cymene with 0.8 g. of 10% palladium-on-charcoal. The warm solution was filtered from catalyst, and on cooling colorless needlys of VI slowly crystallized: yield 0.7 g . ; in. p. 158-160". Recrystallization from acetic acid diluted Lyith a little water, or from 95% ethanol, gave needles of m . p. 162-163". The identity of the product was demonstrated by analysis and by mixed melting point with an authentic sample.6 lO-Methoxy-1,2-benzanthracene (VIII).-Two grams of compound [I* was methylated i i i inethanolic alkali, using tliinethyl sulfate as alkylating agent. The oil obtained in this iiiaiiner could not be crystallizedso it was refluxed in 50 cc. of +cymene with 1.O g. of 20yopalladiumon-charcoal for twenty-four hours. The catalyst was filtered off and the filtrate concentrated to dryness. The residue was triturated with Skellysolve B and several successive 50-cc. portions of Skellysolve B were distilled from thc product, which solidified to give 0.45 g. of yellow crystals of in. 11. 104.-106". Two recrystallizations from Skellysolve B gave colorless platelets of i n . p. 109.5110.5'. T h e identity of this product was established by analysis aiitl 1):r inistiire melting point with an authentic specimeii .h lO-Hydroxy-l,2-benzanthracene (IX) .---Two grains of coinpouiitl I V \vas heatect with a mixture of 3 g. of sodium chloride. 111 g. of zinc chloritlc and 4 g. of zinc dust a t 270-XOOo for t\reiity iiiiiiutes, accorrling t o the method of CIar.; Thc product could not be purified so i t was refluxed for tiretity-four hours in 20 cc. of @-cymene with 1.3 g. of 10yopalladium-on-charcoal. Filtration and cooling gave 0.3 g. of yellow crystals of in. p . 148-154". TKO recrystailizations from benzene gave golden yellow leaf lets, ni. p . 153--155" (lit.a m . p. 154-155.5"). Ilirect dehydrogenation of compound 1x7 in refluxing p cyrneiie, withoiit previous zinc dust treatment, gave IX
(in a much poorer yield) contaminated with a large amount of the bimolecular dehydrogenation protiuct X. The Bimolecular Dehydrogenation Product X.--Tn.o grams of coinpoutid IT' was hcatrtl iii a n oil-bath a t 230240" for three hours Ii-ith 0 . 3 g. of 1070 pallatliutn-on-charcoal. 7hc cooled residue as taken up i r r 100 cc. of 95% ethanol and filtered.
The filtratc was roiicentratcd to idiie, consisting of a iiiirture of a product. Rccr~-itallizatioiidit1 iiot result in purificatioii so the solid was subliiiicd a t a bath teinperaturc of 14-5' aiid under a vacuuiii of 0.2 inin. The sublimed, dark colored material could not be purified but the non-volatile residue consisted of 0.3 g. of colorless material of m . p . 230-235" (dec.). Recrystallization from 50 cc. of 95% ethanol gave fine colorless neetllcs of m . p . 241-244" (dec.). A m l . Calcd. for CaaHynO. (compound X ) : C , 88.86; 13, 4.56. Found: C, 88.90; €3, 4 . i l .
Acknowledgments.-The help of Dr. IJ3lliam Sidon in the preparation of starting materials is gratefully acknowledged. For the microanalyses, the author is indebted t o hlr. E. F. Shelherg, chief microan:dyst, Abhott Laboratories. Summary The application of a novel cyclization reaction to the synthesis of oxygenated benzanthracene derivatives has been studied. -1modification i n the preparation of the important intermediate, ethyl y-phenylacetoacetate, is reported. RECEIVED JLXY 77, 1946
NORTHCHICAGO, ILLINOIS
[ CONTRIBUTIOS FROM THE DEPARTMENT O F CHEMISTRY, MASSACHUSETTS ISSTITCTE
O F TECHNOLOGY]
Some N-(2-Diethylaminoethy1)-anilines' BY MARKA. STAHMANN AND ARTHURC. COPE .
