᎐
1297s and 1097vs; δH (250 MHz; CDCl3) 4.46 (2H, q,
J 7.2, ester CH2), 3.65 (2H, t, J 6.4, ClCH2CH2CH2-)*, 3.40
(2H, t, J 7.4, ClCH2CH2CH2-)*, 2.31 (2H, pentet, J 6.5,
ClCH2CH2CH2-) and 1.46 (3H, t, J 7.1, ester Me); δC (63 MHz;
CDCl ) 165.4 (C᎐O ester), 160.2, 150.1, 62.2 (OCH CH ), 44.1
᎐
3
2
3
(ClCH2), 30.65, 28.25 and 14.15 (OCH2CH3); m/z 234 (M+,
16%), 188 (100, M Ϫ EtOH), 172 (30), 153 (67, M Ϫ EtOH Ϫ
Cl) and 139 (89). (* assignments uncertain)
173.0385); νmax (Nujol mull)/cmϪ1 1740vs (C᎐O) 1445s, 1408vs,
᎐
1287vs and 1156vs; δH (250 MHz; D2O) 4.40 (3H, s, 5-Me), 4.09
(3H, s, ester Me) and 3.05 (3H, s, 4-Me); m/z (FABϩ) 173 (M+,
100%).
The reaction of ethyl α-(pyrrolidin-2-ylidene)acetate 10
(233 mg, 1.2 mmol) and trithiazyl trichloride (440 mg,
1.8 mmol) in CCl4 at room temperature for 18 h afforded the
title compound (17 mg. 6%).
Reaction of methyl 2-acetamidoacrylate 16a with trithiazyl
trichloride
The reaction of methyl 3-N-methylaminocrotonate 14 with
trithiazyl trichloride
To a refluxing solution of methyl 2-acetamidoacrylate 16a
(286 mg, 2 mmol) in CCl4 (10 ml), trithiazyl trichloride
(489 mg, 2 mmol) in CCl4 (15 ml) was added dropwise. The
reaction mixture was heated under reflux for 1 h. The reaction
mixture was cooled to room temperature and filtered through a
short pad of silica. The filtrate was concentrated under reduced
pressure. Column chromatography of the residue on silica with
DCM gave methyl 1,2,5-thiadiazole-3-carboxylate 17a (151 mg,
53%) as a pale yellow solid, identical with an authentic sample,
mp 40–41ЊC (lit.,13 41–42ЊC).
To a refluxing solution of methyl 3-N-methylaminocrotonate 14
(129 mg, 1 mmol) in CCl4 (10 ml), trithiazyl trichloride
(294 mg, 1.2 mmol) in CCl4 (10 ml) was added dropwise. The
reaction mixture was heated under reflux for 18 h. The reaction
mixture was cooled and filtered through a short pad of
silica and the filtrate was concentrated under reduced pressure.
Column chromatography of the residue on silica with DCM–
light petroleum (1 : 1) afforded methyl 4-methyl-1,2,5-
thiadiazole-3-carboxylate 3b (30 mg, 19%), identical with an
authentic sample.
The same reaction, carried out at room temperature for 4 h
and worked up as above, afforded methyl 1,2,5-thiadiazole-3-
carboxylate 17a (15%).
Ethyl 4H,5H,6H-pyrrolo[1,2-b][1,2,5]thiadiazol-7-ium-3-
carboxylate chloride 12
Reaction of methyl 2-acetamido-3-phenylacrylate 16b with
trithiazyl trichloride
To a solution of ethyl α-(pyrrolidin-2-ylidene)acetate 10
(200 mg, 1.3 mmol) in CCl4 (10 ml), trithiazyl trichloride
(380 mg, 1.55 mmol) in CCl4 (10 ml) was added dropwise with
stirring at room temperature under nitrogen. A brown precipi-
tate separated and the reaction mixture was stirred for 10 min.
The reaction mixture was then allowed to stand and the super-
natant solution was removed through a filter cannula, and the
resulting brown solid was washed repeatedly with CCl4 under
nitrogen to remove excess of trithiazyl trichloride. The brown
solid was then dissolved in water (20 ml) and extracted with
DCM (3 × 30ml). The aqueous solution was treated with acti-
vated charcoal and filtered. The resulting clear solution was
evaporated to dryness in high vacuum to give a pale yellow
solid. The yellow solid was dissolved in water (5 ml) and a
saturated solution of ammonium hexafluorophosphate was
added dropwise until a white precipitate started to appear.
The title compound (35 mg, 8%) was filtered off, dried under
vacuum and obtained as colourless microcrystalline needles,
mp 160–162ЊC (Found M+ 199.0563. C8H11N2O2S+ requires M
To a refluxing solution of methyl 2-acetamido-3-phenylacrylate
16b (219 mg, 1 mmol) in CCl4 (10 ml), trithiazyl trichloride
(245 mg, 1 mmol) in CCl4 (10 ml) was added dropwise. The
reaction mixture was heated under reflux for 1 h. The reaction
mixture was cooled to room temperature and filtered through
a short pad of silica. The filtrate was concentrated under
reduced pressure. Column chromatography of the residue
on silica with DCM gave methyl 4-phenyl-1,2,5-thiadiazole-3-
carboxylate 17b (84 mg, 38%) as a pale yellow solid, mp
42–43ЊC (lit.,13 45–46ЊC), m/z 220 (M+, 100%), 205 (29,
M Ϫ Me), 189 (47, M Ϫ MeO), 135 (54, PhCNS) and 103 (19,
PhCN).
