Synthesis of α-hydroxy-β,β-difluoro-γ-ketoesters via [3,3]sigmatropic rearrangements

Article abstract of DOI:10.1039/b004766j

Readily available γ,γ-difluorinated allylic alcohols obtained from trifluoroethanol were esterified efficiently. Exposure to strong base (LDA) afforded the ester enolates, in which chelation both controlled configuration and stabilised against fragmentation, which were trapped as their silyl ketene acetals. Rearrangement occurred to afford base-sensitive acid products. Esterification under mild conditions afforded the purifiable methyl esters in which the masked ketone had been released. Educts with either a benzyloxy or an allyloxy group at the α-position could be deprotected releasing the alcohols. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004766j

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Synthesis of ꢀ-hydroxy-ꢁ,ꢁ-difluoro-ꢂ-ketoesters via
[3,3]sigmatropic rearrangements
Michael J. Broadhurst,a Samantha J. Brown,b Jonathan M. Percy*b and Michael E. Prime†b
1
a Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire,
UK AL7 3AY
b School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, UK B15 2TT
Received (in Cambridge, UK) 14th June 2000, Accepted 31st July 2000
First published as an Advance Article on the web 11th September 2000
Readily available γ,γ-difluorinated allylic alcohols obtained from trifluoroethanol were esterified efficiently. Exposure
to strong base (LDA) afforded the ester enolates, in which chelation both controlled configuration and stabilised
against fragmentation, which were trapped as their silyl ketene acetals. Rearrangement occurred to afford
base-sensitive acid products. Esterification under mild conditions afforded the purifiable methyl esters in which
the masked ketone had been released. Educts with either a benzyloxy or an allyloxy group at the α-position could be
deprotected releasing the alcohols.
Sigmatropic rearrangements provide an extremely powerful
way of transforming simple fluorinated species into more com-
plex substrates, and for the elaboration of readily available
fluorinated building blocks.1 The correct location of fluorine
atoms within the rearrangement system can result in significant
rate enhancements both in neutral [3,3] rearrangements such as
Cope,2 Claisen3 and oxy-Cope,4 and in neutral5 and anionic6
[2,3] rearrangements. [3,3] Claisen rearrangements of readily
available γ,γ-difluorinated allylic alcohols 2 (obtained via
the addition of fluorinated vinylmetals 1 to aldehydes or
ketones) locate a CF2 centre β to a carboxy carbonyl group
(3 in Scheme 1).
Scheme 2 Possible disconnections from the target molecules.
Given the generality of the difluoroenol ether synthesis
reported by Portella and co-workers,9 this looks like an attract-
ive reaction. Though aldol and related10 reactions have been
reported, electrophiles of the level of functionality used by
McCarthy have not been used to our knowledge. Alternatively,
rearrangements of alkoxyacetates of γ,γ-difluorinated allylic
alcohols derived from trifluoroethanol have been used to syn-
thesise novel difluorinated ketoamino acids 4b;11 here we wish
to show how rearrangement chemistry can be used to synthesise
α-hydroxy-β,β-difluoro-γ-ketoesters12 on 1–22 mmol scales
Scheme 1 Outline route to masked β,β-difluoro-γ-oxocarboxylic acid
from trifluoroethanol.
derivatives.
Results and discussion
In analysis, disconnections of targets that contain this func-
tionality pattern along bonds a or b could be considered
(Scheme 2). The addition of an acyl anion equivalent to an
α-alkoxy difluoroalkenoate (making bond a) of the type
described by Shi and co-workers7 could be considered, but
such additions normally proceed to monofluorocompounds
via addition–elimination mechanisms. Alternatively, McCarthy
and co-workers reported8 the synthesis of a Kynureninase
inhibitor 4b in which bond b was made from a difluorinated
silyl enol ether (Scheme 2).
The generation of enolates from alkoxyacetate esters of allylic
alcohols occurs stereoselectively (Scheme 3).13 Coordination of
the metal counterion (usually lithium) between two oxygen
atoms controls the configuration of the developing enolate 5.
Trapping as a silyl ketene acetal 6 then locks this stereochemical
information in place and the rearrangement can be used to
transcribe the information into a vicinal pair of stereogenic
centres (in 7), or to effect chirality transfer or asymmetric
induction. Recent applications have been made in natural
product synthesis,14 while attractive combinations with ring-
closing metathesis procedures afford interesting heterocycles.15
The reaction is not limited to alkoxyacetate esters; enolates
† Current address: School of Chemistry, University of York,
Heslington, York, UK YO10 5DD.
DOI: 10.1039/b004766j
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
This journal is © The Royal Society of Chemistry 2000
3217

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Table 1 Preparation of esters used for rearrangement
R
Alcohol
RЈ = Me
Yield (%)
RЈ = Bn
Yield (%)
RЈ = allyl
Yield (%)
H
Me
Et
i-Pr
t-Bu
Ph
8a
8b
8c
8d
8e
8f
9a
—
9c
9d
9e
9f
79a
—
85
81
82
79
72
—
—
—
—
11c
11d
—
—
—
—
—
83
80
—
—
—
10b
10c
10d
10e
10f
—
92b,c
82
75
85
79
—
CH᎐CH2
8g
9g
᎐
a This ester was only moderately stable and could not be characterised fully. b Esterification started at 0 ЊC. c Obtained in 96% purity and
used without purification.
Scheme 5 Reagents and conditions: i, LDA, THF, Ϫ78 ЊC; ii, Me3SiCl;
iii, ∆ then work-up; iv, SOCl2, MeOH, 0 ЊC to rt, 18 hours.
Scheme 3 Reagents and conditions: i, LDA, THF, Ϫ78 ЊC; ii, Me3SiCl;
iii, ∆ then work-up.
methanol. Prior to quenching, the ester was no longer visible by
TLC, and NMR of the crude acid after work-up indicated
(in each case) the presence of a single fluorinated compound
12–14.
In the case of 13b (from 10b), the crude product also exhib-
ited satisfactory NMR spectra (though most products were
from esters of lactic16 and hydroxybutyric17 acids have also
proved sufficiently stable for trapping and rearrangement
though the range of examples is more limited. The main limi-
tation to the method arises from the tendency of ester enolates
to fragment to the corresponding ketene–alkoxide pair;18 trap-
esterified directly, see later). Procedures using other bases were
ping with the silicon electrophile must therefore be efficient at
less successful; the same procedure with LTMP (TMP = 2,2,6,6-
low temperature. When a difluoroallylic ester is deprotonated,
elimination appears to be particularly facile and we were not
able to perform simple Ireland ester enolate Claisen rearrange-
ments. However, alkoxyacetates could be deprotonated and
tetramethylpiperidine) returned the starting ester, while mostly
starting material (ca. 75%) was recovered when LiHMDS was
used, along with a small amount (ca. 25%) of rearranged
material and a number of unidentified minor products. The
Lewis acid-mediated procedure described by Oh et al.20 led to
trapped successfully, presumably because the chelation of the
lithium atom stabilises the enolates against fragmentation as
the recovery of starting material and fragmentation product
well as controlling their configuration.
only. No advantage in yield accrued when more than one
equivalent of silicon electrophile was added (we tried up to a
six-fold excess).
We were not able to purify the acids and instead investigated
Difluoroallylic alcohols 8 were synthesised according to our
published method19 and methoxy (9), benzyloxy (10) and
allyloxy (11) esters were prepared (Scheme 4, Table 1) from the
the preparation of the esters directly. Treatment with diazo-
methane (generated in situ) resulted in decomposition; we were
not able to isolate any identifiable products from the reaction
mixtures. The observation of a similar pattern of behaviour
under the iodomethane–N,N,NЈ,NЈ-tetramethylguanidine
(TMG) conditions used by Kocienski and co-workers,21
suggested a decarboxylative pathway involving β-fluoride
elimination. However, esterification was successful under acidic
conditions;22 simply taking the crude acid into cold (0 ЊC)
Scheme 4 Reagents and conditions: i, MeOCH2COCl or BnOCH2-
methanol and adding thionyl chloride led to the formation of
COCl, pyridine, DMAP, DCM, rt, 18 hours then extractive work-up; ii,
the methyl esters 15–17 (Table 2), from which the MEM-group
had been cleaved.
H2C᎐CHCH2OCH2CO2H, EDC, DMAP, DCM, rt, 18 hours then
extractive work-up.
᎐
In the case of 9g, rearrangement is possible at either of two
vinylic termini; the dienyl ester fragmented when exposed to
LDA at Ϫ78 ЊC so we carried out the deprotonation under
trapping conditions at Ϫ100 ЊC and isolated crude material that
contained only 18 in an estimated yield of 71%, and none of
the product (12g) of rearrangement through the fluorinated
terminus (Scheme 6). When we rearranged 8g under Eschen-
moser conditions (Scheme 7), the major rearrangement product
was 21 at the expense of 22.23
commercial acid chlorides in the first two cases, and from
allyloxyacetic acid in the last using a diimide coupling. Chro-
matography was not always necessary; for example, ester 10b
was obtained direct from the work-up in 96% purity (by GC) on
a 20 g scale.
Rearrangements were executed cleanly (Scheme 5) when the
esters were added slowly to freshly generated LDA in THF
at Ϫ78 ЊC. The silicon electrophile was added five minutes
after the end of the addition, then the mixture was allowed to
warm to room temperature over one hour and quenched with
These observations suggest that Claisen and related
rearrangements occur more slowly when fluorine atom sub-
3218
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Table 2 Ketoesters prepared by rearrangement and methanolysis
R
RЈ = Me
Yield (%)
RЈ = Bn
Yield (%)
RЈ = allyl
Yield (%)
Me
Et
i-Pr
t-Bu
Ph
—
—
54
56
65
61
16b
16c
16d
16e
—
74
58
54
76
—
—
—
63
60
—
—
15c
15d
15e
15f
17c
17d
—
—
Scheme 6 Reagents and conditions: i, LDA–Me3SiCl, THF, Ϫ100 ЊC, inverse addition; ii, warm to rt; iii, aqueous work-up; iv, TMSCHN2, MeOH.
alcohols to construct highly functionalised branched acids with
moderate stereocontrol; adequate ester enolate stabilisation by
Scheme 7 Reagents and conditions: i, HC(OMe)2NMe2, PhMe, 60 ЊC.
β-alkoxy groups does not appear to be established, whereas
stituents are located at C-6 and are consistent with the general
conclusion of Purrington and Weeks24 that “no acceleration of
rearrangement of the esters derived from 3,3-difluoroallyl
alcohols compared with their non-fluorinated analogs was
observed,” whereas the effect of fluorination at C-1 and C-2
is unambiguously accelerative, as documented by Normant,25
Gelb26 and Gerhart27 inter alia. In contrast, Dauben–Dietsch
rearrangement of 8c occurred at 40 ЊC, an unusually low
temperature,28 and was followed by dehydrofluorination. How-
ever, we are not able to rule out the possibility that this
unusually facile rearrangement is mercury()-catalysed or
-mediated.29 Burkhart and co-workers concluded that [3,3]
Claisen rearrangements of γ,γ-difluoroallylic (C-6-difluorin-
ation) alcohols are accelerated relative to the non-fluorinated
congeners, though the systems described in their paper
lack control experiments and were not capable of competitive
reactions. We suggest that the observations of Schemes 6 and 7
reinforce strongly the conclusion of Purrington and Weeks.
