Ni-Catalyzed 1,2-Diarylation of Alkenyl Ketones: A Comparative Study of Carbonyl-Directed Reaction Systems

Article abstract of DOI:10.1021/acs.orglett.1c01447

A nickel-catalyzed 1,2-diarylation of alkenyl ketones with aryl iodides and arylboronic esters is reported. Ketones with a variety of substituents serve as effective directing groups, offering high levels of regiocontrol. A representative product is diversified into a wide range of useful products that are not readily accessible via existing 1,2-diarylation reactions. Preliminary mechanistic studies shed light on the binding mode of the substrate, and Hammett analysis reveals the effect of electronic factors on initial rates.

Full text of DOI:10.1021/acs.orglett.1c01447

pubs.acs.org/OrgLett
Letter
Ni-Catalyzed 1,2-Diarylation of Alkenyl Ketones: A Comparative
Study of Carbonyl-Directed Reaction Systems
Roman Kleinmans,§ Omar Apolinar,§ Joseph Derosa, Malkanthi K. Karunananda, Zi-Qi Li, Van T. Tran,
Steven R. Wisniewski, and Keary M. Engle*
Cite This: Org. Lett. 2021, 23, 5311−5316
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A nickel-catalyzed 1,2-diarylation of alkenyl ketones
with aryl iodides and arylboronic esters is reported. Ketones with a
variety of substituents serve as effective directing groups, offering
high levels of regiocontrol. A representative product is diversified into
a wide range of useful products that are not readily accessible via
existing 1,2-diarylation reactions. Preliminary mechanistic studies
shed light on the binding mode of the substrate, and Hammett
analysis reveals the effect of electronic factors on initial rates.
regioselective 1,2-diarylation methodology to substrates con-
he catalytic addition of two distinct carbogenic fragments
Tacross an alkene using a transition metal via conjunctive taining native ketone functional groups, presumably binding the
metal through an O(sp2) atom.6
cross-coupling has recently emerged as a powerful strategy to
synthesize complex molecules.1 In general, reactions of this type
At the same time, we were aware of two potential challenges:
(1) the decreased Lewis basicity of the carbonyl lone pair
compared to amides and carboxylates, which can impact
productive binding to the nickel catalyst in the key migratory
insertion step, and (2) the increased acidity of the α-C−H
bonds, which can lead to undesired isomerization of the alkene
substrate. In a series of important previous studies, Giri has
established that preformed ketimines can effectively engage in
conjunctive cross-coupling2d,5a,b and that the resulting products
can be hydrolyzed to the corresponding ketones. This chemistry
is limited to substrates containing unsaturation at the γ,δ-
position, presumably due to the highly acidic α-protons that
contribute to isomerization in the presence of organozinc
nucleophiles, underscoring the difficulty of this type of
transformation. Herein, we describe a selective 1,2-diarylation
of alkenyl ketone substrates enabled by carefully tuned reaction
conditions that minimize alkene isomerization (Scheme 1B).
To initiate our investigation, we elected to use aryl ketone 1 as
our standard substrate, with 4-iodotoluene (p-Tol−I) and
phenylboronic acid neopentyl glycol ester (PhB(nep)) (nep =
neopentyl glycolato) as coupling partners, and Ni(cod)2 as the
precatalyst with dimethyl fumarate (DMFU) as ligand (Table
1).8 After extensive optimization and fine-tuning of reaction
conditions to minimize isomerization, we were able to identify
involving an initial 1,2-migratory insertion step have historically
required conjugated alkene substrates for reactivity and
selectivity control.2 In an effort to bridge this synthetic gap,
our group and others have employed directing groups3 to
facilitate 1,2-dicarbofunctionalization of nonconjugated alkenes
under nickel catalysis.4−6 This concept was initially executed
using N(sp2)-containing directing auxiliaries that require at least
two concession steps for installation and removal, detracting
from the practicality of the approach (Scheme 1A).2d,4a−d,5b Our
laboratory went on to demonstrate the use of simple alkenyl
amides and carboxylates in nickel-catalyzed 1,2-diarylation
reactions (Scheme 1B).4e,g Given the complementary utility of
ketone functional groups in synthesis,7 we sought to extend this
Scheme 1. Background and Synopsis of Current Work
Received: May 1, 2021
Published: July 2, 2021
https://doi.org/10.1021/acs.orglett.1c01447
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5311−5316
5311

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Optimization of Reaction Conditions
% yield
b
entry
deviation from standard conditions
none
% yield
1a:1a′
10:1
−
1a″
1
2
83 (77)
8
9
−
conditions from alkenyl amide
c
diarylation (ref 4e)
3
4
5
6
7
no Ni(cod)2
no DMFU
SIPr instead of DMFU
1.5 equiv of NaOMe (solid)
n.d.
