Asymmetric transfer hydrogenation of α-amino and α-alkoxy substituted ketones

Article abstract of DOI:10.1055/s-1999-2906

Through the use of appropriate protecting groups, the asymmetric transfer hydrogenation of ketones bearing heteroatoms at the α- position may be achieved in high yield and enantioselectivity.

Full text of DOI:10.1055/s-1999-2906

LETTER
1615
Asymmetric Transfer Hydrogenation of a-Amino and a-Alkoxy Substituted
Ketones
Jennifer A. Kenny,a Matthew J. Palmer,a Athene R. C. Smith,a Tim Walsgrove,b Martin Willsa*
a Department of Chemistry, Warwick University, Coventry, CV4 7AL, UK
Fax +24 7652 4112; E-mail: m.wills@warwick.ac.uk
b SmithKline Beecham Pharmaceuticals, Old Powder Mills, Nr Leigh, Tonbridge, Kent, TN11 9AN, UK
Received 18 August 1999
As a part of an ongoing series of investigations into the ap-
Abstract: Through the use of appropriate protecting groups, the
plications of b-amino alcohols such as 2 in transfer hydro-
asymmetric transfer hydrogenation of ketones bearing heteroatoms
genation, the reductions of a-heteroatom substituted
ketones seemed an obvious extension of our studies.
However we were surprised to find that both a-chloro
and a-methoxy acetophenone 3 and 4 respectively failed
to be reduced under conditions which were effective for
acetophenone hydrogenation (Scheme 1). In a simple ex-
periment designed to probe the reasons for these failures,
a 1:1 mixture of acetophenone and a-methoxy acetophe-
none was subjected to reduction conditions (Scheme 2).
Neither ketone was reduced, suggesting that the methoxy-
substituted reagent, or its reduction product, was inhibit-
ing the reduction process. A possible mechanism for this
involves the chelation of the ruthenium by the methoxyke-
tone reduction product, a process which then triggers de-
composition of the catalyst (Figure 1).
at the a- position may be achieved in high yield and enantioselectiv-
ity.
Key words: enantioselective, catalysis, aminoalcohol, transfer,
hydrogenation
The asymmetric transfer hydrogenation of ketones has re-
cently been the subject of intense research efforts.1-3 Many
excellent new catalyst systems have been developed for
this application, perhaps the most notable of which are
those based on ruthenium(II) arene complexes of monoto-
sylated diamine 1.1 Using as little as 0.5 mol% of such a
complex, a range of ketones may be reduced with ex-
tremely high enantioselectivities. Furthermore the reduc-
tion may be achieved with formic acid/triethylamine1a or
isopropanol1b as the hydride source. Ruthenium(II) com-
plexes of b-amino alcohols such as cis-1-aminoindan-2-
ol 2,2a provide excellent levels of acceleration in ketone
reduction using the iso-propanol/KOH system.2 In con-
trast to monotosylated diamines, however, ruthenium
complexes of aminoalcohols are not compatible with the
formic acid/triethylamine system.
Reduction of acetophenone derivatives using (1R,2S)-2
Scheme 1
Despite the high level of interest in the area, the majority
of published work has focussed largely on the reduction of
unsubstituted ketones of simple structure. In contrast very
few studies have addressed the reduction of ketone sub-
strates substituted at the a- position with, for example, an
alkoxy or amino group. Reports have appeared on the
asymmetric transfer hydrogenation of a,b-diketones4 and
a-ketoesters,1a,4,5 and Noyori has employed the monotosy-
lated/diamine system for the reduction of propargylic ke-
tones bearing a-benzyloxycarbonylamino substitutents.1c
In a very recent paper, scientists at Oxford Asymmetry In-
ternational reported an effective reduction of a-chloroac-
Attempted reduction of acetophenone and a-methoxy acetophenone
Scheme 2
etophenone using
a
supported version of the
monotosylated diamine system.6
Synlett 1999, No. 10, 1615–1617 ISSN 0936-5214 © Thieme Stuttgart · New York

