From 1,2,4-Triazine Derivatives

Most of the reported triazinothiadiazines have been prepared from 1,2,4-triazine derivatives. Treatment of amino-1,2,4-triazine 28 with chloroacetyl chloride in dioxane in the presence of triethylamine at 10 °C resulted in the formation of 6-methyl-4-(A -chloroacetamido)-3-thioxo-5-oxo-2,3,4,5-tetrahydro-l,2,4-triazine 29 and 3-methyl-4,7-dioxo-4,6,7,8-tetrahydro-l,2,4-triazino[3,4-A][l,3,4]thiadiazine 15 (Scheme 1) <2005JHC935>. 

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. 

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 Mitsunobu reaction was applied to the synthesis of pyrrolo[l,2-d [, 2,4]triazines from pyrrole derivative 71. Thus reduction of 71 gave alcohol 72, which on treatment with diethylazodicarboxylate and triphenyl phosphine gave 74 via the open chain intermediate 73. Hydrolysis of 74 gave 75 (84AG517) (Scheme 18). 

Amination of triazine derivative 412, obtained from 411, with propar-gylamine gave 413, which was cyclized to give (89CZ252) imidazotriazine 414 (Scheme 90). 

Pyrimido[5, 4 4,5]pyrazolo[3,2-c][l,2,4]triazine derivatives 1049and 1050 were prepared by treatment of diazo compound 1048, prepared from 1047, with pentane-2,4-dione and ethyl acetoacetate, respectively [92JCS(Pl)239]. 

The former was demonstrated by converting the triazinylidene(ethylidene)oxazolone 137 in xylene or in formic acid to the pyrido[l,2- /][l,2,4]triazine derivative 138. The same ring system was also obtained starting from N-acetylated analogs of 137 with heating in formic acid via deacetylation by the acid followed by cyclization (Equation 19) <1995JHC425>. 

Pyrazolo[4,3-e][l,2,4]triazine derivatives have been prepared from oximes of 5-aryl- and 5-formyl-l,2,4-triazines <06MI191 >. Novel pyrazolo[5,1 -c][ 1,2,4]triazines incorporating an Af-(2-oxoethyl)phthalimide moiety have been reported <06JCR(S)6>. 

Thiadiazolines are less stable compared to 1,2,4-thiadiazoles and this can be attributed to the loss of aromatic character. They are readily cleaved at the N-S bond under fairly mild conditions (H2S in pyridine) in some cases, the product from ring cleavage can recyclize to give new heterocyclic ring systems. The 3-imino-l,2,3-thiadiazoline 24 when reduced with H2S affords the two J-triazine derivatives 25 and 26 (Scheme 3) <1996CHEC-II(4)307>. 

A novel type of heterocyclisation reaction involving the dipolar cycloaddition of jV,A-dialkylamino substituted thioisomunchnones and azodicarboxylates giving 1,2,4-triazine derivatives has been reported. The cycloadduct 26 is initially formed from the isomunchnone 24 and the azodicarboxylate 25, it then undergoes a selective fragmentation to give the 1,2,4-triazine 27 <99TL8675>. 

The synthesis of pyrazolo[4,3-rf]-l,2,3-triazine starting from a pyrazolo-3-carbaldehyde derivative has been reported <00JIC168>. Azolo-l,2,4-triazine derivatives have been prepared via the reaction of functionalized thiazole derivatives with several heterocyclic diazonium salts <00JCR(S)206>. The reaction of 1,2,4-triazolium salt 67 with alkene 68 gives the pyrrolo[2,l-/][l,2,4]triazine 69 <00H(53)213>. 

Highly substituted pyrrolo[l,2- ][l,2,4]triazines were synthesized from pyrrole derivatives, by closure of the triazine ring. Thus, hydrolytic cleavage of some 1,2-diaminopyrroles having a 1-NH-BOC-protected amino function 43 followed by reaction with 1,2-dicarbonyl compounds afforded a one-pot access to the corresponding bicyclic heterocycles 44 (BOC = f-butoxycarbonyl Equation 6) < 1997J(P 1)1829>. 

In the reactions with phosphonio-a-methoxycarbonyl-alkanides, the products of type 261 derived from 1,3-cycloaddition can rearrange to the tautomeric lif-pyrazolo-triazole (87MI2). The reaction of 3-diazopyra-zoles and 3-diazoindazole with acyl-substituted phosphonium ylides led to pyrazolo-triazine and indazolo-triazine derivatives 266 instead of the expected triazole compounds (8IJHC675). In this case, the ylides, which can exist as phosphonium enolates, possess nucleophilic and electrophilic centers in a /8-relationship, giving [7 + 2] or [11 -I- 2]cycloaddition reactions. With dimethylsulfonio-a-aroyl-methanides, very complex, temperature-dependent mixtures were obtained, in some cases with sulfur retention (87MI3). 

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. 

Interest in the thermal and photochemical reactions of condensed 1,2,3-triazine derivatives dates from 1962, when first Gibson and then Hey, Rees, and Todd reported independently on the reactions of 3-phenyl-l,2,3-benzotriazin-4(3H)-one (10, R = Ph) at elevated... 

Pyrimidotl, 4]triazine derivatives 84 and 85 have been synthesized from 2-thio-4-phenyl-6-pyrimidinone and their antibacterial and antifungal activities tested <99ZN(B)788>. 

A convenient approach to the synthesis of 2-aryl-4-alkyl-13 -triazino[l,2-ajbenzimidazoles 113 from 2-aminobenzimidazole has been reported <98IJC(B)1283>. New 8-cyanopyridothieno[l,23]triazines 114 as inhibitors of nitric oxide and eicosanoid biosynthesis have been described <99JMC4720>. Synthesis of pyridodithienotriazines 115, from dithienopyrimidine derivatives, and their antihistaminic and cytotoxic activities have been reported <98EJM887>. 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

Synthesis of 1,3,5-triazine derivatives from the reaction of ammonia with aldehydes 508... 

Cyanuric chloride is the most important of these compounds. The uses of chloro-1,3,5-triazines derived from cyanuric chloride will be discussed within the same section. The uses of tris-iV- chloroisocyanuric acid were mentioned in Section 2.20.6.4. 

Electrocyclization of the nitrilimine intermediate 179 (87JHC1341) generated in situ from 5e gave the pyrazolo[5,l-d]-1,2,4-triazole derivative 180. In another report [78ZN(B)216] this same nitrilimine 179, claimed to be generated by the action of concentrated sulfuric acid on 181, yielded the pyrazolo[5, l-cj-as-triazine derivative 182 instead of the expected pyra-zolo[5,1-t/]triazole 180 (87JHC1341). The structure of the product 182 seems to need further investigation. 

But let us return to the problem of selecting, out of the myriads of possible 2,4,6-s-triazine derivates, those which have herbicidal activity and from these, those which would be useful under practical conditions. Starting from the structure of G-25804 we initiated variation along four main lines in order to explore the consequences with regard to the biological characteristics. 

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