Ni-Catalyzed C(sp2)-H alkylation ofN-quinolylbenzamides using alkylsilyl peroxides as structurally diverse alkyl sources

Article abstract of DOI:10.1039/d1cc02983e

A Ni-catalyzed direct C-H alkylation ofN-quinolylbenzamides using alkylsilyl peroxides as alkyl-radical precursors is described. The reaction forms a new C(sp³)-C(sp²) bondviathe selective cleavage of both C(sp³)-C(sp³) and C(sp²)-H bonds. This transformation shows a high functional-group tolerance and, due to the structural diversity of alkylsilyl peroxides, a wide range of alkyl chains including functional groups and complex structures can be introduced at theortho-position of readily availableN-quinolylbenzamide derivatives. Mechanistic studies suggest that the reaction involves a radical mechanism.

Full text of DOI:10.1039/d1cc02983e

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Ni-Catalyzed C(sp2)–H alkylation of
N-quinolylbenzamides using alkylsilyl peroxides
as structurally diverse alkyl sources†
Cite this: Chem. Commun., 2021,
57, 7942
Received 8th June 2021,
Accepted 5th July 2021
a
b
ac
Saori Tsuzuki,a Shunya Sakurai,
Akira Matsumoto,
Taichi Kano
and
abd
Keiji Maruoka
*
DOI: 10.1039/d1cc02983e
rsc.li/chemcomm
A Ni-catalyzed direct C–H alkylation of N-quinolylbenzamides using diverse precursors for alkyl radicals.7 Using this method, we have
alkylsilyl peroxides as alkyl-radical precursors is described. The reaction recently developed a Cu-catalyzed cross-coupling reaction between
forms a new C(sp3)–C(sp2) bond via the selective cleavage of both the alkyl radical generated in situ from an ASP and an arylboronic
C(sp3)–C(sp3) and C(sp2)–H bonds. This transformation shows a high acid, which afforded a variety of alkylarenes (Scheme 1b).5f While
functional-group tolerance and, due to the structural diversity of this process allows using arylboronic acids that can bear various
alkylsilyl peroxides, a wide range of alkyl chains including functional functional groups, the preparation of these boronic acids, some of
groups and complex structures can be introduced at the ortho-position which are relatively unstable, is limited to some extent.8 To expand
of readily available N-quinolylbenzamide derivatives. Mechanistic stu- the synthetic utility of our chemistry, the development of a novel
dies suggest that the reaction involves a radical mechanism.
coupling strategy using more readily available arenes and ASPs is
required.
The cleavage of the most abundant chemical bonds in a molecule
Transition-metal catalysis assisted by directing groups is a
represents one of the most attractive yet challenging transforma- powerful strategy for the regioselective cleavage of strong C–H
tions in modern organic chemistry. As the majority of most organic bonds.9 While these transformations have been achieved using
molecules consist of carbon–carbon (C–C) and carbon–hydrogen several transition-metal catalysts, particular interest has been
(C–H) bonds, synthetic methodologies involving the selective cleav- focused on nickel-based catalysts, given their low cost and high
age of these bonds allow greatly simplified synthetic routes to abundance. These reactions have been intensively researched
access complex molecules.1 Accordingly, tremendous effort has
been devoted to the development of efficient methods for the
cleavage of C–C and C–H bonds.2,3 Among these methods,
chemical reactions that involve radical species enable diverse
functionalization of organic molecules via homolytic bond
cleavage.2d,3e Indeed, we have reported a series of efficient methods
for the generation and subsequent functionalization of alkyl radi-
cals via the cleavage of C(sp3)–C(sp3) bonds in alkylsilyl peroxides
(ASPs) (Scheme 1a).4,5 ASPs are bench-stable organic peroxide
derivatives that can be readily prepared from various tertiary
alcohols or alkenes.6 Thus, they can be considered structurally
a Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo,
Kyoto 606-8502, Japan. E-mail: maruoka.keiji.4w@kyoto-u.ac.jp
b Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo,
Kyoto 606-8501, Japan
c Department of Applied Chemistry, Graduate School of Engineering,
Tokyo University of Agriculture and Technology, Koganei, Tokyo, 184-8588, Japan
d School of Chemical Engineering and Light Industry,
Guangdong University of Technology, Guangzhou 510006, China
Scheme 1 Various reactions using organic peroxides as the alkyl-radical
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
precursor.
