A simple stereoselective synthesis of biologically important 2-halo-2,3-dideoxy-arabinose derivatives from 1,1,1,2-tetrafluoroethane (134a) and 1-chloro-2,2,2-trifluoroethane (133a)

Article abstract of DOI:10.1016/S0022-1139(99)00241-9

A simple stereoselective three step synthesis of 2-fluoro- and 2-chloro-2,3-dideoxy arabinose derivatives from the readily available starting materials, (R)-glycidol and either 1,1,1,2-tetrafluoroethane (134a) or 1-chloro-2,2,2-trifluroethane (133a), is d

Full text of DOI:10.1016/S0022-1139(99)00241-9

Journal of Fluorine Chemistry 102 (2000) 43±50
A simple stereoselective synthesis of biologically important
2-halo-2,3-dideoxy-arabinose derivatives from 1,1,1,2-tetra¯uoroethane
(134a) and 1-chloro-2,2,2-tri¯uoroethane (133a)
Paul L. Coe*, James Burdon, Iain B. Haslock
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 11 May 1999; received in revised form 28 June 1999; accepted 19 July 1999
Dedicated to Professor Paul Tarrant, to whom organo¯uorine chemists owe a great deal, on his 85th birthday
Abstract
A simple stereoselective three step synthesis of 2-¯uoro- and 2-chloro-2,3-dideoxy arabinose derivatives from the readily available
starting materials, (R)-glycidol and either 1,1,1,2-tetra¯uoroethane (134a) or 1-chloro-2,2,2-tri¯uroethane (133a), is described. This
compares very favourably with the multistep syntheses previously described in the literature. A mechanistic interpretation of the reaction
via an unfavourable 5-endo-trig cyclisation is given. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Tri¯uorovinyllithium; Sugar analogues; Stereospeci®c; De-novo synthesis
1. Introduction
of epoxides catalysed by boron tri¯uoride etherate were of
considerable interest [8]. We have recently shown [9,10] that
it is relatively simple, without the use of specialist condi-
tions, to generate 1 from 134a and chlorodi¯uorovinyl-
lithium 2 from 133a. We now report reactions of these
reagents with suitable epoxides to generate precursors of
the desired arabinose derivatives.
A number of ¯uorinated di-deoxy nucleosides have shown
promise in the treatment of HIV infections but progress on
the study of these and related compounds has been hampered
by the lack of good de-novo syntheses which in the event of
good therapeutic indications could be scaled up. For exam-
ple, the ®rst ``practical''de-novo synthesis of 2,3-dideoxy-2-
¯uoro-b-D-threo-pentofuranosyl) cytosine (F-ddC) gives a
7.9% yield based on D-xylose [1]. More recently, Patrick
[2,3] has reported a better synthesis based on D-mannose as
a source of D-glyceraldehyde. To devise a simpler stereo-
selective synthesis of these interesting molecules provides a
challenge to the organo¯uorine chemist. The use of tri¯uor-
ovinyllithium (1) and tri¯uorovinylmagnesium bromide as
synthetic precursors was recognised by Tarrant, Knunyants
and Seyferth almost simultaneously in the 1960s [4±6] but
the reactions were at that time very dif®cult to perform.
Subsequently, Normant used chlorotri¯uoroethene as start-
ing material to generate 1, and he also found it important to
use rather carefully controlled conditions. Nevertheless, the
Normant group showed that a wide range of reactions of 1
could be successfully carried out as reviewed [7]. From the
point of view of the present study the ring opening reactions
2. Results and discussion
At the outset of this work we believed there were three
major problems to be solved to enable us to prepare our
desired compounds. Firstly, the opening of a suitable chiral
epoxide without epimerisation and without the Payne rear-
rangement [11] occurring: it is well known that chiral
epoxides with acidic hydrogen atoms can readily epimerise
and that the Payne rearrangement also readily occurs. Sec-
ondly, to cyclise the resulting alcohol to give us the desired
tetrahydrofuran structure and thirdly to obtain the ¯uorine
atom in the desired stereochemistry. The synthetic strategy
we proposed to use was to investigate the whole reaction
sequence using racemic material and when we had obtained
optimum conditions to use the appropriate chiral epoxide.
The work of Normant [8,12] using both lithium and copper
reagents has clearly shown the epoxides open much more
readily in the presence of boron tri¯uoride etherate. Thus,
* Corresponding author. Tel.: ‡44-121-414-4360;
fax: ‡44-121-414-4403.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 4 1 - 9

44
P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
Scheme 1. Reaction of trifluoro and chlorodifluoro-vinyllithium reagents.
