July, 1946
hlONOALKYL-SUBSTIlUTED IIIAMINES WITH 4,'i-DIC€ILOROQUINOLINES
methanol, gave 2..1 g. of tall crystals, m. P. 245-251 (dec.). After purification by sublimation under reduced pressure and further recrystallization, the compound melted at 249-251 and did not show a depression of melting point when mixed with synthetic 4-rnethylamino-7-chloroquinoline. I t showed a neutral equivalerit of 196 against standard hydrochloric acid. A sample of authentic I-methyla1nino-7-chloroquinoline was prepared in 6774 yield by the condensation of methylamine with 4,i-dichloroquinoline. After purification by recrystallization from methanol it melted at 251.5-252.5'. Anal. Calcci. for CIIJIyC1S2: C, 62.34; H, 1.71; N, 14.54; neutral equivalent, 193, Foundl4: C, 62.11, 62.30; H, 4.71, 4.62; N, 14.70, 14.54.
12253
carrying out some of the elementary analyses.
Summary 4 - (4'- Amino - 1 ' - methylbutylamino) - 7 - chloroand six drugs of the series of 4-i4t-monoalkylamine- 1'-methYlbutYlamino) - 7-chloroquino h e s were synthesized, with alkyl groups as foll0\sTs: methyl, ethyl, isopropyl, %-butyl,isobutyl , and s-butyl. An improved procedure for the preparation Of 4-amino-1-pentanol was developed. 1-EthylamAcknowledgment,-~~e wish to thank 1 3 ~ . ino - 4 - aminopentane and 1 - (.U - acetyl) - ethylLiebe Cavalieri for assistance in several of the amino-4-aminopentane were Prepared. preparations described i n this paper and for PHILADELPHIA, PENNSYLVANIA RECEIVED APRIL 5, 1946
[COS1RIIiUTION FROM THE
DEPARTMENT O F CHEMISTRY,
MASSACHUSETTS INSTITUTE O F TEC€iSOI,OGI.]
Synthesis of Monoalkyl-substituted Diamines and their Condensation Products with 4,7-Dichloroquinoline BY D. E. PEAR SON,^ W. H. JONES AND ARTHURC.COPE The antimalarial activity of a number of 7 chloro-4-dialkylaminoalkylaminoquinolines (I) prepared and tested as part of the antimalarial program sponsored by the Committee on Medical Research suggested that similar compounds with side chains terminating in a secondary amino group (11) should be investigated.
which have been used for preparing primary alkyl h o m ~ l o g s . ~1 - Cyclohexylamino - 3 - amino - 2propanol was prepared in a similar manner from cyclohexanone and 1,3-diamino-2-propanol. Hydrogenation with Adams platinum catalyst a t room temperature or 60' in each case gave better yields than reductions in the presence of Raney nickel a t higher temperatures and pressures. KIsopropyltrimethylenediamine was prepared by adding isopropylamine to acrylonitrile and hydrogenating the addition producta6 Three 1-alkyl amino-4-aminopentanes, RNH(CH2)3CH(CH3)"2, in which R was isopropyl, isobutyl and I, R1and Rz are alkyl tertiary-butyl were prepared by reaction of 511, R, is H, Rz is alkyl chloro-2-pentanone with the respective primary amines, followed by reaction with hydroxylamine Compounds prepared by condensation of 4:,7dichloroquinoliine with ethylenediamine, 1,3-di- to give the 5-alkylamino-%pentanone oximes. amino-2-propanol and some of their monoalkyl The procedure used was based on one employed derivative's are described in this paper. Also for the ethylamino homolog by Carmack, Bullitt, included are several similar compounds with the Handrick, Kissinger and Vom4 Catalytic hydrofollowing types of side chains, which were investi- genation of 5-isopropylamino-2-pentanoneoxime gated more extensively in other laboratories : produced extensive cleavage and gave low yields of 1-isopropylamino-4-aminopentaneunder all con-NH (CH2)3N13R3; -NHCH (CH,) (CH2)sNHR. ditions which were investigated, but a sodium and Monoisopropyl arid cyclohexyl derivatives of ethylenediamine were prepared by reductive butyl alcohol reduction procedure was applied alkylation of the diamine with acetone and cyclo- successfully to each of the oximes. The diamines which were prepared and are dehexanone. This synthesis appears to be a simpler scribed in Table I were condensed with 4,7-dimethod for preparing these compounds than alkylation procedures employing alkyl halides chloroquinoline by heating the reactants alone or in the presence of phenol with careful temperature (1) T h e work described in this paper was done under a contract, control, according to procedures similar to those recommended b y the Committee o n Medical Research, between t h e Office of Scientific Research arid Development and t h e Massachusetts I n s t i t u t e of Technology. (2) Present addrem: Vandcrbilt University, Nashville, Tennessee. (3) Tarbell, Shakespeare, Claus a n d Bunnett, THISJ O U R N A L , 68, 1217 (1946). (4) Carmack, Bullitt, Handrick, Kissinger a n d Von. i b i d . , 68, 1.220 (1946).
( 5 ) Aspinall, ibid., 63, 862 (1941). h a s prepared monomethyl, ethyl a n d benzylethylenediamine b y alkylating N-benzenesulfonylN'-acetylethylenediamine in alkaline solution a n d hydrolyzing t h e products. Linsker a n d E v a n s , ibid., 67, 1581 (1945), have prepared higher molecular weight primary monoalkylethylenediamines b y direct alkylation with alkyl chlorides or bromides. ( 6 ) See ref. 3 for application of this synthesis t o other amines a n d references t o t h e earlier literature.
D. E.
1226
PEARSON,
w.H. JONES
AND
c.
Vol. 6s
ARTHUR COPE
TABLE I ~ ~ ~ N O A L K Y I . - S W S T I T U T EDIAMINES D
R. p.
Yield,
Yo
Compound
c~~Io-CBH~~SHCHICH~NTH? iso-CBH7NHCH2CH2NH? cyclo-CeH,,~HCH~CHOHCHpNH? ~~O-C~I-I~N€I(CH?)~~L"~ 5 iso-C,H,NH(CH,),C~~(CHa) NH? 6 ~ ~ O - C ~ H ~ N H ( C H ~ ) * C PiHz H(CHI) 7 t .C4H9SII(CHz);CH(CH,) S H ?
1 2 3 4
Formula
,-Carbon, 3 ', Calcd. Found
OC.
83 50 77 54 58 01 53
101-102 135.5-137.5 126-12gb 101-lti2 55-56 6041 84-87
Mm.
n'5D
0 5 4
14
1 4800
$07 2
1.4350
770 3 1
13
0 0153 ,8332 1.0135 0 8271 ,8166 ,8198 ,8178
1.4997 1.4394 1.4100 1.4411 1.4398
Molecular refraction Calcd. Found
43.98 32.32 50.12 36.94 46.18 50.80 50 80 _
Analyses Hydrogen, % Nitrogen, qo Calrd. Found Calcd. Found
44.15 32.39 49.97 36.99 46.56
$50.99 50.99 _
.
_
Neutral i.qiii\-alent Calc
