Synthesis of N,N′-alkylated tetrahydroquinoxalines by the reaction of 4-bromo-5-nitrophthalonitrile with secondary diamines

Article abstract of DOI:10.1023/A:1019565330611

The reaction of 4-bromo-5-nitrophthalonitrile with aliphatic secondary diamines to give dicyano tetrahydroquinoxalines alkylated on the nitrogen atoms has been investigated for the first time. The latter can be used to prepare imides, phthalocyanines, hex

Full text of DOI:10.1023/A:1019565330611

Chemistry of Heterocyclic Compounds, Vol. 38, No. 5, 2002
SYNTHESIS OF N,N'-ALKYLATED
TETRAHYDROQUINOXALINES BY THE
REACTION OF 4-BROMO-5-NITROPHTHALO-
NITRILE WITH SECONDARY DIAMINES
I. G. Abramov, A. V. Smirnov, M. B. Abramova, S. A. Ivanovskii, and M. S. Belysheva
The reaction of 4-bromo-5-nitrophthalonitrile with aliphatic secondary diamines to give dicyano
tetrahydroquinoxalines alkylated on the nitrogen atoms has been investigated for the first time. The
latter can be used to prepare imides, phthalocyanines, hexazocyclanes, and other compounds
containing isoindoline fragments.
Keywords: bifunctional nucleophiles, 4-bromo-5-nitrophthalonitrile,
nucleophilic substitution.
tetrahydroquinoxaline,
The reaction of haloalkanes and activated nitrohalobenzenes with secondary aliphatic amines has been
described in the literature and is widely used practically. At the same time, the reaction with secondary amines
leading to sequential nucleophilic substitution of the halo and nitro groups in a single benzene ring is almost
unknown. Similar reactions, taking place under rather mild conditions as discussed in this work, become
possible with the use of strongly activated nitroaromatic substrates.
Such a substance is 4-bromo-5-nitrophthalonitrile (BNPN), in which the carbon bearing the
bromine atom is activated by an ortho-nitro group. Two cyano groups add to the accepting effect of the nitro
group on the indicated carbon atom and simultaneously activate the carbon atom bearing the nitro group. As a
result, the SNAr reactions with various O-, N-, and S-nucleophiles primarily substitute the highly mobile
bromine atom [1-3]. When the reaction is carried out with bifunctional nucleophiles which have ortho-placed
reaction centers there are formed the corresponding dicyano containing dibenzo[b,e][1,4]dioxin,
10H-phenoxazine etc. [2].
When refluxed in ethanol in the presence of triethylamine, compound 1 reacts equally readily with
primary aromatic, aliphatic and secondary aliphatic amines to give the corresponding arylamines, e.g. product 2
(Scheme 1). Triethylamine acts as acceptor of the hydrogen bromide evolved. In its absence, the reaction uses
up half of the starting reagent and the remainder is left as the corresponding amine hydrobromide.
The remaining nitro group can be substituted only by reactive nucleophiles under more rigid conditions.
Thus heating compound 2 with 1,3-benzothiazole-2-thiol in DMF in the presence of K2CO3 gives
4-(1,3-benzothiazol-2-ylthio)-5-morpholinophthalonitrile (3). Primary and secondary amines are not active
under these conditions due to the strongly deactivating effect of the morpholine fragment in compound 2.
__________________________________________________________________________________________
Yaroslavl
State
Technical
University,
Yaroslavl
150023,
Russia;
e-mail:
abramov.orgchem@staff.ystu.yar.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5,
pp. 660-664, May, 2002. Original article submitted February 21, 2001.
576
0009-3122/02/3805-0576$27.00©2002 Plenum Publishing Corporation

