Nickel/N-Heterocyclic Carbene Complex-Catalyzed Enantioselective Redox-Neutral Coupling of Benzyl Alcohols and Alkynes to Allylic Alcohols

Article abstract of DOI:10.1021/acscatal.8b04198

The nickel-catalyzed enantioselective redox-neutral coupling of alcohols and alkynes to access chiral allylic alcohols is reported. The reaction proceeds via a hydrogen transfer process under ambient temperature, converting abundant feedstock alcohols and alkynes to chiral allylic alcohols with high stereoselectivities in one chemical step. Key to the success of this process was the development of a bulky chiral N-heterocyclic carbene, (R,R,R,R)-SIPE, a chiral version of SIPr, as the ligand for nickel. Notably, we found that the utilization of P(OPh)₃ as secondary ligand for nickel was crucial to inhibit the isomerization of products.

Full text of DOI:10.1021/acscatal.8b04198

Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 1−6
Nickel/N-Heterocyclic Carbene Complex-Catalyzed Enantioselective
Redox-Neutral Coupling of Benzyl Alcohols and Alkynes to Allylic
Alcohols
Yuan Cai, Jia-Wen Zhang, Feng Li, Jia-Ming Liu, and Shi-Liang Shi*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China
S
* Supporting Information
ABSTRACT: The nickel-catalyzed enantioselective redox-neutral coupling of
alcohols and alkynes to access chiral allylic alcohols is reported. The reaction
proceeds via a hydrogen transfer process under ambient temperature, converting
abundant feedstock alcohols and alkynes to chiral allylic alcohols with high
stereoselectivities in one chemical step. Key to the success of this process was the
development of a bulky chiral N-heterocyclic carbene, (R,R,R,R)-SIPE, a chiral
version of SIPr, as the ligand for nickel. Notably, we found that the utilization of
P(OPh)3 as secondary ligand for nickel was crucial to inhibit the isomerization of products.
KEYWORDS: asymmetric catalysis, nickel, ligand design, N-heterocyclic carbenes, transfer hydrogenation, redox-neutral coupling,
alkynes, alcohols
Scheme 1. Synthesis of Chiral Allylic Alcohols
nantioenriched allylic alcohols represent important chiral
Ebuilding blocks because of their synthetic versatility and
the common occurrence of this substructure in a variety of
pharmaceuticals and natural products. Consequently, the
general asymmetric construction of chiral allylic alcohols is
an important objective in organic synthesis.1 Among the
reported methods, the classical asymmetric addition of vinyl
organometallics to carbonyl compounds2 is a general method
to synthesize chiral allylic alcohols, although vinyl organo-
metallics need to be preformed, often through multistep
procedures (Scheme 1A). Alternatively, the nickel-catalyzed
asymmetric reductive coupling of aldehydes and alkynes3 has
been advanced as a more efficient approach for the preparation
of chiral allylic alcohols (Scheme 1B).4 While the direct use of
widely available alkynes as coupling partner in lieu of a vinyl
organometallic in this process is advantageous, stoichiometric
organometallic reductants (e.g., ZnEt2 or Et3B) are still
required.
Recently, we questioned whether an alcohol could serve as
both a “greener” hydride source and also as a precursor for a
transient aldehyde for the overall redox-neutral asymmetric
coupling of alkynes and alcohols to form chiral allylic alcohols
(Scheme 1C).5−7 If successful, such a direct asymmetric C−H
alkenylation of alcohols via hydrohydroxyalkylation of alkynes
represents a nearly ideal method to access chiral allylic alcohols
given the abundance of both starting materials and excellent
atom-, step-, and redox economy of the process.8 We noted
that the Krische group,9 and the Matsubara group,10 has
developed elegant alcohol-alkyne coupling reactions for the
synthesis of achiral allylic alcohols using ruthenium and nickel-
based catalysts, respectively. However, the methods for the
enantioselective C−H alkenylation of alcohols with alkynes to
form chiral allylic alcohols, have previously not been reported.
Despite recent advances made in the field of asymmetric
redox-neutral coupling of alcohols and unsaturated hydro-
carbons,5−7 base metal-catalyzed enantioselective examples
Received: October 18, 2018
Revised: November 19, 2018
© XXXX American Chemical Society
1
DOI: 10.1021/acscatal.8b04198
ACS Catal. 2019, 9, 1−6

