Asymmetric Radical Process for General Synthesis of Chiral Heteroaryl Cyclopropanes

Article abstract of DOI:10.1021/jacs.1c04655

A highly efficient catalytic method has been developed for asymmetric radical cyclopropanation of alkenes with in situ-generated α-heteroaryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the cavity-like environments of newly-synthesized D2-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based metalloradical system is broadly applicable to α-pyridyl and other α-heteroaryldiazomethanes for asymmetric cyclopropanation of wide-ranging alkenes, including several types of challenging substrates. This new catalytic methodology provides a general access to valuable chiral heteroaryl cyclopropanes in high yields with excellent both diastereoselectivities and enantioselectivities. Combined computational and experimental studies further support the underlying stepwise radical mechanism of the Co(II)-based olefin cyclopropanation involving α- and γ-metalloalkyl radicals as the key intermediates.

Full text of DOI:10.1021/jacs.1c04655

pubs.acs.org/JACS
Article
Asymmetric Radical Process for General Synthesis of Chiral
Heteroaryl Cyclopropanes
Xiaoxu Wang, Jing Ke, Yiling Zhu, Arghya Deb, Yijie Xu, and X. Peter Zhang*
Cite This: J. Am. Chem. Soc. 2021, 143, 11121−11129
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A highly efficient catalytic method has been developed for asymmetric radical cyclopropanation of alkenes with in
situ-generated α-heteroaryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the cavity-like
environments of newly-synthesized D2-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based
metalloradical system is broadly applicable to α-pyridyl and other α-heteroaryldiazomethanes for asymmetric cyclopropanation of
wide-ranging alkenes, including several types of challenging substrates. This new catalytic methodology provides a general access to
valuable chiral heteroaryl cyclopropanes in high yields with excellent both diastereoselectivities and enantioselectivities. Combined
computational and experimental studies further support the underlying stepwise radical mechanism of the Co(II)-based olefin
cyclopropanation involving α- and γ-metalloalkyl radicals as the key intermediates.
stereoselective synthesis of valuable chiral heteroaryl cyclo-
propanes. With this in mind, we sought to explore the
feasibility of developing a catalytic process that would employ
α-heteroaryldiazomethanes for asymmetric cyclopropanation
of alkenes via Co(II)-MRC (Scheme 1). In view of the
intrinsic properties of heteroaryl moieties, the proposed
Co(II)-based catalytic process presented several fundamental
challenges. Besides the concerns with efficiency of metal-
loradical activation of α-heteroaryldiazomethanes 1′ generated
in situ from the corresponding hydrazones 1 in the presence of
base, whether the subsequent radical addition of the initially
formed α-Co(III)-heterobenzyl radicals I to the alkene
substrates 2 could be rendered enantioselective is an
unanswered question, primarily owing to the potential
competitive coordination of the heteroaryl moieties to the
metal center. On this basis, additional uncertainty of
controlling reactivity and diastereoselectivity might also arise
from the following 3-exo-tet cyclization of the resulting γ-
INTRODUCTION
■
Radical chemistry has been increasingly explored for the
development of new synthetic tools in modern organic
synthesis.1 Despite tremendous endeavors, long-standing
challenges associated with control of reactivity and enantiose-
lectivity remain largely unresolved for many radical reactions.2
Among recent advances,3 metalloradical catalysis (MRC),
which involves the generation and utilization of metal-
stabilized organic radicals as catalytic intermediates to harness
the potential of radical chemistry, has emerged as a
conceptually new approach to guide the discovery of catalytic
solutions toward controlling the reactivity and stereoselectivity
of radical processes.4−6 As stable 15e-metalloradicals, cobalt-
(II) complexes of porphyrins ([Co(Por)]) exhibit the unique
capability of homolytically activating diazo compounds to
generate α-Co(III)-alkyl radicals as key intermediates for
various radical transformations.7 Specifically, with D2-symmet-
ric chiral amidoporphyrins (D2-Por*) as the supporting
ligands, these Co-stabilized carbon-centered radicals can
engage in asymmetric radical cyclopropanation of alkenes for
the preparation of optically active three-membered carbo-
cycles.8 While donor-substituted diazo compounds such as in
situ-generated α-aryldiazomethanes have recently been dem-
onstrated as suitable radical precursors for Co(II)-based
asymmetric radical cyclopropanation,8k,n the analogous α-
heteroaryldiazomethanes have remained underexploited for
Received: May 4, 2021
Published: July 20, 2021
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129
© 2021 American Chemical Society
11121

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Co(II)-based catalytic system that is highly efficient for
asymmetric cyclopropanation of alkenes with in situ-generated
α-heteroaryldiazomethanes. Through the support of a new
bridged D2-symmetric chiral amidoporphyrin ligand, the
Co(II)-catalyzed system allows for efficient activation of 2-
pyridyldiazomethanes and other common α-heteroaryldiazo-
methanes for asymmetric cyclopropanation of a broad range of
alkenes, affording the valuable chiral heteroaryl cyclopropanes
in high yields with excellent both diastereoselectivities and
enantioselectivities. Furthermore, we present detailed compu-
tational and experimental studies that shed light on the
underlying stepwise radical mechanism.
Scheme 1. Working Proposal for Synthesis of Heteroaryl
Cyclopropanes from Alkenes via Co(II)-Based MRC
RESULTS AND DISCUSSION
■
Catalyst Development. At the outset of this project, 2-
pyridyldiazomethane (1a’), which was in situ generated from
the corresponding tosylhydrazone 1a in the presence of
Cs2CO3, was investigated as the representative α-heteroar-
yldiazomethane for asymmetric radical cyclopropanation of
styrene (2a) by Co(II)-based metalloradical catalysts [Co-
(Por)] (Scheme 2). It was found that the Co(II) complex of
D2h-symmetric achiral amidoporphyrin [Co(P1)] (P1 = 3,5-
DitBu-IbuPhyrin)15 could effectively catalyze the cyclopropa-
nation reaction to afford the desired 2-pyridylcyclopropane 3a
in nearly quantitative yield (99%) with moderate diaster-
eoselectivity (44% de). To evaluate the feasibility of
asymmetric induction during the proposed catalytic cycle,
Co(II) complexes of a series of D2-symmetric chiral
amidoporphyrin ligands [Co(D2-Por*)] were employed as
the catalysts. While first-generation chiral metalloradical
catalyst [Co(P2)] (P2 = 3,5-DitBu-ChenPhyrin)8a could
furnish 3a in a similarly high yield (95%) with higher
diastereoselectivity (72% de), it only exhibited insignificant
asymmetric induction (5% ee). Switching to second-generation
metalloradical catalyst [Co(P3)] (P3 = 3,5-DitBu-Tao(tBu)-
Phyrin)16 bearing chiral amide units with ester moieties
resulted in the formation of 3a in 86% yield with further
improved diastereoselectivity (88% de) and a significant level
of enantioselectivity (40% ee). To further enhance the
asymmetric induction of this catalytic system, we then turned
our attention to new-generation metalloradical catalysts
[Co(HuPhyrin)], the Co(II) complexes of bridged D2-
symmetric chiral amidoporphyrins featuring more rigid
cavity-like environments. When the C6-bridged [Co(P4)]
(P4 = 3,5-DitBu-Hu(C6)Phyrin)16 was employed as the
catalyst under the same conditions, it indeed enhanced both
reactivity and stereoselectivities of the cyclopropanation
reaction substantially, generating 3a in high yield (94%) with
excellent both diastereoselectivity (98% de) and enantiose-
lectivity (92% ee). Subsequent use of analogous catalyst
[Co(P5)] (P5 = 2,6-DiMeO-Hu(C6)Phyrin),17 which bears
2,6-dimethoxyphenyl instead of 3,5-di-tert-butylphenyl groups
as the 5,15-diaryl substituents, led to the production of 3a in a
comparable yield (91% yield) with the same stereoselectivities
(98% de and 92% ee). Aiming at further improving the
catalytic system, we synthesized a new C6-bridged catalyst
[Co(P6)] (P6 = 2,6-DiPhO-Hu(C6)Phyrin) by replacing the
methoxy groups in P5 with phenoxy groups. Gratifyingly,
[Co(P6)] could catalyze the cyclopropanation reaction to
afford 2-pyridylcyclopropane 3a in almost quantitative yield
(99%) with high diastereoselectivity (92% de) and outstanding
enantioselectivity (99% ee).
