One-pot near-ambient temperature syntheses of aryl(difluoroenol) derivatives from trifluoroethanol

Article abstract of DOI:10.1039/c1ob06372c

Difluoroalkenylzinc reagents prepared from 1-(2′-methoxy- ethoxymethoxy)-2,2,2-trifluoroethane and 1-(N,N-diethylcarbamoyloxy)-2,2,2- trifluoroethane at ice bath temperatures underwent Negishi coupling with a range of aryl halides in a convenient one pot

Full text of DOI:10.1039/c1ob06372c

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PAPER
One-pot near-ambient temperature syntheses of aryl(difluoroenol) derivatives
from trifluoroethanol†
Sara H. Kyne,a Jonathan M. Percy,*a Robert D. C. Pullin,‡b Joanna M. Redmondc and Peter G. Wilsona
Received 11th August 2011, Accepted 15th September 2011
DOI: 10.1039/c1ob06372c
Difluoroalkenylzinc reagents prepared from 1-(2¢-methoxy-ethoxymethoxy)-2,2,2-trifluoroethane and
1-(N,N-diethylcarbamoyloxy)-2,2,2-trifluoroethane at ice bath temperatures underwent Negishi
coupling with a range of aryl halides in a convenient one pot procedure. While significant differences
between the enol acetal and carbamate reagents were revealed, the Negishi protocol compared very
favourably with alternative coupling procedures in terms of overall yields from trifluoroethanol.
they were under used until recently due to their reported air
Introduction
and moisture sensitivity.14–16 The availability of new and more
The major strategic importance of palladium-catalysed coupling
reliable methods of generating organozinc reagents has rekin-
reactions within the canon of synthetic organic chemistry was
dled interest in this powerful coupling chemistry, and there
recognised recently by the award of the Nobel Prize for Chemistry
have been some spectacular recent results. Knochel and co-
to Heck, Negishi and Suzuki. Their methods are now used
workers have previously demonstrated a zincation of aromatic
routinely in academic and industrial facilities for applications
and heteroaromatic compounds bearing sensitive functionalities
ranging from discovery to production chemistry. For high atom
efficiency and low environmental impact, few palladium-catalysed
coupling procedures can rival the coupling first described by
Negishi in 1977.1,2 Organozinc species were found to be excellent
with 2,2,6,6-tetramethylpiperidide zinc chloride·lithium chloride
(TMP-ZnCl·LiCl).17 More recently this base has been shown to
participate in a remarkable zincation of alkenes a- to nitro and
cyano functionalities, with the subsequent organometallic species
able to undergo Negishi coupling.18
coupling partners and participated in a wide range of palladium-
catalysed aryl–aryl,1 aryl–alkenyl3 and alkenyl–alkenyl4 coupling
reactions.5 Negishi coupling has also been widely used in natural
product synthesis, demonstrated by the groups of Schreiber6
and Smith7 in their syntheses of discodermolide A. Schreiber
performed Negishi coupling with an alkenylzinc reagent while
Smith utilised an alkylzinc fragment in an alkyl–alkenyl coupling.
Negishi performed no fewer than 6 zinc-based couplings in his
synthesis of xerulin8 and further demonstrated the usefulness of
Negishi coupling in constructing linear unsaturated systems with
a short synthesis of b-carotene.9 More recently enigmazole A was
synthesised using a key oxazolylzinc intermediate in an heteroaryl–
alkenyl coupling step.10
Palladium-catalysed coupling methods have also been used
effectively for the synthesis of selectively fluorinated molecules;
the availability of metallated difluoroalkenes from new refrigerants
like HFC-134a (1), and from other bulk compounds like trifluo-
roethanol (2), has ensured valuable entry points which we and
others have used in syntheses of fluorinated analogues of natural
products.19,20 For example, the dehydrofluorination/metallation
reactions of acetal 3a and carbamate 3b have been used to
prepare stannanes 4a and 4b. We deployed 4a in a synthesis
of pentulose analogues21 and 4b in syntheses of difluorinated
carbasugar analogues.22,23 We were also able to prepare small
libraries of compounds structurally related to inhibitors of pro-
teases and other enzymes, using a divergent approach enabled
by Stille coupling of 4a with 4-iodophenyl triflate (Scheme 1).24
Selective coupling set the stage for subsequent Suzuki couplings
of 5 with a range of boronic acids (40–84%). Protolysis of the
Organozinc species are reactive, yet tolerate many functional
groups, including some which bear acidic protons;11–13 however,
aWestChem Department of Pure and Applied Chemistry, Thomas Graham
Building, 295 Cathedral Street, Glasgow, UK, G1 1XL. E-mail: jonathan.
percy@strath.ac.uk; Tel: +44 141 548 4398
bDepartment of Chemistry, University of Leicester, University Road, Leices-
ter, UK, LE1 7RH
cRespiratory CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels
Wood Road, Stevenage, UK, SG1 2NY
† Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and spectra, and Cartesian coordinates
and energies. See DOI: 10.1039/c1ob06372c
‡ Current address: Chemistry Research Laboratory, 12 Mansfield Road,
Oxford, UK, OX1 3TA.
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alkenylzinc reagent 10 could be generated at 0 ◦C by exposing 1 to
LDA in the presence of zinc chloride.37,38
We also wished to qualitatively evaluate the effects of groups
capable of coordinating to zinc, on the outcomes of coupling
reactions. Relatively little is known about the identities of the
reactive organozinc species which undergo transmetallation to
palladium during the catalytic cycle, though important recent
discoveries by Lei and co-workers,39 Hevia40 and Organ41 have
indicated that a range of organozinc and organozincate species
may all play parts in the reaction. In this manuscript, we will
describe the development of a near ambient (0 ◦C) dehydroflu-
orination/zincation and Negishi coupling protocol, survey its
scope and limitations, and compare and contrast its performance
with selected Stille and Suzuki couplings. We will also make a
preliminary in silico exploration of the structures available to the
organozinc reagents.
Scheme 1
difluoroenol acetals 6 completed the sequence, revealing a valuable
difluoromethyl ketone motif;25–27 small libraries of ketones 7
could be prepared in this way. This reaction also proceeded
smoothly with halogen and sulfur electrophiles affording an entry
to a range of halodifluoromethyl and (arylthio)difluoromethyl
ketones.28 This chemistry represents a concise and versatile
way of preparing a very wide range of difluoromethyl ketones.
Competitive methods, such as Uneyama’s reductive defluorination
of trifluoromethyl ketones,29,30 which can operate close to ambient
temperature, have significant advantages over low temperature
chemistry, even though each trifluoromethyl ketone must be made
separately. Carrying out reactions at low temperature at scale
is very expensive; refrigeration plant is costly to buy and run,
and special reactors can be required. Solvent viscosity rises at
low temperatures and inefficient agitation can lead to poor heat
transfer and the development of hot spots in reactions. As there are
few methods for the preparation of selectively fluorinated reactions
which are practical at scale (because of reagent cost, toxicity
or the requirement for low temperature), moving our versatile
trifluoroethanol chemistry up from -78 ◦C towards ambient would
be a promising development.
Recently, a group from Merck showed that the trifluorob-
orate technology pioneered by Geneˆt31,32 and elaborated by
Molander33,34 could be adapted for the synthesis of selectively flu-
orinated molecules from trifluoroethanol via Suzuki coupling.35,36
Though the synthesis of crystalline borate 8 required a low
temperature (-78 ◦C) reaction, the subsequent chemistry avoided
the use of toxic tin reagents. Reagent 8 coupled with a range of
aryl bromides in the presence of palladium dichloride pre-catalyst
and bulky RuPhos ligand.