ACS Catalysis
Letter
remain elusive.11 One factor that has impeded the develop-
ment of asymmetric base metal-catalyzed reactions is the lack
of suitable chiral ligands with efficient control of both reactivity
and selectivity.
Table 1. Ligand Screening and Reaction Optimization
Chiral N-heterocyclic carbenes (NHCs) have become
increasingly common in asymmetric catalysis,12 especially for
nickel(0)-catalysis,3b,c,13 as a result of their modular prepara-
tion, steric and electronic tunability, and robustness as
monodentate ligands for transition-metals. We recently
developed a bulky chiral NHC ligand, namely, ANIPE (Figure
1, L1),14 which could be considered a chiral version of IPr,
a
a
b
entry NHC
additive
yield (%)
E/Z
e.r.
1
2
L1
L2
L3
L3
L3
L3
L3
L3
L3
L4
L5
L6
--
--
--
68
42
84
<2
68
<2
60
69
82(76)
84
88:12
88:12
94:6
nd
93:7
nd
90:10
93:7
99:1
97:3
96:4
96:4
92.5:7.5
91.5:8.5
95.5:4.5
nd
nd
nd
nd
nd
95.5:4.5
94.5:5.5
94.5:5.5
95:5
3
4
5
6
PPh3
ethyl acrylate
dimethyl fumarate
NEt3
7
8
9
P(OEt)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
10
11
12
72
70
a
Determined by NMR analysis with 1,1,2,2-tetrachloroethane as
internal standard using crude sample; isolated yield shown in
b
parentheses. Determined by HPLC analysis with a chiral stationary
phase.
Figure 1. NHCs designed and applied in this study.
whose design draws inspiration from Gawley’s carbene (L2).15
The use of L1 enabled a highly enantioselective copper
catalyzed hydroboration of α-olefins.14 Subsequently, Cramer
reported a nickel-catalyzed enantioselective intramolecular
alkylation of pyridone substrates based on a similar ligand
system.13g Herein, we describe the development of SIPE
ligands (Figure 1), a new class of bulky chiral analogues of
saturated NHCs, like SIPr. It is practically important that the
precursor of SIPE ligands, air- and moisture-stable salts, could
be easily prepared on multigram scale.16 The SIPE ligands
were successfully applied to the nickel-catalyzed enantiose-
lective redox-neutral coupling of alcohols and alkynes to form
chiral allylic alcohols. To the best of our knowledge, this is the
first example of base metal-catalyzed enantioselective transfer
hydrogenative C−C bond forming reactions.
dramatically improved E/Z ratio of 99:1 (entry 9).
Interestingly, other members of the SIPE family of ligands
exhibited slightly lower levels of selectivity (L4−L6, entries
10−12).
With our optimized conditions, we next set out to
investigate the scope of this novel enantioselective alcohol-
alkyne coupling protocol (Table 2). First, various benzylic
alcohols were coupled with 4-octyne. Both electron-rich and
electron-poor benzylic alcohols were suitable, and electronic
properties had little influence on the enantioselectivity,
although electron-poor benzylic alcohols required a higher
catalyst loading to achieve good conversion. Generally, chiral
allylic alcohol products were obtained in moderate to high
yields (52−86%) and high stereoselectivities (≥96:4 E/Z) and
enantioselectivities (94:6−95.5:4.5 e.r. in most cases).
Importantly, this mild protocol tolerated many functional
groups, such as ethers (3e, 3i, 3j, and 3y) and silyl ethers (3z),
a thioether (3q), a trifluoromethyl ether (3f), aryl halides (F,
Cl) (3g and 3k), a benzofuran (3h), a trifluoromethyl (3m),
an ester (3n), and a ketone (3o). It is noteworthy that an aryl
chloride was compatible with reaction conditions (3k),
considering well-established, mild protocols for nickel-
catalyzed cross coupling of aryl chlorides.4 Remarkably, simple
aliphatic alcohol (phenylpropanol) could also be employed in
this transformation, providing the coupling product 3r with
moder ate enantioselectivity, though with excellent control of
double bond geometry.
Next, we examined the scope of alkynes coupling partner. In
addition to 4-octyne, we found that symmetric internal alkynes,
including 3-hexyne, 5-decyne, 6-dodecyne, and 7-tetradecyne,
were all competent substrates, providing products in 94:6−
96:4 e.r. and 74−92% yields (3s−3v). In the case of 2-butyne
(the smallest internal alkyne), bulkier ligand L6 was employed,
affording product 3w in 86.5:13.5 e.r.20 Given that efficient
enantiocontrol of a nickel-catalyzed reductive coupling of
dialkyl internal alkynes and aldehydes is challenging, the
enantioselectivities obtained in this novel protocol are
considerably high.3 Moreover, the use of unsymmetric internal
We began our study by examining the coupling of benzyl
alcohol (1a) and 4-octyne (2a) to form chiral allylic alcohol 3a
in the presence of 2 mol % Ni(cod)2 and chiral ligand. Initially,
a range of commonly used chiral phosphine and N-heterocyclic
carbene ligands were tested, none of which provided the
desired product 3a (see Supporting Information (SI)). The use
of our previously disclosed ligand L1, however, gave
encouraging results, providing product 3a in 68% yield and
92.5:7.5 e.r. with an E/Z selectivity of 88:12 (Table 1, entry 1).
Although the use of L2 resulted in lower yield (entry 2), the
use of L3, a newly design saturated NHC led to an
improvement in the yield and selectivity (entry 3, E/Z 94:6,
95.5:4.5 e.r.). During the course of optimization, we found that
partial isomerization17 of 3a occurred under the reaction
