Enantioconvergent Amination of Racemic Tertiary C-H Bonds

Article abstract of DOI:10.1021/jacs.0c11103

Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in traditional radical halogenation reactions of optically active tertiary C-H bonds. If the facile process of radical racemization could be effe

Full text of DOI:10.1021/jacs.0c11103

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Enantioconvergent Amination of Racemic Tertiary C−H Bonds
Kai Lang,§ Chaoqun Li,§ Isaac Kim, and X. Peter Zhang*
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ABSTRACT: Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in
traditional radical halogenation reactions of optically active tertiary C−H bonds. If the facile process of radical racemization could be
effectively combined with an ensuing step of bond formation in an enantioselective fashion, then it would give rise to deracemizative
functionalization of racemic tertiary C−H bonds for stereoselective construction of chiral molecules bearing quaternary
stereocenters. As a demonstration of this unique potential in radical chemistry, we herein report that metalloradical catalysis can be
successfully applied to devise Co(II)-based catalytic system for enantioconvergent radical amination of racemic tertiary C(sp3)−H
bonds. The key to the success of the radical process is the development of Co(II)-based metalloradical catalyst with fitting steric,
electronic, and chiral environments of the D2-symmetric chiral amidoporphyrin as the supporting ligand. The existence of optimal
reaction temperature is recognized as an important factor in the realization of the enantioconvergent radical process. Supported by
an optimized chiral ligand, the Co(II)-based metalloradical system can effectively catalyze the enantioconvergent 1,6-amination of
racemic tertiary C(sp3)−H bonds at the optimal temperature, affording chiral α-tertiary amines in excellent yields with high
enantiocontrol of the newly created quaternary stereocenters. Systematic studies, including experiments utilizing optically active
deuterium-labeled C−H substrates as a model system, shed light on the underlying mechanistic details of this new catalytic process
for enantioconvergent radical C−H amination. The remarkable power to create quaternary stereocenters bearing multiple
functionalities from ubiquitous C−H bonds, as showcased with stereoselective construction of bicyclic N-heterocycles, opens the
door for future synthetic applications of this new radical technology.
radical addition, H-atom abstraction, and subsequent radical
substitution, but in a controlled and selective manner, creating
new catalytic systems for asymmetric radical transformations.7
Our recent efforts to control the enantioselectivity of radical
heterocyclization uncovered two basic modes of asymmetric
induction in intramolecular radical C−H amination of organic
azides via Co(II)-MRC (Scheme 1).7d,e,8 The two modes differ
in the enantiodetermining step of the stepwise radical process:
H-atom abstraction in Mode A (Scheme 1A) and radical
substitution in Mode B (Scheme 1B). Although they were both
derived from studying the amination reactions of secondary
C−H bonds, we were fascinated by the exciting possibility of
enantioconvergent amination of racemic tertiary C−H bonds
via Mode B (Scheme 1C). As illustrated for 1,6-C−H
amination of sulfamoyl azides, efficient H-atom abstraction of
INTRODUCTION
■
Homolytic radical chemistry has been increasingly explored for
the development of new synthetic tools to construct organic
molecules in light of its rich reactivities and practical
attributes.1 Despite significant advancements, control of
enantioselectivity remains a major challenge for many radical
reactions, calling for innovative new solutions and fundamental
mechanistic studies. Among recent approaches,2 metalloradical
catalysis (MRC) represents a conceptually distinct strategy for
achieving stereoselective radical reactions by exploiting metal-
centered radicals as a new class of catalysts that are capable of
activating substrates homolytically while translocating the spin
density to generate metal-bonded organic radicals for
subsequent radical processes under the catalyst control.3−5
To this end, Co(II) complexes of porphyrins, as stable 15e-
metalloradicals, have recently been demonstrated to be
effective catalysts for the homolytic activation of organic
azides to form the fundamentally new α-Co(III)-aminyl
radicals.6 Supported by D2-symmetric chiral amidoporphyrin
(D2-Por*) ligands, the resulting Co-stabilized N-centered
radicals, which are situated inside a pocket-like chiral
environment, can undergo common radical reactions, such as
Received: October 21, 2020
https://dx.doi.org/10.1021/jacs.0c11103
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© XXXX American Chemical Society
A

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metalloradical catalysis that utilizes the facile nature of radical
racemization and enables, for the first time, asymmetric
intramolecular amination of tertiary C−H bonds. We show
that the Co(II)-based metalloradical system can catalyze
enantioconvergent 1,6-C(sp3)−H amination of various sulfa-
moyl azides containing racemic tertiary C−H bonds, affording
six-membered chiral cyclic sulfamides in excellent yields with
high enantiocontrol of the newly generated quaternary
stereocenters. Additionally, we present mechanistic studies
that offer insights into the underlying radical mechanism and
reveal the origin of enantioconvergence in the Co(II)-catalyzed
amination of racemic tertiary C−H bonds. To showcase the
synthetic applications of this new methodology, we also
describe the stereoselective construction of several fused-
bicyclic N-heterocycles.
