SULFANILAMIDES FROM p-AZOBENZENESULFONYL CHLORIDE1

IRWIN A. PEARL. J. Org. Chem. , 1945, .... from ACS Catalysis. This year the Dalian Institute of Chemical Physics (DICP), Chinese Academy of Sciences ...
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SULFANILAMIDES FROM p-AZOBENZENESULFONYL CHLORIDE' IRWIN A. PEBRL

Received January 99, 1945

Most of the N'-substituted sulfanilamide derivatives in common use today are prepared by the reaction of p-acetaminobenzenesulfonyl chloride with the desired amino compound to obtain the N4-acetylated derivative, CHaCONHCsHB02NHR (where R can be H or any radical such as pyridine, thiazole, diazine, guanidine, etc.) and subsequent hydrolysis of this compound by strong acid or base to the desired H2NCsHd302NHR. This method is convenient and relatively inexpensive. However, a number of important N1-derivatives are sensitive to and are hydrolyzed by strong acids or bases and, therefore, must be prepared in another manner. At the present time, these compounds are obtained by treating the desired amino compound with p-nitrobenzenesulfonyl chloride and reducing the resulting nitro compound by the neutral iron process or by catalytic hydrogenation. This mtkhod is convenient but, unfortunately, p-nitrobenzenesulfonyl chloride can be prepared only by indirect and costly processes. Therefore, an alternate method is desirable. The preparation of azobenzene (I) and sodium p-azobenzenesulfonate (11) by the reduction of nitrobenzene with sulfite waste liquor has recently been reported (1, 2). Because azobenzenesuli'onyl derivatives yield the same reduction products as the corresponding nitro compounds,because (11)already contains the azo group in the para position, and because (I)sulfonates and chlorosulfonates in the para position (3-6), the use of these reduction products of nitrobenzene for the preparation of sulfanilamide derivatives appeared promising according to the following scheme:

I11

-1

0 OSO~NH -N=N--

IV

-1

+ N.H?C>SO~NHR V 1 This paper represents a portion of the results obtained in the research program sponsored by the Sulphite Pulp Manufacturers' Committee on Waste Disposal and conducted for t h e Committee by The Institute of Paper Chemistry. rlcknowledgment is made by t h e Institute for permission on the part of the Committee to publish these results. 205

206

IRWIN A. PEARL

This paper recites a number of experiments on the preparation of p-ambenzenesulfonyl chloride (111) and p-azobenzenesulfonamides (IV), and the reduction of (IV) to sulfanilamides (V) and hydrazobenzenesulfonamides (VI).

C>-KH-NH-

~ S O ~ N H R

VI Skandarow (7) treated potassium p-azobenzenesulfonate [prepared according to Griess (3)] with phosphorus pentachloride and obtained a chloride (111) melting a t 82". More recently Chrzaszczewska and Dobrowolski (8) repeated the experiment and obtained (111) as orange needles melting at 124.5-125". The latter authors assumed that they had obtained a stereoisomer of Skandarow's product. Chlorination with phosphorus pentachloride of (11) from sulfite waste liquor reductions of nitrobenzene yielded orange crystals melting a t 124-125", which were identical with those obtained by Chrzaszczewska and Dobrowolski. No trace of Skandarow's product was obtained (2). Because the use of phosphorus compounds is restricted by the war effort, the use of other chlorinating agents for transforming (11) t o (111) was attempted. Thionyl chloride wm found to be without effect but chlorosulfonic acid produced the desired (111) melting a t 124-125'. Several investigators (4,5, 6) have reported the preparation of (111) from (I) by reaction with chlorosulfonic acid at temperatures below 100". However, in all cases the (111) was not isolated, but was converted directly to p-azobenzenesulfonamide (VII). Treatment of (I) with chlorosulfonic acid a t 125" gave a 90% yield of (111), isolated in pure condition as nearly odorless, bright orange crystals which can be kept without decomposition. This stability is an advantage of (111) over p-acetaminobenzenesulfonyl chloride, which decomposes when warmed in the presence of moisture (9) and is too unstable for storage over a long period of time. The chloride (111) was quantitatively transformed to the amide (VII) by shaking with aqueous ammonium hydroxide (2). Treatment of (€11) with 2-aminopyridine in pyridine or in acetone-pyridine yielded 2-(p-azobenzenesu1fonamido)pyridine (VIIJ). Tin and acid reduction of (VII) and (VIII) gave sulfanilamide (IX) and "sulfapyridine" (2-sulfanilamidopyridine) (X), respectively. Reduction of (VII) with sodium hydrosulfite in alkaline solution yielded a mixture of (IX) and p-hydrazobenzenesulfonamide (XI) and the corresponding reduction of (VIII) yielded a mixture of (X) and 2-(p-hydrazobenzenesu1fonamido)pyridine (XII). The formation of (XI) and (XII) in these reactions is analogous to the hydrosulfite reduction of (11) to sodium,p-hydrazobenzenesulfonate (2) and of p ,p'-azobisbenzenesulfonamide to p ,p'-hydrazobisbenzenesulfonamide (10). The fact that hydrosulfite reduction of (VII) and (VIII) yielded mixtures of amino rind hydrazo compounds indicates that this type of reduction is not specific, as might be inferred from 6he cited literature. The reductions of (VII) a.nd (VIII) to (IX) and (X), respectively, were per-

