Reaction of 2-(2-azahetaryl)-4-chloro-3-oxobutyronitriles with substituted benzaldehyde hydrazones. Unexpected formation of 4-arylideneamino-2-(1-R-benzimidazol-2-YL)-3-oxobutyronitriles

Article abstract of DOI:10.1023/A:1012407826196

The reaction of 2-(2-azahetaryl)-3-oxo-4-chlorobutyronitriles with substituted benzaldehyde hydrazones gives 4-arylideneamino-2-(1-R-benzimidazol-2-yl)-3-oxobutyronitriles, the structures of which were proved using spectroscopic data, the results of elemental analysis, and through their chemical reactions. It was found that the reaction course depends on the basicity of the heterocyclic fragment in the starting nitrile. A likely mechanism for the process is proposed.

Full text of DOI:10.1023/A:1012407826196

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
REACTION OF 2-(2-AZAHETARYL)-
4-CHLORO-3-OXOBUTYRONITRILES
WITH SUBSTITUTED BENZALDEHYDE
HYDRAZONES. UNEXPECTED FORMATION
OF 4-ARYLIDENEAMINO-2-(1-R-BENZIMIDAZOL-
2-YL)-3-OXOBUTYRONITRILES.
Yu. M. Volovenko, A. V. Tverdokhlebov, and T. A. Volovnenko
The reaction of 2-(2-azahetaryl)-3-oxo-4-chlorobutyronitriles with substituted benzaldehyde hydrazones
gives 4-arylideneamino-2-(1-R-benzimidazol-2-yl)-3-oxobutyronitriles, the structures of which were
proved using spectroscopic data, the results of elemental analysis, and through their chemical
reactions. It was found that the reaction course depends on the basicity of the heterocyclic fragment in
the starting nitrile. A likely mechanism for the process is proposed.
Keywords: 2-(2-azahetaryl)-4-chloro-3-oxobutyronitriles, 4-arylideneamino-2-(1-R-benzimidazol-2-yl)-
3-oxobutyronitriles, hydrazones, benzaldehydes.
The 2-(2-azahetaryl)- 4-chloro-3-oxobutyronitriles 1-4 [1] are convenient precursors in the preparation
of pyrrole derivatives and pyrrole annelated heterocycles via reaction with various amines [2-5]. In this paper
we present the results of a study of the reaction of compounds 1-4 with the substituted benzaldehyde hydrazones 5.
The reaction between 2-(1-R-benzimidazol-2-yl)- 4-chloro-3-oxobutyronitriles 1, 2 and the hydrazones
5a-g in the presence of N,N-dimethylaniline gives the 4-arylideneamino-2-(1-R-benzimidazol-2-yl)-3-
oxobutyronitriles 8a-g, 9a-g in 70-90% yields (Scheme 1) instead of the expected products of alkylation of the
hydrazones at the amine nitrogen atom 6a-g, 7a-g [6-16]. Hence, in this case we observe a rare, but none the
less known alkylation at the imine nitrogen atom [17-19].
1
Elemental analysis of compounds 8, 9 agrees with the proposed structures (Table 1). The H NMR
spectra of these products recorded in DMSO-d6 show a two proton singlet for the methylene group in the range
4.36-4.47 and also a one proton singlet in the range 8.99-8.47 ppm, corresponding to the azomethine fragment.
The signal for the benzimidazole NH proton is seen as a singlet exchanging with D2O (one or two protons for
compounds 9 and 8 respectively) to low field 12.90-13.40 ppm and this can be explained by the presence of an
intramolecular hydrogen bond. The remaining protons of the heterocyclic fragment and of the aryl substituent
resonate in typical regions (Table 2). In the 1H NMR spectra of compounds 8 and 9, an absorption in the region
4.00-5.50 ppm for the proton of a secondary amino group in aldehyde alkylhydrazones [20-22] is absent. The IR
spectra of the arylideneaminobutyronitriles 8, 9 have a strong absorption band for the stretching vibrations of
__________________________________________________________________________________________
Taras Shevchenko University, Kiev 252601, Ukraine; e-mail: atver@mail.univ.kiev.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 952-961, July, 2001. Original article submitted June 25,
1999.
