The chemistry of polyazaheterocyclic compounds. Part VII. Extensions of av-triazolo1,5-aquinazoline synthesis and a new route to 4-aminoquinazoline derivatives

摘要

534 J.C.S. Perkin IThe Chemistry of Polyazaheterocyclic Compounds. Part VIIml Exten-sions of a v-Triazolol,5-aquinazoline Synthesis and a New Route to4-Aminoquinazoline DerivativesBy Derek R. Sutherland and George Tennant,' Department of Chemistry, University of Edinburgh, WestThe base-catalysed condensation of o-azidobenzonitrile with active methylene compounds containing a cyano-group (phenylacetonitrile. cyanoacetic acid, ethyl cyanoacetate, cyanoacetamide, and malononitrile) gives highyields of 5-amino-v-triazolol.5-aquinazolines (6). Breakdown of the triazole ring in these heterocycles occursunder a variety of acidic conditions affording new 4-aminoquinazoline derivatives.Mains Road, Edinburgh EH9 3JJFUSED v-triazoles containing a bridgehead nitrogenatom are of current interest as substrates for the in situgeneration of a variety of reactive heterocyclic species,notably carbenes and nitrenes,2 and diazonium cations.3The ' diazo-like ' reactivity of such fused triazoles can beexplained in terms of diazoalkylideneamine-triazolering-chain tautomerism, support for the existence ofwhich has recently been presented.l As a continuationof these studies on the synthesis and reactivity of fusedv-triazoles containing bridgehead nitrogen atoms, wenow describe a synthetic route to 5-amino-v-triazolo- 1,5-aquinazolines and their acid-catalysed conversioninto relatively inaccessible 4-aminoquinazoline de-rivat ives .4o-Azidobenzoic acid condenses with phenylacetonitrilein the presence of base to afford5 the v-triazolol,5-a-1 Part VI, D.R. Sutherland, G. Tennant, and R. J. S. Vevers,J.C.S. Perkin I, 1973, 943.2 W. D. Crow, M. N. Paddon-Row, and D. S. Sutherland,Tetrahedron Letters, 1972, 2239; R. Gleiter, C. Mayor, and C .Wentrup, Helv. Chirn. Acta, 1972, 55, 2628.quinazolone derivative (llb) in high yield. The readilyavailable o-azidobenzonitrile reacted similarly withphenylacetonitrile, cyanoacetamide, and malononitrile,in the presence of sodium methoxide to afford high-melting products whose properties and transformationsare consistent with the amino-v-triazoloquinazolinestructures (6b-d). The i.r. spectrum of the phenylcompound (6b) showed absorption due to a primaryamino-group, but lacked bands attributable to a cyano-group thereby excluding the alternative amino-v-tri-azole structure (3b).In accord with the primaryamino-structure (6b), acetylation led to a readily separ-ated mixture of the mono- and di-acetyl derivatives,(9b) and (lob). In the case of the nitrile (6d), the3 M. Regitz, Chem. Ber., 1966, 99, 2918; Tetrahedron Letters,1965, 3287; M. Regitz and H. Schwall, Anpzalen. 1969, 728, 99;G. Holt and D. K. Wall, J . Chem. Soc., 1966, 1428.D. R. Sutherland and G. Tennant, Chem. Comm., 1969, 423.ti G. Tennant, J . Chem. Soc. (C), 1966, 2290.M. 0. Forster and H. M. Judd, J . Chem. SOC., 1910, 97, 254.0. Dimroth, Annalen, 1909, 364, 1831974 535diacetyl derivative (10d) formed on acetylation wasunstable and afforded the monoacetyl compound (9d)on attempted crystallisation.The amide (6c) gave alabj le triacet yl product which is tentatively assignedONN=CN / ( 3 )IttNEEEN 0 N=N11( 7 ) / ( 5 )N=N N=NRa; Wb; Phd ; CNe; C02HC ; CO.NH2f ; C02Et9; CO-NHAcN=Nthe structure (log) on the basis of its i.r. and lH n.m.r.absorption and the known 8 capacity for a v-triazolecarboxamide group to undergo acetylation. Partialhydrolysis of the triacetyl compound (log) occurred inhydroxylic solvents giving a stable diacetyl productwhose spectral properties are consistent with either ofthe possible structures (9g) and (1Oc).The angular structure (6b) for the phenyl compound13 D. R. Sutherland and G. Tennant, J. Chem. Soc. (C), 1971,Q G. Tennant, unpublished work.706.(as opposed to the linear structure (8b), the end productof Dimroth rearrangement prior to (3) + (4) +(5) or subsequent to (6) *.