Dehydrogenative Coupling of Benzylic and Aldehydic C-H Bonds

Article abstract of DOI:10.1021/jacs.9b13920

A photoinduced dehydrogenative coupling reaction between benzylic and aldehydic C-H bonds is reported. When a solution of an alkylbenzene and an aldehyde in ethyl acetate is irradiated with visible light in the presence of iridium and nickel catalysts, a coupled α-aryl ketone is formed with evolution of dihydrogen. An analogous C-C bond forming reaction occurs between a C-H bond next to the nitrogen of an N-methylamide and an aldehydic C-H bond to produce an α-amino ketone. These reactions provide a straightforward pathway from readily available materials leading to valued structural motifs of pharmacological relevance.

Full text of DOI:10.1021/jacs.9b13920

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Dehydrogenative Coupling of Benzylic and Aldehydic C−H Bonds
Tairin Kawasaki, Naoki Ishida,* and Masahiro Murakami*
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ABSTRACT: A photoinduced dehydrogenative coupling reaction between benzylic and aldehydic C−H bonds is reported. When a
solution of an alkylbenzene and an aldehyde in ethyl acetate is irradiated with visible light in the presence of iridium and nickel
catalysts, a coupled α-aryl ketone is formed with evolution of dihydrogen. An analogous C−C bond forming reaction occurs between
a C−H bond next to the nitrogen of an N-methylamide and an aldehydic C−H bond to produce an α-amino ketone. These reactions
provide a straightforward pathway from readily available materials leading to valued structural motifs of pharmacological relevance.
Scheme 1. Dehydrogenative Coupling of 1 with 2
t would offer a straightforward method to construct organic
Iskeletons if two different C−H bonds are site-selectively
cleaved and dihydrogen is removed to form a new C−C bond.1
Such a process of σ-bond metathesis is kinetically difficult to
execute due to the inertness of C−H bonds. Furthermore, it is
often unfavorable in terms of thermodynamic balances based
on bond dissociation energies; generalized bond energies of
C−H, C−C, and H−H bonds are ca. 98,2 81,2 and 104 kcal/
mol,3 respectively. It is also formidable to facilitate cross-
coupling in preference to homocoupling. The examples of such
dehydrogenative C−H/C−H cross-coupling reported to date
are limited to (1) those using phenols and tetrahydroisoquino-
lines, which possess low oxidation potentials,4 and (2)
reactions using benzene derivatives substituted by heteroatom
functional groups that direct metals to approach a specific
aromatic C−H bond.5 Herein reported is a dehydrogenative
C−H/C−H cross-coupling reaction of alkylbenzenes with
aldehydes to form α-aryl ketones, which is promoted by
collaboration of light, iridium, and nickel. An analogous C−H/
C−H cross-coupling reaction of N-methylamides with
aldehydes furnishes α-amino ketones. The present study offers
a direct access from readily available substances to α-
substituted ketones, which are valued structural motifs found
in a number of biologically active molecules and their synthetic
intermediates.
formed as the major product, and only a small amount of
bibenzyl 4 (ca. 0.02 mmol) was detected. The excess amount
of 1 remained unreacted. The formation of H2 was confirmed
by GC analysis of the gas phase in the headspace of the
reaction vessel. Purification of the reaction mixture by silica gel
chromatography afforded analytically pure ketone 3 in 73%
yield based on 2.
A variety of substituted alkylarenes underwent the
dehydrogenative coupling reaction with octanal (2) under
analogous conditions to give the corresponding ketones 5−23
(Table 1). In the cases of methyl-substituted arenes (5−22),
only small amounts (typically less than 0.02 mmol) of
bibenzyl-type side products were observed. When 3,4-
dimethylanisole was employed as the toluene derivative, the
It has been reported that C(sp3)−H bonds undergo direct
arylation,6 acylation,7 alkoxycarbonylation,8 alkenylation,9
alkylation,10 and carboxylation11 reactions by cooperative
actions of a nickel catalyst and a photocatalyst under
photoirradiation. We tried to expand the scope of the reaction
partner of C(sp3)−H bonds and examined the use of
aldehydes. After a number of trials, we finally found conditions
suitable for a dehydrogenative C−H/C−H coupling reaction
between toluene derivatives and aldehydes, producing α-aryl
ketones. A solution containing 4-methoxytoluene (1, 1.0
mmol, 5.0 equiv), octanal (2, 0.20 mmol, 1.0 equiv), Ir cat.
