395
NOTES
May 1965
NH
I
Figrire 6.--S.m.r. spectrum (60 1Ic.) of 2-chloro-i-methoxyphenothiazinein perdeuteriodimethyl sulfoxide. Field increases from left to right. Chemical shifts are in C.P.S. downfield from an internal tetramethylsilane reference.
The Synthesis, Proof of Structure, and Biological Activity of Some Ilonosubstituted Aminoguanidines' J.
.4UGBTEIIV,
tive. As this compound (guanoclor4) displayed both dopaiiiine p-oxidase inhibitory and antihypertensive proper tie^,^ it was of interest to synthesize the isonier
s. 11.GREEN,A. R. KATRITZKY, 11.R I O X R O
.4XD
Research Dicision, Pfizer Ltd., Sandwich, Kent, England, and fhe School of Chemical Sciences, Cniversity of Ensf Anglia, Sorwich, England Received -\-overnber 2, 1964
The reaction of nionosubstituted hydrazines with Sinethylisothiourea sulfate (I) has been claimed2 to yield substituted aiiiinoguanidines of type 11. We have found that 2-(2,6-disubstituted phenoxy) ethylhydraKH
RPiHNH,
4
+RXC
I \
NH
//
or R N H N H C
\
NH? S H I
I1
NHz
I11
zines react with I to give, as the niain product, aniinoguanidines of type 111. React ion of 2- (2,6-dichlorophenoxy) et hylhydrazine with I yielded a compound which was assigned structure IVa,3011 the basis of its failure to give a benzal deriva(1) Presented in part before the Division of Medicinal Chemistry, 9th National Nedicinal Chemistry Symposium of the .imerican Chemical Society, hlinneapolis, Minn., J u n e 21-24, 1964. (2) (a) J. E. Robertson. J. H. Riel, and F. DiPierro, J . X e d . Chem., 6, 381 (1963); (hj E. G. Podrebarac, \T, H. Nyberg, F. A. French, and C . C. Cheng, ibid., 6 , 283 (1963); ( c ) J . H. Short, E. Riermacher, D . A. Dunnigan, and T. D. Leth, ibid., 6, 275 (1963); (d) C. Cipens and V. Grinsteins, Z h . Obshch. Rhim.. 32, 3811 (1962); ( e ) .I. IlI('.kl. $HIFT:, ( 7 ) O F 3 I E T H Y L E S E PROTOSS
IS Two
C1?3c02H-.-
...~
r___-.-
Compd.
B
a
(hrOCH2CHzS-i'
SOLVEXTS H?SOa----
,_
a
8
I\-& 1-
6 , 32h 5.5Sb ca. s . 8 ~ ea. 5 . 3 cu. 5 6 c cu. 5 . i c ea. 5 . 5 d a 01 and 6 refer to relat,ive position to the nitrogen atom. * Triplet, J = 5 C.P.S. Overlapping complex multiplets. d Broad singlet.
Experimentalg
2-12,6-Dichlorophenoxy jethylhydra~ine.~-%(2, 6-Uichluruphenoxy)ethyl bromidelo (20 g., 0.074 mole) in ethanol (75 nil.) was added slowly to hydrazine hydrate (37 g., fl.74 mole) in ethanol ( 2 5 ml.), and the mixture v a s heated under reflux for 16 hr. The solvent and excess hydrazine were reriiuved under (ir) Synthesis.-The K-benzyl-2-(2,6-diiiiethylphereduced pressure, and the residue was treated with 50"; aqueous noxy)ethylamine intermediate TI' was nitrosated and SaOH. The product, obtained in Sur; yield by extraction with chloroform and distillation [b.p. 1:32-140° (1 mm.),n ? 4 ~I) ,50631, reduced with lithium aluminuni hydride to give the hywas somewhat unst:hle hut could be stored in the f o m i of:the drazine VII. This was treated Tvith l-ainidino-3,5-dihydrochloride, r1i.p. 110-11 1" ifroni methanol-ether). HXOL A n a l . Calcd. for CsHL1C1&:O: C, 37.31; H, 4.30; S , lO.\i. ArOc CH?):NHCH:CDH~ ArO( CH?):XCH:CeH, Foiind: C, 37.44; H, 4.03: S , 11.00. L14lII4 I 2-(2,6-Dimethylphenoxy)ethylhydrazine3 was prep:ireti i l l :ti1 XH? identical riiaiiiier froin 2-(2,6-dinieth~lpheiiox~-)eth~-l hrolnitl~~" \I \ I1 in 61-80';; yield. I t had h.p. 112---120°(0.7 111111.4 11% 1 2-(2,6-Dichlorophenoxy)ethylaminoguanidine Sulfate (1V inethylpyrazole sulfate and catalytically hydrogenated ., 0.052 mcile! : i i i t l 2-1?,tiS-~leth!-lisothiour~~ sulfate f 11 to IYb, identical with the material obtained directly g., 0.104 i i i o l c I i i i i r : ( t ~ i ' tiichlorophenux y jet Iiqlhydra x iiie r 4 hr. Tlie produ(,l i 14..i from the reaction of I with 2-(2,G-din~eth~~lp2ienoxy)cw)led reartion niisl \ l w 3 :in(l: ethylhydrazine. Application of the reductive alkyla___f
tion procedure of l'innegan, et al.,' to 2,6-dimethylpheiioxyacetaldehyde aiid aiiiirioguaiiiditie failed to yield a pure product. The isoiiier V was synthesized by the following uiiequivocal method, albeit iii poor yield. 2-(2,6-Dich1orophenoxy)ethylliydraziiir was treated with cyanogen bromide in aqueous ethaiiol to give a inisture of the cyanohydrazines VI11 aiid IX. The alkali-soluble derivative Y I I I was reiiioved froiii the reaction mixture by extraction with dilute sodium hydroxide, and the remaining IX was treated with aninioriia and aniiiioniuiii sulfate to give T'. This compound was distinct froiii IVa in its infrared spectroscopic and chroinatographic characteristics. AiO(CH2)2NHNHCS TI11
XrO(CH2)2N(h":)CN
IS
(6) J . J. Pitha, H. IIughes, a n d G. €3. L. Sniitb, J . A m . Chem. Soc., 70, 2823 (1948). (7) W. G. Finnegan, R. A . Henry, a n d G . B. L. Sniitli, ibid., 74, 2981 (1952).
1675 and 1630 C I I I . - ~ . AM^, C:~l(d.for ( ' l ~ H l ~ C I ~ N , O bC, S : i34.62: 11. 4.2!): 17.95; S> 3.12. Folintl: C, 34.60: H, 4.20: S ,1 7 . G ; li. 4 2-(2,6-Dimethylphenoxy)ethylaminoguanidine Sulfate I IV -111 the same maiiner> 2-(L',(i-tlinieth!.lpheniJx!.)etl~ylh!.tl~:i/.ilic~ \vas treated with ~ - 1 r i ~ ~ t h ~ l i s i i t 1 i i c isulfate r i ~ t ~ : i t i 1 ~ i I v\ ~ ~ J1 ,i i . 1 1 . 214-216" (from itqiieoiis erh:tiiol), u,,,.,, 16SO aiiti 1645 c'iii. . - I . .1,~~1. C:llcd. for C,2H,3,S80ti$:
