Nano aluminium nitride as a solid source of ammonia for the preparation of hantzsch 1,4-dihydropyridines and bis-(1,4-dihydropyridines) in water via one pot multicomponent reaction

Ghorbani-Choghamarani, Arash; Zolfigol, Mohammad Ali; Hajjami, Maryam; Goudarziafshar, Hamid; Nikoorazm, Mohsen; Yousefi, Somaieh; Tahmasbi, Bahman

doi:10.1590/S0103-50532011000300016

Abstracts

Nano aluminium nitride in the presence of water acts as solid source of ammonia, which is used for the preparation of 1,4-dihydropyridines and bis-(1,4-dihydropyridines). An efficient and simple procedure for the one-pot synthesis of 1,4-dihydropyridine and bis-(1,4-dihydropyridine) derivatives was achieved by combination of methyl acetoacetate or ethyl acetoacetate with aldehydes or dialdehydes and aluminium nitride at 80 ºC in water in high purity and good yields

1,4-dihydropyridine; bis-(1,4-dihydropyridine); ethyl acetoacetate; methyl acetoacetate; nano aluminium nitride

O trabalho mostra a atuação de nanopartículas de nitreto de alumínio em presença da água agindo como a fonte geradora de amônia, empregada na preparação de 1,4-diidropiridinas e bis-(1,4-diidropiridinas). Um procedimento eficiente e simples, "one-pot", é apresentado para síntese de 1,4-diidropiridina e dos derivados de bis-(1,4-diidropiridina), obtidos pela reação do acetoacetato de metila ou acetoacetato de etila com os aldeídos ou dialdeídos e nitreto de alumínio em água a 80 ºC, com elevada pureza e com bons rendimentos

ARTICLE

Nano aluminium nitride as a solid source of ammonia for the preparation of hantzsch 1,4-dihydropyridines and bis-(1,4-dihydropyridines) in water via one pot multicomponent reaction

Arash Ghorbani-Choghamarani^I,^* * e-mail: arashghch58@yahoo.com ; Mohammad Ali Zolfigol^II; Maryam Hajjami^II; Hamid Goudarziafshar^I; Mohsen Nikoorazm^I; Somaieh Yousefi^I; Bahman Tahmasbi^I

^IDepartment of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran

^IIFaculty of Chemistry, Bu-Ali Sina University, P.O. Box 6517838683, Hamadan, Iran

ABSTRACT

Nano aluminium nitride in the presence of water acts as solid source of ammonia, which is used for the preparation of 1,4-dihydropyridines and bis-(1,4-dihydropyridines). An efficient and simple procedure for the one-pot synthesis of 1,4-dihydropyridine and bis-(1,4-dihydropyridine) derivatives was achieved by combination of methyl acetoacetate or ethyl acetoacetate with aldehydes or dialdehydes and aluminium nitride at 80 ºC in water in high purity and good yields.

Keywords: 1,4-dihydropyridine, bis-(1,4-dihydropyridine), ethyl acetoacetate, methyl acetoacetate, nano aluminium nitride

RESUMO

O trabalho mostra a atuação de nanopartículas de nitreto de alumínio em presença da água agindo como a fonte geradora de amônia, empregada na preparação de 1,4-diidropiridinas e bis-(1,4-diidropiridinas). Um procedimento eficiente e simples, "one-pot", é apresentado para síntese de 1,4-diidropiridina e dos derivados de bis-(1,4-diidropiridina), obtidos pela reação do acetoacetato de metila ou acetoacetato de etila com os aldeídos ou dialdeídos e nitreto de alumínio em água a 80 ºC, com elevada pureza e com bons rendimentos.

Introduction

One of the most attractive synthetic strategies favored by organic chemists is the multi-component coupling reactions (MCRs), which allow the creation of several bonds in a single operation.^1-6Numerous heterocyclic compounds have the ability to mimic structures of peptides and to bind reversibly to proteins.⁷ An interesting example of useful scaffold is the 1,4-dihydropyridine (DHP) system, because of its ability to act as NAD(P)H analogue of 1,4-dihydronicotinamide.⁸ It is the most important class of calcium-channel modulators^9,10 and has been introduced for the treatment of cardiovascular diseases such as nifedipine, nicradipine and amlodipine.

