Nickel-Catalyzed C(sp3)-H Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones

Article abstract of DOI:10.1021/acs.orglett.1c02074

An efficient nickel(0)-catalyzed addition of benzyl nitriles to terminal vinyl ketones via C(sp3)-H functionalization has been developed. The reaction provides a novel and efficient protocol for the synthesis of α-functionalized benzyl nitriles with a wide range of structural diversity under mild reaction conditions while obviating the use of a strong base. The work might be potentially useful toward the development of an enantioselective variant using chiral nitrogen ligands.

Full text of DOI:10.1021/acs.orglett.1c02074

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed C(sp3)−H Functionalization of Benzyl Nitriles:
Direct Michael Addition to Terminal Vinyl Ketones
Ninghui Zhang, Chunli Zhang, Xiaoping Hu, Xin Xie, and Yuanhong Liu*
Cite This: Org. Lett. 2021, 23, 6004−6009
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ABSTRACT: An efficient nickel(0)-catalyzed addition of benzyl
nitriles to terminal vinyl ketones via C(sp3)−H functionalization
has been developed. The reaction provides a novel and efficient
protocol for the synthesis of α-functionalized benzyl nitriles with a
wide range of structural diversity under mild reaction conditions
while obviating the use of a strong base. The work might be
potentially useful toward the development of an enantioselective
variant using chiral nitrogen ligands.
also be generated by a base, a strong base such as LDA5 or
ransition-metal-catalyzed C(sp3)−H bond activation or
Tfunctionalization reactions have attracted much interest proazaphosphatranes6 is usually required due to the low acidity
of α-protons in nitriles (for PhCH2CN, pKa = 21.9 in
DMSO),7 which may cause undesirable side products.
Michael-type reactions of nitriles with α,β-unsaturated carbon-
yl compounds could also be achieved through metal-2b or
Brønsted base (organocatalysis)-catalyzed8 C−H functionali-
zation reactions9 (Scheme 1, eq 2). However, in both methods
the scope of the nitriles is usually restricted to those bearing an
additional geminal electron-withdrawing (EWG) group with
higher α-C−H acidity to be able to engage in the reaction
processes, such as α-cyano esters, α-cyanoacetic acids, α-
sulfonyl nitriles, malononitriles, α-fluorobenzylnitriles, α,α-
dithioacetonitriles, etc. (Scheme 1, eq 2). Reports on the use of
benzyl nitriles without an additional EWG group at the
benzylic position are significantly scarce, especially when
terminal vinyl ketones are employed as the Michael acceptors.
Possibly, terminal vinyl ketones tend to oligomerize in the
presence of the transition metal catalysts or under strong basic
conditions.10 It was reported that benzyl nitriles bearing a
strong electron-withdrawing group (−NO2) at the phenyl ring
were able to participate in organocatalytic Michael additions to
α,β-unsaturated aldehydes.11 To our knowledge, there is no
report for the metal-catalyzed Michael reaction of terminal
vinyl ketones with normal benzyl nitriles. Herein we report the
first example of a Ni(0)-catalyzed Michael-type reaction of
benzyl nitriles without an additional EWG group at the
benzylic position with terminal vinyl ketones under the mild
in recent years because they provide the atom-economic routes
for the construction of carbon−carbon or carbon−heteroatom
bonds.1 Among the various reactions, metal-catalyzed2 and
cooperative soft-metal Lewis acid- or base-3 catalyzed α-
functionalizations of organonitriles represent some of the most
efficient approaches for the synthesis of diversely substituted
nitriles, which not only serve as common structural motifs in
pharmaceuticals and agrochemicals but also work as important
building blocks in organic chemistry.4 Upon the coordination
of the cyano group with the transition metal, the α-C−H
acidity of the nitrile substrate could be enhanced, resulting in
either the α-metalated nitrile I or the N-bound complex II,
which undergoes further reactions with electrophiles such as
aldehydes or imines to furnish the functionalized products
(Scheme 1, eq 1). Although the α-deprotonated nitriles could
Scheme 1. Metal- or Brønsted Base-Catalyzed C−H
Functionalization of Nitriles
Received: June 21, 2021
Published: July 8, 2021
https://doi.org/10.1021/acs.orglett.1c02074
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6004−6009
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reaction conditions. This new method offers an expanded
substrate scope with respect to both nitriles and α,β-
unsaturated ketones.
