Copper-Catalyzed ortho-Functionalization of Quinoline N-Oxides with Vinyl Arenes

Article abstract of DOI:10.1002/anie.202007699

An efficient copper-catalyzed regioselective C?H alkenylation and borylative alkylation of quinoline N-oxides with vinyl arenes in the presence of pinacol diborane has been developed. The reaction proceeds through the borylcupration of the vinyl arenes followed by nucleophilic attack of the resulting alkyl copper species to the quinoline N-oxides. Benzoquinone and KO^tBu were identified as the necessary additives at the second step of the reaction that are crucial for the success of the reaction. A wide range of C2-functionalizaed quinolines were obtained with good functional group tolerance, which may find utilities in pharmaceuticals and synthetic chemistry.

Full text of DOI:10.1002/anie.202007699

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Accepted Article
Title: Copper-Catalyzed ortho-Functionalization of Quinoline N-Oxides
with Vinyl Arenes
Authors: Hui Hu, Xiaoping Hu, and Yuanhong Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007699
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Copper-Catalyzed ortho-Functionalization of Quinoline N-Oxides
with Vinyl Arenes
Hui Hu, Xiaoping Hu, Yuanhong Liu*
Dedicated to Professor Tamotsu Takahashi on the occasion of his retirement from Hokkaido University
Abstract: An efficient copper-catalyzed regioselective C-H
alkenylation and borylative alkylation of quinoline N-oxides with vinyl
arenes in the presence of pinacol diborane has been developed. The
reaction proceeds through the borylcupration of the vinyl arenes
followed by nucleophilic attack of the resulting alkyl copper species
to the quinoline N-oxides. Benzoquinone and KOtBu were identified
as the necessary additives at the second step of the reaction that
are crucial for the success of the reaction. A wide range of C2-
functionalizaed quinolines were obtained with good functional group
tolerance, which may find utilities in pharmaceuticals and synthetic
chemistry.
at the C2-position of N-heterocycles.[4] A wide variety of
chemical transformations including deoxgenative or non-
deoxgenative reactions has been developed employing pyridine
or quinoline N-oxides as the substrates, such as arylation,[5]
alkylation,[6] radical reaction,[7] 1,3-dipolar cycloaddition,[8]
transition-metal-catalyzed C-H bond functionalization[9] etc.[10]
Although much progress has been achieved, the regioselective
C-C bond formation reactions of N-Oxides with unsaturated -
systems such as alkenes have less been developed. For
instance, Chang et al. reported
a
Pd-catalyzed C-H
functionalization of pyridine N-oxides with electron deficient
olefins, in which the N-oxide activator was removed in a
subsequent reaction with PCl3.[11a] Cui and Wu developed a C2-
vinylation of quinoline N-Oxides under external-oxidant-free
conditions.[11b] However, only linear alkenes can be obtained
through these methods (Scheme 1a).[11-12] Recently, Ge reported
a copper-catalyzed enantioselective alkylation of N-Oxides via a
chiral Cu-H species[13] (Scheme 1b). On the other hand, copper-
catalyzed 1,2-difunctionalization of alkenes through trapping of
the Csp3-Cu intermediate with C, N or O-electrophiles has
received significant attention, since these methods could install
both the boronate and other functional groups, and the resulting
alkylboranes can be elaborated further.[14-15] However, the
catalytic borylcuprations using heteroaryl N-oxides as
electrophiles have not yet been reported. This might be due to
Quinoline derivatives are known to have a wide application in
pharmaceutical, agrochemical and industrial chemistry, which
also serve as useful building blocks in synthetic organic
chemistry.[1] Especially, C2-substituted quinoline derivatives
have been found to exhibit various biological activities, such as
CysLT1 antagonist,[2a] antileishmanial activity,[2b] antimalarial
activity[2c] and P-selectin inhibitors for the treatment of
atherosclerosis and deep vein thrombosis[2d] etc. (Figure 1).[2]
Consequently, much efforts have been made to develop the
efficient methodologies for the synthesis of C2-substituted
quinolines.[3]
Figure 1. Bioactive C2-substituted quinoline derivatives
Recently, pyridine or quinoline N-oxides, which serve as N-
activated pyridines, have emerged as ideal and versatile
synthetic intermediates for the introduction of functional groups
[*]
H. Hu, Xiaoping Hu, Prof. Y.-H. Liu
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032 (P. R. China)