79
59
63
40
−
47
−
2
−
27
8:1
5:1
8:1
10:1
1.5 equiv of PhB(nep) and p-Tol−I
instead of 3.0 equiv
8
9
PhB(OH)2 instead of PhB(nep)
PhB(pin) instead of PhB(nep)
p-Tol−Br instead of p-Tol−I
5 mol % Ni(cod)2 instead of 15 mol % 43
NiBr2·glyme instead of Ni(cod)2 32
NiCl2 or Ni(acac)2 instead of Ni(cod)2 n.d.
Ni(cod)(DMFU) instead of Ni(cod)2 75
Ni(cod)(DQ) instead of Ni(cod)2
29
17
8
−
−
−
9:1
6:1
−
10:1
−
−
31
25
29
35
−
10
11
12
13
14
15
Figure 1. Comparison of 1,2-diarylation conditions. aPercentages
1
b
represent H NMR yields using CH2Br2 as internal standard. Yield
taken from ref 4e. cYield taken from ref 4g.
11
42
solvent, and temperature are key variables in being able to
successfully extend this methodology to different substrate
classes. For example, the amide substrate requires DMFU as a
ligand to bolster the product yield, whereas DMFU has only a
minor effect with ketone substrates;11 added ligand had no
benefit in the carboxylate system. Also, less Lewis basic ketones
benefited from the use of a NaOMe stock solution, compared to
solid NaOMe. Both the amide and ketone substrates work well
with i-BuOH, whereas s-BuOH is essential with the carboxylate
substrate. Interestingly, carboxylate substrates are incompatible
with the optimal temperature (rt) for other classes, presumably
owing to the elevated temperatures required to prevent
inhibitory carboxylate binding to the nickel catalyst. Collec-
tively, these results illustrate the subtleties of reaction
optimization across these systems, while providing end users
with an idea of what variables to prioritize.
Having identified optimal reaction conditions, we moved on
to examine the electrophile scope using PhB(nep) as the
nucleophilic coupling partner (Scheme 2).12 Aryl iodides,
bearing electron-donating substituents in the para- and meta-
positions, reacted to deliver the desired products in good to
excellent yields with moderate to excellent regioselectivity (1a,
1c−1e, 1i,j,m,o). Aryl iodides with substitution in the ortho-
position offered good to excellent yields and gave the desired
products with excellent regioselectivity (1k,p). Electron-with-
drawing substituents resulted in diminished reactivity, but still
delivered the desired products in moderate yields (1f,g,l) with
excellent regioselectivity. Notably, aryl iodides containing
−NHAc and −Ac groups were compatible in this reaction,
allowing for potential downstream modification (1h,n). It is
worth mentioning that, for sterically similar electrophiles, r.r.
tends to be lowest for electron-rich aryl iodides and highest for
electron-poor aryl iodides. Heteroaryl iodides, 4-iodobenzalde-
hyde, and 4-iodophenol coupling partners were incompatible
under the optimized reaction conditions (see Supporting
Information (SI)).
n.d.
a
Reaction were performed on a 0.1 mmol scale. Percentages represent
1H NMR yields using CH2Br2 as internal standard; n.d. = not
detected. Percentages in parentheses represent isolated yields.
