Jnruinry 1967
KOTES
was removed by distillation. T o the cooled mixture was added dropwise 44 g (0.36 mole) of 1-dimethylamino-2-propyl chloride (prepared by treatment of a slurry of the hydrochloride in ether containing 1yo of water nrith powdered NaOI-T, decantation, cxt,raction hy three portions of ether, drying, arid distillattion, 1)p 118-120'). The mixtiire was refluxed with stirriug for 16 hr, cooled, and treated with 100 ml of water. The organic phasc was washed wit,h water and then added to dilute HC1. The aqueous phase was treated with dilute NaOH, and the mixture was extracted with ether. After drying (Na2S04),the ether was evaporated and the residue was distilled under reduced pressure [47.4 g, bp 160-170" (0.1 mm)]. This material was dissolved in 250 ml of ether and treated with an equivalent quant,ity of HCl in ethanol. The solvent was evaporated t o give 46.5 g of colorless solid, mp 168" (mixture of 33 and 32, 80:20 by vpc analysis). The solid was dissolved in 100 ml of hot acetonitrile and cooled to give 32 g of pure 33. An ethereal extract of the corresponding base was chromatographed (injection port a t 450') on a 2-m alkaline Carbowax 2031 column a t 120'; a single peak was observed whose retention time was identical with 2-dimethylamino-1-allyloxypropane;on a 2-m SE 30 gum silicone column a t 200" a peak, developed as anthracene, was observed. 11-( 2-Dimethylamino-l-methylethoxymethyl)-9,lO-dihydro9,lO-ethanoanthracene Hydrochloride (32). Method G.-A mixture of 21.5 g (0.15 mole) of 1-dimethylamino-2-allyloxypropane, 26.7 g (0.15 mole) of anthracene, and 0.4 g of hydroquinone ill 50 ml of toluene was stored in a pressure bottle at, 210" for 15 hr. After cooling and extraction with dilute HC1, the aqueous acid layer was made basic with NaOH solution and extracted with ether. The ether extract was dried (Na2S04) and evaporated in 2iacuo. The residual oil was converted to the hydrochloride by dissolving in dry ether and treating with HCl. Reclystallization from acetonitrileether gave 17.2 g of analytically pure 32. An ethereal extract of the corresponding base was chromatographed as above t o give on Carbowax 20M a single peak the retention time of which was identical with l-dimethylamino-2allyloxypropane and, on SE 30 gum silicone, a peak of anthracene.
91
9- [ 2-Methyl-3-(4-methyl-l-piperazinyl)propoxy]-9,lO-dihydro9,lO-ethanoanthracene Dihydrochloride (64). Method H.-A solution of 22.2 g (0.1 mole) of 9,10-dihydro-9,10-ethano-9anthrol in 250 ml of anhydrous toluene wits treated with 5.3 g (0.11 mole) of a 50% dispersion of XaII i n mineral oil. The mixture was refluxed with stirring iitider ail atmosphere of dry nitrogen iintil the evolution of hydrogel1 ceased and the sodium salt precipitated (ca. 3 hr). To this suspension was then added 20.4 g (0.11 mole) of l-chloro-2-methyl-3-(4-methyl-l-piperaziny1)propyl chloride's and the resulting mixture was stirred and refluxed under nitrogen for 24 hr. The mixture was filtered and the filtrate was evaporated to yield an oily residue. A solution of this material in 50 ml of ether was treated with a n equivalent quantit,y of HC1 in 100 ml of ethanol to give 21 g of white crystals: XS5' 2zFoH264 mp ( E 1145), 271 mp ( E 1410). 9-(2-Methylaminoethoxy)-9,lO-dihydro-9,lO-ethanoant~acene (38). Method 1.-A solution of 10.85 g (0.1 mole) of ethyl chloroformate in 50 ml of benzene was added dropwise to a solution of 14.65 g (0.05 mole) of 40 in 50 ml of benzene, and the mixture was refluxed for 6 hr. After cooling, the solution was treated with 200 ml of 2 iV HC1 and with water. The solvent was removed under reduced pressure. The residual oily liquid (15.6 g, 86.57,) of crude 9-(N-carbethoxy-S-methyl-2-aminoethoxy)-9,10-dihydro-9,10-ethanoanthrscene was added t o a stirred solution of KOH (14 g ) in 100 ml of diethylene glycol. The mixture was t'hen refluxed for 8 hr and added t o 200 ml of water. The solution was extracted with ether. Evaporation of the ether solution gave 10.5 g of product. For analysis the latter was cryst.allized from 200 ml of pentane t o give 6 g of colorless solid.
