A highly efficient and useful synthetic protocol for the cleavage of tert-butyldimethylsilyl (TBS) ethers using a catalytic amount of acetyl chloride in dry methanol

Article abstract of DOI:10.1055/s-2003-38360

A wide variety of tert-butyldimethylsilyl (TBS) ethers as well as tert-butyldiphenylsilyl (TBDPS) ethers 1 can be easily deprotected to the corresponding parent hydroxyl compounds 2 by employing catalytic amounts of acetyl chloride in dry MeOH at 0°C to room temperature in good yields. Some of the major advantages are mild conditions, high efficiency, high selectivity, high yields, easy operation, and also compatibility with other protecting groups. Furthermore, no acetylation nor chlorination takes place under the experimental conditions.

Full text of DOI:10.1055/s-2003-38360

694
LETTER
A Highly Efficient and Useful Synthetic Protocol for the Cleavage of
tert-Butyldimethylsilyl (TBS) Ethers Using a Catalytic Amount of Acetyl
Chloride in Dry Methanol
T
he Cleavage of te
b
rt-Butyldime
u
thylsilyl (TBS) T. Khan,* Ejabul Mondal
Department of Chemistry, Indian Institute of Technology, North Guwahati, Guwahati-781039, Assam, India
Fax +91(361)2690762; E-mail: atk@postmark.net
Received 21 January 2003
Consequently, what is needed is a methodology, which
Abstract: A wide variety of tert-butyldimethylsilyl (TBS) ethers as
well as tert-butyldiphenylsilyl (TBDPS) ethers 1 can be easily
deprotected to the corresponding parent hydroxyl compounds 2 by
employing catalytic amounts of acetyl chloride in dry MeOH at
might work under mild conditions by involving economi-
cally cheaper reagents. During the development of new
methodologies for protection and deprotection of organic
0 °C to room temperature in good yields. Some of the major advan- functional groups particularly carbonyl group as dithioac-
etals and oxathioacetals,8 we have observed that acetyl
tages are mild conditions, high efficiency, high selectivity, high
yields, easy operation, and also compatibility with other protecting
chloride in methanol can be used as a source for generat-
groups. Furthermore, no acetylation nor chlorination takes place un-
ing dry hydrochloric acid in situ, which can be utilized for
der the experimental conditions.
protection of various carbonyl compounds as dithioace-
tals or dithioketals.9 This result prompted us to look
Key words: deprotection, tert-butyldimethylsilyl (TBS) ethers,
tert-butyldiphenylsilyl (TBDPS) ethers, acetyl chloride
whether acetyl chloride in combination with methanol can
be used also for deprotection of tert-butyldimethylsilyl
(TBS) ethers or not. In this communication, we would like
Protection-deprotection strategy is a very common tactics
to report our successful results for deprotection of various
in polyfunctional natural product and non-natural product
tert-butyldimethylsilyl (TBS) ethers and tert-butyldiphe-
syntheses. As far as hydroxyl group protection is con-
nylsilyl (TBDPS) ethers by using catalytic amounts of
cerned, silyl ethers play a pivotal role in carbohydrate
acetyl chloride in dry methanol (Scheme 1).
