Nickel-Catalyzed 1,2-Carboamination of Alkenyl Alcohols

Article abstract of DOI:10.1021/jacs.1c07112

An alcohol-directed, nickel-catalyzed three-component umpolung carboamination of unactivated alkenes with aryl/alkenylboronic esters and electrophilic aminating reagents is reported. This transformation is enabled by specifically tailored O-(2,6-dimethoxybenzoyl)hydroxylamine electrophiles that suppress competitive processes, including undesired β-hydride elimination and transesterification between the alcohol substrate and electrophile. The reaction delivers the desired 1,2-carboaminated products with generally high regio- and syn-diastereoselectivity and exhibits a broad scope of coupling partners and alkenes, including complex natural products. Various mechanistic experiments and analysis of the stereochemical outcome with a cyclic alkene substrate, as confirmed by X-ray crystallographic analysis, support alcohol-directed syn-insertion of an organonickel(I) species.

Full text of DOI:10.1021/jacs.1c07112

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Nickel-Catalyzed 1,2-Carboamination of Alkenyl Alcohols
Taeho Kang, Nana Kim, Peter T. Cheng, Hao Zhang, Klement Foo, and Keary M. Engle*
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ABSTRACT: An alcohol-directed, nickel-catalyzed three-compo-
nent umpolung carboamination of unactivated alkenes with aryl/
alkenylboronic esters and electrophilic aminating reagents is
reported. This transformation is enabled by specifically tailored O-
(2,6-dimethoxybenzoyl)hydroxylamine electrophiles that suppress
competitive processes, including undesired β-hydride elimination
and transesterification between the alcohol substrate and electro-
phile. The reaction delivers the desired 1,2-carboaminated products with generally high regio- and syn-diastereoselectivity and
exhibits a broad scope of coupling partners and alkenes, including complex natural products. Various mechanistic experiments and
analysis of the stereochemical outcome with a cyclic alkene substrate, as confirmed by X-ray crystallographic analysis, support
alcohol-directed syn-insertion of an organonickel(I) species.
reactions using various mechanistic paradigms. Such trans-
formations have historically been fraught with issues, including
competitive two-component coupling, difficulty in controlling
regioselectivity, and formation of undesired side products that
arise from unstable alkylmetal or alkyl radical intermediates.
Thus, three-component carboamination has been limited to
conjugated alkenes,7,8 strained cyclopropenes,9 or alkenes
bearing directing auxiliary groups.10−12 For instance, in 2019
our lab developed a nickel-catalyzed umpolung 1,2-carboami-
nation that unites alkenes bearing the strongly coordinating 8-
aminoquinoline (AQ) directing auxiliary with electrophilic
aminating reagents and alkylzinc nucleophiles (Figure 1B).
Although this system offered high regio- and stereoselectivity,
the method has an intrinsic limitation in requiring two
additional steps for auxiliary installation and removal. In
addition, the use of air- and moisture-sensitive alkylzinc
reagents, which are less readily available compared with bench-
stable alternatives, also diminishes the synthetic flexibility and
practical utility of the method. Moreover, C(sp2) nucleophiles
showed poor reactivity under these conditions (a single
example, 27% yield), and thus the three-component carboami-
nation of unactivated alkenes with C(sp2) nucleophiles remains
an unresolved problem.
