Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N′-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.

Among the quinazoline and thienopyrimidine diones described in the literature, most of the compounds contain a substituent in position 3. The biological significance causes the emergence of a number of methods for the synthesis of 3-substituted quinazoline-2,4diones, including (i) the treatment of 2-aminobenzamides with phosgene, (ii) the reaction of isatoic anhydride with amines or isocyanates, (iii) the condensation of 2-halobenzoates with Scheme 1. Methods for synthesis of substituted quinazolin-2,4-diones.
The access to 3-substituted thienopyrimidine-2,4-diones is another significant point that does not have a convenient and general synthetic solution. In the literature, only two methods for the preparation of these compounds are described. One of them is a nucleophilic attack of an aminothiophene derivative on an isocyanate in the presence of a catalytic amount of triethylamine in refluxing 1,4-dioxane followed by treatment of formed intermediates with NaOR in refluxing ROH [54][55][56]. The other is a reaction of aminothiophene carboxamides with 2,2,6-trimethyl-4H-1,3-dioxin-4-one in xylene followed by formed enamino amides' fragmentation and cyclization [57].
Another significant goal is the introduction of the pyridyl moiety into organic molecules. In addition to being important pharmacophore themselves, this heterocycle can improve pharmacokinetic properties such as aqueous solubility and permeability through biological membranes. Therefore, it is of considerable interest to find convenient access to quinazolin-2,4-diones substituted in position 3 with pyridyl moiety. Unfortunately, a general synthetic method for obtaining a wide range of substituted 3-(pyridin-2-yl)quinazolin-2,4-diones is unknown hitherto. One of the best synthetic approaches to these compounds is a copper-catalyzed domino C-C bond cleavage of 2,3-unsubstituted indole/indolines/oxindoles through oxidation followed by insertion of 2-aminopyridines [58]. However, this method utilizes pyridine-2-amines, which are characterized by insufficient diversity and a rather high cost of commercially available compounds.
At present, our research is focused on the development of simple methods for introducing pyridin-2-yl and quinolin-2-yl fragments into organic and organometallic Scheme 1. Methods for synthesis of substituted quinazolin-2,4-diones.
The access to 3-substituted thienopyrimidine-2,4-diones is another significant point that does not have a convenient and general synthetic solution. In the literature, only two methods for the preparation of these compounds are described. One of them is a nucleophilic attack of an aminothiophene derivative on an isocyanate in the presence of a catalytic amount of triethylamine in refluxing 1,4-dioxane followed by treatment of formed intermediates with NaOR in refluxing ROH [54][55][56]. The other is a reaction of aminothiophene carboxamides with 2,2,6-trimethyl-4H-1,3-dioxin-4-one in xylene followed by formed enamino amides' fragmentation and cyclization [57].
Another significant goal is the introduction of the pyridyl moiety into organic molecules. In addition to being important pharmacophore themselves, this heterocycle can improve pharmacokinetic properties such as aqueous solubility and permeability through biological membranes. Therefore, it is of considerable interest to find convenient access to quinazolin-2,4-diones substituted in position 3 with pyridyl moiety. Unfortunately, a general synthetic method for obtaining a wide range of substituted 3-(pyridin-2-yl)quinazolin-2,4-diones is unknown hitherto. One of the best synthetic approaches to these compounds is a coppercatalyzed domino C-C bond cleavage of 2,3-unsubstituted indole/indolines/oxindoles through oxidation followed by insertion of 2-aminopyridines [58]. However, this method utilizes pyridine-2-amines, which are characterized by insufficient diversity and a rather high cost of commercially available compounds.

