1972Reduction of Some Fused (Benzod- and Pyrido3,2-d-) PyrimidinonesBy W. J. Irwin, Department of Pharmacy, University of Aston in Birmingham, Gosta Green, Birmingham B4 7ETThe reduction of some fused pyrimidin-4(1 H)- and -4(3H)-ones with sodium borohydride and with lithium alumin-ium hydride is described. When N-phenyl substituents are present a specific ring-opening reaction occurs.KEDUCTION of pyrimidines,l quinazolines,2 quinazolin-4(3H)-0nes,~-~ pteridines,' and pyridopyrimidin-4(3H)-ones 6 y 8 has been shown to yield di- and tetra-hydro-derivatives and also products derived from fission ofthe pyrimidine ring. No ring-opening reactions havebeen observed with quinazolin-4( 1H)-ones, althoughdihydro-derivatives have been isolated from the sodiumborohydride reduction of l-alkylaminoalkyl compound^.^Previous work 6*8 suggested that ring opening would befavoured by the presence of l-aryl substituents, and inan attempt to realise this reaction the preparation ofl-phenylquinazolin-4( 1H)-one (1) was undertaken.A synthesis of this compound from N-phenlyanthran-ilic acid and formamide has been described,lo but arepetition of this preparation did not yield any of therequired quinazolinone, although in an analogous pre-paration iV- benzylanthranilic acid and formamide givethe expected l-benzylquinazolin-4( lH)-one.ll The pro-duct which was isolated showed an i.r.absorption at 3100cm-1 (N-H) in addition to the expected carbonyl peak at1660 cm-l, and a two-proton doublet lH n.m.r. signal atT 5.0, which collapsed to a singlet on shaking withdeuterium oxide.It was thus identified as l-phenyl-2,3-dihydroquinazolin-4( 1H)-one (2). The mass spectralPh Ph( 1 1 a , ( 2 1 a(4 1Reagents: i, NaBH, or HCO-NH,; ii, Pd-C; iii, KMnO,;iv, LiAIH,.fragmentation pattern confirmed this assignment, in-dicating a molecular ion (m/e 224) and a main breakdowninitiated by H loss (m/e 223) with subsequent loss of COto yield the base peak (m/e 195).Oxidation of the dihydro-compound (2) with aqueous1 S. David and P. Sinay, Bull. SOC. chim. France, 1965, 2301.H. Ott and M. Denser, J . Org. Chem., 1968, 33, 4263; R. F.Smith, P. C. Briggs, R. A. Kent, J. A. Albright, and E. J. Walsh,J . Hetcvocyclic Chem., 1965, 2, 157.B. Okumura, T.Oine, Y . Yamada, G. Hayashi, and M.Nakama, J . SIedicin. Chem., 1968, 11, 348.I. W. Elliot, F. Hamilton, and D. K. Ridley, J . HeterocyclicChew., 1968, 5, 707; E. Cohen, B. Klarberg, and J . R. Vaughan,j u n . , J . A m e v . Chem. SOC., 1960, 82, 2731.,4. R. Osborn and K. Schofield, J . Chem. SOC., 1956, 3977.T . R. Gelling, W. J. Irwin, and D. G. Wibberley, Chem.Comm., 1969, 1138.permanganate yielded l-phenylquinazoline-2( 1H) ,4(3H)-dione (3), but dehydrogenation with palladised charcoalin xylene yielded the required 1 -phenylquinazolin-4( 1H) -one (1) in high yield. The disappearance of N-Habsorption and the reduction in carbonyl frequency(1655 cm-l) indicated that aromatisation had beeneffected, and this was confirmed by the appearance of alH n.m.r. singlet (2-H) at T 1-75 together with the loss ofthe absorption at T 5.0. The mass spectrum showed amolecular ion (m/e 222) which underwent successivelosses of HCN (m/e 195, base peak) and CO (m/e 167).The production of l-phenyl-2,3-dihydroquinazolin-4( 1H)-one (2) from