Scheme 1. Modes of Asymmetric Induction and
Enantioconvergence in Radical C−H Amination via Co(II)-
MRC
RESULTS AND DISCUSSION
■
Catalyst Development. At the onset of this study, we
selected N-benzyl sulfamoyl azide ( )-1a bearing racemic
tertiary C−H bonds substituted with ester and phenyl groups
as a testing substrate for the proposed enantioconvergent
amination via Co(II)-MRC (Scheme 2). After initial
optimization of conditions, the catalytic intramolecular C−H
amination of azide ( )-1a was conducted at 50 °C in benzene
with the use of different [Co(D2-Por*)] complexes as chiral
metalloradical catalysts. As detailed below (Scheme 3B), the
Scheme 2. Ligand Effect on Co(II)-Catalyzed Enantio-
convergent Amination of Racemic Tertiary C−H Bonds
a b
,
tertiary C−H bonds by the initially formed α-Co(III)-aminyl
radicals I serves as a prerequisite. However, the central
challenge for achieving such unparalleled enantioconvergent
C−H amination lies in the contrasting ligand environments
required by the two subsequent radical steps. While capacious
space is needed for the two chiral faces in the resulting ζ-
Co(III)-alkyl radicals (Re)-II and (Si)-II to undergo facile
racemization, confined space will benefit asymmetric induction
in the last step of radical substitution to ensure high
enantioconvergence (Scheme 1C). Considering the tunability
of the modular D2-Por* chiral platform, we envisioned the
prospect of identifying a suitable ligand with fitting steric,
electronic, and chiral environments that could accommodate
the seemly opposite demands. If this feat could be achieved,
then it would lead to a new radical process that would be able
to deracemize racemic tertiary C(sp3)−H bonds in hydro-
carbons for the production of valuable α-tertiary amines as a
single enantiomer (see Figure S1 in Supporting Information,
SI).9
Catalytic intramolecular C(sp3)−H amination represents an
attractive approach for the construction of chiral N-hetero-
cycles through direct functionalization of ubiquitous C−H
bonds in organic molecules.10 Despite considerable efforts,
enantioselective variants of intramolecular C−H amination
remain underdeveloped.11,12 Until now, there has been limited
success of catalytic systems that are capable of converting both
enantiomers of tertiary C−H substrates into a single
enantiomer of α-tertiary amine derivatives.13 This is perhaps
no surprise considering that existing catalytic systems for C−H
amination typically proceed via a concerted C−H insertion
pathway involving metallonitrene intermediates, which lacks a
mechanism for racemization like the radical processes. We
herein report a new catalytic radical process via Co(II)-based
a
Carried out in benzene at 50 °C for 24 h using 2 mol % [Co(Por*)]
on 0.10 mmol scale under N2 in the presence of 4 Å MS; [azide 1a] =
b
0.1 M; Isolated yields. [R] Absolute configuration determined by X-
ray crystallography.
B
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DitBu-QingPhyrin)15 was used, a considerable improvement in
enantioselectivity (from 81:19 er to 86:14 er) was observed
while the high product yield (94%) was restored. Interestingly,
the major enantiomer switched from (S)-2a to (R)-2a. Further
enhancement in asymmetric induction was achieved with the
replacement of the catalyst by [Co(P4)] (P4 = 2,6-DiMeO-
QingPhyrin), which maintained the high yield for 2a
production with (R)-2a as the major enantiomer. Under
optimized conditions, the enantioconvergent 1,6-amination of
the racemic tertiary C−H bond of ( )-1a could be effectively
catalyzed by [Co(P4)] to deliver the cyclic α,γ-diamino acid
derivative 2a in 93% yield with 93:7 er. The absolute
configuration of the newly created quaternary stereocenter in
the major (R)-2a was established by X-ray crystallography.
