2-Phenyl-1,8-naphthyridin-4-one

Chart 3 General structure of 2-phenyl-4-quinolones (X=CH) and 2-phenyl-1,8-naphthyridin-4-ones (X=N) used by Weigt and Weise to generate their CoMFA model... 

According to the Friedlander method, the condensation of the readily available 2-aminoiiicotinic aldehyde (20a) (74JOC726) or its 6-phenyl derivative (20b) [66JCS(C)315] with nitroacetic acid (21) in boiling ethanol with piperidine as catalyst is another example of this method, which affords in fair yields the corresponding 3-nitro-l,8-naphthyridin-2(lFI)-ones (22a, 74%) and (22b, 47%), respectively [66JCS(C)315]. 

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315]. It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

Tlie products of nitration of 2-amino-5-phenyl-l,8-naphthyridin-7(8H)-one (63) vary depending on whether the reaction is carried out with nitric acid in sulfuric acid or in acetic anhydride (74GCI499). In sulfuric acid the phenyl ring was found to be nitrated more easily than the naphthyridine ring, yielding a mixture of 3- and 4-nitrophenyl derivatives (64) in acetic... 

Treatment of 4-hydroxy-l-phenyl-l,8-naphthyridin-2-(lH)-one (76) with sodium nitrite gave the 3-nitroso derivative (77), which could be oxidized to 4-hydroxy-3-nitro-l-phenyl-l,8-naphthyridin-2(lH)-one (30a) (94SC3289). According to the authors, this method of preparing (30a) is more convenient for large-scale preparation than the one using A-phenyl-3-azaisatoic anhydride as starting material (see Section II,A,4,a) [(29a) (30a)]. 

Catalytic reduction of 3-nitro-7-phenyl-l,8-naphthyridin-2(lH)-one (136) with palladium on carbon in 2-ethoxyethanol gave the l,2-di(l,8-... 

Heating 6-bromo- and 6-chloro-2-halomethyl- (99JHC1065) and 6-bromo-, 6-chloro- and 6-fluoro-2-phenyl-4/f-pyrido[l, 2-u]pyrimidin-4-ones (00JMC2814) in phenyl ether at 220 °C for 10 min yielded the appropriate 7-halo-1,8-naphthyridin-4-ols. 6-Amino-2-trifluoromethyl-4//-pyrido[l, 2-a]-pyrimidin-4-one was transformed into 7-amino-2-trifluoromethyl-l,4-dihy-dro-l,8-naphthyridin-4-one in 90% yield (98EJM383). 

Only the head-to-tail adducts were obtained in the [2+2] photoaddition of 4-hydroxy-l-phenyl[l,8]naphthyridin-2(l//)-one with various alkenes in methanol (Scheme 3). The photolysis of the hypoiodites generated by the in situ reaction of the cycloadducts with excess mercury(ll) oxide-iodine reagent in benzene induced a regioselective scission of the non-ring junction bond of the alkoxyl radical to give substituted 3,9-dihydro-9-phenylyfuro[2,3- ][l,8]naphthyridin-4(2//)-one and/or 3,5-dihydro-5-phenylfuro[3,2-f][l,8]naphthyridin-4-(2//)-ones <1996T6125>. 

Chloramine-T reacts with (2-oxo-3-phenyl-27/-[l,8]naphthyridine-l-yl)acetic acid arylidenehydrazides to generate 1-(5-aryl-[1,3,4]-oxadiazol-2-ylmethyl)-3-phenyl-17/-[l,8]naphthyridin-2-ones <2004IJB2014>. 

Another structurally related series is the 2-ary 1-1,8-naphthyridin-4-ones (37 to 48, see Table 6.7), which contain a second nitrogen in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or a-naphthyl groups at the C-2 position showed potent cytotoxicity in the NCI 60 human tumor cell line panel with GI50 values in the low micromolar to nanomolar range (Tables 6.7 and 6.8).51 The tumor cell line selectivity varies with the various substituents. 2-(3 -Methoxyphenyl)-naphthyridinone (37) was significantly more cytotoxic in several cancer cell lines than the corresponding 2-(3 -meth-oxyphenyl)-quinolone (36). Both compound classes were potent inhibitors of tubulin polymerization the 2-ary 1-1,8-naphthyridin-4-ones had activity nearly comparable with those... 

An interesting CoMFA study was conducted by Weigt and Wiese on a set of 58 variously substituted 2-phenyl-4-quinolone and 2-phenyl-l,8-naphthyridin-4-one CSI (Chart 3) [27],... 