(7) + (S) cyclisation)was firmly established by its conversion by forcingalkaline hydrolysis into the known triazoloquinazolone(llb). The angular structure of the amide (6c) and thenitrile (6d) follow from their similar conversion into thetriazoloquinazolone (1 lc) of established constitution.9The hydrolysis of the amino-group involved in the trans-formations (6b-d) __t ( l l b or c) is akin to the wellknown l o hydrolysis of 4-aminoquinazolines to quin-azolin-4(3H) -ones.The ethoxide-catalysed condensation of ethyl cyano-acetate and cyanoacetic acid with o-azidobenzonitrilegave the same product, C,H,N5, which showed i.r.absorption due to a primary amino-group, but lackedi.r.carbonyl absorption. Alkaline hydrolysis to theknown triazoloquinazolone (lla) identified this productas 5-amino-v-triazolo 1,5-aquinazoline (6a). The ester(6f) and the acid (6e) are probable intermediates in thereactions of the azide (1) with ethyl cyanoacetate andcyanoacetic acid to give the amine (6a).The absence of diazo-absorption at ca. 2200 cm-1 inthe i.r. spectra of the triazoloquinazolines (6a-d)excludes the existence of ring-chain tautomerism(6) + (7), at least in the solid phase at room tem-perature. The insolubility of compounds (6a-d) pre-cluded the study of their i.r. absorption in solution.However, as in v-triazolol,5-apyrimidines 1*11 andv-triazo101,5-aquinazolones,~ scission of the triazolering in compounds (6a and b) occurred readily in acidicmedia.Heating the phenyl derivative (6b) in glacialacetic acid afforded a compound which could be crystal-lised unchanged from aprotic solvents and gave ana-lytical data consistent with the molecular formulaC1,Hl,N,O,, corresponding to an acetic acid solvate ofthe expected acetoxybenzylquinazoline scission product(12c). The spectral properties and transformations ofthe scission product are fully consistent with thisstructure. 1.r. absorption at 3400-3200 and 1739 cm-lcan be attributed to a primary amino-group and anacetoxy carbonyl group, respectively; bands at 3100-2700 and 1695 cm-l correspond to the hydroxy- andcarbonyl-absorptions of acetic acid.The lH n.m.r.spectrum (solvent trifluoroacetic acid) contains signalsat T 3.02 and 7-57 assigned to the benzyl and acetoxy-groups, respectively, and a signal at T 7.73 correspondsto the methyl absorption of acetic acid. Acetylation ofthe scission product yielded a monoacetyl derivative(13c), which was also the product when the acetamido-triazoloquinazoline (9b) was heated in acetic acid. Mildalkaline hydrolysis of the acetoxy-compound (12c) or ofits acetyl derivative (13c) gave an amino-alcohol. Thebenzylic structure (12b) for this product follows from10 W. L. F. Armarego, in Quinazolines,' ' The Chemistry ofHeterocyclic Compounds,' ed. A. Weissberger, Interscience-Wiley, New York, 1967, pp. 333-334.11 D.R. Sutherland and G. Tennant, J . Chem. SOC. (C), 1971,2166536 J.C.S. Perkin Ithe spectrum contained a singlet at 7 2.94 (Table 1)consistent with complete conversion into the trifluoro-acetate (12d). After ca. 26 h the presence of a newsignal at T 3.78 indicated the presence of the alcohol(12b) produced by hydrolysis l y l l of the ester (12d). Incontrast to the phenyl compound (6b), the amide (6c) andthe nitrile (6d) were unaffected by prolonged heating inglacial acetic acid, and the lH n.m.r. spectra of solutionsin trifluoroacetic acid showed no sign of benzylicabsorption after 27 h a t room temperature. Thereluctance of fused v-triazoles bearing electron-with-its oxidation by manganese dioxide l2 to an amino-ketone (18a), which formed a monoacetyl derivative(18b), and was reconverted into the alcohol (12b) byR RNHAc( 1 3 1Ra ; H drawing groups at C-3 to undergo acid-citalysed scissionb ; OH has also been observed in the v-triazolol,5-apyrimidinec ; OAc ring system,lpll and may be reasonably explained inN HAc d ; O.COCF~ terms of destabilisation of the conjugate acid of thee ; C l triazole see Scheme; (21), the probable species under-f ; Br going scission in acidic media.In support of