Acknowledgment.--We are indebted to Dr. J. Hirtz and his staff for the analytical da.ta. We wish to t h m k Nr. C. Demosthene for technical assistance. (15) J. P. Bourquin, G . Schxarb, G. Gamboni, R. Fischer, L. Ruesch, S. Guldimann, V. Theus, E. Schenker, and J. Rena, Helu. Chzm. Acta, 41, 1072 (1958).
Notes A survey of the literature revealed that very few analogs of 4-acyl-5,5-disubstituted A2-1,3,4-oxadiazoline had been reported. Such compounds have been syn1,3,4-oxadiazolines thesized by four methods. Stolle4 and later Fahr, et U L . , ~ treated the silver salt of a n acylhydrazone with HOMER A. BURCH an acid chloride. Yale, et u Z . , ~ and Sagitullin and Kost' improved this method by treating an acylhydrazone ChPniistry Division, The Yorwich Pharmacal Compnn?], Norwich, N e w Y o r t with an acid anhydride. A novel rearrangement of 5benzyltetrazole to 2-benzylidene-3-aroyl-5-aryl-A2Received J u l y 8, 1966 1,3,4-oxadiazoline on treatment with an aroyl chloride in pyridine was report'ed by Huisgen, et ~ 1 Finally, . ~ A continuing search for nitrofuryl heterocyclic chenioBreslow9 obtained 4-acyl-A2-1,3,4-0xadiazolines from therapeutic agents led to an investigation of 2-(5-nitrothe reaction of azodicarbonyl compounds with aliphatic 2-furyl)-1,3,4-oxadiazole analogs (111). It was rediazo compounds. ported by Sherman? that 2-(5-nitro-2-furyl)-A2-1,3,4The method of Yale, et u Z . ~ (Scheme I), was chosen oxadiazolin-5-one possessed excellent antibacterial propfor this project because of the availability of starting erties both in vitro and in vivo. Furthermore, anti(4) R. Stolle. J . Prakt. Chem.. [2] 6 8 , 413, 418, 421 (1903); 70, 412, 419 fungal and trichomonacidal activities have been re(1904); R. Stolle and G . Muench, ibid., 70, 408, 410 (1904). ported recently for a series of 2-(5-nitro-2-furyl)-5(5) E. Fahr. K. Doeppert, and F. Scheckenbach, Angew. Chem., 7 5 , 670 (1963). alkyl-1,3,4-oxadiazoles. Thus, further work in this (6) H. L . Tale. K. Losee, J. Martins, 11. Hoking, F. 11. Perry, and J. area appeared promising. Bernstein, J . A m . Chem. SOC.,76, 1933 (1953). Nitrofuryl Heterocycles.
V.
4-Acyl-5,5-dialkyl-2-(5-nitro-2-furyl)-Az-
(1) For t h e preTious paper in this series see H. -4.Rurch, J . M e d . Chem.. 9, 408 (1966). (2) W. R . Sherman, J . Org. Chem., 2 6 , 88 (1961). (3) T.Haraoka, .4. Sugihara, and M ,I t a . Japanese Patents 19.451 (1961) and 20,164 (1964): Chrm. Abstr., 62, 10444e, 11821d (196.5).
