Low-Temperature Nickel-Catalyzed C?N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand

Article abstract of DOI:10.1002/anie.202103803

The transition-metal-catalyzed C?N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as ?50 °C), enantioselective Ni-catalyzed C?N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C₂-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.

Full text of DOI:10.1002/anie.202103803

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Accepted Article
Title: Low-Temperature Ni-Catalyzed C−N Cross-Coupling via Kinetic
Resolution Enabled by a Bulky yet Flexible, Chiral N-Heterocyclic
Carbene
Authors: Zi-Chao Wang, Pei-Pei Xie, Youjun Xu, Xin Hong, and Shi-
Liang Shi
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10.1002/anie.202103803
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RESEARCH ARTICLE
Low-Temperature Ni-Catalyzed C−N Cross-Coupling via Kinetic
Resolution Enabled by a Bulky yet Flexible, Chiral N-Heterocyclic
Carbene
Zi-Chao Wang [a, d], Pei-Pei Xie [b], Youjun Xu [d], Xin Hong *[b], Shi-Liang Shi *[a, c]
[a]
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
E-mail: shiliangshi@sioc.ac.cn
[b]
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou 310027, China
E-mail: hxchem@zju.edu.cn
[c]
[d]
School of Pharmacy, Fudan University, Shanghai 201203, China
School of Pharmaceutical Engineering and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical
University, Shenyang 110016, China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The transition-metal-catalyzed C−N cross-coupling has
revolutionized the construction of amines. Despite the innovations of
multiple generations of ligands to modulate the reactivity of the metal
center, ligands for the low-temperature enantioselective amination of
aryl halides remain a coveted target of catalyst engineering. Designs
that promote one elementary reaction often create bottlenecks at
other steps. We here report an unprecedented low-temperature (as
low as -50 ℃), enantioselective Ni-catalyzed C−N cross-coupling of
aryl chlorides with sterically hindered secondary amines via a kinetic
resolution process (s factor up to >300). A bulky yet flexible chiral N-
heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative
addition and reductive elimination with low barriers and control the
enantioselectivity. Computational studies indicate that the rotations of
multiple -bonds on the C2-symmetric chiral ligand adapt to the
changing needs of catalytic processes. We expect this design would
be widely applicable to diverse transition states to achieve other
challenging metal-catalyzed asymmetric cross-coupling reactions.
significant transformation is still high; a low-temperature (< 0 ℃)
metal-catalyzed C−N cross-coupling has not been reported.
Low-temperature C−N cross-coupling is highly attractive
because it represents a longstanding unmet challenge and serves
as a desired target for ligand design and development. It may
allow for good functional group compatibility, high levels of
enantiocontrol, and further mechanistic understanding. The
achievement of stereochemical control is particularly noteworthy,
as asymmetric variants of aryl amination have been rarely
reported10, although chiral amines are of high value found in a
wide array of research areas. Moreover, a strategy developed for
low-temperature amination would potentially enable other
challenging cross-couplings. The obstacle to developing low-
temperature amination is due to the intrinsic contradiction of
elementary catalytic steps of C−N cross-coupling, which also is a
common issue for cross-coupling chemistry as a whole.11 In
general, an electron-rich ligand needs small enough to facilitate
the metal-coordination, oxidative addition (OA), and
transmetalation (TM) steps, especially for sterically hindered
substrates, while a bulky ligand assists monoligation of metal and
promotes reductive elimination (RE).12 Thus, classical rigid
ligands often promote one elementary step at the cost of the
others. Consequently, the improvement in the overall kinetic
profile is usually modest, and favorable reactivity is only observed
for certain subclasses of substrates, necessitating the use of high
temperatures to achieve reasonable rates of catalyst turnover.
Furthermore, the requirement for bulky groups on ligands or
substrates to induce stereoselectivity further adds to the
challenge of achieving a favorable kinetic profile. Therefore, the
development of a general strategy to simultaneously facilitate the
three elementary steps of C−N cross-coupling, as well as to
achieve stereocontrol, is highly desirable yet remains elusive.
