Reinvestigation of the synthesis of 3-dimethylallyl-4-hydroxy-2-quinolones. A novel route to tetracyclic heteroaromatic compounds

摘要

2546 J.C.S. Perkin IReinvestigation of the Synthesis of 3-Dimethylallyl-4-hydroxy-2-quinol-ones. A Novel Route to Tetracyclic Heteroaromatic CompoundsBy Richard Oels, Richard Storer, and Douglas W. Young,' School of Molecular Sciences, The University ofThe reaction of diethyl 2-(3-methylbut-2-enyl)malonate with a variety of anilines has been used in the past as amethod of alkaloid synthesis. It has now been found that this reaction yields, in addition to the expected 3-di-methylallyl-4-hydroxy-2-quinolones. 3,3'-methylenebis-4-hydroxy-2-quinolones, and dibenzo [ b h ] [1,6] naph-thyridin-6(5H)-ones. A mechanism is suggested to explain this unusual reaction.Sussex, Brighton BN1 9QJTHE reaction of diethyl 2-(3-methylbut-2-enyl)malonatewith anilines has been used as a general method ofsynthesis of 3-dimethylallyl-4-hydroxy-2-quinolones .,9These compounds were then converted into naturallyoccurring alkaloid^.^,^ When we isolated the alkaloidpreskimmianine (1 ; R = Me)4 from the root of Dictam-nus albus L, therefore, it seemed that the most straight-forward method of confirming the structure would be toexhibited amide carbonyl absorption at 1 665 cm-l.Then.m.r. spectrum showed the presence of four methoxy-groups and four ortho-coupled aromatic protons, oneof which lay to unusually low field at T 1.30. There wasa further aromatic singlet at T 0.88.Several structures are consistent with the quoted data.The structure (2a) seemed the most attractive of theseto us and we were able to obtain f samples of (2b) andM eOMe0 HR1 R 2 R 3 R 4 R5 R sa; OMe OMe OMe OMe H HH H H H MeC; H NMe, H H OMe Med; OMe OMe OMe OMe H Mef ; OMe H OMe H H Hg; OMe OMe OMe H OMe HR 2 e; H H H H H HOHR H( 4 ) a; R = Hb ; R = OMe(PhHN0C)zCH( 5 )H( 6 )synthesise the alkaloid by this method.The synthesisindeed proved to be successful4 but a second productwas found in the reaction of 2,3-dimethoxyaniline withdiethyl 2-(3-methylbut-2-enyl)malonate in refluxingdiphenyl ether in addition to the expected quinolone(1; R = H). This compound crystallised from aceticacid as needles, m.p. 247-249 "C, C,,H,,N,O,. It hada characteristic U.V. spectrum and the i.r. spectrumf We thank Dr. F. G. Mann. F.R.S., Cambridge, and Dr. H.Harnisch, Bayer A.G., for gifts of samples.Preliminary communication, R.Oels, R. Storer, and D. W.Young, Chem. and Ind., 1974, 499.E. A. Clarke and M. F. Grundon, J . Chew. SOC., 1964, 438.(2c) 6 to compare with our compound.had an n.m.r. spectrum which showed an ortho-coupledaromatic doublet at T 0.88 and a singlet at T 0.66, whilecompound (2c) showed an ortho-coupled doublet a tT 1.33 and a singlet at T 1.04. The U.V. spectra of thetwo model compounds had similarities to that of the newcompound and all three spectra showed a bathochromicshift on addition of acid.Compound (2b)3 R. M. Bowman and M. F. Grundon, J . Chem. SOC. ( C ) , 1966,R. Storer and D. W. Young, Tetrahedron Letters, 1972,2199;J. T. Braunholtz and F. G. Mann, J . Chem. SOC., 1955, 381.1084.Tetrahedron, 1973, 29, 1217.6 H.Harnisch and A. Brack, Annalen, 1970, 740, 1641977The new compound, C,,H,,N,O,, could be N-methyl-ated using methyl iodide and sodium hydride