Metalloradical activation of carbonyl azides for enantioselective radical aziridination

Article abstract of DOI:10.1016/j.chempr.2021.03.001

The carbonyl azide TrocN₃ (2,2,2-trichloroethoxycarbonyl azide) is a potent nitrogen radical precursor for radical olefin aziridination via Co(II)-based metalloradical catalysis (MRC). The cobalt(II) complex of D₂-symmetric chiral amidoporphyrin 3,5-Di^tBu-QingPhyrin proves to be an efficient catalyst that can activate TrocN₃ at room temperature to aziridinate various styrene derivatives, providing chiral N-carbonyl aziridines in high yields with excellent enantioselectivities. The new Co(II)-based catalytic system can even enable asymmetric aziridination of electron-deficient alkenes, such as methyl and ethyl acrylates. In addition to facile removal of Troc group for generation of unprotected aziridines, the resulting N-Troc-aziridines can be effectively opened by different types of nucleophiles to afford a series of chiral amine derivatives with excellent stereospecificity. Several lines of computational and experimental evidence support the underlying stepwise radical mechanism for Co(II)-catalyzed olefin aziridination. This represents the first example of asymmetric intermolecular olefin aziridination that employs carbonyl azides as the nitrogen source.

Full text of DOI:10.1016/j.chempr.2021.03.001

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Metalloradical activation of carbonyl azides for
enantioselective radical aziridination
Xavier Riart-Ferrer, Peng Sang,
Jingran Tao, ..., Xin Cui, Lukasz
Wojtas, X. Peter Zhang
peter.zhang@bc.edu
Highlights
Catalytic system for
enantioselective aziridination of
alkenes with TrocN3
Highly enantioselective synthesis
of chiral N-Troc-aziridines at room
temperature
Systematic demonstration of
chiral N-Troc-aziridines for
stereoselective synthesis
Detailed mechanistic studies on
elucidation of underlying stepwise
radical pathway
A Co(II)-based system has been developed for enantioselective radical
aziridination of alkenes using the carbonyl azide TrocN3 as the nitrogen source.
The catalytic system, which operates at room temperature under neutral and
nonoxidative conditions, is applicable to both aromatic and electron-deficient
olefins and enables the synthesis of N-carbonyl aziridines in high yields with
excellent enantioselectivities. The enantioenriched N-carbonyl aziridines have
been demonstrated as valuable intermediates for stereoselective organic
synthesis. The Co(II)-catalyzed aziridination has been shown to proceed with
stepwise radical mechanism.
Riart-Ferrer et al., Chem 7, 1120–1134
April 8, 2021 ª 2021 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2021.03.001

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Metalloradical activation of carbonyl azides
for enantioselective radical aziridination
Xavier Riart-Ferrer,1,3 Peng Sang,2,3 Jingran Tao,2,3 Hao Xu,1 Li-Mei Jin,1 Hongjian Lu,2 Xin Cui,2
Lukasz Wojtas,2 and X. Peter Zhang1,4,
*
SUMMARY
The bigger picture
Organic azides have been
The carbonyl azide TrocN3 (2,2,2-trichloroethoxycarbonyl azide) is a
potent nitrogen radical precursor for radical olefin aziridination via
Co(II)-based metalloradical catalysis (MRC). The cobalt(II) complex
of D2-symmetric chiral amidoporphyrin 3,5-DitBu-QingPhyrin
proves to be an efficient catalyst that can activate TrocN3 at room
temperature to aziridinate various styrene derivatives, providing
chiral N-carbonyl aziridines in high yields with excellent enantiose-
lectivities. The new Co(II)-based catalytic system can even enable
asymmetric aziridination of electron-deficient alkenes, such as
methyl and ethyl acrylates. In addition to facile removal of Troc
group for generation of unprotected aziridines, the resulting N-
Troc-aziridines can be effectively opened by different types of nu-
cleophiles to afford a series of chiral amine derivatives with excel-
lent stereospecificity. Several lines of computational and experi-
mental evidence support the underlying stepwise radical
mechanism for Co(II)-catalyzed olefin aziridination. This represents
the first example of asymmetric intermolecular olefin aziridination
that employs carbonyl azides as the nitrogen source.
