Action of acids and alkylating agents on 1,4-di-(2-pyridyl)tetraz-2-enes

摘要

1232 J.C.S. Perkin IAction of Acids and Alkylating Agents on 1,4-Di-(2-pyridyl)tetraz-2-enesBy Stephen Anderson, Edward E. Glover,' and Kenneth D. Vaughan, Department of Chemistry, TeessideThe synthesis of the title compounds and their conversion by acids or alkylating agents into 1 -substituted tetrazolo-1,5-apyridinium salts is reported.Polytechnic, Middlesbrough, Cleveland TS1 3BAIN view of the current interest in diquaternary tetrazenesas short-acting non-depolarizing neuromuscular blockingagents,lW2 the synthesis of the diquaternary derivatives(11) and (12) of the 1,4-di-(2-pyridyl)tetraz-2-enes (3) and(4) was undertaken. The tetrazenes (3) and (4) wereobtained during the oxidation of (1). Treatment of thetetrazene (3) or (4) with methyl iodide or methyl fluoro-sulphate, however, did not yield the diquaternary tetra-zene (11) or (12)J but gave instead the respective 1-methyl- and l-phenyl-tetrazolo 1,5-apyridinium saltsReactants ProductPhenyl-2-pyridyl- (2)nitrosamine 4 (4-0 g) inMeOH (60 ml) and HOAc(10 g) + Zn powder (18 g)in H,O (20 ml) 0Ac,O (0.46 g) in Et,O(5 ml) a(2) (0-86 g) in bkOH (6 ml) + Bra (0.8 g) in MeOH(2) (0-8 g) in Eta0 (10 ml) + (9)N-(fi-Bromophenyl)-2-pyridylaminehydrobromideN-(p-Bromophenyl) -2-pyridylamine 0N-(p-Bromophenyl) -2-pyridylamine picrate(6 ml) 'TABLE 1Pyridine bases() M.p. ("C) Cryst.solvent C H N C H N26.5 c 70.9 6.2 22.4 71.3 6.0 22.7Found (yo) Rqd. ()Yield --68-3 5.9 18.66 68.7 6.8 18.6 77 163 8 MeNOo41 220-222 EtOH-Eta0 40.0 3.2 8.3 40.0 3.06 8.6128-130 MeOH-H,O 52.6 3.0 11.2 53.0 3-6 11-28234-238 MeNO, 42-6 2.8 14.76 42.7 2.6 14.6The solution of the nitroso-compound was added dropwise to the ice-cold aqueous suspension of zinc powder and the mixturestirred for a further hour.Water (60 ml) was thenadded to the combined filtrate and washings and the solution extracted with ether, each extract being washed with a little water.The combined aqueous Iayer was the^ basified to pH 11 with 26 sodium hydroxide and re-extracted with ether (2 x 200 ml), eachextract being in turn washed with water (15 ml) . The combined ether extracts were evaporated and the residue was again extractedwith ether. Lit.,6 b.p. 140' a t 0.2mmHg. 6 The melt re-solidified to form needles which remelted at 186".Etherwas then added and the precipitated Eydrobromide filtered off. The position of the bromine atom followed from the 1H n.m.r.spectrum in deuteriochloroform containing 0.3 mol. equiv. of theshift reagent tris-(2,2,6,6-tetramethylheptane-3,6-dionato)europium-(1x1). The signals due to the heteroaromatic and benzene ring protons were well separated and the signal of the latter showed thecharacteristic AA'XX' pattern.The solution was then filtered and the residue washed with methanol (10 ml).The dried eytract was ;then evaporated and the residual hydrazine purified by disillation.C B.p. 123' a t 0-6 mmHg. The acetyl derivative which separated was filtered off and recrystallized.f The solution was stirred and the bromine solution added dropwise.TABLE 2Oxidations with bromineFound (yo) Rqd- ()Yield Cryst.r- 7-Reactants Product (yo) M.p. ("C) solvent C H N C H N(1) (2.0 g) in MeOH (3 ml) + sat. aq. Br, (30 ml) (3) 22 137-138 MeOH 69.2 6-9 34-4 69.5 6-8 34.7(2) (1.3 g) in MeOH (3 ml) + sat. aq. Br, (30 ml) (4) 19 146O MeCN 71-8 5.0 23.0 72.1 4-96 22-9(10) (0-3 g) (sat. aq. soln.) + sat. aq. Br, (36 ml) (16) 19 293-294 EtOM 42.1 4-0 7.96 41.9 3.6 8.1(16) 163-166 MeCN 44.0 3.3 14.1 43.9 2-9 14.2picratea The saturated aqueous bromine was added in bulk to the stirred solution. The mixture was then basified and triturated givingthe tetrazene which was atered off. Recrystallization fromchloroform gave a compound, m.p. 243', analytical data for which were consistent with structure (6) (Found: C, 36.0; H, 3.1;N, 21.6.ClaHl,Br,N, requires C, 36-0; H, 3.0; N, 21.0). Decomp. Added in bulk. The solution was then triturated givinga dark oil which was separated and boiled with acetone. Addition of ether t o the acetone solution gave a yellow oil which wasseparated and triturated with ethanol, giving the bromide which was iiltered off. eAlso obtained in 78 yield by treating amethanolic solution of (14) with methanolic bromine and boiling the precipitated perbromide salt with acetone.A small amount of methanol-insoluble material was obtained.obtained in moderate yield bp oxidation of the corres-ponding 2-pyridylhydrazines (1) and (2) with bromine,a small amount of the brominated tetrazene (5) being1 C.E. Blogg, T. M. Savage, J. C. Simpson, L. A. Ross, andB. R. Simpson, Pvoc. Roy. Soc. Med., 1973, 66, 1023.a D. Jack and E. E. Glover, B.P. 1,342,713/1974.A. E. Tschitschibabin and I. L. Knunjanz, Bey., 1928 61,2216. 