Zinc-Catalyzed Alkene Cyclopropanation through Zinc Vinyl Carbenoids Generated from Cyclopropenes

Article abstract of DOI:10.1002/anie.201505954

The zinc-catalyzed reaction of cyclopropenes with alkenes leading to vinylcyclopropane derivatives is reported. A broad range of alkenes (including highly substituted or functionalized alkenes) is compatible with this protocol. On the basis of trapping experiments and computational studies, this cyclopropanation reaction is proposed to proceed through initial formation of an electrophilic zinc vinyl carbenoid intermediate, which may be involved in a concerted cyclopropanation reaction. The reported protocol represents an unprecedented and simple strategy for the catalytic generation of zinc vinyl carbenoids, which are promising intermediates in organic synthesis.

Full text of DOI:10.1002/anie.201505954

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505954
German Edition: DOI: 10.1002/ange.201505954
Small-Ring Compounds
Zinc-Catalyzed Alkene Cyclopropanation through Zinc Vinyl
Carbenoids Generated from Cyclopropenes
María J. Gonzµlez, Javier Gonzµlez, Luís A. López,* and RubØn Vicente*
Dedicated to Professor Antonio Echavarren on the occasion of his 60th birthday
Abstract: The zinc-catalyzed reaction of cyclopropenes with
alkenes leading to vinylcyclopropane derivatives is reported. A
broad range of alkenes (including highly substituted or
functionalized alkenes) is compatible with this protocol. On
the basis of trapping experiments and computational studies,
this cyclopropanation reaction is proposed to proceed through
initial formation of an electrophilic zinc vinyl carbenoid
intermediate, which may be involved in a concerted cyclo-
propanation reaction. The reported protocol represents an
unprecedented and simple strategy for the catalytic generation
of zinc vinyl carbenoids, which are promising intermediates in
organic synthesis.
G
round-breaking reports on the generation of zinc carbe-
noids for the cyclopropanation of alkenes was already
described by Simmons and Smith in 1958.[1,2] Nowadays, the
Simmons–Smith cyclopropanation (SSC) still remains one of
the most employed methods to synthesize cyclopropanes. In
spite of the age of this venerable transformation, the standard
procedures for the generation of these intermediates rely on
the use of a large excess of zinc sources, generally Et2Zn,[3]
and diiodoalkanes, mainly CH2I2, as the carbenoid precursors
(Scheme 1a).[4] Less common stoichiometric approaches to
zinc carbenoids make use of diazo compounds or carbonyl
derivatives (including acetals and orthoesters; Sche-
me 1a).[5,6]
Scheme 1. Zinc carbenoids: A) Classical stoichiometric approaches.
B) Proposed catalytic approach using cyclopropenes as carbene
source. C) Optimized reaction conditions. TMS=trimethylsilyl.
identification of alternative carbene sources and their imple-
mentation in organic synthesis would be very convenient.