Results and Discussion
Recently, we described the reaction of N-pyridyl ureas with a broad spectrum of amines [59]. During this study, the reaction of 1,1-dimethyl-3-(4-methylpyridin-2-yl)urea (1a) with anthranilic acid ethyl ester 2a was carried out and unexpectedly quinazoline-2,4-dione 3a was identified as the main product (the isolated yield of 51% Product 3a was characterized by high-resolution mass spectrometry and 1 H and 13 C NMR spectroscopies. The structure of the compound was confirmed by single-crystal X-ray diffraction (XRD, Figure 1 and Table S1). We investigated the influence of the reaction conditions on the yield of 3a (Table 1). We have determined that increasing the reaction time and temperature does not affect the yield (Table 1, entries 1 and 2). We enlarged the excess of anthranilic acid ethyl ester 2a step by step in the reaction mixture and found that 5 equiv. of the one affords a higher yield (Table 1, entries 3-5). Then, we carried out the reaction under solvent-free conditions and the desired product 3a was obtained in a better yield (Table 1, entry 6). A further increase in the 2a excess reduced the yield of the product (Table 1, entry 7), so for the further experiments we used a 5-fold excess. Finally, we tested whether anthranilic acid could be used instead of its ester and found that the desired quinazoline-2,4-dione 3a was formed, albeit in a lower yield (Table 1, entry 8). Product 3a was characterized by high-resolution mass spectrometry and 1 H and 13 C NMR spectroscopies. The structure of the compound was confirmed by single-crystal X-ray diffraction (XRD, Figure 1 and Table S1). compounds based on the use of masked isocyanates-N,N-dialkyl-N′-(pyridine-2-yl)ureas [59][60][61][62][63][64]. These compounds are easily synthesized from the corresponding pyridines [65][66][67][68]. In this paper, we report a simple one-step protocol for the synthesis of 3-pyridyl-substituted quinazoline-and thienopyrimidine-2,4-diones from anthranilic or 2-aminothiophene-3-carboxylic acid esters that uses this approach. Taking into account the wide range of commercially available pyridines, the proposed method has potential in the design of pharmaceutically relevant fused heterocycles.

Results and Discussion
Recently, we described the reaction of N-pyridyl ureas with a broad spectrum of amines [59]. During this study, the reaction of 1,1-dimethyl-3-(4-methylpyridin-2-yl)urea (1a) with anthranilic acid ethyl ester 2a was carried out and unexpectedly quinazoline-2,4-dione 3a was identified as the main product (the isolated yield of 51%). The more detailed study showed that the initially formed ethyl 2-(3-(5-methylpyridin-2-yl)ureido)benzoate (4a) undergoes further cyclocondensation under the reaction conditions to afford quinazolin-2,4-dione 3a (Scheme 2). Product 3a was characterized by high-resolution mass spectrometry and 1 H and 13 C NMR spectroscopies. The structure of the compound was confirmed by single-crystal X-ray diffraction (XRD, Figure 1 and Table S1). We investigated the influence of the reaction conditions on the yield of 3a (Table 1). We have determined that increasing the reaction time and temperature does not affect the yield (Table 1, entries 1 and 2). We enlarged the excess of anthranilic acid ethyl ester 2a step by step in the reaction mixture and found that 5 equiv. of the one affords a higher yield (Table 1, entries 3-5). Then, we carried out the reaction under solvent-free conditions and the desired product 3a was obtained in a better yield (Table 1, entry 6). A further increase in the 2a excess reduced the yield of the product (Table 1, entry 7), so for the further experiments we used a 5-fold excess. Finally, we tested whether anthranilic acid could be used instead of its ester and found that the desired quinazoline-2,4-dione 3a was formed, albeit in a lower yield (Table 1, entry 8). We investigated the influence of the reaction conditions on the yield of 3a (Table 1). We have determined that increasing the reaction time and temperature does not affect the yield (Table 1, entries 1 and 2). We enlarged the excess of anthranilic acid ethyl ester 2a step by step in the reaction mixture and found that 5 equiv. of the one affords a higher yield (Table 1, entries 3-5). Then, we carried out the reaction under solvent-free conditions and the desired product 3a was obtained in a better yield (Table 1, entry 6). A further increase in the 2a excess reduced the yield of the product (Table 1, entry 7), so for the further experiments we used a 5-fold excess. Finally, we tested whether anthranilic acid could be used instead of its ester and found that the desired quinazoline-2,4-dione 3a was formed, albeit in a lower yield (Table 1,

