Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;11(12):e202200252.
doi: 10.1002/open.202200252.

Phenolate-Induced N-O Bond Formation versus TiemannType Rearrangement for the Synthesis of 3-Aminobenzisoxazoles and 2-Aminobenzoxazoles

Benedikt Hufnagel  1 , W Felix Zhu  1 , Hanna M Franz  1 , Ewgenij Proschak  2   1 , Victor Hernandez-Olmos  2
Affiliations

Phenolate-Induced N-O Bond Formation versus TiemannType Rearrangement for the Synthesis of 3-Aminobenzisoxazoles and 2-Aminobenzoxazoles

Benedikt Hufnagel et al. ChemistryOpen. 2022 Dec.

Abstract

A novel oxadiazolone-based method for the synthesis of 3-aminobenzisoxazoles by N-O bond formation and of 2-aminobenzoxazoles through a Tiemann-type rearrangement has been developed. The synthesis of these two pharmaceutically relevant heterocycles was realized by an unexplored retrosynthetic disconnection using a cyclic nitrenoid precursor-based strategy. The selective formation of the two isomers was significantly influenced by steric and electronic effects of substituents. However, tetrabutylammonium chloride (TBACl) efficiently promoted the Tiemann-type rearrangement over N-O bond formation. Control experiments indicate that deprotonation of the phenol induces both rearrangements.

Keywords: 2-aminobenzoxazoles; 3-aminobenzisoxazoles; Tiemann rearrangement; nitrenoid precursors; oxadiazolone.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Approved, investigational new or experimental drugs, which contain 3aminobenzisoxazole (dark blue) or 2aminobenzoxazole (green) scaffold.
Scheme 1
Scheme 1
Synthetic approaches towards 3‐aminobenzisoxazole and 2‐aminobenzoxazole.
Scheme 2
Scheme 2
Scope of reaction with substituted amidoximes. Reactions were usually carried out on a 0.5 mmol reaction scale. n.o.=not obtained.
Scheme 3
Scheme 3
Control experiments: (A) Thermal rearrangement of 1 affords the N−O bond formation product. (B) Deprotonation of oxadiazolone deactivates reaction. (C) Methylated oxadiazolone undergoes N−O bond formation. (D) Aldoxime and chlorinated analogue undergo neither N−O bond formation nor Tiemann‐type rearrangement.
Scheme 4
Scheme 4
Proposed mechanism for cyclic nitrenoid‐based N−O bond formation and for the Tiemann‐type rearrangement.
See this image and copyright information in PMC

References

    1. None
    1. Bradford P. A., Miller A. A., O′Donnell J., Mueller J. P., ACS Infect. Dis. 2020, 6, 1332; - PubMed
    1. Juric D., de Bono J. S., LoRusso P. M., Nemunaitis J., Heath E. I., Kwak E. L., Macarulla Mercadé T., Geuna E., de Miguel-Luken M. Jose, Patel C., Kuida K., Sankoh S., Westin E. H., Zohren F., Shou Y., Tabernero J., Clin. Cancer Res. 2017, 23, 5015; - PMC - PubMed
    1. Kunz R. K., Rumfelt S., Chen N., Zhang D., Tasker A. S., Bürli R., Hungate R., Yu V., Nguyen Y., Whittington D. A., Meagher K. L., Plant M., Tudor Y., Schrag M., Xu Y., Ng G. Y., Hu E., Bioorg. Med. Chem. Lett. 2008, 18, 5115; - PubMed
    1. Voss M. H., Gordon M. S., Mita M., Rini B., Makker V., Macarulla T., Smith D. C., Cervantes A., Puzanov I., Pili R., Wang D., Jalal S., Pant S., Patel M. R., Neuwirth R. L., Enke A., Shou Y., Sedarati F., Faller D. V., H. A. Burris III , Br. J. Cancer 2020, 123, 1590; - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources