Towards energetically viable asymmetric deprotonations: Selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

Article abstract of DOI:10.1039/c0cc04939e

A novel chiral magnesium bisamide has enabled the development of effective asymmetric deprotonation protocols at substantially more elevated temperatures. This new, structurally simple, C₂-symmetric magnesium complex displays excellent levels o

Full text of DOI:10.1039/c0cc04939e

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Towards energetically viable asymmetric deprotonations: selectivity at
more elevated temperatures with C2-symmetric magnesium bisamidesw
Linsey S. Bennie, William J. Kerr,* Michael Middleditch and Allan J. B. Watson
Received 12th November 2010, Accepted 22nd December 2010
DOI: 10.1039/c0cc04939e
A novel chiral magnesium bisamide has enabled the development
of effective asymmetric deprotonation protocols at substantially
more elevated temperatures. This new, structurally simple,
C2-symmetric magnesium complex displays excellent levels of
asymmetric efficiency and energy reduction in the synthesis of
enantioenriched enol silanes.
production of effective methods for use in organic synthesis, a
specific objective has been the design of more efficient and,
indeed, energetically viable asymmetric deprotonation processes.
Asymmetric deprotonation reactions6 are useful methods
for the preparation of enantioenriched chiral enolates and enol
silanes, which are valuable precursors for a host of powerful
diastereoselective transformations.7 Chiral lithium amides
have been developed extensively in this area and several
systems provide very good levels of enantioinduction at low
reaction temperatures.6,8 In this regard, it should be noted
that, while enantioselective deprotonation processes are typi-
cally conducted at ꢀ78 1C, several groups have demonstrated
the ability of chiral lithium amides to afford high levels of
selectivity at more elevated temperatures in the area of epoxide
rearrangement.9 In addition to all of this, work within our
laboratory has revealed that chiral magnesium amides are also
particularly effective within the domain of asymmetric enoli-
sation and, more significantly, were found to exhibit greater
asymmetric efficiency than the equivalent lithium amides.10
In relation to the developing applications noted above,
magnesium amides are known to possess greater thermal
stability11 and exhibit less complex solution aggregation than
analogous lithium amides in THF (Fig. 1).12 As such, we
recently began examining the potential for exploitation of
these unique attributes to enable effective asymmetric induction
at substantially more elevated temperatures. Herein, we
The ability to perform intricate chemical manipulations is
essential for the continued production of the myriad organic
compounds that our society consumes. By their very nature,
many of these transformations must be carried out at energy
intensive temperatures. However, the energy expenditure of
chemical processes is becoming a continually more important
consideration,1 and with escalating environmental, financial,
and political pressures, the demand for energetic efficiency
within the chemical industry is only likely to increase. The
financial impact of energy input is perhaps felt most dramatically
when performing reactions on larger scale.2 Figures used
within Chemical Development at GlaxoSmithKline suggest
that performing reactions at temperatures of lower than ꢀ40 1C
incurs an additional energetic cost of at least d250 000
per annum per batch tonne process.3 Moreover, this is supp
lementary to the initial and appreciable expense of installing
the necessary low temperature process scale equipment.
Consequently, the task of alleviating the energetic burden of
the chemical industry, through the continued development of
more effective synthetic protocols that generate a smaller
energy footprint than preceding technologies, is of global
relevance. In this regard, contributions by several research
groups have already illustrated the potential for considered
experimental design in this area of enhanced sustainability.2,4,5
For example, the metallation processes pioneered by Knochel
enable a more convenient and widely applicable preparation of
nucleophilic organometallic species,4 while several groups
have also focused on the development of catalyst systems that
facilitate effective cross-coupling processes at more moderate
temperatures.5 As part of a wider programme targeting the
Department of Pure and Applied Chemistry, WestCHEM,
295 Cathedral Street, Glasgow, G1 1XL, Scotland, UK.
E-mail: w.kerr@strath.ac.uk; Fax: +44 (0)141 548 4822;
Tel: +44 (0)141 548 2959
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for products. See DOI: 10.1039/
c0cc04939e
Fig. 1 Towards energy-effective asymmetric deprotonations: lithium
vs. magnesium amides.
c
2264 Chem. Commun., 2011, 47, 2264–2266
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describe an approach towards the development of both more
generally efficient and, in addition, energy effective asymmetric
deprotonations through the deployment of simple and readily
accessible C2-symmetric chiral magnesium bisamides.
