Lithium in ethylamine

The alkyl group R of certain carboxylic esters can be reduced to RH by treatment with lithium in ethylamine. The reaction is successful when R is a tertiary or a sterically hindered secondary alkyl group. A free-radical mechanism is likely. Similar reduction, also by a free-radical mechanism, has been reported with sodium in HMPA-r-BuOH. In the latter case, tertiary R groups give high yields of RH, but primary and secondary R are converted to a mixture of RH and ROH. Both of these methods provide an indirect method of accomplishing 10-81 for tertiary R. 

The 1,5-diene (19) was obtained from the salt (18) by alkylation of the ylide with allyl bromide and reduction of the resulting salt with lithium in ethylamine. 

In a variation of these reactions, Grieco and Masaki used p-toluenesulfonyl groups to direct alkylation reactions in the formation of carbon chains and then cleaved the sulphones with lithium in ethylamine. This type of synthetic construction involving the use of sulphur-containing molecules has become a typical sequence in organic syntheses. In this case, the reactions formed part of successful syntheses of squalene and sesquifenchene and were carried out without any migration or loss of stereochemical integrity of the double bonds. Similar sequences have been reported by Trost (prenylation reactions) and Marshall (synthesis of a cembranoid precursor). 

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. 

Dihydrobenzopyran (chromane) and its methyl homologs were reduced by lithium in ethylamine and dimethylamine to 3,4,5,6,7,8-hexahydrobenzo-pyrans in 84.5% yields [424. ... 

Results of the reduction of unsaturated alcohols depend on the respective positions of the hydroxyl and the double bond. Since the hydroxyl group is fairly resistant to hydrogenolysis by catalytic hydrogenation almost any catalyst working under mild conditions may be used for saturation of the double bond with conservation of the hydroxyl [608]. In addition, sodium in liquid ammonia and lithium in ethylamine reduced double bonds without affecting the hydroxyl in non-allylic alcohols [608]. 

AUylic ethers were reduced by treatment with lithium in ethylamine to alkenes [636]. Benzyl ethers are hydrogenolyzed easily, even more readily than benzyl alcohols [637], 3,5-Bis(benzyloxy)benzyl alcohol gave 3,5-dihydroxy-benzyl alcohol on hydrogenation over palladium on carbon at room temperature and atmospheric pressure in quantitative yield [638. Hydrogenolysis of benzylic ethers can also be achieved by refluxing the ether with cyclohexene (as a source of hydrogen) in the presence of 10% palladium on carbon in the presence of aluminum chloride [639]. 

While initial attempts to hydrogenate ferrocene under relatively mild conditions were not successful, extensive treatment with hydrogen in the presence of a nickel catalyst at 300° to 350° and under 280-atm. absolute pressure results in the formation of cyclopentane (64). In contrast to the extreme resistance of ferrocene to catalytic hydrogenation, this aromatic-type compound can be readily reduced by lithium in ethylamine, the products being metallic iron and cyclopen tadiene (121). 

In this synthesis the geometry of the acyclic double bonds is controlled through their formation as part of the thiane ring. Thiacyclohexanone (711) was converted to 4-thia-l-methylcyclohexene by reaction with methylmagnesium iodide and subsequent dehydration. Metallation of (712) with s-butyllithium and alkylation of the anion with the epoxide (713) gave a tertiary alcohol which was dehydrated to yield (714). A second alkylation of (714) with trails-4-chloro-3-methyl-2-butene 1-oxide (715) completed the carbon skeleton of the Cis juvenile hormone. Reduction of (716) with lithium in ethylamine and then desulfurization with Raney nickel led to trienol (717), a product converted previously to (718). 

Chiral allylic alcohols.1 Desulfuration of the (3-hydroxy sulfoxides 1 with Raney nickel (11, 292) proceeds with simultaneous reduction of the double bond, but can be effected selectively with lithium in ethylamine at - 78° to give optically active allylic alcohols (2). 

Diene - 1,4-diene. An interesting way to convert 3/ -acetoxy-5,7-cholesta-diene (1) into the 5,8-cholestadiene (4) proceeds via the adduct (2) of the 5,7-diene with diethyl azodicarboxylate (1, 246). The adduct is converted to the 5,8-diene by reduction with lithium in ethylamine (1,574-581). 

Reductive desulfonylation.1 A stereocont rolled method for addition of the steroid side chain to a 17-keto steroid is outlined in scheme (I). The various steps proceed selectively to the sulfone 5. Reductive desulfonylation of 5 with Na/Hg, Na2HP04 in CH3OH gives the desired 6 (57% yield) and the undesired alkene in a 2 1 ratio. The desired stereoselectivity was obtained with lithium in ethylamine. The final step was hydrogenation of the 17(20)-double bond to give a protected cholesterol (7). 

