After-effects of lithium-mediated alumination of 3-iodoanisole: isolation of molecular salt elimination and trapped-benzyne products

Abstract

Gaining a deeper understanding of the modus operandi of heterometallic lithium aluminate bases towards deprotonative metallation of substituted aromatic substrates, we have studied the reactions and their aftermath between our recently developed bis-amido base '(i)Bu(2)Al(μ-TMP)(2)Li'3 and 3-halogenated anisoles. Ortho-metallation of 3-iodoanisole with 3 results in a delicately poised heterometallic intermediate whose breakdown into homometallic species and benzyne cannot be suppressed, even at low temperature or in a non-polar solvent (hexane). Homometallic components [LiI·TMP(H)](4) (5) and (i)Bu(2)Al(TMP)·THF (6) have been isolated while the reactive benzyne intermediate has been trapped via Diels-Alder cyclization with 1,3-diphenylisobenzofuran yielding 1-methoxy-9-10-diphenyl-9-10-epoxyanthracene (7). In polar THF solution, nucleophilic addition of LiTMP across the benzyne functionality followed by electrophilic quenching with iodine yields the trisubstituted aromatic species 1-(2-iodo-3-methoxyphenyl)-2,2,6,6-tetramethylpiperidide (8). Compounds 5-8 have been characterized by single-crystal X-ray diffraction in the solid state and multinuclear NMR spectroscopy in solution. By considering these collated results, a plausible reaction mechanism has been proposed for the breakdown of the aforementioned intermediate bimetallic framework. Interestingly, the metallation reaction can be controlled by changing to 3-chloroanisole with an excess of base 3, as evidenced by electrophilically trapping the deprotonated aromatic with iodine to give 2-iodo-3-chloroanisole (9).

TMP (2,2,6,6-tetramethylpiperidide)-aluminate bases: lithium-mediated alumination or lithiation–alkylaluminium-trapping reagents?

“…Arrived at by simply balancing the stoichiometry of the equilibrium reaction, the putative co-product "[{Li(THF) 4 } + {Al(TMP) 2 ( i Bu) 2 } − ]", 2•(THF) 4 inspired us to the idea of employing the bis-TMP species "LiTMP•Al(TMP)( i Bu) 2 ", 2 in AMMAI reactions (see later). Knochel's subsequent discovery that a closely related equilibrium may be operating in THF solution mixtures of TMPMgCl•LiCl and Al(Et) 3 leading to the tetraalkylaluminate "MgCl•Al(Et) 4 " (characterised in part by a sharp resonance at 159 ppm in 27 Al NMR spectra) and the alkylaluminium amide (TMP)Al(Et) 2 •THF 14 motivated us to revisit in greater detail the comparison between the THF solutions of crystalline 1•THF and its in situ form 1. Our findings detailed below were unexpected.…”

Trans‐Metal‐Trapping: Concealed Crossover Complexes En Route to Transmetallation?

“…The best traps should: (i) have sufficient steric bulk to ensure they cannot cocomplex with LiTMP; and (ii) their molecular constitutions should be stable to dismutation. Both points are satisfied by the alkyl‐amido complex [ i Bu 2 Al(TMP)] as it does not engage in cocomplexation with LiTMP and in THF it forms a secure tetrahedral complex [ i Bu 2 Al(TMP)⋅THF] . In contrast, ( i Bu 3 Al) exists as a dimer‐monomer equilibrium in solution and its reduced steric profile enables it to engage with LiTMP.…”

“…A limit to this iodine‐tolerance is seen when the initial metallation occurs adjacent ( ortho ) to the halogen position as with 3‐iodoanisole . LiTMP lithiation between the two substituents coupled with Al trapping generates an unstable crossover intermediate.…”

“…The best traps should:( i) have sufficient steric bulk to ensure they cannotc ocomplex with LiTMP;and (ii)their molecular constitutions should be stable to dismutation.B oth points are satisfied by the alkyl-amido complex [iBu 2 Al(TMP)] as it does not engage in cocomplexation with LiTMP and in THF it forms as ecure tetrahedral complex [iBu 2 Al(TMP)·THF]. [28] In contrast, (iBu 3 Al) exists as ad imer-monomer equilibrium in solution and its reduced steric profile enables it to engage with LiTMP.T his engagement takes the form of complicated equilibria comprising five species in THF solution (Scheme 10). Significantly,t he only speciesc apable of aromatic CÀHd eproto-nation to any significant extenti sL iTMP.T he inertness of the ate species, [THF·Li(TMP)Al(iBu) 3 ]a nd its charge-separated variant [{Li(THF) 4 } + {Al(TMP)(iBu) 3 } À ], provides ac ontrastw ith the aforementioned magnesiate and zincate bases which have broad scope in aromatic deprotonation applications.…”

“…[30] Thisp rovides entry to anisole derivatives containing three different halogen substituents as in 2-bromo-4-iodo-6-chloroanisole, whereby initial alumination produced intermediate Alimit to this iodine-tolerance is seen when the initial metallation occurs adjacent (ortho)t ot he halogen position as with 3-iodoanisole. [28] LiTMP lithiation betweent he two substituents coupled with Al trapping generatesa nu nstable crossover intermediate. This fallsapart in hexane solution even at À78 8Ct o the homometallic species [LiI·TMP(H)] and iBu 2 Al(TMP)·THFa nd ab enzyne (provedv ia Diels-Alder cyclization), while in THF solution LiTMP adds across the benzyne functionality to yield the trisubstituted product after iodine interception.…”