1972 2485Synthesis and Sta bi I ity of 2- Methyl -2,4-d iaza- and 2- Methyl-2,5-diaza-indene t (2-Methyl-pyrrolo3,4-bpyridine and -pyrroIo3,4=cpyridine)By W. L. F. Armarego,’ Beverly A. Milloy, and S. C. Sharma, Department of Medical Chemistry, John CurtinSchool of Medical Research, Australian National University, Canberra, A.C.T., Australia2-Methyl-2,4-diaza- (2) and 2-methyl-2.5-diaza- (3) indenes have been prepared by oxidation of 2.3-dihydro-2-methyl-IH-2.4-diaza- (1 0) and 2.3-dihydro-2-methyl-1 H-2,5-diaza- (1 4) indene, respectively with 2.3-dichloro-5,6-dicyano-l,4-benzoquinone. They are more stable than 2-methyl-2-azaindene (1) in dilute acid, as neutralspecies in aqueous solution, and to aerial oxidation, and form stable picrates. The two diazaindenes (2) and (3) arerelatively strong bases ; and although protonation occurs predominantly on N - 4 and N-5, respectively, to formresonance-stabilised cations, the ease of exchange of H-1 and H-3 (the former being greater) by deuterium indilute acid, suggests that some protonation also takes place on C-1 and C-3, separately, as in 2-methyl-2-azaindene.The n.m.r. chemical shifts of H-1 and H-3 in the three azaindenes (1)-(3) indicate that they arearomatic systems.ISOINDOLE (2-azaindene) has been shown to be unstable,but its existence as a transient intermediate has beenconfirmed by trapping as the Diels-Alder adducts withmaleic acid and N-phenylma1eimide.l 2-Methylisoin-dole (2-methyl-2-azaindene) (1), on the other hand,has been isolated in crystalline form.Although it ismore stable than isoindole, it deteriorates at roomtemperature and darkens rapidly in solution.2 Wehave now studied the analogues, 2-methy1-2,4-diaza- (2)and 2-methyl-2,Ei-diaza- (3) indene ; the insertion ofthe extra nitrogen atom was expected to make the systemmore stable see resonance structures (4) and (5).Also, electron withdrawal by the inserted nitrogenatom presumably makes the pyrrole ring less reactivetowards electrophilic attack, which is most probablythe basis of its instability. Stable isoindoles with oneand two nitrogen atoms in the benzene ring have beenprepared but these examples had several substituentsin one or both rings and were not compared directlywith the benzene Isoindoles with severalsubstituents (e.g.methoxycarbonyl, alkyl, aryl, benzo)are known to be more stable than the parent compound.6We have synthesised the diazaindenes (2) and (3) andhave found, by direct comparison, that they are morestable than 2-azaindene (2-methylisoindole) .Dimethyl pyridine-2,3-dicarboxylate (6) was reducedwith lithium aluminium hydride to the correspondingdiol (7). The crude diol was converted into the un-stable hydrochloride of 2,3-bischloromethylpyridine (8) ,which when treated with an excess of ethanolic methyl-amine at room temperature formed 2,3-dihydro-2-methyl-lH-2,4-diazaindene (10). Dehydrogenationwith 2,3-chloro-5,6-dicyano- 1,4-benzoquinone gave2-methy1-2,4-diazaindene (2) in 21 yo yield. This re-action was carried out according to the method recentlydescribed for the dehydrogenation of dimethyl 2,3-di-hydro-1H-2-azaindene-l,3-dicarboxylates with tetra-chloro-1,4-ben~oquinone.