In situ generation of Mes2Mg as a non-nucleophilic carbon-centred base reagent for the efficient one-pot conversion of ketones to silyl enol ethers

Article abstract of DOI:10.1039/b802082e

Treatment of commercially available MesMgBr with 1,4-dioxane produces the key Mes₂Mg reagent in situ which then mediates the deprotonation of ketones to deliver trimethylsilyl enol ethers, at readily accessible temperatures and without any nucleophilic addition, in an expedient and high yielding one-pot process. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802082e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
In situ generation of Mes2Mg as a non-nucleophilic carbon-centred base
reagent for the efficient one-pot conversion of ketones to silyl enol ethers
William J. Kerr,*a Allan J. B. Watsona and Douglas Hayesb
Received 5th February 2008, Accepted 11th February 2008
First published as an Advance Article on the web 25th February 2008
DOI: 10.1039/b802082e
Treatment of commercially available MesMgBr with 1,4-dioxane produces the key Mes2Mg reagent
in situ which then mediates the deprotonation of ketones to deliver trimethylsilyl enol ethers, at readily
accessible temperatures and without any nucleophilic addition, in an expedient and high yielding
one-pot process.
Most importantly, such processes would require fewer added
Introduction
components, e.g. alkoxides (as used in the Schlosser-type systems)
The use of organometallic reagents to install functionality within
or amines (as required in the ubiquitous LDA reagent), thus
molecules is of paramount importance in organic synthesis. Of the
expediting reaction set-up and generating fewer reaction by-
products.4
wealth of transformations that are possible using organometallic
species, the classical use of lithium- and magnesium-based reagents
to introduce a particular group in a nucleophilic manner remains
a widely used and successful methodology.1 Having stated this,
certain problems can arise when attempting the addition of such
organometallic reagents into an enolisable carbonyl group. In
particular, yields are often reduced due to deprotonation at the a-
position, resulting in the formation of an enolate ion, thus lowering
the efficiency of the intended addition process (Scheme 1).1
Methods to overcome this enolisation have been developed, and
include the addition of cerium salts which can dramatically reduce
enolisation and so improve the yields of addition products in such
reactions.2
Results and discussion
Development of magnesium based carbon-centred bases
Following on from that stated above, we recently reported the
development of bismesitylmagnesium (Mes2Mg, 2) as an effective
reagent for the deprotonation of a range of ketone substrates and
the formation of silyl enol ethers.5 This reagent was shown to be a
non-nucleophilic and thermally stable carbon-centred base, which
can be used at more readily accessible temperatures (e.g. 0 ◦C)
and, compared to more standard deprotonation methods, avoids
the wasteful use of amine additives. However, one drawback to this
technique is that the requisite Mes2Mg reagent is not commercially
available. Nonetheless, this species 2 can be efficiently prepared in a
separate process from 2-mesitylmagnesium bromide6 (MesMgBr,
1) and 1,4-dioxane (Scheme 2).7 Having stated this, this procedure
requires some degree of practical manipulation, including removal
of the prepared Mes2Mg solution via cannula without transferral
of the precipitated MgBr2·1,4-dioxane polymer, 3 (Scheme 2). Ad-
ditionally, the Mes2Mg solution must then be stored appropriately,
under air- and moisture-free conditions, before use. Therefore, to
enhance the applicability of bismesitylmagnesium as a carbon-
centred base species, a deprotonation protocol which operates
from commercially available MesMgBr solution, and without the
prior isolation of Mes2Mg, would clearly be advantageous. Our
endeavours towards this goal are delineated here.
Scheme
1
Reaction of organometallic reagents with carbonyl
compounds.
While the enolisation of carbonyl groups is therefore possible
using carbon-centred organometallic reagents, this process is
generally viewed as a detrimental side reaction which must
be avoided. Having stated this, in a series of seminal studies,
Schlosser et al. showed how the kinetic basicity of reagents such
as n-butyllithium could be appreciably and usefully enhanced
by the addition of species such as potassium tert-butoxide to
increase deprotonation rates.3 Despite this, scant attention has
been directed towards the direct use of magnesium-based reagents
as base species. However, when considered more closely, use of
carbon-centred organomagnesium reagents has the potential to
provide an effective method of performing such deprotonations.
Scheme 2 Preparation of Mes2Mg.
In order to establish a practically more efficient Mes2Mg-
mediated deprotonation protocol, we envisaged the development
of a system which combined the preparation of the key Mes2Mg
reagent with the deprotonation and electrophilic quench process.
Towards this objective, initial reactions using a combination of
MesMgBr and 1,4-dioxane, with an optimised quantity of TMSCl
aDepartment of Pure and Applied Chemistry, WestCHEM, University
of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK G1 1XL.
