The Dimroth rearrangement. Part XVIII. Syntheses and rearrangement of 4-iminoquinazolines and related systems

摘要

2182 J.C.S. Perkin IThe Dimroth Rearrangement. PartXV1II.l Synthesesand Rearrangementof 4-lminoquinazolines and Related SystemsBy Desmond J. Brown and Kazuharu lenaga, John Curtin School of Medical Research, P.O. Box 334,Canberra City, Australia 2601o- Aminobenzonitrile is converted by triethyl orthoformate-acetic anhydride into its N-ethoxymethylene derivative(2). which can undergo alkylaminolysis followed by spontaneous cyclization to 3-alkyl-3.4-dihydro-4-imino-quinazolines (3 ; X = CH) ; these rearrange in alkali to 4-alkylaminoquinazolines. The related 3.4-dihydro-4-imino-2.3-polymethylenequinazolines (8 ; X = NH) are also prepared from o-aminobenzonitrile, either bycondensation with appropriate cyclic imino-ethers or by cyciodehydration with lactams ; when the 2,3- poly-methylene chain is longer than five CH, units, Dimroth rearrangement occurs in alkali to give the isomeric p-bridged2,N(4)-polymethylene-4-aminoquinazolines (9 ; X = CH).Aza-analogues of the above systems are prepared byanalogous routes. Rates of rearrangement are discussed.WE have reported recently some new synthetic routes to1,6-dihydro-6-iminopyrimidines bearing a l-alkyl sub-stituent or a 1,Z-polymethylene bridge; also thesubsequent Dimroth rearrangement of such imines into6-alkylaminopyrimidines or 2,N( 6) -polymethylene-6-aminopyrimidines, respectively. This work is nowextended to the 4-iminoquinazolines (3; X = CH) and(8; X = NH) and to the related systems (3; X = N)and (10) ; Dimroth rearrangement has been studied onlybriefly in the 2-iminoquinazoline series and even lessin the 4-iminoquinazoline group by use of unsatisfactorycompounds such as the imine (3a).For the synthesis of simple 3-alkyl-3,4-dihydro-4-iminoquinazolines (3; X = CH), a method analogous tothat used for 64minopyrimidines proved effective:o-aminobenzonitrile (1; X = Y = CH, R = H) con-densed with triethyl orthoformate in the presence ofacetic anhydride to give et hoxymet hyleneaminobenzo-nitrile (Z), which underwent ready aminolysis by methyl-,isopropyl-, or t-butyl-amine followed by spontaneouscyclization to give the imines (3b-d) ; a similar reactionwith triethyl orthoacetate gave the 2,3-dimethyl imine(3e) but when 2-amino-6-methylbenzonitrile (1 ; X =Y = CH, R = Me) was treated with triethyl ortho-formate followed by methylamine, the isomer (4f) of theexpected irnine (3f) was the sole product.The samegeneral synthesis was used to convert 2-aminopyridine-3-carbonitrile (1; X = N, Y = CH, R = H) into theiminopyridopyrimidine (3g). The imine (3e) was alsomade by a new single-stage route involving condensationof o-aminobenzonitrile with methyl N-methylacetimi-date MeC(:NMe)*OMe in boiling xylene containingphosphorus pentoxide.The simple imines (3b-e and g) rearranged to theirrespective isomers (4b-e and g) by warming in M-alkali;in a single case (3e) some hydrolysis occurred also to givea little of the quinazolinone (5).The tricyclic imines (8; X = NH, n = 5-7) wereeach made by two methods: (a) fusion of o-amino-Part XVII, D.J. Brown and K. Ienaga, Austral. J . Chem.,D. J. Brown and K. Ienaga, J.C.S. Perkin I, 1974, 372.H. L. Wheeler, T. B. Johnson, and D. F. McFarland,J . Amer. Chem. SOC., 1903, 25, 787; R. J. Grout and M. W.Partridge, J . Chem. SOC., 1960, 3540; D. J. Brown and B. T.England, Austral. J . Chem., 1968, 21, 2813.1976, 28, 119.benzonitrile with the cyclic imino-ethers (6; n = 5-7) ;and (b) cyclodehydration of the same nitrile with thelactams (7; n = 5-7) by use of phosphorus