876
0009-3122/01/3707-0876$25.00©2001 Plenum Publishing Corporation

the nitrile group in the range 2170-2200 cm-1 and a medium sized band in the range 3140-3240 cm-1, due to the
N–H stretching vibrations. Hence the elemental analysis and the spectroscopic data exclude structures of type 6,
7 and are in full agreement with the structure of the corresponding compounds 8, 9.
Scheme 1
CN
X
H
N
N
N
H
Ar
O
6a–g, 7a–g
Z
n-BuOH, Me2NPh (1, 2)
CN
Cl
N
H
Het
O
CN
O
Ar
CN
X
N
N
Ar–CH=N–NH2
N
5a–g
H
O
8a–g, 9a–g
Ar
+
Z
n-BuOH (1, 2) or
Het
CN
Cl
n-BuOH, Me2NPh (3, 4)
CN
N
O
O
13a–c
1–4
Ar–CH=N–N=CH–Ar
+
14
(from 1 or 3 and 5d)
X
X
N
1–3, 6–9, 13a,c Het =
, Z =
;
Z =
;
,
4, 13b Het =
1, 6, 8, 13c X = NH; 2, 7, 9 X = NMe; 3, 13a X = S;
N
5–9 a Ar = C6H4OMe-4, b Ar = C6H4NMe2-4, c Ar = C6H4Cl-4, d Ar = C6H4NO2-3,
e Ar = C6H4OH-2, f Ar = C6H3Cl2-2,4, g Ar = C6H2(OMe)3-3,4,5
In view of the fact that this reaction of the nitriles 1, 2 with the hydrazones 5 is quite unexpected, we
have obtained additional evidence for proving the structure of the products 8, 9. It was found that the reaction of
halonitriles 1, 2 with anisaldehyde methylhydrazone (10) gave compounds 8a and 9a respectively and these
were identical to those synthesized from the unsubstituted aldehyde hydrazone 5a. The results unambiguously
show that the amine nitrogen atom of the hydrazones is lost during the course of the reaction and is not included
in the composition of the products 8 and 9.
The arylideneaminobutyronitriles 8, 9 are, in fact, imines formed from 4-amino-2-(2-benzimidazolyl)-3-
oxobutyronitrile and variously substituted benzaldehydes. As is known, in the reaction of hydrazine derivatives,
amines are readily lost from aldimines [23-26]. Short heating of compounds 8a-g with an excess of hydrazine
hydrate in dioxane gives the 2-amino-3-(2-benzimidazolyl)-4,5-dihydro-4-oxopyrrole 11a in 50-60% yield
depending on the starting azomethine 8a-g (Scheme 2). The product 11a is formed as a result of the
heterocyclization of the intermediate amine 12 due to intramolecular addition of the amino group to the nitrile
[2, 4, 5, 27, 28]. In the case of hydrazinolysis of azomethine 8a there were isolated from the reaction mixture not
only the pyrrolone 11a but also a second product identified by comparison with a known sample which was
anisaldehyde hydrazone 5a. It was noted that the aminopyrrolone 11a does not react with an excess of hydrazine
hydrate and this is in agreement with data for derivatives of 11a substituted at the 1 position [29].
877

TABLE 1. Characteristics of 4-Arylideneamino-2-(1-R-benzimidazol-2-yl)-
3-oxobutyronitriles 8a-g, 9a-g
Found N, %
Calculated N, %
Com-
pound
Empirical
formula
Solvent for
——————
Yield, %
mp, °С
recrystallization
C19H16N4O2
C20H19N5O
16.88
16.86
20.12
20.29
16.58
16.64
20.00
20.16
17.44
17.60
15.21
15.09
14.38
14.29
16.26
16.18
19.30
19.49
16.15
15.98
19.40
19.38
16.72
16.87
14.43
14.55
13.58
13.78
239
234
253
249
248
260
246
204
210
222
202
203
216
199
n-Butanol
86
75
80
96
82
74
87
86
87
93
83
68
65
86
8а
n-Propanol
n-Butanol
i-Propanol
n-Butanol
Acetonitrile
Ethanol
8b
8c*
8d
C18H13ClN4O
C18H13N5O3
C18H14N4O2
C18H12Cl2N4O
C21H20N4O4
C20H18N4O2
C21H21N5O
8e
8f*2
8g
n-Propanol
n-Butanol
n-Butanol
Ethanol
9а
9b
9c*3
C19H15ClN4O
C19H15N5O3
C19H16N4O2
C19H14Cl2N4O
C22H22N4O4
9d
n-Butanol
n-Butanol
Ethanol
9e
9f*4
9g
Scheme 2
H
N
.
