592 J.C.S. Perkin ICi n no1 ines. Part XVI I.and Preparation of 2,3- Di hyd ro-3- i mi no-I H- pyrazolo [4,3-c]cin no1 i nesReact ions of 4- C h lorocin no1 ine-%car bon it ri leBy Donald E. Ames and Christopher J. A. Byrne, Chemistry Department, Chelsea College, Manresa Road,London SW3 6LXReaction of 3-bromo-4(1 H)-cinnoline with copper(i) cyanide in pyridine yields 1.4-dihydro-4-oxocinnoline-3-carbonitrile, which is converted into 4-chlorocinnoline-3-carbonitrile by treatment with phosphoryl chloride.Catalytic hydrogenation of the chloro-compound in the presence of base gives 4,4’-bicinnolyl-3,3‘,-dicarbonitrile.Condensation reactions of the chloro-compound yield 1.4-dihydro-4-thioxocinnoline-3-carbonitriIe (withthiourea), 3-cyanocinnolin-4-ylmalononitrile and similar products (with carbanions), methyl 2.3-di hydro-3-imino-thieno[3,2-c]cinnoline-2-carboxylate (with methyl thioglycolate), and 2,3-dihydro-3-imino-lh’-pyrazolo-[4,3-c] cinnoline and related compounds (with hydrazine and substituted hydrazines).THE action of copper (I) cyanide in NN-dimethylform-amide on 3-bromo-6,7-methylenedioxy-4( 1H)-cinnolonegives 1,4-dihydro-6,7-methylenedioxy-4-oxocinnoIine-3-carbonitrile. a 1,4-Dihydro-Poxocinnoline-3-carbo-nitrile has now been prepared similarly from 3-bromo-4( 1H)-cinnolone ; pyridine was a more satisfactorysolvent in this case.Alkaline hydrolysis of the productgave 1,4-dihydro-4-oxocinnoline-3-carboxylic acid. Thecyanocinnolone reacted with phosphoryl chloride to fonn4-chlorocinnoline-3-carbonitrile (Ia) , previously preparedfrom 1 ,4-dihydro-4-oxocinnoline-3-carboxamide.3 Wereport here some reactions of the chloro-nitrile (Ia) for thepreparation of 3,4-disubstituted cinnolines, includingcompounds with a heterocyclic ring fused at the 3- and4-positions.Catalytic hydrogenation of the chloro-nitrile (Ia) in thepresence of base yielded 4,4’-bicinnolyl-3,3’-dicarbo-nitrile, which gave 4,4’-bicinnolyl on hydrolysis anddecarb~xylation.~ 1,4-Dihydro-4-thioxocinnoline-3-carbonitrile was prepared by the reaction of the chloro-nitrile (Ia) with methanolic thiourea and by the action ofphosphorus pentasulphide on 1,4-dihydro-4-oxocinnoline-3-carb0nitrile.~ Methylation of the thione gave 4-methylthiocinnoline-3-carbonitrile (Ib), but attempts toprepare 4-methylsulphonylcinnoline-3-carbonitrile byoxidation were unsuccessful.In each case, 1,4-dihydro-4-oxocinnoline-3-carbonitrile was obtained, presumablyby displacement of the good leaving group (MeSO,-) bywater-the activation of the 4-substituent in the cin-noline ring 6 being enhanced by the effect of the 3-cyano-€PUP.4-Chlorocinnolines condense readily with carbanions ;the chloronitrile (Ia) reacted similarly with acetylacetone,phenylacet onit rile, ethyl cyanoacet ate, and malononit rile(by use of sodium hydride in 1 ,a-dimethoxyethane).Several other ‘ reactive methylene ’ compounds gave nocondensation product under these conditions (cf. refs.7a-c) . Oxidation