Cycloaddition reactions of 1,2,4-triazines

A few cases of [4 + 2] cycloaddition reactions of 1,2,4-triazines with C=N double bonds have been reported. Reaction of 1,2,4-triazines (441) with benzamidine (442) in boiling toluene led to the isolation of the 1,3,5-triazines (443). It may be supposed that here the dienophile adds to the 2- and 5-positions of the 1,2,4-triazine, as in the reaction with ynamines, then a nitrile (R6CN) is eliminated and aromatization follows by loss of ammonia. In one case, the initially formed 1,3,5-triazine (443) reacted with a second molecule of benzamidine by [4 + 2] cycloaddition and elimination of R3CN and ammonia, resulting finally in triphenyl-1,3,5-triazine (444). This is a known reaction in the 1,3,5-triazine series (see Chapter 2.20) (81TL1393). 

Over the last twenty years, the cycloaddition reactions of 1,2,4-triazines have been studied intensively. 1,2,4-Triazincs arc clcctron-dcficicnt systems and readily undergo Diels-Alder reactions with inverse electron demand with electron-rich dienophiles, such as enamines and ynamines, or with systems containing strained double bonds. Inter- and intramolecular cycloaddition reactions have been observed, giving pyridines and pyrimidines or condensed pyridines and pyrimidines. 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

Cycloaddition reactions have been reported only for nonaromatic 1,2,4-triazines.422-426 For [3 + 2]-cycloaddition reactions of 1,2,4-triazine 4-oxides,145 see p 630. 

Intramolecular cycloaddition reactions of 1,2,4-triazines with the C=C double bond of pyrrole <93JOC5l6> or indole <92JOC5285> have also been observed. 

Figure 3 Ring systems from cycloaddition reactions of 1,2,4-triazines.

For preliminary studies on the scope of the [4 + 2] cycloaddition reactions of 1,2,4-triazines with electron-rich dienophiles including enol ethers, enamines, ketene acetals, ynamines and strained or reactive olefins, see Dittmar, W., Sauer, J., and Steigel, A. (1969). Tetrahedron Lett., 5171 Reim, H., Steigel, A., and Sauer, J. (1975). Tetrahedron Lett., 2901. 

The cycloaddition reaction of 1,2,4-triazines N-oxides proceeds differently from the reaction of the corresponding 1,2,4-triazines. Thus the 1,2,4-triazine 4-oxide 55 acts only as a diene in the reaction with 1 -diethylaminopropyne to afford 2-methyl-4-(dimethylamino)pyrimidines 111. At the same time the 1,2,4-triazine 4-oxides 55 react with l-(dimethylamino)-l-ethoxyethylene by 1,3-dipolar cycloaddition to give 5-methyl-1,2,4-triazines 112 (78CB240). 

The reaction of 1,2,4-triazines with ketene derivatives such as the 0,0-acetals (42la), 0,iV-acetals (421b), Af,Af-aminals (421c) and (V.S-aminals (421d) has been studied extensively. In all cases pyridines (422) were isolated (Scheme 14). These reactions follow the usual cycloaddition route. Again it is found that the orientation is dominated by secondary... 

In addition to intermolecular cycloaddition reactions of 1,2,4,5-tetrazines with various dienophiles, intramolecular cycloaddition reactions with alkene367 and acetylene 360 367 dienophiles or nitrile groups355-356 have also been reported. By this method condensed pyrid-azines 15 or 1,2,4-triazines 16 (see Section B.2.2.1.3.) are obtained. In most cases the side chain is bound to the 1,2,4,5-tetrazine ring by a heteroatom (O, S or In ). In a few cases the side chain is bound by a carbon atom or contains an additional heteroatom. The general reaction scheme is shown. 

The most extensively studied reaction of 1,2,4-triazines is the Diels-Alder reaction with inverse electron demand, in which the triazines behave as reactive electron-deficient dienes. Electron-rich alkenes and acetylenes have been most often used as dienophiles but alkenes with strained double bonds and nitriles can also react. Besides intermolecular Diels-Alder reactions, which were discussed in detail in CHEC-I, intramolecular cycloadditions have been studied widely and used in the synthesis of condensed heterocyclic systems. A review on intermolecular Diels-Alder reactions was published by Roger and Weinreb in 1987 , Sauer published an account of his studies in 1992 <92BSB52l>, and a summary by Taylor of his own work on intramolecular Diels-Alder reactions was published in 1988 <88BSB599>. 

Reactions of electron-r/cA acetylenes with heteroaromatic compounds are rare. Such (2 + 2>cycloadditions have been proposed as the first step in the boron-trifluoride-catalyzed reaction of isoquinoline with l-dimethylamino-2-phenylacetyleneM and in the reaction of 1,2,4-triazines with 1-diethylamino-l-propyne, 1 but no experimental... 

Cascade reactions of substituted 1,2,4-triazines are of great interest as simple ways to a dramatic increase in molecular complexity, from planar 1,2,4-triazine unit into a polycyclic system. Indeed, in this multistep process, the diallylamine and cyclopentanone react first in situ to give the corresponding enamine, which undergoes an inverse electron demand cycloaddition reaction with 1,2,4-triazine to give an intermediate dihydropyridine compound. A spontaneous intramolecular Diels-Alder reaction between the allyl moiety and the dihydropyridine gives the tetracyclic compound (Scheme 99) <2004JA12260>. 

Another well-studied cycloaddition of 1,2,4-triazines is the reaction with ynamines (423). In this the dienophile often attacks the 1,2,4-triazines across the 2- and 5- rather than the 3- and 6-positions. This can perhaps be due to the transition state of the cycloaddition with ynamines being more polar than that in the cycloaddition with alkenes, and a partial negative charge in the 1,2,4-triazine ring is better stabilized at a nitrogen (N-2) than at a carbon (C-6). The products isolated from these reactions are pyrimidines (424). It was shown by using lsN-labelled 3-methyl-l,2,4-triazine that the reaction is in fact a [4 + 2] cycloaddition to N-2 and C-5 and not a [2 + 2] cycloaddition to the N(4)—C(5) bond (72LA(758)125). 

In 1969 the reaction of 1,2,4,5-tetrazines (39) with imidates (198) was reported. The formation of the 1,2,4-triazine products (199) is explained by a [4 + 2] cycloaddition of the tetrazine with the C=N double bond of the imidate to give the bicyclic intermediate (200) which eliminates nitrogen and alcohol (69JHC497). Further studies on this reaction seem to... 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

In addition, the efficiency of inverse electron demand Diels-Alder reactions with 1,2,4-triazines has been improved to include microwave-activated procedures <07T8286>. The approach allows access to higher reaction temperatures, which results in shorter reaction times. Several highly substituted dihydrofuro- and dihydro-2//-pyranopyridines 25 are produced from alkylnol-substituted triazines 26 in excellent yields via a one-pot cycloaddition/ aromatization protocol. 

Imidazole and 2-phenylimidazole undergo intramolecular Diels-Alder reaction with 1,2,4-triazines tethered between an imidazole nitrogen and the triazinyl C-3 position to produce tetrahydro-l,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of N2, followed by a presumed stepwise loss of a nitrile. Addition of antioxidant BHT inhibits aromatization to greatly improve the yield of tetrahydronaphthyridine 504 (Scheme 115) <2004JOC7171, 1997TL7499>. 

---