to yielda derivative, C,,H,N,O,, which presumably had thestructure (2d). I t could also be converted into anunstable chloride (3) on reaction with POCl,.I t was now necessary to confirm the structure sug-gested for our new compound and to see whether similarinteresting products might be formed in synthesis of other3-d imet hylallyl-4-hydroxy-2-quinolones. We theref orereinvestigated the reaction of aniline with diethyl 2-(3-methylbut-2-eny1)malonate in refluxing diphenylether. This reaction had been reported3 to yield thequinolone (4a). We obtained this product in additionto 2-(3-methylbut-2-enyl)malondianilide (5) and acompound Cl6Hl0N,O which had spectral similarities tothe putative compound (2a).The compound wastherefore considered to have the structure (2e) beingeasily methylated with methyl iodide and sodiumhydride to yield compound (2b).An authentic specimen of the N-methyl derivative(2b) was prepared from the known compound (6).’Initial attempts to oxidise this compound led not un-naturally to dibenzo[b,h] [1,6]naphthyridine, but whencompound (6) was methylated using methyl iodide andsodium hydride under an atmosphere of nitrogen, thedesired compound (2b) was obtained. Oxidation to theamide had presumably occurred during the work-upprocedure for the N-met hyl-5,g-dih ydro-derivat ive.The authentic specimen of (2b) thus obtained was identi-cal in all respects to the sample obtained via the 3-dimethylallyl-4-hydroxy-2-quinolone synthesis.The unusual products from the synthesis of 3-dimethyl-allyl-4-hydroxy-2-quinolones had been obtained in twoseparate reactions.In a further example of the synthesisof 3-dimethylallyl-4-hydroxy-2-quinolones, ortho-anisi-dine had been used to prepare the quinolone (4b)., Wefound that the yield of the corresponding product (2f)was not high enough in this reaction to permit characteris-ation. When, however, the quinolone (4b) was allowedto react with ortho-anisidine in refluxing diphenyl ether,the desired compound (2f) was obtained.Having shown that the reaction of diethyl 2-(3-methylbut-2-eny1)malonate with anilines produced notonly the ‘ normal ’ products but also gave the unusualproducts of general structure (2), it was necessary toinvestigate the reaction conditions to see if the yield ofthe tetracyclic compounds could be optimised.Thereaction of diethyl 2-(3-methylbut-2-enyl)malonate withaniline was, therefore, monitored by U.V. spectroscopyand t.1.c. I t was found that formation of the tetracyclicproduct (2) was encouraged by prolonged heating. Aninitial product in some reactions was the dianilide (5),a compound which yielded mixtures of the quinolone’ G. R. Clemo and W. H. Perkin, J . Chem. SOC., 1924,125,1608.A. B. Turner, Quart Rev., 1964, 18, 347. ’ See M. J. S. Dewar in ‘ Molecular Rearrangements,’ ed.P. del o R. H. Baker, G. R. Lappin, and B. Riegel, J. Amer. Chem.Mayo, Interscience, New York, 1963, vol. 1. p. 295.SOC., 1946, 68, 1284.