Regular trends in nucleophilic substitutions in 2-alkylamino-4- chloronitrobenzenes

Article abstract of DOI:10.1007/s11178-005-0146-6

The effect of substituents in position 2 on the reactivity of 2-alkylamino-4-chloronitrobenzenes in nucleophilic substitution by N-nucleophiles of various character was studied. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0146-6

Russian Journal of Organic Chemistry, Vol. 41, No. 2, 2005, pp. 214-217. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 2, 2005,
pp. 224-227.
Original Russian Text Copyright Ó 2005 by Zotova, Kushakova, Kuznetsov, Rodin, Garabadzhiu.
Regular Trends in Nucleophilic Substitutions
in 2-Alkylamino-4-chloronitrobenzenes
N.V. Zotova, P.M. Kushakova, V.A. Kuznetsov,A.A. Rodin, andA.V. Garabadzhiu
St. Petersburg State Technological Institute, St. Petersburg, 198013 Russia
e-mail: gar@sitecs. spb.ru
Received March 10, 2004
Abstract—The effect of substituents in position 2 on the reactivity of 2-alkylamino-4-chloronitrobenzenes in
nucleophilic substitution by N-nucleophiles of various character was studied.
It is known that the replacement of an amino for nitro
group in the 2 position of 1,2-dinitro-4-chlorobenzene (I)
results in a sharp decrease in chlorine mobility in
nucleophilic substitutions. However publications on
studies of reactivity of the arising aromatic systems are
virtually lacking. Only some descriptions of preparation
procedures for specific compounds were reported [1, 2].
abnormal substitution product strongly depended on the
nucleophile character: The more sterically hindered and
the less basic was the nucleophilic agent, the larger was
the yield of abnormal substitution product. It should be
noted that apart from the reduction of the target product
yield due to formation of abnormal substitution products
a partial tarring also occurred. Therefore the yields of
the target products after purification by crystallization
did not exceed 40%.
The scanty published data demonstrate that the
nucleophilic substitution in aromatic systems with
a halogen of reduced mobility is as a rule performed in
solvents characterized by a high boiling point and a low
dielectric constant, like DMSO, DMF, and HMPA. The
presence of a catalyst is also necessary, and the most
common catalyst is a copper(II) salt. Note that the yields
of the target substitution products in these processes vary
in a wide range (from 20 to 90%) and depend on the
mobility of the halogen in the initial substrate, on the
nucleophile character, and on reaction conditions.
5
&O
5
1X
1X
2 1
2 1
B
B
B
B
,, ꢀꢀ,,Xꢀꢀ9 ꢀꢀ9X
, ꢀꢀꢀ,X
I–V, R = MeNH (a), EtNH (b), i-BuNH (c), t-BuCH2NH (d),
Ph(CH2)2NH (e), Me(Ph)CHNH (f), cyclopropylamino (g),
BnNH(h), HO(CH2)2NH (i), HO(CH2)3NH (j),
HOCH2(NH)CHCH3 (k),AllNH (l), (2-furylmethyl)amino
(m), pyrrolidino (n), piperidino (o), morpholino (p),
N-methylpiperazino (q), N-phenylpiperazino (r),
N-benzylpiperazino (s), (3-pyridylmethyl)amino (t),
azacycloheptane (u); Nu: pyrrolidino (IIa–IIu), piperidino
(IIIa, IIIe–IIIk, IIIm, IIIo, IIIu), morpholino(IVa, IVb, IVd–
IVk, IVm–IVp, IVq, IVr, IVu), N-methylpiperazino (Va,
Vb, Ve–Vk, Vm–Vp, Vu).
We made an attempt to investigate the effect exerted
by substituents in position 2 on the reactivity of (alkyl-
amino)chloronitrobenzenes Ia–Iu in the nucleophilic
substitution by various N-nucleophiles.
It turned out in the course of the study that the reaction
of alkylaminochloronitrobenzenes Ia–Iu with N-nucleo-
philes in DMSO resulted in strong tarring. At the use as
solvents of DMF and HMPA the target products of the
chlorine substitution by the nucleophile were obtained
alongside the products of an abnormal substitution of the
chlorine by a dimethylamino group. We already mentioned
formerly the similar behavior of DMF and HMPA in the
nucleophilic substitution [3]. We concluded from
observations during this research that the amount of
To avoid the above mentioned complications we
carried out the reactions between alkylaminochloronitro-
benzenes Ia–Iu and N-nucleophiles in the medium of
the nucleophile itself. The application of the latter as
solvent significantly reduced the side products formation
and increased the yield of the target compounds. However
this procedure is limited to a large extent by the boiling
point of the nucleophile and by its nature. It turned out
1070-4280/05/4102-0214Ó2005 Pleiades Publishing, Inc.

