A mild and efficient synthesis of 4-aryl-quinolin-2(1H)-ones via a tandem amidation/Knoevenagel condensation of 2-amino-benzophenones with esters or lactones

Article abstract of DOI:10.1016/S0040-4039(03)00889-X

Using LiHMDS as the base, a tandem amidation/Knoevenagel condensation of 2-aminobenzophenones with α-methylene esters or lactones gives 4-aryl-quinolin-2(1H)-ones in 65-96% yield. This method is mild, highly efficient, and amenable to scaleup.

Full text of DOI:10.1016/S0040-4039(03)00889-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4271–4273
A mild and efficient synthesis of 4-aryl-quinolin-2(1H)-ones via
a tandem amidation/Knoevenagel condensation of
2-amino-benzophenones with esters or lactones
Jianji Wang,* Robert P. Discordia, Gerard A. Crispino, Jun Li, John A. Grosso,
Richard Polniaszek† and Vu C. Truc
Bristol-Myers Squibb Pharmaceutical Research Institute, Process Research & Development, One Squibb Drive, New Brunswick,
NJ 08903, USA
Received 10 March 2003; revised 3 April 2003; accepted 3 April 2003
Abstract—Using LiHMDS as the base, a tandem amidation/Knoevenagel condensation of 2-aminobenzophenones with a-methyl-
ene esters or lactones gives 4-aryl-quinolin-2(1H)-ones in 65–96% yield. This method is mild, highly efficient, and amenable to
scaleup. © 2003 Elsevier Science Ltd. All rights reserved.
4-Aryl-quinolin-2(1H)-ones 1 are inhibitors of acyl
coenzyme A and cholesterol acyltransferase1 and are
potent openers of the high conductance, calcium-acti-
vated K+-channels.2 These compounds are useful as
hypolipidemic, antiatherosclerosis agents and in afflic-
tions arising from dysfunction of cellular membrane
polarization and conductance. As part of our research
program, we required an efficient synthesis of 4-aryl-
quinolin-2(1H)-ones. In particular, we were interested
in a practical synthesis of compound 7, which we
needed in large quantities.
expanded to synthesize 4-aryl-quinolin-2(1H)-ones by
condensation of 2-amino aryl aldehydes or ketones with
a-methylene esters or carboxylic acids. However, an
additional activating group, such as -COR, -COOR,
-CONR1R2, -CN, -NO2, or -COOH, is required at the
a-position of the ester or carboxylic acid in order to
obtain a good yield of 4-aryl-quinolin-2(1H)-ones.6–8
It has been reported that with unactivated a-methylene
esters or carboxylic acids, such as PhCH2COOEt, the
reaction using piperidine as the base at elevated temper-
ature (100–180°C) gave an impure product in poor
yield (17%).8 With t-BuOK as the base, the reaction
afforded the cyclic hydroxyl intermediate, and POCl3
was required to finish conversion to the expected
product.9 In this communication we describe our efforts
toward the mild and efficient synthesis of 4-aryl-quino-
lin-2(1H)-ones via a tandem amidation/Knoevenagel
condensation of 2-aminobenzophenones with unacti-
vated a-methylene esters or lactones using LiHMDS.
Under the reaction conditions described in Scheme 1,
the tandem amidation/Knoevengel condensation of
commercially available or readily prepared 2-amino-
benzophenones with a-methylene esters or lactones
gave 4-aryl-quinolin-2(1H)-ones in good to excellent
yields (Table 1).10 As the proposed reaction path shown
in Scheme 2 indicates, 3 equiv. of LiHMDS are
required for reaction completion. The first equivalent of
LiHMDS deprotonates the aniline NH2 to activate the
nitrogen for amidation with g-valerolactone. In our
The most common method for synthesis of quinolines is
the Friedlander quinoline synthesis, condensation of
2-amino aryl aldehydes or ketones with a-methylene
aldehydes or ketones.3–5 This methodology has been
* Corresponding author. Fax: (732)-519-1745; e-mail: jianji.wang@
bms.com
† Present address: Gilead Science, 333 Lakeside Drive, Foster City,
CA 94404, USA.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00889-X

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J. Wang et al. / Tetrahedron Letters 44 (2003) 4271–4273
Scheme 1.
Table 1. Synthesis of 4-aryl-quinolin-2(1H)-ones 1a–j from 2-aminobenzophenones 2a–j
Entry
R1
R2
R3
Ester (R5, R6) or lactone (Z)
(equiv.)
LiHMDS
(equiv.)
R4
Product
Isolated yield
(%)
1
2
3
4
5
6
7
8
9
5-Cl
H
H
R5=H; R6=Et (2 equiv.)
R5=Et; R6=Et (2 equiv.)
R5=H; R6=n-Bu (2 equiv.)
Z=CHMe (4.5 equiv.)
Z=(CH2)2 (4.5 equiv.)
Z=CHMe (4.5 equiv.)
Z=CHMe (4.5 equiv.)
Z=CH2 (4.5 equiv.)
5
5
5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
H
Et
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
96
80
92
82
65
76
93
66
75
90
5-CF3
5-CF3
H
H
4-Me
5-Cl
5-CF3
5-CF3
5-CF3
5%-Cl
5%-Cl
H
H
H
OMe
OMe
H
H
H
H
OBn
OMe
CH2CHOHMe
(CH2)3OH
CH2CHOHMe
CH2CHOHMe
CH2CH2OH
CH2CH2OH
CH2CH2OH
H
5%-Cl
5%-Cl
5%-Cl
Z=CH2 (4.5 equiv.)
10
MOM Z=CH2 (4.5 equiv.)
1j
Scheme 2. Proposed reaction path for the tandem amidation/Knoevenagel condensation.
previous report,11 we demonstrated that quenching the
reaction at this stage by addition of water afforded the
amidation products in high yield. The second equiva-
lent of LiHMDS effects deprotonation of the amide
NH to form dianion 3. The third equivalent of LiH-
MDS is necessary to deprotonate the a-H of the amide,
the resulting anion subsequently attacking the carbonyl
group to form trianion 4. Quenching the reaction at
this stage by addition of water and rapid extraction
afforded the cyclic tertiary alcohol 5. In another experi-
ment, intermediate 5 was isolated in 72% yield and its
structure demonstrated by NOE experiments (Scheme
2). Finally, the syn dehydration of 5 by LiOH (during
prolonged workup) generated the expected product 1d.
It is noteworthy that in the series of the a-methylene
lactones, 7.5 equiv. of LiHMDS and 4.5 equiv. of
lactone were necessary, while in the series of a-methyl-
ene esters only 5 equiv. of LiHMDS and 2 equiv. of
ester were required for reaction completion. This differ-
ence could be attributable to the relative propensity for
self-condensation of a-methylene lactones and a-meth-
ylene esters in the presence of LiHMDS with the former
being more reactive. Indeed, the self-condensation
product 6 of g-valerolactone was identified during the

