Tetrahedron 70 (2014) 4991e5031

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/tet

Tetrahedron report number 1043

Recent developments in the synthesis and reactivity of methyleneand alkylidenecyclopropane derivatives 
ne Pellissier *
Aix Marseille Universit
e, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France

a r t i c l e i n f o
Article history:
Received 30 January 2014
Received in revised form 7 April 2014
Accepted 18 April 2014
Available online 13 May 2014
Strained molecules



Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4992
Synthesis of methylene- and alkylidenecyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4992
Formation of the cyclopropane ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4992
From preformed cyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4996
Reactivity of methylene- and alkylidenecyclopropanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4998
Transition metal-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4998
Nickel-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4998
Rhodium-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5003
Gold-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5008
Palladium-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5012
Ruthenium-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5014
Copper-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5014
Other transition metal-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5015

Abbreviations: acac, acetylacetonate; Ad, adamantyl; AIBN, 2,20 -azobisisobutyronitrile; Ar, aryl; Bn, benzyl; Boc, tert-butoxycarbonyl; Bppf, 9,9-bis[4-(pyrenyl)phenyl]-9Hfluorene; Bs, p-bromobenzenesulfonyl (brosyl); Bz, benzoyl; Cod, cyclooctadiene; Cy, cyclohexyl; Dba, dibenzylideneacetone; DBU, 1,8-diazabicyclo[5.4.0]undecen-7-ene; DCE,
1,2-dichloroethane; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; de, diastereomeric excess; DIBAL, diisobutylaluminum hydride; DMAc, N,N-dimethylacetamide; DMF,
dimethylformamide; DMP, DesseMartin periodane; DMSO, dimethylsulfoxide; DOSP, N-(dodecylbenzenesulfonyl); E, electrophile; ee, enantiomeric excess; EWG, electronwithdrawing; Fu, furyl; HMDS, hexamethyldisilazide; Hept, heptyl; Hex, hexyl; IBAZ, isobutyl 2-oxoazetidin-4-carboxylate; L, ligand; LDA, lithium diisopropylamide; MAD,
methyl aluminium bis(2,4,6-tri-tert-butyl-4-methylphenoxide); MEM, 2-methoxyethoxymethyl; Mes, mesyl; MOM, methoxymethyl; MS, molecular sieves; Naph, naphthyl;
NBS, N-bromosuccinimide; NMO, N-methylmorpholine N-oxide; Ns, nosyl; Oct, octyl; Pent, pentyl; PFL, Pseudomonas fluorescens; PHANEPHOS, 4,12-bis(diphenylphosphino)[2.2]-paracyclophane; Phth, phthaloyl; Pin, pinacol; Piv, pivalate; rt, room temperature; TBAF, tetra-n-butylammonium fluoride; TBS, tert-butyldimethylsilyl; t-Bu-XPhos, 2-ditert-butylphosphino-3,4,5,6-tetramethyl-20 ,40 ,60 -triisopropyl-1,10 -biphenyl; TCE, 2,2,2-trichloroethanol; TEA, triethylamine; Tf, trifluoromethanesulfonyl; TFA, trifluoroacetic
acid; THF, tetrahydrofuran; TMEDA, tetramethylethylenediamine; TMS, trimethylsilyl; Tol, tolyl; TPAP, tetrapropylammonium perruthenate; Ts, 4-toluenesulfonyl (tosyl);
Xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
* Corresponding author. Tel.: þ33 4 91 28 27 65; e-mail address: h.pellissier@univ-amu.fr.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.


H. Pellissier / Tetrahedron 70 (2014) 4991e5031



Lewis and Brønsted acid-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5016
Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5016
Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5016
Miscellaneous reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5018
Thermal cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5020
Miscellaneous non-catalysed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5023
Radical reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5026
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5028
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5028
Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5031

1. Introduction
The importance of strained carbocycles has long been recognised in organic chemistry.1 In particular, organic chemists have
always been fascinated by the cyclopropane subunit,2 which has
played and continues to play a prominent role in organic chemistry.
Its strained structure, interesting bonding characteristics, and value
as an internal mechanistic probe have attracted the attention of the
physical organic community. Due to the limited degrees of freedom
in the system, these conformationally constrained molecules have
very pronounced steric, stereoelectronic and directing effects,
which make them versatile probes for the study of regio-, diastereo- and enantioselectivity.3 Furthermore, a diverse reactivity
pattern resulting from the significant strain energy accounts for the
use of small carbocycles as convenient models for the investigation
of organic and organometallic reaction mechanisms.4 The growing
interest in small carbocycles is also closely related to the fields of
medicinal and biological chemistry.5 Indeed, while the cyclopropane ring is a highly strained entity, it is nonetheless found in
a wide variety of naturally occurring compounds including terpenes, pheromones, fatty acid metabolites and unusual amino
acids.6 Cyclopropane subunits also occur in many natural products
of primary and secondary metabolism. Indeed, the prevalence of
cyclopropane-containing compounds with biological activity,
whether isolated from natural sources or rationally designed
pharmaceutical agents, such as among many others G1499-2,
amphimic acids, and 9-hydroxymethylcyclopropylidene-methylenyladenine,7 has inspired chemists to find novel and diverse approaches to their synthesis.8 Naturally occurring and synthetic
cyclopropanes bearing simple or complex functionalities are
endowed with a large spectrum of biological properties, including
enzyme inhibition, and insecticidal, antifungal, herbicidal, antimicrobial, antibiotic, antibacterial, antitumour and antiviral activities.9 It must be noted that methylenecyclopropane is the smallest
carbocycle with an exo-methylene moiety.10 A number of methylenecyclopropanes have been recently developed by the group of
Zemlicka as unusual analogues of nucleosides and established as
powerful antiviral agents against a broad range of viruses.11 Among
the class of cyclopropanes, methylene- and alkylidenecyclopropane
derivatives have been well documented as useful synthetic intermediates in organic chemistry over the past few decades. Arguably, the chemistry of these compounds is the most rapidly
developing among all small-ring compounds. Indeed, alkylidenecyclopropanes and methylenecyclopropanes are highly interesting
compounds. Surprisingly, in spite of their highly strained structure
(40 kcal mol1), they usually exist as stable compounds at room
temperature, allowing their use in many synthetic applications
with an otherwise unattainable chemical reactivity. Because of this
strained nature, associated with a large structural differentiation
available, methylene- and alkylidenecyclopropanes show various
reactivities and have long been widely used in organic synthesis for
their enormous potential,12 in particular to achieve heterocycles.13

In this context, numerous efficient and straightforward syntheses
of different types of methylene- and alkylidenecyclopropanes have
appeared in the literature.12b,14 The goal of the present review is to
cover the recent advances in the synthesis and reactivity of methylene- and alkylidenecyclopropane derivatives, focussing on those
published in the last four years. This area was previously reviewed
by Guo and Yu in 2011, covering the literature until the beginning of
2010.12b This review is subdivided into two parts, dealing successively with the synthesis and the reactivity of methylene- and
alkylidenecyclopropanes. The first part is subdivided into two
sections, according to the different methods employed to prepare
these compounds, such as those based on the formation of the
cyclopropane ring, and those based on the use of preformed cyclopropane ring. The second part of the review is subdivided into
five sections, according to the different types of reactions, such as
transition metal-catalysed reactions, Lewis and protic acidcatalysed reactions, thermal cycloadditions, miscellaneous noncatalysed reactions and radical reactions.
2. Synthesis of methylene- and alkylidenecyclopropanes
Since the methylenecyclopropane moiety is found in many biologically active natural substances, the synthesis of methyleneand alkylidenecyclopropanes remains a considerable challenge. In
addition, their attractive feature is their surprising stability, accompanied by a high level of strain, conferring on them an otherwise unattainable chemical reactivity. The growing interest in the
chemistry of these compounds has in its turn stimulated the development of alternative approaches to their skeleton, aimed at
selectively introducing structural and chemical diversification. The
two principal methods to synthesise these important compounds
are based on the formation of the cyclopropane ring, and the use of
preformed cyclopropanes. During the last several years, chemists
have developed various novel reactions leading to methylene- and
alkylidenecyclopropanes. The last methodologies allowing a more
direct access to these structures are collected in this section.
2.1. Formation of the cyclopropane ring
The carbene (or carbenoid) addition to unsaturated compounds
is undoubtedly the most useful and straightforward preparative
method for alkylidenecyclopropane derivatives. It is one of the first
general methods thoroughly applied for the assembly of the alkylidenecyclopropane moiety, with reports appearing since the early
1960s. There are two variants for these addition reactions, which
are the addition of alkylidenecarbenes to olefins, and the addition
of generated carbenes to allenes, as summarised in Scheme 1.
The first variant for preparative method for alkylidenecyclopropane derivatives consists in the addition of alkylidenecarbenes
to olefins, and has been investigated for more than 40 years. It must
be noted that, however, most of the work reported on this subject
has been focused on mechanistic and theoretical aspects with the

H. Pellissier / Tetrahedron 70 (2014) 4991e5031

Scheme 1. Two variants for carbene additions.

aim of determining the intermediary of an alkylidenecarbene
species and its nature,15 rather than on a synthetic perspective.
However, many procedures able to furnish good yields of a variety
of rather unusual alkylidenecyclopropanes have been developed, so
that this method can be synthetically very useful. The alkylidenecarbene species have been generated through a great variety of
methods, the majority of which consists in 1,1-eliminations from
substituted alkenes, either base-, thermally-, or photochemicallyinduced, depending on the nature of the starting substrate. The
second variant for preparative method for alkylidenecyclopropane
derivatives, consisting in the addition of variously substituted carbenes or carbenoid systems to allenes, has also been extensively
developed. The methylenecarbene required for the cyclopropanation of the allene can be generated by decomposition of
a diazomethane. It is well known that the cyclopropanation of
olefins using the transition-metal-catalysed decomposition of
diazoalkanes is one of the most extensively studied reactions in the
organic chemist’s arsenal.16 Indeed, the synthesis of cyclopropanes
by transition-metal-mediated carbene transfer from aliphatic diazo
compounds to carbonecarbon double bonds is not only a major
method for the preparation of cyclopropanes, but is also among the
best developed and most general methods available to the synthetic organic chemist.17 Highly effective and stereocontrolled
syntheses of functionalised cyclopropanes have been achieved, in
particular, with catalysts based on copper, ruthenium, and rhodium. On the other hand, the synthesis of optically active methylene- and alkylidenecyclopropanes is still limited, which represents
a limitation for the development of their chemistry. The first example of asymmetric synthesis of chiral methylenecyclopropanes
was reported by Noyori et al., dealing with the cyclopropanation of
phenylallene with diazomethane catalysed by a chiral copper
complex.18 The observed asymmetric induction was, however, very
poor (12% ee). Since this preliminary result, there have been
few reports on the degree of enantioselectivity that might be
feasible given the wide array of available chiral catalysts. Among
recent examples, Gregg et al. reported high enantioselectivities
of up to 90% ee for the reaction of a series of monosubstituted
allenes with methyl aryldiazoacetates mediated by rhodium tetraprolinate catalyst, Rh2(S-DOSP)4.19 In this study, monosubstituted
alkyl- and arylallene substrates provided the corresponding
methylenecyclopropanes in 54e76% yields while yields for 1,1disubstituted allenes were generally significantly lower (30e33%).
The authors explained these reduced yields by the fact that a simple
alkene can approach the carbenoid face in a concerted transition
state and project the substituents away from the reactive centre,
whereas the 1,1-disubstituted allene would project one of its
groups away from, and one towards, the approaching carbenoid. In
this hypothesis, a second group on the allene, even a methyl group,
slows the cyclopropanation to the point that the diazoacetate
competes more successfully for the carbenoid, resulting in decreased yield and increased byproduct. On the other hand, the
cyclopropanation of 1-methyl-1-(trimethylsilyl)allene with parabromophenyl methyldiazoacetate proceeded in higher yield (79%)
than the other 1,1-disubstituted substrates, suggesting a rate enhancement mediated by a significant b-silicon effect despite the
steric hindrance. Therefore, it was demonstrated that the silyl


substituent was responsible for a more than 10-fold increase in the
cyclopropanation rate compared to the methyl substituent. Considering the rate acceleration provided by a silyl group, the authors
investigated later the possibility of performing enantioselective
cyclopropanation on 1,3-disubstituted allenes.20 Such reactions led
to alkylidenecyclopropanes exhibiting an additional chiral centre.
As shown in Scheme 2, it was found that 1-(trimethylsilyl)-1,2butadiene reacted with para-bromophenyl methyldiazoacetate in
the presence of Rh2(S-DOSP)4 to provide the corresponding chiral
alkylidenecyclopropane as a single regio- and diastereomer in
enantioselectivity of 91% ee. On the other hand, in the case of 1,3disubstituted allenes without a silyl substituent, it was shown
that rate and regioselectivity were compromised since they gave an
inseparable mixture of cyclopropanation products, indicating limited differentiation of the two ends of the allene in the reaction.
This work constitutes a major contribution reported in the last few
years dealing with the synthesis of alkylidenecyclopropanes in
remarkable diastereo- and enantioselectivities with the advantage
of using a low catalyst loading.

Scheme 2. Enantioselective rhodium-catalysed addition of para-bromophenyl methyldiazoacetate to allenes.

While Gregg et al. reported this elegant enantioselective
rhodium-catalysed cyclopropanation of allenes with aryldiazoacetate (Scheme 2), no catalytic enantioselective method has been
described for the synthesis of diacceptor alkylidenecyclopropanes
until 2013, which has prohibited their use as chiral precursors for
asymmetric synthesis for a long time. In light of this, Charette et al.
recently investigated the scope of accessible racemic products using
aryl- and alkylallenes as substrates with a variety of diacceptor
diazo reagents in the presence of Rh2(OPiv)4 as an achiral catalyst.21
Presumably due to the low nucleophilicity of allenes, only the most
reactive cyano-substituted carbenes provided useful amounts of
the corresponding alkylidenecyclopropane products with a-cyano
diazo esters, affording the highest yields of up to 99% (Scheme 3).
Remarkably, it must be noted that for all aromatic allenes evaluated,
only the E-alkene of the product was observed. These studies have
permitted the authors to identify a-cyano diazo tert-butyl ester as
an ideal substrate for investigating the asymmetric version of this
novel methodology of rhodium-mediated alkylidenecyclopropanation of allenes. Therefore, the authors have demonstrated that
using Rh2(S-IBAZ)4 as chiral catalyst under mild conditions allowed
a range of chiral diacceptor alkylidenecyclopropanes to be achieved
in moderate to high yields (29e92%) in combination with generally
high enantioselectivities of up to 97% ee and good to high diastereoselectivities of 60e94% de in favour of the E-diastereomers, as
shown in Scheme 3.
This nice work constituted the first catalytic enantioselective
synthesis of diacceptor alkylidenecyclopropanes and probably
represents along with that described in Scheme 2 ones of the best


H. Pellissier / Tetrahedron 70 (2014) 4991e5031

Scheme 3. Rhodium-catalysed additions of diacceptor diazo compounds to allenes.

contributions reported in the last four years dealing with the synthesis of alkylidenecyclopropanes.
On the other hand, Schomaker et al. recently reported a coppercatalysed intramolecular cyclisation of highly substituted allenecontaining diazomalonates into the corresponding bicyclic alkylidenecyclopropanes.22 As shown in Scheme 4, the success of this
cyclopropanation was quite sensitive to the steric environment of
the allene. Therefore, yields were moderate to good (up to 77%) for
1,3-disubstituted substrates, while a 1,3,3-trisubstituted allene
gave a poor yield (23%). High E/Z ratios of up to 96:4 were generally
obtained. Interestingly, additional substitution in the tether between the allene and the diazo group greatly increased the E/Z
ratios. The authors have demonstrated that using a rhodium catalyst instead of CuI promoted a divergent reactivity of the allenic
diazomalonate, generating an allene bearing a pendant lactone or
cyclopentanone as the final product.

Scheme 4. Cu-catalysed intramolecular cyclisation of allene-containing diazomalonates.

