Lithium Compounds Benzyllithium

Lithium Compounds Benzyllithium, 56 t-Butyl lithiopropionate, 252 Butyllithium, 56, 94, 150, 157, 165,... 

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

The effect of a 3-substituent on the orientation of the addition of alkyl- and aryl-lithium compounds is interesting and salient results appear in Table 23. Attack at C-2 is favoured over that at C-6 unless either, or both, the C-3 substituent and the attacking alkyl group are very large. Reaction of isopropyllithium with 3-methylpyridine does not follow this trend. Benzyllithium is anomalous in that it attacks preferentially at C-4. A study of the relative rates of these alkylations revealed the remarkable fact that a 3-methyl or 3-ethyl group activates the 2-position (but not the 6-) towards attack by phenyllithium but not methyllithium. However, a 3-isopropyl and 3-cyclohexyl group deactivates C-2 relative to... 

Fig. 13. The reaction of 1,1-diphenylethylene with various lithium compounds in tetrahydrofuran. Variation of rate with formal concentration of lithium alkyl or aryl. (A) n-Butyllithium ( ) benzyllithium (- ) allyllithium (o) methyllithium ( ) vinyl-lithium (0) phenyllithium. Solvent tetrahydrofuran [101].

The (Z)- or (E)-phenylhexenyl carbamates 172 are smoothly deprotonated by s-BuLi/(-)-sparteine, and the lithium compound cyclizes during approximately 20 h at -78°C to form the (cyclopentyl)benzyllithium 173 which is in equilibrium with its epimer 174 [Eq. (45)] [110]. Trapping this mixture yields the essentially enantiomerically and diastereomerically pure side-chain substituted fra s-2-benzylcyclopentyl carbamates 175 in fair yields. Some of the intermediate 174 is lost due to 1,3-elimination resulting in formation of the achiral bicycle [3.1.0] hexane derivative 176 [111, 112]. Related results have been reported by Nakai et al., when allowing the ( )-6-phenylhex-5-enyl Md f-diisopropylcarb-amate to react under similar conditions [111]. 

A benzyl radical pathway as opposed to the intermediacy of benzyllithium cannot be ruled out a priori. However, the /t-tolyl/phenyl migration rates argue against this. Furthermore, the Elcb-like benzylmetal-generating bond scission is especially privileged with lithium compounds. Concerted aryl [l,2]-migration becomes competitive with potassium and dominant with cesium analogs. ... 

The reactions of a benzylzinc chloride TMEDA adduct with either benzyllithium or benzyl(trimethylsilyl)lithium TMEDA adduct yielded both homoleptic dibenzylzinc (37, Figure 16) and heteroleptic monobenzylzinc compounds as TMEDA adducts. The heteroleptic diorganozinc compounds do not disproportionate as long as TMEDA is present, but removal of the chelating nitrogen ligand in the gas phase does cause disproportionation. 

A number of cycloalkyl-, vinyl-, aryl-, and benzyllithium compounds (predominantly benzyl-lithiums) are converted into fluoro derivatives in good to excellent yields, e.g. formation of 4, 5, and 6 19 however, when this method was applied to the synthesisof 3-fluorobenzocyclobutene from the lithium salt a violent explosion occurred when the reaction mixture was warmed from — 70 C to room temperature.20 Various fluoro-substituted thiophenes 7 are obtained when the starting compounds (thiophene, 2-methylthiophene, etc.) arc transformed with al-kyllithium compounds to the corresponding lithium derivatives then fluorinated with perchloryl fluoride at 0 C.21 Potassium tricyanomethanidc is converted at —15 C in triglyme into tricyanofluoromethane in 81 % yield.22... 

Volume 8a of the Science of Synthesis series has reviewed the synthesis and applications in organic synthesis of the following organolithium compounds alkyl- and cycloalkyl-lithium,49 alkenyllithium,50 allyllithium,51 benzyllithium and (lithiomethyl) hetarenes,52 /-i-liihiocarboxylic acids and related compounds,53 and bis(organosulfan-yl)- and bis(organoselanyl)-methyllithium compounds.54... 

Exceptions are the few secondary benzyllithiums which show configurational stability on the microscopic (but not macroscopic) timescale - in other words, they racemise slower than they react with electrophiles, though they still cannot be maintained in stereoisomerically pure form for periods of minutes or more. These are the carbamates 288 and the sulfones 289, discussed in sections 5.1.4 and 5.I.7.6 It is significant that both of these compound classes contain powerful lithium-coordinating oxygen atoms, which may hold the lithium counterion close to one face of the benzylic system.134-120... 

The benzophenonedilithium compound 50, formed by reduction of benzophenone with lithium metal, crystallizes as a dimer (69). The four lithium atoms in the structure are divided into two different sets. The two benzophenone moieties are bridged, through the carbonyl oxygen atoms, by two symmetry-equivalent lithium atoms. Each of the two other lithiums is bonded to one phenyl ring and the ketone functionality reminiscent of that observed in benzyllithium (29), dilithiodibenzyl ketone (42), and dilithiodibenzylacetylene (49). The two different types of lithium atoms are complexed further to THE and TMEDA. 

