A new tetrasubstituted α-fluoro cyclohexanone bearing a fluoroisopropyl group at C5

Article abstract of DOI:10.1016/j.jfluchem.2006.06.021

A new tetrasubstituted cyclohexanone 5 fluorinated at C2 and having a fluoroisopropyl group at C5 has been synthesized in five steps from 3-methyl cyclohexenone and the structure of both diastereomers fully assigned. It is shown that diastereomer Ia havin

Full text of DOI:10.1016/j.jfluchem.2006.06.021

Journal of Fluorine Chemistry 127 (2006) 1510–1514
www.elsevier.com/locate/fluor
A new tetrasubstituted a-fluoro cyclohexanone bearing
a fluoroisopropyl group at C5
a,
Arlette Solladie-Cavallo , Khalid Azyat ,
a,1
*
´
Loıc Jierry , Dominique Cahard
a,1
b
¨
a
´ ´ ´ ´ ´
Laboratoire de Stereochimie Organometallique associe au CNRS, ECPM/Universite L. Pasteur,
25 rue Becquerel, 67087 Strasbourg, France
´
UMR 6014 CNRS de l’IRCOF, Universite de Rouen, 76821 Mont Saint Aignan, France
b
Received 16 May 2006; received in revised form 29 June 2006; accepted 29 June 2006
Available online 6 July 2006
Abstract
A new tetrasubstituted cyclohexanone 5 fluorinated at C2 and having a fluoroisopropyl group at C5 has been synthesized in five steps from 3-
methyl cyclohexenone and the structure of both diastereomers fully assigned. It is shown that diastereomer Ia having the fluorine atom at C2 in the
axial position (in the most populated conformer of this diastereomer) is major and is a good catalyst for epoxidation of trans-olefins by oxone while
diastereomer IIe is not. Moreover, only 0.3 equiv. of 5-Ia are necessary and the ketone is totaly recovered after reaction (no Baeyer–Villiger).
# 2006 Published by Elsevier B.V.
Keywords: Fluorocyclohexanone; NMR; Organic catalyst; Epoxidation catalyst
1. Introduction
populated conformer for high reactivity and enantioselectivity,
and disubstitution at C5 for high enantioselectivity but with a 2-
fluoroisopropyl group instead of a phenyl.
During work [1–6] on a-fluorinated tri- (1–3) and tetra- (4)
substituted cyclohexanones, we have shown that the (2S,5R)
diastereomers with an axial fluorine at C2 (diastereomers Ia)
were more efficient in the asymmetric epoxidation of trans-
olefins [1–3], providing higher yields and enantioselectivities,
than the (2R,5R) with an equatorial fluorine at C2 (diaster-
eomer IIe), Fig. 1 (compare the results obtained with ketones
1–3 between diastereomers Ia and IIe).
We present here the synthesis of the desired diastereomer of
this ketone (5-Ia), determination of its structure and some
assays of epoxidation of trans-olefins using racemic-5-Ia to
check if this ketone was a catalyst as expected and to determine
its stability under the epoxidation-conditions.
2. Results and discussion
It was observed also that replacement of the hydrogen atom
of the isopropyl group located at C5 by a fluorine [2,4–8]
increased drastically the enantioselectivity (ketone 1-Ia
provides 40% e.e. while ketone 3-Ia provides 90% e.e.,
Fig. 1) as did disubstitution at C5 with a methyl and a phenyl [3]
(ketone 1-Ia provides 40% e.e. while ketone 4-Ia provides 90%
e.e.).
2.1. Synthesis
Racemic 2-fluoro-2-methyl-5-methyl-5-[2-fluoroisopropyl]-
cyclohexanone5was obtainedfrom 3-methylcyclohexenone 6 in
five steps and as a 95/5 mixture of 5-Ia and 5-IIe, Scheme 1.
Conjugated addition of isopropenyl Grignard onto 7 went
smoothly in presence of CuBr/Me2S [9] and provided a high
yield (94%). Fluorination of the double bond was performed
with 30% HF/pyridine in THF then the thermodynamic
silylenolate 10 was obtained in almost quantitative yield by
using a slightly modified process [10]. Electrophilic a-
fluorination was performed in the last step with SelectfluorTM
(1.4 equiv.) to provide the desired racemic 5 (60% yield) in
We thus designed ketone 5 (Fig. 1) whose structure included
all necessary substitutions: an a-fluorine axial in the most
* Corresponding author. Tel.: +33 6 82 01 10 37; fax: +33 3 90 24 27 42.