and nucleoside chemistry due to their easy installation and
To verify our assumption, we prepared a wide variety of
inherent stability under basic and mild acidic conditions,
tert-butyldimethylsilyl (TBS) ethers as well as tert-butyl-
with tert-butyldimethylsilyl (TBS) ether1 and tert-butyl-
diphenyl-silyl (TBDPS) ethers by following the reported
diphenylsilyl (TBDPS) ether2 being two of the most im-
procedure.1,2 First, we attempted the reaction of tert-bu-
tyldimethylsilyl ether of 1-octanol (1a) with 0.15 equiva-
lents amounts of acetyl chloride in dry methanol at 0–
portant examples. Though a wide variety of reagents have
been developed3 for their removal, still there is a need to
develop better alternatives, which might work under mild
5 °C. After 5 min, usual work-up of the reaction mixture
conditions. For this purpose, a variety of fluoro
provided the corresponding desired alcohol 2a in 98%
yield. Similarly, tert-butyldimethylsilyl ether of 1-dode-
compounds4 have been developed over the years in order
to facilitate such deprotection. Similarly, deprotection of
canol (1b) was deprotected smoothly to the corresponding
TBS ethers are also known using various bromo com-
alcohols 2b by following identical reaction conditions.10 It
pounds.5 Likewise, some methods have also been devised
is important to mention that no acetylation occurs during
by employing chloro compounds for their cleavage such
the experimental conditions. Next, we observed that vari-
as cerium(III) chloride in combination with sodium io-
ous tert-butyldiphenylsilyl ethers 1c–e can be deprotected
easily to the corresponding alcohols 2c–e in very good
yields, on treatment with 0.15 equivalents amount of
dide,6a cerium(III) chloride,6b LiCl in DMF,6c and TMSCl
in H2O.6d Moreover, a few methods are also reported re-
cently by using TMSOTf,7a Sn(OTf)3,7b I2,7c Oxone in
acetyl chloride in methanol on stirring at room tempera-
aqueous methanol,7d and DDQ.7e Unfortunately, some of
ture. We have noticed that it requires relatively longer re-
the methods mentioned as above have some drawbacks
action times for deprotection of TBDPS ethers than TBS
such as harsh reaction conditions, failure to deprotect aryl
ethers.
tert-butyldimethylsilyl ethers, long reaction times, in-
volvement of expensive reagents, incompatibility with
OP
OH
other protecting groups such as a thio group at the ano-
meric position of the carbohydrate compounds,5f over ox-
idation,7e unwanted product such as acetate instead of
alcohol,5c and requirement a large excess of reagents.6a–c
AcCl / dry MeOH
0–5 °C, r.t.
R1
R2
R1
R2
1
2
R1 = aryl / alkyl / sugar residue / nucleoside
R2 = H / alkyl; P = TBS / TBDPS
Synlett 2003, No. 5, Print: 10 04 2003.
Art Id.1437-2096,E;2003,0,MM,0694,0698,ftx,en;G00703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 1

LETTER
The Cleavage of tert-Butyldimethylsilyl (TBS)
695
Table 1 Deprotection of Various TBS Ethers (1) to the Parent Hydroxyl Compounds (2) Using Catalytic Amounts of CH3COCl in
Dry MeOH
Entry
a
Substrate
Time min (h)
5
Producta
Yieldb (%)
98
97
97
95
96
OTBS
OH
OH
OH
OH
OH
n
n
n = 4
n = 4
b
c
d
e
7
OTBS
n
n
n = 8
n = 8
(2.0)
(4.0)
(2.3)
OTBDPS
OTBDPS
OTBDPS
n
n
n = 4
n = 4
n
n
n = 8
n = 8
n
n
n = 12
n = 12
f
2
2
80
82
AcO
BzO
OTBS
OTBS
AcO
BzO
OH
OH
n
n
n = 3
n = 3
g
n
n
n = 3
n = 3
h
i
5
3
8
87
98
96
BnO
OH
BnO
OTBS
n
n
n = 3
n = 3
MeO2C
OTBS
n
n = 9
MeO2C
OH
n
n = 9
j
O
CH2OTBS
O
CH2OH
k
(5)
95
S
S
S
S
OTBS
OH
l
35
4
85
86
OTBS
OH
OTBDPS
n
O
O
m
TBSO
OTBDPS
HO
n
n = 3
n = 3
n
45
80
TBSO
HO
CH2OH
TBSO
CH2OTBS
OTBS
o
p
7
87
94
TBSO
OH
CH2OH
10
CH2OTBS
q
r
(5)
15
93
89
CH2OTBS
OTBS
CH2OH
OH
s
5
85
O2N
CH2OTBS
O2N
CH2OH
Synlett 2003, No. 5, 694–698 ISSN 0936-5214 © Thieme Stuttgart · New York

696
A. T. Khan, E. Mondal
LETTER
Table 1 Deprotection of Various TBS Ethers (1) to the Parent Hydroxyl Compounds (2) Using Catalytic Amounts of CH3COCl in
Dry MeOH (continued)
Entry
t
Substrate
OTBS
Time min (h)
35
Producta
OH
Yieldb (%)
82
u
(4.0)
90
TBSO
HO
v
8
88
90
OTBS
O
OH
O
BnO
BnO
BnO
SEt
BnO
SEt
BnO
BnO
w
40
OBn
OBn
O
TBSO
O
HO
BnO
BnO
BnO
BnO
OMe
OMe
x
y
40
87
90
OTBS
OH
O
O
O
O
O
O
O
O
O
O
O
(2.5)
O
N
Me
Me
HN
HN
TBSO
HO
O
O
N
O
O
OTBS
OH
z
(1)
95
O
N
O
N
Me
Me
HN
HN
TBSO
HO
O
O
O
O
OAc
OAc
a All final products were characterized by IR, 1H NMR, 13C NMR and elemental analysis.
