Efficient preparation of N′,N″-1H-isoindole-1,3-diylidenedicarbohydrazides via 1,1,3-trichloro-1H-isoindole, and their characterization

Article abstract of DOI:10.1016/j.tet.2009.05.031

N′,N″-1H-Isoindole-1,3-diylidenedialkyl(aryl,heteroaryl)carbohydrazides were prepared in good yields via 1,1,3-trichloro-1H-isoindole, which was shown to be a versatile reagent for their synthesis. Tautomeric structure and conformational behaviour of dica

Full text of DOI:10.1016/j.tet.2009.05.031

Tetrahedron 65 (2009) 6218–6225
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient preparation of N0,N00-1H-isoindole-1,3-diylidenedicarbohydrazides
via 1,1,3-trichloro-1H-isoindole, and their characterization
,
a
a
a
b
Olga V. Hordiyenko a , Igor V. Rudenko , Angelina V. Biitseva , Aleksandr V. Turov , Axelle Arrault ,
*
b
b
b
c
c
´
Nicolas Brosse , Olivier Fabre , Brigitte Jamart-Gregoire , Roman I. Zubatyuk , Oleg V. Shishkin
a Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrs’ka St., Kyiv 601, Ukraine
b Laboratoire de Chimie Physique Macromole´culaire, UMR 7568, ENSIC-INPL, BP 451, 54001 Nancy, France
c STC ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine
a r t i c l e i n f o
a b s t r a c t
N0,N00-1H-Isoindole-1,3-diylidenedialkyl(aryl,heteroaryl)carbohydrazides were prepared in good yields
via 1,1,3-trichloro-1H-isoindole, which was shown to be a versatile reagent for their synthesis. Tauto-
meric structure and conformational behaviour of dicarbohydrazides in solid state as well as in solution
have been studied by X-ray crystallography, NMR spectroscopy and quantum calculations. The de-
pendence of Z/E amide-type isomerism upon steric effects and solvent polarity is discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 27 January 2009
Received in revised form 5 May 2009
Accepted 14 May 2009
Available online 21 May 2009
Keywords:
1H-Isoindole
Carbohydrazides
NMR spectroscopy
X-ray diffraction
Structure elucidation
1. Introduction
1-imino-1H-isoindole-3-amine with N-nucleophiles.6 Another com-
monly used method relies on the base catalyzed addition of N-
Carboxylic acid hydrazides are known to possess a wide range of
pharmacological activities, among them antitubercular and anti-
bacterial properties.1 Recently, adamantane and norbornane car-
boxylic acid hydrazides were reported as HIV inhibitors.2 At the
same time, little data has been reported on 1-imino-1H-isoindole-
3-amine activities, among them a series of 1,3-disubstituted 1,3-
diiminoisoindolines were described as potential C3a antagonists.3
From the other hand, a previously described disubstituted hydra-
zone derivativedphthalimide dithiosemicarbazone was found to
be useful as an analytical reagent for spectrophotometric de-
termination of metals by means of complex formation.4
nucleophiles, including amines, hydrazine and its derivatives,
to phthalonitrile.7,8 A series of N0-(3-amino-1H-isoindol-1-ylide-
ne)alkyl(aryl,heteroaryl)carbohydrazides bearing one N-acyl hydra-
zone residue were synthesized by us in good yields by this method.5
Unfortunately, in our hands, this cyclization reaction did not allow
synthesis of dicarbohydrazide 1H-isoindole derivatives, contrary to
the published data,8 most probably due to reduced electophilicity of
N0-(3-amino-1H-isoindol-1-ylidene)carbohydrazides. Known N0,N00-
1H-isoindole-1,3-diylidenedicarbohydrazidedphthalimide dithio-
semicarbazone was synthesized by exchange reaction from phthali-
mide dioxime and thiosemicarbazide.9
In pursuance of our work5 on the synthesis of 1H-isoindole car-
bohydrazide derivatives we set out to study the preparation and
structure elucidation of compounds inwhich two hydrazide moieties
are present in the molecule possessing an isoindole skeleton. Of the
methodologies that were described in the literature for the synthesis
of 1-imino-1H-isoindole-3-amine derivatives, two approaches are
particularly widely explored. One of them includes reamination of
3-Amino-1-imino-1H-isoindole and its N-alkyl(aryl) derivatives
are known to demonstrate amino–imino type tautomerism.10,11 The
equilibrium between two tautomeric forms of 3-amino-1-imino-
1H-isoindole and 1,3-diimino-1H-isoindole depends on the nature
of the substituents at nitrogen atoms as well as on solvent polarity
and the temperature (Scheme 1).
N0-(3-amino-1H-isoindol-1-ylidene)alkyl(aryl,heteroaryl)carbohy-
drazides A studied earlier were shown to exist predominantly in the
amino–imino form both in crystal and in the solvents studied and
confirmed by quantum calculations.5 Besides this, carbohydrazides A
derived from aliphatic carboxylic acids demonstrate amide-type
isomerism in solutions at the N-acyl hydrazone chain, and the
* Corresponding author. Tel.: þ38 044 239 33 15; fax: þ38 044 235 12 73.
E-mail address: ov_hordiyenko@univ.kiev.ua (O.V. Hordiyenko).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.031

O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
6219
O
O
The advantage of this methodology is the fast nucleophilic
substitution of all three chlorine atoms at both positions of 1,1,3-
trichloro-1H-isoindole 1 by two carbohydrazide residues.
The reactions were carried out in dry aprotic solvents (toluene,
DCM, dioxane) by heating the reaction mixture at 40–70 ꢀC for 1 h
until the precipitation of the solid products finishes. The best sol-
vent for the reaction is toluenedit was found to be a good alter-
native to polar solvents. The resulting carbohydrazides 2a–m were
obtained in 62–93% yields and were purified by recrystallization.
