Yonemitsu-type condensations catalysed by proline and Eu(OTf)₃

Abstract

We report a Yonemitsu-type trimolecular condensation of aromatic heterocycles, aldehydes, and active methylene compounds to afford polyfunctionalised heterocycles. The reaction is catalysed by L-proline and Eu(OTf)3, takes place in methanol at room temperature, and in some cases is highly diastereoselective (d.e. >90%). The reaction offers two advantages with respect to the previously reported Ti(IV)-promoted condensation: (1) it adheres to some principles of green chemistry, and (2) it provides access to compounds that cannot be obtained by classical methodology

Diastereomer Interconversion via Enolization: A Case Study

“…). In both cases, the absence of further peaks allowed the presence of the enol form to be excluded, in line with previous 1 H NMR spectroscopic observations . The absence of the enol of 1 is in contrast with the behavior of analogous 2‐substituted β‐ketoesters, which all enolize in solution to some extent, especially in a solvent of low polarity that has been recognized to favor the enol tautomer …”

“…Asymmetric transformations of diastereomers are an important tool for the resolution of chiral compounds, as they allow the conversion of a mixture of diastereomers into a single diastereomer or into a mixture in which one diastereomer predominates. In this context, we recently reported the three‐component reaction of methyl acetoacetate, isobutyraldehyde, and indole to afford methyl 2‐(acetyl)‐3‐(3‐indolyl)‐3‐(1 H ‐indol‐3‐yl)‐4‐methylpentanoate (Scheme ) . The reaction is promoted by TiCl 4 or TiCl 2 (O i Pr) 2 in the presence of Et 3 N, or by a lanthanide salt and an α‐amino acid .…”

“…In this context, we recently reported the three‐component reaction of methyl acetoacetate, isobutyraldehyde, and indole to afford methyl 2‐(acetyl)‐3‐(3‐indolyl)‐3‐(1 H ‐indol‐3‐yl)‐4‐methylpentanoate (Scheme ) . The reaction is promoted by TiCl 4 or TiCl 2 (O i Pr) 2 in the presence of Et 3 N, or by a lanthanide salt and an α‐amino acid . Under both reaction conditions, the product is isolated as a single diastereomer racemate ( 1 ) with relative configuration (2 R *,3 R *) (Scheme )…”

“…We have proposed that the observed high diaste‐reoselectivity arises from a crystallization‐induced asymmetric transformation . This type of transformation is commonly observed in diastereomers, either diastereomeric salts or covalent diastereomers, although it is possible with enantiomers as well.…”

para‐Toluenesulfonic Acid‐Catalyzed, Ultrasound‐Promoted, One‐Pot, Three‐Component Coupling of Aldehydes, β‐Dicarbonyls/Amides, and Electron‐Rich Arenes

“…In 1978, Yonemitsu developed a one‐pot three component coupling of aldehydes, Meldrum's acid, and indoles to generate biologically relevant motifs . Since then, several methods of Yonemitsu reactions are reported using Brønsted bases such as d,l ‐proline or Lewis acidic species such as TiCl 4 , Yb(OTf) 3 or Eu(OTf) 3 . Recently, heterogeneous catalysts such as hydromagnesite rectangular thin sheets, Fe 3 O 4 @SiO 2 ‐PEG/NH 2 , and graphene oxide supported ionic liquids, have been developed for this particular three‐component coupling reaction.…”