Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis

Hexamethylenetetramine, readily obtainable from ammonia and formaldehyde, is a rather stable reagent with an adamantane-like structure. In acidic media the reagent can be cleaved to give C-N-subunits or ammonia + formaldehyde. These fragmentation products can then undergo synthetically useful reactions with appropriate substrates. The present article gives a summary of the formation of hexaminium salts and their use for the introduction of amino and formyl groups. There follows a discussion of the use of hexamethylenetetramine for the synthesis of some triaza- and tetraaza systems and for ring-closure reactions to form five-, six-, or seven-membered ring systems. 1. Introduction 2. Hexaminium Salts 2.1. Salts with Acids 2.2. Quaternary Salts of Hexamethylenetetramine 3. Introduction of Amino Groups via Hexaminium Salts 4. Introduction of Formyl Groups via Hexaminium Salts 5. Formation of Triaza- and Tetraaza-Heterocyclic Derivatives 6. Ring Closure Reactions using Hexamethylenetetramine 6.1. Formation of Five-Membered Rings 6.2. Formation of Six-Membered Rings 6.3. Formation of Seven-Membered Rings 7. Conclusions