LETTER
775
A Clean Conversion of Aldehydes to Nitriles Using a Solid-Supported
Hydrazine
C
lean Co
a
nversion
o
n
f
A
ldehydes to
Nitr
R
ile
s
. Baxendale, Steven V. Ley,* Helen F. Sneddon
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 31 January 2002
Abstract: A polymer-supported hydrazine reagent has been ap-
plied to the conversion of a range of aldehydes to nitriles, providing
a clean and efficient route to more diverse building blocks for com-
binatorial chemistry programmes.
Key words: aldehydes, nitriles, polymer-supported reagents
Scheme
For this study the resin bound hydrazine 1 was prepared11
by substitution of the chloride of the Merrifield resin with
the methylated nitrogen of N-methylhydrazine.12 While it
was not possible to quantify properly the loading of this
immobilised hydrazine due to possible cross-linking or
coupling via the non-methylated nitrogen, later reactions
gave some indication of the high efficiency of this pro-
cess.13
The inherent value of combinatorial chemistry as a pre-
parative technique lies not only in the multitude of com-
pounds that can be synthesised but, more importantly, in
the structural diversity that can be realised through the
combination of the correct monomer sets. Unfortunately,
commercial supplies of many key starting materials for
combinatorial chemistry programmes are limited. For ex-
ample, at present there are approximately only 4,000 com-
mercially available aldehydes,1 while there are of the
order of 76,000 available alcohols from which the corre-
sponding carbonyl compounds can be obtained by oxida-
tion.2 Likewise, there are relatively few commercially
available nitriles,1 despite their common usage in the syn-
thesis of agrochemical and drug-like fragments. It is
known that aldehydes can be converted to the correspond-
ing nitriles by the dehydration of aldoximes,3 but current
methods of converting aldehydes to nitriles tend to be
based on solution phase oxidation of the aldimines,
formed in situ by condensation of aldehydes and ammo-
nia, with oxidants such as iodine,4 lead tetraacetate,5 nick-
el peroxide,6 oxygen-copper (II) chloride,7 copper powder
and ammonium chloride8 and tetrabutylammonium per-
oxydisulfate with a nickel copper formate catalyst.9 These
methods involve laborious work-up and so are unsuitable
for generation of large monomer sets of nitriles for chem-
ical library preparation. We reasoned that transferral to an
immobilised system, via the application of solid support-
ed reagents, could lead to a more efficient and cleaner
route to these important starting materials.
The immobilised hydrazine 1 was reacted with various al-
dehydes to give the hydrazones which underwent reac-
tions with 3-chloroperbenzoic acid14 (mCPBA) to give the
N-oxide which eliminates to form the corresponding ni-
triles.15 In order to obtain clean products it was found nec-
essary to use an excess of mCPBA and then scavenge any
unreacted oxidant by the addition of polyvinylpyridine.
This process could be carried out sequentially by removal
of the spent hydrazine resin, followed by addition of poly-
vinylpyridine. Alternatively, since the spent hydrazine
resin cannot be recycled, the polyvinylpyridine could be
added directly to the reaction mixture after oxidation, and
both simultaneously removed by filtration. A final wash
of the filtrate with aqueous bicarbonate ensured complete
removal of 3-chlorobenzoic acid.
Following the general procedure, as described in the foot-
note,16 a small collection of nitriles was prepared in paral-
lel (Table). In all the reactions, except entries 5 and 6,
which contained over-oxidation impurities, the nitriles
were obtained in greater than 95% purity as determined by
1H NMR.
We have previously demonstrated the application of poly-
mer-supported reagents to the smooth, clean and high
yielding conversion of alcohols to aldehydes.10 Conse-
quently a process that would perform a secondary trans-
formation to the nitrile would allow access to many
previously unknown components (Scheme).
The reaction conditions are sufficiently mild to be used on
molecules without removing protecting groups such as
TBS (entries 12 and 14). Chiral aldehydes (13 and 14)
were also converted to nitriles without the loss of optical
purity. The range of aldehydes investigated included aro-
matic (1, 7 and 8), substituted aromatic (2 and 9), hetero-
cyclic (5, 6, 10 and 11) and aliphatic (3 and 4) aldehydes.
While electron-withdrawing substituents such as a nitro
group on an aromatic aldehyde reduced the yield, as might
be expected from the mechanism of the reaction, the iso-
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0775,0777,ftx,en;D02002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214