Kinetic resolution in the [2+2] cycloaddition of ketenes: An experimental and theoretical study

Article abstract of DOI:10.1002/chem.201405393

The kinetic resolution of Z and E olefins by [2+2] cycloaddition with ketenes allows the isolation of pure E olefin, as well as the synthesis of pure cis-cyclobutanones, starting from Z/E mixtures. A computational rationale for this kinetic difference is reported. The obtained difference of energy of activation matches with the experimental results.

Full text of DOI:10.1002/chem.201405393

DOI: 10.1002/chem.201405393
Communication
&
Kinetic Resolution
Kinetic Resolution in the [2+2] Cycloaddition of Ketenes:
An Experimental and Theoretical Study
Pauline Rulliꢀre,[a] Sꢁbastien Carret,[a] Anne Milet,[b] and Jean-FranÅois Poisson*[a]
Abstract: The kinetic resolution of Z and E olefins by
[2+2] cycloaddition with ketenes allows the isolation of
pure E olefin, as well as the synthesis of pure cis-cyclobu-
tanones, starting from Z/E mixtures. A computational ra-
tionale for this kinetic difference is reported. The obtained
difference of energy of activation matches with the experi-
mental results.
Figure 1. Kinetic resolution of olefins with ketenes.
Despite numerous progresses, the selective formation of
stereodefined olefins remains a challenge for the synthesis of
a number of substrates. For instance, methods for synthesizing
stereodefined silyl enol ethers are scarce: with most methods,
E and Z mixtures of olefins are obtained.[5] Even a simple olefin
such as the commercially available crotyl alcohol is sold as a Z/
E mixture. In this regard, E-olefins are often formed as the
major isomer, but rarely as the unique isomer, as opposed to
Z-olefins, more easily accessible by selective hydrogenation of
triple bonds. In addition, the separation of the two isomers of
an alkene is often impossible by standard chromatographic
techniques.[6] Considering the potential kinetic resolution of Z-
and E-olefin in the [2+2] cycloaddition with ketenes, we decid-
ed to test the efficiency and synthetic utility of the process
with the aim to selectively expunge Z-olefins from Z/E mix-
tures.[7] Indeed, as Z-olefins are meant to be much more reac-
tive in the [2+2] cycloaddition with ketenes, it could be ex-
ploited to gain access to pure E isomer of a broad range of al-
kenes otherwise very difficult, or often impossible to isolate.
The first substrate chosen to test the kinetic resolution was
triisopropylsilyl crotyl ether 1, directly obtained from crotyl al-
cohol, commercially available as a 5:95 Z/E mixture of isomers.
Treated with 0.15 equivalent of in situ-generated dichloroke-
tene, the pure E triisopropylsilyl allylic ether (E)-1 was isolated
in 90% yield (Table 1, entry 1). In this process, there was no
trace of remaining Z-alkene in the crude reaction mixture. This
first experiment showed the great Z/E kinetic difference as
only a few percent of Z-olefin reacted not only preferentially
but seemingly exclusively. A second experiment was conduct-
ed with a 12:88 mixture of methyl oleate and methyl elaidate
2: upon addition of 0.25 equivalent of dichloroketene, no trace
of the Z-olefin (methyl oleate) remained in the crude product.