INTRODUCTION
■
Substituted aliphatic amines are substructures with essential
biological importance in medicines, agrochemicals, and natural
products.1 Thus, the invention of methods to prepare such
prized motifs from readily available starting materials in a
manner that is rapid, selective, and modular is a captivating
pursuit. In this context, alkene carboamination, in which a
nitrogen substituent and a carbon substituent are added across
a CC bond, has been actively pursued as a strategy with
great promise in organic synthesis (Figure 1A). Early
pioneering examples of alkene carboamination centered on
various two-component strategies. This includes use of
carbon/nitrogen functional groups tethered to the alkene of
interest. For example, Wolfe and others have developed
carboamination reactions using intramolecular azacyclization
of nitrogen-tethered alkenes under palladium, copper, or nickel
catalysis, which enables facile preparation of various azahetero-
cycles.2−4 Additionally, several groups independently demon-
strated heteroannulations in which alkenes are coupled with
bifunctional coupling partners using different transition metal
catalysts.5 Moreover, use of ambiphilic reagents possessing
activatable heteroatom−heteroatom bonds has also enabled
carboamination of electronically activated alkenes or 1,3-
dienes.6
Despite these remarkable achievements, two-component
alkene carboamination possesses inherent limitations in terms
of modularity and structural diversity since two of the three
putative reaction components must be colocalized on the same
molecule. Moreover, existing methods generally require use of
nonbasic amine coupling partners that are less likely to cause
catalyst poisoning, such as sulfonamides, amides, carbamates,
and anilines, which limits direct access to valuable aliphatic
amine products. To address these shortcomings, we and others
have endeavored to develop three-component carboamination
To invent a next-generation carboamination system that
overcomes these obstacles, we sought to employ common,
readily available alkene starting materials containing only
native chemical functionality in conjunction with bench-stable
Received: July 8, 2021
Published: August 20, 2021
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pendant alkene, interfering with the desired transformation.15
Moreover, many late transition metals are known to directly
oxidize alcohols to the corresponding aldehydes or ketones,16
which can then undergo functionalization at the carbonyl
group.17 For these reasons, seemingly straightforward exten-
sion of late-transition-metal-catalyzed alkene functionalization
reactions directed by protected amines or carbonyl groups18 to
alkenyl alcohol substrates is generally not possible without
introduction of a protecting group or directing auxiliary.19,20
Indeed, free-alcohol-directed alkene functionalizations have
generally been limited to oxophilic early transition metal
catalysts, with the most notable success being in epoxidation.21
Using stoichiometric titanium along with a catalytic chiral
ligand, Burns and co-workers have recently achieved three-
component dihalogenations and haloazidation reactions of
allylic alcohols.22 To the best of our knowledge, alcohol-
directed metal-catalyzed three-component alkene difunctional-
ization has not yet been demonstrated. Herein, we describe the
catalytic three-component coupling of alkenyl alcohols, various
aliphatic amine electrophiles, and organoboronic acids enabled
by the combined use of nickel catalysis and fine-tuned nitrogen
activating groups (Figure 1D).
RESULTS AND DISCUSSION
■
Optimization. We initiated our study with 3-buten-1-ol
(1a) as the model substrate, O-benzoyl hydroxylmorpholine
(2a) as an electrophilic aminating reagent,11,23 and Ni(cod)2 as
the precatalyst (Table 1). In place of air- and moisture-
sensitive organozinc nucleophiles, we opted for PhB(nep) as
the standard bench-stable nucleophilic coupling partner. After
initial exploratory screening, we were able to observe the
desired three-component conjunctive cross-coupling product
in 17% yield with t-BuOH as solvent and KOt-Bu as base. In
addition to the desired product, we detected three major side
products: (1) styrenyl alcohol product 4, likely arising from an
oxidative Heck pathway, (2) benzoyl ester product 5 from
transesterification between the starting material 1a and the
1
amine electrophile 2a, and (3) small amounts (5−10% by H
NMR) of the hydroarylation product of 1a, 4-phenylbutanol.
We envisioned that the yield of the desired 1,2-arylamination
product could be improved by suppressing the formation of
these side products through the use of sterically and
electronically tuned N−O reagents. Introducing a bulky O-
pivaloyl group on the hydoxylamine (2b) successfully inhibited
transesterification with the alcohol starting material and
increased the desired product yields, although the Heck
byproduct 4 was still present. Furthermore, we observed a
general trend that more electron-rich benzoyl groups on the
electrophile delivered higher yields of desired product (2c−
2e). On the basis of these two observations, we expected that
electron-donating groups at the ortho-positions of the electro-
phile would enhance the yield of the desired product by
suppressing undesired side product formation both sterically
and electronically. Interestingly, use of a sterically bulkier
mesityl group on the electrophile (2g) gave higher yields of
desired product along with only trace amounts of both side
products. In addition, more electron-donating substituents on
the benzoyl electrophiles (2h and 2i) further increased the
product yield. A control experiment with 2f, which has 2,6-
disubstitution but possesses electron-withdrawing fluorine
substituents, revealed the importance of both the substitution
pattern and electronic properties of the benzoyl activating
group. The 2,6-dimethoxybenzoyl activating group (as in 2h)
Figure 1. Summary of previous and current work.
