Oxy-Cope rearrangements of fluorinated divinylcyclohexanols: A modular method for the construction of selectively fluorinated cyclic ketones

Article abstract of DOI:10.1039/a908450i

Oxy-Cope rearrangements of fluorinated divinylcyclohexanols afford access to cyclodecenones containing from two to five fluorine atoms.

Full text of DOI:10.1039/a908450i

Oxy-Cope rearrangements of fluorinated divinylcyclohexanols: a modular
method for the construction of selectively fluorinated cyclic ketones
Gianluca Dimartino,a Thomas Gelbrich,b Michael B. Hursthouse,b Mark E. Light,b Jonathan M. Percy*a and
Neil S. Spencera
a
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK B15 2TT.
E-mail: jmpercy@chemistry.bham.ac.uk
EPSRC National X-Ray Crystallography Service, Department of Chemistry, University of Southampton, Highfield,
b
Southampton, UK SO17 1BJ
Received (in Liverpool, UK) 25th October 1999, Accepted 10th November 1999
Oxy-Cope rearrangements of fluorinated divinylcyclohex-
anols afford access to cyclodecenones containing from two to
five fluorine atoms.
The oxy-Cope rearrangement has become a tool of awesome
transformative power;1,2 ring systems can be constructed and
interconverted with ease, opening routes to highly complex and
densely functionalised polycyclic molecular architecture. How-
ever, oxy-Cope rearrangements of fluorinated substrates have
remained uncharted territory.3 The effect of fluorine atom
substituents upon the thermodynamic parameters of simple
Cope rearrangement systems is well known, thanks to the
extensive and rigorous efforts of Dolbier.4 Terminal fluorine
atom substituents lower the enthalpy of activation, while the
entropy of activation usually increases; overall, the rearrange-
ment reaction in which the CF2 centre rehybridises from sp2 to
sp3 is favoured.
Cyclic (especially medium to large ring) difluoro ketones
Scheme 1 Reagents and conditions: i, cyclohexene oxide, BF3·OEt2, THF,
have a relatively unexplored chemistry because there are few
278 °C; ii, DMSO, (COCl)2, 278 °C, then Et3N; iii, alkenylmetal, THF,
rational routes for their synthesis. More highly fluorinated
278 °C (see text).
cyclic ketones show interesting keto/enol tautomerisation5
behaviour that is quite different from that of acylic congeners,6
an important class of compounds with well-defined and useful
hydration behaviour.7 Routes to conformationally-restricted
difluoro ketones may therefore be of interest and there is also
potential for novel transannular interactions and reactions.8 We
therefore decided to examine the oxy-Cope rearrangement as a
possible novel strategy for the construction of medium to large
rings with controllable patterns of selective fluorination.
We chose the divinyl cyclohexanol/cyclodecenone system,
studied originally by Marvell and Whalley,9 as our starting
point and followed their synthetic strategy. Cyclohexene oxide
was opened with metallated fluoroalkenes 1a,10a 1b10b and
1c10c to afford alcohols 2a–c in 69, 64 and 76% isolated yields.
Swern oxidation of each followed to afford the corresponding
ketones 3a (83%), 3b (52%) and 3c (72%). We were happy to
note that these b,g-unsaturated species, which are presumably
destabilised by the vinylic CF2 centre, did not isomerise and
could be purified by column chromatography (Scheme 1).
Next, we added vinylmetals, with the intention of demon-
strating that a degree of flexibility was possible in precursor
construction. Vinyllithium reacted smoothly with 3a and 3c to
afford dienols 4a and 4c in 78 and 68% yields respectively.
When the metallated fluoroalkene derived from HFC-134a 1c
was added to 3a, a mixture of diastereoisomeric dienols 5a with
distinct 19F NMR spectra were obtained (2.3+1 mixture, 57%).
Finally lithiodihydropyran was added to 3a–c to afford 6a–c,
completing a preliminary range of representative species. The
three latter dienols in particular could not be purified because of
decomposition during column chromatography, but crude
material could be obtained directly from the addition reaction
with satisfactory 1H and 19F NMR spectra. In general, we were
not able to free any of the preceding dienols completely from
trace amounts of hydrocarbon impurities so they were taken on
without being characterised fully.
We chose to investigate the neutral oxy-Cope in anticipation
of problems arising from the high nucleophilicity of potassium
alkoxides and enolates, the potential for fluoride ion loss, and
the known high electrophilicity of perhaloalkenes. The re-
arrangements were initiated by heating small samples of the
dienols in dry xylene in sealed (Ace) tubes at progressively
higher temperatures until appropriate 19F NMR spectral
changes were observed, or 1H NMR changes in the case of 10.
No attempt was made at this stage to measure rate constants or
determine activation parameters but we did run a number of
substrates at 150 °C to allow some qualitative comparisons to be
made (Table 1) with 10.
Substrates 4a, 5a and 6a all reacted smoothly at 150 °C in
short reaction times; however, 10 failed to react at all in one
week at that temperature and only underwent a slow conversion
at 225 °C in xylene. Of the three series of compounds, the
chlorinated congeners appeared to be more reactive than the
fluorinated or oxygenated counterparts.11 The relatively low
temperatures of the rearrangements are most encouraging and
suggest that a rather general method of fluoro ketone synthesis
may be available.12 Structural assignment was made by 1H
Chem. Commun., 1999, 2535–2536
This journal is © The Royal Society of Chemistry 1999
2535

