A Stereoconvergent Cyclopropanation Reaction of Styrenes

Article abstract of DOI:10.1002/anie.201610924

The first stereoconvergent cyclopropanation reaction by means of photoredox catalysis using diiodomethane as the methylene source is described. This transformation exhibits broad functional group tolerance and it is characterized by an excellent stereocontrol en route to trans-cyclopropanes regardless of whether E- or Z-styrene substrates were utilized.

Full text of DOI:10.1002/anie.201610924

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610924
German Edition: DOI: 10.1002/ange.201610924
Photoredox Catalysis
A Stereoconvergent Cyclopropanation Reaction of Styrenes
Ana M. del Hoyo+, Ana G. Herraiz+, and Marcos G. Suero*
In memory of Josꢀ Barluenga Mur
Abstract: The first stereoconvergent cyclopropanation reac-
tion by means of photoredox catalysis using diiodomethane as
the methylene source is described. This transformation exhibits
broad functional group tolerance and it is characterized by an
excellent stereocontrol en route to trans-cyclopropanes regard-
less of whether E- or Z-styrene substrates were utilized.
corresponding biradical species.[6b] Taking this into account,
we wondered whether a stereoconvergent cyclopropanation
could be within reach using a synthetic equivalent of a triplet
carbene containing a radical adjacent to an appropriate
leaving group [Eq. (c)].[7] We hypothesized that such radical
carbenoid species[8] might lead to stabilized radical inter-
À
mediates that would be in equilibrium through a simple C C
T
he catalytic transfer of a methylene group to alkene
bond rotation, thus leading to the most stable trans-config-
ured cyclopropane. Herein, we report the successful develop-
ment of such a method using simple CH2I2 as the methylene
source by means of visible-light photoredox catalysis
[Eq. (d)].
molecules for the synthesis of cyclopropane cores is a long-
standing challenge in chemical synthesis.[1] At present,
classical methods rely on the use of well-defined iodomethyl-
zinc reagents[2] or diazomethane,[3] which possess problems
with efficiency, availability, and safety [Eq. (a)].[4] Although
reliable control of the stereochemistry is achieved, these
processes remained confined to the utilization of isomerically
pure alkenes. Taking into consideration the inherent difficul-
ties for accessing stereodefined substituted alkenes, the
means to design a stereoconvergent cyclopropanation using
E,Z-alkene mixtures with easy to handle and commercially
available methylene sources would be highly appreciated.
Despite the potential advantages, it is rather surprising that
such strategies remains largely underdeveloped,[5] probably
owing to the need for a new reactivity principle by using less-
conventional carbene precursors.
It is well established that the electronic configuration of
carbenes determines their reactivity and reaction outcome
[Eq. (b)].[6] While singlet methylene carbene reacts with E-
alkenes to give trans-cyclopropanes in a stereospecific
manner, triplet methylene reacts to isomeric cyclopropane
mixtures through a pre-existing equilibrium of the two
Macmillan and Stephenson, among others, have shown
that photoredox catalysis allows the generation of transient
carbon-centered radicals from activated halide compounds
involving a single-electron reduction process.[9] Additionally,
Guo recently described a photoredox cyclopropanation that
involves a double single-electron reduction of dibromomal-
onates and generation of a-bromomalonate carbanion inter-
mediates.[5d] However, this method is unable to transfer
a simple methylene group. We envisioned that our cyclo-
propanation reaction mechanism using CH2I2 (2) would
proceed as depicted in Scheme 1. Irradiation of the widely-
used ruthenium catalyst [Ru(bpy)3]2+ (4; bpy = 2,2’-bipyri-
dine) with visible light would convert to the long-lived
[*] Dr. A. M. del Hoyo,[+] A. G. Herraiz,[+] Dr. M. G. Suero
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
E-mail: mgsuero@iciq.es
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201610924.
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During the course of these studies, we recognized the
À
possibility of I2/I3 formation species, which are known to
quench the photoexcited state *[Ru(bpy)3]2+ (5) and would be
detrimental for the progress of the reaction.[13] In this sense,
we were pleased to find that by adding water and sodium
thiosulfate as a suitable iodine quencher to the reaction
mixture, the yield of 3a successfully increased up to 76%
(entry 2).
