It could be established that the reaction between hydrazine
and enamines, formed from ethyl 2(or 3)-aminopyridine-3(or 2)carboxylates and diethyl ethoxymethylenemalonate or ethyl ethoxymethylenecyanoacetate, afforded 3-aminopyrido(2,3-d)pyrimidin-
4(3H)one or 3-aminopyrido(3,2-d)pyrimidin-4(3H)one, respectively.
Similarly, these aminopyridinecarboxylates condense with N,N-
dimethylformamide dimethylacetal and react further with
hydrazine to give the same bicyclic compounds

B. Stanovnik

M. Tišler

English

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CR 0 AT IC A CHEM I CA ACT A 44 (1972) 243 CCA-700 547.85.07 Original Scientific Paper Synthesis of Isomeric 3-Aminopyridopyrimidin-4(3H)ones* B. Stanovnik and M. TisLer Department of Chemistry, Universit y of Ljubljana, 61000 Ljubljana, Slovenia, Yugoslavia Received December 24, 1971 It could be established that the reaction between hydrazine and enamines, formed from ethyl 2(or 3)-aminopyridine-3(or 2)car-boxylates and diethyl ethoxymethylenemalonate or ethyl ethoxy-methylenecyanoacetate, afforded 3-aminopyrido(2,3-d)pyrimidin--4(3H)one or 3-aminopyrido(3,2-d)pyrimidin-4(3H)one, respectively. Similarly, these aminopyridinecarboxylates condense with N,N--dimethylformamide dimethylacetal and react further with hydrazine to give the same bicyclic compounds. It has been proposed that 1,3,4-benzotriazepines are formed in the reaction between 2-aminobenzophenones and diethyl ethoxymethylenemalonate and sub-sequent treatment of the intermediate enamine with hydrazine.1 We would like to present evidence that related reactions which we have investigated in the pyridine field led only to pyridopyrimidones. Esters of 2-aminopyridine-3-carboxylic or 3-aminopyridine-2-carboxylic acids when condensed with diethyl ethoxymethylenemalonate or ethyl ethoxy-methylenecyanoacetate afforded the corresponding condensation products (V, R1 = COOEt or CN). In view of the possibility that the enamines formed in the reaction with the last mentioned reagent may exist as cis or_ trans isomers (I or II) or as a mixture of both, we have examined the product w hich was obtained from the reaction between 3-amino-2-carb.ethoxypyridine and ethyl ethoxymethylenecyanoacetate. From NMR spectroscopic assignements it could be established that the relative amounts of the cis-enamine (I) and trans-ena-mine (II) were present in a ratio of about 3 : 2. As anticipated, the · signal for the olefinic proton of the trans-enamine is at lower field than that of the cis-enamine. These enamines, when treated in cold with excess of hydrazine hydrate formed readily 3-aminopyrido(2,3-d)pyrimidin-4(3H)one (III, R = NH2} or 3-ami-nopyrido(3,2-d)pyrimidin-4(3H)one (IV, R = NH2}. The formation of these by-cyclic compounds can be envisaged as to result by addition of hydrazine to the exocyclic double bond followed by elimination of the diethyl malonate or-ethyl cyanoacetate part and cyclization. This is consistent with the observation that substituted methylenemalonates add hydrazines2 or form hydrazones,2 ,3 the diethyl malonate moiety being in this case the leaving group. Further support for intermediates of the type VI is given in the reaction between aminopyridinecarboxylates and N,N-dimethylformamide dimethyl-acetal, a well documented reaction also for some aminoheterocyclic compounds.4 * Part XCII in the Series Heterocycles. 