“This is the peer reviewed version of the following article: New alkene cyclopropanation reactions enabled by
photoredox catalysis via radical carbenoids which has been published in final form at DOI: 10.1055/s-00371611872. This article may be used for non-commercial purposes in accordance with Thieme Terms and Conditions
for Self-Archiving”.

New alkene cyclopropanation reactions enabled by photoredox catalysis
via radical carbenoids
Ana G. Herraiza,b
Marcos G. Sueroa*
a

Institute of Chemical Research of Catalonia ICIQ, The
Barcelona Institute of Science and Technology; Països Catalans
16, 43007 Tarragona, Spain. mgsuero@iciq.es

The recent emergence of radical cyclopropanations enabled by photoredox catalysis

Universitat Rovira i Virgili, Departament de Química Analítica
i Química Orgánica, c/ Marcelli Domingo, 1, 43007-Tarragona,
Spain
* indicates the main/corresponding author.

photoredox
catalyst

LG

b

alkenes

X
carbenoid-like radicals

commercial or
easy to make

Received:
Accepted:
Published online:
DOI:

Table of Contents
1.
Introduction
2.
Photoredox-catalyzed alkene cyclopropanations with radical
carbenoids
3.
Conclusions and outlook
Key words photoredox catalysis, radicals, carbenoids, cyclopropanes,
cyclopropanation

Introduction

The cyclopropane ring is an important carbon structure class
present in a large variety of natural products and medicines as
well as in agrochemicals and perfumes (Scheme 1).1 This threemembered ring is also a versatile building block in organic
synthesis; its innate ring strain and “double bond character” has
permitted the development of a wide plethora of reactions such
as ring-openings, cycloadditions and rearrangements.2
Cyclopropanes are also recognized as privilege scaffolds in drug
discovery because (i) it is an alkyl bioisostere that improves
metabolic stability compared to other alkyl groups and (ii) it

R

visible light

excellent functional group tolerance

Abstract
We describe the recent emergence of a new approach for the synthesis of
cyclopropane rings by means of photoredox catalysis. This methodology relies
on the photocatalytic generation of radical carbenoids or carbenoid-like
radicals as cyclopropanating species, and its characterized by an excellent
functional group tolerance, chemoselectivity and ability to cyclopropane E/Z
alkene mixtures with excellent stereocontrol. The mild reaction conditions and
the employ of user-friendly reagents are highly attractive features that may
find immediate use in academic and industrial laboratories.

R

H

R
X

Click here to insert a dedication.

1

radical carbenoids

operationally simple

complementary to current methods

Medicines

Perfumes
F

HN

Me
Me

N

N

N
N

cyclopropane ring

N

Me

Me

OH

F
S

H

Me

R
Ticagrelor

Javanol

Agrochemicals

Natural products
HO Me

H O
Me

NH

Me

O

O

OH

O
Me

N

N

CHF2

Cyclopropane

HO

OH
OH

Sedaxane

(+)-plaquloside

unique
building blocks

for complex
molecule synthesis

provides a conformationally restricted distribution of the
substituents.3

Scheme 1 Prevalence of cyclopropane rings

Nature constructs cyclopropane rings through biosynthetic
pathways that often involves ring-closing events with alkenes
and carbocations.4 Synthetic chemists also employ alkenes as