Results and discussion
Acetal 3a, carbamate 3b and stannane 4a were prepared by our
published procedures.42,43 Borate 8 (55%) was prepared in one
pot from 3a by an adaptation of a procedure of Geneˆt and
co-workers;32 in contrast to the observations of Katz and co-
workers, isolation of an intermediary boronic acid or ester was
unnecessary.36 Dehydrofluorination/metallation of carbamate 3b
was carried out with tert-butyllithium (2 equivalents) in THF at
-78 ◦C in the first instance. These conditions were chosen to allow
the unambiguous preparation of the organolithium reagent.22
A
solution of freshly-fused zinc chloride (1.1 equivalents) in THF
was added and the mixture was held at -78 ◦C for 2 h, then
allowed to warm to room temperature (15–18 ◦C). After 30 min,
the mixture was cannulated onto a mixture of 4-iodoanisole 16a
(1.1 equivalents) and tetrakis(triphenylphosphino)palladium(0)
(5 mol%), and heated at 65 ◦C for 16 h. After work-up and
purification, we obtained 12ba as the sole fluorinated product in ca.
70% yield (Scheme 2). This result showed that 9b was both stable
at room temperature and available for coupling under palladium-
catalysed conditions at higher temperatures. We then implemented
a series of step changes by replacing the alkyllithium base
with LDA, raising the dehydrofluorination/metallation reaction
temperature to 0 ◦C and having the zinc(II) salt present from the
beginning of the sequence, as described by Burton.37,38 Freshly-
prepared LDA (2.5 equivalents)44 was added to a mixture of
3b and freshly-fused zinc chloride in THF at 0 ◦C. A yellow
solution formed immediately and this colour persisted after
◦
stirring for 1 h at 0 C and a further hour at room temperature
(15–18 ◦C). Reagent 9b was cannulated onto a mixture of 16a
(1.1 equivalents) and tetrakis(triphenylphosphino)palladium(0)
(5 mol%), and heated at 65 ◦C overnight. Once again, we were able
to isolate 12ba in good (65%) yield from 3b. We were very pleased
We wished to see if this type of procedure could be used to
generate 9a and 9b from 3a and 3b, and deploy them in coupling
reactions. Burton had showed that HFC-134a 1 could be used to
begin a Negishi-coupling approach to trifluorostyrenes; the key
Scheme 2
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with this result; while Burton’s precedent was a very strong one,
the effect of strongly coordinating groups within the alkenylmetal
was difficult to predict. Pleasingly, reducing the palladium catalyst
loading to 2 mol% did not lower the reaction yield so subsequent
reactions were carried out at this loading.
improvement was obtained from the use of this less THF-soluble
complex.
It is known that the (N,N-diethylcarbamoyloxy) group ranks
more highly than the methoxymethyl (MOM) group in the DoM
hierarchy;47,48 DMPU (12% v/v) was added to mimic the ability
of the carbamate moiety of 3b to de-aggregate and increase the
reactivity of the metal amide base (entry 7).49–51 The presence of the
co-solvent resulted in full conversion of 3a, a higher isolated yield
and a reduced reaction time. A range of co-solvent concentrations
(12–65% v/v) were screened; however, it was observed that DMPU
concentrations above 12% v/v yielded similar conversions and
isolated yields. This much improved procedure was adopted as the
standard protocol for generating styrenes from acetal 3a.
The order of addition of the reactants was investigated briefly,
but no advantage accrued from, for example, mixing base and
zinc(II) salt before the addition of 3b. The addition of LDA
(2.5 equivalents) to a solution of 3b and zinc(II) chloride (1.1
equivalents) in THF appeared to be the most straightforward
protocol because it minimised the number of reagent transfers.
This procedure was applied to the potentially more problem-
atic acetal 3a (Scheme 3); the (methoxy)ethoxymethyl (MEM)
protecting group is cleaved by Zn(II) salts45 and so reagent and
product stability were uncertain. Low conversions of 3a were
observed under the conditions used for 3b (as indicated by
the 19F NMR spectra of the crude coupling reaction mixtures).
Table 1 summarises initial investigations of the reaction of
acetal 3a. Whereas 3b was consumed completely after 2 h, 3a
underwent dehydrofluorination/metallation more slowly, with
only a moderate conversion (65%) of 3a after 3.5 h (total reaction
time, Table 1, entry 2). These results indicate that 3a and 3b
undergo dehydrofluorination/metallation at different rates, and
that incomplete conversion of the trifluoroethyl starting material
leads to a low yield of coupled product. There was little to be
gained from increasing the reaction time further (entry 3). The
use of 3 equivalents of LDA (entry 4) delivered a disappointing
yield of product after isolation (34%) despite high conversion
(93%); the 19F NMR spectrum had a low signal-to-noise ratio, and
very broad peaks, strongly suggestive of extensive defluorination.
Similar results were observed when LDA was added at room
temperature (entry 5). We noted that the reaction was slightly
exothermic at room temperature; decomposition may be the
consequence of failure to control it. The non-hygroscopic zinc(II)
chloride·TMEDA complex synthesised using the protocol of
Isobe46 was investigated as a zinc(II) source (entry 6) but no yield
The effect of the co-solvent appears to be on the dehydrofluo-
rination/metallation. Given that DMPU is unnecessary for good
conversion of 3b to 9b, the carbamate was ideal to probe this
effect. Generation of vinylzinc 9b in the presence of 12% v/v (or
higher proportion of) DMPU resulted in 100% conversion and
subsequent Negishi coupling with 11k afforded styrene 12bk in
33% isolated yield. The same procedure without the co-solvent
resulted in a similar 36% isolated yield, establishing that DMPU
does not have any effect on the efficiency of the coupling step. We
were also able to shorten the reaction time for the coupling step
from 16 to 0.5 h without any reduction in yield; in some cases, the
shorter time was advantageous (vide infra). During the course of
this investigation, we were pleased to find that the reactions could
be carried out smoothly using commercial LDA as a solution in
THF/heptane/ethylbenzene, further simplifying our protocol.
Scheme 3
Table 1 Optimising the reaction conditions for dehydrofluorination/metallation and coupling of 3a
Time at
Entry
LDA (eq.)
Zn salt (eq.)
0 ◦C (h)
15–18 ◦C (h)
Conversiona (%)
Yieldb (%)
1
2
3
4
5
6
7d
2.0
2.5
2.5
3.0
2.5
2.5
2.5
1.0
1.1
1.1
1.1
1.1
1.1c
1.1
1
1
1
1
0
1
1
1
2.5
4
4
4
3
1
27
65
67
93
88
81
95
—
—
—
34
—
47
60
a Measured by integration of the 19F NMR spectrum. b Isolated yield of 12aa after chromatography. c ZnCl2·TMEDA complex was used. d The solvent
was 12% v/v DMPU/THF.
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Table 2 Scope and limitations of the Negishi coupling protocol
Halide
Precursor
Methodd
Product (overall yield)
11a
3a
3b
a
b
12aa, X = OMEM (60%);
12ba, X = ODEC (65%).
11b
11c
11d
11e
11f
3a
3b
a
12ab, X = OMEM (73%);
12bb, X = ODEC (63%).
b
3a
3b
a
b
12ac, X = OMEM (53%);
12bc, X = ODEC (65%).