~ Similarly dimethyl pyridine-3,4-dicarboxylate (1 1) was converted into 2-methyl-The azaindene terminology is used to facilitate comparisonsbetween isoindoles and the analogous pyrrolopyridines.R.Kreher and J. Seubert, 2. Naturforsch., 1965, 2Ob, 76. * G. Wittig, H. Tenhaeff, W. Schoch, and G. Koenig, Annalen,E. Benary, B e y . , 1918, 51, 567.1961, 572, 1.2,5-diazaindene (3) via the intermediates (12), (13),and (14). The higher yield (50) in the last step ofthis synthesis compared with the previous one is attri-buted to the greater stability of the isomer (3) compared1(61 R = C02Me(7) R=CH,.OH(81 R CH2Cl(91 R =CHz*OAcii 115)HHN+.m M e HN ;Me /(16)with (2) at the high pH values used in the isolation of thefree bases.4 R. C. Anderson and R. H. Fleming, Tetrahedron Letters,6 R. Kreher and G. Vogt, An.gew. Chem. Internat. Edn., 1970,6 J. D. White and M. E. Mann, Adv. Hetevocyclic Chem., 1969,7 G. Cignarella and A. Saba, Ann. Chinz. (Italy), 1970, 60,1969, 1581.9, 955.10, 113.765J.C.S. Perkin IThe two diazaindenes (2) and (3) are stable crystallinesolids which can be recrystallised and sublimed and formstable monopicrates. These can be stored at roomtemperature without appreciable deterioration and areunchanged when kept at 0" for a few months. They areunaltered when kept in deuteriochloroform solutionfor at least 2 days.In comparison, 2-methyl-2-aza-indene darkens rapidly, and decomposes on treatmentwith picric acid in ethanol or benzene. In deuterio-chloroform solution containing 2-methyl-2-azaindene abrown colour is fonned at the air-solution interfaceafter 15 min at 33" which is most probably caused byaerial oxidation. The diazaindenes did not give ad-ducts similar to those of 2-methyl-2-azaindene withmaleic anhydride.The diazaindenes (2) and (3) are relatively strongbases, pK, (water) 6.46 and 8-67, respectively. Nodficulty was experienced in obtaining these values,each of which is the mean of at least seven measurements.They are stronger bases than pyridine (5.29) andlH-l-pyrindene (5.7; note that the pK, value of 8.7for 1-methyl-1H-l-pyrindene is meaningless lo).Theincrease in basic strength, which is contrary to whatwould be expected on making the system more x-de-ficient l1 by inserting a nitrogen atom into the benzenering of 2-methyl-2-azaindene (estimated pK, ( 0 ;cj. pK, of l-methylpyrrole,s -2.90) , can be explained bythe greater resonance stabilisation in the cations (15)and (16) compared with the neutral species (4) and (5) ,respectively. The U.V. spectra of the neutral species(pH 11) and cations (pH 4) of the diazaindenes (2) and(3) in aqueous buffers have three main bands (seeExperimental section) and are in this respect similarto the spectrum of 2-methyl-2-azaindene (1) in waterat pH 6.8. However, the spectra of the diazaindenesare barely altered after 2 days at 20°, whereas thespectrum of 2-methyl-2-azaindene changes immediatelyon mixing the solution and after 18 h the solutionI I I f I .L7.5 7 4 6.56 IP.P.rn.1FIGURE 1 lH N.m.r. spectrum of 2-methyl-kazaindene (1)(CDCl,; 100 MHz) ; the methyl signal is not showndarkens and strong absorption appears between 220and 380 nm (see Experimental section).* D. D. Perrin, ' Dissociation Constants of Organic Bases inAqueous Solution,' Buttenvorths, London, 1966.The lH n.m.r. spectra of 2-methyl-2-azaindene and thediazaindenes in deuteriochloroform are shown inFigures 1-3. The assignments of peaks and couplingJ8.50 600 7.5 0 7 4 0. .I I 1 I I t6 IP.P.rn.1FIGURE 2 lH N.m.r. spectrum of 2-methyl-2,4diazaindene(2) (CDCl,; 100 MHz); the methyl signal is not shownI I I 1 I8 4 0 7.00 7.50 6 .