Reinvestigating the reaction of 1H-pyrazol-5-amines with 4,5-dichloro-1,2,3-dithiazolium chloride: A route to pyrazolo[3,4-c]isothiazoles and pyrazolo[3,4-d]thiazoles

Article abstract of DOI:10.1021/jo500509e

The reaction of Appel salt 1 with 1H-pyrazol-5-amines 2 gives main products N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 3, and 6H-pyrazolo[3,4-c]isothiazole-3-carbonitriles 5, together with several minor side products. When the pyrazoles are N-1 methylated, the product ratio 3:5 can be modified by adjusting the pH of the reaction medium: acidic conditions favor formation of the dithiazolylidenes 3, while basic conditions favor formation of pyrazolo[3,4-c]isothiazoles 5. Furthermore, thermolysis of N-(4-chloro-5H-1,2,3- dithiazol-5-ylidene)-1H-pyrazol-5-amines 3 gives 1H-pyrazolo[3,4-d]thiazole-5- carbonitriles 4. Single crystal X-ray crystallography supports the structure of 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5a) and helps resolve a previous incorrect structural assignment of 1H-pyrazolo[3,4-d]thiazole-5- carbonitriles 4.

Full text of DOI:10.1021/jo500509e

Article
pubs.acs.org/joc
Reinvestigating the Reaction of 1H‑Pyrazol-5-amines with 4,5-
Dichloro-1,2,3-dithiazolium Chloride: A Route to
Pyrazolo[3,4‑c]isothiazoles and Pyrazolo[3,4‑d]thiazoles†
Maria Koyioni, Maria Manoli, Manos J. Manolis, and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
S
* Supporting Information
ABSTRACT: The reaction of Appel salt 1 with 1H-pyrazol-5-amines
2 gives main products N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-
pyrazol-5-amines 3, and 6H-pyrazolo[3,4-c]isothiazole-3-carbonitriles
5, together with several minor side products. When the pyrazoles are
N-1 methylated, the product ratio 3:5 can be modified by adjusting
the pH of the reaction medium: acidic conditions favor formation of
the dithiazolylidenes 3, while basic conditions favor formation of
pyrazolo[3,4-c]isothiazoles 5. Furthermore, thermolysis of N-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 3 gives
1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 4. Single crystal X-ray
crystallography supports the structure of 4,6-dimethyl-6H-pyrazolo-
[3,4-c]isothiazole-3-carbonitrile (5a) and helps resolve a previous
incorrect structural assignment of 1H-pyrazolo[3,4-d]thiazole-5-
carbonitriles 4.
1. INTRODUCTION
Monocylic and benzo-fused thiazoles are important com-
pounds, and their synthesis, chemistry, and applications have
been extensively reviewed.1 Less well studied are azole-
condensed thiazoles;2 nevertheless, several analogues show
diverse bioactivity, while others are useful in the material
sciences. For example, 4H-pyrrolo[2,3-d]thiazoles, 4H-pyrrolo-
[3,2-d]thiazoles, 1H-pyrazolo[3,4-d]thiazoles, and 1H-pyrazolo-
[4,3-d]thiazoles can modulate or inhibit various protein kinases,
which are important in cancer therapy.3 Furthermore, azole-
fused thiazoles can influence the progress of neurological
diseases such as schizophrenia or Alzheimer’s disease: 4H-
Pyrrolo[2,3-d]thiazoles and 4H-pyrrolo[3,2-d]thiazoles can
inhibit D-amino acid oxidase,4 while 1H-pyrazolo[3,4-d]-
thiazoles and 1H-pyrazolo[4,3-d]thiazoles can modulate the
mGluR4 receptor activity (Figure 1).5 4H-Pyrrolo[2,3-d]-
thiazoles and 4H-pyrrolo[3,2-d]thiazoles can also act as anti-
inflammatory agents (e.g., as cannabinoid hCB2 receptor
agonists)6a and as inhibitors of MCP-1,6b or show antiallergic
Figure 1. Representative structures of some biologically active azole-
fused thiazoles.
activity (e.g., as modulators of CRTH2) (Figure 1).7
In the material sciences, thiazolo[5,4-d]thiazoles have been
incorporated into donor/acceptor polymers or oligomers for
use in organic semiconductors8 and are components of silver
halide photographic materials.9 Despite their broad applications
and unlike the 6−5 fused thiazoloheteroarenes,1e−g,10 the
synthesis of condensed 5−5 thiazoles via construction of the
thiazole ring has not been extensively explored.2
route to benzothiazole-2-carbonitriles, discovered and devel-
oped by Rees,11 involves thermolysis of N-(dithiazolylidene)-
anilines.12 Recently, an addition of the nucleophile, ring-
opening, and ring closure (ANRORC)13 mediated ring
transformation of N-(dithiazolylidene)heteroazinamines14 pro-
Many syntheses for benzothiazoles, the most common 6−5
fused thiazole, focus on the preparation of the thiazole
ring,1a,b,d−g and a mechanistically interesting and efficient
Received: March 3, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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vided an efficient route to heteroazine-fused thiazole-2-
carbonitriles.15 Interestingly, while several N-(dithiazolylidene)-
heterolamines are known,16 only one report of their trans-
Scheme 2. Reactions of Enamines 6 and 7 with Appel Salt 1
To Give Isothiazole-5-carbonitriles 8 and 9, Respectively
formation into fused 5−5 thiazoles exists: L’abbe
́
et al.17
claimed the reaction of 4,5-dichloro-1,2,3-dithiazolium chloride
(1) (Appel salt)12 with 1H-pyrazol-5-amines 2 gave 1H-
pyrazolo[3,4-d]thiazole-5-carbonitriles 4 via the in situ
formation of the N-(dithiazolylidene)pyrazolamines 3
(Scheme 1).
Scheme 1. Reaction of Appel Salt 1 with 1,3-Disubstituted
1H-Pyrazol-5-amines 2 To Give 1H-Pyrazolo[3,4-d]thiazoles
4 (R1, R2 = Me, Ph)17
to a stirred suspension of Appel salt 1 (1.0 g, 1 equiv) in DCM
(20 mL) under argon at ca. 20 °C followed by stirring for 1 h
was reported to give 1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-
5-carbonitrile (4a) in 81% yield.17 In our hands, however, the
reaction gave a complex mixture from which we isolated five
products: 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbon-
itrile (5a), N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1,3-di-
methyl-1H-pyrazol-5-amine (3a), 5-amino-1,3-dimethyl-1H-
pyrazole-4-carbothioyl cyanide (10), (3Z,3′Z)-N′,N″-
trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-
carbimidoyl chloride) (11), and (Z)-N-{[(Z)-1-(5-amino-1,3-
dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)amino]vinyl]disulfanyl}-4,6-dimethyl-6H-
pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride (12) in 12, 5,
4, 12, and 13% yields, respectively (Scheme 3).
While the structure assignment for 1H-pyrazolo[3,4-d]-
thiazoles 4 was presumably influenced by the known trans-
formation of N-(dithiazolylidene)anilines into benzothiazoles,11
we considered the spectral data provided to be inconclusive. In
addition, the typical ring transformation of N-
(dithiazolylidene)anilines into thiazoles requires thermolytic
temperatures, and to the best of our knowledge, there are no
reports of room temperature transformations. As such, the
reported in situ transformation to give 1H-pyrazolo[3,4-
d]thiazoles 4 was unique.
4,6-Dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile
(5a) was isolated as colorless needles, mp 102−106 °C (from c-
hexane). Microanalysis and mass spectrometry supported the
formula C7H6N4S. The NMR and IR spectroscopic data
matched that reported for the isomeric 1,3-dimethyl-1H-
pyrazolo[3,4-d]thiazole-5-carbonitrile (4a);17 however, single
crystal X-ray diffraction studies (Supporting Information,
Figure S1) identified the structure to be the fused isothiazole
5a and not the fused thiazole 4a as previously reported.
The N-(dithiazolylidene)pyrazolamine 3a was obtained as
yellow prisms, mp 154−156 °C (from c-hexane), and was stable
at room temperature; no decomposition was observed during a
hot recrystallization. Differential scanning calorimetry (DSC) of
N-(dithiazolylidene)pyrazolamine 3a gave a decomposition
with an onset point at 158.2 °C, and its thermolysis on a
quantitative scale (0.1 mmol) under argon atmosphere at ca.
170 °C gave S8 (78%), traces (by TLC) of an unidentified side
product, and 1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-5-car-
bonitrile (4a) (77%) (see Table 2, entry 1). The spectroscopic
data collected for pyrazolo[3,4-d]thiazole-5-carbonitrile 4a
prepared in this manner differed significantly from that
reported in the literature.17 With the single crystal X-ray
diffraction study of the above fused isothiazole 5a, we therefore
concluded that the earlier structural assignment for the fused
thiazole 4a was incorrect.
Furthermore, 1H-pyrazol-5-amines 2 are ambident nucleo-
philes,18 which can react with electrophiles via the C-4 ring
carbon (enaminic attack) as well as via the exocyclic amino
group (normal attack). As such, we hypothesized that 6H-
pyrazolo[3,4-c]isothiazoles 5 may have been formed as well as,
or instead of, the proposed 1H-pyrazolo[3,4-d]thiazoles 4.
These two bicyclic hetarenes would have similar spectroscopic
properties, making a conclusive assignment difficult.
Reactions reported by Rees19 and Kim,20 in which primary
enamines such as methyl 3-aminocrotonate (6) and 6-amino-
1,3-dialkyluracils 7 react with Appel salt 1 to give 5-cyano-3-
methylisothiazole-4-carboxylate 8 and 5,7-dialkyl-4,6-dioxo-
4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitriles
9, respectively (Scheme 2), support our hypothesis.
Herein, we describe our reinvestigation of the reaction of
Appel salt 1 with 1H-pyrazol-5-amines 2, which gives 6H-
pyrazolo[3,4-c]isothiazoles 5, previously misassigned as 1H-
pyrazolo[3,4-d]thiazoles 4,17 and N-(dithiazolylidene)-
pyrazolamines 3, which on thermolysis give 1H-pyrazolo[3,4-
d]thiazoles 4.
5-Amino-1,3-dimethyl-1H-pyrazole-4-carbothioyl cyanide
(10) was obtained as orange plates, mp 212−213 °C (from
CHCl3). Microanalysis and mass spectrometry supported the
formula C7H8N4S. The 1H NMR spectrum showed the
presence of two methyl groups, the absence of the pyrazole
H-4 resonance, and the presence of a D2O exchangeable NH2
resonance at δH 7.23 ppm, which was further supported by IR
spectroscopy ν(N−H) 3339 cm−1. In addition to the two Me
2. RESULTS AND DISCUSSION
2.1. Reaction of Appel Salt 1 with 1H-Pyrazol-5-
amines 2. Adding a solution of 1,3-dimethyl-1H-pyrazol-5-
amine (2a) (1 equiv) and lutidine (2 equiv) in DCM (20 mL)
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Scheme 3. Reaction of Appel Salt 1 with 1,3-Dimethyl-1H-pyrazol-5-amine (2a)
resonances, the 13C NMR data showed the presence of five
Scheme 4. Behavior of Trisulfide 11 and Disulfide 12 under
quaternary carbon resonances, one of which fitted for a nitrile
at δC 116.2 ppm, as supported also by the FTIR stretching
frequency at ν(CN) 2226 cm−1. The structural assignment of
compound 10 is tentative.
Thermal or Acidic Conditions
(3Z,3′Z)-N′,N″-3-Trisulfanediylbis(4,6-dimethyl-6H-
pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride) (11) was
obtained as yellow needles, mp 201−208 °C (from DCE).
Microanalysis and mass spectrometry tentatively supported the
formula C14H12Cl2N8S5, which fitted for two molecules of
either fused pyrazoles 4a or 5a and S3Cl2. Interestingly, FTIR
spectroscopy showed an absence of amino or cyano stretching
frequencies. 1H and 13C NMR spectroscopy also supported the
presence of four high-field quaternary signals corresponding to
at least two dimethylpyrazoles. The absence of the H-4 pyrazole
1
resonance in the H NMR suggested the pyrazoles units have
undergone substitution at the C-4 position; this was also
supported by the 13C NMR data. No resonances were visible in
either of the 13C NMR data that corresponded to the presence
of sp-hybridized carbons, further supporting the absence of
nitrile groups. On the basis of the above data, we suspected that
a symmetrical trisulfur dichloride adduct of either fused
pyrazole 4a or 5a had formed.
The data from these studies confirmed that the side products
were composed of pyrazolo[2,3-c]isothiazoles or their possible
intermediates. To resolve their structures conclusively, single
crystals of both side products 11 and 12 were grown, and the
structures were solved by single crystal X-ray crystallography
(Supporting Information, Figures S2 and S3, respectively).
