1
PERKIN
DOI: 10.1039/b004766j J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226 3217
This journal is © The Royal Society of Chemistry 2000
Synthesis of -hydroxy-,-difluoro--ketoesters via
[3,3]sigmatropic rearrangements
Michael J. Broadhurst,
a
Samantha J. Brown,
b
Jonathan M. Percy *
b
and Michael E. Prime †
b
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
Claisen
3
and oxy-Cope,
4
and in neutral
5
and anionic
6
[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 CF
2
centre β to a carboxy carbonyl group
(3 in Scheme 1).
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-workers
7
could be considered, but
such additions normally proceed to monofluorocompounds
via addition–elimination mechanisms. Alternatively, McCarthy
and co-workers reported
8
the synthesis of a Kynureninase
inhibitor 4b in which bond b was made from a difluorinated
silyl enol ether (Scheme 2).
Scheme 1 Outline route to masked β,β-difluoro-γ-oxocarboxylic acid
derivatives.
† Current address: School of Chemistry, University of York,
Heslington, York, UK YO10 5DD.
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 related
10
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-ketoesters
12
on 1–22 mmol scales
from trifluoroethanol.
Results and discussion
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
Scheme 2 Possible disconnections from the target molecules.
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3218 J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
Table 1 Preparation of esters used for rearrangement
R Alcohol R⬘ = Me Yield (%) R⬘ = Bn Yield (%) R⬘ = allyl Yield (%)
H
Me
Et
i-Pr
t-Bu
Ph
CH᎐
᎐
CH
2
8a
8b
8c
8d
8e
8f
8g
9a
—
9c
9d
9e
9f
9g
79
a
—
85
81
82
79
72
—
10b
10c
10d
10e
10f
—
—
92
b,c
82
75
85
79
—
—
—
11c
11d
—
—
—
—
—
83
80
—
—
—
a
This ester was only moderately stable and could not be characterised fully.
b
Esterification started at 0 ⬚C.
c
Obtained in 96% purity and
used without purification.
from esters of lactic
16
and hydroxybutyric
17
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-
ping with the silicon electrophile must therefore be efficient at
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
trapped successfully, presumably because the chelation of the
lithium atom stabilises the enolates against fragmentation as
well as controlling their configuration.
Difluoroallylic alcohols 8 were synthesised according to our
published method
19
and methoxy (9), benzyloxy (10) and
allyloxy (11) esters were prepared (Scheme 4, Table 1) from the
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 ⫺78 ⬚C. 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
Scheme 3 Reagents and conditions: i, LDA, THF, ⫺78 ⬚C; ii, Me
3
SiCl;
iii, ∆ then work-up.
Scheme 4 Reagents and conditions: i, MeOCH
2
COCl or BnOCH
2
-
COCl, pyridine, DMAP, DCM, rt, 18 hours then extractive work-up; ii,
H
2
C᎐
᎐
CHCH
2
OCH
2
CO
2
H, EDC, DMAP, DCM, rt, 18 hours then
extractive 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
esterified directly, see later). Procedures using other bases were
less successful; the same procedure with LTMP (TMP = 2,2,6,6-
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
the recovery of starting material and fragmentation product
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
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,N⬘,N⬘-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 ⬚C)
methanol and adding thionyl chloride led to the formation of
the methyl esters 15–17 (Table 2), from which the MEM-group
had been cleaved.
In the case of 9g, rearrangement is possible at either of two
vinylic termini; the dienyl ester fragmented when exposed to
LDA at ⫺78 ⬚C so we carried out the deprotonation under
trapping conditions at ⫺100 ⬚C 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
These observations suggest that Claisen and related
rearrangements occur more slowly when fluorine atom sub-
Scheme 5 Reagents and conditions: i, LDA, THF, ⫺78 ⬚C; ii, Me
3
SiCl;
iii, ∆ then work-up; iv, SOCl
2
, MeOH, 0 ⬚C to rt, 18 hours.
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J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226 3219
Scheme 6 Reagents and conditions: i, LDA–Me
3
SiCl, THF, ⫺100 ⬚C, inverse addition; ii, warm to rt; iii, aqueous work-up; iv, TMSCHN
2
, MeOH.
