A Sequentially Copper-Catalyzed Alkyne Carboxylation–Propargylation–Azide Cycloaddition (CuACPAC) Synthesis of 1,2,3-Triazolylmethyl Arylpropiolates

Dedicated to Prof. Dr. Günter Szeimies on the occasion of his 80^th birthday.

Abstract

Concatenation of copper-catalyzed alkyne carboxylation–alkylation and copper-catalyzed alkyne–azide cycloaddition gives a novel sequentially copper-catalyzed alkyne carboxylation–propargylation–azide cycloaddition (CuACPAC) process furnishing 1,2,3-triazolylmethyl arylpropiolates via a consecutive four-component synthesis. The CuACPAC can be expanded to a five-component synthesis of 1,2,3-triazolylmethyl 3-amino arylacrylates by a concluding Michael addition in the same pot.

Key words

alkynes - azides - carboxylation - catalysis - cycloaddition - multicomponent reaction

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• 19 Typical Procedure for the Synthesis of Compound 5a In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 μmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:3), compound 5a (278 mg, 64%) was obtained analytically pure as a yellow solid; mp 83–85 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.27 (s, 2 H), 5.45 (s, 2 H), 7.19–7.93 (m, 8 H), 7.46 (m, 1 H), 7.48 (m, 1 H), 7.51 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 54.4 (CH₂), 59.0 (CH₂), 80.3 (C_quat), 87.3 (C_quat), 119.4 (C_quat), 124.0 (CH), 128.3 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 130.9 (CH), 133.1 (CH), 134.3 (C_quat), 142.4 (C_quat), 153.9 (C_quat). MS (EI⁺): m/z (%) = 317 (2) [M]⁺, 129 (45) [C₉H₅CO⁺], 91 (100) [C₆H₅CH₂ ⁺]. Anal. Calcd for C₁₉H₁₅N₃O₂ (317.4): C, 71.91; H, 4.76; N, 13.24. Found: C, 72.11; H, 4.83, N, 13.14.
• 20 Typical Procedure for the Synthesis of Compound 7e In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 µmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. Then, methyl benzylamine (6e; 182 mg, 1.50 mmol) was added, and the suspension was stirred at 50 °C for 16 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:1), compound 7e (311 mg, 52%) was obtained analytically pure as a yellow resin. ¹H NMR (300 MHz, CDCl₃): δ = 2.81 (s, 3 H), 4.17 (br, 2 H), 4.91 (s, 1 H), 5.01 (s, 2 H), 5.46 (s, 2 H), 7.20–7.40 (m, 16 H). ¹³C NMR (75 MHz, CDCl₃): δ = 38.0 (CH₃), 54.2 (CH₂), 55.7 (CH₂), 56.3 (CH₂), 87.0 (CH), 123.2 (CH), 126.9 (CH), 127.5 (CH), 128.2 (CH), 128.4 (CH), 128.4 (CH), 128.8 (CH), 128.8 (CH), 128.8 (CH), 129.0 (CH), 134.7 (C_quat), 136.2 (C_quat), 137.3 (C_quat), 144.7 (C_quat), 164.1 (C_quat), 167.4 (C_quat). MS (ESI⁺): m/z = 439 [M + H]⁺. HRMS (ESI⁺): m/z calcd for [C₂₇H₂₆N₄O₂ + H]⁺: 439.2134; found: 439.2129.
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