Radical-Polar Crossover Annulation: A Platform for Accessing Polycyclic Cyclopropanes

Article abstract of DOI:10.1002/adsc.201901051

Photoredox-mediated radical/polar crossover (RPC) processes provide unique solutions to challenging annulations. Herein, we describe an approach to the cyclopropanation of olefins that are embedded within bicyclic scaffolds. Whereas these systems are noto

Full text of DOI:10.1002/adsc.201901051

Title: Radical-Polar Crossover Annulation: A Platform for Accessing
Polycyclic Cyclopropanes
Authors: John Milligan, Kevin Burns, Anthony Le, Viktor Polites, Zheng-
Jun Wang, Gary Molander, and Christopher Kelly
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901051
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Radical-Polar Crossover Annulation: A Platform for Accessing
Polycyclic Cyclopropanes
John A. Milligan,a Kevin L. Burns,b,c Anthony V. Le,b,c Viktor C. Polites,a Zheng-Jun
Wang,a,d Gary A. Molander,*a and Christopher B. Kelly*b,c
a
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, USA. Email: gmolandr@sas.upenn.edu. Phone: (215) 573-8604
Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, P.O. Box 842006, Richmond,
b
Virginia 23284, USA. Email: cbkelly@vcu.edu. Phone: (804) 828-1298.
Medicines for All Institute, Virginia Commonwealth University, Biotech 8, 737 North Fifth Street, Richmond, Virginia,
c
23219, USA
d
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering,
Hunan University, Changsha 41000, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Photoredox-mediated radical/polar crossover (RPC)
processes provide unique solutions to challenging annulations.
Herein, we describe an approach to the cyclopropanation of
olefins that are embedded within bicyclic scaffolds. Whereas
these systems are notoriously recalcitrant toward classical
cyclopropanation approaches, RPC cyclopropanation can be
executed with ease, leading to polycarbocyclic and
polyheterocyclic cyclopropanes. The cyclopropanation
proceeds through a photoredox-enabled Giese-type radical
addition followed by an intramolecular anionic substitution
reaction on a neopentyl leaving group.
Keywords: Cyclopropanes; Photoredox Catalysis;
Cyclization; Radical/Polar Crossover; Radicals
because of the stronger, shorter cyclopropyl C-H
bonds.[2] Cyclopropanes adjacent to aromatic rings
can serve as isosteres of styrenes with improved
metabolic stability. Several polycyclic cyclopropanes
with this substructure have been reported by
pharmaceutical companies and academic groups for
antiviral (hepatitis C),[3] antitumor,[4] and anti-
neurodegenerative[5] indications.
The polycyclic cyclopropane scaffolds reported in
these and other studies are commonly accessed
through the cyclopropanation of styrene precursors,
typically with carbene or sulfur ylide chemistry
(Figure 2).[6] Aside from the need to have a
predetermined cyclopropane structure (i.e., the
cyclopropane substituents must be pre-installed as a
polysubstituted alkene), these traditional methods
possess inherent limitations. The classical Simmons-
Smith cyclopropanation, although robust and well-
proven, is sluggish with polysubstituted styrenes[5]
and generally intolerant of Lewis basic functional
groups (such as pyridines), although these limitations
can be overcome in certain cases.[1],[6] The Corey-
Chaykovsky method has been used for the synthesis
of α-aryl cyclopropanes such as those shown in
Introduction
The cyclopropane scaffold is of longstanding
interest because of its unique structural attributes and
frequent occurrence in bioactive molecules.
Consequently, substantial efforts have been made in
developing cyclopropanation strategies.[1] Inclusion
of the cyclopropyl motif in polycyclic, bioactive
molecules has been demonstrated to increase their
rigidity, potency, and metabolic stability
Figure 1. Examples of polycyclic α-aryl cyclopropanes
with bioactive properties.
1
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
Figure 1, but these reactions require an activated
alkene acceptor and strong bases that can limit
pathways in accomplishing otherwise challenging or
harsh transformations.[13]
functional
group
tolerance.
