On the one pot syntheses of chromeno[4,3-b]pyridine-3-carboxylate and chromeno[3,4-c]pyridine-3-carboxylate and dihydropyridines

ARTICLE

On the one pot syntheses of chromeno[4,3-b]pyridine-3-carboxylate and chromeno[3,4-c]pyridine-3-carboxylate and dihydropyridines

Patricio A. Navarrete-Encina^I,*; Ricardo Salazar^II; Christian Vega-Retter^I; Karina Pérez^I,II; Juan A. Squella^II; Luis J. Nuñez-Vergara^II

^ILaboratorio de Síntesis Orgánica y Fisicoquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Sergio Livingston P. 1007, 8380492 Santiago, Chile

^IILaboratorio de Bioelectroquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Sergio Livingston P. 1007, 8380492 Santiago, Chile

ABSTRACT

Substituted chromenos, dihydropyridines and pyridines have been important in the syntheses of compounds having interesting pharmacological properties. Therefore, we found of interest to synthesize chromenopyridines and chromenodihydropyridines (i.e., fused chromeno and dihydropyridine or pyridine rings) to further study their biological activity. Here, we propose one-pot syntheses for substituted ethyl-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylates, ethyl-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-3-carboxylates and their respective 1,4-dihydropyridines based on a modified Hantzsch pyridine synthesis using 2-hydroxyaryl aldehydes, with electron withdrawing and electron donating groups on the phenyl ring, as starting reactants. Sixteen compounds were synthesized by the described method and fully characterized. An average yield of 37% was obtained for the different derivatives.

Keywords: chromeno[4,3-c]pyridine, chromeno[3,4-c]dihydropyridine, chromenopyridine synthesis, chromenopyridine cyclization

RESUMO

Os cromenos, dihidropiridinas e piridinas substituídos têm-se revelado importantes na síntese de compostos com propriedades farmacológicas interessantes. Consequentemente, achamos importante a síntese de cromenopiridinas e cromenodihidropiridinas (ou seja, anéis fundidos do cromeno e da dihidropiridina ou da piridina) de forma a pesquisar a sua atividade biológica. Neste estudo, propomos a síntese "one-pot " para 2,4-dimetil-5-oxo-5H-cromeno[4,3-b]piridina-3-carboxilatos de etilo, 2,4-dimetil-5-oxo-5H-cromeno[3,4-c]piridina-3-carboxilatos de etilo substituídos e as suas respectivas 1,4 dihidropiridinas, baseada numa síntese modificada da piridina de Hantzsch usando 2-hidroxiaril aldeído, com os grupos que retiram e doam elétrons no anel fenil, como reagentes iniciais. Dezesseis compostos foram sintetizados pelo método descrito e completamente caracterizados. Um rendimento médio de 37% foi obtido para os diferentes derivados.

Introduction

The chromene moiety appears as an important structural component in both biologically active and natural compounds. Chromene fragments occur in alkaloids, flavonoids, tocopherols and anthocyanins. Moreover, functionally substituted chromenes have played increasing roles in synthetic approaches to promising compounds in the field of medicinal chemistry.^1-4 Only few synthetic approaches to chromenopyridines employing different reaction conditions and using salicylaldehyde have been previously described in literature by Sakurai et al.⁵ and O'Callaghan et al.^6,7 Sakurai et al.⁵ obtained two benzopyrano[3,4-c]pyridines in 7-10% yields working with salicylaldehydes, ethyl acetoacetic ester and ammonium acetate in ethanol. The main product of the reaction was a tetrahydropyridine derivative. They did not obtain dihydropyridines in any case.

O'Callaghan states in the last communication⁷ that the previously reported compounds obtained by Sakurai⁵ and himself⁶ were incorrectly formulated. This author also described reactions between substituted salicylaldehydes (R²=MeO, R³= MeO, Cl) and aminocrotonate in acetic acid at room temperature for four days with yields of 22-36%. The reaction of aromatic aldehydes and α,β-unsaturated carbonyl compounds with ethyl-3-aminocrotonate generally gives dihydropyridines and pyridines.^8-10 The condensation of salicylaldehyde derivatives with active methylene compounds in the presence of ammonium acetate, pyridine, or piperidine usually leads to coumarins,¹¹ or coumarin imines, which can be hydrolyzed to coumarins.¹² Here we propose a facile synthesis of 7,8,9-substituted-1-ethoxycarbonyl-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridines; 7,8,9-substituted-1-ethoxycarbonyl-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]dihydropyridines and their respective pyridines in one easy step. Both, electro-attracting and donating groups were tested as substituents on the phenyl ring of the molecules. The reaction may be applied to any aromatic aldehyde having a hydroxyl group at 2-position in the aromatic ring. The synthesized compounds are described in Table 1.

