Mechanistic Insights into Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC): Observation of Asymmetric Amplification

Dedicated to Professor Peter Vollhardt for his peerless contribution to the broad discipline of organic chemistry

Abstract

A mechanistic study of copper-catalyzed azide–alkyne cy­cloaddition (CuAAC) was examined using an enantioposition-selective asymmetric CuAAC as a probe reaction system. Based on the observed asymmetric amplification (a positive nonlinear effect), we proposed that a dimeric chiral copper complex is involved as a reactive intermediate in the copper-catalyzed azide–alkyne cycloaddition.

Key words

asymmetric catalysis - azide–alkyne cycloaddition - Huisgen reaction - nonlinear effect

• References and Notes

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• 9 The curve fittings were generated from ee_product = 2ee₀ee_ligand/(1 + ee_ligand ²) for the enantioposition-selective CuAAC or from DKEE = 2DKEE₀ee_ligand/(1 + ee_ligand ²) for the kinetic resolution by the asymmetric CuAAC [K = 4, g = 0; statistical distribution conditions were applied for the formation of the potential reactive intermediates {chiral dimeric complexes (ML^R)₂, (ML^s)₂, and meso dimeric complex [(ML^R)(ML^s)]}.
• 10 The reaction of 1a with 2 was examined with homochiral [Cu^I(L*)(triazole)]₂(OTf)₂ (metal/ligand = 1:1), which was prepared, isolated, and fully characterized (unpublished) to give (R)-3a in 65% yield and 82% ee, along with a 24% yield of bistriazole 4a, being in good agreement with the results shown in Table 1. This observation demonstrated that the catalytically active species should be a 1:1 Cu–L* complex. Thus, we excluded the possibility that a positive NLE is induced via the formation of an inactive 1:2 metal–ligand heterochiral complex, cf.: Saaby S, Nakama K, Lie MA, Hazell RG, Jørgensen KA. Chem. Eur. J. 2003; 9: 6145
• 11 Procedure for the Copper-Catalyzed Cycloaddition In a glove box, CuOTf·(C₆H₆)_0.5 (3.1 mg, 0.0125 mmol Cu) was charged into a screw vial. A solution of L* (12.6 mg, 0.025 mmol) in 1,2-DCE (250 μL) was added, and the mixture was stirred for 30 min. After addition of a solution of dialkyne 1a (0.125 mmol) in 1,2-DCE (250 μL) to the mixture, the reaction vial was taken from the glove box. After addition of benzyl azide (2, 24 μL, 0.188 mmol), the mixture was stirred at r.t. for 3 h. The resulting mixture was purified by flash SiO₂ column to give the products 3a and 4a. Compound 3a: ¹H NMR (396 MHz, CDCl₃, 25 °C): δ = 8.39 (d, J = 7.5 Hz, 1 H, Ar), 7.80 (t, J = 7.5 Hz, 2 H, Ar), 7.67 (d, J = 7.5 Hz, 1 H, Ar), 7.52 (t, J = 7.9 Hz, Ar), 7.41 (t, J = 7.9 Hz, 2 H, Ar), 7.33–7.25 (m, 4 H, Ar), 7.19 (t, J = 7.5 Hz, 2 H, Ar), 6.68 (d, J = 7.1 Hz, 2 H, Ar), 5.61 (s, 1 H, triazole-H5), 5.08 (s, 2 H, PhCH₂), 2.69 (s, 1 H, CH). ¹³C{¹H} NMR (100 MHz, CDCl₃, 25 °C): δ = 145.52, 140.31, 137.33, 133.97, 133.26, 132.60, 131.54, 131.14, 128.86, 128.47, 128.30, 128.23, 128.15, 128.12, 127.54, 127.31, 126.50, 126.00, 125.39, 125.24, 123.41, 121.88, 82.30, 80.49, 53.58. HRMS: m/z calcd for C₂₇H₁₉N₃: 385.1579; found: 385.1576. IR (ATR, neat): 3286, 3261, 3057, 2959, 2936, 1945, 1878, 1721, 1606, 1593, 1574, 1547, 1496, 1453, 1438, 1391, 1370, 1348, 1296, 1261, 1247, 1229, 1214, 1156, 1121, 1094, 1074, 1050, 1026, 1007, 976, 962, 912, 893, 871, 846, 827, 798, 778, 756, 727, 691, 676, 661, 640, 628, 610, 589, 577, 566 cm^–1. 91% ee from 1.5 equiv of 2 (HPLC conditions: Chiralpak IA column, MTBE, flow rate 1 mL min^–1, wavelength = 255 nm, t _R = 9.5 min for minor isomer, t _R = 11.6 min for major isomer). [α]_D ²⁶ –82.5 (c 0.83, CHCl₃). The absolute configuration of 3a was determined to be R based on the crystal structure of 3 bearing chloro group at the 4-position of the phenyl ring. For details, see ref. 6. Compound 4a: ¹H NMR (396 MHz, CDCl₃, 25 °C): δ = 8.32 (dd, J = 7.5, 1.2 Hz, 2 H, Ar), 7.73 (d, J = 8.3 Hz, 1 H, Ar), 7.68 (t, J = 7.9 Hz, 2 H, Ar), 7.39 (t, J = 7.9 Hz, 1 H, Ar), 7.33–7.13 (m, 4 H, Ar), 6.68 (d, J = 7.9 Hz, 4 H, Ar), 5.66 (s, 2 H, triazole-H5), 5.10 (s, 4 H, PhCH₂). ¹³C{¹H} NMR (100 MHz, CDCl₃, 25 °C): δ = 146.10, 137.74, 135.07, 134.11, 133.11, 131.66, 131.14, 128.81, 128.75, 128.28, 128.24, 128.18, 127.65, 127.52, 126.92, 126.29, 125.48, 125.09, 121.72, 53.54. HRMS: m/z calcd for C₃₄H₂₆N₆Na₁: 541.2117; found: 541.2116. IR (ATR, neat): 3157, 3051, 2929, 2853, 2389, 2279, 1957, 1724, 1661, 1629, 1590, 1549, 1497, 1433, 1389, 1342, 1292, 1248, 1223, 1158, 1106, 1072, 1048, 921, 800, 779, 751, 704, 612, 588 cm^–1.