Transformations, ring, of uracils

The mechanism shown in Scheme 150 suggests that the presence of a terminal nucleophile in the sidechain on a uracil ring enables the ring transformation of uracil into other rings by an intramolecular rearrangement. In fact, in the presence of sodium ethoxide 5-(2-carbamoyI-vinyl)uracil-5-carbohydrazides are easily converted into pyridines and 3-... 

The recently developed dealkylation of phenol ethers with trimethylsilyl iodide has been shown to work well for OO -dialkyl-uracils. A number of ring transformations of uracils have been reported. The [2 + 2]cyclo-adducts (232) can be transformed into pyridones (233) by treatment with base overall yields of pyridines from the starting uracils (231) can be quite reasonable. The reaction is thought to proceed via electrocyclic ring-opening of the dianion of (232) (Scheme 92). 

The reaction was found to fail with l-methyl-5-nitrouracil and 5-nitrouracil. This is because both uracils, containing dissociable protons, exist in the basic solution in the anionic forms, which inhibit the addition of the nucleophiles at the C-6 position. Attempts to bring about these pyrimidine-to-pyrimidine ring transformations with cyanoacetamide, ace-toacetamide, and phenylacetamide were not successful. A substituent at C-6 of 5-nitrouracil suppressed the reaction l,3,6-Trimethyl-5-nitrouracil was recovered almost quantitatively. 

An interesting transformation of carbamoylaspartic acid (30a) or ethoxy-carbonylasparagine (30b) to uracil (31) was performed by electrochemical oxidative decarboxylation.77 The same ring-closure reaction occurs in a biological system via an enzyme-catalyzed oxidation. Good yields and mild conditions of the electrochemical transformations give promise of wide application [Eq. (34)]. 

Azine approach. The fused uracil (58) has been prepared from 5-amino-l,3,6-trimethyl-uracil diazotization of the latter yields a fused triazine A-oxide (57), which has its triazine ring transformed into an isoxazole ring by tin(II) chloride treatment (62USP3056781). 

Another original transformation of a 5-nitrouracil into a 5-carbamoylura-cil was observed on treatment of 1,3-dimethyl-5-nitrouracil with malona-mide in ethanolic sodium ethoxide. In this case, the N(3)—C(4)—C(5) element of the uracil ring is replaced [81TL2409 84JCS(P1) 1859] (Scheme 141). 

A special case of these ring transformation reactions is the 5-insertion reaction of 4-phenyl-1,2,4-triazolin-3,5-diones (4 Ph-TAD) [750PP251 81AG832, 81AG(E)797] into uracils, for example, the reaction of 5-(3,5-dioxo-4-phenyl-l,2,4-triazolidin-l-yl)-l,3-dimethyluracils with hydrazine... 

The ring structure of the ribose residue was ascertained" in the same general manner as for adenosine and guanosine. Triacetyl-dihydrouridine was prepared by the hydrogenation of triacetyl-uridine. On simultaneous deacetylation and methylation this was transformed to the fully methylated dihydro-uridine. By simultaneous hydrolysis and oxidation of this product, with hydrobromic acid and bromine, trimethyl -D-ribonolactone was formed, its identity being confirmed by oxidation to meso-dimethoxy-succinic acid. It follows that the ribose component has the furanose ring structure, and that uridine is 3 -D-ribofuranosyl-uracil. 

The synthesis of 132, starting from S-benzyloxy propanal (131), involved the ring opening of an optically active epoxide 133 with a xanthate anion (Scheme 37)J22 Stereoselective synthesis of 133 by Sharpless epoxidation allowed preparation of the 2-deoxy-4-thio-D- and L-ezyr/zro-pentoses, " which were transformed into the corresponding pyrimidine nucleosides with silylated uracil and McaSiOTf. and then deprotected with Bu NF. 

More complex, but still feasible, is the synthesis of pyrimidine bases from simple prebiotic substrates, although the reported yields of these reactions are relatively low. In this context, two main prebiotic precursors have been identified cyanoethine and a primary product of its hydrolysis, cyanoacetaldehyde. These compounds contain a preformed C-C bond which is incorporated in the C5-C6 position of the pyrimidine ring. In 1968 Ferris and co-workers reported that the reaction of cyanoethine with cyanate at 30 °C yields cytosine and, after its hydrolysis, uracil in acceptable yield [27]. trans-Cyanovinylurea was recovered as a key intermediate for this transformation. However, this reaction requires relatively high concentrations of cyanate (>0.1 mol/1), unlikely to occur in aqueous media due to its rapid degradation to carbon dioxide and ammonia. Cyanoethine also reacts with cyanate and yields cytosine and uracil at elevated temperatures. In this reaction urea or guanidine (also considered as prebiotic organic compounds) can easily replace cyanate (Figure 8.8) [26]. 

The conversion of 1,3-dimethylnracil into a mixture of iV,Ai -dimethylurea and the disodium salt of formylacetic acid begins with the addition of hydroxide at C-6. The propensity for uracils to add nucleophiles can be pnt to synthetic nse by reaction with double nucleophiles, such as ureas or guanidines, when a seqnence of addition, ring opening and reclosure can achieve (at first sight) extraordinary transformations. 

Compounds of the type 65 have been prepared by opening of the epoxide ring of l-(2,3-anhydro-5-0-trityl-P-D-lyxofuranosyl)uracil with a variety of carbon nucleophiles such as ethynyl lithium, vinylmagnesium bromide/cuprous iodide and l,3-dithian-2-yl lithium. These reactions afforded regioselectively 3 -C-substituted-3 -deoxy-P-D-arabinofuranosyl nucleosides 69-71 in 10-68% yield [84, 87] (Fig. 12). These intermediates have been transformed into a variety of other 3 -C-substituted-3 -deoxy-arabinofuranosyl uridines 72-77 [84]. 9-(3-Deoxy-3-C-methyl-P-D-xylofuranosyl)adenine has been prepared by glycosidation reaction of a 3-deoxy-3-C-methyl-P-D-xy/ofuranosyl chloride with adenine [90]. 

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