O-Dealkylation General Overview

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

O-dealkylation is almost exclusively employed to remove protecting groups unmasking free hydroxyl functions.  Many different classes of alkyl function have been used to protect alcohols.

These include:
alkyl ethers – methyl, ethyl, isopropyl, benzyl, p-methoxy benzyl, t-Bu ethers and esters, allyl ethers and esters, 2-tetrahydropyranyl and benzylidine ethers. A wide range of reagents has been used for deprotection. These can be divided into:

  • Strong acids
  • Lewis acids and metal salts
  • Nuclophiles/bases
  • Hydrogenation and other metal-catalysed processes

Reagent selection depends on the class of ether to be deprotected, compatible selectivity with other functional groups in the molecule and environmental and impurity considerations. Care needs to be taken with Lewis acids, protic acids and metal salts that generate reactive by-products like methyl iodide/bromide, methyl mesylate, methyl tosylate etc. Some are undesirable, volatile environmental pollutants and known or potential genotoxic impurities (PGI). Several of the references in this guide detail technology for removing reactive volatiles, and guidance can be found in other publications – see ref below:

Org. Process res. Dev. 2008, 12, 781 The Use of Methyltricaprylammonium Chloride as a Phase Transfer Catalyst for the Destruction of Methyl Bromide in Air Streams

Org. Proc. Res. Dev., 2002, 6, 407 Development and Scale-Up of an Aqueous Ethanolamine Scrubber for Methyl Bromide Removal

Generation of PGI by-products, especially if non-volatile, may require analysis of the API to detect and quantify, particularly if generated towards the end of the synthetic sequence. Therefore if such operations are absolutely required, they should be placed as early in the synthesis as feasible.

Org. Process Res. Dev. 2013, 17, 221 Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies To Demonstrate Control.

Green Criteria for O-dealkylation

  1. Reagents have no major toxicity or safety issues.
  2. Process has no major safety issues and the generation of hazardous waste is minimised and   controlled.
  3. Adequate consideration has been given to the impact of undesirable volatiles and PGI’s.
  4. Solvents should be chosen to minimise any potential impact. Many O-dealkylations are   carried out in reprotoxic  dipolar aprotic or chlorinated solvents which should be minimised   or replaced wherever possible.

General reviews on O-dealkylation

Tetrahedron 2005, 61, 7833 Recent advances in ether dealkylation

Synthesis, 1988, 10, 749  Selective dealkylations of aryl alkyl ethers, thioethers, and selenoethers

Org. Prep.  Proc. Int. 1996, 28, 371   Dealkylation of ethers. A review

Chemical Reviews 1954, 54, 615 The cleavage of ethers

Tetrahedron 1998, 54, 2967 Allylic protecting groups and their use in a complex environment 

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