Formation of pyrazol-1,3,4-thiadiazoles through 1,3-dipolar cydoaddltlons of 3-thioxo-[1,2,4]-triazepin-5-one with nitrilimines: An experimental and computational study

Article abstract of DOI:10.1002/poc.1421

In this work the experimental results and the computational study of the title compounds and some ancillary compounds are reported. Two bicyclic pyrazol-1,3,4-thiadiazole derivatives were synthezised by reaction between 6-dimethyIaminomethyIene-3-thioxo-[

Full text of DOI:10.1002/poc.1421

Research Article
Received: 15 April 2008,
Revised: 12 June 2008,
Accepted: 13 June 2008,
Published online in Wiley InterScience: 17 July 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1421
Formation of pyrazol-1,3,4-thiadiazoles
through 1,3-dipolar cycloadditions of
3-thioxo-[1,2,4]-triazepin-5-one with
nitrilimines: an experimental and
computational studyy
a
a
a
b
c
*
´
M. Esseffar , M. El Messaoudi , S. Azzouzi , R. Jalal , J. A. Saez ,
d
e
c**
´
L. R. Domingo , J. Latorre and M. Liu-Gonzalez
In this work the experimental results and the computational study of the title compounds and some ancillary
compounds are reported. Two bicyclic pyrazol-1,3,4-thiadiazole derivatives were synthezised by reaction between
6-dimethylaminomethylene-3-thioxo-[1,2,4]-triazepin-5-one 1 and several nitrilimines 2a–f to give corresponding
spirocycloadducts 3a–f, which undergo a rapid rearrangement leading to the new bicyclic compounds, 4a–f and 5a–f.
1
These obtained bicyclic products were characterized by H and 13C NMR spectroscopy and finally by X-ray crystal-
lography. Theoretical calculations have been carried out using DFT methods to rationalize the formation of the two
new bicyclic compounds. Two reaction types are involved in the formation of the compounds 4a–f and 5a–f. The first
one is a 1,3-dipolar cycloaddition (13DC) reaction between 1 acting as dipolarophile and 2a–f as dipoles. The results
indicate that the cycloaddition between 1 and 2g, as model of 2a–c, takes place via a high asynchronous
bond-formation process. The regioselectivity obtained from the calculations is in complete agreement with the
formation of the unique spirocycloadducts 3a–f. The second reaction leading to the formation of the final products is a
domino process that is initiated by the quick and irreversible cleavage in a catalytic acid environment of triazepenic
ring. Copyright ß 2008 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
the bicyclic compounds 4a–f and 5a–f. Herein, we present the
experimental results of the title reaction together with a
INTRODUCTION
Triazepine derivatives have attracted a great deal of attention
because of their ability to act as anti-convulsant and anti-anxiety.
Their oxo and thioxo derivatives have acquired both pharma-
ceutical and economical relevance.[1] Triazepines and diazepines
have attracted a great attention as starting materiel in the
synthesis of fused heterocyclic systems of potential pharmaco-
logical activities.[2–9] Different triazepine derivatives have exhib-
ited significant biological activities.[10–13] The area of biological
interest of this family of compounds have been extended to
various diseases such as cancer,[7] viral infections (HIV)[8] and
cardiovascular disorders.[9,10] It is known that the pharmacologi-
cal activity appears to be enhanced when a further heterocyclic
ring is linked to the heptatomic nucleus.[14,15] They are reported
as excellent ligands with transition metals inducing a large
application in organometallic chemistry.[16–18]
´ ´
Correspondence to: M. Esseffar, Departement de Chimie, Faculte des Sciences-
´
Semlalia, Universite Cadi ayyad, B.P. 2390, Marrakech, Morocco.
E-mail: esseffar@ucam.ac.ma
*
´
** Correspondence to: M. Esseffar, Departamento de Qu´ımica Organica, Uni-
versidad de Valencia, Dr Moliner 50, 46100 Burjassot, Valencia, Spain.
E-mail: domingo@utopia.uv.es
a
b
c
M. Esseffar, M. El. Messaoudi, S. Azzouzi
´
Departement de Chimie, Faculte des Sciences-Semlalia, Universite Cadi
ayyad, B.P. 2390, Marrakech, Morocco
´
´
R. Jalal
´
Departement des Sciences Chimique, Faculte des Sciences et Techniques,
Universite Cadi ayyad, B.P. 549, Marrakesh, Morocco
´
´
´
J. A. Saez, L. R. Domingo
´
Departamento de Qu´ımica Organica, Universidad de Valencia, Dr Moliner 50,
46100 Burjassot, Valencia, Spain
In the context of our current interest in the synthesis of novel
heterocyclic compounds,[19–23] susceptible to have biological
activity, we have now studied the 1,3-dipolar cycloaddition
(13DC) reaction between 6-dimethylaminomethylene-3-thioxo-
[1,2,4]-triazepin-5-one 1 and C,N-disubstituted nitrilimines 2a–f
(Scheme 1), which were generated in situ from the appropriate
precursors and triethylamine. However, we have found that along
the purification of reaction mixture by column chromatography,
the corresponding spirocycloadducts 3a–f were transformed into
d
e
J. Latorre
Instituto de Ciencia de Materiales, Universidad de Valencia, Poligono la coma
s/n, 46980 Paterna, Spain
´
M. Liu-Gonzalez
S.C.S.I.E (RX) Universidad de Valencia, Dr. Moliner 50, Burjassot 46100, Spain
y
Dedicated to the memory of Tourya El Messaoudi 1975–2003.
J. Phys. Org. Chem. 2009, 22 31–41
Copyright ß 2008 John Wiley & Sons, Ltd.

M. ESSEFFAR ET AL.
Scheme 1.
for 1-Z attributed to the carbon of exocyclic double bond (—C
—
—
theoretical study providing an explanation for the formation of
the two new bicyclic compounds. Firstly, we describe the
synthesis of the novel triazepine 1 and the 13DC reaction with the
nitrilimines 2a–f. Then, a theoretical study of the molecular
mechanism of the chemical reactions experimentally observed is
performed.
CH), permitted to confirm again the presence of this exocyclic
double bond. The carbons of thioxo and oxo groups are also
clearly identified in this spectrum (177.5 and 168.2 ppm for 1-E
and 177.2 and 164.9 ppm for 1-Z, respectively).
1,3-Dipolar cycloaddition of 3-thioxo-[1,2,4]-triazepin-5-one 1 with
N-aryl-C-ethoxycarbonyl-nitrilimines and diarylnitrilimines 2a–f.
RESULTS AND DISCUSSION
Experimental results
Nitrilimines 2a–f were generated in situ by treating appropriate
ethylhydrazono-a-bromoglyoxylate for 2a–c and a-chloroarylidene
phenylhydrazones for 2d–f with triethylamine. After treatment of
the 3-thioxo-[1,2,4]triazepin-5-one 1 with nitrilimines 2a–c at
room temperature over 72 h, the spirocycloadducts 3a–c were
isolated as a mixture of two stereoisomers 3E and 3Z in a ratio 7:3
(as shown in Scheme 1 and Table 2). In the case of the addition of
nitrilimines 2d–f, the cycloadducts 3d–f were not obtained when
the dichloromethane was used as solvent of extraction. However,
when this solvent was replaced by benzene, the thin-layer
chromatography and the NMR spectra of the reaction crude
showed the presence of three compounds: 3d–f, 4d–f and 5d–f.
Note that, during the separation of the reaction mixture on
column chromatography, the cycloaducts 3a–f were transformed
to the bicyclo compounds 4a–f and 5a–f. It is to note that this
type of spirocycloaducts are described as unstable products
(Table 1).[23,24]
Synthesis of 3-thioxo-[1,2,4]-triazepin-5-one 1
The 3-thioxo-[1,2,4]-triazepin-5-one 1 was obtained in good yield
(70%) by stirring
a mixture of [1,2,4]-triazepine 6 and
dimethylformamide-dimethylacetal (DMF-DMA) during 1 h at
5 8C (as shown in Scheme 2).
