Chemoselective Union of Olefins, Organohalides, and Redox-Active Esters Enables Regioselective Alkene Dialkylation

Article abstract of DOI:10.1021/jacs.0c09922

Multicomponent catalytic processes that can generate multiple C(sp3)-C(sp3) bonds in a single step under mild conditions, particularly those that employ inexpensive catalysts and substrates, are highly sought-after in chemistry research for complex molecule synthesis. Here, we disclose an efficient Ni-catalyzed reductive protocol that chemoselectively merges alkenyl amides with two different aliphatic electrophiles. Starting materials are readily accessible from stable and abundant feedstock, and products are furnished in up to >98:2 regioisomeric ratios. The present strategy eliminates the use of sensitive organometallic reagents, tolerates a wide array of complex functionalities, and enables regiodivergent addition of two primary alkyl groups bearing similar electronic and steric attributes across aliphatic C=C bonds with exquisite control of site selectivity. Utility is underscored by the concise synthesis of bioactive compounds and postreaction functionalizations leading to structurally diverse scaffolds. DFT studies revealed that the regiochemical outcome originates from the orthogonal reactivity and chemoselectivity profiles of in situ generated organonickel species.

Full text of DOI:10.1021/jacs.0c09922

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Chemoselective Union of Olefins, Organohalides, and Redox-Active
Esters Enables Regioselective Alkene Dialkylation
Tao Yang,∥ Yi Jiang,∥ Yixin Luo, Joel Jun Han Lim, Yu Lan,* and Ming Joo Koh*
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ABSTRACT: Multicomponent catalytic processes that can generate
multiple C(sp3)−C(sp3) bonds in a single step under mild conditions,
particularly those that employ inexpensive catalysts and substrates, are
highly sought-after in chemistry research for complex molecule
synthesis. Here, we disclose an efficient Ni-catalyzed reductive protocol
that chemoselectively merges alkenyl amides with two different
aliphatic electrophiles. Starting materials are readily accessible from
stable and abundant feedstock, and products are furnished in up to
>98:2 regioisomeric ratios. The present strategy eliminates the use of
sensitive organometallic reagents, tolerates a wide array of complex
functionalities, and enables regiodivergent addition of two primary alkyl
groups bearing similar electronic and steric attributes across aliphatic
CC bonds with exquisite control of site selectivity. Utility is
underscored by the concise synthesis of bioactive compounds and postreaction functionalizations leading to structurally diverse
scaffolds. DFT studies revealed that the regiochemical outcome originates from the orthogonal reactivity and chemoselectivity
profiles of in situ generated organonickel species.
two organohalides are electronically and/or sterically distin-
guishable11 (Scheme 1a). In cases where there is imperceptible
bias (e.g., two primary alkyl halides), regioisomeric ratios
severely diminish. As exemplified in Scheme 1b, attempts to
carry out dialkylation of olefin 4a with benzyl halide 1 and 1-
iodobutane 2a under Ni-catalyzed reductive conditions only
led to a complex mixture of products, generating regioisomeric
5 and 5′ in low yields and selectivity (3:1−1:1 ratio).
Significant amounts of homodialkylation (6 and 7) and cross-
electrophile coupling byproducts were also detected. We
surmised that the poor regiochemical outcome stems from the
inability of the catalytic organonickel species to discern the
inappreciable reactivity differences between the two aliphatic
halides, consequently leading to nonselective alkene insertions
and mixtures of regioisomeric products.
INTRODUCTION
■
Transition-metal-catalyzed difunctionalization of unsaturated
hydrocarbons represents one of the most important classes of
reactions in chemistry and has extensive applications in organic
synthesis.1 In this regard, a versatile set of transformations that
have emerged as a powerful way through which molecular
complexity can be expeditiously generated is the site-selective
addition of two different carbon-based moieties across CC
bonds.2 These reactions enable the direct incorporation of
functionalities without the unnecessary intermediacy of
precursors that otherwise have to be subjected to further C−
C bond-forming derivatizations.3 Notwithstanding the advan-
ces thus far, conceiving a general protocol for the regioselective
insertion of sp3-hybridized carbogenic groups remains a
prevailing goal in multicomponent catalytic alkene dicarbo-
functionalizations. Compared to sp2-hybridized species,
aliphatic substrates often exhibit attenuated reactivity (e.g.,
reluctance to undergo oxidative addition4,5) and/or are prone
to undesirable side pathways (e.g., β-H elimination of the alkyl
unit4). Reports in olefin dialkylation are scarce and often
involve activated π-frameworks6,7 or two-component systems8
with organometallic nucleophiles.
RESULTS AND DISUSSION
■
Reaction Design and Mechanistic Investigations. In
contemplating a plausible solution to the problem described in
Scheme 1b, we wondered if electrophilic N-(acyloxy)-
Received: September 16, 2020
An attractive approach to deliver alkyl additions to less-
activated aliphatic olefins that obviates the need for unstable
presynthesized alkylmetal reagents9 relates to the direct use of
organohalide electrophiles in the presence of a Ni-based
catalyst and an inexpensive stoichiometric reducing agent.10
To date, high site selectivity can only be obtained when the
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(Scheme 2a, dashed inset). Following catalyst recombination
and further conversions, the desired difunctionalization
product can be secured in high site selectivity, although only
one regioisomer can be accessed in most disclosures.
