Nickel-Catalyzed, para-Selective, Radical-Based Alkylation of Aromatic Ketones

Article abstract of DOI:10.1021/acs.orglett.9b04327

A direct, para-selective, radical-based alkylation of aromatic ketones with alkanes has been developed using a nickel catalyst with oxamide as the ligand. Acetophenones bearing electron-withdrawing substituents were functionalized directly with simple alkanes with high para-selectivity while acetophenones with electron-donating groups were mainly para-functionalized. A mechanistic study indicated that C-H bond activation of the aromatic ring may be the rate-determining step of the reaction.

Full text of DOI:10.1021/acs.orglett.9b04327

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Letter
Nickel-Catalyzed, para-Selective, Radical-Based Alkylation of
Aromatic Ketones
Jie Wang,† Yu-Bo Pang,† Na Tao, Runsheng Zeng,* and Yingsheng Zhao*
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ABSTRACT: A direct, para-selective, radical-based alkylation of
aromatic ketones with alkanes has been developed using a nickel
catalyst with oxamide as the ligand. Acetophenones bearing
electron-withdrawing substituents were functionalized directly
with simple alkanes with high para-selectivity while acetophenones
with electron-donating groups were mainly para-functionalized. A
mechanistic study indicated that C−H bond activation of the aromatic ring may be the rate-determining step of the reaction.
ketones has also been widely studied.6 For example the
romatic ketones are important scaffolds that occur in a
Tung group reported the hydroxylation and etherification7 of
Awide range of materials, fine chemistry, and biologically
arenes,8 respectively. Recently, fluoroalkylation of aromatic
compounds has received research attention9 with function-
alized fluorinated moieties selectively added to aromatics. In
2018, our group10 reported a palladium-catalyzed highly para-
selective difluoromethylation of aromatic ketones and the Qing
group11 successfully introduced a trifluoromethyl group into
aromatic rings using a rhodium catalyst. However, direct
alkylation of aromatic ketone derivatives remains challenging.
Only the Nakao group reported a method that ensures the
selective alkylation of aromatic ketones at the para-position via
cooperative nickel/aluminum catalysis in 201612 (Scheme 1b).
And recently, Zhou13 and co-workers reported a para-selective
alkylation of electron-deficient arenes using alkyl halides as
alkyl sources, but only part of the acetophenone substrate
reacted which limits the utility of this reaction.14 Herein, we
report a nickel-catalyzed, para-selective, radical-based alkyla-
tion of aromatic ketones with a wide variety of substrates and
functional group tolerance.
active molecules.1 Regiocontrolled functionalization of aro-
matic ketones has been a longstanding topic of research efforts,
and in recent decades, various approaches for direct
introduction of functionalized moieties have been explored
extensively.2 For example, in 20143 the group of Li developed a
ruthenium-catalyzed para-selective alkylation reaction of
arenes; a variety of arenes bearing electron-withdrawing
substituents such as the phenylacetyl compound was function-
alized directly with high para-selectivity. Subsequently, In
2017,4 the Yu group developed a ligand-accelerated non-
directed C−H functionalization of arenes. This protocol is
compatible with a broad range of aromatic substrates include
including aromatic ketones (Scheme 1a). And later, the
nondirected C−H alkenylation of aromatics was reported by
the Yu group;5 however, acetophenone suffered from poor site
selectivity. Lately, heteroatom introduction into aromatic
The construction of carbon−carbon bonds is fundamental in
the synthesis of organic materials. Friedel−Crafts-type electro-
philic substitution of arenes comprises important synthesis
methods for preparing aromatic ketones in classical synthesis
chemistry.15 With the development of coupling reactions, the
combination of alkyl metal/alkyl halide and acetophenone
halide became the primary method for the synthesis of
acetophenone; however, the reaction system inevitably
produces a large number of metal salts and requires
prefunctionalization.16 Therefore, direct carbon−carbon (C−
C) bond formation from carbon−hydrogen (C−H) bonds via
Scheme 1. Novel Approach for the Selective Alkylation of
Aromatic Ketones
Received: December 3, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04327
© XXXX American Chemical Society
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A