Scheme 2. Cyclisation reaction using trifluorovinyllithium.
we ®rst reacted 1 with racemic 1,2-epoxy-3-phenoxy- pro-
pane (3) in the presence of an equimolar amount of the
etherate at 788C. The product was puri®ed by column
chromatography and was identi®ed by physical methods as
the expected alcohol, 1,1,2-tri¯uoro-5-phenoxypent-1-en-4-
ol (4), in 65% yield. In the same way reaction of 2 afforded
2-chloro-1,1-di¯uoro-5-phenoxypent-1-en-4-ol (5) in 32%
yield, identi®ed by standard physical methods. These results
are shown in Scheme 1. Thus, we had shown that the ®rst
step in our sequence was successful and we now turned our
attention to the possible cyclisation step. Our rationale for
proceeding along this pathway was based on two observa-
tions. Firstly, our reported results [10] that the reaction at the
terminal CF2 group of the introduced tri¯uorovinyl function
with nucleophiles easily leads to the formation of ¯uoro-
quinolines (Scheme 2) and secondly to the elegant work of
Lipschutz [13] and Knight [14] who studied the use of
iodoetheri®cation reactions for the stereoselective forma-
tion of substituted ®ve-membered heterocycles as shown in
Scheme 3. The latter reactions are thought to proceed via the
formation of the iodonium cation which then cyclises to
form the corresponding furan derivatives by an unfavour-
able 5-endo-trig reaction. The reactions can be extremely
stereoselective depending on the substituents and are pos-
tulated to be controlled by the transition state geometry. We
believe that the tri¯uorovinyl group in 4 is a reasonable
mimic for the iodonium cation and this could lead, by a
similar process to that proposed by Lipschutz and Knight, to
our desired stereoselective cyclisation. An alternative
mechanism leading to an unfavourable 5-endo±trig cyclisa-
tion has been proposed by Baldwin who showed that reac-
tions leading to dioxolanes can proceed via oxycarbenium
ions, in this mode [15], however this mode of reaction it
unlikely to be relevant in our case. We thus treated 4 with a
large (10-fold) excess of sodium hydride in re¯uxing THF
and obtained a white crystalline solid. The 19F NMR
spectrum showed two signals of equal intensity at d±125
and ±192, both of which showed a doublet coupling of
1
23 Hz in the range for a cis FF coupling. The H and 13C
spectra were consistent with the product being 2,3-di¯uoro-
4,5-dihydro-5-(phenoxymethyl) furan (6). This structure
was further con®rmed by consideration of the mass spectral
data and elemental analysis. In the same way, 5 afforded the
corresponding chloro¯uoroderivative 3-chloro-2-¯uoro-
4,5-dihydro-5-(phenoxymethyl) furan (7), characterised
by physical methods as for 6. When the reaction of 4
was repeated but using only a slight excess of sodium
Scheme 3. Iodoetherifications.

P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
45
hydride two products were isolated in the ratio of 7:3 and
these were readily separated by column chromatography.
Both compounds gave a parent ion peak of m/z 232 in their
mass spectra corresponding to an empirical formula of
C11H11F3O2. 19F NMR spectroscopy showed the presence
of a CF2 group and a CFH group in each compound and the
1H spectrum showed a series of peaks for highly coupled
protons. Signi®cantly there was a complex doublet which
showed a coupling constant of 52 Hz attributable to the
presence of a CHF group. These data together suggest that
the two compounds are two pairs of enantiomers of 2,2,3-
tri¯uoro-4,5-dihydro-5-(phenoxymethyl) furan (8a, 8b).
This pattern of products can be explained by consideration
of the diastereotopicity of the faces of the tri¯uorovinyl
group in the ene-ol (4): the oxyanion generated in the
reaction can react at either face. The stereoselectivity in
this reaction is interesting and potentially useful (see
below). We believe, on the basis of comparison of NMR
data with literature reports of related compounds [1,3], that
the major product pair has the cis structure 8a and the minor
pair the trans structure 8b. We had thus established that our
synthetic strategy so far had led to potential precursors of
the desired sugar analogue.
These results are shown in Scheme 4. It is now necessary
to elaborate 7 or 8 to the ®nal structure. Previously, we had
shown that it was possible to catalytically hydrogenate a
CF ˆ CH system in a nucleoside stereoselectively to the
arabino con®guration [16], and recently this has also been
shown to occur in sugar analogues [8]. Thus, we hydro-
genated 6 under our previously described conditions and
obtained the desired 2,3-di¯uoro-5-(phenoxymethyl)tetra-
hydrofuran (9) in almost quantitative yield. The structure of
9 was readily determined by physical methods as shown in
the experimental section. In the same way the hydrogena-
tion of 7 afforded the corresponding 3-chloro-1-¯uoro-5-
(phenoxymethyl) tetrahydrofuran (10) again readily char-
acterised by physical methods. The ®nal experiments we
carried out to test our strategy were to consider the hydro-
lysis of 6 under both acidic and basic conditions. Much to
our surprise hydrolysis with a saturated solution of sodium
hydroxide in wet THF gave only the starting material.
However, hydrolysis with a mixture of aqueous 4 M hydro-
chloric acid in THF at re¯ux for 2.5 days afforded a mixture
of unreacted starting material and 3-¯uoro-5-(phenoxy-
methyl)-tetrahydrofuran-2-one (11) (see below). When 6
was re¯uxed in THF with Dowex 50 (H) for 2.5 days a
mixture of two products in the ratio 13:2 was observed;
column chromatography afforded a pure sample of the
major product shown to be 11, as a mixture of enantiomers.