1616
J. A. Kenny et al.
LETTER
action. In contrast the major product has probably under-
gone a small level of racemisation following reduction via
a reversal of the initial reduction process. This cannot oc-
cur with 15 because the esterification of the newly formed
alcohol prevents its oxidation.
Proposed intermediate leading to catalyst inactivation by a chelating
product
Figure 1
We reasoned that the introduction of a sterically large
group on the oxygen atom would hinder chelation and
thus prevent catalyst inactivation. However both a-tert-
butyl and a-tert-butyldiphenylsilyloxy acetophenones 5
and 6 respectively proved resistant to reduction (Figure
2). In contrast a-phenyloxy acetophenone 7 was an excel-
lent substrate, giving a product 8 of 88% e.e. in 97% yield
(Scheme 1, Table). This observation is consistent with our
explanation for inhibition given above, since the lone
pairs on the phenoxy group are less available for co-ordi-
nation to the metal due to conjugation with the aromatic
group.
Given the above results it was unsurprising that a-dimeth-
ylamino acetophenone 16 proved inert to reduction (Fig-
ure 2). In contrast, substrate 17 containing a N-tert-
butoxycarbonyl group was readily reduced to give 18 in
86% yield and 79% e.e. (Scheme 1, Table).11 The latter re-
sult thus provides an entry to enantiomerically enriched b-
amino substituted alcohols.
It is also noteworthy that throughout our work in this area,
we had found that the optimum ratio of ligand to rutheni-
um atoms was ca. 2:1, although this can be reduced to
1.5:1 without loss of activity or selectivity. However we
had found that the use of more than two equivalents of
ligands per ruthenium resulted in a considerable reduc-
tion, and ultimately inhibition, of the rate of reduction.
The results in this paper provide a rationale to explain
these observations, since it is clear that an excess of the
chelating ligand must result in inhibition and decomposi-
tion of the catalytic species by an identical process to that
for the product inhibition in this study. These observations
may be of value to other workers in this field.
Substrates which fail to undergo reduction
Figure 2
In conclusion, the results reported herein represent the
first examples of asymmetric transfer hydrogenation of
heteroatom substituted ketones using a combination of an
enantiomerically pure ruthenium(II) b-aminoalcohol with
isopropanol as hydrogen source. Furthermore, the insights
which this work has provided into the mechanism of the
transfer hydrogenation are anticipated to greatly increase
the versatility of this valuable transformation.
Further evidence for the proposed catalyst inactivation
process came from the observation that incorporation of a
longer chain between the ketone and the co-ordinating
group furnishes a substrate more compatible with the re-
action. Both b- and g- methoxyacetophenone 9 and 10 re-
spectively were successively less resistant to reduction
and, whilst isolated yields were low, both substrates were
reduced in good enantioselectivity to give products 11 and
12 respectively, both in 84% e.e. (Scheme 1, Table).7,8
Having observed that an electron withdrawing group on
the a-oxygen was beneficial, we examined the use of a
benzoyloxy group at this position. The reduction of this
substrate would be highly valuable, since the protecting
group is readily removable. In the event the reduction of
13 proceeded cleanly and in good yield, to give a mixture
of two products 14 and 15 in a ca. 3:1 ratio (Scheme 1, Ta-
ble).9,10 Chiral HPLC analysis of each product revealed
that they had been formed with e.e.s of 84% and 90% re-
spectively. The minor product, 15, is presumably a rear-
rangement product of 14, and the higher e.e. for this
compound reflects the kinetic enantioselectivity of the re-
General procedure for asymmetric transfer hydroge-
nation of substrates 7, 9, 10, 13, 17): A solution of (p-
cymene)ruthenium(II) chloride dimer (7.7 mg, 0.0125
mmol) and (1S,2R)-(+)-cis-1-aminoindan-2-ol (7.5 mg,
