Decarboxylative palladium(II)-catalyzed synthesis of aryl amidines from aryl carboxylic acids: development and mechanistic investigation.
Bottom Line: The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids.Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction.The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism.
Affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, 751 23 Uppsala (Sweden).Show MeSH
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Mentions: Finally, a scale-out (scale-up) of the reaction (Figure 1), utilizing a non-resonant microwave system for continuous-flow organic synthesis,49–52 was performed. With this new equipment for direct scale-out we were able to achieve a high throughput of 11 mmol h−1 (corresponding to 3 g h−1). The experiment used a stock solution with 0.2 m of yield-determining 2 a, compound 1 a (1.1 equiv), along with [Pd(O2CCF3)2] (2 %), compound 4 (3 %), and TFA (1 equiv) in N-methylpyrrolidinone (NMP). After a minor adjustment of the reaction conditions, we achieved an excellent yield of 92 % of 3 a (Table 1, entry 13) at 1 mL min−1 and 120 °C, which corresponds to 1 min in the heated zone.
Affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, 751 23 Uppsala (Sweden).