(Ir[dF(CF3)ppy]2(dtbbpy)PF6, 0.004 mmol, 2 mol %), and
NiBr2(dtbbpy) (0.01 mmol, 5 mol %) in ethyl acetate (4.9
mL) was irradiated with blue LEDs (40 W, λmax = 463 nm) at
ambient temperature for 20 h (Scheme 1). The ketone 3 was
Received: December 28, 2019
Published: February 3, 2020
https://dx.doi.org/10.1021/jacs.9b13920
J. Am. Chem. Soc. 2020, 142, 3366−3370
© 2020 American Chemical Society
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Communication
a
nickel. The reactions of halo-substituted toluenes were sluggish
under the standard reaction conditions (5.0 equiv). When 50
equiv of toluene derivatives were used, however, the
corresponding ketones 16−18 were obtained in yields ranging
from 51% to 66%. Of note was that the chloro and even the
bromo substituents remained intact in the products. In
addition to toluene derivatives, 2-methylthiophene proved to
be an eligible substrate, giving the product 20 in 62% yield.
The reactions of 2,5-dimethylfuran and N-acetyl-2-methyl-
indole also gave the corresponding cross-coupling products 21
and 22, respectively, albeit less efficiently. In the case of
ethylbenzene, the secondary benzylic C−H bond was site-
selectively abstracted to furnish the substituted ketone 23 in
46% yield together with a small amount of bibenzyl-type
byproduct (2,3-diphenylbutane, 0.033 mmol as a diastereomer
mixture). The lower yield of the cross-coupling product 23 can
be ascribed to steric hindrance. Accordingly, sterically more
congested isopropylbenzene failed to undergo the dehydrogen-
ative cross-coupling reaction, and instead, the corresponding
bibenzyl (2,3-dimethyl-2,3-diphenylbutane, 0.22 mmol, 44%)
was formed as the major product.
Table 1. Scope of Alkylbenzenes
Shown in Table 2 are the results using various aliphatic
aldehydes, which successfully underwent the dehydrogenative
cross-coupling reaction with 1 to give the corresponding
ketones 24−34. Both linear (24−26) and α-branched (27−
29) aldehydes could be employed. Acetal (32), hydroxy (33),
and carbamate (34) functionalities remained intact under the
present reaction conditions. The reaction of benzaldehyde was
sluggish and the dibenzyl 4 was formed as the major product,
suggesting the abstraction of aldehydic hydrogen is slow due to
the electron-withdrawing nature of the phenyl group.
α-Aryl ketones often serve as the key intermediates for the
synthesis of various pharmaceuticals. For example, ketone 37
(Scheme 2) is the intermediate in the synthesis of
Tofisopam,12 which is an anxiolytic agent marketed in several
countries. The present method offers a straightforward access
to 37 starting from acetaldehyde (36) and methyl eugenol, an
abundant naturally occurring compound. First, hydrogenation
of methyl eugenol quantitatively gave 35. It successfully
underwent the dehydrogenative C−H/C−H cross-coupling
reaction with acetaldehyde (36) at the benzylic position to
furnish 37 (0.22 mmol, 22%, 22 equiv to Ni).
Constructive mechanistic information was obtained by the
following experiments. When Ir[dF(CF3)ppy]2(dtbbpy)PF6
was treated with NiBr2(dtbbpy) in CDCl3, the hexafluor-
ophosphate anion was replaced with a bromo ligand to form
Ir[dF(CF3)ppy]2(dtbbpy)Br, which was supported by 1H
NMR spectroscopy.13 It has been reported that photo-
irradiation of Ir[dF(CF3)ppy]2(dtbbpy)Br induces single-
electron transfer from the bromide anion to iridium,14 and
that the resulting bromine radical abstracts hydrogen from
alkanes and aldehydes. No coupling product 3 was formed
from toluene 1 and aldehyde 2 when NiBr2(dtbbpy) was
replaced with a catalyst formed in situ from Ni(OAc)2 and
dtbbpy.15 The product formation resumed upon addition of
(n-Bu)4NBr to the Ni(OAc)2/dtbbpy catalyst. Replacement of
NiBr2(dtbbpy) with its chloride counterpart, NiCl2(dtbbpy),
decreased the yield of 3 to 9%, presumably because of the
higher oxidation potential of a chloride anion than that of a
bromide anion.16 All the experimental results mentioned above
are consistent with the mechanism which involves an oxidation
of a bromide anion to a bromine radical.
a
Reaction conditions: alkylarenes (1.0 mmol, 5.0 equiv), octanal (2,
0.2 mmol, 1.0 equiv), NiBr2(dtbbpy) (0.01 mmol, 5 mol %),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.004 mmol, 2 mol %), AcOEt (4.9
mL), blue LEDs (40 W, λmax = 463 nm), ambient temperature, 20 h.
b
c
Alkylarenes (1.4 mmol, 7.0 equiv). Alkylarenes (1.6 mmol, 8.0
d
e
equiv). Alkylarenes (0.40 mmol, 2.0 equiv). Alkylarenes (10 mmol,
50 equiv). 72 h.
f
benzylic C−H bond para to the methoxy group preferentially
participated in the acylation reaction to give 10 as the major
product (para/meta = 89:11). Whereas electron-donating
groups such as tert-butyl (11) and siloxy (12) groups were
eligible substituents on the benzene ring, electron-withdrawing
substituents such as alkoxycarbonyl, acyl, and cyano groups
gave no cross-coupling products. This electronic contrast
suggests that the benzylic hydrogen is abstracted in an
electrophilic fashion. The reaction of p-cresol afforded benzyl
ketone 13, i.e., C-acylated product in 32% yield along with the
formation of the O-acylated product (27% yield). The toluene
substrate having an ester moiety not on the benzene ring but
on the alkoxy side chain afforded the product 14 in 58% yield.
