Evaluating the thermal vinylcyclopropane rearrangement (VCPR) as a practical method for the synthesis of difluorinated cyclopentenes: Experimental and computational studies of rearrangement stereospecificity

Article abstract of DOI:10.1002/chem.201403737

Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). The trans-E isomer (18a), prepared in 70% yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99 %). Rearrangements were monitored by ¹⁹F NMR (100-180 °C). While cis/trans cyclopropane stereoisomerisation was facile, favouring trans-isomers by a modest margin, no E/Z alkene isomerisation was observed even at higher temperatures. Neither cis nor trans Z-alkenoates underwent VCPR, even up to much higher temperatures (180 °C). The cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored by using electronic structure calculations, and UB3LYP/6-31G methodology allowed the energy barriers for cyclopropane stereoisomerisation, diastereoisomeric VCPR and [3,3]-rearrangement to be ranked in agreement with experiment.

Full text of DOI:10.1002/chem.201403737

DOI: 10.1002/chem.201403737
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&
Rearrangements
Evaluating the Thermal Vinylcyclopropane Rearrangement (VCPR)
as a Practical Method for the Synthesis of Difluorinated
Cyclopentenes: Experimental and Computational Studies of
Rearrangement Stereospecificity
David Orr,[a] Jonathan M. Percy,*[a] Tell Tuttle,[a] Alan R. Kennedy,[a] and Zoꢀ A. Harrison[a, b]
Abstract: Vinyl cyclopropane rearrangement (VCPR) has
been utilised to synthesise a difluorinated cyclopentene ste-
reospecifically and under mild thermal conditions. Difluoro-
cyclopropanation chemistry afforded ethyl 3-(1’(2’2’-difluoro-
3’-phenyl)cyclopropyl) propenoate as all four stereoisomers
(18a, 18b, 22a, 22b) (all racemic). The trans-E isomer (18a),
prepared in 70% yield over three steps, underwent near
quantitative VCPR to difluorocyclopentene 23 (99%). Rear-
rangements were monitored by 19F NMR (100–1808C). While
cis/trans cyclopropane stereoisomerisation was facile, favour-
ing trans-isomers by a modest margin, no E/Z alkene isomer-
isation was observed even at higher temperatures. Neither
cis nor trans Z-alkenoates underwent VCPR, even up to
much higher temperatures (1808C). The cis-cyclopropanes
underwent [3,3]-rearrangement to afford benzocyclohepta-
diene species. The reaction stereospecificity was explored by
using electronic structure calculations, and UB3LYP/6-31G*
methodology allowed the energy barriers for cyclopropane
stereoisomerisation, diastereoisomeric VCPR and [3,3]-rear-
rangement to be ranked in agreement with experiment.
Introduction
Rearrangements which can be carried out at lower tempera-
ture are desirable because they minimise the risk of competing
and unwanted stereoisomerisation[11,12] and homodienyl [1,5]-
hydrogen shifts.[13]
The rearrangement of vinylcyclopropanes to cyclopentenes
(the vinylcyclopropane rearrangement, VCPR) has developed
rapidly from its initial discovery by Neureiter over 70 years
ago,[1] becoming an important transformation in the synthesis
of a variety of complex natural
The activation energy for the prototypical VCPR was inde-
pendently reported by Wellington[14] ((50ꢀ0.3) kcalmolꢁ1) and
Baldwin[15] ((51.7ꢀ0.5) kcalmolꢁ1) to be approximately 13 kcal
molꢁ1 less than the energy required to break a cyclopropane
CꢁC bond.[16] The similarity of that quantity to the resonance
stabilisation energy of the allyl radical (calculated as (12.4ꢀ
0.6) kcalmolꢁ1[17]) supports the idea that the rearrangement
proceeds via diradical intermediates strongly. Difluorinated
3[18,19] and perfluorinated 4a[20] precursors (Figure 1) have lower
products.[2] The synthetic scope of
the reaction has expanded signifi-
cantly;[3,4] while the prototypical
reaction of 1 to 2 required high
temperatures for the rearrange-
Scheme 1. Prototypical vinyl-
cyclopropane rearrangement
ment of the simple parent hydro-
(VCPR).
carbon[5,6] (Scheme 1), substrate
modifications[7] and the deploy-
ment of transition metal cata-
lysts[8–10] have even allowed the rearrangement to be carried
out at room temperature in some cases.
Figure 1. Fluorinated VCPR precursors from the literature.
[a] D. Orr, Prof. Dr. J. M. Percy, Dr. T. Tuttle, Dr. A. R. Kennedy, Dr. Z. A. Harrison
WestCHEM Department of Pure and Applied Chemistry
University of Strathclyde, Thomas Graham Building
295 Cathedral Street, Glasgow G1 1XL (UK)
activation energies by up to 10.3 and 17.1 kcalmolꢁ1, respec-
tively. More recently, Smart and co-workers reported that pen-
tafluorinated 4b underwent facile rearrangement, with the
lowest reported activation energy of 28.4 kcalmolꢁ1 (23.3 kcal
molꢁ1 less than the prototypical VCPR).[21] This was attributed
to the higher strain energy of fluorinated cyclopropanes.
O’Neal and Benson[22] proposed that the strain energy increas-
Fax: (+44)141-548-4822
E-mail: jonathan.percy@strath.ac.uk
[b] Dr. Z. A. Harrison
Refractory Respiratory Inflammation DPU
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road
Stevenage, SG1 2NY (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403737.
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es by approximately 5 kcalmolꢁ1 per fluorine atom; this idea
was later supported by experimental[19] and computational
work.[23] Extensive studies by Dolbier and co-workers[24,25]
showed that gem-difluorinated cyclopropanes undergo regio-
specific ring opening via cleavage of the weaker distal carbon–
carbon bond.
Figure 2. Selected reagents used for difluorocyclopropanation.
Despite these seminal and fundamental studies of reactivity,
the VCPR has not been deployed as a method for the synthesis
of difluorinated cyclopentenes. Because of Dolbier’s recent sig-
nificant progress in difluorocyclopropanation methodology,[26]
we sought to develop a building block approach[27] to difluori-
nated cyclopentenes based on the VCPR, which would exploit
fluorine atom effects to decrease the reaction temperatures of
the simple thermal rearrangements.
One prerequisite for a successful route would be a highly effi-
cient difluorocyclopropanation of 9.
A very wide range of difluorocyclopropanation reagents is
now available (Figure 2).[29–31] Inexpensive sodium chlorodi-
fluoroacetate has been used to transform relatively electron-
deficient substrates like 9 but significant excesses of the re-
agent are usually required.[32–34]
Seyferth’s reagent[35,36] was unacceptable, so we sought
more recent methods. Hu et al.[37] used (chlorodifluoromethyl)-
trimethylsilane 14a (prepared from bromochlorodifluorome-
thane[38]) as a difluorocarbene precursor, securing difluorocy-
clopropanes from a range of alkenes and alkynes. More recent-
ly the same group reported that a more general reagent, (bro-
modifluoromethyl)trimethylsilane 14b, could not only effect cy-
clopropanation but also difluoromethylate oxygen, sulfur,
nitrogen and phosphorus nucleophiles.[39] While the reagent
was effective in many cases, the yield of cyclopropane ob-
tained from benzyl acrylate was only moderate (43%).
