Triazines and related products. Part XVI. Synthesis of triazolotriazines by cyclisation of 3-hydrazino-1,2,4-triazines and 3-hydrazino-1,2,4-triazoles

摘要

1492 J.C.S. Perkin ITriatines and Related Products. Part XV1.l Synthesis of Triazolotriazinesby Cyclisation of 3-Hydrazino-l,2,4-triazines and 3-Hydrazino-182,4-tri-azolesBy Elizabeth Jane Gray and Malcolm F. G. Stevens,* Department of Pharmacy, University of Aston in Bir-Cyclisation of 3-hydrazino-5.6-diphenyl-I 2.4-triazine with cyanogen bromide afforded 3-amino-6.7-diphenyl-1,2,4-triazolo[4,3-b] [1,2,4]triazine, whereas interaction of 3-amino-5-hydrazin0-1.2.4-triazole and benzilyielded the isomeric 2-amino-6.7-diphenyl-1,2,4-triazolo[5.1 -c] [1,2,4]triazine : both amines were deaminatedwith amyl nitrite in boiling tetrahydrofuran without rearrangement of the heterocyclic skeleton. 6.7-Diphenyl-1,2.4-triazolo[5,1 -c] [1,2,4]triazine, also formed from 3-hydrazino-l.2.4-triazole and benzil in alcoholic sodiumacetate, formed a covalent hydrate which could be detected spectroscopically in solution, and a covalent methanol-ate and ethanolate which could be isolated.The alcoholates reverted to the aromatic system on being heated, orin hot acetic acid or pyridine.mingham, Birmingham B4 7ETA FEATURE of the chemistry of N-alkyl heterocycles ofgeneral structure (1) is their rearrangement to morestable aromatic alkylaminoazines (2) .2 This Dimrothrearrangement, involving the apparent migration of anN-alkyl group (labelled with an asterisk) from an endo-to an exo-cyclic position proceeds via a ring-openedspecies (a ' Dimroth intermediate '). Similar trans-formations complicate the chemistry of those bi- andpoly-cyclic systems formed by fusion of a 1,2,4-triazolering to an azine with a common bridgehead N atom.Ithas been established empirically that bicyclic systems(3) ( 4 )of type (3) with N-4 of the triazole at the ring junction,which may be prepared by cyclisation of 2-hydrazino-azines with carbon-inserting reagent^,^ readily rearrangevia ring-opened intermediates to the more thermo-dynamically stable isomers (4) conjoined at N-1 of thetria~ole.~ There appear to be no exceptions.In a previous paper5 the chemistry of diphenyl-1,2,4triazines bearing a fused 1,2,4-triazole or tetrazolering was explored; we now report an extension of thiswork.Reaction of 5,6-diphenyl-3-hydrazino-1,2,4-triazine(5) with cyanogen bromide in methanol afforded thehydrobromide of a weakly basic aminotriazolotriazine.This salt dissociated in water to give a red base whichPart XV, T.B. Brown and M. F. G. Stevens, J.C.S. Perkin I ,1976, 1023.Mechanisms of Molecular Migrations,' ed.B. S. Thyagarajan, vol. 1, Wiley, New York, 1968, p. 209.J. Daunis, R. Jacquier, and P. Viallefont, Bull. SOG. chim.France, 1969, 3670; J . Daunis and M. Follet, ibid., 1975, 857.4 P. Guerret, R. Jacquier, and G. Maury, J . Heterocyclic Chem.,1971, 8, 643.6 M. F. G. Stevens, J.C.S. Perkin I , 1972, 1221.A. Pollak, S. Polanc, B. Stanovnik, and M. TiSler, Monatsh.,2 D. J. Brown, in1972,103, 1891.was further characterised as a diacetyl derivative.Although the presumed intermediate cyanohydrazino-triazine (6) can cyclise in two ways, previous experiencewith this type of cyclisation has established that N-2 ofthe triazine (rather than N-4) acts in a nucleophilic~apacity.