Cleavage of the MEM-group of 18 occurred upon standing
in CDCl3; we speculated that C-protonation of the enol acetal
might be occurring intramolecularly,30 so the acid was esterified
with TMS-diazomethane. However, column chromatography
of the product returned enone 20 in 50% yield; presumably, the
increased conjugation increases the reactivity of the system
towards C-protonation through stabilisation of the conjugate
acid 19 implying a mechanism for MEM cleavage as described
in Scheme 6.
β-amino groups have been exploited successfully.31 In any case,
the conditions described by Kurth led only to decomposition
and a number of attempts using trapping conditions met with a
similar fate. We suggest that the difluoroallylic alkoxides are too
competent as leaving groups for the derived enolates to persist
when the chelation effect is weaker.
Deprotection of the C-2 hydroxy group could be achieved by
palladium-catalysed hydrostannation of allyl ethers32 17c
and 17d, but debenzylations33 (H2/20 wt% Pd(OH)2–C, MeOH,
1 atm) of 16c and 16d were cleaner reactions and afforded
pleasing yields of the alcohols 25c and 25d respectively. Studies
of the relative propensities for hydration of 2-alkoxy and
2-hydroxy ketoesters are in progress. Once again, trifluoro-
ethanol serves as a useful starting material for the preparation
of highly functionalised difluorocompounds. In this case, the
CF2 centre is surrounded by three oxygen functions differenti-
ated by their oxidation states. The sequences are short, the
chemistry is scalable and the penultimate educts 15–17 can be
isolated with a minimum of chromatography. The route
complements the well-known and often used Reformatsky34
entry to highly functionalised difluorocompounds.
Experimental
1H and 13C NMR spectra were recorded on a Bruker AC-300
(300.13 and 75.47 MHz respectively) spectrometer. 500 MHz
NMR spectra were recorded on a Bruker DRX500 spec-
trometer. All spectra were recorded relative to tetramethylsilane
as the internal standard. 19F NMR spectra were recorded on
Bruker AC-300 (282.41 MHz) relative to chlorotrifluoro-
methane as the internal standard. The 19F NMR spectra of
Though suspicious that we were operating close to the limit
of enolate stability, we explored the less common rearrange-
ments of 3-hydroxybutyrate17 and 3-methoxypropionate13
esters 23 and 24. Kurth used the former esters of simple allylic
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
3219

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2
2
rearrangement educts reveal an AB quartet in which each
d, JF–F 64.9), Ϫ109.6 (1F, d, JF–F 64.9); δC (75 MHz, CDCl3)
1 2
“doublet” is further split by 3JH–F coupling (to provide a doublet
154.0 (dd, JC–F 291.3, 285.7), 118.9 (td, JC–F 36.5, 9.9),
97.9, 71.4, 68.4, 63.0 (dd, 3JC–F 3.9, 1.7), 58.9, 20.1 (t, 4JC–F 2.3).
The alcohol was taken on to the ester without further
characterisation.
2
of doublets). The much larger JF–F coupling (greater than 25
times) means that the overall appearance of these is one of an
AB quartet. This descriptor is therefore retained in describing
these more complex multiplicities using the modification:
chemical shift (1F, dd, one half of an AB quartet, 2JF–F, 3JH–F).
Chemical ionisation (CI) and electron impact (EI) mass spectra
were recorded on a Kratos MS-80 mass spectrometer or a VG
ProSpec mass spectrometer with a DS-90 data system. Chem-
ical ionisation (CI) methods used ammonia as the reagent gas.
Fast atom bombardment (FAB) mass spectra were recorded
using a VG Zabspec instrument. A Micromass LCT mass spec-
trometer was used for both low resolution (ES-TOF) mass
spectra (using a methanol mobile phase) and HRMS measure-
ments (using a lockmass incorporated into the mobile phase).
HRMS measurements were also obtained from either the VG
ProSpec spectrometer or a VG Autospec instrument. Elemental
analyses were performed at the University of North London.
Thin layer chromatography was performed on precoated
aluminium-backed silica gel plates supplied by E. Merck, A. G.
Darmstadt, Germany (silica gel 60 F254, thickness 0.2 mm,
Art. 5554). Visualisation was achieved by UV light and/or an
anisaldehyde–sulfuric acid or potassium permanganate stain.
Flash column chromatography was performed using an air
compressor on silica gel (E. Merck A. G. Kieselgel 60, Art.
9385). THF was dried by refluxing with benzophenone over
sodium wire until a deep purple colour developed. It was then
distilled and collected by dry syringe as required. Dichloro-
methane was dried by refluxing with calcium hydride, sub-
sequently distilled and collected by dry syringe as required.
Methanol was dried by refluxing with iodine and magnesium
turnings for 3 hours, and subsequently distilled onto 3 Å
molecular sieves. n-Butyllithium was titrated before use against
1,3-diphenylpropan-2-one p-tolylsulfonylhydrazone. Thionyl
chloride was distilled from 10% triphenyl phosphite (w/w)
under an atmosphere of nitrogen. Diisopropylamine was dis-
tilled from calcium hydride and stored over calcium hydride
under an atmosphere of nitrogen. DCC and EDC [1-(3-
3,3-Difluoro-2-[(methoxyethoxy)methoxy]prop-2-en-1-yl
(methoxy)acetate 9a
In a typical procedure, pyridine (0.61 ml, 7.6 mmol), followed
by methoxyacetyl chloride (1.18 ml, 7.6 mmol), was added to a
stirred solution of 8a (1.5 g, 7.6 mmol) in DCM (20 ml) con-
taining DMAP (0.35 g, 3.04 mmol). The mixture was stirred at
room temperature and followed by TLC. After 18 hours, all of
the starting material had been converted to a new product
(Rf = 0.33, 50% ethyl ether in light petroleum). The solution was
then concentrated in vacuo and the residue taken up in DCM.
The solution was washed with HCl (20 ml, 0.1 M) then water
(20 ml), dried (MgSO4), filtered and concentrated in vacuo to
afford a yellow oil. Kugelrohr distillation afforded ester 9a (1.62
g, 79%) as a colourless oil; bp 85 ЊC/0.05 mmHg; Rf (50% ethyl
ether in light petroleum) 0.33; δH (300 MHz, CDCl3) 4.92 (2H,
4
s, OCH2O), 4.80 (2H, t, JH–F 2.6, CCH2O), 4.05 (2H, s,
CH2OCH3), 3.85–3.78 (2H, m, OCH2CH2O), 3.55–3.50 (2H, m,
OCH2CH2O), 3.45 (3H, s, OCH3), 3.35 (3H, s, OCH3); δF (282
2
2
MHz, CDCl3) Ϫ96.0 (1F, d, JF–F 52.2), Ϫ106.0 (1F, d, JF–F
1
52.2); δC (75 MHz, CDCl3) 169.8, 155.7 (t, JC–F 289.2), 111.5
(dd, 2JC–F 52.3, 16.4), 95.8, 71.4, 69.4, 68.1, 59.2, 58.8, 58.5; mass
spectra and microanalysis could not be obtained, as surpris-
ingly, the compound is unstable and decomposes upon storage.
Further transformations of this compound were not pursued.
1,1-Difluoro-2-[(methoxyethoxy)methoxy]pent-1-en-3-yl
(methoxy)acetate 9c
From 8c (2.0 g, 8.85 mmol), methoxyacetyl chloride (0.9 ml,
8.85 mmol), pyridine (0.71 ml, 8.85 mmol) and DMAP (0.4 g,
3.5 mmol) in DCM (50 ml). Usual work-up then Kugelrohr
distillation afforded ester 9c (2.23 g, 85%) as a colourless oil, bp
80 ЊC/0.05 mmHg; Rf (50% ethyl ether in light petroleum) 0.29;
νmax (film)/cmϪ1 1748br s (C᎐O); δ (300 MHz, CDCl3) 5.45
dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride]
᎐
H
(1H, t, 4JH–F 7.3, CH), 4.95 (1H, d, one half of an AB quartet,
2JHa–Hb 6.2, OCHaHbO), 4.80 (1H, d, one half of an AB quartet,
2JHa–Hb 6.2, OCHaHbO), 4.00 (2H, s, C(O)CH2OCH3), 3.90–3.70
(2H, m, OCH2CH2O), 3.55 (2H, t, 3JH–H 5.1, OCH2CH2O), 3.40
(3H, s, OCH3), 3.35 (3H, s, OCH3), 1.85–1.70 (2H, m, CH2-
were used as supplied by the Aldrich Chemical Co. Ltd. All
organic extracts were dried using oven-dried magnesium sulfate.
Light petroleum refers to the fraction boiling in the range
40–60 ЊC. Difluoroallylic alcohols were prepared according to
our published procedure,19 except for 8b which was prepared as
described below.
3
CH3), 0.85 (3H, t, JH–H 7.3, CH2CH3); δF (282 MHz, CDCl3)
Ϫ97.00 (1F, d, JF–F 55.3), Ϫ105.39 (1F, d, JF–F 55.3); δC (75
2
2
1
MHz, CDCl3) 169.3, 155.7 (quat, t, JC–F 292.2), 112.9 (quat,
4,4-Difluoro-3-[(methoxyethoxy)methoxy]but-3-en-2-ol 8b
dd, 1JC–F 53.1, 14.7), 97.2, 71.7, 71.5, 69.6, 68.4, 59.3, 58.9, 23.9,
9.5 [HRMS (ES, M[Na]ϩ) Found: 321.1139. Calc. for C12H20-
O6F2Na 321.1126]; m/z (CI) 316 (20%, [M ϩ NH4]ϩ), 209 (12),
89 (100).
