Insertion of Isocyanides, Isothiocyanates, and Carbon Monoxide into the Pd−C Bond of Cyclopalladated Complexes Containing Primary Arylalkylamines of Biological and Pharmaceutical Significance. Synthesis of Lactams and Cyclic Amidinium Salts Related to the Isoquinoline, Benzo[g]isoquinoline, and β-Carboline Nuclei

Abstract

Cyclometalation of 3-(2-naphthyl)-d-alanine methyl ester is achieved by reacting the corresponding hydrochloride salt and Pd(OAc)2 in a 1:1 molar ratio (acetonitrile, room temperature, 6 days). Although the chloro-bridged dimer (A) cannot be isolated in a pure form, addition of RNC to the reaction mixture affords the mononuclear derivatives (R)-[Pd{κ2(C,N)-C10H6CH2CH(CO2Me)NH2-2}Cl(CNR)] (R = tBu (1a-tBu), Xy (C6H3Me2-2,6) (1a-Xy)). Similar complexes (S)-[Pd{κ2(C,N)-C8H5N(CH2CH(CO2Me)NH2)-2}Cl(CNR)] (R = tBu (1b-tBu), Xy (1b-Xy)) are prepared from RNC and a previously reported cyclometalated derivative of l-tryptophan methyl ester, (S,S)-[Pd2{κ2(C,N)-C8H5N(CH2CH(CO2Me)NH2)-2}2(μ-Cl)2] (B). Compound 1b-Xy reacts with XyNC to give the iminoacyl complex (S)-[Pd{κ2(C,N)-C(═NXy)C8H5N(CH2CH(CO2Me)NH2)-2}Cl(CNXy)] (2b), whose crystal structure has been determined by X-ray diffraction studies. The cyclopalladated dimer B or those containing phenethylamine (C) or phentermine (D; see Chart ) reacts with RNC (R = tBu, Xy) in refluxing chloroform or toluene to render, depending on the reaction conditions, the cyclic amidines (3c-tBu, 3d-Xy) or the amidinium salts (4b-tBu, 4c-tBu, 4c-Xy, 4d-tBu, 4d-Xy). The amidines 3a-tBu and 3a-Xy and the amidinium salts 4a-tBu and 4a-Xy are synthesized from complexes 1a-tBu and 1a-Xy. When D reacts with isothiocyanates RNCS (R = Me, To (C6H4Me-4)), the cyclic amidinium salts 4d-Me and 4d-To are isolated. Amidinium triflates derived from phentermine with an aryl substituent at the exocyclic nitrogen atom (4d-Xy, 4d-To) present E/Z isomerism in CHCl3 or CH2Cl2 solution. CO reacts with A−D to give, after depalladation, the corresponding lactams: (R)-1-oxo-3-(methoxycarbonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (5a), (S)-1-oxo-3-(methoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (5b), 1-oxo-1,2,3,4-tetrahydroisoquinoline (5c), and 1-oxo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (5d). The crystal structures of compounds 4b-tBu, 4c-tBu, 4d-tBu, 4d-Xy, 4d-Me, 4d-To, and 5a−d have been determined by X-ray diffraction studies.