SbCl5-wet acetonitrile: A new system for chemoselective O-desilylation

Article abstract of DOI:10.1016/j.tetlet.2003.09.191

A new efficient method for deprotection of TBDMS derivatives of phenols, primary alcohols, carboxylic acids and secondary amines, consisting of SbCl ₅ and MeCN with 0.1% water (w/v), is reported. It effects inter alia desilylation of a CH₂OTBDMS group in the presence of a ketal function.

Full text of DOI:10.1016/j.tetlet.2003.09.191

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8819–8821
SbCl5–wet acetonitrile: a new system for chemoselective
O-desilylation
Paulo M. C. Glo´ria, Sundaresan Prabhakar,* Ana M. Lobo* and Ma´rio J. S. Gomes (in part)
Secc¸a˜o de Qu´ımica Orgaˆnica Aplicada, Departamento de Qu´ımica, CQFB-REQUIMTE and SINTOR-UNINOVA,
campus FCT-UNL, Quinta da Torre, 2829 Monte de Caparica, Portugal
Received 8 August 2003; revised 17 September 2003; accepted 23 September 2003
Abstract—A new efficient method for deprotection of TBDMS derivatives of phenols, primary alcohols, carboxylic acids and
secondary amines, consisting of SbCl5 and MeCN with 0.1% water (w/v), is reported. It effects inter alia desilylation of a
CH2OTBDMS group in the presence of a ketal function.
© 2003 Elsevier Ltd. All rights reserved.
The application of silyl groups as protecting groups for
O, N, S, etc., in synthesis is well known.1 Since its
introduction to organic chemistry by Corey,2 one such
group namely, the t-butyldimethylsilyl group (TBDMS)
has occupied a privileged position. Its popularity, espe-
cially with respect to O-protection, is undoubtedly due
to its enhanced stability in basic and mildly acidic
conditions, compared with other common silicon-based
analogues, and the mildness of conditions under which
it can be removed. In connection with our current
studies on the synthesis of heterocyclic compounds, an
attempted desilylation of substance 1, and other struc-
turally related compounds,3 with a variety of F− ion
sources in THF led to intractable mixtures. However, a
solution of 1 in wet acetonitrile, 0.1% water (w/v), on
treatment with a sub-stoichiometric quantity of SbCl5
(0.1 equiv.) cleanly afforded the nitrone 1a in good
yield (Eq. (1)).
system brings about an efficient deprotection of
TBDMS derivatives of phenols, primary alcohols, car-
boxylic acids, and primary and secondary amines in
good to excellent yields.5
The different rates of desilylation observed (Table 1;
entries 1, 2, 3 and 4) prompted us to examine the
existence if any, of substrate selectivity in a mixture
consisting of different silyl ethers. With this end in
view, an equimolar mixture (0.06 M) of 3, 4 and 5 in
wet acetonitrile (0.1% H2O) was exposed, in a competi-
tive reaction, to the action of SbCl5 (0.1 equiv.) at rt
and the following results were obtained (Eq. (2)).
(1)
(2)
This observation led us to examine the scope of this
reaction for the deprotection of other silylated com-
pounds.4 Our results (Table 1) show that the same
* Corresponding author. Tel.: +351-21-2948300; fax: +351-21-
2948550; e-mail: sprabhakar@fct.unl.pt
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.191

8820
P. M. C. Glo´ria et al. / Tetrahedron Letters 44 (2003) 8819–8821
Thus, whilst no discrimination was observed in the
cleavage between the phenolic and the alcoholic
TBDMS groups in 3 (Eq. (2)), high chemoselectivity
was noted for the p-nitro silyl ester 5 in the presence of
the p-nitro silyl ether 4 (Eq. (3)). A similar rate differ-
ence noted for the TBDMS derivatives of p-bromo and
p-nitro phenols, 2 and 4 respectively, was again
reflected in the preferential conversion of 2 into 2a (Eq.
(4)). However, no such selectivity was observed between
the silyl ester of benzoic acid 9 and its p-nitro derivative
5 (Eq. (5)).
(6)
(7)
A similar selectivity in favour of desilylation was also
observed in a competition experiment involving the
ketal-ester 13 and the phenolic OTBDMS ether 2 as
shown in Eq. (8).
(3)
(4)
(8)
In principle these reactions could be yet another
example7 of a simple protic acid catalysed process (i.e.
HCl generated in situ from SbCl5 and the water present
in MeCN) (Eq. (9)).
(5)
(9)
In experiments involving substances 10, 11 and 12, all
of which contained both ketal and O-TBDMS groups,
it is the latter that are selectively deprotected to provide
the corresponding primary alcohols 10a, 11a and 12a in
excellent yields6 (Eq. (6) and (7)).
That water is clearly implicated in these reactions is
supported by the observation that they became progres-
sively slower as the water content in the acetonitrile was
reduced by successive distillations from CaH2 and P2O5.
In spite of similar readings by a pH meter8 for both a
solution of SbCl5 (6×10−3 M) in MeCN containing 0.1%
water and a 0.265 M solution of HCl in the same
solvent system, the OTBDMS cleavage in 10 with aq.
HCl occurred non-selectively (Eq. (6)). A similar result
was observed for the competition process shown in Eq.
(2). Instead only glycerol, in the former, and a mixture
of varying proportions of 3a, 4a and 5a, in the latter,
were obtained. On the basis of these observations the
following mechanism involving an Sb(V) intermediate
of type 14 for the O-desilylation9 of 10 is suggested (the
precise number of OH groups attached to Sb(V)
remains undetermined) (Scheme 1).
Table 1. Silyl compounds deprotected by SbCl5/MeCN
(0.1% H2O) at rt
Entry Silyl compound
Product
Time
Yield (%)
p-R1-C6H4-R2
p-R1-C6H4-R2
1
2
2 R1=OTBDMS
R2=Br
2a R1=OH
R2=Br
15 min
10 min
93
92
3 R1=OTBDMS
3a R1=OH
R2
R2
=(CH2)2OTBDMS
4 R1=OTBDMS
R2=NO2
=(CH2)2OH
4a R1=OH
R2=NO2
3
4
5
6
31 h
94
5 R1=CO2TBDMS
R2=NO2
5a R1=CO2H 40 min
R2=NO2
85
6 R1=NHTBDMS
6a R1=NH2ae 5 min
62a
72a
In conclusion, SbCl5, in sub-stoichiometric quantity, in
moist acetonitrile, is introduced as an efficient and mild
system for the deprotection of TBDMS derivatives of
amines, phenols, primary alcohols and aryl carboxylic
acids in good to excellent yields. High selectivity for
OTBDMS cleavage is noted in the presence of a ketal
group. A similar discrimination was observed for aryl
R2=CH3
R2=CH3
7
7a
5 min
R1=CH2NHTBDMS R1=CH2NH2
R2=H
R2=H
8a (CH2)5NH 5 min
7
8 (CH2)5NTBDMS
75a
a Estimated by 1H NMR.