Buono et al. have demonstrated that palladium(II) complexes
stabilised by secondary phosphine oxide ligands catalysed a very
unique [2þ1] cycloaddition of norbornene derivatives with various
terminal alkynes to afford functionalised alkylidenecyclopropanes.23
As an extension of this work, the authors have recently developed palladium-catalysed [2þ1] cycloadditions of norbornadienes or norbornenes with various ynamides, affording the
corresponding aminomethylenecyclopropanes in moderate to high
yields of up to 88%.24 As shown in Scheme 5, the conditions were
successfully applied to a range of bicyclo[2.2.1]hepta-2,5-diene
derivatives and bicyclo[2.2.1]hept-2-ene derivatives. In the case of
norbornadiene substrates, the reaction always occurred on the less
hindered double bond. It must be noted that 7-oxygen substituted

Scheme 5. Pd-catalysed [2þ1] cycloadditions of norbornadienes and norbornenes
with ynamides.

norbornadienes were tolerated but led to moderate yields
(45e61%) or longer reaction times compared to electron-rich
substituted equivalents. On the other hand, 1,4-dihydro-1,4epoxynaphthalene and 1,4-dihydro-1,4-ethanonaphthalene did
not lead to the corresponding tricyclo[,4]oct-6-enes. In the
case of norbornene substrates, the reactivity was found to be lower.
Furthermore, these authors have developed an enantioselective
version of the palladium-catalysed reaction between norbornadiene and yne phenyl sulfonamide by using a chiral phosphapalladacycle.24 Whereas the reaction proceeded smoothly at room
temperature, giving the corresponding product in 80% yield, the
chiral induction observed remained modest (21% ee).
In addition to ynamides, a range of alkynes have been succesfully
submitted to [2þ1] cycloaddition with norbornadienes, however,
phenyl- and alkyl-substituted alkynes were used in mot cases. In
2013, Hou et al. demonstrated that high yields of up to 88% could be
reached by using alkyl as well as phenyl propiolates or ethynyl
amide as alkyne partners in reaction with a range of 7-oxa and
7-azanorbornadienes in the presence of a palladacycle as catalyst, as
shown in Scheme 6.25 The authors have proposed the mechanism
depicted in Scheme 6 to explain the results, in which the reaction of
the palladacycle with the propiolate produced alkynylpalladium(II)
1, which added to the oxabicyclic alkene to form intermediate 2.
Intermediate 2 evolved through an intramolecular insertion to form
intermediate 3, which underwent intermolecular protonolysis to
release the final product and the palladacycle catalyst.
In another context, Harada et al. have reported an alkylative
carbocyclisation reaction of 4-iodobut-1-ynyl tosylates with gemdisubstitution with alkynyllithium compounds to give the corresponding (Z)-(1-iodoprop-2-ynylidene)cyclopropanes in moderate
to high yields (37e80%).26 Indeed, high Z-selectivity was observed
when the kinetically favourable Z-isomers were not prone to isomerising to the thermodynamically more stable E-isomers, with
observed Z/E diastereomeric ratios of up to 94:6. In order to explain
their results, the authors have proposed the carbenoid-chain
mechanism depicted in Scheme 7 in which the formation of the
product implied the generation of TsO,Li-cyclopropylidenecarbenoid
4 through the exo-cyclisation of lithium acetylide 5. Then, the
vinylic substitution of 4 by 1-hexynyllithium gave alkenyllithium

preparation of strained three-membered rings has remained a considerable challenge. A plausible mechanism is illustrated in Scheme 8. The subsequent reductive elimination from 9 yielded the final product and regenerated the initial palladium complex. Pellissier / Tetrahedron 70 (2014) 4991e5031 4995 intermediate 6. which guaranteed the exclusive stereocontrol of the resulting double bond. Pd-catalysed [2þ1] cycloaddition of norbornadienes with propiolates or ethynylamide.28 Under palladium/Xantphos catalysis in the presence of caesium carbonate. Scheme 7. Pd-catalysed arylative cyclisation of propargyl-substituted malonate esters with aryl halides. Palladium-catalysed intramolecular arylative cyclisation of unsaturated compounds having a nucleophilic moiety with aryl halides represents an attractive method to construct cyclic compounds. Cycloisomerisation of iodobutynyl tosylates with alkynyllithium compounds. Scheme 6. which was subsequently iodinated with 1-iodo-1hexyne to give the final product. Scheme 8. involving the initial oxidative addition of the aryl halide to zerovalent palladium to afford arylpalladium bromide or triflate 7. evolving through anti-carbopalladation pathway. Oshima et al. the process allowed a range of alkylidenecyclopropanes to be achieved in good to high yields (53e91%). .H. Deprotonation of the acidic methine proton by caesium carbonate induced intramolecular cyclisation onto the activated alkyne to form vinylpalladium 9 through anti-carbopalladation. have developed a novel stereoselective synthesis of alkylidenecyclopropanes based on a palladium-catalysed reaction of propargyl-substituted malonate esters with aryl halides.27 Although the method has provided a number of five-membered cyclic compounds so far. In this context. as shown in Scheme 8. Intermediate 7 then activated the alkyne moiety of the malonate through p-coordination. The scope of the reaction was wide since arylbromides as well as aryltriflates reacted with a range of malonates having either an alkyl or an aryl moiety.

31 In 2010.and alkylidenecyclopropanes. Scheme 9. which took up a t-BuOH molecule generated during the process to give intermediate 11. Nucleophilic displacements of substituted cyclopropenes by Grignard reagents to give the corresponding alkylidenecyclopropanes have also been successfully achieved by Marek et al. the same authors have developed a novel efficient methodology to achieve methylenecyclopropanes from the corresponding terminal cyclopropenes based on a one-pot sequential alkylation/base-promoted rearrangement reaction. Therefore. .30 As shown in Scheme 10. which was subsequently submitted to a thermal rearrangement.2-disubstituted 3(hydroxymethyl)cyclopropenes and various Grignard reagents. Synthesis of methylenecyclopropane analogues of nucleosides through elimination of HCl. From preformed cyclopropanes The formal elimination of a hydrohalic acid from a preformed substrate containing a cyclopropyl ring is one of the most common processes for the synthesis of methylene. an alkyl-halo-substituted cyclopropane undergoes HX elimination by treatment with a base. while CuBr$SMe2 was found to be the catalyst of choice for the addition of aryl Grignard reagents. Pellissier / Tetrahedron 70 (2014) 4991e5031 2. For example.34 As shown in Scheme 12. Nucleophilic displacements of substituted cyclopropenes have been reported to lead to methylene. The authors showed that the best results for the addition of alkyl and allyl Grignard reagents were reached by using CuI as catalyst. and heating the reaction mixture at 35  C. high syn-diastereoselectivities of up to >90% de were observed. Audran et al. they demonstrated that it was possible to obtain the methylenecyclopropane depicted in Scheme 13 in 73% yield by forming the dianion of 1-hexyl-3-hydroxymethylcyclopropene in THF by treatment with a base. have employed this methodology to synthesise the bicyclic methylenecyclopropane depicted in Scheme 9 in 76% yield starting from a 4:1 diastereomeric mixture of the corresponding chlorocyclopropane.or alkylidenecyclopropane. such as MeLi in the presence of TMEDA as an additive. Fox et al. In another context. and then adding an electrophile. Synthesis of chiral alkylidenecyclopropanes through a one-pot sequential carbomagnesation/1. Generally. yielding the corresponding methylene. Subsequent dehydrochlorination of the latter intermediate led to the final methylidenecyclopropane. Fox et al. have previously developed a regio. the domino reaction began with the elimination of a phenol molecule with formation of the corresponding highly reactive chloro(methyl)cyclopropene 10.35 Indeed. these authors reported a stereospecific synthesis of chiral alkylidenecyclopropanes via sequential cyclopropene carbomagnesation/1. Zefirov et al.29 This methylenecyclopropane was further converted into the corresponding enantiopure acetic acid 2hydroxymethyl-3-methylenecyclopropylmethyl ester.3-carbon shift reaction.32 The first step of the sequence consisted in a nucleophilic displacement with the Grignard reagent to give the corresponding methylenecyclopropane. Synthesis of tert-butoxy-substituted methylenecyclopropane through a domino elimination/addition/elimination reaction. Scheme 12. evolving through complete inversion of the stereochemistry.and diastereoselective synthesis of chiral methylenecyclopropanes based on the reaction between chiral cyclopropene derivatives and Grignard reagents. In recent years. As shown in Scheme 11. Scheme 11. constituting a key synthon in the synthesis of three novel antiviral nucleoside analogues (Scheme 9).and alkylidenecyclopropanes could be prepared on the basis of this methodology by using t-BuOK or TEA as a base. a range of highly substituted methylenecyclopropanes could be diastereoselectively prepared in good to high yields (48e91%) from the corresponding 1. such as KOt-Bu.33 In 2013. such as MeI. In 2013. Scheme 10.and alkylidenecyclopropanes. which unexpectedly produced tert-butoxy-substituted methylenecyclopropane as a single product in 48% yield. reported the dehydrochloration of 1chloro-1-methyl-2-phenoxycyclopropane with t-BuOK in DMSO. expanded the scope of these reactions to 1-(alkoxymethyl)cyclopropenes. high to excellent levels of chirality transfer of up to >99% ee were observed.3-carbon shift reaction of chiral 3-hydroxymethyl1-methoxyethoxymethoxymethyl-3-phenylcyclopropene with alkyl Grignard reagents.2-disubstituted 3-(hydroxymethyl)cyclopropenes with Grignard reagents. in the presence of a catalytic amount of CuI. Synthesis of highly substituted methylenecyclopropanes through Cu-catalysed reaction of 1.2.4996 H. a number of methylene. This work has revealed previously unknown formal nucleophilic substitution of phenoxy group in cyclopropane ring by the action of t-BuOK.

the cyclopropane ringopening of intermediate 13 took place. the reaction of this dibromide with a purine. However.and E-methylenecyclopropanes in moderate to excellent yields. Compared to methylenecyclopropanes. In this context. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 13. It was shown that the electronic property of the aryl group did not have significant impact on the reaction outcomes. The authors have proposed the plausible mechanism depicted in Scheme 14 for the formation of these dimethylenecyclopropane aldehydes. vinylidenecyclopropanes exhibit a higher reactivity related to higher strain energy and the presence of the allene moiety and consequently the investigations on these molecules are even more challenging. In the oxidative isomerisation process. Shi et al.and E-diastereomers. Therefore. leading to the formation of intermediates 14 and 15. Scheme 15. .36 Reports on isomerisation of vinylidenecyclopropanes into dimethylenecyclopropanes under mild conditions remain rare. most of them took place upon heating at high temperatures (130e160  C). as shown in Scheme 15.11 A number of these biologically important first-generation methylenecyclopropane analogues of nucleosides have been prepared from ethyl 2bromo-2-bromomethylcyclopropane-1-carboxylate (R1¼Br. It was demonstrated that the biological activities generally resided in the Z-isomers of the purine derivatives Scheme 14.H. Scheme 16) on the basis of a one-pot alkylation/elimination sequence. which underwent recyclisation to afford the final dimethylenecyclopropane aldehyde along with regeneration of ruthenate(V) species. affording the corresponding alkylidenecyclopropanes in high yields. In the last decade. a wide number of nucleoside analogues based on a methylenecyclopropane structure have been synthesised by the group of Zemlicka with the aim of evaluating their broad-spectrum antiviral activities. DBU-mediated intramolecular isomerisation of arylmethylcyclopropenes to alkylidenecyclopropanes. Synthesis of a methylenecyclopropane through a one-pot sequential alkylation/rearrangement reaction. performed in the presence of K2CO3 in DMF. developed an interesting base-mediated intramolecular isomerisation of arylmethylcyclopropenes under mild conditions. the starting primary alcohol reacted rapidly with the tetrahedral perruthenate ion [RuVIIO4] to give an alkoxyperruthenate ion 12. R2¼H. R3¼CO2Et.38 It must be noted that in almost all cases of substrates studied.37 As shown in Scheme 14. provided a mixture of the corresponding Z. 4997 In 2013.39 The subsequent reduction of these products by treatment with DIBAL furnished the expected corresponding nucleoside analogues as mixtures of Z. After a quick hydrogen migration. Shi and Lu recently described the first example of an oxidative isomerisation of vinylidenecyclopropanes to dimethylenecyclopropanes using tetrapropylammonium perruthenate (TPAP)/4methylmorpholine N-oxide (NMO) as an efficient catalytic system under mild conditions. the presence of the arylmethylene group was required for the reaction. Only organic bases were efficient in this process with the best results reached by using DBU as organic base in THF as the solvent of choice. Oxidative isomerisation of vinylidenecyclopropanes to dimethylenecyclopropanes. a range of products were achieved in moderate to good yields (62e72%) along with high Z/E ratios of up to 95:5. only the E-diastereomer was obtained.

This methodology was applied by Zemlicka et al. Synthesis of second-generation methylenecyclopropane nucleoside analogues through alkylation/elimination method. A Scheme 17.50.and stereoselective construction of new rings by simple addition of two or more generally simple and readily available molecules. these authors have developed a novel nickel-catalysed [3þ2þ2] cycloaddition between alkylidenecyclopropanes and various activated alkenes.43 3. In general. opening the way for improved reactivity and novel chemistry. to give through a two-stage one-pot reaction the corresponding methylenecyclopropane in 65% yield as a 1:1 mixture of Z. and maximisation of efficiency are some of the more relevant challenges for the new age of organic synthesis.46 Reduction in the number of synthetic steps.44 Over the past few decades. occupy a central position among the available tools of synthetic organic chemistry.45 3. Undoubtedly. which requires a more complicated synthesis to execute with good enantiomeric excess.6-diaminopurines.and alkylidenecyclopropanes has been widely explored in the presence of transition metal catalysts. fewer cycloaddition reactions are available for the synthesis of seven-membered carbocycles.51 the current method provided complementary. 2-amino-6alkoxypurines. occupy a leading position among the tools available to the synthetic chemist that best meet the above requirements. The synthesis and subsequent development of these firstgeneration products have been complicated. have recently developed various transition-metal-catalysed cycloaddition reactions of alkylidenecyclopropanes. or alkyne significantly modifies the reactivity of this moiety. In this case.48 Compared to the rich chemistry of the cycloaddition reactions available for the synthesis of sixmembered carbocycles. particularly in the field of cycloadditions. Moreover.14a. commercially available 2-amino-5-chloropurine reacted with the dibrominated diester depicted in Scheme 17 in the presence of a base. Reactivity of methylene.1.40 In 2013.41 These products were also generated through sequential alkylation/elimination reaction according to Zemlicka’s methodology and further evaluated for antiviral activities. Synthesis of first-generation methylenecyclopropane nucleoside analogues through alkylation/elimination method. which eliminate this chiral centre by adding a second hydroxymethyl group to the cyclopropyl ring has been further synthesised by the same authors and tested for antiviral activity.4). mainly those that employ unusual conditions.1.1. allowing a wide number of complex natural products and important biologically active products featuring relatively complex polycyclic skeletons to be achieved. synthetically useful 6. such as DBU.and E-diastereomers. the nickelcatalysed reactions are more economical. whereas the E-isomers were generally ineffective. Metal catalysts provide new opportunities for highly selective cycloaddition reactions since complexation of the metal to an olefin. reported the synthesis of a wide range of novel monohydroxymethyl methylenecyclopropane nucleoside analogues bearing ether and thioether substituents at the 6-position of the purine.7-fused bicyclic . the chemistry of methylene.and stereocontrolled fashion. by the presence of a chiral centre in the molecule. Prichard et al. cycloadditions are of unique value for increasing molecular complexity and thereby achieving step brevity.49 In contrast to previous palladium. a potential prodrug of antiviral cyclopropavir starting from 2-amino-6chloropurine methylenecyclopropane. Many of these reaction conditions require the presence of polarised functional groups in the substrate to facilitate the transformation. nickel is an efficient catalyst for organic synthesis. the reaction of unactivated substrates is notoriously poor and extreme conditions or special methods are necessary to achieve good yields in cycloadducts. or thiolates. Cycloaddition reactions.4998 H. which provided cycloadducts arising from the distal opening of the cyclopropane (Sections 3. In this context. The catalysis of organic reactions by metals still constitutes one of the most useful and powerful tools in organic synthesis. allowing a range of polycarbocyclic structures to be achieved. diene. minimisation of waste production.and alkylidenecyclopropanes. Mascarenas et al. Indeed. or 2-amino-6-alkylthiopurines in moderate to high yields (Scheme 17). providing the corresponding 2.13.2 and 3.47 In this context.and rhodium-catalysed cycloadditions of alkylidenecyclopropanes.1. to the synthesis of 6-deoxycyclopropavir. among the classes of reactions. Pellissier / Tetrahedron 70 (2014) 4991e5031 subsequent displacement of the 6-chloro group on the purine of this diol was readily achieved with amines. Transition metal-catalysed reactions Scheme 16. which allow two new bonds to be formed in one operation in a regio. As an example. nickel-catalysed reactions have recently attracted the interest of chemists. however. Situated in the same column as palladium. In the field of methylene.42 The chemistry used to synthesise these secondgeneration methylenecyclopropanes has been adapted from that of the first-generation methylenecyclopropanes.1. Nickel-catalysed reactions. cycloaddition reactions. alkoxides. because it is much cheaper than palladium. due to their unique structural and electronic properties. Some of these analogues showed a broader spectrum of antiviral activity than cyclopropavir. This mixture was further submitted to saponification to afford the corresponding diol. a second generation of methylenecyclopropane nucleoside analogues. by virtue of allowing the regio.and alkylidenecyclopropanes 3.

