Synthesis of 3-quinolinecarboxylic acid esters from the Baylis-Hillman adducts of 2-halobenzaldehyde N-tosylimines

Article abstract of DOI:10.1016/S0040-4039(01)00552-4

3-Quinolinecarboxylic acid ethyl esters 4 were prepared from 1, the Baylis-Hillman adducts of o-halobenzaldehyde N-tosylimines, in a one-pot reaction.

Full text of DOI:10.1016/S0040-4039(01)00552-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3737–3740
Synthesis of 3-quinolinecarboxylic acid esters from the
Baylis–Hillman adducts of 2-halobenzaldehyde N-tosylimines
Jae Nyoung Kim,* Hong Jung Lee, Ka Young Lee and Hyoung Shik Kim
Department of Chemistry, Chonnam National University, Kwangju 500-757, South Korea
Received 26 February 2001; revised 27 March 2001; accepted 30 March 2001
Abstract—3-Quinolinecarboxylic acid ethyl esters 4 were prepared from 1, the Baylis–Hillman adducts of o-halobenzaldehyde
N-tosylimines, in a one-pot reaction. © 2001 Elsevier Science Ltd. All rights reserved.
The Baylis–Hillman reaction is one of the most power-
ful carbonꢀcarbon bond-forming methods in organic
synthesis.1 The Baylis–Hillman adducts, which are
allylic alcohol or allylic amine derivatives, can be
formed most often by the reaction of activated vinyls
and carbonyl compounds or N-tosylimines.1 Besides
the usefulness of these Baylis–Hillman adducts them-
selves, further derivatization with various nucleo-
philic reagents toward synthetically useful compounds
has been studied in depth by us and other groups.2
Some papers reported on the formation of hetero-
cyclic compounds, including quinoline from the Baylis–
Hillman adducts.3
cations as pharmaceuticals and agrochemicals, as well
as being general synthetic building blocks.4b Many syn-
thetic methods have been developed for the preparation
of quinolines,5 but due to their great importance, the
development of novel synthetic methods remains an
active research area.6
Recently, we reported on the synthesis of 4-hydroxy-3-
ethoxycarbonylquinoline N-oxide derivatives from the
Baylis–Hillman adducts of 2-nitrobenzaldehydes.3a As a
continuation of our work, we intended to examine the
possibility of transforming the Baylis–Hillman adducts
of o-halobenzaldehyde N-tosylimines 1 into the corre-
sponding quinolines.
Quinolines and their derivatives occur in numerous
natural products.4 Many quinolines display interesting
physiological activities and have found attractive appli-
The choice of the Baylis–Hillman adducts 1 as sub-
strates was based on the following assumptions: (1)
NHTs
COOEt
COOEt
NHTs
TsNH2 (0.2-1.0 equiv.)
Xn
Xn
K2CO3 (2.0-3.0 equiv.)
DMF, 80-90 oC, 1-10 h
X
X
1a-f
2a-f (E)
X, Xn = Cl, F
COOEt
COOEt
SNAr
- HX
- TsH
Xn
Xn
N
N
Ts
4a-f
3a-f
Scheme 1.
Keywords: 3-quinolinecarboxylic acid ethyl esters; Baylis–Hillman adducts.
* Corresponding author. Fax: 82-62-530-3381; e-mail: kimjn@chonnam.chonnam.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00552-4

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J. N. Kim et al. / Tetrahedron Letters 42 (2001) 3737–3740
catalytic amounts of tosylamide might effect the rear-
rangement of 1 toward the thermodynamically more
stable rearranged tosylamide derivatives 2; (2) nucleo-
philic aromatic substitution reaction can be easily con-
ducted at the ortho position; and (3) elimination of
p-toluenesulfinic acid is possible to give the quinolines 4
directly in a one-pot reaction, as shown in Scheme 1.
Table 1. In some cases, when we used catalytic amounts
of tosylamide in the reaction, long reaction times were
needed to obtain appreciable amounts of products. In
such cases (entries c, d, and f in Table 1), we used
0.5–1.0 equiv. of tosylamide.
However, reaction of 1g under the reaction conditions
gave the 1,2-dihydroquinoline derivative 3g in 81%
yield instead of the expected quinoline 4g. Elimination
of p-toluenesulfinic acid was not efficient under the
reaction conditions even after a long reaction time.
Synthesis of quinoline 4g was realized by the reaction
of 3g and DBU in THF in 69% yield (Scheme 2). As we
already stated in other cases, 3a–f, elimination of p-
Reaction of the Baylis–Hillman adduct 1a in N,N-
dimethylformamide in the presence of potassium car-
bonate (2.0 equiv.) and tosylamide (0.2 equiv.) at
80–90°C afforded the desired quinoline 4a in 76% yield
in a short time.7 The reaction conditions and yields of
products for the representative examples are shown in
Table 1. One-pot synthesis of 3-ethoxycarbonylquinolines 4
Entry
Conditions
B-H adducts (1)
Quinolines ( )
Yield (%)
76a
4
Cl
NHTs
Cl
Cl
COOEt
COOEt
TsNH2 (0.2 equiv.)
K2CO3 (2.0 equiv.)
1 h
a
1a
4a
N
N
N
N
N
N
NHTs
COOEt
COOEt
TsNH2 (0.2 equiv.)
K2CO3 (2.0 equiv.)
7 h
79b
b
c
4b
1b
Cl
Cl
Cl
Cl
Cl
NHTs
COOEt
COOEt
TsNH2 (0.5 equiv.)
K2CO3 (3.0 equiv.)
2 h
77
4a
1c
F
F
NHTs
F
COOEt
COOEt
TsNH2 (1.0 equiv.)
K2CO3 (3.0 equiv.)
7 h
75
d
e
f
1d
4d
F
NHTs
COOEt
COOEt
TsNH2 (0.2 equiv.)
K2CO3 (3.0 equiv.)
5 h
75
1e
4e
F
F
F
NHTs
F
COOEt
COOEt
TsNH2 (1.0 equiv.)
K2CO3 (3.0 equiv.)
10 h
71c
4f
1f
F
F
aN-(p-Toluenesulfonyl)-3-ethoxycarbonyl-5-chloro-1,2-dihydroquinoline (3a) was obtained in 8% yield.
b
obtained in 10% yield.
N-(p-Toluenesulfonyl)-3-ethoxycarbonyl-7-chloro-1,2-dihydroquinoline (3b) was
cN-(p-Toluenesulfonyl)-3-ethoxycarbonyl-7-flouro-1,2-dihydroquinoline (3f) was obtained in 6% yield.
3-Ethoxycarbonyl-7-(p-toluenesulfonamido)quinoline (5f) was
also isolated in 11% yield.

