Physical Chemistry

V. M. Potapov, Corresponding Member of the Academy of Sciences of the USSR, A. P. Terent’ev, and L. I. Serova

Dispersion of Optical Rotation of 2,2-Dimethyl-6-phenylpiperidone-4

In numerous works by Djerassi and other investigators, certain regularities have been established in the rotatory dispersion (r.d.) of optically active compounds with a carbonyl chromophore (¹). In the overwhelming majority of cases these were carbocyclic compounds—simple and complex derivatives of cyclohexane. In view of these results, and in connection with our work on the r.d. of nitrogen-containing compounds, it seemed of interest to us to study the r.d. of nitrogen-containing analogs of cyclohexanone and thereby obtain material for answering the question: does the presence of a nitrogen atom in the ring affect the anomalous r.d. curve produced by the carbonyl chromophore, and are the regularities established for alicyclic ketones preserved in nitrogen heterocycles?

As the simplest object we chose piperidones, whose spectropolarimetric study may serve as a step toward the investigation of natural alkaloids.

Only a few optically active piperidones have been described in the literature. The most accessible method for obtaining them is the destruction of natural compounds and synthesis from intermediate compounds previously resolved into optical isomers. Examples have been described of the resolution of 1,2-dimethyl-2-ethylpiperidone-3 with dibenzoyltartaric acid in ether (²), and of the ketoxime of 2,6-diphenylpiperidone-4 with d-camphorsulfonic acid (³). An attempt to resolve the ketoxime of 1-methyl-3,5-diphenylpiperidone-4 with d-camphorsulfonic, d-camphoric, d-tartaric, d-dibenzoyltartaric, and N-p-nitrobenzoylglutamic acids proved unsuccessful (⁴).

For our investigations we chose 2,2-dimethyl-6-phenylpiperidone-4, which is relatively easily synthesized according to the scheme: acetone—diacetonamine—piperidone (⁵). Diacetonamine, described in the literature as a liquid (⁶), was obtained by us in crystalline form: small white crystals with m.p. 35–36° (from ethanol).

For the resolution of 2,2-dimethyl-6-phenylpiperidone-4 we tested menthylsulfuric acid (⁷) in dichloroethane, dibenzoyltartaric anhydride in dioxane, and d-tartaric acid in ethanol, acetone, and n-butanol. The best results were obtained when d-tartaric acid in n-butanol was used as the asymmetric reagent. In this way a piperidone with rotation ([\alpha]_D - 26.85^\circ) ((C = 7.3,) benzene) was obtained.

A study of the rotatory dispersion of (−)-2,2-dimethyl-6-phenylpiperidone-4 in methanol, ethanol, n-butanol, n-heptane, dioxane, benzene, dimethylformamide, and pyridine showed that in all solvents there are r.d. curves with a negative Cotton effect, with a trough located in the region of 320 mµ (Fig. 1). The course of the r.d. curve of the piperidone hydrochloride and acetate in methanol, ethanol, n-butanol, dioxane, and water is analogous to the course of the r.d. curve of the free base. In this case the r.d. curves have a trough in the region of 305–310 mµ; the absolute values of the rotations decrease considerably (Fig. 1). The r.d. curves of the ketoxime of 2,2-dimethyl-6-phenylpiperidone-4 (⁸) in methanol and benzene run parallel to the r.d. curves of the piperidone hydrochloride (Fig. 1). Addition of a drop of concentrated hydrochloric acid to the methanolic solution of the ketoxime of (−)-piperidone was accompanied by reversal of the sign of rotation and a change in the course of the r.d. curve: a smooth positive curve was observed in the region from 600 mµ to 200 mµ. Apparently, in this case formation of the hemiacetal occurs and the ketone anomaly disappears (¹, ⁹).

Experimental Part

Diacetonamine was obtained by passing dry gaseous ammonia, with water cooling, into acetone containing 200 g of anhydrous calcium chloride per liter, as described in the literature (^{6}). Yield 40%, m.p. 35–36°. In the literature the yield is not given; the substance is described as an oil.

Acid oxalate of diacetonamine was obtained by mixing methanolic solutions of equimolecular amounts of the amine and oxalic acid. Yield 53%, m.p. 125–126° (from ethanol).

Found, %: N 6.80, 6.80, 6.63
(\mathrm{C_8H_{15}O_5N}). Calculated, %: N 6.83

2,2-Dimethyl-6-phenylpiperidone-4 was obtained by boiling diacetonamine oxalate for 70 hours with freshly distilled benzaldehyde in methanolic solution, as described in the literature (^{5}). Piperidone oxalate was obtained, m.p. 208–210°. Yield 66%. Liberation of the free base from the oxalate was carried out with a 10–15% aqueous ammonia solution, with quantitative yield. M.p. 62°, which agrees with the literature data (^{5}).

Found, %: C 76.74, 76.63; H 8.44, 8.49
(\mathrm{C_{13}H_{17}ON}). Calculated, %: C 76.81; H 8.43

Fig. 1. Curves of rotational dispersion of piperidone (1), piperidone ketoxime hydrochloride (2), piperidone hydrochloride ketoxime (3)

Resolution of 2,2-dimethyl-6-phenylpiperidone-4. To a warm solution of 2.22 g of (d)-tartaric acid in 40 ml of (n)-butanol was added a solution of 3 g of 2,2-dimethyl-6-phenylpiperidone-4 in 10 ml of (n)-butanol. After 1 hour the precipitate was filtered off, giving 1.8 g of tartrate having ([\alpha]_D + 10.31) ((C = 3.4,) water), m.p. 129.5–143°. After four recrystallizations from (n)-butanol, tartrate was obtained with m.p. 132–145.5°, ([\alpha]_D + 19.21^\circ) ((C = 1.32,) water). From the tartrate, by adding solid KOH to the aqueous solution with cooling, 1.1 g of ((-))-2,2-dimethyl-6-phenylpiperidone was isolated, m.p. 62°, ([\alpha]_D - 26.85^\circ) ((C = 7.3,) benzene). The tartrate remaining in the mother liquor could not be made to crystallize after removal of the solvent. The oil was dissolved in water and, by adding solid KOH with cooling, the free base was isolated, m.p. 62°, ([\alpha]_D + 11^\circ) ((C = 10.84,) benzene), yield 1 g.

Measurement of the ORD curves was carried out with a standard domestic spectropolarimeter of VNIIEKIprodMash—a semiautomatic instrument making it possible to measure rotation of the plane of polarization in the region 720–230 mµ with a reading accuracy of (\pm 0.003^\circ). For the substances measured, the region of measurements was limited by their own absorption.

Received
30 III 1964

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