Isomeric Senzyldiaminodihydrotriazines
I
n NHCH,C,H, I
VI
NOTES
September 1965
703
et ~ l . ' ~The infrared spectra of isomers IV and V were clearly different and served as a basis for differeutiating between the two (see Experimental). The ultraviolet spectra of the two isomers were, on the other hand, quite similar [A":"" 245 mp ( 6 10,300) and 241 mp (e 14,150), respectively, for IV and That extensive work by various g r o ~ p s ~ ~ " . on ~~-~~b the dihydro-s-triazine-forming reactions of arylbiguanides has failed to disclose the formation of type I1 compounds (in the presence of excess mineral acid) may be related to a preference of the arylbiguanides for the tautomeric form A over B owing to conjugation with the aromatic ring. Reaction a t the doubly bonded nitrogen would seem reasonable by analogy with the established fact's that protonation of an amidine takes place on the imino nitrogen. NHz NH ArN=hHC--NH2 II
A
NH NH ArNHL-NH&NHI
B
Biological Data-Compounds IV and V exhibited no interesting biological activity. In coccidiosis in the chick, they were inactive a t 0.5% in the diet against a severe challenge of Eimeria teneZla.ls They were inactive a t 0.1% hy drug diet against SalmoneZla cholerasuis in the mouse. I n the anthelmintic screening program they were inactive in mice when fed a t O.lyo in the diet for 7 days.
Figure 1.-Infrared spectra. in Nujol of (A) 4,6-diamino-lbenzyl-l,Zdihydro-2,Zdimethyl-s-triazine hydrochloride (IV), and (B) 4amino-6henzylsmino-l,2-dihydro-2,2-dimethyl-s-triazine hydrochloride (V).
that of authentic V prepared according t o the method of Birtwell16 (see below). The remaining aqiieoiis filtrate wa8 evaporated to dryness, the eolorless solid residue was acidified with saturated ethanolic HCI, and the mixture was again evaporated to dryness, the last traces of solvent being removed by pumping (vacuum pump) for 2 br. The solid residue was extracted with hot ethanol. Evaporation of the ethanol extract left a gummy residue which was heated in Experimenialm boiling acetone and kept a t room temperature overnight. R e moval of the acetone left a pasty solid (0.6 g., 26%) which gave a Reaction of Benzylhiguanide Hydrochloride with Acetone. positive higuanide test (formation of B lavender solid) with amFormation of 4,6-Diamino-l-henzyl-l,~-dihydro-2,2-dimethyl-~- moniacal CuSO.. Its infrared spectrum was essentially identical biazine Hydrochloride (IV) and 4-Amino-6-henzylamino~l,2-diwith that of s n authentic sample of henzylbiguanide dihydrochlohydro-2.2-dimethyl-s-triazine Hydrochloride (V).-A suspension ride, m.p. 231-232", prepared from the monohydrochloride by of 2 g. (0.009 mole) of henaylhigusnide hydrochloride in a mixture recrystallieation from saturated ethanolic HCI. uf 25 ml. of commercial absolute ethanol and 10 ml. of reagent Anal. Calcd. for CeHlaCbNa: C, 40.91; H, 5.72; CI, 26.84; grade acetone containing 1 ml. (0.01 mole) of concentrated HCI N, 26.51. Found: C , 41.15; H, 5.81; CI, 26.74; N, 26.46. wa8 heated under reflux for 24 hr. The reaction mixture became With 2 molar equiv. of concentrated HCI only a 10% yield of homogeneous after 4 hr. of heating. After the solvents were IV was obtained. removed under reduced pressure, the yellow syrupy residue was Reaction of Benzylhiguanide Hydrochloride with Acetone taken up in 10 ml. of water, and the pH of the solution was at 110". 4-Amino-6-benzylamino-l,2-dihydro-2,2-dime~l-a-tr~adjusted to 6 7 (alkacid test paper) with 2 N NaOH; azine Hydrochloride (V).