substrates in cyclopropane construction. The most common
strategies rely on metal-carbenoids, metal-carbenes & free
carbenes, as well as sulfur and nitrogen ylides as divalent carbon
sources (Scheme 2A).5 With only these three major strategies,
chemists have literally delivered thousands of alkene
cyclopropanation reactions. The main challenge over the years
has been to develop general catalytic methodologies for the
diastereo- and enantioselective cyclopropane synthesis under
mild conditions, avoiding the use of highly toxic or explosive
precursors.6 These three main methodologies, among others,
have extensively been highlighted over the years in many
reviews, and what is remarkable is to find the absence of
methodologies involving radical species able to cyclopropanate
alkenes.
The aim of this short review is to highlight the recent emerge of
radical carbenoids or carbenoid-like radicals as novel reactive
species for alkene cyclopropanation enabled by photoredox
catalysis (Scheme 2B). These carbon-centered radicals have the
particular feature of bearing a halogen atom (X) in alpha position
and can be generated via single-electron transfer process from
photoreducible or photooxidable sources. These radical species
are able to attack olefins with an excellent selectivity profile and
form new radicals that evolve to the corresponding cyclopropane
ring through two well-distinguished pathways (i) radical (SH2) 3exo-tet cyclization or (ii) single-electron reduction/anionic (SN2)
3-exo-tet cyclization. The common and distinguished features as
well as the proposed mechanisms of the presented individual
works are highlighted in this review.

based on the activation of organic molecules through singleelectron/energy transfer processes with metal complexes or
organic dyes. The catalyst absorbs light in the visible region of the
electromagnetic spectrum to give long-lived photo-excited states,
which have the remarkable properties of being both more
oxidizing and more reducing than the ground-state species. One
of the most important features of this methodology is the ability
to generate radical cation or anion species that evolve into
transient radical species.
The groups of Macmillan and Stephenson, in 2008 and 2009,
respectively, demonstrated the ability of photoredox catalysis to
enable generation of carbon-centered radicals from alkyl halides
using visible-light irradiation.8 These works clearly
demonstrated that visible-light photoredox catalysis was a more
efficient alternative in the generation of radical species than
classic methods relying on photoinduced electron transfer with
UV-light,9 or in the use of stoichiometric amounts of toxic
reagents, such as tributyltin hydride.10
Inspired by the works of Macmillan and Stephenson, our group
recognized the suitability of photoredox catalysis to enable a
general platform for methylene transfer to alkenes using
commercially available diiodomethane (CH2I2).11 It has an
accessible reduction potential (Ered= -1.44 V vs. SCE) with
common photoredox catalysts and importantly, does not share
the intrinsic drawbacks of other classic methylene sources (high
oxygen and moisture sensitivity, explosiveness and toxicity) such
as halomethyl organometallics (i.e. ICH2ZnI) or diazomethane.
We hypothesized that photoredox catalysis would enable the
generation of iodomethyl radical ()CH2I as radical carbenoid
species. We anticipated that ()CH2I may behave as a novel triplet
carbene equivalent able to form trans-cyclopropanes from E,Z
styrene mixtures in a stereoconvergent manner.

2
Photoredox-catalyzed alkene cyclopropanations
with radical carbenoids

In 2017, we reported the first stereoconvergent
cyclopropanation reaction of styrenes with diidomethane and
N,N-diisopropylethylamine using the well-known photocatalyst
[Ru(bpy)3][PF6]2 3 (Scheme 3).12 We demonstrated the utility of
this new cyclopropanation reaction in a broad range of substituted styrenes 1 as E,Z mixtures, decorated with diverse
functionalities. A notable feature of this process is the excellent
functional group tolerance. For instance, aldehydes (2a), tertiary
amines (2f) or sulfides (2e) are typical functionalities not
tolerated by classic methodologies. Moreover, we observed an
excellent site-selectivity in styrenes functionalized with an
inactivated alkene (2e) and absolute stereoconvergence for a E,Z
mixture of trisubstituted olefin (2f), which represent a rare
example in alkene functionalization. Current limitations of this
cyclopropanation are (i) low efficiency for styrenes substituted
with electron-withdrawing groups, (ii) incompetence to
cyclopropanate terminal and α-substituted styrenes (2g h), and
(iii) inability of accessing the cis-cyclopropane isomer. To reach
full conversion in the cyclopropanation was necessary the
degasification of the reaction mixture prior to irradiation and the
addition of Na2S2O3 and water as additive and co-solvent,
respectively. In analogy to most of the photoredox processes, our
cyclopropanation is robust and operationally simple and in
addition, it required a simple 21W compact fluorescent lamp
(CFL) as visible-light source.

