KHCO3- and DBU-Promoted Cascade Reaction to Synthesize 3-Benzyl-2-phenylquinolin-4(1 H)-ones

Article abstract of DOI:10.1002/asia.201600901

A novel and convenient one-pot route for the synthesis of 3-benzyl-2-phenylquinolin-4(1 H)-ones has been developed under transition-metal-free conditions. This new strategy features high yield and good functional group tolerance. In addition, a proposed mechanism has been confirmed for this reaction.

Full text of DOI:10.1002/asia.201600901

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Accepted Article
Title: KHCO3 and DBU Promoted Cascade Reaction to Synthesize 3-benzyl-2-
phenylquinolin-4(1H)-ones
Authors: Haojie Ma; Xiaoqiang Zhou; Daidong Wei; Jnhui Cao; Chong Shi; Yuxing
Fan; Guosheng Huang
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Chemistry - An Asian Journal
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KHCO3 and DBU Promoted Cascade Reaction to Synthesize 3-
benzyl-2-phenylquinolin-4(1H)-ones
Haojie Ma, Xiaoqiang Zhou, DaiDong Wei, Jinhui Cao, Chong Shi, Yuxing Fan and Guosheng Huang*
(scheme 2, c),7 in this procedure, simple narylmethyl-2-
A novel and convenient one-pot route for the synthesis of 3-benzyl-
aminophenyl ketones was used as starting materials.
2-phenylquinolin-4(1H)-ones has been developed under transition-
Nevertheless there are only methyl or no functional groups at
metal-free conditions. This new strategy is featured by high yield and
the C-3 position of 2-aryl-4-quinolone that could be synthesized
good functional groups tolerance. In addition, proposed mechanistic
by this approach.
study has been confirmed for this reaction.
Scheme 2. Novel routes to synthesize 4-Quinolones.
4-Quinolones, as an indispensable class of bicyclic structures,
are frequently found in natural products and biologically active
2
compounds (Scheme 1).1,
They are also regarded as
“privileged building blocks” for pharmaceutics in anticancer and
antibiotic medicines.3 Especially, 2-aryl-4-quinolones and their
derivatives have been found as potential treatments for a range
of diseases because they exhibit antiviral activities,4
antiplatelet,5 antimalarial,6 xanthine oxidase,7 cathepsins
inhibitory activities8 and have positive cardiac effects.9 For
example, current researches present kinesin spindle protein
(KSP) inhibitors as promising anti-proliferative agents for cancer
chemotherapy through potent antimitotic antitumor effects.2
More recently, certain 3-benzyl-2-phenylquinolin-4(1H)-ones
were evaluated and proved to have potent inhibitory activities in
KSP ATPase.2 Due to the “privileged” status, quinolones have
attracted considerable attentions in the development of practical
synthesis.
Scheme 1. Examples of bioactive compounds and nature products containing
4-quinolones.
Although the synthetic routes of 4-quinolones have been well
developed, in general they require multiple steps15, 17, transition
metal catalysts.15, 18 and harsh reaction conditions, such as high
11
temperature and strong acids.10,
Moreover, various C-3
modified products are still difficult to form due to the unefficient
way for the preparation of starting materials. Herein, inspired by
pioneering works, we have developed a novel route for the
synthesis of 3-benzyl-2-phenylquinolin-4(1H)-ones from N-(2-
acetylphenyl)-picolinamides and aldehydes under base
conditions. To our knowledge, transition-metal-free synthesis of
3-benzyl-2-phenylquinolin-4(1H)-ones has not been reported
before.
Numerous synthetic strategies, especially Conrad-Limpach,10
Niementowski reactions11 and transition-metal catalyzed
reactions including titanium-mediated reductive coupling,12
palladium-catalyzed carbonylation,13 and ruthenium-catalyzed
reduction reactions,14 have been developed to construct
varieties of this valuable scaffolds. In 2007, Buchwald’s group
Our initial efforts commenced with N-(2-acetylphenyl)-
picolinamide 1a and benzaldehyde 2a as the model substrates
in the presence of 2 equiv of K2CO3 at 100 oC for 10 h in DMSO,
and the desired 3-benzyl-2-phenylquinolin-4(1H)-one 3aa was
able to isolated in 47% yield (Table 1, entry 1). The structure of
3aa was further confirmed by X-ray crystallography.19 Then the
investigation of the solvent effects on the yield of the target
product was carried out. As a result, toluene and xylene failed to
come up with any useful conversions, and DMSO was superior
to DMA and DMF (Table 1, entries 2-5). In order to find the best
additives, we chose K2CO3, Na2CO3, KHCO3, NaHCO3, DBU,
DABCO, Et3N and KOtBu as candidates, the results showed that
KHCO3 was more favorable than other bases, the yield of 3aa
was increased to 55%(Table 1, entries 1, 6-12). Gratifyingly, the
yield of 3aa was dramatically increased to 64% by using the
combination of KHCO3 and DBU as additive (Table 1, entry 13).