Substrate Scope. Under the optimized conditions, the
[Co(P4)]-based system proved to be generally effective for the
enantioconvergent 1,6-amination of racemic tertiary C(sp3)−
H bonds in sulfamoyl azides ( )-1 bearing different
substituents (Table 1). In addition to the reaction of sulfamoyl
azide ( )-1a with ethyl ester, the Co(II)-based enantiocon-
vergent amination could be effectively applied to tertiary C−H
bonds in sulfamoyl azides having various ester functionalities
such as methyl (( )-1b), isopropyl (( )-1c), and isobutyl
(( )-1d) esters, affording the cyclic α,γ-diamino esters
(+)-2a−2d in equally high yields with similar enantioselectiv-
ities (Table 1; entries 1−4). Similarly, tertiary C−H bonds in
sulfamoyl azides bearing different aryl substituents with varied
electronic properties, including those with 4-methyl (( )-1e),
4-methoxy (( )-1f), 3-methoxy (( )-1g), 4-bromo (( )-1h),
4-chloro (( )-1i), 4-fluoro (( )-1j), 4-nitro (( )-1k), and 4-
trifluoromethyl (( )-1l) phenyl groups, could all be
enantioconvergently aminated to form the corresponding six-
membered cyclic sulfamides (+)-2e−(−)-2l bearing quater-
nary stereocenters in high yields with high enantioselectivities
(Table 1; entries 5−12). Besides the substrates with ester
functionalities, the Co(II)-catalyzed enantioconvergent amina-
tion system could also be applied to tertiary C−H substrates
with ketone functionality as exemplified by the enantioselective
transformation of sulfamoyl azide ( )-1m to cyclic α,γ-
diamino ketone (+)-2m in high yield (Table 1; entry 13).
Likewise, the catalytic system by [Co(P4)] could tolerate
Scheme 3. Time Course and Temperature Dependence of
Co(II)-Based Enantioconvergent Tertiary C−H Amination
reaction temperature was recognized as an important factor in
achieving the enantioconvergent process. To our delight, the
first-generation catalyst [Co(P1)] (P1 = 3,5-DitBu-ChenPhyr-
in)14 could effectively catalyze 1,6-amination of the racemic
tertiary C−H bond of ( )-1a, affording six-membered cyclic
sulfamide 2a in high yield (93%) at a significant level of
enantioselectivity (81:19 er) with (S)-2a as the major
enantiomer. These preliminary results serve as a proof of
concept for the enantioconvergent amination of racemic C−H
bonds. In the hopes of improving the enantioconvergence of
the Co(II)-catalyzed process, the effect of D2-Por* chiral
ligands was systematically evaluated (see Figure S2 in the SI).
Switching the catalyst to [Co(P2)] (P2 = 2,6-DiMeO-
ChenPhyrin),14 which bears the same chiral amide units but
more sterically hindered achiral meso-aryl groups, led to no
change in the enantioselectivity and sense of asymmetric
induction, but substantial decrease in product yield (22%).
When the second-generation catalyst [Co(P3)] (P3 = 3,5-
a b
,
Table 1. [Co(P4)]-Catalyzed Enantioconvergent Amination of Racemic Tertiary C−H Bonds in Different Sulfamoyl Azides
a
Carried out in benzene at 50 °C for 24 h using 2 mol % [Co(P4)] on 0.10 mmol scale under N2 in the presence of 4 Å MS; [azide 1] = 0.1 M.
b
Isolated yields.
C
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a
Table 2. Assessment of Asymmetric Induction Mode in Radical 1,6-C−H Amination through KIE Study of Isotopomers
a
Carried out in benzene at 50 °C for 48 h using 2 mol % [Co(Por)] on 0.10 mmol scale under N2 in the presence of 4 Å MS; [azide 1q] = 0.1 M;
b
c
d
e
yields in SI. 4 mol % [Co(Por)]. Ratio of H:D determined by 1H NMR spectroscopy. Calculated based on the ratio of H:D. ee of 2q calculated
on the basis of stereoretentive RS. ee of 2q determined by chiral HPLC analysis, which offered no separation of (R)-2qH from (R)-2qD and (S)-
2qH from (S)-2qD. [R] Absolute configuration determined by comparison of HPLC data with that of nondeuterated (R)-2q, the structure of
f
g
which was confirmed by X-ray crystallography.
substrates containing formyl functionality as demonstrated
with the chemoselective amination of C−H bonds in sulfamoyl
azides ( )-1n and ( )-1o, affording the desired chiral cyclic
α,γ-diamino aldehydes (+)-2n and (+)-2o in high yields with
high enantioconvergence (Table 1; entries 14 and 15).