E-mail: w.kerr@strath.ac.uk; Fax: +44 141 548 4246; Tel: +44 141 548
2959
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Steve-
nage, Hertfordshire, UK SG1 2NY
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◦
at 0 C,5 provided a moderate 50% conversion to the desired
silyl enol ether, using cyclohexanone as the ketone substrate
(Scheme 3). However, a 16% conversion to side (addition) products
was also noted. Comparatively, without 1,4-dioxane, a decreased
39% conversion to silyl enol ether product was registered, while
the conversion to side products increased to 34% (Scheme 3). This
indicated that the 1,4-dioxane additive was essential in order to
moderate the nucleophilic characteristics of the parent Grignard
reagent, presumably by promotion of in situ disproportionation to
the less nucleophilic Mes2Mg reagent.5
Scheme 4 Assessment of reaction time.
formation of only the kinetic deprotonation product 5f from
ketone 4f. Furthermore, using these one-pot conditions with the
more sensitive ketone, 4-chlorobutyrophenone 4h, the silyl enol
ether 5h was obtained in 80% isolated yield, with no addition,
substitution, or elimination products being observed (Table 2,
entry 8); with this example the stereoselectivity of the process
was also excellent, with only the Z-silyl enol ether isomer, Z-4h,
1
being detected by H NMR. Moreover, control reactions have
Table 2 Silyl enol ether formation in a one pot protocol with MesMgBra
Scheme 3 Preliminary one-pot reactions with MesMgBr.
With these somewhat encouraging results in hand, optimisation
of the system began with the inclusion of controlled quantities
of LiCl. As shown in Table 1, the inclusion of LiCl as an
additive, in addition to 1,4-dioxane, within this developing one-
pot process, appreciably enhanced the efficiency of the silyl enol
ether formation. More specifically, using two molar equivalents
of LiCl delivered an almost quantitative conversion to the silyl
enol ether 5a, now with no trace of side (addition) products (entry
1). If the 1,4-dioxane additive was omitted, conversion increased
from the 50% observed in the control reaction to an improved
72%, however, the level of side products also increased to 27%
(Scheme 3 vs. Table 1, entry 2). Lowering of the LiCl loading level
only resulted in less efficient conversion to silyl enol ether (Table 1,
entry 3), while halving the quantity of 1,4-dioxane decreased the
conversion to product and, once again, increased the side product
ratio (Table 1, entry 4).
Entry
1
Ketone
Product
Yieldb
92%
2
3
85%
96%
4
94%
In addition to the optimisation shown in Table 1, an analysis
of reaction time indicated that the conversion to silyl enol ether
within the emerging one-pot method proceeded significantly more
quickly than when pre-isolated Mes2Mg was employed. As shown
in Scheme 4, the silyl enol ether product is delivered in 93%
conversion after only 1 h, compared to the 96% achieved after 8 h
using the previously developed protocol with preformed Mes2Mg.5
Having established these optimised conditions, we next sought
to assess their generality by application to a range of substrates
at the readily accessible 0 ◦C reaction temperature (Table 2).
Pleasingly, the developed one-pot protocol performed effectively
in all cases explored, giving the silyl enol ether products in high
isolated yield, with no addition products being detected in any
case. This method also delivered some steric selectivity with the
5
6
85%c
93%d
7
8
9
93%
80%
96%
Table 1 Optimisation of LiCl and 1,4-dioxane additives
Entry 1,4-Dioxane/eq. LiCl/eq. Conversion to 5a (side products)a
1
2
3
4
1.05
—
1.05
0.525
2
2
1
2
98% (—)
72% (27%)
81% (—)
84% (13%)
a See Experimental section. b Isolated yield after purification. c Z : E 4.9 :
1. d The only product detected was that (5f) from kinetic deprotonation.
a Determined by G.C. analysis; see Experimental Section.
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shown further benefits of this carbon-centred magnesium base
protocol over those with analogous lithium reagents: treatm◦ent
of cyclohexanone with MesLi, under similar conditions at 0 C,
delivered only 13% conversion to the desired enol ether, with
the major product being C-silylated mesitylene.4f Additionally,
use of LDA in the reaction with 4-chlorobutyrophenone 4h,
under analogous conditions to those employed here, led only to
elimination products.
Consideration of the structure of Mes2Mg·LiCl
Mes2Mg is known to exist as the solvated dimer
Mes2Mg·(THF)2.7a–c However, in the presence of LiCl it is
likely that this structure will change. It is conceivable that, upon
introduction of LiCl, Mes2Mg will form an ‘ate-type complex.9
Indeed, ‘ate complexes have been suggested as the reactive species
in magnesium–halogen exchange reactions mediated by Grignard
reagents in the presence of LiCl, as pioneered by Knochel and
co-workers.10 Two possibile ‘ate complex structures are shown in
Fig. 2.
