Synthesis of N-alkylanilines and substituted quinolines by reaction of aniline with alcohols and CCl4 effected with Ni-containing catalysts

Article abstract of DOI:10.1134/S1070428012050107

Syntheses of N-alkylanilines and 2,3-disubstituted quinolines by the reaction of aniline with CCl₄ and aliphatic alcohols under the action of nickel-containing catalysts, in particular, Ni(OAc)₂· 4H₂O-Et₃N.

Full text of DOI:10.1134/S1070428012050107

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 5, pp. 690−693. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © R.I. Khusnutdinov, A.R. Baygusina, R.I. Aminov, U.M. Dzhemilev, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 5, pp. 679−682.
Synthesis of N-Alkylanilines and Substituted
Quinolines by Reaction of Aniline with Alcohols
and ССl4 Effected with Ni-Containing Catalysts
R. I. Khusnutdinov, A. R. Baygusina, R. I. Aminov, and U. M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, 450075 Russia
е-mail: ink@anrb.ru
Received June 10, 2011
Abstract—Syntheses of N-alkylanilines and 2,3-disubstituted quinolines by the reaction of aniline with CCl4 and
aliphatic alcohols under the action of nickel-containing catalysts, in particular, Ni(OAc)2·4H2О–Et3N.
DOI: 10.1134/S1070428012050107
2,3-Disubstituted quinoline heterocycles are present
in the composition of many highly efficient malaricidal,
anticonvulsant, and antibacterial drugs [1–5].
1:5:100:100:200.
The aniline conversion depended on the reaction
time: After 8 h it attained 40–60%, and after 16 h,
Recently the classic methods of quinolines syntheses
by reactions of Skraup and Döbner–Miller were supple-
mented by catalytic processes underlain by reactions
involving anilines, various organic substrates (alkenes,
alkynes, aldehydes, alkyl- and allylamines) and unsatu-
rated alcohols catalyzed by complexes of Rh, Pd, Pt,
Ru, and Pr [6–13].
Scheme 1.
+ CCl4 + RCH2CH2OH
NH2
_
.
Ni(OAc)2 4H2O Et3N
135_145oC
R
In this study we established that quinolines could be
synthesized by the reaction of aniline with aliphatic alco-
hols in the presence of catalysts containing nickel com-
pounds: NiF2, NiCl2·6H2O, Ni(acac)2, Ni(OAc)2·4H2O,
Ni(NO3)2·6H2O, Ni(BF4)2. The best among them were
nickel(II) acetate Ni(OAc)2·4H2O and acetylacetonate
Ni(acac)2 activated with triethylamine. The aniline
conversion at the use of all other catalyst activated with
Et3N did not exceed 44–48%. We also tested as ligands
formamide, pyridine, 2,2’-dipyridyl, 4,4’-dipyridyl,
acetonitrile, and triphenylphosphine that were less active
than triethylamine.
N
_
H
Iа Ic
R
+
R
N
IIа_IIc
R = H (а), CH3 (b), C2H5 (c).
Yield, %
Reaction con- Aniline con-
ditions
version, %
I
II
60
50
40
75
70
65
29 (а)
26 (b)
24 (c)
9 (а)
12 (b)
16 (c)
24 (а)
20 (b)
14 (c)
50 (а)
41 (b)
35 (c)
8 h
The reaction is of a general character, it proceeds with
ethanol, 1-propanol, and 1-butanol.
16 h
The optimum reaction conditions and the preferred
reagents ratios were selected by an example of aniline
reaction with 1-propanol. The best results were obtained
when performing the reaction at 135–145°С and the
molar ratio catalyst–ligand–aniline–СCl4–C3H7OH
87
78
70
1 (а)
1 (b)
2 (c)
86 (а)
76 (b)
68 (c)
3-stage charge,
140оC, 6 h
690

