Mild water-promoted selective deacetalisatison of acyclic acetals

Article abstract of DOI:10.1039/c0gc00280a

Various aliphatic and aromatic dimethyl and diethyl acetals and ketals were found to hydrolyse in essentially quantitative yield when heated to 80 °C in neat water or aqueous 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. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0gc00280a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
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
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1919–1921 | 1919
©

View Article Online
Table 2 Hydrolysis of acetals in watera
excellent hydrolyses (Table 2, entries 24, 25, 28, 29). In the case
of the 2-nitrobenzaldehyde derivatives (Table 2, entries 13–16;
compare with the 2-OMe analog results in entries 9–12), the
lack of reactivity can be explained by the electron-withdrawing
effect of the 2-nitro group which would destabilise cationic
intermediates presumably formed during the hydrolysis.9 4-
Nitroacetophenone derivatives (Table 2, entries 32–33) were not
plagued by this lack of reactivity, possibly because of a reduction
in the electron-withdrawing inductive and field effects10 due
to the remoteness of the electron-withdrawing group from the
active site of the acetal. Such a reduction in the net effect of
the nitro group would pose less of a destabilising influence
of that group on cationic intermediates. In the case of the
acetals of cinnamaldehyde (Table 2, entries 19–21), three of
the acetal substrates were so reactive that the hydrolyses could
be performed at ambient temperature. The particular reactivity
presumably arises as a direct consequence of the presence of
the alkene which would act to resonance stabilise the cationic
intermediates usually expected of the standard acetal hydrolysis
mechanism (SN1-type).8
It is clear from Table 2 that the cyclic acetals of all substrates
but one, namely of cinnamaldehyde, were resistant to hydrolysis
under these conditions, mostly giving negligible hydrolysis. This
particular observation leads to the useful insight that cyclic
and acyclic acetals may be differentially deprotected simply by
heating the substrate in water to remove the acyclic acetal (OMe
and OEt acetal types in Table 2) under these mild conditions
while retaining the cyclic protecting group.
Such selective deprotection was shown with substrates 1111
and 13 where only the acyclic acetal in the system spontaneously
hydrolysed while the cyclic protecting group was retained intact
in both cases (Scheme 3). Here, neat water failed to effect
the desired hydrolysis but the addition of 20% THF to the
aqueous mixture readily facilitated the deprotection reaction
in essentially quantitative yield. It is clear from this example
that the new finding holds significant potential, especially for
otherwise acid- and base-sensitive protecting groups.
Entry
Substrate: acetal typeb
Product
Yield (%)c
1
2
3
4
5
6
7
8
1a: OMe
2a: OE
3a: EG
4a: PG
1b: OMe
2b: OEt
3b: EG
4b: PG
1c: OMe
2c: OEt
3c: EG
4c: PG
1d: OMe
2d: OEt
3d: EG
4d: PG
1e: OMe
2e: OEt
4e: PG
5a
97
5a
100
<5d
0d
100
100
<5d
0d
5a
5a
5b
5b
5b
5b
9
5c
93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
5c
100
5c
0d
5c
0d
5d
<5d
<5d
<5d
0d
5d
5d
5d
5e
97
5e
95
5e
0d
1f: OMe
2f: OEt
3f: EG
5f
100e
100e
100e
17d
5f
5f
4f: PG
5f
1g: OMe
2g: OEt
3g: EG
4g: PG
1h: OMe
2h: OEt
3h: EG
4h: PG
6a: OMe
7a: OEt
8a: EG
9a: PG
6b: OMe
7b: OEt
8b: EG
9b: PG
6c: OMe
7c: OEt
8c: EG
9c: PG
5g
100f
100f
0d,f
5g
5g
5g
0d,f
5h
100f
100f
0d,f
5h
5h
5h
0d,f
10a
10a
10a
10a
10b
10b
10b
10b
10c
10c
10c
10c
100 (50)g
98 (7)g
0d
0d
100
100
5d
0d
100 (<5)g
100 (10)g
<5d
0d
a 12.5 mmol acetal, 15 mL deionised water, 80 ◦C, 2 h. b OMe = dimethyl
acetal; OEt = diethyl acetal; EG = acetal of 1,2-ethanediol (ethylene
glycol); PG = acetal of 3,3-dimethyl-1,3-propanediol (propylene glycol).
c Yields refer to isolated products. d 24 h reaction. e rt, 2 h. f 10 : 4 : 1
Et2O/THF/H2O, 8 bar nitrogen pressure (autoclave reactor), 80 ◦C.
g rt, 24 h.
(in a few instances room temperature comparisons are given).
With the exception of the 2-nitrobenzaldehyde derivatives and
the aliphatic acetals (Table 2, entries 13–16, 24–31), all methyl
and ethyl acetals tested were susceptible to virtually complete
hydrolysis in neat water at 80 ◦C. The aliphatic acetals (Table 2,
