Tandem Dipolar Cycloaddition-Mannich Cyclization as an Approach to Tricyclic Nitrogen Heterocycles

A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids undergo facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomünchnone-type intermediates. Subsequent 1,3-dipolar cycloaddition across the pendant olefin affords intramolecular cycloadducts in high yield. Exposure of these cycloadducts to boron trifluoride etherate results in a Lewis acid-induced ring opening to generate N-acyliminium ions which then undergo Mannich cyclization onto the neighboring pi-framework attached to the amide nitrogen atom. The cis stereochemistry of the resulting A/B ring fusion is analogous to similar erythrinane products obtained via a Mondon-enamide-type cyclization. The stereochemical assignment of the final cyclized products was determined by X-ray crystallography. Molecular mechanics calculations show that the ground state energy of the cis-fused diastereomer is 4.6 kcal lower than that of the trans diastereomer, and presumably some of this thermodynamic energy difference is reflected in the transition state for cyclization. In certain cases, proton loss from the initially formed N-acyliminium ion occurs prior to cyclization to give acyl enamides which subsequently cyclize producing epimeric products.