Reactions of2-methyl-4H-pyrido2,3-d3,1oxazin-4-one with activemethylene compounds: a new efficient route to 3-substituted4-hydroxy-1,8-naphthyridin-2(1H)-ones

摘要

J. Chem. Soc. Perkin Trans. 1 1997 1487 Reactions of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one with active methylene compounds a new eYcient route to 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones Vassiliki Delieza Anastasia Detsi Vassilios Bardakos and Olga Igglessi-Markopoulou * Laboratory of Organic Chemistry Department of Chemical Engineering National Technical University of Athens Zografou Campus 157 73 Athens Greece 3-Substituted 1,8-naphthyridine-2,4-diones compounds of very important pharmaceutical use have been synthesized using a new efficient route. The reaction of 2-methyl-4H-pyrido-2,3-d3,1oxazin-4-one 1b with active methylene compounds furnishes the 1-acetyl-3-substituted-4-hydroxy-1,8-naphthyridin-2-ones 3ndash;5 in good yields. In the case of cyanoacetic esters the intermediate C-acylation compounds 7 and 8 were isolated and subsequently cyclized to 1-acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6.Spectral data and physical characteristics for all compounds are reported. 1,8-Naphthyridine-2,4-dione derivatives (X = N Fig. 1) substituted at position 3 form a class of fused ring heterocycles which present interesting pharmacological and biological properties. These compounds occur widely among natural products and have importance in medicine. A series of substituted 1,8- naphthyridin-2(1H)-ones are orally active potent inhibitors of allergic and non-allergic bronchospasm in animal models.1 Recent reports describe a class of 1-aryl-1,8-naphthyridinone derivatives as potent orally active inhibitors of the release of the leukotriene mediators of anaphylaxis in vitro and in vivo.2 Moreover 3-carboxy-1,8-naphthyridin-2-one derivatives showed potent gastric anti-secretory properties in rat models.3 Recently novel anti-inflammatory drugs having the 1,8- naphthyridine structure with a mode of action different from that of the classical acidic nonsteroidal anti-inflammatory drugs (NSAIDs) were designed and synthesized by Suzuki et al.4 Several immunomodulators such as roquinimex and Sch 12 223 (Fig.2) containing the 4-hydroxyquinolinone and 4-hydroxynaphthyridinone system have been reported.5 The 1,8-naphthyridine skeleton in Sch 12 223 is known to be a bioisostere of quinoline.4 1,8-Naphthyridine derivatives have proved to inhibit type IV phosphodiesterase and are therefore useful in the treatment of respiratory inflammatory systemic or local joint diseases inflammations accompanying organ transplantation diseases associated with urination and those involving tumour necrosis Fig.1 X N X N Fig. 1 1 2 3 4 5 6 7 8 4a 8a OH Y O O Y O Fig. 2 Roquinimex (LS-2616) Fig. 2 Sch 12223 N N O OH Me Me Ph O N N O OH Ph factors and other cytokines.6a Numerous 1,8-naphthyridine derivatives are useful as modulators of cytokine synthesis immunomodulatory and anti-inflammatory agents.6b The importance of these fused ring heterocycles has encouraged the development of numerous routes for their preparation. The 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones have been prepared by a standard Dieckmann condensation using azaisatoic anhydride derivatives 4,7 or 2-aminonicotinic acid esters as starting material.1,2c,3,8 Alternatively 3-substituted 4- hydroxy-1,8-naphthyridin-2(1H)-ones have been synthesized by thermal condensation of 2-aminopyridines with malonic esters.9 However most of the above methods are less than convenient since they require several steps and vigorous conditions.As part of our program for the synthesis and evaluation of nitrogen heterocycles containing the lsquo;enolic b-dicarbonyl moietyrsquo; such as 3-substituted 4-hydroxypyrrolin-2-ones (tetramic acids) 10a we have recently described a new approach for the synthesis of 3-substituted 4-hydroxyquinolin-2(1H)-ones (X = CH Fig. 1).10b Our interest in 1,8-naphthyridinones arose from their gross similarity to quinolinones and our desire to prepare 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones possessing the lsquo;enolic b-dicarbonyl moietyrsquo;.In the 3-substituted 4-hydroxyquinolin-2(1H)-one (X = CH) series we used the 2-methyl-3,1-benzoxazin-4-one 1a as starting material (Scheme 1). This compound was replaced by the 2- methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b in order to synthesize the corresponding 3-substituted 4-hydroxy-1,8- naphthyridin-2(1H)-ones. The new synthetic approach includes the C-acylation of an active methylene compound with an oxazinone the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b. The intermediate 3a 4a or 5a,b (not isolated) undergoes an in situ intramolecular cyclization to a 3-substituted 4-hydroxy-1,8- Scheme 1 X N Y X N O a X=CH b X=N X=CH or N 1 CH3 O O OH 1488 J. Chem. Soc. Perkin Trans. 1 1997 naphthyridin-2(1H)-one (Scheme 2). In a typical C-acylationndash; cyclization the active methylene compound 2 (3 mol equiv.) was treated with potassium tert-butoxide (2 mol equiv.) in tertbutyl alcohol or sodium hydride (3 mol equiv.) in anhydrous benzene at room temperature.After ca. 15 min 2-methyl-4Hpyrido 2,3-d3,1oxazin-4-one 1b (1 mol equiv.) was added to the mixture which was then stirred for 30 minndash;1 h before treatment with water and diethyl ether; the aqueous layer on acidifi- cation gave the 3-substituted 4-hydroxy-1,8-naphthyridin- 2(1H)-ones in good yields (60ndash;80 see Experimental section). The active carbon of the methylene compound ultimately becomes the 3-carbon of the naphthyridine ring and any substituents attached to this carbon will subsequently reside in the correct position while the azabenzoxazinone ring supplies the remainder of the molecule.The 2-methyl-4H-pyrido2,3-d- 3,1oxazin-4-one has been known to be a useful synthon as an acylating agent in which both the carboxylate activation and the amino group protection are achieved simultaneously. It is suggested that the in situ conversion of compound 1b into 3 4 or 5 involves the intermediate formation of 3a 4a or 5a,b respectively. Attempts to isolate such intermediates in a pure form were unsuccessful. However reinvestigation by 1H NMR of the transformation of compound 1b into the cyclized compounds revealed in addition to the signals of the final product the presence of signals which are attributed to the formation of the intermediate compounds 3a 4a or 5a,b during the course of the C-acylationndash;cyclization reactions. In the case of cyanoacetic esters the C-acylation compounds 7 and 8 were isolated in their enolic form in good yields (60ndash; 70) without further cyclization under the reaction conditions (Scheme 2) .In an attempt to induce cyclization compounds 7 and 8 were heated in refluxing ethanolndash;benzene using sodium ethoxide (2 equiv.). After 3 h consumption of the C-acylation compound was completed and a new product the 1-acetyl-3- cyano-4-hydroxy-1,8-naphthyridin-2-one 6 was formed. The structure of the newly prepared C-acylation compounds 7 and 8 was assigned on the basis of their analytical and spectral data (see Experimental section). Characteristically the IR spectra of the above C-acylation compounds show a sharp nitrile absorption at 2210 cm21 and two absorption bands for the b-keto ester in the 1720ndash;1670 cm21 range attributable to the carbonyl of the keto and enol forms.It is noteworthy that the IR spectrum of the cyclization product 6 still exhibits a characteristic prominent nitrile absorption at 2200 cm21 therefore ruling out cyclization with the nitrile. Scheme 2 Reagents and