NMR spectra of the obtained product showed the presence of
a mixture of two stereoisomers 1-Z and 1-E. The percentage of
1
these stereoisomers was deduced by H NMR spectrum: 34 and
66% respectively. The structures of the two stereoisomers were
assigned easily by NMR spectra and mass spectrum. In H NMR
spectrum, the presence of the exocyclic double bond C C is
—
pointed out by two singlets at 7.05 and 7.55 ppm attributables
1
—
—
respectively to ethylenic proton —C CH of structures 1-Z and
—
1-E. This attribution of these values is supported by a simulation
of 1H RMN chemical shifts related to ethylenic protons. The higher
chemical shift of the ethylenic proton of 1-E is due to the proton
proximity to the carbonyl group. The 13C NMR spectrum of these
stereoisomers is characterized mainly by the absence of
resonance signal of methylene group in position 6 and by the
presence of signal of carbon C6 at 96.5 ppm for 1-Z and 96.1 ppm
for 1-E. The chemical shifts at 154.5 ppm for 1-E and 154.1 ppm
Formation of the spirocycloadducts 3a–c was detected by NMR
and mass spectra of their crude reaction. The orientation in the
structures 3a–c and the active site of 1 were unequivocally
determined on the basis of diagnostic 1H and 13C NMR data. This
result was confirmed also by X-ray diffraction analysis of 4e
and 5d compounds (Fig. 1). In the proton NMR spectrum of
Scheme 2.
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 31–41

FORMATION OF PYRAZOL-1,3,4-THIADIAZOLE
Table 1. Reaction of 3-thioxo-[1,2,4]-triazepin-5-one 1 with nitrilimines 2a–f
2
R1
R2
3
(E/Z) percentagea
Yield (%)
Ratio (4:5)
2a
2b
2c
2d
2e
2f
p-CH3C6H4
p-ClC6H4
p-NO2C6H4
C6H5
CO2Et
CO2Et
CO2Et
p-CH3C6H4
p-ClC6H4
p-NO2C6H4
3a
3b
3c
3db
3eb
3fb
68–32
67–33
72–28
—
—
—
67
70
66
48
48
42
55:45
54:46
53:47
54:46
56:44
56:44
C6H5
C6H5
a Estimated from NMR spectra of the reaction mixture.
b 3d–f were obtained as a mixture with 4d–f and 5d–f and the percentage were not estimated.
3-E and 3-Z cycloadducts, the presence of the exocyclic double
bond was justified clearly by two singlets at (7.72–7.75) ppm for
3-E and (7.01–7.07) ppm for 3-Z characteristics of olefinic protons.
The observed shielding of methyl group linked to N2 at
(2.58–2.60) ppm for 3-E and (2.50–2.58) ppm for 3-Z (instead
of 3.50 ppm initially) permits to confirm the preferential attack
spectrum of the two stereoisomers, the chemical shifts of the
carbon atoms at (144.2–145.8) ppm and (118.2–118.9) ppm for
3E and (144.5–146.0) ppm and (117.6–118.4) ppm for 3Z assigned
—
respectively to CH and C exclude categorically the addition on
—
the exocyclic double bond dipolarophile site. The reactive C
6
—
—
S
site of the addition was confirmed again in this spectrum by the
absence of thioxo group signal. The carbon chemical shifts at
(97.2–98.5) ppm and (98.2–98.6) ppm assigned respectively to
spiranic carbons of 3-E and 3-Z are consistent with these
structures. The proposed regiochemistry of the addition is in
good agreement with that observed for other related systems.[25]
The nitrogen atom of the dipole is linked to the carbon atom of
site (C S) of the addition of 1. On the other hand, in 13C NMR
—
—
—
dipolarophile site C S. No condensation products of the dipole
—
—
—
—
on the other dipolarophile sites (C C, C N and C O) has
—
—
—
been observed. It is to note that while the extraction was made
using a more polar solvent, as dichloromethane, the cycloadduct
3 was not isolated evolving directly the conversion to the
compounds 4 and 5.
For the isolated 1,2-pyrazol-1,3,4-thiadiazole 4e and 5d, the
X-ray diffraction and spectral data are in accordance with the
proposed structures (Scheme 1). Thus, the examination of NMR
spectra and mass spectrum shows that these products are formed
—
by monocycloaddition of nitrilimine on the C S double bond.
—
Then the corresponding cycloadducts are transformed into 4a–f
and 5a–f compounds. In 1H NMR spectra of 4a–f compounds, we
noted in particular the chemical shift of aldehyde proton at about
—
(9.74–9.83) ppm. The C—CH and N—CH protons resonate as
—
3
3
singlet at (2.38–2.56) ppm and (3.50–3.84) ppm, respectively.
Methyl and methylene of CO2Et group show triplet and quartet at
about (1.32–1.43) ppm and (4.37–4.49) ppm, respectively. In
13C NMR spectra of 4a–f the aldehyde carbonyl is confirmed again
by the presence of the pick at (182.4–183.3) ppm. The signals of the
0
0
carbon atoms C5 (151.4–153.0) ppm, C4 (108.4–109.1) ppm, C5
(149.8–151.3) ppm and C2 (160.5–162.0) ppm confirm also the
proposed structures. For compounds 5a–f, the presence of the
olefinic protons is pointed out by a singlet at about (7.82–7.89)
ppm. On the other hand, the 13C NMR spectra reveal mainly the
signal of carbon of carbonyl group at about (171.3–171.8) ppm and
the signals at (118.3–119.1), (135.1–136.7), (147.9–151.8),
(151.9–156.3) and (163.4–164.9) ppm, attributed respectively to
0
0
0
carbons C4 , C5 , C3 , C5, C2.
To sum up, the 13DC reactions of 3-thioxo-[1,2,4]-triazepin-
5-one 1 with the nitrilimines 2a–f are completely chemo and
regioselective. In all cases the carbon atom of dipoles is linked to
Figure 1. The molecular structure of compound 4e and 5d (ORTEP: XTAL
3.6) with the numbering scheme. Displacement ellipsoids are drawn at
30% probability
—
the sulfur atom of dipolarophile C S site of 1. No addition of
—
—
—
dipoles were observed on the C N and C O double bonds,
—
—
J. Phys. Org. Chem. 2009, 22 31–41
Copyright ß 2008 John Wiley & Sons, Ltd.
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M. ESSEFFAR ET AL.
—
and the exocyclic C C double bond. However, along the
—
bond present on 1 were also considered. An analysis of the
stationary points found along the four reaction paths points out
that these 13DC reactions have one-step mechanism. Thus, four
TSs, TS1-E, TS1-Z, TS2-E, TS2-Z, and four [3 þ 2] spirocycload-
ducts 3g-E, 3g-Z, 7g-E and 7g-Z were located and characterized
purification of reaction mixture, the corresponding spirocycload-
ducts 3a–f were quickly transformed into the bicycle compounds
4a–f and 5a–f.
*
(as shown in Scheme 3). The B3LYP/6-31G total and relative
energies are collected in Table 2.
