a t 3 atni for 16 hr. Filtration and evaporation of the filtrate t o dryness under vacuum yielded a yellow oil. This was treated with 80 mg of picric acid in the minimum of boiling CHCI,. OII cooling and addition of a few drops of n-hexane, 155 rrig (91ri,) of dark red crystals were obtained; nip 110-112" d e r . Three crystallizations of the pimate from CHCI, cwitniiiiiig :I few drops of n-hexane gave pure TII, mp 11.2-114.5" de(*. rtnal. Calcd for C19H&&: C, 47,ill: 13, 3.70; S j 11.71. Foruid: C, 47.64; H, 3
Acknowledgment.-The authors wish to thank 111.. ,Tense Green, 11r. Robert L\7agar, Mrs. Kathleen Rice, and 11r. IIartin Kampe for technical assist,ance.
Heterocyclic Amines. 111. 3-Dirnethylaminofuran'
Experimental Sect'on
:3-Dimethylaniiriofur:in h : ~ q heen prepared from 3iuroyl azide by rearrarigerneiit to the urethan, methylatioii, and reduction, a route analogous to that recently reported for the synthe of 3-dimethylaminotliioi ) l i e ~ i e . The ~ free babe, 1:tted by preparative gai chromatography, was stable under vacuum or inert atniosphere, but it 1)olyiuerizcd very rapidly in contact with the air. The ainine re:idily reacted with methyl iodide to produce the yuuteriiury wlt, a hitc>crystallitic compound stable i i i air. Pharma~ology.~-3-I~urplt rimethylammonium iodide, administered iritravenoudy i n a dose of 100 nig/kg, \\-a- fatal to two mice. The next lower dose, 31.(i mg kg, was not lethal but produced ptoqit, decreased wtivity, and irregular respiratory movements. A dobc of 1 nig 'kg administered quickly intravenously to 'I rat induced a biphaiic vawiiotor responoe of small magnitude; a similar rezponbe followed slow injectioii of 5 mg/kg. After thi- latter doie, epinephrine elicited :t vasodepressor reipon-e. the preabor effect of norei)iiiephririe was retiuretl, atid the fall in blood 1)req-iirc' cvoked by acetylcholine n a+ markedly enhanced :i~id prolonged. I:or comparison, ~-tlii~~iyltriniethylarllrnoriiu~i~ ioclickJ administered intravenoudy in doses of 100, 31.6, a d 10 mg/kg to g r o u p of t m mice produced res1)ectively 2 , 1, arid 0 fatalitie-. Ptosis, decreased locomotor activity, ataxia, and respiratory irregularitic,- were observed it1 the -urvivors. In the rat, ail ititravenous dose of 0.5 nig kg evoked a transient 1iyi)otensive response, and a dose of 3 m g k g increasxl the magnitude and cluratioii of the depressor response evoked by acetylcholine. 111 :L cat, an intravenoui tloici of 1 nig/kg elic-itd :i 4i:iri), brief fall in blood I 1) (a) Tliis uork has been enpported in part IJJ C b Public Health ( 1 1 ) Presented before tlie Disision i e r \ i c e Research Grant KO G l I 10264 of XIedicinal Chemistry a t the 148th Sational Meeting of ttie .imerican ( llemical Society, Chicago 111 111y I 5 b 4 ( c ) PreTious paper J B SiilliLan and rf C J I c C a r t h j , I H e t e r o c u d i c Cheni , 2, 103 (1965) i 2) Felloir of the .\meriran l'oundatiirn f o r Pharmaceut~calEducation and losiali Kirby Li11p Jlemorial rel10w f o r 1(462-19C,I ( 1 ) I B Snlliran and 11 c' \IC( artti! .I Org Chem , SO, 662 11'465) (4) \ \ e u i s l i to acknouledye our indeljtedness t o Ilr T I innie Teeters of
llaileton Lalioratories In1 1 col~iqicaltest5 reported l i ~ r t
dl1'i
fhun
11
Va u h o performed the
()lldrilla-
