Selective deprotection of alkyl t-butyldimethylsilyl ethers in the presence of aryl t-butyldimethylsilyl ethers with bismuth bromide

Article abstract of DOI:10.1016/S0040-4039(00)01012-1

Alkyl t-butyldimethylsilyl ethers can be selectively cleaved in the presence of aryl ethers using a catalytic amount of bismuth bromide in wet acetonitrile at ambient temperatures. (C) 2000 Elsevevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01012-1

Tetrahedron Letters 41 (2000) 6021±6024
Selective deprotection of alkyl t-butyldimethylsilyl ethers
in the presence of aryl t-butyldimethylsilyl ethers with
bismuth bromide
Joginder S. Bajwa,* James Vivelo, Joel Slade, Oljan Repic and Thomas Blacklock
Process R&D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, 59 Route 10,
East Hanover, NJ 07936, USA
Received 26 April 2000; accepted 6 June 2000
Abstract
Alkyl t-butyldimethylsilyl ethers can be selectively cleaved in the presence of aryl ethers using a catalytic
amount of bismuth bromide in wet acetonitrile at ambient temperatures. # 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: alkyl ethers; aryl ethers; selective hydrolysis; bismuth bromide; group transformation.
The transformation of an alcohol to its corresponding t-butyldimethylsilyl (TBS) ether has
been a common and useful method1 for protecting the hydroxyl group since its introduction by
Corey2 in 1972. The alkyl TBS ethers are stable towards basic and mildly acidic conditions.1
Although tetra-n-butylammonium ¯uoride is the most common reagent for the cleavage of TBS
ethers, the strong basicity of the ¯uoride anion makes it inappropriate for base-sensitive
substrates.3 There are several other methods for the deprotection of TBS ethers, some of which
include catalytic transfer hydrogenation using Pd,4 reductive cleavage by DIBAL-H,5 ultrasonic
cleavage in MeOH/CCl4,6 DDQ,7 CAN,8 I2,9 K2CO3/EtOH,10 LiCl/DMF/H2O/90ꢀC,11 DMSO/
H2O/90ꢀC,12 CBr4/MeOH/65ꢀC,13 TASF/DMF,14 I2/MeOH,15 TMSCl/MeCN/H2O16 and
Sc(OTf)3.17 However, these methods involve basic, reducing, oxidizing or high-temperature con-
ditions that limit their scope. We report here a mild method for the cleavage of TBS ethers using
a catalytic amount of bismuth bromide18 in wet acetonitrile.
* Corresponding author. E-mail: joginder.bajwa@pharma.novartis.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01012-1

6022
Table 1 contains a few representative examples which demonstrate the mildness of this
procedure. Esters, ethers, sulfonamides and benzyl carbamates are inert under the conditions
employed.
Table 1
Deprotection of TBS ethers with BiBr3 in wet MeCN at room temperature
Since few methods exist for the selective deprotection of alkyl TBS ethers in the presence of
aryl TBS ethers,15 17,19 we also examined the use of the BiBr3 procedure for this purpose.
Initially, the experiment was performed with bis-TBS ether 3, and the reaction was followed by
HPLC (Table 2). It is apparent from the results in Table 2 that the hydrolysis of the alkyl TBS
ether is fast, and the optimum time for the selective hydrolysis of alkyl TBS ether is around 15±30
min. Longer reaction times increase the yield of dideprotected compound 5 at the expense of
mono-TBS ether 4. After 24 hours, dideprotected compound 5 is obtained in 58% yield.
Table 2
Selective deprotection of bis-TBS diethers with BiBr3 in MeCN at room temperature

