L,2,3-Benzotriazin-4

Oxopentanoic acid, see Cyclohexene, Cyclopentene 3,3 -Oxybis(methylene)bis(l,2,3-benzotriazin-4(3/D-on... 

There are two general ring syntheses available for the preparation of 3-substituted l,2,3-benzotriazin-4(3//)-ones, namely, (i) diazotization of anthranilamide and its derivatives and (ii) cyclization of 1-alkyl- or 1-aryl-3-(o-carbalkoxy)triazenes, and both reactions have been studied in considerable detail. 3-Substituted l,2,3-benzotriazin-4(3//)-ones have also been obtained by alkylation and acylation of l,2,3-benzotriazin-4-one these last reactions are discussed separately (see Section II, C, 3). 

Diazotization of anthranilamide and its derivatives is the most common and widely exploited reaction for the preparation of 1,2,3-benzo-triazine derivatives. The reasons for this are 3-fold (i) many nuclear substituted anthranilic acid derivatives are readily available (ii) the diazotization reactions generally proceed smoothly and in high yield, and the product triazinones are usually very stable and easily handled and (iii) many 3-substituted l,2,3-benzotriazin-4(3i/)-ones have been found to possess a wide range of pronounced pharmacological activity, while others undergo a number of very interesting chemical transformations, and hence a very large number of these compounds have been prepared. 

Diazotization of anthranilamide gives l,2,3-benzotriazin-4(3fl)-one (10, R = H) in good yield. Treatment of isoatoic diamide (33) with nitrous acid also gives 10 (R = H), and a great many 3-substituted... 

Treatment of 36 with nitrous acid in dilute acetic acid gives a mixture of anthranilazide (37) and 3-amino-1,2,3-benzotriazin-4(3/f)-one (10, R = NH2). When the same reaction is carried out in dilute hydrochloric acid, the sole product formed initially with one mole equivalent of nitrous acid is 10, R = NHj, but this readily reacts further to give 10, R = Diazotization of acetophenone anthranylhydrazone followed by mild acid hydrolysis is a superior route to 10, R = NHj, and gives a much purer product. l,2,3-Benzotriazine-4(3/0-thione (39, R = H) and the 3-substituted derivatives (39) are readily available by diazotization of thioanthranilamide (38, R = H) and its derivatives. ... 

Acylhydrazides of anthranilic acid (35, R = NHCOR ) give 3-acylamino-l,2,3-benzotriazin-4(3H)-ones (10, R = NHCOR on treatment with nitrous acid. The triazine hydroxamic acid (40) and its benzo-substituted derivatives are available by diazotization of the corresponding o-aminobenzohydroxamic acids. The pyrido[2,3-e]triazine analog (41) was prepared similarly from 3-aminoisonicotino-hydroxamic acid, but the isomeric 2-aminonicotinohydroxamic acid failed to react under the same conditions to give 42. ... 

Hydrolysis of 3-alkyl-l,2,3-benzotriazin-4(3i/)-ones (10, R = alkyl) with cold, aqueous potassium hydroxide leads to anthranilic acid derivatives. The related 3-aryl-l,2,3-benzotriazin-4(3H)-ones (10, R = aryl) react less readily, but on treatment with hot aqueous or alcoholic potassium hydroxide are converted into 3-aryltriazenes (53, R = aryl) which, on further reaction, give anthranilic acids. ... 

The reactions of 3-amino-l,2,3-benzotriazin-4(3//)-one and a number of its derivatives (lOla-g) under both acidic and basic media have been investigated in some detail by Gibson and Green. Earlier work by Heller and his colleagues had apparently established that treatment of lOla-e with hot aqueous sodium hydroxide solution gave o-azido-benzoic acid (102), and Gibson and Green showed that lOlf behaved similarly. The benzylidenamino derivative 10 Ig, however, was reported by Heller to yield benzaldehyde o-carboxyphenylhydrazone (103) under basic conditions, and benzimidazolone (104) under acidic conditions. 

In contrast to the above situation with respect to oxidation of the ring nitrogen atoms of 1,2,3-triazines, oxidation of derivatives of 3-amino-l,2,3-benzotriazin-4-(3/0-one (101a) has proved to be of considerable interest and has been investigated in some detail by Rees and his colleagues. Treatment of 101a with lead tetraacetate at 80° has been shown to give benzyne in very low yield, but at room... 

It has been reported that the UV spectra of l,2,3-benzotriazin-4(3/f)-one (10, R = H), the corresponding triazinethione (39, R = H) and the 4-alkylamino-l,2,3-benzotriazines (56) formed by treatment of 39, R = H, with alkylamines are nearly identical, and this has been taken as evidence that the compounds 56 actually exist as the 3,4-dihydro-4-imino tautomers. This claim has not, however, been substantiated, and, in the absence of more definitive evidence, structure 56 is almost certainly the more accurate representation for these compounds. 

