摘要:

1976 713A New Synthesis of Pyrimido[LC,S-e] -as-triazine 4-Oxides by NitrosativeCyclization of Aldehyde Uracil-6-ylhydrazones in the Presence of DiethylAzodiformateBy Fumio Yoneda * and Tomohisa Nagamatsu, Faculty of Pharmaceutical Sciences, Kumamoto University,Kazuko Shinomura, Pharmaceutical Institute, Keio University, Shinanomachi, Shinjuku-ku 160, Tokyo, JapanThe nitrosative cyclization of the aldehyde uracil-6-ylhydrazones in the presence of diethyl azodiformate gives thecorresponding pyrimido[5.4-e] -as-triazine 4-oxides ; several toxoflavin and fervenulin 4-oxides were preparedby this method. The compounds showed characteristic U.V. spectra.(I&-k) as the exclusive products (see Table 1). Toxo-flavin 4-oxide (IIa) itself was synthesized without isol-ation of the corresponding formaldehyde hydrazone (Ia) ,TABLE 1Toxoflavin 4-oxidesOe-honmachi, Kumamoto 862, JapanNITROSATION of the aldehyde 3-methyluracil-6-ylhydra-zones results in simultaneous cyclization to give pyr-imido[5,4-e]-as-triazine derivatives, e.g.toxoflavin andfervenulin.2 The process may involve intermediatehydroxylamines, which give the pyrimido[5,4-e]-as-triazines by intramolecular dehydration. We consideredthat dehydrogenation of the intermediates should lead to Product rc) (%) Product (“C) (%)64 191 73[%$4: >315 80pyrimido[5,4-e]-as-triazine 4-oxides (Scheme), and there- (IIa) 4 189fore examined the utility of diethyl azodiformate (DAD),209 76 I:?&: 210 71MeNP,, I f R 3 *____Q NO + ..N5QR3OAN NYNM.p. Yield M.p.Yield168 76221 8086 [Ej) 4 230 86CBH,N,O, requires C,43.05; H, 4.05; N, 31.4%. bFound: C, 64.9; H, 4.86;N, 26.46.204 66 (Hi) 233 80 (IIC) 4(IId); 207a Found: C, 43.1; H, 3.85; N, 31.36.C,,H,,N,P, requires C, 64.86; H, 4.9; N, 26.0%.OANI 1R ’ R Z1 1R ’ R 2R ’ = H , R ~ = ~eR’ = Me,R2 = HNH-N H, + EtOZC’ CO2EtMeSCHEMEa strong hydrogen-abstracting agent, as a reagent for theexclusive formation of the 4-0xides.~Treatment of the N-met hyl-N- (3-methyluracil-I -yl) -hydrazones (Ib-k) in acetic acid with saturatedaqueous sodium nitrite in the presence of a slight excess ofDAD afforded the corresponding toxoflavin 4-oxidesF. Yoneda, K. Shinomura, and S . Nishigaki, TetrahedronLetters, 1971, 861.G.Blankenhorn and W. Pfleiderer, Chenz. Ber., 1972, 105,3334.Preliminary report, F. Yoneda, S. Nishigaki, and K. Shino-mum, Chem. and Phavm. Bull. (Japan), 1971, 19, 2647.which was prepared iiz sit% from aqueous formaldehydeand 3-methyl-6-( l-methylhydrazino)uracil, because of itsinst ability. Diet hyl hydrazodif ormate was isolatedfrom the mother liquor. In this connection, the nitros-ation of (Ic) in the presence of nitrosobenzene instead ofDAD also gave 3-phenyltoxoflavin 4-oxide (IIc), albeitin less satisfactory yield.The structures of compounds (IIa-k) were demon-strated by elemental analyses, the presence of the strongparent ions and pronounced M - 16 ions in their massspectra (see later), and the formation of the correspondingtoxoflavins (111) by reduction with sodium dithionite inwater.DAD was also used for the preparation of the fervenulin4-oxides (Va-g).For example, treatment of acetalde-hyde 1,3-dimethyluracil-6-ylhydrazone (IVa) in aceticacid with saturated aqueous sodium nitrite in the presenceof a slight excess of DAD caused separation of 3-methyl-fervenulin 4-oxide (Va). Similarly, other aldehydehydrazones (IVb-g) gave the corresponding S-sub-stituted fervenulin 4-oxides (Vb-g) exclusively (seeTable 2).The mass spectra of the products (V) revealed strongparent and M- 16 ions, and an M- 17 ion in the case of(Va). Saha and Pfleiderer 6 reported that pronouncedM-17 as well as M-16 ions can be observed in the massspectra of pteridine N-oxides having alkyl and arylsubstituents in the position next to the N-oxide group.However, M - 17 ions were not observed in the spectra offervenulin 4-oxides other than (Va) or of toxoflavin 4-oxides having the same 3-substituents.Treatment ofF. Yoneda and T. Nagamatsu, Chew. and Pharm. Bull.