Synthesis of fused 1,2,4-dithiazines and 1,2,3,5-trithiazepines

Article abstract of DOI:10.1021/jo501881y

Reacting ( Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 5 with Et₂NH and then with concd H₂SO₄ gives 5H-pyrazolo[3,4-e ][1,2,4]dithiazine-3-carbonitriles 7 in good yields (74-85%) and 6H-pyrazolo-[3,4-f][1,2,3,5]trithiazepine-4-carbonitriles 9 as minor products (0-6%). Furthermore, the 1,3-dimethylpyrazole analogue 5a was transformed into the dithiazine 7a in two discrete steps, allowing the isolation of a disulfide intermediate (Z)-2-[(diethylamino)disulfan-yl]-2-[(1H-pyrazol-5-yl)imino]-acetonitrile (8a). The one-pot, two-step reaction also worked with electron-rich hydroxy- and methoxy-substituted anilines. Thermolysis of the pyrazolo[3,4-e][1,2,4]dithiazines 7 gave the ring-contracted 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 6 (94-100%). With active sulfur, 1,3-dimethyl-5H-pyrazolo[3,4-e ][1,2,4]dithiazine-3-carbonitrile (7a) gave 1,3-dimethyl-6Hpyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile (9a), but on prolonged reaction times, it gave 5,7-dimethyl-5H-[1,2,3]-dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine (13). Finally, in the absence of acid, heating a solution of (Z)-2-[(diethylamino)-disulfanyl]-2-[(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) gave 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]pyrazolo-[3′,4′:4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12 b(10H)-dicarbonitrile (19) (67%). (Chemical Equation Presented).

Full text of DOI:10.1021/jo501881y

Article
pubs.acs.org/joc
Synthesis of Fused 1,2,4-Dithiazines and 1,2,3,5-Trithiazepines
Maria Koyioni, Maria Manoli, and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
S
* Supporting Information
ABSTRACT: Reacting (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-1H-pyrazol-5-amines 5 with Et2NH and then with
concd H2SO4 gives 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitriles 7 in good yields (74−85%) and 6H-pyrazolo-
[3,4-f ][1,2,3,5]trithiazepine-4-carbonitriles 9 as minor prod-
ucts (0−6%). Furthermore, the 1,3-dimethylpyrazole analogue
5a was transformed into the dithiazine 7a in two discrete steps,
allowing the isolation of a disulfide intermediate (Z)-2-
[(diethylamino)disulfan-yl]-2-[(1H-pyrazol-5-yl)imino]-
acetonitrile (8a). The one-pot, two-step reaction also worked
with electron-rich hydroxy- and methoxy-substituted anilines.
Thermolysis of the pyrazolo[3,4-e][1,2,4]dithiazines 7 gave the ring-contracted 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 6
(94−100%). With active sulfur, 1,3-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (7a) gave 1,3-dimethyl-6H-
pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-carbonitrile (9a), but on prolonged reaction times, it gave 5,7-dimethyl-5H-[1,2,3]-
dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine (13). Finally, in the absence of acid, heating a solution of (Z)-2-[(diethylamino)-
disulfanyl]-2-[(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) gave 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f ]pyrazolo-
[3′,4′:4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile (19) (67%).
Scheme 1. Known Syntheses of 1,2,4-Dithiazines
1. INTRODUCTION
1,2-Dithiines,1 which are six-membered heterocycles with two
adjacent sulfur atoms, have attracted considerable attention
because of their unusual red color,2 questions about their
structure and their potential antiaromaticity,2a,3 their occur-
rence in plants,4 and their interesting biological activities,5 such
as antibiotic,6 antiviral,7 nematicidal,8 insecticidal,9 and
antifungal activities10 and DNA-cleaving properties.11
Aza analogues of 1,2-dithiines are less well-known. The two
isomeric monoaza dithiines, the 1,2,3- and 1,2,4-dithiazines, are
both rare systems with limited reports on their synthesis and
chemistry. To the best of our knowledge, there are three
reports describing the synthesis of monocyclic 8π 1,2,3-
dithiazines,12 whereas for 8π 1,2,4-dithiazines, there are only
two reports on the synthesis of benzo-fused analogues (Scheme
1).13
ones are also present in natural products and possess
interesting biological activities such as antibacterial (e.g.,
hyalodendrin),15 antiviral (e.g., aranotin),16 and antitumor
(e.g., gliotoxin).17
The first, and more general, synthesis of 3-anilino-1,2,4-
benzodithiazines 2 involved the condensation of N-ethylaniline
or 4-bromo-N-ethylaniline with substituted o-thiocyanatophe-
nylisothiocyanates 1,13a whereas more recently, another benzo-
fused analogue 4 was isolated from the reaction of 2,2′-
diaminodiphenyl disulfide (3) with N-benzoyl thiocyanate.13b
Interestingly, di- and tetrahydro-1,2,4-dithiazines are more
common.14 Bridged analogues of 3,6-dihydro-1,2,4-dithiazin-5-
Received: August 14, 2014
Published: September 19, 2014
© 2014 American Chemical Society
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During our recent work on the thermolysis of readily
available (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-
pyrazol-5-amines 5,18 which gives elemental sulfur and
pyrazolo[3,4-d]thiazoles 6, we also obtained an unidentified
minor side product. Herein, we report the structural elucidation
of this minor product, which is a rare example of a fused 1,2,4-
dithiazine. Furthermore, we describe an optimized synthesis of
this heterocycle and studies related to its chemistry.
dithiazine 7a in low to moderate yields or no formation of the
desired product.
Nevertheless, Kim et al. have described the synthesis of stable
disulfides from N-(dithiazolylidene)amines on treatment with
either phosphoranes20h or dialkylamines.22 As such, a two-step
route to the dithiazine 7a was developed via the synthesis and
isolation of the postulated disulfide intermediate. In our hands,
the dialkylamine-mediated ring opening of dithiazolylidene 5a
worked well with Et2NH (3 equiv) in combination with
2. RESULTS AND DISCUSSION
Hunig’s base (i-Pr NEt, 1 equiv) in MeCN at ca. 20 °C for 25
̈
2
min to give disulfide 8a in 89% yield (Scheme 4). Spectroscopic
2.1. Synthesis of Pyrazolo- and Benzo-Fused 1,2,4-
Dithiazines. Thermolysis of (Z)-N-(4-chloro-5H-1,2,3-dithia-
zol-5-ylidene)-1,3-dimethyl-1H-pyrazol-5-amine (5a) at ca. 170
°C for 15 min gave S8, 1,3-dimethyl-1H-pyrazolo[3,4-d]-
thiazole-5-carbonitrile (6a), and a minor previously unidenti-
fied red colored side product 7a.18 Spectroscopic data for this
minor side product, which included single-crystal X-ray
crystallography (see Supporting Information, section S1.1),
identified the compound as 5,7-dimethyl-5H-pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitrile (7a) (Scheme 2).
Scheme 4. Preparation of (Z)-2-[(Diethylamino)disulfanyl]-
2-[(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8)
Scheme 2. Thermolysis of (Z)-N-(4-Chloro-5H-1,2,3-
dithiazol-5-ylidene)-1,3-dimethyl-1H-pyrazol-5-amine (5a)
data and single-crystal X-ray diffraction study supported the
structure of the disulfide (see Supporting Information, section
S1.2). Additional details on the optimization of this reaction are
presented in the Supporting Information (section S2.1).
Attempts to convert disulfide 8a into the desired dithiazine
7a under nonacidic reaction conditions failed to give the
expected dithiazine, presumably owing to the poor nucleofu-
gality of the diethylamide, but they did lead to interesting new
chemistry (see Section 2.4). As such, we treated disulfide 8a
with a range of acids. Fortunately, a solution of disulfide 8a in
MeCN treated with a slight excess of concd HCl (1.25 equiv) at
ca. 20 °C for 5 min gave the red colored dithiazine 7a in 82%
yield together with a yellow colored minor side product,
identified from the spectroscopic data and by X-ray
crystallography (see Supporting Information, section S1.3) as
6,8-dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-car-
bonitrile (9a) (Scheme 5).
A plausible addition of the nucleophile, ring opening, and
ring closure (ANRORC)19 mechanism can be proposed for the
formation of the pyrazolo[3,4-e][1,2,4]dithiazine 7a: thiophilic
attack on the S-2 sulfur atom of the dithiazolylidene 5 by
chloride or an equivalent nucleophile released during the
thermolysis can give the intermediate disulfide 8. In the
presence of the electron-rich enaminic C-4 position of the
pyrazole ring, the disulfide 8 could undergo an intramolecular
cyclization to give the observed product 7 (Scheme 3).
Scheme 5. Acid-Mediated Conversion of the Disulfide 8a
into the 1,2,3,5-Trithiazepine 9a and the 1,2,4-Dithiazine 7a
Scheme 3. Proposed Disulfide Intermediate 8 Involved in
the Transformation of Dithiazole 5 into Dithiazine 7
Interestingly, the choice of acid used for this transformation
was important: the use of concd H2SO4 instead of concd HCl
led to mainly unreacted starting disulfide and low yields (12%)
of the desired dithiazine. Further details on the optimization
can be found in the Supporting Information (section S2.2).
