Reduction lithium-ammonia

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

Ketonic carbonyl groups are commonly encountered in steroids and their reduction is facile, even in the absence of an alcohol. The lithium-ammonia reduction of androsta-l,4-diene-3,17-dione affords androst-4-ene-3,17-dione in 20% yield but concurrent reduction of the C-17 ketone results in formation of testosterone in 40% yield, even though the reduction is performed rapidly at —40 to —60° and excess lithium is destroyed with solid ammonium chloride. Similar reduction of the C-17 carbonyl group has been observed in other compounds. In the presence of an alcohol, a ketone is complete-... 

Lithium-ammonia reductions of most steroidal enones of interest create one or two new asymmetric centers. Such reductions are found to be highly stereoselective and this stereoselectivity constitutes the great utility of the reaction. For conjugated enones of the normal steroid series, the thermodynamically most stable products are formed predominantly and perhaps exclusively. Thus the following configurations are favored 5a, 8/ , 9a, and in certain cases 14a (see page 35). Starr has listed numerous examples illustrating these facts and Smith " and Barton have tabulated similar data. 

A study of the lithium-ammonia reduction of 14-en-16-ones would extend our understanding of the configuration favored at C-14 in metal-ammonia reductions. Although several simple 14-en-16-ones are known, their reduction by lithium and ammonia apparently has not been described in the literature. Lithium-ammonia reduction of A-nortestosterone, a compound that structurally is somewhat analogous to a 14-en-16-one, affords roughly equal amounts of the 5a- and 5 -dihydro-A-nortestosterones. " This finding was interpreted as indicating that there is little difference in thermodynamic stability between the two stereoisomeric products. 

Lithium-ammonia reduction of l7a-ethyl-19-nortestosterone (68) using Procedure 8a (section V) affords the 4,5a-dihydro compound (69) in 85% yield after a reaction time of 12 minutes after a reaction time of 80 minutes, the yield of (69) is 76%. Lfsing sodium in the same reduction, the yields of compound (69) are 79 and 77 % after reaction times of 8 and 80 minutes respectively. Both the lithium and sodium enolates appear to be reasonably stable in liquid ammonia in the presence of alkali metal. Since the enolate salts are poorly soluble in ammonia, their resistance to protonation by it may be due in part to this factor. 

In section V-A it has been pointed out that catalytic reduction of conjugated enones is usually a good method for the preparation of p- or y-labeled ketones. To overcome certain stereochemical problems, however, it is occasionally necessary to use the lithium-ammonia reduction. In this case deuteration takes place at the / -carbon and generally leads to the thermodynamically more stable product (see chapter 1). 

A useful alternate procedure which allows the generation and alkylation of the less stable enolate anion has been reported by Stork.This method takes advantage of the fact that the thermodynamically less stable enolate anion formed in the lithium ammonia reduction of a conjugated enone... 

In this experiment, advantage is made of the fact that lithium-ammonia reduction usually proceeds to give trans-fused Decalins 4). Thus, hydrogenation of A -octal one-2 over palladium catalyst gives essentially cw-2-decalone as the product, whereas the lithium-ammonia reduction of the octalone gives the trans ring fusion. 

Mechanism of the lithium/ ammonia reduction of an alkyne to produce a trans alkene. 

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... 

Lithium-ammonia reduction of a,/ -unsaturated ketones (entry 6, Scheme 1.4) provides a very useful method for generating specific enolates.26 The desired starting materials are often readily available, and the position of the double bond in the enone determines the structure of the resulting enolate. This and other reductive methods for generating enolates from enones will be discussed more frilly in Chapter 5. Another very important method for specific enolate generation, the addition of organometallic reagents to enones, will be discussed in Chapter 8. 

Cleavage of cyclopropyl ketones.8 Cyclopropyl ketones are converted by lSi(CH3)3 under very mild conditions into y-iodo ketones. The regioselectivity is usually high and is similar to that observed in lithium-ammonia reductions. 

The proper double-bond stereochemistry may be achieved by using 2-heptyne as a reactant in the final step. Lithium-ammonia reduction of 2-heptyne gives the trans alkene hydrogenation over Lindlar palladium gives the cis isomer. The first task is therefore the alkylation of propyne to 2-heptyne. 

Two further papers report lithium-ammonia reductive cleavage of some A3-THC-related compounds374 and selenium dioxide oxidation of A -THC and A6-THC.375 In the latter, it is shown that A -THC yields oxidation products predominantly from attack at C-6, whereas A6-THC is oxidized preferentially at the exocyclic allylic C-7 methyl group, to yield, for example, (269). 

Alternatively, lithium/ammonia reduction of 4-octyne, followed by addition of HBr, gives 4-bromooctane. 

The most general synthetic route to benzene oxides-oxepins is that initially developed by Vogel for 1. 1,4-cyclohexadienes (readily available from [2+4] cycloaddition of alkynes and butadienes, lithium-ammonia reduction of arenes, or dehydration of cyclohexenols) were converted to dibromoepoxides, the immediate precursors of benzene oxides. Modifications of this route have been used to prepare Ic and Id. Treatment of the monosubstituted arene oxide 43 (Figure 3) with (Et)4NF or thermal isomerization of 3-oxaquadricyclane provide additional synthetic routes to la. Similarly, the thermal (or photochemical) isomerization of the monoepoxide of Dewar benzene yielded la. ... 

The reduction of the p-acyloxy sulfone is most often carried out with sodium amalgam, as the examples below indicate. The reductive elimination can be buffered with disodium hydrogenphosphate for sensitive substrates. In certain applications it has proven advantageous to utilize lithium or sodium in ammonia. For example, Keck s synthesis of pseudomonic acid C made use of the lithium/ammonia reductive elimination to simultaneously form an alkene and deprotect a benzyl ether.In studies directed toward the same target, Williams made use of a reductive elimination procedure developed by Lythgoe, involving the formation of the xanthate ester followed by reduction with tri-n-butyltin hydride. ... 

Stoik et al. have shown that heteroannular extended dienolates such as (73), which contain substituents at both the a- and y-positions, undergo predominantly equatorial alkylation (Scheme 35). The dienolate (73) was product by lithium-ammonia reduction of the tricyclic dienone (72) and the product of its alkylation wiA I-bromo-3-chloro-2-butene and hydrolysis of the resulting enol ether, i.e. (74), was a key intermediate in a short, highly stereoselective synthesis of ( )-adrenosterone. It was pointed out that equatorial alkylation is obtained with dienolates such as (73) and related compounds brcause a peri interaction (Me OMe) of the a- and y-substituents forces the ring a to adopt a half-boat conformation in which the a-face of the ir-system is accessible to attack. 

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