Helena C. Malinakova

Divergent Reaction Pathways of Homologous and Isosteric Propargyl Amides in Sequential Ru/Pd-Catalyzed Annulations for the Synthesis of Heterocycles

Cu-catalyzed three-component coupling of imines with benzoyl chloride and terminal arylalkynes followed by enyne ring-closing metathesis (RCM) and Heck cyclization afforded medicinally relevant benzoindolines, cyclopropane-fused indenopyridines, pyrroloquinolines, or 1,7-tetrahydrophenanthrolines via divergent cyclization pathways. Unexpectedly, the Pd-catalyzed cyclization of heterocyclic dienes proceeded via regiodivergent 5-exo or 6-endo pathways depending on the ring size (n = 1, 2) or the presence of isosteric groups (CH vs N). A one-pot protocol for the enyne-RCM/Heck annulation featuring a sequential addition of the Ru and Pd catalysts was developed maximizing the synthetic efficiency.

Palladium(IV) Complexes as Intermediates in Catalytic and Stoichiometric Cascade Sequences Providing Complex Carbocycles and Heterocycles

Palladium-catalyzed multicomponent coupling and annulation reactions have become important tools in organic synthesis. Recently, palladium(IV) complexes have been proposed as intermediates in catalytic cycles of these transformations, although experimental evidence for their involvement is frequently lacking. Examples of such catalytic annulation reactions are discussed, followed by a review of studies performed with stoichiometric isolable or semistable palladium(IV) complexes seeking experimental evidence for feasibility of the participation of palladium(IV) intermediates in cascade carbon–carbon and carbon–heteroatom bond-forming sequences.

Sequential Cu(I)/Pd(0)-Catalyzed Multicomponent Coupling and Annulation Protocol for the Synthesis of Indenoisoquinolines

Copper-catalyzed coupling of imines, vinylstannanes, or alkynes and o-bromoaroyl chlorides followed by Pd(0)-catalyzed annulations afforded indenoisoquinolines. Protocols requiring minimal purifications were developed, providing new methods for the construction of combinatorial libraries.

Application of Sequential Cu(I)/Pd(0)-Catalysis to Solution-Phase Parallel Synthesis of Combinatorial Libraries of Dihydroindeno[1,2-c]isoquinolines

Parallel solution-phase synthesis of combinatorial libraries of dihydroindenoisoquinolines employing a sequential Cu(I)/Pd(0)-catalyzed multicomponent coupling and annulation protocol was realized. The scope and limitations of the protocol with respect to the substitution pattern in the aryl ring of the indene core, as well as the N-substituent have been defined, revealing that the methodology is compatible with a wide-range of aliphatic linear, branched, and ester functionalized N-substituents. Unexpectedly, the formation of regioisomers featuring a 1,2,3-contiguous substitution pattern in the aromatic ring of the indene core was observed. Three distinct combinatorial libraries with a total of 111 of members were synthesized, and 80 highly substituted dihydroindenoisoquinolines structurally related to known medicinal agents including some consisting of mixtures of two regioisomers were made available for biological activity testing.

Palladacycles: Effective catalysts for a multicomponent reaction with allylpalladium(II)-intermediates

Palladium(II) complexes with an auxiliary bidentate ligand featuring one C-Pd bond and a Pd-N-donor bond (palladacycles) have been shown to afford improved yields of homoallylic amines from a three-component coupling of boronic acids, allenes and imines in comparison to the yields of homoallylic amines achieved with the originally reported catalyst (Pd(OAc)2/P(t-Bu)3), thus extending the scope of the reaction. 31P NMR monitoring studies indicate that distinct intermediates featuring Pd-P bonds originate in the reactions catalyzed by either Pd(OAc)2/P(t-Bu)3 or the pallada(II)cycle/P(t-Bu)3 systems, suggesting that the role of the pallada(II)cycles is more complex than just precatalysts. The importance of an additional phosphine ligand in the reactions catalyzed the pallada(II)cycles was established, and its role in the catalytic cycle has been proposed. Insights into the nature of the reactive intermediates that limit the performance of the originally reported catalytic systems has been gained.

Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via sequential Cu/Pd/Ru catalysis.

Aryl-fused 2-azabicyclo[2.2.2]octanes were prepared by a novel sequence of Cu-catalyzed three-component coupling of diversely substituted N-benzyl o-bromoaryl imines with methacryloyl chloride and vinyltributyl stannane followed by Pd-catalyzed Heck annulation. Subsequent diversification of the aryl-fused 2-azabicyclo[2.2.2]octane core was achieved by attaching a flexible linker and a potential second pharmacophore via Ru-catalyzed cross-metathesis and a nucleophilic substitution.

Final Report for: "Bis-pi-allylpalladium Complexes in Catalysis of Multicomponent Reactions"

The research project involved the development of new and functionally improved Pd(II) catalyst for a three-component reaction of boronic acids, allenes and imines to afford homoallylic amines that are useful in synthesis of biologically active heterocycles. Furthermore, insights into the reaction mechanism and the structure and reactivity of the catalytically active intermediates involved in this process were sought. As a result of this work, a new type of Pd-catalysts possessing an auxiliary ligand attached to the Pd center via a C-Pd and N-Pd bonds were identified, and found to be more active than the traditional catalysts derived from Pd(OAc)2. The new catalysts provided an access to a broader range of homoallylic amine products. Although the final unequivocal evidence regarding the structure of the Pd(II) complex involved in the nucleophilic transfer of the allyl fragment from the palladium center to the imine could not be obtained, mechanistic insights into the events that are detrimental to the activity of the originally reported Pd(OAc)2-based catalytic systems were uncovered.