entry 8).
After finding the optimal reaction conditions, we determined the range of possible substrates that can participate in the process. First, we studied various substituted (pyridin-2-yl)ureas 1 and showed that the reaction proceeds in all cases, but the reaction yields vary. This indicates the sensitivity of the reaction to electronic effects of substituents in the pyridine ring (Scheme 3), but the nature of this influence is ambiguous. It can be said that electron-donating groups in positions 4 and 5 of the pyridine ring have a positive effect on the yields of quinazoline-2,4-diones 3. The presence of two methyl groups at positions 3 and 5 of the pyridine ring (ortho and para with respect to the nitrogen atom of the ureide fragment entering into the cyclocondensation) provides the target product 3e with the highest yield (86%). It should be noted that quinazoline-2,4-dione 3c bearing 5-methylpyridyl moiety was obtained in a slightly lower yield (48%). After finding the optimal reaction conditions, we determined the range of possible substrates that can participate in the process. First, we studied various substituted (pyridin-2-yl)ureas 1 and showed that the reaction proceeds in all cases, but the reaction yields vary. This indicates the sensitivity of the reaction to electronic effects of substituents in the pyridine ring (Scheme 3), but the nature of this influence is ambiguous. It can be said that electron-donating groups in positions 4 and 5 of the pyridine ring have a positive effect on the yields of quinazoline-2,4-diones 3. The presence of two methyl groups at positions 3 and 5 of the pyridine ring (ortho and para with respect to the nitrogen atom of the ureide fragment entering into the cyclocondensation) provides the target product 3e with the highest yield (86%). It should be noted that quinazoline-2,4-dione 3c bearing 5-methylpyridyl moiety was obtained in a slightly lower yield (48%). The presence of electron-withdrawing groups in the heterocyclic ring also decreased the yield of products 3. Perhaps this is due to such substituents adversely affecting the cyclocondensation step. Particularly, in the case of the substrate containing a nitro-group at position 4 of the pyridine ring, the desired quinazoline-2,4-dione was formed in only 19% yield (according to 1 H NMR data for the reaction mixture), whereas the main product was the corresponding intermediate urea. Moreover, the presence of the electron-withdrawing cyano-group in position 5 (para with respect to the nitrogen atom of the ureide fragment) completely suppressed the cyclocondensation. In this case, urea 4b Scheme 3. Synthesis of quinazolin-2,4-diones substituted in the pyridine moiety.
The presence of electron-withdrawing groups in the heterocyclic ring also decreased the yield of products 3. Perhaps this is due to such substituents adversely affecting the cyclocondensation step. Particularly, in the case of the substrate containing a nitro-group at position 4 of the pyridine ring, the desired quinazoline-2,4-dione was formed in only 19% yield (according to 1 H NMR data for the reaction mixture), whereas the main product was the corresponding intermediate urea. Moreover, the presence of the electron-withdrawing cyano-group in position 5 (para with respect to the nitrogen atom of the ureide fragment) completely suppressed the cyclocondensation. In this case, urea 4b was isolated in 40% yield as the main product. The prolonged heating of 4b at 120 • C only led to its degradation to the 2-aminopyridine 5 and the starting anthranilic acid ethyl ester 2a (Scheme 4).  Substituents in position 6 of the starting N-pyridylureas 1 slightly reduced the yield of target quinazolin-2,4-diones 3 (Scheme 3). The reason for this is the steric hindrances, but their effect is not very significant. Therefore, using ureas bearing quinoline and isoquinoline moieties 1l-q as starting compounds, we synthesized 6 corresponding Substituents in position 6 of the starting N-pyridylureas 1 slightly reduced the yield of target quinazolin-2,4-diones 3 (Scheme 3). The reason for this is the steric hindrances, but their effect is not very significant. Therefore, using ureas bearing quinoline and isoquinoline moieties 1l-q as starting compounds, we synthesized 6 corresponding quinazolin-2,4diones (3l-q) in moderate to good yields (47-78%, Scheme 3).
