2023
DOI: 10.1021/jacs.3c11504
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A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates

Jake D. Selingo,
Jacob W. Greenwood,
Mary Katherine Andrews
et al.

Abstract: Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine… Show more

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Cited by 5 publications
(2 citation statements)
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“…Our group has a longstanding interest in the reactivity of N Tf-azinium salts, and Scheme B shows our proposed method to synthesize 15 N-pyridines. In 2022, we disclosed that N Tf-activated pyridines undergo facile ring-opening with dibenzylamine to form N Tf-Zincke imines as part of a method for 3-selective halogenation. , Ring-closing with 15 NH 4 X salts would therefore be a trivial way to incorporate the 15 N atom. There are three distinct advantages of this approach.…”
mentioning
confidence: 99%
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“…Our group has a longstanding interest in the reactivity of N Tf-azinium salts, and Scheme B shows our proposed method to synthesize 15 N-pyridines. In 2022, we disclosed that N Tf-activated pyridines undergo facile ring-opening with dibenzylamine to form N Tf-Zincke imines as part of a method for 3-selective halogenation. , Ring-closing with 15 NH 4 X salts would therefore be a trivial way to incorporate the 15 N atom. There are three distinct advantages of this approach.…”
mentioning
confidence: 99%
“…Scheme shows two reaction protocols for 15 N-labeling that vary based on the pyridine substitution pattern. For 2-substituted pyridines, such as 2-phenylpyridine 1a , our previously reported ring-opening conditions using Tf 2 O, dibenzylamine, and collidine at low temperatures are appropriate. , Washing the reaction mixture with an aqueous solution of CuSO 4 removes dibenzylamine, and a significant advantage of this approach is the solubility properties of Zincke imines that precipitate when we add the organic extracts to hexanes. Isolating 2a in this fashion ensures that unlabeled 1a does not advance into the subsequent ring-closing step.…”
mentioning
confidence: 99%