The preparation of benzyllithium from benzyl halides and alkyllithiums is not feasible because the benzyllithium initially formed reacts with the starting benzyl halides, producing 1,2-diphenylethane. Metalation of toluene with n-BuLi in the presence of TMEDA at 30 °C results in a 92 8 ratio of benzyllithium and ring metalated products. Metalation of toluene with n-BuLi in the presence of potassium rert-butoxide, and treatment of the resultant organopotassium compound with lithium bromide, affords pure benzyllithium in 89% yield. Alternatively, benzyllithiums are accessible by cleavage of alkyl benzyl ethers with lithium metal. " ... 

Compounds of Group 1. - (6Li, 15N) and (6Li, 13C) couplings were observed for mixed complexes formed between LiCH2CN and chiral lithium amides (1H, 6Li, 13C, 15N data).1 7Li and 31P H) HMQC experiments were used to assign the structures of benzyllithium complexes of /V-methyl-/V-ben-zylphosphinamide, e.g. (I).2 111 and 13C NMR and 13C-111 correlation spectra were used to confirm the presence of a C-Si-Ni-Li 4-membered heterocycle in [benzylbis(dimethylamino)-methylsilyl-K2-C,7V](7V, N, N, N -tetramethylenedia-mine-K2-iV,/V)lithium(I).3... 

Synthetic Application of (Benzyllithium —TMED A and Benzyl-lithium—TED. All the synthetic application studies were run with an aged (benzyllithium)2-TMEDA toluene solution that had 0.8% of the total organolithium compounds present as the tolyllithium isomers (only meta present) or with benzyllithium-TED crystalline complex free of ring isomers. 

The discovery of the powerful metalating agent, n-BuLi-N,N,N, N -tetramethylethylenediamine, opened a new chapter in anionic grafting. This complex has been reported to metalate toluene and benzene within a few minutes to give quantitative yields of benzyllithium and phenyl-lithium, respectively (4). It also has been reported to polylithiate aromatic compounds (24, 25). 

Further lithiation, however, seems to take place by a different mechanism. Among the disilyl compounds, only ortho and para trimethyl-silyl isomers are obtained (Scheme 4). To account for this shift in isomer preference, West and Jones suggest that the high negative charge present in the benzyllithium causes a change in mechanism to one in which electrophilic attack on the carbon by the positive lithium predominates... 

Two different reaction conditions for the synthesis of the diastereomerically enriched benzyllithium compounds have been used in the study a kinetically controlled route, diastereotopos-differentiating deprotonation at low temperatures, mostly observed in nonpolar solvents (e.g. in toluene, n-pentane) or a thermodynamically controlled route, epimerization between two diastereomeric lithium alkyls at higher temperatures, mostly observed in polar solvents (e.g. in THF) (Scheme 1). 

Polar solvents such as ethers and amines react with organometallic initiators, as well as propagating polystyryl and polydienyl carbanions, to decrease the concentration of active centers (21-23). The rate of reaction with ethers decreases in the order Li > Na > K. For example, dilute solutions of poly(styryl)lithium in tetrahydrofuran (THF) at room temperature decompose at the rate of a few percent each minute. Alkyllithium initiators also react relatively rapidly with ethers the order of reactivity of organolithium compoimds with ethers is tertiary RLi > secondary RLi > primary RLi > phenyllithium > methyllithium > benzyllithium (21). An approximate order of reactivity of ethers toward alkylithium compounds is dimethoxyethane, THF > tetrahydropyran> diethyl ether> diisopropyl ether. Tertiary amines can also react with alkyllithium compoimds. The importance of these reactions can be minimized by working at lower temperatures (eg, <0°C) it is also advisable to use only the minimum amounts of ethers and other Lewis bases required as additives. 

Numerous examples exist in which TMEDA not only facilitates the lithiation of aromatic and heteroaromatic substrates but also controls the regioselectivity of lithiation. While tertiary ben-zamides are susceptible to nucleophilic attack by n-butyllithium to give aryl butyl ketones, the use of s-ButyllithiumnMEDA in THF at —78 °C provides the synthetically useful ortho metalated tertiary benzamide which may be treated with a large variety of electrophiles (eq 4). Even with compounds having a second more acidic site the above conditions allow ortho lithiation to take place under kinetic control. Thus a p-toluamide is ortho lithiated with s-butyllithium/TMEDA in THF at —78 °C, but when Lithium Diisopropylamide is used as the base in THF at 0 °C the thermodynamically favored benzyllithium species is obtained (eq 5). The very marked influence of TMEDA on the lithiation of naphthyl methyl ether in hydrocarbon solvents is dramatically illustrated in the example in eq 6. ... 

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