Metalation of Aryl Ethers

Aryllithium reagents are familiar to us as the products of the reaction of aryl halides with lithium. A second route to aryllithiums is hy deprotonation of an aromatic ring with an alkyllithium reagent. This process is called metalation. 

X = 0CH3, OCH2OCH3, CH2OH, C02, N(CH3)2, CH2N(CH3)2, CNHR, and others 

These directed metalations are regioselective for lithiation at carbons ortho to the substituent. The substituents contain atoms, especially oxygen and nitrogen, capable of coordinating to lithium. This coordination is reflected in the transition state for proton abstraction and causes lithiation to be fastest 

Typical conditions for metalation involve treating a diethyl ether or tetrahydrofuran solution of the aryl derivative with an alkyllithium in hexane. A,iV,A, Al -Tetramethylethylenediamine [(CH3)2NCH2CH2N(CH3)2, TMEDA] is sometimes added to increase the rate of metalation. 

Once formed, the ortho-metalated daivative undergoes the usual reactions of oiganoUthium reagents. 

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With the platinum group metals, the hydrogenolysis of aryl ethers, in general, tends to occur more extensively over osmium, iridium, and platinum (the third-row metals) than over ruthenium, rhodium, and palladium (the second-row metals).145,146 The... 

Eisch, J. J., Kovacs, C. A., Rhee, S.-G. Rearrangements of organometallic compounds. X. Mechanism of 1,2-aryl migration in the Wittig rearrangement of a-metallated benzyl aryl ethers. J. Organomet. Chem. 1974, 65, 289-301. 

A very useful method to prepare carbocyclic enol ethers is the Birch reduction of aryl ethers. In the simplest example, metal ammonia reduction of methoxybenzene gives methoxycyclohexadiene (21). The reaction has been applied to numerous aryl ethers of complex structures. 

Fission of aryl ethers can also be effected by metallic sodium or potassium. For instance, diphenyl ether, which is one of the most resistant ethers, is decomposed by liquid potassium-sodium alloy at room temperature.38 Weber and Sowa have cleaved 4,4 -disubstituted diphenyl ethers into benzene and phenol derivatives by sodium in liquid ammonia.39 Diallyl ether is converted by sodium dust at 35° into allylsodium and sodium allyl oxide, which provides a suitable method for preparation of allylsodium.3 7a Anisole, phenetole, benzyl phenyl ether, and diphenyl ether give the phenols in 90% yield, without by-products, when boiled with sodium or potassium in pyridine.40... 

The formation of aryl ethers of (hydroxyalkyl)-phosphonic or -phosphinic derivatives from the corresponding haloalkyl phosphorus(V) acid derivative and a metal phenate may present unfortunate difficulties depending on the particular halogen, but these have been overcome by the use of sulphonate substrates, in particular the 0-4-chlorobenzenesulphonyl esters of the phosphonic or phosphinic derivative, in reactions with sodium phenates. A study of the alcoholysis reactions of the O-p-tosylates of the cis and trans isomers of diethyl (2-hydroxycyclo-hexyl)phosphonate, has shown that with a 60° dihedral angle between the two functions, the rate of reaction is sensitive to solvent nucleophilicity, and the evidence supports a bimolecular displacement. When the dihedral angle is 180°, the lack of dependence of rate on solvent and other features, support the involvement of carbocationic intermediates, with their stabilization by the phosphono group . ... 

Other metal salts and complexes also catalyze the formation of C-N, C-O, and C-S bonds from organic electrophiles. Thus, a mixture of [Ni(COD)2] and a bidentate phosphine catalyzes the formation of aryl ethers from aryl halides and alkoxides [410]. In some cases, the reactions occur under milder conditions and with higher yields than when catalyzed by Pd complexes. 

Nucleophilic aromatic substitution reactions of haloarenes complexed to transition metal moieties with oxygen-, sulfin-, and nitrogen-containing nucleophiles allows for the synthesis of a wide variety of aryl ethers, thioethers, and amines. These metal-mediated reactions proceed under very mild conditions and allow for the incorporation of a number of different functional groups. Nucleophilic substitution reactions of chloroarenes complexed to the cyclopentadienyliron moiety have been the focus of many studies directed toward the design of functionalized organic monomers. ... 