coupling partners. Specifically, we were attracted to alkenyl
alcohol substrates because these bear the most common,
readily available, and synthetically versatile functional group,
the hydroxyl group. Employing a hydroxyl group as a directing
group in late-transition metal catalysis for reactions beyond
hydrogenation is challenging for a number of interrelated
reasons (Figure 1C). First, coordination of the hydroxyl group
with late-transition metals is relatively weak, meaning the
resultant alkylmetal intermediate may not form a rigid
metallacycle and may instead possess dynamic coordination
chemistry and conformational flexibility. This in turn opens the
possibility for β-H elimination resulting in chain-walking
processes, where the alcohol can serve as a redox terminating
group.13,14 In addition, the innate nucleophilicity of alcohols
(or metal alkoxides) can result in direct nucleophilic attack on
the electrophilic coupling partners or cyclization onto the
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Table 1. Optimization of Reactions
a
a
entry
variation from standard conditions (with 2h)
yield (3a)
yield (4 + 5)
b
1
2
3
4
5
6
7
8
PhB(OH)2 instead of PhB(nep)
PhB(pin) instead of PhB(nep)
rt/70 °C instead of 50 °C
5 mol %/25 mol % Ni(cod)2 instead of 15 mol %
KOH instead of KOt-Bu
LiOt-Bu/NaOt-Bu instead of KOt-Bu
2 equiv of KOt-Bu instead of 2.5 equiv of KOt-Bu
NiBr2·glyme (without glovebox) instead of Ni(cod)2
43% [66%]
33%
60%, 72%
72%, 71%
nd
70%, 82%
67%
79%
trace
trace
trace
trace
trace
trace
trace
trace
a
1
Percentages represent H NMR yields using 1,3,5-trimethoxybenzene as internal standard. See Supporting Information for details regarding
b
additional optimization tables. The yield in brackets was obtained using 2 equiv of NaOt-Bu instead of 2.5 equiv of KOt-Bu.
was ultimately selected for further study due to its comparative
ease of installation. Notably, the Buchwald group has
previously documented the benefits of using electron-rich
benzoyl activating groups for accelerating LnCuH regeneration
in copper-catalyzed umpolung alkene hydroamination.24 Our
data expand upon these earlier findings to encompass
alternative catalytic manifolds, demonstrating that precisely
tailored activating groups on the electrophile can not only
increase product yield but also allow for control of pathway
selectivity (i.e., product distribution) in a complex multi-
component nickel-catalyzed reaction system (vide infra).
The reaction was further evaluated under different
conditions. Corresponding PhB(OH)2 and PhB(pin) nucleo-
philes also delivered the desired product, albeit in lower yields
than standard PhB(nep) (entries 1 and 2). Lower (room
temperature) or higher temperature (70 °C) did not improve
the product yield (entry 3).
We found that lower catalyst loading (5 mol %) also gave an
excellent yield, but higher catalyst loading (25 mol %) did not
further increase the yield (entry 4). In addition, the weaker
base, potassium hydroxide, was found to be incompatible,
while tert-butoxide salts with varying countercations were
nearly equally effective (entries 5 and 6). Importantly, the
bench-stable precatalyst, NiBr2·glyme, could be used in place
of Ni(cod)2, allowing the reaction to be performed without an
inert atmosphere glovebox with only slightly diminished yield
(entry 8, see Supporting Information for additional details).
Nucleophile and Electrophile Scope. Having identified
the optimal reaction conditions, we next examined the scope of
nucleophilic coupling partners (Scheme 1). Arylboronic ester
nucleophiles bearing electron-donating substituents in the para
position reacted in excellent to good yields (3b−3d). In
addition, fluoro-, chloro, and protected amino substituents
were compatible under the reaction conditions (3e−3g). On
the other hand, arylboronic ester nucleophiles bearing
electron-withdrawing groups in the para position resulted in
lower yields, presumably due to less favorable migratory
insertion of the arylnickel species in these cases (3h−3j).