increasingly employed as
nitrogen sources for catalytic
olefine aziridination due to their
ease of preparation and
generation of benign N2 as the
only byproduct. Among common
organic azides, carbonyl azides
have not been previously
demonstrated as effective
nitrogen sources for
intermolecular olefin aziridination
despite the synthetic utilities of N-
carbonyl aziridines. As a new
application of metalloradical
catalysis, we have developed a
catalytic system that can
effectively employ the carbonyl
azide TrocN3 for highly
asymmetric aziridination of
alkenes at room temperature. The
resulting enantioenriched N-Troc-
aziridines have been shown as
valuable chiral synthons for
stereoselective synthesis of other
chiral aziridines and various chiral
amines. The Co(II)-based
INTRODUCTION
The development of selective radical reactions for applications in stereoselective
organic synthesis has attracted growing research interest.1 While radical reactions
have a number of inherent synthetic advantages, such as fast reaction rate and func-
tional group tolerance, their synthetic applications have been hampered by
outstanding issues associated with control of reactivity and selectivity, especially
in the context of enantioselectivity.2 As stable metalloradicals, cobalt(II) complexes
of D2-symmetric chiral amidoporphyrins [Co(D2-Por*)] have emerged as a family of
open-shell transition metal catalysts for enantioselective radical transformations
through catalytic generation of metal-supported organic radical intermediates via
metalloradical catalysis (MRC).3–5 Specifically, metalloradical catalysts [Co(D2-
Por*)] have shown to be particularly effective in activating organic azides to generate
the corresponding a-Co(III)-aminyl radicals as key intermediates for catalytic radical
aziridination of alkenes,6 producing the smallest three-membered N-heterocycles
with effective control of reactivity and enantioselectivity.7,8 While previous reports
involved the use of phosphoryl, sulfonyl, and aryl azides,6 we were attracted to
the possibility of using carbonyl azides, such as 2,2,2-trichloroethoxycarbonyl azide
(TrocN3), for radical olefin aziridination via Co(II)-MRC, especially its asymmetric
variant by [Co(D2-Por*)] (Scheme 1). Although [Co(TPP)] (TPP = 5,10,15,20-tetraphe-
nylporphyrin) was previously shown to activate TrocN3, it required elevated temper-
ature and elongated reaction time, as well as the use of high catalyst loading.9 We
metalloradical system, which
proceeds with distinctive stepwise
radical mechanism, may provide a
general method for asymmetric
synthesis of chiral aziridines from
alkenes with organic azides.
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Scheme 1. Proposed mechanism for radical aziridination of alkenes with carbonyl azide TrocN3
via Co(II)-MRC
reasoned that the metalloradical activation of TrocN3 to generate a-2,2,2-trichloroe-
thoxycarbonyl-a-Co(III)-aminyl radical intermediate I could be facilitated by [Co(D2-
Por*)] as a result of the putative H-bonding interaction between the carbonyl moiety
in the azide and the amide unit of the catalyst (Scheme 1).6d,6f In view of the spin
delocalization in the a-carbonylaminyl radical intermediate I, however, it was unclear
whether it could function as effective nitrogen-centered radical to proceed
radical addition to olefins for generation of g-Co(III)-alkyl radical intermediate II
(Scheme 1). Moreover, in order to form the expected aziridines, the resulting car-
bon-centered radical in intermediate II must undergo competitive 3-exo-tet radical
cyclization over 5-endo-trig radical cyclization,10 which would produce oxazolines
after subsequent b-scission. More importantly, could the desired 3-exo-tet radical
cyclization proceed in an enantioselective fashion? We envisioned to address these
and related issues of reactivity and selectivity through the judicious choice of metal-
loradical catalysts [Co(D2-Por*)]. If successful, it would offer a new radical protocol
for stereoselective synthesis of chiral N-carbonyl aziridines (Scheme 1), which have
found synthetic and biological applications (see Figure S1).11
1Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, MA 02467,
USA
Organic azides have been increasingly employed as nitrogen sources for catalytic
aziridination of alkenes due to their attractive attributes, such as ease of preparation
and generation of benign N2 as the only byproduct.3g,11d,12 Among common
organic azides, carbonyl azides have not been previously demonstrated as effective
nitrogen sources for intermolecular olefin aziridination,7b,13 despite the potential
formation of useful aziridines bearing N-carbonyl functionality, which can also be
easily deprotected to yield N–H aziridines.11e This underdevelopment is mainly
