The preparation of dicyano-1,3,4-thiadiazole and tricyanothiazole via 1,2,3-dithiazole chemistry

Article abstract of DOI:10.1016/j.tet.2009.10.003

Treatment of 1,2-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene)hydrazine 4 with benzyltriethylammonium iodide (1 equiv) affords dicyano-1,3,4-thiadiazole 3 and 5-cyano-1,3,4-thiadiazole-2-carboxamide 5 in 79 and 21% yields, respectively. By using polymer boun

Full text of DOI:10.1016/j.tet.2009.10.003

Tetrahedron 65 (2009) 9967–9972
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The preparation of dicyano-1,3,4-thiadiazole and tricyanothiazole via
1,2,3-dithiazole chemistry
*
Irene C. Christoforou, Andreas S. Kalogirou, Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 1,2-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene)hydrazine 4 with benzyltriethylammonium io-
dide (1 equiv) affords dicyano-1,3,4-thiadiazole 3 and 5-cyano-1,3,4-thiadiazole-2-carboxamide 5 in 79 and
21% yields, respectively. By using polymer bound triphenylphosphine instead of benzyltriethylammonium
iodide the dicyano-1,3,4-thiadiazole 3 can be isolated in 70% yield without chromatography. The reaction of
DAMN with Appel salt 8 gave 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-5H-1,2,3-dithia-
zol-5-ylidene)acetonitrile 7 (14%), 2,3-bis-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)fumaronitrile 10
(14%), and 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)maleonitrile 11 (24%) together with other
products. The maleonitrile 11 isomerizes into the fumaronitrile 10 on irradiation at 365 nm. Reaction of
aminoacetonitrile with Appel salt 8 gives the (dithiazolylidene)acetonitrile 7 in 33% yield. Treatment of
(dithiazolylidene)acetonitrile 7 with polymer bound triphenylphosphine gives tricyanothiazole 6 in 76%
yield. A rational general mechanism for the transformation of bisdithiazoles to percyanoheteroles is
proposed.
Received 28 July 2009
Received in revised form
14 September 2009
Accepted 2 October 2009
Available online 7 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
conducting39 or magnetic properties,40,41 or find uses as neutral or-
ganic
p
acceptors for anion recognition.42 However, their synthesis
4,5-Dichloro-1,2,3-dithiazolium chloride (Appel salt)1,2 was pre-
pared over 20 years ago and its chemistry has been exploited ex-
tensively to prepare many neutral 5H-1,2,3-dithiazoles. Several
excellent reviewshave appeared,3–6 andsome1,2,3-dithiazolesshow
interesting biological activity as fungicides,7–9 or as antibacte-
rials.10–12 1,2,3-Dithiazolyls are also of interest in the materials sci-
ences as potential conductors and/or organic magnets.13,14
was often laborious, and involved the dehydration of carboxamide
precursors using P2O5. We considered the possibility that several
percyanoheteroles could be more efficiently prepared via 1,2,3-
dithiazole chemistry, thus further demonstrating their usefulness.
Herein we report the preparation of 1,3,4-thiadiazole-2,5-dicarboni-
trile and thiazole-2,4,5-tricarbonitrile via dithiazole precursors.
Additionally, neutral 4-chloro-1,2,3-dithiazoles are useful for
the preparation of difficult to access cyano substituted hetero-
arenes. In particular N-substituted 1,2,3-dithiazolimines have been
converted via thermolysis to benzothiazoles,15,16 benzimidazoles,17
thiazolopyridines,18 and benzoxazines,19 while selected 1,2,3-
dithiazolylidenes have been converted into isothiazoles20–22 and
the rare 3H-pyrrole system.23 Acyclic functionalities such as iso-
thiocyanates, and thiocyanoformamides can also be prepared from
neutral 1,2,3-dithiazolimines.24–26
2. Results and discussion
2.1. Synthesis of 1,3,4-thiadiazole-2,5-dicarbonitrile 3
1,3,4-Thiadiazole-2,5-dicarbonitrile 3, an excellent fungicide
for aspergillus,36 has been prepared in five-steps starting from the
commercially available 2,5-dimethyl-1,3,4-thiadiazole 1. The pro-
cedure involved chlorination, methoxylation, hydrolysis, and
aminolysis followed by dehydration of 1,3,4-thiadiazole-2,5-
dicarboxamide 2 using P2O5 at 200 ꢀC at 2 mmHg (Scheme 1). This
procedure was time-consuming, involved the use of hazardous
chlorine gas, and had a moderate overall yield (38%).36
A retrosynthetic analysis of thiadiazole-2,5-dicarbonitrile 3
suggested the nitriles could be derived from the N-3 and C-4 atoms
of two dithiazole units. ANRORC18,43,44 type ring transformations of
1,2,3-dithiazoles often lead to cyano functionalized heteroarenes,
where the nitrile is derived from the carbon–nitrogen backbone of
Several percyanoheteroles are known (e.g., pyrrole,27,28 furan,29
thiophene,28,30 pyrazole,31 imidazole,32 thiazole,33 1,2,4-thiadia-
zole,34 1,2,5-thiadiazole,35 and the 1,3,4-thiadiazole36). Furthermore,
percyanoheteroacenes often show interesting electrochemistry,37,38
and readily form charge transfer salts that can have interesting
* Corresponding author. Tel.: þ357 22 892783; fax: þ357 22 892809.