Results and Discussion

The key for the achievement of the products depends on the availability of an ortho-hydroxy group on the aromatic aldehyde. Reaction yields are comparable with total yields of previously described syntheses of chromenopyridines, starting either from an aldehyde or by using other synthetic strategies.^12-15

The end product of the reaction is strongly dependent on the conditions of temperature, reactants and solvents used. In Table 2 are summarized the optimal reaction conditions for obtaining either [3,4-c]dihydropyridines or [4,3-b]pyridines moieties. We obtained the best results working always in anhydrous medium for obtaining both types of regioisomers.

Concerning the reactants and solvent used, if the reaction is carried out in acetic acid/absolute ethanol (1/1), aldehyde, ethyl acetoacetate and ammonium salts, the main product corresponds to the chromeno[3,4-c]dihydropyridine as it is shown in the synthesis of the non-substituted derivative chromeno[3,4-c]dihydropyridine (1a) and 9-bromo-chromeno[3,4-c]dihydropyridine (1b). These compounds can be easily oxidized to the corresponding chromeno[3,4-c]pyridines (2a-b). If the reaction is carried out in acetic acid, aldehyde and ethylaminocrotonate, the main products are the chromeno[4,3-b]pyridines (3a-l) (see Figure1 and Table 1).

It seems that working in pure glacial acetic acid favours the 1,4-amino addition to the coumarin moiety shown in step 3 (Figure 3) on the proposed mechanism of formation of the [4,3-b] compounds. Working with AcOH/EtOH (1:1) decreases the acidity of the medium favouring the 1,4 addition of the C_a on the aminocrotonate to the coumarin system (Figure 2, step 3).

A proposal for key intermediates leading from the aromatic aldehydes to chromenopyridines could be as follows (Scheme 1).

In a previous paper of O'Callaghan,⁷ it was stated that heating the reactants in acetic acid solution destroys any 1,2-dihydropyridines which may be formed leaving 1,4-dihydropyridines as the only stable, isolable product. Our investigation shows, however, that heating a mixture of 2-hydroxy aromatic aldehydes with 3-aminocrotonates in anhydrous acetic acid yield the chromeno[4,3-b]pyridines instead. We tested the reaction with twelve 2-hydroxyaryl aldehydes with both electron donating and electron withdrawing groups as substituents in the aldehydes. The resulting chromenopyridines are shown in Table 1. It includes three previously synthesized chromeno pyridines by O`Callaghan himself and we compare their IR and ¹H NMR spectra for the compounds having R= 9-Cl (3k), R= 9-MeO (3i), R= 8-MeO (3g). Since, ¹H NMR and FT-IR spectra of synthesized compounds did not permit the discrimination between chromeno[4,3-b]pyridines and chromeno[3,4-c]pyridines derivatives, HMQC, HMBC and ¹³C NMR were applied to differentiate them. The HMQC spectrum permits us to correlate the protons with their respective carbon atoms. In the HMBC spectrum, the protons at carbons A and F (Figure 4), are coupled long range with the common quaternary carbons, C and D. This coupling can only be observed in the chromeno[4,3-b]pyridine compounds ( II ) and therefore it is possible to differentiate between regioisomers I and II.

Experimental

Synthesis of ethyl substituted-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c] dihydropyridine -3-carboxylates: general procedure

To a mixture of 5 mmol of aldehyde and 15 mmol of ethyl acetoacetate in ethanol/acetic acid (1/1, 120 mL) is added an excess of ammonium acetate. The reaction mixture is refluxed under nitrogen during 8 h. The crude product is extracted with dichloromethane and purified using column chromatography (stationary phase: alumina, mobile phase:dichloromethane/ethyl acetate: 4/1).

