Nickel-catalyzed redox-economical coupling of alcohols and alkynes to form allylic alcohols

Article abstract of DOI:10.1021/ja500666h

We have developed a redox-economical coupling reaction of alcohols and alkynes to form allylic alcohols under mild conditions. The reaction is redox-neutral as well as redox-economical and thus free from any additives such as a reductant or an oxidant. This atom-economical coupling can be applied for the conversion of both aliphatic and benzylic alcohols to the corresponding substituted allylic alcohols in a single synthetic operation.

Full text of DOI:10.1021/ja500666h

Communication
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Nickel-Catalyzed Redox-Economical Coupling of Alcohols and
Alkynes to Form Allylic Alcohols
Kenichiro Nakai,† Yuji Yoshida,† Takuya Kurahashi,*,†,‡ and Seijiro Matsubara*,†
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
Scheme 2. Transition-Metal-Catalyzed Alkyne-Alcohol
Coupling Reactions
a
ABSTRACT: We have developed a redox-economical
coupling reaction of alcohols and alkynes to form allylic
alcohols under mild conditions. The reaction is redox-
neutral as well as redox-economical and thus free from any
additives such as a reductant or an oxidant. This atom-
economical coupling can be applied for the conversion of
both aliphatic and benzylic alcohols to the corresponding
substituted allylic alcohols in a single synthetic operation.
llylic alcohols are among the most fundamental organic
A
compounds and are versatile building blocks for organic
synthesis. In the past decade, transition-metal-catalyzed direct
coupling of alkynes and aldehydes was identified as a
significant methodology for the divergent synthesis of allylic
alcohols.1−3 Nickel-catalyzed reductive coupling of alkynes
and aldehydes in the presence of organometallic reagents
(e.g., organozincs and organoboranes) is an example of
seminal work on such a transformation (Scheme 1).4 The
a
(a) Ruthenium-catalyzed transfer hydrogenative redox-neutral
Scheme 1. Nickel-Catalyzed Alkyne-Aldehyde Reductive
Coupling Reactions
coupling and (b) nickel-catalyzed redox-economical coupling.
reactions involving the aforementioned reductive coupling
with an organometallic reagent (Scheme 1). The formation of
such oxa-nickelacycles has been well investigated by a
stoichiometric reaction and confirmed by X-ray single-crystal
structural analysis in some cases.8−10 Therefore, we
hypothesized that (1) if the oxa-nickelacycle is reduced by
an alcohol via hydrogen transfer (oxidation of an alcohol by
protonation of the oxa-nickelacycle and subsequent β-hydride
elimination to provide an aldehyde),11 an allylic alcohol would
be obtained (Scheme 2b); and (2) if the newly produced
aldehyde could participate in the oxidative cyclization with an
alkyne and Ni(0) to regenerate the initial oxa-nickelacycle,
redox-economical coupling of an alcohol and an alkyne would
be achieved.
To prove our hypothesis, we first examined the coupling of
benzyl alcohol 1a and alkyne 2a in the presence of a catalytic
amount of benzaldehyde to facilitate the initial oxa-nickela-
cycle formation (Table 1). Allylic alcohol 3aa was obtained in
78% yield when nickel bis(1,5-cyclooctadiene) (Ni(cod)2) and
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) were
more recent ruthenium-catalyzed “redox-neutral” coupling
reaction of alkynes and alcohols in the presence of an
external hydrogen source (e.g., iPrOH and HCO2H) is
another straightforward route to diverse allylic alcohols.
(Scheme 2a).5,6 However, to the best of our knowledge,
there is only one report on the use of transition-metal
catalysts for the “redox-neutral as well as redox-economical”
coupling of alcohols and alkynes to form allylic alcohols.7
Herein, we demonstrate the feasibility of the aforementioned
processdirect coupling of alcohols and alkynesto form
allylic alcohols without using any reductant or oxidant
(Scheme 2b).
Oxidative cyclization of an aldehyde and an alkyne with
Ni(0) to afford the corresponding oxa-nickelacycle, a key
intermediate, is a well-known step in various catalytic
Received: January 21, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja500666h | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Effects of Ligand and Additive on the Formation
of Allylic Alcohol
Table 2. Nickel-Catalyzed Coupling Reaction between
Alkyne 1 and Alcohol 2
a
a
b
entry
ligand
aldehyde
yield (%)
c
1
2
3
4
5
6
7
IPr
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
−
78
64
12
5
d
SIPr
e
IMes
PCy3
PPh3
PPr3
IPr
<1
<1
f
80 (77)
a
Reactions were carried out using Ni(cod)2 (5 mol %), ligand (5 mol
%), 1a (0.2 mmol), and 2a (0.24 mmol) in 2 mL of benzene for 12 h.
b
Determined by 1H NMR analysis using CHBr3 as the internal
c
standard. IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
d
SIPr: 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene.
e
f
IMes: 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene. Isolated
yield.
employed as the catalysts, in benzene at ambient temperature
(entry 1). Other N-heterocyclic carbene ligands such as 1,3-
bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene
(SIPr) and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
(IMes) were less effective for the reaction and afforded
lower yields of 3aa (entries 2−3). The reaction in which
phosphine ligands were used in place of the IPr ligand
afforded only a trace amount of 3aa, regardless of their steric
or electronic properties (entries 4−6). Further examination
revealed that the redox-economical coupling proceeded in the
absence of a catalytic amount of aldehyde (additive) to
