Synthesis of fluorinated amphiphiles by the reaction of protected hydroxy carbaldehyde with perfluorinated organomagnesium compounds

Article abstract of DOI:10.1016/S0022-1139(01)00544-9

Fluorinated amphiphilic compounds with enhanced chemical stability were synthesized by the reaction of 5-(2,2,5-trimethyl-1,3-dioxane)carbaldehyde (1) with perfluoroalkylmagnesium bromides (2), followed by deprotection. The key aldehyde 1 was prepared by

Full text of DOI:10.1016/S0022-1139(01)00544-9

Journal of Fluorine Chemistry 113 (2002) 195–200
Synthesis of fluorinated amphiphiles by the reaction of protected hydroxy
carbaldehyde with perfluorinated organomagnesium compounds
*
Jaroslav Kv ´ı cala , Jean-Christophe Mouyrin, Oldrich Paleta
Department of Organic Chemistry, Institute of Chemical Technology, Technick a´ 5, 166 28 Prague 6, Czech Republic
Received 24 August 2001; accepted 27 September 2001
Abstract
Fluorinated amphiphilic compounds with enhanced chemical stability were synthesized by the reaction of 5-(2,2,5-trimethyl-1,
-dioxane)carbaldehyde (1) with perfluoroalkylmagnesium bromides (2), followed by deprotection. The key aldehyde 1 was prepared by
3
Swern oxidation of 5-(2,2,5-trimethyl-1,3-dioxane)methanol (3). # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluorophilic; Amphiphilic; Polyfluorinated polyol; Grignard reaction; Perfluoroalkylmagnesium iodide; Polyfluoroorganometallic; Nucleophilic
addition
1
. Introduction
secondly, the possibility of HF elimination in the –CH2–
CF grouping has been reduced by making the hydrogen in
2
Amphiphilic compounds possessing a perfluoroalkyl moi-
the vicinal position to the perfluorinated chain less acces-
sible by steric hindrance.
ety display, among other properties, high surface activity.
They can generally be applied as surfactants. Fluorinated
surfactants are significantly more surface active than their
hydrocarbon analogs and display higher tendency to self-
assembly, thus forming stable supramolecular assemblies
such as vesicles, tubules, etc. [1]. Fluorosurfactants gener-
ally do not extract membrane proteins [2]. Those with good
hemocompatibility and low toxicity can be applied for
various medical uses, e.g. oxygen carriers, intravenous
transport of drugs and oxygen transporting gels for surgery
In this paper, amphiphilic compounds with a perfluori-
nated hydrophobic part were constructed by the coupling of
perfluoroalkylated organomagnesiums with a protected
dihydroxyaldehyde. Fluorinated organometallic compounds
are of lower stability than their non-fluorinated counterparts
[8], and therefore, have not found such an extensive applica-
tion in organic chemistry. Nevertheless, two general meth-
ods can be employed for the attachment of a perfluorinated
chain to substrate, viz. the addition reaction of in situ
generated perfluoroalkylzinc reagent [9], or perfluoroalkyl-
magnesium reagent [10]. As the latter method appeared to be
more convenient for our purposes, we have applied it for the
preparation of the title amphiphilic compounds.
[
1–5].
Fluorinated surfactants usually contain a non-fluorinated
spacer connecting the hydrophilic and perfluorinated
hydrophobic and fluorophilic) parts with a CH –CF -(per-
(
2
2
fluoroalkyl) grouping, from which hydrogen fluoride can
easily be eliminated [6,7]. Moreover, some fluorinated
amphiphilic compounds contain hydrolyzable moieties
2. Results and discussion
[
4], e.g. ester groups, that can also cause chemical instability
in potential in vivo applications. We hence directed our
research to the preparation of amphiphilic compounds of
higher (bio)chemical stability. We have designed the struc-
tures as follows: firstly, the reactive ester groups that com-
bine hydrophilic and hydrophobic parts were excluded;
2.1. Preparation of 5-(2,2,5-trimethyl-1,3-
dioxane)carbaldehyde (1)
5-(2,2,5-Trimethyl-1,3-dioxane)carbaldehyde (1) was
prepared in two steps from commercially available 2-
(hydroxymethyl)-2-methylpropan-1,3-diol by protection of
two hydroxy groups in the form of acetale with acetone [11],
followed by Swern oxidation with Me SO–(COCl) reagent
[12] (see Scheme 1).
*
Corresponding author. Tel.: þ42-2-2435-4242; fax: þ42-2-2435-4288.
2
2
E-mail address: kvicalaj@vscht.cz (J. Kv ´ı cala).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 1 ) 0 0 5 4 4 - 9

196
J. Kv ´ı cala et al. / Journal of Fluorine Chemistry 113 (2002) 195–200
Scheme 1.
Scheme 2.
2.2. Model reaction and optimisation of the reaction
conditions
change of the reactant ratios, transmetallations proceeded
with nearly complete conversion and the products, protected
polyfluorinated triols 7a–d, were formed in acceptable
yields (Scheme 3, Table 1).
