Rhodium-Catalyzed Alkenylation of C-H Bonds in Aromatic Amides with Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b00709

The rhodium-catalyzed alkenylation of C-H bonds of aromatic amides with alkynes is reported. A variety of functional groups, including OMe, OAc, Br, Cl, and even NO₂, are applicable to this reaction to give the corresponding hydroarylation prod

Full text of DOI:10.1021/acs.orglett.7b00709

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Alkenylation of C−H Bonds in Aromatic Amides
with Alkynes
Kaname Shibata, Satoko Natsui, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The rhodium-catalyzed alkenylation of C−H bonds of
aromatic amides with alkynes is reported. A variety of functional groups,
including OMe, OAc, Br, Cl, and even NO2, are applicable to this reaction to
give the corresponding hydroarylation products. The presence of an 8-
aminoquinoline group as the directing group is crucial for the success of the
reaction.
umerous advances in transition-metal-catalyzed C−H
the rhodium-catalyzed alkenylation of aromatic amides that
contain a bidentate directing group with internal alkynes.16 The
hydroarylation of alkynes represents a powerful method for
constructing styrene derivatives in an atom-economical
manner.17,18
N
bond functionalizations have been made recently.1
Transition-metal-catalyzed C−C bond-forming reactions in-
volving C−H bond activation are currently one of the most
extensively studied research topics in organic synthesis. In most
cases, the presence of a directing group in the substrate is
required to achieve a high degree of regioselective C−H
functionalization. A bidentate chelation system has recently
been shown to be a powerful system for developing new types
of C−H functionalizations. One such successful example was
reported by Daugulis and co-workers.2 After their seminal work,
a wide variety of reactions, including arylation, alkylation,
amination, sulfenylation, halogenation, oxidation, and so on,
has been developed in which a bidentate chelation system is
used.3 Alkynes have also been found to serve as the coupling
partner in C−H functionalizations involving a bidentate system
(Scheme 1). In 2011, we reported on the Ni(0)-catalyzed
oxidative cyclization of C−H bonds of aromatic amides that
contain a 2-pyridinylmethylamine moiety as the directing group
with alkynes leading to the production of isoquinolinones.4
Later, a similar type of oxidative cyclization reaction using
Ru(II), Co(II), and Fe(III) complexes as catalysts were
reported by Swamy,5 Daugulis,6 and Nakamura.7 The same
type of reaction using aryl sulfonamides or aryl phosphinic
amides instead of aromatic amides was also reported.8 In 2016,
we and Huang independently developed the Ni(II)-catalyzed
oxidative cyclization of C−H bonds leading to the production
of naphthalene skeletons into which two molecules of alkynes
are incorporated.9,10 Cu(II)-mediated and Ni(II)-catalyzed
oxidative alkynylation reactions using terminal alkynes have
also been reported.11 Furthermore, Cu(II)-mediated and
Co(II)- and Ni(II)-catalyzed reactions in which a product
containing a five-membered ring was obtained by cyclization
after oxidative alkynylation were reported.12 In addition, the
Rh(I)-, Ni(II)-, and Pd(II)-catalyzed alkenylation of C−H
bonds with alkynes was reported in which a picolinamide or an
8-aminoquinoline group was used as the bidentate directing
group.13−15 However, alkenylation reactions of C−H bonds in
aromatic amides bearing an 8-aminoquinoline bidentate
directing group remain undeveloped. Herein, we report on
In a preliminary study, the reaction of amide 1a and
diphenylacetylene (2a) was used as a model reaction. The
reaction of amide 1a (0.3 mmol) with alkyne 2a (0.45 mmol)
in the presence of [Rh(OAc) (cod)]2 (0.0075 mmol) as the
catalyst in toluene (1 mL) at 140 °C for 12 h gave a mixture of
E- and Z-isomers of the alkenylation product 3aa in 88%
isolated yield (the E/Z ratio could not be determined) along
with the cyclized isoquinolinone derivative 4aa in 8% yield
(Scheme 2). A variety of conditions were examined in an
attempt to avoid the formation of the undesired 4aa, but these
attempts were unsuccessful. However, fortunately, the desired
product 3aa and the byproduct 4aa were easily separated by
silica gel column chromatography.
Scheme 3 shows some representative results for the reaction
of 1a with various alkynes. In all cases, trace amounts of
cyclized products (equivalent to 4aa) were formed. However,
they were easily separated from the major product by column
chromatography. When the 6-dodecyne was used as the
coupling partner, the desired product 3ab was obtained in
only 63% (NMR yield) along with the cyclized product 4ab
(not shown) in 21% (NMR yield), and 15% (NMR yield) of
the starting amide remained unreacted. After optimization of
the reaction conditions,19 the addition of 1 equiv of AcOH was
found to be effective for the reaction to proceed smoothly and
to achieve a high degree of selectively (81%, E/Z + inseparable
structural isomers = >13/1). In the case of alkynes that contain
