Lithium bromide reaction with ethers

Lithium bromide-Boron trifluoride etherate. Aliphatic ethers can be cleaved by reaction with lithium bromide and boron trifluoride etherate in acetic anhydride at room temperature for 30 hrs. Methoxycyclohexane, for example, is converted into a 7 1 mixture of acetoxycyclohexane and cyclohexene. Saturated steroid ethers are cleaved to mixtures of enes and acetates under these conditions choles-teryl methyl ether gave about equal parts of cholesteryl acetate and cholesteryl bromide. However, Narayanan reports that the lithium halide is not essential and indeed often detrimental. Thus cholesteryl methyl ether treated with boron trifluoride etherate and acetic anhydride in ether at 0° (14 hrs.) gave cholesteryl acetate in 93% yield. 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

The first example of chemically induced multiplet polarization was observed on treatment of a solution of n-butyl bromide and n-butyl lithium in hexane with a little ether to initiate reaction by depolymerizing the organometallic compound (Ward and Lawler, 1967). Polarization (E/A) of the protons on carbon atoms 1 and 2 in the 1-butene produced was observed and taken as evidence of the correctness of an earlier suggestion (Bryce-Smith, 1956) that radical intermediates are involved in this elimination. Similar observations were made in the reaction of t-butyl lithium with n-butyl bromide when both 1-butene and isobutene were found to be polarized. The observations were particularly significant because multiplet polarization could not be explained by the electron-nuclear cross-relaxation theory of CIDNP then being advanced to explain net polarization (Lawler, 1967 Bargon and Fischer, 1967). 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

The combination of equimolar amounts of tris(trimethylsilyl)methyllithium and zinc bromide in a THF/diethyl ether mixture, Scheme 27, furnished tris(trimethylsilyl)methylzinc bromide, as a lithium bromide/ether adduct.43 The compound, which may also be formulated as a lithium alkyldibromozincate, showed no ligand redistribution reactions. It is monomeric in solution and can be treated with 1 equiv. of an organolithium reagent to afford heteroleptic diorganozinc compounds. 

Precursors for this task were obtained by addition of /-butylmagnesium bromide to the central bond of [1.1.1 ]propellane 40a followed by conversion of the 3-f-butylbicyclo[ 1.1.1 Jpentyl-1 -y 1-magnesium bromide (88) into the ketones 89 by standard methods.27 Reaction of ketones 89 with tosyl hydrazide afforded the hydrazones 90, which gave the corresponding lithium salts 91 by reaction with MeLi in ether. These salts were dried under high vacuum and then pyrolized at 4 x 10 5 torr in the temperature range of 100-130°C and the volatile products condensed in a liquid nitrogen-cooled trap. 

The beneficial effect of added phosphine on the chemo- and stereoselectivity of the Sn2 substitution of propargyl oxiranes is demonstrated in the reaction of substrate 27 with lithium dimethylcyanocuprate in diethyl ether (Scheme 2.9). In the absence of the phosphine ligand, reduction of the substrate prevailed and attempts to shift the product ratio in favor of 29 by addition of methyl iodide (which should alkylate the presumable intermediate 24 [8k]) had almost no effect. In contrast, the desired substitution product 29 was formed with good chemo- and anti-stereoselectivity when tri-n-butylphosphine was present in the reaction mixture [25, 31]. Interestingly, this effect is strongly solvent dependent, since a complex product mixture was formed when THF was used instead of diethyl ether. With sulfur-containing copper sources such as copper bromide-dimethyl sulfide complex or copper 2-thiophenecarboxylate, however, addition of the phosphine caused the opposite effect, i.e. exclusive formation of the reduced allene 28. Hence the course and outcome of the SN2 substitution show a rather complex dependence on the reaction partners and conditions, which needs to be further elucidated. 

Ethyl (2Z)-3-bromopropenoate. To a three-necked, round-bottomed flask are added lithium bromide (10.0 g, 0.115 mol, Note 1), acetonitrile (100 mL, Note 2), acetic acid (7.0 g, 0.116 mol, Note 3), and ethyl 2-propynoate (9.0 g, 0.092 mol, Notes 4, 5) under nitrogen. The reaction is carried out with magnetic stirring under reflux and monitored by GLC (Note 6). The reaction is complete after 24 hr. The reaction is cooled, water (20 mL) is added to the flask, and the mixture is cautiously neutralized with solid potassium carbonate, added in portions (Note 3). The organic layer is separated, and the aqueous layer Is extracted with ether (3 x 20 mL) (Note 3). The combined organic layers are dried with magnesium sulfate and filtered. After removal of the solvent, ethyl (2Z)-3-bromopropenoate is obtained by vacuum distillation (14.0 g, yield, 85%, Note 7). 

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