The 19F NMR spectrum showed only one band at d±193 as a
multiplet and among the observable couplings was a large
doublet of 52 Hz characteristic of a CHF group with a
smaller doublet coupling (24.4 Hz) characteristic of a trans
vicinal HF coupling in a ®ve-membered ring. The 1H
spectrum which was essentially that of the major isomer
due to the relatively small amounts of the minor isomer
present showed the expected peaks for the proposed struc-
ture and in particular the characteristic shift pattern
observed in the literature for the 5-methine proton in similar
compounds known to have the 3F and the 5-phenoxymethyl
groups in the trans arrangement [1,8]. From the 19F and
1H NMR spectra of the crude material we were able to
identify the minor isomer as the cis product. It is interesting
to note that hydrolysis in the presence of Dowex resin
appears to proceed more readily than in aqueous hydro-
chloric acid/THF. This may well be a re¯ection of the
greater acidity of the sulfonic acid moiety in the resin being
a stronger acid than HCl under these conditions. This is in
line with the greater reactivity of sulfonic acids in electro-
philic additions to ¯uoroalkenes [17]. These reactions are
summarised in Scheme 5. Thus, we have been able to show
that our strategy worked using racemic materials.
We now turn our attention to using (R)-3-(benzyloxy)-
1,2-epoxypropane (12). We choose to use the benzyl pro-
Scheme 4. Cyclisation of pent-1-en-4-ols (6 and 7) [single enantiomers only shown].

46
P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
Scheme 5. Reactions of dihydrofurans 6 and 7 [only one enantiomer shown].
an optical rotation of ‡5.48. Apart from minor differences
due to the different group at position 5 the NMR spectra of 4
and 15 were very similar as would be expected. In a similar
reaction 12 yielded the dihydrofuran (R)-5-(benzyloxy-
methyl)-3-chloro-2-¯uoro-4,5-dihydrofuran (16). Catalytic
hydrogenation of 16 as above for 6 afforded the desired
product, 1(R), 2 (R), 3(R)-5-(benzyloxymethyl)-2,3-di¯uor-
otetrahydrofuran (17). The unoptimised overall yield was
29%. The low yielding step in the sequence was reaction of
tri¯uorovinyllithium with the glycidyl ether (14) at 43%
isolated yield, although GC indicated a yield of ca 75%, and
thus it may be possible to increase the overall yield by a
better work-up procedure. These reactions are summarised
in Scheme 7. Since the condensation of related molecules
with pyrimidine and purine bases has been previously
reported we have in effect achieved our original objective.
We have shown that it is possible by a series of very simple
reactions to prepare sugar derivatives directly in good yield
from readily available materials in a much smaller number
of steps than previously reported.
Scheme 6. Degenerate Payne rearrangement of glycidol.
tecting group since it is much easier to remove than phenyl
group at later stages in a potential nucleoside synthesis. The
preparation of the ether (12) from the commercially avail-
able (R)-glycidol was straightforward using the method of
Ichikawa [18]. Although this reaction uses sodium hydride
to generate the oxyanion which could lead to a Payne
rearrangement [11] as shown in Scheme 6 this presents
no problem in our case since as can be seen the rearrange-
ment exists as a degenerate equilibrium reforming the (R)-
epoxide. The epoxide (12) was reacted as above with
tri¯uorovinyllithium (1) to form the expected chiral alcohol
(R)-5-(benzyloxy)-1,1,2-tri¯uropent-1-en-ol (13). The alco-
hol was readily characterised by physical means and had an
optical rotation of ±6.18. In the same way the epoxide (14)
reacted with the vinyllithium (2) to give the alcohol (R)-5-
(benzyloxy)-2-chloro-1,1-di¯uoro-pent-1-en-4-ol (14) again
fully characterised by physical methods and with an optical
rotation of ±3.78. The alcohol (13) was treated as above with
a large excess of sodium hydride to form the expected (R)-5-
(benzyloxymethyl)-2,3-di¯uoro-4,5-dihydrofuran (15) with
3. Experimental
The 1H NMR (300 MHz) and the 13C NMR spectra
(75 MHz) were measured on a Bruker AC 300 NMR spec-
Scheme 7. Formation of chiral di and tetrahydrofurans.

P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
47
trometer unless stated otherwise. The 1H NMR spectra
(400 MHz) were measured on a Bruker AMX 400 NMR
spectrometer. The 19F NMR spectra were carried out either
on a Jeol NMR spectrometer, type FX 90 Q (84.26 MHz) or
on a Bruker AC 300 NMR spectrometer (282.4 MHz);
Tetramethylsilane and ¯uorotrichloromethane were used
as internal references. For the characterisation of the signals
the following abbreviations are used: s ˆ singlet,
d ˆ doublet, t ˆ triplet, q ˆ quartet, quin ˆ quintet, sex-
t ˆ sextet, m ˆ multiplet, dd ˆ doublet of doublets,
dt ˆ doublet of triplets, ``quin'' ˆ pseudo quintet etc. J
values are given in Hz. The mass spectra (CI-MS/EI-MS)
were measured on a VG-Prospec-triple focusing mass
spectrometer. For GC-MS analysis, a Carlo Erba, 8000
series GC was used with a 50 m column (BPX 5, helium
carrier gas).
Thin layer chromatography was performed on TLC plas-
tic sheets (silica gel 60 F254), pre-coated with a layer
thickness of 0.2 mm from Merck, Art. 5735. Gas chromato-
graphic analysis was carried out using a Philips PYE Uni-
cam, Series 304 chromatograph with a 50 m CD-SIL-CB 19
column. The data were registered by a JCL 600 chromato-
graphy data system.