NH2–NH2 H2O
H
N
8a–g
9a–g
N
H
H
N
– 5a–g
N
..
NH2
O
N
R
N
Ph–NH–NH2
O
R
– Ar–CH=N–NH–Ph
11a,b
12a,b
11, 12 a R = H, b R = Me
The IR spectrum of compound 11a shows the absence of the absorption band for the nitrile group and
the presence of a strong absorption in the range 3080-3360 cm-1 due to the N–H bond stretching vibrations. The
1H NMR spectrum of pyrrolone 11a, recorded in DMSO-d6, shows a two proton methylene group singlet at 3.87
and a one proton 1-H pyrrole ring singlet which exchanges in D2O. It was of interest that the signals for the
primary amino group protons were seen as two singlets, each of one proton, at 8.30 and 7.80 ppm and this non-
equivalence is due to the intramolecular hydrogen bond. All of the spectroscopic parameters for compound 11a
agree well with known data for its 1-substituted derivatives [4, 5, 27, 28] and allow one to propose that, as in the
latter, it exists in the amino ketone tautomeric form.
878

TABLE 2. Spectroscopic Characteristics of Compounds 8a-g, 9a-g
Com- IR spectrum,
1H NMR spectrum (DMSO-d6), δ, ppm, spin-spin coupling (J), Hz
pound
cm-1
2200 (CN), 12.98 (2H, s, 2NH); 8.62 (1H, s, –N=CH–); 7.82 (2H, d, J = 9.0, 2'- and
8а
3240 (NH)
6'-HAr); 7.54 (2H, m, HBi); 7.28 (2H, m, HBi); 7.05 (2H, d, J = 9.0, 3'- and
5'-HAr); 4.40 (2H, s, CH2); 3.82 (3H, s, OCH3)
2180 (CN), 12.87 (2H, s, 2NH); 8.47 (1H, s, –N=CH–); 7.67 (2H, d, J = 9.0, 2'- and
8b
8c
8d
3220 (NH)
6'-HAr); 7.54 (2H, m, HBi); 7.28 (2H, m, HBi); 6.77 (2H, d, J = 9.0, 3'- and
5'-HAr); 4.37 (2H, s, CH2); 3.00 (6H, s, N(CH3)2 )
2185 (CN), 12.92 (2H, s, 2NH); 8.68 (1H, s, –N=CH–); 7.91 (2H, d, J = 8.5, 2'- and
3220 (NH)
6'-HAr); 7.56 (4H, m and d, J = 8.5, 3'- and 5'-HAr and HBi);
7.28 (2H, m, HBi); 4.37 (2H, s, CH2)
2185 (CN); 12.92 (2H, s, 2NH); 8.88 (1H, s, –N=CH–); 8.72 (1H, t, J = 1.5, 2'-HAr);
3225 (NH); 8.35 (2H, m, J = 8.0, J = 1.5, 4'- and 6'-HAr); 7.83 (1H, t, J = 8.0, 5'-HAr);
1520, 1335
(NO2)
7.56 (2H, m, HBi); 7.28 (2H, m, HBi); 4.38 (2H, s, CH2)
2180 (CN); 12.93 (2H, s, 2NH); 11.07 (1H, s, OH); 8.97 (1H, s, –N=CH–); 7.69 (1H, d,
8e
3080-3220
J = 8.5, 6'-HAr); 7.55 (2H, m, HBi); 7.40 (1H, t, J = 7.5, 4'-HAr); 7.21 (2H, m,
(OH, NH)
HBi); 6.97 (2H, d and dd, J = 7.5, J = 8.5, 3'- and 5'-HAr); 4.38 (2H, s, CH2)
2180 (CN), 12.80 (2H, s, 2NH); 8.87 (1H, s, –N=CH–); 8.13 (1H, d, J = 8.5, 6'-HAr);
