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1854 J.C.S. Perkin IPolycyclic Fused Amidines. Part 11.l~~ Synthesis of Dihydroimidazo-fusedSystems by Use of 2-Aminoethylammonium Toluene-p-sulphonateBy Ronald F. Cookson and Ronaid E. Rodway, Nicholas Research Laboratories, 225 Bath Road, Slough,Heating 2-aminoethylammonium tosylate (EDMT) with various aromatic bicyclic amides at 200-250 'C providesa convenient single-stage synthesis of the corresponding dihydroimidazo-compounds. The procedure workedwell with phthalazinones (1 ), quinolones (7), and isoquinolone, but no reaction occurred with analogous mono-cyclic pyridazones (1 2) and 2-pyridone. Only low yields of dihydroimidazo-derivatives were obtained from3,4-dihydroisoquinoline-l(2H)-thione (1 0) and indeno[l,2,3-de]phthalazin-3-ones (1 4). Side reactionsdominated the reactions of EDMT with quinoxalinones and benzanilide.Berskhire SL1 4AUTHE usual procedure s-5 for synthesis of dihydroimidazo-compounds involves the reaction of aromatic heterocyclicamides such as the phthalazinones (1) with phosphoryl0f-fy"L p f N \ / N I& 72 , i i i&y\ / NR R1l)R:H or Ph ( 2 ) liv 4 iiNH* CHiCHiOH+/ N \ / NR R13) 1 4 )base; iv, NH,*CH,CH,*NH,+ p-MeC,H,*SO,- (EDMT)chloride to give the chloro-heterocycles (2).Displace-ment of the chlorine with 2-amino-ethanol, followed bysequential treatment of the hydroxyalkylamines (4) withthionyl chloride and base provides the dihydroimidazo-systems (3). We have found that certain dihydro-imidazo-compounds are readily prepared in one step byheating the corresponding amide with a 2-5 molarexcess of 2-aminoethylammonium tosylate (EDMT) at200-250 "C.Thus the phthalazinone (1; R = H) gave2,3-dihydroimidazo[2, l-alphthalazine (3 ; R = H), iden-tical with the compound described by Castle andT a k a n ~ . ~ The 6-phenyl derivative (3; R = Ph) wassimilarly prepared and identical with a sample obtainedby the route through compound (4; R = Rh). Theyield from both approaches was >SOY0.Reagents : i, POCl, ; ii, NH,*CH,*CH,*OH ; iii, SOCl,, thenPart 1, R. F. Cookson and R. E. Rodway, preceding paper.Preliminary communication, R. F. Cookson and R. E.Rodway, J.C.S. Chem. Comm., 1972,611; see also R. E. Rodwayand R. F. Cookson, B.P. 1,347,493/1974.0. Bremer, Annulen, 1936, 521, 286; T. Yoshikawa, R.Kiyota, and Y.Urabe, Yakugaku Zasshi, 1969, 89, 767 (Chem.Abs., 1969, 71, 81,111); M. D. Nair and S. R. Mehta, Indian J .Chem., 1967, 5, 403.Phenanthridone gave >90% yield of the dihydro-imidazo-compound (5) on reaction with EDMT.1Similarly treatment of isoquinolin-l-one with EDMTat 230 "C gave 2,3-dihydroimidazo[2,l-a]isoquinoline(6). The quinolones (7) gave the expected products (8)in ca. 40% yield. The diphenylquinolone (9) gave amuch lower yield of the fused system, presumablybecause of steric hindrance.As primary amines, in the presence of acid catalysts,react with amides to give amidine~,~~' the EDMTannulation reaction presumably proceeds through theor-(2-aminoethylamin0)-derivative of the correspondingheterocyc1e.l The sensitivity of the reaction betweenn( 5 1nI N@Jo- / @JR R( 8 ) (71 R=H,Me, or PhQfJ: Ph(9 1amides and amines to a delicate balance of factors hasalready been outlined.6 Similarly, the formation of4 R.N. Castle and S. Takano, J . Heterocyclic Chem., 1966, 3,381.5 H. Otomasu, K. Yoshida, and H. Takahashi, YakuguktlZasshi, 1970, 90, 1391 (Chem. Abs., 1971, 74, 63,730).6 R. I. Fryer, J. V. Earley, G. F. Field, W. Zdly, and L. H.Sternbach, J . Urg. Chem., 1969, 34, 1143; J . D. Wilson, C. F.Hobbs, and H. Weingarten, ibid., 1970, 35, 1542.7 