Before starting nucleophilic additions with the protected
aldehyde 1 we optimised the reactions conditions by
carrying out the reactions with easily available phenylace-
taldehyde (4) as a model substrate. Four perfluoroalkylmag-
nesium bromides 2a–d were prepared by transmetallation
of the corresponding perfluoroalkyl iodides with ethylmag-
nesium bromide in diethyl ether at À40 to À35 8C. First
we followed the procedure according to [10] using molar
equivalents of perfluorinated alkyl iodide and EtMgBr,
short reaction time for transmetallation (procedure A) and
subsequent addition of aldehyde 4 to the reaction mixture.
Surprisingly, along with the target products, polyfluorinated
2.4. Deprotections
Among a number of methods for the removal of isopro-
pylidene protecting group, we chose reacetalisation by
refluxing methanol in the presence of a catalytic amount
of pyridinium 4-toluenesulfonate [13] (Scheme 3). In this
way, the isolation of amphiphilic polyfluorinated triols 8 by
the extraction from an aqueous medium has been avoided.
On the other hand, it has been surprising that the yields of the
deprotections substantially decreased with the length of the
perfluorinated chain, which has been a subject of our further
study.
1
-phenylalkan-2-ols 5a–d, large amounts of side 2-phenyl-
butan-2-ol (6), formed by the reaction of ethylmagnesium
bromide with the substrate 4 were obtained (Scheme 2).
We, therefore, employed a larger excess of perfluoroalkyl
iodide (up to 150%) and extended the transmetallation time
to 3 h (procedure B). As shown in Table 1, the amounts of the
side product 6 were decreased, but its formation not com-
pletely suppressed, thus indicating that the metal–halogen
exchange reactions with the perfluoroalkyl iodides have still
not been completed.
Table 1
Results of reactions of aldehydes 1, 4 with perfluoroalkylmagnesium
bromides 2
a
Aldehyde Alkyl-MgBr Procedure Product
Yield
(%)
Side
b
product (%)
4
4
4
4
4
4
1
1
1
1
2a
2a
2b
2b
2c
2d
2a
2b
2c
2d
A
B
A
B
A
B
C
C
C
C
5a
5a
5b
5b
5c
5d
7a
7b
7c
7d
31
51
44
55
58
44
48
49
72
61
46
17
33
22
21
17
2.3. Nucleophilic additions to 5-(2,2,5-trimethyl-1,3-
dioxane)carbaldehyde (1)
To improve the transmetallation in the reaction of per-
fluoroalkylmagnesium compounds 2 with protected alde-
hyde 1, we increased the excess of both starting
perfluoroalkyl iodide (200%), and ethylmagnesium bromide
a
Preparative yields.
Relative yield.
b
(
150%) relative to 1 (as procedure C, Table 1). After this

J. Kv ´ı cala et al. / Journal of Fluorine Chemistry 113 (2002) 195–200
197
Scheme 3.
3
. Conclusions
4.2. 5-(2,2,5-Trimethyl-1,3-dioxane)carbaldehyde (1)
We succeeded in the preparation of amphiphilic poly-
A solution of Me SO (5.0 ml, 75 mmol) in dichloro-
2
fluorinated triols by the reactions of protected dihydroxyal-
dehyde 1 with perfluoroalkylmagnesium bromides 2, formed
by in situ reaction of perfluoroalkyl iodides with ethylmag-
nesium bromide. Transmetallations did not proceed as
smoothly as reported [10], therefore, a higher excess of
perfluoroalkyl iodides and longer reaction time had to be
employed to avoid the side reaction of non-transmetallated
ethylmagnesium bromide with aldehyde 1. Amphiphilic
polyfluorinated triols 8 prepared display enhanced stability
against bases, since elimination of HF is suppressed due to
lower accessibility of hydrogen atoms by the base.
methane (30 ml) was slowly added to a solution of oxalyl
chloride (4.5 ml, 50 mmol) in dichloromethane (150 ml) at
À78 8C. After stirring for 15 min, the solution of 5-(2,2,5-
trimethyl-1,3-dioxane)methanol (3, 3.6 g, 22 mmol) in
dichloromethane (10 ml) was added dropwise. The mixture
was stirred for 10 min at À78 8C and 60 min at À45 8C.
Triethylamine (30 ml, 0.21 mol) was added and temperature
was left to rise slowly to 0 8C. After 20 min at 0 8C, 200 ml
of a saturated aqueous solution of NH Cl was added, the
4
organic layer was separated and the aqueous layer was
extracted twice with dichloromethane (200 ml). Combined
organic layers were dried with MgSO , solvents were eva-
4
porated and the aldehyde 3 was obtained by distillation
under nitrogen as colourless liquid (2.72 g, 76.2%,
4
. Experimental details
1
bp ¼ 60À90 8C/80–660 Pa). H NMR (CDCl ) d: 9.75 (s,
4
.1. General comments
3
2
1
H), 4.05 (d, 2H, JHH ¼ 12:0 Hz); 3.72 (d, 2H,
1
2
Temperature data were not corrected. H NMR spectra
were recorded with a Varian Gemini 300 HC spectrometer at
00.1 MHz using TMS as internal standard, 13C NMR
JHH ¼ 12:0 Hz); 1.42 (s, 3H); 1.32 (s, 3H); 0.84 (s, 3H);
1
3
C NMR (CDCl ) d: 97.6 (s); 64.6 (s); 44.8 (s); 27.4 (s);
3
3
19.1 (s); 14.3 (s); IR (CHCl ): 832 (m), 1087 (s), 1208 (s),
1718 (m), 2992 (s). Anal. Calcd. for C H O : C, 60.8; H,
3
spectra (at 100.6 MHz using TMS as internal standard)
and 19F NMR (at 376.5 MHz using CFCl3 as internal
standard with upfield values designed negative) were mea-
sured with a Bruker AM 400 spectrometer. FT-IR spectra
were recorded with a Nicolet 740 instrument in KBr. Ele-
mentary analyses were carried out by the Laboratory of
Elementary Analyses of ICT Prague.