AMIDES FROM AZOBENZENESULFONYL CHLORIDE

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formed with tin and acid, because it w8,s known in advance that this agent would reduce the azo linkage to two amino groups and that (IX) and (X) were stable toward these drastic conditions. However, if this process is to be useful for producing derivatives which are sensitive to severe conditions, a milder reducing agent must be found. The first method tried was the neutral iron reduction employed by Roblin and Winnek (11) for the successful reduction of acid- and base-sensitive p-nitrobenzenesulfonamide derivatives. Under these conditions (VIIT) was reduced in good yield to (XII). No trace of (X) could be found. Catalytic hydrogenation of (VIII) a t atmospheric pressure in the presence of Raney nickel resulted in (XII), but under slight pressure the desired (X) was the only product. The ease of this latter reduction made a search for other mild reducing agents unnecessary. Very recently Huang-Minlon, Chien-Pen Lo, and Chu (12) prepared a number of p ,p'-azobisbenzenesulfonamides by oxidizing potassium sulfanilate, chlorinating the resulting azobisbenzenesulfonicacid, and treating the azobisbenzenesulfonyl chloride with amines. These authors suggested that these azo compounds could be reduced to sulfanilamides, but reported no experimental data. This reduction was accomplished by Seikel (10) and also in this study. EXPERIMENTAL

All melting points given are uncorrected. Preparation of p-azobenzenesulfonyl chloride (IZI). (a) Chlorination of sodium p-azobenzenesulfonate (11)with phosphorus pentachloride. Dry (11) (40 g.) was thoroughly mixed with 40 g. of phosphorus pentachloride in a 5(H)-ml. flask. The flask was immersed in warm water to initiate the reaction. When the original vigorous reaction had subsided, the mixture was heated for one hour at 110". After cooling somewhat, the viscous liquid was poured slowly onto cracked ice with vigorous stirring. The bright orange precipitate which separated was filtered and dried in a vacuum desiccator. The crude (111) melting a t 118120°J was obtained in 85-90% yield. Recrystallization from ether gave orange crystals melting at 124-125' and not lowering a mixed m.p. with authentic (111) (8). High-boiling pe1,roleum ether (65-110") was found t o be an ideal solvent for recrystallizing (111). (b) Chlorination of (11)with chlorosulfonic acid. Ten cubic centimeters of chlorosulfonic acid was gradually treated under constant stirring with 7.5 g. of powdered dry (11). The temperature of the reaction mixture was maintained below 60" during the addition by a n ice-bath. After all the (11) had been added, the temperature of the bath was gradually increased to boiling, and the boiling temperatyre was maintained for 15 minutes. The dark liquid was cooled and stirred into a mixture of cracked ice and water. The yield of crude ( I I I ) , melting a t 116-120", was 95%. Recrystallization from petroleum ether yielded orange crystals melting at 124-125'. (c) Chlorosulfonation of azobenzene ( I ) with chlorosulfonic acid. A mixture of 45.5 g. of (I) and 145 g. of chlorosulfonic acid was gradually warmed with stirring t o 125" and maintained at t h a t temperature for one hour. The mixture was carefully stirred into cracked ice and water, and the orange precipitate which separated was filtered, washed with cold water, and dried. Recrystallization from petroleum ether yielded 55.5 g. or approximately 90% of pure (111), m.p. 124-125'. Prepmution of p-azobenzenesulfonamide ( V I I ). (VII) was prepared as described earlier (2) by shaking (111) with a n excess of ammonium hydroxide and filtering the yellow crystalline precipitate. The yield of crude (VII) melting at 218-220" mas quantitative. Crystallization from ethanol yielded orange-yellow crystals melting a t 220-221"; a mixed m.p. with authentic (VII) (8) showed no depression.