3200 (NH) 7.47-7.74 (4H, m, 3'-, 5'-HAr and HBi); 7.27 (2H, m, HBi); 4.36 (2H, s, CH2)
8f
2190 (CN), 12.90 (2H, s, 2NH); 8.62 (1H, s, –N=CH–); 7.55 (2H, m, HBi);
8g
3220 (NH)
7.27 and 7.21 (4H, m and s, HBi and 2'-,6'-HAr); 4.37 (2H, s, CH2);
3.85 (6H, s, 3'- and 5'-OCH3); 3.75 (3H, s, 4'-OCH3)
2170 (CN), 13.35 (1H, s, NH); 8.61 (1H, s, –N=CH–); 7.82 (2H, d, J = 9.5, 2'- and
9а
9b
9c
9d
3140 (NH)
6'-HAr); 7.67 (2H, m, HBi); 7.36 (2H, m, HBi); 7.06 (2H, d, J = 9.5, 3'- and
5'-HAr); 4.46 (2H, s, CH2); 3.96 (3H, s, NCH3); 3.82 (3H, s, OCH3)
2170 (CN), 13.40 (1H, s, NH); 8.49 (1H, s, –N=CH–); 7.72 and 7.65 (4H, m and d,
3150 (NH)
J = 9.0, HBi and 2'-, 6'-HAr); 7.37 (2H, m, HBi); 6.77 (2H, d, J = 9.0, 3'- and
5'-HAr); 4.46 (2H, s, CH2); 3.97 (3H, s, NCH3); 3.00 (6H, s, N(CH3)2)
2180 (CN), 13.28 (1H, s, NH); 8.67 (1H, s, –N=CH–); 7.88 (2H, d, J = 8.5, 2'- and
3140 (NH)
6'-HAr); 7.65 (2H, m, HBi); 7.54 (2H, d, J = 8.5, 3'- and 5'-HAr); 7.31 (2H, m,
HBi); 4.43 (2H, s, CH2); 3.92 (3H, s, NCH3)
2180 (CN); 13.30 (1H, s, NH); 8.92 (1H, s, –N=CH–); 8.71 (1H, t, J = 2.0, 2'-HAr);
3145 (NH); 8.38 (2H, m, J = 8.0, J = 2.0, 4'- and 6'-HAr); 7.84 (1H, t, J = 8.0, 5'-HAr);
1515, 1350
(NO2)
7.70 (2H, m, HBi); 7.36 (2H, m, HBi); 4.47 (2H, s, CH2); 3.98 (3H, s, NCH3)
3220-3060
(OH, NH);
2190 (CN)
13.30 (1H, s, NH); 11.08 (1H, s, OH); 8.99 (1H, s, –N=CH–); 7.70 and 7.55
(3H, dd and m, J = 8.0, J = 2.0, 6'-HAr and HBi); 7.41 (1H, dt, J = 8.0,
J = 2.0, 4'-HAr); 7.19 (2H, m, HBi); 6.96 and 6.94 (2H, t and d, J = 8.0,
3'- and 5'-HAr); 4.45 (2H, s, CH2); 3.97 (3H, s, NCH3)
9e
3150 (NH), 13.31 (1H, s, NH); 8.88 (1H, s, –N=CH–); 8.14 (1H, d, J = 8.5, 6'-HAr);
9f
2180 (CN)
7.75, 7.67 and 7.56 (4H, d, J = 2.0, m and dd, J = 8.5, J = 2.0, 3'-HAr, HBi
and 5'-HAr); 7.34 (2H, m, HBi); 4.44 (2H, s, CH2); 3.97 (3H, s, NCH3)
2175 (CN), 13.30 (1H, s, NH); 8.61 (1H, s, –N=CH–); 7.63 (2H, m, HBi); 7.37 (2H, m,
9g
3150 (NH)
HBi); 7.21 (2H, s, 2'- and 6'-HAr); 4.44 (2H, s, CH2); 3.97 (3H, s, NCH3);
3.86 (6H, s, 3'- and 5'-OCH3); 3.77 (3H, s, 4'-OCH3)
Reaction of the azomethines 9a-g with phenylhydrazine occurs through the amino nitrile 12b to the
aminooxopyrrole 11b in 50-55% yields (Scheme 2). The spectroscopic characteristics of the product 11b are
similar to those of the product 11a. In the case of compound 9a, also anisaldehyde phenylhydrazone was
separated from the reaction mixture.