X-ray crystallography analysis
The activation energies associated to the formation of the
spirocycloadducts 3g-E and 3g-Z, via TS1-E and TS1-Z, present
very low values: 3.5 and 3.7 kcal/mol, respectively. The E/Z
The molecular structures of 4e and 5d (C21H18N5OS, triclinic
and C21H16ClN5OS, monoclinic) determined X-ray crystallography
in this work are shown in Fig. 1. The structures of 4d and 5e were
obtained by slowly evaporating a benzene solution. Analysis of
these X-ray structures allows to obtain some interesting features
for the conversion of the spirocycloadducts 3a–f in the
compounds 4a–f and 5a–f: (i) the [1,2,4]triazepine ring is not
present in these compounds, (ii) the five-membered ring formed
along the 13DC reaction remains in these structures, (iii) the
enamine substituent present in triazepine 1 is hydrolysed along
these processes, (iv) two new five-membered heterocycle
compounds are formed along the reaction and (v) these
heterocycle compounds contain an a,b-unsaturated carbonyl
group: one aldehyde on 4e and one ketone on 5d.
—
configuration of the exocyclic C C double bond has not any
—
appreciable incidence on the activation energies. These
cycloadditions are strongly exothermic: ꢀ23.6 (3g-E) and
ꢀ23.2 (3g-Z) kcal/mol. On the other hand, formation of the
regiosiomeric cycloadducts 7g-E and 7g-Z present very large
activation energies: 21.0 (TS2-E) and 21.7 (TS2-Z) kcal/mol. These
energy results are in agreement with the complete regioselec-
tivity experimentally observed. Formation of the regioisomeric
cycloadducts are also less exothermic: ꢀ12.9 (7g-E) and
ꢀ15.1(7g-Z) kcal/mol.
The geometries of the TSs involved in these 13DC reactions are
depicted in Fig. 2. At the more favourable regioisomeric TSs,
TS1-E and TS1-Z, the length of the S1—C5 forming bond is 2.408
Theoretical study
˚
and 2.407 A, while the distance between the C2 and the N3 atoms
˚
is 3.288 and 3.321 A, respectively. These values point out to very
asynchronous bond-formation processes in which the S1—C5
bond-formation is anticipated to the C2—N3 one. At the more
unfavourable regioisomeric TSs, TS2-E and TS2-Z, the length of
˚
the C2—C5 forming bond is 2.096 and 2.092 A, while the length of
˚
the S1—N3 bond is 2.482 A. These TSs are more advanced and
more synchronous.
Study of the 1,3-dipolar cycloaddition reaction between
3-thioxo-[1,2,4]-triazepin-5-one 1 and
C-methoxycarbonyl-nitrilimine 2g
Firstly, the 13DC reaction between 3-thioxo-[1,2,4]-triazepin-
5-one 1 and the C-methoxycarbonyl-nitrilimine 2g, as a model of
the nitrilimines 2a–c, was studied (as shown in Scheme 3). As it
has been indicated in the experimental part, in spite of the
Analysis of the bond orders (BO) and the charge transfer (CT) at
the TSs allows to establish the electronic nature of these 13DC
reactions. At the more favourable regioisomeric TSs, TS1-E and
TS1-Z, the BO values of the S1—C5 forming bond are 0.33 and
0.34, while the BO values between the C2 and the N3 atoms are
0.03. These BO values indicate that only the S1—C5 bond is being
formed at these asynchronous TSs. On the other hand, at the
more unfavourable regioisomeric TSs, TS2-E and TS2-Z, the BO
values of the C2—C5 and S1—N3 forming bonds are 0.43 and
presence of four dipolarophile sites in 1, these reactions take
—
participates as dipolarophile in these 13DC reactions.[23]
According to the experimental result, we decided to perform
place with a total chemoselectivity; only the C S double bond
—
the computational study of the addition of the nitrilimine 2g to
—
the C S double bond of 1. For this 13DC reaction, the two
—
regioisomeric channels associated to the addition of 2g to the
—
unsymmetric C S double bond of 1 were studied. In addition,
—
the E/Z configurational dispositions of the exocyclic C C double
—
—
Scheme 3.
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Copyright ß 2008 John Wiley & Sons, Ltd.
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FORMATION OF PYRAZOL-1,3,4-THIADIAZOLE
Table 2. Total (E, au) and relative (DE, kcal/mol) energies, in gas-phase and benzene, and total (G, au) and relative (DG, kcal/mol) free
energies in benzene for stationary points involved in the 13DC reactions of 1-E and 1-Z with 2g
Gas-phase
Benzene
E
DE
E
DE
G
DG
1-E
1-Z
2g
ꢀ1043.772302
ꢀ1043.772618
ꢀ607.634412
ꢀ1651.401206
ꢀ1651.401206
ꢀ1651.444258
ꢀ1651.443973
ꢀ1651.373260
ꢀ1651.372481
ꢀ1651.427249
ꢀ1651.431159
ꢀ1043.781561
ꢀ1043.781063
ꢀ607.638885
ꢀ1651.413185
ꢀ1651.412283
ꢀ1651.454657
ꢀ1651.453334
ꢀ1651.383731
ꢀ1651.382129
ꢀ1651.435868
ꢀ1651.438630
ꢀ1043.598519
ꢀ1043.597913
ꢀ607.528673
ꢀ1651.100245
ꢀ1651.100349
ꢀ1651.134958
ꢀ1651.130806
ꢀ1651.068242
ꢀ1651.066401
ꢀ1651.118121
ꢀ1651.119144
TS1-E
TS1-Z
3g-E
3g-Z
TS2-E
TS2-Z
7g-E
7g-Z
3.5
4.6
16.9
16.8
ꢀ4.9
ꢀ2.3
37.0
37.8
5.3
3.7
ꢀ23.6
ꢀ23.2
1.0
4.8
ꢀ21.5
ꢀ20.9
23.0
21.7
ꢀ12.9
23.7
ꢀ9.7
ꢀ15.1
ꢀ11.7
4.7
0.30, respectively. These values point to concerted bond
formation process where the C2—C5 bond formation is more
advanced than the S1—N3 one.
The CT at these cycloadditions was analysed sharing the
natural charges between the dipole and the dipolarophile
fragments. At the more favourable regioisomeric TSs, the CT that
fluxes from the 3-thioxo-[1,2,4]-triazepin-5-one 1 to the nitrili-
mine 2g is 0.26 e at both E/Z TSs. This large value indicates that
these TSs have some zwitterionic character. On the other hand, at
the more unfavourable regioisomeric TSs the CT is negligible,
0.05 e, and it takes place in the opposite direction. This analysis
indicates that the two regioisomeric cycloadditions are associ-
ated to unlike chemical processes. While the TSs associated to the
most favourable regioisomeric channels can be associated to
two-centre interactions between the most nucleophilic site of
the 3-thioxo-[1,2,4]-triazepin-5-one 1, the sulfur S1 atom, and the
most electrophilic site of nitrilimine 2g, the carbon C5 atom, the
TSs associated to the more unfavourable regioisomeric channels
can be related to four-centre interactions characteristic of
concerted cycloaddition processes. The flux of the CT found at
the more favourable TSs is in agreement with the large
electrophilic character of the nitrilimine 2g, v ¼ 1.75 eV, than
that of 3-thioxo-[1,2,4]-triazepin-5-one 1-E, v ¼ 1.30 eV.[26]
As these cycloadditions have some polar character, and solvent
can modify the energies, effect of benzene was considered. In
benzene, all species are stabilized between 3 and 8 kcal/mol. The
more stabilized species are TS1-E and TS1-Z due to their polar
character, 7.5 and 7.0 kcal/mol, respectively. However, the
separated reagents become slightly more solvated. As a
consequence, the activation energies increase to 1.1 kcal/mol.
Solvent effects have not any incidence on the regioselectivity of
the studied reaction.
