Bismesitylmagnesium: A thermally stable and non-nucleophilic carbon-centred base reagent for the efficient preparation of silyl enol ethers

Article abstract of DOI:10.1039/b711407a

Bismesitylmagnesium has been established as an accessible, practical, convenient, and non-nucleophilic carbon-centred base reagent for efficient access to silyl enol ethers from a series of ketone substrates at readily utilisable temperatures. The Royal Society of Chemistry.

Full text of DOI:10.1039/b711407a

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Bismesitylmagnesium: a thermally stable and non-nucleophilic carbon-
centred base reagent for the efficient preparation of silyl enol ethers{
William J. Kerr,*a Allan J. B. Watsona and Douglas Hayesb
Received (in Cambridge, UK) 26th July 2007, Accepted 13th September 2007
First published as an Advance Article on the web 27th September 2007
DOI: 10.1039/b711407a
excess of Mes2Mg in an internal quench process (using four
equivalents of TMSCl). A temperature study found the best
conversion was obtained at a convenient 0 uC (although similar
outcomes were observed at 240 uC and r.t.). Our initial system
operated satisfactorily delivering a moderate 69% conversion
(Scheme 1).
Bismesitylmagnesium has been established as an accessible,
practical, convenient, and non-nucleophilic carbon-centred base
reagent for efficient access to silyl enol ethers from a series of
ketone substrates at readily utilisable temperatures.
Enolisation with lithium amide reagents is employed extensively
throughout preparative chemistry.1 In this regard, lithium di-iso-
propylamide (LDA) is perhaps the reagent of this class which is
most commonly used in organic synthesis.2,3 Additionally,
asymmetric variants have been widely developed and are now
well-established, delivering good levels of reactivity and selectivity.4
Furthermore, the use of magnesium-based amide reagents is now
becoming more widespread due to a series of potential practical
advantages over their lithium counterparts, as well as their
increasing accessibility.5 However, stoichiometric metal-amide
systems can have several drawbacks: they require (i) (at least) a
stoichiometric quantity of amine; (ii) a stoichiometric quantity of
metal; and typically (iii) low temperatures to utilise. Moreover,
problems of addition and reduction can exist, even with the
normally more stoic LDA.6
Scheme 1 Use of Mes2Mg in a recycling amide base protocol.
Following these preliminary observations, necessary control
experiments were performed. To our surprise, these subsequent
investigations revealed that an amine was not required for the
deprotonation process to proceed with efficiency and that Mes2Mg
was, itself, capable of mediating the formation of the desired silyl
enol ether (Scheme 2). It is also worth noting that there was no
evidence of ketone reduction or addition by-products. These initial
studies, therefore, provided the basis for a system by which such
deprotonations could be carried out with a magnesium-based
carbon-centred base reagent without the requirement for any
additional amine components. Indeed, this provides the first
example of a carbon-based magnesium species reacting selectively
in this fashion, as a base reagent, without any concomitant issues
of addition or reduction. In terms of precedent, it should be noted
that 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-butyllithium9 and also with trimethylaluminium9,10 using, at
least, stoichiometric quantities of the organometallic reagent.
Additionally, the bulky triphenylmethyllithium11 and triphenyl-
methylpotassium11,12 reagents have been used to mediate the
enolisation of certain ketones. More recently, gallium-based
reagents, such as GaEt3, have been used to deprotonate methylene
protons with some selectivity, although elevated temperatures
(125 uC) and 1.5 molar equivalents of the organometallic reagent
are required.13
Following on from our extensive studies on asymmetric
deprotonations using stoichiometric magnesium amide bases,7 we
sought to develop a recycling system, which would operate using
sub-stoichiometric quantities of amine, with the requisite amide
being (re-)generated by a suitable source of magnesium. Our
preliminary investigations demonstrated that attempted ketone
deprotonations using lowered quantities of amines coupled with
primary and secondary bisalkylmagnesium reagents (nBu2Mg and
iPr2Mg) led to high proportions of alkylated (i.e. addition) and
reduced products. Consequently, we realised that a more bulky,
non-nucleophilic, source of R2Mg, without b-hydrogens, would be
required to (re-)generate the desired magnesium amide in situ.
