New potentially dhelating chiral magnesium amide bases for use in enantioselective deprotonation reactions

Article abstract of DOI:10.1055/s-0030-1259282

A series of chiral secondary amines, incorporating a five- or six-membered heterocycle, were synthesised and used to prepare novel chiral magnesium bisamide reagents. These amide bases were subsequently applied within asymmetric deprotonation reactions to

Full text of DOI:10.1055/s-0030-1259282

LETTER
177
New Potentially Chelating Chiral Magnesium Amide Bases for Use in
Enantioselective Deprotonation Reactions
Chelating Chiral
M
agne
i
sium
A
l
mide
B
l
ases iam J. Kerr,* Michael Middleditch, Allan J. B. Watson
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
Fax +44(141)5484246; E-mail: w.kerr@strath.ac.uk
Received 12 November 2010
reactivity/selectivity profile of these, so-called, chelating
base systems was attributed to the potential for intramo-
lecular ligation from the pendant tertiary amine: the Lewis
base function renders the amide more reactive, while also
Abstract: A series of chiral secondary amines, incorporating a five-
or six-membered heterocycle, were synthesised and used to prepare
novel chiral magnesium bisamide reagents. These amide bases were
subsequently applied within asymmetric deprotonation reactions to
probe the potential for chelation-assisted selectivity enhancement. imparting greater rigidity to the complex, resulting in add-
Good levels of selectivity could be achieved [up to 87:13 er (R/S)]
across a range of prochiral cyclohexanone substrates when employ-
ing a thiophene-derived magnesium bisamide complex.
ed selectivity.
Despite this growing level of performance, the amines
used to prepare bases such as (R,R)-4 are considerably
Key words: asymmetric synthesis, enantioselectivity, heterocy-
more complex than the simple and readily available parent
cles, enolate, magnesium
amine used to prepare (R)-3 and, therefore, require a more
laborious synthesis.2g Consequently, we became interest-
ed in the possibility of preparing more accessible ana-
logues of (R,R)-4. As such, we selected the key structural
Over recent years, chiral magnesium amide bases have
proven to be effective reagents for the asymmetric depro-
tonation of prochiral ketones.1,2 Initial studies, using mag-
nesium bisamide (R)-3 (Scheme 1),2a derived from a
structurally simple and commercially available chiral
amine,3 revealed levels of selectivity appreciably greater
than the corresponding lithium-derived equivalent.4 Sub-
sequently studies, focused on the structural development
of chiral magnesium amide complexes, revealed some of
the requirements and limits for selectivity with these
structurally simple complexes.2d Additionally, a series of
more complex chiral amines, incorporating potentially
chelating side arms [e.g., (R,R)-4] were prepared and eval-
uated.2g The corresponding magnesium bisamides pre-
pared from these amines provided enhanced reactivity and
selectivity over a range of substrates.2g The increase in the
elements of the two previously employed and successful
chiral magnesium base structures and formulated a new
hybrid series of chiral amines to, in turn, deliver magne-
sium amides that possess the structural simplicity of (R)-
3 with the potential chelating ability of (R,R)-4
(Scheme 2).
Ph
N
H
Ph
Ph
N
2
Ph
N
X
Mg
H
X
• potential chelation
Ph
NH
• more rigid base structure
hybrid parent amine
• selectivity enhancement?
N
Ph
Scheme 2 Conceptual plan for new potentially chelating Mg bases
O
OSiMe3
Analysis of previously successful chelating bases, such as
(R,R)-4, suggested that the Lewis basic function should be
located in the position b to the secondary amine for the
purpose of establishing a five-membered chelate in the
magnesium amide derivative.2g Based on this, two series
of heterocyclic amines were targeted: these would be de-
rived from aromatic and aliphatic heterocycles
(Scheme 3).
(R)-
3
(90:10)2a
(93:7)2g
chiral Mg bisamide
(R,R)-
4
t-Bu
1a
t-Bu
2a
Mg
It was envisaged that these chiral amines would be synthe-
sised using a reductive amination procedure for the aro-
matic targets and an acylation–reduction pathway for the
aliphatic series. These routes would also employ commer-
cially available (R)- or (S)-1-phenylethylamine5 as the
requisite chiral entity, based on the highly successful us-
age of this motif within previous magnesium amide com-
plexes.1,2
Ph
N
2
2Mg
Ph
N
Ph
N
Ph
(R,R)-4
(R)-
3
Scheme 1 Simple Mg complex (R)-3 vs. chelating complex (R,R)-4
in the deprotonation of 4-tert-butylcyclohexanone 1a2a,g
SYNLETT 2011, No. 2, pp 0177–0180
Advanced online publication: 23.12.2010
x
x.
x
x.
2
0
1
1
DOI: 10.1055/s-0030-1259282; Art ID: D30010ST
© Georg Thieme Verlag Stuttgart · New York

