A rapid access to new fluorinated 1,3-dienes and benzylic fluorides via metathesis on propargylic fluorides

Article abstract of DOI:10.1055/s-2008-1078179

The cross enyne metathesis reaction of propargylic fluoride (+)-12 with ethylene affords the enantioenriched 1,3-diene (+)-14 having fluorine-containing side chain at 2-position in good yield. Upon Diels-Alder reaction, followed by aromatization, this diene affords the new benzylic fluorides (+)-16 and (+)-17 in high ee values. This new strategy has been successfully extended to the corresponding gem-difluoro diene 21 and benzylic fluorides 23 and 24. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078179

LETTER
2503
A Rapid Access to New Fluorinated 1,3-Dienes and Benzylic Fluorides via
Metathesis on Propargylic Fluorides
Rapid
Access
a
to
N
ew Flu
n
orinated 1, 3-
d
D
iene
s
and
B
i
enzyli
p
c
Fluorides A. Pujari,a Krishna P. Kaliappan,*a Alain Valleix,b Danielle Grée,c René Grée*c
a
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
b
c
Euriso–top, Centre d’Etudes Nucléaires de Saclay, 91191 Gif sur Yvette, France
Chimie et Photonique Moléculaires, CNRS UMR 6510, Université de Rennes 1, Avenue du Général Leclerc,
35042 Rennes Cedex, France
E-mail: rene.gree@univ-rennes1.fr
Received 1 June 2008
This publication is dedicated to the memory of Dr. Charles Mioskowski (1946–2007), a superb chemist and a wonderful friend.
ylmethanols like 7, could be conveniently prepared in op-
tically active form5 their dehydroxyfluorination reaction
seems to be extremely challenging, especially in terms of
regio- and stereocontrol.
Abstract: The cross enyne metathesis reaction of propargylic fluo-
ride (+)-12 with ethylene affords the enantioenriched 1,3-diene (+)-
14 having fluorine-containing side chain at 2-position in good yield.
Upon Diels–Alder reaction, followed by aromatization, this diene
affords the new benzylic fluorides (+)-16 and (+)-17 in high ee val-
ues. This new strategy has been successfully extended to the corre-
sponding gem-difluoro diene 21 and benzylic fluorides 23 and 24.
E
F
F
E
Diels–Alder
R
9
Key words: dehydroxyfluorination, enyne metathesis, Diels–Alder
reaction, aromatization, benzylic fluorides
R
aromatization
OH
5
R
F
R
3
7
The presence of fluorine atom(s) in organic molecules is
known to modify their physical, chemical and biological
properties significantly.1 Due to this, introduction of fluo-
rine atom(s), especially by the selective replacement of
C–H or C–OH bonds by C–F bonds is an important trans-
formation practiced routinely in bioorganic and medicinal
chemistry.2 Furthermore, the stereoselective installation
of fluorine is still a challenging task when optically active
fluorides are required and it is worth mentioning that ef-
forts are always on to synthesize new chiral fluorinated
molecules.3 Nevertheless, introduction of fluorine stereo-
selectively at positions vicinal to p-systems happens to be
a tedious task,4 and this is the case in particular for benzyl-
ic fluorides, such as shown in Figure 1, which are attrac-
tive target molecules in life and material sciences.
