11 3,597,444 United States Patent 0 ice Patented Aug. 3, 1971 1 2 to poor yields, and no single procedure can be univer 3,597,444 sally used to prepare all types of selenoureas. METHOD OF SYNTHESHZING SELENOUREAS Selenoureas have a wide variety of uses to form seleno FROM THIOUREAS Daniel L. Klayman, Chevy Chase, and Robert J. Shine, substituted medicinal compounds. Mautner and Clayton West Hyattsville, Md., assignors to the United States of in J. Am. Chem. Soc., -81 6270 (1959) used selenourea to America as represented by the Secretary of the Army prepare 2-selenobarbiturates to increase lipid solubility. No'Drawing. Filed Apr. 2, 1969, Ser. No. 812,872 Segalotf and Gabbard in Steroids, 5, 219 (1965) and Int. Cl. (307d 49/34 US. Pat. No. 3,372,173, used selenoureas to prepare 319 US. Cl. 260-3097 4 Claims Selenosteroids. Mautner, Kurnler, Okano, and Pratt in 10 Antibiotics and Chemotherapy, 6, 51 (1956) used seleno ureas to prepare selenosemicarbazones having antifungal ABSTRACT OF THE DISCLOSURE and antitubular activity. This invention relates to the preparation of selenoureas SUMMARY having either aliphatic or aromatic substituents by dis placement of the thiomethyl moiety from S-methylthio This invention includes the use of the hydroselenide pseudoureas by hydroselenide ions in solutions having a ion as the attacking nucleophile on S-methylthiopseudo pH of 8 to 9. This method provides yields of substituted ureas possessing a variety of N-substitution patterns. selenoureas in the range of 60-70 percent. Selenoureas Accordingly, it is an object of this invention to provide are useful in synthesizing a wide variety of seleno sub a method of synthesizing stable selenoureas with a high stituted compounds, for example the seleno substituted 20 yield. steroids of US. Pat. No. 3,372,173. It is another object to provide a method of synthesis applicable to a wide variety of substituted selenoureas. These and other objects will become apparent with ref The invention described herein may be manufactured erence to the following description. and used by or for the Government for governmental pur 25 DESCRIPTION OF THE PREFERRED poses without the payment to us of any royalty thereon. EMBODIMENTS BACKGROUND OF THE INVENTION It has been discovered that selenoureas can be prepared, (1) Field of the invention for the most part, in good yield from all thiopseudoureas 30 regardless of the degree or nature of the N-substitution In the course of investigation of the behavior of S-meth according to the following reactions; yl derivatives of various thioureas toward alkali, it was found that the S-methyl derivatlves_ _ of all but trisubstituted CH3l r) CH3I thioureas‘ form methyl mercaptan and the corresponding. R1\ S|| / R3 CHBI R1\ S| / R3 Hse- R1\ k,S /R3 urea. Subsequent work with sul?de ion as the nucleophile 35 /N—C-N\ ——> /N—C+= \ ———» /N—(IJ—N showed that the thiomethyl moiety could be displaced R, R, R, 1- R, R, (58 \R, from all S-methylthiopseudoureas, including those which II1 are trisubstituted to regenerate the original thiourea. (2) Description of the prior art 40 l Selenium analogs of ureas have been synthesized by R, Se 3, various methods. For example, selenoureas and mono- \N_(l|J N/ CH SH and 1,1-disubstituted selenoureas have been prepared by / \ + 3 the reaction of hydrogen selenide with cyanarnides, while R1 R4 Analysis Calc’d Found M.P., Percent ________ Number R1 R2 R3 R4 ° 0. yield Recryst. solvent N Se N Se H 1 223-225 10 H2O _____________ .. 22.77 64.19 22.29 63.37 H 1 123-125 74 CHCl3-heXane_____ 1s. 54 52.27 18.52 52.73 H 1190492 79 14.07 39.66 14.07 39.55 H 1 205207 . 28. 69 10. 22 28. 74 H 1 178.182 28. 69 9. 93 2s. 81 H 108-110 34.76 11. 85 34. 71 0H3 79-81 44. 08 15. 92 44. 36 H 1 189-191 57. 20 30. 22 56. 79 H 1 195-197 36. 87 19. 57 36. 91 H 1 185-188 43. 36 22. 86 42. 7s ______________________ _.1 230-232 71 19.05 53. 70 18.96 53. 94 1 Decomposition. the reaction of hydrogen selenides with carbodiimides has 65 Especially noteworthy is the preparation of the difficult resulted in the formation of mono- and 1,3-disubstituted 1y attainable 1,1,3,3-tetramethyl-2.-selenourea: selenoureas. The reaction of alkyl, acyl, and aryl iso selenocyanates with ammonia or amines has led to the preparation of mono-, 1,3-di, and trisubstituted seleno ureas. 