A facile synthesis of 2,2,4-trisubstituted-1,2-dihydroquinolines catalyzed by zinc triflate under solvent-free conditions

Article abstract of DOI:10.1002/jccs.200800175

An efficient process has been developed for the synthesis of 2,2,4-trisubstituted-1,2-dihydroquinolines in good yields through a simple one-pot condensation between anilines and ketones in the presence of zinc triflate as a catalyst at room temperature under solvent-free conditions.

Full text of DOI:10.1002/jccs.200800175

1186
Journal of the Chinese Chemical Society, 2008, 55, 1186-1190
Note
A Facile Synthesis of 2,2,4-Trisubstituted-1,2-dihydroquinolines Catalyzed
by Zinc Triflate under Solvent-free Conditions
Dhiman Kundu, Shrishnu Kumar Kundu, Adinath Majee* and Alakananda Hajra*
Department of Chemistry, Visva-Bharati University, Santiniketan 731235, India
An efficient process has been developed for the synthesis of 2,2,4-trisubstituted-1,2-dihydroquino-
lines in good yields through a simple one-pot condensation between anilines and ketones in the presence
of zinc triflate as a catalyst at room temperature under solvent-free conditions.
Keywords: Zinc triflate; Dihydroquinolines; Skraup-Doebner-Von Miller reaction; Solvent-free;
Condensation.
INTRODUCTION
Owing to the widespread occurrence in nature, as
their derivatives under mild conditions at room tempera-
ture in cost-effective way. As a part of our program to study
solvent-free reactions,15,16 we would like to present here a
zinc(II)-catalyzed one-pot procedure for the synthesis of
2,2,4-trisubstituted-1,2-dihydroquinolines at room temper-
ature under solvent-free conditions (Scheme I).
well as the breadth of biological activity, the synthesis of
dihyroquinolines and their derivatives have been the sub-
ject of continued interest among organic and medicinal
chemists for many years.1 Several derivatives of 2,2,4-tri-
substituted-1,2-dihydroquinolines are known to exhibit a
wide range of pharmacological properties such as bacteri-
cidal,2 antidiabetic,3 anti-inflammatory,4 antimalarial,5
lipid peroxidation inhibitors,6 HMG-CoA reductase inhibi-
tors,7 ileal bile acid transporter inhibitors,8 progesterone
agonists9 and antagonists.10 Among the most general ap-
proaches for this ring formation is Skraup cyclizationwhich
involves the heating a mixture of nitroethane, aniline, and
glycerol with concentrated sulfuric acid.11 Doebner and
Von Miller modified this procedure by using an a,b-unsat-
urated ketone with an aromatic amine by heating in the
presence of acid catalyst or iodine.12
Scheme I Zn(OTf)2-catalyzed synthesis of 1,2-dihy-
droquinolines
RESULTS AND DISCUSSION
Representative results of the screening of the Zn-cat-
alyst and the reaction conditions as studied for the conden-
sation between aniline and acetone to synthesize dihydro-
quinolines are summarized in Table 1.
Over the last century, a number of other methods have
been made to improve the yields and reproducibility of
Skraup cyclization involving a variety of catalysts.13,14
However, in spite of the potential utility, some of these
methods suffer from drawbacks including the use of non-
available and costly reagents, higher temperature, longer
reaction times, lower yields and the use of hazardous sol-
vents. Another important issue is that most of these proce-
dures involve either conventional heating or microwave-ir-
radiation. Thus, there are still scopes for renovation to-
wards simple one-pot synthesis of dihydroquinolines and
In the course of the optimization study we found that
Zn(OTf)2 was the optimal catalyst in terms of conversion
and yields at room temperature under solvent-free condi-
tions among other Zn-catalysts (entries 5, 9 and 10). Al-
though CH2Cl2 was better solvent than other common sol-
vents such as THF, CH3COOEt, CH3CN but overall yield
was lower than solvent-free conditions (entries 1-5). Use of
* Corresponding author. Fax: +91-3463261728; E-mail: adinath.majee@visva-bharati.ac.in; alakananda.hajra@visva-bharati.ac.in

