Table 2 Enantioselective deprotonations and silyl enol ether formation with
Mg-amide (R)-3
To this stirred solution, dibutylmagnesium (0.85 mL of a 1.1 M solution in
heptane, 1 mmol) was added dropwise and the mixture heated to reflux for
90 min. The reaction solution was then allowed to cool followed by removal
of all solvent in vacuo and replacement by the solvent of choice for the
1
subsequent deprotonation reaction. H NMR spectroscopic analysis of the
resultant yellow oil, after removal of the reaction solvent, is consistent with
the formation of the bisamide (R)-3: (400 MHz, C6D6, 25 °C): d 7.22–7.02
(m, 10H, Ph), 3.57–3.48 (m, 2H, 2 3 CH), 3.40–3.35 (m, 1H, CH), 1.11 (d,
J 6.6 Hz, 3H, CH3).
‡ The beneficial use of HMPA as a co-solvent has been reported previously
for various Li-mediated enantioselective reactions.1a,c
§ From the 94% conversion (by GC) shown as entry 5 in Table 1, following
alumina column chromatography, an isolated yield of 64% was obtained for
5a with a 90% recovery of the starting amine (R)-2.
¶ Formation of the (S)-silyl enol ether, (S)-5a, is consistent with the
selectivity of the analogous Li-base (R)-1.8 Additionally, GC analysis, by
comparison with that of Knochel and co-workers2b allowed confirmation of
the assignment of absolute stereochemistry for the enol ether 5a.
∑ The typical procedure for the enantioselective deprotonation reactions is
illustrated by a preparation of 5a: a Schlenk flask containing base (R)-3 (1
mmol) suspended in THF (10 mL) was cooled to 278 °C under N2. The
flask was then charged with TMSCl (0.5 mL, 4 mmol) and HMPA (0.09
mL, 0.5 mmol). After stirring for 20 min at 278 °C, 4-tert-butylcyclohex-
anone (123 mg, 1 mmol) was added as a solution in THF (2 mL) over 1 h
using a syringe pump. The reaction was allowed to stir at 278 °C for a
further 5 h and then quenched by the addition of saturated aqueous NaHCO3
(5 mL). After warming to room temperature the reaction mixture was
extracted with diethyl ether (50 mL) and washed with saturated aqueous
NaHCO3 (2 3 20 mL). The combined aqueous phase was extracted with
diethyl ether (2 3 20 mL), the combined organic phase was then dried over
Na2SO4, followed by removal of solvent in vacuo. The reaction conversion
was determined as 82% by GC analysis [DB 179 fused silica capillary
column, carrier gas H2 (80 kPa), 60–190 °C; temperature gradient: 45 °C
min21, tr = 3.1 min (4a), tR = 3.3 min (5a)]. The resultant yellow oil was
then filtered through a silica plug and washed with a light petroleum–diethyl
ether solution (9+1). This afforded 5a as a colourless oil. The enantiomeric
ratio was determined by GC analysis as 91+9 [Chirasil-DEX CB capillary
column, carrier gas H2 (30 kPa), 80 °C (1 min)–120 °C; temperature
gradient: 1.5 °C min21, tR = 32.2 min [(S)-5a], tR = 32.8 min [(R)-
5a)]].
Scheme 1 Reagents and conditions: i, (R)-3, HMPA (0.5 equiv.), TMSCl (4
equiv.), THF, 278 °C, 65 h.
Finally, in attempts to find a more practically acceptable
additive to replace HMPA, equivalent quantities of DMPU were
introduced to reactions of 4a with (R)-3. In THF solvent at
278 °C, when 0.5 mol equiv. of DMPU were used, pleasingly
an enantiomeric ratio of 90+10 in favour of (S)-5a was achieved
in 89% conversion (Scheme 2); use of 1 mol equiv. of DMPU
led to comparable conversion (93%) and e.r. (86+14).
** Enantiomeric ratios were determined by GC analysis. Additionally, the
absolute configuration of the major and minor enantiomers for 5b, 5c, 5d
and 5f were assigned by correlation of optical rotation measurements with
those of Koga and coworkers;9 for 5e the major and minor isomer
configurations were tentatively assigned by comparison with 5a–d.
Furthermore, all compounds exhibited satisfactory analytical and spectral
data.
