Send to

Choose Destination
See comment in PubMed Commons below
Acc Chem Res. 2009 Aug 18;42(8):1172-82. doi: 10.1021/ar900059r.

Utilization of N-X bonds in the synthesis of N-heterocycles.

Author information

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.


Nitrogen-containing heterocycles--such as aziridines, pyrrolidines, piperidines, and oxazolines--frequently show up as substructures in natural products. In addition, some of these species show potent biological activities. Therefore, researchers would like to develop practical and convenient methods for constructing these heterocycles. Among the available methods, the transfer of N(1) units to organic molecules, especially olefins, is a versatile method for the synthesis of N-heterocycles. This Account reviews some of our recent work on the synthesis of N-heterocycles using the N-X bond. A nitrogen-halogen bond bearing an electron-withdrawing group on the nitrogen can be converted to a halonium ion. In the presence of C-C double bonds, these species produce three-membered cyclic halonium intermediates, which can be strong electrophiles and can produce stereocontrolled products. N-Halosuccinimides are representative sources of halonium ions, and the nitrogen of succinimide is rarely used in organic synthesis. If the nitrogen could act as a nucleophile, after releasing halonium ions to C-C double bonds, we expect great advances would be possible in the stereoselective functionalization of olefins. We chose N-chloro-N-sodio-p-toluenesulfonamide (chloramine-T, CT), an inexpensive and commercially available reagent, as our desired reactant. In the presence of a catalytic amount of CuCl or I(2) and AgNO(3), we achieved the direct aziridination of olefins with CT. The reaction catalyzed by I(2) could be carried out in water or silica-water as a green process. The reaction of iodoolefins with CT gave pyrrolidine derivatives under extremely mild conditions with complete stereoselectivity. We also extended the utility of the N-chloro-N-metallo reagent, which is often unstable and difficult to work with. Although CT does not react with electron-deficient olefins without a metal catalyst or an additive, we found that N-chloro-N-sodiocarbamates react with electron-deficient olefins in the presence of a phase transfer catalyst to give the corresponding aziridines. We also used this method to synthesize asymmetric aziridines using quaternary cinchona alkaloid catalysts. We also developed a facile synthetic method for preparing N-heterocycles that involves the in situ generation of an N-X bond using tert-butyl hypochlorite or tert-butyl hypoiodite (tert-BuOI). Treatment of alkenylamides containing an active hydrogen on the nitrogen with tert-BuOI led to the production of various N-heterocycles via intramolecular cyclization. Iodination of readily available sulfonamides or carboxamides with tert-BuOI generated reactive N-iodinated amides, which smoothly reacted with olefins to give aziridines or oxazolines. The reaction of fullerene, C(60), with CT also led to aziridination: the resulting aziridinofullerene underwent a unique rearrangement to an azafulleroid. Chlorination of readily available amide derivatives with tert-BuOCl, followed by a reaction with C(60) in the presence of an organic base, afforded aziridinofullerenes with various substituents on the nitrogen. The results in this Account contribute to the development of convenient methods for constructing simple and useful heterocycles.

PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society
    Loading ...
    Support Center