4.1 (dd, 1H, 2JHH 9.5, 3JHH 3.5, H5'), 4.3 (m, H 4), 6.9±7.3
3
2
(m, 5H, Ar); dF ±103 (dd, 1F, JFF 33.6, JFF 82.5,
CF2 ˆ CF) ±122 (dd, 1F, 3JFF 112.7, 3JFF 82.5, CF2 ˆ CF)
3
3
3
±172 (ddt, 1F, JFF 112.9, JFF 33.6, JHF 22.9 CH2CFˆ);
dC 33 (CH2), 67 (CHOH), 71(CH2), 115(Ar), 122(Ar),
1
2
2
124 (ddd, JCF 234, JCF 53.6, JCF 16.9, ±CFˆ), 130
1
1
2
(Ar), 150 (ddd, JCF 287, JCF 274, JCF 46.4, ˆCF2)
158.3 (Ar).
3.1.3. Preparation of
2-chloro-1,1-difluoro-5-phenoxypent-1-en-4-ol (5)
In the same manner as above, reaction of 3 (9.6 mmol)
with 1-chloro-2,2-di¯uorovinyllithium (10 mmol) afforded
2-chloro-2,2-di¯uoro-5-phenoxy-pent-1-en-4-ol(5) (nc)
0.8 g m.p. 31±328C; (Found: C, 53.3; H, 4.7%
C11H11ClF202 requires C, 53.1; H4.5%); MS m/z 250
‡
[37ClM ‡], 248[35ClM‡], 157 [M-OPh ‡], 155 [M ±Oph ],
‡
2
3
4
94 [PhOH ]; dH 2.6 (m, 2H, JHH 14,5, JHH 8, JHF 4.5,
4JHF 3, JHF 1.5, JHF 1, H3 and H3'), 4 (dd , 2H, JHH 9,
3JHH 5.5, 3JHH 4.5, 4JHH, 1, 4JHH 0,5, H 5 and H 5'), 4.2 (m,
3
3
2
3
1H, CHOH), 4.5 (d, 1H, exchangeable with D2O, JHH 5,
OH), 6.9±7.2 (m, Ar); dF 89 (d, 1F, 3JFF 48.8, ˆCF2), 95
3
(d, JFF 45.8, ˆCF2); dC 35 (CH2), 67 (CHOH), 72 (CH2),
2
2
91 (dd, JCF 39, JCF 19 CCl ˆ CF2), 115 (Ar), 122(Ar) ,
1
3.1. Preparation of trifluorovinyllithium (1)
130(Ar), 152 (t, JCF 284), 159.9 (Ar).
Under a dry nitrogen atmosphere n-butyllithium (8 cm3,
2.5 M in hexanes ) was added via a syringe pump over 0.5 h
to a solution of 1,1,1,2-tetra¯uoroethane (134a) (3 cm3) in
ether (40 cm3) at 788C. The mixture was allowed to stir for
a further 1 h at this temperature and was then used for the
other experiments described below.
3.1.4. Preparation of
2,3-difluoro-4,5-dihydro-5(phenoxymethl) lfuran (6)
Sodium hydride (0.5 g, 20 mmol) was added to a solution
of 4 (0.5 g, 2.2 mmol) in dry THF (30 cm3) and the mixture
was heated under re¯ux for 2 days. Ice (10 g) was added
carefully to the cooled mixture followed by brine (20 cm3).
The organic layer and ether extracts of the aqueous layer
(3 Â 30 cm3) were dried (MgSO4) and the solvent removed
to yield a white powder. Recrystallisation from chloroform/
methanol 9:1 afforded 2,3-di¯uoro-4,5-dihydro-5-(phenox-
ymethyl) furan (6) (0.31 g) (nc) m.p. 44±468C; (Found; C,
62.1; H, 4.5% C11H10F2O2 requires C, 62.3; H, 4.7%),
Accurate mass measurement: 212.064986; calc. for
3.1.1. Preparation of 1-chloro-2,2-difluorovinyllithium 2
In the same manner as above but using 1-chloro-2,2,2-
tri¯uoroethane (3 cm3) (133a) a solution of 1-chloro-2,2-
di¯uorovinyllithium was prepared ready for use in the
experiments described below.
2
3
3.1.2. Preparation of
C11H10F2O2212.064984; dH 2.9 (m, 1H, JHH 18.5, JHH
3
4
2
1,1,2-trifluoro-5-phenoxy-pent-1-en-4-ol (4)
8, JHF 5.5, JHF 2.5, CH2±CHF), 3.1 (m, 1H, JHH 18.5,
2
1,2-epoxy-3-phenoxypropane (3) (1.3 cm3, 9.6 mmol)
and boron tri¯uoride etherate (1.2 cm3, 9.8 mmol) were
added to a solution of 1 (10 mmol) at ±788C. The reaction
mixture was allowed to warm slowly to room temperature
over 2 h, saturated NaHCO3 solution (20 cm3) was added,
the aqueous layer extracted with ether (4 Â 30 cm3) and the
ether layers combined, dried (MgSO4) and the solvent
removed. The residual oil (2.1 g) was puri®ed by column
chromatography (Silica, Hexane/ether 4:1) to give 1,1,2-
tri¯uoro-5-phenoxy-pent-1-en-4-ol (4) (nc) b.p. 1408C/
0.2 mmHg; (Found: C, 56.7; H,4.5% C11H11F3O2 requires
3JHH 10, JHF 5, JHF 4, CH2±CHF), 4.1 (dd, 1H, JHH 10,
3
4
3JHH 4.5, OCH2CH), 4.2 (dd, 1H, JHH 10, JHH 6,
OCH2CH), 4.9 (m, 1H CH2CHO), 6.9 (m, Ar), 7(m, Ar),
7.3 (m, Ar); dF ±125 (d, 1F, 3JFF 23.5, CFˆ), 192 (d, 1F,
3JFF 23.6, CFˆ); dC 29 (d, 2JCF 18.1, CH2CFˆ), 69 (s, CH2),
2
3
3
1
2
74 (d, JCF 7, CHCH2CF), 114 (dd, JCF 239, JCF 10),
1
2
115(Ar), 122 (Ar), 130 (Ar), 143 (dd, JCF 260, JCF 20,
OCF ˆ CF), 158 (Ar).