1 (a) P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439; (b) N. S.
Simpkins, Pure Appl. Chem., 1996, 68, 691; (c) K. Koga, Pure Appl.
Chem., 1994, 66, 1487; (d) P. J. Cox and N. S. Simpkins, Tetrahedron:
Asymmetry, 1991, 2, 1.
2 For recent examples, see: (a) V. K. Aggarwal, P. S. Humphries and A.
Fenwick, J. Chem. Soc., Perkin Trans. 1, 1999, 2883; (b) C.-D. Graf, C.
Malan and P. Knochel, Angew. Chem., Int. Ed., 1998, 37, 3014.
3 For relevant examples of Mg-based reagents as used in different classes
of organic transformations, see: D. A. Evans and S. G. Nelson, J. Am.
Chem. Soc., 1997, 119, 6452; C. L. Elston, R. F. W. Jackson, S. J. F.
MacDonald and P. J. Murray, Angew. Chem., Int. Ed. Engl., 1997, 36,
410; M. E. Bunnage, S. G. Davies, C. J. Goodwin and I. A. S. Walters,
Tetrahedron: Asymmetry, 1994, 5, 35.
4 (a) J. F. Allan, W. Clegg, K. W. Henderson, L. Horsburgh and A. R.
Kennedy, J. Organomet. Chem., 1998, 559, 173; (b) J. F. Allan, K. W.
Henderson and A. R. Kennedy, Chem. Commun., 1999, 1325.
5 P. E. Eaton, C. H. Lee and Y. Xiong, J. Am. Chem. Soc., 1989, 111, 8016;
G. Lesse`ne, R. Tripoli, P. Cazeau, C. Biran and M. Bordeau, Tetrahedron
Lett., 1999, 40, 4037.
6 D. Armstrong, K. W. Henderson, A. R. Kennedy, W. J. Kerr, F. S. Mair,
J. H. Moir, P. H. Moran and R. Snaith, J. Chem. Soc., Dalton Trans.,
1999, 4063.
Scheme 2 Reagents and conditions: i, (R)-3, DMPU (0.5 equiv.), TMSCl (4
equiv.), THF, 278 °C, 6 h.
In conclusion, having prepared a novel homochiral magne-
sium bisamide system, we have demonstrated, for the first time,
that such bases can successfully mediate enantioselective
deprotonation reactions. Indeed, significant levels of selection
in these asymmetric processes have been realised, and to an
extent that they are already approaching the optimum enantio-
meric ratios achievable by more complex Li-base systems.1
Furthermore, and more importantly for the widespread use of
the Mg-based approach, this efficient enantioselection has been
achieved using a reagent which is easily prepared from a simple,
readily available, and inexpensive amine. The application of
further Mg-bisamide systems and the development of related
methodology is currently under investigation and will be
reported in due course.
We gratefully acknowledge The Carnegie Trust for the
Universities of Scotland for a postgraduate studentship
(J. H. M.) and The Royal Society for a University Research
Fellowship (K. W. H.). We also thank AstraZeneca Pharmaceu-
ticals, Alderley Park for generous funding of our research
endeavours via Strategic Research Funding, and the EPSRC
Mass Spectrometry Service, University of Wales, Swansea for
analyses.
7 For previous studies into the formation of bis(amido)magnesium
compounds, see: K. W. Henderson, J. F. Allan and A. R. Kennedy, Chem.
Commun., 1997, 1149; W. Clegg, F. J. Craig, K. W. Henderson, A. R.
Kennedy, R. E. Mulvey, P. A. O’Neil and D. Reed, Inorg. Chem., 1997,
36, 6238.
8 R. P. C. Cousins and N. S. Simpkins, Tetrahedron Lett., 1989, 30,
7241.
9 K. Aoki, H. Noguchi, K. Tomioka and K. Koga, Tetrahedron Lett., 1993,
34, 5105; H. Kim, R. Shirai, H. Kawasaki, M. Nakajima and K. Koga,
Heterocycles, 1990, 30, 307.
Notes and references
† Preparation of Mg-amide base (R)-3: a Schlenk flask was charged with a
solution of amine (R)-2 (0.42 mL, 2 mmol) in dry hexane (8 mL) under N2.
Communication b000425l
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Chem. Commun., 2000, 479–480