pentaoxide0 C " c H .o E tNHR' NHR3(3)X R' R2 R3a: CH H SH Phb: CH H H MeC : CH H H Prid: CH H H Bute: CH H Me Mef : CH Me H Meg: N H H Me0( 5 ) (6) (7)in xylene. The imine (8; X = NH, n = 9) was pre-pared only by method (b) with the lactam (7; n = 9);the imine (10; n = 5) was made by fusion of 4-amino-pyrimidine-5-carbonitrile with the cyclic imino-ether(6; n = 5); but attempts to prepare the homologousimine (10; n = 7) from the same nitrile with the imino-ether (6; n = 7) gave only an isomer (9; X = N, n = 7).In aqueous alkali, the imine (8; X = NH, n = 5)4 E.C . Taylor and R. V. Ravindranathan, J . Org. Chem.,6 H. U. Sieveking and W. Liittke, Angew. Chem.. 1969, 81,1962, 27, 2622.4321975 2183gave only the corresponding oxo-compound (8; X = 0,n = 5) because the chain of five methylene groups wasNH NHIOH(11)too short to permit the existence of a rearranged isomer(9; X = CH, n = 5) without considerable strain; thenext higher homologous imine (8; X = NH, n = 6) gavea mixture of the oxo-analogue (8; X = 0, n = 6) andthe p-bridged isomer (9; X = CH, n = 6); and thehomologues (8; X = NH, n = 7 or 9), with adequatelylong chains, gave only their respective rearrangedisomers (9; X = CH, n = 7 or 9), in high yield.ApaItfrom ammonia, no identifiable product was obtainedfrom the imine (10; n = 5) in alkali.The pK, values and U.V. spectra (Experimental section)of the above imines and their derived isomers indicatedthat the rearrangements could be followed spectrometri-cally at pH 13. Thus at 70 "C, the spectra of most of theimines changed progressively to those of their respectiveisomers, maintaining good isosbestic points for >90of each reaction. The changes in optical density provedto be first-order and rates are expressed as ti values in theTable.Rearrangement of imines at pH 13Imine ti (70 OC)/min Analyt.h/nm4.8 31535 31537 31568 295b< 2 300(8; X = NH, n = 5) c( 8 ; X = NH, n = 6) d(8; X = NH, n = 7) 185 295(8; X = NH, n = 9) 124 295(10; n = 6) c(10; n = 7) b(3b)( 3 4( 3 4(3e)( 3f)(3g)a 280 niin at 20 "C. b Fast rearrangement during attemptedpreparation. Hydrolysis only. d Rearrangement muchslower than hydrolysis.The imines (3c and d), each bearing a bulky branchedN-alkyl group, rearranged much more slowly than thelower N-methylated homologue (3b). The reason@) for* For details of Supplementary Publications see Notice toAuthors No. 7, J.C.S. Perkin I , 1974, Index issue.D.J. Brown in ' Mechanisms of Molecular Migrations,' ed.B. S. Thyagarajan, Interscience, New York, 1968, vol. 1, p. 209et seq.this could have been (a) steric hindrance to hydration ofthe 2,3-bond prior to its fission to yield the intermediate(11) and/or (b) a steric interference between the bulkygroup (R3) and the ortho-hydrogen atom (Rl) in theintermediate (11) during the 180" rotation of the amidinegroup necessary for recyclization to the rearranged pro-duct. Reason (a) was consistent with the 14-folddecrease in rearrangement rate observed between theimine (3b) and its 2-methyl derivative (3e) ; in contrast,5-methylation of the imine (3b) to give the derivative(3f) actually increased the rearrangement rate, a factapparently inconsistent with reason (b) .However,models suggested that this increase could have resultedfrom instability engendered by steric interferencebetween the imino- and the methyl group in the imine(3f). The marked effect of electron withdrawal by adoubly bonded nitrogen on the rate of Dimroth re-arrangement 6 was exemplified in the relative 4 valuesfor the imine (3b) and its 8-aza-analogue (3g).As expected from the behaviour of simple analogues,lrearrangement of the