E-mail address: koutenti@ucy.ac.cy (P.A. Koutentis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.003

9968
I.C. Christoforou et al. / Tetrahedron 65 (2009) 9967–9972
Table 1
N
N
N
N
N
N
N
N
N
N
Transformation of the bisdithiazole 4 into the 1,3,4-thiadiazoles 3 and 5
Me
Me
Cl3C
MeO2C
NC
CCl3
CO2Me
CN
S
S
S
N
N
N
N
4
S8
+
+
1
NC
CN
NC
CONH2
S
S
N
N
3
5
(MeO)3C
C(OMe)3
S
Reagent (equiv)
Conditions
Yields (%)
3
5d
BnEt3NCl (1)
BnEt3NBr (1)
BnEt3NI (1)
BnEt3NI (1)
BnEt3NI (1)
BnEt3NI (1)
BnEt3NI (0.50)
BnEt3NI (0.25)
BnEt3NI (0.25)
BnEt3NI (0.10)
PPh3 (5)a
PhCl, 132 ꢀC, 14 h, air
PhCl, 132 ꢀC, 51 h, air
PhCl, 132 ꢀC, 1 h, air
PhCl, 132 ꢀC, 0.67 h, Ar
PhCl, 132 ꢀC, 0.67 h, Ar
PhCl, 160 ꢀC (MW)b, 5 min
PhCl, 132 ꢀC, 2 h, Ar
67
53
55
79
60c
72
78
76
33
40
27
21
d
23
19
18
24
d
d
d
d
d
d
H2NOC
CONH2
S
S
2
3
Scheme 1.
PhCl, 132 ꢀC, 6 h, Ar
PhCl, 160 ꢀC (MW)b, 10 min
PhCl, 132 ꢀC, 72 h, Ar
DCM, 20 ꢀC, 24 h, air
DCM, 20 ꢀC, 0.5 h, air
DCM, 20 ꢀC, 1 h, air
55
d
d
the dithiazole. An ideal precursor (synthon) for this reaction was
identified to be the bisdithiazole 4, which had been prepared by
Oakley and Preuss in 33% yield.45 To our knowledge, the use of
a bisdithiazole to provide all the components of a monocyclic
heteroarene via a ring transformation was new.
PPh3 (6)a
69
69
70
47
PPh3 (6)a
PPh3 (6)a
DCM, 20 ꢀC, 0.5 h, Ar
DCM, 20 ꢀC, 0.5 h, air
PPh3 (7)a
a
PPh3–polymer bound (3.2 mmol/g).
b
c
Sealed tube reaction in Microwave reactor (MW, 250 W, 160 ꢀC, 120 PSI).
Isolated by Kugelrohr bulb-to-bulb distillation (60 ꢀC, 4 mmHg).
Incomplete reaction.
S
d
N
S
N
N
Cl
N
N
Cl
NC
CN
The formation of 5-cyano-1,3,4-thiadiazole-2-carboxamide 5
S
S
N
was caused by hydration of the dicyanothiadiazole 3 during chro-
matography; this reactivity on silica was confirmed by a 2D TLC
study. Isolation of dicyanothiadiazole 3 directly from the reaction
mixture by a Kugelrohr bulb-to-bulb distillation gave the product
in only 60% yield. In a control study a pure sample of dicyano-
thiadiazole 3 was unstable towards benzyltriethylammonium
iodide (1 equiv) in hot chlorobenzene and this could explain the
reduced yields during the Kugelrohr distillation. Isolation of
dicyanothiadiazole 3 could be simplified by the use of an alterna-
tive thiophile, polymer bound triphenylphosphine, that could also
‘mop-up’ any elemental sulfur formed. Treatment of the bisdi-
thiazole 4 with polymer bound triphenylphosphine (6 equiv)
afforded the desired product cleanly, by filtration, in 69% yield
(Table 1). The use of less phosphine led to incomplete reactions,
while extending the reaction time or using more triphenylphos-
phine (6 equiv) did not improve the product yield. Unlike the re-
actions with the tetraalkylammonium halides, there was no
significant advantage in running the triphenylphosphine reactions
under an argon atmosphere. Furthermore, the use of free triphenyl-
phosphine led to incomplete reactions and gave only traces of the
dicyanothiadiazole 3 (by TLC). Pure dicyanothiadiazole 3 in the
presence of free triphenylphosphine (2 equiv) in DCM at reflux was
surprisingly stable.
S
3
4
2.2. Preparation of bisdithiazole 4 and transformation into
dicyanothiadiazole 3
The bisdithiazole 4 was synthesized according to the literature,
by reacting anhydrous hydrazine with Appel salt (2 equiv) in 1,2-
DCE.45 By modifying the work-up, [the mixture was evaporated and
the residue extracted (3 d,1,2-DCE) in a Soxhlet apparatus] we were
able to improve significantly the product yield from 33 to 58%.
The bisdithiazole 4 was then reacted with various tetraalkyl-
ammonium halides. While the ring transformation of (1,2,3-dithia-
zolylidene)malononitrile into 3-chloroisothiazole-4,5-dicarbonitrile
using benzyltriethylammonium chloride (5 mol %) was almost
quantitative,20,22 the reaction of catalytic benzyltriethylammonium
chloride with the bisdithiazole 4 could not be driven to completion.
Nevertheless, the use of (1 equiv) of either benzyltriethylammonium
chloride, bromide or iodide gave moderate to good yields of the de-
sired thiadiazole 3 along with 5-cyano-1,3,4-thiadiazole-2-carbox-
amide 5 (Table 1). Performing the reactions under an argon
atmosphere gave cleaner reaction mixtures and overall higher yields,
presumably due to the hygroscopic nature of the tetraalkylammonium
halides. Under these conditions benzyltriethylammonium iodide was
superior and could be used in catalytic amount (0.25 equiv) despite
2.3. Synthesis of thiazole-2,3,4-tricarbonitrile 6
2.3.1. Preparation of bisdithiazole 11. In view of the success of the
synthesis of dicyanothiadiazole 3 via the bisdithiazole 4, the anal-
ogous synthesis of thiazole-2,3,4-tricarbonitrile 6 was considered.