~ The product was therefore assigned structure(7) and proved to be stable to heat, boiling acetic acid,and pyridine.There is no plausible mechanism wherebythis aminotriazolotriazine can further rearrange unlessone invokes an unlikely fission of the triazine N-N bond.(N-N Bond fission has been observed in 1,2,4-triazolo-[4,3-b]pyridazine and 1,2,4-triazolo [3,4-a] phthalazine 7but is not mechanistically feasible in the present case.)In corroboration of this assignment, the amine (7) wasdeaminated with pentyl nitrite in boiling tetrahydro-furan to 6,7-diphenyl-l,2,4-triazolo[4,3-b] [1,2,4]triazine(8), which has been synthesised previously from thehydrazinotriazine (5) and carbon-inserting reagent^,^and from 3,4-diamino-1,2,4-triazole (10; R = H) andbenzil.5.9 Furthermore, the aminotriazolotriazine hadphysical characteristics in accord with those reported lofor the amine formed unequivocally from 3,4,5-triamino-1,2,4-triazole (10; R = NH,) and benzil.We expected that nitration of the unsubstituteddiphenyltriazolotriazine (8), followed by reduction,would provide an alternative synthesis of the amine (7).However, the only nitrating conditions which wereexamined (nitric acid in acetic anhydride at 0 "C) led,unexpectedly, to the oxidised product (9) which wasidentical with the fused triazolone formed from hydrazine(5) and urea.11 The inter-relationships of all the afore-mentioned triazolotriazines are depicted in Scheme 1.3-Amino-5-hydrazino-l,2,4triazole (I la), prepared asa dihydrochloride by reduction with tin(I1) chloride ofdiazotised 3,5-diamino-1,2,4-triazole,12 reacted slowlywith benzil in boiling methanol, with or without sodiumacetate, to afford a single pale yellow product isomericwith (7); the product formed mono- and di-acetylK.T. Potts and C . A. Lovelette, Chem. Comm., 1968, 845. * J. I. G. Cadogan and G. A. Molina, J.C.S. Pevkin I, 1973,lo E. C . Taylor, W. H. Gumprecht, and R. F. Vance, J . Amer.11 A. Dornow, W. Abele, and H. Menzel, Chem. Bey., 1964, 97,l2 R. Stolld and W. Dietrich, J . prakt. Chern., 1934,139, 193.541.E.Hoggarth, J. Chem. Soc., 1952, 4811.Chem. SOC., 1954, 76, 619.21791976 1493derivatives. Significantly, this new aminotriazolotri-azine was stable above its m.p. or in boiling acetic acid,pyridine, or piperidine. The evidence points conclu-sively to structure (13a) , which could be formed (Scheme2) either directly from the intermediate hydrazone (12a)would hinder development of the transition state leadingto the isomer (l4a).We experienced considerable difficulty in preparingthe unsubstituted 3-hydrazino-lJ2,4-triazole (llb). Aconventional procedure based on the diazotisation of(9 1SCHEME 1(12) L I-... ilR Ph R(141a; R = N H ,b ; R = HSCHEME 2by cyclisation at the triazole N-1, or indirectly by 3-arnino-l,2,ktriazole in hydrochloric acid, followed byDimroth rearrangement of the isomeric aminotriazolo- reduction with tin(I1) chloride, was unreliable : further-triazine (14a).Dimroth rearrangements in bicyclic more 3-chlorotriazoles, 3-nitrosoaminotriazoles, and 1,3-systems are known to be accelerated by electron de- bis(triazo1-3-yl) triazenes have been variously reported aspletion in the azine ring,13 and such factors could products of the diazotisation of 3-amin0-1,2,4-triazoles.