MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders?

Rhodium-Catalyzed Direct Annulation of Aldehydes with Alkynes Leading to Indenones: Proceeding through in Situ Directing Group Formation and Removal

It would not be practical to attempt to deal with all the advances that have informed our understanding of the behavior and functions of this enzyme over the past 90 years. This account concentrates key advances that explain why the monoamine oxidases remain of pharmacological and biochemical interest and on some areas of continuing uncertainty. Some issues that remain to be understood or are in need of further clarification are highlighted.

90 years of monoamine oxidase: some progress and some confusion.

Indene derivatives are known to show various pharmacological properties, such as enzyme inhibitors, reuptake blocking, biogenic transporters, and anti-arrhythmic activity. In addition, they have also found applications in material science as discotic liquid crystals, coating materials for steel, conducting polymers, ligands for metallocene complexes, and so forth. Indenamine derivatives were recently synthesized by reacting chloroindan with the desired amines and by nucleophilic addition into nitrile derivatives, whereas indenones were prepared by oxidation of the corresponding indene derivatives and by catalytic intramolecular isomerization–aldolization of allyl alcohol with aldehyde. In this paper, we report a new convenient method for the regioselective synthesis of indenamine from the corresponding o-halobenzaldehyde, amine, and alkyne in the presence of zinc powder catalyzed by cobalt complexes. Moreover, these compounds can be conveniently converted to the corresponding substituted indenone derivatives. Recently, we and other groups had found methods for the synthesis of isoquinoline derivatives from 2-iodobenzaldimines (1) and alkynes catalyzed by nickel and palladium complexes, respectively. Our interests in the cobalt-catalyzed reactions and the recent observation of activation of arylhalides by cobalt complexes have prompted us to investigate the use of cobalt complexes for the reaction of Ntert-butyl-2-iodobenzaldimine (1a) with alkyne. To our surprise, when we treated 1a with 4-octyne in the presence of [CoCl2ACHTUNGTRENNUNG(dppe)] and zinc powder in acetonitrile, the corresponding indenamine (5a ; Scheme 1, R=R=nPr) was obtained in 78% yield. This is in sharp contrast to the nickeland palladium-catalyzed reactions that gave the corresponding isoquinoline derivative as product. The structure of the indenamine was established based on its H, C NMR, and MS spectral data. To simplify the reaction, we observed that by using the corresponding o-iodobenzaldehyde and amine to replace 1a, the same indenamine product can be obtained. Thus, o-iodobenzaldehyde (2a), p-toluidine (3a), and 4-octyne underwent three-component reaction in the presence of [CoCl2ACHTUNGTRENNUNG(dppe)] in an acetonitrile and THF mixture (optimization studies are given in the Supporting Information) to afford indenamine 5b in essentially quantitative yield (entry1, Table 1). In a similar manner, diphenylacetylene (4b) afforded product 5c in 78% yield. The three-component reactions of unsymmetrical alkynes with 2a and 3a were carefully studied by using the same catalyst system. Terminal alkyne 4c gave a single regioisomer 5d with the propyl group adjacent to the amino group in 82% yield (entry 3). For disubstituted unsymmetrical alkyne 4d, two regioisomers 5e (R=Ph, R=Et) and 5e3 (R=Et, R=Ph) in 60 and 36% yields, respectively, were observed. The application of alkynes with electron-withdrawing substituents 4e–g in the cyclization reaction with 2a and 3a gave highly regioselective indene–enamine derivatives 6a–c in moderate yields (entries 5–7, Table 1). It is worth noting that product 6 arises from a double-bond migration of the corresponding product 5. Always, the electron-withdrawing ester or keto groups of alkynes are adjacent to the amine group. The re[a] C.-C. Liu, Dr. R. P. Korivi, Prof. Dr. C.-H. Cheng Department of Chemistry, National Tsing Hua University Hsinchu, 30043 (Taiwan) Fax: (+886)35724698 E-mail : chcheng@mx.nthu.edu.tw

A. J. Plummer

Papers

N-methyl-n-2-propynyl-l-indanamine. A protent monoamine oxidase inhibitor.