Efficient Synthesis of N-(Difluoropropenyl)amides/Amines from Fluorinated Olefins under Base Promotion

Abstract

N-(Difluoropropenyl)amides/amines are an important class of fluorinated compounds. Here, we report an efficient method for synthesizing these compounds without the use of transition metals. Under simple base-promoted conditions, 3-bromo-3,3-difluoroprop-1-ene reacts with N-methylanilines or N-arylacrylamides, with the elimination of one molecule of HBr, to give the target compound. Another efficient method for synthesizing difluoroalkenes is the reaction of 2-bromo-3,3,3-trifluoroprop-1-ene with indole or its analogues.

Key words

difluoropropenylamides - base catalysis - fluoroalkenes - dehydrohalogenation - transition-metal-free synthesis - indoles

Publication History

Received: 22 January 2024

Accepted after revision: 15 April 2024

Accepted Manuscript online:
15 April 2024

Article published online:
08 May 2024

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• 30 N-(3,3-Difluoroprop-2-en-1-yl)-N-(4-methoxyphenyl)acrylamide; Typical Procedure A 35.0 mL glass reaction tube was charged with N-(4-methoxyphenyl)acrylamide (1a; 1.0 mmol), 3-bromo-3,3-difluoropropene (2; 2.0 mmol) t-BuOK (2.0 mmol), and MeCN (2.0 mL), and the tube was placed in an autoclave. The autoclave was sealed, purged three times with N₂, and heated in an oil bath at 100 °C for 8 h. The autoclave was then cooled to r.t. and the crude product was purified by column chromatography [silica gel, PE–EtOAc (30:1 to 10:1)] to give a yellow liquid; yield: 39.2 mg (55%). ¹H NMR (400 MHz, CDCl₃): δ = 7.05–6.70 (m, 4 H), 6.28 (d, J = 16.8 Hz, 1 H), 6.02–5.80 (m, 1 H), 5.44 (d, J = 10.3 Hz, 1 H), 4.48–4.30 (m, 1 H), 4.25 (d, J = 7.9 Hz, 2 H), 3.76 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 159.2, 157.7 (t, J = 289.0 Hz), 133.9, 129.2, 128.4, 127.8, 114.8, 74.9 (dd, J = 18.8, 23.2 Hz), 55.5, 42.7 (d, J = 7.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –85.75 (d, J = 38.09 Hz, 1 F), –88.17 (dd, J = 24.52, 37.41 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₃F₂NNaO₂: 276.0812; found: 276.0810.