J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S.P.3,644,336119721975 1855dihydroimidazo-compounds from cyclic amides is in-fluenced markedly by the structures of the amides andamines in the reaction.H1121 R =Me or PhR R(131 a;R:H, X '0, Nuc :NHiCHiCHiNH;b;R:Me,X-H, NUC: H20The annulation reaction is favoured if the initial amideis part of an aromatic system.Thus the dihydroiso-quinoline-l(2H)-thione (10) gave only an 8% yield of thetetrahydro-compound (1 1), which contrasts with the 56%yield of the dihydro-compound (6) from the aromaticisoquinolone.Only starting material was recovered when 2-pyridonewas treated with EDMT at 200 "C. Similar results wereobtained with the pyridazinones (12). The contrasting.ease of reaction of the benzologues of 2-pyridone andcompounds (13) parallels the ready hydrolysis of, for,example, N-methylquinolinium chloride, as comparedwith the relative stability to hydrolysis of N-methyl-pyridinium salts8 Both these reactions involve, for themonocyclic systems, complete loss of aromaticity afternucleophilic attack (13).However, in the benzologuesX'NH -+NN 7c-Y l L l X - 0 or S 116)only partial loss of aromatic character occurs, and hencereaction is more favoured for these systems.As it is well known that thioamides react more readilywith amines than do the corresponding O X O - C O ~ ~ O U ~ ~ S , ~the reactivity of the amide-thioamide pair (14) wasexamined. Even after prolonged heating the indeno-phthalazone (14; X = 0) gave (1% of the dihydro-imidazo-compound (15), whereas the thioxo-compound(14; X = S) gave a 7% yield after 16 h at 240 "C. Thea A. Albert in ' Physical Methods in Heterocyclic Chemistry,'ed.A. R. Katritzky, Academic Press, London, 1963, vol. I, p. 1.C. Djerassi and C. R. Scholz, J . Org. Chem., 1948, 13, 830;G. Forssel, Bey., 1892, 25, 2132.R F. Cookson, Chem. Rev., 1074,74, 5 .product (15) was also obtained by way of the amino-compound (16).The reaction of EDMT with quinoxalin-2-one (17)resulted in extensive decomposition ; the only productsisolated were the pyrazinoquinoxaline (19) and benzimid-azole. When the 3-position of compound (17) wasblocked as in the 3-phenyl compound (18), the mainproduct obtained was the aromatic system (21 ; R = Ph),formed together with a smaller amount of the knowndihydroimidazo[ 1,2-a]quinoxaline (20). The large differ-ence in the acidity constants (pK'; determined in 50%aqueous Methylcellosolve lo) of the two products (20)(pK' 6.50) and (21 ; R = Ph) ; (pK' (2.6) enabled readyseparation of the mixture.The imidazo[l,2-a]quinoxalines (21) were obtainedby acid-catalysed cyclisation of the products from thereaction of aminoacetaldehyde dimethyl acetal with thecorresponding 2-chloroquinoxalines. The low yieldsobtained by this approach are in line with the pooreryield of imidazo[l ,Za]pyrazine reported from the amino-acetal and 2-chloropyrazine.11 Recently the parent ring(191n nI201 (211 R - H or Phsystem (21; R = H) has been obtained by otherapproaches.12An attempt to extend the EDMT annulation reactionto linear secondary amides was unsuccessful.Thetrans-amide benzanilide (22) reacted only slowly withEDMT, forming the monophenylimidazoline (24) andaniline.Steric hindrance would prevent elimination ofammonia from the aminoethylamino-intermediate (23)but would allow the observed expulsion of aniline.PhNH2I - 112 - + &'Ph122)NH2 Ce , > P hEXPERIMENTAL1.r. spectra were recorded with a Perkin-Elmer 157instrument for Nujol mulls and n.m.r. spectra with a Perkin-Elmer R12 machine operating a t 60 MHz. Generally nol1 W. L. F. Armarego, J . Chem. SOL, 1966, 2778.12 A. M. Simonov and I. G. Uryukina, Khim. geterotsiRZ.Soedinenii, 1971, 7 , 670 (Chem. Abs., 1972, 76, 26,242); R. G. R.Bacon and S. D. Hamilton, J.C.S. Perkin I, 1974, 19701856attempt was made to maximise yields. Identity ofsamples was established by mixed m.p.and i.r. spectralcomparisons. Solutions were dried over magnesium sul-phate monohydrate. pK' Values were determined in 50%v/v aqueous Methylcellosolve by the method of Albert andSerjeant .I3Reaction of Cyclic Amides with EDMT.