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Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates.

ABSTRACT: Straightforward calculations such as determinations of pK_a values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored fused N-heterocycle imidazo[1,2-a]pyrazine. Thus, regioselective metalations of 6-chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl·LiCl and TMP₂Zn·2MgCl₂·2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMP₂Zn·2MgCl₂·2LiCl as base for the first metalation allowed an alternative regioselective metalation. Nucleophilic additions at position 8 as well as selective Negishi cross-couplings complete the set of methods for selectively decorating this heterocycle of the future.

SUBMITTER: Kastrati A

PROVIDER: S-EPMC10583695 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates.

Kastrati Agonist A Kremsmair Alexander A Sunagatullina Alisa S AS Korotenko Vasilii V Guersoy Yusuf C YC Rout Saroj K SK Lima Fabio F Brocklehurst Cara E CE Karaghiosoff Konstantin K Zipse Hendrik H Knochel Paul P

Chemical science 20230928 40

Straightforward calculations such as determinations of pKa values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored fused N-heterocycle imidazo[1,2-a]pyrazine. Thus, regioselective metalations of 6-chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl·LiCl and TMP2Zn·2MgCl2·2LiCl provided Zn- and Mg-interm ...[more]

PMID: 37860644

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Project description:Reactions of three magnesium(i) dimers, [{(ArNacnac)Mg-}2] (ArNacnac = [(ArNCMe)2CH]-; Ar = xylyl (Xyl), mesityl (Mes) or 2,6-diethylphenyl (Dep)), with either 1,1-diphenylethylene (DPE), α-methylstyrene (MS), trans-stilbene (TS) or diphenylacetylene (DPA) led to the 1,2-addition of the Mg-Mg bond across the substrate, giving rise to the 1,2-dimagnesioethanes, [{(XylNacnac)Mg}2(μ-DPE)], [{(DepNacnac)Mg}2(μ-MS)], [{(ArNacnac)Mg}2(μ-TS)] (Ar = Mes or Dep); and a 1,2-dimagnesioethene, [{(MesNacnac)Mg}2(μ-DPA)]. The reactions involving the 1,1-substituted alkenes are shown to be readily redox reversible, in that the reaction products are in equilibrium with a significant proportion of the starting materials at room temperature. Variable temperature NMR spectroscopy and a van't Hoff analysis point to low kinetic barriers to these weakly exergonic reactions. [{(MesNacnac)Mg}2(μ-DPE)] and [{(MesNacnac)Mg}2(μ-DPA)] behave as 1,2-di-Grignard reagents in their reactions with very bulky amido-zinc bromides, yielding the first examples of a 1,2-dizincioethane, [(L*Zn)2(μ-DPE)] (L* = -N(Ar*)(SiPri 3); Ar* = C6H2Me{C(H)Ph2}2-4,2,6), and a 1,2-dizincioethene, [(TBoLZn)2(μ-DPA)] (TBoL = -N(SiMe3){B(DipNCH)2}, Dip = 2,6-diisopropylphenyl), respectively. Divergent reactivity is shown for [{(MesNacnac)Mg}2(μ-DPE)], which behaves as a two-electron reducing agent when treated with amido-cadmium and amido-magnesium halide precursors, yielding the cadmium(i) and magnesium(i) dimers, [PhBoLCdCdPhBoL] (PhBoL = -N(SiPh3){B(DipNCH)2}) and [L†MgMgL†] (L† = -N(Ar†)(SiMe3); Ar† = C6H2Pri{C(H)Ph2}2-4,2,6), respectively. A further class of reactivity for [{(MesNacnac)Mg}2(μ-DPE)] derives from its reaction with the bulky amido-germanium chloride, L*GeCl, which gives a magnesio-germane, presumably via intramolecular C-H activation of a highly reactive magnesiogermylene intermediate, [:Ge(L*){Mg(MesNacnac)}]. [{(MesNacnac)Mg}2(μ-DPE)] can be considered as acting as a two-electron reducing, magnesium transfer reagent in this reaction.

Dataset Information

Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates.

Publications

Calculation-assisted regioselective functionalization of the imidazo[1,2-<i>a</i>]pyrazine scaffold <i>via</i> zinc and magnesium organometallic intermediates.

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