Solvent-free Synthesis of 1,2-Dihydroquinolines
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1187
Table 1. Effect of catalyst and solvent on reaction between
aniline and acetone
Table 2. Synthesis of 2,2,4-trisubstituted 1,2-dihydroquinolines
Time Yielda
Entry
Anilines R
R1
R2
Ref
Conditions temp, time, Yielda
(h)
(%)
Entry
Zn-cat.
solvent
(%)
a
b
c
d
e
f
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
22
22
22
24
24
26
26
22
23
21
21
24
24
24
78
77
80
74
76
a78b
77
80
77
80
15
15
15
15
17
15
15
2-Me
1
Zn(OTf)2, 10 mol%
Zn(OTf)2, 10 mol%
Zn(OTf)2, 10 mol%
Zn(OTf)2, 10 mol%
Zn(OTf)2, 10 mol%
Zn(OTf)2, 10 mol%
Zn(OTf)2, 20 mol%
Zn(OTf)2, 5 mol%
ZnCl2, 10 mol%
r.t., 22 h, THF
r.t., 22 h, CH3CN
r.t., 22 h, DCM
r.t., 22 h, EtOAC
r.t., 22 h, neat
70 °C, 12 h, neat
r.t., 22 h, neat
r.t., 22 h, neat
r.t., 22 h, neat
r.t., 22 h, neat
20
22
53
34
78
74
80
72
24
66
4-Me
2
2-OMe
4-OMe
3-Cl
3
4
5
g
h
i
4-Cl
6
4-F
7
4-CO2Et
2,3-dimethyl
8
j
9
k
l
3,4-methylenedioxy Me
a77c 13d
10
Zn(ClO4)2, 10 mol%
H
Me
Me
Me
70
72
75
a Pure isolated yields.
m
n
Me
Et
4-CO2Et
Et
a Yields refer to pure isolated products, properly characterized by
spectral and analytical data.
just 10 mol% Zn(OTf)2 was sufficient to push the reaction
forward (entry 5). Elevated temperature did not improve
the yields but the amount of undesired and unidentified
products increased (entry 6). Higher amount of Zn(OTf)2
did not improve the result (entry 7). Having identified the
best conditions, we explored the scope of the reaction, and
the results are summarized in Table 2.
b p-Cyclization pdt.
c 6,7-Methylenedioxy-substituted dihydroquinoline as a major
regioisomer.
oxy-substituted dihydroquinoline as a major regioisomer
under the present reaction conditions (entry k). The cy-
clization between a variety of anilines with ethyl methyl
ketone also proceeded very smoothly at room temperature
to give the dihydroquinoline derivatives in good yields
without difficulty. It was found that secondary anilines and
aromatic ketones were failed to produce dihydroquino-
lines. 1-Naphtylamine also produced dihydrobenzoquino-
line in good yields. Interestingly, the condensation between
anilines and mesityl oxide also produced the similar kind of
the dihyroquinoline derivatives under the present reaction
conditions. More hindered ketone gave lower yields com-
pare to acetone.
In a typical experimental procedure, a mixture of ani-
line (2 mmol) and anhydrous acetone (8 mmol, 0.587 mL)
was stirred at room temperature in the presence of catalytic
amount of Zn(OTf)2 (73 mg, 10 mol%) for a certain period
of time as required for the completion (TLC). After com-
pletion of the reaction, the reaction mixture was diluted
with diethyl ether and filtered through a plug of silica gel.
After removal of solvent, purification with silica gel chro-
matography gave as a colorless liquid. All these reactions
were carried out at room temperature under inert atmo-
sphere and afforded the desire products in good yields.
Several sensitive functionalities such as OMe (entries d
and e), Cl (entries f and g), CO2Et (entries i and n), meth-
ylenedioxy (entry k) were unaffected under the present re-
action conditions. Fluoroaniline also reacted well to give
the desired product in good yields (entry 8). In case of m-
substituted aniline, major regioisomeric dihydroquinoline
corresponding to p-cyclization was obtained (entry f).
3,4-Methylenedioxyaniline produced 6,7-methylenedi-
The mechanism in Scheme II is proposed for the cou-
pling reactions between aniline and ketones. Though two
regioisomers of the enolates (A & B) are possible, B formed
faster as it is kinetic enolate. The sole product aldol is prob-
ably due to the reaction of the ketone with B only. Subse-
quently a,b-unsatured ketone formed after dehydration.
The intermediate tertiary alcohol formed by Michael addi-
tion followed by cyclisation produced dihydroquinoline af-

1188 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Kundu et al.
Scheme II Plausible mechanism for the formation of dihydroquinoline
ter dehydration. During the specific aldol condensation
process, the other possible thermodynamic enolate did not
react. It may be due to the steric hinderence among the two
methyl and ethyl groups of thermodynamic enolate and
ketone.
strument at 300 MHz for 1H and at 75 MHz for 13C NMR.
IR spectra were measured on a FT 8400S Shimadzu spec-
trometer. Melting points are determined on a glass disk
with an electric bath (Reichert, Austria) and are uncor-
rected. Elemental analyses were done by a Perkin-Elmer
autoanalyzer. Column chromatography was performed on
silica gel (60-120 mesh, SRL, India). Anilines and ketones
were distilled before use. Zn(OTf)2 was purchased from
Aldrich.
In conclusion, the work presented here demonstrates
a straightforward and mild procedure for the efficient syn-
thesis of dihydroquinoline derivatives at room temperature
under solvent-free conditions. The reaction possesses the
following synthetic features: (a) mild conditions, (b) sim-
ple operation, (c) good yields, (d) nontoxic and cheap metal
catalyst, and (e) the compatibility with various functional
groups. The easy formation of substituted dihydroquino-
lines from inexpensive starting materials makes this an
important synthetic procedure.
General procedure for the synthesis of dihydroquino-
lines: representative procedure for 2,2,4-trimethyl-
1,2-dihydroquinoline 3a
Amixture of aniline (186 mg, 2 mmol) and anhydrous
acetone (8 mmol, 0.587 mL) was stirred at room tempera-
ture in the presence of catalytic amount of Zn(OTf)2 (73
mg, 10 mol%) for 22 h (TLC). After completion of the reac-
tion, the reaction mixture diluted with diethyl ether (20
mL) and filtered through a plug of silica gel. After removal
EXPERIMENTAL SECTION
NMR spectra were recorded on a Bruker DPX 300 in-

