Ring transformation of (4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitriles to 3-haloisothiazole-5-carbonitriles

Article abstract of DOI:10.1039/c3ra47261b

Ring transformation of readily prepared (4-chloro-5H-1,2,3-dithiazol-5- ylidene)acetonitriles afford 3-haloisothiazole-5-carbonitriles in good to excellent yields. The transformation can be mediated using HBr (g), HCl (g) or BnEt₃NCl. Mechanism

Full text of DOI:10.1039/c3ra47261b

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Ring transformation of (4-chloro-5H-1,2,3-
dithiazol-5-ylidene)acetonitriles to
Cite this: RSC Adv., 2014, 4, 7735
3-haloisothiazole-5-carbonitriles†
Andreas S. Kalogirou, Irene C. Christoforou, Heraklidia A. Ioannidou, Manolis J. Manos
*
and Panayiotis A. Koutentis
Ring transformation of readily prepared (4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitriles afford
3-haloisothiazole-5-carbonitriles in good to excellent yields. The transformation can be mediated
using HBr (g), HCl (g) or BnEt3NCl. Mechanisms for the transformations are discussed, together with
rationalizations for the formation of side products. Furthermore, single crystal X-ray structures are
Received 3rd December 2013
Accepted 7th January 2014
provided
for
(Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile
and
(E)-2-bromo-2-
DOI: 10.1039/c3ra47261b
(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile confirming the stereochemistry of the exocyclic
www.rsc.org/advances
ethene bond.
dehydrogenase type 1 (11b-HSD1) for the treatment of meta-
bolic syndrome and related disorders, which includes disorders
1. Introduction
such as type 2 diabetes, obesity and CNS disorders such as early
dementia (Fig. 2).
Isothiazoles nd uses as pharmaceuticals, agrochemicals,
stabilizers, dyes as well as electronic materials and their
synthesis, chemistry and applications have been extensively
reviewed.1 Commercial isothiazoles include methylchlor-
oisothiazolone (MCIT), a major component of the Kathon
preservatives, the antibacterial sulfa drug sulfasomizole and the
fungicide isotianil (Stout®) which is particularly effective
against rice blast (Fig. 1).
Furthermore, interest in isothiazoles as agrochemicals
continues with recent patents on antibacterial/antifungal,11
insecticidal,11c,12 herbicidal,13 and plant growth regulator
behavior.14 Isothiazoles have also recently been studies as azo
dyes,15 or as dyes with high dichroism for display devices.16
Recent developments in pharmacologically interesting
monocyclic isothiazoles include the selective Checkpoint kinase
2 inhibitor 3-hydroxyisothiazole-4-amidine 1, which is useful as
a radiation protection agent in anticancer radiotherapy,2 while
other isothiazoles inhibit tyrosine,3 MEK-1 and MEK-2,4 and
p38a MAP kinases.5 Some isothiazole-4-carboxamides behave as
prodrugs for the treatment of cancerous and noncancerous
hyperproliferative disorders,6 while 3-methylsulfanyl-5-phenyl-
isothiazole-4-carbonitrile (2) displayed antiviral activity against
polio,7 and 3-benzyloxyisothiazole-4/5-carboxylic acids (3a and
3b) exerted moderate activity to protect C8166 cells from HIV-1
infection.8 The 3,4-diarylisothiazole-5-amide 4 (ref. 9) acts as
selective negative allosteric modulators (NAMs) for metabo-
tropic glutamate receptor 5 (mGlu5) related to the treatment of
chronic pain conditions, while the 5-pyrazolyl-isothiazole-3-
Fig. 1 Commercially important isothiazoles.
carboxamide
5
(ref. 10) inhibits 11b-hydroxysteroid
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus.
E-mail: koutenti@ucy.ac.cy
† Electronic supplementary information (ESI) available: Copies of 1D 1H and 13
C
NMR spectra of all new compounds. Mass spectra for all mixtures and structure
elucidation discussion for compound 27b. CCDC 963573 and 963574. See DOI:
10.1039/c3ra47261b
Fig. 2 Chemical structures of selected biologically active isothiazoles.
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Most routes to isothiazoles involve construction of the ring
with the desired carbon substituents in place, as such the routes
are oen product specic.1e The availability of haloisothiazoles
combined with modern transition metal-catalyzed C–C bond
forming reactions enables useful nonproduct specic routes to
alkyl-,17 alkenyl-,18 alkynyl-,18a,b,19 aryl-,17,18b,20 and hetaryl-sub-
stituted17b,18b,20 isothiazoles. Furthermore, palladium catalyzed
direct C–H arylation and hetarylation has recently been
demonstrated on C-5 unsubstituted 3-bromoisothiazole-4-
carbonitrile.21
Scheme 1 Preparation of 3-chloro- and 3-bromoisothiazole-4,5-
dicarbonitriles 9a and 9b.
substituted heterocycles involves the thermal or addition of
nucleophile-ring opening-ring closure (ANRORC)34 ring trans-
formation of carefully designed 4-chloro-5H-1,2,3-dithiazoles.35
In particular N-substituted 1,2,3-dithiazolimines have been
converted via thermolysis to benzothiazoles,36 benzimid-
azoles,37 thiazolopyridines38 and benzoxazines.39 While iso-
thiazoles,40 thiazoles,41 1,3,4-thiadiazoles41 and heteroazine
fused thiazoles,38b have been prepared using ANRORC type
transformations.38a Neutral 1,2,3-dithiazolimines have also
been used to prepare acyclic functionalities such as iso-
thiocyanates42 and thiocyanoformamides.43
Particularly interesting was the reaction of 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)malononitrile (11)40,44 with either
catalytic chloride, or anhydrous HBr to give in high yield
3-chloro- or 3-bromoisothiazole-4,5-dicarbonitriles 9a (ref. 40a)
Fig. 3 Chemical structures of common haloisothiazolecarbonitriles.
Haloisothiazolecarbonitriles are a particularly useful class of
compounds (Fig. 3). Nitriles can readily be transformed into a and 9b,40b respectively (Scheme 1).
wide range of useful functional groups,22 and activate arenes
towards nucleophilic aromatic substitution, furthermore,
nitriles can ortho direct transition metal catalysed reactions via
coordination with the metal catalyst.23
Below we describe our efforts to generalize this (dithiazol-
ylidene)acetonitrile to isothiazole transformation and indicate
several notable limitations.
Interestingly, while all three dichloroisothiazolecarbonitriles
6,24 7a (ref. 25) and 8a (ref. 26) are known, their chemistry up
until recently was limited to nucleophilic aromatic substitution
of the halogen,24,25,27 functional group transformations of the
nitrile24,25,28 and alkylation of the ring nitrogen.29 We recently
demonstrated the broader potential of these haloiso-
thiazolecarbonitrile building blocks by carrying out a wide
range of C5-regioselective transition metal catalysed reactions
on 3,5-dichloro- and 3,5-dibromoisothiazole-4-carbonitriles (7a
and 7b, respectively)17b,18b and also a C-5 regioselective proto-
dehalogenation to give the 3-chloro- and 3-bromoisothiazole-4-
carbonitriles 10a and 10b, respectively.30
The methods for synthesizing isothiazolecarbonitriles
such as 7a (ref. 25) and 8a (ref. 26, 28 and 31) oen involve
hazardous chemicals such as chlorine gas (TOXIC),25,26,28,31
sodium cyanide (TOXIC),26,28 carbon disulde (HIGHLY FLAM-
MABLE)26,28,32 or disulfur dichloride (SMELLY).31 In the case of
3,4-dibromoisothiazole-5-carbonitrile (8b),33 the need for low
temperatures (ꢀ50 ꢁC) and exotic reaction solvents such as
liquid sulfur dioxide can limit the practical availability of these
useful isothiazoles.
2. Results and discussion
2.1. Synthesis of (dithiazolylidene)acetonitriles
The number of (dithiazolylidene)acetonitriles reported in the
literature is currently very limited. The (dithiazolylidene)-
malononitrile 11,40,44 the methyl and ethyl (dithiazolylidene)-
2-cyanoacetates 12 and 13 (ref. 45a) and the dithiazole ketones
(Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4,4-dimethyl-3-
oxopentanenitrile (14) and (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-3-oxo-3-phenylpropanenitrile (15)46 have all been
prepared in moderate to good yields by condensing active
methylenes with 4,5-dichloro-1,2,3-dithiazolium chloride (16)45
(Appel salt), followed by the addition of pyridine (2 equiv.)
(Scheme 2).
In light of this, there is a need to develop new routes to these
and other potentially useful haloisothiazolecarbonitriles. A
surprisingly efficient route to difficult to access cyano Scheme 2 Route to known (dithiazolylidene)acetonitriles 11–15.
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The isolation of these neutral dithiazoles on a gram scale
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typically involved at least one chromatographic step, however,
by modifying the work-up procedures we were able to avoid
chromatography. As such, the esters 12 and 13 and the ketones
14 and 15 could be isolated in multigram quantities (10 g)
without the need for chromatography by following a wash
sequence [acetone (2ꢂ), H2O (1ꢂ) and MeOH (1ꢂ)]. Further-
more, the available range of (dithiazolylidene)acetonitriles was
enlarged by preparing unsubstituted and halo-substituted
acetonitrile analogs. The shortest route to these was considered
to be via the hydrolysis and (halo)decarboxylation of the avail-
able methyl and ethyl esters. However, alkali hydrolysis of the
esters 12 and 13 led only to decomposition of both starting
dithiazoles; a strong odor of H2S indicated reductive/hydrolytic
ring cleavage. Attempted demethylation of the methyl ester
using either BBr3 in DCM (ref. 47) or NaI, TMSCl in MeCN
Scheme 4 Reagents and conditions: (i) c. H2SO4, ca. 20 ꢁC, 15 min,
100%; (ii) POCl3, ca. 110 ꢁC, 4 h, 90%.