3-Furoyl Azide.j--Froiii 10.5 g (0.0Sl inole) of 3-furc)yl vliloride6 i n rold acetone and exre ueous .odium azide, \vorked r i p as reported for the thiophene p ~ u n dthere , ~ was obtained 9.2 g (84%) of crude oily azide. Some crystallization occurred while evrtporating the ether solution, h i t these crystals melted below room temperature. Methyl N-(3-Fury1jcarbamate.-Crude 3-furoyl azide [!).:3 g. 0.06S mole) refluxed with 100 nil of ahcolute methanol for 12 h r : suhequent evaporation of the solvent gave 9.3 g of crude prodiic~l, mp i6-83". This crude material \vas satisfactor). for methyl:ition and ttie compound could be more readily purified a t the ni'zt step. Recrystallization from ligroin gave 4.4 g (465;) of purifieil produrt, nip 81-83", \rhic,h upciii va(vum sublimation K a r t . white carystnlr: mp S2-S3"; iiinr spectrum' i i i CI>CI,I, 6 = 3.i4 ( 5 , CHI, 3 €I), 6.:% (4,4-1%of riiig, 1 Hj, 7.24 i t , .?-I1 i i t ring, I I{), 7.49 (broad s, NH.8 I I I ) , 7 . i 4 (hroad s, 2-H of ritig, 1 11) p p m ; J 2 , = 0.9 cps, J.: = l.!) VIIS, .I4: = 1.9 cps. *1nuz.q Calctl for C~H;ru'od: C', 51.06; 11, 0, :3.2.(!1. Found: C, 5l.W: 11, 4.9:; Methyl N-Methyl-N-( 3-fury1 jcarba i,3-fur!-l)c,:irh:irnnte (14.1 g, 0.1 rnole), I 1. of a11 :$2 nil (0.5 mole) of iiieifiyl i(idide, : t i i d 45.h g 52,,5c di~persioii of XaH i t 1 riiiiirr:iI oil were reflusetl uiiciei, nitrogen for 12 lir, with agitatioii 11y riieatib of n T'ihro l l i x e r . i ied NaI n n d excess S a l 1 were reniov tie was evaporated under reduced chroniatographed 011 450 g of h oil from the S a f I dispersion wns rc.rimveti 1,.: bvasliiiig w i t h petroleuni ether. T h e niethylatetl ~ w t i s n i : i t t . product \\-a,-eluted with 4 1. of beimenr. (Ciiriiethyln(ed st wtirig material remained OIL ttie coluniii arid could tie su1)sequrirt I>. eluted \\ ith ether.) Ev:tporatioii of tlie benzene eluates gave. \vhic,h distilled at 50-36' ( 0 . 2 nini) i t i a yield of 13.4 g . h i aua1ytic~:tlsunple ax redistilled at 42" ill.OG nini 1 , iiitir 5pectruni i i i ClY&, 6 = 3.26 ( 3 , S C H , , :3 11). :;.SO f a , OCI13,,3 IT), G.G(I (m, 4-ll (Jf ring, 1 11 I , i.30 ( t , 5-E1 i i f ring, 1 11 7.3.; (1)road r , 2--H of ring. 1 I T ) 1111n: .I.-, = 1.7 q s , J1; = 1 .7 ) I
('pa.
:Ind. Calcd for Ci.tIgX03: c:, 54.19: 11, 5.b.i; S , !).I):;: 0, 30.94. Found: C, 54.34, 54.32; H, .i.O3. 5.77; S , 9.10. 9.12: 0, 30.81, 31.02. 3-Dimethylaminofuran.--~letl-i~-l S-niet hyl-S-[ 3-fury1 Ji~ari)airi:itr ( 5 g, 0.032 niole), dissolved i i i 50 nil of :mhydrous tetrahydrofuran m s added t o :I ~olutioiiof 2.4 g (0.064 inole) of Li.4lHI i i i 100 r i l l of a i i l i y d r ~ ~~etrahydrofurati. ii~ The mixture KL- rtafluxed under dry iiitrogeii for 70 fir, cooled t o room ternperat iire. 5 nil of water waa added with vigorous stirriiig, followed t)y t tic, :idditioii of 2 nig Of ~iydrcicliiiiioiit.. The -(did w:ic removed - ,1 15) I'regarecl witlioiit istrla1iori liy a different rnetliod and utilized for s i ~ t a aeriiient syntheses by R.1%.Bortner. 17n. Clirm Soc., 66, 666 (1934). (6) (a) 11. Gilman and K. R . Riirtner, ibid.,66, 2903 (1933). (13) Tlie .4fiiroir acid was yrepared acrordinp to 9. Gronowitz and G . Sorlin. .irkti, X r m i , 19, 515 (1962:. !i) Kmr spectra uere taken a t 6 0 3 I c a n d rel~ortedas 6 values in ripin from tetramethylsilanP (internal reference). C'oupling constants are r e i i n r t d in i'p' z 0 . 2 . ( 8 ) Identified by deuteration i n heavy water plus deiiteriometharrol. ( 8 1 Elemental analyses by A . Bernhardt, lliilheim (Ruhr), German). 110) I n similar runs with conventional stirring. yields of only a l i o u t 40'; were nlrtained, apparently because t h e sodium salt of tile iirrtlian formmi :I iimtine o n ttie S a H particles.
