COMMUNICATION
Mild water-promoted selective deacetalisatison of acyclic acetals†
D. Bradley G. Williams,* Adam Cullen, Alex Fourie, Hendrik Henning, Michelle Lawton, Wayne Mommsen,
Portia Nangu, Jonathan Parker and Alicia Renison
Received 1st July 2010, Accepted 15th September 2010
DOI: 10.1039/c0gc00280a
Table 1 Deprotection of acetalsa
Various aliphatic and aromatic dimethyl and diethyl acetals
and ketals were found to hydrolyse in essentially quantita-
Yield (%)b
tive yield when heated to 80 ◦C in neat water or aqueous
c
Substrate
Product
M(OTf)3
100
Hf(OTf)4
100
No cat.
97
medium without a catalyst or any other additive, while
cyclic acetals were stable under these conditions. Selective
deprotection is possible when both types of acetal are
present.
5a
Introduction
5b
100
100
100
75 (100)d
One of the most successful carbonyl protecting strategies is
to make use of acetals and ketals.1 These entities are usually
prepared by reaction of the aldehyde or ketone with an alcohol or
diol in the presence of a drying agent2 or by transacetalisation,3
together with an acid catalyst which may be a Lewis acid such
as Al(OTf)3 as we have recently shown.4 Acetals have varying
stabilities; the cyclic species are usually more stable than the
acyclic analogs thereof, generating some preference for the cyclic
over the acyclic acetals. Despite these reactivity differences, the
literature is replete of examples of the use of acyclic acetals as
protecting groups.1
10a
100d
100d
a 12.5 mmol acetal, 15 mL deionised water, 5 mol% M(OTf)x, 25 ◦C, 1 h.
b Yields refer to isolated products. c M = Al, In, Sc. d Reaction performed
at 80 ◦C.
Deprotection strategies for such acetals vary in their mildness
and include, amongst many others, aqueous formic acid5 and
p-toluenesulfonic acid in acetone.1 Super heated water (180 ◦C,
10 bar pressure) in the presence of CaCl2 has also been used for
acetal deprotections.6 What appears not to be known, and what
we disclose in the present manuscript, is that many acetals depro-
tect spontaneously and rapidly when mixed with neat water at
80 ◦C and in some cases at ambient temperature, as will become
clear. This finding is remarkable given the obvious advantages
it holds over other solvent-based acid-catalysed acetal depro-
tection methods. Our initial work performed when pursuing
these investigations made use of tetrahydrofuran/water (4 : 1)
mixtures but it was soon established that the use of the organic
solvent was unnecessary in most instances.
Scheme 1 Hydrolysis of acetals. 1a, 2a, 3a, 4a, 5a: R = 4-MeO-C6H4;
1b, 2b, 3b, 4b, 5b: R = C6H5; 1c, 2c, 3c, 4c, 5c: R = 2-MeO-C6H4; 1d, 2d,
3d, 4d, 5d: R = 2-NO2-C6H4; 1e, 2e, 3e, 4e, 5e: R = 2-HO-C6H4; 1f, 2f,
3f, 4f, 5f: R = C6H5CH CH; 1g,2g, 3g, 4g, 5g: R = n-C5H11; 1h, 2h, 3h,
4h, 5h: R = n-C9H19.
As an extension of our previous work on acetals,4 we
investigated the deprotection of a range of acetals and ketals
(Schemes 1 and 2) in neat deionised water (pH 6.4) with
various metal triflates (Table 1).7 In all catalysed cases (Table 1),
the free aldehydes were isolated in quantitative yield after
one hour reactions at ambient temperature (for the nitrobenzene
derivative the reaction was performed at 80 ◦C since the substrate
Scheme 2 Hydrolysis of ketals. 6a, 7a, 8a, 9a, 10a: R = 4-NO2-C6H4;
6b, 7b, 8b, 9b, 10b: R = C6H5; 6c, 7c, 8c, 9c, 10c: R = 2-naphthyl.
is solid at ambient temperature).‡ As a control experiment
to assess the rate of background spontaneous hydrolysis, the
metal triflates were altogether omitted and, astonishingly, the
aldehydes and ketones were isolated in excellent yield also within
one hour!
Research Centre for Synthesis and Catalysis, Department of Chemistry,
University of Johannesburg, P.O. Box 524, Auckland Park, 2006, South
Africa. E-mail: bwilliams@uj.ac.za
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, analytical data, copies of NMR spectra. See DOI:
10.1039/c0gc00280a
To elaborate the scope of the catalyst-free reaction, a range
of aromatic and aliphatic acetals and ketals was subjected
to these simple deprotection conditions (Table 2). For ease
of experimental set-up, and to avoid problems with solid
substrates, all subsequent reactions were performed at 80 ◦C
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The Royal Society of Chemistry 2010
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