The mechanism of the Pd-catalyzed diamination and carboamination of alkenes promoted by N-fluorobenzenesulfonimide (NFBS) was investigated. Stereochemical labeling experiments established that the diamination reaction proceeds via overall syn addition of the two nitrogen groups, whereas carboamination is the result of an anti addition of arene and nitrogen to the alkene. The intermediate Pd-alkyl complex arising from aminopalladation was observed, and an X-ray crystal structure of its 2,2'-bipyridine (bipy) complex was obtained, revealing strong chelation of the amide protecting group to palladium. Aminopalladation was shown to be an anti-selective process in both the presence and the absence of added ligands, proceeding via external attack of the nitrogen on a Pd-coordinated alkene. The intermediate Pd-alkyl complex was converted to diamination product upon exposure to NFBS with inversion of configuration via oxidative addition followed by dissociation of the benzenesulfonimide anion and S(N)2 displacement of the Pd-C bond. Conversely, arylation of the Pd-alkyl complex proceeds via retention of stereochemistry, consistent with C-H activation of the arene at the Pd(IV) center. A small intermolecular isotope effect (k(H)/k(D) = 1.1) and a large intramolecular isotope effect (k(H)/k(D) = 4) were measured for this process, indicating that C-H activation occurs via a poorly selective product-determining coordination of the arene followed by a highly selective C-H activation. Competition between arenes reveals an unusual reactivity order of toluene > benzene > bromobenzene > anisole.

This report describes a unique Pd-catalyzed oxidative carboamination of protected aminoalkenes in which inexpensive unactivated nucleophilic arenes are incorporated to give carboamination products in good yields. A variety of protected amide and carbamate groups are tolerated, and various five-, six-, and seven-membered rings are formed in good yields. Under these conditions, halobenzenes are activated at the C-H bond rather than the C-X bond, and very high regioselectivity for the para substitution product is observed in all cases. We propose that this carboamination takes place via electrophilic aromatic substitution of a Pd(IV) alkyl intermediate.

The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the alpha carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl beta carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS). Substrate labeling measured by MS and site-directed mutagenesis experiments show that the designed active-site residues are responsible for activity, although rate acceleration over background is modest. To characterize the designed proteins, we developed a fluorescence-based screen for intermediate formation in cell lysates, carried out microsecond molecular dynamics simulations, and solved X-ray crystal structures. These data indicate a partially formed active site, and suggest several clear avenues for designing more active catalysts.

A Pd-catalyzed alkoxyamination of protected aminoalkenes promoted by N-fluorobenzenesulfonimide is described. This mild transformation allows the direct formation of ethers from carbon-carbon double bonds. An unusual switch from exo to endo selectivity in polar solvents was discovered, allowing the selective formation of either regioisomer by careful choice of reaction conditions.

The formation of highly substituted carbon centers using catalysis has been a widely sought after goal, but complexes of highly substituted carbon atoms with transition metals are rare, and the factors that affect the relative stability of complexes with differentially substituted carbon atoms are poorly understood. In this study, a set of equilibrating alkyl-palladium complexes were subtly tuned to form either a primary or trisubstituted alkyl complex as the more thermodynamically favored state, depending on either the substrate or reaction conditions. An X-ray crystal structure of the trisubstituted alkyl-palladium complex is presented and compared with the corresponding primary alkyl complex. The mechanism for rearrangement and the factors that drive the change in stability are discussed.

The formation of highly substituted carbon centers using catalysis has been aw idely sought after goal, but complexes of highly substituted carbon atoms with transition metals are rare,and the factors that affect the relative stability of complexes with differentially substituted carbon atoms are poorly understood. In this study,aset of equilibrating alkylpalladium complexes were subtly tuned to form either ap rimary or trisubstituted alkylc omplex as the more thermodynamically favored state,d epending on either the substrate or reaction conditions.A nX -ray crystal structure of the trisubstituted alkyl-palladium complex is presented and compared with the corresponding primary alkylc omplex. The mechanism for rearrangement and the factors that drive the change in stability are discussed.Alkyl-metal complexes are key intermediates in aw ide variety of important organic reactions.[1] Among the more challenging goals of organic synthesis is the formation of highly substituted carbon centers,a nd metal-catalyzed reactions have the potential to be powerful tools in the realization of this goal.[2] However,s uch reactions are still quite challenging because of the scarcity of highly substituted alkyl-metal complexes.U nderstanding the factors that control the structure and stability of alkyl-metal intermediates is critical to expanding the scope of these metal-catalyzed processes.Ther elative stability of primary,s econdary,a nd tertiary alkyl-metal complexes is generally expected to follow the trend for organolithium compounds, [3] in which the highly polarized CÀLi bond results in alarge negative-charge density at the carbon atom. Increasing the substitution of the carbon atom with electron-donating alkyl groups increases the negative charge at the carbon center,a nd thus destabilizes tertiary alkyllithium compounds relative to primary alkyllithium compounds.T his model works well for many alkylmetal complexes,b ut the analysis is more complicated for transition metals such as palladium. Information on the relative stability of alkyl-palladium complexes is sparse, contradictory,a nd without clear general trends.Tw oexperimental studies of the relative stability of alkylpalladium complexes have been reported. Reger et al. [4] studied Pd complexes bearing dithiocarbamate ligands,i n which the small size of the ligands presumably minimizes any steric effects on stability.Inthis study,the stability of the alkyl complexes followed the traditional order:p rimary > secondary @ tertiary.However,alkyl groups bearing electron-withdrawing groups,such as CF 3 or CN,overrode this preference to put those groups next to the PdÀCb ond. More recently, Brookhart and co-workers [5] studied the isomerization of alkyl-palladium complexes with ad iimine ligand. Here,t he relative stability of the alkyl complexes was highly dependent on the structure of the fourth ligand. When no ligand or acetonitrile was bound in cis position to the alkyl ligand, [6] the secondary alkyl complex was more stable,b ut when bulkier ligands were pre...

Ring closure reactions O 0130Palladium-Catalyzed Carboamination of Alkenes Promoted by N-Fluorobenzenesulfonimide via C-H Activation of Arenes. -A novel method is presented for the intramolecular amination of aminoolefins, e.g. (I), using N-fluorobenzenesulfonimide as oxidant in the presence of weakly nucleophilic arenes. A variety of five-, six-and seven-membered azacycles (III), (V), (VIII), (X) and (XII) is formed in moderate yields. -(ROSEWALL, C. F.; SIBBALD, P. A.; LISKIN, D. V.; MICHAEL*, F. E.; J. Am. Chem. Soc. 131 (2009) 27, 9488-9489; Dep. Chem., Univ. Wash., Seattle, WA 98195, USA; Eng.) -Mischke 50-030

The Pd/ fluorobenzenesulfonimide‐mediated treatment of 5 aminopentenes with alcohols and AcOH allows a mild access to pyrrolidines like (III), (VI), and (IX).