Enantioselective Intermolecular Radical C-H Amination

Article abstract of DOI:10.1021/jacs.0c10415

Radical reactions hold a number of inherent advantages in organic synthesis that may potentially impact the planning and practice for construction of organic molecules. However, the control of enantioselectivity in radical processes remains one of the longstanding challenges. While significant advances have recently been achieved in intramolecular radical reactions, the governing of asymmetric induction in intermolecular radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling enantioselectivity as well as reactivity of the intermolecular radical C-H amination of carboxylic acid esters with organic azides via Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in intermolecular radical reactions. The Co(II)-catalyzed intermolecular C-H amination, which operates under mild conditions with the C-H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working details of the underlying stepwise radical pathway for the Co(II)-based C-H amination.

Full text of DOI:10.1021/jacs.0c10415

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Enantioselective Intermolecular Radical C−H Amination
Li-Mei Jin,† Pan Xu,† Jingjing Xie, and X. Peter Zhang*
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ABSTRACT: Radical reactions hold a number of inherent
advantages in organic synthesis that may potentially impact the
planning and practice for construction of organic molecules.
However, the control of enantioselectivity in radical processes
remains one of the longstanding challenges. While significant
advances have recently been achieved in intramolecular radical
reactions, the governing of asymmetric induction in intermolecular
radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling
enantioselectivity as well as reactivity of the intermolecular radical C−H amination of carboxylic acid esters with organic azides via
Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent
attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This
noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in
intermolecular radical reactions. The Co(II)-catalyzed intermolecular C−H amination, which operates under mild conditions with
the C−H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to
valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working
details of the underlying stepwise radical pathway for the Co(II)-based C−H amination.
formation and release of the aminated product (Scheme 1A).
In principle, the analogous stepwise radical mechanism should
also operate for the intermolecular version of the radical C−H
amination, involving the corresponding intermediates IB and
IIB (Scheme 1B). However, there are additional challenges
INTRODUCTION
■
Nitrogen-centered radicals have been frequently exploited as
reactive intermediates for the development of new methods in
organic synthesis.1 Among different applications, free aminyl
radicals have been demonstrated with the potential for the
direct functionalization of C(sp3)−H bonds to form valuable
nitrogen-containing compounds.2 Despite significant progress
on this potentially powerful synthetic methodology, the control
of enantioselectivity in regard to radical C−H amination
remains a formidable task and largely unaddressed.3 Among
considerable efforts in surmounting this challenge,4 metal-
loradical catalysis (MRC) represents a conceptually new
approach that utilizes metalloradical complexes as a new kind
of catalyst for the generation of metal-supported organic
radicals as key intermediates to regulate subsequent radical
reactions.5−7 To this end, Co(II) complexes of porphyrins, a
family of stable 15e-metalloradicals, have been shown to
homolytically activate organic azides to generate α-Co(III)-
aminyl radicals, a new type of aminyl radical supported by
metal complexes.8 With the employment of D2-symmetric
chiral amidoporphyrins as the supporting ligands, we recently
achieved enantioselective intramolecular radical C−H amina-
tion for stereoselective construction of chiral N-heterocycles.9
These catalytic reactions proceed through a stepwise radical
pathway that involves metalloradical activation of organic
azides to generate α-Co(III)-aminyl radical intermediates IA,
followed by intramolecular H atom abstraction (HAA) to form
ω-Co(III)-alkyl radical intermediates IIA, and subsequent
intramolecular radical substitution (RS) resulting in the
Scheme 1. Intra- and Intermolecular Pathways for Radical
C−H Amination via Co(II)-Based Metalloradical Catalysis
Received: September 29, 2020
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A

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a
Scheme 2. Ligand Effect on Co(II)-Based Asymmetric System for Intermolecular C−H Amination with Organic Azides
a
Carried out with 1 (0.10 mmol) and 2a (0.15 mmol) in the presence of 4 Å molecular sieves by [Co(Por*)] (4 mol %) in trifluorotoluene (0.5
b
mL) at 40 °C for 48 h. Isolated yields. Enantiomeric excess was determined by chiral HPLC. Structure of P6 was determined by X-ray
crystallography.
