Reactions >> Protecting Groups >> Stability

tert-Butyldimethylsilyl ethers

TBDMS-OR, TBDMS ether

T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 127-141, 708-711.

Stability

H₂O:	pH < 1, 100°C	pH = 1, RT	pH = 4, RT	pH = 9, RT	pH = 12, RT	pH > 12, 100°C
Bases:	LDA	NEt₃, Py	t-BuOK	Others:	DCC	SOCl₂
Nucleophiles:	RLi	RMgX	RCuLi	Enolates	NH₃, RNH₂	NaOCH₃
Electrophiles:	RCOCl	RCHO	CH₃I	Others:	:CCl₂	Bu₃SnH
Reduction:	H₂ / Ni	H₂ / Rh	Zn / HCl	Na / NH₃	LiAlH₄	NaBH₄
Oxidation:	KMnO₄	OsO₄	CrO₃ / Py	RCOOOH	I₂, Br₂, Cl₂	MnO₂ / CH₂Cl₂

General

Trimethylsilyl ethers are too susceptible to solvolysis for them to have any utility as protecting groups. The tert-butyldimethylsilyloxy group is ca. 10⁴ times more hydrolytically stable and holds more promise for such applications.

When the commercially available tert-butyldimethylsilyl chloride (TBDMS-Cl) was initially used as a silylation agent, it was found by E. J. Corey (J. Am. Chem. Soc. 1972, 94, 6192) to react very slowly and to give unsatisfactory yields with alcohols. Even forcing silylation techniques (excess silyl chloride, dry pyridine, elevated temperatures) were not successful. The use of 2.5 eq. imidazole as catalyst with 1.2 eq. of TBDMS-Cl and dimethylformamide as solvent proved to be effective, and resulted in the mild conversion of various alcohols to tert-butyldimethylsilyl ethers in high yield.

The reaction proceeds via N-tert-butyldimethylsilylimidazole, a very reactive silylating agent:

Another key discovery by E. J. Corey (J. Am. Chem. Soc. 1972, 94, 6192) was the rapid cleavage of the silyl ethers to alcohols by treatment with 2-3 eq. tetra-n-butylammonium fluoride (TBAF) in THF at 25°C.

Nucleophilic attack of the small fluoride anion leads to a pentavalent silicon centre which is permitted due to hybridisation with the vacant d-orbitals of silicon. In addition, the formation of the strong Si-F bond is the driving force for a fast cleavage:

tert-Butyldimethysilyl ethers are stable to aqueous base, but may be converted back to the alcohols under acidic conditions (2:1 acetic acid / water at 25°C).

Protection of Hydroxyl Compounds

Reactions of alcohols with silyl chlorides in the presence of N-methylimidazole were significantly accelerated by addition of iodine. A general and high yielding method for efficient silylation of primary, secondary, and tertiary alcohols was developed.
A. Bartoszewicz, M. Kalek, J. Nilsson, R. Hiresova, J. Stawinski, Synlett, 2008, 37-40.

A commercially available proazaphosphatrane is an efficient and mild catalyst for the silylation of a wide variety of alcohols and phenols, including acid-sensitive, base-sensitive, and hindered substrates, using tert-butyldimethylsilyl chloride (TBDMSCl). The reactions are carried out in acetonitrile from 24 to 40°C and on rare occasions in DMF from 24 to 80°C. Although representative primary alcohols, secondary alcohols, and phenols were silylated using the more sterically hindered reagent tert-butyldiphenylsilyl chloride (TBDPSCl), tertiary alcohols were recovered unchanged.
B. A. D'Sa, D. McLeod, J. G. Verkade, J. Org. Chem., 1997, 62, 5057-5061.

