High chemoselectivity of C=S dipolarophile in 1,3-dipolar cycloaddition of nitrilimines and 1,2,4-triazepin-5-one derivatives: Experimental, theoretical and X-ray study

Article abstract of DOI:10.1002/poc.892

Substituted 2,7-dimethyl-3-thioxo-3,4,5,6-tetrahydro-2H-[1,2,4]triazepin-5- one reacts as a dipolarophile with several N-aryl-C-ethoxycarbonylnitrilimines, in equimolar quantities, to give, in all cases, two types of products: diethyl 3-(p-aryl)-2-[N′-(p-aryl)-N′-(2′,7′-dimethyl-5′- oxo-5′,6′-dihydro-2H-[1,2,4]triazepin-3′-yl)-hydrazino]-2, 3-dihydro[1,3,4]thiadiazole-2,5-dicarboxylate (3a-3c in 20-25% yield) and ethyl 4-(p-aryl)-5-imino-1,4-dihydro[1,3,4]thiadiazole carboxylate (4a-4c in 45-50% yield). When 1:2 stoichiometry was used, the formation of product 3 (50%) was favoured. The reaction is entirely chemo- and regioselective. The structures of the compounds obtained, where aryl stands for p-chloro-phenyl (3b) in the first type and for tolyl (4a) in the second type, were determined by X-ray crystallography and analysed by spectral methods (NMR and mass spectroscopy). The global and local electrophilicity/nucleophilicity have been analysed to rationalize the chemical reactivity of the reactants. Copyright

Full text of DOI:10.1002/poc.892

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 522–528
Published online 2 February 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.892
High chemoselectivity of C == S dipolarophile in
1
1
,3-dipolar cycloaddition of nitrilimines and
,2,4-triazepin-5-one derivatives: experimental,
theoretical and X-ray study
1
1
1
2
3
Saida Azzouzi, Malika El Messaoudi, * M’hamed Esseffar, * Rachid Jalal, F e´ lix H. Cano,
3
4
Mar ´ı a del Carmen Apreda-Rojas and Luis R. Domingo
1
Universit e´ Cadi Ayyad, Facult e´ des Sciences-Semlalia, D e´ partement de Chimie, BP 2390, Marrakech, Maroc
Universit e´ Cadi Ayyad, Facult e´ des Sciences et Techniques, D e´ partement de Chimie, BP 549, Marrakech, Maroc
Instituto de Qu ı´ mica F ı´ sica Rocasolano-CSIC Serrano, 119 E-28006 Madrid, Spain
2
3
4
Instituto de Ciencia Molecular, Departamento de Qu ´ı mica Org a´ nica, Universidad de Valencia, Dr. Moliner 50,
E-46100 Burjassot, Valencia, Spain
Received 24 April 2004; revised 6 October 2004; accepted 22 October 2004
ABSTRACT: Substituted 2,7-dimethyl-3-thioxo-3,4,5,6-tetrahydro-2H-[1,2,4]triazepin-5-one reacts as a dipolaro-
phile with several N-aryl-C-ethoxycarbonylnitrilimines, in equimolar quantities, to give, in all cases, two types of
0
0
0
0
0
0
0
0
products: diethyl 3-(p-aryl)-2-[N -(p-aryl)-N -(2 ,7 -dimethyl-5 -oxo-5 ,6 -dihydro-2H-[1,2,4]triazepin-3 -yl)-hydra-
zino]-2,3-dihydro[1,3,4]thiadiazole-2,5-dicarboxylate (3a–3c in 20–25% yield) and ethyl 4-(p-aryl)-5-imino-1,4-
dihydro[1,3,4]thiadiazole carboxylate (4a–4c in 45–50% yield). When 1:2 stoichiometry was used, the formation of
product 3 (50%) was favoured. The reaction is entirely chemo- and regioselective. The structures of the compounds
obtained, where aryl stands for p-chloro-phenyl (3b) in the first type and for tolyl (4a) in the second type, were
determined by X-ray crystallography and analysed by spectral methods (NMR and mass spectroscopy). The global
and local electrophilicity/nucleophilicity have been analysed to rationalize the chemical reactivity of the reactants.
