Steric Effects of N-Alkyl Group on the Base-Induced Nitrogen to Carbon Rearrangement of Orthogonally Protected N-Alkyl Arylsulphonamides

The rearrangement of a total of 56 members of 22 series of orthogonally protected N-alkyl arylsulphonamides of general structure 4-XC6H4SO2NR1CO2R2 [X = H, CH3, F, Cl, Br, CH3O, CN, CF3 or C(CH3)3; R1 = CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2; R2 = CH3, C2H5 or C(CH3)3] when treated with lithium di-isopropylamide in tetrahydrofuran at −78 °C has been studied. The competition between directed ortho metalated rearrangement, to form 4-X-2-(R2O2C)C6H3SO2NHR1 and the production of a substituted saccharin, is strongly influenced by the size of R1 and R2, especially in the series with X = CH3. When R1 = CH3 or to a lesser degree, C2H5, formation of the saccharin competes to a significant extent, especially when the migrating group is CO2CH3 or CO2C2H5. In contrast, when R1 is a larger alkyl group, particularly if it is branched at either the α- or β-carbon atom [CH(CH3)2 or CH2CH(CH3)2], the increased steric hindrance essentially prevents cyclisation, thus facilitating rearrangement to 4-X-2-(R2O2C)C6H3SO2NHR1 in high yield. The size of the migrating CO2R2 group also exerts an effect on the competition between the reactions: when R2 = C(CH3)3, clean rearrangement is possible even when R1 = CH3 in each series of X. These results have implications for further elaboration and rearrangement of 4-X-2-(R2O2C)C6H3SO2NHR1 in order to prepare substituted saccharins containing a 6-CO2R3 group.