-General Pro-cedure. An intimate 1 : 2 mixture of the cyclic amide andEDMT was heated in an open flask for several h, cooled, andextracted with hot 5~-hydrochloric acid; any unchangedamide was then filtered off. Basification of the filtrateprovided an oil which was taken up in chloroform, washedthoroughly with water, dried, and treated with etherealhydrogen chloride or, when appropriate, maleic acid.Crystallisation of the salt, or basification of an aqueoussolution of the salt, gave the dihydroimidazo-heterocycle(see Table).J.C.S.Perkin Ifollowed by extraction with ether gave a solid (4.8 g) whichwas shown by n.m.r. analysis to be a mixture of compounds(20) (17%) and (21; R = Ph) (83%). A portion (2 g) wasdissolved in 5~-hydrochloric acid (50 ml) and the solutionwas basified to pH 3. The precipitate was dissolved inchloroform and washed thoroughly with water (pH 5).Evaporation of the dried solution gave a solid which wascrystallised from industrial methylated spirits to give 4-PhenyZimidazo[ 1,2-a]quinoxaline (2 1 ; R = Ph) ( 1.4 g) ,m.p. 153" (Found: C, 78.2; H, 4.5; N, 17.0. C,,H,,N,requires C, 78.4; H, 4.5; N, 17.1%); 8 (CDCI,) 7.4-8.35(9 H, m) and 8.6-8.85 (2 H, m) ; pK' < 2.6 (too low to bedetermined by titration). The filtered aqueous solution(pH 3) was adjusted to pH 5 and washed with ether.Thewashings were discarded and the aqueous layer was basifiedto pH 13. Extraction with ether gave crude 1,2-dihydro-4-phenylimidazo[2,l-a]quinoxaline (20) as a gum (0.3 g) ;Reactions of cyclic amides with 2-aminoethylammonium tosylateFound (yo) Required (yo) 7-z-T Scale Reaction Temp. YieldStarting material (mol) time (h) ("C) Cryst. solvent Product (%) h1.p. ("C) FormulaPhthalazin-l-one 0.14 6 220 EtOH (3; R = H) 20 337-3390 57.5 5.0 20.6b C,,H,N,,HCI 57.8 4.8 20.34-Phenylphthalazin-l-one 0.10 20 240 C,H, (3; R = Ph) 42 156-157 77.4 5.3 17.1 Cl,H13N, 77.5 5.3 17.063.9 5.3 13.6Quinolin-2-one 0.06 6 240 PdOH [?; R = H) 37 282-283 62.8 4.9 9.8 C,,H,,N,O,e 62.9 4.9 9.84-Methylquinolin-2-one 0.10 7 230 EtOH (8; R = Me) 43 ca.335 65.2 6.0 13.Of CIBHIINI,HCI 65.3 5.9 12.74-Phenylquinolin-2-one 0.10 18 235 PriOH-Et,O (8; R = Ph) 41 327-334 72.1 5.4 9.9 C,,H,,N,,HCI 72.2 5.3 9.93,4-Diphenylquinolin-2-one 0.06 18 260 EtOH 10 241-244 85.9 5.9 8.7 CZsH1,Ng 85.7 5.6 8.7Isoquinolin-l-one 0.09 17 245 PriOH 26 C 303-307 63.8 5.4 13.4d C,,H1,N,,HCI3,4-Dihydroisoquinoline- 0.07 4 220 PrlOH (11) 8 221-223r 53.9 6.7 11.3 C1,H,,N,,HCI,PH,O 53.9 7.0 11.4Indeno[l,2,3-de]phthalazin- 0.1 30 250 C,H, (15) 0.4 173-174l(2H)-thione3-one3- thione (decornp.)Calc.: C1 17.lq;C1, 17.1.and J. P. Verge, U.S.P.,3,692,570/1972), hFound: C1, 14.2. Required: CI, 14.5%. (Found: C1, 12.1. Required: C1, 12.6%.C16HllN,Indeno[l,2,3-de]phthalazine- 0.05 16 240 H,O-EtOH (15) 7 >360 68.1 4.5 14.6 CI6HllN,,HCI 68.2 4.3 14.9a Base, m.p.105-107° (lit,,, 103-104°); ref. 4mentions adihydrochloride, m.p. 335-336'. b Found: CI, 16.9. c Yieldofcrudebase 56O/ d Found-u Lit. m.p.*220-222" (M. W. Git'tos,'g: W. James- Required: C1, 17.2%. c Hydrogen maleate, C1,H10NI,C,H,04. /Found: C1. 