Base-Catalyzed, Three-Component Coupling of Aldehydes, Terminal Aryl Acetylenes, and Amines: Application to Synthesis of Propargylamines

Abstract

Propargylamines are formed in high yield by three-component coupling reaction of aldehydes, terminal aryl acetylenes, and amines in DMSO in the presence of catalytic tetraalkylammonium hydroxide. This reaction does not require a transition-metal catalyst.

three-component coupling - aldehydes - aryl acetylenes - amines - tetraalkylammonium hydroxide

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16

General Procedure for the Synthesis of Propargylamines A 25 mL round-bottom flask was charged with DMSO (3 mL), aldehyde (1.0 mmol), amine (1.3 mmol), alkyne (1.3 mmol), and TBAOH (0.1 mmol). The resulting solution was stirred at r.t., for the time indicated in Table  [¹] . The reaction mixture was poured into H₂O (60 mL), and the suspension was stirred for 30 min. Then, it was extracted with EtOAc (2 × 25 mL), and the combined organic extracts were dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude products. Purification by silica gel column chromatography (hexane-EtOAc) gave pure materials. Representative Spectroscopic Data N -(1,3-Diphenyl-2-propynyl)piperidine (3a) ^¹H NMR (400 MHz, CDCl₃): δ = 7.62-7.60 (m, 2 H), 7.53-7.50 (m, 2 H), 7.37-7.27 (m, 6 H), 4.79 (s, 1 H), 2.56 (m, 4 H), 1.61-1.56 (m, 4 H), 1.45-1.44 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 131.6, 128.5, 128.2, 128.0, 127.4, 123.2, 87.6, 86.0, 62.3, 26.8, 26.1, 24.4. MS: m/z (%) = 275 (20) [M⁺], 198 (81), 191 (100), 115 (14).
N -[1-(4-Methoxyphenyl)-3-phenyl-2-propynyl]-piperidine (3b)
^¹H NMR (400 MHz, CDCl₃): δ = 7.55-7.50 (m, 4 H), 7.33-7.30 (m, 3 H), 6.90-6.87 (m, 2 H), 4.74 (s, 1 H), 3.80 (s, 3 H), 2.56-2.54 (m, 4 H), 1.64-1.53 (m, 4 H), 1.46-1.42 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 158.9, 131.7, 130.6, 129.6, 128.2, 128.0, 123.3, 113.3, 87.6, 86.3, 61.7, 55.2, 50.6, 26.1, 24.4. MS: m/z (%) = 307 (4) [M⁺], 221 (38), 135 (30), 87 (100), 43 (73).
N -(1,3-Diphenyl-2-propynyl)pyrrolidine (3h) ^¹H NMR (400 MHz, CDCl₃): δ = 7.68-7.66 (m, 2 H), 7.56-7.53 (m, 2 H), 7.37-7.30 (m, 6 H), 4.90 (s, 1 H), 2.72 (m, 4 H), 1.81 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 131.5, 128.2, 128.1, 127.5, 123.1, 86.8, 86.6, 59.0, 50.2, 23.4. MS: m/z (%) = 261 (8) [M⁺], 184 (61), 115 (13).
N -1[(4-Cyclohexyl-3-phenyl-2-propynyl)]morpholine (3l) ^¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.44 (m, 2 H), 7.29-7.28 (m, 3 H), 3.79-3.74 (m, 4 H), 3.13 (d, J = 9.9 Hz, 1 H), 2.70-2.69 (m, 2 H), 2.53-2.50 (m, 2 H), 2.14-2.04 (m, 2 H), 1.77-1.59 (m, 4 H), 1.32-0.96 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 131.6, 128.1, 127.7, 123.3, 86.7, 86.5, 67.0, 63.8, 49.8, 38.9, 30.9, 30.2, 26.6, 26.1, 25.9. MS: m/z (%) = 283 (5) [M⁺], 200(100), 115 (20), 77 (2), 55 (9), 41 (10).