Introduction
Transition-metal-catalyzed C−N cross-coupling reactions serve
as a critical platform to prepare aniline derivatives, a common
structural element found in bioactive natural products, active
pharmaceutical agents, and advanced functional materials.1,2
Over the past few decades, the amination reactions have moved
forward through the iterative discovery and optimization of
multiple generations of ligands to tune the behavior of the metal
center.1,3 For example, the discovery of biarylphosphine ligands
by Buchwald3a and oxalic diamide ligands by Ma1d has remarkably
accelerated the evolution of Pd- and Cu-catalyzed aryl amination,
respectively (Figure 1A). Most of these reactions, however,
require elevated temperatures due to the respective rate-limiting
elementary steps. Alternatively, earth-abundant nickel4 has
emerged as a "spirited horse" for cross-coupling reactions
because of its unique reactivity towards less reactive
electrophiles.5-7 The reductive elimination of Ni(II)-amido
complexes have usually needed heat conditions.5 Several elegant
strategies, including rational ligand design,5,6 photo-induced
pathway,8 and electrochemically-driven method,9 have recently
been developed to enable more mild and efficient Ni-catalyzed
aryl aminations. However, despite tremendous progress in the
past decades, the reaction temperature for this historically
We felt that the identification of suitable bulky yet flexible chiral
NHC ligands would permit an elusive, general low-temperature
enantioselective C-N cross-coupling reaction.13,14 In 2003, Glorius
and coworkers first proposed a concept of "flexible steric bulk"
and developed tricyclic NHCs possessing three different
conformers that interconvert through cyclohexane chair-flips.15
These bulky but conformationally flexible NHC allow room-
temperature Suzuki-Miyaura coupling of sterically hindered aryl
chlorides through favoring three elementary steps.12a While the
"flexible steric bulk" strategy has been widely applied in ligand
1
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Results and Discussion
Table 1. Reaction Optimization
Figure 1. Metal-catalyzed C−N cross-couplings.
design for cross-coupling reactions, chiral ligands with a bulky yet
flexible property are rarely developed.14, 15c
In this regard, we have recently developed a family of sterically
demanding C2-symmetric chiral NHC, namely, ANIPE- and SIPE-
type ligands, and successfully applied them to various metal-
catalyzed asymmetric transformations.16 These reactions include
the first highly enantioselective chiral NHC-metal-catalyzed
Suzuki-Miyaura
cross-coupling,16c
C-H
activation,16d-f
hydrofunctionalization,16a-b and carbonyl addition16g. On the basis
of X-ray crystal structures of several metal/NHC complexes,16 we
were aware that the conformational flexibility of our ligands
through the rotation of single bonds might be applicable to flexible
docking of substrates and subsequent C–N bond formation. In
particular, we envisaged that the rotation of multiple C−C and
C−N single bonds on the flexible C2-symmetric chiral aniline
fragments on the ligands (Figure 1B) would make space to allow
for rapid OA and TM, especially for sterically hindered substrates;
the subsequent conformation recovery would promote the crucial
RE step. Notably, the presence of C2-symmetric chiral axes in the
NHCs renders them capable of excellent enantiocontrol ability
during the rotation events of catalysis processes. Herein, we
describe an unprecedented low-temperature (as low as -50 ℃),
highly enantioselective Ni-catalyzed C−N bond-forming kinetic
resolution of sterically hindered -branched secondary amines
with aryl chlorides to afford chiral amine products (Figure 1B).
Computational studies suggest that our bulky yet flexible chiral
NHC would drive low barriers for both OA and RE and control the
stereoselectivity. DFT calculations reveal that the rotations of
multiple -bonds on the C2-symmetric chiral NHC are leveraged
to enable the dynamic fit of catalyst pockets with substrates. We
expect this bulky yet flexible chiral NHC design based on -bond
rotations would be broadly applicable to adapt to distinct transition
states to promote many asymmetric metal-catalyzed cross-
coupling reactions.
a Calculated conversions (Conv.) and s factors were calculated from ee values,
Conv. = eeSM/(eeSM + eePR), s = ln[(1−C(1+eePR)] / ln[(1−C(1−eePR)]; b ee
values were determined by chiral HPLC analysis.