´
E-mail address: cavallo@chimie.u-strasbg.fr (A. Solladie-Cavallo).
1
Fax: +33 3 90 24 27 42.
0022-1139/$ – see front matter # 2006 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2006.06.021

´
A. Solladie-Cavallo et al. / Journal of Fluorine Chemistry 127 (2006) 1510–1514
1511
2.2. Structural determination of ketones 5-Ia and 5-IIe by
NMR
1
1H NMR (CDCl3, TMS): full assignment of the H signals
has been done using 2D C/H correlations, COSYand analysis of
the multiplicity.
A NOESY experiment on isomers 5-Ia (major) and 5-IIe
(traces) showed that in both cases the singlet of the Me at C5
was correlated with one H at C6, one H at C4 and one H at C3. It
can thus be concluded that the Me at C5 are axial in both
diastereomers. As a consequence, these multiplets were
assigned to be H6e, H4e and H3a in both diastereomers.
Moreover, while the doublet of the Me at C2 has no
correlation spot with H6a (the remaining C6 proton) indicating
its equatorial position and the axial position of the fluorine in 5-
Ia, in 5-IIe the doublet of the Me at C2 is correlated with H6a
indicating its axial position and the equatorial position of the
fluorine, Fig. 2.
Therefore, the major diastereomer (43% overall isolated
yield) was assigned the 5-Ia structure (2S,5R/2R,5S) having the
fluorine at C2 and the methyl at C5 axial in the most populated
conformer. As a consequence the minor (traces) diastereomer
was assigned the 5-IIe structure.
Fig. 1. Fluoro cyclohexanones structures used or to be used as epoxidation
catalysts.
which diastereomer 5-Ia was major (95% of the mixture). After
chromatographic purification rac-5-Ia (2S,5R/2R,5S) was
obtained pure [11,12].
These assignments are consistent with the 5.5 Hz value of
the 4JHF found for H6e in 5-IIe and with the 6 Hz value of the
4JHF found for H6a in 5-Ia, Fig. 1, values already found in
previous a-fluorinated ketones [13,14].
Introduction of the fluorine atoms at the desired positions
was checked using 19F NMR. Ketone 9 and silylenolate 10
having both a (Me)2CF– group exhibit a septuplet for the
fluorine at, respectively, À148.9 ppm (3JFH = 22.6 Hz) and at
À150.3 ppm (3JFH = 22.6 Hz) while 5-Ia having two fluorine
atoms exhibits two signals: the expected septuplet at
À148.0 ppm (3JFH = 22.6 Hz) corresponding to the fluorine
of the (Me)2CF– group and a new multiplet at À154.2 ppm
corresponding to the fluorine a to the carbonyl group.
2.3. Epoxidation assays
Epoxidation of trans-b-methylstyrene and trans-ethyl p-
methoxycinnamate by oxone using both diastereomers of
ketone 5 (5-Ia and 5-IIe) has been tested and the results are
gathered in Table 1. In all cases 0.3 equiv. of ketone were used;
the reactions conditions were either A (DME/H2O/AcOH;
Scheme 1.

´
A. Solladie-Cavallo et al. / Journal of Fluorine Chemistry 127 (2006) 1510–1514
1512
Fig. 2. Ketones 5-Ia and 5-IIe: NOESY experiments and characteristic coupling constants.
Table 1
Moreover, ketone 5-Ia undergoes no Baeyer–Villiger
oxidation and is totally recovered after the reaction.
Epoxidation of trans-olefins using ketone 5 as catalyst.
3. Conclusion
It is worth noting that, in consistency with previous results
[1–6] and theoretical calculation [15], ketone 5-Ia, in which the
most populated conformer is expected to be the most reactive
because the a-fluorine atom is axial, is indeed an efficient
catalyst for epoxidation of trans-olefins with oxone while
ketone 5-IIe, in which the a-fluorine atom has an equatorial
position (in the most populated conformer) is, as expected, less
reactive and indeed does not catalyze epoxidation of trans-
olefins with oxone.