3.1.5. Preparation of
3-chloro-2-fluoro-4,5-dihydro-5-(phenoxymethyl)furan (7)
In the same way as above for the preparation of 6, the
alcohol 5 (0.3 g, 1.2 mmol) and sodium hydride (0.3 g,
15 mmol) afforded 3-chloro-2-¯uoro-4,5-dihydro-5-phe-
noxymethyl-furan (7) (nc) (0.26 g) m.p. 61-638C, (Found:
‡
‡
C, 56.9:H, 4.8%); MS m/z 232 [M ], 181 [M ± CHF2 ], 137
‡
‡
[M ± C3H2F3 ] 77 [ Ph ]; dH 2.5 (s, 1H, exchangeable with
D2O, OH), 2.6 (AB, 2H, 3JHF 24, 3JHF 24, 3JHH 6, 2JHH 4 ,
3JHH 2, H 3 and H 3'), 3.9 (dd, 1H, 2JHH 9.5, 3JHH, 6.5, H5)

48
P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
C, 57.6:H, 4.2% C11H10ClFO2 requires C, 57.8; H, 4.4%);
3JHH 3.0, CH2), 4.85 (m, 1H, CH CHO), 5.3 (d of m, 1H,
MS m/z 230 [37ClM ], 228 [35ClM ]; dH 2.9 (ddd, 1H, 2JHH
13, 3JHH 7, 4JHF 4.5, CH2CCl ˆ CF), 3.1 (ddd, 1H, 2JHH 13,
3JHH 10, 4JHF 4.5, CH2CCl ˆ CF), 4.25 (m, 2H, OCH2CH),
5.2 (m, 1H, CH2CHO), 6.95 (m, Ar), 7.3(m, Ar); dF ±116 (s,
F); dC 34 (CH2), 70 (CH2CClˆ), 79 (CH2CHO), 116 (Ar),
121 (d, 2JCF 18, CCl ˆ CF), 122 (Ar), 130 (Ar) 154 (d, 1JCF
269, CF ˆ CCl), 160 (Ar).
2JHF 53.2, CH2CHF), 5.65, (d of m, 1H, JHF 52,
‡
‡
2
CHFCHFO), 6.85 (Ar), 6.95 (Ar), 7.3(Ar); dF 137 (m, 1F
CHFCHFO), 193 (m 1F, CH2CHF), dC 31 (d, JCF 20.9,
2
1
CH2CF ˆ CF), 68(CH2CHO), 79 (CH2CHO), 92 (dd, JCF
2
190.5, JCF 47.2, CHFCHF), 115 (Ar), 122 (Ar), 129 (dd,
2
1JCF 246, JCF 26.6), 132 (Ar),159 (Ar).
3.1.8. Preparation of 3-chloro-2-fluoro-5-(phenoxymethyl)
tetrahydrofuran (10)
3.1.6. Preparation of
2,2,3-trifluoro-4,5-dihydro-5-(phenoxymethyl) furan (8)
The alcohol 4 (2.32 g, 10 mmol) was heated under re¯ux
with sodium hydride (0.4 g, 16 mmol) in dry THF (50 cm3)
for 22 h. Ice was added to the cooled reaction mixture
followed by brine (20 cm3). The separated organic layer
and the combined ether extracts of the aqueous layer
(3 Â 30 cm3) were dried (MgSO4) and the solvents removed
to leave a semi-solid product (1.9 g) m.p. 20±308C. A
portion of this latter was puri®ed by column chromatogra-
phy(silica, hexane/ethyl acetate 4:1) to give the two pairs
of enantiomers of 2,2,3-tri¯uoro-4,5-dihydro-5-(phenoxy-
methyl) furan (8a and 8b) (nc) in the ratio 7:3: (Found (for
the mixture of isomers): C, 56.6; H, 5.0% C11H11F3O2
requires C, 56.9; H, 4.8%); dH (major isomer) 2.45 (m,
1H, CH2), 2.55 (m, 1H, CH2), 4.05 (dd, 1H, 2JHH 10, 3JHH
4.5, CH2O), 4.15 (dd, 1H, 2JHH 10, 3JHH 3.0, CH2), 4.95 (m,
In the same way as above hydrogenation of 7 (0.25 g,
0.11 mmol) afforded 3-chloro-2-¯uoro-5- (phenoxymethyl)
tetrahydrofuran (10) (nc) as an oil (0.22 g); (Found: C,
57.1:H, 5.1% C11H12ClFO2 requires C, 57.3; H, 5.2%);
dH 2.4 (m, CH2CHCl), 2.73 (m, CH2CHCl), 3.96 (m, 1H,
CH2CHClCHF) 4.16 (dd, 1H, 2JHH 10, 3JHH 3.3, CH2), 4.23
(dd, 1H, 2JHH 10, 3JHH 3.0, CH2), 4.8 (m, CH2CHO), 5.3 (d
of m, 1H, 2JHF 53.2, CH2CHF), 6.8(Ar), 6.95 (Ar), 7.3(Ar);
dF 143 (d of m, 2JHF 53.1 CHFO); dC 31 (CH2CHCl), 69
(CH2CHO), 79(CH2CHO), 91(d, 2JCF 40.5 CHClCFH), 115
(Ar), 121 (Ar) 127 (d, 1JCF 263, CHClCFHO), 130 (Ar) 156
(Ar).