178
W. J. Kerr et al.
LETTER
aromatic heterocyclic series
O
X
NaH, Et2O, Δ
N
Ph
Ph
NH2
EtO
ArCHO
Ph
N
Ar
(R)-5
Ph
NH2
H
X
O
X
LiAlH4, Et2O, Δ
N
N
Ar =
N
H
Ph
N
N
H
O
S
H
N
X = CH2; (R)-13, 100%
X = O; (R)-14, 100%
X = NMe; (R)-15, 100%
X = CH2; (R)-10, 84%
X = O; (R)-11, 89%
X = NMe; (R)-12, 63%
aliphatic heterocyclic series
O
Scheme 5 Synthesis of aliphatic heterocyclic amines (R)-13–15
NR2
NR2
Ph
N
H
Ph
N
NH2
EtO
N
Disappointingly, many of these new complexes failed to
function as desired. While moderate to good levels of re-
activity were obtained for some, very little selectivity was
observed, with most reactions providing (close to) racem-
O
NMe
NR2
=
N
Scheme 3 Proposed routes towards chiral heterocyclic amines
Table 1 Evaluation of Mg Amides 16–22 in the Benchmark Asym-
metric Deprotonation of 4-tert-Butylcyclohexanone (1a)
Firstly, pyridine 2-carboxaldehyde smoothly underwent
reductive amination with (R)-1-phenylethylamine [(R)-5],
resulting in quantitative formation of the desired product
(R)-6 (Scheme 4).6 Disappointingly, the same reductive
amination procedure failed to yield the desired product
when employing furan-2-carboxaldehyde. Therefore, an
alternative two-step approach was adopted in that the imi-
ne was first isolated by reaction of (S)-57 with furan-2-car-
boxaldehyde in the presence of MgSO4. Subsequent
reduction with LiAlH4 provided the desired product (S)-7
in quantitative overall yield (Scheme 4).8 Based on the
success of this approach, the same two-step procedure
was followed for the synthesis of the 2-pyrroyl and 2-
thiophenyl derivatives, (S)-8 and (S)-9, respectively.
O
OSiMe3
chiral Mg bisamide
Me3SiCl, DMPU, THF, –78 °C
t-Bu
t-Bu
1a
2a
Mg bisamide
Conv. (%)a er (S/R)a
12
19
1
49:51
42:58
24:76
14:86
2Mg
Ph
Ph
Ph
Ph
N
N
(R)-16
N
2Mg
NaHB(OAc)3
O
(S)-17
Ph
N
Ar
ArCHO
H
DCE, r.t.
Ph
NH2
(R)-5
(S)-5
Ar = 2-pyridyl; (R)-6, 100%
Ar = 2-furyl; (R)-7, 0%
N
Mg
N
(S)-18
i) MgSO4, Et2O, r.t.
ArCHO
Ph
N
Ar
Ph
NH2
ii) LiAlH4, Et2O, 0 °C to r.t.
H
83
N
2Mg
Ar = 2-furyl; (S)-7, 100%
Ar = 2-pyrrolyl; (S)-8, 100%
Ar = 2-thiophenyl; (S)-9, 56%
S
(S)-19
Scheme 4 Synthesis of aromatic heterocyclic amines (R)-6 and (S)-
7–9
N
43
64
79
50:50
50:50
51:49
Ph
Ph
Ph
N
N
2Mg
The aliphatic series was readily accessed following a
straightforward two-step sequence comprising acylation
with the suitable a-amino ester9 and reduction with
LiAlH4. In this manner, the parent amines (R)-13–15 were
delivered in excellent overall yield (Scheme 5).
(R)-20
O
N
N
2Mg
(R)-21
With the parent heterocyclic amines in hand, the corre-
sponding magnesium bisamides were prepared following
previously described protocols, utilising n-Bu2Mg.10 We
then sought to establish the performance of these novel
chiral magnesium amide complexes as chiral base re-
agents within the benchmark asymmetric deprotonation
of 4-tert-butylcyclohexanone 1a (Table 1).
NMe
2Mg
N
(R)-22
a Determined by GC analysis; see the experimental section.
Synlett 2011, No. 2, 177–180 © Thieme Stuttgart · New York