Reaction Optimization. Although the enzymatic kinetic
resolution and classical resolution by crystallization of chiral salts
are often used for chiral amine synthesis,17 kinetic resolution of
amines via a Ni-catalyzed N-arylation remains an elusive but
attractive strategy. We commenced our studies with a model
coupling reaction of 4-chlorobenzotrifluoride with racemic 2-
methyl-1,2,3,4-tetrahydroquinoline. After intensive investigation
of the reaction parameters, we found that the desired chiral
2
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Table 2. Substrate Scopea
aYields of isolated products on 0.2 mmol scale. Data are reported as isolated yield in parentheses and calculated conversion outside of parentheses; isolated yields
were determined by isolation after chromatographic purification; calculated conversions (C = eeSM/(eeSM + eePR)) and s factors were calculated from enantiomeric
excesses (ee) values, s = ln[(1− C(1+eePR)] / ln[(1−C(1−eePR)]; ee values were determined by chiral HPLC analysis.
3
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crystal X-ray diffraction. In addition to tetrahydroquinolines, other
cyclic amines including piperidine (4o), tetrahydroisoquinoline
(4p), and dihydrobenzoazepines (4q) also served as suitable
substrates, providing related products in good yields and
enantioselectivities. Furthermore, a 4-mmol-scale reaction was
successfully performed, delivering product 3a with similar
efficiency and selectivity (see SI for details). The chiral amine
architectures obtained by our protocol are all highly appealing,
given their prevalence in medicinally relevant compounds.20
N-arylated product 3a could be obtained in high conversion (43%
conv., the theoretical conversion is 50%) and excellent
enantioselectivity (92% ee) in the presence of a low loading of
Ni(cod)2 catalyst (1.5 mol%), an air-stable NHC precursor (L1/HCl,
1.5 mol%), and 1.0 equivalent of both LiOtBu and KOtBu in
cyclopentane at 0 oC for 24 h (Table 1, entry 1). Interestingly, the
large acenaphthoimidazolylidene framework of L1 (ANIPE) was
found to be necessary, as the use of less bulky ligands such as
L2 or L3 resulted in almost no conversions (entries 2-3). We
believe that the acenaphthyl backbone of L1 would buttress the
four 1-phenethyl groups on the NHC closer to the reactive center,
thus further accentuate the steric effect.16a,18 In addition, the
amount and ratio of LiOtBu and KOtBu (1/1) were crucial to
maintaining a nearly homogenous reaction mixture under low
temperatures (entries 4-7). Use of THF (entry 8) or toluene (entry
9) as solvent resulted in a lower s value. Conducting the reaction
Low Temperature Aryl Amination. An important
breakthrough of current enantioselective C−N cross-coupling is
its ability to run at very low temperatures. To demonstrate this
point, we conducted the amination reactions at -30 ℃, and even
-50
℃
(Table 2). We were able to couple a series of
tetrahydroquinolines with 4-CN-substituted aryl chlorides (5a-5e),
delivering products in good yields and enantioselectivities (76-
93% ee). Interestingly, the use of electronically similar but less
bulky NHC (L4, with 2,6-diisopropylaniline fragments) or more
hindered NHC (L5, with 2,6-dibenzhydrylaniline fragments)
instead of L1 both resulted in no desired conversions at -30 ℃.
We attribute the lack of reactivity to ineffective RE in L4 and
inefficient OA, TM, or coordination in the case of L5 due to
unfavorable steric environments at different catalysis stages. To
the best of our knowledge, this is the first time for a C(sp2)−N
cross-coupling reaction to run at such low temperature (< -30 ℃).
These facts indicate that elementary catalytic steps of this
challenging Ni-catalyzed C−N cross-coupling of aryl chlorides
with sterically hindered secondary amines are well-balanced,
highlighting the advantages of the suitable "flexible steric bulk" of
our chiral NHC ligand.
at 30 °C led to
a slightly higher yield but moderate
enantioselectivity (entry 11). We found that other commonly used
chiral NHC or phosphine ligands did not provide the product
(entries 12-14). Finally, control experiments revealed the critical
role of both nickel and L1 for this efficient amination reaction, as
no desired product was detected in the absence of either nickel
or NHC ligand (entry 15). It bears mentioning that a Ni-catalyzed
arylation of -branched secondary amines has previously
unexplored.19
Reaction Scope. With the optimized reaction conditions in
hand, we next set out to survey the generality of aryl chlorides for
this asymmetric amination protocol. As shown in Table 2,
electron-neutral and electron-deficient aryl chlorides were
successfully transformed into the corresponding chiral amines in
high yields and enantioselectivities (81-99.5% ee). Aryl chlorides
bearing a wide range of functional groups, such as trifluoromethyl
(3a) and trifluoromethoxy groups (3l), fluoride (3e), ethers (3f),
ketones (3g), esters (3h), amides (3i), sulfones (3j), and
sulfonamides (3k), were all well-tolerated under the reaction
conditions. Importantly, potentially deleterious oxidative additions
of nickel catalysts into ethers, ketones, esters, or amides were not
detectable, probably due to the mild reaction conditions.
