Friedlaender synthesis of quinolines using a lewis acid-surfactant- combined catalyst in water

Article abstract of DOI:10.1002/adsc.200600527

In water, Friedlaender annulation using Lewis acid-surfactant-combined catalyst provides a mild and efficient route for the synthesis of quinolines. Employing a catalytic amount of scandium tris(dodecyl sulfate) [Sc(O ₃SOC₁₂H₂

Full text of DOI:10.1002/adsc.200600527

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DOI: 10.1002/adsc.200600527
Friedländer Synthesis of Quinolines Using a Lewis Acid-Surfac-
tant-Combined Catalyst in Water
Liang Zhanga and Jie Wua,b,*
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Peopleꢀs Republic of China
Fax : (+86)-216-510-2412; e-mail: jie_wu@fudan.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, 354 Fenglin Road, Shanghai 200032, Peopleꢀs Republic of China
Received: October 13, 2006
Abstract: In water, Friedländer annulation using
Lewis acid-surfactant-combined catalyst provides a
mild and efficient route for the synthesis of quino-
lines. Employing a catalytic amount of scandium
tris(dodecyl sulfate) [Sc(O3SOC12H25)3], various
polysubstituted and polycyclic quinolines were ob-
tained in exellent yields.
clic compounds,[7] we became interested in the possi-
bility of developing a novel and efficient method to
construct the quinoline scaffold. It is well-known that
the protocol reported by Friedländer is one of the
most simple and straightforward methods for the syn-
thesis of polysubstituted quinolines, although some
methods such as Skraup, Doebner von Miller, and
Combes reactions[8] are available. Brønsted acids like
sulfamic acid, hydrochloric acid, sulfuric acid, p-tolue-
nesulfonic acid and phosphoric acid were widely used
as reagents or catalysts.[9] Recently, various Lewis
acids have been reported to be effective for the syn-
thesis of quinolines.[10] However, many of these proce-
dures are complicated by harsh reaction conditions,
Keywords: Friedländer annulation; Lewis acids;
quinoline; surfactant
Lewis acid catalysis has attracted much attention in low yields, difficulties in work-up, and the use of stoi-
organic synthesis.[1] Recently, a new type of catalyst, chiometric and/or relatively expensive reagents. And
“Lewis acid-surfactant-combined catalyst (LASC)”, in some cases, high catalyst loadings had to be em-
has shown high efficiency in various organic transfor- ployed in order to obtain respectable yields. Since
mations. These reactions are promoted in water with- quinoline derivatives are increasingly useful and im-
out organic cosolvents.[2] Proposed by Kobayashi,[3] portant in pharmaceuticals and industry, the develop-
this kind of catalyst acts both as a Lewis acid to acti- ment of a simple, eco- and environmentally benign
vate the substrate molecules and as a surfactant to protocol is still desirable. Inspired by the recent ad-
form emulsions in water. The high efficiency of LASC vances of “Lewis acid-surfactant-combined catalysts
in reactions, as well as creation of environmentally (LASC)”, we envisioned that we could exploit the
benign processes promoted us to explore the possibili- property of LASC to effect the Friedländer annula-
ty of methodological development in the scaffold con- tion in water. Herein, we disclose our preliminary re-
struction of natural product-like compounds.
sults for this transformation.
The availability of a practical route for the genera-
Our studies commenced with reaction of 2-amino-
tion of small molecules-based natural products is of benzophenone 1a with ethyl acetoacetate 2a catalyzed
utmost urgency and importance in biomedical re- by various Lewis acid-surfactant-combined catalysts
search. As a privileged fragment, quinoline is a ubiq- (10 mol%) in water at room temperature (Table 1).
uitous subunit in many quinoline-containing natural Among the LASC screened, scandium tris(dodecyl
products with remarkable biological activities.[4] Mem- sulfate) [Sc(O3SOC12H25)3] shows the best result.
