Tert-butyllithium, reaction with

Metalated epoxides can react with organometallics to give olefins after elimination of dimetal oxide, a process often referred to as reductive alkylation (Path B, Scheme 5.2). Crandall and Lin first described this reaction in their seminal paper in 1967 treatment of tert-butyloxirane 106 with 3 equiv. of tert-butyllithium, for example, gave trans-di-tert-butylethylene 110 in 64% yield (Scheme 5.23), Stating that this reaction should have some synthetic potential , [36] they proposed a reaction pathway in which tert-butyllithium reacted with a-lithiooxycarbene 108 to generate dianion 109 and thence olefin 110 upon elimination of dilithium oxide. The epoxide has, in effect, acted as a vinyl cation equivalent. 

However, reaction of 218 (E = P, R = R = H, R = r" = Me) with rerr-butyl-lithium most probably yields 221. The phospholyl loses its electrophilicity and the iron atom bears a considerable negative charge. Addition of rerr-butyllithium (one equivalent) followed by methyl iodide (one equivalent) does not give any isolable product but leads to recovery of the starting 218 only. In excess tert-butyllithium and methyliodide, 222 (R = r-Bu, R = Me) was isolated (81IC3252). 

Treatment of sulfmylaziridine 73 (Scheme 3.23) with MeMgBr and then with tert-butyllithium gave aziridinyllithium 74, which reacted with ethyl chloroformate to afford aziridine-2-carboxylate 75 in 64% yield [70]. The reaction was stereospecific, giving 75 as a single diastereomer. 

Reaction of N-(2-bromoallyl)-N-prop-2-ynylamines 72 with tert-butyllithium, followed by reaction with zirconocene methyl chloride and subsequent cyclization gives 1,1-lithio-zirconioalkenes 73 via 74 and intermediate 75 (Scheme 7.23) [144,145], Treatment of the lithiozirconium complex 73 with deuterated sulfuric acid leads to the trideuterated pyrrolidine 76. 

The synthetic usefulness of reactions of lithiated methoxyallene 42 with suitable electrophiles was demonstrated by several syntheses of bioactive natural products or substructures thereof [52-58]. An interesting application was described by Fall et al. [52] after addition of alkyl iodide 55 to lithiated methoxyallene 42, deprotonation by tert-butyllithium and addition of carbon dioxide occurred at the terminal y-carbon and thus provided butenolide 57 after acidic workup. Desilylation of this intermediate with TBAF finally gave bicyclic oxepane derivative 58 in good overall yield (Scheme 8.14). 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

Although the preparation of the substituted allene ether substrates for the Nazarov reaction is not the topic of this chapter, it is necessary to mention a few aspects of their synthesis. Lithioallene 1 (Eq. 13.13) can be trapped with chlorotri-methylsilane to give 35 [6]. Exposure of 35 to sec- or tert-butyllithium leads to allenyl-lithium 36, which can be trapped with alkyl halides or other electrophiles to give 37. Desilylation of 37 leads to 38. This is somewhat laborious, but it leads to allene 38 uncontaminated by propargyl ether 39. Exposure of 39 to n-butyllithium, followed by quenching with acid, typically produces mixtures of 38 and 39 that are difficult to separate. Fortunately, one need not prepare allenes 38 in order to access the C6-sub-... 

The germaallene 194 was prepared by reaction of fluoroalkynylgermane 195 with tert-butyllithium at -78°C in about 85% yield.174 Elimination of LiF occurred at low temperature. 194 was the first allenic compound of germanium structurally characterized (Scheme 41). 

Self-condensations are another set of important reactions of organolithium compounds. Tamao and Kawachi had reported that [(tert-butoxy diphenyl)silyl]lithium (20) exhibited ambiphUic character, and underwent a self-condensation reaction to give a [2- tert-butoxy)disilynyl]lithium derivative in THF as shown in Scheme 4, and also a nucleophilic substitution reaction with n-butyllithium . 

General. All reactions were performed under nitrogen. H NMR and NMR spectra were recorded in ppm (5) on a 300 MHz instrument using TMS as internal standard. Elemental analyses were performed by Robertson Micolit Laboratories. Anhydrous THE, toluene, and tert-butyllithium in pentane (1.7 M) were purchased. Flash chromatography was performed with silica gel 60 (230-400 mesh). Melting points were determined and are uncorrected. 

Difluorovinyllithium was prepared in high yield via reaction of 1,1-dif-luoroethylene with sec-butyllithium in THF and ether (80/20) [120,121] or tert-butyllithium [122] in pentane and ether at -110°C (Scheme 44). 

