Synthesis and structure of new imidazo- and pyrazolo[5,1-d][1,2,3,5] thiatriazines based on the reaction of diazoazoles with acyl isothiocyanates controlled by Sa?O interaction

Article abstract of DOI:10.1016/j.tet.2013.06.062

5-Diazoimidazoles and 5-diazopyrazoles have been shown to react with acyl isothiocyanates yielding the imidazo- and pyrazolo[5,1-d][1,2,3,5]thiatriazines stabilized by a nonbonded Sa?O interaction. In contrast to acyl isothiocyanates, alkyl-, aryl-, and arylsulfonyl isothiocyanates do not react with 5-diazoazoles. The nature and the strength of stabilizing intramolecular interaction between non-bonded S and O atoms have been studied by X-ray analysis for mono crystals and DFT calculations for selected azolo[5,1-d][1,2,3,5] thiatriazines. The interaction was described in terms of Weinhold covalence ratio factors, NBO, and AIM schemes. The reaction discovered was used to develop an efficient approach toward the new 8-substituted 4-ethoxycarbonylimino-4- benzoyl- and 4-(3,4,5,6-tetrafluorobenzoyl)iminoimidazo(pyrazolo)[5,1-d][1,2,3, 5]thiatriazines.

Full text of DOI:10.1016/j.tet.2013.06.062

Tetrahedron xxx (2013) 1e6
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and structure of new imidazo- and pyrazolo[5,1-d][1,2,3,5]
thiatriazines based on the reaction of diazoazoles with acyl
isothiocyanates controlled by S/O interaction
,
a,
Elena V. Sadchikova a, Vasiliy A. Bakulev a , Julia O. Subbotina c, Darya L. Privalova a,
Wim Dehaen b, Kristof Van Hecke b, Koen Robeyns b, Luc Van Meervelt b,
Vladimir S. Mokrushin a
*
a TOS Department, Ural Federal University named after the first President of Russia B.N. Yeltsin, Mira str. 19, 620002 Yekaterinburg, Russia
b Department of Chemistry, University of Leuven, B-3001 Leuven, Belgium
c I. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of Russian Academy of Sciences, S. Kovalevskaya Str. 20, 620219 Yekaterinburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Diazoimidazoles and 5-diazopyrazoles have been shown to react with acyl isothiocyanates yielding the
imidazo- and pyrazolo[5,1-d][1,2,3,5]thiatriazines stabilized by a nonbonded S/O interaction. In contrast
to acyl isothiocyanates, alkyl-, aryl-, and arylsulfonyl isothiocyanates do not react with 5-diazoazoles. The
nature and the strength of stabilizing intramolecular interaction between non-bonded S and O atoms
have been studied by X-ray analysis for mono crystals and DFT calculations for selected azolo[5,1-d]
[1,2,3,5]thiatriazines. The interaction was described in terms of Weinhold covalence ratio factors, NBO,
and AIM schemes. The reaction discovered was used to develop an efficient approach toward the new 8-
substituted 4-ethoxycarbonylimino-4-benzoyl- and 4-(3,4,5,6-tetrafluorobenzoyl)iminoimidazo(pyr-
azolo)[5,1-d][1,2,3,5]thiatriazines.
Received 10 April 2013
Received in revised form 30 May 2013
Accepted 17 June 2013
Available online xxx
Keywords:
Cycloaddition
Diazoazoles
Thiatriazines
Nonbonded S/O interaction
Covalence ratio factor
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
heterocyclic diazo compounds as an efficient approach to fused
azoles is very important for medicinal chemistry. Reactions of 5-
1,3-Dipolar cycloaddition reactions of aliphatic diazo com-
pounds to triple and double bonds are well known and doc-
umented.1e3 They have been widely used in the synthesis of various
heterocyclic azoles. Thus, it is well known that an efficient and
convenient method for the synthesis of 5-amino-1,2,3-thiadiazoles
includes the cycloaddition reactions of alkyl and aryl iso-
thiocyanates with aliphatic diazo compounds.4 Nevertheless, the
study of the cycloaddition reactions of aliphatic diazo compounds
as a model for various types of pericyclic processes continues to
interest physical organic chemists.5e8
diazoazoles with isocyanates are known to take place in very
mild conditions to afford azolo[5,1-d][1,2,3,5]tetrazines. Two com-
pounds of the imidazole series 1a,b exhibited a high level of anti-
tumor activity and have been used in both medicinal sciences and
practice (Scheme 1).13e15
CONH2
N
CONH2
NH2
CONH2
N2
N
N
R-NCO
N
N
N
Heterocyclic diazo compounds, where the
a carbon atom has
N
R
N
H
N
O
been incorporated into the heteroaromatic system, are known to
react as 1,7-dipoles with electron-rich olefins,9 acetylenes,1 and
isocyanates10e12 leading to six-membered heterocyclic com-
pounds. In comparison with aliphatic diazo compounds, hetero-
cyclic diazo compounds have been studied poorly. At the same
time, expanding the scope of the cycloaddition reaction of
3a
2a
1a,b
Scheme 1. Reactions of diazoimidazoles with isocyanates leading to mitozolomide 1a
(R¼CH2CH2Cl) and temozolomide 1b (R¼CH3).
It is also reported that diazoimidazole 2a does not react with
methyl isothiocyanate either in Me2SO at 40 ꢀC or in an inert sol-
vent containing either the Lewis acids, such as zinc iodide and
boron trifluoride-etherate or triethylamine.16 The reasons for the
* Corresponding author. E-mail address: v.a.bakulev@ustu.ru (V.A. Bakulev).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.062
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2
E.V. Sadchikova et al. / Tetrahedron xxx (2013) 1e6
different reactivity of isocyanates and isothiocyanates in their re-
action with diazoazoles are not rationalized.