Inter-[5],[7]
or
intramolecular[8] cyclopropanation with diazo species
has also been used to access polycyclic cyclopropane
scaffolds; however, these reactions sometimes pose
operational and selectivity challenges. Several
intermolecular cyclopropanation methods have
recently been developed that provide facile
alternatives to these methods.[9]
Results and Discussion
The requisite cyclopropanation substrates were
prepared through a straightforward sequence starting
from commodity ketones such as α-tetralone or 1-
indanone (Scheme 1). The known β-ketoesters
derived from these ketones were alkylated with
electrophiles such as iodomethane or benzylic
In the course of our studies on the development of
bench-stable radical precursors for application in
photoredox catalysis,[10] we have identified an
alternative cyclopropanation approach we refer to as
radical/polar crossover (RPC) annulation. The initial
work in this area made use of an iodomethylsilicate
reagent that served as a formal carbene equivalent for
the cyclopropanation of α-CF3-substituted alkenes,
acrylates, and styrenes.[11] More recent studies
revealed that homoallylic tosylates can undergo
cyclopropanation when irradiated with visible light in
the presence of a radical precursor reagent.[12] Both
reaction classes are proposed to proceed through
radical addition to an alkene, single electron
reduction of the radical adduct to an anion, and
anionic 3-exo-tet ring closure. Though the
mechanisms of these two reaction classes are
convergent, the latter benefits from a modular
character (i.e., different subunits of the 1,1-
disubstituted cyclopropane can be introduced from
the two respective partners).
Scheme 1. Commodity ketones to cyclopropane linchpins.
bromides. Enantioselective alkylation of these
ketoesters
has
been
demonstrated
using
enantioselective phase transfer catalysis,[14] and this
strategy could be employed to set the absolute
stereochemistry of the
Table 1. Optimization of the radical/polar crossover
cyclopropanation process.[a]
Figure 2. Comparison and context of current work.
Motivated by the success of these mild,
operationally simple radical/polar crossover reactions,
we sought to address the synthesis of highly
substituted cyclopropanes that are challenging to
access. The success of such a proposition would
largely be dependent on the success of anionic
cyclization on a neopentyl center. To test the
feasibility of this approach, we designed a series of
olefins that could serve as linchpins to construct an
array of polycyclic cyclopropanes. Treatment of these
substrates with photocatalytically-generated radicals
would provide access to tetra-substituted, polycyclic
cyclopropanes (Figure 2) that would be challenging
to access by state-of-the-art approaches. Further, the
process should accommodate multiple radical sources,
thus allowing easy access to bicyclic cyclopropanes
with diverse functional groups. The reaction
effectively highlights the utility of single-electron
[a]Optimization reactions performed using 0.025 mmol of
1a in the presence of 4,4′-di-tert-butylbiphenyl as internal
standard (IS) (0.0125 mmol) for 16 h at 30 oC; Ratios of 1a
2
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
and 2 to IS determined by HPLC analysis of the crude
these conditions proved broadly applicable over a
range of substrates and for larger scale reactions.
Control reactions confirmed that this was indeed a
photocatalyst-driven process, requiring both the
reaction mixture.
[b]2,4,5,6-Tetrakis(3,6-dichloro-9H-
carbazol-9-yl)isophthalonitrile.
[c]2,4,5,6-Tetra(9H-
carbazol-9-yl)isophthalonitrile. [d]Reaction conducted in
the absence of light.
photocatalyst
and
irradiation
to
effect
cyclopropanation.
The developed conditions were applied to the
cyclopropanation of tetralone-derived tosylates.
Various sterically disparate alkyl fragments were
appended to the olefin and used to facilitate the ring-
closing cascade. Protic functional groups (9-11) and
heterocycles (12, 17) posed no problem to the
cyclopropanation reaction. The reaction also tolerated
a polyfluorinated arene without evidence of products
derived from radical/polar SNAr-type processes.[17]
Alteration of the tetralone structure was similarly
well-tolerated and allowed various groups to be
installed on the cyclopropane fragment (16, 17) as
well as on the arene (6b-c, 10b) emphasizing the
modular nature of this approach. Electronic changes
on the aryl ring appear to have little impact on
cyclopropanation reactivity, as evidenced by the lack
of variablity in yield between 6a-6c and the results of
a head-to-head competition study (See Supporting
Information). Our previous studies on the photoredox
cyclopropanation of acyclic systems showed that the
electronics of the arene contribute substantially to
reaction success, whereas for the rigid systems
investigated here, the influence of electronics is
minimal.[11],[12]
linchpin, and ultimately, the resulting tetra-
substituted cyclopropane. A series of simple, high-
yielding steps (Wittig olefination of the ketone,
reduction of the ester, and tosylation of the resulting
alcohol) provided the requisite cyclopropanation
substrates.