The proposed strategy was based on the synthesis of di-
fluorinated analogue 8 of a dictyopterene pheromone found
in brown algae, reported by Boland and Erbes[28] (Scheme 2).
The current benchmark reagent, trimethylsilyl fluorosulfonyl-
difluoroacetate (TFDA) 15a was reported by Dolbier and co-
workers in 2000.[40] Fluoride-catalysed decomposition of 15a in
the presence of alkenes results in efficient cyclopropanation;
for example, the reaction with benzyl acrylate afforded the cy-
clopropane in 73% yield. More recently, the Gainesville group
reported that the more robust methyl 2,2-difluoro-2-(fluorosul-
fonyl)acetate (MDFA) 15b would effect many of the TFDA reac-
tions successfully.[26] These reagents looked like extremely
promising starting points for our study.
Scheme 2. Boland and Erbes’ synthesis of Dictyopterene analogue 8.
The conversion of alkenoate 5 to cyclopropane 6 required
the use of Seyferth’s reagent (PhHgCF3), the most reactive di-
fluorocarbene transfer reagent available. The reaction was sac-
rificial in 5, and the yield of cyclopropanation was only moder-
ate (51% based on the reagent). Seyferth’s reagent is highly
toxic and is not readily available, limiting its utility considera-
bly. With the alkenyl groups in place, the diyl rearrangement of
7 to 8 was efficient and facile.
Difluorocyclopropanation of E-cinnamyl acetate 9, then ester
hydrolysis to 11, followed by tandem oxidation/olefination
would secure VCPR precursor 12 via a simple and direct se-
quence (Scheme 3), setting the stage for rearrangement to 13.
Results and Discussion
Following disappointing results with a range of carbene pre-
cursors (see the Supporting Information for details), carbene
formation and trapping was attempted with 9 and MDFA 15b
under the conditions described by Dolbier. We failed to ach-
ieve full conversion of alkene 9 and isolated a previously unob-
served side product (Table 1, entry 1). The presence of iodide
in the reaction mixture could result in (SN2’) nucleophilic ring
opening with strain relief to afford iodide 16; this side product
could be isolated successfully from the crude reaction mixture
using column chromatography, but the yellow/brown oil de-
composed after storage in the refrigerator (see the Supporting
1
Information for the H and 19F NMR spectra which support the
assignment). A 0.25-fold increase in reagent excess over alkene
9 increased the conversion to 95% after 17 h (Table 1, entry 2).
The Dolbier group experienced similar problems during their
optimisation, reporting that reducing the reaction concentra-
tion led to poorer yields.
Scheme 3. Proposed route to difluorinated cyclopentene 13.
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by NOESY and H NMR spectros-
Table 1. Optimisation with MDFA 15b.
copy, respectively, for all four
products (see the Supporting In-
formation).
We found that 18a rearranged
smoothly to difluorocyclopen-
tene 23 even at 908C (Table 2,
entry 1). Cyclopropane stereoiso-
merisation was also observed
(by 19F NMR spectroscopy after
6 h); the cis diastereoisomer 22a
was formed from pure trans-18a,
but thermolysis of the 18a/22a
mixture resulted in the forma-
tion of unique difluorocyclopen-
tene product 23. The product
Entry
15b
[equiv]
TMSCl
[equiv]
Dioxane
[equiv]
Diglyme
[equiv]
KI
[equiv]
Time
[h]
Conversion
(9:10)[a]
Yield
[%][b]
1
2
3
4
2
2
1.7
1.87
0
0.1
2.25
2.77
2.77
2.77
48
17
24
4
4:80[c]
1:19
0:1
32
43
94
85
2.46
2.46
2.46
2.46
2.46
2.46
0.11
1.2[d]
1.2
0
0:1
[a] Determined by crude 1H NMR spectroscopy. [b] Isolated yield. [c] Crude reaction mixture contained 16% 16
(1H NMR spectroscopy). [d] Reaction mixture went to dryness after 5 h and an extra 1.2 equiv of diglyme was
added.
The reaction in diglyme alone afforded 10 in high yield
(94%; Table 1, entry 3) if an additional portion of diglyme was
added when the reaction mixture started to solidify. When the
reaction was stopped after only 4 h, full conversion was ach-
ieved and the high yield of 10 was maintained (85%; Table 1,
entry 4).
connectivity was established by 2D NMR spectroscopy (HSQC/
HMBC) and the trans-configuration was assigned from 1H/1H
1
and H/19F NMR coupling constant analysis (see the Supporting
Information for details). The assignment was confirmed when
23 was oxidised to crystalline epoxide 24 (Scheme 5) using
methyl(trifluoromethyl)dioxirane prepared according to a modi-
fication of a published procedure[42] described by the Baran
group.[43] The original trans-relationship and the unexpected
facial selectivity (vide infra) were
Ester 10 was saponified to afford alcohol 11 in high yield
(Scheme 4). Gram quantities of material could be brought
shown by the elucidation of the
molecular structure in the crystal
(see the Supporting Information
for more details and a discus-
sion).
Microwave irradiation resulted
in
slower
rearrangement
(Table 2, entry 2), but neat 18a
was consumed more rapidly
under conventional heating
((Table 2, entry 3). Under these
conditions, side product 25a was
also formed. [3,3]-Rearrange-
ment[44] of cis-cyclopropane 22a,
Scheme 4. Synthesis of VCPR precursors 18 and 22. Conditions: i) MDFA (2.46 equiv), TMSCl (2.46 equiv), KI
(2.77 equiv), diglyme (1.2 equiv), 1208C, 24 h; ii) K2CO3 (1 equiv), MeOH/H2O, 608C, 2 h; iii) TEMPO (2,2,6,6-tetrame-
thylpiperidine 1-oxyl, 0.1 equiv), BAIB (PhI(OAc)2, 1.15 equiv), DCM, r.t., 6 h; iv) Ph3P=CHCO2Et (1.3 equiv) 2–14 h;
v) H2 (1 equiv, atm), Lindlar cat. (5 mol% Pd), EtOH, r.t., 10 h; vi) Ac2O (1.05 equiv) DMAP (10 mol%), DCM/pyridine,
r.t., 22 h.
through (8 mmol scale from 9), giving access to syn-
Table 2. Selected optimisation results for thermal VCPR of 18a and 22a.
thetically useful quantities of alcohol 11 over two
steps. Vatꢂle’s one-pot oxidation/olefination condi-
tions[41] were implemented next because they avoid-
ed isolation of potentially fragile aldehyde 17. Oxida-
tion of 11 by a TEMPO–BAIB combination, gave full
conversion to aldehyde 17 after 6 h (the reaction was
monitored by 19F NMR spectroscopy). Addition of
(carbethoxymethylene)triphenylphosphorane afford-
ed a separable mixture of 18a and 18b (95:5 by
1HNMR spectroscopy).
Entry
1
VCP
Temp.