Additionally, allylic tertiary C−H bonds could also be
enantioconvergently aminated by [Co(P4)] as illustrated by
the effective reaction of cyclopentene-derived azide ( )-1p,
leading to the stereoselective construction of spirobicyclic
sulfamide (−)-2p in high yield without affecting the endocyclic
CC double bond (Table 1; entry 16). It is worthy to
appreciate the peculiar ability of catalyst [Co(P4)] to
discriminate the two endocyclic chiral faces that differ by
only one π-bond for enantioconvergent formation of (−)-2p,
albeit with the relatively lower enantioselectivity. It should be
noted that the catalytic system by [Co(P4)] was found to be
sensitive to both the steric hindrance and the nature of the
substituents around the tertiary C−H bond. For example,
sulfamoyl azides bearing ortho-substituted arenes and esters,
including even those derived from 1-naphthalen and 3-indole,
were shown to be ineffective substrates for the catalytic
transformation. When the aryl/ester substituents in the
sulfamoyl azides were replaced by either alkyl/ester or aryl/
alkyl groups, they afforded the corresponding C−H amination
products in similarly high yield but with much lower
enantioselectivities. It is evident that new Co(II)-based
catalytic systems supported by different D2-symmetric chiral
amidoporphyrins need to be developed in order to effectively
catalyze enantioconvergent 1,6-amination of racemic tertiary
C(sp3)−H bonds in sulfamoyl azides bearing substituents
beyond the combination of aryl and ester groups.
(Scheme 3A). The enantiomeric excess of amination product
(+)-2a reached to a maximum level at the beginning that
remained unchanged throughout the entire reaction. Interest-
ingly, the remaining azide 1a was found to undergo steady
enantioenrichment during the course of the catalytic reaction,
starting from racemic and becoming highly enriched by the
end. This result indicates that the pocket-like chiral catalyst
[Co(P4)] preferentially bound one of the two enantiomers of
azide ( )-1a and then irreversibly activated it for generation of
the corresponding α-Co(III)-aminyl radical intermediate I1a,
which was in turn transformed to the specific (Re)- or (Si)-ζ-
Co(III)-alkyl radical II1a by subsequent 1,6-H-atom abstrac-
tion (Scheme 1C). However, the stereoselective generation of
intermediates (Re)-II1a or (Si)-II1a was clearly nonconsequen-
tial to the enantioselectivity of amination product 2a as it
remained the same throughout the catalytic process. Together,
it is evident that the two chiral faces in the resulting ζ-Co(III)-
alkyl radicals (Re)-II and (Si)-II could undergo facile
racemization, rendering the final radical substitution as the
enantiodetermining step (Scheme 1C). During the course of
the study, we uncovered an unusual dependence of
enantioselectivity on reaction temperature, which further
illustrates the combined importance of racemization and
radical substitution in the enantioconvergent process. As
shown in Scheme 3B, the C−H amination reaction of azide
( )-1a by [Co(P4)] was carried out at varied temperatures
under the otherwise same standard conditions. When the
reaction temperature was gradually elevated from room
temperature, the enantioselectivity progressively increased
until reaching a maximum ee of 86% at 50 °C (Scheme 3B).
Further elevation of the reaction temperature up to 70 °C led
to a decrease in enantioselectivity. Collectively, these results
agree well with the proposed catalytic mechanism for
enantioconvergent amination that demands a high enough
temperature to accelerate the racemization between the radical
intermediates (Re)-II and (Si)-II but a low enough temper-
ature to favor asymmetric induction for subsequent radical
substitution (Scheme 1C). Consequently, there exists an
optimal reaction temperature at which a given catalytic system
Time Course and Temperature Dependence. To shed
light on the working details of the enantioconvergent process, a
time-course study for asymmetric amination of the racemic
tertiary C−H bond in azide ( )-1a by [Co(P4)] was
performed under the standard conditions. The yield and
enantiomeric excess of the amination product (+)-2a, along
with the remaining azide 1a and its enantiomeric excess, were
continuously monitored over the course of the reaction
D
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Scheme 4. Detection, Trapping, and Probing of Radical Intermediates in Co(II)-Catalyzed Amination of Tertiary C−H Bonds
can achieve maximal enantioselectivity for enantioconvergent
C−H amination.
