Oxidative amidation of benzaldehyde using a quinone/DMSO system as the oxidizing agent

An efficient transition-metal-based heterogeneous catalyst free procedure for obtaining the oxidative amidation of benzaldehyde using quinones as oxidizing agents in low molar proportions is described here. Pyrrolylquinones (PQ) proved to be more suitable than DDQ and 2,5-dimethylbenzoquinone to conduct the oxidation process. Although the solvent itself acted as the oxidant with low to moderate yields, PQ/DMSO provided an efficient system for carrying out the reaction under operational simplicity, mild reaction conditions, short reaction times and high yields of the desired product. The scope of the method was evaluated with substituted benzaldehydes and secondary amines. Theoretical foundations are given to explain the participation of quinones as an oxidizing agent in the reaction.


General Procedure for Oxidative Amidation.
A mixture of aldehyde (100 mg, 0.66 mmol), secondary amine (1.2 eq 0.79 mmol), quinone (0.02 mmol), in DMSO (2 mL) was stirred at 70 ºC for 19 h. in absence of light. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to obtain tertiary amide products.

Theoretical calculations
Three definitions of are obtained from the finite difference scheme, 6 which are helpful ( ) descriptors to evaluate a chemical specie for nucleophilic attacks , electrophilic ( ( ) + ) attacks and for free radicals attacks by using the following equations: where , and are the electronic densities at point for the + 1 ( ) ( ) -1 ( ) system with , and electrons respectively.
The form of the Fukui functions was used as a stability descriptor pursuing ( ) 0 zones within the pyrrolyl quinones that could stabilize a free radical. The ( ) 0 descriptor indicated regions in the pyrrolyl quinones in which an unpaired electron could potentially be localized after redistribution of the initial electronic density.
The left panel of Scheme 1 presents the isocontours of in the gas phase. The ( ) 0 right side of Scheme 1 plots the isovalues of in the presence of DMSO as the ( ) 0 solvent. The lowest energy conformers of 4 and its derivatives indicated the formation of a hydrogen bond between O 9 of the quinone and H of the pyrrole ring, with a length of 1. 93, 1.92, 1.98, or 1.95 Å for 4, 4a, 4b, and 4c, respectively, in the gas phase. Although the presence of DMSO promoted hydrogen bonding, the hydrogen bond length increases with respect to the gas phase (being 1.98, 1.95, 2.01, and 1. 99 Å for 4, 4a, 4b, and 4c, respectively).
The highest values of suggested that the oxygen atoms O 8 and O 9 of the ( ) 0 quinones were the most favorable sites for stabilizing a free radical, with a subtle preference for O 8 over O 9 . O 9 participates in non-bonded interactions, whereas O 8 can accept one electron to form a radical. Radical formation raises an interesting question: Do the pyrrolyl quinones accept or donate the electron? To address this question, we calculated the values of and of the Fukui functions in the ( ) + ( )open shell scheme (after radical formation). The value provides information ( ) + about sites that stabilize incoming charges on the PQs. The value of gives ( )information about the electron donor sites from which a charge may "exit" to stabilize the PQs in a subsequent step. . Once the radical formed, O 8 preferably accepted the incoming ( ) + charge. It is important to note that increased in the presence of DMSO by up ( ) + to 7.2%, in agreement with our proposed mechanism that the quinones promoted radical formation in the presence of DMSO with synergic effects.