Several ortho- and meta-substituted aryl nucleophiles also gave
the desired product in moderate yields (3k−3p). Gratifyingly,
alkenylboronic ester nucleophiles worked well to yield
homologated alkenyl alcohol products with only slightly
lower yields than those of aryl nucleophiles (3q−3u). On
the other hand, alkyl-, highly electron-deficient aryl-, and
heterocycle-containing B(nep) coupling partners were in-
effective under the reaction conditions.
We next explored the nitrogen electrophile scope.
Pharmaceutically relevant six-membered azaheterocycles, in-
cluding piperidine, N-Boc-protected piperazine, and thiomor-
pholine-derived electrophiles, gave excellent to moderate yields
(3v−3x). Additionally, various substituted cyclic amines also
delivered the corresponding products in excellent to syntheti-
cally viable yields (3y−3ac). Notably, the piperidine in product
3z could be used as a primary amine surrogate through simple
deprotection, and a commercial drug (paroxetine) derived
electrophile was also compatible with the reaction conditions
(3ac). Moreover, five- and seven-membered cyclic amine
electrophiles were also successful, although with diminished
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b
Scheme 1. Nucleophile and Electrophile Scope
a
b
N,N-Diethyl-O-(2,4,6-trimethylbenzoyl)hydroxylamine was used as the electrophile. Reaction conditions: 1a (0.1 mmol), aryl/alkenylB(nep)
(0.2 mmol), N−O electrophile (0.2 mmol), KOt-Bu (0.25 mmol), Ni(cod)2 (0.015 mmol), t-BuOH (1 mL), 50 °C, 16 h. Percentages represent
1
isolated yields. Values in parentheses are H NMR yields using CH2Br2 as internal standard.
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c
Scheme 2. Alkene Scope
a
The value in brackets corresponds to 1H NMR yield from an experiment in which a second batch of the reagents and catalyst were added after 16
b
c
h. Fc = ferrocenyl; see Supporting Information for X-ray crystallography data. Reaction conditions: 1 (0.1 mmol), PhB(nep) (0.2 mmol), N−O
electrophile (0.2 mmol), KOt-Bu (0.25 mmol), Ni(cod)2 (0.015 mmol), t-BuOH (1 mL), 50 °C, 16 h. Percentages represent isolated yields.
yields (3ad−3ag). We also investigated the acyclic amine
scope and observed attenuated reactivity, especially for bulky
acyclic amine electrophiles. Indeed, using dimethylamine as
electrophile gave a moderate yield, but slightly bulkier
methylallylamine and diethylamine electrophiles showed low
yields (3ah−3aj). In addition, a secondary amine, N-Boc-
protected amine, imines, electron-deficient phthalimide, and
other heterocyclic electrophiles did not afford desired product
under the reaction conditions.
Alkene Scope. Next, we examined the scope of alkenyl
alcohols. The reaction performed well with allyl and bis-
homoallyl alcohols (3ak and 3al), demonstrating tolerance for
varying chain lengths. Additionally, secondary alcohols (3am−
3ao), tertiary alcohols (3ap), and phenol (3aq) were viable
native directing groups that deliver the desired products in
moderate to excellent yields. We then investigated disub-
stituted alkene substrates, which pose a formidable challenge
compared to terminal alkenes due to the sterically encumbered
nature of the migratory insertion step. A representative 1,1-
disubstituted alkene was compatible under the reaction
conditions (3as), and various 1,2-disubstituted alkenes also
delivered the corresponding products with excellent diaster-
eoselectivity, albeit in low yields (3at−3ba). The relative all-
cis-stereochemistry of 3ba was confirmed by single-crystal X-
ray diffraction, establishing unambiguously that the reaction is
syn-stereoselective and alcohol-directed. In addition to alkenyl
alcohol substrates, we demonstrated that our reaction is
compatible with sulfonamide directing groups,18i which can be
further deprotected and diversified to give interesting diamine
structures (3bb and 3bc). On the other hand, 5-hexen-1-ol,
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b
Scheme 3. Large-Scale Reaction and Synthetic Application
a
b
Linear step count from alkene substrate 1a, four steps total including N−O reagent synthesis. See Supporting Information for details regarding
scale and specific conditions.