2-[(Methoxyethoxy)methoxy]-1,1,1-trifluoroethane (18.8 g, 0.1
mol) was added slowly to a stirred solution of LDA (generated
from n-butyllithium (140 ml of a 1.43 M solution in hexanes,
0.20 mol) and dry diisopropylamine (26 ml, 0.205 mmol)) in
THF (100 ml) at Ϫ78 ЊC. The dark orange suspension was
stirred at Ϫ78 ЊC for 30 minutes, then freshly fractionated acet-
aldehyde (4.4 g, 0.1 mol) was added in a thin stream. The
mixture was allowed to warm to Ϫ30 ЊC over 2 hours then
quenched with methanolic ammonium chloride (100 ml) and
allowed to warm to room temperature. The mixture was then
poured into water (800 ml) and extracted with ethyl ether
(3 × 100 ml). The combined organic extracts were dried
(MgSO4), filtered and concentrated at reduced pressure (> 40
mmHg). Reduced pressure short path distillation afforded 8b as
a colourless oil (13.2 g, 74%, 97% pure by GC) bp 57 ЊC/0.15
mmHg; δH (300 MHz, CDCl3) 5.00 (1H, d, one half of an AB
quartet, 2JHa–Hb 6.6, OCHaHbO), 4.88 (1H, d, one half of an AB
1,1-Difluoro-2-[(methoxyethoxy)methoxy]-4-methylpent-1-en-3-
yl (methoxy)acetate 9d
From 8d (1.0 g, 4.20 mmol), methoxyacetyl chloride (0.65 ml,
4.20 mmol), pyridine (0.34 ml, 4.20 mmol) and DMAP (0.2 g,
1.70 mmol) in DCM (25 ml). Usual work-up and Kugelrohr
distillation afforded ester 9d (1.06 g, 81%) as a colourless oil,
bp 80 ЊC/0.05 mmHg (Found: C, 50.20; H, 7.14. Calc. for
C13H22O6F2: C, 50.00; H, 7.10%); Rf (40% ethyl ether in light
3
petroleum) 0.3; δH (CDCl3, 300 MHz) 5.17 (1H, d, JH–H 3.1,
2
CH), 4.95 (1H, d, one half of an AB quartet, JHa–Hb 6.2,
OCHaHbO), 4.80 (1H, d, one half of an AB quartet, 2JHa–Hb 6.2,
OCHaHbO), 4.00 (2H, s, CH2), 3.88–3.65 (4H, m, OCH2CH2O),
3.35 (3H, s, OCH3), 3.30 (3H, s, OCH3), 2.20–2.00 (1H,
2
quartet, JHa–Hb 6.6, OCHaHbO), 4.51–4.39 (1H, br s, OH),
3
3.99–3.90 (2H, m, OCH2CH2O), 3.82–3.73 (2H, m, OCH2-
CH2O), 3.58–3.52 (1H, m, CHOH), 3.48 (3H, s, OCH3), 1.35
m, CH(CH3)2), 0.95–0.80 (6H, d, JH–H 12.0, CH(CH3)2);
δF (CDCl3, 282 MHz) Ϫ97.2 (1F, d, 2JF–F 56.4), Ϫ105.5 (1F, d,
3
1
(3H, d, JH–H 7.3, CHCH3); δF (282 MHz, CDCl3) Ϫ100.9 (1F,
2JF–F 56.4); δC (CDCl3, 75 MHz) 169.4, 155.9 (t, JC–F 297.6),
3220
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226

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2
114.2 (dd, JC–F 57.1, 14.3), 97.2, 75.4, 71.5, 65.6, 59.5, 59.3,
4,4-Difluoro-3-[(methoxyethoxy)methoxy]but-3-en-2-yl
(benzyloxy)acetate 10b
59.0, 29.1, 18.2 [HRMS (CI, M[NH4]ϩ) Found: 330.174323.
Calc. for C13H26NO6F2 330.172819]; m/z (CI) 330 (100%,
[M ϩ NH4]ϩ).
Pyridine (5.22 ml, 64.6 mmol), followed by benzyloxyacetyl
chloride (11.93 g, 64.6 mmol), was added slowly (over 20 min-
utes) to a stirred solution of 8b (11.56 g, 64.6 mmol) in DCM
(100 ml) containing DMAP (2.7 g, 22 mmol) at 0 ЊC. The mix-
ture was allowed to warm to room temperature and stirred
overnight; TLC then showed the reaction to be complete. The
solution was poured into cold HCl (100 ml of a 0.1 M aqueous
solution) and extracted with ethyl ether (3 × 40 ml) then the
combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo to afford 10b as a pale yellow oil (20.72 g,
92%) which was used without further purification (96% pure by
GC); Rf (50% ethyl ether in light petroleum) 0.42; νmax (film)/
1,1-Difluoro-2-[(methoxyethoxy)methoxy]-4,4-dimethylpent-1-
en-3-yl (methoxy)acetate 9e
From 8e (0.6 g, 2.45 mmol), methoxyacetyl chloride (0.40 ml,
2.45 mmol), pyridine (0.20 ml, 2.45 mmol) and DMAP (0.11 g,
0.98 mmol) in DCM (20 ml). Usual work-up and purification
by Kugelrohr distillation afforded the ester 9e (0.64 g, 82%) as a
colourless oil, bp 82 ЊC/0.1 mmHg; Rf (40% ethyl ether in light
4
petroleum) 0.36; δH (CDCl3, 300 MHz) 5.17 (1H, d, JH–F 2.9,
2
CH), 4.92 (1H, d, one half of an AB quartet, JHa–Hb 5.9,
cmϪ1 2921br s, 1761br s (C᎐O), 1604w, 1496s, 1454s, 1248br s,
OCHaHbO), 4.82 (1H, d, one half of an AB quartet, 2JHa–Hb 5.9,
᎐
2
1194br s, 1128br s, 1044br s, 942s, 855m, 733s, 697s; δH (CDCl3,
300 MHz) 7.37–7.28 (5H, m, Ph), 5.73–5.65 (1H, m, CH), 4.97
(1H, d, one half of an AB quartet, 2JHa–Hb 6.3, OCHaHbO), 4.90
(1H, d, one half of an AB quartet, 2JHa–Hb 6.3, OCHaHbO), 4.63
OCHaHbO), 4.05 (1H, d, one half of an AB quartet, JHa–Hb
16.5, CHaHbOCH3), 3.95 (1H, d, one half of an AB quartet,
2JHa–Hb 16.5, CHaHbOCH3), 3.82–3.71 (2H, m, OCH2CH2O),
3.55–3.49 (2H, m, OCH2CH2O), 3.40 (3H, s, OCH3), 3.35 (3H,
s, OCH3), 0.90 (9H, s, C(CH3)3); δF (CDCl3, 282 MHz) Ϫ97.4
2
(1H, d, one half of an AB quartet, JHa–Hb 11.8, OCHaHbPh),
4.58 (1H, d, one half of an AB quartet, 2JHa–Hb 11.8, OCHaHb-
Ph), 4.06 (2H, s, C(O)CH2O), 3.88–3.73 (2H, m, OCH2CH2O),
3.57–3.52 (2H, m, OCH2CH2O), 3.38 (3H, s, OCH3), 1.44 (3H,
d, 3JH–H 7.3, CHCH3); δF (CDCl3, 282 MHz) Ϫ97.3 (1F, d, 2JF–F
2
4
2
(1F, dd, JF–F 56.4, JH–F 2.9), Ϫ104.8 (1F, d, JF-F 56.4);
1
δC (CDCl3, 75 MHz) 169.5, 156.2 (t, JC–F 289.9), 112.6 (dd,
2JC–F 54.8, 14.8), 97.7, 76.0, 71.6, 69.6, 68.6, 59.4, 58.9, 35.3,
26.2 (3 signals) [HRMS (ES, M[Na]ϩ) Found: 349.1429. Calc.
for C14H24O6F2Na 349.1439]; m/z (ES) 349 (60%, [M ϩ Na]ϩ),
257 (100).
2
55.1), Ϫ104.7 (1F, d, JF–F 55.1); δC (CDCl3, 75 MHz) 169.3,
155.9 (t, 1JC–F 292.1), 137.2, 128.6, 128.2, 114.1 (dd, 2JC–F 36.2,
4
14.7), 97.4, 73.5, 71.5, 68.6, 67.2, 59.2, 24.1, 17.1 (t, JC–F 2.3);
m/z (ES) 360 (78%, Mϩ), 192 (100).
3,3-Difluoro-2-[(methoxyethoxy)methoxy]-1-phenylprop-2-en-1-
yl (methoxy)acetate 9f
1,1-Difluoro-2-[(methoxyethoxy)methoxy]pent-1-en-3-yl
(benzyloxy)acetate 10c
From 8f (1.23 g, 4.48 mmol), methoxyacetyl chloride (0.56 ml,
4.48 mmol), pyridine (0.36 ml, 4.48 mmol) and DMAP (0.21 g,
1.80 mmol) in DCM (35 ml). Usual work-up and purification
by Kugelrohr distillation afforded the ester 9f (1.23 g, 79%) as a
colourless oil, bp 93 ЊC/0.1 mmHg; Rf (40% ethyl ether in light
petroleum) 0.41; νmax (film)/cmϪ1 1762br s (C᎐O); δ (300 MHz,
CDCl3) 7.40–7.30 (5H, m, Ph), 6.62 (1H, t, JH–F 1.6, CH),
4.90 (1H, d, one half of an AB quartet, JHa–Hb 6.9, OCHa-
HbO), 4.70 (1H, d, one half of an AB quartet, JHa–Hb 6.9,
From 8c (0.9 g, 3.89 mmol) in DCM (20 ml), pyridine (0.31 ml,
4.28 mmol), benzyloxyacetyl chloride (0.48 ml, 4.28 mmol) and
DMAP (0.20 g, 1.56 mmol). Usual work-up and column chro-
matography afforded ester 10c (1.16 g, 82%) as a colourless oil;
Rf (50% ethyl ether in light petroleum) 0.45 (Found: C, 58.03;
H, 6.50. Calc. for C18H24O6F2: C, 57.75; H, 6.46%); δH (CDCl3,
300 MHz) 7.48–7.32 (5H, m, Ph), 5.50–5.42 (1H, m, CH), 4.98
(1H, d, one half of an AB quartet, 2JHa–Hb 5.9, OCHaHbO), 4.88
(1H, d, one half of an AB quartet, 2JHa–Hb 5.9, OCHaHbO), 4.64
᎐
H
4
2
2
OCHaHbO), 4.20 (2H, s, CH2OCH3), 3.75–3.61 (2H, m,
OCH2CH2O), 3.55–3.45 (2H, m, OCH2CH2O), 3.44 (3H, s,
OCH3), 3.35 (3H, s, OCH3); δF (282 MHz, CDCl3) Ϫ96.4 (1F,
2
(1H, d, one half of an AB quartet, JHa–Hb 11.8, OCHaHbPh),
4.58 (1H, d, one half of an AB quartet, 2JHa–Hb 11.8, OCHaHb-
Ph), 4.05 (2H, s, C(O)CH2O), 3.88–3.70 (2H, m, OCH2CH2O),
3.55–3.52 (2H, m, OCH2CH2O), 3.35 (3H, s, OCH3), 1.85–1.70
(2H, m, CH2CH3), 0.91 (3H, t, 3JH–H 7.3, CH2CH3); δF (CDCl3,
282 MHz) Ϫ96.70 (1F, d, 2JF–F 54.9), Ϫ105.1 (1F, d, 2JF–F 54.9);
2
2
d, JF–F 54.5), Ϫ104.7 (1F, d, JF–F 54.5); δC (75 MHz, CDCl3)
1
169.0, 155.7 (t, JC–F 288.6), 135.7, 128.6 (4 signals), 126.5,
2
112.8 (dd, JC–F 55.2, 14.6), 97.5, 71.5, 71.0, 69.7, 68.5, 59.5,
59.0 [HRMS (ES, M[Na]ϩ) Found: 369.1151. Calc. for
C16H20O6F2Na 369.1126]; m/z (CI) 364 (42%, [M ϩ NH4]ϩ),
254 (33), 108 (76), 59 (100).
