Lithium reductive cleavage

SUylated 2-oxidienes and bis-silylated 2,3-dioxidienes are prepared from a , -unsaturated ketones and 1,2-dicarbonyl compounds, respectively in the latter case, the reagent employed for the first silylation is tiimethylsilyl bromide while TMSOTf is required for the second silylation. 1,3-Bis-silyloxydienes are prepared by direct silylation of 1,3-dicarbonyl compounds with TMSOTf(Et3N. They also can be obtained as mixtures of Z/E-isomers by lithium reductive cleavage of isoxazoles followed by the slow addition of an excess of TMSOTfKEt3N (eq 38). ... 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Reductive cleavage of oxiranes to alcohols by lithium aluminum hydride is an important reaction (64HC(19-1)199), but the most powerful hydride donor for this purpose is lithium triethylborohydride (73JA8486). 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

A 17-steroidal ketone was deprotonated by LDA to protect it from reduction during a lithium naphthalenide cleavage of a benzyl ether. ... 

Reduction of epoxide 21 with lithium aluminium hydride gave a crystalline branched-chain methyl heptoside derivative 24. The NMR spectra of compounds 21 and 24 were very similar. In the spectrum of compound 24 the disappearance of the two sharp doublets at r 6.80 and 7.45 (2 protons) and the appearance of a singlet at r 8.65 (3 protons) is consistent with the reductive cleavage of epoxide 21 to give a substance 24 with a methyl substituent. The multiplet at r 7.40-8.50 ( 5 protons ) was assigned to the four protons of the two methylene groups and the hydroxylic proton. 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

The alkoxycarbonyl group activates the N — N bond, so that a racemization-free reductive cleavage by treatment with a large excess of lithium in liquid ammonia is possible (sec procedure below). This method is not suitable for hydrazines containing a benzylic C-N bond, because it is cleaved under the reducing conditions. 

The a-sulfonyl carbanions can be trapped with a variety of electrophiles19. The method provides a synthetically useful synthon for a propylene 1,3-dipole. Reductive cleavage of the sulfone 28 thus prepared, with lithium phenanthrenide in THF, furnishes bicyclooctane 29 (equation 19)16. 

Truce also examined a few examples of the cleavage of sulphones with sodium in liquid ammonia97 and found essentially similar results except that diaryl sulphones were reduced to sulphinate salts instead of to arylthiolates as with the lithium reductions. Dialkyl sulphones were unreactive towards sodium in liquid ammonia. 

Subsequently, Julia, Uguen and Callipolitis104 105 used both lithium metal in ethyl-amine and sodium amalgam in ethanol to effect reductive cleavages of j8-hydroxysulphones or of allylic sulphones. The latter reaction is part of a synthetic sequence for the construction of alkenes that has been used with some considerable success... 

TABLE 2. Reductive cleavage reactions of sulphones induced by lithium in methylamine or ethylamine... 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Vinyl ethers were reductively cleaved by lithium, sodium or potassium in liquid ammonia especially in the absence of alcohols (except terf-butyl alcohol) A mixture of l-methoxy-1,3- and l-methoxy-l,4-cyclohexadiene gave in this way first methoxycyclohexene and, on further reduction, cyclohexene Reductive cleavage of a-alkoxytetrahydrofurans and pyrans will be discussed in the chapter on acetals (p. 104). 

Me. A third possibility would be that the a-chloroenolate intermediate, which is a carbenoid, would a-eliminate a chloride ion to yield carbene 229, which would subsequently intramolecularly cycloadd onto the double bond of the enone moiety. When = H, Me as in 231 a, b, reductive cleavage of the C - bond (e.g. with lithium in liquid NH3) can produce bicyclo[2.2.2]octane derivatives 230. The... 

FIGURE 17a. Alternative routes for vinylogous birch reductive cleavage of cinnamyl ether promoted by lithium naphthalenide. Reprinted with permission from Reference 22. Copyright 1996 American Chemical Society... 

The classical preparation of alkyllithium compounds by reductive cleavage of alkyl phenyl sulfides with lithium naphthalene (stoichiometric version) was also carried out with the same electron carrier but under catalytic conditions (1-8%). When secondary alkyl phenyl sulfides 73 were allowed to react with lithium and a catalytic amount of naphthalene (8%) in THF at —40°C, secondary alkyllithium intermediates 74 were formed, which finally reacted successively with carbon dioxide and water, giving the expected carboxylic acids 75 (Scheme 30) °. 

The corresponding benzylic reductive cleavage was carried out using aryl-substituted 1,3-dioxanes 419, lithium and a catalytic amount of naphthalene (10%) in THF at temperatures ranging from —78 to —40°C. The obtained benzylic intermediates 420 were then treated with different electrophiles giving, after hydrolysis, the corresponding products 421 (Scheme 118) 3,i94... 

Since only very few examples for the synthesis of poly lithium compounds by a reductive cleavage of earbon-sulphur bonds had been reported before, all examples for this method of synthesis will be presented. 

Polymetalated systems of this type without phenyl substitution at the lithiated carbon centre are only accessible when solutions of LiCioHg (144a) or LiDBB (145) in THF instead of a suspension of metallic lithium in THF are reacted with bis(phenylthiomethyl)silanes of type 155. In our group, variously substituted bis(lithiomethyl)silanes 117a, 156b-e and 101 were synthesized by reductive cleavage of the carbon-sulphur bond with LiCioHg... 

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