8
14 3
8.9. Found: C, 59.8%; H, 8.5%.
4.3. Reactions of perfluoroalkylmagnesium bromides 2
with aldehydes 1 and 4
4.3.1. General procedure A
2
-(Hydroxymethyl)-2-methylpropane-1,2-diol, phenyla-
To a solution of perfluoroalkyl iodide (120%) in diethyl
ether (3 ml/mmol) cooled to À45 8C and protected from
light, ethylmagnesium bromide (120%) was added drop-
wise. The reaction mixture was stirred at À35 to À40 8C for
0.5 h. The aldehyde (100%) was dissolved in diethyl ether
(2 ml/mmol) and dropwise added to the reaction mixture at
À35 to À40 8C. The temperature of the reaction mixture was
left to rise slowly to À10 8C in 2 h. Then the reaction
cetaldehyde (4), ethyl bromide, oxalyl chloride and pyridi-
nium 4-toluenesulfonate (Aldrich) were used without further
purification. Perfluoroalkyl iodides were kindly gifted by Elf
Atochem. Ethylmagnesium bromide was prepared and its
concentration estimated according to [14]. Diethyl ether,
dichloromethane, methanol and DMSO were dried accord-
ing to [15]. Silica (60–200 mm, Merck) was used for column
chromatography. 5-(2,2,5-Trimethyl-1,3-dioxane)methanol
mixture was washed with saturated solution of NH Cl
4
(
3) was prepared according to [10] in a 64% yield.
(2 ꢀ 20 ml), and the aqueous layer was extracted twice with

198
J. Kv ´ı cala et al. / Journal of Fluorine Chemistry 113 (2002) 195–200
diethyl ether (20 ml). The combined organic layers were
dried with MgSO and solvent was evaporated. Products
were isolated by column chromatography.
3466 (w). Anal. Calcd. for C H F O: C, 38.2; H, 2.1.
14 9 13
Found: C, 38.7%; H, 2.5%.
4
4.3.6. 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluoro-1-phenyldecan-2-ol (5c)
4
.3.2. General procedure B
This procedure followed general procedure A, but larger
Reaction of phenylacetaldehyde (0.87 g, 7.4 mmol), per-
fluorooctyl iodide (4.7 g, 8.7 mmol) and EtMgBr (5.9 ml,
1.44 M, 8.5 mmol) after procedure A was carried out with a
transmetallation time increased to 1 h and afforded a 79:21
mixture of polyfluorodecanol 5c and side product 6. Pure
excess of perfluoroalkyl iodide (150%) and larger transme-
tallation time (3 h) were used.
4
.3.3. General procedure C
This procedure also followed general procedure A, but
polyfluorodecanol 5c (2.32 g, 57.9%) was obtained as crys-
1
even larger excess of perfluoroalkyl iodide (200%) and
ethylmagnesium bromide (150%) were used. Instead of
purification of the crude reaction mixture by column chro-
matography, the side product 6 was removed from the crude
reaction mixture by heating in vacuo (80 8C/200 Pa, 3 h).
tals. H NMR (CDCl ) d: 7.20–7.40 (m, 5H); 4.33 (m, 1H);
3
2
2
3.13 (d, 1H, JHH ¼ 14:3 Hz); 2.86 (dd, 1H, JHH
¼
3
3
14:3 Hz, J ¼ 10:4 Hz); 2.00 (d, 1H, J ¼ 6:6 Hz);
HH
HH
1
9
F NMR (CDCl ) d: À81.2 (t, 3F, J ¼ 10 Hz); À120.7
FF
3
2
FF
(dm, 1F, J ¼ 285 Hz); À121.9 (m, 2F); À122.3 (m, 4F);
2
À122.5 (m, 2F); À123.0 (dm, 1F, J ¼ 298 Hz); À123.4
FF
2
2
4
2
.3.4. 3,3,4,4,5,5,6,6,6-Nonafluoro-1-phenylhexan-
-ol (5a)
Reaction of phenylacetaldehyde (4, 0.28 g, 2.3 mmol),
(dm, 1F, J ¼ 298 Hz); À126.4 (dm, 1F, J ¼ 299 Hz);
2
FF
FF
FF
À126.9 (dm, 1F,
J
¼ 299 Hz); À127.2 (dm, 1F,
2
13
J
FF
¼ 285 Hz); C NMR (CDCl ) d: 135.6 (s); 129.5
3
perfluorobutyl iodide (1.4 g, 4.0 mmol) and EtMgBr
2.4 ml, 1.44 M, 3.5 mmol) after general procedure B
afforded a 83:17 mixture of polyfluorohexanol 5a and the
(s); 128.9 (s); 127.3 (s); 107–120 (m); 71.0 (dd,
2
2
(
J ¼ 28 Hz, J ¼ 24 Hz); 35.6 (s); IR (KBr) 660 (w),
F
CF
1151 (s), 1202 (s), 1230 (s), 3463 (w). Anal. Calcd. for
C H F O: C, 35.6; H, 1.7. Found: C, 35.0%; H, 1.8%.
