Dicumyl Peroxide as a Methylating Reagent in the Ni-Catalyzed Methylation of Ortho C-H Bonds in Aromatic Amides

Article abstract of DOI:10.1021/acs.orglett.6b00658

The direct methylation of ortho C-H bonds in aromatic amides with dicumyl peroxide (DCP) using a nickel complex as the catalyst is reported. The reaction shows a high functional group tolerance and is inhibited by radical scavengers. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C-H bonds.

Full text of DOI:10.1021/acs.orglett.6b00658

Letter
pubs.acs.org/OrgLett
Dicumyl Peroxide as a Methylating Reagent in the Ni-Catalyzed
Methylation of Ortho C−H Bonds in Aromatic Amides
Teruhiko Kubo and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The direct methylation of ortho C−H bonds in aromatic
amides with dicumyl peroxide (DCP) using a nickel complex as the catalyst
is reported. The reaction shows a high functional group tolerance and is
inhibited by radical scavengers. In reactions of meta-substituted aromatic
amides, the reaction proceeds in a highly selective manner at the less
hindered C−H bonds.
he transition-metal-catalyzed functionalization of C−H
bonds is emerging as a powerful method for use in C−C
generated during the reaction. We herein report the Ni-
catalyzed methylation of C−H bonds in aromatic amides with
DCP (Scheme 1).
T
bond formation and has received a great deal of attention in
recent years.1 Various C−C bond formation reactions such as
arylation, alkylation, benzylation, allylation, and carbonylation
with the cleavage of C−H bonds have been reported to date.
However, methylation of C−H bonds continues to remain an
undeveloped area2 compared with the other types of C−C
bond formation reactions. Although the methyl group is one of
the simplest functional groups, the introduction of a methyl
group at a C−H bond can have a significant effect on the
biological and physical properties of a drug, an effect that is
known as the magic methyl effect.2a The most extensively
studied direct methylation of C−H bonds involves the use of
electrophilic reagents, such as MeI and its equivalents3 and
PhMe3NI.4 Nucleophilic organometallic reagents, such as
Me4Sn,5 methylboron reagents,6 MeMgCl,7 Me3Al,8 and
Me2Zn9 also can be used in the oxidative methylation of C−
H bonds. In addition, peroxide,10 DMSO,11 and other
reagents12 have also been found to function as methylating
reagents.
Scheme 1. Dicumyl Peroxide as an Ortho C−H Bond
Methylating Reagent in the Ni-Catalyzed Reaction of
Aromatic Amides
When amide 1 (0.3 mmol) was reacted with DCP (0.6
mmol) in the presence of a Ni(II) complex as a catalyst and
Na2CO3 as a base in tert-butylbenzene at 140 °C for 18 h, the
expected methylation product 2 was not produced (Table 1,
entries 1−3). However, the addition of PPh3 gave 2, albeit in
low yields (entries 4−7). To our delight, the yield was
dramatically increased when PCy3 was used as a ligand (entries
8 and 9). The efficiency of the reaction was also significantly
affected by the nature of the base used, and Na2CO3 was found
to be the base of choice (entries 9−11). The use of TBP
decreased the yield of 2 (entry 12). Carrying out the reaction at
120 °C (entry 13), for a shorter reaction time (e.g., 12 h; entry
14), or with a decreased amount of DCP (entry 15) had no
effect on the efficiency of the reaction. Pd(OAc)2, CoBr2, and
[RuCl2(p-cymene)]2 did not show any catalytic activity. Finally,
the standard reaction conditions were determined to be as
follows: 1 (0.3 mmol), DCP (0.6 mmol), NiCl2(PCy3)2 (0.03
mmol), and Na2CO3 (0.9 mmol) in tert-butylbenzene as the
solvent (0.7 mL) at a temperature of 140 °C for 18 h.
We recently reported a series of Ni-catalyzed chelation-
assisted functionalizations of C−H bonds in which a
combination of a Ni(II) catalyst and an 8-aminoquinoline
directing group was found to be a superior system for Ni-
catalyzed chelation-assisted C−H bond activation.3m,4,13,14 This
represents the first general system for Ni-catalyzed chelation-
assisted functionalization of C−H bonds. Although the precise
mechanism responsible remains unclear, a radical species is
thought to be involved as a key intermediate on the basis of
mechanistic experiments.3m Peroxides such as di-tert-butyl
peroxide (TBP) and dicumyl peroxide (DCP) are known to
undergo thermal decomposition to generate a methyl radical
through β-scission of an alkoxy radical, which initiates the
polymerization of alkenes15 or functions as a methylating
reagent.16 In addition, the functionalization of C−H bonds with
a radical species would demonstrate the potential for a new
generation of C−H bond activation reactions.17,18 Our working
hypothesis involves a reaction sequence in which an
intermediate nickelacycle reacts directly with a methyl radical
The scope of this methylation reaction with respect to the
amide and functional group tolerance was explored under the
standard reaction conditions (Table 2). Methoxy, benzyloxy,
fluoro, chloro, bromo, ketone, trifluoromethyl, and cyano
groups were tolerated under the reaction conditions. In the case
Received: March 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00658
