Microwave enhanced solvent-free synthesis of a library of quinoline derivatives

Article abstract of DOI:10.1016/S0040-4039(02)02499-1

A minilibrary of 12 quinoline derivatives was synthesized in the presence of 0.1-0.5 equiv. of diphenylphosphate without any solvents. Each compound was obtained with high yield in 4 min of microwave irradiation.

Full text of DOI:10.1016/S0040-4039(02)02499-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 255–257
Microwave enhanced solvent-free synthesis of a library of
quinoline derivatives
Suk Jin Song,a Seong Jin Cho,a Dong Kyu Park,a Tae Woo Kwona,* and Samson A. Jenekheb
aCollege of Science, Kyungsung University, Busan 608-736, South Korea
bDepartment of Chemical Engineering, University of Washington, Seattle, WA 98195-1750, USA
Received 16 October 2002; revised 7 November 2002; accepted 8 November 2002
Abstract—A minilibrary of 12 quinoline derivatives was synthesized in the presence of 0.1–0.5 equiv. of diphenylphosphate
without any solvents. Each compound was obtained with high yield in 4 min of microwave irradiation. © 2002 Elsevier Science
Ltd. All rights reserved.
Quinolines are well known not only for their significant
biological activities1 but also for their formation of
conjugated molecules and polymers that combine
enhanced electronic, optoelectronic, or nonlinear opti-
cal properties with excellent mechanical properties.2,3
Diblock and triblock copolymers incorporating
polyquinoline blocks have been found to undergo
hierarchical self-assembly into a variety of nanostruc-
tures and mesostructures with electronic and photonic
Herein we report the Friedlander7 coupling condensa-
tion reactions between various acetophenones (1; R1=
H, n-hexyl, Br and NH2) and 2-aminoacetophenone (2;
R2=CH3, R3=H) or benzophenone (2; R2=Ph, R3=H
or Br) under microwave irradiation.
We first examined the reaction time and temperature
effects when 1.0 equiv. of DPP was used under
microwave irradiation. As time increased, the reaction
temperature also increased and the maximum yield
(78%) was obtained after 4 min at 110°C as shown in
Table 1, entry 4. The temperature was one of the
important factors that improved the yields but a longer
time and a higher temperature did not increase the yield
(Table 1, entry 5).
functions.4 Previously we reported
a variety of
polyquinolines prepared from 2-aminoacetophenones
and benzophenones.2,3 To carry out the synthesis of
quinoline molecules and polymers, it was usually
required to heat the reaction mixture for several or even
more than 24 hours in the presence of 5–10 equiv. of an
acidic catalyst such as diphenylphosphate (DPP) and in
highly toxic m-cresol solvent.2,3a,b
Table 1. Optimization of the reaction time in the synthesis
of 2,4-DPQ (3; R1, R2 and R3=H) under microwave irra-
diation or conventional heating in a thermostated oil bath
(scale=3 mmol, ratio of 1:2:DPP=1:1:1)
Recently, much attention has focused on microwave-
assisted organic reactions in the absence of solvent.5
Often, thermal demanding reactions take hours in solu-
tion, and may require repetitive treatments with excess
reagents to drive them to completion. However, with
microwave irradiation these same reactions may be
completed in minutes.5,6
Entry
Time (min) Temp. (°C)a
Yield (%)
Microwaveb Conventional
1
2
3
4
5
1
2
3
4
6
52
87
104
108
112
34
69
72
78
77
–
–
–
24c
–
a Temperature of reaction mixture was recorded after the microwave
irradiation at the given reaction time.
b The reactions were carried out in
a 2450 MHz commercial
microwave oven (Sam Sung, Model c RE-555 TCW).
* Corresponding author. Tel.: +82-51-620-4637; fax: +82-51-627-4115;
e-mail: twkwon@star.kyungsung.ac.kr
c Oil bath temperature=108°C.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02499-1