Copper-catalyzed Aryl Ether Formation. Traditional methods for formation of aryl ethers involve stoichiometric Ullmann couplings. A new system was developed exploiting catalytic CuCl and NMI as a ligand. The title compound was chosen due to its similarities to histidine, a common amino acid for binding metals. This methodology was applied to the synthesis of the insecticide diafenthiuron that produced the desired aryl ether in greater than 98% yield compared to 39% reported in current patents (eq 32). ... 

Furthermore, more recent strategies relying on nickel based catalytic systems have described the functionalization of aryl ethers, carboxylates, carbamates and so forth, thereby dramatically increasing the scope of transition metal catalysis [47]. 

Ullman reaction The synthesis of diaryls by the condensation of aromatic halides with themselves or other aromatic halides, with the concomitant removal of halogens by a metal, e.g. copper powder thus bromobenzene gives diphenyl. The reaction may be extended to the preparation of diaryl ethers and diaryl thio-ethers by coupling a metal phenolate with an aryl halide. 

The rearrangement of an ether 1 when treated with a strong base, e.g. an organo-lithium compound RLi, to give an alcohol 3 via the intermediate a-metallated ether 2, is called the Wittig rearrangement. The product obtained is a secondary or tertiary alcohol. R R can be alkyl, aryl and vinyl. Especially suitable substrates are ethers where the intermediate carbanion can be stabilized by one of the substituents R R e.g. benzyl or allyl ethers. 

Although the sulfone activated biphenyl and the ketone activated naphthalene moiety for the displacement polymerization have been reported by Attwood et al. [11], these were rediscovered by Cummings et al. [12] and Hergenrother et al. [13], respectively, for the synthesis of poly(aryl ethers). Recently, Singh and Hay [14] reported polymers containing 0-dibenzoyl benzene (1,2,3) moiety by reaction between bis(O-fluorobenzoyl) benzene or substituted benzene with bisphenates of alkali metal salt in DMAC as follows ... 

When we allowed pentafluorophenyl-lithium to decompose in ether in the presence of an excess of N, ZV-dimethy laniline we obtained the compounds (92) 70, X = F), (94), the latter as the major compound, and a product which was shown to be (97). That this latter compound did not arise by metallation of 2V,lV-dimethylaniline followed by addition to tetrafluorobenzyne was shown by quenching the reaction mixture with deuterium oxide. No deuterium incorporation was detected. The compound (97) provides a rare example of a product derived by a Stevens rearrangement in which aryl migration has occurred b>. 

The high-valent metal species required for activation of an alkyne has also been generated by the oxidative addition to an allylic or propargylic system. For example, with an allyl aryl ether as the substrate, this type of reaction achieves a cycloisomerization that occurs through an 0- to C-allyl migration (Equation (92)) 323,324 similarly, (9-propargyl derivatives lead to a mixture of allenyl and propargyl products (Equation (93)).325,326... 

In addition to /3-H elimination, olefin insertion, and protonolysis, the cr-metal intermediate has also proved to be capable of undergoing a reductive elimination to bring about an alkylative alkoxylation. Under Pd catalysis, the reaction of 4-alkenols with aryl halides affords aryl-substituted THF rings instead of the aryl ethers that would be produced by a simple cross-coupling mechanism (Equation (126)).452 It has been suggested that G-O bond formation occurs in this case by yy/z-insertion of a coordinated alcohol rather than anti-attack onto a 7r-alkene complex.453... 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

The Birch reduction has been used by several generations of synthetic organic chemists for the conversion of readily available aromatic compounds to alicyclic synthetic intermediates. Birch reductions are carried out with an alkali metal in liquid NH3 solution usually with a co-solvent such as THF and always with an alcohol or related acid to protonate intermediate radical anions or related species. One of the most important applications of the Birch reduction is the conversion of aryl alkyl ethers to l-alkoxycyclohexa-l,4-dienes. These extremely valuable dienol ethers provide cyclohex-3-en-l-ones by mild acid hydrolysis or cyclohex-2-en-l-ones when stronger acids are used (Scheme 1). 

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