b
c
Combined yield of 1a and 1a′. Reaction conditions: 15 mol %
Ni(cod)2, 15 mol % DMFU, 1.5 equiv of ArI, 1.5 equiv of ArB(nep), 2
equiv of NaOH, 0.1 M i-BuOH, at rt.
conditions that delivered an 83% combined yield of the two
possible regioisomers in 10:1 r.r., with the major product
corresponding to electrophile incorporation distal to the
directing group (entry 1). We found the addition of NaOMe
as a stock solution to be vital for high yields, presumably owing
to the slow dissolution rate of the solid base (entry 6).9 Under
our previously published reaction conditions for simple alkenyl
amide substrates, the 1,2-diarylated product(s) could be
detected in only 8% yield (entry 2). Interestingly, the reaction
proceeded in good yield without an ancillary ligand or with 1,3-
bis(2,6-di-isopropylphenyl)imidazolidine-2-ylidene (SIPr) in-
stead of DMFU, with SIPr leading to lower regioselectivity
(entries 4 and 5). Phenylboronic acid and the corresponding
pinacol ester were low-yielding (entries 8 and 9). Encouragingly,
NiBr2·glyme was a competent Ni(II) source, giving the desired
products in 32% combined yield (entry 12). NiCl2, Ni(acac)2,
and Ni(cod)(DQ) (DQ = duroquinone) were found to be
ineffective (entries 13 and 15). Preligation of the DMFU did not
offer any advantage, with the products furnished in 75% yield
when Ni(cod)(DMFU) was used as the precatalyst (entry 14).
At this stage, we sought to compare the optimized conditions
in each of our carbonyl-directed 1,2-diarylation reactions to gain
a better understanding of the subtle effects of changes to
reaction conditions across different substrate classes (Figure 1).
In all cases, the Ni(cod)2 precatalyst and alcohol solvents were
necessary for obtaining high yields. In addition, the superior
reactivity of ArB(nep) coupling partners is a shared feature,
reflecting its privileged nature in nickel catalysis.10 Cross-
screening of the optimized reaction conditions for various 1,2-
diarylation reactions against amide, carboxylate, and ketone
substrates revealed that the choice of ligand, base, alcohol
Next, we investigated the nucleophile scope of the reaction,
using iodobenzene as the electrophilic component. In general, a
wide range of electron-rich and electron-poor ArB(nep)
5312
https://doi.org/10.1021/acs.orglett.1c01447
Org. Lett. 2021, 23, 5311−5316

Organic Letters
pubs.acs.org/OrgLett
Letter
a
a
Scheme 2. Electrophile and Nucleophile Scope
Scheme 3. Ketone and Alkene Scope
a
Reactions performed on a 0.1 mmol scale. Percentages represent
b
1
isolated yields. Percentages represent H NMR yields using CH2Br2
as internal standard.
a
a
Scheme 4. Product Diversification
Reactions performed on a 0.1 mmol scale. Percentages represent
b
isolated yields. Reactions were performed in i-BuOH (0.50 M).
coupling partners performed well under optimized conditions,
giving the desired products in good to excellent yields (1q−1z)
with moderate to excellent regioselectivity. ArB(nep) coupling
partners containing tethered alcohols (1u), −Cl (1s), and −Ac
(1y) groups were tolerated in moderate to good yields.
We next explored the scope and limitations of this method by
testing other representative alkenyl ketones (Scheme 3). Given
the simplicity and modularity of synthesizing allyl ketones
through a Barbier allylation/oxidation sequence (see SI), we
envisioned that this method could serve as a powerful tool for
rapid assembly of β,γ-diarylated ketones. Indeed, across several
different substrates, moderate to excellent yields (3a−3p) and
moderate to good regioselectivity were obtained. Aryl ketones
with electron-donating substituents were found to be effective
directing groups, while electron-withdrawing substituents led to
lower yields (3a−3j).13 Heterocycle-containing ketones could
be utilized (3k,l), and a conjugated ketone was also tolerated
(3m). Finally, alkyl-substituted ketones were suitable substrates,
delivering the desired products in moderate to good yields (3n−
3p). We then assessed the scope with respect to the alkenyl
fragment of the substrate. Encouragingly, γ,δ-unsaturated and α-
methyl ketones were viable substrates in 1,2-diarylation
(5a,b).14
To showcase the versatility of this method, we subjected
representative ketone product 1e to a series of diversification
reactions (Scheme 4). Classical functional group interconver-
sions were performed to deliver a range of synthetically useful
products (6a−6e). A Baeyer−Villiger oxidation reaction
provided the corresponding aryl ester in good yield (6a).