Scheme 1. Challenges in Reductive
Dicarbofunctionalization of Aliphatic Olefins
Taking advantage of the susceptibility of redox-active N-
(acyloxy)phthalimides 9 to SET processes in the presence of a
nickel-based complex12 (vs halogen atom abstraction/radical
recombination with alkyl halides), we postulated that a
combination of 9 and haloalkane 2 may provide the requisite
reactivity differentiation for regioselective dialkyl additions to
unactivated CC bonds in the presence of a directing
auxiliary and a reductant (Scheme 2b). Successful implemen-
tation of this strategy requires that 9 first reacts with an
organonickel species in the catalytic cycle, possibly generating
intermediate iii that undergoes migratory insertion across the
Ni-coordinated olefin, before preferentially engaging with 2 to
furnish the final product 5 (or vice versa). Such a reaction
trajectory (vs the radical relay sequence in Scheme 2a) is
relatively unexplored in the context of N-(acyloxy)phthalimide
additions to alkenes. Furthermore, by reversing the aliphatic
electrophiles employed (i.e., exchanging G1 and G2), access to
the opposite regioisomer of 5 could be accomplished. In
contrast to using bimetallic catalysis to promote orthogonal
substrate activation,15,16 designing a single-catalyst system for
site-selective dialkylation demands a greater degree of
chemoselectivity with which the catalytic intermediates react
with 2 and 9 without a large excess of either electrophilic
reagent. This is more challenging to overcome compared to
dialkylations that utilize distinct alkylmetal nucleophiles and
haloalkane electrophiles,9 where chemoselectivity is less
problematic.
phthalimides (stable and readily accessible from abundant and
inexpensive carboxylic acids)12 may be leveraged as reagents
(vs alkyl halides)11d to promote alkyl additions to aliphatic
olefins. However, as shown in Scheme 2a, redox-active esters 9
Scheme 2. Design of a New Catalytic Regime Employing
Haloalkanes and N-(Acyloxy)phthalimides for Site-Selective
Dialkylation of Unactivated CC Bonds
A general catalytic reductive manifold for regioselective
alkene dialkylation that tolerates commonly occurring func-
tional groups would be a significant addition to an important
but limited set of transformations, facilitating the convergent
synthesis of bioactive compounds and new analogues (see
below for further discussion). What is more, by facile
hydrolysis of the amide directing group followed by established
catalytic decarboxylative reactions,13c,17,18 5 could be further
converted to a wider assortment of highly functionalized
compounds which might aid the development of chemical
libraries for screening. Finally, the mechanistic insights derived
from our studies could provide inspiration for designing new
multicomponent processes that exploit the orthogonal
reactivity exhibited by in situ-generated organonickel species
toward different electrophiles. Herein, we disclose the details
of a directed nickel-catalyzed protocol that delivers site-
selective dialkylation of unactivated alkenyl amides.
We commenced our studies by examining conditions that
promote the union of directing group-tethered aliphatic olefins
with 2a and N-(acyloxy)phthalimide 9a. After an extensive
evaluation of conditions including directing auxiliaries, Ni-
based salts, solvents and reducing agents (see Tables S1−4 for
details), best results were secured when 8-aminoquinoline-
tethered alkene 4a was merged with 2a and 9a in the presence
of 20 mol % NiI2 and 3 equiv. Mn in DMSO/MeCN,
furnishing 5a in 71% yield and complete site selectivity with
trace amounts of homodialkylation byproduct (Scheme 3a).
This unexpected outcome is a remarkable improvement
compared to the analogous reaction using alkyl halides in
which 5a was generated in poor yield as a 50:50 regioisomeric
mixture with significant formation of side products (cf. Scheme
1b).
have only been employed in catalytic difunctionalization
reactions involving activated alkenes (e.g., styrenes, acrylates,
and trifluoromethylated olefins)13 or 1,3-dienes.14 Under the
established conditions, 9 is prone to undergo decarboxylation
through single electron transfer (SET) pathways that
ultimately generate an alkyl radical i, which is subsequently
trapped by the olefin substrate in a relay process to afford ii
B
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a
Scheme 3. Underlying Mechanistic Principles for Regioselective Reductive Alkene Dialkylation
a
Regioisomeric ratios were determined by GC analysis with n-tridecane as internal standard. Yields are for isolated and purified products. The total
activation energy (ΔE‡act) = distortion energy (ΔE‡dist) + interaction energy (ΔE‡int). The distortion energy consists of two reacting partner terms
[ΔE‡dist(a) + ΔE‡dist(b)]. All energies are reported in kcal/mol. All bond distances are reported in ångstrom. G, functional group; X, halide; Phth,
phthaloyl; DMSO, dimethyl sulfoxide; NMP, N-methyl-2-pyrrolidone; COA, concerted oxidative addition; ISET, inner-sphere single electron
transfer; OSET, outer-sphere single electron transfer; int, intermediate; ts, transition state; ΔG, Gibbs free energy; ΔG‡, Gibbs free energy of
activation; ΔE‡act, total activation energy; ΔE‡dist, distortion energy; ΔE‡int, interaction energy; spin, spin densities; D, dihedral angle.
Based on the above experimental observations, density
functional theory (DFT) method M06-L19 was employed to
investigate the mechanistic nuances that account for the
orthogonal reactivity of the two electrophiles in the Ni-
catalyzed reductive alkene dialkylation (Scheme 3b). In the
presence of Mn, nickel(II) salts may be reduced to Ni(0)
species,10a10g which could associate with 8-aminoquinoline-
tethered olefin 4a to generate Ni(0) complex v, the key species
to be considered in the following processes. Under the reaction
conditions, either N-(acyloxy)phthalimide 9b or iodoethane
2b (model substrates) could serve as the oxidant to react with
v. Specifically, the competition between these two electrophilic
reagents in the Ni oxidation steps will influence the
regiochemical outcome of the olefin dialkylation. In our
C
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theoretical study, three types of oxidative mechanisms20
involving inner-sphere single electron transfer (ISET), outer-
sphere single electron transfer (OSET) and concerted
oxidative addition (COA) were examined for the reaction of
9b or 2b with different Ni species. When 2b was used as
oxidant to react with Ni(0) complex v, the calculated free
energy barrier for the ISET process was 13.1 kcal/mol via an
ISET-assisted homolytic C−I bond cleavage transition state ts-
7 leading to the formation of a Ni(I)-iodide species int-6 and
an ethyl radical. Subsequent recombination with ethyl radical
furnishes Ni(II)-alkyl intermediate int-7. Although intermedi-
ate int-7 could also be generated from a COA process via
three-membered ring transition state ts-11, such a pathway
could be excluded by the relatively higher free energy barrier of
18.9 kcal/mol.
