Synthesis and reactivity of Z and E functionalized allylic fluorides

Article abstract of DOI:10.1016/j.tet.2003.08.068

The allylic fluorides 1 and 2 are used as models to study the effect of the allylic C-F bond on the diastereoselectivity of reactions occurring on the vicinal double bond, as well as the compatibility of this C-F bond with various reagents. The configurational stability of the Z double bonds in enals and enones 1 and 3 is noteworthy. This allowed us to perform various types of reactions (including thermal Diels-Alder cycloadditions) on derivatives 1 with full control of the Z geometry.

Full text of DOI:10.1016/j.tet.2003.08.068

Tetrahedron 59 (2003) 8833–8841
Synthesis and reactivity of Z and E functionalized allylic fluorides
*
´
´ ´
¨
Michael Prakesch, Danielle Gree and Rene Gree
` ´ ´ ´
ENSCR, Laboratoire de Syntheses et Activations de Biomolecules, CNRS UMR 6052, Avenue du General Leclerc, 35700 Rennes, France
Received 30 June 2003; revised 19 August 2003; accepted 21 August 2003
Abstract—The allylic fluorides 1 and 2 are used as models to study the effect of the allylic C–F bond on the diastereoselectivity of reactions
occurring on the vicinal double bond, as well as the compatibility of this C–F bond with various reagents. The configurational stability of the
Z double bonds in enals and enones 1 and 3 is noteworthy. This allowed us to perform various types of reactions (including thermal Diels–
Alder cycloadditions) on derivatives 1 with full control of the Z geometry.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
proved to be very sensitive to basic conditions leading to
slight loss of enantiomeric purity.9 We have reported
recently that propargylic routes could be very useful for
the stereocontrolled synthesis of monofluorinated allylic
derivatives such as 1a and 2a.10 The latter compound was an
excellent intermediate for the enantiocontrolled synthesis of
fluorinated analogues of bioactive lipids (Fig. 1).11
The introduction of fluorine atom(s) strongly modifies the
physical, chemical and biological properties in a molecule.1
This explains why fluorinated compounds are intensively
studied and used in areas as diverse as pharmaceuticals,
agrochemicals and polymers for instance. In fluoro-
bioorganic chemistry the replacement of strategic C–H or
C–OH bonds by C–F could lead to important informations
regarding the structure and mechanism of action of
enzymatic systems. It could give as well compounds
which are more stable from the chemical point of view
and/or have a better bioactivity.2 Therefore, it is important
to control the regio- and stereoselectivity of the fluorination
step. Particularly, the difficulties encountered during
selective monofluorination in a position vicinal to unsatu-
rated derivatives are well recognized. This is the case for
allylic systems and it is particularly true when enantio-
control is required.3 For instance the dehydroxyfluorination
of allylic alcohols with diethylamino sulfur trifluoride
(DAST) is neither regio-, nor stereocontrolled.4 Several
methods have been developed in order to afford a solution to
this problem: for instance it is possible to use transition
metal complexes of the corresponding p complexed
alcohol.5–7 In the case of allylic alcohols it afforded a
complete regio- and stereocontrol, however the required
rhenium complexes are expensive derivatives which further,
are obtained in a multistep sequence.8 Therefore other
strategies using fluorinated key intermediates have been
developed. Davis et al. reported an elegant approach using
a-fluorocarbonyls as precursors to a Horner–Wadworth–
Emmons olefination process. However such intermediates
Figure 1.
As part of our program dealing with the development of
novel methodologies for the preparation of such chiral
fluorides, the purpose of this paper is:
to report an easy and efficient synthesis of corresponding
ketones and especially the Z isomer 1b. This led us to
prepare also the corresponding Z and E enals 3 and 4
where fluorine was formally exchanged by a methoxy
group or hydrogen. The thermal stability of 1b, together
with the results obtained from 3, establish that the
configurational stability of Z enals has been generally
underestimated
to extend our previous studies on the steric and electronic
effects induced by the C–F bond on the diastereo-
selectivity of reactions.12 This will include Diels–Alder,
Keywords: fluorine; allylic fluoride; enone; enal.
*
Corresponding author. Tel.: þ33-2-23238070; fax: þ33-2-23238108;
e-mail: rene.gree@ensc-rennes.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.068

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M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
1,2 and 1,4 additions and it will give further information
on the compatibility of allylic fluorides with various
chemical reagents.
preparation of fluorides (Scheme 3). They start from
propargylic derivatives 7 which are submitted to a semi
hydrogenation with Lindlar’s catalyst followed by formo-
lysis. The Z enals 3c and 3d have been purified by
chromatography.
2. Synthesis and thermal stability
We have reported recently the synthesis of 1a and 2a,
starting from propargylic alcohols: the key steps involved a
stereospecific dehydroxyfluorination with DAST at low
temperature, followed by a cis hydrogenation using
Lindlar’s catalyst and a deprotection with pure formic
acid leading to a 9:1 mixture of 1a and 2a separated by
chromatography (Scheme 1).11
Scheme 3. Reagents and conditions: (i) Py (1 equiv.), Lindlar cat. (20%
weight), pentane, rt, 8c (87%), 8d (99%); (ii) HCO2H (156 equiv.), CH2Cl2,
rt, 3c (46%), 3d (23%).
Both compounds exhibited a thermal stability similar to
compound 1a: no isomerisation was observed after 3 days in
benzene at 608C! (NMR control). These results first
demonstrate that the polar (C–OMe or C–F) bond are not
responsible for the good thermal stability; they also clearly
establish that the stability of Z enals and enones has been
largely underestimated and that such compounds have real
potentialities in stereoselective synthesis.
Scheme 1. Reagents and conditions: (i) DAST, (ii) H2, Lindlar; (iii)
HCO2H excess; for details see Ref. 11.
Both isomers were used for the synthesis of the two
corresponding ketones: addition of PhLi on 1a afforded in
91% yield the alcohols 5 as a 1:1 mixture of stereoisomers at
the carbinol center, but as exclusive Z stereochemistry at the
double bond. MnO2 oxidation of this mixture afforded the
ketone 1b in 86% yield and again without double bond
isomerisation. In both cases, the stereochemistry is clearly
established by 1H NMR (JH–H¼11.2 Hz). Similar reactions
have been performed starting from 2a affording the E
isomer 2b via the allylic alcohols 6 (also obtained as a 1:1
mixture of diastereoisomers). Therefore such allylic fluor-
ides appear compatible with these strong nucleophiles and
both the 1,2 addition and the oxidation occur without Z to E
isomerisation (Scheme 2).
3. Reactivity studies
A first series of reactions have been performed using
stabilized Wittig reagents and the results are given in
Scheme 4. The Z enal afforded exclusively the E,Z diene 9
while the E isomer led to a 7:3 mixture of the E,E and E,Z
dienes 10 and 11. These isomers could be separated by
chromatography.
Scheme 4. Reagents and conditions: (i) Ph3PvCHCO2Me (1.2 equiv.),
Tol, 758C, 9 (83%), 10 (45%), 11 (15%).
Therefore, such Wittig type reactions are not only
compatible with the allylic fluorides but furthermore, they
are stereospecific with regard to the geometry of the starting
enal. These results appear of much interest since:
Scheme 2. Reagents and conditions: (i) PhLi (1.6 equiv.), THF, 2508C, 5
(91%), 6 (82%); (ii) MnO2 (10 equiv.), CH2Cl2, rt, 1b (86%), 2b (82%).
The thermal stability of these allylic fluorides, and
especially 1a and 1b, was of special interest with regard
to some synthetic applications such as thermal cyclo-
additions for instance. To our surprise 1a was found to be
relatively thermally stable: after 24 h at 608C in benzene, or
even in DMSO, there is no evidence for E to Z isomerisation
(NMR control).13,14 These results led us in a first approach
to explore the possible role of the polar C–F bond on this
high thermal stability. Therefore, for comparison purposes
we prepared the two Z enals 3 and 4 where the fluorine has
been replaced respectively by OMe and H. The synthesis
followed routes similar to the previously used in the
1. They could probably be extended to homochiral
derivatives taking into account that starting enals 1a
and 1b have been obtained previously in optically pure
form.11
2. They offer a complementary route to the use of
dienetricarbonyliron complexes which could afford
only the E,E dienes with the fluorine in allylic position.5
1,4 Addition reactions of thiocresol have been performed on
the E and Z enals and enones 1 and 2: in both cases they
afforded the same inseparable racemic mixture of stereo-
isomeric adducts 12. Like in the 1,2 addition there is again

M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
8835
no induction by the allylic C–F bond in these 1,4 additions.