Now we have found that they also did not react with phenyl-
sulfonyl isothiocyanate bearing a strong electron acceptor sub-
stituent. Indeed, 3-methyl-, 3-phenylsulfonyl-, and 3-phenylazolo
[5,1-d][1,2,3,5]tetrazine-4(3H)-thiones of type 6 could not be pre-
pared in the same way as their oxygen analogs. In contrast to the
reactions with methyl- and phenyl isothiocyanate the analogous
reactions of diazoazoles 2bej with isothiocyanates containing
carbonyl groups, such as ethoxycarbonyl isothiocyanate 4a, benzoyl
isothiocyanate 4b and tetrafluorobenzoyl isothiocyanate 4c occur
readily in solution of anhydrous ethyl acetate to give azolo[5,1-d]
[1,2,3,5]thiatriazines 5 as the only products (Scheme 3, Table 1).
In a preliminary report17 we described a new cycloaddition re-
action of 5-diazoazoles with benzoyl isothiocyanate leading to
a few examples of novel 1,2,3,5-thiatriazines fused to imidazole and
pyrazole rings. Interestingly, at the same time Ali Deeb and Mah-
mud Kolb published an alternative regiochemistry for the reaction
of 3-diazopyrazolo[3,4-c]pyridazine with phenyl- and ethox-
ycarbonyl isothiocyanates, leading to 1,2,3,5-triazine-4-thione de-
rivatives.18 These authors did not consider the possibility for
formation of a 1,2,3,5-thiatriazole in this reaction. Furthermore the
structures of the products prepared by these authors18 were con-
firmed by 1H NMR spectra only, which may not be conclusive proof
for such heteroatom-rich compounds. Therefore, for the better
understanding of the direction of cyclization and with the aim of
developing a general approach to azolo[1,2,3,5]thiatriazines we
have further studied the reaction of a series of 5-diazoimidazoles
and 5-diazopyrazoles, and 2-diazoimidazole-4,5-dicarbonitrile in-
volving apart of benzoyl isothiocyanate, tetrafluorobenzoyl, phe-
nylsulfonyl,- and ethoxycarbonyl isothiocyanates and have made
a careful study of the structures of the reaction products by X-ray
diffraction analysis, IR-, and NMR spectroscopy and theoretical
calculations. Special attention has been paid to the factors that
stabilize the reaction products because we have recently shown by
calculations with HartreeeFock and DFT methods19 that the re-
action of diazo compounds 5 with acyl isothiocyanates is thermo-
dynamically controlled.
R1
R1
8
4
Y
X
7Y
X
R1
N2
R2-CONCS
4a-c
9
Y
X
6
5
N
N
N3
N
68-96%
1
S
N
N 2
N
N
S
N
R2
R2
O
O
5a-t
2b-j
6
2b-f X = CH, Y = N, b R1 = COOC2H5, c R1 = CONHCH3,
d R1 = COPyrrolidinyl, e R1 = COPiperidinyl, f R1 = COMorpholinyl;
2g X = N, Y = CH, R1 = COOC2H5; 2h-j X = N, R1 = H,
h Y = C-C6H5, i Y = C-C6H4-CH3-p, j Y = C-C6H4-OCH3-p.
4 a R2 = OC2H5, b R2 = C6H5, c R2 = C6HF4
Scheme 3. Reactions of diazoazoles 2bej with acylisothocyanates 4aec.
Table 1
2. Results and discussion
Characteristics of azolo[5,1-d][1,2,3,5]thiatriazines 5
The starting 5-diazoimidazoles 2bef are prepared according to
a modified procedure20e23 by diazotization of the corresponding
amines 3bef in dilute hydrochloric acid with sodium nitrite at
ꢁ5 ꢀC. It is worth noting that diazotization of 5-aminopyrazoles
3gej under these conditions leads to the corresponding pyr-
azolyl-5-diazonium salts, which can be easily transformed to 5-
diazopyrazoles 2gej by treatment of the reaction mixture with
10% sodium bicarbonate solution at pH 5.5, followed by extraction
with chloroform. The diazonium salts themselves are inert in the
investigated type of reactions.
In principle, both the C]N and C]S bonds of isothiocyanates 4
can take part in the cycloaddition reaction with diazoazoles 2 to
form either 1,2,3,5-thiatriazine 5 or 1,2,3,5-tetrazine 6 or their
mixture. In our preliminary report17 we have shown that both 5-
diazoimidazoles 2aef and 5-diazopyrazoles 2gej do not react
with methyl or phenyl isothiocyanates (Scheme 2).
X
Y
R1
R2
Yield, % Duration of
reaction, h
5a
5b
5c
5d
5e
5f
CH
CH
CH
CH
CH
CH
CH
N
N
N
N
N
N
N
N
COOC2H5
COOC2H5
CONHCH3
CONHCH3
OC2H5 79
18
3.5
19
3.5
20
4
C6H5
OC2H5 69
C6H5 76
88
COPyrrolidinyl OC2H5 70
COPyrrolidinyl C6H5 68
OC2H5 73
C6H5 78
5g
COPiperidinyl
COPiperidinyl
20
4
20
4
16
3.5
18
4
5h CH
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
CH
CH
N
N
N
N
N
N
N
N
N
N
N
N
N
CH
CH
CeC6H5
CeC6H5
CeC6H5
CeC6H4eCH3-p
CeC6H4eCH3-p
CeC6H4eCH3-p
CeC6H4eOCH3-p
CeC6H4eOCH3-p
CH
COMorpholinyl OC2H5 72
COMorpholinyl C6H5 81
OC2H5 72
C6H5 84
OC2H5 87
C6H5 83
COOC2H5
COOC2H5
H
H
H
H
H
H
H
H
C6HF4 78
OC2H5 96
C6H5
C6HF4 83
OC2H5 70
C6H5
6
15
3
98
5
15
3
R1
N2
R1
NH2
89
5u
COOC2H5
PhSO2
Is not
formed
Y
X
Y
X
for 3g-j
+
N
H
N
H
The method of choice involves conducting the experiment at
room temperature, under an atmosphere of argon and in the ab-
sence of light. The use of other solvents increases the reaction time.