In this regard, given that alkynes and cyclopropenes share
a number of features,[12] we hypothesized that zinc salts could
activate the p bond of a cyclopropene, thus triggering a ring-
opening to generate a zinc vinyl carbenoid intermediate,
which could be further trapped by alkenes and lead to the
corresponding vinyl cyclopropane and catalyst turnover
(Scheme 1b).[13–15] From a synthetic standpoint, this method
could represent a convenient catalytic entry to the vinyl-
cyclopropane framework,[16] a key structural motif in relevant
compounds such as sesquiterpenoids or chrysantemic acid
derivatives.[17]
This working hypothesis was evaluated using the reaction
of the easily accessible 3,3-dialkylcyclopropene 1a[18] with
different commercially available zinc salts in the presence of
styrene (2a) as the alkene (Scheme 1c). Various zinc salts
proved capable of promoting the formation of the vinyl-
cyclopropane 3a under mild reaction conditions. The forma-
tion of 3a points to the participation of a zinc vinyl carbenoid
intermediate, thus supporting our hypothesis. Optimal results
involved the use of inexpensive, low toxicity ZnCl2
(10 mol%) and 5.0 equivalents of 2a in CH2Cl2 at ambient
Because of the growing significance of zinc catalysis in
organic synthesis,[7] notable efforts to develop zinc-catalyzed
cyclopropanations have been recently performed. Thus,
Charette and co-workers reported the use of phenyldiazo-
methane to generate zinc carbenoids in a catalytic fashion.[8]
Besides, considering the ability of zinc salts to activate alkynes
towards nucleophiles,[9] we reported the catalytic generation
of 2-furyl zinc carbenoids using conjugated enynones as the
carbene source.[10] These intermediates were trapped by
alkenes and other reagents.[11]
Despite these recent advances in zinc-catalyzed cyclo-
propanations, the development of catalytic versions of the
SSC still remains a significant goal. In particular, the
[*] M. J. Gonzµlez, Dr. J. Gonzµlez, Dr. L. A. López, Dr. R. Vicente
Departamento de Química Orgµnica e Inorgµnica
Instituto Universitario de Química Organometµlica “Enrique Moles”
Universidad de Oviedo, c/Juliµn Clavería 8, 33006-Oviedo (Spain)
E-mail: lalg@uniovi.es
vicenteruben@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505954.
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temperature, thus leading to 3a in 82% yield upon isolation
(cis/trans = 12:1; Z/E = 1.5:1).[19]
In general, the reaction showed a noticeable preference for
the formation of the cis isomer.[20] Mono- and 1,1-disubsti-
tuted alkenes were converted into the corresponding com-
pounds 3k–s, mostly in good yields (52–89%) and moderate
cis/trans selectivity (ca. 3:1 for 3k–l,s; Scheme 2b). Notably,
economically relevant raw materials such as propylene and
isobutylene could be processed under these reaction condi-
tions. The use of cyclic or acyclic 1,2-disubstituted alkenes was
next explored (Scheme 2c). Under the optimized reaction
conditions, the corresponding 1,2,3-trisubstituted cyclopro-
panes 3t–ab were obtained in yields ranging from moderate to
By using the optimized reaction conditions, the scope of
this zinc-catalyzed vinylcyclopropane synthesis was next
evaluated. As shown in Scheme 2, the present protocol
shows a remarkably broad scope. First, 3,3-dialkylsubstituted
cyclopropenes, employed as the carbenoid source, were
initially trapped with various styrene derivatives to afford
the compounds 3b–j in good yields (Scheme 2a). The method
tolerated a variety of substitution patterns on the phenyl
group without significantly influencing the reaction outcome.
Scheme 2. ZnCl2-catalyzed cyclopropanation using cyclopropenes 1 as a vinyl carbene source: Scope (e–i). Yields are those of the isolated
products. The d.r. value was determined by 1H NMR spectroscopy. [a] At 508C in 1,2-DCE. [b] 3j has axial chirality. [c] Alkene was condensed (ca.
1 mL) and the reaction was accomplished in a sealed tube. [d] d.r.=1:1 with respect to the chiral carbon at the epoxide. [e] Major isomer(s) not
determined. NPhth=phthalamide, TBS=tert-butyldimethylsilyl.
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good (35–85%). Interestingly, as observed in the classical
stoichiometric SSC, these transformations took place with
complete stereospecificity with respect to the starting alkene.
Moreover, increasing substitution in the alkene had no
deleterious effect on the reaction outcome. Thus, tri- and
tetrasubstituted alkenes were employed and lead efficiently
to the compounds 3ac–ae (Scheme 2d). Once the ability of
styrene derivatives and electronically unbiased alkenes to
participate in this zinc-catalyzed cyclopropanation reaction
was demonstrated, the role of the electronic properties of the
alkene was next studied. Hence, electron-rich alkenes such as
enol ethers were converted into the alkoxycyclopropanes
3af–ah in useful yields with moderate selectivity (Sche-
me 2e). In contrast, methyl vinyl ketone and methyl acrylate,
representative electron-deficient alkenes, were unreactive.