From the above discussion it is evident that alkylation of 1,2,3-benzotriazin-4-one results almost entirely in substitution at Nj and/or Nj, and that alkylation on oxygen is at most a minor reaction. Alkylation of l,2,3-benzotriazine-4(3//)-thione (39, R = H), on the other hand, leads to predominant or exclusive substitution on sulfur, presumably as a result of the greater nucleophilicity of sulfur compared to oxygen. This difference in reactivity between the oxygen (10, R = H) and sulfur (39, R = H) compounds has been elegantly demonstrated by Murray and Vaughan. Treatment of the sodium salt of 10, R = H, with phenacyl bromide gives the Nj-substituted derivative 127, which, on... 

As mentioned above, condensed 1,2,3-triazine derivatives can be arylated by treatment with nitro-activated aryl halides. The only other report of direct arylation of the 1,2,3-triazine system is due to McKillop and Kobylecki, who studied the reaction of l,2,3-benzotriazin-4-one (10, R = H) with diaryliodonium salts in the presence of base. Treatment of 10, R = H, with diphenyl- and di-p-bromophenyliodonium chloride results in exclusive arylation at N2 and gives the corresponding triazinium betaines (77, R = Ph, p-BrCjH4) in good yield. When di-p-tolyliodonium chloride is used, a mixture of the Nj-, Nj-, and 0-arylated... 

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... 

NMR spectroscopy has been little used in the 1,2,3-triazine field and, like IR spectroscopy, is useful only for confirmation of the presence of specific substituent groups. °- - Attempts to extend this technique to more demanding problems, such as the site of alkylation or arylation " of l,2,3-benzotriazin-4(3/0-one, have been unsuccessful. 

Two major fragmentation pathways have been observed in the mass spectrum of l,2,3-benzotriazin-4-one (10, R = H), and these are outlined in Scheme 1. The primary mode of cleavage (Path a) involves loss of nitrogen and formation of the y3-lactam (179), which undergoes further fragmentation as shown. Alternatively, loss of HCNO or HNj (Path b) leads to a diazonium ion or acylium radical ion which then decomposes to CjH by loss of nitrogen or carbon monoxide. The mass... 

Many simple 3-substituted l,2,3-benzotriazin-4(3fl)-ones of the type 126 have been found to possess insecticidal properties and are of considerable commercial importance. They are readily prepared (see p. 

Many other simple esters of 3-hydroxymethyl-1,2,3-benzotriazin-4(3//)-one and the thiomethyl analog have been prepared and also found to possess insecticidal properties. 3-Trichloromethylthio-l,2,3-benzotriazin-4(3//)-one (10, R = SCClj) has been shown to have nematocidal properties, as do other 3-5-alkyl ethers, while the 3-... 

Considerable interest has developed during the last ten years in the potential utility of condensed 1,2,3-triazine derivatives as medicinals, although the first indication that these compounds might be useful appears to be the report by Woolley and Shaw in 1951 that the 2-azadenine derivative (183) inhibited hypoxanthine activity in Lactobacillus brevis. l,2,3-Benzotriazin-4-one (10, R = H) is reported... 

A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3//)-ones show depressant activity, while the benzoate esters of substituted 3-(2-hydroxyethyl)-l,2,3-benzotriazin-4(3f0-one are reported to function as coronary dUating agents," as do certain other compounds of this type." 3-(o-Haloaryl)-l,2,3-benzotriazin-4(3i/> ones are claimed to have antisecretory," anoretic, anticonvulsant, and hypoglycemic activity, and a variety of other 3-aryl derivatives are stated to be relaxants, tranquilizers, sedatives, hypnotics, or cramp inhibitors. A number of derivatives of 10, R = H, in which the 3-substituent is a long alkyl chain containing a terminal sulfonamide group have been claimed to act. as antidiabetics. ... 

The highly substituted derivative 186, in the form of the potassium salt, has been recommended for use in detonators in place of the more dangerous mercury fulminate. l,2,3-Benzotriazine-4-thione (39, R — H) has been used in photographic transfer emulsions as an inhibitor and toning agent, and heavy metal salts of the oxygen analog 10, R = H are employed as photodevelopable emulsions. The latter compound is also claimed to be useful as a stabilizer in olefin polymers and as an antioxidant in certain other polymers. Dimeric derivatives of 10 have... 

A number of 2-alkyl-1,2,3-benzotriazinium salts similar to those described earlier have b n used in protective coatings and in the formulation of adhesives. 3-Alkyl-l,2,3-benzotriazin-4(3fl)-ones have been examined as potential irreversible inhibitors of chymotrypsin, and the 3-(l-adamantyl) derivative as a potential virus inhibitor. Some unspecified 1,2,3-benzotriazine derivatives have been tested as radioprotectant compounds (to complement the well-known mercap-toethylamine and mercaptoalkylisothiouronium compounds), but were found to be ineffective. ... 

Diazotization of anthraniloanthranilamide (613) gave 3-(2-carbamoyI-phenyl)-l,2,3-benzotriazine-4(3//)-one (614), which underwent base-catalyzed cyclization to the quinazolino[3,2-c]l,2,3-benzotriazin-8-one (615) (78CJC1616). 

Oxazines and thiazines are unstable with respect to ring-opened isomers (cf. 30—>31). l,2,3-Benzotriazin-4-ones on protonation undergo ring-chain tautomerism to yield diazonium ions (Scheme 8 see CHEC 2.18). 

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