Tricyanothiazole 6 has been prepared in the literature via a three-
step process:33 The reaction of diethyl 2-chloro-3-oxosuccinate and
ethyl thiooxamate gave triethyl thiazole-2,4,5-tricarboxylate, ami-
nolysis afforded thiazole-2,4,5-tricarboxamide and dehydration
with P2O5 at 200 ꢀC and 10ꢁ3 mmHg gave tricyanothiazole 6 in an
overall yield of 14%. A retrosynthetic analysis of tricyanothiazole 6
gave the bisdithiazole 7 as a possible precursor.
a
longer reaction time (6 h). Lower amounts of benzyl-
triethylammonium iodide (0.10 equiv) failed to drive the reaction to
completion, even using microwave heating. The highest obtained
yield of 1,3,4-thiadiazole-2,5-dicarbonitrile 3 (79%) was from the
reaction of benzyltriethylammonium iodide (1 equiv) in refluxing
PhCl, under an argon atmosphere. With the use of benzyl-
triethylammonium iodide (1 equiv) and microwave heating (ca.
160 ꢀC) the reaction time was significantly reduced (5 min) as
expected (Table 1).

I.C. Christoforou et al. / Tetrahedron 65 (2009) 9967–9972
9969
S
resonance (dH 3.90 ppm).48 The data suggested the bisdithiazole
adduct of DAMN, however, the geometry of the ethene bond could
not be determined.
Interestingly the second minor product 10 (14%) [mp (DSC on-
set) 274 ꢀC (decomp.) (from PhCl)], was a highly insoluble, purple
solid. Microanalysis gave the formula C8Cl2N6S4 and LREI mass
spectrometry gave a molecular parent ion of m/z 378 Da (11%) with
an isotope pattern indicative of two chlorine atoms, suggesting it
was isomeric to compound 11. Its UV/vis spectrum was more red-
N
S
NC
CN
N
Cl
N
Cl
NC
CN
S
S
N
S
6
7
shifted [lmax (DCM) 524 nm (log 3 3.46)] indicating more extensive
The bisdithiazole 7 has been reportedly prepared in 39%
yield by reacting Appel salt with diaminomaleonitrile
conjugation than product 11 while IR spectroscopy again confirmed
the presence of a C^N group (nmax 2197 cmꢁ1). Owing to the high
insolubility of product 10 1H and 13C NMR spectroscopic data could
not be obtained.
8
(DAMN).46 However, in our hands product 7 could be obtained
in only 14% yield and was surprisingly not the main reaction
product (Scheme 2). Together with the typical Appel salt re-
action minor byproduct 4-chloro-1,2,3-dithiazole-5(H)-thione
9,47 three other products were also isolated from the reaction
mixture, the bisadducts 10 and 11 and the monoadduct 12
(Scheme 2). Efforts to improve the yield of the bisdithiazole 7
included: performing the reaction at ca. 39 ꢀC (refluxing DCM),
using excess Appel salt 8 (3 equiv), manipulating the reaction
time, the concentration, using dry MeCN as solvent, and also
starting from the monoadduct 12.46 However none of these
efforts gave an increased yield of the bisdithiazole 7. It was
interesting though to investigate the structure of the other
products 10 and 11.
Interestingly, heating a sample of isomer 11 gave some 10 rais-
ing the suspicion that compound 10 was in fact the trans isomer of
11. Having in mind the cis–trans isomerization of DAMN,49,50 we
attempted the photochemical isomerization of isomers 10 and 11.
After irradiating a solution (DCM) of bisdithiazole 10 with UV/vis
light of 365 nm for 12 h we observed no change (by TLC), however,
irradiation of isomer 11 led to its complete transformation into the
insoluble isomer 10. This tentatively suggested that compound 10
was the trans isomer 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylide-
neamino)fumaronitrile 10, which would be expected to be the most
thermodynamically stable and owing to the trans geometry more
conjugated, while compound 11 should be the cis isomer 2,3-bis(4-
chloro-5H-1,2,3-dithiazol-5-ylideneamino)maleonitrile 11.
Unable to get a respectable yield of the bisdithiazole 7 from the
reaction with DAMN, a different approach was pursued. A retro-
synthetic analysis of the bisdithiazole 7 revealed that it could be
prepared from two molecules of Appel salt 8 and one molecule of
aminoacetonitrile. The reaction of commercially available amino-
acetonitrile hydrogen sulfate salt with Appel salt 8 (2 equiv), at ca.
20 ꢀC for 24 h, followed by the addition of pyridine (6 equiv) gave
the desired product 7 in only 8–10% yield. The use of free amino-
acetonitrile,51 however, and Appel salt 8 (2 equiv) in DCM at reflux
for 24 h followed by the addition of pyridine (4 equiv) gave the
desired product 7 in 33% yield (Scheme 3).
S
N
S
CN
S
Cl
Cl
+S
Cl
Cl
Cl
N
NC
NC
NH2
NH2
+
+
N
S
N
S
N
S
S
S
Cl_
8 (2 equiv.)
9 (18%)
7 (14%)
N
Cl
S
S
S
N
S
S
N
S
NH2
CN
N
CN
Cl
N
NC
NC
+
Cl
+S
Cl
Cl
Cl
N
N
S
Cl
N
Cl
N
Cl
NC
NC
NC
9 (23%)
+
+
NC
NH2
+
+
N
S
N
N
S
N
S
N
S
S
S
Cl _
S
S
8 (2 equiv.)
7 (33%)
10 (14%)
11 (24%)
12 (18%)
Scheme 3.
Scheme 2.
2.4. Ring transformation of bisdithiazole 7 into
thiazoletricarbonitrile 6
The major product 11 (24%) [mp (DSC onset) 212 ꢀC (decomp.)