Alternatively, the ketone could be converted into an amide in a
high-yielding Beckmann rearrangement (6b) or to a CC bond
through a Wittig olefination (6c). The ketone directing group
would be removed altogether with LiAlH4 and AlCl3 to afford 6d
a
(a) mCPBA, TFA, anhydrous DCM, rt. (b) H2NOH·HCl, TFA, 70
°C. (c) Ph3PCH2Br, n-BuLi, THF, 70 °C. (d) LiAlH4, AlCl3, Et2O/
DCM, rt. (e) NaBH4, THF, reflux.
in good yield, while reduction of the ketone to the
corresponding secondary alcohol was performed with NaBH4
and took place in moderate yield, albeit with no diastereose-
lectivity (6e).
To gain insight into mechanistic aspects of this ketone-
directed alkene 1,2-diarylation, we considered the binding mode
of the directing group to the nickel catalyst. Under basic
conditions, the substrate could in principle coordinate to the
catalyst through the O atom in either its ketone or enolate form
(Scheme 5A).5c To probe this point, we first ran control
experiments. Given that we observed isomerization of the
starting materials to form the corresponding conjugated enones
(such as 1a″; see Table 1) under the reaction conditions, we
questioned whether these byproducts were competent inter-
mediates. In an enolate mechanism, conjugated enones could
plausibly still participate in β,γ-diarylation through base-
mediated dienolate formation. In contrast, in the ketone
mechanism, the conjugated enones would be dead ends.
When we subjected independently prepared 1a″ to the reaction
conditions, only unreacted starting material was observed
(Scheme 5B). We next tested alkenyl ketone substrate 4c,
5313
https://doi.org/10.1021/acs.orglett.1c01447
Org. Lett. 2021, 23, 5311−5316

Organic Letters
pubs.acs.org/OrgLett
Letter
were turnover-limiting. Hence, the data are consistent with
migratory insertion as the turnover-limiting step. In terms of the
aryl ketone electronic properties, we observed a moderately
faster rate for electron-deficient aryl ketones, despite the fact that
these substrates are ultimately low-yielding (ρ = 0.19). One
potential explanation for this dichotomy is that electron-poor
ketones succumb to off-cycle processes (e.g., isomerization)
more easily, despite being inherently faster for the desired
catalytic reaction. On the productive cycle, the increased
reaction rate with more electron-deficient carbonyl groups
could reflect increased electronic activation of the alkene via
inductive effects, as shown in the 13C resonances of the alkenyl
carbon atoms across this series (see SI). An alternative
explanation that cannot be ruled out at this time is that the
carbonyl group partially dissociates during migratory insertion
(and possibly recoordinates subsequently to prevent β-H
elimination).
Scheme 5. Mechanistic Experiments
In conclusion, we have demonstrated that a simple ketone can
be used to direct nickel-catalyzed 1,2-diarylation of alkenes.17
The products can be further manipulated using classical
methods to yield a range of valuable building blocks.
Mechanistic studies support an L-type carbonyl binding mode,
while Hammett studies point to migratory insertion as the
turnover-limiting step. We anticipate that the addition of
ketones to the growing toolkit of native-directed 1,2-
difunctionalization reactions will expand the utility of this
suite of transformations.
which lacks enolizable protons; under standard conditions we
isolated desired product 5c in 31% yield (Scheme 5C). We
attribute the low yield in this case to steric hindrance introduced
by the gem-dimethyl group (for comparison see 5a, Scheme 3).
