A sequential tetra-n-propylammonium perruthenate (TPAP)-Wittig oxidation olefination protocol

Article abstract of DOI:10.1016/j.tetlet.2003.08.081

A convenient sequential oxidation-olefination protocol is reported using tetra-n-propylammonium perruthenate (TPAP) as oxidant and phosphonium salts as olefin source. The oxidation reaction mixture is added directly to the phosphorane facilitating an efficient method for this transformation that avoids work-up of potentially sensitive aldehyde intermediates.

Full text of DOI:10.1016/j.tetlet.2003.08.081

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7779–7781
A sequential tetra-n-propylammonium perruthenate
(TPAP)–Wittig oxidation olefination protocol
Rachel N. MacCoss, Emily P. Balskus and Steven V. Ley*
BP Whiffen Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 31 July 2003; revised 14 August 2003; accepted 20 August 2003
Abstract—A convenient sequential oxidation–olefination protocol is reported using tetra-n-propylammonium perruthenate
(TPAP) as oxidant and phosphonium salts as olefin source. The oxidation reaction mixture is added directly to the phosphorane
facilitating an efficient method for this transformation that avoids work-up of potentially sensitive aldehyde intermediates.
© 2003 Elsevier Ltd. All rights reserved.
The oxidation of alcohols to aldehydes and ketones and
their subsequent transformation to alkenes using a Wit-
tig olefination is an important functional group manip-
ulation, which is frequently used in natural product
synthesis.1,2 However, the utility of this sequence can be
limited when applied to aldehydes that are problematic
to isolate due to their instability or volatility. This
product intermediates. Primarily, they are restricted to
stabilised ylides in the oxidation–Wittig processes. Only
the most thorough study by Taylor and co-workers6
has investigated nonstabilised ylides with MnO2 as oxi-
dant, but the success of the reaction was mainly
confined to benzylic alcohols and other activated
systems.
research investigates
a tetrapropylammonium per-
ruthenate (TPAP) oxidation, followed by immediate
Wittig olefination without work-up, to prepare alkenes
from alcohols with improved efficiency and scope over
previously reported one-pot methods (Scheme 1).
TPAP is an air stable and nonvolatile reagent that has
been widely applied to the oxidation of alcohols to
aldehydes and ketones.7 It is commercially available,
readily soluble in organic solvents, catalytic in the
presence of NMO or O2, active at room temperature,
and devoid of noxious or explosive side products. In
our procedure,8 the oxidations are complete in less than
30 min and then the reaction mixtures are added,
without work-up, directly into a flask of the phospho-
rane. The work-up of these sequential reactions is a
simple extraction followed by a filtration through a pad
of silica or commercially available Bond Elut™ car-
tridge with hexanes to obtain clean alkene product. The
general utility of this method is demonstrated by the
oxidation and nonstabilised Wittig olefination of the
series of alcohols depicted in Table 1.
Recently, several oxidation–Wittig procedures have
been developed that circumvent the need to isolate
unstable products. Various oxidising reagents, including
MnO2,3 BaMnO4,4 and Dess–Martin periodinane,5 have
been utilised but are restricted with respect to their
scope and applicability to complex substrates. Requir-
ing harsh conditions and large excess of reagents, these
methods are often not compatible with sensitive natural
Naphthalene methanol 1 and biphenyl methanol 3
afforded the desired ethylene products 2 and 4 in good
yields. Thiazole alcohol 5 was investigated in order to
illustrate the applicability of this method to heterocy-
cles. The ethylene product 6 was obtained in lower
yield, presumably due to competing oxidation of the
heteroatoms during the TPAP oxidation. All aldehyde
formed reacted further to give alkene product 6.
Although the reaction of dodecanol 7 seemed to pro-
ceed by TLC, some of the product alkene 8 may have
Scheme 1. Sequential TPAP oxidation–Wittig olefination
reactions.
* Corresponding author. E-mail: svl1000@cam.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.081

