MAY
1961
1443
ADDITION O F T H I O U R E A T O A C R Y L O N I T R I L E
hydroxide, as described in the case of VIIa, resulted in the formation of 0.31 g. of colorless crystals of 1,5-diphenyl-4cnrboxy-IH-1,2,4-triazole(VIa).2 Extraction of the reaction mixture with aqueous sodium carbonate, followed by extraction with ether and evaporation of the latter gave pthiocresol, identified as p-tolylthiobenzoate. Preparation of 4-aryl~o-Z-phenylozazoline-5-ones (Vb-d): 4-Arylazo-2-phenyloxazoline-5-ones(Vb-d) were obtained according to Sawdeyz as follows: To a solution of 0.2 mole of the appropriate aromatic amine in 200 mi. of glacial acetic acid was added 40 ml. of concd. hydrochloric acid, then, dropwise, 0.23 mole of isoamyl nitrite a t room tempera-
[CONTRIBUTION FROM
THE
ture. To the diazonium mixture 30 g. of anhydrous sodium acetate was added. Hippuric acid, 0.25 mole, was heated in 200 ml. of acetic anhydride until a clear solution was obtained. This solution was cooled to room temperature, added slowly with agitation to the diazonium mixture. The mixture was then cooled and the precipitate was collected. The reaction products, listed in Table I are readily crystallized from acetone. GIZA,EGYPT U.A.R.
DEPARTMENT O F CHEMISTRY, COLLEGE O F PHARMACY, UNIVERSITY OF ILLINOIS]
Addition of Thiourea to Acrylonitrile and Acrylamides’ LUDWIG BAUER
AND
THOMAS L. WELSH
Received August 8, 1960 The addition of salts of thiourea to acrylonitrile and acrylamides is reported. This reaction presents an expeditious route to the synthesis of S-(fl-cyanoethyl)- and S-(8-carboxamidoethyl)isothiuroniumsalts in excellent yields. Hydrolysis of these salts with ice-cold sodium hydrGxide solution afforded 8-mercaptopropionitrile and 8-mercaptopropionamides.
The recent report2 on the reaction of thiourea to derivatives of maleic acids, prompts us to report the facile acid-catalyzed addition of thiourea to acrylonitrile and acrylamides. An attempt3 to add thiourea to acrylonitrile under base-catalyzed conditions a t 100’ failed, but it is claimed4 in the patent literature that this addition does occur. However the compound so formed is not characterized. Base-catalyzed additions of several substituted thioureas to acrylonitrile have been reported t o yield N-(P-cyanoethyl) derivatives. Thus, N-phenylthiourea5 and N,N’-o-phenylenethiourea thioureaa yield N-phenyl-N-(P-cyanoethyl) and N,N’ -di(@-cyanoethy1)-N,N’ - (0-phenylene)thiourea respectively. We have found that salts of thiourea viz., the hydrochloride, hydrobromide, or p-toluencsulfonate, readily add to acrylonitrile to afford S-(P-cyanoethy1)isothiuronium salts (I X = C1, Rr, or p-CH3CeH,S03). These salts are formed in excellent yield. It is postulated that the mechanism for this reaction is similar to that advanced for the acid-catalyzed addition of thiourea to 2and 4-vinylpyridine.’ Protonation of the nitrile (1) The authors hereby acknowledge the generous support for this study by a grant from the Surgeon-General, U. S. Army, Contract DA-49-193-MD-2047. ( 2 ) A. N. Arakelian, H. Dunn, Jr., L. L. Grieshammer, and L. E. Coleman, J . Org. Chem., 25, 485 (1960). (3) C. D. Hurd and L. L. Gershbein. J . Am. Chem. Soc.. 69; 2329 (1947). (4) H. A. Bruson. Oro. Reacticms. 5. 96 (1949): and C h e m istjy’of Acrylonitrile (Second Editibnj published by American Cyanamid Company, 1959, p. 239, quotes M. W. Harman, U. S. Patent 2,413,917 (1947) [Chem. Abstr., 41, 2446 (1947)l. (5) 0. Bayer, Angew. Chem., 61, 236 (1949). (6) A. M. Efros, J . Gen. Chem., ( U S S R ) , Eng. Transl., 28,599 (1958).