(from 1,2-DCE)] was deep red in colour [lmax(DCM) 502 nm (log
3
3.30)] suggesting extended conjugation and possibly an intact
dithiazole ring. Compound 11 gave a correct microanalysis for the
formula C8Cl2N6S4$C2H2Cl2 suggesting a 1:1 co-crystallization with
1,2-DCE. The sample on vacuum drying gave a correct analysis for
C8Cl2N6S4 and LREI mass spectrometry gave a molecular parent ion
of m/z 378 Da (15%) with an isotope pattern indicative of two chlo-
rine atoms. IR spectroscopy supported the presence of a C^N group
The reaction of bisdithiazole 7 with benzyltriethylammonium
chloride (1 equiv) in refluxing PhCl gave the tricyanothiazole 6 and
the hydrated thiazole 13 in 70 and 15% yields, respectively. Good to
moderate yields of the tricyanothiazole 6 were also achieved with
benzyltriethylammonium bromide (1–0.1 equiv) and benzyl-
triethylammonium iodide (1 equiv). This data suggested that the
bisdithiazole 7 was more reactive than bisdithiazole 4 and this could
arise from the presence of the (dithiazolylidene)acetonitrile moiety,
which was expected to show reactivity similar to that of (1,2,3-
dithiazolylidene)malononitrile20–22 and therefore more susceptible
to the thiophiles. The use of polymer bound triphenylphosphine
(5 equiv) allowed the chromatography-free isolation of the tricyano-
thiazole 6 in 76% yield. The use of less phosphine again led to in-
complete reactions, while extending the reaction time or using
(
nmax 2210 cmꢁ1) while 13C NMR spectroscopy showed a total of 5
resonances, one sp hybridized (dC 113.2 ppm) corresponding to the
C^N group, and three sp2 hybridized carbon resonances (dC 163.6,
147.2, and 120.4 ppm), typical of dithiazolimines. The data suggested
a symmetrical structure. The remaining sp3 carbon resonance cor-
responded to the co-crystallized 1,2-DCE and this was confirmed by
1H NMR spectroscopy that showed the presence of one singlet

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I.C. Christoforou et al. / Tetrahedron 65 (2009) 9967–9972
Table 2
3 or 6 (Scheme 4). Since the bisdithiazole 7 was more reactive than
bisdithiazole 4 it could tentatively be surmised that the dithiazo-
lylidene moiety of bisdithiazole 7 was more susceptible to ring
cleavage owing to its more electrophilic character.
Transformation of the bisdithiazole 7 into the thiazoles 6 and 13
NC
NC
N
N
7
S8
+
+
NC
CN
NC
CONH2
S
S
3. Summary
6
13
A remarkably short and chromatography free synthesis of
1,3,4-thiadiazole-2,5-dicarbonitrile 3 has been achieved using
1,2,3-dithiazole chemistry. The strategy also provided a route to
thiazole-2,4,5-tricarbonitrile 6 although this synthesis required to
the difficult to access bisdithiazole 7. In an effort to obtain bisdi-
thiazole 7 in higher yields, an alternative synthesis involving ami-
noacetonitrile and Appel salt 8 was developed to complement the
known synthesis using DAMN.
Reagent (equiv)
Conditions
Yields (%)
6
13
BnEt3NCl (1)
BnEt3NCl (0.1)
BnEt3NBr (1)
BnEt3NBr (0.5)
BnEt3NBr (0.1)
BnEt3NI (1)
BnEt3NI (0.1)
PPh3 (4)a
PhCl, 132 ꢀC, 1 h, Ar
PhCl, 132 ꢀC, 48 h, Ar
PhCl, 132 ꢀC, 5 min, Ar
PhCl, 132 ꢀC, 15 min, Ar
PhCl, 132 ꢀC, 5 h, Ar
PhCl, 132 ꢀC, 35 min, Ar
PhCl, 132 ꢀC, 48 h, Ar
DCM, 20 ꢀC, 24 h, air
DCM, 20 ꢀC, 2 h, air
DCM, 20 ꢀC, 4 h, air
DCM, 20 ꢀC, 2 h, Ar
DCM, 20 ꢀC, 1 h, air
70
15
b
63
68
63
11
20
17
14
56
b
b
d
d
d
d
d
4. Experimental section
4.1. General
PPh3 (5)a
76
76
74
68
PPh3 (5)a
PPh3 (5)a
PPh3 (6)a
DCM was freshly distilled from CaH2 under argon. Anhydrous
hydrazine was prepared by distillation of hydrazine monohydrate
from KOH under argon and stored over 4 Å molecular sieves. Re-
actions were protected from atmospheric moisture by CaCl2 drying
tubes. Anhydrous Na2SO4 was used for drying organic extracts, and
all volatiles were removed under reduced pressure. All reaction
mixtures and column eluents were monitored by TLC using com-
mercial glass backed thin layer chromatography (TLC) plates (Merck
Kieselgel 60 F254). The plates were observed under UV light at 254
and 365 nm. The technique of dry flash chromatography was used
throughout for all non-TLC scale chromatographic separations using
Merck Silica Gel 60 (less than 0.063 mm).54 Melting points were
determined using a PolyTherm-A, Wagner & Munz, Koefler–Hot-
stage Microscope apparatus. Decomposition points (decomp.) and
mp >250 ꢀC were determined using a TA Instruments DSC Q1000
with samples hermetically sealed in aluminium pans under an argon
atmosphere; using heating rates of 5 ꢀC/min. Solvents used for re-
crystallization are indicated after the melting point. UV spectra were
obtained using a Perkin–Elmer Lambda-25 UV/vis spectrophotom-
eter and inflections are identified by the abbreviation ‘inf’. IR spectra
were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer
with a Pike Miracle Ge ATR accessory and strong, medium and weak
peaks are represented by s, m and w, respectively. 1H and 13C NMR
spectra were recorded on a Bruker Avance 300 machine (at 300 and
75 MHz, respectively). Deuterated solvents were used for homonu-
clear lock and the signals are referenced to the deuterated solvent
peaks. Low resolution (EI) mass spectra were recorded on a Shi-
madzu Q2010 GC–MS with direct inlet probe. Photochemical isom-
erizations were performed using a UVitec LF-204.LS (4 W) hand held
UV lamp. 4,5-Dichloro-1,2,3-dithiazolium chloride 81 was prepared
according to the literature procedure.
a
PPh3–polymer bound (3.2 mmol/g).
Incomplete reaction.
b
more than 5 equiv did not improve the product yield. Again
free triphenylphosphine gave only traces of the tricyanothiazole 6
(Table 2).
