From Ketones, Amines, and Carbon Monoxide to 4-Quinolones: Palladium-Catalyzed Oxidative Carbonylation

Article abstract of DOI:10.1021/acs.orglett.7b03337

A novel method of palladium-catalyzed oxidative carbonylation of ketones, amines, and carbon monoxide for the synthesis of 4-quinolones has been developed. This protocol provides a straightforward route to construct useful 4-quinolone derivatives from ine

Full text of DOI:10.1021/acs.orglett.7b03337

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
From Ketones, Amines, and Carbon Monoxide to 4‑Quinolones:
Palladium-Catalyzed Oxidative Carbonylation
Jiwei Wu,† Yuchen Zhou,† Ting Wu,† Yi Zhou,† Chien-Wei Chiang,† and Aiwen Lei*,†,‡
†The Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R.
China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A novel method of palladium-catalyzed oxidative
carbonylation of ketones, amines, and carbon monoxide for the
synthesis of 4-quinolones has been developed. This protocol
provides a straightforward route to construct useful 4-quinolone
derivatives from inexpensive chemicals.
4-Quinolones represent one of the major classes of nitrogen-
containing heterocycles and is widely found in natural products
and biological active molecules.1 Furthermore, compounds
containing 4-quinolone scaffolds exhibit various pharmaceutical
activities such as antiviral,2 antimalarial,3 or anticancer.4 Many 4-
quinolone derivatives, such as oxolinic acid, ciprofloxacin,
besifloxacin hydrochloride, ozenoxacin, etc., have emerged as
potent antibiotics and have been used in daily life (Scheme 1).5
economy,12 and green chemistry.13 Recently, palladium-
catalyzed carbonylation14 for constructing 4-quinolones by
using CO as carbonyl source have been reported (Scheme
2a,b).15 However, these reactions use aryl halogen (usually
Scheme 2. Palladium-Catalyzed Carbonylative Synthesis of 4-
Quinolinones
Scheme 1. Representative Drug Compounds Containing 4-
Quinolone Scaffolds
synthesized from C−H compounds) as raw material, which do
not meet step economy. In addition, these methods also suffer
from the requirement of high pressures of CO gas, which made
them hazardous for large-scale industrial applications. To
overcome these obstacles and on the basis of a continuous
interest in the synthesis of heterocycles via oxidative carbon-
ylation in our group,16 we envisioned that the goal of
constructing 4-quinolones could be achieved via palladium-
catalyzed oxidative carbonylation using CO as carbonyl source at
atmospheric pressure (Scheme 2c).
The synthesis of 4-quinolone scaffolds has attracted considerable
interest, and various methods for the synthesis of 4-quinolone
scaffolds have been documented, such as Camps cyclizations,6
Conrad−Limpach reaction,7 Niementowski reaction,8 etc.9
However, these methods usually required harsh reaction
conditions, such as high temperatures and strong bases or
acids, which dramatically limit its application. Therefore, a more
efficient and straightforward method for the synthesis of 4-
quinolones is highly desired.
In light of retrosynthetic analysis, we know that 4-quinolones
could be constructed by enamine B with CO. Enamine B is
Carbon monoxide (CO), the simplest carbonyl source, has
been widely used in the synthesis of carbonyl compounds,10
which meets the requirements of atom economy,11 step
Received: October 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generated via tautomerization of imine A. Imine A was formed
from ketone and amine by dehydration condensation. Ketones
and amines, as simple and commercially available chemical
materials, were the ideal raw material for synthesis of 4-
quinolones. Thus, oxidative carbonylation between simple
ketones, amines, and CO for the synthesis of 4-quinolones was
designed (Scheme 3). To the best of our knowledge, the
oxidative carbonylation for the synthesis of 4-quinolones from
simple ketones, amines, and CO has not been reported.
Pd(dba)2, Xantphos, KI, CuBr(Me2S), and PhCOONa were
added in the presence of 1 atm of CO to react another 24 h
(Table 1, entry 1). Unfortunately, when they were all added into
a
Table 1. Optimization of the Reaction Conditions
Scheme 3. Reaction Design of the Oxidative Carbonylation
for the Synthesis of 4-Quinolones from Ketones, Amines, and
CO
entry
1
variation from the standard conditions
none
yield (%)
75
b
2
none
n.d.
