The first proline-catalyzed Friedlander annulation: Regioselective synthesis of 2-substituted quinoline derivatives

Article abstract of DOI:10.1002/ejoc.200800121

The first proline-catalyzed Friedlander annulation for the synthesis of 2-substituted 4-trifluoromethyl quinoline derivatives is described. Excellent regioselectivity as well as good yields were shown in a variety of cases, and a tandem aldolcyclization pathway might be involved. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800121

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800121
The First Proline-Catalyzed Friedlander Annulation: Regioselective Synthesis
of 2-Substituted Quinoline Derivatives
Biao Jiang,*[a] Jia-jia Dong,[a] Yun Jin,[a] Xiao-long Du,[a] and Min Xu[a]
Keywords: Aldol reactions / Quinoline / Cyclization / Proline
The first proline-catalyzed Friedlander annulation for the
synthesis of 2-substituted 4-trifluoromethyl quinoline deriva-
tives is described. Excellent regioselectivity as well as good
yields were shown in a variety of cases, and a tandem aldol-
cyclization pathway might be involved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
methods for the synthesis of quinoline compounds starting
from aniline, such as Skraup, Doebner–Miller and Combes,
were inappropriate for the preparation of trifluoromethyl
quinoline compounds owing to the unavailability of starting
materials and poor regioselectivity.[14] An indirect synthetic
protocol for these types of compounds via the quinolinone
intermediate was also reported, although the overall yield
was low.[15] Previously, our group disclosed the first ZnII-
catalyzed one-pot reaction of alkynes with o-trifluoroacetyl
anilines toward the synthesis of 4-trifluoromethyl quinoline
derivatives.[16] Herein, we report the first proline-catalyzed
Friedlander annulation toward the synthesis of 4-trifluoro-
methyl quinoline derivatives. We envisioned that 4-trifluoro-
methyl quinoline derivatives could be synthesized by the
proline-catalyzed aldol reaction followed by the acid-cata-
lyzed cyclization sequence as outlined in Scheme 1.
Introduction
The Friedlander synthesis,[1] which involves the forma-
tion of quinoline derivatives by condensation of aromatic
o-aminoaldehydes or o-aminoketones with an aldehyde- or
a ketone-containing methylene group alpha to the carbonyl
moiety, was regarded as one of the most simple and
straightforward methods for the synthesis of substituted
quinolines. Depending on the catalyst employed, two dif-
ferent reaction pathways that include an aldol cyclization
and a Schiff base cyclization sequence have been pos-
tulated.[2] Over the past years, several catalysts such as
amines,[3] Brønsted acids,[4] Lewis acids[5] and molecular io-
dine[6] were developed for the Friedlander reaction. In ad-
dition, some metal complexes such as Ru,[7] Ir[8] and Rh[9]
were found to be successful catalysts for the modified Fried-
lander reaction.[10] However, most of the methods suffered
from harsh reaction conditions, poor yields or the use of
expensive catalysts. In recent years, proline, the bifunctional
and cheap catalyst, played an important role in the direct
aldol reaction between an aldehyde and an unmodified
ketone via an enamine intermediate.[11] By considering the
postulated Friedlander annulation pathway, it is possible
that the proline-catalyzed aldol reaction followed by a cycli-
zation sequence would deliver substituted quinolines. To
our surprise, it was found that research on proline-catalyzed
Friedlander annulation has been mostly ignored so far.[12]
Fluorine-containing quinoline derivatives, particularly
trifluoromethyl quinoline derivatives, have attracted con-
siderable attention because of their unique physical, chemi-
cal and biological properties.[13] However, conventional
Scheme 1. Proposed pathway for the synthesis of 4-trifluoromethyl
quinolines.
