Facilitating the transmetalation step with aryl-zincates in nickel-catalyzed enantioselective arylation of secondary benzylic halides

Weichen Huang,Mei Hu,Xiaolong Wan,Qilong Shen

doi:10.1038/s41467-019-10851-4

Weichen Huang, Mei Hu + Show 2 more

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https://doi.org/10.1038/s41467-019-10851-4

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Abstract

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph2ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph2ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr2 was described.

Highlights

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers
Over the past two decades, nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles has emerged as powerful methods for the construction of chiral tertiary carbon centers[1,2,3,4]
Since the seminar work by Fu and co-workers in 20055, a number of activated racemic alkyl halides such as α-bromoamides[5], α-bromoketones[6], benzylic bromides and chlorides[7,8], allylic chlorides[9] or 1-bromo-1fluoroalkane[10] and unactivated racemic alkyl halides such as β- or γ-ether, amide or sulfonyl-substituted alkyl bromides[11,12], and αhaloboronates[13] were effectively employed as the coupling partners, while the choice of nucleophiles was originally mainly focused on alkyl zinc halides

Summary

Introduction

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. We report that the use of lithium aryl zincate [Ph2ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph2ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr2 was described. 1234567890():,; Over the past two decades, nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles has emerged as powerful methods for the construction of chiral tertiary carbon centers[1,2,3,4]. In 2017, we discovered that the transmetalation step in nickelcatalyzed asymmetric Suzuki-Miyaura coupling of CF3Osubstituted secondary benzylic bromide was much faster when available, air-insensitive lithium organoboronate instead of a Alk ZnBr

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