ABSTRACT:Conditions for an attractive and productive protocol for the position-selective intramolecular C-H amination of aliphatic groups (Hofmann-Löffler reaction) are reported employing sulfonimides as nitrogen sources. N-Iodosuccinimide is the only required promoter for this transformation, which is conveniently initiated by visible light. The overall transformation provides pyrrolidines under mild and selective conditions as demonstrated for 17 different substrates.The intramolecular C-H amination of aliphatic groups has recently attracted significant interest from the synthetic community. Major work has focused on the identification of suitable transition metal catalysts to provide the aforementioned transformation. 1 Directed evolution of metalloproteins has recently emerged as a complimentary approach. 2 An alternative consists of the use of small organocatalysts 3 as non-metallic promoters, which, due to their capability to avoid metal contamination, is of major importance to fields such as biological and medicinal synthesis.From a historical perspective, the halide-mediated C-N bond formation at non-activated hydrocarbons was discovered over a century ago and is well established as the Hofmann-Löffler reaction. 4 The general conditions call for preformation of a halogenated amine, which upon irradiation in the presence of strong acid promotes C-H halogenation, which is usually followed by basemediated pyrrolidine formation. A useful modification providing significantly milder reaction conditions was introduced by Suarez, 5 who reported that Hofmann-Löffler-type cyclization reactions can be conducted in the presence of a mixture of molecular iodine and a hypervalent iodine reagent of the general structure ArI(O 2 CR) 2 . 6 This protocol was employed by Fan, who demonstrated its compatibility with sulfonamides as nitrogen sources. 7 We have recently demonstrated that this reaction can be conducted with catalytic amounts of iodine and the use of a single equivalent of hypervalent iodine(III) as the terminal oxidant. 8 This accomplishment has demonstrated that iodine catalysis is indeed feasible within the borders of the Hofmann-Löffler reaction, provided that the iodine concentration is maintained at a sufficient level to perpetuate the two intertwined catalytic cycles. However, the permanent requirement of using a hypervalent iodine reagent as a terminal oxidant 9 has triggered interest in whether the reaction could also be conducted with just a single amount of halide reagent as a stoichiometric promoter. Such a reaction would serve as an important addition to the existing protocols for Hofmann-Löffler reactions.

A catalytic method to synthesize 1,3,-dienes from propargylic precursors is reported. This palladium-catalyzed carbon–nitrogen bond-forming reaction furnishes 2-amino-1,3-dienes in excellent yields (up to 98%) and shows a broad tolerance to functional group diversity. The reaction has been demonstrated for over 30 amine substrates, including anilines and indoles, and proceeds under mild neutral conditions. The resulting 1,3-dienes are of great synthetic interest because of their further reaction potential.

An innovative approach to position-selective polyhalogenation of aliphatic hydrocarbon bonds is presented. The reaction proceeded within the Hofmann-Löffler manifold with amidyl radicals as the sole mediators to induce selective 1,5- and 1,6-hydrogen-atom transfer followed by halogenation. Multiple halogenation events of up to four innate C-H bond functionalizations were accomplished. The broad applicability of this new entry into polyhalogenation and the resulting synthetic possibilities were demonstrated for a total of 27 different examples including mixed halogenations.

The highly enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl-β-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl-α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl-β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl-α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.