With a two-step procedure successfully developed, a one-pot,
two-step process was elucidated: treatment of dithiazolylidene
5a with Et2NH (3 equiv) and i-Pr2NEt (1 equiv) at ca. 20 °C
for 25 min led to formation of the desired disulfide 8a (by
TLC). To the reaction mixture was then added concd HCl (4
equiv), and after 5 min, the reaction was worked-up to afford
the desired dithiazine 7a and trithiazepine 9a as major and
minor products in 61 and 5% yields, respectively. Interestingly,
Intermediates analogous to disulfide 8 are frequently
proposed in reactions involving thiophile-mediated ring
transformations of N-(5H-1,2,3-dithiazolylidene)amines.20
Typical thiophiles that induce ring transformation of 5H-
1,2,3-dithiazolylidenes include triphenylphosphine (Ph3P),20f,21
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),20d tetraalkylammo-
nium halides (R4NHal),20a and dialkylamines,20g,i,22 whereas
other less common reagents include Grignard reagents,20e
phosphoranes,20h and sodium hydride.23 Reaction of the
dithiazolylidene 5a with common thiophiles (R4NHal, Ph3P,
DBU), however, gave either mixtures of thiazole 6a and
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under these one-pot conditions, the concd HCl could be
substituted for concd H2SO4 (5 equiv), which gave dithiazine
7a in an improved yield of 74%. Further details on the
optimization can be found in the Supporting Information
(section S2.3). This one-pot, two-step reaction protocol was
successfully applied to a range of 1,3-disubstituted
(dithiazolylidene)pyrazolamines 5 (Table 1).
to the formation of 1,2,4-benzodithiazine 11d in a 70% yield
together with a small quantity of the benzothiazole 12d (13%).
Interestingly, the isolated reaction products indicated the
cyclization occurred regioselectively para to the more dominant
electron-releasing substituent.
2.2. Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitrile to 6,8-Dimethyl-6H-
pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-carbonitrile. The
formation of the 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbon-
itriles 7 was, in most cases, accompanied by a small quantity of
1,2,3,5-trithiazepines 9, which were relatively unstable and on
silica (2D-TLC) converted back into 1,2,4-dithiazines 7. The
formation and instability of trithiazepines 9 suggested that an
equilibrium may exist between the dithiazine, the trithiazepine,
and an active form of sulfur, similar to that observed between
1,2,3-trithioles and 1,2,3,4,5-pentathiepins.24 Related trans-
formations also included the conversion of bridged 3,6-
dihydro-1,2,4-dithiazin-5-ones to bridged 4,7-dihydro-1,2,3,5-
trithiazepin-6-ones and vice versa25 and an interesting
quantitative conversion of (1R,1′R)-diborn-2-eno[2,3-c;3′,2′-
e][1,2]dithiine to (1R,1′R)-diborn-2-eno[2,3-d;3′,2′-f ][1,2,3]-
trithiepine, which was facilitated by the release of ring strain on
going from a six- to a seven-membered ring.26
Initially, we investigated the transformation of 5,7-dimethyl-
5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (7a) into
6,8-dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-car-
bonitrile (9a) by heating to reflux a mixture of the dithiazine 7a
and sulfur (10 equiv) in various solvents (MeCN, DMF,
acetone, DCM, CHCl3, THF, PhCl, 1,4-dioxane, CS2, n-
heptane, and c-hexane). Degradation was observed (by TLC) in
either DMF or acetone, whereas a small amount of trithiazepine
9a was observed in MeCN, THF, and 1,4-dioxane. A significant
formation of trithiazepine 9a was noted only in PhCl; however,
at the reflux temperature of PhCl (bp 131 °C), the formation of
thiazole 6a (15%) was also observed (Table 2, entry 1).
Repeating the reaction in PhCl at a lower temperature (ca. 100
°C) led, after 16 h, to only a small quantity of trithiazepine 9a
(6%) (Table 2, entry 2). Gratifyingly, when either a catalytic
(0.1 equiv) or stoichiometric (1.0 equiv) quantity of DABCO
was added to the reaction mixture (Table 2, entries 3 and 4),
after only 20 and 6 min, respectively, trithiazepine 9a could be
isolated in 43 and 47% yields, based on recovered unreacted
dithiazine 7a. This conversion could also be achieved more
slowly (ca. 5 h) at lower reaction temperatures, ca. 40 °C, but
the overall yields of trithiazepine 9a and recovered dithiazine 7a
were poor (Table 2, entry 5).
Table 1. One-Pot Transformation of (Z)-N-(4-Chloro-5H-
1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 5 (0.2
mmol) into 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-
a
carbonitriles 7
entry
R1
R2
yields (%)
1
2
3
4
5
Me
Me
Bn
Bn
Ph
Ph
Me
Ph
9a (5)
9b (5)
9c (6)
9d (−)
9e (0)
9f (0)
7a (74)
7b (75)
7c (78)
7d (85)
7e (85)
7f (80)
Me
Ph
b
b
Me
Ph
c
6
a
Reagents and conditions: (i) Et2NH (3 equiv), i-Pr2NEt (1 equiv),
MeCN, ca. 20 °C, 25 min; (ii) concd H2SO4 (5 equiv), ca. 20 °C, 5
b
1
min Compounds 7d and 9d (ratio 7d/9d, 14:1 by H NMR) were
inseparable by chromatography; however, a microanalytically pure
c
sample of dithiazine 7d was obtained after recrystallization. A trace of
the pyrazolothiazole 6f was observed (by TLC).
With these results in hand, we envisioned that the
transformation of (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-yli-
dene)-1H-pyrazol-5-amines 5 to 5H-pyrazolo[3,4-e][1,2,4]-
dithiazine-3-carbonitriles 7 could also be applied to other
electron-rich arenes. As such, a series of N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)anilines 10 was subjected to the optimized
one-pot conditions (Scheme 6).
Treatment of the least activated N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)aniline (10a) with Et2NH and then concd
H2SO4 led only to a complex reaction mixture, and no traces of
either 1,2,4-benzodithiazine 11a or benzothiazole 12a were
detected. Nevertheless, the introduction of electron-releasing
groups such as methoxy and hydroxy groups (10b−d) did lead
to formation of the 1,2,4-benzodithiazines. In particular, the
most activated dithiazolylidene 10d (R1 = HO, R2 = MeO) led
Interestingly, under these conditions, a trace of a new orange
colored side product was observed, which, from the
Scheme 6. Conversion of N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)anilines 10 into Benzo[e][1,2,4]dithiazine-3-carbonitriles
11
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irradiation at 365 nm from a hand-held UV/vis lamp appeared
to be stable. Nevertheless, DSC studies indicated that the
dithiazines 7 were thermally labile, and the subsequent
thermolysis of the dithiazines 7 in diphenyl ether at ca. 250
°C gave the corresponding thiazoles 6 in near quantitative
yields (Table 3).
Table 2. Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitrile (7a) (0.1 mmol) to 6,8-
Dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-
carbonitrile (9a)
Table 3. Thermolysis of 5H-Pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitriles 7 (0.1 mmol) To Give
1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles 6
a
yields (%)
temp
DABCO
(equiv)
time
(h)
b
entry
(°C)
7a
9a
18
6a
13
1
2
3
4
5
6
7
131
100
100
100
40
0
16
33
69
44
45
31
22
0
0
0
16
19
43
47
20
trace
7
0
0.1
1.0
1.0
1.0
1.0
0.33
0.10
5
0
trace
trace
trace
23
a
entry
R1
R2
decomp onset (°C) time (min) yields 6 (%)
0
b
0
1
2
3
4
5
6
Me
Me
Bn
Bn
Ph
Ph
Me
Ph
30
30
25
35
20
25
6a (100)
6b (95)
6c (95)
6d (94)
6e (100)
6f (100)
100
60
16
trace
17
15
175.9
171.8
187.3
157.2
149.2
27
12
27
Me
Ph
a
b
Yields based on recovered dithiazine 7a. Recovered dithiazine 7a.
Me
Ph
spectroscopic and crystallographic data, was identified as 5,7-
dimethyl-5H-[1,2,3]dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]-
thiazine (13) (see Supporting Information, section S1.4).
When 1 equiv of DABCO and longer reaction times (16 h)
were used the pyrazolo[3,4-e][1,4]thiazine 13 was isolated in
23%, accompanied by the formation of thiazole (17%) (Table
2, entry 6). Decreasing the reaction temperature to ca. 60 °C
did not improve the yield of the thiazine 13, nor did it avoid the
formation of thiazole 6a (Table 2, entry 7).
Presumably, ring opening of dithiazine 7a or even
trithiazepine 9a mediated by the postulated thiophilic
DABCO/S8 adduct 1427 afforded a species such as compound
15. Rotation of the imine bond can bring the nitrile group close
to the pyrazole C-4 thiolate (species 16), and a cascade
cyclization and concomitant loss of sulfur via a chain extension
mechanism28 could lead to the formation of the tricyclic 1,4-
thiazine 13 (Scheme 7).
a
Decomp onset temperatures determined using DSC at a heating rate
b
of 5 °C/min under an argon atmosphere. No decomp onset was
determined, as compound 7a had a low bp (onset, 189.6 °C; peak
max, 198.3 °C) and escaped from the sealed DSC pan.