(4a) and the tetracyclic compound (2e) when heated inthe absence of a solvent.In many of the reactions in which we had obtainedcompounds of type (2) additional by-products werefound. These proved to be the appropriate substituted3,3’-methylenebis-4-hydroxy-2-quinolones (7), identicalwith authentic samples prepared from the substituted4-hydroxy-2-quinolones by reaction with formaldehyde,Since in the reaction of diethyl 2-(3-methylbut-2-eny1)malonate with anilines the yields of compounds oftype (2) were raised by an increase in the reflux time andfurther, since reaction of the quinolone (4a) with ortho-anisidine gave the tetracyclic compound (2f), it seemedreasonable to assume that the quinolwes (4) were inter-mediates in the reaction.This was supported by thefact that when the compound (1 ; R = H) was treatedwith 2,4-dimethoxyaniline in refluxing diphenyl etherthe ‘ mixed ’ tetracyclic compound (2g) was obtained.A possible explanation for the formation of compound(2) in this reaction is suggested in the Scheme. Thequinolone (8) might cyclise via internal Markownikoffaddition of the 4-hydroxy-group to the side-chainolefinic bond to yield the tricyclic derivative (9). Thiscompound might then undergo retro-Diels-Alder reactionat the high temperature of the reaction to yield the‘ quinone methide ’ type of compound (10).Additionof aniline to this compound should by precedent,* yieldthe Mannich base (11) which might rearrange to theintermediate (12). Alternatively, aniline might adddirectly to the quinone methide (10) to yield the inter-mediate (13). The intermediates (12) and (13) wouldboth be capable of cyclisation to the tetracyclic com-pound (14) which might oxidise readily to (2).The formation of the 3,3’-methylenebis-4-hydroxy-2-quinolones (7) might also be explained by this Scheme.A retro-Mannich reaction would allow the Mannichbase (1 1) to yield the parent 4-hydroxy-2-quinolone.This might then condense with the ‘ quinone methide ’(10) to yield the bisquinolone (7).The feasibility of the cyclisation of the quinolone (8)to the tricyclic compound (9) in this Scheme was testedby allowing aniline to react with diethyl 2-(prop-2-eny1)malonate in refluxing diphenyl ether.This re-action had been reportedlo to yield no characterisableproducts, but we were able to isolate the diphenyl-malonamate (15) and a compound with an n.m.r.spectrum completely in accord with the tricyclic struc-ture (16). The absence of a shift to shorter wavelengthsin the U.V. spectrum in hexane compared to that inmethanol l1?l2 and the absence in the n.m.r. spectrum ofthe low-field C, proton l3 which would be expected in thealternative linear 4-quinolone supported this structure.Thus Markownikoff cyclisation had occurred under thereaction conditions. In this case, the direction ofcyclisation yielded a five-membered ring and so thel1 H.Rapoport and K. G. Holden, J . Amer. Chem. SOC., 1900,82, 4395.l2 J. A. Bosson, M. Rasmussen, E. Ritchie, A. V. Robertson,and W. C . Taylor, Austral. J . Chem., 1963, 16, 480.Is A. V. Robertson, Austral. J . Chem., 1963, 16, 4512548MeJ.C.S. Perkin IMe Me/H H\HSCHEMEretro-Diels-Alder I eact ion and the subsequent react ionsin the Scheme were precluded.The sequence of steps in the Scheme from the Mannichbase (1 1) through the intermediate compounds (12) and(14) to (2) has an analogy in the known reaction 14p*5of the Mannich base (17) which yields the dibenzacridine(18) via the intermediate compound (19). An attemptwas made to stop the reaction sequence at the oxidationlevel of compound (14) by using N-methylaniline in thereaction.The only tetracyclic compound to be isolatedfrom this reaction was the compound (2b). ThermalN-demethylation had, therefore, occurred in the reaction.The bisquinolone ( 7 ; R1 = Me, RZ = H), was alsoobtained in this reaction.We are currently examining the possibility of exploit-ing this interesting but low-yielding reaction by develop-ing it into a useful and general synthesis of polycyclicheteroaromatic compounds.EXPERIMENTAL( 1 7 1 M.p.s were determined on the Kofler block and areuncorrected. 