provided 3a in only 7−26% yields (Table 1, entries 9 and 10,
respectively). 1,10-Phenanthroline-type ligands bearing a
substituent at the C-2 or C-9 position, such as neocuproine
(L1) and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (L2),
gave 3a in 66−70% yields, while the use of L4 without a
substituent at the C-2 position afforded 3a in a low yield
(Table 1, entries 11−13, respectively). Possibly, the stability of
the nickel-containing intermediates could be enhanced by
more encumbered ligands of L1−L3. Employing oxazoline- or
pyridine−oxazoline-type ligands or terpyridine led to 3a in
46−55% yields (Table 1, entries 14−16, respectively). The
reaction could also proceed efficiently in dioxane, while DMF
or CH3CN were less effective (Table 1, entries 18 and 19,
respectively). No desired product was observed in the absence
of Ni(cod)2. However, 3a could also be formed without a
ligand, albeit with a low yield of 32% (Table 1, entries 20 and
21). Reactions catalyzed by pincer-type Ni(II) complexes that
involve the addition of alkyl nitriles such as acetonitrile to
aldehydes or aldimines have been developed by Ozerov,3d
Shibasaki,13 and Guan et al.;14 however, the use of a Ni(0)
catalyst for the activation of nitriles is quite rare.
Initially, we chose the benzyl nitrile 1a bearing an ortho-
alkynyl substituent as the model substrate for optimizing the
reaction conditions with 1-phenylprop-2-en-1-one 2a. It is
known that vinyl ketones undergo oligomerization in the
presence of a low-valent nickel catalyst,12 and such a side
reaction might compete with the main reaction pathway. We
reasoned that the judicious choice of the reaction conditions
might solve the problem. After the evaluation of the reaction
parameters, such as nickel catalysts, ligands, additives, solvents,
and substrate concentration (see the Supporting Information
for details), we were pleased to find that the desired Michael
reaction of 1a with 2a occurred at 80 °C when using Ni(cod)2
as the catalyst, a 1,10-phenanthroline-type ligand (L3) as the
ligand, and 4 mol % PhNHTs as the additive. The expected
product 3a was formed in a 76% yield (Table 1, entry 1).
a
Table 1. Optimization of the Reaction Conditions
Next, the substrate scope of these nickel-catalyzed reactions
of nitriles with vinyl ketones was examined (Scheme 2). To
our delight, a wide range of o-alkynylbenzyl nitriles and
vinylketones could be accommodated in this reaction. The
scope of o-alkynylbenzyl nitriles was first investigated using 2a
as the reaction partner. Alkynes bearing p-F or p-OMe groups
at the terminal aryl rings were well-tolerated, leading to the
corresponding ketones 3b−3c in 65−68% yields. Alkyl-
substituted alkynes such as those bearing an n-pentyl or
cyclopropyl substituent reacted with 2a smoothly to give 3d
and 3e, respectively, in good yields. A TMS-substituted alkyne
was also suited (3f). Next, the scope of the vinyl ketones was
examined. Aryl vinyl ketones bearing either electron-with-
drawing (p-CN and p-CF3) or electron-donating (p-OMe and
p-tBu) substituents on the aryl rings transformed efficiently to
the corresponding products 3g−3j. Generally, the more
electron-rich vinyl ketones afforded the products in higher
yields, possibly due to the diminished side reactions. A m-
OTBS-substituted aryl vinyl ketone was also suitable (3k).
Substrates with a sterically demanding group such as mesityl
and 2-naphthyl groups also worked well, leading to the
corresponding products 3l and 3m in 57−66% yield. Besides,
various alkyl-substituted vinyl ketones also smoothly under-
went the addition of nitriles, and the phenyl, alkenyl, 1,3-
benzodioxole, and ester groups on the alkyl side chains were
well-tolerated (3n−3q, respectively). It was noted that using
1.0 equiv of NaHCO3 instead of PhNHTs in the presence of
10 mol % Ni(cod)2 and 12 mol % L3 gave higher yields of
these products. No desired products were observed when
styrene or phenyl acetylene was employed instead of 2a. It was
also noted that products purified through column chromatog-
raphy on silica gel contained a trace amount of impurity in
some cases. These products were further purified using
recycling preparative HPLC. Alternatively, the ketone products
3 could be easily reduced to the corresponding alcohols by
NaBH4, and the alcohols were then purified with a high purity
by column chromatography (see the Supporting Information
for details).
