Palladium-catalyzed synthesis of quinolines from allyl alcohols and anilines

Article abstract of DOI:10.1039/c7ra06425j

A process for quinoline synthesis through palladium-catalyzed oxidative cyclization of aryl allyl alcohols and anilines is described. This process works in the absence of acid, base and any other additive and has a broad substrate scope, tolerating electron-withdrawing groups such as nitryl, trifluoromethyl and so on. A series of quinolines are prepared in satisfactory yields.

Full text of DOI:10.1039/c7ra06425j

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Palladium-catalyzed synthesis of quinolines from
allyl alcohols and anilines†
Cite this: RSC Adv., 2017, 7, 36242
*
Jingxiu Xu, Jing Sun, Jinwu Zhao,
Bin Huang, Xiaohan Li and Yulun Sun
Received 8th June 2017
Accepted 15th July 2017
A process for quinoline synthesis through palladium-catalyzed oxidative cyclization of aryl allyl alcohols and
anilines is described. This process works in the absence of acid, base and any other additive and has a broad
substrate scope, tolerating electron-withdrawing groups such as nitryl, trifluoromethyl and so on. A series of
quinolines are prepared in satisfactory yields.
DOI: 10.1039/c7ra06425j
rsc.li/rsc-advances
substrates and aniline derivatives under harsh conditions,
namely strong acidic or strong basic conditions.5 Recently,
Introduction
signicant attention has been paid to the development of
transition metal-catalyzed protocols for the synthesis of quin-
oline molecules owing to their advantage of voiding the use of
strong acids or strong bases in contrast with traditional
methods.6 Among them, the condensation of anilines with
alcohols has also been developed.7 For example, Trillo and
Pastor reported that quinolines could be prepared from allyl
alcohols and anilines under the catalysis of iron(III)-based Lewis
acidic ionic liquid,8 and Jiang group disclosed that quinoline
derivatives could be obtained from simple aliphatic alcohols
and anilines under the Pd(OAc)2/2,4,6-Collidine/Brønsted acid
catalytic system.9 More recently, Kapur and his coworkers
demonstrated a ruthenium catalyzed [3 + 3] annulation of
anilines with allyl alcohols to provide substituted quinolines
based on a traceless directing-group strategy.10 Although these
elegant developments could provide a range of alternatives, the
development of novel and expeditious methods for the
synthesis of quinoline is still in demand. Herein, we report
a process for the synthesis of quinoline from allyl alcohols and
anilines under the catalysis of Pd(OAc)2 without any ligand or
additive (Scheme 1).
The quinoline skeleton occurs extensively as an integral part of
many natural products, especially in alkaloids, and synthetic
pharmacologically active substances due to their biological
activities, such as anticancer, antiviral, antibacterial, anti-
fungal, anti-inammatory and antiplatelet aggregation.1 For
example, Camptothecin (A) is a cytotoxic quinoline alkaloid
clinically used to treat cancer by inhibiting DNA enzyme topo-
isomerase I; Quinoline compound (B) has been developed as
a corticotropin releasing factor-1 receptor antagonists for the
treatment of depression or other stress-related disorders;2 2-
phenylquinolinyl moiety is deemed as the critical pharmaco-
phore of Linsitinib (C), a clinical dual inhibitor of insulin-like
growth factor-1 receptor (IGF-1R) and insulin receptor (IR) for
various cancers treatment (Fig. 1).3
In view of the importance of quinolines, great endeavors
have been made to develop the procedures for their synthesis
over the past few decades.4 Traditionally, the classical strate-
gies, such as Doebner–von Miller reaction, Skraup, reaction,
¨
Gould–Jacobs reaction, Combes synthesis, and Friedlander
synthesis, employ the condensation reaction of carbonyl
Results and discussion
Our studies began by optimizing the reaction conditions for the
synthesis of quinolines, choosing aniline (1a) and cinnamic
alcohol (2a) as model substrates. The results are collected in
Table 1. When this reaction was carried out catalyzed by
Pd(OAc)2 in the presence of 20 mol% TsOH in DMSO at 100 ꢀC
Fig. 1 Examples of bioactive quinolines.