1.r. spectra were recorded on a Perkin-Elmer237 machine and U.V. spectra on a Unicam SP 800 spectro-photometer. N.m.r. spectra were recorded on Varian T60and HA100 instruments and mass spectra on Hitachi\ 2 \ RMU-6 (low-resolution spectra) and A.E.I.MS9 machinesl4 R. S. Corley and E. R. Blout, J . Amer. Chem. Soc., 1947, 60,E. R. Rlout and R. S. Corley, J . Amer. Chem. Soc., 1947, 80.W8-B\ 0 \ OH H2N / N 761.( 1 8 ) ( 1 9 ) 7631977 2549(high-resolution spectra). We thank Mr. and Mrs. A. G.Olney for microanalyses and Mr. P. Dew and Mr. A. Green-way for n.m.r. and mass spectra respectively.Reaction of 2,3-Dimethoxyaniline with Diethyl 2-( 3-Methylbut-2-enyl)rnaZonate.-Diethyl 2-(3-methylbut-2-eny1)malonate (8.1 g, 35.3 mmol) and 2,3-dimethoxyaniline(5.45 g, 35.6 mmol) were dissolved in redistilled diphenylether (70 ml) and heated at reflux under nitrogen for 2.5 h.The reaction mixture was cooled and 4-hydroxy-7,8-dimethoxy-3-dimethylaZZyl-2-quinolone (3.11 g, 31 yo) separ-ated out of solution.The solution was filtered and hexanewas added to the filtrate when a yellow powder (526 mg,4%) separated out. This wa,s filtered off, washed withwater, and recrystallised from glacial acetic acid as yellowneedles (374 mg), m.p. 248-249 "C (Found: C, 65.55;H, 5.1; K, 7.6. C,,Hl,N20, requires C, 65.55; H, 4.95;N, 7.65y0), m/e 366 (M+); vmZ (Nujol) 3 180 (NH),1 710, and 1 640 cm-l; vmx. (CHC1,) 3 380 (NH) and 1 665cm-l (amide); A,,,. (MeOH) 216, 232sh, 252, 262sh,295sh, 301, and 358 nm (log E 4.49, 4.34, 4.45, 4.29, 4.594.60, and 3.78); A,,, (H+-MeOH) 219, 235sh, 250, 277,306, 316, and 424 nm (log E 4.58, 4.47, 4.29, 4.42, 4.35,4.37, and 4.26); z (CDC1,) 0.88 [l H, s, HB in (2)], 1.40[ l H, d, J 9.5 Hz, HLL in (2)], 2.31, 2.68, and 3.13 (all 1 H,d, J = 9.5 Hz, ortho-coupled ArH), 5.80 (3 H, s, OMe),6.00 (3 H, s, OMe), and 6.08 (6 H, s, OMe). An NH protonabsorption a t z 1.16 was exchangeable with D20.Thecompound was concluded to be 3,4,10,1 l-tetramethoxy-dibenzo[b,h][1,6]na~hthyridin-6(5H)-one (2a).of 3,4,10,11- Tetramethoxydibenzo [ b, h] [ 1,6] -naphthyridin-6( 5H) -one (2a) .-The tetracyclic productfrom the above reaction (60 mg, 0.164 mmol) was suspendedin dry benzene (18 ml) with sodium hydride (15 mg) in anatmosphere of dry nitrogen. The mixture was heated toreflux with stirring for 3 h and dry methyl iodide (3 ml) indimethylformamide (5 ml) was added. The mixture washeated for a further 5 h a t reflux under nitrogen and thencooled and poured into a mixture of ice-water.The mix-ture was extracted thoroughly with chloroform. Theextracts were dried (Na,SO,) and the solvent was removedin vacuo to yield a yellow solid (56 mg, 90%) which wascrystallised from 95% ethanol as yellow needles, m.p.169-170 "C (Found: C, 66.0; H, 5.4; N, 7.05. C,,H,,-N,O, requires C, 66.3; H, 5.3; N, 7.35%), m/e 380 (M+);v,,,. (Nujol) 1655 cm-l (amide); Amx. (MeOH) 225, 236sh,257, 303, 363, and 374 nm (log E 4.27, 4.17 4.26, 4.44, 3.65,and 3.65) ; A,,,. (H+-MeOH) 223, 240sh, 279, 307, 321sh, and429 nm (log E 4.35, 4.27, 4.22, 4.22, 4.16, and 3.93); z(CDC1,) 0.90 [ l H, s, H, in (2)], 1.13, 2.26, 2.65, and 3.01(each 1 H, d, J = 9 Hz, ortho-coupled ArH), 5.76, 5.93, and6.18 (each 3 H, s, OMe or NMe), and 6.01 (6 H, s, OMe orNMe).Treatment of 3,4,10,1 l-Tetramethoxydibenzo[b,h][1,6]-naphthyridin-6(5H)-one (2a) with POCl,.