Jared E. M. Fernando’s research while affiliated with Monash University (Australia) and other places

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine. Die Umpolung von Iminen ist ein wenig erforschter Bereich der enantioselektiven Katalyse. N‐heterocyclische Carbene (NHCs) wurden zur Katalyse einer enantioselektiven Aza‐Stetter‐Reaktion verwendet. Im Gegensatz zu Acyl‐Umpolung mit NHCs erfordert diese Reaktion stark nukleophile Katalysatoren. Die Reaktion ist enantioselektiv (≥96:4 er) und kann mit verschiedenartigen Iminen und 3‐Methylenchroman‐2‐onen durchgeführt werden.

2-Cinnamoylimidazolium ions 4 have been synthesized by treatment of 2-cinnamoylimidazoles 8 with methyl triflate. They were characterised by NMR and mass spectroscopy, in one case (4f) also by X-ray analysis. The kinetics of their reactions [and also those of cinnamoyl fluoride (1)] with stabilised carbanions 9a–e and silyl ketene acetal 9f (reference nucleophiles) were measured photometrically. The correlation log k(20 °C) = sN (E + N) was used to calculate the electrophilicity parameters E of the cinnamoyl azolium ions 4 from the resulting second-order rate constants k and the previously reported N and sN parameters of the reference nucleophiles 9. All 2-cinnamoylimidazolium ions 4 were found to be 2–4 orders of magnitude more electrophilic than cinnamoyl fluoride (1) showing that the direct attack of nucleophiles at 1 can be avoided if sufficient concentrations of 4 are produced in the NHC-catalysed reactions of 1 with nucleophiles. From the range of electrophilicity(–12 < E < − 10) for the cinnamoylimidazolium ions 4 one can derive that only nucleophiles stronger than N ≈ 7 will react with 4 at 20 °C in reasonable time, suggesting that in NHC-catalysed reactions of cinnamoyl fluoride (1) with silyl enol ethers (typically 4 < N < 7), enolate ions, produced by fluoride-induced desilylation of silyl enol ethers, are the active nucleophiles.

Herein we report the enantioselective N‐heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio‐ and diastereo‐enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6‐addition/β‐lactonization. Die 1,6‐Addition von Enolaten an Dienylacylazolium mit nachfolgender β‐Lactonisierung bietet Zugang zu einer vielseitigen Reihe von polycyclischen β‐Lactonen. Die Reaktion verläuft mit hoher Enantioselektivität, Diastereoselektivität und guten Ausbeuten und stellt das erste Beispiel einer enantioselektiven Katalyse mit Dienylacylazolium, dem höheren Homologen des α,β‐ungesättigten Acylazoliums, dar.

Herein we report the enantioselective N‐heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio‐ and diastereo‐enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6‐addition/β‐lactonization. 1,6‐Addition of enolates into the dienyl acyl azolium followed by β‐lactonization provides a diverse array of polycyclic β‐lactones. The reaction proceeds with high enantioselectivity, diastereoselectivity and good yields and represents the first example of enantioselective catalysis using the dienyl acyl azolium, the higher homologue of the α,β‐unsaturated acyl azolium.

The N-heterocyclic carbene (NHC) catalyzed transformylation has been developed for the conversion of 1°, 2°, and 3° alcohols to the corresponding formates. The reaction employs low catalyst loadings and methyl formate as the formyl transfer reagent. The scope of the reaction is broad with 23 examples reported with good yields (59–96%). The reaction is insensitive to common nitrogen and oxygen protecting groups and can be achieved in the presence of a number of heterocycles.

Donor-acceptor cyclopropanes are known to serve as dipole precursors capable of engaging in (3+2) annulations with electron-deficient π-systems. In 2013, the reaction of donor-acceptor cyclopropanes with α,β-unsaturated acyl fluorides in an all-carbon (3+2) annulation was discovered. The reaction proceeds in good yields using the IMes NHC to provide diastereomerically pure β-lactone-fused cyclopentanes bearing four contiguous stereocentres. Subsequent studies demonstrated that N-t-butyl substituted homochiral morpholinone NHCs allowed the reaction to be achieved in up to 98 % ee. In this account, a background to this reaction is introduced, along with a complete account of the strengths, limitations and challenges encountered while developing this chemistry.