On the other hand, an analogous substrate having a nitrile in
place of an ester gave 15 in 27% yield. The lower yield is
probably because of the coordination of the nitrile moiety to
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Communication
a
Table 2. Scope of Aldehydes
Scheme 3. Reaction in the Presence of TEMPO
Scheme 4. Possible Mechanistic Pathway
a
Reaction conditions: p-methoxytoluene (1, 1.0 mmol, 5.0 equiv),
aldehydes (0.2 mmol, 1.0 equiv), NiBr2(dtbbpy) (0.01 mmol, 5 mol
%), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.004 mmol, 2 mol %), AcOEt
(4.9 mL), blue LEDs (40 W, λmax = 463 nm), ambient temperature,
20 h.
Scheme 2. Synthesis of α-Aryl Ketone 37
We also performed the reaction of 1 with 2 in the presence
of TEMPO under the conditions that were otherwise identical
to those shown in Scheme 1 (Scheme 3). The TEMPO
adducts 38 and 39 were produced, corroborating the
intermediacy of both benzylic and acyl radical species.
Depicted in Scheme 4 is one of the possible mechanistic
scenarios for the formation of the cross-coupling product. It
consists of five steps (Steps 1−5). Step 1: Anion exchange
between cationic iridium(III) hexafluorophosphate A and
nickel(II) bromide B forms iridium(III) bromide complex C.
Step 2: When C absorbs light to get excited, a single electron
transfers from the bromide anion to iridium(III) to produce
iridium(II) species E and a bromine radical.13,14 The
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Communication
iridium(II) E (E1/2[Ir(III)/Ir(II)] = −1.37 V vs SCE)17
donates a single electron to Ni(II) species B (E1/2[Ni(II)/
Ni(0)] = −1.2 V vs SCE),18 giving rise to Ni(I) species F and
the iridium(III)bromide C. Step 3: The bromine radical
generated in Step 2 abstracts hydrogen atoms from benzylic
and aldehydic C−H bonds to furnish benzylic and acyl radical
species13,19 along with HBr. Step 4: The acyl and benzylic
radical species sequentially add to the nickel(I) species F to
produce nickel(III) complex H. The following reductive
elimination gives the ketone 3 and the nickel(I) species
F.20,21 Step 5: The nickel(I) species F reacts with HBr to
generate H222 and the Ni(II)Br2 species B, which re-enters the
catalytic cycle of Step 1.
Japan; orcid.org/0000-0003-2162-3605; Email: naisida@
sbchem.kyoto-u.ac.jp
Masahiro Murakami − Department of Synthetic Chemistry and
Biological Chemistry, Kyoto University, Kyoto 615-8510, Japan;
Email: murakami@sbchem.kyoto-u.ac.jp
Author
Tairin Kawasaki − Department of Synthetic Chemistry and
Biological Chemistry, Kyoto University, Kyoto 615-8510, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b13920
Notes
Aromatic groups participate in the stabilization of benzylic
radicals. Similarly, a nitrogen atom also stabilizes its bound
carbon radical species. We briefly examined whether C−H
bonds next to nitrogen atoms could take part in the
dehydrogenative coupling with an aldehydic C−H bond, and
suitable reaction conditions were found by modifying the
conditions for alkylarenes (Scheme 5). When a solution
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Numbers
15H05756 (M.M.) and 18H04648 (Hybrid Catalysis) (N.I.).
We thank Prof. Kenji Matsuda, Prof. Kenji Higashiguchi, and
Mr. Yusuke Nakakuki (Kyoto Univ.) for their assistance with
photophysical analysis, and Prof. Ryu Abe, Prof. Masanobu
Higashi, and Prof. Osamu Tomita (Kyoto Univ.) for their
assistance with analysis of the evolved hydrogen gas.
Scheme 5. Synthesis of α-Amino Ketones
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b13920.
■
sı
Details of experimental procedures including spectro-
scopic data of products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
Naoki Ishida − Department of Synthetic Chemistry and
Biological Chemistry, Kyoto University, Kyoto 615-8510,
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Communication
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possibly because the reversion via the benzylnickel species is faster
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̈
̈
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(14) It has been proposed that a photoexcited iridium(III) complex
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