SYNTHESIS OF 2,2′-DIPHENYL-bis-GLYOXAL

P. D. BELENKO, A. N. NOVIKOV

(Presented by the scientific seminar of the departments and laboratories of organic synthesis, KhTF)

Many glyoxal derivatives are active against influenza and hepatitis viruses [1]. Some of them, recommended for use in medical practice [2], contain a biphenyl system, for example, biphenylglyoxal.

\[ \mathrm{ \begin{array}{c} \text{biphenyl–} \mathrm{C(=O)-C(=O)-H} \end{array} } \]

Among this series of compounds, 4,4′-diphenyl-bis-glyoxal and certain products of its condensation with various compounds also exhibited high antiviral activity.

Antiviral agents must possess a highly selective action on the protein envelope of the virus. In the opinion of M. Ya. Kraft [3], the mutual arrangement of the reactive groups, and the shape and dimensions of the molecule, should probably be of great importance for the selectivity of the preparation. It is necessary to ensure that the molecule of the hypothetical preparation corresponds strictly only to the protein of the viral envelope.

In accordance with these assumptions, it was of interest to obtain diphenyl derivatives with a different, closer arrangement of the glyoxal residues and to study their antiviral activity.

For this purpose we synthesized diphenyl-2,2′-bis-glyoxal, which has not been described in the literature. The starting material for its preparation was phenanthrene, which, by a known method [4], was converted into diphenyl-2,2′-diformyl. From the latter, by means of a magnesium-organic synthesis, diphenyl-2,2′-bis-α-hydroxyethyl was prepared; upon oxidation this gave 2,2′-diacetyldiphenyl, which under the action of selenious acid was converted into the final product.

\[ \begin{gathered} \text{anthracene} + O_3 + CH_3OH \longrightarrow \text{bis(methyl hemiacetal)} \xrightarrow{+HJ} \text{diphenylglyoxal} \xrightarrow{+JMgCH_3} \\ \text{bis(magnesium alcoholate)} \xrightarrow{+HOH} \text{2,2′-bis-}\alpha\text{-hydroxyethyldiphenyl} \xrightarrow{+CrO_3} \\ \text{2,2′-bis-}\alpha\text{-oxoethyldiphenyl} \xrightarrow{+H_2SeO_3} \text{2,2′-diphenyl-bis-glyoxal} \end{gathered} \]

Experimental Part

Preparation of 2,2′-bis-α-hydroxyethyldiphenyl. Magnesium turnings were placed in a 500 ml round-bottom flask, and the flask was connected, by means of a two-neck adapter, to a reflux condenser and a dropping funnel. The upper opening of the condenser was closed with a calcium chloride tube. Through the dropping funnel, about 30 ml of a mixture obtained by dissolving 15 ml of methyl iodide in 100 ml of absolute diethyl ether was added to the flask. To initiate the reaction, the flask was warmed by hand. The remainder of the mixture was added dropwise in such a way that the ether boiled gently throughout. If the reaction proceeded too vigorously, the flask was cooled with cold water. To complete the reaction, the flask was heated on a water bath until almost all of the magnesium had dissolved. After this, a solution of the dialdehyde was added dropwise to the hot solution (21 g of dialdehyde were dissolved completely in absolute ether). To bring the reaction to completion, the mixture was heated for 15–20 minutes on a water bath. After cooling, the resulting addition product was decomposed by adding 60 g of ice; the magnesium salt that separated was dissolved in hydrochloric acid (20 ml of concentrated hydrochloric acid and 20 ml of water). The ether layer was separated, and the aqueous solution was again treated in a separatory funnel with a small amount of ether.

