Regioselective Preparation of Saturated Spirocyclic and Ring-Expanded Fused Pyrazoles

Abstract

Saturated bicyclic pyrazoles represent an important class of biologically active molecules, but their preparation can be hampered by labor-intensive synthesis of required starting materials. A convenient one- or two-step procedure for the synthesis of saturated spirocyclic and fused pyrazoles is reported. The synthesis benefits from the use of readily available alkynes and bench-stable tosylhydrazones, which are easily prepared from their parent ketones. Sigmatropic rearrangement of spirocyclic pyrazoles to fused analogues occurs with concomitant one-carbon expansion of the saturated ring, allowing rapid access to a range of pharmaceutically and agrochemically relevant polycyclic structures featuring a broad scope of saturated ring sizes.

Luxury of N‐Tosylhydrazones in Transition‐Metal‐Free Transformations

“…[50] Under the optimized reactionc onditions,v arious cyclic ketones such as cyclohexanone,c ycloheptanone, cyclooctanone,a damantanonea nd 6-membered heterocyclic ketones were well tolerateda nd smoothly converted into the corresponding fused pyrazoles.M oreover, some spirocyclic substratesu nderwent spontaneous rearrangement to afford their fused analogues 107.T he angular strain and more electrond ensity adjacent to the carbonyl group were responsible for the expansion of the spirocyclic ring. [52] Reaction of saturated cyclich ydrazones 108 and different alkyne partners furnished al ibrary of spirocyclic pyrazoles with a range of ring sizes under basic conditions.F urthermore,t hese spirocycles in the presence of BF 3 ·THF experience ar egioselective sigmatropic rearrangement to form the ring-expanded fused pyrazoles 110. [51] Thes pirocyclic pyrazoles 109 andr ing-expanded fused pyrazoles 110 were reported by the research team of Allwood as productso faregioselective twostep process (Scheme 45).…”

“…The spirocyclic pyrazoles 109 and ring‐expanded fused pyrazoles 110 were reported by the research team of Allwood as products of a regioselective two‐step process (Scheme ) . Reaction of saturated cyclic hydrazones 108 and different alkyne partners furnished a library of spirocyclic pyrazoles with a range of ring sizes under basic conditions.…”

Synthesis of spirocyclic dihydropyrazoles from tosylhydrazones and electron-deficient alkenes

“…Therefore, novel synthetic methodologies for the preparation of highly three-dimensional core scaffolds are of significant interest to both academic and industrial medicinal chemists. [1][2][3][4][5][6][7][8] One strategy for increasing molecular three-dimensionality is the incorporation of spirocyclic ring junctions into the core scaffold of the drug, since the rings joined by the spirocyclic atom are mutually orthogonal and thereby effectively engage all three dimensions. Spirocycles therefore represent an inviting synthetic target for medicinal chemists due to the inherent three-dimensionality present but also the broad range of biological activities demonstrated by this compound class.…”

Cycloaddition reactions of acetylenic iminium salts and diazoacetates leading to pyrazole iminium salts

“…Since the chemical and thermal stability of some classes of diazo compounds is not high, variations of the cycloaddition method have been developed which allow their in situ preparation. In this manner, they were generated from tosylhydrazones of aldehydes [16], alkyl-arylketones [17] and saturated cyclic ketones [18]. The in situ preparation of 2,2,2-trifluoro-diazoethane by amine diazotization in combination with a silver-mediated cycloaddition at terminal alkynes has been applied to the synthesis of 3-CF 3 -substituted pyrazoles including the antiarthritic drug Celecoxib [19].…”