Copyright # 2005 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: 1,3-dipolar cycloadditions; chemoselectivity; nitrilimines; triazepines; electrophilicity/nucleophilicity
INTRODUCTION
condensation of a 1,2,4-triazepin-3,5-dithione on the same
—
dipole occurred at the C—N dipolarophile site of tauto-
—
meric form 1B. Curiously, in this study only the C—S
In view of their well-known anticonvulsant and anti-
anxiety activity, many benzodiazepines and their oxo-
derivatives have acquired both pharmaceutical and
dipolarophile site of tautomeric form 1Awas affected. It is
—
13–17
worth noting that the reactivity of the C—S double bond
1–4
economical relevance.
Diazepines and triazepines
is well documented by Huisgen et al.
thiones act as ‘superdipolarophiles’ in 1,3-dipolar cycload-
where the
have attracted particular attention as starting materials in
the synthesis of fused heterocyclic systems susceptible to
18
ditions, and by Sauer et al. where the thiones act also as
‘superdienophiles’ in Diels–Alder reactions.
5–8
present pharmacological activities. As in our previous
studies using heterocyclic compounds as dipolarophiles in
In what follows, we present the experimental results of
the cycloaddition between 1,2,4-triazepin-5-one 1 and
some substituted nitrilimines to elucidate the chemo- and
regioselectivity of the reaction. Because 1,2,4-triazepine-
5-one 1 presents several dipolarophile sites, a density
functional theory-based reactivity index analysis has
9–11
,3-dipolar cycloaddition reactions,
1
we consider in this
work the condensation of several N-aryl-C-ethoxycarbo-
nylnitrilimines on 1,2,4-triazepin-5-one 1 in order to ac-
cess new triazepine derivatives of biological interest. This
molecule holds great chemical interest because of the
existence of different tautomeric forms that contain several
—
been used to explain why and how the C—S dipolar-
ophile is the most reactive.
—
dipolarophile sites (C—N, C—C, C—S and C—O)
—
—
—
7
Scheme 1). In another study, we have shown that the
(
RESULTS AND DISCUSSION
*
Correspondence to: M. El Messaoudi and M. Esseffar, Universite´
Cadi Ayyad, Facult e´ des Sciences-Semlalia, D e´ partement de Chimie,
BP 2390, Marrakech, Maroc.
E-mail: elmessaoudi@ucam.ac.ma; essaffar@ucam.ac.ma
The condensation of N-aryl-C-ethoxycarbonylnitrili-
mines, generated in situ from the appropriate precursors
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 522–528

—
CHEMOSELECTIVITY OF C—S DIPOLAROPHILE
523
precise characterization of the structures of compounds
a–3c and 4a–4c of the cycloaddition reaction so we have
3
determined these structures on the basis of X-ray crystal-
lographic analysis of single crystals of 3b and 4a (Figs 1
and 2).
X-Ray crystallographic analysis
The molecular structures of 3b (C H Cl N O S, tricli-
27
26
2 7 5
nic; CCDC no. 206077) and 4a (C H ClN O S, mono-
3 2
12
13
clinic; CCDC no. 206077) as determined in this work are
shown in Figs 1 and 2. The most relevant parameters are
given in Tables 1S and 2S in the supplementary material,
available at the epoc website (http://www.wiley.com/
epoc).