Finally, the inclusion of the thermal corrections and entropies
to the total energies in benzene raises the free energies between
12 and 19 kcal/mol due to the bimolecular nature of these
cycloadditions (as shown in Table 2). The free activation energies
associated to TS1-E and TS1-Z are 16.9 and 16.8 kcal/mol. The
regioisomeric TSs remains ca. 20 kcal/mol above the more
favourable TSs. Finally, formation of the spirocycloadducts 3g-E
and 3g-Z are slightly exergonic, ꢀ4.9 and ꢀ2.3 kcal/mol,
respectively.
Study of conversion of spirocycloadducts 3a–f into
bicycloderivatives 4a–f and 5a–f
The spirocycloadducts 3a–f are very unstable, and they are
converted quickly into the two bicyclo compounds 4a–f and 5a–f
(as shown in Scheme 1). Therefore, we have considered to study
these conversions. Based on these observations obtained from
the X-ray crystallography analysis of the compounds of 4e and 5d
Figure 2. Transition structures for the 13DC reactions of
3-thioxo-[1,2,4]-triazepin-5-one 1-E and 1-Z with 2g. The values of the
˚
bond lengths are given in A
J. Phys. Org. Chem. 2009, 22 31–41
Copyright ß 2008 John Wiley & Sons, Ltd.
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M. ESSEFFAR ET AL.
Scheme 4.
(refer to Section 1.3) we have proposed a mechanism for the
conversions that considers all structural changes (as shown in
Scheme 4). In a first step, the triazepine ring is opened by a
N1—C2 breaking bond process to give the intermediate 8. Then,
the enamine substituent present in 8 is hydrolysed to the
corresponding aldehyde, yielding the dicarbonylic intermediate
9. Note that the ring cleavage and the enamine hydrolysis
are independent. However, due to the large instability of
these spirocompounds in an acid medium (mentioned later)
we assume that the ring cleavage takes place firstly. After the
enamine hydrolysis, the two carbonyl groups on 9 can
experiment an intramolecular condensation reaction with the
terminal amine N1 atom. Formation of the new N—C bond via
the intramolecular nucleophilic attack of the amine to each
carbonyl group present on 9 allows the formation of the two new
five-membered heterocycles. Finally, a water elimination process
on the bicyclic intermediates 10 and 11 allows the formation of
4g and 5g.
Due to the complexity of this mechanism, we decided to study
the two more significant elementary steps (as shown in A and B in
Scheme 4). They include the ring cleavage of the triazepine ring,
step A, and the ring closure of the dicarbonylic intermediate 9
with formation of the new bicyclic intermediates 10 and 11, step
B. Note that hydrolysis of enamines and condensation reactions
Scheme 5.
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FORMATION OF PYRAZOL-1,3,4-THIADIAZOLE
Table 3. Total (E, au) and relative (DE, kcal/mol) energies, in gas-phase and dichloromethane and total (G, au) and relative (DG, kcal/
mol) free energies in dichloromethane, for the more relevant stationary points corresponding to the reaction model for
transformation of spirocycloadduct 3g–4g and 5g products
*
*
*
B3LYP/6-31G
B3LYP/6-31G
B3LYP/6-31 þ G
Gas-phase
DE
Dichloromethane
E
E
DE
E
DE
G
DG
IN1
TS3
IN2
IN3
TS4
IN4
IN5
ꢀ1192.905939
ꢀ1192.928240
ꢀ1192.977586
ꢀ1192.974637
ꢀ1193.011543
ꢀ1134.236299
ꢀ1134.234001
ꢀ1134.238627
ꢀ1134.274285
ꢀ1192.75108
ꢀ1192.74961
ꢀ1192.78486
ꢀ1134.07706
ꢀ1134.07179
ꢀ1134.07442
ꢀ1134.10736
ꢀ1192.901739
ꢀ1192.944099
ꢀ1134.158984
ꢀ1134.157262
ꢀ1134.161908
ꢀ1134.198415
2.6
ꢀ23.9
ꢀ1192.924370
ꢀ1192.965038
ꢀ1134.180397
ꢀ1134.163718
ꢀ1134.183691
ꢀ1134.220647
2.4
ꢀ23.1
1.9
ꢀ21.3
0.9
ꢀ21.2
1.1
ꢀ1.8
10.5
-2.1
ꢀ25.3
1.4
ꢀ1.5
3.3
1.7
ꢀ19.0
ꢀ24.7
ꢀ23.8
of carbonyl compounds with amines are common reactions in
the chemistry of the carbonyl group. In addition, due to that the
thiazole ring does not participate in the domino reaction, the
methoxycarbonyl and phenyl groups present in the thiazole ring
have been replaced by two hydrogen atoms in order to work with
a more reduced model.
atom and the aldehyde carbonyl C7 carbon atom and the ketone
˚
carbonyl C3 carbon atom is 2.909 and 2.787 A, respectively. These
large distances point out the early character of this TS.
At the intermediate IN3 the protonation takes place at the
most basic ketone O7 oxygen atom, but the proton forms also a
strong hydrogen bond with the aldehyde O9 oxygen atom, with a
˚
bond length of 1.615 A. This behaviour remains also at TS4. The
All steps of the proposed mechanism need an acid catalysis in
order to facilitate the breaking- and forming-bond processes
associated to each elementary process (as shown in Scheme 5).
After the protonation of the N1 nitrogen atom of the triazepinone
ring of the spirocycloadduct 3, the activation energy associated
to the N1—C2 breaking-bond of the intermediate IN1 via TS3, is
only of 2.6 kcal/mol. This ring cleavage process is very exothermic,
ꢀ23.9 kcal/mol. These energy results indicate that in acid
environment the spirocycloadducts 3a–f are kinetically and
thermodynamically very unstable, yielding irreversibly the open
intermediates as 8 (as shown in Scheme 4). Note that the N1
nitrogen atom of these spirocycloadducts corresponds to the
most basic centre of these molecules.
IRC from TS4 to IN4 shows that along the nucleophilic attack of
the amine N1 nitrogen atom to the aldehyde C7 carbon atom, the
proton moves from the ketone O7 oxygen atom to the aldehyde
O9 oxygen atom, thus stabilizing the negative charge that
develops at the aldehyde O9 oxygen atom along the nucleophilic
attack to the C8 carbon atom. The same mechanism, related to
the synthesis of pyrazoles reaction of hydrazines with
b-dicarbonyl compounds, has been studied by Elguero and
coworkers.[27–29]
Dichloromethane stabilizes all structures between 42 and
49 kcal/mol, as a consequence of the cationic character of these
species. However, the inclusion of solvent effect does not modify
For the ring-closure step with formation of the five-membered
heterocycles present in 4g and 5g, we found a unique TS4
followed by a downhill intrinsic reaction coordinate (IRC) until the
path bifurcates into two equivalent downhill pathways allowing
the formation of the intermediate IN4, result of the nucleophilic
attack of the amine N1 nitrogen atom to the ketone C3 carbon
atom, and the intermediate IN5, result of the attack of this
nitrogen atom to the aldehyde C7 carbon atom. TS4 is located
only 1.1 kcal/mol above the intermediate IN3. Formation of the
intermediates IN4 and IN5 is exothermic in ꢀ1.8 and ꢀ24.7 kcal/
mol, respectively. The low exothermic character of IN4 can be
related to the loss of the conjugation associated to the
nucleophilic attack to the ketone group. Spite of the low
exothermic character of formation of the intermediate IN4, the
quick exchange of the N1 proton by an acid/base process can
turn irreversible this step after water elimination. Full optimiz-
ation of the stationary points associated to the paths A and B at
*
the B3LYP/6-31 þ G does not produce appreciable changes (as
shown in Table 3). Only the relative energy of TS4 increases to
10.5 kcal/mol.