1,1,3,3-tetramethyl-Z-selenourea has ‘been made by 70 the reaction of phosphorus pentaselenide with tetramethyl 3-selenosemicarbazide, and l-phenyl-3-selenosemicarba urea. The prior art procedures all have limited utility due zide The previously unknown 2-seleno-4-thiobiuret was 8,597,444 synthesized from 2-methyl-2,4-dithiopseudobiuret hydro Ammoniacal silver nitrate was found to react with all iodide: the selenoureas but Z-imidazolineselenone to give a black s SCH; Se precipitate of silver selenide. In contrast, the analogous tri substituted thioureas and l,1,3,3-tetramethyl-2-thiourea failed to react with this reagent to give silver selenide. Hydrogen selenide was generated by addition of dilute Selenourea, itself, however, could not be prepared in good sulfuric acid to ?nely pulverized aluminum selenide, in yield. the manner of Bennett and Zingaro. See Organic Syn The selenoureas prepared according to this invention thesis, Coll. vol. IV, John Wiley and Sons, Inc., New were relatively stable if stored in the dry state in the ab 10 York, N.Y., p. 359 (1963). Their procedure was modi?ed sence of air and light, and could be recrystallized from in that no external heat was applied to the exothermic re chloroform-hexane or ethanol. Heating the selenoureas action. The in situ generation of hydrogen selenide by ad in water and in some instances in ethanol caused slight dition of aluminum selenide to an aqueous solution of decomposition of the selenoureas. the S-methyl thiopseudourea was tried, but the di?iculties The process of this invention may be described as fol- ' 15 encountered in separating the product from the inorganic lows. A solution of sodium hydroselenide, prepared by by-product (mainly aluminum hydroxide) negated what the addition of hydrogen selenide gas to an aqueous ever advantage was gained by this technique. ethanolic solution of sodium bicarbonate, was combined We claim: with an ethanolic solution of S-methyl thiopseudourea 1. The method of synthesizing selenourea comprising: hydroiodide. The pH of the solution was then immediately 20 (a) reacting S-methylthiopseudourea hydroiodide with adjusted to 8-9 by the addition of sodium bicarbonate. hydrogen selenide in a solution having a pH of 8 2-methyl-2 thiopseudourea hydroiodides for conversion to 9; and to selenoureas were prepared as follows. An ethanol solu (b) isolating selenourea crystals from the said solution. tion of a thiourea was heated under re?ux for 0.5-1.0 2. The method of synthesizing 2-seleno-4 thiobiuret hours with 1.1 equivalents of methyl iodide. Evaporation 25 comprising: of the solvent under reduced pressure gave the 2-methyl-2 (a) reacting 2-methyl-2,4-dithiopseudobiuret hydroio thiopseudourea hydroiodide which generally could be dide with hydrogen selenide in a solution having a puri?ed by recrystallization from ethanol-ether. pH of 8 to 9; and 2-methyl-2,4-dithiopseudobiuret hydroiodide for con (b) isolating 2-seleno-4 thiobiuret crystals from the version to 2-seleno-4 thiobiuret was prepared by adding 30 said solution. 20.3 grams (0.15 mole) dithiobiuret suspended in 75 ml. 3. The method of synthesizing a selenourea compris of acetonitrile to 35.5 grams (0.25 mole) of methyl io mg: dide. The mixture was then heated under re?ux for 40 (a) reacting by heating under re?ux a thiourea having minutes. The solution was concentrated and cooled, giv ing white crystals (34.1 grams or 82% yield) of 2-methyl a formula of 2,4-dithiopseudobiuret hydroiodide having a melting point 35 R1 S Ra of ISO-152°, recrystallized from acetonitrile. Analysis.-—Calculated for C3H8IN3S2 (percent): C, 13.00; H, 2.91; I, 45.79; N, 15.16; S, 23.14. Found (per \R‘ cent): C, 12.78; H, 2.77; I, 45.81; N, 15.28; S, 23.47. wherein R1 is member selected from the group consisting Selenoureas are synthesized according to the following 40 of hydrogen, methyl, ethyl, amino, phenyl, anilino, and example. Hydrogen selenide, generated by adding 50 ml. thiocarbamoyl; R2 is a member selected from the group of 6 N sulfuric acid to 11.5 grams of powdered aluminum consisting of hydrogen, methyl, and penyl; R3 is a mem selenide (90% purity), was passed slowly into a solution ber selected from the group consisting of hydrogen, meth yl, and phenyl; and R4 is a member selected from the of 8.25 grams (0.10 mole) of sodium bicarbonate in 250 45 ml. of water and 100 ml. of ethanol maintained at 0°. group consisting of hydrogen and methyl; with methyl The resulting clear red solution contained about 0.10 mole iodide to form the corresponding 2-methyl-2 thiopseudo of sodium hydroselenide. urea hydroiodide; To a solution of 0.05 mole of a 2~methylthiopseudourea (b) reacting the 2-methyl-2 thiopseudourea hydroio hydroiodide in 50 ml. ethanol was added 350 ml. of the dide with a hydroselenide solution having a pH of sodium hydroselenide solution described above, contain 8 to 9 to form the corresponding selenourea; and ing an additional 0.05 mole of sodium bicarbonate.