An efficient copper-catalyzed coupling reaction of pyridin-2-ones with aryl and heterocyclic halides based on Buchwald’s protocol Chun Sing Li * and Darryl D. Dixon Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., PO Box 1005, Pointe-Clarie Dorval, Quebec, Canada H9R 4P8 Received 17 March 2004; accepted 6 April 2004 Abstract—An efficient copper-catalyzed coupling reaction based on the Buchwald’s protocol has been established for pyridin-2-ones with aryl iodides, aryl bromides, and heterocyclic bromides. Ó 2004 Elsevier Ltd. All rights reserved. Pyridin-2-one is an important component of many pharmacological active substances 1 and N-aryl substi- tution is frequently a key structural feature. Our ability to synthesize these N-aryl substituted pyridin-2-ones in a diverse and efficient manner would therefore offer the possibility to broaden the scope of SAR studies. N-arylation of amines under the copper-catalyzed Ull- mann reaction usually requires drastic reaction condi- tions and produces moderate yields of the desired products. 2 However, improved conditions for the N-arylation of heterocyclic compounds have been reported. 3;4 Lam has also developed a copper-catalyzed cross-coupling reaction of N-heterocyclic compounds with aryl boronic acids to give N-aryl substituted het- erocycles in fair to excellent yields. 5 Scope of this N-arylation has been studied with different substituted pyridin-2-ones. 6 Recently, Buchwald has developed an efficient copper-catalyzed system for the amination and amidation of aryl and heterocyclic halides. 7 This copper- catalyzed system provides an opportunity to easily access a number of N-aryl heterocyclic analogs, but the poten- tial of this copper-catalyzed system in the synthesis of N- aryl substituted heterocyclic system has not yet been fully investigated. One recent example is the application to the synthesis of a N-aryl oxazolidinone, 8 which is a key structural feature of a new class of oxazolidinone antibiotics. Herein, we report our application of the Buchwald copper-catalyzed system to the cross-coupling reaction of pyridin-2-ones with aryl halides and discuss the scope and limitation of this synthetic reaction. Buchwald’s group has extensively investigated effects of ligands and bases on the copper-catalyzed coupling reaction. 9 We were pleased to see that N,N 0 -dimethyl- ethylenediamine as the ligand and K 3 PO 4 as the base could be conveniently used and gave very satisfactory results in our present study. Other ligands such as 1,2- diaminocyclohexanane were less effective although this ligand was successful in the oxazolidinone synthesis. 8 Replacement of K 3 PO 4 with CsCO 3 gave poorer yield of the coupling product. The following conditions were used throughout this study: A screw cap 2-dram vial was charged with 1,4-dioxane (1.5mL), pyridin-2-one (1mmol), and aryl halide (1.2mmol). CuI (40mg, 0.2mmol), N,N 0 -dimethyethylenediamine (44L, 0.4 mmol), and K 3 PO 4 (425 mg, 2 mmol) were added. The mixture was then flushed with nitrogen, capped and placed in an oil bath at 110 °C, and stirred for 16–24 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. Purification over silica gel and elution with hexanes– ethyl acetate provided the desired coupling product. 10 The coupling reaction of some representative pyridin-2- ones and aryl iodides were summarized in Table 1. Yields were in general very good. There were two exceptions. While a mild electron-withdrawing sub- stituent on the pyridin-2-one such as a carboxylic ester in 1d posed no problem in the coupling reaction, a strong electron-withdrawing substituent such as nitro Keywords: Pyridin-2-ones; Aryl halides; Copper-catalyzed coupling reaction. * Corresponding author. Tel.: +1-514-428-3217; fax: +1-514-428-4900; e-mail: chunsing_li@merck.com 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.04.019 Tetrahedron Letters 45 (2004) 4257–4260 Tetrahedron Letters