Benzene derivatives lithiation

In the introduction of exp. 3 it is mentioned that lithiated acetylenes react very slowly at 70 C with dimethylfonnamide. However, lithiated benzene derivatives in most cases add very quicldy to DMF at these low temperatures. This difference in basicity may explain the specific reaction of the ortho-aryl negative center in dilithiated phenylacetylene with dimethyl-formamide. 

However, in contrast to benzene, ferrocene is sensitive to oxidation, and the ferrocenium cation, FeCpj, a paramagnetic 17-electron species, is readily formed in the presence of various oxidants. The ferrocenium cation is reluctant to undergo electrophilic substitution, and therefore reactions such as halogenation and nitration, which are important routes to substituted benzene derivatives, cannot be used for the synthesis of substituted ferrocenes. Only electrophilic substitution under nonoxidizing conditions (e.g., Friedel-Crafts acylation, Mannich reaction, borylation, lithiation or mercuration), and radical substitution are available as an entry into the chemistry of substituted ferrocenes. 

Reactivity of Some Orffco-Lithiated Benzene Derivatives... 

Benzotellurophene (R = H) is stable only in benzene solution at low temperature, but the diester and disulphonyl derivatives (obtained by the bis-lithiation and subsequent reaction with alkyl chloroformates and p-toluenesulphonic anhydride) as well as the nitroderivative are more stable. 

Klumpp and Sinnige proceeded similarly, using ec-butyl alcohol to protodelithi-ate the anisoles and other lithiated aryl ethers in di-n-butyl ether. The protodelithiation enthalpies for all the lithiated aryl ethers, as monomers, from the latter study are listed in Table 3. The reaction enthalpies for the o- and p-lithioanisoles are ca 20 kJmop more negative from Reference compared to the ones from Reference, presumably due to differences in the reaction media. From the exchange reaction, equation 17, and the enthalpies of formation of phenyl lithium, benzene and the relevant aryl ether, the enthalpies of formation of the lithiated aryl ethers can be derived. The calculated values are shown in Table 3. 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

A much more general method for acyl silane synthesis involving silyl diazo intermediates is illustrated in Scheme 1688. The lithiated derivative of trimethylsilyl diazomethane reacts smoothly with alkyl halides in THF solution to give a-trimethylsilyl diazoalkanes in good yields. Oxidative cleavage of the diazo moiety is effected using 3-chloroperbenzoic acid in benzene solution, to give access to a wide variety of acyl silanes in yields of up to 71%. A phosphate buffer (pH 7.6) is used to prevent side reactions. Aromatic acyl silanes clearly cannot be prepared by this chemistry since an aromatic nucleophilic substitution reaction would be required. 

Electrophilic Substitution Reactions of o/7/io-Lithiated Benzene and Naphthalene Derivatives... 

Certain derivatives of benzene and naphthalene can be lithiated with sec-butyllithium (sec-BuLi). This reaction is regioselective. It takes place exclusively in the ortho-position (Directed ortho Metalation, DoM) to a so-called Directed-Metalation Group (DMG), whose presence, accordingly, is a prerequisite for such a metalation. Figure 5.37 gives examples of DMGs that are bound through a C, an O, or an N atom to the aromatic compound. 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

Various bis( -arene)vanadium(0) derivatives are prepared through substitution on the arene ring. Bis( -benzene)vana-dium(O) (7) undergoes lithiation and coupling with electrophiles to give the substituted bis( -arene)vanadium compoimds, like the silyl-bridged derivative (8) (Scheme 4). ... 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

The lithiated derivative (LiCgH5)Cr(CO)3 has been prepared in high yield by the reaction of [(CO)3Cr](CaHgHgC6H5)[Cr(CO)3] with re-butyl lithium. Complexes, such as 2-phenylpyridine chromium tricarbonyl and (Ph2PCgHg)Cr(CO)3, which are not otherwise obtainable were prepared by the reaction of the lithiated derivative with pyridine and PhaPCl, respectively 348). Benzene chromium tricarbonyl has been metalated by treatment with re-butyl lithium in THF and after carbona-tion yielded w-benzoic acid chromium tricarbonyl 304). 

The third approach to obtain diarylmethylpiperazine derivatives uses the highly stereospecific chiral oxazaborolidine-catalyzed reduction, using catecholborane as the reductant of the 4-bromobenzophenone chromium tricarbonyl complex, as described by Corey and Helal [59], followed by the stereospecific displacement of the hydroxyl benzyl group by the /V-substituted-piperazine [44]. As outlined in Scheme 2, Delorme et al. [44] used this approach for the enantioselective synthesis of compound 31, (+)-4-[ (aS)-a-(4-benzyl-l-piperazinyl)benzyl]-lV,lV-diethylben-zamide. Lithiation of the readily available benzene chromium tricarbonyl with n-BuLi in the presence of TMEDA in THF at —78 °C, followed by addition of... 

A readily hydrolysable ether of a phenol is its methoxymethyl derivatives. The methoxymethyl ethers are hydrolysed in dil. HCl or by traces of pTSA in benzene. Besides ready removability, CH2OCH3 is also readily introduced. The phenols then are preferably converted into their methoxymethyl derivatives before a lithiation reaction is carried out... 

Although lithiation of hydroquinone had no useful outcome the 2-bromo derivative gave the 2-lithio intermediate by haloge-metal exchange and thence 2-methyfthio-1,4-dihydroxy benzene by reaction with dimethyldisulphide.togetherwith some hydroquinone by reduction (ref.159,160). 

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