Scheme 1
KNO2 + K2CO3
N
O
N
O
N
O
O
N
N
N
N
HN
O
+
+
HN
O
N
N
–
–
O
O
Br
N
K2CO3
N
O
4
1
2
N
SH
S
K2CO3
K2CO3
N
N
N
N
N
O
O
N
N
S
S
O
N
N
O
3
N
5
Heating the phthalonitrile 1 in DMF with a twofold molar amount of secondary aliphatic or
cycloaliphatic amine with the aim of sequential substitution of the bromine atom and the nitro group in the
presence of potassium carbonate only bromine atom substitution occurred to give compound 2. Other
substitution products, e.g. the phthalonitrile 4, were not fixed.
The disubstitution product 4 (in 12% yield) was unexpectedly obtained during attempts to substitute the
remaining nitro group in compound 2 by a hydroxy group via the participation of nitrite ion [4]. As of now we
have not been able to explain how, in the presence of a mixture of KNO2 and K2CO3, there occurs the
substitution of the nitro group for the morpholine fragment. In the absence of morpholine, and when carrying
out the indicated reaction with potassium carbonate alone, the symmetrically substituted diphenyloxide 5 is
formed and, in the presence of just potassium nitrite, a tarry product is formed which has not been identified.
The given examples clearly illustrate the difference in mobility of the bromine and nitro group in the
4-bromo-5-nitrophthalonitrile molecule when reacting with N-nucleophiles. At the same time, heating equimolar
amounts of BNPN and secondary aliphatic diamines (alkylated N,N'-ethylenediamines) 6a-d in DMF in the
presence
of
K2CO3
gives
the
previously
unreported
1,4-dibenzyl-1,2,3,4-tetrahydro-6,7-
quinoxalinedicarbonitriles (8a-d) (Scheme 2).
The intermolecular nucleophilic substitution reaction of the halogen atom starts with attack by one of
the amino groups of the nucleophile 6a-d on the carbon atom of compound 1 which directly bears the bromine
atom. The intermediate formed 7a-d contains simultaneously a nitro group and a nucleophilic center quite active
towards further substitution. This second nucleophile then takes part in an intramolecular substitution reaction
of the nitro group situated in the same molecule and this leads to the ring substitution and to the products 8a-d.
It did not prove possible to prepare the tetracarbonitrile 9a by carrying out the indicated reaction with a
twofold molar excess of the BNPN 1. In this case compound 8a was obtained from the reaction mixture in 8%
yield.
577

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
IR spectrum,
Com-
Empirical
formula
1H NMR spectrum, δ, ppm (J, Hz)
Yield, %
94.1
mp, °C
188-190
> 300
Calculated, %
ν, cm-1
pound
С
H
N
C12H10N4O3
55.79
55.81
3.79
3.90
21.61
21.70
2220 (–CN),
8.45 (1H, s); 8.10 (1H, s); 3.75-3.66 (4H, m);
3.32-3.24 (4H, m)
2
3
1350 (NO2),
1115 (C–O–C)
C19H14N4OS2*
60.13
60.30
3.74
3.73
14.81
14.80
2230 (–CN),
8.30 (1H, s); 8.00 (1H, dd, J = 8.09, 2.10);
7.92 (1H, dd, J = 8.00, 1.27); 7.85 (1H, s);
7.55 (td, J = 8.00, 7.37, 1.20); 7.40 (td, J = 8.09,
7.37, 1.27); 3.62-3.55 (4H, m); 3.27-3.20 (4H, m)
68.4
1115 (C–O–C)
C16H18N4O2
C24H20N6O3
64.22
64.41
6.09
6.08
18.70
18.78
184-186
275-277
2235 (–CN),
7.45 (2H, s); 3.76-3.66 (8H, m); 3.25-3.16 (8H, m)
28.7
82.3
4
5
1120 (C–O–C)
65.30
4.59
19.17
2235 (–CN),
7.75 (2H, s); 7.70 (2H, s); 3.60-3.52 (8H, m);
3.26-3.18 (8H, m)
65.45
4.58
19.08
1260 (C–O–C),
1120 (C–O–C)
С24Н20N4
С28Н30N6
78.85
79.09
5.54
5.53
15.36
15.37
172-174
222-224
2230 (–CN)
7.40-7.35 (4H, m); 7.30-7.25 (6H, m); 6.90 (2H, s);
4.65 (4H, s); 3.55 (4H, s)
7.10 (4H, dd, J = 8.43, 2.11); 6.90 (2H, s);
6.70 (4H, dd, J = 8.43, 2.30); 4.50 (4H, s);
3.50 (4H, s); 2.90 (12H, s)
79.7
86.2
8a
8b
74.43
6.72
18.59
2230 (–CN)
74.64
6.71
18.65
С24Н18Сl2N4
С26Н24N4
66.34
66.52
4.20
4.19
12.99
12.93
198-200
189-191
2230 (–CN)
2230 (–CN)
7.30 (4H, dd, J = 8.40, 2.44); 7.10 (4H, dd,
J = 8.40, 2.11); 6.90 (2H, s); 4.68 (4H, s);
3.60 (4H, s)
7.20 (4H, dd, J = 8.05, 2.21); 6.90 (2H, s);
6.78 (4H, dd, J = 8.05, 2.11); 4.55 (4H, s);
3.53 (4H, s); 2.25 (6H, s)
81.5
78.8
8c
79.33
79.56
6.16
6.16
14.29
14.27
8d
_______
* Found: S 16.97%; calculated: S 16.94%.