E
F
F
enyne
F
F
E
metathesis
Diels–Alder
R
10
R
aromatization
O
6
F
R
R
F
8
E = CO2Et
Scheme 1 Retrosynthetic analysis for benzylic fluorides 3 and 4 and
dienes 5 and 6
In fact, it is well established that the dehydroxyfluorina-
tion reaction of allylic alcohols occurs usually with
isomerization and racemization.6 An alternative possibili-
ty would be to use the stereodirecting effect of diene-tri-
carbonyl iron complexes during dehydroxyfluorination.7
However, the iron complexes corresponding to 1,3-buta-
dien-2-ylmethanols are available in optically active form
only after tedious resolution processes.8 On the other
hand, synthesis of type 6 dienes would be also very chal-
lenging, especially if one considers the gem-difluorination
of the corresponding 1,3-dien-2-ones.8 First of all, such
derivatives are known to be unstable, prone to dimeriza-
tion processes,9 and isolated mostly as the corresponding
iron-tricarbonyl complexes.8 Moreover the gem-difluori-
nation of enones is known to be very challenging and the
desired compounds are obtained only in very poor yields,
except when using ultra high pressure reaction condi-
tions.10
F
F
F
R
R1
R
R1
2
1
Figure 1 Targeted benzylic fluorides
This challenge could perhaps be circumvented if there is
an efficient method to synthesize 1,3-dienes like 5 and 6
which then can undergo Diels–Alder reaction and aroma-
tization to afford benzylic fluorides 3 and 4 (Scheme 1).
Unfortunately, though it is known that the 1,3-butadien-2-
In view of the importance of the benzylic fluorides and
our efforts to develop efficient synthesis of novel fluori-
nated key intermediates11 which could act as useful build-
ing blocks, we became interested in designing a new
SYNLETT 2008, No. 16, pp 2503–2507
Advanced online publication: 10.09.2008
DOI: 10.1055/s-2008-1078179; Art ID: G17808ST
x
x
.x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

2504
S. A. Pujari et al.
LETTER
strategy for these benzylic fluorides. While various new 14 in 63% yield (Scheme 2). This compound was isolated
approaches were evaluated, it occurred to us that based on by chromatography on SiO2 and characterized by its spec-
our earlier work,12 dienes of type 5 and 6 could be synthe- tral and analytical data. It was then subjected to a Diels–
sized easily starting from alkynes 9 and 10 via cross enyne Alder reaction with diethyl acetylenedicarboxylate to ob-
metathesis with ethylene (Scheme 1). Herein, we report a tain the cyclohexadiene ( )-15 in 71% yield. Aromatiza-
rapid access to these new 1,3-dienes with the fluorine- tion was performed by using a suspension of MnO2 in
containing side chain at 2-position using enyne cross-me- refluxing dichloromethane affording the desired benzylic
tathesis reaction,12 and then to the corresponding benzylic fluoride ( )-16 in 81% yield [21% overall yield from al-
fluorides through a Diels–Alder-aromatization sequence. cohol ( )-11]. Reduction by LiAlH4 was compatible with
The purpose of this publication is to demonstrate that this the fluoride in benzylic position affording the correspond-
strategy offers a short and efficient route to such mono- ing diol ( )-17. By using naphthaquinone as dienophile, a
fluorinated molecules, including in optically active form, similar series of reactions (cycloaddition followed by aro-
and extension to corresponding gem-difluorinated deriva- matization) yielded the new benzylic fluoride ( )-18 in
tives has been also demonstrated.
17% overall yield from alcohol ( )-11 (Scheme 2).
The cross enyne metathesis reaction has been found to be It is important to note that this strategy is complementary
very fruitful for the preparation of new 1,3-dienes, of to a previous work involving Diels–Alder reactions per-
much use later on in synthesis.13 Furthermore, this reac- formed on electrophilic propargylic fluorides.17 The sub-
tion was found to be compatible with heteroatoms in pro- stitution pattern of the groups on the aromatic ring are
pargylic position including free, or protected alcohols.12,14 different in the two processes. Taking into account the
However, to the best of our knowledge, except in a very challenges of preparing optically active benzylic fluo-
recent paper and in the intramolecular mode,15 this reac- rides,17,18 the next key issue was the extension of this strat-
tion has never been used starting from propargylic fluo- egy to enantioenriched compounds. For that purpose, the
rides. To demonstrate our strategy the known propargylic (S)-propargylic alcohol (–)-11 was prepared in 88% ee
fluoride 12 (Scheme 2) has been selected as a model com- (determined through the NMR analysis of the correspond-
pound for these studies since it is easily accessible, includ- ing Mandelic esters) by asymmetric reduction of ketone
ing in optically active form, by diethylaminosulfur 19 using (S)-alpine borane (Scheme 3). The R fluoride
trifluoride (DAST) mediated dehydroxyfluorination of (+)-12 was obtained through the DAST-mediated dehy-
the corresponding propargylic alcohol 11.16
droxyfluorination of (–)-11.16a The corresponding diene
(+)-14 was synthesized by the enyne cross-metathesis re-
action. Using the same sequence of reactions as described
previously in racemic series, the cycloadduct 15 and the
benzylic fluorides (+)-16 and (+)-17 were obtained. For
the latter derivative, a 84% ee value was measured by
chiral HPLC analysis.19 Therefore, this complete se-
quence of reactions, starting from enantioenriched propar-
gylic alcohol (–)-11 up to (+)-17, occurs with very little
loss (£4%) of optical purity and validates this new strate-
gy (Scheme 3).
