The Pd-catalyzed decarboxylative allylation of α-(diphenylmethylene)imino esters (1) or allyl diphenylglycinate imines (2) is an efficient method to construct new C(sp(3))-C(sp(3)) bonds. The detailed mechanism of this reaction was studied by theoretical calculations [ONIOM(B3LYP/LANL2DZ+p:PM6)] combined with experimental observations. The overall catalytic cycle was found to consist of three steps: oxidative addition, decarboxylation, and reductive allylation. The oxidative addition of 1 to [(dba)Pd(PPh(3))(2)] (dba = dibenzylideneacetone) produces an allylpalladium cation and a carboxylate anion with a low activation barrier of +9.1 kcal mol(-1). The following rate-determining decarboxylation proceeds via a solvent-exposed α-imino carboxylate anion rather than an O-ligated allylpalladium carboxylate with an activation barrier of +22.7 kcal mol(-1). The 2-azaallyl anion generated by this decarboxylation attacks the face of the allyl ligand opposite to the Pd center in an outer-sphere process to produce major product 3, with a lower activation barrier than that of the minor product 4. A positive linear Hammett correlation [ρ = 1.10 for the PPh(3) ligand] with the observed regioselectivity (3 versus 4) supports an outer-sphere pathway for the allylation step. When Pd combined with the bis(diphenylphosphino)butane (dppb) ligand is employed as a catalyst, the decarboxylation still proceeds via the free carboxylate anion without direct assistance of the cationic Pd center. Consistent with experimental observations, electron-withdrawing substituents on 2 were calculated to have lower activation barriers for decarboxylation and, thus, accelerate the overall reaction rates.

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A library of 4,5-disubstituted 2-aminoimidazole triazole amide (2-AITA) conjugates has been successfully assembled. Upon biological screening, this class of small molecules was discovered as enhanced biofilm regulators through non-microbicidal mechanisms against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB), with active concentrations in the low micromolar range. The library was also subjected to synergism and resensitization studies with β-lactam antibiotics against MRSA. Lead compounds were identified that suppress the antibiotic resistance of MRSA by working synergistically with oxacillin, a β-lactam antibiotic resistant to penicillinase. A further structure-activity relationship (SAR) study on the parent 2-AITA compound delivered a 2-aminoimidazole diamide (2-AIDA) conjugate with significantly increased synergistic activity with oxacillin against MRSA, decreasing the MIC value of the β-lactam antibiotic by 64-fold. Increased anti-biofilm activity did not necessarily lead to increased suppression of antibiotic resistance, which indicates that biofilm inhibition and resensitization are most likely occurring via distinct mechanisms.

Antibiotic resistance is a significant problem and is compounded by the ability of many pathogenic bacteria to form biofilms. A library of N-substituted derivatives of a previously reported 2-aminoimidazole/triazole (2-AIT) biofilm modulator was constructed via α-bromoketone cyclization with 1,3-bis(tert-butoxycarbonyl)guanidine, followed by selective substitution. Several compounds exhibited the ability to inhibit biofilm formation by three strong biofilm forming strains of methicillin resistant Staphylococcus aureus (MRSA). Additionally, a number of members of this library exhibited synergistic activity with oxacillin against planktonic MRSA. Compounds with this type of dual activity have the potential to be used as adjuvants with conventional antibiotics.

Interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with appropriately functionalized Michael acceptors, followed by Heck cyclization, allows for the efficient construction of relatively complex organoamine frameworks in one reaction vessel. The initial intercepted decarboxylative allylation is remarkably insensitive toward solvent and catalyst, typically proceeding under ambient conditions.