Copper(II)‐Catalyzed meta‐Selective Direct Arylation of α‐Aryl Carbonyl Compounds

Abstract

Substituted arenes dominate the properties of many natural products, medicines, and materials.[1] Therefore, the development of new methods for direct and selective aromatic functionalization is a persistent challenge for synthetic chemists.[2] A particularly important class of substituted aromatic compounds is the a-aryl carbonyl structure. These molecules represent broadly useful starting materials for complex molecule synthesis, and the basic structural framework is present in a wide range of medicinally relevant molecules.[3] Despite the importance of these structures, surprisingly few direct methods are available to selectively functionalize the arene nucleus in the absence of other groups: aromatic substitution reactions require directing functionality to control reactivity and selectivity; cross coupling processes need pre-installed functional groups; and while the acidity of the CÀH bonds between the arene and carbonyl groups facilitates a wealth of enolate chemistry, it precludes the use of directed ortho-lithiation reactions. [4] A potential solution to some of these limitations has recently been presented through the development of orthoselective Pd II -catalyzed C À H bond functionalization reactions. [5,6] The cyclometalation strategy employed in these transformations, however, cannot be used to facilitate metaor para-functionalization of these molecules due to restrictive geometric constraints. [7,8] The synthetic utility of the generic a-aryl acetic acid motif would be significantly expanded by a methodology that provides direct access to isomeric molecules of potentially beneficial therapeutic value (Scheme 1 A). Herein, we report a copper-catalyzed meta-selective arylation of the a-aryl carbonyl scaffold with diaryliodonium salts that is directed by a remote and versatile Weinreb amide group (Scheme 1 B). This method provides a novel synthetic route to arenes displaying diverse substitution, benzylic chirality and quaternary centers. Its potential is further enhanced through its compatibility with iterative C À H bond functionalization methods that will have broad utility in the synthesis of highly functionalized arenes.As part of our studies towards meta-selective functionalization processes, [8d] we postulated that the location of a carbonyl group plays a key role in determining the selectivity of our Cu II -catalyzed meta-arylation of pivanilides. To test this hypothesis, we speculated that the a-aryl carbonyl would also provide a similar reactivity platform because the carbonyl motif is displayed in a similar position relative to the arene nucleus. Notably, the arene nucleophilicity of the electronically neutral a-aryl carbonyl motif is drastically different to the electron-rich pivanilide.To test whether a-aryl carbonyl compounds could be functionalized at the meta-position, we prepared diethylamide 1 a and treated it with diphenyliodonium triflate and 20 mol % Cu(OTf) 2 in dichloroethane at 70 8C, conditions that are identical to those used for the arylation of pivanilides.[8d]After reacti...

A meta-selective C–H borylation directed by a secondary interaction between ligand and substrate

“…Fourth, hypervalent iodine-mediated arylation affords meta-arylated products from aromatic amides and α-aryl carbonyl compounds (Fig. 1d) 20,21 . In Fig.…”

Diaryliodonium Salts in Organic Syntheses: A Useful Compound Class for Novel Arylation Strategies

“…The products could be obtained at elevated temperatures without adding copper, albeit in lower yields, what might indicate a more complicated mechanistic profile. As an extension, further developments were performed by Gaunt and the copper catalyzed meta-selective direct arylation of α-aryl carbonyl compounds 60 was reported. Diaryliodonium triflates containing EDG and EWG groups were both tolerated in the reaction.…”

“…51 Their methodology applies Simpkin's base to generate the nucleophilic enolate intermediate (Scheme 24). The presence of bulky substituents on the C4 carbon of the cyclohexanone ring was necessary to reach good enantioselectivity for the appropriate arylated products (60). To demonstrate the power of this transformation, it was utilized in the short total synthesis of (-)-epibatidine.…”

“…[54][55][56][57][58][59][60][61][62][63][64][65][66][67] Utilizing this concept, several syntheses of diverse heterocyclic skeletons were developed in the last few years in our and other laboratories. The copper catalyzed synthesis of new oxazoline derivatives (89) from propargyl amides (88) and diaryliodonium salts was recently developed by our research group.…”

Meta‐Selective C−H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

“…[2] Select strategies include designer templates that orient the metal in close proximity to a meta C–H bond, [3] steric-controlled processes, [4] or transformations that are predicated on a specific mechanistic pathway selective for meta reactivity. [5] A separate approach using Pd catalysis was developed by the Yu and Dong groups independently, [6,7] where they draw inspiration from the Catellani reaction involving norbornene insertion/deinsertion [8] to achieve metalation at the meta position from an initial ortho -directed functionalization (Figure 1). Further studies illustrated the capacity of this palladium-catalyzed process to be utilized in derivatives of phenylacetic acids, phenethyl amines, benzyl amines, anilines, and phenols.…”