b
Scheme 4. Mechanistic Investigations and Proposed Catalytic Cycle
a
b
Percentages represent 1H NMR yields using 1,3,5-trimethoxybenzene as internal standard. (A) Directing group control experiments. (B) Control
experiment with potential intermediate. (C) Radical clock experiment. (D) Substrate loading experiments and product-determining step. (E)
Proposed catalytic cycle. M = K, H, or free lone pair (overall anionic complex).
cyclopentenol, cyclohexenol, and several trisubstituted alkenes
were found to be ineffective substrates. Here it is worth noting
that all alkenyl alcohol substrates used in Scheme 2 were
obtained directly from commercial suppliers, illustrating the
widespread availability of this substrate class.
Large-Scale Reaction and Synthetic Application. To
illustrate the synthetic utility of this alcohol-directed 1,2-
carboamination reaction, we performed a large-scale reaction
and showcased several real-world applications preparing
bioactive molecules (Scheme 3). Indeed, the desired
carboaminated product 3v was successfully obtained on a 5
mmol scale from 3-buten-1-ol (1a) in good yield (Scheme 3A).
Additionally, two bioactive molecules in the literature were
successfully synthesized from the same homoallylic alcohol
using our method followed by functionalization of the versatile
hydroxyl group (Scheme 3B). First, the hydroxyl group of
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aminoalcohol 3a was triflated in situ and further reacted with
an amine nucleophile to give the desired SKP2 inhibitor 6 in
only two total steps.25 In addition, the TRPA1 agonist
precursor 7 was synthesized in two steps using the presented
1,2-arylamination followed by oxidation of the alcohol to the
carboxylic acid.26 These routes not only are step-economical
but also provide new divergent synthetic pathways that are
amenable toward rapid structural diversification of the
carboamination products for drug discovery.
Interestingly, we observed that the carboaminated (3a) to
hydroarylated (13) product ratio increased when the N−O
reagent concentration was increased, while alkene concen-
tration does not affect the product ratio (Schemes 4D, S1, and
S2). These data show that the N−O reagent, and not the
alkene, is involved in the product-determining step, which
provides support for pathway 1, the TM−MI−OA sequence.
On the basis of these experiments and literature precedents,
a plausible catalytic cycle is proposed in Scheme 4E.11,28,29
Here we propose a Ni(I)/Ni(III) catalytic cycle based on the
observed erosion of stereospecificity (3at, 3au, 3ax, and 3ay),
which may arise from a competitive process involving
reversible alkyl−Ni(III) homolysis to generate an alkyl radical
and Ni(II), followed by recombination.30 The proposed
catalytic cycle initiates with formation of an organonickel
species via transmetalation of the carbon nucleophile. Next,
alcohol-directed syn-1,2-migratory insertion occurs to afford a
putative alcohol-coordinated alkyl nickelacycle. This inter-
mediate then oxidatively adds to the electrophilic aminating
reagent, setting up the final carbon−nitrogen reductive
elimination step that delivers the 1,2-carboaminated product.
We next performed the late-stage difunctionalization of
complex natural products that contain allylic/homoallylic
alcohol moieties (Scheme 3C). Gratifyingly, linalool, sclareol,
allylestrenol, and altrenogest were successfully carboaminated
in good to excellent yields (3bd−3bg) without having to install
an additional directing auxiliary or any protecting groups.
Mechanistic Studies and Proposed Catalytic Cycle.