Recent studies have revealed that 1,4-dihydropyridines exhibit several other medicinal applications including neuroprotectant and platet anti-aggregation activity in addition to acting as cerebral antiischemic agents in the treatment of Alzheimer's disease and as a chemosensitizer in tumor therapy.^11-13 The classical method for the synthesis of these compounds is the Hantzsch reaction involving a multicomponent condensation of an aldehyde with a 1,3-dicarbonyl compound and NH₃.¹⁴Recently, much effort has been devoted to developing more efficient methods for the synthesis of 1,4-dihydropyridines.^15-20

Results and Discussion

Recently we have reported a new procedure for the preparation of 1,4-dihydropyridines by one-pot three-component condensation of an aliphatic or aromatic aldehyde, methyl acetoacetate or ethyl propiolate, and NH₄OAc under neat conditions (Scheme 1).¹⁹

In continuation of this investigation we decided to disclose a novel synthetic protocol for the preparation of 1,4-dihydropyridine and bis-(1,4-dihydropyridine) derivatives by combination of nano aluminium nitride, aldehyde and methyl acetoacetate or ethyl acetoacetate in water as solvent at 80 ºC.

Aluminium nitride serves to generate a solution of ammonia via its reaction with water (equation 1), which is known reaction.^20-22

Initially, to find optimal amount of nano aluminium nitride, 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine and 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine were prepared via combination of 4-chlorobenzaldehyde (1 mmol), methyl acetoacetate (3 mmol) or ethyl acetoacetate (3 mmol) and different amounts of nano aluminium nitride in water (3 mL) in a sealed tube at 80 ºC (Scheme 2). The results of the preparation of 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine and 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine as a function of the amounts of aluminium nitride are shown in Figure 1. The results showed 3 mmol as the optimal amount of aluminium nitride, which was used in all reactions.

With optimal conditions in hand, a wide variety of 1,4-dihydropyridines were synthesized via combination of an aldehyde (or dialdehyde), alkyl acetoacetate and nano aluminium nitride, as a solid source of ammonia, in water at 80 ºC (Scheme 3 and Table 1).

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All of Hantzsch 1,4-dihydropyridines were prepared easily by mixing of the aldehyde, alkyl acetoacetate, aluminium nitride and water in a sealed tube at 80 ºC. After 6 h, sealed tube was cooled down to room temperature and the crude product extracted by dichloromethane. Dichloromethane was removed by evaporation. High pure 4-substituted 1,4-dihydro-2,6-dimethyl-3,5-bis(alkoxycarbonyl)pyridines were obtained by recrystallization in the mixture of H₂O and EtOH. Figure 2 shows scanning electron microscope (SEM) of aluminium nitride (a) and of the reaction mixture (b), after completion of the reaction of the transformation of entry 22.

To investigate the efficiency of this synthetic protocol in comparison with common reported procedures, where ammonium acetate was used instead of nano aluminium nitride, we prepared 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine by our new reported procedure (Scheme 4).¹⁹ As indicated in Scheme 4, 2,6-dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine was obtained in 38% yield (crude yield was 96%). Consequently, this new procedure produces 1,4-dihydropyridines with high purity and yield in comparison with common procedures.

Conclusion

In conclusion, we have demonstrated that the combination of different mono or di-aldehydes, alkyl acetoacetate and nano aluminium nitride in water allows a rapid and practical preparation of Hantzch 1,4-dihydropyridines. The reaction does not require the use of harsh conditions as well as harmful metal catalysts. Thus, this is an ecofriendly and environmentally friendly procedure for the synthesis of 1,4-dihydropyridine derivatives.

Experimental

Apparatus

¹H and ¹³C NMR spectra were recorded on a Bruker DPX400 spectrometer (¹H NMR, 400 MHz; ¹³C NMR, 100 MHz). Chemical shifts (δ) are reported in ppm and are referenced to the solvent, i.e., 7.26 / 77.1 for CDCl₃ and 2.49 / 39.5 for DMSO-d₆. Multiplicities are described as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Coupling constants (J) are reported in Hertz (Hz). IR spectra were measured with a Bomem (FT-IR) spectrometer. Thin layer chromatography (TLC) was performed on Merck Kieselgel 60 TLC plates. Purity and homogeneity of all materials was determined from TLC, ¹H NMR, and ¹³C NMR.