Methyl elaidate (E)-2 could thus be obtained in pure form in
an outstanding 98% yield out of the 88% present in the start-
ing material (Table 1, entry 2). The cycloaddition thus repre-
sents a practical method for obtaining pure methyl trans-9-oc-
taenoate, with the trans isomer being twelve to twenty times
more expensive than the cis isomer. Commercial cyclodode-
The [2+2] cycloaddition of two olefins certainly represents the
most useful method for the synthesis of cyclobutanes, which
abound in nature as biologically active substances and are also
key synthetic intermediates toward medicinal compounds.[1] In
this area, the thermal [2+2] cycloaddition of ketenes with ole-
fins offers a unique and very selective entry to a wide array of
cyclobutanones.[2] This cycloaddition proceeds regio-, stereo-,
and often chemioselectively as a result of the orbital-controlled
transformation in a concerted asynchronous mechanism.[3] The
stereochemistry of the alkene partner is therefore conserved in
the cyclobutanone product: a Z-alkene leads to a cis-cyclobuta-
none and a E-alkene leads to a trans-cyclobutanone. Another
very interesting feature of this reaction, overall far less docu-
mented, is the enhanced reactivity of Z-alkenes over E-al-
kenes.[2,4] This interesting property is not only underused, but
in addition no theoretical study has been undertaken to ex-
plain this unusual kinetic difference. In this communication, we
will first test the usefulness of this feature and next address
theoretically the effect of olefin stereochemistry in the cycload-
dition process in regard to the energetic and stereoselective
aspects of the reaction in its intermolecular version. (Figure 1)
[a] P. Rulliꢀre, Dr. S. Carret, Prof. J.-F. Poisson
Universitꢁ Joseph Fourier, CNRS
Dꢁpartement de Chimie Molꢁculaire, SERCO
UMR 5250, ICMG FR-2607
BP 53, 38041 Grenoble CEDEX 9 (France)
Fax: (+33)4-76-63-57-54
E-mail: jean-francois.poisson@ujf-grenoble.fr
[b] Prof. A. Milet
Dꢁpartement de Chimie Molꢁculaire
ꢁquipe Chimie Thꢁorique
UMR 5250, ICMG FR-2607
CNRS, Universitꢁ Joseph Fourier
BP 53, 38041 Grenoble CEDEX 9 (France)
Fax: (+33)4-76-63-57-54
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405393.
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ration of isomeric mixture of olefins, to isolate pure E-olefins,
either alkenes or enol ethers.
Table 1. Isolation of the E isomer starting with a Z/E mixture of isomers.
A useful complement to the isolation of pure E-olefins by
using kinetic resolution is the selective synthesis of cis-cyclobu-
tanones starting from Z/E mixtures of olefins. By treatment of
dichloro, dimethyl, or diphenyl ketenes with alkenes or enol
ethers, only the cis-cyclobutanones were obtained, with com-
plete conversion of the Z material, thus affording the cis-cyclo-
adduct in high yields and with excellent diastereoselectivity
(Table 2). For instance, the treatment of dichloroketene with
cyclododecene 3 followed by dechlorination led to cyclobuta-
none 8 as a single diastereoisomer (Table 2, entry 1). The cyclo-
addition of dichloroketene with ethyl propenyl ether 4 fol-
lowed by reduction led to cyclobutanol 9 in moderate yield
Entry Alkene
Z/E[a] R3[b]
Recovered
alkene
Yield[c]
1
2
5:95
Cl (0.15)
90[d]
98[d]
1
2
(E)-1
(E)-2
12:88 Cl (0.25)
3
71:29 Cl (1.0)
78[d]
3
4
(E)-3
(E)-4
Table 2. Isolation of cis-cyclobutanones starting with a Z/E mixture of iso-
mers.
4
5
6
7
63:37 Ph (0.8)
83:17 Ph (1.08)
70:30 Ph (0.88)
64:36 Ph (1.55)
81[e]
(50)[d]
66[e]
5
6
(E)-5
(E)-6
77[e]
89[e]
Entry Alkene
Z/E[a] R3[b]
Product
Yield[c] d.r.[a]
1
71:29 Cl (0.9)
57[d]
98:2
96:4
7
(E)-7
3
8
1
[a] Determined by using H NMR spectroscopy. [b] Equivalent of ketene in
parenthesis. [c] Based on the proportion of the E isomer in the starting
material. [d] Isolated pure product. [e] Yield based on the cyclobutane/E
enol ether ratio; see the Supporting Information.
