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43673-AC1
Improving Turnover Numbers of Palladium N-Heterocyclic Carbene Catalysts in Challenging Processes: Intramolecular Direct Arylation Reactions with Aryl Chlorides
The utility of the biaryl structural motif has prompted intense research directed at discovering efficient and high yielding methods for its preparation. Transition metal catalysis has featured prominently in these efforts, leading to the establishment of a range of useful cross coupling reactions. A common element in all of these processes is the need for two activated arenes that can react selectively with the metal catalyst. While high yields can be achieved with pre-activated substrates, the need for dual pre-activation is inherently wasteful since these groups may require multiple steps for their installation, and none of the pre-activation groups appear in the final product. Furthermore, not all regioisomers of the organometallic or aryl halide are readily available making some biaryl compounds difficult to access. In some instances the pre-activated species may not be stable thus complicating application of this methodology.
In recent years, direct arylation reactions have emerged as attractive alternatives to these more commonly employed cross coupling reactions. These reactions substitute one of the pre-activated arenes with a simple arene. Importantly, it is typically the more expensive and difficult to prepare organometallic coupling partner that is replaced. Despite the advances in this field, when we initiated our work several important challenges remained. For example, the predominance of direct arylation reactions employs aryl iodides as coupling partners. Even with electron rich heterocyclic arenes, use of aryl chlorides is rare despite the fact that aryl chlorides are more readily available and less expensive. Furthermore, prior to our work, no single catalyst has been shown to be capable of achieving catalytic arylation with simple arenes and aryl iodides, bromides and chlorides.
During the past two years we have accomplished the following objectives: (1) the development of an operationally simple catalyst system for direct intramolecular arylation processes exhibiting broad scope for aryl chlorides, bromides and iodides including previously incompatible sterically encumbered aryl chlorides and bromides; (2) evidence that, despite their widespread use, aryl iodides exhibit inferior reactivity compared to aryl bromides and chlorides in the direct arylation reactions studied; (3) insight into catalyst poisoning with aryl iodides leading to new reaction conditions showing increased reactivity; (4) application of these processes to the synthesis of a carbazole natural product, Mukonine, in three steps from simple starting materials; (5) conditions for the efficient formation of tetra-ortho substituted biaryls and their conversion to acyclic tetra-ortho substituted biaryls; (6) mechanistic studies pointing to a kinetically significant C-H bond cleavage step in the direct arylation of simple arenes; and, (7) the development of the first intermolecular direct arylation reactions of a simple arene with aryl chlorides and bromides thus setting the stage for further expansion in these previously inaccessible processes.
As part of these studies we also carried out mechanistic studies dealing with catalyst decomposition that will have implications not only in direct arylation but in other palladium-catalyzed reactions as well. N-Heterocyclic carbene (NHC) ligands have become increasingly employed in transition metal catalysis. The 1:1 NHC:metal complexes typically exhibit enhanced reactivity compared to analogous 2:1 species and these observations have prompted the development of several methods to prepare NHC metal complexes with a well defined 1:1 ligand to metal ratio. Despite the impressive reactivity of these catalysts, they can be prone to decomposition after insertion of the aryl halide. Cavell, Caddick and Grushin have shown that in the absence of a good nucleophile, NHC aryl palladium(II) species are unstable and undergo facile aryl-NHC reductive elimination to give the arylimidazolium salts and catalyst death. The study of NHC catalysts in the context of direct arylation reactions provided an opportunity to study and learn to circumvent NHC-catalyst decomposition since these reactions must be able to occur in the absence of a strong nucleophile. These studies resulted in the discovery of a generally applicable catalyst system for the efficient intramolecular direct arylation of aryl chlorides. As part of these studies we found that the X-ligands of the palladium pre-catalyst influence the efficiency of catalyst activation. We also found that the addition of NHC salts to reactions employing palladium mono-NHC pre-catalysts can lead to improvements in catalyst turnover number (TON). These observations should be of broader implication in other cross coupling reactions.