Synthesis of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3j), as a typical procedure

Aluminium nitride (0.123 g, 3 mmol) was added to a stirring mixture of 3-nitrobenzaldehyde (0.151 g, 1 mmol) and methyl acetoacetate (0.348 g, 3 mmol) at room temperature. The reaction vessel was sealed and allowed to warm to 80 ºC over 6 h. Then reaction mixture cooled down to room temperature and the crude product extracted by dichloromethane. Dichloromethane was removed by simple evaporation. Finally crude product (0.343 g, 99%) recrystallized from EtOH/H₂O to afford pure 2,6-dimethyl-4-(3-nitrophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine in 60% yield (0.207 g) as yellow crystalline solid; mp: 204.1-205.9 ºC; IR (KBr) v_max/cm^-¹: 3349 (N-H), 1704 (C=O), 1650, 1641, 1529, 1464, 1377, 1344, 1219; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 8.00-8.02 (d, 1H, J 8.8 Hz), 7.63-7.65 (d, 1H, J 8.0 Hz), 7.39-7.41 (t, 1H, J 8.0 Hz), 5.72 (s, 1H), 5.11 (s, 1H), 3.66 (s, 6H), 2.38 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 149.6, 148.4, 145.0, 134.2, 128.7, 122.7, 121.4, 103.1, 52.9, 39.6, 19.6 .

2,6-Dimethyl-4-(iso-propyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3a)

Pale yellow crystalline solid; mp 162.2-163.4 ºC; IR (KBr) v_max/cm^-¹: 3336 (N-H), 1706 (C=O), 1652, 1463, 1435, 1377, 1219; ¹H NMR (400 MHz, CDCl₃) δ 5.64 (s, 1H), 3.90-3.89 (d, 1H, J 5.2 Hz), 3.71 (s, 6H), 2.31 (s, 6H), 1.58-1.62 (sep, 1H, J 6.8 Hz), 0.75-0.73 (d, 6H, J 6.8 Hz); ¹³C NMR (100 MHz, CDCl₃) d 169.2, 145.1, 101.3, 50.8, 38.8, 35.4, 19.2, 18.2.

2,6-Dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine(3e)

Pale yellow crystalline solid; mp 192.8-194.0 ºC; IR (KBr) v_max/cm^-¹: 3323 (N-H), 1702 (C=O), 1650, 1488, 1465, 1377, 1219; ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.19 (m, 4H), 5.64 (s, 1H), 4.98 (s, 1H), 3.65 (s, 6H), 2.35 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 167.9, 146.0, 144.4, 131.8, 129.1, 128.1, 103,6, 51.1, 39.0, 19.5.

1,3- Bis-(2,6-diethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene(3'a)

Pale yellow crystalline solid; mp 181-185 ºC; ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 2H), 6.85-7.00 (m, 4H), 4.79 (s, 2H), 3.93-3.98 (q, 8H, J 6.8 Hz), 2.23 (s, 12H), 1.08-1.12 (t, 12H, J 6.8 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.4, 147.9, 145.7, 127.7, 126.7, 125.3, 102.3, 59.3, 18.6, 14.6.

1,4- Bis-(2,6-diethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'b)

Pale yellow crystalline solid; mp 289-293 ºC; ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 2H), 6.95 (s, 4H), 4.76 (s, 2H), 3.93-4.00 (q, 8H, J 7.2 Hz), 2.22 (s, 12H), 1.07-1.11 (t, 12H, J 7.2 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.5, 147.9, 146.1, 145.7, 127.3, 102.3, 59.4,18.7, 14.6.

1,3-Bis-(2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'c)

Pale yellow crystalline solid; mp 118-121 ºC; ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 2H), 6.84-7.01 (m, 4H), 4.78 (s, 2H), 3.51 (s, 12H), 2.24 (s, 12H); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.9, 147.8, 146.1, 128.1, 126.3, 125.0, 102.0, 51.0, 18.6.

1,4-Bis-(2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'd)

Pale yellow crystalline solid; mp 175-179 ºC; ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 2H), 6.93-7.12 (m, 4H), 4.86 (s, 2H), 3.54 (s, 12H), 2.24 (s, 12H); ¹³C NMR (100 MHz, DMSO-d₆) d 167.9, 146.3, 145.6, 127.1, 101.8, 51.1, 18.7.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br, as PDF file.

Acknowledgments

The authors acknowledge Bu-Ali Sina University Research Council (Grant Number 32-1716), Center of Excellence in Development of Chemical Methods (CEDCM), National Foundation of Elites (BMN), and Ilam University, Ilam, Iran for financial support of this work.

Submitted: August 18, 2010

Published online: November 4, 2010

Supplementary Information

General methods

¹H NMR and ¹³C NMR spectra were recorded 400 MHz (¹H) or 100.6 MHz (¹³C). Chemical shifts are reported in ppm (δ) and are referenced to the solvent, i.e., 7.26/77.1 for CDCl₃ and 2.49/39.5 for DMSO-d₆. Multiplicities are described as br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Coupling constants (J) are reported in Hertz (Hz). IR spectra were measured with a FT-IR spectrometer. Thin layer chromatography (TLC) was performed on Merck Kieselgel 60 TLC plates. Purity and homogeneity of all materials was determined from TLC, ¹H NMR, and ¹³C NMR.

