1.3.5- Triazine derivatives, pyrimidine base

All these findings, as well as the similarity of UV spectra - caused dioxotetrahydrotriazine to be classified as the simplest member of the formerly known 6-substituted derivatives. These derivatives are not interesting in connection with the analogs of natural pyrimidine bases and have been reviewed elsewhere. The structure of allantoxaidine and its appurtenance to the triazine series have been recently demonstrated by its unequivocal synthesis. 

The chemistry of the 6-aza analogs of pyrimidine bases which has been developed from the biochemical aspect since about 1956 was based on work reported in relatively numerous older papers. In spite of the fact that 6-azauracil was prepared only in 1947 and suitable syntheses were described only quite recently, substances of this type and methods of their preparation had been known for a long time. The chemistry of 6-aza analogs of pyrimidine bases is therefore relatively closely linked with the chemistry of the 1,2,4-triazine derivatives. 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

The catalytic effect of protons, of bifunctional catalysts, and of base is demonstrated in the amination of chloro derivatives of pyridazine, pyrimidine, and s-triazine (Tables V and VI). Anilino-s-triazines containing NH groups act as catalysts in their own formation. The catalytic action of protons on anhino-dechlorination of 2-chloro-4,6-diamino-s-triazine and of 2-amino-4-chloropyrimidine was reported in the classic paper by Banks. ... 

The above reactions are relatively straightforward in terms of mechanism. There are, however, a number of important transformations based on 1,3,5-triazine as starting material, and which result in formation of either pyridine or pyrimidine derivatives. 1,3,5-Triazine reacts very readily with nucleophiles, probably as outlined in equation (197) if X in (31) is a suitable electrophile, cyclization can take place. Thus, when X = CN, 4-amino-5-cyanopyrimidine is obtained, and other illustrative examples are shown in equation (198). This procedure is particularly useful for the preparation of 2-unsubstituted pyrimidines, a class of compound which is not readily accessible by other types of ring formation. The reverse type of transformation, i.e. of pyrimidines to 1,3,5-triazines, is also an important synthetic method, and one which has been studied in detail. Two types of substituted... 

In contrast, some substituted anilines, e.g. 2-nitroaniline,143 2-chIoro-4-(trifluoromethyI)ani-Iine,143 benzene-1,3-diamine,150 or 4-chlorobenzene-1,3-diamine,150 give only very low yields of product or formed tars under the fluorination conditions. The diazotization followed by in situ fluorodediazoniation of the corresponding diazonium salts have been systematically studied in hydrogen fluoridc/base solutions of different composition to ascertain the most important influences on the reaction.329 Besides numerous examples of substituted anilines, various derivatives of pyridine, pyrimidine, 1.3,5-triazine, and benzthiazole have been included in these investigations (yields 45—99%). 

A number of 1,2,4-triazines are of interest owing to their biological activity. 1,2,4-Triazine-3,5-diones (6) represent aza analogues of pyrimidine nucleic acid bases, a number of natural antibiotics are derivatives of pyrimido[5,4-e][l,2,4]triazine (7), and 4-amino-6-r-butyl-3-methylthio-l,2,4-triazin-5-one (8) and 4-amino-3-methyl-6-phenyl-l,2,4-triazin-5-one (9) are used as herbicides. 

Reactions of 1,3,5-triazine (1) with amidines, amidine salts or nitriles which have acidic a-methylcne groups are of great preparative value. The base-catalyzed reactions produce 5-substituted pyrimidin-4-amines 3 (R3 = NH2) in good yield. The corresponding imidate or thioamidate hydrochlorides yield 4-alkoxy- and 4-(alkylsulfanyl)pyrimidines, respectively.24 Some other malonic acid derivatives react in a similar manner as shown below. In these cases, a sodium alkoxide is needed as condensing agent.18,25... 

The most common method for the preparation of thioureas is, however, based on the reaction of isothiocyanates with amines, and, not unexpectedly, the majority of papers deal with this particular reaction. 6-2 1 Among the N-substituent groups thus introduced into thiourea are 3-cyclo-pentenyl, 1-adamantyl, furfuryl, diphenylphosphinoyl, diphenyl-phosphinothioyl, AW-9,10-diacetyldihydro-2-phena2inyl, and variously substituted aryls. - If the isothiocyanate or the amine contains other reactive groups, cyclization to heterocyclic compounds containing the thiourea grouping may occur, either spontaneously or promoted by external influence, as recently demonstrated in the synthesis of thiones derived from imidazoline, pyrimidine, - and j-triazine. - ... 

There have been many reports of syntheses of deoxy nucleosides by standard sugar-base condensation reactions. These include 5 -deoxy-ribo nucleosides and 5 -mono- or 5",5-di-deuterated analogues, as well as derivatives of 5-deoxy-D-xylose and 5-deoxy-D-glucose, 5-alkylated thymidine derivatives, 2 -deoxy-6-methyl-5-azacytidine and its a-anomer, the thymidine analogue 4-(2-deoxy-B-D-erythro-pento-furanosyl)-6-methyl-l,2,4-triazine 3(HH)-one-1-oxide, 6-aza-3-deaza analogues of 2 -deoxy-cytidine and 2 -deoxyuridine,3 -deoxycytidine from a 3-deoxy-ribofuranose obtained from a fermentation broth producing the 3 -deoxy nucleoside antibiotic, cordycepin, 4-deoxy-DL-threo-pentopyranosyl pyrimidine nucleosides, and 5 -C-methyluridines derived from 6-deoxy-D-allose and 6-deoxy-D-talose. A range... 

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