Octalones reduction

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. 

The procedure given in the preceding experiment can be applied to the reduction of lO-methyl-J -octalone-2 prepared in Chapter 10, Section VI. The product of the reduction has bp 94-9673 mm. 

The stereochemistry of conjugate reduction is established by the proton transfer to the (3-carbon. In the well-studied case of A1,9-2-octalones, the ring junction is usually trans,213... 

A difference in the reactivities and selectivities between tetra-n-butylammonium borohydride and sodium borohydride in the reduction of conjugated ketones is well illustrated with A1-9 2-octalone (Scheme 11.3) [17], Reduction with the sodium salt in tetrahydrofuran is relatively slow and produces the allylic alcohol (1) and the saturated alcohol (2) in a 1.2 1 ratio whereas, in contrast, tetra-n-butylammonium borohydride produces the non-conjugated alcohol (3) (50%) and the saturated alcohol (2) (47%), with minor amounts of the ketone (4), and the allylic alcohol (1) [16]. It has been proposed that (3) results from an initial unprecedented formation of a dienolate anion and its subsequent reduction. 

Ai(9)-octalone, 46, 80 reductive, aromatic nitro compounds to heterocyclic com >ounds, 48, 115... 

In the reduction of octalone of the type 212, the resulting enolate dianion 213 can adopt three different half-chair conformations 216, 217, and 218. Of these, only conformations 216 and 217 have the carbanion electron pair parallel to the a orbital of the enolate system allowing an electronic de-... 

This stereochemistry is similar to that in the reduction of a,/3-unsaturated ketones. Stork found that octalones like 7.88 were reduced exclusively to the frans-decalone 7.90, even in cases when the trans- was less stable than the corresponding c/.v-decalin. In this reaction, an electron is fed into the LUMO... 

A typical dimerization reaction in a conjugated system has been found on reduction of the octalone (14) with zinc amalgam in concentrated hydrochloric acid under reflux, which gave a geometrical mixture of the dehydro dimers (30-40%) along with octalin (15 equation 9). ... 

The ease and the stereochemical course of hydrogenation of a,p-unsaturated ketones are particularly influenced by the nature of the solvent and the acidity or basicity of the reaction mixture. Some efforts have been made to rationalize the effect of the various parameters on the relative proportions of 1,2- to 1,4-addition, as well as on the stereochemistry of reduction. For example, the product distribution in -octalone hydrogenation in neutral media is related to the polarity of the solvent if the solvents are divided into aprotic and protic groups. The relative amount of cis- -decalone decreases steadily with decreasing dielectric constant in aprotic solvents, and increases with dielectric constant in protic solvents, as exemplified in Scheme 21 (dielectric constants of the solvents are indicated in parentheses). Similar results were observed in the hydrogenation of cholestenone and of testosterone. In polar aprotic solvents 1,4-addition predominates, whereas in a nonpolar aprotic solvent hydrogenation occurs mainly in the 1,2-addition mode. 

Three independent syntheses of fukinone (335) have been published. In the first of these, Piers and Smillie ° converted the octalone (336), which they had previously used in connection with their synthesis of aristolone, into (337) by treatment with ethyl formate followed by catalytic reduction. Dehydrogenation of (337) with 2,3-dichloro-5,6-dicyanobenzoquinone and subsequent oxidation and esterification yielded (338). This keto-ester was converted into fukinone (335) by hydrogenation followed by methylation of the enolate ester and dehydration of the resultant keto-alcohol (339). Torrence and Finder have also completed the synthesis of fukinone using the octalone (336) as the key intermediate. 

Stork deduced that the octalone (1) should be convertible into the less stable of iwo possible enolates by reaction with lithium in liquid ammonia, and experimentation showed this prediction to be correct. Reduction of the unsaturated ketone (1) afforded only the fru/ij-jS-decalone (3) as the initial product. The reaction is considered to involve addition of an electron from lithium to ketone (1) to produce a hybrid intermediate (2) with carbanion character at the j3-carbon, and this intermediate abstracts a proton from ammonia to form the product (3). These observations suggested a new method of alkylation." Alkylation of the t .v-2-decalone (4) in the presence of base proceeds through the mure stable enolaie and gives (.5). However, the leas stable enulate (2) can be generated by l.i-NH,i reduction of the unseturated ketone (I) and alkylated to give the liomarlu methylated product (A). 

Stable conformation of an excited enone which has a substantially pyramidalized P-carbon. For example, addition of allene to octalone (19) produces (20) which results from addition of allene oiqmsite the angular substituent (equation 30). Similar results are obtained in the dissolving metal reductions of... 