pentamethyleneimine (8; X =NH, n = 5) proved impossible because the chain was tooshort to form a stable p-bridged amine (9; X = CH,n = 5); for the same reason, rearrangement of theimine (8; X = NH, n = 6) was very slow. However,the higher homologues (8; X = NH, = 7 or 9) re-arranged satisfactorily at 70 "C with ti values of 185 and124 min, respectively.The latter figure approachedthat (ti 68 min) for the 2,3-dimethyl imine (3e), whichmight be considered akin to an imine (8; X = NH,n = a).EXPERIMENTALAnalyses were performed by the Australian NationalUniversity Analytical Services Unit. The rearrangementrates were measured at pH 13 as described previously.2Ionization constants were measured spectrometrically(analytical wavelength 285 nm) at 20 "C and 10-3~ con-centration in buffers8 of 10-ZM ionic strength; therrno-dynamic corrections were not applied. 1H N.m.r. andU.V. spectral data are available as Supplementary Public-ation No. SUP 21481 (5 pp.).*3,4-Dihydro-4-imino-3-methyZquinazoZine (3b) .-o- Amino-benzonitrile (5.9 g), triethyl orthoformate (45 ml), andacetic anhydride (5 ml) were heated under reflux for 10 min.The residue from evaporation was triturated with lightpetroleum to give crude o-(ethoxymethyleneamino) benzo-nitrile (2) which was added to ethanolic methylamine (ca30; 50 ml) a t room temperature.After 15 min, thesolution was evaporated. Trituration of the residue withlight petroleum gave the imino-3-methylquinazoZine (97 yo),m.p. 178" (from ethanol) (Found: C, 67.75; H, 5.9; N,26.2. CQHQN, requires C, 67.9; H, 5.7; N, 26.4); pK,8.19 f 0.03.3,4-Dihydro-4-irnino-3-isopropylquinazoline (3c) .-Thecrude intermediate (2), prepared on the same scale as above,was stirred in ethanolic 30 isopropylamine (55 ml) at25 "C for 15 h.Partial evaporation and filtration gave theirnino-3-iso~ropyZquinazoline (92), m.p. 123-125" (fromDetermination of IonizationConstants,' Chapman and Hall, London, 1971.A. Albert and E. P. Serjeant,8 D. D. Perrin, Austral. J . Chem., 1963, 16, 572J.C.S. Perkin Iethanol) (Found: C, 70.3; H, 7.0; N, 22.6. C11H13N3requires C, 70.6; H, 7.0; N, 22.4); PKa 8.06 0.03.3,4-Dihydro-4-imino-3-t-butylquinazoline (3d) .-The inter-mediate (2) and ethanolic t-butylamine reacted as above for3 weeks to give the t-butyl-4-irninoquinazoline (81 ), m.p.95-96" (from ethanol) (Found: C, 71.4; H, 7.6; N, 21.3.C1,Hl,N3 requires C, 71.6; H, 7.5; N, 20.9).3,4-Dihydro-4-imino-2,3-dimethylquinazoZine (3e) .-(a) o-Aminobenzonitrile (1.18 g), triethyl orthoacetate (7.5 ml),and acetic anhydride (2.5 ml) were heated under reflux for20 min.The residue from evaporation was stirred with30 ethanolic methylamine (45 ml) for 10 days a t 25 "C togive the iminodimethylquinazoline (60), m.p. 157-158'(from ethanol) (Found: C, 69.2; H, 6.4; N, 24.2. Cl,Hll-N3 requires C, 69.3; H , 6.4; N, 24.3); PKa 8.35 0.04.(b) Phosphorus pentaoxide (10 g) was added to a stirredsolution of o-aminobenzonitrile (1.2 g) and methyl N-methylacetimidate (1.1 g) in anhydrous xylene. Thesuspension was then boiled under reflux for 15 min andallowed to cool. The solid were added to stirred ice-water(500 ml), which was then made alkaline with aqueous 50potassium hydroxide and immediately extracted withchloroform. Evaporation of the extract and columnchromatography (alumina ; chloroform) gave a product(32) identical with that from (a) (mixed m.p.and spectra).3,4-Dihydro-4-imino-3-methyZpyrido2,3-dpy~imidine (3g).