Microwave-assisted Friedl?nder synthesis of polysubstituted quinolines based on poly(ethylene glycol) bound acetoacetate

Article abstract of DOI:10.1002/jccs.201190052

Polysubstituted quinolines were efficiently prepared on the soluble polyethylene glycol (PEG) by microwave irradiation Friedl?nder condensation of PEG bound acetoacetate with 2-aminoarylketones promoted by catalytic amount of polyphosphoric acid, and subsequently cleavage from the PEG withMeONa in MeOH. The polymer-supported synthesis provided the target compounds in excellent yield and purity with a facile work-up procedure.

Full text of DOI:10.1002/jccs.201190052

18
Journal of the Chinese Chemical Society, 2011, 58, 18-23
Communication
Microwave-assisted Friedländer Synthesis of Polysubstituted Quinolines
Based on Poly(ethylene glycol) Bound Acetoacetate
Xiao-Liang Zhang,a Qiao-Sheng Hu,b Sheng-Ri Sheng,a* Chen Xiaob and Ming-Zhong Caia
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P. R. China
bCollege of Chemistry and Life Science, Gannan Normal University, Ganzhou 341000, P. R. China
Received September 2, 2010; Accepted December 2, 2010; Published Online January 12, 2011
Polysubstituted quinolines were efficiently prepared on the soluble polyethylene glycol (PEG) by mi-
crowave irradiation Friedländer condensation of PEG bound acetoacetate with 2-aminoarylketones pro-
moted by catalytic amount of polyphosphoric acid, and subsequently cleavage from the PEG with MeONa
in MeOH. The polymer-supported synthesis provided the target compounds in excellent yield and purity
with a facile work-up procedure.
Keywords: Liquid-phase synthesis; PEG bound acetoacetate; 2-Aminoarylketone; Polysubstituted
quinoline.
INTRODUCTION
methods required high temperature (150-200 oC) and ex-
tended reaction times, which led to several side reactions.
Under thermal and basic conditions, 2-aminobezophenone
failed to react with cyclohexanone, deoxybenzoin and b-
ketoesters.7 Recently, iodine,8 Lewis acids and inorganic
salts9 such as FeCl3, Mg(ClO4)2, CuSO4·5H2O, FeSO4·
7H2O, SnCl2, AlCl3, Bi(OTf)3, Sc(OTf)3, Y(OTf)3, CeCl3·
7H2O, NaF, NaAuCl4·2H2O, Nd(NO3)3·6H2O and
Ag3POW12O40, and a combination of acidic catalysts and
microwave irradiation,10 ionic liquids,11 chlorotrimethyl-
silane,12 cyanuric chloride,13 1-methylimidazolium trifluo-
roacetate,14 [RuCl2(p-cymene)]2 15 and dodecylphosphonic
acid,16 as well as poly(N-bromo-N-ethylbenzene-1,3-disul-
fonamide)17 have been utilized for this synthesis. Although
these methods are valuable for the preparation of quinoline
derivatives, some of the reported protocols suffered form
harsh reaction conditions, low yields, high temperatures,
tedious work-up and the use of stoichiometric and rela-
tively expensive reagents. Therefore, the development of
simple, convenient and environmentally benign approaches
for the preparation of quinolines is still desirable. In the
past years, there has been a considerable growth in interest
in the use of soluble polymer-supported catalysts and re-
Quinolines are very important compounds because of
their wide occurrence in natural products1 and their inter-
esting biological activities such as antimalarial, anti-in-
flammatory agents, antiasthmatic, antibacterial, antihyper-
tensive, and tyrosine kinase inhibiting agents.2 In addition,
quinolines have been used for the preparation of nanostruc-
tures and polymers that combine enhanced electronic, op-
toelectronic or non-linear optical properties with excellent
mechanical properties.3 As a result of their importance as
substructures in a broad range of natural and designed
products, significant effort continues to be directed toward
the development of new quinoline-based structures and
new methods for their construction.4 Among these meth-
ods, the Friedländer annulation,5 an acid or base catalyzed
condensation followed by a cyclodehydration between an
aromatic 2-aminoaldehyde or ketone and a carbonyl com-
pound containing a reactive a-methylene group, is still one
of the simplest and most straightforward procedure for the
synthesis of polysubstituted quinolines. Brønsted acids cat-
alysts, such as NH2SO3H, HCl, H2SO4, p-TSA, H3PO4,
TFA, NaHSO4-SiO2 and HClO4-SiO2 were widely used6
for the Friedländer annulation. However, many of these
* Corresponding author. E-mail: shengsr@jxnu.edu.cn

Liquid-phase Organic Synthesis of Polysubstituted Quinolines
J. Chin. Chem. Soc., Vol. 58, No. 1, 2011 19
agents in organic synthesis because of their low cost, easy
of preparation and simple workup.18 As part of an ongoing
research program focused on the use polyethylene glycol
(PEG) as support in liquid-phase organic synthesis,19 we
report herein a novel method to the soluble polymer-sup-
ported synthesis of polysubstituted quinolines based on
PEG bound acetoacetate with 2-aminoarylketones as shown
in Scheme I.
