Issue 31, 2015

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Abstract

We report a new synthetic approach that opens up the possibility of large scale, one-pot pyrazole derivatization by a wide variety of functionalities, including alkyl, halogen, hydroxyl, amino, azido, carbonyl, and organo-element (e.g., B, Si, P) groups. The approach is illustrated by the highly efficient synthesis of fourteen 3(5)-alkylpyrazoles, including the novel isopentyl- and n-hexadecyl derivatives, as well as 1,6-bis(pyrazol-3(5)-yl)hexane. The value of the new approach lies in the discovery of a green (solvent- and catalyst-free, quantitative) protection of pyrazole, followed by a high-yield lithiation/alkylation/deprotection sequence in the same pot. For the first time, the corresponding N-tetrahydropyran-2-yl (THP) intermediates have been isolated and characterized. Thermal isomerization of the 5-alkyl-1-(THP) to the 3-alkyl-1-(THP) isomer is shown to be an advantageous, green alternative to the acid-catalyzed, sequential protecting-group switching methodology in pyrazole chemistry. The X-ray crystal structures of 1,6-bis(pyrazol-3(5)-yl)hexane and 5-n-hexadecyl-1-(tetrahydropyran-2-yl)pyrazole reveal supramolecular architectures that shine light on the remarkable affinity for water and unexpected insolubility in organic solvents of alkylene-bridged bis(pyrazoles). 3(5)-Alkylpyrazoles are obtained in high yield from pyrazole by a one-pot procedure.

Graphical abstract: Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Supplementary files

Article information

Article type
Paper
Submitted
14 Jan 2015
Accepted
24 Feb 2015
First published
26 Feb 2015

RSC Adv., 2015,5, 24081-24093

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

B. M. Ahmed and G. Mezei, RSC Adv., 2015, 5, 24081 DOI: 10.1039/C5RA00837A

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