The geometries of TS3 and TS4 are given in Fig. 3. At TS3, the
˚
length of the N1—C2 breaking bond is 2.138 A, while the BO
value is 0.31. At TS4, the distance between the amine N1 nitrogen
Figure 3. Transition structures involved in the reaction model for the
transformation of spirocycloadduct 3g–4g and 5g products
J. Phys. Org. Chem. 2009, 22 31–41
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

M. ESSEFFAR ET AL.
the gas-phase relative energies. Finally, the inclusion of the
thermal corrections and entropies to the total energies in
dichloromethane causes minor changes on the relative free
energies associated to this domino process due to the
intramolecular nature of the two elementary steps. The activation
free energies for the two elementary steps present very low
values, 0.9 kcal/mol (TS3) and 3.3 kcal/mol (TS4) (as shown in
Table 3). These values support the feasibility of these steps. On
the other hand, formation of the intermediate IN2 is a strongly
exergonic process, ꢀ21.2 kcal/mol. Therefore, in an acid medium,
the spirocycloadducts as 3g are kinetically and thermodynami-
cally very unstable in clear agreement with the experimental
outcome.
further its identity and also map out a minimum energy reaction
pathway. Net atomic charges of the stationary points were
obtained by using the natural bond orbital (NBO) approach.[38,39]
*
The solvent effects have been considered by B3LYP/6-31G single
point calculations over the gas phase optimized structures using
a self-consistent reaction field[40] (SCRF) based on the PCM
method of the Tomasi’s group.[41–43] Since these reactions are
carried out in benzene and dichloromethane, we have selected
its dielectric constants at 298.0 K. The values of the free energies
in benzene and dichloromethane were calculated with the
standard statistical thermodynamics at 298.15 K and 1 atm.[36]
Thermodynamic calculations were scaled by a factor of 0.96.
In conclusion, both energy results and geometries associated
to the A and B elementary steps studied in Scheme 5 support the
mechanism proposed in Scheme 4 for the transformation of the
spirocycloadduct 3g into the bicyclo compounds 4g and 5g.
Note that for the other non-studied elementary steps of
Scheme 4, it is assumed that they take place easily.
EXPERIMENTAL
Melting points were taken on a Buchi 510 apparatus and were
uncorrected. The 1H NMR spectra were recorded with the
following instruments: Bruker WP 400 CW and AC 250. TMS
was used as an internal reference. The 13C NMR spectra were
measured on a Varian FT 80 (20.0 MHz). Mass spectra were
recorded with a JEOL JMS DX 300. Column chromatography
was carried out using E-Merck silica gel 60F254. Reagents and
solvents were purified in the usual way. The data collections of
X-ray structures were performed at 293 K on a Nonius k-CCD
CONCLUSION
New bicyclic pyrazol-1,3,4-thiadiazole derivatives 4a–f and 5a–f
have been synthesized by reaction between the 3-thioxo-
[1,2,4]-triazepin-5-one 1 and several nitrilimines 2a–f. The studied
reactions take place through two reaction types: a 13DC reaction
between 1 and 2a–f, and a domino reaction allowing the
conversion of the corresponding spirocycloadducts 3a–f into the
final bicyclic compounds 4a–f and 5a–f, which were character-
ized by NMR and X-ray analyses. The mechanism of the two
reaction types have been theoretically studied using DFT
˚
single crystal diffractometer, using Mo Karadiation (l ¼ 0.7173 A).
Crystal-detector distance was fixed at 35 mm, and a total of 220/
325 images were collected using the oscillation method, with
scan angle per frame 28 oscillation and 20 s. exposure time per
image. Data collection strategy was calculated with the program
Collect.[44] Data reduction and cell refinements were performed
with the programs HKL Denzo and Scalepack.[45,46] The crystal
structure was solved by direct methods, using the program
SIR-97.[47] Anisotropic least-squares refinement was carried out
with SHELXL-97.[48] All non hydrogen atoms were anisotropically
refined. Some Hydrogen atoms were located in a difference
Fourier maps and the remaining ones located geometrically.
Geometrical calculations were made with PARST.[49,50] The
crystallographic plots were made with mercury.[51]
*
calculations at the B3LYP/6-31G level. The spirocycloaduct 3g
is obtained through a 13DC reaction via a high asynchronous
mechanism with a very low activation energy. The computational
results support the total regioselectivity experimentally
observed. For the conversion of the spirocycloadducts 3a–f into
the two biciclyc compounds 4a–f and 5a–f, a domino reaction
that comprises the cleavage of the triazepin ring, hydrolysis of the
enamine substituent, and two intramolecular condensation
reactions to form the two new five-membered heterocycles
has been proposed. The elementary steps responsible for the
N2—C3 cleavage of the triazepin ring and the intramolecular
nucleophilic addition reaction to the carbonyl groups to yield the
thiazolo and diazolo rings have been studied. The energy results
obtained for these elementary steps support the suitability of the
proposed mechanism, allowing to explain formation of the two
bicyclic pyrazol-1,3,4-thiadiazole derivatives.
Synthesis of [1,2,4]triazepine 1
A solution of 3-thioxo[1,2,4]triazepin-5-one 6 (5.8 mmol.) and
DMF-DMA (20 ml) was stirred for 1 h at 5 8C. The precipitated
solid was filtered off under reduced pressure and the crude
solid subjected to silica-gel using 80/20% ethyl acetate/hexane
mixture as eluent gave a 66:34 mixture of two isomers 1-E and 1-Z
in good yield 65%.
(E)-6-(dimethylaminomethylene)-2,7-dimethyl-3-thioxo-3,4,5,6-
tetrahydro-2H-[1,2,4] triazepin-5-one 1-E
COMPUTATIONAL METHODS
Percentage: 66, 1H NMR (CDCl3): d ppm: 2.08 (s, 3H, C7—CH3), 3.07
Quantum chemical calculations were performed with the use of
the Gaussian 03 set of programs.[30] All structures were fully
optimized with the density functional theory (DFT) using Becke’s
three parameter hybrid method[31] and correlation functional of
—
(s, 6H, N(CH ) ), 3.57 (s, 3H, N —CH ), 7.55 (s, 1H, H—C ), 7.84 (s,
—
3 2
2
3
1H, NH). 13C NMR (CDCl3): d ppm: (C7—CH3), 44.95 (N—(CH3)2),
45.3 (N —CH ), 154.5 (H—C ), 96.1 (C ), 164.2 (C ), 168.2 (C ),
—
—
2
3
6
5
177.4 (C3), Mass spectrum (FAB) m/z: 475 [M þ H]þ7.
Lee–Yang–Parr (B3LYP)[32–35] in conjunction with the 6-31G and
*
6-31 þ G [36] basis sets. The stationary points were characterized
*
(Z)-6-(dimethylaminomethylene)-2,7-dimethyl-3-thioxo-3,4,5,6-
tetrahydro-2H-[1,2,4] triazepin-5-one 1-Z
by harmonic vibrational frequency analysis in order to verify that
minima and transition structures have zero and one imaginary
frequency, respectively. Starting from a transition structures, the
IRC[37] pathway has also been constructed in order to verify
Percentage: 34, 1H NMR (CDCl3): d ppm: 2.18 (s, 3H, C7—CH3), 3.07
—
(s, 6H, N(CH ) ), 3.50(s, 3H, N —CH3), 7.05 (s, 1H, H—C ), 7.90 (s,
—
3 2
2
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 31–41

FORMATION OF PYRAZOL-1,3,4-THIADIAZOLE
—
4.28–4.37 (m, 2H, —CH2—O), 7.01 (s, 1H, C6 CH), 6.73 (s, 1H,
—
1H, NH). 13C NMR (CDCl3): d ppm: 22.0 (C7—CH3), 44.9
—
(N—(CH ) ), 44.7 (N —CH ), 154.1 (H—C ), 96.5 (C ), 163.6
—
NH), 7.13 (d, 2H, J ¼ 9.31 Hz, H—Ar), 7.87 (d, 2H, J ¼ 9.31 Hz,
H—Ar). 13C NMR (CDCl3): d ppm: 14.2 (COOCH2CH3), 14.3
(C7—CH3); 21.8, (N2—CH3), 40.8 (N(CH3)2), 63.6 (—CH2—O), 98.3
3 2
2
3
6
(C7), 164.9 (C5), 177.2 (C3), Mass spectrum (FAB) m/z: 475 [M þ H]þ.