Alternatively, when 9b undergoes reaction with v, DFT
calculations revealed that the free energy barrier for the ISET
pathway (homolytic N−O bond dissociation) is only 10.5
kcal/mol via transition state ts-1. In this process, the
coordination of phthalimide nitrogen to the Ni center
promotes N−O bond cleavage in 9b, generating a Ni(I)-
phthalimide species int-1 with concomitant release of a
phenylacetate radical 9″. Facile decarboxylation of 9″ ejects
a benzyl radical, which can further oxidize int-1 via transition
state ts-3 to afford Ni(II)-benzyl intermediate int-2. In
contrast, the free energy barrier for the COA pathway was
found to be much higher (20.7 kcal/mol) than that of the
ISET process. On the other hand, 9b may serve as a single-
electron acceptor and participate in a OSET process as
commonly proposed in the literature.12 The calculated
activation free energy for this pathway by using approximation
of modified Marcus theory21 is 12.1 kcal/mol to deliver a
cationic Ni(I) intermediate int-4 that is 11.3 kcal/mol
endergonic. However, after the ensuing phthalimide anion
transfer to form int-1 via ts-5, the calculated activation free
energy of the overall process is as high as 22.6 kcal/mol. Thus,
the OSET pathway is likely to be unfavorable.
On the basis of the above calculations, N-(acyloxy)-
phthalimide 9b is found to chemoselectively react with
Ni(0) complex v through stepwise ISET-type oxidation,
contrary to previously established pathways, to afford Ni(II)-
benzyl intermediate int-2. Following intramolecular 1,2-alkene
insertion into the Ni−C(benzyl) bond and single-electron
reduction by Mn, a Ni(I)-alkyl species ix-b is formed, which
can subsequently react with either 9b or iodoethane 2b.
Further DFT studies indicated that ix-b readily reacts with 2b
through a ISET process via transition state ts-12 with an
activation free energy of only 5.4 kcal/mol. The resulting
Ni(II)-iodide int-9 then captures the ethyl radical to furnish
Ni(III)-dialkyl intermediate int-10, which is susceptible to
reductive elimination to yield the desired dialkylation product.
For comparison, we also evaluated the reactivity profile of ix-
b with N-(acyloxy)phthalimide 9b. The calculated free energy
barrier for the ISET pathway is 14.6 kcal/mol via transition
state ts-16, which is 9.2 kcal/mol higher than that with 2b via
ts-12. Furthermore, the corresponding OSET and COA
pathways were also found to be energetically less favorable
compared to the calculated ISET pathway with 2b. Therefore,
the excellent site selectivity that was observed in Scheme 3a
primarily arose from the orthogonal reactivity of N-(acyloxy)-
phthalimide 9b and iodoethane 2b with different organonickel
species (i.e., v and ix-b) generated in the catalytic system.
The origin of the high regioselectivity cannot be simply
rationalized by conventional electronic and/or steric argu-
ments involving the two electrophiles and the in situ generated
Ni complexes v and ix-b. To gain further insights, careful
distortion/interaction analysis22 of the four ISET-type
transition states ts-1, ts-7, ts-12, and ts-16 was carried out,
where the total activation energy (ΔE‡act) was separated into
the distortion energy of two reacting partners (ΔE‡dist) and the
interaction energy between those two distorted partners
(ΔE‡int). As shown in Scheme 3c, when N-(acyloxy)-
phthalimide 9b reacts with Ni(0) species v, a large interaction
energy of −40.2 kcal/mol was observed in transition state ts-1.
This can be explained by the strong association of the
phthalimide nitrogen with the Ni center. The distortion energy
of ts-1 largely arises from dissociation of the 8-aminoquinoline
amide nitrogen, which may be nullified by the coordination of
9b. On the contrary, the interaction between iodoethane 2b
and v in transition state ts-7 is significantly lower. Hence,
ΔE‡ becomes more favorable in ts-1 (vs ts-7), and v is
act
predicted to preferentially undergo oxidation with 9b (instead
of 2b). Intriguingly, the interaction between 2b and the more
electron-deficient Ni(I) species ix-b is dramatically enhanced
in transition state ts-12, whereas the distortion energy remains
almost unchanged (vs ts-7). On the other hand, the association
of ix-b with 9b causes greater distortion within ts-16 (D,
dihedral angle; DN1−Ni−N2‑C = 133.0° vs reaction with 2b via ts-
12, DN1−Ni−N2‑C = 167.5°). Therefore, the second oxidation
involving ix-b would selectively occur in the presence of 2b
(instead of 9b).
