Synthesis of substituted quinolines by the reaction of anilines with alcohols and CCl4 in the presence of Fe-containing catalysts

Article abstract of DOI:10.1007/s11172-013-0019-z

Substituted quinolines were synthesized by the reaction of aniline derivatives with aliphatic alcohols and CCl₄ upon the action of the FeCl₃·6H₂O catalyst.

Full text of DOI:10.1007/s11172-013-0019-z

Russian Chemical Bulletin, International Edition, Vol. 62, No. 1, pp. 133—137, January, 2013
133
Synthesis of substituted quinolines by the reaction of anilines with alcohols
and CCl4 in the presence of Feꢀcontaining catalysts
R. I. Khusnutdinov, A. R. Bayguzina, and R. I. Aminov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347) 284 2750. Eꢀmail: ink@anrb.ru
Substituted quinolines were synthesized by the reaction of aniline derivatives with aliphatic
alcohols and CCl4 upon the action of the FeCl3•6H2O catalyst.
Key words: metal complex catalysis, ironꢀcontaining compounds, anilines, quinolines, alkyl
hypochlorite, oxidation, heterocyclization, Schiff bases.
Quinoline and its derivatives are widely used in pracꢀ
tice for the preparation of inhibitors of metal acid corroꢀ
sion, extragents, sorbents, and cyanine dyes. Highly effiꢀ
cient antimalaria, antispasmodic, and antibacterial meꢀ
dicinal drugs were developed based on quinoline derivaꢀ
tives.1—5
In the last years, metal complex catalysts became freꢀ
quently used in the synthesis of substituted quinolines.
Complexes of such metals as Ru, Pt, Pd, Ir, Ln, and Fe
catalyze reactions of available anilines with aldehydes and
allylamines leading to quinolines.6—14
the best result. The optimal conditions for the process were
found experimentally. The reaction was effected by a twoꢀ
stage loading of the starting reagents with the molar ratio
[Cat] : [XC6H4NH2] : [CCl4] : [ROH] = 1 : 50 : 100 : 200
(Cat is the catalyst) in CCl4 at 140 C for 4 h (Scheme 1).
The structures of compounds obtained were confirmed by
NMR spectroscopy and GLCꢀMS spectrometry and
agreed with the literature data. The results are summaꢀ
rized in Table 1.
Scheme 1
Results and Discussion
In the present work, a goal was set to synthesize
tri(tetra)substituted quinolines from substituted anilines
according to the original procedure successfully tested by
us for aniline. According to the results of this study,
a quinoline molecule was formed by the conjugate reacꢀ
tion involving aniline, CCl4, and aliphatic alcohol assisted
by a metal complex catalyst. A mechanism suggested for
this reaction includes an oxidation step of the alcohol with
CCl4 and sequential formation of alkyl hypochlorite and
then aldehyde. In the following step, the aldehyde reacts
with aniline, giving a Schiff base, which dimerizes under
the reaction conditions. The dimer, in turn, undergoes
heterocyclization and dehydrogenation, giving rise to subꢀ
stituted quinoline.15
We found that the reaction of substituted anilines 1—10
(XC6H4NH2, where X = H, o(m,p)ꢀMe, oꢀEt, pꢀOMe,
o(m,p)ꢀCl, 3,4ꢀCl2) with alcohols ROH (R = Et, Prn,
Bun) in the presence of an ironꢀcontaining catalyst resulted
in substituted quinolines 11—23. The reaction takes place
in the presence of the following catalysts based on iron
compounds: FeCl3•6H2O, FeCl3, FeCl2•4H2O, Fe(C5H5)2,
Fe(acac)3, Fe(OAc)2, Fe2(CO)9, with FeCl3•6H2O showing
R = Et, Prn, Bun; R´ = H (a), Me (b), Et (c); X = H (1, 11),
oꢀMe (2, 12), mꢀMe (3, 13, 14), pꢀMe (4, 15), оꢀEt (5, 16),
оꢀCl (6, 17), mꢀCl (7, 18, 19), pꢀCl (8, 20), pꢀOMe (9, 21),
3,4ꢀCl (10, 22, 23)
2
It should be noted that the high yields of substituted
quinolines were observed for the paraꢀsubstituted anilines
(methylꢀ, methoxyꢀ, chloroꢀsubstituted), that can be exꢀ
plained by steric factors. oꢀ, mꢀ, pꢀAminophenols, oꢀ,
mꢀmethoxyanilines, oꢀnitroaniline, 2ꢀaminoꢀ, 4ꢀaminoꢀ
benzoic, 4ꢀaminoꢀ, 5ꢀaminosalicylic acids did not give
the reaction, that can be explained by the deactivation of
the catalyst resulted from its reaction with the functional
group of the anilines indicated. We found that an increase
in the length of the alkyl chain in alcohols resulted in the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0134—0138, January, 2013.
