Alkali-metal mediated zincation of N-heterocyclic substrates using the lithium zincate complex, (THF)Li(TMP)Zn(tBu)2 and applications in in situ cross coupling reactions

This study investigates the ability of the mixed-metal reagent [Li(TMP)Zn(tBu)₂] 1 to promote direct Zn-H exchange reactions (zincations) of a wide range of N-heterocyclic molecules. The generated metallated intermediates from these reactions are intercepted with I₂ and some of them are also employed as precursors in Pd-catalysed Negishi cross-coupling applications. A comparison with recent precedents in metallation chemistry reveals that for some of these heterocycles, 1 allows improved conversions, under milder conditions and in certain cases, even gives unique regioselectivities.     

Shedding new light on ZnCl2-mediated addition reactions of Grignard reagents to ketones: structural authentication of key intermediates and diffusion-ordered NMR studies

Building on recent advances in synthesis showing that the addition of inorganic salts to Grignard reagents can greatly enhance their performance in alkylation reactions to ketones, this study explores the reactions of EtMgCl with benzophenone in the presence of stoichiometric or catalytic amounts of ZnCl(2) with the aim of furthering the understanding of the role and constitution of the organometallic species involved in these transformations. Investigations into the metathesis reactions of three molar equivalents of EtMgCl with ZnCl(2) led to the isolation and characterisation (X-ray crystallography and (1)H and (13)C NMR spectroscopy) of novel magnesium "zinc-rich" zincate [{(THF)(6)Mg(2)Cl(3)}(+){Zn(2)Et(5)}(-)] (1), whose complicated constitution in THF solutions was assessed by variable-temperature (1)H DOSY NMR studies. Compound 1 reacted with one equivalent of benzophenone to yield magnesium magnesiate [{(THF)(6)Mg(2)Cl(3)}(+){Mg(2)(OC(Et)Ph(2))(2)Cl(3)(THF)}(-)] (3), whose structure was determined by X-ray crystallography. (1)H NMR monitoring of this reaction showed two equivalents of ZnEt(2) formed as a co-product, which together with the "magnesium only constitution" of 3 provides experimental insights into how zinc can be efficiently recycled in these reactions, and therefore used catalytically. The chemoselectivity of this reaction can be rationalised in terms of the synergic effect of magnesium and zinc and contrasts with the results obtained when benzophenone was allowed to react with EtMgCl in the absence of ZnCl(2), where the reduction of the ketone takes place preferentially. The reduction product [{(THF)(5)Mg(3)Cl(4){OC(H)Ph(CF(3))}(2)] (4) obtained from the reaction of EtMgCl with 2,2,2-trifluoroacetophenone was established by X-ray crystallography and multinuclear ((1)H, (13)C and (19)F) NMR spectroscopy. Compounds 3 and 4 exhibit new structural motifs in magnesium chemistry having MgCl(2) integrated within their constitution, which highlights the new role of this inorganic salt in providing structural support for the newly generated alkoxide ligand.     

Structural variations in bimetallic sodium-magnesium and sodium-zinc ketimides, and a sodium-zinc alkide-alkoxide-amide: connections to ring-stacking, ring-laddering, and inverse crown concepts

The first sodium-magnesium and sodium-zinc ketimido complexes display contrasting inverse crown ring and pseudo-cubane structures respectively, while a sodium-zinc heterotrianionic alkide-alkoxide-amide adopts a third type of structure with a stepped ladder motif.     

Alkali-metal-mediated zincation of anisole: synthesis and structures of three instructive ortho-zincated complexes

The new concept of alkali-metal-mediated zincation (AMMZ), formally a zinc-hydrogen exchange reaction but one that requires the participation of an alkali metal, is applied here to the alkyl aryl ether anisole, an important molecule for studying directed ortho-metalation (DoM) chemistry. Treating one molar equivalent of anisole with the lithium dialkyl-TMP zincate reagent [THF.Li(mu-TMP)(mu-tBu)Zn(tBu)] (1) in hexane solution affords the mono-ortho-zincated complex [THF.Li(mu-TMP)(mu-o-C6H4OMe)Zn(tBu)] (2), which establishes that 1 functions as an alkyl base although previously it was regarded as an amido (TMP) base in other DoM applications. Treating two molar equivalents of anisole with 1, and increasing the reaction time, affords the bis-ortho-zincated complex [THF.Li(mu-TMP)(mu-o-C6H4OMe)Zn(o-C6H4OMe)] (3), which establishes that 1 can also function as a dual alkyl base. Omitting THF and rerunning the reaction with one or two molar equivalents of anisole affords [Ph(Me)O.Li(mu-TMP)(mu-o-C6H4OMe)Zn(tBu)] (4), which remarkably contains a combination of neutral and ortho-deprotonated anisole ligands. On isolating crystalline 4 from solution and adding THF, it converts to 2 and then to 3 on further stirring of the solution, as determined by NMR studies. This fact, along with other observations, would suggest that a complex-induced proximity effect does not need to be invoked to explain the observed zincation of anisole. The crystal structures of 2-4 are presented, as are their 1H, 13C, and 7Li NMR spectra recorded in C6D6 solution.     

New lithium-zincate approaches for the selective functionalisation of pyrazine: direct dideprotozincation vs. nucleophilic alkylation

Comparing the reactivity of the related lithium zincates [(THF)LiZn(TMP)(t)Bu(2)] (1) and [(PMDETA)LiZn(t)Bu(3)] (2) towards pyrazine discloses two new bimetallic approaches for the selective 2,5-dideprotonation and room temperature C-H alkylation of this sensitive heterocycle.