Regio- and stereoselective synthesis of fluoroalkadienes using β-fluoroalkenyliodonium salt

Article abstract of DOI:10.1039/b101836l

(E,E)-δ-Fluoro-α,β,γ,δ-unsaturated carbonyl compounds and (3E)-4-fluoro-1,3-dienes were stereoselectively synthesized by the palladium-catalyzed coupling reaction of (2-fluoroalkenyl)(p-tolyl)iodonium fluorides with α,β-unsaturated carbonyl compounds and

Full text of DOI:10.1039/b101836l

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Regio- and stereoselective synthesis of fluoroalkadienes using
ꢀ-fluoroalkenyliodonium salt
Masanori Yoshida, Dai Nagahara, Tsuyoshi Fukuhara, Norihiko Yoneda and Shoji Hara*
1
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo, 060-8628, Japan
Received (in Cambridge, UK) 27th February 2001, Accepted 7th August 2001
First published as an Advance Article on the web 4th September 2001
(E,E)-δ-Fluoro-α,β,γ,δ-unsaturated carbonyl compounds and (3E)-4-fluoro-1,3-dienes were stereoselectively
synthesized by the palladium-catalyzed coupling reaction of (2-fluoroalkenyl)(p-tolyl)iodonium fluorides
with α,β-unsaturated carbonyl compounds and tributylvinyltin, respectively.
Introduction
A fluorine atom on a conjugated double bond has been inten-
sively used as a label for obtaining structural information and
mechanistic details of natural compounds from 19F NMR
measurements.1 Moreover, the introduction of a fluorine atom
onto the conjugated double bonds of bioactive compounds was
found to be effective for increasing the stability and bioactivities
of these compounds.2 Therefore, much effort has been made
towards the stereoselective synthesis of fluorinated polyenes,
and some successful studies have been reported.3 However, in
order to introduce a fluorine atom into any position on the
conjugated double bonds of natural compounds, new method-
ologies for stereoselective fluoropolyene synthesis are required.
Recently, we found that (E)-(2-fluoroalk-1-enyl)(p-tolyl)-
iodonium fluorides 2 can be regio- and stereoselectively prepared
by the reaction of alk-1-ynes with iodotoluene difluoride 1 and
Et3N–5HF.4 On the other hand, Moriarty et al. reported that
hypervalent iodine compounds showed unusually high reactiv-
ities in the transition metal-catalyzed Heck-type reaction5 and
in cross-coupling reactions with alkenyltin reagents.6 We exam-
ined the Heck-type coupling reaction and the cross-coupling
reaction of 2 for the development of new methodology
applicable to the stereoselective synthesis of natural com-
Scheme 1
pound analogs having a fluorine atom on their polyene func-
tions (Scheme 1). We have previously reported our preliminary
findings7 and now provide a full account of the work.
and C-3 while no NOE was observed between H on C-6 and
C-4. The coupling constant between H on C-2 and H on C-3
was 14.9 Hz which showed that the newly formed double bond
also had E-stereochemistry. Consequently, ethyl (2E,4E)-4-
fluorotrideca-2,4-dienoate 4a was obtained with more than
95% stereoselectivity. Various alk-1-ynes having functional
groups such as an ester, ketone, and chloride were subjected
to the reaction with 1, and the resulting iodonium salts 2a–e
were used for the reaction with ethyl acrylate 3a, acrolein 3b,
and α,β-unsaturated ketones 3c, 3d (Table 1). The expected δ-
fluoro-α,β,γ,δ-unsaturated carbonyl compounds 4a–r could be
obtained in 51–68% yield with high stereoselectivity (>95%)
based on the alkynes. The yields were not high because they are
the overall yields of two steps.9 As by-products, β-tolyl-α,β-
unsaturated carbonyl compounds, formed by the Heck-type
reaction between 3 and the p-tolyl group on 2, were obtained in
2–5% yield with the starting alkynes formed by the decom-
position of 2. As the reaction proceeded under mild conditions,
the functional groups in the substrates remained unchanged
under the stated reaction conditions, and consequently the
polyfunctionalized fluoroalkadienes could be synthesized in
few steps with high selectivity.
Results and discussion
Heck-type reaction
(E)-(2-Fluorodec-1-enyl)(p-tolyl)iodonium fluoride 2a was
prepared by the reaction of dec-1-yne with 1, which had been
electrochemically prepared from iodotoluene, in the presence of
1
Et3N–5HF. In the H-NMR spectrum of the crude reaction
mixture, the characteristic signal of the olefin hydrogen was
observed at δ 6.7 with a 15.1 Hz coupling constant which
showed that the H and F on the double bond had cis(Z)-
stereochemistry.8 The crude 2a was used for the Heck-type reac-
tion with ethyl acrylate 3a in the presence of NaHCO3 and a
catalytic amount of Pd(OAc)2 in DMF.5 The reaction was com-
plete at room temperature after 2 h, and the desired fluorinated
alkadienyl ester 4a was obtained in 55% yield based on the
decyne. The coupling constant between F and H on C-4 was
18.3 Hz which showed that the double bond at the γ,δ position
had E-stereochemistry. This assignment was also supported by
an NOE experiment; an NOE was observed between H on C-6
DOI: 10.1039/b101836l
J. Chem. Soc., Perkin Trans. 1, 2001, 2283–2288
This journal is © The Royal Society of Chemistry 2001
2283

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Table 1 Heck-type coupling reaction using (E)-(2-fluoroalkenyl)-
iodonium salts 2a
Table 2 Influence of Pd catalyst in the synthesis of 5ea
Product
R1
R2
Yield/%b
4ac
4bc
4cc
4dc
4ed
4fd
4gd
4hd
4id
Oct
Oct
Oct
Oct
OEt
H
Me
Ph
OEt
H
Me
Ph
OEt
H
Me
Ph
55
54
53
57
56
55
60
68
61
56
65
54
(CH2)8COOMe
(CH2)8COOMe
(CH2)8COOMe
(CH2)8COOMe
(CH2)9Cl
(CH2)9Cl
(CH2)9Cl
(CH2)9Cl
Entry Pd cat.
