Ni-Catalyzed Intermolecular Carboacylation of Internal Alkynes via Amide C-N Bond Activation

Article abstract of DOI:10.1021/acs.orglett.0c01607

The Ni-catalyzed carboacylation of alkynes with amide electrophiles and triarylboroxines is presented. The reaction generates all-carbon tetrasubstituted alkene products in up to 62% yield. NiCl2·glyme is used as an inexpensive precatalyst in the absence

Full text of DOI:10.1021/acs.orglett.0c01607

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Letter
Ni-Catalyzed Intermolecular Carboacylation of Internal Alkynes via
Amide C−N Bond Activation
Mason T. Koeritz, Russell W. Burgett, Abhishek A. Kadam, and Levi M. Stanley*
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ABSTRACT: The Ni-catalyzed carboacylation of alkynes with amide
electrophiles and triarylboroxines is presented. The reaction generates all-
carbon tetrasubstituted alkene products in up to 62% yield. NiCl2·glyme is
used as an inexpensive precatalyst in the absence of any external reductant or
exogenous ligand. Design of Experiment (DoE) was used to achieve the best
combination of yield and stereoselectivity in this acylative carbodifunction-
alization of alkynes to generate highly substituted enones.
Scheme 1. Current Methods for Tetrasubstituted Enone
Synthesis
etrasubstituted alkenes containing four carbon substitu-
ents form a synthetically challenging yet versatile class of
T
molecules prevalent in several pharmaceuticals and biologically
active compounds.1 With the advent of transition-metal-
catalyzed cross-coupling reactions, alkynes have emerged as
coupling partners for a variety of carbodifunctionalization
reactions to generate tetrasubstituted alkenes.2 Among these
alkyne carbodifunctionalization reactions, acylative approaches
to generate fully substituted enones are underdeveloped.
Nomura and co-workers reported rhodium-catalyzed coupling
of acid chlorides and alkynes in the presence of a disilane
reductant to generate fully substituted enones (Scheme 1a).3
Recently, Wu and co-workers developed palladium-catalyzed
carbonylative arylacylations of alkynes with aryl iodides and
arylboronic acids in the presence of carbon monoxide as the
carbonyl source (Scheme 1b).4 While each of these approaches
provides access to highly substituted enones from simple
starting materials with high diastereoselectivity, they involve
precious metal catalysts and require either a stoichiometric
reductant and high reaction temperatures to drive decarbon-
ylation or carbon monoxide gas and stoichiometric copper(II)
trifluoroacetate.
We sought to identify an earth-abundant catalyst for
coupling of alkynes with a carboxylic acid derivative and an
arylboron nucleophile to generate fully substituted enones.
Our group has developed a series of nickel-catalyzed acylative
alkene difunctionalization reactions triggered by activation of a
carboxylic acid derivative.5 However, related acylative
difunctionalizations of alkynes utilizing carboxylic acid
derivatives as acyl electrophiles are underdeveloped. Herein,
we disclose the Ni-catalyzed intermolecular carboacylation of
internal alkynes with amides and triarylboroxines (Scheme 1c).
