LETTER
675
Catalytic Polymer-Supported Potassium Thiophenolate in Methanol as a
Method for the Removal of Ester, Amide, and Thioacetate Protecting Groups
Method for the
R
a
emoval of
Ester,
A
mid
h
e, and
T
hioa
e
cetate Prote
l
cting
G
roupsN. MacCoss,a Dara J. Henry,a Christopher T. Brain,b Steven V. Ley*a
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
E-mail: svl1000@cam.ac.uk
b
Novartis Institute for Medical Sciences, 5 Gower Place, London, WC1E 6BS, UK
Received 22 November 2003
drying the combined washings in vacuo. Neither column
chromatography nor aqueous work-up is necessary to
afford clean products.
Abstract: Polymer-supported potassium thiophenolate to remove
ester, activated amide, and thioacetate protecting groups catalytical-
ly in the presence of methanol is reported.
Initially, this procedure was solely devised for the remov-
al of pivaloate groups protecting indoles as demonstrated
with indole 2 (Table 1). We also observed that when this
procedure was applied to indole 4, the indole was de-
protected while the pivaloate on the amide remained
untouched.
Key words: polymer-supported, thiophenolate, deprotection
Hydroxyl, amino, and thiol groups are frequently protect-
ed as esters, amides, and thioacetates, respectively.1 Typ-
ically, these functional groups are deprotected under
either strongly acidic or basic conditions. In this work, we
report a procedurally simple approach using catalytic
polymer-supported potassium thiophenolate2 1 for the
removal of these protecting groups (Scheme 1).
We have since discovered, that polymer-supported potas-
sium thiophenolate 1 can also remove pivaloate groups
from other compounds (Table 1). For example, activated
aniline 6 was deprotected in good yield, while the resin
was ineffective without the nitro group present. The
deprotection of phenols 8 and 10 occurred in essentially
quantitative yield. For some reason, the primary alcohol
13 was obtained after deprotection of pivaloate-protected
alcohol 12 at a more elevated temperature and in only a
modest yield of 50%.
O
R2NH
R2N
R1
R2
(cat.)
S K
O
O
1
ROH
RSH
RO
RS
MeOH/THF
It was determined that this general deprotection protocol
could also be applied for the removal of benzoyl groups.
This was demonstrated with tri-deprotection to produce
methyl-a-D-galactopyranoside (15) as shown in Table 2.
A benzoate group was also removed from phenyl
benzoate 16.
R1 = CH3, t-Bu
R2 = CH3, t-Bu, Ph, Ot-Bu
Scheme 1 Removal of ester, amide, and thioacetate protecting
This procedure was also used for the removal of acetates
and carbonates catalytically (Table 2). Phenyl acetate 17
and acyl-protected indole 18 were both deprotected in ex-
cellent yield. The acetate was also removed from the C2
hydroxyl of mannopyranoside 20 without affecting the
anomeric group or the benzyl protecting groups. The
thiophenolate resin 1 was also employed to deprotect both
carbonate-protected phenols, 22 and 23. Sulfonyl groups
could be removed from indoles, but remained stable when
associated with other amines.
groups using thiophenolate resin catalytically
Advantages of utilizing polymer-supported reagents3 are
their compatibility with reaction monitoring with conven-
tional solution-phase methods like TLC, NMR, HPLC,
and LCMS, and ease of work-up by filtration without the
necessity for aqueous extractions. Additionally, these
methods can be used with design of experiments (DoE) or
principal component analysis (PCA) software to rapidly
optimize reaction processes.4
As esters and amides could be removed from oxygen- and
nitrogen-containing functionalities with this procedure,
we investigated protected thiols, as described in solution
by Wallace et al.8 Phenyl thioacetate 27 was deprotected
in 94% yield at room temperature in 2.5 hours. Similarly,
primary thiol 30 was obtained in excellent yield.
The facile method5 described in this paper required stir-
ring a catalytic amount of thiophenolate resin6 1 with the
protected compound in a 1:1 mixture of THF and either
methanol or ethylene glycol. When the deprotection is
complete, the resin can be removed by filtration and
washed with THF. The product7 can then be obtained by
In order to study the mechanism of this reaction, various
experiments were performed. Thiophenol resin itself
failed while thiophenolate resin 1 was only effective in the
presence of a proton source, such as methanol. Addition-
SYNLETT 2004, No. 4, pp 0675–0678
Advanced online publication: 17.02.2004
DOI: 10.1055/s-2004-817786; Art ID: D27903ST
© Georg Thieme Verlag Stuttgart · New York
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