XOTES
July 1967
et aZ.2 For the preparation of 1-alkyl- arid 1-aryl-5(5-nitro - 2-furyl) tetrazoles (compounds 2a-m) the method of Harvill, et u L . , ~ was utilized. The synthesis of the tetrhzoles proceeded smoothly in all cases except when 3n was used as the starting amide. I n that instance, the product isolated from the reaction mixture (4) was not the expected tetrazole, but a compound having a n imino chloride structure. This compound was unusually stable and resisted reaction with solutions of sodium azide and hydrazoic acid. Screening Results.-The in tlitro antibacterial testing data, given in Table I, mere determined using methods described p r e v i ~ u s l y . ~Data for nitrofurazone5 are included for comparison. S o n e of the compounds prepared possessed activity that was significantly better than that of nitrofurazone. Experimental Section All meltiiig points were determined on a hot stage (Mel-Temp) melting point apparatus arid are uncorrected. The infrared spectrum was obtained on a Perkin-Elmer infrared spectrophotometer lIodel21. 5 4 5-Nitro-2-fury1)tetrazole (l).-A mixture of 5-nitro-2furonitrile6 (138 g, 1.0 mole), sodium azide (72 g, 1.1 moles), aiid NHlCl (58 g, 1.1 moles) in D l I F (500 ml) was stirred and heated cautiously. At first a very exothermic reaction occurred which quickly subsided. Stirring was continued for 3 hr a t 100'. The solvent was removed under redured pressure. After the residue was dissolved in water, the solution was acidified to pH 2 with concentrated HCl. .4 black, tarry mass formed which slowly crystallized upon cooling. The crude material was collected aiid recrystsllized from glacial acetic acid. N-Cyclohexyl-5-nitro-2-furamide(3f).-A solution of cyclohexylamine (182 g, 1.84 moles) in dioxane (to0 ml) was placed in the flask and stirred while 5-nitro-2-furoyl chloride7 (161 g, 0.92 mole) dissolved in dioxane (800 ml) was added. The reaction mixture was refluxed for 1 hr and poured into a large volume of water. After collecting, the product was recrystallized from 2-propanol (charcoal). Other derivatives of 3 listed in Table I except 3e were prepared in a similar manner from the appropriate amine and were recrystallized from methanol or %-propanol. Ethyl Ir;-(5-Nitro-Z-furoyl)glycinate(3e).-Ethyl glycinate hydrochloride (560 g, 4 moles) was placed in the flask together with water (1000 ml) and ethylene chloride (1000 ml). Calcium carbonate (340 g) was added and the mixture was stirred vigorously for 15 min. The stirring was continued while 5-1iitro-2furoyl chloride (350 g, 2 moles) in ethylene chloride (1000 ml) was added. Stirring was continued for 3 hr, and the mixture was allowed to st,arid overnight a t room temperatiire. The mixtiire was filtered and the two layers were separated. Aft,er t'he solveiit was removed from the organic layer under reduced pressure, the crystallized residue was recrystallized from 2propanol (charcoal). l-Methyl-5-(5-nitro-2-furyl)tetrazole(Za).-Beiizene (500 ml) was placed in a flask together Kith 3a (44 g, 0.28 mole). The mixture was stirred while PCls (54 g, 0.26 mole) was added in small portions which was accompanied by a slight endothermic reaction arid the evolut,iori of HC1. The reaction mixture was stirred a t room temperature while a solution of H S a 8 (13 g, 0 . 3 mole) in benzene (220 ml) was added. After stirring the mixtiire a t room temperature for 1 hr, it was stirred a t reflux for about 18 hr. a f t e r the benzene was removed imder reduced pressure, the residue was poured into water arid the crude prod(2) W. G. Finnegan, R. A. Henry, and R. Lofquist, J . Am. C h e m . Soc., 80, 3908 (1958). (3) E. K. Hctrvill, R. AI. Herbst, E. C. Schreiner, and C . W. Robeits, J . O w . Chem., 15, 662 (1950). (4) F. F. Ebetino, \$-. F. Carey, and B. F. Stevenson, J . J l e d . Chem., 6 , 663 (1963). (5) Furacins, 5-nitro-P-furaldehyde semicarbazone. ( 6 ) W.R . Sherman and A. Von Esch, J . .Ired. Chem., 8 , 2 5 (1965). (i) II. Gilman and R. V. Young, J. Bm. Chem. Soc.. 66, 464 (1934). ( 8 ) H. Wolff, Org. Reacfaons, 3, 327 (1946).