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oxidative cross-coupling has emerged as a powerful method for
synthesizing acetophenone; this process does not require
substrate prefunctionalization and is synthetically simple. In
addition, free radical chemistry is an important and widely
utilized tool for many organic syntheses.17 A nickel-catalyzed
para-selective radical-based alkylation of aromatic ketones has
been developed.
We initially treated acetophenone (1a) with cyclohexane
(2a) in the presence of Ni(acac)2 (10 mol %), dppb (10 mol
%), and DTBP (2.5 equiv) in cyclohexane at 140 °C for 16 h
to investigate whether the alkylation product could be realized.
Fortunately, a mixture of the para- and meta-alkylated products
(4a and 5, respectively; para/meta (p/m) = 7:1) was obtained
in 31% yield (Table 1, entry 1). Encouraged by this result, we
Li3PO4, and LiN(Tf)2, altered both yield and selectivity for this
transformation (entries 9−13). When 40 mol % of LiN(Tf)2
was used, a product mixture of 4a and 5 was obtained in 85%
yield with good site selectivity (p/m = 16/1; Table 1, entry
13). The control experiment showed the nickel catalyst and
DTBP were indispensable for this transformation (entries 14−
15).
Once the reaction conditions had been optimized, we
examined a wide variety of acetophenone derivatives (Scheme
2). Functional groups at the meta-position such as Me, OMe,
a
Scheme 2. Substrate Scope of Acetophenone
Table 1. Optimization of the Nickel-Catalyzed Alkylation of
a
1a with 2a
ab
,
entry
catalyst
ligand additive (40%) yield (%)
5/4a
1
2
3
4
5
6
7
8
Ni(acac)2
dppb
dppb
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
−
−
−
−
−
−
−
−
31
38
43
21
45
65
60
57
70
78
76
79
85
−
1/7
1/7
1/9
1/6
1/9
1/10
1/7
1/9
1/7
1/10
1/9
1/7
1/16
−
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
Ni(acac-6F)2
−
a
Reaction conditions: 1 (0.2 mmol), 2a (0.25 mL), Ni(acac-6F)2 (10
9
LiCl
mol %), L4 (10 mol %) and DTBP (2.5 equiv), 140 °C, 16 h.
10
11
12
13
14
LiOH
Li2CO3
Li3PO4
LiN(Tf)2
LiN(Tf)2
LiN(Tf)2
OAc, Nphth, NHMe,19 Cl, Br, and CN were all well-tolerated
and afforded highly para-selective alkylated aromatic ketones
(3a−3h) in moderate to good yields (45−85%). Impressively,
all ortho-substituted acetophenones also performed well under
the optimized reaction conditions and gave the para-alkylated
products in moderate yields (3i−3k). Further study revealed
that disubstituted aromatic ketones (1l−1o) reacted well,
leading to highly para-selective alkylated products in moderate
yields (3l−3o; 45−60%). Unfortunately, 1-(2,6-dimethoxy-
phenyl)ethan-1-one (1p) only afforded the alkylated product
3p in trace amounts, along with recovery of the starting
materials.
c
15
Ni(acac-6F)2
−
−
a
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), ligand (10
mol %), DTBP (2.5 equiv) in cyclohexanone (2a) (0.25 mL), 140 °C,
b
16 h. Yields based on GC using tridecane as an internal standard.
c
No DTBP.
next screened various catalysts, such as RuCl3, Co(acac)2,
Fe(acac)2, Ni(acac)2, and Ni(acac-6F)2, to improve the yield
and selectivity of the para-selective product 4a (see Supporting
Information (SI)). Using Ni(acac-6F)2 as the catalyst
improved the product yield slightly (4a + 5; entry 2) but
resulted in poor site selectivity. A variety of ligands including
N-protected amino acids, pyridine, and phosphine-type ligands
were further screened; none of these ligands surpassed the
yields obtained using dppb. Interestingly, ligands derived from
oxalyl chloride provided better yields and better selectivity
(entries 3−8). Yields of 4a reached 65% with improved
selectivity (1/10). A variety of additives were further explored
and showed that lithium salts, such as LiCl, LiOH, Li2CO3,
Subsequently, we explored different alkanes using the
optimized conditions (Scheme 3). Diverse alkylated products
were obtained in moderate yields (40−45%) using alkyl
substrates such as cyclopentane and cycloheptane heterocycle
derivatives (4b−4c). Reactions with bridged hydrocarbons
gave moderate yields of alkylated products 4d and 4e (45%
and 41%). A cyclic ether (dioxane 2f) reacted smoothly with
acetophenone and its derivatives to afford the corresponding
para-alkylated products 4f−4h in moderate yields.
To explore the mechanism of this alkylation reaction and
explain the basis of para-selectivity, various parallel reactions
