Formamidine Acetate

[40730-94-7]  · C3H8N2O2  · Formamidine Acetate  · (MW 104.13)

(condensing agent for the synthesis of pyrimidine1 and imidazole2 heterocycles)

Alternate Name: FA.

Physical Data: mp 162-164 °C.

Solubility: sol H2O, hot alcohol.

Form Supplied in: white crystalline solid, widely available.

Handling, Storage, and Precautions: is nonhygroscopic and is stable on storage.

Synthesis of Pyrimidine Heterocycles.

The pyrimidine ring can be conveniently constructed by the reaction of unsaturated 2-aminonitriles (o-aminonitriles) with FA, as exemplified by the synthesis of 4-aminopyrimido[4,5-d]pyrimidine (eq 1)2a and 7-amino-2-(phenylamino)thiazolo[5,4-d]pyrimidine (eq 2).3 4-Amino-8-methyl-1,2,3-triazolo[1,5-a]-1,3,5-triazine is obtained from the reaction of 5-amino-4-cyano-4-methyl-4H-1,2,3-triazole with FA by translocative rearrangement (eq 3).4 FA has also been widely used for the formation of fused pyrimidines in the synthesis of C-nucleosides (eqs 4 and 5).5

Pyrimidones are obtained by the reaction of FA with 5,8-dihydroisatoic anhydride (eq 6)6 or with o-amino esters (eq 7).7 No aromatization or conjugation of double bonds in the product is observed in the former case (eq 6).

A dihydropyrimidine is obtained by the reaction of FA with mesityl oxide (eq 8).8

Synthesis of Imidazole Heterocycles.

FA has been used as a reagent providing a one-carbon fragment in the synthesis of a wide variety of imidazole derivatives.2 The reaction conditions are often mild, and therefore it is the reagent of choice in the Traube synthesis of 9-glycosylpurines (eq 9).9 Imidazoles have also been synthesized by the reaction of FA with a-chloro ketones (eq 10)2e and a-hydroxy ketones (eq 11).10

The trifluoromethyl group, which is usually inert in most reactions, can change the outcome of the condensation of FA with a-halo ketones if it is located at an a-position to the ketone group. For example, the reaction of FA with a-chloro-b-trifluoromethyl ketones gives 4-substituted imidazoles (eq 12). However, a-chloro-a-trifluoromethyl ketones afford 5-substituted 4-fluoro-6-chloromethylpyrimidines (eq 13).11

Similarly, the structure of the product obtained from the reaction of FA with azirines is highly dependent upon the substitution of the azirine ring (eq 14).12

Advantages of Formamidine Acetate over Formamidine Hydrochloride.

It has been found that formamidine acetate could replace formamidine hydrochloride in syntheses previously reported using the latter. FA is nonhygroscopic and is stable on storage. FA, as the salt of a strong base and a weak acid, could often be used in most condensations without prior liberation of free formamidine. By contrast, formamidine hydrochloride is extremely deliquescent and cannot be used in most condensations but must be converted into the free base. The same restriction applies to the hydrogen methyl sulfate salt of formamidine; in addition, complications in synthesis may be anticipated from the fact that methyl hydrogen sulfate itself is an effective methylating agent.2a

Related Reagents.

Ammonium Formate; t-Butoxybis(dimethylamino)methane; N-Cyclohexyl-N,N-dimethylformamidine; (S)-N,N-Dimethyl-N-(1-t-butoxy-3-methyl-2-butyl)formamidine; N,N-Dimethylformamide Diethyl Acetal; Ethyl Chloroformate; Formic Acid; Methyl Formate; N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine; 1H-Pyrazole-1-carboxamidine Hydrochloride; Triethyl Orthoformate; Tris(dimethylamino)methane; Tris(formylamino)methane.

1. Review: Albert, A. In Advances in Heterocyclic Chemistry; Academic: New York, 1982; Vol. 32, pp 1-81 and references therein.
2. (a) Taylor, E. C.; Ehrhart, W. A. JACS 1960, 82, 3138. (b) Itoh, T.; Kitano, S.; Mizuno, Y. JHC 1972, 9, 465. (c) Cristalli, G.; Franchetti, P.; Grifantini, M.; Vittori, S.; Lupidi, G.; Riva, F.; Bordoni, T.; Geroni, C.; Verini, M. A. JMC 1988, 31, 390. (d) FF 1967, 1, 403. (e) FF 1972, 3, 147.
3. Freeman, F.; Kim, D. S. H. L. JOC 1991, 56, 4645.
4. Oakes, F. T.; Leonard, N. J. JOC 1985, 50, 4986.
5. (a) Buchanan, J. G.; Smith, D.; Wightman, R. H. JCS(P1) 1986, 1267. (b) Bhattacharya, B. K.; Lim, M.-I.; Otter, B. A.; Klein, R. S. TL 1986, 27, 815.
6. Stevenson, T. M.; Kaźmierczak, F.; Leonard, N. J. JOC 1986, 51, 616.
7. McNamara, D. J.; Berman, E. M.; Fry, D. W.; Werbel, L. M. JMC 1990, 33, 2045.
8. Kashima, C.; Shimizu, M.; Omote, Y. JHC 1989, 26, 251.
9. Melguizo, M.; Nogueras, M.; Sánchez, A. S 1992, 491.
10. Griffith, R. K.; DiPietro, R. A. S 1983, 576.
11. de Nanteuil, G. TL 1991, 32, 2467.
12. Kascheres, A.; Oliveira, C. M. A.; de Azevedo, M. B. M.; Nobre, C. M. S. JOC 1991, 56, 7.

Joginder S. Bajwa

Sandoz Research Institute, East Hanover, NJ, USA

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