Co(III)-alkyl radicals II while forging the second C−C bond
(Scheme 1). Furthermore, the presence of heteroatoms was
anticipated to engage in potential H-bonding interactions with
the amide units of the amidoporphyrin ligands that could pose
potential complication in controlling both reactivity and
selectivity in these Co(II)-based radical processes. To address
these and related issues, we envisioned the prospect of
designing a suitable D2-symmetric chiral amidoporphyrin
ligand with proper steric, electronic, and chiral environments
that could direct the Co(II)-based catalysis for productive
cyclopropanation with effective stereocontrol. If realized, it
would enable the development of a new catalytic system for
asymmetric olefin cyclopropanation with in situ-generated α-
heteroaryldiazomethanes to furnish chiral heteroaryl cyclo-
propanes 3, which are ubiquitous structural motifs in many
pharmaceuticals and biologically important molecules (see
Figure S1 in Supporting Information).9
Transition-metal catalyzed asymmetric cyclopropanation of
alkenes with heteroaryldiazomethanes represents an appealing
approach for the synthesis of valuable chiral heteroaryl
cyclopropanes with the potential to control both diastereose-
lectivity and enantioselectivity.9b,10 In contrast to the well-
precedented asymmetric cyclopropanation with other types of
diazo compounds,11 only a few catalytic systems involving the
use of heteroaryldiazomethanes have been reported.12 This
underdevelopment is largely attributed to their inherent
instability as well as high propensity for unwanted formal
dimerization.12,13 Moreover, it is known that rhodium- and
other existing metal-based catalytic systems of cyclopropana-
tion could suffer from the notorious catalyst poisoning effect in
the presence of nitrogen- and sulfur-containing heterocy-
cles.9b,10g Recently, Chattopadhyay and co-workers14f reported
a [Co(TPP)]-catalyzed (TPP = 5,10,15,20-tetraphenylpor-
phyrin) metalloradical cyclopropanation with 2-pyridyldiazo-
methanes, which could be generated in situ from readily
accessible N-tosylhydrazone precursors in the presence of
base.14 While this in situ protocol offers a novel alternative for
catalytic synthesis of 2-pyridylcyclopropanes in their racemic
forms, the enantioselective variant of this transformation is an
attractive process that remains elusive. In addition to 2-
pyridylcyclopropanes, it would be desirable to develop new
catalytic systems that are generally applicable for stereo-
selective synthesis of diverse types of chiral heteroaryl
cyclopropanes. We herein report the development of a new
11122
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
of the newly generated quaternary stereogenic centers (entries
7 and 8). In addition to the extended aromatic olefins such as
formation of 3i from 2-vinylnaphthalene (entry 9), both
conjugated dienes and enynes could be regio- and chemo-
selectively cyclopropanated to form cyclopropanes 3j−3l in
high yields with excellent stereoselectivities (entries 10−12).
The Co(II)-based cyclopropanation was further highlighted by
its unique reactivity toward various heteroaromatic olefins as
shown with the highly stereoselective synthesis of 1,2-
bisheteroaryl cyclopropanes 3m−3t containing pyridine,
thiophene, benzofuran, benzothiophene, indole, and quinoline
(entries 13−20). Given that both heteroarene and cyclo-
propane are prevalent structural motifs in bioactive com-
pounds, the access of bisheteroaryl cyclopropanes in high
enantiopurity may find potential applications in drug research
and development. Moreover, electron-deficient olefins such as
acrylketones, acrylates, acrylamides, and acrylonitriles, which
are known to be challenging substrates, could all be utilized for
asymmetric cyclopropanation by [Co(P6)], furnishing the
functionalized electrophilic cyclopropanes 3u−3z in high
yields with excellent control of stereoselectivities (entries
21−26). Similar to electron-deficient olefins, the catalytic
cyclopropanation could also be applied to electron-rich olefins
such as vinyl benzoate and vinyl propyl ether for highly
stereoselective formation of cyclopropyl ester 3aa and
cyclopropyl ether 3ab albeit in relatively lower yields (entries
27 and 28). Notably, the [Co(P6)]-based system proved to be
similarly effective for the asymmetric cyclopropanation of
aliphatic olefins, affording the alkyl-substituted pyridylcyclo-
propanes 3ac and 3ad in moderate yields with moderate to
excellent stereoselectivities (entries 29 and 30). Gratifyingly,
internal olefins such as indene and benzofuran, which are
typically challenging substrates for asymmetric cyclopropana-
tion due to steric factors, could also be cyclopropanated to
form the fused cyclopropanes 3ae and 3af in moderate yields
with high enantioselectivities despite varied diastereoselectiv-
ities (entries 31 and 32). It is worth mentioning that the
Co(II)-based system was amenable to late-stage derivatization
of biologically complex molecules as exemplified by the high-
yielding formation of cyclopropane derivative of estrone 3ag
with excellent diastereoselectivity (entry 33).
Scheme 2. Ligand Effect on Co(II)-Catalyzed Radical
Cyclopropanation of Styrene with 2-Pyridyldiazomethanes
a
a
Carried out with 1a (0.10 mmol), 2a (0.15 mmol), and Cs2CO3
(0.20 mmol) using [Co(Por)] (2 mol %) in toluene (1.0 mL) at 80
°C for 16 h; Isolated yields; Diastereomeric excess (de) determined
1
by H NMR of crude reaction mixture; Enantiomeric excess (ee) of
the major (E)-isomer determined by chiral HPLC; Ts = 4-
In addition to the representative 2-pyridyldiazomethane
(1a’), it was demonstrated that metalloradical catalyst
[Co(P6)] could effectively activate different types of α-
heteroaryldiazomethanes for asymmetric cyclopropanation of
alkenes (Table 1). For instance, 3-pyridyldiazomethane (1b’)
generated from the corresponding trishydrazone (2,4,6-
triisopropylbenzenesulfonyl hydrazone) was found to be a
competent radical precursor even at room temperature for the
Co(II)-based asymmetric cyclopropanation. As shown with
styrene (monosubstituted olefin), α-bromostyrene (1,1-dis-
ubstituted olefin), 1-phenyl-1,3-butadiene (conjugated diene),
and methyl acrylate (electron-deficient olefin) as representative
substrates, [Co(P6)] could effectively activate in situ-
generated 1b’ at room temperature for highly asymmetric
cyclopropanation reactions, leading to productive formation of
the corresponding 3-pyridylcyclopropanes 3ah, 3ai, 3aj, and
3ak with exceptional control of stereoselectivities (entries 34−
37). Likewise, other heteroaryldiazomethanes, including those
generated in situ from the trishydrazones derived from 5-
bromo-3-pyridyl, 4-pyridyl, 3-thienyl, 3-indolyl, and 3-
quinolinyl carboxaldehydes, were all shown to be effective
radical precursors for [Co(P6)]-catalyzed asymmetric olefin
toluenesulfonyl.
