Synthesis of 2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine via Oxidative Cleavage and Reductive Amination Strategies

Abstract

Preparations of 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine (5) from benzonorbornadiene (1) by oxidative cleavage and reductive amination sequences were investigated. Osmium-mediated dihydroxylation of 1 followed by NaIO₄ cleavage, reductive amination and debenzylation provides 5 in 64-73% yield overall in three operations. A tandem ozonolysis-reductive amination procedure gives 5 as the tosylate salt from benzonorbornadiene with no isolation of intermediates in 28% yield.

Key words

oxidation - ozonolysis - amination - reduction - bicyclic compounds

References

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6

This process could be initiated by adding seed crystals of 6.

7

As an additional benefit of this preparation, the osmium containing filtrate, after partial concentration, could be reused with fresh benzonorbornadiene, NMO and solvent.

10

An alternative method with sodium chlorite-K₂OsO₄·2H₂O achieved more rapid conversion in slightly lower yield. See experimental details.

16

The reduction of the hydroperoxide 9, reductive amination of 10 and N-benzyl cleavage of 8 to 5 could all be executed in a single pot using 10% Pd/C as the sole catalyst for hydrogenolysis and p-toluene sulfonic acid (rather than HCOOH or HOAc for the reductive amination). Because the activity of Pd/C was relatively higher than Pt/C and p-toluene sulfonic acid was less optimal than HCOOH for the reductive amination, the yield suffered (14-16%).