nitrogen atom facilitates nucleophilic attack by thiourea at the electrophilic carbon atom a t the end of the conjugated system and this reaction path is shown by the following equation:
Tautomeric shift of nitrogen atom t o p oton from imine a-carbon atom nitrogen atom to a-carbon atom
* NHz@Xe
II
HIN--C-S-CH&H~CN
I
The structure of S-(P-cyanoethy1)isothiuronium chloride (I X = C1) was proved by comparing a sample of it with one obtained from the conventional reaction of f3-chloropropionitrile with thiourea? Also, hydrolysis of I with hot concentrated hydrochloric acid yielded S-(P-carboxyethy1)isothiuronium chloride which was identical with a specimen prepared by the addition of thiourea hydrochloride to acrylic acid.9 We have extended this reaction to the addition of salts of thiourea to acrylamides and obtained 8-(p-carboxamidoethy1)isothiuroniumsalts, 11,(R = H; X = C1, Br, or p-CH3C6H4SO3)as expressed by the equation below. Best yields of these salts (11) were procured when the reaction was carried ( 7 ) L. Bauer and L. A. Gardella, Jr., J . Org. Chem., 26, 82 (1961). (8) This salt waa mentioned by R. Shapira, D. G. Doherty, and W. T. Burnett, Jr., Radiation Research, 7, 25 (1957) and by private communication from Dr. Doherty. (9) H. Behringer and P. Zillikens, Ann., 574, 140 (1951).
1444
BAUER AND WELSH
R
I
CIIFC-CONHI~'
-A S=C(NFIzh
VOL.
26
R
I
Cll~-CII--CON€I~t'
€IX
L N H P XQ
I
NHz (11)
out in ethanol at moderate temperature. Thiourea (as the hydrochloride or p-toluenesulfonate) also added to methacrylnmide to form the homologs of I1 (R = CH,; R' = H). Hydrolysis with concentrated hydrochloric acid of the addendum of thiourea hydrochloride and acrylamide also afforded S-(B-carboxycthy1)isothiuroniumc h l ~ r i d e . ~ Cleavage of the isothiuronium salts, I and 11, with ice-cold sodium hydroxide solution yielded the corresponding mercaptans. Thus, S-(p-cyanoethyl) isothiuronium chloride (I X = C1) was hydrolyzed to @-mercaptopropionitrile at 0' in 36y0 yield, which makes this compound readily available. An attempt to prepare this mercaptonitrile by the addition of hydrogen sulfide to acrylonitrile catalyzed by trimethylbenzylammonium hydroxide yielded only @-cyanoethyl sulfide,lo S(CHzCH2CN)?, while catalysis by diethylamine gave only (3 - (thiocarbamy1)ethyl sulfide, S(CH2CH2CSN:Hz)z.l1But in a patent it is claimedI2 that pmercaptopropionitrile is synthesized by the addition of hydrogen sulfide to acrylonitrile at temperatures less than 75' (at 220 pounds per square inch). There are two additional references to the synthesis of P-mercaptopropionitrile from the alkaline CH3hydrolysis of S-(p-cyanoethyl) thi~lacetate,'~ COSCHZCHZCN. Similarly, ice-cold sodium hydroxide hydrolyzed several of the isothiouronium amide salts (11) to the corresponding mercapto amides. For example, S- [p - ( N - phenylcarboxamido)ethyl]isothiuronium p-toluenesulfonate (I1R = H, R' = CsHs; X = p CHsCsH4SO3)was converted to B-mercaptopropionanilide which had previously been synthesized14 by treating 2-mercapt0-5,6-dihydrollH-1,3-thiazin4-Olle with aniline to afford 8-dithiocarbamoylpropionanilide, HZN - CS -S - GH~CH~CONHC~HS, which mas hydrolyzed by aqueous sodium hydroxide to the mercaptan. EXPERIMENTAL'
General procedures for the addition of thiourea salts to acrylamides are described below. The physical constants,
mxx
(10) L.L.Gershbein and C. D. Hurd. J. Am. Chem. Soc ., 69,241(1947) ( 1 1) R. Ilahlbom, Acta. chem. scand., 5, 693 (1951). (12) J. D. Wordie, U. S. Patent, 2,748,155 (1956), [Chem.Abstr., 51, 1245(1957)]. (13)W. W. Crouch and R. T. Werkman, U. S. Patent, 2,630,452(1953)and U.S. Patent 2,630,448(1953) [ c h . Abslr., 48, 1426 and 1431 (1954)respectively]. (14) J. E. Jansen, U. S. Patent, 2,709,706(1955) [Chem. Abstr., 50,5746 (1956)l.