3a
3b
a
b
12ad, X = OMEM (48%);
12bd, X = ODEC (57%).
3a
3b
a
b
12ae, X = OMEM (40%);
12be, X = ODEC (0%).
3a
3b
a
b
12af, X = OMEM (54%);
12bf, X = ODEC (51%).
11g
11h
3a
3b
aa
ba
12ag,b X = OMEM (25%);
12bg,b X = ODEC (60%).
3a
3b
a
b
12ah,b X = OMEM (41%);
12bh,b X = ODEC (53%).
11j
3a
3b
aa
b
12aj, X = OMEM (20%);
12bj, X = ODEC (37%).
11k
11l
3a
3b
aa
b
12ak, X = OMEM (25%);
12bk, X = ODEC (36%).
3a
3b
aa
b
12al,b X = OMEM (33%);
12bl,b X = ODEC (29%).
11m
3a
3b
a
12am,b X = OMEM (41%);
12bm,b X = ODEC (42%).
bc
11n
3a
3b
aa
b
12an,b X = OMEM (31%);
12bn, X = ODEC (18%).
a Coupling reaction time 0.5 h. b Commercial LDA was used. c Coupling reaction time 0.25 h. d Method a: i) from 3a, LDA (2.5 eq.), ZnCl2 (1.1 eq.), 12%
v/v DMPU/THF, 0 ◦C (1 h) then 15 ◦C (1 h), then ii) aryl halide, Pd(PPh3)4, 65 ◦C, 16 h. Method b: i) from 3b, LDA (2.5 eq.), ZnCl2 (1.1 eq.), THF,
0 ◦C (1 h) then 15 ◦C (1 h), then ii) aryl halide, Pd(PPh3)4, 65 ◦C, 16 h.
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Table 3 Coupling method comparison for selected substrates
Coupling method (% isolated overall yield from 3a)
delivers 12an in 31% yield. In general, p-electron rich and
neutral aryl halides couple with both 9a and 9b in moderate
to good yields. The most successful coupling partners were 3-
(methoxy)- and 4-(methoxy)bromobenzene. The potential for
scale up was demonstrated with 4-chloro species 11f; only a
slightly lower yield of 12bf (38%) was obtained when the coupling
reaction was scaled to 10 mmol. Suzuki–Miyaura coupling of
aryl chlorides can now be effected in the presence of bulky
phosphine ligands,53 so these intermediates may be a potential
entry point to the difluoromethylketone libraries. Only one result
suggested a clear difference between 9a and 9b as coupling
partners. Product 12ae was generated in 40% yield from 2-
bromotoluene; however, attempts to couple carbamate 9b with
11e were unsuccessful. Interchanging the transmetallating and
oxidative addition species54-56 by using a Suzuki coupling reaction
between iodide 13 and (o-tolyl)boronic acid afforded styrene 12be
in 60% overall yield from 3b, suggesting that transmetallation
from 9b to an (o-tolyl)palladium phosphine complex may be slow
(Scheme 5). We were able to improve upon the previous43 low
temperature generation of 13 by quenching 9b (generated close
to ambient temperature) with a solution of iodine in THF. Aryl
halides containing electron withdrawing groups generally coupled
less efficiently, though there were some notable exceptions. Our
initial investigations used 1-iodo-4-nitrobenzene57 in the standard
procedure; after stirringfor 16hat 65 ◦C, the 19F NMR spectrum of
the crude reaction mixture revealed only traces of desired styrene
12bm. Previous evidence that the Negishi coupling to generate
methoxystyrene 12ba was complete after 30 min prompted a
short GC-MS study to derive a crude profile of the coupling
of 11m and 9b. The reaction was undertaken as normal and an
aliquot was removed every 15 min for 1 h. These aliquots were
exposed to a crude work-up, then GC-MS analysis was performed,
revealing a complex mixture. This is in contrast to the clean spectra
obtained for the generation of methoxystyrene 12ba. Even after
16 h no degradation products developed, indicating that 12ba
is much more robust than 12bm. Not all of the species could
be identified, but styrene 12bm was present, with HF adduct
14,58 protonated species 15 and unreacted 11m. After 15 min
a significant quantity of styrene 12bm was produced, but the
quantity seemed to remain constant for the monitoring period of
60 min. After stirring for 16 h at 65 ◦C, a significant reduction in the
concentration of 12bm was observed by GC-MS. A considerably
improved isolated yield of 42% was achieved when the reaction was
quenched after just 15 min. Although significant quantities of the
coupled products can be obtained from 11m and 11n, purification
is difficult and contamination with some unidentifiable material
is apparent (~95% purity by NMR), representing a limit to the
current Negishi methodology. The improvement in yield brought
about by shortening the reaction time was not general for all p-
electron deficient aryl halides. Only a few returned better yields
Product
Negishia
Suzukib
Stillea
12aa
12ab
12ae
12ag
12ah
12ak
12am
12an
4-OMe 60
3-OMe 73
2-Me 40
4-OTf 25
4-CF3 41
50
55
48
36d
53
(-)c
(-)c
0
50
(-)c
(-)c
67
(-)c
46
4-CN
25
4-NO2 41
3-NO2 31
61
(-)c
a This study. b Ref. 36 c Not done. d Ligand-free procedure (see text).
Scope and limitations
With high conversion conditions in hand for both 3a and 3b, the
scope of the Negishi coupling could be explored with a palette of
aryl bromides and iodides 11a–11n. Table 2 summarises the results.
These reactions were usually carried out by preparing a batch of
the organozinc reagent and transferring the appropriate quantity
by syringe to reaction tubes. Organozinc reagents are sometimes
avoided because of their sensitivity to moisture and are usually
formed in situ for immediate consumption; however, Leitner and
co-workers discovered that a solution of 2-pyridylzinc bromide
could be stored for more than 12 months at room temperature
without any significant decomposition.52 A solution of reagent 9b
was stored in the refrigerator for 7 days prior to Negishi coupling
with 16a using the standard conditions. A 65% yield of styrene
12ba was obtained from a coupling carried out at the end of
that period, revealing that 9b is relatively stable in solution, and
certainly amenable to batch preparation.
Pleasingly, the total yield of coupling product from 3a is
competitive with that from the Suzuki–Miyaura protocol (which
required a low temperature step) described by Katz and co-
workers. Table 3 highlights some interesting comparisons between
the two methods with benchmark Stille couplings from 4a; these
were carried out according to Scheme 4. The Suzuki yields in Table
3 were taken from the paper of Katz et al., with the exception
of 12ag. For this substrate, we adapted the published procedure
by running the coupling reaction with a Pd(dba)2 (5 mol%)
catalyst (instead of the published PdCl2) in n-propanol containing
triethylamine, and without the expensive bulky monophosphine
ligand RuPhos. This allowed us to generate 12ag in 36% overall
yield from 3a (the addition of RuPhos did not increase the yield).
Scheme 4
Our Negishi method is at least competitive with the Suzuki–
Miyaura protocol and has the great advantage of requiring no
cooling beyond ice bath temperature; this has strategic impli-
cations for the scalability of our methodology. It is interesting
that the nitro-congener 12an could not be synthesised by Suzuki
coupling of trifluoroborate 8, whereas our Negishi protocol
Scheme 5
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at 0 ◦C, eliminating the cost of low temperature chemistry and
removing an isolation step. These are obvious advantages if scale-
up is anticipated. As with the Suzuki–Miyaura method, however,
overall yields of p-electron deficient styrenes were moderate to
poor. Use of stannane 4a improved these overall yields and
demonstrated that Stille coupling is a robust and viable option
when other approaches are less available. Though stannane
synthesis currently requires low temperature conditions, the Stille
coupling of 4a is so reliable that it may be the preferred protocol
for coupling partners of value.