SYNTHESIS OF N-ALKYLANILINES
691
Scheme 2.
[Ni]
To test this assumption we carried out an experi-
ment replacing 1-propanol for propanal. In this case the
conversion of initial aniline in 8 h at 140°С was by 15%
higher than with 1-propanol and reached 65%, the yield
of 3-methyl-2-ethyl-quinoline (IIb) attained 50%, of
N-пропилaniline, 3%. In the absence of ССl4 the aniline
conversion decreased to 46%, the yield of compound
IIb, to 30%, and the yield of compound Ib grew to
14%. Consequently, the role of CCl4 is not limited to the
participation in the alcohol oxidation to aldehyde, and it
evidently is involved into further reaction of quinoline
synthesis as a specific solvent (Scheme 4).
C3H7OH + CCl4
C2H5CHO
C3H7OCl
_HCl
_CHCl3
65–75%. The reaction products were the corresponding
N-alkylanilines Iа–Ic and 2,3-disubstituted quinolines
IIа–IIc (Scheme 1).
In order to increase the yield of compounds IIа–IIc
we used the addition of reagents (alcohol and CCl4) by
portions with a fresh portions of the catalyst (by 1/3 frac-
tion). The three-stage charging of the reagents made it
possible to raise the selectivity of the reaction with respect
to 2,3-disubstituted quinolines IIа–IIc up to ~98% and
to increase their yield to 68–86%.
As to the side product, N-propylaniline, it may form
along two routes. The first way comprises the aniline
alkylation at the NH2 group by the alcohol under the ac-
tion of the metallocomplex catalyst [15]. The second route
involves the condensation of aniline with propanal to
form Schiff base III which under the reaction conditions
undergoes the hydrogenation with hydrogen liberated in
the stage of pyridine ring formation from intermediate
compound VI.
The reaction did not occur in the absence of CCl4.
In order to elucidate the role of ССl4 in the process we
subjected the reaction mixture to GLC and GC-MS
analysis and found in the reaction mixture chloroform
and propionic aldehyde. The iodometric titration proved
the presence in the reaction mixture of propyl hypochlo-
rite (0.6 mg ml−1). Thus apparently the process started
by 1-propanol oxidation with the help of CCl4 with the
successive formation of first propyl hypochlorite and then
of propionic aldehyde along Scheme 2 [14].
Both routes are possible in our case since the optimum
ratio ROH–CCl4 is 2 : 1, whereas for the formation of
compound IIa through the Schiff base the required ratio
ROH–CCl4 is 1 : 1.
The structure of 3-methyl-2-ethylquinoline (IIb) was
proved with the help of 1D (1Н, 13С) and 2D (COSY,
HSQC, HMBC) NMR spectra. For instance, in the HMBC
experiment the cross-peaks of the protons of the methyl
group at 1.38 ppm (t, 3Н, СН3, J 7 Hz), of the methylene
group at 2.96 ppm (q, 2Н, СН2, J 7 Hz) correlate with the
downfield signal of atom C2 (163.15 ppm) unambiguously
indicating the position of the ethyl group at the atom С2.
In its turn the prtons of the methyl group (δ 2.38 ppm)
In the third stage the aldehyde reacted with aniline
to give Schiff base III, which dimerized in the reaction
conditions (Scheme 3). Dimer IV in its turn suffered
heterocyclization and dehydration converting in the case
of 1-propanol into 3-methyl-2-ethylquinoline (IIb). The
suggested mechanism is analogous to the scheme of
2,3-disubstituted quinolines formation on ruthenium-
containing catalysts [10, 12].
Scheme 3.
Ph
N
HN
CHO
+
_H2O
NH2
N
III
H
IV
H
[Ni]
Ph
Ph
N
N
[Ni]
[Ni]
[Ni]
_PhNH2, _H2
N
N
N
H
VI
H
V
IIb
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

