Synthesis of a highly fluorinated fatty acid analog

Article abstract of DOI:10.1016/S0022-1139(02)00254-3

A five-step synthesis of Z-11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,18- heptadecafluoro-octadec-8-enoic acid is reported, starting from 1,8-octanediol and 1,1,2,2,3,3,4,4.5,5,6,6,7,7,8,8-heptadecafluoro-10-iododecane. The key step is a Wittig react

Full text of DOI:10.1016/S0022-1139(02)00254-3

Journal of Fluorine Chemistry 119 (2003) 207±209
Short communication
Synthesis of a highly ¯uorinated fatty acid analog
Gerald W. Buchanan*, Rufus Smits, Elena Munteanu
Department of Chemistry, Ottawa-Carleton Chemistry Institute, Carleton University, Ottawa, Canada K1S 5B6
Received 10 September 2002; received in revised form 24 September 2002; accepted 25 September 2002
Abstract
A ®ve-stepsynthesis of Z-11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,18-heptadeca¯uoro-octadec-8-enoic acid is reported, starting
from 1,8-octanediol and 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadeca¯uoro-10-iododecane. The key step is a Wittig reaction to form the C8±C9
double bond with a Z:E isomeric ratio of 10:1. The route should be generally applicable to the synthesis of highly ¯uorinated monounsaturated
fatty acids.
# 2002 Published by Elsevier Science B.V.
Keywords: Heptadeca¯uoro-oleic acid analog
1. Introduction
in the position (i.e. C9 versus C8) of the requisite Z-carbon±
carbon double bond.
Present initiatives in this laboratory are directed towards
the synthesis of highly ¯uorinated fatty acids with at least 10
¯uorine atoms per chain for possible use in the preparation
of novel delivery agents in hyperpolarized xenon magnetic
resonance imaging (MRI). No reports of the synthesis of
highly ¯uorinated oleic acids have appeared in the literature,
despite substantial efforts devoted to the preparation of other
highly ¯uorinated unsaturated analogs. For example, the
early work of Brace [1,2] used free radical initiated addition
of per¯uoroalkyl iodides (RFI) to unsaturated esters to
generate C12 and C14 iodoesters which can be dehydroha-
logenated. Similarly, addition of RFI to terminally unsatu-
rated alkenols generates after HI elimination, a Z/E mixture
(primarily E) of isomers. More recently, it was found [3] that
addition of RFI to terminal alkynols gives good yield of
monounsaturated alcohols, in which the E-isomer again
predominates. It was found, however, that the E-isomers
can be converted ef®ciently to Z forms. An excellent review
of the scope of free radical RFI additions to functionalized
alkenes and alkynes is available [4].
2. Results and discussion
The ®rst stepin our sequence involves monotetrahydro-
pyranolation of 1,8-octanediol to produce the known 8-
(tetrahydro-2H-pyran-2yloxy)-octan-1-ol 1 in 64% yield.
We were unable to reproduce the 95% yield of this com-
pound reported previously [5]. Subsequent oxidation with
pyridinium dichromate (PDC) gives the aldehyde 2 in 95%
yield.
The highly ¯uorinated (F17) phosphonium salt 3 can be
prepared in high yield (83%) provided that a high boiling
solvent (xylene) and an inert atmosphere (argon) are
employed.
We wish to report the synthesis of Z-heptadeca¯uoro-
octadec-8-enoic acid via a procedure which employs a
Wittig reaction as its key stepand generates the Z-isomer
almost exclusively. Hence, this represents a general
approach to the preparation of oleic acids, which differ only
CF3ꢀCF2†7ÀCH2CH2ÀI
‡ ꢀC6H5†3Pxy!leneCF3ꢀCF2†7ÀCH2CH2ÀꢀC6H5†3P ‡ IÀ
Ar
For the key Wittig reaction between 2 and 3, conditons
were chosen [6,7] to optimize the proportion of Z-isomeric
ole®n 4, namely a polar aprotic solvent (THF), low reaction
temperature (0 8C) and a non-lithiated base, potassium
* Corresponding author. Tel.: ‡1-613-520-3841; fax: ‡1-613-520-3749.
E-mail address: geraldbuchanan@pigeon.carlton.ca (G.W. Buchanan).
0022-1139/02/$ ± see front matter # 2002 Published by Elsevier Science B.V.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 2 5 4 - 3

