Nickel-catalyzed three-component reductive alkylacylation of electron-deficient activated alkenes

Article abstract of DOI:10.1021/acs.orglett.0c03210

Herein, we present a nickel-catalyzed three-component reductive alkylacylation of electron-deficient activated alkenes with tertiary alkyl bromides and acid anhydrides. This method enables the efficient preparation of a variety of ketones with broad substrate scope and high functionality tolerance starting from simple precursors. On the basis of the preliminary mechanistic investigations, a catalytic cycle involving the synergistic interaction of nickel, zinc, and MgCl₂ is proposed as the major reaction pathway.

Full text of DOI:10.1021/acs.orglett.0c03210

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Letter
Nickel-Catalyzed Three-Component Reductive Alkylacylation of
Electron-Deficient Activated Alkenes
Lin Wang and Chuan Wang*
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ABSTRACT: Herein, we present a nickel-catalyzed three-
component reductive alkylacylation of electron-deficient activated
alkenes with tertiary alkyl bromides and acid anhydrides. This
method enables the efficient preparation of a variety of ketones
with broad substrate scope and high functionality tolerance starting
from simple precursors. On the basis of the preliminary mechanistic investigations, a catalytic cycle involving the synergistic
interaction of nickel, zinc, and MgCl2 is proposed as the major reaction pathway.
Scheme 1. Transition-Metal-Catalyzed Three-Component
1,2-Carboacylation of Various Types of Alkenes
ransition-metal-catalyzed 1,2-dicarbofunctionalization of
alkenes represents a powerful method for rapid increasing
T
of molecular complexity via concomitant formation of two C−C
bonds across an olefinic unit in one step and thus has
experienced a surge of developments in recent years.1−3
Among various dicarbofunctionalizations, carboacylation4−8 of
alkenes is an important subset, providing a novel approach to
prepare ketones, which are not only a ubiquitous moiety in
natural products, pharmaceuticals, and agrochemicals but also
versatile building blocks in organic synthesis. Fully intermo-
lecular three-component carboacylation allows for preparation
of structurally complex products starting from simple precursors
and thus is highly desirable. However, major advances in
carboacylation are constrained to an intramolecular one-
component version4 and a few two-component variants.5 In
most of these cases, the substrates tether a pendant alkene
moiety. To date, successful examples of transition-metal-
catalyzed three-component carboacylation are rare. In 2002,
Miura et al. reported a rhodium-catalyzed phenylacylation of
norbornene with sodium tetraphenylborate and acid anhydrides
(Scheme 1A, eq 1).6 Very recently, Stanley et al. successfully
applied imides as an acyl source in the nickel-catalyzed
arylacylation of bridged cyclic alkenes (Scheme 1A, eq 2).7
Since the pioneering work of Nevado,2w rapid progress has been
achieved in nickel-catalyzed reductive three-component difunc-
tionalization of alkenes using alkyl and aryl (pseudo)-
halides.2x−ad,8,9 According to this strategy, Chu and co-workers
developed a perfluoroalkyl acylation of monosubstituted alkenes
bearing a chelation functionality as a directing group under
reductive nickel catalysis (Scheme 1B).10 The key step of this
reaction lies in the addition of electron-deficient perfluoroalkyl
radicals to electron-rich alkyl-substituted unactivated alkenes
followed by trapping with an acyl Ni(II) complex. Therefore,
expansion of the scope of transition-metal-catalyzed three-
component carboacylation regarding the alkene precursors is
still needed. Herein, we report a nickel-catalyzed reductive
alkylacylation of electron-deficient activated alkenes with
tertiary alkyl bromides and acid anhydrides, which is
complementary to the aforementioned methods (Scheme
1C).11
For optimization of the reaction conditions, tert-butyl
bromide (1a), benzoic anhydride (2a), and tert-butyl acrylate
(3a) were utilized as the benchmark substrates. Systematic
Received: September 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03210
© XXXX American Chemical Society
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A