16.0. Required: C1, 16.1%.Quinoxalin-2-one. An intimate mixture of quinoxalin-2-one (10 g, 0.068 mol) and EDMT (40 g, 0.172 mol) washeated a t 180-190 "C for 5 h. The cooled mixture wasdissolved in 5~-hydrochloric acid (300 ml) and the solutionwas washed with ether. Basification of the aqueous layergave an oil which was taken up in methylene chloride; thesolution was washed, dried, and evaporated to dryness.Thesolid obtained (2.7 g) was crystallised from industrialmethylated spirits (250 ml) to give 1,2,3,4-tetrahydro-pyrazino[2,3-b]quinoxaline (19) (0.3 g), m.p. 317-318"(lit.,14 >350") (Found: C, 64.3; H, 5.6; N, 29.9. Calc.for C,,H,,N,: C, 64.5; H, 5.4; N, 30.1%). Evaporation ofthe mother liquors from the crystallisation gave a residuewhich was treated with chloroform. A further 0.6 g of thetetrahydropyrazinoquinoxaline (m.p. 3 15-3 18O) was filteredoff. The chloroform solution was treated with etherealhydrogen chloride and an excess of dry ether, and theprecipitate was collected and dissolved in water. Theaqueous solution was washed with chloroform and thenbasified. Extraction with ether gave a solid which wasrecrystallised twice from benzene to give benzimidazole(0.3 g), m.p.170-172" (lit.,15 170") (Found: C, 71.3;H, 5.3; N, 23.8. Calc. for C,H,N,: C, 71.2; H, 5.1; N,23.7 yo).3-Phenylquinoxalin-2-one. A finely ground mixture of3-phenylquinoxalin-2-one (9.3 g, 0.042 mol) and EDMT(19.4 g, 0.084 mol) was heated in an open flask at 200 "C for19 h. The cooled mixture was treated with 5~-hydro-chloric acid (250 ml) and filtered. Basification of the filtratel3 A. Albert and E. P. Serjeant, ' Determination of IonizationConstants,' 2nd edn., Chapman and Hall, London, 1971.l4 R. A. Ogg, jun., and F. W. Bergstrom, J. Amer. Chem. Soc.,1931, 53, 1846.8 (CDCI,) 4.0-4.3 (4 H, m), 6.6-7.8 (7 H, m) and 8.3-8.5(2 H, m). The gum was dissolved in chloroform and treatedwith ethereal hydrogen chloride and an excess of dry ether.The precipitate was crystallised from propan-2-01 to give thehydrochloride (0.1 g), m.p.268-270" (Found C, 67.6;H, 4.9; N, 14.7. Calc. forC,,H,,N,,HCl: C, 67.7; H, 4.9;N, 14.8%); pK' 6.50 f. 0.02.1-(2-HydroxyethyZamino)-4-phenyZ~hthalazi~te.-A solu-tion of 2-chloro-4-phenylphthalazine (24 g, 0.1 niol) and2-aminoethanol (30.5 g, 0.5 mol) in dry dioxan (150 ml) washeated under reflux for 19 11. Evaporation yielded an oilwhich was treated with water to give a solid. Crystallis-ation from industrial methylated spirits gave 1-( 2-hydroxy-ethylamino)-4-phenylp~t~~a~azine monohydrate (23.8 g, 84%).m.p. 157-169" (Found: C, 68.0; H, 6.0; N, 14.8.C1,Hl5N,O,H,O requires C, 67.8; H, 6.0; N, 14.8%).2,3-Dihydro-6-phenylimidazo[2,l-a]phthalazine (3; R =Ph) .-Phosphoryl chloride (6 ml) was added cautiously to1-(2-hydroxyethylarnino)-4-phenylphthalazine monohy-drate (3 g, 0.01 mol).When the reaction had subsided themixture was heated under reflux for 0.5 h. The residueobtained on evaporation of the phosphoryl chloride wastaken up in chloroform (150 ml) and the solution .wasstirred with chilled ammonium hydroxide solution and thenwith saturated potassium carbonate solution. Evaporationof the washed and dried chloroform layer gave a solid(2.6 g, 99%), m.p. 145-147", which on crystallisation fromaqueous industrial niethylated spirits afforded 2,3-dihydro-6-phenyZimidazo[2,l-a]phthaZazine (1.2 g, 48%), m.p. 158-159" (Found: C, 77.4; H, 5.4; N, 17.2.C1,H13N3 requiresl5 M. A. Phillips, J. Chem. Soc.. 1928, 2393.I6 M. Hartmann and J . Druey, U.S.P. 2,484,029/1949 (Chem.Abs., 1950, 44, 4046f)1975 1857C, 77.7; H, 5.3; N, 17.0%), identical with the product fromthe reaction between 4-phenylphthalazin- l-one and EDMT.5,6-Dihydroimidazo[2,l-a]indeno[ 1,2,3-de]+hthaZazine (15).