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Synlett 2010(20): 3053-3056  
DOI: 10.1055/s-0030-1259069
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Takaaki Okamura, Keisuke Asano, Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoutodaigaku-katsura,Nishikyo, Kyoto 615-8510, Japan
Fax: +81(75)3832459; e-Mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp;
Further Information

Publication History

Received 15 October 2010
Publication Date:
24 November 2010 (online)

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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.

Key words

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

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16

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.

18

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.

19

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