attributed to the well-known challenges associated with the high lability of carbonyl
2Department of Chemistry, University of South
Florida, Tampa, FL 33620, USA
3These authors contributed equally
4Lead contact
*Correspondence: peter.zhang@bc.edu
https://doi.org/10.1016/j.chempr.2021.03.001
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azides toward thermal and photolytic rearrangements.14 Yoon and coworkers
recently reported the use of Ir-based catalysts as photosensitizers for activation of
TrocN3 with visible light to generate triplet free nitrenes that can be selectively trap-
ped by various alkenes for non-asymmetric aziridination.15 As a novel alternative to
carbonyl azides, Lebel and coworkers successfully employed chiral N-tosyloxycarba-
mates as nitrogen sources for Rh2-catalyzed diastereoselective aziridination of
alkenes.16 To the best of our knowledge, there has been no previous report on asym-
metric catalytic system for olefin aziridination using TrocN3 as nitrogen source. In
comparison with other nitrene precursors, TrocN3 offers several advantages: (1)
straightforward synthesis from the commercially available 2,2,2-trichloroethoxy
chloroformate in near quantitative yield; (2) generation of environmentally benign
dinitrogen as the only byproduct; and (3) ease of deprotection form the resulting
aziridine products to afford N–H aziridines. As a new application of Co(II)-MRC,
we herein wish to report the development of the first asymmetric catalytic system
that can effectively employ TrocN3 for highly asymmetric aziridination of aromatic
alkenes. Supported by D2-symmetric chiral amidoporphyrin ligands, the Co(II)-
based catalytic process allows for efficient synthesis of chiral N-Troc-aziridines
with a high degree of enantiocontrol. In addition to the convenient access of chiral
N–H-aziridines through mild deprotection, the utilities of the resulting chiral N-Troc-
aziridines are further showcased by the synthesis of chiral amines through stereospe-
cific ring-opening with nucleophiles of different nature without erosion of the orig-
inal enantiopurity. We also describe our mechanistic studies on the proposed step-
wise radical mechanism of the Co(II)-catalyzed aziridination.
RESULTS AND DISCUSSION
Reaction optimization
Our efforts started with the use of styrene (2a) as the model substrate for asymmetric
aziridination with TrocN3 (1) by metalloradical catalysts [Co(Por)] (Figure 1). While
[Co(TPP)] was ineffective (Figure 1; entry 1), the Co(II) complex of D2h-symmetric
achiral amidoporphyrin [Co(P1)] (P1 = 3,5-DitBu-IbuPhyrin)6d could catalyze the re-
action even at room temperature to form the desired N-Troc-aziridine 3a in a low
but significant yield (Figure 1; entry 2), indicating ligand-accelerated catalysis as a
result of the putative H-bonding interaction between the carbonyl moiety in the
azide and the amide unit of the catalyst. The first-generation chiral metalloradical
catalyst [Co(P2)] (P2 = 3,5-DitBu-ChenPhyrin)17 could give rise to significant asym-
metric induction for the formation of chiral aziridine 3a while slightly improving
the yield (Figure 1; entry 3). Taking advantage of the modularity and tunability of
the D2-symmetric chiral amidoporphyrin ligand platform, we synthesized the sec-
ond-generation metalloradical catalyst [Co(P3)] (P3 = 3,5-DitBu-QingPhyrin) by re-
placing one of the methyl groups on the chiral amide units of [Co(P2)] with a phenyl
group, resulting in a [Co(D2-Por*)] complex bearing chiral amides with two contig-
uous stereogenic centers.18 Gratifyingly, [Co(P3)] could further enhance both reac-
tivity and enantioselectivity of the catalytic aziridination reaction, affording 3a in
50% yield with 94% ee (Figure 1; entry 4). On the assumption that the presence of
adventitious water might negatively affect the yield of the aziridine product, molec-
ular sieves were employed as additives in the catalytic system. Indeed, the yield of
aziridine 3a was improved to 81% with preservation of the 94% ee (Figure 1; entry
5). It was further found that addition of anhydrous K2CO3 could lead to quantitative
formation of the desired aziridine 3a with the same excellent enantioselectivity
(Figure 1; entry 6). While its exact role was difficult to ascertain, we speculated
that anhydrous K2CO3 might, in addition to the removal of adventitious water-like
molecular sieves, prevent Co(III)-intermediates from functioning as potential Lewis
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Figure 1. Enantioselective aziridination reaction of styrene with carbonyl azide TrocN3 by [Co(Por)]
aCarried out at room temperature for 24 h with TrocN3 (0.1 mmol) and styrene (0.3 mmol);
[TrocN3] = 0.10 M.
