Palladium-catalyzed carbonylative synthesis of 3-arylquinolin-2(1H)-ones from benzyl chlorides and o-nitrobenzaldehydes

Article abstract of DOI:10.1016/j.mcat.2021.111842

A palladium-catalyzed carbonylative cyclization of benzyl chlorides with o-nitrobenzaldehydes has been developed for the synthesis of 3-arylquinolin-2(1H)-ones. Mo(CO)₆ played a dual role as both a CO surrogate and a reductant in this carbonylative transformation.

Full text of DOI:10.1016/j.mcat.2021.111842

Molecular Catalysis 514 (2021) 111842
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
Palladium-catalyzed carbonylative synthesis of 3-arylquinolin-2(1H)-ones
from benzyl chlorides and o-nitrobenzaldehydes
,
,*
Jian-Li Liua, Chen-Yang Houa, Xinxin Qia *, Xiao-Feng Wub
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China
b Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023, Dalian, Liaoning, China; Leibniz-Institut für
Katalyse e.V., Albert-Einstein-Straße 29a, Rostock 18059, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords:
A palladium-catalyzed carbonylative cyclization of benzyl chlorides with o-nitrobenzaldehydes has been
developed for the synthesis of 3-arylquinolin-2(1H)-ones. Mo(CO)6 played a dual role as both a CO surrogate and
a reductant in this carbonylative transformation.
Palladium catalyst
Carbonylation
Benzyl chloride
O-nitrobenzaldehyde
Quinolinones
Quinolin-2(1H)-ones represent one of the most important N-hetero-
cycles being found in natural products and synthetic molecules [1]. They
have attracted much attentions because of their unique molecular
skeletons and broad range of pharmaceutical activities [2-6]. For ex-
amples, nybomycin and deoxynybomyin, as promising antibiotics are
found to be quite active against bacteria [2].c In addition, quinolin-2
(1H)-ones are valuable building scaffolds, which could undergo further
modifications in organic synthesis [7]. Therefore, various classical
procedures, such as Vilsmeier-Haack [8], Knorr [9], and Friedlander
reactions [10], together with modern methods, including
transition-metal-catalyzed variation [11], as well as RCM[12] have been
reported. Nevertheless, the exploration of novel strategy toward qui-
nolin-2(1H)-ones remains of long-lasting interest.
benzyl chlorides with o-nitrobenzaldehydes toward the synthesis of
3-arylquinolin-2(1H)-ones.
Initially, o-nitrobenzaldehyde 1a (0.2 mmol) and benzyl chloride 2a
(0.4 mmol) were used as model substrates to evaluate this carbonylative
cyclization reaction. To our delight, 63% yield of desired product 3aa
was obtained with Pd(OAc)2 (5 mol%), DPEPhos (5 mol%), Mo(CO)6
(1.0 equiv.), Et3N (2.0 equiv.), MgSO4 (1.0 equiv.), in DME at 100 ◦C for
22 h (Table 1, entry 1). Next, different ligands, involving PPh3, SPhos,
DPPP, and BINAP were examined, lower yields were observed (Table 1,
entries 2–5). Catalysts screening showed that Pd(OAc)2 was the optimal
catalyst (Table 1, entries 6–8). The yield of 3aa increased to 76% by
using DBU as the base (Table 1, entry 10), whereas other bases resulted
in even lower yields (Table 1, entries 9, 11–12). When the reaction time
was prolonged to 30 h, the target product was isolated in 92% yield
(Table 1, entry 13). As the hydrogen source, H2O played a significant
role in this carbonylation reaction. However, extra H2O will be gener-
ated as the reaction proceeding, which would affect the reaction. Hence,
the amount of MgSO4 was very important, only 48% yield of 3aa was
resulted without MgSO4 (Table 1, entry 14), while with 2 equivalent of
MgSO4, the corresponding product was produced in 99% yield (Table 1,
entry 15).
In the last few decades, palladium-catalyzed carbonylation reaction
provides an alternative access for the construction of N-heterocycles,
and carbonylative protocols toward quinolin-2(1H)-ones have been re-
ported [13]. On the other hand, the utilization of nitroarenes as a type of
convenient nitrogen sources in recent years is becoming more and more
popular because they are stable, less expensive, and easily available.
Thus, the study of nitroarenes as nitrogen alternatives have been dis-
closed in a series of aminocarbonylation reactions [14]. For examples,
Hu’s group developed a nickel-catalyzed reductive aminocarbonylation
of aryl halides with nitroarenes [14].e Cheung and Ma reported an
aminocarbonylation reaction of arylboronic acid with nitroarenes using
nickel metal as both a mediator and a reductant [14].f Herein, we wish
to describe a new palladium-catalyzed carbonylative cyclization of
With the optimal reaction conditions in hand, the scope and gener-
ality of this carbonylation reaction toward benzyl chlorides were stud-
ied. As summarized in Scheme 1, a broad range of benzyl chlorides were
tolerated well to provide the corresponding quinolin-2(1H)-ones in
moderate to excellent yields. Substrates with electron-donating groups,
* Corresponding authors.
E-mail addresses: xinxinqi@zstu.edu.cn (X. Qi), xiao-feng.wu@catalysis.de (X.-F. Wu).
https://doi.org/10.1016/j.mcat.2021.111842
Received 2 August 2021; Received in revised form 17 August 2021; Accepted 18 August 2021
Available online 30 August 2021
2468-8231/© 2021 Elsevier B.V. All rights reserved.