256
S. J. Song et al. / Tetrahedron Letters 44 (2003) 255–257
Table 2. Optimization of the DPP equivalents and reac-
tion time in the synthesis of 2,4-DPQ (3; R1, R2 and
R3=H) under microwave irradiation (scale=3 mmol, ratio
of 1:2=1 equiv.:1 equiv.)
microwave irradiation effect was not observed in the
synthesis of DPQ at 108°C (Table 2, entry 1). However,
when 0.1 equiv. of DPP was added, the yield was
significantly increased up to 73% (Table 2, entry 2).
DPP in excess of 0.5 equiv. did not help to increase the
yield (Table 2, entries 6 and 7).
Entry
DPP (equiv.) Time (min)
Yield (%)
Microwave Conventional
To check the possibility of intervention of specific (non
purely thermal) microwave effects, the reaction has also
been examined using a pre-heated oil-bath for the same
duration and at the same final temperature as measured
at the end of exposure during the microwave-assisted
synthesis. It was found that reaction proceeded slowly
with 15–24% yield in 4 min (Table 2, entries 4 and 5)
whereas 70% of DPQ was obtained after 330 min under
conventional heating at 136°C (Table 2, entry 8).
1
2
3
4
5
6
7
8
0
4
4
4
4
4
2
4
330
15
73
75
78
78
77
62
–
2a
–
–
0.1
0.3
0.5
1.0
5.0
5.0
5.0
15a
24a
–
–
70b
a Oil bath temperature=108°C.
b Oil bath temperature=136°C.
It is well established that microwave-reactants interac-
tions are increased with the polarity of the material.8
Therefore microwave effects can be easily understood
by considering the possible microwave activation effects
by dipole–dipole interactions according to mechanistic
considerations and to an increase of the polarity of the
system during the progress of the reaction.9
In order to evaluate the influence of DPP, the reactions
were carried out using different DPP equivalents. It
should be pointed out that cyclization is enhanced by
DPP as shown in Table 2. In the absence of DPP,
Table 3. Solvent-free quinoline library synthesis of 3 under microwave irradiation (scale=3 mmol, equivalent ratio of
1:2:DPP=1:1:0.5, 4 min)

S. J. Song et al. / Tetrahedron Letters 44 (2003) 255–257
257
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To investigate further the scope and limitations of the
above optimal condition, a minilibrary of quinoline
derivatives was synthesized. Long chain alkyl, bromo,
and amino substituted acetophenones with 2-amino
aceto- or benzophenones were subjected to the above
optimal reaction conditions. The results are summa-
rized in Table 3. It is noteworthy that under the same
reaction conditions, bromo (Table 3, entries 7–9) or
basic amino (Table 3, entries 10 and 11) functionality
remained intact and aqueous work-up was not
required.3
In summary, microwave-assisted solvent-free (under
conditions of so-called ‘Green Chemistry’) reactions
were employed to synthesize quinoline derivatives. The
method not only offers substantial improvement in
yield over conventional heating methods but also elimi-
nates the use of hazardous solvents and excess expen-
sive acidic catalyst. Advantages of this method include
the fact that it is environmentally benign, an economi-
cal procedure, has a short reaction time and the sim-
plicity of the performance with non-aqueous work-up.
Typical microwave procedure for 2,4-diphenylquinoline
(Table 3, entry 1). Acetophenone (0.36, 3.0 mmol),
2-aminobenzophenone (0.59 g, 3.0 mmol) and 0.5
equiv. of DPP (0.38 g, 1.50 mmol, purchased from
Aldrich) were mixed in the absence of any organic
solvent and then submitted for 4 min to microwave
irradiation inside a domestic microwave oven (Sam
Sung, RE-555 TCW). After the reaction, the product
was purified by column chromatography (20% ethyl
acetate/80% hexane, v/v, Rf=0.64) to give 2,4-
diphenylquinoline (0.66 g, 2.34 mmol, 78%) as a color-
less solid. mp=112–113°C (lit.10=112°C).
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S.; Kang, C. J.; Kwon, T. W.; Chung, S. K.; Chang, Y.
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This work was supported by grant from the Basic
Research Program of the Korea Science and Engineer-
ing Foundation (KOSEF R01-2000-000-00039-0).
Work at the University of Washington was supported
by the US Office of Naval Research. We thank Profes-
sor Andre´ Loupy (Universite´ Paris-Sud, France) and
Dr. X. X. Kong (the University of Washington, USA)
for helpful discussion.
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