On the One Pot Syntheses of Chromeno [ 4 , 3-b ] pyridine-3-carboxylate and Chromeno [ 3 , 4c ] pyridine-3-carboxylate and Dihydropyridines

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.2][3][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 communication 7 that the previously reported compounds obtained by Sakurai 5 and himself 6 were incorrectly formulated.This author also described reactions between substituted salicylaldehydes (R 2 =MeO, R 3 = MeO, Cl) and aminocrotonate in acetic acid at room temperature for four days with yields of 22-36%.][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. 12Here we propose a facile synthesis of 7,8,9-substituted-1ethoxycarbonyl-2,4-dimethyl-5-oxo-5H-chromeno [4,3-b]  pyridines; 7,8,9-substituted-1-ethoxycarbonyl-2,4dimethyl-5-oxo-5H-chromeno [3,4-c]dihydropyridines and their respective pyridines in one easy step.Both, electroattracting 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.[14][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.
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 α 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 1 H NMR spectra for the compounds having R= 9-Cl (3k), R= 9-MeO (3i), R= 8-MeO (3g).Since, 1 H 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 13 C 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.

Synthesis of ethyl substituted-2,4-dimethyl-5-oxo-5Hchromeno[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] Synthesis of ethyl 7,8,9-substituted-2,4-dimethyl-5-oxo-5Hchromeno [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/H 2 O: 1/1 and oven dried at 50 ºC.

Table 1 .
Substitutions of synthesized chromenodihydropyridines and chromenopyridines

Table 2 .
Summary of reaction conditions for optimal yields A dark, viscous oily mixture of products is obtained when using aqueous ammonia solution instead of ammonium acetate.Increasing the time reaction does not improve the yields of the syntheses.Decomposition when heating over 60 ºC.Increasing the time reaction does not improve the yields of the syntheses.