Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands

Article abstract of DOI:10.1021/jacs.0c09839

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

Full text of DOI:10.1021/jacs.0c09839

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Article
Enantioselective C−H Amination Catalyzed by Nickel Iminyl
Complexes Supported by Anionic Bisoxazoline (BOX) Ligands
Yuyang Dong, Colton J. Lund, Gerard J. Porter, Ryan M. Clarke, Shao-Liang Zheng, Thomas R. Cundari,
and Theodore A. Betley*
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ABSTRACT: The trityl-substituted bisoxazoline (TrHBOX) was
prepared as a chiral analogue to a previously reported nickel dipyrrin
system capable of ring-closing amination catalysis. Ligand metalation
with divalent NiI2(py)4 followed by potassium graphite reduction
afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4
equiv of a benzene solution of 1-adamantylazide to 4 generated the
tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct
(
TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray
crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its
dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C−H bond amination to afford N-heterocyclic products
from 4-aryl-2-methyl-2-azidopentanes. Catalytic C−H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and
provides pyrrolidine products in decent yield (29%−87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution
on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted
using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 0.03) suggests an H-atom abstraction
step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate
concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom
abstraction and radical recombination steps due to the comparable rate between radical rotation and C−N bond formation.
Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the
preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by
theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines
is demonstrated with good yield (50−78%) and moderate ee (up to 79%).
catalysts that template the C−H bond activation followed by a
C−N bond forming step. Several groups have contributed to
developing this method using different catalytic systems,
including iron/cobalt porphyrins,22−24 cobalt corroles,25 iron
bound within redox-active pincer ligands,26 and iron beta-
diketiminate metal organic frameworks (Figure 1).27 Never-
theless, little progress has been made toward the enantiose-
lective synthesis of these 5-membered N-heterocycles using such
approaches. To the best of our knowledge, only two reported
systems have demonstrated enantioselective pyrrolidine syn-
thesis via nitrene insertion catalysis.24,28 A chiral Co(II)
porphyrin converts linear alkyl azides to pyrrolidines in low
overall yields (22%) and moderate enantiomeric excess (ee,
46%),24 whereas a dual catalytic system comprising of a chiral-
1. INTRODUCTION
Selective amination of C−H bonds remains one of the most
challenging objectives in organic synthesis due to the ubiquity of
saturated N-heterocycles in bioactive alkaloids,1 pharmaceutical
agents,2,3 and as chiral elements in enantioselective catalysis.4
Asymmetric pyrrolidine motifs, in particular, are common
building blocks for numerous bioactive materials.2,5,6 Chiral
amine heterocycles traditionally are accessed by four methods:
(1) selective deprotonation facilitated by chiral auxiliaries-
bound base, followed by transmetalation mediated C−C bond
formation;7,8 (2) asymmetric addition to Ellman’s aldimines;9,10
(3) enantioselective catalytic hydroamination;11 and (4)
enantioselective chemical or enzymatic imine hydrogena-
tion.12−18 An alternative to this method could entail direct,
enantioselective C−H bond amination cyclization. Transition
metal mediated nitrene transfer methods have emerged as a
viable path for amination catalysis, providing atom economical
access to substituted pyrrolidine products from simple aliphatic
azide substrates.19−21
Received: September 14, 2020
Published: January 4, 2021
The current state of the art method in pyrrolidine synthesis via
C−H bond amination largely depends on late transition metal
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are enantiodetermining,45 providing the unique opportunity to
synthesize asymmetric, fully substituted 2,5-bis-tertiary pyrroli-
dines that are otherwise difficult to access.
2. RESULTS AND DISCUSSION
2.1. Preparation of a Ni(I) Synthon Supported by a
Novel Monoanionic Bisoxazoline Ligand. Bisoxazoline
ligands have been successfully employed in numerous
enantioselective catalytic transformations, including hydro-
genation, carbenoid cyclopropanation, nitrenoid aziridination,
Michael addition, Nazarov cyclization, aldol-type, Mannich-
type, Diels−Alder, and ene reactions.44,46−48 In all instances,
transition metals are supported by neutral BOX ligands. To
simulate the electronic features of dipyrrinato ligands, however,
we set out to prepare a monoanionic BOX ligand instead.49 To
the best of our knowledge, few studies on monoanionic BOX
scaffolds have been reported, most of which make use of a meso-
cyano group to increase the ligand meso-H acidity and stabilize
the monoanionic form.49−51 To expand upon this series, BOX
ligands prepared52,53 from commercially available or synthetic54
enantiopure substituted 2-aminoethanols (1a−c) were depro-
tonated using potassium hydride49 to cleanly afford the
corresponding monoanionic BOX ligands (2a-c) at ambient
temperature (25 °C, Scheme 1).
