Structural elaboration of the surprising ortho-zincation of benzyl methyl ether

Breaking with convention, the reaction of the sodium zincate, [(TMEDA)Na(μ-TMP)(μ-tBu)Zn(tBu)] with benzyl methyl ether (PhCH2OMe) produces exclusively an ortho-zincated intermediate [(TMEDA)Na(μ-TMP)(μ-C6H4CH2OMe)Zn(tBu)] instead of the expected 'thermodynamic' α-metallated product

Towards understanding synergic s-block chemistry, new insights from zincate and magnesiate reactions

Metallation, in which an inert carbon-hydrogen bond is transformed into a labile carbonmetal bond, is a useful tool for constructing substituted aromatic compounds. Routinely, highly polar organolithium reagents are employed for this purpose; however, there are limitations to their use. This project was based on further developing an alternative metallation strategy, namely Alkali-Metal-Mediated Metallation (AMMM), with emphasis on zincation by exploiting the synergic chemistry that can be generated when pairing a group 1 metal amide with a low polarity dialkyl zinc reagent. AMMM reactions of the sodium TMP-zincate [(TMEDA)Na(μ-TMP)(μ-tBu)Zn(tBu)] (1) were explored leading to the development of a new concept within Directed-ortho- Metallation (DoM) chemistry with three electron-rich aromatic substrates cleanly zincated ortho to the directing metallation group (DMG) under ambient temperatures; while reaction with benzyl methyl ether produced an ortho-zincated intermediate instead of the thermodynamic α-metallated product. Additionally, a remarkable structural variety was observed when investigating the competition between a DMG and a heteroatom in the N,N-diethyl thiophene-2-carboxamide ring for the site of metallation. Through structurally mapping these reactions and subsequent electrophilic quenches, these studies established reagent 1 as a powerful metallating agent. A case study of the metallation of N,N-dimethylaniline offers complementary insight into the selectivity and mechanism of the base underlining how the cooperative action of the bi-metal partnership promotes special reactions beyond the scope of homometallic reagents. Outwith metallation, some unexpected highlights were the product of this research. Courtesy of a novel four-step domino sequence, a series of unique zwitterionic zincabicyclic complexes were prepared from the reaction of synergic reagents and chlorobenzene. Complementing its Brønsted basicity, zincate 1 underwent single electron transfer with the radical TEMPO; while, treating TEMPO with sodium metal and crystallisation from a hexane/TMEDA mixture produced a ladder structure which represents a rare example of elemental-metal single electron reduction of the radical.Metallation, in which an inert carbon-hydrogen bond is transformed into a labile carbonmetal bond, is a useful tool for constructing substituted aromatic compounds. Routinely, highly polar organolithium reagents are employed for this purpose; however, there are limitations to their use. This project was based on further developing an alternative metallation strategy, namely Alkali-Metal-Mediated Metallation (AMMM), with emphasis on zincation by exploiting the synergic chemistry that can be generated when pairing a group 1 metal amide with a low polarity dialkyl zinc reagent. AMMM reactions of the sodium TMP-zincate [(TMEDA)Na(μ-TMP)(μ-tBu)Zn(tBu)] (1) were explored leading to the development of a new concept within Directed-ortho- Metallation (DoM) chemistry with three electron-rich aromatic substrates cleanly zincated ortho to the directing metallation group (DMG) under ambient temperatures; while reaction with benzyl methyl ether produced an ortho-zincated intermediate instead of the thermodynamic α-metallated product. Additionally, a remarkable structural variety was observed when investigating the competition between a DMG and a heteroatom in the N,N-diethyl thiophene-2-carboxamide ring for the site of metallation. Through structurally mapping these reactions and subsequent electrophilic quenches, these studies established reagent 1 as a powerful metallating agent. A case study of the metallation of N,N-dimethylaniline offers complementary insight into the selectivity and mechanism of the base underlining how the cooperative action of the bi-metal partnership promotes special reactions beyond the scope of homometallic reagents. Outwith metallation, some unexpected highlights were the product of this research. Courtesy of a novel four-step domino sequence, a series of unique zwitterionic zincabicyclic complexes were prepared from the reaction of synergic reagents and chlorobenzene. Complementing its Brønsted basicity, zincate 1 underwent single electron transfer with the radical TEMPO; while, treating TEMPO with sodium metal and crystallisation from a hexane/TMEDA mixture produced a ladder structure which represents a rare example of elemental-metal single electron reduction of the radical

A mu(4)-oxide-containing a dimeric variant of a sodium dialkyl(amido)zincate reagent

Post-metallation derivatives of the sodium dialkyl(amido)zincate reagent (TMEDA) Na(mu-TMP)Zn(Bu-t)(2) (TMEDA is N,N,N',N'-tetramethylethylenediamine and TMP is 2,2,6,6-tetramethylpiperidide) have been of structural interest due to the insight they give into aromatic metallation mechanisms. Here, the aromatic substrate is formally replaced with [ZnO](2) to give tetra-tert-butyldi-mu(4)-oxido-bis(tetramethylethylenediamine-kappa N-2,N')bis(mu(2)-2,2,6,6-tetramethylpiperidin-1-ido-kappa N-2:N)-disodiumtetrazinc hexane 0.59-solvate, [Na2Zn4(C4H9)(4)-(C9H18N)(2)O-2(C6H16N2)(2)]center dot 0.59C(6)H(14). The crystallographically centrosymmetric complex retains many of the structural features of its parent monomer but has an unusual dimeric structure, with a central planar Zn-O-Zn-O ring joined to two orthogonal near-planar Zn-O-Na-N rings through the distorted tetrahedral geometries of the oxide ions