208
G.W. Buchanan et al. / Journal of Fluorine Chemistry 119 (2003) 207±209
t-butoxide. The Z:E isomer ratio was approximately 10:1 as
1
column (grade 40, 6±12 mesh) and eluted with 4:1 hexa-
ne:ethylacetate. The initial fractions contained 2 (4.7 g, 95%
yield) as a clear oil. IR 1727 cmÀ1 1H NMR 9.71 (t, J ˆ 1:7,
1H), 4.53 (m, 1H), 3.63±3.80 (m, 2H), 3.29±3.44 (m, 2H),
2.25±2.44 (m, 2H), 1.72±1.81 (m, 2H), 1.34±1.65 (m, 14H).
13C NMR 202.9, 98.9, 67.7, 67.6, 62.4, 43.9, 30.8, 29.7,
estimated from H NMR integration of the ole®nic proton
signals. The isomers were readily separable via column
chromatography and the Z-stereochemistry of the major
1
isomer was determined from a H NMR NOESY experi-
ment. The isolated yield of the Z-isomer 4 is 43%.
Removal of the tetrahydropyranyl group from 4 can be
accomplished in 99% yield using an excess of methanol in
the presence of Dowex 50 acid resin.
29.2, 26.2, 25.5, 22.0, 19, 7. Anal. calcd. for C13H26O3: C,
68.39; H 10.59. Found: C 68.17; H 10.81.
3.3. 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-Heptadecafluoro-10-
triphenylphosphonyldecyl iodide (3)
To 50 ml of dry xylene, were added 1,1,1,2,2,3,3,4,4,5,5,
6,6,7,7,8,8-heptadeca¯uoro-10-iododecane (Aldrich), 4.7 g
(0.008 mol) and triphenylphosphine 2.1 g (0.008 mol). The
mixture was re¯uxed overnight under argon. Upon cooling
to ambient temperature a white crystalline salt precipitated,
which was washed with ether and dried to give 3, 5.7 g
(83%), mp174±176 8C. 1H NMR 7.85±7.92 (m, 9H), 7.73±
7.79 (m, 6H), 4.09±4.16 (dt, J ˆ 7:6, 7.2, 2H), 2.52±2.64 (m,
2H). 13C NMR 135.7 (d, J ˆ 3:0), 133.8 (d, J ˆ 4:8), 130.9
(d, J ˆ 12:8), 118.5 (m), 117.2 (m), 116.8 (d, J ˆ 87:3),
115.6 (m), 113.5 (m), 110.9 (m), 110.6 (m), 110.3 (m), 107.9
(m), 24.6 (t, J ˆ 22:3), 16.3 (d, J ˆ 56:0).
Finally mild oxidation of the alcohol 5 can be done
successfully using PDC to give the target Z-heptadeca-
¯uoro-octadec-8-enoic acid 6 in good yield.
3.4. Z-1-(Tetrahydro-2H-pyran-2-yloxy)-11,11,12,12,13,
13,14,14,15,15,16,16,17,17,18,18,18-heptadecafluoro-
octadec-8-ene (4)
3. Experimental
To 50 ml of dry THF was added 3 (4.7 g, 0.0056 mol) and
10 ml of potassium t-butoxide (0.06 mol) in THF solution
under argon at 0 8C. The resulting orange solution was
stirred for 30 min after which time 2 (1.4 g, 0.006 mol) in
10 ml of dry THF was added dropwise with stirring and the
cooling bath was removed. After 18 h of stirring, the reac-
tion mixture was poured into 100 ml of brine and extracted
with ether. The combined ether extracts were dried over
magnesium sulfate and the solvent was removed under
reduced pressure. The resulting crude product mixture
was stirred with 50 ml of hexane and ®ltered to remove
the solid triphenylphosphine oxide. Removal of the hexane
by roto-evaporation yielded 3.2 g of crude ole®n as a dark
red oil. Column chromatography on silica gel with 5% ethyl
acetate 95% hexane was carried out. The fraction having an
Rf value of 8.3 in 4:1 hexane:ethylacetate on TLC was
3.1. General
Melting points are uncorrected. NMR spectra were
recorded in CDCl3 unless otherwise noted with tetramethyl-
silane as internal standard for both H (400 MHz) and 13C
(100 MHz) spectra. All reagents and solvents were com-
mercial grade (Aldrich) and puri®ed according to estab-
lished convention. Elemental analyses were performed by
Guelph Analytical Laboratories.
1
3.2. 8-(Tetrahydro-2H-pyran-2-yloxy)-octanal (2)
To a solution of 1, 5.0 g (0.02 mol) in 40 ml of dichlor-
omethane, was added pyridinium dichromate (PDC), 12.8 g
(0.03 mol) at room temperature with stirring. The suspen-
sion was stirred for 20 h after which extraction with ether
(3 Â 40 ml) was performed. The ether was removed by roto-
evaporation and the resulting oil was applied to a silica gel
1
collected, yielding 4 (1.6 g, 43%) as a light orange oil. H
NMR 5.72±5.78 (m, 1H), 5.37±5.44 (m, 1H), 4.56±4.58 (m,
1H), 3.85±3.89 (m, 1H), 3.70±3.76 (m, 1H), 3.40±3.52 (m,