Figure 1. Pyrrolidine synthesis via cyclization C−H amination using
base metal catalysts.
at-metal Ru complex and a phosphine achieves excellent
enantioselectivity (up to 99% ee), albeit with relatively low
product yields (15−57%).28 Considering the need for a precious
metal in the latter system, as well as the requirement for product
sequestration with tert-butyloxycarbonyl (Boc) to increase the
turnover numbers for either catalyst, more sustainable and atom-
economical alternatives are of interest. To overcome these
limitations, it is thus critical to understand the nature and
reactivity profile of key reactive intermediates implicated in
transition metal mediated C−H amination processes.24,29−40
We recently reported a dipyrrin-supported Ni(I) system that
catalyzes conversion of unactivated, alkyl azides into pyrroli-
dines in high yield, at low catalyst loadings, and without
requiring product sequestration.41 Additionally, a Ni(II)-iminyl
species (i.e., NiII(2NR)) was isolated and identified as the
species responsible for the C−H activation event.33 To take
advantage of the efficiency of this system, we explored ways to
induce enantioselective pyrrolidine formation. To this end, it
was reasoned that deprotonated bisoxazoline ligands (BOX) are
structurally and electronically similar to the weak-field dipyrrin
platform,42,43 yet more sterically enforcing and offer access to a
chiral environment around the Ni center.44 Specifically, we
sought to address the following questions: (1) can we access
BOX-Ni nitrene moieties akin to those isolated with the dipyrrin
platform? If so, (2) how is the electronic structure of such
species impacted by the BOX ligand? (3) Can these BOX-Ni
complexes aminate C−H bonds and impart enantioselectivity?
And (4) what is the mechanism through which the asymmetrical
formation of product is enforced?
Scheme 1
Following previously reported protocols for preparing the
dipyrrinato-supported Ni(I) precatalyst ((AdFL)Ni(py); AdFL:
1,9-di(1−4 adamantyl)-5-perfluorophenyldipyrrin),33 dropwise
addition of a THF-solution of variants of 2 to a frozen
suspension of NiI2(py)4 in THF resulted in an instantaneous
color change from light yellow to dark red. The 1H NMR spectra
of the crude reaction mixtures showed total consumption of the
deprotonated ligands 2 with clean conversion to new para-
magnetic products. Crystals of each product were obtained by
layering hexanes onto a concentrated solution of the material in
benzene at room temperature. Single-crystal X-ray diffraction
analysis revealed that bis-substitution (L2M) is thermodynami-
cally favored for ligands with phenyl or tert-butyl substituents
(2b−c), preventing access to the Ni complex of interest.
However, the enhanced steric protection of trityl substituents
(
TrHBOX−, 2a) inhibits bis-substitution and enables isolation of
a dark-red, pseudo tetrahedral pyridine-bound complex
(
TrHBOX)NiI(py) (3, Scheme 2, Figure 2a). Complex 3 displays
1
Herein, we report the synthesis and characterization of a
BOX-supported Ni(I) synthon, which can be readily converted
to a Ni nitrenoid upon exposure to organic azides.33 The
electronic structure of the resulting metal nitrenoid is best
described as a Ni(II) iminyl radical akin to its dipyrrinato
congeners. The Ni(I) complex is an effective catalyst for
enantioselective C−H amination with decent yields (29−87%)
and moderate ee (as high as 73%). A comprehensive mechanistic
investigation corroborated by theoretical calculations indicates
that both H-atom abstraction and radical recombination steps
a paramagnetically shifted H NMR spectrum, indicative of a
triplet (S = 1) ground state.33
Chemical reduction of 3 with KC8 in a frozen-thawing THF
solution cleanly generates the Ni(I) pyridine adduct (TrHBOX)-
Ni(py) (4, Scheme 3 and Figure 2b) as a dark yellow solid. The
EPR spectrum of 4 collected at 77 K in toluene indicates a
doublet spin ground state (S = 1/2) in a rhombic environment
(g1 = 2.43, g2 = 2.13, g3 = 2.07; Figure 2c).56 Layering hexanes on
a concentrated benzene solution of 4 at room temperature
overnight afforded needle-shaped yellow crystals suitable for
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Scheme 2
Scheme 3
Scheme 4
single-crystal X-ray diffraction analysis. The solid-state structure
of 4 (Figure 2b) reveals an unusual pyramidally distorted, T-
shape geometry around the Ni(I) center with the NL−Ni−Npy
angle of 146.4(2)°, akin to the previously reported three-
coordinated Ni(I) dipyrrinato and β-diketiminate com-
plexes.33,57 Complex 4 decomposes instantaneously upon
exposure to air; however, it is stable at room temperature in
the solid state for a month under a nitrogen atmosphere,
showing only a trace amount of decomposition as indicated by
NMR and EPR spectroscopies.
occupying a rhombic environment (g1 = 2.33, g2 = 2.17, g3 =
2.01; Figure 3b).
2.2. Isolation and Structural Characterization of a BOX
Supported Terminal Iminyl Complex. With a well-
characterized Ni(I) synthon in hand, we next sought to probe
the general reactivity of 4 with azides and compare the electronic
nature of the resulting Ni-nitrenoid species with its dipyrrinato
congeners.33 Treatment of 4 with 1.4 equiv of AdN3 in benzene
resulted in a slow color change from dark yellow to dark orange
along with effervescence over 12 h. The EPR spectrum of the
resulting mixture revealed disappearance of 4 along with
formation of two new S = 1/2 paramagnetic species (Scheme
4). Fortunately, one of the species is only marginally soluble in
diethyl ether, enabling the two species to be separated. Indeed,
the orange residue following diethyl ether extraction can be
recrystallized by layering hexanes on a concentrated THF
solution. After standing at room temperature overnight, long
needle-shaped dark orange crystals suitable for single-crystal X-
ray diffraction were obtained to reveal a tetrazido complex
The second species formed upon addition of AdN3 to 4 can be
recrystallized from a concentrated THF solution slowly through
vapor-diffusion with hexanes at −35 °C to afford dark green
plate-shaped crystals suitable for single-crystal X-ray diffraction.
