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Derivatives of Biphenylsulfonamide. 11.' Derivatives of p-( o-Arninopheny1)-benzene~ulfonamide.~ BY ALEXANDER H. POPKIN AND GERTRUDE M. PERRETTA 'The preparation of p-(0-aminophenyl) -benzene- the position of the amino group does not increase sulfonamide has been described.' The present the activity. work is concerned with some derivatives of this It was noted during the deacetylation that the compound in which a hydrogen of the sulfon- six amino derivatives gave hydrochlorides which amide nitrogen was replaced by an aromatic: group. were non-ionic in behavior, i. e., they had distinct These were prepared by two methods, the first melting points and were insoluble in water. employing p - (0 - acetamidophenyl) - benzene- This distinction from the water-soluble hydrosulfonyl chloride, and the second, p-(0-nitro- chlorides of the parent compound, p-(0-aminophenyl)-benzenesulfonyl chloride. The identi- phenyl) -benzenesulfonamide and the isomer pties of the sulfonamide derivatives prepared by (fi-aminophenyl)-benzenesulfonamide6may be at the two processes were proved by melting points tributed to the increase in molecular weight. and mixed melting points. The insoluble hydrochlorides were used to advantage in isolation of the amino compounds obtained by reduction. The customary procedure requires the precipitation of tin with hydrogen sulfide. I n the present work, the alcoholic solution of the tin reduction was concentrated. The hydrochloride which precipitated was washed with water until free of tin salts. The desired derivatives then were obtained in substantially pure forms and in good yields. The following amino compounds were used in I t was reported previously' that p-(0-acetathe preparations: (1) aniline, (2) benzylamine, midopheny1)-benzenesulfonyl chloride could not (3) 2-aminobiphenyl, (4) 4-aminobiphenyl, ( 5 ) be purified in the conventional manner since airp-aminobenzenesulfonamide and (6) p-(0-amino- drying or vacuum-drying gave decomposition. phenyl)-benzenesulfonamide. These were chosen This instability is now c o n h e d . A purified in order that the resulting derivatives be isomeric sample of the above, recrystallized several times with some of the compounds prepared by Van from benzene, was found to undergo decomposition when stored in a closed glass container for Meter and L ~ w y . ~ Bactericidal tests4 on 9-(0-aminopheny1)-ben- one month. This was evidenced by the liberation zenesulfonamide and the derivatives reported here of acid vapors and a decrease of five degrees in indicate that these compounds are inactive in the melting point. vitro against concentrations of E. Coli and in vivo The following new compounds were prepared against streptococcal infected mice. A similar in this work: inactivity was reported for p-(p-aminopheny1)I p-(o - acetamidophenyl) - benzenesulfon - N-phenylbenzenesulfonamide,6 indicating that the shift in amide (1) Paper I , THISJOURNAL, 65, 2043 (1943). (2) Presented before the Divirion of Organic Chemistry, Detroit meeting of the American Chemical Society, April, 1943. (3) Van Meter and Lowg, THISJOURNAL, 89, 1330 (1941). (4) By Dr. W. FIarry Feinrtone, Stamford Laboratory, American Cyanamid Company. ( 6 ) Kumler and Halvuatadt. THIB JOWBNAL, 63, 2183 (1941).
I1 p-(o-nitropheny1)-benzenesulfon-N-phenylamide 111 p-(o-aminopheny1)-benzenesulfon-N-phenylamide I V p - (o-acetamidophenyl) -benzenesulfon- N - benzylamide (6) Van Meter,Bknculli and L o a r , ibid., 68, 8146 (1940).
Nov., 1943
DERIVATIVES OF p - (0-AMINOPHENYL)-BENZENESULFONAMIDE
2047
V p-( o-nitropheny1)-benzenesulfon-N-benzylamide warmed t o 50' and then permitted to stand a t room temVI p-(o-arninopheny1)-benzenesulfon-N-benzylamide perature for twelve hours. The resulting solution was concentrated t o one-half the VI1 p-( o-acefamidophenyl)- benzenesulfon N - o - xenylvolume. Addition of 350 cc. of water produced an oil amide VI11 fi-(o-nitropheny1)-benzeuesulfon-N-a-xenylamide which solidified on standing for twenty-four hours The I X p-( o-aminopheny1)-benzenesulfon-N-o-xenylarnide weight of this material was recorded as the yield in Table I. X p - ( o - acetamidophenyl) -benzenesulfon-N-p-xenyl- This was justified by the close agreement of the melting point for the crude product with the melting point of the amide X I p-(o-nitropheny1)-benzenesulfon-N-p-xenylamide purified final product. Each compound was purified by XI1 p-(o-aminopheny1)-benzenesulfon-N-pxenylamide treatment with Norite and several crystallizations from XI11 K 4 [ p-( o-acetamidophenyl) -benzenesulfonyl]-sulf- dilute methanol. I n this manner, compounds I, IV, VII,X, XI11 and XVI anilamide XIV E'-[ p- (0- nitrophenyl) - benzenesulfonyl] - sulfanil- were prepared and purified. Condensation of p-( o-Nitropheny1)-benzenesulfonyl amide XV IT4-[P-(o-aniinophenyl) benzenesulfonyl] - sulfanil- Chloride with Aromatic Amino Compounds.-#-( o-Nitrophenyl)-benzenesulfonyl chloride' was condensed with the amide XVI 2 - ( p - ( o - acetamidophenyl) - benzenesulfonamidol- aromatic amino compounds used above and by essentially the same procedure. A solution was made of 4.80 g., 0.0161 biphenyl-4'-sulfonamide XVII 2-~p-(a-nitrophenyl)-benzenesulfonamido]-biphenyl-mole, of P-(o-nitropheny1)-benzenesulfonylchloride, m . p. 75-77', in 65 cc. of dry acetone. To this was added 5 CC. 4'-sulfonamide XVIII 2 - [ p - ( 0 - arninophenyl) benzenesulfonarnido] - bi- of pyridine and a solution of 0.0163 mole of the amino compound in acetone. The addition produced no appreciphenyl-1'-sulfonamide able rise in the temperature of the reaction mixture. This 'The formulas, melting points, yields, and analyses was then warmed to 60' and allowed t o stand at room of these compounds are given in Table I. temperature for sixteen hours.