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IRWIN A. PEARL

Preparatzon of 2-(p-azobenzenesulfona,nido)py,.Ldine ( V I Z I ) . (a) I n p y z d i n e solutzon. 2-dminopyridine (22.6 g. or 0.24 mole) was dissolved in 125 cc. of pyridine in a 503-cc. 2-neck flask. With constant stirring, 63.5 g. (0.26 mole) of (111) n a s added in sinal1 portions. The flask was cooled with ice-water, and the temperature of the reaction mixture was not alloued t o rise above 60". Most of the (111)did not dissolve. The temperature was raised to 100" and the mixture was heai,ed on the steam-bath for 2 hours. Most of the pyridine n as removed by distillation under reduced pressure. The viscous residue was triturated with 300 cc. of 1:2 hydrochloric x i d and poured with stirring onto 1 kilogram of cracked ice and nater. The light orange precipitate which separated was filtered, washed with water, and dried in a vacuum desiccator. The crude material weighed 62g. (76%) and melted a t 234-236'. After mashing with boiling ethanol and recrystallization from methyl cellosolve, i t melted a t 239-240". A n a l . Calc'd for CI7H14N4O2S: S ,16.58; S, 9.47. Found: S , 16.53,16.61; S, 9.57. (b) I n acetone-pyridine solutitsn. This is essentially the method reported by Popkin and Perretta (13) for the preparakion of acetylsulfanilamides. To a solution of 14 g. (0.05 mole) of (111)dissolved in 200 cc. of dry acetone were added, successively, 15 cc. of pyridine and 4.7 g. (0.05 mole) of 2-aminopyridine dissolved in 50 cc. of dry acetone. The flask was stoppered with a calcium chloride tube, and the clear solution was warmed t o 50" and then allowed t o stand a t room temperature. After several hours bright orange crystals separated. These were filtered and dried. The yield was 6.3 g. of pure (VIII) melting a t 239-240". The mixed 1n.p. with authentic (VIII) showed no depression. The acetone was concentrated to one-third its volume and diluted with 800 cc. of a a t e r . The light orange precipitate was filtered, washed with water, and recrystallized from methyl cellosolve. An additional yield of 5.2 g. melting a t 237-238" was obtained. The total yield corresponds t o 6870 of (VIII). The yield was slightly less than t h a t obtained using larger amounts of pyridine, but the method was much simpler and the materials were more easily handled I n addition, the product was obtained initially in a much purer form. Reduction of (VIZ) wzth t i n and acid. Preparation of sulfanilamide ( I X ) . (VII) ( 2 g.) was suspended in dilute hydrochloric acid and 5 g. of tin foil (in small pieces) was gradually added. The mixture was heateli to boiling until it became colorless. After cooling, the mixture was made alkaline and e>tractedwith ether. The ether, upon drying and distilling, yielded aniline which was identified as its benzoyl derivative (m p. 160-161"). The aqueous mixture (containing insoluble inorganic material) was centrifuged, and the clear centrifugate \vas exactly neutralized wi .h dilute hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried; m.p. 164-165". Recrystallized from ethanol, it formed microscopic white needles, n1.p. 164-165"; mixed m.p. with authentic (IX), 164-165". Reduction of ( V I I I ) wzth t i n and acid. Preparataon of L ' ~ ~ l f a p y r i d a n e( "X ) . Reduction of (VIII) in the same manner with tin and hydrochloric acid yielded aniline and (XI. The crude (X) was recrystallized from ethanol, giving white crystals, m.p. 190-191", mixed m.p. with authentic (X) 19C!-19I0. Reduction of ( V I I ) with sodium hydrosulfite. A suspension of 5 g. of (VII) in 200 cc. of boiling 5% sodium hydroxide solution was gradually treated with powdered sodium hydrosulfite until the orange color disappeared. The colorless solution was cooled, filtered, and evactly neutralized with dilute hydrochloric acid, causing the separation of a white crystalline precipitate. The crude washed and dried precipitate (4.5 9.) melted a t 168-170'. I t was dissolved in an excess of hot ethanol, boiled with decolorizing carbon, and filtered hot. Cooling gave a light yellow crystalline precipitate which, upon recrystallization from ethanol, melted a t 178-179". The yield was 1.8 g. (3570). A n a l . Calc'd for p-hydrazobenzenesulfonamide (XI), C12H1802NSS: N, 15.07; S, 12.1G. Found: N, 16.07, 15.80; S, 12 14. The alcoholic filtrate was diluted with water, which caused a white crystalline precipit a t e t o separate. This was filtsred, washed with dilute ethanol, and recrystallized from

