1.3.5- Triazine amidine synthesis

A convenient synthesis of trisubstituted 1,3,5-triazines uses acylamidines 1 and amidines < 95JOC8428 >, whilst l,3,5-triazin-2(l/f)-ones 3 are obtained from N-acyl-lV -carbamoyl-S-methylisothioureas 2 <96H(43)839>. 

Synthesis of the sym-Triazine System. I. Trimerization and Cotrimerization of Amidines. J. Amer. chem. Soc. 81, 1466 (1959)-... 

Nearly all such syntheses are based on the use of amidines as one of the starting reagents. The role of amidines in the synthesis of 1,3,5-triazines has been reviewed recently by Gautier et al. (B-75M122000). 

Substituted amidines are of limited use in the synthesis of symmetric 1,3,5-triazines. Only formamidine or amidines bearing strongly electron withdrawing groups react readily. The proposed mechanism (59JA1466) resembles that of the trimerization of imidates (Scheme 87). 

Table 18 Synthesis of 1,3,5-Triazines from the Reaction of Imidates and Amidines (62JOC3608)...

A new, simple, synthesis of 2,4-diaryl-l, 3,5-triazines is shown in Scheme 1. It arose from an attempt to obtain the pyrano[4,3-rf]pyrimidine system by reacting aryl amidines with the 3-methoxymethylenedihydropyran-2,4-dione (1 X= CH2). As well as the desired products, diaryl-I,2,3-triazines were obtained in 30-40% yield. The use of 5-methoxymethylene-2,2-dimethyl-l,3-dioxan-4,6-dione (1 X= 0)(derived from Meldrum s acid) gives the triazines in better yield (> 50%). It was also observed that 3-methoxymethylenefuran-2,4-dione reacted with 5-methylisothiouronium bromide to yield 2,4-bismethylthio-l,3,5-triazine [95M99]. 

Pinner triazine synthesis. Preparation of 2-hydroxy-4,6-diaryl-i-triazines by reaction of aryl amidines and phosgene. 

A route that allows the synthesis of 1,3,5-triazines with different substituents at each carbon is exemplified below - an A -acyl-iV,iV-dimethylamidme reacts with an amidine (shown) or guanidine to form a... 

Symmetrical six-membered triazine rings can be synthesized from C-N units which are parts of nitrile groups, imidoyl halides, ureas, imido esters, amidines and guanidines. These reactants may be generated during the synthesis. 

Amidines themselves also cyclize with carboxylic acid anhydrides or esters to give the corresponding 1,3,5-triazines 322 323 the reactions have a mechanism similar to the Pinner synthesis. 

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... 

A -Acylchloroformimidamides 7 are suitable building blocks for the synthesis of 1,3,5-tri-azines,411 414 reacting with amidines under mild conditions to provide several monoamino-1,3.5-triazines 8. The reaction presumably proceeds via an initial nucleophilic substitution of the chlorine atom, followed by a ring-closure reaction with the carbonyl carbon of the TV-acyl group 411... 

In a related conversion the synthesis of substituted diphenyl-1,3,5-triazines can be achieved in 47-64% by reaction of amidines or guanidines with 2-aza-l-(methylsulfanyl)-l,3-diphenyl-buta-l,3-diene-4,4-dicarbonitrile in the presence of sodium hydride.477... 

Mono- and bis(2-hydroxyphenyl)-l,3,5-triazines 23 can be prepared by the reaction of 477-1,3-benzoxazin-4-oncs 22 with amidines. The first examples of this synthesis were described in 1911428-429 as an extension to Pinner s condensation of ethyl salicylate with two equivalents of benzimidamide.430... 

With /V-acylthioamides the reaction proceeds very slowly and the products are difficult to purify. Therefore, the Af-acylthioamides 32 are first converted into the S -alkyl derivatives 33 by the reaction with alkyl halides under strongly basic conditions. The resulting A -acylthioimi-dates 33 react with amidines and guanidines in alcoholic solution in the presence of sodium alkoxide to form 2,4,6-trisubstituted 1,3,5-triazines 34 in moderate to good yields.438,439 This procedure is an extension of the synthesis of trisubstituted 1,3,5-triazines from A -acylimidates 17 and amidines (vide supra).325... 

A new synthesis of 6-arylamino-2-heteroarylimino-l,2-dihydro-l,3,5-triazines from 2,4-bis-(heteroarylimino)-l,3-diazetidines and amidines has been developed by Molina et al. The formation of the triazines was explained as an initial addition of the imino nitrogen of the amidine to the exocyclic C=N bond, followed by formation of an open chain intermediate. This intermediate cyclized, followed by elimination of 4-amino-6-methyl-3-methylthio-l,2,4-triazin-5(47/)-one to give the triazine product (Scheme 62) <87S150>. 1,3,5-Triazines (207) and (208) have been prepared from 2-acylimino-l,3-thiazetidines (204) by treatment with iso thioureas or guanidines respectively (Scheme 63) <91JHC177>. 

The generality of the synthesis of 1,3,5-triazines from 7V-cyano-amidines and amide chlorides that was reported last year has been further developed this route allows the preparation of s-triazines with a wide variety of substi-... 

Thallium complexes amidines, 205 phthalocyanines, 863 porphyrins, 821 triazines, 205 Thallium(I) complexes hexafluoroacetylacetone, 372 Thallium III) complexes carboxylic acids reactions, 443 1,3-diketones synthesis, 377... 

The synthesis of diaryl-1,3i5-triazines 10, a new class of potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been reported. The requisite amidines 8 were readily prepared from the corresponding phenylacelonitrilcs, while the isourea partners 9 were obtained in modest yields by the reaction of diphenyl cyanocarbonimidate with the appropriate aniline <01BMCL2229>. 

The formation of a pyrimidine ring via an inverse-electron-demand Diels-Alder reaction turned out to be the key step in the total synthesis of (—)-pyrimidoblamic acid (40) reported by Duerfeldt and Boger in 2014 (Scheme 27) (14JA2119). Pyrimidine 41 was prepared via reaction of 1,2,3-triazine 42 (2.0 equivalents) with amidine 43 (1.0 equivalent) in anhydrous acetonitrile.The reaction mixture was first stirred for 14 h at 5 °C then another 6 h at 25 °C, furnishing the desired pyrimidine, 41, as a single diastereomer.With this intermediate, the authors were able to introduce the required stereochemistry for the desired product in one step. 

The [4 + 2] cycloaddilion reaction of 1,2,3-triazines 5 with functionalized amidine 6 leading to the corresponding pyrimidines was successfully used for a total synthesis of (—)-pyrimidoblamic acid 7 and P-3A 8. The powerful reaction of the pyridine core formation was central in the complex synthesis and introduced all necessary stereochemistry in a single step (14JA2119). 

---