CuL (mol%)
5e : 10b
Yield of 5e/%c
4jd
1
2
3
4
5
6
7
PdCl2(CH3CN)2
Pd(PPh3)4
PdCl2
BnPdCl(PPh3)2
PdCl2(CH3CN)2
PdCl2
80 : 20
80 : 20
80 : 20
80 : 20
80 : 20
80 : 20
90 : 10
51
32
45
49
52
44
61
4kd
4ld
8
8
8
8
8
4me
4ne
Me
Ph
51
51
BnPdCl(PPh3)2
a The reaction conditions are described in the Experimental section.
b Determined by GC analysis. c Isolated yield based on dodecyne used.
4of
4pf
4qf
4rf
(CH2)8CO-tBu
(CH2)8CO-tBu
(CH2)8CO-tBu
(CH2)8CO-tBu
OEt
H
Me
Ph
57
53
61
66
Table 3 Synthesis of fluorodienes 5a
a The reaction conditions are described in the Experimental section.
b Isolated yield based on alkyne used. c It took 2 h to make 2. d It took 8
h to make 2. e It took 12 h to make 2. f It took 14 h to make 2.
Entry
Product
R1
R3
Yield/%b
1
2
5a
5b
(CH2)8COOMe
(CH2)9Cl
H
H
63(15)
65(16)
3
5c
H
62(13)
Application to the synthesis of the fluorinated analog of a natural
compound
4
5
6
5d
5e
5f
(CH2)8CO-tBu
Dec
Dec
H
H
Ph
59(14)
61(7)
30(3)
(9Z,11E)-13-Hydroxyoctadeca-9,11-dienoic acid (13-HODE,
9) is known to have interesting bioactive properties10 and its
fluorinated analogs have been attractive targets for organic
chemists.11 We attempted to synthesize the methyl ester of
9-fluoro-13-HODE (8) which has a fluorine atom on the con-
jugated double bond of 9. Methyl dec-9-ynoate (6) was allowed
to react with 1 in the presence of Et3N–5HF at 0 ЊC and the
resulting (fluoroalkenyl)iodonium salt was used for the reaction
with oct-1-en-3-one to give methyl (9E,11E)-9-fluoro-13-
oxoocta-9,11-dienoate (7) in 55% yield from 6. The desired
methyl ester of 9-fluoro-13-HODE, compound 8, was quanti-
tatively obtained from 7 by reduction of the keto function
(Scheme 2).
a The reaction conditions are described in the Experimental section.
b Isolated yield based on alkyne used. In parentheses, yield of tolylated
products.
Vinylation reaction using tributylvinyltin reagent
The cross-coupling reaction of (E)-(2-fluorododec-1-enyl)(p-
tolyl)iodonium fluoride with tributylvinyltin was carried out as
reported6 and the desired (E)-4-fluorotetradeca-1,3-diene (5e)
was obtained in 51% yield based on the dodec-1-yne (Entry 1 in
Table 2). As a by-product, p-vinyltoluene (p-methylstyrene) 10,
formed by the reaction of tributylvinyltin with the tolyl group
on 2, was obtained in 10% yield. As the formation of no identi-
fiable by-products was reported for the reaction of the tributyl-
vinyltin with alkenyl(phenyl)iodonium salts,6 the cis-substituted
alkyl group to iodine12 or a strongly electronegative fluorine
substituent in 2 retarded the oxidative addition of the pal-
ladium catalyst to the iodine–alkenyl bond3d–g,13 and the selec-
tive formation of the dienyl product 5e was disturbed. Various
kinds of Pd catalysts with or without CuI were used in an
attempt to improve the result, but the formation of 10 could not
be suppressed. The best result was obtained when Bn(PPh3)2-
PdCl was used without CuI and 5e was obtained in 61% yield
based on dodec-1-yne, with 7% of 10. Various (fluoroalkenyl)-
iodonium salts 2 were used for the cross-coupling reaction with
the vinyltin reagent and the corresponding fluoroalkadienes
(5a–e) could be obtained in 59–65% yields with high stereo-
selectivity (Table 3). The reaction proceeded at room temper-
ature and the various functional groups remained unchanged
under the given reaction conditions (Entries 1, 2, 4, Table 3).
However, the application of 2 to the cross-coupling reaction
with tributyl(β-styryl)tin resulted in a poor yield of 5f (Entry 6).
Conclusions
(E,E)-δ-Fluoro-α,β,γ,δ-unsaturated carbonyl compounds 4
and (E)-4-fluoro-1,3-dienes 5, were stereoselectively obtained
Scheme 2 Pen = C5H11-n.
2284
J. Chem. Soc., Perkin Trans. 1, 2001, 2283–2288

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using the Heck-type reaction or cross-coupling reaction with
(2-fluoroalk-1-enyl)iodonium salts 2 obtained from the corres-
ponding alk-1-ynes and 1. The reaction proceeded at room
temperature and many functional groups in the substrate could
tolerate the reaction conditions. Consequently, various kinds
of fluoroalkadienes having functional groups could be syn-
thesized, and the reaction was used for the synthesis of a
fluorinated analog of a natural compound. Further studies on
the stereoselective synthesis of fluorinated alkenes using 2 are
currently under investigation.
used as the carbonyl compound, 6 equivalents of NaHCO3 to
the alk-1-yne were necessary.
Ethyl (2E,4E )-5-fluorotrideca-2,4-dienoate 4a. Rf 0.60
(hexane–diethyl ether 10 : 1); δH(CDCl3) 0.88 (3H, t, J 7.1 Hz),
1.28–1.33 (13H, m), 1.53–1.61 (2H, m), 2.48 (2H, dt, J 7.6,
3JH–F 20.4 Hz), 4.21 (2H, q, J 7.1 Hz), 5.84 (1H, d, J 14.9 Hz),
3
5.86 (1H, dd, J 11.9, JH–F(olefin) 18.3 Hz), 7.31 (1H, dd, J 11.9,
3
3
14.9 Hz); δF(CDCl3) Ϫ87.95 (1F, dt, JH–F(olefin) 18.3, JH–F 20.4
2
Hz); δC(CDCl3) 14.09, 14.32, 22.63, 26.33, 28.83 (d, JC-F 25.9
Hz), 28.94, 29.12, 29.24, 31.80, 60.31, 107.06 (d, 2JC-F 28.9 Hz),
120.10 (d, 4JC-F 9.9 Hz), 138.48 (d, 3JC-F 14.1 Hz), 166.94, 169.50
(d, 1JC-F 266.0 Hz); ν(neat)/cmϪ1 1718 [Calc. for C15H25FO2 (M):
256.1832. Found: Mϩ, 256.1853] (Calc. for C15H25FO2: C,
70.28; H, 9.83; F, 7.41. Found: C, 70.37; H, 9.79; F, 7.71%).
