Xarch 1WS
37 1
XOTEY SGAIKST Histomonas meleagridis T a n ~ sI : ACTIVITY
Colr1l)d
I I I I 11
I1 11
Concri in feed. %
x o . of expts
0 . 015-0.05b 0.0125 0.0075 0 .00.; 0 . 03 0.03 0,025 0.015 0,0038-0.012.i 0,012.5-0.025 0.0075
9 1 4 3 4
Total no. of turkeys
31
J
10
SO
% survival
100 100 27 27 100 80 80 40
60 10 0 0 0 33 18 100 100 44 56 9 2 !5 All died of blackhead 2.j No blackhead infections At, O.O5',L tlic birds dcnionatrated slight neurologicnl disturI
I1 3 I1 S 1,2-1Xmethyl-33 nitroimidazole 2 Infected controls ... 9 riiiiifected controls ... $1 u Total absence of cecal or liver lebious at postmortem examination. t)anc.es as evidenced by movenieiit,s charact,eristic of intoxication.
a1is.j Because certain compounds have shown activity against both Trichomonas sp. and Histomonas nzeleagridis, the causative organism of blackhead (histomoniasis) in poultry, the investigation of I and I1 for histomonastatic activity in vivo was particularly significant . 6 , 7 The synthesis of 1-111 was accomplished by treating 4(5)-nitroimidazole or 2-methyl-4(5)-nitroimidazole with ethylene oxide to form the hydroxyethylimidasoles (Ia, IIIa). Subsequent treatment of Ia or IIIa with thionyl chloride or thionyl bromide gave the desired haloethylimidazole. The efficacies of 1-111 were determined against the protozoan H . iiieleagridis in Broad Breasted Bronze or Broad Breasted White turkeys. Poults which were reared in wire-bottom cages were orally inoculated with approximately 1000 embryonated cecal worm (Heterakis gallinarum) ova per bird at approximately 6 weeks of age. Prior experimentation had confirmed the presence of Histomonas organisms in these ova. ,411 tests were 28 days in duration. Turkeys were infected on the first day of the test. Medicated feed was given the first 21 days and nonniedicated the final 7 days of each experiment. Results shown in Table I demonstrate that I has greater histomonastatic activity at lower concentrations than 11. This is in accordance with the efficacy reported for the corresponding hydroxyethyl compounds Ia and IIIa against b l a ~ k h e a d . ~In contrast, I and I a are reported to be less effective than I1 and IIIa against Tt~ichomonas .s The corresponding bromoethyl derivative at a concentration of 0.05% provided 1007, blackhead preventive efficacy in two experiments. It was only little effective at 0.025%, and no efficacy was provided at concentrations of 0.015 and 0.005%. All concentrations were palatable and nontoxic to the poults. comparison of the efficacy of 1-111 with that of 1,2dimethyl-5-1iitroimidazole,~ a well-known antiblackhead product, shows that I compared favorably with the standard drug while I1 and 111 did not.
1,> 11 10
100 80 13 0 100
J
1
-----l.;~lic~c~------. "70 \ritliout" blackhead
1)
Experimental Section'O 1-( 2-Chloroethyl)-5-nitroimidazole(I).-Ethylene oxide (100 g, 2.27 moles) was slowly added over a period of 6 hr to 98 g (0.29 mole) of 4(S)-nitroimidazole11 in 830 ml of S 8 q formic acid at 35". The mixture was then filtered to give a yellow filtrate and a white residue of unreacted 4(5)-nitroimidazole. The formic acid was distilled from the filtrate under vaciiiim, $50ml of H20 was added to the residue, and the mixture was made basic with 30% KaOH. The basic solution was then extracted (EtOAc). The EtOAc extracts were dried (NasSO1) and callcentrated to an oily residue under vacuum. The oil was dissolved in anhydrous CHC13 and heated at reflux for 4 hr with SOC1,. The mixture was then distilled under vaciiiim t o give a solid residiie which was dissolved in H20 and made basic with NaOH while chilling in an ice bath. The crude product precipitated, was collected, and dried to give 21.5 g ( 4 2 5 ) of yellow solid, mp 49-51', Recrystallization (CHCl,) gave a pale yellow solid with mp 49-51', lit.5 mp 51'. dnal. Calcd for CjH&IS~Os: C, 34.20; H, 3.43: X, 23.93; C1, 20.20. Found: C, 34.10; H, 3.79: S , 23.98; C1, 20.03. 1-( 2-Chloroethyl)-2-methyl-5-nitroimidazole (III).- I-( 2-Hydroxyethyl)-2-methyl-.j-nitroimidazole~? (20 g, 0.117 mole) was added to 100 ml of SOCl, and the resulting mixture was heated a t reflux for 3.5 hr. The react,ion mixture was then treated as described for I to give 17 g (76.6%) of cream-colored solid with mp i7-79". Recrystallization from Et20 gave a white solid, mp 78-80', lit.5 mp 78". Anal. Calcd for C6H,C1N302: C, 38.01: H, 4.26; N, 22.16; C1, 18.70. Found: C, 38.29; H, 4.43; N, 21.91; C1, 18.98.