of 4-( l-acetylacetony1)cinnoline-3-carbonitrile (Ic) with potassium permanganate oralkaline hydrogen peroxide gave l-acetyl-2-methyl-pyrido[3,4-c]cinnolin-4(3H)-one (11).This structure was1 Part XVI, D. E. Ames, S. Chandrasekhar, and R. Simpson,J.C.S. Perkin I , 1975, 2035.W. A. White, G.P., 2 006 104/1971.N. H. Kurihara, U.S.P., 3 667 24111972.Cf. J. S. Morley, J . Chem. Soc., 1961,1971-Cf. R. N. Castle, H. Ward, N. White, and K. Adachi, J . Oyg.Chem., 1960, 2!5, 570.indicated by the absence of the CEN i.r. band and by theappearance of the methyl signals as two separate peaksat 6 2.42 and 2.30 in the lH n.m.r. spectrum; in the caseof the diketone (Ic) the methyl groups are equivalent(I) a; R = C lb; R=SMec ; R = CHAc2d ; R = NPh.NHPhe ; R = GMeyNH2.0H-(JI)&C=NHR’ y -?R*(IQ ~ ; R ’ = R ~ = Hb ; R’=Me,R2=Hc ;R’=H,RL=Phd ; R’= HI R2=SO&HLMe -p(6 1.85).The product is presumably formed by hydro-lysis of the cyano-group to amide and condensation withan acetyl group.4-Chloropyrimidine-&carbonitrile reacts with thio-glycolate esters to form thienopyrimidines; 4 chloro-cinnoline-3-carbonitrile reacted similarly to give methyl2,3-dihydro-3-iminothieno [3,2-c] cinnoline-Zcarboxylat e(111) in good yield. This structure is assigned, ratherthan the alternative aminothiophen form, because then.m.r. spectrum includes peaks at 6 3.9 (CHC0,Me) and7.4 (NH, exchanging with D,O).6 Cf. G. W. Barlin and W. V. Brown, J . Chem. SOC. (B), 1967,736; J . Chem. SOC. ( C ) , 1967, 2473.7 (a) R.N. Castle and F. H. Kruse, J . Org. Chem., 1962, 17,1671; (b) R. N. Castle and D. B. Cox, ibid., 1964, 19, 1117;(G) Y. Mizuno, K. Adachi, and K. Ikeda, Pharm. BUZZ. (Japan),1964, 2, 226.8 A. A. Santilli, D. H. Kim, and S. V. Wanser, J . HeteevocycZicChem., 1971, 9, 4461976 593Pyrazolopyrimidines, prepared from chlorocyano-pyrimidines and hydrazines, show various phanna-cological effects .g 2,3-Dihydro-3-imino-lH-pyrazolo-[4,3-c]cinnoline (IVa) was prepared by the reaction of 4-chlorocinnoline-3-carbonitrile with hydrazine in ethanol.Formulation as the imino-form (IVa) rather than theamino-tautomer is based on i.r. maxima at 3 300br (NH)and 1640 cm-l (C=N). Attempts to hydrolyse ordiazotise this product gave unsatisfactory results.Hinman lo has shown that, although substitution of analkyl group for a hydrogen atom in hydrazine is accom-panied by a decrease in basic strength, the ease of alkyl-ation increases as successive alkyl groups are introduced.According to Hinman, the positive charge which developsin the transition state is better stabilised on the nitrogenbearing the larger number of alkyl groups so that furtheralkylation occurs at the alkylated nitrogen atom.Thus2-chloropyridine and methylhydrazine give only N-methyl-N-(2-pyridyl) hydrazine u and chloro-nitriles 9band chloro-esters l2 react so that the halogen is displacedby the a-nitrogen atom of alkylhydrazines but by the p-nitrogen atom of arylkydrazines. The products ofreaction of 