Synthesis of 6-Nitro-1,2,3,4-tetrahydroquinoline: An Experimental and Theoretical Study of Regioselective Nitration

A revision of the literature on the nitration of tetrahydroquinolines yielded a number of inconsistencies. Thus, we have carried out a thorough study on the nitration of tetrahydroquinoline and several of its N-protected derivatives both experimentally and at theoretical level. Usually, nitration is carried out in acidic conditions and, thus, tetrahydroquinoline would be N-protonated; however, if the amino group is protected, the neutral system will be the one undergoing nitration. Different protecting groups have been explored varying, not only electronic and steric effects, but also deprotection conditions. Additionally, different reagents and reaction conditions have been investigated. From this study we have been able to achieve total regioselectivity for nitration at the 6-position. A very detailed NMR study has been carried out to unequivocally characterise the four nitro isomers. In parallel, a computational study has been performed that is in agreement with the experimental results obtained. With this purpose, all the sigma complexes of the four nitro isomers neutral and N-protonated have been optimized both in gas and water condensed phases by using the B3LYP/ 6-31++G** level of computation.