at least one alkyl group (3ab−ae), the addition of an acid was
required for the reaction to proceed efficiently. The unsym-
metrical 1-phenylpropyne 2f was found to participate in the
reaction, although the regioselectivity was low (A/B = 1.4:1).
4,4-Dimethyl-2-pentyne was also applicable to this reaction
Received: March 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00709
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Scheme 1. Reaction of Aromatic Amides with Alkynes Utilizing a Bidentate Directing Group
with excellent regioselectivity (3ae). The functionalization of
C−H bonds with unsymmetrical alkynes generally gave the
corresponding vinyl products in which a small substituent
group is positioned on the carbon atom adjacent to an aryl ring
of the substrate.20 However, the present reaction gave 3ae, in
which a bulky substituent group, such as a tert-butyl group, is
attached to the carbon atom adjacent to an aryl ring. When
terminal alkynes, such as phenylacetylene and triisopropylsily-
lacetylene, were used as the coupling partners, only trace
amounts of products were obtained.
Scheme 2. Rh-Catalyzed Alkenylation of C−H Bonds in
Aromatic Amides with Alkynes
Scheme 4 shows the results for the reaction of various
aromatic amides with 6-dodecyne.21 To our delight, various
functional groups were tolerated in the reaction, with the
Scheme 3. Rh-Catalyzed Reaction of the Aromatic Amide 1a
with Alkynes
a
Scheme 4. Rh-Catalyzed Reaction of Aromatic Amides with
a,b
6-Dodecyne
a
Isolated yields. The number in parentheses refers the ratio of E/(Z +
a
b
c
Reaction conditions: amide (0.3 mmol), alkyne (0.45 mmol),
[Rh(OAc) (cod)]2 (0.0075 mmol), AcOH (0.3 mmol), toluene (1
inseparable structural isomers). In the absence of AcOH. n.d. = not
determined. Alkyne (0.6 mmol) and [Rh(OAc) (cod)]2 (0.015
mmol) for 24 h. The reaction was run on a 1 mmol scale.
d
b
e
mL), at 140 °C for 12 h. Isolated yields. The number in parentheses
is the ratio of cis and trans isomers. Alkyne (0.6 mmol), [Rh(OAc)
c
(cod)]2 (0.015 mmol) for 24 h.
B
DOI: 10.1021/acs.orglett.7b00709
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Letter
corresponding alkenylated products being produced in
moderate to high yields. Since Br survived under the reaction
conditions, the product 3fb could be elaborated to give more
complex compounds by using it in additional coupling
reactions. Even a NO2 group was tolerated under the reaction
conditions, leading to the production of 3ib.
Scheme 6. Plausible Mechanism
To gain insights into the reaction mechanism, deuterium-
labeling experiments were carried out (Scheme 5). When the
Scheme 5. Deuterium-Labeling 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.7b00709.
Experimental procedures and the characterization of new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
ORCID
reaction was carried out in the absence of an alkyne, H/D
exchange was detected only at the ortho-position of the
aromatic amide, even when the reaction was carried out for a
short time, such as 15 min (eq 1), indicating that the C−H
bond cleavage step is reversible and rapid. In addition, the
addition of acetic acid had little effect on the efficiency of H/D
exchange. A deuterium-labeling experiment was also carried out
in the presence of an alkyne (eq 2). After 1 h, the alkenylated
product 8 was obtained in 16% yield, along with the recovery of
63% of the original 1a-d8. Although AcOD was used as the
additive, a proton atom was incorporated at the ortho position
of the recovered 1a-d8 (0.18H). Deuterium was incorporated
only at the vinyl position, but the ratio was not 100%. We
currently have no explanation for what caused such a lowering
of the deuterium mass balance at the present stage.
Naoto Chatani: 0000-0001-8330-7478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JST Strategic Basic Research
Programs “Advanced Catalytic Transformation Program for
Carbon Utilization (ACT-C)” from the Japan Science and
Technology Agency (JPMJCR12YS). K.S. expresses his special
thanks for receiving a JSPS Research Fellowship for Young
Scientists. We also thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance with
collecting the MS and HRMS data.
A plausible mechanism for the formation of the main product
3 and byproduct 4 is shown in Scheme 6. The reaction of the
amide 1 with Rh(I) forms the rhodium hydride complex C,
which undergoes hydrometalation with an alkyne, after which
reductive elimination and protonation gives the major product
3. The carbometalation of C with an alkyne followed by
reductive elimination gives the byproduct 4. An alternative
route to 4 from B is also possible. The mechanism is not clear
at the present stage.
In summary, we report on the rhodium-catalyzed direct
ortho-alkenylation of C(sp2)−H bonds in aromatic amides with
internal alkynes. The presence of an 8-aminoquinoline moiety22
as the directing group is crucial for the success of the reaction.
Further studies will target a more complete investigation of the
reaction mechanism which leads to this new type of reaction.
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