thiscontention, the 3-unsubst ituted aminotriazoloquinazoline 9 ; OEt(6a) was smoothly converted in hot glacial acetic acidinto the amino-acetate (14c). The structure of thisproduct was established by its hydrolysis under mildconditions to give the amino-alcohol (14b), and underN~ C H , RdNNH2( 1 4 ) ( 1 5 )0( 1 6 )0(17 Icatalytic reduction.Catalytic reduction of the benzylicacetate (12c) resulted in its hydrogenolysis to the H+( 2 0 ) f *( 2 1 )NHR( 1 8 ) R ( 1 9 ) x a ; Hb ; A caminobenzylquinazoline (12a). This compound was alsoobtained by hydrolysis of the acetamidoquinazoline(13a), the product of the hydrogenolysis of the acetoxy-benzylquinazoline (13c). The latter reaction also gavea compound, CI,H1,N30, whose spectral properties arein accord with the 3,4-dihydroquinazoline structure (19).The catalytic reduction of 4-aminoquinazolines to 3,4-dihydro-derivatives is well known.13 The structure ofthe acetyl compound (13c) and hence that of the parentamine (12c)l was firmly established by forcing alkaline oracidic hydrolysis to the known quinazolone (l6b).Triazole scission in the phenyl compound (6b) alsooccurred in trifluoroacetic acid at room temperature, butnot so readily as in the cases of v-triazolol,5-apyr-imidines.l,ll The lH n.m.r.spectrum of a solution ofthe phenyl compound (6b) in trifluoroacetic acid left atroom temperature for 1 h showed no signal due to abenzylic proton (Table l ) , demonstrating the presenceof the intact fused structure (6b). However, after 24 h( 2 4 1( A = OH, CI, Br, OAc, or,0.COC'F3 )SCHEMEforcing conditions to give the known l4 S-hydroxy-methylquinazolone (17b). In contrast to their morel2 L. F. Fieser and M. Fieser in ' Reagents for Organic Syn-l3 Ref. 10, pp.398-399.thesis,' Wiley. New York, 1967, p. 638. 14 M. Uskokovic, J. Iacobelli, V. Toome, and W. Wenner, J -Org. Chem., 1964, 29, 6821974 537reactive benzyl counterparts (12b and c), the alcohol(14b) and the derived acetate (14c) were inert to man-ganese dioxide oxidation and hydrogenolysis, re-spectively. The compound (6a) also underwent scissionin trifluoroacetic acid. The lH n.m.r. spectrum of asolution of (6a) in trifluoroacetic acid kept at roomtemperature for 24 h showed a singlet of intensityequivalent to one proton at 7 4.75, attributable to thebenzylic protons of the trifluoroacetate (14d).Breakdown of the triazole ring in the triazoloquin-azolines (6a and b) also occurred in the presence of acidhalides 175711 to afford 2-halogenoalkyl- or 2-halogeno-aralkyl-quinazolines.Thus, heating the amine (6b) orits acetyl derivative (9b) with acetyl chloride in acetic acidafforded the chlorobenzylquinazoline (13e). The identi-fication of this product is based on its hydrogenolysis toa mixture of the acetamido-compound (13a) and thedihydro-derivative (19), and on its acidic hydrolysis tothe amino-alcohol (12b). Reaction of the chloro-compound (13e) with ethanolic sodium carbonateresulted in both hydrolysis and nucleophilic displace-ment to give the ether (12g). The amine (6b) alsoreacted with acetyl bromide in acetic acid to afford aproduct whose lH 1i.m.r. spectrum showed it to be amixture of the benzyl compound (13a) and the bromo-benzylquinazoline (13f), from which the latter wasisolated by fractional crystallisation.Formation of thebenzylquinazoline (13a) is explicable in terms of re-duction of the bromo-compound (13f) by the hydrogenbromide produced by the interaction of acetyl bromidewith acetic acid.5 Reaction of the parent aminotriazolo-quinazoline (6a) with acetyl chloride and acetyl bromidein acetic acid likewise gave the halogeno-compounds(15e and f), both of which were converted by acidichydrolysis into the amino-alcohol (lab). The absenceof 4-amino-2-methylquinazoline (14a) as a product ofthe reaction of the amine (6a) with acetyl bromide inacetic acid reflects the lower reactivity (towards re-duction) of an alkyl bromide compared with an aralkylbromide.Hot aqueous mineral acid also cleaved the triazolering in the aminotriazoloquinazolines (6).Scission