Results and Discussion
[a] Shanghai Institute of Organic Chemistry
Chinese Academy of Science
Initially, acetone and o-trifluoroacetyl anilines were used
as model substrates for the aldol reaction. For comparison,
a variety of catalysts were tried, and the results are shown
in Table 1. Surprisingly, in addition to proline, an inorganic
354 Fenglin Road, Shanghai 200032, P. R. China
Fax: +86-21-6416-6128
E-mail: jiangb@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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B. Jiang, J.-j. Dong, Y. Jin, X.-l. Du, M. Xu
SHORT COMMUNICATION
base such as NaOH as well as an organic base such as am-
When the unsymmetrical methyl ketone such as methyl
monia and piperidine led to the formation of 4-trifluorome- ethyl ketone was investigated, excellent regioselectivity[17]
thyl quinoline 2a directly in one pot at room temperature was obtained when using proline as the catalyst (Table 2,
in good yields (Entries 5, 6, 8). Interestingly, the amino acid Entry 1). The methyl residue reacted in preference to the
alanine also gave a moderate yield for the product (Entry much bulkier methylene moiety, and the 2-ethyl 4-trifluoro-
4). In particular, when 30 mol-% proline was used as the methyl quinoline product was formed exclusively in good
catalyst, the desired quinoline was obtained in an almost yield. When a base such as NaOH was used as the catalyst,
quantitative yield, and the reaction time was significantly 4-trifluoromethyl quinoline products were obtained as a
shorter (12 h, Entry 2). When the catalyst loading was de- mixture of isomers because of the poor regioselectivity of
creased to 5 mol-%, a much longer reaction time was re- the aldol reactions (Entry 2).
quired (Entry 3). In addition, it was found that no other
intermediate was isolated when proline was used as the cat-
alyst, which prompted us to investigate the reaction path-
way.
Table 2. Regioselectivty investigations with methyl ethyl ketone as
the substrate.
Table 1.Catalysts studied in the Friedlander annulation with ace-
tone and o-trifluoroacetyl anilines as substrates.
Entry
Catalyst
t [h]
Yield [%][a]
1
2
3
4
none
48
12
36
48
24
24
72
48
no reaction
Conver-
98[b]
96
Entry Catalyst
Solvent
T [°C]
t [h]
2f/4/5[a]
sion [%][a]
proline
proline[c]
alanine
NaOH
NH3·H2O
NEt3
1
proline
NaOH
DMSO
DMSO/
H2O
50
48
4
100
100
100:0:0
66
85
89
Ͻ5
72
5[d]
6[e]
7
2[b]
r.t.
38:52:10
3
4
FeCl3·6H2O EtOH
50
70
48
5
0
97
–
CF3COOH[c]
–
64:36:0
8
piperidine
[a] Determined by 19F NMR and H NMR spectroscopy. [b] 20%
Aqueous solution was used. [c] Neat CF3COOH was used.
1
[a] Yield was determined by 19F NMR spectroscopy. [b] Isolated
yield. [c] 5 mol-% Proline was used. [d] 20% Aqueous solution was
used. [e] 28% Aqueous solution was used.
19F NMR and 1H NMR spectroscopy were used to mon-
itor the reaction. However, neither the Schiff base interme-
diate nor the aldol adduct, with the exception of the sub-
strate and product, was detected. The result indicates that
the generated intermediate was highly reactive and under-
went automatic dehydration and cyclization to provide the
final quinoline product. Therefore, in order to trap the in-
termediate by slowing down the tandem reaction, bulky tri-
phenylmethyl (Tr) protected o-trifluoroacetyl aniline was
employed as the substrate. The aldol adduct 3 was isolated
in 81% yield, which suggests that this reaction possibly fol-
lows the aldol-cyclization pathway when proline is used as
the catalyst (Scheme 2).
Other typical Friedlander annulation catalysts, such as
the Lewis acid FeCl3·6H2O,[18] could not catalyze such a
reaction at all (Entry 3). When the Brønsted acid
CF3COOH was used as the catalyst,[19] poor regioselectivity
was still obtained (Entry 4).
On the basis of the above results, a variety of unsymmet-
rical methyl ketones and substituted o-trifluoroacetyl ani-
lines with different electronic proprieties were investigated
for the catalytic activity of proline. As shown in Table 3,
the desired 2-substutited 4-trifluoromethyl quinolines were
exclusively obtained in excellent yields.
