• 10.1021/jo971802o
  • The Journal of Organic Chemistry
  • Volume 63
  • March 1998
  • pp 1727-1729

Desymmetrization Reactions:  Efficient Preparation of Unsymmetrically Substituted Linker Molecules

Innovative,one-pot method to synthesize bifunctional linkers


The paper presents an innovative way to synthesis bi functional linker (in this case azido-amine linkers). The method used described as concurrent reaction-extraction taking place in one pot has attracted a lot of attention. In the synthesis of compound 1 a linker containing an azido group at one end and a primary amine at the other end, the authors carry out a selective azide-to-amine reduction of a diazide (with azido groups at both ends) using triphenylphosphine in the presence of phosphoric acid. The "trick" in the success of the mono-reduction lies in the solvent used. They use a mixture of water and ether under vigorous stirring such that once the mono-decution occurs the azido-amine is protonated by the acid and is soluble in water and is therefore "extracted" from ether where the triphenylphosphine is soluble.

The synthesis of the same azido-amine linker I followed the same protocol as repoted for compound 2a. Care must be taken when adding the triethyl amine as the reaction is extremely exothermic especially for large scale reactions. The ice-bath cooling must be sufficient and the reaction allowed to vent and ample time allowed between dropsiwe additions. 

The purification of the azido-amine product 1a is however cumbersome. The authors report the by product (triphenylphosphine oxide) can be removed by column chromatography, extraction or crystalization. I could not get pure azido-amine 1a free of the triphenylphosphine. After column chromatography using the solvent system reported, I could still see aromatic peaks by proton NMR presumably from the by product. Interestingly, when I substituted the phosphoric acid with hydrochloric acid in the reduction step, the proton NMR of the product purified only by extraction showed no peaks at the aromatic region. The yield of the product was high (90 %) comparable with 82 % reported in reference

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