The reaction mechanism for this ring contraction is probably
similar to that for the ring contraction of the analogous 1,2-
dithiins into thiophenes.26,29c,31 A thermally mediated 6π
electrocyclic ring opening of the dithiazine can lead to the
formation of a [4-thioxo-1H-pyrazol-5(4H)-ylidene]-
carbamothioyl cyanide 17, which, aided by the electron-
releasing pyrazole N-1 atom, can then recyclize to the thiazolo
intermediate 18. This can then lose sulfur via a sulfur chain
extension mechanism28 to afford the fully aromatic pyrazolo-
[3,4-d]thiazole 6 (Scheme 8).
2.4. Unexpected Chemistry of Disulfide 8a. TLC
analysis of a solution of the disulfide 8a in MeCN that had
been left to stand at ca. 20 °C over 3 days indicated the gradual
disappearance of the disulfide and formation of some elemental
sulfur, Et2NSnNEt2 (n = 1−3) (by TLC), and a colorless
product isolated in 40% yield, which was identified by single-
crystal X-ray diffraction study as 4,6,10,12-tetramethyl-6H-
2.3. Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithia-
zine-3-carbonitriles 7. 1,2,4-Dithiazines are structurally
similar to 1,2-dithiines and therefore could readily extrude
sulfur thermally26,29 or photochemically30 to give the more
aromatic and thermally stable thiazoles. In our hands, a DCM
solution of dithiazine 7a exposed to intense sunlight or to
Scheme 7. Tentative Mechanistic Rationale for the Formation of 5,7-Dimethyl-5H-[1,2,3]dithiazolo[4,5-b]pyrazolo[3,4-
e][1,4]thiazine (13)
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Formally, this tetracyclic product 19 can form from the
Diels−Alder cycloaddition of one dithiazine 7a and one
trithiazepine 9a followed by loss of diatomic sulfur; however,
preliminary studies suggest that this cycloaddition/retro-
cycloaddition pathway was not valid: a 1:1 equimolar mixture
of dithiazine 7a and trithiazepine 9a in MeCN heated to reflux
gave no tetracycle 19. As such, we tentatively propose a
stepwise mechanism that invoked the enaminic character of one
pyrazole and the highly electrophilic carbon of the exocyclic
imine of a second pyrazole 8a (Scheme 10).
Scheme 8. Tentative Mechanism for the Ring Contraction of
1,2,4-Dithiazines 7 into Thiazoles 6
Electrophilic substitution at the pyrazole C-4 carbon by the
imine of a second pyrazole 8a can give a coupled species 20
that can undergo an intramolecular cyclization to provide the
pyrazolo[3,4-d]pyrimidine intermediate 21 and a species akin
to N,N-diethyldisulfanamine. The latter small molecule can act
as an active form of sulfur to extend the disulfide chain of 21 to
give a species similar to 22 that undergoes as final cyclization to
the observed tetracyclic 19.
To the best of our knowledge, monocyclic or fused 1,2,3,5-
trithiazepines have not been reported. Bridged 4,7-dihydro-
1,2,3,5-trithiazepin-6-ones, however, appear in several fungal
metabolites and, like their analogous 3,6-dihydro-1,2,4-
dithiazin-5-ones, possess interesting biological activities.32 The
scope of this transformation, details regarding its mechanism,
and the biological properties of tetracycle 19 are now under
investigation.
pyrazolo[3,4-f ]pyrazolo[3′,4′:4,5]pyrimido[6,1-d][1,2,3,5]-
trithiazepine-8,12b(10H)-dicarbonitrile (19) (see Supporting
Information, section S1.5). When a solution of the disulfide 8a
(0.2 mmol) in MeCN (4 mL) was heated at ca. 82 °C for ca. 1
h, tetracycle 19 was obtained in a surprisingly good yield of
67% (Scheme 9). Interestingly, at ca. 82 °C, a trace of the
Scheme 9. Formation of 4,6,10,12-Tetramethyl-6H-
pyrazolo[3,4-f]pyrazolo[3′,4′:4,5]pyrimido[6,1-
d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile (19)
from Disulfide 8a
3. CONCLUSIONS
An efficient one-pot, two-step route to pyrazole fused 1,2,4-
dithiazine-3-carbonitriles 7 has been developed starting from N-
(4-chloro-1,2,3-dithiazolylidene)pyrazol-5-amines 5, which can
be readily prepared in one-step from 4,5-dichloro-1,2,3-
dithiazolium chloride (Appel salt) and the appropriate 5-
aminopyrazole.18 The reaction requires the use of a dialkyl-
amine to ring open the dithiazole to afford an isolable disulfide
intermediate 8, which on treatment with acid cyclizes to give
mainly the desired dithiazines 7 (74−85%) accompanied by
small quantities of 1,2,3,5-trithiazepines 9 (0−6%). In the
presence of active sulfur, 1,3-dimethyl-5H-pyrazolo[3,4-e]-
[1,2,4]dithiazine-3-carbonitrile (7a) can be converted into
expected dithiazine 7a was observed (by TLC) at the beginning
of the reaction, but this was quickly consumed. Furthermore, a
pure sample of the tetracycle 19 in PhCl heated to ca. 131 °C
for 12 h was stable (by TLC).
Scheme 10. Tentative Mechanism for the Formation of 4,6,10,12-Tetramethyl-6H-pyrazolo[3,4-
f]pyrazolo[3′,4′:4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile (19) from Disulfide 8a
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4.2.2. Treatment of (Z)-2-[(Diethylamino)disulfanyl-2-(1,3-di-
methyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) with Concentrated
HCl. To a stirred solution of (Z)-2-[(diethylamino)disulfanyl-2-(1,3-
dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) (28.3 mg, 0.1
mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion
concd HCl (11 μL, 0.125 mmol). After 5 min stirring, the mixture was
adsorbed onto silica and chromatographed (n-hexane/t-BuOMe,
90:10) to give 6,8-dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-
4-carbonitrile (9a) (1.3 mg, 5%) as yellow needles: mp (DSC) onset,
66.7 °C; peak max, 71.7 °C; decomp. onset, 166.8 °C; peak max, 185.7
°C (from n-pentane at ca. −20 °C). Rf 0.40 (n-hexane/t-BuOMe,
80:20). (Found: C, 34.57; H, 2.41; N, 23.24. C7H6N4S3 requires: C,
34.69; H, 2.50; N, 23.12%.) λmax(DCM) 301 (log ε 3.58), 373 (3.65),
414 inf (3.26). vmax/cm−1 2949w and 2922w (CH3), 2218w (CN),
1584m, 1481m, 1427m, 1422s, 1387m, 1342m, 1306m, 1198w, 1121w,
1080m, 1042s, 1018m, 995m, 901m, 754s. δH (500 MHz, CDCl3) 3.96
(3H, s), 2.28 (3H, s). δC (125 MHz, CDCl3) 146.1 (s), 140.7 (s),
127.8 (s), 121.0 (s), 114.6 (s), 36.7 (q), 12.5 (q). MALDI-TOF MS
(m/z): 243 (M+ + 1, 28%), 242 (M+, 65), 241 (M+ − 1, 100), 178
(32), 177 (75). Further elution (n-hexane/t-BuOMe, 90:10) gave 5,7-
dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (7a) as
red needles (17.2 mg, 82%): mp (DSC) onset, 98.2 °C; peak max,
98.6 °C, bp onset, 189.6 °C; peak max, 198.3 °C (from n-hexane). Rf
0.32 (n-hexane/t-BuOMe, 80:20). (Found: C, 40.10; H, 2.69; N,
26.54. C7H6N4S2 requires: C, 39.98; H, 2.88; N, 26.65%.) λmax(DCM)
288 (log ε 3.82), 357 inf (3.60), 377 (3.64), 521 (2.81). vmax/cm−1
2943w (CH3), 2218m (CN), 1504s, 1495m, 1452m, 1377m,
1337w, 1292m, 1209w, 1177w, 1103m, 1065s, 1045m, 1038m, 988w,
912m, 764w, 746m. δH (500 MHz, CDCl3) 3.78 (3H, s), 2.19 (3H, s).
δC (125 MHz, CDCl3) 146.3 (s), 143.2 (s), 126.2 (s), 113.0 (s), 94.5
(s), 35.4 (q), 12.1 (q). MALDI-TOF MS (m/z): 212 (M+ + 2, 26%),
211 (M+ + 1, 81), 210 (M+, 100), 195 (56).
trithiazepine 9a in yields as high as 47%. Interestingly,
extending the reaction times (>16 h) serendipitously afforded
pyrazolo[3,4-e][1,4]thiazine 13. Other unexpected chemistry
occurred when disulfide 8a was heated in neat acetonitrile,
affording the unusual tetracyclic 6H-pyrazolo[3,4-f ]pyrazolo-
[3′,4′:4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine 19. The reac-
tions described above demonstrate that 4-chloro-1,2,3-
dithiazoles can now can be used to provide facile access to
fused 1,2,4-dithiazines, a difficult-to-access and potentially
interesting ring system.