Remarkably, substituted acrylates as methyl 3,3-dimethyl-
acrylate or methyl 3-methoxyacrylate participated in the
reaction, thus providing the cyclopropane 3ai (37%) and
push-pull cyclopropane 3aj (56%), respectively (Scheme 2 f).
Functional-group compatibility was also addressed (Sche-
me 2g). As shown, a broad range of functional groups were
found to be compatible under the standard reaction con-
ditions, including chloride, bromide, protected alcohol or
amine, ketone, and ester, thus affording the corresponding
cyclopropanes 3ak–ap in moderate to good yields (50–83%).
Even Lewis acid sensitive functionalities such as epoxides
were also tolerated as demonstrated the preparation of
cyclopropane derivative 3aq in a passable 50% yield.
Scheme 4. Mechanistic studies. Bond lengths in Š, DG° in kcal
rel
molÀ1
.
Taking advantage of this remarkably broad scope, we
attempted the modification of representative naturally occur-
ring alkenes (Scheme 2h). Under the standard reaction
conditions, b-pinene was transformed into the cyclopropane
3ar in moderate yield (50%; d.r. = 1:1) without the observa-
tion of rearrangement byproducts. Similarly, (+)-longifolene
or (+)-camphene were converted into the corresponding
cyclopropanes 3as–at. In line with our expectations, the most
electron-rich alkene was in l-(À)-carvone chemoselectively
cyclopropanated to afford 3au in good yield (62%, d.r. =
3:3:1:1). Interestingly, O-acetyl-protected glycals such as
d-glucal and d-galactal were suitable alkenes as illustrated
by the preparation of the cyclopropanes 3av–3aw in decent
yields as a mixture of diastereoisomers (Scheme 2i).
Aryl substituents in the 3-position of the cyclopropene
have a remarkable effect on reactivity (Scheme 3). Thus,
when using 1 f (R = Ph) with or without styrene (2a), under
standard reaction conditions, the indene 4a was the only
isolated product.[21,22] Interestingly, the reaction with 1g (R =
Me) led to the indane derivative 5a (51%) as a single
isomer.[23]
level of theory,[24] on the model reaction of 3,3-dimethylcy-
clopropene (A) and ethylene with ZnCl2. (Scheme 4a).
According to our calculations, coordination of A to ZnCl2
forms the p-type complex B, which is 2.4 kcalmolÀ1 more
stable than the reactants. Interestingly, this complex evolves
À
by cleavage of C2 C3 bond as can be seen in the analysis of
the transition state (TSB-C) identified for this reaction, whose
activation free energy is 9.7 kcalmolÀ1. The normal mode
associated with the imaginary vibrational frequency of TSB-C
3
2
À
shows an elongation of the C2 C3 bond and a sp to sp
hybridization change for C3. The intrinsic reaction coordinate
(IRC) algorithm indicates that this first-order saddle point is
connected with a minimum (C), whose structure could be
viewed as an electrophilic carbene intermediate. Then,
transition state TSC–D, showing an activation free energy of
12 kcalmolÀ1, was found for the [2+1]-cycloaddition reaction
of zinc carbenoid intermediate C with ethylene, and evolves
into the vinylcyclopropane D. While TSC-D is a slightly
asynchronous transition structure, the cycloaddition is a con-
certed process according to the IRC.[25] This result is in good
agreement with the stereospecificity observed experimentally,
and the absence of rearrangements in the reaction with b-
pinene. An important piece of evidence about the nature of
the intermediate involved in these reactions comes from the
ZnCl2-promoted ring-opening of 3,3-diphenylcyclopropene
(1 f). Transition structures for a Nazarov-type intramolecular
cyclization of the corresponding carbene intermediate F
(Scheme 4b), thus leading to 4a, and those for the cyclo-
addition to styrene were found. According to our calculations,
To gain support for the mechanism proposed in Scheme 1,
we carried out a computational study, at the B3LYP/6-31G*
Scheme 3. Reactivity of 3-phenyl-substituted cyclopropenes (1 f–g).