Next, we checked the possibility of synthesizing quinazolin-2,4-diones bearing substituents in the quinazoline fragment via the developed procedure. For this goal, the scope of functionalized anthranilic esters was investigated. Reactions were carried out with 1.5 equiv. of esters 2b-j in DMF at 120 • C. We found that neither electron-donating nor electron-withdrawing substituents prevented the reaction and the corresponding quinazolin-2,4-diones (3r-x,z) were successfully obtained in 47-89% yields (Scheme 5). In addition, this method allows us to obtain N1-alkylsubstituted quinazolin-2,4-diones, however, with less yield. Particularly, the reaction between urea 1a and N-methyl anthranilic ester 2h provided target product 3y with 32% yield only. Presumably, such poor yield of 3y is caused by instability of N-alkyl-N-aryl urea (the proposed intermediate) in the reaction conditions and its side transformation into 1,3-bis(4-methylpyridin-2-yl)urea, which was also detected in the reaction mixture. This process was described in our previous work [59]. Substituents in position 6 of the starting N-pyridylureas 1 slightly reduced the yield of target quinazolin-2,4-diones 3 (Scheme 3). The reason for this is the steric hindrances, but their effect is not very significant. Therefore, using ureas bearing quinoline and isoquinoline moieties 1l-q as starting compounds, we synthesized 6 corresponding quinazolin-2,4-diones (3l-q) in moderate to good yields (47-78%, Scheme 3).
Next, we checked the possibility of synthesizing quinazolin-2,4-diones bearing substituents in the quinazoline fragment via the developed procedure. For this goal, the scope of functionalized anthranilic esters was investigated. Reactions were carried out with 1.5 equiv. of esters 2b-j in DMF at 120 °C. We found that neither electron-donating nor electron-withdrawing substituents prevented the reaction and the corresponding quinazolin-2,4-diones (3r-x,z) were successfully obtained in 47-89% yields (Scheme 5). In addition, this method allows us to obtain N1-alkylsubstituted quinazolin-2,4-diones, however, with less yield. Particularly, the reaction between urea 1a and N-methyl anthranilic ester 2h provided target product 3y with 32% yield only. Presumably, such poor yield of 3y is caused by instability of N-alkyl-N-aryl urea (the proposed intermediate) in the reaction conditions and its side transformation into 1,3-bis(4-methylpyridin-2-yl)urea, which was also detected in the reaction mixture. This process was described in our previous work [59]. To expand the reaction scope, we studied the reactivity 2-aminothiophene-3-carboxylates (products of the Gewald reaction) in this process. It turned out that when ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a) was used as a starting amine, the reaction stopped at the stage of the urea 7a formation and any traces of a desired thienopyrimidine-2,4-dione were not observed in the reaction mixture (Scheme 6). To expand the reaction scope, we studied the reactivity 2-aminothiophene-3-carboxylates (products of the Gewald reaction) in this process. It turned out that when ethyl 2-amino-4,5,6,7tetrahydrobenzo[b]thiophene-3-carboxylate (6a) was used as a starting amine, the reaction stopped at the stage of the urea 7a formation and any traces of a desired thienopyrimidine-2,4-dione were not observed in the reaction mixture (Scheme 6). Then, the conditions search for the implementation of the cyclocondensation was performed. Since the occurrence of similar reactions under basic conditions is described in the literature [50,69], we tested several bases and t-BuONa gave the best results. Having chosen the conditions for the cyclocondensation of the intermediate urea 7, we synthesized thienopyrimidine-2,4-diones 8a-f in the overall yield of 35-56% according to the two-stage one-pot procedure (Scheme 7). Then, the conditions search for the implementation of the cyclocondensation was performed. Since the occurrence of similar reactions under basic conditions is described in the literature [50,69], we tested several bases and t-BuONa gave the best results. Having chosen the conditions for the cyclocondensation of the intermediate urea 7, we synthesized thienopyrimidine-2,4-diones 8a-f in the overall yield of 35-56% according to the two-stage one-pot procedure (Scheme 7). Scheme 6. Coupling of ureas 1a with 2-aminothiophene-3-carboxylates 6a.
Then, the conditions search for the implementation of the cyclocondensation was performed. Since the occurrence of similar reactions under basic conditions is described in the literature [50,69], we tested several bases and t-BuONa gave the best results. Having chosen the conditions for the cyclocondensation of the intermediate urea 7, we synthesized thienopyrimidine-2,4-diones 8a-f in the overall yield of 35-56% according to the two-stage one-pot procedure (Scheme 7). Scheme 7. Two-stage one-pot synthesis of thienopyrimidine-2,4-diones 8a-f.