(ref. 48) gave only recovered starting material. Nevertheless, the Scheme
5 Resonance structures of dithiazolylidenes supporting
b-carbonyl groups.
methyl and ethyl (dithiazolylidene)-2-cyanoacetates 12 and 13
were stable to acid (HCl 37% or TFA neat). In light of this, we
prepared (Z)-tert-butyl 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-
2-cyanoacetate (17) from t-butyl 2-cyanoacetate and Appel salt
16 in a chromatography free multigram (10 g) scale in 48%
yield. t-Butyl esters are typically expected to be acid labile49 and
not surprisingly, treating the t-butyl (dithiazolylidene)cyano-
Kim et al.,50 and shows the most electron rich carbonyl group to
be syn to the dithiazole ring sulfur S-1, owing to stabilized
charge separated resonance forms or “non-bonding” interac-
tions between the carbonyl oxygen and the dithiazole
(Scheme 5).
ꢁ
acetate 17 with c. H2SO4 at ca. 0 C for 5 min gave the desired
In the absence of such stabilizing interaction the stereo-
chemistry of the new (dithiazolylidene)acetonitrile 19 was less
predictable. 1H NMR spectroscopy of the (dithiazolylidene)-
acetonitrile 19 gave a single peak at dH 5.81 ppm and 13C NMR
spectroscopy gave four carbon signals in the range of dC 158.2–
83.2 ppm indicating the existence of a single isomer on the
NMR time scale. The stereochemistry of the (dithiazolylidene)-
acetonitrile 19 was eventually determined by single crystal X-ray
crystallography (Fig. 4), which showed the nitrile group to be syn
to the ring sulfur S-1 (i.e., the thermodynamically more stable
stereoisomer).
(Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetic acid
(18) in 93% yield. This could then be protodecarboxylated in
PhCl with TsOH$H2O (10 mol%) heated at ca. 132 ꢁC for 4 h to
give (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile (19)
in 87% yield. The two steps could also be performed in one pot
to give the desired (dithiazolylidene)acetonitrile 19 in 94%
together with a small quantity of the carboxylic acid 18 (6%)
(Scheme 3).
Furthermore, the selective hydration of one cyano-group of
the (dithiazolylidene)malononitrile 11 using c. H2SO4 at ca.
20 ꢁC for 15 min gave (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)-2-cyanoacetamide (20) in 100% yield. Attempts to
independently prepare the latter from Appel salt 16 and cya-
noacetamide gave a complex reaction mixture that was not
resolved. Interestingly, the cyanoacetamide 20 could be dehy-
drated back to the malononitrile 11 on treatment with neat
POCl3 at ca. 110 ꢁC for 4 h in 90% yield (Scheme 4).
Presumably, the exocyclic ethene has some single bond
character owing to electron release from the dithiazole sulfur
atoms towards the nitrile that could allow, under the reaction
The stereochemistry of dithiazolylidenes bearing exocyclic
alkenes with carbonyl functional groups has been studied by
Scheme 3 Reagents and conditions: (i) c. H2SO4, ca. 20 ꢁC, 5 min, Fig. 4 Ellipsoid (probability level of 50%) representation of the crystal
93%; (ii) TsOH (10 mol%), PhCl, 132 ꢁC, 4 h, 87%; (iii) TsOH (10 mol%), structure of (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile
PhCl, 132 ꢁC, 4 h, 94%.
(19) with crystallographic atom labelling.
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N-chlorosuccinimide (2 equiv.) in PhCl heated at reux, gave
2-chloro-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile
(22) in 78% yield (Scheme 7). Attempts to prepare the 2-
iodo(dithiazolylidene)acetonitrile from dithiazolylidene 19 and
N-iodosuccinimide led only to the recovery of unreacted starting
dithiazole 19.
Scheme
exocyclic ethane bond.
6 Resonance structures supporting rotation around the
Owing to the difficulty of obtaining single crystals of the
chloro(dithiazolylidene)acetonitrile 22 the stereochemistry of
the exocyclic C]C bond could not be veried. Single crystal
X-ray crystallography of the bromo(dithiazolylidene)acetonitrile
21, however, indicated the nitrile group to be anti to the ring
sulfur S-1 (Fig. 5). This orientation presumably avoided the
steric clash between the bromo and the C-4 chlorine
substituents.
The stereochemical information deduced from the
substituted (dithiazolylidene)acetonitriles 17, 19 and 21 sup-
ported that the stereochemistry of the exocyclic C]C bond can
change. The dithiazole ester 17 has an anti orientation with
respect to the nitrile group and the ring sulfur atom S-1,
however, decarboxylation to afford the (dithiazolylidene)aceto-
nitrile 19 leads to syn stereochemistry, while subsequent
bromination switches the stereochemistry back to anti
(Scheme 8).
conditions, a degree of rotation and attainment of the ther-
modynamically most stable stereoisomer (Scheme 6).
13C NMR data tentatively supports some delocalization
extending between the dithiazole ring and the nitrile group
since the data for the exocyclic double bond was dC 158.2
(CCHC^N) and 83.2 ppm (CC^N) indicating a relatively
polarized double bond. Nevertheless, an analysis of the bond
lengths obtained from the single crystal X-ray structure showed
˚
that the C(2)–C(3) and C(1)–N(1) bonds [1.344(5) and 1.277(5) A,
respectively] had pronounced double bond character (typical
˚
˚
C]C and C]N bond lengths are 1.34 A and 1.29 A, respec-
tively) while the C(1)–C(2) and C(3)–C(4) bonds [1.456(5) and
˚
1.413(5) A, respectively] were shorter than a typical single C–C
˚
bond (1.54 A) and closer to the bond length associated with an
˚
˚
aromatic C–C bond (1.40 A). The C(2)–S(1) bond (1.729 A) are
˚
midway between a typical C–S single (1.82 A) and C]S double
2.2. Reactions with HBr (g) and HCl (g)
˚
(1.60 A) bond. While this data is somewhat contradictory, it is
Having access to a number of (dithiazolylidene)acetonitriles, we
then investigated their transformations into isothiazoles. The
(dithiazolylidene)acetonitriles were treated with either HBr (g)
or HCl (g) to investigate their transformation into 3-bromo- or
3-chloroisothiazole-5-carbonitriles, respectively (Table 1).
Initially, two different reaction set ups were used: the rst
involved briey (30 s) purging a stirred solution of the dithiazole
with gaseous HBr or HCl and then leaving the reaction to stir at
worthy of note that single crystal X-ray data provides bond
lengths and angles for the molecule in the solid state and this
may not reect accurately the situation of the compound in
solution.
Having successfully prepared the (dithiazolylidene)aceto-
nitrile 19, the synthesis of the halogenated derivatives was
pursued. Treatment of the ylidene 19 with N-bromosuccini-
mide (1 equiv.) in PhH heated at reux, gave (E)-2-bromo-2-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile (21) in 93%
yield while the chlorination reaction needed more vigorous
conditions. As such, treating the ylidene 19 with
Fig. 5 Ellipsoid (probability level of 50%) representation of the crystal
Scheme 7 Preparation of 2-bromo and 2-chloro(dithiazolylidene) structure of (E)-2-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
acentonitriles 21 and 22.
acetonitrile (21) with crystallographic atom labelling.
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conversion of the dithiazolylidenes into the desired isothiazoles
and some elemental sulfur, the procedure involving the purge
gave higher yields. Furthermore, the choice of solvent was
critical; presumably this was attributed to solubility issues, both
of the anhydrous hydrogen halides and of the starting
dithiazolylidenes.
Early investigations on the conversion of the (dithiazolyli-
dene)malononitrile 11 into 3-chloro- or 3-bromoisothiazole-4,5-
dicarbonitrile (9a)40a and (9b),40b using HCl (g) or HBr (g),
respectively determined that while DCM and aromatic solvents
such as PhH, PhMe, xylene and PhCl were suitable for use with
HBr (g) these solvents were not suitable with the use of HCl
(g).38a,40b The reported solubilities of the two gases in organic
solvents show that in general HBr is more soluble than HCl and
solubilities are much greater in ether solvents.51 As such, we
pursued the use of ethers as solvents for performing this
transformation.
Scheme 8 Stereochemical changes on transforming dithiazole 17
into 21.
Table 1 Reaction of (dithiazolylidene)acetonitriles with HCl (g) or HBr
(g) in either Et2O or THF at ca. 20 ꢁC to give 3-chloro or 3-bromo-
isothiazole-5-carbonitriles, respectively
Furthermore, the use of dry solvents and glassware improved
the product yields, which was not altogether surprising, since
the nitrile substituent at the isothiazole C-5 position was highly
electrophilic and susceptible to hydration.52 In particular, per-
forming the reaction of the (dithiazolylidene)malononitrile 11
with HBr (g) in wet toluene led to isolation of 3-bromoisothia-
zole-4,5-dicarbonitrile (9b) and 3-bromo-4-cyanoisothiazole-5-
carboxamide (23) in 39 and 35% yields, respectively indicating
partial hydration of the isothiazole 9b under the reaction
conditions. The carboxamide 23 could be also synthesised
independently from reaction of the dicyanoisothiazole 9b with
NaOH in dioxane is 90% yield.