Scheme 1
19,20
ethylhydrazono-ꢀ-bromoglyoxalateandtriethylamine,
with 1,2,4-triazepin-5-one 1 in dry benzene at room
temperature, in equimolar quantities, leads, in all cases,
For 3b there are two independent molecules in the unit
cell. Owing to intermolecular Nꢀ ꢀ ꢀH, Oꢀ ꢀ ꢀH, Sꢀ ꢀ ꢀH,
CTꢀ ꢀ ꢀH (CTare the centroids of the six-membered rings)
and ꢁꢀ ꢀ ꢀH contacts, the molecules seem to arrange in
columns through centres of symmetry and translations
along the a-axis. Columns form sheets along the (011)
direction through centres of symmetry and then pile up to
form the crystal structured in a distorted hexagonal
0
to two types of products: diethyl 3-(p-aryl)-2-[N -
0
0
0
0
0
0
(p-aryl)-N -(2 ,7 -dimethyl-5 -oxo-5 ,6 -dihydro-2H[1,2,4]
triazepin-3 -yl)-hydrazino]-2,3-dihydro[1,3,4]thiadiazole-
0
2
(
,5-dicarboxylate 3a–3c in 20–25% yield and ethyl 4-
p-aryl)-5-imino-1,4-dihydro [1,3,4]thiadiazole-2-carbo-
21
xylate 4a–4c in 45–50% yield (Scheme 2). When 1:2
stoichiometry was used in the case of 1 with N-p-
chlorophenyl-C-ethoxycarbonylnitrilimine, the two pro-
ducts 3b and 4b are obtained in 49% and 37% yields,
respectively. This shows that the 1:2 stoichiometry fa-
vours unambiguously the pathway leading to the main
product 3b resulting from the double condensation
mode of the mentioned columns. Intramolecular con-
tacts contribute to the conformation of the molecule.
For 4a the unit cell contains four molecules. Two
molecules related by a centre of symmetry at (000),
plus translations along the a-axis arranged in columns
through intermolecular Nꢀ ꢀ ꢀH and Oꢀ ꢀ ꢀH contacts.
These columns, which form sheets along the (011)
direction, pile up to form hexagonal packing supported
mostly by hydrogen contacts through glide planes and
screw axes. The intramolecular contacts Sꢀ ꢀ ꢀH, Nꢀ ꢀ ꢀH
and Oꢀ ꢀ ꢀH contribute to fix the planar conformation of
the molecule. Bond distances and angles of the five-
membered ring compare well with those in analogous
compounds sought from the CSDS and are within
the expected range (ref. codes: BIPTDZ, FOLHAP,
21
(
Scheme 3).
It is worth mentioning that our numerous attempts to
purify the other fragments 5a–5c failed.
1
13
Spectral data ( H NMR, C NMR and mass spectro-
scopy) allowed the predominant orientation of the
addition Ndipole—Cdipolarophile (regioselectivity) and pre-
—
ferential C—S attack site of the triazepine 1 (chemos-
electivity) to be determined. However, they do not permit
Scheme 2
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 522–528

5
24
S. AZZOUZI ET AL.
—
the dipole on C5—C6 of tautomeric forms 1D and 1E.
The value of the chemical shift of the methyl group in
position 7 (ꢂ ¼ 2.25 ppm) discards also the condensation
—
of the dipole on the dipolarophile site C7—N1 of
triazepine 1. On the other hand, the absence of the signal
13
of the carbon of the thioxo group of 1 in C NMR spectra
justifies clearly the addition of the dipole to the dipolar-
—
ophile site C3—S of triazepine 1. The chemical shift of
the carbon atom C2 at 99.6 ppm indicates the orientation
of the addition Ndipole—Cdipolarophile and rules out un-
ambiguously the formation of the other possible regioi-
somer. In the opposite regioisomer, this carbon chemical
shift should appear at a lower frequency of ꢂ ¼ 60.0 ppm.
It is noteworthy that the observed value (99.6 ppm) is
in very good agreement with those described in the
7
,22
literature for a similar environment.
spectra (FAB), we noted essentially molecular peaks to
In the mass
þ
þ
þ
m/z ¼ 580 [MþH] , 620 [MþH] and 642 [MþH] for
3
a, 3b and 3c, respectively.
For compounds 4a–4c, the chemical shifts in the case
1
13
of H and C NMR are consistent with the proposed
thiadiazolic structure. In the mass spectra all compounds
gave the molecular ion.
Scheme 3
GOZLAI, SIPSOZ, SIPTEQ, SOJNEK, SUWCIW and
VAHYAE).