The structural assignment of the synthesized compounds is
complicated due to their possible existence in different isomeric
and tautomeric forms: two amidrazone fragments, C]N double
bonds and amide-type bonds can contribute to this ambiguity.
From the structural investigations presented herein, the desired
products have the symmetrical form of type B resulting from
a tautomeric shift.
R
R
NH
NH
N
N
NHR
NR
NH
NR
diimino
N
NH
N
NR
NH2
N
NH
R
amino-imino
A
B
O
R = H, Alk, Ar
Scheme 1. Possible tautomeric forms of 3-amino-1-imino-1H-isoindole and 1,3-dii-
mino-1H-isoindole.
equilibrium was shown to be determined by solvent polarity and the
nature of the substituent R in favour of Z isomer, being totally pre-
dominant for aryl and bulky adamantyl derivatives.5,12
In this paper we describe an efficient synthesis of 1,3-di-
substituted 1H-isoindoles B containing two hydrazide acid moieties,
via the nucleophilic substitution reaction between 1,1,3-trichloro-
1H-isoindole 1 and carboxylic acid hydrazides, and their structural
elucidation.
2.1. Crystal structure determination of N0,N00-1H-isoindole-
1,3-diylidenebis(2-methylpropanohydrazide) 2b
An X-ray diffraction study showed that the dihydrazide 2b (R¼
i-Pr) in crystal form exists in the symmetrical tautomeric form B
(Fig. 1) in contrast to N0-(3-amino-1H-isoindol-1-ylidene)carbohy-
drazides A.5
2. Results and discussion
Highly reactive 1,1,3-trichloro-1H-isoindole13 1 can serve as
a versatile reagent for preparation of variety of 1,3-disubstituted
1H-isoindoles that are hardly available or even sometimes could
not be synthesized by other methods.10,14 In this case, reactions
usually proceed through nucleophilic substitution of chlorine
atoms in the 1,1,3-trichloro-1H-isoindole 1 under treatment with
amines, as well as sometimes in the presence of a tertiary amine as
the HCl scavenger.
To prepare N0,N00-1H-isoindole-1,3-diylidenedicarbohydrazides
according to the strategy outlined in Table 1, equimolar amounts of
1 and the corresponding carbohydrazide were reacted in dry sol-
vents to give the substitution products 2a–m in good yields. Tri-
ethylamine was found to be a good scavenger of the HCl. Notably,
synthetically useful Boc-protected hydrazine derivative 2m was
also synthesized by this methodology.
Table 1
Synthesis of N0,N00-1H-isoindole-1,3-diylidenedicarbohydrazides 2a–ma
R
O
NH
N
Cl
Figure 1. Molecular structure of 2b according to X-ray diffraction study.
Cl
2 eq. RC(O)NHNH2
3 eq. Et3N
NH
N
This is confirmed by quantum calculations. Tautomeric form B is
5 kcal molꢁ1 more stable than the amino–imino form for com-
pound 2b. Both substiutents have the similar Z conformation at the
amide bonds and orientation relative to isoindole heterocycle. The
values of the N–C–N–N, C–N–N–C and N–N–C–C torsion angles are
ꢁ0.3(3)ꢀ, 168.2(2)ꢀ and 179.2(2)ꢀ for the substituent at C(7) and
4.6(3)ꢀ, ꢁ152.5(2)ꢀ and ꢁ173.1(2)ꢀ for the substituent at C(8). Thus,
the N–H bonds are orientated inside a cavity formed by the sub-
stituents (Fig. 2). In the crystal a water molecule resides within this
cavity. However, it forms only two hydrogen bonds with the NH
groups of parent molecule: N(1)–H(1N)/O(1W) (H/O 1.94 Å, O–
H/O 168ꢀ) and N(5)–H(5N)/O(1W) (H/O 2.04 Å, O–H.O 169ꢀ).
The N(3)–H(3N) bond is oriented slightly outside the pocket and it
forms H-bond with carbonyl group of adjacent molecule: N(3)–
H(3N)/O(20) [xꢁy, ꢁ1þx, 1–z] (H/O 2.03 Å, N–H/O 169ꢀ). This
cavity is completed (Fig. 2) by two neighbouring molecules bonded
by hydrogen bonds to a water molecule as a proton donor O(1W)–
H(1W)/O(10) [1(1/3)ꢁxþy, (2/3)ꢁx, ꢁ(1/3)þz] (H/O 1.87 Å, O–
N
Cl
2a-m
NH
1
R
O
Entry
Compound 2
R
Yield of 2 (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Me
i-Pr
76
93
71
86
70
87
83
79
76
90
68
62
77
1-Adamantyl
Ph
4-MeC6H4
4-BrC6H4
4-FC6H4
2-Pyridyl
2-BrC6H4
2-ClC6H4
2-IC6H4
2-Thiophenyl
O-t-Bu
9
10
11
12
13
j
k
l
m
a
Reaction conditions: carbohydrazide (20 mmol), triethylamine (30 mmol), 1
(2.205 g, 10 mmol), dry toluene (50 mL) at 60–70 ꢀC for 1 h.

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O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
H/O 153ꢀ), O(1W)–H(2W)/O(20) [xꢁy, ꢁ1þx, 1ꢁz] (H/O 2.19 Å,
O–H/O 133ꢀ) and O(1W)–H(2W)/N(40) [xꢁy, ꢁ1þx, 1ꢁz] (H/N
2.23 Å, O–H/N 151ꢀ). It is interesting to note that in the crystal
very large channels are formed along the 3 axes (Fig. 3), with a ra-
dius of about 4.5 Å. Very probably these cavities contain disordered
solvent molecules.
solution reveals up to seven NH proton signals of relative intensity
0.2H, 0.6H, 0.6H, 0.6H, 0.6H, 0.3H, 0.3H. Upon heating to 80 ꢀC they
coalesce and transform into a broad signal at 9.9 ppm. Such be-
haviour indicates that several interconverting forms of 2b exist in
the solution. This conclusion is confirmed by 13C NMR data that
reveal several signals for all carbons.