2.2. Optimization of the Reaction. Having identified the
major products from the reaction of 1,3-dimethyl-1H-pyrazol-5-
amine (2a) with Appel salt 1, we investigated the influence of
time and mode of reagent addition on the reaction. As shown
above (section 2.1.), when a solution of pyrazol-5-amine 2a in
DCM was mixed with lutidine before the addition of Appel salt
1 and then stirred for 1−3 h, the reaction mixture was complex.
Nevertheless, allowing the reaction to stir for longer (6−15 h)
provided a significantly simpler reaction mixture (by TLC), and
only 6H-pyrazolo[3,4-c]isothiazole 5a could be isolated,
although in a moderate 52% yield (Scheme 5, Conditions A).
Alternatively, if the pyrazol-5-amine 2a was left stirring with
Appel salt 1 for 12 h before the addition of base, then N-
(dithiazolylidene)pyrazolamine 3a was isolated as the major
product in 44% yield, together with a small quantity of
pyrazoloisothiazole 5a (14%). This result alerted us to the
effect the amine base had on the yield of the N-(dithiazol-
ylidene)pyrazolamine 3a. Because pyrazol-5-amine 2a itself can
act as a base (e.g., 1-methyl-1H-pyrazol-5-amine has a pKa of
9.77),21 we carried out the reaction under nonbasic conditions
by preparing the HCl salt of the pyrazolamine: adding Appel
salt 1 to a suspension of pyrazolamine hydrochloride 2a·HCl in
(Z)-N-{[(Z)-1-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-
chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]-
vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-
carbimidoyl chloride (12) was obtained as red needles, mp
143−145 °C (from n-pentane/DCM). Microanalysis and mass
spectrometry tentatively supported the formula C16H14Cl3N9S5.
FTIR spectroscopy showed the presence of amino stretching
frequencies v(N−H) 3327w and 3196w cm−1, which was also
1
supported by a broad signal in the H NMR spectrum at δH
3.77 ppm that integrated for two hydrogens and was D2O
exchangeable. The 1H and 13C NMR spectra also indicated the
presence of four methyl groups, suggesting the presence of at
least two dimethylpyrazole units.
On the basis of the above spectroscopic data, we were unable
to confidently assign structures for side products 11 and 12. As
such, we attempted to elucidate further information on these
products by investigating their stability toward heat or acid:
heating pure samples of side products 11 and 12 gave 6H-
pyrazolo[3,4-c]isothiazole 5a (89 and 48%, respectively), while
treating them with concd H2SO4 at ca. 20 °C gave carboxamide
13 (99 and 34%, respectively), dehydration of which using
POCl3 gave carbonitrile 5a in 98% (Scheme 4).
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(dithiazolylidene)pyrazolamines 3d and 3f (73 and 55%,
respectively) (Table 1, entries 4 and 6, condition B).
Unexpectedly, under conditions B, 1-benzyl-3-methyl-1H-
pyrazol-5-amine (2e) reacted with Appel salt 1 to give
pyrazolo[3,4-c]isothiazole 5e (26%) as a major product and
the desired N-(dithiazolylidene)pyrazolamine 3e in only trace
amounts. 1-Benzyl-N-(dithiazolylidene)pyrazolamine 3e was
formed in somewhat higher yield (17%) when the free base of
1-benzyl-3-methyl-1H-pyrazol-5-amine (2e) was used (Table 1,
entry 5, conditions B). Reaction of Appel salt 1 with 1-(tert-
butyl)-3-methyl- and 1-(tert-butyl)-3-phenyl-1H-pyrazol-5-
amines 2g and 2h using either conditions A or B gave only
the 6-(tert-butyl)-4-methyl- and 6-(tert-butyl)-4-phenyl-6H-
pyrazolo[3,4-c]isothiazole-3-carbonitriles 5g and 5h, respec-
tively, and none of the corresponding 1-(tert-butyl)-N-
(dithiazolylidene)pyrazolamines (Table 1, entry 7 and 8).
Presumably, the bulky tert-butyl group at N-1 shielded the
neighboring C-5 amine, promoting attack at the enaminic C-4
position. For 1-phenyl-1H-pyrazol-5-amines 2i and 2j, using
both sets of reaction conditions, the reaction mixtures were
more complex, and the products 3i, 3j, 5i, and 5j were obtained
in low to moderate yields (Table 1, entries 9 and 10).
Scheme 5. Reaction of Appel Salt 1 with Pyrazol-5-amine 2a
under Basic and Acidic Conditions
DCM or to a solution of pyrazolamine 2a in DCM purged with
HCl (g) led to the formation of N-(dithiazolylidene)-
pyrazolamine 3a in 68 and 69% yields, respectively (Scheme
5, Conditions B).
With these partially optimized conditions in hand, we
screened the reaction of Appel salt 1 with a series of pyrazol-5-
amines 2a−i (Table 1). With 1-unsubstituted 1H-pyrazol-
2.3. Mechanistic Rationale. The formation of N-
(dithiazolylidene)pyrazolamine 3 was a result of the expected
normal attack of the exocyclic primary amine at the highly
electrophilic C-5 position of Appel salt 1. The formation of 6H-
pyrazolo[3,4-c]isothiazole 5, however, can result from the
ambident activity of 1H-pyrazol-5-amines 2, for example, their
ability to also react via the C-4 position (enaminic attack)
(Scheme 6).
Table 1. Reaction of Appel Salt 1 with Pyrazol-5-amines 2 (1
equiv) in DCM at ca. 20 °C
Scheme 6. Proposed Reaction Mechanism for the Formation
of 6H-Pyrazolo[3,4-c]isothiazoles 5
yields (%)
a
b
entry
R1
R2
Conditions A
Conditions B
1
2
Me
H
Me
Me
Ph
5a (51)
5b (4)
3a (0)
3b (65)
3c (58)
3d (0)
3e (0)
3f (0)
3g (0)
3h (0)
3i (0)
5a (1)
5b (0)
5c (0)
5d (5)
5e (29)
5f (9)
3a (70)
3b (74)
3c (92)
3d (73)
3
H
5c (7)
4
Me
Bn
Bn
tBu
tBu
Ph
Ph
Ph
5d (45)
5e (47)
5f (41)
5g (39)
5h (38)
5i (36)
5j (34)
c
c
5
Me
Ph
3e (17)
3f (55)
3g (0)
3h (0)
3i (22)
3j (9)
6
7
Me
Ph
5g (21)
5h (37)
5i (6)
8
9
Me
Ph
10
3j (0)
5j (19)
a
Conditions A: (i) DCM, lutidine (2 equiv), ca. 20 °C, 15 h.
b
Conditions B: (i) DCM, HCI (g), ca. 20 °C, 12 h; (ii) lutidine (2
c
equiv), ca. 20 °C, 3 h. No HCI (g) was used.
amines 2b and 2c, regardless of which conditions were used,
the major products were N-(dithiazolylidene)pyrazolamines 3b
and 3c, while isothiazoles 5b and 5c were observed in very low
yields (Table 1, entries 2 and 3). The reactions of Appel salt 1
with 1-methyl-3-phenyl-1H-pyrazol-5-amine (2d) and 1-benzyl-
3-phenyl-1H-pyrazol-5-amine (2f) were similar to the reactions
with 1,3-dimethyl-1H-pyrazol-5-amine (2a) described above;
that is, under basic conditions, the major products were 6H-
pyrazolo[3,4-c]isothiazoles 5d and 5f (45 and 41%, respec-
tively) (Table 1, entries 4 and 6, conditions A), while under
acidic conditions, the major products were N-
While the proposed ylidene 15 was not observed in the
reaction mixture, similar intermediates have been invoked for
the reaction of Appel salt 1 with the primary enamines (E)-
methyl 3-aminobut-2-enoate 619 and 6-amino-1,3-dialkyluracils
7 (Scheme 2).20 The exocyclic imine of intermediate 15
assisted by the pyrazole N-1 ring nitrogen can cyclize onto the
dithiazole S-1 atom, leading to the formation of the isothiazole
with concomitant cleavage of the dithiazole that gives N-
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mercaptocarbimidoyl chloride intermediate 16. From this
intermediate, the dithiazole S-2 sulfur atom can extrude as S8
via a bimolecular sulfur chain extension process,22 and the
isolation of trisulfide 11 tentatively supports this. Interestingly,
chloride-mediated thiophilic ring-opening of the proposed
dithiazolium intermediate 14 can lead to isomeric sulfenyl
chloride 17 that can lose sulfur dichloride to afford carbothioyl
cyanide 10 (Scheme 7). The isolation of carbothioyl cyanide 10
adds tentative support for the above mechanistic rationale.
is the pH of the reaction medium. Under basic conditions
(conditions A), reaction at the C-4 pyrazole carbon (enaminic
attack) was favored, while under acidic conditions (conditions
B), the expected direct (normal) attack of the pyrazole exocylic
primary amine was observed. This could be explained in terms
of the initial protonation of 5-aminopyrazoles that occurs on
the ring nitrogens,21 thus reducing the electron density of the
pyrazole ring and deactivating enaminic-like behavior. The
results become more complex, however, when the N-1
substituent is changed. In the case of bulky tert-butyl groups
at N-1 (e.g., pyrazol-5-amines 2g and 2h), only the formation
of isothiazole is observed in reasonable quantities. The
reactions of 1-phenylpyrazolamines 2i and 2j were also
complex, affording the desired products in only low to
moderate yields. Presumably, this was owed to a combination
of both steric and electronic effects; the N-1 phenyl group was
both considerably more bulky and inductively less electron
releasing than the methyl group, simultaneously shielding the 5-
amino group and deactivating enaminic C-4 position from
reaction with the Appel salt 1. Lastly, 1-unsubstituted
pyrazolamines 2b and 2c, regardless the reaction conditions,
reacted mainly via the exocyclic amino group, possibly owing to
the 1H-pyrazol-3-amine prototautomeric form being more
favorable than the 1H-pyrazol-5-amine form.24
2.4. Synthesis of 1H-Pyrazolo[3,4-d]thiazole-5-car-
bonitriles 4 via Thermolysis of N-(Dithiazolylidene)-
pyrazolamines 3. With a series of N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-1H-pyrazol-5-amines 3 in hand, we then
investigated their thermal behavior. Using differential scanning
calorimetry (DSC), we determined the thermal decomposition
points of each compound. Then, neat samples (0.1 mmol) were
thermolyzed at temperatures slightly above their decomposition
onset points under an argon atmosphere (Table 2).
In general, thermolysis of 1,3-disubstituted N-
(dithiazolylidene)pyrazolamines 3 gave the desired 1H-
pyrazolo[3,4-d]thiazole-5-carbonitriles 4, in 69−85% yields
(Table 2, entries 1 and 4−8). The reactions were accompanied
by the formation of elemental sulfur (S8), traces of unreacted
N-(dithiazolylidene)pyrazolamines 3, and, in some cases, minor
unidentified side products, which could be avoided by raising
the thermolysis temperature. In the case of the 1-unsubstituted
analogues N-(dithiazolylidene)pyrazolamines 3b and 3c,
thermolysis gave mainly S8 and intractable black solids (Table
2, entries 2 and 3).
Scheme 7. Possible Route to 5-Amino-1,3-dimethyl-1H-
pyrazole-4-carbothioyl Cyanide (10)
The structure of disulfide 12 provides further evidence that
pyrazolamine 2a reacted with Appel salt 1 via the enaminic C-4
carbon, a necessary criteria for the formation of pyrazoloiso-
thiazoles 5. A tentative but plausible mechanism for the
formation of disulfide 12 can involve the condensation of three
components: the proposed N-mercaptocarbimidoyl chloride
intermediate 16 could add to carbothioyl cyanide 10 to give a
disulfide intermediate that then captures a molecule of Appel
salt 1 to give the ketenimine 18. The thiophilic addition of
thiols to thiones to give disulfides is well documented.23 The
highly electrophilic ketenimine 18, now activated by the
dithiazolium cation, can rapidly capture chloride to give the
neutral species 12 (Scheme 8).
It is not possible at this stage to predict the order of events
leading to the final product; nevertheless, the structures of
disulfide 12, carbothioyl cyanide 10, and pyrazoloisothiazoles 5
clearly support that, in these cases, Appel salt 1 reacted at the
pyrazoles enaminic C-4 carbon. Interestingly, on extending the
reaction time, the minor side products 10−12 disappeared
from the reaction mixture (by TLC), suggesting that they could
be possible intermediates to the final products.