(p.p.m.1(a) lH N.m.r. spectrum of 2-methyl-2,6-diazaindene(3) (CDCl,; 100 MHz) : (b) decoupled spectrum obtained byirradiation at frequency of H-4 (the methyl signals are notshown)FIGURE 3constants are straightforward except for those of H-1and H-3 in 2-methyl-2,5-diazaindene. In this case theupfield multiplet is from H-1; irradiation at the H-4resonance frequency causes the multiplet from H-1to collapse to a sharp doublet (still coupled with H-3).The coupling constants of 2-methyl-2-azaindene aretoo complex for first-order analysis. Like isobenzo-C. B. Reese, J. Amer. Chem. SOL, 1962, 84, 3979.l o A. G. Anderson, jun., and H.L. Ammon, Tetrahedron, 1967,11 A. Albert, ' Heterocyclic Chemistry,' Athlone Press, London,23, 3601.1968, p. 671972furan,12 the chemical shifts of the signals from H-1and H-3 of the three azaindenes are in the aromaticregion and suggest that the five-membered rings aresustaining a ring current. The spectra of the diaza-indenes in 0*5~-deuterium chloride in deuterium oxide(pH ca. 1) showed the characteristic downfield shifts andit was clear that exchange of H-1 and H-3 by deuteriumwas taking place. The exchange reactions took placeas follows : 2-methyl-2,4-diazaindene, H-1 (goyo), H-3(0) after 15 min; H-1 (loo), H-3 (80) after 2 h;signals from H-1 and NMe appearing at 8 4.68 and 3.50p.p .m . , respectively (cf. te tramethyl-2-azaindene cationin ref.13) ; the colour of this solution darkened but thespectrum remained unchanged during 24 h.The mass spectra of the azaindenes (1)-(3) aresimilar to one another and the molecular ion peaksare the base peaks. The second most intense peakcorresponds to M+ - 1 and is only 30 of the base peakindicating that the molecular ions are very stable. Inthe three compounds fragmentation takes place by lossProton magnetic resonance spectra of pyridines and azaindenes (60 MHz; 33'; 6 in p.p.m.; J in Hz) aPyridine H-1 H-2 H-22,3-Dimethoxy-carbonyl-2,3-Bis-hydroxy-methyl- b2,3-Bisacetoxy-methyl-3,4-Dimethoxy-carbonyl-meFyl- b3,4-Blsacetoxy-methyl-3,4-Bischloro-methyl- b3-hfethoxycarbonyl-4-methyl-3-Hydroxyme thyl-4-methyl-4-Hydroxymethyl-3-methyl-2,4-Diazaindene3,4-Bk-hydroxy-8.25(~)2-Methyl- 6*95(d, Ji,r 2-51 7*29(q, Js 2.5,J ~ , ~ id 2-Methyl- (cation) 7*46br(s) 7.65br(s)2.3-Dihydro- 3-95(s)2-methyl-1H-methyl-1-0x0-1H-4-oxide2,3-Dihydro-3-hydroxy-3-3*95(s)2,3-Dihydro-2- 3.85(s)2,3-Dihydro-2,2- 5.04(s)methyl-la-dimethy 1-1 H-(iodide)7.48(d, Js,s 5.5) 8*34(d, 5.5)4-70(s, CHI), D,O 04-791~, CH,)2*10(s, CH,),2*14(s, CH,)5*21(s, 2 x CH,), CDCI,4.65(s, 2 X CH,) CDCI,2.58(s, C-CH,), CDCI,3*90(~, OCH,)4.63(~, CH,O),5.45(s, OH)2.29(~, C-CHs), CDCI,2*20(~, C-CH,), CDCI,4.69(~, CH,O),5*17(~, OH) 07*84(octet, J7,, 1.0, 3.99(s, N-CH,) CDCIJJ7.s 1.6, J I , I 8-718*49(q, J 7 , s 2, J7.0 6) 4.16(sj N-CHJ 0.5N-DCI-DZO 0, u7.5O(q, J 7 .s 1.5, 2*63(~, N-CH,) CDCI,7-57(d,a J 4-0) 1*82fs, C-CH,), (CD,),SOJape 7-816*58br(s, OH),@9.34br (s, NH) e7.26(sextet, J7,r 0.9,h 3.98(s, N-CH,) CDCIJ7.636, J,,, 6.6; 4.20(s, N-CH,! O-~N-DCI- D.0 c. LJJ I O W J , 8-212-Methyl-2-aza- 6.97(s) 6.97(~)indene(cation) 4-68(~) 8*58(s) 4 t 3*50(~, N-CH,) D,SO,8 First-order analysis of spectra; tetramethylsilane as internal standard; coupling constants are from an expanded scale (error f0-2). 