4,5-Dicyanothiazole-2-carboxamide 13, mp 162–163 ꢀC (from
PhMe), has not been previously reported in the literature. The po-
sition of the carboxamide substituent was tentatively determined
by mass spectroscopy. The LRMS-EI spectrum gave two character-
istic peaks, which tentatively correspond to the loss of the SCC^N
(108 Da, 27%) and N]CCN fragments (126, 4%), and also five peaks,
which correspond to the fragments NCC]CCN (76, 7%), N]CCONH2
or SCC^N (70, 23%), NC]CCN (64, 5%) and C]CC^N (50, 4%). The
fragments NCC]CCN (76, 7%) and NC]CCN (64, 5%) tentatively
supported the formation of 4,5-dicyanothiazole-2-carboxamide 13.
Furthermore, the donor–acceptor concept concerning the general
reactivity of the thiazole ring, supports that the C-2 position was the
most electron-deficient while the C-5 position was electron-rich
and the C-4 position was neutral.52,53 As such, the reactivity of the
substituents linked to carbon atoms of the thiazole ring depended
on their position on the heterocyclic nucleus. The nitrile group that
was linked to the C-2 carbon atom, the most electron deficient
carbon, was therefore expected to hydrate preferentially.
2.5. Mechanistic rationale for the ring transformations
Soft thiophilic nucleophiles can cleave 1,2,3-dithiazoles to afford
the disulfide intermediates 14. These intermediates can be a source
of both electrophilic and nucleophilic sulfur. As such, a second thio-
phile can attack the thiophile bound sulfur of the disulfide infusing
nucleophilic character to the adjacent sulfur, which can then be
trapped by the electrophilic C-5 ring carbon atom of the remaining
1,2,3-dithiazole unit affording the synthesis of percyanoheterocycles
4.2. 1,2-Bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene)hydrazine 4
A solution of anhydrous hydrazine (1 mL, 32 mmol) in 1,2-di-
chloroethane (DCE) (60 mL) was added dropwise to an ice-bath
cooled slurry of Appel salt 8 (12.5 g, 60 mmol) in DCE (200 mL). The
reaction mixture was then stirred at ca. 20 ꢀC for 18 h and heated to
reflux for 4 h. The mixture was then allowed to cool to room
temperature and the volatiles removed to afford a black residue.
The residue was transferred to a Soxhlet apparatus (30 mL) and
extracted with DCE (200 mL) for 72 h. Evaporation of the DCE ex-
tracts and crystallization gave the title compound 4 (5.28 g, 58%) as
black-green plates, mp 246–247 ꢀC (lit.,46 249 ꢀC) (from PhCl);
identical to an authentic sample.
S
N
S
X
Y
Cl
X
Y
NC
Cl
X
Y
Cl
S
S
N
NC
CN
S
S
S
S
N
Nu
Nu
S
4 [X = Y = N]
7 [X = C(CN), Y = N]
14
3 [X = Y = N]
6 [X = C(CN), Y = N]
Scheme 4.

I.C. Christoforou et al. / Tetrahedron 65 (2009) 9967–9972
9971
4.3. 1,3,4-Thiadiazole-2,5-dicarbonitrile 3
ylideneamino)maleonitrile 11 (91.0 mg, 24%) as black-green nee-
dles, mp (DSC onset) 212 ꢀC (decomp.) (from DCE); Rf (hexane–
DCM, 1:2) 0.47; (Found: C, 25.2; H, 0.9; N, 17.6. C8Cl2N6S4$C2H2Cl2
requires C, 25.1; H, 0.8; N, 17.6); after drying in a vacuum oven
(24 h) at 60 ꢀC (Found: C, 25.4; N, 22.1. C8Cl2N6S4 requires C, 25.3; N,
To a stirred solution of 1,2-bis(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)hydrazine 4 (100 mg, 0.33 mmol) in PhCl (3 mL) at ca. 20 ꢀC,
benzyltriethylammonium iodide (105.3 mg, 0.33 mmol) was added
and the reaction was heated to reflux, under an argon atmosphere.
The mixture was kept at reflux for 40 min, until no starting material
remained (TLC). The reaction mixture was then allowed to cool to ca.
20 ꢀC and adsorbed on silica. Chromatography (hexane) gave sulfur
(31.7 mg, 100%). Further elution (hexane–DCM, 1:1) gave the title
compound 3 (35.5 mg, 79%) as colourless plates, mp 118–119 ꢀC
22.2); lmax (DCM)/nm 230 (log 3 3.03), 258 (2.89), 395 (2.93), 502
(3.30), 553 inf (3.02); nmax/cmꢁ1 2210w (C^N),1549s,1477s,1236s,
1150m, 984m, 897w, 876s, 800s, 777w; dH (300 MHz; DMSO-d6)
3.90 (s, ClCH2CH2Cl, lit.,48 3.90); dC (75 MHz; CDCl3) 163.6 (C-5),
147.2 (C-4), 120.4 (C]C), 113.2 (C^N), 45.0 (ClCH2CH2Cl, lit.,48
45.02); m/z (EI) 382 (Mþþ4, 4%), 380 (Mþþ2, 11), 378 (Mþ, 15), 281
(23), 279 (53), 216 (11),149 (8),127 (7),125 (14),102 (12), 93 (15), 85
(10), 76 (19), 70 (30), 64 (100). A final elution (DCM) gave 2-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene-amino)-3-aminomaleonitrile
12 (41.2 mg, 16%) as orange needles, mp 201–203 ꢀC (lit.,46 205–
207 ꢀC) (from DCE); Rf (DCM) 0.47; identical to an authentic sample.