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R. N. MacCoss et al. / Tetrahedron Letters 44 (2003) 7779–7781
Table 1. Sequential TPAP oxidation–nonstabilised Wittig
olefination of alcohols to ethylenes
product 10 was obtained. Oxidation of secondary alco-
hol 11 went to completion; however, subsequent Wittig
reaction of the ketone went poorly as is often the case
with these types of reactions. Nevertheless, this result is
an improvement on other sequential oxidation–Wittig
techniques involving stabilised ylides3 which report even
lower yields for secondary alcohols. Notably, no
epimerisation was observed when a chiral centre was
present at the a-position of alcohol 13, an intermediate
available from our laboratory.
In order to investigate the scope of the Wittig reaction,
this oxidation–olefination technique was also used in
methylenation reactions with butane diacetal derivative
15 and chiral alcohol 13 (Table 1). In addition, vinyl
halides 18, 19, and 20 were obtained in good yields
using (chloromethyl)triphenyl phosphonium chloride
and (bromomethyl)triphenyl phosphonium bromide.9
Stabilised ylides10 were also incorporated into the olefi-
nation step of this technique using a one-pot method
that was applied successfully to several alcohols (Table
2).
Dodecanol 7, benzyl alcohol 22, and biphenyl methanol
3 all produced the corresponding esters 21, 23, and 24
in good to moderate yields and good selectivity for the
E isomer. Once again, when this method was performed
on the chiral alcohol 13 the ester product 25 was
obtained without epimerisation.
In summary, this sequential TPAP oxidation–Wittig
olefination technique is efficient and simple. It is widely
applicable to a range of alcohols, including aromatic,
aliphatic, heterocyclic, secondary, and chiral alcohols,
with both stabilised and nonstabilised Wittig reagents
to synthesise methylenes, ethylenes, vinyl halides, and
esters. This method has potential for use in natural
product synthesis.
Acknowledgements
Table 2. One-pot TPAP oxidation–stabilised Wittig olefi-
nation of various alcohols to ethyl esters
We gratefully acknowledge financial support from the
Novartis Research Fellowship (to S.V.L.) and The
Winston Churchill Foundation of the US.
References
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1999, 1337–1338.
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been lost due to its high volatility. With the intention of
determining a yield for a non-volatile, aliphatic alcohol,
phenylpentanol 9 was chosen as a substrate. Only the Z

R. N. MacCoss et al. / Tetrahedron Letters 44 (2003) 7779–7781
7781
7. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639–666.
8. Nonstabilised procedure (ethylene and methylene products):
Alcohol (100 mg, 1.0 equiv.) was dissolved in dry CH2Cl2
(2 ml/mmol) and stirred at rt under argon in the presence
was then eluted through a Bond Elut cartridge (20 g, 60
ml) with hexanes (50 ml) and fractions collected and
dried in vacuo to give the desired product.
9. Nonstabilised procedure (vinyl halide products): Ethylene
procedure8 except that (chloromethyl) triphenylphospho-
nium chloride (1.50 equiv.) replaced the phosphorane.
Use excess nBuLi (3.6 equiv.) to keep its bright yellow
colour.
,
of NMO (1.05 equiv.) and 4 A molecular sieves (200
mg/mmol). After 15 min, TPAP (0.05 equiv.) was added
in small portions to give a black slurry. In a separate
flask, triphenylphosphonium bromide (1.50 equiv.) was
stirred at rt under argon in dry THF (3 ml), and nBuLi
(2.5 M in hexanes, 1.43 equiv.) was added dropwise to
give a bright orange slurry. After stirring the phospho-
rane for 1 h, it was cooled to −78°C and the TPAP
reaction was added dropwise. The reaction mixture was
warmed slowly to rt. Upon aldehyde consumption, the
reaction mixture was diluted with saturated, aqueous
NH4Cl (15 ml) and stirred for 15 min. The mixture was
extracted with Et2O (45 ml) and the organic layer dried
over MgSO4, filtered, and concentrated in vacuo. The oil
10. Stabilised procedure (ester products): Ethylene procedure8
except that (ethoxycarbonylmethylene)triphenylphos-
phorane (1.5 equiv.) was added directly to the oxidation
reaction mixture, which was stirred for a further 16 h at
rt. The crude reaction mixture was poured into 1:1 H2O/
CH2Cl2 and brine added until the two layers separated.
The aqueous layer was extracted with CH2Cl2 and the
combined organic layers dried over Na2SO4, filtered, and
concentrated in vacuo to give the crude product mixture.
The alkene was purified by flash chromatography on
silica gel (5% ethyl acetate/hexanes).