It can be noticed also that cuprates appear incompatible with
such allylic fluorides since reactions of dimethylcuprate on
1 or 2 led only to decomposition products (Scheme 5).
In order to confirm the key role of such a substituent in
position cis to the allylic fluoride we have performed similar
Diels–Alder reactions on Z enal 1a and Z enone 1b; for
comparison purposes we did also the same reactions on
corresponding E isomer 2a. The results are given in
Schemes 6 and 7: starting from 2a and after 15 h at reflux
adducts 13a and 14a were obtained as a 2:1 mixture of the
anti and syn isomers (NMR control). The stereochemistry
has been established by NMR and by analogy with the data
from 13b and 14b.12 In the case of the Z isomers 1a and 1b,
the syn adducts 16a and 16b were the only isolated
compounds. Careful analysis of the crude reaction mixture
by 19F NMR excluded the presence of adducts 13a-b and
14a-b. Therefore, these reactions are stereospecific with
regard to the double bond geometry and this is in agreement
with the previous studies establishing that no Z to E
isomerisation of 1a was occurring after 24 h at 608C.
Further, these results confirm the key role of the electron-
withdrawing group cis to the allylic C–F bond for the
stereoselectivity since we obtain here the same syn
stereoselectivity than in the case of the fluoride 15.
Scheme 5. Reagents and conditions: (i) ArSH, THF, Na2CO3 (cat), 08C to
rt, 12a (49%), 12b (86%).
Next we studied Diels–Alder cycloadditions on alkenes 1
and 2. Previous experiments have established that for E
allylic fluoride 2b the anti adduct was the major isomer,
with a 76:24 ratio for 13b–14b (Scheme 6).12
4. Conclusion
In summary, we have reported a short and versatile route to
Z and E enals and enones with a fluorine in allylic position.
Such Z enals, as well as the methoxy analogue and the non-
fluorinated derivative have a good thermal stability which
allows them to be of further synthetic use in maintaining the
stereochemistry of the Z double bond. This has been
illustrated by 1,2 additions and Wittig reactions; the latter
results open new routes to prepare various type of
unsaturated or polyunsaturated derivatives with fluorine in
allylic position and they would be especially useful in the
case of systems containing a Z double bond. For the Diels–
Alder reactions we could confirm the key role of the
substituent cis to the allylic fluoride with regard to the syn
diastereoselectivity. Extension to the preparation of other
chiral allylic fluorides is under active study, as well as their
application to the preparation of natural product analogues.
Scheme 6. Reagents and conditions: (i) 2,3 dimethylbutadiene (42 equiv.),
reflux, 48 h, 13a (25%), 14a (14%), 13b (62%), 14b (34%).
For the gemdisubsituted olefin 15 the derivative 16c was the
only compound detected in the crude reaction mixture
(Scheme 7). High level computational studies on corre-
sponding transition states have been performed and they
have indicated that for the E series the transition state with
the F‘inside’ is slightly favored while for the gemdiactivated
olefin the TS with the F‘outside’ was strongly disfavored. The
latter result was attributed to the strong electronic repulsion
between fluorine and the cis ester group which appears in
the TS corresponding to the ‘inside’ F (Scheme 7).12
5. Experimental
5.1. General
All reactions were carried out in flame-dried glassware
under an atmosphere of nitrogen with magnetic stirring.
Thin-layer chromatography (TLC) was done on Merck (Art.
1.05554) precoated silica gel 60 F254 aluminum sheets
(layer thickness 0.2 mm). Visualisation was effected with a
UV lamp (254 nm) and/or either by staining with
p-anisaldehyde/H2SO4 solution or by staining with
KMnO4 solution. Flash column chromatography was
performed using silica gel 60 (Geduran, 40–63 mm,
Merck). Solvents were purified as follows: tetrahydrofuran
was freshly distilled from sodium benzophenone ketyl under
N2. Diethyl ether and dichloromethane were distilled from
˚
P2O5 and stored over 3 A molecular sieves. Triethylamine
was distilled from CaH2. The petroleum ether (PE) used had
a boiling range of 30–608C. NMR spectra were recorded on
a Bruker ARX 400 MHz spectrometer. All chemical shifts
Scheme 7. Reagents and conditions: (i) 2,3-dimethylbutadiene (25 equiv.),
reflux, 16a (57%), 16b (44%), for 16c, see Ref. 11.

8836
M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
1
are reported in parts per million (d). H NMR (400 MHz)
spectra were recorded at rt in CDCl3 or C6D6 solutions and
referenced to residual CHCl3 (7.27 ppm) or C6H6
(7.16 ppm). Fully decoupled 13C NMR (100 MHz) spectra
were recorded in CDCl3 or C6D6 solutions. The center peaks
of CDCl3 (77.0 ppm) and C6D6 (128.7 ppm) were used as
the internal reference. 19F NMR (376.5 MHz) spectra were
recorded in CDCl3 or C6D6 solutions using CFCl3 as
internal reference. Elemental analyses were performed by
the department of microanalyses (C.R.M.P.O.) in Rennes
(France). Mass spectra were carried out on a VARIAN MAT
311 spectrometer at the C.R.M.P.O. in Rennes (France).
5.2.2. 4-Fluoro-1-phenyl-non-2-(E)-en-1-ol (6). To a
solution of commercially available phenyllithium (2 M
solution in cyclohexane–ether, 70 to 30; 0.7 mL, 1.4 mmol)
in 10 mL dry THF and cooled to 2608C was slowly added a
solution of aldehyde 2a (139 mg, 0.88 mmol) in 0.5 mL of
dry THF. The reaction mixture was then stirred for 30 min.
at the same temperature and treated with a saturated solution
of NH4Cl. The product was extracted with ether and the
organic layer was dried over MgSO4. The solvents were
evaporated in vacuo and the residue was chromatographed
on silica gel (eluent: pentane/ether, 8/2) to afford an
inseparable racemic mixture of diastereomers 6 (169 mg,
82% yield).
5.1.1. 4-Fluoro-non-2-(Z)-enal (1a) and 4-fluoro-non-2-
(E)-enal (2a). See Ref. 11.
For the two diastereomers. Oil, 1H NMR (CDCl3, 400 MHz)
d 7.40–7.22 (m, 5H, Ph), 6.01–5.94 (m, 1H, CHvCH),
5.93–5.81 (m, 1H, CHvCH), 5.29–5.23 (m, 1H, CHOH),
5.02–4.83 (m, 1H, CHF), 2.00 and 2.01 (2d, J¼3.1 Hz, 1H,
OH), 1.81–1.53 (m, 2H, CHFCH2), 1.50–1.24 (m, 6H,
CH2), 0.85–0.93 (m, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d 142.3, 134.7 (d, J¼11.2 Hz), 129.5 and 129.3
(2d, J¼19.3 Hz), 128.6 (2C), 127.94 and 127.93, 126.3
(2C), 93.0 (d, J¼166.2 Hz), 74.3, 74.2, 35.3 (d, J¼21.7 Hz),
31.50 and 31.49 (2C), 24.5 and 24.4 (2d, J¼4.8 Hz), 22.5,
14.0; 19F NMR (CDCl3, 376.5 MHz) d 2175.27 (m) and
2175.32 (m); HRMS (EI) 70 eV: calcd for C15H21OF [Mþz]
236.1576, found 236.158 (2 ppm).
5.2. 1,2 Additions
5.2.1. 4-Fluoro-1-phenyl-non-2-en-(Z)-1-ol (5). To a
solution of commercially available phenyllithium (2 M
solution in cyclohexane–ether, 70 to 30; 0.7 mL, 1.4 mmol)
in 10 mL dry THF and cooled to 2508C was slowly added a
solution of aldehyde 1a (134 mg, 0.85 mmol) in 0.5 mL of
dry THF. The reaction mixture was then stirred for 20 min at
the same temperature and treated with a saturated solution
of NH4Cl. The product was extracted with ether and the
organic layer was dried over MgSO4. The solvents were
evaporated in vacuo and the residue was chromatographed
on silica gel (eluent: pentane/ether, 8/2) to afford a racemic
mixture of diastereomers 5 (182 mg, 91% yield). Enriched
mixture of one diastereomer allowed the identification of
the spectral data of each diastereomer.
