Condensed 1,2,4-triazines, synthesis

The synthesis of the bicyclic 6-6 systems with one ring junction N atom and four extra heteroatoms available in literature during the last decade are presented in this chapter. However, for earlier reported methods for the syntheses of heterocyclics 1-14, refer to CHEC-II(1996) <1996CHEC-II(8)733>. The triazine unit is the most frequently used building block for the syntheses of different condensed triazine heterocycles. The various methods for their syntheses from different triazine precursors have been elaborated below. 

The mainstay of 1,2,4-triazine synthesis is the double condensation of a 1,2-dicarbonyl unit with an amidrazone, an approach pioneered by Neunhoffer (see 96CHEC(6)507 and references therein) and continually exploited since. Recently, Hudson et al. (06NJC1171) have applied this methodology to the preparation of new bis(triazinyl)p3uidines 3 for the extraction of americium(III) (Scheme 1). More recently, Yu et al. (07JOM... 

A large number of 1,2,4-triazines that are condensed with one or more heterocycles are well known and a wide variety of synthetic methods for their preparations are available. Compounds containing the 1,2,4-triazine moiety are in use as pharmaceuticals, dyes, pesticides, herbicides, etc., and a great number of reports have been directed to the synthesis of the title heterocycles having potentially useful biological properties. 

Acenaphtheno[l,2-e][l,2,4]triazolo[4,3-h][l,2,4]triazine 747 was prepared (79AP147) by cyclizing 3-hydrazinoacenaphtheno[l,2-e][l,2,4]tria-zine 746 with formic acid. Reaction of 746 with sugars gave the hydrazones, which cyclized with iron(III) chloride to give 748 (93BCJ00). Similarly, the acetaldehyde derivative of 746 was cyclized to 748. The structure of 748 (R = Me) rather than 747 (R = Me) was deduced by unequivocal synthesis of the latter by condensation of acenaphthenequinone with 3,4-diamino[l,2,4]triazole (Scheme 155). 

The synthesis of RDX via the Triazine Process (Ref 13) involves the condensation of formaldehyde with acetonitrile followed by nitration ... 

Thyagarajan and Majumdar (Ref 18) have studied the condensations of urethanes with formaldehyde under various exptl conditions and accomplished the selective synthesis of either six-membered 1,3,5-triazines or eight-membered 1,3,5,7-tetrazocines. These are nonnitrated analogs of RDX and HMX respectively. Their results are summarized in Fig 4... 

The synthesis of the novel condensed ring system4,5-dihydro[l,2,3]triazolol5,l-/ [l,2,4] triazine 69 has been achieved by the method shown in Scheme 11 <%JHC599>. 

Several 3-mercapto-l,2,4-trizines have been synthesized through the condensation of thiosemicarbazide with diketones under microwave irradiation in a solventless system <06PS87>. The synthesis and cyclocondensation reactions of 3-substituted-5-(2-aminobenzyl)-l//-[l,2,4]triazin-6-ones have been reported <06JHC613>. 

Dagley and co-workers reported the synthesis of 2-nitrimino-5-nitrohexahydro-1,3,5-triazine (100) from the Mannich condensation of nitroguanidine (98), formaldehyde and t-butylamine, followed by nitrolysis of the t-butyl group of the resulting product, 2-nitrimino-5-fert-butylhexahydro-l,3,5-triazine (99). The triazine (100) has also been synthesized from the reaction of nitroguanidine and hexamine in aqueous hydrochloric acid, followed by nitration of the resulting product (97) with a solution of nitric acid in acetic anhydride. ... 

Only a limited number of derivatives of this ring system have been reported in literature. The only efficient synthesis utilized azoaroyl-1,2,4-triazines. Thus, condensation of 138 with hydrazines afforded the hydra-zones (139), which give 140 on reflux in acetic acid [85MI2,85PHA(39)504] (Scheme 20). It has been reported that derivatives of 74 were synthesized by cyclization of pyrazoline-4,5-dion-4-isothiosemicarbazones and 4-amidinohydrazones in phenol at 180-200°C (88JPR57). 

