Benzyllithium intermediate

The naphthalene-catalyzed (2.5%) lithiation of phthalan 330 (or its substituted derivatives ) in THF at room temperature allowed the preparation of the functionalized benzyllithium intermediate 331, which reacted with electrophiles at —78°C to give, after hydrolysis, the corresponding functionalized benzyl alcohols 332 (Scheme 97). When carbon dioxide was used as the electrophilic reagent, the corresponding 5-lactone was directly obtained . When carbonyl compounds were used as electrophiles, the cyclization of the resulting products 332 under acidic conditions (85% H3PO4) allows the synthesis of substituted isochromans. 

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). 

Cyclohexanone Annulation. The benzyllithium intermediates formed by metalation of o-toluamide derivatives with LDA at —78°C react with 1-trimethylsilyl-l-phenylthioethylene. The resulting adduct anions undergo intramolecular cyclization on to the adjacent amide moiety to provide a convenient route for cyclohexanone annulation (eq 6). ... 

Lithium A number of Michael-type additions of organolithiums have been described. This is also the case of the reaction of aryllithiums with nitroalkene (389). Deprotonation of the benzylic fluoride (455) with LDA, directed by the neighbouring sulfoxide group, generated the benzyllithium intermediate (456), which underwent addition to the Michael acceptor R CH=CHY (Y = CO2BU, S02Ph R = Ar, alkyl, alkenyl) in a diastereoselective manner controlled by the chiral sulfur to afford the 5yn-configured product (457) with <99 1 dr ... 

A related isomerization, that of phenylacetylcobalt carbonyl to o-toluyl-cobalt carbonyl, has recently been studied (143). It also appears to proceed via a tricarbonyl but could not proceed via Eqs. (9) and (10). This rearrangement has much in common with the so-called abnormal reactions of benzyl Grignard and benzyllithium reagents to produce ortho-substituted products (13, 13f). It is possible that a cyclic intermediate similar to that postulated in the Grignard rearrangements may be involved, Eq. (87). 

With sulfides as intermediates, alkenes can be used as precursors to organolithiums with regioselectivity in the formation of 56 determined by whether a radical11 or polar73 thiol addition is employed. Easy lithiation of phenyl benzyl sulfide 57 makes substituted benzyllithiums such as 58 readily available.73 Reductive C-S cleavage is probably the best way of making benzylic organolithiums. 

Similar results were obtained with the secondary benzyllithium 44, which reacted with MeOD with retention and with MeOTf with inversion. A similar cyclisation with departure of chloride also proceeds with inversion,41 but rearrangement reaction described below has a similar intermediate 59 which reacts with retention. 

The high yyw-selectivity seems to be independent of the stereochemistry of the starting material, since the use of 39Z also resulted in the preferential formation of the svn-isomer in a similar ratio. To explain this, the authors proposed 5-membered cyclic benzyllithium species having a. sy 2-like carbon to which two lithium atoms coordinate from both upper and lower sites as shown in 43 (Scheme 18). Such a dilithiated species would selectively react with electrophiles from the opposite site of the O—Li substituent. Another intermediate, 44, in which the benzylic lithium is coordinated with the heteroatom, may also be considered53. Both intermediates are likely, since in each of them the steric hindrance between the phenyl group and the alkyl group is minimal. Assuming that the reaction with... 

Trying to carry out 3 -exo carbolithiation reactions with the tertiary benzyllithium 147, generated by selenium-lithium exchange, Krief and Barbeaux have reported66 an isolated example of the reaction of this homoallylic lithium reagent with ethylene and further intramolecular carbolithiation reaction of intermediate 148 onto the suitably positioned carbon-carbon double bond. The resulting 1,3-dimethyl-l-phenylcyclopentane was isolated in modest yield and as a 1 1 mixture of diastereoisomers (Scheme 41). 