The solid-state structure of the product reveals a terminal iminyl
adduct, (TrHBOX)Ni(NAd) (6, Scheme 4 and Figure 3c) with a
Ni−Nim bond length of 1.680(8) Å, similar to those reported for
both dipyrrinato- and β-diketiminate-supported nickel nitrenoid
adducts.32,33,57 Two different molecules of 6 are found in the
asymmetric unit and display significantly different Ni−Nim−C
bond angles [139.5(7)° and 152.8(8)°], potentially due to
crystal packing effects. The local geometry at nickel is close to
planar [∑ N−Ni−N (avg) = 355.6°], consistent with previously
reported three-coordinate Ni nitrenoid species.33,57−61
2.3. Electronic Structure Considerations of Ancillary
Ligands. With the isolation of terminal iminyl 6, we sought to
compare the electronic effects of BOX ligand 2a to dipyrrin
(
TrHBOX)Ni(κ2-N4Ad2) (5, Scheme 4 and Figure 3a). The
(
AdFL) on the bound Ni center. In our previous studies with Ni-
solid-state molecular structure of 5 (Figure 3a) resembles those
of previously published tetrazido complexes supported by
dipyrrinato ligands.37,39 The N1−N2, N2−N3, and N3−N4
bond lengths of 1.300(4), 1.348(4), and 1.302(4) Å,
respectively (Figure 3a) fall between typical N−N single and
double bonds, suggesting a monoanionic tetrazido radical
formulation.37,39 The EPR spectrum of 5 collected at 77 K in
toluene indicates an S = 1/2 spin state with the unpaired electron
dipyrrinato system, we discovered that the amount of radical
density on the nitrenoid nitrogen atom was critical to effecting
H-atom abstraction (HAA).34,35,41,57 From a molecular orbital
perspective, the unpaired electron resides in a singly occupied
molecular orbital (SOMO) with contributions from both the
metal 3dxz and nitrogen 2px orbitals (Figure 4a); therefore, a
SOMO with lower energy would delocalize more unpaired
electron density onto the nitrenoid nitrogen due to smaller
Figure 2. Solid-state molecular structure for (a) (TrHBOX)NiI(py) (3) and (b) (TrHBOX)Ni(py) (4) with thermal ellipsoids at 50% probability level.
Color scheme: Ni, pink; N, blue; C, gray; O, red; I, purple. H atoms (except for the ones on chiral centers and meso carbon) and solvent molecules
omitted for clarity. (c) Frozen solution EPR spectrum of (TrHBOX)Ni(py) (4) collected at 77 K in toluene (red). Blue line represents a fit of the data
using the program EasySpin.55 Fitting parameters: S = 1/2, g1 = 2.43, g2 = 2.13, g3 = 2.07.
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Figure 3. Solid-state molecular structure for (a) (TrHBOX)Ni(κ2-N4Ad2) (5) and (c) (TrHBOX)Ni(NAd) (6) with thermal ellipsoids at 50%
probability level. Color scheme: Ni, pink; N, blue; C, gray; O, red. H atoms (except for the ones on chiral centers and meso carbon) omitted for clarity.
(b) Frozen solution EPR spectrum of (TrHBOX)Ni(κ2-N4Ad2) (5) collected at 77 K in toluene (red). Blue line represents a fit of the data using the
program EasySpin.55 Fitting parameters: S = 1/2, g1 = 2.33, g2 = 2.17, g3 = 2.01. (d) Frozen solution EPR spectrum of (TrHBOX)Ni(NAd) (6) collected
at 77 K in toluene (red). Blue line represents a fit of the data using the program EasySpin.55 Fitting parameters: S = 1/2, g1 = 2.19, g2 = 2.06, g3 = 1.93
with hyperfine splitting constant, A = 20.9 G (14N, I = 1).
Figure 4. (a) Molecular orbital picture of (LX)Ni(NR); SOMO plot for (b) (TrHBOX)Ni(NAd) and (c) (AdFL)Ni(NAd) from geometry optimized
DFT calculations. Nitrogen 2px and nickel 3dxz contributions toward SOMO are listed. uB3LYP/def2-TZVP(Ni,N,O)+def2-SVP(C,H).
energy gap with N-valence shell. The σ-donation ability of the
bidentate ancillary ligand impacts the metal dyz orbital, whereas
the dxz orbital is of appropriate symmetry to participate in π-
interactions with the ligand and raises energy of the SOMO. The
most notable difference between the two ligand platforms arises
from the greater π-donor ability of BOX that is attenuated in the
dipyrrin (AdFL) owing to its extended π-delocalization.34,42 Due
to the structural similarities between terminal iminyls supported
by these ligand platforms (6, (AdFL)Ni(NAd)), the amount of
radical density delocalized onto the nitrenoid nitrogen can be
crudely correlated with the observed 14N hyperfine splitting
constants. The EPR spectrum of 6 collected at 77 K in toluene
revealed an S = 1/2 spin ground state with a rhombic
environment for the unpaired electron (g1 = 2.19, g2 = 2.06, g3
= 1.93; Figure 3d) and an 14N hyperfine splitting constant of
20.9 G (14N, I = 1), similar to those reported for (AdFL)Ni(NAd)
(AN = 21.3 G).33 Previous N K-edge X-ray absorption studies for
and Ahlrich’s def2-SVP (C, H, F) and def2-TZVP (Ni, N, O)
basis sets.66,67 Indeed, the SOMO of 6 has only marginally
smaller contribution from the nitrogen 2px orbital as compared
to (AdFL)Ni(NAd) (Figure 4b,c), 52.0 vs 55.3%, revealing
minimal impact of the π-donating ability of BOX ligand on the
spin distribution and energy of SOMOs.33
2.4. Enantioselective Ring-Closing Amination Catal-
ysis Using 4. Having established the similar ligand strength of
dipyrrinato and anionic BOX platforms, we next sought to
examine the catalytic efficacy of 4 for pyrrolidine formation via
C−H amination. As the 1H NMR spectra of both 5 and 6 show
very few, indiscernible broad features, a pentafluorophenyl
group was introduced at the meso position of the ligand to
monitor the identity of metal containing species during catalysis
via 19F NMR spectroscopy.33,41,42 Treatment of monoanionic 2a
with five equivalence of hexafluorobenzene in THF and heating
at 95 °C for 12 h afforded the perfluorophenyl-substituted BOX
ligand with concomitant production of a stoichiometric
equivalent of KF as evidenced by 1H and 19F NMR
spectroscopies (TrFBOX−, 2d; Scheme 5). The corresponding
Ni precatalyst 4F was prepared using the same procedure as
outlined for 4 (Scheme 5). The 19F NMR spectrum of 4F
displays three features (Figure S8), indicating rapid rotation of
the perfluorophenyl group on the NMR time scale.33,41,42 We
note that the reactivity results in the following discussion were
the same regardless of catalyst (i.e., 4 or 4F).
