Nickel-Catalyzed Carbonylative Coupling of Alkylzinc Reagents and α-Bromo-α,α-difluoroacetamides

Abstract

We report a nickel-catalyzed carbonylative cross-coupling of alkyl zinc reagents with α,α-difluorobromoacetamides to obtain α,α,-difluoro-β-ketoamides in moderate to good yields. The reaction is catalyzed by a bench-stable nickel(II) pincer complex, in contrast to other reports involving palladium catalysts. The carbonylative reaction is performed in a two-chamber system (COware) in which carbon monoxide (CO) is generated ex situ from the solid precursor SilaCOgen, and then consumed in the adjacent chamber. The reaction operates at low temperatures using near-stoichiometric amounts of CO. Isotopically labeled products can be effortlessly accessed, as demonstrated by using ¹³C-labeled SilaCOgen.

Key words

nickel catalysis - isotopic labeling - carbonylation - difluoro keto amides - alkyl nucleophiles - cross-coupling

Publication History

Received: 13 January 2023

Accepted after revision: 15 February 2023

Accepted Manuscript online:
15 February 2023

Article published online:
10 March 2023

• References and Notes

• 1a Brennführer A, Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 4114
• 1b Wu X.-F, Neumann H, Beller M. Chem. Soc. Rev. 2011; 40: 4986
• 2 Peng J.-B, Wu F.-P, Wu X.-F. Chem. Rev. 2019; 119: 2090
• 3a Feng Z, Min Q.-Q, Xiao Y.-L, Zhang B, Zhang X. Angew. Chem. Int. Ed. 2014; 53: 1669
• 3b Tarui A, Shinohara S, Sato K, Omote M, Ando A. Org. Lett. 2016; 18: 1128

For general fluorine properties, see:
• 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 4b Wang J, Sánchez-Roselló M, Aceña JL, de Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 4c Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 5a Andersen TL, Frederiksen M, Domino K, Skrydstrup T. Angew. Chem. Int. Ed. 2016; 55: 10396
• 5b Zhao HY, Feng Z, Luo Z, Zhang X. Angew. Chem. Int. Ed. 2016; 55: 10401
• 5c Yin H, Kumke JJ, Domino K, Skrydstrup T. ACS Catal. 2018; 8: 3853
• 6 Andersen TL, Kramer S, Overgaard J, Skrydstrup T. Organometallics 2017; 36: 2058
• 7 Zhao H.-Y, Gao X, Zhang S, Zhang X. Org. Lett. 2019; 21: 1031
• 8 Andersen TL, Donslund AS, Neumann KT, Skrydstrup T. Angew. Chem. Int. Ed. 2018; 57: 800
• 9 Donslund AS, Neumann KT, Corneliussen N, Grove E, Herbstritt D, Daasbjerg K, Skrydstrup T. Chem. Eur. J. 2019; 25: 9856
• 10 Friis SD, Taaning RH, Lindhardt AT, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 18114
• 11 Hermange P, Lindhardt AT, Taaning RH, Bjerglund KM, Lupp D, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 6061
• 12 Friis SD, Lindhardt AT, Skrydstrup T. Acc. Chem. Res. 2016; 49: 594
• 13a Breitenfeld J, Ruiz J, Wodrich MD, Hu X. J. Am. Chem. Soc. 2013; 135: 12004
• 13b Breitenfeld J, Wodrich MD, Hu X. Organometallics 2014; 33: 5708
• 13c Shi R, Zhang Z, Hu X. Acc. Chem. Res. 2019; 52: 1471
• 14 α,α-Difluoro-β-ketoamides 2a–p and α-Fluoro-β-ketoamides 4a–c: General Procedure The following steps were carried out in an argon-filled glovebox. Chamber A of the two-chamber system (20 mL total volume) was charged with NiL1 (19.4 mg, 15 mol%, 0.15 equiv). The second chamber (Chamber B) was charged with SilaCOgen (145.4 mg, 0.6 mmol, 1.5 equiv) and KF (23.3 mg, 0.4 mmol, 1.0 equiv). The appropriate α-bromo-α,α-difluoroacetamide (0.4 mmol, 1.0 equiv) and alkylzinc reagent (0.8 mmol, 2.0 equiv) were then added to Chamber A, along with MeCN to a total volume of 4 mL (depending on the concentration of the alkylzinc reagent). Chamber A was then sealed tightly with a screwcap equipped with a Teflon seal. Finally, THF (1 mL) was added to Chamber B, and the chamber was sealed tightly with a screwcap equipped with a Teflon seal. The two-chamber system was removed from the glovebox and placed in a heat block at 35 °C before stirring was commenced. After 24 h, the mixture was transferred to a round-bottomed flask with CH₂Cl₂. The crude product was concentrated on Celite or silica gel and subjected to flash column chromatography. 2,2-Difluoro-1-(pyrrolidin-1-yl)hexane-1,3-dione (2a) Prepared according to the general procedure from 2-bromo-2,2-difluoro-1-(pyrrolidin-1-yl)ethan-1-one (91.2 mg, 0.40 mmol) and propylzinc bromide in DMA (1.0 M, 0.80 mL, 0.80 mmol) and MeCN (3.20 mL), and purified by flash chromatography (silica gel, 20% EtOAc–pentane) as a pale-yellow oil; yield: 66.0 mg (72%). ¹H NMR (400 MHz, CDCl₃): δ = 3.67 (t, J = 6.8 Hz, 2 H), 3.53 (t, J = 7.0 Hz, 2 H), 2.71 (t, J = 7.2 Hz, 2 H), 1.98 (quint, J = 6.6 Hz, 2 H), 1.88 (quint, J = 6.7 Hz, 2 H), 1.69 (h, J = 7.4 Hz, 2 H), 0.96 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 198.4 (t, J = 27.1 Hz), 160.1 (t, J = 27.7 Hz), 110.4 (t, J = 266.4 Hz), 47.4, 46.4 (t, J = 5.3 Hz), 39.3, 26.4, 23.4, 16.3, 13.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –112.4. HRMS: m/z [M + H]⁺ calcd for C₁₀H₁₆F₂NO₂: 220.1144; found: 220.1149.