NOTES
nlay 1965
393
/-
418
Y
i a8cps
spectrum (60 Me.) of 2,7-dichlorophenoFigure 2.--N.m.r. thiazine in perdeuteriodimethyl sulfoxide. Field increases from left to right. Chemical ,shifts are in c.p.s. downfield from an interiial tetramethylsilane reference. Figure l.--?i.m.r. spectrum (60 Me.) of 3,i-dichlorophenothiazine in perdeuteriodimethyl sulfoxide. Field increases from left to right. Chemical shifts are in C.P.S. downfield from an internal tetramethylailane reference.
gave the values suiiiiiiarized in Table 11. The strong interaction between neighboring hydrogens (spin-spin coupling) which exists between ortho hydrogens ( J = 5 to 10 c.P.s.), and the weaker couplings by ineta hydrogens ( J = 1 to 5 c.P.s.), are very sensitive to substitution. When substitution takes place in the 3-position, the 3,4-ortho coupling disappears arid only the large 1,2-, 6,7-, arid 8,9-ortho couplings remain. Disubstitution at the 2,8-positions leaves only the 3,4- and 6,7-ortho couplings and weak ineta coupling of H-1 and H-9. Disubstitution a t 3,: leaves only 1,2- and 8,9ortho couplings and weak mefa coupling of H-4 and H-6. A combination of cheiiiical shift, spin-spin couplings, and integration data permits the identification of individual hydrogens at each site in the aroniatic rings. The general features of the 1i.ni.r. spectra are illustrated by the typical curves reproduced in Figures 1-4, which show the effect of substitution on the resonance frequencies of the aroiiiatic hydrogens in these coinpounds. TABLE I1 CHEMICAL SHIFTS O F A R O X A T I C HYDROCIESS IN CHLORO-SUBSTITUTED P H E S O T H I A Z I K E S
H
6
4
Coupling constants, Hydrogen
Cheinical shifts,a c.p s.
c p.5.
1 2
395(m)-401(0) 423(0)
Ji,z = 9
3 4 6 7 8
404(0)
414(m)-418(0) 419( m)-420( 0 ) J6,s = 2 405(0) 422(0) 9 396( m)-401( 0) J s ,= ~ 8 Shifts are listed for hydrogens substituted either ortho or ineta ( m )to a chlorine atom.
(0)
413
401
i,Ji
Figure 3.--S.m.r. spectrum (60 Me.) of 2,B-dichloropheiiothiazine in perdeuteriodimethyl sulfoxide. Field increases from left to right,. Chemical shifts are in c.p.s. downfield from an internal tetramet.hylsilane reference.
In 3,7-dichlorophenothiazine (Figure 1) the doublet centered a t 395 c.p.s. is one-half of an AB systein belonging to the C-l hydrogen with J12 = 9 c.p.s. The other half of the ,4B due to the C-2 hydrogen at 423 C.P.S. is further split by the weta hydrogen on C-4 with J2,4= 2.5 c.p.s. The tall sharp line at 418 C.P.S. is a superposition of the C-4 hydrogen and part of the h B coupling froin the C-3 hydrogen. The ratio of the integrated intensities of the two groups of hydrogens was 2:l. The spectrum of 2,i-dichlorophenothiasine(Figure 2 ) shows two pealis centered about 396 c.p.s. which are due to part of the AB coupling between hydrogens a t C-8 and C-9 and are assigned to the C-9 hydrogen (J8,g= 8 c.P.s.). The adjacent line at 402 c.p.s. is caused by the hydrogen on C-1. The low-field doublet at 421 C.P.S. is the other half of the AB system, arising froin the C-8 hydrogen, and is further split by ineta coupling with the C-6 hydrogen (Jeg = 2 c.P.s.). The line a t 419 C.P.S. is assigned to the hydrogen on C-6, while the inultiplet centered about 412 C.P.S. is part of an AB systein involving the C-3 and C-4 hydrogens, the re-
sUTES
394
Figiire t?.--S.~n.r. spectrum (ti0 1 1 ~(if~ ~) , i - d i n ~ e t ~ h o s ~ p i i e n o thiaziiie ill perderit,el.iodimeth?.1 s~ilfoside. Field increanes Crorn left t o right. Chemical shifts arr i i i (t,p,s. doniifield from :iii iti t rriial t et rsniethylsilaiie refereiiw..
tiiaiiiiiig halt oi n-hicah I I C ~ Siiiidci the pealis assigned 1 0 Iiydiogetis at C-6 aiid C-1 Iiitegralioii gave a 1 1 .1 iatio, as experted. T l i ~assigiiiiie~itsfor 3 , i - a i d 'L.,T-dichloropheno~liiaziiic' iiiay be further verified by comparing the overlappiiig peaks of the two spectra. The peaks at 407-413 ~ . s.p i n 2,7-dtchloi*opheriothiazine ale absent iii t h e 3,i-dichloro compound. as 1s the sharp peak at 400 c4.p.a. Siiire oiie ring 111 these hvo substances is the saniC. the resonanre lilies qhould be identical, provided that there is no interartioii across the thiazine ring 'l'hcrefore, ilie peaks n7hic.h ai(. present oiily in the 2 , 7 dichIol.opheiiothiazllie spec1rum niust belong t o t Lit, hydrogelis at C-3 and C-4 as suggcsted above. 111 ",8-dic'hlorophenothiaziiie(Figure 3 ) both aroniat i ( ~riiigs arc' identical. The doublet ceiitwed aboui
1'01. s
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,3 011 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. I