244 B. STANOVNIK AND M. TISLER (XCOOEt ~ I fol -~ ~AycN H ""C o"" 'oEt ex. N COCEt -: H . ~~COOEt H CN Ill Here, the intermediate N,N-dimethylaminomethylene derivative could be iso-lated and characterized and is readily converted with hydrazine into the cor-responding bicyclic 3-amino compound (III or IV). Another approach to the formation of the bicyclic system represents the reaction between 2-aminonicotinic acid hydrazide and diethoxymethyl acetate. The formed 3-ethoxymethyleneamino compound (III, R = -N=CHOEt) is converted into the 3-amino compound (III, R = NHJ upon hydrolysis. The spectral evidence which is in accord with the above structure as a 6/6 and not as a 6/7 bicycle is supported also by chemical evidence. Both 3-amino deri-H R ~N'CH=C,.. 1 ~. 'COOEt COOEt v vatives (III, IV, R = NH2) when treated under mild reaction conditions with amyl nitrite in the presence of glacial acetic acid are transformed into their desamino derivatives (III, IV, R = H) which were found identical with au-thentic specimens5,6• Although the 3-amino group of related 3-aminoquinazolines behaves normally in chemical reactions as anticipated for an amino group, 3-aminopyrido(2,3-d)pyrimidin-4(3H)one did not condense with benzaldehyde, but a monoacetyl derivative could be prepared. Furthermore, it is noteworthy that under normal conditions 2-amino-3--carbethoxypyridine-N-oxide did not form the corresponding enamine w ith diethyl ethoxymethylenemalonate. However, the amino group of methyl 2-3-AMINOPYRIDOPYRIMIDIN-4(3H)ONES 245 -aminopyridine-3-carboxylate reacted with cis,trans-2,5-diethoxytetrahydro-furan to give the corresponding pyrrolopyridine (VII). In an attempt to convert (~N N~ 1 QOOMe VII , ,, this compound into a tricyclic system with polyphosphoric acid the pyrrole ring was eliminated and methyl 2-aminopyridine-3-carboxylate was isolated and identified. EXPERIMENT AL Melting points were determined on a Kofler micro hot stage and are corrected. NMR spectra were recorded on a JEOL JNM-C-60HL spectrometer (TMS as internal standard) and mass spectra were obtained on a CEC 21-llOC instrument. Diethyl [3-carbomethoxy-N(2-pyridinyl)]aminomethylenemalonate Methyl 2-aminopyridine-3-carboxylate (4.56 g.), and diethyl ethoxymethylene-malonate (6.5 g.) were heated at about 160° and heating was discontinued in order to moderate the exothermic reaction. Thereafter heating was continued and the mixture was heated at about 180° for 10 min. Upon cooling the oily mass crystallized after standing on ice. Crystallization from aqueous ethanol afforded the pure compound (2.86 g.) with m. p. 79-80°. Anal. C15H1sN206 (322.31) calc'd .: C 55.89; H 5.63 ; N 8.69°/o found: C 55.58; H 5.44; N 8.870/o The following compounds were prepared in a similar manner: Ethyl [3-carbomethoxy-N(2-pyridinyl]aminomethylenecyanoacetate M. p. 136-137° (from ethanol). IR spectrum: (KBr) 2217 (CN), 1715 and 1695 cm-1 (COOMe and COOEt). Mass spectrum: M+ = 275. Anal. C1sH1sNs04 (275.26) calc'd .: C 56.72 ; H 4.76 ; N 15.270/o found: C 56.65; H 4.70; N 15.4go/() Diethyl [3-carbamoyl-N(2-pyridinyl)]aminomethylenemalonate