Experimental
General
The IR spectra were recorded using a JASCO FT/IR-410. The
1H-NMR (400 MHz) and 19F-NMR (376 MHz) spectra were
recorded in CDCl3 on a JEOL JNM-A400II FT NMR and the
chemical shifts, δ, are referred to TMS (1H) and CFCl3 (19F),
respectively. The EI low- and high-resolution mass spectra
were measured on a JEOL JMS-700TZ, JMS-FABmate or
JMS-HX110. The elemental microanalyses were done using a
Yanagimoto CHN Corder MT-5. For column chromatography,
Merck silica gel 7734 was used, and for analytical thin-layer
chromatography, Merck silica gel 5715 was used. Et3N–5HF
was prepared by the addition of freshly distilled Et3N to
anhydrous HF at 0 ЊC. Dec-1-yne, dodec-1-yne, undec-10-ynoic
acid, undec-10-yn-1-ol, PdCl2, PdCl2(CH3CN)2, Pd(PPh3)4 and
Pd(OAc)2 were purchased from Tokyo Kasei Co., Ltd., and used
without further purification. 11-Chloroundec-1-yne and methyl
dec-9-ynoate were prepared from undec-10-yn-1-ol and dec-9-
enoic acid, respectively. 3-Cyclohexylprop-1-yne,14 tributylvinyl-
tin15 and tributyl[(E)-β-styryl]tin16 were prepared according
to the literature. 2,2-Dimethyltridec-12-yn-3-one was prepared
from undec-10-yn-1-ol by the PCC oxidation reaction with
tBuMgBr, and the PCC oxidation sequences.
(2E,4E )-5-Fluorotrideca-2,4-dienal 4b. Rf 0.38 (hexane–
diethyl ether 5 : 1); δH(CDCl3) 0.88 (3H, t, J 7.4 Hz), 1.32–
1.34 (10H, m), 1.58–1.65 (2H, m), 2.50 (2H, dt, J 7.3, 3JH–F 23.4
3
Hz), 6.01 (1H, dd, J 11.9, JH–F(olefin) 18.0 Hz), 6.14 (1H, dd,
J 7.8, 15.1 Hz), 7.16 (1H, dd, J 11.9, 15.1 Hz), 9.55 (1H, d,
J 7.8 Hz); δF(CDCl3) Ϫ82.58 (1F, dt, 3JH–F 18.0, 3JH–F(olefin) 23.4
2
Hz); δC(CDCl3) 14.02, 22.57, 26.21, 28.90, 28.93 (d, JC-F 24.7
2
Hz), 29.05, 29.15, 31.73, 107.68 (d, JC-F 29.7 Hz), 130.96 (d,
3
1
4JC-F 9.9 Hz), 145.99 (d, JC-F 14.0 Hz), 170.63 (d, JC-F 270.9
Hz), 192.85; ν(neat)/cmϪ1 1689 [Calc. for C13H21FO (M):
212.1576. Found: Mϩ, 212.1585].
(3E,5E )-6-Fluorotetradeca-3,5-dien-2-one 4c. Rf 0.36
(hexane–diethyl ether 5 : 1); δH(CDCl3) 0.88 (3H, t, J 7.1 Hz),
1.27–1.30 (10H, m), 1.55–1.60 (2H, m), 2.26 (3H, s), 2.47 (2H,
3
3
dt, J 7.6, JH-F 23.7 Hz), 5.87 (1H, dd, J 11.7, JH-F(olefin)
18.5 Hz), 6.16 (1H, d, J 15.3 Hz), 7.19 (1H, dd, J 11.7,
3
3
15.3 Hz); δF(CDCl3) Ϫ85.62 (1F, dt, JH-F(olefin) 18.5, JH-F
23.7 Hz); δC(CDCl3) 14.06, 22.61, 26.28, 28.09, 28.89 (d, JC-F
2
2
25.6 Hz), 28.91, 29.09, 29.21, 31.78, 107.43 (d, JC-F 28.9 Hz),
4
3
128.93 (d, JC-F 10.7 Hz), 136.93 (d, JC-F 13.2 Hz), 170.18 (d,
1JC-F 267.6 Hz), 197.59; ν(neat)/cmϪ1 1653 [Calc. for C14H23FO
(M): 226.1733. Found: Mϩ, 226.1736].
Preparation of p-iodotoluene difluoride 1
p-Iodotoluene difluoride was prepared from iodotoluene by an
electrochemical method in a divided cell made of Teflon PFA
(25 mL × 2) with a Nafion 117 cation-exchange membrane.
Each cell was equipped with a smooth platinum electrode (20
mm × 20 mm) and a magnetic stirrer bar. Et3N–5HF (22 mL)
was introduced into both cells, and p-iodotoluene (654 mg, 3
mmol) was added to the anodic cell. By passing 2 F molϪ1 of
electricity at a constant current (50 mA hϪ1) and room temper-
ature, iodotoluene could be completely converted to 1. The
resulting Et3N–5HF solution of 1 was used for the further
reactions.