CH2Cl2 in the presence of catalytic amount of non-volatile,
high boiling point and non-oxidant polyphosphoric acid
(PPA) in a MW domestic oven (400 W) adapted for the use
of a reflux condenser only for 5 min.
The reaction transformation of the PEG support was
feasible monitored directly using conventional microscopy
FT-IR and 1H NMR spectroscopy. After the cyclodehydra-
tion 1 with 2a, the FT-IR spectrum of the PEG bound inter-
mediate 3a showed complete disappearance of the ketone
carbonyl stretch at 1718 cm-1 corresponding to the ketone
carbonyl group of PEG bound acetoacetate 1, and the ap-
pearance of a new carbonyl stretch group in pyridine ring
near 1730 cm-1. Furthermore, this reaction process was fur-
ther confirmed by 1H NMR spectroscopy of the intermedi-
ate 3a since the methyl proton (CH3) of the PEG-bound
acetoacetate 1 was shifted downfield from 2.27 to 2.55
ppm.
Scheme I PEG support synthetic route to polysubsti-
tuted quinolines
O
R1
PPA, CH2Cl2
O
O
R2
NH2
+
MW, 400 w, 4 - 5 min
O
O
2
1
R2
R2
1N MeONa/MeOH
rt , 18 h
R1
R1
COOMe
CH3
Upon completion of the optimal Friedländer reaction
conditions, PEG immobilized quinoline-3-carboxylate 3a
was selectively precipitated out after the addition of diethyl
ether to the reaction mixtures. The target compound 4a was
obtained in 93% yield and 96% (Entry 1) HPLC purity of
crude product by cleavage from the PEG support under the
treatment of the PEG bound intermediate 3a with MeONa
in MeOH with stirring for 18 h. Completed cleavage of the
PEG support was also verified by observing an upfield shift
of a-methylene protons in the polymer attachment site
from 4.3 to 3.7 ppm.
O
H3C
N
N
4
3
RESULTS AND DISCUSSION
Our current methodology takes place from PEG 4000
bound acetoacetate 1,19a simply prepared by acetoacetyla-
tion of dihydroxyl PEG 4000 with 2,2,6-trimethyl-4H-
1,3-dioxin-4-one (toluene, 111 oC, 5 h). The quantitative
conversion of PEG to 1 was observed following the pres-
ence of the C=O absorptions at 1743 and 1718 cm-1 in FT-
IR spectrum, which corresponded to ester and ketone car-
bonyl group, respectively. Apparently, the first step of
Friedländer condensation of PEG-bound acetoacetate 1
with 2-aminoarylketones 2 in our present idea would be the
key step for the success of this protocol. As a model study,
the condensation of acetoacetate 1 and 2-aminoacetophe-
none (2a) was chosen for optimization. In view of a green
chemistry, and on the basis of the previously reported pro-
tocols, some catalysts such as such as p-TSA, NaHSO4,
NaF, I2, FeSO4·7H2O and TMSCl, as well as microwave ir-
radiation (MW) technique were used, and the correspond-
ing reaction conditions, for example, the different solvents
such as CH3OH, CH3CN and CH2Cl2, the reaction time,
and the amount of catalyst were varied for the present
Friedländer reaction. After a series of experiments, the
condensation reaction between 1 and 2a was completed in
It was worthy to note that, the same reaction of 1 and
2a promoted only by PPA in refluxing CH2Cl2 took 6 h to
achieve the completion, and the corresponding yield of
compound 4a cleaved from PEG was about 85%. It indi-
cates that the MW-induced protocol could not only achieve
significantly improved yield, but also decrease the reaction
time over those under traditional Friedländer reaction con-
ditions.
