Lithiations tert-butyllithium

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. 

Direct C-l deprotonation-lithiation occurs on treatment of the O-benzyl-ated or -silylated glycals with strong bases such as tert-butyllithium at low temperatures, and the vinyllithiums (such as 120) can subsequently be stannylated with tributylstannyl chloride.135 Otherwise, compound 121 can be produced from S-phenyl tetra-C-benzyl-l-thio-/f-D-glucopyranoside via sulfone 122 by treatment with tributylstannane and a radical initiator.132... 

This procedure consists of the synthesis of a precursor, methoxymethyl vinyl ether, an a-hydroxy enol ether, and the intramolecular hydrosilylatlon of the latter followed by oxidative cleavage of the silicon-carbon bonds. The first step, methoxymethylation of 2-bromoethanol, is based on Fujita s method.7 The second and third steps are modifications of results reported by McDougal and his co-workers. Dehydrobromination of 2-bromoethyl methoxymethyl ether to methoxymethyl vinyl ether was achieved most efficiently with potassium hydroxide pellets -9 rather than with potassium tert-butoxide as originally reported for dehydrobromination of the tetrahydropyranyl analog.10 Potassium tert-butoxide was effective for the dehydrobromination, but formed an adduct of tert-butyl alcohol with the vinyl ether as a by-product in substantial amounts. Methoxymethyl vinyl ether is lithiated efficiently with sec-butyllithium in THF and, somewhat less efficiently, with n-butyllithium in tetrahydrofuran. Since lithiation of simple vinyl ethers such as ethyl vinyl ether requires tert-butyllithium,11 metalation may be assisted by the methoxymethoxy group in the present case. 

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). 

An iterative directed-metallating approach to 4,5-substituted indoles starting from gramine was documented <05T6886>. Treatment of gramine 173 with tert-butyllithium and trimethylsilylmethylazide followed by Boc protection gave 4-aminoindole 174. Directed lithiation by the carbamate followed by treatment with DMF gave indole 175. 

Although n-butyllithium lithiated the TMEDA efficiently at a convenient rate, sec-butyllithium worked even more smoothly. Surprisingly tert-butyllithium was quite poor, although some of the problem was caused by the low-boiling solvent, pentane. For instance tert-butyl-lithium in refluxing pentane took 14 hours to completely react with TMEDA. 

In one series of experiments the a-lithiated silanes were produced by a nucleophilic addition of tert-butyllithium to the C=C double bond of a vinylhalosilane so that the 1,2-elimination led to a silene carrying a neopentyl substituent on the unsaturated carbon... 

A second major class of acyl anion equivalents are the enol ethers such as methyl 1-propenyl ether (359). When 359 was treated with tert-butyllithium (note the need for a stronger base with the less acidic vinyl hydrogen) and then condensed with benzaldehyde, the product was 260. Lithiation of vinyl derivatives was described in Section 8.5. Facile hydrolysis with aqueous acid liberated the corresponding ketone (361), completing the acyl anion equivalency. Schlosser co-workers found that a mixture of 5ec-butyllithium and potassium tert-butoxide could be used to generate the lithium anion of O-tetrahydropyranyl enol ethers.360 This modification generates a product that is more easily hydrolyzed to the ketone. 

Ruhland reported a novel solid-phase C2-lithiation of the indole ring [279] using a linker that resembled the MOM-protecting group (Scheme 16). Lithiation of resin-bound indole 73 was accomplished by treatment with tert-butyllithium in toluene followed by quenching with benzonitrile. Reductive cleavage of 74 then gave amine 75 in an overall yield of 2%, proof of principle that this type of transformation is possible. 

The lithiation of (aminomethyl)benzylsilane 1 was carried out with tert-butyllithium at -90 °C in toluene/n-pentane (Scheme 2). At -30 °C, yellow colored needles of the metalated product (/ ,5)-2 could be isolated as crystals in 80 % yield. The result of the single-crystal X-ray diffraction study is shown in Fig. 2. 

Phosphonation of poly(aryloxyphosphazenes) via lithiophenoxy intermediates was realized via addition of tert-butyllithium to a solution of the polymer in THF at -75 °C. The lithiated polymers were then treated with diphenyl chlorophosphate, and subsequent basic hydrolysis and acidification yielded phenylphosphonic groups, as shown in Scheme 26. 

A, A, iV ,A -tetramethylethylenediamine (TMEDA) and A,A,A ,iV -tetramethyl-methylenediamine are treated with 5ec-butyllithium or tert-butyllithium. n-Butylpotassium converts dimethyl ether readily to methoxymethylpotassiumJ Ethyl and methyl vinyl ether require sec- or rm-butyllithium to undergo a-metalation, whereas n-butyllithium suffices to bring about the or// o-lithiation of anisole and the a-lithiation (at the oxygen-adjacent position) of allyl phenyl ether and benzyl phenyl ether. 

Finally, even phosphine-derived ate complexes have been brought into being. Lithium bis(2,2 -biphenylene)phosphinate (65) is readily produced from (2 -bromo-biphenyl-2-yl)-2,2 -biphenylenephosphine by halogen/metal permutation and the ensuing spontaneous cyclization of the lithiated intermediate (Scheme 1-46, lower part). Alternatively, it may be obtained by converting bis(2,2 -biphenylene)phosphonium iodide first into hydridobis(2,2 -biphenylene)phosphorane and treating the latter with tert-butyllithium (Scheme 1-46, upper part). ... 

The tert-butyl carbamate ester of 4-amino-1,2-dimethoxybenzene (veratrylamine) was lithiated with n-butyllithium and carboxylated regiospedfically to afford a combined 70% yield of the 3- and the 5-carboxylic acids (20 1) while with... 

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