~~stabilise a zwitterionic intermediate (15a). Intuitively,we prefer direct cyclisation at the triazole N-1 sincesteric repulsions between the amino- and phenyl groups19yo,$; zlPtts and '* R* Surapanenij J . Heterocyczic14 R. N. Butler, Chewz. Rev., 1975, 75, 2411494 J.C.S. Perkin IHowever, reduction with zinc dust and acetic acid of3-nitroamino-l,2,4-triazole l5 proved an efficient routeto the required hydrazine (llb), which was purified asits hydrochloride.Interaction of this hydrochlorideand benzil in ethanol containing an excess of sodiumacetate gave a single product with a U.V. spectrumtypical of a bicyclic system (A,, 349 and 248 nm), anda mass spectrum showing the appropriate molecular ionat m/e 273. This product, 6,7-diphenyl-l,2,4-triazolo-[5,1-c] [1,2,4]triazine (13b) was, as expected, stable toheat and a range of boiling organic acids and bases, andH-2 - 300 HrdLboiled in alcohols in the absence of sodium acetate,products were obtained in high yield which affordedanalytical figures corresponding to a diphenyltriazolo-triazine with incorporation of methanol or ethanol, butwhich were converted into the aromatic bicyclic system(13b) on heating alone or in boiling acetic acid orpyridine.That the alcohols were covalently bound wasevident from their mass spectra, which showed molecularions a t m/e 305 and 319 for the methanolate andethanolate, respectively. Conclusive proof of covalentsolvation was obtained from the unusual lH n.m.r.CHI I 1 I I I I 110 9.0 8.0 7.0 6.0 5.0 4-0 3.0 20 1.0I;100 MHz lH N.m.r. spectrum of 7-ethoxy-4,7-dihydro-6,7-diphenyl[l,2,4]triazolo[5, l-c] [l, 2,4] triazine (18) in deuteriochloroforniwas identical with the product formed by deamination(pentyl nitrite-tetrahydrofuran) of the correspondingaminotriazolotriazine (13a), which has been previouslydeduced to have the same skeletal arrangement of Natoms.The chemical shift of the triazole proton(6 8.66) in the triazolotriazine (13b) lies within the rangeexpected for this type of fused triazole,16 and contrastswith the more deshielded proton (6 9.17) in the isomer (8).When 6,7-diphenyl-1,2,4-triazolo[5,1-c][1,2,4]triazine(13b) was warmed in N-hydrochloric acid the U.V.spectrum underwent a rapid change, and the two peakswere replaced by a single broad band (at 294 nm) ; thesechanges were reversed at pH 10. We attribute theseshifts to the formation of a covalent hydrate (16) inaqueous acid, and similar spectral changes were notedwhen methanolic and ethanolic solutions of the triazolo-triazine were treated with N-hydrochloric acid.Indeed,when 3-hydrazinotriazole hydrochloride and benzil werel5 C.