In most cases, the reactions carried out in THF led to faster
consumption of the starting (dithiazolylidene)acetonitriles,
the notable exceptions were the reactions of the methyl and
ethyl (dithiazolylidene)-2-cyanoacetates 12 and 13 with HBr
(g) which required more time in THF than in Et2O, and in
these cases (entries 13, 14, 17 and 18), the yields of iso-
thiazoles were higher in the reactions with the shortest reac-
tion times. Furthermore, in nearly all cases, shorter reaction
times correlated with higher isothiazole yields and the use of
THF as solvent. The exception to this was the reaction of the 2-
chloro(dithiazolylidene)acetonitrile 22 with HCl (g) which
consistently gave a higher yield of 3,4-dichloroisothiazole-5-
carbonitrile (8a) in Et2O than in THF (64 vs. 45%) despite a
signicantly longer reaction time (48 vs. 24 h) (entries 11 and
12). In several cases, the ring transformation proceeded in
excellent and synthetically useful yields: the unsubstituted
(dithiazolylidene)acetonitrile 19 with HCl (g) or HBr (g) gave
the corresponding 3-chloro- and 3-bromoisothiazole-5-car-
bonitriles 24a (84%) and 24b (97%), respectively (entries 4
and 2), the 2-bromo(dithiazolylidene)acetonitrile 21 with HBr
(g) in Et2O gave 3,4-dibromoisothiazole-5-carbonitrile (8b) in
83% yield (entry 5), while the methyl and ethyl 3-bromo-5-
cyanoisothiazole-4-carboxylates 25b and 26b could be isolated
from THF in 78 and 87% yields, respectively (entries 13
and 17) and 3-bromoisothiazole-4,5-dicarbonitrile 9b in 96%
Entry Dithiazole
Y
X
Solvent Time
Yield (%)
1
2
3
4
5
6
7
8
19
19
19
19
21
21
21
21
22
22
22
22
12
12
12
12
13
13
13
13
11
11
11
11
H
H
H
H
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Br Et2O
Br THF
Cl Et2O
Cl THF
Br Et2O
Br THF
Cl Et2O
Cl THF
Br Et2O
Br THF
Cl Et2O
Cl THF
10 min 24b (82)
5 min
48 h
3 h
24b (97)
24a (59)
24a (84)
10 min 8b (83)
5 min
24 h
5 h
8b (18) + 24b (50)
Mixa + 24a (34)
Mixa + 24a (68)
9
10 min Mixb
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
10 min Mixc + 24b (15)
48 h
24 h
5 h
24 h
24 h
18 h
2 h
48 h
24 h
18 h
1 h
5 min
72 h
20 h
8a (64)
8a (45)
25b (78)
25b (71)
nrd
CO2Me Br Et2O
CO2Me Br THF
CO2Me Cl Et2O
CO2Me Cl THF
CO2Et Br Et2O
CO2Et Br THF
CO2Et Cl Et2O
CO2Et Cl THF
CN
CN
CN
CN
nrd
26b (87)
26b (65)
nrd
nrd
Br Et2O
Br THF
Cl Et2O
Cl THF
9b (65)
9b (96)
9a (50)
9a (55)
a
Inseparable mixture of 3,4-dichloroisothiazole-5-carbonitrile (8a), 3,4-
dibromoisothiazole-5-carbonitrile (8b), 3-bromo-4-chloroisothiazole-5-
carbonitrile (27b) and an unknown compound (by 13C NMR).
b
Inseparable mixture of 3,4-dibromoisothiazole-5-carbonitrile (8b)
and 3-bromo-4-chloroisothiazole-5-carbonitrile (27b) (8b : 27b ¼ 1 : 3
c
by NMR).
Inseparable mixture of 3,4-dibromoisothiazole-5-
carbonitrile (8b) and 3-bromo-4-chloroisothiazole-5-carbonitrile (27b)
d
(8b : 27b ¼ 1 : 9 by NMR). nr ¼ no reaction, recovered starting
dithiazoles (>82%).
ꢁ
ca. 20 C, while the second involved stirring a solution of the yield (entry 22). Although not shown in Table 1, we were
dithiazolylidene under an atmosphere of HBr (g) or HCl (g). surprised to see no reaction of the dithiazole ketones 14
While both sets of conditions led, in most cases, to the and 15, the (dithiazolylidene)cyanoacetic acid 18 or the
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(dithiazolylidene)cyanoacetamide 20 with either HBr (g) or
HCl (g) in either Et2O or THF; in all cases the starting
dithiazoles were recovered in over 80% yields from these
reactions.
Nevertheless, the reactions that led to mixtures of isothiazoles
were also informative: the reaction of the 2-bromo(dithiazolyli-
dene)acetonitrile 21 with HBr (g) in THF led to a separable
mixture of the desired 3,4-dibromoisothiazole-5-carbonitrile (8b)
(18%) and also the protodehalogenated 3-bromoisothiazole-5-
carbonitrile (24b) (50%) (entry 6). The reaction of the 2-bromo-
(dithiazolylidene)acetonitrile 21 with HCl (g) in both Et2O and
THF (entries 7 and 8, respectively) gave as major product
3-chloroisothiazole-5-carbonitrile (24a) together with an insepa-
rable mixture of 3,4-dichloroisothiazole-5-carbonitrile (8a), 3,4-
dibromoisothiazole-5-carbonitrile (8b), 3-bromo-4-chloroisothi-
azole-5-carbonitrile (27b) and an unknown product, as judged by
13C NMR spectroscopy and mass spectrometry (see ESI†).
The reaction of 2-chloro(dithiazolylidene)acetonitrile 22 with
HBr (g) in either Et2O or THF (entries 9 and 10), led to insepa-
rable mixtures of 3,4-dibromo- and 3-bromo-4-chloroisothizole-
5-carbonitriles 8b and 27b in a 1 : 3 ratio when the reaction was
performed in Et2O. The reaction in THF gave 3-bromoisothizole-
5-carbonitrile (24b) along with an inseparable mixture of 3,4-
dibromo- and 3-bromo-4-chloroisothizole-5-carbonitriles 8b
and 27b in a 1 : 9 ratio. The identity of the products from these
inseparable mixtures (entries 7–10) were tentatively deduced by
NMR and MS while the ratios were crudely deduced from 13C
NMR spectroscopy by increasing the relaxation time (D1 ¼ 6 s)
and integrating the fully relaxed signals. The identity of iso-
thiazole 27b was based on a fragmentation analysis of a low
resolution electron impact GC-MS of the mixture from entry 9
(see ESI†) and its presence in other mixtures was supported by
13C NMR spectroscopy. The reactions above (entries 6–10)
indicate that both protodehalogenation and halogen scram-
bling can occur.
Scheme 9 General mechanism for the ring transformation of dithia-
zoles to give isothiazoles.
however, that these reactions were occurring prior to the
formation of the isothiazoles since the 3,4-dihaloisothiazole-5-
carbonitriles 8a (Hal ¼ Cl) and 8b (Hal ¼ Br) were stable to
ꢁ
either HCl (g) or HBr (g), in dry THF at ca. 20 C for 20 h. As
such, we propose that the dithiazolylidenes capture not only
protons but also electrophilic halogen, particularly bromine, at
the terminus of the exocyclic alkene to give either species such
as the dithiazolium 30 which can either equilibrate to its neutral
form 31 and loose ZY to afford a new dithiazolylidene 32
(Scheme 10).
The elimination of ZY could be assisted by electron release
from the ring sulfurs or by X-philic54 attack by an external halide
(e.g., Z). Since bromine substituents are more prone to X-philic
attack than chlorine substituents54 then this could explain why
protodebromination was more prevalent than proto-
dechlorination. Furthermore, worthy of note was that HBr in
the presence of light or oxygen can oxidize to Br2,55 while HCl
under similar conditions was considerably more stable leading
to more protodehalogenation than halogen exchange than HBr
(Scheme 10).
2.3. Mechanistic rationale
Tentatively, we propose that initially the dithiazolylidenes
protonate to give the dithiazoliums 28, thus allowing free
rotation around the exocyclic ylidene. The 13C NMR data
suggests considerable electron density is concentrated at the
alkene terminus [dC C-5 155.1–158.2 and C(CN)2 74.6–90.5 ppm]
assisted by the electron release of the dithiazole ring sulfurs.
The dithiazolium salt is presumably in equilibrium with its
ketenimine prototautomer which can trap the halide to give the
neutral imine 29. Subsequent intramolecular cyclisation onto
the dithiazole S-1 ring sulfur is followed by a concomitant ring
cleavage and loss of HCl and elemental sulfur presumably via a
sulfur chain extension mechanism.53 The reaction is potentially
thermo-dynamically driven owing to the formation of a new
stable nitrile bond (Scheme 9).
2.4. Reactions with chloride
The (dithiazolylidene)acetonitrile to 3-haloisothiazole-5-car-
bonitrile conversion can also be triggered with catalytic
Tentatively, the side reactions that were observed with the 2-
halo(dithiazolylidene)acetonitriles 21 (Hal ¼ Br) and 22 (Hal ¼
Cl), which included protodehalogenation (Table 1, entries 6–8
and 10) at the isothiazole C-4 position or halogen exchange
(Table 1, entries 7–10), support this mechanism. It was clear, Scheme 10 Y ¼ H or HaI, X ¼ Z ¼ HaI or X ¼ H, Z ¼ HaI.
7740 | RSC Adv., 2014, 4, 7735–7748
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chloride,40a as such we investigated the transformation
further by treating all the new (dithiazolyliedene)acetonitriles
with BnEt3NCl (10 mol%) in dry benzene, heated to reux;
analogous conditions to those reported for the quantitative
conversion of the (dithiazolylidene)malononitrile 11 to
3-chloroisothiazole-4,5-dicarbonitrile (9a).40a Reaction of the
ethyl (dithiazolylidene)cyanoacetate 13 pleasingly gave ethyl
3-chloro-5-cyanoisothiazole-4-carboxylate (26a) in 67% yield,
however, the methyl (dithiazolylidene)cyanoacetate 12 reac-
ted more slowly and gave only a trace of what appeared to be
isothiazole 25a. Tentatively, we believe this difference in
reactivity was attributed to possible demethylation of the
ester by chloride under the reaction conditions and subse-
quent degradation of the carboxylic acid formed. Unfortu-
nately, treating the available (dithiazolylidene)cyanoacetic
acid 18 with BnEt3NCl (10 mol%) in PhH heated at reux led
to a complex reaction mixture from which the proto-
decarboxylated dithiazole 19 could be observed (by TLC).
