Allenes. Part 50. Pyrimido1,2-apyrimidines and pyrimido1,6-apyrimidines and their hydrolysis products from allenic nitrites and phenylpropynenitrile

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 609 Allenes. Part 50.' Pyrimido[l,2-a]pyrimidines and Pyrimido[l,6-a]pyrimidines and their Hydrolysis Products from Allenic Nitriles and Phenylpropynenitrile Stephen R. Landor * Department of Chemistry, University of Exeter, Exeter EX4 40D Andrew Johnson University of West lndies, Jamaica Z. Tanee Fomum and A. Ephraim Nkengfack University of Yaounde, Cameroon 2 -Am in opyri m id ine and 2-amino-4- met hyl pyri m id ine react with aIlen ic n itri les to give, in itiaIly, 2-imino-4-alkylpyrimido[1,2-a]pyrimidines (2) which rapidly add water and cleave to 3-(4-amino-6-alkyl-2-pyrimidy1amino)aldehydes (6). 2-Amino-4,6-dimethylpyrimidine similarly gives the corresponding ketones (5;R3 = R4 = Me). 2-lmino-4-alkylpyrimido[l,6-a] pyrimidines (11) areformed as intermediates from 4-amino-2,6-dimethylpyrimidine and allenic nitriles and are hydrolysed to amides (12).We have recently synthesised pyrido[ 1,2-a]pyrimidines from allenic nitriles and have shown that such heterocycles hydrolyse spontaneously under mild basic conditions. We now feT6i7 that pyrimidoc 1,2-a]pyrimidines are formed similarly from allenic nitriles and 2-amino- and 4-amino-pyrimidines but are spon- taneously hydrolysed by a completely different route. Pyrim- ido[1,2-a]pyrimidines have been shown to be of potential pharmaceutical importance. 2-Aminopyrimidine (la) heated under reflux with allenic nitriles in ethanol gives hydrolysis products of pyrimido[ 1,2-a]- pyrimidines which show a carbonyl carbon in the I3C n.m.r.spectrum at 197. However, the mass and 'H n.m.r. spectra exclude the enaminic ketone structure (7a) which would result from the addition of water in the 4-position, as they neither eliminate the alkyl side chain (-CHR'R2) on fission nor show the chelated NH O=C at 6, 14 in the 'H n.m.r. spectrum, typical of such compounds.2 Instead a doublet is found at 6, 9.315 which is assigned to an aldehyde proton, O=CH-CH= and, in all cases, the molecular ion Mf loses CHO (29) to give the base peak. There is only one aldehyde which can be obtained from the hydrolysis of the pyrimido[1,2-a]pyrimidine (2; R4 = H), which must result from attack by a water molecule at the C-6 position. Pyrimidopyrimidines contain two pyrimidine rings which may be attacked by a nucleophile at one of the positive centres, either at C-4 or C-6 next to the positive nitrogen [shown in resonance form (3)].Conclusive evidence presented here shows that they are always attacked at C-6 (unlike the pyridoc 1,2-a]pyrimidines which have only one pyrimidine ring and are therefore always attacked at C-4) and if C-6 is unsubstituted an aldehyde is always obtained. Starting with 2-amino-4-methylpyrimidine,the ring nitrogen furthest from the methyl adds to the central carbon of the allene (electronically more