Divergent Rearrangements of Vinylcyclopropane into Skipped Diene and Cyclopentene: Mechanism, Scope, and Limitations

Article abstract of DOI:10.1002/ejoc.202100430

Vinylcyclopropanes are versatile intermediates in organic synthesis which undergo various rearrangements. We report a new rearrangement of vinylcyclopropane into skipped diene. A detailed mechanistic study revealed that this transformation involves regioselective ring-opening of the cyclopropane ring followed by 1,2-migration of one of the cyclopropane substituents. Interestingly, our investigations showed that skipped diene is the kinetic product of the process but formation of a more stable cyclopentene is also accessible. The fundamental understanding of the processes involved enabled the development of divergent methodologies allowing to obtain cyclopentene or skipped diene from vinylcyclopropane in a selective and controlled manner.

Full text of DOI:10.1002/ejoc.202100430

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Divergent Rearrangements of Vinylcyclopropane into
Skipped Diene and Cyclopentene: Mechanism, Scope, and
Limitations
Arnaud Delbrassinne+,[a] Maximilien Richald+,[a] Julien Janssens,[a] and Raphaël Robiette*[a]
Vinylcyclopropanes are versatile intermediates in organic syn-
thesis which undergo various rearrangements. We report a new
rearrangement of vinylcyclopropane into skipped diene. A
detailed mechanistic study revealed that this transformation
involves regioselective ring-opening of the cyclopropane ring
followed by 1,2-migration of one of the cyclopropane sub-
stituents. Interestingly, our investigations showed that skipped
diene is the kinetic product of the process but formation of a
more stable cyclopentene is also accessible. The fundamental
understanding of the processes involved enabled the develop-
ment of divergent methodologies allowing to obtain cyclo-
pentene or skipped diene from vinylcyclopropane in a selective
and controlled manner.
Introduction
1,1-dicarbonylester vinylcyclopropane 1 selectively into either
skipped diene 2 or cyclopentene 3 (Scheme 1c).
The special reactivity of donor-acceptor cyclopropanes has
been extensively studied over the last decades, showing their
high versatility as building blocks in organic synthesis.[1] Indeed,
the highly strained character of the ring and the polarization of
the intracyclic CÀ C bond between the donor and the acceptor
substituents favor the heterolytic ring-opening of the cycle to
generate a 1,3-zwitterion intermediate. This latter can then be
engaged into a variety of synthetically useful transformations
such as (3+2),[1a,g,2] (3+3)[1a,d,g,3] or (4+3)[1a,4] cycloadditions, or
reactions with nucleophiles and electrophiles[5] (Scheme 1a). In
the case of vinylic substitution, i.e. vinylcyclopropane (VCP)
derivatives, the cyclopropane can also rearrange into cyclo-
pentene (CP) or be involved in (5+2) cycloadditions.[6] The
synthetic interest of these specific reactivities of donor-acceptor
cyclopropanes has been illustrated by their exploitation in key
steps of total syntheses of many important targets, including
natural products.[7]
Recently, serendipity led us to discover a new rearrange-
ment of donor-acceptor vinylcyclopropane into skipped diene 2
(Scheme 1b).[8] In the course of its study, we observed that
varying reaction conditions led in some cases to the formation
of a cyclopentene 3 as the main product, instead of the skipped
diene 2. We now have carried out a comprehensive mechanistic
study of the processes involved in these rearrangements which
enables us to develop reaction conditions allowing to rearrange
[a] A. Delbrassinne,+ Dr. M. Richald,+ J. Janssens, Prof. R. Robiette
Institute of Condensed Matter and Nanosciences
Université catholique de Louvain
Place Louis Pasteur 1 box L4.01.02, 1348 Louvain-la-Neuve, Belgium
E-mail: raphael.robiette@uclouvain.be
https://perso.uclouvain.be/raphael.robiette/
[+] These authors contributed equally to this work.
Scheme 1. Reactivity of donor-acceptor (vinyl)cyclopropane and our diver-
gent strategies toward skipped dienes and cyclopentenes.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100430
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Results and Discussion
B it will be positioned on the double bond in the skipped diene.