3.1.9. Preparation of 3-fluoro-5-(phenoxymethyl)
tetrahydrofuran-2-one (11)
A solution of 6 (1.06 g 5 mmol) in THF (30 cm3) was
stirred under re¯ux with Dowex(H) (14 g) for 2.5 days. The
mixture was ®ltered and the solvent removed to give an
inseperable mixture in the ratio 13:2 of 3-¯uoro-5-(phenox-
ymethyl) tetrahydrofuran-2-one (11) (nc) m.p. 67±718C;
(Found for the mixture: C, 62.6; H, 5.1% C11H11FO3
requires C, 62.9; H, 5.3%); MS, exact mass 210.068728,
C11H11FO3requires 210.069223; dH 2.5 (m, 1H, CH2CHF),
2
CH2CHO), 5.2 (d of m, JHF 52, CHFCF2), 6.85(Ar), 6.95
(Ar), 7.25(Ar); (minor isomer) 2.3 (m, 1H CH2CHF), 2.35
(m, 1H, CH2CHF), 4.15 (m, 1H, OCH2), 4.2 (m, 1H, OCH2),
4.75 (m, 1H, CH2CHO), 5.1 (m, 1H, CHFCF2), 6.85 (Ar),
2
7.05 (Ar), 7.35 (Ar); dF ±71 (major isomer) (d, 1F, JFF
2
3
149.5, CF2CFH),
12.2,CF2CFH), 194 (m, 1F, CHFCF2); (minor isomer)
90 (dd, 1F, JFF 153, JFF
2
2
2
3
±74 (d, 1F, JFF 153, CF2CFH), 89 (dd, 1F, JFF 149.5,
3JFF 12.2 CF2CFH), 189 (m, 1F, CHFCF2); dC (major
isomer) 32 (d, JCF 21.1, CH2CHF), 69 (CH2), 78
2.85 (m, 1H CH2CHF ), 4.1 (dd, 1H, JHH 10.5, JHH 4.5
3
2
CH2CH), 4.2 (dd,1H, JHH 10.5, JHH 3.55 CH2CH), 4.8
(m, 1H, CHO), 5.3 (dt, 1H, JHF 51, JHH ˆ 3JHH 8.5,
2
2
3
1
2
2
(CH2CHO), 90 (ddd, JCF 192, JCF 46.1, JCF 24.2,
1
CH2CHF), 6.9 (Ar), 7.0 (Ar), 7.3 (Ar); dF 193 (d of d
2
CHFCF2), 115 (Ar), 122 (Ar), 128 (dt, JCF ˆ 1JCF
of m, 1F, CH2CHFO); dC 31 (d, JCF 19.95, CH2CHF), 68
260.5, JCF 21.7, CF2CFH ), 130 (Ar), 158 (Ar); (minor
isomer) 31 (d, 2JCF 20.4), 69 (CH2), 77(CH2CHO), 89 (ddd,
1JCF 193.4, 2JCF 46.55, 2JCF 24.5, CHFCF2), 115 (Ar), 122
(CH2), 74 (d, 3JCF 6.3 CH2CHO), 85 (d, 1JCF 192.1, CHF),
2
2
115 (Ar), 122 (Ar), 130 (Ar), 158( Ar), 171(d, JCF 21.2,
CHFCO).
(Ar), 128 (dd, JCF ˆ 1JCF 262, 2JCF 37.73, CHFCF2), 130
1
(Ar) 156 (Ar).