KHUSNUTDINOV et al.
692
Scheme 4.
CСl4
Ib, 3% + IIb, 50%
Ib, 14% + IIb, 30%
Conversion
of aniline 65%
Ni(OAc)2. 4H2O_Et3N
140°C, 8 h
+ C2H5CHO
NH2
Conversion
of aniline 46%
correlate with methane atom C4 (135.63 ppm) confirming
the structure of 3-methyl-2-ethylquinoline.
General procedure. Into an ampule in an argon flow
was charged 1 mmol of Ni(OAc)2·4H2O, 5 mmol of
triethylamine, 100 mmol of aniline, 100 mmol of tet-
rachloromethane, and 200 mmol of alcohol. The sealed
ampule was placed into the pressure reactor, it was tightly
closed and heated for 8–16 h at 135–140°С while con-
tinuous stirring. On the completion of the reaction the
reactor was cooled to room temperature, the ampule was
opened, the reaction mixture was diluted with hydrochlo-
ric acid. The water layer was separated, neutralized with
10% solution of sodium hydroxide, and extracted with
dichloromethane. The extract was filtered, the solvent
was distilled off, the residue was distilled in a vacuum.
Thus in the reaction of aniline with alcohols and CCl4
effected by the catalytic system Ni(OAc)2·4H2O–Et3N we
synthesized N-alkylanilines (alkyl = С2H5, C3H7, C4H9)
and substituted quinolines (2-methylquinoline, 3-methyl-
2-ethylquinoline, 2-propyl-3-ethylquinoline).
EXPERIMENTAL
1Н and 13С NMR spectra were registered on spectrom-
eter BrukerAvance-400 (400.13 and 100.62 MHz respec-
tively) in CDCl3, chemical shifts referred to TMS. Mass
spectra were taken on an instrument Shimadzu GCMS-
QP2010Plus (capillary column SPB-5 30 m × 0.25 mm,
carrier gas helium, ramp from 40 to 300°C at a rate 8deg/
min, vaporizer temperature 280°C, ion source temperature
200°C, ionizing energy 70 eV). Cromatographic analysis
was performed on an instrument Shimadzu GC-9A, GC-
2014 [column 2 m × 3 mm, stationary phase silicone SE-
30 (5%) on Chromaton N-AW-HMDS, ramp from 50 to
270°С at a rate 8deg/min, carrier gas helium (47 ml/min)].
N-Ethylaniline (Iа). Yield 29%. Light-yellow liquid
oily substance, bp 72–73°С (10 mm Hg) {bp 91–92°С
(24 mm Hg) [16]}. nD20 1.550 ( nD20 1.554 [17]).
N-Propylaniline (Ib). Yield 26%. Yellow oily fluid,
bp 96°С (10 mm Hg) {bp 98.5–100°С (11 mm Hg) [16]},
nD20 1.552 (nD20 1.549 [18]).
N-Butylaniline (Ic). Yield 24%. Yellow oily fluid,
bp 112–113°С (10 mm Hg) {bp 124–126°C (25 mm Hg)
[16]}, nD20 1.534 (nD20 1.532 [17]).
Elemental analysis of samples was carried out on an
analyzer Karlo Erba 1106.
2-Methylquinoline (IIa). Yield 86%. Yellow oily
fluid, bp 80–81°С (2 mm Hg) {bp 105–107°С (10 mm Hg)
As initial reagents were used commercial aniline,
ethanol, 1-propanol, 1-butanol, tetrachloromethane that
were preliminary distilled.
1
[17]}, nD20 1.609 (nD20 1.612 [17]). H NMR spectrum, δ,
ppm: 2.78 s (3H, CH3), 7.22 d (1H, С3H, J 8 Hz), 7.68 t
(1H, С7H, J 4 Hz), 7.46 t (1H, С6H, J 6.4 Hz), 7.73 d
(1H, С5H, J 9.2 Hz), 7.91 d (1H, С4H, J 9.2 Hz), 7.91 d
(1H, С8H, J 9.2 Hz). 13С NMR spectrum, δ, ppm: 25.12
(СН3), 121.74 (C3), 125.45 (C6), 126.32 (C4а), 127.37
(C5), 128.80 (C8), 129.19 (C7), 135.84 (C4), 147.76 (C8a),
158.67 (C2). Mass spectrum, m/z (Irel, %): 143.18 [M]+
(100), 128 (20), 115 (22), 101 (5), 89 (4), 75 (5), 51 (4).
Nickel-containing catalysts [NiF2, NiCl2·6H2O,
Ni(acac)2, Ni(OAc)2·4H2O, Ni(NO3)2·6H2O, Ni(BF4)2],
ligands (formamide, pyridine, 2,2'-dipyridyl, 4,4'-dipyridyl,
acetonitrile, triphenylphosphine, triethylamine) were
commercial products.
The reactions were performed in a glass ampule of
10 ml capacity placed in a small pressure reactor from
stainless steel of 17 ml capacity at the constant stirring
and controlled heating.
3-Methyl-2-ethylquinoline (IIb). Yield 76%.
Yellow oily fluid, bp 97–99°С (2 mm Hg) {bp 73–83°С
(0.57 mm Hg) [18], 84–85°С (0.35 mm Hg) [18]},
1
nD20 1.600 (nD20 1.598 [19]). H NMR spectrum, δ, ppm:
N-Alkylanilines and 2,3-disubstituted quinolines.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 5 2012