From the X-ray structures and spectral data, the me-
chanism reported in Scheme 3 is proposed. The formation
of the products can be explained by a monocondensation
—
of the dipole with the C—S dipolarophile site of tauto-
NMR and mass spectrum analysis
meric form 1a to give the cycloadduct intermediate IN1.
This unstable cycloadduct evolves in two ways: by open-
ing of the thiadiazole cycle leading to intermediate IN2,
which by a second cycloaddition of the nitrilimine dipole
The presence of a resonance signal at 3.50–3.65 ppm in
1
H NMR spectra of products 3a–3c, attributed to the
methylene group in position 6, rules out the addition of
—
on the C—S dipolarophile site of IN2 gives triazepine
Figure 1. The molecular structure of compound 3b (ORTEP: XTAL 3.6) with the numbering scheme. Displacement ellipsoids
are drawn at 30% probability
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 522–528

—
CHEMOSELECTIVITY OF C—S DIPOLAROPHILE
525
Figure 2. The molecular structure of compound 4a (ORTEP: XTAL 3.6) with the numbering scheme. Displacement ellipsoids are
drawn at 30% probability
3
a–3c (see way 1 in Scheme 3); and by a nucleophilic
au) is higher than those of the phenyl-substituted nitrili-
mines 2a–2d (in the range ꢁ0.1327 to ꢁ0.1657 au),
therefore it is expected that in a polar process the charge
transfer will take place from 1 to the nitrilimines 2a–2d.
attack of the nitrogen N2 lone pair on the carbon C3 of
the triazepine, followed by opening of the triazepine
cycle to form the thiazolic structure 4a–4c (see way 2
in Scheme 3). It is noteworthy that the same chemoslec-
tivity has been observed by one of us in the case of the
condensation of mesitonitrile oxide with triazepine 1.
Grubert et al. also have found, from different kinds of
—
potential reactive sites, that the C—S double bond is the
most reactive of the pyrimidinethione using a nitrilimine
—
as a dipole. This indicates the high reactivity of the C—S
2
8
1,2,4-Triazepin-5-one 1 has an electrophilicity value
of ! ¼ 1.36 eV. According to the absolute scale of elec-
26a
23
trophilicity based on ! indices, this compound may be
24
classified as a moderate electrophile.
The phenyl
nitrilimines 2a–2d have electrophilicity values in the
range 1.67–2.72 eV. According to this scale they may
be classified as strong electrophiles. The electrophilicity
of these nitrilimines increases with the electron-with-
drawing character of the substituent present at the phenyl
ring. Thus, nitrilimine 2c with the strong electron-with-
dipolarophile site.
Global and local electrophilicity analysis
drawing NO group has the largest electrophilicity value
2
of this series (see Table 1). The large Á! value of 1.36 eV
for the reaction with nitrilimine 2c
26a,29
These 1,3-dipolar cycloadditions have been analysed
using the global and local indexes defined in the context
indicates that this
cycloaddition will have a large polar character. Thus, in
this cycloaddition, although nitrilinime 2c will act as a
good electrophile, 1,2,4-triazepin-5-one 1 will act as a
nucleophile.
25
of density functional theory (DFT). Recent studies
26
devoted to 1,3-dipolar cycloadditions have shown that
27
these indexes are powerful tools to acquire mechanism
details of these reactions. In Table 1 the static global
properties of 1,2,4-triazepin-5-one 1 and of phenyl sub-
stituted nitrilimines 2a–2d are displayed. The electronic
3
0
Analysis of the reactants with Fukui functions allows
the regioselectivity of the polar processes to be explai-
26c
ned.
The values of the Fukui functions for 1,2,4-
2
5
chemical potential of 1,2,4-triazepin-5-one 1 (ꢃ ¼ ꢁ0.1319
triazepin-5-one 1 and phenylnitrilimine 2d (Scheme 4)
are summarized in Table 2. 1,2,4-Triazepin-5-one 1 has
Table 1. Electronic chemical potential (ꢃ, in au), chemical
hardness (ꢄ, in au) and global electrophilicity (!, in eV) of the
1
,2,4-triazepin-5-one 1 and the phenyl nitrilimines 2a, 2b,
2
c and 2d
ꢃ
ꢄ
!