-Compound (2a)(20 mg, 0.055 mmol) and POC1, (2 ml) were heated togetherfor 2 h during which time the temperature of the oil-bathwas raised to 125 "C.Heating was continued a t thistemperature for a further 30 min and then excess of POCl,was removed in vacuo. The resultant red glass was dis-solved in chloroform and added to a mixture of ice (15 g)and 5% aqueous ammonia solution (25 ml). The mixturewas stirred well and the colour of the chloroform layerchanged from red to yellow. The chloroform layer wasseparated off and the remaining aqueous layer was extractedwell with chloroform.The combined chloroform layersMethy Zationwere dried (Na,SO,) and the solvent was removed invacuo to yield an orange semi-solid, which appeared as onespot on t.l.c., v-. (CHC1,) 1618 and 1598 cm-l (Ar); Lx.(MeOH) 243, 251, 270, 294, 310sh, and 392 nm;A(H+-MeOH) 242, 250sh, 300sh, and 410 nm. The massspectrum had parent ions a t m/e 383 and 385 of intensityratio 3 : 1 as expected for compound (3) ; z (CDCl,) 0.93(1 H, s, ArH), 1.03,2.16,2.54, and 2.61 (each 1 H, d, J = 9 Hz,ortho-coupled ArH), and 5.69, 5.84, 5.90, and 5.95 (each 3 H,s, OMe).Reaction of Aniline and Diethyl 2-( 3-Methylbut-2-enyl) -mazonate.-Diethyl 2-( 3-methylbut-2-eny1)malonate (2.9 g,12.7 mmol) and aniline (redistilled; 7 g, 75.3 mmol) wereheated in diphenyl ether (30 ml) at reflux for 15 h.Thediphenyl ether was removed by distillation in vacuo andthe residue was treated with dichloromethane. Theinsoluble material was a high-melting solid, m.p. 350 "C,with an i.r. spectrum identical to that of a sample of 3,3'-methylenebis-4-hydroxy-2-quinolone (7 ; R1 = R2 = H) pre-pared by the method of Menzer et aZ.16 The dichloro-methane solution was evaporated to dryness and the result-ant material was dissolved in glacial acetic acid. With timecrystals of dibenzo [b, h] [ 1,6] naphthyridin- 6 (5H) -one (2e)separated out. This compound was purified by sublimationin vacuo (46 mg, 1.5y0), m.p. 329-330 "C (Found: C, 78.2;H, 4.5; N, 11.55. C16Hl,N,0 requires C, 78.05; H, 4.1;N, 11.4%); vmaX. (Nujol) 1670 cm-l; Amx.(MeOH) 265sh,273 and 287 nm (log E 4.30, 4.50, and 4.09) ; hX. (H+) 260sh,273, 288, 299, and 358 nm (log E 4.0, 4.13, 4.05, 4.0, and2.99; T [(CD,),SO] 0.7 (1 H, s, ArH), 1.21 (1 H, d, J = 7 Hz,ArH) and 1.65-2.80 (m, ArH).In one such experiment, refluxing the above mixture for18 h gave a good yield [4.01 g from 2.9 g of diethyl 2-(3-methylbut-2-enyl)malonate] of a compound which crystal-lised from methanol, m.p. 184-186 "C (Found: C, 75.0;H, 7.0; N, 8.4. C2,H2,N20, requires C, 74.5; H, 6.9;N, 8.7%); vmx. 1670 cm-l; z (CDCl,) 0.78 (2 H, s,NH), 2.36-2.96 (10 H, m, ArH), 4.82 (1 H, t, J = 7.5 Hz,olefinic), 6.58 (1 H, t, J = 7.5 Hz, COCHCO), 7.23 (2 H, t,J = 7.5 Hz, allylic CH,), 8.36 and 8.40 (6 H, 2 x s, Me).This was evidently 2-( 3-methylbut-2-eny1)malondianilide (5).Methylation of Dibenzo[b,h] [ 1,6]naphthyridin-6( 5H)-one.