Acknowledgment.-The authors are indebted to N r . llarvin Carr for assistance with some of the experiments. (10) Melting points were determined in open glass capillaries with a Nel-Temp heated block and are corrected. Microanalyses were performed b y t h e Schwarzkopf Microanalytical Laboratory, IVoodside, N . Y. (11) R. G. Fragher and F. L. Pyman, J . Chem. Soc., 115, 217 (1919). (12) From extraction of FlagylE tablets with CH?CI? or b y hydroxyethylation of 2-methyl-4(j)-nitroimidazole; mp 158-160'.
S p t h e s i s of cis-9-Tetradecen-1-01Acetate, the Sex Pheromone of the Fall Armyworm D ~ V I DW ~ R T H E N Entomology Research Dzvzszon, C. S . Department of Agrzcultnre, Beltsville, Mar7Jand 20705 R P C C O(lob~r ~ ~ ~ C 6~, l,W?
During the course of an iiivestigation of potential insect sex attractants,l the four possible geometric iso(1) U. \\arthen and
&I. Jdwbson, J . M e d . C h ~ ? n10, , llY0
(1Ybi).
373 double I,oiid inipnrity. Gas chromatography revealed a single dorsalis (Hendel) ; melon flies, Dacus cucurbifae (Coquilsharp peak, ret,eiition time 282 sec a t 170' and 30 r c of Ns/min. let) ; male fall armyworm, Spodoptera frugiperda (J. E. .Lnn/. Calcd for C1JI,,02: C, 73.53; €1, 11.89. F O U I I ~ : Smith) ; codling moths, Carpocapsa pomonella 1,.; C, 7.5.37; H,12.02.
Acknowledgment.-The author wishes to thank 3Ir. l h r t i n Jacobson of this division, Beltsville, Md., for liclpful suggestions and discussions.
Insect Sex Attractants.
gypsy moths, Porfhetria dispar L. ; cabbage loopers and pink bollworm moths, Pectinophora yossypiella (Saunders). The cis and trans isomers of 5-dodecen-1-01 acetate were found in laboratory tests to be less attractive to cabbage loopers than cis-7-dodecen-1-01 acetate. All other test results were negative.
X. 5-Dodecen-1-01
Acetates, Analogs of the Cabbage Looper
Experimental Section8.9
2-(5-Hexynyloxy)tetrahydropyran (l).--I~ili~dropy~sll (2.5.2 Sex Attractant' g, 0.30 mole) was added to 24.5 g (0.25 mole) of 5-hexyn-I-ol and 5 drops of concentrated HCI, with stirring. The soliition as I).IYID \\'.\~wass.isu 11.wr1x J.\cuusus cooled to keep the temperature below 40" arid theii stirred at room temperature for 3 hr. Excess NaHC03 was added to the E ~ ~ l c ~ ~ iliesearch i d o y ~ Division, C. S. Uepurtnienl of Ayriculture, solution, and stirring was continued for an additional 1 hr. Ueltsville, Jluryland 20705 After filtration, the filtrate u'as distilled to yield, after a smsll forerun, 42.6 g (93%) of colorless liquid, bp 52-57' (0.03 mm), Received October 6 , 1967 12% 1.4579 (lit.'" bp 70-80" (0.3 mm), n % 1.4556). 2-(5-Dodecynyloxy)tetrahydropyran (2).-Compound 1 (40.0 In a continuing investigation of sex attractants for g, 0.22 mole) was added with stirring to a mixture of 5.1 g (0.22 mole) of LiYH2 and 250 ml of dry dioxane (purified by refluxing the control of insect pests,2 the cis and trans isomers of over Na and then distilling) under Sz. The reaction mixture was 5-dodecen-1-01 acetate xere synthesized. These comrefluxed for 3.5 hr and cooled, and 36.3 g (0.22 mole) of hexyl pounds are analogs of cis-7-dodecen-1-01 acetate, the sex bromide was added dropwise. Refluxing was continued for 17 attractant produced by the female cabbage looper, hr; then HzO (250 ml) was added to the mixture. The solution Trichoplusia ni (Hubner)) and synthesized by Berger was extracted three times with ether, and the ether extracts were washed ( S a c 1 solution). The combined ether extracts and Green, et were dried (Na2SO4) and distilled t,o give, after a small forerun, The method used t o prepare the 5-dodecen-1-01 27.2 g (47Tc) of colorless liquid: bp 105-108° (0.06 mm); n Z 4 ~ acetates is shown in Chart I. The tetrahydropyranyl 1.4630; ir, 2930 (broad CH) and 1200-1040 cm-1 (t'etrahydropyranyl); gas chromatography, single sharp peak, retention time 336 sec a t 150" and 40 cc of KZ/min. CH.LRT I Anal. Calcd for C17H3002: C, 76.64; H, 11.35. Found: C, 76.50; H, 11.41. 