(lit.,36 121 ꢀC) (from cyclohexane); Rf (hexane–DCM, 1:1) 0.30; nmax
/
cmꢁ1 2249w and 2182w (C^N), 1396w, 1366m, 1340w, 1302w,
1263w, 1227w, 1203s, 1181w, 1157s, 1101w, 892w; dC(75 MHz;
CDCl3) 142.4, 108.2 (C^N); m/z (EI) 136 (Mþ, 100%), 108 (6), 84 (4),
82 (4), 72 (5), 71 (3), 70 (100), 58 (10), 56 (3), 52 (10). Further elution
(hexane–EtOAc, 3:7) gave 5-cyano-1,3,4-thiadiazole-2-carboxamide
5 (10.8 mg, 21%) as colourless plates, mp 207–208 ꢀC (decomp.)
(from PhH); Rf (hexane–EtOAc, 3:7) 0.74; (Found: C, 31.3; H, 1.3; N,
36.3. C4H2N4OS requires C, 31.2; H, 1.3; N, 36.35); nmax/cmꢁ1 3401m,
3324w, 3294w, 3270m and 3198w (NH2), 2260 (C^N), 1679s
(C]O),1600m,1454w,1388w,1367m,1330w,1249w,1197m,1179w,
1126m,1089m,1081w, 803w; dH(300 MHz; DMSO-d6) 8.91 (1H, br s,
NH), 8.48 (1H, br s, NH); dC(75 MHz; DMSO-d6) 170.0 (C]O), 158.1,
143.7, 110.8 (C^N); m/z (EI) 154 (Mþ, 23%), 126 (17), 111 (59), 84 (8),
82 (3), 70 (10), 59 (27), 58 (12), 53 (6), 52 (2).
5.1. Reaction of Appel salt 8 with 2-(4-chloro-5H-1,2,3-
dithiazol-5-ylideneamino)-3-aminomaleonitrile 12
To a stirred solution of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylide-
neamino)-3-aminomaleonitrile 12 (107 mg, 1 mmol) in dry DCM
(10 mL) at ca. 20 ꢀC, 4,5-dichloro-1,2,3-dithiazolium chloride 8
(208.5 mg, 1 mmol) was added in one portion. After 24 h pyridine
(161 mL, 2 mmol) was added and the mixture was stirred for a further
30 min. Then the reaction was adsorbed on silica and chromatogra-
phy (hexane–DCM, 8:1) gave 4-chloro-5H-1,2,3-dithiazole-5-thi-
one 9 (25.5 mg, 29%) as red needles, mp 75–76 ꢀC (lit.,1 78–79 ꢀC)
(from pentane); Rf (hexane–DCM, 8:1) 0.52; identical to an
authentic sample and further elution (hexane–DCM, 2:1) gave 2-(4-
chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)acetonitrile 7 (26.2 mg, 8%) as a deep purple
solid, mp 241–242 ꢀC (lit.,46 244–245 ꢀC) (from PhH); Rf (hexane–
DCM, 2:1) 0.48; identical to an authentic sample. Further elution
(hexane–DCM, 1:1) gave 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-yli-
deneamino)fumaronitrile 10 (22.7 mg, 6%) as purple needles, mp
(DSC onset) 274 ꢀC (decomp.) (from PhCl); Rf (hexane–DCM, 1:1)
0.56; identical to that described above. A further elution (hexane–
DCM, 1:2) gave 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene-
amino)maleonitrile 11 (98.5 mg, 26%) as black-green crystals, mp
(DSC onset) 212 ꢀC (decomp.) (from DCE); Rf (hexane–DCM, 1:2)
0.47; identical to that described above. A final elution (DCM) gave
recovered 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-3-ami-
nomaleonitrile 12 (141.6 mg, 55%) as orange needles, 201–203 ꢀC
(lit.,46 205–207 ꢀC) (from DCE); Rf (DCM) 0.47; identical to an au-
thentic sample.
4.4. 1,3,4-Thiadiazole-2,5-dicarbonitrile 3 using polymer
bound triphenylphosphine
To a stirred solution of 1,2-bis(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)hydrazine 4 (30 mg, 0.10 mmol) in dry DCM (3 mL) at ca.
20 ꢀC, polymer bound triphenylphosphine 3.2 mmol/g (185.63 mg,
0.594 mmol) was added and the reaction was kept at ca. 20 ꢀC until
no starting material remained (TLC). The polymer bound triphenyl-
phosphine was filtered from the reaction mixture and the solvent
was evaporated to give the title compound 3 (9.3 mg, 69%) as col-
ourless plates, mp 118–119 ꢀC (lit.,36 121 ꢀC) (from cyclohexane)
identical to that described above.
5. Reaction of Appel salt 8 with DAMN
To a stirred solution of diaminomaleonitrile (107 mg,1 mmol) in
dry DCM (10 mL) at ca. 20 ꢀC, 4,5-dichloro-1,2,3-dithiazolium
chloride 8 (417 mg, 2 mmol) was added in one portion. After 24 h
pyridine (323 mL, 4 mmol) was added and the mixture was stirred
for a further 30 min. Then the reaction mixture was adsorbed on
silica and chromatography (hexane–DCM, 8:1) gave 4-chloro-5H-
1,2,3-dithiazole-5-thione 9 (30.5 mg, 18%) as red needles, mp 75–
76 ꢀC (lit.,1 78–79 ꢀC) (from pentane); Rf (hexane–DCM, 8:1) 0.52;
identical with an authentic sample. Further elution (hexane–DCM,
2:1) gave 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile 7 (45.8 mg, 14%)
as a deep purple solid, mp 241–242 ꢀC (lit.,46 244–245 ꢀC) (from
PhH); Rf (hexane–DCM, 2:1) 0.48; identical to an authentic sample.
