Catalytic Enantioselective α-Arylation of Carbonyl Compounds

Abstract

Enantioselective creation of benzylic quaternary centers still is a continuous challenge to many synthetic organic chemists. Among the existing methods for installation of this type of center, the direct asymmetric a-arylation of carbonyl compounds is very attractive due to the ready availability of the coupling substrates. Herein, we present some new tools to the catalytic asymmetric aarylation of carbonyl compounds that overcame many of the drawbacks posted in previous methods for this type of reaction.Benzylic quaternary centers are widely found in the structure of a considerable number of natural and pharmaceutically important compounds. Possessing either simple or complex molecular architectures ( Figure 1) these compounds still challenge many synthetic organic chemists, especially with respect to the enantioselective creation of those benzylic quaternary centers. 1 Figure 1 Examples of molecules possessing benzylic quaternary centersAmong the emerged methods for installation of this type of center, the direct asymmetric a-arylation of carbonyl compounds is very attractive due to the ready availability of the coupling substrates. Considering the versatility of the carbonyl group, asymmetric a-arylation of carbonyl compounds is not only limited to the creation of the benzylic center a to a carbonyl, but it can also be employed to generate benzylic centers with other functionalities. Two main methods can be outlined as direct and simple tools for the a-arylation of carbonyl compounds: (1) the nucleophilic aromatic substitution between enolates and aryl halides 2 and (2) transition-metal-catalyzed a-arylation of carbonyl compounds. 3 Although both methods can furnish a-arylated carbonyl compounds in a direct fashion, the former suffers many drawbacks such as the requirement of aromatic compounds with good electron-withdrawing substituents (F, NO 2 ). Based on this fact, the later method has become the one of choice for this type of transformation and many different protocols have been described to date. Nevertheless, much effort is still necessary to put this emerging method in a mature position, especially in the field of catalytic asymmetric a-arylation of carbonyl compounds. For example, high enantioselective a-arylation of carbonyl compounds has only been achieved in a very limited number of cases and with specific substrates. Another point is the limitation of those methods to provide only quaternary centers, which brings a challenge when epimerizable tertiary centers containing an aryl group are desirable. Herein, first, we would like to call the attention for this important and versatile emerging area giving an up-to-date overview of these main methods. Second, stimulate new contributions to this field. Third, to present very recent literature results as new tools to the catalytic asymmetric a-arylation of carbonyl compounds that overcame some of the drawbacks posted above.The first three general methods for the direct transitionmetal-catalyzed a-arylation of carbonyl compounds appeared independently in ...

α‐Arylation by Rearrangement: On the Reaction of Enolates with Diaryliodonium Salts

“…Yet, there are few synthetic routes to this important compound class. [2] Direct a-arylation of enolates is much harder to realize than the corresponding alkylation reaction, and has been reported only in recent decades. These protocols are mostly based on transition-metal catalysis or stoichiometric use of heavy metal compounds, such as aryl lead reagents.…”

“…These protocols are mostly based on transition-metal catalysis or stoichiometric use of heavy metal compounds, such as aryl lead reagents. [2] Hypervalent iodine reagents have recently received considerable attention as mild, selective and non-toxic reagents in many areas of organic synthesis. Diaryliodonium salts, which are iodineA C H T U N G T R E N N U N G (III) compounds with two aryl ligands, are versatile arylation agents for a variety of nucleophiles.…”

“…[20] The chosen PTC* + should block one face of enolate 2 as demonstrated in asymmetric S N Ar reactions of 2 (Scheme 2 b). [21] Both approaches were expected to deliver the enantiomerically enriched iodane intermediate 3, which would yield product 4 upon reductive elimination (i.e., [1,2] rearrangement). [22] Several variations of the two approaches depicted in Scheme 2 were tested, as outlined in the Supporting Information.…”

α-Functionalization of Carbonyl Compounds Using Hypervalent Iodine Reagents

“…[97] 5 Arylation α-Arylated carbonyl compounds are commonly occurring subunits in biologically active molecules and are therefore of high interest to the pharmaceutical industry. [98] The introduction of aryl moieties to the α-position of carbonyl compounds, particularly in an asymmetric fashion, is an ongoing challenge in organic synthesis. [98] Conventional procedures often use stoichiometric amounts of toxic reagents and harsh reaction conditions.…”

“…[98] The introduction of aryl moieties to the α-position of carbonyl compounds, particularly in an asymmetric fashion, is an ongoing challenge in organic synthesis. [98] Conventional procedures often use stoichiometric amounts of toxic reagents and harsh reaction conditions. There are several metal-catalyzed methods to accomplish α-arylation using aryl halides, but these routes suffer from high temperatures, long reaction times and drawbacks associated with the use of heavy metals in industry.…”