Table 4 Comparison of coupling efficiencies of aryl iodides and bromides
Coupling partner (Yield%)
Aryl halide
9aa
9bb
11a
16a
11h
16h
11k
16k
60
58
41
29
22
22
65
65
53
53
36
32
a i) from 3a, LDA (2.5 eq.), ZnCl2 (1.1 eq.), 12% v/v DMPU/THF, 0 ◦C
(1 h) then 15 ◦C (1 h), then ii) aryl halide, Pd(PPh3)4, 65 ◦C, 16 h. b i) from
3b, LDA (2.5 eq.), ZnCl2 (1.1 eq.), THF, 0 ◦C (1 h) then 15 ◦C (1 h), then
ii) aryl halide, Pd(PPh3)4, 65 ◦C, 16 h.
On the relationship between structure and reactivity in the
organozinc reagents
While our understanding of the relationship between organozinc
constitution and structure, and reactivity in coupling reactions
is still in its infancy, the recent work of Lei and co-workers,39
Hevia40 and Organ41 has begun to reveal the complexity inherent
in Negishi coupling chemistry. The importance of organozincate
species is becoming established and the nature of the nucleophilic
reagent (organozinc or organozincate) appears to control which
step determines the rate. Lei and co-workers recorded reaction
kinetics (followed by IR spectroscopy), and interpreted the results
with a set of simple DFT calculations to attempt to identify the
organozinc species from which the organic ligand would transfer
most rapidly. The calculations involved separating the Zn–C bond
to produce an ion pair; geometries were optimised (B3LYP/6-
31G*, gas phase), and electronic energies were also calculated as
single points using a simple model for THF solvation. Scheme 6
shows the reaction considered; mixed metal complex 17 (generated
from Grignard reagent) has a much lower (electronic) energy of
ion pair separation to 18 (and phenyl anion) than any of the other
species considered (gas phase or THF).
after quenching the reaction at 30 min. para-Trifluoromethyl
styrenes 12ah and 12bh were generated in moderate yield, as were
the cyano derivatives 12ak, 12bk, 12al and 12bl. Yields of triflates
12ag and 12bg were also improved when the reaction time was
reduced to 30 min. While all three methods are competitive for
the formation of 12aa, the Stille coupling with p-electron deficient
aryl iodides delivers the best yields. The general trends observed
in the Negishi results are similar to those obtained by Burton
and co-workers38 for trifluorostyrene synthesis from HFC-134a
and aryl iodides, with the highest yields obtained using p-electron
rich aryl iodides, and lower yields obtained when the arene was
p-electron deficient. We also compared aryl bromide and iodide
coupling partners in selected cases (Table 4), finding no advantage
in the use of the more reactive iodides; the isolated purified yields
are comparable or better with the bromides. As aryl iodides would
be expected to undergo oxidative addition significantly faster than
the analogous bromides, it would appear that oxidative addition
is not the rate-determining step in the catalytic cycle. This is an
observation that will be investigated further within our laboratory,
but lies beyond thescopeof this manuscript;however, itis clear that
no advantage accrues from the use of the iodides. Coupling a range
of aryl chlorides was not attempted as 4-(methoxy)chlorobenzene
did not couple with 9a under our standard Negishi conditions.
Finally, we carried out a limited number of experiments generating
9a in the presence of magnesium chloride and then coupling, but
we saw no significant and consistent increase in reaction yield over
the zinc-only protocol (see the Supplementary Information† for
more details).39,40 The continuing value of the Stille coupling is
shown in Table 3; the Stille coupling reaction may still be the most
effective protocol when the aryl component is more costly than
the stannane, but the yield advantage must be weighed against the
toxicity of the organotin reagent and waste. The Negishi method
is competitive because it avoids toxic reagents, is direct and can be
implemented close to ambient temperature.
Scheme 6
Complex 17 was also characterised by X-ray structure elucida-
tion from single crystals. We have invoked the coordinating abilities
of MEM and carbamoyl groups to explain the ease with which 9a
and 9b (and their organolithium precursors) form and we were
interested in anticipating the effects of these groups upon the
ease of alkenyl ligand transfer from zinc. We therefore carried
out some modelling for 17, 18 and 19–22 using Spartan’0859
(B3LYP/LACP*(6-31G*)) to produce preliminary structures, and
Gaussian’0960 [(B3LYP/SDD(6-31G*)] for reoptimisation and
frequency calculations in the gas phase.61 The geometry of the
[(THF)4MgZnCl3] cation 18 was found by ablating the phenyl
group and minimising the structure. Lei calculated a value of
155 kcal mol-1 for Etransfer from 17; we obtained the very similar
value of 151.5 kcal mol-1. The difference is due to a lower energy
being obtained for the phenyl anion. Given the failure of any
advantage to accrue from the presence of magnesium(II) chloride
This Negishi protocol clearly offers some distinct advantages
over the related Suzuki–Miyaura and Stille coupling methods.
Access to the alkenylzinc coupling partner is achieved in situ
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in our couplings, we will consider only the monomeric and dimeric
zinc complexes, rather than complexes analogous to 17.
Trigonal bipyramidal geometries were found for monomer
complexes, without THF displacement. A trigonal bipyramidal
centre at zinc results in some stereochemical complexity and we
looked at a wide range of structures. Fig. 1 shows the most
important structures. In 20b, the lowest energy species found
for this complex (and one to which a number of quite different
stereoisomers optimised), the Zn ◊ ◊ ◊ O C(carbamate) distance is
Fig. 1 Complex geometries used for the electronic structure calculations.
Red/blue atom labelling is used to identify the apical ligands at each
zinc centre. Distances were measured from the B3LYP/LACVP*(6-31G*)
structures.
˚
2.38 A, the same as the apical (THF)O ◊ ◊ ◊ Zn distance and only
˚
0.2 A longer than the equatorial (THF)O ◊ ◊ ◊ Zn distance. The bite
angle (C–Zn ◊ ◊ ◊ O) of the ligand is 76◦ so the occupancy of one
apical and one equatorial site represents the ideal disposition.
The trigonal bipyramidal geometry in 20b is slightly distorted; the
(THF)O–Zn ◊ ◊ ◊ O C(carbamate) angle (the oxygens are apical)
is 167◦, and the angles between the equatorial bonds are not
from 20d to 20e) so the effect of the fluorine atoms is only slightly
smaller than those of the chelating groups. These lower values of
E
transfer must arise from destabilisation of the neutral complexes, or
˚
equal. In 20d, the Zn ◊ ◊ ◊ OCH2O distance is longer at 2.74 A
inductive stabilisation of the anionic fragment in the ion pair, or
both. The dimeric species presented considerable stereochemical
complexity, though a key observation allowed us to simplify the
range of structures which required examination. We found that the
coordinating groups tended to bridge across to the cationic zinc
during optimisation of cations 24, illustrated by 24b and 24d in
Fig. 1. For this reason, we used the lowest energy dimer complexes
which present the coordinating group in an orientation from which
it can reach across to the cationic zinc centre.
