Technical Library

Outline

The synthesis of organic molecules frequently involves the manipulation of several functional groups, thus resulting in the conversion of one functional group in the presence of one or more other functional groups. This can lead to concerns regarding competing reaction pathways taking place with a negative effect on yield and purification of the desired product. The accommodation of an effective preparation of a synthetic target can often require the protection of certain groups in order to limit their reactivity. Functional groups that commonly require protection are those containing a reactive hydrogen as encountered with alcohols, amines, thiols, and carboxylic acids. In addition, the protection of these groups must be reversible such that the original functionality can be regenerated after the desired chemical transformations elsewhere in the molecule have been carried out. Organosilanes have shown to be particularly effective in the protection of the reactive hydrogen functionalities and have been successfully employed in the protection of these groups for many years. Organosilanes are an excellent fit for this application as they are hydrogen-like, can be introduced in high yield, and can be removed under selective conditions. A number of representative examples of the application of organosilane protection of various functional groups are to be found in this brochure.

The ideal protecting group for an active hydrogen moiety such as an alcohol or amine would be one that would mimic the hydrogen atom itself, but have more flexibility in its reactivity. It would be readily introduced in high yield onto the substrate to be protected, be stable over a wide range of reaction conditions and, at the same time, could be selectively removed in high yield in the presence of other functional groups including other protecting groups, both silyl and non-silyl. While no single silyl group can fulfill all of these requirements in all cases, the available range of silicon-based blocking agents offers the synthetic chemist viable answers for nearly every protection–reaction(s)-deprotection challenge. The ability to vary the organic groups on silicon introduces the highly-useful potential to alter the organosilyl groups in terms of steric demand and electronic nature, thus allowing one to select the appropriate organosilyl protecting group to fit a particular set of synthetic needs.

The commonly used tri-substituted organosilane blocking agents, along with their common acronyms, are shown in Figure 1. The use of silicon-based blocking agents has been reviewed with regards to reaction/deprotection,1-8 oxidation of silyl ethers,9 and selective deprotection.10-12

In general, smaller organosilyl groups make the silyl group easier to introduce, easier to remove and, at the same time, less stable to a wider variety of reaction conditions. A general reactivity scale based on steric factors is shown in Figure 2.

The leaving group on silicon also plays a significant role in the reactivity of the organosilane. The general relative reactivity of R3Si-X as a function of the leaving group X is: CN > OTf > I > Br > Cl >> CF3CONH > CH3CONH > R2N > RO. Other organosilane derivatives, such as trimethylsilylperchlorate and bis(trimethylsilyl)sulfate, though very reactive, have not proven practical. The reactivity trends shown will not apply to all sets of reaction conditions and substrates, but serve to present a useful and practical working guide.

The introduction of a silyl group onto an active hydrogen substrate results in the formation of the corresponding protonated leaving group from silicon. This protonated by-product can be acidic, basic or neutral as shown by some examples:

Acidic: HCl, HBr, HI, HO3SCF3, HCN
Basic: NH3, R2NH
Neutral: MeCONH2, MeCONHMe, CF3CONH2

In terms of the leaving group, various considerations need to be addressed when evaluating a potential silicon-based blocking agent including safety, potential effect of the by-product on the molecule and final product purification issues.

The relative stabilities of the silyl-protected functional groups, for example alcohols as silyl ethers, parallels their relative rates and ease of introduction—in general, “the easier to introduce the easier to remove”. However, although the stability of the system does depend strongly on the nature of the silyl group, its surrounding environment and reaction conditions (in particular pH) play a significant role on the stability as well. For instance, phenyl-substituted silyl ethers are equal to or even more reactive than their less encumbered trimethylsilyl counterparts under basic conditions, but can be more stable under acid conditions. The reader is referred to three excellent compilations of numerous protocols for the selective deprotection of one silyl group in the presence of other silyl protecting groups and to Tables 7 through 20 of this brochure.10-12 A general study of the relative stabilities of silyl-protected alcohols to a variety of reaction conditions is summarized.

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Blocking groupSubstrateHCL-THFKF-methanolCH3MgBr in ethern-Butyl lithiumLAH-THFPyridinium chlorochromate
(CH3)3Si-n-butanol< 15 min2 min48 h2 h30 min< 30 min
cyclohexanol< 15 min2 min> 48 h3 h1 h< 30 min
t-butanol< 15 min24 h> 48 h50 h24 h< 30 min
(C2H5)3Si-n-butanol< 15 min2 hno reaction24 h1 h< 30 min
cyclohexanol< 15 min20 hno reaction> 48 h2 h< 30 min
t-butanol< 15 minno reactionno reactionno reactionno reaction1 h
cyclohexylMe2Si-cyclohexanol< 15 min10 hno reaction> 36 h2 h< 30 min
iPr(CH3)2Si-cyclohexanol10-30 min24-30 hno reaction> 60 h3 h< 30 min
tBuMe2Si-n-butanol> 3 hno reactionno reactionno reaction25 h10 h
cyclohexanol> 3 hno reactionno reactionno reaction> 50 h> 20 h
t-butanolno reactionno reactionno reactionno reactionno reaction>20 h
tHexylMe2Si-n-butanol16 hno reactionno reactionno reaction> 30 h22 h
cyclohexanol30 hno reactionno reactionno reactionno reaction50 h
t-butanolno reactionno reactionno reactionno reactionno reactionno reaction
iPr3Si-cyclohexanolno reactionno reactionno reactionno reactionno reaction> 72 h
tBuPh2Si-n-butanolno reactionno reactionno reactionno reactionno reactionno reaction
cyclohexanolno reactionno reactionno reactionno reactionno reactionno reaction
t-butanolno reactionno reactionno reactionno reactionno reactionno reaction
t1/2 for Si-OR bond scission at room temperature