Ethoxy-4-methylaminobut-3-en-2-one (13) with acetyl chloride (14) gave 3-acetyl-l,4,6,7-tetramethyl-l,6-naphthyridine-2,5 (l//,6//)-dione (14) (reflux, 6h 46%) similar procedures furnished several homologs, of which 3-ben-zoyl-7-methyl-4-phenyl-1,5-naphthyridine-2,5( 1 H,6H)-dione was confirmed in structure by X-ray analysis.636... 

Dimethyl-2-phenylethynyl-3-pyridinecarboxamide (52) gave 2,4-dimethyl-7-phenyl-l,6-naphthyridin-5(6//)-one (53) (EtONa, EtOH, reflux, 3 h ... 

Phenyl-2-styryl-3-pyriidnecarboxanilide (57) gave 2,6,7-triphenyl-7,8-dihydro-l,6-naphthyridin-5(6//)-one (58) (P2O5, H3P04, 135°C, 4h 66%) 992 analogs somewhat similarly.793 972 1025... 

Bromo-5-methyl-l,6-naphthyridin-2-amine (53) with potassium O-ethylxanthate gave 8-methylthiazolo [4,5-b] L,6]naphthyridin-2(3//)-thione (54) (reactants, l-methylpyrrolidin-2-one, 165°C, 7h >95%) the 3-phenyl analog was made similarly.928... 

Cyclocondensations involving thioxo or alkylthio substituents are represented by the conversion of 6-methyl-4-(thien-2-yl)-2-thioxo-l,2,5,6,7,8-hexahydro-l,6-naphthyridine-3-catbonitrile into 4-hydroxy-9-methyl-4-(thien-2-yl)-7,8,9,10-tetrahydropyrido 2, 3 4,5 thieno 2.3-ft [ l,6Jnaphthyridin-2(17/)-one (3) (ClCH2C0CH2C02Et, EtOH, EtONa, reflux, 10 min 88%) 1429 also of 2-acetonylithio-8-benzylidene-6-isopropyl-4-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridine-3-carbonitrile into 2-acetyl-8-benzylidene-6-isopropyl-4-phe-nyl-5,6,7,8-tetrahydrothieno 12,37 1,6]naphthyridin-3-amine (4) (EtONa, EtOH, 20°C 15 min 75%).946... 

Ethoxalylmethyl-2-methoxy-5-nitropyridine (3, R = H) gave 3-hydroxy-6-methoxy-3,4-dihydro-1,7-naphthyridin-2( 1 //)-one (4, R = H) (Pt02, EtOH, H2, 3 atm, 2 h 75%),152,234 that underwent subsequent dehydration to afford 6-methoxy-l,7-naphthyridin-2(l //)-one (TsCl, pyridine, 150°C, sealed , 4 h 79%) 234 similarly, 4-oc-ethoxybenzyl-2-methoxy-5-nitropyridine (3, R=Ph) gave 3-hydroxy-6-methoxy-4-phenyl-3,4-di hydro-1,7-naphthyridin-4(l//)-... 

Bromo-4-pyridinecarbaldehyde (33) with phenylacetamide gave 3-phenyl-l,7-naphthyridin-2( 1 //)-one (34) [reactants, tris(dibenzylideneacetone)dipalla-dium, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, CS2CO3, PhMe, N2, 100°C, 18 h 75%].117... 

Methyl 2-[A -phenyl-/V-(pyrrolidin-l-y]acetyl jamino -2-pyridinecarboxylate (15) gave 4-hydroxy-1 -phenyl-3-pyrrolidin-l-yl)-1,8-naphthyridin-2( I //)-one (16)... 

Bromo-3-pyridinecarbaldehyde (39) with 2-phenylacetamide gave 2-phenyl-l,8-naphthyridin-2(l//)-one (40) (reactants, CS2CO3, P- and Pd-catalysts ... 

Phenyl-2//-pyrido 2,3-<7 [l,3]oxazine-2,4(l//)-dione (64) with diethyl malo-nate gave ethyl 4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-l,8-naphthyridine-3-carboxylate (65) (reactants, NaH, 150°C 85%) 453,407 the same substrate (64) with ethyl nitroacetate gave 4-hydroxy-3-nitro-l-phenyl-1,8-naphthyr-idin-2(lfl)-one (66) (NaH/MeCONMe2, 100°C 77%).1191... 

Bromo-2-phenyl-l,8-naphthyridin-4(177)-one gave 2-bromo-5-ethoxy-7-phenyl-1,8-naphthyridine (14) (NaH, Me2SO then EtI, 80°C 32%).263... 

Hydroxy-1 -phenyl-l,8-naphthyridin-2( 1 //)-one underwent cycloaddition by isobutene to give 8b-hydroxy-1,1-dimethyl-4-pheny 1-1,2,2a,8b-tetrahydrocy-clobuta c] 1,8 naphthyridin-3-(4//)-one (22) MeOH, hv 95%) analogs hkewise.603... 

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