Lewis Acid Catalyzed Multicomponent Reaction of Aliphatic Aldehydes, Ynamides, Carboxylic Acids, and Amines to Access β³-Acylamino Amides

Abstract

An atom-economical strategy for the synthesis of alkylated β³-acylamino amides via Lewis acid catalyzed one-pot multicomponent reaction of ynamides, carboxylic acids, and aromatic amines with aliphatic aldehydes is described. In addition to the synthetic utility and scalability, the method exhibits excellent substrate scope and functional-group tolerance. The products can easily be transformed into valuable building blocks, such as peptide chains.

Key words

multicomponent reactions - β-acylamino amides - ynamides - Ugi reaction - Lewis acids

Publication History

Received: 31 May 2023

Accepted after revision: 25 July 2023

Accepted Manuscript online:
25 July 2023

Article published online:
21 September 2023

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• 13 Synthesis of β³-Alkyl-β-acylamino Amides; General Procedure To a Schlenk tube was added ynamide (0.12 mmol) and acid (0.12 mmol), and the tube was evacuated and purged with argon three times. DCM (1 mL) was then added as solvent and the solution was stirred at room temperature until the starting material was fully consumed (6–12 h). Aldehyde (0.12 mmol) and aniline (0.1 mmol) were then added at a temperature below –30 °C, then BF₃·OEt₂ (10 mol%) was added. Upon completion, silica gel was added to the flask and volatiles were evaporated under vacuum. Purification by flash column chromatography on silica gel (ethyl acetate/petroleum ether) gave the desired product. N-(1-(Benzyloxy)-4-((N,4-dimethylphenyl)sulfonamido)-4-oxobutan-2-yl)-N-(3,5-dibromophenyl)benzamide (5a): ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.35–7.22 (m, 11 H), 7.18–7.14 (m, 4 H), 4.90 (s, 1 H), 4.54 (dd, J = 18.0, 11.6 Hz, 2 H), 3.82 (s, 1 H), 3.73–3.69 (m, 1 H), 3.33 (s, 1 H), 3.31 (s, 3 H), 3.16 (dd, J = 17.2, 4.4 Hz, 1 H), 2.39 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.0, 170.8, 145.0, 137.7, 136.0, 136.0, 132.7, 131.3, 130.0, 129.9, 128.5, 128.2, 128.0, 127.8, 127.7, 127.5, 122.3, 73.3, 69.8, 57.3, 36.5, 33.2, 21.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₁Br₂N₂O₅S: 713.0315; found: 713.0317. N-(1-(Benzyloxy)-4-oxo-4-(propylamino)butan-2-yl)-N-(3,5-dibromophenyl)benzamide (7): ¹H NMR (400 MHz, CDCl₃): δ = 7.40 (s, 1 H), 7.34–7.30 (m, 4 H), 7.27–7.25 (m, 4 H), 7.20 (d, J = 4.4 Hz, 4 H), 5.97 (s, 1 H), 4.81–4.74 (m, 1 H), 4.49 (s, 2 H), 4.01 (t, J = 8.8 Hz, 1 H), 3.72 (dd, J = 9.6, 5.2 Hz, 1 H), 3.24–3.09 (m, 2 H), 3.02–2.96 (m, 1 H), 2.61 (dd, J = 16.4, 5.6 Hz, 1 H), 1.49–1.40 (m, 2 H), 0.87 (t, J = 7.6 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.5, 170.0, 137.7, 136.0, 132.5, 130.8, 130.2, 128.5, 128.3, 128.1, 127.8, 127.6, 122.4, 73.2, 69.8, 59.8, 41.5, 37.0, 22.8, 11.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₉Br₂N₂O₃: 587.0540; found: 587.0542.