MAY
lOGl
ADDITION OF THIOUREA TO ACRYLONITRILE
yields, and analytical figures for S-(pcarboxamidoethy1)isothiuronium salts, 11, are compiled in Table I. A. Hydrochlorides (11. X = Cl). Thiourea (30.4 g.; 0.4 mole) was dissolved in hot concd. hydrochloric acid (50 ml.). The resultant solution was evaporated in vacuo. The residue of thiourea hydrochloride (m.p. 130"; lit.1s m.p. 136-137') was dissolved in ethanol (130 ml.) a t the reflux. The solution was then cooled to 0' and with stirring, a solution (or slurry) of the amide" (0.4 mole) in ethanol (50 ml.) was added and the resultant mixture was stirred one additional hour. In several instances more ethanol had to be added to the reaction mixture to allow the mixture to be stirred. The colorless salts so formed were filtered, washed with icecold ethanol (40 ml.) and dried. The salts were recrystallized either from ethanol or acetone-water (8:1). B. Hydrobromides (11. X = Br). Thiourea (30.4 g.; 0.4 mole) was dissolved in boiling ethanol (240 ml.). The source of heat was removed and the amide (0.4 mole) added. Hydrogen bromide gas was then passed through the warm solution for 0.3 hr. Then the flask was immersed in an ice bath and hydrogen bromide gas passed through the solution for an additional 0.5 hr. The colorless salts which precipitated wer'e filtered, washed with ice-cold ethanol (40 ml.) and recrystallized from ethanol. C. p-Toluenesulfonates (11. X = p-CH3C6H2303). An equimolar solution of thiourea and p-toluenesulfonic acid monohydrate were dissolved in hot ethanol (700 ml.). The solution was cooled to 0' and while being stirred a solution or slurry of the amide in ethanol (1 mole in 400 ml.) was added. After this addition, the mixture was stirred for 1 to 2 hr. The salts were filtered and washed with several portions of ice-cold ethanol. The products were crystallized conveniently from either ethanol or acetone-water (8: 1). S-(j3-Cyanoethy1)isothizlronium salts (I). (a) Chloride. A solution of thiourea hydrochloride in ethanol was prepared as described in procedure A . Acrylonitrile (40 ml.) waLi added and the mixture refluxed for 2 hr. The solvents were stripped off and the residue recrystallized from ethanol. The salt (20.4 g.; 61%) melted a t 163-165'. Anal. Calcd. for C4H&1N8 (165.7): c, 39.00; H, 4.87; N, 25.36; S, 19.35. Found: C, 29.21; H, 4.70; N, 25.19; S, 18.88. This salt was also prepared by treating b-chloropropionitrile (13.0 g.; 0.2 mole) with thiourea (15.2 g.; 0.2 mole) in boiling ethanol (75 ml.) for 20 hr. The mixture was worked up as above and the product (17.5 g.; 62%) recrystallized from acetone-water (8: l), m.p. 155-158". One further recrystallization raised the n1.p. to 163-165". The infrared spectra of this salt was identical with the one of the salt from acrylonitrile. (b) Bromide. This salt was prepared as outlined in procedure B except that hydrogen bromide gas was passed through a hot solution of acrylonitrile (21.2 g . ; 0.4 mole) and thiourea (0.4 mole) in ethanol (240 ml.). The colorless salt weighed 63.6 g. (76%), m.p. 173'. Recrystallization from ethanol raised the m.p. to 176'.