side product 6. Pure polyfluorohexanol 5a (0.42 g, 51%) was
1
1
6 9 17
obtained as crystals. H NMR (CDCl ) d: 7.20–7.40 (m,
3
2
5
1
H); 4.33 (m, 1H); 3.13 (d, 1H, JHH ¼ 13:7 Hz); 2.89 (dd,
4.3.7. 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
Henicosafluoro-1-phenyldodecan-2-ol (5d)
Reaction of phenylacetaldehyde (4, 0.59 g, 5.1 mmol),
perfluorodecyl iodide (4.6 g, 7.1 mmol) and EtMgBr
(4.0 ml, 1.44 M, 5.8 mmol) after general procedure B
afforded a 82:18 mixture of polyfluorododecanol 5d and
2
3
19
H, J ¼ 13:7 Hz, J ¼ 10:4 Hz); 2.00 (bs, 1H);
F
HH
HH
NMR (CDCl ) d: À81.4 (t, 3F, J ¼ 10 Hz); À120.6 (dm,
3
FF
2
2
1
F,
J
¼ 285 Hz); À122.5 (dm, 1F,
J
FF
¼ 299 Hz);
FF
2
2
À123.4 (m, 1F, JFF ¼ 299 Hz); À126.0 (dm, 1F, JFF ¼
2
3
00 Hz); À127.4 (dm, 1F, JFF ¼ 300 Hz); À127.5 (dm, 1F,
2
13
JFF ¼ 285 Hz); C NMR (CDCl ) d: 135.6 (s); 129.5 (s);
side product 6. Pure polyfluorododecanol 5d was obtained
1
3
2
1
2
28.9 (s); 127.3 (s); 108–119 (m); 71.1 (dd, JCF ¼ 28Hz,
(1.44 g, 44.0%) as crystals. H NMR (CDCl ) d: 7.20–7.40
3
2
JCF ¼ 23 Hz); 35.6 (s); IR (CHCl ): 712 (m), 1136 (s),
(m, 5H); 4.33 (m, 1H); 3.13 (d, 1H, J ¼ 13:7 Hz); 2.88
HH
3
1
2
236 (s), 3473 (m). Anal. Calcd. for C H F O: C, 42.4; H,
1
(dd, 1H, 2JHH ¼ 14:1 Hz 3JHH ¼ 10:4 Hz); 2.00 (d, 1H,
2 9 9
19
3JHH ¼ 6:0 Hz); F NMR (CDCl ) d: À81.2 (t, 3F,
.7. Found: C, 42.6%; H, 3.1%.
3
2
JFF ¼ 10 Hz); À120.7 (dm, 1F, JFF ¼ 284 Hz); À121.9
4
1
.3.5. 3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-
-phenyloctan-2-ol (5b)
Reaction of phenylacetaldehyde (4, 0.31 g, 2.6 mmol),
(m, 2F); À122.2 (m, 8F); À122.4 (m, 2F); À123.2 (m, 2F);
2
13
FF
À126.6 (m, 2F); À127.2 (dm, 1F, J ¼ 284 Hz); C NMR
(CDCl ) d: 135.6 (s); 129.5 (s); 128.9 (s); 127.3 (s); 107–120
3
2
2
perfluorohexyl iodide (1.8 g, 4.0 mmol) and EtMgBr
2.0 ml, 1.44 M, 2.9 mmol) after procedure B afforded a
8:22 mixture of polyfluorooctanol 5b and side product 6.
(m); 71.1 (dd, J ¼ 27 Hz, J ¼ 24 Hz); 35.6 (s); IR
CF
CF
(
7
(KBr) 649 (w), 1151 (s), 1206 (s), 3467 (s). Anal. Calcd. for
C H F O: C, 33.8, H, 1.4, Found: C, 33.7%; H, 1.7%.