Table 1 Performance of base (R,R)-8 over a range of temperatures in
the asymmetric deprotonation of 4-tert-butylcyclohexanone (1a)
Entry
Ta (1C)
Conv.b (%)
e.r.b (S : R)
1
2
3
4
5
6
ꢀ78
ꢀ60
ꢀ40
ꢀ20
0
97
93
95
97
93
89
94 : 6
92 : 8
90 : 10
88 : 12
86 : 14
75 : 25
Over recent years, we have probed the structure of magne-
sium bisamides in efforts to understand the key aspects that
engender these complexes with comparatively enhanced levels
of asymmetric efficiency (for example, complexes (R)-3–7,
Scheme 1).10 While good levels of selectivity could be achieved
in this benchmark asymmetric deprotonation process, based
on some precedent within our laboratory,10f we envisaged that
appropriate modification of the parent amine would lead to a
highly utilisable process at less energy intensive temperatures,
i.e. above ꢀ78 1C. From the outset, we considered two key
items as essential for an energy-effective chiral base system: (i)
the requisite parent amine must be simple in structure and, in
turn, either readily prepared or, preferably, commercially
available; and (ii) the system must operate at more readily
used temperatures of ꢀ40 1C or above.
23
a
b
Bath temperature. Determined by G.C. analysis; see ESI.
demonstrates the same level of enantioselectivity at 0 1C as the
analogous lithium complex achieves at ꢀ78 1C (entry 5).z It is
also worth noting that this new reagent system is capable of
delivering appreciable levels of enantioselection at room tem-
perature (23 1C; entry 6).
Encouraged by the degree of temperature tolerance of
complex (R,R)-8, we proceeded to further optimise the quan-
tities of additive and silyl agent loading. Consequently, we
found that only one equivalent of both DMPU and Me3-
SiCl17,18 provided a chiral base system that could now deliver
excellent asymmetric efficiency at ꢀ78 1C for a range of
substrates (Table 2, entries 1–5). Indeed, the levels of selecti-
vity displayed here are amongst the highest levels obtained in
such deprotonation reactions. More significantly, these experi-
mental conditions have now also been shown to instil unpre-
cedented levels of enantioinduction at ꢀ20 1C (entries 6–10).z
These results are especially notable when considering the
overall simplicity of the parent amine from which this reagent
is derived. Additionally, yields of products were consistent
regardless of the reaction temperature.
Based on all of this, we next moved to evaluate the perfor-
mance of the readily accessible C2-symmetric magnesium amide
(R,R)-8 (Scheme 1). Pleasingly, this complex displayed greatly
improved enantioselectivity in the benchmark asymmetric
deprotonation reaction, providing levels of enantioinduction
greater than the corresponding lithium amide, including the
typically more selective LiCl-based ate complex.13 Furthermore,
the parent amine is structurally simple and is either readily
prepared via the method of Alexakis et al.14 or can be purchased
commercially.
Based on these initial screening results, base complex (R,R)-8
was selected for further investigation. We next sought to
ascertain the temperature dependence of our developing
C2-symmetric base system, in accordance with our design
criteria. As such, we evaluated the performance of complex
(R,R)-8 at more elevated temperatures ranging from ꢀ60 1C
to 0 1C (Table 1). Remarkably, this C2-symmetric amide
maintained very good levels of enantioinduction over an almost
80 1C temperature range (entries 1–5). In fact, base (R,R)-8
The unprecedented selectivity exhibited by this simple mag-
nesium base system can perhaps be explained through the
thermal stability and solution aggregation of magnesium
amides in general. Magnesium amides typically exist in
Table 2 Performance of base (R,R)-8 in the asymmetric deprotona-
tion of prochiral ketones at ꢀ78 and ꢀ20 1C
Entry
R
T (1C)
Yielda (%)
e.r.b (S : R)
1
2
3
4
5
6
7
8
9
10
t-Bu (a)
n-Pr (b)
i-Pr (c)
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
93 (66)
92 (65)
96 (67)
96 (69)
91 (68)
93 (83)
96 (68)
95 (70)
96 (69)
92 (70)
93 : 7
94 : 6
93 : 7
Me (d)
95 : 5
OTBS (e)
t-Bu (a)
n-Pr (b)
i-Pr (c)
Me (d)
OTBS (e)
92 : 8c
88 : 12
89 : 11
87 : 13
90 : 10
87 : 13c
a
Determined by G.C. analysis; values in parentheses are isolated
b
Scheme 1 Evaluation of simple Mg amides in the asymmetric deproto-
nation of 4-tert-butylcyclohexanone (1a). (Enantiomeric ratio given as
(S :R), DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone).
c
yields of pure products. Determined by G.C. analysis. Determined
by optical rotation; see ESI.
c
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solution as monomers or dimers.11 This is in stark contrast to
lithium amides that are known to display a complex mixture of
oligomeric forms that can have markedly different reactivity
and selectivity profiles.12b,c Considering the small difference in
selectivity of complex (R,R)-8 across the temperature range
applied, at present we postulate that the aggregation state of
this magnesium bisamide does not differ drastically from
ꢀ78 to ꢀ20 1C. As such, the structurally robust nature of this
magnesium species serves to permit ‘‘warming’’ of the base
solution without significant decomposition, and the observed
temperature independence of the solution structure enables
comparable selectivity at considerably more elevated tempera-
tures. The exact nature of the active species is currently under
investigation.
J. Org. Chem., 2010, 75, 2131; (f) S. C¸
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and M. G. Organ, Angew. Chem., Int. Ed., 2010, 49, 2014.
