From Aryl Iodides to 1,3-Dipoles: Design and Mechanism of a Palladium Catalyzed Multicomponent Synthesis of Pyrroles.

A palladium-catalyzed multicomponent synthetic route to polysubstituted pyrroles from aryl iodides, imines, carbon monoxide, and alkynes is described. To develop this reaction, a series of mechanistic studies on the [Pd(allyl)Cl]2/P(t)Bu3 catalyzed synthesis of imidazolinium carboxylates from aryl iodides, imines, and carbon monoxide were first performed, including model reactions for each individual step in the transformation. These show that this reaction proceeds in a concurrent tandem catalytic fashion, and involves the in situ formation of acid chlorides, N-acyl iminium salts, and ultimately 1,3-dipoles, i.e., Münchnones, for subsequent cycloaddition. By employing a Pd(P(t)Bu3)2/Bu4NCl catalyst, this information was used to design the first four-component synthesis of Münchnones. Coupling the latter with 1,3-dipolar cycloaddition with electron deficient alkynes or alkenes can be used to generate diverse families of highly substituted pyrroles in good yield. This represents a modular and streamlined new approach to this class of heterocycles from readily accessible starting materials.

Palladium Catalyzed, Multicomponent Synthesis of Fused-Ring Pyrroles from Aryl Iodides, Carbon Monoxide, and Alkyne-Tethered Imines.

A palladium-catalyzed multicomponent route to polycyclic pyrroles is described. Pd(PtBu3)2 was found to catalyze the coupling of (hetero)aryl iodides, two equivalents of carbon monoxide and alkyne-tethered imines into 1,3-dipoles (Münchnones), which undergo spontaneous, intramolecular 1,3-dipolar cycloaddition to form polycyclic pyrroles. The systematic variation of the alkyne, tethered-imine, or aryl iodide can allow the buildup of a range of pyrrole derivatives, where any of the substituents can be independently varied. In addition, the same palladium catalyst can be employed in an initial Sonogashira-type coupling with aryl iodides, which upon the addition of CO can allow the novel tandem catalytic, five component synthesis of diversely substituted products.

Palladium-Catalyzed, Multicomponent Approach to ß-Lactams via Aryl Halide Carbonylation.

A palladium-catalyzed multicomponent method for the synthesis of ß-lactams from imines, aryl halides, and CO has been developed. This transformation proceeds via two tandem catalytic carbonylation reactions mediated by Pd(PtBu3)2 and provides a route to prepare these products from five separate reagents. A diverse range of polysubstituted ß-lactams can be generated by systematic variation of the substrates. This methodology can also be extended to the use of iodo-substituted imines to produce novel spirocyclic ß-lactams in good yields and selectivity.

A dual light-driven palladium catalyst: Breaking the barriers in carbonylation reactions.

Transition metal-catalyzed coupling reactions have become one of the most important tools in modern synthesis. However, an inherent limitation to these reactions is the need to balance operations, because the factors that favor bond cleavage via oxidative addition ultimately inhibit bond formation via reductive elimination. Here, we describe an alternative strategy that exploits simple visible-light excitation of palladium to drive both oxidative addition and reductive elimination with low barriers. Palladium-catalyzed carbonylations can thereby proceed under ambient conditions, with challenging aryl or alkyl halides and difficult nucleophiles, and generate valuable carbonyl derivatives such as acid chlorides, esters, amides, or ketones in a now-versatile fashion. Mechanistic studies suggest that concurrent excitation of palladium(0) and palladium(II) intermediates is responsible for this activity.

A general approach to intermolecular carbonylation of arene C-H bonds to ketones through catalytic aroyl triflate formation.

The development of metal-catalysed methods to functionalize inert C-H bonds has become a dominant research theme in the past decade as an approach to efficient synthesis. However, the incorporation of carbon monoxide into such reactions to form valuable ketones has to date proved a challenge, despite its potential as a straightforward and green alternative to Friedel-Crafts reactions. Here we describe a new approach to palladium-catalysed C-H bond functionalization in which carbon monoxide is used to drive the generation of high-energy electrophiles. This offers a method to couple the useful features of metal-catalysed C-H functionalization (stable and available reagents) and electrophilic acylations (broad scope and selectivity), and synthesize ketones simply from aryl iodides, CO and arenes. Notably, the reaction proceeds in an intermolecular fashion, without directing groups and at very low palladium-catalyst loadings. Mechanistic studies show that the reaction proceeds through the catalytic build-up of potent aroyl triflate electrophiles.