Access to α,α-Difluoro-γ-amino Acids by Nickel-Catalyzed Reductive Aryldifluoroacetylation of N-Vinylacetamide

Abstract

A nickel-catalyzed reductive aryldifluoroacetylation of N-vinylacetamide with ethyl chloro(difluoro)acetate and aryl iodides is described. This chelating amide carbonyl group-assisted strategy provides rapid access to a variety of protected α,α-difluoro-γ-amino acids that might have potential applications in peptide chemistry and protein engineering. An advantage of this method is its synthetic simplicity, with no preparation of organometallic reagents.

Key words

dicarbofunctionalization - enamides - fluoro amino acids - cross-coupling - nickel catalysis - vinylacetamide

Publikationsverlauf

Eingereicht: 09. September 2020

Angenommen nach Revision: 28. September 2020

Artikel online veröffentlicht:
02. November 2020

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• 14 Ethyl 4-Aryl-4-(acetylamino)-2,2-difluorobutanoates 4a–n; General Procedure A 25 mL Schlenk tube was charged with N-vinylacetamide (1; 34.0 mg, 0.4 mmol, 1.0 equiv), the appropriate aryl iodide 2 (0.6 mmol, 1.5 equiv), NiCl₂·DME (5 mol%), phen (5 mol%), and Zn (2.0 equiv) under an argon atmosphere. DMA (2 mL) was added and the mixture was stirred for 5 min at rt. ClCF₂CO₂Et (3b; 0.6 mmol, 1.5 equiv) and DMA (2 mL) were then added, the tube was screw-capped, and the mixture was stirred at rt for 12 h. The mixture was then diluted with EtOAc and washed with H₂O. The organic phase was dried (Na₂SO₄), filtered, and concentrated, and the residue was purified by chromatography (silica gel).
• 15 Ethyl 4-(Acetylamino)-4-biphenyl-4-yl-2,2-difluorobutanoate (4a) Prepared by the general method and purified by chromatography [silica gel, PE–EtOAc (2:1)] as a white solid; yield: 102 mg (70%); mp 166–168 °C. IR (thin film): 3294, 3084, 2995, 2926, 1766, 1651 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.51 (m, 4 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.40–7.31 (m, 3 H), 6.26 (d, J = 7.6 Hz, 1 H), 5.41–5.31 (m, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 2.84–2.55 (m, 2 H), 1.98 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.2, 163.7 (t, J = 32.4 Hz), 140.9, 140.4, 139.5, 128.8, 127.5, 127.4, 127.0, 126.9, 115.0 (t, J = 255.6 Hz), 63.1, 47.9 (t, J = 4.7 Hz), 40.2 (t, J = 22.8 Hz), 23.2, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –102.7 (dt, J = 267.8, 15.5 Hz, 1 F), –103.5 (dt, J = 267.8, 15.7 Hz, 1 F).