( 7 ) R . S. Sagitullin and A. N. Kost. Vestn. M o s k . Cniu., Ser. M a l . , M e khan.. Aslron.. F i z . i K h i m . , 14 ( 4 ) , 187 (1959): Chem. Abslr., 64, 17383h (1960). ( 8 ) R . Huisgen, J. Sauer, H . J. Sturm, and J. H. Markgraf, Chem. Rm., 93, 2111 (1960). (9) R . Bredow, Chem. Ind. (London), 1061, (1961).
\.Ill, I O
!)L'
1
111
Experimental Section -111 nieltiiig 1 ) o i i i t a were cleterrniiirti oii :t hot stage (FisherJotin..) meltiiiy puiiit npparat 11. and are uricorrertecl.
5-Nitro-2-furoic Acid Isopropylidenehydrazide (IIa).--.4 mixture of 5-nitro-2-furoic :wid hydrazide6 (75.0 g, 0.44 mole) iii 1 I.
NOTES
,Janiiary 1967
of acetone was refluxed with stirring overnight, concentrated under reduced pressure t o about, 300 ml, and chilled. The crude prodiirt was filt.ered and air dried to yield 88.4 g. Forty-four illizrd twice frcini iiit,iumethaiie (charcoal) to yield 29.5 g of piire product as pale yellow needles. The other analogs of I1 in Table I were prepared from the appropriate cxrhonyl cwmpoiiiid Lising ethanol :is it solmiit. 4-AcetyI-5,5-dimethy1-2-( 5-nitro-2-furyl)-~~-1,3,4-oxadiazoline (IIIa).--A solution of I I a (42.0 g, 0.20 mole) in 150 ml of acetic anhydride was refluxed for 1 hr, cooled, and poured into 500 ml of ice arid water. Solid ?l;a2C03was added in small portions with vigorous stirring until the mixt,ure was neutral. The gummy puidiict was washed ait,h cold water by decantation until crystallization occurred. The solids were filtered and recrystallized twice from 9 5 5 , ethanol (charcoal) to yield 31.1 g of product as ,short, yellow needles. The other analogs of I11 in Table I1 were prepared from the appropriate acid anhydride and 11. I-(~-Acetoxy-5-nitrofurfuryl)-l,2,2-triacetylhydrazine(VI).-A solution of 5-nitro-2-furaldehyde acetylhydrazone12 (100 g, 0.31 mole) in 450 ml of acetic anhydride was refluxed for 1 hr. The product was obtained in the same manner as was IIIa. Four recrystallizations from IGc0 ethanol (charcoal) gave the product as pale yellow needles melting at, 157-158.5'; yield 24.4g(14.170). Anal. Calcd for ClaHl&\;,O~:C, 45.i5; H, 4.43; N,12.31. Foiind: C, 45.94; H, 4.35; S, 12.12. Carbonyl stretching bands were observed a t 1695, 1710, and IT45 cm-1 in the infrared spectriim of a sample prepared as a Niijol mull iising a Perkin-Elmer Model 21 spectrophotometer.
Acknowledgments.-The author wishes t.o t.hank N r . Grant Gustin and N r . Marvin Tefft for the element,a,l analyses and :\h. R. A. Dobson and N r , A. P. Moon for the t,esting da,ts.