4-chlorocinnoline-3-carbonitrile with methyl-hydrazine and phenylhydrazine are therefore formulatedas (IVb and c ) respectively.The U.V. spectra of theproducts (IVa-c) were similar (Table), consistent withU.V. spectra of pyrazolocinnolines (Iv) (in ethanol)h,,.lnm E h,,,./nm E Lax./nm E234 24500 287 4500 343 1600(Iva) 234 17 500 290 5500 348 2000(IVb) UVC) 231 18500 294 16500 362 3000the structures assigned, and confirmed the presence ofthe imino-group; in the case of (IVc) the only possibleamino-tautomer (V) would be quinonoid. A cyclicproduct (IVd) was also obtained from 4-chlorocinnoline-3-carbonitrile and p-tolylsulphonylhydrazine, but NN'-diphenylhydrazine gave a nitrile (Id) and NN-dimethyl-hydrazine formed a quaternary compound, isolated as thehydroxide (Ie) the i.r.red spectrum of which showedCEN and NH, absorptions.EXPERIMEXTALEvaporations were carried out under reduced pressure ;petrol refers to light petroleum (b.p. 60-80'). lH N.m.r.spectra mere measured on a Perkin-Elmer R10 spectrometera t 60 MHz. U.V. spectra were recorded on a Perkin-Elmer 402 spectrophotometer with ethanol as solvent.3-Bromo-4(1H)-cinnolone13 ( 1 1 g) and copper(1) cyanide (7.7 g) indry pyricline (100 ml) were boiled under reflux for 16 h andthe cooled mixture was added to a solution of iron(Ir1)chloride (18 g) in 4~~hydrochloric acid (300 ml). Filtrationand crystallisation from ethanol gave the nitrile (7.75 g,92%), m.p. 260-261" (Found: C, 63.0; H, 2.9; N, 24.4.(a) P. Schmidt, K. Eichenberger, M.Wilhelm, and J. Druey,Helv. Chilit. Acta, 1959,42, 763; ( b ) P. Schmidt, K. Eichenberger,and M. Wilhelm, Angew. Chem., 1961, 73, 15; (G) A. Dornow andW. Abele, Chem. Ber., 1964, 97, 3349; (d) cf. T. L. P. Hatt andJ. R. Vass, Chem. Comm., 1966, 293.1,4- Dihydro- 4-oxocinnoline- 3-carbonitrile .-lo R. L. EIinman, J . Org. Chem., 1958, 23, 1587.C,H,N,O requires C, 63.2; H, 2.9; N, 24.6y0), vmx. 2 240cm-l ( C N ) .4-Chlorocinnoline-3-cnrbonitrile.-A suspension of thenitrile (0.5 g) in phosphoryl chloride ( 3 ml) was heated(bath a t 140 "C for 2 rnin and then 110 "C for 8 rnin), cooled,and poured onto ice. Basification and isolation with ethylacetate gave the chloro-nitrile (0.3 g, 50%), m.p. 179-181'(from benzene), v- 2 230 cm-1 (lit.,3 m.p.177-178.5').Hydrolysis of the nitrile (0.25 g) by boiling with 4 ~ -sodium hydroxide for 2.5 h, acidification, filtration, andcrystallisation from aqueous ethanol gave 1,4-dihydro-4-oxocinnoline-3-carboxylic acid (0.16 g), m.p. 266-267"(lit. ,I4 268-268.5') .4,4'-BicinnoEyZ-3, 3'-dicavbonitriZe .- 4-Chlorocinnoline- 3-carbonitrile (0.5 g) in ethanol (76 ml) and triethylamine (3ml) was hydrogenated over palladium-barium sulphate(0.2 g, 10%). Filtration, evaporation, and crystallisationfrom methanol gave the bicinnoZyZ(O.16 g, 39y0), m.p. 296-297" (Found: C, 69.9; H, 2.7; N, 27.2. C,,H,N, requiresC , 70.1 ; H, 2.6; N, 27.3%), vmE 2 250 cm-l ( E N ) ; A,, 253and 315 nm ( 8 20 000 and 4 000). A solution of the dinitrile(0.2 g) in ethanol (5 ml) and 2~-sodium hydroxide (10 ml)was boiled under reflux for 5 h.Removal of ethanol andacidification with concentrated hydrochloric acid precipi-tated the crude dicarboxylic acid which was collected anddried and then heated (bath 240 "C) for 1 h. Crystallisationof the residue from benzene gave 4,4'-bicinnolyl, m.p. andmixed m.p. 228-230°.