INVESTIGATION OF THE ACYLATION REACTION OF N-SUBSTITUTED ARYLALKYLUREAS IN THE PRESENCE OF VARIOUS ACID CHLORIDE–FORMING AGENTS

A. G. PECHENKIN, L. G. TIGNIBIDINA, T. V. ANTONOVA

(Presented by the scientific-methodological seminar of the CTF)

This work is devoted to finding the best acid chloride–forming agents in acylation reactions of arylalkylureas. The need for such studies is due to the fact that acylated ureas possess anticonvulsant action and may find practical application in the treatment of the corresponding diseases.

Acylated ureas can be obtained in the reaction of substituted N-aryl-, alkylureas with acid chlorides and anhydrides of carboxylic acids [1—4]; methods have also been proposed for acylating ureas with carboxylic acids in the presence of acid chloride–forming agents of the type $\mathrm{SOCl_2}$ [5], $\mathrm{PCl_3}$ [6], $\mathrm{HOSO_2Cl}$ [7]. Acylation with carboxylic acids in the presence of $\mathrm{SOCl_2}$ or $\mathrm{PCl_3}$ is more prolonged (8—12 hours) than with acid chlorides (2—5 hours); however, in the former method the separate preparation of acid chlorides is not required.

We carried out the acylation of benzhydrylurea (I)—$(\mathrm{C_6H_5})_2\mathrm{CHNHCONH_2}$—with propionic acid in the presence of the following acid chloride–forming agents: $\mathrm{SOCl_2}$, $\mathrm{PCl_3}$, $\mathrm{PCl_5}$, $\mathrm{POCl_3}$, and performed a comparative quantitative analysis of the results obtained, which are presented in Table 1.

It is evident from the table that phosphorus oxychloride is the best acid chloride–forming agent. After a single recrystallization of the final product of the reaction with $\mathrm{POCl_3}$, its melting point (122—127°) approaches the melting point of pure benzhydrylpropionylurea (II) (128—129°), whereas with the other acid chloride–forming agents a single recrystallization gives a product with a melting point of 103—115°C. It should be noted, however, that in reactions with $\mathrm{POCl_3}$ and $\mathrm{PCl_5}$ diacylation products of the type $(\mathrm{C_6H_5})_2\mathrm{CHNHCON(COC_2H_5)_2}$ are formed, which upon recrystallization do not dissolve in hot alcohol. Elemental analysis for carbon, hydrogen, and nitrogen confirms the formation of the diacylated product with m.p. 196—198°C: N—found—7.90, calculated—8.29; C—found—70.48, calculated—70.80. In the acylation reaction with $\mathrm{SOCl_2}$ and $\mathrm{PCl_3}$, formation of the diacylated product was not observed.

For quantitative determination of unacylated (I), the method used in spectrophotometric analysis for determining the concentration of urea and its N-alkyl-, aryl derivatives was employed; it is based on the interaction of urea with Ehrlich’s reagent with the formation of stable complexes colored yellow [8]. This color,

Table 1

Yield and m.p. of N-benzhydryl-N′-propionylurea (II)
after acylation with various acid chloride–forming agents

The reaction was used by us for the photocolorimetric analysis of (I) in a mixture with (II) and (III)—the latter do not give a colored yellow complex with Ehrlich’s reagent. It was found that the relationship between the concentration of (I) and the optical density of the prepared solutions obeys the Bouguer–Lambert–Beer law within the concentration range from 2.4 to 30 mg per 25 ml of solution:

On the basis of the data given, a calibration plot was constructed for the dependence of optical density on the concentration of (I), which was subsequently used to determine the quantitative yield of (I) after acylation.

The acylation reaction of benzhydrylurea with propionic acid in the presence of SOCl₂, POCl₃, PCl₅, and PCl₃ was carried out according to [6]. We took 10 g of (I) (0.0442 mole), 1.80 g of propionic acid (0.0486 mole), PCl₃, PCl₅, POCl₃, SOCl₂ (0.0486 mole), and 50 ml of dry benzene. The reaction time was 8 hours at a bath temperature of 90°C. The yields of the products and their m.p. are given in Table 1.

Quantitative determination of N-benzhydrylurea

Preparation of Ehrlich’s reagent: 2.00 g of p-dimethylaminobenzaldehyde is dissolved in 95% ethyl alcohol in a 100-ml volumetric flask, 0.50 ml of concentrated sulfuric acid is added, and the volume is brought to the mark with ethyl alcohol.

Preparation of the solutions under investigation. After completion of the acylation reaction, the benzene solution is evaporated in air. The resulting residue is washed with a 10% aqueous solution of Na₂CO₃ and with water to neutral reaction and dried. From the resulting precipitate a 100 mg sample is taken, which is dissolved in 25 ml of ethyl alcohol. Then 5—10 ml of the prepared solution is poured into a 25-ml flask, 5 ml of Ehrlich’s reagent is added, and the volume is brought to the mark with ethyl alcohol. Before measurement the solutions are allowed to stand for 15 minutes. The complex of benzhydrylurea with Ehrlich’s reagent is fairly stable; its color does not change for 3—4 hours.

The optical density was measured on an FEK-56 instrument with light filter No. 3 in a 30.100 mm cuvette. The concentration of unreacted (I) in the solutions prepared after completion of the acylation reaction was determined from the calibration plot of density versus concentration.

Conclusion

1. The reaction of acylation of benzhydrylurea with propionic acid in the presence of various chlorinating agents \((\mathrm{SOCl_2}, \mathrm{POCl_3}, \mathrm{PCl_5}, \mathrm{PCl_3})\) has been studied; as a result it was established that, along with \(\mathrm{PCl_3}\) and \(\mathrm{SOCl_2}\), \(\mathrm{POCl_3}\) and \(\mathrm{PCl_5}\) can be used in the acylation reaction.

2. On the basis of photocolorimetric analysis of the acylation products, it was found that the highest yield of benzhydrylpropionylurea is achieved when \(\mathrm{POCl_3}\) is used.

3. It has been established that in the acylation reaction with \(\mathrm{PCl_5}\) and \(\mathrm{POCl_3}\), diacylated products are formed, which were not detected in reactions with \(\mathrm{SOCl_2}\) and \(\mathrm{PCl_3}\).

Literature

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