In principle, there are two structural elements responsible for
appearance of isomers (rotamers). First, Z/E isomers at the exocyclic
C]N double bonds can be expected. However, interconversion of
the isomeric forms is not probable in this case due to the high
energetic barrier. Therefore, we suggest the existence of the three
amide conformers in the solution (Scheme 2), which are present
due to the hindered rotation at the hydrazide residues. Such effects
were observed for simpler N0-(3-amino-1H-isoindol-1-ylidene)-
carbohydrazides A.5
Two symmetrical rotamers and one unsymmetrical might be
present in the solution. The symmetrical one should reveal two NH
proton peaks with the ratio 1:2 that belong to one heterocyclic and
two hydrazide NH. The unsymmetrical conformer should demon-
strate three nonequivalent NH proton signals of equal intensity.
Analysis of the 1H NMR spectrum of 2b showed that the sym-
metrical forms are minor in the mixture (15% and about 25%). Most
likely, signals at 10.52 ppm (0.19H) and 9.58 ppm (0.34H) belong to
the minor rotamers. As a matter of fact, for both compounds 2b
(R¼i-Pr) and 2a (R¼Me), quantum calculations reveal that the most
stable conformationꢁi1n vacuo is the EE conformer, followed by the
EZ one (2.1 kcal mol above for 2b, 2.2 kcal molꢁ1 for 2a) and the
ZZ one (4.5 kcal molꢁ1 above EE for compound 2b, 4.8 kcal molꢁ1
above EE for compound 2a). It is thus plausible that they coexist in
solution, even though the X-ray results only show the ZZ
conformer.
Figure 2. A cavity formed in crystals of 2b containing hydrogen-bonded water
molecule.
Additional information was obtained from the NOESY experi-
ment. Correlation peaks between NH resonances at 10.38 and
10.10 ppm and isopropyl CH resonance were found. They indicate
that both NH signals are hydrazide type at the exocyclic residues
possessing Z configuration. Such residues are characteristic of the
unsymmetrical and one of the symmetrical rotamers.
The 1H NMR spectrum of compound 2b shows also two sets of
CH isopropyl proton multiplets of similar intensity observed at 2.50
and 3.38 ppm. Their appearance can be explained by the presence
of three Z/E conformers described above suggesting that one of the
multiplets corresponds to the overall signal of Z fragments of iso-
meric mixture and the second onedto the total signal of E con-
formers (Scheme 2).
This conclusion is in an agreement with the 13C NMR spectrum
of 2b that reveals three isopropyl C–H peaks at 29.8, 33.7 and
33.8 ppm. The latter peaks could be observed as two due to some
chemical shift difference of both symmetrical EE and un-
symmetrical ZE isomers.
Figure 3. View of crystal packing of 2b showing void channels along c axis.
2.2. Spectroscopic studies
Full assignment in the 13C NMR was done using HMQC and
HMBC experiments. The result is shown in Table 2 and Figure 4.
Dynamic NMR experiments were applied for the study of am-
ide-type isomerism in solution of other aliphatic carbohydrazide
derivative 2a (R¼Me) which, in principle, could exist as three amide
It is very likely that the tautomeric form B observed in crystals is
stabilized due to the formation of intermolecular H-bonds. How-
ever, the behaviour of dicarbohydrazide 2b (R¼i-Pr) in solution is
much more complex. Thus, 1H NMR spectrum of 2b in DMSO-d6
(CH3)2CH
O
(CH3)2CH
O
CH(CH3)2
O
NOE
10.38
10.04
N
N
N
N
N
N
H
H
H
10.15
10.19
9.58
10.52
N
H
N
H
N
H
10.38
10.10
NOE
CH(CH3)2
9.58
H
H
H
N
N
N
NOE
N
N
N
O
CH(CH3)2
(CH3)2CH
EE 15%
Scheme 2. NH signals assignment of three amide conformers of 2b according to HMQC, HMBC and NOESY data (400 and 100 MHz, DMSO-d6).
O
O
ZZ 25%
EZ 60%

O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
6221
Table 2
correspond to the E form and the minor set at 2.0 ppm to the Z
form because of the chemical shifts of the C–H protons of E
carbohydrazide conformers are known to be shifted downfield
while those for the corresponding Z conformers are shifted up-
field.5,12 It should be noted that E form for compound 2a slightly
predominates (E/Z 10:9) as in the case of corresponding mono-
hydrazide derivative.5
The above conclusions can be confirmed by the analysis of the
NH resonances of 2a. Seven NH protons singlets at 9.7–10.5 ppm
appear in the spectrum of 2a in DMSO-d6 (see Supplementary
data): three of pyrroline NHa from ZZ, ZE and EE forms, and four
hydrazide NHdfrom three conformers as in the case of methyl
groups. Heating the sample causes rapid interconversion of isomers
and at the temperature 343 K the spectrum exhibits one broad
signal at ca. 10 ppm. The reversibility of the spectral changes was
also confirmed.
Heteronuclear 1H–13C correlations found for compound 2b
d
, ppm
HMQC
HMBC
1.11
19.3; 20.2
33.7; 33.8
29.8; 33.7; 33.8; 173.3; 173.5; 178.4; 178.8
20.2; 173.3; 173.5
2.50
3.38
7.61
29.8
19.3; 178.4; 178.8
131.4; 131.7
122.1; 121.6
121.6; 122.1; 133.2; 133.6
131.4; 131.7; 133.2; 133.6
29.8; 141.0; 178.4
133.2; 133.6; 145.1
146.3; 173.3; 173.5
29.8; 140.4; 178.8
133.2; 133.6; 140.4; 146.3
145.1; 173.5
7.78
9.58
10.04
10.10
10.15
10.19
10.38
10.52
d
d
d
d
d
d
d
133.2; 141.0
2.50
33.7 H
CH3
O
33.8
Full assignment of signals for 2a in DMSO-d6 based on HMQC,
HMBC (Table 3) and NOESY experiments is proposed on Scheme 3
and Figure 6.