furnish 3aa in 80% yield (entry 7).
a
Reactions were carried out using Ni(cod)2 (5 mol %), IPr (5 mol %),
1 (0.2 mmol), and 2 (0.24 mmol) in 2 mL of benzene for 12 h.
b
c
Isolated yields are given. Ratio of regioisomers.
Next, we carried out the nickel-catalyzed redox-economical
coupling of various substituted benzylic and aliphatic alcohols
with alkynes to obtain the corresponding allylic alcohols
(Table 2). Benzylic alcohols having electron-donating groups
such as methyl and methoxy groups reacted with 4-octyne 2a
to give the corresponding allylic alcohols (3ba, 3ca, 3da) in
high yields. The reactions of benzylic alcohols with electron-
withdrawing groups also afforded the desired products, albeit
in moderate yields (3ea, 3fa, 3ga). Of note, benzylic alcohol
1h possessing an acetyl group also participated in the reaction
to give 3ha in 70% yield; clearly, the acetyl group was
tolerated under the reaction conditions, and the coupling
reaction proceeded chemoselectively. Aliphatic alcohols such
as cyclohexanemethanol and cyclopropanemethanol, too, were
successfully coupled with alkyne 2a under the same reaction
conditions to afford the corresponding substituted allylic
alcohols (3ja, 3ka) in good yields. Various functional groups
were tolerated in the coupling reaction of benzyl alcohol 1a
with alkynes: alkynes possessing an alkoxy group participated
in the reaction to provide allylic alcohols 3ad and 3ae in 71%
and 74% yields, respectively. Both acyclic and cyclic alkynes
participated in the reaction; cyclopentadecyne 2f coupled with
benzyl alcohol 1a to furnish allylic alcohol 3af.
Scheme 3. Deuterium-Labeling Experiment
generated in situ? Accordingly, we performed the coupling
of α,α-dideuteriobenzyl alcohol 1a−d with 7-tetradecyne 2b
under the standard reaction conditions, as shown in Scheme
3, and obtained allylic alcohol 3ba−d with 92% deuterium
labeling at the olefinic position. This result indicated that the
coupling reaction proceeds via the formation of an oxa-
nickelacycle, which undergoes reduction by proton transfer
from the hydroxy hydrogen and hydride transfer from the
benzylic hydrogen. Detailed observation of the deuterium-
labeling reaction revealed the formation of cis-7-tetradecene
4b−d in 11% yield, with 99% deuterium labeling at the
olefinic position, as a minor product along with the main
coupling product 3ab−d. This result indicated that the alkyne,
which exists in a slightly excess amount as compared to the
alcohol (1.2 equiv), acts as the oxidant for the alcohol to
We next carried out a deuterium-labeling experiment to
address the following questions: (1) which of the hydrogen
atoms on alcohol 1 acts as a proton or hydride source to
reduce the oxa-nickelacycle to afford the final product 3? and
(2) how is the initial oxa-nickelacycle key intermediate
B
dx.doi.org/10.1021/ja500666h | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
generate a catalytic amount of the aldehyde, which then
participates in the formation of the initial reactive oxa-
nickelacycle through oxidative cyclization of an aldehyde and
an alkyne with Ni(0).
widely used to form molecular frameworks in an atom-
economical manner. In this context, the aforesaid coupling of
alkynes and alcohols represents a rare example of the
isomerization of the π bond of an alkyne to construct a
new C−C σ bond with an alcohol. Efforts to expand the
scope of the reaction and develop an asymmetric variant of
this reaction are underway; the results will be reported in due
course.
Scheme 4. Plausible Reaction Pathway
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic and analytical data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
kurahashi.takuya.2c@kyoto-u.ac.jp
matsubara.seijiro.2e@kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JST, ACT-C and Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.K. also acknowledges the Asahi Glass
Foundation, The Uehara Memorial Foundation, Tokuyama
Science Foundation, and Kurata Memorial Hitachi Science
and Technology Foundation. K.N. also acknowledges the
Japan Society for the Promotion of Science for Young
Scientists for fellowship support.
On the basis of our observations, we proposed a plausible
mechanism for the redox-economical coupling of α,α-
dideuteriobenzyl alcohol 1a−d and 7-tetradecyne 2b (Scheme
4). As the first step toward the generation of the reactive oxa-
nickelacycle intermediate, 1a−d is oxidized to benzaldehyde
5a−d via hydrogen transfer with alkyne 2b as the reductant
(hydrogen scavenger) to yield alkene 4b−d (induction step).
Then, 5a−d and 2b participate in the formation of oxa-
nickelacycle 6 by oxidative cyclization with Ni(0) (catalytic
process). Another alcohol 1a−d would then protonate 6 with
its hydroxy hydrogen atom to afford acyclic intermediate 8.
Subsequent β-hydride elimination affords nickel hydride
complex 9 along with aldehyde 5a−d, followed by reductive
elimination to provide allylic alcohol 3ab−d and regenerate
Ni(0).12 An alternative reaction pathway would involve β-
hydride elimination of enone 10ab−d on oxa-nickelacycle 6
and reduction of the resulting 10ab−d with alcohol 1a by
hydrogen transfer under the reaction conditions. However, the
attempted reduction of enone 10aa with alcohol 1a under the
standard reaction conditions did not afford allylic alcohol 3aa
(Scheme 5), thus ruling out this alternative pathway.
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Scheme 5. Reduction of Enone with Alcohol
C
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Journal of the American Chemical Society
Communication
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