[8C]
Time
[h]
Conversion[a]
Yield
[%][b]
18a
22a
23
25a
18a
90
6
26
6
22
17
24
1
1
1
1
0
0
0.19
0
0.14
0
0.63
4.6
0.11
33
1
0
0
0
17
0
–
2[c]
3[d]
4
18a
18a
18a
22a
90
90
100
100
–
–
[e]
The cis-precursors were prepared from 19, via Lin-
dlar reduction and acetylation (86% over 2 steps);
elaboration as before afforded 22a (71%) and 22b
(17%) after the oxidation/olefination step. Cyclopro-
pane and alkene relative configuration was confirmed
0
99
93
5
0
1
0
[a] Ratio determined by 19F NMR spectrscopy. [b] Isolated yield. [c] Microwave irradia-
tion. [d] Neat reaction mixture. [e] Compound 25a isolated in 19% yield.
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Scheme 5. Dioxirane oxidation of VCPR product 23. Conditions: i) Methyl(tri-
fluoromethyl)dioxirane (ca. 3.4 equiv) in trifluoroacetone, ꢁ788C, 1 h then
r.t., 1 h.
followed by dehydrofluorination/rearomatisation of the initial
precursor (vide infra) results in the formation of 25a; the con-
nectivity was established by 2D NMR methods (see the Sup-
porting Information for details). The side reaction could be
avoided when the reaction was run in toluene at 1008C
(Table 2, entry 4). Upon full conversion (determined by 19F NMR
spectroscopy) under these conditions, the reaction solvent was
removed to afford a very high yield of 23 from 18a (99%); 22a
also rearranged exclusively to 23 in excellent (93%) yield
under the same conditions (Table 2, entry 5) (see the Support-
ing Information for examples of crude VCPR spectra). The rela-
tively high reactivity of our precursor system is consistent with
the presence of the CF2 centre and the development of benzyl-
ic radical character; Ingold and co-workers[45] and Newcomb et
al.[46,47] showed that cyclopropyl radical ring opening was accel-
erated strongly when the product radical was benzylic. Roth
and co-workers showed that the VCPR of 3 only occurred
above 2008C[19] so the phenyl group is providing strong activa-
tion.
This VCPR represents a direct and effective way of making
difluorinated cyclopentenes. Whereas radical cyclisation meth-
ods (based on tin hydride chemistry) were deployed by several
groups to access difluorinated cyclopentanes,[48–50] diethylami-
nosulfur trifluoride (DAST) or DeoxoFluor ketone transforma-
tions have secured difluorinated cyclopentanones,[51 ]and Naza-
rov cyclisations[52] difluorinated cyclopentenones. Difluorinated
cyclopentenes are relatively unusual motifs in the synthetic lit-
erature.[53] Qing and co-workers[54] used ring-closing metathesis
(RCM) to form the key cyclopentene ring of carbanucleosides
in which CF2 replaces a furanyl ring oxygen, and Itoh has also
used an RCM approach in which difluorocyclopropane ring-
opening fulfils a pivotal role.[55] Our VCPR-based approach
combines ease of preparation (four high-yielding steps from
commercially available reagents) with an attractive range of
functional groups for further transformation. Previously we
have used difluorinated cycloalkenes as precursors to difluori-
nated carbasugar analogues,[56–58] and exploited the Sharpless
oxidation of phenyl groups in syntheses of difluorinated aldo-
ses.[59]
Figure 3. Experimental (points) and simulated (lines) concentration/time pro-
file for thermolysis (373 K) of a) 18a; b) 22a; 18a=*, 22a=*, 23=~).
started from 22a; within 15 min, most of the cis-cyclopropane
had isomerised to the trans-diastereoisomer 18a, which then
reacted through to 23 (Figure 3b).
The concentration/time profiles could be simulated success-
fully as far as experimental endpoints at 10 h using numerical
integration software (see the Supporting Information for de-
tails) based on the simple model of Scheme 6.
Scheme 6. Kinetic model used in the simulation of parallel VCPR and stereoi-
somerisation pathways.
To investigate the role of cyclopropane stereoisomerisation
more fully, the reactions of both 18a and 22a were monitored
by 19F NMR spectroscopy at 373 K in [D8]toluene (see the Sup-
porting Information for experimental details). As shown in
Table 2, 18a transformed smoothly to 23, but 22a also formed,
reaching a maximum at about 13% of the reaction mixture
after 10 min, and then decaying slowly, showing that cyclopro-
pane stereoisomerisation (Figure 3a) competes effectively with
VCPR. This was observed more clearly when the reaction was
Deconvolution of the rate constants (Table 3) highlighted
the modest equilibrium constant between trans and cis cyclo-
propanes (5.4 starting from trans, 5.6 starting from cis, in
favour of the trans-diastereoisomer) and the facile stereoiso-
merisation (the rate constant is an order of magnitude higher
than that for VCPR).
An approximate Arrhenius determination of activation pa-
rameters was carried out by taking the best first-order fit of
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Stronger heating of 22b also returned a very similar mixture
of 25a and 25b (9:1 by 19F NMR integration). De-aromatised in-
termediate 26 was never observed; elimination of HF driven
by re-aromatisation would be anticipated strongly. Heating iso-
lated 25a to 1808C (Ph2O, 17.5 h) returned more fully conjugat-
ed 25b, presumably via an [1,5]-H shift; 25c (the product of
[1,3]-H shift from 25a) was not detected.
Table 3. Rate constants extracted from reaction simulation.
Substrate
104 k1 [sꢁ1
]
104 k2 [sꢁ1
]
104 k [sꢁ1
]
kꢁ2/k2
ꢁ2
18a
22a
1.6
1.1
3.5
2.6
19.1
14.7
5.4
5.6
The inertness of the Z-alkenoate precursors towards VCPR
surprised us, but we failed to find examples of Z-alkenyl
groups participating, apart from the deuterated species of
Baldwin and co-workers.[60,61] Sustmann[62] and co-workers pre-
pared precursors with Z-alkenyl groups but did not report
their behaviour under rearrangement conditions. Smart et al.[21]
heated a 5:1 mixture of 27a and 27b, to form a 19:1 mixture
of pentafluorocyclopentene 28 and unreacted Z-isomer 27b
(Scheme 8). To our knowledge, Smart’s result provides the only
the data from VCPR of 18a from NMR experiments (363-393 K,
[D8]toluene) (see the Supporting Information for experimental
details); a value for Ea of (29.2ꢀ0.6) kcalmolꢁ1, not unlike that
obtained by Smart and co-workers (28.4 kcalmolꢁ1 at 373 K)
for thermolysis of 4b.
We failed entirely to detect VCPR from either Z species (18b
or 22b) (Figure 4); only stereoisomerisation was detectable
Scheme 8. Convergence of diastereoisomeric alkene precursors through
VCPR.
example of a Z-alkenyl motif taking part in VCPR; DG° (373 K)
for the VCPR of 27b was measured at 31.1 kcalmolꢁ1, only ap-
proximately 3 kcalmolꢁ1 higher than that for 27a (28.5 kcal
molꢁ1).
Figure 4. Experimental (points) and simulated (lines) concentration/time pro-
file for thermolysis of 18b and 22b (starting from: * 18b from 18b; ~
18b from 22b; * 22b from 22b; D 22b from 18b ([D8]toluene, 373 K)).
The E/Z reactivity difference is more dramatic in our system.
This and other aspects of the reaction stereospecificity were
now examined using electronic structure calculations.