-3-(2-Hydroxyethylamino)indeno[ 1,2,3-&)phthalazine l7(12.6 g, 0.048 mol) in phosphoryl chloride (100 ml) washeated under reflux for 28 h. The cooled solution waspoured onto ice and ammonium hydroxide solution, and themixture was basified to pH 12 with saturated potassiumcarbonate solution and extracted with chloroform. Eva-poration of the washed and dried extracts gave a yellowsolid (10 g) which was taken up in chloroform and treatedwith ethereal hydrogen chloride (15 ml) and an excess ofdry ether.The precipitate was collected, dried, and treatedwith water (500 ml). Basification of the filtered solutionwith potassium carbonate solution gave a yellow solidwhich was crystallised from benzene to yield yellow crystalsof 5,6-dihydroinzidazo[2,l-a]indeno[ 1,2,3-de]phthaZazine(4.2 g, 36%), m.p. 176-178' (Found C, 78.2; H, 4.6; N,17.2. C,,HllN, requires C, 78.4; H, 4.5; N, 17.1%);6 (CDCl,) 4.11 (4 H, s, H-5 and -6) and 7.20-8.25 (7 H, m,aromatic), identical with that obtained from indeno[l,2,3-deJphthalazin-3-one and EDMT.Imidazo[ 1,2-a]quinoxaZine (21 ; R = H).-2-Chloro-quinoxaline (16 g, 0.097 mol) in bis-(2-methoxyethyl) ether(100 ml) was heated under reflux with aminoacetaldehydedimethyl acetal (30.4 g, 0.29 mol) for 8 h.Treatment withwater followed by extraction with ether gave an oil (16.3 g)which was boiled with B~-hydrochloric acid for 2 h. Basific-ation with potassium carbonate solution gave a solid whichwas dissolved in chloroform, and treated with etherealhydrogen chloride and an excess of dry ether. The solidobtained was crystallised from a mixture of industrialmethylated spirits (charcoal) and ether to give whitecrystals of imidazo[ 1,2-alquinoxaline hydrochloride (2.6 g ,13%), m.p. 267-269" (Found C, 58.4; H, 4.0; C1, 17.0;N, 20.2. Calc. for Cl,H,N,,HC1: C, 58.4; H, 3.9; C1,17.3; N, 20.4%).4-PhenyZimidazo[l,2-a]quinoxaZine (21 ; R = Ph).-Asolution of 2-chloro-3-phenylquinoxaline (18.4 g, 0.76 mol)and aminoacetaldehyde dimethyl acetal (23 g, 0.22 mol)in bis-(2-methoxyethyl) ether (150 ml) was heated underreflux for 16 h, then poured into water.Extraction withether gave an oil which was boiled with 5~-hydrochloric acidfor 2 h. Basification of the filtered solution gave a solidwhich was crystallised from industrial methylated spirits(charcoal) to give 4-phenyZimidazo[ 1,2-a]quinoxaZine (2.7 g,14.5%), m.p. 15A157' (Found: C, 78.5; H, 4.6; N, 16.8.Cl,Hl,N, requires C, 78.4; H, 4.5; N, 17.1%).Reaction of Benzanilide with EDMT.-An intimatemixture of benzanilide (8 g, 0.041 mol) and EDMT (20 g,0.086 mol) was heated at 260 'C for 24 h, cooled, andextracted with hot 5~-hydrochloric acid (ca. 250 ml) ; thecooled extract was then filtered and basified to pH 10.The precipitate was washed, dried, and taken up in chloro-form (25 ml). Treatment of the solution with etherealhydrogen chloride and an excess of dry ether gave an oilwhich was separated and taken up in water. Basificationof the aqueous solution gave a white solid which on crystal-lisation from a small volume of benzene gave white crystalsof 2-phenylimidazoline (1.2 g, 20%), m.p. 94-96' (lit.,l*101') (Found C, 73.9; H, 7.0; N, 19.5. Calc. for C,H,,N,:C, 74.0; H, 6.9; N, 19.2%).We thank Mr. M. S. Rogers and his staff at N.R.L. foranalytical results and the pK' determinations.[5/600 Received, 2nd April, 19751l7 R. E. Rodway and R. G. Simmonds, B.P. 1,341,698/1973.la P. Oxley and W. F. Short, J . Chem. SOC., 1947,497

ISSN:1472-7781    

DOI:10.1039/P19750001854

出版商:RSC    

年代:1975

数据来源: RSC