Substrate Scope. Under the optimized conditions, the
scope and versatility of [Co(P6)]-catalyzed asymmetric
cyclopropanation with in situ-generated 2-pyridyldiazome-
thane (1a’) were explored by employing different types of
alkenes as the substrates (Table 1). Like formation of 3a from
styrene (entry 1), its derivatives bearing electron-donating and
electron-withdrawing aryl substituents could also be effectively
cyclopropanated by [Co(P6)] with 1a’, producing the desired
cyclopropanes 3b and 3c in similarly high yields and
stereoselectivities (entries 2 and 3). The absolute configuration
of the major enantiomer of 3b was established as (R,R).
Additionally, this [Co(P6)]-based metalloradical system was
shown to tolerate various functional groups as exemplified by
the stereoselective formation of 3d−3f containing aryl
substituents of halogen, pinacolborane, and formyl function-
alities at different positions (entries 4−6). Besides mono-
substituted olefins, 1,1-disubstituted olefins like α-substituted
styrenes could serve as suitable substrates as well, affording the
trisubstituted cyclopropanes 3g and 3h with excellent control
11123
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 1. Scope of Co(II)-Catalyzed Asymmetric Radical Cyclopropanation of Alkenes with Heteroaryldiazomethanes
a
Carried out with 1 (0.10 mmol), 2 (0.15 mmol), and Cs2CO3 (0.20 mmol) at 80 °C for 16 h using [Co(P6)] (2 mol %) in toluene (1.0 mL); R =
1
4-methylphenyl; Isolated yields; Diastereomeric ratio (dr) determined by H NMR of crude reaction mixture; Enantiomeric excess (ee) of the
major isomer determined by chiral HPLC. Absolute configuration determined by X-ray crystallography. With 2 (0.30 mmol). With 2 (1.0
mmol). At 22 °C; R = 2,4,6-triisopropylphenyl. At 60 °C.
b
c
d
e
f
cyclopropanation as exemplified with the room temperature
reactions of styrene as the model substrate, affording the
corresponding heteroaryl cyclopropanes 3al−3ap in moderate
to high yields with excellent stereoselectivities (entries 38−42).
The absolute configurations of the newly generated stereogenic
centers in 3al and 3ao were both established as (R,R) by X-ray
crystallography. In addition, 3-quinolinyldiazomethane (1g’)
was also investigated for Co(II)-based cyclopropanation
reactions of selected alkenes ranging from α-chlorostyrene to
electron-deficient olefins. Gratifyingly, almost all of these
alkene substrates could be effectively cyclopropanated,
allowing for the high-yielding formation of 3-quinolinylcyclo-
propanes 3aq−3at with excellent stereoselectivities (entries
43−46). The only exception was observed for the reaction of
methyl vinyl ketone, which afforded the corresponding
cyclopropane 3ar with excellent enantioselectivity but in
lower yield with diminished diastereoselectivity (entry 44).
The absolute configuration of the major enantiomer of 3aq was
determined to be (S,S) by X-ray crystallography.
Considering that the [Co(P6)]-based catalytic system could
productively utilize various α-heteroaryldiazomethanes con-
taining heteroatom at different positions, we sought to explore
the possibility of employing α-aryldiazomethanes for asym-
metric cyclopropanation (Table 2), which has been largely
11124
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
aromatic systems, including p-biphenyldiazomethane (1r’) and
2-naphthyldiazomethane (1s’), delivering the corresponding
cyclopropanes 3be and 3bf in high yields with excellent control
of stereoselectivities. Evidently, [Co(P6)] represents a power-
ful new catalyst that is generally applicable for asymmetric
olefin cyclopropanation with both α-heteroaryldiazomethanes
and α-aryldiazomethanes.
Table 2. Scope of Co(II)-Catalyzed Asymmetric Radical
Cyclopropanation of Styrene with Aryldiazomethanes
a
Mechanistic Studies. To gain insight into the proposed
stepwise radical mechanism (Scheme 1), combined computa-
tional and experimental studies were conducted (Scheme 3).
First, density functional theory (DFT) calculations were
performed to elucidate the details of the catalytic pathway
and associated energetics for the cyclopropanation reaction of
styrene (2a) with 2-pyridyldiazomethane (1a’) by [Co(P6)]
(Scheme 3A; see Supporting Information for details). The
DFT calculations reveal the initial formation of intermediate B
between the catalyst and 2-pyridyldiazomethane through
multiple noncovalent attractive interactions, including H-
bonding and π-stacking interactions. The noncovalent
complexation, which is exergonic by 8.7 kcal/mol, positions
the α-carbon atom of diazo 1a’ in close proximity to the
Co(II)-metalloradical center of [Co(P6)] (C−Co: ∼2.91 Å)
for further interactions (Scheme 3A; see Scheme S7 in
Supporting Information). The ensuing metalloradical activa-
tion, which is slightly exergonic by 1.2 kcal/mol, is found to be
associated with a relatively high but accessible activation
barrier (TS1: ΔG‡ = 19.7 kcal/mol), affording α-Co(III)-
pyridyl radical intermediate C with the release of dinitrogen as
the byproduct (see Scheme S6 in Supporting Information).
The subsequent radical addition of the resulting radical
intermediate C to alkene 2a, which is highly exergonic by
22.4 kcal/mol, proceeds through an exceedingly low activation
barrier (TS2: ΔG‡ = 2.3 kcal/mol), delivering γ-Co(III)-alkyl
radical intermediate D (see Scheme S6 in Supporting
Information). As illustrated in the DFT-optimized structure
of TS2 (Scheme 3A; see Scheme S7 in Supporting
Information), there exists a network of noncovalent attractive
interactions, such as multiple H-bonding and π-stacking
interactions, between the substrates and the catalyst that
synergistically lower the activation barrier of the transition
state. According to the DFT calculations, the final step of 3-
exo-tet cyclization of γ-Co(III)-alkyl radical intermediate D,
which is exergonic by 12.6 kcal/mol (see Scheme S6 in
Supporting Information), is a nearly barrierless process, leading
to the formation of cyclopropane product 3a while
regenerating the metalloradical catalyst [Co(P6)].