On the other hand, the increase of temperature leads to the for-
mation of tar-like products. The absence of oxygen and the pro-
tection of the reaction mixture from light diminish the
decomposition of the diazoazoles that may occur via the formation
of radicals. The completion of the reaction was estimated by the
disappearance of the diazo compound according to IR and TLC
analysis. The reaction time depends on the nature of the acyl iso-
thiocyanates and takes 3e3.5 h for benzoyl isothiocyanate 4b, 6 h
for tetrafluorobenzoyl isothiocyanate 4c and 15e20 h for the less
electron poor ethoxycarbonyl isothiocyanate 4a. It should be noted
that 2-diazoimidazole-4,5-dicarbonitrile is found to be inactive in
3b-j
3b-f
for
R1
R1
R1
Y
X
Y
X
R-NCS
R-NCS
Y
N
N
N
N
N
X
N2
N
N
N
R
S
S
N
R
2b-j
R = CH3, C6H5, C6H5SO2
Scheme 2. Synthesis of 5-diazoazoles.
6
5
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E.V. Sadchikova et al. / Tetrahedron xxx (2013) 1e6
3
reactions with any isothiocyanate. Because both 5-diazoimidazoles
and 5-diazopyrazoles do not react neither with alkyl- and aryl
isothiocyanates nor with phenylsulfonyl isocyanate in spite of the
latter containing a strong electron acceptor group, we have con-
cluded that the presence of the carbonyl group in the iso-
thiocyanate molecules is needed for their reaction with 5-
diazoazoles.
According to the X-ray diffraction data, molecules 5k,l are in the
crystalline form a nearly planar structure. The maximum deviation
5
ꢀ
from the best plane through the heterocycle is 0.008(1) A for N in
ꢀ
5k and ꢁ0.038(2) A for C6 in 5l. The five- and six-membered rings
in 5l make an angle of 1.68(8)ꢀ. Bond angles N2eN3eO12 are near to
180ꢀ. The configuration of the external imine substituent is Z and
ꢀ
ꢀ
the S1/O17 distance is 2.613(1) A in 5k and 2.496(1) A in 5l. This is
The thiatriazines 5aet are isolated in high yields (68e98 %) (See
Table 1) and gave satisfactory elemental analyses. The NMR spectra
for cycloadducts 5aet demonstrate that all of the compounds be-
long to the same structural type with the same heterocyclic systems
present. Thus, the 1H NMR and 13C NMR spectra contain signals of
the substituents attached to either the azole rings or the imino
group of the thiatriazine ring. As expected, for fused azoles the
signal assigned to the azole proton of compounds 5aes is signifi-
cantly shifted downfield (Dd¼1.44e1.95 for proton and 29 ppm for
carbon NMR spectra, respectively) compared to the diazoazole
in both cases shorter than the sum of the corresponding van der
ꢀ
Waals radii (3.2 A), and in the case of 5l also shorter than the
Huggins constant energy distance of 2.58 A,26 indicating a degree of
ꢀ
covalent bonding. Both short OeS contacts and near linear ar-
rangement of fragment NeSeO makes possible the overlapping of
a nonbonded orbital located on the oxygen of the carbonyl group
(nO/s*
SeN).27
The study of so-called ‘nonbonded SeO interactions’ are of in-
terest both in theoretical and experimental research27e30 due to its
importance in different fields. For example, the consequence of the
presence of this type of interaction in certain compounds could be
the stabilization of isomers supporting a planar structure, that is,
required to interact with some enzymes and exhibit biological ac-
tivity.31 Thus, nonbonding sulfureoxygen interaction can control the
stereoselectivity of some reactions.32 Quite recently, the easiness of
oxidative cyclizationsof N-acyl 2-arylhydrazonothioacetamides to 5-
acylimino-2,5-dihydro-1,2,3-thiadiazoles was explained by the ex-
istence of very strong nonbonded SeO interactions and the aroma-
ticity of the reaction products.33
precursors 2bej. Signals at
5b,d,f,h,j,l,n,p,o,q,r,t are assigned to the benzoyl carbon, and the
signals at
d
¼176e180 ppm in compounds
d
¼160e162 ppm in 5a,c,e,g,i,k,m,p,s to the ethox-
ycarbonyl carbons and this is in agreement with literature data for
these groups in similar compounds.24,25
Signals at 155.1e160.8 ppm were assigned to carbons of the
C4]N groups of the 1,2,3,5-thiatriazine ring based on the careful
analysis for spectra of series of compounds 5aes. The signals
corresponding to C9 of the bicycle compounds 5 were observed
in broad region of 134e147 ppm depending on the substituents
and nature of azole rings.
To evaluate these stabilizing SeO interactions quantitatively, the
difference of Gibbs energies for two conformations (DE) (See Table 2)
We have shown by NMR study that compounds 5 are not stable
in the presence of water and alcohols therefore all NMR measure-
ments were made just after the samples were dissolved.
It is worth noting that all spectroscopic data are in good
agreement with both thiatriazine 5 and tetrazine 6 structures. The
final decision in favor of structure 5 is made by single crystal X-ray
analysis, which was executed for the most stable pyrazolothia-
triazines 5k,l. Structural parameters for compounds 5k,l are given
in the Supplementary data and a view of compound 5k is depicted
in Fig. 1 and for compound 5l is available from our preliminary
study.17
were calculated at the B3LYP/6-31G* level of theory. These data
confirm that structures 5 with hypervalent thiadiazole sulfur atom
(conformation A) are more stable than the ones where nonbonded
S/O through-space interaction are absent (conformation B).
R1
R1
Y
Y
X
X
N
N
N
N
R2
N
N
S
S
N
N
.
O
.
.