J.-L. Liu et al.
Molecular Catalysis 514 (2021) 111842
Table 1
Screening of Reaction Conditions.[a]
.
Entry
[Pd]
Ligand
Base
Yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(tfa)2
DPEPhos
PPh3
Et3N
63
2
Et3N
trace
25
3
SPhos
Et3N
4
DPPP
Et3N
trace
52
5
BNIAP
Et3N
6
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
Et3N
35
7
Pd(acac)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Et3N
52
8
Et3N
42
9
DIPEA
DBU
43
10
76
11
NaOCH3
Cs2CO3
DBU
23
12
40
13[b]
14[b,c]
15[b,d]
92
DBU
48
DBU
99
[a] Reaction conditions: o-nitrobenzaldehyde 1a (0.2 mmol), benzyl chloride 2a
(0.4 mmol), [Pd] (5 mol%), ligand (10 mol% for monodentate ligand, 5 mol%
for bidentate ligand), Mo(CO)6 (1.0 equiv.), base (2.0 equiv.), MgSO4 (1.0
equiv.), DME (1 mL), 100 ◦C, 22 h. Isolated yields. [b] 30 h. [c] Without MgSO4.
[d]MgSO4 (2.0 equiv.).
including methyl, tert‑butyl, methoxy, and phenoxy groups afforded the
target products in good to high yields (3ab-3ai). The steric encumbered
3-(2-methoxyphenyl)quinolin-2(1H)-one product could be synthesized
without significant effect on the yield (3ah). Electron-withdrawing
groups, such as ester, cyano, and trfluoromethyl moieties were all well
tolerated, the desired products were obtained in good yields (3aj-3al).
Halogen substituents were tolerated as well, the final products were
formed in moderate to excellent yields (3am-3ap). Moreover, biphenyl
and naphthyl related substrates were also reacted with o-nitro-
benzaldehyde 2a successfully to afford the quinolin-2(1H)-one products
in 84%, 75% and 81% yields (3aq-3at). In addition, pyridine groups
could be incorporated into quinolin-2(1H)-ones as well, the expected
products were resulted in 91% and 72% yields (3as-3at).
We next went on our study on the substrate scope of o-nitro-
benzaldehydes. As illustrated in Scheme 2, an array of o-nitro-
benzaldehydes was carried out under the standard reaction conditions,
affording the corresponding quinolin-2(1H)-ones in good to excellent
yields. o-Nitrobenzaldehyde bearing methyl, ethoxy, ester and acetal
substituents could react with 1a efficiently, the desired products were
isolated in high yields (3ba-3ea). This protocol allowed various quino-
lin-2(1H)-ones to be synthesized with fluoro and chloro groups at
different positions, resulting the expected products in good to high
yields (3fa-3ia). Finally, o-nitroacetophenone was also tested with
benzyl chloride and 15% yield of the corresponding product was
detected with significant amount of o-aminoacetophenone formed.
In addition, a control experiment of o-aminobenzaldehyde 1a as
reductant was performed (eq a). Under the standard conditions, the
target product 3aa was obtained in 14% yield along with large amount
of 1a remained. This is mainly due to the dimerization effect (conden-
sation between aldehyde and amine groups) from o-
aminobenzaldehyde.
Scheme 1. Substrate Scope of Benzyl Chlorides. Reaction conditions: o-nitro-
benzaldehyde 1a (0.2 mmol), benzyl chlorides 2 (0.4 mmol), Pd(OAc)2 (5 mol
%), DPEPhos (5 mol%), Mo(CO)6 (1.0 equiv.), DBU (2.0 equiv.), MgSO4 (2.0
equiv.), DME (1 mL), 100 ◦C, 30 h. Isolated yields.
Based on the above results and previous reports [10,15], a possible
reaction pathway is proposed in Scheme 4. Firstly, an oxidative addition
step of Pd0Ln with benzyl chloride 2a occurred to give intermediate
benzylpalladium complex I, followed by a coordination and insertion of
CO (released from Mo(CO)6) to provide acylpalladium complex II. Sec-
ondary,
a reaction of acylpalladium complex II with o-amino-
benzaldehyde 4a, which was generated from the reduction of
o-nitrobenzaldehyde 1a in the presence of Mo(CO)6 and H2O [15],
furnishing intermediate III and meanwhile releasing HCl which will be
neutralized by DBU. Subsequently, a reductive elimination of interme-
diate III lead to intermediate IV and regenerated Pd0Ln for the next
catalytic cycle. Finally, the target product 3aa was obtained through an
intramolecular condensation of intermediate IV assisted by DBU.
In summary, we have explored a general and straightforward syn-
thesis of 3-arylquinolin-2(1H)-ones through a palladium-catalyzed
aminocarbonylation reaction of benzyl chlorides with o-
To further reveal the potential utility of this approach in organic
synthesis, a late-stage modification of natural product was conducted
(Scheme 3). L-Menthol was reacted with 4-(chloromethyl)benzoyl
chloride to afford intermediate 4, followed by a carbonylative cycliza-
tion with o-nitrobenzaldehyde under the standard reaction conditions to
deliver the corresponding quinolin-2-(1H)-one 5 in 74% isolated yield. It
was a positive outcome, which might be applied as an efficient strategy
in potent drug synthesis and discovery.
2