SYNTHESIS OF N-ALKYLANILINES
693
4. Dube, D., Blouin, M., Brideau, C., Chan, C.-C., Des-
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1.38 t (3H, CH3, 7 Hz), 2.38 s (3Н, CH3), 2.96 q (2Н,
J
CH2, J 7 Hz), 7.40 t (1H, С7H, J 8 Hz), 7.58 t (1H, С6H,
J 8 Hz), 7.62 d (1H, С5H, J 8 Hz), 7.70 s (1H, С4H,
J 7 Hz), 8.06 d (1H, С8H, J 8 Hz). 13С NMR spectrum, δ,
ppm: 12.79 (СH2CH3), 18.57 (СН3), 29.43 (CH2), 125.55
(C7), 126.70 (C5), 127.31 (C4а), 128.24 (C6), 128.53 (C8),
129.32 (C3), 135.63 (C4), 146.68 (C8a), 163.15 (C2). Mass
spectrum: m/z 171.23 [M]+.
2-Propyl-3-ethylquinoline (IIc). Yield 68%.
Yellow oily fluid, bp 99–100°С (0.5 mm Hg)
{bp 92°С (0.3 mm Hg) [20], 118°C (1 mm Hg) [21]},
7. Cho, C.S., Oh, B.H., and Shim, S.C., Tetrahedron Lett.,
1999, vol. 40, p. 1499.
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1
nD20 1.576 (nD20 1.579 [22]). H NMR spectrum, δ, ppm:
9. Anguille, S., Brunet, J.-J., Chu, N.C., Diallo, O., Pages, C.,
and Vincendeau, S., Organometallics, 2006, vol. 25,
p. 2943.
10. Cho, C.S., Kim, J.Ss., Oh, B.H., Kim, T.-J., Shim, S.C.,
and Yoon, N.S., Tetrahedron, 2000, vol. 56, p. 7747.
11. Brunet, J.-J., Chu, N.C., Diallo, O., and Vincendeau, S.,
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0.97 t (3H, CH3, J 7.2 Hz), 1.11 t (3H, CH3, J 7.2 Hz),
1.80–1.90 m (2H, CH2CH2CH3), 2.82 q (2Н, СH2CH3,
J 7.2 Hz), 2.99 t (2Н, CH2CH2CH3, J 8 Hz), 7.44 t (1H,
С7H, J 7.6 Hz), 7.62 t (1H, С6H, J 7.2 Hz), 7.72 d (1H,
С5H, J 7.6 Hz), 7.84 s (1H, С4H), 8.08 d (1H, С8H,
J 8 Hz). 13С NMR spectrum, δ, ppm: 14.39 [(СH2)2CH3],
14.46 (СH2CH3), 22.88 (СH2СH2CH3), 25.16 (СH2CH3),
37.75 (СH2СH2CH3), 125.57 (C7), 126.94 (C5), 127.50
(C4а), 128.35 (C8), 128.44 (C6), 129.21 (C4), 133.88
(C3), 146.44 (C8a), 162.04 (C2). Mass spectrum:
m/z 199.28 [M]+.
13. Selimov, F.A., Dzhemilev, U.M., and Ptashko, O.A., Metal-
lokompleksnyi kataliz v sinteze piridinovykh osnovanii,
Moscow: Khimiya, 2003, p. 303.
14. Khusnutdinov, R.I., Shchadneva, N.A., Bayguzina, A.R.,
Lavrent’e-va, Yu.Yu., and Dzhemilev, U.M., Izv. Akad.
Nauk, Ser. Khim., 2002, p. 1919.
ACKNOWLEDGMENT
15. Watanabe, Y., Tsuji, Y., and Ohsugi, Y., Tetrahedron Lett.,
1981, vol. 22, p. 2667.
16. Rice, R.G. and Kohn, E.J., J. Am. Chem. Soc., 1955, vol. 77,
p. 4052.
The study was carried out under a financial sup-
port of the Russian Foundation for Basic Research
(grants nos. 09-03-00472, 12-03-00183).
17. Aldrich. Catalog Handbook of Fine Chemicals, 2007–2008,
p. 2864.
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