1H-Pyrazol-5-amines are widely used in synthesis;18 however,
predicting their selectivity toward electrophiles (i.e., 5-NH2 vs
C-4 attack) is not trivial as many factors can influence the
course of the reaction. In our case, where Appel salt 1 is used as
the electrophile and 1-alkylpyrazol-5-amines as the nucleophile,
the results described above indicate that the determining factor
2.5. Routes to N-Unsubstituted Pyrazolo[3,4-c]-
isothiazole-3-carbonitriles and Pyrazolo[3,4-d]thiazole-
5-carbonitriles. The above syntheses worked particularly well
for 1-alkyl or aryl-substituted 1H-pyrazol-5-amines but not for
Scheme 8. Tentative Mechanism for the Formation of Disulfide 12
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a
Table 2. Thermolysis of N-(Dithiazolylidene)pyrazol-5-
Scheme 9
amines 3
dec onset
(°C)
temp
(°C)
time
(min)
yields 4
(%)
entry
R1
R2
1
2
3
4
5
6
7
8
Me
H
Me
Me
Ph
158.2
158.4
196.3
149.0
142.1
161.6
126.8
160.6
170
170
210
170
180
200
150
180
15
10
10
15
15
15
15
15
4a (77)
a
4b ( )
a
H
4c ( )
Me
Bn
Bn
Ph
Ph
Ph
4d (83)
4e (69)
4f (85)
4g (83)
4h (78)
Me
Ph
a
Reagents and conditions: (i) Br2 (3 equiv), AIBN (0.4 equiv), PhH/
Me
Ph
H2O (2:1), ca. 80 °C, 7 h; (ii) NaOH (1 equiv), EtOH, ca. 78 °C, 12
h.
a
Intractable black solids.
5f, however, the reaction was not very successful, and
degradation was observed. Subsequent dehydration of carbox-
amides 20a and 20b with neat POCl3 at ca. 60 °C gave the
desired carbonitriles 5b and 5c, respectively, in good overall
yields (50−90%). Nevertheless, similar treatment of the 1-
benzyl-1H-pyrazolo[3,4-d]thiazoles 4e and 4f with neat concd
H2SO4 at ca. 60 °C led to degradation, while selective hydration
of the nitriles could be achieved by carrying out the reaction at
ca. 20 °C for 2 h to give carboxamides 21a (85%) and 21b
(88%) (Scheme 10). Extended reaction times at ca. 20 °C also
led to degradation.
1-unsubstituted pyrazolamines: The reaction of 1-unsubstituted
pyrazolamines 2b and 2c with Appel salt 1 gave the 6-
unsubstituted pyrazolo[3,4-c]isothiazole-3-carbonitriles 5b and
5c in low yields [Table 1, entries 2 (4%) and 3 (7%),
respectively], while the thermolysis of the readily obtained 1-
unsubstituted N-(dithiazolylidene)pyrazolamines 3b and 3c
gave mainly S8 and intractable black solids (Table 2, entries 2
and 3). As such, we proposed alternative syntheses via either
protodebenzylation of 6-benzylpyrazolo[3,4-c]isothiazoles (5e
and 5f) and 1-benzylpyrazolo[3,4-d]thiazole-5-carbonitriles (4e
and 4f) or protodebutylation of 6-(tert-butyl)pyrazolo[3,4-
c]isothiazoles (5g and 5h).
3. CONCLUSIONS
1H-Pyrazol-5-amines 2 react with Appel salt 1 either via normal
or enaminic attack, depending on the pH of the medium. Basic
conditions favor formation of 6H-pyrazolo[3,4-c]isothiazole-3-
carbonitriles 5 (enaminic attack), while acidic conditions favor
the formation of (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)-1H-pyrazol-5-amines 3 (normal attack). Exceptions
were 1-(tert-butyl)pyrazol-5-amines 2g and 2h and 1-unsub-
stituted pyrazol-5-amines 2b and 2c, which, independent of the
reaction conditions, gave as major products pyrazoloisothia-
zoles 5g and 5h and dithiazolylidene-1H-pyrazol-5-amines 3b
and 3c, respectively. On thermolysis, (Z)-N-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 3 gave 1H-
pyrazolo[3,4-d]thiazoles 4 in good yields. Furthermore, single
crystal X-ray crystallography supported the structure of 4,6-
dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 5a, which
was previously mistaken to be 1,3-dimethyl-1H-pyrazolo[3,4-
d]thiazole-3-carbonitrile 4a.
Initial efforts to debenzylate pyrazolothiazole 4f or
pyrazoloisothiazole 5f using typical debenzylation methods
[Pd/C (5 mol %), H2 (2 atm); BBr3 (10 equiv) in DCM;25
cerium ammonium nitrate (CAN) (6 equiv) in MeCN/H2O;26
Na, NH3(l)] failed. Nevertheless, by using dibromine and
AIBN27 followed by an alkali work-up needed to hydrolyze any
N-benzoylated side products, we were able to obtain both 3-
phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile (4c) and 4-
phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5c) in
good yields (76 and 92%, respectively). Unfortunately, for
the methyl analogues 4e and 5e, the Br2/AIBN debenzylation
conditions worked less well, affording complex mixtures (by
TLC) and only a low yield (19%) of N-unsubstituted
pyrazoloisothiazole 5b was obtained from the latter (Scheme
9).
An alternative route to 6-unsubstituted pyrazolo[3,4-c]-
isothiazoles 5b and 5c involved treating the available N-benzyl
and N-(tert-butyl) analogues 5e−h with acid. Initially, the 4-
phenyl-6H-pyrazolo[3,4-c]isothiazoles 5f and 5h were treated
with neat AcOH (pKa 4.76)28 and heated to ca. 118 °C for 3 d,
but only the corresponding carboxamides 19a and 19b were
obtained, both in 83% yield. Fortunately, by using concd
4. EXPERIMENTAL SECTION
4.1. General Methods and Materials. DCM was freshly distilled
from CaH2 under argon. Reactions 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 commercial glass-backed thin-layer chromatography
(TLC) plates (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 silica gel 60 (less than 0.063
mm).30 Melting points were determined using a Koefler-Hotstage
29
H2SO4 and raising the reaction temperature to ca. 60 °C for
1−5 h, pyrazolo[3,4-c]isothiazoles 5e−5h were fully converted
into the corresponding 6H-pyrazolo[3,4-c]isothiazole-3-carbox-
amides 20a and 20b in 59−98% yields. For 6-(tert-butyl)-6H-
pyrazolo[3,4-c]isothiazoles 5g and 5h, the debutylation was also
effective when the reaction was performed at ca. 20 °C for 1 d.
In the case of 6-benzyl-6H-pyrazolo[3,4-c]isothiazoles 5e and
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Scheme 10. Preparation of 6-Unsubstituted Pyrazoloisothiazoles 5b and 5c and 1-Benzyl-1H-pyrazolo[3,4-d]thiazole-5-
carboxamides 21
microscope apparatus or a DSC with samples hermetically sealed in
aluminum pans under an argon atmosphere and using heating rates of
5 °C/min. Solvents used for recrystallization are indicated after the
melting point. UV/vis spectra were obtained using a UV/vis
spectrophotometer, and inflections are identified by the abbreviation
“inf”. IR spectra were recorded on an FTIR spectrometer with a Ge
ATR accessory; strong, medium, and weak peaks are represented by s,
elution (DCM/t-BuOMe, 98:2) gave (Z)-N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-1,3-dimethyl-1H-pyrazol-5-amine (3a) (58 mg,
5%) as yellow prisms; mp (DSC) onset, 146.3 °C; peak max, 156.6
°C; dec onset, 158.2 °C; peak max, 158.9 °C (from c-hexane/DCE); Rf
0.67 (DCM/t-BuOMe, 9:1). Found: C, 34.13; H, 2.76; N, 22.81.
C7H7ClN4S2 requires: C, 34.07; H, 2.86; N, 22.71%). λmax (DCM) 250
(log ε 2.83), 270 (2.58), 382 inf (2.86), 389 inf (2.85), 401 (2.91), 418
inf (2.79); vmax/cm−1 2932w (CH3); 1578s, 1555w, 1514m, 1443m,
1410w, 1373w, 1360w, 1292m, 1192m, 1148m, 1049w, 1013m, 878s,
856m, 777s; δH (500 MHz; CDCl3) 6.23 (1H, s), 3.90 (3H, s), 2.34
(3H, s); δC (125 MHz; CDCl3) 153.9 (s), 149.0 (s), 147.6 (s), 145.9
(s), 94.5 (d), 34.9 (q), 14.2 (q); m/z (EI) 248 (M+ + 2, 40%), 246
(M+, 92), 211 (M+−Cl, 73), 182 (6), 179 (22), 170 (8), 152 (31), 147
(20), 137 (8), 127 (14), 125 (18), 120 (100), 110 (8), 106 (20), 102
(31), 95 (20), 93 (23), 80 (21), 70 (46), 64 (64), 52 (25), 42 (38).
Further elution (DCM/t-BuOMe, 98:2) gave 5-amino-1,3-dimethyl-
1H-pyrazole-4-carbothioyl cyanide (10) (33.5 mg, 4%) as orange
plates; mp 212−213 °C (from CHCl3); Rf 0.23 (DCM/t-BuOMe,
9:1). Found: C, 46.53; H, 4.33; N, 30.95. C7H8N4S requires: C, 46.65;
H, 4.47; N, 31.09%. λmax (DCM) 253 (log ε 3.76), 367 (4.06), 414
(4.11); vmax/cm−1 3339m (NH2), 3211w, 3165w, 3011w, 2988w,
2965w, and 2930w (CH3); 2226w (CN), 1632s, 1562m, 1557m,
1526m, 1493s, 1452m, 1435m, 1389m, 1339m, 1238w, 1215w, 1128w,
1024m, 989m, 972m, 955m, 862w, 739w; δH (500 MHz; CDCl3) 7.23
(2H, br s), 3.59 (3H, s), 2.57 (3H, s); δC (125 MHz; DMSO-d6) 165.2
(s), 154.0 (s), 145.7 (s), 122.6 (s), 116.2 (s), 33.9 (q), 14.0 (q);
MALDI-TOF MS (m/z) 181 (MH+ + 1, 39%), 181 (MH+, 100), 154
(79), 111 (29). Further elution (DCM/t-BuOMe, 95:5) gave
(3Z,3′Z)-N′,N″-3-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]-
isothiazole-3-carbimidoyl chloride) (11) (125 mg, 12%) as yellow
needles; mp (DSC) onset, 178.7 °C; peak max, 184.0 °C; dec onset,
191.4 °C; peak max, 198.6 °C (from DCE); Rf 0.67 (DCM/t-BuOMe,
8:2). Found: C, 32.22; H, 2.11; N, 21.50. C14H12Cl2N8S5 requires: C,
32.12; H, 2.31; N, 21.40%. λmax (DCM) 310 (log ε 3.60), 408 (3.60);
vmax/cm−1 2990w, 2959w, and 2913w (CH3); 1578m, 1557m, 1510m,
1454m, 1435m, 1406m, 1377m, 1335m, 1244m, 1219m, 1190m,
1040m, 989m, 966m, 935w, 845m, 800s; δH (500 MHz; CD2Cl2) 3.81
(3H, s), 2.56 (3H, s); δC (125 MHz; CD2Cl2) 167.3 (s), 150.9 (s),
137.1 (s), 132.3 (s), 124.9 (s), 34.6 (q), 15.9 (q); MALDI-TOF MS
(m/z): 525 (M+ + 3, 27%), 523 (M+ + 1, 78), 521 (M+ − 1, 65), 485
(12), 460 (7), 458 (9), 425 (15), 389 (4), 309 (14), 307 (23), 276
(12), 249 (56), 247 (100), 244 (74), 227 (9), 213 (40). Further
1
m, and w, respectively. H and 13C NMR spectra were recorded at
either 300 and 75 MHz, respectively, or at 500 and 125 MHz,
respectively. Deuterated solvents were used for homonuclear lock, and
the signals are referenced to the deuterated solvent peaks. DEPT or
APT NMR studies identified quaternary and tertiary carbons, which
are indicated by (s) and (d) notations, respectively. Low resolution
(EI) mass spectra were recorded on a GCMS fitted with a direct inlet
probe. MALDI-TOF MS were conducted on a time-of-flight (TOF)
mass spectrometer. 4,5-Dichloro-1,2,3-dithiazolium chloride (1),12 1,3-
dimethyl-1H-pyrazol-5-amine (2a),31 3-methyl-1H-pyrazol-5-amine
(2b),32 3-phenyl-1H-pyrazol-5-amine (2c),33 1-methyl-3-phenyl-1H-
pyrazol-5-amine (2d),33 1-benzyl-3-methyl-1H-pyrazol-5-amine
(2e),34 1-benzyl-3-phenyl-1H-pyrazol-5-amine (2f),35 1-(tert-butyl)-3-
methyl-1H-pyrazol-5-amine (2g),36 1-(tert-butyl)-3-phenyl-1H-pyra-
zol-5-amine (2h),37 3-methyl-1-phenyl-1H-pyrazol-5-amine (2i),38
and 1,3-diphenyl-1H-pyrazol-5-amine (2j)33 were prepared according
to literature procedures.