The synthesis of FQ (Fig. 20) is simple and quite economical, which renders FQ attractive for the development of an antimalarial drug intended for use in areas, concerned by malaria, that are mostly overlaying with low-income countries. FQ was obtained starting from the commercially available AQV-dimethyl-1-ferrocenylmethanamine. The ferrocenic aldehyde results from a C-C bond formation, a two-step sequence involving metallation with tert/o-butyllithium and a reaction with DMF. This step has been previously studied and the 1,2 orientation of the two substituents of the cyclopentadienyl has been unambiguously established [125], The aldehyde is converted to the corresponding oxime, which is then reduced to the primary amine. The SNat reaction between the amine and 4,7-dichloroquinoline leads to the desired FQ [121]. 

The first cyclophyne, incidentally, for which this name was also coined, was 1-cyclophyne (140), generated as a highly reactive intermediate from the vinyl chloride 139 by treatment with tert-butyllithium and heating of the resulting organolithio intermediate. Not surprisingly, 140 is unstable under the reaction conditions and trimerizes (inter alia) to trifolia-phane (141, Scheme 31) [80]. 

The optional site selective metallation of fluorotoluenes158 with the superbasic mixture of butyllithium and potassium fert-butoxide has been applied to the synthesis of the anti-inflammatory and analgesic drug Flurbiprofen.171 3-Fluorotoluene is selectively metallated in the 4-position with LIC-KOR in THF at — 75 °C to afford, after reaction with fluorodimethoxyborane and hydrolysis, the corresponding boronic acid in 78% yield. A palladium-catalyzed coupling with bromobenzene gives the 2-fluoro-4-methylbiphenyl in 84% yield. This four-step sequence can also be contracted to a one-pot procedure with an overall yield of 79%. A double metallation with the superbasic mixture lithium diisopropylamide/potassium tert-butoxide (LIDA-KOR)172 173 is then required to produce flurbiprofen. 

Jin and Fuchs reported that vinyl sulfones, using basic phase-transfer catalyst conditions, were regiospecifically alkylated at the a-position.78 No P-elimination products were observed in systems capable of undergoing anion-promoted P-elimi-nation. He also reported that y-methoxy vinyl sulfones 116 can be converted to the corresponding substituted enones 119 using this protocol (Scheme 32).79 On reaction with tert-butyllithium, 116 is converted to the y-methoxy allylsulfonyl anion 117, which was regiospecifically trapped by a variety of electrophiles to provide the enol ether 118. On hydrolysis the -substituted enone 119 was obtained. 

As shown in Equation (83), 2-iodobenzo[ ]furan was also prepared by reaction of benzo[, ]furan 82 with tert-butyllithium in ether at -78 °C, followed by reaction with iodine <2002JOC7048>. 

Question 13.4 Attempts to make the tert-butyl compound ThCp 2(CMe3)2 by the reaction of ThCp 2Cl2 with tert-butyllithium were unsuccessful, the hydride ThCp 2H2 Cp 2Th(H)(/u.-H)2Th(H)Cp 2 being obtained. Suggest why. 

Fig. 2. CIDNP during the reaction of tert.-butyllithium with n-butylbromide...

While some of the aforementioned transformations of 3 and its derivatives are in a way similar to those described earlier e.g. in the adamantane series), a number of reactions of 3 have little precedence. For example, it was truly surprising to discover that 3 turned out to be very reactive towards dichlorocarbene. As a result, the respective dichloromethyl derivative 29 can be formed in a very good yield under conventional conditions of phase transfer generation of dichlorocarbenes. Subsequent treatment of adduct 29 with tert-butyllithium leads to cyclopropadodecahedrane 30. Thus, the formation of 30 from 3 implies the sequence of two consecutive C-H insertions of carbene-like species (Scheme 4.7). 

We investigated this lithiation reaction with sec- and tcrr-butyllithum and higher regioselectivity was attained with i ec-butyllithium (2a 2b = 98.5 1.5) (with tert-butyllithium 2a 2b = 96 4). The diastereoselectivity was measured by H NMR analysis after treatment of the lithioferrocene 2 with trimethylchlorosilane [1]. Lithiation of (R)-l with i ec-butyllithium in ether and subsequent iodination with iodine in THF gave (R)-M,iV-dimethyl-l-[(5)-2-iodoferrocenyl]ethylamine (3) (82% yield, 97% de) (Scheme 3-3). Optically pure 3 (the precursor of 2a) could be obtained by recrystallization from acetonitrile m.p. 79 °C, [a]o = 9.32 (c = 1.01, EtOH). 

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