*1,4-Dihydro-4-thioxoc~nnoline-3-carbonitri~e.-(a) A solu-tion of 4-chlorocinnoline-3-carbonitrile (1.65 g) and thiourea(1.5 g) in methanol (15 ml) was heated under reflux for 10min. On cooling, the product separated and, after crystal-lisation from benzene-methanol, the thione (1.4 g ) wasobtained as orange crystals, m.p. 292-293" (Found:C, 57.4; H, 2.7; N, 22.4. C,H5N3S requires C, 57.7; H,2.7; N, 22.5%); v,, 2 230 cm-l ( E N ) , A,, 237 and 470 nm(E 23 500 and 1 300).(b) 1,4-Dihydro-4-oxocinnoline-3-carbonitrile ( 1 g) ,phosphorus pentasulphide (0.7 g), and sodium hydrogencarbonate (50 mg) in acetonitrile (25 ml) were boiled underreflux for 20 h.After evaporation, the residue was warmeda t 40 "C with 4~-potassium hydroxide (50 ml) for 30 min.Filtration, acidification of the filtrate, and recrystallisationsof the precipitate from benzene-methanol gave the thione(0.6 g, 55y0), m.p. and mixed m.p. 292-293". Attempts toisolate the thione by chromatography in benzene on alumina(type 0) gave a red aluminium hydroxide complex, m.p. 300'[Found: C, 40.3; H, 2.6; N, 15.3. C,H,N,S,Al(OH),requires C, 40.7; H, 3.0; N, 15.7%].4-Methylthiocinnoline- 3-carbonitrile .- 1 ,4-Dihydro-4-thioxocinnoline-3-carbonitrile (0.5 g) was dissolved inbutan-2-one (25 ml) and anhydrous potassium carbonate( 1 g) and methyl iodide (0.6 g) were added.The mixturewas stirred and boiled under reflux for 2 h, and filtered;addition of water and acidification with acetic acid gave abrown precipitate. This was collected and purified bychromatography on alumina (type 0) in benzene-chloroformto give 4-methylthiocinnoliae-3-carboni~r~le (0.31 g, 64%) asyellow cubes, m.p. 133-134' (Found: C, 59.7; H, 3.3;l1 G. E. Ficken and J. D. Kendall, J . Chem. SOC., 1959, 3202.l2 M. Hauser, E. Peters, and H. Tieckelmann, J . Ovg. Chem.,l3 D. E. Ames, R. F. Chapman, H. 2. Kucharska, and D. Waite,l4 K. Schofield and J .C . E. Simpson, J . Chem. SOG., 1945, 618.1960,25, 1570.J . Chem. SOG., 1965, 5391594 J.C.S. Perkin IN, 20.9. C,,H,N,S requires C, 59.7; HI 3.5; N, 20.9%);vmz 2 230 cm-I ( E N ) and 1310 cm-1 (SMe).Acetyl-acetone (0.3 g) was added to a suspension of sodium hydride(0.1 g , 60%) in l12-dimethoxyethane (30 ml) and the mix-ture was stirred for 20 min. 4-Chlorocinnoline-3-carbo-nitrile (0.5 g) in lJ2-dimethoxyethane (20 ml) was addedgradually and the mixture was stirred and boiled underreflux for 4 h. Evaporation and addition of 0.h-aceticacid (100 ml) gave a solid which was collected and crystal-lised from benzene-methanol to yield the pale yellow dioxo-nitrile (0.28 g), m.p. 