[2440-60-0]  · C2H6N2O  · O-Methylisourea  · (MW 74.10)

(synthesis of heterocycles;2 guanylation reagent;3 selective alkylating agent4)

Physical Data: mp 44-45 °C; bp 82 °C/9 mmHg; pKa 9.9 (25 °C).

Solubility: free base readily sol most organic solvents. Salts sol water, methanol, ethanol.

Form Supplied in: commercially available as O-methylisourea hydrogen sulfate [29427-58-5] (MW 172.16) or O-methylisourea sulfate [52328-05-9] (MW 246.24).

Preparative Methods: O-methylisourea hydrochloride is prepared in 69-80% yield by adding 1.15 equiv HCl(g) with ice cooling to cyanamide dissolved in excess anhydrous methanol. The free base is obtained from the salt using powdered KOH in a water-ether mixture or with sodium methoxide in methanol.5 The monoacetate salt can be prepared from the free base with 1 equiv of HOAc.6 Drying: vacuum desiccator over P2O5.

Handling, Storage, and Precautions: salts are hygroscopic and should be stored in a desiccator even for brief periods. Heating O-methylisourea to decomposition can liberate toxic fumes of NOx. Use in a fume hood.

Heterocycle Synthesis.

O-Methylisourea has been used to prepare a variety of substituted pyrimidines by condensation with b-diketones.7 Interestingly, if the condensation is conducted at rt with 30% aqueous K2CO3, the 2-methoxy analogs are isolated in good yield (eq 1), whereas reactions performed in refluxing ethanol afforded the 2-hydroxy derivatives directly (eq 2). An attractive synthesis of uracils, which obviates problems encountered using thiourea or an alkylisothiourea, involves condensation of O-methylisourea with a b-keto ester in aqueous ethanol. The resulting 2-methoxy-6-alkyl- or 2-methoxy-5,6-dialkyl-4(3H)-pyrimidinone is smoothly hydrolyzed to the corresponding uracil with dilute acid.8

Conjugate addition of O-methylisourea hydrogen sulfate to a preformed a-alkylidene-b-keto ester, subsequent cyclization, and acid hydrolysis affords 1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylic acid esters, thus providing an attractive alternative to the Biginelli condensation (eq 3).9a Mixtures of both 1,4- and 1,2-dihydropyrimidines are obtained. Substitution of an alkylisothiourea affords the 2-thioxo derivatives after hydrolysis.9b Selective functionalization of the pyrimidine N-3 nitrogen with a variety of electrophiles, an otherwise difficult transformation, is possible using the 1,4-dihydropyrimidine.9c

A general synthesis of 2-substituted 5-formylpyrimidines from 2-iminovinamidinium salts and a variety of amidines including O-methylisourea has been described.10 Cyclization of an unsaturated b-keto ester with O-methylisourea afforded a 1,4-dihydropyrimidine ester which was smoothly converted to the acyl portion of the bicyclic guanidine alkaloids crambine A and crambine B. Attempts to incorporate the guanidine moiety directly using guanidine itself were uniformly unsuccessful.11 Oxidation of O-methylisourea p-toluenesulfonate12 in a Graham reaction13 generated bromomethoxydiazirine, a precursor to fluoromethoxycarbene.14 Reaction of O-ethylisourea with Methyl Chloroformate followed by o-phenylenediamine produced 2-aminobenzimidazoles protected as the methylurethane.15

Guanylation Reagent.

Guanylation of primary and secondary aliphatic amines has been accomplished in good to excellent yields using O-methylisourea sulfate.16 Diamines yield the analogous bis-guanidines, while amino alcohols produce hydroxy guanidines. Reaction of ornithine17 and lysine18 containing peptides with O-methylisourea sulfate at pH 10-11 smoothly generates the arginine and homoarginine analogs without guanylation of the N-terminus.19 Incorporation of C-13 labels into homoarginine-containing derivatives of cytochrome c was accomplished using 13C-labeled O-methylisourea.20

Alkylating Agent.