In fact, the rearrangement of 1a-D led to the exclusive
formation of 2a-D providing support to our proposed mecha-
nism and indicating that the ring opens on the styryl side with
the phenyl group migrating (pathway B in Scheme 2).
Mechanism
In order to get a fundamental understanding of the mechanism
of observed rearrangements leading to 2 (see Scheme 1b–c),[8]
we set up a combined experimental and computational study.
We hypothesized that the rearrangement into skipped diene 2
could involve the heterolytic cleavage of the three-membered
ring, to form a 1,3-zwitterion intermediate, followed by the 1,2-
migration of the group in β position of the so-formed
carbocation. This leaves us however with two possibilities: the
ring-opening can occur either on the benzylic side with the 1,2-
migration of the styryl group or instead on the styryl side with
the phenyl group migrating (pathway A and B in Scheme 2,
respectively). In order to support our mechanistic postulate and
determine which group migrates, we carried out the rearrange-
ment on a deuterium labelled VCP 1a-D. Indeed, if this is
pathway A which is operating, the deuterium atom will end up
in the central benzilic position whereas in the case of pathway
In our search for optimal reaction conditions to perform the
rearrangement of VCP 1 into skipped diene 2, we found that
extension of the reaction time leads to the formation of a
cyclopentene 3 as the main product (Scheme 3a). This observa-
tion suggests that formation of skipped diene 2a is reversible
and that the cyclopentene 3a is the thermodynamic product. In
order to test this hypothesis, we isolated skipped diene 2a and
then subjected it to the reaction conditions. We found that,
upon treatment with 5 eq. TiCl4 for 24 h, skipped diene 2a leads
to cyclopentene 3a (Scheme 3b). This control experiment
demonstrates that cyclopentene 3a can be formed from
skipped diene 2a and hence supports the fact that this latter is
the kinetic product whereas the cyclopentene is the thermody-
namic one. The monitoring of skipped diene and cyclopentene
yields over time provided results which are also in good
agreement with this proposition (see Supporting Information).
In order to give further support to our proposed mechanism
for the transformation of vinylcyclopropane 1 into skipped
diene 2 and understand how this latter rearranges into cyclo-
pentene, we have explored the different possible pathways by
computational means using the model vinylcyclopropane 1co
(Scheme 4). Calculations were carried out at the M06-2X/6-311
+G**//M06-2X/6-31+G* level, including a continuum descrip-
tion of dichloromethane as the solvent (see the Supporting
Information for computational details). Obtained results are in
good agreement with our experimental results and shed light
on the mechanism of observed rearrangements.
First, our calculations indicate that, in the presence of TiCl4,
a rapid isomerization (ΔG� =18.4 kcalmolÀ 1) from cis to trans
VCP must take place by epimerization of the allylic strereo-
center, via
a
ring-opening/rotation/ring-closing sequence
(Scheme 4). This epimerization is predicted to be much faster
than any other transformation, as also supported by experimen-
tal observations showing full conversion of 1a-cis into 1a-trans
in less than 1 min under the rearrangement conditions (see
Supporting Information). Accordingly, only the reaction of the
most stable trans isomer of VCP (1co-trans-E-TiCl4) will be
discussed further.
Scheme 2. Postulated mechanisms for skipped diene formation and deuter-
iation experiment.
We modelled both possibilities for the ring-opening of the
cyclopropane, pathways A and B in Scheme 2. Obtained results
indicate that heterolytic cleavage of the C1À C3 bond between
the diester substituted and the allylic carbon atoms is more
Scheme 3. Influence of reaction conditions on skipped diene/cyclopentene
selectivity and rearrangement of skipped diene 2a.
Scheme 4. Cis-trans isomerization mechanisms (free energy in kcal/mol
relative to 1co-trans-TiCl4). See Supporting information for full details.