Our DFT results are supported by control experiments in
which both the N-(acyloxy)phthalimide and alkyl halide
reagent likely reacted through ISET-type radical processes
(Scheme 4a,c). With 9ag, calculations show that radical
cyclization is more favored than trapping of the initially
generated tertiary radical (Scheme 4b). Although the use of
(iodomethyl)cyclopropane 2s delivered the expected product
5bf with no trace of ring rupturing, computations showed that
the ring-opening rate of the cyclopropylmethyl radical
intermediate (generated from iodine abstraction/radical
recombination) is comparatively slower than the rate of radical
association with the catalytic organonickel species (Scheme
4c). This result is in contrast to a previous dialkylation
disclosure in which only the ring-cleaved product was
detected.9
Consolidating the information derived from experimental
and theoretical studies, we propose a possible catalytic cycle
(Scheme 3d) that begins with initial formation of a putative
Ni(0) species iv (possibly from reduction of the Ni(II)
precatalyst by Mn),10a10g that undergoes ligand exchange with
substrate 4a to generate Ni(0) complex v. Instead of engaging
with the alkyl halide 2, v chemoselectively reacts with the N-
(acyloxy)phthalimide 9 through an ISET process to afford a
Ni(I)-phthalimide intermediate vi and a carboxylate radical.
Facile extrusion of CO2 furnishes an alkyl radical that
recombines with vi to give Ni(II)-alkyl intermediate vii. An
intramolecular site-selective alkylnickelation across the che-
lated π bond to form viii followed by reduction of the Ni
center by Mn could proceed to generate Ni(I)-alkyl complex
ix. At this stage, ix preferentially reacts with 2 through another
ISET pathway to deliver a new Ni(III)-alkyl species xi (via x)
that reductively eliminates to release the desired dialkylation
adduct 5, before an ensuing reduction process and ligand
exchange regenerate v.
D
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adducts 5c−5p in 34−69% yield and ≥95:5 regioisomeric
ratios. These include products containing heterocycles (5k,
5n) as well as a halogen motif (5f) and a protic N−H group
(5g, 5o) that might otherwise react if the corresponding
alkylmetal reagent is utilized.23
Scheme 4. Radical Clock Studies
N-(Acyloxy)phthalimides derived from multifunctional and
biologically active carboxylic acids also reacted to deliver 5q−
5r, further underscoring the method’s exceptional functional
group tolerance. Reactions with α-branched alkenyl amides
furnished the expected products 5t−5u in good diastereose-
lectivity. Yields were somewhat diminished when reagents
bearing long-chain alkyl units were involved (5o−5p, 5s, and
5v−5w) owing to competitive formation of homodialkylation,
cross-electrophile coupling, and other side products (see
Tables S5−11 for details). Nevertheless, the catalytic protocol
is amenable to the selective generation of either regioisomer
(5v−5w) simply by exchanging G1 and G2 moieties within 9
and 2.
Reactions with secondary and tertiary alkyl-substituted N-
(acyloxy)phthalimides were similarly effective to deliver
regioisomerically pure products 5x−5ag in up to 58% yield.
These comprise molecules that bear heteroatom-substituted
(5z, 5ag) and all-carbon quaternary (5ac−5af) stereogenic
centers, offering a broader range of adducts compared to a
previous protocol involving largely primary alkyl additions with
organozinc reagents.9 For reactions that employed tertiary
alkyl redox-active esters, DFT calculations suggested that both
intramolecular alkylnickelation (cf. Scheme 2b) and radical
relay-based process (cf. Scheme 2a) are energetically
comparable, which means that either pathway may be
operative under the reaction conditions to deliver the same
sense of regioselectivity (see Figure S10 for details). Extending
the carbon-chain length to γ,δ-unsaturated alkenyl amides did
not appreciably affect dialkylation as the corresponding
adducts 5ah−5al could be generated in 35−52% yield.
Dialkylation of β-branched alkenyl amide gave 5al in 20:1
diastereomeric ratio. However, substrates with 1,1- or 1,2-
disubstituted CC bonds were unreactive (<5% conv. to
product).
The nature of the alkyl iodide 2 could also be varied under
the optimized reductive dialkylation conditions (Scheme 6).
Various functionalized products 5am−5bb, including those
that bear an acid-labile acetal (5aq), an alkyne (5ar),
carboxylic esters (5at−5au), a Lewis basic phthalimide
(5av), a Brønsted acidic phenol (5aw), an aldehyde (5ay),
as well as a cyclic enoate (5ba) could be secured in up to 73%
yield as single regioisomers. As highlighted by the formation of
5bb, the catalytic method is also compatible with reagents
derived from complex molecules such as β-lactamase inhibitor
sulbactam, whose sensitivity to alkaline conditions24 might
pose problems with basic organometallic reagents.
The ability to construct two C(sp3)−C(sp3) bonds in one
step with exceptional site selectivity under mild reaction
conditions presents an opportunity to devise new synthesis
routes for a number of important compounds of interest
(Scheme 7a). In one instance, amide deprotection of the
dialkylation product 5bc (synthesized on 2 mmol scale) led to
the known acid 10a, a precursor of antibiotic potentiator 11a,
in 51% overall yield. The three-step sequence from
commercially available starting materials is more concise than
a previous five-step route.25 Furthermore, this approach
potentially allows new substituted analogues to be more
readily accessed for evaluation of medicinal properties by
Substrate Scope and Synthetic Applications. We first
surveyed the reaction scope by merging different classes of
aliphatic N-(acyloxy)phthalimides 9 with alkene 4 and
iodoalkane 2 under the optimized conditions (Scheme 5). A
wide assortment of primary alkyl-substituted redox-active
esters underwent reductive dialkylation, affording the desired
E
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a
Scheme 5. Scope of Redox-Active Esters in Catalytic Reductive Dialkylation
a
Unless otherwise stated, all dialkylation products were obtained as single regioisomers. Regioisomeric ratios were determined by GC analysis with
n-tridecane as internal standard. Yields are for isolated and purified products. For 5z−5ab, NHPI ester (2.0 equiv) was used. For 5ac, 5ah, 5aj, 5ak,
and 5al, Ni(cod)2 was used as catalyst. For 5ah−5al, NMP was used as solvent and NHPI ester (2.5 equiv) was used. See the Supporting
Information for details.
merging different combinations of N-(acyloxy)phthalimides
and alkyl halides. An exemplary case relates to the facile
preparation of methoxy-derivative 11b, which may be
generated from 5ap via 10b.
