NHC-catalysed, chemoselective crossed-acyloin reactions

Abstract

It has been shown for the first time that relatively electron deficient triazolium pre-catalysts promote (at low loadings in the presence of base) highly chemoselective crossed acyloin condensation reactions between aldehydes and a-ketoesters to afford densely functionalized products incorporating a quaternary stereocentre of considerable synthetic potential. Hydroacylation pathways which have hitherto been dominant in these reactions can be completely avoided. The scope of the process is extraordinarily broad with respect to both coupling partners, and a preliminary study has established the principle that a high degree of stereochemical control over the reaction can also be exercised via the use of a chiral NHC precursor. It has also been shown for the first time that coupling of benzyl a-ketoesters with aldehydes followed by acylation and simple hydrogenolysis furnishes a product formally derived from the chemoselective 1 : 1 coupling of two different aliphatic aldehydes in high yield with absolute control over which coupling partner behaves as the acyl-anion equivalent.

Catalytic Asymmetric Cross‐Aza‐Benzoin Reactions of Aliphatic Aldehydes with N‐Boc‐Protected Imines

“…[1,2] Nature has long utilized the concept of "umpolung" (reversal of polarity) in the form of thiamine-dependent enzymes, which are required for life. [4] The inherent problem with this transformation lies in the lack of chemoselectivity between aldehyde partners. [4] The inherent problem with this transformation lies in the lack of chemoselectivity between aldehyde partners.…”

N‐Heterocyclic‐Carbene‐Catalyzed Synthesis of 2‐Aryl Indoles

“…Importantly, the ability to cycle this undesired Umpolung product back into the desired reaction allows for less aldehyde substrate (i.e., 1.2 equiv) than typical intermolecular acyl anion reactions. [22],[23] Further improvement in yield was achieved by reducing the equivalents of benzaldehyde and cesium carbonate (entry 6-7).…”

“…At this time, reactions with ortho -substituted aryl aldehydes provide recovery of unreacted starting materials or low conversion to the intermediate ketone. [22] Either production of the nucleophilic Breslow intermediate ( 1b ) is slow and/or disfavored due to destabilizing interactions or once formed, the strain engendered promotes a conformational change placing the aryl ring orthogonal to the enol thiazolium system, thus sterically encumbering the nucleophilic acyl anion carbon (eq 1). Investigation of heteroaryl-aldehydes produced indoles containing 2-naphthyl ( 4l ), pyridyl ( 4m ), and thiophenyl ( 4n ) C-2 substitutions.…”

Carboranes as Aryl Mimetics in Catalysis: A Highly Active Zwitterionic NHC‐Precatalyst

“…We started out with classical umpolung transformations, in which N ‐pentafluorophenyl‐substituted precatalysts (Figure , II and VI ), representing electron‐withdrawing N ‐aryl residues, are well established and are known for increased rates for the initial adduct formation. Using triazolium precatalyst 5 , we examined a broad set of homo‐ and cross‐benzoin reactions employing aromatic ( 8 a, d – e ) and aliphatic ( 8 b, c ) aldehydes as well as trifluoromethylketones ( 8 f ) and α‐keto esters ( 8 g ) (Scheme , bottom left). Interestingly, our catalyst was highly selective for the transformation of aromatic substrates, whereas other electrophilic partners could not be converted.…”