1
δC (CDCl3, 75 MHz) 169.6, 155.9 (t, JC–F 292.1), 137.2, 128.6,
2
128.2, 113.2 (dd, JC–F 15.5, 36.8), 97.4, 73.5, 71.9, 71.5, 68.6,
67.2, 59.2, 24.1, 9.7; m/z (CI) 392 (26%, [M ϩ NH4]ϩ), 300 (36),
1,1-Difluoro-2-[(methoxyethoxy)methoxy]penta-1,4-dien-3-yl
(methoxy)acetate 9g
242 (76), 184 (87), 91 (100).
From 8g (2.0 g, 8.9 mmol), methoxyacetyl chloride (1.38 ml, 8.9
mmol), pyridine (0.72 ml, 8.9 mmol) and DMAP (0.43 g, 1.80
mmol) in DCM (35 ml). Usual work-up and purification by
column chromatography afforded the ester 9g (1.89 g, 72%) as a
colourless oil; Rf (50% ethyl ether in light petroleum) 0.38; νmax
(film)/cmϪ1 1738s (C᎐O); δ (300 MHz, CDCl3) 6.05 (1H, d,
1,1-Difluoro-2-[(methoxyethoxy)methoxy]-4-methylpent-1-en-3-
yl (benzyloxy)acetate 10d
From alcohol 8d (1.0 g, 4.16 mmol), benzyloxyacetyl chloride
(0.71 ml, 4.60 mmol), pyridine (0.37 ml, 4.60 mmol) and
DMAP (0.2 g, 1.70 mmol) in DCM (25 ml). Usual work-up and
column chromatography afforded 10d (1.22 g, 75%) as a colour-
less oil; Rf (20% ethyl acetate in light petroleum) 0.57; νmax
᎐
H
3JH–H 6.0, CH), 5.98–5.85 (1H, m, CCHCH2), 5.38 (1H, d, 3JH–H
3
15.0, CHЈ), 5.33 (1H, d, JH–H 9.0, CHЈ), 4.95 (1H, d, one half
of an AB quartet, 2JHa–Hb 7.5, OCHaHbO), 4.88 (1H, d, one half
(film)/cmϪ1 1761 (C᎐O) (Found: C, 58.92; H, 6.88. Calc. for
᎐
2
of an AB quartet, JHa–Hb 7.5, OCHaHbO), 4.05 (2H, s,
C19H26O5F2: C, 58.75; H, 6.75%); δH (CDCl3, 300 MHz) 7.40–
7.25 (5H, m, Ph), 5.25–5.15 (1H, m, CH), 4.95 (1H, d, one half
of an AB quartet, 2JHa–Hb 6.2, OCHaHbO), 4.85 (1H, d, one half
of an AB quartet, 2JHa–Hb 6.2, OCHaHbO), 4.66 (1H, d, one half
CH2OCH3), 3.72–3.70 (2H, m, OCH2CH2O), 3.50–3.33 (2H,
m, OCH2CH2O), 3.45 (3H, s, OCH3), 3.35 (3H, s, OCH3);
δF (282 MHz, CDCl3) Ϫ96.4 (1F, d, 2JF–F 53.0), Ϫ104.2 (1F, d,
1
2
2JF–F 53.0); δC (75 MHz, CDCl3) 168.9, 155.5 (t, JC–F 292.3),
of an AB quartet, JHa–Hb 11.8, OCHaHbPh), 4.61 (1H, d, one
2
2
131.4, 119.2, 113.3 (dd, JC–F 36.2, 15.3), 97.2, 71.5, 70.6,
half of an AB quartet, JHa–Hb 11.8, OCHaHbPh), 4.10 (2H, s,
69.6, 68.5, 59.3, 59.0 [HRMS (CI, M[NH4]ϩ) Found:
314.142009. Calc. for C12H22NO6F2 314.141519]; m/z (CI) 314
(100% [M ϩ NH4]ϩ.
C(O)CH2O), 3.85–3.70 (2H, m, OCH2CH2O), 3.65–3.45 (2H,
m, OCH2CH2O), 3.35 (3H, s, OCH3), 2.25–2.05 (1H, m,
3
CH(CH3)2), 0.95 (3H, d, JH–H 6.6, CH(CH3)2), 0.91 (3H, d,
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
3221

View Article Online
2JH–H 6.6, CH(CH3)2); δF (CDCl3, 282 MHz) Ϫ97.1 (1F, d, 2JF–F
NH4]ϩ) which was used without further characterisation or
purification.
2
55.9), Ϫ105.4 (1F, d, JF–F 55.9); δC (CDCl3, 75 MHz) 169.6,
155.9 (t, 1JC–F 292.0), 137.2, 128.6, 128.1, 112.8 (dd, 2JC–F 36.2,
14.9), 97.3, 75.5, 73.4, 71.6, 68.5, 67.1, 59.1, 29.2, 18.9, 18.3;
m/z (CI) 406 (55%, [M ϩ NH4]ϩ), 184 (65), 108 (82), 59 (100).
1,1-Difluoro-2-[(methoxyethoxy)methoxy]pent-1-en-3-yl
(allyloxy)acetate 11c
In a typical procedure, EDC (1.99 g, 9.73 mmol) was added to a
cool (0 ЊC) solution of the alcohol 8c (2.0 g, 8.85 mmol),
DMAP (0.41 g, 3.54 mmol) in dry DCM (20 ml). The mixture
was stirred until all of the EDC had dissolved, then allyl-
oxyacetic acid (1.13 g, 9.73 mmol) was added and the reaction
mixture was left to stir overnight. The mixture was then concen-
trated in vacuo and the residue taken up in a mixture of ethyl
acetate (30 ml) and HCl (10 ml of a 1 M aqueous solution). The
aqueous layer was removed and the organic layer washed with
water (20 ml), saturated sodium bicarbonate (20 ml) and brine
(20 ml) before being dried (MgSO4), filtered and concentrated
in vacuo to afford a pale yellow oil. Column chromatography
afforded allyloxyacetate 11c (2.37 g, 83%) as a colourless oil; Rf
(50% ethyl ether in light petroleum) 0.48; δH (CDCl3, 300 MHz)
1,1-Difluoro-2-[(methoxyethoxy)methoxy]-4,4-dimethylpent-1-
en-3-yl (benzyloxy)acetate 10e
From 8e (0.80 g, 3.16 mmol), benzyloxyacetyl chloride (0.54 ml,
3.50 mmol), pyridine (0.28 ml, 3.50 mmol) and DMAP (0.11 g,
1.26 mmol) in DCM (25 ml). Usual work-up and column
chromatography afforded 10e (1.30 g, 85%) as a colourless oil;
Rf (20% ethyl acetate in light petroleum) 0.51 (Found: C, 59.81;
H, 6.84. Calc. for C18H24O6F2: C, 59.69; H, 7.01%); δH (CDCl3,
300 MHz) 7.40–7.21 (5H, m, Ph), 5.25–5.19 (1H, m, CH), 4.93
(1H, d, one half of an AB quartet, 2JHa–Hb 5.9, OCHaHbO), 4.82
(1H, d, one half of an AB quartet, 2JHa–Hb 5.9, OCHaHbO), 4.65
2
(1H, d, one half of an AB quartet, JHa–Hb 11.8, OCHaHbPh),
4.56 (1H, d, one half of an AB quartet, 2JHa–Hb 11.8, OCHaHb-
Ph), 4.12 (2H, s, C(O)CH2O), 3.80–3.68 (2H, m, OCH2CH2O),
3.50–3.41 (2H, m, OCH2CH2O), 3.30 (3H, s, OCH3), 1.00 (9H,
5.98–5.81 (1H, m, CH᎐CH ), 5.50–5.40 (1H, m, CF CCH),
᎐
2
2
5.32–5.18 (2H, m, CH᎐CH ), 4.97 (1H, d, one half of an AB
᎐
2
2
s, C(CH3)3); δF (CDCl3, 282 MHz) Ϫ97.4 (1F, d, JF–F 56.4),
quartet, 2JHa–Hb 5.9, OCHaHbO), 4.89 (1H, d, one half of an AB
2
4
2
Ϫ104.7 (1F, dd, JF–F 56.4, JH–F 1.97); δC (CDCl3, 75 MHz)
quartet, JHa–Hb 5.9, OCHaHbO), 4.10–4.02 (4H, m, C(O)CH2,
1
169.7, 156.3 (t, JC–F 296.2), 137.3, 128.6, 128.1, 112.8 (dd,
OCH2CH), 3.88–3.49 (2H, m, OCH2CH2O), 3.56–3.51 (2H, m,
OCH2CH2O), 3.37 (3H, s, OCH3), 1.83–1.71 (2H, m, CHCH2-
CH3), 0.90 (3H, t, 3JH–H 10.7, CH2CH3); δF (CDCl3, 282 MHz)
Ϫ96.8 (1F, d, 2JF–F 54.8), Ϫ105.1 (1F, dd, 2JF–F 54.8, 4JH–F 1.70);
2JC–F 35.7, 15.0), 97.9, 76.3, 73.5, 71.7, 68.7, 67.2, 59.2, 35.5,
26.4; m/z (CI) 420 (26%, [M ϩ NH4]ϩ), 252 (15), 184 (55), 106
(100).
1
δC (CDCl3, 75 MHz) 169.5, 155.7 (t, JC–F 292.6), 133.7, 118.2,
97.3, 94.1 (dd, 2JC–F 14.7, 36.7), 72.3, 71.7, 71.5, 68.5, 67.0, 59.0,
23.9, 9.51 [HRMS (ES, M[Na]ϩ) Found: 347.1289. Calc. for
C14H22O6F2Na 347.1282]; m/z (FAB) 347 (90%, [M ϩ Na]ϩ),
229 (100).