Visible-light photoredox catalysis has emerged as a new smallmolecule activation mode.7 In a general sense, this approach is

In the proposed mechanism, visible-light irradiation of the Ru
catalyst generates the long-lived photoexcited state

Scheme 2 Reactive species in cyclopropane synthesis and new radical
methodologies enabled by visible-light photoredox catalysis.

*[Ru(bpy3)]2+ 4 , which is reduced by N,N-diisopropylethylamine
to [Ru(bpy3)]+ 5 by a well-established single-electron transfer
(SET) process. The strong reductant generated Ru(I) 5 (Ered(II/I)=1.33V vs. SCE), donates an electron to CH2I2 (Ered=-1.44V vs. SCE)
to form a transient radical anion that subsequently fragments
into carbenoid ()CH2I 6. This SET is slightly endergonic,
however, the overall process may be driven by an exergonic
radical addition to the E,Z-alkene mixtures that conducts to
intermediates 7 and 8, which might be in equilibrium through a
CC bond rotation. The ring closing event occurs on intermediate
8 with the anti-orientation of the substituents, to yield the most
stable trans-cyclopropane 2. The ring-closing event involves a
radical SH2-type 3-exo-tet cyclization; this homolytic substitution
reaction that generates an I() has been observed previously
from 1,3-dihaloalkanes via 3-halo-propyl radicals.13 Control
experiments clearly discarded isomerizations of both styrene
starting materials or cyclopropane products under our reaction
conditions.

reaction of Michael acceptors 9 by using same reaction
conditions previously developed (Scheme 4).14 We
demonstrated this process in a wide range of substrates,
including chalcones bearing electron-rich and electron-poor
aromatic rings, heterocycles (10a), as well as ,-unsaturated
aldehydes (10c) and ketones with moderate to excellent yields
(36-93%). Excellent site-selectivity was observed and only transcyclopropane products obtained when using isomeric E,Zmixtures of chalcones. Moreover, we demonstrated that more
complex cyclopropane cores (10d) can be formed by using 1,1diiodoethane as a source of iodoethyl radical carbenoid 11. As
limitation, we observed that α,β-insaturated esters were no
tolerated under our reaction conditions (10e). Previosly, the
generation of iodomethyl radical species with CH2I2/BEt3/O2 and
subsequent 1,4-addition to methyl vinyl ketone was reported.15
However, a Michael adduct was obtained and no cyclopropane
was observed.

R1

1 mol% Ru(bpy)3(PF6)2
i-Pr2EtN, Na2S2O3

O

O
R2

R1

R2

CH2I2

CH3CN/H2O
CFL, 18 h, rt
28 examples, 36-93% yield

9

O
R2

R1

10

selected examples
O

O
O
H

N

OMe
10a 80% yield
Me

10b 93% yield

MeO

10c 72% yield

O
H

O

I
via
OMe

N
O

10d 69% yield (2:1)

Me

OMe

11
iodoethyl radical

10e n.d.

Scheme 4 Photoredox-catalyzed cyclopropanation reaction of Michael
Acceptors by Suero et. al.

Scheme 3 Stereoconvergent cyclopropanation reaction enabled by
photoredox catalysis with diiodomethane by Suero et. al.