Improvements to the one-pot procedure
Having successfully established this general one-pot process, some
further investigations were made in an attempt to enhance the
potential overall scope and applicability of this procedure. Firstly,
to this stage we had utilised a one hour syringe pump addition of
the ketone substrate, since this had been the standard procedure
used for all of our previous investigations into asymmetric
deprotonation reactions with chiral magnesium amide bases.8
However, it was unknown whether this slow addition procedure
was necessary for reactions utilising Mes2Mg, either as a pre-
formed reagent or as generated in situ. To address this, we
performed the deprotonation of cyclohexanone, 4a, under the
optimised one-pot conditions and with the introduction of the
ketone being completed manually over 10 minutes (Scheme 5).
Pleasingly, the reaction utilising simple manual addition delivered
comparable yields of the desired product 5a.
Fig. 2 Possible structures of Mes2Mg·LiCl.
While the charge-separate complex 6 is a possibility, the Li-
bridged structure 7 is considered more likely due to literature
precedent for a similar ‘ate complex, 8, which has been isolated
from the treatment of (2,4,6-iPr3C6H2)2Mg with (2,4,6-iPr3C6H2)Li
(Fig. 3).7b
Scheme 5 Manual vs. syringe pump addition.
Fig. 3 Analogous ‘ate complex [Li(THF)0.6(Et2O)0.4][Mg(2,4,6-iPr3C6H2)3].
Following this useful practical development, the scalability of
the one-pot Mes2Mg procedure was assessed by carrying out
gram-scale reactions under the optimised one-pot conditions
with manual addition of the ketone substrates, as detailed in
Fig. 1. Gratifyingly, the developed MesMgBr conditions could be
successfully applied on enhanced scale to the deprotonation of the
substrates illustrated: the benchmark substrate 4a (cyclohexanone)
and also the more sensitive substrate 4h (4-chlorobutyrophenone)
gave the corresponding silyl enol ether products 5a and 5h in
90% and 83% yield, respectively. The efficiencies of these gram-
scale reactions compare very favourably with the results achieved
previously and as delineated above (Table 2).
Further support for an ‘ate-type structure comes from the
observation that ‘ate complexes derived from dialkylmagnesium
reagents and cryptands displayed increased nucleophilicity and
basicity compared to the parent reagent alone.11 Endeavours
towards the isolation and identification of the species generated
from Mes2Mg and LiCl are ongoing.
Further applications of Mes2Mg
A final exploratory reaction was performed to expand the
possible applications of our developed conditions. Here, Mes2Mg,
prepared in situ from MesMgBr and 1,4-dioxane, was treated with
ethyltriphenylphosphonium bromide and the resultant ylide was
used in a Wittig reaction with acetophenone (Scheme 6). Using
Scheme 6 Wittig reaction using in situ generated Mes2Mg as the base
Fig. 1 Gram-scale one-pot processes.
reagent.
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in situ generated Mes2Mg, a 97% isolated yield of olefin 9 was
obtained with 4 : 1 (E : Z) ratio. This promising initial foray into
Wittig chemistry has now paved the way for future applications of
our developed carbon-centred base protocols.
General experimental procedure
A Schlenk tube was charged with LiCl (2 mmol, 85 mg) and flame-
dried under vacuum. The tube was purged three times with N2
before cooling to room temperature and charging with MesMgBr
(1 M solution in THF, 1 mmol, 1 mL), 1,4-dioxane (1.05 mmol,
88 mg, 0.09 mL) and THF (9 mL). The mixture was stirred
Conclusions
◦
for 15 min at room temperature before cooling to 0 C. TMSCl
In conclusion, we have further developed our magnesium-based
carbon-centred base protocols to provide a practically more con-
venient procedure which operates from a commercially available
Grignard reagent. In addition, while employing only 1 equivalent
of MesMgBr to generate 0.5 mol of Mes2Mg in situ, this new
procedure delivers the desired products in high yield and with
greatly increased efficiency in comparison to our previously de-
scribed methods.5 Furthermore, these processes can be performed
on gram-scale and without the requirement for any slow addition
procedures. Throughout, the protocols led to carbon-centred
base species which are completely non-nucleophilic, even at the
routinely employed temperature of 0 ◦C.
(1 mmol, 109 mg, 0.13 mL) was added and the mixture was stirred
for 5 min before addition of the ketone (1 mmol) as a solution in
THF (2 mL) over 1 h via syringe pump. The reaction mixture was
stirred at 0 ◦C under N2 for 1 h before being quenched with sat. aq.
NaHCO3 solution (10 mL). The mixture was allowed to warm to
room temperature before extracting with Et2O ((1 × 40 mL) + (2 ×
25 mL)). The combined organic extracts were dried (Na2SO4) and
a representative sample was analysed by GC to obtain the ketone
to silyl enol ether conversion. The solution was then filtered and
concentrated in vacuo to afford a residue which was purified by
column chromatography eluting with 1% Et2O–petrol to afford
the silyl enol ether product.