N-phenylanthranilic acid and form-amide undoubtedly proceeds via the quinazolinone (1),which undergoes reduction in situ.A possible reducingagent in this reaction is formate,12 and although theconversion (1) ---t (2) could not be effected with formicacid alone, the dihydro-compound (2) was obtained whenl-phenylquinazolin-4( lH)-one (1) was heated withf ormamide. l-Phenyl- and 1 -benzyl-quinazolin-4( 1H) -ones were converted into the corresponding 2,3-dihydro-derivatives by treatment with sodium borohydride.More vigorous reduction of the l-phenyl compounds (1)and (2) with lithium aluminium hydride resulted in thedesired ring fission to yield 2-(methylaminomethy1)-N-phenylaniline (4), presumably via the anions (5) and (6).2-Methyl-3-phenylquinazolin-4(3H)-one ( 7 ) has beenshown to yield 2-ethylaminobenzanilide (10) on treat-ment with sodium borohydride at 100" but is unchangedat room temperature.3-Phenylquinazolin-4(3H)-one(euro;9, however, yields the 1,2-dihydro-derivative (12) whentreated with borohydride at room temperature. Thequinazolinones (8) and (12) yielded 2-(anilinomethy1)-N-methylaniline (13) on treatment with lithium alumin-ium hydride. 2-Met hyl-3-phenylpyrido3,2-d pyrimidin-4(3H)-one (9) was found to be more susceptible toA.Albert and S. Matsuura, J . Chem. SOC., 1961, 5131;I . R. Gelling and D. G. Wibberley, J . Chem. SOL. ( C ) , 1971,K. H. Hauptmann, Arzneim. Forsch., 1965, 15, 610.1962, 2162.780.l o S. Somasekhara, G. M. Shah, and S. L. Mukherjee, CurrentSci., 1964, 33, 521.l1 H. C. Scarborough and J. L. Minielli, L.S.P. 3,119,824/1964(Chem. Abs., 1964, 60, 9292).12 I. Baxter, L. T. Allan, and G. A. Swan, J . Chewz. SOC., 1965,3645; R. N. Icke and B. B. Wise, Org. Synth., Coll. vol. 111, 1955,p. 723354 J.C.S. Perkin Ireduction, and yielded 3-ethylamino-N-phenylpyridine-2-carboxamide (1 1) on treatment with borohydride atroom temperature. More vigorous reduction of the0( 7 ) Fa = Me,X = C H (10) R = Me,X =CH( 8 ) R = H , X = CH ( 1 1 ) R = Me,X = N( 9 ) R = Me,X = N0(121 R = H,X = CH(131 R = H,X = CH(141 R = Me,X = N 1 ii(15)Reagents: i, NaBH,; ii, LiAlH,.pyridopyrimidines (9) and (15) with lithium aluminiumhydride yielded 2-anilinomethyl-3-ethylaminopyridineThe fused pyrimidin-4(3H)-ones have two sites whichare susceptible to hydride attack; the endocyclic C=Nand the exocyclic GO. The specificity of the ring-opening reactions observed suggests that the initialattack takes place at the C=N system, probably pro-ducing an intermediate (16) which initiates bond cleavageto yield a stabilised anion (17).(14) -EXPERIMENTALlH N.m.r.spectra were determined for solutions indeuteriochloroform with a Varian A60A spectrometer(tetramethylsilane as internal reference).1.r. spectra wereobtained with a Unicam SP 200 spectrophotometer. Massspectra were measured with an A.E.I. MS9 spectrometer(ionising voltage 70 eV, trap current 100 PA, acceleratingvoltage 8 kV). Samples were introduced through theheated inlet system a t 200".2,3-Dihydro- l-phenyZquinazoZin-4( 1H)-one (2) .-(i) N-Phenylanthranilic acid (5 g) and formamide (10 g) wereheated together under reflux for 4 h. The cooled melt waswashed with water to yield the quinazolinone (4.8 g, 91yo),prisms, m.p. 198-199" (from 2-ethoxyethanol).