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. 2024 Feb 7;146(5):2939-2943.
doi: 10.1021/jacs.3c11618. Epub 2024 Jan 12.

15NRORC: An Azine Labeling Protocol

Zachary A Tolchin  1 , Joel M Smith  1
Affiliations

15NRORC: An Azine Labeling Protocol

Zachary A Tolchin et al. J Am Chem Soc. .

Abstract

A practical method for the synthesis of 15N-labeled azines with a high degree of isotopic enrichment is described. Activation of azine heterocycles with an electron-deficient arene allows for the facile substitution of the nitrogen atom with a specifically designed 15N-labeled reagent that undergoes a canonical ANRORC-type mechanism. A wide range of azines can be converted to their corresponding 15N isotopologs using this method, and it also allows for dearomative access to reduced heterocyclic congeners. A short dearomative formal synthesis of 15N-solifenacin is accomplished as well to demonstrate a practical application of this method for generating labeled pharmaceuticals.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(A) Importance of 15N-labeling based on synthetic and translational applications. (B) Classical Zincke reaction. (C) Hypothetical 15NRORC transformation and design challenges. (D) Investigation of azine activation with Tf2O and displacement.
Scheme 1.
Scheme 1.. Scope and Limitations of the 15NRORC Displacement Procedure
aIsolated yields are given. b%15N enrichment as determined by relative abundance in HRMS. cProduct yield was low due to volatility. d1 mmol scale. eIsolated as TMB salt. fOne-pot procedure with activation and labeling.
Scheme 2.
Scheme 2.
Limitations and Formal Synthesis of 15N-Solifenacin
See this image and copyright information in PMC

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