Based on previous studies4e and Hammett data (see below),
migratory insertion was identified as a likely candidate for the
turnover-limiting step (for a depiction of the proposed catalytic
cycle, see Scheme S11). Hence, to gain additional insight into
the favored coordination mode, we compared plausible
migratory insertion transition states using density functional
theory (DFT; see Scheme 5D). This analysis revealed that the
neutral ketone form (TS1, ΔG‡ = 14.9 kcal/mol) is lower in
energy, in comparison to both the neutral enolate (TS2, ΔG‡ =
18.1 kcal/mol) and anionic enolate forms (TS3, ΔG‡ = 16.9
kcal/mol).15,16 Collectively, the experimental and computa-
tional data are consistent with the carbonyl mechanism as the
preferred pathway.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01447.
Detailed experimental procedures, compound character-
ization data, and copies of NMR spectra for new
compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1, 1a−1z, 2a−2p, 3a−3p, 5a−5c, 6a−6e,
S12−S13 (ZIP)
Accession Codes
Finally, we investigated the effects of varying the electronic
properties of the aryl iodide, arylboronate, and aryl ketone
components on the reaction rate (see Scheme 6 and SI).
CCDC 1957926 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Initial Rate Trends
AUTHOR INFORMATION
Corresponding Author
■
Keary M. Engle − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-2767-6556; Email: keary@
scripps.edu
Authors
Mirroring our previous findings using alkenyl amide sub-
strates,4e we observed a negligible influence of ArB(nep)
electronic properties on the initial rate, whereas electron-neutral
and -rich aryl iodides reacted faster than electron-poor
electrophiles (ρ = −1.3). This trend points to a step involving
the electrophile-derived aryl group as turnover-limiting, but is
the opposite trend that would be expected if oxidative addition
Roman Kleinmans − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Omar Apolinar − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Joseph Derosa − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0001-8672-4875
5314
https://doi.org/10.1021/acs.orglett.1c01447
Org. Lett. 2021, 23, 5311−5316

Organic Letters
pubs.acs.org/OrgLett
Letter
Alkyl Suzuki Cross-Couplings of Unactivated Electrophiles. J. Am.
Chem. Soc. 2012, 134, 5794−5797.
Malkanthi K. Karunananda − Department of Chemistry, The
Scripps Research Institute, La Jolla, California 92037, United
States; orcid.org/0000-0002-8697-8864
(4) (a) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K.
M. Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl
Compounds via Conjunctive Cross-Coupling. J. Am. Chem. Soc. 2017,
139, 10657−10660. (b) Li, W.; Boon, J. K.; Zhao, Y. Nickel-Catalyzed
Difunctionalization of Allyl Moieties using Organoboronic Acids and
Halides with Divergent Regioselectivities. Chem. Sci. 2018, 9, 600−607.
(c) Thapa, S.; Dhungana, R. K.; Magar, R. T.; Shrestha, B.; KC, S.; Giri,
R. Ni-Catalysed Regioselective 1,2-Diarylation of Unactivated Olefins
by Stabilizing Heck Intermediates as Pyridylsilyl-Coordinated Tran-
sient Metallacycles. Chem. Sci. 2018, 9, 904−909. (d) Derosa, J.; van der
Puyl, V. A.; Tran, V. T.; Liu, M.; Engle, K. M. Directed Nickel-
Catalyzed 1,2-Dialkylation of Alkenyl Carbonyl Compounds. Chem. Sci.
2018, 9, 5278−5283. (e) Derosa, J.; Kleinmans, R.; Tran, V. T.;
Karunananda, M. K.; Wisniewski, S. R.; Eastgate, M. D.; Engle, K. M.
Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides. J. Am.
Chem. Soc. 2018, 140, 17878−17883. (f) Tran, V. T.; Li, Z.-Q.;
Gallagher, T. J.; Derosa, J.; Liu, P.; Engle, K. M. Integrating Allyl
Electrophiles into Nickel-Catalyzed Conjunctive Cross-Coupling.