In an effort to directly trap α-Co(III)-heterobenzyl radical
intermediate I, the metalloradical activation of 3-pyridyldiazo-
methane (1b’) by [Co(P1)] was carried out in the presence of
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) without alkene
substrates, resulting in the isolation of bis-TEMPO-trapped
product 4 in 19% yield (Scheme 3B). The observation of
compound 4 evidently implies the initial formation of α-
Co(III)-pyridyl radical I1b, which was presumably captured by
TEMPO through radical recombination to generate Co(III)-
alkyl intermediate III1b. Subsequent radical substitution
reaction of intermediate III1b with a second molecule of
TEMPO was likely responsible for the final formation of 4.
Similarly, bis-TEMPO-trapped product 5 was isolated in 12%
yield from the metalloradical activation of 3-quinolinyldiazo-
methane (1g’) by [Co(P1)] in the presence of TEMPO,
indicating the existence of α-Co(III)-heterobenzyl radical
a
Carried out with 1 (0.10 mmol), 2a (0.15 mmol), and Cs2CO3 (0.20
mmol) using [Co(P6)] (2 mol %) in toluene (1.0 mL) at 22 °C for
16 h; Isolated yields; Diastereomeric ratio (dr) determined by H
NMR of crude reaction mixture; Enantiomeric excess (ee) of the
major (E)-isomer determined by chiral HPLC; Tris = 2,4,6-
triisopropylbenzene sulfonyl.
1
limited to those with α-aryl groups containing H-bonding
acceptors at the ortho-position.8k,n To our delight, it was found
that [Co(P6)] could effectively activate α-phenyldiazomethane
(1h’) derived from benzaldehyde trishydrazone (1h) as the
radical precursor for asymmetric cyclopropanation of styrene
(2a) under the standard conditions, affording the desired 1,2-
diphenylcyclopropane (3au) in high yield with high diaster-
eoselectivity and excellent enantioselectivity (entry 1).
Encouraged by this positive outcome, we then evaluated a
wide array of α-aryldiazomethanes without H-bonding accept-
ors for asymmetric cyclopropanation by [Co(P6)]. In addition
to nonsubstituted α-phenyldiazomethane, α-aryldiazomethanes
bearing methyl substituent at different aryl positions, including
p-Me (1i’), m-Me (1j’), and o-Me (1k’), could all be efficiently
activated by [Co(P6)] for cyclopropanation of 2a, furnishing
the corresponding arylcyclopropanes 3av−3ax in similarly high
yields with the same high level of stereoselectivities (entries 2−
4). Notably, the sterically encumbered o-ethylphenyldiazo-
methane (1l’) was found to be also suitable for the catalytic
reaction, forming cyclopropane 3ay with high stereoselectiv-
ities albeit in lower yield (entry 5). It was further shown that
the [Co(P6)]-based system could use α-aryldiazomethanes
containing substituents with varied electronic properties at
different aryl positions, such as p-OMe (1m’), p-CF3 (1n’), p-
CO2Me (1o’), and m-NO2(1p’), for the reaction, enabling
high-yielding formation of the desired cyclopropanes 3az−3bc
with excellent stereoselectivities (entries 6−9). Additionally,
halogenated aryldiazomethanes were also suitable for the
catalytic process as exemplified by the stereoselective synthesis
of cyclopropane 3bd with o-bromophenyldiazomethane (1q’)
(entry 10). Furthermore, the Co(II)-based catalytic system
could be applicable to α-aryldiazomethanes bearing extended
11125
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a,b,c
Scheme 3. Mechanistic Studies on Co(II)-Catalyzed Radical Olefin Cyclopropanation with Heteroaryldiazomethanes
a
b
DFT calculations on energetics for catalytic cyclopropanation of styrene (2a) with 2-pyridyldiazomethane (1a’) by [Co(P6)]. TEMPO-trapping
c
experiments for metalloradical activation of 3-pyridyl trishydrazone (1b) and 3-quinolinyl trishydrazone (1g) by [Co(P1)]. Catalytic
cyclopropanation reactions of (E)- and (Z)-β-deuterostyrenes with 2-pyridyl tosylhydrazone (1a) by [Co(P1)], [Co(P2)], and [Co(P6)].
intermediate I1g and the following Co(III)-alkyl intermediate
III1g (Scheme 3B).
(E,Z)-3aD could be accurately determined by the combination
of 1H and 2H NMR analysis. When the bridged [Co(P6)] was
used as the catalyst, the isotopomeric ratio of (E,E)-3aD to
(E,Z)-3aD was determined to be 95:5 and 8:92 for the
cyclopropanation reactions of (E)-2aD and (Z)-2aD, respec-
tively. This observation of both (E)- and (Z)-isotopomers of
(E)-3a in both reactions evidently suggested the rotation of β-
C−C bond in the corresponding γ-Co(III)-alkyl radical
intermediates II1a/(E)‑2aD and II1a/(Z)‑2aD. When the nonbridged
[Co(P2)] was employed as the catalyst, the isotopomeric ratio
of (E,E)-3aD to (E,Z)-3aD changed for both reactions of (E)-
2aD (from 95:5 to 91:9) and (Z)-2aD (from 8:92 to 13:87),
indicating a higher degree of the β-C−C bond rotation in the
less-hindered catalyst environment. Accordingly, the use of
even less-hindered catalyst [Co(P1)] allowed a further
increase in the degree of the β-C−C bond rotation, changing
the isotopomeric ratio of (E,E)-3aD to (E,Z)-3aD to 87:13 and
To probe the involvement of the γ-Co(III)-alkyl radical
intermediate II in the proposed mechanism (Scheme 1), both
isotopomers of β-deuterostyrene (E)-2aD and (Z)-2aD were
employed as substrates for Co(II)-catalyzed cyclopropanation
with 2-pyridyl tosylhydrazone (1a). Unlike a concerted
mechanism that results in stereospecific cyclopropane prod-
ucts, a stepwise radical mechanism may give rise to the
formation of four possible diastereomers of cyclopropanes due
to the potential rotation of the β-C−C bond in γ-Co(III)-alkyl
radicalintermediate II before cyclization. As expected, both
reactions of (E)-2aD and (Z)-2aD with 1a afforded the
cyclopropane products as a mixture of four different
diastereomers: (E,E)-3aD, (Z,Z)-3aD, (Z,E)-3aD, and (E,Z)-
3aD (Scheme 3C; see Supporting Information for details).
Among them, the ratio between isotopomers (E,E)-3aD and
11126
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
17:83, respectively, for the two reactions. Collectively, these
experimental results, together with the DFT calculations,
provided corroborating evidence for the proposed stepwise
radical mechanism of the Co(II)-catalyzed asymmetric cyclo-
propanation with heteroaryldiazomethanes.