3,3-Difluoro-2-[(methoxyethoxy)methoxy]-1-phenylprop-2-en-1-
yl (benzyloxy)acetate 10f
From alcohol 8f (1.23 g, 4.48 mmol), benzyloxyacetyl chloride
(0.56 ml, 4.48 mmol), pyridine (0.36 ml, 4.48 mmol) and
DMAP (0.21 g, 1.80 mmol) in DCM (35 ml). Usual work-up
and column chromatography afforded 10f (1.56 g, 79%) as a
colourless oil; Rf (40% ethyl ether in light petroleum) 0.41;
δH (CDCl3, 300 MHz) 7.49–7.26 (10H, m, Ph), 6.67–6.63 (1H,
1,1-Difluoro-2-[(methoxyethoxy)methoxy]-4-methylpent-1-en-3-
yl (allyloxy)acetate 11d
From 8d (1.50 g, 6.30 mmol), DMAP (0.29 g, 2.52 mmol), EDC
(1.41 g, 6.90 mmol) and allyloxyacetic acid (0.80 g, 6.90 mmol)
in DCM. Usual work-up and column chromatography afforded
allyloxyacetate 11d (1.5 g, 80%) as a colourless oil; Rf (50%
ethyl ether in light petroleum) 0.26; νmax (film)/cmϪ1 1760br s
2
m, CH), 4.88 (1H, d, one half of an AB quartet, JHa–Hb 5.7,
OCHaHbO), 4.67 (1H, d, one half of an AB quartet, 2JHa–Hb 5.7,
OCHaHbO), 4.46 (2H, s, OCH2Ph), 4.22 (2H, s, C(O)CH2),
3.75–3.61 (2H, m, OCH2CH2O), 3.49–3.42 (2H, m, OCH2-
CH2O), 3.32 (3H, s, OCH3); δF (CDCl3, 282 MHz) Ϫ96.4 (1F, d,
(C᎐O); δ (CDCl , 300 MHz) 5.97–5.78 (1H, m, CH᎐CH ),
᎐
᎐
H
3
2
2
2JF–F 53.6), Ϫ104.6 (1F, d, JF–F 53.6); δC (CDCl3, 75 MHz)
5.36–5.12 (3H, m, CHCF , CH᎐CH ), 4.93 (1H, d, one half of
᎐
2 2
1
169.1, 155.6 (t, JC–F 289.9), 137.0, 135.7, 128.6, 128.5, 128.0,
an AB quartet, 2JHa–Hb 6.2, OCHaHbO), 4.87 (1H, d, one half of
2
2
113.6 (dd, JC–F 35.7, 15.3), 97.5, 73.4, 71.4, 70.9, 68.5, 67.1,
an AB quartet, JHa–Hb 6.2, OCHaHbO), 4.12–4.01 (4H, m,
58.9 [HRMS (ES, M[Na]ϩ) Found: 445.1444. Calc. for
C22H24O6F2Na 445.1439]; m/z (ES) 423 (100%, [M ϩ H]ϩ).
C(O)CH2, CH2CHCH2), 3.87–3.68 (2H, m, OCH2CH2O), 3.57–
3.49 (2H, m, OCH2CH2O), 3.46 (3H, s, OCH3), 2.18–2.11 (1H,
m, CH(CH3)2), 0.93 (3H, d, 3JH–H 6.6, CH(CH3)2), 0.90 (3H, d,
3JH–H 7.0, CH(CH3)2); δF (CDCl3, 282 MHz) Ϫ97.2 (1F, d, 2JF–F
(Allyloxy)acetic acid
2
55.3), Ϫ105.4 (1F, d, JF–F 55.3); δC (CDCl3, 75 MHz) 169.6,
A solution of allyl alcohol (5.80 ml, 0.09 mol) in THF (20 ml)
was added dropwise to a cool (0 ЊC) solution of sodium hydride
(5.16 g, 0.13 mol, of a 60% dispersion from which the oil had
been washed with hexane) in THF (30 ml). The grey coloured
suspension was stirred at 0 ЊC for an hour, then a solution of
chloroacetic acid (4.06 g, 0.04 mol) in THF (20 ml) was added
dropwise. Upon completion of the addition, the reaction mix-
ture was heated to reflux and maintained there for a further two
hours before being cooled and quenched (CAUTION) with
HCl (20 ml, of a 1 M aqueous solution). The reaction mixture
was then extracted with NaOH (3 × 20 ml, of a 2 M aqueous
solution), and the aqueous layers were combined and carefully
re-acidified (with a minimum volume of concentrated HCl) to
pH 3 before being extracted with diethyl ether (3 × 50 ml). The
organic extracts were combined, dried (MgSO4), filtered and
concentrated in vacuo to afford allyloxyacetic acid (7.01 g, 70%)
as a pale yellow oil; δH (CDCl3, 300 MHz) 10.82 (1H, br s,
1
2
155.9 (t, JC–F 292.0), 133.7, 118.1, 112.1 (dd, JC–F 36.7, 14.7),
97.3, 75.4, 72.4, 71.6, 68.4, 66.9, 59.0, 29.1, 19.2, 18.8 [HRMS
(ES, M[Na]ϩ) Found: 361.1429. Calc. for C15H24O6F2Na
361.1439]; m/z (ES) 361 (30%, [M ϩ Na]ϩ), 284 (40), 243
(100).
Methyl 3,3-difluoro-2-methoxy-4-oxoheptanoate 15c
(rearrangement, esterification and enol acetal methanolysis with
thionyl chloride)
In a typical procedure, ester 9c (0.60 g, 2.0 mmol) was added to
a stirred solution of freshly prepared LDA (2.0 mmol) in THF
(25 ml) at Ϫ78 ЊC. Approximately five minutes after the add-
ition of the ester was complete, chlorotrimethylsilane (0.3 ml,
2.2 mmol) was added to the yellow solution in one portion and
the reaction mixture was allowed to warm to room temperature
with stirring over one hour. After this time, TLC indicated that
consumption of the starting material was complete, and
methanol (3 ml) was added and the mixture was stirred for a
further 15 mins before being poured onto NaOH (20 ml of a
CO H), 5.91–5.79 (1H, m, H C᎐CH), 5.20–5.11 (2H, m,
᎐
2
2
H C᎐CH), 4.18–4.00 (4H, m, 2 × CH ); δ (CDCl3, 75 MHz)
᎐
2
2
C
175.8, 133.3, 118.8, 72.4, 66.5; m/z (CI) 134 (100%, [M ϩ
3222 J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226

View Article Online
2 M aqueous solution). The aqueous layer was removed and the
organic layer was extracted with NaOH (2 × 20 ml, 2 M). The
aqueous layers were combined and carefully re-acidified to pH
3 using a minimum amount (ca. 5 ml) of concentrated HCl
before being extracted with ether (3 × 25 ml). The organic
extracts were combined, dried (MgSO4), filtered and concen-
trated in vacuo to afford the crude carboxylic acid as a yellow oil
(0.49 g, 82%). Thionyl chloride (0.14 ml, 1.91 mmol) was
added slowly to a cool (0 ЊC) solution of the crude acid (0.49
g, 1.64 mmol) in methanol (25 ml). The reaction mixture was
then allowed to stir overnight at room temperature. The
methanol was then removed in vacuo and water (25 ml) was
added. Extractive work-up with ethyl acetate followed by dry-
ing of the organic extracts (MgSO4), filtration and concentra-
tion in vacuo afforded a yellow oil. Column chromatography
afforded ketoester 15c (0.20 g, 54%) as a colourless oil; Rf
(10% ethyl acetate in light petroleum) 0.32; νmax (film)/cmϪ1
Methyl 3,3-difluoro-2-methoxy-4-oxo-5-phenylpentanoate 15f
From 9f (0.8 g, 2.30 mmol), LDA (2.30 mmol) and chloro-
trimethylsilane (0.32 ml, 2.53 mmol) in THF (35 ml) which
afforded crude carboxylic acid 12f as a yellow oil [0.71 g, 88%
(estimated from mass recovery)]. This material was treated with
thionyl chloride (0.17 ml, 2.31 mmol) in methanol (25 ml).
Usual work-up and column chromatography afforded ketoester
15f (0.35 g, 61%) as a colourless oil; Rf (10% ethyl acetate
in light petroleum) 0.45 (Found: C, 57.60; H, 5.27. Calc. for
C13H14O4F2: C, 57.35; H, 5.27%); δH (CDCl3, 300 MHz) 7.39–
7.15 (5H, m, Ph), 4.37 (1H, dd, 3JH–F 13.8, 10.6, CHCF2), 4.05
(2H, s, C(O)CH2), 3.82 (3H, s, OCH3), 3.51 (3H, s, OCH3);
δF (CDCl3, 282 MHz) Ϫ113.4 (1F, dd, one half of an AB
quartet, 2JF–F 268.8, 3JH-F 10.6), Ϫ117.7 (1F, dd, one half of an
AB quartet, 2JF–F 268.8, 3JH–F 13.8); δC (CDCl3, 75 MHz) 197.5
2
1
(t, JC–F 26.1), 166.9, 131.8, 129.9, 128.7, 127.5, 114.4 (t, JC–F
2
261.8), 79.5 (t, JC–F 26.5), 60.4, 53.0, 44.3; m/z (CI) 290 (26%,
1721 (C᎐O) (Found: C, 48.32; H, 6.19. Calc. for C H O F :
᎐
[M ϩ NH4]ϩ), 186 (72), 84 (100).
9
14
4
2
C, 48.21; H, 6.19%); δH (CDCl3, 300 MHz) 4.30 (1H, dd,
3JH–F 10.3, 9.9, CH(OCH3)), 3.80 (3H, s, OCH3), 3.50 (3H, s,
Attempted preparation of 12g: 7,7-difluoro-6-[(methoxyethoxy)-
methoxy]-2-methoxyhepta-4,6-dienoic acid 18
3
OCH3), 2.65 (2H, t, JH–H 6.9, CH2CH2CH3), 1.70–1.50 (2H,
3
m, CH2CH2CH3), 0.90 (3H, t, JH–H 7.3, CH2CH2CH3);
Ester 9g (1.0 g, 3.38 mmol) was added dropwise to a cold
(Ϫ100 ЊC) solution of LDA (3.38 mmol) and chlorotrimethyl-
silane (0.47 ml, 3.71 mmol) in THF (25 ml). The solution was
stirred at this temperature for a further 5 minutes before being
warmed to room temperature and stirred for an hour, after
which time TLC indicated complete consumption of the start-
ing material. The reaction was stopped by addition of HCl (10
ml of a 1 M solution) before being poured on to NaOH (20 ml
of a 2 M solution). The aqueous layer was removed and the
organic layer was extracted with NaOH (2 × 20 ml of a 2 M
solution). The aqueous layers were combined and carefully re-
acidified to pH 3 using a minimum (ca. 5 ml) amount of con-
centrated HCl before being extracted with ether (3 × 25 ml).
The organic extracts were combined, dried (MgSO4) and con-
centrated in vacuo to afford the crude acid 18 as a yellow oil
[0.71 g, 71% (estimated)]; δH (CDCl3, 300 MHz) 9.46 (1H, br s,
δF (CDCl3, 282 MHz) Ϫ113.6 (1F, dd, one half of an AB
2
3
quartet, JF–F 270.5, JH–F 10.3), Ϫ118.7 (1F, dd, one half
2
3
of an AB quartet, JF–F 270.5, JH–F 9.9); δC (CDCl3, 75 MHz)
2
1
198.0 (t, JC–F 26.6, C-4), 166.7, 113.8 (t, JC–F 259.3), 79.1 (t,
2JC–F 24.9), 60.0, 52.7, 39.3, 15.8, 13.2; m/z (CI) 242 (100%,
[M ϩ NH4]ϩ).
