Martin Hulla
The thesis describes a simple approach for N-formylation of amines with CO2 and hydrosilane reducing agents, the use of organic salts as N-formylation catalysts, their physical properties required for high catalytic activity and their role in the catalytic cycle. The investigation is then extended to the synthesis of quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and CO2 as well as other C-N bond forming reactions. Basicity, as measured by pKb, is identified as the key property required for high catalytic activity of organic salt catalysts. Minor variations in catalytic activity among salts of equal basicity are assigned to the ion pairing energy, hydrogen bonding ability and steric factors.
The N-formylation reaction catalysed by organic salts proceeds by the activation of the hydrosilane reducing agent. Although, the catalytic activity was originally assigned to the nucleophilicity of the anion, a detailed investigation of the reaction mechanism and physical parameters of numerous salt catalysts revealed that they are more active as bases. Extensive substituent exchange around the hydrosilane silicon centre confirms its activation and supports the proposed reaction mechanism, where in-situ formed carbamate salt acts as the reaction nucleophile. Accounting for small detrimental effect of ion paring, a linear relationship between the pKa of the salt and catalytic activity is observed. The onset of the base catalysed reaction mechanism is substrate dependent with further variations for amines of high basicity. Nevertheless, highly basic salt catalysts, such as tetra-n-butylammonium fluoride ([TBA]F), promote rapid N-formylation of all types of amines under extremely mild conditions.
A linear relationship between the basicity of salt catalysts and their catalytic activity was also observed in the synthesis of quinazoline-2,4(1H,3H)-dione. Similarly, the reaction proceeds by in-situ formation of a carbamate salt, which requires a base catalyst. However, here the reaction mechanism is limited by the acidity of the quinazoline-2,4(1H,3H)-dione product. Quinazoline-2,4(1H,3H)-dione is deprotonated by more basic catalysts (pKa of conjugate acid > 14.7 in DMSO) leading to the neutralization of the base catalyst and the formation of the quinazolide anion, which then acts as the reaction catalyst.
Analysis of the reported literature reveals that the findings are directly applicable to the vast majority of C-N bond forming reactions of amines with CO2 and to almost all types of organocatalysts. The reactions proceed by carbamate salt formation in the form [BaseH][RR'NCOO]. The anion of the carbamate salt then acts as a nucleophile in hydrosilane reductions of CO2 towards formamides, N-methylamines and aminals or internal cyclization reactions to quinazoline-2,4-diones, oxazolidinones and oxazin-2-ons or after dehydration as an electrophile in the synthesis of urea derivatives. The role of organocatalysts in the reactions indicates that all bases of sufficient strength should be able to catalyse the reactions.
EPFL2019