The electronic properties of the substituted o-trifluoro-
acetyl anilines substrates did not dramatically affect the
yield (Entries 1–5). In addition to the linear alkyl methyl
ketones, bulky unsymmetrical methyl ketones, such as cy-
clopropyl methyl ketone, also gave satisfactory yields at ele-
vated temperatures (50 °C) with excellent regioselectivity
(Entries 6–11). In particular, for cyclic ketone substrates,
such as cyclohexanone, the desired Friedlander annulation
proceeded smoothly as well (Scheme 3). Other function-
alized ketones, such as ethyl pyruvate and ethyl acetylace-
tate, were also tried, but only a low conversion (≈5%) was
obtained, which needs to be optimized in the future.
Scheme 2. Reaction with the N-protected o-trifluoroacetyl aniline
afforded the aldol adduct.
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Eur. J. Org. Chem. 2008, 2693–2696

The First Proline-Catalyzed Friedlander Annulation
CDCl3): δ = –62.2 ppm. MS (EI): m/z (%) = 245 (100) [M+]. IR
Table 3. Proline catalyzed Friedlander annulation for the synthesis
of 4-trifluoromethyl quinoline derivatives.[a]
(KBr): ν = 3067, 1959, 1615, 1495, 1382, 1349 cm–1. HRMS (EI):
˜
calcd. for C11H8ClF3N+ 246.0302; found 246.0292.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and 1H NMR and 13C NMR spectra
for 2a–2l and 3.
Entry R1
R2
Product t [h]
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Et
Pr
iBu
c-C3H5 p-Cl
nHex
p-Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
24
24
24
48
24
48
48
72
48
48
48
r.t.
r.t.
r.t.
r.t.
r.t.
50
50
50
50
50
50
98
94
95
93
95
93
93
92
85
90
91
Acknowledgments
p-OMe
o-OMe
p-CF3
H
p-Cl
p-Cl
This work was supported by the Shanghai Municipal Committee
of Science & Technology and the National Natural Science Foun-
dation of China.
p-Cl
9
10
11
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Conclusions
We have demonstrated the highly regioselective synthesis
of 2-substituted 4-trifluoromethyl quinoline derivatives by
unprecedented proline-catalyzed Friedlander annulation.
This method probably involves a tandem aldol-cyclization
reaction, which gives way to a novel, mild, efficient and
cheap route for a wide range of 2-substituted 4-trifluorome-
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Experimental Section
General Procedure for Preparation of 2a–l and 3: A mixture of pro-
line (, or  or ) (17 mg, 0.15 mmol), o-trifluoroacetyl aniline
(0.5 mmol) and methyl ketone (3.5 mmol) in DMSO (2 mL) was
stirred at the temperature indicated in Table 3. After the reaction
was complete, H2O (6 mL) was added and the reaction mixture was
extracted with ethyl acetate. The combined organic phases were
washed with brine and dried with anhydrous Na2SO4. Concentra-
tion under reduced pressure provided the crude product, which was
purified by flash chromatography on silica gel (hexane/ethyl ace-
tate, 20:1) to afford 4-trifluoromethyl quinoline derivatives.
[12] In ref.[3a] proline was employed as a catalyst for screening; how-
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6-Chloro-2-methyl-4-(trifluoromethyl)quinoline (2a): Yield: 98%;
1
white solid. H NMR (300 MHz, CDCl3): δ = 8.05–8.10 (m, 2 H),
7.70 (dd, J = 9.0, 2.4 Hz, 1 H), 7.63 (s, 1 H), 2.77 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 158.6, 146.8, 133.4, 133.2, 130.9,
123.0, 122.7, 121.7, 121.7, 119.6, 25.2 ppm. 19F NMR (282 MHz,
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Eur. J. Org. Chem. 2008, 2693–2696
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B. Jiang, J.-j. Dong, Y. Jin, X.-l. Du, M. Xu
SHORT COMMUNICATION
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Received: February 1, 2008
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Published Online: April 15, 2008
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