The cross-metathesis reaction of ( )-12 with ethylene (1
atm) in the presence of 10 mol% Grubbs II catalyst 13 in
refluxing dichloromethane afforded the desired diene ( )-
13 (10 mol%),
F
OH
ethylene
DAST, CH2Cl2
CH2Cl2,
reflux, 15 h,
63%
–50 °C, 45 min
59%
C9H19
( )-11
C9H19
( )-12
F
F
O
EtO2C
CO2Et
C9H19
C9H19
OEt
OEt
It is worth mentioning that type 14 fluorinated dienes, eas-
ily synthesized in a few steps by this route, appear very
difficult to obtain by alternative methods. The extension
of this strategy to corresponding gem-difluorodienes was
also of interest. The gem-difluoropropargylic derivative
20 was easily obtained in 72% yield by reaction of DAST
with ketone 19 (Scheme 4).
60 °C, 3 h,
71%
( )-14
( )-15
O
F
O
O
MnO2,
CH2Cl2
C9H19
OEt
OEt
LAH, THF
reflux,
2 d, 81%
0 °C, 1 h,
90%
( )-16
F
Using again Grubbs II catalyst 13 (at 5 mol%) the enyne
cross-metathesis reaction afforded the desired diene 21 in
80% yield (Scheme 4). This intermediate was purified by
chromatography on silica gel chromatography and char-
acterized by the spectral and analytical data. Diels–Alder
reaction of 21 with diethyl acetylenedicarboxylate gave
the cyclohexadiene 22 in 75% yield. Aromatization using
a suspension of MnO2 in refluxing dichloromethane af-
forded the desired benzylic gem-difluoride 23 in 89%
yield (31% overall yield from alcohol 11). In the same
way, by using naphthaquinone as dienophile, the con-
densed system 24 was obtained (34% overall yield from
alcohol 11). Therefore, in the case of these gem-difluoro-
C9H19
OH
OH
MesN
NMes
Ph
Cl
Cl
Ru
PCy3
( )-17
13
1) 1,4-naphtha-
quinone,toluene,
70 °C, 2 d
F
O
( )-14
C9H19
2) Et3N, silica,
CHCl3, r.t., 3 h
46% (2 steps)
( )-18
O
Scheme 2 Synthesis and reactions of diene ( )-14
Synlett 2008, No. 16, 2503–2507 © Thieme Stuttgart · New York

LETTER
Rapid Access to New Fluorinated 1,3-Dienes and Benzylic Fluorides
2505
O
gem-difluorinated dienes and their benzylic derivatives
using the same Diels–Alder aromatization sequence.
OH
DAST, CH2Cl2
ref. 16
–50 °C, 45 min
59%
C9H19
19
C9H19
(–)-11
F
Acknowledgment
13 (10 mol%),
F
ethylene
C9H19
S.A.P. thanks the French Embassy in India for a Sandwich thesis
fellowship.
CH2Cl2,
reflux, 15 h,
63%
C9H19
(+)-14
(+)-12
F
O
References and Notes
EtO2C
CO2Et
C9H19
OEt
OEt
(1) (a) Kitazume, T.; Yamazaki, T. Experimental Methods in
Organic Fluorine Chemistry; Gordon and Breach Science
Publishers: Tokyo, 1998. (b) Hudlicky, M.; Pavlath, A. E.
