Chemical Synthesis

α-Bromo Amides–Use in Asymmetric Nickel-Catalyzed Negishi Couplings

Introduction

There have been significant advances in cross-couplings utilizing both primary and secondary alkyl electrophiles. In 2005, Fu and coworkers published the first catalytic asymmetric cross-coupling of secondary alkyl electrophiles. This work was preceded by Fu and coworkers’ demonstration of Negishi couplings of unactivated secondary alkyl halides using a Ni(cod)2/s-Bu-Pybox system. After some investigation, they found that utilizing racemic α-bromo amides (such as 704911 below (Figure 1)) coupled with a catalyst comprised of a NiCl2•glyme precatalyst and the (i-Pr)-Pybox ligand provided the best yields and enantioselectivities in the presence of a variety of unfunctionalized and functionalized organozinc reagents.

Negishi Coupling of a-bromo amides with hexylzinc bromide

Figure 1:  Negishi Coupling of α-bromo amides with hexylzinc bromide

References:

  1. Zhou, J. and Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726.
  2. Fischer, C. and Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594.

Advantages

  • Catalyst system is selective for coupling α-bromo amides with primary or secondary alkyl electrophiles
  • Exceptional scope, wide range of functionalized and unfunctionalized organozinc reagents utilized
  • Amide moiety readily functionalized to other useful functionalities

Representative Applications

   Preparation of α-Chiral Amides

The preparation of enantiopure α-chiral amides from racemic α-bromo amides using the NiCl2•glyme/(i-Pr)-Pybox catalyst system is an exceptionally useful and robust method which is well-suited for screening purposes. Organozinc reagents containing various functionalities including olefin, benzyl ethers, acetals, imides and nitriles were effective in the coupling.

Negishi Cross-Coupling with α-bromo amides-Scope

Table 1: Negishi Cross-Coupling with α-bromo amides-Scope

Table 1: Negishi Cross-Coupling with α-bromo amides-Scope

The mechanism of the Ni-catalyzed Negishi coupling utilizing the α-bromo amides and other alkyl electrophiles is still currently under investigation. Vicic has proposed a radical-mechanism for Negishi couplings; however, a radical mechanism is unlikely to be operative in the Negishi coupling of α-bromo amides as evidenced by the exceptional levels of enantioselectivities obtained. Fu and coworkers did, however, determine that a resolution was not occurring in the reaction as treatment of the starting material (rac) with 0.8 eq of the alkylzinc reagent led to recovered starting material, rather than enantioenriched product (Figure 2).

Mechanistic Evidence Against Resolution in Negishi coupling



Figure 2:  Mechanistic Evidence Against Resolution in Negishi coupling


The use of alkyl electrophiles is generally challenging because of the risk of β-hydride elimination. However, the NiCl2•glyme/(i-Pr)-Pybox system is not only selective for couplings of α-bromo amides, but works efficiently enough to avoid undesired and historically detrimental side reactions.


Prod. No. Product Name Structure
704938  N-Benzyl-2-bromo-N-phenylpropionamide  
704911  N-Benzyl-2-bromo-N-phenylbutanamide  

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