Application of the Mannich Reaction for the Synthesis of Azamacroheterocycles

Efficient approaches for the preparation of azamacroheterocycles of different topologies using the aminomethylation (Mannich) reaction are described. Three modifications of this method have been reported: 1) Template cyclization of appropriate amines with formaldehyde (C-H acids or NH₃ participate in the cyclization); 2) Interaction of C-H acids, formaldehyde and azacrown ethers or secondary amines to functionalize the macrocyclic framework; 3) Synthesis of lariat azacrown macrocycles or three-dimensional molecules using N-methoxymethyl-substituted azacrown ethers (aminomethylation on cyclization step occures without a template). A great variety of functionalized mono- and diazacrown ethers have been prepared from the N-methoxymethyl-substituted azacrown ethers. Inexpensive intermediates are available from commercial sources to carry out the above reactions. A number of azacrown macrocycles containing proton-ionizable functions were prepared and found to be highly selective ligands and potential sensoring agents. The temperature dependence of aminomethylation of phenols allowed both ortho positions of the phenol ring to be substituted with different azacrown moieties. Convenient methods based on self-assembly cyclization of appropriate bisphenols or bisamides with N,N’-bis(methoxymethyl)diazacrown ethers have been elaborated to construct bi- and tricyclic molecular frameworks. This modified Mannich method was used as a key strategy for the synthesis of benzoazacrown ethers and new benzocryptands. Short synthetic pathways and excellent yields of the cryptands allow their preparation on a large scale.

azamacroheterocycles - cryptands - preparation - aminomethylation - proton-ionizable azacrown ethers - Mannich reaction