3-diynes were compatible to the process. the process afforded the corresponding highly functionalised cycloheptadienes in moderate to good yields (32e80%). Pellissier / Tetrahedron 70 (2014) 4991e5031 systems.3-diynes and an ynol ether.52 As shown in Scheme 20.5-fused polycyclic systems. under almost similar reaction conditions.52 The process was induced by [Ni(cod)2] in the presence of a ligand such as PPh3. In order to explain the formation of these products. Furthermore. acrolein and phenyl vinyl sulfone. The subsequent insertion of ethyl cyclopropylideneacetate followed by a rearrangement would provide the final product. an alkyl or a methylenealkoxy substituent on the alkyne to give the corresponding cycloadducts in low to excellent yields of up to 96%. In another context. In the same area. 4999 As an extension of the precedent [3þ2þ2] cycloaddition methodology. reacted in the presence of [Ni(cod)2] with yne-alkylidenecyclopropanes bearing an ester. general and efficient method for the synthesis of cyclopenta[a]indenes. As shown in Scheme 19.and alkylidenecyclopropanes with arylalkynes. [3þ2þ2] Cycloaddition of ethyl cyclopropylideneacetate with ynol ethers and three-component reaction of ethyl cyclopropylideneacetate with an ynol ether and 1. the authors have proposed that a nickelacycle was generated from the ynol ether and the 1. It must be noted that symmetrical as well as unsymmetrical 1.53 The lowest-energy pathway involved the formation of a p-complex between the methylenecyclopropane moiety and the nickel atom and occurred through a sequence of ring-opening and ring-closing reactions with CeC bond formation as the rate-determining step. Saito et al.3-diynes. A plausible mechanism depicted in Scheme 21 was proposed by the authors in which the reaction began with the oxidative addition of nickel(0) to the proximal CeC s bond of the cyclopropylalkene to give a nickelacyclobutane species. providing a novel.3diynes were compatible to the process. both monosubstituted and disubstituted methylenecyclopropanes underwent the reaction smoothly in the presence of [Ni(cod)2]/PPh3 as catalyst system.3-diynes. [3þ2þ2] Cycloaddition of ethyl cyclopropylideneacetate with ynamides or an ynamine and three-component reaction of ethyl cyclopropylideneacetate with an ynamine and 1. have reported a novel nickelcatalysed intramolecular cycloaddition of methylene. various alkenes. for the first time. Scheme 18. In the same study.3-diyne and an ynamide or an ynamine provided the corresponding highly functionalised cycloheptadienes as single products in good yields (53e66%). . Scheme 20. to explore the complete reaction mechanism of the nickel-catalysed [3þ2þ2] cycloaddition of ethyl cyclopropylideneacetate and alkynes.54 Indeed. This work constituted the first nickelcatalysed [3þ2þ2] cycloaddition involving nonactivated alkylidenecyclopropanes. providing the corresponding cycloheptadienes. resulting from cleavage of the proximal bond of the ring. ethyl acrylate. the authors have also investigated the nickelcatalysed [3þ2þ2] cycloaddition of ethyl cyclopropylideneacetate with an ynamide or an ynamine. occurring through the cleavage of proximal CeC bond. the authors have investigated the three-component cocyclisation of ethyl cyclopropylideneacetate with 1. DFT calculations were employed by Wang et al. have developed nickel-catalysed [3þ2þ2] cycloaddition of ethyl cyclopropylideneacetate with heteroatom-substituted alkynes.H. this other type of heteroatom-substituted alkynes were compatible substrates for this reaction since the corresponding cycloadducts were achieved in good yields (36e72%). Zhang et al. It must be noted that symmetrical as well as unsymmetrical 1. the threecomponent reaction between ethyl cyclopropylideneacetate.3-dione derivatives by treatment with TFA in moderate to good yields (20e82%). As shown in Scheme 18. [3þ2þ2] Cycloaddition of yne-alkylidenecyclopropanes with activated alkenes. such as methyl vinyl ketone. The crucial conversion of nickelacycloheptadiene to an eightmembered nickelacycle was suggested to occur in a stepwise mechanism instead of the previously proposed cyclopropenylbutenyl rearrangement. which were achieved in moderate to high yields (32e84%). In 2012. an aryl ring moiety was employed as the linker of methylenecyclopropanes and alkynes. As shown in Scheme 21.3-diyne. which were further converted into more stable cyclohept-4-ene-1. a 1. The subsequent intramolecular addition of this intermediate into the CeC triple bond generated the corresponding six-membered nickel cycle. leading to the formation of valuable 5. which underwent the reductive elimination to liberate the final cyclopenta[a]indene with regeneration of the nickel(0) catalyst. Scheme 19.

Pellissier / Tetrahedron 70 (2014) 4991e5031 membered carbocycles were produced in moderate to high yields as mixtures of E.and Z-isomers by using [Ni(cod)2]/PPh3 as catalyst system. beginning with the oxidative cyclisation of the enone with a nickel(0) complex to furnish oxanickelacycle 16. . the reaction was initiated by the oxidative cyclisation of the enone with nickel(0) complex to furnish a five-membered oxa-nickelacycle. Matsubara et al. insertion of the alkylidenecyclopropane to a carbonenickel bond of intermediate 16 was followed by ring Scheme 21. which further incorporated the alkylidenecyclopropane as a one-carbon fragment. Then. [4þ1] Cycloaddition of alkylidenecyclopropanes with enones. a range of nine- Scheme 22. the use of PMe2Ph as ligand instead of an iminophosphine ligand provided higher yields and also higher regioselectivities. and the right choice of the linker improved the yield of the reaction. reported a novel nickel-catalysed [4þ1] cycloaddition of enones with alkylidenecyclopropanes. The synthesis of nine-membered carbocyclic compounds by transition-metal-catalysed cycloadditions remains a very challenging issue. In 2011. Scheme 23.and alkylidenecyclopropanes with arylalkynes.56 Induced by [Ni(cod)2] in the presence of a phosphine ligand. In this context.55 As shown in Scheme 22. It was shown that the linker moiety played an important role in the efficiency of the reaction by keeping the alkyne and diene moieties in positions necessary to their effective reaction. leading to dihydrofurans in moderate to excellent yields of up to 99% (Scheme 23). [4þ3þ2] Cycloadditions of ethyl cyclopropylideneacetate with dienynes. Intramolecular cycloaddition of methylene. A plausible mechanism for this reaction is depicted in Scheme 23.5000 H. have reported a novel synthesis of this type of products based on a nickel-catalysed [4þ3þ2] cycloaddition reaction of ethyl cyclopropylideneacetate with various dienynes. Generally. Saito et al.

Scheme 24. their use as C1 synthetic units offer an advantage in introducing a quaternary carbon directly into a ring system.6-di-tert-butyl-4-methylphenoxide) (MAD). transition metal-catalysed ringopening reactions of alkylidenecyclopropanes have been widely explored over the past decades. which stemmed from the [3þ3] cyclodimerisation reaction of ethyl cyclopropylideneacetate. metal halides. while the addition of vinylmagnesium chloride provided the distal cleavage ones. but also troublesome. the regioselectivity of the ring-opening reaction is one of the attractive issues in exploring this field of chemistry. Lewis acids. With its cyclopropane unit. In this context. To explain these results. for the reactions with unsymmetrical alkylidenecyclopropanes. providing the corresponding cyclohexane derivatives in excellent yields.and alkylidenecyclopropanes is their diverse reactivities that may lead to the formation of a variety of products through the addition to a C]C double bond and cleavage of proximal or distal bonds of the three-membered ring. and the selectivity is controlled by the selection of the metal reagents or catalysts and/or the structure of the cyclopropane substrates. the regiochemistry generally affords different possible products. along with the corresponding [3þ2] cycloadducts as byproducts (Scheme 25). The methylenecyclopropane was then inserted into the thioenickel bond to 5001 give intermediate 22. Pellissier / Tetrahedron 70 (2014) 4991e5031 expansion to form eight-membered oxa-nickelacycle 18 via a cyclopropylmethylehomoallyl metal type rearrangement. a mechanism depicted in Scheme 24 was proposed by the authors. which allows methylenecyclopropanes to behave as if they were carbene species. Methylene. sulfonamides. Teral et al.2-bis(exo-alkylidene)cyclohexane ligand. Subsequent b-hydride elimination afforded acyclic intermediate 19. alcohols. which was then submitted to a reductive elimination to afford the final product. In particular. carboxylic acids. On the other hand. water. An attractive.58 Scheme 25. Indeed. Reductive elimination afforded the final product and regenerated the starting Ni(0) complex. The reaction could be expanded to a Ni(0)-catalysed [3þ3] cyclodimerisation reaction of estersubstituted methylenecyclopropanes. beginning with the oxidative addition of the thioanhydride to nickel(0) and a subsequent decarbonylation.60 Depending on the nature of the Grignard reagent. [3þ3] Cyclodimerisation of ester-substituted methylenecyclopropanes. in 2011. So far.59 Ring-opening reactions of methylene.E)-1. intermediate 23 provided the thermally more stable six-membered nickelacycle 24. feature of methylene. Indeed. etc. the carbonenickel bond underwent a facile cyclopropylmethylehomoallyl metal-type rearrangement to furnish nickelacycle 23. As shown in Scheme 24. Moreover. The authors have proposed the mechanism depicted in . After b-hydride elimination and insertion of the newly formed hydrideenickel bond to the carbonecarbon double bond. These reactions can be achieved by using transition metal catalysts. and also Brønsted acids. have reported a nickel-catalysed addition of Grignard reagents to methylenecyclopropanes. methylenecyclopropanes reacted with thioanhydrides in the presence of [Ni(cod)2]/PMe2Ph as catalyst system associated to a Lewis acid. to afford the corresponding sulfur-containing heterocyclic compounds through a [4þ1] cycloaddition. the reaction catalysed by NiCl2 proceeded through the proximal or distal CeC cleavage. Ogoshi et al. alkyl or silicon functional groups could be introduced in the presence of the corresponding halo compounds. These results highlighted the potential of methylenecyclopropanes as C1 synthetic units in a cyclic compound.13 while less attention has been paid to the Lewis acid.and alkylidenecyclopropanes undergo a variety of ring-opening reactions because the relief of ring strain provides a potent thermodynamic driving force. such as methylaluminum bis(2.57 Indeed. Another novel use of methylenecyclopropanes as possible onecarbon building blocks to replace carbon monoxide was reported by the same authors.H. a range of highly substituted thiophthalides were generated in high yields of up to 87%. the generated hydrideenickel species of which reacted with an olefin moiety intramolecularly to provide more thermally stable six-membered nickelacycle 20. [4þ1] Cycloaddition of methylenecyclopropanes with thioanhydrides. such as amines. have shown that the treatment of ethyl cyclopropylideneacetate with [Ni(cod)2] in the presence of PCy3 as ligand resulted in an unpredicted formation of a Ni(0) complex bearing an (E. as shown in Scheme 26. Furthermore. Addition of arylmagnesium chloride gave proximal cleavage products.and alkylidenecyclopropanes can be completed with various nucleophiles.or Brønsted acid-mediated reactions of alkylidenecyclopropanes. which afforded nickelacycle 21. thiols. the crucial factor to determine the mode of ring-opening of alkylidenecyclopropanes is not clear. This nice three-component reaction allowed the synthesis of polysubstituted dienes to be achieved in good yields.

and eight-membered bicyclic methylenecyclopropanes as well as a cisdialkyl-chain-substituted methylenecyclopropane. was formed by the reaction of a nickel phosphine complex with the enone. Ogata et al. This was followed by cleavage of the nickeleoxygen bond by s-bond metathesis of the nickelacycle with triisopropylsilane 31 to afford hydrideenickel intermediate 32. In contrast.5002 H. involving coordination of the borane moiety to the carbonyl carbon. A mechanism for this reaction was proposed by the authors in which there was the initial formation of 2-alkylidene-1-nickelacyclobutane complex 28 from the nickel(0) complex system by reaction with the methylenecyclopropane as already shown in precedent Scheme 26. and borane. as shown in Scheme 28. In addition to a range of aryl aldehydes. the NieC bond of intermediate 28 underwent insertion into the aldehyde substrate to give intermediate 29. Next. aldehydes. the formation of metallacycle 30. Scheme 27. reductive elimination from intermediate 32 occurred to afford the silylated allylic alcohol product. as shown in Scheme 29. . reductive elimination from intermediate 38 afforded the stereodefined final product.62 Again. such as 1hexanal and cyclohexanecarbaldehyde. Three-component reaction of methylenecyclopropanes. leading to the corresponding g. the nickelacyclopentane intermediate 33. enones and triethylborane.and stereoselectively the corresponding reductive coupling products bearing a quaternary stereogenic carbon centre as single diastereomers in remarkable yields. Complex [LnNiCl2] could be reduced by 2 equiv of Grignard reagents to afford [LnNi0] by the reductive elimination of [LnNiR2]. First. seven.and eight-membered bicyclic methylenecyclopropanes as well as cis-dialkyl-chain-substituted methylenecyclopropanes provided high yields. followed by a ring-opening was also possible. another nickel-catalysed three-component reaction was described by Ogata et al. A possible mechanism for the coupling reaction is shown in Scheme 28. Finally. the reaction afforded the corresponding silylated allylic alcohols exhibiting an alkyl substituent at the 2-position through cleavage of the proximal CeC bond of the methylenecyclopropane. Scheme 26. The latter then underwent transmetalation of the ethyl group from the borane moiety to the nickel metal (intermediate 36) via the oxa-p-allyl intermediate 35 to produce the nickeleethyl intermediate 37. The distal bond cleavage of the methylenecyclopropane led to intermediate 26. A subsequent isomerisation of the latter into intermediate 27 followed by reductive coupling afforded the corresponding final carbomagnesiation product along with regenerated Ni0 catalyst. and triisopropylsilane as the substrates. these authors developed another and unprecedented nickel-catalysed three-component reaction between methylene cyclopropanes. methylenecyclopropane. good to high yields were reached by using electron-donating as well as electron-withdrawing arylaldehydes. On the other hand. Moreover.63 Induced by a mixture of [Ni(cod)2] and PCy3 as ligand. seven. Next. and methylenecyclopropane bearing a cyclohexyl group all provided good to high yields. The borane enolate of intermediate 37 reacted with methanol to give intermediate 38. The subsequent reaction of [LnNi0] with the Grignard reagent and the methylenecyclopropane yielded nickelate complex 25. The use of six-. Pellissier / Tetrahedron 70 (2014) 4991e5031 this Scheme to explain the results. involving methylenecyclopropanes. alkylaldehydes. aldehydes and triethylborane occurred with conservation of the cyclopropane ring.. Most of the time. alkyl aldehydes. Later. In 2010. such as 1-pentanal and cyclohexylaldehyde. In addition to this mechanism.61 Induced by a mixture of [Ni(cod)2] and an N-heterocyclic carbene catalyst bearing mesityl substituents. aldehydes and triisopropylsilane. the use of six-. these products were achieved as single diastereomers. intermediate 33 underwent a b-carbon elimination to generate intermediate 34. have demonstrated that a nickelcatalysed three-component reaction between methylenecyclopropanes. Three-component reaction of methylenecyclopropanes. the reaction afforded regio. did not participate in this reaction. also participated in the three-component reaction albeit in generally lower yields. Finally.d-unsaturated carbonyl compounds in good to high yields. As shown in Scheme 27. vinylmagnesium chlorides and electrophiles. the stereospecific cleavage of the proximal CeC bond of the methylenecyclopropane occurred.