Scheme 8.
Gram-scale syntheses of 3a and 8a. To achieve these yields, a 100 mL flask has to be used.

General
The starting N-oxides, used to obtain the N-piridyl ureas, were synthesized according to the literature procedures [65,[70][71][72]. All other reagents and solvents were purchased and were used as is. Column chromatography was carried out with silica gel grade 60 (0.040-0.063 mm) 230-400. NMR spectra were recorded on Bruker Avance DPX 400 (400 MHz, 101 MHz, and 376 MHz for 1 H, 13 C, and 19 F, respectively) in DMSO-d6 or CDCl3. Chemical shifts are reported as parts per million (δ, ppm). The 1 H and 13 C spectra were calibrated using the residual signals of nondeuterated solvents as internal reference Then, the conditions search for the implementation of the cyclocondensation was performed. Since the occurrence of similar reactions under basic conditions is described in the literature [50,69], we tested several bases and t-BuONa gave the best results. Having chosen the conditions for the cyclocondensation of the intermediate urea 7, we synthesized thienopyrimidine-2,4-diones 8a-f in the overall yield of 35-56% according to the two-stage one-pot procedure (Scheme 7). Scheme 7. Two-stage one-pot synthesis of thienopyrimidine-2,4-diones 8a-f.

Scheme 8.
Gram-scale syntheses of 3a and 8a. To achieve these yields, a 100 mL flask has to be used.

General
The starting N-oxides, used to obtain the N-piridyl ureas, were synthesized according to the literature procedures [65,[70][71][72]. All other reagents and solvents were purchased and were used as is. Column chromatography was carried out with silica gel grade 60 (0.040-0.063 mm) 230-400. NMR spectra were recorded on Bruker Avance DPX 400 (400 MHz, 101 MHz, and 376 MHz for 1 H, 13 C, and 19 F, respectively) in DMSO-d6 or CDCl3. Chemical shifts are reported as parts per million (δ, ppm). The 1 H and 13 C spectra were calibrated using the residual signals of nondeuterated solvents as internal reference Scheme 8. Gram-scale syntheses of 3a and 8a. To achieve these yields, a 100 mL flask has to be used.