6 These spectra are of the crudesubstances but do not contain other signals from impurities. 8 Sodium 3-(trimethylsilyl)propane~ulphonate as internal standard. d This is a deceptively simply ABXspectrum. 8 Exchanged by D,O. I At 100 MHz see Figures. 0 pH ca. 1.0. Value obtained from decoupled spectrum, and from measurement of signals from H-7.Multiplet not amenable to first-order analysis.j'A quartet which is further coupled with H-1 and H-3.H-1 ( l O O ~ o ) , H-3 (100) after 19 and 26 h; 2-methyl-2,5-diazaindene, H-1 (30), H-3 (0) after 5 min;H-1 (looyo), H-3 (20) after 2 h ; H-1 (loo), H-3(looyo) after 19 and 26 h. The signals (and particularlythe sharp signals from the methyl group) in the re-mainder of the spectra remained unchanged duringthis period, indicating that no appreciable chemicalchanges had occurred. Cations of the type (17) and(18) are probably formed in acid solution, with isomer(17) being more favoured than isomer (18), and accountfor the deuterium exchange. 2-Methyl-2-azaindene,on the other hand, became black and polymerised assoon as the dilute deuteriated acid was added to it.However, in concentrated deuteriosulphuric acid thespectrum can be assigned to the cation (19) with theof CH3+ and HCN+.In comparison the dihydro-derivatives (10) and (14) give intense base peaks atm/e 133 attributable to cations such as (15) and (16)or (17) or (18), which lose CH3+ and HCN+. 2,3-Di-hydro-2,2-dimethyl-lH-2,5-diazaindene (20) also givesan intense base peak at mie 133.Several unsuccessful attempts to synthesise 2,4-and 2,5-diazaindenes were made and will be describedbriefly. 2-Methylpyrrolo3,4-bquinoxaline was pre-pared in high yield by dissolving 2,3-bisbromomethyl-quinoxaline 1-oxide in anhydrous methylamine at-8OO.4 Similar treatment of 2,3-bisbromomethyl-pyridine 1-oxide hydrobromide (21), however, did notl2 R. N.Warrener, J . Amer. Chem. SOL, 1971, 93, 2346.l3 C. 0. Bender and R. Bonnett, Chem. Comm., 1966, 1982488 J.C.S. Perkin Igive the desired product (2). All attempts to reduce2,3-dihydro-3-hydroxy-3-methyl-lH-2,4-diazainden-l-one 4-oxide (22) or its 4-deoxy-derivative in severalsteps in order to obtain 3-methyl-ZJ4-diazaindene wereunsatisfactory because reduction of the pyridine ring00,H Br 0( 2 1 ) ( 2 2 )always occurred simultaneously with loss of oxygen.2,3-Dihydro-2,2-dimethyl-lH-2,5-diazaindenium iodide(20) did not give the diazaindene (3) when treated withphenyl-lithium, a reagent which converts 2,3-dihydro-2,2-dimethyl-1H-2-azaindenium salts into Z-methyl-2-azaindenes in high yield.2 This is probably becausethe reagent also adds across the C=N bond of the pyri-dine ring.14 In earlier attempts a t reducing dimethylpyridine-3,4-dicarboxylate with sodium bis-(2-methoxy-ethoxy) aluminium hydride we isolated 4-hydroxy-methyl-3-methylpyridine which was different from theknown 3-hydroxymethyl-4-methylpyridine which wesynthesised as described in the 1iterat~re.l~EXPERIMENTALFor general instrumentation see ref.16. All extractswere dried over anhydrous sodium sulphate and evapora-tions were performed below 30" and a t 20 mmHg. JValues are in Hz and tetramethylsilane was used as internalstandard for lH n.m.r. spectra. 