In order to explain the mechanism of formation of compounds 8, 9 we first examined the effect of the
basicity of the heterocyclic substituent in the halonitriles 1-4 on the course of the reaction. It was found that the
2-benzothiazolyl- and also the 2-pyridyl derivatives 3, 4 and the hydrazones 5 did not form the corresponding
hetero analogs of compounds 8, 9 under the same conditions. Instead, there were isolated from the reaction
mixture only the products of intramolecular alkylation of the starting halo nitriles 3 and 4 which are the known
879

compounds 13a and 13b respectively [1, 4] (Scheme 1). Hence the nature of the reaction of the halo nitriles 1-4
with the hydrazones 5 depends on the basicity of the heterocycle in compounds 1-4 and occurs at the imine
nitrogen atom to give the products 8, 9 only in the case of the highly basic benzimidazolyl derivatives 1, 2.
The reaction of the benzothiazolyl derivative 3 with m-nitrobenzaldehyde hydrazone 5d gave a reaction
mixture which contained both compound 13a and also 3,3'-dinitrobenzaldazine 14, i.e. the formation of the
products of intramolecular alkylation 13 is accompanied by the symmetrization of hydrazone 5 to the
corresponding azine 14 (Scheme 1). We therefore propose that compounds 13a,b are formed with the direct
participation of hydrazones 5.
It was of no less interest that the absence of N,N-dimethylaniline in the reaction mixture influences the
reaction course in a basic way. Hence reaction of the halo nitrile 1 with hydrazone 5d in n-butanol in the
absence of N,N-dimethylaniline leads to the formation of the corresponding intramolecular alkylation product
13c and 3,3'-dinitrobenzaldazine 14 while, in the presence of N,N-dimethylaniline, compound 8d is formed.
This means that, on the one hand, N,N-dimethylaniline takes part in the formation of compounds 8, 9 directly as
reagent. On the other hand, the possibility of forming compound 13c along with the azine 14 in the absence of
N,N-dimethylaniline confirms the proposal regarding formation of the products 13 via direct participation of the
hydrazones 5. It appears likely that the formation of the arylideneaminobutyronitriles 8, 9 and oxonitriles 13
along with the aldazines 14 occurs via a single, general intermediate, and the pathway depends both on the
basicity of the heterocyclic fragment and the presence or absence in the reaction mixture of
N,N-dimethylaniline. On this basis we propose the following mechanism for the formation of compounds 8, 9
(Scheme 3).
Scheme 3
Ar
Ar
O
N
H
O
NC
N
NC
N
+
.
NH2
HCl
NH2
–
1–4
+
5
Cl
NH
.
.
Z
16
Z
15
Ar
O
H
..
Me
N
Me
NC
N
–
NH2
Me2NPh
+
–
H2N
Ph Cl
+
8, 9
H
N
+
Cl
17
Z
16A
Ar
H
H
Ar
H
NH2
O
O
+
H
NH2
–
:
+
NC
N NH2
N
NC
N
H
:
5
13
+
Cl
14
–
.
– N2H4 HCl
Cl
Ar
N
+
N
:
–
Cl
19
18
16B
Z
Z
The first stage involves alkylation of the hydrazone 5 by the halo nitrile 1-4 at the imine nitrogen atom to
give the immonium intermediates 15. The oxygen atom of the latter occurs within a -enamino ketone fragment.
β
An oxygen of this type has a significant excess of electron density due to conjugation with the unshared electron
pair of the nitrogen atom of the -amino group and, as a consequence, a marked nucleophilicity [30]. On the
β
other hand, there is also present an electrophilic center in the intermediates 15 which is the azomethine carbon
880

atom of the immonium fragment. Hence there is the possibility of an intramolecular O-aminoalkylation, as a
result of which there are formed intermediate oxazolidines 16 which are the general intermediates referred to
above. In the oxazolidines 16 there exist two basic centers which are the nitrogen atoms of the heterocyclic
substituent and the hydrazine fragment. Hence for the intermediates 16 there are two possible protonated forms
16A and 16B, between which there can be established an acid-base equilibrium, the position of which is
determined only by the basicity of the heterocyclic substituent, since the basicity of the second center is
virtually the same for all of the oxazolidines 16 with different Ar. Hence for the highly basic benzimidazolyl
derivatives the equilibrium must be shifted towards protonation at the heterocyclic substituent form 16A, while
for the less basic pyridyl- and benzothiazolyl derivatives the alternative form 16B predominates. The different
protonated forms of intermediate 16 subsequently undergo different reactions. Hence the heterocyclic
substituent proves to have an effect on the equilibrium position for the protonated forms A and B, thus
influencing the whole reaction course.
