LETTER
1575
Indium as a Reducing Agent: Deprotection of 4-Nitrobenzyl Ethers and Esters
Christopher J. Moody, Michael R. Pitts
School of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
Fax: 01392 263434; E-mail: c.j.moody@exeter.ac.uk
Received 5 August 1999
involves filtration, and acidification, before extraction
Abstract: Indium in aqueous ethanolic ammonium chloride is an
into organic solvent.7 The acidification is usually to low
pH, but neutralisation of the aqueous layer is sufficient for
effective method for the deprotection of 4-nitrobenzyl ethers and es-
ters.
basic substrates or acid sensitive materials. The recovered
Key words: indium, nitro group reduction, deprotection
substance requires little or no further purification, the 4-
toluidine by-product being washed out into the aqueous
layer. The results are shown in Table 1.
Indium metal has found a few uses in organic chemistry
of late, most notably in the generation of synthetically
useful allylindium species.1,2 However, the first ionisation
potential of indium (5.8 eV),1 which is lower than zinc
(9.4 eV) or tin (7.3 eV) and close to that of alkali metals
such as sodium (5.1 eV), suggests that the metal ought to
be a potent reducing agent. In this context we have recent-
ly reported that indium is a useful reagent for the reduc-
tion of aromatic nitro groups,3 and for the reduction of the
heterocyclic ring in quinolines, isoquinolines, and qui-
noxalines.4 We now report the use of indium metal in the
deprotection of 4-nitrobenzyl ethers and esters.
The 4-nitrobenzyl protecting group has seen use in the
protection of alcohols, thiols, amines (as the 4-nitrobenzyl
carbamates), and carboxylic acids.5,6 For example, 4-ni-
trobenzyl esters are much more stable to acidic hydrolysis
than other benzyl esters, and are recommended for
glutamic acid and aspartic acid side chain protection in
solid-phase peptide synthesis. Such protecting groups
have also seen extensive use in the b-lactam field. Meth-
ods of deprotection include: Na2S or Na2S2O4 reduction,
catalytic hydrogenolysis, TBAF, or oxidative cleavage
with alkaline hydrogen peroxide. Electrochemical meth-
ods have also been used, especially for the unmasking of
alcohols, either direct electrolytic reduction, or oxidative
All substrates were cleaved in good yield, and benzyl car-
electrolysis following initial chemical reduction of the ni-
bamates and benzyl ethers remained intact, demonstrating
tro group. Despite the undoubted usefulness of the 4-ni-
the selectivity of the reaction. Other functional groups
trobenzyl protecting group, many of the methods of
were also unaffected by the conditions; thus carbonyl
deprotection have drawbacks in that they are not compat-
groups (in the form of aldehydes and ketones), and chlo-
ible with the presence of other functionalities or protect-
rides were not reduced, and in the case of 6-(4-nitroben-
ing groups. Therefore we investigated the use of indium
zyloxy)quinoline, the protecting group was removed
metal as a mild method for nitro group reduction with con-
faster than the reduction of the heterocyclic ring. These re-
comitant cleavage of the benzylic C-O bond.
sults further demonstrate the utility of metallic indium as
A range of alcohols, phenols and carboxylic acids were
a reducing agent in organic synthesis.
protected as their 4-nitrobenzyl ethers or esters using stan-
dard methodology. On treatment with indium metal, the
Acknowledgement
nitro group is reduced, and the benzylic C-O bond is
cleaved to liberate the deprotected compound and form 4-
toluidine as the by-product. The method is simple to ef-
fect: the substrate is simply heated in the presence of indi-
um and ammonium chloride in aqueous ethanol. Work-up
We thank Dr Alison Franklin for helpful discussions, and the
EPSRC for support of this work.
Synlett 1999, No. 10, 1575–1576 ISSN 0936-5214 © Thieme Stuttgart · New York