conditions Method A ButOKndash;ButOH room temp.; Method B NaHndash;anhydrous benzene room temp. N N Ac N N O N NHAc Y HO CO2R N NHAc Y HO CO2R + Method A or B 1b 2 3 Y = CO2Me Scheme 2 7 Y = CN R = Me Method A EtONa / EtOH H2C Y CO2R O CH3 3a Y = CO2Me R = Me 4a Y = CO2Et R = Et 5a Y = Ac R = Me 6a Y = Ac R = Et 8 Y = CN R = Et 4 Y = CO2Et 5 Y = Ac 6 Y = CN OH Y O The 1H NMR spectra of the cyclization products 3 4 and 5 show an enol hydrogen at 15.56ndash;15.70 ppm as a broad signal. The 2,4-diketone form (Fig. 1) can be readily ruled out on the basis of 1H NMR spectral data by the lack of the methinyl proton at position 3.All the aromatic protons are sharply differentiated with the expected multiplicity H-5 being observed at 8.98ndash;9.06 ppm H-6 at 7.48ndash;7.73 ppm and H-7 at 9.26ndash;9.93 ppm. Integration of these signals gave the ratio 1 1 1. Structure assignment was made by comparison with data reported in the literature for products of similar structure.11 Compounds 3 4 and 5 are of additional interest since they have the potential to exist in the tautomeric enolic forms a and b as shown in Scheme 3. Since only one set of signals is observed in the 1H NMR spectra in CDCl3 solution it is assumed that if tautomerism exists it is fast on the NMR timescale. 10a In conclusion we have described a new and efficient route to the preparation of 3-substituted 1,8-naphthyridine-2,4-diones using the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one as starting material.Current research is dedicated towards further application of the proposed method to the synthesis of compounds containing the 1,8-naphthyridine-2,4-dione system bearing various substituents on the aromatic ring and the 3- position using the suitably substituted oxazinones and the appropriate active methylene compounds. Experimental Mps were determined on a Gallenkamp MFB-595 melting point apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer 267 spectrometer. The NMR spectra were recorded on either Varian EM-360 60 MHz or Varian Unity Plus 300 MHz spectrometers using Me4Si as internal reference. Chemical shifts are quoted in ppm (s = singlet d = doublet t = triplet q = quartet m = multiplet br = broad); J values are given in Hz.Elemental analyses were obtained from the microanalytical laboratory of CNRS (France). Preparation of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b 2-Aminonicotinic acid (1.9 g 0.014 mol) was added to acetic anhydride (10 ml) and the mixture was refluxed at 165ndash;170 8C for ca. 1 h. The solution after being cooled to 80 8C was evaporated in vacuo. Light petroleum was added to the solid residue formed to give 2-methyl-4H-pyrido2,3-d3,1oxazin-4- one 1b as a solid (2.23 g 90) mp 165ndash;166 8C (lit.,12 mp 175ndash;178 8C). The product thus obtained was used for the C-acylation-cyclization reactions without further purification. General procedures for the reactions of active methylene compounds with 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one Method A.Potassium tert-butoxide (2.24 g 0.02 mol) was stirred in tert butyl alcohol (100 ml) at room temperature until it dissolved (ca. 15 min) after which the active methylene compound 2 (0.03 mol) was added dropwise to the mixture. Stirring was continued for 1 h after which compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued at room temperature for 30 minndash;1 h. Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath. Scheme 3 N N b Scheme 3 a C Me O O H O N N C Me O O H O J. Chem. Soc. Perkin Trans. 1 1997 1489 The precipitate thus formed was filtered off and washed with water. Method B. The active methylene compound 2 (0.03 mol) was added dropwise to a mixture of sodium hydride (55ndash;60 sodium hydride in oil; 0.03 mol) in anhydrous benzene (90 ml) and the thick white slurry thus formed was stirred at room temperature for 1 h.Compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued for 1ndash;2.5 h. Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath. The precipitate thus formed was filtered off and washed with water. 1-Acetyl-3-methoxycarbonyl-4-hydroxy-1,8-naphthyridin-2- one 3. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tert-butyl alcohol 100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 3 (2.13 g 82) mp 175ndash;176 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 3 (1.23 g 48) mp 173ndash;175 8C (from CHCl3) (Found C 54.94; H 3.97; N 10.67. C12H10O5N2 requires C 54.96; H 3.84; N 10.68); dH(60 MHz; CDCl3; Me4Si) 2.70 (3 H s COCH3) 4.00 (3 H s CO2CH3) 7.50 (1 H pseudotriplet 6-H) 9.06 (1 H dd J5,6 7 J5,7 1 5-H) 9.33 (1 H dd J6,7 7 J5,7 1 7-H) and 15.56 (1 H br OH).1-Acetyl-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-2-one 4. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 4 (2.37 g 87) mp 155ndash;157 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 4 (1.35 g 40) mp 157ndash;159 8C (from CHCl3) (Found C 56.70; H 4.46; N 10.25. C13H12O5N2 requires C 56.52; H 4.38; N 10.14); dH(300 MHz; CDCl3; Me4Si) 1.43 (3 H t J 7,CH2CH3) 2.68 (3 H s COCH3) 4.46 (2 H q J 7 CH2CH3) 7.48 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8.1 J5,7 1.6 5-H) 9.28 (1 H dd J6,7 6.5 J5,7 1.6 7-H) and 15.89 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 164.51 (CO ester) 163.09 (C-4) 162.22 (C-2) 153.91 (COCH3) 149.30 (C-8a) 144.68 (C-7) 132.05 (C-5) 122.49 (C- 4a) 116.22 (C-6) 109.77 (C-3) 62.03 (CH2CH3) 23.27 (COCH3) and 14.21 (CH2CH3). 1,3-Diacetyl-4-hydroxy-1,8-naphthyridin-2-one 5. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (2.3 g 0.02 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (2.6 g 0.02 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (130 ml) was stirred for 1 h.Compound 5 was obtained as a solid 1.88 g (62) when methyl acetoacetate was used as the active methylene compound and 1.53 g (50) when ethyl acetoacetate was used as the active methylene compound mp 170ndash;171 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (3.5 g 0.03 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (3.9 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h. Compound 5 was obtained as a solid 2.04 g (67) when methyl acetoacetate was used as the active methylene compound and 1.64 g (54) when ethyl acetoacetate was used as the active methylene compound mp 167ndash;170 8C (from CHCl3) (Found C 58.01; H 4.07; N 11.38.C12H10O4N2 requires C 58.53; H 4.09; N 11.38); dH(300 MHz; CDCl3; Me4Si) 2.69 (6 H s COCH3 and NCOCH3) 7.50 (1 H pseudotriplet 6-H) 8.98 (1 H dd J5,6 7.5 J5,7 1.9 5-H) 9.26 (1 H dd J6,7 7.5 J5,7 1.9 7-H) and 15.75 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 198.81 (C-COCH3) 163.87 (C-4) 163.00 (C-2) 155.30 (N-COCH3) 149.18 (C-8a) 144.85 (C-7) 131.90 (C-5) 122.56 (C-4a) 116.37 (C-6) 115.04 (C-3) 31.87 (C-COCH3) and 23.91 (N-COCH3). Methyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 7. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 7 as a solid (1.57 g 65) mp 176ndash;178 8C (from EtOH) (Found C 55.18; H 4.36; N 15.87.C12H11O4N3 requires C 55.17; H 4.24; N 16.09); nmax(Nujol)/cm21 2210s (CN) 1720 and 1700s (CO ester keto form) and 1600s (C C ring stretching); dH(60 MHz; CDCl3; Me4Si) 2.80 (3 H s COCH3) 3.78 (3 H s CO2CH3) 7.08 (1 H dd J4,5 8 J5,6 5 5-H) 8.25ndash;8.48 (2 H m 4-H and 6-H) 9.30 (1 H br NH) and 12.76 (1 H br OH). Ethyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 8. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 8 as a solid (1.80 g 71) mp 106ndash;108 8C (from CHCl3) (Found C 56.67; H 4.82; N 15.91. C13H13O4N3 requires C 56.72; H 4.76; N 15.27); nmax(Nujol)/cm21 3500m (OH) 2210w (CN) 1710w (CO ester keto form) 1670s (CO ester enol form) and 1600s (C=C ring stretching); dH(60 MHz; CDCl3; Me4Si) 1.36 (3 H t J 7 CH2CH3) 2.83 (3 H s COCH3) 4.26 (2 H q J 7 CH2CH3) 7.09 (1 H dd J4,5 8 J5,6 5 5-H) 8.28ndash;8.53 (2 H m 4-H and 6-H) 7.73 (1 H br NH) and 12.83 (1 H br OH).1-Acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. The C-acylation compound 0.002 mol 7 (0.50 g) or 8 (0.55 g) dissolved in a small quantity of ethanol was added to a solution of sodium ethoxide in ethanol prepared from sodium (0.09 g 4 mmol) in absolute ethanol (10 ml) containing anhydrous benzene (10 ml). The reaction mixture was refluxed for 3 h and set aside overnight at room temperature. Water and diethyl ether were then added to the reaction mixture after which the aqueous layer was separated acidified with 10 hydrochloric acid and extracted with ethyl acetate and diethyl ether.The organic layers were combined dried (Na2SO4) and evaporated in vacuo. The resulting red solid was triturated with diethyl ether filtered off and washed with small amounts of diethyl ether to give the title compound 6 0.26 g (59) from 7 and 0.25 g (60) from 8 mp 213ndash;214 8C; nmax(Nujol)/cm21 2210w (CN) 1690m (CO stretching amide I) and 1610 (C C ring stretching); dH(60 MHz; CDCl3ndash;2H6DMSO; Me4Si) 2.76 (3 H s COCH3) 6.78 (1 H br OH) 7.73 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8 J5,7 1 5-H) and 9.93 (1 H dd J6.7 8 J5,7 1 7-H). References 1 M. H. Sherlock W. C. T. Kaminski J. F. Lee S.-C. Wong W. Kreutner R. W. Bryant and A. McPhail J. Med. Chem. 1988 31 2108. 2 (a) T. Duelfer and D. Gala J.Labelled Compd. Radiopharm. 1991 29 651; (b) W. Kreutner J. Sherwood S. Sehring C. Rizzo R. W. Chapman M. I. Siegel and R. W. Egan J. Pharmacol. Exp. Ther. 1988 247 997; (c) D. J. Blythin H.-J. Shue E. Carlon J. Spitler and W. Kreutner Bioorg. Med. Chem. Lett. 1994 4 1327. 3 A. A. Santilli A. C. Scotese R. F. Bauer and S. C. Bell J. Med. Chem. 1987 30 2270. 4 T. Kuroda F. Suzuki T. Tamura K. Ohmori and H. Hosoe J. Med. Chem. 1992 35 1130. 1490 J. Chem. Soc. Perkin Trans. 1 1997 5 (a) N. G. Ilback J. Fohlman S. Slorach and G. Friman J. Immunol. 1989 142 3225; (b) J. Bjork and D. Kleinau Agents Actions 1989 27 319; (c) S. R. Smith and M. I. Siegel PCT Int. Appl. WO 8607 537/1986 (Chem. Abstr. 1986 107 183 554d; 108 118 982y). 6 (a) T. Kazuhisa I. Masahiro O. Yoshinori A.Motonori N. Akira and I. Yasuo PCT Int. Appl. WO 9 606 843/1996 (Chem. Abstr. 1996 125 86 620); (b) J. C. Gill and B. W. Leslie PCT Int. Appl. WO 9 611 198/1996 (Chem. Abstr. 1996 125 114 579). 7 (a) H. Hayashi Y. Miwa S. Ichikawa N. Yoda I. Miki A. Ishii M. Kono T. Yasusawa and F. Suzuki J. Med. Chem. 1993 36 617; (b) S. Peroutka Trends Neurosci. 1988 11 496. 8 Jian-long Chen and W. Steglich J. Heterocycl. Chem. 1993 30 909. 9 B. D. Schober and T. Kappe J. Heterocycl. Chem. 1988 25 1231. 10 (a) A. Detsi J. Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Chem. Commun. 1996 1323; (b) A. Detsi V. Bardakos J. Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Perkin Trans. 1 1996 2909. 11 E. Breitmaier Structure Elucidation by NMR in Organic Chemistry J. Wiley amp; Sons 1993.12 A. Stempel and L. H. Sternbach US Patent 3 415 835/1968 (Chem. Abstr. 1969 57657u). Paper 6/08509A Received 19th December 1996 Accepted 24th January 1997 J. Chem. Soc. Perkin Trans. 1 1997 1487 Reactions of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one with active methylene compounds a new eYcient route to 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones Vassiliki Delieza Anastasia Detsi Vassilios Bardakos and Olga Igglessi-Markopoulou * Laboratory of Organic Chemistry Department of Chemical Engineering National Technical University of Athens Zografou Campus 157 73 Athens Greece 3-Substituted 1,8-naphthyridine-2,4-diones compounds of very important pharmaceutical use have been synthesized using a new efficient route. The reaction of 2-methyl-4H-pyrido-2,3-d3,1oxazin-4-one 1b with active methylene compounds furnishes the 1-acetyl-3-substituted-4-hydroxy-1,8-naphthyridin-2-ones 3ndash;5 in good yields.In the case of cyanoacetic esters the intermediate C-acylation compounds 7 and 8 were isolated and subsequently cyclized to 1-acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. Spectral data and physical characteristics for all compounds are reported. 1,8-Naphthyridine-2,4-dione derivatives (X = N Fig. 1) substituted at position 3 form a class of fused ring heterocycles which present interesting pharmacological and biological properties. These compounds occur widely among natural products and have importance in medicine. A series of substituted 1,8- naphthyridin-2(1H)-ones are orally active potent inhibitors of allergic and non-allergic bronchospasm in animal models.1 Recent reports describe a class of 1-aryl-1,8-naphthyridinone derivatives as potent orally active inhibitors of the release of the leukotriene mediators of anaphylaxis in vitro and in vivo.2 Moreover 3-carboxy-1,8-naphthyridin-2-one derivatives showed potent gastric anti-secretory properties in rat models.3 Recently novel anti-inflammatory drugs having the 1,8- naphthyridine structure with a mode of action different from that of the classical acidic nonsteroidal anti-inflammatory drugs (NSAIDs) were designed and synthesized by Suzuki et al.4 Several immunomodulators such as roquinimex and Sch 12 223 (Fig.2) containing the 4-hydroxyquinolinone and 4-hydroxynaphthyridinone system have been reported.5 The 1,8-naphthyridine skeleton in Sch 12 223 is known to be a bioisostere of quinoline.4 1,8-Naphthyridine derivatives have proved to inhibit type IV phosphodiesterase and are therefore useful in the treatment of respiratory inflammatory systemic or local joint diseases inflammations accompanying organ transplantation diseases associated with urination and those involving tumour necrosis Fig.1 X N X N Fig. 1 1 2 3 4 5 6 7 8 4a 8a OH Y O O Y O Fig. 2 Roquinimex (LS-2616) Fig. 2 Sch 12223 N N O OH Me Me Ph O N N O OH Ph factors and other cytokines.6a Numerous 1,8-naphthyridine derivatives are useful as modulators of cytokine synthesis immunomodulatory and anti-inflammatory agents.6b The importance of these fused ring heterocycles has encouraged the development of numerous routes for their preparation. The 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones have been prepared by a standard Dieckmann condensation using azaisatoic anhydride derivatives 4,7 or 2-aminonicotinic acid esters as starting material.1,2c,3,8 Alternatively 3-substituted 4- hydroxy-1,8-naphthyridin-2(1H)-ones have been synthesized by thermal condensation of 2-aminopyridines with malonic esters.9 However most of the above methods are less than convenient since they require several steps and vigorous conditions.As part of our program for the synthesis and evaluation of nitrogen heterocycles containing the lsquo;enolic b-dicarbonyl moietyrsquo; such as 3-substituted 4-hydroxypyrrolin-2-ones (tetramic acids) 10a we have recently described a new approach for the synthesis of 3-substituted 4-hydroxyquinolin-2(1H)-ones (X = CH Fig. 1).10b Our interest in 1,8-naphthyridinones arose from their gross similarity to quinolinones and our desire to prepare 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones possessing the lsquo;enolic b-dicarbonyl moietyrsquo;.In the 3-substituted 4-hydroxyquinolin-2(1H)-one (X = CH) series we used the 2-methyl-3,1-benzoxazin-4-one 1a as starting material (Scheme 1). This compound was replaced by the 2- methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b in order to synthesize the corresponding 3-substituted 4-hydroxy-1,8- naphthyridin-2(1H)-ones. The new synthetic approach includes the C-acylation of an active methylene compound with an oxazinone the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b. The intermediate 3a 4a or 5a,b (not isolated) undergoes an in situ intramolecular cyclization to a 3-substituted 4-hydroxy-1,8- Scheme 1 X N Y X N O a X=CH b X=N X=CH or N 1 CH3 O O OH 1488 J.Chem. Soc. Perkin Trans. 