The coordinated oxygen is apical in these complexes with an
equatorial C–Zn bond and m-bridging via equatorial chlorine
atoms. The lowest energy dimer complexes were unsymmetrical
around the Zn2Cl2 core, locating the chelating groups in distinct
environments; carbamate and MEM O ◊ ◊ ◊ Zn distances were
similar to those in the monomers.
and the angle made between the apical oxygen atoms at zinc
is slightly wider at 172◦ in consequence.67 Structures in which
the potential coordinating group was placed as far as possible
from the metal centre always brought the group into coordination
during the optimisation. These are gas phase calculations, so they
do not anticipate the presence of bulk coordinating solvent and
it may be that THF molecules replace our coordinating groups
in solution. However, chelate formation is highly entropically
favourable because a solvent molecule is released a◦nd given that
the concentration of pure THF is only 12 M at 20 C, it may be
these species are chelated even in THF solution.
Alkenyl transfer then affords the cationic [(THF)2ZnCl]+ species
as in the reaction considered by Marder. Alkenyl transfer is less
favourable than phenyl transfer by ca. 14 kcal mol-1 from monomer
or dimer. In the monomers, the introduction of a carbamoyloxy
group (ODMC) or a OMEM group lowers the values of Etransfer
by 18.6 (from 20b) and 16.9 kcal mol-1 (from 20d), respectively. In
each case difluorination brings about a further lowering in energy
(a further 9.5 kcal mol-1 from 20b to 20c, and 10.7 kcal mol-1
In the bridged cations, the O ◊ ◊ ◊ Zn distances shorten (consistent
˚
with the cationic nature of the zinc centre) at 1.98 A for the m-
bridging carbamoyloxy group (Zn ◊ ◊ ◊ O1 in 24b), and 2.17 and
˚
2.16 A for the two MEM oxygens (Zn ◊ ◊ ◊ O1 and Zn ◊ ◊ ◊ O1¢
respectively in 24d) (both Fig. 1). The effect of fluorination on
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Table 5 Ligand transfer energies (Etransfer) calculated for monomeric and
dimeric alkenzylzinc chlorides
Table 6 Selected interatomic distances for complexes 28a–28c
˚
Interatomic distances (A)
Etransfer (Kcal mol-1)a
Structure
Zn ◊ ◊ ◊ O1
Zn ◊ ◊ ◊ O2
Zn ◊ ◊ ◊ O3
Transferring ligand
X
Y
Monomer
Dimer
28a
28b
28c
2.77
2.49
2.86
2.14
2.13
2.08
2.19
2.13
2.14
Phenyl30
Phenyla
Alkenyl
—
—
H
ODMC
ODMC
OMEM
OMEM
—
—
H
H
F
H
F
19
182.2 21
179.5 21
193.3 22a 193.9
174.7 22b 156.7
165.2 22c 147.1
176.4 22d 155.0
165.7 22e 144.5
183.6
181.2
19
20a
20b
20c
20d
20e
symmetrical trigonal bipyramidal complexes 28a–28c (20b is
3.6 kcal mol-1 more stable than 28a [B3LYP/SDD(6-311G**)]);
starting from a less stable geometry might predispose the trigonal
bipyramid to collapse to a tetrahedral structure. Replacing the
two THF molecules with DMF or DMPU failed to labilise the
pentacoordinate structure, though there are changes in interatomic
distances (Table 6). Interestingly, the distance between the carba-
mate oxygen and the zinc centre is shortest when DMF ligates
the metal, though the DMF oxygens are neither closer nor more
distant from the zinc than those of the other solvents.
The status of the cation-stabilising interactions cannot be
evaluated without a more rigorous treatment of solvation, but
it seems that the coordinating groups may have a significant
role to play in the organozinc chemistry. These are interesting
predictions which cannot be evaluated using reaction yields, and
more detailed calculations and kinetic investigations lie outwith
the scope of this manuscript.65 It is certain that more useful insights
will only evolve once the entire pathway via transmetallation and
reductive elimination can be modelled,66 and of course, strongly
coordinating groups and solvents may influence those steps. We
propose to investigate these aspects of the reaction pathway and
will report our findings elsewhere.
a B3LYP/SDD(6-31G*), gas phase (Gaussian’09); DMC = CONMe2.
Etransfer is still around 10 kcal mol-1, and while there is a clear
difference between the carbamate and acetal series in terms of
geometry, with both oxygens in the methoxyethoxy chain recruited
(24d and 24e), the net effects of the OMEM and ODMC groups on
Etransfer are very similar at 49 and 47 kcal mol-1 respectively. Both
the carbamate and MEM dimer complexes have Etransfer values
comparable to the value calculated for phenyl complex 17.
The formation of pentacoordinate species requires some com-
ment because tetrahedral coordination is well established for
zinc(II).62 Jackson and co-workers have used a higher level of
theory [B3LYP/SDD(6-311G**)] to distinguish between penta-
coordinate and tetracoordinate geometries for alkylzinc iodides
in DMF.63 Monomer complex 20b was therefore examined at this
level of theory and the integrity of the pentacoordinate geometry
was maintained. Non-coordinated tetrahedral geometry 25 (Fig.
2) was also optimised using Jackson’s method [B3LYP/SDD(6-
311G**)]. The pentacoordinate species is 6.6 kcal mol-1 more
stable than 27 at this level of theory.64 Part of this energy difference
is steric in origin and can be revealed by considering the enol
carbamate alone; conformer 26 is 3.7 kcal mol-1 less stable than
27 (B3LYP/6-311G**). The remainder of the energy difference
(3 kcal mol-1) represents the favourable (presumably electrostatic)
interaction between carbamate oxygen and zinc. This is a very
modest energy difference and it indicates that the conclusions
drawn from Table 5 will be affected minimally whether the
organozinc species are tetra- or pentacoordinate.
Conclusions
We have developed
a dehydrofluorination/metallation and
Negishi coupling procedure that brings useful C–C bond forming
chemistry from trifluoroethanol derivatives away from the low
temperature regimes (-78 ◦C or below) required previously and
up to near ambient temperature. This is a major strategic advance
in the synthesis of selectively fluorinated molecules, enabled by
the seminal contribution of Burton. Our method delivers yields of
coupling products competitive with those reported by Katz and
co-workers, while using fewer preparative steps and avoiding low
temperature conditions entirely. Batches of the key organozinc
reagents were successfully prepared and stored, highlighting the
chemistry’s utility for parallel synthetic applications. The use of
commercial LDA solution is an additional attractive feature. The
presence of the coordinating groups in these complexes may
have interesting consequences for the structure and reactivity
of the organozinc species; using an accepted method of theory
with a large basis set, we have found favourable pentacoordinate
structures, where only tetrahedral structures were anticipated.
Preliminary electronic structure calculations predict that trans-
metallation from zinc to palladium may be assisted by the
-OMEM and -ODEC groups at the a-position; the presence of
two fluorine atoms appears to result in a similar effect. The
electrophilicity of the coupling products and the vulnerability of
certain types of products towards HF addition may ultimately
impose limitations upon the type of coupling reactions that can
Fig. 2 Complexes used to probe the effect of chelation and pentacoordi-
nation at zinc.
To explore the effect of solvent donor ability on the integrity of
the pentacoordinate geometry, we examined slightly less stable
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be executed; nevertheless, a range of valuable new chemistries
accessible close to ambient temperature may be made available
by these discoveries with profound strategic consequences for the
synthesis of selectively difluorinated molecules at scale.