R2
O
Conformation A
Conformation B
Table 2
Quantum chemical descriptors calculated to describe the S/O interaction
n(S/O)a E(2)b r(SO)c
a
(NeSeO)d ce
r
(BCP)f
RCPg
D
Eh
ti
5k 0.0695
5l 0.0915
5o 0.0844
5u 0.0387
5.58 2.62 178.5
6.98 2.56 178.5
7.02 2.59 178.8
2.40 2.77 172.3
0.489 2.606$10ꢁ2
0.527 2.946$10ꢁ2
0.511 2.793$10ꢁ2
0.389 1.925$10ꢁ2
þ
þ
þ
þ
3.006 16
5.023 3.5
3.894 6.0
d
d
a
Wiberg bond indexes in the NAO basis (NBO, B3LYP/6-31þG**).
b
The stabilization energy gained by donation from NBO of donor to NBO of ac-
ceptor, calculated with a help of second order perturbation theory in kcal/mol (NBO,
B3LYP/6-31þG**).
c
ꢀ
S/O distance, in A (B3LYP/6-31þG**).
d
ꢀ
Bond angle NeSeO, in (B3LYP/6-31þG**).
e
Covalency index as introduced by F. Weinhold.29
f
The electron density in (3,ꢁ1) bond critical point in a.u. (AIM, B3LYP/6-31þG**).
g
‘þ’ symbolizes that (3,þ1) ring critical point was located for SeCeNeCeO se-
quence (AIM, B3LYP/6-31þG**).
h
The stabilization energy calculated as the difference in electronic energies be-
tween two conformers A and B and corrected with ZPE values, in kcal/mol (B3LYP/6-
Fig. 1. Obtained geometry of ethyl 8-ethoxycarbonyl-iminopyrazolo[5,1-d][1,2,3,5]
thiatriazine-4-carboxylate 5k.
31þG**).
i
The reaction time, h.
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4
E.V. Sadchikova et al. / Tetrahedron xxx (2013) 1e6
The benefit of stabilization, quantitatively expressed as an en-
from the literature and examples of monocyclic 1,2,3,5-thiatriazines
are limited to a very few compounds described in a single paper.36
The acyl substituent on the isothiocyanate led to a stabilization
of the final product 5 due to an S/.O interaction, which is in
agreement with both X-ray data for thiatriazines 5k,l and calcula-
tions of the structures of 5k,l,o,u. Probably this is the main reason
of the difference in the reactivity of acyl isothiocyanates and alkyl
and aryl isothiocyanates in their reaction with diazoazoles and this
may be the driving force for the reaction.
ergy difference between two conformations, was decreasing in the
series 5l>5o>5k. It should be mentioned that two equal confor-
mations A and A0 were found for 5u (See Supplementary data for 3D
representations of located structures). As a result, no energy dif-
ference
DE was calculated for 5u (Table 2). Analysis of the length
differences for bonds C]O, C]N, and CeN of conformations A and
B calculated at the B3LYP/6-31G* level of theory for compounds
5k,l,o has shown that they are slightly distorted in conformation A.
The double bonds became longer and CeN single bonds shorter in
ꢀ
comparison with conformation B for 0.01e0.027 A (See Table 2).
3. Conclusions
Calculated dseo distances were used to obtain the Weinhold
covalence ratio factors c29 for these compounds. Values were
varying in a 0.389e0.527 interval (See Table 2), suggesting that the
strongest S/O interactions are to be found in 5l and 5o.
In summary, we have developed an efficient method for the
synthesis of imidazo- and pyrazolo[5,4-b][1,2,3,5]thiatriazines
based on cycloaddition reaction of diazoazoles with acyl iso-
thiocyanates. The prepared compounds are shown by both X-ray
data for thiatriazines 5k,l and by calculations for the structures
5k,l,o to have relatively strong SeO nonbonded interactions. These
studies reveal that the introduction of an acyl group to the nitrogen
atom of isothiocyanates is essential for the formation of the thia-
triazine ring in the studied reactions with diazoazoles.
The expansion of the oxygen lone pair electron density to vacant
s*(SeN) orbital was studied within an NBO (Natural Bond Orbitals)
framework34 (See Fig. 2). The Wiberg bond indexes and electron
population for the corresponding atoms were also calculated.
Second order perturbation theory analysis of the Fock matrix in
a NBO basis was applied to estimate the stabilization energy, E(2)
gained as a result of electron delocalization from one orbital to
another (See Table 2). Correlating experimentally observed reaction
time and calculated stabilization descriptors, one can see that
stronger S/O interaction correlates with lower reaction time. For
example, compound 5l reacts faster and has a higher Wiberg bond
4. Experimental section
4.1. General
index n, energy of n/
and energy stabilization
s
* interaction E(2), covalency ratio factor
c
,
IR spectra were recorded on a Perkin Elmer 1600 Series FTIR in
KBr pellets. The 1H and 13C NMR spectra were recorded in [2H6]
DMSO solution with Bruker WR-300 and Bruker DRX-400, 300 and
400 MHz for 1H, 75 and 100 MHz for 13C using TMS as internal
standard. X-ray diffraction measurements were made on a Bruker
DE comparing to compounds 5o and 5k.
Remarkably, the compound 5u bearing arylsulfonyl group at ni-
trogen atom that was not formed in reaction of diazo compounds 2
with phenylsulfonyl isocyanate, distinguished drastically from
5k,l,o in respect of all calculated characteristics (See Table 2). The
existence of S/O dative bond and formation of new cyclic fragment
within the molecule were also confirmed in AIM (Atoms in Mole-
SMAART 6000 diffractometer equipped with CCD detector using
ꢀ
CuKa
radiation (
l
¼1.54178 A).
cule) notations.35 The (3,ꢁ1) bond critical points of
r
for S/O bond
4.2. General procedure for the synthesis of the azolo[5,1-d]
[1,2,3,5]thiatriazines (5aet)
and the (3,þ1) ring critical points for five-membered rings con-
taining sulfur and oxygen atoms were located for all selected cal-
culated structures (See Table 2). Thus, all quantum chemical
descriptors, used to describe the S/O interaction, advocate that
compounds 5 contain a pseudoheterocyclic oxathiazole ring fused
to the 1,2,3,5-thiatriazine ring and thus are similar in this respect to
the family of thiapentalenes.27 To the best of our knowledge, this is
the first example of the existence of a relatively strong SeO in-
teraction, where sulfur belongs to a six-membered ring.
The corresponding acyl isothiocyanate 4aec (1.0 mmol) in an-
hydrous ethyl acetate (3 mL) was added to a cooled solution of 5-
diazoazole 2bej (0.5 mmol) in anhydrous ethyl acetate (5 mL), in
a dropwise manner at ꢁ10 ꢀC, in the dark. The mixture was stirred
at room temperature until the compounds 2 according TLC analysis
taken disappeared. Then, activated charcoal was added and the
mixture was filtered. Then, the solvent was removed in vacuo
(temperature <40 ꢀC). The residue was triturated with diethyl ether
or hexane, collected, air-dried, and purified by flash chromatogra-
phy with CH3COOC2H5/CH2Cl2 as the eluant to give 5aet.