5.3. Preparation of the substrates 1b, 2b, 7c, 8c, 3c, 4c,
7d, 8d, 3d and 4d
5.3.1. 4-Fluoro-1-phenyl-non-2-(Z)-en-1-one (1b). To a
solution of alcohol 5 (159 mg, 0.67 mmol) in 5 mL dry
CH2Cl2 was added at rt MnO2 (586 mg, 6.74 mmol). After
6 h stirring, the reaction mixture was filtered through celitew
and the solvent was evaporated in vacuo. The residue was
chromatographed on silica gel (eluent: pentane/ether, 9/1) to
afford the title compound 1b (135 mg, 86% yield). Colorless
oil, 1H NMR (CDCl3, 400 MHz) d 7.98–7.95 (m, 2H, Ph),
7.63–7.58 (m, 1H, Ph), 7.53–7.48 (m, 2H, Ph), 6.94 (ddd,
J¼11.9, 1.5 Hz, JH–F¼0.9 Hz, 1H, CHvCH), 6.46 (ddd,
JH–F¼17.7 Hz, J¼11.9, 7.3 Hz, 1H, CHvCH), 5.85 (ddtd,
JH–F¼51.7 Hz, J¼4.7, 7.3, 1.5 Hz, 1H, CHF), 1.90–1.77
(m, 2H, CHFCH2), 1.62–1.51 (m, 2H, CHFCH2CH2),
1st Diastereomer. Colorless oil, 1H NMR (CDCl3,
400 MHz) d 7.46–7.36 (m, 4H, Ph), 7.35–7.29 (m, 1H,
Ph), 5.88 (dddd, J¼11.2, 8.8 Hz, JH–F¼2.9 Hz, J¼1.1 Hz,
1H, CHvCH), 5.66 (dddd, JH–F¼12.1 Hz, J¼11.1, 8.0,
1.0 Hz, 1H, CHvCH), 5.57 (ddd, J¼9.0, 3.2, 1.0 Hz, 1H,
CHOH), 5.39 (dtdd, JH–F¼49.5 Hz, J¼8.0, 5.1, 1.1 Hz, 1H,
CHF), 2.16 (d, J¼3.2 Hz, 1H, OH), 1.92–1.59 (m, 2H,
CHFCH2), 1.57–1.26 (m, 6H, CH2), 0.92 (t, J¼6.9 Hz, 3H,
CH3); 13C NMR (CDCl3, 100 MHz) d 142.6 (d, J¼1.8 Hz),
135.4 (d, J¼8.8 Hz), 129.5 (d, J¼21.1 Hz), 128.7 (2C),
127.9, 126.1 (2C), 89.1 (d, J¼163.2 Hz), 70.1, 35.5 (d,
J¼22.5 Hz), 31.4, 24.3 (d, J¼4.2 Hz), 22.5, 13.9; 19F NMR
(CDCl3, 376.5 MHz) d 2171.38 (dddd, J¼49.0, 28.0, 15.3,
14.0 Hz).
1.44–1.32 (m, 4H, CH2), 0.93 (t, J¼6.9 Hz, 3H, CH3); 13
C
NMR (CDCl3, 100 MHz) d 190.7 (d, J¼1.6 Hz), 147.2 (d,
J¼27.3 Hz), 137.5 (d, J¼1.0 Hz), 133.2, 128.7 (2C), 128.4
(2C), 123.8 (d, J¼10.2 Hz), 91.3 (d, J¼160.2 Hz), 34.6 (d,
J¼22.1 Hz), 31.5, 24.6 (d, J¼2.8 Hz), 22.6, 14.0; 19F NMR
(CDCl3, 376.5 MHz) d 2175.96 (dddd, J¼51.4, 27.6, 22.9,
17.7 Hz); HRMS (EI) 70 eV: calcd for C15H19OF [Mþz]
234.1420, found 234.142 (0 ppm).
2nd Diastereomer. Colorless oil, 1H NMR (CDCl3,
400 MHz) d 7.46–7.36 (m, 4H, Ph), 7.35–7.29 (m, 1H,
Ph), 5.82 (dddd, J¼11.1, 9.0 Hz, JH–F¼2.7 Hz, J¼1.1 Hz,
1H, CHvCH), 5.66 (dddd, JH–F¼12.1 Hz, J¼11.1, 8.0,
1.0 Hz, 1H, CHvCH), 5.61 (dd, J¼9.0, 3.7 Hz, 1H,
CHOH), 5.41 (dtdd, JH–F¼49.5 Hz, J¼8.0, 5.1, 1.1 Hz,
1H, CHF), 2.03 (d, J¼3.7 Hz, 1H, OH), 1.92–1.59 (m, 2H,
CHFCH2), 1.57–1.26 (m, 6H, CH2), 0.94 (t, J¼6.9 Hz, 3H,
CH3); 13C NMR (CDCl3, 100 MHz) d 142.6 (d, J¼1.8 Hz),
135.7 (d, J¼8.8 Hz), 129.6 (d, J¼19.3 Hz), 128.6 (2C),
127.8, 125.9 (2C), 89.2 (d, J¼163.2 Hz), 70.1, 35.7 (d,
J¼22.5 Hz), 31.5, 24.4 (d, J¼4.4 Hz), 22.5, 14.0; 19F NMR
(CDCl3, 376.5 MHz) d 2172.07 (dddd, J¼49.0, 28.0, 15.3,
14.0 Hz); HRMS calcd (EI) 70 eV: for C15H21OF [Mþz]
236.1576, found 236.158 (2 ppm).
5.3.2. 4-Fluoro-1-phenyl-non-2-(E)-en-1-one (2b). To a
solution of alcohol 6 (150 mg, 0.64 mmol) in 5 mL dry
CH2Cl2 was added at rt MnO2 (552 mg, 6.35 mmol). After
4 h stirring, the reaction mixture was filtered through celitew
and the solvent was evaporated in vacuo. The residue was
chromatographed on silica gel (eluent: pentane/ether, 9/1) to
afford the title compound 1b (122 mg, 82% yield). Colorless
oil, 1H NMR (CDCl3, 400 MHz) d 8.01–7.97 (m, 2H, Ph),
7.62–7.57 (m, 1H, Ph), 7.52–7.47 (m, 2H, Ph), 7.18 (ddd,
J¼15.5, 1.7 Hz, JH–F¼0.9 Hz, 1H, CHvCH), 7.01 (ddd,

M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
8837
JH–F¼21.6 Hz, J¼15.5, 3.7 Hz, 1H, CHvCH), 5.23 (ddtd,
JH–F¼48.4 Hz, J¼3.7, 6.2, 1.7 Hz, 1H, CHF), 1.78 (ddt,
JH–F¼25.0 Hz, J¼6.2, 7.9 Hz, 2H, CHFCH2), 1.57–1.40
(m, 2H, CHFCH2CH2), 1.39–1.30 (m, 4H, CH2), 0.91 (t,
J¼6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d 189.8,
145.1 (d, J¼17.7 Hz), 137.4, 133.1, 128.6 (2C), 128.6 (2C),
123.9 (d, J¼9.6 Hz), 91.9 (d, J¼175.1 Hz), 34.8 (d,
J¼20.9 Hz), 31.5, 24.3 (d, J¼4.0 Hz), 22.4, 14.0; 19F
NMR (CDCl3, 376.5 MHz) d 2184.79 (ddt, J¼47.0, 22.0,
24.0 Hz); HRMS (EI) 70 eV: calcd for C15H19OF [Mþz]
234.1420, found 234.142 (0 ppm).
70 eV: calcd for C13H24O2 [M2MeOH]þz 212.1776,
found 212.177, calcd for C12H23O2 [M2zOEt]þ 199.1698,
found 199.170.
5.3.5. 4-Methoxy-non-2-(Z)-enal (3c) and 4-methoxy-
non-2-(E)-enal (4c). A stirred solution of acetal 8c
(0.23 g, 0.9 mmol) in CH2Cl2 (10 mL) was reacted with
formic acid (5.4 mL, 140.7 mmol). After 5 min at rt, the
reaction mixture was neutralized with solid Na2CO3 (7.5 g)
and diluted with saturated Na2CO3 solution. The layers were
separated and the aqueous phase was extracted with Et2O
(3£10 mL). The combined organic layers were dried over
MgSO4 and concentrated. NMR analysis showed a 6/4 Z/E
ratio. Purification of the crude product by flash chromato-
graphy on silica gel (petroleum ether/Et2O, 95/5) gave the
two title isomers: Z 3c (74 mg, 46% yield) and E 4c
(15.8 mg, 10% yield).