Enantiodifferentiative pro-R H-atom abstraction was also
observed with chiral catalysts [Co(P3)] (Table 2; entries 9
and 10) and [Co(P4)] (Table 2; entries 11 and 12) but to a
lesser extent. The measured KIE values were translated to give
the ratios of the initially established prochiral faces (Re)-II1q
and (Si)-II1q. These ratios were then used to generate
calculated enantiomeric excesses (ee%cal) for the amination
product 2q by assuming no racemization of the facial chirality
in the subsequent radical substitution step. The observation of
much lower enantiomeric excesses than predicted for the
reactions catalyzed by achiral catalysts [Co(P5)] and [Co-
(P6)] indicates significant but incomplete racemization of the
initial facial chirality via α-C−C bond rotation prior to radical
substitution (Table 2; entries 1−4). For both chiral catalysts
[Co(P1)] and [Co(P2)], in addition to much lower
enantiomeric excesses than predicted, they catalyzed the
production of (S)-2q as the major enantiomer with identical
ee values for both reactions with (S)-1q and (R)-1q (Table 2;
entries 5−8), revealing facile interconversion between (Re)-
II1q and (Si)-II1q and confirming radical substitution as the
major enantiodetermining step. Enantioconvergence was also
exhibited by chiral catalyst [Co(P3)], which produced the
opposite (R)-2q as the major enantiomer with higher averaged
enantioselectivity of 32% ee (Table 2; entries 9 and 10).
Further enhancement in enantioconvergence was achieved by
chiral catalyst [Co(P4)], which afforded (R)-2q as the same
major enantiomer with averaged enantioselectivity of 70% ee
(Table 2; entries 11−13). Specifically, [Co(P4)] enabled
stereoretentive amination of (S)-1q to produce (R)-2q with
94% ee while catalyzing the stereoinvertive amination of (R)-
1q to produce (R)-2q with 46% ee. Together with the time-
course study (Scheme 3A) and the existence of optimal
Asymmetric Induction Mode. To gain insight into the
likely origin of asymmetric induction in the enantioconvergent
process, isotopomeric sulfamoyl azides (S)-1q and (R)-1q
were prepared in optically pure forms and employed as the
substrates to study kinetic isotope effects (KIE) (Table 2). It
should be noted that (S)-1q and (R)-1q are the best possible
deuterated tertiary C−H models for the actual substrates in
Table 1 to study KIE of asymmetric amination of racemic
tertiary C−H bonds. Using the achiral catalyst [Co(P5)] (P5
= 3,5-DitBu-IbuPhyrin), the intramolecular kinetic isotope
effects (KIE) for both reactions of azides (S)-1q and (R)-1q
were determined to have the same value of 13.0 (Table 2;
entries 1 and 2). Similarly, matching KIE values of 11.0 were
obtained for both of the reactions when the analogous achiral
catalyst [Co(P6)] (P6 = 2,6-DiMeO-IbuPhyrin) was used
(Table 2; entries 3 and 4). These high values of primary KIE
are in accordance with the proposed step of C−H bond
cleavage through the 1,6-H-atom abstraction of tertiary C−H
bonds by the initially formed α-Co(III)-aminyl radicals I
(Scheme 1C). When a chiral catalyst is employed, deviation
from the intrinsic KIE will be anticipated (higher in the
chirality-matched case and lower in the chirality-mismatched
case) if the H-atom abstraction is enantioselective. With the
use of chiral catalyst [Co(P1)], the same KIE values of 12.0
were obtained for both (S)-1q and (R)-1q (Table 2; entries 5
and. 6), indicating a non-enantiodifferentiative H-atom
abstraction by [Co(P1)]. However, switching to chiral catalyst
[Co(P2)] raised the KIE to 27.0 for (S)-1q while lowering it
to 10.0 for (R)-1q, suggesting preferential abstraction of pro-R
over pro-S H-atom by [Co(P2)] (Table 2; entries 7 and 8).
E
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Scheme 5. Synthetic Applications of Catalytic Products for Stereoselective Construction of Fused-Bicyclic N-Heterocycles
temperature (Scheme 3B), these results from the deuterated
model system suggest Mode B (Scheme 1) as a major pathway
for the observed enantioconvergence. In addition to effective
enantiocontrol of the radical substitution step, these data
clearly signified the equal importance of facile interconversion
between intermediates (Re)-II and (Si)-II to achieve highly
enantioconvergent process for the amination of racemic
tertiary C−H bonds (Scheme 1C).