(Japan), 1976,23, 2001.F. Yoneda and T. Nagamatsu, Bull. Chew. SOC. J a j a n , 1976,48, 1484.S. K. Saha and VCT. Pfleiderer, Tetvahedmn Lettevs, 1973, 1441714 J.C.S. Perkin Ithe $-oxides (V) with sodium dithionite in water gave thecorresponding fervenulins (VI), also obtained by fusionor by refluxing the 4-oxides in dimethylfonnamide.We consider this oxidative cyclization involvinghydrogen abstraction as possessing considerable potential0H Me( 1 1a; Rbj RC; Rd; Re ; Rf ; R0M e H(TY 1Q; Rb ; RC ; Rd ; R0U.V.absorption maxima for the toxoflavin andfervenulin Poxides are presented and compared withthose of the corresponding toxoflavins and fervenulins inTables 3 and 4. In the toxoflavin series, the spectra of(11) and (111) were very similar except for a small red? - 00 ? - 0Me( Y )MerY-I 1TABLE 2Fervenulin 4-oxidesFound (%)I-A\ M.p. ("C) Yield (yo) C H N138 40 43.1 3.9 31.16229 60 54.7 3.9 24.6257 80 48.86 3.06 22.06222 85 43.85 2.65 19.65330 50 47.35 3.2 25.66266 45 63.4 4.2 21.9305 42 64.66 4.9 26.76(decomp . )(decornp .)for the syntheses of other heterocycle N-oxides. More-over, the foregoing pyrimido[5,4-e]-as-triazine 4-oxidescannot be obtained by conventional peroxyacid oxidation.The Figure shows the x-electron distributions oftoxoflavin and fervenulin calculated by the HuckelLCAO-MO method.The most reactive site of toxoflavinfor peroxyacid oxidation is position 8 and that offervenulin is position 1 if steric hindrance is neglected.In fact, Blankenhorn and Pfleiderera report that theoxidation of fervenulin derivatives with trifluoroperaceticacid led to l-oxides.2 Toxoflavin derivatives are un-stable towards acetic acid and other nucleophilic reagents,undergoing 1-demethylation.7 Compounds (11) are notoxidised by m-chloroperbenzoic acid in chloroform. Thisis ascribed to the lack of x-electron density at position 4as well as to steric hindrance at position 8.Require d (%)< c1 Formula C H NC*H,N50* 43.06 4.06 31.4C1SH11N50S 54.75 3.9 24.66C13H10C1N50S 48.86 3.16 21.9ClSH*C12N5OS 44.1 2.65 19.8C1BH10N605 47.26 3.06 25.46C14H13Ni504 53.35 4.16 22.2C15H16N603 54.86 4.9 26.6shift in going from (11) to (111). In the fervenulinseries, the spectral relationship between (V) and (VI)varied according to the nature of the 3-substituent.However the spectrum of fervenulin 4-oxides having aelectron-releasing substituent, such as (Vf and g), weresimilar to those of the fervenulins (VIf and g).EXPERIMENTALM.p.s (corrected) were determined with a Mettler FP-1apparatus.Aldehyde N-methyl-N- (3-methyluracil- 6-yl) hydrazones *and 1,3-dimethyluracil-6-ylhydrazones 5 were synthesized byreported procedures.ToxofEavifi 4-Oxide (1Ia)-A mixture of 3-methyl-6-(1-methy1hydrazino)uracil (2 g, 0.012 mol) and 37%F.YonedaandY. Nagamatsu, J. Amer. Chem. SOC., 1973,95,67361976formaldehyde (1.4 g, 0.017 mol) in acetic acid (20 ml) wasstirred a t 5 "C for 10 min. To this solution DAD (3 g,0.017 mol) was added, followed by saturated aqueoussodium nitrite (1.2 g , 0.017 mol), dropwise with continuouscooling a t 5 "C. The solution was then stirred a t roomtemperature for 2 h. The crystals which separated werefiltered off and the filtrate was diluted with ethanol (40 ml)and stored in a refrigerator; more crystals of (IIa) separated0le7l3 I t 10-008)M e -1I(0.729) MeM e - N . i i L N y : II ( 0 . 