Table 1 Rearangement conditions and outcomes for fluorinated dienols
more complex species can be developed from simple fluoroalk-
ene building blocks. Work to define the scope and kinetic
parameters of oxy-Cope rearrangement systems that contain
fluorinated vinylic components is in progress.
We thank the Engineering and Physical Sciences Research
Council of Great Britain for a Project Studentship (to G. D.)
under the ROPA Scheme.
Dienol
Ta/°C
tb/h
Product
Yieldc (%)
4a
4a
4c
5a
6a
6b
6c
10
10
125
150
125
150
150
155
140
150
225
8
3
46
1.75
3
9
17
168
24
7a
7a
7c
8a
9a
9b
9c
11
11
67
58
72
73
65
62
84
—
49
Notes and references
1 C. J. Roxburgh, Tetrahedron, 1995, 51, 9767.
2 L. A. Paquette, Tetrahedron, 1997, 53, 13971.
3 For reviews of [3,3]-rearrangements of fluorinated substrates, see: S. T.
Purrington and S. C. Weeks, J. Fluorine Chem., 1992, 56, 165; V. G.
Andreev and A. F. Kolomiets, A. F. Usp. Khim., 1993, 62, 594.
Rearrangements in the context of fluorinated building block chemistry
are discussed in: J. M. Percy, Top. Curr. Chem., 1997, 193, 131; J. M.
Percy and M. E. Prime, J. Fluorine Chem., 1999, in the press.
4 W. R. Dolbier and K. W. Palmer, J. Am. Chem. Soc., 1993, 115,
9349.
a Reactions in sealed tubes in xylene. b Time for complete consumption of
starting dienol by NMR. c Isolated yield.
5 P. E. Lindner and D. M. Lemal, J. Org. Chem., 1996, 61, 5109; P. E.
Lindner, R. A. Correa, J. Gino and D. M. Lemal, J. Am. Chem. Soc.,
1996, 118, 2556.
6 P. E. Lindner and D. M. Lemal, J. Am. Chem. Soc., 1997, 119, 3259.
7 D. Schirlin, J. M. Rondeau, B. Podlogar, C. Tardif, C. Tarnus, V.
Vandorsselaer and R. Farr, ACS Symp. Ser., 1996, 639, 169; H. L. Sham,
ACS Symp. Ser., 1996, 639, 184.
8 D. Colclough, J. B. White, W. B. Smith and Y. L. Chu, J. Org. Chem.,
1993, 58, 6303; Y. L. Chu, D. Colclough, D. Hotchkin, M. Tuazon and
J. B. White, Tetrahedron, 1997, 53, 14235.
9 E. N. Marvell and W. Whalley, Tetrahedron Lett., 1970, 509.
10 (a) J. M. Bainbridge, S. J. Brown, P. N. Ewing, R. R. Gibson and J. M.
Percy, J. Chem. Soc., Perkin Trans. 1, 1998, 2541; (b) J. A. Howarth,
W. M. Owton, J. M. Percy and M. H. Rock, Tetrahedron, 1995, 51,
10289; (c) J. Burdon, P. L. Coe, I. B. Haslock and R. L. Powell, Chem.
Commun., 1996, 49.
11 N. Y. Jing and D. M. Lemal, J. Am. Chem. Soc., 1993, 115, 8481. In a
study of a Cope rearrangement of a perfluorinated hexadiene, the