Xost antimalarial drugs contain one or more relatively weakly basic groups and in addition an alkylamino side chain which is more strongly basic. For example, 8-aminoquinolines of the Plasmochin type, similarly substituted 4-aminoquinolines, and Atebrin have a strong basic center in the side chain and weaker basic centers provided by the heterocyclic nitrogen and the secondary amino group attac:hed to the heterocyclic nucleus. These common structural features suggest that the presence of these basic centers is associated with the antimalarial activity of the compounds. Some e-vidence in this direction is furnished by the observation that the toxic effects of Atebrin and quinine t o certain microorganisms may be overcome or antagonized by small amounts of several polybasic amines, notably spermine and spermidine.* In such experiments the basic centers of the polybasic amines presumably compete with those of the antimalarial drugs for the same enzyme surface, and provide the enzyme with some degree
of protection from inactivation by combin a t'ion with the drugs. It appears possible, therefore, that the antimalarial drugs function by inactivating an essential enzyme of the malaria parasite by combining with the enzyme, and that the basic groups of the drugs are involved in this combination. Enzymatic processes are known which depend upon combination of the enzyme with basic centers in the substrate. For example, the hydrolysis of peptides by aniinopeptidases depends upon the presence of a basic center (the a-amino group) in the peptide.:' Such a process might be blocked by a basic antimalarial drug which could combine with and inactivate the enzyme. -4s part of a study of the relationship of chemical structure to antinialarial activity directed along the lines indicated above, we have prepared a series of N-(2-cliethylaminoethyl)-anilines(I) and N,Kbis-(2-diethylaminoethyl)-anilines (11). These
(1) T h e work described in this paper wab done under a contract recommended b y 1.he Committee o n Medical Research, between t h e Office of Scientific Research and Development a n d t h e Xassachusetts I n s t i t u t e of Technology. (2) Silverman a n d Evans, J . Aiol. Chem., 154, 521 (1044).
compounds were investigated to determine whether such simple aromatic amines with alkylamino side chains have antimalarial properties. They
rlr SI-ICH-CH. S ( C2Hji2
.4rS (CH,CH, S (C?H:)?)?
I
I1
(3) See Johnson a n d Berger, Advances i?z Eizzynio/,, 2, 69 (1942).
Dec., 1946
SOME
N-(2-DIETI-IYLAMINOETfIYL)-ANILINES
xx
3
7$.9 74.8
10 5
10 (j
li!l
li
..?
:I :3
8 4 S 4 8 1 (iU
8 4 8.I
xs
61.0 43.3
60.7 72.9
61.0 72.8
79.3
7!1.3
74.2 OG3 li6 3
74.3
11 4
li6.0 fin 0
!).!I
72.9
72.8
J
3
L
l!)