Chemistry of Organic Fluorine Compounds II: A Critical
Review, ACS Monograph 187; American Chemical Society:
Washington DC, 1995. (c) Smart, B. E. In Organofluorine
Chemistry: Principles and Commercial Applications;
Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum: New
York, 1994, Chap. 3, 57–88; and references therein.
(2) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical
Frontiers in Fluorine Chemistry, ACS Symposium Series
639; American Chemical Society: Washington DC, 1996.
(b) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley Interscience: New York, 1991.
(c) Welch, J. T. Tetrahedron 1987, 43, 3123; and references
therein.
60 °C, 3 h,
71%
(R)-15
O
F
O
MnO2, CH2Cl2
C9H19
OEt
OEt
reflux, 2 d,
81%
(+)-16
O
F
LAH, THF
C9H19
OH
OH
0 °C,1 h,
90%
(+)-17
Scheme 3 Synthesis and reactions of diene (+)-14
(3) For recent examples, see: (a) Thibaudeau, S.; Fuller, R.;
Gouverneur, V. Org. Biomol. Chem. 2004, 2, 1110.
(b) Hunter, L.; O’Hagan, D.; Slawin, A. M. Z. J. Am. Chem.
Soc. 2006, 128, 16422. (c) Hunter, L.; Slawin, A. M. Z.;
Kirsch, P.; O’Hagan, D. Angew. Chem. Int. Ed. 2007, 46,
7887.
(4) See for instance: Prakesch, M.; Grée, D.; Grée, R. In
Fluorine-Containing Synthons, ACS Symposium Series 911;
Soloshonok, V. A., Ed.; American Chemical Society:
Washington DC, 2005, 173; and references therein.
(5) Soundararajan, R.; Li, G.; Brown, H. C. J. Org. Chem. 1996,
61, 100.
(6) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) 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.
(7) Grée, D. M.; Kermarrec, C. J. M.; Martelli, J. T.; Grée, R. L.;
Lellouche, J. P.; Toupet, L. J. J. Org. Chem. 1996, 61, 1918.
(8) Franck-Neumann, M.; Martina, D.; Heitz, M. P.
J. Organomet. Chem. 1986, 301, 61.
dienes, the route through the propargylic fluorides is again
highly advantageous (Scheme 4).
In conclusion, we have demonstrated that the enyne cross-
metathesis reaction is compatible with propargylic
monofluorides, affording directly and efficiently the de-
sired 1,3-dienes including in optically active form.20–23
Such dienes are excellent starting material for the prepa-
ration of new enantioenriched benzylic fluorides through
a Diels–Alder aromatization sequence. This route was
successfully extended to synthesize the corresponding
O
OH
DAST
IBX, CHCl3,
60 °C, 15 h,
80%
55 °C, 4 h,
72%
11
19
C9H19
C9H19
13 (5 mol%),
ethylene
F
F
F
F
C9H19
CH2Cl2, reflux,
15 h, 80%
C9H19
20
(9) Hoffmann, H. M. R.; Eggert, U.; Poly, W. Angew. Chem. Int.
21
Ed. 1987, 26, 1015.
O
F
F
(10) (a) McClinton, M. A. J. Chem. Soc., Perkin Trans. 1 1992,
2149. (b) Box, J. M.; Harwood, L. M.; Whitehead, R. C.
Synlett 1997, 571. (c) Ohba, T.; Ikeda, E.; Takei, H. Bioorg.
Med. Chem. Lett. 1996, 6, 1875; and references therein.
(11) See, for example: (a) Prakesch, M.; Grée, D.; Grée, R. Acc.
Chem. Res. 2002, 35, 175. (b) Prakesch, M.; Kerouredan,
E.; Grée, D.; Grée, R.; De Chancie, J.; Houk, K. N.
