Revisiting the Synthesis of 4,6‐Difluorobenzofuroxan: A Study of Its Reactivity and Access to Fluorinated Quinoxaline Oxides

Abstract

New quinoxaline 1,4‐dioxide derivatives have been synthesized from novel fluorinated benzofuroxans such as 4‐fluorobenzofuroxan, which is prepared for the first time. Furthermore, the preparation 4,6‐difluorobenzofuroxan has been revisited because we were unable to reproduce the reported synthetic method. Several synthetic pathways have thus been investigated, and the optimal way to prepare this disubstituted benzofuroxan was from the 3,5‐difluoro‐2‐nitroaniline. The various synthetic attempts have allowed the isolation of interesting new compounds such as hydroxybenzotriazole‐like heterocycles or benzoquinone 2‐diazide. In the latter case, our study reveals some interesting features in the mechanism of their formation. The first structural elucidation of benzoquinone 2‐diazide through an X‐ray crystallographic study is also reported. This study has unambiguously shown that benzoquinone 2‐diazide can be involved in Diels–Alder reactions. The first case of a reaction involving a nitro‐substituted benzoquinone 2‐diazide and cyclopentadiene is also reported. To understand better the influence of the fluorine atoms on the reactivity of benzofuroxans and benzofurazans, a wide array of new fluorinated heterocycles were synthesized together with some already known compounds. This has enabled an extensive investigation of their electrophilic behavior to be undertaken through a theoretical and an electrochemical study. From these studies, it could be deduced that the replacement of nitro groups by fluorine atoms results in a significant decrease in the electrophilic character of benzofuroxan. Nevertheless, these compounds could undergo SNAr processes, leading to new functionalized heterocycles. The first examples of aromatic nucleophilic substitution of fluorine with these compounds are also described.

A Synthetic Pathway to Substituted Benzofuroxans through the Intermediacy of Sulfonates: The Case Example of Fluoro‐Nitrobenzofuroxans

“…As has been previously reported, the 13 C NMR spectra of compounds 9 and 10 show some characteristic features. [10] Also, in accordance with the structures of 9 and 10 was the observation in the 19 F NMR spectra of broad signals at -118.6 and -107.7 ppm, respectively, characteristic of the aromatic ring fluoride. The two resonances corresponding to C 5 and C 7 are readily determined whereas the resonances of C 8 and C 9 are key features of NMR spectra of benzofuroxans.…”

“…The two resonances corresponding to C 5 and C 7 are readily determined whereas the resonances of C 8 and C 9 are key features of NMR spectra of benzofuroxans. [10] . The data summarized in Table 3 clearly show that signals corresponding to C 8 and C 9 are in close agreement with those peviously reported for DNBF, 1 and DFBF, 5.…”

“…In such cases, the methoxy group, being electrondonating, enables facile dinitration leading to dinitrofluoroanisoles 21 and 22 in moderate yields. [10] A water-free synthesis in neutral experimental conditions, implying the use of tertbutyl nitrite (tBuONO) as nitrosation agent with TMSN 3 , has been employed leading to azides 19 and 20 in 90 % yield (Scheme 8). [17] Phenoxide ions 15 and 16 (as their potassium salts) can then be obtained in quantitative yields by heating a solution of the dinitroanisoles in ethanol in the presence of potassium iodide (Scheme 7).…”

“…The yields for anisole nitration are lower than those for phenol nitration; the global yield for the synthesis of the benzofuroxans 9 and 10 are 40 % and 45 %, respectively. Summary of yields for production of 4-fluoro-6-nitrobenzofuroxan (9) and 6-fluoro-4-nitrobenzofuroxan (10) to prepare 4-fluoro-6-nitrobenzofuroxan (9) and 6-fluoro-4nitrobenzofuroxan (10). As a matter of fact, the nitration step of aniline often requires protection of the amino group as an amide and subsequent deprotection of the dinitroamide intermediate in acidic media following nitration.…”

“…sodium hypochlorite in basic alcoholic solu-abling us to carry out structural and reactivity comparisons, with DNBF and 4,6-difluorobenzofuroxan. [10] However, the preparation of fluoronitrobenzofuroxan has been much less often described in the literature. Two main synthetic pathways involving fluoroanisoles and fluorophenols, cheap and easily available chemicals, have been successfully developed.…”