Photoredox-Catalyzed Cyclopropanation of Michael Acceptors

Article abstract of DOI:10.1002/ejoc.201601604

A new protocol for the catalytic cyclopropanation of α,β-unsaturated carbonyl compounds with diiodomethane by means of photoredox catalysis has been successfully developed. The transformation is characterized by its mild conditions, functional-group compatibility, and excellent selectivity profile.

Full text of DOI:10.1002/ejoc.201601604

A Journal of
Accepted Article
Title: Photoredox-catalyzed Cyclopropanation of Michael Acceptors
Authors: Ana M del Hoyo and Marcos García Suero
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601604
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601604
Supported by

10.1002/ejoc.201601604
European Journal of Organic Chemistry
SHORT COMMUNICATION
Photoredox-catalyzed Cyclopropanation of Michael Acceptors
Ana M. del Hoyo,[a] and Marcos G. Suero*[a]
Dedicated to Prof. Josefa Flórez González
Abstract: A new protocol for the catalytic cyclopropanation of α,β-
unsaturated carbonyl compounds with diiodomethane by means of
photoredox catalysis has been successfully developed. The
transformation is characterized by its mild conditions, functional
group compatibility, and excellent selectivity profile.
carbonyl compounds. In this process, the nucleophilic
iodomethyl radical would attack the C–C double bond generating
an α-carbonyl radical intermediate, which might be able to
conduct to the cyclopropane ring.[11] Herein, we report the
successful
development
of
a
new
photocatalytic
cyclopropanation reaction of α,β-unsaturated carbonyl
compounds using diiodomethane as methylene transfer reagent
(Scheme 2b).
Introduction
The cyclopropane ring is an important cyclic structural motif
found in many natural products, medicines and crop protection
agents.[1] Over the past decades, the development of catalytic
methodologies for the synthesis of these carbocycles has been
an area of intense study.[2] In particular, the simple methylene
transfer into alkenes has provided the conceptual basis for the
development of a range of useful methodologies involving
iodomethylzinc carbenoids,[3] diazomethane[4] and sulfur or
nitrogen ylides.[5],[6] In contrast, it is rather surprising to see the
scarcity of synthetic methods based on radical species.[7]
Recently, our group has introduced a novel reactivity concept
based on the catalytic generation of radical carbenoid species
by means of photoredox catalysis (Scheme 1).[8] These radicals
are substituted with an excellent leaving group and its reactivity
is reminiscent of carbene species.
(a) Previouls work:
I
H
Ru(bpy)3(PF6)2
CH2I2
Ar
Ar
H
Ar
amine
visible light
benzyl radical
styrenes
aryl-cyclopropanes
(b) This work:
O
O
O
I
Ru(bpy)3(PF6)2
H
CH2I2
amine
visible light
H
α-carbonyl radical
Michael acceptor
carbonyl-cyclopropanes
Scheme 2. Photocatalytic alkene cyclopropanation with diiodomethane.
Results and Discussion
LG
photoredox catalyst
H
H
LG
LG (−)
LG
H
H
single-electron reduction
We started our study using commercial (E)-chalcone (1a) as a
model substrate (Table 1) and analogous reaction conditions
developed previously for the cyclopropanation of styrene
derivatives [Ru(bpy)3(PF6)2 (1 mol %), CH2I2 (2.5 equiv), i-Pr2EtN
(5 equiv), Na2S2O3 (5 equiv), CH3CN/H2O (4:1)]. It was highly
gratifying to observe that the same reaction conditions were
suitable for the cyclopropanation of 1a, and a 69% NMR yield of
the expected trans-cyclopropane 3a was obtained as the only
reaction product (Table 1, entry 1). In order to improve the
efficiency of this process, we performed different experiments
modifying the reaction variables. A dramatic decrease of yield
was observed when no sodium thiosulfate and water were
added (entry 2) or no degasification of the reaction mixture was
carried out (entry 3). Further modification of the standard
reaction conditions using alternative polar solvents (entry 4,5),
visible-light sources (entry 6) or photocatalysts (entry 7–10) did
not improve the efficiency of the process (see supporting
information for further experiments).[12]
easy to reduce
radical carbenoids
unexplored
Scheme 1. Generation of radical carbenoids via SET process.
By using this concept, we have developed a new alkene
cyclopropanation reaction using commercial diiodomethane as
methylene transfer reagent via photoredox catalysis (Scheme
2a).[9] This process is characterized by its mild conditions, broad
functional group compatibility, and excellent selectivity profile.
Iodomethyl radical carbenoid ICH2(Ÿ) is the key intermediate
photocatalytically generated that is able to cyclopropanate
mixtures of E,Z-styrenes in a stereoconvergent manner. A
benzyl radical has been proposed to explain the
stereoconvergence phenomena and the ring-closing step
(Scheme 2a).[10] With the aim of expanding the scope of this
radical cyclopropanation reaction, we questioned whether a
related catalytic process could be developed for α,β-unsaturated
[a]
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology
Av. Països Catalans 16 – 43007 Tarragona (Spain)
E-mail: mgsuero@iciq.es
http://www.iciq.org/research/research_group/dr-marcos-g-suero/
Supporting information for this article is available on the WWW
under http://dx.doi.org/
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601604
European Journal of Organic Chemistry
SHORT COMMUNICATION
Table 1. Optimization Studies.[a]
Table 2. Cyclopropanation reaction of chalcone substrates.[a]
O
O
O
O
1 mol % Ru(bpy)3(PF6)2
1 mol % Ru(bpy)3(PF6)2
CH2I2
CH2I2
2
i-Pr2EtN, Na2S2O3
CH3CN, H2O
21 W CFL, 18 h, rt
i-Pr2EtN, Na2S2O3
CH3CN, H2O
21 W CFL, 18 h, rt
Ar
Ar
Ar
Ar
1
3
1a
2
3a
Entry[a]
Modification of the standard conditions
None
Yield [%][b]
O
O
R = Me 3b 80%
R = OMe 3c 93%(65%)[b]
R = CF3 3d 52%
1
2
3
4
69
35
17
10
R = Br 3e 63%
R
Na2S2O3 and H2O no added
Reaction mixture no degassed
DMSO instead CH3CN
3a 69%
O
O
O
O
PMP
PMP
PMP
Me
MeO
5
6
DMF instead CH3CN
Blue LED strips instead of 21 W CFL
Ir(ppy)2(dtbbpy)PF6 instead Ru(bpy)3(PF6)2
Ir(ppy)3 instead Ru(bpy)3(PF6)2
5
3f 52%
3g 82%
3h 57%
35
22
59
21
42
O
O
O
PMP
PMP
PMP
PMP
7
N
Cl
NC
8
O
3i 98%
3j 56%
3k 62%
9
Cu(dap)2Cl instead Ru(bpy)3(PF6)2
Eosin Y instead Ru(bpy)3(PF6)2
O
O
O
Ph
10
PMP
PMP
N
O
N
F3C
[a] Reaction conditions: 1a (0.10 mmol), 2 (0.25 mmol), i-PrEt2N (0.50 mmol),
CH3CN (4 mL), Na2S2O3 (0.50 mmol), H2O (1 mL). Reactions were degassed
prior to irradiation. [b] NMR Yields calculated using 1,2-dimethoxyethane as
internal standard. bpy = 2,2’-bipyridine. ppy = 2-phenylpyridine. dtbbpy = 4,4’-
Ph
H
3l 44%
3m 89%
3n 61%
O
O
O
S
PMP
O
PMP
PMP
NC
bis(1,1-dimethylethyl)-2,2’-bipyridine.
dap
=
2,9-bis(para-anisyl)-1,10-
N
N
phenanthroline.