The strong polarization and hence lability of the 1–2 bond must serve as a strong driving force in the
subsequent reactions of the intermediates 16A. The latter results from the opportunity for conjugation of the
p-electrons of the oxygen atom with the two strong acceptors, i.e. the nitrile group and the nitrogen atom of the
heterocyclic substituent which bears the positive charge. Because of this, such an oxygen atom is an excellent
nucleofuge. In itself, fission of the O–CHAr bond would lead only to the initial immonium intermediate 15
which implies a likely reversible formation of the oxazolidines 16. However in the presence of a nucleophile
such as, in this case, N,N-dimethylaniline, fission of the O–CHAr bond becomes possible with its help. In
addition, the direct nucleophilic attack of N,N-dimethylaniline at position 2 of the oxazolidine ring of the
intermediate 16A is significantly sterically hindered. The primary amino group at position 3 in the indicated
intermediates is sterically fully available and, along with the moderate energy of the N–N bond, this makes
possible its fission via nucleophilic attack of N,N-dimethylaniline. As a result of such a process, accompanied
by the redistribution of electron density (Scheme 3), there are formed the arylideneaminobutyronitriles 8, 9 and
N,N-dimethyl-N-phenylhydrazinium chloride 17. The given process can be considered as a nucleophilic
substitution at the primary amino group nitrogen atom in which the N,N-dimethylaniline takes the part of the
nucleophile and the leaving group is the whole remaining oxazolidine fragment 16A. A similar formation of a
N,N-dimethyl-N-phenylhydrazinium salt 17 from N,N-dimethylaniline and a compound of the type H2NX where
X is a leaving group has been reported in the literature [31, 32]. In the light of the proposal presented,
experiments were undertaken to separate from the reaction mixture salts of the type 17 with different anions.
Unfortunately no kind of identifiable products were obtained other than compounds 8, 9. According to literature
data [31, 32], salts of type 17B are prepared under mild conditions and data concerning their thermal stability is
not available. Since, in our case, the reaction occurs under quite forcing conditions (117°C, 10-15 h), further
reactions of the indicated salts 17 are quite possible.
The oxazolidine forms 16B protonated at the hydrazine nitrogen (Scheme 3) undergo a standard
intramolecular, nucleophilic substitution at a carbon center. The heterocyclic substituent nitrogen atom takes the
part of the nucleophile, having an unshared electron pair, and the leaving group is the quaternary nitrogen atom
which bears the overall positive charge. As a result, the intermediates 18 are formed. These are effectively
O-substituted polyaminals which are labile intermediates in the preparation and hydrolysis of imines and related
compounds (hydrazones, oximes etc.) and decompose with the formation of carbonyl compounds or imines,
depending on the reaction route. Of course, the O-substituted polyaminals can decompose only in the direction
of formation of imines. Thus the standard reaction of the polyaminal intermediates 18 leads to formation of the
products 13 and of the protonated hydrazones 19. In turn, the protonated molecules of the hydrazone are the first
stage of a known acid catalyzed symmetrization reaction of N-unsubstituted hydrazones to azines [33, 34] and
the reaction of the salts 19 with a molecule of the hydrazone 5 present in the reaction mixture can give the
azines 14. The direct formation of the latter from the hydrazones 5 without participation of the halo nitriles 1-4
cannot be ruled out.
881

It is likely that, with the N,N-dimethylaniline absent from the reaction mixture, the benzimidazolyl
derivatives 1, 2 are converted to the corresponding pyrrolo[1,2-a] heterocycles 13 via the protonated forms of
the oxazolidine intermediates of type 16B. Although the latter, in this case, are present in the equilibrium
mixture with the protonated forms 16A only in very small amount, the possibility of their irreversible
conversion to compound 13 promotes this reaction. With the N,N-dimethylaniline present in the reaction
mixture the basic process becomes the formation of the arylideneaminobutyronitriles 8, 9.