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screening of various parameters allowed us to define the optimal
conditions as follows: NiBr2·diglyme (20 mol %) as a precatalyst,
bis(pyridine) L1 (30 mol %) as a ligand, Zn as a reductant (3
equiv), and MgCl2 (1 equiv) as an additive in DMAc at room
teperature for 24 h.12 Under this condition, the alkylacylation
product 4aaa was obtained in 80% yield. After establishing the
optimal reaction conditions, we started to evaluate the substrate
scope of this Ni-catalyzed three-component 1,2-alkylacylation
reaction. First, a series of tertiary alkyl bromides 1a−l were
reacted with benzoic anhydride (2a) and tert-butyl acrylate (3a),
and the results are summarized in Scheme 2. To our delight, all
Scheme 3. Evaluation of the Substrate Scope by Variation of
Acids Anhydrides
a b
,
Scheme 2. Evaluation of the Substrate Scope by Variation of
a b
,
tert-Alkyl Bromides
a
a
Reactions were performed on a 0.2 mmol scale of tert-butyl acrylate
(3a) or p-methoxybenzyl acrylate (3b) using 1.5 equiv of tert-butyl
bromide (1a), 1.5 equiv of the acid anhydrides 2b−o, 20 mol % of
NiBr2·diglyme, 30 mol % of ligand L1, 3 equiv of Zn, and 1 equiv of
Reactions were performed on a 0.2 mmol scale of tert-butyl acrylate
(3a) using 1.5 equiv of the tertiary bromides 1a−l, 1.5 equiv of
benzoic anhydride (2a), 20 mol % NiBr2·diglyme, 30 mol % of ligand
L1, 3 equiv of Zn, and 1 equiv of MgCl2 in 0.5 mL of DMAc at room
b
b
MgCl2 in 0.5 mL of DMAc at room temperature for 24 h. Yields of
temperature for 24 h. Yields of the isolated products after column
c
the isolated products after column chromatography. Reaction was
chromatography.
d
performed at 15 °C. Reactions were performed with 2 equiv of 2p or
2q, 4 equiv of Zn, 2 equiv of MgCl2, and 4 Å molecular sieves.
of these reactions proceeded smoothly under the standard
conditions, furnishing the corresponding products 4aaa−laa in
good to high yields. Unfortunately, primary and secondary alkyl
bromides and iodides turned out to be unsuitable precursors for
our reaction due to a high tendency to undergo a direct cross-
coupling reaction with benzoic acid anhydride.13,14 Moreover,
the use of tertiary alkyl chlorides as substrates was also
unsuccessful because the relatively inert carbon−chlorine
bond could not be cleaved efficiently under this catalytic system.
Next, we continued to investigate the substrate spectrum of
this Ni-catalyzed reaction by varying the structure of the acid
anhydrides (Scheme 3). Both electron-donating and electron-
withdrawing groups on different positions of the phenyl ring of
benzoic anhydrides were tested. Gratifyingly, these reactions
afforded the desired coupling products 4aba−aoa in moderate
to good efficiency. In general, higher yields were achieved in the
case of electron-donating substituents. Under modified reaction
conditions, aliphatic anhydrides posed no problem, and the
corresponding products 4apb and 4aqb were obtained in good
yields. No desired product was formed in the case of cinnamic
acid anhydride as a precursor.13
Subsequently, we explored the generality of our method with
respect to the alkene component (Scheme 4). First, various
nonsubstituted alkyl, benzyl, and phenyl acrylates 3b−h turned
out to be pertinent substrates, providing products 4aab−aah in
moderate to good yields. Notably, the homoallyl acrylate 3d
selectively underwent the alkylacylation on the electron-
deficient C−C double bond. However, in the case of β-
substituted acrylates, no carboacylation reaction occurred.13
Under the amended reaction conditions (4 equiv of Zn, 2 equiv
of MgCl2, and 4 Å molecular sieves), α-substituted acrylates 3i−
n could be successfully employed as the starting materials,
B
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Letter
a b
,
Scheme 4. Evaluation of the Substrate Scope by Variation of Activated Alkenes
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of alkenes 3b−y using 1.5 equiv of tert-butyl bromide (1a), 1.5 equiv of
the anhydride 2a, 20 mol % of NiBr2·diglyme, 30 mol % of ligand L1, 3 equiv of Zn, and 1 equiv of MgCl2 in 0.5 mL of DMAc at room temperature
b
c
d
1
for 24 h. Yields of the isolated products after column chromatography. Reaction was performed on a 6 mmol scale. Determined by H NMR
e
spectroscopy. Reactions were performed with 2 equiv of 2a, 2e, 2p, or 2r, 4 equiv of Zn, 2 equiv of MgCl2, and 4 Å molecular sieves.
delivering the coupling products 4aai−aam, 4apm, and 4aen
bearing a quaternary center in moderate to good yields. This
method was also applicable to the α,β-unsaturated amide,
ketone, and sulfone (4aao−aaq). Moreover, styrenes 3r−x with
electron-withdrawing substitution proved to be competent
precursors in this Ni-catalyzed reaction, furnishing the
corresponding products 4aar, 4apr, 4arr, and 4aas−aax in
moderate to high yields. Additionally, the reaction employing 2-
vinylpyridine (3y) also formed the alkylacylation product 4aay
in a moderate yield. Notably, this reaction could be simply scaled
up to 6 mmol, giving compound 4aac in 75% yield.
We conducted a set of control experiments to shed light on