inherently associated with the control of reactivity and
enantioselectivity in the intermolecular radical process. In the
absence of the linkage between the N-centered radical and C−
H bond (as in the case of intermediate IA), intermolecular H
atom abstraction from the C−H bond of the substrate by α-
Co(III)-aminyl radical intermediate IB could be complicated
by issues with regioselectivity and chemoselectivity. Further-
more, without the covalent linkage in the resulting ∞-Co(III)-
alkyl radical intermediate IIB, the C-centered radical aIIB would
be virtually “free” to escape from the Co(III)-amido complex
bIIB, which would terminate the desired catalytic cycle.
Consequently, it could lead to side reactions and radical
chain processes, resulting in further loss of reactivity and
selectivity. Moreover, considering that the concentrations of
both aIIB and bIIB are equally low (not higher than the catalyst
concentration), the last step of intermolecular radical
substitution would be intrinsically difficult as a bimolecular
second-order reaction. Besides the issue of reactivity, the
control of enantioselectivity in intermolecular radical sub-
stitution is a topic virtually unexplored. With “free”
interconversion between two prochiral faces of typical C-
centered radicals, we wondered what factors could be exploited
to govern the asymmetric induction of C−N bond formation
our recent success in the development of enantioselective
radical processes for intramolecular C−H amination,9 we
envisioned that the key to addressing these issues would be the
catalyst development to maximize noncovalent attractive
interactions through fine-tuning of the environments of D2-
symmetric chiral amidoporphyrin ligand. If achieved, inter-
molecular radical C−H amination via Co(II)-based MRC
could potentially provide a generally applicable strategy for
stereoselective synthesis of chiral amines directly from
omnipresent C−H bonds with a wide range of organic azides.
Development of catalytic systems for direct functionalization
of ubiquitous C(sp3)−H bonds with nitrogen sources
represents a highly attractive approach for general synthesis
of valuable amines.10 Despite intensive research efforts,
development of enantioselective catalytic systems for the
synthesis of chiral amines by intermolecular C−H amination is
still in its infancy. Notable examples include asymmetric
amination systems by chiral catalysts based on metal
complexes of rhodium,11 ruthenium,12 and manganese,13,12b
which typically proceed via concerted C−H insertion involving
electrophilic metallonitrene intermediates. Enantioselective
intermolecular C−H amination has also been demonstrated
with engineered iron−heme enzymes14 and rhodium-based
catalyst under photoredox conditions.15 While they represent
significant advances, these catalytic systems experienced
a
b
via radical substitution between IIB and IIB. Encouraged by
B
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a
Table 1. Enantioselective Intermolecular Radical Amination of C(sp3)−H Bonds with Fluoroaryl Azides via Co(II)-MRC
a
Carried out with 1 (0.10 mmol) and 2 (0.15 mmol) in the presence of 4 Å molecular sieves by [Co(P6)] (4 mol %) in trifluorotoluene (0.5 mL)
b
c
at 40 °C for 48 h. Isolated yields. Enantiomeric excess was determined by chiral HPLC. Performed on 3.0 mmol scale. Absolute configuration
determined by X-ray crystallography. In benzene (0.5 mL). Allylic regioisomers were observed as minor products. With 1 (0.10 mmol) and 2a
d
e
f
(0.12 mmol).
