Pyrazole is a remarkably versatile moiety with a wide range of applications, including medicinal products, agricultural chemicals, dyes, and ligands used in various areas of coordination and materials chemistry. Nanojars, a new class of selective anion extraction agents developed in our laboratory, are also based on pyrazole ligands. Consequently, we aim at finding green, high-yield and inexpensive approaches for the derivatization of pyrazole. We illustrate a new approach for the highly efficient, telescoping (one-pot) synthesis of pyrazole derivatives by the preparation and characterization of a series of 3-alkylpyrazoles and 3,5-dialkylpyrazoles. Green (solvent- and catalyst-free, quantitative) protection of pyrazole was achieved by using inexpensive 3,4-dihydro-2H-pyran. Lithiation with n-BuLi, followed by alkylation with iodo- or bromoalkanes, and deprotection with aqueous HCl leads to 3-alkylpyrazoles. Thermal isomerization (catalyzed of iodine) of 5-alkyl-1-(tetrahydropyran-2-yl)-1H-pyrazoles at 125 °C provides 3-alkyl-1-( tetrahydropyran-2-yl)-1H-pyrazoles, which can be further derivatized by lithiation with n-BuLi, alkylation with iodo- or bromoalkanes, and deprotection with aqueous HCl, leading to 3,5-dialkylpyrazoles. Computational studies show that in contrast to the deprotonation of methyl-substituted, six-membered aromatic molecules, which produces exocyclic benzylic carbanions stabilized by π-conjugation, deprotonation of methyl-substituted, five-membered aromatic rings occurs at an endocyclic CH group. The more favorable deprotonation of an endocyclic carbon rather than of the ‘benzylic’ position is a result of diminished π-conjugation, reduced bond angles and strengthened induction of Csp2 versus Csp3 in five-membered rings. We also show that the resistance of 5-alkyl-1-(tetrahydropyran-2-yl)-1H-pyrazole isomers to deprotonation by n-BuLi, previously attributed to the “adjacent lone pair effect”, is mainly due not to electron pair repulsion, but rather to reduced π-resonance and electrostatic interactions within the pyrazole ring.

Green protection of pyrazole, catalytic thermal isomerization of tetrahydropyranylpyrazoles, and telescoping synthesis of 3-alkyl- and 3,5-dialkylpyrazoles

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.