6023
For the examples illustrated in Table 3, it can be seen that this procedure works well on more
complex substrates as well as those which contain electron-rich aromatic rings. In all cases,
independent of the aryl group and the substitution pattern, monodesilylation of the alkyl TBS
group was observed.
Table 3
Selective deprotection of bis-TBS diethers with BiBr3 in MeCN at room temperature
Recently, Lipshutz15 and Grieco16 have reported on the use of I2/MeOH and TMSCl/H2O/
MeCN, respectively, to e€ect a similar deprotection of an alkyl TBS ether. It was shown15 that HI
generated in situ in the above case might be the species responsible for the hydrolysis of the alkyl
TBS ethers. Also in our case, the hydrolysis may be catalyzed20 by HBr that is generated in situ
from the reaction of bismuth bromide with water.21
ꢁ1†
In summary, the use of bismuth bromide in wet acetonitrile provides a mild and e€ective means
of removing alkyl TBS ethers in the presence of aryl TBS ethers. Bismuth bromide is a bright-
yellow stable solid, readily available commercially and is much easier to handle than iodine or
chlorotrimethylsilane.
Typical experimental procedure: To a solution of bis-TBS ether 3 (3.96 g, 10.0 mmol) in
acetonitrile (25 mL) was added bismuth bromide (0.14 g, 0.31 mmol) followed by the addition of
water (0.46 mL, 25.5 mmol). The reaction mixture was stirred at 22ꢀC, and the progress of the
reaction was monitored by TLC. After 20 min, TLC indicated completion of the reaction. The
reaction mixture was quenched with water. The product was isolated by extraction with ethyl
acetate. The combined organic extracts were washed with water and concentrated in vacuum. The
crude product was puri®ed on silica gel. Elution with hexane:ethyl acetate (20:1) a€orded 2.25 g
(80%) of 4.

6024
References
1. (a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd Ed.; John Wiley & Sons: New York,
1991. (b) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag: New York, 1994.
2. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190±6191.
3. Clark, J. H. Chem. Rev. 1980, 80, 429±452.
4. Cormier, J. F. Tetrahedron Lett. 1991, 32, 187±188.
5. Corey, E. J.; Jones, G. B. J. Org. Chem. 1992, 57, 1028±1029.
6. Lee, A. S.-Y.; Yeh, H.-C.; Tsai, M.-H. Tetrahedron Lett. 1995, 36, 6891±6894.
7. Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc. Perkin Trans. 1 1992, 2997±2998.
8. DuttaGupta, A.; Singh, R.; Singh, V. K. Synlett 1996, 69±71.
9. Vaino, A. R.; Szarek, W. A. J. Chem. Soc., Chem. Commun. 1996, 2351±2352.
10. Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1997, 38, 187±190.
11. Farras, J.; Serra, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 327±330.
12. Maiti, G.; Roy, S. C. Tetrahedron Lett. 1997, 38, 495±498.
13. Lee, A. S.-Y.; Yeh, H.-C.; Shie, J.-J. Tetrahedron Lett. 1998, 39, 5249±5252.
14. Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Co€ey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63,
6436±6437.
15. Lipshutz, B. H.; Keith, J. Tetrahedron Lett. 1998, 39, 2495±2498.
16. Grieco, P. A.; Markworth, C. J. Tetrahedron Lett. 1999, 40, 665±666.
17. Oriyana, T.; Kobayashi, Y.; Noda, K. Synlett 1998, 1047±1048.
18. Commercial bismuth(III) salts are mostly nontoxic and are easy to handle. As a matter of fact, low toxicity of
bismuth has led to various bismuth-based preparations being administered orally for treatment of intestinal
disorders (Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249±267).
19. Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985, 26, 681±684.
20. In a control experiment, treatment of a disilyl ether 3 in CH3CN±H2O with one drop of 48% HBr at rt in <5 min
led to monodeprotected product 4 (93.5%), dideprotected product 5 (5.3%) and unreacted starting material 3
(1.2%). This supports Eq. (1) shown above whereby BiBr3 reacts with water releasing HBr that may well be
e€ecting these selective deprotections. However, the `pH' (water±wet indicator paper) for this BiBr3/CH3CN/H2O
solution is 4±5, whereas that for CH3CN/H2O/HBr is ca. 1. In a separate experiment, a silyl ether (Table 1, entry
1) remained essentially unchanged upon treatment with BiBr3 in anhydrous CH3CN for up to 24 h.
21. The Merck Index, 20th Ed.; Whitehouse Station, NJ, 1996; p. 1303.