Effects of a Flexible Alkyl Chain on an Imidazole Ligand for Copper-Catalyzed Mannich Reactions of Terminal Alkynes

Abstract

Copper-catalyzed Mannich reactions of terminal alkynes and secondary amines with aqueous formaldehyde can be accelerated by the use of a catalytic amount of an imidazole ligand carrying a long alkyl chain. The alkyl chain shows an efficient steric effect and helps the reaction. This imidazole ligand is efficient for various substrates, including even bulky alkynes.

alkyl chain - imidazole - steric effect - copper - Mannich reaction

References and Notes

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Similar investigations corresponding to Table  [³] were also performed with 4c and 4d, which carry alkyl chains of other lengths; also in those cases, a drastic acceleration such as occurred in the case of 4e was not observed.

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General Procedure for Mannich Reactions of Terminal Alkynes and Secondary Amines with Formaldehyde
To a 5 mL vial were added sequentially terminal alkyne 1 (1.0 mmol), secondary amine 2 (1.0 mmol), formaldehyde (37% aq solution, 1.2 mmol), 1-hexadecylimidazole (4e, 0.01 mmol), and CuI (0.005 mmol, 1.0 mg). The mixture was stirred in an oil bath kept at 25 ˚C for 1.5 h. The mixture was diluted with EtOAc, dried (anhyd Na₂SO₄), and concentrated in vacuo. Purification by flash column chromatography (silica gel, hexane-EtOAc) gave the corresponding propargylamine 3.
1-(3-Phenylprop-2-yn-1-yl)piperidine (3aa)
CAS [2568-57-2]. Orange oil. ^¹H NMR (500 MHz, CDCl₃): δ = 7.43 (m, 2 H), 7.30-7.27 (m, 3 H), 3.48 (s, 2 H), 2.57 (br s, 4 H), 1.64 (tt, J = 5.5, 6.0 Hz, 4 H), 1.45 (br s, 2 H). ^¹³C NMR (125,7 MHz, CDCl₃): δ = 131.7, 128.2, 127.9, 123.3, 85.1, 84.9, 53.5, 48.5, 26.0, 23.9.

<A NAME="RU09310ST-19">19</A>

The reactions of dibutylamine and dicyclohexylamine could be performed to afford the corresponding products quantitatively even without any ligand.