J. Fluorine Chem. 2004, 125, 537. (c) Manthati, V.; Grée,
D.; Grée, R. Eur. J. Org. Chem. 2005, 3825. (d) Das, S.;
Chandrasekhar, S.; Yadav, J. S.; Grée, R. Tetrahedron Lett.
2007, 48, 5305. (e) Blayo, A.-L.; Le Meur, S.; Grée, D.;
Grée, R. Adv. Synth. Catal. 2008, 350, 471.
EtO2C
CO2Et
C9H19
OEt
OEt
60 °C, 4 h,
75%
22
O
O
F
F
MnO2,CH2Cl2
C9H19
OEt
OEt
reflux, 36 h,
89%
23
O
1) 1,4-naphtha-
quinone, toluene,
reflux, 30 h
O
F
F
C9H19
(12) (a) Kaliappan, K. P.; Ravikumar, V. Org. Biomol. Chem.
2005, 3, 848. (b) Kaliappan, K. P.; Ravikumar, V.; Pujari,
S. A. Tetrahedron Lett. 2006, 47, 981. (c) Kaliappan, K. P.;
Subrahmanyam, A. V. Org. Lett. 2007, 9, 1121.
21
2) silica, Et3N,
CHCl3, r.t., 2 h,
73% ( 2 steps)
24
O
(d) Kaliappan, K. P.; Ravikumar, V. Synlett 2007, 977.
Scheme 4 Synthesis and reactions of diene 21
Synlett 2008, No. 16, 2503–2507 © Thieme Stuttgart · New York

2506
S. A. Pujari et al.
LETTER
purified by flash column chromatography on silica gel to
(13) For enyne cross-metathesis reactions with ethylene, see:
(a) Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000, 65, 1788.
(b) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271.
(c) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43,
2235. (d) Giessert, A. J.; Snyder, L.; Markham, J.; Diver,
S. T. Org. Lett. 2003, 5, 1793.
(14) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271.
(15) Arimitsu, S.; Fernández, B.; del Pozo, C.; Fustero, S.;
Hammond, G. B. J. Org. Chem. 2008, 73, 2656.
afford the corresponding aromatized product.
(22) General Procedure for One-Pot Diels–Alder Reaction
with 1,4-Naphthaquinone and Aromatization: A solution
of diene (1 mmol) in anhyd toluene (15 mL) was treated with
1,4-naphthaquinone (1.2 mmol) and the resulting mixture
was heated at 70 °C for 2 d. The solvent was removed and
the crude product was dissolved in CHCl3 (4 mL). To this
solution silica gel purged in Et3N (2 g) was added and the
mixture was stirred for another 3 h at r.t. The reaction
mixture was concentrated and the crude material was
purified by column chromatography to afford the
(16) (a) Madiot, V.; Lesot, P.; Grée, D.; Courtieu, J.; Grée, R.
Chem. Commun. 2000, 169. (b) Filmon, J.; Grée, D.; Grée,
R. J. Fluorine Chem. 2001, 107, 271.
(17) Grée, D.; Grée, R. Tetrahedron Lett. 2007, 48, 5435; and
corresponding aromatized adducts.
references therein.