REGULAR TRENDS IN NUCLEOPHILIC SUBSTITUTIONS
215
that secondary aliphatic amines did not react with
(alkylamino)chloronitrobenzenes Ia–Iu, and primary
aliphatic amines reacted very slowly. Even at prolonged
heating in amines (up to 20 h) the conversion did not
exceed 50%. Besides we found that the reaction of
compounds Ia–u with the primary aliphatic amines started
at the reaction mixture temperature over 120°C, whereas
the prolonged heating resulted in the tarring of the reaction
mixture.
chloroform–hexane, 2:1 by volume; chloroform–methanol,
9:1 by volume; hexane–acetone–ethyl ether, 5:2:1 by
volume; chloroform–methanol–ammonia 9:1:0.5 by
volume.
N-Methyl-2-nitro-5-pyrrolidinoaniline (IIa).
A solution of 2.0 g (10.7 mmol) of chloroaniline (Ia) in
10 ml of pyrrolidine was boiled for 45 min. On completion
of reaction the mixture was poured into water. The
separated precipitate was filtered off, washed with water,
and recrystallized from a mixture dichloromethane–
methanol, 1:2 by volume, yield 2.3 g (92%), mp 205–
Good results were obtained in reactions of (alkyl-
amino)chloronitrobenzenes Ia–Iu with secondary alicyclic
amines. The process carried out in the amine afforded
the target products in 60–90% yields. We established that
the yields of target products depend on the character of
the alicyclic amine and on the nature of the substituent in
the position 2 of alkylaminochloronitrobenzenes Ia–Iu.
The most readily the substitution occurred with pyrrolidine,
the least easily with morpholine. It should be noted that
pyrrolidine present as substituent in the position 2 of the
substrate exerts the strongest deactivating effect on the
chlorine atom. For instance, to attain the 100% conversion
in the reaction of morpholinochloronitrobenzene (Ip) with
pyrrolidine the reaction mixture should be boiled for 40
min, whereas the 100% conversion in the reaction of
pyrrolidinochloronitrobenzene (In) was reached only after
4 h of boiling.
1
207°C. H NMR spectrum, d, ppm.: 1.99 t (4H, 2CH2),
2.90 d (3H, CH3), 3.38 t (4H, 2CH2N), 5.49 s (1H,
CHNH), 6.03 d (1H, CHN), 7.87 d (1H, CHNO2), 8.32 s
(1H, NH). Found: M+ 220. C11H15N3O2. Calculated:
M 221.261.
Likewise were obtained compounds IIb–IIu.
2-(2-Nitro-5-pyrrolidin-1-ylanilino)-1-ethanol
1
(IIi). Yield 2.4 g (90%), mp 219–221°C. H NMR
spectrum, d, ppm: 2.02 t (4H, 2CH2), 3.32 d (2H,
CH2NH), 3.40 t (4H, 2CH2N), 3.68 m (2H, CH2OH),
4.82sC (1H, OH), 5.58 s (1H, CHNH), 6.02 d (1H, CHN),
7.88 d (1H, CHNO2), 8.49 s (1H, NH). Found: M+ 251.
C12H17N3O3. Calculated: M 251.268.
2-(2-Nitro-5-pyrrolidin-1-ylanilinomethyl)furan
1
(IIm). Yield 2.5 g (80%), mp 173–175°C. H NMR
Thus we established that at performing the nucleophilic
substitution in chloronitrobenzenes Ia–Iu the use of
DMSO, DMF, and HMPA as solvents was unsuitable
for it led to the formation of a lot of side products.
Therefore the process should be carried out in the medium
of the nucleophile proper. Among the N-nucleophiles
tested the most reactive toward chloronitrobenzenes Ia–
Iu were the secondary alicyclic amines, the secondary
aliphatic amines did not enter into the reaction, and the
primary aliphatic amines reacted very slowly even at
prolonged boiling.
spectrum, d, ppm: 1.99 t (4H, 2CH2), 3.55 t (4H, 2CH2N),
4.52 d (2H, CH2NH), 5.69 s (1H, CHNH), 6.08 d (1H,
CHN), 6.37 s (2H, 2CH), 7.54 s (1H, CHO), 7.89 d (1H,
CHNO2), 8.65 s (1H, NH). Found: M+ 286. C15H17N3O3.
