Synlett 2023; 34(12): 1452-1456
DOI: 10.1055/a-2036-4809
cluster
Special Issue Honoring Masahiro Murakami’s Contributions to Science

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

Nicklas P. Corneliussen
,
Ebbe K. Grove
,
Anne-Sofie O. Schøler
,
Anton H. Andersen
,
Aske S. Donslund
,
,
Troels Skrydstrup
We thank the Danish National Research Foundation (grant no. DNRF118), NordForsk (grant no. 85378), and Aarhus University for financial support.


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.

Supporting Information



Publication History

Received: 13 January 2023

Accepted after revision: 15 February 2023

Accepted Manuscript online:
15 February 2023

Article published online:
10 March 2023

© 2023. Thieme. All rights reserved

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 14 α,α-Difluoro-β-ketoamides 2ap and α-Fluoro-β-ketoamides 4ac: 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.