School of Pharmacy, Guangdong Medical University, Dongguan 523808, China.
E-mail: jwzhao@gdmu.edu.cn
† Electronic supplementary information (ESI) available: NMR of all products. See
DOI: 10.1039/c7ra06425j
Scheme
alcohols and anilines.
1 Palladium-catalyzed synthesis of quinolines from allyl
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Table 1 Optimizing the reaction conditions for palladium-catalyzed Table
2
Scope of anilines for Pd(OAc)2-catalyzed synthesis of
synthesis of quinolinesa
quinolinesa,b
Entry
Catalyst
Solvent
Temperature
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Dioxane
Toluene
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
130
150
79
75
16
8
Pd2(dba)3
Pd(CH3CN)2Cl2
Pd(PPh3)4Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Trace
5
Trace
Trace
26
Trace
Trace
Trace
Trace
90 (85)d
82
NMP
DMAC
DMSO
DMSO
a
All reactions were performed with 1a (0.5 mmol), 2a (0.5 mmol),
catalyst (10 mol%), in the indicated solvent (2.0 mL) under 1 atm
b
c
oxygen at selected temperature for 12 h. GC yield based on 2a. 20
mol% TsOH was used. d Isolated yield.
for 12 h, the expected quinoline 3aa was obtained in 79% GC
yield (entry 1). Unexpectedly, the reaction worked well in
absence of acid (entry 2). Our experimental results showed that
Pd(TFA)2 and PdCl2 could not drive this reaction efficiently
(entries 3–4). We then examined other palladium catalysts
containing special ligands, such as Pd2(dba)3, Pd(CH3CN)2Cl2,
Pd(PPh3)4Cl2, Pd(PPh3)4, and found that they could not promote
the transformation preferably either (entries 5–8). The effect of
solvents was next investigated. Using dioxane as the reaction
medium provided the target product 3aa in 26% yield (entry 9).
However, trace amount of product 3aa was detected when the
reaction was performed in toluene or amide solvents such as
DMF, NMP, and DMAC (entries 10–13). The results of testing
reaction temperature revealed that increasing the temperature
to 130 ꢀC could improve the yield of quinoline product to 90%
while higher temperature gave rise to a lower yield (entries 14–
15). On the basis of the experimental results mentioned above,
the optimal reaction conditions are listed in entry 14.
The scope of the protocol was further evaluated aer the
optimal reaction conditions were established. Cinnamic
alcohol 2a was reacted with s series of substituted anilines
under the best reaction conditions, and the results are listed in
Table 2. para-substituted anilines were rstly probed. Generally,
moderate to excellent yields could be achieved from both
electron-donating groups and electron-withdrawing groups
substituted anilines (3ba–3ka). For example, 4-methoxyaniline
and 4-(triuoromethyl)aniline afforded the corresponding
quinolines in 80% and 84% yield, respectively (3ba, 3ka). meta-
Substituted anilines were then explored. When 3-methylaniline
a
Reactions were performed with 1a (0.5 mmol), 2 (0.5 mmol), Pd(OAc)2
b
(10 mol%), in DMSO (2 mL) at 130 ꢀC for 12 h. Isolated yield.
was subjected to the optimized conditions, 7-methyl substituted
product 3la and 5-methyl substituted product 3la' were ob-
tained in the ratio of 5 : 1, which suggested that steric
hindrance of the substituents had signicant inuence on the
regioselectivity of the oxidative cyclization reaction, and 3,4-
disubstituted anilines furnished 6,7-disubstituted quinoline
products selectively (3ma–3oa). ortho-Substituted anilines were
nally tested. As shown in Table 2, all ortho-substituted anilines
went through the transformation smoothly, producing the
desired quinoline compounds in good yields (3pa–3sa). More-
over, beta-naphthylamine was also found to be a good partner of
cinnamic alcohol under the standard conditions and gave 2-
phenylbenzo[g]quinoline in 76% yield (3ta).