This led to the selection of Mes2Mg8 as a potentially viable
stoichiometric source of magnesium. In due course and with work
in the asymmetric arena underway, the possibility of establishing a
more generally utilisable catalytic achiral base procedure was
envisaged.
Preliminary deprotonation reactions utilised di-iso-propylamine
(20 mol%) as the sub-stoichiometric amine source, with a slight
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 (0)141 548 4246;
Tel: +44 (0)141 548 2959
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, UK , SG1 2NY
{ Electronic supplementary information (ESI) available: Experimental
procedures, IR and H NMR for known compounds, full data for novel
compounds. See DOI: 10.1039/b711407a
1
Scheme 2 A Mes2Mg-mediated deprotonation protocol.
Chem. Commun., 2007, 5049–5051 | 5049
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Table 1 Optimisation of the Mes2Mg deprotonation conditions
Entry Mes2Mg/mol LiCl/mol TMSCl/mol T/uC Time/h Conv.a (%)
Table 2 Application of the Mes2Mg deprotonation processa
Entry
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
a
1.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
—
—
—
2
1
2
2
2
2
2
4
4
4
4
1
1
1
1
1
0
0
0
0
0
16
16
16
16
16
8
8
8
8
68
62
94
72
98
98
86
16
0
1
2b
2a
88
2
3
88
90
0
240
278
0
Determined by G.C. analysis.14
2c
Returning to our investigations with Mes2Mg, a detailed
programme of optimisation was undertaken in attempts to
improve the overall efficiency of the emerging system (Table 1).
While reasonable results were obtained using an excess (1.1 mol) of
Mes2Mg, a similar conversion was observed with only 0.5 mol of
this reagent (entry 2, Table 1), exploiting the availability of the two
anionic aryl units present. Moreover, addition of LiCl dramatically
increased the efficiency of the system, with 2 mol of this additive
appearing to be optimal (entries 3 and 4). Pleasingly, reducing the
quantity of the TMSCl electrophile to only 1 mol equiv. led to a
sustained high conversion (entry 5),15 whilst entry 6 shows that the
reaction approaches completion after only 8 h at 0 uC. Table 1 also
shows that the Mes2Mg deprotonation protocol can be performed
effectively at 240 uC, again with only 0.5 mol of the
organometallic reagent, whilst lowering the temperature further
leads to only low conversion.
4
5
6
2d
2e
2f
89
76
82
7
8
9
2g
2h
2i
85
89
76
Having established the optimum system as described, the
applicability of this protocol was assessed with a range of ketones.
Gratifyingly, the developed conditions worked well for all
substrates applied, with good isolated yields of enol ethers being
obtained throughout (Table 2). In this regard, the result realised
with 4-chlorobutyrophenone is particularly notable. In this case,
the product enol ether 2k was obtained in a good yield, again at
the conveniently accessible temperature of 0 uC, further emphasis-
ing the non-nucleophilicity of the developed reagent system.
Comparatively, treatment of the same chloroketone with LDA,
under similar conditions, led only to elimination products.
Moreover, treatment of cyclohexanone with the equivalent
lithiated species, MesLi, using the same protocol at 0 uC, delivered
only 13% conversion to the desired enol ether, with the major
product being C-silylated mesitylene.16
10
11
a
2j
2k
b
83
81
In order to probe the stereoselectivity of enol ether formation
with Mes2Mg, propiophenone was employed as a suitable and
well-known substrate.17 As shown in Scheme 3, the favoured
Z-isomer remained predominant throughout, with an optimum
30 : 1 ratio of stereoisomers being achieved at 240 uC, compared
For a typical procedure, see supporting data. Isolated yield after
purification.
to that (4.8 : 1) achieved at 0 uC. It should also be further noted
here that reaction of the same ketone 1l led to an 89% yield of enol
ether 2l at 40 uC, with no observed by-product formation. This
Scheme 3 Deprotonation of propiophenone using Mes2Mg.