Meanwhile, when the dosage of KHCO3 and DBU was increased
to 2 equiv, the yield was improved to 71% (Table 1, entries, 14).
Further surveys of the reaction temperature indicated that
120 °C was beneficial for the formation of the desired product
presented
a base-promoted synthetic methodology for 4-
quinolones by using N-(2-propionylphenyl)-acetamide (scheme 2,
a).15 In 2012, Pitchumani's group obtained 2-aryl-2,3-dihydro-4-
quinolone from 1-(2-aminophenyl)ethan-1-one and aldehyde
(scheme 2, b).16 Subsequently in 2015, Long’s group reported a
novel synthesis of diverse 2-aryl-4-quinolone derivatives via a
TEMPO-promoted intramolecular oxidative Mannich reaction
[a]
H. Ma, X. Zhou, D. Wei, J. Cao, C. Shi, Y. Fan, Prof. G. Huang
State Key Laboratory of Applied Organic Chemistry, Key Laboratory
of Nonferrous Metal Chemistry and Resources Utilization of Gansu
Province, Department of Chemistry, Lanzhou University, Lanzhou,
P. R. China.
E-mail: hgs@lzu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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3aa and the yield was raised to 84% (Table 1, entries, 15-16).
The research of reaction atmosphere presented that air was
more outstanding than N2 and O2 (Table 1, entries 17-18).
Furthermore, the choice of an adequate reactant 1 for this
conversion is evaluated. We attempted to use N-acetyl, N-
benzoyl, N-pyrazine-2-carbonyl, N-6-methylpicolinoyl, N-6-
chloropicolinoyl amides and N-H amine as reactants under
standard conditions, the results showed that all these substrates
could transform this reaction successfully with moderate yields.
And the highest yield was given when N-picolinoyl amide was
employed (Scheme 3). These results matched well with the role
of N-aryl groups which stabilized the iminium intermediate and
increased the yield. Finally, the optimized reaction conditions are
as follows: N-picolinoyl amide 1 (0.2 mmol), aldehyde 2 (3 equiv),
Scheme 4. Synthesis of 3-benzyl-2-phenylquinolin-4(1H)-ones from
substituted aldehydes and N-(2-acetylphenyl)-picolinamidea.
o
KHCO3 (2 equiv) and DBU (2 equiv) in 1mL of DMSO at 120 C
under air for 10 h.
Table 1. Optimization of reaction conditionsa.
Entry
1
2
3
4
5
6
7
8
additive (equiv)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
Na2CO3 (2)
KHCO3 (2)
NaHCO3 (2)
Solvent
DMSO
DMA
Temp (oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
Yields[b] (%)
47
14
5
trace
trace
20
55
25
40
trace
trace
43
64
71
41
84
69
50
DMF
Toluene
Xylene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
DBU (2)
DABCO (2)
10
11
12
13
14
15
16
17[c]
18[d]
Et3N (2)
KOtBu (2)
KHCO3 (1)+ DBU (1)
KHCO3 (2)+ DBU (2)
KHCO3 (2)+ DBU (2)
KHCO3 (2)+ DBU (2)
KHCO3 (2)+ DBU (2)
KHCO3 (2)+ DBU (2)
120
120
120
[a]Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.6 mmol, 3 equiv), additive
(2 equiv), solvent (1 mL), 10 h. [b]Isolated yields. [c]Reaction was performed
under N2 atmosphere. [d]Reaction was performed under O2 atmosphere.
diverse array of aldehydes, bearing electron-donating, electron-
withdrawing or sterically hindered group substituted aromatic
rings, and heterocycle-aldehyde were examined. All of them
underwent the reaction conditions smoothly and gave the
corresponding products in excellent yields (Scheme 4, 3aa−3ay),
ensuring a broad range of substrate scope. It can be seen
clearly that the electron-withdrawing groups exhibited more
outstanding results in terms of providing the desired compounds
than electron-donating groups (Scheme 4, 3ab–3av), which
indicated that electron-withdrawing groups on the aromatic ring
were more compatible with this reaction process. Furthermore,
substrates having ethyl or aryl group at the para position of
benzaldehyde also furnished the reaction in good yields
(Scheme 4, 3aj–3ak). In addition, the reactions of benzaldehyde
with substituents at the ortho, meta, and para positions were
carried out, and the results showed that those with groups at the
ortho position gave higher yields, followed by meta and para
position (Scheme 4, 3ab–3ad, 3af-3ag, 3al-3an, 3ap-3at).
