Deprotonative Metalation of Aromatic Compounds by Using an Amino‐Based Lithium Cuprate

Abstract

Deprotonative cupration of aromatic compounds by using amino-based lithium cuprates was optimized with 2,4-dimethoxypyrimidine and 2-methoxypyridine as the substrates and benzoyl chloride as the electrophile. [(tmp)(2)CuLi] (+2 LiCl) (tmp=2,2,6,6-tetramethylpiperidino) was identified as the best reagent and its use was extended to anisole, 1,4-dimethoxybenzene, other substituted pyridines, furan, thiophene and derivatives, and N-Boc-indole (Boc=tert-butyloxycarbonyl). Of the electrophiles employed to attempt the interception of the generated aryl cuprates, aroyl chlorides, iodomethane, and diphenyl disulfide efficiently reacted. In addition, different oxidative agents were identified to afford symmetrical biaryls. Finally, palladium-catalyzed coupling with aryl halides was optimized and allowed the synthesis of different aryl derivatives in medium to good yields.

Functionalization of pyridyl ketones using deprotolithiation-in situ zincation

“…17 Accordingly, when similarly reacted by using LiTMP at -55 °C, the iodo derivatives 2d-g were isolated in improved yields, in line with the long range effects of fluorine and chlorine (entries 4-7). In contrast, the reaction from 1h proved more complex, giving the iodide 2h in a modest yield (entry 8).…”

Amidocuprates for Directed ortho Cupration: Structural Study, Mechanistic Investigation, and Chemical Requirements

“…In this context, we have recently proposed new uses for amidocuprates, TMP‐Cu‐ates ([RCu(TMP)(CN)Li]; R=alkyl, phenyl, and TMP; TMP=2,2,6,6‐tetramethylpiperidido), which promote the highly chemoselective, directed ortho cupration of multifunctionalized aromatic compounds under mild conditions. The aryl cuprate intermediate can be employed not only in the trapping of electrophlies, but also in oxidative ligand coupling to form new CC bonds with alkyl/aryl groups or to introduce a hydroxy group (Scheme ) 4–6…”

Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships

“…34 As for 3-methoxypyridine (1a), mesityllithium can be used in THF at room temperature. 20 Bimetallic combinations such as 1:1 LiTMP-Al(iBu) 3 ("trans-metal trapping" 12 in THF at -78 °C), 35 putative LiCo(TMP) 3 (in THF at room temperature), 36 LiCu(TMP) 2 (in THF at room temperature) 37 and putative LiFe(TMP) 3 (in THF at room temperature), 38 can be employed for the same purpose. The regioselectivity of the reaction can be switched from the more acidic 3 to the less acidic 6 position by recourse to BuLi-LiDMAE in hexane at 0 °C, conditions that favor coordination-over acidity-driven reaction.…”

“…Turning to Li 2 (TMP)MgBu 3 30 and LiCu(TMP) 2 37 in THF allows 5a to be deprotometalated at -10 °C and rt, respectively. This higher reactivity of 2-fluoropyridine (5a) over 4a, probably in relation with lower pK a values, was here evidenced by reaction with 1:1 LiTMP-Zn(TMP) 2 to give under the same reaction conditions 2-fluoro-3-iodopyridine (5b) as the main product together with 15% of 2-fluoro-3,6-diiodopyridine (5c) ( Table 6).…”