bIsolated yields.
cEnantiomeric excess determined by chiral HPLC.
d
˚
With 50 mg of 4 A molecular sieves.
eWith 0.5 mmol of anhydrous K2CO3.
fTrocN3 (0.12 mmol) and styrene (0.1 mmol) were used.
gNot determined.
acids to promote aziridine isomerization.19 Switching the ratio of 2a:1 from 3:1 to
1:1.2 resulted in decrease in the yield of 3a without affecting the enantioselectivity
(Figure 1; entry 7). Among different solvents tested (see Figure S2), chlorobenzene
proved to be the choice of reaction medium, affording aziridine 3a in high yield with
excellent enantioselectivity at room temperature (Figure 1; entries 6–10). As ex-
pected, no reaction was observed in the absence of a catalyst (Figure 1; entry 11).
Substrate scope
Under the optimized reaction conditions, the [Co(P3)]/TrocN3-based system was
found to be effective for enantioselective aziridination of various styrene derivatives
(Figure 2). Like styrene, the Co(II)-catalyzed aziridination was suitable for styrene de-
rivatives bearing alkyl substituents at the para-, meta-, and ortho-positions, afford-
ing the desired aziridines 3b–3e in moderate to high yields with excellent
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Figure 2. Co(II)-catalyzed enantioselective aziridination of styrene derivatives with carbonyl
azide TrocN3
aCarried out with 1 (0.1 mmol), 2 (0.3 mmol), and K2CO3 (0.5 mmol) by [Co(P3)] (2 mol %) in
chlorobenzene at room temperature for 24 h; [TrocN3] = 0.10 M; Isolated yields; Enantiomeric
excess determined by chiral HPLC.
bUsed [Co(P3)] (5 mol %), 2 (0.5 mmol), and Cs2CO3 (0.5 mmol).
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Figure 2. Continued
cAt 0ꢀC for 24 h.
dAt 40ꢀC for 24 h.
eAbsolute configuration determined by anomalous dispersion effects in X-ray diffraction
measurements on the crystal.
f51% Yield (815 mg); 92% ee when carried out on a gram scale with 1 (4.6 mmol), 2 (13.7 mmol), and
K2CO3 (22.9 mmol) with [Co(P3)] (1 mol %).
gAt –20ꢀC for 48 h.
hUsed [Co(P3)] (5 mol %) with addition of Pd(OAc)2 (10 mol %) in the presence of 4 A molecular
˚
sieves (50 mg) instead of K2CO3 at 40ꢀC for 48 h.
enantioselectivities (Figure 2; entries 1–4). Fluorinated styrenes having different sub-
stitution patterns could be employed as effective substrates, providing the corre-
sponding fluorinated aziridines 3f–3i in high yields with excellent enantioselectivities
(Figure 2; entries 5–8). Other halogenated aromatic olefins, such as brominated and
chlorinated styrenes, could also be effectively aziridinated with TrocN3, affording
the halogenated aziridines 3j–3n in high yields with excellent enantioselectivities
(Figure 2; entries 9–13), which may be potentially transformed to other aziridine de-
rivatives by cross-coupling and related reactions. Furthermore, the Co(II)-based sys-
tem could tolerate functional groups as exemplified by productive formation of the
desired aziridine 3o and 3p with high enantioselectivities (Figure 2; entries 14 and
15). To demonstrate the synthetic practicality, a gram-scale synthesis of aziridine
3p was performed using 1 mol % of [Co(P3)] under otherwise the same conditions,
affording the desired product with the same high enantioselectivity (92% ee) but
in a relatively lower yield (from 71% to 51%). The reduction of the catalyst loading
from 2 to 1 mol % is likely responsible for the lower yield. Additionally, styrene de-
rivatives containing electron-withdrawing substituents, such as –CF3 and –NO2
groups at different positions, could serve as suitable substrates for the aziridination
system, affording the corresponding three-membered N-heterocycles 3q–3t in
enantioenriched forms although in relatively lower yields (Figure 2; entries 16–19).