(2E,4E )-5-Fluoro-1-phenyltrideca-2,4-dien-1-one 4d. Rf 0.56
(hexane–diethyl ether 5 : 1); δH(CDCl3) 0.88 (3H, t, J 7.1 Hz),
1.27–1.31 (10H, m), 1.56–1.63 (2H, m), 2.52 (2H, dt, J 7.6, 3JH-F
23.7 Hz), 6.02 (1H, dd, J 12.2, 3JH-F(olefin) 18.3 Hz), 6.99 (1H, d,
J 14.9 Hz), 7.46–7.58 (4H, m), 7.96 (2H, d, J 7.1 Hz); δF(CDCl3)
Ϫ85.22 (1F, dt, 3JH-F(olefin) 18.3, 3JH-F 23.7 Hz); δC(CDCl3) 14.06,
22.61, 26.40, 28.96, 29.00 (d, 2JC-F 24.3 Hz), 29.10, 29.23, 31.77,
107.91 (d, 2JC-F 28.9 Hz), 124.01 (d, 4JC-F 10.7 Hz), 128.31 (2C),
128.57 (2C), 132.71, 138.05, 138.73 (d, 3JC-F 13.3 Hz), 171.01 (d,
1JC-F 268.5 Hz), 189.75; ν(neat)/cmϪ1 1675 [Calc. for C19H25FO
(M): 288.1883. Found: Mϩ, 288.1916] (Calc. for C19H25FO: C,
79.13; H, 8.74; F, 6.59. Found: C, 79.04; H, 8.90; F, 6.58%).
General procedure for (E,E )-ꢁ-fluoro-ꢂ,ꢀ,ꢃ,ꢁ-unsaturated
carbonyl compounds 4 and 7
To a CH2Cl2 solution (6 mL) of an alk-1-yne (2 mmol) was
added, at 0 ЊC, an Et3N–5HF solution (22 mL) of p-
iodotoluene difluoride prepared from p-iodotoluene (654 mg,
3 mmol). After stirring at 0 ЊC for 2–14 h, the reaction mixture
was poured into water and the separated aqueous phase was
extracted with CH2Cl2. The combined organic phase was dried
over MgSO4 and concentrated under reduced pressure. The
remaining viscous yellow oil was washed with hexane (10 mL)
and the hexane layer was removed by decantation. The residue
was dissolved in DMF (10 mL), and NaHCO3 (504 mg, 6
mmol), Pd(OAc)2 (31 mg, 0.14 mmol), and an α,β-unsaturated
carbonyl compound (5 mmol) were added. The reaction mix-
ture was stirred at room temperature for 2 h and saturated aq.
NH4Cl was added. After extraction with diethyl ether, the
organic phase was dried over MgSO4 and concentrated under
reduced pressure. The product 4 was isolated by column chrom-
atography (silica gel/hexane–diethyl ether). When acrolein was
1-Ethyl 14-methyl (2E,4E )-5-fluorotetradeca-2,4-dienedioate
4e. Rf 0.47 (hexane–diethyl ether 2 : 1); δH(CDCl3) 1.27–1.31
(11H, m), 1.53–1.64 (4H, m), 2.30 (2H, t, J 7.6 Hz), 2.45 (2H,
dt, J 7.6, 3JH-F 23.4 Hz), 3.67 (3H, s), 4.21 (2H, q, J 7.1 Hz), 5.85
(1H, d, J 14.9 Hz), 5.87 (1H, dd, J 12.2, 3JH-F(olefin) 18.5 Hz), 7.31
(1H, dd, J 12.2, 14.9 Hz); δF(CDCl3) Ϫ88.03 (1F, dt, 3JH-F(olefin)
3
18.5, JH-F 23.4Hz); δC(CDCl3) 14.29, 24.87, 26.26, 28.78 (d,
2JC-F 25.6 Hz), 28.81, 29.03 (2C), 29.05, 34.05, 51.43, 60.28,
2
4
107.07 (d, JC-F 28.9 Hz), 120.12 (d, JC-F 9.9 Hz), 138.40 (d,
3JC-F 14.1 Hz), 166.89, 172.47 (d, JC-F 266.0 Hz), 174.26;
1
ν(neat)/cmϪ1 1739, 1716 [Calc. for C17H27FO4 (M): 314.1886.
Found: Mϩ, 314.1915] (Calc. for C17H27FO4: C, 64.94; H, 8.66.
Found: C, 64.97, H, 8.75%).
Methyl (10E,12E )-10-fluoro-13-formyltindeca-10,12- dienoate
4f. Rf 0.53 (hexane–diethyl ether 1 : 1); δH(CDCl3) 1.26–1.38
(8H, m), 1.60–1.63 (4H, m), 2.30 (2H, t, J 7.6 Hz), 2.49 (2H, dt,
J. Chem. Soc., Perkin Trans. 1, 2001, 2283–2288
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2
4
J 7.3, 3JH-F 23.4 Hz), 3.67 (3H, s), 6.01 (1H, dd, J 11.7, 3JH-F(olefin)
18.1 Hz), 6.15 (1H, dd, J 7.8, 15.1 Hz), 7.15 (1H, dd, J 11.7,
15.1 Hz), 9.56 (1H, d, J 7.8 Hz); δF(CDCl3) Ϫ82.68 (1F, dt,
107.44 (d, JC-F 28.9 Hz), 128.90 (d, JC-F 9.9 Hz), 136.82
3 1
(d, JC-F 14.0 Hz), 170.08 (d, JC-F 267.6 Hz), 197.54; ν(neat)/
cmϪ1 1652 [Calc. for C15H24ClFO (M): 274.1500. Found: Mϩ,
274.1523].
3
3JH-F(olefin) 18.1, JH-F 23.4 Hz); δC(CDCl3) 24.82, 26.19, 28.83,
28.94 (d, 2JC-F 24.7 Hz), 29.00 (3C), 34.00, 51.45, 107.73 (d, 2JC-F
4
3
28.9 Hz), 131.01 (d, JC-F 9.8 Hz), 145.97 (d, JC-F 14.9 Hz),
(2E,4E )-14-Chloro-5-fluoro-1-phenyltetradeca-2,4-dien-1-one
4l. Rf 0.62 (hexane–AcOEt 5 : 1); δH(CDCl3) 1.30–1.42 (10H,
m), 1.54–1.62 (2H, m), 1.73–1.80 (2H, m), 2.52 (2H, dt, J 7.6,
3JH-F 23.4 Hz), 3.52 (2H, t, J 6.6 Hz), 6.02 (1H, dd, J 11.9,
3JH-F(olefin) 18.3 Hz), 6.99 (1H, d, J 14.9 Hz), 7.46–7.59 (4H, m),
170.53 (d, JC-F 270.9 Hz), 174.21, 192.89; ν(neat)/cmϪ1
1
1738, 1686 [Calc. for C15H23FO3 (M): 270.1631. Found: Mϩ,
270.1636].