d1cc02983e
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as has the discovery of various alkyl sources.10 In 2008, the Li group 1 using ASP 2a as the ethylating agent (Table 2). The reactions
reported dicumyl peroxide as a methyl source for the Pd-catalyzed of meta-methyl-, methoxy-, and trifluoromethyl-substituted
aryl C(sp2)–H methylation.11 Later, the Chatani group achieved the benzamides proceeded at the less hindered of the ortho-C–H
Ni-catalyzed ortho-C–H methylation of N-quinolylbenzamide using bonds, and 3b–3d were obtained in good yield (72–73%). ortho-
the same methyl source (Scheme 1c).10h This report is the first Alkynyl-substituted benzamide and 2-naphthalenecarboxamide
example of the use of an organic peroxide as an alkyl radical were also well tolerated under these reaction conditions to
precursor in a Ni-catalyzed C(sp2)–H alkylation. However, the lack furnish the corresponding products 3e and 3f in 79% and
of structural diversity in the organic peroxides has hampered their 71% yield, respectively. Although the reaction could be applied
wider use as alkyl sources beyond being methylating agents in to a,b-unsaturated amides, the yield of the final product 3g was
C(sp2)–H alkylation reactions. Therefore, we were interested in the merely moderate (52%). Fortunately, we found that the addi-
possibility of designing Ni-catalyzed C(sp2)–H alkylation reac- tion of 1.0 equiv. of LiBr improved the yield of 3g to 75%.13 We
tions where ASPs are used as versatile alkyl radical precursors then examined substrates which have two equivalent ortho-C–H
(Scheme 1d). This transformation can be expected to proceed via bonds as potential reaction sites. While the reactions of para-
the selective cleavage of C(sp3)–C(sp3) and C(sp2)–H bonds to form substituted benzamides resulted in mixtures of mono- and
a new C(sp3)–C(sp2) bond. Thus, we envisaged that a range of di-ethylated products, the use of an excess of 2a (4.0 equiv.)
functionalized alkyl groups could be introduced at the ortho- and 1.0 equiv. of LiBr predominantly afforded the di-ethylated
position of the benzamide derivatives.
products 3h and 3i in 71% and 73% yield, respectively. How-
Initially, we optimized the reaction conditions of the Ni- ever, the reaction of a meta-fluoro-substituted benzamide
catalyzed C(sp2)–H ethylation starting from benzamide 1a and under these adapted conditions gave both a small amount of
ASP 2a (Table 1). When the reaction was performed in DMF at the mono-ethylated product 3j0 (at the 6-position, 8%) and the
100 1C for 18 h using 1.0 equiv. of 1a and 2.0 equiv. of 2a with di-ethylated product 3j (44%).
NiCl2(PCy3)2 as the catalyst and Na2CO3 as the base, the desired
To synthesize benzamides with a variety of functionalized
ortho-ethylated product (3a) was obtained in 20% NMR yield alkyl moieties, ASPs with different structures were used in the
(entry 1). An investigation of different Ni catalysts revealed that the C(sp2)–H alkylation of benzamide 1a (Table 3). When cyclic
use of Ni(OAc)2ꢀ4H2O slightly improved the product yield (entries 2 ASPs were used, LiBr significantly affected the yield. In the
and 3). We then examined a variety of bases and ligands to further absence of LiBr only a trace amount of the alkylated product 3k
improve the yield of 3a (entries 4–8). The use of Et3N as the base and was obtained from the reaction of benzamide 1a with the six-
2-pyridone as the ligand was found to be optimal, affording 3a in membered cyclic ASP 2b, while the addition of LiBr significantly
80% isolated yield.12 Finally, when the reaction was conducted at
lower temperature (80 1C), the yield of 3a decreased (entry 9).