-2-Aminopyridine-3-carbonitrile 5 (1; X = N, Y =CH, R = H) (0.30 g), triethyl orthoformate (4.5 ml), andacetic anhydride (1 ml) was heated under reflux for 90 min.The residue from evaporation was added to ethanolic 30methylamine (3 ml). After 20 min, evaporation and tritur-ation with light petroleum gave the imanopy~idopyrimidin~(41), m.p. 243" (Found: C, 60.25; H, 4.9; N, 35.4.C8H8N4 requires C, 60.0; H, 5.0; N, 36.0).4-Alkylaminoquinazolines (4; X = CH) .-The imine(3 b) (0.50 g) and M-sodium hydroxide (50 ml) were warmedSO "C for 1 h.Evaporation of a chloroform extract gavethe crude product, which was purified by passing throughan alumina column in chloroform to give methylamino-quinazoline (94), m.p. 201" (from ethanol) (1it.,lo 196") ;pK, 6.37 f 0.06.The imine (3c) rearranged similarly 80 "C for 12 h to give4-iso~opylaminoquinazoline (4c) (91 ), m.p. 175" (Found :C, 70.6; H, 7.0; N, 22.5. C1,H1,N, requires C, 70.6; H,7.0; N, 22.4); pK, 6.39 f 0.05.The imine (3d) gave lo0 "C for 24 h 4-t-butylamino-guinazoline (4d) (93), m.p. 95-96' (Found: C, 71.4; H,7.6; N, 21.3. Cl,Hl,N3 requires C, 71.6; H, 7.5; N,The imine (3e) gave 80 "C for 6 h 2-methyl-4-methyl-aminoquinazoline (4e) (82), m.p. 134" (Found: C, 69.5;H, 6.2; N, 24.2.C1,H1,N, requires C, 69.3; H, 6.4; N,24.3) ; pKa 7.43 f 0.04; and 2,3-dimethylquinazolin-4-one (6) (5), m.p. 111" (Found: C, 69.1; H, 6.9; N, 16.1.Cl,Hl,N20 requires C, 68.95; H, 5.8; N, 16.1).2-Amino-6-methylbenzonitrile l1 (1; X = Y = CH, R =Me) (6.6 g), triethyl orthoformate (50 ml), and acetic anhy-dride (5 ml) were heated under reflux for 15 min. Theresidue from evaporation was ground with a little lightpetroleum, filtered off, and then added to methylamine(20 g) in etbanol (40 ml). After 10 rnin the solution wasevaporated. Trituration of the residue with light petroleumgave 5-methyE4-methyZaminoquinazoline (4f) (85), m.p.Q H. Bredereck, F. Effenberger, and E. Henseleit, Chew. Ber..1966, 98, 2764.2O.9Y0).178" (from ethanol) (Found: C, 68.9; H, 6.4; N, 23.9.C10HllN3 requires C, 69.3; H, 6.4; N, 24.3)4-1Methylaminopyrido2,3-dpyrimidine (4g) .-The imine(3 g) (80 mg) was warmed in M-sodium hydroxide (10 ml)at 60 "C for 30 rnin to give, as for the quinazoline (4b), themethylaminopyridopyrimidine (64y0), m.p.231" (Found : C,60.1; H, 5.05; N, 34.8. C,H,N4 requires C, 60.0; H, 5.0;6,7,8,9,10,12-Hexahyd~o-l 2-iminoazepino2,l-bquinazo-N, 35.0).line (8; X = NH, n = 5).-(a) o-Aminobenzonitrile (1.18g) and 7-ethoxy-3,4,5,6-tetrahydro-2H-azepine (6; n = 5)(1.6 g) were fused together a t 150 "C for 24 h. The cooledmixture was dissolved in the minimum quantity of ethanoland then a little hydriodic acid was added. Evaporationand trituration of the residue with ethyl acetate gave theiminoazepinoquinazoline hydriodide (86) , m.p.281"(Found: C, 45.8; H, 4.8; N, 12.1. C,,H,,IN, requires C,45.8; H, 4.7; N, 12.3).(b) Phosphorus pentaoxide (10 g) was added to a stirredmixture of o-aminobenzonitrile (1.18 g), hexane-6-lactam(7; n = 5), and anhydrous xylene (50 ml). The suspensionwas boiled under reflux for 15 min and then cooled. Thesolid w m added with stirring to icewater (500 ml) andthen made alkaline with aqueous 50 potassium hydroxide.Extraction with chloroform and evaporation of the extractgave the base (71y0), m.p. 124-125" (from ethanol) (Found:C, 72.9; H, 7.0; N, 14.4. C13H15N3 requires C, 73.2; H,7.1; N, 19.7), identical with a specimen prepared fromthe hydriodide in (a).quinazoline (8; X = NH, 'tc = 6).-(a) o-Aminobenzo-nitrile (1.18 g) and 2-ethoxy-3,4,5,6,7,8-hexahydroazocine 1(6; n = 6) (1.18 g) were heated at 190 "C for 36 h to givethe iminoazocinoquinazoliins (68), m.p. 153" (from ethanol)(Found: C, 74.1; H, 7.3; N, 18.4.Cl4H1,N3 requires C,74.0; H, 7.5; N, 18.5).