These conditions were adapted for a larger scale reaction
using 1 gram of (E)-anethole (1a) without compromising the
efficiency of the process (85% yield, entry 2). Control
experiments showed that i-Pr2EtN (entry 3) and visible light
(entry 4) are essential for this reaction, and also the necessity
of degassing the reaction mixture prior to irradiation
(entry 5).[14] More importantly, we found what E/Z-mixtures
of 1a (E/Z, 1:2) resulted in the exclusive formation of 3a, thus
demonstrating the feasibility of conducting a stereoconver-
gent cyclopropanation reaction.[15] Additional control experi-
ments showed that (Z)-1a to (E)-1a or cis-3a to trans-3a
isomerizations did not occur during the course of the reaction
and UV light (300 nm) does not promote the cyclopropana-
tion as previously described by Kropp for alkyl-substituted
alkenes (see the Supporting Information).[11a–c]
Scheme 1. Working hypothesis.
photoexcited state *[Ru(bpy)3]2+ (5; E1/2(II)*/(I) = 0.77 V vs.
SCE), which is reduced to [Ru(bpy)3]+ (6) with N,N-diiso-
propylethylamine by a well-established SET process. The RuI
intermediate is a strong reductant (E1/2(II)/(I) = À1.33 V vs.
SCE) and would donate an electron to CH2I2 (Ered = À1.44 V
vs. SCE),[10] thereby generating a transient anion radical
[CH2I2]ÀC, which evolves into iodomethyl radical (7).[11]
Addition to E,Z-alkenes 1 would conduct to intermediates
Having the optimized reaction conditions in hand, we next
investigated the scope of this cyclopropanation by examining
a wide range of styrenes 1a–x. As shown in Table 2, this
process was successfully applied in substrates functionalized
with electron-donating and electron-withdrawing groups (3b–
j) and also with heterocycles (3k,l).
À
int I and int II, which would be in equilibrium through a C C
bond rotation. Finally, a cyclization step would take place by
homolytic substitution preferentially on intermediate int II,
in which both R1 and R2 groups are in a favorable relative anti
orientation.[12] Our envisaged cyclopropanation was initially
evaluated using (E)-anethole (1a) as the alkene substrate. To
our delight, in a first round of experiments we identified that
the cyclopropanation reaction took place with 59% yield of
desired trans-cyclopropane 3a as a single diastereoisomer by
using 1 mol% Ru(bpy)3(PF6)2 (4), diiodomethane (2;
2.5 equiv), N,N-diisopropylethylamine (5 equiv), acetonitrile
(0.1m) and a 21 W compact fluorescent lamp (CFL) as visible
light source (Table 1, entry 1).
We noticed that styrenes bearing electron-rich substitu-
ents converted to the corresponding cyclopropane in a more
efficient manner (3a–c). It is possible that the nucleophilic
character of the benzyl radical int II plays an important role
in the cyclization event (Scheme 1, R1 = Ar). In fact, no
product (3h) or low yield (3i,j) was observed for styrenes
bearing moderate/strong electron-withdrawing groups, and
alkene decomposition was observed. Having established that
the electronics of the aromatic moiety have a direct impact in
the outcome of the cyclopropanation reaction, we next
evaluated the alkyl substitution for alkenes 1m–w. This
procedure was successfully applied to a wide range of alkyl
groups functionalized with aromatic rings (3m), cycloalkanes
(3n), acetals (3o), alcohols (3p–s), imides (3t,u), alkyl iodides
(3v), or alkenes (3w). The excellent level of efficiency for this
radical cyclization is notable because no other reaction
products have been observed for substrates bearing embed-
ded nucleophiles, which could potentially intercept a benzylic
radical intermediate (Table 2; 3m,s,w), as well as for substrate
Table 1: Optimization studies.[a]
Entry
Alkene 1a
Additive
Yield 3a [%][b]
À
1v bearing a C I bond, which could participate in a compet-
1
2
3
4
5
6
E
E
E
E
E
E/Z
–
59
Na2S2O3,H2O
Na2S2O3,H2O
Na2S2O3,H2O
Na2S2O3,H2O
Na2S2O3,H2O
76(85)[c]
0[d]
itive cyclization for the synthesis of a cyclobutane analogue.
However, only cyclopropane 3v was observed as only product
of the reaction. The excellent functional group tolerance of
this radical cyclopropanation is illustrated in substrates
bearing tertiary amines (3b,m–o) or sulfides (3c,u,w), which
generally react with iodomethylzinc reagents generating the
corresponding ylide.[16] Furthermore, directing groups were
not needed to ensure site-selectivity for a substrate bearing
two reactive alkenes (3w). Remarkably, only the alkene
conjugated with the aromatic group was selectively cyclo-
0[e]
45[f]
79
[a] Reaction conditions: 1a (0.10 mmol), 2 (0.25 mmol), i-PrEt2N
(0.50 mmol), CH3CN (1 mL); Na2S2O3 (0.50 mmol), H2O (0.4 mL).