1-Trimethylsilyloxycyclohexene (5a).13,14,15a,16 Using the general
experimental procedure above with cyclohexanone 4a gave 1-
trimethylsilyloxycyclohexene 5a as a colourless oil (157 mg, 92%):
mmax (DCM): 1668 cm−1; dH (400 MHz, CDCl3): 0.18 (s, 9H,
Si(CH3)3), 1.48–1.54 (m, 2H, CH2), 1.63–1.69 (m, 2H, CH2), 1.97–
2.03 (m, 4H, 2 × CH2), 4.86–4.88 (m, 1H, CH).
1-Trimethylsiloxycyclopentene (5b).13,14,15b,17 Using the general
experimental procedure above with cyclopentanone 4b gave 1-
trimethylsiloxycyclopentene 5b as a colourless oil (133 mg, 85%):
mmax (DCM): 1645 cm−1; dH (400 MHz, CDCl3): 0.20 (s, 9H,
Si(CH3)3), 1.82–1.90 (m, 2H, CH2), 2.24–2.29 (m, 4H, 2 × CH2),
4.62–4.63 (m, 1H, CH).
Experimental
All reactions were carried out using flame dried Schlenk apparatus.
Purging refers to an evacuation/nitrogen-refilling procedure. So-
lutions and solvents were added via syringe. THF and 1,4-dioxane
were dried by heating to reflux over sodium wire using benzophe-
none ketyl as indicator, and then distilled under N2. Diethyl ether
and light petroleum were used as purchased from suppliers without
further purification. Light petroleum (petrol) refers to the fraction
of bp 30–40 ◦C. 2-Mesitylmagnesium bromide,6 obtained as a 1 M
solution in THF, was standardised using salicaldehyde phenyl-
hydrazone as indicator.12 Cyclohexanone 4a, cyclopentanone 4b,
cycloheptanone 4c, propiophenone 4e, 2-methylcyclohexanone 4f,
acetophenone 4g, 4-chlorobutyrophenone 4h, and a-tetralone 4i,
were dried by heating to reflux over calcium chloride and distilled
either under reduced pressure or under nitrogen and stored over
1-Trimethylsilyloxycycloheptene (5c).18 Using the general ex-
perimental procedure above with cycloheptanone 4c gave 1-
trimethylsilyloxycycloheptene 5c as a colourless oil (177 mg, 96%):
mmax (DCM): 1660 cm−1; dH (400 MHz, CDCl3): 0.18 (s, 9H,
Si(CH3)3), 1.50–1.59 (m, 4H, 2 × CH2), 1.66–1.70 (m, 2H, CH2),
1.97–2.01 (m, 2H, CH2), 2.22–2.24 (m, 2H, CH2), 4.86–4.88 (m,
1H, CH).
˚
4 A molecular sieves under N2. 4-tert-Butylcyclohexanone 4d was
recrystallised twice from dry hexane at 4 ◦C and stored under N2.
˚
Chlorotrimethylsilane was distilled under N2 and stored over 4 A
molecular sieves and under N2.
Gas chromatography was carried out using a Hewlett Packard
5890 Series 2 Gas Chromatograph fitted with a Varian WCOT
Fused Silica Column containing a CP-SIL 19CB coating and
using H2 as carrier gas (80 kPa): (i) injector/detector temperature,
200 ◦C; (ii)◦initial oven temperature, 45 ◦C; (iii) temperature
gradient, 20 C min−1; (iv) final oven temperature, 190 ◦C; and (v)
detection method, FID. Thin layer chromatography was carried
out using Camlab silica plates coated with indicator UV254. These
were analysed using a Mineralight UVGL-25 lamp or developed
using a vanillin solution. Flash column chromatography was
carried out using Prolabo silica gel (230–400 mesh). IR spectra
were obtained on a Perkin Elmer Spectrum One machine. 1H and
13C spectra were recorded on a Bruker DPX 400 spectrometer at
400 MHz and 100 MHz, respectively. Chemical shifts are reported
in ppm. Coupling constants are reported in Hz and refer to
3JH–H interactions unless otherwise specified. High resolution mass
spectra were obtained using a JEOL JMS-700 high resolution mass
spectrometer. The ionization method used was electron impact
(EI) with perfluorokerosene (PFK) as the reference compound.
