Reaction of N3-phenylbenzamidrazone with cis-1,2-cyclohexanedicarboxylic anhydride

Article abstract of DOI:10.1016/j.tetlet.2010.03.116

An analysis of the products of the reaction of N³-phenylbenzamidrazone with cis-1,2-cyclohexanedicarboxylic anhydride at various temperatures is presented. The identification of the reaction products is carried on with the support of computational techniques. The most stable conformers of the isoindole and triazole derivatives are found within the DFT approach. The theoretical calculations reveal the possible structure of a triazole derivative not available experimentally because of the presence of two diastereoisomers of equal energy.

Full text of DOI:10.1016/j.tetlet.2010.03.116

Tetrahedron Letters 51 (2010) 2951–2955
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reaction of N3-phenylbenzamidrazone with cis-1,2-cyclohexane-
dicarboxylic anhydride
Marta Ziegler-Borowska a, Marzena Ucherek b, Jolanta Kutkowska c, Liliana Mazur c,
Bozena Modzelewska-Banachiewicz , Dariusz Ke˛dziera , Anna Kaczmarek-Ke˛dziera
b
a
a,
*
_
a Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Torun´, Poland
b Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
c Department of Chemistry, Maria Curie-Skłodowska University, 20-031 Lublin, Poland
a r t i c l e i n f o
a b s t r a c t
An analysis of the products of the reaction of N3-phenylbenzamidrazone with cis-1,2-cyclohexanedicarb-
oxylic anhydride at various temperatures is presented. The identification of the reaction products is car-
ried on with the support of computational techniques. The most stable conformers of the isoindole and
triazole derivatives are found within the DFT approach. The theoretical calculations reveal the possible
structure of a triazole derivative not available experimentally because of the presence of two diastereo-
isomers of equal energy.
Article history:
Received 18 December 2009
Revised 26 March 2010
Accepted 29 March 2010
Available online 1 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Amidrazones have been shown to act as important precursors
or intermediates in the synthesis of various chemical compounds
widely applied in industry.1 Moreover, the amidrazone moiety
(the NCNN group) is an essential part of numerous molecules
demonstrating high biological activity. Examples of bioactive
amidrazone derivatives include vardenafil (Levitra) and lamotri-
gine (Lamictal). Vardenafil inhibits phosphodiesterase type 5
(PDE5) and is used in the treatment of erectile disfunction. Lamo-
trigine is a well-known anticonvulsant agent. Furthermore, open
chain or cyclic derivatives of amidrazones and their metal com-
plexes are known to exhibit antithrombotic,3,2 antiinflammatory,
antifungal, antimycobacterial,4–6 antimalarial,7 antihypertensive,8
anticancer,7,10,9,11 cytotoxic12 and insulin-mimetic13 activity. In
organic synthesis, amidrazone derivatives have been found to be
effective building blocks for nitrogen heterocyclic ring systems.
By introducing an electron-withdrawing group on the amidrazone
moiety the relative reactivity of the three N-nucleophiles in the
molecule can be modified. This has an important consequence in
synthetic chemistry, leading to regiocontrolled reactions.14,15
For the above-mentioned reasons the chemistry of amidrazones
has been widely studied. However, only recently has the synthetic
significance of N3-substituted amidrazones been noticed.16 The
reaction of N3-substituted amidrazones with maleic anhydride
always leads to 3-(3,4-diaryl-1,2,4-triazol-5-yl)propenoic acid
derivatives, irrespective of the amidrazone substituents (Scheme 1).
Some of the synthesized 1,2,4-triazoles show anticonvulsive and
antinociceptive activity and have been reported as effective agents
against a number of bacterial species.16
Despite the interesting chemistry and numerous applications of
isoindole or 1,2,4-triazole derivatives, hardly any data on this class
of compounds are present in the literature.20,18,21,17,19 Therefore,
the aim of the present contribution is the analysis of the products
of the reaction of N3-phenylbenzamidrazone 1 with cis-1,2-cycloh-
exanedicarboxylic anhydride 2 at various temperatures. The syn-
thetic and analytical part of the project are supported by
computational investigations.
N3-Phenylbenzamidrazone 1 was synthesized by the method
described earlier in the literature.22,23 cis-1,2-Cyclohexanedicarb-
oxylic anhydride 2 is available commercially.
The substrates were dissolved in anhydrous toluene prior to
mixing them together in the molar ratio 1:1. Whereas the
cyclocondensation reaction of compound 1 with cis-1,2-cyclohex-
anedicarboxylic anhydride in boiling toluene (Scheme 2) gave the
* Corresponding author. Fax: +48 56 654 24 77.
E-mail address: teoadk@chem.umk.pl (A. Kaczmarek-Ke˛dziera).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.116

