Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships

Abstract

A series of methoxy-and fluoro-pyridines have been deprotometalated in tetrahydrofuran at room temperature by using a mixed lithium-zinc combination obtained from ZnCl 2 •TMEDA (TMEDA =

Structural and Synthetic Insights into Pyridine Homocouplings Mediated by a β‐Diketiminato Magnesium Amide Complex

“…Interestingly,i t should be noted that formation of 5 and 3e involves the initial C2-magnesiation of 4-OMe-pyridine. This regioselectivity is very unusual, as in agreement with calculated pKav alues, [10] deprotonation of 4-MeO-pyridine has been largely described at its C3 site. [28,29] These results hint againa tt he influence of the bulky { Dipp Nacnac} ligand in tuning the regioselectivity of magnesium base 1.…”

“…In this regard, the regioselective metallation of pyridines has been described by Schlosser as a “tightrope walk”, due largely to the tendency of these molecules to undergo competing nucleophilic addition processes . Mongin recently reported a correlation between the regioselectivities observed for the metallation of a wide range of substituted pyridines and their computed C−H acidities, revealing that judicious choice of the organometallic reagent and the reaction conditions are key to control selectivity . Thus, several mono‐ and bimetallic systems have been reported that can execute the metallation of pyridines under certain reaction conditions (typically at low temperature) .…”

Focused ortho‐Lithiation and Functionalization of p‐Bromo‐ and p‐Iodoanisole

“…So, what is the cause of the observed acidity enhancement of the p ‐bromo‐ and p ‐iodoanisoles? Recent experimental and computational investigations have indicated some generality to the observed acidifying of the position(s) meta ‐ to a bromine substituent. This is exactly the relationship of the ortho ‐H to the p ‐Br substituent in p ‐BrA.…”

“…Recently, this was demonstrated by comparative surrogate metalation studies of both p ‐BrA and p ‐IA . Related low‐temperature experimental metalations as well as computational studies have afforded the insight that a bromine substituent provides a distinct acidification of the proton(s) meta ‐ to it. For a p ‐substituted aryl such as anisole, this would translate as a measureable acidification of the ortho ‐proton, i.e., the proton that undergoes ortho ‐lithiation.…”

Synthetic, Optical and Theoretical Study of Alternating Ethylenedioxythiophene–Pyridine Oligomers: Evolution from Planar Conjugated to Helicoidal Structure towards a Chiral Configuration

“…Treatmentw ith an in situ prepared mixture of 0.5 equiv of ZnCl 2 ·TMEDA( TMEDA = N,N,N',N'-tetramethylethylenediamine) and 1.5 equiv of [Li(tmp)] (tmp = 2,2,6,6-tetramethylpiperidino) in tetrahydrofuran (THF) at room temperature led to metalation at the C-3 and C-4 position in an 83:17 ratio, ar esult evidenced by subsequent iodine trapping. [16] The resulting dihalogenopyridine mixture was then reacted with [Li(da)] in THF at À75 8Ct o allow iodine migration from the 3-to the 4-position. [17] Under these conditions, the 4-iodo isomer 5a was isolated in 51 % overall yield.…”