1066ꢀ5285/13/6201ꢀ133 © 2013 Springer Science+Business Media, Inc.

134
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Khusnutdinov et al.

Synthesis of substituted quinolines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
135
Table 1. Results of the synthesis of substituted quinolines 11—23 by the reaction of anilines 1—10 with alcohols ROH with R = Et, Prn,
Bun upon the action of FeCl3•6H2O (conditions: 140 C, 4 h, CCl4, twoꢀstage loading of reagents)
X
Quinoline (yield (%))
Reference
X
Quinoline (yield (%))
Reference
Et
Prn
Bun
Et
Prn
Bun
mꢀCl
pꢀCl
18a (11), 18b (12), 18c (15),
19a (67) 19b (65) 19c (70)
20a (70) 20b (82) 20c (89)
6, 11
H
oꢀMe
11a (94) 11b (87) 11c (81)
12a (85) 12b (76) 12c (64)
7—10, 13—15
6, 7, 9, 10, 11,
13, 14
6, 7, 9, 10, 11
6, 7, 9, 10, 11,
12, 13, 14
pꢀOMe 21a (94) 21b (91) 21c (83)
mꢀMe
13a (90) 13b (70), 13c (68), 6, 7, 9, 11, 14
14b (12) 14c (13)
3,4ꢀCl2 22a (47), 22b (41), 22c (42),
23a (45) 23b (29) 23c (23)
19 (for 23а)
pꢀMe
oꢀEt
oꢀCl
15a (94) 15b (91) 15c (82)
16a (92) 16b (80) 16c (65)
17a (64) 17b (70) 17c (72)
6, 7, 9, 10, 11, 14
9, 16
17, 18
Fig. 1. NMR spectroscopic data for compounds 22a—c and 23a—c;  values are given in ppm.

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Khusnutdinov et al.
at the rate of 8 C min–1, the injector temperature 280 C, the
temperature of source of ions 200 C, the ionization energy
70 eV). Chromatographic analysis was carried out on a Shimadꢀ
zu GCꢀ9A, GCꢀ2014 instrument (a 2×3ꢀmm column, stationary
phase silicon SEꢀ30 (5%) on Chromaton NꢀAWꢀHMDS, the
temperature was programmed from 50 to 270 C at the rate of
8 C min–1, carrier gas helium (47 mL min–1)).
decrease in the yield of the corresponding quinolines
by 5—22%. However, in the case of paraꢀ, metaꢀ, and
orthoꢀchloroꢀsubstituted anilines, a reversed pattern was
observed.
This approach to the preparation of quinolines is diꢀ
stinguished by the absence of side products such as monoꢀ
and dialkylꢀNꢀanilines formed when other methods were
used for the synthesis of quinolines.
Elemental composition of the samples was determined on
a Karlo Erba 1106 elemental analyser.
It should be noted that 3,4ꢀdichloroaniline under the
selected conditions reacted by both orthoꢀpositions with
the formation of a poorly separable mixture of 5,6ꢀ and
6,7ꢀdichloroꢀsubstituted quinolines, attempted isolation
of which in the individual state by GLC and HPLC failed.
The structures of compounds 22a—c and 23a—c were
confirmed by 1D (1H, 13C) and 2D (COSY, HSQC,
HMBC) NMR spectroscopy (Fig. 1).