b Isolated yield.
Various TBS ethers 1f–l were transformed smoothly into (entry 1m and 1n) in the presence of TBDPS ether and
the corresponding alcohols 2f–l in good yields under iden- aryl TBS ether due to reactivity difference. By following
tical reaction conditions. These results show that our pro- the above procedure, TBS ethers 1o and 1p were also
tocol can be employed in the presence of other protecting deprotected into the corresponding compound 2o and 2p
groups such as acetyl, benzoyl, benzyl, ester, allyl and in good yield without chlorination either at the double or
thioketal. Remarkably, a highly acid sensitive group such triple bond. By following our methodology, various TBS
as ester functionality (for instance 1i) remains unaffected ethers 1q–u were transformed into the corresponding
under the reaction conditions. Moreover, a highly acid deprotected alcohols 2q–u in good yields. The results are
sensitive substrate 1l can also be deprotected into the cor- summarized in Table 1 and the structures of the deprotect-
responding hydroxy compound 2l. It is also important to ed products were confirmed by usual spectroscopic tech-
highlight that a TBS ether containing a thioketal group niques and elemental analysis.11 It is pertinent to mention
(entry 1k) might be difficult to cleave by other reported that the deprotection of TBS ether 1u to the corresponding
methods.6d,9 Interestingly, our protocol can be further ex- alcohol 2u required longer reaction times5d than our
tended for chemoselective deprotection of TBS ethers method.
Synlett 2003, No. 5, 694–698 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Cleavage of tert-Butyldimethylsilyl (TBS)
1999, 709. (g) Metcalf, B. W.; Burkhart, J. P.; Jund, K.
Tetrahedron Lett. 1980, 21, 35. (h) Ranu, B. C.; Jana, U.;
Majee, A. Tetrahedron Lett. 1999, 40, 1985.
(5) (a) Lee, A. S.; Yeh, H.; Shie, J. Tetrahedron Lett. 1998, 39,
5249. (b) Bajwa, J. S.; Vivelo, J.; Slade, J.; Repi, O.;
Blacklock, T. Tetrahedron Lett. 2000, 41, 6021.
697
Lastly, we had turned our attention to the deprotection of
various TBS ethers of carbohydrates and nucleosides. The
TBS ethers 1v–x were converted into the respective parent
hydroxy compounds 2v–x in good yields under similar
reaction conditions. Importantly, a thio group at the ano-
meric position is unaffected under the experimental con-
ditions, whereas it is usually affected by the earlier
reported procedure.5f It is also noteworthy to mention that
OMe ether group at the anomeric position as well as high-
ly acid sensitive isopropylidene group did also survive un-
der the reaction conditions. Likewise, the silyl ethers of
nucleosides 1y–z were deprotected smoothly to the parent
nucleosides in good yields. All these hydrolyzed products
(c) Oriyama, T.; Oda, M.; Gono, J.; Koga, G. Tetrahedron
Lett. 1994, 35, 2027. (d) Gopinath, R.; Patel, B. K. Org.