Moreover, heteroaryl chlorides possessing quinolines (3m, 3n),
pyridines (3o), and benzoxazole (3p) were all competent coupling
partners. However, an electron-rich aryl chloride was found less
reactive under the mild reaction conditions, affording products in
moderate yield and high enantioselectivity (91% ee) (3f).
Computational studies. We next performed density functional
theory (DFT) calculations to investigate the origins of the high
reactivity of this unexpected low-temperature aryl amination. The
DFT-computed free energy profile of the overall catalytic cycle is
shown in Figure 2A. From the substrate-coordinated complex, OA
occurs smoothly with a low barrier of 8.9 kcal/mol. The ligand
exchange of OA intermediate 8 occurs through an association-
dissociation mechanism. The coordination of tetrahydroquinoline
anion is exergonic by 14.0 kcal/mol, generating the anionic
tetracoordinated species 9. Subsequent dissociation of chlorine
anion produces the pre-reductive elimination intermediate 10. The
subsequent rate-determining RE step proceeds with only a 14.7
kcal/mol barrier, consistent with the ability to carry out the reaction
under low-temperature conditions. The calculated free energy
profiles for the corresponding potassium or lithium cation
processes are found very close to that of the anionic pathway,
which confirmed the mechanistic information from the anionic
pathway (see SI, Figure S3-4). Besides, our computations
indicate that the Ni(I/III) mechanism has a high barrier for OA and
thus unlikely to occur (see SI, Figure S1).21
Subsequently, we examined the scope of amine coupling
components. An array of enantioenriched N-arylated
tetrahydroquinoline products with different substituents were
obtained in high to excellent yields and enantioselectivities (86-
99% ee) (4a-4n). Regardless of the presence of a methyl group
(4a-4e) or long aliphatic chains such as butyl, isobutyl, phenethyl
groups at the adjoining stereocenter (4f-4j), the products were
generated in high yields and enantioselectivities. Surprisingly, the
use of sterically demanding 2-aryl substituted tetrahydroquinoline
substrates (4l-4n) did not reduce the reaction efficacy but gave
increased s factor (up to >300, 4n); the unproductive reduction of
electrophiles through competitive -H elimination was not
observed. We attribute this success to a highly efficient and well-
controlled reductive elimination process. Besides, a tricyclic
amine with two adjacent stereocenters was successfully arylated
under the kinetic resolution condition (4k); the absolute
stereochemistry of the product 4k was determined by single-
We ascribe the low barrier of RE to the large steric hindrance
of L1. The low barrier of OA probably due to the conformational
flexibility and strong electron-donating ability of the ligand. We
calculated the buried volume (%V Buried)22 to quantify the
difference in steric encumbrance of L1 (with 2,6-
diphenethylaniline fragments) and L4' (with 2,6-diisopropylaniline
fragments) as shown in Figure 2B. L1 with a buried volume of
58.0 % is found far bulkier than (51.0 %V Buried) and thus
expected to undergo far more difficult OA step than the
electronically similar L4'. However, the OA barrier of catalyst
4
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10.1002/anie.202103803
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Figure 2. DFT calculations. (A) DFT-computed Gibbs free energies changes. (B) Comparisons of buried volume and OA barrier of L1 and L4' derived catalysts.
(C) Transition-state structures of the enantioselectivity-determining RE step.
5
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are found to rotate dramatically (from 124.9o to 64.7o; from 127.3o
to 105.6o). These rotations are clearly confirmed by comparisons
on the orientations of aniline fragments on the overlaid ligand
structures in the three key optimized transition states (i.e., before
OA (6), OA complex (8), before RE (10), Figure 3A). These
rotations are likely critical to accommodate each substrate to fit
the changing steric environments at various catalysis stages.