Methyl 3,3-difluoro-2-methoxy-4-oxo-6-methylheptanoate 15d
From 9d (0.5 g, 1.6 mmol), LDA (1.6 mmol) and chloro-
trimethylsilane (0.23 ml, 1.8 mmol) in THF (20 ml) which
afforded crude carboxylic acid 12d as a yellow oil [0.38 g, 76%
(estimated)]. Treatment of this material with thionyl chloride
(0.09 ml, 1.34 mmol) in methanol (20 ml) followed by the usual
work-up and column chromatography afforded ketoester 15d
(0.16 g, 56%) as a colourless oil; Rf (10% ethyl acetate in light
petroleum) 0.35 (Found: C, 50.48; H, 6.78. Calc. for C10H16-
O4F2: C, 50.42; H, 6.77%); δH (CDCl3, 300 MHz) 4.34 (1H, dd,
3JH–F 14.1, 9.9, CH(OCH3)), 3.82 (3H, s, OCH3), 3.49 (3H, s,
OCH3), 2.59 (2H, d, 3JH–H 9.0, CH2CH(CH3)2), 2.30–2.10 (1H,
3
CO2H), 6.00 (1H, dd, one half of an AB quartet, JH–H 15.8,
4JH–F 1.5, CF2C(OMEM)CHaCHb), 5.87–5.78 (1H, m including
3
d, JH–H 15.8, CF2C(OMEM)CHaCHb), 4.89 (2H, s, OCH2O),
3.90–3.81 (2H, m, OCH2CH2O), 3.61–3.53 (2H, m, OCH2-
CH2O), 3.42 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.70–2.52 (3H,
m, CH(OCH3)CO2H, CH2CH(OCH3)CO2H); due to the onset
of acetal cleavage (during the acquisition time of a 13C NMR
spectrum), the acid was esterified directly without further
characterisation.
3
m, CH(CH3)2), 0.95 (6H, d, JH–H 8.7, CH(CH3)2); δF (CDCl3,
2
282 MHz) Ϫ113.6 (1F, dd, one half of an AB quartet, JF–F
3
270.8, JH–F 9.9), Ϫ118.8 (1F, dd, one half of an AB quartet,
3
2
2JF–F 270.8, JH–F 14.1); δC (CDCl3, 75 MHz) 199.4 (t, JC–F
27.1), 166.7, 113.6 (t, 1JC–F 261.6), 79.0 (t, 2JC–F 27.1), 59.9, 52.6,
46.1, 23.2, 11.1 [HRMS (FAB, M[Na]ϩ) Found: 261.091703.
Calc. for C10H16O4F2Na 261.091435]; m/z (CI) 256 (5%,
[M ϩ NH4]ϩ), 239 (7), 85 (100), 57 (47).
Methyl (E)-7,7-difluoro-2-methoxy-6-oxohept-4-enoate 20
Trimethylsilyldiazomethane (1.28 ml, 2.56 mmol) was added
slowly to a cool (0 ЊC) solution of acid 18 (0.69 g, 2.33 mmol) in
methanol (10 ml) and the solution stirred at this temperature
for 10 minutes before being warmed to room temperature and
stirred overnight. The methanol was removed in vacuo to afford
an orange oil. Purification by column chromatography afforded
enone 20 (0.37 g, 50%) as a colourless oil; Rf (40% ethyl ether in
light petroleum) 0.19; δH (CDCl3, 300 MHz) 7.24–7.10 (1H, m,
Methyl 3,3-difluoro-2-methoxy-4-oxo-6,6-dimethylheptanoate
15e
From 9e (0.3 g, 0.92 mmol), LDA (0.92 mmol) and chloro-
trimethylsilane (0.13 ml, 1.0 mmol) in THF (15 ml) which
afforded crude carboxylic acid 12e as a yellow oil [0.24 g, 81%
(estimated)]. Treatment of this material with thionyl chloride
(0.06 ml, 0.84 mmol) in methanol (15 ml) followed by usual
work-up and column chromatography afforded ketoester 15e
(0.12 g, 65%) as a colourless oil; Rf (10% ethyl acetate in light
petroleum) 0.47; δH (CDCl3, 300 MHz) 4.32 (1H, dd, 3JH–F 14.7,
9.9, CH(OCH3)), 3.83 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.60
(2H, s, CH2C(CH3)3), 1.06 (9H, s, C(CH3)3); δF (CDCl3, 282
3
C(O)CHCHCH2), 6.49 (1H, d, JH–H 15.8, C(O)CHCHCH2),
2
3
5.83 (1H, t, JH–F 54.0, CHF2), 3.93 (1H, d, JH–H 5.1,
CH(OCH3)CO2CH3), 3.80 (3H, s, OCH3), 3.42 (3H, s, OCH3),
2.79–2.69 (2H, m, C(O)CHCHCH2); δF (CDCl3, 282 MHz)
2
Ϫ126.3 (2F, d, JH–F 54.0); δC (CDCl3, 75 MHz) 171.6, 147.8,
1
125.0, 110.3 (t, JC–F 252.9), 78.7, 58.5, 52.2, 36.2 (one carbon,
2
believed to be C-6 could not be observed) [HRMS (ES,
M[Na]ϩ) Found: 245.0603. Calcd. for C9H12O4F2Na 245.0601];
m/z (CI) 240 (100%, [M ϩ NH4]ϩ).
MHz) Ϫ113.6 (1F, dd, one half of an AB quartet, JF–F 268.8,
2
3JH–F 9.9), Ϫ118.6 (1F, dd, one half of an AB quartet, JF–F
3
2
268.8, JH–F 14.7); δC (CDCl3, 75 MHz) 199.2 (t, JC–F 32.1),
163.3, 113.8 (t, 1JC–F 241.5), 79.1 (t, 2JC–F 27.3), 59.9, 52.6, 46.9,
30.6, 29.1 [HRMS (CI, M[NH4]ϩ) Found: 270.150694. Calc. for
C11H22O4F2N 270.151690]; m/z (CI) 270 (34%, [M ϩ NH4]ϩ),
233 (25), 97 (52), 70 (100).
2-Benzyloxy-3,3-difluoro-4-[(methoxyethoxy)methoxy]hex-4-
enoic acid 13b (rearrangement only)
A solution of LDA was generated from n-butyllithium (3.86 ml
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
3223

View Article Online
of a 2.2 M solution in hexanes, 8.49 mmol) and diisopropyl-
amine (1.2 ml, 8.6 mmol) in THF (10 ml). The solution was
diluted with THF (10 ml) then ester 10b (3.0 g, 8.3 mmol)
was added dropwise. After 5 minutes, chlorotrimethylsilane
(1.62 ml, 12.8 mmol) was added dropwise and the reaction was
allowed to warm to room temperature over one hour. The reac-
tion was quenched with cold HCl (17 ml of a 1 M aqueous
solution) and stirred for 3 minutes. The pH was adjusted to ca.
10 with concentrated NaOH (5 M aqueous solution) and the
solution was washed with diethyl ether (3 × 20 ml). The organic
washings were discarded and the pH was lowered to ca. 1 by the
careful dropwise addition of concentrated HCl (10 M), then the
aqueous phase was extracted further with diethyl ether (3 × 25
ml). The combined organic extracts were dried (MgSO4), fil-
tered and evaporated in vacuo to afford acid 13b as a pale yellow
oil (2.02 g, 75%); νmax (film)/cmϪ1 3620–2680br m (COO-H),
NO4F2 318.151690]; m/z (CI) 318 (57%, [M ϩ NH4]ϩ), 123 (10),
91 (100), 71 (28).
Methyl 2-benzyloxy-3,3-difluoro-4-oxo-6-methylheptanoate 16d
From 10d (0.43 g, 1.11 mmol), LDA (1.11 mmol) and chloro-
trimethylsilane (0.16 ml, 1.22 mmol) in THF (20 ml) which
afforded crude carboxylic acid 13d as a yellow oil [0.33 g, 77%
(estimated)]. Treatment of this material with thionyl chloride
(0.07 ml, 0.94 mmol) in methanol (20 ml) followed by usual
work-up and column chromatography afforded ketoester 16d
(0.15 g, 54%) as a colourless oil; Rf (20% ethyl acetate in light
petroleum) 0.51; νmax (film)/cmϪ1 1744.5 (C᎐O); δH (CDCl3, 300
᎐
MHz) 7.40–7.24 (5H, m, Ph), 4.76 (1H, d, one half of an AB
2
quartet, JHa–Hb 9.7, OCHaHbPh), 4.58 (1H, d, one half of an
2
3
AB quartet, JHa–Hb 9.7, OCHaHbPh), 4.51 (1H, dd, JH–F 14.4,
3
10.2, CHCF2), 3.78 (3H, s, OCH3), 2.57 (2H, d, JH–H 7.50,
2922s, 1722s (C᎐O); δH (CDCl3, 300 MHz) 8.37–8.17 (1H, br s,
᎐
3
4
CH2CH(CH3)2), 2.25–2.09 (1H, m, CH(CH3)2), 0.94 (6H, d,
3JH–H 8.0, CH(CH3)2); δF (CDCl3, 282 MHz) Ϫ113.5 (1F, dd,
one half of an AB quartet, 2JF–F 270.3, 3JH–F 10.2), Ϫ118.0 (1F,
CO2H), 7.40–7.27 (5H, m, Ph), 5.68 (1H, dq, JH–H 7.1, JH–F
2
1.29, CHCH3), 4.95 (1H, d, one half of an AB quartet, JH–H
5.9, OCHaHbPh), 4.91 (1H, d, one half of an AB quartet, 2JH–H
2
3
3
3
dd, one half of an AB quartet, JF–F 270.3, JH–F 14.4);
5.9, OCHaHbPh), 4.40 (1H, dd, JH–F 14.7, JH–F 8.1, CH-
(OBn)CO2H), 3.89–3.73 (2H, m, OCH2CH2OCH3), 3.55 (2H, t,
3JH–F 4.6, OCH2CH2OCH3), 3.36 (3H, s, OCH3), 1.71 (3H, dt,
3JH–H 7.1, 5JH–F 2.8, CHCH3); δC (CDCl3, 75 MHz) 170.0, 145.1
2
δC (CDCl3, 75 MHz) 199.6 (t, JC–F 26.6), 167.0, 135.7, 128.5,
1
2
113.9 (t, JC–F 261.6), 76.3 (t, JC–F 23.6), 74.3, 52.8, 46.3, 23.4,
22.4 [HRMS (ES, M[Na]ϩ) Found: 337.1217. Calc. for
C16H20O4F2Na 337.1227]; m/z (ES) 337 (100%, [M ϩ Na]ϩ).