-F. Kroger and R. Miethchen, 2. Chem., 1969, 9, 378.l6 J. Daunis, R. Jacquier, and P. Viallefont, Bull. SOC. chinz.France, 1969, 2492.spectrum of the ethanolate (see Figure): the triazoleproton signal had moved upfield (to 6 7.85), and theO*CH2*CH, signal appeared as a complex multipletcentred at 6 3.37, characteristic of the AB part of anABX, system; the O*CH2*CH, signal appeared as aconventional triplet at 6 1.28 and the (exchangeable)NH signal at 6 -2.5. The methylene protons aremagnetically non-equivalent because of the adjacentasymmetric centre.17 The methoxy-derivative had asimilar arrangement of aromatic C-H absorptions and amethoxy-singlet at 6 3.24.We prefer structures (17) and (18) for the methanolateand ethanolate rather than the isomers (19) and (20)since acid-catalysed nucleophilic attack at the x-deficienttriazine ring is more likely than at the x-excessivetriazole ring.18 Nucleophilic addition to the mostelectrophilic centre (C-7) of the triazolotriazine (Scheme3) is precisely analogous to the process known to initiatel7 G.R. Bedford, RI. W. Partridge, and 31. F. G. Stevens,J . Chem. SOC. (C), 1966, 1214.A. Albert, ‘ Heterocyclic Chemistry,’ A4thlone Press,London, 2nd edn., 1968, p. 1251976 1495the Diinroth rearrangement in other mono- and bi-cyclic systems.2~4 Covalent adducts are only rarelyisolated, and addition is normally followed by ringPh/ b R(16) R = H(17) R = Me(18) R = E tI ' Ph, 0-R1 H (19) R = Me(20) R = E tSCHEME 3opening and rearrangement.Although the bicyclicwater adduct (16) may well exist in equilibrium with itsacyclic isomer (12b), recyclisation to the less favouredtriazolo[3,4-c]triazine isomer (14b) does not occur.EXPERIMENTALU.V. spectra were measured for solutions in ethanol andi.r. spectra for KBr discs. lH N.m.r. spectra were run on aVarian HA-100D spectrometer for solutions in CDC1,(Me,Si as internal standard).3-A nzino-6,7-diplzenyl- 1,2,4-triazolo[4,3-b] [ 1,2,4]triazine(7) .-3-Hydrazino-5,6-diphenyl-l,2,4-triazine (2.63 g) l9and cyanogen bromide (1.16 g, 1.1 mol) were boiled inmethanol (125 ml) for 2 h. Addition of cold ether (150 ml)precipitated a hydrobromide salt, which was collected andstirred in aqueous sodium acetate.The red triazolotriazine(73%) crystallised from ethanol with m.p. 263-264" (1it.,lo263-264') (Found: C, 66.7; H, 4.1; N, 29.1. Calc. forCl,H12N,: C, 66.7; H, 4.2; N, 29.2%); Lx 420, 335infl,284, and 243 nm (log E 3.38, 3.80, 4.17, and 4.17); v-3 395 (NH), 3 060br (bonded NH), and 1623 cm-l (C=N).The triazolotriazine was stable to dry heat (270 "C for I h)and in boiling acetic acid, pyridine, or piperidine (14 h).The diacetyl derivative (92y0), from the base and aceticanhydride (1 h a t 100 "C), had m.p. 190-191" (frommethanol) (Found: C, 64.2; H, 4.2; N, 22.7. C,,H,,N,O,requires C, 64.5; H, 4.3; N, 22.9y0) ; hxa 340 and 229 nm(log E 3.84 and 4.41); vmX.1740 and 1723 cm-l (GO);8 7.45-7.10 (10 H, m, 2 x Ph) and 2.21 (6 H, s, 2 x Me).The triazolotriazine (0.12 g) in anhydrous tetrahydro-furan (25 ml) was added dropwise (2 h) to a boiling solutionof pentyl nitrite (0.44 g) in tetrahydrofuran (5 ml). Thesolution was boiled for a further 3 h and evaporated. TheThe product, purified by column chromatography on neutralalumina with elution by benzene-chloroform, afforded 6,7-diphenyl- 1,2,4-triazolo[4,3-b] [ 1,2,4]triazine (8) (0.07 g)identical (i.r. and mass spectra) with an authentic sampleprepared by treating 3-hydrazino-5,6-diphenyl-1,2,4-triazinewith lOOo/, formic acid or triethyl orth~formate.