Lett. 2000, 2, 4177. (e) Barros, M. T.; Maycock, C. D.;
Thomassigny, C. Synlett 2001, 1146. (f) Kartha, K. P. R.;
Field, R. A. Synlett 1999, 311.
(6) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.;
Torregiani, E. Synlett 1998, 209. (b) Ankala, S. V.;
Fenteany, G. Tetrahedron Lett. 2002, 43, 4729. (c) Farras,
J.; Serra, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 327.
(d) Grieco, P. A.; Markworth, C. J. Tetrahedron Lett. 1999,
40, 665.
(7) (a) Hunter, R.; Hinz, W.; Richards, P. Tetrahedron Lett.
1999, 40, 3643. (b) Oriyama, T.; Kobayashi, Y.; Noda, K.
Synlett 1998, 1047. (c) Lipshutz, B. H.; Keith, J.
were characterized by H NMR, 13C NMR, elemental
analyses and in full agreement with the expected products.
1
The formation of the product can be rationalized as fol-
lows. We believe that acetyl chloride reacts with methanol
to generate dry hydrochloric acid, which reacts with silyl
ether to provide the parent hydroxy compounds.
Tetrahedron Lett. 1998, 39, 2495. (d) Sabitha, G.; Syamala,
M.; Yadav, J. S. Org. Lett. 1999, 1, 1701. (e) Paterson, I.;
Cowden, C. J.; Rahn, V. S.; Woodrow, M. D. Synlett 1998,
915.
In summary, we have described a new, efficient, and re-
gio- as well as chemoselective protocol for deprotection
of TBS- and TBDPS ethers using a catalytic amount of
acetyl chloride in dry methanol under very mild condi-
tions. The salient features of the present method include:
i) the ease of operations ii) high efficiency iii) mild condi-
tions iv) chemoselectivity, which may be used extensively
in organic synthesis. In addition, the selective deprotec-
tion of alkyl tert-butyldimethylsilyl ether can be possible
in the presence of aryl-tert-butyldimethylsilyl ethers.
Moreover, a wide variety of other protecting groups such
as acetyl, benzyl, benzoyl, thioketals, esters and iso-
propylidene survived under the experimental conditions.
A similar transformation might be possible by using other
acid chlorides, which will be reported in due course.
(8) (a) Mondal, E.; Bose, G.; Khan, A. T. Synlett 2001, 785.
(b) Mondal, E.; Bose, G.; Sahu, P. R.; Khan, A. T. Chem.
Lett. 2001, 1158. (c) Khan, A. T.; Boruwa, J.; Mondal, E.;
Bose, G. Indian J. Chem, Sect. B 2001, 40, 1039.
(d) Mondal, E.; Sahu, P. R.; Bose, G.; Khan, A. T.
Tetrahedron Lett. 2002, 43, 2843. (e) Mondal, E.; Sahu, P.
R.; Khan, A. T. Synlett 2002, 463. (f) Mondal, E.; Sahu, P.
R.; Bose, G.; Khan, A. T. J. Chem. Soc., Perkin Trans. 1
2002, 1026. (g) Khan, A. T.; Mondal, E.; Sahu, P. R.; Islam,
S. Tetrahedron Lett. 2003, 44, 919. (h) Khan, A. T.;
Mondal, E.; Sahu, P. R. Synlett 2003, 377.
(9) Khan, A. T.; Mondal, E. unpublished results.