0]octene derivatives in moderate to good yields in the presence of [RhCl(CO)(PPh3)2] as catalyst. This intermediate underwent carbometalation to give intermediate 46. Reductive elimination of intermediate 46 produced the corresponding final cycloadduct and regenerated the Rh(I) complex 39 to complete the catalytic cycle. followed by isomerisation to intermediate 41 through a trimethylenemethane-like transition state and carbometalation to afford intermediate 42.0]octene derivatives in even higher yields of up to 76% (Scheme 30). Scheme 29. Evans et al. Enantioselective [3þ2þ1] carbocyclisations with alkylidenecyclopropanes remain very rare. Pellissier / Tetrahedron 70 (2014) 4991e5031 5003 multicomponent reactions described in Schemes 26e29 represent relevant and modern contributions of the last four years in the reactivity of methylenecyclopropanes. Moreover. Noyori and Binger reported that methylene.and alkylidenecyclopropanes could participate in intermolecular [3þ2] cycloaddition reactions with alkenes or alkynes when treated with specific nickel or palladium catalysts. Almost at the same time.64 In addition.1. Shi et al. Lautens. Motherwell and Nakamura demonstrated that the annulation could also be carried out through an intramolecular way.and eight-membered bicyclic methylenecyclopropanes as well as a cis-dialkyl-chain-substituted methylenecyclopropane yielded the corresponding products without formation of ring-opened products.3.0]octane derivatives have been proposed by the authors and are depicted in Scheme 30. which provided the corresponding cis-fused bicyclohexenones in a highly efficient and stereoselective manner. In particular. envisaged the possibility of developing alternative transition metal-catalysed intramolecular [3þ2] cycloadditions that could allow a more straight entry to bicycles featuring a five-membered carbocycle. It must be noted that the four 3. aldehydes and BEt3 with conservation of the cyclopropane ring. Some years later. Mascarenas et al. providing the corresponding cis-fused bicyclohexenones in general high yields (59e99%) and diastereoselectivities of >90% de in almost all cases of substrates studied. Scheme 28. which furnished a series of aza. although the reported examples usually involved very specific substrates the synthesis of which was not particularly straightforward. Rhodium-catalysed reactions. enones and BEt3. In the 1970s and 1980s. In this context. which could presumably rearrange to intermediate 45. As shown in Scheme 31. A first possible catalytic cycle involved the initial insertion of the metal at the distal position of the alkylidenecyclopropane to give metallacyclobutene 40.65 In 2012.3. In the last few years.3. Three-component reaction of methylenecyclopropanes.and oxabicyclic cyclohexanone derivatives in moderate to good yields in a highly regio.H. It was shown that carbon. the propargylic ester produced enyne 43 in the presence of Rh(I) complex 39. the authors have applied the same reaction conditions to alkylidenecyclopropane-enynes. which afforded the corresponding bicyclo[3. six-.47h In view of these precedents. developed a rhodium-catalysed [3þ2þ1] carbocyclisation of alkylidenecyclopropanes with carbon monoxide. these authors recently investigated the intramolecular cycloaddition of alkylidenecyclopropanes containing propargylic esters. the process was promoted by [RhCl(OCOCF3)(CO)(PPh3)2] in situ generated from [Rh(CO)2Cl] and PPh3 in the presence of a silver salt such as [AgCO2CF3]. which also produced the corresponding bicyclo[3. a very efficient enantioselective version of this reaction was successfully developed by the same authors by using a chiral aminophosphine ligand in the presence of TMEDA.66 As shown in Scheme 31.as well as heteroatom-tethered alkylidenecyclopropanes were both compatible in the reaction. In the second possible catalytic cycle.2. this reaction afforded a chiral cis-fused bicyclohexenone in a high enantioselectivity of 89% ee. several authors have successully developed [3þ2þ1] carbocyclisations of alkylidenecyclopropanes with carbon monoxide. Two plausible mechanisms for the formation of these bicyclo[3. Reductive elimination of intermediate 42 provided the final product along with the release of AcOH. seven. investigated a novel rhodiumcatalysed intramolecular [3þ2þ1] cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide. Three-component reaction of methylenecyclopropanes. Oxidative addition into the distal bond of the cyclopropane afforded the metallacyclobutene 44.and .

Interestingly. Intramolecular [3þ2] cycloadditions of alkylidenecyclopropanes containing propargylic esters and alkylidenecyclopropane-enynes.5-ring structures containing spirocyclopropane motifs (Scheme 33).2-tetrachloroethane as the solvent. Intramolecular [3þ2þ1] cycloaddition of ene-alkylidenecyclopropanes with carbon monoxide.5004 H. The authors also attempted to employ ene-vinylidenecyclopropanes as substrates. the reaction induced by [Rh(cod)Cl]2 allowed various 5.and alkylidenecyclopropanes have been developed so far. At the last step. which were submitted to a reductive elimination followed by the formation of the final cycloadduct. Indeed.6fused bicyclic cyclohexanones to be achieved in yields of up to 73% and diastereoselectivities of up to >90% de. as shown in Scheme 34. as shown in Scheme 34.6-fused and 6.69 Screening the reaction conditions revealed that using 10 mol % of [RhCl(CO)(PPh3)2] as the catalyst in toluene at 100  C in the absence of MeCN allowed a range of tricyclic products having a cyclobutene unit to be produced as single regioisomers in high yields (55e78%). Insertion of CO into intermediate 48 generated two regioisomers 49 and 50. Scheme 32. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 31. one of which was reported by these authors. the best catalyst was shown to be [RhCl(CO)2]2 in the presence of a mixed solvent of toluene and MeCN. The authors have proposed the mechanism depicted in Scheme 33 to explain the results.2. the same authors have reported another rhodiumcatalysed intramolecular [3þ2þ1] cycloaddition reaction of enevinylidenecyclopropanes with carbon monoxide for the synthesis of a series of fused 6. Scheme 30. the species Rh(I) was regenerated for the catalytic cycle. These products derived from the enevinylidenecyclopropanes arose from an allylic CeH bond activation pathway resulting from the coordination of the tethered terminal alkene and acetonitrile by the catalyst.1. In this case. they developed the synthesis of functionalised polycyclic compounds on the basis of a rhodium-catalysed intramolecular [2þ2] cycloaddition of ynevinylidenecyclopropanes. a low catalyst loading of only 2 mol % was sufficient to reach these results when using 1. This work constitutes a major contribution of the last four years in the reactivity of alkylidenecyclopropanes. In addition. Only few examples of [2þ2] cycloadditions of methylene. The latter subsequently underwent an oxidative cyclisation to give the rhodacycle intermediate 48.68 This remarkable reaction allowed a range of tricyclic products to be achieved in general excellent yields of >90% in all cases of substrates studied. whereas the tricyclic [2þ2] cycloadducts arisen from the reaction of ynevinylidenecyclopropanes resulted from the selective coordination of the internal double bond of the allene and alkyne moiety by the . the coordination of Rh(I) with alkene and allene moieties in the vinylidenecyclopropane led to the formation of intermediate 47. Intramolecular [3þ2þ1] cycloaddition of ene-vinylidenecyclopropanes with carbon monoxide.67 As shown in Scheme 32. Under these conditions. cis-diastereoselective manner. First. the process afforded another type of products since a range of aza-cyclooctene derivatives were generated as single diastereomers in high yields (69e80%).

In the rhodium(I)-catalysed [2þ2] cycloaddition of the yne-vinylidenecyclopropane. Subsequently. The final aza-cyclooctene could be formed from intermediate 55 through reductive elimination along with the regeneration of rhodium(I) catalyst. In 2012. This work also constitutes a major contribution of the last few years in the reactivity of alkylidenecyclopropanes. Plausible mechanisms for the formation of the tricyclic products arisen from the reaction of yne-vinylidenecyclopropanes and that of the aza-cyclooctenes from the reaction of enevinylidenecyclopropanes have been proposed by the authors and are depicted in Scheme 34. Evans and Inglesby reported a remarkable and highly diastereoselective rhodium-catalysed ene/cycloisomerisation reaction of carbon and heteroatom-tethered alkylidenecyclopropanes to provide the corresponding five-membered carbo. catalyst. Intramolecular cycloadditions of yne. MeCN was found to play a crucial role in controlling the reaction towards the formation of cyclooctenes instead of [2þ2] cycloadducts.71 As shown in Scheme 36.H. the neighbouring allylic CeH bond gave a p-allyl rhodiumehydrogen species 57. Indeed. Intramolecular [3þ2þ1] cycloaddition of ene-vinylidenecyclopropanes with carbon monoxide. the scope of this methodology was extended to the highly efficient synthesis of a wide number of bicyclo[5. intramolecular insertion to the internal double bond of the allene moiety led to the rhodium hydrogen species 55. As shown in Scheme 35. The corresponding polycyclic product containing a cyclobutene moiety could be afforded after cyclometalation/reductive elimination. which led to a seven-membered carbocyclic rhodiumehydrogen species 58 through an intramolecular cycloaddition to the allene moiety.and heterocyclic aldehydes and dienes were generated in high yields of up to 97% with a general excellent diastereoselectivity of >90% de.and heterocycles exhibiting two novel stereogenic centres. Pellissier / Tetrahedron 70 (2014) 4991e5031 5005 Scheme 33. a reductive elimination afforded the final product along with rhodium(I) catalyst regeneration. A plausible mechanism for this intramolecular ene reaction is outlined in Scheme 35. Next. It was shown that under CO atmosphere.70 These products were formed as single diastereomers in high yields of up to 91%. Acetonitrile and the tethered terminal alkene could be coordinated onto Rh(I) metal centre to generate intermediate 56. In contrast. A key and striking feature of this protocol was that the alkene geometry did .0]octylene derivatives starting from the corresponding diarylvinylidenecyclopropanes. Then. for the rhodium(I)-catalysed intramolecular cycloaddition of the ene-vinylidenecyclopropane.1.and ene-vinylidenecyclopropanes. a range of five-membered carbo. a selective coordination of the internal double bond of the allene and alkyne moiety by the rhodium(I) complex gave intermediate 51. which underwent oxidative addition of the rhodium(I) catalyst onto the neighbouring allylic CeH bond to give the p-allyl rhodium hydrogen species 54. the rhodium catalyst could be better stabilised. the oxidative addition of rhodium(I) complex into Scheme 34. and the reaction rate accelerated. acetonitrile and the tethered terminal alkene could coordinate to the rhodium(I) metal centre to give intermediate 53.

as shown in Scheme 38. The synthetic utility of this process was highlighted in a concise eight-step total synthesis of ()-a-kainic acid in 17% overall yield. starting from an enantiopure alkylidene cyclopropane. the authors have obtained the corresponding aldehyde as a single diastereomer in 85% yield and with an enantioselectivity of >95% ee (Scheme 37).and alkylidenecyclopropanes with pinacol borane. (E). these authors also investigated the hydrosilylation reaction of alkylidenecyclopropanes with PhMe2SiH in the presence of the same catalyst. An asymmetric version of the reaction was undertaken starting from an enantiopure alkylidenecyclopropane.and alkylidenecyclo propanes. Stereoselective carbometalation of the alkene provided the cis-fused metallacycle 62. For instance.and alkylidenecyclopropanes under mild conditions into acyclic aldehydes.5006 H. the authors have proposed the catalytic cycle depicted in Scheme 36 in which the oxidative addition of complex 59 into the distal bond of the enealkylidenecyclopropane generated the metallacyclobutene 60.04 mol % allowed a range of these substrates to be converted into the corresponding aldehydes as mixtures of Zand E-diastereomers in high yields (81e93%). as shown in Scheme 37. the same authors have investigated rhodium-catalysed ring-opening of methylene. First hydroformylation reaction of methylene. ene/cycloisomerisation reactions of ene- In another context. which underwent a selective b-hydride elimination at the terminal position to afford metal/enol 63. demonstrating that the stereointegrity of the quaternary stereogenic centre remained unaffected during the hydroboration reaction. not impact the efficiency and diastereocontrol. which were directly submitted to oxidation by treatment with hydrogen peroxide followed by hydrogenation of the double bond to give the final saturated alcohols in high yields (81e87%). To explain the results. which provided excellent synthetic versatility through simplifying the preparation of the alkene precursors. As an extension of the precedent methodology. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 35. Marek and Simaan reported the first clean and reliable hydroformylation reaction of methylene. Intramolecular ene reaction of ene-diarylvinylidenecyclopropanes. which remained unaffected in the process. One of the most remarkable features of this reaction was the high selectivity of the catalytic process that resulted in the exclusive formation of the expected linear aldehydes. In 2010. Tautomerisation of 63 and concomitant reductive elimination provided the final aldehyde product. Scheme 36. which afforded the corresponding chiral alcohol in enantioselectivity of >96% ee.73 The process catalysed by the Wilkinson catalyst provided the corresponding unstable boronate esters. and the stereointegrity of the quaternary carbon centre. Intramolecular alkylidenecyclopropanes.and (Z)-allylic alcohols furnished the corresponding aldehydes with similar efficiency and selectivity. Scheme 37.73 .72 A low catalyst loading of only 0. This work constitutes a major contribution of the last four years in the reactivity of alkylidenecyclopropanes. which underwent a rearrangement to afford intermediate 61. Indeed.

Hydrosilylation reaction of alkylidenecyclopropanes. Cui et al. developed a facile and chemoselective rhodium-catalysed intramolecular hydroacylation of a. Scheme 39. Then. the reaction was shown to be highly stereoselective as the E/Z ratios of homoallylsilanes corresponded to the initial E/Z ratios of alkylidenecyclopropanes. followed by isomerisation to form intermediate 68 through a trimethylenemethane-like transition state. which could further undergo a 1. In 2011. Surprisingly. Then. swift ring enlargement and reductive elimination of intermediate 65 led to the final cycloheptenone product. Aïssa et al. Then. Pellissier / Tetrahedron 70 (2014) 4991e5031 5007 and affording the corresponding cycloheptenones in good to excellent yields (70e99%). Hydroboration reaction of methylene. which could isomerise to produce p-allylic Rh(III) complex 70. Scheme 38. Moreover. providing the corresponding homoallylsilanes in good to excellent yields (85e94%). an asymmetric version of this process was developed starting from enantiopure alkylidenecyclopropanes. spiroindolenine intermediate 72 was formed.75 As shown in Scheme 41. the hydrosilylation reaction proceeded with selective cleavage of the less-substituted carbonecarbon bond of the cyclopropane. when alkylidenecyclopropanes were treated with N-(pivaloyloxy)furan-2-carboxamides.a-disubstituted 4-alkylidene cyclopropanals.and C3-positions are nucleophilic. which were subsequently submitted to hydrogenation of the double bond followed by oxidation to provide the corresponding saturated alcohols in enantioselectivities similar to those of the starting materials. Shi et al. suggesting that a migratory insertion of the alkylidenecyclopropane moiety in intermediate 64 provided the formation of pentarhodacycle intermediate 65. Intramolecular hydroacylation reaction of a. Finally. Similarly. as shown in Scheme 42. they led to the exclusive formation of the corresponding furan-fused azepinones in moderate to high yields (30e85%). since both the indole C2.2-alkyl shift to afford the six-membered ring intermediate 73. a range of tetrahydro-bcarboline derivatives could be synthesised in good to high yields (52e95%). Intermediate 68 underwent a b-H elimination to give rhodiumehydrogen species 69. recently investigated the reaction of alkylidenecyclopropanes with benzamides in the presence of a rhodium catalyst such as [CpRhCl2]2. recently reported a novel convenient access to polycyclic indole derivatives on the basis of a cycloisomerisation of nitrogen-tethered indoles and alkylidenecyclopropanes. two competing pathways could occur for the cyclisation. ranging from 88 to 97% ee (Scheme 39). A mechanism depicted in Scheme 40 was proposed by the authors. This proved . The latter was subsequently submitted to deprotonation to give the final product. Alternatively. avoiding decarbonylation Scheme 40. Using the same catalyst. nucleophilic attack of the indole C2position on the diene moiety led directly to intermediate 73. Through indole C3-position attack on the conjugated diene. generating the corresponding chiral homoallylsilanes. a range of benzamides with valuable functional groups reacted smoothly with alkylidenecyclopropanes to give the corresponding spiro dihydroisoquinolinones in moderate to excellent yields (55e95%).H. A plausible mechanism for this reaction is outlined in Scheme 41 in which the initial insertion of the metal at the distal position of the alkylidenecyclopropane gave metallacyclobutene 67. Again.76 As shown in Scheme 42.a-disubstituted 4-alkylidenecyclopropanals. conjugated diene 71 could be obtained from intermediate 70 through reductive elimination along with regeneration of the Rh(I) complex.74 It must be noted that the reaction was proved to be chemoselective in favour of the alkylidenecyclopropane moiety when an alkene or an alkyne was tethered to the substrate.and alkylidenecyclopropanes.