3o 65%
3p 51%
3q 80%
O
With these conditions in hand, we next turned our attention to
assessing the scope of this radical cyclopropanation reaction by
varying the aromatic substituent at C1 (Table 2). We found that
electron-rich aromatic rings led to excellent yields (3b–c) in
comparison for electron-poor ones (3d,e). Although full
conversion is accomplished for the latter substrates,
cyclopropane decomposition is clearly observed under the
reaction conditions.[13] In this sense, we later extensively
explored the substrate scope at the C3 position keeping an
electron-rich aromatic group at C1 position. We found that the
process worked well for aromatic rings substituted with alkyl (3f),
alkoxide (3g,h), amino (3i), halogen (3j), ciano (3k), CF3 (3l) or
aldehyde groups (3m). Additionally, substrates bearing five- and
six-membered ring heterocycles (3n–r) worked well and no
products from a Minisci-type C–H bond iodomethylation were
observed.[14] It is noteworthy the excellent site-selectivity profile
observed for the cyclopropanation of the conjugated alkene
moiety versus other functionalities such us alkyl-substituted
alkenes (3h), nitriles (3k,o) or aldehyde groups (3m), that might
undergo methylene transfer by using classic protocols.
Additionally, we were delighted to find that the efficiency of the
cyclopropanation reaction was not decreased for trisubstituted
chalcones (3s) or for substrates bearing an alkyl group at C3
position instead of an aromatic ring (3t).[15]
O
MeO
PMP
Me
PMP
3t 53%
N
Cl
3r 36%
3s 93%
[a] Reaction conditions: 1 (0.40 mmol), 2 (1.00 mmol), i-PrEt2N (2.00 mmol),
CH3CN (10 mL), Na2S2O3 (2.00 mmol), H2O (1.5 mL), Reactions were
degassed prior to irradiation. [b] Reaction carried out with 1 gram of (E)-1c.
PMP = para-methoxyphenyl.
This new cyclopropanation reaction was also amenable for
isomeric E/Z mixtures of chalcones 1a,c,j and permitted the
steroconvergent synthesis of the desired trans-cyclopropane
3a,c,j with total stererocontrol (Scheme 3). These results
highlights a unique feature of this radical cyclopropanation
reaction based on the novel radical carbenoid species ICH2(Ÿ).
O
O
1 mol % Ru(bpy)3(PF6)2
diiodomethane (2)
i-Pr2EtN, Na2S2O3
CH3CN, H2O
R1
R2
R1
R2
1a (E/Z = 1.5:1); R1, R2 = H
1c (E/Z = 2:1); R1 = OMe, R2 = H
1j (E/Z = 1.6:1); R1 = OMe, R2 = Cl
21 W CFL, 18 h, rt
3a 51%
3c 80%
3j 51%
Scheme 3. Stereoconvergent chalcone cyclopropanation.
Later, we believed that alternative Michael acceptors could be
cyclopropanated by using the process developed for the
chalcone derivatives. We were pleased to find that α,β-
unsaturated aldehydes (4a), methyl ketones (4b),[16] amides (4c)
or simple alkyl-substituted enones (4d) were suitable substrates
for the synthesis of the corresponding cyclopropanes 5a–d
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601604
European Journal of Organic Chemistry
SHORT COMMUNICATION
(Scheme 4). In contrast with these results, ester substrates (4e),
imines (4f) or alkenes bearing ciano (β-cianostyrene) or nitro
groups (β-nitrostyrene) were not suitable for this radical
cyclopropanation reaction.[17]
Acknowledgements
ICIQ Foundation, CERCA Programme (Generalitat de
Catalunya), MINECO (Severo Ochoa Excellence Accreditation
2014-2018; SEV-2013-0319), the CELLEX Foundation through
the CELLEX-ICIQ high-throughput experimentation platform and
the ICIQ Starting Career Program are gratefully acknowledged
for financial support. ADH thanks CELLEX Foundation for a
post-doctoral contract. We thank also Ana Andrea Escobar for
the preparation of some starting materials and to the Research
Support Area of ICIQ.
