Fervenulin 1-oxide

The reaction of the fervenulin 1-oxides 100 with secondary amines results in contraction of the 1,2,4-triazine ring to form 2-amino-5,7-dimethylimidazo[4,5-e] pyrimidine-4,6(5/7,7//)-diones 101. The reaction of the same fervenulin 1-oxides 100 with ammonia leads to the 1,2,4-triazine ring cleavage product, 1,3-dimethyl-5-imino-6-isonitrosouracil 102 (94KGS1253). 

Fervenulin 1-oxide (90) reacts with secondary amines to give low yields of 8-aIkyamino-theophyllines (91), but with ammonia or with primary amines the final product is 1,3-dimethyl-5-imino-6-hydroxyiminouracil (92) (Scheme 30) [94CHE(30)1087],... 

Thermal deoxygenation of fervenulin 4-oxides 12 takes place after refluxing in DMF, giving fervenulin 13 (78JOC469). 

Reaction of the fervenulin 4-oxides 12 with HCl in ethanolic solution results in ring opening, yielding l,3-dimethyl-5-nitroso-6-hydrazinouracil 105 (78JOC469, 86KFZ1228). 

Heteroannelated 1,2,4-triazine 4-oxides—fervenulin 4-oxides 12—were obtained starting from 6-hydrazino-l,3-dimethyl-5-nitrosouracil. Orthocarboxylates, formic acid, dimethyl sulfate, or DMF in the presence of POCI3 were used as cyclization agents (77H273, 78JOC175, 78JOC469). 

To prepare fervenulin 4-oxides 12 or toxoflavine 4-oxides 146, it is convenient to use the reaction of l,3-dimethyl-2,4-dioxopyrimidin-6-yl hydrazone 147 or N-(3-methyl-2,4-dioxopyiimidin-6-yl) iV-methylhydrazone 148 with potassium nitrate in acetic acid [75CPB1885,76CPB338,76JCS(CC)658,82JHC1309,93CPB362]. Diethyl azodicarboxylate can be used instead of potassium nitrate [76JCS(P1 )713]. 

Reaction of 338 with orthossters afforded the corresponding 3-substituted fervenulin 4-oxide 342 (78JOC469). 

Treatment of 6-benzyIidenehydrazinouradls 86 with potassium nitrate and sulfuric acid in acetic acid affords fervenulin-4-oxides 87 <99M819>. 

The fervenulin-4-oxides 22 show a stable parent ion together with loss of 16 mass units as prominent peaks in the electron impact mass spectra. Loss of dinitrogen is a further common process and other fragmentation by loss of HNCO and ArCN leads to the prominent miz 81 fragment <1999M819>, as shown in Scheme 1. 

The fervenulin-4-oxides 22 show excellent thermal stability with melting points in excess of 240 and 320 °C (R = H and Cl, respectively) when recrystallized from methanol. The same compounds show good thermal stability in the presence of acid <1999M819>. 

It is of interest that the methyl alcohol 81 underwent oxidation with chromic acid to afford 3-acetylfervenulin 83 in good yield, whereas the same conditions resulted in the conversion of alcohol 79 into fervenulin 8. The desired product of this latter transformation, that is, fervenulin-3-carboxaldehyde 82, could, however, be obtained, albeit in low yield, by the oxidation of alcohol 79 with manganese dioxide. Fervenulin-3-carboxaldehyde 82 could be obtained in much better yield from the treatment of 3-styrylfervenulin 68 with periodate in the presence of osmium tetroxide, or by ozonolysis of the same substrate. 

Azine A-oxides and azine A-imides undergo a deep ring transformation on interaction with various dipolarophiles. Thus, fervenulin-4-oxides (423) react with DMAD to afford derivatives of pyrrolo[3,2-first step of the reaction is assumed to involve the formation of cycloaddition products (424) which transform by subsequent multi-stage process into (425) (79JOC3830). 

Reaction of Fervenulin 4-Oxide with DMAD The Role of Solvent... 

Treatment of fervenulin 4-oxide 1 with 1.5 equivalents of DMAD in toluene at 95°C for 3 hours resulted in the formation of the pyrrolopyrimidine 2 in 62% yield. It was suspected that water in the solvent was participating in the formation of 2. Evidence in support of this hypothesis was obtained by carrying out the reaction in anhydrous toluene. The product obtained (56%) was the pyrrolopyrimidine 3. Unexpectedly, use of ethanol as the solvent gave the pyrrolopyrimidine 4 in 34% yield, together with 29% of recovered starting material. 

Fervenulin 4-iV-oxide (302) acting as a 1,3-dipole can undergo cycloaddition with ethyl phenyl-propiolate, leading ultimately to product (303). This interesting reaction involves a ring contraction with loss of nitrogen, and a possible mechanism is shown in Scheme 19 <85J0C2413>. 

Azodicarboxylates undergo Michael addition to the electron-rich 5-position. The intermediate hydrazino ester is converted with bases to fervenu-lones or converted with Vilsmeier reagent (POCl3-DMF) to fervenulins, which are available by oxidation of the corresponding hydrazone using lead tetraacetate [75JOC2321 76JCS(P 1)2398] (Scheme 82). 

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