-Dibenzo[b,h][l,6]naphthyridin-6(5H)-one (60 mg, 0.24mmol) was suspended in dry benzene (18 ml) and heatedwith a 60% dispersion of sodium hydride in mineral oil(10 mg) in an atmosphere of nitrogen for 3 h a t reflux.Drydimethylformamide (5 ml) and dry methyl iodide (6 ml)were added and heating was continued for a further 5 h atreflux. The cooled mixture was poured into ice-waterand extracted with chloroform. The extracts were dried(Na,SO,) and the solvent was removed in vacuo to yield asolid which recrystallised from aqueous ethanol (46 mg),m.p. 224-225 "C (lit.,2 m.p. 218 "C), vmx. (Nujol) 1650cm-l (amide); A,,,. (MeOH) 230, 266sh, 275, 290, and301sh nm (log E 4.58, 4.64, 4.76, 4.34, and 4.19); A,,,. (H+)230, 257, 275, 285, 300, and 360 nm (log E 4.58, 4.37, 4.43,4.33, 4.24, and 3.79); z (CDCl,) 0.66 [ l H, s, H s in (Z)],0.90[1H,dd, J8and2Hz,HAin(2)], 1.72[1H,d, J = 8Hz, Ar], 1.94 (1 H, d, J = 8 Hz, Ar), 2.0-2.7 (5 H, ArH),and 6.15 (3 H, s, NMe).Permangamate Oxidation of 5,6-Dihydrodibenzo[b,h][ 1,6]-naphthyridine (6) .-5,6-Dihydrodibenzo[b, h] [ 1,6]naphthyr-idine (400 mg, 1.72 mmol) was dissolved in acetonel6 C.Menzer, P. Meunier, J. LeCocq, and D. Billet, Bull. SOC.chim. France, 1945, 12, 430J.C.S. Perkin I(minimum) and a small excess of a saturated solution ofpotassium permanganate was added dropwise to the solution.This mixture was shaken for 1 h and then filtered; theresidue was then further extracted with boiling acetone.The acetone solutions were combined and the solvent wasremoved in vacuo to yield a solid which crystallised fromacetone as cream needles (373 mg, 93%). This compoundhad all the characteristics of dibenzo[b,h] [ 1,6]naphthyv-idine, with m.p.186-187 "C (reported m.p. 186-187 "C),v,. (Nujol) 1600 cm-l (Ar), m/e 230 (M+), T (CDC1,) 0.71(1 H, s, Ar), 1.28 (1 H, s, Ar), and 1,6-1.8 (8 H, Ar).Oxidative Methylation of 5,6-Dihydrodibenzo[b,h] [l,6]-naphthyridine (6) .-5,6-Dihydrodibenzo[b, h] [ 1,6]naphthyr-idine (60 mg, 0.26 mmol) was suspended in dry benzene(18 ml). A 60% dispersion of sodium hydride in mineraloil (10 mg) was added to the suspension which was thenheated to reflux in an atmosphere of nitrogen for 3 h.Drydimethylformamide ( 5 ml) and dry methyl iodide (5 b l )were added. Reflux was continued for a further 5 h. Themixture was cooled, poured into ice-water, and extractedwith chloroform. The extracts were dried (Na2S04) andthe solvent was removed in vacao to yield a solid which wasrecrystallised from aqueous ethanol (20 mg, 30%), m.p.224-225 "C. The spectra of this compound were identicalto those of the product from methylation of dibenzo[b,h]-[1,6]naphthyridin-6(5H)-one. When the reaction wasattempted in the absence of a nitrogen atmosphere, intract-ible gums were obtained.Reaction of ortho-Anisidine with Diethyl 2-( 3-Methylbut-2-enyl)malonate.-ortho-Anisidine (2.94 g, 23.9 mmol) anddiethyl 2-(3-methylbut-2-enyl)malonate (5.55 g, 24.3 mmol)were dissolved in diphenyl ether and the mixture was heateda t reflux for 3 h in an atmosphere of nitrogen. 4-Hydroxy-8-methoxy-3-dimethylallyZ-2-quinolone (670 mg, 11 yo) pre-cipitated from the solution on cooling.This was recrystal-lised from ethanol, m.p. 224-228 "C (lit.,2 m.p. 228-230 "C), Amx. (MeOH) 244, 250, 279, 287, and 320 nni(lit.,2 A,,,. 