B
https://dx.doi.org/10.1021/acs.orglett.9b04327
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Letter
a
indicating a radical pathway is involved (Scheme 4b).
Interestingly, when the reaction was quenched by deuterated
acetic acid, the deuterated product 4a-[d] was obtained.
Furthermore, when benzophenone (1q, with both α-positions
blocked) was employed as the substrate, the para-alkylated
product 3q was not detected. These outcomes indicated that
lithium ions from the salts participated in deprotonation of the
α-methyl on acetophenone and generated a quaternary ring
nickel intermediate (Scheme 4e), in which the Ni(II) complex
acts as the Lewis acid to activate the aromatic ring. A control
experiment was performed to test this hypothesis whereby 4-
methylacetophenone (1r, the para position is blocked by a
methyl group) was used as a substrate; only trace amounts of
the alkylated product and 95% of 4-methylacetophenone were
obtained (see SI).
Scheme 3. Substrate Scope of Alkane
Based on the above results and previous reports,10,18
a
plausible catalytic cycle is proposed in Scheme 5. The lithium
Scheme 5. Plausible Mechanism
a
Reaction conditions: 1a (0.2 mmol), 2 (0.25 mL), Ni(acac-6F)2 (10
b
mol %), L4 (10 mol %), and DTBP (2.5 equiv), 140 °C, 16 h.
1
c
mmol scale synthesis. Isolated yields. 1 (0.2 mmol), 2 (2.5 equiv),
Ni(acac-6F)2 (10 mol %), L4 (10 mol %), and DTBP (2.5 equiv) in
0.25 mL of n-hexane, 140 °C, 16 h.
were performed (Scheme 4). Acetophenone was mixed with 4-
deutero acetophenone in a 1:1 ratio and added to the reaction
Scheme 4. Preliminary Mechanistic Study
salts initially participate in deprotonation of the acetophenone
α-methyl and form the quaternary ring nickel intermediate A,
which would trap the cyclohexyl radical to form the complex B,
followed by deprotonion by the t-BuO− species and a SET
process to generate the product.
In summary, we have developed a highly efficient approach
to realize a C(sp3)−C(sp2) coupling reaction using Ni(acac-
6F)2 as the catalyst. Various functional groups were well-
tolerated in the reaction affording the corresponding para-
alkylated products in moderate to good yields. A mechanistic
study indicated that lithium salts participate in deprotonation
of the acetophenone α-methyl, thereby promoting a highly
para-selective alkylation reaction. Compared with previous
classical coupling reactions, this reaction has the advantages of
being simple, highly atomic economic, and green, without
generating a large amount of metal salts.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04327.
Detailed experimental procedures and characterization
data (PDF)
system (see SI); the KIE value was 3.6 (Scheme 4a). When
acetophenone and 4-deuteo acetophenone were added to the
reaction system, the KIE value was 3.3. This suggested that C−
H bond activation of the aromatic ring may be the rate-
determining step of the reaction. In addition, the free radical
inhibitor TEMPO completely shut down the reaction,
AUTHOR INFORMATION
Corresponding Authors
■
Runsheng Zeng − Soochow University, Suzhou, China;
Email: zengrunsheng@suda.edu.cn
C
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Rivera, C. A.; Liu, P.; Ngai, M.-Y. Redox-Active Reagents for
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H Trifluoromethoxylation. Angew. Chem., Int. Ed. 2018, 57, 13795−
13799.
Yingsheng Zhao − Soochow University, Suzhou, China;
orcid.org/0000-0002-6142-7839; Email: yszhao@
suda.edu.cn
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Other Authors
Jie Wang − Soochow University, Suzhou, China
Yu-Bo Pang − Soochow University, Suzhou, China
Na Tao − Soochow University, Suzhou, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04327
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Author Contributions
†J.W. and Y.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from Natural Science
Foundation of China (Nos. 21772139, 21572149), Jiangsu
Province Natural Science Fund for Distinguished Young
Scholars (BK20180041), Prospective Study Program of Jiangsu
(BY2015039-08), Project of Scientific and Technologic
Infrastructure of Suzhou (SZS201708), Prospective Study
Program of Jiangsu (BY2015039-08), and the PAPD Project
are also gratefully acknowledged.
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