Yiling Zhu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Arghya Deb − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Yijie Xu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0002-6433-0610
CONCLUSIONS
■
In summary, we have applied Co(II)-based metalloradical
catalysis (MRC) for the successful development of asymmetric
radical cyclopropanation of alkenes with heteroaryldiazo-
methanes. With the newly synthesized bridged D2-symmetric
chiral amidoporphyrin 2,6-DiPhO-Hu(C6)Phyrin as the
optimal supporting ligand, the Co(II)-based metalloradical
system can effectively activate different types of heteroar-
yldiazomethanes even at room temperature for olefin cyclo-
propanation, offering a general approach for stereoselective
synthesis of chiral heteroaryl cyclopropanes. In addition to
styrene derivatives, the Co(II)-catalyzed cyclopropanation is
highlighted by an extraordinarily broad scope of alkenes,
including several types of challenging substrates, affording a
diverse range of heteroaryl cyclopropanes in high yields with
excellent both diastereoselectivities and enantioselectivities.
Furthermore, our combined computational and experimental
studies have provided several lines of evidence in elucidating
the underlying stepwise radical mechanism of the Co(II)-based
olefin cyclopropanation involving α- and γ-metalloalkyl radicals
as the key intermediates. In view of the ubiquity of the
resulting enantioenriched heteroaryl cyclopropanes in bio-
logically important compounds, we hope this Co(II)-catalyzed
asymmetric radical cyclopropanation process will find wide
applications in organic synthesis related to drug discovery.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04655
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support by NIH (R01-
GM102554) and in part by NSF (CHE 1900375).
REFERENCES
■
(1) For selected books, see: (a) Zard, S. Z. Radical Reactions in
Organic Synthesis; Oxford University Press: 2003. (b) Chatgilialoglu,
C.; Studer, A. Encyclopedia of Radicals in Chemistry, Biology, and
Materials; John Wiley & Sons: 2012. (c) For selected reviews, see:
Zard, S. Z. Recent Progress in the Generation and Use of Nitrogen-
Centred Radicals. Chem. Soc. Rev. 2008, 37, 1603−1618. (d) Nar-
ayanam, J. M.; Stephenson, C. R. Visible Light Photoredox Catalysis:
Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102−
113. (e) Quiclet-Sire, B.; Zard, S. Z. Fun with Radicals: Some New
Perspectives for Organic Synthesis. Pure Appl. Chem. 2010, 83, 519−
551. (f) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (g) Studer,
A.; Curran, D. P. Catalysis of Radical Reactions: A Radical Chemistry
Perspective. Angew. Chem., Int. Ed. 2016, 55, 58−102.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(2) For selected reviews, see: (a) Bar, G.; Parsons, A. F.
Stereoselective Radical Reactions. Chem. Soc. Rev. 2003, 32, 251−
263. (b) Sibi, M. P.; Manyem, S.; Zimmerman, J. Enantioselective
Radical Processes. Chem. Rev. 2003, 103, 3263−3295. (c) Brimioulle,
R.; Lenhart, D.; Maturi, M. M.; Bach, T. Enantioselective Catalysis of
Photochemical Reactions. Angew. Chem., Int. Ed. 2015, 54, 3872−
3890.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04655.
Experimental details and analytical data for all new
compounds (PDF)
Accession Codes
(3) For selected examples on approaches to controlling radical
reactivity and stereoselectivity, see: (a) Du, J. N.; Skubi, K. L.;
Schultz, D. M.; Yoon, T. P. A Dual-Catalysis Approach to
Enantioselective [2 + 2] Photocycloadditions Using Visible Light.
Science 2014, 344, 392−396. (b) Huo, H.; Shen, X.; Wang, C.; Zhang,
L.; Röse, P.; Chen, L.-A.; Harms, K.; Marsch, M.; Hilt, G.; Meggers,
E. Asymmetric Photoredox Transition-Metal Catalysis Activated by
Visible Light. Nature 2014, 515, 100−103. (c) Kainz, Q. M.; Matier,
C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C.
Asymmetric Copper-Catalyzed C−N Cross-Couplings Induced by
Visible Light. Science 2016, 351, 681−684. (d) Zhang, W.; Wang, F.;
McCann, S. D.; Wang, D. H.; Chen, P. H.; Stahl, S. S.; Liu, G. S.
Enantioselective Cyanation of Benzylic C−H Bonds via Copper-
Catalyzed Radical Relay. Science 2016, 353, 1014−1018. (e) 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. (f) Morrill, C.; Jensen, C.; Just-
Baringo, X.; Grogan, G.; Turner, N. J.; Procter, D. J. Biocatalytic
Conversion of Cyclic Ketones Bearing -Quaternary Stereocenters into
Lactones in an Enantioselective Radical Approach to Medium-Sized
Carbocycles. Angew. Chem., Int. Ed. 2018, 57, 3692−3696. (g) Proctor,
R. S. J.; Davis, H. J.; Phipps, R. J. Catalytic Enantioselective Minisci-
Type Addition to Heteroarenes. Science 2018, 360, 419−422.
(h) Biegasiewicz, K. F.; Cooper, S. J.; Gao, X.; Oblinsky, D. G.;
CCDC 2083336−2083339 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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
Authors
Xiaoxu Wang − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0003-0444-6950
Jing Ke − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0001-8006-6541
11127
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Kim, J. H.; Garfinkle, S. E.; Joyce, L. A.; Sandoval, B. A.; Scholes, G.
D.; Hyster, T. K. Photoexcitation of Favoenzymes Enables a
Stereoselective Radical Cyclization. Science 2019, 364, 1166−1169.
(i) Huang, H.-M.; McDouall, J. J. W.; Procter, D. J. SmI2-Catalysed
Cyclization Cascades by Radical Relay. Nat. Catal. 2019, 2, 211−218.
(j) Nakafuku, K. M.; Zhang, Z.; Wappes, E. A.; Stateman, L. M.;
Chen, A. D.; Nagib, D. A. Enantioselective Radical C−H Amination
for the Synthesis of β-Amino Alcohols. Nat. Chem. 2020, 12, 697−
704.
Co-Catalyzed Transannulation of Pyridotriazoles with Isothiocyanates
and Xanthate Esters. Org. Lett. 2020, 22, 8500−8504.
(7) (a) Dzik, W. I.; Xu, X.; Zhang, X. P.; Reek, J. N. H.; de Bruin, B.
‘Carbene Radicals’ in CoII(por)-Catalyzed Olefin Cyclopropanation. J.
Am. Chem. Soc. 2010, 132, 10891−10902. (b) Belof, J. L.; Cioce, C.
R.; Xu, X.; Zhang, X. P.; Space, B.; Woodcock, H. L. Characterization
of Tunable Radical Metal-Carbenes: Key Intermediates in Catalytic
Cyclopropanation. Organometallics 2011, 30, 2739−2746. (c) Lu, H.;
Dzik, W. I.; Xu, X.; Wojtas, L.; de Bruin, B.; Zhang, X. P.
Experimental Evidence for Cobalt(III)-Carbene Radicals: Key
Intermediates in Cobalt(II)-Based Metalloradical Cyclopropanation.
J. Am. Chem. Soc. 2011, 133, 8518−8521.
(4) For selected reviews and highlights on Co(II)-based MRC, see:
(a) Lu, H. J.; Zhang, X. P. Catalytic C−H Functionalization by
Metalloporphyrins: Recent Developments and Future Directions.
Chem. Soc. Rev. 2011, 40, 1899−1909. (b) Pellissier, H.; Clavier, H.
