In recent years, palladium(aryl)(amido) complexes have been shown to serve as key intermediates in the synthesis of aniline derivatives.[1] Although the propensity of these intermediates to undergo CÀN bond-forming reductive elimination has been well established, [1] small molecule (alkene) insertion reactions of these complexes have been largely unexplored and have not been exploited in catalytic processes. [2] In fact, only a single example of the stoichiometric insertion of an activated alkyne into an isolated [Pd(Ar)(NR 2 )] complex has been reported, [2b] and insertions of alkenes have not been demonstrated. Herein we describe a new, stereoselective, palladium-catalyzed synthesis of pyrrolidines from g-(Narylamino) alkenes and aryl bromides, and present mechanistic evidence that suggests the transformation proceeds by a chemoselective intramolecular insertion of an unactivated alkene into the PdÀN bond of an intermediate [Pd(Ar)(NRR')] complex.[3] This reaction allows convergent access to substituted pyrrolidines, which are found in a variety of natural products.[4] In contrast to most methods available for the synthesis of substituted pyrrolidines, [5] this reaction effects intramolecular CÀN bond formation with concomitant intermolecular formation of a C1'ÀC bond. [6] In preliminary studies we employed g-aminoalkene substrates with N-aryl substituents because of their ease of preparation and handling. After optimization of the reaction conditions we found that the reaction of N-phenyl-4-pentenylamine (1 a) with 2-bromonaphthalene in the presence of NaOtBu and a catalytic amount of [Pd 2 (dba) 3 ]/dppb (1 mol %; dppb = 1,4-bis(diphenylphosphanyl)butane) at 60 8C in toluene afforded the desired N-aryl 2-(b-naphthylmethyl)pyrrolidine 2 a and regioisomeric product 3 a in 94 % yield and a 25:1 ratio [Eq. (1)].As shown in Table 1, the reactions of electron-rich, electron-neutral, and electron-deficient N-aryl amine derivatives with a variety of aryl bromide coupling partners proceeded in good yield. A number of functional groups are

The Pd/phosphine-catalyzed reaction of 1 with aryl bromides leads to the selective synthesis of either 6-aryl octahydrocyclopenta[b]pyrroles (3), the corresponding 5-aryl isomers 5, diarylamine 2, or hexahydrocyclopenta[b]pyrrole 4 depending on the structure of the phosphine ligand. These transformations are effective with a variety of different aryl bromides and provide 3-5 with excellent levels of diastereoselectivity (dr > or = 20:1). The changes in product distribution are believed to derive from the influence of Pd-catalyst structure on the relative rates of reductive elimination, beta-hydride elimination, alkene insertion, and alkene displacement processes in a mechanistically complex reaction. The effect of phosphine ligand structure on product distribution is described in detail, along with analysis of a proposed mechanism for these transformations.

N-Sulfonyl aziridines undergo oxidative addition to palladium(0) complexes generated in situ from mixtures of Pd2(dba)3 and 1,10-phenanthroline. The resulting azapalladacyclobutane complexes undergo intramolecular carbopalladation in the presence of copper(I) iodide to afford azapalladabicyclo[3.2.1]octanes. A deuterium-labeling experiment indicates that the oxidative addition proceeds via SN2-type attack of palladium(0) on the less-hindered carbon of the aziridine ring and that alkene insertion occurs in a syn fashion. The azapalladabicyclo[3.2.1]octane complexes undergo oxidative palladium-carbon bond functionalization in the presence of copper(II) bromide.

[reaction: see text] A new method for the synthesis of N-tosylketimines via the palladium-catalyzed isomerization of N-tosylaziridines is described. The mild reaction conditions tolerate the presence of a variety of functional groups including ketones, esters, and acetals. The reactions are believed to proceed via the oxidative addition of the aziridine to Pd(0) and represent the first examples of transformations involving Pd(0)-mediated oxidative additions of aziridines that do not proceed through allylpalladium intermediates.

The tandem N-arylation/carboamination of γ-amino alkenes with two different aryl bromides provides rapid entry to differentially arylated N-aryl-2-benzyl pyrrolidine derivatives in good yields with good to excellent levels of diastereoselectivity. The selective diarylation is achieved in a onepot process by an in situ modification of the palladium catalyst via phosphine ligand exchange.In recent years much effort has been devoted to the development of tandem or sequential reactions that effect the formation of several different bonds, stereocenters, and/or rings in onepot transformations. 1 These types of reactions lead to the conversion of simple starting materials to relatively complex molecules in a rapid and efficient manner, and have considerable potential utility for the construction of diverse libraries of compounds. Transition metal catalysis has played a central role in the development of many of these processes. 1, 2 Transformations effected through tandem metal-catalyzed reactions can be broadly grouped into two categories: 1) sequences that involve multiple iterations of the same reaction, 2 and 2) sequences that involve two or more fundamentally different reactions. 3 The latter tend to be more challenging as the efficiency and selectivity of many metal-catalyzed reactions is highly dependent on catalyst structure.We have recently described a new method for the stereoselective synthesis of N-aryl-2-benzylpyrrolidines via Pd-catalyzed reactions of γ-(N-arylamino)alkenes with aryl bromides (Scheme 1, eq 1). 4,5,6 In our initial studies, several of the substrates for these transformations were prepared by Pd-catalyzed N-arylation of primary amines. 7 Since both the carboamination and the N-arylation reactions were effected using palladium/phosphine catalysts, we reasoned that a modular synthesis of N-aryl-2-benzylpyrrolidines might be achieved in a one-pot, Pdcatalyzed process via sequential treatment of a 4-pentenylamine derivative with two different aryl bromides (Scheme 1, eq 2). A transformation of this type would lead to the formation of two C-N bonds, one C-C bond, one ring, and one stereocenter in a single operation. Additionally, this protocol could potentially be employed in the conversion of readily available jpwolfe@umich.edu . starting materials into pyrrolidine libraries in which two groups on the heterocycle could be easily varied. 8 Our preliminary studies on the development of this one-pot reaction sequence are described herein. NIH Public AccessAuthor Manuscript Org Lett. Author manuscript; available in PMC 2009 September 24.Both palladium-catalyzed N-arylations of amines and Pd-catalyzed carboamination reactions are known to be very sensitive to catalyst structure. 4,7 A search of the literature revealed that relatively few ligands are highly effective and selective for the Pd-catalyzed monoarylation of primary aliphatic amines; (rac)-BINAP (2) 9 and 2-di-tert-butylphosphinobiphenyl (3) appeared to be the most general with respect to substrate scope. 7 Our previous studies ...