(ii) 1-Phenylquinazolin-4( 1H)-one (1 g), sodium boro-hydride (0.65 g) and propan-2-01 (20 cm3) were stirredtogether a t room temperature for 18 h. Dilution withwater (30 cm3) and extraction with chloroform yielded thequinazolinone (0.82 g, 81).(iii) 1-Phenylquinazolin-4( lH)-one (0.2 g) and formamide(5 cm3) were heated together under reflux for 4 h to yieldthe quinazolinone, vmX.(Nujol) 3100 (N-H) and 1660 cm-1(GO), T (CDC1,) 5-0 (d, collapsing to s on shaking withD,O,CH,), 2,5-3.2 (aromatic protons), and 1-98 (9, 5-H)(Found: C, 75.2; H, 5.4; N, 12.4. Cl,H1,N,O requires C,75; H, 5.4; N, 12.5), mje 225 (6), 224 ( M f , 40),223 (27), 222 (7), 196 (19), 195 (loo), 168 (5), 167 (29), 166(13), 140 (6), 139 (8), 78 (4), 77 (27), 76 (4), 64 (7), 63 (7),58 (4), 50 (8), and 39 (7).l-PhenyEquinazoZin-4( lH)-one (1) .-2,3-Dihydro-l-phenyl-quinazolin-4( 1H)-one (1 g) and 10 palladised charcoal(0.2 g) were heated together under reflux in xylene for 8 h.Filtration of the hot suspension through Celite and coolingof the clear filtrate yielded the quinazolinone (0.7 g, 70y0),prisms, m.p.180-181" (from ethyl acetate), vmx. (CHC1,)1655 cm-1 (GO), T (CDC1,) 2.28-3.18 (aromatic protons),1-75 (s, 2-H), and 1.63 (m, 5-H) (Found: C, 75.4; H, 4.6;N, 12.3. C,,H1,N,O requires C, 75.6; H, 4.5; N, 1 2 ~ 6 ) ~m/e 223 (14), 222 (M+, 84), 196 (15), 195 (loo), 194 (6),168 (4), 167 (32), 166 (15), 140 (7), 139 (9), 97-5 (6), 92 (12),83.5 (15), 78 (3), 77 (28), 76 (6), 75 (6), 74 (6), 70.5 (6),64 (7), 63 (6), 58 (4), 51 (23), 50 (9), 44 (21), and 39 (7),wz* 171.1 (222 --t 195) and 143 (195- 167).l-PhenyZquinuzoZine-2( 1H) ,4(3H)-dione (3) .-2,3-Dihydro-1-phenylquinazolin-4( 1H)-one (1 g) was stirred withpotassium permanganate (0.8 g) in water (10 cm3) for 4 h.Excess of oxidant was destroyed with ethanol and themanganese dioxide was removed.The residue and theneutralised filtrate were extracted with chloroform to yieldthe quinazolinedione (0.68 g, 64), plates, m.p. 296-297"(from 2-ethoxyethanol) (Found: C, 70.6; H, 4.3; N, 11.6.Calc. for Cl,Hl,N,02: C, 70.6; H, 4.2; N, 11.8yo), m/e238 (amp;If).2- (MethyZauninomethyZ)-N-phenyZaniline (4) .-(i) 2,3-Di-hydro-1-phenylquinazolin-4( lH)-one (1.5 g), lithium alu-minium hydride (0.75 g), and dry ether (15 cm3) wereheated together under reflux for 4 h. The cooled mixturewas treated with water (0.8 cm3), sodium hydroxidesolution (15; 0.8 cm3), and water (2.5 cm3), and theethereal solution was separated and dried (MgSO,) .Evaporation and bulb-distillation yielded the diphenyl-amine (1.2 g, 84) as a yellow oil which gave an acetyZderivative, m.p.96-97' (from light petroleum), v,, (CHC1,)3300 (N-H) and 1640 cm-1 (GO), T (CDC1,) 7.92 (s, Ac),7.05 (s, NMe), 5.42 (s, CH,), 2-6-3.3 (aromatic protons),and 2.2br (s, exchangeable NH) (Found: C, 75.8; H, 7.1;N, 11.0. C,,H18N20 requires C, 75.6; H, 7.1; N, ll.O),m/e 254 (M+).(ii) Reduction of 1-phenylquinazolin-4( 1N) -one undersimilar conditions yielded the diphenylamine (SOYo),T (CDC1,) 7.72 (s, Me), 6-38 (s, CH,), and 2-7-3-3 (aromaticprotons) (Found: M+, 212.130541. C1,H,,N, requires M ,21 2- 13 1342).l-BenzyZ-2,3-dihydroquinazolin-4( 1H) -one.