Davidson and Gajewski,[63] and Houk and co-workers,[64,65]
have used computational methods to study the vinylcyclopro-
pane rearrangement. A detailed dynamics treatment has also
been reported.[66] The parent system 1 undergoes VCPR and
stereoisomerisation competitively but the major reaction chan-
nel involves VCPR via the Woodward–Hoffmann “allowed” su-
prafacial inversion (si) transition state TS1 leading to cyclopen-
tene 2 (Scheme 9).
when either 18b or 22b was heated in [D8]toluene at 373 K.
Equilibrium constants of 3.7 (from 18b) and 3.6 (from 22b) fa-
vouring 18b were extracted from the simulation data and con-
firmed by integration of the 19F NMR spectra (see the Support-
ing Information).
At higher temperature (1808C), 18b underwent [3,3]-rear-
rangement to 25a and 25b (10:1 by 19F NMR integration)
(Scheme 7).
In their seminal study,[65] Houk and co-workers reported that
unrestricted B3LYP[67,68] (UB3LYP/6-31G*) predicted experimen-
tal VCPR activation energies well. However, more recent
work[62] has proposed a combination of Truhlar’sM05-2X hybrid
functional[69–71] and the 6-311+G** basis as a benchmarking
method.
Scheme 9. VCPR si-transition state TS1, showing the exchange of the Ha and
Scheme 7. [3,3]-Rearrangement of Z-alkenoate precursors 18b and 22b.
Hb ligands through inversion at the migratory carbon centre.
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Figure 5. VCPR precursors and their corresponding transition states.
We chose to explore the effectiveness of a small matrix of
methods for the prediction of VCPR barriers. We selected VCP/
VCPR systems 1, 3, 4b and 29a (a conformationally simpler an-
alogue of 18a) (Figure 5), and used B3LYP, M05-2X, M06-2X[72]
and B97-D[73,74] functionals (all in unrestricted mode) with 6-
31G*, 6-31+G* and 6-311+G** basis sets to calculate barrier
energies (DG°). Geometry optimisations were performed in
Gaussian’09,[75] Spartan’08[76] or Spartan’10;[77] the optimised
geometries were characterised as minima or transition struc-
tures by performing harmonic frequency calculations.
Figure 6. Differences between experimental DG° (298 K, re-calculated from
activation parameters) and DG° from electronic structure calculations
(298 K), plotted as DDG° (DG°(ESC)ꢁDG°(experimental), kcalmolꢁ1). Expect-
ed error associated with data is ꢀ0.5 kcalmolꢁ1
.
(298 K) calculated from experimental Arrhenius parameters (Ea,
A) from the literature and from this work.
As the focus of our work is primarily synthetic, we wished to
establish an effective method of lowest cost, so that we could
use it for the design of new reaction systems which would un-
dergo relatively facile rearrangement. In each case, the s-trans
Z or s-trans E cyclopropane geometry and the transition struc-
ture on the suprafacial inversion (si) pathway were optimised
with full frequency calculation. Because the dipoles of all the
precursors and transition structures were small and similar
(2.25–3.00 Debyes), and the toluene solvent used for the ex-
perimental work has a low dielectric constant (e=2.38), we
have not applied solvation methods.
We used Houk’s Cartesian coordinates[65] for TS1 as a starting
point for structure building and transition state searching; in
the case of TS29a, a range of diastereoisomeric and conforma-
tionally isomeric species was explored (vide infra). Table 4 and
Figure 6 compare the computational results to values of DG°
There were significant differences between the levels of per-
formance of the functionals. UB3LYP underestimated the ex-
perimental barriers for all systems, with the discrepancy in-
creasing with basis set size. UB97-D performed best with
Smart’s highly fluorinated system but under-estimated barriers
for the other systems with all basis sets. The imaginary fre-
quencies calculated for TS4b and TS29a with UB97-D were
much lower than with the other functionals, and the values of
the spin operator <S2 > were 0 for 4b and 0.251–0.311 for
TS29a, whereas consistently higher values were obtained with
the other methods for all systems (see the Supporting Informa-
tion for details).
The closest agreement with experimental values was ob-
tained with UM05-2X/6-31+G* and UM05-2X/6-311+G**
methods with DDG° within 1 kcalmolꢁ1 (overestimate) for 1, 3
and 29a, and within 2 kcalmolꢁ1 (underestimate) for 4b. We
also calculated the barriers to VCPR for diastereoisomeric 27a
and 27b using the M05-2X/6-31+G* method, obtaining values
of DG° (at 298 K) of 26.2 and 29.9 kcalmolꢁ1 respectively, com-
pared to the (approximate) experimental values (at 298 K) of
27.8 and 29.9 kcalmolꢁ1, respectively.
The UM06-2X functional[70] overestimated the rearrangement
barrier for 1, 3 and 29a by 4 kcalmolꢁ1 or more, performing
better for more highly fluorinated 4b. Smart’s highly fluorinat-
ed 4b involves a different type of radical terminus from the
other three systems; in 4b, the inverting radical centre is di-
fluorinated and pyramidal, whereas it is a trigonal centre
(methylene, -CH2 in TS1, TS3) or a trigonal (benzylic methine,
-CHPh in TS29a) in the other systems. While there is no
a priori reason why the level of theory used should deal with
the highly fluorinated system less well, there is a step change
in structure between Smart’s system and the other members
of the test set.
Table 4. Barriers (DG°, gas phase, 298 K, kcalmolꢁ1) for VCPR from elec-
tronic structure calculations (ESC) and recalculated[78] from Arrhenius
data.[15,18,21]
Method
1!TS1
3!TS3
4b!TS4b
29a!TS29a
UB3LYP 6-31G*
46.9
46.2
45.9
50.8
50.0
49.5
55.1
54.0
53.2
45.3
44.6
44.4
49.2
38.3
36.0
36.0
41.6
39.4
39.5
46.4
44.0
43.6
36.2
33.9
36.8
39.0
24.8
22.9
23.0
28.5
26.4
26.8
31.8
29.9
29.8
29.7
28.0
27.9
28.5
26.6
25.1
24.8
31.1
29.8
29.8
36.0
34.7
34.6
22.5
21.3
21.1
28.6
UB3LYP 6-31+G*
UB3LYP 6-311+G**
UM05-2X 6-31G*
UM05-2X 6-31+G*
UM05-2X 6-311+G**
UM06-2X 6-31G*
UM06-2X 6-31+G*
UM06-2X 6-311+G**
UB97-D 6-31G*
UB97-D 6-31+G*
UB97-D 6-311+G**
experiment
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While the UM05-2X/6-31+G* method gave the closest
agreement between prediction and experimental values for
this small test set, the consistency of performance of the
UB3LYP/6-31G* method suggested that it would be worthwhile
to assess its ability to rationalise and predict the reaction ste-
reospecificity. Both methods were applied and the different
free energies obtained are identified by a suffix in GUM05-2X or
Table 5. Relative free energies (G, gas phase, 298 K, kcalmolꢁ1) for cyclo-
propanes (29, 34), ring-opened triplets (32, 35) and triplet interconver-
sion transition states (33, 36).
Species
(GUM05-2X
)
(GUB3LYP
)
Species
(GUM05-2X
)
(GUB3LYP)
rel
rel
rel
rel
29a
32a
33
32b
29b
0.0
0.0
34a
35a
36
35b
34b
0.0
0.0
23.4
24.5
24.1
0.5
19.4
22.0
20.5
0.6
24.1
27.7
26.6
0.0
19.8
23.0
20.1
0.8
GUB3LYP
.