4-tert-Butyl-1-trimethylsilyloxy-1-cyclohexene (5d).8c,19,20 Using
the general experimental procedure above with 4-tert-
butylcyclohexanone 4d gave 4-tert-butyl-1-trimethylsilyloxy-1-
cyclohexene 5d as a colourless oil (213 mg, 94%): mmax (DCM):
1672 cm−1; dH (400 MHz, CDCl3): 0.19 (s, 9H, Si(CH3)3), 0.90
(s, 9H, 3 × CH3), 1.21–1.29 (m, 2H, CH2), 1.78–1.85 (m, 2H,
CH2), 1.98–2.09 (m, 3H, CH+CH2), 4.84–4.86 (m, 1H, CH); dC
(100 MHz, CDCl3): 0.1, 24.1, 24.8, 26.9, 30.6, 31.8, 43.8, 103.6,
150.0.
1-Phenyl-1-silyloxyprop-1-ene (5e).13,17,21,22 Using the general
experimental procedure above with propiophenone 4e gave 1-
phenyl-1-silyloxyprop-1-ene 5e as a colourless oil (175 mg, 85%):
mmax (DCM): 1686, 1652 cm−1; dH (400 MHz, CDCl3): Z-isomer:
0.17 (s, 9H, Si(CH3)3), 1.76 (d, 3H, CH3, J = 6.9 Hz), 5.35 (q, 1H,
CH, J = 6.9 Hz), 7.23–7.49 (m, 5H, 5 × ArCH); E-isomer: 0.15
(s, 9H, Si(CH3)3), 1.73 (d, 3H, CH3, J = 7.3 Hz), 5.13 (q, 1H, CH,
J = 7.3 Hz), 7.23–7.49 (m, 5H, 5 × ArCH).
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6-Methyl-1-trimethylsilyloxy-1-cyclohexene (5f).13,14,16 Using
the general experimental procedure above with 2-methyl-
cyclohexanone 4f gave 6-methyl-1-trimethylsilyloxy-1-cyclohe-
xene 5f as a colourless oil (171 mg, 93%): mmax (DCM): 1660 cm−1;
dH (400 MHz, CDCl3): 0.19 (s, 9H, Si(CH3)3), 1.04 (d, 3H, CH3,
J = 7.0 Hz), 1.36–1.41 (m, 1H, CH), 1.45–1.49 (m, 1H, CH),
1.57–1.59 (m, 1H, CH), 1.78–1.82 (m, 1H, CH), 1.98–2.02 (m,
2H, CH2), 2.14–2.15 (m, 1H, CH), 4.81 (td, 1H, CH, J = 3.9,
1.2 Hz).
Silyl enol ether preparations on enhanced scale
The general procedure detailed above for manual addition was
used in the following preparations:
i) For the gram-scale preparation of 5a: LiCl (22 mmol,
935 mg); MesMgBr (1 M solution in THF, 11 mmol, 11 mL);
THF (99 mL); 1,4-dioxane (11.55 mmol, 1.02 g, 0.98 mL); TMSCl
(11 mmol, 1.2 g, 1.41 mL); cyclohexanone 4a (11 mmol, 1.08 g,
1.14 mL); a reaction time of 2.5 h delivered the product 1-
trimethylsilyloxycyclohexene (5a) as a colourless oil (1.68 g, 90%).
Spectral details as above.
ii) For the gram-scale preparation of 5h: LiCl (12 mmol,
255 mg); MesMgBr (1 M solution in THF, 6 mmol, 6 mL); THF (99
mL); 1,4-dioxane (6.3 mmol, 555 mg, 0.54 mL); TMSCl (6 mmol,
652 mg, 0.77 mL); 4-chlorobutyrophenone 4h (6 mmol, 1.1 g,
0.96 mL); a reaction time of 2.5 h delivered the product Z-4-
chloro-1-phenyl-1-trimethylsilyloxybut-1-ene (5h) as a colourless
oil (1.27 g, 83%). Spectral details as above.
1-Phenyl-1-trimethylsiloxyethylene (5g).14,15c,23 Using the gen-
eral experimental procedure above with acetophenone 4g gave
1-phenyl-1-trimethylsiloxyethylene 5g as a colourless oil (179 mg,
93%): mmax (DCM): 1620 cm−1; dH (400 MHz, CDCl3): 0.28 (s, 9H,
Si(CH3)3), 4.45 (d, 1H, CH2, J = 1.7 Hz), 4.93 (d, 1H, CH2, J =
1.7 Hz), 7.27–7.36 (m, 3H, 3 × ArH), 7.60–7.62 (d, 2H, 2 × ArH,
J = 8.4 Hz).