Further elution (hexane–DCM,1:1) gave 2,3-bis(4-chloro-5H-1,2,3-
dithiazol-5-ylideneamino)fumaronitrile 10 (53.1 mg, 14%) as pur-
ple needles, mp (DSC onset) 274 ꢀC (decomp.) (from PhCl); Rf
(hexane–DCM, 1:1) 0.56; (Found: C, 25.3; N, 22.1. C8Cl2N6S4 re-
5.2. Photochemical isomerization of 2,3-bis(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)maleonitrile 11 to 2-(4-
chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)acetonitrile 10
A solution of 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidenea-
mino)maleonitrile 11 (10 mg, 0.021 mmol) in DCM (5 mL) was ra-
diated with UV light at 365 nm using a UV-lamp. After 12 h a purple
precipitate was formed and TLC confirmed the complete con-
sumption of 11. After evaporation of the solvent, 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)acetonitrile 10 was isolated (7.5 mg, 96%) as purple needles
mp (DSC onset) 274 ꢀC (decomp.) (From PhCl) identical to that
described above.
quires C, 25.3; N, 22.2); lmax (DCM)/nm 228 (log 3 3.13), 269 (3.07),
389 (2.43), 482 inf (3.23), 524 (3.46), 550 (3.40); nmax/cmꢁ1 2197w
(C^N), 1533s, 1518s, 1452s, 1283m, 1236w, 1198w, 1128w, 1094w,
1024w, 984w, 932m, 901m, 866s, 808m, 746w, 710s; m/z (EI) 382
(Mþþ4, 3%), 380 (Mþþ2, 9), 378 (Mþ, 11), 281 (15), 279 (40), 125
(10), 102 (12), 93 (14), 76 (15), 70 (23), 64 (100). A further elution
(hexane–DCM, 1:2) gave 2,3-bis(4-chloro-5H-1,2,3-dithiazol-5-
5.3. Reaction of Appel salt 8 with aminoacetonitrile
To a stirred solution of aminoacetonitrile (13.4 mg, 0.24 mmol)
in dry DCM (3 mL) at ca. 20 ꢀC, 4,5-dichloro-1,2,3-dithiazolium

9972
I.C. Christoforou et al. / Tetrahedron 65 (2009) 9967–9972
chloride 8 (100 mg, 0.48 mmol) was added in one portion and the
mixture was heated at ca. 39 ꢀC. After 24 h pyridine (77
L,
generous donations of chemicals and glassware: the State General
Laboratory, the Agricultural Research Institute and the Ministry of
Agriculture. Furthermore we thank the A.G. Leventis Foundation for
helping to establish the NMR facility in the University of Cyprus.
m
0.96 mmol) was added and the mixture was stirred for a further
30 min. Then the reaction mixture was adsorbed on silica and
chromatography (hexane–DCM, 8:1) gave 4-chloro-5H-1,2,3-
dithiazole-5-thione 9 (9.3 mg, 23%) as red needles, mp 75–76 ꢀC
(lit.,1 78–79 ꢀC) (from pentane); Rf (hexane–DCM, 8:1) 0.52; iden-
tical to an authentic sample and further elution (hexane–DCM, 2:1)
gave 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-(4-chloro-
5H-1,2,3-dithiazol-5-ylidene)acetonitrile 7 (25.9 mg, 33%) as a deep
purple solid, mp 241–242 ꢀC (lit.,46 244–245 ꢀC) (from PhH); Rf
(hexane–DCM, 2:1) 0.48; identical to an authentic sample.
References and notes
1. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632.
2. Koutentis, P. A. Molecules 2005, 10, 346.
3. Rakitin, O. A. (eds. in Chief Katritzky, A.R.; Ramsden, C.A.; Scriven, E.F.V.; Taylor,
R.J.K.) In Comprehensive Heterocyclic Chemistry III; Zhdankin, V. V., Ed.; Elsevier:
Oxford, 2008; Vol. 6, Chapter 6.01, p 1.
4. Konstantinova, L. S.; Rakitin, O. A. Russ. Chem. Rev. 2008, 77, 521.
5. Kim, K. Sulfur Rep. 1998, 21, 147.
6. Kim, K. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120, 229.
7. Moore, J.E. US Pat. 4 059 590, 1977.
5.4. Thiazole-2,4,5-tricarbonitrile 6
To a stirred solution of 2-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)acetonitrile
7
8. Appel, R.; Janssen, H.; Haller, I.; Plempel, M. DE Pat. 2 848 221, 1980.
9. Besson, T.; Rees, C. W.; Cottenceau, G.; Pons, A. M. Bioorg. Med. Chem. Lett. 1996,
6, 2343.
10. Cottenceau, G.; Besson, T.; Gautier, V.; Rees, C. W.; Pons, A. M. Bioorg. Med.
Chem. Lett. 1996, 6, 529.
(50 mg, 0.153 mmol) in PhCl (3 mL) at ca. 20 ꢀC, benzyl-
triethylammonium chloride (34.9 mg, 0.153 mmol) was added and
the reaction was kept at reflux, under an argon atmosphere for 1 h
until no starting material remained (TLC). The reaction mixture was
then allowed to cool to ca. 20 ꢀC and adsorbed on silica. Chroma-
tography (hexane) gave sulfur (12.5 mg, 100%). Further elution
(hexane–DCM, 1:1) gave the title compound 6 (17.1 mg, 70%) as
colourless plates, mp 122–123 ꢀC (lit.,33 127 ꢀC) (from PhH); Rf
(hexane–DCM, 1:1) 0.24; nmax/cmꢁ1 2246w and 2236w (C^N),
1477w, 1418m, 1333m, 1205w, 1183w, 1153s, 969w, 950w, 885w,
736w, 703m; dC(75 MHz; CDCl3) 142.4, 135.4, 119.7, 109.5 (C^N),
109.4 (C^N), 107.0 (C^N); m/z (EI) 160 (Mþ, 55%), 110 (5), 109 (6),
108 (100), 91 (4), 83 (3), 82 (26), 76 (9), 72 (3), 71 (5), 70 (57), 69 (3),
64 (11), 58 (9), 57 (8), 56 (13), 55 (5), 52 (8), 50 (10). Further elution
(hexane–EtOAc, 3:7) gave 4,5-dicyanothiazole-2-carboxamide 13
(4.1 mg, 15%) as colourless needles, mp 162–163 ꢀC (from PhMe); Rf
(hexane–EtOAc, 3:7) 0.70; (Found: C, 40.3; H, 1.0; N, 31.3. C6H2N4OS
11. Thiery, V.; Rees, C. W.; Besson, T.; Cottenceau, G.; Pons, A. M. Eur. J. Med. Chem.
1998, 33, 149.