The important competing pathways are the cis/trans cyclo-
propane stereoisomerisation and the [3,3]-rearrangement of
the cis-cyclopropane. We therefore set out to establish a mini-
mal pathway for the former, because the full PES accessible
from VCP 1 and mapped by Houk and co-workers was quite
complex.[65] IRCs were computed by Houk and co-workers from
s-trans vinylcyclopropane for the facile stereomutation; Houk
identified intermediate 30 and transition state 31, connected
by rotation around a CꢁC s-bond (which cost ca. 15 kcalmolꢁ1
Conversion to cisoid triplet 32b could be achieved either by
rotation around C-4/C-5 (dihedral f1) or C-5/C-6 (dihedral f2)
bonds; carbons C-1, C-2, C-3 and C-4 stay mutually coplanar to
preserve radical stabilisation via conjugation (which explains
why alkenoate E/Z stereoisomerisation was never observed).
We found triplets 32a and 32b as minima, and connecting
transition state 33 related by rotation around f2 (Figure 7).
from
single-point
calculations)
as
accessible
from
1 (Scheme 10).
Scheme 10. Diradical species implicated in cyclopropane stereoisomerisa-
tion.
We checked that an IRC lead to intermediates of this type
by stretching the ring bond distal to the CF2 centre (using
AM1 and the energy profile algorithm in Spartan’10). We then
built a minimal set of triplet diradicals corresponding to the
full VCPR systems.
Stretching the distal ring bond in the s-trans conformer of
TS29a led to transoid triplet diradical 32a (Scheme 11); the lo-
cations of the C-4 and C-6 CꢁH bonds echo their relative orien-
tations in the VCP.
Figure 7. Triplet diradical structures which interconnect cis- and trans-cyclo-
propane structures for a) E-alkenoate and b) Z-alkenoate series.
The interconversion was predicted to be more facile than
VCPR by both methods (Table 5), consistent with the experi-
mental findings, with the UM05-2X/6-31+G* method predict-
ing a significantly higher barrier.
The Z-cyclopropane 34a and 34b could be interconverted by
rotation around f2 via triplets 35a and 35b, passing through
transition state 36 (see the Supporting Information for details)
at similar cost.
The VCPR transition state develops from precursors in the
gauche conformation; isotopic labelling has been used exten-
sively in the literature to show that while the si pathway is the
major one, it competes with others (ar, ai and sr) to varying
degrees depending on the number and site of isotopic
labels.[65] The introduction of much bigger groups could lead
to one pathway being favoured more decisively; this was our
expectation given the formation of a single trans-cyclopentene
product.
The most logical progression of 29a would be through
TS29a or TS29b (Scheme 12) which differ only in the ester
conformation; inversion in the migrating benzylic centre
means that by the time the transition state is reached, the
phenyl group has swung into the correct orientation for the
formation of the trans-cyclopentene product 37. TS29a
Scheme 11. Cyclopropane trans/cis stereoisomerisation via triplets.
(DG°
29.8 kcalmolꢁ1 from 29a in the the s-trans confor-
UM05-2X
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The other four transition states from the set started from
the Z-alkenoate; only one (TS39d) of the four optimised to
a geometry recognisable as a VCPR transition state, 34.7 kcal
molꢁ1 above 34a (DG°UM05-2X), so there is only one pair of dia-
stereoisomeric structures related by opposite alkene configura-
tions. The additional cost of access to this structure may arise
from close approach (2.65 ꢃ) between the benzylic proton and
the alkenoate carbonyl carbon. When the ester was posed in
the alternate s-trans syn conformation, a different (6,5 bicyclic)
ring closure with a very high barrier (DG°UM05-2X =55.2 kcal
molꢁ1) was indicated.
The two alternate transition structures failed to optimise to
structures which corresponded to VCPR. Figure 8 shows the
Scheme 12. Diastereoisomeric VCPR transition states.
mation, referring to the orientation of cyclopropane and
alkene) has the alkenoate in the s-cis syn conformation, which
is the favoured orientation for simpler systems like methyl ac-
rylate;[79] TS29b has the ester s-trans syn at a cost of an addi-
tional 1 kcalmolꢁ1 at the barrier (DG°
30.8 kcalmolꢁ1).[80]
UM05-2X
Because the reactions appeared so stereospecific from the
NMR experiments, we built and investigated a further six si
transition states; the variables were the alkene configuration
(E- or Z-) and the orientations of the Ph and -CO2Me groups.
The formation of cis-cyclopentene product 38 from these
competitive transition states would be anticipated strongly,
contrary to the experimental findings. Simulation of the reac-
tion profile (see the Supporting Information) predicts that cis-
cyclopentene would make up to 20% of the product mixture
when the rates of VCPR are the same for both cyclopropane
diastereoisomers. An alternative explanation for the completely
stereoselective VCPR would involve product epimerisation;
there is a modest calculated driving force (DDGUM05-2X) for the
cis/trans isomerisation of 38 to 37 of only 1.4 kcalmolꢁ1 (or K=
6.3 at 373 K) which is inadequate to explain the outcome. In
contrast, the UB3LYP method predicted a kinetically trans-se-
lective VCPR, with bigger free energy differences between the
Figure 8. Alkene diastereoisomeric transition structures, both with s-trans,
syn alkenoate conformation: a) TS29d from E-alkenoate series (DG°
UM05-
2X =30.8 kcalmolꢁ1 and DG°UB3LYP =28.9 kcalmolꢁ1); b) TS39d from Z-alke-
noate series (DG°UM05-2X =34.7 kcalmolꢁ1 and DG°UB3LYP =32.8 kcalmolꢁ1
)
showing the H···C close contact.
pair of transition structures (TS29d and TS39d) which differ
only in the alkene configuration and thus lead to cis and trans
products respectively. These transition structures lie 30.8 and
34.7 kcalmolꢁ1, respectively, above their precursors from the
UM05-2X data, and 28.9 and 32.8 kcalmolꢁ1, respectively,
above their precursors from UB3LYP, showing the higher cost
(3.9 kcalmolꢁ1 with both methods) of rearrangement from the
Z-series.
diastereoisomeric transition states. The value of DDG°
of
The concerted [3,3]-rearrangement pathway was examined
for the formation of the benzocycloheptadienes from the cis-
cyclopropanes; from M05-2X calculations, the cis-E TS 40 lies
27.7 kcalmolꢁ1 above precursor 29b; cis-Z TS 41 has a higher
barrier at 34.7 kcalmolꢁ1 above the cis-Z precursor 34b
(Figure 9). The corresponding values from the B3LYP calcula-
tions were 27.8 and 32.9 kcalmolꢁ1, respectively.
UB3LYP
2.3 kcalmolꢁ1 corresponds to a kinetic ratio of 37:38 of >20:1,
which would predict that cis-product 38 would not be detect-
ed in product mixtures by 19F NMR spectroscopy. Table 6 sum-
marises the outcomes using the two methods.
There is an eclipsing interaction between a CꢁH bond and
a CꢁC bond in 41, which results in the higher barrier. Once
again, the alkene configuration has a decisive effect on reactiv-
ity, consistent with the experimental observations in which the
Z-species only reacted at significantly higher temperature.