Angew. Chem., Int. Ed. 2020, 59, 7029−7034. (g) Derosa, J.; Kang,
T.; Tran, V. T.; Wisniewski, S. R.; Karunananda, M. K.; Jankins, T. C.;
Xu, K. L.; Engle, K. M. Nickel-Catalyzed 1,2-Diarylation of Alkenyl
Carboxylates: A Gateway to 1,2,3-Trifunctionalized Building Blocks.
Angew. Chem., Int. Ed. 2020, 59, 1201−1205. For related work
involving sulfonamide coordination, see: (h) Apolinar, O.; Tran, V. T.;
Kim, N.; Schmidt, M. A.; Derosa, J.; Engle, K. M. Sulfonamide
Directivity Enables Ni-Catalyzed 1,2-Diarylation of Diverse Alkenyl
Amines. ACS Catal. 2020, 10, 14234−14239.
(5) (a) Basnet, P.; Dhungana, R. K.; Thapa, S.; Shrestha, B.; KC, S.;
Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective β,δ-Diarylation of
Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of
Transient Nickellacycles: Rapid Access to Remotely Diarylated
Ketones. J. Am. Chem. Soc. 2018, 140, 7782−7786. (b) Basnet, P.;
KC, S.; Dhungana, R. K.; Shrestha, B.; Boyle, T. J.; Giri, R. Synergistic
Bimetallic Ni/Ag and Ni/Cu Catalysis for Regioselective γ,δ-Diary-
lation of Alkenyl Ketimines: Addressing β-H Elimination by in Situ
Generation of Cationic Ni(II) Catalysts. J. Am. Chem. Soc. 2018, 140,
15586−15590. (c) Dhungana, R. K.; KC, S.; Basnet, P.; Aryal, V.;
Chesley, L. J.; Giri, R. Ni(I)-Catalyzed β,δ-Vinylarylation of γ,δ-Alkenyl
α-Cyanocarboxylic Esters via Contraction of Transient Nickellacycles.
ACS Catal. 2019, 9, 10887−10893.
(6) For representative examples of radical-based, nickel-catalyzed,
carbonyl-directed 1,2-dicarbofunctionalization of alkenes, see: (a) Gu,
J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Tandem Difluoroalkylation-
Arylation of Enamides Catalyzed by Nickel. Angew. Chem., Int. Ed.
2016, 55, 12270−12274. (b) García-Domínguez, A.; Li, Z.; Nevado, C.
Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes. J. Am.
Chem. Soc. 2017, 139, 6835−6838. (c) Zhao, X.; Tu, H.-Y.; Guo, L.;
Zhu, S.; Qing, F.-L.; Chu, L. Intermolecular Selective Carboacylation of
Alkenes via Nickel-Catalyzed Reductive Radical Relay. Nat. Commun.
2018, 9, 3488. (d) Xu, C.; Yang, Z.-F.; An, L.; Zhang, X. Nickel-
Catalyzed Difluoroalkylation−Alkylation of Enamides. ACS Catal.
2019, 9, 8224−8229. (e) Yang, Z.-F.; Xu, C.; Zheng, X.; Zhang, X.
Nickel-Catalyzed Carbodifunctionalization of N-Vinylamides Enables
Access to γ-Amino Acids. Chem. Commun. 2020, 56, 2642−2645.
(f) Wei, X.; Shu, W.; García-Domínguez, A.; Merino, E.; Nevado, C.
Asymmetric Ni-Catalyzed Radical Relayed Reductive Coupling. J. Am.
Chem. Soc. 2020, 142, 13515−13522. (g) Tu, H.-Y.; Wang, F.; Huo, L.;
Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F.-L.; Chu, L. Enantioselective
Three-Component Fluoroalkylarylation of Unactivated Olefins
through Nickel-Catalyzed Cross-Electrophile Coupling. J. Am. Chem.
Soc. 2020, 142, 9604−9611. For related work involving copper
catalysis, see: (h) Zhou, S.; Zhang, G.; Fu, L.; Chen, P.; Li, Y.; Liu, G.
Copper-Catalyzed Asymmetric Cyanation of Alkenes via Carbonyl-
Assisted Coupling of Alkyl-Substituted Carbon-Centered Radicals. Org.