Reactions of the 2-unsubstituted, 2-bromo- and 2-chloro-
(dithiazolylidene)acetonitriles 19, 21 and 22 gave a complex
mixture of products. From the 2-unsubstituted (dithiazolyli-
dene)acetonitrile 19 only a trace of 3-chloroisothiazole-5-car-
bonitrile (24a) was isolated, while reaction of the
2-chloro(dithiazolylidene)acetonitrile 22 fortunately gave
3,4-dichloroisothiazole-5-carbonitrile (8b) in a useful 63%
yield. The 2-bromo(dithiazolylidene)acetonitrile 21, however,
3. Conclusions
The ring transformation of 2-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)acetonitriles into 3-haloisothiazole-5-carbonitriles using
HBr (g) or HCl (g) successfully led to the preparation of useful
isothiazoles: 3-bromo- and 3-chloroisothiazole-5-carbonitriles
were prepared in 97 and 84% yields, respectively, 3,4-dibromoi-
sothiazole-5-carbonitrile in 83% yield, methyl and ethyl 3-bromo-
5-cyanoisothiazole-4-carboxalates in 78 and 87% yields,
respectively and 3-bromoisothiazole-4,5-dicarbonitrile in 96%
yield. Side reactions that lead to protodehalogenation or halogen
scrambling have been observed and partially rationalized. The
complementary ring transformation using catalytic BnEt3NCl
(10 mol%) was also extended to provide 3,4-dichloroisothiazole-5-
carbonitrile and ethyl 3-chloro-5-cyanoisothiazole-4-carboxylates
in moderately good yields 63 and 67%, respectively.
4. Experimental
4.1. General procedures
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
commercial 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 ash chro-
matography was used throughout for all non-TLC scale chro-
matographic separations using Merck Silica Gel 60 (less than
0.063 mm). Melting points were determined using a PolyTherm-
A, Wagner & Munz, Koeer – Hotstage Microscope apparatus or
were determined using a TA Instruments DSC Q1000 with
samples hermetically sealed in aluminium paꢀn1s under an argon
gave
a mixture of 3,4-dichloro- and 3-bromo-4-chlor-
oisothiazole-5-carbonitriles 8a and 27b in a 1 : 2 ratio as
judged by integration of 13C NMR spectra obtained with a
long D1 relaxation time (6 s) (Table 2). The ketones 14, 15 and
the carboxamide 20 were unreactive to the reaction
conditions.
ꢁ
atmosphere; using heating rates of 5 C min (DSC mp listed
by onset and peak values). Solvents used for recrystallization are
indicated aer the melting point. UV spectra were obtained
using a Perkin-Elmer Lambda-25 UV/vis spectrophotometer and
inections are identied by the abbreviation “inf”. IR spectra
were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrom-
eter with Pike Miracle Ge ATR accessory and strong, medium
Table 2 Reaction of (dithiazolydene)acetoniriles with BnEt3NCl (10
mol%) in dry PhH heated at ca. 80 ꢁC to give 3-chloroisothiazole-5-
carbonitriles
1
and weak peaks are represented by s, m and w respectively. H
and 13C NMR spectra were recorded on a Bruker Avance
500 machine (at 500 and 125 MHz, respectively). Deuterated
solvents were used for homonuclear lock and the signals are
referenced to the deuterated solvent peaks. 13C NMR multi-
plicity assignments were determined using APT or DEPT NMR
experiments. Low resolution (EI) mass spectra were recorded on
a Shimadzu Q2010 GCMS with direct inlet probe or on a
Micromass AutoSpec machine at 70 eV, while ESI-APCI+ mass
spectra were recorded on a Model 6110 Quadrupole MSD, Agi-
lent Technologies. 2-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)
malononitrile (11)44 and 4,5-dichloro-1,2,3-dithiazolium chlo-
ride (16)45 were prepared according to literature procedures.
Entry
Dithiazole
Y
Time (h)
Yield (%)
a
b
1
2
3
4
5
6
19
21
22
12
13
11
H
Br
Cl
CO2Me
CO2Et
CN
0.5
7
7
72
48
48
8a (63)
c
26a (67)
9a (100)
a
Complex reaction mixture with only a trace of 3-chloroisothiazole-
b
4.2. Preparation of dithiazolylidenes
5-carbonitrile
3,4-dichloroisothizole-5-carbonitrile
(24a)
by
TLC.
Inseparable
(8a) and
1 : 2 by NMR).
mixture
3-bromo-4-
of
4.2.1. (Z)-tert-Butyl
dene)-2-cyanoacetate (17). To
2-(4-chloro-5H-1,2,3-dithiazol-5-yli-
stirred suspension of
chloroisothiazole-5-carbonitrile (27b) (8a : 27b
¼
c
Degradation, only intractable baseline on TLC.
a
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4,5-dichloro-1,2,3-dithiazolium chloride (16) (20.85 g, 100 (DCM)/nm 304 (log 3 2.31), 389 (3.07); nmax/cmꢀ1 3077w and
mmol) in DCM (160 mL) was added tert-butyl 2-cyanoacetate 3035w (CH), 2205s (C^N), 1534s, 1505w, 1497w, 1367w, 1280w,
(14.12 g, 100 mmol) and the reaction mixture was stirred at ca. 1262w, 1177s, 882s, 874m, 794, 749m; dH (500 MHz; CDCl3) 5.82
ꢁ
20 C for 4 h. Pyridine (16.16 mL, 200 mmol) was then added (1H, s, CH); dC (125 MHz; CDCl3) 158.2 (s), 144.0 (s), 117.8 (s),
and the reaction mixture was stirred for another 2 h. The solvent 83.3 (d); m/z (EI) 178 (M+ + 2, 43%), 176 (M+, 100), 141 (5), 115
was then evaporated and acetone (20 mL) was added to form a (60), 105 (6), 102 (4), 95 (15), 93 (38), 88 (10), 83 (34), 76 (9), 70
suspension which was ltered and washed with H2O (2 ꢂ (21), 64 (40), 57 (8), 51 (10).
20 mL) and MeOH (20 mL) and then dried (Na2SO4) to afford the
4.2.3.2. Method 2, via one-pot saponication–proto-
title compound 17 (13.28 g, 48%)ꢁ as yellow plates, (DSC) mp decarboxylation of (Z)-tert-butyl 2-(4-chloro-5H-1,2,3-dithiazol-5-
ꢁ
ꢁ
onset: 164.5 C, peak max: 173.4 C, decomp. onset: 178.9 C, ylidene)-2-cyanoacetate (17). To a stirred solution of (Z)-tert-butyl
peak max: 180.6 ꢁC (from cyclohexane); Rf 0.54 (n-hexane–DCM, 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetate
(17)
ꢁ
1 : 1); (found: C, 39.07; H, 3.36; N, 10.29. C9H9ClN2O2S2 requires (500 mg, 1.81 mmol) in PhCl (20 mL) at ca. 20 C, TsOH$H2O
C, 39.06; H, 3.28; N, 10.12%); lmax (DCM)/nm 414 inf (log 3 (9.5 mg, 10 mol%) was added and the reaction was heated to ca.
3.15), 432 (3.21), 454 inf (3.01); nmax/cmꢀ1 3003w, 2990w and 132 ꢁC. During the heating a yellow-orange precipitate was
2941w (CH3), 2208m (C^N), 1648s (C]O), 1479m, 1473m, formed which was later dissolved. The mixture was kept at ca.
1456w, 1449w, 1391w, 1375w, 1370w, 1307s, 1257m, 1228m, 132 ꢁC until no starting material remained (TLC) and allowed to
1154s, 1110m, 964w, 950w, 880m, 844m, 835s, 792m, 769m; dH cool to ca. 20 ꢁC. Filtration and wash (DCM) gave (Z)-2-(4-chloro-
(500 MHz; CDCl3) 1.59 [9H, s, C(CH3)3]; dC (125 MHz; CDCl3) 5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetic acid (18) (24 mg,
166.6 (s), 161.9 (s), 144.4 (s), 113.4 (s), 92.8 (s), 84.9 (s), 28.0 (q); 6%) as yellow-orange cubes, mp 151–152 ꢁC (from PhCl); Rf
m/z (EI) 278 (M+ + 2, 8%), 276 (M+, 21), 222 (40), 220 (92), 203 0.35 (n-hexane–DCM, 1 : 1); identical to that described above.
(21), 185 (83), 114 (7), 110 (6), 99 (7), 82 (10), 64 (15), 57 (100).
The ltrate was adsorbed onto silica and chromatography (n-
4.2.2. (Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cyano- hexane–DCM, 6 : 4) gave (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-
acetic acid (18). To a sample of (Z)-tert-butyl 2-(4-chloro-5H- ylidene)aꢁcetonitrile (19) (300 mg, 94%) as yellow needles, mp
1,2,3-dithiazol-5-ylidene)-2-cyanoacetate
(17)
(100
mg, 113–114 C (from cyclohexane); Rf 0.43 (n-hexane–DCM, 6 : 4);
0.361 mmol) was added conc. H2SO4 (3 mL) at ca. 0 ꢁC and the identical to that described above.
reaction mixture was stirred at this temperature until no start-
4.2.4. (E)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cya-
ing material remained (TLC, 5 min). The mixture was poured noacetamide (20). To 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
onto ice and the yellow precipitate that formed was isolated by malononitrile (11) (100 mg, 0.496 mmol) was added conc.