Thus, the presence in the 13C NMR spectrum of two
sets of signals of equal intensity indicates the formation of
both theoretically possible isomers 22a and 23a. Two lowꢀ
field singlet signals for the protons at (H(5)) = 8.11 and
(H(8)) = 7.83 are unambiguously assigned to the protons
at C(5) and C(8) carbon atoms of compound 22a, whereas
the lowꢀfield doublet signals are attributable to the vicinal
protons of three ABꢀsystems centered at  7.59, 7.91, and
7.76, with the most highꢀfield doublet signal at (H(3)) =
= 7.28 belonging to isomer 22a. The latter signal has
a crossꢀpeak with the signal of the vicinal proton at (H(4)) =
= 7.91 (Jvic = 8.4 Hz) in the COSYꢀexperiment, whereas
in the HMBC experiment it correlates with the signal
for the methine carbon atom at (C(4a)) = 125.53,
which interacts with two protons: H(5)) = 8.11 and
(H(8)) = 7.83.
Commercially available substituted anilines, ethanol, proꢀ
panꢀ1ꢀol (Acros), butanꢀ1ꢀol (analytical grade, Reakhim),
carbon tetrachloride (reagent grade, Component—Reactive)
were used as the starting agents with distillation before use.
Ironꢀcontaining catalysts FeCl3•6H2O (Sigma—Aldrich),
FeCl3, FeCl2•4H2O, Fe(C5H5)2, Fe(acac)3, Fe(OAc)2, and
Fe2(CO)9 (Acros) were recrystallized and dried in a vacuum
desiccator before use.
Reactions were carried out in 10ꢀmL glass tubes placed in
a 17ꢀmL microautoclave made of stainless steel with constant
stirring and controlled heating.
Synthesis of substituted quinolines 11—23 (general procedure).
The catalyst FeCl3•H2O (0.0219 mmol), substituted aniline
(2.19 mmol), CCl4 (2.19 mmol), and ROH (4.38 mmol) were
placed into a tube under argon. The sealed tube was placed into
autoclave, the autoclave tightly capped and heated for 2 h at
140 C (stage 1), then, the autoclave was cooled down to ~20 C,
the tube was unsealed, the reaction mass was neutralized with
10% aqueous Na2CO3 (stirring with a magnetic stirrer for 0.5—1 h),
the organic layer was extracted with dichloromethane and filꢀ
tered. The solvent was evaporated, the residue was placed into
a tube, and a new portion of the reagents was added: FeCl3•H2O
(0.0219 mmol), CCl4 (2.19 mmol), and ROH (4.38 mmol). Then,
the sealed tube was placed into autoclave, the autoclave was
tightly capped and heated for 2 h at 140 C (stage 2). After the
reaction reached completion, the autoclave was cooled to ~20 C,
the tube was unsealed, the reaction mass was neutralized with
10% aqueous Na2CO3 (stirring with a magnetic stirrer for
0.5—1 h), the organic layer was extracted with dichloromethane
and filtered. The solvent was evaporated, the residue was disꢀ
tilled in vacuo.
Isomer 23a contains two interacting ABꢀsystems of
protons, which correlate with the signals of the ꢀmethine
carbon atoms at C(2)) = 159.82 and (C(8a)) = 146.73
of the molecule pyridine fragment, respectively.
Physicochemical constants and spectroscopic characterisꢀ
tics of the products completely agree with the literature data for
compounds 11—21.
Replacement of the methyl group with the ethyl one at
C(2) atom and replacement of H(3) proton with the meꢀ
thyl group lead to the appearance of two singlet signals at
(H(4)) = 7.79 and 8.84 for 22b and 23b, respectively,
with the ratio of intensities being 3 : 2, that indicates
a predominance of isomer 22b.
The results obtained allow us to draw a conclusion that
the substituted anilines react with alcohols and CCl4 upon
the action of a FeCl3•6H2O catalyst with the exclusive
formation of tri(tetra)substituted quinolines 11—23.
5,6ꢀDichloroꢀ2ꢀmethylquinoline (23a).19 The yield was 45%.