—
0
(C2 ); 118.4 (C6), 121.1, 125.0 (CHAr), 130.5, 137.2 (CAr), 144.5 (C6
—
General procedure for preparation of products 3a–c, 4a–c
and 5a–c
—
0
CH), 153.7 (C ); 160.0 (C ), 165.6 (C OC H ), 169.9 (C ).
—
7
5
2
5
5
To a solution of 1,2,4-triazepine 1 (5 mmol) and ethylhydrazo-
no-a-bromoglyoxylate (5.5 mmol) in dry benzene (30 ml),
triethylamine (7.2 mmol) dissolved in dry benzene (10 ml) was
added dropwise. After stirring for 72 h at room temperature, the
solvent was then removed under vacuum and the mixture was
diluted with water (25 ml) and extracted with dichloromethane
(3 ꢁ 50 ml). The organic layers were dried over anhydrous sodium
sulphate, concentrated under reduced pressure and the yellow
crystalline product thus obtained 3a–c was further transformed
to pure 4a–c and 5a–c compounds by chromatography on a silica
gel column (eluent: hexane/ethylacetate, 75/25).
Ethyl (6E)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H [1,2,4]triazepine-3-spiro-20-(30-(p-
nitrophenyl)-20,30-dihydro[1,3,4]thiadiazole-50-carboxylate 3c
1H NMR (CDCl3): d ppm: 1.36–1.39 (m, 3H, COOCH2CH3), 2.08 (s,
3H, C7—CH3), 2.60 (s, 3H, N2—CH3), 3.15 (s, 6H, N(CH3)2),
—
4.31–4.41 (m, 2H, —CH2—O), 7.75 (s, 1H, C6 CH), 6.45 (s, 1H,
—
NH), 7.79 (d, 2H, J ¼ 9.35 Hz, H—Ar), 8.11 (d, 2H, J ¼ 9.35 Hz,
H—Ar). 13C NMR (CDCl3): d ppm: 14.5 (COOCH2CH3), 14.6
0
(C7—CH3), 24.6, (N2 —CH3), 40.4 (N(CH3)2), 63.0 (—CH2—O), 97.9
—
—
0
(C2 ), 118.6 (C6), 118.3, 125.3 (CHAr), 138.4, 143.4 (CAr), 145.8 (C6
—
0
CH), 153.9 (C ), 160.1 (C ), 165.7 (C OC H ), 169.7 (C ).
—
7
5
2
5
5
Ethyl (6E)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H-[1,2,4]triazepine-3-spiro-20-(30-(p-tolyl)-20,30-
dihydro[1,3,4]thiadiazole-50-carboxylate 3a
Ethyl (6Z)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H [1,2,4]triazepine-3-spiro-20-(30-(p-
nitrophenyl)-20,30-dihydro[1,3,4]thiadiazole-50-carboxylate 3c
1H NMR (CDCl3): d ppm: 1.26–1.30 (m, 3H, COOCH2CH3), 2.04 (s,
3H, C7—CH3), 2.60 (s, 3H, N2—CH3), 3.10 (s, 6H, N(CH3)2),
1H NMR (CDCl3): d ppm: 1.36–1.39 (m, 3H, COOCH2CH3), 2.00 (s,
3H, C7—CH3), 2.58 (s, 3H, N2—CH3), 3.15 (s, 6H, N(CH3)2),
—
4.22–4.33 (m, 2H, —CH2—O), 7.75 (s, 1H, C6 CH), 6.40 (s, 1H,
—
—
4.31–4.41 (m, 2H, —CH2—O), 7.07 (s, 1H, C6 CH), 6.76 (s,1H, NH),
—
NH), 6.92 (d, 2H, J ¼ 9.31 Hz, H—Ar), 7.36 (d, 2H, J ¼ 9.31 Hz,
H—Ar). 13C NMR (CDCl3): d ppm: 14.4 (COOCH2CH3), 14.7
(C7—CH3), 24.7 (N2—CH3), 40.7 (N(CH3)2), 62.8 (—CH2—O), 98.5
7.81 (d, 2H, J ¼ 9.33 Hz, H—Ar), 8.05 (d, 2H, J ¼ 9.331 Hz, H—Ar).
13C NMR (CDCl3): d ppm: 14.3 (COOCH2CH3) 14.4 (C7—CH3), 21.3
0
(N2—CH3), 40.9 (N(CH3)2), 63.9 (—CH2—O), 98.6 (C2 ), 118.1 (C6),
—
0
(C2 ), 118.2 (C6), 117.4, 129.7 (CHAr), 134.4, 135.6 (CAr), 144.9 (C6
—
—
118.2, 124.8 (CHAr), 138.5, 144.0 (CAr), 146.0 (C6 CH), 154.7 (C ),
—
7
—
0
CH), 154.5 (C ), 160.4 (C ), 165.6 (C OC H ), 169.2 (C ).
—
7
5
2
5
5
—
0
161.8 (C ), 165.8 (C OC H ), 169.8 (C ).
—
5
2
5
5
Ethyl (6Z)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H [1,2,4]triazepine-3-spiro-20-(30-(p-tolyl)-20,30-
dihydro[1,3,4]thiadiazole-50-carboxylate 3a
Ethyl (E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-3-p-
tolyl-2,3-dihydro [1,3,4]thiadiazole-5-carboxylate 4a
mp: 151–152 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.32 (t, 3H,
J ¼ 7.19 Hz, —CH2—CH3), 2.33 (s, 3H, Ar—CH3), 2.38 (s,
1H NMR (CDCl3): d ppm: 1.26–1.30 (m, 3H, COOCH2CH3), 1.99 (s,
3H, C7—CH3), 2.50 (s, 3H, N2—CH3), 3.10 (s, 6H, N(CH3)2),
0
0
3H, C3 —CH3), 3.50 (s, 3H, N1 —CH3), 4.37 (q, 2H, J ¼ 7.19 Hz,
—O—CH2—), 7.21, 7.67 (2d, J ¼ 9.25 Hz, 4H, HAr), 9.74 (s, 1H,
CHO). 13C NMR (CDCl3): d ppm: 13.4 (COOCH2CH3), 14.5
—
4.22–4.33 (m, 2H, —CH2—O), 7.02 (s, 1H, C6 CH), 6.87 (s,1H, NH),
—
6.87 (d, 2H, J ¼ 9.31 Hz, H—Ar), 7.30 (d, 2H, J ¼ 9.31 Hz, H—Ar).
13C NMR (CDCl3): d ppm: 14.3 (COOCH2CH3), 14.4 (C7—CH3), 21.4
0
0
(C3 —CH3), 21.5 (Ar—CH3), 34.8 (N1 —CH3), 63.6 (O—CH2),
0
(N2—CH3), 41.1 (N(CH3)2), 63.5 (—CH2—O), 98.2 (C2 ), 117.6 (C6);
0
0
108.8 (C4 ), 124.5, 129.9, 135.8, 138.9 (CAr), 141.5 (C3 ), 151.3,
—
117.2, 129.3 (CHAr); 134.5, 135.1 (CAr), 145.1 (C6 CH), 155.3 (C ),
—
7
0
151.4 (C5 , C5), 158.1 (CO2Et), 162.0 (C2), 183.0 (CHO). Mass
—
0
spectrum (FAB): m/z 386 [M þ H]þ 100%.