21
3
no 4 Å MS
4
no Pd(dba)2
n.d.
17
5
no KI
6
no Xantphos
54
7
no CuBr(Me2S)
trace
trace
62
8
no PhCOONa
9
Pd(PPh3)4 instead of Pd(dba)2
Pd(OAc)2 instead of Pd(dba)2
PdCl2 instead of Pd(dba)2
CuBr instead of CuBr(Me2S)
Cu(OAc)2 instead of CuBr(Me2S)
K2CO3 instead of PhCOONa
DABCO instead of PhCOONa
0.01 mmol Pd(dba)2 instead of 0.02 mmol
CO/O2 = 15/1 instead of CO/O2 = 3/1
10
11
12
13
14
15
16
17
54
53
47
58
We propose that the palladium-catalyzed oxidative carbon-
ylation of ketones, amines, and CO for syntheses of 4-quinolones
proceeds through the catalytic cycles shown in Scheme 4. First,
trace
17
60
59
Scheme 4. Proposed Catalytic Cycles
a
Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), 4 Å MS (200
mg), in 0.5 mL of PhCH3, at 110 °C for 6 h, then Pd(dba)2 (0.02
mmol), Xantphos (0.02 mmol), KI (0.2 mmol), CuBr(Me2S) (0.2
mmol), PhCOONa (0.3 mmol), in 2 mL of PhCH3 and 0.4 mL
DMSO, at 110 °C under CO/O2 = 3/1 for 24 h. Yields shown are of
b
isolated products. All added together in 2 mL of PhCH3 and 0.4 mL
of DMSO, at 110 °C under CO/O2 = 3/1 for 24 h. n.d. = not
detected.
the reaction together for 24 h, no desired product was obtained
(Table 1, entry 2). Without molecular sieves, the yield of 3a was
reduced to 21% due to the low reactivity of 1a and 2a to form
imine (Table 1, entry 3). Control experiments indicate that
Pd(dba)2, CuBr(Me2S), and PhCOONa were necessary for this
reaction (Table 1, entries 4, 7, and 8). KI also played a critical role
in this transformation;17 without KI, only 17% yield of 3a was
obtained (Table 1, entry 5). Xantphos as a ligand can improve the
yield of 3a from 54% to 75% (Table 1, entry 6). Then, different
palladium salts such as Pd(PPh3)4, Pd(OAc)2, and PdCl2 were
studied, and the results showed that Pd(dba)2 was still the best
choice (Table 1, entries 9−11). CuBr and Cu(OAc)2 were not
suitable for this reaction as that afforded the desired product in
lower yield (Table 1, entries 12−13). Further base study revealed
that PhCOONa was the best choice for this reaction (Table 1,
entries 14−15). The reaction could also proceed smoothly to
give the desired product 3a in 59% yield under nonexplosive
conditions (CO/O2 = 15/1) (Table 1, entry 17). Furthermore, a
77% yield of 3a was observed when imine 4a was directly used
under standard conditions (Scheme 5).
imine A is formed from ketone and amine by dehydration
condensation. Then, enamine B derived from imine/enamine
isomerization can be electrophilically attacked by Pd(II) to form
intermediate C. Intermediate C would then undergo intra-
molecular C−H activation and CO insertion to generate
intermediate D. Subsequently, reductive elimination of D affords
the final product 3 and releases a Pd(0), which is oxidized by
copper and O2 to regenerate Pd(II) and complete the catalytic
cycle.