ofthe amino-compound (6b) in hot aqueous ethanolicsulphuric acid was accompanied by hydrolysis of theamino-group and gave the quinazolone (16b). Similartreatment of the unsubstituted aminotriazoloquinazoline(6a) likewise gave the quinazolone (17b), which was alsothe product of the forcing acidic hydrolysis of the amide(6c) and the nitrile (6d). In view of the stability ofcompounds (6c and d) to scission in acetic acid, theirdecomposition in aqueous mineral acid is best explainedin terms of prior hydrolysis and decarboxylation to a3-unsubstituted species, either (6a) or (1 la), followed byscission.The foregoing reactions demonstrate the viability ofacid-catalysed scission of readily accessible 5-amino-u-triazolo1,5-aquinazolines as a synthetic route to2-substituted 4-aminoquinazolines.In general, thesereactions can be rationalised in terms of the solvolysis ofa diazonium cation (23) produced by ring-opening of theconjugate acid of the triazole (21) (Scheme). Thealternative formation of the cation (23) by protonationof a diazo-intermediate (22) (Scheme) is irrcoiisistentwith the stability of the amide (6c) and the nitrile (6d)to hot acetic acid, since electron-withdrawal at C-3should promote ring-opening (20) += (22)l and henceacid-catalysed scission, rather than inhibit it as observed.On the other hand, the inertness of the amide (6c) andthe nitrile (6d) is readily explained on the basis ofdestabilisation of the conjugate acid (21) by electron-withdrawal at C-3.The controlling influence of proton-ation on the course of the acid-catalysed reactions of thetriazoloquinazolines (6) is further emphasised by thefact that their scission under electron impact withoutexception occurs by loss of nitrogen to give primaryfragment ions of mass (M+ - 28). These ions corre-spond to the base peaks in the mass spectra of com-pounds (6a, b, and d), whereas in the spectrum of theamide (6c), the peak a t (Mf - 28) is subsidiary to apeak at (M+ - 83). The mass spectrum of the amide(llc) lacks a peak at (A$+ - 28); again the base peakcorresponds to an ion of mass (Jf+ - 83). Primaryfragmentation to ions of mass (M' - 83) is also a featureof the mass spectra of ~-triazolol,5-apyrirnidine-3-carboxamides.lEXPERIMENTAL1.r. and U.V.spectra were recorded for Nujol suspensionsand ethanolic solutions, respectively, with Unicam SP 200and SP 800 instruments. lH 3.m.r. spectra were measureda t 60 and 100 MHz for solutions in deuteriochloroform orTABLE 1lH N.1n.r. signals (7) of v-triazolol,5-aquinazolinesArH1 .45-2 1 9 (in) d4.30, 4.75 f 1.30-2.30(m)'i 2.13-2.37(m) g2.94 f 1.44---2.58(m)2.945 3-78f 1-44-2.60(m) 1'1.08-2-16(m)J 1-09-1.85(m) J1 3.23-2.351m) dOthers4-30Acr 1.11-1*95(111)1 ~10-2*20(m) d7.121(9g)/(lO;) 7-21, 7.36 1.10-2.10frn) d1*05---.10(m) dSpectra taken a t 100 MHz on a Varian HA 100 instrument;solutions in trifluoroacetic acid a t 28" with tetramethylsilancas internal standard. Signals were sharp singlets unlessdesignated as m (multiplet).b Spectra taken at 60 MHz on aPerkin-Elmer R10 instrument. c H-3. d 4H. Spectrumrun after 24 h in trifluoroacetic acid. 9 5II.h9H. 'Spectrum run after 26 h in trifluoroacetic acid.j NHXc. NAc,.7-37 k 0-90-1 a95 (In) (104(log) 7-21, 7.37, 7-72f Benzylic H.trifluoroacetic acid, a t 28", with tetramethylsilane asinternal standard, with Perkin-Elmer R10 and VarianHA-100 instruments. lH N.m.r. data for triazoloquin538 J.C.S. Perkin Iazolines and quinazolines are collected in Tables 1 and 2.Mass spectra were measured at 70 eV and 150" (probeTABLE 2lH N.m.r. signals ( T ) of 4-aminoquinazolines a(12a) b 7-15 1 -00-2-06 (m)(12b) 3-80 2-56 C( 1 2 ~ ) 342 1;:;; :, 1,49-2-71(m)Compd. H NHAc Others ArH1.55--2-10(m) g1 .30-2.10 (m) h(12g) 4.25 ~ : ~ ~ $ ' { 2.66 A2-63 0 (13a) 5.30 7.30(134 5-70 7.55 .,(13~) 2.76(13e) 3-51(13f) 3.44(14b) 4.84(14~) 4.45(16e) a 4.88(16e) 5-20(16f) 6-36(19) 5.821-61-1-73jmj2-33-2.59(m) 01.30-1.80(m) 02.22-2.60(m) k1.48 (dd) 11-73-2.19(m) 6-92 {7-57 1.35-2.15(m) h7-25 1.80--2.60(m) h7-26 1.86-2.61(m) k7.307.277-15 1.1 