Application of Pd-NHC Complexes in Challenging Amination Reactions

Among Pd-catalyzed carbon-heteroatom cross-coupling reactions, C-N bond formation, known as Buchwald-Hartwig amination (BHA), is by far the most studied reaction owing to the prevalence of arylated amines in pharmaceuticals, natural products, organic materials, and catalysts. Despite the tremendous progress that has been achieved with respect to improving the efficiency and expanding the scope of BHA of (hetero)aryl halides and amine nucleophilic partners, some challenges remain to be addressed. These challenges include selective monoarylation of primary alkyl amines, enantioretentive N-arylation of -amino esters and arylation of amide nucleophiles. This research is mainly focused on evaluating the reactivity of Pd-NHC pre-catalysts, in particular Pd-PEPPSI (Pyridine Enhanced Pre-catalyst Preparation Stabilization and Initiation) complexes in such challenging BHA reactions. Pd-PEPPSI-IPentCI, was identified as one of the most reactive and selective pre-catalysts yet reported in the literature in the arylation of primary alkyl amines. The high level of selectivity that was exhibited by Pd-PEPPSI-IPentCI is assured by the use of the mild, soluble and sterically demanding sodium salt of butylated hydroxytoluene (NaBHT) as the base in this transformation. PdPEPPSIIPentClopicoline was shown to effectively couple a variety of amino acids as the tertbutyl ester with heteroaryl chlorides in high yields and with excellent stereoretention of the acidic proton adjacent to the ester. Control experiments revealed that racemization is basemediated, with no evidence of Pdmediated hydride elimination, and that racemization occurs only after the product is formed. Studies also revealed that increasing the steric bulk of the ester moiety on the amino acid (e.g., ethyl to tertbutyl) drastically slows racemization of the product. Boron-derived Lewis acids such as (secBu)3B, Et3B, and BCF have been shown to effectively promote the coupling of amide nucleophiles to a wide variety of oxidative addition partners using (DiMeIHeptCl)Pd(cinammyl)Cl. Through a combination of NMR spectroscopy and control studies with and without oxygen and radical scavengers, we propose that boron-imidates form under the basic reaction conditions that aid coordination of nitrogen to PdII, which is rate limiting, and directly delivers the intermediate for reductive elimination. During the course of optimization of aryl amidation, we found the hydrodehalogenated arene as the side product when NaBHT was employed as base. Extensive control experiments revealed that NaBHT can serve as a hydride delivering agent in Pd-catalyzed hydrodehalogenation of (hetero)aryl halides. During the course this study, the structure of the phenolate was found to be critical to the success of this protocol, that is, bulky di-ortho- substituents on phenolate are required to achieve optimal results.