E-mail: yhliu@sioc.ac.cn
[**]
We thank the National Key R&D Program of China (2016YFA0202900),
the Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000), Science and Technology Commission of
Shanghai Municipality (18XD1405000) for financial support.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Scheme 1. Regioselective functionalization of pyridine or quinoline N-oxides
with alkenes
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the following challenges: 1) the direct trapping of the alkyl-
copper intermediate with carbon-based electrophiles is more
difficult due to the instability of the Csp3-Cu bond, currently, most
studies focused on the use of alkyl- or acyl halides, or
pseudohalides as the electrophiles.[15] 2) The resulting
deoxgenated heterocycles may coordinate with the metal to
induce catalyst deactivation. 3) Side reactions such as
dimerization of quinoline N-oxides under the basic conditions[16]
or N-O bond reduction by diborane reagent[17] might compete
with the main reaction pathway. In this paper, we describe the
first example of copper-catalyzed C2-functionalization of
quinoline N-oxides with alkenes in the presence of diborane and
a base. Notably, the additives used in the additional step in this
one-pot operation play important roles for obtaining the desired
products, thus, either a 1,1’-disubstituted alkene or a borylated
product could be obtained selectively (Scheme 1c).
Control experiments demonstrated that copper catalyst and
ligand were essential for the reaction (entries 17-18).
Table 1. Optimization studies for the formation of 3aa
Initially, in order to understand the possible background
reactions, several control reactions were examined. Indeed, the
N-O bond of the quinoline N-oxide could be reduced by
bis(pinacolato)diboron (B2pin2) (30% yield of quinoline was
formed after 24 h in THF at room temperature). Stirring a
mixture of quinoline N-oxide and a base such as KOtBu in THF
led to the deoxygenated dimmer 2,2'-biquinoline in 39% yield.
When addition of B2pin2, KOtBu and quinoline N-oxide in THF
simultaneously, quinoline was observed as a major byproduct,
and the dimerization product could be minimized.[18]
Nevertheless, we reasoned that a proper choice of the reaction
conditions might solve the problem associated with the reactivity
and chemo-selectivity. We then optimized the reaction
conditions using styrene (1a), B2pin2 and quinoline N-oxide (2a)
as the model substrates. However, although
a thorough
screening of the copper-catalysts, ligands, bases, diboron
reagents and additives was performed, no desired borylated
product was formed. Interestingly, in some cases, trace of
Under the optimized conditions (Table 1, entry 5), the
substrate scope was investigated (Scheme 2). The method was
applicable to a wide range of substituted vinyl arenes. Alkenes
alkenylated product 2-(1-phenylvinyl)quinoline (3a) was detected. bearing electron-donating groups (-Me, -OMe) or electron
Occasionally, it was found that when the reaction mixture was
exposed to the air for 12 h at room temperature after the
reaction was complete, the yield of 3a could be improved. We
speculated that the oxygen might serve as an oxidant to
facilitate the formation of 3a. To our delight, when 1,4-
benzoquinone was added after the reaction was complete, 3a
could be formed rapidly and cleanly within 0.5 h. With this in
mind, we screened again the reaction conditions by adding
benzoquinone at the end of the reaction (Table 1). In the
presence of 10 mol% CuCl and PCy3, 1.5 equiv of KOtBu and
B2pin2, the desired alkene 3a could be formed as the major
product in 45% yield (Table 1, entry 1). To overcome this side
reaction, the effect of ligands was investigated. Bidentate
phosphine ligands of dppb and dppf showed low reactivity
(entries 2-3). Gratifyingly, with the bulky ligands Cyxantphos and
Xantphos, the yields of 3a could be improved remarkably to 56%
and 71%, respectively (entries 4-5). The strongly electron-
donating ligand of N-heterocyclic carbene (NHC) complex such
as IPr was not effective in this reaction (entry 7). Possibly, the
reaction is not only governed by the electronic effects of the
alkyl-copper species, but also relys on its stability. The yields
were diminished when KOtBu was replaced by NaOtBu and
LiOtBu, whereas the weaker bases such as K3PO4 and NaHCO3
failed to give the desired product (entries 8-11). The amounts of
the base and B2Pin2 were also crucial to the reaction efficiency.
