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Caution! Hexamethylphosphoric triamide vapors have been reported to cause cancer in rats [J. A. Zapp, Jr., Science, 190, 422 (1975)]. All operations with hexamethylphoephoric triamide should be performed in a good hood, and care should be taken to keep the liquid off the skin.
A. 10-Methyl-Ä1 (9)-2-octalone N,N-Dimethylhydrazone. 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 charged with 7.4 g. (0.045 mole) of 10-methyl-Ä1(9)-2-octalone [2 (3#) -N aphthalenone, 4,4a,5,6,7,8-hexahydro-4a-methyl-] (Note 2), 9.0 g. (0.15 mole) of ^,^-dimethylhydrazine, 150 ml. of dry benzene, and 0.02 g. of 2>-toluenesulfonic acid. This mixture is refluxed for 10-14 hours, after which time no further water separates. Benzene and excess iV,iV-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-10-methyl-k.U9)-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. (0.032-0.035 mole) of 55-60% sodium hydride dispersion in mineral oil
and put under a dry nitrogen atmosphere. The mineral oil is then removed by washing the sodium hydride three or four times with 5-ml. portions of dry toluene (Note 5). A solution of 6.12 g. (0.030 mole) of 10-methyl-A1<9)-2-octalone A^iV-dimethylhydrazone in 100 ml. of dry toluene is placed in the flask and 10 ml. of dry hexamethylphosphor-amide is added. The rubber septum is replaced with a glass stopper. The solution is warmed with an oil bath to reflux the toluene; hydrogen evolution is observed. Reflux is maintained for 14-16 hours, during this time the solution becomes dark brown. The solution is then cooled to
— 10° and 4.5 g. (0.033 mole) of 1-bromobutane in 10 ml. of dry toluene is slowly added. The solution is warmed to 60° and maintained at that temperature for 4-5 hours. An abundant precipitate of sodium bromide is formed. The solution is cooled to 0° and an acetate-buffer solution (Note 6) is added. The mixture is refluxed for 4-5 hours to complete the hydrolysis. It is then cooled and decanted. The aqueous phase is extracted three times with 25-ml. portions of ethyl ether. The combined organic layers are successively washed three times with 80- to 100-ml. portions of 10% hydrochloric acid, three times with 50-ml. portions of a saturated sodium hydrogen carbonate solution, twice with 50-ml. portions of a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents are removed by rotary evaporation (Note 7). The residue is distilled under high vacuum using a short column. After a small forerun, 4.3-4.7 g. (65-72%) of pure 1-butyl-10-methyl-A1(9)-2-octalone, b.p. 84-92° (0.2 mm.), is obtained (Note 8).
1. A positive pressure of nitrogen is maintained using a mercury bubbler.
2. The 10-methyl-A1(9)-2-octalone, which can be prepared from
4-(diethylamino)-2-butanone, 2-methylcyclohexanone, and sodium,3 has b.p. 65-70° (0.1 mm.) and n20d 1.523. Infrared (neat) cm.-1: 1610, 1670; proton magnetic resonance (carbon tetrachloride) 8 (assignment): 5.6 (vinyl ÑH), 1.25 (angular ÑH3).
3. The hydrazone should be stored under dry nitrogen at — 10°.
4. Proton magnetic resonance (carbon tetrachloride) 8 (multiplicity, assignment): 6.35 (40%) and 5.70 (60%) (singlets, vinyl hydrogens of diastereomeric hydrazones), 2.35 (singlet, N(('H3)2), 1.15 (singlet, Ñ—CH3); infrared (neat) cm.”1: 1620, 1680; n20D 1.505.
5. A 5-ml. portion of dry toluene is introduced into the flask with a syringe, and sodium hydride dispersion is stirred for 1 minute. Then 4 ml. of the supernatant toluene is carefully removed from the flask with a syringe.
6. The buffer solution is prepared by dissolving 20 g. of anhydrous sodium acetate in a mixture of 40 ml. of acetic acid and 40 ml. of water.
7. 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-A1(S)-2-octalone and 85% of the desired alkylated product.
8. Proton magnetic resonance (carbon tetrachloride) 8 (multiplicity, assignment): 1.2 (singlet, angular CHa); 0.9 (triplet, CH3); infrared (neat) cm."1: 1660, 1600; n25D = 1.511.
Alkylations of enamines of a,/?-unsaturated ketones with alkyl halides often give very poor yields of C-alkylated products because of competing jV-alkylation.4"5 In the type of transformation illustrated here, direct alkylations of enamines are completely unsuccessful, even in cases where hindered enamines6 are used. On the other hand, the metalloenamine method7 can be applied generally with good success in the problem of monoalkylation of a,/9-unsaturated ketones.8