Table 2 Ketoesters prepared by rearrangement and methanolysis
RR⬘ = Me Yield (%) R⬘ = Bn Yield (%) R⬘ = allyl Yield (%)
Me
Et
i-Pr
t-Bu
Ph
—
15c
15d
15e
15f
—
54
56
65
61
16b
16c
16d
16e
—
74
58
54
76
—
—
17c
17d
—
—
—
63
60
—
—
stituents are located at C-6 and are consistent with the general
conclusion of Purrington and Weeks
24
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
Gelb
26
and Gerhart
27
inter alia. In contrast, Dauben–Dietsch
rearrangement of 8c occurred at 40 ⬚C, 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 CDCl
3
; 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.
Though suspicious that we were operating close to the limit
of enolate stability, we explored the less common rearrange-
ments of 3-hydroxybutyrate
17
and 3-methoxypropionate
13
esters 23 and 24. Kurth used the former esters of simple allylic
Scheme 7 Reagents and conditions: i, HC(OMe)
2
NMe
2
, PhMe, 60 ⬚C.
alcohols to construct highly functionalised branched acids with
moderate stereocontrol; adequate ester enolate stabilisation by
β-alkoxy groups does not appear to be established, whereas
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 ethers
32
17c
and 17d, but debenzylations
33
(H
2
/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
CF
2
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 Reformatsky
34
entry to highly functionalised difluorocompounds.
Experimental
1
H and
13
C 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.
19
F NMR spectra were recorded on
Bruker AC-300 (282.41 MHz) relative to chlorotrifluoro-
methane as the internal standard. The
19
F NMR spectra of
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3220 J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226
rearrangement educts reveal an AB quartet in which each
“doublet” is further split by
3
J
H–F
coupling (to provide a doublet
of doublets). The much larger
2
J
F–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,
2
J
F–F
,
3
J
H–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-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride]
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 ⬚C. Difluoroallylic alcohols were prepared according to
our published procedure,
19
except for 8b which was prepared as
described below.
4,4-Difluoro-3-[(methoxyethoxy)methoxy]but-3-en-2-ol 8b
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 ⫺78 ⬚C. The dark orange suspension was
stirred at ⫺78 ⬚C 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 ⫺30 ⬚C 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
(MgSO
4
), 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 ⬚C/0.15
mmHg; δ
H
(300 MHz, CDCl
3
) 5.00 (1H, d, one half of an AB
quartet,
2
J
Ha–Hb
6.6, OCH
a
H
b
O), 4.88 (1H, d, one half of an AB
quartet,
2
J
Ha–Hb
6.6, OCH
a
H
b
O), 4.51–4.39 (1H, br s, OH),
3.99–3.90 (2H, m, OCH
2
CH
2
O), 3.82–3.73 (2H, m, OCH
2
-
CH
2
O), 3.58–3.52 (1H, m, CHOH), 3.48 (3H, s, OCH
3
), 1.35
(3H, d,
3
J
H–H
7.3, CHCH
3
); δ
F
(282 MHz, CDCl
3
) ⫺100.9 (1F,
d,
2
J
F–F
64.9), ⫺109.6 (1F, d,
2
J
F–F
64.9); δ
C
(75 MHz, CDCl
3
)
154.0 (dd,
1
J
C–F
291.3, 285.7), 118.9 (td,
2
J
C–F
36.5, 9.9),
97.9, 71.4, 68.4, 63.0 (dd,
3
J
C–F
3.9, 1.7), 58.9, 20.1 (t,
4
J
C–F
2.3).
The alcohol was taken on to the ester without further
characterisation.