Similarly, the Co(II)-catalyzed aziridination could be applied for styrene derivatives
bearing electron-donating groups as demonstrated by the highly asymmetric forma-
tion of 3u and 3v albeit in lower yields (Figure 2; entries 20 and 21). In addition, the
aziridination system by [Co(P3)] could be applied to extended aromatic olefins as
shown by the construction of aziridines 3w–3y in moderate to high yields with excel-
lent enantioselectivities (Figure 2; entries 22–24). The absolute configurations of the
newly generated stereogenic centers in both 3p and 3w were established as (R) by X-
ray crystallography. Besides mono-substituted styrene derivatives, the catalytic sys-
tem could be applicable to 1,1-disubstituted styrenes as exemplified by the produc-
tive formation of aziridine 3z bearing a tertiary fluoride stereocenter from the reac-
tion of a-fluorostyrene although in lower yield and enantioselectivity (Figure 2; entry
25). Assisted by a catalytic amount of Pd(OAc)2,6e we found that the Co(II)-based
metalloradical system could even aziridinate electron-deficient alkenes as shown
for the successful reactions of ethyl and methyl acrylates to form the corresponding
aziridines 3aa and 3ab, respectively, in moderate yields but with significant levels of
enantiocontrol (Figure 2; entries 26–27). It is worth mentioning that electron-defi-
cient alkenes are known to be challenging substrates for aziridination by existing cat-
alytic systems involving electrophilic metallonitrenes as the key intermediate. When
heteroaromatic olefins were used, however, it generated an unidentified mixture of
products in low yields without observation of the corresponding aziridines. Catalyst
[Co(P3)] were found to be ineffective for aziridination reactions of aliphatic and inter-
nal olefins with TrocN3, as well as dienes. Evidently, a more effective catalyst needs
to be developed for asymmetric aziridination with a broader scope of alkenes.
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Scheme 2. Mechanistic studies for the [Co(P3)] catalyzed aziridination of styrene with TrocN3
aAll relative Gibbs free energies (DGꢀ) for intermediates and transition states, as well as activation
energies (DGz), are reported in kcal/mol.
bCarried out with 1 (0.1 mmol), 2aD (0.3 mmol), and K2CO3 (0.5 mmol) by [Co(Por)] (2 mol %) in
chlorobenzene at 40 ꢀC for 24 h; [TrocN3] = 0.10 M; (Z)-3aD:(E)-3aD ratio determined by 1H-NMR and
2H-NMR analysis of crude reaction mixture; see Supplemental information for details.
Mechanistic studies
Combined computational and experimental studies were performed for the pro-
posed stepwise radical mechanism of the Co(II)-catalyzed aziridination (Scheme 1).
First, density functional theory (DFT) calculations were carried out to study the cat-
alytic pathway for aziridination reaction of styrene with TrocN3 with the use of the
actual catalyst [Co(P3)] (Scheme 2A).20 The computational study indicates the exis-
tence of intermediate B, which is formed upon coordination of the internal nitrogen
atom in TrocN3 to the cobalt center of the catalyst. The formation of intermediate B
is slightly exergonic by –1.6 kcal/mol due to additional H-bonding stabilization (see
Schemes S6 and S7). Upon further activation, the coordinated azide undergoes dini-
trogen elimination to generate a-Co(III)-aminyl radical C. The metalloradical activa-
tion step, which is exergonic by –12.2 kcal/mol, has a relative low activation energy
(TS1: DGz = 14.0 kcal/mol). As shown in the middle of the catalytic cycle (see
Schemes S6 and S7), the optimized TS1 structure reveals strong double H-bond in-
˚
˚
teractions (N–H—N: 2.34 A; N–H—O: 2.22 A) between [Co(P3)] and TrocN3, as well
as the strengthening of Co–N bonding interaction (as indicated by the decrease of
˚
bond distance from 2.10 to 1.90 A). According to the DFT calculation, the subse-
quent radical addition of radical intermediate C to styrene is associated with a rela-
tively high but accessible activation barrier (TS2: DGz = 21.0 kcal/mol), leading to the
formation of g-Co(III)-alkyl radical intermediate D (Scheme 2A). The final step of
3-exo-tet cyclization via radical substitution, which is highly exergonic by
–27.2 kcal/mol, is found to be almost barrierless, resulting in the formation of the
three-membered aziridine 3a and the regeneration of catalyst [Co(P3)]. For all
computational details including cartesian coordinates of intermediates and transi-
tion states, see Data S1.
