Organocatalytic Enantio‐ and Diastereoselective Conjugate Addition to Nitroolefins: When β‐Ketoamides Surpass β‐Ketoesters

Abstract

Our findings on the bifunctional squaramide-catalyzed enantioselective conjugate addition of β-ketoamides to nitroolefins are disclosed. It appears that simple acyclic methylene β-ketoamides, unlike the extensively studied β-ketoesters, afford the products in excellent diastereoselectivities, and maintain high yields and enantioselectivities. Moreover, competition and kinetic studies were conducted to rationalize the observed reactivity and selectivity. The high level of diastereocontrol, along with the amenability of the amide group to postfunctionalization, dramatically increase the synthetic usefulness of the transformation.

Creation through Immobilization: A New Family of High Performance Heterogeneous Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts

“…Conjugate Addition of β-Keto Amides to Nitrostyrene a a Absolute stereochemistry determined by comparison with literature compounds25 and by analogy (see Supporting Information). b Determined by 1 H NMR analysis of the crude reaction mixture.…”

Weinreb β-Ketoamides in Enantioselective Organocatalysis: A Balance between Reactivity and Selectivity

“…They occupy a special position halfway between β-ketoesters and other β-ketoamides, which allow to find a fine balance between reactivity and selectivity. Their unique features could be exemplified by the control of diastereoselectivity in their Michael addition to nitroolefins in the presence of a bifunctional hydrogen-bonding catalyst, 17 and the reversal of regioselectivity in the preparation of tetrahydropyridines through a MCR with iminium activation. 39 We strongly believe that their systematic evaluation in organocatalyzed transformations involving β-dicarbonyl compounds as substrates will result in other important findings in the near future.…”

“…26 Table 2 Scope of nitroolefins in the organocatalyzed Michael addition of -ketoamide 9a. 17 Yield of product isolated by flash chromatography. dr determined by 1 H NMR spectroscopy of the crude reaction mixture.…”

“…17 Yield of product isolated by flash chromatography. dr determined by 1 H NMR spectroscopy of the crude reaction mixture.…”

Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

“…As previously mentioned, one of the remaining challenges in the organocatalytic asymmetric addition of dicarbonyl compounds to nitroalkenes is the search for new pro-nucleophiles which allow further elaboration of the resulting adducts for the search of bioactive compounds. Thus, the quinine-squaramide derivative 114 has turned out to be an efficient organocatalyst for the enantio- and diastereoselective conjugate addition of β-ketoamides to aryl- and alkyl-nitroolefins, to afford adducts 115 ( Scheme 28 ) [ 130 ]. These starting β-ketoamides, despite being more difficult to activate due to the lower acidity of the hydrogen placed in α-position, present some advantages compared to other dicarbonyl compounds.…”