C
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limitations such as the need for excess C−H substrates, limited
substrate scope, or low level of enantiocontrol. Evidently, there
persists an unmet need of general and efficient catalytic
systems for highly enantioselective intermolecular C−H
amination. In comparison to ionic reactions, radical reactions
are inherently more reactive and less sensitive to the electronic
requirements of substrates, characteristics that may lead to the
development of more effective catalytic systems with a broad
substrate scope, including the amination of challenging
electron-deficient C−H bonds. We herein report the first
catalytic radical system via Co(II)-MRC for enantioselective
intermolecular C−H amination. Specifically, we describe the
development of Co(II)-based metalloradical system that can
activate fluoroaryl azides16 for enantioselective amination of α-
C−H bonds in carboxylic acid esters, a class of electron-
deficient C−H bonds. This new Co(II)-catalyzed C−H
amination provides a straightforward method for stereo-
selective synthesis of chiral α-amino acid derivatives directly
from widely available carboxylic esters. We hope to show the
importance of catalyst development in achieving effective
control of both reactivity and enantioselectivity in this
intermolecular radical process.
proved to be an even more effective catalyst, producing α-
amino acid ester 3aa in excellent yield (95%) with exceptional
enantioselectivity (97% ee). The difference in performance
between [Co(P6)] and [Co(P5)] demonstrates that even a
ligand modification as subtle as heteroatom substitution of O
atoms by S atoms can give rise to remarkable improvements in
both reactivity and enantioselectivity, manifesting the effective-
ness of catalyst development in controlling the radical process.
As depicted in the proposed stereochemical model on the basis
of DFT calculations (Scheme 2B), the effectiveness of
[Co(P6)] in controlling reactivity and enantioselectivity may
be attributed to the cooperative interplay of several non-
covalent interactions among the two substrates and the
catalyst, including multiple H-bonding and π-stacking inter-
actions as well as van der Waals forces (see Supporting
Information for details). Together, these attractive weak forces
hold the two reacting substrates within the catalyst’s pocket in
proximity and orient them in proper conformations to facilitate
the stereoselective C−N bond formation. According to the
DFT-optimized model, [Co(P6)] catalyzes the preferred
formation of product 3aa as (R)-enantiomer over (S)-
enantiomer, an outcome that is consistent with the
experimental observation (see Table 1). As comparison,
intermolecular C−H amination reactions were conducted
under the same optimized conditions for substrates ethyl-
benzene (1A) and N,N-diethyl-2-phenylacetamide (1B), which
have no and similar H-bonding ability to 1a, respectively
(Scheme 2C). While the reaction of 1B afforded the
corresponding α-aryl α-amino acid amide 3Ba in 91% yield
with 97% ee, amination of 1A produced the desired α-
aminoethylbenzene 3Aa in 47% yield with 17% ee. Together,
these results clearly revealed the importance of H-bonding
interaction as suggested by the DFT model.
Substrate Scope. Using the optimized catalyst [Co(P6)],
we then investigated the scope of fluoroaryl azides 2 for
Co(II)-catalyzed C−H amination using arylacetate ester 1a as
the standard substrate (Table 1A). Similar to 4-trifluorometh-
yl-2,3,5,6-tetrafluorophenyl azide (2a), analogues bearing other
para-substituents such as −CN (2b), −NO2 (2c), −SO3Ph
(2d), and −CO2Me (2e) could also be used as effective
nitrogen sources for the C−H amination, generating the
corresponding α-aryl α-amino acid esters 3ab−3ae in good to
excellent yields with high enantioselectivities (Table 1; entries
1−5). In addition, both pentafluorophenyl azide (2f) and 4-
bromotetrafluorophenyl azide (2g) were suitable aminating
reagents for the catalytic process, leading to productive
formation of N-fluoroaryl α-amino acid esters 3af and 3ag
with excellent enantioselectivities (Table 1; entries 6 and 7).
Interestingly, 4-tetrafluoropyridinyl azide (2h) could serve as a
competent nitrogen precursor for highly enantioselective C−H
amination of 1a to form the amino acid derivative 3ah without
complications from the pyridine unit (Table 1; entry 8).
