Anisole, deprotonation

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

Stratakis showed that a similar situation exists for the deprotonation of anisole by BuLi in Et20 or TMEDA. The kinetic isotope effects are much lower, but give no evidence regarding the existence of an anisole-BuLi complex prior to deprotonation. 

Detailed NMR and theoretical studies have identified and characterized a number of the complexes along the proposed reaction pathways for anisole, 1,2-dimethoxybenzene and Al,Al-dimethylaniline ° . For example, anisole deaggregates the BuLi hexamer to form a tetrameric BuLi-anisole complex 4. Adding TMEDA displaces the anisole from the tetramer and breaks it down further to give a BuLi-TMEDA dimer 5, which deprotonates anisole at >0°C yielding 6 (Scheme 4). 

It has usually been assumed that the lithiation step involves loss of TMEDA and reformation of a BuLi-anisole complex prior to the deprotonation itself. However, the kinetics of the deprotonation step are inconsistent with this proposition both TMEDA molecules remain part of the complex during the deprotonation, which may therefore involve no 0-Li coordination and be directed purely by the acidifying effect on nearby protons of the a-electron-withdrawing MeO substituent. ... 

By careful optimization, Widdowson and coworkers were able to show that methoxy-methyl ethers of phenols are better substrates for alkyllithium-diamine controlled enan-tioselective deprotonation, and (—)-sparteine 362 is then also the best ligand among those surveyed the BuLi-(—)-sparteine complex deprotonates 447 to give, after electrophilic quench, compounds such as 449 in 58% yield and 92% ee (Scheme 180) . Deprotonation of the anisole complex 410 (see Scheme 169) under these conditions gave products of opposite absolute stereochemistry with poor ee. 

The organolithium compounds, formed by deprotonation of Af-benzylic-Af-Boc p-anisole carbamates, react with imines to yield tran5-4,5-disubstituted 1,3-imidazolin-2-ones in good yield and excellent stereoselectivity (Scheme 52). Benzaldehydes gave poor stereoselectivity, and the nse of imines as electrophiles is critical. The stereoselectivity can be explained by the transition states shown, in which the aryl and R substituents on the 4-membered ring are trans to one another. 

A peculiar complex is formed by if coordination of Os(II) ammine complex to one of the double bonds of benzene rings, rather than rf coordination, and the coordinated benzene rings show interesting reactivity [82]. For example, Os(II) coordinates regioselectively to the 2,3-double bond of anisole to form the complex 333, and hence localization of the remaining 7r-electrons occurs. As a result, at 20 °C an electrophile attacks easily at C(4) due to electron-donation of the methoxy group. The 4H-cationic intermediate 334 is stabilized by backdonation from the metal, and the monosubstitution product 334 is formed without deprotonation. The / ara-substituted anisole 335 is... 

The t]2 complex 333 can be prepared in 98% yield by the reaction of anisole with Os(NH3)5(OTf)3 in the presence of Mg. Michael addition of methyl vinyl ketone to the complex at 20 °C using TfOH afforded 336, which was converted to 337 by deprotonation with tertiary amine [83]. The diketone 340 was obtained by the Michael addition of methyl vinyl ketone to C-4 of the 4-methylanisole complex 338 to generate 339, followed by intramolecular nucleophilic attack of the keto enolate in 339. 

The para positions of A,A-dimethylanihne, diphenylamine, phenol, and anisole are electron-rich and accordingly attack 2-alkylthio-l,3-dithiolium cations at C-2, yielding various 2-aryl-1,3-dithiolium cations. A similar reaction occurs with 2,6-bis(/er/-butyl)phenol and with 2-naphthol, and by subsequent deprotonation ketones such as 174 and 175 are obtained. ... 

Capture of phenyl cations with methyl n-propyl ether gives products in which rearrangement has taken place.Initial capture gives the oxonium ion drawn to the left in equation 14. Most of this ion eliminates propene, and deprotonation of the resulting ion affords anisole (PhOR, where R = methyl), which constitutes 75% of the radiochemical yield. Among the other products are isopropyl phenyl ether (roughly 3% of the radiochemical yield, about 3 times more abundant than -propyl... 

Anisole)Cr(CO)3 can be deprotonated stereo selectively with a chiral base... 

A major side reaction is ortho deprotonation of the anisole ligand... 

Since deprotonation of the heteroatom with a moderate base is difficult for anilines and impossible for anisoles, the electrophilic addition reactions for os-mium(II) complexes of these ligands must be activated by Lewis acids. The ad-... 

One of the first eye-catching synthetic applications of arene-chromium chemistry was the synthesis of the sp/ro-sesquiterpenes ( )-acorenone and ( )-acorenone B (rac-7) disclosed by Semmelhack and Yamashita in 1980 [14]. These authors twice exploited the meta-selective nucleophile addition to anisole-Cr(CO)3 derivatives (Scheme 1). Starting from complex rac-1, such a reaction is first used for the regioselective introduction of an acyl sidechain to give 2 after oxidative workup. A few steps later, the nitrile rac-4 (obtained from rac-3 by complexation and separation of the diastereomeric products by preparative HPLC) is deprotonated to form the spiro addition product rac-5, from which the enone rac-6 is obtained after protonation and hydrolysis of the initially formed dienol ether. The final conversion of rac-6 into acorenone B (rac-7) efficiently proceeds over five steps and involves a diastereoselective hydrogenation of an exo-methylene group. 

An enantioselective total synthesis of (+)-ptilocaulin (79), a marine alkaloid with high antimicrobial and cytotoxic activity, was reported by Schmalz (Scheme 14) [40, 41]. The synthesis starts from anisole-Cr(CO)3, which is converted to the planar-chiral building block 74 with >99% ee by enantioselective deprotonation/silylation [42] and subsequent recrystallization. After attachment of a 2-butenyl side-chain ( 75) [43], nucleophilic addition of 2-lithio-l,3-... 

Arenechromium tricarbonyls are considerably more acidic than ferrocenes. Complexation to Cr(CO)3 allows even electron-rich ring systems such as anisole to be deprotonated by lithium amides [66]. In 1994, Simpkins showed that chiral lithium amides [83] could be used to achieve this transformation enantioselec-tively [84]. Anisole complex 125 was treated with the chiral base 83 in the pres-... 

A "cascade" reaction, the preparation of isobutyric acid dianion, was achieved by a one-pot sequence, the formation of butyllithium, deprotonation of di-i-propyl amine to LDA, then formation of the acid dianion. Quenching with benzal-dehyde gives the hydroxyacid in 78% yield. 2-Lithio-furan and -anisole were prepared and used in several synthetic reactions. some instances, it can be advantageous to replace THF by tetrahydropyran (THP), a solvent with a better stability in the presence of strong bases. 

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