Yoshiharu Sakuma

Reactivity of 4a,5-epoxy-5-deazaflavins

Abstract Reactions of 4a,5-epoxy-5-deazaflavins with aqueous potassium carbonate, Vilsmeier reagent (dimethylformamide-phosphorus oxychloride), acetic anhydride-acetic acid, pyridine and triethanolamine gave the corresponding oxazolonoquinolines, 5-chloro-5-deazaflavins, 4a,5-diacetoxy-5-deazaflavins, 1,5-dihydro-5-deazaflavin-5-ones, and deoxygenated 5-deazaflavins, respectively.

A novel synthesis of pyrimido[4,5-b]quinoline-2(3H),4(10H)-diones (5-deazaflavins) and analogues by the oxidative cyclization of 5,5′-arylmethylenebis-(6-alkylamino-3-methyluracils)

The oxidative coupling of 5,5′-arylmethylenebis-(6-alkylamino-3-methyluracils), prepared by the condensation of 6-alkylamino-3-methyluracils and arenecarbaldehydes, with diethyl azodiformate afforded the corresponding pyrimido[4,5-b]quinoline-2(3H),4(10H)-diones (5-deazaflavins). This synthetic method was successfully applied to the preparation of 5-deazaflavin-type compounds such as a benzologue, a thiophen analogue, or a nitrogen analogue of 5-deazaflavin. The 8-chloro-5-deazaflavin was converted into the corresponding 8-amino-derivatives by treatment with amines.

Dehydrogenation of alcohols by pyrimido[4,5-b]quinoline-2(3H),4(10H)-dione (5-deazaflavin)

Pyrimido[4,5-b]quinoline-2(3H),4(10H)-dione (5-deazaflavin) oxidizes alcohols under alkaline conditions in the dark to yield the corresponding carbonyl compounds, while it is itself hydrogenated to 1,5-dihydro-5-deazaflavin.

Syntheses of isoalloxazines, alloxazines, toxoflavins, and fervenulins by oxidative cyclization of the Michael-type adducts from substituted 6-aminouracils and azo-compounds

Treatment of the Michael-type adducts from 6-anilinouracil derivatives and diethyl azodiformate (DAD) or 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) with an oxidizing agent caused oxidative rearrangement, followed by thermal or photochemical cyclization, to give the corresponding (iso)alloxazines. Similarly, oxidative cyclization of the Michael-type adducts from 6-benzylidenehydrazinouracil derivatives and DAD gave toxoflavin and fervenulin derivatives.

Syntheses of 5-deazaflavines.

Treatment of 6-(N-alkylanilino)uracils with Vilsmeier-type reagents (dimethylformamide–phosphoryl chloride or dimethylformamide–ethyl chloroformate) gave 5-deazaflavines {10-alkylpyrimido[4,5-b]quinoline-2,4(3H,10H)-diones}; this cyclization was also achieved with triethyl orthoformate. Treatment of 3-methylbarbituric and barbituric acids with dimethylformamide–phosphoryl chloride gave 6-chloro-5-formyl-3-methyluracil and 2,4,6-trichloro-5-formylpyrimidine, respectively. Reactions of these 6-chloro-5-formylpyrimidines with N-substituted anilines gave directly the corresponding 5-deazaflavines.

Dehydrogenation of alcohols by pyrimido[4,5-b]quinoline-2(3H),4(10H)-diones (5-deazaflavins) as autorecycling oxidizing agents

Pyrimido[4,5-b]quinoline-2(3H),4(10H)-diones (5-deazaflavins) and related compounds oxidize alcohols under alkaline conditions in the dark to yield the corresponding carbonyl compounds, while they themselves are hydrogenated to the 1,5-dihydro-derivatives. The substituent effect in the 5-deazaflavin series was examined in terms of the oxidizing ability toward benzyl alcohol. In some cases, the benzyl alcohol oxidation by the 5-deazaflavins have been shown to recycle automatically, and a > 100% yield of benzaldehyde (based on the 5-deazaflavin) was obtained.

Disproportionation in hydrolysis of pyrimido[4,5-b]quinoline-2(3H),4(10H)-diones (5-deazaflavins)

Treatment of 5-deazaflavins with concentrated aqueous potassium hydroxide led to the exclusive formation of 1,5-dihydro-5-deazaflavins and 1,5-dihydro-5-deazaflavin-5-ones via intermolecular oxidation–reduction between initially formed 5-hydroxy-1,5-dihydro-5-deazaflavins and unchanged 5-deazaflavins; under dilute alkaline conditions the reverse oxidation–reduction between 1,5-dihydro-5-deazaflavins and 1,5-dihydro-5-deazaflavin-5-ones occurred to form the original 5-deazaflavins and 5-hydroxy-1,5-dihydro-5-deazaflavins, which were oxidized to 1,5-dihydro-5-deazaflavin-5-ones by air. When hydrolysis was carried out with dilute alkaline solution, the corresponding 2-oxoquinoline-3-carboxylic acids were obtained besides the disproportionation products 1,5-dihydro-5-deazaflavins and 1,5-dihydro-5-deazaflavin-5-ones. This disproportionation and hydrolytic scission at the 2-position compete with each other. Higher concentrations of hydroxide ion favoured the formation of the reduced 5-deazaflavins and 5-ketones by disproportionation and reduced the proportion of 2-quinolones formed by hydrolytic scission.

Oxidation–reduction in hydrolysis of pyrimido[4,5-b]quinoline-2(3H),4(10H)diones (5-deazaflavins)

Treatment of pyrimido[4,5-b]quinoline-2(3H), 4(10H)-diones (5-deazaflavins) with concentrated aqueous potassium hydroxide led to the exclusive formation of 1,5-dihydro-5-deazaflavins and 1,5-dihydro-5-deazaflavin-5-ones via intermolecular oxidation–reduction between initially formed 5-hydroxy-1,5-dihydro-5-deazaflavins and unchanged 5-deazaflavins; under dilute alkaline conditions reverse oxidation–reduction between 1,5-dihydro-5-deazaflavins and 1,5-dihydro-5-deazaflavin-5-ones occurred to form the original 5-deazaflavins and 5-hydroxy-1,5-dihydro-5-deazaflavins, which were oxidized into 1,5-dihydro-5-deazaflavin-5-ones by air.

Micellar catalysis of oxidation of nitroethane by isoalloxazine (flavin)

Oxidation of nitroethane by flavins to acetaldehyde and nitrite ion, usually not possible in nonenzymatic systems, does take place with an isoalloxazine (flavin) bound to a cationic micelle.

A new synthesis of alloxazines by the reaction of diethyl azodiformate with 6-anilinouracils

Treatment of 6-anilinouracils with diethyl azodiformate led the corresponding alloxazines (benzo[g]pteridine-2,4-diones). This synthesis involves initial formation of Michael-type adducts [6-anilino-5-(1,2-bisethoxy-carbonylhydrazino)uracils] followed by dehydrogenative cyclization with further diethyl azodiformate.