1 1997 naphthyridin-2(1H)-one (Scheme 2). In a typical C-acylationndash; cyclization the active methylene compound 2 (3 mol equiv.) was treated with potassium tert-butoxide (2 mol equiv.) in tertbutyl alcohol or sodium hydride (3 mol equiv.) in anhydrous benzene at room temperature. After ca. 15 min 2-methyl-4Hpyrido 2,3-d3,1oxazin-4-one 1b (1 mol equiv.) was added to the mixture which was then stirred for 30 minndash;1 h before treatment with water and diethyl ether; the aqueous layer on acidifi- cation gave the 3-substituted 4-hydroxy-1,8-naphthyridin- 2(1H)-ones in good yields (60ndash;80 see Experimental section). The active carbon of the methylene compound ultimately becomes the 3-carbon of the naphthyridine ring and any substituents attached to this carbon will subsequently reside in the correct position while the azabenzoxazinone ring supplies the remainder of the molecule.The 2-methyl-4H-pyrido2,3-d- 3,1oxazin-4-one has been known to be a useful synthon as an acylating agent in which both the carboxylate activation and the amino group protection are achieved simultaneously. It is suggested that the in situ conversion of compound 1b into 3 4 or 5 involves the intermediate formation of 3a 4a or 5a,b respectively. Attempts to isolate such intermediates in a pure form were unsuccessful. However reinvestigation by 1H NMR of the transformation of compound 1b into the cyclized compounds revealed in addition to the signals of the final product the presence of signals which are attributed to the formation of the intermediate compounds 3a 4a or 5a,b during the course of the C-acylationndash;cyclization reactions.In the case of cyanoacetic esters the C-acylation compounds 7 and 8 were isolated in their enolic form in good yields (60ndash; 70) without further cyclization under the reaction conditions (Scheme 2) . In an attempt to induce cyclization compounds 7 and 8 were heated in refluxing ethanolndash;benzene using sodium ethoxide (2 equiv.). After 3 h consumption of the C-acylation compound was completed and a new product the 1-acetyl-3- cyano-4-hydroxy-1,8-naphthyridin-2-one 6 was formed. The structure of the newly prepared C-acylation compounds 7 and 8 was assigned on the basis of their analytical and spectral data (see Experimental section). Characteristically the IR spectra of the above C-acylation compounds show a sharp nitrile absorption at 2210 cm21 and two absorption bands for the b-keto ester in the 1720ndash;1670 cm21 range attributable to the carbonyl of the keto and enol forms.It is noteworthy that the IR spectrum of the cyclization product 6 still exhibits a characteristic prominent nitrile absorption at 2200 cm21 therefore ruling out cyclization with the nitrile. Scheme 2 Reagents and conditions Method A ButOKndash;ButOH room temp.; Method B NaHndash;anhydrous benzene room temp. N N Ac N N O N NHAc Y HO CO2R N NHAc Y HO CO2R + Method A or B 1b 2 3 Y = CO2Me Scheme 2 7 Y = CN R = Me Method A EtONa / EtOH H2C Y CO2R O CH3 3a Y = CO2Me R = Me 4a Y = CO2Et R = Et 5a Y = Ac R = Me 6a Y = Ac R = Et 8 Y = CN R = Et 4 Y = CO2Et 5 Y = Ac 6 Y = CN OH Y O The 1H NMR spectra of the cyclization products 3 4 and 5 show an enol hydrogen at 15.56ndash;15.70 ppm as a broad signal.The 2,4-diketone form (Fig. 1) can be readily ruled out on the basis of 1H NMR spectral data by the lack of the methinyl proton at position 3. All the aromatic protons are sharply differentiated with the expected multiplicity H-5 being observed at 8.98ndash;9.06 ppm H-6 at 7.48ndash;7.73 ppm and H-7 at 9.26ndash;9.93 ppm. Integration of these signals gave the ratio 1 1 1. Structure assignment was made by comparison with data reported in the literature for products of similar structure.11 Compounds 3 4 and 5 are of additional interest since they have the potential to exist in the tautomeric enolic forms a and b as shown in Scheme 3. Since only one set of signals is observed in the 1H NMR spectra in CDCl3 solution it is assumed that if tautomerism exists it is fast on the NMR timescale.10a In conclusion we have described a new and efficient route to the preparation of 3-substituted 1,8-naphthyridine-2,4-diones using the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one as starting material. Current research is dedicated towards further application of the proposed method to the synthesis of compounds containing the 1,8-naphthyridine-2,4-dione system bearing various substituents on the aromatic ring and the 3- position using the suitably substituted oxazinones and the appropriate active methylene compounds. Experimental Mps were determined on a Gallenkamp MFB-595 melting point apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer 267 spectrometer.The NMR spectra were recorded on either Varian EM-360 60 MHz or Varian Unity Plus 300 MHz spectrometers using Me4Si as internal reference. Chemical shifts are quoted in ppm (s = singlet d = doublet t = triplet q = quartet m = multiplet br = broad); J values are given in Hz. Elemental analyses were obtained from the microanalytical laboratory of CNRS (France). Preparation of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b 2-Aminonicotinic acid (1.9 g 0.014 mol) was added to acetic anhydride (10 ml) and the mixture was refluxed at 165ndash;170 8C for ca. 1 h. The solution after being cooled to 80 8C was evaporated in vacuo. Light petroleum was added to the solid residue formed to give 2-methyl-4H-pyrido2,3-d3,1oxazin-4- one 1b as a solid (2.23 g 90) mp 165ndash;166 8C (lit.,12 mp 175ndash;178 8C).The product thus obtained was used for the C-acylation-cyclization reactions without further purification. General procedures for the reactions of active methylene compounds with 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one Method A. Potassium tert-butoxide (2.24 g 0.02 mol) was stirred in tert butyl alcohol (100 ml) at room temperature until it dissolved (ca. 15 min) after which the active methylene compound 2 (0.03 mol) was added dropwise to the mixture. Stirring was continued for 1 h after which compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued at room temperature for 30 minndash;1 h. Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath. Scheme 3 N N b Scheme 3 a C Me O O H O N N C Me O O H O J.Chem. Soc. Perkin Trans. 1 1997 1489 The precipitate thus formed was filtered off and washed with water. Method B. The active methylene compound 2 (0.03 mol) was added dropwise to a mixture of sodium hydride (55ndash;60 sodium hydride in oil; 0.03 mol) in anhydrous benzene (90 ml) and the thick white slurry thus formed was stirred at room temperature for 1 h. Compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued for 1ndash;2.5 h. Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath. The precipitate thus formed was filtered off and washed with water. 1-Acetyl-3-methoxycarbonyl-4-hydroxy-1,8-naphthyridin-2- one 3. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tert-butyl alcohol 100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 3 (2.13 g 82) mp 175ndash;176 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 3 (1.23 g 48) mp 173ndash;175 8C (from CHCl3) (Found C 54.94; H 3.97; N 10.67.C12H10O5N2 requires C 54.96; H 3.84; N 10.68); dH(60 MHz; CDCl3; Me4Si) 2.70 (3 H s COCH3) 4.00 (3 H s CO2CH3) 7.50 (1 H pseudotriplet 6-H) 9.06 (1 H dd J5,6 7 J5,7 1 5-H) 9.33 (1 H dd J6,7 7 J5,7 1 7-H) and 15.56 (1 H br OH). 