Methylation of the SH group of mercaptoethanol can be achieved using O-methylisourea at pH 8.5. Functionalized side chains of simple amino acids such as arginine, aspartic acid, histidine, methionine, glutamine, and serine do not react under these conditions, although some guanylation of the N-terminal amino group was observed.4 Selective methylation of the cysteine residues, with subsequent inactivation of papain, has been reported based on these observations.21 When O-methylisourea was heated with 2 equiv KI, methyl iodide was obtained in excellent yield.22

Related Reagents.

Aminoiminomethanesulfonic Acid; Cyanogen Bromide; Diphenyl Cyanocarbonimidate; Formamidine Acetate; Guanidine; S-Methylisothiourea; 1H-Pyrazole-1-carboxamidine Hydrochloride.

1. (a) Sandler, S. R.; Karo, W. Organic Functional Group Preparations; Academic: New York, 1971; Vol 2, pp 166-185. (b) Mathias, L. J. S 1979, 561. (c) Mathias, L. J. OPP 1980, 12, 311.
2. (a) Kenner, G. W.; Todd, A.; Elderfield, R. C., Eds.; Heterocyclic Compounds; Wiley: New York, 1957; Vol. 6, pp 234-324. (b) Brown, D. J. The Pyrimidines. The Chemistry of Heterocyclic Compounds; Interscience: New York, 1962; pp 31-81.
3. Hughes, W. L., Jr.; Saroff, H. A.; Carney, A. L. JACS 1949, 71, 2476.
4. Banks, T. E.; Shafer, J. A. B 1970, 9, 3343.
5. Kurzer, F.; Lawson, A. OSC 1963 4, 645-649.
6. Miura, Y.; Asada, T. CA 1987, 106, 32 380x.
7. Kreutzberger, A.; Tesch, U.-H. CB 1976, 109, 3255.
8. (a) Botta, M.; Cavalieri, M.; Ceci, D.; De Angelis, F.; Finizia, G.; Nicoletti, R. T 1984, 40, 3313. (b) Botta, M.; Artico, M.; Massa, S.; Gambacorta, A. JHC 1989, 26, 883.
9. (a) O'Reilly, B. C.; Atwal, K. S. H 1987, 26, 1185. (b) Atwal, K. S.; O'Reilly, B. C.; Gougoutas, J. Z.; Malley, M. F. H 1987, 26, 1189. (c) Atwal, K. S.; Rovnyak, G. C.; O'Reilly, B. C.; Schwartz, J. JOC 1989, 54, 5898.
10. 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.
11. Snider, B. B.; Shi, Z. JOC 1992, 57, 2526.
12. Smith, N. P.; Stevens, I. D. R.; JCS(P2) 1979, 1298.
13. Graham, W. H. JACS 1965, 87, 4396.
14. Moss, R. A.; Fedorynski, M.; Terpinski, J.; Denney, D. Z. TL 1986, 27, 419.
15. Yamakawa, H.; Saito, Y.; Hayashi, M.; Ishlkawa, N.; Nagoya, T. CA 1978, 88, 190 826m.
16. Weiss, S.; Krommer, H. CZ 1974, 98, 617.
17. Cosand, W. L.; Merrifield, R. B. PNA 1977, 74, 2771.
18. Granier, C.; Pedroso Muller, E.; Van Rietschoten, J. Eur. J. Biochem. 1978, 82, 293.
19. Chervenka, C. H.; Wilcox, P. E. JBC 1956, 222, 635.
20. (a) Stellwagen, E.; Smith, L. M.; Cass, R.; Ledger, R. Wilgus, H. B 1977, 16, 3672. (b) Kennelly, P. J.; Timkovich, R.; Cusanovich, M. A. J. Mol. Biol. 1981, 145, 583.
21. Banks, T. E.; Shafer, J. A. B 1972, 11, 110.
22. Weiss, S. CZ 1975, 99, 244.

David C. Palmer

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

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