J.-L. Liu et al.
Molecular Catalysis 514 (2021) 111842
prepared in moderate to high yields with good functional group
compatibility. Moreover, the late-stage modification of natural species
has been successfully conducted via this carbonylation process as well.
General procedure
o-Nitrobenzaldehydes 1 (0.2 mmol), Pd(OAc)2 (5 mol%), DPEPhos (5
mol%), Mo(CO)6 (0.2 mmol) and MgSO4 (0.4 mmol) were added to an
oven-dried tube (15 mL), which was then placed under vacuum and
refilled with nitrogen for three times. Benzyl chlorides 2 (0.4 mmol),
DBU (0.4 mmol) and DME (1 mL) were added into the tube via a syringe.
The tube was sealed and the mixture was stirred at 100 ◦C for 30 h. After
the reaction was completed, the crude mixture was filtered and
concentrated under vacuum. The crude product was purified by column
chromatography (DCM/EA = 20/1 to 5/1) on silica gel to afford the
desired products 3.
Author statements
X.F.Wu and X. Qi supervised this project. X. Qi prepared the manu-
script and X.F.Wu did the revision and corrections. J.L. Liu performed all
the experiments. C.-Y. Hou purified part of the products.
Scheme 2. Substrate Scope of o-Nitrobenzaldehydes. Reaction conditions: o-
nitrobenzaldehydes 1 (0.2 mmol), benzyl chloride 2a (0.4 mmol), Pd(OAc)2 (5
mol%), DPEPhos (5 mol%), Mo(CO)6 (1.0 equiv.), DBU (2.0 equiv.), MgSO4
(2.0 equiv.), DME (1 mL), 100 ◦C, 30 h. Isolated yields.
Declaration of Competing Interest
There are no conflicts to declare.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.mcat.2021.111842.
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