General procedure for the synthesis of 1,4-dihydropyridines

Aluminium nitride (0.123 g, 3 mmol) was added to a stirring mixture of 3-nitrobenzaldehyde (0.151 g, 1 mmol) and methyl acetoacetate (0.348 g, 3 mmol) at room temperature. The reaction vessel was sealed and allowed to warm to 80 oC over 6 h. Then reaction mixture cooled down to room temperature and the crude product extracted by dichloromethane. Dichloromethane was removed by simple evaporation. Finally crude product (0.343 g, 99%) recrystallized from EtOH/H₂O to afford pure 1,4- dihydropyridine.

Synthesis of 2,6-dimethyl-4-(3-nitrophenyl)-3,5- dicarbomethoxy-1,4- dihydropyridine (3j): as a typical procedure

Aluminium nitride (0.123 g, 3 mmol) was added to the stirring mixture of 3-nitrobenzaldehyde (0.151 g, 1 mmol), methyl acetoacetate (0.348 g, 3 mmol) at room temperature. The reaction vessel was sealed and allowed to warm to 80 oC over 6 h. Then reaction mixture cooled down to room temperature and the crude product extracted by dichloromethane. Dichloromethane was removed by simple evaporation. Finally crude product (0.343 g, 99%) recrystallized from EtOH/H2O to afford pure 2,6-dimethyl-4-(3-nitrophenyl)-3,5-dicarbomethoxy- 1,4-dihydropyridine in 60% yield (0.207 g) as yellow crystalline solid; mp 204.1-205.9 ºC; IR (KBr) v_max/cm^-1: 3349 (N-H), 1704 (C=O), 1650, 1641, 1529, 1464, 1377, 1344, 1219; 1H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H), 8.00-8.02 (d, 1H, J 8.8 Hz), 7.63-7.65 (d, 1H, J 8.0 Hz), 7.39-7.41 (t, 1H, J 8.0 Hz), 5.72 (s, 1H), 5.11 (s, 1H), 3.66 (s, 6H), 2.38 (s, 6H) ppm; 13C NMR (100 MHz, CDCl₃): δ 167.5, 149.6, 148.4, 145.0, 134.2, 128.7, 122.7, 121.4, 103.1, 52.9, 39.6, 19.6 ppm.

2,6-Dimethyl-4-(iso-propyl)-3,5-dicarbomethoxy-1,4- dihydropyridine (3a)

Pale yellow crystalline solid; mp 162.2-163.4 ºC; IR (KBr) v_max/cm^-1: 3336 (N-H), 1706 (C=O), 1652, 1463, 1435, 1377, 1219; ¹H NMR (400 MHz, CDCl₃): δ 5.64 (s, 1H), 3.90-3.89 (d, 1H, J 5.2 Hz), 3.71 (s, 6H), 2.31 (s, 6H), 1.58-1.62 (sep, 1H, J 6.8 Hz), 0.75-0.73 (d, 6H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 169.2, 145.1, 101.3, 50.8, 38.8, 35.4, 19.2, 18.2 ppm.

2,6-Dimethyl-4-(n-propyl)-3,5-dicarbomethoxy-1,4- dihydropyridine (3b)

Pale yellow crystalline solid; mp 133-135 ºC; IR (KBr) v_max/cm^-1: 3343 (N-H), 1703 (C=O), 1650, 1492, 1435, 1329, 1218; ¹H NMR (400 MHz, CDCl₃): δ 5.54 (s, 1H), 3.92 (m, 1H), 3.72 (s, 6H), 2.29 (s, 6H), 1.28-1.20 (m, 4H), 0.85-0.83 (t, 3H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.6, 145.0, 103, 50.9, 39.2, 32.8, 19.4, 17.9, 14.3 ppm.

2,6-Dimethyl-4-(2-phenylethylene)-3,5-dicarbomethoxy- 1,4-dihydropyridine (3c)

Pale yellow crystalline solid; mp 172-173.5 ºC; IR (KBr) v_max/cm^-1: 3335 (N-H), 1698 (C=O), 1647, 1489, 1465, 1377, 1226; ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.17 (m, 5H), 6.20-6.17 (m, 2H), 5.67 (s, 1H), 4.63-4.62 (d, 1H, J 5.2 Hz), 3.74 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.0, 145.4, 137.7, 131.8, 128.4, 128.0, 126.9, 126.3, 101.2, 51.2, 36.2, 19.4 ppm.