ꢁ
ltration to give the title compound 18 (41 mg, 52%). The ltrate H2SO4 (4 mL) and the reaction mixture was stirred at ca. 20 C
was extracted with EtOAc (3 ꢂ 10 mL) and the organic phase was until no starting material remained (TLC). The mixture was
then dried (Na2SO4) and evaporated to afford a further quantity poured onto ice and extracted with Et2O (3 ꢂ 20 mL). The
of the title compound 18 (32ꢁmg, 41%, total yield 93%) as yellow- organic layer was dried (Na2SO4) and evaporated to afford the
orange cubes, mp 151–152 C (from PhCl); Rf 0.35 (n-hexane– title compounꢁd 20 (109 mg, 100%)ꢁas yellow needles, (DSC) mp
ꢁ
DCM, 1 : 1); (found: C, 27.19; H, 0.51; N, 12.87. C5HClN2O2S2 onset: 213.8 C, peak max: 223.4 C, decomp. onset: 230.8 C,
ꢁ
requires C, 27.22; H, 0.46; N, 12.70%); lmax (EtOH)/nm 416 inf peak max: 231.8 C (from PhH); Rf 0.78 (t-BuOMe); (found: C,
(log 3 3.09), 430 (3.13), 447 inf (3.99); nmax/cmꢀ1 3038w, 2942w, 27.46; H, 0.87; N, 19.21. C5H2ClN3OS2 requires C, 27.34; H, 0.92;
2825w, 2657w, 2531w, 2224m (C^N), 1643m (C]O), 1467m, N, 19.13%); lmax (DCM)/nm 207 (log 3 3.10), 217 inf (3.00), 241
1442w, 1414s, 1270s, 1229s, 1180w, 1126w, 1112m, 1037w, inf (2.60), 258 inf (2.51), 276 inf (2.30), 414 inf (3.00), 430 (3.07),
1009w, 958w, 945w, 876s, 827s, 772w, 767w, 731s; dC (125 MHz; 443 inf (2.95); nmax/cmꢀ1 3408br, 3329br, 3265br and 3206br
DMSO-d6) 168.7 (s), 163.9 (s), 142.9 (s), 114.9 (s), 88.6 (s); m/z (EI) (NH), 2195m (C^N), 1667s (C]O), 1599m, 1470m, 1458m,
222 (M+ + 2, 12%), 220 (M+, 29), 187 (9), 185 (100), 178 (3), 176 1391m, 1233s, 1111s, 1049w, 879s, 825s, 764s; dH (500 MHz;
(7), 115 (12), 93 (22), 82 (25), 77 (23), 70 (22), 64 (38), 56 (7).
4.2.3. (Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)acetoni-
trile (19)
DMSO-d6) 7.97 (1H, s, NH2), 7.57 (1H, s, NH2); dC (125 MHz;
DMSO-d6) 166.5 (s), 160.8 (s), 142.3 (s), 115.3 (s), 90.4 (s); m/z (EI)
219 (M+, 19%), 203 (3), 184 (100), 176 (5), 149 (3), 115 (12), 93 (8),
4.2.3.1. Method 1, via decarboxylation of (Z)-2-(4-chloro-5H- 82 (14), 77 (22), 70 (12), 64 (20).
1,2,3-dithiazol-5-ylidene)-2-cyanoacetic acid (18). To a stirred
4.2.5. Conversion of (E)-2-(4-chloro-5H-1,2,3-dithiazol-5-
solution of (Z)-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cya- ylidene)-2-cyanoacetamide (20) to 2-(4-chloro-5H-1,2,3-dithia-
noacetic acid (18) (400 mg, 1.81 mmol) in PhCl (20 mL) at ca. 20 zol-5-ylidene)malononitrile (11). To (E)-2-(4-chloro-5H-1,2,3-
ꢁC, TsOH$H2O (9.5 mg, 10 mol%) was added and the reaction dithiazol-5-ylidene)-2-cyanoacetamide (20) (44 mg, 0.20 mmol)
ꢁ
was heated to ca. 132 ꢁC. The mixture was kept at ca. 132 ꢁC until was added POCl3 (1 mL) and the mixture heated to ca. 110 C.
no starting material remained (TLC) and then allowed to cool to The reaction mixture was kept at ca. 110 ꢁC until no starting
ca. 20 ꢁC. The mixture was then adsorbed onto silica and material remained (TLC, 4 h), then allowed to cool to ca. 20 ꢁC
chromatography (n-hexane–DCM, 6 : 4) gave (Z)-2-(4-chloro-5H- and the volatiles evaporated in vacuo. The mixture was then
1,2,3-dithiazol-5-ylidene)acetonitrile (19) (348 mg, 87%) as adsorbed into silica and chromatography (DCM) of the residue
ꢁ
yellow needles, mp 113–114 C (from cyclohexane); Rf 0.43 (n- gave 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile (11)
hexane–DCM, 6 : 4); (found: C, 27.29; H, 0.52; N, 15.82. (36 mg, 90%) as orange crystals, mp 178–179 ꢁC (ref. 40a, 181–
C4HClN2S2 requires C, 27.20; H, 0.57; N, 15.86%); lmax 182 ꢁC) (from cyclohexane); Rf 0.37 (DCM); nmax/cmꢀ1 2219s and
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2189w (C^N), 1457s, 1249w, 1142m, 941m, 891m, 810m, 722w;
dC (125 MHz; CDCl3) 167.3 (s), 143.2 (s), 115.6 (s), 110.4 (s), 67.3
(s); identical to an authentic sample.40a
4.3.2. 3,4-Dibromoisothiazole-5-carbonitrile (8b), Table 1,
entry 5. Similar treatment of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)acetonitrile (21) (254 mg, 1.00 mmol) in Et2O
(10 mL) with HBr (g) gave the title compound 8b (222 mg, 83%)
as colorless needles, mp (DSC) onset: 105.2 ꢁC, peak max: 106.1
ꢁC (from n-pentane/0 ꢁC) (ref. 33a, 107–108 ꢁC from EtOH–H2O);
Rf 0.56 (n-hexane–DCM, 7 : 3); nmax/cmꢀ1 2230m (C^N), 1476m,
1448w, 1357w, 1317w, 1283s, 1148m, 912m, 822w, 806w, 783m;
dC (125 MHz; CDCl3) 141.7 (s), 133.4 (s), 121.8 (s), 108.8 (s); m/z
(EI) 270 (M+ + 4, 49%), 268 (M+ + 2, 100), 266 (M+, 48), 189 (76),
187 (12), 163 (35), 161 (33), 137 (11), 113 (23), 111 (23), 108 (22),
82 (56); identical to an authentic sample.
4.2.6. (Z)-2-Bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-
acetonitrile (21). To a stirred solution of (Z)-2-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)acetonitrile (19) (300 mg, 1.70 mmol)
in PhH (15 mL) at ca. 20 ꢁC, N-bromosuccinimide (302.6 mg,
1.70 mmol) was added and the reaction was heated to ca. 80 ꢁC.
The mixture was kept at ca. 80 ꢁC until no starting material
remained (TLC), then allowed to cool to ca. 20 ꢁC and adsorbed
on silica. Chromatography (n-hexane–DCM, 6 : 4) gave the title
ꢁ
compound 21 (404 mg, 93%) as yellow needles, mp 176–177 C
(from cyclohexane); Rf 0.47 (n-hexane–DCM, 1 : 1); (found: C,
19.03; N, 10.94. C4BrClN2S2 requires C, 18.80; N, 10.96%); lmax
(DCM)/nm 256 (log 3 2.69), 291 (2.09), 400 (3.11); nmax/cmꢀ1
2192s (C^N), 1513s, 1486w, 1195s, 1156w, 1057w, 1021w, 894s,
845m, 811w, 770s; dC (125 MHz; CDCl3) 157.6 (s), 138.8 (s), 113.8
(s), 74.6 (s); m/z (EI) 258 (M+ + 2, 49%), 257 (M+ + 1, 11), 256 (M+,
100), 254 (98), 221 (2), 195 (18), 193 (17), 177 (29), 175 (71), 163
(6), 161 (6), 114 (35), 93 (11), 82 (12), 70 (8), 64 (7).
4.2.7. 2-Chloro-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-
acetonitrile (22). To a stirred solution of (Z)-2-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)acetonitrile (19) (300 mg, 1.70 mmol)
in PhCl (15 mL) at ca. 20 ꢁC, N-chlorosuccinimide (454 mg,
3.40 mmol) was added and the reaction was heated to ca.
132 ꢁC. The mixture was kept at ca. 132 ꢁC until no starting
material remained (TLC), then allowed to cool to ca. 20 ꢁC and
adsorbed on silica. Chromatography (n-hexane–DCM 6 : 4) gave
the title compound 22 (279.8 mg, 78%) as yellow needles, mp
164–165 ꢁC (ref. 46, 166–168 ꢁC) (from cyclohexane); Rf 0.47 (n-
hexane–DCM, 1 : 1); (found: C, 22.83; N, 13.18. C4Cl2N2S2
requires C, 22.76; N, 13.27%); lmax (DCM)/nm 255 (log 3 2.62),
293 (2.14), 396 (3.10); nmax/cmꢀ1 2201s (C^N), 1518s, 1488w,
1204s, 1164w, 1087w, 1074w, 1034w, 913w, 901m, 882w, 862m,
815w, 782s; dC (125 MHz; CDCl3) 155.1 (s), 139.3 (s), 113.1 (s),
90.5 (s); m/z (EI) 214 (M+ + 4, 17%), 212 (M+ + 2, 71), 210 (M+,
100), 177 (8), 175 (18), 151 (19), 149 (44), 117 (26), 114 (15), 105
(28), 93 (67), 82 (55), 79 (39), 76 (22), 70 (55), 64 (66).
4.3.3. 3-Chloroisothiazole-4,5-dicarbonitrile (9a); Table 1,
entry 24. Similar treatment of 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)malononitrile (11) (202 mg, 1.00 mmol) in THF (10 mL)
with HCl (g) gave the title compound 9a (94 mg, 55%) as
colorless needles, mp (DSC) onset: 96.9 C, peak max: 98.5 C
(from cyclohexane, ref. 40a, 98 ꢁC); Rf 0.43 (n-hexane–DCM,
1 : 1); nmax/cmꢀ1 2247m and 2239m (C^N), 1510s, 1354s, 1196s,
1174s, 1146w, 1020m, 980w, 856m, 829m; dC (125 MHz; CDCl3)
151.8 (s), 142.5 (s), 115.9 (s), 108.4 (s), 106.9 (s); identical to an
authentic sample.
