SYNTHESIS OF SOME UREA DERIVATIVES

A. G. PECHENKIN, L. G. TIGNIBIDINA, T. V. ANTONOVA, Z. M. MURAV’EVA

(Presented by the scientific seminar of the Faculty of Chemical Technology)

As a continuation of work [1] on the synthesis of \(N_1N^1\)-substituted ureas, with the aim of searching for preparations with anticonvulsant activity, we obtained compounds of the general formula \(R—NHCONHCO—R^1\), which are given in the table.

The starting primary amines were obtained by the Leuckart reaction, by hydramination of ketones [2].

The synthesis of the compounds listed in the table was carried out by condensation of the corresponding amines with nitrourea according to the scheme

\[ \underset{\|}{\mathrm{NO_2HNCNH_2}} + R—NH_2 \to R—NH—C—NH_2 + N_2O + H_2O. \]
\[ \underset{O}{\phantom{\mathrm{NO_2HNCNH_2}}} \qquad\qquad\qquad \underset{\|}{\phantom{R—NH—}O} \]

This method is general and was applied by T. L. Davis [3] for the synthesis of a number of alkyl- and aryl-derivatives of urea; we used it to obtain urea derivatives not described in the literature. Previously known urea derivatives were also synthesized; however, they had been obtained by other methods, for example by the interaction of amine hydrochlorides with potassium isocyanate [4]

\[ R—NH_2\cdot HCl + KOCN \to R—NH—C—NH_2 + KCl \]
\[ \qquad\qquad\qquad\qquad\qquad\quad \underset{\|}{O} \]

and by the interaction of alkyl and aryl isocyanates with amines [5]

\[ R—NH_2 + ROCN \to R—NHCONH—R. \]

It should be noted that the Davis method has advantages over the others, since when it is used the reaction yields are considerably higher and there are no impurities of inorganic salts, which complicate the purification of alkylureas.

We obtained aryl- and alkyl-substituted ureas in yields of 60–100%, calculated on the amine taken into the reaction; however, during purification much material is lost, and the yields of the final products reach only 30–70%.

Since acylation of substituted ureas possessing anticonvulsant activity considerably lowers the toxicity

Table 1

preparations [6], it was of interest to obtain acyl derivatives of some of the \(N\)-substituted ureas synthesized by us.

Experimental Section

All the compounds of the type \(\mathrm{R—NHCONH_2}\) listed in the table were obtained as follows: into a three-necked round-bottom flask equipped with a reflux condenser, a mechanical stirrer, and a dropping funnel, a suspension of 1.1 moles of nitrourea in 500 ml of water is placed, and, with stirring, 1 mole of amine is gradually added from the dropping funnel.

After the addition of the amine, the reaction mixture is heated for 1 hour on a water bath at a temperature of \(60^\circ\mathrm{C}\); during this, evolution of gas bubbles and complete dissolution of the nitrourea are observed in the flask.

All the urea derivatives listed in the table, except isopropyl-, isobutyl-, and sec-butylureas, after heating of the reaction mixture to \(60^\circ\mathrm{C}\), precipitate as white flocculent solids, which after standing for 48 hours at room temperature are filtered off. The filtrate is evaporated in a porcelain dish on a boiling water bath and gives an additional amount of product. Isopropyl- and isobutylureas are soluble in water, and therefore, to isolate them, the aqueous solution is evaporated to dryness on a boiling water bath.

sec-Butylurea is evaporated in air at room temperature, since on evaporation on a boiling water bath it decomposes into urea and amine, which volatilizes with the water vapor.

Acylation of isoamylurea and \(\beta\)-phenylisopropylurea was carried out with fatty acids: acetic, propionic, butyric, valeric, and isovaleric, according to the general method [7]—into a three-necked round-bottom flask equipped with a mechanical stirrer, reflux condenser, and dropping funnel are charged 0.1 mole of amyl- or \(\beta\)-phenylisopropylurea and 0.2 mole of acid. To this are added 75 ml of dry benzene. The flask with its contents is placed on an oil bath, which is heated to \(75^\circ\mathrm{C}\). From the dropping funnel, at \(75^\circ\mathrm{C}\), 0.2 mole of phosphorus trichloride is added dropwise over 30 min. The temperature of the bath is then raised to \(90^\circ\mathrm{C}\), and the reaction mixture is maintained at this temperature for 12 hours.

After completion of the reaction, the benzene layer is separated from the precipitated phosphorous acid, the benzene is evaporated, and the residue is purified by recrystallization from a water–alcohol mixture (1:2) 2–3 times.

Acyl derivatives of \(\beta\)-phenylisopropylurea containing butyric and valeric acid residues in the \(N'\)-position could not be isolated by us from the syrupy mass that remains after evaporation of the benzene.

LITERATURE

1. A. G. Pechenkin, L. G. Tignibidina. Izv. TPI, vol. 198 (in press).
2. B. M. Bogoslovskii, Reactions and Methods of Investigation of Organic Compounds, vol. 3, Goskhimizdat, 1954 (225–314).
3. T. L. Davis. “Journal of the Chemical Society,” 51, 1790 (1929), ibid., 44, 2595 (1922), ibid., 45, 1816 (1923).
4. Berichte, 22, 1409 (1889).
5. I. Guben. Methods of Organic Chemistry, vol. 4, book 1, Goskhimizdat, 77–78, 1949.
6. P. P. Kulev, N. S. Dobychina. ZhVKhO, VIII, 701, 6, 1963.
7. N. S. Dobychina, A. G. Pechenkin, L. G. Tignibidina. Author’s certificate No. 188957 of 15/XII-1966.