Jlarch 1966
255
NOTES
filtration and the filtrate was stored a t 0" under nitrogen. After evaporating part of the solvent under reduced pressure, the pure amine was isolated by preparative-scale gas chromatography on a 5-ft Carbowax column at 100"; nmr spectrum in CCla, 6 = 2.59 (s, CH3, 6 H), 6.03 (4, 2-H of ring, 1 H), 6.74 (9, 4-H of ring, 1 H), 7.15 (t, 5-H of ring, 1 H) ppm; J24 = 1.1 cps, J26 = 1.8 cps, Jas = 1.8 cps. Anal. Calcd for C6H8NO: C, 64.84; H, 8.16; N, 12.60; 0, 14.40. Found: C, 64.72, 64.64; H, 8.09, 8.03; N, 12.56, 12.57; 0, 14.61, 14.52. 3-Furyltrimethylammonium Iodide.-The amine was added to excess methyl iodide at 0" and the salt was recrystallized from anhydrous ethanol. No satisfactory melting point could be obtained; it started to turn brown at 160", with progressive decomposition above that temperature until a black mass was obtained a t 190". Anal. Calcd for CVHJNO: C, 33.22; H, 4.78. Found: C, 33.24, 33.09; H, 4.70, 4.78.
Poly--L-a,y-diaminobutyric Acid Hydrochloride MARGARET J. FRIDECKY ~ S D WILLIAMH. MCGREGOR
I'nion Carbide Research Institute, P. 0. Box 278, Tarrytown, .Vew York Receiaed October 18, 1965
The biocidal properties of polylysine and polyornithine' has prompted us to prepare a polymer of the next lower homolog. A crude poly-a, y-diaminobutyric acid had been prepared by Schmidt degradation of polyglutaniic acid? but the preparation of this polymer by polynierization of I\'"-carbobenzoxy-L-a, y-diaminobutyric S-carboxyanhydride has not been reported. The action of phosphorus pentachloride on i S " 1 Y dicarbobenzoxydiamiriobutyric acid yielded l-carbobenzoxy-3-carbobenzoxyaniinopyrrolid-2-oneand riot the expected S-~arboxyanhydride.~ More recently,j NY-tosyl-L-a,y-diaminobutyric acid was phosgenated mid then treated with hydrochloric acid resulting in a sequence of ring closure, opening, decarboxylation, and ring closure. The presumed intermediate, an Scarboxyanhydride ( S C A ) , was neither isolated or characterized but the results suggested the NCA could be prepared in this manner. The polymer was then synthesized by methods already described for polylysine6 except for minor details. The polymer mas an effective inhibitor of the growth of Alternaria species at levels of 0.501, (by weight) and caused lysis of Pamneciuni cauclatuin at levels equivalent to polylysine arid polyornithine (see Table I). The polymer was not attacked by trypsin or pepsin under the usual conditions. Experimental Section 11elting points are uncorrected. Elementary analyses were performed by Schwarzkopf llicroanalytical Laboratory. h i i n 0 acid analybis was performed by Analytica Corp.
(1) A I . S d a and E. Katchalski, A d a m . Protein Chem., 14, 391 (1959). ( 2 ) K. KO\-acs. G. Denes, A. Botai. and L. Polgar, Xaturwiss.. 42, 628
(1955). (3) E. Katchalski and M. Sela. Adoan. Protein Chem., 19, 402 (1958). (4) S.Wilkinson, J . Chem. Soc., 104 (1951). (5) K. Poduska and J. Rudinger, Collection Czech. Chem. Commun., 24, 3449 (1959). (6) G. D. Fasman. AI. Idelson, and E. R. Blout, J . A m . Chem. Soc., 8S, 709 (1961).
TABLE I ACTIVITY A G ~ I N S TParamecium caudatum Prepn
DPa
Poly-L-lysine 5-10 Poly-L-lysine 25 Poly->ornithine 25 Poly-L-a, 7-diaminobutyric acid 50 Streptomycin a Degree of polymerization. lysis in seconds.
Surrival oi paramecium' of prepn----Concn 10-5 .\I 10-4 .If 10-8 .\I
>3000 10-12 13-17
>3000 3-5 5-7
...