Tris(pentafluorophenyl)borane, B(C₆F₅)₃, is an effective catalyst for a mild and efficient dehydrogenative silation of alcohols using a variety of silanes. Only the most bulky silanes (Bn₃SiH and iPr₃SiH) were not reactive under these conditions. Generally, the reactions are clean and high yielding, with dihydrogen as the only byproduct.
J. M. Blackwell, K. L. Foster, V. H. Beck, W. E. Piers, J. Org. Chem., 1999, 64, 4887-4892.

R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F. Coelho, Synthesis, 2005, 2297-2306.

Deprotection

Various tert-butyldimethylsilyl (TBDMS) ethers as well as tert-butyldiphenylsilyl (TBDPS) ethers can be easily deprotected by employing a catalytic amount of acetyl chloride in dry MeOH in good yields. This mild and convenient method tolerates various other protecting groups and does not lead to acylated or chlorinated byproducts.
A. T. Khan, E. Mondal, Synlett, 2003, 694-698.

Various tert-butyldimethylsilyl ethers are easily removed in excellent yields by treatment with a catalytic amount of N-iodosuccinimide in methanol. This method allows a selective deprotection of TBDMS ethers of alcohols in the presence of TBDMS ethers of phenols.
B. Karimi, A. Zamani, D. Zarayee, Tetrahedron Lett., 2004, 45, 9139-9141.

PMA supported on SiO₂ is found to be an efficient catalyst for the chemoselective, mild deprotection of TBDMS ethers. Various labile functional groups such as isopropylidene acetal, OTBDPS, OTHP, Oallyl, OBn, alkene, alkyne, OAc, OBz, N-Boc, N-Cbz, N-Fmoc, mesylate, and azide are tolerated. The supported catalyst and the solvent can be readily recovered and recycled.
G.D. K. Kumar, S. Baskaran, J. Org. Chem., 2005, 70, 4520-4523.

A chemoselective, efficient and operationally simple desilylation of O-tert-butyldimethylsilyl ethers was achieved using chlorotrimethylsilane and potassium fluoride dihydrate in acetonitrile.
Y. Peng, W.-D. Z. Li, Synlett, 2006, 1165-1168.

With either 1.0 or 0.10 equivalent of DBU, smooth desilylation of various aryl silyl ethers was accomplished selectively in the presence of base-sensitive groups such esters and alkyl silyl ethers. A direct transformation of aryl silyl ethers into biaryl ethers was possible through tandem desilylation and S_NAr reaction with activated aryl fluorides.
C.-E. Yeom, H. W. Kim, S. Y. Lee, B. M. Kim, Synlett, 2007, 146-150.

Conversion of TBDMS Ethers to Other Functional Groups

Benzyl alcohols and benzyl TBDMS ethers were efficiently oxidized to the corresponding carbonyl compounds in high yield with periodic acid catalyzed by CrO₃ at low temperature (-78 °C). The oxidation procedure was highly functional group tolerant and very selective for the TBDMS group over the TBDPS group.
S. Zhang, L. Xu, M. L. Trudell, Synthesis, 2005, 1757-1760.

Various silyl ethers were readily and efficiently transformed into the corresponding alkyl ethers in high yields by the use of aldehydes combined with triethylsilane in the presence of a catalytic amount of iron(III) chloride.
K. Iwanami, K. Yano, T. Oriyama, Synthesis, 2005, 2669-2672.

A mild and efficient interconversion from silyl ethers to sulfonates esters proceeds readily in acetonitrile at room temperature in the presence of p-toluenesulfonyl fluoride and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7ene (DBU). This method can be used with trimethysilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl (TBDMS) ethers.
V. Gembus, F. Marsais, V. Levacher, Synlett, 2008, 1463-1466.

TBDMS-Protected Hydroxyl Groups in Multi-step Syntheses

Selective hydrogenation conditions of olefin, benzyl ether and acetylene functionalities in the presence of TBDMS or TES ether have been developed.
H. Sajiki, T. Ikawa, K. Hattori, K. Hirota, Chem. Commun., 2003, 654-655.

R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F. Coelho, Synthesis, 2005, 2297-2306.