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

180
W. J. Kerr et al.
LETTER
amine CAS# [3886-69-9]; and (S)-1-phenylethylamine
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
CAS# [2627-86-3].
(6) Brunner, H.; Reiter, B.; Reipl, G. Chem. Ber. 1984, 117,
1330.
(7) Due to limited availability of (R)-phenylethylamine during
the course of this study, we were compelled to use the more
readily obtainable S-enantiomer for the preparation of
several of the desired chiral amines.
(8) (a) Zylber, J.; Tubul, A.; Brun, P. Tetrahedron: Asymmetry
1995, 6, 377. (b) Rogatchov, V. O.; Bernsmann, H.;
Schwab, P.; Froehlich, R.; Wibbeling, B.; Metz, P.
Tetrahedron Lett. 2002, 43, 4753.
Acknowledgment
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.
(9) For amine acylation with a-amino esters, see: Juaristi, E.;
Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.;
Simson, M.; Seebach, D. Synthesis 1993, 1271.
(10) Commercially available from Aldrich Chemical Co., CAS#
[1191-47-5].
(11) Thiophene is commonly used as a phenyl isostere within
medicinal chemistry; for example, see: Silverman, R. B. The
Organic Chemistry of Drug Design and Drug Action, 2nd
ed.; Academic Press: New York, 2004, 32.
(12) The absolute solution-state structure of (R)-3 is currently
unknown and efforts to crystallise this complex have so far
been unsuccessful. However, the structure of the related
achiral bisamide complex derived from dibenzylamine is
known, see: (a) Clegg, W.; Craig, F. J.; Henderson, K. W.;
Kennedy, A. R.; Mulvey, R. E.; O’Neil, P. A.; Reed, D.
Inorg. Chem. 1997, 36, 6238. (b) Conway, B.; Hevia, E.;
Kennedy, A. R.; Mulvey, R. E.; Weatherstone, S. Dalton
Trans. 2005, 1532. (c) Andrikopoulos, P. C.; Armstrong,
D. R.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T.;
Rowlings, R. B.; Weatherstone, S. Inorg. Chim. Acta 2007,
360, 1370.
References and Notes
(1) For a review on the use of magnesium amide reagents, see:
Henderson, K. W.; Kerr, W. J. Chem. Eur. J. 2001, 7, 3430.
(2) (a) Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem.
Commun. 2000, 479. (b) Henderson, K. W.; Kerr, W. J.;
Moir, J. H. Synlett 2001, 1253. (c) Henderson, K. W.; Kerr,
W. J.; Moir, J. H. Chem. Commun. 2001, 1722.
(d) Anderson, J. D.; García García, P.; Hayes, D.;
Henderson, K. W.; Kerr, W. J.; Moir, J. H.; Fondekar, K. P.
Tetrahedron Lett. 2001, 42, 7111. (e) Henderson, K. W.;
Kerr, W. J.; Moir, J. H. Tetrahedron 2002, 58, 4573.
(f) Carswell, E. L.; Hayes, D.; Henderson, K. W.; Kerr,
W. J.; Russell, C. J. Synlett 2003, 1017. (g) Bassindale, M.
J.; Crawford, J. J.; Henderson, K. W.; Kerr, W. J.
Tetrahedron Lett. 2004, 45, 4175.
(3) Commercially available from Aldrich Chemical Co., CAS#
[38235-77-7], catalogue no. 431737.
(4) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins,
N. S. Tetrahedron 1990, 46, 523.
(5) Commercially available from BASF SE (ChiPros®) (http://
www.intermediates.basf.com/en/intermed/products/chipros/
amines/) or the Aldrich Chemical Co.: (R)-1-phenylethyl-
Synlett 2011, No. 2, 177–180 © Thieme Stuttgart · New York

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