2-(cis-5-Dodecenyloxy)tetrahydropyran (3a).-A solution of 10.0 g (0.038 mole) of 2 in 40 ml of absolute EtOH was hydroS a - N H 3 or genated at room temperature, by using 300 mg of 5% Pd-CaC03 l~O(CHz),C~C(CHz)jCI13 and 2 drops of quinoline. When the required amount of HZ for 2 Hz, Pd-CaCOa one double bond had been absorbed (920 ml a t 26' and 760 mm), hcOH-AcCI the reaction was interrupted. The mixture was filtered, freed l~O(CH,),CH=CII(CH,)jCH3 + of solvent', and distilled to yield 8.8 g ( 8 7 7 , ) of colorless liquid, 3a, c i s 4 ~ The ir spectrum showed bp 96-99' (0.04 mm), n z 51.4578. b, trans-5 absorption at 720 cm-1 (cis CH=CH) and a very weak bond at CH~CO~(CIIZ),~H=C€I(CI-~?),CH~ 965 cm-I representing trans double bond impurity. Gas chro4a, cis-5 matography showed a single sharp peak, retention time 102 sec b, trans-5 a t 150" and 40 cc of Nz/min. Anal. Calcd for C17H3202: C, 76.06; H, 12.02. Found: C, R = 2-tetrahydropyranyl 75.86; H, 12.04. 2-(trans-5-Dodecenyloxy)tetrahydropyran(3b).-To a mixture ether of 3-hexyn-1-01 was alkylated with hexyl bromide. of 4.0 g (0.18 g-atom) of Na in about 400 ml of liquid ?jH, was added dropwise, with stirring, 10.0 g (0.038 mole) of 2 at, -76'. Reduction of 2 in sodium-liquid ammonia or in the Ether (20 ml) was added, and the KH3 was alloxed to reflux for presence of poisoned Pd-CaC03 yielded almost exclu5 hr. The reaction mixture was again cooled to -76", and sively the trans or cis isomer,j-' respectively, of the excess NH4C1and 40 ml of ether were added. After the mixture tetrahydropyranyl ethers of 5-dodecen-1-01 (3). Substood overnight, 100 ml of ether and HzO (50 ml) were added sequent refluxing with acetic acid-acetyl chloride under Nz. The aqueous phase was extracted twice with ether; the combined ether layers were washed (cold HyO, cold 5% cleaved the tetrahydropyranyl group to form the desired HCI, 5% NazCOa, and NaCl solution). The ether solution was 5-dodecen-1-01 acetates (4). dried (KanSO4)and dist,illed to give 9.2 g (91%) of colorless liquid, The acetates 4a arid 4b were evaluated as attractants bp 94-96' (0.03 mm), n 2 5 ~1.4569, ir absorption at 965 (trans for male and female Nexican fruit flies, Anastrepha CH=C€I) and a very weak bond a t 720 em-' representing cis Zudens (Loew) ; Mediterranean fruit flies, Ceratitis double bond impiirity. Gas chromatographic analyses showed single sharp peaks, retention times 114 and 108 sec a t 150" and capifata (Wiedemann) ; oriental fruit flies, Dacus 40 and 55 cc of Xn/min, respectively. ~
1
.
~
3
~
~
(1) P a r t I S : A l . Jacobson and C. Harding, J . Bcon. Entomol., in press. (2) Rf. Jacobson a n d hl. Beroaa, Science, 140, 1367 (1963); Sei. Am.. 211 ( 2 ) , 20 (1964). (3) R. S. Berger, Ann. Entomol. SOC.Am.. 59, 767 (1966). (4) N. Green, &I.Jacobson, T. J. Henneberry, and A. N.Hishaba, J . M e d . Chem., 10, 533 (1967). ( 5 ) H. 0. House, "Modern Synthetic React,ions," W.A. Benjamin. Inc., New York, X. Y., 1965, p 71. (6) I(. N . Campbell and L. T. E h y , J. Am. Chem. SOC.,63, 216 (1941). (7) R. L. Augustine, "Catalytic Hydrogenation," Marcel Dekker, Inc., New Tork. S . T., 1965, p 71.
(8) Boiling points are uncorrected. Elemental analyses were performed b y Galbraith Laboratories, Inc., Knoxville, Tenn. Infrared spectra were obtained with a Perkin-Elmer 521 spectrophotometer. Gas chromatographic analyses were performed on a Varian Aerograph Autoprep i o 0 gas chromatograph with a thermal conductivity detector b y using a column of 570 Carbowax 2 0 R I on 60-80 mesh base-washed Chromosorb IV (60.9 X 0.03 cm) and helium a s t h e carrier gas. (9) Company and trade names are given for identification purposes only and d o not constitute endorsement by t h e U. S. Department of Agricultiire. (10) W. A. Jones, 111. Jacobson, and D. F. Martin, Science, 162, 1816 (1966).