Additionally, the Co(II)-based system could use 2,3,5,6-
tetrafluorophenyl azide (2i) for the amination reaction,
producing the desired product 3ai with excellent enantiose-
lectivity, albeit in low yield (Table 1; entry 9). When 2,4,6-
trifluorophenyl azide (2j) was used, however, the correspond-
ing amination product 3aj was obtained in low yield with only
moderate enantioselectivity (Table 1; entry 10). It is worth
noting that the use of 2,4,5-trifluorophenyl azide afforded only
RESULTS AND DISCUSSION
■
Catalyst Development. To assess the feasibility of the
proposed intermolecular radical process, we first examined the
α-C(sp3)−H amination reaction of ethyl (4-methoxyphenyl)-
acetate (1a) with 4-trifluoromethyl-2,3,5,6-tetrafluorophenyl
azide (2a) by Co(II) complexes of porphyrins (Scheme 2A
and Table S1). With the use of the first-generation metal-
loradical catalyst [Co(P1)] (P1 = 3,5-DitBu-ChenPhyrin),17 it
was gratifying to find that the C−H amination reaction could
afford the desired α-aryl α-amino acid ester 3aa in high yield
(81%) with low but significant enantioselectivity (20% ee).
Replacing the catalyst by the analogous [Co(P2)] (P2 = 2,6-
DiMeO-ChenPhyrin), which has methoxy groups at the 2,6-
positions instead of tert-butyl groups at the 3,5-positions,
resulted in some improvement in enantioselectivity (32% ee)
but led to considerable decrease in reactivity (40% yield).
Encouraged by these initial results, we then systematically
investigated the ligand effect on the reactivity and selectivity of
the Co(II)-catalyzed reaction. When second-generation metal-
loradical catalyst [Co(P3)] (P3 = 3,5-DitBu-QingPhyrin),18
which bears cyclopropanecarboxyamides with two contiguous
stereocenters, was employed, the reaction occurred in a better
reactivity (62% yield) but with almost no enantioselectivity.
However, switching the catalyst [Co(P3)] to its analogous
[Co(P4)] (P4 = 2,6-DiMeO-QingPhyrin) gave rise to even
higher yield (85%) and resumed asymmetric induction at a low
but significant level (12% ee), indicating once again the
significant influence of the nonchiral substituents in the ligand
on the catalytic reaction. To our delight, the use of [Co(P5)]
(P5 = 2,6-DiPhO-QingPhyrin), in which the methoxy groups
were replaced with phenoxy groups at the 2,6-positions, led to
a significant increase in enantioselectivity (86% ee) without
affecting the high reactivity (85% yield). Further catalyst
development by substituting the O atoms at the 2,6-positions
of the nonchiral substituents in [Co(P5)] with S atoms led to
the development of [Co(P6)] (P6 = 2,6-DiPhS-QingPhyrin;
see the Supporting Information for X-ray structure), which
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Scheme 3. Mechanistic Studies on Co(II)-Catalyzed Intermolecular C−H Amination with Organic Azides
a trace amount of the corresponding C−H amination product
while no product was observed with the use of 3,4,5-
trifluorophenyl azide under the same conditions, suggesting
the importance of 2,6-difluoro substituents on the aryl azides
E
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for effective intermolecular C−H amination. In addition to
rendering the Co(III)-aminyl radical electrophilic, both of the
ortho-fluoro atoms may play important roles in facilitating the
cooperative interplay of the multiple noncovalent interactions
(Scheme 2B).
Mechanistic Studies. Comprehensive studies were carried
out to gain insight into the underlying stepwise radical
mechanism of the Co(II)-catalyzed intermolecular C−H
amination (Scheme 3). To directly detect the α-Co(III)-
aminyl radical intermediate I, the isotropic X-band electron
paramagnetic resonance (EPR) spectrum was recorded at
room temperature for the reaction mixture of [Co(P1)] with
azide 2h in benzene without C−H substrate (Scheme 3A).
The spectrum displays notable signals that are characteristic of
α-Co(III)-aminyl radicals.9,8a The observed isotropic g-value of
∼2.00 is consistent with the generation of organic radical
I[Co(P1)]/2h upon spin translocation from the Co(II) center to
the N atom during the process of metalloradical activation.