4.2. Reaction of 1,3-Dimethyl-1H-pyrazol-5-amine (2a) with
4,5-Dichloro-1,2,3-dithiazolium Chloride (1). To a stirred
suspension of 4,5-dichloro-1,2,3-dithiazolium chloride (1) (1.00 g,
4.8 mmol) in DCM (20 mL) at ca. 20 °C under argon atmosphere was
added in one portion a solution of 1,3-dimethyl-1H-pyrazol-5-amine
(2a) (0.53 g, 4.8 mmol) and lutidine (1.12 mL, 9.6 mmol) in DCM
(20 mL). The mixture was stirred for 1 h and then adsorbed on silica
and chromatographed (DCM) to give 4,6-dimethyl-6H-pyrazolo[3,4-
c]isothiazole-3-carbonitrile (5a) (99 mg, 12%) as colorless needles;
mp 102−106 °C (from c-hexane); Rf 0.45 (DCM). Found: C, 47.31;
H, 3.38; N, 31.30. C7H6N4S requires: C, 47.18; H, 3.39; N, 31.44%.
λmax (DCM) 291 (log ε 2.73), 369 (2.39); vmax/cm−1 2992w, 2928w,
and 2851w (CH3); 2218s (CN); 1582s, 1514m, 1441m, 1410m,
1383m, 1331m, 1246m, 1229m, 1034m, 986m, 934w, 899s, 841m,
745m; δH (500 MHz; CDCl3) 3.90 (3H, s), 2.53 (3H, s); δC (125
MHz; CDCl3) 165.7 (s), 135.4 (s), 130.3 (s), 120.4 (s), 110.3 (s), 34.8
(q), 13.1 (q); m/z (EI) 178 (M+, 100%), 163 (22), 150 (7), 135 (5),
123 (5), 108 (9), 91 (10), 70 (24), 64 (7), 46 (8), 43 (41). Further
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elution (DCM/t-BuOMe, 6:4) gave (Z)-N-{[(Z)-1-(5-amino-1,3-
dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithia-
zol-5-ylidene)amino]vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo[3,4-
c]isothiazole-3-carbimidoyl chloride (12) (154 mg, 13%) as red
needles; mp 143−145 °C (from n-pentane/DCM); Rf 0.27 (DCM/t-
BuOMe, 4:6). Found: C, 32.13; H, 2.21; N, 20.94. C16H14Cl3N9S5
requires: C, 32.12; H, 2.31; N, 21.04%. λmax(DCM) 313 (log ε 4.18),
417 (4.28), 465 inf (4.16); vmax/cm−1 3327w and 3196w (NH2),
2934w (CH3), 1649m, 1557s, 1512m, 1485m, 1423m, 1404m, 1383m,
1339m, 1298m, 1227m, 1161s, 1107w, 1043w, 993w, 968m, 897w,
859s, 845m, 799s, 785s, 735m; δH(500 MHz; CDCl3) 3.83 (3H, s),
3.77 (2H, br s), 3.57 (3H, s), 2.58 (3H, s), 2.03 (3H, s); δC(125 MHz;
CDCl3) 166.7 (s), 152.8 (s), 151.1 (s), 149.3 (s), 147.2 (s), 143.6 (s),
136.9 (s), 130.0 (s), 129.3 (s), 128.9 (s), 124.2 (s), 99.3 (s), 34.3 (q),
34.2 (q), 15.7 (q), 13.7 (q); MALDI-TOF MS (m/z): 603 (M+ + 6,
18%), 601 (M+ + 4, 51), 599 (M+ + 2, 96), 597 (M+, 100), 530 (19),
499 (14), 385 (32), 383 (33), 351 (19), 349 (34), 347 (67), 285 (28),
283 (97), 247 (12), 212 (9), 176 (6).
4.3. Thermolysis of Side Products 11 and 12 (Scheme 4).
4.3.1. Thermolysis of Trisulfide 11 (Typical Procedure). A stirred neat
sample of (3Z,3′Z)-N′,N″-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo-
[3,4-c]isothiazole-3-carbimidoyl chloride) (11) (20.0 mg, 0.04 mmol)
under an argon atmosphere was immersed into a preheated Wood’s
metal bath at ca. 250 °C. After 4 min, the mixture was allowed to cool
to ca. 20 °C and extracted with DCM (3 × 1 mL). The combined
extracts were adsorbed onto silica and chromatographed (n-hexane) to
give S8. Further elution (DCM/t-BuOMe, 99:1) gave 4,6-dimethyl-
6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5a) (12.1 mg, 89%) as
colorless needles; mp 102−106 °C (from c-hexane); Rf 0.45 (DCM);
identical to that described above.
and chromatographed (DCM/t-BuOMe, 99:1) to give 4,6-dimethyl-
6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5a) (17.5 mg, 98%) as
colorless needles; mp 102−106 °C (from c-hexane); Rf 0.45 (DCM);
identical to that described above.
4.6. Reaction of 1H-Pyrazol-5-amines 2 with 4,5-Dichloro-
1,2,3-dithiazolium Chloride (1). See Table 1 for yields.
General Procedure A: To a stirred solution of the appropriate 1H-
pyrazol-5-amine 2 (0.48 mmol) in DCM (4 mL) at ca. 20 °C and
protected with CaCl2 drying tube was added in one portion lutidine
(112 μL, 0.96 mmol). The reaction mixture was then stirred for 5 min,
and then Appel salt 1 (100 mg, 0.48 mmol) was added. After an
additional 15 h of stirring at ca. 20 °C, the reaction mixture was
adsorbed onto silica and chromatographed.
General Procedure B: A stirred solution of the appropriate 1H-
pyrazol-5-amine 2 (0.48 mmol) in dry DCM (4 mL) at ca. 20 °C was
purged for 30 s with HCl (g). After the purge was complete, to the
reaction mixture was added in one portion Appel salt 1 (100 mg, 0.48
mmol). The reaction mixture was then stirred for 12 h, and lutidine
(112 μL, 0.96 mmol) was added in one portion. The reaction mixture
was stirred for an additional 3 h, adsorbed onto silica, and
chromatographed.
4.6.1. (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-1H-
pyrazol-5-amine (3b). Procedure A: 72.5 mg, 65%. Procedure B: 83
mg, 74%. Chromatography eluent: DCM/t-BuOMe, 95:5. Orange
prisms; mp (DSC) onset, 150.8 °C; peak max, 154.8 °C; dec onset,
158.4 °C; peak max, 161.1 °C (from c-hexane/DCE); Rf 0.48 (DCM/
t-BuOMe, 98:2). Found: C, 31.06; H, 2.19; N, 23.92. C6H5ClN4S2
requires: C, 30.97; H, 2.17; N, 24.08%. λmax (DCM) 250 (log ε 3.98),
255 inf (3.93), 274 inf (3.41), 375 inf (3.93), 389 (4.02), 406 inf
(3.90); vmax/cm−1 3208m (NH), 3150w, 2928w and 2862w (CH3),
1578m, 1543s, 1533m, 1491m, 1449w, 1396m, 1375m, 1281m,
1175m, 1136m, 1026w, 1003m, 876s, 868s, 826w, 779m, 768s;
δH (500 MHz; DMSO-d6) 12.93 (1H, s), 6.24 (1H, s), 2.30 (3H, s);
δC (125 MHz; DMSO-d6) 154.5 (s), 154.2 (s), 148.2 (s), 141.5 (s),
101.4 (d), 11.4 (q); MALDI-TOF MS (m/z) 235 (MH+ + 2, 56%),
233 (MH+, 100), 197 (91), 140 (67).
4.6.2. (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-phenyl-1H-
pyrazol-5-amine (3c). Procedure A: 82 mg, 58%. Procedure B: 130
mg, 92%. Chromatography eluent: DCM. Orange needles; mp (DSC)
onset, 190.9 °C; peak max, 193.8 °C; dec onset, 196.3 °C; peak max,
199.9 °C (from c-hexane/DCE); Rf 0.44 (DCM). Found: C, 44.80; H,
2.32; N, 18.94. C11H7ClN4S2 requires: C, 44.82; H, 2.39; N, 19.01%.
λmax (DCM) 258 (log ε 4.50), 378 inf (4.05), 391 (4.14), 408 inf
(4.00); vmax/cm−1 3341m (NH), 3154w, 3065w, and 3017w (Ar CH),
1549m, 1522w, 1501w, 1487m, 1472m, 1456m, 1396w, 1314w,
1296w, 1273w, 1204m, 1159m, 1009m, 957w, 914w, 868m, 816w,
795w, 727s; δH (500 MHz; DMSO-d6) 13.72 (1H, s), 7.83 (2H, d, J
7.5), 7.50 (2H, dd, J 7.8, 7.8), 7.40 (1H, dd, J 7.3, 7.3), 6.98 (1H, d, J
2.0); δC(125 MHz; DMSO-d6) 154.8 (s), 154.3 (s), 147.6 (s), 144.2
(s), 129.0 (d), 128.8 (s), 128.6 (d), 125.2 (d), 99.4 (d); MALDI-TOF
MS (m/z) 297 (MH+ + 2, 28%), 295 (MH+, 100), 205 (13).
4.6.3. (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-1-methyl-3-
phenyl-1H-pyrazol-5-amine (3d). Procedure A: 0%. Procedure B:
108 mg, 73%. Chromatography eluent: n-hexane/DCM, 40:60. Yellow
needles; mp (DSC) onset, 140.0 °C; peak max, 140.6 °C; dec onset,
149.0 °C; peak max, 150.6 °C (from c-hexane); Rf 0.52 (n-hexane/
DCM, 30:70). Found: C, 46.71; H, 3.01; N, 18.20. C12H9ClN4S2
requires: C, 46.67; H, 2.94; N, 18.14%. λmax (DCM) 251 (log ε 4.36),
300 inf (3.59), 376 inf (3.92), 392 inf (4.03), 409 (4.09), 428 inf
(3.94); vmax/cm−1 3065w (Ar CH), 2930w and 2847w (CH3), 1585m,
1547w, 1531w, 1512w, 1491m, 1460m, 1427w, 1352w, 1300m,
1188m, 1144m, 1107w, 1072w, 1034w, 955m, 918w, 870m, 845m,
773s, 748s; δH (500 MHz; CDCl3) 7.83 (2H, d, J 7.0), 7.43 (2H, dd, J
7.8, 7.8), 7.34 (1H, dd, J 7.3, 7.3), 6.73 (1H, s), 4.03 (3H, s); δC (125
MHz; CDCl3) 154.5 (s), 150.2 (s), 149.0 (s), 146.5 (s), 133.1 (s),
128.7 (d), 128.0 (d), 125.4 (d), 91.8 (d), 35.4 (q); MALDI-TOF MS
(m/z) 311 (MH+ + 2, 53%), 309 (MH+, 100), 289 (57), 205 (90).
4.6.4. (Z)-1-Benzyl-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-
methyl-1H-pyrazol-5-amine (3e). Procedure A: 0%. Procedure B:
26.5 mg, 17%. Chromatography eluent: DCM. Yellow plates; mp
4.3.2. Thermolysis of Disulfide 12. Similar treatment of (Z)-N-
{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)amino]vinyl]disulfanyl}-4,6-di-
methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride (12)
(20.0 mg, 0.03 mmol) at ca. 200 °C for 2 min gave 4,6-dimethyl-
6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5a) (5.8 mg, 49%) as
colorless needles; mp 102−106 °C (from c-hexane); Rf 0.45 (DCM);
identical to that described above.
4.4. Reaction of Trisulfide 11 and Disulfide 12 with
Concentrated H2SO4 (Scheme 4). To concd H2SO4 (1 mL) at
ca. 20 °C was added either (3Z,3′Z)-N′,N″-trisulfanediylbis(4,6-
dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride) (11)
(20.0 mg, 0.04 mmol) or (Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-
pyrazol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-
amino]vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-
carbimidoyl chloride (12) (20.0 mg, 0.03 mmol). On consumption of
either compound 11 or 12 (by TLC), the reaction mixture was poured
onto crushed ice, left to warm to ca. 20 °C, neutralized (sat. NaHCO3)
and extracted with t-BuOMe (4 × 10 mL). The combined extracts
were then dried (Na2SO4), filtered, and evaporated to dryness. The
residue was dissolved in THF (5 mL), adsorbed onto silica, and
chromatographed (t-BuOMe) to give 4,6-dimethyl-6H-pyrazolo[3,4-
c]isothiazole-3-carboxamide (13) (14.8 mg, 99% from 11 and 4.0 mg,
34% from 12) as colorless needles; mp 181−182 °C (from c-hexane/
EtOH); Rf 0.33 (t-BuOMe). Found: C, 42.79; H, 4.13; N, 28.40.