243, 250, 280, 288, and 320 nm). The diphenylether-soluble material was refluxed for a further 3 h whenfurther material (3.4 g) was obtained by precipitation.Recrystallisation from ethanol gave ethanol-insolublematerial (64 mg), m/e 394, with an i.r. spectrum identicalto that of a sample of 3,3'-methylenebis-4-hydroxy-8-methoxy-2-quinolone (7; R1 = H, R2 = OMe) obtained by indepen-dent synthesis, The ethanol-soluble material yielded afurther sample of the quinoline (4b) (3.12 g).Reaction of 4-Hydroxy-8-methoxy-3-dimethyZallyl-2-quino-lone with ortho-A nisidine.-The 2-quinolone (4b) (500 mg,1.93 mmol) and ortho-anisidine (240 mg, 1.95 mmol) were re-fluxed in dry diphenyl ether (5 ml) in an atmosphere of nitro-gen for 7 h.On cooling, the bisquinolone (7; R1 = H, R2 =OMe) (104 mg) separated out. This insoluble solid, m.p. 350 "C (m/e 394) (Found: C, 63.75; H, 5.0; N, 7.0. C,,H,,-N20, requires C, 63.95; H, 4.6; N, 70y0), had an i.r. spectrumidentical with a sample prepared by independent synthesis.The diphenyl ether was removed in vacuo from the filtrateand the resultant mixture was dissolved in chloroform.Thesolution was washed well with 2~-aqueousodium hydroxideand water and dried (Na,SO,) . The solvent was removed invacao to yield a solid which was subjected to preparative t.1.c.and sublimed to yield the tetracyclic compound (2f), m.p.271-273 "C (Found: C, 70.35; H, 4.9; N, 8.8. C,,H,,N,O,* This compound (m.p. 233 "C) has been prepared by an inde-pendent method.17 We thank Professor Kappe for bringing thiswork to our attention.requires C, 70.6; H, 4.6; N, 9.15%), v,, (Nujol) 1665cm-l (amide); Am,. (MeOH) 226, 244, 252, 293, and 356nm (log E 4.47, 4.48, 4.47, 4.61, and 3.76); Amx. H+-MeOH) 226, 240, 255, 293, 312, and 376 nm (log E 4.43,4.41, 4.41, 4.47, 4.07, and 3.86); T [(CU,),SO] 0.78 (1 H,s, HB), 2-3 (6 H, Ar), 5.91 (3 H, s, OMe), and 6.05 (3 H,s, OMe).Synthesis of 3,3'-Methylenebis-4-hydroxy-8-nzethoxy-2-quin-olone (7; R1 = H, R2 = OMe).-4-Hydroxy-8-methoxy-2-quinolone (1 g, 2.55 mmol) was dissolved in boiling water(70 ml) and 40% aqueous formaldehyde solution ( 5 ml) wasadded to it.The mixture was heated at reflux for 2 min.The product precipitated on cooling and was washed wellwith ethanol and dried. The resultant solid (450 mg),m.p. 350 "C, v,,,. (Nujol) 1 650 cm-l, was extremelyinsoluble in most solvents.Pyrolysis of 2-( 3-Methylbut-2-enyZ)malondianilide ( 5 ) .-2-(3-Methylbut-2-enyl)malondianilide (5) (1 g , 3.1 mmol)was heated in an atmosphere of nitrogen at 260 "C withoutsolvent for 4.5 h. The resultant product was dissolved inethanol to leave the insoluble dibenzo[b,h] [ 1,6]naph-thyridin-6(5N)-one (2e) (80 mg, 10.5%). The ethanol-soluble portion of the product proved to be a mixture of un-changed dianilide and 3-dimethylallyl-4-hydroxy-2-quino-lone (4a).Reaction of 4-Hydroxy-7,8-dimethoxy-3- (S-methyZbut-2-enyl)-2-quinolone (1 ; R = H) with 2,4-Dirnethoxyaniline.