Consistent with the spin delocalization in α-arylaminyl radical
intermediate I[Co(P1)]/2h, the observed signals were broad and
could be fittingly simulated by involving its three resonance
forms on the basis of couplings by 59Co (I = 7/2), 14N (I = 1),
Subsequently, a wide range of arylacetate esters 1 were
examined as C−H substrates for Co(II)-catalyzed amination
by [Co(P6)] using azide 2a as a representative nitrogen source
(Table 1B). Similar to ethyl ester (1a), various esters of
phenylacetate, such as methyl (1b), ethyl (1c), isopropyl (1d),
and phenyl (1e) esters, could be productively aminated to
form the corresponding α-amino acid esters 3ba−3ea with
excellent enantioselectivities (Table 1; entries 11−14). It is
worth mentioning that the amination process for the synthesis
of α-amino acid derivatives could be scaled up, as
demonstrated by the synthesis of optically active compound
3ba on a 3.0 mmol scale in 75% yield with 96% ee. In addition
to para-OMe-substituted 1a, arylacetate derivatives bearing
substituents with varied electronic properties at different
positions on the aromatic ring, such as meta-OMe (1f),
ortho-OMe (1g), para-Me (1h), para-tBu (1i), para-CF3 (1j),
para-Cl (1k), and para-Br (1l) groups, could all act as
adequate C−H substrates for the Co(II)-based enantioselec-
tive amination, allowing for the convenient access to highly
enantioenriched α-amino acid derivatives 3fa−3la bearing
various functionalized α-aryl units (Table 1; entries 15−21).
The C−H amination could also be applied to arylacetates with
extended aromatic and heteroaromatic systems as shown in
high-yielding formation of α-amino acid derivatives with α-
naphthyl (3ma), α-indolyl (3na), α-pyrrolyl (3oa), and α-
thiophenyl (3pa) groups with excellent enantioselectivities
(Table 1; entries 22−25). The absolute configurations of the
newly generated stereogenic centers in 3ha and 3ma were both
established as (R) by X-ray crystallography.
Furthermore, the [Co(P6)]-based catalytic system could be
expanded to the enantioselective C−H amination of both
arylcrotonate esters (Table 1C) and aryltetrolate esters (Table
1D). For example, the allylic C−H bonds of ethyl phenyl-
crotonate (1q) could be effectively aminated by [Co(P6)]
with azide 2a, producing the γ-aryl γ-amino acid ester 3qa in
good yield with high enantioselectivity (Table 1; entry 26).
The Co(II)-based system proved to be similarly effective for
highly enantioselective amination of allylic C−H bonds in
arylcrotonate esters (1r−1u) bearing aryl substituents (Table
1; entries 27−30). In all the cases, the corresponding allylic
regioisomer γ-aryl α-amino acid esters were also generated but
as the minor products. Likewise, [Co(P6)] was capable of
catalyzing enantioselective amination of the propargylic C−H
bonds in aryltetrolate esters as exemplified by efficient
reactions of tetrolate derivatives 1v−1z containing disparate
aryl groups with azide 2a, delivering the functionalized γ-aryl γ-
amino acid derivatives 3va−3za in high yields with good
enantioselectivities (Table 1; entries 31−35). The absolute
configuration of the major enantiomer of 3va was established
as (R) by X-ray crystallography, which is the same as 3ha and
3ma. Notably, the C−H amination process catalyzed by
[Co(P6)] exhibited chemoselectivity as the normally more
reactive CC and CC bonds were unaffected. It is also
worth noting that the [Co(P6)]-catalyzed amination displayed
high regioselectivity at the γ-position over the α-position, two
possible reactive sites that are associated with both the allylic
and propargylic radical intermediates.
