Lithium amide reduction

An isolated acetoxyl function would be expected to be converted into the alkoxide of the corresponding steroidal alcohol in the course of a metal-ammonia reduction. Curiously, this conversion is not complete, even in the presence of excess metal. When a completely deacetylated product is desired, the crude reduction product is commonly hydrolyzed with alkali. This incomplete reduction of an acetoxyl function does not appear to interfere with a desired reduction elsewhere in a molecule, but the amount of metal to be consumed by the ester must be known in order to calculate the quantity of reducing agent to be used. In several cases, an isolated acetoxyl group appears to consume approximately 2 g-atoms of lithium, even though a portion of the acetate remains unreduced. Presumably, the unchanged acetate escapes reduction because of precipitation of the steroid from solution or because of conversion of the acetate function to its lithium enolate by lithium amide. 

Unless a proton donor is added, the lithium-ammonia reduction of an cnone leads to the lithium enolate and lithium amide. The latter is a sufficiently strong base to rapidly convert the mono-alkylated ketone into its enolate, which can be further alkylated. The function of the... 

In a related procedure, tellurium tetrachloride is treated with lithium amides giving tellurium(II) amides via the successive reduction and amination of TeCl4. 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

Pridefine (80) is a somewhat structurally related antidepressant. It is a centrally active neurotransmitter blocking agent. It blocks norepinephrine in the hypothalamus but does not affect dopamine or 5-hydroxytryptamine. Its synthesis be-(jins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78. Heating in the presence of ethylamine gives N-ethylsuccinimide 79. Lithium aluminum hydride reduction completes the synthesis of pridefine (80)... 

The enolates of fluoroacetate or fluorothioacetate esters are generated either through deprotonation with a lithium amide or by an in situ reduction of ethyl bromofluoroacetate with zinc. These enolates can undergo diverse reactions with electrophiles (Figure 2.7) ... 

Amide reduction with lithium aluminum hydride, 39, 19 Amine oxide formation, 39, 40 Amine oxide pyrolysis, 39, 41, 42 -Aminoacetanilide, 39, 1 Amino adds, synthesis of, 30, 7 2-Amino-4-anilino-6-(chloro-METHYl) -S-TRIAZINE, 38, 1 -Aminobenzaldehyde, 31, 6 hydrazone, 31, 7 oxime, 31, 7 phenylhydrazone, 31, 7 > -Aminobenzoic add, 36, 95 2-Aminobenzophenone, 32, 8 c-Aminocaproic acid, 32, 13 6-Aminocaproic acid hydrochloride,... 

The first successful catalytic animation of an olefin by transition-metal-catalysed N—H activation was reported for an Ir(I) catalyst and the substrates aniline and norbornene 365498. The reaction involves initial N—FI oxidative addition and olefin insertion 365 - 366, followed by C—FI reductive elimination, yielding the animation product 367. Labelling studies indicated an overall. vyw-addition of N—FI across the exo-face of the norbornene double bond498. In a related study, the animation of non-activated olefins was catalysed by lithium amides and rhodium complexes499. The results suggest different mechanisms, probably with /5-arninoethyl-metal species as intermediates. 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

The diamine precursor 108 to the chiral lithium amide 4 introduced by Asami is accessible by different routes starting from (, >)-proline. In Asami s own synthesis, (S)-CBZ-proline was activated by DCC and then coupled by an amine such as pyrrolidine (Scheme 80). The reduction of the formed amide could then be carried out with LiAlHj or BH3, with the latter giving a cleaner reaction. After deprotection, the diamine was obtained by distillation in 44-48% yield from (.S j-CBZ-prolinc. 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

Disubstituted pyrrolidinones are formed when the bicyclic lactam is tieaiedvjith AllyltrimethylsilanelJitaniumilV) Chloride. The remaining phenylglycinol moiety is cleaved with Li/NHs (see Lithium Amide) (eq 12). Further reduction with lAthium Aluminum Hydride affords 2,2-disubstituted pyrrolidines. 

Liquid ammonia (b.p. -33°C) is a solvent which is not encountered frequendy, but which does have several important general uses, in particular dissolving metal reductions ("Birch" type reductions) and most reactions involving lithium amide or sodium amide as bases. Ammonia gas from a cylinder is condensed directly into the flask (Fig. 14.5). 

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