Abstract
Despite a large number of synthesis procedures for pyrazoles known today, those directly employing primary amines as substrates are rare. Herein, we report an original method for the preparation of N-alkyl and N-aryl pyrazoles from primary aliphatic or aromatic amines as a limiting reagent of the reaction. The protocol utilizes no inorganic reagents and requires a short reaction time, mild conditions, and the use of structurally simple and commercially available starting reagents. During this study, pyrazoles containing a wide variety of N-substituents were obtained using the same procedure for both aliphatic and aromatic amines.
Highlights
Pyrazoles can be obtained by numerous synthetic methods,[1−5] but their versatile applicability as pharmaceuticals,[6,7] crop protection chemicals,[8,9] building blocks for organic and inorganic chemistry[10,11] still propels research to develop new synthetic methodologies
In contrast to N-alkyl indazoles for which synthetic methodology starting from primary aliphatic amines is wellknown and broadly used,[19−21] N-alkyl pyrazoles are usually synthesized from difficult to handle hydrazines or hydrazine derivatives.[2−4,22−24] With a great variety of synthetic methods for N-alkyl pyrazoles, there are just two reports describing primary aliphatic amine as a limiting reagent that introduces an N-linked substituent into a product’s structure (Scheme 1).[25,26]
Electrophilic amination of primary aliphatic amines is a wellknown strategy for the preparation of hydrazines.[27−29] in all cases, a large excess of the amine is required due to hydrazine’s enhanced nucleophilicity relative to the corresponding origin amine.[30]. This problem might be solved by utilizing N-protected electrophilic amination reagents that form hydrazines that are stable under reaction conditions, but Scheme 1
Summary
Pyrazoles can be obtained by numerous synthetic methods,[1−5] but their versatile applicability as pharmaceuticals,[6,7] crop protection chemicals,[8,9] building blocks for organic and inorganic chemistry[10,11] still propels research to develop new synthetic methodologies. Electrophilic amination of primary aliphatic amines is a wellknown strategy for the preparation of hydrazines.[27−29] in all cases, a large excess of the amine is required due to hydrazine’s enhanced nucleophilicity relative to the corresponding origin amine.[30] This problem might be solved by utilizing N-protected electrophilic amination reagents that form hydrazines that are stable under reaction conditions, but Scheme 1. Pyrazoles from Aliphatic Amines as a Limiting Reagent this requires a further deprotection step.[25,31,32] Transformation with commercially available amination reagents that form unprotected hydrazine has practical advantages. We report a fast and straightforward method for the preparation of pyrazoles from primary aliphatic and aromatic amines as limiting reagents using bench-stable, commercially available amination reagent
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