favourable and to minimise steric inter- action) and the resulting pyrimidopyrimidine (2) has R3 = Me, R4 = H which on hydrolysis again gives an aldehyde. Detailed examination of high-field proton, carbon, and mass spectra shows that E and 2, (6)=(5), and ringhain tautomeric forms, (5) c(4), are often encountered (see Table), although the proportions vary considerably according to the substituents present and the experimental conditions.Where R3 = R4 = H the E form (6) predominates with the coupling constant of H' and H2of the aldehyde side chain J = 8-10 Hz. Where R3 = Me, R4 = H the product is almost entirely in the Z form (5);the coupling constant for H'and H2 J = 3-4 Hz, with the strongly hydrogen bonded NH O=C signal being at 6 12-13. In their mass spectrum all the aldehydes give a base peak of M -29 for loss of CHO and form the stable imidazolo- pyrimidine radical cation (9). This is usually cleaved further by loss of C2H2N or C2H3N (azirine) to give the 4-amino-6- alkylpyrimidine fragment (10).However, in addition to this Mi M- 29 M -29 -41 (100% 1 (30- 50% I (91 (10) principal mode of fission, substantial peaks for A4 -18 are observed and these fragments are usually further degraded by loss of alkyl from the side chain on C-4, either by McLafferty rearrangement or alkyl radical fission. This supports a ring- chain equilibrium and, under mass spectral conditions, a reversal of the hydrolysis. M -18 It should be noted that the same structure (5) and (6) would also result from the hydrolysis of the alternative 4-imino-2- alk ylpyrimidopyrimidine (S), but in the absence of any evidence to the contrary and in view of the conclusive evidence of the 610 J.CHEM. SOC. PERKIN TRANS. I 1989 (2) 1 R’ 1 R’ (7) (6) E (8) (i) R’ = R2= Me (ii) R’ = Me, R2 = Et (iii) R’ = R2 = Et (iv) R’ = Pr, R2 = H (v) R’ = Pr, R2 = Me (a) R3 = R4 = H (b) R3 = Me, R4 = H (c) R3 = R4 = Me Scheme 1. structure of 2-iminopyridopyrimidine~,~the 4-alkyl-2-imino- the ketones are entirely in the 2 form*; a doublet at 6 2.51 (J0.4 pyrimido[ 1,2-a]pyrimidine pathway is preferred. Hz) for the methyl on C-1’ (long-range coupling with proton on With an alkyl group in the 6-position hydrolysis either by C-2’) and a singlet at 6 2.101 for the 4’-methyl fit structure (5) attack at C-4 or C-6 must form a ketone. However, attack again but not (7c), as do a doublet for the proton on C-2’ at 6 5.93-takes place at the 6-position as shown by the following 5.95 (J 0.3 Hz) and a singlet for the proton at C-5 of the spectroscopic data which confirm the structure as ketone (5)in pyrimidine ring at 6 5.196.The molecular ion in each case loses the 2 form. Both 13Cand ‘H n.m.r. signals for the ketone side CH3C=0to give the stable imidazopyrimidine as the base peak chain show constant values regardless of R’and R2. A signal at at M -43,with a small M -15 peak for the alternative loss of 6, 197.2 shows a ketone carbonyl (C-3’) while the methyl on Me from the acetyl. C-1’ resonates at 6, 