Z-4-Chloro-1-phenyl-1-trimethylsilyloxybut-1-ene (5h).5 Using
the general experimental procedure above with 4-chloro-
butyrophenone 4h gave Z-4-chloro-1-phenyl-1-trimethylsilyloxy-
but-1-ene 5h as a colourless oil (204 mg, 80%): mmax (DCM):
1649 cm−1; dH (400 MHz, CDCl3): 0.15 (s, 9H, Si(CH3)3), 2.68 (q,
2H, CH2, J = 7.1 Hz), 3.59 (t, 2H, CH2, J = 7.2 Hz), 5.27 (t, 1H,
CH, J = 7.1 Hz), 7.26–7.34 (m, 3H, 3 × ArCH), 7.47 (dd, 2H, 2 ×
ArH, J = 6.8, 1.5 Hz); dC (100 MHz, CDCl3): 0.8, 29.9, 44.4, 106.6,
125.8, 128.1, 128.3, 138.9, 151.6. High resolution mass spectrum
(EI) m/z: 35Cl 254.0890; 37Cl 256.0839; C13H19ClOSi (M+) requires
35Cl 254.0894; 37Cl 256.0864.
2-Phenylbut-2-ene (9)24
A 20 mL round bottomed flask was charged with LiCl (2 mmol,
85 mg) and flame dried under high vacuum. The flask was purged
three times and allowed to cool to room temperature. MesMgBr
(1 M solution in THF, 1 mmol, 1 mL), THF (5 mL) and 1,4-
dioxane (1.05 mmol, 88 mg, 0.09 mL) were added and the solution
was stirred for 30 minutes. A separate 50 mL flask was flame dried
under high vacuum, cooled and purged with nitrogen then charged
with EtPPh3Br (1 mmol, 371 mg) and THF (5 mL) and cooled to
0 ◦C. The prepared Mes2Mg solution was then introduced to the
second flask via cannula. The resulting solution was then stirred
for 1 h before addition of acetophenone (1 mmol, 120 mg, 0.12 mL)
as a solution in THF (2 mL) over 1 h via syringe pump, followed
by stirring at 0 ◦C for 18 h. The mixture was concentrated in vacuo
to give a residue which was dry loaded onto silica using DCM
as the dissolving solvent. Purification by column chromatography
using 10% Et2O–petrol afforded the product 9 as a colourless
oil (128 mg, 97%): mmax (DCM): 3025, 1498 cm−1; dH (400 MHz,
CDCl3): E-isomer: 1.82 (dd, 3H, CH3, J = 5.4, 1.5 Hz), 2.01 (d,
(3,4-Dihydro-1-naphthyloxy)trimethylsilane (5i).15d,18 Using the
general experimental procedure above with a-tetralone 4i, gave
(3,4-dihydro-1-naphthyloxy)trimethylsilane 5i, as a colourless oil
(210 mg, 96%): mmax (DCM): 1638 cm−1; dH (400 MHz, CDCl3):
0.38 (s, 9H, Si(CH3)3), 2.42–2.47 (m, 2H, CH2), 2.89 (t, 2H, CH2,
J = 7.8 Hz), 5.32 (t, 1H, CH, J = 4.6 Hz), 7.21–7.36 (m, 3H, 3 ×
ArCH), 7.54 (d, 1H, ArCH, J = 7.4 Hz).
General experimental procedure for non-syringe pump (manual)
addition process
=
3H, CH3, J = 1.1 Hz), 5.88 (q, 1H, C CH, J = 5.5 Hz), 7.21–7.25
(m, 2H, 2 × ArH), 7.30–7.40 (m, 3H, 3 × ArH); Z-isomer: 1.61
(dd, 3H, CH3, J = 5.4, 1.5 Hz), 2.01 (d, 3H, CH3, J = 1.1 Hz),
A Schlenk tube was charged with LiCl (2 mmol, 85 mg) and flame-
dried under vacuum. The tube was purged three times with N2
before cooling to room temperature and charging with MesMgBr
(1 M solution in THF, 1 mmol, 1 mL), 1,4-dioxane (1.05 mmol,
88 mg, 0.09 mL) and THF (9 mL). The mixture was stirred
=
5.59 (q, 1H, C CH, J = 5.5 Hz), 7.21–7.25 (m, 2H, 2 × ArH),
7.30–7.40 (m, 3H, 3 × ArH).
Acknowledgements
◦
for 15 min at room temperature before cooling to 0 C. TMSCl
(1 mmol, 109 mg, 0.13 mL) was added and the mixture was stirred
for 5 min before addition of cyclohexanone 4a (1 mmol, 98 mg) as
a solution in THF (2 mL) manually (by syringe) over 10 min. The
reaction mixture was stirred at 0 ◦C under N2 for 1 h before being
quenched with sat. NaHCO3 aq. solution (10 mL). The mixture
was allowed to warm to room temperature before extracting with
Et2O ((1 × 40 mL) + (2 × 25 mL)). The combined organic extracts
were dried (Na2SO4) and a representative sample was analysed
by GC to obtain the ketone to silyl enol ether conversion. The
solution was then filtered and concentrated in vacuo to afford a
residue which was purified by column chromatography eluting
with 1% Et2O–petrol to afford the silyl enol ether product 5a as a
colourless oil (148 mg, 87%).