Olefin
Ketone
Conditions
Yielda (%)
b-Methylstyrene (11)
b-Methylstyrene (11)
Ethyl p-methoxycinnamate (12)
Ethyl p-methoxycinnamate (12)
Ethyl p-methoxycinnamate (12)
–
A
A
B
B
B
10
100
14
5-Ia
–
5-Ia
5-IIe
100
13
a
The yields have been determined by combining weights and 1H NMR
(400 MHz) of solvent-free crude products compared to the weight of starting
olefin; then epoxides were isolated by flash chromatography on silica gel and
identified by NMR: epoxides 13 and 14 have the same NMR spectra as the
racemic compounds purchased from Aldrich (13) and Sylachim in collaboration
with Tanabe-Seiyaku Co. Ltd. (14).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on Bruker AC 200
(200 MHz) or Bruker Avance 400 (400 MHz) spectrometers
with CDCl3 or C6D6 as solvent. Chemical shifts (d) are given in
ppm downfield from TMS and coupling constants in Hz. 19F
NMR spectra were recorded on Bruker Avance DPX 300
(282 MHz) with CDCl3 as solvent. Chemical shifts (d) are given
in ppm refered to CFCl3. A Perkin-Elmer IR spectrum one has
been used to check the presence of carbonyl absorption bands
for all compounds synthesized. TLC were performed on Merck
glass plates with silica gel 60 F254. Silica gel Si 60 (40–60 mm)
from Merck was used for the chromatographic purifications. 3-
Methylcyclohexenone was purchased from Fluka. Oxone1,
SelectfluorTM and isopropenyl Grignards THF solutions have
been purchased from Aldrich.
oxone: 1.4 equiv. added during 8 h at 0 8C) or B (dioxane/H2O/
AcOH; oxone: 3 equiv. added during 6 h at ambient) and in all
cases the pH was monitored and maintained at 8.5–9 by slow
and progressive addition of K2CO3.
It appears that ketone 5-Ia is a good catalyst for epoxidations
(100% yield in epoxide in both cases compared with 10–14%
without ketone under identical conditions: Table 1, compare
lines 2 and 4 with 1 and 3).
It appears also that diastereomer 5-Ia which has the fluorine
axial in the most populated conformer [2] is a better
epoxidation catalyst (100% yield in epoxide) than diastereomer
5-IIe (13% yield in epoxide) which has the fluorine equatorial
in the most populated conformer [2], Table 1 (compare lines 4
with 5).

´
A. Solladie-Cavallo et al. / Journal of Fluorine Chemistry 127 (2006) 1510–1514
1513
4.2. 3,6-Dimethylcyclohexenone, 7
15–20 min. After evaporation of THF, H2O (25 mL) and
CH2Cl2 (30 mL) were added. The organic phase was recovered
and the aqueous phase extracted with CH2Cl2 (3Â 10 mL). The
joined organic phases were dried over Na2SO4. After filtration
and evaporation of the solvent, the crude product was purified
by column chromatography to give 9 (colorless oil, 0.976 g,
87% yield) as an 86/14 mixture of the two possible
diastereomers; which could be separated by chromatography
(Rf = 0.42 and 0.40 using hexane/AcOEt, 90/10). However, the
following step has been conducted on the mixture as one of the
chiral center (C2) will be destroyed in step d (Scheme 1).
9, 86/14 diastereomers mixture used for the next steps. Anal.
Calcd for C11H19FO: C, 70.92; H, 10.28. Found: C, 70.61; H,
Compound 7 has been prepared by methylation of 3-
methylcyclohexen-1-one following a known literature procedure
[16] as a colorless oil: Rf = 0.48 (hexane/ether, 50/50); 1H NMR
(CDCl3, 400 MHz): d 1.14 (d, 3H, CH3), 1.72 (m, 1H), 1.94 (s,
2
3
3-
3H, CH3), 2.06 (dq, 1H, H5e, Jae = 12, J5e6a = 3J5e4a
=
J5e4e = 4), 2.32 (m, 3H), 5.85 (s, 1H). 13C NMR (CDCl3,
100 MHz): d 15.5, 24.6, 31.0, 31.1, 40.8, 126.6, 161.9, 202.5. IR,
n
COconj.: 1685 cmÀ1; nC Cconj (weaker): 1620 cmÀ1
.