J. N. Kim et al. / Tetrahedron Letters 42 (2001) 3737–3740
3739
NHTs
TsNH2 (0.2 equiv.)
COOEt
COOEt
COOEt
DBU/THF
rt, 24 h
K2CO3 (2.0 equiv.)
DMF, 80-90 oC, 2 h
N
F
N
Ts
4g (69%)
3g (81%)
1g
Scheme 2.
NHTs
CN
TsNH2 (0.2 equiv.)
K2CO3 (3.0 equiv.)
DMF, 80-90 oC, 2 h
F
F
1h
CN
CN
NHTs
+
+
CN
N
F
F
F
F
N
Ts
2h-Z (26%)
3h (2%)
4h (11%)
Scheme 3.
OH
NO2
NHTs
X
OH
Xn
Xn
Xn
Xn
COOEt
COOEt
COOEt
1. TFA, 60-70 oC
2. Ph3P, THF, reflux
(reference 3a)
N
H
N
COOEt
TsNH2, K2CO3
DMF, 80-90 oC
(this paper)
Scheme 4.
The nitrile substituted Baylis–Hillman adduct 1h pro-
duced low yields of dihydroquinoline 3h (2%) and
quinoline 4h (11%). Instead, we could obtain the rear-
ranged tosylamide derivative 2h (Z-form) as the major
product,2a–c which cannot undergo the requisite SNAr
reaction (Scheme 3).
toluenesulfinic acid occurred readily under the reaction
conditions to give the corresponding quinolines 4a–f in
a one-pot reaction. The discrepancy between 1g and
1a–f might be due to the subtle difference in the acidity
of the proton at the 2-position of the corresponding
dihydroquinolines 3g and 3a–f. Depending on the sub-
strate, we could isolate low yields of 3 and/or other
compounds, such as 5f (see footnotes a–c in Table 1).
Quinoline 5f was generated from the initially formed 4f
by successive SNAr reactions with tosylamide at the
7-position.
It is interesting to compare these results with our
previous paper.3a As shown in Scheme 4, 4-hydroxy-3-
ethoxycarbonylquinolines can be synthesized from the
Baylis–Hillman adducts of o-nitrobenzaldehydes,3a
whereas 3-ethoxycarbonylquinolines can be prepared
from the Baylis–Hillman adducts of o-halobenzalde-
hyde N-tosylimines.
The reaction mechanism is shown in Scheme 1 (vide
sufra) and is as follows: (1) tosylamide catalyzed succes-
sive SN2% type reactions of 1a–f to form the primary
rearranged allylic tosylamides 2a–f (selective formation
of the E-isomer);2a–c (2) SNAr reaction with the aid of
potassium carbonate to produce dihydroquinolines 3a–
f; and, finally, (3) elimination of p-toluenesulfinic acid
gave quinolines 4a–f.
Acknowledgements
This work was supported by a Korea Research Foun-
dation Grant (KRF-2000-015-DP0275).

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J. N. Kim et al. / Tetrahedron Letters 42 (2001) 3737–3740
rocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.;
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7. Typical procedure for the synthesis of 4a and some
selected spectroscopic data were as follows: A stirred
solution of 1a (860 mg, 2 mmol),8 tosylamide (70 mg, 0.4
mmol), and K2CO3 (552 mg, 4 mmol) in N,N-dimethylfor-
mamide (5 mL) was heated at 80–90°C for 1 h. After
cooling to room temperature, the reaction mixture was
poured into a cold HCl solution and extracted with ether.
After the usual work-up process, column chromatographic
purification (hexane/ether, 8:2) gave 4a as a white solid,
360 mg (76%); mp 97–98°C; IR (KBr): 3299, 2987, 1724,
1
1279 cm−1; H NMR (CDCl3): l 1.48 (t, J=7.2 Hz, 3H),
4.51 (q, J=7.2 Hz, 2H), 7.66–7.78 (m, 2H), 8.09 (dt,
J=8.1 and 1.2 Hz, 1H), 9.22 (dd, J=2.1 and 0.9 Hz, 1H),
9.48 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3): l 14.33,
61.75, 124.10, 125.26, 127.45, 128.63, 131.38, 132.68,
135.44, 150.41, 150.70, 164.99; MS (70 eV) m/z (rel. int.):
99 (38), 162 (66), 190 (100), 192 (35), 207 (54), 235 (M+,
60), 237 (M++2, 20).
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see Refs. 2b and 2c.
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