The stereochemistry of the reaction products is dependent on the nature of the a-sulfinyl carbanion. Thus (i) its kinetic acidity, controls the stereochemistry of the organometallics initially formed (ii) its thermodynamic acidity defines the stereochemistry or the conformation of the intermediate organometal-lic and (iii) reactivity of the organometallic towards the electrophile controls the stereochemistry of the product. The alkylation reaction has proved to be far more selective than is the metallation. Therefore the contribution of kinetic acidity can be neglected because the carbanion in THF has sufficient time to reorganize into its most stable conformation before it reacts with an electrophile. The a-sulfinyl benzyllithiums produced from S(srd) and S(r -(2) should adopt the more stable conformations shown in... 

Allyl- and benzyllithiums. Wurtz coupling of the halides is avoided during formation of the organolithium reagents, when they react with BuTeLi (from Te -F BuLi) and then BuLi. The one-pot process involves RTeBu intermediates. 

In our synthetic investigations we have noticed considerable differences in reactivity of the various types of polar organometallic intermediates towards alkyl halides and epoxides. Exceptionally high alkylation rates were observed in reactions of benzyllithium (or potassium) and allyllithiums (or potassium) with primary alkyl bromides in mixtures of THF and hexane. Under preparative conditions (concentration of reagents 0.5 to 0.8 mol/liter) the characteristic orange colour of benzylalkali solutions disappeared completely within a few seconds upon addition at — 90 °C of a slight excess of alkyl bromide. The allylic intermediates reacted with comparable ease. 

The solution of benzyllithium (containing 10% of ring-lithiated intermediates, which give no coupling product with cyclohexyl bromide) is cooled to — 40 °C and cyclohexyl bromide (0.08 mol, I3.0g) is added over a few min. The cooling bath is then removed and the temperature allowed to rise to 0 °C. After the usual work-up the product (b.p. 117°C/12mmHg, nD(20) 1.5179) is isolated in 60% yield by careful distillation. 

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]. 

With this acetal, instead of hydrolyzing the intermediate benzyllithium, one can let it warm to room temperature, and an internal nucleophilic substitution takes place, whereby the acetal moiety behaves as a leaving group, and a trans-disubstituted cyclopropane is formed in 60-70% yield [39,41]. The first-formed stereogenic center remains unaffected in this second step, whereas the benzylic lithiated carbon is able to epimerize [38,39], leading to the more stable trans-cyclopropane [42-44] (Scheme 20). 

Reverting to the simple phenylated substrate of Scheme 33, if the styryl moiety is orf/jo-substituted by a phenyldimethylsilyloxy group, the 5-exo-trig cych-zation is now followed by a retro-[ 1,4]-Brook rearrangement. Whatever the ( ) or (Z) configuration of the styryl group, the intermediate benzyllithium epimer-izes, and a pentacoordinated silicon allows transfer of the silicon moiety diaster-eoselectively to form a unique C-silylated adduct (er>98 2, dr>99 l) [59] (Scheme 35). 

A soln. of ( -methoxyphenyl)lithium (prepared in THF from anisole and 1.7 M -butyllithium in cyclohexane) stirred at room temp, overnight, treated with 0.5 eqs. Mg-2-ethoxyethoxide at 5°, stirred at room temp, for 1 h, cooled in ice, 1 eq. di-methylformamide added, the mixture stirred at bath temp, for 1 h, then at room temp, for 2 h, benzophenone (as oxidant) added, and stirring continued overnight - N,N-dimethyl-o-methoxybenzamide. Y 71%. The Mg-alkoxide functions by stabilizing the intermediate 1-aminoalkoxide and as a catalyst in the Oppenauer oxidation. F.e., incl. reaction of -BuLi, 2-lithiofuran, 2-lithiomethylpyridine, and benzyllithium, also from diorganomagnesium compds., s. C.G. Screttas, B.R. Steel, J. Org. Chem. 53, 5151-3 (1988). 

In general, in the reaction of benzyl halide with lithium, the yield of benzyl-lithium is low since the Wurts coupling reaction proceeds. How ever, with the addition of ketones to this reaction system and ultrasound irradiation, Barbier reaction then proceeds. It is believed that this reaction yields benzyllithium as an intermediate and the benzyllithium reacts with ketone [23]. 

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