4.3. 2,5-Dimethyl-5-isoprenyl-cyclohexanone, 8: Grignard
addition
1
10.68. H NMR (C6D6, 400 MHz): d (86%) 0.87 (s, 3H, Me),
1.04 (d, 3H, Me, 3J = 6.5), 1.32 (d, 3H, Me, 3JHF = 22), 1.35 (d,
3H, Me, 3JHF = 22), 1.48 (m, 1H), 1.62 (m, 1H), 2.02 (m, 2H),
To a stirred suspension of CuBr:S(Me)2 (75 mg, 0.11 equiv.)
in anhydrous THF (5 mL) were successively added (under
argon and at À20 8C) a solution of 3,6-dimethylcyclohexen-1-
one (4.464 g, 1 equiv.) in THF (10 mL) and a 2 M THF solution
of the desired isoprenyl Grignard (1.4 equiv.). After stirring for
3 h (the temperature reaching ambient), the reaction mixture
was poured into a cold solution of hydrochloric acid 2 M
(4 mL), crushed ice (two spatulae spoons) and extracted with
ether (8Â 10 mL). The combined organic phases were dried
over Na2SO4 and concentrated. The crude product was purified
by column chromatography to give 8 (pale yellow oil, 5.61 g,
94% yield) as a 52/48 mixture of the two possible diastereomers
which could be separated by chromatography (Rf = 0.30 and
0.27 using hexane/AcOEt, 90/10). However, the following step
has been conducted on the mixture as one of the chiral center
(C2) is destroyed in step d (Scheme 1).
2
4
2.23 (dd, 1H, J = 13, J = 2.5), 2.35 (m, 1H), 2.56 (d, 1H,
2J = 13) and (14%) 0.93 (s, 3H, Me), 1.13 (d, 3H, Me, 3J = 7),
3
3
1.36 (d, 3H, JFH = 23.5), 1.39 (d, 3H, JFH = 23.5), 1.50 (m,
1H), 1.75 (m, 1H), 1.97 (m, 1H), 2.05 (d, 1H, 2J = 13), 2.15 (m,
2
1H), 2.36 (m, 1H), 2.75 (d, 1H, J = 13). 13C NMR (C6D6,
100 MHz) d (major) 14.2 (CH3), 19.4 (CH3, d, 3JCF = 6), 22.3
2
2
(CH3, d, JCF = 25), 22.7 (CH3, d, JCF = 24), 30.1 (CH2, d,
3JCF = 6), 47.5 (CH2, d, 3JCF = 5), 31.0 (CH2), 44.2 (CH), 48.0
2
(Cq, d, JCF = 21), 98.9 (Cq, d, JCF = 172), 213.1 (Cq) and
1
3
(minor) 15.8 (CH3), 22.7 (CH3, d, JCF = 6), 23.1 (CH3, d,
2
3
2JCF = 20), 23.1 (CH3, d, JCF = 20), 29.6 (CH2, d, JCF = 7),
3
43.4 (CH2, d, JCF = 5), 29.7 (CH2), 45.1 (CH), other signals
not detected. 19F NMR (CDCl3, 282 MHz) d (refered to CFCl3)
À148.9 ppm (3JFH = 22.6 Hz). IR, nCO: 1720 cmÀ1
.
1
8, 52/48 diastereomers mixture used for the next step. H
NMR (CDCl3, 400 MHz) d (52%) 0.95 (d, 3H, Me), 1.13 (s, 3H,
4.5. 2,5-Dimethyl-2-fluoro-5-(2-fluoroisopropyl)-
cyclohexanone, 5
2
3
3-
Me), 1.32 (dq, 1H, H3e, J3e3a = 13.5, J3e2a = 3J3e4a
=
J3e4e = 3.5),
1.59
(dt,
1H,
H3a,
2J3a3e = 13.5,
3
3J3a2a = 3J3a4a = 11, J3a4e = 0), 1.68 (s, 3H, Me), 1.87 (m,
1H), 2.02 (m, 1H), 2.18 (d, 1H, H6e, 2J6e6a = 12), 2.20 (m, 1H),
4.5.1. Silylenol ether: general procedure
To a solution of the 86/14 diastereomers mixture of ketone 9
(2.224 g, 11.96 mmol) in dry pentane (25 mL) was added,
dropwise and under argon, freshly distilled NEt3 (3.32 mL,
24 mmol, 2 equiv.), freshly distilled TMSCl (3.04 mL,
24 mmol, 2 equiv.) followed by a solution of anhydrous NaI
(3.58 g, 24 mmol, 2 equiv.) in dry CH3CN (60 mL). After reflux
for 3 h stirring was stopped and the upper pentane layer was
transfered into a dry flask. The remaining mixture was extracted
with anhydrous pentane (3Â 10 mL). The pentane phases were
gathered and evaporated to give 10 as a colorless oil (3.01 g,
98% yield) which was pure as determined by NMR analysis
(based on integration of the Me3Si group compared to the four
other methyl groups and on patterns of the various signals) and
has been used without purification. 10: 1H NMR (CDCl3,
400 MHz): d 0.19 (s, 9H, Me3Si), 0.91 (s, 3H, Me), 1.33 (d, 3H,
Me, 3JHF = 22), 1.34 (d, 3H, Me, 3JHF = 22), 1.45 (m, 2H), 1.58
(s, 3H, Me), 2.20 (m, 4H). 19F NMR (CDCl3, 282 MHz) d
(refered to CFCl3) À150.3 ppm (3JFH = 22.6 Hz).