2,6-Dimethyl-4-(phenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3d)

Pale yellow crystalline solid; mp: 195.5-196.5 ºC; IR (KBr) v_max/cm^-1: 3342 (N-H), 1699 (C=O), 1649, 1464, 1377, 1344, 1220; ¹H NMR (400 MHz, CDCl₃): δ 7.26- 7.14 (m, 5H), 5.64 (s, 1H), 5.02 (s, 1H), 3.66 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.1, 147.4, 144.3, 128.0, 127.6, 126.2, 103.8, 51.0, 39.3, 19.5 ppm.

2,6-Dimethyl-4-(4-chlorophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3e)

Pale yellow crystalline solid; mp 192.8-194.0 ºC; IR (KBr) v_max/cm^-1: 3323 (N-H), 1702 (C=O), 1650, 1488, 1465, 1377, 1219 cm^‑1; ¹H NMR (400 MHz, CDCl₃): δ 7.26- 7.19 (m, 4H), 5.64 (s, 1H), 4.98 (s, 1H), 3.65 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.9, 146.0, 144.4, 131.8, 129.1, 128.1, 103,6, 51.1, 39.0, 19.5 ppm.

2,6-Dimethyl-4-(4-bromophenyl)-3,5-dicarbomethoxy-1,4- dihydropyridine (3f)

Pale yellow crystalline solid; mp 197.8-198.9 ºC; IR (KBr) v_max/cm^-1: 3319 (N-H), 1698 (C=O), 1650, 1483, 1462, 1435, 1215; ¹H NMR (400 MHz, CDCl₃): δ 7.35- 7.33 (d, 2H, J 8.4), 7.16-7.14 (d, 2H, J 8.4), 5.71 (s, 1H), 4.97 (s, 1H), 3.65 (s, 6H), 2.34 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.9, 146.5, 144.4, 131.1, 129.5, 120.0, 103.5, 51.1, 39.0, 19.6 ppm.

2,6-Dimethyl-4-(4-methoxyphenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3g)

Pale yellow crystalline solid; mp 187.0-187.6 ºC; IR (KBr) v_max/cm^-1: 3346 (N-H), 1697 (C=O), 1649, 1606, 1465, 1377, 1302, 1216; ¹H NMR (400 MHz, CDCl₃): δ 7.20-7.18 (d, 2H, J 8.8), 6.77-6.75 (d, 2H, J 8.8), 5.58 (s, 1H), 4.95 (s, 1H), 3.76 (s, 3H), 3.66 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.1, 158.0, 143.9, 139.9, 128.6, 113.4, 104.2, 55.1, 51.0, 38.4, 19.6 ppm.

2,6-Dimethyl-4-(4-flourophenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3h)

Pale yellow crystalline solid; mp 171.0-172.0 ºC; IR (KBr) v_max/cm^-1: 3349 (N-H), 1707 (C=O), 1650, 1465, 1435, 1377, 1343, 1218; ¹H NMR (400 MHz, CDCl₃): δ 7.24-7.21 (m, 2H), 6.92-6.88 (m, 2H), 5.62 (s, 1H), 4.99 (s, 1H), 3.66 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.0, 162.6, 160.2, 144.3, 143.4,143.3, 129.1, 129, 114.8. 114.6, 103.8, 51.0, 38.7, 19.5 ppm.

2,6-Dimethyl-4-(3,4-dimethoxyphenyl)-3,5-dicarbomethoxy-1,4-dihydropyridine (3i)

Pale yellow crystalline solid; mp 148.5-149.5 ºC; IR (KBr) v_max/cm^-1: 3313 (N-H), 1698 (C=O), 1649, 1492, 1463, 1377, 1267, 1213; ¹H NMR (400 MHz, CDCl₃): δ 6.88 (s, 1H), 6.79-6.72 (q, 2H, J 8 Hz), 5.62 (s, 1H), 4.97 (s, 1H), 3.85 (s, 3H), 3.83 (s 3H), 3.67 (s, 6H), 2.35 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.1, 148.4, 147.4, 144.0, 140.3, 119.4, 111.5, 111.0, 77.3, 55.8, 50.98, 38.8, 19.6 ppm.

2,6-Dimethyl-4-(iso-propyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3k)

Pale yellow crystalline solid; mp 97.0-99.0 ºC; IR (KBr) v_max/cm^-1: 3341 (N-H), 1696 (C=O), 1652, 1464, 1377, 1216; ¹H NMR (400 MHz, CDCl₃): δ 5.55 (s, 1H), 4.25-4.12 (m, 4H), 3.94-3.92 (d, 1H, J 5.6 Hz), 2.31 (s, 6H), 1.32-1.29 (t, 6H, J 7.2 Hz), 0.77-0.75 (d, 6H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 162.2, 144.6, 101.7, 59.5, 38.8, 35.5, 19.3, 18.5, 14.4 ppm.

