An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic gamma- and delta-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

Tosyl-o-allylaniline 1 undergoes oxidative cyclization to produce tetracycle 2 upon treatment with Cu(OAc)(2) and Cs(2)CO(3) at 120 degrees C. The scope of the reaction was extended to other N-sulfonylated aromatic systems.

The scope of the intramolecular copper(II)-catalyzed carboamination and aminooxygenation reactions of olefins has been extended to include N-aryl-2-allylanilines. These substrates exhibit divergent reactivity under catalytic vs. stoichiometric conditions. Keywords alkenes; copper; heterocycles; TEMPO Nitrogen heterocycles make up an abundant and important class of biologically active molecules. As such, new synthetic transformations that allow for the rapid assembly of these molecules are of great importance in organic chemistry.[1] Recently we have developed a number of copper-catalyzed and -promoted reactions that involve the intermolecular addition of amines to olefins: carboamination [2a-d] (addition of a nitrogen and a carbon across an olefin), diamination [3] (addition of two amines across an olefin), and aminooxygenation (addition of a nitrogen and an oxygen across an olefin). [2b,4] Both the carboamination and aminooxygenation reactions have proved to be efficient for the reaction of N-arylsulfonamides, providing dihydroindoline products [Eq. (1) and Eq. (2)]. The carboamination reaction has also been reported on amides. [2c] (1) To widen the scope of the effective carboamination and aminooxygenation reactions, we initiated a study involving N-arylanilines. Some N-arylindolines have demonstrated α2 adrenergic receptor and ORL1 antagonist activities, which have been linked to the treatment of anxiety and depression.[5] We first attempted the reaction with N-phenyl-2-allylaniline (1a). To our surprise, treating this substrate with a stoichiometric amount of copper(II) acetate and heating in DMF resulted in the formation of aminoacetoxylation products (2a and 3a) in a 4.5:1 ratio favoring the 6-membered ring [Eq. (3)]. With all of our previous substrates (vide supra) the products obtained result from 5-exo-trig cyclization of the amine onto the olefin. The structure of the major regioisomer (2a) was determined by hydrolysis to the known alcohol.[6]The aminoacetoxylation reaction also proceeded with good yield for the fluoro-and methoxysubstituted N-aryl-2-allylaniline substrates (1b and 1c) [Eq. (4)], and in both cases favored the formation of the 6-membered tetrahydroquinoline products (2). The reaction of 1a with copper (II) acetate in the less polar solvent, α,α,α,-trifluorotoluene, provided a 4.6:1 ratio of 2a:2b, albeit in a lower yield. The reaction of 1a with stoichiometric copper(II) triflate gave the tetrahydroquinoline product predominatly, but with only 30% conversion (see Supporting Information).When the reaction conditions were changed to catalytic conditions,[2d] using manganese dioxide as a stoichiometric oxidant, we did obtain our expected intra-molecular carboamination product [4a, Eq. (5)]. Under these conditions, a variety of substituted arylanilines underwent cyclization, providing 10a,11-dihydro-10H-indolo[1,2-a]indoles (4a-h) in good yield (Table 1). The functional group range of this reaction is broad, as both electron-rich and electron-deficient N-arylanilines unde...

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An expanded substrate scope and in depth analysis of the reaction mechanism of the copper(II) carboxylate promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic γ-and δ-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. NBenzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.