1. CeN bond formation took place to afford intermediate 82 along with NeO bond cleavage. Finally. Then. a range of cobalt-catalysed reactions of methylene.5008 H. which underwent a cyclopropyl carbinyl-butenyl rearrangement to generate intermediate 81. This was followed by coordination with the alkylidenecyclopropane and mild insertion in the CeC double bond to afford rhodacycle 76. Its coordination with the alkylidenecyclopropane and subsequent insertion formed rhodacycle 80. Scheme 42. Cycloisomerisation reaction of indole-alkylidenecyclopropanes. Then. 3. the first step was also a concerted metalation/deprotonation involving CeH activation to generate intermediate 78. that alkylidenecyclopropanes exhibited dramatically different reactivity with common benzamides and furan-derived amides. In the case of formation of azepinones.3. The final step was protonation of intermediate 82 to provide the final azepinone product with Rh(III) catalyst regeneration. Gold-catalysed reactions. Owing to the efficiency with which alkenes. significant developments in many organic gold-catalysed transformations have been developed in recent years.and alkylidenecyclopropanes have been reported in the last few years. It started from a carboxylate-assisted CeH activation via a concerted metalation/ deprotonation process to form intermediate 74. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 41. CeN bond formation took place to afford intermediate 77 along with NeO bond cleavage. disclosing that substituents on the terminus of the double bond or cyclopropyl ring of these compounds significantly affected the . A plausible mechanism for these reactions is depicted in Scheme 42 in which an initial rhodium dicarboxylate was generated from [CpRhCl2]2 and CsOAc for spiro dihydroisoquinolinones synthesis. intermediate 77 was protonated to furnish the final spiro dihydroisoquinolinone product with concomitant Rh(III) catalyst release. alkynes and allenes can be activated by homogeneous gold catalysis. undergoing divergent cycloadditions while coupling with CeC double bonds and CeC proximal bonds selectively.77 In particular. Tandem CeH activation/cycloaddition reactions of alkylidenecyclopropanes with benzamides.

a novel chiral Au(I) catalyst was developed by Gagne et al. in which intermediate 85 was the preferred active species based on the formation of the (E)-isoxazolidine product. Among them.82 As shown in Scheme 45. good to high yields (50e93%) were obtained arisen from highly regioselective cleavage of the cyclopropyl ring. to be applied to an enantioselective Cope rearrangement of ene-alkylidenecyclopropanes. Scheme 46. which underwent oxidative addition with PhI(OAc)2 to provide Au(III) intermediate 90.79 The process occurred by transferring three Scheme 43. the corresponding multisubstituted benzene derivatives in moderate to good yields (50e85%).2] hydride shift to generate intermediate 92.80 In this context. a variety of novel types of gold-catalysed tandem reactions have been reported by the group of Shi in particular. Shi et al.and alkylidenecyclopropanes have become an established methodology for accessing a large number of carbocyclic and heterocyclic structures. This intermediate 91 further underwent a facile [1.81 As shown in Scheme 44. the addition of the nitrogenehydrogen bond of amines to carbonecarbon multiple bonds (hydroamination) is an ideal and challenging method for this purpose. a variety of 4substituted isoxazolidine derivatives have been synthesised in the presence of a gold catalyst from the corresponding sulfonamidesubstituted 2-(arylmethylene)cyclopropylcarbinols. hydrogen atoms from the cyclohexane ring to the cyclopropane ring. when induced by [(PPh3)AuCl]/ AgOTf as catalyst system. Tandem intramolecular alkylidenecyclopropanes. The hydrolysis of intermediate 87 produced the final 4-substituted isoxazolidine derivative and regenerated the Au(1) complex 83 to complete the catalytic cycle. In the last few years. activation of the alkylidenecyclopropane by the Au(I) complex induced a nucleophilic attack by AcO to afford intermediate 88 or allylic Au(I) species 89.83 A plausible mechanism was proposed by the authors in which a cationic Au(I) complex first coordinated to the alkyne moiety of the alkylidenecyclopropane.84 The reaction proceeded at low temperature. enamines and imines. The formation of carbonenitrogen bonds is one of the most important processes in organic synthesis.78 Gold-catalysed reactions are particularly suited for the development of tandem processes for the ready formation of complex architectures. A plausible mechanism for the reaction is outlined in Scheme 44 in which cationic Au(I) complex 83 first coordinated to the alkene moiety of the substrate to give intermediate 84. Tandem dehydrogenation/rearrangement reaction of alkylidenecyclo propanes. The reductive elimination of intermediate 90 produced the final diacetoxylated product in good to excellent yield (40e99%). as shown in Scheme 47. as shown in Scheme 44. which evolved to give the cyclopropyl Auecarbene intermediate 91 via 6-endo-dig cyclisation. offering an efficient synthetic route to amines. Intermediate 85 underwent a common intramolecular hydroamination along with the ring-opening of cyclopropane to give the corresponding five-membered heterocyclic intermediate 87.  In 2012. As an example. these authors reported a novel gold-catalysed cycloisomerisation of nitrogen. providing an easy access to tricyclic spiro products in high yields (71e99%) under very mild conditions. providing the corresponding vinylcyclopropanes in moderate to high yields (35e98%) and good to high enantioselectivities of up to 93% ee. There might be an equilibrium between intermediate 85 and intermediate 86. Density functional theory calculations predicted that the reaction was thermodynamically driven by the relief of ring strain from the . followed by elimination of Au(I) complex to give the final product. In particular. Moreover. containing different sized skeletons. Pellissier / Tetrahedron 70 (2014) 4991e5031 5009 reaction pathways. as shown in Scheme 43. For example. these authors have found that cyclohexane-containing alkylidenecyclopropanes could undergo tandem CeH and CeC bond activation through dehydrogenated rearrangement to give.and oxygen-tethered alkylidenecyclopropanes. hydroamination/ring-opening reaction of Scheme 45. which then produced a carbocationic intermediate 85. gold-catalysed tandem reactions of methylene.H. have investigated intramolecular nucleophilic additions of alkylidenecyclopropanes bearing a nucleophilic group. Diacetoxylation reaction of alkylidenecyclopropanes. The same authors also discovered an interesting diacetoxylation reaction of alkylidenecyclopropanes performed in the presence of PhI(OAc)2 catalysed by a Au(I)/Au(III) catalytic cycle.

Shi et al. was used instead of oxygen. Then. the products were formed as mixtures of E/Z isomers (ratio¼1:1). Tandem oxidative ring-opening/CeC bond cleavage reaction of vinylidenecyclopropanes. a tandem protonation and ring-opening of the dioxetane via intermediate 99 produced the final product along with the release of one molecule of ketone. vinylcyclopropane could be formed via a cyclic tertiary carbenium ion intermediate 94. Unlike simple arylvinylidenecyclopropanes. Moreover. such as pyridine Noxide.85 The authors proposed that the reaction began with the activation of the vinylidenecyclopropane by gold(I) complex followed by nucleophilic addition of amine to afford intermediate 95. Cope rearrangement of ene-alkylidenecyclopropanes. as shown in Scheme 48. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 46. Then. and further rearrangement gave a new cyclopropane intermediate 97.86 When R1 and R2 were different aromatic groups. followed by a ring expansion rearrangement to form a more stable cyclobutyl goldecarbene intermediate 102. and then the final Scheme 48. the vinylidenecyclopropane was initially activated by coordination with gold species to give intermediate 100. After an oxidation reaction by pyridine N-oxide. Cycloisomerisation reaction of yne-alkylidenecyclopropanes. Scheme 47. leading to the corresponding fully substituted acrylamides in good yields (40e82%). Coordination of the Au(I) complex to the alkene of the alkylidenecyclopropane moiety generated intermediate 93. As shown in Scheme 49. functionalised vinylidenecyclopropanes tethered with nucleophilic moieties exhibit a different reactivity. As an example. in which the CeC double bond underwent an addition with gold catalyst.5010 H. when another strong oxidant. The formation of the product could be rationalised. pyridine 103. affording cationic intermediate 101. the authors showed that vinylidenecyclopropanes underwent a novel tandem oxidative ring expansion/rearrangement reaction catalysed by [(PPh3)AuCl]/ AgSbF6. Shi et al. demonstrated that vinylidenecyclopropanes depicted in Scheme 50 underwent a novel tandem addition/ring-opening reaction catalysed by . in which the CeC double bond was further activated by the gold(I) complex. intermediate 102 was then converted into the final alkylidenecyclobutanone along with the formation of a byproduct. Subsequent oxygen fixation formed a dioxogold intermediate 96. providing the corresponding alkylidenecyclobutanones in moderate to high yields (23e95%). and that the Au(I) catalyst greatly lowered the barriers for rearrangement. as depicted in Scheme 47. developed a novel gold-catalysed tandem ringopening/CeC bond cleavage reaction of vinylidenecyclopropanes with a variety of secondary amines under oxygen atmosphere. alkylidenecyclopropane moiety. the intramolecular nucleophilic attack along with the corresponding ring-opening of the cyclopropane took place to give the corresponding allylic gold intermediate 98. In 2011.

the final dienone was achieved in good yield (74e88%). Tandem oxidative ring expansion/rearrangement reaction of vinylidene cyclopropanes. Scheme 49.88 As shown in Scheme 51. Both pathways led to the same intermediate 104 through the Scheme 52. After protodeauration. In addition. followed by protonation generating the final product. the CeC triple Scheme 50. Scheme 51.87 In the case of unsymmetrical diarylvinylidenecyclopropane derivatives as substrates. Tandem addition/ring-opening reaction of vinylidenecyclopropanes. On the other hand. they investigated the reactivity of another type of functionalised vinylidenecyclopropanes in which the cyclopropane moiety beared an adjacent secondary alcohol group.H. these substrates underwent in the presence of [(PPh3)AuCl] an intramolecular nucleophilic addition via gold activated intermediate 105 to form a protonated furan derivative 106. The first one involved the allene functionality activation by gold cation (pathway 1) while the second one involved the gold(I)-catalysed ring-opening reaction of the cyclopropane (pathway 2). Pellissier / Tetrahedron 70 (2014) 4991e5031 5011 intramolecular nucleophilic addition by the hydroxyl group. Therefore. followed by a CeO bond cleavage giving cationic intermediate 107. Furthermore. and a subsequent cation-induced ring-opening of the cyclopropane led to ketone intermediate 108. the same authors developed an interesting tandem intramolecular hydroamination/ring-opening reaction of sulfonamide-substituted vinylidenecyclopropane-diesters depicted in Scheme 52. The authors have proposed that this process could occur through two possible pathways. the authors have found that changing the length of the tethered alkane chain was also possible. the allene moiety of the vinylidenecyclopropane was activated.89 Upon catalysis with [(PPh3)AuCl] in the presence of AgOTf. Tandem intramolecular hydroamination/ring-opening sulfonamide-substituted vinylidenecyclopropanes. a combination of [(PPh3Au)3O]BF4 with AgOTf to provide the corresponding allene-containing tetrahydropyran derivatives in good yields (45e69%). and then intramolecular hydroamination occurred along with ring-opening reaction of cyclopropane to give the intermediate 110 via intermediate 109. the corresponding tetrahydropyran products were obtained as pairs of diastereomers with a ratio of 1:1. reaction of . Intramolecular rearrangement of vinylidenecyclopropanes.

Shi et al.1. Then. Oxidative aromatisation of alkylidenecyclopropanes. which evolved through a tandem intramolecular CeH and CeC bond activation and aromatisation via dehydrogenated rearrangement. The CaeH or Ca0 eH bond of the alkylidenecyclopropane was activated by Pd(II) to generate allylic intermediate 113. which could not proceed through the b-carbon elimination pathway smoothly to give the ring-opened intermediate because of the steric repulsion between the aryl and .4-dienylidene)cyclopropanecarbaldehydes in moderate to good yields (52e76%). as shown in Scheme 55. On the other hand. On the other hand. The pathways for the palladium-catalysed reactions of (Z). Notably. Intramolecular [3þ2þ2] cycloaddition of enynylidenecyclopropanes. have been thoroughly investigated by Shi et al. (E)-alkylidenecyclopropylcarbaldehydes also isomerised into the corresponding penta-2. Then. and the final ketone product was afforded in good yield (55e74%) through a classical alkyne hydration. which further afforded the final tricycles through a subsequent carbometalation and reductive elimination sequence. reported the synthesis of isoprenylbiaryl derivatives on the basis of a reaction of alkylidenecyclopropanes in the presence of palladium acetate. Mascarenas et al. hydropalladation of (Z)-alkylidenecyclopropylcarbaldehyde gave intermediate 123. in the presence or absence of an acid source such as AcOH.90 The formation of these products in good yields (54e75%) was explained by the mechanism depicted in Scheme 54. Reductive elimination of 120 and isomerisation afforded the final product.91 It was found that the reaction of (E)-alkylidenecyclopropylcarbinols in the absence of AcOH isomerised into the corresponding pent-4-enals in moderate to good yields (37e80%).4-dienals in good to high yields (40e93%).5012 H. the reaction of enynylidenecyclopropanes was induced by Pd2(dba)3 in the presence of a bulky phosphite in dioxane at 90  C. as shown in Scheme 55. Palladium-catalysed reactions. Hydropalladation of (E)-alkylidenecyclopropylcarbaldehyde gave intermediate 121. whereas (Z)alkylidenecyclopropylcarbaldehydes led to the corresponding 2-(3formylpenta-2. in which a palladacyclobutane intermediate 119 was first formed from the substrate and the catalyst with the insertion of the metal into the proximal bond (C2eC3). Insertion of O2 into the PdeH bond then produced a peroxy intermediate that reacted with acetic acid to regenerate the catalyst. which provided intermediate 120 through regioselective anti-b-hydrogen elimination. which was followed by elimination of acetic acid to subsequently give intermediate 117.and (E)alkylidenecyclopropanecarbaldehydes with AcOH are shown in Scheme 55. In 2010. b-Carbon elimination of intermediate 121 occurred subsequently to afford intermediate 122. Scheme 53. one of the hydrogen atoms at the methyl group was derived from CaeH or Ca0 eH bond. through reductive elimination intermediate 115 was obtained. It must be noted that in some cases. the authors showed that in the presence of AcOH. a byproduct arisen from a competitive [3þ2] cycloaddition was formed. A plausible mechanism for the formation of these products is depicted in Scheme 55. On the other hand. in which the substituents can be either hydroxymethyl or formyl. In another way.50 As shown in Scheme 53. followed by ring-opening and rearrangement to afford intermediate 114. reported a palladium-catalysed intramolecular [3þ2þ2] cycloaddition of alkylidenecyclopropanes to alkynes that provided an efficient entry to synthetically relevant 5-7-5 tricyclic structures. In 2010. 3. the alkylidenecyclopropane reacted with the palladium catalyst to form complex 112. Pellissier / Tetrahedron 70 (2014) 4991e5031 bond of intermediate 110 could be further activated by the regenerated gold(I) catalyst. palladium(II) inserted into the allylic CeH bond of the cyclohexene to give intermediate 116.3cyclohexadiene 118 and a palladium hydride species. The further dehydrogenated elimination of 118 afforded the final 4isopropenylbiaryl product. Scheme 54. It was supposed to evolve through the generation of a palladacyclohexane intermediate 111 (Scheme 53). the major [3þ2þ2] cycloadduct was always obtained as a single diastereomer with the fused-hydrogens in a cis-configuration in moderate to high yields (16e84%). which underwent dehydrogenation elimination to provide 1.4-dienal product. which released the final penta-2. Initially.4. palladium-catalysed reactions of 3substituted alkylidenecyclopropanes.

by single-bond rotation of intermediate 124. the same authors demonstrated that cyclopropyliden ecycloalkanes. Alternatively. which are highly strained alkylidenecyclopropanes containing a cycloalkane moiety. Isomerisation of (E)-alkylidenecyclopropylcarbinols and reactions of (Z)and (E)-alkylidenecyclopropanecarbaldehydes with AcOH. In another context. b-carbon elimination of intermediate 125. Initially. Reaction of cyclopropylidenecycloalkanes with carbon dioxide. have developed a highly efficient palladium-catalysed hydrostannation of methylene. as shown in Scheme 57. The negatively charged oxygen atom attacked the allyl palladium moiety to produce the corresponding final lactones. Scheme 55. Marek et al. reacted with carbon dioxide smoothly to give the corresponding five-membered lactone derivatives as mixtures of two regioisomers in moderate to good yields (65e91%) through a cyclopropane ring-opening process in the presence of a Pd(0) catalyst and PCy3 as ligand (Scheme 56). In this case. Therefore. Pellissier / Tetrahedron 70 (2014) 4991e5031 5013 formyl groups.H. and b-hydrogen elimination of intermediate 126 afforded the final 2-(3-formylpenta-2. the catalyst reacted with the substrate to give intermediate 127. which underwent a ring-opened process to produce intermediate 128 in which Ca position was negatively charged. Scheme 56. via intermediate 129. allowing their desymmetrisation to be achieved with general .4-dienylidene)cyclopropanecarbaldehyde and regenerated catalyst AcOPdH. Later. Suginome et al. respectively. carbon dioxide could approach Ca either from the upside or the underside to produce intermediate 130 and intermediate 131. developed a highly enantioselective silaboration of meso-1.and alkylidenecyclopropanes to provide the corresponding homoallylstannanes in excellent yields (88e94%).92 The authors have explained the results on the basis of the mechanism depicted in Scheme 56. intermediate 123 added to another molecular of substrate to give intermediate 124.73 Later.2-dialkylsubstituted-3-methylenecyclopropanes.