Furthermore, we quantified the dynamic change of ligand's buried
volume during the catalytic process.22 As shown in Figure 3B, the
ligand's buried volume decreases substantially during OA (from
58.0% (6) to 55.3% (TS7)) and TS (from 56.9% (8) to 50.6% (10))
processes, while increases in the course of RE (from 50.6% (10)
to 51.8% (TS11)). These results suggest that more space in the
binding pocket is induced by the ligand-substrate repulsions to
allow for rapid OA and TS processes. Subsequent conformation
recovery of the ligand makes the catalyst pocket getting smaller
to promote the RE process. Taken together, these computational
findings and experimental outcomes under low temperature
(Figure 2) are consistent with our initial hypothesis that our bulky
but flexible C2-symmetric chiral ligand through rotations of
multiple -bonds during the catalysis event would balance
operations to achieve an overall favorable kinetic profile, and
enable high levels of stereocontrol simultaneously.
derived from L1 (8.9 kcal/mol) is very close to L4' (8.7 kcal/mol).
These results suggest that the conformational flexibility of L1
compensates for the unfavorable steric effect in the OA step. In
addition, the RE barrier of catalyst derived from L4' is significantly
higher than L1 (16.7 kcal/mol vs. 14.7 kcal/mol), which indicates
the importance of ligand steric hindrance.
Further calculation verified that the amine coordination step is
reversible, and the RE step is the enantio-determining step (see
SI, Figure S2). To understand the origin of the high enantiocontrol,
we studied the RE transition states that produce both enantiomers
of amine products (Figure 2C). In (S)-TS11a and (R)-TS11b, the
methyl group of amine substrate is distal to the forming C−N bond,
while in (R)-TS11a and (S)-TS11b, the same methyl groups are
proximal to the forming C−N bonds. Due to the increased steric
repulsions, the latter two cases' free energies are less favorable
than (S)-TS11a by 3.6 and 6.4 kcal/mol. In (S)-TS11a, the
unfavorable repulsion between the phenyl group of phenethyl
moiety on L1 and the methyl group of amine substrate is avoided,
thereby leading to the preferential formation of the (S)-aminated
product 5a, with an activation free energy that is 5.7 kcal/mol
lower than that of the disfavored transition state (R)-TS11b.
Conclusion
In summary, we have developed an unprecedented low-
temperature asymmetric Ni-catalyzed C−N cross-coupling of aryl
chlorides with sterically hindered -branched secondary amines,
delivering chiral amine products in a highly selective kinetic
resolution manner. The key to the success of the transformation
is the use of our ANIPE, a bulky but flexible chiral NHC ligand, to
drive low barrier elementary catalytic steps and control the
enantioselectivity. More broad applications of these ligands in
other challenging yet important enantioselective cross-coupling
reactions are currently underway in our laboratory and will be
reported in due course.
60
Oxidative Addition
Transmetalation
Reductive Elimination
58
56
54
52
50
48
46
6
TS7
8
9
10
TS11
12
Acknowledgements
The authors thank Profs. Steve Buchwald (MIT) and Yiming Wang
(University of Pittsburgh) for helpful discussions. The authors are
grateful to the National Natural Science Foundation of China
(Grant No. 91856111, 21871288, 21690074, 21821002, S.-L.S.;
Grant No. 21702182, 21873081, XH), the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
No. XDB 20000000, S.-L.S.), and the Fundamental Research
Funds for the Central Universities (2019QNA3009, XH).
Figure 3. (A) Overlay of catalyst structures of involved intermediates. (B)
Change of buried volume of nickel catalyst throughout the catalytic cycle.
To demonstrate the proposed conformational flexibility of our
ligand through the rotation of single bonds, we calculated the
dihedron angle changes of aniline fragments during the catalysis
process (see SI, Figure S6-8). Substantial rotations of C−CPh
bonds of stereogenic centers and C−N bonds of the aniline group
are observed throughout the catalytic process. In particular, two
phenyl groups of phenylethyl moieties close to the nickel center
Keywords: low-temperature • asymmetric catalysis • C-N
coupling • NHC ligand • nickel
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10.1002/anie.202103803
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
An unprecedented low-temperature, asymmetric Ni-catalyzed C−N cross-coupling of sterically hindered secondary amines with aryl
chlorides via kinetic resolution is reported. A bulky yet flexible, chiral NHC ligand enables both low barrier oxidative addition and
reductive elimination and high levels of enantiocontrol. Computational studies indicate that multiple -bond rotations of the C2-
symmetric chiral NHC adapt to the changing needs of catalytic processes.
8
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