Building on our prior studies in nickel-catalyzed alkene
carboacylation, we chose to study the reaction of N-benzoyl-N-
phenylbenzamide 1a, 4-octyne 2a, and a variety of boron
nucleophiles with Ni(cod)2 as the precatalyst. The reaction
with sodium tetraphenylborate 3a produced the carboacylation
Received: May 11, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01607
© XXXX American Chemical Society
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A

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Letter
a
Table 1. Identification of Reaction Conditions
b
b
entry
precatalyst (mol %)
ligand (mol %)
nucleophile (equiv) additive (mol %) temp (°C)
solvent
benzene
benzene
benzene
benzene
benzene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
yield (%) dr (Z/E)
1
2
3
4
5
6
7
8
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
Ni(cod)2 (10)
NiCl2·glyme (10)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
NiCl2·glyme (20)
none
none
NaBPh4 (2)
H3BO3 (200)
95
95
95
95
95
95
95
95
95
95
95
95
80
80
80
80
80
80
75
75
23
50
62
<5
31
41
36
32
35
46
66
90
78
65
22
27
66
69
62
23
1.3:1
0.8:1
0.7:1
BPh3 (2)
BPh3 (2)
PhBpin (2)
BrettPhos (10)
BrettPhos (10)
BrettPhos (10)
BrettPhos (10)
BrettPhos (5)
none
none
none
none
none
none
none
none
none
none
none
none
none
c
nd
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (5)
PhB(OH)2 (5)
PhB(OH)2 (5)
PhB(OH)2 (3)
PhB(OH)2 (1.5)
PhB(OH)2 (1)
(PhBO)3 (1)
(PhBO)3 (1)
(PhBO)3 (1)
(PhBO)3 (1)
2.1:1
1.9:1
1.8:1
1.7:1
1.7:1
1.5:1
0.7:1
0.7:1
1.6:1
2.5:1
4.5:1
8.7:1
4.9:1
4.2:1
5.3:1
6.0:1
9
10
11
12
13
14
15
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (20)
Al(OtBu)3 (10)
Al(OtBu)3 (10)
d
16
d
17
dioxane
d
18
de
1:1 dioxane/toluene
1:1 dioxane/toluene
1:1 dioxane/toluene
,
19
20
df
,
a
Reaction conditions: 1a (0.100 mmol), 2a (0.500 mmol), boron nucleophile 3 (0.200 mmol), K2CO3 (0.200 mmol), Ni precatalyst (0.010
b
c
d
mmol), solvent (1 mL, 0.1 M), 18 h. Determined by GC with tridecane as an internal standard. dr: not determined. Reaction run at 0.500 M
e
concentration. Optimized conditions: 1a (0.100 mmol), 2a (0.500 mmol), triphenylboroxine 3e (0.100 mmol), NiCl2·glyme (0.020 mmol),
f
K2CO3 (0.225 mmol), Al(OtBu)3 (0.010 mmol), 1:1 dioxane/toluene (0.200 mL, 0.500 M), 75 °C, 18 h. Reaction run at 1.00 mmol scale.
products 4a and 4a′ in 23% yield as a 1.3:1 ratio of Z and E
stereoisomers (Table 1, entry 1). We have previously
established that the addition of boric acid to sodium
tetraphenylborate generates triphenylborane in situ and that
triphenylborane can be an active nucleophile in alkene
carboacylation reactions.5a Adding triphenylborane 3b as the
nucleophile increased the yield to 50% with a 0.8:1 dr (Table
1, entry 2). After evaluating a variety of exogenous ligands, we
found that a nickel complex of BrettPhos catalyzes the alkyne
carboacylation in the presence of triphenylborane 3b as the
nucleophile and forms the enone products in 62% yield as a
0.7:1 diastereomeric mixture (Table 1, entry 3). The limited
commercial availability of sodium tetraarylborates and
triarylboranes led us to study the development of alkyne
carboacylation reactions with arylboronic acid nucleophiles
and their boronate ester derivatives. The reaction of imide 1a,
4-octyne 2a, and PhBpin does not form enone 4a in
measurable yield with a nickel complex of BrettPhos as the
catalyst (entry 4). However, the analogous reaction with
phenylboronic acid as the arylboron nucleophile leads to the
formation of enone 4a in 31% yield with 2.1:1 diastereose-
lectivity (entry 5). During our initial attempts to improve the
yield of the model reaction with phenylboronic acid, we found
that using 1,4-dioxane as the solvent led to slightly higher
yields of the enone products (entry 6). Due to the large
number of potentially significant variables in this reaction, we
turned to Design of Experiment to more efficiently explore the
chemical space relevant to this reaction.6 An initial screen of
variables showed us that ligand loading did not have a
significant effect on the yield of the reaction (Table 1, entries
6−8, and Table S3). The model reaction generated enone 4a
in 32% yield in the absence of the BrettPhos ligand (entry 8).