An assessment of pertinent reaction parameters
was conducted (Table 1). Suitable reaction conditions
were identified through screening using 1a as a
model linchpin and bis(catecholato)cyclohexylsilicate
as a model radical precursor (RP). An alkylsilicate
was selected because such species are versatile
radical forebears[15] that readily furnish both 1o and 2o
alkyl radicals with an array of photocatalysts, and
various parameters for their use are less restrictive
than other RP classes. Moreover, they produce benign
by-products that would not impede nor degrade
cyclopropane 2. Solvents that have proven adequate
for radical generation using alkylsilicates were
assessed, and ultimately, DMSO was found to be the
most suitable solvent, likely because of the polar
nature of the anionic transition state for cyclization.
Ultimately, 4CzIPN[16] proved to be the ideal
photocatalyst (especially considering the high
conversion, low cost of the catalyst, and its metal-free
nature), and no additives were required. Further,
To augment the modularity of this approach,
alternative RPs such as organotrifluoroborates could
be used in place of alkylsilicates without any need for
Table 2. Cyclopropanation of the tetralone-derived core via RPC.[a]
3
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
[a]Unless otherwise noted, the reactions were carried out on a 0.2-0.3 mmol scale of the corresponding tosylate at 30 °C for
2-16 h; RP = radical precursor; isolated yields after purification, see Supporting Information for details regarding
purifications and alterations to radical precursor loading.
re-optimization. Using these alternate radical
progenitors, an array of complex oxygen-containing
fragments could be installed. Other 2° and 3o alkyl
radicals generated from alkyltrifluoroborates were
also used to install tert-butyl (19) and heterocyclic
(22) motifs on the polycyclic core. In the case of the
latter, both quaternary and tertiary centers were set in
[a]Unless otherwise noted, the reactions were carried out on
a 0.2-0.3 mmol scale at 30 °C for 2-16 h; isolated yields
after purification, see Supporting Information for details
regarding purifications and alterations to radical precursor
loading. [b]Reaction conducted on 1.2 mmol scale.
a
singular operation. Given the inherent
In an effort to elucidate the limitations of this
approach toward polycyclic cyclopropanes, the
preparation of larger bicyclic systems was attempted
diastereospecific nature of this reaction,
enantioselective alkylation of the requisite starting
materials would thereby render this process an
(Table
4).
In
initial
efforts
with
a
enantiospecific
cyclopropanes.
means
to
generate
these
benzocycloheptanone-derived
cyclopropanation
linchpin, somewhat discouraging results were
obtained. The cycloheptanone-based tosylate (and
even its mesylate) mostly failed to react and produced
very low amounts of the desired cyclopropane
product and unknown alkene byproducts. No
significant degradation occurred when the sample
containing the tosylate was irradiated in the presence
A series of indanone-derived tosylates were
assembled in an analogous manner and subjected to
the cyclopropanation process (Table 3). As with the
tetralone-based system, radical addition followed by
anionic ring closure occurred to provide an array of
heretofore unknown polycyclic cyclopropanes.
Fragments containing heterocycles, fluorinated motifs, of 4CzIPN but in the absence of a radical precursor. It
and synthetically useful functional handles were all
introduced with ease. Likewise, alteration of the
structure of the cyclopropanation linchpin did not
was noted that, unlike the tosylates of the indanone
and tetralone systems, the cycloheptanone based
1
system has unusual broadening of the H NMR
substantially
impact
the
propensity
for
signals of this tosylate (and mesylate) and a distinctly
different chemical shift for the alkenyl protons. This
suggests that the radical addition or stability of the
resulting benzylic radical may be impacted by
conformational variation within this ring system,
providing a possible explaination for the lack of
reactivity.
cyclopropanation. The use of a brominated indanone
variant provided polycyclic cyclopropane 24 that
could be diversified through traditional cross-
coupling. Scale-up of this process posed no issue and
gave a comparable yield to that of smaller scale
cyclopropanations.