2,6-Dimethyl-4-(n-propyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3l)

Pale yellow crystalline solid; mp 125.2-126.3 ºC; IR (KBr) v_max/cm^-1: 3350 (N-H), 1699 (C=O), 1465, 1378, 1299, 1213; ¹H NMR (400 MHz, CDCl₃): δ 5.49 (s, 1H), 4.25-4.12 (m, 4H), 3.96-3.93 (t, 1H, J 5.2 Hz), 2.29 (s, 6H), 1.32-1.29 (t, 6H, J 7.2 Hz), 1.25-1.23 (m, 4H), 0.87-0.83 (t, 3H, J 7.2 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 168.2, 144.7, 103.4, 59.6, 39.3, 32.7, 19.4, 18.0, 14.4, 14.3 ppm.

2,6-Dimethyl-4-(phenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3m)

Pale yellow crystalline solid; mp 157.3-158.3 ºC; IR (KBr) v_max/cm^-1: 3340 (N-H), 1687 (C=O), 1650, 1486, 1464, 1374, 1247, 1211; ¹H NMR (400 MHz, CDCl₃): δ 7.30-7.13 (m, 5H), 5.57 (s, 1H), 5.00 (s, 1H), 4.13-4.08 (q, 4H, J 7.2 Hz), 2.34 (s, 6H), 1.25-1.21 (t, 6H, J 7.2 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 147.8, 144.0, 128.0, 127.8, 126.1, 104.0, 59.7, 39.6, 19.5, 14.3 ppm.

2,6-Dimethyl-4-(4-chlorophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3n)

Pale yellow crystalline solid; mp 149.5-151.0 ºC; IR (KBr) v_max/cm^-1: 3357 (N-H), 1695 (C=O), 1652, 1486, 1463, 1377, 1214; ¹H NMR (400 MHz, CDCl₃): δ 7.23- 7.21 (d, 2H, J 6.8 Hz), 7.18-7.16 (d, 2H, J 8 Hz), 5.56 (s, 1H), 4.96 (s, 1H), 4.10 (m, 4H), 2.34 (s, 6H), 1.24-1.21 (t, 6H, J 6.4 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.5, 146.4, 144.1, 131.7, 129.4, 127.9, 103.8, 59.8, 39.3, 19.5, 14.3 ppm.

2,6-Dimethyl-4-(4-bromophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3o)

Pale yellow crystalline solid; mp 165.5-166.5 ºC; IR (KBr) v_max/cm^-1: 3360 (N-H), 1693 (C=O), 1652, 1486, 1463, 1377, 1214; ¹H NMR (400 MHz, CDCl₃): δ 7.34- 7.32 (d, 2H, J 8.4 Hz), 7.18-7.15 (d, 2H, J 8.4 Hz), 5.61 (s, 1H), 4.95 (s, 1H), 4.11-4.08 (q, 4H, J 4.8 Hz), 2.33 (s, 6H), 1.25-1.21 (t, 6H, J 7.2 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.4, 146.9, 144.1, 130.9, 129.8, 119.9, 103.7, 59.8, 39.3, 19.5, 14.3 ppm.

2,6-Dimethyl-4-(4-methoxyphenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3p)

Pale yellow crystalline solid; mp 158.0-159.0 ºC; IR (KBr) v_max/cm^-1: 3340 (N-H), 1689 (C=O), 1649, 1488, 1464, 1373, 1301, 1211; ¹H NMR (400 MHz, CDCl₃): δ 7.22-7.19 (d, 2H, J 8.8 Hz), 6.77-6.75 (d, 2H, J 8.4 Hz), 5.60 (s, 1H), 4.94 (s, 1H), 4.13-4.06 (q, 4H, J 5.2 Hz), 3.76 (s, 3H), 2.33 (s, 6H), 1.25-1.22 (t, 6H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 143.7, 140.4, 128.9, 113.2, 104.3, 59.7, 55.1, 38.8, 19.5, 14.3 ppm.

2,6-Dimethyl-4-(4-fluorophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3q)

Pale yellow crystalline solid; mp 149.0-150.5 ºC; IR (KBr) v_max/cm^-1: 3342 (N-H), 1686 (C=O), 1650, 1488, 1461, 1373, 1299, 1211; ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H), 7.16-7.00 (m, 4H), 4.83 (s, 1H), 3.99-3.96 (q, 4H, J 7.2 Hz), 2.24 (s, 6H), 1.13-1.10 (t, 6H, J 7.2 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 162.2, 159.8, 145.9, 144.9, 144.8, 129.6, 129.5, 115.0, 114.7, 102.3, 59.4, 38.8, 18.6, 14.5 ppm.