-A mixture of 2.27 g. (0.01 mole) of 4,6diamino-l-benzyl-l,~dihydro-2,2-dimethyl-~-triazine hydrohenaylhiguanide hydrochloride, 25 ml. of commercial absolute chloride separated as a colorless solid. After refrigerating the ethanol, 10 ml. of reagent grade acetone, and 1 ml. (0.01 mole) suspension for 1 hr., the compound was collected by filtration, of concentrated HCI were placed in a Fisher-Porter glass pipe weshed with a small amount of cold water, and air dried; yield sealed at one end and closed a t the open end by means of a Teflon 0.7 g. (29%), m.p. 191-194", AM": 245 mp ( e 10,300). The gasket and aluminum fittings. The reaction mixture was heated analytical sample was obtained by recrystallization from water; in an oil bath a t 110' for 20 hr. (reaction mixture became bomom.0. 194-197". geneous within 15 min.), eooled, transferred t o B round-bottom Anal. Calcd. for CuHt&INs.HzO: C, 50.43; H, 7.05; C1, flask, and evaporated under reduced pressure. The SYNPY resi12.41; N, 24.50; H,O, 6.30. Found: C, 50.39; H, 7.15; due was taken up in 10 ml. of water, the pH of the solution was CI, 12.33; N, 24.58; H,O, 5.21. adjusted to 6-7 (alkacid test paper) with 2 N NaOH, and the Treatment of the aqueous filtrate (-10 ml.) with 3-4 ml. of solution wm refrigerated. No solid separated even after 2.5 hr. 10% aqueous NsnCOs resulted in the seperation of 0.9 g. (35%) of (compare with the preparation of IV above). After 18 hr. 0.41 g. the bicarbonate of 4amino-6benzylamino-l,2-dihydro-2,2-di- (15%) of crystalline V separated, m.p. 192-194', m.m.p. 174methyl-s-triazine, m.p. 18W184' eff., which wasin turn converted 185" with unrearranged IV. Its infrared spectrum was identical to the hydrochloride salt, m.p. 19(t194', as described under with that of authentic V prepared as described below. The the following section. Its infrared spectrum was identical with aqueous mother liquor was treated with 10% NazCOs solution. The cream-eolared bicarbonate which separated (1.6 g., 55%), m.p. 178-182" eff., was converted to the hydrochloride salt in 70% yield by treatment with a minims1 amount of 10% HCI. (16) S. Dirtwell. F. Curd, .l. Hendry. and F. Rose. J . Clrem. Sor.. 1045 Partial solution accompanied by effervescence took place with (1Y48). concurrent formation of a new solid. A small amount of water (17) Had we only one of the two isomers in hand.'bb it would have waved ~ u i t eimDoasible to assign a struature to it on the baais of apeotral data wa8 added to the resulting pasty solid, the suspension was refrigerBLOVJB."b ated for 30 min., and the solid was collected by direct transfer (18) R. C. Neuman. Jr., 0. S. Hammond. and T. J. Douahertv. J . A n . onto B filter pad without the use of any additional water; m.p. Chcm. Soc., 84,1506 (1802). 19W194". Recrystdimtion from acetonitrile gave V melting a t (18) E. Waletaky and C. 0. Hughes, Am. J . Vet. Res., 1 , 3 6 5 (1948). 19&197', 241 mp ( 6 14,150). Its infrared spectrum was 120) . . Meltin.I .oointa m e corrected. Microanalvses are bv Galbraith identical with that of authentic V prepared as deacrihed below. Laboratories. Inc.. Knoxville. Tenn. Infrared apectra were taken as Anal. Calcd. for CnHI.CINa: C, 53.82; H, 6.77; CI, 13.24; Nujol mull8 with a Perkin-Elmer Infracord spectrophotometer. Ultraviolet N, 26.16. Found: C, 53.40; H, 7.02; CI, 13.22; N, 26.09. spectra were measured with B Cary recording apeotrophotometer.
\Viieri ttic re:rc.liuii t.iriie w:ts decreahed 1 0 ,j lir., 1\. \V:IS it1s.o o l i h h e d . The ratio of 11-to 1. was roughly 1:2 iii cant r I : 1 rat io of the Iwo oht ained in reflrixiiig acetone--et1 :hove). 'The irifr:tred hpectrit of IT : ~ r i t l 1' were tlihiiii(,i1). tliif't~rt~ii t t hroiiglioiit the eiitire q)ect,r:il riiiigt: (Figure I ). 'L'ha~ 11. ~ : t i i l i i ~ t i i i t x i~)iire, i i i i ( ' i i i i t i j , n i i i i i i t c ( ~\vith its rrariniiKe(l isolncar \ , ib iridic,ated t)y thc-Ii:trp mediiiiri-iiiteii.itybaiid : i t !I),? p p r w ~ i ii i ~ i 1 t i c l l l l l l l qlec~tr!lm of' 1- : I f i d c~onlpletely>IlIse.nr frllfll 111:1i i l l
Spiranes. I \ . Amides of 3,Y-Uicarboxj 2, k,8, I O - tt:traosaspiro[j.j]undccanc.'