bers of this family have wide applications in medicinal Complete conversion and a 90% isolated yield of
chemistry.[4] Because of their importance as substruc- ethyl 2-methyl-4-phenylquinoline-3-carboxylate 3a
tures in a broad range of natural and designed prod- was obtained. Further studies showed that the result
ucts, a significant effort continues to be given over to was improved when the reaction was performed at
the development of new quinoline-based structures[5] 408C (12 h, 99% yield). Next, we examined the cata-
and new methods for their construction.[6]
lytic requirement of Sc(O3SOC12H25)3 (1–10 mol%)
As part of a continuing effort in our laboratory for the reaction in water at 408C. Reducing the
toward the development of new methods for the ex- amount of catalyst retarded the reaction. For exam-
peditious synthesis of biologically relevant heterocy- ple, only a trace amount of desired product 3a was
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Liang Zhang and Jie Wu
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Table 1. Reaction of 2-aminobenzophenone 1a with ethyl
acetoacetate 2a catalyzed by various Lewis acid-surfactant-
combined catalysts (10 mol%) in water at room tempera-
ture.
Friedländer annulation in water. This simple system
offers a mild and very efficient route for the synthesis
of polysubstituted and polycyclic quinolines. It not
only provides an excellent complement to quinoline
synthesis via Friedländer annulation, but also avoids
the use of hazardous acids or bases and harsh reaction
conditions. The advantages of this method include ex-
cellent yields, the use of a catalytic amount of catalyst
under mild conditions, environmentally benign and
simple experimental operations.
Entry
LASC (catalyst)
Yield [%][a]
1
2
3
4
5
6
7
In(O3SOC12H25)3
In(O3SC12H25)3
67
50
82
56
45
58
90
Experimental Section
Sm(O3SOC12H25)3
Gd(O3SOC12H25)3
Dy(O3SOC12H25)3
Fe(O3SOC12H25)3
Sc(O3SOC12H25)3
Scandium Tris(dodecyl Sulfate)
Scandium tris(dodecyl sulfate) was synthesized according to
the literature method.[11]
[a]
Isolated yield based on 2-aminobenzophenone 1a.
General Procedure
observed after
5
days when
1
mol% of
A mixture of the 2-aminoaryl ketone (0.25 mmol), a-methyl-
ene ketone (1.5 equivs.) and scandium tris(dodecyl sulfate)
(5 mol%) in water (4 mL) was stirred at 408C. After com-
pletion of the reaction as indicated by TLC, the reaction
mixture was extracted with EtOAc (2”10 mL). Evaporation
Sc(O3SOC12H25)3 was employed in the reaction. Grati-
fyingly, 94% yield of 3a was generated when 5 mol%
of catalyst was used although a prolonged reaction
time was needed for completion (24 h). When Sc-
(OTf)3 alone was used under these conditions, the re- of the solvent followed by purification on silica gel afforded
pure quinoline. (All the products are known compounds.
The characterizations of these compounds are identical with
action did not go to completion even after 5 days. The
desired product was only obtained in 56% yield.
the literature reports.[10]
)
To demonstrate the generality of this method, we
next investigated the scope of this reaction under the
optimized conditions [5 mol% of Sc(O3SOC12H25)3,
air, 408C] and the results are summarized in Table 2.
The operation was simple: A mixture of the 2-amino-
aryl ketone (0.25 mmol), a-methylene ketone
(1.5 equivs.) and Sc(O3SOC12H25)3 (5 mol%) in water
(4 mL) was stirred at 408C. After completion of the
reaction as indicated by TLC, the reaction mixture
was extracted with EtOAc (2”10 mL). Evaporation
of the solvent followed by purification on silica gel af-
forded the pure quinoline. As shown in Table 2, this
method is equally effective for both cyclic and acyclic
ketones. The reaction employing ethyl 4-chloro-3-oxo-
butanoate also proceeded efficiently to provide the
desired product which is ready for further elabora-
tion. Various substituted 2-aminoaryl ketones such as
Ethyl 2-methyl-4-phenylquinoline-3-carboxylate (3a)[10s]
:
1H NMR(500 MHz, CDCl 3): d=0.94 (t, J=7.1 Hz, 3H),
2.79 (s, 3H), 4.04–4.09 (m, 2H), 7.36–7.72 (m, 8H), 8.07 (d,
J=8.4 Hz, 1H).