5.3.3. 1,1-Diethoxy-4-methoxy-non-2-yne (7c). To a
suspension of sodium hydride (60% dispersion in mineral
oil; 0.54 g, 13.5 mmol) in a mixture of 20 mL of dry ether
and 1.5 mL of distilled DMSO cooled to 08C was added a
solution of 1,1-Diethoxy-4-hydroxy-non-2-yne (2.05 g,
9.0 mmol) in 4 mL of dry ether. The reaction mixture was
then stirred at reflux during 18 h. After cooling at rt, 20 mL
of ether and methyl iodide (2.8 mL, 44.9 mmol) were added.
The resulting mixture was again stirred at reflux during
10 h. The mixture was then cooled to rt before adding
10 mL of H2O. The product was extracted with ether and the
organic layer was dried over MgSO4. The solvents were
evaporated in vacuo and the residue was chromatographed
on silica gel (eluent: petroleum ether/ether, 9/1) to give the
Isomer Z (3c). Pale yellow oil, 1H NMR (CDCl3, 400 MHz)
d 10.10 (d, J¼7.7 Hz, 1H, CHO), 6.42 (dd, J¼11.5, 8.8 Hz,
1H, CHvCH), 6.10 (ddd, J¼11.5, 7.7, 1.0 Hz, 1H,
CHvCH), 4.48 (dtd, J¼8.8, 6.8, 1.0 Hz, 1H,
CHOMe),3.33 (s, 3H, OCH3), 1.76–1.65 (m, 2H,
CHOMeCH2), 1.59–1.47 (m, 2H, CHOMeCH2CH2),
1.46–1.22 (m, 4H, CH2), 0.88 (t, J¼6.9 Hz, 3H, CH3);
13C NMR (CDCl3, 100 MHz) d 191.1, 152.3, 131.3, 76.7,
56.9, 35.2, 31.6, 24.7, 22.5, 13.9.
1
title compound 7c (1.72 g, 79% yield). Colorless oil, H
NMR (CDCl3, 400 MHz) d 5.29 (d, J¼1.0 Hz, 1H,
(EtO)2CH), 3.97 (td, J¼6.5, 0.8 Hz, 1H, CHOMe), 3.72
(dq, J¼10.7, 7.1 Hz, 2H, CH3CH2O), 3.57 (dq, J¼9.3,
7.1 Hz, 2H, CH3CH2O), 3.37 (s, 3H, OCH3), 1.74–1.63 (m,
2H, CHOMeCH2), 1.48–1.37 (m, 2H, CHOMeCH2CH2),
1.31–1.24 (m, 4H, CH2); 1.21 (t, J¼7.1 Hz, 6H,
CH3CH2O), 0.86 (t, J¼6.8 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 91.2, 84.2, 81.1, 71.1, 60.7, 60.7,
56.5, 35.3, 31.4, 24.8, 22.4, 15.0 (2C), 13.9; MS (EI) 70 eV:
m/z (% rel. int.) 241 (0.7, [M2zH]þ), 197 (100.0,
[M2zOEt]þ); HRMS (EI) 70 eV: calcd for C14H25O3
[M2zH]þ 241.1804, found, 241.181, calcd for C12H21O2
[M2zOEt]þ 197.1542, found 197.154.
Isomer E (4c). Pale yellow oil, 1H NMR (CDCl3, 400 MHz)
d 9.60 (d, J¼7.8 Hz, 1H, CHO), 6.69 (dd, J¼15.8, 6.1 Hz,
1H, CHvCH), 6.25 (ddd, J¼15.8, 7.8, 1.0 Hz, 1H,
CHvCH), 3.86 (qd, J¼6.1, 1.1 Hz, 1H, CHOMe), 3.33 (s,
3H, OCH3), 1.70–1.52 (m, 2H, CHOMeCH2), 1.47–1.24
(m, 6H, CH2), 0.89 (t, J¼6.9 Hz, 3H, CH3).
5.3.6. 1,1-Diethoxy-non-2-yne (7d). First step. Synthesis of
non-2-ynal. A solution of octyn (4.35 mL, 29.9 mmol) in
anhydrous THF (20 mL) was reacted with n-butyllithium
(19.9 mL of a 1.6 M solution in hexanes, 31.8 mmol) under
nitrogen at 2608C. The solution was stirred for an
additional 20 min and anhydrous HMPA (25.4 mL,
144.6 mmol) was added. The temperature was raised to
2358C in 35 min. and then lowered again to 2658C. Freshly
distilled DMF (4.5 mL, 57.8 mmol) was added. The reaction
mixture was slowly allowed to warm to 2168C in 130 min.
and quenched at this temperature by adding aqueous NH4Cl.
The crude product was extracted with Et2O (3£10 mL),
dried (MgSO4) and concentrated under reduced pressure.
The product was purified on silica gel (pentane/Et2O, 95/5)
5.3.4. 1,1-Diethoxy-4-methoxy-non-2-(Z)-ene (8c). To a
solution of acetal 7c (0.11 g, 0.43 mmol) and pyridine
(35 mL, 0.43 mmol) in 3 mL of pentane at rt was added
Lindlar catalyst (20.6 mg, 20% weight). The black suspen-
sion was stirred under hydrogen atmosphere. When analysis
of an aliquot by NMR showed no starting material (24 h),
the reaction mixture was filtered through celitew and
concentrated under reduced pressure to obtain 90.6 mg of
the title compound 8c. NMR analysis showed a clean crude
product compound, which was used directly for the next
steps. (8c, 87% yield). Colorless oil, 1H NMR (CDCl3,
400 MHz) d 5.67 (ddd, J¼11.4, 6.6, 1.0 Hz, 1H, CHvCH),
5.45 (ddd, J¼11.4, 9.3, 1.0 Hz, 1H, CHvCH), 5.21 (dd,
J¼6.6, 1.0 Hz, 1H, (EtO)2CH), 3.99 (dt, J¼9.3, 5.9 Hz, 1H,
CHOMe), 3.70–3.56 (m, 2H, CH3CH2O), 3.57–3.45 (m,
2H, CH3CH2O), 3.26 (s, 3H, OCH3), 1.46–1.33 (m, 2H,
CHOMeCH2), 1.33–1.23 (m, 6H, CH2), 1.21 (t, J¼7.1 Hz,
3H, CH3CH2O), 1.19 (t, J¼7.1 Hz, 3H, CH3CH2O), 0.87 (t,
J¼6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d 135.3,
130.2, 97.4, 76.9, 60.6, 60.1, 56.2, 35.4, 31.8, 24.8, 22.6,
15.20, 15.17, 14.0; MS (EI) 70 eV: m/z (% rel. int.) 212 (6.8,
[M2MeOH]þz), 199 (53.2, [M2zOEt]þ); HRMS (EI)
1
to give the non-2-ynal (3.37 g, 84%). Pale yellow oil, H
NMR (CDCl3, 400 MHz) d 9.17 (s, 1H, CHO), 2.40 (td,
J¼7.1, 0.5 Hz, 2H, CuCCH2), 1.59 (q, J¼7.1 Hz, 2H,
CH2), 1.45–1.36 (m, 2H, CH2), 1.35–1.25 (m, 4H, CH2),
0.86 (t, J¼7.0 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz)
d 177.2, 99.4, 81.6, 31.1, 28.4, 27.4, 22.4, 19.1, 13.9; MS
(EI) 70 eV: m/z (% rel. int.) 123 (11.7, [M2zCH3]þ), 110
(12.2, [M2CO]þz), 109 (27.7, [M2zCHO]þ), 95 (24.1,
[M2C3H7]þ), 43 (100.0, [C3H7]þ); HRMS (EI) 70 eV:
calcd for C8H11O [M2zCH3]þ 123.0810, found 123.082.
Second step. A solution of non-2-ynal (49.6 mg,
0.36 mmol), anhydrous triethyl orthoformate (73 mL,
0.43 mmol), p-toluenesulfonic acid monohydrate (41 mg,

8838
M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
0.25 mmol) in 5 mL ethyl alcohol was stirred at rt for 29 h.
The reaction mixture was neutralized with solid Na2CO3
and diluted with water and Et2O. The phases were separated
and the extraction was completed with Et2O (3£20 mL).