(
AdFL)Ni(NAd) identified a low-energy, pre-edge absorption,
suggesting a NiII(2NAd−) formulation (i.e., iminyl radical anion
as opposed to imido, NiIII(NAd2−)).33 Although the corre-
sponding data is not available for 6, a similar electronic structure
is proposed herein in light of the similarity between their
structural and electronic properties observed spectroscopically.
To further probe the frontier molecular orbital structure of these
iminyl complexes, geometry optimizations of 6 and (AdFL)Ni-
(NAd) were conducted to produce coordinates from which to
carry out electronic structure calculations. The complete
structures for both complexes were optimized using the
unrestricted Kohn−Sham methods, B3LYP functional62−65
As an initial test, 10 mol % of 4F was subjected to (4-azido-4-
methylpentyl)fluorobenzene (7) in C6D6 (Table 1, entry 1).
Tertiary azides were used to inhibit the unproductive α-H
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With the identified optimized reaction conditions, we next
sought to examine the enantio-inducing effect of the chiral BOX
ligand. A 28% ee was determined by condensing 8 with (S)-
(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (S-
Mosher acyl chloride) and integration of representative peaks
in both 1H and 19F NMR spectra.41,68−71 Lowering the reaction
temperature to 40 °C (entry 4) increases the ee for 8 to 33%,
albeit at longer reaction times (72 h) and lower yield (22%) due
to catalyst decomposition. The catalysis can also be carried out
in either toluene or THF (Table 1, entries 6 and 7) with
comparable results, but diethyl ether or hexanes are not suitable
solvents due to low catalyst solubility. Additionally, catalyst 4F
reacts with DCM to generate (TrFBOX)NiCl(py) through
halogen atom abstraction, akin to the Ni-dipyrrin system.33,41
To systematically probe the effect of the steric profile on
enantioselectivity, we surveyed a series of organic azides
featuring different methyl substitution patterns on both the
aliphatic chain and the aryl moiety in 9 (Table 2). Increasing the
steric profile on the aliphatic chain proved to have an adverse
effect (11−13), resulting in lower enantioselectivity (0−6% ee)
for the respective products. Substitutions on the aryl moiety,
however, produced significant results (14−25). For substrates
with monomethyl substitutions (14−16) on the phenyl group,
the highest ee was observed with meta substitution (15, 38%).
Likewise, introducing two methyl groups at the meta positions
of the aromatic group (22) induces the highest enantioselec-
tivity comparing to other substitution patterns (17−21),
achieving a moderate ee of 53% (22). Interestingly, when one
meta position is occupied by a methyl group, substitution at para
(18) or ortho (20−21) sites results in a diminished ee as
compared to 15. Given the significant improvement on ee upon
bis-meta substitution, different functional groups were intro-
duced at the meta positions in an attempt to increase the
enantioselectivity (23−25). Despite significantly improved
results obtained with both sterically bulky electron-donating
Scheme 5
a
Table 1. Optimization of Amination Conditions
b
c
cat. loading
(mol %)
time
(h)
temp.
yield
(%)
ee
solvent
C6D6
C6D6
C6D6
C6D6
C6D6
d8-toluene
d8-THF
(°C)
(%)
1
2
3
4
5
6
7
10
5
1
5
5
12
24
168
72
12
24
60
60
60
40
80
60
60
85
85
36
22
73
78
88
28
28
28
33
22
28
28
5
5
15
a
Hexanes and ether are not suitable due to low catalyst solubility;
DCM reacts with catalyst to generate (TrFBOX)NiCl(py).33 Isolation
b
t
yield. Determined by Mosher analysis.41,68−71
c
(23, Bu−, 73% ee) and withdrawing (24, CF3−, 67% ee)
substituents, phenyl substitution resulted in an attenuated ee of
24% (25).
