Nucleophilic substitutions 1,3,5-triazines formation

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

A recent communication is based on the nucleophilic substitution of N-silylated iminophosphoranes (Scheme 8), where activated chloro- (12) and nitro heterocycles (13) (triazines, pyrazines, and pyridines) are transformed into monosubstituted iminophosphoranes (14). Of special advantage are the mild reaction conditions and the preferential formation of monosubstituted... 

A special hetero substituent is the cyano group, which is readily substituted by other nucleophiles, e.g. formation of 3, especially in the 5-position of 1,2,4-triazines.186,289,43 5 For 1,2,4-triazine-3- and -6-carbonitriles in addition to substitution, addition of a nucleophile to the cyano group has also been reported.289... 

Aryl cyanates and other stabilized cyanates can be acylated with various acyl halides to yield /V-acylchloroformimidatcs 15416 (cf. Houben-Weyl, Vol. E4, p 546). These compounds, which are surprisingly stable, easily react with amidincs to form 1,3,5-triazines 16.417 This reaction is believed to proceed via a nucleophilic substitution of the halide atom, followed by cyclization to the carbonyl carbon of the acyl group.417. In the case of phosgene (R2 = Cl), addition of amidines to the activated cyanates is not selective417,418 for formation of the 1,3,5-triazines. 

Another special feature connected with the 1,3,5-triazine moiety is spontaneous formation of a long-lived glassy state, by bisarylamino-1,3,5-triazines. A wide series of differently substituted derivatives 49 was synthesized by nucleophilic substitution of chlorine atoms in cyanuric chloride 20 with methylamine in the first step and then two equivalents of substituted aniline in the second step (13NJC3881). 

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... 

The stabilities of pyridine-2- and -4-diazonium ions resemble those of aliphatic rather than benzenoid diazonium cations. Benzenediazonium ions are stabilized by mesomerism which involves electron donation from the ring, but such electron donation is unfavorable in 2- and 4-substituted pyridines. On formation, pyridine diazonium cations normally immediately react with the aqueous solvent to form pyridones. However, by carrying out the diazotization in concentrated HC1 or HBr, useful yields of chloro- and bromopyridines 752 can be obtained. Iodinated pyridines can be obtained in good yield using the Sandmeyer reaction. Aminopyridazines and -pyrazines, 2- and 4-aminopyrimidines, and amino-1,2,4-triazines behave similarly. Nucleophilic fluorination via the BalzSchiemann reaction of diazonium fluoroborates yields fluoropyridines, including 2-fluoropyridines. Fluoroborates can also be converted into fluoro compounds by ultraviolet irradiation. 

Formation of imidazo[4,5-e]-1,2,4-triazines 119 has been observed to occur when 6-ethylamino-5-methylamino-1,2,4-triazines 118 react with benzamidine. However, in this case only the methylamino group at C-5 is substituted by the amidine, while the ethylamino group at C-6 participates itself as a nucleophile in an intramolecular cyclization reaction (Scheme 68) (78CPB3154). 

Interesting results were obtained by reaction of substituted 1,2-dihydro-1,3,5-triazines with esters of acetylenedicarboxylic acid (DMAD) and of propiolic acid.254 In the case of the reaction with DMAD, formation of the different products 175 and 176 has been reported,254 presumably due to differences in the nucleophilicity of the secondary nitrogen atom of the triazines. 

The susceptibility of 1,3,5-triazine to nucleophilic attack with ring opening makes it a synthetically useful equivalent of formate, or formamide, particularly for the synthesis of other heterocycles, such as imidazoles and triazoles (see above). Despite the high susceptibility of 1,2,4-triazines to nucleophilic addition, 3-substituted-6-methoxy-l,2,4-triazines can be successfully lithiated. ... 

It is worth noting that 2,4,6-trifluoro-l,3,5-triazine 55 is less active than cyanuric chloride in the reaction of with aniline (Scheme 49) [84]. N,N-Dimethylaniline and l,8-bis(dimethylamino)naphthalene react with cyanuric fluoride 55 as C-nucleophiles to give 2,4-difluoro-6-(4-dimethylaminophenyl)-l,3,5-triazine 119 and l,8-bis(dimethylamino)-4,5-(2,4-difluoro-l,3,5-triazinyl-6)naphthalene 123 (Scheme 49) [8], Contrary to it, N,N-diethylaniline, and ortho- or para-substituted N,N-dimethylanilines react with trifluoro-l,3,5-triazine 55 as N-nucleophiles. These reactions are accompanied by elimination of N-alkyl group and the formation of 2,4-difluoro-6-arylamino-l,3,5-triazines 120-122 (Scheme 49). 

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