Table 3. Cyclopropanation of the indanone-derived core
Table 4. Cyclopropanation of larger ring sizes via RPC.[a]
via RPC.[a]
[a]Unless otherwise noted, the reactions were carried
out on a 0.2-0.3 mmol scale at 30 °C for 2-16 h;
isolated yields after purification, see Supporting
Information for details regarding purifications and
alterations to radical precursor loading.
4
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
At this juncture, we posited that the introduction of
heteroatoms in the ring architecture would not only
be feasible, but perhaps beneficial for restricting or
changing the conformation of the ring. As such,
benzoazepines and benzoxepines were examined. The
requisite tosylates of these systems were readily
prepared from commodity salicylate or anthranilic
acid derivatives on multi-gram scale. Subjecting these
tosylates to the established conditions for annulation
led to facile cyclopropanation, albeit in somewhat
lower yield than their smaller carbocyclic congeners.
cyclization by displacement of the tosylate, resulting
in C-C bond formation (and thus formation of a
strained bicyclic system IX). It is likely that ring
conformation can be determinant of reaction success,
impacting both the radical addition and anionic
cyclization.
Conclusion
The modular cyclopropanation strategy described
here affords easy access to previously difficult to
access and medicinally relevant polycyclic systems
under mild conditions. Using commodity materials,
an array of bench-stable linchpins can be assembled
that are poised for cyclopropanation. The described
radical/polar crossover approach thus enables these
linchpins to be appended with an array of fragments
while simultaneously triggering annulation. The
radical source has a minimal effect on the success of
cyclopropanation. This process ultimately provides a
mild, metal-free strategy for assembling an array of
diverse polycyclic stuctures containing the
cyclopropyl motif.
Although
a
mild strategy for polycyclic
cyclopropane construction, this approach is not
without limitations. Clearly, conformation is critical
for the success of cyclization. The conformationally
rigid tetralone- and indanone-based systems
underwent cyclopropanation with ease. Further,
synthetic limitation can hamper this approach. For
example, attempts to prepare the iodide, bromide, or
chloride of the aforementioned cycloheptanone
system were met with failure because of the steric
constraints of displacement on a neopentyl leaving
group. Likewise, because of the rather sterically
congested nature of the transition state, attempts
using 2o tosylates were met with failure. In addition,
attempts to install other electrophilic fragments
beyond methyl, benzyl and allyl were met with
significant difficulty using the streamlined route
devised from commodity precursors. However, when
these systems were prepared (e.g. ethyl or homoallyl
in place of methyl), successful cyclopropanation was
observed.
Experimental Section
To an 8 mL reaction vial equipped with a stir bar were
added the appropriate radical precursor (1.2-1.5 equiv), the
appropriate cyclopropane linchpin (0.3 mmol, 1 equiv) and
4CzIPN (0.0118 g, 0.0150 mmol, 5 mol %). The vial was
sealed with a cap containing a TFE-lined silicone septa and
placed under an N2 atmosphere through evacuating and
purging with N2 three times via an inlet needle. The vial
was then charged with degassed anhyd DMSO (6 mL) via
a syringe The cap was sealed with Parafilm®, and the now
bright-yellow soln was irradiated with blue LEDs in the a
photoreactor. The temperature of the reaction was
o
maintained at approximately 30 C via fan cooling. The
soln was stirred vigorously while being irradiated. After
confirmation of reaction completion by HPLC/TLC
(typically 3-16 h), the now dark (or in some cases clear)
soln was transferred to a separatory funnel and diluted with
Et2O (~20 mL) and 2 M aq NaOH (~20 mL). The layers
were separated, and the aq layer was extracted with
additional Et2O (2 × ~10 mL). The combined organic
layers were washed with additional 2 M aq NaOH (2 × ~10
mL). The organic layer was then washed with deionized
H2O (2 × ~20 mL) followed by brine (~25 mL). The
combined organic layers were dried (Na2SO4), and the
solvent was removed in vacuo by rotary evaporation.
Further purification was accomplished by SiO2 column
chromatography (typically eluting with hexanes/EtOAc or
hexanes/Et2O).
Figure 3. Proposed mechanism for cyclopropanation.