The high pathway selectivity of this three-component coupling
process and the importance of the tailored N−O electrophile
prompted us to investigate the reaction mechanism. To this
end, we first examined the importance of the alcohol directing
group through a series of control experiments. Notably, 4-
phenyl-1-butene (8) and a representative alkenyl ether (9),
both of which lack an alcohol directing group, did not result in
any product formation (Scheme 4A). Moreover, Heck or
hydroarylated products were not observed in either case,
signaling a significant role of the alcohol directing group in the
migratory insertion step. We next tested cinnamyl alcohol (10)
as a starting material, and in this case, we did not observe any
hydroaminated or carboaminated product, with unreacted 10
detected as the major component of the crude reaction mixture
(Scheme 4B). This result rules out a stepwise mechanism
consisting of oxidative Heck arylation followed by hydro-
amination of the resulting styrenyl intermediate. Finally, a
radical clock experiment using 1,6-heptadien-4-ol (11) was
performed to probe the generation of a carbon-centered radical
intermediate (Scheme 4C). Interestingly, acyclic carboami-
nated product 12 was observed as the major product, and no
evidence of the cyclized product was observed. This result is
consistent with a nonradical pathway or, alternatively, a radical
pathway involving a radical capture rate faster than that of the
radical cyclization step (>105 M−1 s−1).27
With a general picture of the mechanism established, we
next considered all of the different possible orders in which the
three key elementary steps (TM, transmetalation; OA,
oxidative addition; MI, migratory insertion) could take place
prior to C−N reductive elimination (see Supporting
Information for details). The three most plausible pathways
are (1) TM−MI−OA, (2) OA−TM−MI, and (3) TM−OA−
MI. To evaluate the viability of these possible sequences, we
analyzed the ratio of carboaminated product (3a) to
hydroarylated side product (13), the latter of which was
obtained in 6% yield under the standard conditions, as a
function of reagent concentrations. In a sequence in which MI
precedes OA, both the desired product (3a) and hydroarylated
product (13) would be generated from a common alkylnickel-
(I) intermediate (14); in this case the product ratio should be
determined by the relative rates of bimolecular oxidative
addition versus protodemetalation (both of which are expected
to be irreversible)28 and should thus be dependent on the
concentration of the N−O reagent. In an alternative OA-first
mechanism, the thusly generated alkylnickel(III) intermediate
would already bear the amido ligand, and the product ratio
should be independent of the N−O reagent concentration.
CONCLUSIONS
■
In summary, we have demonstrated an alcohol-directed, nickel-
catalyzed three-component 1,2-carboamination of unactivated
alkenes. Sterically and electronically modulated O-(2,6-
dimethoxybenzoyl)hydroxylamine electrophiles are critical in
enabling productive three-component coupling and minimiz-
ing undesired pathways. This method tolerates various aryl/
alkenylboronate nucleophiles and amine electrophiles as
coupling partners, with the nucleophile scope complementing
previous amide-directed methodology from our group that
employs alkylzinc reagents.11 In addition, diverse alkene
substrates, including alkenyl alcohols of varying chain lengths,
secondary alcohols, tertiary alcohols, disubstituted alkenes,
natural products, and sulfonamide-protected alkenylamines,
react to furnish the corresponding 1,2-carboaminated products
with high regio- and diastereoselectivity. On the basis of the
all-cis-conformation of cyclopentene-derived product 3ba and
the results of various control experiments, hydroxyl groups
were shown to function as directing groups for the nickel
catalyst, thereby controlling chemo- and regioselectivity.
Finally, a gram-scale reaction and applications to construct
bioactive compounds exemplify the synthetic utility of this
alcohol-directed alkene 1,2-carboamination.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge on the
ACS Publications Web site. The Supporting Information is
available free of charge at https://pubs.acs.org/doi/10.1021/
jacs.1c07112.
Experimental details, NMR, X-ray, and other data (PDF)
NMR data in MNova format (ZIP)
Accession Codes
CCDC 2061172 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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(4) Yang, H.-B.; Pathipati, S. R.; Selander, N. Nickel-Catalyzed 1,2-
Aminoarylation of Oxime Ester-Tethered Alkenes with Boronic Acids.
ACS Catal. 2017, 7, 8441−8445.
AUTHOR INFORMATION
■
Corresponding Author
Keary M. Engle − Department of Chemistry, Scripps Research,
La Jolla, California 92037, United States; orcid.org/
0000-0003-2767-6556; Email: keary@scripps.edu
(5) (a) Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.; Rovis,
T. Expedient Access to 2,3-Dihydropyridines from Unsaturated
Oximes by Rh(III)-Catalyzed C−H Activation. J. Am. Chem. Soc.