(23) Spectral data for selected compounds: Compound (+)-16: Rf
0.30 (pentane–Et2O, 9:1); [a]D20 14.8 (c = 0.2, CHCl3). IR
(neat): 3020, 1966, 1731, 1650, 1216, 1045, 758 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.75 (d, J = 8.0 Hz, 1 H, H6),
7.65 (s, 1 H, H3), 7.49 (dd, J = 8.0, 1.6 Hz, 1 H, H5), 5.55
(ddd, J = 47.7, 8.0, 4.7 Hz, 1 H, CHF), 4.35–4.43 (m, 4 H,
2 × CH2), 1.87–1.91 (m, 2 H, CH2), 1.19–1.44 (m, 20 H,
7 × CH2, 2 × Me), 0.89 (t, J = 6.4 Hz, 3 H, Me). 13C NMR
(75 MHz, CDCl3): d = 167.5 (COOCH2), 167.2 (COOCH2),
144.1 (d, J = 20.6 Hz, C4), 132.6, 131.6 (d, J = 1.4 Hz),
129.2, 127.6 (d, J = 7.4 Hz, CAr), 125.7 (d, J = 7.6 Hz, CAr),
92.9 (d, J = 173.2 Hz, CHF), 61.7 (OEt), 61.6 (OEt), 37.2 (d,
J = 22.9 Hz, CH2CHF), 31.8, 29.5, 29.4, 29.3, 29.2, 24.8 (d,
J = 3.9 Hz), 22.7 (7 × d, J = 3.9 Hz, 7 × CH2), 14.2, 14.1 (2
× Me). 19F NMR (282 MHz, CDCl3): d = –178.9 (ddd,
JH–F = 47.5, 28.9, 18.8 Hz). HRMS: m/z [M]+ calcd for
C22H33O4F: 380.2362; found: 380.2381. Compound 17: Rf
0.28 (pentane–Et2O, 7:3); mp 65–67 °C; [a]D20 3.0 (c = 0.2,
CHCl3). IR (KBr): 3430, 3019, 1653, 1215, 1045 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.27–7.38 (m, 3 H, HAr), 5.43
(ddd, J = 47.8, 8.0, 4.9 Hz, 1 H, CHF), 4.74 (s, 2 H, CH2OH),
4.73 (s, 2 H, CH2OH), 3.67 (br s, 2 H, OH), 1.37–1.97 (m, 2
H, CH2), 1.09–1.22 (m, 14 H, 7 × CH2), 0.89 (t, J = 6.9 Hz,
3 H, Me). 13C NMR (75 MHz, CDCl3): d = 140.9 (d, J = 19.9
Hz, C4), 139.6, 139.2 (d, J = 2.0 Hz), 129.7, 126.7 (d, J = 6.6
Hz, CAr), 125.5 (d, J = 6.8 Hz, CAr), 94.4 (d, J = 170.3 Hz,
CHF), 63.8 (CH2OH), 63.6 (CH2OH), 37.2 (d, J = 23.4 Hz,
CH2CHF), 31.8, 29.5, 29.4, 29.3, 29.2, 25.1, 22.7 (d, J = 4.2
Hz), 14.1 (Me). 19F NMR (282 MHz, CDCl3): d = –174.64
(ddd, JH–F = 46.7, 29.6, 17.9 Hz). HRMS: m/z [M – F]+ calcd
for C18H29O2: 277.2167; found: 277.2178. Chiral HPLC
analysis: column Chiralpack AD, eluent: hexane–EtOH,
98:2; flow rate: 1 mL/min; UV detection at l = 225 nm;
tR(17) = 16.8 min; tR (ent-17) = 19 min. Compound 18: Rf
0.70 (pentane–Et2O, 9:1); mp 99–101 °C. IR (KBr): 2919,
2849, 1676, 1593, 1351, 1290, 1156, 1021 cm–1. 1H NMR
(300 MHz, CDCl3): d = 8.30–8.35 (m, 2 H, HAr), 8.24 (s, 1
H, HAr), 7.28–7.85 (m, 4 H, HAr), 5.62 (ddd, J = 47.7, 7.9, 4.8
Hz, 1 H, CHF), 1.89–2.02 (m, 2 H, CH2), 1.22–1.52 (m, 14
H, 7 × CH2), 0.88 (t, J = 7.0 Hz, 3 H, Me). 13C NMR (75
MHz, CDCl3): d = 182.9 (COOCH2), 182.7 (COOCH2),
147.3 (d, J = 20.5 Hz, CAr), 134.2, 134.1, 133.6, 133.5, 133.1
(d, J = 1.4 Hz), 130.7 (d, J = 7.6 Hz, CAr), 127.7, 127.3,
127.2, 124.0 (4 × d, J = 7.5 Hz, CAr), 92.6 (d, J = 173.9 Hz,
CHF), 37.2 (d, J = 22.7 Hz, CH2CHF), 31.8, 29.5, 29.4, 29.3,
29.2, 24.8, 22.6 (d, J = 3.9 Hz), 14.1 (Me). 19F NMR (282
MHz, CDCl3): d = –179.9 (ddd, JH–F = 47.7, 28.7, 19.1 Hz).
