1.2.4- Triazine-3-carboxylic acid derivatives

Preparation of 5-amino-6-oxo-l,6-dihydro-1,2,4-triazine-3-carboxylic acid derivatives and the synthesis of compound libraries thereof have been reported <04TL2791>. Intramolecular inverse electron demand Diels-Alder reactions of imidazoles with 1,2,4-triazines have been described as a new route to obtain l,2,3,4-tetrahydro-l,5-naphthyridines and related heterocycles... 

When aldehydes or ketones are used instead of the carboxylic acid derivatives, the corresponding l,2-dihydro-l,3,5-triazines are formed (equation 52). The reaction is acid catalyzed (61MI22000, p. 697). 

Since the discovery of the synthesis of 1,3,5-triazine-2,4-diamines from biguanide and its derivatives,328-329 a large variety of carboxylic acid derivatives, e.g. acid chlorides,332 342,346 lactones,333 amides,334,335 imides,336,337 ortho esters,338 amidines,338 esters334, 339- 343 and acid anhydrides,332,344,345 have been used as starting materials in the preparation of these triazines (Table 8).330,331 The preferred procedure is the reaction of biguanides 1 with esters 2 in alcoholic solution, sometimes in the presence of a basic catalyst. The reaction mechanism is thought to be as indicated.341... 

Some other five-atom components, which are more or less closely related to biguanides, also react with carboxylic acid derivatives to form 1,3,5-triazine derivatives. 

Substances of this type have hitherto received little attention. One of the reasons appears to be the limited possibilities of preparation. The only known method of preparation, described by Woolley et ai./ proceeds from the derivatives of 4-aminoimidazole-5-carboxylic acid. The amide of this acid (142) is treated with nitrous acid to yield 4-hydroxyimidazo [4,5-d]-i -triazine (2-azahypoxanthine) (143), the amidine (144) yielding the 4-amino derivative (2-azaadenine) (145) under the same conditions. 2-Azahypoxanthine was probably obtained in the same way earlier but was not identified. ... 

The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system 2-[l,3,5]triazin-2-yl-l,2-dihydro[l,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

In 2001, De Luca and GiacomeUi " reported a new simple and high-yielding one-flask synthesis of Weinreb amides from carboxylic acids and A-protected amino acids that uses different 1,3,5-triazine derivatives (such as 236) as the coupling agents (Scheme 104). The method allows the preparation of Weinreb amides 237 and hydroxamates as O-benzyl and 0-silyl hydroxamates that can be easily transformed into hydroxamic acids. 

Synthesis of 1,3,5-triazine derivatives from iminoesters of carboxylic acids 92KGS1587. 

Syntheses of perimidine 109 and naphtho[l,8-<7, ]triazine 110 derivatives usually start from 1,8-diaminonaphthalene by procedures which are quite similar to the synthesis of benzimidazoles and benzotriazoles from 1,2-diaminobenzene <1995AQ151>. For example, 2-alkyl and 2-arylperimi-dines 112 can be readily obtained in good yield by heating carboxylic acids with 1,8-naphthalenediamine 111 under microwave conditions (Scheme 54) <2005ASJ2411>. 

This series of compounds is prepared by ring closure of the appropriate 4-hydrazino-1,2,4-triazines with carboxylic acids, carbon disulfide, cyanogen bromide, etc. to give the 3-unsubstituted or 3-substituted (alkyl, thiol, amino) derivatives (67CB3467,81JHC1353). 

Let us assume that the nitro ester (I.I) is to be converted into a novel tricyclic compound (1.2). No useful references are to be found in Chapter 72 (carboxylic acid or its derivative and nitro) because the nitro group has to be reduced before this kind of cyclization can occur. Chapter 48, which includes cyclization of amino esters, is more promising and Section II. I (p. 228) offers at least one example of the direct conversion of a nitro ester into a pyridin-2-one ring the conditions given [821] are also likely to be applicable to the synthesis of triazine (1.2). 

Activation of carboxylic acids. The coupling reagent 1, derived from N-methylmorpholine and 2-chloro-4,6-dimethoxy-l,3,5-triazine, reacts with RCOOH to form heteroaryl esters that are susceptible to alcoholysis and serve as transacylating agents in peptide synthesis. ... 

Substituted-tetrahydropyridazine-3,6-dione-3-hydrazones 27 react with strong carboxylic acids and with some acyl chlorides to give A-acyiated products and/or triazolo[4,3-6]pyridazines. Derivatives of this type are also obtained in reactions of 27 with triethyl orthoformate and orthoacetate. In reactions with phosgene, triazolo[4,3-6]pyrazine-3,6-diones are obtained and with oxaly chloride pyridazino[6,1-c]triazine-3,4,7-triones are formed (Scheme 4) <96MI01 97CA( 126)251121>. 

It is worth noting that the C-N-C-C fragment can be derived from heterocyclic compounds. For instance, interaction of triethyl l,3,5-triazin-2,4,6-tricarboxylate 269 with arylhydrazines affords esters of 5-amino-6-oxo-l,6-dihydro-l,2,4-triazin-3-carboxylic acid 270 in good yields (Scheme 160) <2004TL2791>. 

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