After finishing the cleavage reaction, the residual
polymer was recovered with about 90% yield based on
original PEG by addition of diethyl ether to the reaction
mixtures. The recovered PEG was reacted again with 2,2,6-
trimethyl-4H-1,3-dioxin-4-one to regenerate PEG-bound
ester 1 cleanly.19a To show the reactivity of the regenerated
PEG-bound ester 1, the reaction of polymeric reagent 1
with 2-aminoacetophenone (2a) was repeated four times in
the same reaction. As seen from Table 1 (entries 2 and 3),

20 J. Chin. Chem. Soc., Vol. 58, No. 1, 2011
Zhang et al.
In conclusion, a novel and efficient liquid-phase syn-
thesis method for the construction of polysubstituted quin-
olines on soluble PEG support was developed, which used
Friedländer condensation of PEG-bound acetoacetate with
2-aminoarylketones in the presence of catalytic amount of
PPA under microwave promotion, followed by the cleav-
age from the PEG. The coupling of MW technology with
liquid-phase synthetic strategy provided a new procedure
for the rapid generation of polysubstituted quinolines in ex-
cellent yields with simple workup. This versatile method
has potential applications in combinatorial synthesis of
analogous heterocyclic compounds libraries for chemical
biological screening and the drug discovery process.
Table 1. The yields and purities of polysubstituted quinolines 4a-
4k
Crude
purity (%) b
Entry
R1
R2
Product Yield (%) a
1
H
H
CH3
CH3
4a
4a
4a
4b
4c
4d
4e
4f
93
89 c
84 d
90
88
93
92
90
94
93
91
92
93
96
93
90
95
95
96
94
95
97
96
93
96
96
2
3
H
CH3
4
H
C6H5
5
H
2-ClC6H4
CH3
6
Cl
7
Cl
C6H5
8
Cl
2-ClC6H4
CH3
9
NO2
NO2
H
4g
4h
4i
10
11
12
13
C6H5
C6H5CH2
C6H5CH2
C6H5CH2
Cl
4j
NO2
4k
EXPERIMENTAL SECTION
a Isolated yield based on loading of original HO-PEG-OH.
b Determined on HPLC analysis of crude products before
purification. c With the third regenerated reagent 1. d With the
fourth regenerated reagent 1.
General Procedure
Melting points were determined on X4 melting point
apparatus and were uncorrected. 1H and 13C NMR (400
MHz) spectra were recorded on a Bruker AVANCE (400
MHz) spectrometer. FT-IR spectra were taken on a Perkin-
Elmer SP One FT-IR spectrophotometer. Microanalyses
were performed with a Carlo Erba 1106 Elemental Ana-
lyzer. HPLC analysis was carried out on Agilent 1100 auto-
mated system having a PDA detector (lmax = 254 nm) using
a gradient from 100% of the aqueous 0.1% TFA (eluent A)
to 60% eluent A-40% of 0.5% TFA in acetonitrile (eluent
B) over 35 min (0.8 mL/min) on a RP-18e column (100 ´
4.6 mm). MW experiments were performed on a Galaz WP
800J-823 microwave oven altered with a reflux condenser.