Concerning the structures of alkali-metal-mediated ortho zincation of benzamides and phenyl o-carbamate

As a further contribution to alkali-metal-mediated metalation, a method for converting C-H bonds directly to C-Zn bonds without the need for an additional salt metathesis step, reactions of the sodium TMP-zincate [(TMEDA)Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)] (1) with three different electron-rich aromatic substrates, have been investigated. Under ambient-temperature conditions, N,N-diethyl-benzamide, N,N-diethyl-3-methoxybenzamide, and N,N-diethyl phenyl O-carbamate were zincated ortho to the substituent group (in between both substituents in the second case) in the crystalline products [(TMEDA)Na(mu-TMP){mu-2-[1-C(O)NEt2]C6H4}Zn(Bu-t)] (3), [(TMEDA)Na(mu-TMP){mu-2-(1-C(O)NEt2) (3-OMe)C6H3}Zn(Bu-t)] (4), and [(TMEDA)Na(mu-TMP){mu-2-(1-C(O)NEt2)C6H4}-Zn(Bu-t)] (6). X-ray crystallography established that, in each case, the deprotonated aromatic fragment is captured by the residue of the bimetallic base, giving rise to seven-membered (NaNZnCCCO) ring structures for 3 and 4 and an eight-membered (NaNZnCCOCO) ring. structure for 6. The new zincated aromatics were also characterized by solution-state H-1 and C-13 NMR spectroscopy. Reactivity studies of 3, 4, and 6 were also performed with iodine. In each case, three molar equivalents of iodine in THF solution gave the ortho-iodo products N,N-diethyl-2-iodobenzamide (7), N,N-diethyl-2-iodo-3-methoxybenzamide (8), and N,N-diethyl-2-iodophenyl-O-carbamate (9) in quantitative, 71% and 75% yields as determined by NMR analysis, respectively

Meta-metallation of N,N-dimethylaniline: Contrasting direct sodium-mediated zincation with indirect sodiation-dialkylzinc co-complexation

Previously we reported that direct zincation of N,N-dimethylaniline by the mixed-metal zincate reagent 1 ((TMEDA)Na(TMP)(t-Bu)Zn(t-Bu)) surprisingly led to meta-metallation (zincation) of the aniline, as manifested in the crystalline complex 2 ((TMEDA)Na(TMP)(m-C6H4-NMe2)Zn(t-Bu)), and that iodination of these isolated crystals produced the meta-isomer N,N-dimethyl-3-iodoaniline quantitatively. Completing the study here we find that treating the reaction solution with iodine produces a 72% conversion and results in a mixture of regioisomers of N,N-dimethyliodoaniline, with the meta-isomer still the major product (ortho:meta:para ratio, 6:73:21), as determined by NMR. In contrast to this bimetallic method, sodiation of N,N-dimethylaniline with n-BuNa produced the dimeric, ortho-sodiated complex 3 (((TMEDA)Na(o-C6H4-NMe2))2), as characterised by X-ray crystallography and NMR. No regioisomers were observed in the reaction solution. Introducing t-Bu2Zn to this reaction solution afforded a cocrystalline product in the solid-state, composed of the bis-anilide 4 ((TMEDA)Na(o-C6H4-NMe2)2Zn(t-Bu)) and the Me2N–C cleavage product 5 ({(TMEDA)2Na}+{(t-Bu2Zn)2(µ-NMe2)}−), which was characterised by X-ray crystallography. NMR studies of the reaction mixture that produces 4 and 5 revealed one additional species, but the mixture as a whole contained only ortho-species and a trace amount of para-species as established by iodine quenching. In an indirect variation of the bimetallic reaction, TMP(H) was added at room temperature to the reaction mixture that afforded 4 and 5. This gave the crystalline product 6 ((TMEDA)Na(TMP)(o-C6H4-NMe2)Zn(t-Bu)), the ortho-isomer of the meta-complex 2, as determined from X-ray crystallographic and NMR data. Monitoring the regioselectivity of the reaction by iodination revealed a 16.6:1.6:1.0 ortho:meta:para ratio. Interestingly, when the TMP(H) containing solution was heated under reflux for 18 hours more meta-isomer was produced (corresponding ratio 3.7:4.2:1.0). It is likely that this change has its origin in a retro reaction that produces the original base 1 as an intermediate. Theoretical calculations at the DFT level using the B3LYP method and the 6-311G** basis set were used to probe the energetics of both monometallic and bimetallic systems. In accord with the experimental results, it was found that ortho-metallation was favoured by sodiation; whereas meta- (closely followed by para-) metallation was favoured by direct sodium-mediated zincation