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. 2020 Jan 3;22(1):1-5.
doi: 10.1021/acs.orglett.9b03434. Epub 2019 Oct 17.

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Aliphatic Amides on the Benchtop

Milauni M Mehta  1 , Timothy B Boit  1 , Jacob E Dander  1 , Neil K Garg  1
Affiliations

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Aliphatic Amides on the Benchtop

Milauni M Mehta et al. Org Lett. .

Abstract

Suzuki-Miyaura cross-couplings of amides offer an approach to the synthesis of ketones that avoids the use of basic or pyrophoric nucleophiles. However, these reactions require glovebox manipulations, thus limiting their practicality. We report a benchtop protocol for Suzuki-Miyaura cross-couplings of aliphatic amides that utilizes a paraffin capsule containing a Ni(0) precatalyst and NHC ligand. This methodology is broad in scope, is scalable, and provides a user-friendly approach to convert aliphatic amides to alkyl-aryl ketones.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Methods for the conversion of amides to ketones, prior studies of Ni-catalyzed Suzuki–Miyaura couplings that utilize a glovebox, and paraffin encapsulation strategy for benchtop delivery (present study).
Figure 2.
Figure 2.
Preparation of Ni(cod)2/Benz-ICy·HCl–paraffin capsules and their use in the benchtop Suzuki–Miyaura coupling of piperidinyl amide 4 and pyrrole boronic ester 5 under optimized conditions. Yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.
Figure 3.
Figure 3.
Scope of the boronic ester coupling partners. General conditions unless otherwise stated: substrate 4 (1.0 equiv, 0.4 mmol), K3PO4 (4.0 equiv), boronic ester (5.0 equiv), Ni(cod)2 (5 mol%), Benz-ICy·HCl (10 mol%), and 1,4-dioxane (1.0 M) heated at 120 °C for 24 h in a sealed vial under an atmosphere of N2. Unless otherwise noted, yields reflect the average of two isolation experiments. Yields in parentheses were obtained by carrying out the reaction in a glovebox utilizing literature conditions without encapsulating Ni(cod)2 and Benz-ICy·HCl in paraffin. a Yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.
Figure 4.
Figure 4.
Scope of the amide substrate. General conditions unless otherwise stated: amide substrate (1.0 equiv, 0.4 mmol), K3PO4 (4.0 equiv), boronic ester 5 (5.0 equiv), Ni(cod)2 (5 mol%), Benz-ICy·HCl (10 mol%), and 1,4-dioxane (1.0 M) heated at 120 °C for 24 h in a sealed vial under an atmosphere of N2. Unless otherwise noted, yields reflect the average of two isolation experiments. Yields in parentheses were obtained by carrying out the reaction in a glovebox utilizing literature conditions without encapsulating Ni(cod)2 and Benz-ICy·HCl in paraffin. a Yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.
Figure 5.
Figure 5.
Gram-scale Suzuki–Miyaura coupling of amide 1 with boronate ester 18 to generate ketone 19.
See this image and copyright information in PMC

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