This intermediate was alkylated with tert. -butyI-cj-iodohexanoate to the ester 30. Conversion to the acid 31 was achieved by cleavage of the fed.-butylester with trifluoroacetic acid at low temperature. The triple bond was reduced to a trans-double bond and simultanously the benzylether groups had been removed with lithium in ethylamine, under formation of the desired 15-deoxy-7-oxaprostaglandin Fla 32 in crystalline form. The ds-isomer was prepared by first reducing the triple bond of compound 30 with palladium on barium sulfate to 33, removal of the ted. -butylgroup with formic acid to 34 and debenzylation of the acid with lithium in ethylamine to 35. 

Selenides are also nucleophilic and produce isolable selenonium salts (9) when treated with alkyl halides. They are easily oxidized to selenoxides (10) and further to selenones (11) under more forcing conditions (see Section 4). Reduction of selenides to the corresponding hydrocarbons is most conveniently achieved with nickel boride,or with tri-n-butyl- or triphenyltin hydride under radical conditions. " Other reagents for reductive deselenization include Raney nickel, lithium triethylborohydride, and lithium in ethylamine (Scheme 4). Benzylic selenides undergo radical extrusion reactions under thermal or photolytic conditions to produce... 

Deoxygenation of aicohols. Esters of hindered alcohols are selectively deoxy-genated with lithium in ethylamine or by potassium solubilized by 18-crown-6 in t-butylamine. Two examples are formulated in equations (1) and... 

Benkeser et al. have reported that the reduction of 3- and 5-octyne with lithium in ethylamine at -78 °C produces the corresponding rran -alkenes in good yield. At 17 "C, however, overreduction of the alkene can occur if excess lithium is present. ... 

Solutions of Group I metals in the lower molecular weight amines are more potent reductants than those in liquid ammonia, and as a general rule substrates are more extensively reduced than by the Birch method. o Naphthalene (49 Scheme 48), for example, is reduced by a solution of lithium in ethylamine to a 1 1 mixture of A W- and A -octalins (214) and (215). If ethylenediamine is employed as the medium, the completely saturated decahydronaphthalene is formed, while the proportion of (215) may be increased to 80% by utilizing a (1 1) mixture of ethylamine with dimethylamine. The formation of the more-substituted alkene appears to be a general result for such primary and secondary amine mixtures and has been used to good effect in the reduction of both toluene and cumene to their 3,4,5,6-tetrahydro derivatives (216) and (217), respectively, in ca. 80% yields. A comprehensive review of these kinds of reducing systems, which also draws comparisons with the Birch method, is available,but more recent-... 

The two limonene epoxides (93) behave differently when treated with lithium in ethylamine. The trans-epoxide (93a) yields exclusively trons-) -terpineol (94a), excess lithium and long reaction periods reducing the double bond, whereas the c/s-epoxide (93b) yields not only cis-)8-terpineol (94b), but also neo- (95) and isodihydrocarveol (96). The menth-l-ene epoxides [e.g. (97)] behave similarly. ... 

The electron is the smallest thinkable nucleophile which—generated from lithium in ethylamine—is even able to open certain unactivated vinylcyclopropanes (equation 142) the spiro[4.5]decane so obtained could be converted into the isocyanide sesquiterpene (— )-axisonitrile-3, which has the opposite absolute configuration of a marine sponge constituent . ... 

The reduction of (3-hydroxyalkyl selenides to alcohols has been achieved - - - by lithium in ethylamine (Scheme 161, a Scheme 162, a Scheme 163, a Scheme 167) or triphenyl- or tributyl-tin hydride in toluene, with or without AIBN. Most of these reactions proceed through radicals. The reactions involving tin hydrides can be carried out thermally around 120 or photochemically at much lower temperature (0-20 The cleavage of the C—SePh bond is faster than that of the... 

Selective reduction of allyl sulfides implies that no scrambling of the carbon-carbon double bond occurs during the process. Effectively this has proved to be the case especially when lithium in ethylamine is used, and the method has allowed the regio- and stereo-selective synthesis of a large variety of 1,5-dienes including squalene (Scheme 25, entry a), mukapolide (Scheme 25, entry b), dendrolasin (Scheme 25, entry c), the basic nucleus of crassin acetate (Scheme 25, entry d) from 7,7-dialkylallyl sulfides and allyl halides, and also of 1,5-enynes " from propargyl sulfides and allyl halides (Scheme 34, entry b). 

Otherwise, reduction of allylic dithiocaitiamates proved regio- and stereo-selective when carried out with lithium in ethylamine (Scheme 32), but leads to a mixture of alkenic compounds when carried out with Raney nickel. 

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