M. p. 199-201° (from ethanol). IR spectrum (KBr): 3367 and 3279 (NH, NH2) and 1887 cm-1 (COOEt). Mass spectrum: M+ = 307. Anal. C11H17N30 5 (307.30) calc'd.: C 54.72; H 5.58; N 13.680/o found: C 54.91; H 5.42; N 13.92°/o Ethyl [2-carbethoxy-N(3-pyridinyl)]aminomethylenecyanoacetate M. p. 188-189° (from ethanol). IR spectrum (KBr): 2217 (CN) and 1692 cm-1 (COOEt). NMR spectrum: DMSO-ds at 80°: i: = 1.85 (dd, H4), 2.46 (dd, H5), 1.58 (dd, H 6), 5.75 (q, 2-COOCH2CHs), 8.70 (t, 2-COOCH2CH3), 5.60 (q, = C(CN)COOCH2CH3), 8.61 (t, = C(CN)COOCH2CH3), 1.70 (s, -NH-CH=, cis), 1.50 (s, -NH-CH=, trans); J 4,5 = = 8.5, J 5,6 = 4.2, J 4,6 = 1.5, J CH2CHs = 7 .5 Hz. Anal. C14H15N304 (289.28) calc'd.: C 58.12; H 5.23; N 14.530/o found: C 58.39; H 5.23; N 14.780/o 3-Aminopyrido(2,3-d)pyrimidin-4(3H)one (III, R = NH2) A. - A solution of diethyl [3-carbomethoxy-N-(2-pyridinyl)]aminomethylene-malonate (1.61 g.) in ethanol (30 ml.) was treated with hydrazine hydrate (1.5 ml. of 1000/o) and the mixture was left at room temperature overnight. The separated cry-246 B. STANOVNIK AND M. TISLER stals were collected (1.37 g.) and crystallized from water. M. p. 249-250°. IR spectrum (KBr): 1689 (CO) and 3311 cm-1 (NH2). Mass spectrum: M+ = 162. NMR spectrum: in DMSO-d6 at 112°: i: = 1.56 (s, H 2), 1.55 (dd, H 5) , 2.53 (dd, H6), 1.10 (dd, H1), 5.1 (broad, NH2); J 5,6 = 8.0, J 6,7 = 5.9; J 5 ,7 = 1.5 Hz. In TFAA at 25°: i: = 1.02 (s, H2), 0.55 (dd, H;), 1.87 (dd, H6), 0.84 (dd, H;); J5,6 = 8.0; J6,7 = 5.9, J;,1 = 1.5 Hz. Anal. C7H 6N40 (162.15) calc'd.: C 51.85; H 3.73; N 34.560/o found: C 52.22; H 3.82; N 34.740/o B. - A mixture of ethyl 2-aminopyridine-3- carboxylate (1.16 g .) and N,N-di-methylformamide dimethylacetal (3.0 ml.) was heated under reflux for 2 hrs. and evaporated in vacuo. A small amount of the residual oil was for analysis distilled at 120-130°/0.1 mm (Anal. C11H 15N30 2 (221.25) calc'd.: C 59.71; H 6.83; N 18.99°/o. Found: C 59.52; H 6.70; N 19.48°/o). The residual crude N,N-dimethylaminomethylene deri-vative was dissolved in some ethanol and treated with excess of 100°/o, hydrazine hydrate. The product had after purification m . p. 249-250° and had identical IR spectrum wTt h the product obtained as described under A and mixed m. p. was w ithout depression. 3-Acetylaminopyrido(2,3-d)pyrimidin-4(3H)one (III, R = CH3CONH) The above amino compound (0.162 g.), acetic anhydride (1.0 ml.) and pyridine (1.5 ml.) were heated under reflux for 15 min. The cooled solution was diluted with water (5.0 ml.), extracted with chloroform and after evaporation of the solvent the residual oil crystallized after several days. Upon crystallization from triethyl ortho-formate the pure compound had m . p. 225-227°. NMR spectrum (in DMSO-d6 at 21°): i: = 1.64 (s, H 2), 1.55 (dd, H 5) , 2.53 (dd, H 6), 1.10 (dd, H1), 7.90 (s, COCH3), - 1,1 (broad, NH); J; ,6 = 7.6, J6,7 = 4.5, J; ,1 = 2.0 Hz. Anal. C9HsN40 2 (204.19) calc'd. : C 52.94; H 3.95 ; N 27.443/o found: C 52.90; H 4.17; N 27.299/o 3-Ethoxymethyleneaminopyrido(2,3-d)pyrimidin-4-(3H)one (III, R = EtOCH=N-) The hydrazide of 2-aminopyridine- 3-carboxylic a cid' (0.87 g. with m. p. 190-191°; lit.7 gives m. p. 176°) was treated with diethoxymethyl acetate (5.1 g.) and the resulting solution was heated under reflux for 15 min. The separated product was filtered, washed with triethyl orthoformate and recrystallized from the same solvent (yield 1.05 g.). M. p . 