Heterocyclic Surgery for Isotopic Labeling

This manuscript is dedicated to the memory of Zachary A. Tolchin

Abstract

Recent developments in the isotopic labeling of heteroarenes may prove to be useful in the realms of biomedical science, materials chemistry, and fundamental organic chemistry. The use of the age-old Zincke reaction, or tactical variants thereof, has become particularly utilitarian in effecting single-atom nitrogen replacement in various azines to generate their desired isotopologues. This chemistry can be synthetically leveraged at an early stage for diversity-oriented heterocyclic labeling of pharmaceuticals and/or natural products. Additionally, given the prevalence of saturated azacycles in biologically relevant molecules, access to these isotopologues becomes relevant through dearomative retrosynthetic analysis from the corresponding ¹⁵N-labeled heteroarenes.

1 Introduction

2 Our Lab’s Development of the ¹⁵NRORC Reaction

3 Other Recent Azine-Labeling Methods

4 Expanded ANRORC Utilization

5 Conclusion and Outlook

Key words

pyridine - azine - isotope - labeling - Zincke - dearomatization - ANRORC

• References

• 1 Theis T, Truong ML, Coffey AM, Shchepin RV, Waddell KW, Shi F, Goodson BM, Warren WS, Chekmenev EY. J. Am. Chem. Soc. 2015; 137: 1404
• 2 Truong ML, Theis T, Coffey AM, Shchepin RV, Waddell KW, Shi F, Goodson BM, Warren WS, Chekmenev EY. J. Phys. Chem. C 2015; 119: 8786
• 3 Chukanov NV, Kidd BE, Kovtunova LM, Bukhtiyarov VI, Shchepin RV, Chekmenev EY, Goodson BM, Kovtunov KV, Koptyug IV. J. Labelled Compd. Radiopharm. 2019; 62–: 892
• 4 Zincke T, Heuser G, Möller WI. Justus Liebigs Ann. Chem. 1904; 333: 296
• 5 Van der Plas HC. Acc. Chem. Res. 1978; 11: 462
• 6 Vanderwal CD. J. Org. Chem. 2011; 76: 9555
• 7 Martin DB. C, Vanderwal CD. J. Am. Chem. Soc. 2009; 131: 3472
• 8 Martin DB. C, Nguyen LQ, Vanderwal CD. J. Org. Chem. 2012; 77: 17
• 9 Martin DB. C, Vanderwal CD. Chem. Sci. 2011; 2: 649
• 10 Hong AY, Vanderwal CD. J. Am. Chem. Soc. 2015; 137: 7306
• 11 Barnes GL, Hong AY, Vanderwal CD. Angew. Chem. Int. Ed. 2023; 62: e202215098
• 12 Burns NZ, Baran PS, Hoffmann RW. Angew. Chem. Int. Ed. 2009; 48: 2854
• 13 Boyle BT, Levy JN, de Lescure L, Paton RS, McNally A. Science 2022; 378: 773
• 14 Wang H, Greaney MF. Angew. Chem. Int. Ed. 2024; 63: e202315418
• 15 Bartholomew GL, Carpaneto F, Sarpong R. J. Am. Chem. Soc. 2022; 144: 22309
• 16 Tolchin ZA, Smith JM. J. Am. Chem. Soc. 2024; 146: 2939
• 17 Barskiy DA, Shchepin RV, Coffey AM, Theis T, Warren WS, Goodson BM, Chekmenev EY. J. Am. Chem. Soc. 2016; 138: 8080
• 18 Takeuchi M, Naito R, Hayakawa M, Okamoto Y, Yonetoku Y, Ikeda K, Isomura Y. US6017927, 1995
• 19 Bartholomew GL, Kraus SL, Karas LJ, Carpaneto F, Bennett R, Sigman MS, Yeung CS, Sarpong R. J. Am. Chem. Soc. 2024; 146: 2950
• 20 Feng M, Norlöff M, Guichard B, Kealey S, Thuéry P, Gee A, Feuillastre S, Audisio D. ChemRxiv 2023; preprint
• 21 Falcone NA, He S, Hoskin JF, Mangat S, Sorensen EJ. ChemRxiv 2024; preprint
• 22 Falcone NA, He S, Hoskin JF, Mangat S, Sorensen EJ. Org. Lett. 2024; 26: 4280
• 23 Uhlenbruck BJ. H, Josephitis CM, de Lescure L, Paton RS, McNally A. Nature 2024; 631: 87