4.2.1 (Z)-Ethyl 4-(ethoxycarbonylimino)-4H-imidazo[5,1-d][1,2,3,5]
thiatriazine-8-carboxylate (5a). Yield 0.12 g (79%), mp 101e102 ꢀC;
nmax (KBr), cmꢁ1: 1677.2, 1728.6, 2932.2, 2980.0, 3068.2, 3128.1; dH
(300.13 MHz, DMSO-d6, 300 K): 1.27 (3H, t, J 7.3 Hz, OCH2CH3), 1.35
(3H, t, J 7.3 Hz, OCH2CH3), 4.29 (2H, q, J 7.3 Hz, OCH2CH3), 4.44 (2H, q, J
7.3 Hz, OCH2CH3), 9.14 (1H, s, 6-H); dC (75.4 MHz, DMSO-d6, 300 K):
13.9, 14.1, 61.5, 63.6, 131.5, 134.3, 134.6, 158.1, 160.0, 160.1. Calcd for
C10H11N5O4S: C, 40.40; H, 3.73; N, 23.56; S,10.79. Found: C, 40.43; H,
3.80; N, 23.54; S, 10.76.
4.2.2 (Z)-Ethyl 4-(benzoylimino)-4H-imidazo[5,1-d][1,2,3,5]thia-
triazine-8-carboxylate (5b)17 and (Z)-Ethyl 8-(methylcarbamoyl)-4H-
imidazo[5,1-d][1,2,3,5]thiatriazin-4-ylidenecarbamate
(5c). Yield
Fig. 2. n(O)/
pound 5l.
s
*(SN) interaction shown in NBO orbitals (B3LYP/6-31þG**) of com-
0.10 g (69%), mp 115e116 ꢀC; nmax (KBr), cmꢁ1: 1655, 1680, 2940,
2980, 3100, 3120; dH (400.13 MHz, DMSO-d6, 298 K): 1.30 (3H, t, J
7.0 Hz, OCH2CH3), 2.86 (3H, d, J 4.7 Hz, NHCH3), 4.29 (2H, q, J7.0 Hz,
OCH2CH3), 8.67 (1H, q, J 4.7 Hz, NHCH3), 9.15 (1H, s, 7-H); dC
(100.62 MHz, DMSO-d6, 298 K): 13.9, 26.0, 63.4, 131.1, 132.6, 137.9,
This newly discovered reaction represents the first example of
cycloaddition of diazoazoles to a C]S bond. It is worth mentioning
that 1,2,3,5-thiatriazines fused to any heterocycles were not known
Please cite this article in press as: Sadchikova, E. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.062

E.V. Sadchikova et al. / Tetrahedron xxx (2013) 1e6
5
158.3, 159.6, 159.9. Calcd for C9H10N6O3S: C, 38.30; H, 3.57; N,
29.77; S, 11.36. Found: C, 38.40; H, 3.54; N, 29.82; S, 11.40.
H), 8.22 (2H, d, J 7.9 Hz, 20,60-H), 8.34 (2H, d, J 7.0 Hz, 200,600-H), 8.39
(1H, s, 8-H); dC (75.4 MHz, DMSO-d6, 300 K): 110.1, 126.8, 129.1,
129.3, 129.4, 130.2, 130.6, 133.7, 134.3, 146.1, 155.2, 177.1. Calcd for
4.2.3 (Z)-4-(Benzoylimino)-N-methyl-4H-imidazo[5,1-d][1,2,3,5]thia-
triazine-8-carboxamide (5d)17 and (Z)-Ethyl 8-(pyrrolidine-1-
carbonyl)-4H-imidazo[5,1-d][1,2,3,5]thiatriazin-4-ylidenecarbamate
(5e). Yield 0.11 g (70%), mp 99e100 ꢀC; nmax (KBr), cmꢁ1: 1675, 2880,
2960, 2975, 3130; dH (250.13 MHz, DMSO-d6, 298 K): 1.30 (3H, t, J
7.0 Hz, OCH2CH3),1.85e1.93 (4H, m, 2CH2), 3.51e3.58 (4H, m, 2CH2),
4.28 (2H, q, J 7.0 Hz, OCH2CH3), 9.13 (1H, s, 6-H); dC (100.62 MHz,
DMSO-d6, 298 K): 13.9, 23.7, 25.6, 46.0, 48.0, 63.4,131.2,132.3,141.0,
158.4,159.4,160.0. Calcd for C12H14N6O3S: C, 44.71; H, 4.38; N, 26.07;
S, 9.95. Found: C, 44.78; H, 4.40; N, 26.02; S, 10.02.
C17H11N5OS: C, 61.25; H, 3.33; N, 21.01; S, 9.62. Found: C, 61.29; H,
3.35; N, 21.06; S, 9.59.
4.2.9 (Z)-2,3,4,5-Tetrafluoro-N-(7-phenyl-4H-pyrazolo[5,1-d][1,2,3,5]
thiatriazin-4-ylidene)benzamide (5o). Yield 0.16
g (78%), mp
187e189 ꢀC; nmax (KBr), cmꢁ1: 1600, 1630, 2925, 3120, 3410; dH
(300.13 MHz, DMSO-d6, 300 K): 7.58e7.63 (3H, m, 30,40,50-H),
8.05e8.10 (1H, m, 600-H), 8.18e8.21 (2H, m, 20,60-H), 8.54 (1H, s, 8-
H); dF (300.13 MHz, DMSO-d6): 134.68; 137.57; 145.34; 153.31.
Calcd for C17H7F4N5OS: C, 50.38; H, 1.74; F 18.75; N, 17.28; S, 7.91.
Found: C, 50.55; H, 1.86; F 18.52; N, 17.45; S, 7.85.
4.2.4
(Z)-N-(8-(Pyrrolidine-1-carbonyl)-4H-imidazo[5,1-d][1,2,3,5]
thiatriazin-4-ylidene)benzamide (5f)17 and (Z)-Ethyl 8-(piperidine-1-
carbonyl)-4H-imidazo[5,1-d][1,2,3,5]thiatriazin-4-ylidenecarbamate
(5g). Yield 0.12 g (73%), mp 103e104 ꢀC; nmax (KBr), cmꢁ1: 1680,
2860, 2930, 2960, 3130; dH (400.13 MHz, DMSO-d6, 298 K): 1.30
(3H, t, J 7.0 Hz, OCH2CH3), 1.48e1.47 (2H, m, CH2), 1.65e1.59 (4H,
m, 2CH2), 3.41e3.38 (2H, m, CH2), 3.69e3.67 (2H, m, CH2), 4.28
(2H, q, J 7.0 Hz, OCH2CH3), 9.12 (1H, s, 6-H); dC (100.62 MHz,
DMSO-d6, 298 K): 13.9, 23.8, 25.3, 26.2, 42.3, 47.5, 63.4, 131.5,
132.0, 140.9, 158.3, 159.9, 160.0. Calcd for C13H16N6O3S: C, 46.42;
H, 4.79; N, 24.98; S, 9.53. Found: C, 46.40; H, 4.82; N, 25.03; S,
9.50.
4.2.10 (Z)-Ethyl 7-(p-tolyl)-4H-pyrazolo[5,1-d][1,2,3,5]thiatriazin-4-
ylidenecarbamate (5p). Yield 0.15 g (96%), mp 122e124 ꢀC; nmax
(KBr), cmꢁ1: 1635, 2320, 2970, 3110, 3400; dH (300.13 MHz, DMSO-
d6, 300 K): 1.31 (3H, t, J 7.0 Hz, PCH2CH3), 2.40 (3H, s, CH3), 4.28 (2H,
q, J 7.0 Hz, PCH2CH3), 7.39 (2H, d, J 7.9 Hz, 30,50-H), 8.05 (2H, d, J
7.9 Hz, 20,60-H), 8.41 (1H, s, 8-H); dC (75.4 MHz, DMSO-d6, 300 K):
13.9, 21.0, 63.1, 109.9, 126.6, 126.9, 129.7, 140.5, 145.8, 155.2, 157.9,
160.8. Calcd for C14H13N5O2S: C, 53.32; H, 4.16; N, 22.21; S, 10.17.
Found: C, 53.38; H, 4.19; N, 22.33; S, 10.18.
4.2.11 (Z)-N-(7-(p-Tolyl)-4H-pyrazolo[5,1-d][1,2,3,5]thiatriazin-4-
ylidene)benzamide (5q). Yield 0.17 g (98%), mp 184e186 ꢀC; nmax
(KBr), cmꢁ1: 1625, 2350, 3125, 3450; dH (300.13 MHz, DMSO-d6,
300 K): 2.42 (3H, s, CH3), 7.43 (2H, d, J 7.9 Hz, 30,50-H), 7.63e7.67
(2H, m, 300,500-H), 7.73e7.77 (1H, m, 400-H), 8.13 (2H, d, J 7.9 Hz, 20,60-
H), 8.32 (2H, d, J 7.0 Hz, 200,600-H), 8.49 (1H, s, 8-H); dC (75.4 MHz,
DMSO-d6, 300 K): 21.0, 109.8, 126.7, 127.0, 129.0, 129.8, 130.2, 133.7,
134.2, 140.5, 146.0, 155.3, 157.5, 177.1. Calcd for C18H13N5OS: C,
62.23; H, 3.77; N, 20.16; S, 9.23. Found: C, 62.29; H, 3.81; N, 20.30; S,
9.28.
4.2.5
(Z)-N-(8-(Piperidine-1-carbonyl)-4H-imidazo[5,1-d][1,2,3,5]
thiatriazin-4-ylidene)-benzamide (5h)17 and (Z)-Ethyl 8-(morpho-
line-4-carbonyl)-4H-imidazo[5,1-d][1,2,3,5]thiatriazin-4-
ylidenecarbamate (5i). Yield 0.12 g (72%), mp 96e98 ꢀC; nmax (KBr),
cmꢁ1: 1675, 2850, 2915, 2975, 3140; dH (400.13 MHz, DMSO-d6,
298 K): 1.30 (3H, t, J 7.0 Hz, OCH2CH3), 3.51e3.50 (2H, m, CH2),
3.56e3.55 (2H, m, CH2), 3.72e3.70 (4H, m, 2CH2), 4.28 (2H, d, J 7.0 Hz,
OCH2CH3), 9.14 (1H, s, 6-H); dC (100.62 MHz, DMSO-d6, 298 K): 13.9,
42.1, 47.0, 63.4, 66.0, 66.4, 131.5, 132.4, 139.8, 158.2, 160.0, 160.1.
Calcd for C12H14N6O4S: C, 42.60; H, 4.17; N, 24.84; S, 9.48. Found: C,
42.66; H, 4.20; N, 24.80; S, 9.44.
4.2.12 (Z)-2,3,4,5-Tetrafluoro-N-(7-p-tolyl-4H-pyrazolo[5,1-d][1,2,3,5]
thiatriazin-4-ylidene)-benzamide (5r). Yield 0.17
g (83%), mp
158e160 ꢀC, nmax (KBr), cmꢁ1: 1620, 2920, 2950, 3115, 3400; dH
(300.13 MHz, DMSO-d6, 300 K): 2.44 (3H, s, CH3), 7.35 (2H, d, J 8.0 Hz,
30,50-H), 8.08 (2H, d, J 8.0 Hz, 20,60-H), 8.10e8.18 (1H, m, 200-H), 8.34
(1H, s, 8-H), dF (300.13 MHz, DMSO-d6): 134.75; 137.62; 145.42;
153.35; dC (75.4 MHz, DMSO-d6, 300 K): 21.6, 99.9,109.9,114.4,114.6,
118.5, 126.5, 127.1, 130.0, 141.7, 145.6, 146.2, 157.1, 158.4, 180.4.
Calcd for C18H9F4N5OS: C, 51.55; H, 2.16; F 18.12; N, 16.70; S, 7.65.
Found: C, 51.48; H, 2.08; F 18.32; N, 16.79; S, 7.56.
