Generation of Functionalized Asymmetric Benzynes with TMP-Zincates. Effects of Ligands on Selectivity and Reactivity of Zincates

Abstract

We have developed new methods for preparing functionalized benzynes through deprotonative zincation as a key reaction using R2Zn(TMP)Li, and we also describes dramatic ligand effects on the benzyne formation. Deprotonative zincation of various meta-substituted bromobenzenes with Me2Zn(TMP)Li proved effective for the one-pot generation of various 3-functionalized benzynes, particularly those electrophilic substituents such as ester, amide, and cyano. On the other hand, zincation with tBu2Zn(TMP)Li, followed by electrophilic trapping (with I2) proved a powerful tool for the preparation of 1,2,3-trisubstituted aromatic compounds.8 The resultant 1,2,3-trisubstituted benzenes are available as precursors for generation of 3-substituted benzynes by halogen-zinc exchange reactions with Me3ZnLi. These methods offer far greater generality than previous methods for the synthesis of functionalized asymmetric benzynes, and should be of value in new syntheses of various natural products and functional materials. In addition, these results underline the utility of spectator ligands on the central metal of ate complexes as a tunable functionality in the development of new ate complex-promoted reactions.

Alkali‐Metal‐Mediated Zincation of Ferrocene: Synthesis, Structure, and Reactivity of a Lithium Tmp/Zincate Reagent

“…NMR ( 1 H, 7 Li, and 13 C) spectroscopic characterization of these crystals in a solution of deuterated benzene established the co-complexed nature of 1, as revealed most diagnostically in the chemical shift of the MÀCH 2 resonance of the MÀnBu linkage. This signal appears at d = 0.24 ppm in 1 relative to d = 0.27, À0.23, and À0.83 ppm in nBu 2 Zn, "[LinBu 3 Zn]", and nBuLi, respectively, thus suggesting that the nBu group in the new mixedmetal co-complex retains much of its original "zinc character". This last point was confirmed when the complete molecular structure of 1 was revealed through an X-ray crystallographic study ( Figure 1).…”

“…Established only in 1999 through the pioneering work on "[LitBu 2 Zn(tmp)]" by Kondo et al, [1] "tmp zincates" have found application as highly chemo-and/or regioselective bases for the metalation of alkyl benzoates and related aza aromatic compounds, bromopyridines, and various halobenzenes. [2,3] Recent reports [4] have highlighted the poverty of structural information available on lithium zincates in general. Tmp zincates are no exception in this regard, with a 13 C NMR spectroscopic study of "[LitBu 2 Zn(tmp)]" in solution [1] providing the only morsel of structural evidence…”

“…It is surprising that prior to this investigation nBu 2 Zn had not been subjected to a transformation to prepare a tmp zincate system given that both the parent organozinc reagent [7] and its homoleptic zincate derivative "[LinBu 3 Zn]" [8] have reasonably well developed chemistries. In the event, the transformation proved straightforward by applying the same method of addition as that used previously to prepare "[LitBu 2 Zn(tmp)]"; [1] however, the bulk solvent was changed from polar THF to nonpolar hexane and then the reaction was completed with the introduction of a stoichiometric amount of the donor solvent, TMEDA, in a deliberate attempt to afford a crystalline zincate [Eq.…”

“…This orange solid, which precipitated from the reaction mixture within minutes, was characterized by NMR spectroscopy and X-ray crystallography (see below). Its formation is both surprising and significant, as it establishes for the first time that intermediate metalo products from the deprotonative metalation of a substrate by a lithium zincate (prior to any electrophilic workup) are not necessarily zincates themselves (in contrast to what appears to be the case with "[LitBu 2 Zn(tmp)]" and related reagents) [1][2][3] but could possibly be, depending on the conditions, distinct Li and Zn compounds. No lithium-containing products could be isolated from solution at this stage, though investigation of the filtrate following removal of 2 suggested the presence of [Li 2 nBu 2 Zn(tmp) 2 (tmeda)], which exists as an oil when prepared independently from a Li(tmp)/ nBu 2 Zn/tmeda (2:1:1) mixture.…”

Long-range Effect of Bromine in the Deprotonative Metalation of Aromatic Compounds

“…Indeed, if its ability to acidify the adjacent hydrogens is good, both from a kinetic and a thermodynamic point of view, [2] the ortho-bromoarylmetals formed are prone to benzyne formation. Such a limitation can be overcome either by using lithium-metal bases such as TMP-zincate ( t Bu 2 Zn(TMP)Li, TMP = 2,2,6,6-tetramethylpiperidino), [3] or using in situ electrophilic trapping, [4] or even in the presence of another substituent (e.g. CF 3 [5] ), capable of stabilizing the arylmetal compound.…”