The reaction conducted in the presence of a cheap, readily
accessible nickel(II) precatalyst, NiCl2·glyme, formed the
enone product in similar yield when compared to the reaction
run with Ni(cod)2 as the precatalyst (entry 9). The addition of
an exogenous ligand to the reaction of 4-octyne with imide 1a
and phenylboronic acid proved detrimental with NiCl2·glyme
as the precatalyst (Table S4). Increasing the catalyst loading to
20 mol % led to the formation of the carboacylation product in
46% yield with 1.5:1 dr (Table 1, entry 10, and Table S5). The
yield of the model reaction could be further improved to 66%
by increasing the loading of phenylboronic acid to 5 equiv
(entry 11). In our attempts to further increase the yield of the
enone product, we observed a plateau in the yield between 60
and 65% with our initial set of reaction variables. In many
cases, conversion of imide 1a was incomplete, which led us to
hypothesize that inhibition of the nickel catalyst by the enone
product may be limiting the efficiency of the alkyne
carboacylation reaction. Addition of 30 mol % of enone 4a
to the reaction led to a decrease in the yield to 13% (Table
S6). To minimize coordination of the enone product to the
nickel catalyst, we studied our model reaction in the presence
of Lewis acid additives (Table S7). The alkyne carboacylation
reaction formed enone 4a in 90% yield with a 0.7:1 dr when 20
mol % of aluminum tert-butoxide was added to the reaction
mixture (Table 1, entry 12, and Table S8). While the yield of
the alkyne carboacylation is excellent, the dr is not synthetically
useful.
B
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a
Scheme 2. Substrate Scope
a
Reaction conditions: 1 (0.100 mmol), 2a (0.500 mmol), 3 (0.100 mmol), NiCl2·glyme (0.020 mmol), K2CO3 (0.225 mmol), Al(OtBu)3 (0.010
b
c
1
mmol), 1:1 dioxane/toluene (0.200 mL, 0.500 M), 75 °C, 18 h. Z/E ratios determined by H NMR. Reaction run with 5 equiv of 2-
MePhB(OH)2.
At this point, we attempted to identify reaction conditions
that led to the best balance between yield and diastereose-
lectivity. We observed that decreasing the temperature of the
reaction to 80 °C and reducing the number of equivalents of
phenylboronic acid led to a decrease in yield of the
carboacylation product but an increase in the diastereoselec-
tivity (entries 13−15). These results suggest that phenyl-
boronic acid may play a key role in isomerization of the
initially formed Z-diastereomer to the E-diastereomer,
presumably through the formation of a nickel hydride by
oxidative addition into the O−H bond of phenylboronic acid.7
Increasing the concentration of the reaction to 0.5 M led to a
slight increase in the yield of enone 4a and significantly
improved the diastereoselectivity (entry 16). If the formation
of a nickel hydride intermediate plays a key role in the
isomerization of the enone product, removal of the O−H
bonds by changing the nucleophile to triphenylboroxine may
minimize the formation of nickel hydride intermediates.
Indeed, the reaction of 4-octyne 2a with imide 1a and
triphenylboroxine generated enone 4a in 66% yield with an
increased diastereoselectivity of 4.9:1 (entry 17). Finally, we
performed two additional Design of Experiments to identify a
mixed solvent system (Table 1, entry 18, and Table S9) and to
arrive at our optimized reaction conditions (Table S10).
Reactions run under our optimized conditions produce the
enone product 4a in 62% yield with a 5.3:1 dr (entry 19).
Lowering the loading of 4-octyne 2a led to a decrease in the
yield of enone product 4a.
imide substrates led to lower yields of enone products 4d−4f
and 4h−4i (20−32%). Notably, halogenated imides reacted to
generate enones 4e, 4h, and 4i with >20:1 diastereoselectivity.
The reaction of N-phenyl-4-(trifluoromethyl)-N-(4-
(trifluoromethyl)benzoyl)benzamide did not produce the
enone product in >5% yield, nor did the reaction of an
asymmetric imide, N-benzoyl-N-phenyl-4-(trifluoromethyl)-
benzamide.
We then studied the scope of the alkyne carboacylation
reaction with respect to triarylboroxine nucleophiles. Reactions
of triarylboroxines containing electron-donating groups pro-
duced the enone products 4j,4k and 4m,4n in 20−57% yield
with 3.2−5.0:1 dr. Triarylboroxines with electron-withdrawing
substitutents were generally unreactive, but the reaction of
tris(4-chlorophenyl)boroxine produced enone 4l in 23% yield
and >20:1 dr. The reaction of tris(2-methylphenyl)boroxine
formed enone 4o in 17% yield with 9.5:1 dr. The low yield and
relatively slow rate of isomerization of enone 4o led us to run
the alkyne carboacylation reaction with 5 equiv of 2-
methylphenylboronic acid. This reaction generated enone 4o
in 43% yield and >20:1 dr. The reactions of imides containing
electron-withdrawing groups led to generally lower yields of
the enone products; however, the yield of the alkyne
carboacylation reactions could be improved by reacting N-
benzoyl-N-phenylbenzamides containing deactivating substitu-
ents with triarylboroxines containing activating substituents.