Scheme 2
Ar
Ar
Ar
N
Ar
Ar
N
N
N
N
HN
HN
N
N
K2CO3
N
H
1
+
:
O
+
–
N
O
Ar
O
8
7
6
1
–
O
.
Ar
+
N
N
Ar
where Ar :
N
N
–
Me
Cl
NMe2
;
O
N
N
N
+
O
;
;
N
d
b
c
a
9
In the reaction under discussion, the use of the less active 4,5-dichlorophthalonitrile in place of the
phthalonitrile 1 gave a mixture of oily products which could also not be identified. The basicity of the starting
diamine must be quite high since the use of phenyl, furyl, or pyridyl substituents in place of the benzyl
substituent in the nucleophiles 6 gave a negative result.
The synthesized dicyano tetrahydroquinoxalines, alkylated at the nitrogen atoms, were put through
further functionalization using known methods and were used for the synthesis of phthalocyanines,
hexazocyclanes, and other compounds which contained imide, isoindoline, and tetrazole fragments. The
prepared nitrile derivatives 2-5 and 8a-d are crystalline materials, the structure of which was confirmed from
their spectroscopic parameters (see Table 1).
Thus, in the IR spectra of these compounds, there are characteristic absorption bands for the stretching
vibrations of the C≡N bond at 2230, ether at 1260, and thioether at 650 cm-1 and the bands typical of NO2
(1560 and 1340 cm-1) and NH (3130-3300 cm-1) were absent [5]. The 1H NMR spectra showed the presence of
signals for the aromatic and the aliphatic protons.
EXPERIMENTAL
1H NMR spectra were obtained on a Bruker AM-300 instrument for 5% solutions of the samples in
DMSO-d6 with TMS as internal standard. IR spectra were recorded on an IR-75 instrument (Czechoslovak
Socialist Republic) for suspensions in vaseline oil.
4-Bromo-5-nitrophthalonitrile (1) was prepared according to the method reported in [1].
4-Morpholino-5-nitrophthalonitrile (2). BNPN (2.52 g, 0.01 mol), morpholine (0.87 g, 0.01 mol),
triethylamine (1.01 g, 0.01 mol), and 2-propanol (50 ml) were placed in a flask fitted with a reflux condenser.
The reaction mixture was refluxed for 2 h, cooled, and the precipitated, orange colored precipitate was filtered
off. Yield 2.43 g.
579

4-(1,3-Benzothiazol-2-ylthio)-5-morpholinophthalonitrile (3). Compound 2 (2.58 g. 0.01 mol),
anhydrous K2CO3 (1.38 g, 0.01 mol), and 2-mercaptobenzothiazole (1.67 g, 0.01 mol) were added successively,
with stirring, to DMF (30 ml). The mixture obtained was stirred vigorously at 130-140°C for 2 h. After cooling
to room temperature, the reaction mass was poured into water (100 ml) and the precipitate formed was filtered
off, washed with water (50 ml), and crystallized from DMF to give compound 3 as a yellow, crystalline powder
(2.59 g).
1,4-Dibenzyl-1,2,3,4-tetrahydro-6,7-quinoxalinedicarbonitrile (8a). N,N'-Dibenyzyl-1,2-ethanediamine
(2.41 g, 0.01 mol), anhydrous K2CO3 (2.8 g, 0.02 mol), and compound 1 (2.52 g, 0.01 mol) were added
successively, with stirring, to DMF (30 ml). The mixture obtained was stirred vigorously at 90-100°C for 2 h.
After cooling to room temperature, the reaction mass was poured into water (100 ml) and the precipitate formed
was filtered off, washed with water (50 ml), and crystallized from DMF to give compound 8a as a light brown,
crystalline powder (2.87 g).
The tetrahydroquinoxalines 8b-d were prepared similarly.
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1.
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3.
I. G. Abramov, M. V. Dorogov, S. A. Ivanovskii, A. V. Smirnov, and M. B. Abramova, Mendeleev
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Geterotsikl. Soedin., 1219 (2000).
I. G. Abramov, V. V. Plakhtinskii, M. B. Abramova, and A. V. Smirnov, Izv. vuzov. Ser. khim. i khim.
tekhnol., 120 (2000).
V. V. Plakhtinskii, V. A. Ustinov, and G. S. Mironov, Izv. vuzov. Ser. khim. i khim. tekhnol., 4 (1985).
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580