Hexahydroazepine ring

The total synthesis of balanol, a fungal metabolite was accomplished by K.C. Nicolaou et al. For the construction of the central hexahydroazepine ring, they have utilized a 7-exo-tet cyclization. The substitution reaction between the mesylate of the primary alcohol and the Cbz-protected amine was effected by a slight excess of base to produce the desired 7-membered ring in high yield. 

Complete reduction of the azepine ring to hexahydroazepine has been effected with hydrogen and palladium,40 or platinum,135 239 catalysts. For example, ethyl 1 f/-azepine-l-carboxylate is reduced quantitatively at room temperature to ethyl hexahydroazepine-l-carboxylate (92% bp 118 —120 3C).134 136 TV-Phenyl-S/Z-azepin -amine (1), however, with platinum(IV) oxide and hydrogen in methanol yields the hexahydroazepine 2 in which the amidine unit is preserved in the final product.34 The same result is obtained using 5% palladium/barium carbonate, or 2 % palladium/Raney nickel, as catalyst. 

In a different approach, the pyrimidine ring was formed when the l-(2-aminomethylphenyl)hexahydroazepine (663) was oxidatively cyclized with Hg(II)-EDTA to 664 (79AP838). 

Examples of the ring expansion of pyrrolidine derivatives to azepine derivatives include the attempted alkylation of vinylpyrrolidine (236 R = aryl) with methyl iodide to afford the tetra-hydroazepinium salt (237 R = aryl) <82AP(315)749> and thermal rearrangement of the thiono-carbonate (238) to furnish the hexahydroazepine (239) <90cpb2981>. 

The compounds in this section are similar to the others in chapter seven, but a nitrogen, oxygen or a sulfur is incorporated in the ring. Since most cases involve a nitrogen, however, the final products are usually substituted aziridines, azetidines, pyrrolidines, piperidines, or hexahydroazepines with a carboxyl group pendant to the ring. Many synthetic strategies are unique to this class of amino acids. 

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