1.1 mmol) and tetrakis(triphenylphosphino)palladium(0) (23 mg,
0.02 mmol) at 65 C overnight. The previous work-up, isolation
◦
and purification afforded styrene 12ba (185 mg, 65%) as a pale
yellow oil; Rf (40% diethyl ether in light petroleum ether) 0.35;
lmax (MeOH)/nm 250 (e/dm3 mol-1 cm-1 17 400); nmax(film)/cm-1
1729, 1611, 1515, 1425, 1269, 1147, 1035, 983, 838, 824, 786, 756;
dH(400 MHz, CDCl3) 1.20 (3 H, t, J 7.1, NCH2CH3), 1.27 (3 H, t,
J 7.1, NCH2CH3), 3.38 (2 H, q, J 7.1, NCH2CH3), 3.46 (2 H, q,
J 7.1, NCH2CH3), 3.83 (3 H, s, OCH3), 6.91–6.95 (2 H, m, ArH),
7.35–7.39 (2 H, m, ArH); dC(100 MHz, CDCl3) 12.7, 13.7, 41.4,
Experimental
Batch generation of alkenylzinc reagents
2,2-Difluoro-1-(N,N-diethylcarbamoyloxy)ethenylzinc chloride
9b. Lithium diisopropylamide (17.9 cm3 of a 1.4 M solution in
THF) was added dropwise to a solution of 2,2,2-trifluoroethyl
carbamate 3b (1.99 g, 10 mmol, 1.63 cm3), freshly fused zinc
chloride (1.5 g, 11 mmol) in dry THF (20 cm3) at 0 ◦C over a
period of 10 min. The resulting yellow solution was stirred at 0 ◦C
for 1 h, then for 1 h at room temperature, to afford 9b (assumed to
be a 0.25 M solution in THF). The appropriate volume was then
used for each Negishi coupling reaction.
2
3
42.0, 54.8, 111.7 (dd, JC-F 38.9, 19.5), 113.6, 122.1 (br. d, JC-F
4
1
6.3), 126.6 (dd, JC-F 6.0, 3.3), 152.5, 154.1 (app. t, JC-F 288.1),
2
158.9; dF(376 MHz, CDCl3) -95.9 (1 F, d, JF-F 54.4), -106.0 (1
F, d, JF-F 54.4); [HRMS (EI, M+) Found: 285.118829; Calc. for
2
C14H17F2NO3: 285.117650]; m/z (CI) 286 (40%, [M + H]+), 169
(90), 100 (100); GC (98%) tR 12.50 min (70–250 ◦C, 20 ◦C min-1).
Effect of order of addition on the preparation of 1-(N,N-diethyl-
carbamoyloxy)-2,2-difluoro-1-(4¢-methoxyphenyl) ethene 12ba
2,2-Difluoro-1-(2¢-methoxy-ethoxymethoxy)ethenylzinc chloride
9a. Lithium diisopropylamide (17.9 cm3 of a 1.4 M solution in
THF) was added dropwise to a solution of 2,2,2-trifluoroethyl
acetal 3a (1.88 g, 10 mmol, 1.55 cm3), freshly fused zinc chlo-
ride (1.5 g, 11 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) (5 cm3) in dry THF (20 cm3) at 0 ◦C over a
period of 10 min. The resulting yellow solution was stirred at 0 ◦C
for 1 h, then for 1 h at room temperature, to afford 4a (assumed to
be a 0.22 M solution in DMPU/THF). The appropriate volume
was then used for each Negishi coupling reaction.
Procedure 1: Addition of LDA/Zn(II) chloride mixture to 3b.
LDA (3.9 cm3 of a 0.64 M solution) was added dropwise to a
solution of freshly fused zinc(II) chloride (150 mg, 1.1 mmol) in
THF (2 cm3) at 0 ◦C over a period of 5 min and the mixture was left
to stir for 1 h. This solution was then cannulated into a solution
of 3b (199 mg, 1.0 mmol) in THF (1 cm3) and stirred for 1 h at
0 ◦C, then for 1 h at room temperature (15–18 ◦C). The solution
turned orange and was cannulated onto a mixture of 4-iodoanisole
(257 mg, 1.1 mmol) and tetrakis(triphenylphosphino)palladium(0)
(23 mg, 0.02 mmol) and stirred at 65 ◦C overnight. The black
mixture was cooled to room temperature and diluted with DCM
(30 cm3) and water (40 cm3) then filtered through a short pad of
Celite. The organic phase was separated and dried by passing
through a hydrophobic frit. The solvent was removed under
reduced pressure and purified by flash column chromatography
on silica (30% diethyl ether in light petroleum ether) to afford
styrene 12ba (145 mg, 51%) as a pale yellow oil; the data were in
agreement with those reported earlier.
Typical coupling procedure with alkenylzinc reagents 9a and 9b
2,2-Difluoro-1-(2¢-methoxy-ethoxymethoxy)-1-(4¢¢-methoxy-
phenyl) ethene 12aa. Alkenylzinc reagent 9a (4.45 cm3 of a 0.22
M solution in THF/DMPU) was added in one portion to a
flask containing 4-bromoanisole 11a (206 mg, 1.1 mmol) and
tetrakis(triphenylphosphino)palladium(0) (23 mg, 0.02 mmol) and
the mixture was heated at 65 ◦C overnight. The black mixture
was cooled to room temperature, diluted with DCM (30 cm3)
and water (40 cm3) then filtered through a short pad of Celite.
The organic phase was separated and dried by passing through a
hydrophobic frit. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography
on silica (30% diethyl ether in light petroleum ether) to afford
styrene 12aa (170 mg, 60%) as a yellow oil; Rf (40% diethyl ether
in light petroleum ether) 0.30; nmax(film)/cm-1 2936, 1737, 1611,
1515, 1465, 1257, 1179, 1151, 1035, 979, 950, 836; dH(400 MHz,
CDCl3) 3.40 (3 H, s, CH2OCH3), 3.56–3.60 (2 H, m, OCH2CH2O),
3.84 (3 H, s, ArOCH3), 3.85–3.90 (2 H, m, OCH2CH2O), 4.87 (2 H,
s, OCH2O), 6.90–6.96 (2 H, m, ArH), 7.38–7.43 (2 H, m, ArH);
Procedure 2: Addition of 3b to LDA/zinc(II) chloride mixture
A solution of 3b (199 mg, 1.0 mmol) in THF (1 cm3) was added
dropwise to a mixture of freshly fused zinc(II) chloride (150 mg,
1.1 mmol) and LDA (3.9 cm3 of a 0.64 M solution) in THF (2 cm3)
◦
at 0 C over a period of 5 min. The mixture was stirred for 1 h
at 0 ◦C, then for 1 h at room temperature (15–18 ◦C). The brown
solution was then cannulated onto a mixture of 4-iodoanisole 16a
(257 mg, 1.1 mmol) and tetrakis(triphenylphosphino)palladium(0)
(23 mg, 0.02 mmol) and stirred at 65 ◦C overnight. The usual work-
up and purification afforded styrene 12ba (74 mg, 26%) as a pale
yellow oil; the data were in agreement with those reported earlier.
