Regioselective synthesis of functionalized 1,4-benzothiazines via intramolecular SNArF and SNArH cyclizations

In the preparation of 1,4-benzothiazines, intramolecular nucleophilic aromatic substitution (S N Ar) cyclizations of thiol-bearing fluoro-nitroanilines exhibited unexpected regioselectivity preferences. Microwave-assisted heating facilitated ring closure but did not alter the intrinsic regiochemical bias. Both standard S N Ar F and a vicarious nucleophilic substitution of hydrogen (S N Ar H ) reactions led to an undesired 1,4-benzothiazine substitution pattern. Frontier molecular orbital (FMO) analysis revealed substantial LUMO polarization at the C-2 position irrespective of fluorine versus hydrogen substitution at this site, providing a mechanistic rationale for the observed regioselectivity. Guided by these insights, a symmetrical dinitro-activated substrate was used to overcome the intrinsic electronic bias and enable access to the desired 1,4-benzothiazinedioxides in a concise seven-step sequence. The selectivity of the final N -carbamoylation step was determined by 13 C NMR chemical shift calculations. This work addresses regioselectivity challenges in benzothiazine synthesis and highlights the power of combining experimental and computational analyse. • A rare S N Ar H reaction. • A computational analysis that provides a rationale for the experimentally observed intrinsic regiochemical preferences. • Strategic substrate design that overcomes the substituent effect bias and enables a controlled access to the desired heterocyclic framework. • General insights into regioselectivity control in intramolecular aromatic substitution reactions that should inform the rational design and synthesis of related heterocyclic systems.