Reduction with lithium in liquid ammonia

A good example is the reduction of 11-keto steroids (69) which gives only the llJ -hydroxy derivatives (70) with metal deuterides. Generally, the 1 la-alcohols are obtained in good yield by reduction with lithium in liquid ammonia-methanol mixtures. By analogy, llj -dj-lla-alcohols (71) are expected when a deuterioammonia-methanol-OD system is used. (For an alternate preparation of an 11/5-dj-l la-hydroxy steroid, see section III-C). 

The superfluous bromine is then removed by reduction with zinc in acetic acid (26-1). The 20 ketone is next protected against the strongly reducing conditions in the subsequent step by conversion to the ethylene glycol acetal (26-2). Birch reduction with lithium in liquid ammonia in the presence of ethanol proceeds as usual to the dihydrobenzene (26-3). Treatment of this last product with mineral acid serves to hydrolyze both the enol ether at the 3 position and the acetal at the... 

Bicyclo[4.2.0]octanes wiLh carbonyl groups adjacent to each bridgehead carbon cleave the central bond on reduction with lithium in liquid ammonia,158,159 with sodium/potassium alloy in the presence of chlorotrimethylsilane,160 with zinc in acetic acid,37 or with zinc amalgam in hydrochloric acid.15 7... 

The two free hydroxy groups are First protected with acetic anhydride. In a second step the acetyl group is reductively cleaved by a Birch reduction with lithium in liquid ammonia.19 Lithium dissolves in the ammonia with the formation of solvated electrons. Stepwise electron transfer to the aromatic species (a SET process) leads first to a radical anion, which stabilizes itself as benzylic radical 38 with loss of the oxygen substituent. A second SET process generates a benzylic anion, which is neutralized with ammonium chloride acting as a proton source (see Chapter 12). 

The use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(l//)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with l-chloro-3-iodopropane or 1-chloro -iodobu-tane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178). 

Deoxygenation of phenols. The reduction of enol phosphates to alkenes by titanium metal (8,482) has been extended to reduction of aryl diethyl phosphates to arenes. Yields are in the range 75-95% reduction with lithium in liquid ammonia (1, 248) usually proceeds in low yield. 

Benzylic and allylic tertiary amines may be reduced to hydrocarbons using one of two methods. Oxidation to an amine oxide followed by reduction with lithium in liquid ammonia provides one of these... 

Sinclair, S., Jorgensen, W. L. Computer Assisted Mechanistic Evaluation of Organic Reactions. 23. Dissolving Metal Reductions with Lithium in Liquid Ammonia Including the Birch Reduction. J. Org. Chem. 1994, 59, 762-772. 

Table 12. Alkylation of Oxoterpenes by Cyclopropanation, Followed by Reduction with Lithium in Liquid Ammonia ...

A regioselective synthesis of 1,4-dienes (69) from a,/3,7,5-unsaturated ketones, e.g. (68), proceeds in excellent yield on alkylation with organolithium reagents followed by reduction with lithium in liquid ammonia. The reaction is not successful with the corresponding aldehydes and the lithamide reduction product must be quenched with ethanol or t-butyl alcohol rather than with conventional protic sources such as ammonium chloride. Where applicable, the 1,4-diene is formed as a mixture of the E- and Z-stereoisomers at the newly developed double bond. 

An alternative method to the Wittig reaction for the ketone-to-methylene transformation is reaction with phenylthiomethyl-lithium (413), acylation, and reduction with lithium in liquid ammonia. As well as being applicable to highly hindered ketones, e.g. the transformation of ( )-norzizanone (414) to ( )-zizaene (415), this procedure is less susceptible to enolate formation... 

Alternative conditions for reductive decyanations can be used. The allylic ether in compound 26, an intermediate in a total synthesis of (-)-roxaticin, was prone to reduction when treated with lithium in liquid ammonia. Addition of the substrate to an excess of lithium di-ferf-butylbiphenylide in THF at -78°C, and protonation of the alkyllithium intermediate provided the reduced product 27 in 63% yield, as a single diastereomer (Eq. 7). a-Alkoxylithium intermediates generated in this manner are configurationally stable at low temperature, and can serve as versatile synthons for carbon-carbon bond forming processes (see Sect. 4). 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

In practice, the equivalent synthon of 2 was l-cyano-4,5-dimethoxybenzocyclobutene 22 (Scheme 3.7) which on heating generates a reactive o-quinodimethane by a conrotatory electrocyclic ring opening process (Cf. Scheme 3.7) and reacts, at 150-160 °C, with the 3,4-dihydroisoquinoleine 23 to give 80-88%yield of 13-cyanoprotoberberine 24. A simple reductive decyanation with lithium in liquid ammonia in the presence of isopropyl alcohol afforded xylopinine (19) in 84.6% yield [19]. 