4.2.6 (Z)-N-(8-(Morpholine-4-carbonyl)-4H-imidazo[5,1-d][1,2,3,5]
thiatriazin-4-ylidene)benzamide (5j)17 and (Z)-Ethyl 4-(ethox-
ycarbonylimino)-4H-pyrazolo[5,1-d][1,2,3,5]thiatriazine-8-
carboxylate (5k). Yield 0.11 g (72%), mp 110e112 ꢀC; nmax (KBr),
cmꢁ1: 1666.0,1708.7, 2910.5, 2992.9, 3110.2, 3395.9; dH (300.13 MHz,
DMSO-d6, 300 K): 1.30 (3H, t, J 7.0 Hz, OCH2CH3), 1.36 (3H, t, J 7.0 Hz,
OCH2CH3), 4.28 (2H, q, J 7.0 Hz, OCH2CH3), 4.42 (2H, q, J 7.0 Hz,
OCH2CH3), 8.78 (1H, s, 7-H); dC (75.4 MHz, DMSO-d6, 300 K): 14.8,
15.0, 62.3, 64.3, 116.0, 143.5, 146.6, 160.8, 161.5, 161.5. Calcd for
4.2.13 (Z)-Ethyl 7-(4-methoxyphenyl)-4H-pyrazolo[5,1-d][1,2,3,5]
C
10H11N5O4S: C, 40.40; H, 3.73; N, 23.56; S,10.79. Found: C, 40.32; H,
thiatriazin-4-ylidenecarbamate (5s). Yield 0.12
g
(70%), mp
3.70; N, 23.63; S, 10.91.
144e146 ꢀC; nmax (KBr), cmꢁ1: 1645, 2340, 2975, 3125, 3450; dH
(300.13 MHz, DMSO-d6, 300 K): 1.37 (3H, t, J 7.0 Hz, OCH2CH3), 3.87
(3H, s, OCH3), 4.29 (2H, q, J 7.0 Hz, OCH2CH3), 7.05 (2H, d, J 8.9 Hz,
30,50-H), 8.08 (2H, d, J 8.9 Hz, 20,60-H), 8.26 (1H, s, 8-H); dC
(75.4 MHz, DMSO-d6, 300 K): 14.8, 56.2, 63.9, 110.6, 115.5, 122.9,
122.9, 129.2, 129.2, 146.7, 156.0, 162.0. Calcd for C14H13N5O3S: C,
50.75; H, 3.95; N, 21.14; S, 9.68. Found: C, 50.86; H, 4.02; N, 20.98; S,
9.59.
4.2.7 (Z)-Ethyl 4-(benzoylimino)-4H-pyrazolo[5,1-d][1,2,3,5]thia-
triazine-8-carboxylate (5l)17 and (Z)-Ethyl 7-phenyl-4H-pyrazolo[5,1-
d][1,2,3,5]thiatriazin-4-ylidenecarbamate (5m). Yield 0.13 g (87%),
mp 182e184 ꢀC; nmax (KBr), cmꢁ1: 1710, 1760, 2350, 2975, 3140; dH
(300.13 MHz, DMSO-d6, 300 K): 1.37 (3H, t, J 7.0 Hz, OCH2CH3), 4.30
(2H, q, J 7.0 Hz, OCH2CH3), 7.49e7.58 (3H, m, 30,40,50-H), 8.15 (2H, d, J
9.8 Hz, 20,60-H), 8.33 (1H, s, 8-H); dC (75.4 MHz, DMSO-d6, 300 K):
14.0, 63.1, 110.1, 126.7, 129.1, 129.7, 129.2, 130.6, 145.9, 155.2, 160.8.
Calcd for C13H11N5O2S: C, 51.82; H, 3.68; N, 23.24; S,10.64. Found: C,
51.88; H, 3.69; N, 23.07; S, 10.58.
4.2.14 (Z)-N-(7-(40-Methoxyphenyl)-4H-pyrazolo[5,1-d][1,2,3,5]thia-
triazin-4-ylidene)-benzamide (5t). Yield 0.16
g
(89%), mp
160e162 ꢀC; nmax (KBr), cmꢁ1: 1620, 2840, 2950, 3115, 3450; dH
(300.13 MHz, DMSO-d6, 300 K): 3.87 (3H, s, PCH3), 7.16 (2H, d, J
8.9 Hz, 30,50-H), 7.60e7.66 (2H, m, 300,500-H), 7.71e7.74 (1H, m, 400),
8.17 (2H, d, J 8.9 Hz, 20,60-H), 8.31 (2H, d, J 7.2 Hz, 200,600-H), 8.43
(1H, s, 8-H); dC (75.4 MHz, DMSO-d6, 300 K): 55.3, 109.6, 114.6,
122.1, 128.4, 128.9, 130.1, 133.7, 134.2, 145.9, 155.1, 157.3, 161.2,
4.2.8 (Z)-N-(7-Phenyl-4H-pyrazolo[5,1-d][1,2,3,5]thiatriazin-4-
ylidene)benzamide (5n). Yield 0.14 g (83%), mp 196e198 ꢀC; nmax
(KBr), cmꢁ1: 1745, 2915, 2325, 2350, 3115; dH (300.13 MHz, DMSO-
d6, 300 K): 7.53e7.61 (5H, m, 30,40,50,300,500-H), 7.66e7.69 (1H, m, 400-
Please cite this article in press as: Sadchikova, E. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.062

6
E.V. Sadchikova et al. / Tetrahedron xxx (2013) 1e6
2. Gioiello, A.; Khamidullina, A.; Fulco, M. C.; Venturoni, F.; Zlotsky, S.; Pellicciari,
R. Tetrahedron Lett. 2009, 50, 5978.
3. Tuktarov, A. R.; Khuzin, A. A.; Korolev, V. V.; Dzhemilev, U. M. Russ. J. Org. Chem.
177.1. Calcd for C18H13N5O2S: C, 59.49; H, 3.61; N, 19.27; S, 8.82.
Found: C, 59.52; H, 3.63; N, 19.36; S, 8.88.
2012, 48, 99.
