Application of 1,1-ADEQUATE, HMBC, and Density Functional Theory To Determine Regioselectivity in the Halogenation of Pyridine N-Oxides

Abstract

The 1,1-ADEQUATE spectrum clearly shows specific two-bond proton to carbon correlations to unequivocally distinguish the major and minor regioisomers of ortho-halogenated pyridines and to aid in assignment of the corresponding proton and carbon chemical shifts. M06-2X/6-31+G(d,p) free energies of the regioisomeric intermediates arising from deprotonation correctly predict the experimentally observed preference and thus can be used to tune the substituent pattern to yield a desired regiochemical outcome.

Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry

“…Control experiments with oxalyl chloride in dibromomethane showed a nearly equal ratio of chloro- to bromopyridine (1.2:1 Cl/Br), indicating that both the solvent as well as the activating agent are potential sources of the halogen. Further computational studies have pointed to a deprotonated ylide-like intermediate involved in halogen capture . In total, we developed two novel methodologies to access differentially 3,5-disbustituted 2-amino- or 2-halopyridines via a highly selective N -oxide rearrangement.…”

“…Indeed, running the halogenation under identical conditions, but replacing oxalyl chloride with oxalyl bromide, the bromination reaction performed equally well. Interestingly, 72 In total, we developed two novel methodologies to access differentially 3,5-disbustituted 2-amino-or 2-halopyridines via a highly selective N-oxide rearrangement. This allowed access to the highly valuable building blocks from inexpensive and readily available 3,5-dibromopyridine N-oxide rather than more highly functionalized starting materials.…”