(b) Cyclodehydration of o-aminobenzonitrile (1.16 g)and heptane-7-lactam (7; n = 6) (1.14 g) with phosphoruspentaoxide as above gave the same product (65) as in (a).bquinazoline (8; X = NH; n = 7).-(a) o-Aminobenzo-nitrile (1.18 g) and 9-ethoxy-3,4,5,6,7,8-hexahydro-2H-azonine 1 (6; n = 7) at 190 "C for 24 h gave the imino-azoninoquinazoline (70), m.p. 146" (from ethanol) (Found :C, 74.4; H, 8.0; N, 17.7. Cl5HI9N3 requires C, 74.65; H,(b) Cyclodehydration of o-aminobenzonitrile (1.16 g) andoctane-lactam (7; n = 7) (1.56 g) gave a product (74)identical with that from (a).undecin02,1-bquinazoline (8; X = NH, n = 9).-Cyclo-dehydration of o-aminobenzonitrile (2.36 g) and decane- 10-lactam (7; n = 9) (3.6 g) gave the iminoazacycloundecino-quinazoline (67), m.p.158" (from ethanol) (Found: C,76.1; H, 8.65; N, 15.6. Cl,H23N3 requires C, 75.8; H,8.6; N, 15.6).Action of Alkali on the Imines (8; X = NH, n = 5-7(w 9) .-The hexahydroiminoazepinoquinazoline (0.50 g)and M-potassium hydroxide (150 ml) were heated on asteam-bath for 18 h. The cooled solution was extractedwith chloroform. The solute in the extract was purified bycolumn chromatography (alumina; chloroform) to give a10 E.Hayashi, T. Higashino, and S. Tomisaki, J . Pharm. SOC.Japan, 1967, 87, 678.11 S. Gabriel and A. Thieme, Ber., 1919, 52B, 1079.6,7,8,9,10,11 -Hexahydro- 13-imino- 13H-azocino2,L-b -6,7,8,9,10,11,12,14-Octahyd~o-l4-~minoazon~no2,1-7.9; N, 17.4).6,7,8,9,10,11,12,13,14,16-Decahydro-l6-im~noazacyclo1975 2185single major product, 7,8,9,10-tetrahydrodroazepino2,1-bquinazolin-l2(6H)-one (8; X = 0, n = 5), m.p. 97"(1it.,l2 95").Similarly, the hexahydroiminoazocinoquinazoline gavestarting material (19) and two products, separatedby chromatography (alumina ; benzene-ethyl acetate).6,7,8,9,10,1 l-Hexahydroazocino2,l-bquinazoZin-13-one ( 8 ;X = 0, n = 6) (43), had m.p. 112" (Found: C, 73.6;€3, 7.1; N, 12.3. C14Hl,N20 requires C, 73.7; HI 7.1; N,12.3).The second product was 4,2-iminohexanoquinam-line (9; X = CH, n = 6) (21y0), m.p. 207" (Found: C ,73.8; H, 7.3; N, 18.5. C14H17N, requires C, 74.0; H, 7.5;N, 18.6).Similar treatment of the octahydroiminoazoninoquinazo-line in 3 : 1 aqueous-ethanolic M-sodium hydroxide gaveonly 4,I-ivninoheptanoquinazoline (9; X = CHI .n = 7)(91), m.p. 244" (from ethanol) (Found: C, 74.6; HI 7.7;N, 17.6. C15Hl,N, requires C, 74.65; H, 7.9; N, 17.4).In the same way, the decahydroiminoazacycloundecino-quinazoline gave 4,2-irninononanoquinazoline (9; X = CH ;l2 0. Meth-Cohn, H. Suschitzky, and M. E. Sutton, J . Chenz.Soc. (C), 1968, 1722.l3 J. Baddiley, B. Lythgoe, and A. R. Todd, J . Chem. SOL,1943, 386.n = 9) (86), m.p. 158" (from ethanol) (Found: C, 76.0,HI 8.7; N, 15.3. Ct7H,,N, requires C, 75.8; HI 8.6; N,15.6).pyrimido l,Z-aaze+ine (10 ; n = 5) .-4-Aminopyrimidine-5-carbonitrile (0.6 g) and 7-ethoxy-3,4,5,6-tetrahydro-2H-azepine (6; n = 5 ) (0.8 g) were heated a t 150 "C for12 h. Trituration of the cooled mixture with light petrol-eum gave the iminopyrimidopyrimidoazepine (93 yo), m.p.ca. 130" (decornp.) (Found: C, 61.3; H, 6.3. Cl1H1,N,requires C , 61.4; H, 6.1).4,2-Iminoheptanopyrimido4,5-dpyrinzidine (9 ; X = N,n = 7) .4-Aminopyrimidine-5-carbonitrile l3 ( 10.7 g) and9-ethoxy-3,4,5,6,7,8-hexahydro-2H-azonine (6; n = 7)(0.93 g) were heated together a t 100 "C for 12 h. Tritur-ation of the residue in light petroleum gave the imino-heptanopyrimidopyrirn~d~ne (91), m.p. 126" (decornp.)(Found: C, 63.8; H, 7.1. Cl,H,,N5 requires C, 64.2; H,5,7,8,9,10,1 l-Hexahydro-5-imino~y~imido4~,5~:4,5-7.070).We thank Dr. GAustralian Nationala scholar.B. Barlin for discussions and theUniversity for supporting K. I. as6/906 Received, 13th May, 1976