Synthetic applications of carbenes in organocatalysis Flashcards
What are the main areas of organocatalysis by NHCs?
Acyl anion catalysis (formation of d1 synthons), catalysis involving extended Breslow-like intermediates (d3 synthons) and catalysis involving acylazolium intermediates and azolium enolates (d2 synthons).
What is the key example reaction and its mechanism?
Benzoin condensation by nucleophilic catalysis. Nucleophile attacks aldehyde to form tetrahedral intermediate. Protonation to give x-hydrin, nucleophilic attack from nucleophile bond to second carbonyl species followed by elimination of nucleophile catalyst to give alpha-hydroxy-carbonyl species.
What is the general mechanism for homobenzoin condensation via NHC catalysis?
Deprotonation of NHC precursor in situ to give active cat. species. Formation of NHC-aldehyde adduct. Deprotonation to give acyl-anion equivalent and resonance form to give Breslow intermediate with key enaminol functionality. Addition of second aldehyde, followed by NHC regeneration by carbonyl formation.
Why is NHC research interested in crossbenzoin reactions?
Important reaction with 4 potential products from cross-reactions. Aim to have regioselectivity and potentially enantioselectivity!
What features of NHCs lead to product selectivity?
Fused ring systems, chiral substituents on the ring, N-aryl substituent, NHC identity giving rise to specific E/Z geometries in intermediates.
What are some general trends in product chemoselectivity by NHCs?
Triazolium catalysts favour formation from alkyl (alkyl attacks first) and thiazolium catalysts favour formation from aryl. Formation from non-ortho-substituted aldehydes for both catalysts.
What is the Stetter reaction?
Acyl anion coupling with an activated Michael acceptor. Intramolecular often used as a benchmark. Intermolecular obtained with extreme, electron-deficient acceptors with N-mesityl catalysts. Competes with homobenzoin reaction.
What is hydroacylation?
Alkene reaction with aldehyde to give longer ketone [acyl anion coupling with an unactivated alkene acceptor]
What are the potential mechanisms for carbon-carbon bond forming step in hydroacylation using NHCs?
Conventional stepwise mechanism - formation of naked anion, highly unlikely to form.
Concerted mechanism - similar to Conia-ene reaction, cyclic movement of arrows to generate negative charge on oxygen atom before NHC regeneration.
Radical mechanism - no evidence for or against this. Formation of radical oxygen and radical alkene, followed by barrierless recombination.
How does chemoselectivity of BACs vs NHCs compare with Stetter and benzoin reactions?
BACS favour Stetter reaction product, and NHCs favour benzoin product. NB. Limited asymmetry has been attempted via chiral BACs.
What is the general mechanism for NHC catalysis involving extended Breslow-like intermediates?
Deprotonation of NHC precursor in situ to give active cat. species. Formation of NHC-alpha-beta-unsaturated-carbonyl adduct. Deprotonation and resonance to give d3 synthon equivalent/extended-Breslow-like intermediate with key enaminol functionality. Addition of electrophile, followed by NHC regeneration.
What reactions can be done using extended Breslow-like intermediates and what is the determining factor?
Choice of acceptor/electrophile. Can undergo beta-functionalisation of enals, lactone and lactam formation.
What reactions can occur involving acylazolium intermediates and azolium enolates? What impacts reactivity?
Reactivity pattern defines the key intermediate. Key examples are:
generation from ynals to give alpha-beta unsaturated esters
generation from acyl fluorides in intermolecular Michael additions
generation from alpha-beta unsaturated esters in N-annulations
generation from alpha-beta unsaturated aldehydes in the presence of oxidants
How do reactions via alpha-beta unsaturated acylazolium via ynal generation work?
Deprotonation of NHC precursor to give active catalyst. Formation of NHC adduct and subsequent deprotonation by attack at carbonyl. Protonation of Breslow-like intermediate to give allenol followed by tautomerisation to give acylazolium. Subsequent attack of alkoxide to regenerate carbene and product.
How can NHC catalysed trans-esterification be done and be used helpfully?
Reaction used for the kinetic resolution of chiral alcohols. Occurs via nucleophilic catalysis, with chiral NHC and chiral ROH forming diasteromers.