Enantioselective Cobalt-Catalyzed Transformations. Chem. Rev. 2014,
114, 2775−2823. (c) Demarteau, J.; Debuigne, A.; Detrembleur, C.
Organocobalt Complexes as Sources of Carbon-Centered Radicals for
Organic and Polymer Chemistries. Chem. Rev. 2019, 119, 6906−6955.
(8) (a) Chen, Y.; Fields, K. B.; Zhang, X. P. Bromoporphyrins as
Versatile Synthons for Modular Construction of Chiral Porphyrins:
Cobalt-Catalyzed Highly Enantioselective and Diastereoselective
Cyclopropanation. J. Am. Chem. Soc. 2004, 126, 14718−14719.
(b) Caselli, A.; Gallo, E.; Ragaini, F.; Ricatto, F.; Abbiati, G.; Cenini,
S. Chiral Porphyrin Complexes of Cobalt(II) and Ruthenium(II) in
Catalytic Cyclopropanation and Amination Reactions. Inorg. Chim.
Acta 2006, 359, 2924−2932. (c) Chen, Y.; Ruppel, J. V.; Zhang, X. P.
Cobalt-Catalyzed Asymmetric Cyclopropanation of Electron-Defi-
cient Olefins. J. Am. Chem. Soc. 2007, 129, 12074−12075.
(d) Fantauzzi, S.; Gallo, E.; Rose, E.; Raoul, N.; Caselli, A.; Issa, S.;
Ragaini, F.; Cenini, S. Asymmetric Cyclopropanation of Olefins
Catalyzed by Chiral Cobalt(II)-Binaphthyl Porphyrins. Organo-
metallics 2008, 27, 6143−6151. (e) Zhu, S.; Ruppel, J. V.; Lu, H.;
Wojtas, L.; Zhang, X. P. Cobalt-Catalyzed Asymmetric Cyclo-
propanation with Diazosulfones: Rigidification and Polarization of
Ligand Chiral Environment via Hydrogen Bonding and Cyclization. J.
Am. Chem. Soc. 2008, 130, 5042−5043. (f) Zhu, S.; Xu, X.; Perman, J.
A.; Zhang, X. P. A General and Efficient Cobalt(II)-Based Catalytic
System for Highly Stereoselective Cyclopropanation of Alkenes with
α-Cyanodiazoacetates. J. Am. Chem. Soc. 2010, 132, 12796−12799.
(g) Xu, X.; Lu, H. J.; Ruppel, J. V.; Cui, X.; de Mesa, S. L.; Wojtas, L.;
Zhang, X. P. Highly Asymmetric Intramolecular Cyclopropanation of
Acceptor-Substituted Diazoacetates by Co(II)-Based Metalloradical
Catalysis: Iterative Approach for Development of New-Generation
Catalysts. J. Am. Chem. Soc. 2011, 133, 15292−15295. (h) Paul, N.
D.; Mandal, S.; Otte, M.; Cui, X.; Zhang, X. P.; de Bruin, B.
Metalloradical Approach to 2H-Chromenes. J. Am. Chem. Soc. 2014,
136, 1090−1096. (i) Reddy, A. R.; Hao, F.; Wu, K.; Zhou, C. Y.; Che,
C. M. Cobalt(II) Porphyrin-Catalyzed Intramolecular Cyclopropana-
tion of N-Alkyl Indoles/Pyrroles with Alkylcarbene: Efficient
Synthesis of Polycyclic N-Heterocycles. Angew. Chem., Int. Ed. 2016,
55, 1810−1815. (j) Chirila, A.; Gopal Das, B.; Paul, N. D.; de Bruin,
B. Diastereoselective Radical-Type Cyclopropanation of Electron-
Deficient Alkenes Mediated by the Highly Active Cobalt(II)
Tetramethyltetraaza[14]annulene Catalyst. ChemCatChem 2017, 9,
1413−1421. (k) Wang, Y.; Wen, X.; Cui, X.; Wojtas, L.; Zhang, X. P.
Asymmetric Radical Cyclopropanation of Alkenes with In Situ-
Generated Donor-Substituted Diazo Reagents via Co(II)-Based
Metalloradical Catalysis. J. Am. Chem. Soc. 2017, 139, 1049−1052.
(l) Wang, Y.; Wen, X.; Cui, X.; Zhang, X. P. Enantioselective Radical
Cyclization for Construction of 5-Membered Ring Structures by
Metalloradical C−H Alkylation. J. Am. Chem. Soc. 2018, 140, 4792−
4796. (m) Wen, X.; Wang, Y.; Zhang, X. P. Enantioselective Radical
Process for Synthesis of Chiral Indolines by Metalloradical Alkylation
of Diverse C(sp3)−H Bonds. Chem. Sci. 2018, 9, 5082−5086.
(n) Lee, W.-C. C.; Wang, D.-S.; Zhang, C.; Xie, J.; Li, B.; Zhang, X. P.
Asymmetric Radical Cyclopropanation of Dehydroaminocarboxylates:
Stereoselective Synthesis of Cyclopropyl α-Amino Acids. Chem. 2021,
7, 1588−1601.
(d) Huang, H.-M.; Garduno-Castro, M. H.; Morrill, C.; Procter, D. J.
̃
Catalytic Cascade Reactions by Radical Relay. Chem. Soc. Rev. 2019,
48, 4626−4638. (e) Singh, R.; Mukherjee, A. Metalloporphyrin
Catalyzed C−H Amination. ACS Catal. 2019, 9, 3604−3617.
(5) For selected examples of Ti(III)-based radical processes, see:
(a) Nugent, W. A.; RajanBabu, T. V. Transition-Metal-Centered
Radicals in Organic Synthesis. Titanium(III)-Induced Cyclization of
Epoxyolefins. J. Am. Chem. Soc. 1988, 110, 8561−8562. (b) Rajanba-
bu, T. V.; Nugent, W. A. Selective Generation of Free-Radicals from
Epoxides Using a Transition-Metal Radical. A Powerful New Tool for
Organic-Synthesis. J. Am. Chem. Soc. 1994, 116, 986−997.
(c) Gansäuer, A.; Hildebrandt, S.; Michelmann, A.; Dahmen, T.;
von Laufenberg, D.; Kube, C.; Fianu, G. D.; Flowers, R. A., II Cationic
Titanocene(III) Complexes for Catalysis in Single-Electron Steps.
Angew. Chem., Int. Ed. 2015, 54, 7003−7006. (d) Funken, N.;
Muhlhaus, F.; Gansäuer, A. General, Highly Selective Synthesis of 1,3-
̈
and 1,4-Difunctionalized Building Blocks by Regiodivergent Epoxide
Opening. Angew. Chem., Int. Ed. 2016, 55, 12030−12034. (e) Hao,
W.; Wu, X.; Sun, J. Z.; Siu, J. C.; MacMillan, S. N.; Lin, S. Radical
Redox-Relay Catalysis: Formal [3 + 2] Cycloaddition of N-
Acylaziridines and Alkenes. J. Am. Chem. Soc. 2017, 139, 12141−
12144. (f) Yao, C. B.; Dahmen, T.; Gansäuer, A.; Norton, J. Anti-
Markovnikov Alcohols via Epoxide Hydrogenation through Cooper-
ative Catalysis. Science 2019, 364, 764−767. (g) Ye, K. Y.; McCallum,
T.; Lin, S. Bimetallic Radical Redox-Relay Catalysis for the
Isomerization of Epoxides to Allylic Alcohols. J. Am. Chem. Soc.