Ruthenium-catalysed reactions.2.96 This reaction was induced by a ruthenium catalyst in situ generated from [RuCl2(cod)]n and a phosphine ligand.5014 H. Wu et al. Scheme 59. without interaction with the internal one. Scheme 60. In addition. excellent enantioselectivities of up to 96% ee along with good to excellent yields (55e97%).10 -binaphthyl.5.1. such as (S)-TFBiphamPhos. Reports on isomerisation of vinylidenecyclopropanes into dimethylenecyclopropanes under mild conditions remain rare.94 As shown in Scheme 59.93 Interestingly. Hydrostannation of methylene. It must be noted that the observed enantioselectivities were higher than those obtained with 2diarylphosphino-1.2. and provided the corresponding cycloadducts in excellent yields (92e98%) with a general excellent endo-diastereoselectivity of up to >96% de in combination with excellent enantioselectivities ranging from 92 to 98% ee. In another context. The 5-aza-spiro[2. 3. whose chirality relied on a singlehanded helical structure of the backbone of poly(quinoxaline-2.3-tetramethylcyclopropylidene)propene in good yield (46e65%).98 This nice reaction was induced by a chiral catalyst in situ generated from CuBF4 and a chiral aminophosphine ligand. as shown in . as shown in Scheme 60. Scheme 58. have developed a ruthenium-catalysed intermolecular hydroarylation reaction of 2-phenylmethylidenecyclopropane through CeH bond functionalisation of various arenes. 3. Cycloisomerisation of 3-cyclopropylideneprop-2-en-1-ones. the process was induced by a polymer-based chiral ligand. the carbopalladation step occurred on the terminal double bond of the vinylidenecyclopropane.6.4]heptane structure motif plays a significant role in structureeactivity relationship of several antibacterial agents. highly substituted vinylidenecyclopropanes have been arylated by Santelli et al. Wang et al. Shi and Lu recently described the first example of an oxidative isomerisation of vinylidenecyclopropanes to dimethylenecyclopropanes using tetrapropylammonium perruthenate (TPAP)/ 4-methylmorpholine N-oxide (NMO) as an efficient catalytic system under mild conditions. Enantioselective silaboration of methylenecyclopropanes. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 57.95 These products obtained in moderate to high yields (32e93%) were further converted into the corresponding 2(3H)furanones bearing a spiro-cyclopropane unit. using a catalytic amount of [Pd(Et) Cl]2 associated to tetradentate ligand Tedicyp.3-diyl). reported a novel and remarkable entry to these important products based on an enantioselective copper-catalysed [3þ2] cycloaddition of ethyl 2-cyclopropylideneacetate with various aryl imino esters.97 In 2011. providing a facile synthesis of highly strained functionalised 2-alkylidenecyclobutanones.3. Scheme 61. most of them took place upon heating at high temperatures (130e160  C). providing the corresponding 3-aryl-2methyl-3-(2. as shown in Scheme 58. leading to the corresponding anti-Markovnikov hydroarylation products in low to good yields (5e78%) with complete conservation of the cyclopropane ring. have developed a novel palladiumcatalysed oxidative cycloisomerisation of 3-cyclopropylideneprop2-en-1-ones.37 A range of dimethylenecyclopropanes were achieved in moderate to good yields (62e72%) along with high Z/E ratios of up to 90:10 as already described in Scheme 14 of Section 2. In this context. Hydroarylation of 2-phenylmethylenecyclopropane.and alkylidenecyclopropanes. Copper-catalysed reactions. as shown in Scheme 61. Heck reaction of a vinylidenecyclopropane.1. Ackermann et al. In another context.

. which provided the corresponding cycloadducts in moderate to good yields (38e70%) along with unexpected minor byproducts (Scheme 64). Cleavage of the C1eC2 bond took place to give intermediate 139. Cascade reaction of 2-ethynylaryl alkylidenecyclopropanes with sulfonyl azides.2]dec-7-en-4-ones in moderate to good yields (32e84%). Finally.and regioisomers.2-H shift to afford intermediate 140 and its resonance-stabilised intermediate 141 along with the regeneration of the rhenium catalyst.2. which underwent nucleophilic attack with H2O to provide intermediates 143 and 144. the 2-ethynylaryl alkylidenecyclopropane reacted with the sulfonyl azide upon catalysis with the copper salt. Then. In 2012. Buono et al.102 In Scheme 63.H. Other transition metal-catalysed reactions. [3þ2] Cycloaddition reaction of an alkylidenecyclopropane with alkynes.1. which provided a novel route to the generation of fused indolines in moderate to good yields (27e75%). In 2011. The NeO bond of intermediate 136 underwent a cleavage to produce radical 137. [3þ2] Cycloaddition of ethyl 2-cyclopropylideneacetate with aryl imino esters. Subsequently. order to explain the results. which proceeded through successive 6-endo cyclisation. In addition. Wu et al. Scheme 64. in which the oxygen anion was bonded to the rhenium catalyst. Pellissier / Tetrahedron 70 (2014) 4991e5031 5015 Scheme 62. [3þ2] cycloaddition reaction of isoquinoline-N-oxide 135 with the alkylidenecyclopropane occurred.2-dihydroisoquinoline 136. all the cycloadducts were obtained as single stereo. leading to fused 1. developed a [3þ2] cycloaddition reaction of an alkylidenecyclopropane with various alkynes catalysed by a platinum-based catalyst. and intramolecular rearrangement. the authors assumed that the rhenium catalyst coordinated with the carbonyl group and the allene moiety simultaneously. evolving through a regioselective carbonecarbon bond cleavage catalysed by Re2(CO)10 to produce the corresponding 2H-pyran-2-one derivatives in good yields (51e70%). This work constitutes a major contribution of the last four years in the reactivity of methylenecyclopropanes. have described a cascade reaction of 2ethynylaryl alkylidenecyclopropanes with sulfonyl azides catalysed by copper(I) iodide under mild conditions. 3. isoquinoline-N-oxide 135 was firstly produced via a silver triflate-catalysed 6-endo cyclisation of the 2-alkynylbenzaldoxime. a novel silver-catalysed tandem reaction of alkylidenecyclopropanes with 2-alkynylbenzaldoximes was reported by Wu et al. intermediate 139 underwent a 1. which subsequently underwent a rearrangement to produce the final fused indoline.. as shown in Scheme 65.7. elimination of R1OH afforded the final tandem product. [3þ2] cycloaddition. which then evolved through ring-opening of cyclopropane and intramolecular radical addition to provide the final product. A consecutive 6p-electrocyclisation occurred to form intermediate 134. Initially. Indeed. giving rise to benzo-7-azabicyclo[4. affording a triazole intermediate 132. as shown in Scheme 66. Wu and Shi developed an interesting intramolecular ring-opening reaction of vinylidenecyclopropane-diesters.100 Notably.101 Diversity and complexity could be easily incorporated during the transformation. Then. Cyclisation of intermediate 141 gave intermediate 142. which then transferred to the reactive ketenimine 133 via a ring-opening rearrangement. Scheme 62.99 The authors have proposed the mechanism depicted in Scheme 63 to explain the formation of the cascade product.

as dienes to afford the cycloadducts. 3. Lewis and Brønsted acid-catalysed reactions Besides transition metal catalysts. as shown in Scheme 67.5016 H. Scheme 66. Alkylidenecyclopropanes can behave as dienophiles or. as shown in Scheme 68. Lewis and protic acids can also be used as catalysts or reagents in the reactions of methyleneand alkylidenecyclopropanes with a variety of substrates.2. affording the corresponding multisubstituted naphthalene derivatives.1. Scheme 67. several groups have involved various alkylidenecyclopropanes as dienophiles in DielseAlder or hetero-DielseAlder reactions. Tandem reaction of alkylidenecyclopropanes with 2-alkynylbenzaldoximes. Shi and Wu reported a Yb(OTf)3catalysed [3þ3] cycloaddition of vinylidenecyclopropanes containing two ester groups with nitrones. In 2010. alkylidenecyclopropanes are still underestimated as valuable partners in these reactions. Sc(OTf)3-catalysed DielseAlder cycloaddition of alkylidenecyclopropanes with salicylaldehydes and CH(OEt)3. Scheme 65. derived from the salicylaldehyde and CH(OEt)3. Scheme 68. Yb(OTf)3-catalysed idenecyclopropanes with nitrones.103 3. Pellissier / Tetrahedron 70 (2014) 4991e5031 3.105 The reaction consisted in a DielseAlder cycloaddition occurring between an o-quinonemethide analogue. and a alkylidene cyclopropane. Shi and Jiang investigated a three-component reaction of alkylidenecyclopropanes.2. In 2010.2. salicylaldehydes and CH(OEt)3 catalysed by a Lewis acid such as Sc(OTf)3. formal [3þ3] cycloaddition of vinyl- Despite the large body of DielseAlder cycloadditions in organic synthesis. Cycloadditions.2. Shi and Tang reported a novel intramolecular ring-opening/ring-expansion rearrangement of alkylidenecyclopropane diarylalcohols catalysed by TfOH under mild conditions. Rearrangements. In recent years. It was shown that the substituents on the aromatic ring of the salicylaldehyde did not have significant influence on the reaction outcome. and some interesting diverse transformations have been developed during the last decade. For example. these . The process produced the corresponding bicyclic cycloadducts in moderate to high yields (61e82%) under mild conditions in the presence of a catalytic amount of Sc(OTf)3. It has been shown that substituents on the terminal of the double bond or cyclopropyl ring of these products significantly affect the reaction pathways.106 As shown in Scheme 69. when properly substituted.104 The corresponding proximal [3þ3] cycloadducts were exclusively obtained in moderate to good yields (42e68%) with a high regioselectivity. Tandem ring-opening/cyclisation reaction of vinylidenecyclopropanes.

2. Submitting dimethylenecyclopropanes to catalytic amounts of TfOH in toluene at room temperature. the reaction afforded the corresponding products as single diastereomers with anti-configuration. Subsequent ring-opening of cyclopropane formed intermediate 153. which involved the in situ generation of cationic intermediate 149. the substrate was probably first protonated at the hydroxy group along with the release of one molecule of water to give a cationic intermediate 151 and a resonance-stabilised intermediate 152. Scheme 69.0]oct-5-ene derivatives in moderate to good yields (15e62%) under mild conditions. The cis/trans ratios ranged from 3:1 to >20:1.106 When using monoaryl. The following intramolecular FriedeleCrafts reaction of 147 afforded intermediate 148. monoalkyl-. Pellissier / Tetrahedron 70 (2014) 4991e5031 5017 Scheme 70. In another context. they underwent an intramolecular cation-induced ring enlargement process to give the corresponding cyclobutanol derivatives in moderate to good yields (38e72%). which produced intermediate 147 through allylic rearrangement. To explain the results. interesting products were obtained in good yields (66e87%) according to the mechanism depicted in this scheme in which the in situ generated cationic intermediate 145 underwent ringopening to give intermediate 146.H. the carbocyclisation process afforded the corresponding chlorinated bicyclo[4. these authors reported that when dialkyl-. Furthermore. TfOH-catalysed intramolecular rearrangement of dimethylenecyclopropanes. the same authors have reported titanium(IV)-mediated intramolecular ring enlargement of Scheme 71. which underwent aromatisation to give the final naphthalene. the authors . as shown in Scheme 71. The latter underwent a ring enlargement to give intermediate 150. which produced the final cyclobutanol through reaction with water. A plausible mechanism for this reaction is shown in Scheme 70. these authors found that an interesting intramolecular rearrangement occurred to afford the corresponding indene derivatives as single stereoisomers in good to high yields (73e97%). as well as monoaryl alcohol alkylidenecyclopropanes were submitted to related reaction conditions.as well as monoalkyl alcohols (R2sR3) as the substrates. TfOH-catalysed intramolecular rearrangement of alkylidenecyclopropanes. which underwent an intramolecular FriedeleCrafts reaction with the adjacent aromatic ring accompanied with a deprotonation to give the final indene product. alkylidenecyclopropanes including a propargylic ester. TfOH-catalysed intramolecular rearrangement of alkylidenecyclopropanes.37 In this interesting process.107 As shown in Scheme 72.

The authors have proposed the mechanism depicted in Scheme 76. chloride ion was transferred to vinyl cation from the in situ generated metal complex.3.2-carbon migration to give intermediate 157. Initially. as shown in Scheme 75. a highly regioselective CeC bond cleavage allowed a range of ring-opened products to be achieved in high yields (78e88%). . Scheme 74. Intermediate 159 could tautomerise to the final product through intermediate 160. As an extension of the precedent methodology. Miscellaneous reactions. have employed FeCl3 as catalyst to induce SeeSe bond cleavage and the further reaction with alkylidenecyclopropanes under mild conditions. In another context.109 As shown in Scheme 76. Yb(OTf)3-catalysed ring-opening reaction of vinylidenecyclopropanes with H2O. which could provide vinyl cationic intermediate 158 through isomerisation.5-dimethylenetetrahydropyrans in moderate yields (17e39%). Yb(OTf)3-catalysed ring-opening reaction of alkylidenecyclopropanes with propargyl alcohols. Electrophilic addition of phenylselenyl cation to the alkylidenecyclopropane led to intermediate 161 as the episelenium cation. The nucleophilic intramolecular addition of the pendant alkylidenecyclopropane to the alkyne moiety along with the release of acyloxy group afforded carbocation 156 containing a vinylidene moiety. Scheme 72.102 As shown in Scheme 73.102 The mechanism depicted in Scheme 73 has been proposed by the authors to explain the results. The geminal installation of two electron-withdrawing groups at the cyclopropane ring significantly facilitated CeC bond cleavage.and Zmonoarylalkylidenecyclopropanes. The rearrangement of 162 constructed the four-membered carbon ring structure unit and gave the ring-enlarged cyclobutyl cation 163.2.1-diesters have been investigated by Wang et al.b-unsaturated ketones. It must be noted that in the case of enyne substrates having electron-rich aromatic ring (Ar¼Ph. Wu and Shi reported a highly efficient Yb(OTf)3-catalysed ring-opening of vinylidenecyclopropanes by H2O to give the corresponding a. This combination of catalysts (Eu(OTf)3/InCl3) was proved to be the most suitable one for this interesting tandem ring-opening/Conia-ene reaction to be achieved.5018 H. which directly afforded starting from the same substrates the corresponding 3. Tol) within the methylenecyclopropane moiety. the authors have developed a combination of this reaction albeit catalysed by Eu(OTf)3 with a subsequent intramolecular Conia-ene cyclisation induced by InCl3. In 2011. The outcome of the reaction was found mainly dependent on the nature of the Lewis acid employed.108 As shown in Scheme 74. Yu et al. the authors showed that vinylidenecyclopropanes underwent a regioselective C1eC2 bond cleavage when activated by a Lewis acid such as Re2(CO)10 to produce the corresponding 2H-pyran-2-one derivatives (Scheme 66). the reaction of FeCl3 with PhSeSePh afforded the corresponding phenylselenyl cation and the phenylselenyltrichloroiron anion. In the same area. Lewis acid-catalysed ring-opening reactions of alkylidenecyclopropane 1. 3. which exclusively took place at C1eC3. have proposed the mechanism depicted in Scheme 72 in which the coordination of the ester group to TiCl4 led to intermediate 155. TiCl4-mediated intramolecular ring enlargement of alkylidenecyclopropanes with propargylic esters. the corresponding chlorinated products were obtained in moderate to good yields whether they were E. The CeC cyclopropane bond was initially activated by Yb(OTf)3 through coordination with the ester moieties and could then easily undergo a nucleophilic attack by H2O to give intermediate 159 through C1eC2 bond cleavage. affording the corresponding final chlorinated product. which could be transformed into intermediate a-phenylselenyl cyclopropylcarbinyl cation 162. this reaction allowed a convenient access to diphenylselenylcyclobutanes in good yields (54e85%) from PhSeSePh and alkylidenecyclopropanes. Subsequently. Then. Indeed. in the presence of propargylic acids. carbocationic intermediate 156 underwent intramolecular ring enlargement of cyclopropane via 1. the process was catalysed by Yb(OTf)3 and provided the corresponding ring-opened products in moderate to good yields (21e70%) and good E-diastereoselectivity (E/Z¼76:24 to >20:1) through regiospecific distal bond cleavage. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 73.