Synthesis and Bacteriostatic Activity of Some Nitrotrifluoromethylanilides
IT.B I K E R , GERALD L. B.IcHnf
.JCI~EPII
n I M E L P. Roll I N ,
IN,
IGS'ITIUS SCHCM lCHER, L. THIRP
AKD -4LAiX
Research Department, Organic Chemicals Division, Xonsanto Company, St. Louis, Jlissouri 63177 Receited August 1 , 1966
I t has been reported for bacteriostatic halosalicylanilide?' and halocarbanilides2 that certain of the halo groups can be replaced with trifluoromethyl groups without lowering activity. I n some instances enhanced activity is claiinecl. -1san extension of our work on the bacteriostatic activity of a series of anilides3 possessing both halo and nitro groups in the P\'-phenyl ring, me have prepared and evaluated a number of analogous anilidcs in which the halo groups are replaced with a trifluoromethyl group (Table I). The anilide. were prepared either by the acid-catalyzed reaction of an anhydride with a substituted aniline or by the condensation of an acid chloride with the aniline alone or in the presence of triethylamine as the hydrogen chloride acceptor. The reaction mixture was refluxed for several hours to expel hydrogen chloride Then no acceptor was present. Compound 15, (1) !a) .J. Rindler and E. Model, LT. S. Patent 2,703,332 (RIarch 1, 1955); (b) H . C . Stecker, U. S. P a t e n t 3,041,236 (.June 26, 1962). ( 2 ) (a) TT. Frick and TT. Stammbach, Swiss P a t e n t 389,841 (March 15, 1962); Chem. d b s t r . , 58, 416 (1963); (b) P. P. Hoffman, R . K. Madison, and W.B. Hardy, J . M c d . Chem., 7, 665 (1964). (3) J. W.Baker, I. Sohumacher, G. L. Bachman. D. P. Roman, and A. L. Tharp, ibid., 9, 428 (1966).
93
an S-methylanilide, was obtained by the action of dimethyl sulfate on the sodium salt of 14. Wh(w Ci-9 arid chloridrs f i * w of ctl whit itumts iwrc allowed to react with 4-nitro-3-trifluoroniethylanilinein the presence of triethylamine, a 1 : l molar complex of tlic ~tnilidcatid aniline was obtained. Thc complexes were quite stable and were readily purified by recrystallization to give a sharp melting point which was depreqsed when admixed with the anilide. The complexes could be broken up by the addition of ethereal HC1 to an ether solution of the complex and removing the 4-nitro-3-trifluoroniethylanilinehydrochloride. The complexes were stable to dilute hydrochloride acid. They were also prepared by dissolving equimolar quantities of the anilide and the aniline in a mixture of methylcyclohexane and toluene and allowing the coniplex to precipitate on cooling. S o complexes were formed when isomeric anilines were used. The infrared spectra of the anilides were examined and displayed the characteristic4 S H stretching band at 3250-3390 cm-l and the amide I band at 1675-1723 cm-l. Sitro stretching absorptions obscured the amide I1 band. The S-methylanilide 15 exhibited no characteristic S H stretching band. A comparison of these spectra with the corresponding coniplexes revealed marked differences. For example, anilide 14 showed a strong S H stretching band at 3320 cm-', a strong amide I band at l i 2 5 cm-', and a very weak band at 16.50 em-l. I n the spectrum of the complex (45) the 3320-cn1-~ band remained unchanged, the amide I band, reduced in intensity, shifted only slightly to 1700 cm-l, and two new medium bands appeared at 3250 and 3450 cni-'. The very weak 1650-em-' band found in the anilide appeared much stronger in the complex suggesting a higher degree of enolization to give the C=S group in the anilide portion of the complex. The in vitro Staphylococcusaureus activity of the nitrotrifluoromethylanilides was obtained. Active structures included those which were substituted in the ineta and para positions of the N-phenyl ring with a nitro and trifluoromethyl group and in which the acidderived moiety incorporates alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkyldienyl, and phenethyl groups and contains 5-12 carbon atoms. The benzyl and phenoxymethyl derivatives were inactive. S,SDisubstituted and ortho-substituted derivatives were also inactive. Those anilides disubstituted in the a position possessed a lower order of activity. hll of the complexes (Table 11) were derivatives of active anilides and exhibited the same order of activity on a weight basis as the anilides themselves. I n general, the scope of activity of this series parallels that obtained for the previously studied halonitroanilide series. Exceptions were 34, the phenethyl derivative, which was active in this series, and 19, the tridecanoic acid-derivative, which was inactive. No direct comparisons were made for the haloalkenyl, alkyldienyl, and the phenyl derivatives between the two series. Experimental Section of the anhydrides, acid chlorides, Chemical Procedures.-All and substituted anilines n-ere obtained commercially except (4) E. J. rorbes, K. J. Morgan, a n d J. Newton, J . Chem. Soc., 835 (1963).