abstraction previously observed with Ni-iminyl species.33,41
Although no reaction was observed at room temperature (25
°C), complete substrate consumption occurred within 12 h
upon heating to 60 °C, leading to isolation of the corresponding
pyrrolidine product 8 in 85% yield. We note that the electron-
rich Ni center permits catalysis without product pyrrolidine
sequestration akin to the previously reported dipyrrin-Ni
catalyst system.41 Conversion of the catalyst to tetrazido species
along with other unidentifiable decomposition products was
noted toward the end of the reaction as evidenced by EPR and
19F NMR spectroscopies. Lowering the catalyst loading to 5 mol
% (entry 2) produces the same outcome, albeit the reaction time
is doubled. A maximum turnover number of 36 is achieved when
1 mol % catalyst loading (entry 3) is used, and no further
conversion is observed after heating the reaction for 1 week at 60
°C. The overall catalyst performance is lower than that of the
dipyrrin system, for which the optimized conditions only require
1 mol % catalyst loading at 25 °C for full conversion of 7 to 8 in 2
h (94% yield) with full regeneration of catalyst at the end.41 We
hypothesize that the comparably lower catalyst activity of 4F is a
result of the formation of tetrazene species.37−39 We propose
that the two vacant quadrants around the Ni center promote
rapid reaction of Ni iminyl with another azide equivalent,
whereas the more directional steric profile of the dipyrrin is
sufficient to block this pathway.
2.5. Mechanistic Evaluation of Ring-Closing Amina-
tion Catalysis. To understand what factors are important for
enantioselectivity, we set out to probe the ring-closing amination
mechanism using kinetic analysis. Due to observed catalyst
transformation into tetrazido complexes at late stage of the
catalysis (80% conversion, Figure S9), initial rate measurements
were conducted to determine the reaction rate dependence on
catalyst and substrate concentrations during the initial phase of
the reaction.39 Concentrations of azide 7 and product 8 during
the catalytic reaction at 60 °C were monitored as a function of
time using 19F NMR spectroscopy. While holding the initial
concentration of azide 7 constant and varying 4F catalyst
loadings, a plot of slopes obtained from the initial 10%
conversion of each run versus catalyst loadings revealed a linear
relationship, indicating a first order rate dependence of the
reaction on catalyst 4F concentration (Figure 5a). Similar
experiments were carried out holding the catalyst 4F
concentration constant while changing the initial concentration
of azide 7. Analogous initial rate analysis reveals a zeroth order
dependence on the substrate (Figure 5b). Of note, the same rate
law was obtained in our previous nickel dipyrrin study.41
Monitoring the catalysis via 19F NMR spectroscopy, three
similar features to those of 4F are detected prior to 30%
conversion of substrate, and no significant amount of catalyst
decomposition or conversion into the tetrazido species is noted
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a
Table 2. Substrate Scope
a
b
Isolation yield. 50 mol % of catalyst was used due to the side product generated by carbocation rearrangement during the substrate preparation
through SN1 mechanism (see the SI).
Figure 5. (a) Initial rate for conversion of 7 into 8 over the first 10% as a function of catalyst loadings while holding initial azide 7 concentration
constant. Every measurement is done in triplicate, and error bars represent standard deviations. (b) Initial rate for conversion of 7 into 8 over the first
10% as a function of initial azide 7 concentration while holding catalyst concentration constant. Every measurement is done in triplicate, and error bars
represent standard deviations. (c) Plotting the first 10% conversion of 9H2 (blue) and 9D2 (red) into 10H and 10D over time, respectively.
Intermolecular KIE is derived by taking the ratio of the slopes of the linear fits [KIE = 1.35 0.03 (60 °C)]. Every measurement is done in triplicate,
and error bars represent standard deviations.
(Figure S8). The Ni-species observed during catalysis can be a
combination of Ni(I) L-type donor coordination compounds
such as pyridine (4F), organoazide (α- and/or γ-binding), as well
as (R)- and (S)-pyrrolidine adducts.
Due to the observation of a tetrazyl species by EPR
spectroscopy at late stages of the transformation (Figure S9),
we set out to probe the viability of Ni tetrazyl complexes to
release azide and reenter the catalytic cycle. Despite our
reported catalytically inactive dipyrrinato cobalt tetrazyl
complexes,38,39 precedent from the Jenkins’ lab establishes
iron tetrazido complexes can release organic azide and the
corresponding imide which can aziridinate olefins.72,73 To test
the reversibility of tetrazyl formation in this system, we heated an
equimolar C6D6 solution of 5F and substrate 9 to 80 °C for 20 h
while monitoring the reaction using 1H and 19F NMR
spectroscopies. If the formation of Ni tetrazyl is reversible, the
cyclized product 10 along with liberated AdN3 should be
observed via sequential azide metathesis reactions (Scheme 6).
Scheme 6
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Figure 6. Product distribution using enantiopure mono D-labeled substrates S-9HD and R-9HD
.
41,74 The two pairs of enantiomers (S-10H and R-10H;
S-10D and R-10D) are resolved using Mosher analysis and the ratios are obtained using 1H NMR spectroscopy.70,71 All reactions were carried out using
standard catalytic conditions at 60 °C. Figure here showcases the product generation using S-9HD as an example. See the SI for detailed analysis for both
41
S-9HD and R-9HD
.
1
Indeed, the H NMR spectrum of the final reaction mixture
shows consumption of substrate 9 as well as generation of 10 and
AdN3, suggesting that the tetrazyl complex 5F is capable of
releasing the iminyl intermediate to reenter the catalytic cycle
(Figure S10). However, due to the zeroth order rate dependence
on azide during our initial rate study, this pathway likely only
contributes during the final stages of catalysis following sufficient
buildup of the tetrazyl complex and lower remaining azide
substrate concentration.
rotation (Re vs Si) and radical recombination, either the HAA or
the radical recombination step is enantio-determining.79
However, if the C−H functionalization follows a concerted
mechanism, the enantioselectivity is directly determined by the
relative barrier of activating different C−H bonds (pro-R vs pro-
S).
