Copper-Catalyzed Double C–H Alkylation of Aldehyde-Derived N,N-Dialkylhydrazones with Polyhalomethanes: Flexible Access to 4-Functionalized Pyrazoles

Abstract

Here, 4-functionalized pyrazoles have been made accessible in a single step from readily available aldehyde-derived N,N-dialkyl hydrazones and functionalized polyhalomethane derivatives. The process is believed to follow copper-catalyzed cascade C­(sp2)–H haloalkylation/C­(sp3)–H cyclization/aromatization reaction sequences.

Radical‐Mediated Formal C(sp2)–H Functionalization of Aldehyde‐Derived N,N‐Dialkylhydrazones

“…In view of their high efficiency, new methodologies then naturally evolved to accommodate a range of other, non‐fluorinated functional groups. For instance, in 2016 our group envisioned that other functionalized polyhalomethanes (e.g., trichloromethyl derivatives, R–CCl 3 ), might participate in the Cu‐catalyzed C–H alkylation process and thereby open up direct access to hitherto unknown polyhalomethylated N , N ‐dialkylhydrazones 33 as expectedly reactive new synthetic intermediates with high potential for further elaboration. In fact, reactions involving trichloromethyl derivatives resulted in the direct formation of pyrazole derivatives 32 , seemingly confirming the high reactivity of the chlorinated reaction adducts.…”

Regiocontrolled Synthesis of 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazines

“…4d Other cyclization strategies to build the pyrazole ring from morpholine precursors have also been investigated, albeit with a very limited reported substrate scope. 8, 9 Recently, we disclosed a flexible strategy for the synthesis of pyrazolo [1,5-a]pyrazines 5 in a regioselective fashion (Scheme 1a). 10 Pyrazole derivatives 3, formed via alkylation of 4-substituted pyrazoles 1 (R 1 = H) with alkyl bromide 2, were shown to successfully undergo regioselective formylation at the most acidic 5-position 11 after treatment with LDA and DMF to give the corresponding pyrazole aldehydes 4.…”

Transition-Metal-Free [3 + 2] Cycloaddition of Nitroolefins and Diazoacetonitrile: A Facile Access to Multisubstituted Cyanopyrazoles

“…Due to the immense usefulness of multisubstituted cyanopyrazoles, efficient construction of these coveted frameworks has gained intensive attention in the fields of synthetic and medicinal chemistry. Traditional approaches to multisubstituted cyanopyrazoles involve direct cyanation of pyrazole derivatives followed by late elaboration of the resulting cyanopyrazoles, the Thorpe–Ziegler cyclization of dicyanohydrazones with activated methylene reagents, three-component reaction of aldehydes with the Bestmann–Ohira reagent and malononitrile, , and copper-catalyzed tandem haloalkylation/cyclization of aldehyde-derived hydrazones with trichloroacetonitrile . However, these methods usually suffered from several disadvantages, such as a tedious synthetic procedure for starting materials, limited substrate scope, release of a toxic byproduct, and/or need for a precious transition metal.…”

“…Traditional approaches to multisubstituted cyanopyrazoles involve direct cyanation of pyrazole derivatives 3 followed by late elaboration of the resulting cyanopyrazoles, 3c the Thorpe− Ziegler cyclization 4 of dicyanohydrazones with activated methylene reagents, 5 three-component reaction of aldehydes with the Bestmann−Ohira reagent and malononitrile, 6,7 and copper-catalyzed tandem haloalkylation/cyclization of aldehyde-derived hydrazones with trichloroacetonitrile. 8 However, these methods usually suffered from several disadvantages, such as a tedious synthetic procedure for starting materials, limited substrate scope, release of a toxic byproduct, and/or need for a precious transition metal. Therefore, it is highly desirable to develop a direct and general method for the construction of diverse cyanopyrazole species.…”