4. EXPERIMENTAL SECTION
4.1. General Methods and Materials. All chemicals were
commercially available except those whose synthesis is described. 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).33 Melting points were determined using a Koefler−
Hotstage microscope apparatus or a DSC with samples hermetically
sealed in aluminum pans under an argon atmosphere, 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 a FTIR spectrometer with a Ge
ATR accessory, and strong, medium, and weak peaks are represented
1
by s, m, and w, respectively. H and 13C NMR spectra were recorded
at 500 and 125 MHz, respectively. Deuterated solvents were used for
homonuclear lock, and the signals are referenced to the deuterated
solvent peaks. APT NMR studies identified quaternary, tertiary,
secondary, and primary carbons, which are indicated by (s), (d), (t),
and (q) notations, respectively. MALDI-TOF MS was conducted on a
time-of-flight (TOF) mass spectrometer or on a EI GC-MS. (Z)-N-(4-
Chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines (5a−f),18
(Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline (10a),34 (Z)-N-
(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methoxyaniline (10b),34 and
(Z)-5-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]-2-methoxyphe-
nol (10d)35 were prepared according to literature procedures.
4.2. Stepwise Synthesis of 5,7-Dimethyl-5H-pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitrile (7a). 4.2.1. (Z)-2-[(Diethyl-
amino)disulfanyl-2-(1,3-dimethyl-1H-pyrazol-5-yl)imino]-acetoni-
trile (8a). To a stirred suspension of (Z)-N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-1,3-dimethyl-1H-pyrazol-5-amine (5a) (49.3 mg,
4.3. One-Pot Transformation of (Z)-N-(4-Chloro-5H-1,2,3-
dithiazol-5-ylidene)-1H-pyrazol-5-amines 5 to 5H-Pyrazolo-
[3,4-e][1,2,4]dithiazine-3-carbonitriles 7. General Procedure. To
a stirred suspension of the appropriate (Z)-N-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-1H-pyrazol-5-amine 5 (0.2 mmol) in MeCN (4
mL) at ca. 20 °C was added Hunig’s base (34.5 μL, 0.2 mmol)
̈
followed by diethylamine (63.0 μL, 0.6 mmol). After 25 min stirring,
to the mixture was added in one portion concd H2SO4 (55 μL, 1
mmol). The mixture was stirred for 5 min and then adsorbed onto
silica and chromatographed to give the corresponding 6H-pyrazolo-
[3,4-f ][1,2,3,5]trithiazepine-4-carbonitriles 9 and 5H-pyrazolo[3,4-
e][1,2,4]dithiazine-3-carbonitriles 7.
4.3.1. 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-car-
bonitrile (7a). Chromatography eluent: n-hexane/t-BuOMe, 90:10.
Obtained as red needles (31 mg, 74%): mp (DSC) onset, 98.2 °C;
peak max, 98.6 °C, bp onset, 189.6 °C; peak max, 198.3 °C (from n-
hexane). Rf 0.32 (n-hexane/t-BuOMe, 80:20). Identical to that
described above.
0.2 mmol) in MeCN (4 mL) at ca. 20 °C was added Hunig’s base
̈
(34.5 μL, 0.2 mmol) followed by diethylamine (63.0 μL, 0.6 mmol).
After 25 min stirring, the reaction mixture was diluted with n-hexane
and poured onto a packed silica column. Elution with DCM/t-BuOMe
(90:10) afforded a mixture from which the volatiles were removed
under vacuum. The remaining residue was diluted with DCM,
adsorbed onto silica, and chromatographed (DCM/t-BuOMe, 95:5) to
give the title compound 8a (50 mg, 89%) as beige needles: mp (DSC)
onset, 64.4 °C; peak max, 65.0 °C; decomp. onset, 91.5 °C; peak max,
99.4 °C (from n-pentane at ca. −20 °C). Rf 0.43 (DCM). (Found: C,
46.53; H, 5.99; N, 24.66. C11H17N5S2 requires: C, 46.62; H, 6.05; N,
24.71%.) λmax(DCM) 246 (log ε 3.96), 352 (4.16). vmax/cm−1 3138w
(Ar CH), 2972m, 2934m and 2870w (CH2 and CH3), 2214m (C
N), 1557m, 1512m, 1470m, 1445m, 1375m, 1368m, 1348m, 1302m,
1173m, 1163m, 1098w, 1065s, 1043s, 1011s, 920m, 914m, 847m,
795m. δH(500 MHz; CDCl3) major 6.27 (1H, s), 3.86 (3H, s), 3.09
(4H, q, J = 7.3 Hz), 2.28 (3H, s), 1.21 (6H, t, J = 7.0 Hz); minor 6.63
(1H, s), 3.85 (3H, s), 3.03 (4H, q, J = 7.2 Hz), 2.28 (3H, s), 1.20 (6H,
t, J = 7.3 Hz) (major/minor, 5:1). δC (125 MHz, CDCl3) major 147.8
(s), 143.5 (s), 138.8 (s), 113.2 (s), 100.8 (d), 52.3 (t), 35.3 (q), 13.93
(q), 13.1 (q); minor 148.2 (s), 144.4 (s), 137.3 (s), 109.8 (s), 95.1 (d),
52.2 (t), 35.0 (q), 13.94 (q), 13.2 (q). MALDI-TOF MS (m/z): 285
(M+ + 2, 57%), 284 (M+ + 1, 99), 213 (100), 181 (69), 104 (47), 71
(52).
4.3.2. 5-Methyl-7-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitrile (7b). Chromatography eluent: n-hexane/t-BuOMe, 98:2.
Obtained as red needles (41 mg, 75%): mp (DSC) onset, 106.8 °C;
peak max, 108.5 °C; decomp. onset, 175.9 °C; peak max, 211.4 °C
(from n-hexane). Rf 0.38 (n-hexane/t-BuOMe, 90:10). (Found: C,
52.86; H, 2.89; N, 20.58. C12H8N4S2 requires: C, 52.92; H, 2.96; N,
20.57%.) λmax(DCM) 255 (log ε 4.31), 325 inf (3.51), 409 (3.59), 508
(2.77). vmax/cm−1 2945w (CH3), 2222w (CN), 1522m, 1481m,
1454m, 1431m, 1308m, 1204w, 1180w, 1169w, 1074m, 1045m,
1009m, 916w, 868w, 772s, 746m. δH (500 MHz, CDCl3) 7.68 (2H, d,
J = 8.0 Hz), 7.45 (2H, dd, J = 7.3, 7.3 Hz), 7.38 (1H, dd, J = 7.5, 7.5
Hz), 3.91 (3H, s). δC (125 MHz, CDCl3) 146.9 (s), 145.6 (s), 130.8
(s), 128.9 (d), 128.8 (d), 126.7 (d), 126.3 (d), 113.0 (s), 93.8 (s), 35.9
(q). MALDI-TOF MS (m/z): 274 (M+ + 2, 15%), 273 (M+ + 1, 59),
272 (M+, 100), 257 (69), 168 (7).
4.3.3. 5-Benzyl-7-methyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitrile (7c). Chromatography eluent: n-hexane/t-BuOMe, 95:5.
Obtained as red oil (45 mg, 78%), (DSC) decomp. onset, 171.8 °C;
peak max, 204.1 °C. Rf 0.31 (n-hexane/t-BuOMe, 90:10). (Found: C,
54.60; H, 3.39; N, 19.54. C13H10N4S2 requires: C, 54.52; H, 3.52; N,
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19.56%.) λmax(DCM) 295 (log ε 3.68), 357 inf (3.59), 377 (3.63), 522
(2.77). vmax/cm−1 3065w and 3032w (Ar CH), 2928w and 2853w
(CH2 and CH3), 2220w (CN), 1514m, 1497m, 1460m, 1454m,
1441m, 1375w, 1358w, 1314m, 1294m, 1279m, 1227w, 1204w,
1182w, 1144m, 1094m, 1061m, 1030m, 1003w, 918m, 907m, 820w,
758m, 735s. δH (500 MHz, CDCl3) 7.35−7.29 (3H, m), 7.24 (2H, d, J
= 7.3 Hz), 5.25 (2H, s), 2.20 (3H, s). δC (125 MHz, CDCl3) 146.1 (s),
143.8 (s), 135.5 (s), 128.8 (d), 128.2 (d), 127.9 (d), 126.2 (s), 113.1
(s), 95.0 (s), 52.3 (t), 12.3 (q). MALDI-TOF MS (m/z): 288 (M+ + 2,
63%), 287 (M+ + 1, 93), 286 (M+, 100), 253 (36), 245 (12), 195 (12),
182 (22), 104 (7), 91 (98).
4.3.4. 5-Benzyl-7-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitrile (7d). Chromatography eluent: n-hexane/t-BuOMe, 95:5.
