Facile and Selective Synthesis of Propargylic Amines and 1,6-Diynes: One-Pot Three-Component Coupling Reactions of Alkynylsilanes, Aldehydes and Amines by a Cooperative Catalytic System Comprised of CuCl and Cu(OTf)2

Norio Sakai; Naoki Uchida; Takeo Konakahara

doi:10.1055/s-2008-1077790

LETTER

Facile and Selective Synthesis of Propargylic Amines and 1,6-Diynes: One-Pot Three-Component Coupling Reactions of Alkynylsilanes, Aldehydes and Amines by a Cooperative Catalytic System Comprised of CuCl and Cu(OTf)₂

Norio Sakai*, Naoki Uchida, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
e-Mail: sakachem@rs.noda.tus.ac.jp;

Abstract

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Abstract

Described herein is a three-component coupling reaction of alkynylsilanes, aldehydes and amines by a cooperative catalytic system comprised of CuCl and Cu(OTf)₂, leading to the production of a variety of propargyl amine derivatives. This catalytic system was successfully applied to the practical preparation of 1,6-diyne derivatives via twice-performed, domino-type coupling reactions.

Keyword

multicomponent coupling reaction - copper catalyst - alkynylsilane - propargylic amine - 1,6-diyne

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References and Notes

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General Procedure for the Synthesis of a Propargyl Amine: To a MeCN solution (300 µL) in a screw-capped vial under an N₂ atmosphere, alkynylsilane 1 (0.45 mmol), aldehyde 2 (0.30 mmol), amine 3 (0.36 mmol), Cu(OTf)₂ (5.4 mg, 0.015 mmol) and CuCl (1.5 mg, 0.015 mmol) were successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction mixture was heated at 100 °C until the reaction was completed as monitored by TLC. After the reaction, the mixture was directly subjected to SiO₂ gel without the usual extraction, and was purified by flash column chromatography (hexane-EtOAc) to give the corresponding propargyl amines in the yields shown in Table [2] .
1-[1-(4-Methoxyphenyl)-3-phenylpropyn-2-yl]-4-methyl-
piperazine (13): pale yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 2.21 (s, 3 H), 2.40 (m, 4 H), 2.59 (m, 4 H), 3.74 (s, 3 H), 4.69 (s, 1 H), 6.82 (d, J = 7.5 Hz, 2 H), 7.23 (m, 3 H), 7.42 (m, 2 H), 7.46 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 46.0, 48.8, 55.3, 55.3, 61.0, 85.7, 88.1, 113.4, 113.5, 123.2, 128.0, 128.2, 129.6, 130.4, 131.8, 159.1. MS (EI): m/z = 320. HRMS (FAB): m/z calcd for C₂₁H₂₄N₂O: 320.1889; found: 320.1876.
N-(tert-Butyl)-1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-amine (17): colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (s, 9 H), 3.80 (s, 3 H), 4.80 (s, 1 H), 6.89 (d, J = 7.5 Hz, 2 H), 7.29 (m, 3 H), 7.42 (m, 2 H), 7.51 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.9, 48.2, 51.2, 55.3, 84.1, 92.8, 113.9, 123.6, 127.9, 128.2, 128.5, 131.4, 135.0, 158.9. MS (EI): m/z = 293. HRMS (FAB): m/z calcd for C₂₀H₂₃NO: 293.1780; found: 293.1785.

When a similar coupling reaction was carried out with phenylacetylene, propargylic amine 4 was obtained in a 61% yield (7 h).

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General Procedure for the Synthesis of a Symmetrical 1,6-Diyne: To a MeCN solution (300 µL) in a screw-capped vial under a N₂ atmosphere, alkynylsilane 1 (0.90 mmol), paraformaldehyde 2h (0.90 mmol), primary amine 3 (0.30 mmol), Cu(OTf)₂ (5.4 mg, 0.015 mmol) and CuCl (1.5 mg, 0.015 mmol) were successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction mixture was heated at 100 °C for 24 h. After the reaction, the mixture was directly subjected to SiO₂ gel without the usual extraction, and was purified by flash column chromatography (hexane-EtOAc) to give the corresponding 1,6-diynes in the yields shown in Table [3] .
N-Benzyl-N,N-bis[3-(tert-butyldimethylsilyl)propyn-2-yl]amine (27): colorless oil. ¹H NMR (500 MHz, CDCl₃):
δ = 0.12 (s, 12 H), 0.96 (s, 18 H), 3.40 (s, 4 H), 3.69 (s, 2 H), 7.32 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = -4.5, 16.5, 26.1, 43.1, 56.9, 88.2, 101.7, 127.3, 128.3, 129.4, 138.0. MS (EI): m/z = 411. HRMS (FAB): m/z calcd for C₂₅H₄₂NSi₂: 412.2856; found: 412.2866.

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Procedure for the Synthesis of 1-Aminoindolizine 9′: To a MeCN solution (300 µL) in a screw-capped vial under a N₂ atmosphere, alkynylsilane 1a (78 mg, 0.45 mmol), aldehyde 2g (48 mg, 0.45 mmol), amine 3a (26 mg, 0.30 mmol) and Cu(OTf)₂ (5.4 mg, 0.015 mmol) were successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction mixture was heated at 100 °C for 1 h. After the reaction, the mixture was directly subjected to Al₂O₃ gel without the usual extraction, and was purified by flash column chromatography (hexane-EtOAc) to give 1-aminoindolizine 9′ in 97% yield (80 mg).
3-Phenyl-1-piperidin-1-ylindolizine (9′): yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.50 (quint, J = 6.0 Hz, 2 H), 1.71 (quint, J = 6.0 Hz, 4 H), 2.94 (t, J = 6.0 Hz, 4 H), 6.30 (t, J = 7.5 Hz, 1 H), 6.44 (t, J = 7.5 Hz, 1 H), 6.60 (s, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.36 (m, 3 H), 7.47 (d, J = 7.0 Hz, 2 H), 8.11 (d, J = 7.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 24.4, 26.5, 55.2, 105.7, 110.7, 114.3, 118.1, 121.6, 126.7, 127.5, 127.7, 128.6, 128.9, 131.1, 132.6. MS (EI): m/z = 276.

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