A variety of allyl alcohols were treated with aniline 1a. And
the results are summarized in Table 3. We found that cinnamic
alcohols, whose phenyl rings were substituted by electron-
donating groups, reacted smoothly with aniline to provide
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Table 3 Scope of allyl alcohols for Pd(OAc)2-catalyzed synthesis of
with anilines is illustrated in Scheme 3. Firstly, cinnamic
alcohol 2a is oxidized by dioxygen under the catalysis of palla-
dium to produce a,b-unsaturated aldehyde A, which goes
through a condensation with aniline to give imine B. Dimer-
ization then takes place to generate diazetidine intermediates C
with the help of palladium. Its C–N bond cleaves and the
following irreversible cyclization forms intermediates E, which
isomerizes readily into F driven by the charge, followed by an
intramolecular nucleophilic attack along with the elimination
of 1 mol of imine, to provide 2-phenyl-1,2-dihydroquinolin
G. Palladium-catalyzed dehydro-aromatization subsequently
occurs to yield the nal product.
quinolinesa,b
Experimental
General information
All reagents were of analytical grade and obtained from
commercial suppliers and used without further purication.
1H and 13C NMR spectra were recorded on a Bruker DRX-400
spectrometer; CDCl3 was used as solvent and TMS as an
internal standard.
a
Reactions were performed with 1 (0.5 mmol), 2a (0.5 mmol), Pd(OAc)2
b
(10 mol%), in DMSO (2 mL) at 130 ꢀC for 12 h. Isolated yield.
Typical procedure for palladium-catalyzed synthesis of
quinolines from allyl alcohols and anilines
target quinolines in moderate to good yields (3ab–3ae). Like-
wise, moderate to good yields could be achieved from cinnamic
alcohols whose phenyl rings were substituted by F and NO2
(3ag–3ah). It is noteworthy that this procedure for the prepa-
ration of quinoline derivatives tolerates aryl bromide which
allows further functionalization (3ah). To our delight, 2,3-
disubstituted quinoline could be obtained from a-methyl cin-
namic alcohol (3ai). Heteroaryl allyl alcohol was nally assessed
and 2-furyl quinoline was successfully isolated in a yield of
65% (3aj).
In order to gain some insight into the mechanism of the
oxidative annulation reaction, some control experiments were
carried out. When cinnamaldehyde reacted with aniline 1a
under the optimal reaction conditions, quinoline 3aa was
detected by in 91% yield (eqn (1)). When N-cinnamylideneani-
line was subjected to the standard reaction conditions, product
3aa was given in 93% GC yield (eqn (2)), which revealed that this
transformation occurred via aldimine as the key intermediate
(Scheme 2).
Allyl alcohol (0.5 mmol), aniline (0.5 mmol), Pd(OAc)2 (11.2 mg,
10 mol%) and DMSO (2 mL) were added into a test tube
attached to an oxygen balloon (1 atm). The system was stirred
magnetically and heated at 130 ꢀC with an oil bath for 12 h.
And then the reaction was quenched by the addition of 10 mL
water. The aqueous solution was extracted with ethyl acetate
(3 Â 10 mL) and the combined extract was dried with anhydrous
MgSO4. The solvent was vacuumed and the crude product was
isolated by TLC (solvent: hexane/ethyl acetate) to give the pure
quinoline product.
On the basis of the above mentioned results and relevant
reports in the literature,11,6a a reasonable reaction pathway for
palladium-catalyzed quinoline synthesis from allyl alcohols
Scheme
3 Possible reaction pathway for palladium-catalyzed
Scheme 2 Control experiments.
synthesis of quinolines from allyl alcohols and anilines.
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In conclusion, we have developed a process for quinoline
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an alternative approach to biologically important quinoline
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (21572040) and Guangdong Natural Science Foundation
(2015A030310371) for nancial support.
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