a
Reaction conditions are as follows: 1a (0.2 mmol), 2a (0.4 mmol),
Ni(cod)2 (0.01 mmol), ligand (0.012 mmol), additive (0.008 mmol),
solvent (2 mL), 80 °C, 12 h. Determined by H NMR using 1,3,5-
b
1
c
trimethoxybenzene as an internal standard. The ee value is −4.0%.
d
The ee value is 10.9%.
Without PhNHTs, a lower yield of 56% was obtained (Table 1,
entry 2). Other N-tosyl or N-mesylamines, PhNH2, and even
H2O and EtOH were also effective for reaction, leading to 3a
in 64−74% yields (Table 1, entries 3−7, respectively). We
found that the steric and electronic properties of the ligands on
the nickel catalyst have a significant influence on the reaction
course, and less basic phosphine ligands such as PPh3 and dppf
The above results encouraged us to evaluate the reactivities
of benzyl nitriles without an alkynyl group (Scheme 3). To our
delight, a series of benzyl nitriles smoothly converted to the
corresponding products. The use of ortho-substituted benzyl
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a
Scheme 2. Scope of the Substrates
Scheme 3. Nickel-Catalyzed Michael Reactions of Common
Benzyl Nitriles
a
a
b
Isolated yields. Used 1.0 equiv of NaHCO3 instead of PhNHTs.
c
d
Twenty-four hours. After reduction with NaBH4.
a
Scheme 4. Transformation of 5b
a
b
a
Isolated yields. Used 10 mol % Ni(cod)2, 12 mol % L3, and 8 mol
Conditions are as follows: (a) 5 mol % Pd(PPh3)4, 3 mol % CuI,
c
% PhNHTs. Used 10 mol % Ni(cod)2, 12 mol % L3, and 1.0 equiv of
NaHCO3.
Et3N, 80 °C, 13 h; (b) 3 mol % PdCl2(PPh3)2, toluene/EtOH/
saturated K2CO3, 80 °C, 12 h; (c) 5 mol % NiCl2·6H2O, 6 mol %
dppf, 20 mol % Zn, 1.0 equiv of DMAP, CH3CN, 80 °C, 5 h; and (d)
NaOH (aq), EtOH, 80 °C, 6 h.
nitriles such as o-Me-, o-Br-, and o-Cl-substituted ones resulted
in good yields of the desired products (5a−5c, respectively).
Notably, a Br or Cl substituent was well-suited and could be
further elaborated through metal-catalyzed coupling reactions.
Benzyl nitrile bearing no substituent on the phenyl ring
afforded the addition product 5d in a lower yield (41%) when
using NaHCO3 instead of PhNHTs. When an alkyl vinyl
ketone was used as the Michael acceptor, a 56% yield of
product 5e was observed. Reactions with secondary benzyl
nitriles were also compatible (5f−5j). However, increasing the
steric bulkiness of the benzylic substituent resulted in a lower
product yield (5j), indicating that the reaction is sensitive to
the steric bulk of the benzyl nitrile. However, an ortho-furanyl-
substituted vinyl ketone worked efficiently in this reaction
(5l′). It was noted that in some cases the starting materials
were not consumed completely. When the reactions for 5d and
5j were carried out for 24 h, the yields could be improved to
46−51%.
onic acid or phenylacetylene afforded 6 or 3a in a high yield,
respectively. The cyanation product 7 was obtained in a 71%
yield when using Zn(CN)2 as the cyanide source in the
presence of a nickel catalyst.15 The treatment of 5b with
NaOH in EtOH gave carboxylic acid 8 in a 95% yield.
To understand the reaction mechanism, we performed the
following experiments (Scheme 5). In the presence of 5 equiv
of CD3OD, significant deuterium incorporation was found at
the benzylic position after treating 1a under the standard
conditions (Scheme 5, eq 1). The result indicates that the α-
C−H bond of benzyl nitrile could be activated under the nickel
catalysis. The Michael reaction of deuterium-labeled 1a-d
afforded the addition product with 38% deuterium incorpo-
ration at the α-position of the ketone moiety (Scheme 5, eq 2).