2
63:37 Cl (0.7)
48[e]
4
9
3
Ph (0.8)
Me (4.0)
99
88
86
94
63
98:2
cene 3 is also sold as a mixture of Z/E isomers (71:29). The sep-
aration of the two isomers has been realized through multiple
recrystallizations of their silver complex.[6] With dichloroketene,
only the Z isomer reacted, affording the pure, less abundant E
isomer in a single operation in 78% yield (Table 1, entry 3).
Starting from simple alkene, the preferential reactivity of the Z
isomer is a unique feature allowing for the isolation of the
pure E-olefin. The isolation of enol ethers in pure isomeric
form, hardly possible to access by standard methods, was next
undertaken. Enol ethers are much more reactive than simple
alkenes in [2+2] cycloaddition with ketene: it was thus decid-
ed to use the less reactive diphenylketene to test the kinetic
resolution in this case. The reaction of diphenyl ketene
(1.2 equiv to the olefin) with ethyl propenyl ether 4 (Z/E=
63:37) led to the pure E enol ether: this enol ether could be
isolated by simple distillation from the crude reaction mixture
in 50% yield. The same result was obtained with enol ether 5.
With silyl enol ethers (6 and 7, Table 1, entry 5 and 7), the cy-
cloaddition also occurred only with the Z isomer, regardless of
the substituent on the enol ether. In all cases, no trace of the Z
isomer remained in the crude product, and only few percent
of the E isomer reacted. The [2+2] cycloaddition of ketene
thus represents a very practical solution for the chemical sepa-
4
10
11
4
>98:2
98:2
4
5
83:17 Ph (1.1)
5
12
13
6
Me (5.0)
>98:2
97:3
5
7
6
8
7
70:30 Ph (0.9)
14
64:36 Ph (0.8)
90
98:2
15
[a] Determined by using NMR spectroscopy. [b] Equivalent of ketene in
parenthesis. [c] Yield of the isolated product based on proportion of start-
ing enol ether. [d] Yield for two steps: cycloaddition and dechlorination.
[e] Yield for two steps: cycloaddition and reduction with LiAlH4.
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and high diastereoselectivity (Table 2, entry 2). With the same
enol ether, the reaction of either dimethyl or diphenylketene
with enol ether 4 was much more efficient, both in terms of
yield and diastereoselectivity: the cis-cyclobutanones 10 and
11 were obtained in good to excellent yields with good to ex-
cellent diastereoselectivities (Table 2, entries 3 and 4). Similar
results were obtained with ethyl butenyl ether 5 (Table 2, en-
tries 5 and 6). Finally, silyl enol ethers 6 and 7 were also con-
verted into the corresponding cis-cyclobutanones 14 and 15
with only traces of the trans products (Table 2, entries 7 and 8).
Overall, in [2+2] cycloaddition involving ketenes, diastereo-
merically enriched cyclobutanones can easily be obtained re-
gardless of the stereochemical purity of the starting olefins.
Having experimentally proven the kinetic non-equivalence
of Z/E-olefin in [2+2] cycloadditions, it seemed important to
gain insight into the mechanistic origin of this dichotomy. To
the best of our knowledge, no theoretical studies have been
realized on this Z/E reactivity since the first theoretical study
on the cycloaddition of ketene with alkene.[3] The mechanistic
basis of ketene–alkene [2+2] cycloaddition were set by the
groups of Houk[8a] and Moyano[8b] in the 1990s. They first
showed the importance of the nearly perpendicular approach
of the ketene to the alkene, and also that the quasi-pericyclic
[p2s+(p2s+p2s)] reaction mechanism is more relevant than
a concerted asynchronous (p2s+p2a) cycloaddition.[8,9] Their re-
activity investigation was realized using respectively ab initio
(HF and MP2 for the simplest examples) and semi-empirical
calculations (AM1). In these works, the difference of reactivity
of Z/E-alkenes was not addressed. However, the enhanced re-
activity of the Z-alkene over the E-alkene has tentatively been
justified by simple steric interactions arguments[10] or by as-
suming that the energetic effects of the alkenes substituents
would be additive.[8a] Applying this shortcut would lead to op-
posite results based on Houk or Moyano’s results (inversion of
relative stability between TS3 and TS4: Table 3, entry 1 and 2).
