Tris(formylamino)methane1

[4774-33-8]  · C4H7N3O3  · Tris(formylamino)methane  · (MW 145.14)

(a source for formamide; for N-formylformamidine (H2N-CH=N-CHO); for the N-formylformimidoyl group (H-C=NH-CHO) as a building block in heterocyclic synthesis)

Alternate Names: TRIFO; N,NN-methylidynetrisformamide; triformamidomethane.

Physical Data: mp 162-164 °C (dec).

Solubility: sol formamide; sol aprotic dipolar solvents such as DMF or DMA on heating.

Form Supplied in: white crystals; commercially available.

Analysis of Reagent Purity: melting point.

Preparative Methods: Triethyl Orthoformate reacts with formamide under catalysis of mineral acids to give TRIFO (eq 1).2,3 The reaction of excess formamide with inorganic and organic acyl chlorides such as PCl3, POCl3, SOCl2, acetyl chloride, benzoyl chloride, and ethyl chloroformate proceeds via iminium salts to afford TRIFO.2,4,5 Analogously, alkylating reagents such as dialkyl sulfates, alkyl sulfonates or triethyloxonium tetrafluoroborate transform formamide to TRIFO. Alkoxymethyleneiminium salts and formamidinium salts are intermediates in these reactions.2 Pure salts of this type are also converted to the reagent by formamide.2 Reaction of Dimethyl Sulfate with formamide is the easiest way to prepare TRIFO.2

Handling, Storage, and Precautions: store at rt in closed bottles. Use in a fume hood.

Reactions.

Strong CH2-acidic compounds such as dimethyl malonate and methyl cyanoacetate are transformed to N-formylaminomethylenated compounds when heated with TRIFO.6 Heterocyclic amines are converted by TRIFO to the corresponding N-formylamines,7,8 whereas primary aromatic amines react with TRIFO to give N,N-diarylformamidines.9

Of more importance are the applications of TRIFO as a building block in heterocyclic synthesis. In the synthesis of oxazoles from TRIFO and a-halo and a-hydroxy ketones, TRIFO contributes a formamide molecule for the ring closure.5 However, in the synthesis of 1,2,4-triazoles from hydrazines1a,10 or amidrazones,11 2-alkylamino-1,3,5-triazine from N-alkylguanidines,5,12-15 and pyrimido[4,5-d]pyrimidines from 6-aminouracils,7,16 as well as pyrazolo[3,4-d]pyrimidines from 3-amino-5-pyrazolones,17 the reagent donates (=CH-N=CH-) fragments (eqs 2-7).

In a pyrimidine synthesis of broad scope (eqs 8-13), TRIFO acts as a donor of formylformamidine which can cyclize a-CH2-containing ketones,5,6,18-24 1,3-cyclohexanediones,20 1,2-, 1,3-, and 1,4-dihydroxynaphthalenes,25 tetrahydrocarbazolones,26-30 arylacetonitriles,31-35 and arylacetamides,32,33 as well as malonates, cyanoacetates,6,36,37 and aminoacetonitriles.31,38

The thermolysis of TRIFO affords s-triazine in good yield (eq 14).4,5,12,39 N-Formylformamidine is thought to be an intermediate. Some methyl heterocycles (2-methylpyridine, 2-methylquinoline, 2-methylpyrazine, and 2-methylbenzothiazole) react with TRIFO on heating in DMF to give heteroarylpyrimidines with low yields (eq 15).40

A few examples are known in which TRIFO acts as a C1 building block in heterocyclic synthesis, e.g. o-phenylenediamine reacts with TRIFO to give benzimidazole (eq 16).1a By the same reaction, 4-amino-5-carbamoylpyrimidines can be cyclized to give pyrimido[4,5-d]pyrimid-4(3H)-ones (eq 17).41,42 On heating urea or S-methylisothiourea sulfate with TRIFO, condensation of the urea derivative occurs first producing biuret and S,S-dimethyldithioisobiuret which undergo cyclization with another TRIFO molecule to give s-triazines (eqs 18 and 19).9,12,13

Vinylogous formamide acetals can be obtained very simply by heating TRIFO with N,N-dialkylformamide acetals in the presence of the corresponding alcohols (eq 20).43

Related Reagents.

t-Butoxybis(dimethylamino)methane; N,N-Dimethylformamide; N,N-Dimethylformamide Diethyl Acetal; Tris(dimethylamino)methane; Dimethylchloromethyleneammonium Chloride.


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Willi Kantlehner

Universität Stuttgart, Germany



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