[2986-19-8]  · C2H6N2S  · S-Methylisothiourea  · (MW 90.17)

(synthesis of heterocycles;1 guanylation reagent;2 source of methanethiol3)

Physical Data: free base not isolated; sulfate salt mp 240-241 °C.

Solubility: salts sol water, methanol, ethanol.

Form Supplied in: commercially available as 2-methyl-2-thiopseudourea sulfate [867-44-7] (MW 278.37).

Preparative Methods: both S-methylisothiourea sulfate4 and S-ethylisothiourea hydrobromide5 can be readily synthesized.

Handling, Storage, and Precautions: salts are toxic; when heated to decomposition, salts emit toxic fumes of SOx and NOx. S-Ethylisothiourea hydrogen sulfate reacts with Cl2 to produce nitrogen trichloride (Trichloramine), a dangerous explosive.6 Use in a fume hood.

Heterocycle Synthesis.

One of the most widely used syntheses of pyrimidines involves condensation of S-methylisothiourea with various 1,3-bis electrophilic compounds including b-dialdehydes, b-keto aldehydes, b-diketones, b-aldehydo esters, b-keto esters, malonic esters, b-alkoxy-a,b-unsaturated malonates, cyanoacetates, and malonitriles.1b,7 The ease of formation of six-membered rings is evidenced in the reaction of ethyl 4-bromoacetoacetate with S-methylisothiourea which led only to the pyrimidine, albeit in low yield,8a whereas base-catalyzed condensation of phenacyl bromide with S-benzylisothiourea afforded only the expected 2-benzylthio-4-phenylimidazole (eq 1).8b

Synthesis of 2-substituted 5-acylpyrimidines is achieved using S-methylisothiourea hydroiodide and ethoxymethylene-b-diketones, with unsymmetrical 1,3-diketones yielding regioisomeric pyrimidines (eq 2).9 Triformylmethane reacts with S-methylisothiourea to give 2-methylmercapto-5-formylpyrimidine in 33% yield,10 whereas use of a 2-iminovinamidinium salt yields this compound quantitatively.11 With equimolar amounts of triacetylmethane and S-methylisothiourea, the expected pyrimidine was not formed.12 Instead, a triazine was isolated which was postulated to arise from condensation of 2 equiv of the isothiourea with the triketone via a biguanidine intermediate (eq 3).

Triarylpyrylium salts react with S-methylisothiourea to yield 2-methylmercapto-4,6-diarylpyrimidines.13 A convenient synthesis of trans-5,6-diphenyl-5,6-dihydrouracils involves condensation of S-methylisothiourea with diphenylcyclopropenone followed by hydrolysis. Although both cis and trans isomers were detected in the crude reaction mixture, prolonged reaction times in the basic medium afforded only the thermodynamic product.14

A new synthesis of 1,3,5-triazines involves ring opening of 2-aroylimino-1,3-thiazetidines with S-methylisothiourea, cyclodehydration, and subsequent loss of thioformaldehyde (eq 4).15

A series of 5,6-dihydro-3-methylthio-4H-1,2,4-thiadiazine 1,1-dioxides have been prepared from S-methylisothiourea and 2-chloroethanesulfonyl chloride derivatives.16 Reaction of an alkyl chloroformate with S-methylisothiourea gives either the mono- or di-N-alkoxycarbonyl derivative,17 while reaction with chloromethanesulfonyl chloride affords the corresponding sulfonamide,18 all useful intermediates for synthesis of a variety of heterocycles.

Guanylation Reagent.

The Rathke synthesis of guanidines using S-methylisothiourea is one of the oldest and most common methods available.2 Selective reactions of primary vs. secondary amines with this reagent are possible,19 while selectivity between primary amines and anilines has also been described.20 Nitration of S-methylisothiourea gives the mono-N-nitro derivative in high yield, a useful reagent for direct preparation of N-nitro-protected guanidines, as well as in solid-phase peptide synthesis (SPPS).21 NG-Methyl-L-arginine has been prepared using S-methylisothiourea.22 A series of N,N,N-trialkylguanidines have been prepared from N-monoalkyl-S-methylisothioureas and secondary amines.23 1H-Pyrazole-1-carboxamidine hydrochloride has been reported as an alternative guanylating agent to O-methylisourea, S-methylisothiourea, or commercially available 1-guanyl-3,5-dimethylpyrazole nitrate for use in SPPS.24 None of these reagents was sufficiently reactive for generalized use in SPPS, although 1-guanyl-3,5-dimethylpyrazole is superior to S-methylisothiourea for synthesis of some guanidines.25

Direct introduction of di-Boc-protected guanidine moieties during the total synthesis of racemic 15-deoxyspergualin26 and caracasanamide27 was achieved with N,N-bis(t-butoxycarbonyl)-S-methylisothiourea, itself readily prepared from S-methylisothiourea and Di-t-butyl Dicarbonate. Analogously, N,N-bis(benzyloxycarbonyl)-S-methylisothiourea, available from S-methylisothiourea and Benzyl Chloroformate, has been used in the synthesis of both L- and D-C-a-methylarginine.28 Guanylation of the tridentate copper complexes of erythro- and threo-2-hydroxy-L-ornithine with S-methylisothiourea gave the (3S)- and (3R)-L-arginines in good yield. O-Methylisourea tosylate was not as efficient in this conversion.29

Source of Methanethiol.