4. Bakulev, V. A.; Dehaen, W. Heterocyclic Compounds. The Chemistry of 1,2,3-
thiadiazoles; John Wiley & Sons: USA, 2004; Vol. 62, pp 241.
5. Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S.; Alekseev, S. G. Chem. Heterocycl.
Compd. 1984, 20, 1038.
5. X-ray diffraction study of 5k
Crystals were grown from ethyl acetate. All measurements were
made on a Bruker SMART 6000 diffractometer equipped with a CCD
6. Bakulev, V. A. Russ. Chem. Rev. 1995, 64, 99.
7. Fabian, W. M. F.; Bakulev, V. A.; Kappe, C. O. J. Org. Chem. 1998, 63, 5801.
8. Fabian, W. M. F.; Bakulev, V. A.; Janoschek, R. J. Mol. Struct. THEOCHEM 2007, 821,
89.
9. Magee, W. L.; Rao, C. B.; Glinka, J.; Hui, H.; Amick, T. J.; Fiscus, D.; Kakodkar, S.;
Nair, M.; Shechter, H. J. Org. Chem. 1987, 52, 5538.
ꢀ
detector using CuK
a
radiation (
l
¼1.54178 A). The crystal system of
compound 5k (C10H11N5O4S, M¼297.30) is orthorhombic, space
ꢀ
group Pbca, a¼8.6546(2), b¼7.8213(2), c¼37.2599(8) A, Z¼8,
3
ꢀ
V¼2522.13(10) A3, Dc¼1.566 g/cm , F(000)¼1232, crystal size:
10. Diana, P.; Barraja, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G. Bioorg. Med. Chem. 2003, 11, 2371.
0.10ꢂ0.60ꢂ0.60 mm,
m(CuK
a
)¼2.524 mmꢁ1, T¼373 K, 11,654 re-
11. Wang, Y.; Stevens, M. F. G.; Chan, T.-M.; DiBenedetto, D.; Ding, Z.-X.; Gala, D.;
Hou, D.; Kugelman, M.; Leong, W.; Kuo, S.-C.; Mas, J. L.; Schumacher, D. P.;
Schutts, B. P.; Smith, L.; Zhan, Z.-Y. J. J. Org. Chem. 1997, 62, 7288.
12. Ege, G.; Gilbert, K.; Maurer, K. Chem. Ber. 1987, 120, 1375.
13. Xu, X.; Stockhammer, F.; Schmitt, A.; Casalegno-Garduno, R.; Enders, A.; Mani, J.;
Classen, C. F.; Linnebacher, M.; Freund, M.; Schmitt, M. Int. J. Oncol. 2012, 40, 764.
14. Pietanza, M. C.; Kadota, K.; Huberman, K.; Sima, C. S.; Fiore, J. J.; Sumner, D. K.;
Travis, W. D.; Heguy, A.; Ginsberg, M. S.; Holodny, A. I.; Chan, T. A.; Rizvi, N. A.;
Azzoli, C. G.; Riely, G. J.; Kris, M. G.; Lee, M. K. Clin. Cancer Res. 2012, 18, 1138.
15. Newlands, E. S.; Stevens, M. F. G.; Wedge, S. R.; Wheelhouse, R. T.; Brock, C.
Cancer Treat. Rep. 1997, 23, 35.
flections collected, 2356 unique reflections, Rint¼0.135. Final R in-
dices: R1¼0.0566 for 2123 reflections with I>2 (I) and R1¼0.0500,
s
wR2¼0.1522 for all data. Crystallographic data (excluding structure
factors) for this structure have been deposited with the Cambridge
Crystallographic Data Centre. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
6. Computational details
16. Wang, Y.; Lowe, P. R.; Thomson, W. T.; Clark, J.; Stevens, M. F. G. Chem. Commun.
1997, 363.
All calculations were performed by G09 suit.37 Structures were
initially optimized at B3LYP/6-31þG** level of theory. To prove the
true character of located minima, Hessian was calculated. No imagi-
naryfrequency modeswere found forall structures. NBO analysis was
done at the same level by NBO 3.0 module implemented in G09.38
Obtained B3LYP/6-31þG** densities were analyzed by AIM scheme
with a help of AIMAll software.39 gOpenMol40,41 and Gabedit42 soft-
ware were used for visualization of results.
17. Sadchikova, E. V.; Bakulev, V. A.; Dehaen, W.; Van Hecke, K.; Robeyns, K.; Van
Meervelt, L.; Mokrushin, V. S.; Padwa, A. Synlett 2004, 2037.
18. Deeb, A.; Kotb, M. Heterocycles 2004, 63, 1143.
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J. Quantum Chem. 2007, 107, 2479.
20. Sadchikova, E. V.; Mokrushin, V. S. Russ. Chem. Bull. 2006, 55, 1255.
21. Shchegol’kov, E. V.; Sadchikova, E. V.; Burgart, Y. V.; Saloutin, V. I. Russ. Chem.
Bull. 2008, 56, 599.
22. Shchegol’kov, E. V.; Sadchikova, E. V.; Burgart, Y. V.; Saloutin, V. I. Russ. J. Org.
Chem. 2009, 45, 572.
23. Sadchikova, E. V.; Mokrushin, V. S. Russ. Chem. Bull. 2003, 52, 1600.
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24. L’abbe, G.; Francis, A.; Dehaen, W.; Bosman, J. Bull. Soc. Chim. Belg. 1996, 105,
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V.A.B. thanks Russian Foundation for Basic Research (grants no.
10-03-00897-a). W.D. thanks the FWO-Vlaanderen, the Ministerie
voor Wetenschapsbeleid and the KU Leuven for continuing finan-
cial support. J.O.S. personally thanks Prof. Arvi Rauk (University of
Calgary, Canada) for assistance. J.O.S. also thanks Compute Canada
e Calcul Canada and Western Canada Research Grid for provided
computational resources. J.O.S. thanks Russian Foundation for Basic
Research (grants no. 12-03-31574 mol_a).
~
ꢁ
~
33. Belskaya, N. P.; Subbotina, J. O.; Bolgova, A. I.; Lugovik, K. I.; Slepukhin, P. A.;
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.062.
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Please cite this article in press as: Sadchikova, E. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.06.062