Calculated: M 287.321.
4-(2-Nitro-5-pyrrolidinophenyl)piperidyl (IIo).
1
Yield 2.5 g (85%), mp 165–167°C. H NMR spectrum,
d, ppm: 2.05 t (4H, 2CH2), 3.02 t (4H, 2CH2), 3.37 t (4H,
2CH2N), 3.83 t (4H, 2CH2O), 5.90 d (1H, CHN), 6.11 d
(1H, NCHN), 8.03 d (1H, CHNO2). Found: M+ 277.
C14H19N3O3. Calculated: M 277.326.
EXPERIMENTAL
1-(2-Nitro-5-pyrrolidinophenyl)-4-phenylpiper-
azine (IIr). Yield 3.0 g (80%), mp 165–167°C. 1H NMR
spectrum, d, ppm: 1.99 t (4H, 2CH2), 3.15 s (4H, 2CH2),
3.27 t (4H, 2CH2N), 3.38 C (4H, 2CH2), 6.05 s (1H,
NCHN), 6.23 d (1H, CHN), 6.79 t (1H, CH), 6.98 d (1H,
CH), 7.23 t (1H, CH), 7.98 d (1H, CHNO2). Found: M+
352. C20H24N4O2. Calculated: M 352.439.
1H NMR spectra were registered on a spectrometer
Bruker DPX-200, solvents DMSO-d6 or deutero-
chloroform, as internal reference served the residual
proton signals of the solvents.
Elemental composition of compounds was determined
from their high resolution mass spectra measured on
Varian MAT-311A instrument, gas xenon, accelerating
voltage 2–6 kV, current 0.1–0.5 mA, resolution 30000.
1-(2-Nitro-5-pyrrolidinophenyl)azacycloheptane
1
(IIu). Yield 2.7 g (85%), mp 170–172°C. H NMR
spectrum, d, ppm: 1.94 t (4H, 2CH2), 3.26 t (4H, 2CH2N),
4.61 d (2H, CH2NH), 5.52 s (1H, CHN), 6.02 d (1H,
The reaction progress was monitored by TLC on
Silufol UV-254 plates using the following eluents:
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216
ZOTOVA et al.
CH), 7.34 t (1H, CH), 7.76 d (1H, CH), 7.89 d (1H,
CHNO2), 8.44 d (1H, CHN), 8.60 s (1H, NCH), 8.88
C (1H, NH). Found: M+ 298. C16H18N4O2. Calculated:
M 298.347.
Likewise were obtained compounds IVb, IVd–IVk,
IVm–IVp, IVq, IVr, IVu.
1-(5-Morpholino-2-nitroanilino)-2-propanol
1
(IVk). Yield 1.7 g (70%), mp 156–158°C. H NMR
N-Methyl-2-nitro-5-piperidinoaniline (IIIa).
A solution of 1.4 g (7.6 mmol) of chloroaniline (Ia) in
15 ml of piperidine was boiled for 1.5 h, and then the
reaction mixture was poured into water. The separated
precipitate was filtered off, washed with water, and
recrystallized from ethanol, yield 1.5 g (82%), mp 103–
spectrum, d, ppm: 1.32 d (3H, CH3), 1.99 d (1H, OH),
3.31 m (6H, 2CH2N+CH2NH), 3.84 t (4H, 2CH2O),
4.15 m (1H, CHOH), 5.95 s (1H, CHNH), 6.21 d (1H,
CHN), 8.07 d (1H, CHNO2), 8.58 s (1H, NH). Found:
M+ 281. C13H19N3O4. Calculated: M 281.314.
4-(2-Nitro-5-pyrrolidinophenyl)morpholine
1
105°C. H NMR spectrum, d, ppm: 1.63 s (6H, 3CH2),
1
(IVn). Yield 1.4 g (58%), mp 115–117°C. H NMR
2.95 d (3H, CH3), 3.44 t (4H, 2CH2N), 5.88 s (1H,
CHNH), 6.32 d (1H, CHN), 7.87 d (1H, CHNO2), 8.28 s
(1H, NH). Found: M+ 235. C12H17N3O2. Calculated:
M 235.288.
spectrum, d, ppm: 1.98 t (4H, 2CH2), 3.22 m (8H,
4CH2N), 3.83 t (2H, 2CH2O), 6.09 s (1H, NCHN),
6.24 d (1H, CHN), 7.79 d (1H, CHNO2). Found: M+ 277.