8-2*00( m) h1.17 *, 1-81 n, 2.32-2.86jmj 0 7-84 {3.330a Unless otherwise stated, spectra were taken at 100 MHzon a Varian HA 100 instrument; solutions in trifluoroaceticacid at 28" with tetramethylsilane as internal standard.Signals were sharp singlets unless otherwise designated.b Spectra taken at 60 MHz on a Perlun-Elmer R10 instrument.e 9H.OAc. Methyl protons of acetic acid. f OEt, J 7Hz. 0 5H. h 4H. 6 Solution in deuteriochloroform. j OAc.fi NH. 2 1H. 3H. fl NET, poorly resolved doublet. * H-4,multiplettemperature) with an A.E.I. MS 902 spectrometer. Lightpetroleum had b.p. 60-80". Unless otherwise stated,chloroform extracts were washed (aqueous sodium hydrogencarbonate and water) and dried (MgSO,) prior to evapor-ation under reduced pressure.5-Amino-v-triazob1,5-aqz~inazoZines (6) .-(a) A mixtureof o-azidobenzonitrile (14.4 g, 0.1 mol) and phenylaceto-nitrile, cyanoacetamide, or malononitrile (0.1 mol) inmethanol (150.0 ml) was mixed with a solution of sodium(9.2 g) in methanol (150.0 ml) . A solid separated from theoriginally homogeneous mixture and the suspension wasstirred at room temperature for 30 min.The solid wascollected, washed with methanol (50.0 ml) and water(100.0 ml), and combined with solid material recoveredfrom the methanolic filtrate and washings by evaporationand treatment with water. Crystallisation afforded thepure 5-amino-3-pl~enyZ-v-t~.iazoZo 1,5-aquinazoZine (6b)(82), m.p. 268" (from glacial acetic acid), vmX. 3400,3250, and 3150 (NH), and 1640 (NH def.) cm-l, Lx, 215,230sh, 254sh, 260, 273, 284, 295sh, and 347 nm (log E 4.46,4-33, 4.35, 4.37, 4.28, 4.27, 4.02, and 3-82), nzle 261 (12,M+) and 233 (loo, M+ - N,) (Found: C, 69.1; H, 4.3;N, 26.9. CI5Hl1N5 requires C, 69-0; H, 4.2; N, 26.8);the 3-carboxanzide (6c) (81), m.p.312' (from glacial aceticacid-dimethylformamide), vmX 3450, 3400, and 3150 (NH),and 1685 (CO) cm-l, nz/e 228 (63, M+), 200 (26, M+ -N,), and 145 (loo, M+ - 83) (Found: C, 52.4; H, 3-2;and the 3-carbonitrile (6d) (quant.), m.p. 286' (decomp.)(from glacial acetic acid-dimethylformamide) , vmX. 3400,3350sh, and 3150 (NH), 2250 (CN), and 1650 (NH def.),N, 36.9. C,,H8N60 requires c, 52.6; H, 3.5; N, 36.8);kx. 219infl, 229~11, 234, 248sh, 271.~11, 280, and 310 nm(log E 4-49, 4.62, 4.63, 4.32, 3-96, 4.01, and 3.97), m/e 210(56, Af') and 182 (loo, MT - N,) (Found: C, 57.0;H, 2.9; N, 39.9. Cl,H6N, requires C, 57.1; H, 2.9; N,40.0).(b) A solution of o-azidobenzonitrile (14.4 g, 0.1 rnol) andethyl cyanoacetate or cyanoacetic acid (0.1 mol) in absoluteethanol (200.0 ml) was treated with a solution of sodium(9.2 g) in absolute ethanol (200.0 ml), added in one portion.A gelatinous solid separated from the initially homogeneoussolution, and the mixture was stirred at 80' for 2.5 h.Thecrude salt was collected, augmented with further materialobtained by concentrating the ethanolic mother liquors,washed with ethanol, and stirred with 50"/b v/v aqueousacetic acid (250.0 ml) at room temperature for 3 h t o afford5-amino-v-triazoZo1,5-a~u~n~zoZine (6a) (quant.), m.p. 266"(decomp.) (from dimethylformamide-water), vmaK 3350 and3150 (NH), and 1680 (NH clef.) cm-1, m/e 185 (loo, M+)and 157 (loo, M* - N,) (Found: C, 58.8; H, 3.6; N,37-7. C,H,N, requires C, 58.4; H, 3.8; N, 37.8).Acetylation of the 5-Amino-v-t~iazoZo~l,5-aquinazoZines(6).-(a) The 3-phenyl derivative (6b) (0.5 g) was heatedunder reflux in acetic anhydride (15.0 ml) for 5 min.Themixture was filtered hot t o give the 5-N-acetyl derivative(9b) (0.4 g), m.p. 265' (from ethanol-dimethylformamide),vmax; 3250 (NH) and 1685 (CO) cm-l, Lx. 209, 227sh, 232,255, 275sh, 290sh, and 356 nm (log E 4.42, 4.46, 4.48, 4.41,4.26, 4-04, and 3-87) (Found: C, 67.8; H, 4.2; N, 2243;M+, 303. C1,H,,N50 requires C, 67.3; H, 4-3; N, 23.1;M , 303). Evaporation of the acetic anhydride motherliquors gave a gum which yielded the solid 5,5-di-N-acetyZderivative (lob) (0.11 g) in contact with ether, m.p. 186"(from benzene-light petroleum), v- 1730 and 1690 (CO)cm-l, Lxe 208, 224, 254, 273sh, 286sh, 312sh, and 326shnm (log E 4.52, 4-47, 4-39, 4.25, 4.03, 3-67, 3-61, and 3.87)(Found: C, 66.8; H, 4.3; N, 20.0; M+, 345.Cl,H1,N50, requires C, 66-5; H, 4.4; N, 20.4 ; M , 345).