Nickel-Catalyzed Regioselective Alkenylarylation of γ,δ-Alkenyl Ketones via Carbonyl Coordination

Article abstract of DOI:10.1002/anie.202104871

We disclose a nickel-catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ-alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with

Full text of DOI:10.1002/anie.202104871

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Accepted Article
Title: Ni-Catalyzed Regioselective Alkenylarylation of γ,δ-Alkenyl
Ketones via Carbonyl Coordination
Authors: Ramesh Giri, Roshan K Dhungana, Vivek Aryal, Doleshwar
Niroula, Rishi R Sapkota, and Margaret G Lakomy
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104871
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Ni-Catalyzed Regioselective Alkenylarylation of ,-Alkenyl
Ketones via Carbonyl Coordination
Roshan K. Dhungana, Vivek Aryal, Doleshwar Niroula, Rishi R. Sapkota, Margaret G. Lakomy, and
Ramesh Giri*
Early work focused on difunctionalizing 1,1-disubstituted terminal[7]
Abstract: We disclose a nickel-catalyzed reaction, which enabled us
and bicyclic[8] alkenes to avoid -H elimination. Recently, a broad
to difunctionalize unactivated ,-alkenes in ketones with alkenyl
class of substrates were functionalized using
a coordination
triflates and arylboronic esters. The reaction was made feasible by the
use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr2•DME
as a catalyst and LiOtBu as base. The reaction proceeded with a wide
range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and
electron-rich and electron-deficient arylboronate esters. The reaction
also worked with both cyclic and acyclic alkenyl triflates. Control
experiments indicate that carbonyl coordination is required for the
reaction to proceed.
approach[1a-f] in which alkylmetal intermediates were stabilized as
transient metallacycles.[9] However, this strategy requires installation
and removal of strong coordinating groups like imines,[10] pyridines,[11]
2-aminopyrimidines,[12] and 8-aminoquinolines[13] for stabilizing
metallacycles.[14] Additionally, this strategy generally works with
substrates that generate rigid and planar five-membered
metallacycles. Limited examples of reactions involving six-membered
metallacycles are known but they either require strongly coordinating
bidentate groups[15] or are derived from vinylarenes containing
activated alkenes[10] to planarize and rigidify metallacycles. Alkene
difunctionalization reactions that involve nonplanar and fluxional six-
membered metallacycles form rearranged products through
contraction of metallacycles by -H elimination.[5a]
Metal-catalyzed alkene dicarbofunctionalization[1] is an emerging
synthetic method for complex molecule synthesis[2] with a promise to
reduce a multistep process to a few-step process.[3] This reaction
integrates two carbon sources into alkenes with high regiofidelity, and
provides branched molecules in one step.[4] However, its development
has been met with formidable challenges largely due to the formation
of Heck products by -H elimination (Scheme 1).[5] The reaction
selectivity toward alkene difunctionalization and the Heck product
depend on the difference in kinetic barriers between a single-step -
H elimination and a two-step transmetallation/reductive elimination
process. In the majority of catalytic processes, -H elimination has
been shown to occur with a much lower kinetic barrier than both the
transmetallation and reductive elimination steps.[6]
We recently introduced a cationic catalysis[16] to suppress the
contraction of metallacycles. While the reaction was successful, the
cationization of organometallic intermediates is also known to
promote -H elimination.[6a, 6b, 17] As such, when weakly coordinating
groups are used, the cationization of metallacycles promotes -H
elimination faster than the transmetallation/reductive elimination
steps.[5b]
For
that
reason,
regioselective
alkene
dicarbofunctionalization in weakly coordinating ketone substrates are
not known.[18] Herein, we disclose a new Ni-catalyzed reaction in the
presence of 5-chloro-8-hydroxyquinoline that addresses the issue of
-H elimination, and materializes alkenylarylation of unactivated ,-
alkenes in simple ketones. To the best of our knowledge, the current
reaction represents the first example of keto carbonyl-assisted
dicarbofunctionalization of unactivated alkenes.[19]
In our initial studies, we examined various ancillary ligands (L1-L7) for
alkenylarylation of ,-alkene in 2-allylcyclohexanone (Scheme 2). We
were pleased to discover that a combination of 20 mol % 8-
hydroxyquinoline (L7) and 10 mol % NiBr2•DME, along with LiOtBu as
a base, generated the alkenylarylation product 3 with cyclohexenyl
triflate and phenylboronic ester B3 in 48% yield. Control experiments
conducted in the absence of L7 and in the presence of L8, a neutral
variant of L7, produced no product, confirming that the anionic
ancillary ligand played a critical role in the reaction. Upon further
evaluation (L9-L12), we found that 5-chloro-8-hydroxyquinoline (L9)
performed optimally and furnished the product 3 in 75% yield.