C14H19N3O3. Calculated: M 277.326.
Likewise were obtained compounds IIIe–IIIk, IIIm,
IIIo, IIIu.
4-[4-Nitro-3-(4-phenylpiperazino)phenyl]-
morpholine (IVr). Yield 2.2 g (68%), mp 180–182°C.
1H NMR spectrum, d, ppm: 3.18 s (4H, 2CH2N), 3.36 m
(8H, 4CH2N), 3.75 s (2H, 2CH2O), 6.47 s (1H, NCHN),
6.57 d (1H, CHN), 6.79 t (1H, CH), 6.96 d (1H, CH),
7.22 t (1H, CH), 7.92 d (1H, CHNO2). Found: M+ 368.
C20H24N4O3. Calculated: M 368.439.
N-(1-Phenylethyl)-2-nitro-5-piperidinoaniline
1
(IIIe). Yield 1.8 g (74%), mp 108–110°C. H NMR
spectrum, d, ppm: 1.42 s (6H, 3CH2), 1.55 d (3H, CH3),
3.24 d (4H, 2CH2N), 4.78 m (1H, CHCH3), 5.73 s (1H,
CHNH), 6.28 d (1H, CHN), 7.31 m (5H, C6H5), 7.86 d
(1H, CHNO2), 8.65 s (1H, NH). Found: M+ 325.
C19H23N3O2. Calculated: M 325.414.
1-(5-Morpholino-2-nitrophenyl)azacycloheptane
1
(IVu). Yield 1.8 g (65%), mp 203–205°C. H NMR
spectrum, d, ppm: 3.28 t (4H, 2CH2N), 3.67 t (4H,
2CH2O), 4.64 d (2H, CH2NH), 5.96 s (1H, CHNH),
6.33 d (1H, CHN), 7.32 t (1H, CH), 7.76 d (1H, CH),
7.92 d (1H, CHNO2), 8.46 d (1H, CHN), 8.62 s (1H,
NCH), 8.80 s (1H, NH). Found: M+ 314. C16H18N4O3.
Calculated: M 314.347.
2-(2-Nitro-5-piperidinoanilino)-1-ethanol (IIIi).
Yield 1.4 g (68%), mp 116–118°C. H NMR spectrum,
1
d, ppm: 1.64 s (6H, 3CH2), 3.35 d (2H, CH2NH), 3.44 s
(4H, 2CH2N), 3.67 d (2H, CH2OH), 4.83 s (1H, OH),
5.94 s (1H, CHNH), 6.28 d (1H, CHN), 7.87 d (1H,
CHNO2), 8.48 s (1H, NH). Found: M+ 265. C13H19N3O3.
Calculated: M 265.315.
N-Methyl-5-(4-methylpiperazino)-2-nitroaniline
(Va). Asolution of 1.7 g (9.2 mmol) of chloroaniline (Ia)
in 15 ml of N-methylpiperazine was boiled for 4 h, then
the reaction mixture was poured in water. The separated
precipitate was filtered off, washed with water, and
recrystallized from dichloromethane–hexane, 1:1 by
volume, yield 1.8 g (80%), mp 81–83°C. 1H NMR
spectrum, d, ppm: 2.22 s (3H, NCH3), 2.41 t (4H,
2CH2NCH3), 2.92 d (3H, CH3), 3.40 t (4H, 2CH2N),
5.91 s (1H, CHNH), 6.35 d (1H, CHN), 7.87 d (1H,
CHNO2), 8.32 s (1H, NH). Found: M+ 250. C12H18N4O2.
Calculated: M 250.303.
4-(2-Nitro-5-piperidinophenyl)piperidine (IIIo).
1
Yield 1.7 g (75%), mp 80–82°C. H NMR spectrum, d,
ppm: 1.67 s (6H, 3CH2), 3.03 s (4H, 2CH2N), 3.36 s
(4H, 2CH2), 3.85 s (4H, 2CH2O), 6.26 s (1H, NCHN),
6.40 d (1H, CHN), 7.98 d (1H, CHNO2). Found: M+
291. C15H21N3O3. Calculated: M 291.353.
N-Methyl-5-morpholino-2-nitroaniline (IVa).
