Eight-Membered Palladacycles Derived from the Insertion of Olefins into the Pd−C Bond of Ortho-Palladated Pharmaceuticals Phenethylamine and Phentermine. Synthesis of Stable Heck-Type Intermediates Containing Accessible β-Hydrogens and Its Use in the Synthesis of 2-Styrylphenethylamines, Tetrahydro

The ortho-metalated complexes derived from phenethylamine and phentermine, [Pd(C,N-C6H4CH2CR2NH2-2)(μ-X)]2 (R = H, X = Br (A); R = Me, X = Cl (B)), react with olefins giving (1) the product of its insertion into the Pd−C bond, [Pd{C,N-CH(R′)CH2C6H4CH2CR2NH2-2}(μ-X)]2 (olefin = CH2CHR′; R = H, X = Br, R′ = C(O)Me (1a), CO2Et (1c); R = Me, X = Cl, R′ = C(O)Me (1b), CO2Et (1d)) and [Pd{C,N-CH(C5H8)CHC6H4(CH2CMe2NH2)-2}(μ-Cl)]2 (olefin = norbornene, C5H8; 1e) or (2) the decomposition products of 1, i.e., Pd(0) and the complexes containing the arylated olefin, trans-[PdX2(NH2CR2CH2C6H4CHCHPh-2)2] (olefin = styrene; R = H, X = Br (3f); R = Me, X = Cl (3g)). While complexes 1c and 1d can be isolated but decompose in solution to afford Pd(0) and the corresponding complexes 3 (R = H, X = Br (3c); R = Me, X = Cl (3d)), the others are surprisingly stable. Neutral ligands L cleave the bridges of complexes 1 to afford [Pd(C∧N)X(L)] (2) (L = 4-methylpyridine (pic), NH3, NHEt2, PPh3, tBuNC, XyNC). Complexes 3 react with 1,10-phenanthroline (phen) to give [PdX2(phen)] and the ortho-vinylated arylalkylamine RCHCHC6H4CH2CR2NH2-2 (R = H (4f), Me (4g)), which in the case of 3c or 3d cannot be isolated, as it undergoes an intramolecular hydroamination process to afford the tetrahydroisoquinoline 5c or 5d, respectively. To prepare the tetrahydroisoquinoline 5b, it is necessary to heat a mixture of complex 1b with 1 equiv of TlOTf. The eight-membered cyclic amidine 7d is obtained from thermal decomposition of complex cis-[Pd{C,N-CH(CO2Et)CH2C6H4CH2CMe2NH2-2}(CNXy)2]OTf (8d), prepared by reaction of 2d-5 with TlOTf and XyNC. The amidinium salt 7e-HOTf is formed by refluxing in toluene a mixture of 2e-4 and TlOTf. The crystal structures of compounds 2a·CHCl3, 2b-1, 2d-3·1/3CH2Cl2, 2e-4·1/2CHCl3, 3d, 3g, 6, and 7e-HOTf have been determined by X-ray diffraction studies.