Umpolung Reactivity of Aldehydes toward Carbon Dioxide

Abstract

Carbon dioxide is an intrinsically stable molecule. Therefore, its activation requires extra energy input in the form of reactive reagents and/or activated catalysts and, often, harsh reaction conditions. Reported here is a direct carboxylation reaction of aromatic aldehydes with carbon dioxide to afford α-keto acids as added-value products. In situ generation of a reactive cyanohydrin was the key to the successful carboxylation reaction under operationally mild reaction conditions (25-40 °C, 1 atm CO ). The resulting α-keto acids served as a platform for α-amino acid synthesis by reductive amination reactions, illustrating the chemical synthesis of essential bioactive molecules from carbon dioxide.

C−H Bond Carboxylation with Carbon Dioxide

“…In 2018, Lee and Juhl reported an interesting umpolung reactivity of aromatic aldehydes with CO 2 (Scheme ) . By using KCN and Ti(O i Pr) 4 , they achieved direct carboxylation of aromatic aldehydes with CO 2 (1 atm) to afford α‐keto acid products under mild reaction conditions.…”

CO2-Enabled Cyanohydrin Synthesis and Facile Homologation Reactions

“…23 We have recently shown the applicability cyanohydrins as a nucleophile via an umpolung strategy (Scheme 1, a-keto acid synthesis). 24 In the absence of Ti(IV) and DBU, we observed facile formation of cyanohydrin in pseudo first order of the aldehyde with KCN under CO2 atmosphere (1 atm) in ethanol (k = 2.50 x 10 -3 ). This is approximately 10 5 -folds rate acceleration compared to the reported values, 19 which is surprising considering that the reaction requires the solubilization of KCN in the organic solvent.…”

“…When subjecting the α,β-unsaturated aldehydes to the reaction conditions the corresponding cyanohydrins (19 and 20) was isolated in excellent yields, without the formation of byproduct derived from 1,4-conjugate addition reactions. Aliphatic aldehydes were tolerated (20)(21)(22)(23)(24) when performed under a CO2 atmosphere, while various aldol condensation products were observed under N2 atmosphere, highlighting the importance of the CO2-mediated cyanohydrin formation conditions. For example, when 3-phenylpropionaldehyde (22) was subjected to the reaction conditions under N2 atmosphere, a complicated reaction mixture was observed due to aldol-reaction related byproducts.…”

Toward ideal carbon dioxide functionalization

“…In this context, recent developments in umpolung carboxylation reactions have shown unprecedented reaction patterns (Scheme 23):61,62,93 for example, umpolung reactivity has been implemented to functionalize CO 2 for an aldehyde carboxylation reaction through a redox-neutral mechanism (Scheme 23a). 93 b The obtained product, α-keto acid, was smoothly converted to the corresponding α-amino acid under reductive amination reaction conditions mimicking the biosynthesis of various amino acids.…”