2
1
(t, JC–F 25.5), 136.2, 128.5, 128.3, 116.8 (t, JC–F 251.2), 115.8,
98.2, 76.8 (t, 2JC–F 29.7), 73.6, 71.6, 68.7, 59.0, 10.9; δF (CDCl3,
282 MHz) Ϫ111.5 (1F, dd, 2JF–F 256.6, 3JH–F 14.7), Ϫ106.3 (1F,
Methyl 2-benzyloxy-3,3-difluoro-4-oxo-6,6-dimethylheptanoate
16e
d, JF–F 256.6) [HRMS (ES, M[Na]ϩ) Found: 383.1279. Calcd.
2
For C17H22O6F2Na 383.1282]; m/z (ES) 383 (100%, [M ϩ Na]ϩ).
The reaction could also be performed on 22 mmol of 10b
From 10e (0.62 g, 1.55 mmol), LDA (1.55 mmol) and chloro-
trimethylsilane (0.22 ml, 1.70 mmol) in THF (25 ml) which
afforded crude carboxylic acid 13e as a yellow oil [0.48 g, 78%
(estimated)]. Treatment of this material with thionyl chloride
(0.10 ml, 1.32 mmol) in methanol (25 ml) followed by the usual
work-up and column chromatography afforded ketoester 16e
(0.31 g, 76%) as a colourless oil; Rf (20% ethyl acetate in light
petroleum) 0.48 (Found: C, 62.14; H, 6.57. Calc. for C17H22-
O4F2: C, 62.18; H, 6.75%); δH (CDCl3, 300 MHz) 7.41–7.28
affording 13b in 60% crude yield with acceptable H, 13C and
1
19F NMR spectra.
Methyl 2-benzyloxy-3,3-difluoro-4-oxohexanoate 16b
Treatment of crude 13b (0.34 g, 0.83 mmol) with thionyl chlor-
ide (0.07 ml, 0.91 mmol) in methanol (15 ml) followed by the
usual work-up and column chromatography afforded ketoester
16b as a pale yellow oil (0.17 g, 74%, 98% pure by GC); Rf (40%
ethyl acetate in light petroleum) 0.61; δH (CDCl3, 300 MHz)
7.39–7.26 (5H, m, Ph), 4.77 (1H, d, one half of an AB quartet,
2JHa–Hb 11.4, OCHaHbPh), 4.57 (1H, d, one half of an AB quar-
2
(5H, m, Ph), 4.76 (1H, d, one half of an AB quartet, JHa–Hb
11.0, OCHaHbPh), 4.57 (1H, d, one half of an AB quartet,
3
2JHa–Hb 11.0, OCHaHbPh), 4.52 (1H, dd, JH–F 9.2, 10.7,
CHCF2), 3.80 (3H, s, OCH3), 2.60 (2H, s, CH2C(CH3)3), 1.02
(9H, s, C(CH3)3); δF (CDCl3, 282 MHz) Ϫ113.3 (1F, dd, one
half of an AB quartet, 2JF–F 268.6, 3JH–F 10.7), Ϫ117.9 (1F, dd,
one half of an AB quartet, 2JF–F 268.6, 3JH–F 9.2); δC (CDCl3, 75
2
3
tet, JHa–Hb 11.4, OCHaHbPh), 4.55 (2H, dd, JH–F 14.3, 10.3,
CHCF2), 3.80 (3H, s, OCH3), 2.73 (2H, q, 3JH–H 7.3, CH2CH3),
1.09 (3H, t, 3JH–H 7.3, CH2CH3); δC (CDCl3, 75 MHz) 200.1 (t,
2
1
2JC–F 27.6), 167.0, 135.8, 128.5, 114.2 (t, JC–F 261.2), 76.9 (t,
1
MHz) 199.2 (t, JC–F 28.1), 166.9, 135.5, 128.4, 113.6 (t, JC–F
2
2JC–F 24.7), 52.8, 31.3, 6.3; δF (CDCl3, 282 MHz) Ϫ113.4 (1F,
dd, one half of an AB quartet, 2JF–F 269.6, 3JH–F 10.2), Ϫ118.1
261.1), 76.5 (t, JC–F 28.2), 74.1, 52.6, 49.1, 29.2, C-6 was not
visible [HRMS (ES, M[Na]ϩ) Found: 351.1376. Calc. for
C17H22O4F2Na 351.1384]; m/z (FAB) 328 (17%, [M]ϩ), 181 (19),
91 (100).
2
3
(1F, dd, one half of an AB quartet, JF–F 269.7, JH–F 15.3)
[HRMS (ES, M[Na]ϩ) Found: 309.0919. Calc. for C14H16O4-
F2Na 309.0914]; m/z (ES) 309 (100%, [M ϩ NH4]ϩ), 123 (10),
91 (100), 71 (28).
Methyl 2-allyloxy-3,3-difluoro-4-oxoheptanoate 17c
From 11c (0.93 g, 2.88 mmol), LDA (3.20 mmol) and chloro-
trimethylsilane (0.41 ml, 3.20 mmol) in THF (30 ml) which
afforded crude carboxylic acid 14c as a yellow oil [0.76 g, 82%
(estimated)]. This material was treated with thionyl chloride
(0.17 ml, 2.58 mmol) in methanol (25 ml) followed by usual
work-and column chromatography to afford ketoester 17c (0.34
g, 63%) as a colourless oil; Rf (50% ethyl ether in light petrol-
eum) 0.59 (Found: C, 52.74; H, 6.70. Calc. for C13H16O4F2: C,
52.80; H, 6.45%); δH (CDCl3, 300 MHz) 5.90–5.78 (1H, m,
CH2CHCH2O), 5.31–5.20 (2H, m, CH2CHCH2O), 4.50 (1H,
Methyl 2-benzyloxy-3,3-difluoro-4-oxoheptanoate 16c
From 10c (0.55 g, 1.50 mmol), LDA (1.50 mmol) and chloro-
trimethylsilane (0.21 ml, 1.65 mmol) in THF (20 ml) which
afforded crude carboxylic acid 13c as a yellow oil [0.43 g, 78%
(estimated)]. Treatment of this material with thionyl chloride
(0.09 ml, 1.26 mmol) in methanol (25 ml) followed by the usual
work-up and column chromatography afforded ketoester 16c
(0.20 g, 58%) as a colourless oil; Rf (20% ethyl acetate in light
petroleum) 0.36; δH (CDCl3, 300 MHz) 7.30–7.18 (5H, m, Ph),
2
3
4.77 (1H, d, one half of an AB quartet, JHa–Hb 9.9, OCHaHb-
dd, JH–F 14.1, 10.3, CHCF2), 4.23 (1H, dd, one half of an AB
2
Ph), 4.58 (1H, d, one half of an AB quartet, JHa–Hb 9.9,
quartet, 3JH–H 5.9, 2JHa–Hb 12.5, CH2CHCHaHbO), 4.05 (1H, dd,
3
2
OCHaHbPh), 4.53 (2H, dd, 3JH–F 14.1, 10.2, CHCF2), 3.80 (3H,
one half of an AB quartet, JH–H 5.1, JHa–Hb 12.5, CH2CH-
3
s, OCH3), 2.66 (2H, t, 3JH–H 6.0, CH2CH2CH3), 1.70–1.51 (2H,
CHaHbO), 3.80 (3H, s, OCH3), 2.70 (2H, t, JH–H 7.0, CH2-
3
3
m, CH2CH2CH3), 0.99 (3H, t, JH–H 9.6, CH2CH2CH3); δC
CH2CH3), 1.71–1.60 (2H, m, CH2CH2CH3), 0.95 (3H, t, JH–H
(CDCl3, 75 MHz) 200.1 (t, 2JC–F 27.6), 167.0, 135.8, 128.5, 114.2
7.73, CH2CH2CH3); δF (CDCl3, 282 MHz) Ϫ113.7 (1F, dd, one
1
2
(t, JC–F 261.2), 76.9 (t, JC–F 24.5), 74.3, 52.8, 39.4, 15.9, 13.4)
[HRMS (CI, M[NH4]ϩ) Found: 318.151582. Calc. for C15H22-
half of an AB quartet, 2JF–F 270.0, 3JH–F 10.3), Ϫ118.1 (1F, dd,
2
3
one half of an AB quartet, JF–F 270.0, JH–F 14.1); δC (CDCl3,
3224
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226

View Article Online
75 MHz) 201.1 (t, 2JC–F 28.5), 167.1, 132.5, 119.7, 114.0 (t, 1JC–F
261.3), 76.4 (t, 2JC–F 25.3), 73.3, 52.8, 39.5, 15.9, 13.4; m/z (ES)
273 (100%, [M ϩ Na]ϩ).
282 MHz) Ϫ100.7 (1F, d, 2JF–F 66.1), Ϫ108.6 (1F, d, 2JF–F 66.1);
1
δC (CDCl3, 75 MHz) 168.1, 154.9 (t, JC–F 285.3), 117.4 (dd,
2JC–F 31.2, 8.7), 98.4, 73.8, 71.5, 68.9, 67.9, 59.0, 44.3, 36.1, 26.1,
20.6. This material was not characterised further as all attempts
at rearrangement under the conditions used for 12–14 or 18
were completely unsuccessful returning only a low yield of 8c.