The combined organic phases were dried over MgSO4 and
evaporated to give a yellow oil which was subjected to flash
chromatography (pentane/Et2O, 95/5) to afford the com-
2.61 (qd, J¼8.2, 1.6 Hz, 2H, CHvCHCH2), 1.52 (q,
J¼7.3 Hz, 2H, CH2), 1.41–1.25 (m, 6H, CH2), 0.90 (t,
J¼6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d 191.0,
153.6, 130.2, 31.5, 29.1, 28.7, 28.0, 22.5, 14.0.
Isomer E (4d). Oil, 1H NMR (CDCl3, 400 MHz) d 9.51 (d,
J¼7.9 Hz, 1H, CHO), 6.86 (dt, J¼15.6, 6.8 Hz, 1H,
CHvCH), 6.13 (ddt, J¼15.6, 7.9, 1.5 Hz, 1H, CHvCH),
2.34 (qd, J¼6.8, 1.5 Hz, 2H, CHvCHCH2), 1.52 (q,
J¼7.2 Hz, 2H, CH2), 1.41–1.23 (m, 6H, CH2), 0.90 (t,
J¼6.9 Hz, 3H, CH3).
1
pound 7d (53.2 mg, 70% yield). Pale yellow oil, H NMR
(CDCl3, 400 MHz) d 5.24 (t, J¼1.6 Hz, 1H, (EtO)2CH),
3.72 (dq, J¼9.5, 7.1 Hz, 2H, CH3CH2O), 3.56 (dq, J¼9.5,
7.1 Hz, 2H, CH3CH2O), 2.22 (td, J¼7.1, 1.6 Hz, 2H,
CuCCH2), 1.51 (q, J¼7.1 Hz, 2H, CH2), 1.41–1.32 (m,
2H, CH2), 1.31–1.24 (m, 4H, CH2), 1.22 (t, J¼7.1 Hz, 6H,
CH3CH2O), 0.87 (t, J¼6.9 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 91.4, 86.5, 75.6, 60.5 (2C), 31.2,
28.5, 28.2, 22.5, 18.6, 15.0 (2C), 14.0; MS (EI) 70 eV:
m/z (% rel. int.) 211 (0.6, [M2zH]þ), 183 (0.9,
[M2zC2H5]þ), 167 (100.0, [M2zOEt]þ); HRMS (EI)
70 eV: calcd for C13H23O2 [M2zH]þ 211.1698, found
211.170, calcd for C11H19O [M2zOEt]þ 167.1436, found
167.144.
5.4. Wittig reactions
5.4.1. 6-Fluoro-undeca-2-(E),4-(Z)-dienoic acid methyl
ester (9). To a solution of the aldehyde 1a (67 mg,
0.42 mmol) in 2 mL of dry toluene was added at rt the
(triphenyl-l5-phosphanylidene)-acetic acid methyl ester
(170 mg, 0.51 mmol). After 14 h of stirring at 758C, the
toluene was removed in vacuo to give a yellow oil.
Purification by flash chromatography (pentane/Et2O, 95/5)
afforded the title compound 9 (76 mg, 83% yield). Colorless
oil, 1H NMR (CDCl3, 400 MHz) d 7.55 (ddt, J¼15.2,
11.8 Hz, JH–F¼JH–H¼1.0 Hz, 1H, MeOCOCHvCH), 6.24
5.3.7. 1,1-Diethoxy-non-2-(Z)-ene (8d). To a solution of
acetal 7d (40.8 mg, 0.19 mmol) and pyridine (16 mL,
0.19 mmol) in 3 mL of pentane at rt was added Lindlar
catalyst (8.2 mg, 20% weight). The black suspension was
stirred under hydrogen atmosphere. When analysis of an
aliquot by NMR showed no starting material (15 h), the
reaction mixture was filtered through celitew and concen-
trated at reduced pressure to obtain 41.1 mg of the title
compound 8d. NMR analysis showed a clean crude product
which was used directly for the next steps. (8d, 99% yield).
Colorless oil, 1H NMR (CDCl3, 400 MHz) d 5.62 (dtd,
J¼11.2, 7.5, 1.1 Hz, 1H, CHvCH), 5.46 (ddt, J¼11.2, 6.8,
1.6 Hz, 1H, CHvCH), 5.20 (dd, J¼6.8, 1.1 Hz, 1H,
(EtO)2CH), 3.64 (dq, J¼9.4, 7.1 Hz, 2H, CH3CH2O), 3.50
(dq, J¼9.4, 7.1 Hz, 2H, CH3CH2O), 2.13 (qd, J¼7.5,
1.5 Hz, 2H, CHvCHCH2), 1.41–1.23 (m, 8H, CH2), 1.21
(t, J¼7.1 Hz, 6H, CH3CH2O), 0.87 (t, J¼6.9 Hz, 3H, CH3);
13C NMR (CDCl3, 100 MHz) d 134.9, 127.1, 97.6, 60.4
(2C), 31.7, 29.3, 28.9, 28.0, 22.6, 15.3 (2C), 14.0; MS (EI)
70 eV: m/z (% rel. int.) 214 (0.4, Mþz), 169 (22.6,
[M2zOEt]þ); HRMS (EI) 70 eV: calcd for C13H26O2 Mþz
214.1933, found 214.192, calcd for C11H21O [M2zOEt]þ
169.1592, found 169.160.
(tdt,
J¼11.8 Hz,
JH–F¼2.1 Hz,
J¼1.0 Hz,
1H,
CHvCHCHF), 5.96 (dd, J¼15.2 Hz, JH–F¼0.8 Hz, 1H,
MeOCOCHvCH), 5.85 (dddt, JH–F¼13.4 Hz, J¼11.8, 8.2,
0.8 Hz, 1H, CHvCHCHF), 5.42 (dddd, JH–F¼48.9 Hz,
J¼8.2, 5.3, 1.1 Hz, 1H, CHF), 3.70 (s, 3H, OCH3), 1.88–
1.74 (m, 1H, CHFCHH) and 1.69–1.53 (m, 1H, CHFCHH),
1.50–1.25 (m, 6H, CH2), 0.90 (t, J¼6.9 Hz, 3H, CH3); 13
C
NMR (CDCl3, 100 MHz) d 167.0, 138.3, 137.0 (d,
J¼20.9 Hz), 128.8 (d, J¼9.6 Hz), 123.8 (d, J¼2.4 Hz),
89.0 (d, J¼163.8 Hz), 51.7, 35.6 (d, J¼22.5 Hz), 31.5, 24.2
(d, J¼4.8 Hz), 22.5, 14.0; 19F NMR (CDCl3, 376.5 MHz) d
2174.50 (dddd, J¼48.9, 26.4, 15.1, 13.4 Hz); HRMS (EI)
70 eV: calcd for C12H19O2F [Mþz] 214.1369, found 214.138
(2 ppm). Anal. calcd for C12H19FO2: C, 67.26; H, 8.94,
found C, 67.17; H, 8.94.
5.4.2. 6-Fluoro-undeca-2-(E),4-(E)-dienoic acid methyl
ester (10) and 6-fluoro-undeca-2-(Z),4-(E)-dienoic acid
methyl ester (11). To a solution of the aldehyde 2a (45 mg,
0.29 mmol) in 2 mL of dry toluene was added at rt the
(Triphenyl-l5-phosphanylidene)-acetic acid methyl ester
(114 mg, 0.34 mmol). After 15 h of stirring at 708C, the
toluene was removed in vacuo to give a pale yellow oil.
NMR analysis of the crude product showed a 7/3 ratio of
10/11. Purification by flash chromatography (pentane/Et2O,
95/5) afforded the two title compounds: 10 (28 mg, 45%
yield) and 11 (9 mg, 15% yield).
5.3.8. Non-2-(Z)-enal (3d) and non-2-(E)-enal (4d). A
stirred solution of acetal 8d (16.3 mg, 0.08 mmol) in
CH2Cl2 (2 mL) was treated with formic acid (100 mL,
34.2 mmol). After 10 min. at rt, the reaction mixture was
neutralized with solid Na2CO3 (0.2 g) and diluted with
saturated Na2CO3 solution. The layers were separated and
the aqueous phase was extracted with Et2O (3£5 mL). The
combined organic layers were dried over MgSO4 and
concentrated. NMR analysis showed a 6/4 Z/E ratio.