and 19F (I = 1/2): 82% of N-centered radical at α-position
Nα
I
(g = 2.04824; A(Co) = 117.9 MHz; A(N) = 139.5
[Co(P1)]/2h
MHz; A(F) = 0 MHz), 8% of C-centered radical at γ-position
Cγ
I
(g = 2.01921; A(Co) = 0 MHz; A(N) = 69.2 MHz;
[Co(P1)]/2h
A(F) = 130.0 MHz), and 10% of N-centered radical at ε-
Nε
position
I
(g = 2.08007; A(Co) = 0 MHz; A(N) =
[Co(P1)]/2h
95.9 MHz; A(F) = 0 MHz). Furthermore, intermediate
I[Co(P1)]/2h could be detected by high-resolution mass
spectrometry (HRMS) with ESI ionization. The obtained
spectrum evidently exhibited a signal corresponding to
[I[Co(P1)]/2h]+ (m/z = 1503.6881), resulting from the neutral
α-Co(III)-aminyl radical I[Co(P1)]/2h by the loss of one electron.
Both the experimentally determined exact mass and isotope
distribution pattern matched well with those calculated from
the formula of [(P1)Co(NC5NF4)]+ (m/z = 1503.6879; see
Supporting Information for details). Correspondingly, α-
Co(III)-aminyl radical intermediate I[Co(P6)]/2a, generated
from the reaction mixture of [Co(P6)] with azide 2a, could
also be detected by EPR with much stronger signals, which
seems consistent with the higher activity of [Co(P6)]
compared to [Co(P1)] (Scheme 3A). Similarly, the broad
EPR signals of I[Co(P6)]/2a could be fitted nicely with three
resonance structures: 88% of N-centered radical at α-position
Nα
I
(g = 2.01362; A(Co) = 116.7 MHz; A(N) = 124.9
[Co(P6)]/2a
MHz; A(F) = 0 MHz), 4% of C-centered radical at γ-position
CγI[Co(P6)]/2a (g = 2.02094; A(Co) = 0 MHz; A(N) = 110.3 MHz;
A(F) = 81.0 MHz), and 8% of C-centered radical at ε-position
CεI[Co(P6)]/2a (g = 2.07664; A(Co) = 0 MHz; A(N) = 0 MHz; A(F)
= 0 MHz).
To determine the kinetic isotope effect (KIE), a direct
competition experiment between the reactions of arylacetate
ester 1i and its bisdeuterated analogue 1iD with azide 2a was
conducted using achiral catalyst [Co(P7)] (P7 = 3,5-DitBu-
IbuPhyrin) (Scheme 3B).19 A mixture of amination products
3ia and 3iaD was formed in a 75% combined yield. Analysis of
1
the product mixture by H NMR provided an intermolecular
KIE value (kH/kD) of 8.1. This high degree of primary KIE is
consistent with the proposed step of C−H bond cleavage via
intermolecular H atom abstraction by α-Co(III)-aminyl radical
9
intermediate I[Co(P7)]/2a
.
To assess the potential electronic
effect of the Co(II)-based radical process, competition
reactions were performed for intermolecular C−H amination
between ethyl phenylacetate ester (1c) and its para-substituted
arylacetate analogs having wide-ranging electronic properties
with azide 2a by [Co(P7)] (Scheme 3C). The results revealed
F
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a strong linear correlation between the log(kX/kH) and the
Hammett constants (σp) of the para-substituents with a
negative slope of −0.77. The Hammett plot signifies the
This new enantioselective intermolecular C−H amination
process, which is fundamentally different from traditional
metallonitrene insertion process, has been shown to proceed
through a stepwise radical pathway, involving sequential steps
of (i) metalloradical activation (MRA) of organic azides, (ii)
intermolecular hydrogen atom abstraction (HAA) from C−H
substrates, and (iii) intermolecular radical substitution (RS)
for C−N bond formation, with effective control of both
reactivity and enantioselectivity. We anticipate that this radical
approach for intermolecular C−H amination, revealed by
Co(II)-based MRC, will become generally applicable. It is our
hope that this work will spur the development of new catalytic
radical systems for direct functionalization of omnipresent
C(sp3)−H bonds to form valuable nitrogen-containing
compounds with potential control of chemo-, regio-, and
stereoselectivity.