1
6 9 21
Pure polyfluorooctanol 5b (0.63 g, 55%) was obtained as
1
crystals. H NMR (CDCl ) d: 7.20–7.40 (m, 5H); 4.33 (m,
4.3.8. 2,2,3,3,4,4,5,5,5-Nonafluoro-1-[5-(2,2,5-trimethyl-
1,3-dioxane)]pentan-1-ol (7a)
Reaction of protected hydroxyaldehyde 1 (0.40 g,
2.5 mmol), perfluorobutyl iodide (1.7 g, 4.9 mmol) and
EtMgBr (1.9 ml, 1.94 M, 3.8 mmol) afforded after general
procedure C a 73:27 mixture of polyfluoropentanol 7a and
3
2
2
1
1
H); 3.13 (d, 1H, J ¼ 13:7 Hz); 2.89 (dd, 1H, J
HH
¼
HH
3
19
3:7 Hz, JHH ¼ 10:1 Hz); 2.00 (bs, 1H); F NMR (CDCl )
3
2
d: À81.3 (t, 3F, JFF ¼ 10 Hz); À120.7 (dm, 1F, JFF ¼
2
2
2
1
83 Hz); À122.0 (m, 2F); À122.2 (dm, 1F, JFF ¼
2
95 Hz); À122.9 (dm, 1F, JFF ¼ 295 Hz); À122.9 (dm,
2
2
F, JFF ¼ 295 Hz); À123.6 (dm, 1F, JFF ¼ 295 Hz);
starting aldehyde 1. Pure polyfluoropentanol 7a was
1
2
À126.2 (dm, 1F,
J
¼ 294 Hz); À127.1 (dm, 1F,
obtained (0.46 g, 48%) as a wax. H NMR (CDCl ) d:
FF
3
2
2
13
3
3
J
¼ 294 Hz); À127.2 (dm, 1F,
J
¼ 283 Hz);
C
4.65 (dd, 1H, J ¼ 25:2 Hz, J ¼ 6:6 Hz); 4.00 (dd,
4
HH
FF
FF
HF
HH
NMR (CDCl ) d: 135.7 (s); 129.5 (s); 128.8 (s); 127.3
1H, 2JHH ¼ 12:1 Hz,
J
¼ 2:7 Hz); 3.91 (dt, 1H,
3
2
2
2J ¼ 12:6 Hz, J ¼ 1:8 Hz); 3.68 (dd, 1H, J ¼ 12:1
2
(
s); 107–120 (m); 71.1 (dd, JCF ¼ 27 Hz, JCF ¼ 24 Hz);
5.6 (s); IR (CHCl ) 699 (w), 1207 (s), 1239 (s), 2922 (w),
HH
HH
4
2
3
Hz, J ¼ 2:7 Hz); 3.52 (d, 1H, J ¼ 12:1 Hz); 3.50
3
HH
HH

J. Kv ´ı cala et al. / Journal of Fluorine Chemistry 113 (2002) 195–200
199
3
(
d,1H, J ¼ 7:6Hz);1.46(s, 3H);1.40(s,3H);0.94(s,3H);
HH
(s); 27.1 (s); 20.1 (s); 14.7 (s); IR (KBr) 653 (w), 1151 (s),
1208 (s), 1375 (w), 3381 (w). Anal. Calcd. for C H F O :
C, 33.2; H, 2.6. Found: C, 32.4%; H, 2.6%.
1
9
F NMR (CDCl ) d: À81.4 (t, 3F, J ¼ 10 Hz); À116.8
3
FF
16 15 17 3
2
2
(
dm, 1F, JFF ¼ 284 Hz); À122.4 (dm, 1F, JFF ¼ 295 Hz);
2
À123.5 (dm, 1F, JFF ¼ 295 Hz); À124.3 (dm, 1F,
2
2
JFF ¼ 284 Hz); À125.6 (dtt, 1F, JFF ¼ 293 Hz, JFF ¼
4.3.11. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
Henicosafluoro-1-[5-(2,2,5-trimethyl-1,3-
dioxane)]undecan-1-ol (7d)
Reaction of aldehyde 1 (0.40 g, 2.5 mmol), perfluorode-
cyl iodide (3.25 g, 5.0 mmol) and EtMgBr (1.9 ml, 1.94 M,
3.8 mmol) afforded after general procedure C a 97:3 mixture
of polyfluoroundecanol 7d and starting aldehyde 1. Pure
polyfluoroundecanol 9d was obtained (1.03 g, 60.8%) as
2
1
5 Hz, JFF ¼ 6 Hz); À127.5 (ddt, 1F, JFF ¼ 284 Hz, JFF
1
3
¼
15 Hz, JFF ¼ 10 Hz); C NMR (CDCl ) d: 108–120 (m);
2 2
CF CF
3
9
3
1
8.7 (s); 68.1 (dd, J ¼ 26 Hz, J ¼ 21 Hz); 67.1 (s);
8.2 (s); 27.1 (s); 20.0 (s); 14.7 (s); IR (CHCl ) 1082 (m),
3
134 (s), 1204 (s), 1235 (s), 2995 (m), 3429 (m). Anal.
Calcd. for C H F O : C, 38.0; H, 4.0. Found: C, 42.0%;
1
2 15 9 3
H, 4.8%.