1.11
20.2
173.3
Z
N 173.5
7.78
H
CH3
N
H10.1308
7.61
145.1
H
146.3
10.04
131.4 121.6 133.2
In Table 4 are given the proportions of the three stereoiso-
mers in function of the polarity of the solvent found from 1H
NMR experiment (Fig. 7). A decrease of the polarity of the me-
dium shifts the equilibrium toward E forms with disappearance
of the ZZ form and in DMSO-d6/CDCl3 1:3 the ratio of E/Z con-
formers is about 2:1. This observation is not in complete agree-
ment with correlations obtained earlier for monoacyl hydrazones
A when decrease of the solvent polarity shifted the equilibrium
towards the E form with less dipole moment. Though the EZ form
of 2a is dramatically less polar (1.2 D), EE and ZZ forms possess
much higher similar dipole momentsd3.7 D and 3.6 D, re-
spectively, as calculated by quantum calculations. It could be
suggested that the key feature of such difference is the relative
orientation of both C]O bonds in two N-acyl hydrazone resi-
dues. On the contrary, by comparison with the ratios observed
for compound 2b in DMSO-d6, it appears that with increasing
size of the alkyl group, the proportion of the E forms decreases,
the Z form being favoured by a lower steric repulsion as pre-
viously demonstrated.
10.19
or
or
or
N
H 10.52
131.7 122.1 133.6
140.4
141.0
7.61
H
9.58
H 10.15
E
N
H
N
7.78
178.4
178.8
O
3.38
H
29.8
CH3
CH3
1.11
19.3
Figure 4. Signals assignment of 1H and 13C spectra for 2b according to HMQC, HMBC
and NOESY data (400 and 100 MHz, DMSO-d6).
conformers with ZZ, ZE and EE configuration at C(O)–NH bond
analogously to compound 2b.
Protons of the methyl groups of each ZZ or EE conformers due to
their chemical equivalence should appear as one signal, contrary to
the methyl proton signals of ZE form that should appear as two
peaks. Indeed, in the 1H NMR spectrum of 2a in DMSO-d6 at room
temperature there is a set of four signals of similar intensity: two
pairs of singlets with 0.21 ppm shift difference (Fig. 5).
On increase of the temperature from 291 to 313 K the pairs of
1, 2 and 3, 4 signals coalesce (Fig. 5), and the further coalescence
of two broad singlets leads to a broad signal at ca. 2.2 ppm
detected at 353 K. It is reasonable to assign the 1H chemical shift
pairs of 1.99, 2.01 and 2.20, 2.22 ppm, respectively, to the methyl
protons of Z and E amide conformers, presented in all three
forms: ZZ, ZE and EE. Thus, the major signals at 2.2 ppm
It was of interest to inspect the influence of different sub-
stituents at the hydrazide residue on Z/E amide isomerism.
Carbohydrazides 2c–l with bulky aliphatic, aromatic and het-
eroaromatic groups were synthesized. 1H NMR spectra of 2c
(R¼Ad), 2d (R¼Ph), 2e (R¼4-MeC6H4), 2f (R¼4-BrC6H4), 2g
(R¼4-FC6H4), and 2h (R¼2-Py) in DMSO-d6 demonstrate only
one set of signals: a symmetrical AA0BB0 system of 4–7 isoindole
protons, one-proton singlet of pyrroline NH, two-proton singlet
of NH–C(O)R moieties and signals from the substituent R.
Hence, at room temperature, exclusive predominance of the
symmetrical diimino tautomeric form B can be observed for 2c–
Table 3
Heteronuclear 1H–13C correlations found for compound 2a
d
, ppm
HMQC
HMBC
1.99; 2.01 22.33; 22.39
2.20; 2.22 20.67
166.06; 166.26
172.49; 172.81
7.61
131.40; 131.70; 131.77
121.58; 121.67; 122.02; 122.14; 133.09;
133.20; 133.54; 133.62
7.78
121.58; 121.67; 122.02; 122.14 131.40; 131.70; 131.77; 133.09; 133.20;
133.54; 133.62; 139.88; 147.49
9.70
10.04
10.13
d
d
d
20.67; 140.91; 172.49
133.09; 133.20; 133.54; 133.62; 145.27
133.09; 133.20; 133.54; 133.62; 139.88;
147.49
10.21
10.34
10.45
10.48
d
d
d
d
147.49; 166.06
20.67; 139.88; 172.81
145.27; 166.26
133.09; 133.20; 133.54; 133.62; 140.91
Figure 5. Temperature-dependent 1H NMR (400 MHz, DMSO-d6) spectra of compound
2a (signals of methyl protons shown only).

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O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
CH3
O
O
CH3
O
O
CH3
NOE
N
N
N
N
N
N
N
N
H
H
H
10.34
10.45
9.70
Ha
N
Ha 10.04
N
Ha 10.13
10.48
10.45
H
10.21
H
9.70
H
N
N
N
N
N
NOE
CH3
NOE
O
CH3
CH3
EE 35%
O
ZZ 15%
EZ 50%
Scheme 3. NH signals assignment of three amide conformers of 2a according to HMQC, HMBC and NOESY data (400 and 100 MHz, DMSO-d6).
1.99, 2.01
3. Conclusions
22.3, 22.4
O
Z
CH3
166.1
7H.78
The present study has established an efficient synthesis of N0,N00-
1H-isoindole-1,3-diylidenedicarbohydrazides via the nucleophilic
substitution of chlorine atoms of highly reactive 1,1,3-trichloro-1H-
isoindole 1 by appropriate carbohydrazides in the presence of trie-
thylamine as the HCl scavenger, and that are not available by the
common route from phthalonitrile or 3-amino-1-imino-1H-isoindole.
