Iridium-Catalyzed Asymmetric Allylic Substitution with Aryl Zinc Reagents

Alexakis, Alexandre; Hajjaji, Samir El; Polet, Damien; Rathgeb, Xavier

doi:10.1021/ol0713842

Cited by 83 publications

(16 citation statements)

References 36 publications

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“…For example, the author’s group has reported intermolecular reactions of sulfur nucleophiles,64 and You’s group has reported decarboxylative reaction of sulfur nucleophiles 65. Alexakis has reported iridium-catalyzed allylic arylation, although with modest regioselectivities 66,67. In addition, Han and You have shown that the iridium catalyst is suitable for decarboxylative reactions to generate carbamate68 and enolate69 nucleophiles.…”

Section: Discussionmentioning

confidence: 99%

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

2010

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ConspectusEnantioselective allylic substitution reactions comprise some of the most versatile methods for preparing enantiomerically enriched materials. These reactions form products that contain multiple functionalities by creating carbon-nitrogen, carbon-oxygen, carbon-carbon, and carbon-sulfur bonds. For many years, the development of catalysts for allylic substitution focused on palladium complexes. However, studies of complexes of other metals have revealed selectivities that often complement those of palladium systems. Most striking is the observation that reactions with unsymmetrical allylic electrophiles that typically occur with palladium catalysts at the less hindered site of an allylic electrophile occur at the more hindered site with catalysts based on other metals. In this Account, we describe an iridium precursor and a phosphoramidite ligand that catalyze reactions with a particularly broad scope of nucleophiles.The active form of this iridium catalyst is not generated by the simple binding of the phosphoramidite ligand to the metal precursor. Instead, the initial phosphoramidite and iridium precursor react in the presence of base to form a metallacyclic species that is the active catalyst. This species is generated either in situ or separately in isolated form by reactions with added base. The identification of the structure of the active catalyst led to the development of simplified catalysts as well as the most active form of the catalyst now available, which is stabilized by a loosely bound ethylene. Most recently, this structure was used to prepare intermediates containing allyl ligands, the structures of which provide a model for the enantioselectivities discussed here.Initial studies from our laboratory on the scope of iridium-catalyzed allylic substitution showed that reactions of primary and secondary amines, including alkylamines, benzylamines, and allylamines, and reactions of phenoxides and alkoxides occurred in high yields, with high branched-to-linear ratios and high enantioselectivities. Parallel mechanistic studies had revealed the metallacyclic structure of the active catalyst, and subsequent experiments with the purposefully formed metallacycle increased the reaction scope dramatically. Aromatic amines, azoles, ammonia, and amides and carbamates as ammonia equivalents all reacted with high selectivities and yields. Moreover, weakly basic enolates (such as silyl enol ethers) and enolate equivalents (such as enamines) also reacted, and other research groups have used this catalyst to conduct reactions of stabilized carbon nucleophiles in the absence of additional base.One hallmark of the reactions catalyzed by this iridium system is the invariably high enantioselectivity, which reflects a high stereoselectivity for formation of the allyl intermediate. Enantioselectivity typically exceeds 95%, regioselectivity for formation of branched over linear products is usually near 20:1, and yields generally exceed 75% and are often greater than 90%. Thus, the development of iridium catalysts ...

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Section: Discussionmentioning

confidence: 99%

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

2010

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“…Hard carbon nucleophiles that do not contain stabilizing electron-withdrawing substituents have been shown to react with allylic carbonates only recently in the [84,85]. The arylzinc reagents were generated from the corresponding aryl Grignard reagent and ZnBr 2 .…”

Section: Allylic Substitution With "Hard" Carbon Nucleophilesmentioning

confidence: 99%

Iridium-Catalyzed Allylic Substitution

Hartwig

Pouy

2010

Topics in Organometallic Chemistry

229

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Iridium-catalyzed asymmetric allylic substitution has become a valuable method to prepare products from the addition of nucleophiles at the more substituted carbon of an allyl unit. The most active and selective catalysts contain a phosphoramidite ligand possessing at least one arylethyl substituent on the nitrogen atom of the ligand. In these systems, the active catalyst is generated by a baseinduced cyclometalation at the methyl group of this substituent to generate an iridium metalacycle bound by the COD ligand of the [Ir(COD)Cl] 2 precursor and one additional labile dative ligand. Such complexes catalyze the reactions of linear allylic esters with alkylamines, arylamines, phenols, alcohols, imides, carbamates, ammonia, enolates and enolate equivalents, as well as typical stabilized carbon nucleophiles generated from malonates and cyanoesters. Iridium catalysts for enantioselective allylic substitution have also been generated from phosphorus ligands with substituents bound by heteroatoms, and an account of the studies of such systems, along with a description of the development of iridium catalysts is included.

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“…[15] Inspired by this work, our group recently developed a general and efficient iridium-catalyzed enantioselective allylic arylation reaction with moderate regioselectivity and good to high enantiocontrol. [16] We present herein a full account of the development of this new methodology that has potential in the synthesis of a number of biologically active compounds (Scheme 2), as demonstrated by its utilization towards the formal synthesis of (+ )-sertraline.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Iridium‐Catalyzed Allylic Arylation

Polet

Rathgeb

Falciola

et al. 2009

Chemistry A European J

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105

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We describe herein the development of the first iridium-catalyzed allylic substitution using arylzinc nucleophiles. High enantioselectivities were obtained from the reactions, which used commercially available Grignard reagents as the starting materials. This methodology was also shown to be compatible with halogen/metal exchange reactions. Its synthetic potential is demonstrated by its application towards the formal synthesis of (+)-sertraline.

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Iridium-Catalyzed Asymmetric Allylic Substitution with Aryl Zinc Reagents

Abstract: Thanks to iridium catalysis, arylzinc reagents undergo regioselective allylic substitution with very high enantioselectivity, when associated with phosphoramidite ligands.

Cited by 83 publications

References 36 publications

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

Iridium-Catalyzed Allylic Substitution

Enantioselective Iridium‐Catalyzed Allylic Arylation

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