To distinguish between these possibilities and elucidate the
enantio-determining step, a pair of enantiopure mono
deuterium-labeled substrates (S-9HD and R-9HD) was prepared
according to modified literature procedures41,74 and subjected
to standard catalytic conditions, leading to four potential
products (S-10H, R-10H, S-10D, and R-10D; Figure 6). The two
pairs of enantiomers (S-10H, R-10H; S-10D, R-10D) were
resolved using Mosher analysis,70,71 and the product distribu-
tions were obtained from integration of 1H NMR spectra of the
final mixture. We note that the integration values derived from S-
and R-10H using S-9HD are relatively small comparing to other
enantiomer pairs. In the event of a concerted C−H activation,
the only products observable from S-9HD (or R-9HD) should be
R-10D and S-10H (or S-10D and R-10H) due to stereospecificity
of the mechanism. However, all four products were found in
both cases, suggesting a radical mechanism for C−H activation.
To further probe the reaction mechanism, the kinetic isotope
effect (KIE) was evaluated by comparing the initial rates of
treating 4F with bis-deutero- (4-azido-4-methylpentyl-1,1-d2)-
benzene (9D2) and corresponding proteo-substrate (9H2, Figure
5c), and an intermolecular KIE of 1.35 0.03 (60 °C) was
determined.75,76 Relative to the large intermolecular KIE of 31.9
1.0 (23 °C) observed with the dipyrrinato nickel system,41 the
small value suggests that the H-atom abstraction step likely
involves a linear yet asymmetric transition state. Nevertheless, a
concerted C−H insertion cannot be excluded.39,77,78
The two possible mechanisms above for C−H activation
(radical-mediated vs concerted) suggest different possibilities
for the enantio-determining step. If the C−H activation is
radical-mediated, depending on the relative rate between radical
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Figure 7. Proposed mechanism for C−H amination.
The HAA step (H-atom vs D-atom abstraction) of the
reaction can be analyzed using the level of deuterium
incorporation in the final product (R-10D + S-10D vs R-10H +
S-10H; Figure 6). Two factors contribute to this distribution: (1)
chiral ligand preference for pro-R or pro-S hydrogen; (2)
intramolecular kinetic isotope effects (HAA favored over DAA).
Upon isolation of the product, the ratio between D-labeled (R-
10D + S-10D) and H-labeled (R-10H + S-10H) product was
determined to be 18:1 and 1.9:1 starting from S-9HD and R-9HD
(Figure 6) as a result of a match or mismatch between the two
effects, respectively. The higher ratio obtained from S-9HD
suggests a lower barrier for pro-R hydrogen abstraction enforced
by the chiral BOX ligand.
Once the H/D-atom is abstracted, two competing processes
occur: (1) rotation of the planar, carbon-based benzyl radical to
expose either the Re or Si face near the iminyl N (Figure 6), and
(2) radical rebound to form the C−N bond. If the radical
trapping process is faster than carboradical rotation (stereo-
retentive radical recombination),79 the final product distribution
is solely determined by the HAA step (enantio-determining
step), and again the only products observable from S-9HD (or R-
the transition states for radical recombination with the Re or Si
face (Curtin-Hammett control).75,79 Hence, similar ratios
between S-10H and R-10H (or S-10D and R-10D) should be
observed regardless of starting material, and the radical
recombination becomes the enantio-determining step.
Mosher analysis revealed that the ratios of S-10H to R-10H
derived from S-9HD and R-9HD are both 2:1, suggesting that the
radical recombination is under Curtin−Hammett control.
However, the ratios of S-10D to R-10D derived from S-9HD
and R-9HD are different (1.8:1 and 3.3:1, respectively; Figure 6),
suggesting the rate of radical recombination is comparable to the
rate for the D-bound carboradical to reach thermo-equilibrium.
The racemization of H-bound carboradical should be faster than
its D-bound counterpart due to 2° KIE; however, since such 2°
KIEs are normally close to unity,75 the rate for radical
recombination is likely very similar to that of the rotation of a
carbon-based radical, indicating that both the HAA and radical
recombination steps can potentially contribute to the
enantioselectivity.79 Interestingly, the preferred prochirality of
the carboradical (Si) is the opposite to that during the HAA step
(pro-R), likely resulting in the low overall enantioselectivity
observed. The similar strategy to probe the rate of radical
rebound has been used to examine the mechanism of C−H
hydroxylation using cytochrome P450,80 intramolecular C−H
insertion using iron-carbene complexes,81 allylic C−H abstrac-
9
HD) should be R-10D and S-10H (or S-10D and R-10H).
Otherwise, if the radical rebound process is sufficiently slow such
that carboradical rotation reaches thermo-equilibrium first, the
final product distribution is determined by the relative energy of
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Figure 8. DFT calculated [B3LYP/6-31+G(d)] free energy diagram (in kcal/mol) for the proposed C−H amination mechanism for the cyclization of
9 into 2-phenyl-5,5-dimethylpyrrolidine (10) mediated by (TrHBOX)Ni(py) (4) with energies corresponding to the S enantiomer in red and the R
enantiomer in blue.
tion by singlet oxygen,82 and more recently the enantioselective
carbene C−H insertion catalyzed by chiral cobalt porphyrin
complexes79 as well as our recently reported dipyrrinato nickel
system for catalytic C−H amination.41
accumulation of the iminyl during catalysis, we note that the
HAA step does contribute to the observed kinetics with the
nonunity KIE in addition to a higher barrier (pro-R: 21.3 kcal/
mol; pro-S: 23.5 kcal/mol) in comparison to the N2 loss step
(9.7 kcal/mol) derived from DFT calculation (vide infra).