162.0 (C ), 165.7 (C OC H ), 169.3 (C ).
—
5
2
5
5
Ethyl (E)-2-(10,30-dimethyl-1H-[1,2]pyrazol-40-ylcarbonylimino)-3-p-
tolyl-2,3-dihydro [1,3,4]thiadiazole-5-carboxylate 5a
Ethyl (6E)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H [1,2,4]triazepine-3-spiro-20-(30-(p-
chlorophenyl)-20,30- dihydro[1,3,4]thiadiazole-50-carboxylate 3b
mp: 183–184 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.44 (t, 3H,
1H NMR (CDCl3): d ppm: 1.35–1.37 (m, 3H, COOCH2CH3), 2.07 (s,
3H, C7—CH3), 2.58 (s, 3H, N2—CH3), 3.14 (s, 6H, N(CH3)2),
0
J ¼ 7.14 Hz, —CH2—CH3), 2.45, 2.50 (2s, 6H, Ar—CH3, C3 —CH3),
0
3.83 (s, 3H, N1 —CH3), 4.49 (q, 2H, J ¼ 7.14 Hz, —O—CH2—), 7.33,
—
4.28–4.37 (m, 2H, —CH2—O), 7.72 (s, 1H, C6 CH), 6.40 (s, 1H,
—
0
7.75 (2d, J ¼ 9.19 Hz, 4H, HAr), 7.84 (s, 1H, C5 —H). 13C NMR
NH), 7.10 (d, 2H, J ¼ 9.31 Hz, H—Ar), 7.93 (d, 2H, J ¼ 9.31Hz,
H—Ar). 13C NMR (CDCl3): d ppm: 14.4 (COOCH2CH3), 14.6
(C7—CH3), 24.6, (N2—CH3), 40.3 (N(CH3)2), 62.8 (—CH2—O), 97.2
0
(CDCll3): d ppm: 14.3, 14.5 (COOCH2CH3 and C3 —CH3), 21.6
0
0
(Ar—CH3), 39.3 (N1 —CH3), 63.5 (O—CH2—), 118.9 (C4 ), 125.4,
0
0
129.8, 135.7, 139.2 (CAr), 136.7 (C5 ), 147.9, 151.9 (C3 , C5), 159.0,
164.9 (CO2Et, C2), 171.8 (CO). Mass spectrum (FAB): m/z 386
[M þ H]þ 100%.
—
0
(C2 ), 118.9 (C6), 121.3, 125.5 (CHAr), 130.4, 136.6 (CAr), 144.2 (C6
—
—
0
CH), 152.8 (C ), 159.3 (C ), 165.8 (C OC H ), 169.8 (C ).
—
7
5
2
5
5
Ethyl (6Z)-(2,7-dimethyl-5-oxo-6-((dimethylamino)methylene)-
3,4,5,6-tetrahydro-2H [1,2,4]triazepine-3-spiro-20-(30-(p-
chlorophenyl)-20,30-dihydro[1,3,4]thiadiazole-50-carboxylate 3b
Ethyl (E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-3-p-
chlorophenyl-2,3-dihydro[1,3,4]thiadiazole-5-carboxylate 4b
mp: 158–159 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.42 (t, 3H,
0
1H NMR (CDCl3): d ppm: 1.35–1.37 (m, 3H, COOCH2CH3), 2.00 (s,
3H, C7—CH3), 2.56 (s, 3H, N2—CH3), 3.14 (s, 6H, N(CH3)2),
J ¼ 7.18 Hz, —CH2—CH3), 2.48 (s, 3H, C3 —CH3), 3.60 (s,
0
3H, N1 —CH3), 4.45 (q, 2H, J ¼ 7.18 Hz, —O—CH2—), 7.49–7.87
J. Phys. Org. Chem. 2009, 22 31–41
Copyright ß 2008 John Wiley & Sons, Ltd.
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M. ESSEFFAR ET AL.
(2d, J ¼ 9.24 Hz, 4H, HAr), 9.80 (s, 1H, CHO). 13C NMR (CDCl3): d
126.2, 127.4, 128.9, 129.8 (5 CH—Ar), 126.8, 138.8, 141.7 (3 CAr),
0
Mass spectrum, (m/z): 389 [M]þ (100%), 208, 91.
0
0
0
ppm: 13.3 (COOC2H5), 14.5 (C3 —CH3), 34.9 (N1 —CH3), 63.9
149.6, 150.7, 153.0 (C3 , C5 , C5), 161.2 (C2), 183.0 (CHO).
0
0
(O—CH2), 109.1 (C4 ), 125.6, 126.5, 134.3, 136.8 (CAr), 142.3 (C3 ),
0
150.7, 151.4 (C5 , C5), 158.0 (CO2Et), 161.7 (C2), 183.2 (CHO). Mass
spectrum (FAB): m/z 406 [M þ H]þ 100%.
(E)-2-(10,30-dimethyl-1H-[1,2]pyrazol-40-ylcarbonylimino)-3-p-tolyl-
5-phenyl-2,3-dihydro-[1,3,4]thiadiazole 5d
Ethyl (E)-2-(10,30-dimethyl-1H-[1,2]pyrazol-40-ylcarbonylimino)-4-p-
chlorophenyl-2,3-dihydro[1,3,4]thiadiazole-5-carboxylate 5b
mp: 175–176 8C (EtOH). 1H NMR (CDCl3): d (ppm): 2.16 (1s, 3H,
0
0
Ar—CH3), 2.41 (s, 3H, C3 —CH3), 3.83 (s, 3H, N1 —CH3), 7.86 (s,
0
1H, C5 —H), 7.26–8.00 (m, 9H, HAr). 13C NMR (CDCl3): d (ppm):
mp: 199–200 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.47 (t, 3H,
0
0
0
0
13.9 (C3 —CH3), 21.5 (Ar—CH3), 38.9 (N1 —CH3), 118.9 (C4 ), 124.7,
126.5, 127.9, 128.7, 129.9 (5 CH—Ar), 127.2, 139.3, 141.6 (3 CAr),
135.1 (C5 ), 151.3, 156.3 (C3 , C5), 163.5 (C2), 171.3 (CO).
Mass spectrum, (m/z): 389 [M]þ 123(100%), 280, 208, 91.
J ¼ 7.13 Hz, —CH2—CH3), 2.54 (s, 3H, C3 —CH3), 3.88 (s,
0
3H, N1 —CH3), 4.52 (q, 2H, J ¼ 7.13 Hz, —O—CH2—), 7.55–7.90
0
0
0
(2d, J ¼ 9.18 Hz, 4H, HAr), 7.86 (s, 1H, C5 —H). 13C NMR (CDCl3): d
0
0
ppm: 14.3, 14.6 (COOCH2CH3 and C3 —CH3), 39.4 (N1 —CH3), 63.7
0
0
(O—CH2—), 118.7 (C4 ), 126.5, 129.4, 134.8, 137.6 (CAr), 135.7 (C5 ),
(E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-3-p-
chlorophenyl-5-phenyl-2,3-dihydro[1,3,4]thiadiazole 4e
0
148.4, 151.9 (C3 , C5), 158.8, 164.8 (CO2Et, C2), 171.7 (CO). Mass
spectrum (FAB): m/z 406 [M þ H]þ 100%.
mp: 165–166 8C (EtOH). 1H NMR (CDCl3): d (ppm): 2.55 (1s,
Ethyl (E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-3-p-
nitrophenyl-2,3-dihydro[1,3,4]thiadiazole-5-carboxylate 4c
0
0
3H, C3 —CH3), 3.60 (1s, 3H, N1 —CH3), 7.35–8.00 (m, 9H, HAr), 9.82
0
(s, 1H, CHO). RMN 13C NMR (CDCl3): 13.8 (C3 —CH3), 34.8
0
0
(N1 —CH3), 108.9 (C4 ), 123.9, 127.9, 128.0, 129.4, 129.8 (5CH—Ar),
128.5, 137.7, 139.0 (3 CAr), 148.7, 151.3, 152.8, 161.2
mp: 167–169 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.43 (t, 3H,
0
J ¼ 7.21 Hz, —CH2—CH3), 2.48 (s, 3H, C3 —CH3), 3.61 (s,
0
0
(C3 , C5 , C5, C2), 183.3 (CHO).
