Metal hydride reduction, preparation

A series of flavan-4-ols, e.g., 108, was conveniently prepared by metal hydride reduction of the corresponding flavanone. The flavan-4-ols were converted into the 4-methoxyflavans, e.g., 109, by acid-catalyzed solvolysis in methanol. Both these classes of compounds are currently evaluated as anticancer drugs. Enantiomerically enriched cA-flavan-4-ols have been prepared by lipase-catalyzed kinetic resolution of racemic counterparts. ... 

Fig (5) The ketoalcohol (34) prepared from ketone (33) has been converted to methoxyabietatriene(38), by standard organic reactions. Hydroboration, oxidation of (38), followed by oxidation, yielded the ketone (39), which is converted to the alcohol (40), by metal hydride reduction. On subjection to transanular oxidation with lead tetracetate and benzene alcohol (40) fiimishes (41) whose conversion to pisiferic acid has already been described. 

Problem 20.5 What aldehyde or ketone is needed to prepare each alcohol by metal hydride reduction ... 

Reductions of cyclic ketones by dissolving metals are frequently highly stereoselective and these reductions have been used to obtain secondary alcohols which are difficult or impossible to prepare by metal hydride reduction. In terms of yield, the best results are usually obtained either by reductions with alkali metals (commonly Li) in liquid NH3 in the presence of proton donors or with active metals in an alcohol. Although a number of explanations have been advanced for the stereoselectivity of these reductions, they are all rationalizations with dubious predictive value." There are, however, a number of empirical generalizations which are based on a considerable body of experimental data, specifically ... 

Scheme 9 Santonin (41) was converted to the derivative (99), whose conversion to alcohol (100) by metal hydride reduction and Mitsunobu reaction. Diol (102), prepared from (100), on acid catalysed cyclization and followed by subjection to Mitsunobu reaction, gave (104), which was converted to ketone (106), whose transformation to homoallylic alcohol (108), was achieved by standard organic reactions. Phenylselenylation afforded (110), which was finally converted to phytuberin.

An alternative route was also developed for the synthesis of ( )-pisiferic acid (196) as described in "Fig (17)". The starting material for the present synthesis was the already described alcohol (15), which on tetrahydropyranylation yielded the derivative (197). Metal hydride reduction of (197) afforded a mixture of alcohols whose tosyl derivative on heating with lithium bromide and lithium carbonate in dimethylformamide afforded the oily olefin (198). These conditions not only provoked the dehydrosulphonation but also the hydrolysis of the tetrahydropyranyl group, thus shortening the reaction sequence by one step. The oily olefin (198) on oxidation yielded the ketone (199), which was formylated, and subjected to Robinson annelation with methyl vinyl ketone prepared in situ following the procedure of Howell and Taylor [74]. The resulting adduct without purification was heated by boiling with sodium methoxide in methanol to obtain the tricyclic ketone (200). It was treated with... 

Fig. (17). The already described alcohol (15) prepared from the methyl analog of Wieland-Miescher ketone (2) is converted to olefinic compound (201) applying the standard organic reactions. Its transformation to the ketone (202) is subjected to hydroboration-oxidation with Jones reagent, metal hydride reduction respectively. Its conversion to pisiferic acid (196) was carried out by the procedures described in Fig. (16)" and thus requires no comments.

Z)-3-(tri-n-butylstannyl)-2-propen-l-ol, prepared from propargylic alcohol by metal hydride reduction and transmetallation, has been coupled with 1-naphthyl triflate to give (Z)-3-a-naphthyl-2-propen-l-ol with retention of the double bond... 

Boron forms a whole series of hydrides. The simplest of these is diborane, BjH. It may be prepared by the reduction of boron trichloride in ether by lithium aluminium hydride. This is a general method for the preparation of non-metallic hydrides. 