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favoured than ring-opening on the benzylic side (C1À C2 bond),
pentene selectivity should be determined at the TSmig and
TScycl level. The computed lower relative free energy of TSmig-
E as compared to TScycl is in good agreement with the
observed highly selective formation of skipped diene in the first
minutes of the reaction (vide supra).
by 12.7 kcalmolÀ 1 (Scheme 5). Formation of skipped diene from
zwitterion 4co-trans-E-TiCl4 is also predicted to be more
favoured than via intermediate 4co’-TiCl4, in good agreement
with our deuterium-labelling experiment (see Scheme 2).
Intermediate 4co-trans-E-TiCl4 can in fact be formed in two
isomeric forms, E and Z (Scheme 6). Both isomers are predicted
to be accessible through a low free energy barrier (ΔG� =15.4
and 19.7 kcalmolÀ 1, respectively) with the E isomer being more
stable than the Z one (ΔG=13.4 and 19.1 kcalmolÀ 1, respec-
tively). Our calculations show that both isomers, 4co-trans-Z-
TiCl4 and 4co-trans-E-TiCl4, can undergo 1,2-migration of the
phenyl group to lead to skipped diene 2co-TiCl4 through a low
free energy barrier (ΔG� =20.0 and 21.0 kcalmolÀ 1 for Z and E
isomer, respectively). However, since the geometrical impossi-
bility for the C1 atom to get close to the electrophilic C5 atom
in 4co-trans-E-TiCl4, only the Z isomer (4co-trans-Z-TiCl4) can
ring-close to lead to cyclopentene 3co-TiCl4 (ΔG� =
22.8 kcalmolÀ 1). The ring-opening of 1co-trans-TiCl4 being
predicted to be reversible, the kinetic skipped diene/cyclo-
The nearly thermoneutral character of the skipped diene
2co-TiCl4 formation presages its reversibility. This reversibility
together with the computed higher stability of cyclopentene
3co-TiCl4 as compared to skipped diene 2co-TiCl4 provide
strong support to our hypothesis that skipped diene is the
kinetic product whereas formation of cyclopentene is the result
of a thermodynamic selectivity.
Overall, our mechanistic study indicate that observed
rearrangements proceed via a reversible ring-opening of the
cyclopropane ring to form a 1,3-zwitterion. This latter can then
undergo either 1,2-migration to lead to skipped diene or
cyclization toward cyclopentene. The free energy barrier to 1,2-
migration is however lower than the one to cyclization,
accounting for the fact that skipped diene (2) is the first
product formed during the reaction (kinetic selectivity). Yet,
skipped diene formation is reversible what leads eventually to
the accumulation of the more stable cyclopentene (3) (thermo-
dynamic selectivity).
The fundamental understanding of the different pathways
provided by this study allows envisioning the selective
divergent synthesis of skipped diene and cyclopentene from
vinylcyclopropane. We thus decided to capitalize on this and on
our experience in vinylcyclopropane synthesis to develop short
strategies toward skipped diene and cyclopentene from
sulfonium ylides and activated olefins or 1,3-dienes.
Synthesis of VCPs
Vinylcyclopropanes 1 were synthesized in one step according to
two strategies previously developed in our group.[9] Both
strategies use sulfonium ylides but in the first case that are
benzylic sulfonium ylides which are reacted with 1,3-dienes
whereas the second methodology involves allylic sulfonium
ylides and activated olefins (Scheme 7). These methodologies
enabled the synthesis of differently substituted vinylcyclopro-
Scheme 5. Regioselectivity for ring-opening (free energies in kcalmolÀ 1
relative to 1co-trans-TiCl4).
Scheme 6. Computed reaction pathways (free energy in kcal/mol relative to
1co-trans-TiCl4).
Scheme 7. Synthesis of VCPs (1).
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panes in good to excellent yields (see Supporting Information
for details).
the only isolated product being cyclopentene (vide infra). Our
computational results suggest that this limitation can be
accounted for by the increased stabilization of the zwitterion (4)
by conjugation and hence the facilitation of the cyclization (see
Supporting Information).