HRMS: m/z [M]+ calcd for C24H27O2F: 366.1995; found:
366.1999. Compound 23: Rf 0.34 (pentane–Et2O, 9:1). IR
(neat): 2956, 2928, 2856, 1731, 1615, 1466, 1287, 1131,
1070, 775 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.83 (d,
J = 1.2 Hz, 1 H, H3), 7.75 (d, J = 8.0 Hz, 1 H, H6), 7.63 (dd,
J = 8.0, 1.2 Hz, 1 H, H5), 4.39 (q, J = 7.1 Hz, 2 H, OEt), 4.38
(q, J = 7.1 Hz, 2 H, OEt), 2.01–2.19 (m, 2 H, CH2), 1.25–
(18) Sai Krishna Murthy, A.; Tardivel, R.; Grée, R. In Science of
Synthesis, Vol. 34; Percy, J. M., Ed.; Thieme: Stuttgart,
2006, 295–317.
(19) All our attempts to measure the ee values of the
intermediates (+)-14 and (+)-15 by NMR in the presence of
chiral shift reagents or by chiral HPLC have been
unsuccessful so far. This is a well known problem for such
chiral monofluorinated molecules, see for instance ref 16a.
(20) General Procedure for Cross Enyne Metathesis: A
solution of propargyl fluoride (1 mmol) in degassed CH2Cl2
(10 mL) was purged with ethylene and treated with the
Grubbs II catalyst 13 (5 or 10 mol%). The reaction mixture
was refluxed for 15 h under ethylene atmosphere. After
being cooled to r.t., the solvent was evaporated under
reduced pressure and the residue was purified by silica gel
column chromatography to afford the fluorodiene. Spectral
data for diene (+)-14: Rf 0.71 (pentane); [a]D20 8.0 (c = 0.2,
CHCl3). IR (neat): 2927, 1966, 1650, 1456, 1216, 1023, 759
cm–1. 1H NMR (300 MHz, CDCl3): d = 6.28–6.38 (m, 1 H,
H2), 5.05–5.31 (m, 5 H, 2 × =CH2, CHF), 1.28–1.52 (m, 14
H, 7 × CH2), 1.72–1.83 (m, 2 H, CH2), 0.90 (t, J = 6.6 Hz, 3
H, Me). 13C NMR (75 MHz, CDCl3): d = 145.1 (d, J = 17.5
Hz, C3), 135.3 (d, J = 3.9 Hz, C2), 115.0 (d, J = 10.5 Hz,
C14), 114.7 (C1), 92.1 (d, J = 171.5 Hz, C4), 34.7 (d, J =
22.6 Hz, CH2CHF), 31.9, 29.5, 29.4, 29.3, 25.1(d, J = 3.5
Hz), 22.7 (6 × d, J = 3.5 Hz, 6 × CH2), 14.1 (Me). 19F NMR
(282 MHz, CDCl3): d = –181.9 (dt, JH–F = 48.7, 23.6 Hz).
HRMS: m/z [M]+ calcd for C14H25F: 212.1940; found:
212.1933. Spectral data for diene 21: Rf 0.91 (pentane). IR
(neat): 2955, 2927, 2855, 1682, 1596, 1467, 1174, 1087,
1004 cm–1. 1H NMR (300 MHz, CDCl3): d = 6.27 (dd, J =
17.7, 11.3 Hz, 1 H, H2), 5.53 (dd, J = 17.7, 1.3 Hz, 1 H, H1),
5.44 (d, J = 5.5 Hz, 2 H, H14), 5.23 (d, J = 11.3 Hz, 1 H, H1),
1.91–2.07 (m, 2 H, CH2), 1.22–1.45 (m, 14 H, 7 × CH2), 0.91
(t, J = 6.8 Hz, 3 H, Me). 13C NMR (75 MHz, CDCl3): d =
142.5 (t, J = 24.2 Hz, C3), 132.6 (t, J = 2.8 Hz, C2), 122.4 (t,
J = 242.4 Hz, C4), 117.3 (t, J = 1.4 Hz, C1), 116.3 (t, J = 9.5
Hz, C14), 36.5 (t, J = 26.1 Hz, CH2CF2), 31.8, 29.4, 29.3,
29.27, 29.23, 22.6, 22.3 (t, J = 4.3 Hz), 14.1 (Me). 19F NMR
(282 MHz, CDCl3): d = –97.44 (t, JH–F = 16.6 Hz). HRMS:
m/z [M]+ calcd for C14H24F2: 230.1846; found: 230.1846.