A kinetic isotope effect (KIE) of kH/kD = 1.3 was observed by
comparing the initial rates for the independent reactions using
either substrate 1a or 1a-d, implying that the C−H bond
cleavage is likely not involved in the rate-determining step
(Scheme 5, eq 3). Interestingly, the conjugate addition of
To illustrate the synthetical utility of this method, various
transformations of product 5b was performed (Scheme 4). The
palladium-catalyzed cross-coupling of 5b with furan-2-ylbor-
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the nickel complex 13, which eliminates the organic product
via proton transfer and regenerates the Ni(0) species.
However, we could not exclude the reaction pathway involving
Ni(II) as the catalyst,3d,13,14 which may be formed in situ. As
suggested by a reviewer, PhNHTs may also play a role as a
“proton shuttle”18 to promote the proton transfer from the
benzylic position of the nitrile to the α-position of the ketone
product.19
Scheme 5. Mechanistic Studies
In summary, we have disclosed an efficient nickel(0)-
catalyzed addition of benzyl nitriles to vinyl ketones. The
reaction provides a novel and efficient protocol for the
synthesis of α-functionalized benzyl nitriles with a wide range
of structural diversity under mild reaction conditions while
obviating the use of strong base. The work would be
potentially useful toward the development of an enantiose-
lective variant using chiral nitrogen ligands. Further inves-
tigations into the reaction mechanism and the explorations of
related transformations using benzyl nitriles are in progress.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02074.
Experimental details and spectroscopic characterization
of all products and new substrates and crystal data and
structural refinement for 3a, (PDF)
PhNHTs with a vinyl ketone occurs efficiently when using
Ni(cod)2/L3 as the catalyst, leading to 9 in a 64% yield
(Scheme 5, eq 4).16 When the nickel-catalyzed reaction of 1a
with 2a was carried out using 9 as the additive instead of
PhNHTs, the desired 3a was also formed in a good yield
(Scheme 5, eq 5). The results indicated that the addition
product 9 might also play a role in promoting the Michael
reaction of benzyl nitriles. Possibly, PhNHTs or 9 acts as a
coligand to stabilize the nickel intermediates and reduce the
number of side reactions.17
Accession Codes
CCDC 2077284 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
A proposed reaction mechanism for this nickel-catalyzed
Michael reaction of nitriles is shown in Scheme 6, which is
Corresponding Author
Yuanhong Liu − Department of Chemistry, Zhengzhou
University, Zhengzhou, Henan 450001, People’s Republic of
China; State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China; orcid.org/
0000-0003-1153-5695; Email: yhliu@sioc.ac.cn;
Fax: (+86) 021-64166128
Scheme 6. Possible Reaction Mechanism
Authors
Ninghui Zhang − Department of Chemistry, Zhengzhou
University, Zhengzhou, Henan 450001, People’s Republic of
China; State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
Chunli Zhang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, People’s Republic of China
Xiaoping Hu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, People’s Republic of China
analogous to those proposed for the Ru-catalyzed reaction.2b
Initially, the coordination of the nitrile to a low-valent LnNi(0)
complex occurs, which can increase the basicity of the metal
and the acidity of the α-proton in the nitrile. The oxidative
addition of LnNi(0) to the α-C−H bond affords the hydrido-α-
cyanobenzyl nickel complex 11, which may form an
equilibrium with the N-bound zwitterionic intermediate 12.
The Michael addition of 11 or 12 to the vinyl ketone delivers
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(5) Viteva, L.; Gospodova, T.; Stefanovsky, Y.; Simova, S.
Diastereoselectivity in addition of nitrile-stabilized carbanions to
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Xin Xie − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02074
Notes
The authors declare no competing financial interest.
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Alkaloid Squaramide-Catalyzed Asymmetric Michael Addition of α-
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ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21772217), the National Key R&D Program of China
(2016YFA0202900), the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000), and the
Science and Technology Commission of Shanghai Municipal-
ity (18XD1405000) for financial support.
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(19) See the Supporting Information for details.
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