Lett. 2020, 22, 6299−6303.
Zi-Qi Li − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Van T. Tran − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Steven R. Wisniewski − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0001-6035-4394
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01447
Author Contributions
§R.K. and O.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Bristol Myers Squibb
and the National Science Foundation (CHE-1800280). We
further acknowledge the DAAD for a PROMOS Scholarship
(R.K.) and the National Science Foundation for Graduate
Research Fellowships (DGE-1842471, O.A.; DGE-1346837,
J.D.). We thank Prof. Arnold L. Rheingold (UCSD) for X-ray
crystallographic analysis and Dr. Phillippa Cooper for careful
proofreading of this manuscript.
REFERENCES
■
(1) For reviews, see: (a) Giri, R.; KC, S. Strategies toward
Dicarbofunctionalization of Unactivated Olefins by Combined Heck
Carbometalation and Cross-Coupling. J. Org. Chem. 2018, 83, 3013−
3022. (b) Derosa, J.; Apolinar, O.; Kang, T.; Tran, V. T.; Engle, K. M.
Recent Developments in Nickel-Catalyzed Intermolecular Dicarbo-
functionalization of Alkenes. Chem. Sci. 2020, 11, 4287−4296. (c) Tu,
H.-Y.; Zhu, S.; Qing, F.-L.; Chu, L. Recent Advances in Nickel-
Catalyzed Three-Component Difunctionalization of Unactivated
Alkenes. Synthesis 2020, 52, 1346−1356. (d) Badir, S. O.; Molander,
G. A. Developments in Photoredox/Nickel Dual-Catalyzed 1,2-
Difunctionalizations. Chem. 2020, 6, 1327−1339. (e) Qi, X.; Diao, T.
Nickel-Catalyzed Dicarbofunctionalization of Alkenes. ACS Catal.
2020, 10, 8542−8556.
(2) (a) Catellani, M.; Chiusoli, G. P.; Concari, S. A New Palladium
Catalyzed Synthesis of cis,exo-2,3-Diarylsubstituted Bicyclo[2.2.1]-
heptanes or Bicyclo[2.2.1]hept-2-enes. Tetrahedron 1989, 45, 5263−
5268. (b) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman,
M. S. A Palladium-Catalyzed Three-Component-Coupling Strategy for
the Differential Vicinal Diarylation of Terminal 1,3-Dienes. Org. Lett.
2014, 16, 4666−4669. (c) Kuang, Z.; Yang, K.; Song, Q. Pd-Catalyzed
1,2-Diarylation of Vinylarenes at Ambient Temperature. Org. Chem.
Front. 2017, 4, 1224−1228. (d) Shrestha, B.; Basnet, P.; Dhungana, R.
K.; KC, S.; Thapa, S.; Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective
1,2-Dicarbofunctionalization of Olefins by Intercepting Heck Inter-
mediates as Imine-Stabilized Transient Metallacycles. J. Am. Chem. Soc.
2017, 139, 10653−10656. (e) Gao, P.; Chen, L.-A.; Brown, M. K.
Nickel-Catalyzed Stereoselective Diarylation of Alkenylarenes. J. Am.
Chem. Soc. 2018, 140, 10653−10657.
(3) For examples of carbonyl-directed two-component C−C cross-
couplings, see: (Pd) (a) Sandrock, D. L.; Jean-Gérard, L.; Chen, C.;
Dreher, S. D.; Molander, G. A. Stereospecific Cross-Coupling of
Secondary Alkyl β-Trifluoroboratoamides. J. Am. Chem. Soc. 2010, 132,
17108−17110. (Ni) (b) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu,
G. C. New Directing Groups for Metal-Catalyzed Asymmetric
Carbon−Carbon Bond-Forming Processes: Stereoconvergent Alkyl−
5315
https://doi.org/10.1021/acs.orglett.1c01447
Org. Lett. 2021, 23, 5311−5316

Organic Letters
pubs.acs.org/OrgLett
Letter
(7) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Transition
Metal-Catalyzed Ketone-Directed or Mediated C−H Functionaliza-
tion. Chem. Soc. Rev. 2015, 44, 7764−7786.