2
2.71 (dd, 1H, H6a, J6a6e = 12, J6a2a = 3), 4.73 (bs, 1H), 4.85
4
(bs, 1H) and (48%) 1.05 (d, 3H, Me), 1.15 (s, 3H, Me), 1.35 (dq,
2
3
1H, H3e, J3e3a = 13, J3e2a = 3J3e4a = 3J3e4e = 3.5), 1.58 (m,
1H), 1.78 (m, 1H), 2.10 (m, 1H), 2.31 (m, 1H), 2.33 (m, 1H),
2
4
2.48 (dd, 1H, H6a, J6a6e = 12, J6a2a = 3), 4.73 and 4.85 (bs,
overlapped with the previous diastereomer). 13C NMR (CDCl3,
100 MHz) d 14.8, 15.0, 19.5 (CH3); 23.5, 29.4 (CH); 30.9, 31.0,
31.2, 35.5 (CH2); 44.5, 45.2 (Cq); 44.7, 44.8 (CH3); 51.9, 52.7
(CH2); 109.4, 113.6 (CH2); 149.0, 152.5, 212.7, 213.8 (Cq).
Anal. Calcd for C11H18O: C, 79.46; H, 10.91. Found: C, 79.27;
H, 11.12. IR, nCO: 1715 cmÀ1
.
4.4. 2,5-Dimethyl-5-(2-fluoroisopropyl)-cyclohexanone, 9:
fluorination
To a stirred solution of 8 as a mixture of both diastereomers
(1.00 g, 6.02 mmol) in THF (10 mL), in a plastic container and
maintained at 0 8C (ice/water bath), was added dropwise
(through a plastic syringe in a well ventilated hood) the HF–
pyridine reagent (6 mL). The mixture was stirred at 0 8C for
2 h, the container was opened and left under air ventilation for
4.5.2. Fluorination: general procedure
To a solution of the silylenol ether 10 (2 g, 7.75 mmol,
1 equiv.) in anhydrous DMF (25 mL) was added dropwise,

´
A. Solladie-Cavallo et al. / Journal of Fluorine Chemistry 127 (2006) 1510–1514
1514
under argon, a solution of SelectfluorTM (3.57 g, 10.08 mmol,
1.3 equiv.) in anhydrous DMF (40 mL). The mixture was stirred
at 0 8C for 3 h. Then, HCl 1% (60 mL) was poured under
stirring into the reaction mixture followed by pentane
(100 mL). The organic phase is separated and the aqueous
phase extracted with pentane (5Â 10 mL). The joined organic
phases were dried over MgSO4. After filtration and evaporation,
the residue was purified by column chromatography (pentane/
ether, 80/20) to give 5: 0.951 g (63% yield) as a mixture of 5-Ia
and 5-IIe (ratio: 5-Ia/5-IIe = 95/5). Anal. Calcd for C11H18
F2O: C, 64.68; H, 8.88. Found: C, 64.31; H, 9.02.
controlled and regulated (8.5–9) by addition of a 1 M solution
of K2CO3. The reaction was quenched by addition of CH2Cl2
(30 mL) and water (10 mL). The mixture was extracted with
CH2Cl2, dried over Na2SO4, and analysed by NMR.