2 5 5 ) Mex-Electron densities and frontier electron densities (in parentheses)of toxoflavin and fervenulin ring systems calculated by HiickelLCAO-MO method.The parameters of the coulomb andresonance integrals for substituent groups are as follows: for=N-, ax = 0.6, a, = 0.1, E = 1 ; for -N<, ax = 1, a, = 0.1,I = 1; for =O, ax = 2, a, = 0.2, E = 1.4; ax is the coulombintegral of the substituent X: ax = a + ax@; a, is the coulombintegral of the carbon atom adjacent to X: a.a = a + arp; Eis the resonance integral between that carbon atom and X:Po-x = EPgradually. The combined crystals were recrystallized fromethanol or dioxan to give yellow needles (1.6 g), m.p. 189'.3-Substituted Toxoj9avin &Oxides (IIb-k) . GeneralProcedure.-To a stirred solution of the hydrazone (Ib-k)(0.008 mol) and DAD (0.01 mol) in acetic acid (40 ml) wasadded drop by drop saturated aqueous sodium nitrite(0.01 mol) with cooling at 6 "C.The mixture was stirred a troom temperature for 2 h and then treated as above to give715yellow or orange needles of the respective toxofZavin 4-oxide(IIb-k), which were recrystallized from ethanol or dioxan.TABLE 3U.V. spectra of toxoflavin 4-oxides (11) and toxoflavins(III) in dioxanArMx./nm (log 4(IIa) 264 (4.29), 321 (3.66),(In) 264 (4.35), 324 (3.65),$:$) 298 (4.63), 436 (3.49) [:::/ 304 (4.66), 460 (3.44)(IIh) 266 (3.20), 367 (4.63)(IIk) 291 (4.46). 431 (3.48)412 (3.37)420 (3.41)290 (4.48), 431 (3.47) (IIIc)(IIId)296 (4.61), 432 (3.47) (IIIe) [i::g)TABLE 4U.V. spectra of fervenulin 4-oxides(VI) in dioxanLax./nm (lot? E)(Va) t 240 (4.38), 301 (3.71),(Vb) 268 (4.34), 283 (4.36), (VIb)(VIa) t361 (3.66)380 (3.47)(Vc) 266 (4.37/, 292 (4.441, (VIc)386 (3.47)(Vd) 262 (4.39). 300 (4.37), (VId)389 (3.37)(Ve) 271 (4.24).308 (4.31), (VIe)376sh (3.64)305 (4.49), 401 (3.37) (VIf)$!) 368 (4.66), 439 (3.39) (VIg)In ethanol.296 (4.49), 433 (3.47)300 (4.54). 436 (3.49)301 (4.48), 434 (3.44)308 (4.64), 456 (3.40)263 (3.86), 369 (4.66)(V) and fervenulinshnax./nm (log E)240 (4.32), 350 (3.64)278 (4.46), 376 (3.65)288 (4.39), 377 (3.44)288 (4.48), 377 (3.57)309 (4.38), 362sh(3.09)303 (4.61), 397 (3.64)353 (4.61), 437 (3.21)3-Substituted Ferventdin 4-Oxides (Va-g) . General Pro-cedwe.-To a stirred solution of the hydrazone (IVa-g)(0.008 mol) and DAD (0.01 mol) in acetic acid (40 ml) wasadded dropwise saturated aqueous sodium nitrite (0.01 mol)with cooling at 5 "C. The mixture was further stirred a t5 "C for 3-20 h until crystals were precipitated. Thecrystals were filtered off and washed with ether. Thefiltrate was diluted with ether to precipitate more crystals of(V) . The combined crystals were recrystallized fromdioxan to give pale yellow needles.3-Substituted Fervenulins (VI-g) by Thermal Deoxygen-ation.-A solution of the 4-oxide (Va-g) (0.05 mol) indimethylformamide (20 ml) was refluxed for 1 h., thenevaporated to dryness under reduced pressure. Theresidue was recrystallized from ethanol to give the fervenulin(VIa-g) in quantitative yield.[5/1107 Received, 6th June, 1975

ISSN:1472-7781    

DOI:10.1039/P19760000713

出版商:RSC    

年代:1976

数据来源: RSC