General
The starting N-oxides, used to obtain the N-piridyl ureas, were synthesized according to the literature procedures [65,[70][71][72]. All other reagents and solvents were purchased and were used as is. Column chromatography was carried out with silica gel grade 60 (0.040-0.063 mm) 230-400. NMR spectra were recorded on Bruker Avance DPX 400 (400 MHz, 101 MHz, and 376 MHz for 1 H, 13 C, and 19 F, respectively) in DMSO-d 6 or CDCl 3 . Chemical shifts are reported as parts per million (δ, ppm). The 1 H and 13 C spectra were calibrated using the residual signals of nondeuterated solvents as internal reference (2.50 ppm for residual 1 H and 39.50 ppm for 13 C in DMSO-d 6 , 7.26 ppm for residual 1 H and 77.16 ppm for 13 C in CDCl 3 ). 19 F NMR spectra were referenced through the solvent lock (2H) signal according to IUPAC recommended secondary referencing method and the manufacturer's protocols and the chemical shifts are reported relative to CFCl 3 (δ 0.0 ppm). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants, J, are reported in Hertz (Hz). Melting points were determined in open capillary tubes on Electrothermal IA 9300 series digital melting point apparatus. High-resolution mass spectra (HRMS) were measured on Bruker Maxis HRMS-ESI-qTOF (ESI ionization).
Singe crystal for X-ray studying was obtained by slow evaporation of DMSO solution of quinazoline-2,4,-dione 3a at RT in air. X-ray diffraction data were collected via Rigaku XtaLAB Synergy-S diffractometer using CuKα (λ = 0.154184 nm) radiation. The structure was solved with the ShelXT [73] structure solution program using intrinsic phasing and refined with the ShelXL [74] refinement program incorporated in the OLEX2 program package [75] using least squares minimization. Empirical absorption correction was applied in the CrysAlisPro [76] program complex using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Supplementary crystallographic data for this paper have been deposited at Cambridge Crystallographic Data Centre and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (CCDC number 2249286) (accessed on 28 March 2023).
Synthesis of methyl 6-(3,3-dimethylureido)picolinate 1h. A mixture of N-oxide (1 mmol), dimethylcyanamide (1.5 mmol), and acetonitrile (2 mL, 20 mmol) was stirred at RT for 2 min, and then methanesulfonic acid (1.5 mmol) was added dropwise over 3 min. Then, the reaction mixture was gently heated to 60 • C and stirred for 3 h, cooled to RT, diluted with a saturated aq. Na 2 CO 3 (2 mL) and aq. NaCl solution (5 mL) and extracted with ethyl acetate (4×15 mL). Combined organic fractions were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in a rotary evaporator. The crude product was subjected to column chromatography on silica gel (EtOAc/hexane) to give target urea 1h in 40% yield Synthesis of ureas 1n-p. A mixture of substituted quinoline N-oxide (1 mmol), dimethylcyanamide (2 mmol), and acetonitrile (0.5 mL, 5 mmol) was stirred at RT for 2 min, and then methanesulfonic acid (1.1 mmol) was added dropwise over 3 min. Then, the reaction mixture was gently heated to 60 • C and stirred for 2 h, cooled, and diluted with a saturated aq. Na 2 CO 3 (2 mL) and distilled water (5 mL). The precipitate formed was filtered off, washed with diethyl ether (10 mL) to give compounds 1n-p.  13

Synthesis of Quinazoline-2,4-Diones 3
General procedure A. Urea 1 (0.2 mmol) and ethyl anthranilate 2 (1 mmol) were placed in a vial and the resulting mixture was stirred at 120 • C for 20 h. The reaction mixture was cooled to RT, treated with diethyl ether (5 mL), and the precipitate was separated, then the precipitate was washed with diethyl ether to give compounds 3a-q.

6-Methyl-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H
8a. Urea 1a (5.6 mmol, 1 g), ester 6a (8.4 mmol, 1.89 g), and DMF (4 mL) were placed in a 100 mL round-bottom flask, the resulting mixture was stirred at 120 • C for 20 h. Then, the reaction mixture was cooled to RT and sodium tert-butoxide (5.6 mmol, 0.54 g) and DMF (17 mL) were added. The reaction mixture was stirred for another 2 h at 120 • C. After completion of the reaction, the reaction mixture was cooled to RT, and DMF was removed by a rotary evaporator. The residue was dissolved in isopropyl alcohol (150 mL) and the resultant solution was diluted with water (350 mL). The precipitate formed was filtered off and dried at 50 • C in air to give thienopyrimidine-2,4-dione 8a in 61% (1.06 g) yield.

Conclusions
Thus, we developed a new route to 3-pyridyl-substituted quinazolin-2,4(1H,3H)diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones via the annulation of anthranilic esters with N-pyridyl ureas, which act as masked isocyanates. The process consists of the formation of N-aryl-N -pyridyl ureas followed by their cyclocondensation into the corresponding diones. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields. The synthetic route we propose will successfully complement the method developed by Ravi et al. [58] for the preparation of quinazolin-2,4(1H,3H)diones based on aminopyridines in cases where the corresponding aminopyridines or quinolines are not commercially available.
Although the nature of the substituent in the pyridine ring has little effect on the product yield, strong electron-withdrawing functionalities such as cyano-group decrease the yield of the desired products or even prevent the cyclocondensation step. The proposed method is characterized by uncomplicated workup and easy gram-scalability.