1.r. spectra of solids(KBr discs) and liquids (films) were measured on a Perkin-Elmer 21 spectrometer.2-Methyl-2-azaindene was prepared from 2,3-dihydro-2,2-dimethyl- 1H-2-azaindenium iodide in ether and n-butyl-lithium in pentane in 58 yield (cf.lit. yields: 75 withphenyl-lithium; 61 and 76 with methyl-lithium andbenzyl-lithium 17); wz/e 132 (25, M+ + l), 131 (100, Mf),130 (30), 116 (24), 105 (9), 103 (lo), 90 (12), 89 (20), 77(lo), and 63 (11). The U.V. spectrum in aqueous buffer14 R. A. Barnes, ' Pyridine and its Derivatives,' ed. E. Klings-16 J. M. Bobbitt and D. A. Scola, J . Org. Chem., 1960, 25, 560.16 W. L. F. Armarego and S. C . Sharma, J . Chem. SOC. ( C ) ,berg, Interscience, New York, 1960, p. 51.1970, 1600.at pH 6.8 after 4 s mixing had maxima a t 216, 260 + 269,320infl, and 386 nm; after 18 h the inflection at 320 nmhad become a very broad band with a maximum at 327 nm,and the maxima a t 260 and 269 nm had become an in-flection.It could not be prepared by oxidation of 2,3-di-hydro-Zmethyl- 1H-2-azaindene with 2,3-dichloro-5,6-di-cyano- 1,4-benzoquinone.Dimethyl Pyridine-2,3-dicarboxyZate.-To pyridine-2,3-di-carboxylic acid (50g) in methanol (200ml) at 0'' concentratedsulphuric acid (50 ml) was carefully added, and the mixturewas heated on a steam-bath for 28 h. Excess of methanolwas evaporated off and the cooled solution (ice-bath)was neutralised with saturated aqueous sodium carbonate.The solid that separated was collected and added to thechloroform extract of the filtrate. The dried extract gavethe dimethyl ester (52 g, 89), m.p.55-56' (lit.,l* 67-57-5" for material prepared from the acid and methanolichydrogen chloride) ; vmax. 1772 and 1302 (ester) cm-1.Similarly dimethyl pyridine-3,4-dicarboxylate, b.p. 104-105" a t 0.8 mmHg, was obtained in 92 yield (lit.,lgb.p. 95-100" a t 15 nimHg); vmaX. 1730 and 1300 (ester)cm.-l.2,3-Dihydr0-2-methyZ- lH-2,4-diazaindene (10) .-Di-methyl pyridine-2,3-dicarboxylate was reduced with lithiumaluminium hydride in ether, as before. 2o 2,3-Bishydroxy-methylpyridine was shown to be in the residue from themethanolic extract of the insoluble reduction product byconversion, with excess of acetic anhydride a t 20" for18 h, into 2,3-bisacetoxy~zethyZ~yridine, b.p. 128" at 1.1mmHg (Found: C, 58.9; H, 6.0; N, 6.6.Cl,H1,NO,requires C, 59.2; H, 5.9; N, 6.3); vmx. 1735 and 1235(ester) cm.-l. The crude diol (3-5 g), which could not bepurified without decomposition, and thionyl chloride(20 ml) were heated under reflux for 30 min; the mixturewas evaporated and the residue kept over potassiumhydroxide irt vacuo overnight. To the cooled (-207residue (containing 2 , 3-bischloromethylpyridine hydro-chloride) suspended in methylene chloride (100 ml) wasadded cold 33 ethanolic methylamine (25 ml), and themixture was shaken until all the black solid dissolved.The product was kept for 1 h a t 0" and a t 20" overnight,then 2~-sodium hydroxide saturated with sodium chloridewas added and the mixture was extracted with methylenechloride. The dried extract was concentrated, passedthrough an alumina column (5 x 0-5 in; B.D.H.), andeluted with methylene chloride.Evaporation gave 2,3-di-hydro-2-methyZ-lH-2,4-diazaindene, b.p. 92' at 4 mmHg(1.9 g, 57y0), as a hygroscopic oil which slowly darkened(Found: C, 71.5; H, 7.7; N, 20-8. C7H,,N2 requiresC, 71.6; H, 7.5; N, 20.9); v,, 2955, 2900, 2850 and2784 (CH str.), 1607 (C=N str.), and 1590 (C=C str.) cm-1;m/e 134 (40, J4+), 133 (100, M+ - l), 118 (15), 106 (lo),92 (15), 79 (6), 78 (6), 77 (6), 65 ( l l ) , and 63 (11). Thedipicrate had m.p. 206-207' (from methanol) (Found :C, 40.5; H, 2.8; N, 18.6. C20H16N801Q requires C, 40.55;H, 2.7; N, 18.9).Similarly dimethyl (or diethyl) pyridine-3,4-dicarboxyl-ate gave 3,4-bisacetoxymethylPyvidine, map.47-48' (fromcyclohexane) (Found: C, 59.1; H, 6.2; N, 6.3y0); vmX.17 G. Wittig and H. Streib, Awzaleiz, 1953, 584, 1.18 E. Spinner and G. B. Yeoh, J . Chem. SOC. (B), 1971, 2891s W. L. F. Armarego and R. F. Evans, J . Appl. Chem.,20 K. Tsuda, N. Ikekawa, R. Takasaki, and Y. Yamakawa,and references therein.1962, 12, 45.Phann. Bull. Jafian, 1953, 1, 14219721730 and 1245 cm-1, except that it was purified via itspicrate, 1ii.p. 119-120" (from aqueous ethanol) (Found:C, 45.1; H, 3.8; N, 12.5. C,,Hl,N,Oll requires C, 45.6H, 3-5; N, 12-3), which was passed through an aluminacolumn and eluted with chloroform.2,3-Dihydro-2-uutethyZ- lH-2,5-diazaindene (14) .-Thecrude 3,4-bishydroxymethylpyridine was similarly con-verted into 3,4-bischloromethylpyridine hydrochloridewhich, after passage through an alumina column in chloro-form, gave crude 3,4-bischloromethylpyridine (stronglylachrimatory) .This decomposed on attempted recrystall-isation from benzene but gave a stable flicrate, m.p. 14105-142.5" (from ethanol) (Found: C, 38-4; H, 2.5; N, 13-6.Cl,Hl,Cl,N40, requires C, 38.5; H, 2.5; N, 13.8);J 7), 5.05 and 5.08 (2 x CH2C1), and 8-55 p.p.m. (s, picrateCH) . Ethanolic methylamine and crude 3,4-bischloro-methylpyridine hydrochloride as before gave 2,3-dihydro-rnethyZ-lH-2,5-diazuindene, b.p. 60" at 1 mmHg (Found:C, 69.7; H, 7-6; N, 20.0. C8Hl,Nz,0.25H20 requiresC, 69.3; H, 7.6; N, 20.2) ; v,,,. 2960, 2908, 2860, 2792(CH str,), 1615, and 1580 (C=C str.), cm-l; wz/e 134 (370/,,M+), 133 (loo), 118 (l6), 106 (9), 92 (6.5), 77 (6), and 63(11); its dipicrate had m.p.214' (from water) (Found:C, 40.G; H, 2.7; N, 19*Oyo).2,3-Dil~ydro-2,2-diwzethyl-lH-2,5-diazaindenium Iodide(20) .-The dihydro-derivative (14) (1 34 mg) in benzene(10 ml) was stirred with methyl iodide (144 mg, 1 mol.equiv.) for 16 h at 20' and the separated solid wascollected and recrystallised from methanol-ether to givethe dimethyl iodide, m.p. 206-207" (192 mg, 70) (Found,C, 39.3; H, 4.9; N, 9.6. C,H131Nz requires C, 39.1; H,4-7; N, 10.1); m/e 150 (16), 142 (49), 134 (28), 133(loo), 128 (53, HIf), 127 (50, I+), 118 (15), and 106 (18).The dipicvate, m.p. 190-191", was prepared in water(Found: c , 41.1; H, 3.0; N, 18.3. C2,H18N8014 requiresC, 41.6; H, 3.0; N, 18.45).2-MethyZ-2,4-diazaindene (2) .-The dihydro-derivative(10) (584 nig) in benzene (25 ml) under nitrogen was addedto a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(1.19 g, 1.1 mol.equiv.) in benzene (150 nil) and the mix-ture was stirred for 1-5 h a t 20". The black precipitate(1.5 g) was filtered off, washed with benzene, and driedin zlucuo. The black solid was ground with aqueous7~-ammonia (50 ml) and extracted with methylene chloride(6 x 50 ml). The extract was evaporated below 20"and a t 18 mmHg, and the residue was extracted withcyclohexane at 40-50" (3 X 40 ml). The extract wasevaporated until pale yellow needles crystallised out.These were washed with light petroleum (b.p. 40-60") togive 2-inethyZ-2,4-diazaindene, m.p.63" (121 mg, 21)(Found: C, 72.4; H, 6-3; N, 21.4. C,H,N, requiresC, 72.7; H, 6.1; N, 21.2); vmsx. 3140, 1610, 1550, 1474,1420, 1372, 1356, 1338, 1153, 1125, 996, 918, 794, 774,and 732 cm-l; m/e 133 (lo, M+ - l), 132 (100, M+),131 (30), 117 (12), 104 (15), 91 (17). 