Increasing or decreasing their amounts led to the lower yields
(entries 12-13).[18] Other copper catalysts such as CuTc or
Cu(OAc)2 could also be used for this reaction (entries 14-15).
withdrawing groups (-F, -CN, -CO2Me) at the para-position of the
aryl rings are well compatible, furnishing the corresponding
products in 35-63% yields (3b-3f). Generally, electron-rich
alkenes gave better product yields than electron-deficient
alkenes. It might be due to the formation of more nucleophilic
alkyl-Cu intermediates derived from electron-rich alkenes. To
our delight, the product yields could be dramatically improved
when 8-methylquinoline N-oxide 2b was used as the electrophile,
likely due to the reduced side reactions such as deoxygenation
etc. For example, electrically neutral styrene provided 3g in 90%
yield. Alkenes bearing various functional groups on the aryl rings
such as p-iBu, p-F, p-CN and p-CO2Me etc. turned out to be
efficient substrates, leading to 3h-3m in 62-78% yields. We
observed again that electron-rich alkenes generally exhibit better
reactivity than electron-deficient alkenes. The Cl substituent on
the aryl ring was well tolerated (3n). Sterically encumbered 2-
Me-styrene proceeded smoothly (3o). Reactions with 1-, 2- or 6-
naphthyl substituted alkenes also worked well, leading to 3q-3s
in 56-73% yields. The reactivity of a variety of quinoline N-oxides
was also examined. N-oxides possessing methyl or OMe groups
at the C-4 or C-7 position converted to the desired products in
moderate yields (3t-3v). 5-Chloro-, 4,7-dichloro- or 8-bromo-
substituted quinoline N-oxides provided the target products in
40-68% yields (3w-3y). Unfortunately, the use of substituted
styrene and alkyl alkene such as (E)-1-methoxy-4-(prop-1-en-1-
yl)benzene or but-3-en-1-ylbenzene as the substrates failed to
give the desired products. Pyridine N-oxide or 2-phenyl pyridine
N-oxide were also not suitable for this reaction.
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Scheme 2. Copper-catalyzed synthesis of 2-alkenylquinolinesa,b
Inspired by above results, we envisioned that the desired
borylated product might be formed in a deoxygenative manner
through variation of different additives used at the second step.
Subsequent screening of the base instead of benzoquinone
derivatives such as NaHCO3, Na2CO3, K3PO4, KOtBu et al.
revealed that KOtBu served as the most effective base. With
styrene 1a and 8-methylquinoline N-oxide 2b as the substrates,
Scheme 3. Copper-catalyzed synthesis of 2-alkylquinolinesa,b
Organoboranes are valuable synthetic intermediates that are
widely used in organic and pharmaceutical chemistry. To
demonstrate the utility of the borane products, the primary
alkylborane 4a was employed as a building block for the
synthesis of various valuable products. Vinylation of 4a with vinyl
Grignard reagent led to 7 in 73% yield. Cross-coupling with aryl
bromide catalyzed by Pd provided arylated product 8. Reaction
with ClCH2Br in the presence of n-BuLi afforded the borane
product 9.[20]
o
after addition of KOtBu at the second step and stirred at 80 C
for 3 h, the expected borane 4a could be formed in 80% NMR
yield (60% isolated yield, Scheme 3). Since some borane-
containing products might be unstable upon column separation,
thus NMR yields were provided for most of the products 4.