The combined ether extracts were shaken for a long time and vigorously with 10 ml of 40% sodium bisulfite to remove the small amount of unreacted dialdehyde. The bisulfite solution was drained off, and the ether layer, to remove dissolved sulfur dioxide, was shaken with a small amount of sodium carbonate solution and dried over calcium chloride. After distilling off the ether, white crystals were obtained, which were purified by crystallization from benzene. Yield of diphenyl-2,2′-bis-α-hydroxyethyl: 38–40%. M.p. 147–148°C. Found, %: C 80.44; H 7.43; \(C_{16}H_{18}O_2\). Calculated, %: C 79.33; H 7.42.

Preparation of 2,2′-diacetyldiphenyl. To a solution of 2.4 g of 2,2′-di(α-hydroxyethyl)diphenyl in 24 ml of benzene, 8.9 g of crystalline sodium dichromate was slowly added, with cooling over 10–15 min and with mechanical stirring; then a mixture of 2.4 ml of acetic acid, 4.3 ml of sulfuric acid, and 14.4 ml of water was gradually added. The reaction mass was stirred for 4 h at 25–30°C. After this, the benzene solution was separated, washed twice with 4.8 ml portions of water, once with 9.6 ml of 5% KOH solution, and again twice with water; it was then dried over calcium chloride, and the benzene was distilled off.

After removal of the benzene, 14.4 ml of ethyl alcohol was added to the syrupy mass, and the solution was placed in a refrigerator for 1.5–2 h; a white crystalline precipitate separated, which was crystallized from cyclohexane. Yield of diacetyldiphenyl 50–55%, mp 92–93°C; literature value 92–93°C [5].

Preparation of 2,2′-diglyoxalyldiphenyl. 2.2 g of SeO₂, 8 ml of dioxane, and 0.4 ml of water were placed in a three-necked flask; the reaction mixture was heated to 70°C, and a solution of 2.4 g of diacetyldiphenyl in 18 ml of dioxane was added dropwise, with mechanical stirring, at this temperature. The reaction mixture was then boiled for 5 h. The hot solution was filtered three times without suction to remove selenium, left overnight, and the selenium was filtered off again; the dioxane was then distilled off. Distilled water was added to the mixture, it was boiled and filtered, and after the solution had cooled the precipitated diphenyldiglyoxal hydrate was filtered off; the water was then removed by azeotropic distillation with benzene. Yellow diphenyldiglyoxal was obtained in 30% yield, mp 103–105°C. On heating with water it is converted into a colorless hydrate form, which precipitates on cooling and, on standing in a desiccator over calcium chloride, loses water and is converted into diphenylglyoxal. The reaction for an aldehyde group with Fehling’s solution is positive. Found, %: C 71.75; H 4.2. C₁₆H₁₀O₄. Calculated, %: C 72.18; H 3.7.

Conclusions

1. Diphenyl-2,2′-bis-α-hydroxyethyl and 2,2′-bis-glyoxalyldiphenyl, not described in the literature, have been synthesized.

REFERENCES

1. Cavallini G., Massarani E., Nardi D., Mauri L., Magrassi F., Farmaco. Ed Scient., 15, No. 8, 503 (1960); RZhKhim, 7Zh 103 (1961). French patent, 596 M, 12.06.61; RZhKhim, 19N106 P (1963). English patent, 897303, 23.05.62; RZhKhim, 18N183 P (1963). Cavallini G., Nardi D., Massarani E., Farmaco Ed Scient., 19, No. 7, 597 (1964); RZhKhim, 10Zh158 (1956). U.S. patent, No. 3128312 (1964); RZhKhim, 23N173 P (1965). U.S. patent, No. 3095443 (1963); RZhKhim, 10N 192 P (1965).

2. U.S. patent, No. 3097138 (1963); RZhKhim, 2N177 P (1965).

3. M. Ya. Kraft. ZhVKhO im. D. I. Mendeleeva, X, No. 6, 630 (1965).

4. P. S. Bailey. J. Am. Chem. Soc., 78, 3811 (1965).

5. Criegee R., Höger E., Huber G., Kruck P., Marktscheffel F., Schellenberger M., Lieb. Ann., 599, No. 2, 81 (1956); RZhKhim, ref. 74302 (1957).