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
(R
f
= 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 (MgSO
4
), 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 ⬚C/0.05 mmHg; R
f
(50% ethyl
ether in light petroleum) 0.33; δ
H
(300 MHz, CDCl
3
) 4.92 (2H,
s, OCH
2
O), 4.80 (2H, t,
4
J
H–F
2.6, CCH
2
O), 4.05 (2H, s,
CH
2
OCH
3
), 3.85–3.78 (2H, m, OCH
2
CH
2
O), 3.55–3.50 (2H, m,
OCH
2
CH
2
O), 3.45 (3H, s, OCH
3
), 3.35 (3H, s, OCH
3
); δ
F
(282
MHz, CDCl
3
) ⫺96.0 (1F, d,
2
J
F–F
52.2), ⫺106.0 (1F, d,
2
J
F–F
52.2); δ
C
(75 MHz, CDCl
3
) 169.8, 155.7 (t,
1
J
C–F
289.2), 111.5
(dd,
2
J
C–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 ⬚C/0.05 mmHg; R
f
(50% ethyl ether in light petroleum) 0.29;
ν
max
(film)/cm
⫺1
1748br s (C᎐
᎐
O); δ
H
(300 MHz, CDCl
3
) 5.45
(1H, t,
4
J
H–F
7.3, CH), 4.95 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.2, OCH
a
H
b
O), 4.80 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.2, OCH
a
H
b
O), 4.00 (2H, s, C(O)CH
2
OCH
3
), 3.90–3.70
(2H, m, OCH
2
CH
2
O), 3.55 (2H, t,
3
J
H–H
5.1, OCH
2
CH
2
O), 3.40
(3H, s, OCH
3
), 3.35 (3H, s, OCH
3
), 1.85–1.70 (2H, m, CH
2
-
CH
3
), 0.85 (3H, t,
3
J
H–H
7.3, CH
2
CH
3
); δ
F
(282 MHz, CDCl
3
)
⫺97.00 (1F, d,
2
J
F–F
55.3), ⫺105.39 (1F, d,
2
J
F–F
55.3); δ
C
(75
MHz, CDCl
3
) 169.3, 155.7 (quat, t,
1
J
C–F
292.2), 112.9 (quat,
dd,
1
J
C–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]
⫹
) Found: 321.1139. Calc. for C
12
H
20
-
O
6
F
2
Na 321.1126]; m/z (CI) 316 (20%, [M ⫹ NH
4
]
⫹
), 209 (12),
89 (100).
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 ⬚C/0.05 mmHg (Found: C, 50.20; H, 7.14. Calc. for
C
13
H
22
O
6
F
2
: C, 50.00; H, 7.10%); R
f
(40% ethyl ether in light
petroleum) 0.3; δ
H
(CDCl
3
, 300 MHz) 5.17 (1H, d,
3
J
H–H
3.1,
CH), 4.95 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.2,
OCH
a
H
b
O), 4.80 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.2,
OCH
a
H
b
O), 4.00 (2H, s, CH
2
), 3.88–3.65 (4H, m, OCH
2
CH
2
O),
3.35 (3H, s, OCH
3
), 3.30 (3H, s, OCH
3
), 2.20–2.00 (1H,
m, CH(CH
3
)
2
), 0.95–0.80 (6H, d,
3
J
H–H
12.0, CH(CH
3
)
2
);
δ
F
(CDCl
3
, 282 MHz) ⫺97.2 (1F, d,
2
J
F–F
56.4), ⫺105.5 (1F, d,
2
J
F–F
56.4); δ
C
(CDCl
3
, 75 MHz) 169.4, 155.9 (t,
1
J
C–F
297.6),
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J. Chem. Soc., Perkin Trans. 1, 2000, 3217–3226 3221
114.2 (dd,
2
J
C–F
57.1, 14.3), 97.2, 75.4, 71.5, 65.6, 59.5, 59.3,
59.0, 29.1, 18.2 [HRMS (CI, M[NH
4
]
⫹
) Found: 330.174323.
Calc. for C
13
H
26
NO
6
F
2
330.172819]; m/z (CI) 330 (100%,
[M ⫹ NH
4
]
⫹
).
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 ⬚C/0.1 mmHg; R
f
(40% ethyl ether in light
petroleum) 0.36; δ
H
(CDCl
3
, 300 MHz) 5.17 (1H, d,
4
J
H–F
2.9,
CH), 4.92 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
5.9,
OCH
a
H
b
O), 4.82 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
5.9,
OCH
a
H
b
O), 4.05 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
16.5, CH
a
H
b
OCH
3
), 3.95 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
16.5, CH
a
H
b
OCH
3
), 3.82–3.71 (2H, m, OCH
2
CH
2
O),
3.55–3.49 (2H, m, OCH
2
CH
2
O), 3.40 (3H, s, OCH
3
), 3.35 (3H,
s, OCH
3
), 0.90 (9H, s, C(CH
3
)
3
); δ
F
(CDCl
3
, 282 MHz) ⫺97.4
(1F, dd,
2
J
F–F
56.4,
4
J
H–F
2.9), ⫺104.8 (1F, d,
2
J
F-F
56.4);
δ
C
(CDCl
3
, 75 MHz) 169.5, 156.2 (t,
1
J
C–F
289.9), 112.6 (dd,
2
J
C–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]
⫹
) Found: 349.1429. Calc.
for C
14
H
24
O
6
F
2
Na 349.1439]; m/z (ES) 349 (60%, [M ⫹ Na]
⫹
),
257 (100).