With the optimized reaction conditions in hand, we subse-
quently examined the substrate scope with respect to the amide
Table 2 Substrate scope of the amide componenta
Table 1 Optimization of the reaction conditionsa
Entry
Ni catalyst
Ligand
Base
1ab (%)
3ab (%)
1
2
3
4
5
6
7
8
9d
NiCl2(PCy3)2
NiBr2
—
—
—
—
—
—
Na2CO3
Na2CO3
Na2CO3
NaOAc
Li2CO3
CaCO3
CaCO3
Et3N
66
86
40
61
26
14
10
03
34
20
11
30
10
64
80
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
2-Pyridone
2-Pyridone
2-Pyridone
88
90 (80c)
53
Et3N
a
Reactions were performed on a 0.2 mmol scale in DMF (1.0 mL) under
a N2 atmosphere. Yields were determined by 1H NMR spectroscopy
b
a
Reactions were performed on a 0.2 mmol scale in DMF (1.0 mL) under
c
b
c
using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yield.
a N2 atmosphere. LiBr (1.0 equiv.) was added. ASP (4.0 equiv.) were
used.
d
Reaction was performed at 80 1C.
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Table 3 Substrate scope of the ASP componenta
a
b
c
Reactions were performed on a 0.2 mmol scale in DMF (1.0 mL) under a N2 atmosphere. Reaction was performed without LiBr. An additional
d
2.0 equiv. of ASP were added after the reaction was performed for 9 h. Performed at 80 1C.
improved the yield of 3k (85%). The use of five- or seven-
membered cyclic ASPs 2c–2e also furnished the corresponding
products (3l–3n) in high yield (81–88%). The reaction with 2f, a
compound bearing a cyclic ether moiety, afforded 3o, albeit in low
yield (24%). We also attempted reactions using acyclic ASPs other
than 2a. The use of ASP 2g with methyl-, octyl-, and phenyl
substituents on the carbinyl moiety selectively afforded the
octyl-substituted benzamide 3p in 58% yield. When using ASP
2h, which contains a cyclopropylmethyl moiety, homoallylated 3q
was obtained in 54% yield via a radical ring-opening process. In
Scheme 2 Access to benzamide bearing a nitrogen-rich xanthine core.
contrast to the successful introduction of primary alkyl groups to
1a, the alkylated benzamide 3r resulting from the transfer of a
secondary alkyl group from ASP 2i was not observed. This may be the presence of ASP 2a (Scheme 3a), which resulted in the
due to the steric hindrance of the isopropyl radical, which inhibits preferential conversion of 1d, i.e., the substrate with an
the Ni-catalyzed coupling process.10b
electron-withdrawing group. This tendency can also be seen
To demonstrate the utility of our method for the functiona- in previous reports for the related C–H activation methods.10,14
lization of bioactive molecules, the reaction was conducted Second, we added an excess of tetrachloromethane (CCl4),
using ASP 2j, which is derived from pentoxifylline, i.e., a drug i.e., a chlorine-atom donor, to the reaction of 1a with 2d
commonly used to treat peripheral artery diseases. To our (Scheme 3b).5h,15 As a result, the formation of 3m was com-
delight, benzamide 3s, which contains a nitrogen-rich xanthine pletely inhibited, and 5-chloro-1-phenylpentan-1-one (4) was
core, was obtained in 50% isolated yield (Scheme 2). In their obtained instead (62% yield based on 2d). It is reasonable to
entirety, the obtained results suggest that ASPs are among assume that 4 is formed via the abstraction of a chlorine atom
the best precursors for highly functionalized alkyl radicals in from CCl4 by alkyl radical 5, which is generated in situ via the
Ni-catalyzed C(sp2)–H alkylation reactions.
cleavage of the C–C bond in 2d. This result, together with the
To better understand the underlying reaction mechanism, observation that the reaction using 2h afforded 3q, suggests
we conducted several control experiments. First, we performed that alkyl radical intermediates are involved in this Ni-catalyzed
a competition experiment using a 1 : 1 mixture of 1c and 1d in ortho-C–H alkylation reaction.16
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In summary, we have developed a Ni-catalyzed C(sp2)–H
alkylation of N-quinolylbenzamide using alkylsilyl peroxides
as versatile alkyl radical sources. The reaction proceeds via the
cleavage of both C(sp3)–C(sp3) and C(sp2)–H bonds and affords
a wide range of ortho-alkylated N-quinolylbenzamide with
highly functionalized and complex structures. Mechanistic
studies suggest that the reaction involves a radical mechanism.
We gratefully acknowledge financial support via JSPS KAKENHI
Grants JP17H06450 and JP20H04815 (Hybrid Catalysis).
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Conflicts of interest
There are no conflicts to declare.
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