Ortho metalation with BuLi

Methoxy-substituted aromatic compound 4 is lithiated metalation with Buli in THF, a step in which it proves useful to include lithium chloride. Because of the greater basicity of /t-butyllithium relative to 4. direct metallation is in fact possible thermodynamically, but /i-butyllithium is generally present in solution as a tetra-mer, and this reduces its reactivity. Addition of lithium chloride destroys these aggregates, and that eliminates the kinetic inhibition. Lithiated aromatic species 18 is further stabilized through chelate formation between lithium and the orr/icr-methoxy groups (ortho effect).8... 

Slocum and co-workers (18) recently examined the effect of TMEDA on directed metalation reactions. N,N-Dimethylbenzylamine, /3-phenyl-ethyldimethylamine, N,N-dimethylaniline, and anisole, all known to undergo ortho metalation with BuLi but at a relatively slow rate, were each lithiated under conditions similar to those previously reported, except that one equivalent of TMEDA was added to each metalation reaction. In three cases, the metalation rate was increased significantly with only a slight loss in overall yield. These workers also found that the site of ring metalation with p-methoxy-N,N-dimethylbenzylamine can be reversed by using TMEDA. 

The trilluoromethyl group behaves in a similar way , but it is now clear that deprotonation of sites ortho to such acidifying but non-coordinating and non-electrophilic substituents is best carried out with BuLi-KOBu-t superbases (see Section VI). A combination of BuLi metallation and superbase metallation of fluoroarenes has been used in the synthesis of components 163 and 164 for fluorinated liquid crystals (Scheme 82). ... 

The ethers PhOBu-t and PhOMe are of equal reactivity despite the differences in steric hindrance to RLi. Steric retardation however, is, observed for o-substitutions to OMe in o-MeOCeH4Bu-t ", but not o-MeOCgH4Me (using n-BuLi, t-BuLi or n-BuLi-TMED). The site of lithiation of p-MeOCgH4CH2NMe2 depends on reaction conditions. Metallation with the (n-BuLi)g aggregate, a good electron-pair acceptor acid, occurs ortho to CHjNMe 2 (kinetic-controlled product), a consequence of coordination of n-BuLi to NMcj in contrast the monomeric n-BuLi-TMED complex, a poor... 

Ortho-Metallation of Hetero-Substituted Benzenes and Naphthalenes with BuLi TMEDA in Hexane... 

Ether groups exert their ortho-directing action in the metallation of aromatic rings mainly via their electron-withdrawing inductive effect. Methoxybenzene has been lithiated with BuLi in Et20 or THF. The metallation in the latter solvent can be carried out in a reasonable time (2-3 h at 20 °C), but part of the butyllithium is consumed by reaction with the solvent, unless a considerable excess of anisole is used. The activating influence of two methoxy groups in 1,3-dimethoxybenzene renders the metallation easier. 

Afefa-methoxy phenyloxazoline and secondary and tertiary benzamides 10 are deprotonated at the C2 position by -BuLi and s-BuLi/TMEDA [107,108], whereas metalation occurs exclusively ortho to the methoxy with a-ethoxyvinyllithium/HMPA [109]. These observations indicate that the directing effect of the DMGs result from both kinetic (coordination) and thermodynamic (acidity) factors. 

Depending on the base used, there is possible competition between ortho and lateral metalation. i-BuLi/TMEDA reacts irreversibly with 4-methyl-iV,lV-diisopropylbenzamide 59 ortho to the amide DMG under kinetic control (CIPE mechanism) to give 60 by trapping with MeOD [108], whereas LDA affords 61 via the thermodynamically more stable benzylic anion (Scheme 26.17). The regioselectivity observed is dependent on many factors (nature of the base, presence of additives, temperature, solvent, etc.). 