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2001, 40, 2326; Angew. Chem. 2001, 113, 2388. For their use in
intramolecular cyclopropanations, see: c) J. A. Bull, A. B. Char-
ette, J. Am. Chem. Soc. 2010, 132, 1895.
the transition structure corresponding to the intramolecular
cyclization is significantly (ca. 6 kcalmolÀ1) more stable than
those located for the cycloaddition to styrene. This result is in
line with the experimental results.
Additional experiments were performed to support the
predicted structure of the zinc carbenoid intermediate C
(Scheme 4c). Its electrophilic nature was established by
trapping with a nucleophile such as methanol, and afforded
the ether 6a, likely by 1,4-addition to species C. Moreover,
the use of diphenylsulfoxide led to the aldehyde 7, supporting
again the participation of a carbene-like species.[26]
In summary, we have reported a novel strategy for the
catalytic generation of zinc vinyl carbenoid intermediates.
This approach relies on the ability of zinc to promote the ring-
opening of cyclopropenes, which serve as a reliable and easy-
to-handle vinyl carbene source. The carbene intermediates
generated can be efficiently trapped with alkenes to yield
valuable vinyl cyclopropane derivatives. The remarkably
broad scope includes raw olefins to highly substituted and
densely functionalized alkenes, thus highlighting the potential
of this transformation in organic synthesis. Moreover, the use
of inexpensive, low toxicity ZnCl2 as the catalyst is attractive
when considering large-scale applications. Preliminary studies
on the structure of the involved intermediate pointed to an
electrophilic zinc vinylcarbenoid, which shows a different
structure from those haloalkylzinc intermediates proposed in
the classical Simmons–Smith reaction. Accordingly, we hope
that this feature will enable the development of new catalytic
transformations using a non-noble metal as zinc. Further
studies on the nature of the involved intermediates as well as
new synthetic applications are currently underway.
[5] For the stoichiometric generation of zinc carbenoids from diazo
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Rilling, J. Am. Chem. Soc. 1971, 93, 1782; d) L. J. Altman, R. C.
Kowerski, D. R. Laungani, J. Am. Chem. Soc. 1978, 100, 6174.
[6] For the stoichiometric generation of zinc carbenoids from
ketones and chlorosilanes, see: a) W. B. Motherwell, L. R.
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Int. Ed. 2013, 52, 10060; Angew. Chem. 2013, 125, 10244.
[7] Zinc Catalysis, Applications in Organic Synthesis (Eds.: S.
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[8] a) S. R. Goudreau, A. B. Charette, J. Am. Chem. Soc. 2009, 131,
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[9] Selected examples: a) A. Zulys, M. Dochnahl, D. Hollmann, K.
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[10] R. Vicente, J. Gonzµlez, L. Riesgo, J. Gonzµlez, L. A. López,
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[11] a) M. J. Gonzµlez, L. A. López, R. Vicente, Org. Lett. 2014, 16,
5780; b) J. Gonzµlez, L. A. López, R. Vicente, Chem. Commun.
2014, 50, 8536; see also: c) B. Song, L.-H. Li, X.-R. Song, Y.-F.
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[12] For example, several studies reported a similar hybridization for
cyclopropenes and alkynes. See for example: a) F. H. Allen,
Tetrahedron 1982, 38, 645; b) A. Fattahi, R. E. McCarthy, M. R.
Ahmad, S. R. Kass, J. Am. Chem. Soc. 2003, 125, 11746.
[13] Selected recent reviews on cyclopropenes: a) L. H. Phun, J.
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Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117.
[14] Generation of metal carbenoid intermediates from cyclopro-
penes has been performed using precious metals. See: a) F.