3
Methyl (10E,12E )-10-fluoro-14-oxopentadeca-10,12-dienoate
4g. Rf 0.51 (hexane–diethyl ether 1 : 1); δH(CDCl3) 1.26–1.37
(8H, m), 1.54–1.64 (4H, m), 2.26 (3H, s), 2.30 (2H, t, J 7.3 Hz),
7.96 (2H, d, J 7.3 Hz); δF(CDCl3) Ϫ85.36 (1F, dt, JH-F(olefin)
18.3, 3JH-F 23.4 Hz); δC(CDCl3) 26.33, 26.81, 28.76, 28.85, 28.95
2
2
(d, JC-F 24.4 Hz), 29.12, 29.23, 32.58, 45.12, 107.96 (d, JC-F
3
4
2.47 (2H, dt, J 7.6, JH-F 23.4 Hz), 3.67 (3H, s), 5.87 (1H, dd,
28.9 Hz), 124.02 (d, JC-F 10.7 Hz), 128.30 (2C), 128.57 (2C),
J 11.9, 3JH-F(olefin) 18.5 Hz), 6.17 (1H, d, J 15.4 Hz), 7.18 (1H, dd,
J 11.9, 15.4 Hz); δF(CDCl3) Ϫ85.71 (1F, dt, 3JH-F(olefin) 18.5, 3JH-F
132.72, 138.01, 138.64 (d, 3JC-F 14.1 Hz), 170.89 (d, 1JC-F 268.5
Hz), 189.69; ν(neat)/cmϪ1 1666 [Calc. for C20H26ClFO (M):
336.1656. Found: Mϩ, 336.1676] (Calc. for C20H26ClFO: C,
71.31; H, 7.78; Cl, 10.52; F, 5.64. Found: C, 71.31; H, 7.89; Cl,
10.46; F, 5.62%).
2
23.4 Hz); δC(CDCl3) 24.84, 26.22, 28.11, 28.81, 28.86 (d, JC-F
2
28.1 Hz), 29.00 (3C), 34.01, 51.41, 107.44 (d, JC-F 28.9 Hz),
4
3
128.93 (d, JC-F 9.9 Hz), 136.84 (d, JC-F 14.1 Hz), 170.06 (d,
1JC-F 268.5 Hz), 174.21, 197.55; ν(neat)/cmϪ1 1738, 1654 [Calc.
for C16H25FO3 (M): 284.1788. Found: Mϩ, 284.1809].
(3E,5E )-7-Cyclohexyl-6-fluorohepta-3,5-dien-2-one 4m. Rf
0.31 (hexane–diethyl ether 5 : 1); δH(CDCl3) 0.93–1.02 (2H, m),
1.10–1.31 (3H, m), 1.60–1.75 (6H, m), 2.26 (3H, s), 2.34 (2H,
dd, J 7.1, JH-F 24.6 Hz), 5.92 (1H, dd, J 11.9, JH-F(olefin) 18.5
Hz), 6.16 (1H, d, J 15.4 Hz), 7.16 (1H, dd, J 11.9, 15.4 Hz);
Methyl
(10E,12E )-13-benzoyl-10-fluorotrideca-10,12-dien-
oate 4h. Rf 0.49 (hexane–diethyl ether 1 : 1); δH(CDCl3) 1.26–
1.37 (8H, m), 1.58–1.61 (4H, m), 2.30 (2H, t, J 7.6 Hz), 2.52
(2H, dt, J 7.6, 3JH-F 23.4 Hz), 3.66 (3H, s), 6.02 (1H, dd, J 11.9,
3JH-F(olefin) 18.3 Hz), 6.99 (1H, d, J 14.9 Hz), 7.46–7.58 (4H, m),
3
3
3
3
δF(CDCl3) Ϫ82.88 (1F, dt, JH-F(olefin) 18.5, JH-F 24.6 Hz);
δC(CDCl3) 26.03 (2C), 26.11, 28.11, 32.89 (2C), 35.54, 36.59 (d,
2JC-F 24.8 Hz), 108.40 (d, 2JC-F 28.9 Hz), 128.91 (d, 4JC-F 9.8 Hz),
3
7.96 (2H, d, J 7.3 Hz); δF(CDCl3) Ϫ85.34 (1F, dt, JH-F(olefin)
3
18.3, JH-F 23.4 Hz); δC(CDCl3) 24.87, 26.33, 28.84, 28.96 (d,
3
1
137.10 (d, JC-F 13.3 Hz), 169.19 (d, JC-F 267.7 Hz), 197.54;
ν(neat)/cmϪ1 1651 [Calc. for C13H19FO (M): 210.1420. Found:
Mϩ, 210.1409].
2
2JC-F 24.0 Hz), 29.01 (2C), 29.04, 34.03, 51.41, 107.94 (d, JC-F
4
28.1 Hz), 124.03 (d, JC-F 10.7 Hz), 128.30 (2C), 128.56
3
1
(2C), 132.71, 138.01, 138.64 (d, JC-F 14.1 Hz), 170.88 (d, JC-F
268.5 Hz), 174.24, 189.70; ν(neat)/cmϪ1 1736, 1675 [Calc. for
C21H27FO3 (M): 346.1937. Found: Mϩ, 346.1966] (Calc. for
C21H27FO3: C, 72.81; H, 7.86; F, 5.48. Found: C, 72.75; H, 7.96;
F, 5.48%).