the mechanism of this Ni-catalyzed reaction (Scheme 5). First, a
radical clock reaction using the α-cyclopropyl styrene 3z as a
precursor was carried out. In this case, the ring opening product
4aaz′ was afforded in 62% yield, whereas the formation of the
direct coupling product 4aaz was not observed (Scheme 5A).
This result indicates an addition of tert-butyl radical to the
olefinic unit, leading to the generation of a benzyl radical 5,
which could induce the cyclopropane ring opening. Next, we
performed a stoichiometric reaction using Ni(COD)2, which
delivered none of compounds 4aaz, 4aaz′, or hydroalkylation
product 4aaz″ (Scheme 5B). However, we noticed that benzoic
anhydride was completely consumed, suggesting that Ni(0)
favors an irreversible oxidative addition with benzoic anhydride
over tert-butyl bromide, and the reaction ceases at this stage.
This observation is consistent with Gong’s report.14a Sub-
sequently, Zn was replaced by tetrakis(dimethylamino)ethylene
(TDAE), and no reaction occurred in this case (Scheme 5C). To
study the effect of Zn in this reaction, we conducted the reaction
in the absence of Ni. Although the carboacylation product was
not formed, it turned out that Zn was capable of promoting the
hydroalkylation reaction, producing compound 4aaz″ in 38%
yield. In the absence of MgCl2, the yield of 4aaz″ decreased to
5%, revealing that MgCl2 could assist the Zn-mediated
hydroalkylation (Scheme 5D). When the acrylates (3a, 3i, or
3k) were used as the precursors instead of the styrene derivative
3z, the reactions without nickel could still deliver the
alkylacylation products 4aaa, 4aai, and 4aak in low yields
(Scheme 5E). These results suggest that Zn is able to mediate
the addition of alkyl bromides to the alkenes in a radical
pathway, whereas nickel plays a crucial role in the step for
installation of an acyl moiety. Furthermore, Ni(0) proved to be
able to mediate the hydroalkylation process, as well, albeit in an
efficiency lower than that with Zn (Scheme 5F). In addition, no
hydroalkylation reaction occurred in the absence of Ni(COD)2.
On the basis of the preliminary results of the mechanistic
investigations, we proposed a plausible catalytic cycle for the
major reaction pathway in Scheme 6. Initially, a Ni(0) species I
was formed under the reductive conditions, which undergoes
subsequent oxidative addition with the anhydrides 2 to afford a
Ni(II) intermediate II. Meanwhile, the alkyl bromides 1 are
reduced by Zn or a low-valent Ni species,15 and the resultant
alkyl radical III performs a Giese addition16 to the electron-
C
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Scheme 5. Control Experiments for Mechanistic Studies
single electron transfer from Zn, which attacks the anhydride 2
as a nucleophile to yield the coupling product 4.
Scheme 6. Proposed Reaction Mechanism
In summary, we have developed a new approach for
expanding the scope of transition-metal-catalyzed three-
component 1,2-carboacylation of alkenes. Under the reductive
nickel catalysis, an array of electron-deficient alkenes including
α,β-unsaturated carbonyl compounds and styrenes with
electron-withdrawing substitution are successfully reacted with
various tertiary alkyl bromides and acid anhydrides to pave a new
path to synthesize a variety of ketones with high functionality
tolerance. According to the preliminary mechanistic studies, the
synergistic interaction of Zn and MgCl2 enables the efficient C−
Br bond cleavage to generate carbon-centered radicals for the
following Giese addition, whereas the nickel catalyst mediates
the elementary step for installation of the acyl moiety as the
framework of the coupling product.
ASSOCIATED CONTENT
■
deficient alkenes 3. Next, the generated carbon-centered radical
IV oxidizes the Ni(II) complex II to provide a Ni(III) species V.
The facile reductive elimination from V furnishes the
alkylacylation product 4 and a Ni(I) species VI. The latter is
reduced by Zn in the final step to regenerate the Ni(0) I for the
next catalytic cycle. In the minor noncatalytic reaction pathway,
the carbon-centered radical IV is reduced to a carbanion VII via
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03210.
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
D
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AUTHOR INFORMATION
Corresponding Author
■
Chuan Wang − Hefei National Laboratory for Physical Science at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P.R.
China; Center for Excellence in Molecular Synthesis of CAS,
Hefei, Anhui 230026, P.R. China; orcid.org/0000-0002-
9219-1785; Email: chuanw@ustc.edu.cn
Author
Lin Wang − Hefei National Laboratory for Physical Science at the
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei, Anhui 230026, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03210
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science Foundation
of China (Grant No. 21772183), Fundamental Research Funds
for the Central Universities (WK2060190086), “1000-Youth
Talents Plan” start-up funding, as well as University of Science
and Technology of China.
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