(15) All melting points are uncorrected. Analyses were performed by Dr. Kurt Eder, Geneva, Switzerland, and by Micro-Tech Laboratories, 8000 Lincoln, Skokie, Ill. (16) A. E. Dixon, J. Chem. SOC.,111, 684 (1917). (17) We would like to thank the American Cyanamid Company for their generous supply of acrylamide, N-lbutylacrylamide, and N,N'-methylenebisacrylamide.
1445
Anal. Calcd. for C4H8BrNIS (210.1): C, 22.86; H, 3.84; N, 20.00. Found: C, 23.18; H, 3.85; N, 19.63. (c) pToluenesulfonate. This salt was prepared as described in procedure C except that the mixture was refluxed for 2 hr. The salt (54.5 g.; 91%) crystallized from ethanol, m.p. 204-207'. Anal. Calcd. for CllHl+NaO& (300.4): C, 43.98; H, 4.71; N, 13.99; S, 21.35. Found: C, 44.00; H, 5.05; N, 14.07; S, 21.17. Acid hydrolysis of S-(j3-cyanoethyl)isothiuroniumchloride. (I. X = Cl). A solution of the salt (10.0 9.) was refluxed in concd. hydrochloric acid (50 ml.) for 3 hr. The solution was evaporated in vacuo. The residue was extracted with boiling acetic acid (50 ml.) and on cooling the acid (6.12 g.; 68'3,) crystallized, m.p. 146'. This sample was identical (m.p., mixed m.p. and infrared spectrum) with one prepared from acrylic acid and thiourea hydrochloride.@ A similar hydrolysis of the amide (11. R = R' = H, X Cl) afforded the corresponding acid, identical with an authentic ample.^ Alkaline hydrolysis of isothiuronium salls. @-Mercaptopropion?trile. S-(8-Cyanoethy1)isothiuronium chloride (I. X = C1; 83.0 g.; 0.5 mole) was stirred with ice-cold 12% sodium hydroxide solution (160 ml.) for 70 min. The solution was acidified with concentrated hydrochloric acid, saturated with sodium chloride, and exacted with chloroform (three 150-ml. portions). Distillation of the organic phase afforded the mercaptonitrile as a colorless oil (15.20 g.; 36%) b.p. 40' a t 3.0 mm., n y 1.4838; h8 1.060; lit.13 b.p. 75'115 mm, n y 1.4877; d20 1.0696. The aqueous acid solution after the extraction was evaporated to dryness i n vacuo. The residue was separated from sodium chloride, by hoe ethanol extraction. On cooling, starting material, I, was recovered. In an attempt to increase the yield of the mercaptonitrile and the mercaptoamides below, this reactrcn waB carried out for a longer period of time, a t elevated temperatures G r with an excess of base. But, these variations resulted in lower yields. N - t - B u l y 1 - ~ - m e ~ c a ~ ~ o p r o p ~ o n&I@-( a ~ ~ iN-&Butylcarboi~e. amido)ethyl]isothii::unium chloride (11. R = H, R ' = t-butyl, X = C1; 27 7 g.; 0.1 mole) when treated with 72 ml. of 12y0 sodium hydroxide solution a t 0' as above, yielded the mercaptutlmide (4.35 g.; 27%), b.p. 95' a t 5.5 mm. but solidified, : n . p 53-55". Recrystallization from petroleum ether (b.p. 33-60') raised the m.p. to 55-57'. Anal. Calcd. for CIW~E.NOS(161.3): C, 52.13; H, 9.38; N, 8.69; S, 19.88. Fouitd: C, 52.09, H, 9.36; N, 8.83; S, 19.73. A similar decomposition of S-[&( N-pheny1carboxamido)ethyl]isothiuronium p-toiuanesulfonate [II. R = H;R' = C&; X = p-CHaCsItSOo] afforded a quantitative yield of j3-mercaptopropionanilide, m.p. 83', lit." m.p. 87-89". Hydrolysis of S-(8-carboxamidoethy1)isothiuronium chloride (11. R = R' = H; X = C1) as described above afforded a very small quantity of 8-mercaptopropionamide, m.p. 94-96', lit.18map.94-96.5". =i
Acknowledgment. The aut.hors thank Mr. Bar ett Moravec for technical assistance in this work. CHICAGO 12, ILL.
(18) Private communication from Dr. Jansen. Ref. 14) does not quote the m.p.