It was thus worthwhile examining simple cycloaddition of ke-
tenes and Z/E-alkenes at the DFT level.
Table 3. Relative activation energy [kcalmolꢀ1] for the transition states of
propene with ketenes.
Entry
R
TS1
TS2
TS3
TS4
1
2
3
4
5
6
H[a]
0
0
0
0
0
0
4.9
1.2
2.9
4.3
3.5
4.3
4.5
6.8
5.2
4.8
5.5
5.7
6.9
6.0
6.0
8.6
9.1
10.7
H[b]
H[c]
Me[c]
Cl[c]
Ph[c]
[a] Results reported by Houk et al. (RHF/3-31G).[8a] [b] Results reported by
Moyano et al. (AM1).[9b] [c] Our calculations (B3LYP/6-31+G(d,p)).
tion are additive is not satisfactory. Moreover, both steric repul-
sion and the effect of positive charge stabilization are inter-
twined, and therefore cannot justify that the Z-alkenes are
more reactive than the E-alkenes. Calculations on the cycload-
dition between symmetrically substituted ketene and disubsti-
tuted Z/E-but-2-ene were therefore next performed. For each
isomer, there are two approaches: one, called “anti”, in which
the alkene molecule approaches the ketene with its substitu-
ents as far as possible from the ketene substituents, and
a second, called “syn”, in which the olefin approach takes place
with alkene substituents close to the ketene substituents. The
results showed that the transition states of disubstituted al-
kenes are very similar to those of mono-substituted alkenes,
with the ketene approaching in a slightly bent perpendicular
fashion (Table 4). The calculated difference of energy of activa-
tion between E- and Z-olefins correlates nicely with the experi-
¼
mental results: the lowest activation energy (DG ) is always as-
sociated with the TS Z anti (Table 4). The increase of size of the
ketene results in an increase of this difference of activation
energy: from 1.2 to 5.5 kcalmolꢀ1 with nonsubstituted- and di-
phenylketene, respectively. It turned out that the steric repul-
sion between the alkene substituents either at C3 or at C4 and
the smaller substituent of the ketene, which points toward the
alkene, is of crucial importance, much more important than
the carbonyl interaction with the alkene. The E anti and E syn
transition states are relatively close in energy, especially for
bulkier ketenes, in which a more perpendicular approach leads
to the merge of the two trajectories. Finally, the TS Z syn is en-
ergetically the highest one since it combines steric repulsions
between the ketene substituent with both C3 and C4 alkene
substituents.
Performing calculations using Gaussian 09 D.01 at DFT
B3LYP/6-31+G(d,p) level,[11] a trend of reactivity similar to the
results of Houk and Moyano was found for all four transition
states (TS). These calculations confirm, without surprise, the
importance of the regioselectivity of the process through stabi-
lization of the positive charge by the methyl group (TS1-2<
TS3-4), and a particular unfavorable steric interaction between
the substituent of the alkene and the ketene (TS1<TS2 and
TS3<TS4; Table 3). These results also confirm that TS3 is lower
than TS4, following the previous order reported by Houk, but
opposite to the one reported by Moyano (Table 3, entries 1
and 2). In addition, these results also show that TS2 is always
lower in energy than TS3, as reported by Moyano, but oppo-
site to the results of Houk: hence, the interaction of the alkene
substituent is greater with the ketene substituent compared
with the ketene carbonyl (in combination with the less favora-
ble initial charge development at C3; Table 3).
As enol ethers are commonly used in the [2+2] cycloaddi-
tion with ketene, and also proved to be good substrate for ki-
netic resolution, the computational study of their Z/E differ-
ence of reactivity in [2+2] cycloaddition was next investigated.