Thus as a result of studying the reaction of the 2-(2-azahetaryl)- 4-chloro-3-oxobutyronitriles 1-4 with
substituted benzaldehyde hydrazones 5 we have found an extremely unusual reaction which forms the
4-arylideneamino-2-(1-R-benzimidazol-2-yl)-3-oxobutyronitriles 8, 9. To our knowledge this is the first example
of a unique reaction between N- unsubstituted hydrazones and -halo ketones which has led to the separation of
α
identifiable products. Additionally, the hydrazones are converted to imines in the given reaction. Within the
scope of many examples of reversible reactions there was known only one case of a reaction of the type
hydrazone
azomethine which was observed for N-arylsulfonyl substituted hydrazones [35]. For a series of
→
N-unsubstituted hydrazones an analogous reaction is reported for the first time. Evidently, these results are
obtained thanks to the extremely specific structure of the -halo ketones 1, 2. We should mention that, in the
α
course of establishing the structure of the products 8, 9, there were synthesized the previously unknown
2-amino-3-(1-R-benzimidazol-2-yl)-4,5-dihydro-4-oxopyrroles 11a,b. It was noted that all of the developed
methods for the synthesis of 2-amino-3-hetaryl-4-oxopyrroles do not allow the preparation of those which are
substituted at the 1 position in this series [4, 5, 27, 28].
EXPERIMENTAL
Monitoring of the course of the reaction and the purity of the compounds obtained was carried out using
TLC on Silufol UV-254 plates in the systems chloroform-methanol (9: 1) and benzene-ethanol (9: 1). IR spectra
1
were recorded on a Pye Unicam SP3-300 instrument for KBr tablets. H NMR spectra were recorded for
DMSO-d6 solutions on a Bruker WP-100 instrument with a working frequency of 100 MHz.
The yields and analytical parameters for compounds 8a-g, 9a-g are given in Table 1 and the
spectroscopic characteristics in Table 2.
The 2-(2-azahetaryl)-4-chloro-3-oxobutyronitriles 1-4 were synthesized by a known method [1, 4].
Hydrazones 5a-g were prepared as reported previously [33, 36-40].
4-(Arylideneamino)-2-(2-benzimidazolyl)-3-oxobutyronitrile (8a-g). N,N-Dimethylaniline (1 ml)
was added to a suspension of the nitrile 1 (1.2 g, 0.005 mol) and the hydrazone 5a-g (0.0055 mol) in n-butanol
(40 ml). The mixture obtained was refluxed for 10-15 h until compound 1 had disappeared on TLC. The
precipitate obtained on cooling the reaction product was filtered off, washed successively with n-butanol, water,
and methanol and then dried in air and recrystallized from the appropriate solvent (see Table 1).
4-(Arylideneamino)-2-(1-methylbenzimidazol-2-yl)-3-oxobutyronitriles (9a-g). N,N-Dimethylaniline
(0.8 ml) was added to a suspension of nitrile 2 (1.0 g, 0.004 mol) and the hydrazone 5a-g (0.0045 mol) in
n-butanol (25 ml) and then worked up as described in the previous method.
Reaction of 2-(1-R-Benzimidazol-2-yl)-4-chloro-3-oxobutyronitriles 1, 2 with Anisaldehyde
Methylhydrazone (10). N,N-Dimethylaniline (1.0 ml) was added to a suspension of the nitrile 1 or 2
(0.005 mol) and the methylhydrazone 10 (0.9 g, 0.0055 mol) in n-butanol (35-40 ml). The reaction mixture was
refluxed for 10-15 h until halo nitriles 1, 2 had disappeared on TLC. The precipitate obtained on cooling the
reaction product was filtered off, washed successively with n-butanol, water, and methanol and then dried and
recrystallized from n-butanol. The nitriles 8a (0.8 g, 46%) or 9a (1.3 g, 75%) obtained were identical to
products synthesized from the nitriles 1, 2 and the hydrazone 5a respectively (no depression in melting point in
either case being found for mixed samples).
882

p
Reaction of 2-(2-Benzimidazolyl)-4-( -methoxybenzylideneamino)-3-oxobutyronitrile 8a with
Hydrazine Hydrate. Hydrazine hydrate (1.2 ml, 0.024 mol) was added rapidly to a hot suspension of the nitrile
8a (2.0 g, 0.006 mol) in dioxane (40 ml). Due to an exothermic reaction a solution was formed which was
refluxed for a further 40 min, cooled, and the white crystals obtained were filtered off, dried, and recrystallized
from dioxane to give 2-amino-3-(2-benzimidazolyl)-4,5-dihydro-4-oxopyrrole 11a (0.8 g, 63%); mp 273°C.