12. Joseph, R.W.; Antes, D.L.; Osei-Gyimah, P. US Pat. 5 688 744, 1997.
13. Barclay, T. M.; Beer, L.; Cordes, A. W.; Oakley, R. T.; Preuss, K. E.; Taylor, N. J.;
Reed, R. W. Chem. Commun. 1999, 531.
14. Beer, L.; Cordes, A. W.; Haddon, R. C.; Itkis, M. E.; Oakley, R. T.; Reed, R. W.;
Robertson, C. M. Chem. Commun. 2002, 1872.
15. Rees, C. W. J. Heterocycl. Chem. 1992, 29, 639.
16. Besson, T.; Dozias, M. J.; Guillard, J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 11998,
3925.
17. Rakitin, O. A.; Rees, C. W.; Vlasova, O. G. Tetrahedron Lett. 1996, 37, 4589.
18. Christoforou, I. C.; Koutentis, P. A.; Michaelidou, S. S. ARKIVOC 2006, 7, 207.
19. Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W. Synlett 1997, 704.
20. Emayan, K.; English, R. F.; Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans.
1 1997, 3345.
21. Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1998, 2505.
22. Christoforou, I. C.; Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 2002,
1236.
23. Koutentis, P. A.; Rees, C. W.; White, A. J. P.; Williams, D. J. J. Chem. Soc., Perkin
Trans. 1 1998, 2765.
requires C, 40.6; H, 1.1; N, 31.5%); lmax (DCM)/nm 229 (log 3 3.19),
24. English, R. F.; Rakitin, O. A.; Rees, C. W.; Vlasova, O. G. J. Chem. Soc., Perkin Trans.
1 1997, 201.
25. Chang, Y. G.; Kim, K. Heterocycles 1999, 51, 2653.
26. Lee, H. S.; Chang, Y. G.; Kim, K. J. Heterocycl. Chem. 1998, 35, 659.
27. Simmons Jr., H. E. US Pat. 3 221 024, 1962.
28. Simmons, H. E.; Vest, R. D.; Vladuchick, S. A.; Webster, O. W. J. Org. Chem. 1980,
45, 5113.
29. Weis, C. D. J. Org. Chem. 1962, 27, 3514.
266 (3.03), 276 (3.05); nmax/cmꢁ1 3376w, 3297w, and 3174w (NH2),
2247w (C^N), 2241w (C^N), 1689s (C]O), 1610w, 1481w, 1458w,
1386m, 1230w, 1130m, 791w, 744w, 735w; dH(300 MHz; DMSO-d6)
8.82 (1H, br s, NH), 8.43 (1H, br s, NH); dC(75 MHz; DMSO-d6) 171.0
(C]O), 158.7, 134.0, 120.3, 111.8 (C^N), 110.0 (C^N); m/z (EI) 178
(Mþ, 36%), 162 (3), 135 (Mþ-CONH, 50), 126 (Mþ-N]CCN, 4), 108
(Mþ-SCCN, 27), 83 (9), 82 (14), 77 (10), 76 (NCC]CCNþ, 7), 71 (5),
70 (N]CCONHþ2 or SCCNþ, 23), 69 (N]CCONHþ, 3), 64 (NC]CCNþ,
5), 59 (10), 58 (N]CSþ, 17), 57 (8), 55 (3), 50 (C]CCNþ, 4).
30. Simmons, H. E.; Vest, R. D.; Blomstrom, D. C.; Roland, J. R.; Cairns, T. L. J. Am.
Chem. Soc. 1962, 84, 4746.
31. Weis, C. D. J. Org. Chem. 1962, 27, 3693.
32. Webster, O.W. DE Pat. 2 317 453, 1973.
33. Erlenmeyer, H.; Junod, J.; Guex, W.; Erne, M. Helv. Chim. Acta 1948, 31, 1342.
34. Roesky, H. W.; Keller, K.; Bats, J. W. Angew. Chem., Int. Ed. Engl. 1983, 22, 1323.
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37. Gleiter, R.; Schehlmann, V.; Spanget-Larsen, J.; Fischer, H.; Neugebauer, F. A. J.
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5.5. Thiazole-2,4,5-tricarbonitrile 6 using polymer bound
triphenylphosphine
38. Del Sesto, R. E.; Arif, A. M.; Novoa, J. J.; Anusiewicz, I.; Skurski, P.; Simons, J.;
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To a stirred solution of 2-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)acetonitrile
7 (50 mg, 0.153 mmol) in dry DCM (3 mL) at ca. 20 ꢀC, polymer
bound triphenylphosphine 3.2 mmol/g (286.9 mg, 0.92 mmol) was
added and the reaction was kept at ca. 20 ꢀC until no starting ma-
terial remained (TLC). The polymer bound triphenylphosphine was
filtered off from the reaction mixture and evaporation of the sol-
vent gave the title compound 6 (18.6 mg, 76%) as colourless plates,
mp 122–123 ꢀC (lit.,33 127 ꢀC) (from PhH) identical to that described
above.
`
39. Berlin, A.; Pagani, G. A.; Sannicolo, F. J. Chem. Soc., Chem. Commun. 1986, 1579.
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43. van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 9.
44. van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 87.
45. Barclay, T. M.; Beer, L.; Cordes, A. W.; Oakley, R. T.; Preuss, K. E.; Reed, R. W.;
Taylor, N. J. Inorg. Chem. 2001, 40, 2709.
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The authors wish to thank the Cyprus Research Promotion
Foundation (Grant Nos. DRASI/TEXNO/0603/18 & NEAYPODOMH/
NEKYP/0308/02) and the following organisations in Cyprus for
54. Harwood, L. M. Aldrichimica Acta 1985, 18, 25.