Sequential Insertion of Alkynes, Alkenes, and CO into the Pd-C Bond of ortho-Palladated Primary Phenethylamines: from η3-Allyl Complexes and Enlarged Palladacycles to Functionalized Arylalkylamines.

The eight-membered metallacycles arising from the insertion of 1 equiv of alkyne into the Pd-C bond of ortho-metalated homoveratrylamine and phentermine can further react with alkenes to give two different types of mononuclear complexes depending on the nature of the olefin. When terminal alkenes (styrene and ethyl acrylate) are used, a mixture of the anti/syn η3-allyl Pd(II) complexes are isolated, which evolve slowly to the syn isomers by heating the mixtures appropriately. These η3-allyl Pd(II) complexes do not react with CO or weak bases, but when they are treated with a strong base, such as KOtBu, they afford Pd(0) and the functionalized starting phenethylamines containing a 1,3-butadienyl substituent in an ortho position. When 2-norbornene was used instead of terminal alkenes, the strained olefin inserts into the alkenyl Pd(II) complex to afford a 10-membered norbornyl palladium(II) complex, in which the new C,N-chelate ligand is coordinated to the metal through an additional double bond, occupying three coordination positions. The reactivity of these norbornyl complexes depends on the substituents on the inserted alkenyl fragment, and thus they can further react with (1) KOtBu, to give Pd(0) and a tetrahydroisoquinoline nucleus containing a tricyclo[3.2.1]octyl ring, or (2) CO and TlOTf, to afford Pd(0) and amino acid derivatives or the corresponding lactones arising from an intramolecular Michael addition of the CO2H group to the α,ß-unsaturated ester moiety. Crystal structures of every type of compound have been determined by X-ray diffraction studies.

C-H Activation in Primary 3-Phenylpropylamines: Synthesis of Seven-Membered Palladacycles through Orthometalation. Stoichiometric Preparation of Benzazepinones and Catalytic Synthesis of Ureas.

The dimeric cyclometalated complexes [Pd2{κ(2)C,N-C6H4CH2CH2C(R)(Me)NH2-2}2(µ-Cl)2] (R = Me (1a), H (1b)) are prepared by reacting 1,1-dimethyl-3-phenylpropylammonium or 1-methyl-3-phenylpropylammonium triflate with Pd(OAc)2 in a 1:1 molar ratio and subsequent treatment with excess NaCl. The mononuclear derivatives [Pd{κ(2)C,N-C6H4CH2CH2C(R)(Me)NH2-2}Cl(L)] (L = PPh3, R = Me (3a), H (3b); L = 4-picoline (4-pic), R = Me (4a), H (4b)) were prepared from 1a,b by splitting the chloro bridges with the neutral ligands L. A conformational analysis of the mononuclear palladacycles in solution has been carried out. Insertion of CO takes place into the Pd-C bond of complexes 1a,b, affording Pd(0) and the tetrahydro-benzazepinone 5a or 5b, which possesses potential pharmacological interest. Additionally, the triflate salt A or B undergoes catalytic carbonylation with CO to afford the corresponding N,N'-dialkylurea, using Pd(OAc)2/Cu(OAc)2, in boiling acetonitrile. The crystal structures of 3a·(1)/2H2O, 3b, 4b·CHCl3, and 5a were determined by X-ray diffraction studies.

Benzyne-benzyne-RNC or CO triple sequential insertion into the Pd-C bond: synthesis of ten-membered N-heterocycles through stable ten- and eleven-membered palladacycles.

Insertion of two molecules of benzyne into the Pd-C bond of an ortho-palladated derivative of homoveratrylamine allows the synthesis and XRD characterization of a ten-membered palladacycle, which further reacts with CO or RCN to afford, upon depalladation, tribenzazecine derivatives. The iminoacyl eleven-membered palladacycle intermediate can also be isolated.

Insertion of benzyne into the Pd-C bond. Synthesis of unnatural amino acid derivatives by sequential insertion of benzyne and CO: 2,2'-functionalized biaryls containing alkylamino and carboxymethyl substituents. Isolation of stable carbopalladated-benzyne intermediates.

Reaction of ortho-palladated derivatives of phentermine and homoveratrylamine with benzyne allows the synthesis of enlarged eight-membered palladacycles resulting from the insertion of the aryne into the Pd-C bond, which subsequently react with CO, to render unnatural amino acid derivatives.