O
O
1 mol % Ru(bpy)3(PF6)2
CH2I2
i-Pr2EtN, Na2S2O3
CH3CN/H2O
21 W CFL, 18 h, rt
4
2
5
O
O
O
H
Me
Ni-Pr2
MeO
Me
MeO
Keywords: photoredox catalysis • carbenoid • cyclopropanation
5a 72%
5b 75%
5c 51%
• radical • cyclopropane
Ts
N
O
O
[1]
[2]
a) D. Y. -K. Chen, R. H. Pouwer, J. A. Richard, Chem. Soc. Rev. 2012,
41, 4631. b) J. Salaün, Cyclopropane Derivatives and their Diverse
Biological Activities; Topics in Current Chemistry, Vol. 207 Springer-
Verlag Berlin Heidelberg, 2000.
OMe
H
Me
MeO
5d 56%
5e 0%
5f 0%
For a review, see: a) H. Lebel, J. F. Marcoux, C. Molinaro, A. B.
Charette, Chem. Rev. 2003, 103, 977. For recent catalytic
cyclopropanation processes, see: b) C. R. Solorio-Alvarado, Y. Wang,
A. M. Echavarren, J. Am. Chem. Soc. 2011, 133, 11952. c) R. Vicente,
J. González, L. Riesgo, J. González, L. A. López, Angew. Chem. Int.
Ed. 2012, 51, 8063. d) P. S. Coelho, E. M. Brustad, A. Kannan, F. H.
Arnold, Science 2013, 339, 307. e) P. Cotugno, A. Monopoli, F.
Ciminale, A. Milella, A. Nacci, Angew. Chem. Int. Ed. 2014, 53, 13563.
f) T. Piou, T. Rovis, J. Am. Chem. Soc. 2014, 136, 11292. g) M. J.
González, J. González, L. A. López, R. Vicente, Angew. Chem. Int. Ed.
2015, 54, 12139. h) S. Manna, A. P. Antonchick, Angew. Chem. Int. Ed.
2015, 54, 14845. i) G. Xu, P. Renaud, Angew. Chem. Int. Ed. 2016, 55,
3657. j) P. Bajaj, G. Sreenilayam, V. Tyagi, R. Fasan, Angew. Chem.
Int. Ed. 2016, 55,16110. k) J. M. Sarria Toro, C. García-morales, M.
Raducan, E. S. Smirnova, A. M. Echavarren, Angew. Chem. Int. Ed.
2017, DOI: 10.1002/anie.201611705.
Scheme 4. Catalytic cyclopropanation of α,β-unsaturated carbonyls.
Finally, we wondered whether the catalytic concept depicted in
Scheme 1 for radical carbenoid generation, could be generalized
by using alternative gem-diiodoalkanes. This generalization
would allow access to complex cyclopropane cores using a
simple and novel catalytic approach. Preliminary studies have
revealed that commercially available 1,1-diiodoethane (6)
worked well under the same reaction conditions developed in
Table 1 and produced tri-substituted cyclopropane 7 in 69%
isolated yield as a mixture of diastereoisomers (Scheme 5). This
result suggested the involvement of a new radical carbenoid
species 8, whose reactivity is analogous to the iodomethyl
radical carbenoid ICH2(Ÿ).
[3]
a) H. E. Simmons, R.D. Smith, J. Am. Chem. Soc. 1958, 80, 5323. b) H.
E. Simmons, R. D. Smith, J. Am. Chem. Soc. 1959, 81, 4256. c) J.
Furukawa, N. Kawabata, J. Nishimura, Tetrahedron Lett. 1966, 7, 3353.
d) S. E. Denmark, J. P. Edwards, J. Org. Chem. 1991, 56, 6974. e) A. B.
Charette, S. Francoeur, J. Martel, N. Wilb, Angew. Chem. Int. Ed. 2000,
39, 4539; Angew. Chem. 2000, 112, 4713; f) A. B. Charette, A.
Beauchemin, S. Francoeur, J. Am. Chem. Soc. 2001, 123, 8139. g) L.
