Polycyclic Pyrazoles from Alkynyl Cyclohexadienones and Nonstabilized Diazoalkanes via [3 + 2]-Cycloaddition/[1,5]-Sigmatropic Rearrangement/Aza-Michael Reaction Cascade

Abstract

An efficient method for the stereoselective synthesis of "all center substituted" polycyclic pyrazoles from alkynyl cyclohexa-2,5-dienones and nonstabilized diazoalkanes via sequential [3 + 2]-cycloaddition/[1,5]-sigmatropic rearrangement and aza-Michael reactions is reported. The developed process is highly regioselective and stereoselective. It employs a wide substrate scope to furnish structurally diverse linear and bridged [4.4.n.0] ring-fused pyrazoles in moderate to good yields. One-pot and gram-scale syntheses and synthetic transformations have also been showcased.

Anion-Relay Double Aza-Michael–Michael Cascades to Enone-Tethered Cyclohexadienones: Access to an Intricate Bridged Ring System

“…An inter- and intramolecular aza-Michael desymmetrization strategy has also been employed to afford cyclohexadienones . In addition, we have reported the synthesis of structurally diverse intriguing polycyclic frameworks via a stereoselective desymmetrization strategy . Cascade annulation reactions are reported with enone-tethered cyclohexadienones ( 1 ) in the presence of external coupling partners and in the presence of transition metals led to bicyclic products [ I (Scheme b)]. , Chegondi et al reported the Lewis acid-catalyzed synthesis of highly strained polycyclic indoles ( II ) from 1 via double Friedel–Crafts alkylation of an indole .…”

“…Cascade annulation reactions are reported with enone-tethered cyclohexadienones ( 1 ) in the presence of external coupling partners and in the presence of transition metals led to bicyclic products [ I (Scheme b)]. , Chegondi et al reported the Lewis acid-catalyzed synthesis of highly strained polycyclic indoles ( II ) from 1 via double Friedel–Crafts alkylation of an indole . As a continuation of our efforts to discover new desymmetrization approaches for prochiral cyclohexadienones, we envisaged that alkaloid-like aza-bridged polycyclic scaffolds ( 3 ) could be achieved directly from suitably substituted alkenyl-cyclohexadienones ( 1 ) with primary amines ( 2 ) through intermediates 4 or 5 via cascade aza-Michael–Michael reactions (Scheme c). As there are multiple reactive sites in the starting materials, significant challenges are anticipated with respect to the selective formation of product 3 along with possible linearly fused and symmetrically bridged aza-bicyclic products ( 5 and 6 ) via double aza-Michael pathways (Scheme c).…”

“…Bridged [3.1.1] aza-heptane ( 6a ) was also not observed under any of our conditions, probably due to the strained ring system (Table , entries 1–7). Acidic or transition-metal catalysis is generally studied for the activation of cyclohexadienones, − and thus, to facilitate the cascade annulation process, a number of Brønsted/Lewis acids (20 mol %) were examined (entries 2–4). Pleasingly, the formation of the desired aza-bridged tricyclic product (±)- 3a was confirmed (<10% yield) in the presence of CF 3 SO 3 H (entry 2).…”