C7H8N4OS requires: C, 42.85; H, 4.11; N, 28.55%). λmax (EtOH) 224
(log ε 2.87), 282 (2.94), 351 (2.64); vmax/cm−1 3356m and 3163m
(NH2), 1692s (CO), 1626m, 1589m, 1516m, 1443m, 1389s, 1377s,
1317m, 1215m, 1123m, 1032m, 989w, 934m, 920w, 827m, 781m;
δH (300 MHz; DMSO-d6) 8.09 (1H, br s), 7.96 (1H, br s), 3.75 (3H,
s), 2.44 (3H, s); δC (75 MHz; DMSO-d6) 166.0 (s), 160.3 (s), 150.9
(s), 135.8 (s), 126.1 (s), 34.1 (q), 14.2 (q); m/z (EI) 196 (M+, 100%),
180 (21), 151 (33), 138 (3), 125 (4), 108 (10), 98 (4), 94 (4), 90 (7),
82 (13), 69 (8), 64 (7).
4.5. Dehydration of 4,6-Dimethyl-6H-pyrazolo[3,4-c]-
isothiazole-3-carboxamide (13). To a stirred solution of 4,6-
dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide (13) (19.6 mg,
0.1 mmol) in toluene (1 mL) was added in one portion POCl3 (100
μL, 1 mmol). The reaction mixture was then heated to ca. 110 °C for 3
h. The mixture was then left to cool to ca. 20 °C, absorbed onto silica,
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(DSC) onset, 138.0 °C; peak max, 140.8 °C; dec onset, 142.1 °C; peak
max, 142.6 °C (from c-hexane); Rf 0.26 (DCM). Found: C, 48.32; H,
3.52; N, 17.23. C13H11ClN4S2 requires: C, 48.36; H, 3.43; N, 17.35%).
λmax (DCM) 252 (log ε 4.04), 303 (3.58), 388 inf (4.17), 405 (4.23),
425 inf (4.09); vmax/cm−1 3061w, 3042w, 2940w, 1560m, 1551m,
1518m, 1495m, 1456w, 1447w, 1437m, 1369m, 1346w, 1331w,
1306w, 1288w, 1209m, 1204w, 1177w, 1152m, 1121w, 1032w, 1016m,
1001w, 935w, 926w, 880m, 849m, 820m, 791m, 762s, 741m; δH (500
MHz; acetone-d6) 7.37 (2H, d, J 7.0), 7.30 (2H, dd, J 7.3, 7.3), 7.24
(1H, dd, J 7.3, 7.3), 6.35 (1H, s), 5.44 (2H, s), 2.26 (3H, s); δC (125
MHz; CDCl3) 154.0 (s), 149.1 (s), 148.1 (s), 145.5 (s), 137.3 (s), 94.9
(d), 51.8 (t), 14.4 (q); MALDI-TOF MS (m/z) 325 (MH++2, 56%),
323 (MH+, 100), 91 (59).
4.6.5. (Z)-1-Benzyl-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-
phenyl-1H-pyrazol-5-amine (3f). Procedure A: 0%. Procedure B:
101.5 mg, 55%. Chromatography eluent: n-hexane/DCM, 60:40.
Yellow needles; mp (DSC) onset, 158.9 °C; peak max, 160.0 °C; dec
onset, 161.6 °C; peak max, 172.9 °C (from c-hexane); Rf 0.30 (n-
hexane/DCM, 50:50) Found: C, 56.12; H, 3.50; N, 14.67.
C18H13ClN4S2 requires: C, 56.17; H, 3.40; N, 14.56%. λmax(DCM)
258 (log ε 4.44), 394 inf (4.09), 411 (4.14), 434 inf (3.98); vmax/cm−1
3065w and 3024w (Ar CH), 2947w (CH3), 1564m, 1549m, 1526w,
1501m, 1493m, 1487m, 1462m, 1454m, 1441m, 1423w, 1354w,
1327w, 1308m, 1292w, 1206m, 1200m, 1177w, 1163m, 1155m,
1136m, 1088m, 1072w, 1028w, 970w, 955m, 922w, 910m, 878m,
849m, 837w, 822w, 791m, 777m, 762s; δH (500 MHz; DMSO-d6)
7.86 (2H, d, J 7.0), 7.42 (2H, dd, J 7.5, 7.5), 7.34−7.25 (6H, m), 6.90
(1H, s), 5.49 (2H, s); δC (125 MHz; DMSO-d6) 157.1 (s), 149.6 (s),
147.7 (s), 146.6 (s), 137.4 (s), 132.8 (s), 128.8 (d), 128.6 (d), 128.1
(d), 127.9 (d), 127.7 (d), 125.2 (d), 91.9 (d), 51.3 (t); MALDI-TOF
MS (m/z) 387 (MH++2, 29%), 385 (MH+, 76%), 90 (100).
4.6.6. (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-1-
phenyl-1H-pyrazol-5-amine (3i). Procedure A: 0%. Procedure B:
32.5 mg, 22%). Chromatography eluent: n-hexane/DCM, 80:20.
Yellow needles; mp (DSC) onset, 121.8 °C; peak max, 122.7 °C; dec
onset, 126.8 °C; peak max, 129.2 °C (from c-hexane); Rf 0.48 (n-
hexane/DCM, 30:70). Found: C, 46.58; H, 2.86; N, 18.24.
C12H9ClN4S2 requires: C, 46.67; H, 2.94; N, 18.14%. λmax (DCM)
243 (log ε 4.27), 263 (4.22), 280 inf (4.09), 397 inf (4.08), 412 (4.11),
432 inf (3.97); vmax/cm−1 3127w (Ar CH), 2928w (CH3), 1578m,
1520m, 1497m, 1462m, 1431m, 1418m, 1371m, 1317w, 1269w,
1179m, 1148m, 1074m, 1026m, 1011w, 1001w, 982w, 905m, 870m,
837m, 773s, 746m; δH (500 MHz; CDCl3) 7.85 (2H, d, J 8.0), 7.44
(2H, dd, J 7.8, 7.8), 7.31 (1H, dd, J 7.5, 7.5), 6.44 (1H, s), 2.44 (3H,
s); δC (125 MHz; CDCl3) 154.8 (s), 149.3 (s), 149.2 (s), 146.0 (s),
139.2 (s), 128.5 (d), 126.7 (d), 124.0 (d), 96.1 (d), 14.4 (q); MALDI-
TOF MS (m/z) 311 (MH++2, 94%), 309 (MH+, 100), 275 (42), 273
(57), 216 (94), 209 (100).
4.6.7. (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-1,3-diphenyl-
1H-pyrazol-5-amine (3j). Procedure A: 0%. Procedure B: 16 mg, 9%.
Chromatography eluent: n-hexane/DCM, 90:10. Yellow needles; mp
92−94 °C (from c-hexane); Rf 0.39 (n-hexane/DCM, 50:50). Found:
C, 55.20; H, 2.86; N, 14.98. C17H11ClN4S2 requires: C, 55.05; H, 2.99;
N, 15.11%. λmax (DCM) 256 (log ε 3.48), 271 inf (3.39), 395 (3.05),
413 (3.06), 431 inf (2.92); vmax/cm−1 3071w (Ar CH), 1578m, 1531m,
1497s, 1456m, 1410w, 1368w, 1304w, 1261w, 1209w, 1186w, 1146m,
1088w, 1074w, 1026w, 1016w, 950m, 916w, 868s, 845w, 829w, 770s,
760m, 745m; δH (500 MHz; CDCl3) 7.97 (2H, dd, J 8.5, 1.0), 7.94
(2H, dd, J 8.5, 1.0), 7.49 (2H, dd, J 8.0, 8.0), 7.46 (2H, dd, J 7.5, 7.5),
7.39−7.34 (2H, m), 6.92 (1H, s); δC (125 MHz; CDCl3) 155.3 (s),
151.3 (s), 149.3 (s), 146.7 (s), 139.2 (s), 132.8 (s), 128.7 (d), 128.6
(d), 128.4 (d), 127.0 (d), 125.7 (d), 124.2 (d), 93.2 (d); MALDI-TOF
MS (m/z) 373 (MH+ + 2, 49%), 371 (MH+, 75), 335 (14), 278 (100),
271 (19).
3292s (NH), 2245m and 2226m (CN), 1585s, 1506m, 1477w,
1439m, 1383m, 1368m, 1302m, 1215w, 1159w, 1082s, 986m, 897s,
841m, 791s; δH (500 MHz; DMSO-d6) NH resonance missing 2.44
(3H, s); δC (125 MHz; DMSO-d6) 166.5 (s), 135.8 (s), 130.4 (s),
119.2 (s), 111.0 (s), 12.8 (q); MALDI-TOF MS (m/z) 165 (MH+,
100%).
4.6.9. 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5c).
Procedure A: 7.5 mg, 7%; Procedure B: 0%. Chromatography eluent:
DCM/t-BuOMe, 90:10. Pale yellow needles; mp 196−197 °C (from c-
hexane/CHCl3); Rf 0.68 (DCM/t-BuOMe, 96:4). Found: C, 58.53; H,
2.56; N, 24.67. C11H6N4S requires: C, 58.39; H, 2.67; N, 24.76%.
λmax (DCM) 258 (log ε 4.09), 295 (4.11), 368 (3.75); vmax/cm−1
3226m (NH), 3051w (Ar CH), 2224m (CN), 1584m, 1512m,
1464m, 1437w, 1385m, 1327m, 1317m, 1298m, 1281m, 1190w,
1101w, 1084m, 1070w, 1013w, 916w, 891s, 856m, 835w, 791s, 777s,
745s; δH (500 MHz; CDCl3) 10.04 (1H, s), 8.04 (2H, dd, J 8.5, 1.5),
7.55 (2H, dd, J 7.5, 7.5), 7.47 (1H, dd, J 7.5, 7.5); δC (125 MHz;
CDCl3) 166.5 (s), 140.9 (s), 130.7 (s), 129.6 (d), 129.2 (d), 127.6 (s),
126.9 (d), 121.9 (s), 111.0 (s); MALDI-TOF MS (m/z) 229 (MH+ +
1, 34%), 227 (MH+, 100), 202 (16), 77 (18).
4.6.10. 6-Methyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-car-
bonitrile (5d). Procedure A: 52 mg, 45%. Procedure B: 6 mg, 5%.
Chromatography eluent: n-hexane/DCM, 60:40. Yellow needles; mp
(DSC) onset, 155.9 °C; peak max, 156.5 °C (from c-hexane); Rf 0.54
(n-hexane/DCM, 40:60). Found: C, 59.85; H, 3.32; N, 23.23.
C12H8N4S requires: C, 59.98; H, 3.36; N, 23.32%. λmax (DCM) 265
(log ε 3.34), 291 (3.30), 391 (2.83); vmax/cm−1 3061w (Ar CH),
2941w (CH3), 2216w (CN), 1574m, 1518m, 1491m, 1456m,
1435m, 1406w, 1346m, 1319w, 1298w, 1287m, 1260m, 1231m,
1182w, 1171w, 1157m, 1074w, 1034m, 1024m, 920w, 907w, 881m,
841m, 772m, 739s; δH (500 MHz; CDCl3) 8.00 (2H, dd, J 8.5, 1.5),
7.52 (2H, dd, J 7.5, 7.5), 7.43 (1H, dd, J 7.4, 7.4), 4.05 (3H, s);
δC (125 MHz; CDCl3) 166.2 (s), 138.0 (s), 130.9 (s), 129.2 (d), 129.1
(d), 127.2 (s), 126.6 (d), 121.6 (s), 111.3 (s), 35.2 (q); MALDI-TOF
MS (m/z) 241 (MH+, 60%), 240 (M+, 100), 229 (14).
4.6.11. 6-Benzyl-4-methyl-6H-pyrazolo[3,4-c]isothiazole-3-car-
bonitrile (5e). Procedure A: 57.5 mg, 47%. Procedure B: 35.5 mg,
29%. Chromatography eluent: DCM. Beige needles; mp 101.5−102
°C (from n-hexane at ca. 20 °C); Rf 0.47 (DCM). Found: C, 61.37; H,
3.87; N, 21.93. C13H10N4S requires: C, 61.40; H, 3.96; N, 22.03%.
