Chemistry

A. O. Vizel, M. A. Zvereva, K. M. Ivanovskaya, I. A. Studentsova, V. G. Dunaev, M. G. Berim

Synthesis and Some Properties of Phosphacyclopentene Derivatives

(Presented by Academician B. A. Arbuzov, July 27, 1964)

In 1955 the first publication by McCormack appeared on the synthesis of phosphacyclopentene derivatives \((^{1, 2})\), to which insecticidal properties were attributed. In 1956 Daem \((^3)\) proposed insecticides which apparently \((^4)\) contain the phosphacyclopentene grouping. Somewhat later Perner \((^5)\) expressed the idea of the possibility of obtaining insecticides based on products of analogous structure, but containing, in the five-membered ring, in addition to the phosphorus atom, one oxygen atom. In 1962 a group of researchers \((^6)\) published data on the synthesis and screening biological examination of certain P-amides containing the 4-oxaphosphacyclopentene grouping.

Table 1

* See Table 2.

The limited information on physiological activity, as well as the availability of phosphacyclopentene derivatives based on the method for their preparation developed by some of us \((^{7–9})\), prompted us to synthesize and begin studying the biological action of preparations of this type.

According to the previously developed procedure \((^{7, 8})\), by reaction of 1-oxo-1-bromo-3-methylphosphacyclopentene-2 with the corresponding alcohols in the presence of triethylamine in ether solution, esters of cyclophosphinic acid were synthesized (II–VII, X, XI). The acids (XIII and XIV) were obtained by saponification of the corresponding bromohydrides and recrystallized from acetone. The sodium salt (I) was prepared from equimolar amounts of acid XIII and sodium hydroxide in aqueous solution. Purification was carried out by reprecipitation with acetone from alcohol. Phosphine oxide (VIII) was obtained by McCormack’s method \((^1)\). The phenyl ester (IX) was synthesized by the method of B. A. Arbuzov and L. A. Shapshinskaya \((^{10})\). The methyl ester (XII) was prepared by the reaction of 2-oxo-2-chloro-3,3,5-trimethyl-1-oxa-2-phosphacyclopentene-4 \((^{11, 12})\) with methanol in the presence of triethylamine. Data on the products obtained are given in Table 2.

The toxicity of the compounds was determined by the Behrens method upon single intraperitoneal administration to white mice. The \(LD_{50}\) values are presented in Table 1. For ester VII it was not possible to determine the toxicity because of its limited solubility in water. Most of the compounds listed in Table 1 gave a uniform picture of poisoning, similar to the action of narcotic substances. On the analogous action of organophospho-

Table 2

* Upper numbers are found values; lower numbers are calculated.

There is mention of such compounds in the report of I. A. Frankov (13). However, the author does not give the formulas of the substances acting in this way. Lethal doses of the compounds studied by us caused sharp depression and cessation of respiration. From the data in Table 1 it is seen that the toxicity of the esters in series II—VII and IX—X increases with increasing length of the hydrocarbon radical. The duration of the “lateral position” of the mice upon administration of the maximum tolerated doses of the preparations, adopted as a criterion for assessing the strength of their action, proved not to be parallel to toxicity and was maximal for the ethyl ester of cyclophosphinic acid III. The action of the preparations was reversible and, after the mice were awakened, did not affect their general condition. Upon administration of the free acids XIII and XIV, as well as of salt I, no phase changes in the condition of the animals were observed; preparation XII likewise produced such an effect only in lethal doses.

The action of the preparations in vitro was investigated on 7 species of pathogenic microbes. Most of the compounds were studied at dilutions of 1 : 100 and 1 : 1000. 250 million microbial bodies of daily agar cultures were placed in 1 ml of a solution of the sterilized preparation and incubated for 1 and 24 hours at 37°. Then, with a standard loop, inoculations were made onto solid nutrient media. The action of the preparations was evaluated by the character of microbial growth after incubation in a thermostat for 3 days. The results are given in Table 3. As is evident from the table, the broadest range of anti—

Table 3

Note. The upper numbers are the bactericidal dilutions of the preparations at one-hour exposure; the lower numbers, at 24-hour exposure. A dash indicates the absence of bactericidal and bacteriostatic action of the preparations. An asterisk marks cases of bacteriostatic action of the preparations.

microbial action is possessed by acids XIII and XIV, as well as by esters XII and VII. Sodium salt I, phosphine oxide VIII, and the lower aliphatic esters did not show bactericidal properties.

Institute of Organic Chemistry
Academy of Sciences of the USSR
Kazan

Kazan Medical Institute

Received
22 VIII 1964

CITED LITERATURE

1. W. B. McCormack, U. S. Pat., 2663737; Chem. Abstr., 49, 7601 (1955).
2. W. B. McCormack, U. S. Pat., 2663738; Chem. Abstr., 49, 7602 (1955).
3. W. T. Dye, U. S. Pat., 2703813; Chem. Abstr., 50, 1892 (1956).
4. N. N. Mel’nikov, Ya. A. Mandel’baum, K. D. Shvedova-Shilovskaya, Chemical agents for plant protection, 1957, No. 3, p. 39.
5. J. C. Pernert, Brit. Pat., 801568; Chem. Abstr., 53, 9251 (1959).
6. D. C. Schroeder, P. O. Corcorgan et al., J. Org. Chem., 27, 1098 (1962).
7. B. A. Arbuzov, A. O. Vizel’, Author’s Certificate No. 162845 of the USSR, application of 20.604, February 18, 1963.
8. B. A. Arbuzov, A. O. Vizel’, DAN, 158, No. 5 (1964).
9. B. A. Arbuzov, A. O. Vizel’ et al., DAN, 159, No. 3 (1964).
10. B. A. Arbuzov, L. A. Shapshinskaya, Izv. AN SSSR, OKhN, 1962, 65.
11. L. R. Drake, C. S. Marvel, J. Org. Chem., 2, 387 (1937).
12. L. Anschutz, E. Klein, G. Germák, Chem. Ber., 77, 726 (1944).
13. I. A. Frankov, Proceedings of the II Conference, Chemistry and Application of Organophosphorus Compounds, Publishing House of the Academy of Sciences of the USSR, 1962, p. 452.