Polyethylene glycol (PEG) 4000, 2-aminoarylketones and
other reagents were obtained from commercial source and
used without further purification.
comparing with the result when the reagent 1 was first
used, the yield and purity of 4a decreased, which indicated
that recycling 3-4 times led to a gradual deterioration of the
reagent 1.
Following the synthesis of 4a on PEG, a set of related
compounds (4b-4k) was prepared using an analogous syn-
thetic protocol. As shown in Table 1, the yields (88-94%)
were excellent and the purities were satisfactory (93-97%).
1
Their H NMR, 13C NMR, and analytical data confirmed
the structures of all final products.
On the other hand, the PEG-bound intermediate 3
cleaved via another process was further investigated as
shown in Scheme II. For example, treatment of 3a with
50% TFA in CH2Cl2 at room temperature for 1 h yielded
2,4-dimethylquinoline-3-carboxylic acid 5a in 90% yield
and 95% HPLC purity.
General Procedure for the Preparation of Polysub-
stituted Quinolines (4a-4k)
To a solution of PEG 4000 bound acetoacetate acet
19a (2.0 g, 1.0 mmol) in CH2Cl2 (15 mL) was added 2-
1
aminoarylketones 2 (3.0 mmol) and PPA (2-3 drops) at
room temperature. The resulting mixture was subjected to
microwave irradiation at 400 W for 5 min at a temperature
of 110 oC, the mixture was then cooled to room temperature
and the solvent was removed under reduced pressure and
the PEG bound quinoline-3-carboxylate 3 was obtained by
precipitating and washing with excess cold ether (5 ´ 10
mL). After drying in vacuo, the intermediate 3 was added to
the MeONa (1N)/MeOH solution (15 mL) to cleave the
Transformation of 3a to the corresponding
carboxylic acid 5a
Scheme II
CH3
O
CH3
50%TFA
COOH
CH3
O
CH2Cl2, rt, 1h
N
H3C
N
3a
5a

Liquid-phase Organic Synthesis of Polysubstituted Quinolines
J. Chin. Chem. Soc., Vol. 58, No. 1, 2011 21
52.7, 24.2, 16.0; IR (KBr): n = 1728, 1610 cm–1; Anal.
Calcd for C13H12ClNO2: C, 62.53; H, 4.84; N, 5.61. Found:
C, 62.38; H, 4.96; N, 5.70.
product at room temperature for 18 h (checked by TLC).
After completion of the reaction, the residual PEG was pre-
cipitated by addition of Et2O (100 mL) to the mixture. For
completion of the precipitation, the suspension was left at 0
oC for another 30 min. The white precipitate was collected
and washed several times with Et2O (2 ´ 5 mL), and dried
in vacuo in 90% yield based on the original PEG. The crude
product was obtained by extraction with Et2O, dilution
with H2O (2 ´ 10 mL) and then removal of the solvent. All
crude products with 93-97% purity determined by HPLC,
were further purified by passing the crude product through
silica gel chromatographic column (10-15% ethyl acetate
in hexane) affording the pure products 4a-4k for their
structure analyses.
Methyl 6-chloro-2-methyl-4-phenylquinoline-3-carbox-
ylate (4e)
o
o
1
Yellow solid, mp 131-133 C (lit.7 mp 135 C); H
NMR: d = 8.02 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.0 Hz,
1H), 7.52-7.44 (m, 4H), 7.37-7.31 (m, 2H), 3.59 (s, 3H),
2.75 (s, 3H); 13C NMR: d = 168.3, 154.8, 148.0, 145.4,
135.0, 132.3, 131.0, 130.4, 129.1, 128.7, 128.4, 127.5,
125.7, 125.1, 52.4, 24.1; IR (KBr): n = 1734, 1586 cm–1;
Anal. Calcd for C18H14ClNO2: C, 69.35; H, 4.53; N, 4.49.
Found: C, 69.22; H, 4.66; N, 4.60.
Methyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-
3-carboxylate (4f)
Methyl 2,4-dimethyl quinoline-3-carboxylate (4a)
Oil (lit.8c oil); 1H NMR: d = 8.04 (d, J = 8.4 Hz, 1H),
7.95 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.45 (t, J =
7.5 Hz, 1H), 3.60 (s, 3H), 2.71 (s, 3H), 2.64 (s, 3H); 13C
NMR: d = 168.5, 154.4, 147.0, 141.3, 129.6, 128.8, 127.7,
126.2, 125.8, 123.6, 52.5, 23.9, 15.8; IR (neat): n = 1730,
1613 cm–1; Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09;
N, 6.51. Found: C, 72.41; H, 6.18; N, 6.60.
Yellow solid, mp 134-136 oC; 1H NMR: d = 8.05 (d, J
= 9.2 Hz, 1H), 7.55-7.26 (m, 6H), 3.58 (s, 3H), 2.78 (s, 3H);
13C NMR: d = 168.3, 154.8, 139.6, 135.5, 134.7, 133.4,
132.3, 130.4, 129.8, 129.2, 128.7, 128.4, 128.0, 127.6,
126.5, 125.8, 52.6, 23.8; IR (KBr): n = 1730, 1604 cm–1;
Anal. Calcd for C18H13Cl2NO2: C, 62.45; H, 3.78; N, 4.05.
Found: C, 62.32; H, 3.90; N, 4.12.
Methyl 6-nitro-2,4-dimethylquinoline-3-carboxylate
Methyl 2-methyl-4-phenylquinoline-3-carboxylate (4b)
White solid, mp 115-117 oC; 1H NMR: d = 8.10 (d, J =
8.4 Hz, 1H), 8.07-7.35 (m, 8H), 3.58 (s, 3H), 2.79 (s, 3H);
13C NMR: d = 167.8, 154.1, 147.5, 145.4, 135.7, 135.5,
130.3, 129.2, 128.9, 128.5, 128.3, 127.3, 126.5, 125.1,
52.2, 23.9; IR (KBr): n = 1730, 1584 cm–1; Anal. Calcd for
C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.80; H,
5.57; N, 5.14.
(4g)
Yellow solid, mp 78-80 oC; 1H NMR: d = 8.43 (d, J =
8.4 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 3.62 (s,
3H), 2.76 (s, 3H), 2.66 (s, 3H), 13C NMR: d = 168.5, 154.5,
148.3, 135.4, 132.8, 130.5, 129.4, 128.7, 127.5, 125.1,
52.8, 24.3, 16.2; IR (KBr): n = 1730, 1618 cm–1; Anal.
Calcd for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found:
C, 59.82; H, 4.81; N, 10.63.
Methyl 4-(2-chlorophenyl)-2-methylquinoline-3-car-
Methyl 2-methyl-6-nitro-4-phenylquinoline-3-carbox-
boxylate (4c)
Yellow solid, mp 123-125 oC; 1H NMR: d = 8.07-7.37
(m, 8H), 3.62 (s, 3H), 2.74 (s, 3H); 13C NMR: d = 168.7,
154.2, 146.8, 141.5, 133.2, 130.1, 129.8, 129.5, 128.8,
128.5, 128.2, 127.6, 127.1, 126.4, 126.2, 125.4, 52.5, 23.8;
IR (KBr): n = 1728, 1610 cm–1; Anal. Calcd for C18H14ClNO2:
C, 69.35; H, 4.53; N, 4.49. Found: C, 69.15; H, 4.68; N,
4.62.
ylate (4h)
Yellow solid, mp 159-161 oC; 1H NMR: d = 8.50-7.40
(m, 8H), 3.68 (s, 3H), 2.73 (s, 3H); 13C NMR: d = 168.5,
155.1, 148.4, 145.6, 135.4, 132.6, 131.2, 130.5, 129.4,
128.8, 128.5, 127.8, 125.6, 124.6, 52.5, 24.4; IR (KBr): n =
1731, 1620, 1526 cm–1; Anal. Calcd for C18H14N2O4: C,
67.08; H, 4.38; N, 8.69. Found: C, 66.91; H, 5.55; N, 8.54.