With enol ethers, their s-cis or s-trans conformation should be
considered, but it has previously been shown for Diels–Alder
and [3+2] cycloaddition that in the transition state, the s-trans
conformation is always preferred, regardless of the ground
state.[14] For [2+2] cycloaddition, we also confirm that despite
a preference for the s-cis conformation for E-enol ethers with
Simply based on these results, it would be very unreliable to
predict the outcome of the cycloaddition for disubstituted al-
kenes: assuming that the energetic effects of methyl substitu-
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Table 4. Transition structures and activation energy [kcalmolꢀ1] of Z- and
E-butene with ketenes.[a]
Table 5. Transition structures and activation energy [kcalmolꢀ1] of Z- and
E-isopropyl propenyl ether with ketenes.[a]
Z anti
E anti
Z anti
E syn
E anti
Z anti
Z syn
Z syn
¼[b]
Entry
E syn
E anti
DDG
E syn
Z anti
Z syn
Z syn
R=H
33.2
31.8
17.6
29.7
33.3
34.3
20.8
34.8
33.7
36.0
21.9
37.3
34.6
36.6
23.2
35.5
0.1
2.5
3.3
5.2
¼[b]
Entry
R
E anti
E syn
DDG
R=Me
R=Cl
R=Ph
1
2
3
4
H
Me
Cl
39.4
36.5
24.5
38.4
40.6
40.9
29.0
44.7
42.9
42.1
29.3
43.9
43.3
44.6
31.7
48.4
1.2
4.4
4.7
5.5
[a] Drawings thanks to molden;[13] calculation using B3LYP/6-31+G(d,p).
[b] Z/E difference of energy of activation: DG (E syn)ꢀDG (Z anti).[12]
Ph
¼
¼
[a] Drawings thanks to molden;[13] calculation using B3LYP/6-31+G(d,p).
[b] Z/E difference of energy of activation: DG (E anti)ꢀDG (Z anti).[12]
¼
¼
olefins, producing with good diastereoselectivity only the cis-
cyclobutanones.
small substituents (H, Me, Et) on the oxygen, the s-trans con-
formation is always the preferred conformation in the transi-
tion state in the reaction with ketenes (see Supporting Infor-
mation). There are eight potential approaches of the ketene to
the enol ether, but only four of them would develop an
oxygen-stabilized positive charge. Hence, only the four ener-
getically lowest approaches were evaluated (Table 5). Again,
the Z anti transition state shows the lowest activation energy
with all ketenes, and Z syn the highest, except for diphenyl
ketene in which the E anti is the highest (Table 5). Unlike with
butene, the E syn approach is now preferred in all cases over
the E anti structure, probably a result of the more favorable
ketene oxygen interaction over the ketene. As expected, as the
ketene hindrance increase, the difference of reactivity between
Z- and E-butene also increases: from 0.1 to 5.2 kcalmolꢀ1 with
nonsubstituted- and diphenylketene, respectively. The ob-
tained energies are also consistent with the higher reactivity of
enol ethers over alkenes.
Experimental Section
Typical experimental procedure
The resolution of olefin with dichloroketene: Trichloroacetyl chlo-
ride (0.15 to 1.0 equiv) was added dropwise to a suspension of Zn/
Cu (0.5 to 2.0 equiv) and the Z/E mixture of alkene (1 equiv) in dry
Et2O (1.5 mL) at 258C under an argon atmosphere. After stirring
the reaction mixture for 2 h at room temperature, pentane was
then added to precipitate zinc salts, the resulting mixture filtered
over Celite, and the solid washed twice with pentane. The filtrate
was dried over Na2SO4 and concentrated under reduced pressure.
Purification of the crude product by flash chromatography on silica
gel (0 to 5% Et2O in pentane) afforded the pure E-alkene.
Resolution of enol ethers with diphenylketene: Diphenyl ketene
(1.2 equiv) was slowly added at 08C to a Z/E mixture of enol ether
(1.0 equiv of Z) and the orange solution was subsequently stirred
at 08C for 20–24 h. Purification of the crude mixture by flash chro-
matography on silica (0 to 5% Et2O in pentane) afforded the pure
E-alkene.