2
2
2
2
1
c (NO2)
ꢁ0.1657
ꢁ0.1425
ꢁ0.1369
ꢁ0.1327
ꢁ0.1319
0.1376
0.1436
0.1467
0.1432
0.1746
2.72
1.92
1.74
1.67
1.36
b (Cl)
d (H)
a (CH3)
Scheme 4
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 522–528

5
26
S. AZZOUZI ET AL.
ꢁ
Table 2. Values of the nucleophilic (f ) and electrophilic
k
COMPUTATIONAL METHODS
þ
(
f ) Fukui functions for 1,2,4-triazepin-5-one 1 and nitrili-
k
mine 2d
28
The global electrophilicity ! is given by the expression
2
!
and the chemical hardness ꢄ. Both quantities may be
¼ (ꢃ /2ꢄ) in terms of the electronic chemical potential ꢃ
1,2,4-Triazepin-5-one 1
MO
25
S1
0.85
C2
0.06
C3
0.00
O4
0.00
ꢁ
4
5
f
approached in terms of the one-electron energies of the
HOMO and LUMO molecular orbitals, "H and " , as
k
Nitrilimine 2d
MO
L
C1
0.21
0.07
C2
0.10
0.48
N3
0.17
0.27
N4
0.12
0.07
25
ꢃꢂ(" þ " )/2 and ꢄꢂ(" þ " ), respectively. The HOMO
þ
H
L
L
H
5
1
f
f
k
þ
and LUMO energies have been calculated at the ground
31
state of the molecules al the B3LYP/6–31G* level.
5
2
k
3
0
Electrophilic and nucleophilic Fukui functions con-
densed to atoms have been evaluated from single-point
calculations performed at the ground state of molecules at
the same level of theory using a method described else-
where. This method evaluates Fukui functions using
the coefficients of the frontier molecular orbitals involved
in the reaction and the overlap matrix.
the largest value of the nucleophilic Fukui function at the
ꢁ
S1 sulphur atom, fk ¼ 0:85, and consequently this is the
most nucleophilic site of 1. Note that the O4 oxygen atom
ꢁ
32
presents a negligible value of fk ¼ 0:00. The large
resolution of the nucleophilic Fukui function at the
sulphur atom also allows to explain the total experimen-
tally observed chemoselectivity to be explaired.
The asymmetric phenyl nitrilimine 2d has the largest
nucleophilic activation at the carbonyl C1 carbon atom
EXPERIMENTAL
þ
(
f
¼ 0:21). Note that this carbon is not involved in the
k
Uncorrected melting points were taken on a Buchi 510
1
apparatus. The H NMR spectra were recorded with a
Bruker WP 400 CW, with Me Si as internal standard and
4
[
3 þ 2] cycloaddition. An analysis of the electrophilic
þ
Fukui function, f , at the molecular orbital LUMO þ 1 of
k
nitrilimine 2d reveals that the C2 carbon atom presents
13
þ
þ
CDCl as solvent. The C NMR spectra were measured
3
the largest fk value of the dipole framework (fk ¼ 0:48;
see Table 2). Therefore, this carbon will be the preferred
position of the N—N—C framework for nucleophilic
attack in a polar cycloaddition. Analysis of the reactivity
indexes indicates that these cycloadditions will take place
with a large chemo- and regioselectivity via an asynchro-
nous transition state where S—C bond formation will be
more advanced than C—N bond formation. This analysis
is in agreement with the chemo- and regioselectivity
proposed for the 1,3-dipolar cycloaddition in Scheme 3.
on a Varian FT 80 (100 MHz). Mass spectra were re-
corded with a Jeol JMS DX 300. Column chromatogra-
phy was carried out using E-Merck silica gel 60F 254.