-
-
-
TABLE I Yield,
%
Yield by rcduction, %
Yield by deacetylation,
%
89 95 98
94
99
92
98
98
97
98
59 68 86 85 92 90
78 92 81
87
97
!Jfi
02 XR
--.
Analyses, % Nitrogen Calcd. Found
7.65 7.62 7.69 7.91 8.20 8.16 8.64 8.58 8.69 7.36 7.16 7.28 7.61 7.86 7.62 8 . 2 8 8.73 8.32 6.33 6.19 6 . 2 1 6 . 5 1 6.50 6.51 7.00 7.04 7.14 6.33 6 . (i5 6 48 6 . 5 1 6.43 6.46 7.00 7.08 7.11 9.43 9.63 9.44 9 70 9 . 9 2 9 91 10.42 10.50 10.i o 8.06 7.92 7.94 8."5 8.32 Y , 30 8 si; 8 BO 8 82
Calcd.
Sulfur
Found
8.75 8.46 9.05 8.85 9.88 9.49 8.43 8.25 8.70 8.65 9.47 9.20 7 . 2 5 6.97 7.45 7.30 8.01 7.73 7.25 6.92 7.45 7.38 8.01 7 8 4 14.39 1-1 12 1-4.80 11.97 15.89 15 70 12.29 12 13 12.58 12 73 1:3 37
13 i l l
8.54 8.96 9.59 8.44 8.54 9.31 7.13 7.38 7.92 7.00 7.45 7.8Cl 14.36
15. O f i 15.89 12.42 12,ifi 13 911
To the resultiiig solutiuii was adtled 4 X J cc. uf water, aud the oil which separated was aliuucd L O starid until solidifiCondensation of p-io-AcetamidophenylJ-benzenesulcation rLsultcb(!. T h e solid KWS separated and washed with fonyl Chloride with Aromatic Amino Compounds.-+( o - water iintil t h e odor of pyridine was gone. 'The resulting .I( c?aiiiidopl:eiiyl -t,ciizc.rie,!ilfl!riyl chloride' wai c(ii1- weight wa.s recorrletl a\ tlic yield in Table I. Agaiti, this rleiijed lritli t i l t 5ix. aii~iiiocoi,,pr,ii!irls lictcd above, d r j was ju4fittl 1,y tl;v c l w . a.grkenieiLt of the nicking point acetone being ucctl a - ~olvetitarid pyridine a> col!denii!:K of the r r u i i r prcidurt ~ ~ i t tila! li of 11ie purifietl product. agcnt. The followiiig i i a general deicription o f t h e r e x Purificatioti t o a cor.-tatit !ri~ltiiigImint w a i olit'iiiird by tioris, A solution i v a j iriadc. rif 5 11') g . , ' I rJlGl rnolc, of p treatriicnt xith Sorilv a i d r-crryztallizalioii from dilutr (o-acetaniidophenyli-l,cnzcii~-itilfoiiylcliloridi, i l l . p . 1-13 mr tliaii~il. l t 3 " , in 80 cc. of d r y acitoiic. T o t l i i i was atltltrrl qj c c , oi Co~iipourids11. 17, V l l i , X i , SI\ di:rl X \ 11 wcrs Drepyridiiie followcd b y a wlurion (Jf O,lJlC:3InCJk of tlic axiiltv? rwrcd I I ! ~ l i t LL\J')YC p r - i m d i i r ~ . compound in 20-70 cc. of acetoric. The addition produce(! Preparation of p-lo-Aminophenyli-benzenesulfon-Nno appreciable rise in tempcratrirr The mixture wai arylamides. Method I. 'l'hc :rwtarnirln rnmpntln!ii