~6,7-DiphenyZ- 1,2,4-triazoZo[4, 3-b] [ 1,2,4]triazin-3( 2H)-one(9) .-6, 7-Diphenyl-1,2,4-triazolo[4,3-b] [ 1,2,4]triazine (5.43g) in acetic anhydride (12 ml) at - 15 "C was treated drop-wise (30 min) with a solution of nitric acid (s.g.1.5; 1.26 g)in acetic anhydride (5 ml). The mixture was allowed t owarm to 0 "C and quenched with ice-water. The pre-cipitated triazolotriazinone (2.7 g) crystallised frommethanol with m.p. 285-286", and was identical (i.r. andmass spectra) with an authentic sample prepared from3-hydrazinod, 6-diphenyl-1,2,4-triazine and urea.l13-Arnino-5-hydrazino-l,2,4-#riazole Dihydrochloyide.-3,5-Diamino-l,2,4-triazole (10.0 g) in 10N-hydrochloric acid(200 ml) was diazotised at 0 "C with sodium nitrite (7.5 g)in water (25 ml). The stirred diazonium solution wastreated in portions (over 1 h) with tin(r1) chloride dihydrateat 0 "C. The mixture was stirred for a further 1 h at 0 "C,heated to 80 "C, and filtered hot, and the filtrate wassaturated with hydrogen chloride gas.The aminohydra-zinotriazole dihydrochloride (8.3 g) separated as a whitecrystalline solid, m.p. 21A216" (efferv.) (1it.,l2 217").2-Amino-6,7-diphenyZ-1,2,4-triazoZo[5, l-c] [ 1,2,4]triazine( 13a) .-3-Amino-5-hydrazino-1,2,4-triazole dihydro-chloride (1.88 g) was boiled in methanol (50 ml) containingbenzil (2.10 g) for 2 h. The triazolotriazine (gay0), depositedfrom the cooled solution, crystallised from aqueous ethanolas yellow needles, m.p. 272-274" (Found: C, 66.4; H, 4.2;N, 29.6. C1,H12N, requires C, 66.7; H, 4.2; N, 29.2%); Lx 350 and 260 nm (log E 3.89 and 4.43) ; vmax 3 470 and3 325 (NH), and 1620 cm-l (C=N).The monoacetylderivative (85y0), formed with boiling acetic acid-aceticanhydride (1 : 1) (1 h) crystallised from ethanol with m.p.29A295" (Found: C, 65.1; H, 4.5; N, 25.7. C,,H,,N,Orequires C, 65.5; H, 4.2; N, 25.5%) ; LL 325 and 257 nm(log E 3.94 and 4.45); vmx. 3 220 (NH) and 1 700 cm-l(GO). The diacetyl derivative (78%) (boiling aceticanhydride (2 h)] had m.p. 195-196" (from aqueous ethanol)(Found: C, 64.6; H, 4.4. C2,H1,N,02 requires C , 64.5;H, 4.3%); 8 7.6-7.2 (10 H, m, 2 x Ph) and 2.26 (6 H, s,2 x Me).2-Amino-6,7-diphenyl- 1,2,4-triazolo[5, l-c] [ 1,2,4]triazinewas unchanged after being subjected to dry heat a t 300 "C(1 h) or boiling acetic acid, pyridine, or piperidine (10 h).3-Hydrazino- 1,2,4-triazole Hydrochloride .-This compoundwas prepared by a process kindly supplied by ProfessorK.T. Potts. 3-Nitroamino-1,2,4-triazole (20 g) l6 andactivated zinc dust (40 g) were moistened with water andground to a paste. The paste was suspended in water(100 ml) at 10 "C and treated with 50% aqueous aceticacid (200 ml) over 2 h, the temperature being maintainedat 10-20 "C. The mixture was stirred a t 20 "C for afurther 4 h, heated to 60 "C (1 h), and allowed to cool.The excess of zinc was filtered off and the filtrate saturatedwith hydrogen sulphide (2 h). After removal of zincsulphide the filtrate and washings were treated with 1 0 ~ -hydrochloric acid. Evaporation afforded a gum, which wasboiled with chloroform (10 ml) for 30 min.3-Hydrazino-1,2,4-triazole hydrochloride (10 g) separated on addition ofabsolute ethanol (50 ml); m.p. 225" (lit.,20 224").