(10) A Typical Procedure for Deprotection:
To a stirred solution of silylated compound 1 (1 mmol) in dry
MeOH (3 mL) was added AcCl (11 µL, 0.15 mmol) at ice-
bath temperature. The reaction mixture was stirred at ice-
bath temperature or r.t. depending upon the substrate (see
Table 1). After completion of the reaction (monitored by
TLC), CH2Cl2 was added (20 mL), the reaction mixture was
neutralized with 10% NaHCO3 (1 mL) and washed with H2O
(10 mL). Finally, the organic layer was dried (Na2SO4) and
concentrated in vacuo to give a ‘crude’ residue, which was
purified on silica gel column chromatography. The final
desired products were obtained in good to excellent yields.
(11) Spectroscopic data for compound 1i:
Acknowledgment
The authors are thankful to the Department of Science and Techno-
logy (DST), New Delhi for financial support (Grant no.: SP/S1/G-
35/98). E. M. is grateful to CSIR, New Delhi for his Senior Rese-
arch Fellowship. The authors are thankful to Prof. D. N. Buragohain
(Director) for providing institutional facilities and Professor M. K.
Chaudhuri for his encouragements. We are grateful to the referees
valuable comments and suggestions.
1H NMR (CDCl3, 200 MHz): δ = 0.01 [s, 6 H, Si(CH3)2],
0.85 [s, 9 H, SiC(CH3)3], 1.19–1.60 (m, 18 H, -CH2), 2.25 (t,
2 H, J = 7.3 Hz, -CH2CO2CH3), 3.55 (t, 2 H, J = 6.4 Hz,
-CH2OTBS), 3.62 (s, 3 H, CO2CH3). Anal. Calcd for
C19H40O3Si: C, 66.22; H, 11.70. Found: C, 66.01; H, 11.65.
For compound 2i: 1H NMR (CDCl3, 200 MHz): δ = 1.20–
1.70 (m, 18 H, -CH2-), 1.80 (br s, 1 H, OH, D2O
exchangeable), 2.30 (t, 2 H, J = 6.8 Hz, -CH2CO2CH3), 3.63
(t, 2 H, J = 5.9 Hz, -CH2OH), 3.67 (s, 3 H, CO2CH3). Anal.
Calcd for C13H26O3: C, 67.78; H, 11.38. Found: C, 67.52; H,
11.26. For compound 1v: 1H NMR (400 MHz, CDCl3): δ =
0.01 [s, 3 H, Si(CH3)2], 0.02 [s, 3 H, Si(CH3)2], 0.85 [s, 9 H,
SiC(CH3)3], 1.25 (t, 3 H, J = 7.3 Hz, SCH2CH3], 2.63–2.71
(m, 2 H, SCH2CH3), 3.21–3.24 (m, 1 H, H-5), 3.46 (t, 1 H,
J = 9.0 Hz, H-3), 3.56 (t, 1 H, J = 9.3 Hz, H-2), 3.61 (t, 1 H,
J = 9.0 Hz, H-4), 3.75 (dd, 1 H, J = 3.8 Hz, J = 11.2 Hz, H-
6), 3.80 (dd, 1 H, J = 2.0 Hz, J = 11.7 Hz, H-6′), 4.38 (d, 1
H, J = 9.8 Hz, H-1), 4.62 (d, 1 H, J = 10.2 Hz, -OCHPh),
References
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Commun. 1979, 9, 295. (b) Collington, E. W.; Finch, H.;
Smith, I. J. Tetrahedron Lett. 1985, 26, 681. (c)Shimshock,
S. J.; Watermire, R. E.; Deshong, P. J. Am. Chem. Soc. 1991,
113, 8791. (d) Zhang, W.; Robins, M. J. Tetrahedron Lett.