P. M. C. Glo´ria et al. / Tetrahedron Letters 44 (2003) 8819–8821
8821
3. Gomes, M. J. S.; Sharma, L.; Prabhakar, S.; Lobo, A. M.;
Glo´ria, P. M. C. Chem. Commun. 2002, 746–747.
4. All silylated substances in Table 1 are known compounds
and were prepared from the corresponding commercially
available precursors by the method of Corey.2
5. These results were presented at the 5th National Meeting
of Organic Chemistry and 1st Portuguese–Japanese Chem-
ical Symposium, held in Aveiro, Portugal (July 2003).
6. Typical experimental procedure: To a stirred solution of
commercial (Aldrich) 5-O-(tert-butyldimethylsilyl)-2,3-O-
Scheme 1. Proposed activation of 10 for the selective O-desi-
lylation.
isopropylidine-D-ribonic acid 12 (25 mg, 0.06 M, 1 equiv.)
in acetonitrile [1.4 ml, 0.1% water (w/v)] was added (0.213
ml, 0.1 equiv.) of SbCl5 (freshly distilled; 0.039 M in
MeCN), under an atmosphere of nitrogen at room temper-
ature. On completion of the reaction (10 min., TLC con-
trol; AcOEt) the product 12a was isolated by evaporating
the solvent under reduced pressure and purifying the
silyl carboxylates and aryl silyl ethers providing the
latter carries a p-nitro substituent. The method was also
found to be useful for the clean O-deprotection of
N-silyloxy-N-allyl-N-vinyl enamines, a class of com-
pounds which led to an array of products with conven-
tional F− ion based desilylating reagents.
resulting residue by PTLC. 2,3-O-Isopropylidene-D-
ribonic g-lactone 12a was obtained in 85% yield as a
colourless solid; mp 136–138°C (lit., 135–139°C); this pos-
sessed spectral data identical with those of the starting
material. See: Beilstein, F. K. Beilstein Handbuch der
Organischen Chemie, 19, IV, Springer: Berlin, 1972; pp.
5144.
Acknowledgements
We thank Fundac¸a˜o para a Cieˆncia e a Tecnologia
(FC&T, Lisbon, Portugal) for partial financial support
(Project POCTI/QUI/36456) and Dr. S. N. Swami
(Pfizer, Sandwich, UK) for the interest shown. Two of
us (P.M.C.G. and M.J.S.G.) are also grateful for the
award of doctoral fellowships.
7. For desilylation, by HI generated in situ from I2/MeOH,
by HCl from TMSCl/H2O, and by HBr from n-Bu4N+
Br3−/MeOH, see, respectively: (a) Lipshutz, B. H.; Keith,
J. Tetrahedron Lett. 1998, 39, 2495–2498; (b) Grieco P. A.;
Markworth, C. J. Tetrahedron Lett. 1999, 40, 665–666; (c)
Gopinath, R.; Patel B. K. Org. Lett. 2000, 26, 4177–4180.
8. Readings obtained using a Schott pH meter with a Schott
Gerate N 65 electrode: for the Sb(V) system, −1.13; for a
HCl solution (0.265 M) in the same solvent system, −1.12.
9. The considerable rate difference observed for the TBDMS
ethers of p-bromophenol (15 min) and p-nitrophenol (31
h) is consistent with the suggested mechanism. Ease of
prior coordination of the Sb(V) species with the oxygen
lone-pair for the cleavage to occur becomes less favoured
when an EWG group such as NO2 is present at the para
position.
References
1. White, J. D.; Carter, R. G. In Science of Synthesis-
Houben-Weyl Methods of Molecular Transformations;
Fleming, I., Ed.; Thieme: New York, 2001; Vol. 4, Chap-
ter 17, p. 371.
2. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190–6191.