Solvent-free Synthesis of 1,2-Dihydroquinolines
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1189
of solvent, purification with silica gel chromatography
(hexane-Et2O, 95:5) gave 2,2,4-trimethyl-1,2-dihydro-
quinoline as a colorless oil (270 mg, 78%) whose spectro-
scopic data (IR, 1H NMR) are in good agreement with those
reported.15
83.67; H, 9.83; N, 6.50. Found: C, 83.32; H, 9.67; N, 6.34.
6-Carboethoxy-2,4-Diethyl-2-methyl-1,2-dihydroquino-
line 3n
Solid (75%); Mp 105-106 °C; Rf 0.60 (hexane-Et2O,
1
9:1); IR (KBr): 3349, 2970, 1688, 1652, 1591 cm-1; H
This procedure was followed for the synthesis of
dihydroquinolines listed in Table 2. The spectral and ele-
mental analyses of the compounds which are not readily
found are provided here.
NMR (CDCl3): d = 7.68 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H),
6.28 (d, J = 8.3 Hz, 1H), 5.08 (s, 1H), 4.12 (q, J = 7.1 Hz,
2H), 4.01 (broad, 1H), 2.34 (q, J = 7.4 Hz, 2H), 1.42 (m,
2H), 1.35 (t, J = 7.1 Hz, 3H), 1.17 (s, 3H), 1.09 (t, J = 7.4
Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3): d =
167.4, 148.6, 134.8, 130.9, 125.5, 124.9, 119.4, 118.1,
111.9, 60.5, 55.8, 37.7, 30.9, 24.7, 14.8, 13.0, 8.9; Anal.
Cald for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C,
74.38; H, 8.31; N, 4.98.
6-Fluoro-2,2,4-trimethyl-1,2-dihydroquinoline 3h
Colorless oil (80%); Rf 0.70 (hexane-Et2O, 9:1); IR
(neat): 3278, 1612, 1029 cm-1; 1H NMR (CDCl3): d = 6.81-
6.77 (m, 1H), 6.73-6.69 (m, 1H), 6.40-6.37 (m, 1H), 5.39
(s, 1H), 4.10 (board, 1H), 1.97 (d, J = 1.4 Hz, 3H), 1.27 (s,
6H); Anal. Cald for C12H14FN: C, 75.36; H, 7.38; N, 7.32.
Found: C, 75.18; H, 7.12; N, 7.06.
ACKNOWLEDGMENTS
6-Carboethoxy-2,2,4-trimethyl-1,2-dihydroquinoline 3i
Solid (77%); Mp 154-156 °C; Rf 0.63 (hexane-Et2O,
9:1); IR (KBr): 3346, 2973, 1683, 16657, 1597, 1509, 1367
cm-1; 1H NMR (CDCl3): d = 7.51 (s, 1H), 7.47 (d, J = 8.3
Hz, 1H), 6.17 (d, J = 8.3 Hz, 1H), 5.10 (s, 1H), 4.09 (q, J =
7.1 Hz, 2H), 1.80 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (s,
6H), N-H (not identified); Anal. Cald for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.12; H, 7.57; N, 5.54.
2,2,4,7,8-Pentamethyl-1,2-dihydroquinoline 3j
Alakananda Hajra appreciates the financial support
from DST (Grant No. SR/FTP/CS-107/2006). We are thank-
ful to DST-FIST and SAP-UGC, India. Dhiman Kundu
thanks to CSIR for his fellowship. The authors also express
our sincere thanks to Prof. B. C. Ranu, Department of
Chemistry, Indian Association for the Cultivation of Sci-
ence, for his advice and constant encouragements.
Received April 22, 2008.
Colorless oil (80%); Rf 0.73 (hexane-Et2O, 9:1); IR
(neat): 3321, 1607, 1551 cm-1; 1H NMR (CDCl3): d = 6.90
(d, J = 7.8 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 5.30 (s, 1H),
3.86 (broad, 1H), 2.26 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H),
1.30 (s, 6H); Anal. Cald for C14H19N: C, 83.53; H, 9.51; N,
6.96. Found: C, 83.24; H, 9.37; N, 6.79.
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