An efficient protocol for the reduction of ketones with tin(II) complexes and PMHS

Article abstract of DOI:10.1016/S0040-4039(00)00652-3

A mixture of tin(II) triflate/pybox and polymethylhydrosiloxane (PMHS) in methanol effects the efficient reduction of ketones; the use of an enantiomerically pure pybox ligand leads to moderate enantioselectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00652-3

Tetrahedron Letters 41 (2000) 4507±4512
An ecient protocol for the reduction of ketones with tin(II)
complexes and PMHS
Nicholas J. Lawrence* and Simon M. Bushell
Department of Chemistry, UMIST, PO Box 88, Manchester M60 1QD, UK
Received 22 March 2000; accepted 20 April 2000
Abstract
A mixture of tin(II) tri¯ate/pybox and polymethylhydrosiloxane (PMHS) in methanol e€ects the ecient
reduction of ketones; the use of an enantiomerically pure pybox ligand leads to moderate enantio-
selectivity. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: polymethylhydrosiloxane; reduction; tin and compounds; asymmetric catalysis.
Polymethylhydrosiloxane (PMHS) is an attractive reducing reagent for environmentally benign
reductive processes because it is inexpensive,1 non-toxic2,3 and stable to air and moisture. Such is
its importance that we recently highlighted its use as a reducing agent in organic synthesis.4
PMHS has featured in only a small number of methods for the asymmetric reduction of
ketonesÐa fundamental and important process in organic synthesis. Asymmetric titanium catalysts
have been developed by Halterman5 and Buchwald for the reduction of ketones6 and imines.7 We
have developed chiral quaternary ammonium ¯uoride catalysts.8 Mimoun and co-workers have
developed asymmetric zinc complexes.9 We now report the ®rst example of the enantioselective
reduction of ketones using PMHS and an asymmetric tin species. The lack of such a protocol is
surprising since tin complexes were the ®rst catalysts to be used with PMHS to reduce
ketones.10,11 The product of these tin-based protocols is an alcohol whereas that of the titanium-,
¯uoride- and zinc-catalysed reactions is a silyl ether which must be subjected to a separate
hydrolysis step, which in some cases can be somewhat extreme.
We chose to investigate a catalyst possessing both a tin±oxygen bondÐcapable of undergoing
s-bond metathesis with PMHSÐand lacking tin-alkyl groups, which generally infer toxicity.
Tin(II) tri¯ate emerged as a good candidate. However, tin(II) tri¯ate (200 mol%) alone in
methanol with PMHS did not reduce acetophenone even after 48 hours at re¯ux. This appears an
inauspicious start; nevertheless, we were hopeful that ligand accelerated catalysis12 would prove
useful. Reduction of acetophenone, in 98% yield, was achieved with a mixture of PMHS and
* Corresponding author. Fax: +44(0)161 236 7677; e-mail: n.lawrence@umist.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00652-3

4508
TMEDA (10 mol%)/tin(II) tri¯ate (10 mol%). Since pyridine13 was also an e€ective ligand we
investigated the use of 2,6-pyridine bis(20-oxazoline) 1 (pybox).14 Pybox is an excellent catalyst in
combination with tin(II) tri¯ate for the reduction of ketones (Scheme 1 and Table 1).
Scheme 1.
Table 1
Reduction of ketones 2 to alcohols 3 with tin(II) tri¯ate (10 mol%)/1 (10 mol%) and PMHS (200 mol%)
Acetophenone was reduced to 3a in excellent yield with 1 (10 mol%)/tin(II) tri¯ate (10 mol%).
a-Ketoesters were also selectively reduced to the corresponding a-hydroxyesters in excellent
yields. The reduction of ethyl ester 2c was accompanied by a small amount of transesteri®cation.
The formation of the accompanying methyl ester 3b was prevented by performing the reaction in
ethanol. It is noteworthy that the reduction of methyl a-ketoesters by common reducing agents
such as sodium borohydride is often complicated by the reduction of the ester group. Thus, the
methodology represents a convenient way to reliably prepare a-hydroxyesters from their ketone
counterparts. Reduction of a-N-phthalimidylacetophenone 2i was again chemoselective with no
evidence of reaction of the phthalimide group giving the alcohol 3i. The ecient reduction of
phthalimidylacetophenones 2i±l illustrates that this is a potentially useful way to prepare 1,2-
aminoalcohol derivatives from readily available starting materials. The tin residue can be
removed simply by ®ltration of the reaction mixture through a plug of silica gel. This contrasts