4
dC(100 MHz, CDCl3) 54.8, 58.5, 67.9, 71.1, 94.6 (t, JC-F 2.8),
2
3
113.5, 114.8 (dd, JC-F 36.1, 18.7), 121.5 (br. d, JC-F 5.8), 127.9
(dd, 4JC-F 5.3, 3.8), 154.6 (app. t, 1JC-F 287.4), 159.1; dF(376 MHz,
CDCl3) -99.9 (1 F, d, 2JF-F 61.5), -108.5 (1 F, d, 2JF-F 61.5); [HRMS
(ES-TOF, [M + Na]+) Found: 297.0901; Calc. for C13H16O4F2Na:
297.0914]; m/z (CI) 292 (100%, [M + NH4]+), 199 (5), 169 (40);
GC (98%) tR 13.81 min (60–300 ◦C, 10 ◦C min-1).
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4¢-methoxyphen-
yl) ethene 12ba; preparation using tert-butyllithium. tert-
Butyllithium (1.18 cm3 of a 1.7 M solution) was added dropwise
to a solution of carbamate 3a (200 mg, 1 mmol) in THF (5 cm3)
over a period of 5 min at -78 ◦C. The colourless solution was
stirred for 30 min, turning from colourless to orange to deep blue.
A solution of freshly fused zinc(II) chloride (150◦mg, 1.0 mmol)
in THF (2 cm3) was added in one portion at -78 C and the blue
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4¢-methoxyphen-
yl) ethene 12ba. Styrene 12ba was prepared from 9b (3.95 cm3
of a 0.25 M solution in THF), 4-bromoanisole 11a (206 mg,
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solution was allowed to warm to room temperature over a period
of 1.5 h, turning yellow during this time. The yellow solution
was cannulated onto a mixture of tetrakis(triphenylphosphino)
palladium(0) (58 mg, 0.05 mmol) and 4-iodoanisole (257 mg,
1.1 mmol) and the solution was stirred at 65 ◦C overnight. The
reaction mixture was diluted with diethyl ether (40 cm3) and water
(40 cm3) and filtered through a short pad of Celite. The organic
phase was separated, dried (MgSO4) and concentrated under
reduced pressure to a dark brown oil. Purification by flash column
chromatography on silica (30% diethyl ether in light petroleum
ether) afforded styrene 12ba as a pale yellow oil (ca. 70%, the
isolated compound being contaminated with some hydrocarbon
from the eluent). The data were in agreement with those reported
earlier.
Stannane 4a (1.83 g, 4.0 mmol) was then added and the mixture
was stirred for 16 h at this temperature. The mixture was allowed
to cool to ambient temperature and diluted with diethyl ether
(20 cm3) and water (100 cm3). KF was added (6 cm3 of a 0.91 M
aqueous solution) and the mixture was stirred rapidly for 30 min,
then filtered under suction to remove the grey precipitate. The
organic phase was separated and the aqueous phase was extracted
with diethyl ether (3 ¥ 25 cm3). The original organic layer and
the extracts were combined, dried (MgSO4) and concentrated
under reduced pressure. Purification by column chromatography
over silica gel (gradient from 5% diethyl ether in light petroleum
ether to 20% diethyl ether in light petroleum ether) afforded
styrene 12ag (0.761 g, 71%) as a pale yellow oil; Rf (40% diethyl
ether in hexane) 0.32; nmax(film)/cm-1 1731, 1504, 1428, 1271,
1251, 1215, 1179, 1142, 1103, 984, 941, 889, 847; dH(400 MHz,
CDCl3) 3.40 (3 H, s, OCH3), 3.55–3.58 (2 H, m, OCH2CH2O),
3.85–3.89 (2 H, m, OCH2CH2O), 4.91 (2 H, s, OCH2O), 7.32 (2
H, br. d, J 8.9, ArH), 7.59 (2 H, br. d, J 8.9, ArH); dC(100 MHz,
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4¢-cyanophenyl)
ethene 12bk using DMPU co-solvent. Lithium diisopropylamide
(1.47 cm3 of a 1.7 M solution in THF) was added dropwise to a
solution of 2,2,2-trifluoroethyl carbamate 3b (0.199 g, 1 mmol),
freshly fused zinc chloride (0.150 g, 1.1 mmol) in dry THF (2 cm3)
and freshly distilled DMPU (0.5 cm3) at 0 ◦C over a period of
10 min. The resulting yellow solution was stirred at 0 ◦C for 1 h,
then for 1 h at room temperature, to afford 9b (assumed to be a
0.25 M solution in THF). The solution of 9b was then added
in one portion to a flask containing 4-bromobenzonitrile 11a
(200 mg, 1.1 mmol) and tetrakis(triphenylphosphino)palladium(0)
(23 mg, 0.02 mmol) and the mixture was heated at 65 ◦C for 1
h. The black mixture was cooled to room temperature, diluted
with DCM (15 cm3) and water (15 cm3) then filtered through a
short pad of Celite. The organic phase was separated and dried
by passing through a hydrophobic frit. The solvent was removed
under reduced pressure and the residue was passed through a short
pad of silica with hexane (100 cm3). The solvent was removed
under reduced pressure and crystalisation was encouraged by
addition of hexane. The pale yellow solid was washed with hexane
to reveal styrene 12aa (93 mg, 33%); Rf (40% diethyl ether in
light petroleum ether) 0.23; mp 80–82 ◦C; (Found: C, 60.55; H,
4.99; N, 9.57; C14H14F2N2O2 requires C, 60.00; H, 5.03; N, 9.57%);
4
2
CDCl3) 58.5, 68.2, 71.0, 95.3 (t, JC-F 3.1), 114.1 (dd, JC-F 35.1,
19.8), 118.2 (q, 1JC-F 320.1), 121.1, 128.0 (dd, 4JC-F 6.3, 3.4), 130.3
3
1
(br. d, JC-F 6.3), 148.4, 155.3 (app. t, JC-F 291.7); dF(376 MHz,
2
CDCl3) -72.8 (3 F, s), -95.6 (1 F, d, JF-F 51.8), -104.4 (1 F, d,
2JF-F 51.8); [HRMS (ES-TOF, [M + Na]+) Found: 415.0247; Calc.
for C13H13O6F5SNa: 415.0251]; m/z (CI) 393 (2%, [M + H]+), 89
(100), 59 (30); GC (98%) tR 11.87 min (70–320 ◦C, 20 ◦C min-1).
Preparation of 12be by interchanging the oxidative
addition/transmetallation species
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene
13.
A solution of iodine (2.54 g, 10 mmol in 10 cm3 of THF) was added
dropwise to alkenylzinc reagent 9b (40 cm3 of a 0.25 M solution in
THF) at 0 ◦C. The reaction mixture was stirred at this temperature
for 1 h and then allowed to warm to room temperature overnight.