λmax (DCM) 295 (log ε 4.00), 371 (3.68); vmax/cm−1 3030w (Ar CH),
2976w and 2938w (CH2 and CH3), 2220m (CN), 1582s, 1510m,
1495m, 1472w, 1454m, 1443m, 1416m, 1387m, 1346m, 1333m,
1298m, 1267s, 1234m, 1204m, 1157w, 1111m, 1107m, 1098m,
1069m, 1069m, 1026w, 903s, 833s, 818m, 770m, 745m; δH (500
MHz; CDCl3) 7.36−7.27 (5H, m), 5.37 (2H, s), 2.53 (3H, s); δC (125
MHz; CDCl3) 165.3 (s), 136.0 (s), 135.9 (s), 130.7 (s), 128.8 (d),
128.2 (d), 128.0 (d), 120.5 (s), 110.3 (s), 52.3 (t), 13.2 (q); MALDI-
TOF MS (m/z) 255 (MH+, 100%), 106 (49), 91 (87).
4.6.12. 6-Benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-car-
bonitrile (5f). Procedure A: 62.5 mg, 41%. Procedure B: 13.5 mg,
9%. Chromatography eluent: n-hexane/DCM, 70:30. Yellow needles,
mp (DSC) 109−110.5 °C (from n-pentane at ca. −20 °C); Rf 0.36 (n-
hexane/DCM, 60:40). Found: C, 68.28; H, 3.71; N, 17.64. C18H12N4S
requires: C, 68.33; H, 3.82; N, 17.71%. λmax (DCM) 266 (log ε 4.21),
289 (4.09), 392 (3.81); vmax/cm−1 3065w and 3030w (Ar CH), 2976w
and 2941w (CH2), 2220m (CN), 1568m, 1516m, 1497w, 1483m,
1458m, 1435m, 1416m, 1352w, 1342m, 1300w, 1263s, 1244w, 1206w,
1163m, 1117m, 1074m, 1047w, 1024w, 1003w, 974w, 939w, 914m,
878m, 839m, 820m, 777m, 772m, 741s; δH (500 MHz; CDCl3) 8.03
(2H, dd, J 8.5, 1.5), 7.52 (2H, dd, J 7.8, 7.8), 7.45−7.41 (3H, m),
7.36−7.29 (3H, m), 5.52 (2H, d); δC(125 MHz; CDCl3) 165.8 (s),
138.5 (s), 135.6 (s), 130.9 (s), 129.3 (d), 129.1 (d), 128.8 (d), 128.3
(d), 128.1 (d), 127.6 (s), 126.8 (d), 121.6 (s), 111.2 (s), 52.7 (t);
MALDI-TOF MS (m/z) 317 (MH+, 70%), 316 (M+, 100), 315 (87),
90 (65).
4.6.8. 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5b).
Procedure A: 3 mg, 4%. Procedure B: 0%. Chromatography eluent:
DCM/t-BuOMe, 90:10. Colorless needles; mp 182−183.5 °C (from c-
hexane/CHCl3); Rf 0.33 (DCM/t-BuOMe, 97:3). Found: C, 43.79; H,
2.37; N, 34.21. C6H4N4S requires: C, 43.89; H, 2.46; N, 34.12%.
λmax (EtOH) 235 (log ε 3.79), 291 (4.61), 351 (3.83); vmax/cm−1
4.6.13. 6-(tert-Butyl)-4-methyl-6H-pyrazolo[3,4-c]isothiazole-3-
carbonitrile (5g). Procedure A: 41 mg, 39%. Procedure B: 22 mg,
21%. Chromatography eluent: n-hexane/DCM, 60:40. Colorless
needles; mp 63−64 °C (from n-pentane at ca. −20 °C); Rf 0.38 (n-
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hexane/DCM, 50:50). Found: C, 54.42; H, 5.55; N, 25.34. C10H12N4S
requires: C, 54.52; H, 5.49; N, 25.43%. λmax (DCM) 238 (log ε 3.89),
293 (4.09), 375 (3.75); vmax/cm−1 2982m, 2940w and 2876w (CH3),
2222m (CN), 1574m, 1493m, 1470m, 1456m, 1435w, 1412m,
1398s, 1373m, 1366m, 1329m, 1269m, 1240s, 1167m, 1123s, 1032m,
1001w, 939w, 905s, 843m, 802m, 746m; δH(500 MHz; CDCl3) 2.52
(3H, s), 1.69 (9H, s); δC(125 MHz; CDCl3) 164.9 (s), 134.1 (s),
131.8 (s), 118.8 (s), 110.6 (s), 59.5 (s), 28.8 (q), 13.1 (q); MALDI-
TOF MS (m/z) 220 (M+, 100%), 218 (35), 204 (15), 175 (8), 164
(9), 149 (8), 72 (46).
4.6.14. 6-(tert-Butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-
carbonitrile (5h). Procedure A: 51.5 mg, 38%. Procedure B: 50 mg,
37%. Chromatography eluent: n-hexane/DCM, 70:30. Yellow needles;
mp 120−121.5 °C (from n-pentane at ca. −20 °C); Rf 0.64 (n-hexane/
DCM, 60:40). Found: C, 63.82; H, 4.91; N, 19.71. C15H14N4S
requires: C, 63.80; H, 5.00; N, 19.84%. λmax (DCM) 265 (log ε 4.62),
293 (4.56), 393 (4.21); vmax/cm−1 2990w, 2978w and 2938w (CH3),
2214m (CN), 1560m, 1508m, 1481m, 1464m, 1404m, 1395m,
1368m, 1344m, 1325w, 1298w, 1283m, 1271w, 1246m, 1231m,
1196w, 1179w, 1159m, 1128m, 1105w, 1098w, 1074w, 1030m,
1022m, 937w, 914m, 878w, 849m, 799m, 770m, 739s; δH (500 MHz;
CDCl3) 8.03 (2H, d, J 7.5), 7.51 (2H, dd, J 7.8, 7.8), 7.41 (1H, dd, J
7.5, 7.5), 1.79 (9H, s); δC (125 MHz; CDCl3) 165.4 (s), 136.5 (s),
131.4 (s), 129.0 (d), 128.8 (d), 128.6 (s), 126.7 (d), 119.9 (s), 111.6
(s), 60.3 (s), 28.8 (q); MALDI-TOF MS (m/z) 283 (MH+, 96%), 282
(M+, 49), 227 (100).
4.6.15. 4-Methyl-6-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-car-
bonitrile (5i). Procedure A: 41.5 mg, 36%. Procedure B: 7 mg, 6%.
Chromatography eluent: n-hexane/DCM, 80:20. Yellow needles; mp
145−145.5 °C (from c-hexane); Rf 0.48 (n-hexane/DCM, 60:40).
Found: C, 60.04; H, 3.45; N, 23.12. C12H8N4S requires: C, 59.98; H,
3.36; N, 23.32%. λmax (DCM) 257 (log ε 3.80), 290 (3.36), 295 inf
(3.34), 396 (2.98); vmax/cm−1 3071w (Ar CH), 2924w (CH3), 2218
(CN), 1591m, 1578m, 1514s, 1501m, 1487m, 1474w, 1445m,
1425m, 1387m, 1341m, 1283m, 1152w, 1117m, 1101m, 1070m,
1059w, 1030w, 1016w, 997w, 903m, 870w, 831w, 752s; δH (500 MHz;
acetone-d6) 8.13 (2H, d, J 8.0), 7.54 (2H, dd, J 8.0, 8.0), 7.28 (1H, dd,
J 7.5, 7.5), 2.62 (3H, s); δC(125 MHz; CDCl3) 163.2 (s), 138.4 (s),
137.4 (s), 132.3 (s), 129.3 (d), 125.3 (d), 120.8 (s), 117.1 (d), 110.0
(s), 13.2 (q); m/z (EI) 240 (M+, 100%), 225 (6), 214 (5), 199 (8),
129 (5), 118 (28), 91 (20), 77 (49), 64 (9), 51 (40).
4.6.16. 4,6-Diphenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile
(5j). Procedure A: 49.5 mg, 34%. Procedure B: 27.5 mg, 19%.
Chromatography eluent: n-hexane/DCM, 90:10. Yellow needles; mp
152.5−154 °C (from c-hexane); Rf 0.60 (n-hexane/DCM, 60:40).
Found: C, 67.65; H, 3.25; N, 18.46. C17H10N4S requires: C, 67.53; H,
3.33; N, 18.53%. λmax (DCM) 246 (log ε 3.48), 278 (3.67), 414
(2.99); vmax/cm−1 3067w (Ar CH), 2218m (CN), 1597m, 1566m,
1514m, 1501s, 1464m, 1450w, 1420m, 1348m, 1306w, 1281m, 1186w,
1163w, 1136s, 1126m, 1101w, 1072m, 1028w, 1013m, 968w, 918w,
901m, 833m, 773m; δH (500 MHz; CDCl3) 8.26 (2H, d, J 8.0), 8.14
(2H, d, J 7.5), 7.58−7.48 (5H, m), 7.30 (1H, dd, J 7.5, 7.5); δC (125
MHz; CDCl3) one C (s) resonance missing 163.8 (s), 139.4 (s), 138.4
(s), 130.4 (s), 129.8 (d), 129.4 (d), 129.1 (d), 127.1 (d), 125.8 (d),
121.9 (s), 117.7 (d), 111.0 (s); m/z (EI) 302 (M+, 100%), 276 (4),
225 (4), 180 (5), 153 (9), 151 (5), 103 (5), 91 (4), 77 (77), 70 (8), 51
(32).
(2.32); vmax/cm−1 2941w (CH3), 2224m (CN), 1551m, 1497m,
1452m, 1420m, 1389s, 1356m, 1271w, 1233m, 1165m, 1144m,
1099m, 1047m, 993w, 926w, 837w, 810w, 781w; δH (500 MHz;
CDCl3) 4.07 (3H, s), 2.47 (3H, s); δC (125 MHz; CDCl3) 159.0 (s),
139.2 (s), 137.9 (s), 114.6 (s), 113.0 (s), 36.1 (q), 13.9 (q); m/z (EI)
178 (M+, 100%), 163 (15), 85 (94), 70 (86), 58 (8).
4.7.2. 1-Methyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (4d). Chromatography eluent: DCM. Colorless needles (19.9
mg, 83%); mp (DSC) onset, 170.5 °C; peak max, 171.3 °C (from c-
hexane); Rf 0.53 (DCM). Found: C, 59.90; H, 3.42; N, 23.29.
C12H8N4S requires: C, 59.98; H, 3.36; N, 23.32%. λmax (DCM) 260 inf
(log ε 3.33), 264 (3.35), 281 inf (3.24), 295 (3.34), 348 (2.67); vmax
/
cm−1 3065w, 3042w and 3007w (Ar CH), 2945w (CH3), 2224m (C
N), 1545m, 1472s, 1462m, 1452m, 1395m, 1364m, 1356m, 1327w,
1304w, 1292m, 1238m, 1206m, 1182w, 1169w, 1155w, 1121m,
1076w, 1045w, 1030m, 1011m, 912w, 893w, 758s, 731m; δH (500
MHz; CDCl3) 7.73 (2H, d, J 7.0), 7.43 (2H, dd, J 7.5, 7.5), 7.34 (1H,
dd, J 7.3, 7.3), 4.14 (3H, s); δC(125 MHz; CDCl3) 159.4 (s), 141.1
(s), 139.7 (s), 130.8 (s), 129.1 (d), 128.9 (d), 125.6 (d), 112.9 (s),
112.5 (s), 36.6 (q); MALDI-TOF MS (m/z) 240 (M+, 100).
4.7.3. 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (4e). Chromatography eluent: DCM. Colorless prisms (17.5
mg, 69%); mp 91−93 °C (from n-pentane at ca. −20 °C); Rf 0.56
(DCM). Found: C, 61.39; H, 3.87; N, 21.84. C13H10N4S requires: C,
61.40; H, 3.96; N, 22.03%. λmax (DCM) 293 (log ε 4.20), 328 (3.75);
vmax/cm−1 3069w, 3034w, 2957w, 2926w, 2230m (CN), 1653m,
1533m, 1500m, 1491m, 1456s, 1445m, 1433m, 1389s, 1358m, 1346w,
1331w, 1325w, 1296m, 1273s, 1206m, 1159m, 1148m, 1117m, 1098m,
1076m, 1026w, 1003m, 930m, 910m, 854w, 824m, 772m, 760w, 748w,
741w, 737w, 731w; δH (500 MHz; DMSO-d6) 7.34−7.25 (5H, m),
5.54 (2H, s), 2.42 (3H, s); δC (125 MHz; DMSO-d6) 158.1 (s), 139.6
(s), 138.4 (s), 136.5 (s), 128.8 (d), 128.0 (d), 127.7 (d), 115.3 (s),
113.4 (s), 52.7 (d), 13.6 (q). MALDI-TOF MS (m/z) 255 (MH+,
100), 242 (15), 91 (55).