Ethyl 2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]dihydropyridine-1-carboxylate (1a)

Physical Characterization: yield 34%, mp 275-277 ºC, IR (KBr) ν_max/cm^-1: 3301.8, 1695.5, 1621.0, 1500.8, 1383.3, 1307.2, 1224.5, 1194.6, 1128.6, 1078.9, 1022.1, 762.9, 473.8. ¹H NMR (300 MHz, DMSO-d₆): 1.1 (t, 3H, CH₂-CH₃, J 7.2), 2.0 (s, 3H, -CH₃), 2.2 (s, 3H, -CH₃), 4.1 (m, 2H, -CH₂-, J 7.2), 4.7 (s, 1H, 10b-H), 6.9 (m, 4H, Ar-H), 8.8 (s, 1H, -NH). ¹³C NMR (75 MHz, DMSO-d₆) δ 14.54, 17.10, 18.76, 33.68, 59.63, 96.32, 97.48, 116.88, 124.14, 124.36, 127.62, 132.52, 146.08, 147.96, 150.28, 165.01, 167.57. Anal. Calc. for C₁₇H₁₇NO₄: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.10; H, 5.74; N, 4.69%.

Ethyl 9-Bromo-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]dihydropyridine-1-carboxylate (1b)

Physical Characterization: yield 14%, mp 116-119 ºC, IR (KBr) ν_max/cm^-1: 3321.2, 1698.7, 1497.0, 1304.2, 1226.1, 1192.8, 1074.6. ¹H NMR (300 MHz, DMSO-d₆): 1.1 (t, 3H, -CH₃, J 7.24), 2.0 (s, 3H, -CH₃), 2.2 (s, 3H, -CH₃), 4.0 (c, 2H, -CH₂-, J 7.24), 4.7 (s, 1H, 10b-H), 7.0 (m, 3H, Ar-H), 9.0 (s, 1H, -NH). ¹³C NMR (75 MHz, DMSO-d₆) δ 13.98, 16.31, 18.37, 33.34, 79.28, 78.99, 94.89, 96.34, 115.56, 118.63, 126.75, 129.79, 134.38, 146.14, 148.28, 149.04, 166.83. Anal. Calc. for C₁₇H₁₆NO₄Br: C, 53.99; H, 4.26; N, 3.70. Found: C, 54.11; H, 4.25; N, 3.69%.

Synthesis of ethyl substituted-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-3-carboxylates: general procedure

Chromium oxide (0.2 mg) in water (0.1 mL) is added to a solution of the dihydropyridine 1 (0.13 mmol) in acetic acid (1 mL). The mixture is stirred at room temperature for about 1 h. An excess of concentrated ammonium solution is added. The precipitate is collected and recrystallized from methanol.

Ethyl 2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-1-carboxylate (2a)

Physical Characterization: yield 66.3%, m.p 137-140 ºC, IR (KBr) ν_max/cm^-1: 3425.4, 1742.8, 1608.4, 1550.5, 1443.1, 1287.1, 1234.8, 1192.3, 1087,9, 1018.2, 768.4. ¹H NMR (300 MHz, CDCl₃) 1.4 (t, 3H, -CH₃, J 7.2), 2.6 (s, 3H, -CH₃), 3.1 (s, 3H, -CH₃), 4.4 (c, 2H, -CH₂-, J 7.24), 7.6 (m, 4H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.84, 22.94, 27.38, 62.43, 112.91, 115.49, 118.04, 121.80, 124.36, 125.76, 132.76, 139.77, 152.63, 159.16, 159.40, 164.55, 169.44. Anal. Calc. for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.50; H, 5.08; N, 4.69%.

Ethyl 9-Bromo-2,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-1-carboxylate (2b)

Physical Characterization: yield 50.1%, m.p 125-128 ºC, IR (KBr) ν_max/cm^-1: 3390.0, 1730.5, 1607.2, 1570.5, 1453.3, 1290.0, 1180.3, 1056,5, 1015.0. ¹H NMR (300 MHz, CDCl₃) 1.5 (t, 3H, -CH₃, J 7.2), 2.7 (s, 3H, -CH₃), 3.1 (s, 3H, -CH₃), 4.5 (c, 2H,-CH₂-, J 7.24), 7.8 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.89, 23.01, 27.58, 62.68, 112.96, 115.69, 118.54, 122.03, 124.41, 124.65, 134.76, 140.27, 153.01, 159.98, 160.01, 164.97, 170.11. Anal. Calc. for C₁₇H₁₄NO₄Br: C, 54.28; H, 3.75; N, 3.72. Found: C, 54.31; H, 3.74; N, 3.73%.

Synthesis of ethyl 7,8,9-substituted-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylates: general procedure

14.5 mmol of the respective aldehyde were weighed and dissolved in 8 mL of glacial acetic acid. This solution is added drop to drop over a mixture previously prepared of 3.74 g (29 mmol) of ethyl-3-aminocrotonate in 4 mL of glacial acetic acid. The mixture is warmed, not exceeding a temperature of 60 ºC, for 5 h with constant stirring. The formation of a precipitate was observed. The solution is left at room temperature during 12 h to assure that all the product precipitates. The precipitate is filtered off and recrystallized in ethanol. The pale yellow coloured precipitate is filtered, washed with EtOH/H₂O: 1/1 and oven dried at 50 ºC.