The immediate product 42 has lost aromaticity and there-
fore lies above precursor 29b; ((GM05-2X)rel =9.3 kcalmolꢁ1,
(GB3LYP)rel =14.5 kcalmolꢁ1) loss of HF leads to 43a-c. Both sets
of calculations identified thermodynamic product 43b correctly
Table 6. Barriers (DG°, gas phase, 298 K, kcalmolꢁ1) for VCPR from diaste-
reoisomeric transition states.
TS
DG°
DG°
UM05-2X
UB3LYP
TS29a
TS29b
TS29c
TS29d
TS39d
29.8
30.8
30.1
30.8
34.7
25.9
26.6
28.2
28.9
32.8
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strongly that the older UB3LYP/6-31G* method may prove
most effective for triage of new synthetic reactions.
Conclusion
We have developed a synthetic route which allows access to
all four isomers of ethyl 3-(1’(2’2’-difluoro-3’-phenyl)cycloprop-
yl) propenoate from commercially available precursors using
Dolbier’s robust and effective difluorocarbene transfer reagent
MDFA. Cyclopropane stereoisomerisation was facile at 1008C
in toluene and this process was monitored with VCPR by
19F NMR spectroscopy. The trans-E isomer (18a) was syntheti-
cally easiest to access and rearranged to difluorocyclopentene
23 in close to quantitative yield. The overall yield of 23 over
four steps from cinnamyl acetate was 70%. Our results show
clearly that the alkene configuration controls which rearrange-
ment pathway is followed; E-isomers underwent VCPR, where-
as [3,3]-rearrangement was more favourable for Z-isomers.
While the UM05-2X/6-31+G* method provided the highest ac-
curacy at lowest cost for the VCPR test set, the agreement be-
tween predicted and experimental reactivity order suggests
strongly that the older UB3LYP/6-31G* method may prove
most effective for triage of new synthetic reactions.
Figure 9. Initial (42) and final (43a–c) [3,3]-rearrangement products and tran-
sition states (40, 41) from cis-cyclopropanes.
(for 43a (GM05-2X)rel =ꢁ19.0 kcalmolꢁ1, (GB3LYP)rel =ꢁ9.4 kcal
molꢁ1
;
for 43b (GM05-2X)rel =ꢁ22.8 kcalmolꢁ1
,
(GB3LYP)rel =
ꢁ14.5 kcalmolꢁ1
;
for
43c
(GM05-2X)rel =ꢁ19.6 kcalmolꢁ1,
(GB3LYP)rel =ꢁ11.1 kcalmolꢁ1). Overall, the VCPR reactions to 37
((GM05-2X)rel =ꢁ26.8 kcalmolꢁ1, (GB3LYP)rel =ꢁ21.1 kcalmolꢁ1) and
38 ((GM05-2X)rel =ꢁ26.8 kcalmolꢁ1
,
(GB3LYP)rel =ꢁ18.4 kcalmolꢁ1
)
were strongly exergonic from precursors 29a and 29b, respec-
tively.
Work is currently underway to design and access more com-
plex difluorocyclopentenes using a combination of computa-
tional triage and synthetic chemistry.
Our initial interest in carrying out electronic structure calcu-
lations based on this set of reactions arose from a wish to
order the reactivities of the competing pathways successfully;
cis/trans cyclopropane stereoisomerisation, stereoselective
trans-cyclopentene formation by VCPR, [3,3]-rearrangement
versus VCPR and the low reactivity of Z-alkenoates versus the
E-diastereoisomers all required explanation. The two computa-
tional methods selected deal with these questions differently,
as summarised in Table 7.
Experimental Section
Screening of other difluorocarbene sources, experimental proce-
dures and spectral data for all new compounds, selected inter-
mediates and crude products, kinetic raw data, simulation data
and Arrhenius plot, summary of computational energies and Carte-
sian coordinates (B3LYP/6–31G* and M05–2X/6–31+G* optimised
structures) are provided in Supporting Information.
Of the two methods used, UB3LYP/6-31G* (with B3LYP/6-
31G* for the closed shell systems) orders the pathways correct-
ly by reactivity, predicts the stereoselectivity of the VCPR in
agreement with experiment and rationalises the effect of
alkene configuration on VCPR and [3,3]-rearrangement rates.
While the UM05-2X/6-31+G* method provided the highest ac-
curacy at lowest cost for the VCPR test set, the agreement be-
tween predicted and experimental reactivity order suggests
General experimental: NMR spectra were recorded on Bruker
DPX-400 and AV-500 spectrometers. 1H, 19F and 13C NMR spectra
were recorded using the deuterated solvent as the lock and the re-
sidual solvent as the internal reference. The multiplicities of the
spectroscopic data are presented in the following manner: s=sin-
glet, d=doublet, dd=double doublet, ddd=doublet of doublet
doublets, dddd=doublet of doublet of doublet of doublets; dt=
doublet of triplets, ddt=doublet of double triplets, dtd=doublet
of triple doublets, t=triplet, tdd=triplet of double doublets, q=
quartet, m=multiplet and br.=broad. Unless stated otherwise, all
couplings refer to 3J homocouplings. All 1H spectra are fully as-
signed. IR spectra were recorded on an ATR IR spectrometer. GC/
MS spectra were obtained on an instrument fitted with a DB5-type
column (30 mꢄ0.25 mm) running a 40–3208C temperature pro-
gram, ramp rate 208C minꢁ1 with helium carrier gas flow at
1 cm3 minꢁ1. Chemical ionisation (CI) (methane) mass spectra were
recorded on an Agilent Technologies 5975C mass spectrometer.
HRMS measurements were obtained from a Thermofisher LTQ Orbi-
trap XL (APCI) or Finnigan MAT 95 XP (EI) spectrometers (EPSRC
National Mass Spectrometry Service Centre, Swansea). Thin layer
chromatography was performed on pre-coated aluminium-backed
silica gel plates (E. Merck A.G., Darmstadt, Germany. Silica gel 60
F254, thickness 0.2 mm). Visualisation was achieved by using po-
tassium permanganate or UV detection at 254 nm. Column chro-
matography was performed on silica gel (Zeochem, Zeoprep 60
Table 7. Barriers (DG°) and differences (DDG°) between barriers (gas
phase, 298 K, kcalmolꢁ1) relating to selectivities between isomerisation,
VCPR and [3,3]-rearrangement pathways.
Pathway/process
M05-2X
B3LYP
cyclopropane isomerisation 29a/29b, DG°
cyclopropane isomerisation 34a/34b, DG°
lowest cost VCPR, DG°
lowest cost [3,3]-rearrangement from 29b, DG°
selectivity for formation of kinetic trans-product,
37 versus 38, DDG°
E versus Z selectivity for VCPR, DDG°
E versus Z selectivity for [3,3]-rearrangement,
40 versus 41, DDG°
24.5
27.7
29.8
27.7
0.3
22.0
23.0
25.9
27.8
2.3
5.5
7.0
3.9
5.1
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HYD, 40–63 mm) using a Bꢅchi Sepacore system. Hexane was dis-
tilled before chromatography. All glassware used in the synthesis
of methyl(trifluoromethyl)dioxirane was washed with an aqueous
solution of ethylenediaminetetraacetic acid (0.1m) to remove trace
metals and then oven dried (1508C) before use. Diglyme was dis-
tilled from CaH2 (608C/23 mbar) and stored under nitrogen over
CaH2.Trimethylsilyl chloride was distilled from CaH2 (608C/
430 mbar) and stored under nitrogen over CaH2 in the refrigerator.
Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA) was purchased
from Fluorochem and stored under a headspace of nitrogen. Po-
tassium iodide (Sigma Aldrich) was dried in the oven (1508C)
before use. DCM (for oxidation/Wittig reactions) was dried using
a PureSolv system from Innovative Technology, Inc. All other chem-
icals were purchased from Sigma Aldrich, Apollo Scientific, Alfa
Aesar, or Fluorochem and used as received.
analytical standard that no purification was required (correspond-
ing NMR data on pages S22–S25 in the Supporting Information).
Rf =0.16 (1:4 diethyl ether/hexane); H NMR (400 MHz, CDCl3): d=
7.38–7.30 (m, ArH, 3H), 7.27–7.25 (m, ArH, 2H), 4.01–3.86 (br. m,
CH2OH, 2H), 2.65 (ddd, JH–F =13.5, J=7.6, 4J=1.4 Hz, PhCH, 1H),
2.23 (m, CHCH2OH, 1H), 1.72 ppm (t, J=5.9 Hz, CH2OH, 1H);
13C NMR (100 MHz, CDCl3): d=132.5, 128.1, 127.6, 126.8, 113.9 (t,
1
1JC–F =289.1 Hz), 59.3 (d,
J
C–F =5.5 Hz), 31.0 (t, 2JC–F =10.7 Hz),
30.7 ppm (t, 2JC–F =9.6 Hz); 19F NMR (376 MHz, CDCl3): d=ꢁ136.2
(dd, 2J=158.1 Hz,
J
F–H =14.0 Hz,
1
F), ꢁ136.9 ppm (dd, 2J=
~
157.6 Hz, JF–H =13.5 Hz, 1 F); n/(film)=3321 (br.), 1500, 1474, 1447,
1269, 1013, 698 cmꢁ1; MS (CI): m/z (%): 185 (4) [M+H]+, 167 (21)
[MꢁOH], 147 (100) [(M+H)ꢁF2]+, HRMS (APCI): calcd for C10H10F2O,
184.0694 [MꢁH]+, found 184.0688; tR (GC)=10.56 min. Alcohol 11
has been reported in the literature but no characterisation data
was reported.[82] The compound was also reported recently by Itoh
and co-workers[55] though the material isolated was of lower quali-
ty than that used in our study.
Preparation of 10: An oven-dried two-necked round-bottomed
flask containing potassium iodide (3.68 g, 22.2 mmol) was sealed
with a SubaSeal, and the salt was stirred and lightly flame dried
under an atmosphere of argon. A low boiling point water condens-
er with a gas outlet connected to an argon/vacuum manifold was
attached and the reaction flask and the atmosphere were purged
three times. Cinnamyl acetate 9 (1.34 mL, 8.0 mmol) followed by
diglyme (1.3 mL) were added and the yellow suspension was
heated to 1208C. Once the reaction temperature had been
reached, TMSCl (2.6 mL, 19.7 mmol) and MDFA (2.6 mL, 19.7 mmol)
were added dropwise in that order. After 5 h, the reaction mixture
had evaporated to dryness and a further portion of diglyme
(1.3 mL) was added. The mixture was stirred for a further 19 h
(total reaction time of 24 h). The resulting brown solution was
cooled to room temperature and the reaction mixture was
quenched with aqueous NaCl (10 mL) and diethyl ether (10 mL)
added. The organic layer was separated and the aqueous layer was
extracted with diethyl ether (2ꢄ10 mL). The original organic layer
and the extracts were combined, dried (MgSO4) and concentrated
Preparation of 18a/18b: Bis(acetoxy)iodobenzene (1.35 g,
4.23 mmol) was added to a solution of alcohol 11 (678 mg,
3.68 mmol) and TEMPO (54 mg, 0.368 mmol) in anhydrous DCM
(15 mL) and the reaction mixture was stirred at room temperature
under nitrogen for 6 h. The 1H NMR spectrum showed complete
conversion to the corresponding aldehyde. (Ethoxycarbonylmethy-
lene)triphenylphosphorane (1.64 g, 4.7 mmol) was then added to
the reaction mixture and stirred for 2 h until the 1H or 19F NMR
spectrum showed complete conversion. The resulting orange solu-
tion was concentrated under reduced pressure and column chro-
matography on silica gel (1:19 diethyl ether in hexane) afforded
18a (728 mg, 78%) and 18b (43 mg, 5%). Data for 18a: Rf =0.30
1
(1:9 diethyl ether/hexane); H NMR (500 MHz, CDCl3): d=7.40–7.31
4
(m, ArH, 3H), 7.27–7.25 (m, ArH, 2H), 6.79 (ddt, J=15.6, 9.5 Hz, JH–
F =1.5 Hz, HC=CHCO2Et, 1H), 6.09 (d, J=15.6 Hz, HC=CHCO2Et, 1H),
4.25 (q, J=7.2 Hz, CO2CH2CH3, 2H), 2.91 (dd, JH–F =14.7, J=7.3 Hz,
PhCH, 1H), 2.66–2.60 (ddd, JH–F =13.4J=9.5, 7.3 Hz, CHCH=CH, 1H),
1.33 ppm (t, J=7.2 Hz, CO2CH2CH3, 3H); 13C NMR (100 MHz, CDCl3):
1
under reduced pressure to remove volatiles. The H NMR spectrum
of the resulting brown oil confirmed full conversion. Column chro-
matography on silica gel (2:23 diethyl ether/hexane) afforded ace-
tate 10 as a pale yellow oil (1.7 g, 94%). Rf =0.26 (1:9 diethyl ether/
hexane); 1H NMR (400 MHz, CDCl3): d=7.36–7.29 (m, ArH, 3H),
1
d=165.0, 139.8, 131.8, 128.2, 127.4, 127.2, 123.2, 112.9 (t, JC–F
=
292.6 Hz), 59.9, 35.4 (t, 2JC–F =9.8 Hz) 33.1 (t, 2JC–F =12.7 Hz),
13.7 ppm; 19F NMR (376 MHz, CDCl3): d=130.6 (dd, 2J=157.4 Hz,
4
7.23–7.21 (br. d, J=7.9 Hz, ArH, 2H), 4.38 (br. ddd, J=11.9, J=2.5
J
F–H =14.7 Hz, 1 F), - 135.6 ppm (dd, 2J=156.6 Hz, JF–H =13.4 Hz,
and 1.0 Hz, CHaHbOAc, 1H), 4.25 (br. dd, J=7.8, 4J=1.6 Hz,
CHaHbOAc, 1H), 2.68 (dd, JHꢁF =14.5 Hz, J=7.8 Hz, PhCH, 1H), 2.33–
2.24 (m, C(H)CH2OAc, 1H), 2.10 ppm (s, OC(O)CH3, 3H); 13C NMR
(100 MHz, CDCl3): d=170.9, 132.7, 128.6, 128.2, 127.5, 113.1 (t,
1 F); n/(film)=2359, 2342, 1715, 1281 cmꢁ1; MS (CI): m/z (%): 233
(100) [MꢁF], 187 (44), 159 (26); HRMS (APCI): calcd for C14H15F2O2,