4.7.4. 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (4f). Chromatography eluent: n-hexane/DCM, 50:50. Beige
needles (26.9 mg, 85%); mp 113.5−114.5 °C (from c-hexane); Rf 0.50
(n-hexane/DCM, 50:50). Found: C, 68.24; H, 3.87; N, 17.77.
C18H12N4S requires: C, 68.33; H, 3.82; N, 17.71%. λmax (DCM) 264
inf (log ε 4.27), 268 (4.28), 297 (4.21), 350 (3.59); vmax/cm−1 3059w,
3032w, and 3009w (Ar CH), 2983w and 2938w (CH2), 2226m (C
N), 1530m, 1497m, 1472s, 1460m, 1456m, 1447m, 1427m, 1395m,
1354m, 1344w, 1323w, 1290m, 1279m, 1200m, 1163w, 1153w, 1119s,
1076m, 1032w, 1011m, 993w, 972w, 937w, 922w, 891w, 820w, 773s;
δH(500 MHz; CDCl3) 7.82 (2H, d, J 7.0), 7.49 (2H, dd, J 7.8, 7.8),
7.44−7.38 (3H, m), 7.37−7.29 (3H, m), 5.66 (2H, s); δC (125 MHz;
CDCl3) 158.9 (s), 141.4 (s), 139.9 (s), 135.5 (s), 130.8 (s), 129.1 (d),
128.9 (d), 128.8 (d), 128.4 (d), 128.1 (d), 125.7 (d), 112.9 (s), 54.0
(t); MALDI-TOF MS (m/z) 317 (MH+, 100%), 91 (90).
4.7.5. 3-Methyl-1-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (4g). Chromatography eluent: n-hexane/DCM, 50:50. Beige
plates (19.9 mg, 83%); mp 127−128.5 °C (from c-hexane); Rf 0.50 (n-
hexane/DCM, 50:50). Found: C, 59.96; H, 3.27; N, 23.29. C12H8N4S
requires: C, 59.98; H, 3.36; N, 23.32%. λmax (DCM) 247 (log ε 3.41),
294 (3.33), 354 (2.88); vmax/cm−1 2926w (CH3), 2224m (CN),
1593m, 1518s, 1495m, 1464m, 1443m, 1391m, 1381m, 1362m,
1335w, 1317w, 1246w, 1167m, 1144s, 1101m, 1074m, 1043w, 1026w,
1005w, 903m, 868w, 760s, 754s; δH (500 MHz; CDCl3) 8.12 (2H, d, J
8.0), 7.51 (2H, dd, J 8.0, 8.0), 7.31 (1H, dd, J 7.3, 7.3), 2.59 (3H, s);
δC (125 MHz; CDCl3) 157.1 (s), 139.6 (s), 139.5 (s), 138.5 (s), 129.4
(d), 126.4 (d), 118.7 (d), 117.5 (s), 112.9 (s), 14.1 (q); MALDI-TOF
MS (m/z) 241 (MH+, 100%), 205 (18).
4.7. 1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles 4 (General
Procedure). A stirred sample of the appropriate neat N-
(dithiazolylidene)pyrazolamine 3 (0.1 mmol) under an argon
atmosphere was immersed into a preheated Wood’s metal bath at
temperatures specified in Table 2. After 10−15 min, the reaction
mixture was allowed to cool to ca. 20 °C and extracted with DCM (3
× 1 mL). The combined extracts were adsorbed onto silica and
chromatographed.
4.7.1. 1,3-Dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile
(4a). Chromatography eluent: DCM/t-BuOMe, 90:10. Colorless
needles (13.7 mg, 77%); mp 99−100.5 °C (from c-hexane); Rf 0.20
(DCM). Found: C, 47.29; H, 3.26; N, 31.34. C7H6N4S requires: C,
47.18; H, 3.39; N, 31.44%. λmax (DCM) 293 (log ε 2.80), 316 inf
4.7.6. 1,3-Diphenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile
(4h). Chromatography eluent: n-hexane/DCM, 60:40. Yellow needles
(23.6 mg, 78%); mp (DSC) onset, 185.2 °C; peak max, 185.6 °C
(from c-hexane); Rf 0.46 (n-hexane/DCM, 70:30). Found: C, 67.44;
H, 3.18; N, 18.40. C17H10N4S requires: C, 67.53; H, 3.33; N, 18.53%.
λmax (DCM) 239 (log ε 3.37), 278 (3.64), 288 inf (3.61), 371 (3.00);
vmax/cm−1 3061w (Ar CH), 2226m (CN), 1595m, 1514s, 1487m,
1476m, 1460m, 1445w, 1393w, 1362s, 1331w, 1321m, 1287m, 1213w,
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1163w, 1150m, 1128w, 1098w, 1076m, 1024w, 1001m, 989m, 916w,
908w, 772m, 758s, 729m; δH (500 MHz; CDCl3) 8.26 (2H, dd, J 8.5,
1.0), 7.93 (2H, dd, J 8.0, 1.0), 7.58−7.53 (4H, m), 7.46 (1H, dd, J 7.3,
7.3), 7.36 (1H, dd, J 7.5, 7.5); δC (125 MHz; CDCl3) one C (s)
resonance missing 142.0 (s), 140.1 (s), 138.6 (s), 130.3 (s), 129.5 (d),
129.4 (d), 129.2 (d), 126.8 (d), 126.0 (d), 119.0 (d), 115.3 (s), 112.8
(s); MALDI-TOF MS (m/z) 303 (MH+, 92%), 302 (M+, 100).
4.8. Debenzylation Reactions with Br2/AIBN. 4.8.1. 3-Phenyl-
1H-pyrazolo[4,3-d]thiazole-5-carbonitrile (4c) (Typical Procedure).
A stirred mixture of 1-benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-
carbonitrile (4f) (31.6 mg, 0.1 mmol), dibromine (7.7 μL, 0.15 mmol),
AIBN (3.3 mg, 0.02 mmol), and PhH/H2O (2:1, 1.5 mL) was heated
to ca. 80 °C for 2 h. The reaction mixture was then allowed to cool to
ca. 20 °C, additional dibromine (7.7 μL, 0.15 mmol) and AIBN (3.3
mg, 0.02 mmol) were added, and the mixture was heated again to ca.
80 °C for a further 5 h. The reaction mixture was then allowed to cool
to ca. 20 °C, and the volatiles were removed in vacuo. To the
remaining residue was added a solution of NaOH in EtOH (2 mL,
0.05 M), and the mixture was heated to ca. 78 °C for 12 h. The
reaction mixture was then allowed to cool to ca. 20 °C, adsorbed onto
silica, and chromatographed (DCM/t-BuOMe, 90:10) to give the title
compound 4c (17.2 mg, 76%) as colorless cotton fibers; mp 191−193
°C (from c-hexane/CHCl3); Rf 0.57 (DCM/t-BuOMe, 90:10). Found:
C, 58.51; H, 2.73; N, 24.88. C11H6N4S requires: C, 58.39; H, 2.67; N,
24.76%. λmax (DCM) 258 inf (log ε 4.30), 262 (4.31), 290 (4.34), 325
inf (3.75); vmax/cm−1 3105w, 3024w and 2895w (NH), 2234w (C
N), 1501m, 1474m, 1437s, 1387w, 1314m, 1298m, 1184m, 1125s,
1096w, 1001w, 986m, 901w, 818m, 756s; δH (500 MHz; acetone-d6)
NH resonance missing 7.91 (2H, d, J 7.0), 7.57 (2H, dd, J 7.8, 7.8),
7.46 (1H, dd, J 7.5, 7.5); δC (125 MHz; TFA-d) 160.7 (s), 149.5 (s),
144.2 (s), 134.4 (d), 131.8 (d), 128.4 (d), 126.1 (s), 115.6 (s), 111.7
(s); MALDI-TOF MS (m/z) 227 (MH+, 100%).
4.8.2. 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5b).
Similar treatment of 6-benzyl-4-methyl-6H-pyrazolo[3,4-c]isothiazole-
3-carbonitrile (5e) (25.4 mg, 0.1 mmol) gave the title compound 5b
(3.1 mg, 19%) as colorless needles; mp 182−183.5 °C (from c-
hexane/CHCl3); Rf 0.33 (DCM/t-BuOMe, 97:3); identical to that
described above.
4.8.3. 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5c).
Similar treatment of 6-benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-
3-carbonitrile (5f) (31.6 mg, 0.1 mmol) gave the title compound 5c
(20.8 mg, 92%) as pale yellow needles; mp 196−197 °C (from c-
hexane/CHCl3); Rf 0.68 (DCM/t-BuOMe, 96:4); identical to that
described above.
4.9. Hydration of 1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles
4e and 4f and 6H-Pyrazolo[3,4-c]isothiazole-3-carbonitriles 5f
and 5h. 4.9.1. 6-Benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-
carboxamide (19a) (Typical procedure). A stirred solution of 6-
benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile (5f)
(31.6 mg, 0.1 mmol) in AcOH (2 mL) was heated to ca. 118 °C
for 3 d. The reaction mixture was allowed to cool to ca. 20 °C, poured
onto crushed ice, neutralized (sat. NaHCO3), and extracted with t-
BuOMe (3 × 20 mL). The combined organic extracts were dried
(Na2SO4), filtered, and evaporated to dryness. The residue obtained
was dissolved in DCM (10 mL), adsorbed onto silica, and
chromatographed to give the title compound 19a (27.8 mg, 83%),
as pale yellow needles; mp 181−183 °C (from c-hexane/CHCl3); Rf
0.50 (DCM/t-BuOMe, 90:10). Found: C, 64.56; H, 4.21; N, 16.62.
C18H14N4OS requires: C, 64.65; H, 4.22; N, 16.75%. λmax (DCM) 258
(log ε 3.97), 289 (3.89), 369 (3.71); vmax/cm−1 3451m, 3439m,
3331w, 3273w and 3130m (NH2), 2931w (CH2), 1670s (CO),
1659m, 1607m, 1572m, 1514w, 1495w, 1477m, 1454m, 1435m,
1412m, 1391m, 1358w, 1352w, 1327m, 1308m, 1273m, 1206w,
1182w, 1157w, 1134m, 1109m, 1076m, 1070m, 1042w, 1022m, 934m,
924m, 887m, 845m, 839m, 791m, 779m, 770m, 758m; δH (500 MHz;
CDCl3) 7.71 (2H, d, J 8.0), 7.52−7.46 (3H, m), 7.43 (2H, d, J 7.5),
7.33 (2H, dd, J 7.5, 7.5), 7.29 (1H, dd, J 7.3, 7.3), 5.75 (2H, br s), 5.50
(2H, s); δC(125 MHz; CDCl3) one C (d) resonance missing 166.6 (s),
161.0 (s), 150.9 (s), 138.2 (s), 136.1 (s), 131.8 (s), 129.5 (d), 129.0
(d), 128.7 (d), 128.13 (d), 128.06 (d), 121.8 (s), 52.3 (t); MALDI-
TOF MS (m/z) 335 (MH+, 100%), 333 (M+ − 1, 27), 324 (31), 318
(28), 292 (15), 281 (13), 257 (10), 90 (67).
4.9.2. 6-(tert-Butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-
carboxamide (19b). Similar treatment of 6-(tert-butyl)-4-phenyl-6H-
pyrazolo[3,4-c]isothiazole-3-carbonitrile (5h) (28.2 mg, 0.1 mmol)
gave the title compound 19b (23.7 mg, 83%), as pale yellow needles;
mp 197.5−198.5 °C (from c-hexane/CHCl3); Rf 0.43 (DCM/Et2O,
90:10). Found: C, 59.86; H, 5.26; N, 18.74. C15H16N4OS requires: C,
59.98; H, 5.37; N, 18.65%. λmax (DCM) 260 (log ε 4.13), 290 (4.10),
373 (3.89); vmax/cm−1 3462m, 3269m, and 3173m (NH), 2980m and
2932w (CH3), 1665m, 1639s (CO), 1611m, 1568m, 1510w,
1466m, 1439w, 1383s, 1329m, 1300w, 1283w, 1263m, 1242m, 1182m,
1134s, 1094m, 1074w, 1020m, 986w, 926m, 914m, 872m, 845m,
804m, 773s, 748s; δH (500 MHz; CDCl3) 7.71 (2H, d, J 7.0), 7.50
(2H, dd, J 7.3, 7.3), 7.45 (1H, dd, J 7.3, 7.3), 6.15 (1H, br s), 5.66 (1H,
br s), 1.78 (9H, s); δC (125 MHz; CDCl3) 166.3 (s), 161.5 (s), 149.1
(s), 136.3 (s), 132.3 (s), 129.2 (d), 128.9 (d), 128.8 (d), 122.9 (s),
59.8 (s), 28.9 (q); MALDI-TOF MS (m/z) 301 (MH+, 100%), 245
(80).
