[Agr. Biol. Chem., Vol. 29, No. 3, p. 243•`248, 1965] Saligenin Cyclic Phosphoramidates and Phosphoramidothionates as Pesticides By Morifusa ETO, Ken KOBAYASHI,_??_ Takeshi KATO,_??_ Kenichi KOJIMA* and Yasuyoshi OSHIMA Department of Agricultural Chemistry, Kyushu University, Fukuoka and *Institute for Agricultural Chemicals, Toa Noyaku Co., Odawara Received October 5, 1964 Several saligenin cyclic phosphoramidates and phosphoramidothionates were synthesized and their pesticidal activities against insects, mites and nematodes were examined. 2- Methylamino-4H-1,3,2-benzodioxaphosphorin-2-oxide and its thiono analog had high acti vities. They were also effective as systemic insecticides. When the size or number of substituent on nitrogen increased, the pesticidal activities decreased. Our investigations on saligenin cyclic phos EXPERIMENTALS phorus esters have started with the finding of Syntheses. the biologically active metabolite of tri-o-tolyl All cyclic phosphoramidates and phosphoramido phosphate.1,2) It has been demonstrated that thionates were synthesized from saligenin and ap methyl phosphate (Salioxon) and methyl phos propriate phosphoramidic dichloride or phosphor amidothioic dichloride by the action of proper phorothionate (Salithion) derivatives in this dehydrogen chloride agent. The reaction of saligenin series have high insecticidal activities.3,4) As with reactive dichloride as monoalkylphosphoramidic some known systemic insecticides" such as dichloride and some others was proceeded by the Schradan (octamethylpyrophosphoramide) and action of tertiary amine such as pyridine (Procedures Mipafox (N, N'-diisopropylphosphorodiamidic Ap and Ap') or triethylamine (Procedure At) in u fluoride) have phosphoramide linkage, it ap cooled condition. Liquid dichloride was usually added peared that systemic insecticidal properties dropwise to the mixture of saligenin and the base would be expected from amidate derivatives in chloroform (Procedures Ap and At). Solid dichlo in this series. The investigations described ride was, however, dissolved in cold chloroform with in this paper are concerned with syntheses saligenin, then the amine was added dropwise to the and pesticidal activities including systemic chilled mixture (Procedure Ap'). When the dichloride is less reactive as almost all phosphoramidothioic and activity of saligenin cyclic phosphoramidates diethyl phosphoramidic dichlorides, heating the mix and phosphoramidothionates. ture of reactants in toluene in the presence of anhydrous potassium carbonate and copper powder was useful (Procedure B). The procedures are illust _??_ Research fellow from Toa Noyaku Co., Odawara. _??_ Present address. Mikasa Chemical Co., Amagi. rated by the following examples. Phosphoramidic 1) J. E. Casida, M. Eto and R. L. Baron, Nature, 191, 1396 dichlorides and phosphoramidothioic dichlorides were (1961). 2) M. Eto, J. E. Casida and T. Eto, Biochem. Pharniacol., prepared according to Michaelis' procedure.6) 11, 337 (1962). 2-Methylamino-4H-1, 3, 2-benzodioxaphosphorin-2- 3) M. Eto, Y. Kinoshita, T. Kato and Y. Oshima, Nature, 200, 171 (1963). oxide (K-19) (Procedure At). To a mixture of 4) M. Eto, Y. Kinoshita, T. Kato and Y. Oshima, This saligenin, 9.2g, triethylamine, 15g, and 90ml chloro- Journal, 27, 789 (1963). 5) P. A. Giang, J. Assoc. Offic. Agr. Chem., 37, 642 (1954). 6) A. Michaelis, Ann., 326, 129 (1903). 244 Morifusa ETO, Ken KOBAYASHI, Takeshi KATO, Kenichi KOJIMA and Yasuyoshi OSHIMA form was dropwise added 12g methylphosphoramidic borer, Chile supressalis Walker, were topically treated dichloride with stirring and cooling in an ice bath. as previously reported.7.8) After the completion of addition,, the reaction mix Pot tests for rice stem-borer were performed by ture was kept overnight at room temperature, and spraying 20ml of 0.025% emulsion to 3 young rice then washed sequentially with ice water, dilute hydro plants cultured in a pot. The spray was applied at chloric acid, aqueous sodium bicarbonate solution distance of 1m with a power sprayer at 5lbs/in2. and water. The solvent was removed in vacuo after Fifteen first instar larvae were made the plants infest drying over anhydrous sodium sulfate. Crude crystals, seven days before the spray. In some experiments, 8.05g, m.p. 86•Ž, were recrystallized from benzene the larvae were made infest three, five or eight days to yield pure crystals, m.p. 87•Ž. after the spray in order to examine the residual activity. Mortality accounts were done three days 2-n-Propylamino-4H-1, 3, 2-benzodioxaphosphorin- 2-oxide (K-41) (Procedure Ap'). To a mixture, chilled after the treatments. All tests were triplicated. at -4•Ž, of 12.3g saligenin, 16.2g propylphosphor Systemic activities. Systemic insecticidal activities amidic dichloride and 100ml chloroform, 16g pyridine against green rice leafhopper were examined by using was dropped with stirring. The mixture was stirred 10 adult females (susceptible Odawara strain) on 3 for four hours at room temperature after the addition young rice plants of which roots were soaked in 20ml of pyridine. After