Regardless of the radical precursor or ring linchpin
used, the mechanism of this process is presumed to
proceed via the following series of events (Figure 3):
1) Photoexcitation of the photocatalyst I (in this case
4CzIPN) to its excited state II; 2) Reductive
quenching of the excited photocatalyst by single
electron transfer (SET) oxidation of the appropriate
radical precursor IV; 3) Homolytic fragmentation of
the radical precursor to generate an alkyl radical V; 4)
Installation of the alkyl fragment via Giese-type
addition of the generated radical to linchpin VI; 5)
Reduction of the resulting α-aryl radical to generate
the corresponding α-aryl anion VIII; 6) Anionic
Acknowledgements
The authors are grateful for the financial support provided by
NIGMS (R35 GM 131680 to G.A.M.). C.B.K. acknowledges start-
up funds from Virginia Commonwealth University and the Bill
and Melinda Gates Foundation. Z.-J.W. acknowledges financial
5
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10.1002/adsc.201901051
Advanced Synthesis & Catalysis
support from the Chinese Scholarship Council (CSC). We thank
Dr. Charles W. Ross, III (University of Pennsylvania) and Dr.
Joseph Turner (VCU) for obtaining HRMS data. We acknowledge
Frontier Scientific for the boron reagents used, Gelest Inc. for
alkyl trimethoxy6silanes, and Kessil Lighting for donation of a
prototype PR160 Rig. We thank Isaias Jacinto (University of
M. Riccardo, B. J. Andreassen, A. Noble, V. K.
Aggarwal, Angew. Chem., Int. Ed. 2018, 57, 15430.
[10] J. K. Matsui, S. B. Lang, D. R. Heitz, G. A. Molander,
ACS Catal. 2017, 7, 2563.
Pennsylvania)
for
preparing
diisopropylammonium
[11] a) J. P. Phelan, S. B. Lang, J. S. Compton, C. B.
Kelly, R. Dykstra, O. Gutierrez and G. A. Molander, J.
Am. Chem. Soc. 2018, 140, 8037. A similar report was
disclosed by Fang and co-workers: b) T. Guo, L. Zhang
X. Liu, Y. Fang, X. Jin, Y. Yang, Y. Li, B. Chen, M.
Ouyang, Adv. Synth. Catal. 2018, 360, 4459; For a
comprehensive review on developments related to this
approach see: c) A. G. Herraiz, M. G. Suero Synthesis
2019, 51, 2821.
bis(catecholato)(2-acetoxyethyl)silicate..
References
[1] a) Z. Rappoport in The Chemistry of the Cyclopropyl
Group. Wiley, New York, 1996; b) H. Lebel, J.-F.
Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977; c) H. Pellissier, Tetrahedron 2008, 64,
7041; d) G. Bartoli, G. Bencivenni, R. Dalpozzo,
Synthesis 2014, 46, 979; e) D. Qian, J. Zhang, Chem.
Soc. Rev. 2015, 44, 677.
[12] a) J. A. Milligan, J. P. Phelan, V. C. Polites, C. B.
Kelly and G. A. Molander, Org. Lett. 2018, 20, 6840.
Recently related processes by Aggerwaal and Fang
respectively have been reported see: b) C. Shu, R. S.
Mega, B. J. Andreassen, A. Noble, V. K. Aggarwal,
Angew. Chem., Int. Ed. 2018, 57, 1543; c) W. Luo, Y.
Yang, Y. Fang, X. Zhang, X. Jin, G. Zhao, L. Zhang, Y.
Li, W. Zhou, T. Xia, B. Chen, Adv. Synth.Catal. 2019,
Early View, doi: 10.1002/adsc.201900708.
[2] T. T. Talele, J. Med. Chem. 2016, 59, 8712.
[3] R. G. Gentles, M. Ding, J. A. Bender, C. P. Bergstrom,
K. Grant-Young, P. Hewawasam, T. Hudyma, S.
Martin, A. Nickel, A. Regueiro-Ren, Y. Tu, Z. Yang,
K.-S. Yeung, X. Zheng, S. Chao, J. H. Sun, B. R. Beno,
D. M. Camac, C.-H. Chang, M. Gao, P. E. Morin, S.
Sheriff, J. Tredup, J. Wan, M. R. Witmer, D. Xie, U.
Hanumegowda, J. Knipe, K. Mosure, K. S. Santone, D.