Synthesis of skipped dienes
Next, we turned our attention to the nature of the migrating
group (R1). The reaction works nicely with aryl bearing electron-
donating (entries 13–16 in Table 1) and slightly electron-with-
drawing (entry 17) substituents as well as with heteroaromatic
and cyclopropyl[11] groups (entries 19–20). In the case of
electron-poor aryl (entry 18) and alkyl (entries 22–23) groups
however no skipped diene could be observed. Instead exclusive
formation of cyclopentene (3) was obtained (vide infra). This
observation is in line with the generally observed low migratory
aptitude of these groups in pinacol[12] and Wagner-Meerwein[13]
rearrangements. Indeed, their low migratory aptitude leads to a
slowing down of the migration whereas the nature of R1 has no
significant impact on the cyclization, this latter thus becoming
the faster pathway (see Supporting Information for computa-
tional results supporting this analysis).
Our mechanistic studies showed that, in the presence of TiCl4,
skipped diene 2 forms very fast from VCP 1 whereas cyclo-
pentene 3 formation is observed only in a second phase of the
reaction. Accordingly, our optimization of reaction conditions
using 1a (R1,R2 =Ph; R3,R4 =H) showed that a reaction time of
15 min in the presence of 1 eq. TiCl4 in dichloromethane is
optimal to obtain skipped diene 2a in excellent yield (entry 1,
Table 1). Other Lewis acids were also tested and shown to
mediate the rearrangement but TiCl4 was found to be the most
efficient one as well as the easiest to handle (See Supporting
Information).
With optimized reaction conditions in hand, we next
explored the scope of this transformation (see Table 1). First, we
evaluated a range of VCP 1 with variously substituted double
bonds (R2, R3 and R4).[10] This transformation exhibits good
tolerance to diverse aromatic substitutions (see entries 1–6 in
Table 1), alkyl groups (entry 7) or polysubstitution (entries 10–
12). We observed one limitation however with highly electron-
rich aromatic groups. Indeed, in the case of R2 =p-MeOC6H4
(entry 6), formation of skipped diene could not be observed,
With respect to the nature of the electron-withdrawing
groups (EWGs), our attempt to change the ester groups by
cyano groups led to exclusive formation of corresponding
cyclopentene (entry 24; Table 1).
In order to observe the migration of electron-poor aryl and
alkyl groups despite their low migratory aptitude, we thought
of disfavouring the competing cyclization to cyclopentene (3).
We reasoned that this could be achieved by increasing the
steric bulk at the C5 position and/or by having no aryl
substituents in this position. Indeed, the cyclization toward
cyclopentene is made possible according to Baldwin’s rules[14]
only because of the delocalization of the positive charge in 5
into the aryl substituent (R2) which leads to a partial 5-exo-trig
character of the cyclization (Scheme 8).
Satisfyingly, both of these strategies proved to be efficient.
Indeed, rearrangement of VCPs substituted on the double bond
by an isopropyl group (R2 =i-Pr) showed that this substitution
allows preventing cyclopentene 3 formation. However, instead
of the formation of the desired skipped diene (2), we observed
Table 1. Synthesis of skipped dienes from VCPs.
Entry EWG
R1
R2
R3
R4
Yield [%][a]
1
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et Ph
CO2Et CH=CHPh
CO2Et p-MeC6H4
CO2Et p-MeOC6H4
CO2Et m-MeOC6H4
CO2Et o-MeC6H4
CO2Et p-FC6H4
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
95
95
quant.
71
2[b]
3
p-CO2MeC6H4
p-FC6H4
p-MeC6H4
p-MeOC6H4
i-Pr
H
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
4
5
6
40
0[c]
7
15(90)
(41)
8[d]
9
H
Me 54
10
11
12
13
14[d]
15
16
17
18
19
20
21
22
23
24
Ph
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
81
25
54
95
quant.
28(37)
25(39)
71
CO2Et p-CO2MeC6H4 Ph
0[c]
CO2Et 2-furyl
CO2Et cyclopropyl
CO2Et CH=CHPh
CO2Et i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
quant.