(b) The amino-compounds (6c and d) (0-4 g) were heatedunder reflux in acetic anhydride (80.0 ml) for 2 h.Thegums obtained by evaporating the mixtures solidified ontreatment with ether to give the triacetyl derivative (log)(0.4 g), vmaX 3300 (NH), and 1710, 1680, and 1660 (CO) cm-1,or the diacetyl derivative (10d) (0-4 g), v,, 2250 (CN) and1710 and 1690 (CO) cm-l respectively, which were convertedby heating with glacial acetic acid or by crystallisation,into the di-N-acetyl derivative (9g) or ( ~ O C ) , m.p. 287'(from dimetliylformamide-water), vmx.3350, 3250, and3150 (NH) and 1730, 1710, and 1680 (CO) cm-l, ?bsol;max 231,270~11, 281sh, and 314 nm (log E 4-34, 3.86, 3.79, and 3.85)(Found: C, 53.2; H, 4-0; N, 26.4; M+, 312, Calc. forC1,H1,N,O,: C, 53.8; H, 3.9; N, 26.9; M , 312), or themono-N-acetyl devivative (9d), m.p. 250" (from glacial aceticacid), vmILx. 3250 (NH), 2250 (CN), and 1690 (CO) cm-1, Lz 230, 263sh, 270sh, and 314 nm (log E 4.46, 4.10, 3.95,and 3-92) (Found: C, 57.0; H, 3.2; N, 33.2; M+, 252.C,,H,N,O requires C, 57.1; euro;3, 3.2; N, 33.3; M , 252).v-T~iazoZol,5-aqzainazoZin-5(4H)-ones (I l).-The amino-triazoloquinazolines ( 6 a - d ) (0.002 mol) were heated underreflux with aqueous 200/, TV/V potassium hydroxide (10.0ml) in 2-ethoxyethanol (60.0 ml) for 3 h.Removal of thesolvent under reduced pressure afforded gums which weredissolved in the minimum of water and acidified (diluteaqueous sulphuric acid) to give the triazoloquinazolones(1 la) (50), m.p. 293" (from dimethylformamide), (1 lb)(91), m.p. 259" (from dimethylformamide), and (1 lc197489 and 91 respectively from (6c) and (6d), 1n.p. 296"(from dimethylformamide), m/e 229 (49, M+) and 146(loo, M+ - 83), which were identified by comparison(mixed m.p. and i.r. spectra) with authentic ~arnples.~,2-A cetoxymethyl- and 2- (a-Acetoxybenzyl) -quinazolines(12c) , (13c), and (14c) .-The aminotriazoloquinazolines(6a and b) and (9b) (0.004 mol) were heated under reflux inglacial acetic acid (60.0 ml) for 2.5 h.The gums obtainedby evaporating the acetic acid solidified when treatedwith ether to yield the acetoxy-compounds (14c) (87),n1.p. 203" (from ethanol-benzene), vmX. 3250 and 3100(NH), 1730 (CO), and 1660 (NH def.) cm-l (Found: C,60.1; H, 5.0; N, 19.6. C11HllN30, requires C, 60.8; H,5.1; N, 19.4y0); (12c) (acetic acid solvate) (98), m.p.102" (from benzene-light petroleum), vmax 3400, 3300,3100, and 2700br (NH,OH), 1735 and 1695 (CO), and 1660(NH def.) cm-l (Found: C, 64.1; H, 5.4; N, 12.1;Mt, 293. Cl7Hl,N30,,CH,CO2H requires C, 64.6; H, 5.4;N, 11.9; M , 293); and (13c) (75), m.p. 168" (frombenzene-light petroleum), vmx, 3250 (NH), 1730 and 1695(CO), and 1570 (NH def.) cm-l (Found: C, 67.5; H, 5-0;N, 12.3. C,,H17N303 requires C, 68.0; H, 5.1; N, 12.5).The acetic acid solvate of the acetoxy-amine (12c) wasconverted in hot acetic anhydride into the acetyl derivative(13c) (77y0), identical (mixed m.p.and i.r. spectrum) witha sample prepared before).The aminotriazoloquinazolines (6c and d) when heatedunder reflux with glacial acetic acid as described before,were unchanged (recovery 84).2-(cc-Hydroxybenzyl)quinazolin-4( 3H)-one (16b) .-(a) Theaminotriazoloquinazoline (6b) (0.15 g) was heated underreflux with aqueous 30 w/v sulphuric acid (7.5 ml) inethanol (7.5 ml) for 30 min. The ethanol was distilled offunder reduced pressure and the residue was treated withdilute aqueous sodium hydroxide, and extracted withchloroform to give a gum, which was crystallised to yieldthe amino-alcohol (12b) (0.07 g), m.p.173" (from benzene-ethanol), identical (mixed m.p. and i.r. spectrum) with asample prepared later. Acidification of the alkaline extractwith glacial acetic acid afforded the alcohol (16b) (0.05 g),n1.p. 208" (from ethanol), identical (mixed m.p. and i.r.Spectrum) with an authentic ample.