G.W. Buchanan et al. / Journal of Fluorine Chemistry 119 (2003) 207±209
209
1H), 3.35±3.39 (m, 1H), 2.84 (dt, J ˆ 7:4, 18.8, 2H), 2.02±
2.21 (m, 2H), 1.78±1.86 (m, 1H), 1.68±1.74 (m, 1H), 1.45±
1.60 (m, 6H), 1.23±1.44 (m, 8H). 13C NMR 137.3, 118.6
(m), 117.6 (m), 116.9 (m), 115.7 (m), 115.5 (m), 115.4,
115.3 (m), 110.1 (m), 110.0 (m), 98.9, 67.7, 62.4, 30.8, 29.8,
29.4, 29.2, 29.1, 27.4, 26.2, 26.1, 25.6, 19.8. Anal. calcd. for
C23H27F17O2: C 41.96; H 4.13; F 49.05. Found: C 42.02; H
4.33; F 49.22.
mixture was poured into 100 ml of water and extracted with
ether. The ether extracts were dried over magnesium sulfate
and the solvent removed in vacuo to give a white solid which
was recrystallized from acetone to give 6 (0.16 g, 79%), mp
37±39 8C. 1H NMR 5.79±5.86 (m, 1H), 5.43±5.48 (m, 1H),
3.01±3.12 (dt, J ˆ 7:7, 19.3, 2H), 2.12±2.17 (m, 2H), 1.36±
1.66 (m, 10H). 13C NMR 174.6, 137.9, 122.1 (m), 121.3 (m),
119.3 (m), 118.8 (m), 116.2, 114.6 (m), 114.3 (m), 111.7
(m), 109.0 (m), 29.8, 29.6, 29.5, 29.4, 29.3, 27.8, 25.4. Anal.
calcd. for C18H17F17O2: C 36.75, H 2.91, F 54.90. Found C
36.46, H 3.06, F 54.77.
3.5. Z-11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,
18-Heptadecafluoro-octadec-8-ene-1-ol (5)
To 4 (1.5 g, 2.3 mmol) dissolved in 10 ml of methanol, was
added 1 g of Dowex 50 (acid) resin and the mixture was
shaken for 2 h. The resin was removed by ®ltration and the
solvent removed to give 5, 1.3 g (99%) as a colorless oil
Acknowledgements
G.W. Buchanan thanks the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) for continu-
ing support via a Research Grant.
1
which solidi®ed on standing, mp32±34 8C. H NMR 5.70±
5.76 (m, 1H), 5.36±5.42 (m, 1H), 3.60±3.64 (m, 2H), 2.77±
2.88 (dt, J ˆ 7:1, 18.4, 2H), 2.00±2.05 (m, 2H), 1.92 (s, 1H),
153±1.60 (m, 2H), 1.27±1.35 (m, 8H). 13C NMR 137.4, 121.7
(m), 120.4 (m), 118.4 (m), 117.8 (m), 115.7, 115.6 (m), 114.1
(m), 111.4 (m), 108.7 (m) 63.1, 32.9, 29.6 (t, J ˆ 22:6), 29.5,
29.4, 29.3, 27.6, 25.9. Anal. calcd. for C18H19F17O: C 37.64;
H 3.34; F 56.23. Found: C 37.44; H 3.60; F 56.51.
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