Lithium-Mediated Zincation of Pyrazine, Pyridazine, Pyrimidine, and Quinoxaline

Abstract

Deprotonation of pyrazine, pyridazine, pyrimidine, and quinoxaline using an in situ mixture of ZnCl2.TMEDA (0.5 equiv) and LiTMP (1.5 equiv) was studied. Pyrazine and pyrimidine were deprotonated in THF at room temperature, a result evidenced by trapping with I2. The competitive formation of dimer observed in net hexane was reduced by using cosolvents (TMEDA or THF). Starting from quinoxaline, the dimer formation took place in THF also, and mixtures of mono- and diiodides were obtained whatever the solvent and conditions used. A similar competitive formation of a diiodide was noted with pyridazine; the use of THF at reflux temperature nevertheless afforded the 3-iodo derivative in good yield.

Deprotonative cadmation of functionalized aromatics

“…This was confirmed by the B3LYP-calculated equilibrium between LiTMP and (TMP) 2 Cd on one side and (TMP) 3 CdLi on the other side, which is in sharp contrast to 85 the corresponding zinc-lithium mixture obtained from LiTMP and ZnCl 2 ·TMEDA (Scheme 1). We next demonstrated that TMP-cadmate was suitable for 15 the chemoselective metalation of a large range of aromatic heterocycles, giving in general higher yields than using Zn 10,12 ( Table 2). The reaction with both π-excessive (substrates 1j, 1k and 1l) and π-deficient (substrates 1m, 1n, 1o, 1p and 1q) heterocycles was found to proceed smoothly at RT.…”

Transforming LiTMP Lithiation of Challenging Diazines through Gallium Alkyl Trans‐Metal‐Trapping

“…This stoichiometric control contrasts with the performance of zincate [(THF)LiZn(TMP) t Bu 2 ], which operates through a synchronized bimetallic synergy distinct to that of stepwise TMT, as it affords only the 2,5‐disubstituted pyrazine even with a 1:1, base:substrate stoichiometry 8. Previously, excess LiTMP (1.5 equivalents) dispensed as 0.5 ZnCl 2 ⋅TMEDA/1.5 LiTMP in THF produced 59 % of the isolated 2‐iodopyrazine that reportedly decomposes at room temperature, but in hexane a significant amount of coupled dimer product was also seen 7a. Note that a control reaction between pyrazine and gallate LiGaR 4 13 did not produce any gallation, but only R group addition, with concomitant dearomatization of the heterocycle (Supporting Information).…”

“…Site selectivity in its metalation is exceptionally challenging, as evident from previous work using excess LiTMP in 0.5 ZnCl 2 ⋅TMEDA/1.5 LiTMP/I 2 , which in hexane at room temperature achieved only 27 % of the 3‐iodo product mixed with the 4‐iodo, and 3,6‐diiodo derivatives as well as 54 % unreacted pyridazine (note yields determined from NMR data) 7a. In THF, the yield of the 3‐iodo product rises to 66 % but only under extreme reflux conditions.…”

Regioselektive Metallierungen von Pyrimidinen und Pyrazinen mit frustrierten Lewis‐Paaren aus BF3⋅OEt2 und sterisch gehinderten Mg‐ und Zn‐Amidbasen

“…[23] Die Verwendung von TMP 2 Mg·2 LiCl (14, 1.1 ¾quiv) bei À78 8C erlaubt eine selektive Magnesierung in Position 5, da dieses das am besten zugängliche, aktivierte Proton ist. [1][2][3][4][5]. [24] Ebenso erfolgt keine Metallierung in Position 6, da diese Position weniger durch die Lewis-Säure aktiviert ist (induktiver Effekt).…”

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Die Funktionalisierung von Diazinen ist von großer Bedeutung, da diese N-Heterocyclen in zahlreichen Naturstoffen sowie pharmazeutischen und agrochemischen Wirkstoffen vorkommen. [2] Die dirigierte Metallierung und weitere Funktionalisierung dieser elektronenarmen N-Heterocyclen kann mittels "at"-Basen [3] und in einigen Fällen auch mit Lithiumbasen [4] erreicht werden. [2] Die dirigierte Metallierung und weitere Funktionalisierung dieser elektronenarmen N-Heterocyclen kann mittels "at"-Basen [3] und in einigen Fällen auch mit Lithiumbasen [4] erreicht werden.

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