3,3-Difluoro-2-[(methoxyethoxy)methoxy]-1-phenylprop-2-en-1-
yl (methoxy)acetate 9f
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 ⬚C/0.1 mmHg; R
f
(40% ethyl ether in light
petroleum) 0.41; ν
max
(film)/cm
⫺1
1762br s (C᎐
᎐
O); δ
H
(300 MHz,
CDCl
3
) 7.40–7.30 (5H, m, Ph), 6.62 (1H, t,
4
J
H–F
1.6, CH),
4.90 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.9, OCH
a
-
H
b
O), 4.70 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.9,
OCH
a
H
b
O), 4.20 (2H, s, CH
2
OCH
3
), 3.75–3.61 (2H, m,
OCH
2
CH
2
O), 3.55–3.45 (2H, m, OCH
2
CH
2
O), 3.44 (3H, s,
OCH
3
), 3.35 (3H, s, OCH
3
); δ
F
(282 MHz, CDCl
3
) ⫺96.4 (1F,
d,
2
J
F–F
54.5), ⫺104.7 (1F, d,
2
J
F–F
54.5); δ
C
(75 MHz, CDCl
3
)
169.0, 155.7 (t,
1
J
C–F
288.6), 135.7, 128.6 (4 signals), 126.5,
112.8 (dd,
2
J
C–F
55.2, 14.6), 97.5, 71.5, 71.0, 69.7, 68.5, 59.5,
59.0 [HRMS (ES, M[Na]
⫹
) Found: 369.1151. Calc. for
C
16
H
20
O
6
F
2
Na 369.1126]; m/z (CI) 364 (42%, [M ⫹ NH
4
]
⫹
),
254 (33), 108 (76), 59 (100).
1,1-Difluoro-2-[(methoxyethoxy)methoxy]penta-1,4-dien-3-yl
(methoxy)acetate 9g
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; R
f
(50% ethyl ether in light petroleum) 0.38; ν
max
(film)/cm
⫺1
1738s (C᎐
᎐
O); δ
H
(300 MHz, CDCl
3
) 6.05 (1H, d,
3
J
H–H
6.0, CH), 5.98–5.85 (1H, m, CCHCH
2
), 5.38 (1H, d,
3
J
H–H
15.0, CH⬘), 5.33 (1H, d,
3
J
H–H
9.0, CH⬘), 4.95 (1H, d, one half
of an AB quartet,
2
J
Ha–Hb
7.5, OCH
a
H
b
O), 4.88 (1H, d, one half
of an AB quartet,
2
J
Ha–Hb
7.5, OCH
a
H
b
O), 4.05 (2H, s,
CH
2
OCH
3
), 3.72–3.70 (2H, m, OCH
2
CH
2
O), 3.50–3.33 (2H,
m, OCH
2
CH
2
O), 3.45 (3H, s, OCH
3
), 3.35 (3H, s, OCH
3
);
δ
F
(282 MHz, CDCl
3
) ⫺96.4 (1F, d,
2
J
F–F
53.0), ⫺104.2 (1F, d,
2
J
F–F
53.0); δ
C
(75 MHz, CDCl
3
) 168.9, 155.5 (t,
1
J
C–F
292.3),
131.4, 119.2, 113.3 (dd,
2
J
C–F
36.2, 15.3), 97.2, 71.5, 70.6,
69.6, 68.5, 59.3, 59.0 [HRMS (CI, M[NH
4
]
⫹
) Found:
314.142009. Calc. for C
12
H
22
NO
6
F
2
314.141519]; m/z (CI) 314
(100% [M ⫹ NH
4
]
⫹
.