washing and drying by usual emulsion diluted with tap water. They were kept in a small net cage at 25•Ž and mortality account manner, the solvent was removed in vacuo. The residue was distilled in vacuo at 135•`140•Ž (0.5 was made after twenty-four hours. The tests were triplicated. mmHg) to yield 8g of liquid. Systemic activity test against rice stem-borer was 2-Dimethylamino-4H-1, 3, 2-benzodioxaphosphorin- carried out as follows: Seven rice plants in a pot 2-sulfide (K-36) (Procedure B). Saligenin, 12.3g, were infested with 10 to 12 first instar larvae four was dissolved in 100ml of toluene by heating. Thirty days before application of insecticide. Acetone solu grams of finely powdered anhydrous potassium carbo tion of chemicals was dropped to water covering soil nate and copper powder, 0.5g, were added thereto, in the pot. Twelve grams chemicals an acre were and the mixture was added dropwise with dimethyl applied. Mortality was counted seven days after the phosphoroamidothioic dichloride, 18g, while being treatment. The test was duplicated. stirred and kept at 60•Ž. After one hour, the tem Acaricidal activity. Primary leaf of kidney bean perature of the reaction mixture was raised to 70 •` 80•Ž, and the mixture stirred for fifteen hours at plants was dipped for ten seconds in aqueous emul sion of test chemicals. The leaf when dry was in that temperature and filtered. The filtrate was washed fested with about 50 adults of Tetranychus telarius. and dryed by ordinary manner. The solvent was They were held for three days before making mor removed in vacuo and the residue distilled in vacuo tality account. at 118•`122•Ž (0.2mmHg) to yield 6.2g of liquid. Nematocidal activity. Rhabditis sp. was suspended Pesticidal Tests. in an aqueous solution of chemicals and kept at 25•Ž Insecticidal activities. Four days old females of for twenty-four hours. The tests were duplicated. oriental house flies, Musca domestica vicina Macquart Takatsugi strain, were topically treated with the RESULTS acetone solution of test chemicals and kept at 25•Ž. Saligenin cyclic phosphoramidates and their The mortality account was made after twenty-four thiono analogs were synthesized by the phos hours. The tests were duplicated. phorylation of saligenin with appropriate Knock down time was measured by a film method. A sheet of filter paper was placed on the bottom of phosphoramidic dichlorides and their thiono analogs respectively in the presence of suitable a beaker (diameter 9cm). Acetone solution contain ing 100ƒÊg of test chemicals was poured on the filter de-hydrogen chloride reagent such as tertiary paper and after the evaporation of the solvent, 2ml amine or potassium carbonate. Their synthetic of sugared milk was spread on the paper. Oriental procedures, yields, physical and analytical house flies of Sapporo strain were used. 7) S. Kitakata, A. Shiino and K. Kojima, Botyu-Kagaku, Adult females of green rice leafhopper, Nephotettix 28, 29 (1963). 8) K. Kojima, T. Ishizuka and S. Kitakata, ibid., 28, 55 bipuntatus cincticeps Uhler, and larvae of rice stem (1963). Saligenin Cyclic Phosphoramidates and Phosphoramidothionates as Pesticides 245 TABLE I. PHYSICAL AND ANALYTICAL DATA OF SALIGENIN CYCLIC PHOSPHORAMIDATES AND PHOSPHORAMIDOTHI.ONATES(I) PRODUCED BY THE REACTION * uncorrected temperature. t Tertiary amine (A) or potassium carbonate (B) was used as de-hydrogen chloride agent. For detail, see the ex perimental part. TABLE 11. TOXICITIES TO INSECTS AND MOUSE OF (II) IN COMPARISONWITH KNOWN INSECTICIDES * Crude sample was used. Numbers in parentheses are mortality percentage at 10ƒÊg dose per female house fly. 246 Morifusa ETO, Ken KOBAYASHI, Takeshi KATO, Kenichi KOJIMA and Yasuyoshi OSHIMA data are shown in Table I. Their infrared desirable properties as insecticides. It killed spectra examined in chloroform solution 100% larvae infesting rice plants by spraying showed characteristic absorption bands as 20ml a pot of 0.025% emulsion. Its oxo sociated with P-O-C (alkyl), P-O-C (aryl), and analog (K-19) killed 78.3%. The homologous N-H (in N-mono-substituted derivatives) in compounds carrying bigger substituent(s) than the regions 1020cm-1, 1250cm-1 and 3400cm-1 methyl group showed only weak activity. respectively. Ethyl parathion killed the insect, 97.2%, by Insecticidal activities against oriental house the same treatment. The residual activity on fly, Musca domestica vicina Macquart Takatsuki rice plants of K-35 against the insect larvae strain, rice stem-borer, Chilo supressalis Walker, was slightly less than Parathion. Sixty-two and green rice leafhopper, Nephotettix bipuntatus percent larvae invading rice plants which had cincticeps Uhler, and toxicity for mouse are been sprayed with K-35 before five days were shown in Table II. Saligenin cyclic methyl killed, while 77% killed by the same treatment phosphoramidate (K-19) and its thiono analog with Parathion. Systemic insecticidal activity (K-35) are most insecticidal for all tested against rice stem-borer in rice plant stem insect species and are comparable to Parathion is shown in Table III.