P. B. Beaulieu, J. F. Schneider, A. B. Charette, J. Am. Chem. Soc.
2013, 135, 7819. h) S. Taillemaud, N. Diercxsens, A. Gagnon, A. B.
Charette, Angew. Chem. Int. Ed. 2015, 54, 14108.
Me
1 mol % Ru(bpy)3(PF6)2
O
O
H
Me CHI2 (6)
i-Pr2EtN, Na2S2O3
CH3CN, H2O
I
8
PMP
PMP
Me
R
R
iodoethyl radical
21 W CFL, 18 h, rt
7 69% (2:1)
1t R = morpholinyl
Scheme 5. Cyclopropanation with 1,1-diiodoethane (6).
[4]
[5]
a) S. E. Denmark, R. A. Stavenger, A. M. Faucher, J. P. Edwards, J.
Org. Chem. 1997, 62, 3375. b) E. V. Guseva, N. V. Volchkov, Y. V.
Tomilov, O. M. Nefedov, Eur. J. Org. Chem. 2004, 3136. c) G. H. Fang,
Z. J. Yan, M. Z. Deng, Org. Lett. 2004, 6, 357. d) B. Morandi, E. M.
Carreira, Science 2012, 335, 1471.
Conclusions
For selected examples with sulfur ylides, see: a) E. J. Corey, M.
Chaykovsky, J. Am. Chem. Soc. 1962, 84, 3782. b) E. J. Corey, M.
Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353. c) V. K. Aggarwal, E.
Alonso, G. Fang, M. Ferrara, G. Hynd, M. Porcelloni, Angew. Chem. Int.
Ed. 2001, 40, 1433. d) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 3240. For a review, see: e) Y. G. Gololobov, A. N.
Nesmeyanov, V. P. Lysenko, I. E. Boldeskul, Tetrahedron 1987, 43,
4057. For selected examples with nitrogen ylides, see: f) C. D.
Papageorgiou, S. V. Ley, M. J. Gaunt, Angew. Chem. Int. Ed. 2003, 42,
828. g) J. M. Sarria Toro, T. den Hartog, P. Chen, Chem. Commun.
2014, 50, 10608.
In summary, we have successfully developed
a
new
cyclopropanation reaction of α,β-unsaturated carbonyl
compounds with CH2I2 by means of photoredox catalysis.
Notable features of this process are the mild reaction conditions
and excellent selectivity profile. The process involves the
catalytic generation of radical carbenoid species, which are able
to transfer a CH2 in a stereocontrolled manner. Additionally, we
were able to transfer for the first time, a CH(Me) group by using
commercial 1,1-diiodoethane.
[6]
For recent alternative catalytic methylenation processes, see: a) T. Den
Hartog, J. M. S. Toro, P. Chen, Org. Lett. 2014, 16, 1100. b) S. A.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601604
European Journal of Organic Chemistry
SHORT COMMUNICATION
Künzi, J. M. Sarria Toro, T. den Hartog, P. Chen, Angew. Chem. Int. Ed.
2015, 54, 10670; Angew. Chem. 2015, 127, 10817. c) Y. Y. Zhou, C.
Uyeda, Angew. Chem. Int. Ed. 2016, 55, 3171. d) J. Xu, N. B. Samsuri,
H. A. Duong, Chem. Commun. 2016, 52, 3372.
[13] An experiment carried out with chalcone 1e during 30 hours, provided
cyclopropane 3e in 22% NMR yield. This result clearly suggested
cyclopropane decomposition under the reaction conditions. We believe
that an unproductive cyclopropane ring-opening could be occurring
[7]
[8]
a) Ž. Čeković, R. Saičić, Tetrahedron Lett. 1990, 31, 6085. b) M.
Journet, M. Malacria, J . Org. Chem. 1994, 59, 718. c) D. P. Curran, A.
