CC Bond-Forming Sequence (original) (raw)

2007, Angewandte Chemie International Edition

Devising novel multicomponent reactions (MCRs) that achieve the formation of multiple bonds in one operation is one of the major challenges in modern organic synthesis. [1] As such processes avoid time-consuming and costly purification processes, as well as protection-deprotection steps, they are inherently environmentally benign and atom economic. Whereas some powerful MCRs such as the Passerini and Ugi [4] reactions proceed in the absence of external reagents, most chemical transformations involve reactants that are not active enough to be self-assembled. Thus, the use of catalytic rather than stoichiometric amounts of external reagents to trigger the reaction is highly desirable to minimize the production of waste. As a continuation of our ongoing project on the development of palladium-catalyzed domino processes as well as direct CÀH functionalization, we report herein a palladium-catalyzed three-component synthesis of 3-(diarylmethylene)indolinones. The underlying principle of our approach is shown in Scheme 1. The Sonogashira coupling of N-aryl-N-alkyl propiolamides 1 with an aryl iodide 2 should give the phenyl propiolamide 5, which would then react with a second aryl halide 3, ideally in the presence of the same catalyst, to afford the target compound 4 through a sequence of intermolecular carbopalladation, C À H activation, and a C À C bond-forming process. Whereas many palladium-catalyzed transformations have been developed and widely used in novel domino processes for the syntheses of heterocycles, the MCR that combines mechanistically distinct reactions by a single catalyst is by far less developed owing to the specificity of each catalytic system to each individual reaction. To our knowledge, the use of a single palladium catalyst to catalyze three different reactions, namely aryl alkynylation, carbopal-ladation, and direct C À H functionalization, has not been reported previously. Very few examples have been reported that deal with the successful Sonogashira reaction of electron-deficient alkynes, such as propiolic esters and propiolamide, [22] with aryl halides. Despite this potential pitfall, we performed a survey of reaction conditions using N-(4-methoxyphenyl)-N-methyl propiolamide (1 a), phenyl iodide (2 a), and 2-nitrophenyliodide (3 a) as test substrates. In the event, stirring a solution of 1 a and 2 a in N,N-dimethylformamide (DMF) in the presence of [Pd(PPh 3 ) 4 ] (5 mol %), copper iodide (15 mol %), and Et 3 N at 60 8C for 1 h followed by addition of 3 a and heating to 110 8C for 15 h afforded the expected oxindole 4 a in 28 % yield. Control experiments indicated that a) Sonogashira coupling between 1 a and 2 a, the presumed first step of this domino process, proceeded smoothly to furnish the phenylpropiolamide 5 a in over 90 % yield, b) copper iodide is required for the successful Sonogashira coupling between 1 a and 2 a, and c) the Sonogashira coupling between 1 a and 2 a proceeded sluggishly under ligand-free conditions, although such conditions were of choice for the carbopalladation/C À H functionalization step. With these results in hand, we set out to focus on the overall reaction efficiency of this novel threecomponent reaction instead of optimizing the individual steps by varying the palladium source, the ligand, the amount of copper, the base, and the solvent. The results are summarized in .