Second, in an effort to detect the a-Co(III)-aminyl radical intermediate I experimen-
tally, the isotropic X-band electron paramagnetic resonance (EPR) spectrum was re-
corded at room temperature for the reaction mixture of [Co(P3)] with TrocN3 (1) in
benzene without alkene substrate (Scheme 2B). The spectrum displays salient sig-
nals akin to those characteristics of a-Co(III)-aminyl radicals (Scheme 2B).8,21 The
observed isotropic g value of 2.00 is consistent with the formation of organic radical
I
[Co(P3)] upon spin translocation from the Co(II) to the N-atom during metalloradical
activation of the azide. In consistence with the spin delocalization in the a-carbony-
laminyl radical intermediate I[Co(P3)], the observed broad signals could be fittingly
simulated by invoking its three resonance forms on the basis of hyperfine couplings
by both 14N (I = 1) and 59Co (I = 7/2): 17% of N-centered radical NI[Co(P3)] (g: 2.00236;
A
(Co): 8.9 MHz; A(N): 50.9 MHz), 78% of C-centered radical CI[Co(P3)] (g: 2.00931; A(Co)
:
:
O
7.5 MHz; A(N): 46.9 MHz), and 5% of O-centered radical I[Co(P3)] (g: 2.00206; A(Co)
0 MHz; A(N): 35.7 MHz) (see the Supplemental information for details). Furthermore,
the a-Co(III)-aminyl radical I[Co(P3)] from the reaction mixture of [Co(P3)] with azide 1
could be detected by high-resolution mass spectrometry (HRMS) with electrospray
ionization (ESI) ionization (see the Supplemental information for details). The ob-
tained spectrum (Scheme 2B) evidently exhibited a signal corresponding to
[I[Co(P3)]
[Co(P3)] by the loss of one electron. Both the exact mass and the isotope distribution
pattern measured experimentally matched well with those calculated from the
]
+ (m/z = 1,776.6666), which resulted from the neutral a-Co(III)-aminyl radical
I
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formula of [(P3)Co(NCO2CH2CCl3)]+. The successful detection of a-Co(III)-aminyl
radical intermediate I[Co(P3)] by EPR and HRMS provided experimental evidence to
support the first step of metalloradical activation in the proposed mechanism of
radical aziridination (Scheme 1).