The predominant symmetrical tautomeric form derived from 1H-
isoindole-1,3(2H)-dione for N0,N00-1H-isoindole-1,3-diylidenedicarbo-
hydrazides has been determined in the solid state as well as in
solution, and amide-type isomerism in N-acyl hydrazone residues of
the molecules with aliphatic and o-substituted aromatic carbohy-
drazide derivatives was observed. The Z amide rotamer pre-
N166.3
N
H10.2415
7.61
145.3
147.5
H
10.04
10.13
121.6- 133.1-
122.1 133.6
131.4-131.8
N H 10.48
139.9
140.9
7.61
H
9.70
H
E
10.34
N
N
H
7.78
172.5
172.8
O
H3C2.20, 2.22
20.7
Figure 6. Signals assignment of 1H and 13C spectra for 2a according to HMQC, HMBC
and NOESY data (400 and 100 MHz, DMSO-d6).
Table 4
dominates in all of the studied compounds whereas the
E
Influence of solvent polarity on the Z/E isomeric ratio of compound 2a
conformation is favoured in solution for the less hindered N0,N00-1H-
isoindole-1,3-diylidenediacetohydrazide. Due to their tautomeric
and conformational behaviour these compounds can be considered
as good candidates to be applied as analytical reagent for spectro-
photometric determination of metals by means of complex
formation.
DMSO-d6/CDCl3
ZZ
EZ
EE
1:0
1:1
1:3
15
0
0
50
63
60
35
37
40
h, as well as only one amide conformer being dominant in so-
lution, with the most probable Z configuration at C–N amide
bond, as it could be extrapolated from their monohydrazide
derivatives A.5 Boc-hydrazono derivative 2m, as evidenced from
its NMR spectra, also exhibits symmetrical diimino tautomeric
form B.
Amide-type isomerism of other derivatives of aromatic or hetero-
aromatic carboxylic acids 2i–l was studied only by analysis of their
NH protons signals, as the aromatic region appears as a quite
complex superposition of signals. Thus, it might be suggested that
o-substituted carbohydrazides 2i–l could demonstrate all three
possible amide conformers. Their equilibrium depends on condi-
tions such as solvent polarity and temperature. At least, the ap-
pearance of sets of six NH proton signals for 2i (R¼2-BrC6H4), seven
for 2j (R¼2-ClC6H4), seven for 2k (R¼2-IC6H4) and six signals for
thiophencarboxylic acid derivative 2l, respectively, could be ob-
served in DMSO-d6/CCl4 (1:1) solution, and fewer signals in pure
DMSO-d6 are detected.
4. Experimental section
4.1. Materials and instrumentation
1H NMR spectra (in DMSO-d6, 20 ꢀC) were measured on a Bruker
Avance 300 (300 MHz for 1H), and Mercury Varian-400 (400 MHz
for 1H) instruments, with tetramethylsilane as an internal refer-
ence. 13C NMR spectra in DMSO-d6 were measured on a Mercury
Varian-400 (100 MHz for 13C) and Bruker Avance 300 (75 MHz for
13C), with tetramethylsilane residual peak as a standard.
The heteronuclear HMQC and HMBC correlation spectra were
measured on a Varian Mercury-400 instrument (400 and 100 MHz,
respectively). All chemical shifts were referenced to the tetrame-
thylsilane residual peak as internal standard. HMQC and HMBC
experiments were carried out with the method of indirect de-
tection of carbon signals and gradient selection of useful signals.
1
The mixing times in the pulse sequences were JCH¼140 Hz and
2–3
J
¼8 Hz, respectively. The number of increments in the HMQC
CH
Figure 7. NH resonance assignment (300 MHz) of compound 2a in (a) DMSO-d6, (b) DMSO-d6/CDCl3 1:1, (c) DMSO-d6/CDCl3 1:3.

O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
6223
spectra was 128 and in the HMBC it was 400. For each increment 32
scans were collected.
d
7.46–7.57 (m, 8H), 7.82 (br s, 2H), 7.92 (d, J¼8.8 Hz, 4H),10.25 (br s,
13
3H, NH); C NMR (75 MHz, DMSO-d6, 20 ꢀC):
d 121.19, 127.40,
The COSY-90 spectra were carried out with gradient selection of
useful signals. For gradient NOESY spectra the mixing time was
200 ms. The temperature was maintained at 293 K. IR spectra were
recorded with a Nicolet Nexus 470 instrument as KBr pellets. TLC
analyses were carried out on silica gel coated aluminium plates
(Silufol UV-254) in CHCl3/MeOH 9:1 and spots were visualized with
UV light. Melting points were determined with a Boetius micro-
scope hot plate apparatus. Toluene was distilled from phosphorus
pentoxide. 1,1,3-Trichloro-1H-isoindole 1 was prepared by phtha-
limide chlorination with phosphorus pentachloride in o-di-
chlorobenzene solution.13
128.54, 130.27, 131.16, 134.24, 163.03. Anal. Calcd for C22H17N5O2
(383.40): C, 68.92; H, 4.47; N, 18.27. Found: C, 69.03; H, 4.51; N,
18.32.
4.2.5. N0,N00-1H-Isoindole-1,3-diylidenebis(4-methyl-
benzohydrazide) (2e)
Yield: 2.87 g (70%) as a light brown solid, mp 290–291 ꢀC. IR
(KBr disk, cmꢁ1): 1684 (C]O); 1H NMR (300 MHz, DMSO-d6,
20 ꢀC):
d
2.38 (s, 6H, CH3), 7.35 (d, J¼10.4 Hz, 4H), 7.67–7.69 (m,
2H), 7.83–7.88 (m, 6H), 10.53 (br s, 1H, NH), 10.80 (s, 2H, NH); 13C
NMR (75 MHz, DMSO-d6, 20 ꢀC):
21.05, 121.45, 127.65, 128.90,
d
130.85, 131.20, 133.04, 141.63, 145.87, 163.25. Anal. Calcd for
C24H21N5O2 (411.46): C, 70.06; H, 5.14; N, 17.02. Found: C, 70.15; H,
5.15; N, 16.94.