(2E,4E )-6-Cyclohexyl-5-fluoro-1-phenyl-2,4-hexadien-1-one
4n. Rf 0.51 (hexane–AcOEt 5 : 1); δH(CDCl3) 0.95–1.04 (2H, m),
1.10–1.30 (3H, m), 1.63–1.76 (6H, m), 2.40 (2H, dd, J 7.1, 3JH-F
24.9 Hz), 6.07 (1H, dd, J 11.9, 3JH-F(olefin) 18.5 Hz), 6.98 (1H, d,
J 14.9 Hz), 7.46–7.58 (4H, m), 7.96 (2H, d, J 7.1 Hz); δF(CDCl3)
Ϫ82.47 (1F, dt, 3JH-F(olefin) 18.5, 3JH-F 24.9 Hz); δC(CDCl3) 26.08
Ethyl (2E,4E )-14-chloro-5-fluorotetradeca-2,4-dienoate 4i. Rf
0.36 (hexane–diethyl ether 10 : 1); δH(CDCl3) 1.28–1.43 (13H,
m), 1.54–1.60 (2H, m), 1.73–1.80 (2H, m), 2.46 (2H, dt, J 7.6,
3JH-F 23.4 Hz), 3.53 (2H, t, J 6.8 Hz), 4.21 (2H, q, J 7.1 Hz), 5.85
(1H, d, J 14.9 Hz), 5.87 (1H, dd, J 12.2, 3JH-F(olefin) 18.5 Hz), 7.31
(1H, dd, J 12.2, 14.9 Hz); δF(CDCl3) Ϫ88.04 (1F, dt, 3JH-F(olefin)
2
(2C), 26.15, 32.92 (2C), 35.67, 36.68 (d, JC-F 24.8 Hz), 108.94
(d, 2JC-F 28.1 Hz), 124.04 (d, 4JC-F 10.7 Hz), 128.35 (2C), 128.59
3
1
(2C), 132.73, 138.08, 138.95 (d, JC-F 13.3 Hz), 170.06 (d, JC-F
268.5 Hz), 189.75; ν(neat)/cmϪ1 1666 [Calc. for C18H21FO (M):
272.1571. Found: Mϩ, 272.1577].
3
18.5, JH-F 23.4 Hz); δC(CDCl3) 14.29, 26.25, 26.81, 28.76 (d,
2JC-F 25.6 Hz), 28.76, 28.81, 29.12, 29.23, 32.58, 45.11, 60.27,
2
4
Ethyl (2E,4E )-5-fluoro-15,15-dimethyl-14-oxohexadeca-2,4-
dienoate 4o. Rf 0.38 (hexane–diethyl ether 5 : 1); δH(CDCl3) 1.13
(9H, s), 1.28–1.31 (11H, m), 1.50–1.58 (4H, m), 2.40–2.50 (4H,
m), 4.20 (2H, q, J 7.3 Hz), 5.85 (1H, d, J 15.1 Hz), 5.86 (1H, dd,
J 11.9, JH-F(olefin) 18.3 Hz), 7.31 (1H, dd, J 11.9, 15.1 Hz);
δF(CDCl3) Ϫ87.97 (1F, dt, JH-F(olefin) 18.3, JH-F 23.3 Hz);
107.07 (d, JC-F 29.7 Hz), 120.11 (d, JC-F 9.8 Hz), 138.40 (d,
3JC-F 14.1 Hz), 166.88, 169.36 (d, JC-F 266.0 Hz); ν(neat)/cmϪ1
1
1716 [Calc. for C16H26ClFO2 (M): 304.1599. Found: Mϩ,
304.1622].
3
3
3
(2E,4E )-14-Chloro-5-fluorotetradeca-2,4-dienal 4j. Rf 0.27
(hexane–diethyl ether 5 : 1); δH(CDCl3) 1.31–1.44 (10H, m),
1.58–1.64 (2H, m), 1.73–1.80 (2H, m), 2.52 (2H, dt, J 7.5, 3JH-F
22.9 Hz), 3.53 (2H, t, J 11.2 Hz), 6.02 (1H, dd, J 12.0, 3JH-F(olefin)
18.2 Hz), 6.15 (1H, dd, J 7.8, 15.3 Hz), 7.15 (1H, dd, J 12.0,
15.3 Hz), 9.56 (1H, d, J 8.1 Hz); δF(CDCl3) Ϫ85.69 (1F, dt,
2
δC(CDCl3) 14.32, 23.89, 26.30, 26.43 (3C), 28.82 (d, JC-F 25.6
Hz), 28.89, 29.16, 29.25, 29.32, 36.41, 44.11, 60.32, 107.09 (d,
2JC-F 28.9 Hz), 120.11 (d, JC-F 10.7 Hz), 138.48 (d, JC-F 13.3
4
3
Hz), 166.96, 169.44 (d, JC-F 266.0 Hz), 216.17; ν(neat)/cmϪ1
1
1708, 1661 [Calc. for C20H33FO3 (M): 340.2405. Found: Mϩ,
340.2408] (Calc. for C20H33FO3: C, 70.55; H, 9.77. Found: C,
70.47; H, 9.70%).
3
3JH-F(olefin) 18.2, JH-F 22.9 Hz); δC(CDCl3) 26.21, 26.77, 28.76,
28.86, 28.94 (d, 2JC-F 25.6 Hz), 29.09, 29.21, 32.54, 45.10, 107.73
(d, 2JC-F 29.7 Hz), 131.00 (d, 4JC-F 9.9 Hz), 145.92 (d, 3JC-F 14.1
Hz), 170.54 (d, 1JC-F 271.0 Hz), 192.84; ν(neat)/cmϪ1 1687 [Calc.
for C14H22ClFO (M): 260.1343. Found: Mϩ, 260.1339].