Obtained as brown needles (59 mg, 85%): mp (DSC) onset, 130.3 °C;
peak max, 134.3 °C; decomp. onset, 187.3 °C; peak max, 208.5 °C
(from c-hexane). Rf 0.52 (n-hexane/t-BuOMe, 90:10). (Found: C,
61.92; H, 3.62; N, 15.94. C18H12N4S2 requires: C, 62.05; H, 3.47; N,
16.08%.) λmax(DCM) 253 (log ε 4.32), 305 inf (3.62), 407 (3.62), 520
(2.77). vmax/cm−1 3063w and 3032w (Ar CH), 2976w and 2940w
(CH2), 2222w (CN), 1530m, 1495m, 1481m, 1464w, 1452m,
1427m, 1354m, 1331m, 1317m, 1294m, 1283m, 1180m, 1132m,
1067m, 1026w, 1009m, 916w, 907w, 872w, 772s, 731s. δH (500 MHz,
CDCl3) 7.71 (2H, d, J = 7.0 Hz), 7.44 (2H, dd, J = 7.5, 7.5 Hz), 7.39−
7.30 (6H, m), 5.39 (2H, s). δC (125 MHz, CDCl3) one C (d)
resonance missing 146.6 (s), 146.0 (s), 135.3 (s), 130.8 (s), 128.87
(d), 128.85 (d), 128.3 (d), 127.9 (d), 126.8 (d), 126.2 (s), 113.1 (s),
94.2 (s), 52.8 (t). MALDI-TOF MS (m/z): 350 (M+ + 2, 36%), 349
(M+ + 1, 80), 348 (M+, 100), 315 (11), 257 (14), 245 (30), 90 (80).
The dithiazine 7d coeluted on chromatography with the trithiazepine
9d; nevertheless, a microanalytically pure sample of compound 7d was
obtained by recrystallization.
4.3.5. 7-Methyl-5-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitrile (7e). Chromatography eluent: n-hexane/t-BuOMe, 95:5.
Obtained as brown needles (46 mg, 85%): mp (DSC) onset, 90.2 °C;
peak max, 91.4 °C; decomp. onset, 157.2 °C; peak max, 179.8 °C
(from n-pentane at ca. −20 °C). Rf 0.44 (n-hexane/t-BuOMe, 90:10).
(Found: C, 53.01; H, 2.87; N, 20.56. C12H8N4S2 requires: C, 52.92; H,
2.96; N, 20.57%.) λmax(DCM) 239 (log ε 4.24), 307 (3.63), 359 inf
(3.60), 401 (3.76), 520 (2.87). vmax/cm−1 3105w, 3082w and 3049w
(Ar CH), 2924 (CH3), 2216w (CN), 1591m, 1504s, 1464m,
1435m, 1418m, 1368w, 1352m, 1319w, 1163m, 1107m, 1074m,
1057m, 1024m, 1001w, 964w, 932w, 907m, 854m, 760s, 733s. δH (500
MHz, CDCl3) 7.59 (2H, d, J = 8.0 Hz), 7.47 (2H, dd, J = 8.0, 8.0 Hz),
7.37 (1H, dd, J = 7.5, 7.5 Hz), 2.32 (3H, s). δC (125 MHz, CDCl3)
146.0 (s), 144.6 (s), 137.6 (s), 129.2 (d), 128.0 (d), 125.4 (s), 122.7
(d), 113.1 (s), 98.1 (s), 12.4 (q). MALDI-TOF MS (m/z): 274 (M+ +
2, 25%), 273 (M+ + 1, 100), 272 (M+, 44), 246 (5), 239 (19), 240
(22), 231 (13), 220 (35), 209 (22), 198 (3), 155 (5).
4.3.6. 5,7-Diphenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbon-
itrile (7f). Chromatography eluent: n-hexane/t-BuOMe, 95:5.
Obtained as orange/brown cotton fibers (54 mg, 80%): mp (DSC)
onset, 144.7 °C; peak max, 147.0 °C; decomp. onset, 149.2 °C; peak
max, 164.2 °C (from n-hexane at ca. −20 °C). Rf 0.56 (n-hexane/t-
BuOMe, 90:10). (Found: C, 61.08; H, 2.94; N, 16.57. C17H10N4S2
requires: C, 61.06; H, 3.01; N, 16.75%.) λmax(DCM) 239 (log ε 4.25),
267 (4.33), 332 inf (3.53), 422 (3.67), 509 inf (2.93). vmax/cm−1
3061w (Ar CH), 2218w (CN), 1595m, 1518m, 1499s, 1477m,
1460m, 1454m, 1427m, 1344m, 1319m, 1300m, 1236w, 1202m,
1152m, 1090m, 1072m, 1055m, 1026m, 1003m, 982m, 903m, 835m,
764s, 758s, 731m. δH (500 MHz, CDCl3) 7.81 (2H, d, J = 7.0 Hz),
7.71 (2H, d, J = 8.0 Hz), 7.53−7.48 (4H, m), 7.45−7.41 (2H, m). δC
(125 MHz, CDCl3) 146.7 (s), 146.6 (s), 137.7 (s), 130.6 (s), 129.23
(d), 129.20 (d), 129.0 (d), 128.3 (d), 127.0 (d), 125.4 (s), 123.1 (d),
113.1 (s), 97.3 (s). MALDI-TOF MS (m/z): 336 (M+ + 2, 22%), 335
(M+ + 1, 63), 334 (M+, 100), 301 (12), 282 (13), 271 (3), 231 (36),
198 (3), 155 (4).
max, 185.7 °C (from n-pentane at ca. −20 °C). Rf 0.40 (n-hexane/t-
BuOMe, 80:20). Identical to that described above.
4.3.8. 6-Methyl-8-phenyl-6H-pyrazolo[3,4-f ][1,2,3,5]-
trithiazepine-4-carbonitrile (9b). Chromatography eluent: n-hexane/
t-BuOMe, 90:10. Obtained as pale yellow needles (3.0 mg, 5%): mp
104−106 °C (from n-pentane at ca. −20 °C). Rf 0.40 (n-hexane/t-
BuOMe, 90:10). (Found: C, 47.30; H, 2.54; N, 18.32. C12H8N4S3
requires: C, 47.35; H, 2.65; N, 18.41%.) λmax(DCM) 250 (log ε 4.32),
295 inf (3.79), 385 (3.95). vmax/cm−1 3059w (Ar CH), 2947w (CH3),
2218w (CN), 1589m, 1558m, 1506m, 1456m, 1448m, 1433m,
1414m, 1387w, 1341w, 1317m, 1306m, 1200w, 1182w, 1157w, 1146w,
1076m, 1020m, 1003m, 914m, 853w, 770s, 758m. δH (500 MHz,
CDCl3) 7.68 (2H, d, J = 8.0 Hz), 7.47 (2H, dd, J = 7.5, 7.5 Hz), 7.42
(1H, dd, J = 7.5, 7.5 Hz), 4.08 (3H, s). δC (125 MHz, CDCl3) 148.9
(s), 141.1 (s), 131.2 (s), 128.9 (d), 128.7 (d), 128.3 (s), 127.8 (d),
120.5 (s), 114.5 (s), 37.2 (q). MALDI-TOF MS (m/z): 306 (M+ + 2,
48%), 305 (M+ + 1, 100), 304 (M+, 86), 242 (18), 241 (70), 240 (33).
Although the compound was obtained microanalytically pure by
recrystallization, it was not very stable in solution and afforded a trace
of dithiazine 7b, which was visible in the NMR.
4.3.9. 6-Benzyl-8-methyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-
4-carbonitrile (9c). Chromatography eluent: n-hexane/t-BuOMe,
90:10. Obtained as yellow needles (3.8 mg, 6%): mp (DSC) onset,
115.0 °C; peak max, 118.7 °C; decomp. onset, 171.6 °C; peak max,
193.3 °C (from n-pentane at ca. −20 °C). Rf 0.52 (n-hexane/t-
BuOMe, 90:10). (Found: C, 48.98; H, 3.06; N, 17.43. C13H10N4S3
requires: C, 49.04; H, 3.17; N, 17.60%.) λmax(DCM) 303 (log ε 3.76),
370 (3.88), 407 inf (3.57). vmax/cm−1 2212w (CN), 1582m, 1558w,
1539w, 1522w, 1506w, 1497m, 1477m, 1454m, 1422m, 1402m,
1360w, 1346w, 1323m, 1296m, 1279w, 1204w, 1152w, 1076m, 1055s,
1028m, 1003m, 947w, 905m, 818w, 795w, 768s, 735s. δH (500 MHz,
CDCl3) 7.36−7.28 (5H, m), 5.47 (2H, s), 2.29 (3H, s). δC (125 MHz,
CDCl3) 146.6 (s), 140.2 (s), 136.0 (s), 128.8 (d), 128.13 (d), 128.12
(d), 128.0 (s), 121.4 (s), 114.5 (s), 53.3 (t), 12.7 (q). MALDI-TOF
MS (m/z): 320 (M+ + 2, 78%), 319 (M+ + 1, 80), 318 (M+, 28), 310
(7), 286 (18), 278 (6), 256 (40), 255 (100), 91 (86).