22.95 and the 4’-methyl at 6, 29.76. The A number of attempts were made to convert 2-amino-alternative scheme which shows water attacking at C-4 of the pyrimidine hydrochloride into 2-amino-4-alkylpyrimido[l,2-pyrimidopyrimidine (2) giving (7c) (in which the 4-and 6-methyls are equivalent) can therefore be rejected.The ‘H n.m.r. signal at 6,12.37 (for NH - - - 0%)shows that * For (7c) the chelated NH signal would be expected near 6, 14. J. CHEM. SOC. PERKIN TRANS. I 1989 611 Table. Preparation of condensation products H (6) Found RequiredA h Time Yield M.p. f \I Entry R' R2 R3 R4 (h) 1 Me Me H H 72 2 Me Et H H 78 3 Et Et H H 78 4 H PrH H 120 5 Et Et Me H 72 6 Me Me Me Me 48 7 Me Et Me Me 48 8 Et Et Me Me 48 9 Me Pr Me Me 48 10 Ph' H H 60 a cu. 40% of starting pyrimidine was recovered.Me R' (5c) (%) ("C) C H N C H N (6):(5):(4) 41" 160 57.9 6.7 26.8 58.3 6.8 27.2 14:l:l 43" 175 59.8 7.4 25.2 60.0 7.27 25.5 14:1:2 42" 173 61.5 7.4 23.7 61.5 7.69 23.9 b 68 140 59.9 7.2 25.2 60.0 7.27 25.5 2:3:2 42" 115 62.7 7.8 22.6 62.9 8.06 22.6 0:l:O 41" 136 61.5 7.7 24.0 61.5 7.69 23.9 0:l:O 40" 150 62.9 8.1 22.7 62.9 8.06 22.6 0:l:O 64 121 64.0 8.4 21.5 64.1 8.40 21.4 0:l:O 50 129 64.1 8.4 21.5 64.1 8.40 21.4 b 56 210 65.1 4.9 23.4 65.0 5.00 23.3 b High-field 'H and 13C n.m.r. signals not determined. R'R2CH=Ph. R' (7c1 pyrimido[1,6-u]pyrimidine (11) by hydrolysis. It shows a 3C carbonyl signal at 6, 170.7, a 'H singlet at 6, 2.168 for the acetamide methyl, a doublet at 6,2.454 (J 1 Hz) for the methyl on C-2 (systematic numbering: C-6) coupled with the proton on C-1' of the side-chain which itself shows a quartet, and mass spectral fission of methyl and acetyl radicals from the relatively stable molecular ion. R' *Rt 'R2 MeyyN3NH* (12) The hydrolysis of pyrimido[ 1,2-u]pyrimidine or pyrim-ido[ 1,6-a]pyrimidines has not previously been reported.The hydrolysis of a dihydropyrimido[ 1,2-a]pyrimidine (13) by evaporation of an aqueous solution of the hydrochloride with potassium carbonate was described as giving the betaine (14) but in the absence of any spectroscopic or other evidence the possibility that the product obtained was the dihydro-pyrimidinone aldehyde (15) cannot be ruled out.*? * 6,7-Dihydro-2H-pyrimido[ 1,2-u]pyrimidine-2,8(9H)-dione hydroiy-ses in boiling water by attack at the 2-po~ition.~ H J.2 -form of hypothetical ketone resulting from attack of water at C-L M -43 ( looo/ol alpyrimidine hydrochlorides by heating with allenic nitriles in ethanol and other solvents (cf: experiments with 2-amino- pyridine hydrochlorides 2). These all foundered because the hydrochloride is virtually insoluble in non-aqueous solvents and mainly starting materials were recovered. However, mass spectral data and t.1.c. showed that 1&20% of the pyrimido- [1,2-u]pyrimidine hydrochlorides were formed but these could not be separated from the starting pyrimidine hydrochloride. Treatment of the mixture with ethanolic sodium carbonate gave the corresponding