1-Acetyl-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-2-one 4. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 4 (2.37 g 87) mp 155ndash;157 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 4 (1.35 g 40) mp 157ndash;159 8C (from CHCl3) (Found C 56.70; H 4.46; N 10.25. C13H12O5N2 requires C 56.52; H 4.38; N 10.14); dH(300 MHz; CDCl3; Me4Si) 1.43 (3 H t J 7,CH2CH3) 2.68 (3 H s COCH3) 4.46 (2 H q J 7 CH2CH3) 7.48 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8.1 J5,7 1.6 5-H) 9.28 (1 H dd J6,7 6.5 J5,7 1.6 7-H) and 15.89 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 164.51 (CO ester) 163.09 (C-4) 162.22 (C-2) 153.91 (COCH3) 149.30 (C-8a) 144.68 (C-7) 132.05 (C-5) 122.49 (C- 4a) 116.22 (C-6) 109.77 (C-3) 62.03 (CH2CH3) 23.27 (COCH3) and 14.21 (CH2CH3).1,3-Diacetyl-4-hydroxy-1,8-naphthyridin-2-one 5. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (2.3 g 0.02 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (2.6 g 0.02 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (130 ml) was stirred for 1 h. Compound 5 was obtained as a solid 1.88 g (62) when methyl acetoacetate was used as the active methylene compound and 1.53 g (50) when ethyl acetoacetate was used as the active methylene compound mp 170ndash;171 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (3.5 g 0.03 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (3.9 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h.Compound 5 was obtained as a solid 2.04 g (67) when methyl acetoacetate was used as the active methylene compound and 1.64 g (54) when ethyl acetoacetate was used as the active methylene compound mp 167ndash;170 8C (from CHCl3) (Found C 58.01; H 4.07; N 11.38. C12H10O4N2 requires C 58.53; H 4.09; N 11.38); dH(300 MHz; CDCl3; Me4Si) 2.69 (6 H s COCH3 and NCOCH3) 7.50 (1 H pseudotriplet 6-H) 8.98 (1 H dd J5,6 7.5 J5,7 1.9 5-H) 9.26 (1 H dd J6,7 7.5 J5,7 1.9 7-H) and 15.75 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 198.81 (C-COCH3) 163.87 (C-4) 163.00 (C-2) 155.30 (N-COCH3) 149.18 (C-8a) 144.85 (C-7) 131.90 (C-5) 122.56 (C-4a) 116.37 (C-6) 115.04 (C-3) 31.87 (C-COCH3) and 23.91 (N-COCH3).Methyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 7. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 7 as a solid (1.57 g 65) mp 176ndash;178 8C (from EtOH) (Found C 55.18; H 4.36; N 15.87. C12H11O4N3 requires C 55.17; H 4.24; N 16.09); nmax(Nujol)/cm21 2210s (CN) 1720 and 1700s (CO ester keto form) and 1600s (C C ring stretching); dH(60 MHz; CDCl3; Me4Si) 2.80 (3 H s COCH3) 3.78 (3 H s CO2CH3) 7.08 (1 H dd J4,5 8 J5,6 5 5-H) 8.25ndash;8.48 (2 H m 4-H and 6-H) 9.30 (1 H br NH) and 12.76 (1 H br OH). Ethyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 8. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 8 as a solid (1.80 g 71) mp 106ndash;108 8C (from CHCl3) (Found C 56.67; H 4.82; N 15.91.C13H13O4N3 requires C 56.72; H 4.76; N 15.27); nmax(Nujol)/cm21 3500m (OH) 2210w (CN) 1710w (CO ester keto form) 1670s (CO ester enol form) and 1600s (C=C ring stretching); dH(60 MHz; CDCl3; Me4Si) 1.36 (3 H t J 7 CH2CH3) 2.83 (3 H s COCH3) 4.26 (2 H q J 7 CH2CH3) 7.09 (1 H dd J4,5 8 J5,6 5 5-H) 8.28ndash;8.53 (2 H m 4-H and 6-H) 7.73 (1 H br NH) and 12.83 (1 H br OH). 1-Acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. The C-acylation compound 0.002 mol 7 (0.50 g) or 8 (0.55 g) dissolved in a small quantity of ethanol was added to a solution of sodium ethoxide in ethanol prepared from sodium (0.09 g 4 mmol) in absolute ethanol (10 ml) containing anhydrous benzene (10 ml). The reaction mixture was refluxed for 3 h and set aside overnight at room temperature.Water and diethyl ether were then added to the reaction mixture after which the aqueous layer was separated acidified with 10 hydrochloric acid and extracted with ethyl acetate and diethyl ether. The organic layers were combined dried (Na2SO4) and evaporated in vacuo. The resulting red solid was triturated with diethyl ether filtered off and washed with small amounts of diethyl ether to give the title compound 6 0.26 g (59) from 7 and 0.25 g (60) from 8 mp 213ndash;214 8C; nmax(Nujol)/cm21 2210w (CN) 1690m (CO stretching amide I) and 1610 (C C ring stretching); dH(60 MHz; CDCl3ndash;2H6DMSO; Me4Si) 2.76 (3 H s COCH3) 6.78 (1 H br OH) 7.73 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8 J5,7 1 5-H) and 9.93 (1 H dd J6.7 8 J5,7 1 7-H).References 1 M. H. Sherlock W. C. T. Kaminski J. F. Lee S.-C. Wong W. Kreutner R. W. Bryant and A. McPhail J. Med. Chem. 1988 31 2108. 2 (a) T. Duelfer and D. Gala J. Labelled Compd. Radiopharm. 1991 29 651; (b) W. Kreutner J. Sherwood S. Sehring C. Rizzo R. W. Chapman M. I. Siegel and R. W. Egan J. Pharmacol. Exp. Ther. 1988 247 997; (c) D. J. Blythin H.-J. Shue E. Carlon J. Spitler and W. Kreutner Bioorg. Med. Chem. Lett. 1994 4 1327. 3 A. A. Santilli A. C. Scotese R. F. Bauer and S. C. Bell J. Med. Chem. 1987 30 2270. 4 T. Kuroda F. Suzuki T. Tamura K. Ohmori and H. Hosoe J. Med. Chem. 1992 35 1130. 1490 J. Chem. Soc. Perkin Trans. 1 1997 5 (a) N. G. Ilback J. Fohlman S. Slorach and G. Friman J. Immunol. 1989 142 3225; (b) J. Bjork and D. Kleinau Agents Actions 1989 27 319; (c) S.R. Smith and M. I. Siegel PCT Int. Appl. WO 8607 537/1986 (Chem. Abstr. 1986 107 183 554d; 108 118 982y). 6 (a) T. Kazuhisa I. Masahiro O. Yoshinori A. Motonori N. Akira and I. Yasuo PCT Int. Appl. WO 9 606 843/1996 (Chem. Abstr. 1996 125 86 620); (b) J. C. Gill and B. W. Leslie PCT Int. Appl. WO 9 611 198/1996 (Chem. Abstr. 1996 125 114 579). 7 (a) H. Hayashi Y. Miwa S. Ichikawa N. Yoda I. Miki A. Ishii M. Kono T. Yasusawa and F. Suzuki J. Med. Chem. 1993 36 617; (b) S. Peroutka Trends Neurosci. 1988 11 496. 8 Jian-long Chen and W. Steglich J. Heterocycl. Chem. 1993 30 909. 9 B. D. Schober and T. Kappe J. Heterocycl. Chem. 1988 25 1231. 10 (a) A. Detsi J. Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Chem. Commun. 1996 1323; (b) A. Detsi V. Bardakos J.Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Perkin Trans. 1 1996 2909. 11 E. Breitmaier Structure Elucidation by NMR in Organic Chemistry J. Wiley amp; Sons 1993. 12 A. Stempel and L. H. Sternbach US Patent 3 415 835/1968 (Chem. Abstr. 1969 57657u). Paper 6/08509A Received 19th December 1996 Accepted 24th January 1997 J. Chem. Soc. Perkin Trans. 1 1997 1487 Reactions of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one with active methylene compounds a new eYcient route to 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones Vassiliki Delieza Anastasia Detsi Vassilios Bardakos and Olga Igglessi-Markopoulou * Laboratory of Organic Chemistry Department of Chemical Engineering National Technical University of Athens Zografou Campus 157 73 Athens Greece 3-Substituted 1,8-naphthyridine-2,4-diones compounds of very important pharmaceutical use have been synthesized using a new efficient route.The reaction of 2-methyl-4H-pyrido-2,3-d3,1oxazin-4-one 1b with active methylene compounds furnishes the 1-acetyl-3-substituted-4-hydroxy-1,8-naphthyridin-2-ones 3ndash;5 in good yields. In the case of cyanoacetic esters the intermediate C-acylation compounds 7 and 8 were isolated and subsequently cyclized to 1-acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. Spectral data and physical characteristics for all compounds are reported. 