conditions, which we ascribed to a sequential hydronickelation
and β-H elimination process initiated by a nickel hydride
species.18 Various Lewis basic additives, such as PPh3, ethyl
acrylate, Et3N, and phosphites, were investigated as secondary
ligands, whose coordination might stabilize the nickel catalyst
and thus suppress isomerization events (entries 4−9). We were
pleased to find that the electron-deficient phosphite ligand
19
P(OPh)3 in combination with L3 at room temperature
delivered 3a in 76% isolated yield and 95.5:4.5 e.r., with a
2
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Letter
a
Table 2. Substrate Scope
a
b
c
d
e
Yields of isolated products on 0.2 mmol scale. Using 5 mol % catalyst (x = 5). Using 10 mol % catalyst (x = 10). toluene as the solvent. Using
f
g
20 mol % catalyst (x = 20, without P(OPh)3). Using L6/HCl as the ligand. 20 mol % benzaldehyde was added.
alkynes, 3-octyne and an aryl-substituted alkyne, gave products
as regioisomeric mixtures with high stereoselectivities for both
regioisomers (3x and 3x′, 4a and 4a′). In the case of an
alkynylarene, 20 mol % benzaldehyde was added to promote
the initial oxa-nickelacycle formation. Finally, regioisomeric
products (3y and 3y′, 3z and 3z′) from alkynes containing
ethers could also be obtained in good yields and stereo-
selectivities. The absolute configuration of the product 3a was
determined as the R-configuration by Mosher ester analysis
(see SI).
A series of experiments were performed to get insight into
the mechanism. First, a deuterium-labeling experiment using
d2-1a in the model reaction gave 87% deuterium incorporation
at the olefinic position of 3a (Figure 2A). On the basis of this
result and previous observations,10 we proposed a catalytic
cycle as outlined in Figure 2B: (1) Alcohol dehydrogenation
initially generates the corresponding aldehyde. (2) A
subsequent oxidative cyclization of aldehyde, alkyne and
Ni(0) catalyst furnishes oxanickelacyle A,21 which is
protonated by alcohol to afford acyclic vinylnickel intermediate
B. (3) A subsequent β-H elimination of B provides nickel
hydride complex C and regenerates the aldehyde. (4) Finally,
reductive elimination affords the allylic alcohol product and
regenerates the nickel catalyst. In support of this proposal,
when d2-1a and nondeuterated 1e was used in a crossover
reaction, partial incorporation at olefinic position was observed
for both products, indicative of scrambling (Figure 2C). In
contrast, no deuterium scrambling on benzylic position of d2-
3a and d1-3e was observed, which suggest the dehydrogen-
ation step of benzylic alcohols is probably irreversible and
3
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Letter
Figure 2. Mechanistic studies and proposed catalytic circle
Notes
oxidative cyclization is fast. In addition, both intermolecular
and intramolecular KIEs were observed (KIE = 2.1 or 2.0,
Figure 2D). Moreover, the X-ray crystal structure of Ni(0)-
complex 5 was obtained. The use of 5 as catalyst gave similar
results to the reaction using nickel catalyst generated in situ,
consistent with monomeric nickel-L3 complex being the active
catalyst (Figure 2E). Finally, an erosion in E/Z ratio of 3a was
observed in the control experiment in the absence of P(OPh)3
using 5 as catalyst, further confirm the important role of the
additive (Figure 2E).
In summary, we have developed the first nickel-catalyzed
enantioselective redox-neutral coupling of alcohols and
alkynes, which also represents the first enantioselective base
metal-catalyzed transfer hydrogenative C−C bond forming
reaction. This mild protocol utilizes two feedstock chemicals
and earth-abundant nickel catalysts to form chiral allylic
alcohols with high stereoselectivities in one chemical step.
Essential for the success of the process was the development of
SIPE-type ligands and the utilization of a basic additive to
suppress the product isomerization. Efforts to expand the
scope of the reaction by further ligand design and exploration
of wider application of these ligands are ongoing in our
laboratory.
The authors declare the following competing financial
interest(s): A patent has been filed.
ACKNOWLEDGMENTS
■
This work was financially supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
No. XDB 20000000), the “1000 Talents Plan”, the National
Natural Science Foundation of China (Grant No. 21690074,
21871288, 21821002). We thank Prof. Yiming Wang
(University of Pittsburgh) for proofreading this manuscript.
DEDICATION
■
Dedicated to Prof. Xiyan Lu on the occasion of his 90th
birthday.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b04198.
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
Crystallographic data for 5 (CCDC 1843290) (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shiliangshi@sioc.ac.cn.
ORCID
Shi-Liang Shi: 0000-0002-0624-6824
4
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(16) The key intermediate chiral aniline could be readily prepared in
45-g scale (>99.5% ee); see SI for the details.
(17) The following byproducts generated from E/Z isomerization,
double bond shift, and dehydrogenation of allylic product 3a
respectively, were observed.
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