The reaction was initiated by the generation of the carbocationic intermediate 164 from the bis(aryl)methanol in the presence of BF3$Et2O.4-migration between two carbon atoms and the subsequent intramolecular FriedeleCrafts reaction pathways in the presence of BF3$Et2O under mild conditions. Scheme 76. Yb(OTf)3-catalysed reaction of alkylidenecyclopropanes with PhSeSePh.and E-diastereomers in moderate to high yields (24e81%). as shown in Scheme 77. Scheme 78. Shi et al. Pellissier / Tetrahedron 70 (2014) 4991e5031 5019 In 2010. When employing another Lewis acid such as Yb(OTf)3. investigated the reaction of vinylidenecyclopropanes with bis(aryl)methanols in the presence of BF3$Et2O as catalyst.111 When vinylidenecyclopropanes reacted with electron-rich bis(p-alkoxyphenyl)methanols. . On the basis of experimental and computational results (DFT calculations).1:1 and excellent yields (90e99%) through a novel cationic 1. the mechanism outlined in Scheme 78 was proposed by the authors. diastereomeric rotamers of the corresponding indene derivatives were produced in anti/syn ratios of up to 7. such as the corresponding ringopened products as mixtures of Z. the authors have found that the reaction of alkylidenecyclopropanes with PhSeSePh led to different products.110 Scheme 77. Eu(OTf)3/InCl3-catalysed tandem ring-opening/Conia-ene reaction of alkylidenecyclopropanes with propargyl alcohols. Further reaction of 163 with the phenylselenyltrichloroiron anion led to the final product and regenerated the catalyst. which attacked the central carbon of the allene moiety of the vinylidenecyclopropane to provide the cationic intermediate Scheme 75. FeCl3-catalysed reaction of alkylidenecyclopropanes with PhSeSePh.H. BF3$Et2O-catalysed reaction of vinylidenecyclopropanes with bis(p-alkoxyphenyl)methanols.

a range of C-aryl nitrones were reacted with dimethyl-2-benzylidene cyclopropane-1. Shi and Wu demonstrated that vinylidene cyclopropane-diesters underwent a 1. when the aromatic ring has an electron-donating group. The latter then immediately underwent ring-opening to afford allylic cation 166 or its resonance structure 167. the 1. It was conceivable that if using a similarly electron-rich xanthydrol as the electrophile in this reaction. In intermediate 167. the 1. the authors found that it was quite interesting to examine what happens in this type of BF3$Et2O-catalysed reaction. 3. This intermediate reacted with the vinylidenecyclopropane to give the corresponding resonancestabilised cationic intermediates 171 and 172 (allylic cation).89 Indeed. the process afforded a series of pyrazole derivatives in low to good yields (10e88%) with good regioselectivities of up to complete in almost all cases of substrates studied under mild conditions. Thermal cycloadditions Scheme 79.3.1.O-heterocyclic products containing an alkyne moiety instead of a ketone moiety in good to high yields (73e95%).1-dicarboxylate to give the corresponding cycloadducts in good yields as single diastereomers (56e68%).3-dipolar cycloaddition reaction of dimethyl-2-benzylidenecyclopropane1. deprotonation of 172 afforded the final triene. successfully investigated the 1. Wu and Shi showed that sulfonamide-substituted 1. These products constitute potent precursors to important products such as b-amino alcohols.114 As shown in Scheme 82. arising from a tandem intramolecular hydroamination/ring-opening reaction in which a highly regioselective C1eC2 bond cleavage occurred.4-aryl migration would not be able to take place. Scheme 52). it was demonstrated In 2010.3. Later. that the employed Lewis acids played a significant role to effect the reaction outcomes as well as the presence or absence of water. the authors found that the use of Yb(OTf)3 as catalyst instead of [(PPh3)AuCl] afforded another type of five-membered N. Yb(OTf)3-catalysed tandem intramolecular hydroamination/ring-opening reaction of sulfonamide-substituted vinylidenecyclopropanes.4-migration took place to afford another allylic cation 168.1vinylidenecyclopropanediesters containing two geminal installed electron-withdrawing groups underwent another type of reactivity when activated by another Lewis acid such as Yb(OTf)3 under anhydrous reaction conditions than that observed when using a gold catalyst in the presence of water (Section 3. . BF3$Et2O-catalysed reaction of vinylidenecyclopropanes with xanthydrol. in the case of using gold catalysis in the presence of water. as shown in Scheme 79. Therefore.1-dicarboxylate with C-amido nitrones. the two reactions afforded the same alkyne 173 through two different pathways but.113 As shown in Scheme 81.4-isoxa zolidine] cycloadducts were produced in good yields (80e89%) as single diastereomers. Then. Scheme 80. Similarly.112 The mechanism of the reaction probably began by the formation of the cationic intermediate 170 by treatment of xanthydrol with BF3$Et2O. this product was subsequently converted into the corresponding ketone through Au(I)-catalysed hydration of its alkyne moiety.3-dipolar cycloaddition reaction with aromatic diazomethanes generated in situ from the corresponding aromatic aldehydes and tosylhydrazine in THF or MeCN at 50  C. In 2011. which underwent an intramolecular FriedeleCrafts reaction to furnish the final product. As shown in Scheme 80. the corresponding spiro[cyclopropane-1. Molchanov et al. They showed that vinylidenecyclopropanes underwent a ring-opening reaction with xanthydrol in the presence of this Lewis acid to give the corresponding conjugate triene derivatives in good yields (41e94%). as shown in Scheme 82. Therefore.5020 H. Pellissier / Tetrahedron 70 (2014) 4991e5031 165.

3-Dipolar cycloadditions of ethyl 2-cyclopropylideneacetate and bicyclopropylidene with enantiopure pyrroline N-oxides. cyclic nitrones. These chiral products were subsequently converted into homoprolines. 1.3-dipolar cycloaddition of a nitrone with an alkylidenecyclopropane resulting from the palladium-catalysed cyclopropanation of a bicyclic alkene with ethyl propiolate.2-a]indoles was developed by Shi et al. the cycloadduct was achieved as a single diastereomer while the cycloadduct arisen from ethyl 2-cyclopropylideneacetate was obtained as a 6:1 mixture of diastereomers. Molchanov et al. Scheme 82.3-Dipolar cycloaddition of an alkylidenecyclopropane with a nitrone. In 2012. corresponding chiral isoxazolidines in good yields (69e78%).3-Dipolar cycloadditions of alkylidenecyclopropane-diesters with Camido nitrones and C-aryl nitrones. 1. Scheme 86. as substrates in reaction with methylenecyclopropanes.117 In the case of bicyclopropylidene as substrate. which constitute building blocks for peptidomimetic synthesis. such as tetrahydropyridine nitrones. On the other hand. Hou et al.3-Dipolar cycloaddition of methylenecyclopropanes with tetrahydropyridine nitrones. on the basis of a 1.25 As shown in Scheme 86.3-dipolar cycloaddition of vinylidenecyclopropanes with nitrones.H. as shown in Scheme 87. In 2011. The presence of a 2-methyl group on the nitrone exerted a steric hindrance on the transition state. which provided a range of biologically important tricyclic products in good to high yields (70e93%). 1. 1. these authors reported the first example of 1. In the same area. Pellissier / Tetrahedron 70 (2014) 4991e5031 5021 Scheme 84.116 Their 1. A novel and efficient synthetic method of functionalised pyrrolo [1. the corresponding isoxazolidine was formed in 83% yield as a mixture of two diastereomers with a moderate diastereoselectivity of 35% de. as shown in Scheme 85.119 The authors . were used by Brandi et al. Scheme 83.118 The nice process evolved through the initial formation of the imine followed by cyclopropane ring-opening and then [3þ2] cycloaddition. an equimolecular mixture of diastereomers was obtained when starting from substituted methylenecyclopropane (R1¼Me). reported a tandem 1. as shown in Scheme 83.3-Dipolar cycloaddition of vinylidenecyclopropane-diesters with in situ generated aromatic diazomethanes. developed the 1.3-dipolar cycloaddition of vinylidenecyclopropanes with nitrones to give the corresponding 4-cyclopropylidene-isoxazolidines in moderate yields (36e48%). First example of 1.3-cycloaddition afforded the corresponding isoxazolidines in moderate yields (28e36%).3dipolar cycloaddition of aniline-tethered alkylidenecyclopropanes with in situ generated imines from aldehydes. Furthermore.3-dipolar cycloaddition/rearrangement reaction of bis(methylene)cyclopropanes with diarylnitrones to give the corresponding dihydropyridinones in moderate yields along with acyclic products. as shown in Scheme 84.115 The nitrones reacted regioselectively with the C10 eC20 double bond of non-activated vinylidenecyclopropanes. 1. leading to single 30 -regioisomers. enantiopure pyrrolidine N-oxides derived from malic acid diastereoselectively cycloadducted with ethyl 2cyclopropylideneacetate or bicyclopropylidene to provide the In 2013. Scheme 81. Scheme 85.

which constituted the key step in a novel route to the naturally occurring indole alkaloid cycloclavine and its C(5)-epimer. On the other hand. the scope of the precedent methodology was extended to the reaction of bis(methylene)cyclopropanes with nitrile oxides in situ generated from the corresponding hydroximoyl chlorides. Tandem 1. which instantaneously underwent a cyclopropane Scheme 89.3-dipolar cycloaddition/rearrangement reaction of acceptor ring substituted alkylidenecyclopropanes with N-arylnitrones.119 Scheme 87. 1. The corresponding tandem 1.3-dipolar cycloaddition/rearrangement reaction afforded the corresponding 1.120 The reaction began with the [3þ2] cycloaddition to give the corresponding spirocycloadduct 177. according to a related mechanism to that of reaction with nitrones (Scheme 89). In addition. pharmaceutically relevant pyrroloquinolines were achieved in moderate to good yields (32e81%) by the same authors.3-dipolar cycloaddition/rearrangement reactions of bis(methylene)cyclopropanes with diarylnitrones. The presence of acceptor ester groups in this intermediate facilitated transannular nucleophilic attack of a lone pair of nitrogen atom to a carbonyl group to form the corresponding azetoquinoline 181. Scheme 88. Because nitrile oxides are more reactive than nitrones. The subsequent rearrangement of this intermediate started with the haemolytic cleavage of its NeO bond to afford diradical 175.121 As shown in Scheme 91. Wipf and Petronijevic have developed a nice intramolecular DielseAlder cycloaddition of a diene-methyl enecyclopropane. This diradical eventually cyclised to provide the corresponding final dihydropyridinone or produced the corresponding final open-chain aminoketone through hydrogen transfer. using a related tandem 1. the latter underwent ring-opening to give 182 and then cyclocondensation to provide the final pyrroloquinoline.3-Dipolar cycloaddition of aniline-tethered alkylidenecyclopropanes with aldehydes. as shown in Scheme 90. Pellissier / Tetrahedron 70 (2014) 4991e5031 ring-opening to form highly reactive diradical intermediate 176. Tandem 1. The generated biradical 179 underwent ring closure to form eight-membered azocynone 180. which then underwent a rearrangement.5022 H. the process began with the quantitative formation of a silyloxy diene from the corresponding . Finally.1-diaryl-2-isopropylidene-3-methylenecyclo propanes in moderate yields without formation of open-chain products.3-dipolar cycloaddition to give the intermediate spiroisoxazolidine cycloadduct 174 (Scheme 88). assumed that the process began with the 1.3-dipolar cycloaddition/rearrangement reaction of bis(methylene)cyclopropanes with nitrile oxides.

Ndichlorotoluenesulfonamide as the nitrogen and halogen sources at room temperature in the absence of any metal catalyst.H. Miscellaneous non-catalysed reactions Like most alkenes. as shown in Scheme 93. .and alkylidenecyclopropanes reacted with electrophiles through addition. Scheme 92. which provided the corresponding ring-remaining aminochlorinated products as major ones along with or without the corresponding ring-opened aminochlorinated byproducts in moderate to good yields. Aminochlorination of alkylidenecyclopropanes. vinylogous amide. Shi et al. The synthesis of fluorinated (aminomethyl)cycloalkane building blocks has not been discussed in the literature until 2013 in spite of their importance as biologically active compounds. Pellissier / Tetrahedron 70 (2014) 4991e5031 5023 Scheme 91.3-dipolar cycloaddition/rearrangement reaction of alkylidenecyclopropanes with nitrones.4. recently investigated the bromofluorination of methylenecyclopropane. Because of the high ring strain. 3. Scheme 90. the resulting cyclopropylcarbinyl cation may rupture or not. leading to homoallylic compounds or ring-remaining products. In spite of its low regioselectivity. as shown in Scheme 92.122 This reaction constituted the first example of metal-free and solvent-free aminochlorination of alkylidenecyclopropanes. In this context. De Kimpe et al. Intramolecular DielseAlder cycloaddition of an in situ generated dienemethylenecyclopropane. have reported the aminochlorination of alkylidenecyclopropanes under CO2 atmosphere using N. In this context.123 They found that the reaction performed in the presence of triethylamine trihydrofluoride and N-bromosuccinimide led to a 1:3 mixture of the corresponding Markovnikov and anti-Markovnikov products in moderate yields. methylene. This diene further smoothly underwent an intramolecular DielseAlder cycloaddition under microwave irradiation to afford the corresponding tricyclic ketone bearing a transconfiguration at the indoline ring fusion bond in 85% yield after removal of the TBS group by treatment with TBAF. Tandem 1. this reaction constituted a novel entry to 1-aminomethyl-1-fluoro cyclopropanes after subsequent amination of the antiMarkovnikov product. It must be noted that the role of CO2 was not explained by the authors.