In summary, the higher reactivity of Z- over E-olefins in
[2+2] cycloaddition originates from the steric repulsion be-
tween the ketene substituent and the substituents of the
olefin. These results are valid for alkenes, and also for enol
ethers as substrates in [2+2] cycloaddition reaction with ke-
tenes. The bulkiest the ketene substituents are, the more Z-se-
lective the reaction is. This high difference of reactivity allowed
for the kinetic resolution of Z/E mixture of olefins in the cyclo-
addition with ketenes, affording pure E-olefins. Moreover, the
[2+2] cycloaddition can be conducted with Z/E mixtures of
Synthesis of cis-cyclobutanones: Distilled isobutyryl chloride
(4.0 equiv) in toluene was added to a solution of Z/E mixture of
enol ether (1.0 equiv) and Et3N (4.0 equiv) in anhydrous toluene
(1 mL, 0.1m) at 708C over 4 h. The reaction mixture was stirred for
further 14 h after completion of addition and then quenched by
addition of water. The aqueous phase was extracted with Et2O and
the combined organic layers were successively washed with a solu-
tion of HCl (1n), a solution of NaOH (1n) and brine, dried over an-
hydrous MgSO4, filtered, and the filtrate concentrated under re-
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3459; d) R. Huisgen, L. A. Feiler, G. Binsch, Chem. Ber. 1969, 102, 3460–
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duced pressure. Purification of the crude mixture by flash chroma-
tography on silica gel (0 to 5% Et2O in pentane) afforded the de-
sired cis-cyclobutanone.
Computational details
[5] For an isolated example of pure Z-enol ether formation, see: L. Xie,
K. M. Isenberg, G. Held, L. M. Dahl, J. Org. Chem. 1997, 62, 7516–7519.
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All geometries were fully optimized and all optimizations were fol-
lowed by a frequency calculation to check the nature of the struc-
tures: minima or transition states. DG Values were deduced from
the frequencies calculations in the gas phase at T=298 K and P=
1 atm.
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The authors thank the Universitꢁ de Grenoble and the CNRS
for financial support. P.R. thanks the French Ministry of Re-
search for a Ph.D. fellowship (AMX). Calculations were per-
formed using the cecic, a platform of the CIMENT infrastruc-
ture, which is supported by the Rhꢃne-Alpes region (GRANT
CPER07_13 CIRA).
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Keywords: cycloaddition
olefins · stereochemistry
· ketenes · kinetic resolution ·
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Secci, A. Frongia, P. P. Piras, Molecules 2013, 18, 15541–15572.
[2] For the reactivity of ketenes in general, see: a) T. T. Tidwell in Ketenes,
Vol. 2, Wiley-VCH, Weinheim, 2006, pp. 449–464. See also: b) B. Darses,
S. C. Coote, A. E. Greene, J.-F. Poisson, Org. Lett. 2008, 10, 821–824; c) B.
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[3] a) L. A. Burke, J. Org. Chem. 1985, 50, 3149–3155; b) F. Bernardi, A. Bot-
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¼
[12] At 298 K, a DDG of 1.0 kcalmolꢀ1 leads to a 5:1 ratio of Z/E products
and of 5.0 kcalmolꢀ1 to a 4000:1 ratio.
[13] G. Schaftenaar, J. H. Noordik, J. Comput.-Aided Mol. Design 2000, 14,
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Received: September 24, 2014
Published online on && &&, 2015
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
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ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
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Kinetic Resolution
P. Rulliꢀre, S. Carret, A. Milet, J.-F. Poisson*
&& – &&
Kinetic Resolution in the [2+2]
Cycloaddition of Ketenes: An
Experimental and Theoretical Study
Resolved by reactivity: The effect of Z/
E-olefin stereochemistry in [2+2] cyclo-
addition with ketenes is presented from
both experimental and theoretical as-
pects. This difference of reactivity al-
lowed pure E-olefins to be isolated from
Z/E mixtures of alkenes or enol ethers
by kinetic resolution (see figure).
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!