The second application involves the preparation of 13, an
intermediate employed in the synthesis of a compound with
antibacterial and anticancer activities.26 Conversion of 5bd
(synthesized on 1 mmol scale) to the corresponding redox-
active ester 12 followed by Ni-catalyzed reductive cross-
coupling17 with 1-(benzyloxy)-4-iodo-2-methoxybenzene de-
livered 13 in 54% yield over three steps. A similar
decarboxylative strategy was adopted to afford a variety of
F
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Scheme 6. Scope of Aliphatic Halides in Catalytic Reductive
Dialkylation
Scheme 7. Access to Medicinally Relevant Molecules and
Further Transformations
a
a
a
All dialkylation products were obtained as single regioisomers. Yields
are for isolated and purified products. For 5an and 5aw,
NiBr2(diglyme) was used as a catalyst. For 5an, 4-methoxybenzyl
chloride was used as reagent and DMPU was used as solvent. See the
Supporting Information for details.
a
All dialkylation products were obtained as single regioisomers. Yields
are for isolated and purified products. See Supporting Information for
details.
different analogues (see the Supporting Information, section
2.4C for details).
multiple C−C bonds between sp3-hybridized moieties that
constitute the skeletal backbone of organic molecules,28 along
with the relative ease of product derivatization, offer a direct
entry to multifunctional entities. The insights gained from
these studies are expected to aid future development of
reactions that involve multiple electrophiles for the assembly of
important compounds of interest.
As shown in Scheme 7b, the appropriate combination of
catalytic reductive dialkylation of unsaturated amides and
catalytic decarboxylative cross-coupling can enable multiple
carbon−carbon linkages to be installed in a regioselective
fashion, thus providing an expedient avenue to create
complexity and diversity for compound library synthesis.27
To further illustrate this versatility, N-(acyloxy)phthalimides
derived from dialkylation adducts were subjected to established
decarboxylative transformations13c,17,18 (furnishing C(sp)−
C(sp3), C(sp2)−C(sp3), and C(sp3)−C(sp3) bonds) to give
15a−c in 81−86% yield (Scheme 7b).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09922.
■
sı
Experimental procedures and analytical data for all
compounds and DFT calculations (PDF)
CONCLUSIONS
■
By leveraging the differences in reactivity and chemoselectivity
patterns of in situ generated organonickel species, we have
successfully developed a directed Ni-catalyzed manifold that
efficiently merges unactivated alkenyl amides with haloalkanes
and aliphatic redox-active esters under reductive conditions.
This approach avoids the use of sensitive organometallic
reagents and overcomes the longstanding challenge of
installing two primary alkyl units, derived from stable
electrophilic reagents, across CC bonds with remarkable
regioselectivity. The present protocol’s capability to forge
AUTHOR INFORMATION
Corresponding Authors
■
Ming Joo Koh − Department of Chemistry, National
University of Singapore, Singapore 117549, Republic of
Singapore; orcid.org/0000-0002-2534-4921;
Email: chmkmj@nus.edu.sg
Yu Lan − School of Chemistry and Chemical Engineering,
Chongqing Key Laboratory of Theoretical and
Computational Chemistry, Chongqing University, Chongqing
G
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(j) KC, S.; Dhungana, R.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet,
P.; Lebrun, R. W.; Giri, R. Ni-Catalyzed regioselective alkylarylation
of vinylarenes via C(sp3)−C(sp3)/C(sp3)−C(sp2) bond formation
and mechanistic studies. J. Am. Chem. Soc. 2018, 140, 9801−9805.
(k) Chierchia, M.; Xu, P.; Lovinger, G. J.; Morken, J. P.
Enantioselective radical addition/cross-coupling of organozinc
reagents, alkyl iodides, and alkenyl boron reagents. Angew. Chem.,
Int. Ed. 2019, 58, 14245−14249. (l) 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. (m) Campbell, M. W.;
Compton, J. S.; Kelly, C. B.; Molander, G. A. Three-component
olefin dicarbofunctionalization enabled by nickel/photoredox dual
catalysis. J. Am. Chem. Soc. 2019, 141, 20069−20078. (n) 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. (o) Mega, R. S.;
Duong, V. K.; Noble, A.; Aggarwal, V. K. Decarboxylative conjunctive
cross-coupling of vinyl boronic esters using metallaphotoredox
catalysis. Angew. Chem., Int. Ed. 2020, 59, 4375−4379. (p) Liu, L.;
Lee, W.; Youshaw, C. R.; Yuan, M.; Geherty, M. B.; Zavalij, P. Y.;
Gutierrez, O. Fe-catalyzed three-component dicarbofunctionalization
of unactivated alkenes with alkyl halides and Grignard reagents. Chem.
Sci. 2020, 11, 8301−8305.
400030, China; College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou, Henan 450001,
China; orcid.org/0000-0002-2328-0020; Email: lanyu@
cqu.edu.cn
Authors
Tao Yang − Department of Chemistry, National University of
Singapore, Singapore 117549, Republic of Singapore
Yi Jiang − Department of Chemistry, National University of
Singapore, Singapore 117549, Republic of Singapore
Yixin Luo − School of Chemistry and Chemical Engineering,
Chongqing Key Laboratory of Theoretical and
Computational Chemistry, Chongqing University, Chongqing
400030, China
Joel Jun Han Lim − Department of Chemistry, National
University of Singapore, Singapore 117549, Republic of
Singapore
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09922
Author Contributions
∥T.Y. and Y.J. contributed equally.