79 (lo), 78 (lo), and63 (18) ; PKa (potentiometric 21) 6.43 -J= 0.05 (mean ofseven points) and 6.49 f 0.05 (mean of eight points inback-titration) at 1 0 - 3 ~ in water at 20"; U.V. (H,O):neutral species at pH 11.0, A,,,. (log C) 227 (4.94), 286(4.00) -+ 294 (3.99), and 356 (3-75), cation at pH 4.0,A,. (1og c) 232 (4.52), 291 (4.05) + 297 (4.03), and 408 nm(3.42). The picrate, m.p. 216" (effervescence with darken-ing above 200°), was prepared in benzene, recrystallisedfrom aqueous methanol, and dried at 80" for 2 h (Found:s(CD,),SO 8.98 (s, H-2), 8.87 (d, H-6, J 7), 8.06 (d, H-5,C, 46.7; H, 3.3; N, 19.2. C14H11N50, requires C, 46.5;H, 3.1; N, 19.4).2-Methyl-2,5-diazaindene (3) .-This was similarly obtainedas needles, m.p.97-98" in higher yield (50) by usingaqueous 2~-sodium hydroxide to decompose the blackquinol salt. It was purified by sublimation at 23" and0.01 mmHg (Found: C, 72.6; H, 6.4; N, 21.3); vmXm3120, 1616, 1598, 1367, 1342, 1243, 1181, 1142, 908, 812,and 763 crn-l; m/e 133 (lo, Mf + l), 132 (100, M+),131 (30), 117 (23), 104 (10.5), 91 (lo), 79 (7), and 63 (20);pKa (spectrophotometric at 293 nm) 21 8.67 f 0.04 (meanof ten points), ionic strength 0.01 and at 0.49 x 10-4~ inwater at 20"; U.V.(H,O): neutral species at pH 11.0,Am= (log E ) 223 (4.64), 260infl (3.37) + 273infl (3.22) +282 (2-95), 342.5 (3.55); cation at pH 5.0, lmx. (log E)231 (4.62), 265 (3.55) + 283 (3.24), and 383 nm (3.50).The flicrute had m.p. 194-5-195-5" (from ethanol) (Found,after drying at 80' for 2 h : C, 46-8; H, 3.4; IS, 19.4).2,3-Bisbromomethylpyridine 1-Oxide Hydrobromide (2 1) .-2.3-Bisacetoxymethylpyridine (3.7 g) in acetic acid (20 ml)and 30 hydrogen peroxide (4 ml) were heated a t 80-90"for 3 h. More 30 hydrogen peroxide (4 ml) was added,heating was continued for 4 h, and the solution was thenkept at 20" overnight and evaporated at 50" and 18 mmHg.The oiIy residue was dissolved in chloroforiii; the solutionwas shaken with saturated aqueous sodium carbonate,dried, and evaporated leaving a thick oil whose n.m.r.spectrum indicated that it was a 2 : 3 mixture of 2,3-bis-acetoxymethylpyridine I-oxide and 2,3-bis-hydroxymethyl-pyridine 1-oxide or 1,3-dihydrofuro3,4-bpyridine 4-oxide(2 g).This mixture (1.4 g) in 48 aqueous hydrobromicacid (10 ml) was heated under reflux for 3-5 h; the solutionwas then evaporated t o dryness. The residue was kept overpotassium hydroxide in vacuo overnight, then recrystall-ised from methanol-ether (1 : 15) to give 2,3-bisbromo-methylfiyridine 1-oxide hydrobromide, m.p. 156-157" (1.17 g,26) (Found, after drying at 90" for 1.5 h: C, 24.2;H, 2.7; Br, 62.2; N, 3.7. C,H8Br3N0,0.75CH,0H re-quires C, 24.1; H, 2.0; Br, 62.1; N, 3.6); v-,.3040,3009, 3005 (OH str.), 2035br, 1604 (C=N str.), and 1523(C=C str.) cm-1.3-CJzZoro-3-methylfuro3,4-bpyridine- 1 (3H) -one N-Oxide($-Chloride of 2-Acetylnicotinic Acid N-Oxide) .