2 3
0 .I1
1
42 1d ::5
4
8 2 1
.... I1
ll,lti3
60.8 43.3
IS
34
lit
174-177 180-18P llii-lO!l
:(I)
'2lI!l211
?!J
13
G I 1 4
1..?137 1.5327 1 .3208 152111
C1-H 1 C I , H .IC1 CIIHV~I\T,CI CmHnN~
14 li 124
12 1 8.1 1 2 1 7.1 1 0 7 (j.!) 7 . 1 10 7 >. I i l . 9 1>,4
10.8 lO.ii
The Survey Suiiilxr (SN---) refers to t lie timnlw by which the coiiipouiid will IX ideiitified in the forthcoining iiionograph [ref. 4). " Dihy itle. 111. 1). 122--124c. :lnui. Calcd. for C12H20S2.2HCl: C, 54.3; H, 8.4; S , 10.6; C1, 26.7. Fouiid: C , ,5,4 ; S , lil.4; C1, W.7. Cleino aiid Perkiii, J . Chem. SOC.,125, 1809 (1924), have prepared the base aut1 report 1). (17 I I I I I I . ~ . I)ihydrochloride, 111. p. 132-133' (very hydroscopic). A n d Calcd. for C,2HIUS2C1,2HC1: C , 18.1; H, 7 . 1 ; S,9.3; C1, 35.5. Found: C, 48.0; H , 7.3; N , 9.3; C1, 39.5. Monohydrochloride, m . p . 141-143". .1u(l1. Calcd. for CInHlaSnCl.HC1: C, 54.8; H, 7.i; S,10.6; C1, 26.9. Found: C, 54.9; Monohydrochloride, ni. p. 161-165". A n d . Calcd. for C12H&2Cls.HCl: C , 48.4; H, H , 7.8; X, 10..5; C1, 26.0. ti.4; S , 9 . 4 ; CI, -35.7. Fouiid: C , t8.:3; H , 6 . 3 ; S ,9.7; C1, 35.8. f The residue iti the distilling flask decomposed suddenly near t h e end of the distillatmi. This coiiipound is a dark red liquid with a brilliant dark blue fluorescence. h English Patent 29L',iil,j i C ' h i u i . Zcnlr., 101, lW7 (1930)) gives h. p. 160" (4 I ~ U I I . ) for this compound. (1
"
I'
failed to shour acti\-ity i l l a\.ian ilialaria at dose levels a t which they were not toxic to the host,' and accordingly withiii the liiiiits investigated the arylaininc) group c:riinot replace the -1- o r quinoliiie or !)-aiiiitic)~tcritliiic iiutlcus wit of usefuE. antiiila1ari:il actiyity. The iimio- and tlisulxtitutecl aiiiliiie derivatives whicli wcrc syiltlicsizctl ant1 arc listed in Table I wer(s prej)are(l Iroiii the corresponding primary ;iroiiiutic. aiiii1ic.s by dkylation with 2diethylaminoetliyl cxliloritle liytlrocliloritle suspended in I)c'nzc~iei l l the preseiicc oE ;ti1 excess of potassium carlxmaLe. .-Isiiiall aniount of copper bronze powder was atldctl as ;t catalyst." N-(2Diethyluiiinc wth>-l)-aniliricwas prepared in TO72 .lcl i l l the al~seiiceof the cxtalyst, and in 7s yield uiitlcr similar conditions in the presence of copper bronze, which \vas thcreforc added in subsequent :ilkylatioiis. The ~iionoalkylaiiiliiicswere the priiicipal products when s o r x w l u t iiiore than two moles of the primary aroinatic aiiiines were treated with one mole of '-diet:hylaiiiiiioetli?.l chloride hydrochloride. \'ields of the alkylation products were lower for />- :tilt1 o-substituted aiiiliiies than for aniline, atid in the group of chloroanilines decreased progressively in the sequence w ,p - , 0-,diand trichloroaniline. The S,N-bis-(,-diethylamino-ei;hyl)-anilines were prepared by alkylation of the primar!: aromatic amines with a large excess of "-tliethylaiiiiiioetliyl cliloritle hydrochlo(4) Pharinaul1ug.c;il dat.i w i l l l i e citeil in a fixihcomini. mrmograph p r e p u e d by the S u r v e y o f .Intimalarial 1)rugs. (5) Kerrneck anti \VrighL, J . C h c i , i . Sx.,1121 (103,;).
ride. In most cases the intermediate monoalkylanilities were not isolated. With aniline itself, the yield was practically the same when K(2-diethylaniinoethy1)-aniline was isolated and realkylated. rltteinpts to prepare the c1ialkyl:tnilincs in which the aryl group was 2,4,Ci-trichloropheii?.l, 4-nitrophenyl and a-naphthyl gave only the inonoalkylanilines. Iieductiori of the basicity of the nitrogen and steric hindrance both should hc a t a maxi~iiuiiiin 2,~,1i-tricliloro:~iiilitic, among- the amines which were alkylated. I n this case, the yield of the iiionoa1kyl;uiiline was only four per cent. and iione of the dialkylaniliti~was isolated.
