Lithium benzyl oxide

The possibility of double inversion to produce opposite stereochemistry at one stereocenter was also investigated. Conversion of bromo boronic ester 55 (the same precursor used for synthesis of 52) into the (3,4-dimethoxybenzyl)oxy derivative 56 was straightforward, and dichlorodicyanoquinone (DDQ) oxidation readily yielded the a-hydroxy boronic ester 57. Conversion of 57 into the methane sulfonate 58 and reaction with lithium benzyl oxide furnished 59, a diastereomer of 52 (Scheme 8.13) [41]. 

In spite of the usefulness of these complexes, it is generally not possible to cause the satisfactory reaction with transition metals in the metallic state [86] under mild conditions due to their poor reactivity. We have reported that activated metallic nickel, prepared by the reduction of nickel halide with lithium, underwent oxidative addition of benzylic halides to give homocoupled products [45]. We reported that carbonylation of the oxidative adducts of benzylic halides to the nickel proceeded smoothly to afford symmetrical 1,3-diarylpro-pan-2-ones in moderate yields, in which the carbonyl groups of alkyl oxalyl chlorides served as a source of carbon monoxide [43] see Equation 7.5. 

Quantitative Analysis of All llithium Initiator Solutions. Solutions of alkyUithium compounds frequentiy show turbidity associated with the formation of lithium alkoxides by oxidation reactions or lithium hydroxide by reaction with moisture. Although these species contribute to the total basicity of the solution as determined by simple acid titration, they do not react with allyhc and henzylic chlorides or ethylene dibromide rapidly in ether solvents. This difference is the basis for the double titration method of determining the amount of active carbon-bound lithium reagent in a given sample (55,56). Thus the amount of carbon-bound lithium is calculated from the difference between the total amount of base determined by acid titration and the amount of base remaining after the solution reacts with either benzyl chloride, allyl chloride, or ethylene dibromide. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

The completion of the synthesis of key intermediate 2 requires only a straightforward sequence of functional group manipulations. In the presence of acetone, cupric sulfate, and camphorsulfonic acid (CSA), the lactol and secondary hydroxyl groups in 10 are simultaneously protected as an acetonide (see intermediate 9). The overall yield of 9 is 55 % from 13. Cleavage of the benzyl ether in 9 with lithium metal in liquid ammonia furnishes a diol (98% yield) which is subsequently converted to selenide 20 according to Grie-co s procedure22 (see Scheme 6a). Oxidation of the selenium atom... 

The C2-symmetric epoxide 23 (Scheme 7) reacts smoothly with carbon nucleophiles. For example, treatment of 23 with lithium dimethylcuprate proceeds with inversion of configuration, resulting in the formation of alcohol 28. An important consequence of the C2 symmetry of 23 is that the attack of the organometallic reagent upon either one of the two epoxide carbons produces the same product. After simultaneous hydrogenolysis of the two benzyl ethers in 28, protection of the 1,2-diol as an acetonide ring can be easily achieved by the use of 2,2-dimethoxypropane and camphor-sulfonic acid (CSA). It is necessary to briefly expose the crude product from the latter reaction to methanol and CSA so that the mixed acyclic ketal can be cleaved (see 29—>30). Oxidation of alcohol 30 with pyridinium chlorochromate (PCC) provides alde-... 

C. Reactions of Phosphoric and Phosphinic Acid Derivatives.—The optically active phosphinate ester (90) has been shown to react with benzyl Grignard reagents or lithium anilide with inversion of configuration. Oxidation of... 

Vinylogs of benzylic alcohols, e.g. cinnamyl alcohol, undergo easy saturation of the double bond by catalytic hydrogenation over platinum, rhodium-platinum and palladium oxides [39] or by reduction with lithium aluminum hydride [609]. In the presence of acids, catalytic hydrogenolysis of the allylic hydroxyl takes place, especially over platinum oxide in acetic acid and hydrochloric acid [39]. 

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