1.2.4- Triazines, reaction with enamines

Pyridine unnelatum. 1,2,4-Triazine can function as a reactive azadicnc in Diels-Aider reactions with enamines, particularly pyrrolidine enamines, to form substituted pyridines. 

Inverse electron demand Diels-Alder/retro-Diels-Alder-type reactions, of di- and especially poly-azines with electron-rich dienophiles, interconvert six-membered rings. 1,2,4-Triazines react with enamines and enol ethers to give pyridines (Scheme 76) (CHEC-n(5)242). 

Triazines on reaction with enamines followed by loss of a nitrogen from the intermediates give pyridine derivatives (85H2789) (Scheme 56). The reaction of 1,3,5-triazine with enamine and enaminoester hydrochlorides in acetonitrile leads to mixtures containing pyrimidines and pyridines... 

Treatment of 1,2,3-triazines 1 with enamines afforded pyridines 2. This reaction has been used for the synthesis of a number of alkaloids.103,286-290 The influence of solvent and temperature on the orientation of the two reactants has been studied.286... 

In addition to 1,2,4-triazines condensed with carbocycles, 1,2,4-triazines condensed with heterocycles can also be used as dienes with inverse electron demand in Diels-Alder reactions. Thus, it has been shown that pyrimido[4,5-e]-1,2,4-triazines react with enamines to yield pyrido[2,3-tflpyrimidines 29 (5-deazapteridines).415... 

These cycloadditions are not limited to the monocyclic triazines. Taylor has shown that also pyrimido[4,5-e]-l,2,4-triazines react with enamines in a Diels-Alder reaction with inverse electron demand, leading to pyrido[2,3-c ]pyrimidines (5-deazapteridines) <87TL1977>. 

Triazine is very useful in aminomethylenation reactions for the preparation of Mannich bases and numerous heterocycles. For example, 4-aminopyridines are obtained on reaction with enamines (see Section 6.12.5.1.4). Hexahydrotriazines are also useful aminomethylenating reagents (see Section 6.12.6.6). 

In an approach to the AB rings of rubrolone 65, Boger examined the use of oxazinones as a replacement for triazines. Reaction of l,3-oxazin-6-one 66 with enamines 67 produced the corresponding pyridines 70. The reaction proceeds in a manner analogous to the triazines however, instead of losing nitrogen, these systems lose CO2 via the intermediate bicyclo[2.2.2]octanes 68. The resultant 69 then loses pyrrolidine as in the triazine example. 

The key step of an interesting synthesis of Sempervirine (327) is a triazine Diels-Alder annulation reaction with an enamine (88T3195). 1-... 

Similar reactivity and regioselectivity is observed with the parent system, 1,2,4-triazine (eq 2) Reduction of this process to a catalytic Diels-Alder reaction with in situ generation of the pyrrolidine enamine does... 

We illustrate this by two examples. Reaction of the 6-phenyl-1,2,4-triazine (407) with the enamine (406) follows orientation A since secondary orbital interactions between the n-electrons of the amino group and the 77-electrons of the phenyl ring are possible. The dihydropyridine (408) can eliminate the amine to form the cyclopenta[c]pyridine (409) since the cis orientated proton at C-3 can shift to the nitrogen to form the 1,4-dihy-dropyridine (410) from which the amine is eliminated. 

Dimeric versions of these triazines have also been reported to undergo the Diels-Alder reaction with preformed enamines to give 2,2 -bipyridines <2005MOL265>. It is possible to carry out the reaction stepwise or in one pot however, the yields are variable for both sequences (10-64%). 

In reaction with cyclic enamines, 1,2,4-triazines have been used to prepare 2,2 -bispyridines <2004T6021> with extensions of this strategy to include a tethered inime-enamine, facilitating the direct conversion of the triazine to the pyridine without the requirement of a separate aromatization step (Scheme 128) <2004CC508>. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

This reaction was investigated particularly as a regioselective route to the pyridyl biaryl CD ring system of the antitumor antibiotic streptonigrin (5). Thus the reaction of the 1,2,4-triazine 2 with the morpholino enamine 3 gives the desired tetracyclic adduct 4 together with some of the adduct formed with reverse regioselectivity. This product was converted in several steps into a known precursor of the natural product. 

Anilines and heterocyclic amines react with 1,3,5-triazine to furnish formamidines, e.g. (363) and (364) (Scheme 64). CH2-acidic compounds, e.g. nitriles, can be formylated by heating with 1,3,5-triazine. In the course of such reactions the enamines thus obtained can be converted to formamid-... 

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