substitution of a chlorine atom for a fluorine atom was reported to exert
only a minimal effect upon rearrangement rate and outcome. Products of
biradical pathways reported by these authors were not detected in our
study.
12 Selected data for 9c: colourless rhombi, mp 94 °C; (Found: C, 59.68; H,
6.61. Calc. for C13H17F3O2: C, 59.54; H, 6.49%); dH(300 MHz, CDCl3)
5.32 (dddd, 3J 32.4, J 11.4, J 6.3, J 3.0, 1H), 4.16 (dd, 2J 11.4, J 5.5, 1H),
3.72 (t, J 3.4, 1H), 3.48 (ddt, 2J 11.4, J 13.0, J 3.1, 1H), 3.10 (dd, J 19.1,
J 10.5, 1H), 2.88 (dddd, 3J 31.6, J 10.8, 3J 5.5, J 2.9, 1H), 2.38–2.30 (m,
2H), 2.19–2.05 (m, 3H), 2.04–1.95 (m, 1H), 1.86 (dtd, J 16.8, 10.9, 5.5,
1H), 1.73 (ddt, J 19.8, 2J 14.3, J 5.5, 1H), 1.63–1.55 (m, 1H), 1.40 (d,
2J 14.3, 1H), 1.31 (q, J 14.0, 1H); dF (282 MHz, CDCl3) 2101.9 (dd, 2J
255.6, 3J 26.7, 1F), 2109.5 (dd, 2J 255.6, 3J 31.7, 1F), 2124.8 (t, 3J
31.2, 1F); 13dC (75 MHz, CDCl3) 207.5, 150.5 (ddd, 2J 260.5, 2J 38.4,
2J 27.7), 117.6 (ddd, 1J 244.7, 1J 252.1, 2J 37.9), 113.0, 83.2, 69.5, 40.9
(dd, 2J 27.1, 2J 21.5), 38.5, 29.1, 28.5, 23.1, 22.0, 20.5; nmax/cm21
1711.9; m/z (CI) 280 (M+NH4+).
NMR COSY and GOESY experiments.13 By 19F NMR, we
were able to detect only products with a single double bond
configuration, assumed trans with respect to the mutual location
of the ring bonds. Unambiguous proof of alkene configuration
was then obtained in the case of 9a when single crystals14 were
grown and subjected to analysis by X-ray diffraction (Fig. 1).
Also, the 3JH-F couplings across the alkene bond in 7c (33.7 Hz)
and 9c (32.4 Hz) were entirely consistent with this arrange-
ment.
We have therefore shown that oxy-Cope systems can be
assembled rapidly, and that fluorinated cyclodecenones and
13 J. Stonehouse, P. Adell, J. Keeler and A. J. Shaka, J. Am. Chem. Soc.,
1994, 116, 6037.
14 Crystal data for 9a: C13H17ClF2O2, M
= 278.7, triclinic, a =
8.0670(2), b = 8.3194(3), c = 10.5779(3) Å, U = 633.65(3) Å3, T =
¯
150(2) K, space group P1, Z = 2, m(Mo-Ka) 0.318 mm21, 10852
reflections measured, 2555 unique (Rint = 0.0441) which were used in
all calculations. The final wR(F2) was 0.0718 (all data). CCDC
182/1482. See http://www.rsc.org/suppdata/cc/1999/2535/ for crys-
tallographic data in .cif format.
Fig. 1 The molecular structure of 9a. The cis-ring junction and trans-ring
bonds can be seen clearly.
Communication 9/08450I
2536
Chem. Commun., 1999, 2535–2536