Detection, Trapping, and Probing of Radical Inter-
mediates. While radical intermediates associated with
secondary C−H amination were previously established,7d,e,8
we were intrigued by whether the α-Co(III)-aminyl radical I
and especially the resulting ζ-Co(III)-alkyl radicals II from 1,6-
H-atom abstraction of tertiary C−H bonds could be detected,
trapped, and probed. To directly detect the radical
intermediates, the isotropic electron paramagnetic resonance
(EPR) spectrum was recorded at room temperature for the
reaction solution of [Co(P5)] with azide ( )-1i in benzene
after heating at 50 °C for 5 min (Scheme 4A). The spectrum
displays diagnostic signals at g-value of ∼2.00 that are
characteristic of α-Co(III)-aminyl radicals and related radical
species.7d,e,8 Consistent with the proposed stepwise radical
mechanism involving the key step of 1,6-H-atom abstraction,
the observed broad signals could be fittingly simulated as a
mixture of α-Co(III)-aminyl radical and ζ-Co(III)-alkyl radical
on the basis of couplings by 59Co (I = 7/2) and 14N (I = 1):
95% of N-centered radical at α-position I[Co(P5)]/1i (g: 2.00258;
tertiary allylic radical by trapping its less sterically hindered
resonance form as a primary allylic radical (Scheme 4B). When
the amination of azide ( )-1r was catalyzed by [Co(P5)] in
the presence of excess TEMPO (5.0 equiv), no formation of
the corresponding six-membered cyclic sulfamide 2r was
detected, indicating complete inhibition of 1,6-C−H amination
by TEMPO. While the acyclic sulfamide 3r from direct
TEMPO-trapping of the tertiary radical intermediate
II[Co(P5)]/1r was expectedly absent from the reaction mixture,
the TEMPO-containing acyclic sulfamide 4r bearing a
trisubstituted (E)-olefin unit was isolated in 62% yield.
Successful formation of 4r from the trapping of the primary
allyl radical III[Co(P5)]/1r by TEMPO implies that the tertiary
allylic radical intermediate II[Co(P5)]/1r was generated following
1,6-H-atom abstraction of the tertiary C−H bond in the
initially formed α-Co(III)-alkyl radical I[Co(P5)]/1r. The high
(E)-stereoselectivity observed for the formation of 4r is likely a
steric outcome of the trisubstituted olefin inside the
amidoporphyrin ligand environment. Furthermore, azides
( )-1s and ( )-1t bearing a cyclopropyl ring were synthesized
as radical-clock substrates to probe the lifetime of the
corresponding ζ-Co(III)-alkyl radical intermediates (Scheme
4C). Under the catalysis of [Co(P5)], the reaction of ( )-1s
afforded acyclic sulfamide 3s in 37% yield in addition to
forming cyclic sulfamide 2s in 37% yield while cyclic sulfamide
2t was obtained in 89% yield without formation of acyclic
sulfamide 3t from the reaction of ( )-1t. In both reactions, the
ring-opening product 4s and 4t were not observed. When the
reaction of ( )-1s was further carried out in the presence of
TEMPO, there was no evidence for formation of any TEMPO-
trapped ring-opening product either.16 Together, these results
indicated that the C−N bond formation via intramolecular
radical substitution was faster than the ring-opening of the
tertiary cyclopropylcarbinyl radicals within the pocket-like
ligand environment of the catalyst.17
A
(Co): 4.2 MHz; A(N): 33.8 MHz) and 5% of C-centered radical
at ζ-position II[Co(P5)]/1i (g: 2.00440; A(Co): 0 MHz; A(N): 0
MHz). In addition to the EPR detection, we made multiple
attempts in trapping ζ-Co(III)-alkyl radical intermediates from
Co(II)-catalyzed tertiary C−H amination of sulfamoyl azides
by TEMPO. However, formation of TEMPO-trapped products
could not be identified. This negative outcome of the trapping
experiments was attributed to the larger steric hindrance of
tertiary alkyl radicals. Accordingly, sulfamoyl azide ( )-1r that
contains an allylic tertiary C−H bond was designed as a
substrate with the aim of probing the intermediacy of the
Synthetic Applications. Considering its capacity for
creating quaternary stereocenters bearing multiple function-
alities, Co(II)-catalyzed enantioconvergent C−H amination
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could potentially be utilized for a variety of synthetic
applications. For instance, the resulting six-membered cyclic
sulfamides serve as convenient precursors for chiral α,γ-
diamino acid derivatives upon desufonylation7d and are also
important chiral heterocycles in their own right (see Figure S1
in the SI).18 To further showcase their synthetic utilities, the
amino and ester groups at the quaternary stereocenter were
demonstrated as useful functionalities for stereoselective
construction of fused-bicyclic N-heterocycles as exemplified
with the three applications of enantioenriched cyclic α,γ-
diamino ester (R)-2a (Scheme 5). The amino group in (R)-2a
could be efficiently alkylated with 2-azidoethylmethanesulfo-
nate to produce azide 3a in excellent yield (97%). Selective
hydrogenation of the azide group in 3a led to the formation of
primary amine, which was converted in situ to cyclic sulfamide-
fused piperazinone 4a through lactamization in the presence of
base. The [4.4.0]-bicyclic N-heterocycle (R)-4a was not only
constructed in excellent yields after two steps (95%) but also
fully retained the original optical purity (Scheme 5A). The
absolute configuration of structure 4a was determined by X-ray
crystallography (Scheme 5A). Alternatively, the ester group in
2a could be selectively reduced with DIBAL-H to give
aldehyde 2n in 87% yield. Subsequent N-alkylation with 2-
azidoethylmethanesulfonate afforded compound 3c, which
contains both formyl and azido functionalities, in 90% yield.