Experimental6 N-(2-Diethylaminoethyl) -anilines (I).---A suspension o f 0.6 mole of the priiiiary aromatic ainiiie, 0.4 mole (69 g . ) of 2-dicthyla1iiitiocthyl chloride hydrochloride, 0.9 mole (125 g.) of anhydrous potassium carbonate, 2 g. of copper bronze powtlcr aiid 350 1111. of benzene was heated under reflux atid stirrctl with a Hershberg stirrer for eleven hours. The reactioii inixturc \vas then cooled, 500 ml. of 10% aqueous sodiuin hydroxide solution was added, and the mixture was extracted with two 300-nil. portions of ether. T h e ether extracts were coinbiiied, washed with water and saturatctl sodiutn chloride solution, and dried over anhydrous tnagncsiuni sulfate. The ether was removed by distillation and the residue was fractionated through a IYidiricr coluiiiii with a six-inch spiral. The forerun consisted largely of the primary aromatic amine which \\.as used iii cxccss; if this amine was a solid, most of it was separated by crystallization or distillatiori through a Claiseii type still head before the residue was fractionated. The second fraction, which containcd the S-(2-diethylatniuoethyl) -aiiiliiie, waz refractionated . In soiiie cases, a small amouiit of the N,IU-bis-(2-diethyIaiiiiiio~thyl! aniline was obtained as a higher boiling fraction
-
( G ) Xlelting a n d boiling points are uncorrected
Vol. OX section. The ether extracts were dried, the ether was reinovetf, a i d the residue was fractionated. A forerun consisting largely of the N-(2-diethylaminoethyl) -aniline tlistillctl iirst, followed by t h e higher boilirig NIN-bis-(2diethylaininocthyl) -aniline.
We are indebted to Mr. S. M. Nagy and Mrs.
C.K. Fitz for analyses. Summary X number of N-(%diethylaminoethyl)-anilines (I) and N,N-bis- (%diethylaminoethyl)-anilines (11) have been prepared by the alkylation of primary aromatic amines with diethylaminoethyl chloride. These compounds have been tested for activity in avian malaria. CA?.lI3RIDGE, MASSACIIUSETTS
/ C m - m r i r r r (I?: moa1
TIIII
RECEIVED AUGUST20, 1946
I’tiww RI.;SL~RCII FOUNDATION AXD THE DEPARTMENT OF CHEMISTRY OF PURDUE UNIVERSITY]
The Ccndensatim of Aldehydes and Amines with Nitrogenous Five-atom Ring Systems’ I ~ YC:. Hw.\wr 1 3 . ~ c i i ~ AND . m LOWELL V. HEISEY~ I
I
\x/
H
H
With dimethyl- or diethylamine colorless, highboiling liquids are obtained which are stable only under vacuum in sealed containers. These liquids possess strong, characteristic and rather pleawnt odors. The products from the higher aliphatic amines, such as di-n-butylamine, decompose on attempted vacuum distillation. While only disubstituted products are obtained with aliphatic amines under various conditions, piperidine and morpholine readily give either mono or disubstituted pyrroles according to the mtio of reactants used. These products are white, crystalline, relatively stable solids and are formed in S5-[35Y0 yields. N-hlethylaniline iilicl thialdine do not react. The Nantiich condensation may proceed by any oiie or all of three different mechanisms3 (A) I< E1 f CH2O +R-CHtOH R C H ~ N R ’ Z HpO KCH,OII R’2NH
+ + + + +
+
(13) R’3SH CH,O+ R’ZNCH~OH R-H +RCH2KR’z 4-HzO IZ’SCHZOH or (C) I< --H CH2O R’29H +RCHtSR’z HzO
+
where C represents a mechanism involving different (but unspecified) intermediates from those shown in A and B. A trimolecular reaction for C is conceivable but improbable without supporting kinetic evitlence. In our experience the best