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Letter
Table 1. Ni-Catalyzed Methylation of C−H Bonds with
Dicumyl Peroxide
Table 2. Ni-Catalyzed Methylation of C−H Bonds with
a
Dicumyl Peroxide
a
b
NMR yields. The value in parentheses is an isolated yield. TBP was
c
d
e
used. Run at 120 °C. Run for 12 h. DCP (0.48 mmol) was used.
f
Na2CO3 (0.9 mmol) was used.
of meta-substituted aromatic amides, only the less hindered C−
H bond was methylated.
We next performed a series of experiments in order to gain
insight into the mechanism. When the reactions were carried
out in the presence of 3 equiv of a typical radical scavenger such
as TEMPO, 1,4-cyclohexadiene, or α-methylstyrene under
otherwise standard reaction conditions, the reaction was
completely inhibited (Scheme 2). TEMPO methyl ether was
detected by high-resolution MS when TEMPO was added.19
These results clearly indicate that a free radical species is
involved in the reaction.
A deuterium labeling experiment was also carried out with
deuterium-labeled amide 1-d7 (Scheme 3). A significant
amount of H/D exchange was observed but only at the ortho
C−H bond in the recovered amide 1-d7, indicating that C−H
bond cleavage is reversible (Scheme 3a). In addition, an
observed intermolecular kinetic isotope effect (KIE) of 1.15
(for parallel experiments) suggests that C−H bond cleavage is
not involved in the rate-determining step (Scheme 3b).20
To collect additional information regarding the mechanism,
we examined the effect of the electronic nature of the
substituents. Similar to the case of alkylation and arylation
reactions,3m,14a,d an electron-withdrawing group on the
aromatic ring facilitated the reaction (Scheme 4).
On the basis of the results obtained in previously reported
Ni(II)-catalyzed functionalization reactions3m,14a,d and the
present observations, a mechanism involving a Ni(II)/Ni(IV)
catalytic cycle is illustrated in Scheme 5. The most important
issues to be addressed involve how the methyl group is
generated and how it is incorporated into the product. The
a
Reaction conditions: 1 (0.3 mmol), DCP (0.6 mmol), NiCl2(PCy3)2
(0.03 mmol), and Na2CO3 (0.9 mmol) in tert-butylbenzene (0.7 mL)
b
c
at 140 °C for 18 h. NiCl2(PCy3)2 (0.045 mmol) was used. Isolated
by GPC.
reaction begins with coordination of amide A to a Ni(II)
species, followed by ligand exchange and subsequent reversible
cleavage of the ortho C−H bond to give nickelacycle B. A
plausible mechanism involves a single electron transfer (SET)-
type process from B to DCP, which gives the Ni(III) species C
and alkoxy radical, which are in close proximity to one another.
The alkoxy radical undergoes decomposition with concomitant
elimination of acetophenone to give a methyl radical, which
immediately reacts with the unstable Ni(III) species C to give
the Ni(IV) species D. Reductive elimination followed by
protonation gives the expected product F with regeneration of
Ni(II).
B
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Scheme 2. Radical Trap Experiments
Scheme 5. Proposed Mechanism
Scheme 3. Deuterium Labeling Experiments
PCy3 ligand is essential for the success of the reaction. The
reaction displays a broad substrate scope and high functional
group tolerance. The reaction is inhibited by radical scavengers,
such as TEMPO, 1,4-cyclohexadiene, and α-methylstyrene. The
results of deuterium labeling experiments and KIE experiments
suggest that the C−H bond cleavage is reversible. The results of
competition experiments suggest that a reductive elimination is
likely to be a rate-determining step.
Scheme 4. Competition Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00658.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
An alternative mechanism involves oxidative addition of the
O−O bond in DCP to the nickel center to give the Ni(IV)
species G. Complex G undergoes β-methyl elimination with
concomitant generation of acetophenone to give D. Reductive
elimination from complex D followed by protonation gives the
final product F with regeneration of Ni(II). However, this
mechanism is inconsistent with the fact that β-phenyl
elimination leading to D′ takes place preferentially over β-
methyl elimination in alkoxymetal species.21 In addition, this
mechanism is not consistent with the results of the radical
trapping experiments, which indicate that a radical species is
involved in the reaction.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from The Ministry of
Education, Culture, Sports, Science and Technology and by
JST Strategic Basic Research Programs “Advanced Catalytic
Transformation Program for Carbon Utilization (ACT-C)”
from the Japan Science and Technology Agency.
In summary, we have reported the successful development of
a highly efficient process for Ni(II)-catalyzed methylation of
C−H bonds. This is the first example of the use of DCP for Ni-
catalyzed methylation of C−H bonds.10 The presence of the
C
DOI: 10.1021/acs.orglett.6b00658
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Letter
(13) For our review, see: Misal Castro, L. C.; Chatani, N. Chem. Lett.
2015, 44, 410.
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