1
3
13: H NMR (CDCl3, 200 MHz); d 1.45 (d, 3H, J = 6.5),
3.05 (qd, 1H, 3J = 6.5 and 2), 3.57 (d, 1H, 3J = 2), 7.25 (m, 5H).
14: 1H NMR (CDCl3, 200 MHz); d 3.52 (d, 1H, 3Jtrans = 1.5),
3.81 (s, 3H, OMe), 3.83 (s, 3H, OMe), 4.05 (d, 1H, 3Jtrans = 1.5),
6.89 (bd, 2H, arom.), 7.20 (bd, 2H, arom.).
Acknowledgment
1
5-Ia (Rf = 0.21): H NMR (C6D6, 400 MHz) d 0.54 (s, 3H,
Me at C5), 0.93 (m, 1H, H4e), 0.94 (d, 3H, Me, 3JHF = 22), 0.97
` ´
We are grateful to Ministere de l’Enseignement Superieur et
de la Recherche for grants (MNERT) to LJ and KA.
3
(d, 3H, Me, JHF = 22), 1.25 (m, 1H, H3e), 1.31 (d, 3H, Me,
2
3JHF = 22), 1.76 (m, 1H, H3a), 2.06 (d, 1H, H6e, J = 12.5),
2.10 (td, 1H, H4a, 2J4a4e = 3J4a3a = 12.5, 3J4a3e = 4.5), 3.04 (dd,
2
4
1H, H6a, J = 12.5, JHF = 6). 13C NMR (C6D6, 100 MHz) d
18.4 (d, 3JCF = 7); 20.1 (d, 2JCF = 25); 22.2 (d, 2JCF = 26); 22.3
(d, 2JCF = 26); 26.0 (dd, 3JCF = 5, 2); 34.8 (d, 2JCF = 24); 44.2
(dd, 3JCF = 4, 2); 46.0 (d, 2JCF = 21); 95.1 (d, 1JCF = 173); 98.2
References
´
´
[1] A. Solladie-Cavallo, L. Bouerat, Org. Lett. 2 (2000) 3531–3534.
[2] A. Solladie-Cavallo, L. Jierry, H. Norouzi-Arasi, D. Tahmassebi, J.
Fluorine Chem. 125 (2004) 1371–1377.
1
2
(d, JCF = 174); 206.1 (d, JCF = 24). 19F NMR (CDCl3,
´ ´
[3] A. Solladie-Cavallo, L. Bouerat, L. Jierry, Eur. J. Org. Chem. (2001)
282 MHz) d (refered to CFCl3) À148.0 ppm (3JFH = 22.6 Hz,
4557–4560.
´
[4] A. Solladie-Cavallo, L. Jierry, P. Lupattelli, P. Bovicelli, R. Antonioletti,
(Me)2CF–), À154.2 (F a to the carbonyl group). IR, nCO
:
1735 cmÀ1
.
Tetrahedron 60 (2004) 11375–11380.
´
[5] A. Solladie-Cavallo, L. Jierry, A. Klein, M. Schmitt, R. Welter, Tetra-
5-IIe (Rf = 0.45): 1H NMR (C6D6, 400 MHz) d 0.45 (s, 3H,
hedron Asymm. 15 (2004) 3891–3898.
´
[6] A. Solladie-Cavallo, L. Jierry, A. Klein, Comptes rendus Chimie (Aca-
3
Me at C5), 0.89 (d, 3H, Me, JHF = 22), 0.90 (d, 3H, Me,
3JHF = 22), 1.14 (m, 1H, H4e), 1.22 (d, 3H, Me, 3JHF = 22), 1.56
demie des sciences, Paris) 6 (2003) 603–606.