142-143°. IR spectrum (in KBr): 1681 cm-1 (CO). Mass spectrum: M+ = 218. NMR spectrum (in DMSO-d6): i: = 1.58 (s, H2), 1.58 (dd, H 5), 2.53 (dd, H6), 1.13 (dd, H ; ), 1.48 (s, =CHOEt), 5.66 (q, -OCH2CH3), 8.62 (t, OCH2CH3); J;,6 = 7.8; J6.7 = 4.8, J ; ,1 = 2.1, JcH2CH3 = 6.8 Hz. Anal. C10H10N402 (218.21) calc'd.: C 55.04; H 4.62; N 25.68% found: C 54.77; H 4.39; N 26 .02°/o The same product was obtained when employing triethyl orthoformate in this reaction. · If the product was heated in the presence of glacial acetic acid for 2 hrs., the solution evaporated to dryness in vacuo and some ammonia was added, upon standing some crystals separated. They were identified as 3-aminopyrido(2,3-d)piri-midin-4(3H)one. Pyrido(2,3-d)pyrimidin-4(3H)one (III, R = H) Compound III (R = NH2) (0.162 g.) was dissolved in glacial acetic acid (10 ml.) and the solution was treated with amyl nitrite (0.2 ml.) . After standing at room temp. for 15 min. the solution was evaporated in vacuo to dryness and the residue w as crystallized from water. M. p. 262-263° and mixed m. p. with an authentic specimen was undepressed (lit.5 gives m. p. 258°). NMR spectrum (in DMSO-d6 at 112°): i: = = 1.92 (s, H2), 1.66 (dd, H;), 2.65 (dd, H6) 1.26 (dd, H 7), -0.5 (broad, NH); J 5,6 = 7.6, J6,7 = 4.5, Js,7 = 2.0 Hz. Anal. C1H5N30 (147.13) calc'd.: C 57.14; H 3.43; N 28.560/o found: C 56.99; H 3.54; N 28.480/o 3-AMINOPYRIDOPYRIMIDIN-4(3H)ONES 247 3-Aminopyrido(3,2-d)pyrimidin-4(3H)one (IV, R = NH2) A . - Ethyl 3-aminopyridine-2-carboxylate (0.83 g.) and diethyl ethoxymethyle-nemalonate (1.08 g.) were heated to 170-180° until the exothermic reaction started. Temperature raised to 200-210° and this temperature was held for 5 min. Upon cooling the residual oil did not crystallize and it was dissolved in absolute ethanol (10 ml.) and hydrazine hydrate (1.5 ml. of lOQ-0/o) was added. The separated crystals were crystallized from ethanol, m. p. 285-287°. NMR spectrum (in DMSO- d 6 at 80°): i: = 1.73 (s, H2) , 1.82 (dd, H 6), 2.35 (dd, H;), 2.04 (dd, Hs); J 6,i = 4.0, J;,s = 7.8, J 6,8 = 1.5 Hz. Anal. C;H6N40 (162.15) calc'd.: C 51.85; H 3.73; N 34.56"/o found: C 52.23; H 3.43 ; N 34.49-0/o B. - Ethyl 3-aminopyridine-2-carboxylate (1.16 g.) and N,N-dimethylformamide dimethylacetal (3.0 ml.) were heated under reflux for 2 hrs. The mixture was eva-porated in vacuo and the residual oil, consisting of the crude dimethylaminomethy-lene derivative, was treated with excess of 1000/o hydrazine hydrate. Tre formed product, m. p. 285-288°, was found to be identical in all respects with the compound prepared as described under A. Pyrido(3,2-d)pyrimidin-4(3H)one (IV, R = H) The above 3-amino compound (0.324 g.) was dissolved in hot glacial acetic acid (15 ml.), the solution was cooled and amyl nitrite (0.3 ml.) was added. After standing at room temp. for 1 hr. the separated product was collected and had m . p. about 350°. It was found to be identical in all respects with an authentic specimen". NMR spectrum (in DMSO-d6 at 1206): i: = 2.08 (s, H2), 1.30 (dd, H 6), 2.40 (dd, H;) , 