entries 24–31) were rather resistant to hydrolysis even after
extended periods of reaction at elevated temperature, most
probably as a result of their hydrophobicity. Such rate-retarding
effects are well-known in biphasic hydroformylation reactions
with alkenes of varying chain lengths reacting at widely different
rates, if negligibly for longer chain substrates. This reflects
their solubility in the aqueous medium.8 The use of THF/H2O
mixtures failed to improve the outcomes but Et2O/THF/H2O
mixtures contained in stainless steel reactors (to contain the
volatile solvents) at 80 ◦C under 8 bar nitrogen pressure afforded
Scheme 3 Selective hydrolysis of acyclic acetals.
Conclusions
This paper highlights the facile uncatalysed deprotection of
dimethyl and diethyl acetals in neat water under mild conditions.
Under identical conditions, cyclic acetals are found to be stable
and only starting materials are recovered. This differential reac-
tivity enables easy discrimination between the deprotection of
1920 | Green Chem., 2010, 12, 1919–1921
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
cyclic and acyclic acetals. This allowed the exclusive deprotection
of an acyclic acetal leaving the cyclic counterpart intact.
PTFE liner which was then placed inside the pressure vessel. The relevant
aqueous solvent mixture as indicated in the main text of this manuscript
was added to the acetal and the pressure vessel sealed and pressurised
with nitrogen from a high pressure cylinder. The vessels was heated in
an oil bath to the temperature and for the time indicated in the main text
of this article. At the end of the reaction the pressure vessel was cooled
and de-pressurised inside a fume hood. The reaction contents were then
treated as usual (see above) to isolate the products.
Acknowledgements
We thank the University of Johannesburg for financial support.
1 P. G. W. Wuts and T. W. Greene, Protective Groups in Organic
Synthesis, 4th edn, Wiley-Interscience, Hoboken, New Jersey, 2007,
ch. 4.
2 D. Crich, W. Cai and Z. Dai, J. Org. Chem., 2000, 65, 1291.
3 D. R. McPhail, J. R. Lee and B. Fraser-Reid, J. Am. Chem. Soc.,
1992, 112, 1905.
4 D. B. G. Williams and M. Lawton, Green Chem., 2008, 10, 914.
5 P. Maunder, P. M. Finglas, A. I. Mallet, F. A. Mellon, M. A.
Razzaque, B. Ridge, L. Vahteristo and C. Wittho¨ft, C., J. Chem.
Soc., Perkin Trans. 1, 1999, 1311.
6 K. Sato, T. Kishimoto, M. Morimoto, H. Saimoto and Y. Shigemasa,
Tetrahedron Lett., 2003, 44, 8623.
7 B. T. Gregg, K. C. Golden and J. F. Quinn, J. Org. Chem., 2007, 72,
5890.
8 R. M. Deshpande, Purwanto, H. Delmas and R. V. Chaudhari, Ind.
Eng. Chem. Res., 1996, 35, 3927.
9 MM. Kreevoy and R. W. Taft, Jr., J. Am. Chem. Soc., 1955, 77, 3146;
M. M. Kreevoy and R. W. Taft, Tr, J. Am. Chem. Soc., 1955, 77,
5590.
Notes and references
‡ Typical experimental procedure for the hydrolysis of acetals. The
reactions were performed in neat deionised water unless otherwise
indicated. No special precautions were taken to exclude oxygen and
standard round bottomed flasks were used. To 12.5 mmol of the acetal
were added 15 mL of deionised water. The reaction vessel was heated
to 80 ◦C for the determined period of time after which the water was
simply removed by evaporation thereof. Alternatively, diethyl ether (3 ¥
5 mL) could be used with which to extract the organic material from the
aqueous layer. The organic phase was dried with anhydrous magnesium
sulfate and the volatile component removed under vacuum. In all cases
the products were isolated directly in >98% purity as determined by
1H NMR and GC analyses without further need for purification. The
aldehyde or ketone products were compared spectroscopically with their
commercially available counterparts.
In instances where the reactions were performed under pressure, stainless
steel autoclaves fitted with a PTFE liner, a pressure gauge, filler fitting
with a tap valve (needle type) and pressure relief safety device were used
(caution: high pressure reactions should be performed only by suitably
trained personnel who understand the risks involved, making use of
appropriate pressure vessels). The acetal was weighed directly into the
10 J. D. Roberts and W. D. Moreland, Jr., J. Am. Chem. Soc., 1953, 75,
2167.
11 H. Nao, K. Kiyoshi, S. Hisashi and S. Tsuneo, Synlett, 2004, 6, 1074.
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1919–1921 | 1921
©