Taking advantage of the reactivity of our radical carbenoid, our
group later developed a photoredox-catalyzed cyclopropanation

In 2018, the Molander group reported a redox-neutral
photocatalytic cyclopropanation via radical/polar crossover
(Scheme 5).16 A key part of this work was the design and
synthesis of the benchtop stable triethylammonium
bis(catecholato)iodomethylsilicate 13 as source of iodomethyl
radical 6, made from commercial chloromethyltrimethoxysilane
12 and commodity chemicals in two steps.17 Using this reagent
and
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-benzene
(4CzIPN) 16 as photocatalyst, Molander and co-workers
demonstrated cyclopropanations in a broad range of olefins 15
substituted with trifluoromethyl (15a-15b) and pinacolboryl
(15d) groups, as well as in styrenes (15a, 15c, 15d, 15e, 15f),
stilbenes, Michael acceptors (15e) and in alkyl-substituted
alkenes. It also showed an excellent tolerance to functional
groups including sulfides, tertiary amines, cyano, carboxylic
acids, and alkynes. In addition, they also highlight that their

protocol was able to cyclopropanate E/Z styrene mixtures with
absolute stereoconvergence (15f).
In comparison to our methodology, the Molander method shows
a much broader scope. The Molander cyclopropanation permit
the use of styrenes substituted in the  position with a boronic
ester 15d, a trifluoromethyl or a phenyl group 15c as well as ,unsaturated esters 15e. Since the radical carbenoid is the same
species in both cases, the distinct reactivity and broader scope
might arise from the different redox environments under two
distinct photoredox catalytic cycles. In fact, the mechanism
proposed by Molander, Gutierrez and co-workers is in sharp
contrast to ours, and rely on an anionic (SN2) 3-exo-tet cyclization.
The plausible mechanism, supported by experimental and
extensive computational data is depicted in Scheme 3. Firstly,
irradiation of 4CzIPN with visible-light generates its excited state
17, able to induce a single-electron oxidation with silicate 13 and
form iodomethyl radical 6. This reductive quenching of 4CzIPN*
is supported by Stern−Volmer emission quenching experiments
and low oxidation potential of silicates (E1/2 = +0.4−0.7 vs SCE).
Addition of 6 to the corresponding alkene leads to a new radical
intermediate 19. The latter species is reduce by (-·)[4CzIPN] 18,
forming anion 19´ that furnishes the corresponding
cyclopropane by an SN2 cyclization. In addition, the origin of the
stereoconvergence for E/Z styrene mixtures has been
rationalized based on a similar argument to our hypothesis
described in Scheme 3. With the difference that a stereoretentive
reduction occurs prior to ring closure event. Alternatively, the
authors also suggested a dynamic kinetic resolution-type
scenario through a photochemical isomerization of the starting
alkenes.

Scheme 5 Redox-neutral photocatalytic cyclopropanation via radical/polar
crossover with iodomethylsilicate 13 by Molander et. al.

A clear experimental evidence that supports the anionic
cyclization in the Molander cyclopropanation is shown in
Scheme 6. When the cyclopropyl radical probe 20 was used as
substrate, bis-cyclopropane 21 was obtained. This result differs
from the outcome that we originally obtained with the analogous
substrate 23, where ring opening product, via 25, was observed.
Computational studies by Molander and Gutierrez showed that
the ring-opening from the benzylic radical is much lower in
energy than radical cyclization. Therefore, to explain formation
of 21, it is proposed a fast SET reduction (to generate 22) that
exceeds the rate of ring opening prior to ring formation.

Scheme 6 Mechanistic experiments

After Molander´s work, Li and co-workers reported an analogous
cyclopropanation reaction using the well-known Ir-based
photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (30) instead of
4CzIPN and analogous reagent (27) that acts as a chloromethyl
radical source (29) (Scheme 7).18 In contrast to the Molander
process, Li showed a more modest diversity scope limited to
electron-poor olefins 26 including -substituted phosphonates
(28a, 28b), Michael acceptors (28c, 28d) and sulfones.

styrene provides low yield (34b, 25%). The borocyclopropanes
were obtained in moderate or low diastereoselectivity and the
yields slightly drop after purification on chromatography
column. However, the authors highlight that yields could be
improved with sterically demanding boronates (34d).22

Scheme 8 Borocyclopropanation mediated by UV-light under continuous flow
conditions with diiodomethylpinnacol boronate 32 by Charette et. al.

