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Volume 77, 1948-49
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Preparation of Alkyl Iso-ureas.

[Received by the Editor, January 19, 1947; issued separately, April, 1948.]

Summary.

1.

Of the reagents that alkylate thiourea, viz.: alkyl halides. phosphates, chlorocarbonates and sulphates, it is shown that only alkyl sulphates alkylate urea.

2.

It is shown that the urea is alkylated by ethyl phosphate to give an ethyl iso-thiourea salt.

Werner(1) has described the action of methyl sulphate on urea and four N-substituted ureas to give methyl iso-urea methyl sulphates. The only other known preparation of iso-ureas is from cyanamide, or substituted cyanamides, hydrogen chloride, and an alcohol(2–7). The disadvantages of this method led to a search for some method of alkylating urea.

Thiourea may be alkylated in the iso-position, either by refluxing with alkyl chloroformates in benzene(8) or with alkyl halides(9), or by treatment with methyl sulphate(10). It was found that, when heated with ethyl phosphate, thiourea gave an ethyl iso-thiourea salt. In contrast to the vigorous alkylation by methyl sulphate, ethyl hydrogen sulphate does not alkylate thiourea. Of the above alkylating agents, only methyl sulphate gives an iso-urea with urea.

Urea has now been shown to react on heating with ethyl, n-propyl, and n-butyl sulphates to give alkyl iso-urea alkyl sulphates. These are mostly viscous oils which give crystalline picrates and salycylates. Although benzene sulphonic acid and its salts give characteristic precipitates with strong bases such as amines(11), calcium benzene sulphonate gave no precipitate with the strongly basic iso-ureas.

Experimental.

Ethyl hydrogen sulphate was prepared from one mole of- sulphuryl chloride and two moles of absolute alcohol. n-butyl sulphate was prepared from butyl alcohol and thionyl chloride via the sulphite(12). All other chemicals were obtained from Eastman Kodak Company, New York.

Urea picrate is said to melt at 142° C.(13). While one form does melt at 142° C., or slightly higher, another form has been prepared which darkens above 240° C., and chars and melts between 250 and 260° C. This will be described in a later paper.

The alkyl iso-urea sulphates were prepared by Werner's method(1). A test tube containing one-tenth mole each of alkyl sulphate and urea was heated gradually and with constant stirring in a glycerine bath until the urea and the sulphate mixed. To prevent undue vigour of reaction and resulting decomposition of iso-urea, the tube was removed and cooled in water immediately the liquid layers mixed.

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Ethyl iso-thiourea ethyl phosphate was prepared by heating ethyl phosphate and thiourea together for one hour at 120°–130° C.

Methyl Iso-urea Methyl Sulphate.

Urea and methyl sulphate reacted, not at 112° C.(1), but at 105° C. The picrate melted at 185° C. (Werner(1), 184° C.). Attempts to prepare the salicylate resulted only in the precipitation of salicylic acid, M.P. 155° C., mixed with authentic salicylic acid, M.P. 155° C. Although Werner(1) describes methyl iso-urea methyl sulphate as a viscous oil, several samples have changed on standing to a deliquescent solid, M.P. 108°–109° C. Since a picrate from this melts at 185° C., there has been no chemical change.

Ethyl Iso-urea Ethyl Sulphate.

Urea and ethyl sulphate reacted at 124° C., and unless the mixture was cooled, the temperature rose to 148° and the iso-urea compound decomposed. It is deliquescent solid, M.P. 60° C. Salicylate, M.P. 155° C. [twice] (Basterfield and Powell(7) 153° C.; mixed with authentic salicylic acid, M.P. 119° C.). Picrate, M.P. 185° C. (decomp.).

n-Propyl Iso-urea n-Propyl Sulphate.

Urea and n-propyl sulphate reacted at 156° C. with no rise in temperature. The compound was a viscous oil. Salicylate, M.P. 146° C. (Basterfield and Powell(7) 146° C.); mixed with authentic salicylic acid, M.P. 110° C. Picrate, M.P. 156° C.; mixed with authentic urea picrate, M.P. 109° C.

n-Butyl Iso-urea n-Butyl Sulphate.

Urea and n-butyl sulphate reacted gradually between 100°–120° C. The compound was a viscous oil. Salicylate, M.P. 157° C. (Basterfield and Powell(7) 159° C.; mixed with authentic salicylic acid, M.P. 112° C.)

Ethyl Iso-thiourea Ethyl Phosphate.

This again is a viscous compound—cf. methyl iso-thiourea methyl sulphate, crystalline, M.P. 235° C.(9). Picrate, 185° C. (Levy and Campbell(16) 188° C.); mixed with picrate from ethyl iso-thiourea hydrobromide, M.P. 185° C.

N-Substituted Iso-ureas.

A number of N-substituted iso-ureas of various types have been prepared by alkylation of corresponding ureas with methyl and ethyl sulphates. These compounds, again mostly oils, will be described later when their picrates have been characterised.

Unsuccessful Attempts to Alkylate Urea.

Urea remained unchanged after being refluxed for 15 hours with n-amyl bromide. Refluxed with ethyl chloroformate in benzene for 12 hours, urea gave a white solid; M.P. 176° C.; soluble in water and alcohol and having the properties neither of urea nor of an iso-urea.

When heated with ethyl phosphate in a glycerine bath for 18 hours at 120°–130° C., urea dissolved in the phosphate. The solution gave a nitrate, M.P. 153° C.; mixed with authentic urea nitrate,

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M.P. 150° C., and a picrate, M.P. 252° C. (decompn.); mixed with authentic urea picrate, M.P. 256° C. (decompn.). The product was therefore probably urea ethyl phosphate.

Alkyl hydrogen sulphates react with urea to form urea alkyl sulphates(14). Urea ethyl sulphate was refluxed 3 hours each with methyl and ethyl alcohols. Picrates from the products melted at 254°–8° C.; mixed with authentic urea picrate, M.P. 254°–8° C. (Methyl iso-urea picrate, M.P. 184° C.(11); ethyl iso-urea picrate, M.P. 184°–5° C.(13).)

Acknowledgments.

Thanks are due to Mr. C. L. Carter, M.Sc., Lecturer in Chemistry, and Mr. T. H. Kennedy, M.Sc., Goitre Research Department, for encouragement and advice.

References.

1. Werner, J.C.S., 105, 923 (1914).

2. Dains, J A.C.S., 21, 136 (1899).

3. Stieglitz and McKee, Ber., 32, 1494 (1899); 33, 1517 (1900).

4. McKee, Am. Chem. J., 24, 209 (1901).

5. Bruce, J.A.C.S., 26, 419 (1904).

6. Stieglitz and Noble, Ber., 38, 2243 (1905).

7. Basterfield and Powell, Can. J. Research, 1, 261 (1929).

8. Dixon, J.C.S., 83, 566 (1903).

9. Stevens, J.C.S., 81, 80 (1902).

10. Blatt, Organic Syntheses, New York, 2, 411 (1943).

11. Forster and Keyworth, J.C.S.I., 43, 165T (1924).

12. Blatt, Org. Syntheses, 2, 111–2.

13. Smolka, Monatsch, 6, 920 (1885).

14. Carter and Ongley, in press.

15. Meerwein et alii, J. prakt. Chem., 154, 3 (1939).