253.1035 [M+H]+, found 253.1034; tR (GC)=12.13 min. Data for
~
1
18b: Rf =0.43 (1:9 ethyl acetate/hexane); H NMR (400 MHz CDCl3):
2
1JCꢁF =289.4 Hz), 60.9 (d, JCꢁF =5.6 Hz), 32.0 (t, JCꢁF =11.2 Hz), 28.0
d=7.40–7.29 (m, ArH, 5H), 6.06–5.99 (m, HC=CHCO2Et, 2H), 4.234
(q, J=7.2 Hz, OCHaHbCH3, 1H), 4.225 (q, J=7.2 Hz, OCHaHbCH3, 1H),
4.18–4.10 (m, HCCH=CHCO2Et, 1H), 2.84 (dd, JH–F =14.8 Hz, J=
7.1 Hz, CHPh, 1H), 1.32 ppm (t, J=7.2 Hz, CH3, 3H); 13C NMR
(100 MHz, CDCl3): d=165.7, 140.1 (d, JC–F =6.3 Hz), 131.7, 128.1,
2
(t, JCꢁF =10.3 Hz), 20.8 ppm; 19F NMR (376 MHz, CDCl3): d=ꢁ135.4
2
2
(dd, J=157.8 Hz, JFꢁH =14.5 Hz, CFaFb, 1 F), ꢁ137.3 ppm (dd, J=
~
158.6 Hz, JFꢁH =14.0 Hz, CFaFb, 1 F); n/(film)=2386, 2354, 1737,
1225, 1017, 999, 972, 696 cmꢁ1; MS (CI): m/z (%): 167 (55)
[MꢁOAc]+, 147 (100); HRMS (EI): calcd for C12H12F2O2, 226.0800 [M],
found 226.0861; tR (GC)=11.37 min. The data was in agreement
with that reported by Kobayashi and co-workers but no 13C NMR
data was reported.[81,82]
1
2
127.7, 127.1, 121.3, 113.5 (t, JC–F =291.1 Hz), 59.8, 36.2 (dd, JC–F
=
11.8, 9.1 Hz), 30.1 (dd, 2JC–F =13.6, 9.9 Hz), 13.7 ppm; 19F NMR
2
(376 MHz, CDCl3): d=ꢁ132.3 (dd, J=154.3 Hz JF–H =14.8 Hz, 1 F),
ꢁ136.2 ppm (dd, 2J=154.6 Hz JF–H =13.7 Hz, 1 F); n/(film)=2359,
~
2342, 1715, 1194, 1018, 806 cmꢁ1; MS (CI): m/z (%): 281 (4) [M+
C2H5]+, 253 (70) [M+H]+, 233 (35) [MꢁF], 225 (36), 205 (60) [(M+
H)ꢁ(F+Et)]+, 187 (100), 179 (30) [MꢁCO2Et], 169 (18) [MꢁF2 +OEt],
159 (45), 141 (28) [MꢁF2 +CO2Et]; HRMS (APCI): calcd for
C14H15F2O2, 253.1035 [M+H]+, found 253.1035; tR (GC)=12.36 min.
Preparation of 11: A solution of potassium carbonate (443 mg,
3.2 mmol) in H2O (2 mL) was added to a solution of acetate 10
(718.7 mg, 3.2 mmol) in MeOH (60 mL, 0.05m) and the mixture was
heated to 608C for 1 hour. Full conversion was confirmed by TLC.
The reaction mixture was concentrated under reduced pressure
and the resulting suspension taken up in MeOH (5 mL) and evapo-
rated onto Celite (6.4 g). The solid was transferred onto a sinter
funnel and the product was eluted with diethyl ether (60 mL). The
filtrate was concentrated under reduced pressure to afford alcohol
11 as a colourless oil (583.5 mg, 99%). Compound was of a high
Preparation of 23: A solution of 18a (104 mg, 0.4 mmol) in tolu-
ene (0.5 mL) was heated to 1008C in a sealed microwave vial for
17 h in a DrySyn block. After cooling and venting the vial, fluorine
NMR confirmed complete conversion. The reaction mixture was
transferred to a round bottom flask using DCM (5 mL) and concen-
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[13] R. J. Ellis, H. M. Frey, J. Chem. Soc. 1964, 5578.
trated under reduced pressure to afford difluorocyclopentene 23
(102 mg, 99%) as a pale yellow oil. Rf =0.34 (1:4 diethyl ether/
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1
hexane); H NMR (400 MHz, CDCl3): d=7.41–7.33 (m, ArH, 5H), 6.50
(dt, J=6.0, 4JH–F =1.6 Hz, =CHCO2Et, 1H), 6.09 (dd, J=6.0, JH–F
=
2.5 Hz, =CHCF2, 1H), 4.18 (q, J=7.1 Hz, OCH2CH3, 2H), 4.04–3.92
(m, CHCO2Et, CHPh, 2H), 1.26 ppm (t, J=7.1 Hz, OCH2CH3, 3H);
4
13C NMR (400 MHz, CDCl3): d=170.3 (d, JC–F =4.8 Hz), 138.6 (t, JC–
1
2
F =10.4 Hz), 133.8, 129.3 (t, JC–F =245.7 Hz), 128.7, 128.5 (dd, JC–F
=
2
25.0, 30.3 Hz), 128.0, 127.3, 61.0, 54.1 (d, JC–F =6.0 Hz), 53.2 (t, JC–
F =24.6 Hz), 13.6 ppm; 19F NMR (376 MHz, CDCl3): d=ꢁ89.3 (ddd,
2J=252.8 Hz,
J
F–H =16.6, 8.9 Hz,
1
F), ꢁ92.7 ppm (ddd, 2J=
~
253.2 Hz, JF–H =14.2, 5.8 Hz, 1 F); n/(film)=2359, 2340, 1732, 1254,
1194, 1167, 698 cmꢁ1; MS (CI): m/z (%): 253 (3) [M+H]+, 233 (100)
[MꢁF], 215 (8), 187 (40), 159 (33); HRMS (APCI): calcd for C14H15FO2,
253.1035 [M+H]+ found 253.1033; tR (GC)=12.13 min.
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Keywords: activation parameters
calculations difluorocyclopentene
stereoselectivity
·
density functional
rearrangements ·
·
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Received: May 29, 2014
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

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FULL PAPER
Run rings around fluorine: A difluori-
nated cyclopentene was accessed in
high yields (70% over 4 steps) from
commercial starting materials using the
thermal vinyl cyclopropane rearrange-
ment (VCPR). Alongside a relatively mild
reaction temperature (1008C), in situ cy-
clopropane stereomutation, a competing
[3,3]-rearrangement pathway and
&
Rearrangements
D. Orr, J. M. Percy,* T. Tuttle,
A. R. Kennedy, Z. A. Harrison
&& – &&
Evaluating the Thermal
Vinylcyclopropane Rearrangement
(VCPR) as a Practical Method for the
Synthesis of Difluorinated
Cyclopentenes: Experimental and
Computational Studies of
a sharp and unexpected dependence
on alkene configuration were all detect-
ed. Kinetic and electronic structure cal-
culations were used to evaluate and ra-
tionalise these observations.
Rearrangement Stereospecificity
Chem. Eur. J. 2014, 20, 1 – 13
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