Reagents and solvents were purified in the usual way. The
X-ray structures were solved by direct methods using the
SHELX-97 and program refined by least-squares analysis
using the SHELXL program. Scattering factors, disper-
sion corrections and absorption coefficients were taken
from International Tables for Crystallography.
33
34
Crystal data for compound 3b
CONCLUSION
Triclinic, space group P-1, T ¼ 293(2) K, a ¼ 10.116(1),
In summary, in the present study we have studied the
synthesis of novel triazepine derivatives to improve
the library of therapeutic compounds. The selectivity of
the 1,3-dipolar cycloaddition reaction of nitrilimines and
˚
ꢃ
b ¼ 10.473(4) and c ¼ 14.676(3) A, ꢀ ¼ 105.04(3) ,
ꢃ
ꢃ
˚
3
ꢅ ¼ 95.60(2) , ꢆ ¼ 100.08(2) , V ¼ 1461.6(6) A , Z ¼ 2;
observed reflections, 4525 with I > 2ꢇ(I), R ¼ 0.050,
Rw ¼ 0.141.
1
,2,4-triazepine 1 has been analysed using NMR, mass
spectroscopy, X-ray and DFT-based reactivity indexes.
We have identified successfully the various products of
the considered reaction and shown that the reaction is
fully regio- and chemoselective. In all the cases studied
here, the sulphur heteroatom of the dipolarophile inter-
—
acts with the carbon atom of the dipole. Only the C—S
dipolarophile site of triazepine 1 reacts with these nitri-
limines. No dipole addition to the other double bonds
Crystal Data for compound 4a
Monoclinic, space group P2 /c, T ¼ 293(2) K,
1
˚
a ¼ 10.871(1), b ¼ 10.375(2) and c ¼ 11.218(2) A,
ꢃ
˚
3
ꢅ ¼ 95.66(1) , V ¼ 1259.1(4) A , Z ¼ 4; observed reflec-
tions, 1900 with I > 2ꢇ(I), R ¼ 0.053, Rw ¼ 0.143.
—
C—N, C—C or C—O) was observed. The results of
—
—
(
General procedure of 1,3-dipolar cycloaddition
reaction
global and local electrophilicity analysis are in good
agreement with experimental predictions. It is of interest
to note that evaluation of the biological activity of all the
synthesized products on the central nervous system and
on the HIV virus is intended.
Triethylamine (7.2 mmol) dissolved in dry benzene
(10 ml) was added dropwise to a solution of 1,2,4-
triazepin-5-one 1 (5 mmol) and ethylhydrazono-ꢀ-
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 522–528

—
CHEMOSELECTIVITY OF C—S DIPOLAROPHILE
527
0
—CH ), 2.95 (s, 3H, N2 —CH ), 3.50–3.65 (AB,
3 3
bromoglyoxylate 2 (5.5 mmol) dissolved in dry benzene
20 ml). After stirring for 3 days at room temperature, the
reaction mixture was washed several times with water
25 ml) and the organic layers were dried over anhydrous
sodium sulphate, concentrated under reduced pressure
and purified by chromatography on a silica gel column
0
(
J ¼ 10.13 Hz, 2H, —C6 H —), 4.20–4.45 (2m, 4H,
0
2 3
2
13
2OCH CH ), 6.80–8.20 (m, 9H, 8HAr, N H). C NMR
(
(100 MHz), ꢂ(ppm): 14.1, 14.6 (2 O—CH —CH ), 23.2
2 3
0 0 0
(C7 —CH ), 42.2 (N2 —CH ), 49.4 (C6 ), 63.7, 65.1
3 3
(2 O—CH —), 99.6 (C2), 116.5, 123.3, 125.7, 125.8
2
00
(hexane/ethyl acetate). The isolated product 3 was re-
crystallized in ethanol.
(8 CHAr), 135.9 (C7 ), 143.7, 145.8, 146.8, 151.1, 155.5,
0
0
159 (4CAr, C5, C3 ), 163.5, 164.7, 165.7 (C5 , 2CO Et).