^(b) The quinazolone (16b) was also obtained (70-90)when the aminotriazoloquinazoline (6b) or the acetoxy-benzylquinazoline (13c) was heated under reflux withaqueous 30 w/v sulphuric acid in ethanol for 2 h, orwhen the compound (13c) was heated under reflux (3h)with aqueous 2004, w/v potassium hydroxide. Work-upwas carried out by evaporation of the mixtures underreduced pressure, treatment with water, neutralisation, andextraction with chloroform.2-HydroxymethylquinazoZin-4(3H)-one (17b) .-(a) Solu-tions of the amines (6a) or (6c and d) (0-005 mol) in 2-ethoxyethanol(80-0 ml) were heated under reflux with aque-ous 30 w/v sulphuric acid (20.0 ml) for 4 h.Alternatively(b) the aminoquinazoline(l4c) (0.5 g) in ethanol (50-0 ml)was heated under reflux with aqueous 20 w/v potassiumhydroxide (15.0 ml) for 3 11. The mixtures were evaporatedunder reduced pressure, treated with water, and adjusted toneutral pH. Extraction with chloroform gave gums whichwere triturated with ether to yield the alcohol (17b) (60-go), m.p. 214" (from ethanol) (lit.,l4 214"), v,, 3200-2700br (OH, NH) and 1670br (CO) cm-l (Found: C, 61.6;H, 4-8; N, 15.5. C,H,N,O, requires C, 61.4; H, 4.5; N,15.904).4-Acetamido-2-(a-chlorobenzyl)qu~nazoline (13e) .-Theaminotriazoloquinazoline (6b) or its acetyl derivative (9b)(0.004 mol) was heated under reflux with acetyl chloride(20.0 ml) and glacial acetic acid (20.0 ml) for 1.5 h.Themixture was evaporated under reduced pressure, treatedwith saturated aqueous sodium hydrogen carbonate, andextracted with chloroform. Evaporation of the extractgave a gum which solidified when triturated with ether toyield the chlorobenzylquinazoline (13e) (75-80), m.p. 174"(from benzene), vmx. 3250 (NH), 1680br (CO), and 1570(NH def.) cm-l (Found: C, 65.3; H, 4-4; N, 13.8.C17Hl,C1N,0 requires C, 65.4; H, 4.5; N, 13.5).The chloro-compound (13e) (0.15 g) was heated underreflux with aqueous N-sodium carbonate (7.5 ml) andethanol (7.5 ml) for 20 min.The mixture was evaporatedand the residue was treated with water and extracted withchloroform to yield the ether (12g) (0.1 g), m.p. 197" (frombenzene), vmX. 3350-3000br (NH), 1670 (CO), and 1560cm-l (Found: C, 73.0; H, 6.6; N, 14.7; M+, 279.C17H1,N,0 requires C, 73.1; H, 6.1; N, 15.0; M , 279).4-A cetamido-2-chlovomethylquina~oline ( 15e) .-The amino-compound (6a) (0.5 g) was heated under reflux with amixture of acetyl chloride (75.0 ml) and glacial acetic acid(50.0 ml) for 4 h. The gum obtained by evaporating themixture solidified in contact with ether-light petroleum toafford the chloromethylquinazoline (15e) (0.4 g ) , m.p. 199"(from benzene-light petroleum), vmz 3250 (NH) and 1690br(CO) cm-l (Found: C, 55.5; H, 4.0; N, 17.6.C,lHloCIN,Orequires C, 56.1; H, 4.2; N, 17-80/,).4-Acetanzido-2-(u-bromobenzyl)quinazoline ( 13f) .-Theaminotriazoloquinazoline (6b) (1.0 g) was heated underreflux with a mixture of freshly distilled acetyl bromide(20.0 ml) and glacial acetic acid (20.0 ml) for 1-5 h. Themixture was evaporated, treated with saturated aqueoussodium hydrogen carbonate, and extracted with chloroformto give a gum which was triturated with ether to yield asolid mixture (0.8 g), m.p. 115-123", of the acetamido-quinazolines (13a) and (13f), T (CDCl,) 1.85-2-85 (m,(ArH), 3.69 (s, CH), 5.69 (s, CH,), 7.28 (s, Ac), and 7.51(s, Ac), in the ratio 3 : 2 as estimated from the integratedintensities of the n.m.r.acetyl signals. Repeated crystal-lisation of the mixture afforded the pure brornobenzyl-quinnzoline (13f), m.p. 178" (from benzene-light petroleum),vmaX 3250 (NH) and 1680br (CO) cni-l (Found: C, 58.0;H, 4.0; N, 11.7. C,,H,,BrN,O requires C, 57.3; H, 3-9;N, 11.8).4-Acetamido-2-bronaonzethylquinazoline (1 5f) .-The tri-azoloquinazoline (6a) (1.0 g) was heated under reflux witha mixture of acetyl bromide (30-0 ml) and glacial acetic acid(30.0 ml) for 4 11. The mixture was evaporated under reducedpressure and the gum obtained was stirred with saturatedaqueous sodium hydrogen carbonate to give the solidproduct, more of which was recovered by extracting theaqueous mother liquor with chloroforni (total 1.1 g).Crystallisation yielded the pure byomomethyl compound(15f), m.p.205" (from benzene-light petroleum), vmax. 3250(NH) and 1680 (CO) cm-l (Found: C, 47.1; H, 3.4; h-,15.3. CllHloBrN30 requires C, 47.2; H, 3.6; N, 15.0).4-Amino-2-(u-hydroxybenzyZ)quinazoZine (12b) .