2019, 141, 9548−9554.
(6) For selected examples of metalloradical-mediated radical
processes, see: (a) Wayland, B. B.; Poszmik, G.; Mukerjee, S. L.;
Fryd, M. Living Radical Polymerization of Acrylates by Organocobalt
Porphyrin Complexes. J. Am. Chem. Soc. 1994, 116, 7943−7944.
(b) Zhang, X.-X.; Wayland, B. B. Rhodium(II) Porphyrin
Bimetalloradical Complexes: Preparation and Enhanced Reactivity
with CH4 and H2. J. Am. Chem. Soc. 1994, 116, 7897−7898. (c) Chan,
K. S.; Li, X. Z.; Dzik, W. I.; de Bruin, B. Carbon-Carbon Bond
Activation of 2,2,6,6-Tetramethyl-piperidine-1-oxyl by a RhII Metal-
loradical: A Combined Experimental and Theoretical Study. J. Am.
Chem. Soc. 2008, 130, 2051−2061. (d) Chan, Y. W.; Chan, K. S.
Metalloradical-Catalyzed Aliphatic Carbon-Carbon Activation of
Cyclooctane. J. Am. Chem. Soc. 2010, 132, 6920−6922. (e) Li, G.;
Han, A.; Pulling, M. E.; Estes, D. P.; Norton, J. R. Evidence for
Formation of a Co-H Bond from (H2O)2Co(dmgBF2)2 under H2:
Application to Radical Cyclizations. J. Am. Chem. Soc. 2012, 134,
14662−14665. (f) Kuo, J. L.; Hartung, J.; Han, A.; Norton, J. R.
Direct Generation of Oxygen-Stabilized Radicals by H· Transfer from
Transition Metal Hydrides. J. Am. Chem. Soc. 2015, 137, 1036−1039.
(g) Roy, S.; Khatua, H.; Das, S. K.; Chattopadhyay, B. Iron(II)-Based
Metalloradical Activation: Switch from Traditional Click Chemistry to
Denitrogenative Annulation. Angew. Chem., Int. Ed. 2019, 58, 11439−
11443. (h) Das, S. K.; Roy, S.; Khatua, H.; Chattopadhyay, B. Iron-
Catalyzed Amination of Strong Aliphatic C(sp3)−H Bonds. J. Am.
Chem. Soc. 2020, 142, 16211−16217. (i) Zhang, Z.; Gevorgyan, V.
(9) (a) Liu, H.; Kerdesky, F. A.; Black, L. A.; Fitzgerald, M.; Henry,
R.; Esbenshade, T. A.; Hancock, A. A.; Bennani, Y. L. An Efficient
Multigram Synthesis of the Potent Histamine H3 Antagonist GT-2331
and the Reassessment of the Absolute Configuration. J. Org. Chem.
2004, 69, 192−194. (b) Butcher, K. J.; Denton, S. M.; Field, S. E.;
Gillmore, A. T.; Harbottle, G. W.; Howard, R. M.; Laity, D. A.;
Ngono, C. J.; Pibworth, B. A. Convergent Asymmetric Synthesis of
11128
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Two Complex TRPV1 Antagonists. Org. Process Res. Dev. 2011, 15,
1192−1200. (c) MacKinnon, C. H.; Lau, K.; Burch, J. D.; Chen, Y.;
Dines, J.; Ding, X.; Eigenbrot, C.; Heifetz, A.; Jaochico, A.; Johnson,
(13) (a) Doyle, M. P.; High, K. G.; Oon, S.-M.; Osborn, A. K.
Diazirines in Carbenoid Reactions Catalyzed by Rhodium(II)
Carboxylates. Tetrahedron Lett. 1989, 30, 3049−3052. (b) Regitz,
M.; Maas, G. Diazo Compounds: Properties and Synthesis; Academic
Press: London, 1996. (c) Aggarwal, V. K.; de Vicente, J.; Bonnert, R.
V. Catalytic Cyclopropanation of Alkenes Using Diazo Compounds
Generated in Situ. A Novel Route to 2-Arylcyclopropylamines. Org.
Lett. 2001, 3, 2785−2788. (d) Fulton, J. R.; Aggarwal, V. K.; de
Vicente, J. The Use of Tosylhydrazone Salts as a Safe Alternative for
Handling Diazo Compounds and Their Applications in Organic
Synthesis. Eur. J. Org. Chem. 2005, 2005, 1479−1492.
A.; Kraemer, J.; Kruger, S.; Krulle, T. M.; Liimatta, M.; Ly, J.;
̈
Maghames, R.; Montalbetti, C. A.; Ortwine, D. F.; Pérez-Fuertes, Y.;
Shia, S.; Stein, D. B.; Trani, G.; Vaidya, D. G.; Wang, X.; Bromidge, S.
M.; Wu, L. C.; Pei, Z. Structure-based Design and Synthesis of Potent
Benzothiazole Inhibitors of Interleukin-2 Inducible T Cell Kinase
(ITK). Bioorg. Med. Chem. Lett. 2013, 23, 6331−6335. (d) Kohn, T.
J.; Du, X.; Lai, S.; Xiong, Y.; Komorowski, R.; Veniant, M.; Fu, Z.;
Jiao, X.; Pattaropong, V.; Chow, D.; Cardozo, M.; Jin, L.; Conn, M.;
DeWolf, W. E.; Kraser, C. F.; Hinklin, R. J.; Boys, M. L.; Medina, J.
C.; Houze, J.; Dransfield, P.; Coward, P. 5-Alkyl-2-urea-Substituted
Pyridines: Identification of Efficacious Glucokinase Activators with
Improved Properties. ACS Med. Chem. Lett. 2016, 7, 666−670.
(e) Talele, T. T. The “Cyclopropyl Fragment” is a Versatile Player
that Frequently Appears in Preclinical/Clinical Drug Molecules. J.
Med. Chem. 2016, 59, 8712−8756.
(14) (a) Zimmerman, H. E.; Ignatchenko, A. Control of the
Stereochemistry of Kinetic Protonation: Intramolecular Proton
Delivery. J. Org. Chem. 1999, 64, 6635−6645. (b) Barluenga, J.;
Quinones, N.; Tomás-Gamasa, M.; Cabal, M.-P. Intermolecular
̃
Metal-Free Cyclopropanation of Alkenes Using Tosylhydrazones. Eur.
J. Org. Chem. 2012, 2012, 2312−2317. (c) Roda, N. M.; Tran, D. N.;
Battilocchio, C.; Labes, R.; Ingham, R. J.; Hawkins, J. M.; Ley, S. V.
Cyclopropanation Using Flow-Generated Diazo Compounds. Org.
