Rhodium-Catalyzed Alkylation of C-H Bonds in Aromatic Amides with Styrenes via Bidentate-Chelation Assistance

Article abstract of DOI:10.1021/acs.orglett.5b01682

Rhodium-catalyzed alkylation reactions of aromatic C-H bonds in aromatic amides with styrene derivatives have been developed by using an 8-aminoquinoline as a bidentate directing group. C-C bond formation selectively occurred between the ortho C-H bonds i

Full text of DOI:10.1021/acs.orglett.5b01682

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Alkylation of C−H Bonds in Aromatic Amides
with Styrenes via Bidentate−Chelation Assistance
Kaname Shibata, Takuma Yamaguchi, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: Rhodium-catalyzed alkylation reactions of aromatic C−H bonds
in aromatic amides with styrene derivatives have been developed by using an 8-
aminoquinoline as a bidentate directing group. C−C bond formation selectively
occurred between the ortho C−H bonds in aromatic amides and the terminal
carbon of the styrene derivatives. The presence of an 8-aminoquinoline moiety
is essential for the success of the reaction.
arbon−hydrogen bond functionalization has become one
The reaction of amide 1a (0.3 mmol) with styrene (0.6
C
of the most reliable methods for introducing a variety of
mmol) in the presence of [RhCl(cod)]2 (0.0075 mmol) as the
catalyst and KOAc (0.075 mmol) as the base in toluene (1 mL)
at 160 °C for 12 h produced the linear alkylation product 2a in
47% NMR yield with a small amount of branched type product
3a and the alkenylation product 4a (Scheme 1).11 The product
functional groups into organic compounds. In recent years, C−
H bond functionalization has been used in the synthesis of
complex naturally occurring molecules, medicinally relevant
structures, or useful materials.1 In most cases, the regioselective
functionalization of the C−H bond involves the use of a
directing group, such as pyridine, oxazole, amide, ester, ketone,
or a related structure.2 In 1993, Murai and co-workers reported
on the ruthenium-catalyzed alkylation of ortho-C−H bonds of
aromatic ketone with vinylsilane.3 The regioselective alkylation
at the ortho position was achieved via the coordination of the
ketone to a ruthenium center. Since this pioneering work, a
variety of regioselective C−H bond functionalization reactions
have been developed. C−H bond alkylation with alkenes is the
most atom-economical reaction compared to the use of alkyl
halides or alkyl metal species as a coupling partner, because all
atoms are incorporated into the desired products through this
transformation. Recently, not only vinylsilanes but also other
alkenes, including acrylic esters, styrenes, and even unreactive
normal olefins, were used as coupling partners.4 In the case of
styrene, significant achievements have been made by Darses,5
Nakamura,6 Yoshikai,7 Shibata,8 and others.9 Herein, we report
on the rhodium-catalyzed alkylation of aromatic C−H bond of
aromatic amides with styrene derivatives by using a bidentate
directing group. The resulting 2-phenethylbenzoic acid moiety
is a common structure in natural products and displays various
bioactivities (Figure 1).10 To the best of our knowledge, this
reaction is the first synthetically useful application of the use of
an amide directing group into the rhodium-catalyzed alkylation
reactions with styrene derivatives.
Scheme 1. Rh-Catalyzed Alkylation of C−H Bonds in
Aromatic Amides with Styrene
yield could be significantly improved by using [Rh(OAc)-
(cod)]2 as a catalyst. To our delight, the addition of pivalic acid
suppressed the formation of the alkenylation product 4a.12 The
reaction occurred predominantly at the β-position of styrene
predominant to produce the desired linear product 2a.
Inspired by transition-metal-catalyzed C−H bond function-
alization reactions that involve the use of a bidentate chelation
system,13 the effect of directing groups was examined (Figure
2). When an N-methyl substituent was introduced in the
directing group, the desired product was not obtained. No
reaction occurred when other directing groups similar to 8-
aminoquinoline were used in the reaction. These results show
that the presence of both of an amide NH and a quinoline
nitrogen is indispensable for the success of this reaction.
Figure 1. Examples of 2-phenethylbonzoic acid moiety containing
naturally occurring compounds.
Received: June 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01682
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Organic Letters
Letter
Scheme 3. Rh-Catalyzed Reaction of Aromatic Amides with
a,b
Styrene Derivatives
Figure 2. Screening of directing groups.
The substrate scope for a variety of functional group
substituted aromatic amides was examined under the standard
reaction conditions (Scheme 2). In all cases, a small amount of
Scheme 2. Rh-Catalyzed Reaction of Aromatic Amides with
a,b
Styrene
a
Reaction conditions: amide (0.3 mmol), styrene (0.6 mmol),
[Rh(OAc)(cod)]2 (0.0075 mmol), PivOH (0.3 mmol), toluene (1
b
mL), at 160 °C for 12 h. Isolated yields. Values in parentheses are the
ratio of linear and branched alkylation products. [Rh(OAc)(cod)]2
(0.015 mmol) was used for 24 h. [Rh(OAc)(cod)]2 (0.0225 mmol)
c
d
was used for 24 h.
groups substituted at the 4-position of the styrene derivative
were tolerated under the standard reaction conditions and gave
the corresponding alkylation products in good yields (9a−e).
The more sterically hindered 2-methylstyrene 9g was also
applicable in this reaction. To our delight, a strong electron-
withdrawing pentafluorophenylethene 9h did not hamper the
reactivity. We were pleased to find that 2-vinylnaphthalene 9i