'739
uct was collected arid recrystallized from 2-propanol (charcoal). Other alkyl derivatives ( 2 b f ) listed in Table I were prepared in a similar manner and recrystallized from methanol or 2-propanol. The aryl derivatives (2g-m) were prepared in a similar manner. However, after the addition of PClj, it was necessary to heat the mixture to affect the formation of the imino chloride intermediate. Once a clear solution was obtained, the reaction mixture was cooled to room temperatiire and the procedure was continued as above. Methyl p - [(~u-Chloro-5-nitrofurfurylidene)amino] benzoate (4). -Compound 3n (126 g, 0.435 mole) was placed in a flask together with PClj (91 g, 0.436 mole) and toluene (1000 ml). T h e mixture was refluxed for 15 hr. The reaction mixture was cooled in an ice bath and filtered. The crude product was washed with water aiid recryst,allizedfrom 2-propanol (charcoal). .4n infrared spectrum in CHCh displayed absorption peaks a t 1720 (C=O) and 1620 em-1 (C=K).
Acknowledgments.-The author is indebted to F. Abbott, C. Benson, and S. Binder for assistance in the preparation of these compounds, to G. Gustin and 11. Tefft for elemental ana,lyses, and to H. E. Russell, R. A. Dobson, and R. Freedman for the microbiological testing data.
N3-(2-Aminoethyl)-5,5-diphenylh~-dantoin and Derivatives' JOHN W. SH ~ F F E R ,RICHARD SHE\ S L E I . , ~ .LND MELDRUM B. RINSTE AD Depaitwaent of Chemistry, Bucknell rniversity, Lewisburg, Pennsylvania 17837 Received February 21, 1467
The imide hydrogen of the hydantoin ring has been found sufficiently acidic t o undergo aminoethylation in an alcoholic solution. Thus, the reaction of 5,j-diphenylhydantoin with ethylenimine produced S3-(2aminoethyl)-5,5-dipheiiylhydantoin (I) in good yield. That the 2-aminoethyl group is located a t 9-3 and riot a t S-1 is suggested by the insolubility of I in aqueous alkali and from the observation that basic hydrolysis of I produced the amino acid, diphenylglycine. Infrared and nmr data also support structure I. Corral and Orazi have shown that the chemical shift of a hydantoin proton located at the S-1position occurs a t a higher field than that of a corresponding S-3 p r o t o ~ i . ~The Sl-H signal of I was coincident with that of the aromatic ring proton signal and was observable in the integration. h number of examples of ethylenimine reacting with compounds containing an active hydrogen are described to form the corresponding 2-aminoethyl derivative, but apparently the only reported example with a hydantoin describes the preparation of the benzoate salt of S3-(2-aminoethyl)-5,5-diphenylhydantoin. The free amine (I) was riot isolated and characterized. We have prepared the benzoate salt of I and obtained a melting point considerably different from that rep ~ r t e d . ~ S3-(2-Benzamidoethyl)-5,5-diphenylhydan(1) Taken in part from t h e 31.6.Thesis of J. TV, S.,B u c k d l Unirersity, 1966. ( 2 ) Undergraduate research participant. Bucknell University, 1965-1966. (3) R. A. Corral and 0. 0. Orazi, Spectrochim. A c t a , a i , 2119 (1965). (4) H. Stamm and E . Stieglitz, German Patent 1,173.101 (1964); Chem. Abstr., 61, 12012 (1964).