Finally, to probe the subsequent steps of radical addition and radical cyclization in the
proposed mechanism (Scheme 1), both isotopomers of b-deuterostyrene (E)-2aD and
(Z)-2aD were applied as substrates for Co(II)-catalyzed aziridination with TrocN3 (1)
(Scheme 2C). While a concerted mechanism associated with metallonitrene intermedi-
ates is usually stereospecific, a stepwise mechanism involving a-Co(III)-aminyl radical
intermediates may lead to the formation of aziridines as a mixture of both diastereo-
isomers (E)-3aD and (Z)-3aD from either (E)-2aD or (Z)-2aD as a result of the b-CꢁC
bond rotation in the resulting g-Co(III)-alkyl radical intermediate II before cyclization
(Scheme 2C; Schemes S1 and S2). As expected, the aziridination of (E)-2aD with azide
1 by the achiral catalyst [Co(P1)] produced an isotopomeric mixture of (Z)-3aD and
(E)-3aD in a ratio of 20:80. Under the identical conditions, aziridination of (Z)-2aD
yielded the isotopomeric mixture in a ratio of 89:11. The formation of isotopomeric
mixture of aziridine 3aD from isomerically pure 2aD is clearly attributed to the rotation
around the b-CꢁC bond in the g-Co(III)-alkyl radical intermediate II. Interestingly, it
was found that the degree of the bond rotation could be influenced by the environ-
ment of the supporting ligand. For example, when the two reactions were carried
out under the same condition but using the chiral catalyst [Co(P2)], the isotopomeric
ratio of (Z)-3aD and (E)-3aD changed from 20:80 to 12:88 for the reaction of (E)-2aD
and from 89:11 to 94:06 for the reaction of (Z)-2aD, indicating a lower degree of rota-
tion in a more hindered ligand environment (Scheme 2C). Accordingly, when the opti-
mized catalyst [Co(P3)], which has an even more confined ligand environment, was em-
ployed for the aziridination reactions of (E)-2aD and (Z)-2aD, minimal isotopomeric
distributions were observed as a result of faster radical cyclization than the b-C–C
bond rotation, leading to a stereospecific process (Scheme 2C). This high stereospec-
ificity for b-deuterostyrenes, together with the high enantioselectivity observed for sty-
rene (Figure 1, entry 6), implies that [Co(P3)]-catalyzed olefin aziridination with TrocN3
involves radical addition as the enantiodetermining step, followed by a stereoreten-
tive radical cyclization. As anticipated for a radical process, it was found that the cat-
alytic aziridination process could be significantly inhibited when a large excess of
TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl) was added. Together with the detec-
tion of the a-Co(III)-aminyl radical intermediate I by EPR and HRMS, these results fully
corroborate the proposed stepwise radical mechanism for the Co(II)-based metallor-
adical aziridination (Scheme 1).
Synthetic applications
For access to aziridine derivatives with various N-substituents for different applica-
tions, it would be desirable that the aziridine products from a catalytic aziridination
process could be effectively converted to the corresponding N–H aziridines through
simple deprotection without opening the three-membered ring structures.11e,22 In
contrast to aziridines with N-protecting groups that require harsh conditions for de-
protection,23 N-carboalkoxy aziridines have been known to proceed facile N-depro-
tection under mild conditions.24 To showcase the synthetic utilities of the resulting
chiral N-Troc-aziridines from the Co(II)-catalyzed process, it was demonstrated
that enantioenriched N-Troc-aziridine (R)-3p could be readily converted to the cor-
responding N–H aziridine 4p in 87% yield without erosion of its optical purity when
treated with lithium hydroxide at room temperature (Scheme 3A). In addition to
N-deprotection, chiral N-Troc-aziridines were shown to undergo facile ring-opening
reactions at room temperature by a wide range of nucleophiles in the presence of
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Scheme 3. Transformations of chiral N-Troc-aziridines
aConditions as reported in the literature.24
bMeOH (0.10 M), BF3,OEt2 (10 mol %).
cH2O (0.10 M), BF3,OEt2 (10 mol %).
dPhSH (0.10 M), BF3,OEt2 (10 mol %).
ePhNH2 (0.10 M), BF3,OEt2 (10 mol %).
fCH2Cl2 (0.10 M), BF3,OEt2 (20 mol %), amines (20 equiv).