´
(m, 1H, H4a, J4a4e = 3J4a3a = 13, J4a3e = 4.5), 1.70 (m, 1H,
2
3
[7] For difference between pseudo-axial/pseudo-equatorial position of a-
fluorine in bridged bicyclic ketone see:
H3e), 1.81 (td, 1H, H3a, J3a3e = 3J3aF = 3J3a4a = 14,
2
S.E. Denmark, Z. Wu, M.C. Crudden, H. Matsuhashi, J. Org. Chem. 62
(1997) 8288–8293;
3J3a4e = 5), 2.13 (dd, 1H, H6e, J6e6a = 13, JHF = 4), 2.42
2
4
(d, 1H, H6a, 2J6a6e = 13). 13C NMR (C6D6, 100 MHz) d 20.8 (d,
A. Armstrong, B. Hayter, Chem. Commun. (1998) 621–623;
A. Armstrong, B. Hayter, W.O. Moss, J.R. Reeves, J.S. Wailes, Tetra-
hedron Asymm. 11 (2000) 2057–2063;
3JCF = 6); 21.8 (d, JCF = 25); 22.4 (d, JCF = 25); 22.6 (d,
2
2
2JCF = 25); 28.5 (dd, 3JCF = 4, 4); 34.8 (d, 2JCF = 22); 45.2 (d,
3JCF = 4); 45.3 (d, JCF = 20); 95.5 (d, JCF = 183); 99.0 (d,
2
1
S. Klein, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (2002) 2686–2688.
[8] For a-chloro-ketones, see: D. Yang, Y.C. Yip, J. Chen, K.K. Cheung, J.
Am. Chem. Soc. 120 (1998) 7659–7660.
1JCF = 174); 204.8 (d, JCF = 20). IR, nCO: 1735 cmÀ1
.
2
[9] H.O. House, W.L. Respess, G.M. Whitesides, J. Org. Chem. 31 (1966)
3128–3133.
4.6. Epoxidation procedure
[10] Quantitative yield of silylenolate is obtained after modification of the
literature work-up: no addition of water at all. Cf. Milan Balaz, Ph.D.
Dissertation, Strasbourg, 2003 and Ref. [13].
A (DME/H2O/AcOH). To a solution of 1 mmol of the desired
olefin and 0.3 mmol of the desired ketone in DME (10 mL) was
added under stirring a solution (6 mL) of a buffer (made from
addition of 0.5 mL of AcOH in 100 mL of an aqueous solution
of K2CO3, 0.1 M). The mixture was cooled to the desired
temperature (0 8C), and a solution of oxone (1.4 mmol) in
distilled water (3.5 mL) was added dropwise over 8 h. During
addition of oxone, the pH was controlled and regulated (8.5–9)
by addition of 1.4 M solution of K2CO3. The reaction was
quenched by addition of CH2Cl2 (30 mL) and water (10 mL).
The mixture was extracted with CH2Cl2, dried over Na2SO4,
and analysed by NMR.
[11] Attempted asymmetric synthesis of 5 through electrophilic a-fluorination
of the silyl enol ether 10 using a chiral fluorinating agent derived from
quinine (F-4ClBzQN-BF4, cf. J.A. Ma, D. Cahard, Chem. Rev. 104 (2004)
6119–6146) under suitable conditions for a kinetic resolution (half
equivalent of the fluorinating agent versus one equivalent of the substrate
10) provided 40% yield of the desired a-fluoro ketone 5-Ia as a single
diastereomer, but the enantiomeric excess was only 10% (determined by
1H NMR using Eu(hfc)3 as chiral shift reagent).
[12] Analytical resolution of racemic 5-Ia was performed by the ASTEC
Company-USA using GC and a BETA DEXTM 120 Fused Silica Capil-
lary column (15 m  0.25 mm  0.25 film thickness). The temperature
program was: 100 8C isotherm (Rt (min) of the enantiomers: 11.8 and
12.3). However, neither preparative nor semi-preparative separation could
be performed.
B (dioxane/H2O/AcOH). To a solution of 1 mmol of the
desired olefin and 0.3 mmol of the desired ketone in dioxane
(20 mL) were added successively and under stirring a solution
(4 mL) of a buffer (made from addition of 0.5 mL of AcOH in
100 mL of an aqueous solution of K2CO3, 0.1 M), 6 mL of H2O
and a solution of oxone (1.850 g, 3 mmol) in distilled water
(7 mL) over 6 h. During addition of oxone, the pH was
´ ´
[13] A. Solladie-Cavallo, L. Jierry, L. Bouerat, P. Taillasson, Tetrahedron
Asymm. 12 (2001) 883–891.
´ ´
[14] A. Solladie-Cavallo, L. Jierry, L. Bouerat, M. Schmitt, Tetrahedron 58
(2002) 4195–4199.
[15] A. Armstrong, I. Washington, K.N. Houk, J. Am. Chem. Soc. 122 (2000)
6297–6298.
[16] J.P. Marino, J.C. Jaen, J. Am. Chem. Soc. 104 (1982) 3165–3168.