2952
M. Ziegler-Borowska et al. / Tetrahedron Letters 51 (2010) 2951–2955
Table 1
Relative energies of the conformers of the low-energy isoindole derivative 3
Conformation
Relative energy
Gas phase
PCM (benzene)
6-31+G(d)
6-31+G(d)
6-311++G(d,p)
3a
1.01
0.75
0.00
0.27
0.70
0.45
0.00
0.22
0.05
0.00
0.52
0.70
3a0
3b
3b0
All values in kcal/mol. Computational data obtained within the B3LYP
approximation.
ically. The energy differences among these four isomers were small
and all were found in the 1 kcal/mol energy gap (see Table 1). The
lowest-energy form, 3b, is presented in Figure 1. Such a small
energy difference suggests that the energetic order is very sensi-
tive to the approximation choice. Hence, the larger basis set
6-311++G(d,p) was applied to confirm the data. However, it did
not change the stability order of the four lowest-energy forms of
compound 3. Moreover, the rotation along the single C13–N15
bond is low-barrier: the rotation requires 4–8 kcal/mol depending
on the conformation. Therefore, the isoindolic amidrazone deriva-
tives are flexible and can undergo rotation relatively easily. The
inclusion of solvent effects in the calculations via the IEF-PCM
model leads to narrowing of the energetic differences between
the various conformers. Additionally, a change of the energetic or-
der is observed in the case of the four lowest-energy forms. The
calculated energy difference between the two forms endo and exo
(3a and 3a0) is virtually zero. Both are additionally stabilized by
an intramolecular hydrogen bond like interaction. Applying the
larger, 6-311++G(d,p), basis set clearly indicates the lowest-energy
conformer corresponding to the crystallographic structure. Within
this approximation the 3a form becomes 2.3 kcal/mol more stable
than that of 3a0. The geometrical parameters (bond lengths, va-
lence angles and dihedral angles) from the crystallographic data
(Figure 2) and computations are available in the Supplementary
data.
Numerous minima on the PES in the gas phase were localized
computationally for compound 4. There are two stereogenic car-
bons in the cyclohexyl moiety: C6 and C11, therefore, the molecule
can exist in various stereoisomeric forms. Figure 3 presents the two
lowest-energy diastereoisomers of 4 (4a and 4b). The lowest-en-
ergy rotamer tends to the maximal separation of the substituents
and therefore, minimization of the intramolecular interactions be-
tween the terminal groups. The existence of isoenergetic equivalent
forms results in the presence of various forms in the reaction mix-
ture and makes simple crystallization impossible.
Two other forms of 4 differing only by slight rotation of the phe-
nyl rings can be found at 0.88 kcal/mol on the energy scale. Next, at
1.62 kcal/mol higher than the lowest-energy conformers, the two
isoenergetic isomers appear different from those depicted in
Figure 3 by rotation of the hydroxy group in the direction of the
triazole ring N5 nitrogen, and they form weak intramolecular
hydrogen bond like interactions. However, the energy of the
H-bonded systems is relatively high with respect to the lowest-en-
ergy rotamers. Moreover, since the low-energy forms are separated
by the relatively low rotation barrier, interconversion of the corre-
sponding rotamers is possible under the reaction conditions.
The forms presented above correspond to the trans isomer of
the substituted cyclohexyl moiety. A similar situation occurs with
the cis-configured isomer, when the carboxyl group is placed in the
axial position. The lowest-energy cis diastereoisomers lie 3.46 kcal/
mol above the 4a and 4b forms.
Scheme 2.
cyclic imide 3 in 78% yield, reaction in anhydrous toluene at room
temperature led to the formation of the heterocyclic five-mem-
bered ring system 4 (Scheme 2) in 75% yield.
In contrast to these findings, our recent work has shown
that from the reactions of N3-(2-pyridyl)-2-picolinamidrazone
and N3-4-nitrophenyl-2-picolinamidrazone with cis-1,2-cyclohex-
anedicarboxylic anhydride, only linear derivatives, exhibiting
antiproliferative activity, were obtained: N-carbonyl-[(2-carbo-
xycyclohexane-1-yl)-N3-pyridin-2-yl]-2-picolinamidrazone and
N1-carbonyl-[(2-carboxy-cyclohexane-1-yl)-N3-4-nitrophenyl]-2-
picolinamidrazone (Scheme 3). All the above-mentioned reactions
were performed in anhydrous diethyl ether at room temperature.
These results suggest that not only the reaction conditions but also
the structure of the substrates (amidrazone and anhydride) may
determine the direction of the investigated reaction.
The size of the investigated system significantly reduces the
number of computational methods available and eliminates high-
level ab initio (‘post-Hartree-Fock’) approximation. However, since
the main attention of the current project is focused on the struc-
tures of the reagents, considerations within the density functional
theory are expected to provide at least qualitatively correct results.
Therefore, the structure of the stationary points on the potential
energy surface has been determined within the B3LYP/6-31+G(d)
approach. The character of the stationary points was verified by
harmonic vibrational analysis. Hence, all the reactions in vitro
are performed in organic solvents, the in silico simulations include
solvent effects via the continuum solvent model (IEF-PCM). All cal-
24
culations were carried out using GAUSSIAN03.
A thorough study of the potential energy surface (PES) of 3 was
initially performed in the gas phase. Local minima on the PES were
located within the B3LYP/6-31+G(d) approach for compound 3 via
rotation along the single C13–N15 and N8–N12 bonds in the amid-
razone moiety and included the exo–endo isomers in the anhydride
system. Various conformations of compound 3 were obtained this
way, however, four seemed to be significantly more stable energet-
The steric strain in the cyclohexyl group disfavours the boat
conformation considerably. The boat isomers appear higher in
Scheme 3.