1H NMR (CDCl3), : 2.72 (s, 3 H, Me); 7.39 (d, 1 H, C(3)H,
J = 8.4 Hz); 7.68 (d, 1 H, C(7)H, J = 8.4 Hz); 7.84 (d, 1 H,
C(8)H, J = 8.4 Hz); 8.42 (d, 1 H, C(4)H, J = 8.4 Hz). 13C NMR,
: 25.07 (Me), 123.49 (C(3)), 124.65 (C(4a)), 128.53 (C(8)),
128.81 (C(5)), 130.55 (C(7)), 132.70 (C(6)), 133.01 (C(4)),
146.73 (C(8a)), 159.82 (C(2)). Found (%): C, 56.66; H, 3.34;
Cl, 33.40; N, 6.60. C10H7Cl2N. Calculated (%): C, 56.63; H, 3.33;
Cl, 33.34; N, 6.60. MS, m/z (Irel (%)): 211 [M]+ (100), 88 (7),
140 (14), 141 (14), 149 (9), 176 (16), 212 (13), 213(63), 214 (7),
215 (10).
Experimental
6,7ꢀDichloroꢀ2ꢀmethylquinoline (22a). The yield was 47%.
1H NMR (CDCl3), : 2.75 (s, 3 H, Me); 7.28 (d, 1 H, C(3)H,
J = 8.4 Hz); 7.83 (s, 1 H, C(8)H); 7.91 (d, 1 H, C(4)H, J = 8.4 Hz);
8.11 (s, 1 H, C(5)H). 13C NMR, : 25.33 (Me), 123.04 (C(3)),
125.53 (C(4a)), 127.95 (C(8)), 129.78 (C(5)), 129.99 (C(6)),
133.70 (C(7)), 134.89 (C(4)), 146.39 (C(8a)), 160.50 (C(2)).
Found (%): C, 56.66; H, 3.34; Cl, 33.40; N, 6.60. C10H7Cl2N.
1
H and 13C NMR spectra were recorded on a Bruker Avanceꢀ
400 spectrometer (400.13 and 100.62 MHz, respectively) in
CDCl3, chemical shifts are given relative to Me4Si. Mass spectra
were recorded on a Shimadzu GCMSꢀQP2010Plus GLCꢀMS
spectrometer (a SPBꢀ5 capillary column 30×0.25 mm, carrier
gas helium, the temperature was programmed from 40 to 300 C

Synthesis of substituted quinolines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
137
Calculated (%): C, 56.63; H, 3.33; Cl, 33.34; N, 6.60. MS, m/z
(Irel (%)): 211 [M]+ (100), 140 (13), 141 (14), 149 (9), 176 (13),
196 (5), 213(60), 215 (10).
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5,6ꢀDichloroꢀ2ꢀethylꢀ3ꢀmethylquinoline (23b). The yield was
1
29%. H NMR (CDCl3), : 1.38 (t, 3 H, Me, J = 7.2 Hz); 2.48
(s, 3 H, Me); 2.98 (q, 2 H, CH2, J = 7.6 Hz); 7.64 (d, 1 H,
C(7)H, J = 8.8 Hz); 7.91 (d, 1 H, C(8)H, J = 8.8 Hz); 8.84
(s, 1 H, C(4)H). 13C NMR, : 12.43 (CH2CH3), 19.29 (Me),
29.10 (CH2), 126.15 (C(3)), 126.25 (C(4a)), 128.41 (C(8)),
129.65 (C(7)), 129.91 (C(5)), 132.57 (C(4)), 133.46 (C(6)),
145.60 (C(8a)), 163.99 (C(2)). Found (%): C, 60.06; H, 4.64;
Cl, 29.49; N, 5.81. C12H11Cl2N. Calculated (%): C, 60.02;
H, 4.62; Cl, 29.53; N, 5.83. MS, m/z (Irel (%)): 239 [M]+ (47),
40 (100), 43 (17), 55 (18), 57 (18), 69 (17), 207 (20), 238 (73),
241 (31), 243 (6).
