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...

Activation of remote meta-C–H bonds assisted by an end-on template

“…Despite the steric hinderance, para -substituted arenes are also olefinated at the meta -position in excellent selectivity ( 17k–n ). In sharp contrast to previously reported meta -selective C–H functionalization reactions, 20,24 the template also effectively overrules the electronic effect of bromide or ester groups at the para position, affording predominantly the meta -olefinated products ( 17m , 17n ). Finally, the template can guide the catalyst to reach and activate the meta -C–H bond in a selective manner in the presence of ortho,ortho -di-fluoro substitution, demonstrating another unique feature of this approach ( 17o ).…”

“…Finally, N -phthaloyl protected Baclofen ( 20h ), a GABA receptor agonist drug, was selectively olefinated at the meta -position to give 21h in 82% yield, providing access to a novel library of unique molecules of medicinal interest. It is worth noting that two previously reported catalytic systems for meta -selective C–H activation 20,24 are not compatible with these substrates.…”

“…1A). Rare examples of non-directed meta - and para - selective C–H functionalization reactions of mono-substituted arenes involving either electrophilic substitution (where the metal is not involved in the C–H cleavage step) 20,21 or inner-sphere metalation 22–27 have been reported in which the regioselectivity is governed by either the electronic or steric properties of the arene substrates. To date, a generally applicable approach for remote meta -C–H activation that overrides the electronic and steric properties of arene substrates remains to be developed (Fig.…”

Ohne dirigierende Gruppen: übergangsmetallkatalysierte C‐H‐Aktivierung einfacher Arene

“…So findet die Funktionalisierung eines Arens in den meisten Fällen ausschließlich in ortho-Position zur DG statt, was die Auswahl an zugänglichen Produkten einschränkt. [6] Zudem sind häufig zusätzliche Syntheseschritte nçtig, um die DG in das Startmaterial einzuführen, aber auch um diese nach der Funktionalisierung wieder zu entfernen. Jedoch muss an dieser Stelle bemerkt werden, dass viele DG, besonders die Carbonsäuren und ihre Derivate, geeignete Gruppen zur weiteren Funktionalisierung darstellen.…”

Copper‐Catalyzed Intramolecular Electrophilic Carbofunctionalization of Allylic Amides

“…[3] Most of these reactions are triggered by heteroatom electrophiles, often activated by a catalyst, and result in the formation of a carbon-oxygen and a carbon-heteroatom bond. Despite these advances, the development of novel methods that catalytically generate carbon electrophiles capable of activating alkenes to nucleophilic attack remains a challenge; the solution to this challenge would be of significant use in complex molecule synthesis.As part of an overarching program aimed at the exploitation of high oxidation state metal species we, [9] and others, [10] have established that the combination of copper catalysts and diaryliodonium salts gives rise to a high oxidation state Cu III / aryl [11] intermediate that displays reactivity of an aromatic electrophile (Scheme 1 b). One possible reason for this is the lack of suitable carbon electrophiles that can activate the carbon-carbon double bond of the allylic amide.…”