1
3
crystals. H NMR (CDCl ) d: 4.67 (dd, 1H, JHF ¼ 25:0 Hz,
3
3
2
4
4.3.9. 2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoro-1-[5-(2,2,5-
trimethyl-1,3-dioxane)]heptan-1-ol (7b)
Reaction of aldehyde 1 (0.30 g, 1.9 mmol), perfluoro-
hexyl iodide (1.7 g, 4.0 mmol) and EtMgBr (1.5 ml,
.94 M, 2.8 mmol) afforded after general procedure C a
0:10 mixture of polyfluoroheptanol 7b and starting alde-
JHH ¼ 5:2 Hz); 4.03 (dd, 1H, JHH ¼ 12:1 Hz, JHH ¼
2
2:2 Hz); 3.92 (dm, 1H, JHH ¼ 12:6 Hz); 3.69 (dd, 1H,
2
4
2
JHH ¼ 12:1 Hz, JHH ¼ 2:4 Hz); 3.53 (d, 1H, JHH ¼
3
11:5 Hz); 2.88 (d, 1H, J ¼ 5:0 Hz); 1.45 (s, 3H); 1.43
HH
1
9
1
9
(s, 3H); 0.97 (s, 3H); 0.90 (bs, 1H); F NMR (CDCl ) d:
3
2
À81.3 (t, 3F, J ¼ 10 Hz); À116.8 (dm, 1F, JFF ¼
FF
hyde 1. Pure polyfluoroheptanol 7b was obtained (0.45 g,
1
286 Hz); À122.0 (m, 2F); À122.3 (m, 10F); À123.2 (m,
2 2
3
4
9%) as a wax. H NMR (CDCl ) d: 4.68 (dd, 1H, JHF ¼
2F); À123.9 (dm, 1F, JFF ¼ 286 Hz); À126.6 (dm, 1F, JFF
2 13
3
3
2
2
4
5:0 Hz, JHH ¼ 6:9 Hz); 4.02 (dd, 1H, JHH ¼ 12:1 Hz,
¼ 289 Hz); À126.7 (dm, 1F, JFF ¼ 289 Hz); C NMR
2
JHH ¼ 2:7 Hz); 3.92 (dm, 1H, JHH ¼ 12:6 Hz); 3.69
(CDCl ) d: 107–119 (m); 98.8 (s); 68.5 (dd,
3
2
4
2
2
(
2
dd, 1H, JHH ¼ 12:6 Hz, JHH ¼ 2:7 Hz); 3.52 (d, 1H,
JCF ¼ 26 Hz, JCF ¼ 21 Hz); 67.1 (s); 38.2 (s); 27.1 (s);
3
JHH ¼ 12:1 Hz); 3.17 (d, 1H,
J
¼ 7:7 Hz); 1.45 (s,
9
20.1 (s); 14.8 (s); IR (KBr) 642 (w), 1154 (s), 1208 (s), 1631
(w), 3390 (w). Anal. Calcd. for C H F O : C, 31.8%; H,
2.2. Found: C, 30.8%; H, 2.2%.
HH
1
3
H); 1.40 (s, 3H); 0.96 (s, 3H); F NMR (CDCl ) d:
3
18 15 21 3
2
À81.3 (t, 3F, J ¼ 10 Hz); À116.7 (dm, 1F, JFF
¼
FF
2
2
1
82 Hz); À121.8 (dm, 1F, JFF ¼ 296 Hz); À121.8 (dm,
2
2
F, JFF ¼ 296 Hz); À122.2 (dm, 1F, JFF ¼ 296 Hz);
4.4. Deprotection of cyclic alkanols 7
to polyfluoroalkylated triols 8
2
2
À122.8 (dm, 1F, JFF ¼ 274 Hz); À123.0 (dm, 1F, JFF ¼
2
2
2
96 Hz); À123.7 (dm, 1F, JFF ¼ 274 Hz); À123.9 (dm, 1F,
2
JFF ¼ 282 Hz); À126.1 (dm, 1F, JFF ¼ 297 Hz); À127.2
4.4.1. General procedure
2
13
(
(
(
dm, 1F, J ¼ 297 Hz); C NMR (CDCl ) d: 107–122
Protected polyfluoralkanols 7 were dissolved in methanol
(10 ml) and pyridinium 4-toluenesulfonate (0.1 g) was
added. The mixture was stirred and heated to reflux for
24 h. Solvent was removed and product, polyfluoroalkylated
triol 8, was isolated by column chromatography (eluent:
dichloromethane/ethyl acetate 1/1).
FF
3
2
2
m); 98.8 (s); 68.2 (dd, J ¼ 26 Hz, J ¼ 22 Hz); 67.1
CF
CF
s); 38.2 (s); 27.1 (s); 20.0 (s); 14.7 (s); IR (KBr) 828 (w),
146 (s), 1205 (s), 1240 (s), 1380 (m), 3002 (w), 3424 (w).
Anal. Calcd. for C H F O : C, 35.1; H, 3.2. Found: C,
1
1
4 15 13 3
3
5.4%; H, 3.2%.
4
.3.10. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluoro-
-[5-(2,2,5-trimethyl-1,3-dioxane)]-nonan 1-ol (7c)
Reaction of protected hydroxyaldehyde 1 (0.50 g,
.2 mmol), perfluorooctyl iodide (3.5 g, 6.3 mmol) and
4.4.2. 4,4,5,5,6,6,7,7,7-Nonafluoro-2-(hydroxymethyl)-2-
methylheptan-1,3-diol (8a)
Reaction of polyfluoropentanol 7a (512 mg, 1.35 mmol)