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Lewis acids with preservation of the high enantiomeric purity (Scheme 3A). For
instance, methanol could effectively open the three-membered ring in (R)-3p in
the presence of boron trifluoride diethyl etherate, generating chiral b-amino ether
5p in 96% yield without any racemization. Notably, even water could function as
an effective nucleophile for ring-opening of (R)-3p under similar conditions, resulting
in highly stereospecific formation of chiral b-amino alcohol 6p in 94% yield. The ab-
solute configuration of 6p was established by X-ray crystallography as (S), indicating
an SN2-type mechanism of the ring-opening reaction. Sulfur-based nucleophiles
could also be applied for the ring-opening process as exemplified by the reaction
of (R)-3p with thiophenol, affording the chiral b-amino thioether 7p in 58% yield
with some loss of the original enantiopurity. The three-membered ring in chiral
N-Troc-aziridines could be readily opened by nitrogen-based nucleophiles,
including both aromatic and aliphatic amines at room temperature to provide valu-
able vicinal diamines.25 For example, both aniline and diethylamine could effectively
react with (R)-3p to afford chiral vicinal diamines 8p and 9p, respectively, in high
yields with no erosion of the original enantiopurity. Interestingly, when primary
aliphatic amines were employed as the nucleophiles, the reactions of N-Troc-aziri-
dines were found to proceed further to generate aziridine-based chiral ureas, a
formal process that transforms carbamates to ureas via amide bond formation
(Scheme 3B).26 As two examples, benzylamine and allylamine reacted readily with
(R)-3p under the similar conditions to form aziridine-based chiral ureas 10p and
11p, respectively, in excellent yields without apparent racemization. Presumably
due to the combined high nucleophilicity of the resulting secondary amines and
good leaving ability of trichloroethyl group, the initial ring-opening products III of
(R)-3p by the primary amines proceeded further to form intramolecular amide bonds
in the presence of Lewis acids to generate imidazolidinones IV, which then under-
went ring-contraction under Lewis acid catalysis27 to yield the final products 10p
and 11p. The N-deprotection and ring-opening reactions could proceed equally
well with other chiral N-Troc-aziridines as exemplified by the stereospecific forma-
tions of N–H aziridine 4r and b-amino ether 5r from enantioenriched aziridine 3r
(Scheme 3C).
Conclusions
In summary, we have developed the first catalytic system that can employ the
carbonyl azide TrocN3 as the nitrogen source for asymmetric aziridination via
Co(II)-based MRC. With the support of 3,5-DitBu-QingPhyrin as the chiral ligand,
the Co(II)-based aziridination system with TrocN3, which proceeds with the underly-
ing stepwise radical mechanism as evidenced by the combined computational and
experimental studies, provides a fundamentally new methodology for stereoselec-
tive synthesis of chiral N-Troc-aziridines from styrene derivatives with varied steric
and electronic properties in high yields with high enantioselectivities. Assisted by
a catalytic amount of Pd(OAc)2, this new [Co(3,5-DitBu-QingPhyrin)]/TrocN3-based
system can further catalyze asymmetric aziridination of electron-deficient alkenes,
such as methyl and ethyl acrylates, which are challenging substrates for the catalytic
systems involving electrophilic metallonitrene intermediates. Among several salient
features, the Co(II)-catalyzed radical aziridination can operate efficiently at room
temperature and has good functional group tolerance. The resulting enantioen-
riched N-Troc-aziridines have been showcased as valuable chiral synthons for ster-
eoselective synthesis of other chiral aziridines and various chiral amine derivatives.
Through fine-tuning the environments of D2-symmetric chiral amidoporphyrins as
the supporting ligand, we hope to develop a more general Co(II)-based catalytic sys-
tem for enantioselective radical aziridination of different alkenes with TrocN3.
1130 Chem 7, 1120–1134, April 8, 2021

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EXPERIMENTAL PROCEDURES
Resource availability
Lead contact
Further information and requests for resources should be directed to and will be ful-
filled by the lead contact, X. Peter Zhang (peter.zhang@bc.edu).
Materials availability
Unique and stable reagents generated in this study will be made available on
request, but we might require a payment and/or a completed materials transfer
agreement if there is potential for commercial application.
Data and code availability
The crystal structure data of compound (R)-3p, (R)-3w, and (S)-6p have been depos-
ited in the Cambridge structural database under reference numbers CCDC:
2025803, 2025804, and 2025805, respectively.
Full experimental procedures are provided in the Supplemental information.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.chempr.
2021.03.001.
ACKNOWLEDGMENTS
We are grateful for financial support by NIH (R01-GM102554) and, in part, by NSF
(CHE-1900375).
AUTHOR CONTRIBUTIONS
X.R.-F., P.S., and J.T. conducted the experiments. J.T. initiated the project. P.S.
advanced the project. X.R.F. completed the project. H.X. carried out the DFT calcu-
lations. L.-M.J., H.L., and X.C. assisted the project. L.W. performed the X-ray crystal-
lography studies. X.P.Z. conceived the work and coordinated the project. X.R.-F.,
P.S., J.T., and X.P.Z. designed the experiments. X.R.-F. and X.P.Z. wrote the
manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: August 31, 2020
Revised: December 9, 2020
Accepted: February 28, 2021
Published: March 29, 2021
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