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

Abstract

SummaryPreviously 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.

Contrasting Synergistic Heterobimetallic (Na–Mg) and Homometallic (Na or Mg) Bases in Metallation Reactions of Dialkylphenylphosphines and Dialkylanilines: Lateral versus Ring Selectivities

“…In both magnesiation reactions no orthoiodonated productswere isolated. In keeping with our findings that the meta-isomer monopolized the selectivity the reported metallation of N,N-dimethylaniline with the mixed metal zincate reagent [(TMEDA)Na(TMP)(tBu)Zn(tBu)] also resultsi nt he isolation of am ixture of the regioisomers [29] upon iodolysis quenching studies, with the meta-isomer the major product.…”

“…[5,6,42,43] X-ray crystallographic analysiso fc ompound 2 ( Figure 1) reveals the first example of lateralm agnesiation of P, P -dimethyl-Scheme1.Structurally characterised examples of the products of metallation of N,N-dimethylaniline and dimethylphenylphosphine. Noteonly metals shown for clarity.Reagents and conditions: [a] nBuLi, hexane, reflux,16h; [33] [b] nBuNa, hexane,08C; [29] [c] [NaTMP(tBu)Zn(tBu)],hexane,r eflux,2h, [28] [d] [Na 4 Mg 2 (TMP) 6 (nBu) 2 ], methylcyclohexane, reflux,4h, [31] [e] nBuLi.TMEDA, hexane. [34] phenylphosphine.…”

“…Wanting to determine if the reactions of base 1 displayed any synergistic character we next sought to probe the reactivity of the homo-metallic components of 1,N aTMP·TMEDAa nd Mg(CH 2 SiMe 3 ) 2 .L iterature examples for the mono-metallation of the dimethyl N/P substrates (Scheme 1) have been reported, [29,33,34] prompting us to investigate the reactivity of the diethyl analogues N,N-diethylaniline and P, P -diethylphenylphosphine. Reactiono famolar equivalent of N,N-diethylaniline or P, P -diethylphenylphosphine with (NaTMP·TMEDA) at room temperaturer esulted in the isolation of the crystalline compounds [{(TMEDA)Na(EtNC 6 H 5 )} 2 ] 5 and [(TMEDA)Na 2 (TMP)(C 6 H 5 PEt)] 2 6 in a4 6a nd 35 %( max yield 50 %) yield, respectively.O nt he other hand, reactionw ith Mg(CH 2 SiMe 3 ) 2 ,e ven under forcing reflux conditions, resulted in quantitative recoveryo ft he starting materials (Scheme 3).…”

“…A notable example is with the sodium zincate, [(TMEDA)Na( t Bu)(TMP)Zn( t Bu)], in which a novel meta ‐zincation of N , N ‐dimethylaniline (Scheme ) was achieved. However, subsequent in situ electrophilic quenching studies with iodine revealed a mixture of ortho ‐, meta ‐ and para‐ iodoanilines …”

“…However,s ubsequent in situ electrophilicq uenching studies with iodine revealed am ixture of ortho-, meta-and para-iodoanilines. [29] More recently as ophisticated template approach [30] has been reported employing the sodium magnesiate base [Na 4 Mg 2 (TMP) 6 (nBu) 2 ]. This powerful method relies on the azametallo ring scaffold, which can override acidity criteria and direct remarkable selectivea nd regiospecific polymetallations.…”