There are relatively few methods available for the preparation of condensed 1,2,3-triazines. By far the most commonly employed procedure is diazotization of a suitably ortho-substituted aniline (4) or amino-substituted heterocycle of the type 5, and examination of the different X substituents which have been used successfully in this synthesis reveals... 

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... 

Most ring synthesis methods focus on formation of the five-membered pyrazole through cyclizations involving condensation of hydrazine with carbonyl moieties attached to the [l,2,4]triazine <1996CHEC-II(7)489>. A typical synthesis of the pyrazole ring to give various pyrazolo[4,3-< ][l,2,4]triazines 84 was reported by Rykowski eta/, using a... 

Pyrazolo[4,3- ][l,3,4]oxadiazine 78, whose preparation is given in Section 10.13.9.1.2(iv), was condensed with various amines to give pyrazolo[3,4- ][l,2,4]triazines 101 (Scheme 78 Table 9) <2002IJB664>. This ring system was earlier reported by synthesis of the fused six-membered ring, through condensation onto pyrazolediones <1996CHEC-II(7)489>. 

Bis-substitution of stilbene produces stronger fluorescence and the bis-triazine derivatives of diaminostilbenes have proved to be the most successful brighteners for cellulosics, in particular, and polyamides (60MI11200). The variety of substitution permutations in (90) is almost endless and many primary and secondary homocyclic and heterocyclic amines, thiols and phenols have been used. Synthesis of such compounds is straightforward and utilizes the convenient selectivity to substitution of cyanuric chloride. 4,4 -Diaminostilbene-2,2 -disulfonic acid condenses readily at 0-5 °C with cyanuric chloride, under slightly acidic conditions. In this case cyanuric chloride behaves as a monofunctional acid chloride and, although some by-products are unavoidable, two molecules of cyanuric chloride condense... 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

The reaction of 1,2-dicarbonyl compounds (452) with amidrazones (453) is the best method for the synthesis of alkyl, aryl or hetaryl substituted 1,2,4-triazines (78HC(33)189, p. 195). No limitation of this synthetic principle is reported, except that it is, of course, preferable for the dione (452) to be symmetrical. The best reaction procedure is to add the dicarbonyl compound to a solution of the free amidrazone, or amidrazonium salt in the presence of one mole of base, and allow a reaction time of about 12 h. Since the first step of this reaction, i.e. condensation of the hydrazono group with one carbonyl group, is fast, while the second, i.e. condensation of the amide group with the other carbonyl, is slow, the intermediate (454) has been isolated in a few cases. This method has been used also for the synthesis of compounds containing more than one 1,2,4-triazine nucleus, and for the parent 1,2,4-triazine (1) (68CB3952). 

The reaction of 1,2-dicarbonyl compounds with amidrazones, semicarbazide, thiosemicarbazide and aminoguanidine has also been used for the synthesis of condensed 1,2,4-triazines. Cyclohexane-, cycloheptane- and cyclooctane-1,2-diones (489) with amidrazones (453) afford the cycloalkatriazines (490) (78HC(33)189, p.66l). 

N -Cyanocarbamimides (112) may be condensed with chloromethyleniminium salts in a similar way (equation 58). Yields are good to excellent, and reaction conditions are mild (Table 12) (81S907). The synthesis provides an easy route to 4-aIkoxy-2-chloro-l,3,5-triazines (113) and the-corresponding mercapto derivatives. 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

Condensed thiophene systems, tetra- and pentacyclic, 32, 127 Condensed 1,2,4-triazines I. Fused to heterocycles with three-, four-, and five-membered rings, 59, 39 Condensed l,2,4-triazolo[3,4-z] heterocycles, synthesis, 49, 277... 

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