Methyl 2-allyloxy-3,3-difluoro-4-oxo-6-methylheptanoate 17d
From 11d (1.22 g, 3.62 mmol), LDA (3.62 mmol) and chloro-
trimethylsilane (0.51 ml, 3.98 mmol) in THF (30 ml) which
afforded crude carboxylic acid 14d as a yellow oil [1.15 g, 94%
(estimated)]. This material was treated with thionyl chloride
(0.28 ml, 3.80 mmol) in methanol (20 ml) and usual work-up
and column chromatography afforded ketoester 17d (0.58 g,
60%) as a colourless oil; Rf (40% ethyl acetate in light petrol-
eum) 0.61 (Found: C, 54.49; H, 6.90. Calc. for C14H18O4F2: C,
54.54; H, 6.87%); δH (CDCl3, 300 MHz) 5.89–5.71 (1H, m,
CHCH2), 5.30–5.20 (2H, m, CHCH2), 4.46 (1H, dd, 3JH–F 14.1,
10.2, CHCF2), 4.18 (1H, dd, one half of an AB quartet, 2JHa–Hb
12.1, 3JH–H 5.9, OCHaHbCHCH2), 4.02 (1H, dd, one half of an
AB quartet, 2JHa–Hb 12.1, 3JH–H 6.2, OCHaHbCHCH2), 3.78 (3H,
Methyl 2-hydroxy-3,3-difluoro-4-oxoheptanoate 25c
(deallylation)
Zinc() chloride (0.1 g, 0.78 mmol) was added to a solution of
allyloxyketoester 17c (0.15 g, 0.6 mmol) in dry THF (10 ml)
and the reaction mixture was stirred at room temperature for
15 minutes. Tetrakis(triphenylphosphino)palladium(0) (0.13 g,
0.15 mmol) was added and the mixture was stirred for a further
10 minutes. Tributyltin hydride (0.32 ml, 1.2 mmol) was added
cautiously to the yellow coloured solution over a period of 10
minutes. Upon completion of the addition, the reaction mix-
ture was stirred at room temperature for 30 minutes when TLC
indicated that the starting material had been consumed com-
pletely. The reaction mixture was diluted with ethyl acetate
(20 ml) and HCl (10 ml of a 1 M aqueous solution) was
added then the mixture extracted with ethyl acetate (3 × 20
ml). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo and purified by column chroma-
tography to afford the hydroxyketoester 25c (0.07 g, 56%) as
a colourless oil; Rf (50% ethyl ether in light petroleum) 0.56
(Found: C, 45.60; H, 5.89. Calc for C8H12O4F2: C, 45.72; H,
5.75%); δH (CDCl3, 300 MHz) 4.66–4.57 (1H, m, CF2CH),
3
s, OCH3), 2.57 (2H, d, JH–H 6.6, CH2CH(CH3)2), 2.26–2.10
3
(1H, m, CH(CH3)2), 0.91 (3H, d, JH–H 1.5, CH(CH3)2), 0.89
3
(3H, d, JH–H 1.5, CH(CH3)2); δF (CDCl3, 282 MHz) Ϫ113.7
2
3
(1F, dd, one half of an AB quartet, JF–F 269.7, JH–F 10.2),
2
3
Ϫ118.3 (1F, dd, one half of an AB quartet, JF–F 269.7, JH–F
2
14.1); δC (CDCl3, 75 MHz) 199.7 (t, JC–F 27.1), 167.1, 132.6,
119.7, 113.9 (t, 1JC–F 260.9), 76.3 (t, 2JC–F 25.2, 73.2, 52.8, 46.3,
23.4, 22.3; m/z (CI) 282 (45%, [M ϩ NH4]ϩ), 265 (12), 85 (100),
58 (29).
3
3.90 (3H, s, OCH3), 3.38 (1H, d, JH–H 6.7, OH), 2.60 (2H, t,
1,1-Difluoro-2[(methoxyethoxy)methoxy]pent-1-en-3-yl
3-hydroxybutyrate 23
3JH–H 6.2, CH2CH2CH3), 1.72–1.59 (2H, m, CH2CH2CH3),
3
0.95 (3H, t, JH–H 7.7, CH2CH2CH3); δF (CDCl3, 282 MHz)
2
3
The procedure for 11c was followed using alcohol 8c (1.0 g, 4.42
mmol), DMAP (0.21 g, 1.77 mmol), DCC (1.0 g, 4.86 mmol)
and 3-hydroxybutyric acid (0.41 ml, 4.42 mmol) in DCM.
Usual work-up and column chromatography afforded hydroxy-
butyrate 23 (0.88 g, 64%) as a colourless oil; Rf (20% ethyl
acetate in light petroleum) 0.30; δH (CDCl3, 300 MHz) 5.42–
5.35 (1H, m, CH), 4.98 (1H, d, one half of an AB quartet,
2JHa–Hb 5.8, OCHaHbO), 4.90 (1H, d, one half of an AB quartet,
2JHa–Hb 5.8, OCHaHbO), 3.90–3.72 (2H, m, OCH2CH2O), 3.69–
Ϫ114.0 (1F, dd, one half of an AB quartet, JF–F 272.2, JH–F
2
8.5), Ϫ119.4 (1F, dd, one half of an AB quartet, JF–F 272.2,
2
3JH–F 14.7); δC (CDCl3, 75 MHz) 200.1 (t, JC–F 27.7), 169.2,
1
2
113.7 (t, JC–F 261.6), 70.3 (t, JC–F 27.4), 53.6, 39.4, 15.8,
13.4; m/z (CI) 228 (100%, [M ϩ NH4]ϩ).
Methyl 2-hydroxy-3,3-difluoro-4-oxo-6-methylheptanoate 25d
From ZnCl2 (0.12 g, 0.92 mmol), 17d (0.18 g, 0.7 mmol),
Pd(PPh3)4 (0.09 g, 0.08 mmol) and Bu3SnH (0.38 ml, 1.4 mmol)
in dry THF (15 ml). Usual work-up and column chromato-
graphy afforded hydroxyketoester 25d as a colourless oil (0.10 g,
63%); Rf (40% ethyl ether in light petroleum) 0.67; δH (CDCl3,
3
3.59 (2H, m, OCH2CH2O), 3.55 (2H, t, JH–H 3.7, CH2CH2-
OCH3), 3.40 (3H, s, OCH3), 3.35 (3H, s, OCH3), 2.54 (2H, t,
3JH–H 3.7, CH2CH2OCH3), 1.86–1.71 (2H, m, CH2CH3), 0.89
(3H, t, 3JH–H 9.6, CH2CH3); δF (CDCl3, 282 MHz) Ϫ97.2 (1F, d,
3
2
300 MHz) 4.62 (1H, dd, JH–F 8.5, 14.3 CF2CH), 3.90 (3H, s,
2JF–F 55.9), Ϫ105.6 (1F, d, JF–F 55.9); δC (CDCl3, 75 MHz)
3
1
2
OCH3), 3.30 (1H, br s, OH), 2.60 (2H, d, JH–H 6.6, CH2CH-
168.6, 154.8 (t, JC–F 291.5), 117.7 (dd, JC–F 36.8, 11.5), 97.9,
71.4, 68.6, 68.4, 58.9, 58.6, 56.6, 39.1, 26.9, 9.9 [HRMS
(CI, M[NH4]ϩ) Found: 330.172838. Calc. for C13H26O6NF2
330.172819]; m/z (ES) 335 (100%, [M ϩ Na]ϩ). This material
was not characterised further as all attempts at rearrangement
under the conditions used for 12–14 or 18 were completely
unsuccessful, returning only a low yield of 8c.
3
(CH3)2), 2.28–1.95 (1H, m, CH2CH(CH3)2), 0.95 (6H, d, JH–H
6.6, CH2CH(CH3)2); δF (CDCl3, 282 MHz) Ϫ114.0 (1F, dd, one
2
3
half of an AB quartet, JF–F 273.4, JH–F 8.5), Ϫ119.0 (1F, dd,
2
3
one half of an AB quartet, JF–F 273.4, JH-F 14.7); δC (CDCl3,
75 MHz) 199.6 (t, 2JC–F 28.2), 169.3, 113.7 (t, 1JC–F 261.8), 70.7
(t, JC–F 12.3), 53.7, 46.3, 23.5, 22.4 [HRMS (ES, M[Na]ϩ)
2
Found: 247.0756. Calc. for C9H14O4F2Na 247.0758]; m/z (CI)
242 (100%, [M ϩ NH4]ϩ).
1,1-Difluoro-2-[(methoxyethoxy)methoxy]pent-1-en-3-yl
3-methoxypropionate 24
Methyl 2-hydroxy-3,3-difluoro-4-oxoheptanoate 25c
β-Butyrolactone (0.35 ml, 4.33 mmol) was added dropwise to a
solution of alcohol 8c (1.0 g, 3.94 mmol) in DCM (25 ml) and
the solution was stirred for 18 hours. The DCM was then
removed in vacuo to afford a pale yellow oil. Column chrom-
atography afforded propionate 24 (1.1 g, 82%); Rf (50% ethyl
ether in light petroleum) 0.55; δH (CDCl3, 300 MHz) 4.99 (1H,
d, one half of an AB quartet, 2JHa–Hb 6.6, OCHaHbO), 4.80 (1H,
d, one half of an AB quartet, 2JHa–Hb 6.6, OCHaHbO), 4.71–4.60
(2H, m, CH, CH2CH(OH)CH3), 3.92–3.65 (2H, m, OCH2-
CH2O), 3.56–3.49 (2H, m, OCH2CH2O), 3.33 (3H, s, OCH3),
3.18 (1H, br s, OH), 3.05 (1H, d, one half of an AB quartet,
2JHa–Hb 4.4, CHaHbCH(OH)CH3), 3.00 (1H, d, one half of
(debenzylation)
Pearlman’s catalyst (0.10 g, 20 wt% Pd) was added to a solution
of benzyloxyketoester 16c (0.41 g, 1.44 mmol) in dry methanol
(15 ml) and the reaction mixture was stirred under a hydrogen
atmosphere at room temperature for 2 hours at which time TLC
indicated that starting material had been consumed completely.
The catalyst was removed by filtration through Celite and the
solvent removed in vacuo to afford the pure hydroxyketoester
25c (0.26 g, 92%) as a colourless oil.
Methyl 2-hydroxy-3,3-difluoro-4-oxo-6-methylheptanoate 25d
2
an AB quartet, JHa–Hb 4.4, CHaHbCH(OH)CH3), 1.53 (3H, d,
From Pearlman’s catalyst (0.21 g, 20 wt% Pd) and benzyloxy-
ketoester 16d (0.85 g, 2.6 mmol) in dry methanol (30 ml) which
3JH–H 5.9, CH2CH(OH)CH3), 1.15 (9H, s, C(CH3)3); δF (CDCl3,
J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
3225

View Article Online
Morikawa, O. Kitagawa, T. Mishima and Y. Kobayashi, Chem.
Pharm. Bull., 1985, 33, 5137.
afforded pure hydroxyketoester 25d (0.57 g, 91%) as a colour-
less oil.
13 H. Frauenrath, in Stereoselective Synthesis, ed. G. Helmchen, R. W.
Hoffmann, J. Mulzer and E. Schaumann, Stuttgart, 1996, D.1.6,
3420.
14 For recent examples in natural product synthesis, see: B. B. Snider
and N. A. Hawryluk, Org. Lett., 2000, 2, 635; P. R. Blakemore,
P. J. Kocienski, A. Morley and K. Muir, J. Chem. Soc., Perkin Trans.
1, 1999, 955; E. K. Dorling and E. J. Thomas, Tetrahedron Lett.,
1999, 40, 471; A. K. Mapp and H. C. Heathcock, J. Org. Chem.,
1999, 64, 23.
15 S. D. Burke and Q. Zhao, J. Org. Chem., 2000, 65, 1489; J. F. Miller,
A. Termin, K. Koch and A. D. Piscopio, J. Org. Chem., 1998, 63,
3158.
16 P. A. Bartlett, D. J. Tanzella and J. F. Barstow, J. Org. Chem., 1982,
47, 3945.
Acknowledgements
The authors wish to thank the EPSRC and Roche Discovery
Welwyn for a CASE Award to M. E. P. and Mr B. K. Foster
for preparing 10b, 13b and 16b in the first instance. J. M. P.
wishes to thank Lancaster Synthesis Ltd for a generous gift of
methoxy(ethoxy)methyl chloride.
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