Abstract
The CuI-catalyzed Ullmann amine cross-coupling between (hetero)aryl halides (Br, I) and aromatic and aliphatic amines has been accomplished in deep eutectic solvents as environmentally benign and recycling reaction media. Under optimized conditions, the reaction proceeds smoothly under mild conditions (60–100°C) in air, in the absence of ligands, with a catalyst (CuI) loading of 10 mol% and K2CO3 (aliphatic primary and secondary amines) or t-BuOK (aromatic amines) as the base. A variety of amines have been synthesized in yields up to 98% with a broad substrate scope.
Highlights
The century “classical” Ullmann reaction is known to be the first transition metal-mediated organic transformation, and it was used for the synthesis of symmetric biaryls from aryl halides (Ullmann, 1901, 1903, 1904; Goldberg, 1906)
As Deep Eutectic Solvents (DESs) are known to be used as solvents, and as catalytic active species, batch reactions to assess the ability of DESs to promote the Ullmann amine synthesis (UAS) with no additional ligands were carried out
We initially investigated as a model reaction the coupling between bromobenzene 1a (0.5 mmol) and N, N-dimethylethylenediamine 2a (1 equiv) in different eutectic mixtures for the preparation of adduct 3aa using CuI (10 mol%) as a catalyst and K2CO3 as a base (Table 1)
Summary
The century “classical” Ullmann reaction is known to be the first transition metal-mediated organic transformation, and it was used for the synthesis of symmetric biaryls from aryl halides (Ullmann, 1901, 1903, 1904; Goldberg, 1906). Building on recent breakthroughs made by our research group (Mallardo et al, 2014; Sassone et al, 2015; Cicco et al, 2016, 2017, 2018; Mancuso et al, 2016; Dilauro et al, 2017, 2018, 2019; Messa et al, 2018; Ghinato et al, 2019) and others (Vidal et al, 2014, 2016; Sánchez-Condado et al, 2019) on the effectiveness of using non-conventional reaction media (e.g., DESs and water) for promoting metal-catalyzed and organolithium/Grignard reagent-mediated deprotonation and nucleophilic addition reactions to unsaturated organic substrates under aerobic conditions, here we report the CuI-catalyzed UAS in DESs. The following features of the proposed protocol are noteworthy: (a) the transformation takes place smoothly in a ChCl/glycerol (Gly) eutectic mixture under air and moderate heating (60–100◦C), (b) commercially available (hetero)aryl bromides and iodides are employed, (c) the reaction proceeds with no additional ligands and with a broad substrate scope, (d) the expected adducts are isolated in yields up to 98%, and (e) the catalyst, the DES and the base were and successfully recycled up to six times (Scheme 1C). DES A, L-proline/L-lactic acid (1:2 mol mol−1); DES B, choline chloride/urea (1:2 mol mol−1); DES C, L-proline/glycerol (2:5 mol mol−1); DES D, choline chloride/glycerol (1:2 mol mol−1); DES E, choline chloride/water (1:2 mol mol−1). bCalculated via 1H NMR analysis of the crude reaction mixture using an internal standard technique (NMR internal standard: CH2Br2). cYield of isolated product. dRoom temperature
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