Synthesis of Chiral Pyrazoles: A 1,3-Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

• Published in: Angewandte Chemie International Edition Vol. 54; no. 46; pp. 13729 - 13733
• Main Authors: Pérez-Aguilar, M. Carmen, Valdés, Carlos
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 09.11.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkynes; Alkynes - chemistry; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; Cycloaddition Reaction; diazo compounds; heterocycles; Hydrazones - chemistry; Migration; Molecular Structure; Physical Sciences; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Quantum Theory; rearrangements; Science & Technology; Stereoisomerism; Strategy; Synthesis; Terminals; tosylhydrazone; Transformations; THERMAL REARRANGEMENTS; ENANTIOSELECTIVE SYNTHESIS; STEREOCHEMISTRY; COMPLEXES; CONFIGURATION; TOSYLHYDRAZONES; ALKYNES; tosylhydrazone; cycloaddition; heterocycles; CYCLOADDITIONS; rearrangements; REGIOSELECTIVE SYNTHESIS; BIOLOGICAL EVALUATION; diazo compounds
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201506881

The reactions between terminal alkynes and α‐chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3‐dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α‐chiral tosylhydrazones, obtained from α‐phenylpropionic acid, α‐amino acids, and 2‐methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation. Maintaining a (con)figur(ation): Retention of configuration in [1,5] sigmatropic shifts are predicted by the Woodward–Hoffmann rules, but are not well‐documented experimentally. Such shifts are observed in the reactions of α‐chiral tosylhydrazones with terminal alkynes. The chiral pyrazole products are formed by a 1,3‐dipolar cycloaddition and subsequent site‐, regio‐, and stereospecific [1s,5s] sigmatropic rearrangement. Ts=4‐toluenesulfonyl.