4.2. General procedure for the preparation of N0-(3-(2-acyl-
hydrazono)-1H-isoindol-1(2H)-ylidene)-
carbohydrazides 2a–m
4.2.6. N0,N00-1H-Isoindole-1,3-diylidenebis(4-bromo-
benzohydrazide) (2f)
To a vigorously stirred suspension of the appropriate carbohy-
drazide (20 mmol) and triethylamine (4.15 mL, 30 mmol) in dry
toluene (30 mL) was added dropwise a solution of 1,1,3-trichloro-
1H-isoindole 1 (2.205 g,10 mmol) in toluene (20 mL). Stirring of the
resulting mixture was continued at 60–70 ꢀC for 1 h to complete
solid precipitation. The precipitate was filtered off and washed once
with hexane, then with water to remove triethylamine hydro-
chloride and recrystallized. Aliphatic carbohydrazide derivatives
were recrystallized from ethanol, and aromatic carbohy-
drazidesdfrom aqueous DMF or acetic acid to yield after drying the
carbohydrazides 2a–m as coloured crystalline solids.
Yield: 4.70 g (87%) as a light yellow solid, mp>300 ꢀC. IR (KBr
1
disk, cmꢁ1): 1655 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
d
7.68–7.89 (m,12H),10.53 (br s,1H, NH),10.98 (s, 2H, NH); 13C NMR
(75 MHz, DMSO-d6, 20 ꢀC):
d 121.54, 125.37, 129.85, 131.32, 131.52,
132.68, 132.94, 146.35, 162.43. Anal. Calcd for C22H15Br2N5O2
(541.20): C, 48.82; H, 2.7; Br, 29.53; N, 12.94. Found: C, 48.90; H,
2.81; Br, 29.60; N, 12.91.
4.2.7. N0,N00-1H-Isoindole-1,3-diylidenebis(4-fluoro-
benzohydrazide) (2g)
Yield: 3.47 g (83%) as a light green solid, mp 287–289 ꢀC. IR (KBr
1
4.2.1. N0,N00-1H-Isoindole-1,3-diylidenediacetohydrazide (2a)
Yield: 1.97 g (76%) as a white solid, mp 280–282 ꢀC (lit. Mp 235–
236 ꢀC8). IR (KBr disk, cmꢁ1): 1701 (C]O); 1H NMR (400 MHz,
disk, cmꢁ1): 1654 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
d
7.31 (t, J¼11.6 Hz, 4H), 7.61–7.63 (m, 2H), 7.84–7.86 (m, 2H), 7.97–
8.01 (m, 4H), 10.21 (br s, 3H, NH); 13C NMR (75 MHz, DMSO-d6,
20 ꢀC):
115.36, 115.64, 121.45, 130.28, 130.94, 133.70, 162.39,
DMSO-d6, 20 ꢀC):
d
1.99, 2.01, 2.20, 2.22 (4ꢂs, 6H, CH3), 7.60–7.62
d
(m, 2H), 7.77–7.79 (m, 2H), 9.71, 10.04, 10.13, 10.21, 10.35, 10.45,
165.71. Anal. Calcd for C22H15F2N5O2 (419.38): C, 63.01; H, 3.61; N,
16.70. Found: C, 62.92; H, 3.55; N, 16.73.
13
10.48 (3H, 7ꢂs, NH); C NMR (100 MHz, DMSO-d6, 20 ꢀC)
d 20.67,
22.33, 22.39, 121.58, 121.67, 122.02, 122.14, 131.40, 131.70, 131.77,
133.09, 133.20, 133.54, 133.62, 139.88, 140.91, 145.27, 147.49, 166.06,
166.26, 172.49, 172.81. Anal. Calcd for C12H13N5O2 (259.26): C,
55.59; H, 5.05; N, 27.01. Found: C, 55.68; H, 5.14; N, 27.12.
4.2.8. N0,N00-1H-Isoindole-1,3-diylidenedipyridine-2-
carbohydrazide (2h)
Yield: 3.04 g (79%) as a light yellow solid, mp>300 ꢀC. IR (KBr
1
disk, cmꢁ1): 1691 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
4.2.2. N0,N00-1H-Isoindole-1,3-diylidenebis(2-methyl-
propanohydrazide) (2b)
Yield: 2.93 g (93%) as light yellow crystals, mp 190–191 ꢀC. IR
(KBr disk, cmꢁ1): 1664 (C]O); 1H NMR (400 MHz, DMSO-d6,
d
7.67–7.69 (m, 4H), 7.89 (br s, 2H), 8.05–8.16 (m, 4H), 8.76–8.77 (m,
2H), 11.26 (s, 2H, NH), 11.36 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6, 20 ꢀC):
122.17, 123.47, 127.69, 131.83, 133.89, 138.81, 145.82,
d
149.13, 149.20, 150.35, 161.28. Anal. Calcd for C20H15N7O2 (385.38):
C, 62.33; H, 3.92; N, 25.44. Found: C, 62.41; H, 3.90; N, 25.59.
20 ꢀC):
d
1.11 (br s, 12H, 4ꢂCH3), 2.50–2.53 (m, 1H, CH), 3.40–3.50
(m, 1H, CH), 7.61 (br s, 2H), 7.78 (br s, 2H), 9.58, 10.04, 10.10, 10.15,
10.19, 10.38, 10.52 (7ꢂs, 3H, NH); 13C NMR (100 MHz, DMSO-d6,
4.2.9. N0,N00-1H-Isoindole-1,3-diylidenebis(2-bromo-
benzohydrazide) (2i)
20 ꢀC):
d 19.32, 20.22, 29.83, 33.67, 33.82, 121.57, 122.09, 131.42,
131.65, 133.21, 133.59, 140.41, 140.97, 145.06, 146.30, 173.28, 173.54,
178.41, 178.77. Anal. Calcd for C16H21N5O2 (315.37): C, 60.94; H,
6.71; N, 22.21. Found: C, 61.08; H, 6.80; N, 22.14.