1
3
afforded after general procedure polyfluoroalkanetriol 8a
1
EtMgBr (2.4 ml, 1.94 M, 4.6 mmol) afforded after general
procedure C polyfluorononanol 7c (1.25 g, 71.8%) as crys-
(353 mg, 77.0%) as a wax. H NMR (DMSO-d ) d: 5.95 (d,
6
1H, J ¼ 8:2 Hz); 4.69 (t, 1H, J ¼ 5:0 Hz); 4.60 (t, 1H, J ¼
1
3
tals. H NMR (CDCl ) d: 4.67 (d, 1H, JHF ¼ 24:7 Hz); 4.01
5:0 Hz); 4.27 (dd, 1H, J ¼ 29:7 Hz, J ¼ 8:8 Hz); 3.3–3.6
3
2
4
2
19
(
dd, 1H, JHH ¼ 12:1 Hz, JHH ¼ 2:2 Hz); 3.92 (d, 1H, JHH
(m, 4H); 0.88 (s, 3H); F NMR (DMSO-d ) d: À80.0 (t, 3F,
6
2
4
2
¼
12:6 Hz); 3.68 (dd, 1H, JHH ¼ 12:6 Hz, JHH ¼ 2:7 Hz);
JFF ¼ 10 Hz); À113.3 (dm, 1F, JFF ¼ 277 Hz); À119.5
2
3
2
2
3
1
.59 (d, 1H, JHH ¼ 12:1 Hz); 3.26 (d, 1H, JHH ¼ 6:0 Hz );
(dm, 1F, JFF ¼ 295 Hz); À122.2 (dm, 1F, JFF ¼
1
9
2
.45 (s, 3H); 1.43 (s, 3H); 0.97 (s, 3H); F NMR (CDCl ) d:
277 Hz); À122.5 (dm, 1F, JFF ¼ 295 Hz); À123.8 (dm,
3
3
2
2
2
13
À81.3 (t, 3F, J ¼ 10 Hz); À116.8 (dm, 1F, J ¼ 282
1F, JFF ¼ 291 Hz); À126.4 (dm, 1F, JFF ¼ 291 Hz);
C
FF
FF
Hz); À122.0 (m, 2F); À122.4 (m, 4F); À122.5 (m, 2F);
NMR (DMSO-d ) d: 107–122 (m); 68.0 (dd, J ¼ 26 Hz,
6
2
2
À123.0 (dm, 1F, JFF ¼ 316 Hz); À123.5 (dm, 1F, JFF ¼
J ¼ 21 Hz); 63.5 (s); 63.0 (s); 44.3 (s); 15.0 (s); IR (KBr)
726 (w), 1031 (m), 1048 (m), 1133 (s), 1238 (s), 3336 (m),
3460 (m). Anal. Calcd. for C H F O : C, 32.0, H; 3.2.
2
3
16 Hz); À126.4 (dm, 1F, JFF ¼ 286 Hz); À127.1 (dm, 1F,
2
13
JFF ¼ 286 Hz); C NMR (CDCl ) d: 105–120 (m); 98.8
3
9 11 9 3
2
2
(
s); 68.4 (dd, JCF ¼ 26 Hz, JCF ¼ 21 Hz); 67.1 (s); 38.2
Found: C, 33.6%; H, 3.8%.

200
J. Kv ´ı cala et al. / Journal of Fluorine Chemistry 113 (2002) 195–200
4
.4.3. 4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluoro-2-
hydroxymethyl)-2-methylnonane-1,3-diol (8b)
(d, 1H, J ¼ 8:2 Hz); 4.69 (broad s, 1H); 4.55 (broad s, 1H);
4.20 (dd, 1H, J ¼ 29:1 Hz, J ¼ 8:2 Hz); 3.3–3.6 (m, 4H);
(
1
9
Reaction of polyfluoroheptanol 7b (789 mg, 1.65 mmol)
afforded after general procedure fluorinated triol 8b (450 mg,
0.84 (s, 3H); F NMR (DMSO-d ) d: -81.0 (t, 3F, JFF ¼
6
2
10 Hz); À113.5 (dm, 1F, JFF ¼ 278 Hz); À119.4 (dm, 1F,
1
2
2
61.8%). H NMR (DMSO-d ) d: 5.97(d, 1H, J ¼ 8:0 Hz);
4
1
JFF ¼ 300 Hz); À120.6 (dm, 1F, JFF ¼ 303 Hz); À121.3
6
2
.69 (t, 1H, J ¼ 5:0 Hz); 4.60 (t, 1H, J ¼ 5:0 Hz); 4.27 (dd,
(dm, 1F, JFF ¼ 300 Hz); À121.6 (m, 9F); À122.6 (m, 3F);
19
2
H, J ¼ 29 Hz); 3.3–3.6 (m, 4H); 0.86 (s, 3H); F NMR
À125.9 (dm, 1F, JFF ¼ 286 Hz); À126.3 (dm, 1F,
2
13
(
2
DMSO-d ) d: À79.7 (t, 3F, J ¼ 10 Hz); À112.9 (d, 1F,
J
FF
¼ 286 Hz); C NMR (DMSO-d ) d: 107–120 (m);
6
6
2
J
¼ 271 Hz); À119.0 (d, 1F, J ¼ 297 Hz); À120.1
FF
68.3 (dd, J ¼ 24 Hz, J ¼ 20 Hz); 63.5 (s); 63.2 (s); 44.1
(s); 14.8 (s); IR (KBr) 555 (w), 647 (w), 1153 (s), 1210 (s),
3401 (m). Anal. Calcd. for C H F O : C, 28.2; H, 1.7.
FF
2
2
(
dm, 1F, J ¼ 303 Hz); À120.8 (dm, 1F, J ¼ 300 Hz);
FF
FF
2 2
À120.9 (dm, 1F, JFF ¼ 297 Hz); À121.6 (dm, 1F, JFF ¼
1
5 11 21 3
2
3
2
03 Hz); À121.7 (dm, 1F, JFF ¼ 271 Hz); À122.0 (dm, 1F,
Found: C, 29.1%; H, 2.6%.
