t-Butyldiphenylchlorosilane1

t-BuPh2SiCl

[58479-61-1]  · C16H19ClSi  · t-Butyldiphenylchlorosilane  · (MW 274.86)

(reagent for the temporary protection of hydroxy groups as their t-butyldiphenylsilyl ethers; selectivity can be obtained for primary vs. secondary hydroxy groups; other protection (carbonyl, amine, etc.) is also possible;2 deprotection is conveniently effected with fluoride ion, strong acid, or base; the TBDPS ether group is compatible with a large number of organic functional group transformations,1-3 in nucleoside chemistry,1 as well as in numerous examples in which polyfunctional molecules are chemically manipulated4)

Alternate Name: TBDPS-Cl.

Physical Data: colorless liquid, bp 93-95 °C/0.015 mmHg; nD20 1.5680; d 1.057 g cm-3.

Solubility: miscible in most organic solvents.

Form Supplied in: colorless liquid 98%.

Preparative Method: a dry 1 L, three-necked round bottomed flask is equipped with a magnetic stirring bar, a 500 mL equalizing dropping funnel fitted with a rubber septum, a reflux condenser, and nitrogen inlet tube. The flask is flushed with nitrogen, then charged with 127 g (0.5 mol) of diphenyldichlorosilane in 300 mL of redistilled pentane. A solution of t-Butyllithium in pentane (500 mL, 0.55 mol), is transferred under nitrogen pressure to the dropping funnel using a stainless steel, double-tip transfer needle. This solution is slowly added to the contents of the flask and when the addition is complete, the mixture is refluxed 30 h under nitrogen with stirring. The suspension is allowed to cool to rt, the precipitated lithium chloride is rapidly filtered through a pad of Celite, and the latter is washed with 200 mL of pentane. The solvent is removed by evaporation, and the colorless residue is distilled through a short (10 cm), Vigreux column, to give 125-132 g of the colorless title compound.

Handling, Storage, and Precautions: the reagent is stable when protected from moisture and protic solvents. A standard M solution of the reagent can be prepared in anhyd DMF and kept at 0 °C under argon in an amber bottle. Use in a fume hood.

Preparation of t-Butyldiphenylsilyl Ethers and Related Transformations.

A standard protocol1 involves the addition of the reagent (1.1 equiv) to a solution of the alcohol (1 equiv) and Imidazole (2 equiv) in DMF at 0 °C or at room temperature. When silylation is complete, the solution is diluted with water and ether or dichloromethane and the organic layer is processed in the usual way. In some instances the addition of 4-Dimethylaminopyridine (DMAP) can enhance the reaction rate.5,6 Selective protection of the primary hydroxy group in carbohydrate derivatives has been achieved using this reagent and Poly(4-vinylpyridine) in CH2Cl2 or THF in the presence of Hexamethylphosphoric Triamide.7 Enol t-butyldiphenylsilyl ethers are easily formed by trapping of enolates with the chloride.8 Amines can be selectively converted into the corresponding primary t-butyldiphenylsilylamines essentially under the same conditions.9 t-Butyldiphenylsilyl cyanohydrins are prepared in the presence of Potassium Cyanide, Zinc Iodide, and a carbonyl compound.10

Selectivity and Compatibility of O- and N-t-Butyldiphenyl Silyl Derivatives.

The O-t-butyldiphenylsilyl ether protective group offers some unique advantages and synthetically useful features compared to other existing counterparts.1,2 Silylation of a primary hydroxy group takes place in preference to a secondary, giving products that are often crystalline, and detectable on TLC plates under UV light, because of the presence of a strong chromophore. The TBDPS group is compatible with a variety of conditions1 used in synthetic transformations such as hydrogenolysis (Pd(OH)2, C/H2, etc.), O-alkylation (NaH, DMF, halide), de-O-acylation (NaOMe, NH4OH, K2CO3/MeOH), mild chemical reduction with hydride reagents, carbon-carbon bond formation with organometallic reagents, transition metal-mediated reactions, Wittig reactions, etc. These reactions were tested during the total synthesis of thromboxane B211 for which the TBDPS group was originally designed. Subsequently, numerous related organic transformations have been carried out in the presence of TBDPS ethers in the context of natural product synthesis3,4 and functional group manipulations.2 It is distinctly more acid stable than the O-trityl, O-THP, and O-TBDMS groups, and is virtually unaffected under conditions that cause complete cleavage of these groups (50% HCO2H, 2-6 h; 50% aq TFA, 15 min; HBr/AcOH, 0 °C, few min; 80% aq acetic acid, few h).1 It is also compatible with conditions used for the acid-catalyzed formation and hydrolysis of acetal groups and in the presence of some Lewis acids (e.g. TMSBr,12 BCl3.SMe2,13 Me2AlCl,8 etc.). The mono-TBDPS derivative of a primary amine9 is stable to base, as well as to alkylating and acylating reagents. Thus a secondary amine can be acylated in the presence of a primary t-butyldiphenylsilylamino group.

Deprotection.1,2

The O-TBDPS group can be cleaved under the following conditions: Tetra-n-butylammonium Fluoride in THF at rt; variations of F--catalyzed reactions (e.g. F-/AcOH; HF/pyridine;14 HF/MeCN,15 etc.); aqueous acids and bases1 (1 N HCl, 5 N NaOH, aq methanolic NaOH or KOH); ion exchange resins;7 Potassium Superoxide, Dimethyl Sulfoxide, 18-Crown-6.16 Selective cleavage of a TBDPS ether in the presence of a TBDMS ether in carbohydrate derivatives involves treatment with Sodium Hydride/HMPA at 0 °C.17 Although the O-TBDPS group is stable to most hydride reagents, Lithium Aluminum Hydride reduction of an amide group has resulted in the cleavage18 of an adjacent O-TBDPS ether, possibly via internal assistance. TBDPS-amines are cleaved by 80% AcOH or by HF/pyridine.9


1. Hanessian, S.; Lavallée, P. CJC 1975, 53, 2975; Lavallée, P. Ph.D. Thesis, Université de Montréal, 1977.
2. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
3. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New York, 1989.
4. Hanessian, S. The Total Synthesis of Natural Products: The Chiron Approach; Pergamon: Oxford, 1983.
5. Ireland, R. E.; Obrecht, D. M. HCA 1986, 69, 1273.
6. Chaudhary, S. K.; Hernandez, O. TL 1979, 99.
7. Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. CI(L) 1983, 643.
8. Horiguchi, Y.; Suehiro, I.; Sasaki, A.; Kuwajima, I. TL 1992, 34, 6077.
9. Overman, L. E.; Okazaki, M. E.; Mishra, P. TL 1986, 27, 4391.
10. Duboudin, F.; Cazeau, P.; Moulines, F.; Laporte, O. S 1982, 212.
11. Hanessian, S.; Lavallée, P. CJC 1981, 59, 870.
12. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515.
13. Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A. B.; Payne, A. N.; Robinson, R. A.; Ward, S. E. SL 1993, 663.
14. Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. JOC 1979, 44, 4011.
15. Ogawa, Y.; Nunomoto, M.; Shibasaki, M. JOC 1986, 51, 1625.
16. Torisawa, Y.; Shibasaki, M.; Ikegami, S. CPB 1983, 31, 2607.
17. Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik, S. TL 1990, 31, 1669.
18. Rajashekhar, B.; Kaiser, E. T. JOC 1985, 50, 5480.

Stephen Hanessian

University of Montreal, Quebec, Canada



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