4.9.3. 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carboxa-
mide (21a). Similar treatment of 1-benzyl-3-methyl-1H-pyrazolo[3,4-
d]thiazole-5-carbonitrile (4e) (25.4 mg, 0.1 mmol) with concd H2SO4
(1 mL) at ca. 20 °C for 2 h gave the title compound 21a as colorless
needles (23.1 mg, 85%); mp 159−161 °C (from c-hexane/CHCl3); Rf
0.29 (DCM/Et2O, 90:10). Found: C, 57.29; H, 4.31; N, 20.46.
C13H12N4OS requires: C, 57.34; H, 4.44; N, 20.57%. λmax (EtOH) 209
(log ε 4.15), 288 (4.02), 316 (3.71); vmax/cm−1 3470m, 3347w, 3275w,
and 3196m (NH2), 1688s (CO), 1585m, 1531m, 1501m, 1485m,
1460m, 1402m, 1377m, 1356w, 1333w, 1319w, 1288w, 1271m,
1204w, 1153m, 1119m, 1070m, 1034w, 1007w, 941w, 924w, 908w,
818w, 766m, 731m; δH (500 MHz; DMSO-d6) 8.32 (1H, s), 8.04 (1H,
s), 7.33 (2H, dd, J 7.3, 7.3), 7.29−7.26 (3H, m), 5.52 (2H, s), 2.39
(3H, s); δC (125 MHz; DMSO-d6) 169.0 (s), 161.2 (s), 158.5 (s),
138.1 (s), 136.9 (s), 128.5 (d), 127.6 (d), 127.3 (d), 114.1 (s), 52.1
(t), 13.5 (q); MALDI-TOF MS (m/z) 273 (MH+, 82%), 257 (22),
229 (7), 91 (100).
4.9.4. 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboxa-
mide (21b). Similar treatment of 1-benzyl-3-methyl-1H-pyrazolo[3,4-
d]thiazole-5-carbonitrile (4f) (25.4 mg, 0.1 mmol) with concd H2SO4
(1 mL) at ca. 20 °C for 2 h gave the title compound 21b as colorless,
cotton-like fibers (29.4 mg, 88%); mp 204−205 °C (from c-hexane/
CHCl3); Rf 0.48 (DCM/Et2O, 90:10). Found: C, 64.57; H, 4.16; N,
16.66. C18H14N4OS requires: C, 64.65; H, 4.22; N, 16.75%.
λmax (DCM) 265 (log ε 4.35), 295 (4.19), 334 inf (3.77); vmax/cm−1
3447m and 3150m (NH2), 1690s (CO), 1595m, 1533m, 1489m,
1452m, 1412m, 1383m, 1360m, 1331m, 1296m, 1281m, 1202w,
1175w, 1155w, 1123m, 1074m, 1013m, 991w, 945m, 920w, 908w,
889w, 835w, 772m, 766m, 733s; δH(500 MHz; DMSO-d6) 8.44 (1H,
s), 8.13 (1H, s), 7.83 (2H, d, J 7.5), 7.52 (2H, dd, J 7.8, 7.8), 7.41 (1H,
dd, J 7.3, 7.3), 7.36−7.34 (4H, m), 7.32−7.28 (1H, m), 5.69 (2H, s);
δC (125 MHz; DMSO-d6) one C (s) resonance missing 169.9 (s),
161.0 (s), 159.1 (s), 140.5 (s), 136.5 (s), 131.0 (s), 129.1 (d), 128.6
(d), 128.4 (d), 127.8 (d), 127.4 (d), 125.1 (d), 112.0 (s), 52.7 (t);
MALDI-TOF MS (m/z) 335 (MH+, 100%), 318 (7), 292 (6), 91
(72).
4.10. N-Debenzylation/Debutylation Reactions Using Con-
centrated H2SO4. General Procedure: To stirred, concd H2SO4 (1
mL) at ca. 20 °C the appropriate 6H-pyrazolo[3,4-c]isothiazole-3-
carbonitrile (5e−5h) (0.1 mmol) was added in one portion. The
reaction mixture was then placed in a preheated oil bath at ca. 60 °C
and stirred at this temperature until completion of the reaction (by
TLC), after which the reaction mixture was allowed to cool to ca. 20
°C, poured onto crushed ice, and neutralized (sat. NaHCO3). The
aqueous phase was extracted with t-BuOMe (3 × 20 mL), the
combined organic phase was dried (Na2SO4), and the volatiles were
removed in vacuo. The residue was dissolved in THF/EtOH 1:1 (10
mL), adsorbed onto silica, and chromatographed. See Scheme 10 for
yields and reaction times.
4.10.1. 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide
(20a). Beige plates; mp (DSC) onset, 239.5 °C; peak max, 248.4
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°C; dec onset, 250.2 °C; peak max, 251.2 °C (from EtOH); Rf 0.35
(Et2O). Found: C, 39.56; H, 3.23; N, 30.69. C6H6N4OS requires: C,
39.55; H, 3.32; N, 30.75%. λmax (EtOH) 229 (log ε 3.21), 284 (3.74),
341 (3.60); vmax/cm−1 3455m, 3261m, and 3183m (NH and NH2),
1651s (CO), 1585m, 1572m, 1510w, 1493m, 1431m, 1381m,
1294m, 1132w, 1078m, 1042m, 991m, 928m, 841w, 795m, 768m,
752w; δH(500 MHz; DMSO-d6) 12.55 (1H, s), 8.09 (1H, br s), 7.89
(1H, br s), 2.44 (3H, s); δC (125 MHz; DMSO-d6) 167.5 (s), 160.8
(s), 149.8 (s), 137.1 (s), 126.5 (s), 14.4 (q); MALDI-TOF MS (m/z)
181 (M+ − 1, 100%), 138 (3).
4.12.2. Crystal Refinement Data for Compound 11.
C14H12Cl2N8S5, M = 523.57, monoclinic, space group C2/c, a =
34.721(5) Å, b = 4.0036(5) Å, c = 14.975(2) Å, β = 100.148(13)°, V =
2049.1(5) Å3, Z = 4, T = 100(2) K, ρcalcd = 1.697 g cm−3, 2θmax = 26.5,
μ(Mo Kα) = 0.847 mm−1. Reflections measured, 4564; independent
reflections, 2101 (Rint = 0.0575). The final R1 and wR(F2) values were
0.0623 and 0.1812 [I > 2σ(I)], respectively. The goodness of fit on F2
was 1.035.
4.12.3. Crystal Refinement Data for Compound 12.
C16H14Cl3N9S5, M = 599.06, triclinic, space group P1, a =
10.4490(4) Å, b = 12.6255(8) Å, c = 21.3511(9) Å, α = 97.143(4)o,
β = 92.352(3)o, γ = 93.441(4)o, V = 2786.5(2) Å3, Z = 4, T = 100(2)
K, ρcalcd = 1.428 g cm−3, 2θmax = 25, μ(Mo Kα) = 0.727 mm−1.
4.10.2. 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide
(20b). Pale yellow plates; mp 261−262 °C (from EtOH); Rf 0.62
(DCM/t-BuOMe, 70:30), Found: C, 54.20; H, 3.17; N, 22.86.
C11H8N4OS requires: C, 54.09; H, 3.30; N, 22.94%. λmax (EtOH) 206
(log ε 4.17), 254 (4.12), 278 (4.13), 346 (3.90); vmax/cm−1 3464w,
3343w, 3287w (NH and NH2), 2833w, 1655m, 1651m, 1589m,
1497w, 1464w, 1437m, 1371m, 1323m, 1302m, 1277m, 1169w,
1105m, 1072m, 1034m, 1015m, 914m, 858m, 783s, 739m; δH (500
MHz; DMSO-d6) 13.24 (1H, br s), 8.19 (1H, br s), 8.09 (1H, br s),
7.83 (2H, dd, J 8.5, 1.5), 7.45 (2H, dd, J 7.5, 7.5), 7.39 (1H, dd, J 7.3,
1.3); δC (125 MHz; DMSO-d6) 167.5 (s), 161.7 (s), 151.2 (s), 139.1
(s), 132.2 (s), 128.52 (d), 128.47 (d), 127.4 (d), 122.7 (s); MALDI-
TOF MS (m/z) 246 (MH++1, 42%), 245 (MH+, 100), 228 (54).
4.11. Dehydration Reactions with POCl3. 4.11.1. 4-Methyl-6H-
pyrazolo[3,4-c]isothiazole-3-carbonitrile (5b) (Typical Procedure).
To stirred POCl3 (3 mL) at ca. 20 °C was added in one portion 4-
methyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide (20a) (18.2 mg,
0.1 mmol). The reaction mixture was then placed in a preheated oil
bath at ca. 60 °C for 4.5 h. The reaction mixture was then allowed to
cool to ca. 20 °C, poured onto crushed ice, neutralized (sat.
NaHCO3), and extracted with CHCl3 (3 × 100 mL). The combined
organic extracts were dried (Na2SO4), filtered, and evaporated to
dryness. The residue obtained was dissolved in DCM, adsorbed onto
silica and chromatographed (DCM/t-BuOMe, 90:10) to give the title
compound 5b (13.9 mg, 85%) as colorless needles; 182−183.5 °C
(from c-hexane/CHCl3); Rf 0.33 (DCM/t-BuOMe, 97:3); identical to
that described above.
Reflections measured, 20504; independent reflections, 9786 (Rint
=
0.0575). The final R1 and wR(F2) values were 0.0824 and 0.2523 [I >
2σ(I)], respectively. The goodness of fit on F2 was 1.000.
Crystallographic data for compounds 5a, 11, and 12 has been
deposited with the Cambridge Crystallographic Data Centre under
deposit numbers CCDC-984832, 984833, and 984834, respectively.
This data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, U.K. (fax, +441223336033; or
e-mail, deposit@ccdc.cam.ac.uk).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of 1D H and 13C NMR spectra of all compounds.
Single-crystal X-ray structures of compounds 5a, 11, and 12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: koutenti@ucy.ac.cy
■
Notes
The authors declare no competing financial interest.
4.11.2. 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile
(5c). Similar treatment of 4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-
carboxamide (20b) (24.4 mg, 0.1 mmol) gave the title compound 5c
(20.7 mg, 92%) as pale yellow needles; mp 196−197 °C (from c-
hexane/CHCl3); Rf 0.68 (DCM/t-BuOMe, 96:4); identical to that
described above.
ACKNOWLEDGMENTS
■
The authors wish to thank the Cyprus Research Promotion
Foundation (Grant No. NEAYPODOMH/NEKYP/0308/02)
and the following organizations and companies in Cyprus for
generous donations of chemicals and glassware: the State
General Laboratory; the Agricultural Research Institute; the
Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and
Biotronics, Ltd. Furthermore, we thank the A. G. Leventis
Foundation for helping to establish the NMR facility at the
University of Cyprus.
4.12. X-ray Crystallographic Studies. Data were collected on an
Oxford-Diffraction Supernova diffractometer equipped with a CCD
area detector utilizing Mo Kα radiation (λ = 0.71073 Å). A suitable
crystal was attached to glass fibers using paratone-N oil and transferred
to a goniostat where they were cooled for data collection. Unit cell
dimensions were determined and refined by using 6074 (3.02 ≤ θ ≤
28.90°) reflections for 5a and 11 and 5674 (3.40 ≤ θ ≤ 26.97°)
reflections for 12. Empirical absorption corrections (multiscan based
on symmetry-related measurements) were applied using CrysAlis RED
software.39 The structure was solved by direct methods using SIR9240
and refined on F2 using full-matrix least-squares using SHELXL-97.41
The following software packages were used: CrysAlis CCD39 for data
collection, CrysAlis RED39 for cell refinement and data reduction,
WINGX for geometric calculations,42 and DIAMOND43 for molecular
graphics. The non-H atoms were treated anisotropically. The
hydrogen atom attached to N3 was located on a difference Fourier
map, whereas all other hydrogen atoms were placed in calculated, ideal
positions and refined as riding on their respective carbon atoms.
4.12.1. Crystal Refinement Data for Compound 5a. C7H6N4S, M
DEDICATION
■
†Dedicated to the memory of Professor Alan R. Katritzky, who
passed away on February 10, 2014.
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