3-p-Nitrophenyl-1,2,5-thiadiazole 21a
To a refluxing solution of 1-tosyl-5-p-nitrophenyl-1,2,3-triazole
18a (111 mg, 0.32 mmol) in CCl4 (10 ml), trithiazyl trichloride
(157 mg, 0.64 mmol) in CCl4 (5 ml) was added dropwise.
The reaction mixture was heated under reflux for 16 h. The
reaction mixture was cooled to room temperature and filtered
through a short pad of silica and the filtrate was concentrated
under reduced pressure. Column chromatography of the
residue on silica with DCM–light petroleum (1 : 1) gave the
title compound (60 mg, 90%) as a colourless solid, mp 174–
175ЊC (lit.,14 172ЊC; δH 9.01 (1H, s, thiadiazole 4-H), 8.38
(2H, dt, J 8.9, 2.2) and 8.19 (2H, dt, J 8.9, 2.2); m/z 207 (M+,
100%), 180 (6, M Ϫ HCN), 177 (20, M Ϫ NO) and 161 (18,
M Ϫ NO2).
199.0541); νmax (Nujol mull)/cmϪ1 1742vs (C᎐O), 1456s, 1417s,
᎐
1380s and 1261s; δH (250 MHz; D2O) 4.87 (2H, t, J 7.8, CH2),
4.50 (2H, q, J 7.2, ester CH2), 3.59 (2H, t, J 7.8, CH2), 3.06 (2H,
pentet, J 7.8, CH2), 1.39 (3H, t, J 7.2, ester Me); m/z (FAB+) 199
(M+, 100%).
Methyl 4,5-dimethyl-1,2,5-thiadiazol-5-ium-3-carboxylate
hexafluorophosphate 15b
To a solution of methyl 3-N-methylaminocrotonate 14 (258 mg,
2 mmol) in CCl4 (15 ml), trithiazyl trichloride (586 mg,
2.4 mmol) in CCl4 (15 ml) was added dropwise with stirring at
room temperature under nitrogen. A brown precipitate separ-
ated and the reaction mixture was stirred for 10 min. The reac-
tion mixture was then allowed to stand and the supernatant
Treatment of 4-p-nitrophenyl-1,2,3-triazole (25 mg, 0.13
mmol) with trithiazyl trichloride (64 mg, 0.26 mmol) under the
same conditions as described above afforded 3-p-nitrophenyl-
1,2,5-thiadizole 21a (18 mg, 67%) identical to that described
above.
666
J. Chem. Soc., Perkin Trans. 1, 2001, 662–667

View Article Online
Reaction of methyl 5-methyl-3H-1,2,3-triazole-4-carboxylate 24
with trithiazyl trichloride
the British Council for a scholarship to T.-Y. Y., MDL Inform-
ation Systems (UK Ltd) for financial support and the Wolfson
Foundation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College and a referee
for a valuable contribution.
To a refluxing solution of methyl 5-methyl-1,2,3-triazole-4-
carboxylate 24 (90 mg, 0.64 mmol) in toluene (10 ml), trithiazyl
trichloride (78 mg, 0.32 mmol) in toluene (5 ml) was added
dropwise. Two more portions of trithiazyl trichloride
(2 × 78 mg) in toluene (2 × 5 ml) were added dropwise after
1 and 2 h. The reaction mixture was heated under reflux for
16 h. The reaction mixture was cooled to room temperature and
filtered through a short pad of silica. The filtrate was concen-
trated under reduced pressure. Column chromatograpy of the
residue on silica with DCM–light petroleum (1 : 1) afforded
methyl 4-methyl-1,2,5-thiadiazole-3-carboxylate 3b (35 mg,
34%) as a pale yellow solid, identical with an authentic sample.
Further elution with DCM–ethyl acetate (70 : 30) afforded the
starting material 24 (41 mg. 46%).
Treatment of methyl 5-methyl-3H-1,2,3-triazole-4-carb-
oxylate 24 (100 mg, 0.71 mmol) with trithiazyl trichloride
(208 mg, 0.85 mmol) under the same conditions as described
above, but with trithiazyl trichloride added in one portion
afforded methyl 4-methyl-1,2,5-thiadiazole-3-carboxylate 3b
(19 mg, 17%) and unreacted starting material 24 (49 mg, 49%).
The same reaction carried out in refluxing CCl4 afforded methyl
4-methyl-1,2,5-thiadiazole-3-carboxylate 3b (10 mg, 9%) and
unreacted starting material 24 (54 mg, 54%).
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Acknowledgements
We thank the Commonwealth Scholarship Commission and
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J. Chem. Soc., Perkin Trans. 1, 2001, 662–667
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