A number of less hindered monoalkylboranes is available by indirect methods, eg, by treatment of a thexylborane—amine complex with an olefin (69), the reduction of monohalogenoboranes or esters of boronic acids with metal hydrides (70—72), the redistribution of dialkylboranes with borane (64) or the displacement of an alkene from a dialkylborane by the addition of a tertiary amine (73). To avoid redistribution, monoalkylboranes are best used /V situ or freshly prepared. However, they can be stored as monoalkylborohydrides or complexes with tertiary amines. The free monoalkylboranes can be hberated from these derivatives when required (69,74—76). Methylborane, a remarkably unhindered monoalkylborane, exhibits extraordinary hydroboration characteristics. It hydroborates hindered and even unhindered olefins to give sequentially alkylmethyl- and dialkylmethylboranes (77—80). 

Primary dialkylboranes react readily with most alkenes at ambient temperatures and dihydroborate terminal acetylenes. However, these unhindered dialkylboranes exist in equiUbtium with mono- and ttialkylboranes and cannot be prepared in a state of high purity by the reaction of two equivalents of an alkene with borane (35—38). Nevertheless, such mixtures can be used for hydroboration if the products are acceptable for further transformations or can be separated (90). When pure primary dialkylboranes are required they are best prepared by the reduction of dialkylhalogenoboranes with metal hydrides (91—93). To avoid redistribution they must be used immediately or be stabilized as amine complexes or converted into dialkylborohydtides. 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

MetaHic potassium and potassium—sodium alloys are made by the reaction of sodium with fused KCl (8,98) or KOH (8,15). Calcium metal and calcium hydride are prepared by the reduction of granular calcium chloride with sodium or sodium and hydrogen, respectively, at temperatures below the fusion point of the resulting salt mixtures (120,121). 

Carbides of the Actinides, Uranium, and Thorium. The carbides of uranium and thorium are used as nuclear fuels and breeder materials for gas-cooled, graphite-moderated reactors (see Nuclearreactors). The actinide carbides are prepared by the reaction of metal or metal hydride powders with carbon or preferably by the reduction of the oxides uranium dioxide [1344-57-6] UO2 tduranium octaoxide [1344-59-8], U Og, or thorium... 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

The reduction of tosylhydrazones by complex metal hydrides has been used very effectively to prepare saturated steroid hydrocarbons in high yields. ... 

Preparation of the aldehyde required for the synthesis of cyclothiazide (182) starts by carbonation of the Grignard reagent obtained from the Diels-Alder adduct (186) from allyl bromide and cyclopentadiene.The resulting acid (187) is then converted to the aldehyde (189) by reduction of the corresponding diethyl amide (188) with a metal hydride. 

The diversity of the substrates, catalysts, and reducing methods made it difficult to organize the material of this chapter. Thus, we have chosen an arrangement related to that used by Kaesz and Saillant [3] in their review on transition-metal hydrides - that is, we have classified the subject according to the applied reducing agents. Additional sections were devoted to the newer biomimetic and electrochemical reductions. Special attention was paid mainly to those methods which are of preparative value. Stoichiometric hydrogenations and model reactions will be discussed only in connection with the mechanisms. 

Hydride reductions of C = N groups are well known in organic chemistry. It was therefore obvious to try to use chiral auxiliaries in order to render the reducing agent enantioselective [88]. The chiral catalyst is prepared by addition of a chiral diol or amino alcohol, and the active species is formed by reaction of OH or NH groups of the chiral auxiliary with the metal hydride. A major drawback of most hydride reduction methods is the fact that stoichiometric or higher amounts of chiral material are needed and that the hydrolyzed borates and aluminates must be disposed of, which leads to increased costs for the reduction step. 

Using different reagents or under various conditions, 2,3-epoxy alcohols can undergo ring-opening reactions with metallic hydrides, giving 1,3-diols or 1,2-diols. As shown in Scheme 4-16, reduction of 3-substituted 2,3-epoxy alcohols with Red-Al leads to the exclusive formation of 1,3-diols, and this can be applied in the preparation of 1,3-diol compounds.31... 

The tin hydrides are usually prepared by reduction of a tin halide, oxide, or alkoxide with a metal hydride such as NaBH4, LiAlH4, or poly(methylhydrosiloxane) [(MeHSiO) (PMHS)]. 

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