SMIDES FROM AZOBENZENESULFONYL CHLORIDE

209

ethanol; m.p. 164-165"; yield, 1.75 g. (54%:1. The melting point of a mixture with pure ( I S ) vas not depressed. In nnot,her experiment (IX) and ( X I ) were separated by initially strongly acidifying the fi1t)eredalkaline reaction mixture with hydrochloric acid. The yields were substantially the sttmc: as those obtained in the above reduction. In these reductions no aniline was recovered, but the odor of aniline TTas very apparent, during the boiling process. It, was probably lost by steam distillation. Rediiction o j (VIIT) w i t h sodium hydroszcljte. Five grams of (VIII) was reduced with sodium hydrosulfite in boiling alkaline solution in the same manner. The colorless solution n-:is exactly neutralized with dilute hydrochloric acid. The copious precipitate was filtered, washed with water, treated with dilute hydrochloric acid, and filtered. The residue w:ts dissolved in dilute sodium hydroxide, boiled with decolorizing carbon, filtered hot, and acidified with dilute hydrochloric acid. The pale tan crystals were filtered and recrystallized twice from ethanol, giving colorless crystals, m.p. 204-205"; yield, 3.4 g. (67%)). A n a l . Calc'd for 2-(p-hydrazobenzenesulfonamido)pyridine (SII), C I ~ I I I ~ S * O S S : N , 16.47; S, 9.42. Found: IY,16.45,16.43; S, 9.45. The acid solution mas exactly neutralized x i t h dilute sodium hydroxide. The white precipitate was filtered, ITashed with water, and recrystallized from ethanol; m.p. 190-191", mixed m.p. with authentic (X) 190-191'; yicld; 0.9 g. (257,). N e v f r a l iron reduction of ( V I I I ) . (VIII: (16.9 g.) was added, with vigorous stirring, t o a suspension of 50 g. of iron powder in a hot solution of 1.5 cc. of 6 N hydrochloric acid in 150 cc. of 95% ethanol, and the resulting mixture was heated on the steam-bath under reflux with occasional shaking for 7 hours. After cooling, the reaction mixture was just neutralized with sodium hydroxide, boiled for several minutes, filtered hot, and the alcoholic filtrate was diluted with 10 volumes of water. A white crystalline precipitate, melting a t 204-206", separated. The yield was 13.7 g. (80yo). Recrystallization from ethanol yielded white crystals, n1.p. 204-205". Mixed n1.p. with authentic ( X I ) 204-205". .Anal. Calc'd for C:i7Hi6N40&3:N , 16.47; El, 9.42. Found: S , 16.41,16.44; S, 9.54. No irace of (X) could be found in this exp'eriment. Catalgtic hydrogenation of ( V I I I )at atmospheric pressure. I n a 500-ml. 3-neck flask fitt,ed with a reflux condenser, a mechanical stirrer, and a gas inlet tube were placed 10 g. of (VIII)?200 cc. of ethanol, and 10 g. of Rane), nickel catalyst. The mixture was heated to boiling with stirring and hydrogen was introduced for 20 minutes. The colorless mixture n-as filtered hot and allowed to cool. White crystals separated from the clear filtrate, but water was added to ensure comp1et.e precipitation of the product. The yield of ( X I I ) melt,ing a t 204-205" was9.2 g. (91yo). A mixed m.p. with authentic (XII) was not depressed. Catalptic hydrogenation of ( V I I I ) under pressure. Ten grams of Raney nickel cat,alyst suspended in alcohol was added to a solution of 10 g. of (VIII) in 60 ml. of warm (65") A' sodiuni hydroxide. The resulting mixture wts shaken under a pressure of 50 lbs. of hydrogen for 30 minutes a,t 60-70". The catalyst mas filtered and the colorless filtrate was exactly neutralized with 6 S hydrochloric acid. A yield of 6.7 g . (91%) of (X) melt,ing at 190-191" was obtained. -4 mixcd m.p. with authentic ( X ) was not depressed. SUMMARY