2
Mass spectrum (FAB) m/z: 642 ([MþH] , 1.5%),
þ
0
0
0
0
Diethyl 3-( p-tolyl)-2-[N -( p-tolyl)-N -(2 ,7 -dimethyl-
5
352(100).
0
0
0
0
- oxo - 5 ,6 - dihydro-2H-[1,2,4] triazepin -3 - yl)-
hydrazino]-2,3-dihydro[1,3,4]thiadiazole-2,5-di-
Ethyl 4-( p-tolyl)-5-imino-1,4-dihydro[1,3,4]thia-
diazole carboxylate (4a). Yield: 657 mg (2.50 mmol,
carboxylate (3a). Yield: 580 mg (1 mmol, 20%), m.p.
ꢃ
1
46–147 C (ethanol). H NMR (400 MHz), ꢂ(ppm): 0.95
ꢃ
1
50%), m.p. 132–133 C (ethanol). H NMR (400 MHz),
1
(
OCH CH ), 2.10, 2.15 (2s, 6H, 2ArCH ), 2.25 (s,
t, J ¼ 7.08 Hz, 3H, OCH CH ), 1.30 (t, J ¼ 7.10, 3H,
ꢂ(ppm): 1.25 (t, J ¼ 7.10 Hz, 3H, OCH CH ), 2.3 (s, 3H,
2
3
2
3
Ar—CH ), 4.25 (q, J ¼ 7.10 Hz, 2H, O—CH ), 7.05–
2
3
3
3
2
0
0
13
3
2
6
H, ¼ C7 —CH ), 2.80 (s, 3H, N2 —CH ), 3.45 (m,
7.40 (m, 5H, 4HAr, NH). C NMR (100 MHz), ꢂ(ppm):
14.6 (OCH CH ), 21.5 (Ar—CH ), 63.3 (OCH —),
124.6, 130.1 (4CHAr), 135.7, 138.2 (2CAr), 138.5,
3
3
0
H, —C H —), 3.95–4.30 (2m, 4H, 2 OCH CH ),
2
6
2
3
2
3
3
2
13
.65–7.25 (m, 9H, 8HAr, NH). C NMR (100 MHz),
—
158.6 (C2, C5), 162.6 (C—O). Mass spectrum (FAB)
m/z: 264 ([MþH] , 100%).
ꢂ(ppm): 14.0, 14.7 (2 OCH CH ), 21.2, 21.3 (2ArCH ),
2
3
3
0
0
0
þ
2
6
1
4
2
2
3.2 (C7 —CH ), 42.3 (N2 —CH ), 49.2 (C6 ), 62.8,
3
3
4.0 (2 OCH CH ), 100.4 (C2), 117.9, 124.6, 129.9,
2
3
0
30.6 (8CHAr), 131.2, 133.9, 136.9, 139.7, 143.0 (C7 ,
0
Ethyl 4-( p-chlorophenyl)-5-imino-1,4-dihydro[1,3,4]
thiadiazole carboxylate (4b). Yield: 710 mg
0
CAr), 157.4, 160.5 (C5, C3 ), 163.1, 165.6, 166.5 (C5 ,
CO Et). Mass spectrum (FAB) m/z: 580 ([MþH] ,
þ
ꢃ
1
(2.51 mmol, 50%), m.p. 140–141 C (ethanol). H NMR
2
.5%), 321(100).
(400 MHz), ꢂ(ppm): 1.30 (t, J ¼ 7.17 Hz, 3H, OCH CH ),
2
3
4
.35 (q, J ¼ 7.17 Hz, 2H, O—CH —), 7.25–7.70 (m, 5H,
2
0
13
Diethyl 3-(p-chlorophenyl)-2-[N -( p-chlorophenyl)-
4HAr, NH). C NMR (100 MHz), ꢂ(ppm): 14.6 (O—
CH —CH ), 63.5 (O—CH —), 125.0, 129.5 (4CHAr),
—
133.2, 137.1 (2CAr), 139.1, 158.6 (C2, C5), 161.8 (C—
0
0
0
0
0
0
N -(2 ,7 -dimethyl-5 -oxo-5 ,6 -dihydro-2H-[1,2,4]
triazepin-3 -yl)-hydrazino]-2,3-dihydro[1,3,4]thiadi-
2
3
2
0
þ
azole-2,5-dicarboxylate
(
(3b). Yield:
770 mg
1.24 mmol, 25%); m.p. 151–152 C (ethanol). H NMR
O). Mass spectrum (FAB) m/z: 284 ([MþH] , 100%);
ꢃ
1
154 (53).
