Triisopropylsilyl Chloride


[131154-24-0]  · C9H21ClSi  · Triisopropylsilyl Chloride  · (MW 192.84)

(hydroxy protecting group;1,2 formation of triisopropylsilyl ynol ethers;3 N-protection of pyrroles;4,5 prevents chelation with Grignard reagents6)

Alternate Names: TIPSCl; chlorotriisopropylsilane.

Physical Data: bp 198 °C/739 mmHg; d 0.901 g cm-3.

Solubility: sol THF, DMF, CH2Cl2.

Form Supplied in: clear, colorless liquid; commercially available (99% purity).

Analysis of Reagent Purity: bp; NMR.

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: moisture sensitive; therefore should be stored under an inert atmosphere; corrosive; use in a fume hood.

Hydroxy Protecting Group.

Several hindered triorganosilyl protecting groups have been developed to mask the hydroxy functionality. Although the t-butyldiphenylsilyl (TBDPS) and t-butyldimethylsilyl (TBDMS) groups are the most widely used, the triisopropylsilyl group (TIPS) has several properties which make it particularly attractive for use in a multi-step synthesis.1,2

Introduction of the TIPS group is most frequently accomplished using TIPSCl and Imidazole in DMF,1 although several other methods exist, including using TIPSCl and 4-Dimethylaminopyridine in CH2Cl2. It is possible to silylate hydroxy groups selectively in different steric environments. For example, primary alcohols can be silylated in the presence of secondary alcohols (eq 1)7 and less hindered secondary alcohols can be protected in the presence of more hindered ones (eq 2).8

A comparison of the stability of different trialkylsilyl groups has shown that TIPS ethers are more stable than TBDMS ethers but less stable than TBDPS ethers toward acid hydrolysis.2 The rate difference is large enough that a TBDMS group can be removed in the presence of a TIPS group (eq 3).7 Under basic hydrolysis, TIPS ethers are more stable than TBDMS or TBDPS ethers.2 The cleavage of TIPS ethers can also be accomplished by using Tetra-n-butylammonium Fluoride (TBAF) in THF at rt.1 This is most convenient if only one silyl protecting group is present or if all of those present can be removed in one synthetic step.

An additional feature of TIPS ethers is that they are volatile enough to make them amenable to GC and MS analysis. In fact, MS fragmentation patterns have been used to discern the structures of isomeric nucleosides.9

Formation of Silyl Ynol Ethers.

Esters can also be transformed into triisopropylsilyl ynol ethers.3 The ester is first converted to the ynolate anion, followed by treatment with TIPSCl to furnish the TIPS ynol ether (eq 4). This method has even proven successful with lactones as starting materials (eq 5).

N-Protection of Pyrroles.

Pyrroles typically undergo electrophilic substitution at the a-(2)-position, but when protected as N-triisopropylsilylpyrroles, substitution occurs exclusively at the b-(3)-position (eq 6).4 It has been shown that 3-bromo-1-(triisopropylsilyl)pyrrole undergoes rapid halogen-metal exchange with n-Butyllithium to generate the 3-lithiopyrrole, which can be trapped by electrophiles to provide the silylated 3-substituted pyrrole (eq 7).5 As expected, the silyl group can be removed with TBAF to furnish the 3-substituted pyrrole. It should also be mentioned that the N-TIPS group also enhances the stability of some pyrroles. For example, 3-bromopyrrole is very unstable, but the N-silylated derivative is stable for an indefinite period of time.5

Prevention of Chelation in Grignard Reactions.

The bulky TIPS protecting group has proven extremely effective in preventing competing chelation of a- and b-oxygen functionalities during Grignard reactions (eq 8).6 It was determined that this effect is steric and not electronic since TMS and TBDMS ethers did not affect selectivity.

Related Reagents.

t-Butyldimethylchlorosilane; t-Butyldiphenylchlorosilane.

1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; p 74.
2. Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
3. Kowalski, C. J.; Lal, G. S.; Haque, M. S. JACS 1986, 108, 7127.
4. Muchowski, J. M.; Solas, D. R. TL 1983, 24, 3455.
5. Kozikowski, A. P.; Cheng, X.-M. JOC 1984, 49, 3239.
6. Frye, S. V.; Eliel, E. L. TL 1986, 27, 3223.
7. Ogilvie, K. K.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. TL 1974, 2865.
8. Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. TL 1974, 2861.
9. Ogilvie, K. K.; Beaucage, S. L.; Entwistle, D. W.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B. J. Carbohydr., Nucleosides, Nucleotides 1976, 197.

Ellen M. Leahy

Affymax Research Institute, Palo Alto, CA, USA

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