4.4. Synthesis of (Z)-3-[(4-Chloro-5H-1,2,3-dithiazol-5-
ylidene)amino]phenol (10c). To a stirred suspension of 4,5-
dichloro-1,2,3-dithiazolium chloride (500 mg, 2.4 mmol) in DCM (10
mL) protected by CaCl2 drying tube at ca. 20 °C was added 3-
aminophenol (262 mg, 2.4 mmol) in one portion. After 2 h, to the
reaction mixture was added Hunig’s base (835 μL, 4.8 mmol). After an
̈
additional 1 h, the mixture was adsorbed on silica and chromato-
graphed (DCM) to give unidentified minor red side products. Further
elution (DCM/t-BuOMe, 95:5) gave (Z)-3-[(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)amino]phenol (10c) as yellow plates (245 mg,
42%): mp 102−104 °C (from c-hexane/1,2-DCE). Rf 0.45 (DCM/t-
BuOMe, 96:4). (Found: C, 39.19; H, 1.93; N, 11.36. C8H5ClN2OS2
requires: C, 39.27; H, 2.06; N, 11.45%.) λmax(DCM) 377 (log ε 3.74).
vmax/cm−1 3242m (OH), 1585s, 1574s, 1518w, 1503w, 1476m, 1462m,
1314m, 1300m, 1281m, 1227m, 1173s, 1136m, 1078m, 997m, 959m,
897s, 866m, 808m, 787m, 754m. δH (500 MHz, DMSO-d6) 9.73 (1H,
br s), 7.27 (1H, dd, J = 8.0, 8.0 Hz), 6.65 (1H, dd, J = 8.0, 1.5 Hz),
6.62 (1H, dd, J = 8.0, 1.5 Hz), 6.59 (1H, dd, J = 2.0, 2.0 Hz). δC (125
MHz, DMSO-d6) 159.0 (s), 158.6 (s), 152.1 (s), 146.7 (s), 130.7 (d),
113.2 (d), 109.7 (d), 105.8 (d). m/z (EI) 246 (M+ + 2, 21%), 244
(M+, 51), 209 (19), 183 (16), 151 (8), 145 (13), 119 (100), 93 (21),
91 (14), 64 (37).
4.5. One-Pot Transformation of N-(4-Chloro-5H-1,2,3-dithia-
zol-5-ylidene)-anilines 10 to Benzo[e][1,2,4]dithiazine-3-car-
bonitriles 11. General Procedure. To a stirred suspension of the
appropriate N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 10 (0.2
mmol) in MeCN (4 mL) at ca. 20 °C was added Hunig’s base (34.5
̈
μL, 0.2 mmol) followed by diethylamine (63.0 μL, 0.6 mmol). After 25
min stirring, to the mixture was added in one portion concd H2SO4
(55 μL, 1 mmol). The mixture was stirred for 5 min and then adsorbed
on silica and chromatographed to give the corresponding benzo[e]-
[1,2,4]dithiazine-3-carbonitriles 11 and benzo[d]thiazole-2-carbon-
itriles 12.
4.3.7. 6,8-Dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-
carbonitrile (9a). Chromatography eluent: n-hexane/t-BuOMe
(90:10). Obtained as yellow needles (2.4 mg, 5%): mp (DSC)
onset, 66.7 °C; peak max, 71.7 °C; decomp. onset, 166.8 °C; peak
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4.5.1. 6-Methoxybenzo[e][1,2,4]dithiazine-3-carbonitrile (11b).
Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as red
plates (7.6 mg, 17%): mp (DSC) onset, 129.1 °C; peak max, 129.5 °C;
decomp. onset, 130.5 °C; peak max, 153.0 °C (from c-hexane). Rf 0.71
(n-hexane/DCM, 50:50). (Found: C, 48.51; H, 2.73; N, 12.50.
C9H6N2OS2 requires: C, 48.63; H, 2.72; N, 12.60%.) λmax(DCM) 258
(log ε 4.13), 279 inf (3.88), 350 (3.56), 481 (2.67). vmax/cm−1 2972w,
2848w, 2228w (CN), 1595m, 1557m, 1530m, 1468m, 1437m,
1398w, 1310m, 1277m, 1236s, 1196w, 1165m, 1128m, 1069m, 1057s,
1024m, 951m, 851m, 816s, 754m. δH (500 MHz, CDCl3) 7.24−7.22
(1H, m), 6.94−6.92 (2H, m), 3.84 (3H, s). δC (125 MHz, CDCl3)
161.0 (s), 145.5 (s), 133.6 (s), 129.7 (d), 117.7 (d), 112.9 (s), 112.5
(d), 109.9 (s), 55.8 (q). MALDI-TOF MS (m/z): 224 (M+ + 2, 19%),
223 (M+ + 1, 64), 222 (M+, 96), 204 (100).
4.5.2. 6-Hydroxybenzo[e][1,2,4]dithiazine-3-carbonitrile (11c).
Chromatography eluent: DCM. Obtained as red prisms (23 mg,
55%): mp (DSC) onset, 148.2 °C; peak max, 150.6 °C; decomp.
onset, 152.9 °C; peak max, 156.7 °C (from CHCl3). Rf 0.60 (DCM/t-
BuOMe, 96:4). (Found: C, 46.25; H, 1.86; N, 13.33. C8H4N2OS2
requires: C, 46.14; H, 1.94; N, 13.45%.) λmax(DCM) 256 (log ε 3.94),
277 inf (3.69), 346 (3.38), 482 (2.41). vmax/cm−1 3379m (OH),
2241m (CN), 1609w, 1560m, 1541m, 1506w, 1470m, 1431m,
1333m, 1290s, 1250m, 1227m, 1217m, 1152s, 1136w, 1126m, 1067m,
1051m, 963m, 878m, 822s, 766m. δH (500 MHz, CDCl3) 7.21−7.20
(1H, m), 6.89−6.87 (2H, m), 5.57 (1H, br s). δC (125 MHz, CDCl3)
157.2 (s), 145.4 (s), 133.9 (s), 130.0 (d), 118.4 (d), 114.6 (d), 112.8
(s), 110.2 (s). MALDI-TOF MS (m/z): 210 (M+ + 2, 17%), 209 (M+
+ 1, 100), 208 (M+, 22).
4.5.3. 6-Hydroxy-7-methoxybenzo[e][1,2,4]dithiazine-3-carboni-
trile (11d). Chromatography eluent: DCM. Obtained as red needles
(33 mg, 70%): mp (DSC) onset, 172.8 °C; peak max, 174.6 °C;
decomp. onset, 175.4 °C; peak max, 177.8 °C (from c-hexane/DCM).
Rf 0.40 (DCM). (Found: C, 45.34; H, 2.46; N, 11.58. C9H6N2O2S2
requires: C, 45.37; H, 2.54; N, 11.76%.) λmax(DCM) 271 (log ε 4.35),
359 (3.76), 485 (3.20). vmax/cm−1 3372m (OH), 3005w (Ar CH),
2990w, 2945w and 2837w (CH3), 2239m (CN), 1609m, 1562m,
1522m, 1497s, 1462m, 1449m, 1433m, 1342m, 1283s, 1260s, 1225m,
1207m, 1179m, 1171m, 1157m, 1061m, 1051m, 1040m, 1009m, 874s,
812m, 766m. δH (500 MHz, CDCl3) 6.98 (1H, s), 6.74 (1H, s), 5.72
(1H, s), 3.96 (3H, s). δC (125 MHz, CDCl3) 148.5 (s), 147.0 (s),
139.9 (s), 128.5 (s), 114.5 (d), 113.1 (s), 110.3 (d), 109.7 (s), 56.5
(q). MALDI-TOF MS (m/z): 240 (M+ + 2, 26%), 239 (M+ + 1, 100),
238 (M+, 63), 220 (30), 212 (10), 206 (22), 205 (12).
4.5.4. 5-Methoxybenzo[d]thiazole-2-carbonitrile (12b). Chroma-
tography eluent: n-hexane/t-BuOMe, 90:10. Obtained as colorless
needles (3.0 mg, 8%): mp 94−96 °C, lit.36 99−100 °C (from c-
hexane). Rf 0.68 (DCM). λmax(DCM) 287 (log ε 4.05), 295 inf (4.05),
349 (3.62). δH (500 MHz, CDCl3) 7.82 (1H, d, J = 9.0 Hz), 7.63 (1H,
d, J = 2.5 Hz), 7.28 (1H, dd, J = 9.0, 2.5 Hz), 3.92 (3H, s). δC (125
MHz, CDCl3) 160.2 (s), 153.9 (s), 137.1 (s), 127.4 (s), 121.9 (d),
120.1 (d), 113.1 (s), 106.1 (d), 55.8 (q). MALDI-TOF MS (m/z):
192 (M+ + 2, 91%), 191 (M+ + 1, 100).
1007m, 907w, 856m, 835m, 827m, 777m. δH (500 MHz, CDCl3) 7.68
(1H, s), 7.31 (1H, s), 6.01 (1H, br s), 4.04 (3H, s). δC (125 MHz,
CDCl3) 149.3 (s), 147.5 (s), 147.3 (s), 133.8 (s), 128.0 (s), 113.3 (s),
108.6 (d), 100.9 (d), 56.5 (q). MALDI-TOF MS (m/z): 208 (M+ + 2,
8%), 207 (M+ + 1, 54), 193 (26), 192 (100), 191 (6), 181 (20), 175
(7).