1,8-Naphthyridine-2,4-dione derivatives (X = N Fig. 1) substituted at position 3 form a class of fused ring heterocycles which present interesting pharmacological and biological properties. These compounds occur widely among natural products and have importance in medicine.A series of substituted 1,8- naphthyridin-2(1H)-ones are orally active potent inhibitors of allergic and non-allergic bronchospasm in animal models.1 Recent reports describe a class of 1-aryl-1,8-naphthyridinone derivatives as potent orally active inhibitors of the release of the leukotriene mediators of anaphylaxis in vitro and in vivo.2 Moreover 3-carboxy-1,8-naphthyridin-2-one derivatives showed potent gastric anti-secretory properties in rat models.3 Recently novel anti-inflammatory drugs having the 1,8- naphthyridine structure with a mode of action different from that of the classical acidic nonsteroidal anti-inflammatory drugs (NSAIDs) were designed and synthesized by Suzuki et al.4 Several immunomodulators such as roquinimex and Sch 12 223 (Fig.2) containing the 4-hydroxyquinolinone and 4-hydroxynaphthyridinone system have been reported.5 The 1,8-naphthyridine skeleton in Sch 12 223 is known to be a bioisostere of quinoline.4 1,8-Naphthyridine derivatives have proved to inhibit type IV phosphodiesterase and are therefore useful in the treatment of respiratory inflammatory systemic or local joint diseases inflammations accompanying organ transplantation diseases associated with urination and those involving tumour necrosis Fig. 1 X N X N Fig. 1 1 2 3 4 5 6 7 8 4a 8a OH Y O O Y O Fig. 2 Roquinimex (LS-2616) Fig. 2 Sch 12223 N N O OH Me Me Ph O N N O OH Ph factors and other cytokines.6a Numerous 1,8-naphthyridine derivatives are useful as modulators of cytokine synthesis immunomodulatory and anti-inflammatory agents.6b The importance of these fused ring heterocycles has encouraged the development of numerous routes for their preparation.The 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones have been prepared by a standard Dieckmann condensation using azaisatoic anhydride derivatives 4,7 or 2-aminonicotinic acid esters as starting material.1,2c,3,8 Alternatively 3-substituted 4- hydroxy-1,8-naphthyridin-2(1H)-ones have been synthesized by thermal condensation of 2-aminopyridines with malonic esters.9 However most of the above methods are less than convenient since they require several steps and vigorous conditions. As part of our program for the synthesis and evaluation of nitrogen heterocycles containing the lsquo;enolic b-dicarbonyl moietyrsquo; such as 3-substituted 4-hydroxypyrrolin-2-ones (tetramic acids) 10a we have recently described a new approach for the synthesis of 3-substituted 4-hydroxyquinolin-2(1H)-ones (X = CH Fig.1).10b Our interest in 1,8-naphthyridinones arose from their gross similarity to quinolinones and our desire to prepare 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones possessing the lsquo;enolic b-dicarbonyl moietyrsquo;. In the 3-substituted 4-hydroxyquinolin-2(1H)-one (X = CH) series we used the 2-methyl-3,1-benzoxazin-4-one 1a as starting material (Scheme 1). This compound was replaced by the 2- methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b in order to synthesize the corresponding 3-substituted 4-hydroxy-1,8- naphthyridin-2(1H)-ones. The new synthetic approach includes the C-acylation of an active methylene compound with an oxazinone the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b.The intermediate 3a 4a or 5a,b (not isolated) undergoes an in situ intramolecular cyclization to a 3-substituted 4-hydroxy-1,8- Scheme 1 X N Y X N O a X=CH b X=N X=CH or N 1 CH3 O O OH 1488 J. Chem. Soc. Perkin Trans. 1 1997 naphthyridin-2(1H)-one (Scheme 2). In a typical C-acylationndash; cyclization the active methylene compound 2 (3 mol equiv.) was treated with potassium tert-butoxide (2 mol equiv.) in tertbutyl alcohol or sodium hydride (3 mol equiv.) in anhydrous benzene at room temperature. After ca. 15 min 2-methyl-4Hpyrido 2,3-d3,1oxazin-4-one 1b (1 mol equiv.) was added to the mixture which was then stirred for 30 minndash;1 h before treatment with water and diethyl ether; the aqueous layer on acidifi- cation gave the 3-substituted 4-hydroxy-1,8-naphthyridin- 2(1H)-ones in good yields (60ndash;80 see Experimental section).The active carbon of the methylene compound ultimately becomes the 3-carbon of the naphthyridine ring and any substituents attached to this carbon will subsequently reside in the correct position while the azabenzoxazinone ring supplies the remainder of the molecule. The 2-methyl-4H-pyrido2,3-d- 3,1oxazin-4-one has been known to be a useful synthon as an acylating agent in which both the carboxylate activation and the amino group protection are achieved simultaneously. It is suggested that the in situ conversion of compound 1b into 3 4 or 5 involves the intermediate formation of 3a 4a or 5a,b respectively. Attempts to isolate such intermediates in a pure form were unsuccessful. However reinvestigation by 1H NMR of the transformation of compound 1b into the cyclized compounds revealed in addition to the signals of the final product the presence of signals which are attributed to the formation of the intermediate compounds 3a 4a or 5a,b during the course of the C-acylationndash;cyclization reactions.In the case of cyanoacetic esters the C-acylation compounds 7 and 8 were isolated in their enolic form in good yields (60ndash; 70) without further cyclization under the reaction conditions (Scheme 2) . In an attempt to induce cyclization compounds 7 and 8 were heated in refluxing ethanolndash;benzene using sodium ethoxide (2 equiv.). After 3 h consumption of the C-acylation compound was completed and a new product the 1-acetyl-3- cyano-4-hydroxy-1,8-naphthyridin-2-one 6 was formed. The structure of the newly prepared C-acylation compounds 7 and 8 was assigned on the basis of their analytical and spectral data (see Experimental section).Characteristically the IR spectra of the above C-acylation compounds show a sharp nitrile absorption at 2210 cm21 and two absorption bands for the b-keto ester in the 1720ndash;1670 cm21 range attributable to the carbonyl of the keto and enol forms. It is noteworthy that the IR spectrum of the cyclization product 6 still exhibits a characteristic prominent nitrile absorption at 2200 cm21 therefore ruling out cyclization with the nitrile. Scheme 2 Reagents and conditions Method A ButOKndash;ButOH room temp.; Method B NaHndash;anhydrous benzene room temp. N N Ac N N O N NHAc Y HO CO2R N NHAc Y HO CO2R + Method A or B 1b 2 3 Y = CO2Me Scheme 2 7 Y = CN R = Me Method A EtONa / EtOH H2C Y CO2R O CH3 3a Y = CO2Me R = Me 4a Y = CO2Et R = Et 5a Y = Ac R = Me 6a Y = Ac R = Et 8 Y = CN R = Et 4 Y = CO2Et 5 Y = Ac 6 Y = CN OH Y O The 1H NMR spectra of the cyclization products 3 4 and 5 show an enol hydrogen at 15.56ndash;15.70 ppm as a broad signal.The 2,4-diketone form (Fig. 1) can be readily ruled out on the basis of 1H NMR spectral data by the lack of the methinyl proton at position 3. All the aromatic protons are sharply differentiated with the expected multiplicity H-5 being observed at 8.98ndash;9.06 ppm H-6 at 7.48ndash;7.73 ppm and H-7 at 9.26ndash;9.93 ppm. Integration of these signals gave the ratio 1 1 1. Structure assignment was made by comparison with data reported in the literature for products of similar structure.11 Compounds 3 4 and 5 are of additional interest since they have the potential to exist in the tautomeric enolic forms a and b as shown in Scheme 3.Since only one set of signals is observed in the 1H NMR spectra in CDCl3 solution it is assumed that if tautomerism exists it is fast on the NMR timescale. 