1
Found, %: N 26.32. C11H10N4O. Calculated, %: N 26.15. H NMR spectrum (DMSO-d6), , ppm: 11.50 (1H, s,
δ
NH···O); 8.30 (1H, s, HNH···N); 7.80 (1H, s, HNH···N); 7.44 (2H, m, HBi); 7.01 (2H, m, HBi); 4.83 (1H, s, 1-H);
3.87 (2H, s, CH2).
Treatment of the nitriles 8b-g with hydrazine hydrate under analogous conditions also gave compound
11a. The filtrate after removal of pyrrolone 11a was evaporated to dryness in vacuo. The dry residue was
triturated with water, filtered, and recrystallized from ethanol using carbon to give the hydrazone 5a (0.8 g,
89%) which was identical to an independently prepared sample [36].
p
Reaction of 4-( -Methoxybenzylideneamino)-2-(1-methylbenzimidazol-2-yl)-3-oxobutyronitrile 9a
with Phenylhydrazine. Phenylhydrazine (1 ml, 0.01 mol) was added to a hot suspension of the nitrile 9a (1.7 g,
0.005 mol) in 2-propanol (40 ml) and the mixture was refluxed for 2.5 h. The yellowish-white precipitate
formed on cooling was filtered off, dried in air, and recrystallized from 2-propanol to give 2-amino-3-(1-
methylbenzimidazol-2-yl)-4,5-dihydro-4-oxopyrrole 11b (0.6 g, 53%); mp 261°C. Found, %: N 24.44.
1
C12H12N4O. Calculated, %: N 24.55. H NMR spectrum (DMSO-d6), , ppm: 7.60 (2H, s, NH2); 7.37 (2H, m,
δ
HBi); 7.00 (2H, m, HBi); 4.23 (1H, s, 1-H); 3.96 (3H, s, CH3); 3.74 (2H, s, CH2).
The reaction of the nitriles 9b-g with hydrazine hydrate under similar conditions gave compound 11b.
The filtrate after removal of pyrrolone 11b from the reaction mixture was evaporated to dryness in vacuo. The
dry residue was triturated with methanol (10 ml), filtered, dried, and recrystallized from n-hexane to give
pinkish-white crystals with mp 120°C and these were identified as anisaldehyde phenylhydrazone (lit. mp 122°C
[41]) by comparison with an independently prepared sample.
Reaction of 2-(2-Benzothiazolyl)- and 4-Chloro-3-oxo-2-(2-pyridyl)butyronitriles 3, 4 with
m
N,N-Dimethylaniline (0.8 ml) was added to a suspension of the
-Nitrobenzaldehyde Hydrazone 5d.
halonitrile 3 or 4 (0.004 mol) and the hydrazone 5d (0.75 g, 0.0045 mol) in n-butanol (35 ml). The mixture
obtained was refluxed for 10-15 h until the starting nitrile had disappeared on TLC. The precipitate formed on
cooling was filtered off, washed successively with n-butanol, water, and methanol, dried in air, refluxed with
dioxane (35-40 ml), and filtered while hot. Compounds 13a (0.6 g, 70%, from nitrile 3) or 13b (0.5 g, 79%,
from nitrile 4) were obtained and were identified by comparison with previously synthesized samples [4]. In the
case of nitrile 3, the white crystals formed on cooling the filtrate and after drying in air were identified as
compound 14 (0.5 g, 42%); mp 193°C (lit. mp 194°C [33]).
m
Reaction of 2-(2-Benzimidazolyl)-4-chloro-3-oxobutyronitrile 1 with
-Nitrobenzaldehyde
Hydrazone in the Absence of N,N-Dimethylaniline. A mixture of nitrile 1 (1.2 g, 0.005 mol), hydrazone 5d
(0.85 g, 0.0055 mol), and n-butanol (40 ml) was refluxed for 10-15 h. After the standard work up (see the
synthesis of compounds 13a,b, 14) 2-oxo-3-cyano-1H,4H-pyrrolo[1,2-a]benzimidazole 13c [4] (0.7 g, 71%) and
3,3'-dinitrobenzaldazine 14 (0.5 g) were obtained.
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