3-Octalone

The 5-oxohexanal 27 is prepared by the following three-step procedure (1) 1,2-addition of allylmagnesium bromide to an a, / -unsaturated aldehyde to give the 3-hydroxy-1,5-diene 25, (2) oxy-Cope rearrangement of 25 to give 26, and (3) palladium catalyzed oxidation to afford 27. The method was applied to the synthesis of A -2-octalone (28), which is difficult to prepare by the Robinson annulation[25]. 

MONOALKYLATION OF a.p-UNSATURATED KETONES via METALLOENAMINE8 l-BUTYL-10-METHYL-Ai< -2-OCTALONE... 

A. 0-Methyl-ls -2-octalone id,lA-Dimethylhydra2one. A 250-ml., round-bottomed flask equipped with a magnetic stirring bar and a Dean-Stark water separator is maintained under a dry nitrogen atmosphere (Note 1) and eharged with 7.4 g. (0.045 mole) of 10-methyl-A -2-oetalone [2(3 f)-Naphthalenone, 4,4a,5,6,7,8-hexahydro-4a-methyl-] (Note 2), 9.0 g. (0.15 mole) of N,N-dimethylhydrazine, 150 ml. of dry benzene, and 0.02 g. of p-toluenesulfonie aeid. This mixture is refluxed for 10-14 hours, after whieh time no further water separates. Benzene and excess N,A -dimethylhydrazine are then removed by simple distillation, and the residue is distilled under reduced pressure to give 8.1 g. (87%) of the dimethylhydrazone as a pale-yellow liquid, b.p. 94-98 (0.2 mm.) (Notes 3, 4). 

B. -Butyl- a-methyl- >-2-octalone. A 250-ml., three-necked flask equipped with a magnetic stirring bar, a reflux condenser, a 50-ml., pressure-equalizing funnel, and a rubber septum is charged with 1.4 g. (0.032-0.036 mole) of 55-60% sodium hydride dispersion in mineral oil... 

At this point the submitters reported 7.07 g. of crude product which by gas chromatographic analysis on an SE 30 column at 200° showed 1-3% of 10-methyl-A < -2-octalone and 85% of the desired alkylated product. 

Table 3-1 illustrates the influence of solvent polarity on the amount of 6W-product e.g. 10) formed from hydrogenation of octalone (9), testo-sterone and cholestenone. The product composition is determined by the amount of 1,2 and 1,4 adsorption of the substrate. 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

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 Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

A -Octalone-2 An 8.5-g (0.058 mole) portion of the above octalone mixture is dissolved in 50 ml of 60-90° petroleum ether in a 125-ml Erlenmeyer flask and cooled in a Dry Ice-acetone bath for 1 hour. zJ -Octalone-2 crystallizes and is collected by suction filtration through a jacketed sintered-glass funnel, which is cooled with Dry Ice-acetone. The residue is washed with cold (—78°) petroleum ether, transferred rapidly to a clean 125-ml Erlenmeyer flask, and the crystallization and filtration steps are repeated. The residue, after the second filtration, is transferred to a small round-bottom flask, brought to room temperature (the solid melts), and distilled. By this procedure, about 5 g (34%) of purified zl" -octalone-2, bp 143-145°/15 mm, is obtained. The purified material contains 1-3% of the -isomer. 

Distillation of the mother liquors affords a fraction enriched in Zl -octalone-2, bp 143-145715 mm. 

By a procedure analogous to that described in the preceding experiment, octalone-2 (12 g, 0.08 mole, Chapter 9, Section III) in ether is added to methylmagnesium iodide in the presence of cuprous bromide (0.2 g). After decomposition with ice-acetic acid, extraction with ether, and washing of the ether extract, the ethereal solution is shaken with an equal volume (50-60 ml) of saturated aqueous sodium bisulfite for 3 hours. The mixture is filtered and the filtrate is reserved. The crystals are washed with ether. The filtrate is separated and the aqueous phase is combined with the filtered solid. The combination is acidified (dilute hydrochloric acid) and heated under reflux for 30 minutes. The product thus liberated is extracted into ether, the ether is washed with bicarbonate, then with saturated aqueous sodium chloride solution, and then dried and evaporated. The residual oil is the desired product, bp 250-254°. 

Ammonia, anhydrous Matheson Co. 10-Methyl-d < -octalone-2 (Chapter 10, Section VI)... 

Cyclohexanecarbonyl chloride EK Triethylamine MCB, EK N-Methyl-A -nitroso-p-toluenesulfonamide A Isophorone MCB, A d < -Octalone-2 (Chapter 9, Section III)... 

A1( -octalone, 45, 80 N-nitioso-N-phenylglycine to N-phenylsydnone, 45, 96 Cyclobutanecarboxylic acid, reaction with hydrazoic acid, 47, 28 Cyclobutene, 1,2,3,4-tetrasiethyl-3,-4-dichloro-, 46, 34 reactions of, 46, 36 Cyclobutylamine, 47, 28 Cyclobutyl isocyanide, 46, 77 Cycloheptanone, 45, 31... 

Michael reaction, A1<9) octalone, 45, 82 N Mono- and N,N disubstitdted UREAS AND THIOUREAS 45, 69 N Monosubstituted thioureas from primary amines and silicon tetra-lsothiocyanate, 45, 69 N Monosubstituted ureas from primary amines and silicon tetraisocyan-ate, 46, 69... 

A1 9 OCTALONE 2, 46, 80 A9(10,-Octdlone 2,45, 80 Octanal, 47, 96 Octanoyl fluoride, 46, 6 M-Octyl iodide, reaction with tnmethyl amine oxide to yield octanal, 47, 96... 

Allenyl Silyl enol ethers, 86 Allyl alcohol trimethylsilyl ether, 84 Allyl carbonates, 114-15 9 Allyl-ay 2 octalone, 34-5 2-Allyl-2 methylcyclohexanone, 106 (Allyldimethylsilyl)methyl chloride, 58, 59 (AUyldimethylsilyl)methylmagnesium chloride, 59... 

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