LETTER
Chelating Chiral Magnesium Amide Bases
179
ic products. Having stated this, complex (S)-18 did pro- isostere.11 Accordingly, we believe that, by adopting a
vide some encouraging levels of selectivity [76:24 (R/S)], similar solution-state structure, (S)-19 is behaving as an
despite the very poor levels of reactivity demonstrated by analogue of (R)-3,12 and that no sulfur-based chelation is
this chiral base. Indeed, efforts to improve the perfor- actually involved. If this is indeed the case, then distortion
mance of (S)-18 by variation of reaction temperature and of the highly successful structure of (R)-3 by insertion of
the addition of various Lewis basic promoters, failed to a Lewis basic motif [such as in complexes (R)-16, (S)-17,
improve this system. In contrast, we were pleased to find and (R)-20–22] has an overwhelming and decisively de-
that complex (S)-19 exhibited excellent levels of reactivi- structive effect on the selectivity of these magnesium base
ty, providing 83% conversion to product, and, more im- complexes. Nevertheless, these results do then suggest
portantly, delivered useful levels of selectivity [86:14 (R/ that ligation is actually occurring in these complexes,
S)].
even though the interaction is, in these complexes, counter
productive in relation to the induction of asymmetry.
Based on the success of base (S)-19 in the benchmark
asymmetric process, we proceeded to assess the overall In summary, we have synthesised a range of chiral hetero-
utility of this new chiral magnesium bisamide by applica- cyclic amines and used these to prepare a series of novel
tion to a series of prochiral ketones (Table 2). Pleasingly, chiral magnesium bisamides. Subsequent application of
complex (S)-19 displayed good levels of reactivity across these complexes towards the asymmetric deprotonation of
this substrate range, with conversions spanning 68–83%, a standard substrate revealed that a thiophene-derived
and provided consistently agreeable levels of selectivity complex provided good levels of enantioselectivity. Fur-
[83:17 to 87:13 (R/S)].
thermore, this novel thiophenyl Mg-centred base was also
generally effective for the deprotonation of a series of
prochiral ketones. In addition to this and based on the full
spectrum of results presented here, we have concluded
that it is unlikely that this complex establishes an intramo-
lecular chelating interaction, as initially envisaged. De-
spite this, we are continuing to explore the possibility of
chelation-assisted selectivity enhancement in this overall
chiral base domain and will present these studies in due
course.
Table 2 Application of Complex (S)-19 within the Asymmetric
Deprotonation of a Series of Prochiral Ketone Substrates
O
Ph
N
2Mg
OSiMe3
S
(S)-19
Me3SiCl, DMPU, THF, –78 °C
R
1a–e
R
2a–e
Representative Experimental Procedure (Table 2, Entry 1)
To a flame-dried and N2-purged Schlenk flask was added n-Bu2Mg
(1 M in heptanes, 1.00 mmol). The heptanes were removed in vacuo
to reveal a white solid. A solution of (S)-1-phenyl-N-[(thiophen-2-
yl)methyl]ethanamine (S)-9 (435 mg, 2.00 mmol) in THF (10 mL)
was added, and the mixture was heated to reflux under an N2 atmo-
sphere for 90 min. After cooling to r.t., the solution was cooled to
–78 °C under N2, and then charged with TMSCl (0.5 mL, 4.00
mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU) (60 mL, 0.5 mmol). After stirring for 10 min, 4-tert-butyl-
cyclohexanone (1a 123 mg, 0.80 mmol) in THF (2 mL) was added
to the mixture over 1 h via syringe pump. The resulting solution was
allowed to stir at –78 °C for a further 15 h (overall reaction time, 16
h) before quenching with sat. aq NaHCO3 solution (10 mL). After
warming to r.t., the mixture was extracted with Et2O (3 × 25 mL).
The combined organic extracts were dried over Na2SO4, and a rep-
resentative sample was analysed by achiral GC to obtain the conver-
sion to product (83%). The solution was then concentrated in vacuo
to a residue that was purified by flash column chromatography [PE
(30–40 °C)–Et2O = 99:1] to afford 4-tert-butyl-1-trimethylsiloxy-1-
cyclohexene (2a) as a colourless oil (120 mg, 75%). The er was de-
termined by chiral GC analysis to be 86:14 (R/S).
Entry
R
Conv. (%)a
83 (75)
73 (55)
72 (55)
68 (49)
71 (55)
75 (62)
er (R/S)b
86:14
1
2
3
4
5
6
a t-Bu
b i-Pr
c n-Pr
d Ph
87:13
83:17
85:15c
84:16c
86:14
e OTBS
f Me
a Determined by GC analysis; see the experimental section. Values in
parentheses are yields of isolated products.
b Determined by GC analysis; see the experimental section.
c Determined by optical rotation; see Supporting Information.
While these results are encouraging for the continued de-
velopment of thiophene-derived chiral amines and the ap-
plication of the corresponding magnesium amide bases in
asymmetric processes, we believe that complex (S)-19 is
not behaving as a chelating base as initially envisaged.
While the enantiomeric outcomes obtained with this com-
plex are respectable and, indeed, are approximately in line
with those achievable using our original chiral magne-
sium bisamide system (R)-3,2a this is in stark contrast to
that observed with the other base complexes evaluated as
part of this study, with the exception of the poorly reactive
pyrrole-derived complex (S)-18. In relation to this, it is
well known that thiophene can be employed as a phenyl
Gas chromatography was carried out using a Hewlett Packard 5890
Series 2 Gas Chromatograph and data were interpreted using Peak-
net computer software.
Achiral GC analysis: CP SIL-19 CB column; H2 carrier gas (80
kPa); 45 °C (1 min) to 190 °C; temperature gradient = 45 °C min–1;
tR (1a) = 5.85 min, tR (2a) = 6.01 min.
Chiral GC analysis: Chiralsil-DEX CB column; H2 carrier gas (80
kPa); 70–130 °C; temperature gradient = 1.7°C min–1; tR [(S)-
2a] = 27.52 min, tR [(R)-2a] = 27.83 min.
Synlett 2011, No. 2, 177–180 © Thieme Stuttgart · New York