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) .

Keywords: decarboxylation; density functional calculations; mass spectrometry; microwave chemistry; palladium.

Scheme 1

Palladium(II)-catalyzed protocols for the 1,2-carbopalladation of nitrile derivatives.

Figure 1

Top: schematic illustration of continuous-flow setup utilizing a non-resonant MW-cavity for heating of the reaction mixture. Bottom left: inside the reactor cavity, the glass reactor and MW antenna are displayed. Bottom right: closed reactor cavity.

Figure 2

Proposed catalytic cycle as adapted from Lindh et al.

Figure 3

Calculated Gibbs energy profile of the reaction of carboxylic acids 1 a (red), 1 b (blue), and 1 c (black) with cyanamide 2 b to give product 3. Full lines indicate that the complexes are verified to be directly connected. For 1 a and 1 c, complex II has two coordinated aryl acids, whereas for 1 b it has one acid and one acetate.

Figure 4

Optimized geometry for the 1,2-carbopalladation transition state TS-II. Bond lengths [Å] between Pd and coordinated atoms as well as the newly forming C–C bond are presented.

Figure 5

ESI-MS scan of reaction mixture at approximately 30–70 % conversion. Spectrum from reaction conditions: [Pd(O₂CCF₃)₂] (0.02 mmol), compound 4 (0.03 mmol), TFA (1 mmol), benzoic acid 1 a (1.1 mmol), cyanamides 2 a (1 mmol), and NMP (3 mL). Also shown are the proposed Pd^II intermediates. The cis and trans geometries are based on the corresponding DFT calculated configurations with [Pd(OAc)₂].