Azide–Alkyne Cycloaddition (CuAAC) in Alkane Solvents Catalyzed by Fluorinated NHC Copper(I) Complex

Abstract

A highly efficient and environmentally benign protocol for copper‐catalyzed alkyne–azide cycloaddition (CuAAC) in industrially important alkane solvents was developed. New copper(I) complexes bearing NHC ligands decorated with bulky hexafluoroisopropylalkoxy group [(CF3)2(OR)C‐] were first introduced for the process. The complex with isopentyl group [(CF3)2(OiAm)C‐] exhibited the best catalytic activity in the reactions of diversely substituted alkyne and azide substrates in alkane solvents, such as hexane, heptane and cyclohexane. The new CuAAC protocol is easily scalable, synthetically robust, and reproducible; it utilizes low catalyst loadings and enables simple isolation of pure products free from any contaminants including residue of the catalyst and starting materials.

Green Methodologies for Copper(I)-Catalyzed Azide-Alkyne Cycloadditions: A Comparative Study

“…Such air-stable catalysts [ 44 , 45 ] have been used to prepare peptidotriazoles [ 46 ]. Recently, a report appeared of an environmentally friendly fluorinated carbene catalyst employed for the preparation of triazoles in a solvent such as hexane at 40 °C [ 47 ].…”

Alkynyl‐ or Azido‐Functionalized 1,2,3‐Triazoles: Selective MonoCuAAC Promoted by Physical Factors

“…In both cases (solvent‐based and neat approaches), the CuAAC reaction is efficiently catalyzed by N‐heterocyclic carbene (NHC) copper(I) complexes. We selected the most catalytically active (NHC)CuX complexes under solvent‐free or apolar conditions: SIMesCuBr ( 1 a ), (6‐Mes)CuBr ( 1 b ), (7‐Mes)CuBr ( 1 c ), abnormal NHC complex (aNHC)CuCl ( 1 d ), (Naph‐8‐Mes)CuBr ( 1 e ) and well‐soluble in apolar media fluorinated (F‐NHC)CuCl ( 1 f) and tested them in the model reaction between phenylacetylene and p ‐tolylazide under following conditions: 1) heptane, 40 °C, 2) neat, 40 °C (Scheme ). The choice of reaction temperature is motivated by the fact that even daily fluctuations in temperature can alter the solubility of the reaction components leading to reproducibility issues; therefore, the temperature slightly higher than RT was chosen.…”

“…Fluorine‐containing NHC copper(I) complex 1 f also showed a good efficiency in heptane, as was shown earlier . The reduced efficiency of copper catalysts 1 a‐c in heptane may be explained by the poor solubility of these catalysts.…”

Base‐Free Copper‐Catalyzed Azide‐Alkyne Click Cycloadditions (CuAAc) in Natural Deep Eutectic Solvents as Green and Catalytic Reaction Media**

“…1‐benzyl‐4‐propyl‐1H‐1,2,3‐triazole ( 3 c ) [49] . Pale yellow solid; mp 28–29 °C; 1 H NMR (500 MHz, CDCl 3 ) δ =7.46–7.30 (m, 3H), 7.29–7.21 (m, 3H), 5.47 (s, 2H), 2.66 (t, J =7.6 Hz, 2H), 1.65 (h, J =7.4 Hz, 2H), 0.93 (t, J =7.3 Hz, 1H).…”

“…1‐benzyl‐4‐(4‐methoxyphenyl)‐1H‐1,2,3‐triazole ( 3 j ) [49] . White solid; mp 144–145 °C; 1 H NMR (500 MHz, CDCl 3 ) δ =7.72–7.66 (m, 2H), 7.59 (s, 1H), 7.39–7.30 (m, 2H), 7.30–7.25 (m, 2H), 5.51 (s, 2H), 3.79 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ =159.7, 134.7, 130.7, 129.2, 128.8, 128.1, 127.1, 123.0, 114.3, 55.3, 54.3; MS (EI) m/z=265.1 [M + ].…”