Miege, C. Meyer, J. Cossy, Beilstein J. Org. Chem. 2011, 7, 717;
b) A. Archambeau, F. Miege, C. Meyer, J. Cossy, Acc. Chem.
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[15] The formation of vinylcyclopropanes through cyclopropanation
reactions involving zinc vinyl carbenoids generated from enals in
a stoichiometric process has been reported (see Ref. [6a]).
[16] a) L. Jiao, Z.-X. Yu, J. Org. Chem. 2013, 78, 6842; b) T. Hudlicky,
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Acknowledgements
Financial support from the Spanish MINECO (grant
CTQ2013-41511-P) is acknowledged. R.V. is a Ramón
y Cajal fellow.
Keywords: alkenes · carbenes · density functional calculations ·
small-ring compounds · zinc
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12139–12143
Angew. Chem. 2015, 127, 12307–12311
[1] 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.
[2] For selected reviews on cyclopropanes, see: a) C. J. Thibodeaux,
W.-C. Chang, H.-W. Liu, Chem. Rev. 2012, 112, 1681; b) M.-N.
Roy, V. N. G. Lindsay, A. B. Charette, Stereoselective Synthesis:
Reactions of Carbon-Carbon Double Bonds, Vol 1. (Science of
Synthesis) (Ed. J. G. de Vries), Thieme, Stuttgart, 2011, pp. 731 –
817; c) C. A. Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051;
d) F. Brackmann, A. de Meijere, Chem. Rev. 2007, 107, 4493.
[3] Originally used Zn/Cu couple was replaced by Et2Zn, which led
to more-reproducible results: J. Furukawa, N. Kawabata, J.
Nishimura, Tetrahedron Lett. 1966, 7, 3353.
[18] Cyclopropene derivatives used in this study were prepared from
olefins by a three-step sequence involving initial dibromocar-
bene addition, partial reduction, and a final base-promoted
dehydrohalogenation reaction. See: M. Rubin, V. Gevorgyan,
Synthesis 2004, 796.
[4] The synthesis of gem-diiodoalkanes is often problematic. For
selected examples, see: a) M. E. Furrow, A. G. Myers, J. Am.
Chem. Soc. 2004, 126, 5436; b) C. C. Gonzµlez, A. R. Kennedy,
E. I. León, C. Riesco-Fagundo, E. Suµrez, Angew. Chem. Int. Ed.
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[19] The gold-catalyzed reaction of 1a and 2a proceeded with lower
yield and selectivity. See: J. T. Bauer, M. S. Hadfield, A.-L. Lee,
Chem. Commun. 2008, 6405.
[20] Although the preference for the formation of cis isomers in the
cyclopropanation reactions of zinc vinyl carbenoids has been
reported (see Ref. [6a]), at present, we have no explanation for
such selectivity.
[24] See the Supporting Information for details of the computational
study.
[25] Participation of a typical SSC intermediate with haloalkylzinc
structure was also evaluated. Even though the Simmons–Smith-
type carbenoid structure could be formed from the structure C,
after an extensive search, no transition structure was located for
the cycloaddition with ethylene. Accordingly, we believe that
SSC-type species are not involved in this process. See the
Supporting Information for further details.
[21] The use of up to 100 equivalents of 2a did not lead to the
cyclopropanation product.
[22] This reactivity trend has been observed in gold-catalyzed
reactions of 3-arylcyclopropenes. See: a) Z.-B. Zhu, M. Shi,
Chem. Eur. J. 2008, 14, 10219; b) C. Li, Y. Zeng, J. Wang,
Tetrahedron Lett. 2009, 50, 2956.
[26] For additional trapping and competition experiments, see the
Supporting Information.
[23] The use of a large excess of 2a (25 equiv) allowed the formation
of the corresponding vinylcyclopropane in low yield (21%, d.r. =
10:1). For additional information, see the Supporting Informa-
tion.
Received: June 29, 2015
Published online: August 25, 2015
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