2015, 137, 8892−8895. (b) Tasker, S. Z.; Jamison, T. F. Highly
Regioselective Indoline Synthesis under Nickel/Photoredox Dual
Catalysis. J. Am. Chem. Soc. 2015, 137, 9531−9534. (c) Zhao, D.;
Vásquez-Céspedes, S.; Glorius, F. Rhodium(III)-Catalyzed Cyclative
Capture Approach to Diverse 1-Aminoindoline Derivatives at Room
Temperature. Angew. Chem., Int. Ed. 2015, 54, 1657−1661. (d) Lee,
S.; Semakul, N.; Rovis, T. Direct Regio- and Diastereoselective
Synthesis of δ-Lactams from Acrylamides and Unactivated Alkenes
Initiated by RhIII-Catalyzed C−H Activation. Angew. Chem., Int. Ed.
2020, 59, 4965−4969. (e) Ni, H.-Q.; Kevlishvili, I.; Bedekar, P. G.;
Barber, J. S.; Yang, S.; Tran-Dubé, M.; Romine, A. M.; Lu, H.-X.;
McAlpine, I. J.; Liu, P.; Engle, K. M. Anti-Selective [3+2]
(Hetero)annulation of Non-Conjugated Alkenes via Directed
Nucleopalladation. Nat. Commun. 2020, 11, 6432.
Authors
Taeho Kang − Department of Chemistry, Scripps Research, La
Jolla, California 92037, United States
Nana Kim − Department of Chemistry, Scripps Research, La
Jolla, California 92037, United States
Peter T. Cheng − Discovery Chemistry, Bristol Myers Squibb
Research & Early Development, Princeton, New Jersey
08543, United States; orcid.org/0000-0002-6289-8341
Hao Zhang − Discovery Chemistry, Bristol Myers Squibb
Research & Early Development, Princeton, New Jersey
08543, United States
Klement Foo − Discovery Chemistry, Bristol Myers Squibb
Research & Early Development, Princeton, New Jersey
08543, United States
(6) (a) Piou, T.; Rovis, T. Rhodium-Catalysed syn-Carboamination
of Alkenes via a Transient Directing Group. Nature 2015, 527, 86−90.
(b) Huang, H.-M.; Koy, M.; Serrano, E.; Pfluger, P. M.; Schwarz, J. L.;
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c07112
Glorius, F. Catalytic Radical Generation of π-Allylpalladium
Complexes. Nat. Catal. 2020, 3, 393−400.
(7) Jiang, H.; Studer, A. Intermolecular Radical Carboamination of
Alkenes. Chem. Soc. Rev. 2020, 49, 1790−1811.
Notes
The authors declare no competing financial interest.
(8) (a) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.; Li, J.-H.
Oxidative 1,2-Carboamination of Alkenes with Alkyl Nitriles and
Amines toward γ-Amino Alkyl Nitriles. Nat. Commun. 2017, 8, 14720.
(b) Wang, D.; Wu, L.; Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G.
Asymmetric Copper-Catalyzed Intermolecular Aminoarylation of
Styrenes: Efficient Access to Optical 2,2-Diarylethylamines. J. Am.
Chem. Soc. 2017, 139, 6811−6814. (c) Pinkert, T.; Wegner, T.;
Mondal, S.; Glorius, F. Intermolecular 1,4-Carboamination of
Conjugated Dienes Enabled by Cp*RhIII-Catalyzed C-H Activation.
Angew. Chem., Int. Ed. 2019, 58, 15041−15045. (d) Xiong, Y.; Ma, X.;
Zhang, G. Copper-Catalyzed Intermolecular Carboamination of
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(e) Kennedy-Ellis, J. J.; Boldt, E. D.; Chemler, S. R. Synthesis of
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ACKNOWLEDGMENTS
■
This work was financially supported by Bristol Myers Squibb,
the National Science Foundation (Grant CHE-1800280), and
the Camille Dreyfus Teacher-Scholar Program. We further
acknowledge the Kwanjeong Educational Foundation for a
Graduate Fellowship (T.K.). We thank Dr. Milan Gembicky
(USCD) for assistance with X-ray crystallographic analysis. Dr.
Jason Chen, Brittany Sanchez, and Emily Sturgell (Scripps
Research Automated Synthesis Facility) are acknowledged for
HRMS analysis. We further thank Omar Apolinar, Van T.
Tran, and Camille Z. Rubel for detailed proofreading of this
manuscript and the Supporting Information and Dr. Joseph
Derosa (Caltech) for helpful discussions.
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