-2-Acetyl-nicotonic acid N-oxide 22 (1.81 g ) and thionyl chloride (6 ml)were heated under reflux for 30 min; the mixture wasevaporated and the residue kept over potassium hydroxidein vacuo overnight. It was recrystallised from benzenet o yield the $-clzloride (1.65 g, 83) as needles, m.p. 142-143" (effervescence) (Found: C, 48.0; H, 2.9; CI, 18.1;N, 6.9. C,H,ClNO, requires C, 48.1; H, 3.0; C1, 17.8;N, 7.0); vmX. 1800 cm-l (GO); S(CD,),SO 8-72 (9,H-5, J 1.5 and 6), 7-99 (4, H-7, J 1.5 and S), 7.84 (9, H-6,J 6 and 8), and 2-38 p.p.m.(s, Me).Similarly 3-chZoro-3-methy~uro3,4-bJfiyridin- 1 (3H) -one(#-chloride of 2-acetylnicotinic acid) m.p. 81.5-82-5" wasprepared (Found: C, 52.2; H, 3.4; N, 7.3. C8H,C1N0,requires C, 52-3; H, 3.3; N, 7.6); v,,,. 1780 (C=O) cm-1;G(CDCl,) 8.98 (4, H-5, J 2 and 6), 8.26 (9, H-7, J 2 and 8),7-60 (9, H-6, J 6 and 8), and 2.28 (s, CH,).2,3-Dihydro-3-hydroxy-3-metJ~yl- lH-2,4-diuzainden- 1-one4-Oxide (22) .-The preceding $-chloride N-oxide (2-8 g )was shaken with saturated ethanolic ammonia (150 ml)21 A. Albert and E. P. Serjeant, ' Ionization Constants ofAcids and Bases,' Methuen, London, 1962.z2 B. M. Bain and J. E. Saxton, J . Chew SOL, 1961, 6216J.C.S. Perkin Ifor-2 h; the mixture was set aside at 20' for 2 days andevaporated to dryness.The residue was passed throughan Amberlite column (100 ml; OH- form) and eluted withaqueous 3~-ammonia to yield the diazaivzdenone oxide (2-2 g,64), m.p. 298-299" (decomp.) (from methanol) (Found :C, 53.3; H, 4.6; N, 15.5. C8H8N,0, requires C, 53.3; H,4.5; N, 16.55); vmX. 3425br (OH str.), 3270 (NH str.),3110 (CH str.), 2690br (hydrogen-bonded OH or NH), and1725 (C=O str.) cm-l.4-HydroxymethyZ-3-meihylPyridisze .-Sodium bis- (2-meth-oxyethoxy)aIuminium hydride (70 in benzene; 35 ml)was added to dimethyl pyridine-3,4-dicarboxylate (10 g)in benzene (50 ml) under nitrogen. The mixture was boiledunder reflux for 1 h and decomposed with saturated aqueoussodium chloride. The benzene layer was separated; theaqueous layer was extracted with chloroform and combinedwith the benzene layer, dried, and evaporated. The residuewas purified by t.1.c. on alumina with chloroform-benzene(9 : 1) as solvent to give 4-hydroxymefhyE-3-methyEpyn'dine,m.p. 81-82O (from cyclohexane) (385 mg, 6.1), R p 0.36(Found: C, 66.0; H, 7.5; N, 10.7. C,H,N0,0-25Hz0requires C, 65.9; H, 7.5; N, 10.9) ; v,, 3140br (OH str.)and 1607 (C=C and C=N str.) cm-1; m/e 123 (53.5, M+),105 (100, M+ - 18), 94 (26), 68 (23), 65 (21), 51 (la), and39 (38).3-Hydroxymethy2-4-methylpyridine.- 4-Methylpyridine-3-carboxylic acid lS was converted into a liquid methylester. Methyl 4-methyEpyridine-3-carboxylate picrate hadm.p. 149-150' (from aqueous ethanol) (Found: C, 43.9;H, 3.2; N, 14.5. C1,N4O9 requires C, 44.2; H, 3.2;N, 14.7). The methyl ester was reduced with lithiumaluminium hydride in ether to give 3-hydroxymethyl-4-methylpyridine (78y0), m.p. 4748O after purificationby t.1.c. like its isomer (Rp 0.35) and recrystallisation fromcyclohexane lit.,l5 m.p. 44-46' (from reduction of theethyl ester) (Found: C, 68.3; H, 7.5; N, 11.4. Calc.for C,HQNO: C, 68.3; H, 7.4; N, 11.4); v- 3300br(OH str.) and 1608 (C=C and C=N str.) cm-l.We thank Drs. D. J. Brown and T. J. Batterham for dis-cussion, Dr J. K. MacLeod for mass spectra, Mr. c. Arandje-lovic for n.m.r. spectra, and Dr. J. E. Fildes and her stafffor microanalysis.1/1346 Received, 2nd August, 1971
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