2,6-Dimethyl-4-(3,4-dimethoxyphenyl)-3,5-dicarboethoxy-4-dihydropyridine (3r)

Pale yellow crystalline solid; mp 132.0-133.0 ºC; IR (KBr) v_max/cm^-1: 3352 (N-H), 1692 (C=O), 1644, 1623, 1463, 1377, 1304, 1122; ¹H NMR (400 MHz, DMSO-d₆): δ 6.89-6.72 (m, 3H), 5.57 (s, 1H), 4.95 (s, 1H), 4.15-4.08 (m, 4H), 3.84 (s, 3H), 3.83 (s, 3H), 2.34 (s, 6H), 1.26-1.23 (t, 6H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.7, 148.1, 147.3, 143.8, 140.8, 119.8, 111.8, 110.9, 104.1, 59.7, 55.8, 55.7, 39.0, 19.5, 14.3 ppm.

2,6-Dimethyl-4-(3-nitrophenyl)-3,5-dicarboethoxy-1,4-dihydropyridine (3s)

Pale yellow crystalline solid; mp 160.0-161.0 ºC; IR (KBr) v_max/cm^-1: 3342 (N-H), 1699 (C=O), 1652, 1464, 1376, 1348, 1211; ¹H NMR (400 MHz, DMSO-d₆): δ 8.13 (s, 1H), 8.02-8.00 (d, 1H, J 8.4 Hz), 5.68 (s, 1H), 5.10 (s, 1H), 4.14-4.06 (q, 4H, J 7.2 Hz), 2.38 (s, 6H), 1.25-1.21 (t, 6H, J 7.2 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.1, 149.9, 148.2, 144.8, 134.5, 128.6, 123.1, 121.3, 103.3, 60.0, 40.0, 19.6, 14.2 ppm.

1,3-Bis-(2,6-diethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'a)

Pale yellow crystalline solid; mp 181-185 ºC; ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 2H), 6.85-7.00 (m, 4H), 4.79 (s, 2H), 3.93-3.98 (q, 8H, J 6.8 Hz), 2.23 (s, 12H), 1.08-1.12 (t, 12H, J 6.8 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.4, 147.9, 145.7, 127.7, 126.7, 125.3, 102.3, 59.3,18.6, 14.6 ppm.

1,4-Bis-(2,6-diethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'b)

Pale yellow crystalline solid; mp 289-293 ºC; ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 2H), 6.95 (s, 4H), 4.76 (s, 2H), 3.93-4.00 (q, 8H, J 7.2 Hz), 2.22 (s, 12H), 1.07-1.11 (t, 12H, J 7.2 Hz) ppm. ¹³C NMR (100 MHz, DMSO-d₆): δ 167.5, 147.9, 146.1, 145.7, 127.3, 102.3, 59.4,18.7, 14.6 ppm.

1,3-Bis-(2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'c)

Pale yellow crystalline solid; mp 118-121 ºC; ¹H NMR (400 MHz, DMSO-d₆): δ 8.86 (s, 2H), 6.84-7.01 (m, 4H), 4.78 (s, 2H), 3.51 (s, 12H), 2.24 (s, 12H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.9, 147.8, 146.1, 128.1, 126.3, 125.0, 102.0, 51.0, 18.6 ppm.

1,4-Bis-(2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine) benzene (3'd)

Pale yellow crystalline solid; mp 175-179 ºC; ¹H NMR (400 MHz, DMSO-d₆): δ 8.88 (s, 2H), 6.93-7.12 (m, 4H), 4.86 (s, 2H), 3.54 (s, 12H), 2.24 (s, 12H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.9, 146.3, 145.6, 127.1, 101.8, 51.1, 18.7 ppm.