0
3H, N1 —CH3), 4.49 (q, 2H, J ¼ 7.21 Hz, —O—CH2—), 8.28–8.36
Mass spectrum, (m/z): 409 [M]þ, 389, 91(100%).
(2m, 4H, HAr), 9.83 (s, 1H, CHO). 13C NMR (CDCl3): d ppm: 13.2
0
0
(COOCH2CH3), 14.5 (C3 —CH3), 35.0 (N1 —CH3), 64.1 (—O—CH2),
(E)-2-(10,30-dimethyl-1H-[1,2]pyrazol-40-ylcarbonylimino)-5-p-
0
0
109.3 (C4 ), 123.8, 124.9, 143.4, 146.6 (CAr), 143.6 (C3 ), 149.8, 151.9
0
(C5 , C5), 157.7 (CO2Et), 161.3 (C2), 183.3 (CHO). Mass spectrum
chlorophenyl-3-phenyl-2,3-dihydro[1,3,4]thiadiazole 5e
(FAB): m/z 417 [M þ H]þ 100%.
mp: 195–196 8C (ETOH). 1H NMR (CDCl3): d (ppm): 2.52 (s,
0
0
0
3H, C3 —CH3), 3.84 (s, 3H, N1 —CH3), 7.82 (s, 1H, C5 —H), 7.26–7.99
Ethyl (E)-2-(10,30-dimethyl-1H-[1,2]pyrazole-40-carbonylimino)-3-p-
nitro-phenyl-2,3-dihydro[1,3,4]thiadiazole-5-carboxylate 5c
0
(m, 9H, HAr). 13C NMR (CDCl3): d (ppm): 14.3 (C3 —CH3), 39.3
(N1 —CH3), 119.1 (C4 ), 125.0, 128.2, 128.5, 129.2, 129.9 (5 CH—Ar),
0
0
0
0
128.9, 137.7, 139.6 (3 CAr), 135.6 (C5 ), 151.8, 155.1 (C3 , C5), 163.7
(C2), 171.7 (CO).
mp: 213–214 8C (EtOH). 1H NMR (CDCl3): d ppm: 1.47 (t, 3H,
0
J ¼ 7.17 Hz, —CH2—CH3), 2.54 (s, 3H, C3 —CH3), 3.88 (s,
Mass spectrum, (m/z): 409 [M]þ, 300, 123(100%), 91.
0
3H, N1 —CH3), 4.53 (q, 2H, J ¼ 7.17 Hz, —O—CH2—), 8.36–8.44
0
(2m, 4H, HAr), 7.89 (s, 1H, C5 —H). 13C NMR (CDCl3): d ppm: 14.3,
(E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-2,3-
0
0
14.5 (COOCH2CH3) and C3 —CH3), 39.4 (N1 —CH3), 63.9
0
dihydro-5-p-nitro-phenyl-3-phenyl[1,3,4]thiadiazole 4f
(O—CH2—), 118.3 (C4 ), 124.8, 125.2, 143.9, 147.0 (CAr), 135.7
0
0
(C5 ), 149.3, 152.2 (C3 , C5), 158.6, 164.7 (CO2Et, C2), 171.5 (CO).
mp: 144–146 8C (EtOH). 1H NMR (CDCl3): d (ppm): 2.48 (s,
Mass spectrum (FAB): m/z 417 [M þ H]þ 100%.
0
0
3H, C3 —CH3), 3.61 (s, 3H, N1 —CH3), 7.26–8.33 (m, 9H, HAr), 9.83
0
(s, 1H, CHO). 13C NMR (CDCl3): d (ppm): 13.2 (C3 —CH3), 34.5
General procedure for preparation of products 3d–f, 4d–f
and 5d–f
0
0
(N1 —CH3), 108.6 (C4 ) 123.7, 124.4, 127.0, 128.0, 129.1 (5 CH—Ar),
0
0
135.2, 138.3, 147.0 (3 CAr); 149.0 (C3 ), 151.1, 151.4 (C5 , C5), 160.5
(C2), 182.4 (CHO).
To a solution of 5 mmol of dimethylaminomethylene-3-thioxo-
1,2,4-triazepin-5-one 1 and 5 mmol of a- chloroarylidenephenyl-
hydrazone in 20 ml of dry benzene was added 1.6 ml of dry
triethylamine dissolved in dry benzene. After stirring for 72 h at
room temperature, the reaction mixture was extracted with
benzene (3 ꢁ 50ml) and the organic layers were dried over
anhydrous sodium sulphate and evaporated under reduced
pressure. The yellow crude solid thus obtained 3d–f were further
transformed to pure 4d–f and 5d–f compounds by chromatog-
raphy on a silica gel column using ethyl acetate/hexane as eluent.
Mass spectrum, (m/z): 420 [M]þ, 123(100%), 91.
(E)-2-(10,30-dimethyl-1H-[1,2]pyrazol-40-ylcarbonylimino)-3-p-
nitrophenyl-5-phenyl-2,3-dihydro[1,3,4]thiadiazole 5f
mp: 210–211 8C (EtOH). 1H NMR (CDCl3): d (ppm): 2.53 (s,
0
0
0
3H, C3 —CH3), 3.85 (s, 3H, N1 —CH3), 7.88 (s, 1H, C5 —H), 7.26–8.38
0
(m, 9H, HAr). 13C NMR (CDCl3): d (ppm): 13.9 (C3 —CH3), 39.0
0
0
(N1 —CH3), 118.5 (C4 ), 124.5, 124.7, 127.3, 128.4, 128.9 (5 CH—Ar),
0
0
135.8, 139.0, 149.0 (3 CAr), 135.3 (C5 ), 151.5, 153.4 (C3 , C5), 163.4
—
(C ), 171.4 (C O).
—
2
(E)-2-(40-formyl-10,30-dimethyl-1H-[1,2]pyrazol-50-ylimino)-5-p-tolyl-
Mass spectrum, (m/z): 420 [M]þ (100%), 91.
3-phenyl-2,3-dihydro[1,3,4]thiadiazole 4d
mp: 141–142 8C (EtOH). 1H NMR (CDCl3): d (ppm): 2.39 (1s, 3H,
Acknowledgements
0
0
Ar—CH3), 2.46 (s, 3H, C3 —CH3), 3.60 (s, 3H, N1 —CH3), 7.23–8.01
(m, 9H, HAr), 9.80 (s, 1H, CHO). 13C NMR (CDCl3): d (ppm): 13.5
This work has been partially supported by the Ministerio de
´
Educacion y Ciencia of the Spanish Government (project
0
0
0
(C3 —CH3), 21.5 (Ar—CH3), 34.4 (N1 —CH3), 108.4 (C4 ), 123.4,
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 31–41

FORMATION OF PYRAZOL-1,3,4-THIADIAZOLE
˜
´
CTQ2006-14297/BQU) and the Agencia Espanola de Cooperacion
Internacional (project A/6409/06). The authors thank also S.C.S.I.E.
(X-ray section) of University of Valencia for provision of the X-ray
crystallographic facilities.
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J. Phys. Org. Chem. 2009, 22 31–41
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