Purification of the crude product by flash chromatography
on silica gel (pentane/Et2O, 98/2) gave one pure fraction of
the title isomers: Z 3d (2.5 mg, 23% yield) and a mixture of
the two isomers Z 3d and E 4c (4.7 mg).
Isomer (2E,4E) (10). Colorless oil, 1H NMR (CDCl3,
400 MHz) d 7.28 (dd, J¼15.5, 11.2 Hz, 1H, MeO-
COCHvCH), 6.40 (ddqd, J¼15.4, 11.2 Hz, JH – H
¼
JH–F¼0.6 Hz, J¼1.0 Hz, 1H, CHvCHCHF), 6.10 (tdd,
JH–F¼JH–H¼15.4 Hz, J¼5.6, 0.6 Hz, 1H, CHvCHCHF),
5.95 (dd, J¼15.5, 0.6 Hz, 1H, MeOCOCHvCH), 5.01 (dqd,
JH–F¼48.6 Hz, J¼5.6, 1.1 Hz, 1H, CHF), 3.76 (s, 3H,
OCH3), 1.82–1.57 (m, 2H, CHFCH2), 1.50–1.25 (m, 6H,
CH2), 0.90 (t, J¼6.9 Hz, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d 167.2, 143.4 (d, J¼1.2 Hz), 139.8 (d,
J¼18.5 Hz), 128.6 (d, J¼12.0 Hz), 122.1 (d, J¼2.0 Hz),
Isomer Z (3d). Oil, 1H NMR (CDCl3, 400 MHz) d 10.09 (d,
J¼8.2 Hz, 1H, CHO), 6.65 (dt, J¼11.2, 8.2 Hz, 1H,
CHvCH), 5.97 (ddt, J¼11.2, 8.2, 1.6 Hz, 1H, CHvCH),

M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
8839
92.3 (d, J¼169.5 Hz), 51.7, 35.1 (d, J¼21.7 Hz), 31.5, 24.3
(d, J¼4.4 Hz), 22.5, 14.0; 19F NMR (CDCl3, 376.5 MHz) d
2179.32 (ddt, J¼48.6, 26.3, 15.4 Hz); HRMS (EI) 70 eV:
calcd for C12H19O2F [Mþz] 214.1369, found 214.138
(2 ppm). Anal. calcd for C12H19FO2: C, 67.26; H, 8.94,
found C, 67.48; H, 9.05.
HRMS (EI) 70 eV: calcd for C22H27SO [M2zF]þ 339.1782,
found 339.1804.
5.6. Diels–Alder reactions
5.6.1. 6a-(1-Fluoro-hexyl)-3,4-dimethyl-cyclohex-3-ene-
b-carbaldehyde (13a) and 6b-(1-fluoro-hexyl)-3,4-
Isomer (2Z,4E) (11). Colorless oil, 1H NMR (CDCl3,
400 MHz) d 7.24 (t, J¼11.2 Hz, 1H, MeOCOCHvCH),
6.32 (dddt, J¼15.3, 11.2 Hz, JH–F¼1.0 Hz, J¼0.5 Hz, 1H,
CHvCHCHF), 6.08 (td, JH–F¼JH–H¼15.3 Hz, J¼5.6 Hz,
1H, CHvCHCHF), 5.90 (dd, J¼10.2, 0.5 Hz, 1H,
MeOCOCHvCH), 4.99 (dqd, JH – F¼48.4 Hz, J¼5.6,
0.6 Hz, 1H, CHF), 3.75 (s, 3H, OCH3), 1.80–1.54 (m, 2H,
CHFCH2), 1.51–1.25 (m, 6H, CH2), 0.88 (t, J¼7.0 Hz, 3H,
CH3); 19F NMR (CDCl3, 376.5 MHz) d 2174.47 (dddd,
J¼48.6, 26.2, 15.0, 13.2 Hz).
dimethyl-cyclohex-3-ene-a-carbaldehyde
(14a).
A
solution of the aldehyde 2a (49 mg, 0.31 mmol) in 2,3-
dimethyl-buta-1,3-diene (1.5 mL, 12.99 mmol) was heated
to reflux for 48 h. The excess of 2,3-dimethyl-buta-1,3-
diene was removed in vacuo to give a viscous pale yellow
oil. The crude product was purified on a flash chromato-
graphy (toluene/Et2O, 99/1) to give a mixture of the two title
compounds 13a/14a (45 mg, ratio: 6/4; as determined by 19F
NMR). The two diastereomers were separated by silica gel
column chromatography (petroleum ether/ether, 99/1)
affording 18 mg of pure 13a (25% yield) and 11 mg of
pure 14a (14% yield).
5.5. Michael addition reactions
5.5.1. 4-Fluoro-3-p-tolylsulfanyl-nonanal (12a). To a
solution of enal 1a (or 2a) (50 mg, 0.316 mmol) in THF
(5 mL) was added, under N2 at 08C, thiocresol (100 mg,
0.79 mmol, 2.5 equiv.) and Na2CO3 (10 mg). The reaction
mixture was allowed to warm to rt and stirred for 10 min.
After addition of saturated Na2CO3 solution, extraction with
ether and washing with water, the organic phase was dried
(MgSO4). After removal of the solvents under vacuum,
NMR of the crude reaction mixture indicated a 1:1 mixture
of the two diastereoisomeric adducts 12a. Chromatography
on SiO2 using as eluent a 1:9 mixture of ether and petroleum
ether afforded 43.7 mg (49% yield) of the mixture of
adducts 12a, as a pale yellow oil. These unstable products
have been characterized only by 1H and 13C NMR. 1H NMR
(CDCl3, 400 MHz) d 9.76–9.70 (m, 1H), 7.40–7.10 (m,
4H), 4.62 (ddt, JH–F¼47.2, 8.6, 3.7 Hz, 1H, dia 1), 4.49
(dddd, JH–F¼48.5, 8.7, 7.3, 3.2 Hz, 1H, dia 2), 3.82–3.68
(m, 1H), 3.62–3.50 (m, 1H), 2.93–2.82 (m, 2H), 2.77–2.66
(m, 2H), 2.35 (s, 3H, dia 1), 2.34 (s, 3H, dia 2), 1.90–1.20
(m, 8H), 0.92–0.86 (m, 3H); 19F NMR (CDCl3, 376.5 MHz)
d 2181.65 (dddd, J¼48.9, 33.4, 18.2, 14.2 Hz, dia 1);
2182.89 (m, dia 2).
More polar, major diastereomer 13a. White solid, mp 388C,
1H NMR (CDCl3, 400 MHz) d 9.57 (dd, JH–F¼5.3 Hz,
J¼3.2 Hz, 1H, CHO), 4.35 (dtd, JH–F¼48.7 Hz, J¼8.9,
2.4 Hz, 1H, CHF), 2.52 (dtd, J¼6.0, 8.1, 3.2 Hz, 1H,
CHCHO), 2.29 (ddt, J¼15.1, 8.9 Hz, JH–F¼JH–H¼8.0 Hz,
1H, CHCHF), AB system: nA¼2.21 (dd, J¼15.2, 7.0 Hz,
1H, CHHCHCHO) and nB¼2.01 (dd, J¼15.2, 6.6 Hz, 1H,
CHHCHCHO), 2.01–1.94 (broad peak, 1H, CHHCHCHF),
1.70–1.60 (broad peak, 1H, CHHCHCHF), 1.65 (s, 3H,
CH3), 1.60 (s, 3H, CH3), 1.42–1.22 (m, 8H, CH2), 0.90
(t, J¼6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d
203.9 (d, J¼2.8 Hz), 123.6, 123.4, 96.1 (d, J¼170.3 Hz),
49.4 (d, J¼2.8 Hz), 38.7 (d, J¼18.5 Hz), 32.7 (d,
J¼21.7 Hz), 31.6, 31.4 (d, J¼8.0 Hz), 29.4, 24.4 (d,
J¼3.2 Hz), 22.5, 19.0, 18.8, 14.0; 19F NMR (CDCl3,
376.5 MHz) d 2179.42 (dddt, J¼48.4, 34.1, 20.6, 6.2 Hz);
HRMS (EI) 70 eV: calcd for C15H25OF [Mþz] 240.1889,
found 240.187 (6 ppm).