-(a) Solu-tions of the acetic acid solvate of (12c) and the acetoxy-compound (13c) (0.001 mol) in ethanol (10.0 ml) wereheated under reflux with aqueous N-sodium carbonate(10.0 ml) for 20 min. Alternatively (b), the chlorobenzyl-quinazoline (13e) (0.001 mol) in ethanol (20.0 ml) washeated under reflux with aqueous 2~-sulphuric acid (10.540 J.C.S. Perkin Iml) for 30 min. The mixtures were concentrated underreduced pressure and extracted with chloroform to givegums which were triturated with ether to yield the solidamino-alcohol (12b) (80-90~0), m.p.173" (from benzene-ethanol), vmx. 3350 and 3200 (NH) and 1650 (NH def.) cm-l(Found: C, 71.0; H, 5.1; N, 16.9. C1,H13N30 requires C,71.7; H, 5.2; N, 16.7).4-A mino-2-hydroxymethylquinazoline ( 14b) .-Hydrolysisof the acetoxymethylquinazoline (14c) with hot aqueousethanolic sodium carbonate or of the halogenomethyl-quinazolines (15e and f ) with hot aqueous ethanolic sul-phuric acid, as described before, gave the amino-alcohol(14b) (50-80), m.p. 212" (from ethanol-benzene), vWx.3350 and 3100 (NH, OH) and 1670 (NH def.) cm-l (Found:C, 61-6; H, 5.2; N, 23-9. C,H,N30 requires C, 61.7; H,5.2; N, 24.0).4-Aunino-2-benzoyZquinazoline ( 1 Sa) .-The amino-alcohol(12b) (0.4 g) was heated under reflux with activatedmanganese dioxide la (1.6 g) in anhydrous acetone (20.0 ml)for 5 min.The filtered, evaporated mixture afforded agum which solidified in contact with ether to yield theketone (1Sa) (0.33 g ) , m.p. 203" (from benzene-lightpetroleum), timas. 3500 and 3300 (NH), 1680 (CO), and 1645(NH def.) cm-l (Found: C, 72.6; H, 4-3; N, 17-0.C,,HllN30 requires C, 72.3; H, 4.5; N, 16.9). Theamino-ketone (18a) was converted in hot acetic anhydrideinto the acetyl derivative (lSb), m.p. 171" (from benzene),vmaK 3300 (NH) and 1685 and 1675 (CO) cm-l (Found: C,70.3; H, 4.6; N, 14.9. C1,H13N302 requires C, 70.1; H,4.5; N, 14~40/~), and when hydrogenated in ethanol over10 palladium-charcoal i t afforded the amino-alcohol(12b) (SO), m.p. 173" (from benzene-ethanol), identical(mixed m.p. and i.r. spectrum) with a sample preparedbefore.The amino-alcohol (14b) was unchanged (85) whenheated with activated manganese dioxide in anhydrousacetone as described before.4-Amino-2-benzylquinazoline ( 12a) .-Hydrogenation ofthe acetoxybenzylquinazoline ( 12c) (acetic acid solvate) inethanol over 10 palladium-charcoal yielded the amine(12a) (quant.), m.p. 221" (from benzene-ethanol), vmaX 3300and 3150 (NH) and 1660 (NH def.) cm-l (Found: C, 76.5;H, 5.7; N, 17.7. C15H13N3 requires C, 76.6; H, 5-6; N,17.9y0). The acetoxy-compound (14c) was unchanged(90) after attempted hydrogenation in ethanol over 10palladium-charcoal.4-Acetamido-2-benzylquinazoline (1 3a) and its Dihydro-derivative ( 19) .-Hydrogenolysis of the acetamidoquin-azolines (13c and e) (0.001 mol) in ethanol over 10palladium-charcoal gave gums which were treated withether to give the insoluble dihydro-compound (19) (0.22 g),m.p. 140" (from benzene), vmaK 3250 (NH), 1665 (CO), and1645 (NH def.) cm-l (Found: C, 72.9; H, 6.3; N, 14-9.C17H17N30 requires C, 73.1; H, 6.1; N, 15-1y0). Evapor-ation of the ether extract yielded the acetamidoquinazoline(13a) (0.08 g ) , m.p. 145' (from benzene-light petroleum),vmax. 3250 (NH), 1680 (CO), and 1570 (NH def.) cm-l(Found: C, 73-5; H, 5.6; N, 15-3. Cl,Hl,N30 requiresC, 73.6; H, 5.5; N, 15.2). The acetamidoquinazoline(1 3a) was hydrolysed with aqueous N-sodium carbonate inethanol as described before to afford 4-amino-2-benzyl-quinazoline (12a) (82y0), m.p. 221" (from benzene-ethanol),identical (mixed m.p. and i.r. spectrum) with a sampleprepared before.We thank the S.R.C. for a research studentship (to3/2147 Received, 19th October, 19731D. R. S.)