E. Gabarda, Tetrahedron 1999, 55, 3327. d) W. I. Dzik, X. Xu, X. P.
Zhang, J. N. H. Reek, B. De Bruin, J. Am. Chem. Soc. 2010, 132,
10891.
through a one-electron reduction of the carbonyl group to the
corresponding radical anion. This photoredox process has been
exploited by Yoon and co-workers for a [3+2] cycloaddition of aryl
cyclopropyl ketones: Z. Lu, M. Shen, T. P. Yoon, J. Am. Chem. Soc.
2011, 133, 1162.
For recent reviews, see: a) M. H. Shaw, J. Twilton, D. W. C. MacMillan,
J. Org. Chem. 2016, 81, 6898. For selected processes involving the
generation of carbon-centered radicals from activated halide
compounds, see: b) D. A. Nicewicz, D. W. C. MacMillan, Science 2008,
322, 77. c) D. A. Nagib, M. E. Scott, D. W. C. Macmillan, 2009, 2,
10875. d) J. M. R. Narayanam, J. W. Tucker, C. R. J. Stephenson, J.
Am. Chem. Soc. 2009, 131, 8756. e) J. D. Nguyen, E. M. D’Amato, J. M.
R. Narayanam, C. R. J. Stephenson, Nat. Chem. 2012, 4, 854. f) C. J.
Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J. Stephenson, J. Am.
Chem. Soc. 2012, 134, 8875.
[14] For
examples
of
photoredox-catalyzed
Minisci-type
C–H
functionalization processes, see: a) D. A. DiRocco, K. Dykstra, S. Krska,
P. Vachal, D. V. Conway, M. Tudge, Angew. Chem. Int. Ed. 2014, 53,
4802. b) J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2015, 54,
1565. c) J. Jin, D. W. C. MacMillan, Nature 2015, 525, 87. d) G.-X. Li, C.
A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G. Chen, Chem. Sci.
2016, 7, 6407.
[15] We observed full starting material conversion for all substrates of Table
2 and no Michael adducts from an incomplete ring-closuring event. The
low yields observed for some of the cyclopropanes could also be
explained as in reference 13.
[9]
A. M. del Hoyo, A. G. Herraiz, M. G. Suero, Angew. Chem. Int. Ed.
2016, 56, 1610.
[16] Corey-Chaykovsky methodologies based on sulfur ylides fail to give the
cyclopropane core with enones like 4b, and instead, the corresponding
oxirane is formed. For a reference, see: M. Lautens, M. L. Maddess, E.
L. O. Sauer, S. G. Ouellet, Org. Lett. 2002, 4, 83.
[10] For a description of the proposed mechanism, see reference [9].
[11] The generation of iodomethyl radical species with CH2I2/BEt3/O2 and
subsequent 1,4-addition to methyl(vinyl)ketone to give a Michael adduct,
has been reported: K. Nozaki, K. Oshima, K. Utimoto, Chem. Soc.
Japan 1991, 64, 403.
[17] Although our original working hypothesis was based on the formation of
an α-carbonyl radical intermediate (Scheme 2b), we cannot rule out the
formation of a benzyl radical intermediate in substrates bearing an
aromatic ring in β position.
[12] Preliminary results showed that the process carried out with no
photocatalyst is sluggish and 15% NMR yield of 3a is obtained in
combination with a mixture of E/Z-chalcone (2.2:1, 82% NMR).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601604
European Journal of Organic Chemistry
SHORT COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
SHORT COMMUNICATION
Key Topic* photoredox catalysis
A. M. del Hoyo, and M. G. Suero*
Page No. – Page No.
Title
Photoredox-catalyzed
Cyclopropanation of Michael
Acceptors
***Please provide a short text (up to 400 characters with spaces; not the same text as the
Abstract) to go with the Table of Contents graphic.***
A new protocol for the cyclopropanation of α,β-unsaturated carbonyl compounds with simple
diiodomethane has been developed by means of photoredox catalysis. The process involves the
phocatalytic generation of iodomethyl radical, a novel carbenoid species able to transfer a CH2 group to
a wide variety of Michael acceptors in a stereocontrolled manner.
This article is protected by copyright. All rights reserved.