Less polar, minor diastereomer 14a. White solid, mp 428C,
1H NMR (C6D6, 400 MHz) d 9.43 (dd, J¼2.4 Hz,
JH – F¼1.7 Hz, 1H, CHO), 4.50 (ddt, JH – F¼48.6 Hz,
J¼9.3, 3.5 Hz, 1H, CHF), 2.34 (dtd, J¼5.8, 9.0, 2.5 Hz,
1H, CHCHO), 1st AB system: nA¼1.96 (broad d,
J¼15.5 Hz, 1H, CHHCHCHF), 1.90 (dtdd, JH–F¼15.0 Hz,
J¼9.0, 3.5, 1.4 Hz, 1H, CHCHF), 2nd AB system: nA¼1.85
(broad dd, J¼16.9, 8.3 Hz, 1H, CHHCHCHO), 1st AB
system: nB¼1.74 (broad d, J¼15.5 Hz, 1H, CHHCHCHF),
2nd AB system: nB¼1.66 (broad dd, J¼16.9, 5.8 Hz, 1H,
CHHCHCHO), 1.61–1.49 (m, 2H, CHFCH2), 1.45 (s, 6H,
CH3), 1.29–1.10 (m, 6H, CH2), 0.87 (t, J¼6.9 Hz, 3H,
CH3); 13C NMR (CDCl3, 100 MHz) d 204.2, 124.7, 122.9,
94.3 (d, J¼170.7 Hz), 48.0 (d, J¼3.2 Hz), 38.2 (d,
J¼20.3 Hz), 31.8 (d, J¼21.1 Hz), 31.6, 30.4, 29.6 (d,
J¼5.2 Hz), 25.2 (d, J¼3.8 Hz), 22.5, 19.0, 18.7, 14.0; 19F
NMR (CDCl3, 376.5 MHz) d 2189.97 (dddd, J¼49.6, 36.3,
23.2, 15.3 Hz); HRMS (EI) 70 eV: calcd for C15H25OF
[Mþz] 240.1889, found 240.189 (1 ppm).
5.5.2. 4-Fluoro-1-phenyl-3-p-tolylsulfanyl-nonan-1-one
(12b). Starting from 1b (or 2b), and using a procedure
similar to the preceding one, was prepared the 1:1
diastereoisomeric mixture of adducts 12b (86% yield), as
1
a pale yellow oil. H NMR (CDCl3, 400 MHz) d 8.0–7.0
(m, 9H), 4.70 (dddd, JH–F¼47.8, 8.5, 4.4, 2.8 Hz, 1H, dia 2)
4.59 (dddd, JH–F¼48.4, 9.3, 6.4, 3.3 Hz, 1H, dia 1) 4.02–
3.82 (m, 1H), 3.52–3.25 (m, 2H), 2.33 (s, 3H, dia1), 2.32 (s,
3H, dia2), 2.0–1.1 (m, 8H); 0.90 (t, J¼6.7 Hz, 3H, dia2),
0.87 (t, J¼6.7 Hz, 3H, dia1); 13C NMR (CDCl3, 100 MHz)
d 197.8 and 197.5, 138.0 and 137.6, 136.8 and 136.7, 133.4,
133.3, 133.2, 132.7, 95.2 (d, J¼176.5 Hz, dia 1), 94.8
(d, J¼174.1 Hz, dia2), 48.3 (d, J¼20.3 Hz, dia2), 47.6
(d, J¼20.1 Hz, dia 1), 40.2 (d, J¼1.8 Hz, dia 2), 39.1 (d,
J¼4.2 Hz, dia 1), 32.7 (d, J¼23.8 Hz, dia 1), 32.0 (d,
J¼20.4 Hz, dia 2), 31.5, 31.4, 25.1 (d, J¼4.2 Hz, dia 2),
24.7 (d, J¼3.2 Hz, dia 1), 22.5 (d, J¼3.4 Hz, dia 1), 21.1 (d,
J¼3.4 Hz, dia 2), 13.98 and 13.96; 19F NMR (CDCl3,
376.5 MHz) d 2182.26 (dddd, J¼49.4, 33.9, 17.8, 16.0 Hz,
dia 1); 2186.14 (dddd, J¼47.8, 32.7, 25.5, 14.8 Hz, dia 2).
5.6.2. [6a-(1-Fluoro-hexyl)-3,4-dimethyl-cyclohex-3-
enyl]-b-phenyl-methanone (13b) and [6b-(1-fluoro-
hexyl)-3,4-dimethyl-cyclohex-3-enyl]-a-phenyl-metha-
none (14b). To a solution of the ketone 2b (539 mg,

8840
M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
0.23 mmol) in 2,3-dimethyl-buta-1,3-diene (1.5 mL,
12.99 mmol) was heated to reflux for 15 h. Then the excess
of 2,3-dimethyl-buta-1,3-diene was removed in vacuo to
give a viscous pale yellow oil. NMR analysis of the crude
product showed a 7/3 ratio of 13b/14b. The crude product
was purified on a flash chromatography (toluene/Et2O, 99/1)
to give the two title compounds: 13b (44 mg, 62% yield)
and 14b (24 mg, 34% yield).
20.0 Hz); HRMS (EI) 70 eV: calcd for C15H25OF [Mþz]
240.1889, found 240.188 (1 ppm).
5.6.4. [6a-(1-Fluoro-hexyl)-3,4-dimethyl-cyclohex-3-
enyl]-a-phenyl-methanone (16b). A solution of the ketone
1b (99 mg, 0.42 mmol) in 2,3-dimethyl-buta-1,3-diene
(2.5 mL, 21.65 mmol) was heated to reflux for 36 h. The
excess of 2,3-dimethyl-buta-1,3-diene was removed in
vacuo to give a viscous pale yellow oil. The crude product
was purified on a flash chromatography (toluene/Et2O, 99/1)
to give the title compound 16b (59 mg, 44% yield). White
solid, mp 438C, 1H NMR (C6D6, 400 MHz) d 7.80–7.76 (m,
2H, Ph), 7.14–7.03 (m, 3H, Ph), 4.81 (dtd, JH–F¼48.9 Hz,
J¼7.0, 3.3 Hz, 1H, CHF), 3.41 (dt, J¼3.4, 6.4 Hz, 1H,
CHCOPh), 1st AB system: nA¼2.77 (dd, J¼17.9, 5.9 Hz,
1H, CHHCHCHF) and nB¼2.30 (broad d, J¼18.0 Hz, 1H,
CHHCHCHF), 2nd AB system: nA¼2.37 (broad d,
J¼18.6 Hz, 1H, CHHCHCOPh) and nB¼2.13 (dd,
More polar, major diastereomer 13b. White solid, mp 368C,
1H NMR (CDCl3, 400 MHz) d 7.99–7.95 (m, 2H, Ph),
7.59–7.44 (m, 3H, Ph), 4.38 (dtd, JH–F¼48.3 Hz, J¼8.0,
3.3 Hz, 1H, CHF), 3.64 (dt, J¼5.7, 8.9 Hz, 1H, CHCOPh),
2.50 (dddd, J¼16.7, 8.8 Hz, JH–F¼7.8 Hz, J¼6.0 Hz, 1H,
CHCHF), 1st AB system: nA¼2.28 (dd, J¼17.0, 8.4 Hz, 1H,
CHHCHCOPh), 2nd AB system: nA¼2.15 (dd, J¼17.0,
5.6 Hz, 1H, CHHCHCHF) and nB¼2.07 (dd, J¼17.0,
5.6 Hz, 1H, CHHCHCHF), 1st AB system: nB¼1.82 (dd,
J¼17.0, 8.4 Hz, 1H, CHHCHCOPh), 1.65 (s, 6H, CH3),
J¼18.6, 5.0 Hz, 1H, CHHCHCOPh), 2.20 (dtd, JH–F
¼
1.60–1.15 (m, 8H, CH2), 0.84 (t, J¼6.9 Hz, 3H, CH3); 13
C
15.1 Hz, J¼7.0, 3.4 Hz, 1H, CHCHF), 1.62 (s, 3H, CH3),
1.50 (s, 3H, CH3), 1.48–0.85 (m, 8H, CH2), 0.77 (t,
J¼7.0 Hz, 3H, CH3); 13C NMR (C6D6, 100 MHz) d 201.9,
138.2, 133.3, 129.5 (2C), 129.1 (2C), 126.1, 123.2, 95.2 (d,
J¼170.1 Hz), 43.1 (d, J¼6.6 Hz), 41.8 (d, J¼20.7 Hz), 34.6
(d, J¼21.7 Hz), 33.7, 33.6 (d, J¼5.4 Hz), 32.5, 25.8 (d,
J¼4.0 Hz), 23.5, 19.8, 19.7, 14.8; 19F NMR (C6D6,
376.5 MHz) d 2185.09 (dddd, J¼48.2, 32.0, 22.0,
15.2 Hz); HRMS (EI) 70 eV: calcd for C21H29OF [Mþz]
316.2202, found 316.220 (1 ppm). Anal. calcd for
C21H29FO: C, 79.70; H, 9.24, found C, 79.63; H, 8.81.