It was discovered that the aliphatic azide unit in 3c could be
effectively activated by metalloradical catalyst [Co(P5)] to
undergo an unusual intramolecular amination of the C(sp3)−
C(sp2) bond associated with the formyl group (Schmidt-type
reaction in the absence of acids). The resulting cyclic
sulfamide-fused imidazoline (R)-4b was isolated in 91% yield
with full retention of the original enantiopurity and absolute
configuration as determined by X-ray crystallography (Scheme
5B). The [Co(P5)]-catalyzed construction of [4.3.0]-bicyclic
N-heterocycle (R)-4b from cyclic sulfamide (R)-2a can be
conceived to proceed through an unprecedented radical
cascade process involving four different types of radicals: the
Co(II)-based metalloradical as well as N-, O-, and C-centered
organic radicals (Scheme 5B). Upon metalloradical activation
of the aliphatic azide in (R)-3c by [Co(P5)], the initially
generated α-Co(III)-aminyl radical intermediate I3c would
proceed 6-exo-trig radical addition to the nearby-located
carbonyl group to form γ-Co(III)-alkoxyl radical intermediate
II3c, which would then undergo radical β-scission to generate
the more stable ε-Co(III)-alkyl radical intermediate III3c.
Subsequent 5-exo-tet radical substitution would transform
intermediate III3c into the final product (R)-4b while
regenerating catalyst [Co(P5)]. Remarkably, both the absolute
configuration and the optical purity of the quaternary
stereocenter were preserved during the catalytic radical
transformation by achiral catalyst [Co(P5)], which is likely
attributed to the configurational stability of the rigid chiral face
in radical intermediate III3c within the catalyst environment.
The amino group in aldehyde 2n could also be alkylated with
o-azido-m-fluorobenzyl bromide to afford compound 3d in
excellent yield (96%). In contrast with the reaction of aliphatic
azide in 3c, it was found that the aryl azide in 3d could be
activated by metalloradical catalyst [Co(P1)] to carry out
intramolecular decarbonylative amination of the closely
positioned formyl group, delivering cyclic sulfamide-fused
tetrahydroquinazoline (R)-4c in 72% yield (Scheme 5C). As
with the formation of the fused 5-membered imidazoline in
(R)-4b, the fused six-membered tetrahydroquinazoline in (R)-
4c was constructed with near complete preservation of the
original enantiopurity and retention of the absolute config-
uration as determined by X-ray crystallography. It is evident
that a different radical cascade process occurred for the
construction of [4.4.0]-bicyclic N-heterocycle (R)-4c (Scheme
5C). Presumably, the corresponding α-Co(III)-aminyl radical
intermediate I3d resulting from metalloradical activation of the
aryl azide in (R)-3d by [Co(P1)] would prefer 1,7-H-atom
abstraction from the aldehydic C(sp2)−H bond over 7-exo-trig
radical addition to the CO bond, forming η-Co(III)-acyl
radical intermediate II3d. Subsequent radical α-scission would
convert the acyl radical II3d to the more stable ζ-Co(III)-alkyl
radical intermediate III3d upon release of CO. The final 6-exo-
tet radical substitution would transform the tertiary radical III3d
to product (R)-4c stereospecifically without racemization of
the configurationally stable chiral face while regenerating
catalyst [Co(P1)]. Considering their unique three-dimensional
structures with the rigid bicyclic framework that contains a
bridgehead quaternary stereocenter bearing multiple function-
alities, this new class of bicyclic sulfamide-fused N-heterocycles
4a−4c may find potential applications in drug research and
development.19
CONCLUSIONS
■
In summary, we have unveiled a new radical approach that
promises deracemizative functionalization of racemic tertiary
C(sp3)−H bonds for the stereoselective synthesis of chiral
molecules with enantioconvergent construction of quaternary
stereogenic centers. Fundamental knowledge acquired from
our ongoing development of the emerging metalloradical
catalysis (MRC) has enabled us to harness the potential of
homolytic radical chemistry for the validation of this attractive