243-244" (Found: C, 66.8; H, 4.4;N, 16.7. C14HllNS08 requires C, 66.4; H, 4.4; N, 16.6%) ;vmx.2 240 ( E N ) and 1 610 cm-l; &= 243 and 288 nm (E58 000 and 23 500); 8 [(CD,),SO] 1.85 (6 H, s, 2 Me) and7.9-8.2 (4 H, m, ArH).The following compounds were prepared similarly:3-cyanoc~nnol~n-4-ylrnalononitrile (68%) , m.p. 265-266"(from benzene-ethyl acetate) (Found: C, 65.7; H, 2.7;N, 31.7. Cl,H,N, requires C, 65.7; €3, 2.3; N, 32.0%),vmx. 2 220 and 2 210 cm-l (EN); ethyl a-cyano-a-(3-cyanocinnolin-4-yl) acetate (hemihydrate ; 54%) , red plates ,decomp. above 195" (Found: C, 61.8; H, 3.7; N, 20.7.C,pH,oN40,,0.5H,0 requires C, 61.1; HI 3.9; N, !20.4%),v- 2 240 and 2 210 (EN), and 1 710 cm-1 (CO,Et), A,, 240and 408 nm (E 59 000 and 600) ; cc-(3-cyanocinnolin-4-yE)-a-phenylacetonitrile (hemihydrate ; 41 %) , yellow crystals,m.p.194-195" (from benzene-ethyl acetate) (Found: C,73.6; H, 3.9; N, 20.3. Cl,H,oN4,0.5H,0 requires C, 73.2;H, 3.9; N, 20.1y0), vmX 2 210 and 2 200 cm-1 (C-N), A,,,232, 282, and 410 nm ( E 50 000, 14 000, and 24 000).1 -A cetyl-2-methylpyrido [ 3 , 4-c] cinnolin-4 (3H) -one .- 4- ( 1 -Acetylacetonyl)cinnoline-3-carbonitrile ( 1 g) was dissolvedin 0.5hf-sodium hydroxide (75 ml) and potassium per-mangate (1.25 g) was added. The mixture was heated a t100 "C for 2 h and filtered (Celite) with thorough washing ofthe solid with warm 0.b-sodium hydroxide. The filtrateswere neutralised with 2~-hydrochloric acid and evaporatedto dryness. Repeated extraction of the residue with meth-anol and evaporation gave the pyridocinnoline (0.38 g), paleyellow needles, m.p.294-4295' (from methanol) (Found:C, 66.5; H, 4.6; N, 16.6. C14H11N,0, requires C, 66.4;H, 4.4; N, 16.6%) ; vm, 3 310 (NH) and 1 660 cm-1 (GO) ; LE 244 and 363 nm (E 17 000 and 5 000); 8 [(CD,),SO]2.3 (3 H, s, Ac), 2.4 (3 H, s, CH,), and 7.8-8.6 (4 H, m,ArH) .Methyb 2,3-Dihydro-3-irninothieno [3 , 2-c]cinnoline-2-carb-oxylate.-4-Chlorocinnoline-3-carbonitrile (0.5 g) , methylthioglycolate (0.35 g) , and anhydrous sodium carbonate(0.3 g) in absolute ethanol (25 ml) were stirred and boiledunder reflux for 4 h. Evaporation, addition of water(75 ml) , filtration, and crystallisations from benzene-methanol yielded the product (0.62 g) , yellow plates, m.p.219-220" (Found: C, 55.8; H, 3.6; N, 16.0.C,,H,N,O,Srequires C , 55.6; H, 3.5; N, 16.2%); v,,, 3460, 3 310(NH), and 1 680 cm-I (C0,Me); Lax. 242, 252, 258infl, 317,and 355infl nm ( E 17 500, 19 000, 18 500, 15 500, and 3 000) ;6 [(CD,),SO] 3.35 (3 H, s, Me), 3.9 (1 HI s, 2-H), 7.4 (1 H, s,NH, exchanges with D,O), and 7.8-8.7 (4 H, m, ArH).Reactions of 4-Chlorocinnoline-3-carbonitrile with Hydra-4- ( l-A cetylacetonyl) cinnoline-3-carbonitrile.-zincs.