NMR (CDCl3, 100 MHz) d 203.7, 137.0, 132.8, 128.6 (2C),
128.2 (2C), 124.2, 123.2, 96.5 (d, J¼171.1 Hz), 42.9 (d,
J¼4.8 Hz), 40.5 (d, J¼18.5 Hz), 34.6, 32.4 (d, J¼21.7 Hz),
32.2 (d, J¼6.4 Hz), 31.5, 24.7 (d, J¼3.2 Hz), 22.4, 18.9,
18.6, 14.0; 19F NMR (CDCl3, 376.5 MHz) d 2179.78
(dddd, J¼48.4, 37.5, 20.3, 7.8 Hz).
Less polar, minor diastereomer 14b. White solid, mp 488C,
1H NMR (CDCl3, 400 MHz) d 8.05–8.01 (m, 2H, Ph),
7.61–7.45 (m, 3H, Ph), 4.50 (dqd, JH–F¼51.4 Hz, J¼4.3,
1.4 Hz, 1H, CHF), 3.79 (dt, J¼6.1, 10.6 Hz, 1H, CHCOPh),
2.33–2.00 (m, 5H, CH2CHCOPh and CH2CHCHF and
CHCHF), 1.69 (s, 3H, CH3), 1.62 (s, 3H, CH3), 1.58–1.20
(m, 8H, CH2), 0.88 (t, J¼6.9 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 205.0, 137.2, 133.2, 128.6 (2C), 128.4
(2C), 124.8, 123.9, 94.0 (d, J¼169.45 Hz), 43.3 (d,
J¼3.2 Hz), 39.6 (d, J¼19.3 Hz), 36.8, 32.3 (d,
J¼20.5 Hz), 31.6, 29.3 (d, J¼3.2 Hz), 25.4 (d, J¼4.8 Hz),
22.5, 19.0, 18.6, 14.0; 19F NMR (CDCl3, 376.5 MHz) d
2196.97 (dtd, J¼48.9, 32.1, 14.1 Hz).
5.6.5. 2-(2-Fluoro-propylidene)-malonic acid diethyl
ester (15) and 6a-(1-fluoro-ethyl)-3,4-dimethyl-cyclo-
hex-3-ene-1,1-dicarboxylic acid diethyl ester (16c). See
Ref. 12.
Acknowledgements
We thank Professor K. N. Houk (UCLA, USA) for very
fruitful discussions. We are grateful to the Centre National
de la Recherche Scientifique (France) and the National
Science Foundation (USA) for their support through a joint
research grant.
5.6.3. 6a-(1-Fluoro-hexyl)-3,4-dimethyl-cyclohex-3-ene-
a-carbaldehyde (16a). A solution of the aldehyde 1a
(82 mg, 0.52 mmol) in 2,3-dimethyl-buta-1,3-diene
(1.5 mL, 12.99 mmol) was heated to reflux for 21 h. The
excess of 2,3-dimethyl-buta-1,3-diene was removed in
vacuo to give a viscous pale yellow oil. The crude product
was purified on a flash chromatography (toluene/Et2O, 99/1)
to give the title compound 16a (71 mg, 57% yield). White
References
1
solid, mp 688C, H NMR (CDCl3, 400 MHz) d 9.69 (td,
1. See, for instance: (a). In Chemistry of Organic Fluorine
Compounds II: A Critical Review; ACS Monograph 187;
Hudlicky, M., Pavlath, A. E., Eds.; ACS: Washington, DC,
1995. (b) In Experimental Methods in Organic Fluorine
Chemistry; Kitazume, T., Yamazaki, T., Eds.; Gordon &
Breach: Tokyo, 1998; and references therein.
JH–F¼2.6 Hz, J¼0.6 Hz, 1H, CHO), 4.70 (dddd,
JH–F¼49.0 Hz, J¼8.8, 6.2, 3.6 Hz, 1H, CHF), 2.56 (dt,
J¼2.6, 5.4 Hz, 1H, CHCHO), AB system: nA¼2.35 (broad
d, J¼19.8 Hz, 1H, CHHCHCHO) and nB¼2.22 (broad d,
J¼19.8 Hz, 1H, CHHCHCHO), 2.18 (s, 2H, CH2CHCHF),
2.08 (ddtd, JH–F¼21.8 Hz, J¼9.7, 6.2, 3.3 Hz, 1H,
CHCHF), 1.66 (s, 3H, CH3), 1.64 (s, 3H, CH3), 1.62–1.24
(m, 8H, CH2), 0.90 (t, J¼6.8 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 205.0 (d, J¼1.6 Hz), 125.5, 123.1,
96.1 (d, J¼168.9 Hz), 48.2 (d, J¼4.6 Hz), 40.4 (d,
J¼20.5 Hz), 32.7, 32.7 (d, J¼21.3 Hz), 31.6, 30.3 (d,
J¼4.0 Hz), 24.7 (d, J¼3.8 Hz), 22.5, 19.0, 18.9, 14.0; 19F
NMR (CDCl3, 376.5 MHz) d 2186.06 (ddt, J¼50.7, 31.9,
2. See, for instance: (a) Welch, J. T. Tetrahedron 1987, 43,
3123–3193. (b) Resnati, G. Tetrahedron 1993, 49,
9385–9445. (c) In Fluorine in Bioorganic Chemistry;
Welch, J. T., Eswarakrishnan, S., Eds.; Wiley Interscience:
New York, 1991. (d) In Biomedical Frontiers in Fluorine
Chemistry; ACS Symposium Series 639; Ojima, I., McCarthy,
J. R., Welch, J. T., Eds.; ACS: Washington, DC, 1996; and
references therein.

M. Prakesch et al. / Tetrahedron 59 (2003) 8833–8841
8841
´
3. Gree, R. L.; Lellouche, J. P. In Enantiocontrolled Synthesis of
´
8. Legoupy, S.; Crevisy, C.; Guillemin, J. C.; Gree, R. J. Fluorine
Fluoro-Organic Compounds: Stereochemical Challenges and
Biomedicinal Targets; Soloshonok, V. A., Ed.; Wiley: New
York, 1999; pp 535–556.
Chem. 1999, 93, 171–173.
9. Davis, F. A.; Qi, H. Tetrahedron Lett. 1996, 37, 4345–4348.
´
10. Prakesch, M.; Gree, D.; Gree, R. Acc. Chem. Res. 2002, 35,
´
4. (a) For a classical example see: Middleton, W. J. J. Org. Chem.
1975, 40, 574–578. (b) For a recent example see: De Jonghe,
S.; Van Overmeire, I.; Poulton, S.; Hendrix, C.; Busson, R.;
Van Calenbergh, S.; De Keukeleire, D.; Spiegel, S.;
Herdewijn, P. Bioorg. Med. Chem. Lett. 1999, 9, 3175–3180.
175–181.
´
11. Prakesch, M.; Gree, D.; Gree, R. J. Org. Chem. 2001, 66,
´
3146–3151.
´
´
12. Gree, D.; Vallerie, L.; Gree, R.; Toupet, L.; Washington, I.;
Pelicier, J.-P.; Villacampa, M.; Perez, J. M.; Houk, K. N.
J. Org. Chem. 2001, 66, 2374–2382.
´
´
5. Gree, D. M.; Kermarrec, C. J. M.; Martelli, J. T.; Gree, R. L.;
Lellouche, J. P.; Toupet, L. J. J. Org. Chem. 1996, 61,
1918–1919.
13. If heating is maintained for longer periods the decomposition
of 1a starts, possibly by autocatalytic processes, affording
unidentified compounds.
´ ´
6. Kermarrec, C.; Madiot, V.; Gree, D.; Meyer, A.; Gree, R.
Tetrahedron Lett. 1996, 37, 5691–5694.
14. It is also possible to use catalytic amounts of iodine in CH2Cl2
at room temperature to perform this Z to E isomerisation.
´
7. Gree, D.; Madiot, V.; Gree, R. Tetrahedron Lett. 1999, 40,
´
6399–6402.