We would like to thank the EPSRC and the Chemistry Innovation
Knowledge Transfer Network (formerly Crystal Faraday) for
a studentship (AJBW), GlaxoSmithKline for further financial
support, and the EPSRC Mass Spectrometry Service, University
of Wales, Swansea for analyses.
References
1 (a) L. Brandsma and H. D. Verkruijsse, Preparative Polar Organometal-
lic Chemistry, Springer-Verlag, Berlin, 1987; (b) L. Brandsma and
H. D. Verkruijsse, Synthesis of Acetylenes, Allenes and Cumulenes,
A Laboratory Manual, Elsevier, Amsterdam, 1981; (c) J. Clayden,
N. Greaves, S. Warren and P. Wothers, Organic Chemistry, Oxford
University Press, New York, 2001.
1242 | Org. Biomol. Chem., 2008, 6, 1238–1243
This journal is
The Royal Society of Chemistry 2008
©

View Online
2 For examples on the use of cerium salts to reduce the basicity of
organolithium and organomagnesium reagents, see: (a) Y. Tamura, M.
Sasho, H. Ohe, S. Aka and Y. Kita, Tetrahedron Lett., 1985, 26, 1549;
(b) T. Imamoto, Y. Sugiura and M. Takiyama, Tetrahedron Lett., 1984,
25, 4233; (c) T. Imamoto, T. Kusumoto, Y. Tawarayama, Y. Suiura,
T. Mita, Y. Hatanaka and M. Yokoyhama, J. Org. Chem., 1984, 49,
3904; (d) T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima and
Y. K a m i y a , J. Am. Chem. Soc., 1989, 111, 4392.
3 (a) M. Schlosser, J. Organomet. Chem., 1967, 8, 9; (b) M. Schlosser,
Pure Appl. Chem., 1988, 60, 1627; (c) M. Schlosser, G. Katsoulos and
S. Takagishi, Synlett, 1990, 747; (d) B. J. Wakefield, The Chemistry of
Organolithium Compounds, Pergamon Press, Oxford, 1974.
8 (a) M. J. Bassindale, J. J. Crawford, K. W. Henderson and W. J. Kerr,
Tetrahedron Lett., 2004, 45, 4175; (b) E. L. Carswell, D. Hayes, K. W.
Henderson, W. J. Kerr and C. J. Russell, Synlett, 2003, 1017; (c) K. W.
Henderson, W. J. Kerr and J. H. Moir, Tetrahedron, 2002, 58, 4573;
(d) J. D. Anderson, P. Garc´ıa Garc´ıa, D. Hayes, K. W. Henderson, W. J.
Kerr, J. H. Moir and K. P. Fondekar, Tetrahedron Lett., 2001, 42, 7111;
(e) K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun., 2001,
1722; (f) K. W. Henderson, W. J. Kerr and J. H. Moir, Synlett, 2001,
1253; (g) K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun.,
2000, 479.
9 For reviews on ‘ate chemistry, see: (a) R. E. Mulvey, F. Mongin, M.
Uchiyama and Y. Kondo, Angew. Chem., Int. Ed., 2007, 46, 3802;
(b) R. E. Mulvey, Organometallics, 2006, 25, 1060.
4 Only a relatively small number of examples of carbon-centred bases
have been described in the literature, presumably due to competing
carbonyl addition; in particular, the enolisation of hindered ketones,
such as trityl ketones, has been achieved with n-butyllithium and also
with trimethylaluminium using, at least, stoichiometric quantities of the
organometallic reagent; additionally, the bulky triphenylmethyllithium
and triphenylmethylpotassium reagents have been used to mediate
the enolisation of certain ketones; mesityllithium has seen rare and
atypical usage for the enolisation of specific ketones, and at appreciably
low temperatures (e.g. −50 ◦C); and, more recently, gallium-based
reagents, such as GaEt3, have been used to deprotonate methylene
protons with some selectivity, although elevated temperatures (125 ◦C)
and 1.5 molar equivalents of the organometallic reagent are required:
(a) D. Seebach, M. Ertas¸, R. Locher and W. B. Schweizer, Helv. Chim.
Acta, 1985, 68, 264 (nBuLi, AlMe3); (b) M. Ertas¸ and D. Seebach,
Helv. Chim. Acta, 1985, 68, 961 (nBuLi, AlMe3); (c) E. A. Jeffery and
A. Meisters, J. Organomet. Chem., 1974, 82, 307 (AlMe3); (d) H. O.
House and B. M. Trost, J. Org. Chem., 1965, 30, 1341 (Ph3CLi,
Ph3CK); (e) H. O. House and V. Kramar, J. Org. Chem., 1963, 28, 3362
(Ph3CK); (f) R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan,
D. E. Ward, B.-W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card, C. H.
Chen, R. B. Cheˆnevert, A. Fliri, K. Frobel, H.-J. Gais, D. G. Garratt, K.