Ethyl 2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3a)

Physical Characterization: yield 54%, mp 114-117 ºC, IR (KBr) ν_max/cm^-1: 3444.2, 3030, 1731.7, 1448.3, 762.90. ¹H NMR (300 MHz, acetone-d₆) 1.3 (t, 3H, -CH₃, J 7.24), 2.5 (s, 3H, -CH₃), 2.6 (s, 3H, -CH₃), 4.37 (c, 2H, -CH₂-, J 7.24), 7.81 (m, 4H, Ar-H). ¹³C NMR (75 MHz, acetone-d₆) δ 13.80, 18.83, 23.23, 62.08, 114.35, 116.69, 119.25, 124.72, 125.52, 132.79, 149.65, 152.26, 153.04, 159.56, 159.80, 160.33, 167.70. Anal. Calc. for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.48; H, 5.10; N, 4.70%.

Ethyl 9-bromo-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3b)

Physical Characterization: yield 40%, mp 178-180 ºC, IR (KBr) ν_max/cm^-1: 3435.8, 3071.4, 2987.2, 1735.6, 1726, 1594.8, 1565.3, 1551.1, 1443.8, 1382.1, 1281.2, 1225.2, 1191.2, 1018.9, 831.1. ¹H NMR (300 MHz, CDCl₃-d₁) 1.37 (t, 3H, -CH₃, J 7.13), 2.62 (s, 3H, -CH₃), 2.73 (s, 3H, -CH₃), 4.42 (q, 2H, -CH₂-, J 7.15), 7.15 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃-d₁) δ 13.2, 18.3, 22.7, 61.1, 112.8, 116.5, 117.3, 119.5, 127, 131.2, 134, 148.9, 149.9, 150.4, 158.2, 159.8, 168.5. Anal. Calc. for C₁₇H₁₄BrNO₄: C, 54.27; H, 3.75; N, 3.72. Found: C, 53.20; H, 3.76; N, 3.31%.

Ethyl 8-hydroxy-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3c)

Physical Characterization: yield 40%, mp 195 ºC, IR (KBr) ν_max/cm^-1: 3330.4, 2998.7, 2984.3, 2936.1, 2917.7, 1724.0, 1699.0, 1629.5, 1565.9, 1441.5, 1241.9. ¹H NMR (300 MHz, DMSO-d₆) 1.35 (t, 3H, -CH₃, J 7,29), 2.5 (s, 3H, -CH₃), 2.6 (s, 3H, -CH₃), 4.4 (q, 2H, -CH₂-, J 7.29), 7.5 (m, 3H, Ar-H), 10.54 (s, 1H, -OH). ¹³C NMR (75 MHz, DMSO-d₆) δ 12.9, 17.9, 22.4, 60.8, 100.1, 109.3, 110.8, 112.3, 125.4, 128.8, 147.9, 151.0, 152.7, 158.6, 160.7, 166.4, 166.9. Anal. Calc. for C₁₇H₁₅NO₅: C, 65.16; H, 4.83; N, 4.47. Found: C, 64.67; H, 4.96; N, 4.84%.

Ethyl 9-hydroxy-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3d)

Physical Characterization: yield 35%, mp 247-249 ºC, IR (KBr) ν_max/cm^-1: 3253.3, 3073.0, 2984.3, 2936.1, 1726.0, 1686.4, 1612.2, 1554.3, 1463.7, 1400.1, 1364.4, 1344.1, 1231.3, 1187.9, 1102.1, 1027.9, 819.6, 619.0. ¹H NMR (300 MHz, DMSO-d₆) 1.35 (t, 3H, -CH₃, J 7.29), 2.55 (s, 3H, -CH₃), 2.62 (s, 3H, -CH₃), 4.43 (q, 2H, -CH₂-, J 7.29), 7.4 (m, 3H, Ar-H), 9.7 (s, 1H, -OH). ¹³C NMR (75 MHz, DMSO-d₆) δ 14.34, 19.36, 23.77, 62.34, 109.49, 114.06, 117.8, 119.38, 121.00, 131.45, 145.84, 149.34, 151.88, 154.48, 159.82, 167.70, 168.46. Anal. Calc. for C₁₇H₁₅NO₅: C, 65.16; H, 4.83; N, 4.47. Found: C, 63.86; H, 4.89; N, 4.56%.