(2E,4E )-5-Fluoro-15,15-dimethyl-14-oxohexadeca-2,4-dienal
4p. Rf 0.60 (hexane–diethyl ether 1 : 1); δH(CDCl3) 1.13 (9H, s),
1.30–1.33 (8H, m), 1.51–1.65 (4H, m), 2.42–2.55 (4H, m), 6.01
(1H, dd, J 11.9, JH-F(olefin) 18.1 Hz), 6.15 (1H, dd, J 7.8, 15.1
Hz), 7.17 (1H, dd, J 11.9, 15.1 Hz), 9.56 (1H, d, J 7.8 Hz);
3
(3E,5E )-15-Chloro-6-fluoropentadeca-3,5-dien-2-one 4k. Rf
0.24 (hexane–diethyl ether 5 : 1); δH(CDCl3) 1.26–1.38 (8H, m),
1.39–1.44 (2H, m), 1.55–1.60 (2H, m), 1.73–1.80 (2H, m), 2.26
(3H, s), 2.47 (2H, dt, J 7.6, 3JH-F 23.4 Hz), 3.53 (2H, t, J 6.8 Hz),
5.87 (1H, dd, J 11.9, 3JH-F(olefin) 18.5 Hz), 6.17 (1H, d, J 15.4 Hz),
7.19 (1H, dd, J 11.9, 15.4 Hz); δF(CDCl3) Ϫ82.65 (1F, dt,
3
3
δF(CDCl3) Ϫ82.64 (1F, dt, JH-F(olefin) 18.1, JH-F 24.8 Hz);
2
δC(CDCl3) 23.80, 26.20, 26.38 (3C), 28.86, 28.92 (d, JC-F 24.0
Hz), 29.04, 29.18, 29.28, 36.33, 44.06, 107.72 (d, 2JC-F 28.9 Hz),
4
3
130.99 (d, JC-F 9.9 Hz), 145.97 (d, JC-F 14.1 Hz), 170.58 (d,
1JC-F 271.0 Hz), 192.88, 216.03; ν(neat)/cmϪ1 1703, 1653 [Calc.
for C18H29FO2 (M): 296.2151. Found: Mϩ, 296.2140].
3
3JH-F(olefin) 18.5, JH-F 23.4 Hz); δC(CDCl3) 26.23, 26.78, 28.15,
28.76, 28.82, 28.85 (d, 2JC-F 25.6 Hz), 29.10, 29.21, 32.56, 45.10,
2286
J. Chem. Soc., Perkin Trans. 1, 2001, 2283–2288

View Article Online
(3E,5E )-6-Fluoro-16,16-dimethylheptadeca-3,5-diene-2,15-
dione 4q. Rf 0.58 (hexane–diethyl ether 1 : 1); δH(CDCl3) 1.13
(9H, s), 1.29–1.31 (8H, m), 1.50–1.60 (4H, m), 2.26 (3H, s),
2.42–2.51 (4H, m), 5.87 (1H, dd, J 11.9, 3JH-F(olefin) 18.5 Hz), 6.17
(1H, d, J 15.3 Hz), 7.19 (1H, dd, J 11.9, 15.3 Hz); δF(CDCl3)
Ϫ85.64 (1F, dt, 3JH-F(olefin) 18.5, 3JH-F 24.1 Hz); δC(CDCl3) 23.82,
6.26 (1H, dd, J 11.2, 16.8 Hz); δF(CDCl3) Ϫ101.05 (1F, dt,
3
3JH-F(olefin) 20.0, JH-F 23.9 Hz ); ν(neat)/cmϪ1 1740 [Calc. for
C14H23FO2 (M): 242.1683. Found: Mϩ, 242.1697].
(E )-13-Chloro-4-fluorotrideca-1,3-diene 5b. δH(CDCl3) 1.30
(8H, s), 1.40–1.44 (2H, m), 1.50–1.56 (2H, m), 1.71–1.80 (2H,
2
3
26.24, 26.38 (3C), 28.10, 28.84, 28.85 (d, JC-F 25.6 Hz), 29.08,
m), 2.34 (2H, dt, J 7.3, JH-F 23.7 Hz), 3.53 (2H, t, J 6.8 Hz),
2
29.19, 29.27, 36.34, 44.05, 107.42 (d, JC-F 28.9 Hz), 128.93
5.00 (1H, d, J 10.2 Hz), 5.14 (1H, d, J 16.6 Hz), 5.78 (1H, dd,
4
3
1
3
(d, JC-F 10.7 Hz), 136.87 (d, JC-F 13.3 Hz), 170.09 (d, JC-F
267.7 Hz), 197.56, 216.02; ν(neat)/cmϪ1 1704, 1652 [Calc. for
C19H31FO2 (M): 310.2308. Found: Mϩ, 310.2306].
J 11.2, JH-F(olefin) 19.7 Hz), 6.27 (1H, dt, J 11.2, J 16.6 Hz);
δF(CDCl3) Ϫ101.05 (1F, dt, 3JH-F(olefin) 19.7, 3JH-F 23.7 Hz) [Calc.
for C13H22ClF (M): 232.1396. Found: Mϩ, 232.1382].
(2E,4E )-5-Fluoro-15,15-dimethyl-1-phenylhexadecadiene-
1,14-dione 4r. Rf 0.62 (hexane–diethyl ether 1 : 1); δH(CDCl3)
1.13 (9H, s), 1.29–1.32 (8H, m), 1.50–1.61 (4H, m), 2.44–2.57
(E )-5-Cyclohexyl-4-fluoropenta-1,3-diene 5c. δH(CDCl3) 0.87–
0.99 (2H, m), 1.09–1.30 (3H, m), 1.54–1.75 (6H, m), 2.22 (2H,
3
dd, J 7.2, JH-F 24.4 Hz), 4.98 (1H, d, J 10.4 Hz), 5.12 (1H, d,
3
3
(4H, m), 6.02 (1H, dd, J 11.9, JH-F(olefin) 18.3 Hz), 6.99 (1H, d,
J 16.8 Hz), 5.80 (1H, dd, J 11.2, JH-F(olefin) 20.0 Hz), 6.25 (1H,
3
J 14.9 Hz), 7.46–7.59 (4H, m), 7.96 (2H, d, J 7.1 Hz); δF(CDCl3)
dt, J 11.2, 16.8 Hz); δF(CDCl3) Ϫ98.09 (1F, dt, JH-F(olefin) 20.0,
Ϫ85.31 (1F, dt, 3JH-F(olefin) 18.3, 3JH-F 23.3 Hz); δC(CDCl3) 23.89,
3JH-F 24.4 Hz); [Calc. for C11H17F (M): 168.1315. Found: Mϩ,
2
26.38, 26.42 (3C), 28.92, 29.00 (d, JC-F 25.5 Hz), 29.16, 29.24,
168.1314].