was also applicable in this reaction. However, α-methylstyrene
failed to give the corresponding alkylation products.
To collect additional mechanistic information regarding the
reactions, deuterium-labeling experiments were carried out
(Scheme 4). When 1a-d7 was subjected to the standard reaction
conditions for 2 h, but in the absence of styrene, H/D exchange
was observed only at the ortho-position on the benzene ring,
and no exchange was observed at the meta- and para-positions.
In addition, H/D exchange took place even at the methyl C−H
bond, although alkylation did not occur at the methyl group. A
small amount of H/D exchange was also observed at the
quinoline ring probably because of acidic conditions.11 These
results indicate that the cleavage of the ortho C−H bond is
reversible. In the reaction of naphthalenecarboxamide with
styrene-d8, nearly two proton atoms were incorporated into the
product 8 (1.01H + 0.91H = 1.92H). Most importantly, proton
atoms were incorporated into both the α and β positions of the
methylene carbon in a nearly comparable ratio.
a
Reaction conditions: amide (0.3 mmol), styrene (0.6 mmol),
[Rh(OAc)(cod)]2 (0.0075 mmol), PivOH (0.3 mmol), toluene (1
b
mL), at 160 °C for 12 h. Isolated yields. Values in parentheses are the
ratio of linear and branched alkylation products. [Rh(OAc)(cod)]2
(0.015 mmol) was used for 24 h. Styrene (1.2 mmol) was used.
c
d
the corresponding alkenylation product (equivalent to 4a) was
formed. Some functional groups, such as OMe, F, OAc, and
CF3, were tolerated under the standard reaction conditions
(2a−f). The number in parentheses denotes the ratio of linear-
and branched-type products. When a m-methyl-substituted
amide was used, the monoalkylation product 5a and the
dialkylation product 6a were formed. However, only the
monoalkylation product 5b was obtained when a m-CF3
substituted amide was used. These results indicate that an
electron-donating group accelerates the reaction. We further
investigated the compatibility of this reaction for heterocycle
and fused ring systems. Gratifyingly, the reaction is also
applicable to furan ring 7 and naphthalene ring-containing
compound 8.
Although we do not currently fully understand the reaction
mechanism, on the basis of the deuterium-labeling experiments
summarized in Scheme 4 and our previous work,14 a proposed
mechanism for the reaction is shown in Scheme 5. The
coordination of a quinoline nitrogen to the rhodium center
followed by a ligand exchange between the amide nitrogen and
Rh-OAc generates intermediate A. The subsequent oxidative
addition of the ortho C−H bond to the rhodium center gives
The scope of the reaction with respect to styrene derivatives
was next examined (Scheme 3). Overall, the desired products
were produced from a wide range of styrene derivatives in
excellent yields with a high linear selectivity. Various functional
B
DOI: 10.1021/acs.orglett.5b01682
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metalation−deprotonation mechanism. In sharp contrast, the
C−H bond-cleavage step in the case of this reaction likely
proceeds through oxidative addition.13b This result suggests
that the N,N′-chelation system has the potential to be
employed in a variety of new types of reactions. Although a
variety of functionalization reactions utilizing the N,N′-
bidentate directing group have been developed, only a limited
number of C−H alkylation reactions with alkenes have been
reported.14,17 Daugulis recently reported on the cobalt-
catalyzed reaction of aromatic amides consisting of an 8-
aminoquinoline directing group with styrene, but the products
obtained were not alkylation products but cyclized products.18
In summary, we report the development of the direct,
rhodium-catalyzed ortho-alkylation of C(sp2)−H bonds in
aromatic amides with styrene derivatives by using a bidentate
chelation system. The presence of an 8-aminoquinoline moiety
as the directing group is crucial for the success of the reaction.
Multiple bond insertion reactions via the use of an N,N′-
bidentate directing group are currently being pursued in our
laboratory and will be reported in due course.
Scheme 4. Deuterium-Labeling Experiments
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 5. Proposed Mechanism
S
Experimental procedure and characterization of new com-
pounds. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01682.
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. K.S. expresses
his special thanks for a JSPS Research Fellowship for Young
Scientists. We also thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance with
the MS and HRMS.
the five-membered Rh−H species B.15 The facile coordination
of styrene to the rhodium center followed by the insertion of
styrene into the Rh−H bond generates a Rh alkyl species D,
and reductive elimination and protonation produce the desired
product with the regeneration of a rhodium(I) species. The H/
D scrambling shown in Scheme 4 suggests that the insertion of
styrene is reversible and that another pathway in which
insertion occurs in the reverse direction is also operative to give
complex C. However, reductive elimination from complex C
would be unfavorable because of steric congestion. The
alkenylation byproduct is produced via the seven-membered
complex E.16
N,N′-Bidentate directing groups have recently been widely
used in many types of C−H functionalization reactions in
which various types of transition-metal catalysts have been
used.13 However, in these reactions, the C−H bond cleavage
step proceeds via σ-bond metathesis or by a concerted
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