N-Heterocyclic Carbene-Promoted [4+2] Annulation of α-Chloro Hydrazones with α-Chloro Aliphatic Aldehydes to Access Enantioenriched Dihydropyridazinones

Abstract

An expeditious protocol for the assembly of chiral 4,5-dihydropyridazin-3­(2H)-ones from α-chloro hydrazones and α-chloro aliphatic aldehydes via N-heterocyclic carbene (NHC) catalysis is outlined. These in situ-generated 1,2-diaza-1,3-dienes undergo asymmetric [4+2] annulation with NHC-bound enolates to afford the desired products bearing a stereogenic center at the C4 position. The notable features of this approach include good to excellent enantioselectivities, high functional group tolerance, mild reaction conditions, simple operating procedures, and compatibility with gram-scale synthesis.

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study

“…50 TS4R is higher than TS4S by 2.1 kcal/ mol, a value that results in an enantioselectivity of 94.4% ee, which is again consistent with experimental results (94% ee). 50 In order to explore the origins of the stereoselectivity, noncovalent interaction (NCI) analysis was performed. The NCI plots of TS4R and TS4S are summarized in 3.4.…”

Diaza-1,3-butadienes as Useful Intermediate in Heterocycles Synthesis

“…1,2-Diaza-1,3-dienes 94 react with NHC-bound enolates 95 , which are formed in situ by the reaction of α-chloro aliphatic aldehydes 96 with N -heterocyclic carbene (NHC), through an asymmetric [4+2] annulation, yielding chiral 4,5-dihydropyridazin-3(2 H )-ones 97 with good yields and excellent enantioselectivities. The reaction proceeds under moderate conditions and is suitable for gram-scale synthesis ( Scheme 19 ) [ 46 ].…”

Iridium(iii)-catalyzed photoredox cross-coupling of alkyl bromides with trialkyl amines: access to α-alkylated aldehydes

“…Functionalized aldehydes have been often employed as precursors towards the syntheses of numerous significant molecules such as carboxylic acids, amines, amides, alcohols, nitriles, and many other carbocyclic as well as heterocyclic systems. 7 They are also well-known vital constituents of many natural products and pharmaceutically important molecules. 8 Functionalized aldehydes have also been utilized as new radical alkylating reagents, 9 as tools for a variety of synthetic, biological and in materials-based applications.…”