the process afforded a third type of products such as divinylketones 185 in good yields (46e66%). In this context. as shown in Scheme 94. The mechanism of these reactions began with an electrophilic interaction of Xþ with the electron-rich C]C bond adjacent to the cyclopropane. Subsequent intramolecular [1.and diastereoselectivity.0]alkanones 184 in good yields (48e75%) also as single diastereomers.1.124 Indeed.2.0]alkanones 184 and divinylketones 185. which subsequently eliminated a phenol molecule to furnish the final product. an efficient method to stereospecifically synthesise trans-substituted cyclopentene derivatives via a tandem thermal ring-opening/rearrangement of E-alkylidenecyclo . a rearrangement occurred with bromine atom migration mediated by HBr to afford intermediate 189. thermally induced rearrangements are relatively limited due to the fact that high temperature is usually required because of the huge activation energy. which was finally transformed into divinylketone 185. As shown in Scheme 95. In this context. Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 93. It must be noted that vinylidenecyclopropanes bearing one aryl group at the cyclopropyl ring (R1¼Ar.and alkylidenecyclopropanes to form a variety of different carbocycles and heterocycles have been extensively investigated during the last decade. a different electrophilic ring-opening of product 190 occurred with high stereoselectivity to give intermediate product 191. In another context.or N-iodosuccinimide at room temperature or 40  C in aqueous DMSO. Halohydroxylations of vinylidenecyclopropanes. Reports on the halohydroxylation of vinylidenecyclopropanes are limited. probably due to the fact that their multiple reaction pathways constitute a tremendous challenge to make this methodology synthetically attractive unless regio. when bicyclic vinylidenecyclopropanes were reacted with N-bromo. Furthermore. allowing three types of potentially useful products.0]alkanols 183. they led to the corresponding vinylbicyclo[(nþ2). On the other hand. R2¼H) afforded the corresponding divinyl ketones in good yields (47e71%) with a complete E selectivity. alkylidenebicyclo[(nþ2). The latter was further nucleophilically attacked by H2O at the phosphorus atom to give intermediate 196. Transition metal and Lewis acid-catalysed ring-opening reactions of methylene.and stereoselectivity could be controlled in a highly efficient manner. showing that in the presence of Xþ. which was selectively attacked by H2O from the less sterically hindered side to produce the ring-keeping halohydroxylation product 183 with complete diastereoselectivity.2]phenyl group migration cleaving the OeO linkage afforded zwitterion 195. With N-bromosuccinimide at 100  C.or N-bromosuccinimide (up to 5 equiv) at 85  C or room temperature. thereby forming a three-membered cyclic halonium ion intermediate 186. as shown in Scheme 94. Scheme 94. as shown in Scheme 94. an unexpected hydroxyphosphonylation of 3-cyclopropylideneprop-2-en-1-ones with phosphines was recently described by Wu et al. The mechanism of the formation of products 185 is also depicted in Scheme 94. such as vinylbicyclo[(nþ2). the reaction started with the attack of triphenylphosphine at the central allenic carbon atom to form zwitterion 192 and the resonance form 193. the addition of bromonium ion to the double bond induced a ring enlargement to give the dibromocyclobutanone 188. the scope of this reaction was extended to monocyclic vinylidenecyclopropanes in addition to bicyclic ones. have developed three novel nice reactions of vinylidenecyclopropanes. which was probably favoured due to the release of strain.0]alkanols 183 in good to high yields (55e90%) as single diastereomers while when heating at 100  C they provided the corresponding alkylidenebicyclo[(nþ2). the cycloaddition reaction of resonance form 193 with O2 produced the five-membered cyclic oxyphosphorane 194. Bromofluorination of methylenecyclopropane. Then.2. Then. the authors found that when using a higher quantity of N-iodo. which underwent an elimination reaction to furnish the ultimate product 184 (Scheme 94).5024 H.125 This unique carbonephosphorous bond cleavage provided an efficient entry to highly functionalised 1dialkylphosphinyl-3-oxo-(1Z)-alkenyl cyclopropanols in good yields (43e94%) with complete regio. Interestingly.1. Huang et al.

providing the corresponding trans-cyclopentene derivatives as single diastereomers in moderate yields (55e77%). The authors have proposed that the process could evolve through a Cope rearrangement. the authors have proposed a mechanism in which 3-amino-2-ethyl4-(3H)-quinazolinone was first oxidised with PhI(OAc)2 to afford active nitrene equivalent 197.128 As shown in Scheme 98. the corresponding domino carbolithiation/Michael/1. a variety of cyclobutylidene hydrazine derivatives were achieved in moderate to good yields as separable Z/E-diastereomeric mixtures. involving a chairlike transition state in which the steric interaction between the substituents was minimal (Scheme 96). Tandem Wittig/Cope rearrangement of alkylidenecyclopropyl aldehydes. Scheme 96. according to the mechanism depicted below.127 This onepot reaction was performed at room temperature in the presence of n-BuLi as a base. It must be noted that the reaction of the corresponding Z-substrates provided the same transsubstituted cyclopentene products without formation of the corresponding cis-products. propanes was described by Tang and Shi. Shi et al. Hydroxyphosphinylation reaction of vinylidenecyclopropanes. The latter reacted with the alkylidenecyclopropane to give the ring expansion rearrangement product via either aziridine intermediate 198 or ionic intermediate 199. these authors developed a tandem Wittig reaction/ Cope rearrangement reaction of alkylidenecyclopropyl aldehydes with cinnamyltriphenylphosphonium bromide. On the basis of these results.129 As shown in Scheme 99. compounds in the absence of a metal complex have been explored. reported a metal-free ring expansion of alkylidenecyclopropanes with 3-amino-2-ethyl-4-(3H)-quinazolinone in the presence of iodobenzene diacetate under mild conditions.126 As shown in Scheme 96. Pellissier / Tetrahedron 70 (2014) 4991e5031 5025 Scheme 97. While metal-catalysed ring expansion rearrangements of methylene. Tandem ring-opening/Cope rearrangement reaction of alkylidenecyclo propanes. As a recent example. the products were achieved as single diastereomers in moderate to good yields (40e76%). Scheme 95.2- .H. in 2010. as shown in Scheme 97. only a few examples of ring expansions of these Scheme 98. On the other hand. a novel pseudo three-component domino carbolithiation reaction of vinylidenecyclopropanes with 2 equiv of but-3-yn-2-one or 1-phenylprop-2-yn-1-one performed in the presence of LDA was reported by the same authors.and alkylidenecyclopropanes to cyclobutene or cybutanone derivatives as well as other large ring systems have been widely developed. Moreover. Ring expansion of alkylidenecyclopropanes.

methyl vinyl ketone and N-sulfonated imines. methyl vinyl ketone and nitroalkenes as well as (phenylmethylidene)malononitrile. Furthermore.5.2 addition reaction the corresponding products in moderate to good yields (45e70%) as anti/syn isomeric mixtures. The initial attack is often followed by the cyclopropane ring-opening. Then. the mechanism of the process was comparable to that of the reaction depicted in the previous scheme. as shown in Scheme 102.112 In this work.6-dicyano-p-benzoquinone (DDQ) to give the corresponding conjugate triene products in moderate to high yields (31e92%). addition adducts were produced in good yields as single diastereomers. in 2010. Pseudo three-component domino carbolithiation/Michael/1. The exo C]C double bond of alkylidenecyclopropanes has been reacted with radical species in a number of recent works.2-addition to the imine to afford the final domino product. It was found that when cyclic enones were employed as the electrophiles. anionic intermediate 201 reacted with methyl vinyl ketone according to a Michael addition to give enolate 206. 201 and 202. none of the corresponding domino products were formed under the same conditions. In this case. the three-component reaction afforded the corresponding domino multifunctionalised products in moderate to good yields (41e60%) as mixtures of anti. The authors assumed that the process began with the . Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 99.3dichloro-5.2-addition with another molecule of alkynone to give the corresponding final domino product.130 Once again. the corresponding products were obtained as E.2-addition reaction of vinylidenecyclopropanes with alkynones. Intermediate 200 could be transformed into anionic intermediates 201 and 202 and there was equilibrium between all these anionic species as intermediates 200. The authors assumed that the process began with the lithiation of the cyclopropyl ring of the vinylidenecyclopropane to give the corresponding cyclopropyl carbanion intermediate 200 by treatment with LDA. suggesting a wide substrate scope for this nice cascade process (Scheme 101). 3. which afforded through LDA-mediated domino carbolithiation/Michael/1. As an extension of the precedent methodology. Radical reactions Radical reactions have become a valuable method for the synthesis of many organic products. the same authors have developed a novel three-component reaction between vinylidenecyclopropanes.and Z-isomeric mixtures with E/Z ratios ranging from 1:1 to 4:1. the authors extended the scope of this methodology to the reaction of vinylidenecyclopropanes. In the case of unsymmetrical vinylidenecyclopropanes.2-addition reaction of vinylidenecyclopropanes with methyl vinyl ketone and N-sulfonated imines. The radical species derived from the initial reaction then give the final products by hydrogen capture or evolve into other species through a radical cascade sequence.130 As shown in Scheme 100. Three-component domino carbolithiation/Michael/1. intermediate 203 was formed by the Michael addition of 201 to the alkynone.5026 H. which subsequently underwent a 1. which subsequently underwent a 1. vinylidenecyclopropanes reacted with xanthene in the presence of 2. An example of radical ring-opening reaction of vinylidenecyclopropanes was reported by Yuan and Shi.and syn-diastereomers. Scheme 100. but this is not the rule.

This intermediate subsequently underwent a H transfer to give ionic pair intermediate 208. Indeed. Pellissier / Tetrahedron 70 (2014) 4991e5031 5027 Scheme 101. the bromide radical added to the central carbon of the . In this case. which led to the final product through deprotonation.1. Xu et al. which underwent an intramolecular radical addition to give radical intermediate 212. leading to the synthesis of 2-bromo-1.6dienes. such as S. In 2013. Then. The scope of the process was wide since vinylidenecyclopropanes bearing electronwithdrawing as well as electron-donating substituents on their aromatic substituents were well tolerated. A plausible mechanism for the formation of these products is shown in Scheme 103. a threecomponent reaction comprising alkylidenecyclopropanes. These products were obtained as single diastereomers except in the case of using vinylidenecyclopropanes in which Ar1 and Ar2 were different aryl groups. Finally. Reaction of vinylidenecyclopropanes with xanthene. the reaction occurred in DCE at 80  C while heating at 220  C was required when using Se or Te as chalcogens.6-dienes in good to high yields (80e97%). intermediate 212 reacted with another molecule of PhSeSePh to give the corresponding final product along with the regeneration of phenyl selenium radical to accomplish the radical reaction cycle.2-addition reaction of vinylidenecyclopropanes with methyl vinyl ketone and a nitroalkene or (phenylmethylidene)malononitrile. carbon monoxide and allylic bromides was achieved under related reaction conditions. The reaction of cationic xanthene intermediate with the vinylidenecyclopropane produced the resonance-stabilised cationic intermediates 209 and 210. Three-component domino carbolithiation/Michael/1. a range of five-membered 1.H. a bromine radical was generated from the allylic bromide through a radical initiation process. since the ring-opening reaction generated homoallylic radicals. methoxy-2. reported a direct synthesis of not easily accessed and useful methylene-1. formation of radical ionic pair 207 by reaction of the vinylidenecyclopropane with DDQ. The originality of this process lied in the direct use of elemental chalcogens. the authors envisaged that these radicals could trap carbon monoxide. the corresponding products were achieved as E/Z isomeric mixtures with a ratio of 1. Initially. On the other hand. It was shown that monosubstituted alkylidenecyclopropanes gave the corresponding products in high yields (80e92%) as Z/E diastereomeric mixtures favouring the Z isomers with Z/E ratios ranging from 64:36 to 73:27. the corresponding bicyclo[3. Se or Te.7dien-5-ones in good yields (71e74%). Then.2-dichalcogenolanes based on a radical [3þ2] cycloaddition of alkylidenecyclopropanes with elemental chalcogens.0]hexane derivatives were achieved in generally moderate to high yields (36e94%). recently developed a bromine radicalmediated cyclopropylcarbinyl-homoallyl rearrangement of alkylidenecyclopropanes accomplished through CeC bond formation with allylic bromides.133 As shown in Scheme 105.4-dimethylvaleronitrile) (V-70) and anhydrous trisodium phosphate as an HBr scavenger afforded a variety of 2-bromosubstituted 1.20 -azobis(4- Scheme 102. Moreover. as shown in Scheme 105.2:1. As shown in Scheme 104. First. providing the corresponding 2-bromo-substituted 1. the reaction of alkylidenecyclopropanes with allylic bromides in the presence of 2. the newly formed phenyl selenium radical in the presence of AIBN added to the allene moiety of the vinylidenecyclopropane to give the corresponding radical intermediate 211. Ryu et al. these authors also developed another novel tandem radical reaction of vinylidenecyclopropanes with diphenyl diselenide in the presence of AIBN. A proposed mechanism for the present homoallylation and the carbonylative bromoallylation of alkylidenecyclopropanes is shown in Scheme 105.2-dichalcogenolane products were achieved in moderate to high yields (22e87%).132 Using S as chalcogen.131 As shown in Scheme 103.

Pellissier / Tetrahedron 70 (2014) 4991e5031 Scheme 103. Indeed. A. 1987. 46. Conclusions The synthesis of methylene.. Bromoallylation and carbonylative bromoallylation reactions of alkylidenecyclopropanes with allylic bromides. which will shorten the access to biomedically relevant polycyclic molecules. In the absence of CO.and alkylidenecyclopropanes remains a considerable challenge due to the fact that the methylenecyclopropane moiety is found in many biologically active natural substances. 1247e1255. N. Vol. Int. In spite of their highly strained structure.. 106. providing the final 2-bromo-substituted 1. 165e198. Chem. Because of this significantly strained nature associated with a large structural differentiation available. [3þ2] Cycloaddition of alkylidenecyclopropanes with elemental chalcogens. an impressive number of very different products have been recently prepared through diverse reactions of methylene. methylene. 2007. these atypical compounds usually exist as stable compounds.5028 H. 349. V. Germany. Y.6-diene. C. Adv. Tse. de Meijere. Rappoport. alkylidenecyclopropanes. 2. Simaan. efforts remain to be undertaken on the development of enantioselective versions in almost all reaction types. 1989. Bagutski. On the other hand. alkylidenecyclopropane to give cyclopropylmethyl radical 213. 4926e4996. M. 89. Chem. 4..-C. In particular. This review updates the principal and versatile methods employed to obtain and to transform these important compounds reported in the literature since the beginning of 2010.and alkylidenecyclopropanes.and alkylidenecyclopropanes have been well documented as useful synthetic intermediates in organic chemistry over the past few decades. however. 2007. Hon. Then.. well illustrating the diversity of acyclic as well as (poly)cyclic products that can be obtained through the chemistry of methylene. 2000. A. (c) de Meijere. these compounds show a peculiar and diverse reactivity pattern that would be achievable from other starting materials only with difficulty. Wiley and Sons: New York. Catal.. J. the pathway to give intermediate 215 operated to sustain the radical chain. Marek.and alkylidenecyclopropanes. C.. it must be noted that. Ed. S. Eds. .-W. Homoallyl radical 214 added to CO to form acyl radical 216. including heteroatoms have been developed in the last four years with notable efficiency and stereocontrol. allowing their use in many synthetic applications with an otherwise unattainable chemical reactivity. A. Kozhushkov. (a) de Meijere. Patai. Spinger: Berlin.and Scheme 105. Synth. 7364e7376. S. Angew.. which underwent a b-fission to give final 2-bromo-substituted 1. (b) Wong. Z... a compilation of methodologies to assemble polycyclic structures containing small. H. in the last few years. (b) Small Ring Compounds in Organic Synthesis VI. Schill. I. such as cyclopropane to cyclononane derivatives. and this particular great variety of products is directly related to the high versatility of this chemistry. 207. I.as well as medium-sized cycles. Scheme 104. 216 added to the allylic bromide to produce intermediate 217. Masarwa. S.. which underwent a rearrangement leading to homoallyl radical 214. Yip..134 Among the class of cyclopropanes. relatively few studies have been reported dealing with asymmetric reactions of methylene. Rev. NY. References and notes 1.. since.... 3. A. Takano. H.7dien-5-one along with a bromine radical. Rev. Reaction of vinylidenecyclopropanes with diphenyldiselenide. (a) The Chemistry of the Cyclopropyl Group. Ed. Chem.-Y. 2006.

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C. France.H. 5031 . After a postdoctoral period in Professor K.D. Gil in Marseille and then entered the Centre National de la Recherche Scientifique in 1988. Berkeley. G. under the superHe vision of Dr.P.3-butadiene and benzocyclobutenes. she joined the group of Professor M. She carried out her Ph. Santelli in Marseille in 1992. Vollhardt’s group at the University of California. Pellissier / Tetrahedron 70 (2014) 4991e5031 Biographical sketch  le ne Pellissier was born in Gap. Thus. she developed several new very short total syntheses of steroids starting from 1. where she focused on the chemistry of diallylsilane and its large application in organic synthesis.