A solution of 1.6 g (8.8 mmol) of chloroaniline (Ia) in
20 ml of morpholine was boiled for 7 h, then the reaction
mixture was poured in water. The separated precipitate
was filtered off, washed with water, and recrystallized
from a mixture hexane–chloroform, 2:3 by volume, yield
1.5 g (74%), mp 187–188°C. 1H, d, ppm: 2.03 s (3H,
CH3), 3.38 s (4H, 2CH2N), 3.72 s (4H, 2CH2O), 5.93 s
(1H, CHNH), 6.35 d (1H, CHN), 7.89 d (1H, CHNO2),
8.31 s (1H, NH). Found: M+ 237. C11H15N3O3.
Calculated: M 237.260.
Likewise were obtained compounds Vb, Ve–Vk, Vm–
Vp, Vu.
N-(1-Phenylethyl)-5-(4-methylpiperazino)-2-
nitroaniline (Vf). Yield 2.1 g (68%), mp 154–156°C.
1H NMR spectrum, d, ppm: 1.57 d (3H, CH3), 2.17 s
(3H, NCH3), 2.29 s (4H, 2CH2N), 3.23 m (4H, 2CH2N),
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REGULAR TRENDS IN NUCLEOPHILIC SUBSTITUTIONS
217
1H NMR spectrum, d, ppm: 1.96 t (4H, 2CH2), 2.32 s
(3H, NCH3), 2.51 t (4H, 2CH2N), 3.21 t (4H, 2CH2N),
3.31 t (4H, 2CH2N), 6.09 s (1H, NCHN), 6.25 d (1H,
CHN), 7.78 d (1H, CHNO2). Found: M+ 290.
C15H22N4O2. Calculated: M 290.368.
4.83 m (1H, CHCH3), 5.81 C (1H, CHNH), 6.33 d (1H,
CHN), 7.32 m (5H, C6H5), 7.88 d (1H, CHNO2), 8.63 s
(1H, NH). Found: M+ 340. C19H24N4O2. Calculated:
M 340.429.
N-Cyclopropyl-5-(4-methylpiperazino)-2-nitro-
aniline (Vg). Yield 1.6 g (62%), mp 102–104°C. 1H NMR
spectrum, d, ppm: 0.63 d (2H, CH2), 0.84 d (2H, CH2),
2.32 s (3H, NCH3), 2.51 t (5H, 2CH2N+CHNH), 3.39 t
(4H, 2CH2N), 6.20 d (1H, CHN), 6.34 s (1H, CHNH),
7.99 d (1H, CHNO2), 8.34 s (1H, NH). Found: M+ 276.
C14H20N4O2. Calculated: M 276.341.
1-[5-(4-Methylpiperazino)-2-nitrophenyl]-
azacycloheptane (Vu). Yield 2.2 g (75%), mp 140–
142°C. 1H NMR spectrum, d, ppm: 2.19 s (3H, NCH3),
2.34 s (4H, 2CH2N), 3.32 s (4H, 2CH2N), 4.62 d (2H,
CH2NH), 5.94 s (1H, CHNH), 6.36 d (1H, CHN), 7.34 t
(1H, CH), 7.76 d (1H, CH), 7.90 d (1H, CHNO2), 8.47 d
(1H, CHN), 8.63 s (1H, NCH), 8.82 s (1H, NH). Found:
M+ 327. C17H21N5O2. Calculated: M 327.389.
2-[5-(4-Methylpiperazino)-2-nitroanilino-
methyl]furan (Vm). Yield 1.9 g (68%), mp 125–127°C.
1H NMR spectrum, d, ppm: 2.22 s (3H, NCH3), 2.40 t
(4H, 2CH2N), 3.40 t (4H, 2CH2N), 4.59 d (2H, CH2NH),
6.11 s (1H, CHNH), 6.39 s (2H, CH+CHN), 7.56 s (1H,
CHO), 7.89 d (1H, CHNO2), 8.60 s (1H, NH). Found:
M+ 316. C16H20N4O3. Calculated: M 316.363.
REFERENCES
1. Fuson, R. C., Bauman, R.A., Howard, E.,and Marvell, E. N.,
J. Org. Chem., 1947, vol. 12, p. 799.
2. Loeve, H. and Urbanietz, J., Arzneim.-Forsch., 1974, vol. 24,
p. 1927.
1-Methyl-4-(4-nitro-3-pyrrolidinophenyl)-
piperazine (Vn). Yield 1.4 g (52%), mp 135–137°C.
3. Kuznetsov, V.A., Garabadzhiu,A.V., and Ginzburg, O. F., Zh.
Org. Khim., 1986, vol. 22, p. 455.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 2 2005