10a In conclusion we have described a new and efficient route to the preparation of 3-substituted 1,8-naphthyridine-2,4-diones using the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one as starting material. Current research is dedicated towards further application of the proposed method to the synthesis of compounds containing the 1,8-naphthyridine-2,4-dione system bearing various substituents on the aromatic ring and the 3- position using the suitably substituted oxazinones and the appropriate active methylene compounds.Experimental Mps were determined on a Gallenkamp MFB-595 melting point apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer 267 spectrometer. The NMR spectra were recorded on either Varian EM-360 60 MHz or Varian Unity Plus 300 MHz spectrometers using Me4Si as internal reference. Chemical shifts are quoted in ppm (s = singlet d = doublet t = triplet q = quartet m = multiplet br = broad); J values are given in Hz. Elemental analyses were obtained from the microanalytical laboratory of CNRS (France). Preparation of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b 2-Aminonicotinic acid (1.9 g 0.014 mol) was added to acetic anhydride (10 ml) and the mixture was refluxed at 165ndash;170 8C for ca. 1 h. The solution after being cooled to 80 8C was evaporated in vacuo.Light petroleum was added to the solid residue formed to give 2-methyl-4H-pyrido2,3-d3,1oxazin-4- one 1b as a solid (2.23 g 90) mp 165ndash;166 8C (lit.,12 mp 175ndash;178 8C). The product thus obtained was used for the C-acylation-cyclization reactions without further purification. General procedures for the reactions of active methylene compounds with 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one Method A. Potassium tert-butoxide (2.24 g 0.02 mol) was stirred in tert butyl alcohol (100 ml) at room temperature until it dissolved (ca. 15 min) after which the active methylene compound 2 (0.03 mol) was added dropwise to the mixture. Stirring was continued for 1 h after which compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued at room temperature for 30 minndash;1 h.Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath. Scheme 3 N N b Scheme 3 a C Me O O H O N N C Me O O H O J. Chem. Soc. Perkin Trans. 1 1997 1489 The precipitate thus formed was filtered off and washed with water. Method B. The active methylene compound 2 (0.03 mol) was added dropwise to a mixture of sodium hydride (55ndash;60 sodium hydride in oil; 0.03 mol) in anhydrous benzene (90 ml) and the thick white slurry thus formed was stirred at room temperature for 1 h. Compound 1b (1.4 g 0.01 mol) was added to the mixture and stirring continued for 1ndash;2.5 h. Water and diethyl ether were added to the reaction mixture and the aqueous layer was separated and acidified with 10 hydrochloric acid in an icendash;water bath.The precipitate thus formed was filtered off and washed with water. 1-Acetyl-3-methoxycarbonyl-4-hydroxy-1,8-naphthyridin-2- one 3. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tert-butyl alcohol 100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 3 (2.13 g 82) mp 175ndash;176 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) dimethyl malonate 2 (Y = CO2Me R = Me) (4 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 3 (1.23 g 48) mp 173ndash;175 8C (from CHCl3) (Found C 54.94; H 3.97; N 10.67. C12H10O5N2 requires C 54.96; H 3.84; N 10.68); dH(60 MHz; CDCl3; Me4Si) 2.70 (3 H s COCH3) 4.00 (3 H s CO2CH3) 7.50 (1 H pseudotriplet 6-H) 9.06 (1 H dd J5,6 7 J5,7 1 5-H) 9.33 (1 H dd J6,7 7 J5,7 1 7-H) and 15.56 (1 H br OH). 1-Acetyl-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-2-one 4. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (100 ml) was stirred for 30 min after which it was acidified with 10 hydrochloric acid to give a coloured precipitate.This was filtered off and washed with water to afford the product 4 (2.37 g 87) mp 155ndash;157 8C (from CHCl3). Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) diethyl malonate 2 (Y = CO2Et R = Et) (4.8 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h after which it was acidified with 10 hydrochloric acid to give a coloured precipitate. This was filtered off and washed with water to afford the product 4 (1.35 g 40) mp 157ndash;159 8C (from CHCl3) (Found C 56.70; H 4.46; N 10.25. C13H12O5N2 requires C 56.52; H 4.38; N 10.14); dH(300 MHz; CDCl3; Me4Si) 1.43 (3 H t J 7,CH2CH3) 2.68 (3 H s COCH3) 4.46 (2 H q J 7 CH2CH3) 7.48 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8.1 J5,7 1.6 5-H) 9.28 (1 H dd J6,7 6.5 J5,7 1.6 7-H) and 15.89 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 164.51 (CO ester) 163.09 (C-4) 162.22 (C-2) 153.91 (COCH3) 149.30 (C-8a) 144.68 (C-7) 132.05 (C-5) 122.49 (C- 4a) 116.22 (C-6) 109.77 (C-3) 62.03 (CH2CH3) 23.27 (COCH3) and 14.21 (CH2CH3).1,3-Diacetyl-4-hydroxy-1,8-naphthyridin-2-one 5. Following method A.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (2.3 g 0.02 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (2.6 g 0.02 mol) and potassium tert-butoxide (2.24 g 0.02 mol) in tertbutyl alcohol (130 ml) was stirred for 1 h. Compound 5 was obtained as a solid 1.88 g (62) when methyl acetoacetate was used as the active methylene compound and 1.53 g (50) when ethyl acetoacetate was used as the active methylene compound mp 170ndash;171 8C (from CHCl3).Following method B.mdash;The reaction mixture compound 1b (1.4 g 0.01 mol) methyl acetoacetate 2 (Y = COMe R = Me) (3.5 g 0.03 mol) or ethyl acetoacetate 2 (Y = COMe R = Et) (3.9 g 0.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene (100 ml) was stirred for 1 h. Compound 5 was obtained as a solid 2.04 g (67) when methyl acetoacetate was used as the active methylene compound and 1.64 g (54) when ethyl acetoacetate was used as the active methylene compound mp 167ndash;170 8C (from CHCl3) (Found C 58.01; H 4.07; N 11.38. C12H10O4N2 requires C 58.53; H 4.09; N 11.38); dH(300 MHz; CDCl3; Me4Si) 2.69 (6 H s COCH3 and NCOCH3) 7.50 (1 H pseudotriplet 6-H) 8.98 (1 H dd J5,6 7.5 J5,7 1.9 5-H) 9.26 (1 H dd J6,7 7.5 J5,7 1.9 7-H) and 15.75 (1 H br OH); dC(75 MHz; CDCl3; Me4Si) 198.81 (C-COCH3) 163.87 (C-4) 163.00 (C-2) 155.30 (N-COCH3) 149.18 (C-8a) 144.85 (C-7) 131.90 (C-5) 122.56 (C-4a) 116.37 (C-6) 115.04 (C-3) 31.87 (C-COCH3) and 23.91 (N-COCH3).Methyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 7. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 7 as a solid (1.57 g 65) mp 176ndash;178 8C (from EtOH) (Found C 55.18; H 4.36; N 15.87. C12H11O4N3 requires C 55.17; H 4.24; N 16.09); nmax(Nujol)/cm21 2210s (CN) 1720 and 1700s (CO ester keto form) and 1600s (C C ring stretching); dH(60 MHz; CDCl3; Me4Si) 2.80 (3 H s COCH3) 3.78 (3 H s CO2CH3) 7.08 (1 H dd J4,5 8 J5,6 5 5-H) 8.25ndash;8.48 (2 H m 4-H and 6-H) 9.30 (1 H br NH) and 12.76 (1 H br OH).Ethyl (2-acetylamino-3-pyridyl)hydroxymethylidenecyanoacetate 8. Following method A.mdash;The reaction mixture was stirred at room temperature for 1 h to give the C-acylation product 8 as a solid (1.80 g 71) mp 106ndash;108 8C (from CHCl3) (Found C 56.67; H 4.82; N 15.91. C13H13O4N3 requires C 56.72; H 4.76; N 15.27); nmax(Nujol)/cm21 3500m (OH) 2210w (CN) 1710w (CO ester keto form) 1670s (CO ester enol form) and 1600s (C=C ring stretching); dH(60 MHz; CDCl3; Me4Si) 1.36 (3 H t J 7 CH2CH3) 2.83 (3 H s COCH3) 4.26 (2 H q J 7 CH2CH3) 7.09 (1 H dd J4,5 8 J5,6 5 5-H) 8.28ndash;8.53 (2 H m 4-H and 6-H) 7.73 (1 H br NH) and 12.83 (1 H br OH). 