approach by sequentially conjoining H-atom abstraction,
radical racemization, and radical substitution in a controlled
and enantioselective fashion. As the first application of this
potentially general approach, we have successfully developed a
new catalytic radical process via Co(II)-based metalloradical
catalysis (Co(II)-MRC) that allows for the enantioconvergent
amination of racemic tertiary C−H substrates. As suggested by
the mechanistic studies, development of D2-symmetric chiral
amidoporphyrin ligand platform that creates a well-balanced
environment for the Co(II)-based metalloradical catalyst is the
key to the success of the catalytic process. This environment
facilitates 1,6-H-atom abstraction of tertiary C−H bonds and
subsequent racemization of the resulting prochiral face while
simultaneously enhancing asymmetric induction of radical
substitution for construction of the quaternary stereogenic
center. Furthermore, the existence of optimal reaction
temperature is recognized as a characteristic feature of such
an enantioconvergent radical process. Under the support of the
optimized ligand 2,6-DiMeO-QingPhyrin, the Co(II)-based
enantioconvergent system can catalyze 1,6-amination of
racemic tertiary C−H bonds in sulfamoyl azides under mild
conditions, leading to the stereoselective construction of six-
membered cyclic sulfamides bearing chiral α-tertiary amines at
the newly generated quaternary stereocenters in excellent
yields with high enantioselectivities. Considering the unparal-
leled power to create quaternary stereocenters bearing multiple
functionalities from ubiquitous C−H bonds, this new
enantioconvergent amination methodology should find broad
applications in organic synthesis, as showcased with the
stereoselective construction of bicyclic N-heterocycles. It is our
hope that this study will stimulate further research efforts in
G
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Article
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11103.
■
sı
Experimental details and analytical data for all new
compounds (PDF)
Analytical data (ZIP)
Analytical data (ZIP)
̈
Shen, X. D.; Wang, C. Y.; Zhang, L. L.; Rose, P.; Chen, L. A.; Harms,
AUTHOR INFORMATION
Corresponding Author
K.; Marsch, M.; Hilt, G.; Meggers, E. Asymmetric Photoredox
Transition-Metal Catalysis Activated by Visible Light. Nature 2014,
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L.; Peters, J. C.; Fu, G. C. Asymmetric Copper-Catalyzed C−N Cross-
Couplings Induced by Visible Light. Science 2016, 351, 681−684.
(i) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S.
S.; Liu, G. Enantioselective Cyanation of Benzylic C−H Bonds via
Copper-Catalyzed Radical Relay. Science 2016, 353, 1014−1018.
■
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
Authors
Kai Lang − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0003-2778-8478
Chaoqun Li − Department of Chemistry, University of South
Florida, Tampa, Florida 33620, United States
Isaac Kim − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
(j) Funken, N.; Muhlhaus, F.; Gansauer, A. General, Highly Selective
̈
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Synthesis of 1,3- and 1,4-Difunctionalized Building Blocks by
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Enantioselective Synthesis of an Ophiobolin Sesterterpene via a
Programmed Radical Cascade. Science 2016, 352, 1078−1082.
(l) Kern, N.; Plesniak, M. P.; McDouall, J. J. W.; Procter, D. J.
Enantioselective Cyclizations and Cyclization Cascades of Samarium
Ketyl Radicals. Nat. Chem. 2017, 9, 1198−1204. (m) Morrill, C.;
Jensen, C.; Just-Baringo, X.; Grogan, G.; Turner, N. J.; Procter, D. J.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11103
Author Contributions
§These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support by NIH (R01-
GM132471) and in part by NSF (CHE-1900375). We thank
James G. Zhang (Johns Hopkins University) for helpful
discussion with valuable suggestions.
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