TY - JOUR
T1 - Rh(DPEPhos)-Catalyzed Alkyne Hydroacylation Using β-Carbonyl-Substituted Aldehydes
T2 - Mechanistic Insight Leads to Low Catalyst Loadings that Enables Selective Catalysis on Gram-Scale
AU - Barwick-Silk, James
AU - Hardy, Simon
AU - Willis, Michael C.
AU - Weller, Andrew S.
PY - 2018/6/13
Y1 - 2018/6/13
N2 - The detailed mechanism of the hydroacylation of β-amido-aldehyde, 2,2-dimethyl-3-morpholino-3-oxopropanal, with 1-octyne using [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF
4]-based catalysts, is described [ArF = (CF3)2C6H3]. A rich mechanistic landscape of competing and interconnected hydroacylation and cyclotrimerization processes is revealed. An acyl-hydride complex, arising from oxidative addition of aldehyde, is the persistent resting state during hydroacylation, and quaternary substitution at the β-amido-aldehyde strongly disfavors decarbonylation. Initial rate, KIE, and labeling studies suggest that the migratory insertion is turnover-limiting as well as selectivity determining for linear/branched products. When the concentration of free aldehyde approaches zero at the later stages of catalysis alkyne cyclotrimerization becomes competitive, to form trisubstituted hexylarenes. At this point, the remaining acyl-hydride turns over in hydroacylation and the free alkyne is now effectively in excess, and the resting state moves to a metallacyclopentadiene and eventually to a dormant α-pyran-bound catalyst complex. Cyclotrimerization thus only becomes competitive when there is no aldehyde present in solution, and as aldehyde binds so strongly to form acyl-hydride when this happens will directly correlate to catalyst loading: with low loadings allowing for free aldehyde to be present for longer, and thus higher selectivites to be obtained. Reducing the catalyst loading from 20 mol % to 0.5 mol % thus leads to a selectivity increase from 96% to ∼100%. An optimized hydroacylation reaction is described that delivers gram scale of product, at essentially quantitative levels, using no excess of either reagent, at very low catalyst loadings, using minimal solvent, with virtually no workup.
AB - The detailed mechanism of the hydroacylation of β-amido-aldehyde, 2,2-dimethyl-3-morpholino-3-oxopropanal, with 1-octyne using [Rh(cis-κ2-P,P-DPEPhos)(acetone)2][BArF
4]-based catalysts, is described [ArF = (CF3)2C6H3]. A rich mechanistic landscape of competing and interconnected hydroacylation and cyclotrimerization processes is revealed. An acyl-hydride complex, arising from oxidative addition of aldehyde, is the persistent resting state during hydroacylation, and quaternary substitution at the β-amido-aldehyde strongly disfavors decarbonylation. Initial rate, KIE, and labeling studies suggest that the migratory insertion is turnover-limiting as well as selectivity determining for linear/branched products. When the concentration of free aldehyde approaches zero at the later stages of catalysis alkyne cyclotrimerization becomes competitive, to form trisubstituted hexylarenes. At this point, the remaining acyl-hydride turns over in hydroacylation and the free alkyne is now effectively in excess, and the resting state moves to a metallacyclopentadiene and eventually to a dormant α-pyran-bound catalyst complex. Cyclotrimerization thus only becomes competitive when there is no aldehyde present in solution, and as aldehyde binds so strongly to form acyl-hydride when this happens will directly correlate to catalyst loading: with low loadings allowing for free aldehyde to be present for longer, and thus higher selectivites to be obtained. Reducing the catalyst loading from 20 mol % to 0.5 mol % thus leads to a selectivity increase from 96% to ∼100%. An optimized hydroacylation reaction is described that delivers gram scale of product, at essentially quantitative levels, using no excess of either reagent, at very low catalyst loadings, using minimal solvent, with virtually no workup.
UR - http://www.scopus.com/inward/record.url?scp=85047741094&partnerID=8YFLogxK
U2 - 10.1021/jacs.8b04086
DO - 10.1021/jacs.8b04086
M3 - Article
C2 - 29763563
AN - SCOPUS:85047741094
SN - 0002-7863
VL - 140
SP - 7347
EP - 7357
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 23
ER -