D. Parker, X. Zhuo, J. Lemm, M. Liu, L. Pelosi, K.
Rigat, S. Voss, Y. Wang, Y.-K. Wang, R. J. Colonno,
M. Gao, S. B. Roberts, Q. Gao, A. Ng, N. A. Meanwell,
J. F. Kadow, J. Med. Chem. 2014, 57, 1855.
[13] M. Yan, J. C. Lo, J. T. Edwards, P. S. Baran, J. Am.
Chem. Soc. 2016, 138, 12692.
[14] E. J. Park, M. H. Kim, D. Y. Kim, J. Org. Chem.
2004, 69, 6897.
[15] Seminal report on alkylsilicate synthesis: a) C. L.
Frye, J. Am. Chem. Soc. 1964, 86, 3170.; Procedural
review: b) K. Lin, C. B. Kelly, M. Jouffroy, G. A.
Molander, Org. Synth. 2017, 94, 16; Examples as
radical precursors in radical polar crossover processes:
c) L. R. E. Pantaine, J. A. Milligan, J. K. Matsui, C. B.
Kelly, G. A. Molander, Org. Lett. 2019, 21, 2317; (d) N.
R. Patel, C. B. Kelly, A. P. Siegenfeld, G. A. Molander,
ACS Catal. 2017, 7, 1766; e) A. Cartier, E. Levernier,
V. Corcé, T. Fukuyama, A.-L. Dhimane, C. Ollivier, I.
Ryu, L. Fensterbank, Angew. Chem., Int. Ed. 2019, 58,
1789; f) S. B. Lang, R. W. Wiles, C. B. Kelly, G. A.
Molander, Angew. Chem., Int. Ed. 2017, 56, 15073.
[4] P. B. Sampson, Y. Liu, N. K. Patel, M. Feher, B.
Forrest, S. W. Li, L. Edwards, R. Laufer, Y. Lang, F.
Ban, D. E. Awrey, G. Mao, O. Plotnikova, G. Leung, R.
Hodgson, J. Mason, X. Wei, R. Kiarash, E. Green, W.
Qiu, N. Y. Chirgadze, T. W. Mak, G. Pan, H. W. Pauls,
J. Med. Chem. 2015, 58, 130.
[5] B. Vacher, P. Funes, P. Chopin, D. Cussac, P. Heusler,
A. Tourette, M. Marien, J. Med. Chem. 2010, 53, 6986.
[6] a) A. B. Charette, A. Beauchemin, Org. React. 2001,
58, 1−395; b) R. Appel, N. Hartmann, H. Mayr, J. Am.
Chem. Soc. 2010, 132, 17894.
[16] For an early report on the use of this organic dye as a
photocatalyst see: J. Luo, J. Zhang, ACS Catal. 2016, 6,
873.
[7] a) E. M. D. Allouche, A. B. Charette, Chem. Sci. 2019,
10, 3802; b) E. M. D. Allouche, A. Al-Saleh, A. B.
Charette, Chem. Commun. 2018, 54, 13256.
[17] A. Arora, J. D. Weaver, Acc. Chem. Res. 2016, 49,
[8] a) B. Bonnaud, P. Funes, N. Jubault, B. Vacher, Eur. J.
Org. Chem. 2005, 3360; b) U. R. Ghatak, P. C.
Chakraborti, B. C. Ranu, B. Sanyal, J. Chem. Soc.,
Chem. Commun. 1973, 548; c) M. M. Fawzi, C. D.
Gutsche, J. Org. Chem. 1966, 31, 1390.
2273.
[18] F. Lecornue, J. Ollivier, Org. Biomol. Chem. 2003, 1,
3600.
[9] a) Z. Liu, X. Zhang, G. Zanoni, X. Bi, Org. Lett. 2017,
19, 6646. b) J. Zhu, H. Chen, S. Liao, Y. Li and Y.
Tang, Org. Chem. Front. 2014, 1, 1035; c) C. Shu, S.
6
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FULL PAPER
Radical-Polar Crossover Annulation: A Platform
for Accessing Polycyclic Cyclopropanes
Adv. Synth. Catal. Year, Volume, Page – Page
John A. Milligan, Kevin L. Burns, Anthony V. Le,
Zheng-Jun Wang, Viktor C. Polites, Gary A.
Molander,* and Christopher B. Kelly*
7
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