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Article Dans Une Revue SYNLETT Année : 2015

Chromium(II)-Catalyzed Amination of N-Heterocyclic Chlorides with Magnesium Amides

Résumé

We report a ligand-free chromium(II)-catalyzed amination reaction of various N-heterocyclic chlorides. CrCl 2 regioselectively cata-lyzes the reaction of chloropyridines and dichloropyridines, dichloro-quinolines, dichloroisoquinolines and dichloroquinoxalines with a range of aliphatic, allylic, benzylic and saturated (hetero)cyclic magnesium amides in the presence of lithium chloride as additive. The reactions were performed at 50 °C in THF and led to the desired aminated products in 56-96% yield. The syntheses of amino-substituted heterocycles are of the utmost importance for the pharmaceutical and agro-chemical industries due to their high biological activity. 1 These molecules are generally prepared by nucleophilic aromatic substitution 2 but transition metal catalysts for ami-nations have also been intensively studied. 3 In 1983, Migita performed the coupling of aryl bromides with tin amides in the presence of a palladium catalyst. 4 More recently, since 1994, Buchwald 5 and Hartwig 6 have revolutionized this field by developing new classes of ligands and highly active palladium catalysts, which allowed a broad range of amina-tion reactions. With the objective of replacing costly palladium and sensitive phosphine ligands, we studied economic, lowly toxic and readily available transition metals catalysts for amination reactions. Previously, we reported the chromi-um(II) chloride 7 catalyzed cross-couplings between (hetero)-aryl halides and (hetero)aryl Grignard reagents under mild and ligand-free conditions. 8 Additionally, direct arylation of pyridines, aryl oxazolines and imines with various aryl-magnesium reagents was promoted by the presence of CrCl 2 as catalyst. 9 Herein we report the chromium(II)-catalyzed amination of N-heterocyclic chlorides with magnesium amides affording a range of aminated pyridines, quinolines and quinoxal-ines. In preliminary experiments, we examined the transition metal -catalyzed amination of 2-chloropyridine (1a) with magnesium chloride pyrrolidin-1-ide (2a), which was prepared by the deprotonation of pyrrolidine (4) with i-PrMgCl in THF at 0 °C and was warmed to 23 °C over one hour (Table 1). 10 The resulting magnesium amide displayed a good thermic stability and a good solubility under the reaction conditions. In the absence of any catalyst, only 13% of the aminated product (3a) was observed at 23 °C after 20 hours of reaction time (entry 1). However, when the Grignard reagent was prepared with an equimolar amount of lithium chloride as additive (use of i-PrMgCl·LiCl), 11 the conversion was increased and 27% of the pyridine 3a was detected by calibrated GC analysis (en-try 2). The use of 3% FeBr 3 or 3% CoCl 2 under the same conditions did not improve the amination (14-12%, entries 3 and 4). Nevertheless, in the presence of 3% CrCl 2 , 3a was obtained in 72% yield, which was improved to 77% using 10% of catalyst (entries 5 and 6). Performing the latter experiment without lithium chloride led to the formation of noticeably less product (64%, entry 7). In an attempt to further accelerate the reaction, the amination was then performed at 50 °C with 10 mol% of chromium(II) chloride. In the presence of 2.0 equivalents of LiCl, the aminated product 3a was isolated in 95% yield, whereas 3a was obtained in only 60% yield without additive (entries 8 and 9). Other chromium catalysts [CrCp 2 , 12 Cr(acac) 3 , 13 CrBr 2 14 ] led to somewhat lower yields (45-81%, entries 10-13). Performing this reaction at 50 °C for three hours without catalyst in the presence of LiCl produced the aminated pyridine 3a in 43% yield and, without LiCl, in 27% yield, confirming the importance SYNLETT0 9 3 6-5 2 1 4 1 4 3 7-2 0 9 6

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Dates et versions

hal-02001058 , version 1 (14-02-2019)

Identifiants

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Paul Knochel, Andreas K Steib, Sarah Fernandez, Olesya M Kuzmina, Martin Corpet, et al.. Chromium(II)-Catalyzed Amination of N-Heterocyclic Chlorides with Magnesium Amides. SYNLETT, 2015, 26 (08), pp.1049-1054. ⟨10.1055/s-0034-1380178⟩. ⟨hal-02001058⟩
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