Methyl 4-benzyl-2-methylquinoline-3-carboxylate (4i)
White solid, mp 103-105 oC; 1H NMR: d = 8.06 (d, J
= 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.5 Hz,
1H), 7.44 (t, J = 7.5 Hz, 1H), 7.36-7.20 (m, 5H), 3.95 (s,
2H), 3.58 (s, 3H), 2.62 (s, 3H); 13C NMR: d = 168.4, 154.5,
147.3, 141.6, 131.2, 129.8, 128.8, 128.5, 128.2, 127.9,
Methyl 6-chloro-2,4-dimethylquinoline-3-carboxylate
(4d)
White solid, mp 64-66 oC; 1H NMR: d = 8.10 (d, J =
8.4 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 3.60 (s,
3H), 2.75 (s, 3H), 2.65 (s, 3H); 13C NMR: d = 168.4, 154.3,
146.3, 135.6, 132.6, 130.2, 129.3, 128.3, 127.4, 124.8,

22 J. Chin. Chem. Soc., Vol. 58, No. 1, 2011
Zhang et al.
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127.7, 126.5, 126.2, 124.2, 51.9, 37.3, 23.5; IR (KBr): n =
1724, 1565 cm–1; Anal. Calcd for C19H17NO2: C, 78.33; H,
5.88; N, 4.81. Found: C, 78.14; H, 6.02; N, 5.96.
Methyl 4-benzyl-6-chloro-2-methylquinoline-3-carbox-
ylate (4j)
White solid, mp 117-119 oC; 1H NMR: d = 8.08 (d, J =
8.4 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.35-
7.25 (m, 2H), 7.22-7.17 (m, 3H), 3.98 (s, 2H), 3.60 (s, 3H),
2.65 (s, 3H); 13C NMR: d = 168.5, 154.2, 146.6, 135.7,
132.5, 131.5, 130.4, 129.2, 128.9, 128.4, 128.2, 127.9,
127.6, 125.2, 52.0, 37.6, 24.0; IR (KBr): n = 1722, 1580
cm–1; Anal. Calcd for C19H16ClNO2: C, 70.05; H, 4.95; N,
4.30. Found: C, 69.77; H, 5.12; N, 4.41.
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Methyl 4-benzyl-2-methyl-6-nitroquinoline-3-carbox-
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Yellow solid, mp 164-166 oC; 1H NMR: d = 8.45 (d, J
= 8.4 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H),
7.45-7.28 (m, 5H), 4.02 (s, 2H), 3.62 (s, 3H), 2.66 (s, 3H);
13C NMR: d = 168.8, 154.5, 148.5, 135.3, 133.1, 131.4,
130.8, 129.6, 129.2, 128.7, 128.3, 127.9, 127.8, 126.0,
52.6, 37.7, 24.5; IR (KBr): n = 1730, 1618 cm–1; Anal.
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C, 67.63; H, 4.95; N, 8.45.
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2,4-Dimethylquinoline-3-carboxylic acid (5a)
o
Colorless solid, mp 270-272 C (lit.20 mp 270-272
oC); 1H NMR (DMSO-d6): d = 11.98 (s, 1H), 7.82-7.21 (m,
4H), 2.45 (s, 3H), 2.32 (s, 3H); 13C NMR: d = 200.2, 160.1,
149.0, 142.5, 130.3, 129.4, 128.2, 127.7, 126.3, 123.6,
31.6, 19.2; IR (KBr): n = 3466, 1690, 1656 cm–1; Anal.
Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C,
71.45; H, 5.75; N, 6.77.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from
the National Natural Science Foundation of China (No.
21062007), NSF of Jiangxi Province (No. 2009GZH0016)
and the Research Program of Jiangxi Province Department
of Education (No. GJJ10385).
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