Notes
(3) Sandford, C.; Aggarwal, V. K. Stereospecific functionalizations
and transformations of secondary and tertiary boronic esters. Chem.
Commun. 2017, 53, 5481−5494.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(4) Frisch, A. C.; Beller, M. Catalysts for cross-coupling reactions
with non-activated alkyl halides. Angew. Chem., Int. Ed. 2005, 44,
674−688.
(5) Ariafard, A.; Lin, Z. Understanding the relative easiness of
oxidative addition of aryl and alkyl halides to palladium(0).
Organometallics 2006, 25, 4030−4033.
(6) Terao, J.; Kato, Y.; Kambe, N. Titanocene-catalyzed
regioselective alkylation of styrenes with Grignard reagents using β-
bromoethyl ethers, thioethers, or amines. Chem. - Asian J. 2008, 3,
1472−1478.
(7) Mizutani, K.; Shinokubo, H.; Oshima, K. Cobalt-catalyzed three-
component coupling reaction of alkyl halides, 1,3-dienes, and
trimethylsilylmethylmagnesium chloride. Org. Lett. 2003, 5, 3959−
3961.
This research was supported by the National University of
Singapore Academic Research Fund Tier 1: R-143-000-A77-
114 (M.J.K.) and the 111 Project: D20003 (Y.L.).
REFERENCES
■
(1) For selected reviews, see: (a) McDonald, R. I.; Liu, G. S.; Stahl,
S. S. Palladium(II)-catalyzed alkene functionalization via nucleopalla-
dation: stereochemical pathways and enantioselective catalytic
applications. Chem. Rev. 2011, 111, 2981−3019. (b) Beller, M.;
Seayad, J.; Tillack, A.; Jiao, H. Catalytic markovnikov and anti-
markovnikov functionalization of alkenes and alkynes: recent
developments and trends. Angew. Chem., Int. Ed. 2004, 43, 3368−
3398. (c) Yin, G.; Mu, X.; Liu, G. Palladium(II)-catalyzed oxidative
difunctionalization of alkenes: bond forming at a high-valent
palladium center. Acc. Chem. Res. 2016, 49, 2413−2423.
(2) For selected reviews and examples, see: (a) Dhungana, R. K.;
KC, S.; Basnet, P.; Giri, R. Transition metal-catalyzed dicarbofunc-
tionalization of unactivated olefins. Chem. Rec 2018, 18, 1314−1340.
(b) Derosa, J.; Apolinar, O.; Kang, T.; Tran, V. T.; Engle, K. M.
Recent developments in nickel-catalyzed intermolecular dicarbofunc-
tionalization of alkenes. Chem. Sci. 2020, 11, 4287−4296. (c) Qi, X.;
Diao, T. Nickel-catalyzed dicarbofunctionalization of alkenes. ACS
Catal. 2020, 10, 8542−8556. (d) Zhang, J.-S.; Liu, L.; Chen, T.; Han,
L.-B. Transition-metal catalyzed three-component difunctionalizations
of alkenes. Chem. - Asian J. 2018, 13, 2277−2291. (e) Liao, L.; Jana,
R.; Urkalan, K. B.; Sigman, M. S. A palladium-catalyzed three-
component cross coupling of conjugated dienes or terminal alkenes
with vinyl triflates and boronic acids. J. Am. Chem. Soc. 2011, 133,
5784−5787. (f) Gao, P.; Chen, L. A.; Brown, M. K. Nickel-catalyzed
stereoselective diarylation of alkenylarenes. J. Am. Chem. Soc. 2018,
140, 10653−10657. (g) 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. (h) 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. (i) Gu, J. W.; Min, Q. Q.; Yu, L.
C.; Zhang, X. G. Tandem difluoroalkylation-arylation of enamides
catalyzed by nickel. Angew. Chem., Int. Ed. 2016, 55, 12270−12274.
́
(8) (a) Phapale, V. B.; Bunuel, E.; García-Iglesias, M.; Cardenas, D.
̃
J. Ni-catalyzed cascade formation of C(sp3)-C(sp3) bonds by
cyclization and cross-coupling reactions of iodoalkanes with alkyl
zinc halides. Angew. Chem., Int. Ed. 2007, 46, 8790−8795 For a two-
component dialkylation method under reductive conditions, see:.
(b) Kuang, Y.; Wang, X.; Anthony, D.; Diao, T. Ni-catalyzed two-
component reductive dicarbofunctionalization of alkenes via radical
cyclization. Chem. Commun. 2018, 54, 2558−2561.
(9) 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.
(10) For selected reviews and examples, see: (a) Weix, D. J.
Methods and mechanisms for cross-electrophile coupling of Csp2
halides with alkyl electrophiles. Acc. Chem. Res. 2015, 48, 1767−1775.
(b) Gu, J.; Wang, X.; Xue, W.; Gong, H. Nickel-catalyzed reductive
coupling of alkyl halides with other electrophiles: concept and
mechanistic considerations. Org. Chem. Front. 2015, 2, 1411−1421.
(c) Knappke, C. E. I.; Grupe, S.; Gartner, D.; Corpet, M.; Gosmini,
C.; Jacobi von Wangelin, A. von. Reductive cross-coupling reactions
between two electrophiles. Chem. - Eur. J. 2014, 20, 6828−6842.
(d) Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed
Reductive Cross-Coupling of Aryl Halides with Alkyl Halides. J. Am.