Ethyl 7-methyl-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3e)

Physical Characterization: yield 29%, mp 114-116 ºC, IR (KBr) ν_max/cm^-1: 3030, 2962, 1722.9, 1550, 1226.6, 779.9. ¹H NMR (300 MHz, CDCl₃) 1.44 (t, 3H, -CH3), 2.469 (s, 3H, -CH₃), 2.670 (s, 3H, -CH₃), 2.79 (s, 3H, -CH₃), 4.499 (c, 2H, -CH₂-), 7.67 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.70, 15.11, 18.91, 20.48, 23.29, 61.51, 113.02, 118.30, 124.64, 124.88, 131.06, 133.08, 149.37, 150.23, 151.86, 159.74, 159.86, 167.58. Anal. Calc. for C₁₈H₁₇O₄: C, 69.44; H, 5.50; N, 4.50; O, 20.56. Found: C, 68.47; H, 6.11; N, 4.16%.

Ethyl 7-nitro-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3f)

Physical Characterization: yield 28%, mp 184-185 ºC, IR (KBr) n_max/cm^-1: 3030, 2962, 1743.6, 1564.4, 1466.2, 1285.6, 798.4. ¹H NMR (300 MHz, CDCl₃) 1.38 (t, 3H, -CH₃), 2.63 (s, 3H, -CH₃), 2.73 (s, 3H, -CH₃), 4.45 (c, 2H, -CH₂-), 7.39 (t, 1H, Ar-H), 8.06 (d, 1H, Ar-H), 8.86 (d, 1H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.12, 17.37, 18.24, 22.75, 57.38, 61.28, 112.79, 120.19, 122.72, 126.77, 129.66, 131.77, 144.22, 149.24, 149.66, 160.33, 166.49. Anal. Calc. for C₁₇H₁₄N2O6: C, 59.65; H, 4.12; N, 8.18; O, 28.04. Found: C, 59.23; H, 4.25; N, 8.03%.

Ethyl 8-methoxy-2,4-dimethyl-5-oxo-5H-chromeno [4,3-b]pyridine-3-carboxylate (3g)

Physical Characterization: yield 40%, mp 137-138 ºC, IR (KBr) ν_max/cm^-1: 3030, 2962, 1722, 1442.9, 1342.0, 799.2. ¹H NMR (300 MHz, CDCl₃) 1.44 (t, 3H, -CH₃), 2.64 (s, 3H, -CH₃), 2.76 (s, 3H, -CH₃), 3.89 (s, 3H, -CH₃), 4.49 (c, 2H, -CH₂-), 7.37 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.18, 18.37, 22.78, 54.72, 60.96, 99.25, 111.14, 111.20, 111.61, 125.60, 129.65, 148.85, 151.51, 153.01, 159.54, 159.88, 162.12, 167.21. Anal. Calc. for C₁₈H₁₇NO₅: C, 66.05; H, 5.23; N, 4.28. Found: C, 64.59; H, 5.39; N, 4.21%.

Ethyl 9-methyl-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3h)

Physical Characterization: yield 37%, mp 114-116 ºC, IR (KBr) ν_max/cm^-1: 3030, 2962, 1724.8, 1569.8, 809.4. ¹H NMR (300 MHz, CDCl₃) 1.44 (t, 3H; -CH₃), 2.44 (s, 3H, -CH₃), 2.66 (s, 3H, -CH₃), 2.77 (s, 3H, -CH₃), 4.49 (c, 2H, -CH₂-), 7.59 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.70, 18.91, 20.48, 23.23, 61.51, 113.25, 115.83, 118.07, 124.64, 131.06, 132.80, 133.72, 149.37, 150.23, 151.86, 159.74, 159.86, 167.58. Anal. Calc. for C₁₈H₁₇O₄: C, 69.44; H, 5.50; N, 4.50; O, 20.56. Found: C, 68.47; H, 6.11; N, 4.16%.