On the basis of the above speculation, acetophenone (1a) and
aniline (2a) in the presence of 1 atm of CO were chosen as the
model substrates to test this reaction. The desired product (3a)
was obtained in 75% yield with the following procedure: first, 1a
reacted with 2a for 6 h in the presence of molecular sieves, then
With the optimal reaction conditions in hand, we turned our
attention to test the substrate scope of this transformation. First,
various ketones (1) were evaluated in the reaction with aniline 2a
B
DOI: 10.1021/acs.orglett.7b03337
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Letter
Then, several anilines (2) were explored as substrates by
reaction with acetophenone 1a. In general, the reactions
proceeded well to afford the desired products in moderate to
good yields. As shown in Scheme 7, anilines with an electron-rich
Scheme 5. Oxidative Carbonylation for the Synthesis of 4-
Quinolones from Imine
Scheme 7. Substrate Scope of Oxidative Carbonylation of
Acetophenone with Anilines
under the standard conditions. As shown in Scheme 6, a wide
range of functional groups were well tolerated, and the desired
Scheme 6. Substrate Scope of Oxidative Carbonylation of
Ketones with Aniline
a
Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), 4 Å MS (200
mg), in 0.5 mL of PhCH3, at 110 °C for 6 h, then Pd(dba)2 (0.02
mmol), Xantphos (0.02 mmol), KI (0.2 mmol), CuBr(Me2S) (0.2
mmol), PhCOONa (0.3 mmol), in 2 mL of PhCH3 and 0.4 mL of
DMSO, at 110 °C under CO/O2 for 24 h. Yields shown are of isolated
b
products. CO/O2 = 15/1.
p-Me and p-tBu (Scheme 7, 3m,n) substituent or halogen such as
p-F (Scheme 7, 3o) all gave the desired products in moderate
yields. It is noteworthy that 4-(methylthio)aniline (Scheme 7,
3p) could be tolerated under the current conditions. For m-
substituted anilines, the reactions also proceeded smoothly with
acetophenone to give the desired products in moderate to good
yields (Scheme 7, 3q,r) but with poor selectivity. Furthermore,
3,5-dimethylaniline reacted smoothly with acetophenone to give
the desired 3s in 68% yield (Scheme 7, 3s).
In conclusion, we have developed a novel method for
palladium-catalyzed oxidative carbonylation of ketones, amines,
and CO for the synthesis of 4-quinolones. This protocol provides
a straightforward route to the synthesis of useful 4-quinolone
derivatives from inexpensive chemicals. Various kinds of ketones,
even heterocyclic ketones, and amines were shown to be
workable substrates, generating the corresponding 4-quinolones
in good yields. Detailed mechanistic studies and the synthetic
application of this method are currently ongoing in our
laboratory.
a
Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), 4 Å MS (200
mg), in 0.5 mL of PhCH3, at 110 °C for 6 h, then Pd(dba)2 (0.02
mmol), Xantphos (0.02 mmol), KI (0.2 mmol), CuBr(Me2S) (0.2
mmol), PhCOONa (0.3 mmol), in 2 mL of PhCH3 and 0.4 mL of
DMSO, at 110 °C under CO/O2 = 3/1 for 24 h. Yields shown are of
b
isolated products. CO/O2 = 15/1.
coupling products were obtained in moderate to good yields.
Acetophenone with electron-rich groups such as p-Me and p-
OMe afforded the corresponding 4-quinolones in good yields
(Scheme 6, 3b,c). Halogen substituents such as F, Cl, and Br
were well tolerated, affording the desired products in moderate to
good yields (Scheme 6, 3d−g). Fortunately, the reaction with 1-
(naphthalen-1-yl)ethan-1-one also proceeded smoothly, result-
ing in the desired product with 61% yield (Scheme 6, 3h).
Propiophenone and 1-phenylbutan-1-one were also tolerated,
affording the corresponding products in 63% and 52% yield,
respectively (Scheme 6, 3i,k). It is noteworthy that 1-(furan-2-
yl)ethan-1-one showed good reactivity and afforded the desired
product with 51% yield (Scheme 6, 3l).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03337.
C
DOI: 10.1021/acs.orglett.7b03337
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Letter
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Experimental procedure, characterization data, and copies
of 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aiwenlei@whu.edu.cn.
ORCID
Aiwen Lei: 0000-0001-8417-3061
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21390400, 21520102003, 21272180,
21302148), the Hubei Province Natural Science Foundation of
China (2013CFA081), the Research Fund for the Doctoral
Program of Higher Education of China (20120141130002), and
the Ministry of Science and Technology of China
(2012YQ120060). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated.
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