Reactions of these combinations of imide electrophiles and
arylboron nucleophiles formed enones 4p−4w in 28−57%
yield and 2.4−7.5:1 dr.
Having identified reaction conditions that generate the
enone product of alkyne carboacylation with a balance of
product yield and diastereomeric ratio, we next evaluated the
scope of our alkyne carboacylation reaction with various N-
benzoyl-N-phenybenzamides (Scheme 2). The reaction of
imides containing electron-donating groups substituted at the
para- or meta-position led to the formation of enone products
4b−4c and 4g in 41−43% yield and 2.6−7.0:1 dr. Deactivating
groups, such as halogens, at the para- or meta-position of the
To evaluate the scope of the reaction with respect to the
alkyne coupling partner, we studied reactions of 3-hexyne, 1-
phenyl-1-propyne, and diphenylacetylene. The carboacylation
of 3-hexyne formed enone 4x in 35% yield and 4.6:1 dr. The
reaction of 1-phenyl-1-propyne with imide 1a and triphenyl-
boroxine generated enone 4y in 27% yield as a single
regioisomeric product. In addition, the reaction of 1-phenyl-
1-propyne with imide 1a and tris(4-methylphenyl)boroxine
C
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occurred with complete regioselectivity but generated the
enone product in 30% yield as a 1:1 mixture of inseparable
diastereomers. Carboacylations of 1,2-diarylacetylenes did not
occur to form enone products in >5% yield.
Scheme 4. Proposed Mechanisms for Isomerization to E-
Isomer
Based on our previous studies of nickel-catalyzed alkene
carboacylation reactions, we propose the following catalytic
cycle for nickel-catalyzed alkyne carboacylation (Scheme 3).
Scheme 3. Proposed Mechanism
Oxidative addition of the Ni(0) catalyst A into the C−N bond
of the imide electrophile 1a generates an acyl-Ni(II)-amido
intermediate B. Migratory insertion of the alkyne 2a into the
Ni(II)-acyl bond affords a vinyl-Ni(II)-amido complex C.
Transmetalation with triphenylboroxine 3a forms vinyl-Ni(II)-
aryl intermediate D. Subsequent reductive elimination yields
the desired carboacylation product 4a and regenerates the
Ni(0) catalyst. We propose that migratory insertion precedes
transmetalation based on the observation of little to no
benzophenone in our reactions.
could potentially be formed in the reaction via oxidative
addition of the nickel catalyst into the O−H bond of
phenylboronic acid. When a sample of the Z-isomer of
enone 4a (>20:1 dr) was exposed to NiCl2·glyme, potassium
carbonate, and 5 equiv of phenylboronic acid for 4 h, a 2.5:1
mixture of Z- and E-isomers was observed. Replacing
phenylboronic acid with triphenylsilane and Ni(cod)2 as a
source of nickel hydride led to the formation of diastereomeric
enone products with 2.7:1 dr within 2 h. These results suggest
that isomerization via nickel hydride species can also occur. If
enone 4a undergoes migratory insertion into a nickel hydride,
the newly formed single bond can freely rotate to place the
nickel anti to the β-hydrogen as in intermediate E. However,
the nickel cannot undergo β-hydride elimination from this
intermediate; therefore, epimerization at the α-center would be
required for β-hydride elimination to occur. We considered
two possible epimerization pathways involving either a nickel
enolate (Scheme 4b, intermediate F) or β-hydride elimination
from the alkyl chain and subsequent reinsertion (Scheme 4b,
intermediate G). If trisubstituted alkene G is formed via β-
hydride elimination from the propyl group, deuterium
incorporation into the propyl group should be observed in
the presence of a nickel deuteride. However, attempts to
generate a nickel deuteride using deuterated phenylboronic
acid, deuterated methanol, or deuterated phenylsilane did not
result in deuterium incorporation into the enone product. This
observation suggests that epimerization does not occur
through a β-hydride elimination and is more likely to occur
through nickel enolate F. Upon epimerization of the nickel
This mechanism accounts for the initial formation of the Z-
isomer of 4a due to syn-addition of the alkyne into the Ni−
C(acyl) bond of intermediate B. In order to understand the
formation of the E-isomer, we considered several potential
mechanistic pathways. Isomerization of vinyl transition-metal
intermediates is known to occur through a pathway involving
zwitterionic intermediates, stabilized by electron-donating
ligands (Scheme 4a).8 In our substrate scope of the alkyne
carboacylation reaction, we observed that reactions of
arylboroxines containing electron-donating groups led to
lower diastereomeric ratios when compared with reactions of
arylboroxines containing electron-withdrawing groups. These
results are consistent with isomerization through the pathway
shown in Scheme 4a, as an electron-rich aryl ligand could
stabilize the zwitterionic nickel intermediate and facilitate
isomerization to the E-isomer. While this isomerization
pathway in Scheme 4a may be operative, it does not account
for the observation that the diastereoselectivity of the alkyne
carboacylation decreases when the loading of phenylboronic
acid increases (Table 1, entries 13−15).
