Sovclllber 1966 beneficial effects on patients suffering from malaria." I t is thus apparent that the synthesis and biological evaluation of 2,8-bis(substituted amino)pheriothiazine 5,s-dioxides (V), which possess the combined structural features of I, 11, and IF', should be of considerable interest.
t,riacet'ylphenothiazine (VIII) prior to the oxidation st'ep, was also attempted. Although the rearrangement was carried out' successfully, difficulty was encount'ered during the oxidation of t'he rearranged product' (IX)18to the corresponding sulfone. CHI
I I
NOH C=O NOH C H I1J - C ~ I ~ C II - C H ~
Va, R1, R,=H b, R I C H ; R,=COCH3 C, RI = H, R2=C2H, d , R i = H ; Rz=CHO e, R 1 = H , R 2 = C H f , R, = CH3, & = CHO g, RI, R2=CH]
VI11 CH3 I
II
CH3-C-NH
'l'wo synthetic routes to 2,8-diaminophenotliiaziiie 5,j-dioxide (Va) have been reported. AIichels and XmstutzlB prepared Va from phenothiazine by an eightstep synthesis involving a Curtius rearrangement. A new synthesis of Va by prolonged heating of bis(2,4diaminophenyl) sulfone with zinc chloride in dilute hydrochloric acid was reported by Bradbury and Smith.Ig Since the first procedure is rather lengthy and the second method could not be repeated in our laboratory,20a niodification of Mchels' and Amstutz's synthesis using a Beckmann rearrangement was examined. Our procedure consists of the conversion of the dioximez1 (T'II) of 2,s-diacetylphenothiazine 5,5-di0xide'~ (VI) to the corresponding diacetamido derivative (Vb) with phosphorus pentachloride. The desired 2,s-dianiinophenothiazine 3.5-dioxide (Va) was readily obtained by acid hydrolysis of Vb. Thus, the present synthesis (shown in Scheme I) provides an easy arcess to T'a and its related compounds. SCHEME
c=o XI ~ N
0
1
0 H - C - C H ,
II
\
IX
Reduct,ion of the acetamido derivative (Vb) with borane in tetrahydr0fura.n readily yielded 2,S-bis(ethy1amino)phenothiazine 5.5-dioxide (Vc). The corresponding methylamirio compound (Ve) was prepared from the formamido derivative (Yd) in a similar manner. Formylation of Ve with acetic formic anhydride followed by reductmionof the resulting compound (Vf) by borane afforded 2,8-bis(dimethylamino)phenothiazine 5,5-dioxide (Vg). Preliminary, antimalarial evaluation results?? indicat,ed t'hat compounds of type T' did not show act,ivit'y against Plasinodiuitz berghei in mice. .ipparently the rigid phenothiazine dioxide ring system failed to retain the original antimalarial activity exhibited by DDS and related compounds. Bis(2,4-diacetaniidophenyl) sulfone,1g prepared in caorinection with the attempt,ed cylization t'o T'a by the method of Bradbury and was also inactive. Experimental Section23
VI CH3(HON=IC
,
H I
Dioxime of 2,8-Diacetylphenothiazine 5,5-Dioxide (VII).-4mixture of 3.15 g (0.01 mole) of 2,8-diacetylphenothiazine j15dioside (VI), 1.8 g (0.0%6 mole) of hydroxylamine hydrochloride,
PCl,
nC\ I=NOH)CH
VI1
Vb
H+
Va
'I'hc alteriiat'e synthet,ic approach, \t 1iic.h involves a Becl