2.11 (dd, H s), cca 2.7 (broad, NH); Jo,1 = 4.5, J; ,s = 7.6, J6.8 = 1.5 Hz. Anal. C;H5N30 (147.13) calc'd.: C 57.14; H 3.43; N 28.560/o found: C 56.82; H 3.32; N 28.320/o 2-A mino-3-car bethoxypyridine-N-oxide A solution of 2-amino-3-carbethoxypyridine (5.0 g.) in glacial acetic acid (60 ml.) was treated with hydrogen peroxide (15 g. of 720/o) and left aside at room temp. for 60 hrs. Thereafter some water was added, the solution was evaporated in vacuo to dryness and the residual oil crystallized after standing. Upon crystallization from acetonitrile the product (2.87 g.) had m. p. 139- 141°. Mass spectrum: M+ = 182. Anal. C8H 10N20 3 (182.18) calc'd.: C 52.74; H 5.53; N 15.380/o found : C 52.52; H 5.62; N 14.98°/o 3-Carbomethoxy-2-(N-pyrrolo )pyridine (VII) A solution of methyl 2- aminopyridine-3-carboxylate (0.15 g.) in glacial acetic acid (2 .0 ml.) was treated with cis, trans-2,5-diethoxytetrahydrofuran (0.16 g.) and the mixture was heated under reflux for 30 min. The solution was evaporated in vacuo and the residual dark oil was distilled at 90-100°/3 mm (yield 80 mg.). Mass spectrum : M+ = 202. NMR (CDCl3): • = 2.02 (dd, H4), 2.95 (dd, H5) , 1.53 (dd, HG), 6.21 (s, COOCH3), 3.00 (m, H2'5'), 3.75 (m, Hs·4.J; J4 ,5 = 7.5, J5,6 = 4.6, J4,6 = 1.7 Hz. Anal. C11H10N20 2 (202.21) calc'd.: C 65.33; H 4.98; N 13.860/o found: C 65.04; H 5.16; N 14.08°/o A mixture of VII (0.125 g.) and polyphosphoric acid (2 g. of acid with 800/o P205) was left to stand at roc .. _1 temp. for 24 hrs. It was poured on crushed ice and neutralized with sodium bicarbonate. Extraction with chloroform afforded a dark oil which was sublimed at 100°/0.l mm. The process was repeated and the product with m . p. 350 was ident ified as methyl 2-aminopyridine-3-carboxylate (mass spectrum: M+ = 152). Acknowledgement. Our thanks are due to Dr. J. Marsel, Institute J. Stefan, for recording the mass spectra. 248 B. STANOVNIK AND M. TISLER REFERENCES 1. C. Pode s v a, G. Kohan, and K. Va g i, Canad. J . Chem. 47 (1969) 489. 2. I. Go 1 d s t e in, Ber. dtsch. chem. Ges. 28 (1895) 1450. 3. W. Wis 1 ice nus, Ann. 279 (1894) 23. 4. H. B re de rec k, F. E ff en berger, and A. Hofmann, Chem. Ber. 97 (1964) 61. 5. R. K. Robins, and G. H. Hitchings, J . Am. Chem. Soc. 77 (1955) 2256. 6. C. C. Price, and D. Y. Curtin, J. Am. Chem. Soc. 68 (1946) 914. 7. V. 0 a k es, R. Pascoe, and H. N. Ry don, J. Chem. Soc. (1956) 1045. IZVLECEK Sinteze izomernih 3-aminopiridopirimidin-4(3H)onov B . Stanovnik in M. Tisler Ugotovili smo, da vodi reakcija med hidrazinom in enamini, ki nastanejo pri reakciji med etilnim estrom 2(ali 3)-aminopiridin-3-(ali 2)karboksilne kisline in dietilnim estrom etoksimetilenmalonove kisline ali etilnim estrom etoksimetilencian-ocetne kisline, do 3-aminopirido(2,3-d)pirimidin-4(3H)ona oziroma do 3-aminopi-rido(3,2-d)pirimidin-4(3H)ona. Na podoben nacin se omenjeni estri aminopiridinkar-boksilnih kislin kondenzirajo z N,N-dimetilformamid dimetilacetalom in nadaljnja reakcija s hidrazinom vodi do istih biciklienih spojin. ODDELEK ZA KEMIJO FAKULTETA ZA NARAVOSLOVJE IN TEHNOLOGIJO Spre jeto 24. decembra 1971. 61000 LJUBLJANA 

Synthesis of Isomeric 3-Aminopyridopyrimidin-4(3H)ones

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