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Synlett 2003, No. 5, 694–698 ISSN 0936-5214 © Thieme Stuttgart · New York

698
A. T. Khan, E. Mondal
LETTER
4.68 (d, 1 H, J = 10.2 Hz, OCHPh), 4.79 (dd, 2 H, J = 4.6 Hz,
J = 10.7 Hz, OCH2Ph), 4.85 (dd, 2 H, J = 4.0 Hz, J = 10.3
Hz, OCH2Ph), 7.19–7.33 (m, 15 H, ArH). 13C NMR: δ =
–5.37, –5.04, 15.19, 18.30, 24.34, 25.89 (3 C), 62.30, 75.06,
75.46, 75.87, 77.68, 80.03, 81.83, 84.40, 86.62, 127.69,
127.81, 127.93, 128.00, 128.29, 128.38, 128.46, 138.09,
138.32, 138.52. Anal. Calcd for C35H48O5SSi: C, 69.04; H,
7.94, S, 5.26. Found: C, 69.35; H, 7.85; S, 5.01. For
compound 2v: 1H NMR (400 MHz, CDCl3): δ = 1.32 (t, 3
H, J = 7.3 Hz, SCH2CH3), 1.95 (br s, 1 H, OH, D2O
exchangeable), 2.71–2.80 (m, 2 H, SCH2CH3), 3.35–3.39
(m, 1 H, H-5), 3.41 (t, 1 H, J = 9.3 Hz, H-3), 3.58 (t, 1 H,
J = 9.3 Hz, H-2), 3.70 (t, 1 H, J = 8.8 Hz, H-4), 3.87 (d, 1 H,
J = 11.5 Hz, -OCHPh), 4.50 (d, 1 H, J = 9.8 Hz, H-1), 4.65
(d, 1 H, J = 11 Hz, -OCHPh), 4.74 (d, 1 H, J = 11 Hz,
OCHPh), 4.86 (d, 2 H, J = 12.4 Hz, -OCH2Ph), 4.89 (d, 1 H,
J = 10.0 Hz, -OCHPh), 4.92 (dd, 2 H, J = 6.8 Hz, J = 11 Hz,
H-6, H-6′), 7.25–7.38 (m, 15 H, ArH). 13C NMR: δ = 15.16,
25.20, 62.15, 75.17, 75.57, 75.74, 75.76, 77.69, 79.27,
81.77, 85.27, 86.47, 127.71, 127.77, 127.89, 127.96, 128.07,
128.29, 128.41, 128.46, 128.52, 137.90 (2 C), 138.41. Anal.
Calcd for C29H34O5S: C, 70.42; H, 6.93, S, 6.48. Found: C,
70.20; H, 6.86; S, 6.24. For compound 1x: 1H NMR
(CDCl3, 300 MHz) δ = 0.07 [s, 6 H, Si(CH3)2], 0.90 [s, 9 H,
SiC(CH3)3], 1.33 [s, 6 H, =C(CH3)2], 1.44 (s, 3 H, =CCH3),
1.54 (s, 3 H, =CCH3), 3.70–3.86 (m, 3 H, H-2, H-3, H-5),
4.30 (dd, 2 H, J = 2.3 Hz, J = 7.2 Hz, H-4, H-6), 4.60 (dd, 1
H, J = 1.6 Hz, J = 7.9 Hz, H-6′), 5.52 (d, 1 H, J = 4.9 Hz, H-
1). Anal. Calcd for C18H34O6Si: C, 57.72; H, 9.15. Found: C,
57.55; H, 9.03. For compound 2x: 1H NMR (CDCl3, 300
MHz): δ = 1.34 [s, 6 H, =C(CH3)2], 1.46 (s, 3 H, =CCH3),
1.54 (s, 3 H, =CCH3), 2.28 (br s, 1 H, OH, D2O exchange-
able), 3.75 (t, 1 H, J = 7.3 Hz, H-4), 3.82–3.90 (m, 2 H, H-2
and H-5), 4.27 (d, 1 H, J = 7.9 Hz, H-3), 4.34 (dd, 1 H,
J = 2.3 Hz, J = 4.9 Hz, H-6), 4.62 (dd, 1 H, J = 2.3 Hz,
J = 7.9 Hz, H-6′), 5.57 (d, 1 H, J = 5.0 Hz, H-1). Anal. Calcd
for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.48; H, 7.69.
Synlett 2003, No. 5, 694–698 ISSN 0936-5214 © Thieme Stuttgart · New York