50
80
0[c]
CO2Et t-Bu
0[c]
CN
Ph
H
0[c]
[a] Yield in isolated, analytically pure, material. In brackets, yield
determined on the crude mixture by 1H NMR using an internal standard.
[b] Reaction performed on isolated trans VCP. [c] Exclusive formation of
cyclopentene was observed. See Table 4. [d] 0.4 eq TiCl4.
Scheme 8. Influence of substitution on the 1,2-migration/cyclization selectiv-
ity.
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quenching of the zwitterionic intermediate 4 by a chloride ion
that in this rearrangement H is a better migrating group than
Me, i-Bu and i-Pr.
providing from the catalyst, TiCl4 (see Supporting Information).
Accordingly, in order to reduce this quenching, we tried to
perform the rearrangement with FeCl3, the other Lewis acid
which was identified by our screening (vide supra). Under these
reaction conditions, skipped dienes resulting from the migra-
tion of t-Bu and electron-poor aryl groups could be obtained,
with no trace of corresponding cyclopentene (see entries 1–2 in
Table 2). Interestingly, the presence of an electron-poor aryl
substituent in R2 position is also sufficient to hamper the
cyclization by decreasing its partial 5-exo-trig character and
observe the migration of t-Bu and H (entries 3 and 7).
Last, we searched for a one-pot procedure allowing to
perform the synthesis of the VCP by cyclopropanation and
rearrangement in one synthetic step. Using 1,3-diene 5a (R2 =
Ph) and sulfonium salt 6a (R1 =Ph) as model substrates, various
one-pot reaction conditions were explored. In the event, we
found that deprotonation of the ylide by NaH to provoke the
cyclopropanation followed by addition of TiCl4, at room temper-
ature, enables isolating skipped diene 2a in 90% yield (entry 1,
Table 3). This one-pot methodology proved to be applicable to
various substrates (entries 1–5).
The increase of the steric bulk at the C5 position by double
phenyl substitution allows also observing skipped dienes
resulting from the migration of p-CO2MeC6H4 with no trace of
corresponding cyclopentene (see entry 8 in Table 2).
Synthesis of cyclopentenes
However, in the case of methyl, isopropyl and isobutyl
migrating groups (entries 4–7; Table 2), no migration of the
alkyl group could be observed, even if cyclopentene (3) was still
not formed. Instead, that is a skipped diene 9 resulting from the
migration of the hydrogen atom which was isolated, indicating
In accordance with our mechanistic understanding, our opti-
mized reaction conditions to obtain cyclopentene 3 involve
24 h reaction at room temperature in the presence of TiCl4
(Table 4). Investigation of the reaction scope showed that the
rearrangement into cyclopentene is not very sensitive to the
nature of the R1 group (see entries 1–6). Interestingly, a total
diastereoselectivity in favor of the cis isomer is observed in all
cases, except when an electron-rich (hetero)aromatic group is
present on the cyclopentene (see entries 7–9). Indeed, in these
cases, the cis isomer is formed but it was found to isomerize to
the more stable trans isomer under reaction conditions (see
Supporting Information).
Table 2. Disfavouring cyclization to allow migration of poor migrating
groups.
The substitution of the double bond showed, on the
contrary, some limitations. Indeed, as discussed above, sub-
stitution by an alkyl group prevents the cyclisation (entry 10,
Table 2).
Yield [%][a]
Entry
R1
R2
R3
2
9
3
In this case, the electron-withdrawing groups (EWG) can
also be varied. Indeed, the biscyano cyclopropane derivatives
(EWG=CN) led to corresponding cyclopentene in excellent
yield (see entry 11; Table 4).
1
2
3
4
5
6
7
8
t-Bu
p-CO2MeC6H4
t-Bu
i-Pr
Me
i-Bu
i-Pr
i-Pr
i-Pr
H
H
H
H
H
H
H
Me
57
12
33
0
0
0
0
5
0
26
39
49
23
6
0
0
7
0
0
0
0
0
p-CO2MeC6H4
i-Pr
i-Pr
i-Pr
p-CO2MeC6H4
Me
0
30
p-CO2MeC6H4
Table 4. Synthesis of cyclopentenes from VCPs
1
[a] Yield determined on the crude mixture by H NMR using an internal
standard.