Electron donating groups on the aryl rings such as -Me, -iBu and
-OMe were well suitable to afford the expect products in
moderate to good yields (4b-4d). Halogens such as -F and -Cl
were also compatible (4e, 4f). 2-Methyl styrene provided 4g in
61% yield. The use of 3,5-di(MeO)-substituted styrene provided
4h in good yield. When vinylnaphthalenes were employed, the
corresponding products were obtained with synthetically
acceptable yields (4i-4k). In the cases of quinoline N-oxides
bearing no substituent or with a substituent at other positions
such as C4 or C-7, the borane products were not stable during
the purification by silica gel column chromatography, then the
products were isolated as the alcohol after oxidation with
NaBO3·4H2O (5l-5o). It was noted that when 5-Cl-quinoline N-
oxide was used, a protodeboronated product 6 was isolated in
40% yield.[19] The instability of these products might be caused
by coordination of the corresponding quinoline nitrogen with the
Bpin group resulting in the enhanced reactivity of the C-Bpin
bond. 8-bromoquinoline N-oxide reacted well with styrene to
Scheme 4. Transformation of compound 4a
To clarify the reaction mechanism, various control
experiments were performed. Reaction with quinoline instead of
quinoline N-oxide under the standard reaction conditions for the
first step did not afford 3a, indicating that quinoline N-oxide was
required in this reaction (Scheme 5, eq 1). Addition of a radical
scavenger TEMPO or galvinoxyl to the reaction mixture after the
afford 4q in 44% yield, along with the formation of
a
deboronated product 4q’. The structure of 4a was confirmed by
the X-ray crystallographic analysis.
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first step of the reaction either gave a lower yield of 3g or
inhibited the reaction efficiently (Scheme 5, eq 2). Thus, a
radical pathway is possibly involved for the second step. Isolated
borane 4a could not convert to 3g under the standard conditions
or through the reaction with benzoquinone or KOtBu (Scheme 5,
eq 3 and 4). The results indicated that borane 4 is not the
intermediate for alkene 3. In addition, since the outcome of the
reaction strongly depends on the additives at the second step,
thus a common intermediate should be involved for their
formation.
Scheme 6. Proposed catalytic cycle
In conclusion, we have developed
a copper-catalyzed
regioselective C-H alkenylation and borylative alkylation of
quinoline N-oxides. Benzoquinone and KOtBu were identified as
the necessary additives at the second step of the reaction that
are crucial for the success of the reaction. A wide range of C2-
functionalized quinolines were obtained with good functional
group tolerance, which may find utilities in pharmaceuticals and
synthetic chemistry. We have also shown that for the first time,
the catalytically formed alkylcopper intermediate generated via
borylcupration of vinyl arenes can be captured by heterocyclic
N-oxides. Further mechanistic studies and the development of
new reactions with N-oxides as electrophiles are currently
ongoing in our laboratory.
Keywords: copper catalysis
•
quinoline N-oxides
•
borylcupration • alkenylation • borylative alkylation
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On the basis of the above results and literatures,[13]
a
proposed catalytic cycle is shown in Scheme 6. Initially, the
copper alkoxide complex 10 reacts with B2pin2 to give a LCu-
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the borylated product 4a is unlikely. Since it can not explain how
3g is formed. We suggest that a comment intermediate 14 is
generated, which accounts for the formation of 3 and 4.
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Hui Hu, Xiaoping Hu, and Yuanhong
Liu*
Page No. – Page No.
Copper-Catalyzed ortho-
Functionalization of Quinoline N-
Oxides with Vinyl Arenes
Borylcupration: An efficient copper-catalyzed regioselective C-H alkenylation and
borylative alkylation of quinoline N-oxides with vinyl arenes in the presence of
pinacol diborane has been developed. The reaction proceeds through the
borylcupration of the vinyl arenes followed by nucleophilic attack of the resulting
alkyl copper species to the quinoline N-oxides. Benzoquinone and KOtBu were
identified as the necessary additives at the second step of the reaction that are
crucial for the success of the reaction.
This article is protected by copyright. All rights reserved.