Fluorobenzothiophene derivative 68 was prepared in 44 % yield starting from 4-(methylthio)-l-(trifluoromethyl)benzene 65 by double metallation with n-BuLi and subsequent reaction with CO2. The primary intramolecular cycUza-tion of 66 was anchimerically assisted by the carboxylate anion in ortho position and gave rise to a nucleophilic substitution of the fluorine atom by the SCH" anion. The resulting intermediate 67 aromatized after acidification into 3-fluorobenzo[b]thiophene 68 [40]. 

Concerning the yldiide Ph3P=CH-Li, the question as to whether it could be obtained by direct lithiation of the ylides 23 (Y=H), for a long time in debate between Schlosser and Corey, could have found an answer. Effectively NMR studies seem to show that a directed ortho-metallation occurs on an aromatic ring when 23 is reacted with t-BuLi [65], leading thus to the formation of 24 whose evolution does not afford Ph3P=CH-Li (Scheme 13). 

Deprotonation of 3-fluorotoluene 623 with n-BuLi—KOBu-f or, better, f-BuLi—KOBu-f follows the selectivity expected with these superbases and leads to metallation at the least hindered position ortho to the fluoro substituent. Trapping the metallated intermediate 624... 

The degree of 4-lithiation with n-BuLi can be increased by the presence of 3-substituents that favor ortho lithiation [68JCS(C)172 76JCS(P1 )994], but in no case has exclusive 4-metalation been seen. However, clean metalation at C-4, even in the presence of C-5 alkyl substituents, can be achieved by the use of halogen-metal exchange reactions (Scheme 73), and both bromo and iodo derivatives have successfully been used for... 

Under n-BuLi or scc-BuLi conditions, 4-pyridyl oxazoline 411 behaves differently than the 3-isomer to give mixtures of ortho metalation (412) and addition (413) products, the latter type having been trapped upon workup by Mel treatment before its oxidation (Scheme 127) (78TL227 82JOC2633). However, if metalation is carried out with MeLi at -78°C and... 

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. 

In the case of phenyl isocyanide, both the addition of f-BuLi and an ortho lithiation took place in the presence of TMEDA to provide the intermediate 53 and finally compounds 54 and 55 (Scheme 15)75. The corresponding 3-metalloindolines (metal = S, P, Si, Ge, Sn) were obtained by reaction of the dilithium intermediate 53 with metal dihalides. The obtained benzazaphospholes and benzazarsoles 54 (M = f-BuP, MeAs) can be converted into the aromatic III-1,3-benzazaphospholes and benzazarsoles 55 by flash vacuum pyrolysis76. 

Metallation of O-aryl carbamates.3 O-Ary 1 carbamates are metallated by sec-BuLi-TMEDA at the ortho-position. Metallation followed by reaction with an electrophile offers an attractive route to -substituted carbamates and phenols. 

The total synthesis of the potent protein kinase C inhibitor (-)-balanol was accomplished by J.W. Lampe and co-workers. They took advantage of the anionic homo-Fries rearrangement to prepare the sterically congested benzophenone subunit. To this end, 2-bromo-3-benzyloxy benzyl alcohol was first acylated with a 1,3,5-trisubstituted benzoyl chloride to obtain the ester precursor in 84% yield. Next, the ester was treated with n-BuLi at -78 °C to perform a metal-halogen exchange. The resulting aryllithium rapidly underwent the anionic homo-Fries rearrangement to afford the desired tetra ortho-substituted benzophenone in 51% yield. 

Directed ortho lithiation of 2-, 3-, and 4-pyridyl diethylcarbamates provides a route to a variety of polysubstituted pyridines. The 2- and 4-pyridyl carbamates are metallated at C-3, whereas the 3-pyridyl carbamate is lithiated at C-4. For example, 3-pyridyl diethylcarbamate (118) on treatment with sec-BuLi/TMEDA/THF (TMEDA = N,N,A, Af -tetramethylethylenediamine) at — 78°C followed by McjSnCI gives 3,4-disubstituted pyridine 120 in 83% yield via lithiated intermediate 119. On warming, the metallated pyridyl... 

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