2
JFF ¼ 300 Hz); À124.5 (dm, 1F, JFF ¼ 291 Hz); À125.6
2
13
(
(
4
1
dm, 1F, JFF ¼ 291 Hz); C NMR (DMSO-d ) d: 107–122
6
m); 68.0 (dd, J ¼ 26 Hz, J ¼ 20 Hz); 63.4 (s); 63.0 (s);
Acknowledgements
4.3 (s); 15.0 (s); IR (KBr) 1022 (m), 1146 (s), 1208 (s),
240 (s), 1632 (w), 2962 (w), 3422 (m). Anal. Calcd. for
The research has been supported by the Grant Agency of
the Czech Republic (Grant nos. 203/98/1174 and 203/01/
C H F O : C, 30.2; H, 2.5. Found: C, 32.5%; H, 3.2%.
11 11 13 3
1311). We are indebted to Elf Atochem for a kind gift
4
.4.4. 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
Heptadecafluoro-2-(hydroxymethyl)-2-methylundecane-
of perfluoroalkyl iodides. We thank heartily Dr. Vladim ´ı r
C ´ı rkva for the preparation of 5-(2,2,5-trimethyl-1,3-dioxane)-
methanol (3).
1
,3-diol (8c)
Reaction of polyfluorononanol 7c (1.50 g, 2.60 mmol)
afforded after general procedure polyfluoroalkanetriol 8c
1
(
0.81 g, 58.1%) as crystals. H NMR (DMSO-d ) d: 5.89 (d,
References
6
1
H, J ¼ 8:2 Hz); 4.68 (t, 1H, J ¼ 4:4 Hz); 4.58 (t, 1H, J ¼
4
(
:4 Hz); 4.25 (dd, 1H, J ¼ 29:1 Hz, J ¼ 8:0 Hz); 3.3–3.6
[1] J.G. Riess, M.P. Krafft, Biomaterials 19 (1998) 1529.
[2] M.P. Krafft, J.G. Riess, Biochimie 80 (1998) 489.
[3] K.C. Lowe, Blood Rev. 13 (1999) 171.
m, 4H); 0.86 (s, 3H); 19F NMR (DMSO-d ) d: À80.3 (t, 3F,
6
2
J ¼ 10 Hz); À113.4 (d, 1F, JFF ¼ 273 Hz); À119.3 (d, 1F,
[
4] J.G. Riess, J. Greiner, in: G. Descotes (Ed.), Carbohydrates as
Organic Raw Materials II., Weinheim, New York, 1993, p. 209 and
references therein.
2
2
JFF ¼ 297 Hz); À120.5 (dm, 1F, JFF ¼ 300 Hz); À120.9
2
2
(
dm, 1F, JFF ¼ 300 Hz); À121.2 (dm, 1F, JFF ¼ 297 Hz);
2
À121.6 (m, 2F); À121.7 (dm, 1F, JFF ¼ 300 Hz); À121.8
[5] J.G. Riess, J. Greiner, Carbohydr. Res. 327 (2000) 147.
[6] V. C ´ı rkva, B. Am e´ duri, B. Boutevin, O. Paleta, J. Fluorine Chem. 83
(1997) 151.
2
2
(
dm, 1F, J ¼ 300 Hz); À122.0 (dm, 1F, J ¼ 311 Hz);
2 2
FF FF
FF
FF
À122.8 (dm, 1F, J ¼ 311 Hz); À125.3 (dm, 1F, J
¼
[
[
7] V. C ´ı rkva, M. Gaboyard, O. Paleta, J. Fluorine Chem. 102 (2000) 349.
2
13
2
91 Hz); À126.2 (dm, 1F,
J
¼ 291 Hz); C NMR
FF
8] D. Burton, J.Y. Yang, Tetrahedron 48 (1992) 189.
(
DMSO-d ) d: 107–122 (m); 68.1 (dd, J ¼ 25 Hz, J ¼
6
[9] R. Miethchen, C. Zur, D. Peters, Synthesis (1998) 1033.
2
1 Hz); 63.4 (s); 63.0 (s); 44.2 (s); 14.9 (s); IR (KBr) 660
w), 1023 (m), 1151 (s), 1205 (s), 1243 (s), 3416 (m). Anal.
Calcd. for C H F O : C, 29.0; H, 2.1. Found: C, 30.4%;
[10] S. Lavaire, R. Plantier-Royon, C. Portella, Tetrahedron Asym. 9
(
1998) 213.
(
[
[
11] V.W. Gash, J. Org. Chem. 37 (1972) 2197.
1
3 11 17 3
12] M. Kalbe, H. Keul, H. Hoecker, Macromol. Chem. Phys. 196 (1995)
3
H, 2.4%.
305.
[
[
13] H. Harada, T. Morie, Y. Hirokawa, S. Kato, Chem. Pharm. Bull. 44
(1996) 2205.
4
1
1
.4.5. 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,
3-Henicosafluoro-2-(hydroxymethyl)-2-methyltridecan-
,3-diol (8d)
14] B.S. Furniss, A.J. Hammford, P.W.G. Smith, A.R. Tatchell, Vogel’s
Textbook of Practical Organic Chemistry, 5th Edition, Wiley, New
York, 1991, p. 443.
Reaction of polyfluoroundecanol 7d (938 mg, 1.38 mmol)
afforded after general procedure polyfluoroalkanetriol 8d
[
15] B.S. Furniss, A.J. Hammford, P.W.G. Smith, A.R. Tatchell, Vogel’s
Textbook of Practical Organic Chemistry, 5th Edition, Wiley, New
York, 1991, p. 395.
1
(
323 mg, 36.9%) as crystals. H NMR (DMSO-d ) d: 5.79
6