Scheme 7 Cyclopropanation reaction with chloromethylsilicate 27 by Li et. al.

Over the last three decades, the group of Charette has developed
powerfull strategies for the diastereo- and enantioselective
construction of cyclopropane rings based on the Simmons-Smith
reaction with haloalkylzinc organometallics.19 In 2017, the group
reported the synthesis of diiodomethylpinnacol boronate 32 as
new reagent for the cyclopropanation of allyl ethers and styrenes
via a Simmons-Smith reaction.20 After this, the authors realized
about the suitability of this reagent as source of
iodo(Bpin)methyl radical 35 enabled by photoredox catalysis
and its application in the synthesis of borocyclopropanes of
alkenes.21 The authors demonstrated the first general
borocyclopropanation of styrenes 31 using xanthone 33 as
photocatalyst under continuous flow conditions and UVA-light
(Scheme 8). The reaction was extensively explored in the styrene
substrate, and worked well in a broad range of substrates
substituted with alkyl chains, sufides, halides, ciano or nitro
groups. The styrene substitution pattern showed to affect the
efficiency of the reaction: whereas non-substituted styrenes or
,-disubstituted styrenes worked well (34a,c,d), -methyl

Charette and co-workers postulated two possible mechanisms
for the borocyclopropanation reaction of styrenes (Scheme 8).
Initially, upon UVA-light irradiation, the corresponding
xanthone* excited state can undergo both, reductive quenching
(A) by N,N-diisopropylethylamine, or oxidative quenching (B) by
boronate reagent 32. However, the authors showed that the
reductive quenching pathway (A) might be more favored, since
(i) a significant excess of the base is used in comparison to 32,
and (ii) it is kinetically favored based on Stern-Volmer
fluorescent quenching studies (kSV i-Pr2EtN=1.31x1010 M-1s-1; 𝑘SV
𝐼2𝐶𝐻𝐵𝑝𝑖𝑛=9.28x109 M-1s-1). Following the reductive quenching
pathway, xanthone radical anion 37 could then undergo a SET
process with 32 to form transient radical anion 38, which evolves
into iodomethyl pinacol ester radical 35 upon fragmentation.
After this, radical carbenoid 35 attacks the corresponding
styrene and forms benzylic radical 39 that evolve to the
borocyclopropane 34 by a radical 3-exo-tet cyclization.
Overall, the Charette method is a valuable contribution to the
repertoire of the new photoredox cyclopropanations. The main
advantage over Molander and our method is that it permits the

construction of borocyclopropanes that can be further diversify
by well-documented transformations.

Finally, a related radical cyclopropanation was reported by Li,
which in contrast to the previous methods, it requires the use of
ethyl diazoacetate (EDA) as radical source (Scheme 9).23 In this
work, a wide range of styrenes 40 were cyclopropanated and
products 42 were obtained in good to excellent yields and with
low diastereoselectivity using [Ru(bpy3)]2+ 3 as photocatalyst.
The tolerance of this reaction towards sensitive functional
groups was not widely explored. In the mechanism, the authors
proposed that excited Ru-polypyridine complex 4 is oxidized by
44 generating radical carbenoid 45. The latter species attacks the
corresponding styrene and provide cyclopropane 42 and iodine
radical by a radical 3-exo-tet cyclization. After this, iodine radical
reacts with iodide to form anionic radical I2(). A second SET
process closes the catalytic cycle ground state regenerating both
ruthenium catalyst 3 and I2. Interestingly, the scope of the
reaction could be improved under thermal activation in the
absence of a photocatalyst by heating EDA at 100 ºC in the
presence of I2. The authors proposed that ethyl diiodoacetate 44
is catalytically generated from EDA and I2.24

Scheme 9 Iodine/photoredox-catalyzed cyclopropanation reaction with ethyl
diazoacetate by Li et. al.

