Methylenetetrahydrofolate in Organic Synthesis

The reactions of 5,10-methylene THF models with mononucleophiles mainly take place in 1 2 stoichiometry but in some highly functionalized systems an alternate 1 1 condensation mode of reaction prevails. The syntheses of various targets obtained through these reactions are elaborated. 

4-Dihydropyridines, Acridine-1,8-diones, 3,4-Dihydropyrimidine-2(lH)-ones, and Related Systems 

4-Dihydropyridines 46 (R = H, Me, Ph R1, R3 = Me and CH2C(Me)2CH2- R2 = Et) having unsymmetrical substitution patterns at C-2, C-6 and C-3, C-5 positions have been formed by reactions of equivalent amounts of ethyl-/ -aminocro-tonate and methyl acetoacetate or dimedone, with respective oxazinanes 31 in acetic acid/acetonitrile (1 10 v/v). Since methyl acetoacetate and dimedone fail to react with oxazinanes under these reaction conditions, it may be visualized that the preference of the reactivity of oxazinanes with enamines over the enols facilitates the generation of intermediate 45, the precursor of 46 (93JCR(S)120). 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

The enaminones 44 (R1 = Me, H) react with oxazolidines 27/28g, f to form partially reduced quinolinones 58a-c. 6-Amino-l,3-dimethyluracil reacts with oxazolidines 27/28f, e to form pyridopyrimidine derivatives 59a, b respectively in over 80% yields as against reported low-yield methodologies. Similarly, 27/28g, i, c react with 6-amino-1,3-dimethyluracil to give 59c, d, e, but in the case of 27/28d, b the un-cyclized products 60a,b are isolated exclusively (98T935). 

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