Yield: 4.10 g (76%) as a light yellow solid, mp 189–190 ꢀC. IR (KBr
1
disk, cmꢁ1): 1658 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
d
7.30–7.95 (m, 12H), 10.14, 10.30, 10.83, 10.97 (4ꢂs, 3H, NH); 13C
NMR (100 MHz, DMSO-d6, 20 ꢀC):
d 119.85, 120.39, 120.48, 121.54,
4.2.3. N0,N00-1H-Isoindole-1,3-diylidenediadamantane-1-
carbohydrazide (2c)
122.26, 128.01, 128.35, 128.41, 129.63, 130.14, 130.20, 131.39, 131.78,
131.90, 132.03, 132.30, 132.78, 133.23, 133.46, 133.63, 133.69, 137.81,
137.87, 138.41, 142.30, 145.63, 146.40, 162.99, 164.03, 164.18, 169.98.
Anal. Calcd for C22H15Br2N5O2 (541.20): C, 48.82; H, 2.79; Br, 29.53;
N, 12.94. Found: C, 48.77; H, 2.80; Br, 29.55; N, 12.81.
Yield: 3.54 g (71%) as a light yellow solid, mp 203–205 ꢀC. IR
(KBr disk, cmꢁ1): 1655 (C]O); 1H NMR (300 MHz, DMSO-d6,
20 ꢀC):
d
1.71 (br s, 12H), 1.99 (br s, 18H), 7.56–7.59 (m, 2H), 7.77 (br
s, 2H), 9.16 (br s, 1H, NH), 10.16 (s, 2H, NH); 13C NMR (75 MHz,
DMSO-d6, 20 ꢀC):
27.74, 35.91, 38.23, 40.02, 121.10, 130.41, 173.54.
d
4.2.10. N0,N00-1H-Isoindole-1,3-diylidenebis(2-chloro-
benzohydrazide) (2j)
Anal. Calcd for C30H37N5O2 (499.65): C, 72.12; H, 7.46; N, 14.02.
Found: C, 72.10; H, 7.54; N, 13.98.
Yield: 4.06 g (90%) as a light yellow solid, mp 196–198 ꢀC. IR
(KBr disk, cmꢁ1): 1661 (C]O); 1H NMR (300 MHz, DMSO-d6,
4.2.4. N0,N00-1H-Isoindole-1,3-diylidenedibenzohydrazide (2d)
20 ꢀC):
d
7.31–7.89 (m, 12H), 10.16, 10.31, 10.86, 10.99 (4ꢂs, 3H,
13
Yield: 3.29 g (86%) as a yellow solid, mp 226–227 ꢀC. IR (KBr
NH); C NMR (100 MHz, DMSO-d6, 20 ꢀC):
127.57, 127.90, 127.95, 129.60, 129.70, 130.14, 130.21, 130.52,
d 121.53, 122.26,
1
disk, cmꢁ1): 1716 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):

6224
O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
130.58, 130.70, 131.37, 131.78, 131.91, 132.04, 132.19, 133.20,
133.24, 133.48, 135.72, 136.24, 142.39, 145.72, 146.49, 161.52,
163.17, 163.31, 169.32. Anal. Calcd for C22H15Cl2N5O2 (452.29): C,
58.42; H, 3.34; Cl, 15.68; N, 15.48. Found: C, 58.39; H, 3.33; Cl,
15.58; N, 15.41.
Crystallographic Data Centre as supplementary publication number
CCDC 691478. Copy of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.4. Computational details
4.2.11. N0,N00-1H-Isoindole-1,3-diylidenebis-
(2-iodobenzohydrazide) (2k)
All calculations have been performed at the CINES calculation
centre with the Gaussian 03 version B5 package,17 with default
conditions. The geometry optimization of compound 2b has been
performed in two tautomeric forms. For compounds 2a and 2b
three (EE, EZ and ZZ) conformations have been optimized using the
B3LYP/6-31G(d,p)18,19 density functional level of theory. Minima
were checked successfully for consistent positive vibration
frequencies.
Yield: 4.31 g (68%) as a light yellow solid, mp 193–194 ꢀC. IR (KBr
1
disk, cmꢁ1): 1655 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
d
7.20–7.36 (m, 3H), 7.46–7.70 (m, 5H), 7.84–8.00 (m, 4H), 10.20,
10.33, 10.75, 10.91 (4ꢂs, 3H, NH); 13C NMR (100 MHz, DMSO-d6,
20 ꢀC):
d 94.53, 95.05, 95.26, 121.55, 122.17, 122.25, 128.39, 128.76,
128.82, 129.13, 129.46, 131.15, 131.75, 131.88, 132.01, 132.16, 133.26,
133.46, 139.08, 140.04, 140.11, 141.56, 141.63, 142.01, 142.49, 145.54,
146.32, 162.99, 165.61, 165.75, 171.35. Anal. Calcd for C22H15I2N5O2
(635.196): C, 41.60; H, 2.38; N, 11.03. Found: C, 41.67; H, 2.42; N,
11.11.
Acknowledgements
The authors thank for the financial support of this work to
French-Ukrainian program ‘DNIPRO’ for a grant (M/104-2007) and
EGIDE, No. 14148VB. The contribution to this work by Alexandre
Hocquet is gratefully acknowledged.
4.2.12. N0,N00-1H-Isoindole-1,3-diylidenedithiophene-2-
carbohydrazide (2l)
Yield: 2.45 g (62%) as a yellow solid, mp 294–295 ꢀC. IR (KBr
1
disk, cmꢁ1): 1622 (C]O); H NMR (300 MHz, DMSO-d6, 20 ꢀC):
d
7.25 (t, J¼6.0 Hz, 2H), 7.71 (br s, 2H), 7.89–8.12 (m, 6H), 10.49,
Supplementary data
10.94, 11.09 (3ꢂbr s, 3H, NH); 13C NMR (100 MHz, DMSO-d6, 20 ꢀC):
d
122.22, 122.49, 127.35, 128.74, 129.44, 129.57, 131.75, 132.12,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.05.031.