( 13b) .-(i) 2-Amino-6,7-diphenyl-1,2,4-triazolo[5,l-c][ 1,2,4]triazine(13a) (0.24 g) in tetrahydrofuran (60 ml) was added drop-wise (2 h) to a boiling solution of pentyl nitrite (0.88 g) intetrahydrofuran (10 ml). The solution was boiled (3 h) andevaporated. The residue was dissolved in benzene andchromatographically fractionated on a neutral aluminacolumn. Evaporation of the benzene eluate afforded thediphenyZtriazoZotriazine (0.09 g), m.p. 193-195" (frommethanol) (Found: C, 70.2; H, 4.3; N, 25.7. Cl,H11N,requires C, 70.3; H, 4.0; N, 25.6%); 6 8.66 (s, H-2) and7.7-7.3 (10 H, m, 2 x Ph); A,, 349 and 248 nm (log E3.84 and 4.32).(ii) 3-Hydrazino-l,2,4-triazole hydrochloride (0.5 g),le P.V. Laakso, R. Robinson, and H. P. Vandrewala, Tetva-2o W. Manchot and R. Noll, Annalen, 1905, 343, 1.6, 'I-Dipheny Z- 1 , 2,4-triazoZo [ 5,141 [ 1,2,4] triazinehedron, 1957, 1, 103J.C.S. Perkin Ibenzil (0.6 g), and sodium acetate trihydrate (2 g) wereboiled in methanol (50 ml) for 2 h. The same triazolo-triazine (40%) was deposited when the solution was dilutedwith water.The triazine was stable at 200 "C (1 h) and in boilingacetic acid, pyridine, or piperidine (10 h).4,7-Dihydro-7-methoxy-6,7-diphenyl-l, 2,4-triazoZo[5,1-c]-[ 1,2,4]triazine ( 17) .-3-Hydrazino- 1,2,4-triazole hydro-chloride (0.5 g) and benzil (0.6 g) were boiled in methanol(6 h) and the solution was evaporated.Crystallisation ofthe residue from methanol afforded the wzethoxytriazolo-triazine (60y0), m.p. 211-212" (Found: C, 66.6; H, 5.0;N, 23.4. C,,H15N,0 requires C, 66.9; H, 5.0; N, 23.4%);A,, 297 nm (log c 4.16) ; 6 7.85 (s, H-2), 7.82-7.25 (10 H,m, 2 x Ph), and 3.24 (s, OMe) (Found: M+, 305.127 264.C17H15N50 requires M , 305.127 653).The methoxytriazolotriazine (0.2 g) in boiling acetic acid(3 nil) was converted into 6,7-diphenyl-1,2,4-triazolo[5,l-c]-[1,2,4]triazine (ix. and u.v.) after 2 h, in 90% yield.7-Ethoxy-4,7-dilzydro-6, 7-diphenyZ[ 1,2,4] triazolo [5,1 -c]-[ 1,2,4]triazine (18) .-Reaction of S-hydrazino-l,2,4-triazolehydrochloride and benzil in ethanol as above afforded theethoxytriazolotriazine (65y0), m.p. 205-206" (from methanol)(Found: C, 67.6; H, 5.4; N, 21.9. C,,H17N,0 requiresC, 67.7; H, 5.3; N, 21.9%); 298 nm (log E 4.16)(Found : A{+, 3 19.142 546. CIBHl,N,O requires M ,319.143 302).The ethoxytriazolotriazine (0.5 g) was boiled in aceticacid (5 ml) for 2 h and the solvent was removed undervacuum. The product (93%) was identical (i.r.) with 6,7-diphenyl- 1,2,4-triazolo[5,I-c] [ 1,2,4]triazine ( 13b). Theethoxytriazolotriazine was similarly converted into thetriazolotriazine (13b) by heat (1 h at 220 "C) and by boilingpyridine (2 h) (90 and 9504 yields, respectively).We thank the 3M Company for a research grant (toE. J. G.) and Dr. G. F. Duffin for discussions.11512204 Received, 12th November, 1976