M. Ziegler-Borowska et al. / Tetrahedron Letters 51 (2010) 2951–2955
2953
Fig. 1. Two low-energy conformers of isoindole derivative 3. Nitrogen atoms are depicted in blue, oxygen atoms in red, carbon atoms in grey and hydrogens in white.
polar solvent within the IEF-PCM approach does not affect the
computed values of the harmonic frequencies for 3 significantly.
Although the theoretically predicted spectra, both in the gas phase
and in solvent, are significantly blue-shifted with respect to the
experimental, the calculations reveal the same structures for the
spectra and help to identify the origin of the individual signals
precisely.
1H NMR chemical shifts calculated theoretically are juxtaposed
with the experimental results in Table 3. It is known that reproduc-
tion of the NMR shifts for labile protons can be problematic.25 Also
in the present study, the calculations in the gas phase or in the sol-
vent described by the continuum IEF-PCM model are not sufficient
for our purpose: the gas phase calculations recover 78% of the
chemical shift value for 3 and only 46.7% for 4, while the PCM cal-
culations give 82.3% of the experimental result for 3 and only 60.8%
for 4. This is caused by the potential hydrogen bonds that can form
between the analyzed system and the solvent (DMSO) molecules
and are not described by the continuum solvation models. How-
Fig. 2. The crystal structure of 3 (CCDC 756299). The displacement ellipsoids are
drawn at the 50% probability level. Dashed line indicates a hydrogen bond. Crystal
atom numbers are available in the Supplementary data.
ever, explicit inclusion of the first solvation shell can improve the
26
obtained data significantly.
Since the size of the investigated
species and the solvent (DMSO) molecules prohibit use of the full
first solvation shell for 3 and 4, in the present study, just one DMSO
molecule was added to the investigated species in the gas phase in
such a way as to make H-bonding with the labile protons possible
(for the analyzed structures, see Figure 4). It can be seen from Ta-
ble 3 that such a simple manipulation shifts the corresponding sig-
nal in the gas phase from 7.575 to 8.548 ppm for 3 and from 5.563
to 10.912 ppm for 4. Therefore, the inclusion of the continuum sol-
energy by more than 6 kcal/mol compared with the lowest-energy
forms.
The IR spectrum measured experimentally for isoindole deriva-
tive 3 has been compared with unscaled computational harmonic
vibrational frequencies to simplify its interpretation. The corre-
sponding data are presented in Table 2. The presence of the non-
Fig. 3. Lowest-energy diastereoisomers of triazoles 4, 4a and 4b. Nitrogen atoms are depicted in blue, oxygen atoms in red, carbon atoms in grey and hydrogens in white.