We theorized that a second isomerization pathway may be
operative and involve migratory insertion of the enone product
into a nickel hydride species (Scheme 4b).9 The nickel hydride
D
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with Tri- and Tetrasubstituted Double Bonds. ACS Sustainable Chem.
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D. G. Novel Isomerically Pure Tetrasubstituted Allylboronates:
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(2) For examples of transition-metal-catalyzed alkyne carbodifun-
cionalizations, see: (a) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi,
R.; Baba, Y.; Hosomi, A. Iron-Catalyzed Regio- and Stereoselective
Carbolithiation of Alkynes. Angew. Chem., Int. Ed. 2001, 40, 621−623.
(b) Shimkin, K. W.; Montgomery, J. Synthesis of Tetrasubstituted
Alkenes by Tandem Metallacycle Formation/Cross-Electrophile
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Component Domino Reactions of Aryl Grignard Reagents, Alkynes,
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Soc. 2015, 137, 3189−3192. (d) Yu, H.; Richey, R. N.; Carson, M.
W.; Coghlan, M. J. Cyclocarbopalladation of Alkynes: A Stereo-
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catalyzed reaction of aroyl chlorides with alkynes or alkenes in the
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Catalyzed Tunable Carbonylative Synthesis of Enones and
Benzofulvenes. Chem. - Eur. J. 2019, 25, 8696−8700.
(5) (a) Kadam, A. A.; Metz, T. L.; Qian, Y.; Stanley, L. M. Ni-
Catalyzed Three-Component Alkene Carboacylation Initiated by
Amide C−N Bond Activation. ACS Catal. 2019, 9, 5651−5656.
(b) Walker, J. A.; Vickerman, K. L.; Humke, J. N.; Stanley, L. M. Ni-
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enolate to intermediate H, syn β-hydride elimination may
occur to form the E-isomer of 4a.
In summary, we have developed a Ni-catalyzed intermo-
lecular carboacylation of alkynes utilizing amides as acyl
electrophiles and readily accessible triarylboroxines as
nucleophiles. This reaction enables the generation of all-
carbon tetrasubstituted enone products in up to 62% yield.
Design of Experiment studies were utilized to identify reaction
conditions that lead to a balance between yield and
diastereoselectivity. Efforts to develop additional alkene and
alkyne carbodifunctionalization reactions are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01607.
Experimental procedures, Design of Experiment data,
and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Levi M. Stanley − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States; orcid.org/
0000-0001-8804-1146; Email: lstanley@iastate.edu
Authors
Mason T. Koeritz − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States
Russell W. Burgett − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States
Abhishek A. Kadam − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01607
Notes
The authors declare no competing financial interest.
(6) For a review of Design of Experiment in organic synthesis, see:
(a) Weissman, S. A.; Anderson, N. G. Design of Experiments (DoE)
and Process Optimization. Org. Process Res. Dev. 2015, 19, 1605−
1633. For selected examples, see: (b) Bowden, G. D.; Pichler, B. J.;
Maurer, A. A Design of Experiments (DoE) Approach Accelerates the
Optimization of Copper-Mediated 18F-Fluorination Reactions of
Arylstannanes. Sci. Rep. 2019, 9, 11370. (c) Murray, P. M.; Bellany, F.;
ACKNOWLEDGMENTS
We thank Iowa State University and the Iowa State University
Center for Catalysis for supporting this work.
■
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