Furthermore, our studies reveal that the enantio-determining
step is impacted by the relative rates of radical recombination
and rotation.
2.6. DFT Evaluation of the Amination Mechanism.
Density functional theory (DFT) was employed to provide
support for the proposed mechanism in Figure 7 and to gain
insight into geometric factors that may influence enantiose-
lectivity during catalysis. Calculations of the reaction trajectory
and relevant intermediates (Figure 8) were performed with the
B3LYP functional62−65 and 6-31+G(d) basis sets84−87 on an
untruncated system. The full computational methodology is
described in detail in the Supporting Information.
The nitrenoid structure (A) was found to favor a doublet spin
state with a T-shaped geometry about the nickel. A quartet
excited state was close in energy, being only 2.9 kcal/mol higher
in free energy. Spin densities of 0.40 e− and 0.54 e− were found
for nickel and iminyl nitrogen atoms, respectively, supporting
the experimentally proposed iminyl character.41 However, the
spin density on the iminyl nitrogen being <1 e− implies an
admixture of iminyl and imido character.
The amide intermediate (C) generated by intramolecular
HAA from the iminyl was identified with a similar T-shaped
geometry to A. Spin densities of 1.45 e− for nickel and 0.39 e− for
the amide nitrogen were calculated, suggesting an amide
description with some aminyl character. The amine product of
radical recombination was determined to favor the S enantiomer
With detailed understanding of the enantio-determining
processes in the stepwise mechanism, the increase in ee from
meta substitution on the aryl group favoring S-pyrrolidine
product can be the result from either less preferential pro-R H-
atom removal or more relatively favored radical recombination
with Si compared to Re face of the carboradical. However, due to
the similar ee increase with meta substitution observed in the
amination of tertiary benzylic C−H bond (vide infra), the higher
ee observed is likely caused by a larger discrepancy between
kinetic barriers toward C−N bond formation with the Si and Re
face of the carboradical either by steric repulsion to disfavor the
R-pyrrolidine formation or attractive dispersion interaction
between the meta-alkyl and ligand-based trityl groups to favor
the S-pyrrolidine synthesis.83
Taken together, we propose the following catalytic cycle
similar to that for the nickel dipyrrin system (Figure 7).41 The
pyridine adduct 4 first undergoes ligand exchange with substrate
9 to generate an azide adduct. Dinitrogen extrusion from the
azide adduct generates a nickel iminyl species.41 Intramolecular
HAA by the iminyl followed by radical recombination between
the Ni-amide and the carboradical intermediate generated in the
previous step furnishes the final pyrrolidine product 10, which is
displaced upon ligand substitution with pyridine or substrate 9.
The iminyl species can also react with another equivalent of
substrate 9 to generate the tetrazyl complex,35,39 which can
release organoazide and the corresponding Ni-iminyl to reenter
the catalytic cycle.72,73 Even though we do not observe
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(E1) with a calculated free energy relative to the R enantiomer
(E2) of −4.6 kcal/mol, both featuring a doublet spin state. The
spin densities of nickel and nitrogen were determined to be 0.99
and −0.01 e−, respectively, indicating a NiI-amine formulation as
expected for a d9 complex.
Table 3. Substrate Scope for Catalytic Enantioselective 2,5-
Bis-Tertiary Pyrrolidine Synthesis
a
The reaction from iminyl to amide is exergonic and has a ΔG
of −4.5 kcal/mol with a reaction barrier of 23.5 (B1, pro-S) and
21.3 kcal/mol (B2, pro-R) for the two isomeric HAA transition
states, favoring abstraction of the pro-R hydrogen atom. The
formation of the S enantiomer via radical recombination (D1) is
also exergonic (ΔG = −13.1 kcal/mol), with a barrier of 9.1
kcal/mol relative to the amide C. The TS from C to the R
enantiomer of the amine (D2) possesses a higher energy barrier
of 11.1 kcal/mol (ΔΔG‡ = 2.0 kcal/mol) and is also a less
exergonic (ΔΔG = 4.6 kcal/mol) reaction with a ΔG of −8.5
kcal/mol for the radical rebound step. These results suggest that
the S enantiomer is favored upon radical recombination,
consistent with isotope labeling experiments. The greater
stability of the S-amine product can be attributed to the
improved steric profile resulting from positioning the phenyl
group at a greater distance from the bulky CPh3 substituents on
the ligand (Figure S27). The calculated result reproduced the
switch in preferred prochirality during the HAA (pro-R) and
radical recombination (Si) transition states, further supporting
the mechanistic proposal in Figure 7.
The barrier toward radical capture with the Si (9.1 kcal/mol)
and Re (11.1 kcal/mol) faces of the radical is close to the upper
limit of a C−C bond rotational barrier for saturated alkanes (3−
10 kcal/mol).88 The actual rotational barrier around the
PhHC•−CH2 bond in the amide intermediate (C) is likely
higher than that of a typical C(sp3)−C(sp3) bond due to two
factors: (1) the •C−CH2 bond is shorter than the other C(sp3)−
C(sp3) bonds present in the optimized structure of C likely due
to hyperconjugation between the radical p-orbital and
neighboring C(sp3)−H σ-bond (Figure S28), resulting in
heightened rotation barrier; and (2) the radical rotation must
occur in a sterically restricted pocket created by the TrBOX
ligand, incurring an additional energetic penalty for C−C
rotation. Despite our best attempts at locating the C−C
rotational transition states for the C-based radical, satisfactory
result was not obtained due to a large ensemble of torsional
modes plausible for the overall radical rotation.