4.3.4. 3-Bromoisothiazole-4,5-dicarbonitrile (9b); Table 1,
entry 22. Similar treatment of 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)malononitrile (11) (202 mg, 1.00 mmol) in THF (10 mL)
with HBr (g) gave the title compound 9b (205 mg, 96%) as
colorless needles, mp (DSC) onset: 138.6 ꢁC, peak max: 139.6 ꢁC
(from cyclohexane, ref. 40b, 141 ꢁC); Rf 0.43 (n-hexane–DCM,
1 : 1); nmax/cmꢀ1 2245m and 2237m (C^N), 1503s, 1379w,
1360w, 1342s, 1186m, 1167m, 1136w, 1007m, 978w, 843s, 800m;
dC (125 MHz; CDCl3) 142.4 (s), 139.8 (s), 119.3 (s), 109.0 (s), 106.7
(s); identical to an authentic sample.
ꢁ
ꢁ
4.3.5. 3-Chloroisothiazole-5-carbonitrile (24a), Table 1,
entry 4. Similar treatment of (Z)-2-(4-chloro-5H-1,2,3-dithiazol-
5-ylidene)acetonitrile (11) (177 mg, 1.00 mmol) in THF (10 mL)
with HCl (g) gave the title compound 2ꢁ4a (122 mg, 84%) as
ꢁ
colorless needles, mp (DSC) onset: 65.2 C, peak max: 66.3 C
(from n-pentane/0 ꢁC); Rf 0.39 (n-hexane–DCM, 7 : 3); (found: C,
33.12; H, 0.64; N, 19.43. C4HClN2S requires C, 33.23; H, 0.70; N,
19.38%); lmax (DCM)/nm 233 (log 3 3.04), 275 (3.00); nmax/cmꢀ1
3109m (CH), 2234m (C^N), 1495s, 1366m, 1337m, 1328m,
1310s, 1271m, 1159m, 1155m, 1126w, 1101w, 910s, 847s, 822m;
dH (500 MHz; CDCl3) 7.54 (1H, s, H-4); dC (125 MHz; CDCl3)
150.5 (s), 135.6 (s), 130.4 (d), 109.5 (s); m/z (ESI-APCI+) 179 [(MH
+ MeOH + 2)+, 36%], 177 [(MH + MeOH)+, 100].
4.3. Reactions of (dithiazolylidene)acetonitriles with HBr (g)
or HCl (g)
4.3.1. 3,4-Dichloroisothiazole-5-carbonitrile (8a): typical
procedure, Table 1, entry 11. A stirred solution of 2-chloro-2-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)acetonitrile (22) (212 mg,
ꢁ
1.00 mmol) in Et2O (10 mL) at ca. 20 C was purged with HCl
4.3.6. 3-Bromoisothiazole-5-carbonitrile (24b), Table 1,
entry 2. Similar treatment of (Z)-2-(4-chloro-5H-1,2,3-dithiazol-
5-ylidene)acetonitrile (19) (177 mg, 1.00 mmol) in THF (10 mL)
with HBr (g) gave the title compound 24b (183 mg, 97%) as
(g) for 30 s. The mixture was stirred until the starting material
was consumed (TLC). The reaction mixture was then adsor-
bed onto silica and chromatographed (n-hexane–DCM, 1 : 1)
to give the title compound 8a (115 mg, 64%) aꢁs colorless
ꢁ
ꢁ
colorless needles, mp (DSC) onset: 71.8 C, peak max: 72.8 C
(from n-pentane/0 ꢁC); Rf 0.59 (n-hexane–DCM, 1 : 1); (found: C,
25.46; H, 0.49; N, 14.94. C4HBrN2S requires C, 25.42; H, 0.53; N,
ꢁ
needles, mp (DSC) onset: 81.1 C, peak max: 81.8 C (from n-
pentane/0 ꢁC) (lref. 56, 83–84 ꢁC from cyclohexane); Rf 0.68 (n-
hexane–DCM, 1 : 1); nmax/cmꢀ1 2236m (C^N), 1495m, 1369m,
1348m, 1317s, 1298m, 1161m, 1126w, 1103w, 1059w, 1034w,
978w, 961m, 941w, 843m, 829m, 812s; dC (125 MHz; CDCl3)
149.8 (s), 131.0 (s), 130.9 (s), 108.2 (s); identical to an
authentic sample.
14.82%); lmax (DCM)/nm 236 (2.89), 245 (2.88), 278 (3.22); nmax
/
cmꢀ1 3109m (CH), 2230m (C^N), 1487s, 1358m, 1300s, 1252w,
1150m, 1119w, 1099w, 881s, 845s, 808s; dH (500 MHz; CDCl3)
7.61 (1H, s, H-4); dC (125 MHz; CDCl3) 137.7 (s), 135.6 (s), 133.9
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(d), 109.3 (s); m/z (EI) 190 (M+ + 2, 100%), 188 (M+, 87), 139 (14), 2234m (C^N), 1493w, 1485w, 1367w, 1358w, 1348w, 1335w,
137 (13), 109 (57), 83 (45), 82 (40), 70 (56), 63 (7), 58 (27), 51 (30). 1317s, 1302s, 1288m, 1157m, 978w, 961m, 939m, 918w, 914w,
4.3.7. Methyl
3-bromo-5-cyanoisothiazole-4-carboxylate 825m, 812m, 802m, 791m; dC (125 MHz; CDCl3) (8a): 149.8 (s),
(25b); Table 1, entry 13. Similar treatment of (Z)-methyl 2-(4- 131.0 (s), 130.9 (s), 108.2 (s); (8b): 141.8 (s), 133.4 (s), 121.8 (s),
chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetate (12) (235 108.9 (s); (27b): 139.3 (s), 134.0 (s), 130.4 (s), 108.0 (s);
mg, 1.00 mmol) in Et2O (10 mL) with HBr (g) gave the title (unknown): 152.0 (s), 133.8 (s), 118.2 (s), 109.0 (s); m/z (ESI-
compound 25b (193 mg, 78%) as colorless needles, mp (DSC) APCI+) 303 [8b, (MH + MeOH + 4)+, 6%], 301 [8b, (MH + MeOH +
onset: 80.2 ꢁC, peak max: 81.5 ꢁC (from n-pentane/0 ꢁC); Rf 0.45 2)+, 8], 299 [8b, (MH + MeOH)+, 5], 259 [27b, (MH + MeOH + 4)+,
(n-hexane–DCM, 1 : 1); (found: C, 29.30; H, 1.06; N, 10.98. 13], 257 [27b, (MH + MeOH + 2)+, 55], 255 [27b, (MH + MeOH)+,
C6H3BrN2O2S requires C, 29.17; H, 1.22; N, 11.34%); lmax 46], 215 [8a, (MH + MeOH + 4)+, 25], 213 [8a, (MH + MeOH + 2)+,
(DCM)/nm 232 inf (log 3 2.77), 243 (2.81), 290 (2.89); nmax/cmꢀ1 76], 211 [8a, (MH + MeOH)+, 100]. Further elution (n-hexane–
2955w, 2924w and 2855w (CH3), 2235m (C^N), 1732s (C]O), DCM, 7 : 3) gave 3-chloroisothiazole-5-carbonitrile (24a) (50 mg,
ꢁ
1499m, 1441m, 1370m, 1344s, 1292w, 1219s, 1198m, 1153m, 34%) as colorless needles mp (DSC) onset: 65.2 C, peak max:
1134s, 1009m, 993m, 925m, 854m, 810w, 781m, 773m; dH 66.3 ꢁC (from n-pentane/0 ꢁC); Rf 0.39 (n-hexane–DCM, 7 : 3); dH
(500 MHz; CDCl3) 4.03 (3H, s, OCH3); dC (125 MHz; CDCl3) 158.6 (500 MHz; CDCl3) 7.54 (1H, s, H-4); dC (125 MHz; CDCl3) 150.5
(s), 139.8 (s), 139.1 (s), 134.2 (s), 108.5 (s), 53.4 (q); m/z (EI) 248 (s), 135.6 (s), 130.4 (d), 109.5 (s); identical to that described
(M+ + 2, 29%), 246 (M+, 27), 217 (100), 215 (97), 189 (4), 167 (59), above.
139 (5), 110 (30), 82 (39), 70 (29), 59 (20).
4.3.8. Ethyl 3-bromo-5-cyanoisothiazole-4-carboxylate dithiazol-5-ylidene)acetonitrile (21) with HCl in THF; Table 1,
(26b); Table 1, entry 17. Similar treatment of (Z)-ethyl 2-(4- entry 8. Similar treatment of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-
chloro-5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetate (13) dithiazol-5-ylidene)acetonitrile (21) (254 mg, 1.00 mmol) in THF
4.3.11. Reaction
of
(Z)-2-bromo-2-(4-chloro-5H-1,2,3-
(249 mg, 1.00 mmol) in Et2O (10 mL) with HBr (g) gave the title (10 mL) with HCl (g) gave (by 13C NMR) an inseparable mixture
compound 26b (227 mg, 87%) as colorless needles, mp (DSC) of 3,4-dichloroisothiazole-5-carbonitrile (8a), 3,4-dibromoiso-
onset: 67.1 ꢁC, peak max: 68.1 ꢁC (from n-pentane/0 ꢁC); Rf 0.32 thiazole-5-carbonitrile (8b), 3-bromo-4-chloroisothiazole-5-car-
(n-hexane–DCM, 1 : 1); (found: C, 32.26; H, 1.89; N, 10.64. bonitrile (27b) and an unknown compound (20 mg) as a
C7H5BrN2O2S requires C, 32.20; H, 1.93; N, 10.73%); lmax colorless solid (8a : 8b : 27b : unknown ¼ 9 : 1 : 3 : 4 by 13C
(DCM)/nm 240 (log 3 3.07), 290 (3.13); nmax/cmꢀ1 2999w, 2978w NMR), mp 35–37 C; Rf 0.45 (n-hexane–DCM, 7 : 3); nmax/cmꢀ1
ꢁ
and 2936w (CH2 and CH3), 1728s (C]O), 1489s, 1467w, 1445w, 2234m (C^N), 1493w, 1485w, 1368w, 1348w, 1335w, 1317s,
1400w, 1381s, 1341s, 1290w, 1225s, 1159m, 1142w, 1022s, 980w, 1302s, 1288m, 1157m, 978w, 961m, 939m, 918w, 914w, 841m,
878m, 845w; dH (500 MHz; CDCl3) 4.50 (2H, q, J 7.2, OCH2), 1.46 825m, 812s, 804m, 791m; dC (125 MHz; CDCl3) (8a): 149.8 (s),
(3H, t, J 7.3, CH3); dC (125 MHz; CDCl3) 158.1 (s), 139.6 (s), 139.1 131.0 (s), 130.9 (s), 108.2 (s); (8b): 141.8 (s), 133.4 (s), 121.8 (s),
(s), 134.3 (s), 108.5 (s), 63.1 (t), 13.9 (q); m/z (EI) 262 (M+ + 2, 108.9 (s); (27b): 139.3 (s), 134.0 (s), 130.4 (s), 108.0 (s);
19%), 260 (M+, 20), 234 (84), 232 (76), 217 (96), 215 (100), 190 (unknown): 151.9 (s), 133.8 (s), 118.2 (s), 109.0 (s); m/z (ESI-
(13), 188 (13), 181 (25), 113 (9), 110 (33), 109 (25), 108 (24), 82 APCI+) 303 [8b, (MH + MeOH + 4)+, 6%], 301 [8b, (MH + MeOH +
(40), 77 (8), 70 (23).