1-Acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. The C-acylation compound 0.002 mol 7 (0.50 g) or 8 (0.55 g) dissolved in a small quantity of ethanol was added to a solution of sodium ethoxide in ethanol prepared from sodium (0.09 g 4 mmol) in absolute ethanol (10 ml) containing anhydrous benzene (10 ml).The reaction mixture was refluxed for 3 h and set aside overnight at room temperature. Water and diethyl ether were then added to the reaction mixture after which the aqueous layer was separated acidified with 10 hydrochloric acid and extracted with ethyl acetate and diethyl ether. The organic layers were combined dried (Na2SO4) and evaporated in vacuo. The resulting red solid was triturated with diethyl ether filtered off and washed with small amounts of diethyl ether to give the title compound 6 0.26 g (59) from 7 and 0.25 g (60) from 8 mp 213ndash;214 8C; nmax(Nujol)/cm21 2210w (CN) 1690m (CO stretching amide I) and 1610 (C C ring stretching); dH(60 MHz; CDCl3ndash;2H6DMSO; Me4Si) 2.76 (3 H s COCH3) 6.78 (1 H br OH) 7.73 (1 H pseudotriplet 6-H) 9.00 (1 H dd J5,6 8 J5,7 1 5-H) and 9.93 (1 H dd J6.7 8 J5,7 1 7-H).References 1 M. H. Sherlock W. C. T. Kaminski J. F. Lee S.-C. Wong W. Kreutner R. W. Bryant and A. McPhail J. Med. Chem. 1988 31 2108. 2 (a) T. Duelfer and D. Gala J. Labelled Compd. Radiopharm. 1991 29 651; (b) W. Kreutner J. Sherwood S. Sehring C. Rizzo R. W. Chapman M. I. Siegel and R. W. Egan J. Pharmacol. Exp. Ther. 1988 247 997; (c) D. J. Blythin H.-J. Shue E. Carlon J. Spitler and W. Kreutner Bioorg. Med. Chem. Lett. 1994 4 1327. 3 A. A. Santilli A. C. Scotese R. F. Bauer and S. C. Bell J. Med. Chem. 1987 30 2270. 4 T. Kuroda F. Suzuki T. Tamura K. Ohmori and H. Hosoe J. Med. Chem. 1992 35 1130.1490 J. Chem. Soc. Perkin Trans. 1 1997 5 (a) N. G. Ilback J. Fohlman S. Slorach and G. Friman J. Immunol. 1989 142 3225; (b) J. Bjork and D. Kleinau Agents Actions 1989 27 319; (c) S. R. Smith and M. I. Siegel PCT Int. Appl. WO 8607 537/1986 (Chem. Abstr. 1986 107 183 554d; 108 118 982y). 6 (a) T. Kazuhisa I. Masahiro O. Yoshinori A. Motonori N. Akira and I. Yasuo PCT Int. Appl. WO 9 606 843/1996 (Chem. Abstr. 1996 125 86 620); (b) J. C. Gill and B. W. Leslie PCT Int. Appl. WO 9 611 198/1996 (Chem. Abstr. 1996 125 114 579). 7 (a) H. Hayashi Y. Miwa S. Ichikawa N. Yoda I. Miki A. Ishii M. Kono T. Yasusawa and F. Suzuki J. Med. Chem. 1993 36 617; (b) S. Peroutka Trends Neurosci. 1988 11 496. 8 Jian-long Chen and W. Steglich J. Heterocycl. Chem. 1993 30 909. 9 B. D. Schober and T.Kappe J. Heterocycl. Chem. 1988 25 1231. 10 (a) A. Detsi J. Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Chem. Commun. 1996 1323; (b) A. Detsi V. Bardakos J. Markopoulos and O. Igglessi-Markopoulou J. Chem. Soc. Perkin Trans. 1 1996 2909. 11 E. Breitmaier Structure Elucidation by NMR in Organic Chemistry J. Wiley amp; Sons 1993. 12 A. Stempel and L. H. Sternbach US Patent 3 415 835/1968 (Chem. Abstr. 1969 57657u). Paper 6/08509A Received 19th December 1996 Accepted 24th January 1997 J. Chem. Soc. Perkin Trans. 1 1997 1487 Reactions of 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one with active methylene compounds a new eYcient route to 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones Vassiliki Delieza Anastasia Detsi Vassilios Bardakos and Olga Igglessi-Markopoulou * Laboratory of Organic Chemistry Department of Chemical Engineering National Technical University of Athens Zografou Campus 157 73 Athens Greece 3-Substituted 1,8-naphthyridine-2,4-diones compounds of very important pharmaceutical use have been synthesized using a new efficient route.The reaction of 2-methyl-4H-pyrido-2,3-d3,1oxazin-4-one 1b with active methylene compounds furnishes the 1-acetyl-3-substituted-4-hydroxy-1,8-naphthyridin-2-ones 3ndash;5 in good yields. In the case of cyanoacetic esters the intermediate C-acylation compounds 7 and 8 were isolated and subsequently cyclized to 1-acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. Spectral data and physical characteristics for all compounds are reported. 1,8-Naphthyridine-2,4-dione derivatives (X = N Fig. 1) substituted at position 3 form a class of fused ring heterocycles which present interesting pharmacological and biological properties.These compounds occur widely among natural products and have importance in medicine. A series of substituted 1,8- naphthyridin-2(1H)-ones are orally active potent inhibitors of allergic and non-allergic bronchospasm in animal models.1 Recent reports describe a class of 1-aryl-1,8-naphthyridinone derivatives as potent orally active inhibitors of the release of the leukotriene mediators of anaphylaxis in vitro and in vivo.2 Moreover 3-carboxy-1,8-naphthyridin-2-one derivatives showed potent gastric anti-secretory properties in rat models.3 Recently novel anti-inflammatory drugs having the 1,8- naphthyridine structure with a mode of action different from that of the classical acidic nonsteroidal anti-inflammatory drugs (NSAIDs) were designed and synthesized by Suzuki et al.4 Several immunomodulators such as roquinimex and Sch 12 223 (Fig.2) containing the 4-hydroxyquinolinone and 4-hydroxynaphthyridinone system have been reported.5 The 1,8-naphthyridine skeleton in Sch 12 223 is known to be a bioisostere of quinoline.4 1,8-Naphthyridine derivatives have proved to inhibit type IV phosphodiesterase and are therefore useful in the treatment of respiratory inflammatory systemic or local joint diseases inflammations accompanying organ transplantation diseases associated with urination and those involving tumour necrosis Fig. 1 X N X N Fig. 1 1 2 3 4 5 6 7 8 4a 8a OH Y O O Y O Fig. 2 Roquinimex (LS-2616) Fig. 2 Sch 12223 N N O OH Me Me Ph O N N O OH Ph factors and other cytokines.6a Numerous 1,8-naphthyridine derivatives are useful as modulators of cytokine synthesis immunomodulatory and anti-inflammatory agents.6b The importance of these fused ring heterocycles has encouraged the development of numerous routes for their preparation.The 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones have been prepared by a standard Dieckmann condensation using azaisatoic anhydride derivatives 4,7 or 2-aminonicotinic acid esters as starting material.1,2c,3,8 Alternatively 3-substituted 4- hydroxy-1,8-naphthyridin-2(1H)-ones have been synthesized by thermal condensation of 2-aminopyridines with malonic esters.9 However most of the above methods are less than convenient since they require several steps and vigorous conditions.As part of our program for the synthesis and evaluation of nitrogen heterocycles containing the lsquo;enolic b-dicarbonyl moietyrsquo; such as 3-substituted 4-hydroxypyrrolin-2-ones (tetramic acids) 10a we have recently described a new approach for the synthesis of 3-substituted 4-hydroxyquinolin-2(1H)-ones (X = CH Fig. 1).10b Our interest in 1,8-naphthyridinones arose from their gross similarity to quinolinones and our desire to prepare 3-substituted 4-hydroxy-1,8-naphthyridin-2(1H)-ones possessing the lsquo;enolic b-dicarbonyl moietyrsquo;. In the 3-substituted 4-hydroxyquinolin-2(1H)-one (X = CH) series we used the 2-methyl-3,1-benzoxazin-4-one 1a as starting material (Scheme 1). This compound was replaced by the 2- methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b in order to synthesize the corresponding 3-substituted 4-hydroxy-1,8- naphthyridin-2(1H)-ones.The new synthetic approach includes the C-acylation of an active methylene compound with an oxazinone the 2-methyl-4H-pyrido2,3-d3,1oxazin-4-one 1b. The intermediate 3a 4a or 5a,b (not isolated) undergoes an in situ intramolecular cyclization to a 3-substituted 4-hydroxy-1,8- Scheme 1 X N Y X N O a X=CH b X=N X=CH or N 1 CH3 O O OH 1488 J. Chem. Soc. Perkin Trans. 1 1997 naphthyridin-2(1H)-one (Scheme 2). In a typical C-acylationndash; cyclization the active methylene compound 2 (3 mol equiv.) was treated with potassium tert-butoxi