- 1-Benzyl-quinazolin-4(1H)-one (1 g) , sodium borohydride (0-65 g),and propan-2-01 (20 cm3) were stirred together a t roomtemperature for 18 h.Dilution with water (30 cm3) andextraction with chloroform yielded the quinazolinone(0.79 g, 78), needles, m.p. 162-163" (from 2-ethoxy1972ethanol and ethyl acetate), 7 (CDC1,) 5.46 (s, PhCH,), 5.37(d, 2-H,), 3-05 (2H, m), 2.72 (s, NH), 2.5 (aromatic protons),and 1.86 (d, 5-H) (Found: C, 75-5; H, 5.9; N, 11.7.ClSH14N2O requires C, 75.7; HI 5.9; N, 11.80/,), m / e238 (M+).Phenylquinazolin-4( 3H) -one ( 1 g), sodium borohydride(1 g) , and propan-2-01 (20 cm3) were stirred together at roomtemperature for 18 h. Dilution with water (30 cm3) andextraction with chloroform yielded the quinazolinone(0.52 g, 58y0), identical with a sample prepared fromanthranilanilide and formalin; l3 m.p.179-180".2-A nilino~nethyl-N-methylaniline (13) .- 1,2-Dihydro-3-phenylquinazolin-4(3H)-one (0.6 g), lithium aluminiumhydride (0.6 g), and dry ether (12 cm3) were heated underreflux for 24 h. Excess of hydride was destroyed andevaporation of the ethereal extract yielded the diamine (13)(0.45 g, 710/,), which gave a diacetyl derivative, m.p. 109-110" (from light petroleum), 7 (CDC1,) 8-54 (s, Ac), 8.02(s, Ac), 7-13 (s, NMe), 5.05 (d, CH,), and 2-2-3.0 (aromaticprotons) (Found: C, 73-2; H, 6.9; N, 9.5. Cl8Hz,,N,O,requires C, 73.0; H, 6.8; N, 9.5), m/e 296 (M+).(ii) 3-Phenylquinazolin-4(3H)-one (0.3 g) , lithium alu-minium hydride (0.3 g), and dry ether (10 cm3) were heatedunder reflux for 8 h to yield the diamine (0-17 g, 59y0),7 (CDC1,) 7.32 (s, Me), 6-6br (s, exchangeable, NH), 5-98(s, CH,), 5.5br (s, exchangeable, NH), and 3.1-3.5 and24--3.0 (aromatic protons) (Found: M+ 212.131441.CI4HiGN2 requires M , 212.131342).3-EthyZamino-N-phenyZ~yridi~ze-2-carboxavPzide (1 1) .-2-Methyl-3-phenylpyrido3,2-dpyrimidin-4( 3H)-one (1 g),1,2- Dihydro- 3-phenylquinazolin-4( 3H) -one (12).-3-355sodium borohydride (0-65 g), and propan-2-01 (20 cm3) werestirred together at room temperature to yield the andide(0-71 g, 72y0), yellow prisms, m.p.65-66' (from lightpetroleum), vmx. (CHC1,) 3340 (N-H), 1660 (CEO), and1530-1500 cm-1 (amide II), 7 (CDCl,) 8-68 (t, J 7 Hz, Me),6.82 (m, collapsing to q, J 7 Hz, when shaken withD,O,CH,), 2-2-3-1 (aromatic protons), and 1.6br (s,exchangeable, NH) (Found: C, 69.8; H, 6-2; N, 17.4.Cl,H15N,0 requires C, 69.7; H, 6.2; N, 17.4y0), m / e241 (M+).2-AnilivtonzethyZ-3-ethylaminoPyridine (14) .-(i) 2-Methyl-3-phenylpyrido3,2-dpyrimidin-4(3H)-one (0.5 g) , lithiumaluminium hydride (0.4 g), and dry ether (10 cm3) wereheated together under reflux for 8 h t o yield the pyridine(0.32 g, 61), yellow prisms, m.p. 55-56' from lightpetroleum (b.p. 40-60").imidine (0.22 g), lithium aluminium hydride (0.2 g), anddry ether (10 cm3) were heated together under reflux for8 h to yield the pyridine (0.11 g, 49), vmak (CHC1,) 3400cm-l (N-H), 7 (CDC1,) 8-89 (t, J 7 Hz, Me), 7.02 (m, col-lapsing to q, J 7 Hz, when shaken with D,O,MeCH,), 5.8(s, which sharpened when shaken with D,O,CH,*NH) ,5-3br (s, exchangeable, NH), 2.65-3.5 (aromatic protons),and 2.13 (9, J5,6 4-5, J4,5 1.5 Hz, 6-H) (Found: C, 73.7;H, 7.3; N, 18.2. C14Hl,N, requires C, 74.0; H, 7-5; N,18-5y0), Yn/e 227 (amp;ff).(ii) 3,4-Dihydro-2-methyl-3-phenylpyrido3,2-dpyr-1/1737 Received, September 22nd, 19711J. R. Feldman and E. G. Wagner, J . Org. Chem., 1942, 7,31
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