2.7. Catalytic Enantioselective Synthesis of 2,5-Bis-
Tertiary Pyrrolidine. With a comprehensive understanding for
enantio-determining steps, the proposed mechanism provides
the unique opportunity for enantioselective synthesis of 2,5-bis-
tertiary pyrrolidines. These products are important precursors
for a range of pharmaceutical agents.89−92 A common pathway
to synthesize chiral pyrrolidines is asymmetric hydrogenation of
cyclic imines via either organometallic or enzymatic cataly-
sis.12−18 However, this strategy necessarily introduces an H-
atom on the α-position to the amino group in the product,
rendering 2,5-bis-tertiary pyrrolidines inaccessible.
a
Isolation yield.
The result suggests that the chiral environment enforced by
the ligand better differentiates the steric of 2,2,5,5-tetra-
substituted pyrrolidines comparing to their 2,2,5-trisubstituted
congeners. Detailed mechanistic and computational investiga-
tions for further improved ligand system are currently under
study.
3. CONCLUSIONS
In conclusion, we have developed a nickel catalyst supported by
a trityl-substituted, monoanionic BOX ligand capable of
enantioselective C−H bond amination. The BOX supported
Ni-imide adopts a similar Ni iminyl electronic structure
formulation as its dipyrrinato congener despite stronger π-
donating ability of the BOX ligand.33 The (TrBOX)Ni system
operates under mild reaction conditions to afford pyrrolidines in
good yield (29%−87%) and with moderate ee (as high as 73%).
A detailed mechanistic study was carried out leading to our
proposal that a similar catalytic cycle to the previously reported
dipyrrinato nickel complex was operative. Inter- and intra-
molecular kinetic isotope labeling experiments point to a radical-
based C−H activation step. Furthermore, due to the similar rate
between competing radical rotation and C−N bond formation,
both the HAA and radical recombination steps contribute to
enantioselectivity of the reaction. However, while HAA favors
the pro-R hydrogen removal, the formation of S-pyrrolidine is
slightly favored for the radical recombination step leading to the
As an initial test, racemic (5-azido-5-methylhexan-2-yl)-
benzene (26, Table 3) was synthesized and subjected to
catalytic conditions. Gratifyingly, upon full conversion the
corresponding product, 2,2,5-trimethyl-5-phenylpyrrolidine
(27), can be isolated in moderate yield (50%) and much
improved ee (53%) as compared to 10. Additionally, replacing
the methyl with an ethyl group at the benzylic position (28) or
elaborating the aryl group with 1,3-bis-dimethyl (30) or bis-di-
tert butyl substituents (32) afforded the corresponding products
in good yield (54−78%) and with enhanced ee (64−79%).
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diminished overall enantiomeric excess observed. Despite that
switch in configurational preference, increasing the steric bulk at
the meta positions on the aryl substituents leads to a higher
observed product ee. We propose that the increased meta-
position bulk either suppresses capture of Re face of the
carboradical by steric repulsion or favors the S-configuration by
attractive dispersion interaction during the radical recombina-
tion step. Theoretical studies corroborate the proposed
mechanistic cycle and the energetically favored radical
recombination transition states leading to S-pyrrolidines.
Following this comprehensive mechanistic investigation, we
conclude that future catalyst designs that operate under a similar
stepwise mechanism aiming for better stereocontrol need to
address: (a) the trajectory of radical capture for rate control with
respect to carboradical rotation to establish the enantio-
determining step; and (b), conform to the geometry of the
corresponding HAA or radical recombination transition state to
improve the overall enantioselectivity. We note that the
previously mentioned Ru system showcasing excellent stereo-
control is proposed to go through a concerted pathway where
the C−H bond activation step solely determines the
enantiomeric outcome.28 The C−H bond functionalization
that operates via a similar two-step mechanism as the one
observed herein can also achieve higher enantioselectivity. For
example, excellent enantioselectivity from Co-porphyrin cata-
lyzed carbene insertion is reported, whose mechanism is
described as occurring via two steps where the HAA is
enantio-determining as the rapid radical recombination step is
stereoretentive.79 Based on our proposed mechanism and
enantio-determining processes, catalytic synthesis of 2,5-bis-
tertiary pyrrolidines inaccessible from the well-established
asymmetric imine hydrogenation is demonstrated in decent
yield (50−78%) and with moderate ee (53−79%).
Ryan M. Clarke − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0003-3356-071X
Shao-Liang Zheng − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0002-6432-9943
Thomas R. Cundari − Department of Chemistry, Center for
Advances Scientific Computing and Modeling (CASCaM),
University of North Texas, Denton, Texas 76203, United
States; orcid.org/0000-0003-1822-6473
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09839
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by a grant from the NIH
(GM-115815), the Dreyfus Foundation (Teacher-Scholar
Award to T.A.B.), and Harvard University. R.M.C. gratefully
acknowledges an NSERC Postdoctoral Fellowship. C.J.L. and
T.R.C. acknowledge support from the U.S. Department of
Energy, Office of Science, Basic Energy Sciences (DE-FG02-
03ER15387) and thank the National Science Foundation for
their generous support of the UNT CASCaM HPC cluster via
Grant No. CHE-1531468.
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■
Corresponding Author
Theodore A. Betley − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-5946-9629;
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University of North Texas, Denton, Texas 76203, United
States
Gerard J. Porter − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
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