2
4
29.32, 36.40, 44.09, 107.97 (d, JC-F 28.9 Hz), 124.05 (d, JC-F
10.7 Hz), 128.34 (2C), 128.60 (2C), 132.75, 138.07, 138.71 (d,
(E )-2,2-Dimethyl-12-fluoropentadeca-12,14-dien-3-one 5d. δH-
(CDCl3) 1.13 (9H, s), 1.29 (8H, s), 1.54–1.58 (4H, m), 2.32
(2H, dt, J 7.3, JH-F 23.7 Hz), 2.46 (2H, t, J 7.3 Hz),
1
3JC-F 13.3 Hz), 170.96 (d, JC-F 268.5 Hz), 189.75, 216.09;
ν(neat)/cmϪ1 1698, 1670 [Calc. for C24H33FO2 (M): 372.2456.
Found: Mϩ, 372.2452] (Calc. for C24H33FO2: C, 77.38; H, 8.93;
F, 5.10. Found: C, 77.34; H, 8.85; F, 5.34%).
3
4.99 (1H, d, J 10.3 Hz), 5.13 (1H, d, J 16.5 Hz), 5.75 (1H, dd,
3
J 11.2, JH-F(olefin) 20.0 Hz), 6.27 (1H, dt, J 11.2, 16.5 Hz);
3
3
δF(CDCl3) Ϫ101.02 (1F, dt, JH-F(olefin) 20.0, JH-F 23.7 Hz)
ν(neat)/cmϪ1 1706 [Calc. for C17H29FO (M): 268.2204. Found:
Mϩ, 268.2185].
Methyl (9E,11E )-9-fluoro-13-oxooctadeca-9,11-dienoate 7.
δH(CDCl3) 0.90 (3H, t, J 7.1 Hz), 1.27–1.34 (10H, m), 1.54–1.66
3
(6H, m), 2.30 (2H, t, J 7.6 Hz), 2.46 (2H, dt, J 7.6, JH-F 23.4
Hz), 2.51 (2H, t, J 7.6 Hz), 3.67 (3H, s), 5.86 (1H, dd, J 11.9,
(E )-4-Fluorotetradeca-1,3-diene 5e. δH(CDCl3) 0.88 (3H, t, J
7.3 Hz), 1.26 (14H, s), 1.50–1.58 (2H, m), 2.34 (2H, dt, J 7.6,
3JH-F 23.6 Hz), 4.99 (1H, d, J 10.2 Hz), 5.13 (1H, d, J 16.8 Hz),
3JH-F(olefin) 18.5 Hz), 6.19 (1H, d, J 15.1 Hz), 7.22 (1H, dd, J 11.9,
3
3
15.1 Hz); δF(CDCl3) Ϫ86.35 (1F, dt, JH-F(olefin) 18.5, JH-F
23.4 Hz); ν(neat)/cmϪ 1739, 1691 [Calc. for C19H31FO3 (M):
326.2249. Found: Mϩ, 326.2272].
3
5.75 (1H, dd, J 11.2, JH-F(olefin) 20.0 Hz), 6.27 (1H, dt, J 11.2,
16.8 Hz); δF(CDCl3) Ϫ101.02 (1F, dt, 3JH-F(olefin) 20.0, 3JH-F 23.6
Hz) [Calc. for C14H25F (M): 212.1942. Found: Mϩ, 212.1938].
Methyl ester of 9-fluoro 13-HODE, Compound 8. To a stirred
MeOH solution (2.5 mL) of 7 (326 mg, 1 mmol) and CeCl3ؒ
7H2O (372 mg, 1 mmol) was added NaBH4 (38 mg, 1 mmol) at
room temperature. After 3 min, the reaction mixture was
poured into water (10 mL) and extracted with diethyl ether. The
organic phase was dried over MgSO4 and concentrated under
reduced pressure. The desired methyl ester 8 of 9-fluoro-13-
HODE (328 mg, quant.) was obtained without further puri-
fication, δH(CDCl3) 0.89 (3H, t, J 6.8 Hz), 1.30–1.32 (14H, m),
1.49–1.64 (5H, m), 2.30 (2H, t, J 7.6 Hz), 2.34 (2H, dt, J 7.1,
3JH-F 23.9 Hz), 3.67 (3H, s), 4.11–4.16 (1H, m), 5.61 (1H, dd,
(1E,3E )-4-Fluoro-1-phenyltetradeca-1,3-diene 5f. δH(CDCl3)
0.87 (3H, t, J 7.1 Hz), 1.26 (14H, s), 1.57–1.62 (2H, m), 2.44
3
3
(2H, dt, J 7.3, JH-F 23.4 Hz), 5.88 (1H, dd, J 11.2, JH-F(olefin)
19.7 Hz), 6.46 (1H, d, J 15.6 Hz), 6.65 (1H, dd, J 11.2, 15.6 Hz),
3
7.19–7.38 (5H, m); δF(CDCl3) Ϫ99.49 (1F, dt, JH-F(olefin) 19.7,
3JH-F 23.4 Hz) [Calc. for C20H29F, (M): 288.2320. Found: Mϩ,
288.2248].
Acknowledgements
3
J 6.8, 15.1 Hz), 5.72 (1H, dd, J 11.2, JH-F(olefin) 19.7 Hz), 6.13
This work was financially supported by the Asahi Glass
Foundation.
(1H, dd, J 11.2, 15.1 Hz); δF(CDCl3) Ϫ101.18 (1F, dt, 3JH-F(olefin)
19.7, 3JH-F 23.9 Hz) [Calc. for C19H33FO3 (M): 328.2414. Found:
Mϩ, 328.2432].
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1.30 (8H, s), 1.50–1.63 (4H, m), 2.30 (2H, t, J 7.8 Hz), 2.33 (2H,
3
dt, J 7.3, JH-F 23.9 Hz), 3.67 (3H, s), 4.99 (1H, d, J 10.2 Hz),
5.13 (1H, d, J 16.8 Hz), 5.75 (1H, dd, J 11.2, 3JH-F(olefin) 20.0 Hz),
J. Chem. Soc., Perkin Trans. 1, 2001, 2283–2288
2287

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9 The yields of the first step are about 60–80% (ref. 4) and those of
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