Fervenulins

Ferretane reactions, 1, 667 Ferrochelatase, 4, 396 Ferrosilacyclopentane properties, 1, 594 Fervenulin applications, 3, 456 Filter dyes... 

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

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). 

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). 

A new synthesis of fervenulins 341 in a single step was developed (77JA7358 78JA7661) by the photolysis of 6-azido-l,3-dimethyIuracil 372 in the presence of acylhydrazines. Their reaction could not be effected by heating, suggesting that photochemical activation is required. Thermol-... 

The synthesis of the /m-benzo-separated analogue 380 of the broad spectrum antibiotic fervenulin was reported (81JOC1699) in five steps from 7-chloro-2,4(l//,3//)quinazolinedione 374. Nitration of 374 gave 375, whose methylation gave 376. Pursuant to the synthesis of 380, 376 was converted into 377 with hydrazine and then formylated with formic acid to give 378 or converted to the ethoxymethylene derivative 379. Catalytic hydrogenation of 378 or preferably 379 gave 380. 

The stability of reumycin, fervenulin, and xanthothricin in acid-base media was studied by H- and l3C-NMR spectroscopy (85MI1). Infrared and absorption spectra of reumycin 311 were studied at low temperature (87MI2). The experimental data corresponded to the quantum chemical calculations of electron transmission. The pKa of 311 in aqueous medium... 

Reumycin and xanthothricin were isolated from Actinomyces rectus bruneus and are useful as antitumor antibiotics. Methylation of reumycin resulted in the formation of the antibiotics, fervenulin, toxoflavine, and 7-methoxyreumycin. A review on their effects on an electron transport mechanism in animal and yeast cells was published in 1975 by Russian authors (75MI1, 75MI2). 

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

Complete N NMR chemical shifts together with H- N coupling constants (referenced externally to NH4C1 in DMSO-1 6 DMSO - dimethyl sulfoxide) have been determined for toxoflavin 7 and fervenulin 8 in CDCI3 using pulsed field gradient heteronuclear multiple bond correlation (HMBC) techniques <2000H(52)811>, and are presented in Table 1. 

A detailed and useful assignment of the H and data for toxoflavin 7 and fervenulin 8 has appeared, and is summarized in Table 3 <2000H(52)811>. 

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. 

Table 6 Selected UV absorption data for 3-substituted fervenulins 24 <1996JHC949>...

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>. 

A similar process was found to occur with the fervenulin-3-carboxyl chloride 54, which upon treatment with an amine gave the bis-adduct intermediate 55, which ring-closed to the imidazo[4,5- ]-l,2,4-triazine bis-carboxamides 56 as shown in Scheme 5 <1996JHC949>. The structure of the products 56 was confirmed by X-ray crystallographic analysis. 

The dealkylation-alkylation of toxoflavin 7 with methyl iodide in DMF at reflux furnishes fervenulin 8, as shown in Scheme 6. Interestingly, heating toxoflavin 7 at reflux in DMF results in demethylation to give the 1-demethyl-ated species, reumycin 57, which can be methylated to give fervenulin 8 <1997H(45)643>. 

The reactivity of the dibromo compounds 72 and 74b was also explored, and it was shown that reaction with ethylene glycol gave the corresponding cyclic acetals 76, while reaction of compound 72 with hydroxylamine furnished the fervenulin-3-carbaldoxime 77, which was found to be resistant to hydrolysis. 

The reaction of the monobromo derivatives 74a and 75 with silver acetate gave 3-(acetoxymethyl)fervenulin 80 and 3-acetylfervenulin 78, respectively, in excellent yields (Scheme 11) <1996JHC949>. 3-Acetylfervenulin 78 and 3-(acetoxymethyl)fervenulin 80 gave the corresponding alcohols 79 and 81 after hydrolysis in methanolic ammonia. 

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. 

Aldehyde 82 was extremely reactive and was best isolated as the hydrate 84a. Indeed, recrystallization of the aldehyde 82 from ethanol gave 3-(l-ethoxy-l-hydroxymethyl)fervenulin 84b, while reaction with ethylene glycol gave the cyclic acetal 76a. The reactivity of the aldehyde 82 was exploited by easy Schiff base formation upon reaction with /i-aminobenzoylglutamic acid, a process that was followed by reduction to give the fervenulin-based folic acid analogue 85 <1996JHC949>. 

Table 7 The synthesis of fervenulin-3-carboxamides and carboxylates 71 (see Scheme 11)...

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