aldehyde (5).Similarly attempts to prepare the internally stabilised hydroxypyrimidoC 1,2-a]pyrirnidines failed as the starting material, 2-amino-4-hydroxy-6-methyl-pyrimidine, was only sparingly soluble in ethanol and the reaction extremely slow.4-Amino-2,6-dimethylpyrimidinerefluxed in 95% ethanol with allenic nitriles gave a product which showed the spectroscopic characteristics of an amide (12), derived from the J. CHEM. SOC. PERKIN TRANS. I 1989 M -15 2L7 M-43 219 -CH3CO ( 5 7 VO 1 / (100 %I Scheme 2. water -Cy3O\N (131 (141 water1 (Y+JOHN 1 0 (15) Experimental 1.r. spectra were determined with Perkin-Elmer 257 and 337 spectrometers, U.V. spectra for ethanolic solutions with Perkin- Elmer 137, Beckman 25, and Cary spectrometers, and n.m.r.spectra with Perkin-Elmer R12, Jeol 60, and Bruker 250 instruments. Allenic nitriles were prepared as previously reported.6 3-[(4-Amino-6-s-butylpyrimidin-2-yl)~mino]propenal(5/6iia) (1 H, br t, J 13.5 Hz, HC=CHNH), 9.315 (1 H, d, J 8.5 Hz, CHO), and 9.704 (1 H, br d, J w 12 Hz, NH); 6, 11.92 (CH,), 19.35 (CH,), 28.68 (CH,), 42.66 (CHMeEt), 92.02 (CH-N), 108.34 (CH-CHO), 150.97 (C-5), 157.33 (C-6), 164.67 (C-4), 174.21 (C-2), and 191.35 (CHO); m/z 220 (M', 2079,191 (loo), 202 (8), and 173 (40). Signals for 6,9-dihydro-6-hydroxy-2-imino-4-s-butylpyrim-ido[ 1,2-a]pyrimidine (4iia) (for proportions see Table); 6, 3.25 (br s,OH), 5.20(d,CH=CHCHOH),7.97 (brtd,CH=CHNH), and 9.91 (br d, NH); 6,97.63 (CHOH), 99.02 (CH=), and 142.63 (NCH=); m/z 202 (M' -18,8%) and 173 (M' -18 -29,40). Signals for the Z-isomer (5iia) (for proportions see Table); 6, 9.375 (dd, CHXHCHO) and 12.1 (br s, NH); 6,190.37 (HC=O).Compounds for entries 1 and 3-10 of the Table were prepared similarly and had 'H and I3C n.m.r. and mass spectra in complete accord with their different side chains. 2-(2- Acetamidoprop- 1 -enyl)-4-amino-6-s-butylpyrimidine (12ii).-4-Amino-2,6-dimethylpyrimidine(2.46 g, 0.02 mol) and 4-methylhexa-2,3-dienenitrile (2.14 g, 0.02 mol) were heated under reflux in ethanol (96%; 100 ml) for 98 h, after which time 50% of the starting material had reacted as monitored by t.1.c. Evaporation and chromatography gave recovered starting pyrimidine (1.1 g) and the title compound (2.1 g, 42%), m.p.99 "C; R, 0.57 (benzene+thyl acetate 3: 2) (Found: C, 62.7; H, 7.9; N, 22.5. C,,H,,N,O requires C, 62.9; H, 8.07; N, 22.58%); vmax, 3 180 and 3 300, 3 320, 3 350 cm-' (NH, NH,); A,,,.and 6,9-dihydro-6-h~ldro.~y-2-imino-4-s-hutyl-2H-pyrimidn-204 (9 000), 254 (9 600), 288 (10 SOO), and 304 nm (10 500); [ 1,2-a]pyrirnidine (1,8-Dihydro-8-imino-6-s-butyl-4H-pyrimido-hEzH 205 (10 500),256 (7 400), and 320 nm (1 6 600); 6,0.82 [ 1,2-a]pyrimidin-4-0/) (4iia).-4-Methylhexa-2,3-dieneni trile (2.14 g, 0.02 mol) and 2-aminopyrimidine (la) (1.9 g, 0.02 mol) were refluxed in ethanol (95%; 100 ml) for 78 h. Evaporation of solvent and chromatography (alumina, activity 2; eluted with hexane-ethylacetate, 3:2) gave the title compounds [mainly (6iia)l as white crystals (1.9 g, 4373, m.p.175 "C (entry 2, Table); vmaX.3 350, 3 300, 3 175 (OH, NH, NH,), 1610 (C=N), 1600, and 1 540 cm-'; A,,,. 