Biomol. Chem. 2015, 13, 2550−2554. (d) Liu, Z.; Zhang, X.; Zanoni,
G.; Bi, X. Silver-Catalyzed Cyclopropanation of Alkenes Using N-
Nosylhydrazones as Diazo Surrogates. Org. Lett. 2017, 19, 6646−
6649. (e) Allouche, E. M. D.; Al-Saleh, A.; Charette, A. B. Iron-
Catalyzed Synthesis of Cyclopropanes by In Situ Generation and
Decomposition of Electronically Diversified Diazo Compounds.
Chem. Commun. 2018, 54, 13256−13259. (f) Roy, S.; Das, S. K.;
Chattopadhyay, B. Cobalt(II)-based Metalloradical Activation of 2-
(Diazomethyl)-pyridines for Radical Transannulation and Cyclo-
propanation. Angew. Chem., Int. Ed. 2018, 57, 2238−2243. (g) Zhang,
Z.; Yadagiri, D.; Gevorgyan, V. Light-Induced Metal-Free Trans-
formations of Unactivated Pyridotriazoles. Chem. Sci. 2019, 10,
8399−8404. (h) Shang, Z.-H.; Zhang, Z.-X.; Weng, W.-Z.; Wang, Y.-
F.; Cheng, T.-W.; Zhang, Q.-Y.; Song, L.-Q.; Shao, T.-Q.; Liu, K.-X.;
Zhu, Y.-P. A Metal- and Azide-free Oxidative Coupling Reaction for
the Synthesis of [1,2,3]Triazolo[1,5-a]quinolines and their Applica-
tion to Construct C-C and C-P Bonds, 2-Cyclopropylquinolines and
Imidazo[1,5-a]quinolines. Adv. Synth. Catal. 2021, 363, 490−496.
(15) Ruppel, J. V.; Jones, J. E.; Huff, C. A.; Kamble, R. M.; Chen, Y.;
Zhang, X. P. A Highly Effective Cobalt Catalyst for Olefin
Aziridination with Azides: Hydrogen Bonding Guided Catalyst
Design. Org. Lett. 2008, 10, 1995−1998.
(10) (a) Charette, A. B.; Molinaro, C.; Brochu, C. Catalytic
Asymmetric Cyclopropanation of Allylic Alcohols with Titanium-
TADDOLate: Scope of the Cyclopropanation Reaction. J. Am. Chem.
Soc. 2001, 123, 12168−12175. (b) Davies, H. M. L.; Townsend, R. J.
Catalytic Asymmetric Cyclopropanation of Heteroaryldiazoacetates. J.
Org. Chem. 2001, 66, 6595−6603. (c) Marcin, L. R.; Denhart, D. J.;
Mattson, R. J. Catalytic Asymmetric Diazoacetate Cyclopropanation
of 1-Tosyl-3-vinylindoles. A Route to Conformationally Restricted
Homotryptamines. Org. Lett. 2005, 7, 2651−2654. (d) Chuprakov, S.;
Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. Rhodium-Catalyzed
Enantioselective Cyclopropanation of Olefins with N-Sulfonyl 1,2,3-
Triazoles. J. Am. Chem. Soc. 2009, 131, 18034−18035. (e) Grimster,
N.; Zhang, L.; Fokin, V. V. Synthesis and Reactivity of Rhodium(II)
N-Triflyl Azavinyl Carbenes. J. Am. Chem. Soc. 2010, 132, 2510−
2511. (f) Jin, C.; Decker, A. M.; Huang, X.-P.; Gilmour, B. P.; Blough,
B. E.; Roth, B. L.; Hu, Y.; Gill, J. B.; Zhang, X. P. Synthesis,
Pharmacological Characterization, and Structure-Activity Relationship
Studies of Small Molecular Agonists for the Orphan GPR88 Receptor.
ACS Chem. Neurosci. 2014, 5, 576−587. (g) Bajaj, P.; Sreenilayam, G.;
Tyagi, V.; Fasan, R. Gram-Scale Synthesis of Chiral Cyclopropane-
Containing Drugs and Drug Precursors with Engineered Myoglobin
Catalysts Featuring Complementary Stereoselectivity. Angew. Chem.,
Int. Ed. 2016, 55, 16110−16114. (h) Fu, L.; Mighion, J. D.; Voight, E.
A.; Davies, H. M. L. Synthesis of 2,2,2,-Trichloroethyl Aryl- and
Vinyldiazoacetates by Palladium-Catalyzed Cross-Coupling. Chem. -
Eur. J. 2017, 23, 3272−3275. (i) Moore, E. J.; Steck, V.; Bajaj, P.;
Fasan, R. Chemoselective Cyclopropanation over Carbene Y-H
Insertion Catalyzed by an Engineered Carbene Transferase. J. Org.
Chem. 2018, 83, 7480−7490. (j) Vargas, D. A.; Khade, R. L.; Zhang,
Y.; Fasan, R. Biocatalytic Strategy for Highly Diastereo- and
Enantioselective Synthesis of 2,3-Dihydrobenzofuran-Based Tricyclic
Scaffolds. Angew. Chem., Int. Ed. 2019, 58, 10148−10152. (k) Wei, B.;
Sharland, J. C.; Lin, P.; Wilkerson-Hill, S. M.; Fullilove, F. A.;
McKinnon, S.; Blackmond, D. G.; Davies, H. M. L. In Situ Kinetic
Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low
Catalyst Loadings. ACS Catal. 2020, 10, 1161−1170. (l) Nam, D.;
Steck, V.; Potenzino, R. J.; Fasan, R. A Diverse Library of Chiral
Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversi-
fication of Cyclopropyl Ketones. J. Am. Chem. Soc. 2021, 143, 2221−
2231.
(16) Hu, Y.; Lang, K.; Tao, J.; Marshall, M. K.; Cheng, Q.; Cui, X.;
Wojtas, L.; Zhang, X. P. Next-Generation D2-Symmetric Chiral
Porphyrins for Cobalt(II)-Based Metalloradical Catalysis: Catalyst
Engineering by Distal Bridging. Angew. Chem., Int. Ed. 2019, 58,
2670−2674.
(17) Lang, K.; Torker, S.; Wojtas, L.; Zhang, X. P. Asymmetric
Induction and Enantiodivergence in Catalytic Radical C−H
Amination via Enantiodifferentiative H-Atom Abstraction and Stereo-
retentive Radical Substitution. J. Am. Chem. Soc. 2019, 141, 12388−
12396.
(11) (a) Doyle, M. P. Catalytic Methods for Metal Carbene
Transformations. Chem. Rev. 1986, 86, 919−939. (b) Doyle, M. P.;
Forbes, D. C. Recent Advances in Asymmetric Catalytic Metal
Carbene Transformations. Chem. Rev. 1998, 98, 911−935. (c) Intrieri,
D.; Carminati, D. M.; Gallo, E. The Ligand Influence in Stereo-
selective Carbene Transfer Reactions Promoted by Chiral Metal
Porphyrin Catalysts. Dalton Trans. 2016, 45, 15746−16048.
(12) Allouche, E. M. D.; Charette, A. B. Cyclopropanation Reactions
of Semi-stabilized and Non-stabilized Diazo Compounds. Synthesis
2019, 51, 3947−3963.
11129
https://doi.org/10.1021/jacs.1c04655
J. Am. Chem. Soc. 2021, 143, 11121−11129