Chem. Soc. 2010, 132, 920−921. (e) Yu, X.; Yang, T.; Wang, S.; Xu,
H.; Gong, H. Nickel-catalyzed reductive cross-coupling of unactivated
alkyl halides. Org. Lett. 2011, 13, 2138−2141. (f) Everson, D. A.;
Jones, B. A.; Weix, D. J. Replacing conventional carbon nucleophiles
with electrophiles: nickel-catalyzed reductive alkylation of aryl
H
https://dx.doi.org/10.1021/jacs.0c09922
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
bromides and chlorides. J. Am. Chem. Soc. 2012, 134, 6146−6159.
(g) Biswas, S.; Weix, D. J. Mechanism and selectivity in nickel-
catalyzed cross-electrophile coupling of aryl halides with alkyl halides.
J. Am. Chem. Soc. 2013, 135, 16192−16197. (h) Arendt, K. M.; Doyle,
A. G. Dialkyl ether formation by nickel-catalyzed cross-coupling of
acetals and aryl iodides. Angew. Chem., Int. Ed. 2015, 54, 9876−9880.
(i) Kadunce, N.; Reisman, S. E. Nickel-catalyzed asymmetric
reductive cross-coupling between heteroaryl iodides and α-chloroni-
triles. J. Am. Chem. Soc. 2015, 137, 10480−10483. (j) Wang, X.;
Wang, S.; Xue, W.; Gong, H. Nickel-catalyzed reductive coupling of
aryl bromides with tertiary alkyl halides. J. Am. Chem. Soc. 2015, 137,
11562−11565. (k) Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Intra- and
intermolecular nickel-catalyzed reductive cross-electrophile coupling
reactions of benzylic esters with aryl halides. Angew. Chem., Int. Ed.
2016, 55, 6730−6733.
(18) Huang, L.; Olivares, A. M.; Weix, D. J. Reductive
decarboxylative alkynylation of N-hydroxyphthalimide esters with
bromoalkynes. Angew. Chem., Int. Ed. 2017, 56, 11901−11905.
(19) Zhao, Y.; Truhlar, D. G. Density functionals with broad
applicability in chemistry. Acc. Chem. Res. 2008, 41, 157−167.
(20) (a) Pan, X.; Fang, C.; Fantin, M.; Malhotra, N.; So, W. Y.;
Peteanu, L. A.; Isse, A. A.; Gennaro, A.; Liu, P.; Matyjaszewski, K.
Mechanism of photoinduced metal-free atom transfer radical
polymerization: experimental and computational studies. J. Am.
Chem. Soc. 2016, 138, 2411−2425. (b) Yuan, M.; Song, Z.; Badir,
S. O.; Molander, G. A.; Gutierrez, O. On the nature of C(sp3)−
C(sp2) bond formation in nickel-catalyzed tertiary radical cross-
couplings: a case study of Ni/photoredox catalytic cross-coupling of
alkyl radicals and aryl halides. J. Am. Chem. Soc. 2020, 142, 7225−
7234. (c) Chen, J.; Xu, M.; Yu, S.; Xia, Y.; Lee, S. Nickel-catalyzed
claisen condensation reaction between two different amides. Org. Lett.
2020, 22, 2287−2292.
(21) (a) Saveant, J. M. A simple model for the kinetics of
dissociative electron transfer in polar solvents. Application to the
homogeneous and heterogeneous reduction of alkyl halides. J. Am.
Chem. Soc. 1987, 109, 6788−6795. (b) Fang, C.; Fantin, M.; Pan, X.;
de Fiebre, K.; Coote, M. L.; Matyjaszewski, K.; Liu, P. Mechanistically
guided predictive models for ligand and initiator effects in copper-
catalyzed atom transfer radical polymerization (Cu-ATRP). J. Am.
Chem. Soc. 2019, 141, 7486−7497. (c) Isse, A. A.; Gennaro, A.; Lin,
C. Y.; Hodgson, J. L.; Coote, M. L.; Guliashvili, T. Mechanism of
carbon-halogen bond reductive cleavage in activated alkyl halide
initiators relevant to living radical polymerization: theoretical and
experimental study. J. Am. Chem. Soc. 2011, 133, 6254−6264.
(d) Pan, X.; Fang, C.; Fantin, M.; Malhotra, N.; So, W. Y.; Peteanu, L.
A.; Isse, A. A.; Gennaro, A.; Liu, P.; Matyjaszewski, K. Mechanism of
photoinduced metal-free atom transfer radical polymerization:
experimental and computational studies. J. Am. Chem. Soc. 2016,
138, 2411−2425. (e) Morales-Rivera, C. A.; Floreancig, P. E.; Liu, P.
Predictive model for oxidative C−H bond functionalization reactivity
with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone. J. Am. Chem. Soc.
2017, 139, 17935−17944. (f) de Aguirre, A.; Funes-Ardoiz, I.;
Maseras, F. Four oxidation states in a single photoredox nickel-based
catalytic cycle: A computational study. Angew. Chem., Int. Ed. 2019,
58, 3898−3902.
(11) (a) García-Domínguez, A.; Li, Z.; Nevado, C. Nickel-catalyzed
reductive dicarbofunctionalization of alkenes. J. Am. Chem. Soc. 2017,
139, 6835−6838. (b) 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.
́
(c) Shu, W.; García-Domínguez, A.; Quiros, M. T.; Mondal, R.;
́
Cardenas, D. J.; Nevado, C. Ni-catalyzed reductive dicarbofunction-
alization of nonactivated alkenes: scope and mechanistic insights. J.