250 (E 10 300), 278 (15 000), and 312 nm (30 900); G,[CDCl, + (CD,),SO] 0.84 (3 H, t, CH,Me), 1.16 (3 H, d, CHMe), 1.51(1 H, sextet, diastereotopic CH,), 2.454 (1 H, sextet, CHI, 5.801 (1 H, dd, J1,,8.5, J2,3 13.5 Hz, E-CHXHCHO), 5.892 (1 H, S, 5-H), 5.972 (2 H, S, NH,), 8.286 t A. Richardson and F. J. McCarty (J. Med. Chem., 1972, 15, 1203) prepared a pyrimido[ 1,2-a]pyrimidone and proposed the structure I. However, no evidence was presented which would exclude structure 11. 0 I) (11) (3 H, t, MeCH,), 1.22 (3 H, d, MeCH), 1.3-1.9 (3 H, m, CH,CH), 2.12 (3 H, s, Ac), 2.40 (3 H, s, MeC=C), 4.80 (2 H, br s, NH,, disappears with D,O), 5.30 (1 H, s, CH=CMe), 6.00 (1 H, s, 5-H), and 12.80 (1 H, s, CONH N=, disappears with D,O); mi; 248 (M', 248).2-(2- Acetamidoprop- l-enyl)-4-arnino-6-( 1-ethy/propyl)-pyrimidine (12iii).--4-Amino-2,6-dimethylpyrimidine(2.46 g, 0.02 rnol) and 4-ethylhexa-2,3-dienenitrile (2.42 g, 0.02 mol) were heated under reflux in ethanol (96%; 150 ml for 78 h) and the reaction was monitored by t.1.c. to show that 45% of starting material had reacted. Evaporation and chromatography gave recovered starting material (I .3 g) and the title compound (1.9 g, 36.3%), m.p. 140°C; R, 0.47 (benzenethyl acetate 3:2) (Found: C, 64.1; H, 8.4; N, 21.2. C,,H,,N,O requires C, 64.12; H, 8.40; N, 21.37%); v,,,.3 420,3 340,3 160 cm-I (NH, + NH);A,,,. 203 (11 500), 254 (11000), 290 (1 1 900), and 304 nm (11 900); 204 (14 OOO), 254 (7 700), and 322 nm (18000); 6, 0.836 [6 H, t, (MeCH,),], 1.690 [4 H, quin, (CH,Me),], 2.168 (3 H, s, Ac), 2.290 (1 H, quin, CH,CHCH,), 2.454 (3 H, d, J 1 Hz, MeC=CH), 4.751 (2 H, br s, NH,), 5.339 (1 H, q, J 1 Hz, CH=CMe), 5.983 (1 H, s, 5-H), and 12.826 (1 H, br s, NH N=); 6,12.12 (MeCH,),, 22.2 (MeCO), 25.38 (MeC=), 27.63 (2 x CH,), 51.22 (CHEt,), 99.73 (CHSMe), 106.59 J. CHEM. SOC. PERKIN TRANS. I 1989 (C-5), 146.86, 162.71, 165.16 and 168.63 [C(Me)=C, C-4, C-6, and C-21, 170.74 (CO); m/z 262 (M', 31%), 247 (M' -15,57), 234 (24), and 219 (37). Acknowledgements We thank Dr* V1ademir Sik for high-fie1d spectra and the Leverhulme Trust for the award of an Emeritus Fellowship to S. R. L. References 1 Part 49, S. R. Landor, Z. T. Fomum, P. F. Asobo, P. D. Landor, and A. L. Johnson, J. Chem. SOC.,Perkin Trans. 1, 1989, 251. 2 S. R. Landor, P. D. Landor, A. Johnson, Z. T. Fomum, J. T. Mbafor, and A. E. Nkengfack, J. Chem. SOC.,Perkin Trans. 1, 1988, 975. 3 A. A. Ramsey, U.S.P. 3 830 812 (Chem. Abstr., 1974,81,136 174g); A. Takamizara, Jap. P. 7034 144 (Chem. Abstr., 1971, 74, 88027a). 4 C. V. Grecor and J. F. Warchol, J. Org. Chem., 1971, 36, 604. 5 K. Sugino and T. Tanaka, J. Org. Chem., 1968,33, 3354; R. B. Angier and W. V. Curran, ibid., 1961, 26, 1891. 6 P. M. Greaves, S. R. Landor, and D. R. J. Laws, J. Chem. SOC.C, 1968, 291. Received 23rd June 1988; Paper 8/024971