2)+, 8], 299 [8b, (MH + MeOH)+, 5], 259 [27b, (MH + MeOH + 4)+,
4.3.9. Reaction of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-dithia- 27], 257 [27b, (MH + MeOH + 2)+, 65], 255 [27b, (MH + MeOH)+,
zol-5-ylidene)acetonitrile (21) with HBr in THF; Table 1, entry 6. 51%], 215 [8a, (MH + MeOH + 4)+, 18], 213 [8a, (MH + MeOH +
Similar treatment of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-dithiazol- 2)+, 47], 211 [8a, (MH + MeOH)+, 65]. Further elution (n-hexane–
5-ylidene)acetonitrile (21) (254 mg, 1.00 mmol) in THF (10 mL) DCM, 7 : 3) gave 3-chloroisothiazole-5-carbonitrile (24a) (98 mg,
ꢁ
with HBr (g) gave 3,4-dibromoisothiazole-5-carbonitrile (8b) 68%) as colorless needles mp (DSC) onset: 65.2 C, peak max:
(48 mg, 18%) as colorless needles, mp (DSC) onset: 105.2 ꢁC, 66.3 ꢁC (from n-pentane/0 ꢁC); Rf 0.39 (n-hexane–DCM, 7 : 3); dH
peak max: 106.1 ꢁC (from n-pentane/0 ꢁC); Rf 0.56 (n-hexane– (500 MHz; CDCl3) 7.54 (1H, s, H-4); dC (125 MHz; CDCl3) 150.5
DCM, 7 : 3), identical to that described above. Further elution (s), 135.6 (s), 130.4 (d), 109.5 (s); identical to that described
(n-hexane–DCM, 1 : 1) gave 3-bromoisothiazole-5-carbonitrile above.
(24b) (95 mg, 50%) as colorless needles, mp (DSC) onset: 71.8
ꢁC, peak max: 72.8 ꢁC (from n-pentane/0 ꢁC); Rf 0.59 (n-hexane– 5-ylidene)acetonitrile (22) with HBr in Et2O; Table 1, entry 9.
DCM, 1 : 1), identical to that described above. Similar treatment of 2-chloro-2-(4-chloro-5H-1,2,3-dithiazol-5-
4.3.10. Reaction of (Z)-2-bromo-2-(4-chloro-5H-1,2,3- ylidene)acetonitrile (22) (210 mg, 1.00 mmol) in Et2O (10 mL)
4.3.12. Reaction of 2-chloro-2-(4-chloro-5H-1,2,3-dithiazol-
dithiazol-5-ylidene)acetonitrile (21) with HCl in Et2O; Table 1, with HBr (g) gave an inseparable mixture of 3,4-dibromoiso-
entry 7. Similar treatment of (Z)-2-bromo-2-(4-chloro-5H-1,2,3- thiazole-5-carbonitrile (8b) and 3-bromo-4-chloroisothiazole-5-
dithiazol-5-ylidene)acetonitrile (21) (254 mg, 1.00 mmol) in Et2O carbonitrile (27b) (135 mg, 8b : 27b ¼ 1 : 3 by NMR); mp (DSC)
(10 mL) with HCl (g) gave (by 13C NMR) an inseparable mixture onset: 89.9 ꢁC, peak max: 92.5 ꢁC (from n-pentane/0 ꢁC); Rf 0.56
of 3,4-dichloroisothiazole-5-carbonitrile (8a), 3,4-dibromoiso- (n-hexane–DCM, 7 : 3); nmax/cmꢀ1 2232m (C^N), 1485m,
thiazole-5-carbonitrile (8b), 3-bromo-4-chloroisothiazole-5-car- 1356w, 1333w, 1298s, 1287s, 1155m, 1148m, 939s, 918m, 912m,
bonitrile (27b) and an unknown compound (11 mg) as a 835w, 824m, 791m, 783w; dC (125 MHz; CDCl3) major (27b):
colorless solid (8a : 8b : 27b : unknown ¼ 9 : 1 : 4 : 5 by 13C 139.3 (s), 134.0 (s), 130.4 (s), 108.0 (s), minor (8b): 141.7 (s), 133.4
NMR), mp 35–37 C; Rf 0.45 (n-hexane–DCM, 7 : 3); nmax/cmꢀ1 (s), 121.8 (s), 108.8 (s); m/z (GCMS-EI) major (27b): 226 (M+ + 4,
ꢁ
7744 | RSC Adv., 2014, 4, 7735–7748
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27%), 224 (M+ + 2, 100), 222 (M+, 70), 145 (10), 143 (28), 139 (13), starting material was consumed (5 min) and then quenched
137 (12), 119 (36), 117 (95), 108 (24), 82 (40), minor (8b): 270 (M+ with a sat. NaHCO3 (5 mL) and extracted with DCM (3 ꢂ 10 mL),
+ 4, 50%), 268 (M+ + 2, 100), 266 (M+, 49), 189 (12), 187 (11), 163 the organic layer was then dried (Na2SO4), ltered and evapo-
(37), 161 (42), 139 (12), 137 (13), 113 (26), 111 (27), 108 (28), 82 rated to give the title product 23 (42 mg, 90%) as colorless
(59).
needles, mp (DSC) onset: 195.9 ꢁC, peak max: 197.7 ꢁC (PhH); Rf
4.3.13. Reaction of 2-chloro-2-(4-chloro-5H-1,2,3-dithiazol- 0.48 (Et2O); dH (500 MHz; acetone-d6) 7.76 (2H, br s, NH2); dC
5-ylidene)acetonitrile (22) with HBr in THF; Table 1, entry 10. (125 MHz; acetone-d6) 171.4 (s), 158.3 (s), 140.0 (s), 113.0 (s),
Similar treatment of 2-chloro-2-(4-chloro-5H-1,2,3-dithiazol-5- 112.0 (s); identical to that described above.
ylidene)acetonitrile (22) (210 mg, 1.00 mmol) in THF (10 mL)
with HBr (g) gave an inseparable mixture of 3,4-dibromoiso-
4.5. Reactions of (dithiazolylidene)acetonitriles with
benzyltriethylammonium chloride
thiazole-5-carbonitrile (8b) and 3-bromo-4-chloroisothiazole-5-
carbonitrile (27b) (123 mg, 8b : 27b ¼ 1 : 9 by 13C NMR); as a
colorless solid; mp 88–89 ꢁC; Rf 0.56 (n-hexane–DCM, 7 : 3);
4.5.1. Reaction of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-dithia-
nmax/cmꢀ1 2234s (C^N), 1485w, 1358w, 1333w, 1298s, 1287m, zol-5-ylidene)acetonitrile (21) with benzyltriethylammonium
1155m, 939s, 914w, 835w, 824m, 791m; dC (125 MHz; CDCl3) chloride; Table 2, entry 2 (typical procedure). To a stirred
major (27b): 139.3 (s), 134.0 (s), 130.4 (s), 108.0 (s), minor (8b): solution of (Z)-2-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
141.8 (s), 133.4 (s), 121.8 (s), 108.8 (s); m/z (ESI-APCI+) 303 [8b, acetonitrile (21) (127 mg, 0.500 mmol) in dry benzene (5 mL) at
(MH + MeOH + 4)+, 9%], 301 [8b, (MH + MeOH + 2)+, 12], 299 ca. 20 ꢁC was added BnEt3NCl (11 mg, 0.050 mmol) and the
[8b, (MH + MeOH)+, 10], 259 [27b, (MH + MeOH + 4)+, 33], 257 mixture heated to reux until the starting material was
[27b, (MH + MeOH + 2)+, 100], 255 [27b, (MH + MeOH)+, 72]. consumed (TLC). The reaction mixture was then cooled to ca.
