SolutionsProtection of functional groups
Exercise 1
Methylmagnesium bromide is to be added to the ketone of methyl 4-acetylbenzoate without touching the ester. Is protection needed? Propose a sequence.
Grignard reagents react with ketones faster than with esters, but with an excess or at room temperature they also attack the ester; at −78 °C and with one equivalent some selectivity can be achieved. Since here it is the ketone that must react, it is the ester that is protected: it is hydrolysed to the acid (the carboxylate, formed by consuming one equivalent of Grignard reagent, is inert) or converted into an oxazoline; MeMgBr is added to the ketone and the methyl ester is regenerated at the end.
Exercise 2
A molecule carries a primary alcohol protected as a TBS ether and a secondary one as a benzyl ether. Say how to release each without touching the other and which reagents would destroy both protections.
The TBS is removed with TBAF in THF (or HF·pyridine), which does not affect the benzyl ether; the benzyl with H2 and Pd/C, which does not cleave the silyl ether. A strong Lewis acid such as BBr3 or BCl3 would cleave both; strong aqueous acid also hydrolyses the TBS and, when hot, can attack the benzyl ether.