As with product 3b, the 1:2 stoichiometry yielded
526 mg (1.85 mmol, 37%).
(
1
3
400 MHz), ꢂ(ppm): 1.00 (t, J ¼ 7.07 Hz, 3H, OCH CH ),
2
3
.30 (t, J ¼ 7.10 Hz, 3H, OCH CH ), 2.15 (s,
2
3
0
0
H, ¼ C7 —CH ), 2.90 (s, 3H, N2 —CH ), 3.45–3.60
3
3
(
AB, J ¼ 9.98 Hz, 2H, —CH —), 4.05–4.30 (2m, 4H,
Ethyl 4-( p-nitrophenyl)-5-imino-1,4-dihydro[1,3,4]
thiadiazole carboxylate (4c). Yield: 660 mg
2
13
2 C
NMR (100 MHz), ꢂ(ppm): 14.0, 14.7 (2O—CH CH ),
O—CH —CH ), 6.65–7.30 (m, 9H, 8HAr, NH).
2
3
ꢃ
1
(2.24 mmol, 45%), m.p. 155–156 C (ethanol). H NMR
2
3
0
0
0
2
6
1
4
2
2
3.4 (C7 —CH ), 42.2 (N2 —CH ); 49.2 (C6 ), 63.2,
3
(400 MHz), ꢂ(ppm): 1.33 (t, J ¼ 7.12 Hz, 3H, O—CH —
3
2
4.4 (2 OCH CH3), 100.1 (C2); 118.7, 125.9, 129.5,
2
CH ), 4.36 (q, J ¼ 7.08 Hz, 2H, O—CH —), 7.63 (s, 1H,
3
2
0
0
13
NH), 8.2–8.74 (m, 4H, 4HAr). C NMR (100 MHz),
30.2 (8 CHAr), 131.3 132.8, 133.0, 140.6, 144.0 (C7 ,
0
CAr) 156.7, 160.1 (C5, C3 ), 163.2, 165.2, 166.2 (C5 ,
CO Et). Mass spectrum (FAB) m/z: 620 ([MþH] ,
ꢂ(ppm): 14.5 (OCH CH ), 63.8 (O—CH —), 122.4,
2
3
2
þ
124.8 (4 CHAr), 125.6, 145.0 (2CAr), 145.6, 158.2
(C2, C5), 161.1 (C ¼ O). Mass spectrum (FAB) m/z:
2
.8%), 341(100).
In order to check the 1:2 stoichiometry we have used
mmol of 1,2,4-triazepin-5-one 1 with 11 mmol of
þ
295 ([M þ H] , 42%), 154 (90), 55 (100).
5
the precursor N-p-chlorophenyl-C-ethoxycarbonylnitrili-
mine 2b, under the experimental conditions described
above; the reaction yields 1.53 g (2.47 mmol, 49%).
Acknowledgements
The authors thank Professor J-L. M. Abboud (CSIC) for
his continuous support, helpful advice and for providing
the synthesis products.
0
Diethyl 3-(p-nitrophenyl)-2-[N -(p-nitrophenyl)-
0
0
0
0
0
0
N -(2 ,7 -dimethyl-5 -oxo-5 ,6 -dihydro ꢁ2H-[1,2,4]
0
triazepin-3 -yl)-hydrazino]-2,3-dihydro[1, 3, 4]thi-
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2
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Copyright # 2005 John Wiley & Sons, Ltd.
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