6 For a review, see: N. S. Simpkins, Top. Stereochem., 2010, 26, 1.
7 For the use of enol silanes in organic synthesis, see:
(a) P. Brownbridge, Synthesis, 1983, 1; (b) P. Brownbridge, Synth-
esis, 1983, 85; (c) S. Kobayashi, K. Manabe, H. Ishitani and
J.-I. Matsuo, Silyl Enol Ethers in Science of Synthesis, ed.
I. Fleming, Thieme, Stuttgart, 2001, vol. 4, p. 317.
8 For examples of effective chiral lithium amide bases, see:
(a) R. Shirai, M. Tanaka and K. Koga, J. Am. Chem. Soc., 1986,
108, 543; (b) R. P. C. Cousins and N. S. Simpkins, Tetrahedron
Lett., 1989, 30, 7241; (c) K. Aoki, H. Noguchi, K. Tomioka and
K. Koga, Tetrahedron Lett., 1993, 34, 5105; (d) B. J. Bunn and
N. S. Simpkins, J. Org. Chem., 1993, 58, 533; (e) B. J. Bunn,
P. J. Cox and N. S. Simpkins, Tetrahedron, 1993, 49, 207;
(f) R. Shirai, D. Sato, K. Aoki, M. Tanaka, H. Kawasaki and
K. Koga, Tetrahedron, 1997, 53, 5963; (g) K. Aoki and K. Koga,
Tetrahedron Lett., 1997, 38, 2505; (h) V. K. Aggarwal,
P. S. Humphries and A. Kenwick, J. Chem. Soc., Perkin Trans.
1, 1999, 2883; (i) C.-D. Graf, C. Malan and P. Knochel, Angew.
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(k) K. Aoki and K. Koga, Chem. Pharm. Bull., 2000, 48, 571;
(l) J. Busch-Petersen and E. J. Corey, Tetrahedron Lett., 2000, 41,
6941.
In summary, utilising unique properties characteristic of
magnesium amides, we have successfully developed a novel
C2-symmetric magnesium bisamide and demonstrated its
unique ability to function efficiently within asymmetric
deprotonation reactions. Significantly, this new reagent operates
extremely effectively at ꢀ78 1C, as well as the substantially
more elevated ꢀ20 1C, maintaining very good levels of
asymmetric efficiency and thereby presenting significant
opportunities for energy conservation in this arena. Following
these studies, we are currently focused on the development of
further new chiral magnesium-centred bases to enable highly
selective processes at ambient temperature.
9 For examples, see: D. M. Hodgson, A. R. Gibbs and G. P. Lee,
Tetrahedron, 1996, 52, 14361. See also ref. 6.
10 (a) K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun.,
2000, 479; (b) K. W. Henderson, W. J. Kerr and J. H. Moir,
Synlett, 2001, 1253; (c) K. W. Henderson, W. J. Kerr and
J. H. Moir, Chem. Commun., 2001, 1722; (d) J. D. Anderson,
P. Garcıa Garcıa, 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, Tetra-
hedron, 2002, 58, 4573; (f) E. L. Carswell, D. Hayes,
K. W. Henderson, W. J. Kerr and C. J. Russell, Synlett, 2003,
1017; (g) M. J. Bassindale, J. J. Crawford, K. W. Henderson and
W. J. Kerr, Tetrahedron Lett., 2004, 45, 4175.
We thank the EPSRC for funding (M.M.; EP/C548981/1)
and the EPSRC Mass Spectrometry Service, University of
Wales, Swansea, for analyses. We are also extremely grateful
to Prof. Dr Klaus Ditrich (BASF SE, Ludwigshafen) for a
generous supply of chiral amines.
11 (a) P. E. Eaton, H. Higuchi and R. Millikan, Tetrahedron Lett.,
1987, 28, 1055; (b) P. E. Eaton, C. H. Lee and Y. Xiong, J. Am.
Chem. Soc., 1989, 111, 8016; (c) J. F. Allan, K. W. Henderson and
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z The corresponding Li complex (lithium (R,R)-bis-(1-phenylethyl)-
amide) is reported to achieve an e.r. of 85 : 15 (S : R) at ꢀ78 1C.15 For
comparison, we also evaluated this Li complex under conditions as
established by Simpkins et al.,13 using both internal quench (IQ) and
external quench with LiCl additive16 (EQ) techniques, at ꢀ20 1C and
0 1C, with the following results (selectivity values given as (S : R)):
ꢀ20 1C: 77 : 23 (IQ), 79 : 21 (EQ); 0 1C: 76 : 24 (IQ), 74 : 26 (EQ).
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J. C. Warner, Green Chemistry: Theory and Practice, Oxford
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selectivity in externally quenched reactions.6,13
(c) T. D. Blumke, F. M. Piller and P. Knochel, Chem. Commun.,
¨
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c
2266 Chem. Commun., 2011, 47, 2264–2266
This journal is The Royal Society of Chemistry 2011