Reductive alkylation and carbomethoxylation. Stork1 has now published details of his method of generating the less stable enol of an a,/3-unsaturated ketone and trapping this intermediate by alkylation or carboxylation before equilibration can occur (1, 601-602). For example, reduction of A1<9>-2-octalone (1) with lithium-ammonia followed by addition of methyl iodide instead of the usual proton source gives in about 50% yield a mixture of l-methyl-fra/is-2-decalone (2, 83%) and the product of reduction, fron.r-2-decalone (3,17%). Direct alkylation of trans-2-... 

The sequence is equally useful for alkylation at a position which already carries an alkyl group. In this case formation of the simple reduction product (such as 3, above) becomes a serious matter. However, if the liquid ammonia is replaced before alkylation by THF, the desired alkylation occurs in reasonable yield. Thus l,IO-dimethyl-A,<9)-2-octalone (7) was alkylated under these conditions to the desired l,l,10-trimethyl-/rans-2-decalone (8) in satisfactory yield. 

Reduction of a,fi-unsaturated ketonesThis highly hindered borane accepts an electron from sodium metal to give a blue solution of the radical anion which can serve as a conductor of electrons for reduction of a,/3-unsaturated ketones. Thus A1,9-octalone-2 (1) is reduced by TMB, sodium, and a proton source (t-butanol) in anhydrous 1,2-dimethoxyethane (nitrogen) in high yield (85-95%) to a mixture of / j-2-decalone (70%) and cw-2-decalone (30%), the equilibration point for this reduction. Overreduction to the alcohol is negligible. If the reduction... 

A classic method for generating regio-defmed enolates is metal-ammonia reduction of an enone. Stork and d Angelo found that the enolate resulting from lithium-ammonia-r-butyl alcohol reduction of octalone (3), followed by evaporation of ammonia, suspension of the enolate in ether and treatment with... 

Dissolving metal reduction of a,/J-unsaturated ketones which are part of an octalone system places the //-hydrogen atom in an axial position (see Section D.2.3.2.). 

Metal in ammonia reduction of bicyclic enones, especially terpenoid or steroid systems, has been intensively investigated and occurs with a high degree of diastereoselectivity. Stork has formulated the general rule that the reduction product is the more stable of the two isomers with the newly induced /1-hydrogen axial to the keto ring41,42. This rule is rationalized in terms of stereoelectronic effects in the transition state. For example, in reductions of octalones of type 1 only two (2 and 3) of three possible anionic transition states are stereochemically allowed. 

It is only in these two conformations that the orbital of the developing carbon —hydrogen bond overlaps with the remainder of the enolate 7i-system. The trans transition state 2 is generally more stable than the ci.i transition state 3, and therefore the trims-prod net is usually found as the major product, as illustrated with the reduction of octalone 443. 

In connection with the potential syntheses of this group of sesquiterpenes, the results of Piers et al. are of interest. They have found that the Birch reduction of 4-alkyl-A -2-octalones is highly sensitive to the configuration of the 4-alkyl group, as is demonstrated by the fact that (102) and (104) gave stereoselectively the ketones (103) and (105) respectively. 

The above stereoelectronic arguments were proposed by Stork and Darling (61) to explain why the more stable isomer is not necessarily always obtained (62). For example, reduction of the octalone 221 with lithium-ammonia-ethanol followed by oxidation afforded the trans-2-decalone 222 even though the isomeric cis-2-decalone 223 is about 2 kcal/mol more stable than 222. Conformation 226 of the enolate dianion is the most favored sterically but it is electronically disfavored. Conformations and 2 are both electronically favored but 225 is less favored sterically than 224. Therefore. 

An additional methodology for the selective reduction of unsaturated acyclic and cyclic carbonyl compounds is composed of refluxing for 15-45 minutes a mixture of limonene and the enone substrate in the presence of 10% Pd/C. For example, the reduction of /3-octalone afforded the cis isomer in 83% selectivity, which is comparable to the results obtained with hydrogen (Scheme 3 and 5) and ammonium formate (Scheme 19). The high yields and selectivity as well as the no need for an acid or basic medium makes this method very convenient. 

Exceptions to the preference for formation of the trans ring fusion by axial protonation can usually be traced to unfavorable steric interactions in the chair-chair conformation of the reduction intermediate. For example, 6-j8-t-butyl-A -2-octalone gives predominantly the cis ring junction because a chair-chair conformation is precluded by the bulky t-butyl substituent. 

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