Am. Chem. Soc. 2019, 141, 13812−13821. (d) Yang, T.; Chen, X.;
Rao, W.; Koh, M. J. Broadly applicable directed catalytic reductive
difunctionalization of alkenyl carbonyl compounds. Chem. 2020, 6,
738−751. (e) Tu, H. Y.; Wang, F.; Huo, L. P.; Li, Y. B.; Zhu, S. Q.;
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. (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) Sun, S.;
Duan, Y.; Mega, R. S.; Somerville, R. J.; Martin, R. Site-selective 1,2-
dicarbofunctionalization of vinyl boronates through dual catalysis.
Angew. Chem., Int. Ed. 2020, 59, 4370−4374.
(12) (a) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang,
J.; Pan, C.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S.
Practical Ni-catalyzed aryl−alkyl cross-coupling of secondary redox-
active esters. J. Am. Chem. Soc. 2016, 138, 2174−2177. (b) Murarka,
S. N-(Acyloxy)phthalimides as redox-active esters in cross-coupling
reactions. Adv. Synth. Catal. 2018, 360, 1735−1753.
(22) (a) Lan, Y.; Wheeler, S. E.; Houk, K. N. Extraordinary
difference in reactivity of ozone (OOO) and sulfur dioxide (OSO): A
theoretical study. J. Chem. Theory Comput. 2011, 7, 2104−2111.
(b) Liu, S.; Lei, Y.; Qi, X.; Lan, Y. Reactivity for the Diels−Alder
reaction of cumulenes: A distortion-interaction analysis along the
reaction pathway. J. Phys. Chem. A 2014, 118, 2638−2645.
(13) (a) Fu, M.; Shang, R.; Zhao, B.; Wang, B.; Fu, Y. Photocatalytic
decarboxylative alkylations mediated by triphenylphosphine and
sodium iodide. Science 2019, 363, 1429−1434. (b) Tlahuext-Aca,
A.; Garza-Sanchez, R. A.; Glorius, F. Multicomponent oxyalkylation of
styrenes enabled by hydrogen bond-assisted photoinduced electron
transfer. Angew. Chem., Int. Ed. 2017, 56, 3708−3711. (c) Qin, T.;
Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.;
Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A general alkyl-alkyl
cross-coupling enabled by redox-active esters and alkylzinc reagents.
Science 2016, 352, 801−805. (d) Lu, X.; Wang, X.; Gong, T.; Pi, J.;
He, S.; Fu, Y. Nickel-catalyzed allylic defluorinative alkylation of
trifluoromethyl alkenes with reductive decarboxylation of redox-active
esters. Chem. Sci. 2019, 10, 809−814.
(23) Manolikakes, G.; Dong, Z. B.; Mayr, H.; Li, J. S.; Knochel, P.
Negishi cross-couplings compatible with unprotected amide func-
tions. Chem. - Eur. J. 2009, 15, 1324−1328.
(24) Haginaka, J.; Yasuda, H.; Uno, T.; Nakagawa, T. Alkaline
degradation and determination by high-performance liquid chroma-
tography. Chem. Pharm. Bull. 1984, 32, 2752−2758.
(25) Blankson, G. A.; Parhi, A. K.; Kaul, M.; Pilch, D. S.; LaVoie, E.
J. Advances in the structural studies of antibiotic potentiators against
Escherichia coli. Bioorg. Med. Chem. 2019, 27, 3254−3278.
(14) Huang, H. M.; Koy, M.; Serrano, E.; Pfluger, P. M.; Schwarz, J.
̈
(26) Yamauchi, S.; Shoji, Y.; Nishimoto, A.; Uzura, M.; Nishiwaki,
H.; Nishi, K.; Sugahara, T. Design of 92 new 9-norlignan derivatives
and their effect on cell viabilities of cancer and insect cells. J. Agric.
Food Chem. 2019, 67, 7880−7885.
L.; Glorius, F. Catalytic radical generation of π-allylpalladium
Complexes. Nat. Catal 2020, 3, 393−400.
(15) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic
catalysed cross-coupling of aryl bromides with aryl triflates. Nature
2015, 524, 454−457.
(27) (a) Beck, J. C.; Lacker, C. R.; Chapman, L. M.; Reisman, S. E.
A modular approach to prepare enantioenriched cyclobutanes:
synthesis of (+)-rumphellaone A. Chem. Sci. 2019, 10, 2315−2319.
(b) Shang, M.; Feu, K. S.; Vantourout, J. C.; Barton, L. M.; Osswald,
H. L.; Kato, N.; Gagaring, K.; McNamara, C. W.; Chen, G.; Hu, L.;
(16) Komeyama, K.; Michiyuki, T.; Osaka, I. Nickel/cobalt-
catalyzed C(sp3)−C(sp3) cross-coupling of alkyl halides with alkyl
tosylates. ACS Catal. 2019, 9, 9285−9291.
(17) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.;
Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.;
Ackerman, L. K. G.; Weix, D. J. Decarboxylative cross-electrophile
coupling of N-hydroxyphthalimide esters with aryl iodides. J. Am.
Chem. Soc. 2016, 138, 5016−5019.
́
Ni, S.; Fernandez-Canelas, P.; Chen, M.; Merchant, R. R.; Qin, T.;
Schreiber, S. L.; Melillo, B.; Yu, J.-Q.; Baran, P. S. Modular,
stereocontrolled Cβ−H/Cα−C activation of alkyl carboxylic acids.
Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 8721−8727.
I
https://dx.doi.org/10.1021/jacs.0c09922
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(28) (a) Geist, E.; Kirschning, A.; Schmidt, T. sp3-sp3 Coupling
reactions in the synthesis of natural products and biologically active
molecules. Nat. Prod. Rep. 2014, 31, 441−448. (b) Lovering, F.;
Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as
an approach to improving clinical success. J. Med. Chem. 2009, 52,
6752−6756.
J
https://dx.doi.org/10.1021/jacs.0c09922
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX