The intramolecular additions of C-centered neutral α-aminoalkyl radicals onto suitably positioned C-C double bonds provide a ready access into functionalized carbocycles and heterocycles. This strategy offers considerable versatility in the selection of starting materials since a number of methods using different functional groups and reagents are available for α-aminoalkyl radical generation. This review covers the recent progress in this field.
Construction of carbon-carbon bonds adjacent to nitrogen is of great importance for the synthesis of many nitrogen-containing compounds of biological significance, including interalia alkaloids and amino acids. Such carbon-carbon bond formation usually occurs via one of three different types of intermediates: (i) iminium ions, 1 (ii) R-amino-substituted carbanions, 2 and (iii) R-aminosubstituted radicals. 3 Regarding the last of these routes, electron-rich R-aminoalkyl radicals (1a,b, Scheme 1), which are strongly nucleophilic, react readily with electron-deficient CdC bonds (e.g., formation of products 4a). 3,4,5b However, attempted intramolecular additions of nonstabilized R-amino radicals (1a) to unactivated CdC bonds (Scheme 1) mostly give reduction products 2 5 or very low yields of cyclization products 4a,6a (for an exception see ref 6b). By contrast, R-amino radicals (1c) with stabilizing groups (e.g., acyl, 7 sulfonyl 5a,6 ) or a quaternized 8 nitrogen undergo intramolecular cyclization to unactivated CdC bonds (Scheme 1).The cyclization of an R-aminoalkyl radical onto an unactivated CdC bond is difficult due to (i) partial loss of the stabilization provided to the radical by the amino substituent in the transition state leading to cyclization, (ii) the nucleophilic nature of the radical, and (iii) the tendency for dimerization of the R-aminoalkyl radical. However, the previously reported 4a,6 formation of small amounts of the cyclized products and the dependence of the cyclization stereochemistry on the stability of the R-amino radical 5b suggested to us that an equilibrium exists between the acyclic radical and the cyclized one (cf. 7 T 8, Scheme 2). Normally, the acyclic radical undergoes reduction 3,5 or dimerization. 5b,9 We reasoned that an additional driving force, such as the rapid reduction of the cyclized radical to the corresponding organosamarium (cf. 8 f 9), could favor the formation of cyclized products. As justification of these speculations, we now report a novel reaction sequence comprising site specific formation of an R-aminoalkyl radical, regioselective addition of this radical to an unactivated double bond, further reduction to a carbanion, and finally carbanion trapping by an electrophile. 10 N-(R-Aminobutyl)benzotriazole (6a) was prepared from the condensation of a secondary amine 5, 11 butyraldehyde, and benzotriazole (Scheme 2). Crude 6a was treated directly with samarium diiodide in THF-HMPA
Condensation between aldehydes and the secondary amino function of 5-(aminoalkyl)furan-2(5H)-ones, obtained by the silyloxyfuran dienolate addition to imine-type derivatives, produces either aminoalkylbenzotriazoles or 1,2,3,4-tetrahydropyridines. The former can be reduced with SmI2 to generate alpha-aminoalkyl radicals that are trapped by the alpha,beta-unsaturated lactone moiety yielding substituted pyrrolidines diastereoselectively, while catalytic hydrogenation of the latter affords isomeric piperidine analogues. Alternatively, SmI2-promoted reduction of tetrahydropyridines in the presence of acid also leads to intermediate alpha-aminoalkyl radicals that participate in inter- or intramolecular olefin addition reactions. Further manipulation of the lactone functionality in various ways gives access to a number of interesting derivatives based upon either a pyrrolidine or a piperidine structural motif. As a result, a high degree of structural diversity is obtained in a few steps starting from a common set of simple materials.
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