Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp2)-C(sp3) Cross-Coupling Methods by Library Synthesis

Abstract

Despite recent advances in the field of C(sp²)-C(sp³) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on "drug-like" aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods. When analyzing the reactions run across all of the methods, a reaction success rate of 50% was achieved. Whereas this is promising, there are still gaps in the scope of direct C(sp²)-C(sp³) coupling methods, like tertiary group installation. The results reported herein should be used to inform future syntheses, assess reaction scope, and encourage medicinal chemists to expand their synthetic toolbox.

Figure 1

Modern strategies to install alkyl groups on heteroaromatic cores.

Figure 2

Comparison of methods using simple alkyl groups. For the linear alkyl Negishi coupling (column 2), R = n-propyl. For all other methods (column 2), R = methyl. For the pendant-ester Negishi coupling (column 5), R = ethyl. For all other methods (column 5), R = methyl. Negishi coupling: 5% Pd-PEPPSI-IPent^Cl, 0.09 M THF. Nickel/photoredox BF₃K coupling: 2% Ir(dF(CF₃)ppy)₂(bpy)PF₆, 5% NiCl₂(dtbbpy), 2 equiv of 2,6-lutidine, 0.05 M 4:1 dioxane/DMA, 450 nm LEDs. Nickel/photoredox BF₃K coupling (tertiary examples): 1% Ir(dF(CF₃)ppy)₂(bpy)PF₆, 10% Ni(TMHD)₂, 10% ZnBr₂, 1 equiv of K₂HPO₄, 0.1 M DMA, 450 nm LEDs. Suzuki BF₃K coupling: 5% CataCXium A Pd G3, 3 equiv of Cs₂CO₃ (7 M in H₂O), 0.2 M toluene, 100 °C. Suzuki MIDA coupling: 5% SPhos Pd G3, 7.5 equiv of K₃PO₄ (3 M in H₂O), 0.5 M dioxane, 60 °C. Nickel/photoredox decarboxylative coupling: 2% Ir(dF(CH₃)ppy)₂(dtbbpy)PF₆, 5% NiCl₂(dtbbpy), 1.5 equiv of BTMG, 0.1 M DMSO, 450 nm LEDs. Nickel/photoredox decarboxylative coupling (phenylacetic acid derivatives): 2% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 5% NiCl₂(dtbbpy), 1.5 equiv of Cs₂CO₃, 0.1 M DMA, 450 nm LEDs. Nickel/photoredox CEC: 1% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 0.5% NiCl₂(dtbbpy), 1.2 equiv of (TMS)₃SiH, 2 equiv of 2,6-lutidine, 0.13 M DME, 450 nm LEDs. Nickel-catalyzed reductive CEC: 7% NiCl₂-glyme, 7% ligand, 25% NaI, 2 equiv of Zn flake, 10% TFA, 0.015 M DMA, 60 °C, ligand = 4,4′-di-tert-butyl-2,2′-bipyridine, [2,2′-bipyridine]-6-carboximidamide hydrochloride or (2Z,6Z)-N′2,N′6-dicyanopyridine-2,6-bis(carboximidamide).

Figure 3

Installing alkyl groups containing polar functionality. Negishi couplings: 5% Pd-PEPPSI-IPent^Cl, 0.09 M THF. Negishi couplings (in situ prepared organozincs): 5% SPhos Pd G4, 0.09 M DMA. Nickel/photoredox BF₃K couplings: 2% Ir(dF(CF₃)ppy)₂(bpy)PF₆, 5% NiCl₂(dtbbpy), 2 equiv of 2,6-lutidine, 0.05 M 4:1 dioxane/DMA, 450 nm LEDs. Suzuki BF₃K couplings: 5% CataCXium A Pd G3, 3 equiv of Cs₂CO₃ (7 M in H₂O), 0.2 M toluene, 100 °C. Nickel/photoredox decarboxylative couplings (α-alkyl carboxylic acids): 2% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 5% NiCl₂(dtbbpy), 1.5 equiv of BTMG, 0.1 M DMSO, 450 nm LEDs. Nickel/photoredox decarboxylative couplings (α-amino and α-oxy carboxylic acids): 2% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 5% NiCl₂(dtbbpy), 1.5 equiv of Cs₂CO₃, 0.1 M DMA, 450 nm LEDs. Nickel/photoredox CEC: 1% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 0.5% NiCl₂(dtbbpy), 1.2 equiv of (TMS)₃SiH, 2 equiv of 2,6-lutidine, 0.13 M DME, 450 nm LEDs. Nickel-catalyzed reductive CEC: 7% NiCl₂-glyme, 7% ligand, 25% NaI, 2 equiv of Zn flake, 10% TFA, 0.015 M DMA, 60 °C, ligand = 4,4′-di-tert-butyl-2,2′-bipyridine, [2, 2′-bipyridine]-6-carboximidamide hydrochloride or (2Z,6Z)-N′2,N′6-dicyanopyridine-2,6-bis(carboximidamide).

Figure 4

Showcase of methods with high monomer availability. (a) Comparison of two CEC methods and (b) use of unique carboxylic acid building blocks. (4a) Nickel/photoredox CEC: 1% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 0.5% NiCl₂(dtbbpy), 1.2 equiv of (TMS)₃SiH, 2 equiv of 2,6-lutidine, 0.13 M DME, 450 nm LEDs. Nickel-catalyzed reductive CEC: 7% NiCl₂-glyme, 7% ligand, 25% NaI, 2 equiv of Zn flake, 10% TFA, 0.015 M DMA, 60 °C, ligand = 4,4′-di-tert-butyl-2,2′-bipyridine, [2,2′-bipyridine]-6-carboximidamide hydrochloride, or (2Z,6Z)-N′2, N′6-dicyanopyridine-2,6-bis(carboximidamide). (4b) Asterisks (*) denote alkyl group overlap with another method in this study. Nickel/photoredox decarboxylative coupling: 2% Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆, 5% NiCl₂(dtbbpy), 1.5 equiv of Cs₂CO₃, 0.1 M DMA, 450 nm LEDs.