Hayakawa, W. Heggie, D. P. Hesson, D. Hoppe, I. Hoppe, J. A. Hyatt,
D. Ikeda, P. A. Jacobi, K. S. Kim, Y. Kobuke, K. Kojima, K. Krowicki,
V. J. Lee, T. Leutert, S. Machenko, J. Martens, R. S. Matthews, B. S. Ong,
J. B. Press, T. V. Rajan Babu, G. Rousseau, H. M. Sauter, M. Suzuki,
K. Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y. Ueda, T.
Uyehara, A. T. Vasella, W. C. Vladuchick, P. A. Wade, R. M. Williams
and H. N.-C. Wong, J. Am. Chem. Soc., 1981, 103, 3210 (MesLi); (g) Y.
Nishimura, Y. Miyake, R. Amemiya and M. Yamaguchi, Org. Lett.,
2006, 8, 5077 (GaEt3).
10 F. Kopp, A. Krasovskiy and P. Knochel, Chem. Commun., 2004,
2288. For recent reviews of this area, see: (a) H. Ila, O. Baron,
A. J. Wagner and P. Knochel, Chem. Commun., 2006, 583; (b) P.
Knochel, W. Dohle, N. Gommermann, K. K. Kneisel, F. Kopp, T.
Korn, I. Sapountzis and V. A. Vu, Angew. Chem., Int. Ed., 2003, 42,
4302.
11 (a) H. G. Richey, Jr. and B. A. King, J. Am. Chem. Soc., 1982,
104, 4672; (b) E. P. Squiller, R. R. Whittle and H. G. Richey, Jr.,
J. Am. Chem. Soc., 1985, 107, 432; (c) H. G. Richey, Jr. and D. M.
Kushlan, J. Am. Chem. Soc., 1987, 109, 2510; (d) A. D. Pajerski,
M. Parvez and H. G. Richey, Jr., J. Am. Chem. Soc., 1988, 110,
2660.
12 B. E. Love and E. G. Jones, J. Org. Chem., 1999, 64, 3755.
13 D. Bonafoux, M. Bordeau, C. Biran, P. Cazeau and J. Dunogues, J. Org.
Chem., 1996, 61, 5532.
14 H. O. House, L. J. Czuba, M. Gall and H. D. Olmstead, J. Org. Chem.,
1969, 34, 2324.
15 (a) Commercially available from Aldrich Chemical Co., CAS# [6651–
36-1], catalogue no. 144819; (b) Commercially available from Aldrich
Chemical Co., CAS# [19980–43-9], catalogue no. 283126; (c) Com-
mercially available from Aldrich Chemical Co., CAS# [13735–81-
4], catalogue no. 235040; (d) Commercially available from Aldrich
Chemical Co., CAS# [38858–72-9], catalogue no. 540390.
16 I. Kopka and M. W. Rathke, J. Org. Chem., 1981, 46, 3771.
17 C. H. Heathcock, S. K. Davidsen, K. T. Hug and L. A. Flippin, J. Org.
Chem., 1986, 51, 3027.
18 R. Rathore and J. K. Kochi, J. Org. Chem., 1996, 61, 627.
19 C. M. Cain, R. P. C. Cousins, G. Coumbarides and N. S. Simpkins,
Tetrahedron, 1990, 46, 523.
20 C.-D. Graf, C. Malan, K. Harms and P. Knochel, J. Org. Chem., 1999,
64, 5581.
5 W. J. Kerr, A. J. B. Watson and D. Hayes, Chem. Commun., 2007, 5049.
6 Commercially available from Aldrich Chemical Company, CAS#
[2633–66-1], catalogue no. 227234.
21 C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E.
Sohn and J. Lampe, J. Org. Chem., 1980, 45, 1066.
7 B. J. Wakefield, Organomagnesium Methods in Organic Synthesis,
Academic Press, London, 1995. For additional preparations, see: (a)
W. Seidel and I. Bu¨rger, Z. Anorg. Allg. Chem., 1978, 447, 195; (b)
K. M. Waggoner and P. P. Power, Organometallics, 1992, 11, 3209; (c)
D. M. Knotter, D. M. Grove, W. J. J. Smeets, A. L. Spek and G. van
Koten, J. Am. Chem. Soc., 1992, 114, 3400.
22 F. A. Davis, A. C. Sheppard, B.-C. Chen and M. S. Haque, J. Am.
Chem. Soc., 1990, 112, 6679.
23 Y. Matano, N. Azuma and H. Suzuki, J. Chem. Soc., Perkin Trans. 1,
1994, 1739.
24 Y. Kawai, Y. Inaba and N. Tokitoh, Tetrahedron: Asymmetry, 2001, 12,
309.
This journal is
The Royal Society of Chemistry 2008
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