Further elution (n-hexane–DCM, 1 : 1) gave 3-bromoisothiazole- 20 ꢁC, adsorbed onto silica and chromatographed (n-hexane–
5-carbonitrile (24b) (29 mg, 15%) as colorless needles, mp (DSC) DCM, 1 : 1) to give an inseparable mixture of tentatively
onset: 71.8 ꢁC, peak max: 72.8 ꢁC (from n-pentane/0 ꢁC); Rf 0.59 3,4-dichloroisothiazole-5-carbonitrile (8a) and 3-bromo-4-
(n-hexane–DCM, 1 : 1); identical to that described above.
chloroisothiazole-5-carbonitrile (27b) (56 mg, 8a : 27b ¼ 1 : 3 by
NMR) as a colorless solid, mp 80–82 ꢁC; Rf 0.56 (n-hexane–DCM,
7 : 3); nmax/cmꢀ1 2234m (C^N), 1487w, 1368w, 1358w, 1348w,
1333w, 1319m, 1300s, 1288m, 1155m, 961m, 939m, 916w,
824m, 814m, 791m; dC (125 MHz; CDCl3) major (27b): 139.3 (s),
(23); 133.9 (s), 130.4 (s), 108.0 (s), minor (8a): 149.7 (s), 130.90 (s),
4.4. Preparation of 3-bromo-4-cyanoisothiazole-5-
carboxamide (23)
4.4.1. 3-Bromo-4-cyanoisothiazole-5-carboxamide
method 1: reaction of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene) 130.86 (s), 108.2 (s); m/z (ESI-APCI+) 259 [27b, (MH + MeOH +
malononitrile (11) with HBr in wet toluene. A stirred solution of 4)+, 31%], 257 [27b, (MH + MeOH + 2)+, 100], 255 [27b, (MH +
2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile
(202 mg, 1.00 mmol) in wet toluene (6 mL) at ca. 20 ꢁC was + MeOH + 2)+, 45], 211 [8a, (MH + MeOH)+, 50].
(11) MeOH)+, 75], 215 [8a, (MH + MeOH + 4)+, 13], 213 [8a, (MH
purged with HBr (g) for 30 s. The mixture was stirred until the
4.5.2. 3,4-Dichloroisothiazole-5-carbonitrile (8a); Table 2,
starting material was consumed (TLC). The reaction mixture entry 3. Similar treatment of 2-chloro-2-(4-chloro-5H-1,2,3-
was then adsorbed onto silica and chromatographed (n-hexane– dithiazol-5-ylidene)acetonitrile (22) (106 mg, 0.500 mmol) in
DCM, 1 : 1) to give 3-bromoisothiazole-4,5-dicarbo-nitrile (9b) benzene (5 mL) with BnEt3NCl (11 mg, 0.050 mmol) on chro-
(83 mg, 39%), mp (DSC) onset: 138.6 ꢁC, peak max: 139.6 ꢁC matography (n-hexane–DCM, 1 : 1) gave the title compound 8a
(from cyclohexane, ref. 40b, 141 ꢁC); Rf 0.43 (n-hexane–DCM, (57 mg, 63%) as colorless needles, mp (DSC) onset: 81.1 ꢁC, peak
1 : 1); identical to that described above. Further elution (Et2O) max: 81.8 ꢁC (from n-pentane/0 ꢁC) (ref. 56, 83–84 ꢁC from
gave the title compound 23 (82 mg, 35%) as colorless needles, mp cyclohexane); Rf 0.68 (n-hexane–DCM, 1 : 1); dC (125 MHz;
(DSC) onset: 195.9 ꢁC, peak max: 197.7 ꢁC (PhH); Rf 0.48 (Et2O); CDCl3) 149.8 (s), 131.0 (s), 130.9 (s), 108.2 (s); identical to that
(found: C, 25.43; H, 0.82; N, 18.04. C5H2BrN3OS requires C, reported above.
25.88; H, 0.87; N, 18.11%); lmax (DCM)/nm 241 (log 3 2.70), 288
4.5.3. Ethyl
3-chloro-5-cyanoisothiazole-4-carboxylate
(2.56); nmax/cmꢀ1 3350br w, 3319m, 3262m and 3196m (NH), (26a); Table 2, entry 5. Similar treatment of (Z)-ethyl 2-(4-chloro-
2255m (C^N), 1692s, 1626m, 1516m, 1399m, 1379m, 1327s, 5H-1,2,3-dithiazol-5-ylidene)-2-cyanoacetate (13) (124 mg,
1300m, 1124m, 1113m, 1005w, 847m, 794m, 774m; dH (500 0.500 mmol) in benzene (5 mL) with BnEt3NCl (11 mg, 0.050
MHz; acetone-d6) 7.76 (2H, br s, NH2); dC (125 MHz; acetone-d6) mmol) on chromatography (n-hexane–DCM, 1 : 1) gave the title
171.4 (s), 158.3 (s), 140.0 (s), 113.0 (s), 112.0 (s); m/z (EI) 233 (M+ compound 26a (73 mg, 67%) as colorless needles, mp (DSC)
+ 2, 35%), 231 (M+, 34), 217 (41), 215 (42), 152 (100), 139 (5), 137 onset: 60.9 ꢁC, peak max: 63.6 ꢁC (from n-pentane/0 ꢁC); Rf 0.55
(5), 109 (34), 108 (34), 82 (64), 56 (7), 51 (17).
(n-hexane–DCM, 1 : 1); (found: C, 38.75; H, 2.29; N, 12.96.
4.4.2. 3-Bromo-4-cyanoisothiazole-5-carboxamide
(23); C7H5ClN2O2S requires C, 38.81; H, 2.33; N, 12.93%); lmax
method 2: alkali hydration.52c of 3-bromoisothiazole-4,5-dicar- (DCM)/nm 242 (log 3 2.57), 287 (2.68); nmax/cmꢀ1 3001w, 2980w
bonitrile (9b) A stirred solution of 1 M NaOH (0.22 mL, 0.22 and 2963w (CH2 and CH3), 2237w (C^N), 1730s (C]O), 1493s,
mmol) in dioxane (0.22 mL), cooled to ca. 0 ꢁC was added 1466w, 1445w, 1404m, 1383s, 1348m, 1227s, 1211m, 1165m,
3-bromoisothiazole-4,5-dicarbonitrile (9b) (43 mg, 0.20 mmol). 1150m, 1115m, 1024s, 989m, 887m, 852w, 839w, 796m, 783s; dH
The reaction mixture was stirred at this temperature until the (500 MHz; CDCl3) 4.48 (2H, q, J 7.2, CH2), 1.45 (3H, t, J 7.1, CH3);
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dC (125 MHz; CDCl3) 157.9 (s), 151.2 (s), 140.0 (s), 131.9 (s), 108.7 following organisations and companies in Cyprus for generous
(s, C^N), 63.0 (t), 13.85 (q); m/z (ESI-APCI+) 218.8 [(MH + 2)+, donations of chemicals and glassware: the State General Labo-
31%], 216.8 (MH+, 100).
ratory, the Agricultural Research Institute, the Ministry of
4.5.4. 3-Chloroisothiazole-4,5-dicarbonitrile (9a); Table 2, Agriculture, MedoChemie Ltd, Medisell Ltd and Biotronics Ltd.
entry 6. Similar treatment of 2-(4-chloro-5H-1,2,3-dithiazol-5- Finally, we thank the A. G. Leventis Foundation for helping to
ylidene)malononitrile (11) (101 mg, 0.500 mmol) in benzene (5 establish the NMR facility in the University of Cyprus.
mL) with BnEt3NCl (11 mg, 0.050 mmol) on chromatography
(n-hexane–DCM, 1 : 1) gave the title compound 9a (85 mg,
References
100%) as colorless needles, mp (DSC) onset: 96.9 ꢁC, peak max:
ꢁ
ꢁ
98.5 C (from cyclohexane, ref. 40a, 98 C); Rf 0.43 (n-hexane–
DCM, 1 : 1); dC (125 MHz; CDCl3) 151.8 (s), 142.5 (s), 115.9 (s),
108.4 (s), 106.9 (s); identical to that reported above.
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Data were collected on an Oxford-Diffraction Supernova
diffractometer, equipped with a CCD area detector utilizing Mo-
˚
Ka radiation (l ¼ 0.71073 A). A suitable crystal was attached to
glass bers using paratone-N oil and transferred to a goniostat
where they were cooled for data collection. Unit cell dimensions
were determined and rened by using 6074 (3.02 # q # 28.90ꢁ)
reections. Empirical absorption corrections (multi-scan based
on symmetry-related measurements) were applied using Cry-
sAlis RED soware.57 The structure was solved by direct
methods using SIR92 (ref. 58) and rened on F2 using full-
matrix least squares using SHELXL97.59 Soware packages
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geometric calculations,60 and DIAMOND61 for molecular
graphics. The non-H atoms were treated anisotropically. The
hydrogen atom attached to C3 was located on a difference
Fourier map.
Crystal renement data for compound 19:† C4HClN2S2, M ¼
176.64, monoclinic, space group P21/c, a ¼ 8.1226(8), b ¼
3
ꢁ
˚
˚
11.280(3), c ¼ 8.138(2) A, b ¼ 108.04(2) , V ¼ 656.1(2) A , Z ¼ 4, T
¼ 100(2) K, rcalcd ¼ 1.788 g cmꢀ3, 2qmax ¼ 50. Renement of 86
parameters on 905 independent reections out of 2781
measured reections (Rint ¼ 0.0291) led to R1 ¼ 0.0527 (I > 2s(I)),
wR2 ¼ 0.1555 (all data), and S ¼ 1.045 with the largest difference
peak and hole of 0.706 and ꢀ0.803 eꢀ3, respectively.
Crystal renement data for compound 21:† C4BrClN2S2, M ¼
255.55, orthorhombic, space group Pnma, a ¼ 7.517(2), b ¼
3
˚
˚
6.7318(7), c ¼ 13.599(2) A, V ¼ 743.6(2) A , Z ¼ 4, T ¼ 100(2) K,
rcalcd ¼ 2.283 g cmꢀ3, 2qmax ¼ 50. Renement of 61 parameters
on 588 independent reections out of 2841 measured reec-
tions (Rint ¼ 0.0333) led to R1 ¼ 0.0274 (I > 2s(I)), wR2 ¼ 0.0715
(all data), and S ¼ 0.950 with the largest difference peak and
hole of 0.701 and ꢀ0.652 eꢀ3, respectively.
Acknowledgements
The authors wish to thank Dr Constantina P. Kapnissi-Chris-
todoulou and Mr Ioannis J. Stavrou for ESI-APCI+ mass spectra
(Grant no. YGEIA/0506/19) and Professor Tomas Torroba
(University of Burgos, Spain) for GC-MS mass spectra. Further-
more, the authors thank the Cyprus Research Promotion
Foundation [Grant no. PENEK/ENISX/0308/83] and the
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