Sulfanilamide and sulfapyridine have been prepared by reaction of p-azobenzenesulfonyl chloride with ammonia and 2-aminopyridine, respectively, and reduction of the resulting compounds. Tin and acid and catalytic hydrogenation have accomplished this reduction. Alkaline hydrosulfite and neutral iron reduction of the azo compounds gave the hydrazo derivatives.

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IRWIN A. PEARL

p-Azobenzenesulfonyl chloride has been prepared by chlorinating sodium p-azobenzenesulfonate with chlorosulfonic acid. This procedure for the production of "-substituted sulfanilamides should be applicable to acid- and base-sensitive derivatives. After this study was completed it was found fortuitously that "Sulfamethylhad been prepared thiazole" [2-(p-aminobenzene~ulfonamido)-4-methylthiazole] by treating p-azobenzenesulfonyl chloride with 2-amino-4-methylthiazole and reducing the 2-(p-azobenzenesulfonamido)-4-methylthiazolethus formed with hydrogen and Raney nickel. This disclosure was hidden in a British Patent (14) as one of 23 examples. Unfortunately, this disclosure has never been abstracted or indexed. APPLETON,WIS RE:FEREK;C'ES (1) PEARLAND LEWIS,Znd. Eng. Chem., 36, 664 (1944). ( 2 ) PEARL,J. Org. Chem., 9, 424 (1944). (3) GRIESS,Ann., 131, 89 (1864). Biochem. J . , 31, 724 (1937). (4) GRAY,BUTTLE,AND STEPHAUSON, (5) STERN8 9 ~ tar-^, J . Am. P h " l . Assoc., 28, 1032 (1939). (6) TRAYAGLI, Ann. chim. jarin., 1940, 148. (7) SKANDAROW, 2. Chem., 1870, 643. (8) CHRZASZCZEWSKA AND DOBROWOLSKI, Roczniki Chem., 17, 411 (1937). (9) S m m s AND STEWART, Org. Syntheses, Coll. Vol. I (2nd Ed.), p. 9. (10) S E I K E LJ. , A m . Chem. SOC.,62, 1214 (1940). (11) I ~ O B L IAND N WINNEK,J.Am. Chem. SOC., 62,1999 (1940). (12) HUANG-MINLON, CHIEN-PEN Lo, AND CHU,J. Chinese Chem. Soc., 9, 57 (1942); Chem, Abstr., 38, 1216 (1944). (13) POPKIKAND PERRETTA, J . A m . Chem. SOC., 66, 2047 (1943). (14) MAYA N D BAKER,NEWBERG, AND VIAUD,British patent 517,272 (Jan. 25,1940).