-A solution of the chloro-compound (0.5 g ) andhydrazine hydrate (0.75 ml) in ethanol (30 ml) was boiledunder reflux for 2 h. After evaporation, the residue waswashed with water and then crystallised from benzene-methanol to give 2,3-dihydro-3-imino- lH-PyrazoZo[4,3-c]-cinnoZine (0.31 g) , yellow needles, m.p. 292-293' (Found :C, 58.2; H, 3.8; N, 37.8.C,H,N, requires C, 58.4; HI3.8; N, 37.8%); v- 3 300 (NH) and 1640 cm-1 (C=N);6 [(CD,),SO] 6.2br (2 H, s, 2NH, exchange with D,O) and7.76-8.6 (4 H, m, ArH). Treatment with ethanolichydrogen chloride gave the hydrochloride, red cubes, m.p.287-288" (decomp.) (Found: C, 49.0; H, 3.8; N, 31.7.C,H,N,,HCl requires C, 48.8; H, 3.6; N, 31.6%).Methylhydrazine similarly gave 2,3-dihydro-3-imino- 1 -1stethyl-lH-~yrazolo[4,3-c]cinnoline (53%) , yellow crystals,m.p. 317-318' (Found: C, 60.2; H, 4.8; N, 35.1. C,,H,N,requires C, 60.3; H, 4.6; N, 35.2%) ; vmx 3 300 and 3 200(NH), and 1 630 cm-I (C=N); 8 [(CD,),SO] 3.45 (3 H, s, Me)and 7.6-8.5 (4 H, m, ArH). Phenylhydrazine gave 2,3-di-hydro-3-imino-2-phenyl- 1H-pyrazolo[4,3-c]cinnoline (49%)'orange needles, m.p.236-237" (decomp.), which could notbe obtained analytically pure (Found: C , 68.1; H, 3.8; N,26.0. Calc. for C,,H,,N,: C , 69.0; H, 4.2; N, 26.8%);v,, 3 320, 3 190 (NH), and 1 660 cm-l (C=N) ; 6 [(CD,),SO}7.2br (2 H, s, 2NH), 7.5-8.5 (9 H, m, ArH). The hydro-chZoride, red needles from benzene-methanol, had M.P.250-251" (decomp.) (Found: C, 60.2; HI 4.1; N, 23.4.C,,H,,N,,HCl requires C, 60.5; H, 4.1; N, 23.5%). NN'-Diphenylhydrazine gave 1- (3-cyanocinnolin-4-yl)- 1,2-di-phenylhydrazine (20%), yellow needles, m.p. 240-242' (frombenzene) (Found: C, 74.5; H, 4.4; N, 20.6. CZ1H,,N5requires C, 74.8; H, 4.5; N, 20.8%), v,, 3 240 (NH) and2 230 cm-1 ( C N ) . NN-Dimethylhydrazine gave (afterheating for 5 h) 1-( 3-cyanocinnolin-4-yl)- 1, l-dirnethyl-hydraziniurn hydroxide (39%), m.p. 204-205", orangecrystals from ethyl acetate (Found: C, 57.8; H, 5.2; N,30.0. C1,Hl3N,O requires C, 57.5; H, 5.3; N, 30.4%), v-3 290 and 3 260 (NH), and 2 200 cm-l (CZN). P-Tolgl-sulphonylhydrazine (3 g) and 4-chlorocinnoline-3-carbonitrile (1 g ) in chloroform (150 ml) were left a t roomtemperature for 7 days. The red precipitate was collectedand recrystallised from benzene-methanol t o give 2,3-dihydro-3-irnino- 2-p-toylsulphonyl- 1H-pyrazolo [4,3-c] cinno-line (1.2 g), red plates, m.p. 271-272" (Found: C, 56.6;H, 3.5; N, 20.6; S, 9.3. Cl,H13N,0,S requires C, 56.6; HI3.8; N, 20.7; S, 9.4%); vmax 3 400 (NH) and 1 650 cm-1A cetylation of 2,3-Dihydro-3-imino- lH-pyrazol0[4,3-c]-cinnoline.-The base (0.3 g) and acetic anhydride (1.0 g) inpyridine (20 ml) were boiled under reflux for 60 h. Evapor-ation, addition of water, isolation with chloroform, andchromatography on alumina (20 g ; type 0) in benzene-ethanol ( I : 3) gave an acetyl derivative (0.21 g), yellowneedles, m.p. 210-211" (from benzene) (Found: C, 57.9;H, 3.7; N, 30.8. C,,H,N,O requires C, 58.1 ; H, 4.0; N,30.8%); v,, 3 190br (NH) and 1690 cm-l (AcN); 8[(CD,),SO] 2.2 (3 H, s, COMe), and 7.9-8.8 ( 4 H, m, ArH).(C=N) .We thank the S.R.C. for a grant (to C. J. A. B.).[6/1776 Received, 16th Septembev, 1975
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