(21) General Procedure for Diels–Alder Reaction with
Diethyl Acetylenedicarboxylate Followed by
Aromatization: A mixture of diene (1 mmol) and diethyl
acetylenedicarboxylate (1.2 mmol) was heated at 60 °C in an
oil bath for 3 h. After bringing the mixture to r.t., the crude
material was purified by silica gel column chromatography
to give the cycloadduct. To a solution of the above
cycloadduct (1 mmol) in CH2Cl2 (40 mL) was added MnO2
(10 mmol) and the mixture was refluxed for 2 d. After being
cooled to r.t., the reaction mixture was passed through a
small pad of celite and the filtrate was concentrated and
Synlett 2008, No. 16, 2503–2507 © Thieme Stuttgart · New York

LETTER
Rapid Access to New Fluorinated 1,3-Dienes and Benzylic Fluorides
2507
1.41 (m, 20 H, 7 × CH2, 2 × Me), 0.87 (t, J = 6.4 Hz, 3 H,
707 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.31–8.41 (m, 4
H, HAr), 7.80–7.91 (m, 3 H, HAr), 2.11–2.27 (m, 2 H, CH2),
1.25–1.50 (m, 14 H, 7 × CH2), 0.86 (t, J = 6.4 Hz, 3 H, Me).
13C NMR (75 MHz, CDCl3): d = 182.5 (2 × COOCH2), 143.3
(t, J = 27.6 Hz, CAr), 134.3, 134.1 (t, J = 1.3 Hz), 130.5 (t,
J = 6.0 Hz), 127.7, 127.4, 127.3, 124.1 (t, J = 6.1 Hz), 122.3
(t, J = 243.3 Hz, CF2), 38.8 (t, J = 26.6 Hz, CH2CF2), 31.8,
Me). 13C NMR (75 MHz, CDCl3): d = 167.1 (COOCH2),
166.8 (COOCH2), 140.3 (t, J = 27.8 Hz, C4), 133.5 (t, J = 1.3
Hz), 132.3, 129.1, 127.6 (t, J = 6.1 Hz), 125.7 (t, J = 6.3 Hz,
CAr), 122.3 (t, J = 243.0 Hz, CF2), 61.9 (OEt), 61.8 (OEt),
38.9 (t, J = 26.7 Hz, CH2CF2), 31.8, 29.4, 29.3, 29.2, 29.1,
22.6, 22.3 (t, J = 4.0 Hz), 14.1 (3 × Me). 19F NMR (282 MHz,
CDCl3): d = –96.25 (t, JH–F = 16.4 Hz). HRMS: m/z [M]+
calcd for C22H32O4F2: 398.2268; found: 398.2261.
29.4, 29.3, 29.2, 29.1, 22.3 (t, J = 3.9 Hz), 14.1 (Me). 19
F
NMR (282 MHz, CDCl3): d = –96.46 (t, JH–F = 16.4 Hz).
HRMS: m/z [M]+ calcd for C24H26O2F2: 384.1900; found:
384.1915.
Compound 24: Rf 0.71 (pentane–Et2O, 9:1); mp 88–90 °C.
IR (KBr): 2920, 2851, 1673, 1594, 1340, 1163, 1129, 1031,
Synlett 2008, No. 16, 2503–2507 © Thieme Stuttgart · New York