0.05 mmol) in dry propan-2-ol (4 ml) was heated at 80oC
for 20 minutes under nitrogen. After cooling to room tem-
perature, the light brown solution was transferred via can-
nula to a large sealed Schlenk flask. A solution of ketone
(5 mmol) in dry degassed propan-2-ol (45 ml) was added
via cannula, followed by KOH (1.25 ml, 0.1M in propan-
2-ol, 0.125 mmol). The reaction was run at room temper-
ature and monitored by TLC until substantially complete
(generally two hours). Work up consisted of filtering the
dark brown solution through a pad of silica under vacuum
(with ethyl acetate washings, 2x50 ml). The combined or-
Synlett 1999, No. 10, 1615–1617 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Transfer Hydrogenation of a-Amino and a-Alkoxy Substituted Ketones
1617
ganic extracts were concentrated in vacuo to give the 18: Reaction time 2h. 86% isolated yield. [a]D -12.7 (c
crude product which was purified by flash column chro- 1.0, methanol); (S enantiomer assigned following trends
matography (SiO2, ethyl acetate-petrol).
with other substrates); dH (250 MHz, CDCl3) 1.44 (9H, s,
C(CH3)3), 2.73 and 2.82 (3H, s, NCH3), 3.22-3.55 (2H, m,
CH2), 4.60 (1H, brs, OH), 4.87 (1H, brs, CH), 7.10-7.38
(5H, m, ArH).11 79% e.e. determined by Chiral HPLC;
OD column (25 cm), i-propanol:hexane:diethylamine
(5:95:0.1), RT 30 min (R) and 31 min (S).
Selected data for reduction products:
8: Reaction time 2 h. 97% yield. [a]D +28.2 (c 1.0,
MeOH). S-Configuration assigned by analogy with other
reductions; dH (250 MHz, CDCl3) 2.79 (1H, s, OH), 4.01
(1H, dd, J 9, 9, CHH), 4.11 (1H, dd, J, 3, 9, CHH), 5.13
(1H, dd, J 3, 9, CH), 6.90-7.01 (3H, m, ArH), 7.25-7.47
(7H, m, ArH). 88% e.e. determined by Chiral HPLC; OD
column (25 cm), ethanol:hexane:diethylamine (5:95:0.1),
RT 29 min (R) and 39 min (S).
All new compounds were fully characterised; selected
data is given above.
Acknowledgement
We thank the EPSRC and SmithKline Beecham for an Industrial
CASE award (to JAK) and J. Ballantine, D. Games and B. Stein of
the EPSRC MS service for analysis of certain compounds.
11: Reaction time 3 days. 38% yield. [a]D +29.9 (c 1.3, cy-
clopentane); (R enantiomer lit7 80% e.e. [a]D +30.1 (c
0.74, cyclopentane)); dH (250 MHz, CDCl3) 1.90-2.10
(2H, m, CH2CH2OH), 3.34 (3H, s, OCH3), 3.39 (1H, brs,
OH), 3.50-3.65 (2H, m, CH2OH), 4.89 (1H, dd, J 4, 8,
CH), 7.21-7.38 (5H, m, ArH). 84% e.e. determined by
Chiral HPLC; OD column (25 cm), n-propanol:hexane:di-
ethylamine (5:95:0.1), RT 18 min (R) and 20 min (S).
References and Notes
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12: Reaction time 3 days. 32% yield. [a]D +44.6 (c 0.82,
cyclopentane); (R enantiomer lit8 38% e.e. [a]D +15.2 (c
4.72, cyclopentane)) ; dH (250 MHz, CDCl3) 1.55-1.90
(4H, m, CH2CH2CO), 3.01, (1H, brs, OH), 3.33 (3H, s,
CH3), 3.41 (2H, t, J 6, CH2OCH3), 4.68 (1H, t, J 5, CH),
7.22-7.40 (5H, m, ArH). 84% e.e. determined by Chiral
HPLC; OD column (25 cm), n-propanol:hexane:diethyl-
amine (5:95:0.1), RT 20 min (R) and 23 min (S).
14: Reaction time 2 h. 34% isolated yield. [a]D +25.6 (c
1.00, dichloromethane); (S enantiomer lit9 65% e.e. [a]D
+20.7 (c 3.28, dichloromethane)); dH (250 MHz, CDCl3)
2.66 (1H, brs, OH), 4.42 (1H, dd, J 12, 8, CHH), 4.53 (1H,
dd, J 12, 3, CHH), 5.11 (1H, dd, J 8, 3, CH), 7.29-7.50
(7H, m, ArH), 7.53-7.62 (1H, m, ArH), 8.01-8.10 (2H, m,
ArH). 84% e.e. determined by Chiral HPLC; OD column
(25 cm), n-propanol:hexane (5:95), RT 30 min (S) and 35
min (R).
15: 10% isolated yield.10 [a]D -39.0 (c 0.94, dichlo-
romethane); (S enantiomer assigned following trends with
other substrates); dH (250 MHz, CDCl3) 2.14 (1H, brs,
OH), 3.88-4.10 (2H, m, CH2), 6.10 (1H, dd, J 4, 7, CH),
7.25-7.51 (7H, m, ArH), 7.51-7.62 (1H, m, ArH), 8.06-
8.17 (2H, m, ArH). 90% e.e. determined by Chiral HPLC;
OD column (25 cm), i-propanol:hexane (5:95), RT 29 min
(R) and 30 min (S).
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Article Identifier:
1437-2096,E;1999,0,10,1615,1617,ftx,en;L12399ST.pdf
Synlett 1999, No. 10, 1615–1617 ISSN 0936-5214 © Thieme Stuttgart · New York