2954
M. Ziegler-Borowska et al. / Tetrahedron Letters 51 (2010) 2951–2955
Table 2
IR spectrum of isoindole derivative 3 and triazole 4 determined experimentally and computationally
Vibration
3
4
Exp.
Calcd (gas)
3614
Calcd (benzene)
3552
Exp.
Calcd (gas)
N–H stretch
3312
C@N stretch
O–H stretch
C–H stretch (arom)
1598
3405
3182
1540
3681
3132
2920
3270, 3212, 3209
3207, 3200, 3195
3193, 3186, 3184
3163
3098, 3091, 3081
3074, 3070, 3038
3037, 3028, 3018
3010
3266, 3197, 3191
3190, 3182, 3177
3174, 3168, 3166
3150
3091, 3087, 3071
3069, 3068, 3037
3035, 3025, 3016
2995
3181, 3187, 3192
3196, 3204, 3205
3212, 3225, 3228
3228
3018, 3024, 3029
3040, 3061, 3068
3072, 3078, 3085
3095
1800
1630, 1638, 1651
1656
1480, 1492, 1541
1559
C–H stretch (aliph)
2920
1630
C@O
1630
1598
1831, 1766
1654, 1652, 1641
1626
1819, 1747
1651, 1649, 1634
1624
Aromatic bending (asym)
1598
1466
Aromatic bending (sym)
1466
1538, 1536
1535, 1533
Vibrational frequencies in cmꢀ1. Computational values are unscaled.
Table 3
1H NMR computational and experimental chemical shifts with respect to TMS [ppm]
3
4
Exp. (DMSO)
Calcd (gas)
Calcd (PCM)
Calcd (DMSO)
Exp. (DMSO)
Calcd (gas)
Calcd (PCM)
Calcd (DMSO)
Aliphatic CH2
Aliphatic CH
Aromatic CH
NH (3)/OH (4)
0.814–1.415
2.763
7.044–7.804
9.644
1.299–2.607
2.709–2.710
6.074–8.465
7.575
1.396–2.405
3.221–3.261
6.205–8.399
7.952
ꢀ0.192–2.464
2.334–2.563
6.954–8.811
8.548
1. 328–2.497
2.565–3.212
7.278–7.580
12.038
1.247–2.173
2.361–3.538
6.431–8.328
5.563
1.334–2.180
2.407–3.530
6.644–8.285
7.329
1.110–2.305
2.717–3.466
6.287–8.618
10.912
Fig. 4. The lowest-energy conformers of 3 and 4 with one DMSO molecule. Nitrogen atoms are depicted in blue, oxygen atoms in red, carbon atoms in grey, sulfur atoms in
yellow and hydrogens in white.
vent medium improves the data by about 5% for 3 and 15% for 4,
however, the addition of just one solvent molecule gives an
improvement of 10% with respect to the gas phase calculations
Table 4
Minimum inhibitory concentrations of compounds 3 and 4 (
l
g/mL)
MIC
for 3 and up to 45% for 4. While the improvement for 3 is relatively
small, because the original error is not that large, the correction for
4 is huge and gives calculated results close to the experimental
with satisfactory accuracy and relatively small computational cost.
Further improvement is not crucial for the purpose of qualitative
comparison of the computational and experimental data to inter-
pret the experimental spectrum. This can be achieved by increas-
ing the basis set size and flexibility, however, this results in a
significant growth in computational time.
Bacteria
3
4
Escherichia coli ATCC 25922
Pseudomonas aeruginosa ATCC 27853
Yersinia enterocolitica O3
Enterococcus faecalis ATCC 29212
Sarcina lutea
Staphylococcus aureus ATCC 25923
Nocardia spp.
Rhodococcus equi
500
500
500
100
250
250
500
250
100
250
100
500
250
100
250
250
500
500
500
250
The standard reference strains (American Type Culture Collec-
tion) and bacterial strains isolated from human clinical materials
were used to study the antibacterial activity. The following strains
Mycobacterium smegmatis
Candida albicans

M. Ziegler-Borowska et al. / Tetrahedron Letters 51 (2010) 2951–2955
2955
were tested: Gram-negative bacteria Escherichia coli ATCC 25922,
Pseudomonas aeruginosa ATCC 27853, Yersinia enterocolitica O3;
Gram-positive Enterococcus faecalis ATCC 29212, Sarcina lutea,
Staphylococcus aureus ATCC 25923; Nocardia spp., Rhodococcus equi,
Mycobacterium smegmatis and the pathogenic fungus Candida albi-
cans. The results are presented in Table 4.
The sensitivities to the derivatives 3 and 4 were of similar or-
ders of magnitude (MIC 100–250 lg/mL) for the following strains:
Gram-positive bacteria S. lutea and E. faecalis ATCC 29212; Gram-
negative Y. enterocolitica O3 and the fungus C. albicans. Moreover,
3 was also active against S. aureus ATCC 25923, while 4 exhibited
a relatively high antibacterial potency against R. equi, M. smegmatis
data are available. Atom numbering in the crystal. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.03.116.
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Acknowledgements
The authors are indebted to Dr. Andrzej Wolan for technical
support and fruitful discussions. Wrocław Supercomputing and
´
Networking Center, AGH Cyfronet Kraków and Poznan Networking
and Supercomputing Center are gratefully acknowledged for the
generous allotment of computational resources.
Supplementary data
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Geometrical parameters for the crystal of the isoindole deriva-
tive 3 and lowest-energy conformer computational geometrical