Multi-component, regio-selective aldol addition of β-ketoesters to aldehydes: scope and applications

Abstract

Simple and effective multi-component one-pot aldol addition/protection reactions of β-ketoesters to a series of aldehydes in the presence Me(3)SiCl and i-Pr(2)EtN have been described. The analysis of the scope of the reaction revealed a dramatic dependence of the reactivity on the substrates used. Thus the effect of a catalytic amount of DMF and different reaction conditions was widely investigated. Further transformations of the aldol adducts were particularly useful to give valuable diols and compounds with quaternary stereocenters, while X-ray structural analysis gave also important stereochemical information about this challenging reaction.

Nanoporous Aluminosilicate-Catalyzed Telescoped Acetalization-Direct Aldol Reactions of Acetals with 1,3-Dicarbonyl Compounds

“…17,18 Currently, only a comparatively small number of synthetic strategies has addressed this limitation, exploiting multicomponent processes, which trap the unstable β-hydroxycarbonyl intermediates to limit the retro–aldol reaction or use very mild reaction conditions employing very weak acids or bases. 18,19 The lack of suitable aldol protocols has led to the development of alternative synthetic strategies to access β-hydroxycarbonyl products, such as the oxy-Michael addition reaction of alkoxide nucleophiles under strongly basic conditions. 20…”

“…The development of synthetically useful routes to access β-hydroxycarbonyl compounds derived from these activated carbonyl compounds is of particular interest as they have been identified as useful intermediates in natural product synthesis. − Additionally, 3-substituted-2,4-pentanedionates have been identified as useful chelating motifs in functionalized materials displaying novel photochemical properties . Typical aldol reaction conditions, employing basic conditions, generate chelated enolate intermediates, which are unreactive, and when successful, the β-hydroxycarbonyl products generated are prone to undergo facile elimination reactions to produce Knovenagel products or retro–aldol reaction to regenerate starting materials. , Currently, only a comparatively small number of synthetic strategies has addressed this limitation, exploiting multicomponent processes, which trap the unstable β-hydroxycarbonyl intermediates to limit the retro–aldol reaction or use very mild reaction conditions employing very weak acids or bases. , The lack of suitable aldol protocols has led to the development of alternative synthetic strategies to access β-hydroxycarbonyl products, such as the oxy-Michael addition reaction of alkoxide nucleophiles under strongly basic conditions …”

“…17,18 Currently, only a comparatively small number of synthetic strategies has addressed this limitation, exploiting multicomponent processes, which trap the unstable β-hydroxycarbonyl intermediates to limit the retro−aldol reaction or use very mild reaction conditions employing very weak acids or bases. 18,19 The lack of suitable aldol protocols has led to the development of alternative synthetic strategies to access β-hydroxycarbonyl products, such as the oxy-Michael addition reaction of alkoxide nucleophiles under strongly basic conditions. 20 Our interest in this area was prompted by the observation that acyclic acetals undergo direct aldol reactions with activated methylene compounds in the presence of strong Lewis acids at very low reaction temperatures to give the corresponding addition products (Scheme 1).…”

Multifaceted Behavior of 2‐Cyanobenzaldehyde and 2‐Acylbenzonitriles in the Synthesis of Isoindolinones, Phthalides and Related Heterocycles

“…To this purpose the use of chlorotrimethylsilane in the presence of a weak base like i ‐Pr 2 EtN (DIPEA) led to the easy isolation of the protected aldol products 44 in high efficiency, in a one‐pot multicomponent process (Scheme 9). [12,13] The isolated protected aldol products were also utilized in different transformations to afford useful synthons [12,13] …”

“…[5][6][7][8][9][10] At that time, we were analyzing the scope of aldol reaction of double activated methylene compounds 41 like dimethylmalonate (Scheme 8). [12,13] Cross aldol reaction of dimethylmalonate with aromatic aldehydes 40 is very challenging, because the reaction is reversible, and the aldol product 42 is not stable. [12,13] When the reaction is forced, the Knoevenagel condensation product 43 is obtained (Scheme 8).…”