5050 | Chem. Commun., 2007, 5049–5051
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4 For recent reviews, see: (a) P. J. O’Brien, J. Chem. Soc., Perkin Trans. 1,
1998, 1439; (b) P. J. O’Brien, J. Chem. Soc., Perkin Trans. 1, 2001, 95; (c)
S. Jones, J. Chem. Soc., Perkin Trans. 1, 2002, 1; (d) J.-C. Plaquevent,
T. Perrard and D. Cahard, Chem.–Eur. J., 2002, 8, 3300.
5 For recent reviews on organomagnesium chemistry, see: (a)
K. W. Henderson and W. J. Kerr, Chem.–Eur. J., 2001, 7, 3430; (b)
H. Ila, O. Baron, A. J. Wagner and P. Knochel, Chem. Commun., 2006,
583.
6 For examples of such side-reactions with LDA, see: C. Kowalski,
X. Creary, A. J. Rollin and M. C. Burke, J. Org. Chem., 1978, 43, 2601.
7 (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.
further illustrates the thermal stability and chemoselectivity of the
Mes2Mg reagent, even at such relatively elevated temperatures.
In summary, we have developed a new magnesium-based
carbon-centred base reagent protocol, which offers a number of
distinct advantages over existing and analogous systems. In
particular, the key Mes2Mg reagent is non-nucleophilic and non-
reductive, even at temperatures above ambient. Additionally, only
0.5 mol of the metal-based reagent is required and no appreciable
reaction cooling needs to be applied, with processes being routinely
performed at 0 uC. Furthermore, the system operates effectively
with lowered amounts of electrophile and, perhaps more
importantly, without any amine reagent (cf. the widely employed
LDA). As such, reaction by-products are limited to the innocuous
mesitylene and inorganic salts, thus expediting work-up proce-
dures. Consequently, we believe that the practical benefits offered
by these processes could lead to their widespread adoption by the
preparative community.
8 Mes2Mg (THF solution) is routinely prepared from readily available
MesMgBr and 1,4-dioxane; see supporting data{.
We thank the EPSRC and the Crystal Faraday Partnership for
a Postgraduate Studentship (AJBW), GlaxoSmithKline for further
studentship funding, and the EPSRC Mass Spectrometry Service,
University of Wales, Swansea, and Mr J. Tweedie, University of
Glasgow, for analyses.
9 (a) D. Seebach, M. Ertas¸, R. Locher and W. B. Schweizer, Helv. Chim.
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13 Y. Nishimura, Y. Miyake, R. Amemiya and M. Yamaguchi, Org. Lett.,
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Notes and references
14 For details, see supporting data{.
15 Such internal quench protocols normally require an excess of
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1984, 25, 495.
1 (a) C. H. Heathcock, in Comprehensive Carbanion Chemistry, ed.
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16 It should be noted that mesityllithium has seen rare and atypical usage
for the enolisation of specific ketones, and at much lower temperatures
(e.g. 250 uC), as part of aldol addition chemistry; for example, see:
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,
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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.
2 For overviews, see: (a) W. I. I. Bakker, P. L. Wong and V. Snieckus, in
Encyclopedia of Reagents for Organic Synthesis, ed. L. A. Paquette,
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A. J. McNeil and A. Ramirez, Angew. Chem., Int. Ed., 2007, 46, 3002.
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97, 6908; (b) G. Stork and S. Raucher, J. Am. Chem. Soc., 1976, 98,
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J. A. Secrist, R. Lett, P. W. Sheldrake, J. R. Falck, D. J. Brunelle,
M. F. Haslanger, S. Kim and S. Yoo, J. Am. Chem. Soc., 1978, 100,
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Chem. Soc., 1982, 104, 5557.
17 C. H. Heathcock, S. K. Davidsen, K. T. Hug and L. A. Flippin, J. Org.
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