3.1.10. Preparation of
(R)-3-(benzyloxymethyl)-1,2-epoxyethane (12)
3.1.7. Preparation of 2,3-difluoro-5-(phenoxymethyl)
tetrahydrofuran (9)
A suspension of sodium hydride (1 g, 4.1 mmol) in THF
(10 cm3) was added to a solution of R-glycidol (2.2 g,
3 mmol) and benzyl bromide (5.13 g, 3 mmol) in THF
(50 cm3). The reaction stirred at room temperature until
the evolution of hydrogen had stopped (1.5 h). The solvent
was removed and ether (20 cm3) and ice (10 g) were added
to the residue. The organic layer was separated, combined
with the ether extracts (3 Â 20 cm3) of the aqueous layer,
dried (MgSO4) and the solvent removed to yield (R)-3-
(benzyloxymethyl)-1,2-epoxyethane (12), Na2a0 ‡ 2.58 with
The dihydrofuran (0.5 g, 2.3 mmol) in ethyl acetate
(20 cm3) was hydrogenated over palladium on carbon
(10%, 0.2 g) at 1 atm for 24 h when no more hydrogen
was absorbed. The mixture was ®ltered through a Celite pad
and the ®ltrate evaporated to dryness to yield 2,3-di¯uoro-5-
(phenoxymethyl) tetrahydrofuran (9) as a racemic mixture
(0.5 g as an oil ) (nc); (Found: C, 61.5; H, 5.4% C11H12F2O2
‡
requires C, 61.7; H, 5.7%); MS, m/z 214 [M ], 121 [M±
‡
1
PhO ], dH 2.4 (m, 1H, CH2CHF), 2.6 (m, 1H, CH2CHF), 4.1
(dd,1H, JHH 10, JHH 4.3, CH2), 4.25 (dd, 1H, JHH 10,
an identical H NMR spectrum to that previously reported
2
3
2
[18].

P.L. Coe et al. / Journal of Fluorine Chemistry 102 (2000) 43±50
49
3.1.11. Preparation of (R)-5-(benzyloxy)-1,1,2-
trifluoropent-1-en-4-ol (13)
13, 3JHH 10.5, 3JHF 5, 4JHF 3, CH2CF ˆ CF2), 3.6 (dd, 1H,
2JHH 10.5, 3JHH 4.5, CH2CHO), 3.7(dd, 1H, 2JHH 10.5, 3JHH
6, CH2CHO), 4.6 (s, 2H CH2Ph), 4.7 (m, 1H, CH2CHO),
7.3±7.4 (m, 5H, Ph); dF 128(d, 1F, 3JHH 24.1, CF ˆ CFO),
196 (d of m, 1F, 3JHH 21.4, CH2CF ˆ CF); dC 29 (d, 2JCF
17.9, CH2CF ˆ CF), 71 (CH2CHO), 74 (PhCH2O), 75 (d,
The epoxide (12) (1.25 g, 7.5 mmol) and boron tri¯uor-
ide/etherate (0.9 cm3, 7.5 mmol) were reacted as above with
a solution of tri¯uorovinyllithium (7.5 mmol) at ±788C for
2 h whilst the mixture slowly warmed to RT. Work up as
described above afforded, after puri®cation by column
chromatography (silica, hexane/ether 4:1), (R)-5-(benzy-
loxy)-1,1,2-tri¯uoropent-1-en-4-ol (13)(nc) as an oil
(0.8 g) Na2a0 ‡ 6.18; (Found: C, 58.3; H, 5.1%
1
2
3JCF 8.3, CH2CHO), 115 dd, JCF 250, JCF 13.1,
CH2CF ˆ CF), 128 (Ar), 128 (Ar), 129 (Ar), 138 (Ar),
1
2
154 (dd, JCF 268, JCF 23.7).
‡
C12H13F3O2 requires C, 58.5; H, 5.3%); MS 246{M ],
3.1.14. Preparation of
‡
‡
226 [M±HF ], 107 [PhCH2O ]. dH 2.6 (m, 2H,
3JHF ˆ 3JHF 24, CH2), 2.85(s, 1H, OH), 3.4 (dd, 1H,
(R)-5-(benzyloxymethyl)-3-chloro-4,5-dihydrofuran (16)
In the same manner as above the alcohol (14) (0.34 g) and
sodium hydride (0.3 g) afforded (R)-5-(benzyloxymethyl)-
3-chloro-4,5-dihydrofuran(16) (nc) (0.21 g) as an oil
Na2a0 ‡ 6.48, (Found: C, 59.1; H, 4.7% C12H12ClFO2
2JHH 9.5, JHH 6.5, CH2CHOH), 3.55 (dd, 1H, JHH 9.5,
3JHH 6.5, CH2CHOH), 4.05 (m, 1H, CHOH), 4.55 (s, 2H,
PhCH2), 7.3±7.4 (m, Ph); dF 104 (dd, 1F JFF 33.6, JFF
85.5 CF2 ˆ CF), 123(dd, 1F, JFF 115.9, JFF 85.5,
3
2
3
2
3
3
2
3
requires C, 59.5; H5%); dH 2.7 (ddd, 1H, JHH 13, JHH
7.5, 4JHF 5, CH2CClˆ), 2.9 (ddd, 1H, 2JHH 13, 3JHH 10, 4JHF
4.5, CH2CClˆ), 3.55 (ddd, 1H, 2JHH 10.5, 4JHF 1.5, 3JHH 4,
3
3
CF2 ˆ CF),
172 (ddt, 1F, JFF 115.9, JFF 33.6,
3
3JHF ˆ 3JHF 24.4, CF2 ˆ CF); dC 30 (dd, JCF 21.3, JCF
2
2
4
3
2.0 CH2CF ˆ CF2), 67 (CHOH), 73 (CH2CHOH), 74
CH2CHO), 3.65 (ddd, 1H, JHH 10.5, JHH 1, JHH 6.5,
CH2CHO), 4.8 (m, 1H, CH2CHO), 7.3 7.4 (m, 5H, Ar); dF
114 (s, 1F, CCl ˆ CF); dC 34 (s, CH2CCl), 71 (s,
1
2
2
(PhCH2), 124 (ddd, JCF 238, JCF 51.7, JCF 15.6,
1
CF ˆ CF2), 129 (Ar), 138 (Ar), 154 (ddd, JCF 320.2,
2
2
1JCF 273.6, JCF 46.5, CF ˆ CF2).