Examination of different arylboron reagents showed that
phenylboronic ester B3 afforded the product 3 in best yield. Replacing
2-allylcyclohexanone with 2-vinyl- and 2-butenylketones also did not
furnish expected products (Scheme 2).
Scheme 1. Alkene 1,2-dicarbofunctionalization and complications by
-H elimination
[*]
Prof. R. Giri, Mr. R. K. Dhungana, Mr. Vivek Aryal, Dr. Doleshwar
Niroula, Dr. Rishi R. Sapkota, Ms. Margaret G. Lakomy
Department of Chemistry
Pennsylvania State University,
University Park, Pennsylvania 16802, USA
E-mail: rkg5374@psu.edu
Supporting information for this article and crystallographic
data (CCDC number: 2059802) for compound 33 are given via a link
at the end of the document.
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10.1002/anie.202104871
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yields with moderate diastereoselectivity (Table 2, A). The reaction
was compatible with various substituents like Me, dioxanyl, OMe,
OCF3 and F, and transition metal-sensitive functional groups such as
Br, nitrile and ester (4-11). This method can be applied to couple
arylboronic esters having polyaromatic hydrocarbons including
naphthyl, methoxynaphthyl and binaphthyl (11-13). The reaction also
tolerates heterocyclic arylboronic esters, such as thiazolyl and
carbozolylboronic esters (14-15), and alkenylboronic esters (16).
Moreover, we evaluated reaction scope with regard to ,-alkenyl
ketones and alkenyl triflates (Table 2, B). Various ,-alkenyl
endocyclic ketones containing both monocyclic and bicyclic scaffolds,
such as cyclohexenonyl, tetralonyl and acenaphthylenonyl, could be
implemented as substrates along with different alkenyl triflates and
arylboronic esters (17-22). The reaction could also be performed with
,-alkenyl exocyclic ketones bearing both cyclic and acyclic aliphatic
backbones such as cyclohexyl and isopropyl (23-25). Surprisingly,
,-alkenyl arylketones furnished products in low yields when the
reactions were conducted in THF (20-30%). Unlike ,-alkenyl
alkylketones for which THF was the solvent of choice at 80 °C, ,-
alkenyl arylketones furnished products in best yields in MeCN at 60
°C. ,-Alkenyl arylketones with p-CF3, o-Me and p-Cl substituents
and a naphthyl group afforded dicarbofunctionalized products in good
yields with different alkenyl triflates and arylboronic esters (26-33).
Reactions of these diverse ,-alkenyl ketones could be conducted
with carbocyclic alkenyl triflates containing cyclopentenyl,
cyclohexenyl, cyclooctenyl and 4-methylcyclohexenyl rings, and
heterocyclic alkenyl triflates, such as 3,6-dihydro-2H-thiopyran-4-yl
(18) and 3,6-dihydro-2H-pyran-4-yl triflates (22 and 27). The reaction
condition was also amenable for difunctionalizing acyclic alkenyl
triflates (34-35). These types of product derivatives form the cores of
pharmaceutical molecules and natural products.[20]
aReactions run at 0.10 mmol scale in 0.5 mL THF. 1H NMR yields
with pyrene as a standard. bThe yield of isolated product from a 0.50
mmol scale reaction in 2.5 mL THF in parenthesis. dr is 1.1:1.
Scheme 2. Examination of reaction parametersa
Table 1. Further reaction optimizationa
We have further demonstrated synthetic applications by
difunctionalizing unactivated alkenes in natural products,
pharmaceuticals and complex spirocyclic molecules, and by using
alkenyl triflates and arylboronic esters derived from complex
molecules (Table 2, C). For example, an alkenyl triflate derived from
a
steroid, cholestenone, was incorporated into ,-alkene in
cyclohexanone (37). In addition, ,-alkenes contained in complex
molecules such as cholestenone, probenecid (a uricosuric drug) and
naproxen (a NSAID drug) could also be difunctionalized with
cyclohexenyl triflate and various arylboronic esters (38-40).
Arylboronic ester derived from 9,9’-spirobifluorene also afforded
products (41-42) with alkenylcyclohexanone and alkenylarylketone.
Furthermore, we examined an internal ,-alkene contained in a
spirobicyclic ketone, which reacted to furnish a cis-difunctionalized
product (43).
aReactions run at 0.10 mmol scale in 0.5 mL solvent. b1H NMR yields
with pyrene as a standard. cThe yield of isolated product from a 0.50
mmol scale reaction in 2.5 mL THF in parenthesis. dr is 1.1:1.
dPd(OAc)2, CuI, Co(OAc)2, FeCl2.