Similar results were achieved when benzene was reduced with alkali metals in anhydrous methylamine at temperatures of 26-100°. Best yields of cyclohexene (up to 77.4%) were obtained with lithium at 85° [396]. Ethylamine [397] and especially ethylenediamine are even better solvents [398]. Benzene was reduced to cyclohexene and a small amount of cyclohexane [397, 398] ethylbenzene treated with lithium in ethylamine at —78° gave 75% of 1-ethyl-cyclohexene whereas at 17° a mixture of 45% of 1-ethylcyclohexene and 55% of ethylcyclohexane was obtained [397], Xylenes m- and p-) yielded non-conjugated 2,5-dihydro derivatives, l,3-dimethyl-3,6-cyclohexadiene and 1,4-dimethyl-1,4-cyclohexadiene, respectively, on reduction with sodium in liquid ammonia in the presence of ethanol (in poor yields) [399]. Reduction of diphenyl with sodium or calcium in liquid ammonia at —70° afforded mainly 1-phenylcyclohexene [400] whereas with sodium in ammonia at 120-125° mainly phenylcyclohexane [393] was formed. 

In an interesting reaction, -santonin was reduced with lithium in liquid ammonia so that the lactone was hydrogenolyzed to an add and one of the double bonds conjugated with the carbonyl was reduced. The other double bond as well as the keto group did not undergo reduction [1091]. 

The stereoselective reduction of meso-bis(bicyclopropylidenyl) (meso-87) with lithium in liquid ammonia gave an almost quantitative yield of the two dia-stereomeric quatercyclopropyls trans,trans-229 and cis,trans-230 in a ratio of 4.4 1 (Scheme 53) [56]. On the other hand, reduction of meso-87 with diimine generated from 2-nitrobenzenesulfonyl hydrazide gave the czs,czs-quatercyclo-propyl (231) (Fig. 6) as the main product (isolated by chromatography) along with the cz s,traz2S-diastereomer 230 (Scheme 53) [56]. 

The desulfurization of 1,4-oxathiane with sodium in refluxing hydrocarbon solvent, which allows the formation of diethyl ether in very good yield (>95%), can be reported here <1998TL2671>. Furthermore, 6-hydroxy-1,4-benzodithiin undergoes a reductive cleavage with lithium in liquid ammonia, provided the 3,4-dimercaptophenol <2004BML3753>. 

Reduction of quinoline with lithium in liquid ammonia in the absence of a proton source gives mainly 1,2,3,4-tetrahydroquinoline. However, if methanol is present throughout the reaction the main product is 5,8-dihydroquinoline (45 R = H). 6-Methoxyquinoline gives (45 R = OMe) together with some 6-methoxy-7,8-dihydroquinoline (46 R = OMe) as main products (Scheme 32) (71JOC279). 

Treatment of this last intermediate with lithium in liquid ammonia and ert-butanol reduces the aromatic A ring to the 1,4-dihydrobenzene stage the benzyl ether at position 17 is cleaved reductively at the same time. The newly exposed hydroxyl group is... 

Pyrroles are not reduced by sodium in liquid ammonia, but the Birch reduction of 2-furoic acid with lithium in liquid ammonia gives the 2,5-dihydro derivative in 90% yield (780PP94). Sodium-liquid ammonia-methanol reduction of thiophene gives a mixture of A2- and A3- dihydrothiophenes together with butenethiols. Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cis- 1,3-dihydro derivative (Scheme 36) (80JOC3982). 

Selective reduction of indole in the benzene ring can be achieved by treatment with lithium in liquid ammonia, which gives a mixture of the 4,7-dihydro and 4,5,6,7-tetrahydro derivatives. 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

---