6,7ꢀDichloroꢀ2ꢀethylꢀ3ꢀmethylquinoline (22b). The yield was
41%. 1H NMR (CDCl3), : 1.39 (t, 3 H, Me, J = 7.6 Hz); 2.55
(s, 3 H, Me); 3.02 (q, 2 H, CH2, J = 7.6 Hz); 7.73 (s, 1 H, C(8)H);
7.79 (s, 1 H, C(4)H); 8.16 (s, 1 H, C(5)H). 13C NMR, : 12.36
(CH2CH3), 19.11 (Me), 29.26 (CH2), 126.38 (C(4a)), 127.18
(C(8)), 129.45 (C(5)), 129.85 (C(6)), 130.88 (C(3)), 134.07
(C(7)), 134.40 (C(4)), 146.32 (C(8a)), 164.68 (C(2)). Found (%):
C, 60.06; H, 4.64; Cl, 29.49; N, 5.81. C12H11Cl2N. Calculatꢀ
ed (%): C, 60.02; H, 4.62; Cl, 29.53; N, 5.83. MS, m/z (Irel (%)):
239 [M]+ (65), 40 (64), 73 (22), 140 (18), 149 (24), 207 (17), 211
(20), 238 (100), 241 (43), 243 (7).
5,6ꢀDichloroꢀ3ꢀethylꢀ2ꢀpropylquinoline (23c). The yield was
23%. 1H NMR (CDCl3), : 0.85—1.00 (m, 3 H, Me); 1.37 (t, 3 H,
Me, J = 8 Hz); 1.80—1.90 (m, 2 H, CH2CH2Me); 2.86 (q, 2 H,
CH2Me, J = 8 Hz); 2.75—2.95 (m, 2 H, CH2CH2Me); 7.59 (d, 1 H,
C(7)H, J = 8.8 Hz); 7.91 (d, 1 H, C(8)H, J = 8.8 Hz); 8.21 (s, 1 H,
C(4)H). 13C NMR, : 14.01 (CH2CH3), 14.29 (CH2CH2CH3),
22.42 (CH2CH2Me), 25.40 (CH2Me), 37.38 (CH2CH2Me),
126.20 (C(4a)), 128.45 (C(8)), 129.65 (C(7)), 130.02 (C(5)),
130.44 (C(4)), 130.58 (C(6)), 137.33 (C(3)), 145.19 (C(8a)),
162.72 (C(2)). Found (%): C, 62.71; H, 5.68; Cl, 26.41; N, 5.20.
C14H15Cl2N. Calculated (%): C, 62.69; H, 5.64; Cl, 26.44;
N, 5.23. MS, m/z (Irel (%)): 267 [M]+ (31), 211 (13), 238 (60), 239
(100), 240 (46), 241 (67), 252 (37), 254 (19), 269 (20), 271 (3).
6,7ꢀDichloroꢀ3ꢀethylꢀ2ꢀpropylquinoline (22c). The yield was
42%. 1H NMR (CDCl3), : 1.00—1.10 (m, 3 H, Me); 1.34 (t, 3 H,
Me, J = 8 Hz); 1.80—1.90 (m, 2 H, CH2CH2Me); 2.80 (q, 2 H,
CH2Me, J = 7.2 Hz); 2.75—2.95 (m, 2 H, CH2CH2Me); 7.70
(s, 1 H, C(8)H); 7.76 (s, 1 H, C(4)H); 8.10 (s, 1 H, C(5)H).
13C NMR, : 14.01 (CH2CH3), 14.29 (CH2CH2CH3), 22.30
(CH2CH2Me), 25.09 (CH2Me), 37.57 (CH2CH2Me), 126.39
(C(4a)), 127.38 (C(8)), 129.33 (C(5)), 129.70 (C(6)), 132.28
(C(7)), 132.34 (C(4)), 136.64 (C(3)), 144.95 (C(8a)), 163.45
(C(2)). Found (%): C, 62.71; H, 5.68; Cl, 26.41; N, 5.20.
C14H15Cl2N. Calculated (%): C, 62.69; H, 5.64; Cl, 26.44;
N, 5.23. MS, m/z (Irel (%)): 267 [M]+ (22), 73 (11), 238 (46), 239
(100), 240 (36), 241 (56), 252 (32), 254 (20), 269 (13), 271 (3).
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 12ꢀ03ꢀ00183ꢀa).
Received October 19, 2012;
in revised form November 13, 2012