Ethyl 9-methoxy-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3i)

Physical Characterization: yield 36%, mp 170-171 °C, IR (KBr) ν_max/cm^-1: 3423, 3085.6, 2994.3, 1722.1, 1609, 1568.5, 1552.4, 1495.9, 1281.2, 1255.4, 1222, 1189.9, 1137.2, 1096.7, 1020.8, 819.6. ¹H NMR (300 MHz, CDCl₃-d₁) 1.46 (t, 3H, -CH₃, J 7.01), 2.70 (s, 3H, -CH₃), 2.81 (s, 3H, -CH₃), 3.85 (s, 3H, -OCH₃), 4.5 (q, 2H, -CH₂-, J 7.14), 7.49 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃-d₁) δ 13.70, 18.95, 23.26, 55.43, 61.56, 106.47, 113.34, 117.28, 118.98, 120.21, 131.28, 146.59, 149.49, 151.70, 155.92, 159.80, 159.90, 167.61. Anal. Calc. for C₁₈H₁₇NO₅: C, 66.05; H, 5.23; N, 4.28. Found: C, 64.42; H, 5.58; N, 3.81%.

Ethyl 9-nitro-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3j)

Physical Characterization: yield 32%, mp 209-210 ºC, IR (KBr) ν_max/cm^-1: 3083.2, 2998,6, 1749.2, 1731.5, 1602.5, 1560.5, 1531.1, 1343.2, 1227.1, 1189.7. ¹H NMR (300 MHz, CDCl₃) 1.44 (t, 3H, -CH₃), 2.67 (s, 3H, -CH₃), 2.78 (s, 3H, -CH₃), 4.49 (c, 2H, -CH₂-), 7.68 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.7, 18.79, 23.29, 61.84, 113.56, 117.46, 119.30, 121.59, 126.53, 132.45, 144.12, 149.76, 150.15, 155.54, 158.23, 161.10, 167.02. Anal. Calc. for C₁₇H₁₄N₂O₆: C, 59.65; H, 4.12; N, 8.18. Found: C, 60.98; H, 4.04; N, 7.99%.

Ethyl 9-chloro-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3k)

Physical Characterization: yield 42%, mp 181-184 ºC, IR (KBr) ν_max/cm^-1: 3030, 2962, 1598.4, 1446.1, 1743.5, 833.29. ¹H NMR (300 MHz, CDCl₃) 1.45 (t, 3H, -CH₃), 2.67 (s, 3H, -CH₃), 2.78 (s, 3H, -CH₃), 4.48 (q, 2H, -CH₂-), 7.95 (m, 3H, Ar-H). ¹³C NMR (75 MHz, CDCl₃) δ 13.70, 18.85, 23.23, 61.66, 113.44, 117.63, 119.80, 124.61, 124.98, 129.72, 131.80, 149.56, 150.51, 150.69, 159.07, 160.35, 167.31. Anal. Calc. for C₁₇H₁₄NO₄Cl: C, 61.55; H, 4.25; N, 4.22; Cl, 10.69; O, 19.29. Found: C, 64.67; H, 4.96; N, 4.84%.

Ethyl 7-hydroxy-2,4-dimethyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (3l)

Physical Characterization: yield 30%, mp 205-207 ºC, IR (KBr) ν_max/cm^-1: 3253.3, 3068.1, 2980.47, 2934.4, 1725.0, 1698.0, 1620.8, 1564.0, 1551.4, 1428.0, 1366.32, 1294.9, 1228.4, 1187.9, 1042.3, 789.7. ¹H NMR (300 MHz, DMSO-d₆) 1,40 (t, 3H, -CH₃, J 7.29), 2,60 (s, 3H, -CH₃), 2.70 (s, 3H, -CH₃), 4,44 (q, 2H, -CH₂-, J 7.29), 7.5 (m, 3H, Ar-H), 10.2 (s, 1H, -OH). ¹³C NMR (75 MHz, DMSO-d₆) δ 14.3, 19.5, 23.8, 62.4, 114.2, 115.1, 119.0, 119.9, 124.7, 131.4, 141.5, 145.3, 149.3, 152.4, 159.5, 159.9, 167.7. Anal. Calc. for C₁₇H₁₅NO₅: C, 65.16; H, 4.83; N, 4.47. Found: C, 64.67; H, 4.92; N, 4.71%.

Conclusions

We did not obtain "normal " Hantszch products using 2-hydroxiphenyl aldehydes in any case and moreover a small modification of the reaction medium leads to chromeno[3,4-c]dihydropyridine or chromeno[4,3-b]pyridine derivatives with yields ranging between 15%-60% depending on the substituents on the phenyl ring of the 2-hydroxyphenylaldehydes.

Acknowledgments

This work has been partially supported by Grant Nº 1080132 from FONDECYT.

Received: March 5, 2009

Web Release Date: November 26, 2009

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Publication Dates

• Publication in this collection
  30 Apr 2010
• Date of issue
  2010

History

• Received
  05 Mar 2009
• Accepted
  26 Nov 2009