electrophilic nature of the key radical intermediate I[Co(P7)/2a
,
which is likely a result of the strong electron-withdrawing effect
of the fluoroaryl group. To directly trap ∞-Co(III)-alkyl
radical intermediate aII generated from intermolecular H atom
abstraction, the amination reaction of arylacetate ester 1b with
azide 2a was conducted in the presence of TEMPO (2.0 equiv)
using chiral catalyst [Co(P6)] (Scheme 3D). Remarkably,
amination product 3ba was still formed with the similarly high
enantioselectivity (95% ee) in spite of excess TEMPO,
although in a much lower yield (34%) than the reaction
without TEMPO. Concurrently, the reaction also produced
compound 4b in 40% yield without any asymmetric induction,
which was evidently formed from trapping of the “free” alkyl
radical intermediate aII1b by TEMPO outside the chiral
environment of the Co(III)-amido complex bII[Co(P6)]. Further
TEMPO trapping experiments in different solvents indicated
that solvent viscosity had some effect but was not a major
factor to affect the outcome (Table S2).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10415.
To further probe the existence of the ∞-Co(III)-alkyl
radical intermediate, the (Z)-isomer of ethyl 4-methoxyphenyl-
crotonate (Z)-1s was employed as the C−H substrate for the
catalytic amination with azide 2a using [Co(P6)] as the
catalyst (Scheme 3E). Besides the C−H amination product
(Z)-3sa and unreacted (Z)-1s with unchanged configuration,
two other products, 5sa and (E)-3sa, were also generated,
indicating the existence of three allylic radical isomers (a1II1s,
a2II1s, and a3II1s). Interestingly, all three amination products
(Z)-3sa, 5sa, and (E)-3sa were formed with high enantiose-
lectivities, suggesting that the allylic radical intermediates were
not “free” when reacting inside the chiral environment of the
Experimental details and analytical data for all new
compounds (PDF)
Crystallographic information (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
X. Peter Zhang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0001-7574-8409; Email: peter.zhang@bc.edu
b
Authors
Co(III)-amido complex II[Co(P6)]/2a. To evaluate diastereose-
Li-Mei Jin − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Pan Xu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Jingjing Xie − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
lectivity of the Co(II)-catalyzed intermolecular C−H amina-
tion, (+)-menthyl phenylacetate (+)-6 and (−)-menthyl
phenylacetate (−)-6 were utilized as chiral C−H substrates
for amination with azide 2a using both [Co(P6)] and
[Co(P7)] (Scheme 3F). While achiral catalyst [Co(P7)]
gave almost no control of diastereoselectivity in both reactions
with (+)-6 and (−)-6, chiral catalyst [Co(P6)] enabled the
stereoselective formation of amination products (+)-7 and
(−)-7, respectively, with excellent diastereoselectivities. These
results indicate that the Co(II)-based catalytic system can
effectively control the stereochemistry of intermolecular C−H
amination over the substrate. The differences in the ratio of the
two diastereomers most likely reflect a matched−mismatched
effect of chirality between the ligand and the substrate.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10415
Author Contributions
†L.-M.J. and P.X. contributed equally.
Notes
CONCLUSIONS
The authors declare no competing financial interest.
■
In summary, we have demonstrated, for the first time, a highly
enantioselective system for intermolecular radical C−H
amination via Co(II)-based metalloradical catalysis (MRC).
The Co(II)-catalyzed amination, which operates under mild
conditions with C−H substrate as the limiting reagent, exhibits
a broad substrate scope and high chemoselectivity, providing
effective access to valuable chiral amino acid derivatives with
high enantioselectivities. The key to the success of controlling
both reactivity and enantioselectivity of this intermolecular
radical process is the development of a Co(II)-based
metalloradical catalyst through fine-tuning of the remote
substituents of the D2-symmetric chiral amidoporphyrin ligand
to maximize cooperative noncovalent attractive interactions.
ACKNOWLEDGMENTS
■
We are grateful for financial support by NIH (Grant R01-
GM132471) and in part by NSF (Grant CHE-1900375). We
thank James Zhang (Johns Hopkins University) for helpful
discussions with valuable suggestions.
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