132.19, 132.96, 133.61, 133.82, 135.70, 135.85, 139.19, 139.91, 146.72,
150.42, 158.69, 162.10. Anal. Calcd for C18H13N5O2S2 (395.46): C,
54.67; H, 3.31; N,17.71; S,16.22. Found: C, 54.61; H, 3.28; N,17.82; S,
16.15.
References and notes
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Volna: Vilnius, 1994; part 1, p 80, part 2, p 278.
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4. (a) Guzman, C. M.; Perez, B. D.; Pino, F. An. Quim. 1976, 72, 651–656; (b) Gir-
idhara, R. K.; Prakash, K. M. M. S.; Hussain, R. K.; Venkata, R. D. Acta Cienc.,
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Microchem. J. 1986, 34, 83–88.
4.2.13. Di-tert-butyl 2,20-(1H-isoindole-1,3-diylidene)-
dihydrazinecarboxylate (2m)
Yield: 2.88 g (77%) as a flesh-coloured solid, mp 201–202 ꢀC
decomp.; 1H NMR (400 MHz, DMSO-d6, 20 ꢀC):
d
1.47 (s, 18H), 7.56–
7.59 (m, 2H), 7.71–7.73 (m, 2H), 9.47 (br s, 2H), 10.26 (br s, 1H); 13C
NMR (100 MHz, DMSO-d6, 20 ꢀC):
28.47, 79.89, 121.35, 130.93,
d
132.18, 142.60, 153.27. Anal. Calcd for C18H25N5O4 (375.42): C, 57.59;
H, 6.71; N, 18.65. Found: C, 57.69; H, 6.68; N, 18.72.
5. Hordiyenko, O. V.; Biitseva, A. V.; Kornilov, M. Yu.; Brosse, N.; Hocquet, A.;
Jamart-Gre´goire, B.; Shishkin, O. V.; Zubatyuk, R. I. Eur. J. Org. Chem. 2006, 12,
2833–2842.
4.3. X-ray crystallographic studies
6. Wolf, W.; Vollmann, H. Bayer AG. DE Patent 941845, 1956; Chem. Abstr. 1959, 53,
6251c.
7. Elvidge, J. A.; Redman, A. P. J. Chem. Soc., Perkin Trans. 1 1972, 2820–2822.
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1972, 77, 126422x.
9. Guzman, C. M.; Perez, B. D.; Pino, F. An. Quim. 1974, 70, 828–832.
10. Negrebetskii, V. V.; Balitskaya, O. V.; Kornilov, M. Yu. Russ. J. Gen. Chem. 1983, 53,
2573–2586.
Crystals of 2b (C16H21N5O2$H2O, Mr¼333.39) are hexagonal, at
100 K. a¼27.750(4) Å, c¼16.430(2) Å, V¼10,958(3) Å3, space group
R3,
Z¼18,
dcalcd¼0.909 g cmꢁ1
,
F(000)¼3204,
m(Mo
Ka
)¼0.065 mmꢁ1, 28,790 reflections were measured at ‘Xcalibur 3’
diffractometer (graphite monochromated Mo Ka, u-scans, CCD
detector) of which 4454 were unique (Rint¼0.040). Structure was
solved by direct methods and refined in anisotropic approximation
for all non-hydrogen atoms using SHELX-97 package.15 Hydrogen
atoms were placed in calculated positions and refined in riding
model with Uiso(H)¼nUeq of the carrier atom (n¼1.5 for methyl
groups and water and n¼1.2 for remaining H-atoms). During re-
finement the C–C bond lengths in disordered isopropyl group were
restrained to 1.53(1) Å. The crystal structure contains very large
intermolecular voids located along 3 axes (three per unit cell) each
of 1155 Å3 volume, presumably containing disordered solvent
molecules. Integrated electron number is 36 per void. In the final
stages of refinement the contribution from this electron density
was eliminated using SQUEEZE procedure implemented in Platon.16
The contribution from disordered solvent was not accounted in
calculations of molecular weight, crystal density, F(000) etc. Final R-
11. Friedrichsen, W.; Traulsen, T.; Elguero, J.; Katritzky, A. R. Tautomerism of Het-
erocycles: Five-membered Rings with One Heteroatom. In Advances in Hetero-
cyclic Chemistry; Academic Press: San Diego, CA, 2000; Vol. 76, p 129.
12. (a) Licandro, E.; Perdicchia, D. Eur. J. Org. Chem. 2004, 665–675; (b) Pihlaja, K.;
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13. Bayer AG. GB Patent 704595, 1954; Chem. Abstr. 1955, 49, 7001.
14. (a) Vollmann, H.; Baumann, F.; Bienert, B. U.S. Patent 2,701,252, 1955; Chem.
Abstr. 1955, 49, 53710; (b) Kornilov, M. Yu.; Makovetsky, V. P. Dopov. Nats.
Akad. Nauk Ukr., Ser. B 1974, 11, 1013–1019; (c) Gordienko, O. V.; Negrebetskii,
V. V.; Ivanchenko, V. I.; Kornilov, M. Yu. Russ. J. Gen. Chem. 1989, 59,
2771–2779.
15. Sheldrick, G. M. SHELX97. Programs for Crystal Structure Analysis (Release 97-2);
University of Go¨ttingen: Germany, 1997.
16. Speck, A. L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University:
Utrecht, The Netherlands, 1998.
17. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery Jr., J. A.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A. Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
values: R1¼0.049 (for 2131 reflections with F>4
s
(F)), wR2¼0.129
(all data), S¼0.996.
Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge

O.V. Hordiyenko et al. / Tetrahedron 65 (2009) 6218–6225
6225
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Gaussian: Pittsburgh, PA, 1998.
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Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200–206; (c) Lee, C.; Yang, W.;
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