(8) For examples of electron-deficient olefin ligands in nickel-catalysis,
see refs 4e, 4h, and the following (a) Jensen, A. E.; Knochel, P. Nickel-
Catalyzed Cross-Coupling between Functionalized Primary or
Secondary Alkylzinc Halides and Primary Alkyl Halides. J. Org. Chem.
2002, 67, 79−85. (b) Estrada, J. G.; Williams, W. L.; Ting, S. I.; Doyle,
A. G. Role of Electron-Deficient Olefin Ligands in a Ni-Catalyzed
Aziridine Cross-Coupling to Generate Quaternary Carbons. J. Am.
Chem. Soc. 2020, 142, 8928−8937. (c) Kim, N.; Tran, V. T.; Apolinar,
O.; Wisniewski, S. R.; Eastgate, M. D. Ni(COD)(DMFU): A
Heteroleptic 16-Electron Precatalyst for 1,2-Diarylation of Alkenes.
Synlett 2021, DOI: 10.1055/a-1344-6040.
(9) Wethman, R.; Derosa, J.; Tran, V. T.; Kang, T.; Apolinar, O.;
Abraham, A.; Kleinmans, R.; Wisniewski, S. R.; Coombs, J. R.; Engle, K.
M. An Under-Appreciated Source of Reproducibility Issues in Cross-
Coupling: Solid-State Decomposition of Primary Sodium Alkoxides in
Air. ACS Catal. 2021, 11, 502−508.
(10) For previous reports describing the superior performance of
ArB(nep) nucleophiles in nickel-catalyzed cross-coupling, see
(a) Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. Nickel-
Catalyzed Cross-Coupling Reaction of Alkenyl Methyl Ethers with Aryl
Boronic Esters. Org. Lett. 2009, 11, 4890−4892. (b) Martin-Montero,
R.; Krolikowski, T.; Zarate, C.; Manzano, R.; Martin, R. Stereospecific
Nickel-Catalyzed Borylation of Secondary Benzyl Pivalates. Synlett
2017, 28, 2604−2608.
(11) One possible explanation for the modest effect of DMFU in the
present system is that the isomerized starting material may act as an
electron-deficient olefin ligand, making the added DMFU somewhat
redundant. This hypothesis is supported by DFT (see SI) and by the
observation that a γ,δ-unsaturated ketone substrate (4a → 5a) is low-
yielding in the absence of DMFU (9% yield; see SI).
(12) Minimal isomerization is observed for the majority of examples
(≤10%), and there is no clear relationship between the amount of
isomerized byproduct and the yield of the desired product.
(13) With the para-Cl and -CF3 aryl ketones, uncharacterized side
1
products were formed, complicating separation. H NMR yields are
reported to illustrate reactivity trends across the entire electronic series.
(14) For ( )-5b, PhI and PhB(nep) were used to simplify analysis to
avoid formation of regioisomers as well as diastereomers.
(15) TS4 and TS5 with L = DMFU and L = COD, respectively, were
computed to be higher in energy than TS2. See the SI for details.
(16) Using d4-methanol under otherwise standard conditions, 19%
deuterium incorporation at the α-position was observed in the product.
This result is inconsistent with an enolate pathway since ≥50%
deuterium incorporation would be expected in this case (see SI).
(17) A previous version of this paper was deposited on a preprint
server: Kleinmans, R.; Apolinar, O.; Derosa, J.; Karunananda, M. K.; Li,
Z.-Q.; Tran, V. T.; Wisniewski, S. R.; Engle, K. M. Nickel-Catalyzed 1,2-
Diarylation of Alkenyl Ketones: A Comparative Study of Carbonyl-
Directed Reaction Systems. ChemRxiv 2021, DOI: 10.26434/chem-
rxiv.14150174.
5316
https://doi.org/10.1021/acs.orglett.1c01447
Org. Lett. 2021, 23, 5311−5316