Hetero‐Diels–Alder and Ring‐Opening Reactions of Furans Applied to the Synthesis of Functionalized Heterocycles

Furans have been explored as a scaffold for the synthesis of a range of heterocyclic compounds, exploring their dienophilic behaviour towards nitroso‐ and azoalkenes as the first step. Acid‐catalysed rearrangements of these cycloadducts, 4a,7a‐dihydro‐4H‐furo[2,3‐e][1,2]oxazines and 1,4,4a,7a‐tetrahydrofuro[3,2‐c]pyridazines, were studied. Using 1 equiv. of TFA, the bicyclic heterocycles derived from furan and 2‐methylfuran were converted into furans bearing side‐chains incorporating oxime and hydrazone groups by ring‐opening of the six‐membered ring with the concomitant aromatization of the furan ring. The use of TFA as solvent led to rearrangement via spirocyclic intermediates, followed by furan ring‐opening to afford functionalized isoxazoles or pyrazoles. Furthermore, furo‐oxazines derived from 2,5‐dimethylfuran, in which furan aromatization is precluded, were converted efficiently into 6H‐1,2‐oxazines through a furan ring‐opening reaction upon thermolysis in the presence of a catalytic amount of p‐toluenesulfonic acid. The tetrahydrofuro[3,2‐c]pyridazines derived from furan and dimethylfuran underwent acid‐catalysed addition reactions, leading to 6‐substituted hexahydrofuro[3,2‐c]pyridazines, when in the presence of alcohols or water. Hetero‐Diels–Alder reactions of furans with nitroso‐ and azoalkenes afforded dihydro‐4H‐furo[2,3‐e][1,2]oxazines and tetrahydrofuro[3,2‐c]pyridazines, which reacted with TFA or PTSA to give a range of heterocycles, namely furans, 1H‐pyrazoles, isoxazoles and 6H‐1,2‐oxazines. Tetrahydrofuro[3,2‐c]pyridazines reacted with alcohols or water and TFA to give hexahydrofuro[3,2‐c]pyridazines.