4.6. Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-e]-
[1,2,4]dithiazine-3-carbonitrile (7a) to 6,8-Dimethyl-6H-
pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-carbonitrile (9a). A mix-
ture of 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile
(7a) (21 mg, 0.1 mmol), S8 (256 mg, 1 mmol), and DABCO (11.2
mg, 0.1 mmol) in PhCl (2 mL) was heated in a preheated Wood’s
metal bath at ca. 100 °C. After 6 min, the reaction was cooled to ca. 0
°C, filtered, and washed with n-hexane to remove excess sulfur. The
filtrate was poured onto packed silica and chromatographed (n-
hexane/t-BuOMe, 90:10) to give 6,8-dimethyl-6H-pyrazolo[3,4-f ]-
[1,2,3,5]trithiazepine-4-carbonitrile (9a) (6.3 mg, 26%) as yellow
needles: mp (DSC) onset, 66.7 °C; peak max, 71.7 °C; decomp. onset,
166.8 °C; peak max, 185.7 °C (from n-pentane at ca. −20 °C). Rf 0.40
(n-hexane/t-BuOMe, 80:20). Identical to that described above.
Further elution (n-hexane/t-BuOMe, 90:10) gave unreacted 5,7-
dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (7a) as
red needles (9.5 mg, 45%): mp (DSC) onset, 98.2 °C; peak max,
98.6 °C, bp onset, 189.6 °C; peak max, 198.3 °C (from n-hexane). Rf
0.32 (n-hexane/t-BuOMe, 80:20). Identical to that described above.
4.7. Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-e]-
[1,2,4]dithiazine-3-carbonitrile (7a) to 5,7-Dimethyl-5H-[1,2,3]-
dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine (13). A mixture of
5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile (7a)
(21 mg, 0.1 mmol), S8 (256 mg, 1.0 mmol), and DABCO (11.2 mg,
0.1 mmol) in PhCl (2 mL) was heated at ca. 100 °C. After 16 h, the
reaction was cooled to ca. 0 °C, filtered, and washed with DCM to
remove excess sulfur. The filtrate was adsorbed onto silica and
chromatographed (n-hexane) to give sulfur. Further elution (DCM)
gave traces of 6,8-dimethyl-6H-pyrazolo[3,4-f ][1,2,3,5]trithiazepine-4-
carbonitrile (9a) and 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]-
dithiazine-3-carbonitrile (7a). Further elution (DCM) gave 1,3-
dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile (6a) as colorless
needles (3.0 mg, 17%): mp 99−100.5 °C, lit.18 99−100.5 °C (from c-
hexane). Rf 0.20 (DCM). δH (500 MHz, CDCl3) 4.07 (3H, s), 2.47
(3H, s). m/z (EI) 178 (M+, 100%), 163 (15), 85 (94), 70 (86), 58 (8).
Identical to an authentic sample. Further elution (DCM) gave 5,7-
dimethyl-5H-[1,2,3]dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine (13)
(5.5 mg, 23%) as orange needles: mp (DSC) onset, 186.6 °C; peak
max, 187.6 °C (from c-hexane). Rf 0.24 (n-hexane/t-BuOMe, 80:20).
(Found: C, 34.58; H, 2.39; N, 22.98. C7H6N4S3 requires: C, 34.69; H,
2.50; N, 23.12%.) λmax(DCM) 275 (log ε 4.19), 347 (3.20), 359 inf
(3.17), 436 inf (3.62), 457 inf (3.77), 480 (3.84), 505 inf (3.70). vmax
/
cm−1 2947w and 2918w (CH3), 1508m, 1504m, 1474m, 1454m,
1369m, 1358m, 1288m, 1101m, 1057m, 989w, 945m, 854m, 735s. δH
(500 MHz, CDCl3) 3.71 (3H, s), 2.08 (3H, s). δC (125 MHz, CDCl3)
171.0 (s), 148.9 (s), 141.1 (s), 140.9 (s), 91.0 (s), 34.2 (q), 12.0 (q).
MALDI-TOF MS (m/z): 244 (M+ + 2, 15%), 243 (M+ + 1, 40), 242
(M+, 100).
4.5.5. 5-Hydroxybenzo[d]thiazole-2-carbonitrile (12c). Chroma-
tography eluent: DCM/t-BuOMe, 95:5. Obtained as colorless needles
(4.2 mg, 12%): mp (DSC) onset, 192.1 °C; peak max, 193.2 °C, lit.37
193.5−194 °C (from c-hexane/CHCl3). Rf 0.40 (DCM/t-BuOMe,
92:8). λmax(DCM) 285 (log ε 4.06), 295 inf (3.99), 341 (3.61). δH
(500 MHz, CDCl3) 7.82 (1H, d, J = 9.0 Hz), 7.62 (1H, d, J = 2.5 Hz),
7.23 (1H, dd, J = 9.0, 2.5 Hz), 5.69 (1H, s). δC (125 MHz, DMSO-d6)
158.0 (s), 153.3 (s), 137.1 (s), 125.8 (s), 123.4 (d) 119.7 (d), 113.5
(s), 108.2 (d). MALDI-TOF MS (m/z): 178 (M+ + 2, 44%), 177 (M+
+ 1, 100), 164 (11), 159 (38), 151 (53).
4.5.6. 5-Hydroxy-6-methoxybenzo[d]thiazole-2-carbonitrile
(12d). Chromatography eluent: DCM/t-BuOMe, 95:5. Obtained as
colorless plates (5.4 mg, 13%): mp 173−175 °C (from c-hexane/
CHCl3). Rf 0.69 (DCM/t-BuOMe, 90:10). (Found: C, 52.50; H, 3.01;
N, 13.58. C9H6N2O2S requires: C, 52.42; H, 2.93; N, 13.58%.)
λmax(DCM) 266 (log ε 3.76), 312 (4.03), 335 (3.75). vmax/cm−1
3292w (OH), 2226m (CN), 1551m, 1485m, 1466w, 1452m,
1423m, 1354w, 1288s, 1234m, 1204m, 1182m, 1128m, 1047m,
4.8. Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-
carbonitriles 7. General Procedure. A stirred solution of the
appropriate 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 7 (0.1
mmol) in Ph2O (1 mL) was heated at ca. 250 °C. After consumption
of the starting material (by TLC) the mixture was adsorbed onto silica
and chromatographed.
4.8.1. 1,3-Dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile
(6a). Chromatography eluent: DCM/t-BuOMe, 90:10. Obtained as
colorless needles (17.8 mg, 100%): mp 99−100.5 °C, lit.18 99−100.5
°C (from c-hexane). Rf 0.20 (DCM). δH (500 MHz, CDCl3) 4.07 (3H,
s), 2.47 (3H, s). m/z (EI) 178 (M+, 100%), 163 (15), 85 (94), 70
(86), 58 (8). Identical to that described above.
4.8.2. 1-Methyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (6b). Chromatography eluent: DCM. Obtained as colorless
needles (22.8 mg, 95%): mp (DSC) onset, 170.5 °C; peak max, 171.3
°C (from c-hexane). Rf 0.53 (DCM). δH (500 MHz, CDCl3) 7.80 (2H,
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d, J = 7.0 Hz), 7.50 (2H, dd, J = 7.5, 7.5 Hz), 7.40 (1H, dd, J = 7.3, 7.3
Hz), 4.21 (3H, s). MALDI-TOF MS (m/z): 240 (M+, 100). Identical
to an authentic sample.18
4.8.3. 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (6c). Chromatography eluent: DCM. Obtained as colorless
prisms (24.1 mg, 95%): mp 91−93 °C (from n-pentane at ca. −20
°C). Rf 0.56 (DCM). δH (500 MHz, DMSO-d6) 7.34−7.25 (5H, m),
5.54 (2H, s), 2.42 (3H, s). MALDI-TOF MS (m/z): 255 (M+ + 1,
100), 242 (15), 91 (55). Identical to an authentic sample.18
4.8.4. 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (6d). Chromatography eluent: n-hexane/DCM, 50:50. Obtained
as beige needles (29.7, 94%): mp 113.5−114.5 °C (from c-hexane). Rf
0.50 (n-hexane/DCM, 50:50). δH (500 MHz, CDCl3) 7.82 (2H, d, J =
7.0 Hz), 7.49 (2H, dd, J = 7.8, 7.8 Hz), 7.44−7.38 (3H, m), 7.37−7.29
(3H, m), 5.66 (2H, s). MALDI-TOF MS (m/z): 317 (M+ + 1, 100%),
91 (90). Identical to an authentic sample.18
4.8.5. 3-Methyl-1-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboni-
trile (6e). Chromatography eluent: n-hexane/DCM, 50:50. Obtained
as beige plates (24 mg, 100%): mp 127−128.5 °C (from c-hexane). Rf
0.50 (n-hexane/DCM, 50:50). δH (500 MHz, CDCl3) 8.12 (2H, d, J =
8.0 Hz), 7.51 (2H, dd, J = 8.0, 8.0 Hz), 7.31 (1H, dd, J = 7.3, 7.3 Hz),
2.59 (3H, s). MALDI-TOF MS (m/z): 241 (M+ + 1, 100%), 205 (18).