936.(6) and (7); the methyl compound (6) was identical witha sample obtained by quaternization of tetrazolol,li-a-pyridine (8) with methyl iodide. Cyclization of thetetrazenes (3) and (4) to the tetrazolopyridinium brom-G. Palazzo and L. Baiocchi, Ann. Clzkm. (Italy), 1966, 56,4 0. Fischer. Ber., 1899, 82, 12971975 1233(12) Phi(131Reactants(9) (0.2 g ) + MeOS0,F(13) (0.4g) + 48 HBr (6ml)(9) (0-6 g) + Me1 (3 ml) and MeOH2-Anilinopyridine (0.86 g) in CHCl,(10 ml) + MeOS0,F (0.67 g )(4) (0.24 g ) + Me1 (3 ml) and MeCN(4) (0.08 g) in EtOH (20 ml) and 48(3) (0.3 g) + Me1 (3 ml) and MeOH(8) a (0.2 g ) + Me1 (2 ml)(3) (0.1 g) in EtOH (20 ml) and 48(3(3 ml)HBr (0-2 ml) f(3 ml) 6HBr (0.07 ml) mOSOzF'(15)SCHEMEe1TABLE 3Quaternary saltsx (I M.P. ("C)Yield80 14328 172-17426 172-17482 166-166I 38 216-217C10,P 31 243-244Br 234I J 3 9 k 199I j 60 200Br 84 234Cryst.solventMeOH-Et,OE tOH-E t,OE tOH-Et a 0EtOHMeNO,MeN0,-Et,OMeN0,-Et,OMeOH-E t,OMeOH-Et,OMeNOa-E tgOFound () Rqd. ()r------i 7-C H N C H N49.5 4.8 12.2 49.3 4.7 12.340.1 4-3 11.8 39.9 4.2 11.650.9 4.96 9.8 60.7 4.6 9-940.8 2-5 17-4 40.8 2.8 17.344.0 3.3 18.7 44.6 3.1 18.946.2 3.5 19.6 46.6 3.8 19*7b27.6 2.95 21.2 27.5 2.7 21.427.6 3.7 21.4 27.5 2.7 21-433.5 3.3 26.05 33.3 3.1 25.8The reaction mixture was maintained at 0 "C until all the solid had dissolved.Trituration then gave the fluorosulphate whichThe residue wasThe residueAdded drop-The solution was boiled under reflux overnight andI The solution was boiled under reflux for 2.6 h and then evaporated to dryness underAttempts to recrystallize the residue from nitromethane-ether gave a gum which was dissolved in chloroformThe chloroform was then evaporated off and the residue recrystallized GrstAlso obtained from the iodide by treatment with 70 .perchloric acid.Addition of ether precipitated the crudeEvaporation of the fitrate and recrystallization of the residue from aqueous methanol gave theBefore recrystallization and based onThe solution was then evapor-The solution was then cooled andThe bromide which separated on cooling was filtered off and the filtrate evaporated toEvaporation of the dried extract and treatment of the residue withwas filtered off.then recrystallized.was then boiled with 16 HBr (6 ml) for 6 min and again evaporated to dryness.wise to the stirred solution.then cooled, and the product was filtered off.reduced pressure.(16 ml) and treated with 70 perchloric acid (3 drops).from ethanol-ether and then from nitromethaneether.product which was filtered off.starting tetrazene (0.16 g).starting material consumed.ated and the residue recrystallized.ether added to incipient precipitation.dryness.alcoholic picric acid gave 2-methylaminopyridine picrate, m.p. 189-190", identical with an authentic sample.The solution was boiled under reflux for 1 h and evaporated to dryness under reduced pressure.e The solution was boiled under reflux overnight and evaporated to dryness underreducedpressure.The residue was then recrystallized.The product separated arid was filtered off.For the hemihydrate.6 The solution was boiled under reflux for 17 h and then cooled.The two samples were identical (ix. spectraand mixed m.p.).The reaction mixture was heated in a sealed tube a t 100 "C for 20 h.m The reaction mixture was boiled under reflux for 2 h.The residue was basified and extracted with ether.' R. G. Fargher and R. Furness, J . Ckem. SOL, 1916, 6881234 J.C.S.Perkin Iides (6) and (7) respectively was also effected by boilingethanolic hydrobroniic acid, and the isolation of 2-methylaminopyridine from such a cyclization of thedimethyltetrazene (3) confirmed the mechanism to be asshown in Scheme 2. In addition to establishing theR RSCHEME 3position of alkylation of tetrazolo 1,5-apyridine thereaction also provides a route to the otherwise inacces-sible 1 -aryltetrazolo 1,5-apyridinium salts.We also considered an alternative route to the di-quaternary tetrazene (12) via oxidation of the quatern-ized pyridylhydrazine (10) with bromine. However, thisgave instead the quaternary bromo-compound (15),identical with samples prepared by direct bromination ofthe anilinopyridinium salt (14) and by quaternization ofN - (4-bromophenyl) -2-pyridylamine with methyl fluoro-sulphate followed by exchange with bromide ion onAmberlite IRA 400 (Br-) resin.EXPERIMENTALM.p.s were determined on a Kofler hot-stage apparatus andn.m.r. spectra on a Perkin-Elmer model R12A spectrometer.We thank Allen and Hanburys for a maintenance grant(to K. D. Vaughan).4/2366 Received, 12th November, 1974