1-(2-Methyl-4-phenylquinolin-3-yl)ethanone
(3b)[10s]
:
1H NMR(400 MHz, CDCl ): d=1.97 (s, 3H), 2.67 (s, 3H),
3
7.32–8.06 (m, 9H).
9-Phenyl-3,4-dihydroacridin-1 :
(2H)-one (3c)[10k] 1H NMR
R
(400 MHz, CDCl3): d=2.23–2.26 (m, 2H), 2.68 (t, J=
6.7 Hz, 2H), 3.36 (t, J=6.4 Hz, 2H), 7.18–8.07 (m, 9H).
3,3-Dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-one
H
1
(3d)[10s]: H NMR(400 MHz, CDCl ): d=1.15 (s, 6H), 2.55
3
(s, 2H), 3.26 (s, 2H), 7.16–8.07 (m, 9H).
Methyl 2-methyl-4-phenylquinoline-3-carboxylate (3e)[10j]
:
1H NMR(400 MHz, CDCl ): d=2.76 (s, 3H), 3.55 (s, 3H),
3
7.32–8.06 (m, 9H).
Ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
1
(3f)[10u]: H NMR(400 MHz, CDCl ): d=0.90 (t, J=7.3 Hz,
3
2-aminoacetophenone, 2-aminobenzophenone, and 2- 3H), 4.01–4.05 (m, 2H), 5.03 (s, 2H), 7.33–8.14 (m, 9H).
Ethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate
amino-5-chlorobenzophenone reacted smoothly with
a-methylene ketones to produce a range of quinoline
derivatives. Complete conversion and good to excel-
lent isolated yields were observed for all substrates
employed. This reaction is very clean and free from
side reactions such as self-condensation of ketones
which are normally observed under basic conditions.
In conclusion, we have described the Lewis acid-
surfactant-combined catalyst, scandium tris(dodecyl
1
(3g)[10k]: H NMR(500 MHz, CDCl ): d=0.93 (t, J=7.1 Hz,
3
3H), 2.75 (s, 3H), 4.04–4.07 (m, 2H), 7.33–8.00 (m, 8H).
1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone
1
(3h)[10k]: H NMR(500 MHz, CDCl ): d=1.96 (s, 3H), 2.65
3
(s, 3H), 7.31–7.98 (m, 8H).
7-Chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one (3i)[10k]
:
1H NMR(500 MHz, CDCl ): d=2.21–2.26 (m, 2H), 2.69 (t,
3
J=6.6 Hz, 2H), 3.34 (t, J=6.4 Hz, 2H), 7.14–7.98 (m, 8H).
7-Chloro-3,3-dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-
1
sulfate) [Sc(O3SOC12H25)3], as an efficient catalyst for one (3j)[10s]: H NMR(500 MHz, CDCl 3): d=1.14 (s, 6H),
1048
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Friedländer Synthesis of Quinolines
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Table 2. Scandium tris(dodecyl sulfate)-catalyzed Friedländer annulation in water.[a]
Entry
1
Substrate 1
Ketone 2
Quinoline 3
Yield [%][b]
94
1a
2a
3a
2
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2b
3b
3c
3d
3e
3f
3g
3h
3i
99
96
99
99
96
99
95
98
93
97
89
3c
4c
5
6
7
8
9[c]
10[c]
11
3j
3k
3l
12
[a]
Reaction conditions: 2-amino ketone (0.25 mmol), ketone (1.5 equivs.), Sc(O3SOC12H25)3 (5 mol%), water (4 mL), 408C.
Isolated yield based on 2-aminoaryl ketone 1.
The reaction was performed at 608C.
[b]
[c]
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Liang Zhang and Jie Wu
COMMUNICATIONS
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Acknowledgements
We thankProfessor Pengyuan Yang for his invaluable advice
during the course of this research. Financial support from
National Natural Science Foundation of China (20502004)
and the Science and Technology Commission of Shanghai
Municipality (05ZR14013) is gratefully acknowledged.
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