Identical to an authentic sample.18
CrysAlis RED38 for cell refinement and data reduction, WINGX for
geometric calculations,41 and DIAMOND42 for molecular graphics.
The non-H atoms were treated anisotropically. All hydrogen atoms
were placed in calculated, ideal positions and refined as riding on their
respective carbon atoms.
4.10.1. Crystal Refinement Data for Compound 7a. C7H6N4S2, M
= 210.30, monoclinic, space group P2 /c, a = 3.9220(3) Å, b =
̅
1
16.8520(14) Å, c = 13.4334(11) Å, α = 90(3)o, β = 94.338(8)o, γ =
90°, V = 885.32(12) Å3, Z = 4, T = 100(2) K, ρcalcd = 1.578 g cm−3,
2θmax = 25. Refinement of 118 parameters on 1565 independent
reflections out of 2092 measured reflections (Rint = 0.0440) led to R1 =
0.0392 [I > 2s(I)], wR2 = 0.1006 (all data), and S = 1.052, with the
largest difference peak and hole of 0.403 and −0.371 e−3, respectively.
4.10.2. Crystal Refinement Data for Compound 8a. C11H17N5S2,
M = 283.44, triclinic, space group P1, a = 7.9239(7) Å, b = 8.1833(6)
̅
Å, c = 11.9333(11) Å, α = 86.140(7)o, β = 78.319(8)o, γ = 65.964(8)o,
V = 691.97(11) Å3, Z = 2, T = 100(3) K, ρcalcd = 1.360 g cm−3, 2θmax
=
25. Refinement of 163 parameters on 2445 independent reflections out
of 4661 measured reflections (Rint = 0.0540) led to R1 = 0.0503 [I >
2s(I)], wR2 = 0.1466 (all data), and S = 1.076, with the largest
difference peak and hole of 0.493 and −0.566 e−3, respectively.
4.10.3. Crystal Refinement Data for Compound 9a. C7H6N4S3, M
= 242.32, triclinic, space group P1, a = 7.8861(6) Å, b = 8.2893(10) Å,
̅
c = 8.3398(9) Å, α = 113.381(11)o, β = 99.470(8)o, γ = 97.678(8)o, V
4.8.6. 1,3-Diphenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile
(6f). Chromatography eluent: n-hexane/DCM, 60:40). Obtained as
yellow needles (30 mg, 100%): mp (DSC) onset, 185.2 °C; peak max,
185.6 °C (from c-hexane). Rf 0.46 (n-hexane/DCM, 70:30). δH (500
MHz, CDCl3) 8.26 (2H, dd, J = 8.5, 1.0 Hz), 7.93 (2H, dd, J = 8.0, 1.0
Hz), 7.58−7.53 (4H, m), 7.46 (1H, dd, J = 7.3, 7.3 Hz), 7.36 (1H, dd,
J = 7.5, 7.5 Hz). MALDI-TOF MS (m/z): 303 (M+ + 1, 92%), 302
(M+, 100). Identical to an authentic sample.18
= 481.53(10) Å3, Z = 2, T = 100(2) K, ρcalcd = 1.671 g cm−3, 2θmax
=
25. Refinement of 128 parameters on 1697 independent reflections out
of 2833 measured reflections (Rint = 0.0343) led to R1 = 0.0442 [I >
2s(I)], wR2 = 0.1059 (all data), and S = 1.036, with the largest
difference peak and hole of 0.418 and −0.395 e−3, respectively.
4.10.4. Crystal Refinement Data for Compound 13. C7H6N4S3, M
= 242.32, monoclinic, space group P21, a = 3.8380(4) Å, b = 7.3609(8)
Å, c = 16.2830(17) Å, α = 90°, β = 92.324(10)o, γ = 90°, V =
459.64(8) Å3, Z = 2, T = 100(2) K, ρcalcd = 1.751 g cm−3, 2θmax = 25.
Refinement of 127 parameters on 1131 independent reflections out of
1598 measured reflections (Rint = 0.0304) led to R1 = 0.0432 [I >
2s(I)], wR2 = 0.1051 (all data), and S = 1.062, with the largest
difference peak and hole of 0.433 and −0.353 e−3, respectively.
4.10.5. Crystal Refinement Data for Compound 19. C14H12N8S3,
M = 388.53, monoclinic, space group P21/c, a = 9.7319(4) Å, b =
18.6419(9) Å, c = 9.2096(5) Å, α = 90°, β = 94.930(4)o, γ = 90°, V =
1664.64(14) Å3, Z = 4, T = 100(2) K, ρcalcd = 1.550 g cm−3, 2θmax = 25.
Refinement of 226 parameters on 2928 independent reflections out of
3538 measured reflections (Rint = 0.0322) led to R1 = 0.0438 [I >
2s(I)], wR2 = 0.1222 (all data), and S = 1.062, with the largest
difference peak and hole of 0.644 and −0.624 e−3, respectively.
4.9. Transformation of (E)-2-[(Diethylamino)disulfanyl-2-
(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) to
4,6,10,12-Tetramethyl-6H-pyrazolo[3,4-f ]pyrazolo[3′,4′:4,5]-
pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile
(19). A stirred solution of (Z)-2-[(diethylamino)disulfanyl-2-(1,3-
dimethyl-1H-pyrazol-5-yl)imino]acetonitrile (8a) (56.7 mg, 0.2
mmol) in MeCN (4 mL) was heated at ca. 82 °C for 1.25 h. The
mixture was left to cool at ca. 20 °C, diluted with n-hexane, and poured
onto a packed silica column. Chromatography (n-hexane) gave sulfur
and Et2NSxEt2N. Further elution (n-hexane/acetone, 90:10) gave
4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f ]pyrazolo[3′,4′:4,5]pyrimido-
[6,1-d][1,2,3,5]trithiazepine-8,12b-(10H)-dicarbonitrile (19) (26.0
mg, 67%) as colorless prisms: mp (DSC) onset, 209.7 °C; peak
max, 211.4 °C; decomp. onset, 213.5 °C; peak max, 215.2 °C (from c-
hexane). Rf 0.60 (DCM/t-BuOMe, 96:4). (Found: C, 43.22; H, 3.14;
N, 28.77. C14H12N8S3 requires: C, 43.28; H, 3.11; N, 28.84%.)
λmax(DCM) 236 (log ε 4.14), 336 (3.82). vmax/cm−1 2995w, 2949w
and 2926w (CH3), 2245w (CN), 1578s, 1555m, 1522m, 1493m,
1452m, 1437m, 1412m, 1377m, 1364m, 1287s, 1242m 1186m,
1113m, 1096m, 1063w, 1040m, 1009w, 989m, 955m, 912m, 847m,
799m, 752s. δH (500 MHz, CDCl3) 3.89 (3H, s), 3.80 (3H, s), 2.37
(3H, s), 2.35 (3H, s). δC (125 MHz, CDCl3) 149.5 (s), 143.6 (s),
140.5 (s), 138.5 (s), 128.6 (s), 119.4 (s), 111.1 (s), 110.3 (s), 94.5 (s),
63.8 (s), 36.2 (q), 34.6 (q), 12.6 (q), 12.0 (q). MALDI-TOF MS (m/
z): 390 (M+ + 2, 15%), 389 (M+ + 1, 22), 388 (M+, 86%), 377 (11),
368 (27), 323 (100), 153 (7).
4.10. 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 it were cooled for data collection. Unit cell
dimensions were determined and refined by using 1396 (3.83 ≤ θ ≤
29.44°) reflections for 7a, 1925 (3.61 ≤ θ ≤ 28.38°) reflections for 8a,
1339 (3.99 ≤ θ ≤ 28.13°) reflections for 9a, 1061 (3.73 ≤ θ ≤ 27.93°)
reflections for 13, and 2589 (3.90 ≤ θ ≤ 28.84°) reflections for 19.
Empirical absorption corrections (multiscan based on symmetry-
related measurements) were applied using CrysAlis RED software.38
The structure was solved by direct methods using SIR9239 and refined
on F2 using full-matrix least-squares with SHELXL97.40 The following
software packages were used: CrysAlis CCD38 for data collection,
ASSOCIATED CONTENT
■
S
* Supporting Information
Structure elucidation discussions, and ellipsoid representations
of the crystal structures for compounds 7a, 8a, 9a, 13, and 19.
Extended discussion on optimizing the conversion of 5a into
8a, 8a into 7a, and 5a into 7a. Copies of 1D 1H and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org. Crystallographic
data for compounds 7a, 8a, 9a, 13, and 19 has been deposited
with the Cambridge Crystallographic Data Centre with deposit
nos. CCDC 1013809, 1013810, 1017374, 1017375, and
1013811, respectively. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +441223336033; e-mail: deposit@
ccdc.cam.ac.uk).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: koutenti@ucy.ac.cy
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Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the Cyprus Research Promotion
Foundation (grant nos. 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.
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DEDICATION
■
Dedicated to the memory of Professor Charles W. Rees, who
passed away on September 21st, 2006.
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