-
11.. Treatment of 4,6-Diamino-l-benzyl-1,2-dihydro-2,2-dimethyls-triazine with HCI. A. In Refluxing Acetone-Ethanol.--4 solution of 100 nig. ( 0 . X rriinole) ( i f I V in a mixture o f 1.3 nil. of corriiiiercd absolute ethanol and 0.5 nil. of reagent grade ac'etone vontaiiiing (J.05 1111. (0.5 niniole) ( i t ' cvnc,entritted HC'I x i s heated under gentle reflux for 27 Iir. The residue obt~aineti The bisalkyi- aiid bisdialky1:ii~iin~all~yl:iiiiidesot after evaporating the solverits was dissolved in I nil. of water ~~,Y-dicarboxy-2,4,8,1O-tetraoxaspiro [3.5]uiidecaiie h:ivc, :irid t.he i3oliition TTW neiitralized with 2 S S a O H . IT (50 ma.) brei1 prepared, and the latter pob5eqs interesting phar\vas recovered (the compound began separating as the pII of the iiiacological :id ivity. TVe 11:n.c previously report cd w l i i t i o n approached neutrality), m.p. 197--198.5". Its infrared 5 1 y t r r i n i wits identical with that of ;iiithent ic I\., Ev:~pi~ratior~ improved methods for the sylithesis of 3,9-dicwt)oof the aqileoiis filtrate left :t 19-mg. re>idiie. Its very simple niethoxy-2,3,8,10-tetraoxaspiro [3.3]undecane (Ib) :iiid infrared specatriini was conaiderably different from either 11. or several of its homologs.2 The preserit report deals nith \ ~ . Thus i2555; of the material isolated was iirirearranged 11.. the preparation of sonic derivat ivw of the p:mmt :ic%l B. In Acetone-Ethanol at 110".-~-Tliere:wtion inist.ure dcla aiid their pharinacological properties. wribed in A WVRS heated :tt 110' (sealed tube) for l i . 5 h r . Tlic resulting yellow d u t i o n W:LS evapoi,ated, the iesidunl oil wits t.:tlten up in 0.7 inl. of \rater, and the pH of the solution iv:ts adjiisted to 6--T (alkacid teat paper) with 2 -v SaOTI. 'I'he S(Jl\it ion rcmairied humogeneoiis (caompnre with .I). After 15 niiii. ion w:ih refrigerated ( 0 to - 19" I liiir solid w1iic.h sepnr:iletl meltetl It.. infrared >pectriini as ideiit iv:rl xvitli that of iiiit.hentic3 Base-Catalyzed Rearrangement of IV to V.---.\ suspc~iisiciiiI I ~ 1,X mg. o f IV in 1 nil. of 2 .\- SaOH was he:rted on ii strani Lxttli For 1.: riiiii. A i i ;idtiition:~1I nil. o f water W V : ~ added, S a n d heating poiiified with reniarknble eiisc. 111c,cintiriiied for 1 111.. The reactioii riiisture \viis vooled :tiid tire. -iiig the ester in water effects sapouip H of the solution \viis adjusted to 6--7 (idla(~id test p:tprr) n-itli fication. Series of bisnlliyl aiid bisdialkylaiiiinoalkyltliliite EIC1. Crystalliiie material began separating froni t h e res1111ing tiirbid sohition xithin 1 h r . After refrigerating :it 1) ainidei: (IC :tiid I d ) , were prepared from tlic ester It) to -10' overnight, 113 mg. (T4";r of 1. ~ v a ac~>llec,tet-l:ni.l,. by reaction n i t fi the appropriate primary :iiiiiii~si i i 1!)4 - 1 0 6 O , iii.ni.p. 1S1-1!K3° with 11'. Its iiifrared spec.triini wa. iiiet hariol. The re:irtion proceeded readily ill all c:i