A mild method for generating methanethiol involves warming an aqueous solution of S-methylisothiourea sulfate with 5N NaOH and trapping the liberated thiol as the sodium salt with sodium ethoxide.3

Related Reagents.

Acetoxime O-(2,4,6-trimethylphenyl)sulfonate; Cyanogen Bromide; Diphenyl Cyanocarbonimidate; Formamidine Acetate; Guanidine; O-Methylisourea; 1H-Pyrazole-1-carboxamidine Hydrochloride.

1. (a) Kenner, G. W.; Todd, A.; Elderfield, R. C., Eds.; Heterocyclic Compounds; Wiley: New York, 1957; Vol. 6, pp 234-323. (b) Brown, D. J. The Pyrimidines. The Chemistry of Heterocyclic Compounds; Interscience: New York, 1962; pp 31-81. (c) Griffin, T. S.; Woods, T. S.; Klayman, D. L.; Katritzky, A. R.; Boulton, A. J., Eds.; Advances in Heterocyclic Chemistry; Academic: New York, 1975; Vol. 18, pp 100-158. (d) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 3, pp 106-116, 129-132.
2. (a) Rathke, B. CB 1881, 14, 1774. (b) Rathke, B. CB 1884, 17, 297.
3. Windus, W.; Shildneck, P. R. OSC 1943 2, 345-347.
4. Shildneck, P. R.; Windus, W. OSC 1943 2, 411-412.
5. Brand, E.; Brand, F. C. OSC 1955, 3, 440-441.
6. Lewis, R. J., Sr. Sax's Dangerous Properties of Industrial Materials, 8th ed.; Van Nostrand: New York, 1992; Vol. III, pp 408, 1630.
7. Taylor, E. C.; McKillop, A. The Chemistry of Cyclic Enaminonitriles and o-Aminonitriles; Wiley: New York, 1970; pp 113-118.
8. (a) Dodson, R. M.; Peterson, E. R.; Seyler, J. K. JACS 1950, 72, 3281. (b) Hoffman, K. Imidazole and Its Derivatives. The Chemistry of Heterocyclic Compounds; Interscience: New York, 1953; Part I, pp 81-82.
9. Takagi, K.; Bajnati, A.; Hubert-Habart, M.; Terada, H. JHC 1990, 27, 1847.
10. Takagi, K.; Bajnati, A.; Hubert-Habart, M. H 1990, 31, 1105.
11. Gupton, J. T.; Gall, J. E.; Riesinger, S. W.; Smith, S. Q.; Bevirt, K. M.; Sikorski, J. A.; Dahl, M. L.; Arnold, Z. JHC 1991, 28, 1281.
12. Takagi, K.; Bajnati, A.; Hubert-Habart, M. JHC 1990, 27, 1565.
13. Zvezdina, E. A.; Zhdanova, M. P.; Dorofeenko, G. N. ZOB 1978, 48, 939 (CA 1978, 89, 109 337d).
14. Kascheres, A.; Kascheres, C.; Augusto, J.; Rodrigues, R. SC 1984, 14, 905.
15. Okajima, N.; Okada, Y. JHC 1991, 28, 177.
16. (a) Etienne, A.; Le'Barre, A.; Giorgetti, J. P. BSF 1973, 985. (b) Etienne, A.; Le'Barre, A.; Giorgetti, J. P. BSF 1973, 2361. (c) Etienne, A.; Le'Barre, A.; Giorgetti, J. P. BSF 1974, 1395.
17. (a) Rajappa, S.; Sreenivasan, R. IJC(B) 1980, 19B, 533. (b) Rao, C. S.; Rambabu, M.; Mistry, N. L. OPP 1988, 20, 419.
18. Demers, J. P.; Sulsky, R.; Klaubert, D. H. JHC 1989, 26, 1535.
19. Short, J. H.; Biermacher, U.; Dunnigan, D. A.; Leth, T. D. JMC 1963, 6, 275.
20. Safir, S. R.; Kushner, S.; Brancone, L. M.; Subbarow, Y. JOC 1948, 13, 924.
21. (a) Fishbein, L.; Gallaghan, J. A. JACS 1954, 76, 1877. (b) Tian, Z.; Roeske, R. W. Int. J. Pept. Protein Res. 1991, 37, 425.
22. Paik, W. K.; Paik, M. K.; Kim, S. AB 1980, 104, 343.
23. (a) Rasmussen, C. R.; Villani, F. J. Jr.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Powell, E. T.; Molinari, A. J. S 1988, 456. (b) Rasmussen, C. R.; Villani, F. J. Jr.; Reynolds, B. E.; Plampin, J. N.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J.; Howse, R. M. Jr.; Molinari, A. J. S 1988, 460.
24. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. JOC 1992, 57, 2497.
25. Bannard, R. A. B.; Casselman, A. A.; Cockburn, W. F.; Brown, G. M. CJC 1958, 36, 1541.
26. Bergeron, R. J.; McManis, J. S. JOC 1987, 52, 1700.
27. Delle Monache, G.; Botta, B.; Della Monache, F.; Espinal, R.; De Bonnevaux, S. C.; De Luca, C.; Botta, M.; Corelli, F.; Carmignani, M. JMC 1993, 36, 2956.
28. Tian, Z.; Edwards, P.; Roeske, R. W. Int. J. Pept. Protein Res. 1992, 40, 119.
29. Wityak, J.; Gould, S. J.; Hein, S. J.; Keszler, D. A. JOC 1987, 52, 2179.

David C. Palmer

R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA

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