4509
nicely with the characteristically dicult removal of trialkyltin residues when tributyltin hydride
is used as a reducing agent. We know from our own tests that tin(II) tri¯ate is not cytotoxic
(IC50 >50 mM, K562 cell line) whereas Bu3SnH, as expected, is considerably cytotoxic (IC50
<1 mM).15
We had chosen to use pybox 1 since it would clearly form the prototype of an asymmetric
system. The tin(II)-pybox complex 4, prepared in dichloromethane using the method described by
Evans and co-workers,16 is a good catalyst for the asymmetric reduction of acetophenone, giving
(S)-3a with moderate enantioselectivity17 (Scheme 2, Table 2). We subsequently found that it is
not necessary to isolate the pybox/tin(II) tri¯ate complex. The components of the reaction mixture
can simply be mixed in methanol and asymmetric reduction ensues with no signi®cant change in
reaction rate or enantioselectivity. The results using several other substituted pybox ligands,
prepared using known methods,18 are summarised in Table 2. The best result, both in terms of
yield and enantioselectivity, was obtained with pybox 5a. The bulkier ligands 5b and 5c gave both
poorer conversions and enantioselectivities. The sense of enantioselectivity seems to be determined
by the con®guration of the chiral centre adjacent to the nitrogen atom of the oxazoline, which is
closest to the reaction centre. The enantioselectivity of the system incorporating 5a in the reduction
of a series of other ketones is summarised in Scheme 3. The enantioselectivities of reduction of
1-indanone and a-tetralone are only a little lower than that of acetophenone. However, the
reaction is clearly sensitive to the structure of the ketone as revealed by the sluggish reduction
of benzosuberone and poor selectivity with 4-chromanone. The conversion of 2-acetylpyridine
is high, but the lack of enantioselectivity possibly suggests that the reaction is catalysed by a
non-pybox bound tin species.
Scheme 2.

4510
Table 2
Reduction of acetophenone to alcohols 3a with tin(II) tri¯ate
(10 mol%)/5a±f (10 mol%), and PMHS (200 mol%)
Scheme 3. Enantioselectivity in the reduction with PMHS and Sn(OSO2CF3)2 (10 mol%)/5a (10 mol%), MeOH, rt,
12±14 h
We propose a reaction cycle similar to those described by Lipowitz and Bowman11 and Fu and
co-workers (Scheme 4).19 Reduction of the species 8 which possesses a tin±oxygen bond by
PMHS to the tin hydride 6 occurs via a known process20 involving s-bond metathesis. We believe
that it is a hydride such as 6 which reduces the ketone in an ionic fashion, thereby producing the
tin oxide 7. Methanolysis of this species generates the tin methoxide 8 and ensures that the tin
hydride is regenerated, since a secondary tin±alkoxy group is not reduced by the PMHS.21 This
appears to be the rate limiting step. We have found that the reaction can be carried out conveniently
in a variety of solvents if 2 equivalents of methanol are included as an additive. Methanol for this
purpose is better than both ethanol and isopropanol; no reaction is observed in the latter case.
We are currently seeking proof that 6, a rare example of a chiral tin hydride,22 is indeed the actual
reducing agent in the catalytic cycle. The system we describe is broadly related to the method
developed by Mukaiyama and co-workers.23 They found that ketones can be reduced with good
enantioselectivity by a reagent prepared from DIBAlH and a chiral diamine such as (S)-1-methyl-
2-(piperidinomethyl)pyrrolidine. However, the system is not catalytic with respect to the tin
species and involves the use of the reactive terminal reducing agent DIBAlH. These drawbacks
are not present in our system.

4511
Scheme 4.
In summary, we have found that the combination of tin(II) tri¯ate/pybox is an ecient catalyst
for the direct synthesis of alcohols by the PMHS reduction of ketones. Asymmetric modi®cation
of the system has led to a conceptually novel way to enantioselectively reduce ketones, which with
improvement may prove useful.
General procedure: The pybox ligand (50 mmol) in methanol (0.25 cm3) is added to a slurry of
tin(II) tri¯ate (21 mg, 50 mmol) in dry methanol (0.25 cm3) under an atmosphere of argon at room
temperature. The resulting yellow homogeneous solution is stirred at room temperature for 2 min
before sequential addition of the ketone (0.5 mmol) in dry methanol (0.25 cm3) and PMHS (1
mmol). The resulting mixture is stirred at room temperature until complete (TLC). The solvent is
removed in vacuo to yield the alcohol after chromatography or distillation.
Acknowledgements
We thank the EPSRC for a studentship (Catalysis and Catalytic Processes Programme; GR/
L57906 to SMB) and Research Grants (GR/L52246: NMR spectrometer; GR/L84391: chroma-
tographic equipment) and the EPSRC Chemical Database Service at Daresbury.24
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4512
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