title: Decarboxylative palladium(II)-catalyzed synthesis of aryl amidines from aryl carboxylic acids: development and mechanistic investigation.
abstract: A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2 CCF3 )2 ], 6-methyl-2,2'-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. 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. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11 mmol h(-1) by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min(-1) .
authors: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, 751 23 Uppsala (Sweden).
authors: Jonas
authors: J
authors: Rydfjord
authors: Fredrik
authors: F
authors: Svensson
authors: Alejandro
authors: A
authors: Trejos
authors: Per J R
authors: PJ
authors: Sjöberg
authors: Christian
authors: C
authors: Sköld
authors: Jonas
authors: J
authors: Sävmarker
authors: Luke R
authors: LR
authors: Odell
authors: Mats
authors: M
authors: Larhed
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry*; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D002384:Catalysis; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*
chemical_list: D000578:Amidines; D002264:Carboxylic Acids; D015082:2,2'-Dipyridyl; D010165:Palladium
keywords: decarboxylation; density functional calculations; mass spectrometry; microwave chemistry; palladium
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