Conclusions and outlook
This Short-Review highlights the impact of photoredox catalysis
in the discovery and development of new methodologies for
cyclopropane synthesis involving radical carbenoids. The
excellent functional group tolerance, mild reaction conditions
and availability of the carbenoid sources are highly attractive
features of these methods that may find immediate use in

academic and industry laboratories. The development of a
general methodology able to cyclopropanate olefins (activated
and
non-activated)
with
excellent
diastereoand
enantioselectivity remains as one of the main challenges. Finally,
we believe in the potential of electrochemistry to deliver, in the
near future, a complementary approach for the cyclopropanation
of alkenes based on the generation of radial carbenoids.25

Acknowledgment
The ICIQ Starting Career Programme, Agencia Estatal de Investigación of
the Ministerio de Ciencia (CTQ2016-75311-P, AEI/FEDER-EU), the
CELLEX Foundation through the CELLEX-ICIQ high-throughput
experimentation platform and the CERCA Programme (Generalitat de
Catalunya) are gratefully acknowledged for financial support. We thank
the CELLEX Foundation for pre-doctoral fellowship (to A.G.H.). Dr
Zhaofeng Wang is gratefully acknowledged for proofreading. M.G.S. is very
grateful to the organizing committee of the 2018 Bü rgenstock Conference
and the Swiss Chemical Society for a JSP fellowship.

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Guo, T.; Zhang, L.; Liu, X.; Fang, Y.; Jin, X.; Yang, Y.; Li, Y.; Chen,
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Benoit, G.; Charette, A. B. J. Am. Chem. Soc. 2017, 139, 1364.
Sayes, M.; Benoit, G.; Charette, A. B. Angew. Chemie Int. Ed.
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During the revision of this review, we realized of a related
borocyclopropanation to Charette reaction: Ohtani, T.;
Tsuchiya, Y.; Uraguchi, D.; Ooi, T. Org. Chem. Front. 2019.
DOI: 10.1039/c9qo00197b.
Li, P.; Zhao, J.; Shi, L.; Wang, J.; Shi, X.; Li, F. Nat. Commun.
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For alternative reports of alkene cyclopropanations enabled
by photoredox catalysis that do not involve radical
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Ana García Herraiz was born in Cuenca (Spain) in 1990. She studied
Chemistry at the University Complutense of Madrid (2008-2012). Her
Bachelor Thesis was carried out during her Erasmus stay in the field of
artificial metalloenzymes under the supervision of Prof. Gerard Roelfes at the
University of Groningen. Then, she continued her studies in Groningen and
performed her Master Thesis in the group of Prof. Ben L. Feringa working on
copper catalysis (2013). After an internship at the pharmaceutical company Eli
Lilly, she joined the group of Marcos García Suero in 2015 at the Institute of
Chemical Research of Catalonia (ICIQ) to pursue PhD studies on the discovery
of new reactivity at carbon enabled by photoredox catalysis.
Marcos García Suero graduated in Chemistry from the Universidad de Oviedo
in 2003 and started organometallic chemistry research in the laboratory of
Profs. José Gimeno and Pilar Gamasa. In February 2009, he obtained his PhD
degree at the Institute of Organometallic Chemistry Enrique Moles and
Department of Organic and Inorganic Chemistry (Universidad de Oviedo),
where he worked under the direction of Prof. José Barluenga and Prof. Josefa
Flórez on Fischer carbene chemistry. During the summer of 2005 he joined the
laboratory of Prof. Andrew Myers at Harvard University working on the
synthesis of novel tetracycline antibiotics as PhD visiting student. In May
2010, he moved to the University of Cambridge to work with Professor
Matthew Gaunt on copper catalysis and methionine bioconjugation as a
Postdoctoral Marie Curie Fellow. In October 2014, he started his independent
research career at the Institute of Chemical Research of Catalonia (ICIQ) with
the ICIQ Starting Career Programme.