-4-Hydroxy-7,8-dimethoxy-3- (3-methylbut-2-enyl)-2-quino-lone (110 mg, 0.397 mmol) and 2,4-dimethoxyaniline (55 mg,0.359 mmol) were dissolved in diphenylether (5 ml) and heatedat reflux for 7 h in an atmosphere of dry nitrogen.The re-action mixture was cooled and hexane (5 ml) was added toprecipitate a solid which was washed with hexane and re-crystallised from glacial acetic acid.This solid was dis-solved in chloroform and the solution washed with 2~-sodiumhydroxide and water and then dried (Na,SO,) . The solventwas removed in vacuo t o yield compound (2g), a yellowsolid (5 mg) which separated from 95% ethanol as yellowplates, m.p. 275-277 "C (Found: m/e 366.119 28. C2,H,,-N20, requires M, 366.121 56), vmx. (CHC1,) 3 370 (NH) and1 665 cm-1 (amide); A,,,. (MeOH) 235sh, 253, 263, 300,345s, and 410 nm; Amx. (H+-MeOH) 234sh, 251, 280, 308,332, 388, and 466 nm; 7(CDCl,) 0.94 (1 H, s, H, in 2), 1.08(1 H, exchangeable with D20, NH), 1.43 (1 H, d, J 9 Hz,Ar), 2.48 (1 H, Ar), 3.06 (1 H, d, J 8 Hz, Ar), 3.16 (1 H,Ar), 5.92, 6.03, 6.05, and 6.09 (all 3 H, s, OMe).Reaction of Diethy2 2-(Prop-2-enyl)malonate with Ani-line.-Diethyl 2-(prop-2-enyl)malonate (5 g, 25 mmol)and aniline (2.32 g, 25 mmol) were dissolved in diphenylether (50 ml) and refluxed for 12 h in an atmosphere ofnitrogen.At this point a solid precipitated out on coolingand this proved to be 2-(prop-2-enyl)malondianiZide, (15),m.p. 199-201 "C (Found: C, 73.15; H, 6.35; N, 9.4.Cl,Hl,N202 requires C, 73.45; H, 6.15; N, 9.5%). Refluxwas therefore continued for a further day. Light petroleum(b.p. 60-80 "C) was added to the solution when the tricycliccompound (16) * was precipitated as a solid (1.25 g, 25%).This product was triturated with diethyl ether and recrystal-lised from acetone, m.p. 232 "C (Found: C, 71.25; H, 5.9;N, 6.2. C12H11N0, requires C, 71.6; H, 5.5; N, 6.9%), m/e201, A,. (MeOH) 279, 290, 315, and 326 nm, A,,, (cyclo-hexane) 280, 292, 319, and 333 nm; T (CDC1,) - 1.92 (1 H, s,l7 T. Kappe, P. F. Fritz, and E. Ziegler, Chem. Ber., 1973, 116,19271977NH, exchangeable with D,O), 2.25-2.9 (4 H, m, Ar), 4.75(1 H, m, CH), 6.57 and 7.12 (2 H, AB, JAB 15 Hz, Jax 10 Hz,Jsx 7 Hz, CH,), and 8.43 (3 H, d, J 6 Hz, Me).Reaction between N-Methylaniline and Diethyl 2-( 3-methyEbut-2-enyl)maEonate.-N-Methylaniline ( 1 g, 9.34mmol) and diethyl 2-( 3-methylbut-2-eny1)malonate ( 1 g,4.4 mmol) were dissolved in dry diphenyl ether (6 ml) andrefluxed for 14 h in an atmosphere of nitrogen. The solventwas removed in vacuo. The resulting material was tritur-ated with light petroleum and digested in boiling ethanol.The ethanol-insoluble material, m.p. 300-302 "C (270 mg),had an i.r. spectrum identical to that of NN'-dimethyl-3,3'-methylenebis-4-hydroxy-2-quinololae (7 ; R1 = Me, R2 = H)prepared by an independent method. The ethanol-solublematerial was recrystallised from ethanol and proved to be5-methyldibenzo[b,h][ 1,6]na~5hthyridin6(5H)-one (2b) identi-cal with an authentic specimen (vide infra) in all respects.NN-Dimethyl- 3,3'-methylenebis-4-hydroxy-2-quinolone ( 7 ;R1 = Me, R2 = H) .- 4-Hydroxy-N-methyl-2-quinolone(200 mg) was added to water (50 ml) and boiled for 5 minwith 40% aqueous formaldehyde solution (excess). Thesolution was cooled and the resultant precipitate waswashed well with ethanol to yield a white solid (120 mg),m.p. 300-302 "C [Found: C, 69.1; H, 5.4; N, 7.75.C,,H,,N204 requires C, 69.6; H, 5.0; N, 7.750/&), 'm/e 362,v,,, (Nujol) 1 645 cm-l (amide).We thank the S.R.C. for studentships (to R. 0. and R. S.).[7/1031 Recpived, 16th June, 1977