Meanwhile, based on the results of benzaldehyde with mono or
methyl or methoxy groups (Scheme 4, 3ab–3ai), it represented
distinctly that the steric effect also has significant influence on
the efficiency. Additionally, heteroaromatic and condensed ring
structures were also competent to produce the products
efficiently (Scheme 4, 3aw–3ay), and 1-naphthaldehyde reacted
Scheme 3. Synthesis of 3-benzyl-2-phenylquinolin-4(1H)-one 3aa from
different amide sourcesa.
a isolated yields of 3aa
With the optimized reaction conditions in hand, we studied the
scope of aldehydes in this reaction. As shown in Scheme 4, a
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To gain insight into the reaction mechanism, we carried out
several control experiments (Scheme 6). Firstly, we carried out a
reaction of 1a and 2a under the optimized conditions for 1.5 h,
the desired product 3aa was gained in low yield，whereas the
intermediate 4aa was harvested as major product (Scheme 6, a).
The structure of 4aa was confirmed by X-ray crystallography.20
Then we performed the intermediate 4aa under standard
conditions and 4aa could convert to 3aa successfully, though the
efficiency was not desirable (Scheme 6, b).
excellently. However, an aliphatic aldehyde can not be
introduced into desired product by this protocol (Scheme 4, 3az).
Scheme 5. Synthesis of 3-benzyl-2-phenylquinolin-4(1H)-ones from
benzaldehyde and Substituted N-(2-acetylphenyl)picolinamidesa.
Scheme 7. Proposed mechanism.
Based on the above results and previous literature, a plausible
mechanism is depicted as shown in Scheme 7. The reaction is
initiated by the formation of intermediate A through Aldol
reaction of 1a and 2a with addition of DBU and KHCO3. Then
DBU and KHCO3 convert A to B by a hydrogen abstraction
process, which may undergo intramolecular cyclization via the
Michael addition to generate intermediate C. Intermediate C
further reacts through Aldol reaction with 2a to gain the
intermediate D. The elimination of hydroxyl give intermediate
4aa, and the isomerization of 4aa affords E, which can
hydrolyze to the desired product 3aa.
Scheme 6. Control Experiments.
In summary, a novel and efficient synthesis of 3-benzyl-2-
phenylquinolin-4(1H)-ones has been developed for the first
time by using
metal-free conditions. This protocol has provided a broad
substrate scope for the synthesis of with good yields
1 and 2 as starting materials under transition-
3
under mild conditions. Step economy and ease of operation
make this transformation highly useful, which will promote
the development of synthesis of natural products and
pharmaceutics in anticancer and antibiotic medicines.
Experimental Section
To further explore the applicability and compatibility of this
synthetic route, we examined the scope of N-(2-
acetylphenyl)picolinamide under the same reaction conditions as
shown in scheme 5. Notably, a wide range of functional groups
was tolerated well under the reaction conditions, such as methyl,
methoxy, halogen, etc. Concerning the electronic effects of
substituents on phenyl rings, the substrates bearing either
electron-withdrawing or electron-donating groups afforded the
desired products in good to excellent yields (Scheme 5, 3ba–
3ma). The results also showed that the electron-withdrawing
groups were more effective for the transformation. Moreover, N-
(acetylphenyl)-picolinamide bearing halogen substituents
(Scheme 5, 3ga–3la) at meta position worked better than those
at para position. The similar effects were also observed towards
N-(acetylphenyl)-picolinamide with methyl substituents (Scheme
5, 3ba–3da).
A test tube was charged with 1a (0.2mmol), 2a (0.6mmol), KHCO3 (0.4
mmol) and DBU (0.4 mmol) in DMSO (1 mL). Then the reaction mixture
o
was stirred at 120 C (oil bath temperature) under air atmosphere for 10
h. After cooling to room temperature, the solvent was extracted with ethyl
acetate and washed with brine, dried with Na2SO4. After the solvent was
evaporated in vacuo, the residues were purified by column
chromatography, eluting with petroleum ether / ethyl acetate to afford
pure 3aa.
Keywords: 4-quinolones • aldol reaction • aldehydes •
cycloaddition • michael addition
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10.1002/asia.201600901
Haojie Ma, Xiaoqiang Zhou, DaiDong
Wei, Jinhui Cao, Chong Shi, Yuxing Fan
and Guosheng Huang*
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KHCO3 and DBU Promoted Cascade
Reaction to Synthesize 3-benzyl-2-
phenylquinolin-4(1H)-ones
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