The reaction mixture was quenched with saturated aqueous
ammonium chloride (30 cm3) and extracted with diethyl ether
(2 ¥ 40 cm3). The organic extracts were combined, washed with
saturated sodium sulfite solution (40 cm3), dried (MgSO4) and
concentrated under reduced pressure to a brown oil. Distillation
afforded iodide 13 (2.17 g, 71%) as a pale yellow oil; bp 50 ◦C/2
mmHg (Kugelrohr); dH(400 MHz, CDCl3) 1.19 (6 H, br. t, J 6.9,
N(CH2CH3)2), 3.25–3.39 (4 H, m, N(CH2CH3)2); dC(100 MHz,
n
max(film)/cm-1 2967, 2932, 2229, 1720, 1415, 1269, 1146, 982, 846,
822; dH(400 MHz, CDCl3) 1.20 (3 H, t, J 7.2, NCH2CH3), 1.29
(3 H, t, J 7.2, NCH2CH3), 3.38 (2 H, q, J 7.2, NCH2CH3), 3.48
(2 H, q, J 7.2, NCH2CH3), 7.53 (2 H, br. d, J 8.3 ArH), 7.69
(2 H, br. d, J 8.3 ArH); dC(100 MHz, CDCl3) 12.7, 13.7, 41.6,
2
CDCl3) 13.2, 14.2, 42.0, 42.9, 60.7 (dd, JC-F 58.2, 27.4), 151.3,
2
4
1
42.3, 111.1, 111.2 (dd, JC-F 37.4, 20.3), 117.9, 125.2 (dd, JC-F
153.8 (dd, JC-F 280.0, 297.7); dF(376 MHz, CDCl3) -84.9 (1 F,
7.4, 3.7), 131.8, 134.5 (br. d,3JC-F 7.4), 152.0, 154.9 (app. t, JC-F
1
d, 2JF-F 42.3), -98.5 (1 F, d, 2JF-F 42.3). These data are consistent
294.0); dF(376 MHz, CDCl3) -89.3 (1 F, d, 2JF-F 39.1), -99.3 (1 F,
d, 2JF-F 39.1); [HRMS (APCI, [M + H]+) Found: 281.1089; Calc.
for C14H15N2O2F2: 281.1102]; m/z (CI) 321 (8), 309 (20%, [M +
C2H5]+), 281 (100%, [M + H]+), 100 (20); GC (98%) tR 12.62 min
(70–320 ◦C, 20 ◦C min-1).
with those reported by Percy and co-workers.43
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(2¢-methylphenyl)
ethene 12be. Iodide 13 (0.153 mg, 0.5 mmol) in dry DMF (3 cm3)
was added to a mixture of 2-methylbenzeneboronic acid (75 mg,
0.55
mmol),
dichlorobis(triphenylphosphino)palladium(II)
(18 mg, 0.025 mmol) and potassium phosphate (160 mg,
0.75 mmol). The mixture was heated at 100 ◦C for 16 h, then
cooled to room temperature. Water (10 cm3) was added and
the mixture was extracted with diethyl ether (3 ¥ 30 cm3); the
combined organic extracts were washed with brine (10 cm3) the
dried (MgSO4). Purification by column chromatography over
silica gel (16% diethyl ether in hexane) afforded styrene 12be
(114 mg, 85%) as a pale yellow oil; Rf (15% diethyl ether in
hexanes) 0.4; nmax(film)/cm-1 1731, 1421, 1385, 1272, 1226, 1150,
Typical Stille coupling procedure for styrene synthesis
2,2-Difluoro-1-(2¢-methoxy-ethoxymethoxy)-1-[4¢¢-(trifluorome-
thanesulfonyloxy) phenyl] ethene 12ag. A mixture of copper(I)
iodide (0.170 g, 0.89 mmol), triphenylphosphine (0.105 g,
0.40 mmol) and palladium(II) acetate (24 mg, 0.11 mmol) was
pump-purged twice with argon, then dry, degassed DMF (45 cm3)
was added. A solution of iodotriflate 11g (0.936 g, 4.0 mmol) in
DMF (2 cm3) was added and the mixture was heated to 50 ◦C.
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987, 752; dH(300 MHz, CDCl3) 0.98–1.21 (6 H, m, N(CH2CH3)2),
2.40 (3 H, s, ArCH3), 3.17–3.39 (4 H, m, N(CH2CH3)2), 7.09–7.41
(4 H, m, ArH); dC(75 MHz, CDCl3) 13.3, 14.1, 19.5, 41.9, 42.4,
Acknowledgements
We thank the EPSRC Pharma Synthesis Studentship Scheme
and GSK (studentship to PGW), the EPSRC Initiative in Phys-
ical Organic Chemistry 2 (EP/G013160/1 and EP/G013020/1,
fellowship to SK), the Nuffield Foundation (Undergraduate
Vacation Bursary for RDCP), the Glasgow Centre for Physical
Organic Chemistry (computing resource), the EPSRC National
Mass Spectrometry Service Centre, Swansea for accurate mass
measurements, Jen Stephen (University of Edinburgh) for pre-
liminary investigations of the coupling of 8 and Dr Tell Tuttle
(University of Strathclyde) for helpful discussions.
2
111.1 (dd, JC-F 46.3, 18.7), 125.7, 129.2, 129.4, 130.1, 130.4,
1
137.8, 153.0, 154.1 (dd, JC-F 291, 283); dF(282 MHz, CDCl3)
-97.2 (1 F, d, 2JF-F 53.7), -106.0 (1 F, d, 2JF-F 53.7); [HRMS (ES-
TOF, [M + Na]+) Found: 292.1129; Calc. for C14H17NO2F2Na:
292.1125]; m/z (EI) 269 (18%, M+), 119 (11), 100 (100), 91 (8) and
72 (35).
Preparation of 12ag by a ligand-free potassium trifluoroborate
coupling protocol
Notes and references
Potassium 2,2-difluoro-1-(2¢-methoxy-ethoxymethoxy)ethenyl
trifluoroborate 8. n-Butyllithium (100 cm3 of a 2.5 M solution
in hexanes, 0.25 mol) was added dropwise to a solution of
diisopropylamine (35.27 cm3, 0.25 mol) in THF (135 cm3)◦at
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◦
-78 C. The colourless solution was a◦llowed to warm to -30 C
for 10 min and then re-cooled to -78 C. Acetal 3a (22.4 g, 0.12
mol) was added dropwise over 30 min via a dropping funnel
and the brown reaction mixture was stirred at -78 ◦C for 2 h.
Trimethylborate (42 cm3, 0.38 mol) was added in one portion and
left to stir and warm to room temperature over 3 h. The now
orange reaction solution was cooled to 0 ◦C and a solution of
KHF2 (117 g in 300 cm3 of water, 1.5 mol) was added dropwise
via a dropping funnel. The reaction mixture was stirred at room
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g, 55%) was collected by filtration as fine colourless needles. mp
131–132 ◦C, dH (400 MHz, D2O); 3.26 (3H, s, OCH3), 3.51–3.55
(2H, m, OCH2CH2O), 3.74–3.78 (2H, m, OCH2CH2O), 4.79 (2H,
s, OCH2O); dC (100 MHz, D2O) 57.6, 67.1, 70.5, 94.7, 159.3 (br.
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2
dd, JC-F 296.3, 277.5); dF (376 MHz, D2O) -93.3 (1F, d, JF-F
2
3
69.0), -110.2 (1F, dq, JF-F 69.0, JF-B 10.8), (-138.7)–(-139.3)
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thanesulfonyloxy) phenyl] ethene 12ag. Triethylamine (2.0 cm3,
14.8 mmol) was added dropwise over 5 min to a mixture of (4-
iodophenyl) trifluoromethanesulfonate (1.56 g, 4.44 mmol), borate
8 (1.35 g, 4.93 mmol) and bis(dibenylideneacetone)palladium(0)
(142 mg, 0.25◦mmol) in n-propanol (22.5 cm3). This mixture was
stirred at 90 C for 21 h, then diluted with Et2O (50 cm3) and
washed with NaHCO3 (30 cm3 of a saturated aqueous solution).
The mixture was filtered through Celite then the organic layer
was separated, dried (MgSO4) and the solvent removed was
under reduced pressure. The residue was purified by flash column
chromatography (10% diethyl ether in light petroleum ether) to
afford triflate 12ag as a yellow oil (1.03 g, 65%, 36% over two
steps from 3a); the data were in agreement with those reported
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8328–8339 | 8339
©