Constitutional isomerism in heterocycles: A structural revision of benzofused isothiazoles

Abstract

During investigations on our deaminative chlorination protocol, a misassignment between two constitutional isomers of a benzofused isothiazole was encountered. Herein, we provide a clue game in order to identify the correct structure of the reported molecule as well as an investigation on the origin of the error. Finally, a revised synthesis of the previously published examples was proposed to provide the practitioners reliable data en route to reproducible science.

Introduction

In some instances, unintentional errors can be found in already published articles. Although the vast majority of such mistakes and inconsistencies are minimal (eg. typos, mislabeling of compounds), others require more profound re-evaluation leading to a corrigendum. In organic synthesis, corrections on absolute configuration or molecular structures can occur, and are important to provide compelling evidence to address the issue. An example of this problematic has been identified in our recently developed deaminative chlorination protocol (Fig. 1A) [1], where the structure of one of the heteroaryl chloride products was erroneously described. Therefore, we started a thorough investigation to elucidate the correct structure and report the origin of such structural misassignment. Fig. 1B shows two possible constitutional isomers of the chlorinated nitro benzoisothiazole (cpd-I and cpd-II). In our original report, cpd-I was described as shown, with the Cl atom sharing the C atom with the N atom in the ring. In cpd-II however, the Cl shares the C with a S atom instead. Hence, both molecules only differ in the position of the N and the S atoms, whose places in the skeleton are formally swapped. For this reason, the respective names are only differentiated by the fusion side of the isothiazole: [d] in cpd-I and [c] in cpd-II. Whereas at first glance, both mass spectrometry and NMR spectroscopy can be very similar, spectroscopic techniques are able to clearly differentiate between both compounds. In an attempt to understand the origin of such error, we retrace the sequence of events, providing compelling evidences to support that the structure of our originally reported cpd-I is in fact cpd-II. This purely academic exercise serves as an example and a reminder that mistakes can happen, and when identified, further analysis is required to provide the most scientifically viable solution in order to clarify them.