4,4-Difluoro-3-[(methoxyethoxy)methoxy]but-3-en-2-yl
(benzyloxy)acetate 10b
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 ⬚C. 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 (MgSO
4
), 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); R
f
(50% ethyl ether in light petroleum) 0.42; ν
max
(film)/
cm
⫺1
2921br s, 1761br s (C᎐
᎐
O), 1604w, 1496s, 1454s, 1248br s,
1194br s, 1128br s, 1044br s, 942s, 855m, 733s, 697s; δ
H
(CDCl
3
,
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,
2
J
Ha–Hb
6.3, OCH
a
H
b
O), 4.90
(1H, d, one half of an AB quartet,
2
J
Ha–Hb
6.3, OCH
a
H
b
O), 4.63
(1H, d, one half of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
Ph),
4.58 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
-
Ph), 4.06 (2H, s, C(O)CH
2
O), 3.88–3.73 (2H, m, OCH
2
CH
2
O),
3.57–3.52 (2H, m, OCH
2
CH
2
O), 3.38 (3H, s, OCH
3
), 1.44 (3H,
d,
3
J
H–H
7.3, CHCH
3
); δ
F
(CDCl
3
, 282 MHz) ⫺97.3 (1F, d,
2
J
F–F
55.1), ⫺104.7 (1F, d,
2
J
F–F
55.1); δ
C
(CDCl
3
, 75 MHz) 169.3,
155.9 (t,
1
J
C–F
292.1), 137.2, 128.6, 128.2, 114.1 (dd,
2
J
C–F
36.2,
14.7), 97.4, 73.5, 71.5, 68.6, 67.2, 59.2, 24.1, 17.1 (t,
4
J
C–F
2.3);
m/z (ES) 360 (78%, M
⫹
), 192 (100).
1,1-Difluoro-2-[(methoxyethoxy)methoxy]pent-1-en-3-yl
(benzyloxy)acetate 10c
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;
R
f
(50% ethyl ether in light petroleum) 0.45 (Found: C, 58.03;
H, 6.50. Calc. for C
18
H
24
O
6
F
2
: C, 57.75; H, 6.46%); δ
H
(CDCl
3
,
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,
2
J
Ha–Hb
5.9, OCH
a
H
b
O), 4.88
(1H, d, one half of an AB quartet,
2
J
Ha–Hb
5.9, OCH
a
H
b
O), 4.64
(1H, d, one half of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
Ph),
4.58 (1H, d, one half of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
-
Ph), 4.05 (2H, s, C(O)CH
2
O), 3.88–3.70 (2H, m, OCH
2
CH
2
O),
3.55–3.52 (2H, m, OCH
2
CH
2
O), 3.35 (3H, s, OCH
3
), 1.85–1.70
(2H, m, CH
2
CH
3
), 0.91 (3H, t,
3
J
H–H
7.3, CH
2
CH
3
); δ
F
(CDCl
3
,
282 MHz) ⫺96.70 (1F, d,
2
J
F–F
54.9), ⫺105.1 (1F, d,
2
J
F–F
54.9);
δ
C
(CDCl
3
, 75 MHz) 169.6, 155.9 (t,
1
J
C–F
292.1), 137.2, 128.6,
128.2, 113.2 (dd,
2
J
C–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 ⫹ NH
4
]
⫹
), 300 (36),
242 (76), 184 (87), 91 (100).
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; R
f
(20% ethyl acetate in light petroleum) 0.57; ν
max
(film)/cm
⫺1
1761 (C᎐
᎐
O) (Found: C, 58.92; H, 6.88. Calc. for
C
19
H
26
O
5
F
2
: C, 58.75; H, 6.75%); δ
H
(CDCl
3
, 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,
2
J
Ha–Hb
6.2, OCH
a
H
b
O), 4.85 (1H, d, one half
of an AB quartet,
2
J
Ha–Hb
6.2, OCH
a
H
b
O), 4.66 (1H, d, one half
of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
Ph), 4.61 (1H, d, one
half of an AB quartet,
2
J
Ha–Hb
11.8, OCH
a
H
b
Ph), 4.10 (2H, s,
C(O)CH
2
O), 3.85–3.70 (2H, m, OCH
2
CH
2
O), 3.65–3.45 (2H,
m, OCH
2
CH
2
O), 3.35 (3H, s, OCH
3
), 2.25–2.05 (1H, m,
CH(CH
3
)
2
), 0.95 (3H, d,
3
J
H–H
6.6, CH(CH
3
)
2
), 0.91 (3H, d,
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Published on 11 September 2000 on http://pubs.rsc.org | doi:10.1039/B004766J
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