Table 3. One-pot synthesis of skipped dienes from benzyic sulfonium
ylides and 1,3-dienes.
Entry
EWG
R1
R2
Yield [%][a]
cis/trans[b]
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
Ph
Ph
Ph
Ph
Ph
Ph
Ph
41
26
27
70
93
82
79
86
(39)
0[c]
90
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
88/12
80/20
>2/98
–
p-CO2MeC6H4
p-FC6H4
i-Bu
t-Bu
i-Pr
Ph
Ph
Ph
Ph
Ph
Entry
R1
R2
Yield [%][a]
1
2
3
Ph
Ph
Ph
Ph
Ph
90
95
80
(43)
45
p-MeC6H4
2-furyl
p-MeOC6H4
i-Pr
p-MeOC6H4
p-MeC6H4
p-FC6H4
Ph
9
10
11
4
5[b]
p-CO2MeC6H4
Ph
50/50
1
[a] Yield in isolated, analytically pure, material. In brackets, yield
determined on the crude mixture by 1H NMR using an internal standard.
[b] 45 min of reaction.
[a] Yield in isolated, analytically pure, material. [b] Determined by H NMR
on the crude reaction mixture. [c] Exclusive formation of skipped diene 2 is
observed (see Table 1).
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All our attempts to develop reaction conditions allowing to
Keywords: Cyclopentenes · Density functional calculations ·
Rearrangement · Skipped dienes · Vinylcyclopropanes
prepare cyclopentenes 3 in one synthetic step from activated
olefins 7 and allylic sulfonium salts 8 led only to poor yields (<
10%).
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Conclusion
We have discovered a new rearrangement of vinylcyclopropane
which opens a way to skipped diene. This rearrangement is
very selective and proceeds rapidly (15 min) at room temper-
ature under TiCl4 or FeCl3 catalysis. Interestingly, we showed
that extending the reaction time enables obtaining instead
cyclopentene as the main product. A combined experimental
and computational study of the mechanism of these rearrange-
ments showed that the first step consists in the ring-opening of
the cyclopropane yielding a zwitterion intermediate. A 1,2-
migration of one of the cyclopropyl substituent can then occurs
to lead to a skipped diene. This 1,2-migration is however
reversible and cyclization of zwitterionic intermediate to a more
stable cyclopentene is eventually observed if the reaction is left
a sufficiently long time.
The fundamental understanding of mechanisms involved
enabled us to identify factors controlling skipped diene/cyclo-
pentene selectivity and develop divergent strategies toward
skipped dienes substituted on the central center and polysub-
stituted cyclopentenes from vinylcyclopropanes just by chang-
ing the reaction conditions.
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Experimental Section
Full details on synthetic methods and analytical data, along with
full computational details and data can be found in the Supporting
Information.
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Acknowledgements
This work was supported by the Fonds de la Recherche
Scientifique-FNRS (F.R.S-FNRS), the Fonds pour la formation à la
Recherche dans l’industrie et dans l’Agriculture (PhD fellowship to
MR) and the Fonds Spéciaux de Recherche (PhD fellowship to AD).
Computational resources have been provided by the supercomput-
ing facilities of the Université catholique de Louvain (CISM/UCL)
and the Consortium des Équipements de Calcul Intensif en
Fédération Wallonie Bruxelles (CÉCI) funded by the F.R.S.-FNRS
under convention 2.5020.11 and by the Walloon Region. We thank
S. Ouk, through the Fondation Louvain, for very kind financial
support. We thank Gabriella Barozzino-Consiglio, Guillaume Dassy
and Tran Trieu-Van for their technical assistance. RR is a Maître de
Recherche of the F.R.S.-FNRS.
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Conflict of Interest
The authors declare no conflict of interest.
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Full Papers
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the outcome of the reaction. This observation is in good agreement
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Manuscript received: April 9, 2021
Revised manuscript received: April 22, 2021
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