Reactions were degassed prior to irradiation. [b] GC/MS yields calculated
using acetophenone as internal standard. [c] Yield of isolated product
using 1 gram of (E)-1a. [d] Reaction carried out without i-Pr2EtN.
[e] Reaction carried out in the dark. [f] Reaction mixture not degassed.
2
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Table 2: Sterereoreoconvergent cyclopropanation.[a]
Scheme 2. Stereoconvergent cyclopropanation of trisubstituted alkene
1y.
Finally, we provided compelling evidence for the forma-
tion of radical 7. While the addition of TEMPO to a reaction
mixture containing CH2I2 did not afford the TEMPO-CH2I
adduct, the presence of one equivalent of 1,1-diphenylethene
(12) allowed for the formation of a cyclic ammonium iodide
salt 13 in 63% yield [Scheme 3, Eq. (e)]. Its formation is
explained through the initial coupling of radical 7 with alkene
12 and the generation of a tertiary radical 14, which couples
with TEMPO via radical–radical coupling/cyclization. The
radical nature of 7 was further confirmed using the cyclo-
propyl radical probe 15 [Scheme 3, Eq. (f)]. Formation of
alkene 16 suggested the involvement of cyclopropylmethyl
radical 17 prior to the ring-opening reaction.[18]
Scheme 3. Mechanistic experiments.
[a] See the Supporting Information for experimental details; yields are of
isolated product. E/Z-alkene mixtures 1 are shown in brackets; reactions
were degassed prior to irradiation; additional 2 (2.5 equiv) and Na2S2O3
(5 equiv) were added after 2 hours of reaction. [b] E isomer was used.
NPhth=phthalimide. PMP=para-methoxyphenyl.
In summary, we have described the first stereoconvergent
cyclopropanation reaction of styrenes with CH2I2 by means of
photoredox catalysis. The transformation is characterized by
its mild conditions, broad functional group compatibility, and
excellent selectivity profile. We have experimentally demon-
strated that the process involves a triplet carbene equivalent
able to transfer a CH2 group to a wide range of E,Z-alkene
mixtures in a stereocontrolled manner.
propanated. In contrast to these results, unsubstituted styr-
enes provided a mixture of cyclopropanes (3x) and a dimeric
product (9), and a-substituted styrenes conducted to open-
chain iodoalkanes (10).
After this, we investigated whether mixtures of isomeric
trisubstituted alkenes could be suited substrates for affecting
an otherwise analogous stereoconvergent cyclopropanation.
We anticipated that the extension to these substrates would
Acknowledgements
ICIQ Foundation, CERCA Programme (Generalitat de
Catalunya), MINECO (Severo Ochoa Excellence Accredita-
tion 2014–2018; SEV-2013-0319), and the CELLEX Founda-
tion through the CELLEX-ICIQ high-throughput experi-
mentation platform and the Starting Career Program are
gratefully acknowledged for financial support. A.D.H. and
A.G.H. thank CELLEX Foundation for pre-doctoral and
post-doctoral contracts. We thank also to Profs. R. Martꢀn,
A. Shafir, and J. Lloret for mechanistic discussions, and to the
Research Support Area of ICIQ.
À
be far from trivial, as the critical C C bond rotation prior to
cyclization was expected to be rather problematic. Gratify-
ingly, this was not the case and 3y was cleanly obtained from
1y (E/Z = 1.5:1) with high efficiency and as a single diaste-
reoisomer, representing a rare example of a stereoconvergent
reaction with trisubstituted olefin mixtures (Scheme 2).[5a,17]
At present, we believe these results suggest the involvement
of int III, in which the aromatic and corresponding methyl
group are in a relative anti orientation.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: carbenoids · catalysis · cyclopropanation ·
photoredox catalysis · radicals
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Manuscript received: November 8, 2016
Revised: November 23, 2016
Final Article published: && &&, &&&&
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4
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Communications
Photoredox Catalysis
A. M. del Hoyo, A. G. Herraiz,
M. G. Suero*
&&&& — &&&&
A Stereoconvergent Cyclopropanation
Reaction of Styrenes
Photocatalytic approach: A stereocon-
vergent cyclopropanation reaction by
means of photoredox catalysis using
diiodomethane as the methylene source
is described. This transformation exhibits
broad functional group tolerance and is
characterized by excellent stereocontrol
en route to trans-cyclopropanes regard-
less of whether E- or Z-styrene substrates
were utilized.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!