ICfiH,)lC - ---?;I{ I
co
t oiii
(11)
:\lid
I
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S3-(L'-acetamidoethyI~-,.-,~-dipheii~.l-
1iyd:tiitoin (111) were prepared bj- the reaction of I with hciizo!,l chioride arid acet,ic aiihydride, respect ively. The reaction of p-~~cetaniidobe!izeiiesuifoiij,l chloride wit>ii I produced St-["(L',,.--dioxo-4,~-dipheiiyl-l-imidazoiidiriyl)ethyi 1- p - acetamidoherizeiiesu1foii~~-
rnide (IT). Pharmacology.--Chemotherapeutic. and 1)iiarin:irologir evaluations of compounds I : ~ n dIT were coiltliirted by 1Ierck Sharp arid Dohme Research Lnlmratorics, Division of 11erck and Co., Iric. The behavior ( ~ these f compounds was studied i n the followiiig progrmis :is previously described? screening agaiwl I:'sc.hPrzchia coli in i i t / ~t)e, h n g i l l iiiiimals for antiiiifl:tinm:itory activit!.. and testing in mice for effects O I I em. 111the E . coli in v i t i v assay hoth inactive at a level of 1 nig/ml. So sigiiific:int effects 011 the riervous em were observed for I , hut, it did show a lorn order of aritiiriflammator!:I(' t i vi t \.. Experimental Section6
K~-(2-Aminoethpl)-5,5-diphenylhydantoin (I).--A
mixture of of absolute ethanol and 100 g (0.4 mole) of 5,S-dipheiiylhytlxr~ioiii was heated and held at reflux temperature while a 5oIiitii)ii of 25.7 g (0.6 mole) of ethyleriimiiie in 90 ml of absolute ethanol was added dropwke over a period of 4 hr. Reflux wab t hrii continued for an additional 6 hr. Approximately 500 ml of ethairril was distilled. The concentrat.ed reactioii mixture was cooled i o room temperatiire and drowned iii 1,500 rnl of iced I n t e r maintained at pII 11 by the addition of 107; S a O H . 1 he white precipitate of prodticmi was filtered, washed alkaline free, arid dried: yield 88.5 g (i.5,ic,i). Repeated recrystallizatioiis from ethanol or benzene gave purified prodrirt, nip 154.3I ,-i.,?,i . hridificatioti of the alkaline fillrate from the drowiied reactioii mist lire allowed recovery of 177: of iinreacted .i,T,-dipheiiylhydantoin, mp 200-292O. llixtiire melting point with piire 5,5tli~~heri?-lhyda~itoiii (nip 294-294.3") showed no depressioii. I'oteiitiometric titration of I (0.5699 g suspended in 100 ml of n.:iter aiid titrated with 0.1003 :V HC1) gave a p k ' h of 6.53: i~ 264, ,257.7 ~mfi ~ ( E 449, '~ 717);" no" change iii CHJ.I€€-KOH or ( ~ l 1 3 0 F ~ - H C ~l : i m r 100 , ~ mg of I/(l.5 ml of CIIC13, pair of CII, iriplets 6 2.78 :tiid 3.4'3, teri aromatic. protoiih and S I - I € c u . 6 7.2,5, N € f r observable iirily o i i iittegraticrii. , l t ~ ~ / Ca1C-d . for Ci;HijX'aOs: C, 611.14; €1, 3.80; E, 14.23; mol a-1, 29.7.3, Fourid: C, 68 X , 14.26; mol w t , s 3 0 nil
2!)6.1 . ' T i ] A I . 13, \\inatead and ('. K . Hamel, . I . .\led. Cherm., 8, 120 (1863). t H ) Xleltina points were determined with a Mel-Temp a p p a r a t ~ sand a r e vorrrcte- Schwarzkopf Rlioroanalytical I,alroratorg., \\-oodside, E.Y. .\ Heckman Rlodel G pH meter with a rlass e l e c t r o d e and a saturated calomel electrode was used in the potentiometric titraiion. staniiardization !vas apainst I