CH2CHO), 74 (s, PhCH2), 121 (d, JCF 26, CCl ˆ CF),
1
128 (Ar), 128 (Ar), 129 (Ar), 138 (Ar) 155 (d, JCF 272.5
CFO).
3.1.12. Preparation of (R)-5-(benzyloxy)-2-chloro-1,1-
difluoropent-1-en-4-ol (14)
In the same way as above but using 1-chloro-2,2-di¯uor-
ovinyllithium (7.5 mmol) and 12 (1.84 g, 7.5 mmol) we
obtained (R)-5-(benzyloxy)-2-chloro-1,1-di¯uoropent-1-
en-4-ol (14) (nc) 1.66 g) as an oil Na2a0 ±3.78; ( Found:
C, 54.6; H, 5.2% C12H13ClF2O requires C, 54.9; H, 5%); dH
2.4 (m, 1H, 2JHH 15, 3JHH 5, 4JHF ˆ 4JHF 3, CH2CF ˆ CF2),
3.1.15. Preparation of 1(R),2(R),3(R)-
5-(benzyloxymethyl)-2,3-difluorotetrahydrofuran (17)
The dihydrofuran (15) (0.8 g, 0.35 mmol) in ethyl acetate
(25 cm3) was hydrogenated over 10% Pd on C (0.2 g) at
room temperature for 24 h. After ®ltration through a Celite
pad the solvent was evaporated to leave an oil which was
puri®ed by column chromatography (silica, hexane/ethyl
acetate 4:1) to yield 1(R),2(R),3(R)-5-benzyloxymethyl-
2,3-di¯uoro-4,5-dihydrofuran (17) (nc) (0.65 g) as an oil;
(Found: C, 64.9; H, 6.3% C12H14F2O2 requires C, 65.2; H,
2
3
4
4
2.55(m, 1H, JHH 14.5, JHH 8, JHF 1, JHF 3,
2
CH2CF ˆ CF2), 3.1 (s, 1H, OH), 3.45 (dd, 1H, JHH 9.5,
2
3
3JHH 6, CH2CHOH), 3.55 (dd, 1H, JHH 9.5, JHH 3.5,
CH2CHOH), 4.1(m, 1H CHOH), 7.3 7.4 (m, 5H, Ph); dF
‡
‡
3
3
88 (d, 1F, JFF 42.7, CF2 ˆ CCl), 94 (d, 1F JFF 42.7,
CF2 ˆ CCl); dC 34 (s, CH2CCl), 67 (CH2CHOH),
6.2%); MS m/z 228 [M ], 218 [M±HF ] 107 [PhCH2O‡];
dH 2.5 (m, 1H, CH2CHF), 2.8 (m, 1H, CH2CHF), 4.2 (dd,
1H, 2JHH 10.5, 3JHH 4.3, CH2), 4.3 (dd, 1H, 2JHH 10.5, 3JHH
3.0, CH2), 4.6 (m, PhCH2), 4.9 (m, 1H, CH2CHO), 5.3 (d of
2
2
73(CH2CHOH), 74 (CH2Ph), 89 (dd, JCF 43.8, JCF
19.8, CCl ˆ CF2), 128 (Ar), 128 (Ar), 129 (Ar),138 (Ar)
154 (t, JCF ˆ 1JCF 286.2 CF2 ˆ CCl).
m, 1H, JHF 53.2, CH2CHF), 5.75, (d of m, 1H, JHF 52,
CHFCHFO), 6.9±7.3 (m 5H, Ar); dF 137 (m, 1F
1
2
2
2
3.1.13. Preparation of (R)-5-(benzyloxymethyl)-2,3-
difluoro-4,5-dihydrofuran (15)
CHFCHFO), 193 (m 1F, CH2CHF); dC 31 (d, JCF
20.9, CH2CHF), 68 (CH2CHO), 74 (PhCH2), 79
The alcohol (13) (0.5 g, 2 mmol) in THF (30 cm3) was
heated under re¯ux with sodium hydride(0.34 g 14 mmol)
for 4 h. The reaction mixture was cooled and ice (10 g) was
carefully added, the organic layer and the ether extracts
(4 Â 25 cm3) of the aqueous layer were combined, dried
(MgSO4) and the solvent removed to leave an oil which was
puri®ed by column chromatography (silica, hexane/ether
4:1) to give (R)-5-(benzyloxymethyl)-2,3-di¯uoro-4,5-
dihydrofuran (15) (0.3 g) (nc) Na2a0 ‡ 5.48; (Found: C,
63.5; H, 5.5% C12H12F2O2 requires C, 63.7; H, 5.35%);
(CH2CHO), 92 (dd, JCF 190.5, JCF 47.2, CHFCHF),
115 (Ar), 122 (Ar), 129 (dd, 1JCF 246, 2JCF 26.6,CHFCHF),
132 (Ar).
1
2
References
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