Control experiments with an alkene lacking carbonyl group support
carbonyl coordination during reaction (Scheme 3). Moreover, alkenyl
ketones bearing less sterically bulky substituents on the carbonyl
group predominantly produced alkenylarylated products 24 and 29
along with trace amounts of Heck products 44 and 45 (Scheme 4). In
contrast, a sterically demanding tert-butyl group on the carbonyl group
generated the Heck product 47 in significant amounts (22%) in
addition to the alkenylarylation product 46 in 35% yield. These
experiments indicate that carbonyl coordination to nickel is required
to generate alkenylarylated products and that the Heck products are
generated due to equilibrium between the cyclic and acyclic
alkylnickel species 48 and 49 (Scheme 4).[21] Intimate analyses of
regioselectivity in products indicated that the reaction should be
catalyzed by a Ni(I) catalyst and transmetallation should precede the
reaction of alkenyl triflates (see SI for details).[22]
Examination of different alkoxide bases indicated that the reaction
was best performed with LiOtBu or LiOAd (Table 1, entries 1-6).
NiBr2•DME could be replaced with NiCl2•DME or NiI2 (entry 7). Other
Ni-catalysts furnished the product in lower yields (entries 8-10) and
other metal-catalysts such as FeCl2, Co(OAc)2, CuI and Pd(OAc)2
generated no product at all (entry 11). The reaction was optimally
performed at 80 °C in THF since other solvents and lower
temperatures either decreased the yield or formed no product (entries
12-17).
After optimization of the reaction conditions, we explored the scope of
the alkenylarylation reaction. Examination of different arylboronic
esters indicated that the reaction tolerated both electron-rich and
electron-deficient arenes, and the products were formed in good
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10.1002/anie.202104871
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Table 2. Reaction scopea
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aReactions run in 0.50 mmol scale in 2.5 mL solvent. Reactions for alkylketones (products 4-22, 34-36) run in THF at 80 °C while those for
arylketones (products 26-33, 39 and 42) run in MeCN 60 °C for 6 h. bReaction run under MeCN conditions. cReactions run under THF conditions
at 60 °C for 6 h. d20 mol % NiBr2•DME. Alkenyl triflate E/Z: 2:1. eA mixture of 4 diastereomers based on 13C NMR (see SI for details).
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In summary, we report a nickel-catalyzed reaction, which addresses
the issue of -H elimination in alkene difunctionalization in carbonyl-
assisted alkene dicarbofunctionalization reaction. The success of the
reaction relied upon the use of a combination of 5-chloro-8-
hydroxyquinoline and Ni(cod)2 in the presence of LiOtBu. This
catalysis enabled us to difunctionalize unactivated ,-alkenes in
ketones with alkenyl triflates and arylboronic esters. The reaction
proceeded with a wide range of cyclic, acyclic, endocyclic and
exocyclic alkenyl ketones along with electron-rich and electron-
deficient arylboronate esters, and cyclic and acyclic alkenyl triflates.
Control experiments with a substrate lacking a carbonyl group and
with a sterically hindered carbonyl group indicated that the carbonyl
coordination was required for the reaction to proceed.
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Acknowledgements
We gratefully acknowledge the NIH NIGMS (R35GM133438) and The
Pennsylvania State University for support of this work, and the PSU
NMR facility for NMR support. We thank Dr. Christy George for help
with stereochemistry determination of compound 43 by NMR.
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Keywords: Alkenyl ketone • alkenylarylation •
dicarbofunctionalization • nickel-catalyzed • 8-hydroxyquinoline
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10.1002/anie.202104871
Angewandte Chemie International Edition
COMMUNICATION
TOC
COMMUNICATION
Roshan K. Dhungana, Vivek Aryal,
Doleshwar Niroula, Rishi R. Sapkota,
Margaret G. Lakomy, and Ramesh Giri*
Page No. – Page No.
Ni-Catalyzed Regioselective
Alkenylarylation of ,-Alkenyl
Ketones via Carbonyl Coordination
A
nickel-catalyzed alkenylarylation reaction of ,-
alkenylketones with alkenyl triflates and arylboronic esters is
described. The reaction was made feasible by the use of 5-
chloro-8-hydroxyquinoline as a ligand along with NiBr2•DME
as a catalyst and LiOtBu as base, and works with cyclic,
acyclic, endocyclic and exocyclic alkenyl ketones. Control
experiments indicate that carbonyl coordination is required for
the reaction to proceed.
This article is protected by copyright. All rights reserved.