Octalones formation

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. 

A Dieckmann reaction of 7 and enol etherification provided trans-octalone 6 in 90% yield. An additional 10% of the transposed /3-ethoxy -enone 24 was also isolated. Compound 24 could easily be removed chromatographically (the first chromatography of the synthesis) and could be isomerized back to the 9 1 mixture in favor of 6 by resubjection to the etherification conditions. Compound 7 had three different CC Et groups, yet only the one adjacent to the CN group was attacked by the nascent ketone enolate. This selectivity, attributed to the effect of the powerfully electron-withdrawing CN group, was expected, as it was observed previously in the preparation of 3c.3 The selectivity of the enol ether formation was also expected from previous work. 

Figure 2 shows the 1,2- and 1,4-diadsorbed octalone, each in the cis and trans configuration. It can be seen that the cis 1,4-diadsorbed species is less hindered than is the trans species, and, thus, m-0-decaione formation should be favored by a 1,4-addition sequence. In the 1,2-diadsorbed species, little difference between cis and trans adsorption can be detected, and, therefore, nearly equal mixtures of the two isomeric decalones should be formed from a 1,2-addition process. Thus, the product distribution data given in Table II can be understood if it is considered that the reaction is a combination of 1,2- and 1,4-addition processes. The more polar the solvent, the more the 1,4-addition occurs and, as... 

The presence of base in the hydrogenation of A4-3-ketosteroids has long been known to lead to the almost exclusive formation of the 5)3 product (9,10), but, when base is added to the reaction medium in the hydrogenation of j3-octalone... 

The different enolate anions that may be obtained from octalone (XII) are shown in Fig. 8. It has been shown that the homoannular enolate corresponding to compound XX is the initial product formed on reaction of A4 -3-ketosteroids with a strong base and the only product formed on reaction with a weak base (28). This enolate isomerizes to the heteroannular species, such as compound XXI, on further treatment with strong base. Similar results have also been observed on reaction of octalone (XII) with strong base (29). This later work as well as a study of enamine formation (29) from XII indicated that the other enolate (XXII) is not present to any large extent. The homoannular enolate (XX) can be adsorbed in the cis and trans arrangement (Fig. 8), but the cis-adsorbed species is the less hindered. The heteroannular enolate (XXI) is almost planar with cis and trans adsorption occurring with almost equal facility. 

The presence of substituents on an unsaturated ketonic species can modify product stereochemistry in a variety of ways. When an angular methyl group is present in an octalone ring (e.g., compound XXIII) (33), the formation of the cis product usually predominates. 

The stereoselectivity in the hydrogenation of bicyclic and polycyclic a,P-unsaturated ketones with the double bond at the ring juncture has been the subject of extensive investigations.252 Formation of cA-2-decalone in the hydrogenation of A1,9-2-octalone (115) with palladium catalysts increases with increasing polarity of aprotic solvents and also in the presence of acid, especially in nonhydroxylic solvents.253,254 Hydro-bromic acid has been found to be more effective than hydrochloric acid for cA-2-de-calone, especially in tetrahydrofuran (eq. 3.72).255 Formation of alcoholic products was also completely depressed in the presence of hydrobromic acid, although the rate of hydrogenation became considerably lower than in the presence of hydrochloric acid.256... 

Any uncyclized diketone precursor to the octalone, formed by hydrolysis of the initial Michael alkylation product (129), may readily be cyclized by treatment with boiling ethanolic potassium hydroxide. The formation of dihydropyrans by cycloaddition of MVK to enamines at low temperature has been discussed in Section III.B. 

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. 

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. 

The photolysis of (/ )-A-10-methyl-2-octalone (125) [350] in homogeneous solution led to the formation of the products shown in Scheme 37. The II/III ratio is solvent dependent, with II favored in nonpolar media. In the a-CD solid complex, II is the major product (20 1). In the photolysis of the complex dissolved in water, a new product was isolated, corresponding to the addition of water. 

The alkylation can also occur under aprotic conditions such as in the formation of the octalone 23. The lithium enolate 22 is added to the ketone 20 in tetrahydrofuran at -78 C, and then the mixture is allowed to reach room temperature. The alkylation process is followed by subjecting the silylated intermediate to 5% sodium methoxide-methanol to give 1-methyl-A -octalone (23) in 80% overall yield. 

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. 

Organocopper )V)V-dimethylhydrazone (DMH) derivatives have been used for the synthesis of a variety of 1,5-dicarbonyl compounds. In contrast to the normal Robinson annelation of 2-methylcyclohexanone, which leads to attachment of methyl vinyl ketone analogues at C-(2) and eventual formation of (56), the organocopper DMH derivative of 2-methylcyclohexanone reacts with methyl vinyl ketone to give the 1,5-diketone (57), which undergoes base cyclization to the octalones (58). 

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. 

---