J. Wang et al. / Tetrahedron Letters 44 (2003) 4271–4273
4273
isolation of 5. The results and equivalents of LiHMDS
10. Representative procedure: A 250 ml, 2-necked flask was
charged with 2j (4.0 g, 11.1 mmol) and THF (10 ml). The
resulting solution was cooled to 0°C and LiHMDS (1 M
in THF, 83.3 ml) was added over 10 min. The internal
temperature was controlled <5°C. The resulting brown
solution was stirred at 0°C for 10 min, then g-butyrolac-
tone (4.3 g, 50.0 mmol) was added over 2 min. The
reaction solution was allowed to warm to rt and stirring
was continued for 1 h. Water (10 ml) was added over 5
min, and the resulting two-phase solution was stirred at
25°C for 2 h. Ethyl acetate (100 ml) was added. The
organic solution was washed with water (30 ml) and brine
(50 ml) and dried over anhydrous sodium sulfate.
Removal of the solvents gave a residue which was
purified by column chromatography on silica gel. The
fraction eluted by ethyl acetate/n-hexane (1:5) was col-
lected. Removal of the solvents gave 4.3 g (90%, HPLC
AP 96) of 1j as a white solid. HRMS FAB (m-NAB)
calcd for C20H17ClF3NO4: (M+1)+ 428.0901; found
428.0876. IR (CHCl3): 3431, 2985, 1654, 1490, 1385,
and the a-methylene esters or lactones are listed in Table
1.
Utilizing the methodology disclosed here, compounds 1h,
1i and 1j were prepared efficiently and readily converted
to the quinolin-2(1H)-one 7 in good to excellent yield by
removal of the protecting groups using the standard
methods. Based on this work, we have developed a
scalable and highly efficient, five-step synthesis of the
target molecule 7 from 4-trifluoromethyl aniline. We will
disclose the experimental details in the near future.
In conclusion, a tandem amidation/Knoevenagel con-
densation of 2-aminobenzophenones with unactivated
a-methylene esters or lactones promoted by LiHMDS
has been described as a general and practical approach
for a mild and efficient synthesis of 4-aryl-quinolin-
2(1H)-ones.
1326, 1285, 1225, 1127, 1035, 955 cm−1 1H NMR (400
;
MHz, DMSO-d6): l 12.28 (s, 1H, NH), 7.78 (d, J=8.7,
1H), 7.56 (d, J=8.2, 1H), 7.39 (d, J=8.2, 1H), 7.39 (s,
1H), 7.35 (d, J=8.7, 1H), 7.02 (s, 1H), 5.17 (d, J=6.8,
1H), 5.05 (d, J=6.8, 1H), 4.55 (b, 1H, OH), 3.43–3.35
(m, 2H), 3.07 (s, 3H); 2.61–2.53 (m, 1H), 2.42–2.38 (m,
1H) ppm; 13C NMR (400 MHz, DMSO-d6): 161.9, 152.5,
143.8, 140.1, 131.3, 130.3, 130.2, 126.6, 126.1, 125.9,
124.5 (q, J=271, CF3), 122.5, 122.3 (q, J=32), 119.6,
116.7, 116.6, 94.3, 59.8, 56.3, 31.8 ppm.
Acknowledgements
The authors would like to thank Mr. J. Friedman for the
preliminary study and Dr. C. Pathirana for the NOE
experiments. We also want to thank Drs. R. Mueller, J.
Scott, and E. Delaney for helpful discussions.
References
Compound 5: MS: (M+H)+ 298; 1H NMR (400 MHz,
DMSO-d6): l 10.45 (s, 1H, N-H), 7.46–6.929 (m, 9H),
6.15 (s, 1H, OH), 4.57 (s, 1H, OH), 3.85–3.81 (m, 1H),
3.20–3.16 (m, 1H), 1.65–1.53 (m, 2H), 1.05 (d, J=6.8,
3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): l
171.8, 143.9, 136.4, 133.2, 128.5, 128.2, 127.2, 126.3,
125.9, 122.8, 115.6, 75.3, 65.4, 49.3, 34.0, 24.7 ppm.
Compound 1c: MS: (M+H)+ 354; 1H NMR (400 MHz,
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(s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
161.8, 155.3, 147.7, 141.6, 130.7, 126.9, 126.3, 125.0,
124.1, 123.6, 122.7, 122.5, 122.1, 118.3, 117.2, 113.9, 56.2
ppm.
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