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1. Kantam, M. L.; Ramani, T.; Chakrapani, L.; Choudary, B. M.; Catal. Commun. 2009, 10, 370.
2. Cui, S. L.; Wang, J.; Wang, Y. G.; Org. Lett. 2008, 10, 1267.
3. Li, L.; Zhang, G.; Zhu, A.; Zhang, L.; J. Org. Chem. 2008, 73, 3630.
4. Ibrahim, M. A.; Abdel-Rahman, R. M.; Abdel-Halim, A. M.; Ibrahim, S. S.; Allimony H. A.; J. Braz. Chem. Soc. 2009, 20, 1275.
5. Navarrete-Encina, P. A.; Salazar, R.; Vega-Retter, C.; Perez, K.; Squella, J. A.; Nunez-Vergara, L. J.; J. Braz. Chem. Soc. 2010, 21, 413.
6. Suarez, M.; Molero, D.; Salfran, E.; Rodriguez, H.; Coro, J.; Saez, E.; Martinez-Alvarez, R.; Martin, N.; J. Braz. Chem. Soc. 2010 (in press).
7. Baskovc, J.; Bevk, D.; Stanovnik, B.; Svete, J.; J. Comb. Chem. 2009, 11, 500.
8. Zhu, X. Q.; Liu, Y.; Zhao, B. J.; Cheng, J. P.; J. Org. Chem. 2001, 66, 370.
9. Daryabari, N.; Akbarzadeh, T.; Amini, M.; Miri, R.; Mirkhani, H.; Shafiee, A.; J. Iran. Chem. Soc. 2007, 4, 30.
10. Shan, R.; Velazquez, C.; Knaus, E. E.; J. Med. Chem. 2004, 47, 254.
11. Suarez, M.; Verdecia, Y.; Illescas, B.; Martinez-Alvarez, R.; Avarez, A.; Ochoa, E.; Seoane, C.; Kayali, N.; Martin, N.; Tetrahedron 2003, 59, 9179.
12. Zarghi, A.; Sadeghi, H.; Fassihi, A.; Faizi, M.; Shafiee, A.; Il Farmaco 2003, 58, 1077.
13. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.; Tetrahedron Lett. 2003, 44, 4129.
14. Simon, C.; Constantieux, T.; Rodriguez, J.; Eur. J. Org. Chem. 2004, 4957.
15. Sabitha, G.; Arundhathi, K.; Sudhakar, K.; Sastry, B. S.; Yadav, J. S.; Synth. Commun. 2009, 39, 2843.
16. Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Sadeghi, A.; J. Iran. Chem. Soc. 2009, 6, 317.
17. Rafiee, E.; Eavani, S.; Rashidzadeh, S.; Joshaghani, M.; Inorg. Chim. Acta 2009, 362, 3555.
18. Kumar, A.; Maurya, R. A.; Tetrahedron 2008, 64, 3477.
19. Ghorbani-Choghamarani, A.; Zolfigol, M. A.; Salehi, P.; Ghaemi, E.; Madrakian, E.; Nasr-Isfahanid, H.; Shahamirian, M.; Acta Chim. Slov. 2008, 55, 644.
20. Wu, L. Q.; Yang, C. G.; Yang, L. M.; Yang, L. J.; Heterocycles 2009, 78, 977.
21. Veitch, G. E.; Bridgwood, K. L.; Rands-Trevor, K.; Ley, S. V.; Synlett 2008, 2597.
22. Bridgwood, K. L.; Veitch, G. E.; Ley, S. V.; Org. Lett. 2008, 10, 3627.
23. Wang, G. W.; Xia, J. J.; Miao, C. B.; Wu, X. L.; Bull. Chem. Soc. Jpn. 2006, 79, 454.
24. Zolfigol, M.A.; Safaiee, M.; Synlett 2004, 827.
25. Hernandez-Gallegos, Z.; Lehmann, P. A.; Hong, E.; Posadas, F.; Hernandez-Gallegos, E.; Eur. J. Med. Chem. 1995, 30, 355.
26. Sivamurugan, V.; Vinu, A.; Palanichamy, M.; Murugesan V.; Heteroat. Chem. 2006, 17, 267.

*

e-mail:

arashghch58@yahoo.com

Publication Dates

Publication in this collection
24 Mar 2011
Date of issue
Mar 2011

History

Accepted
04 Nov 2010
Received
18 Aug 2010

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Kantam, M. L.; Ramani, T.; Chakrapani, L.; Choudary, B. M.; Catal. Commun. 2009, 10, 370.

[2] 2. Cui, S. L.; Wang, J.; Wang, Y. G.; Org. Lett. 2008, 10, 1267.

[3] 3. Li, L.; Zhang, G.; Zhu, A.; Zhang, L.; J. Org. Chem. 2008, 73, 3630.

[4] 4. Ibrahim, M. A.; Abdel-Rahman, R. M.; Abdel-Halim, A. M.; Ibrahim, S. S.; Allimony H. A.; J. Braz. Chem. Soc. 2009, 20, 1275.

[5] 5. Navarrete-Encina, P. A.; Salazar, R.; Vega-Retter, C.; Perez, K.; Squella, J. A.; Nunez-Vergara, L. J.; J. Braz. Chem. Soc. 2010, 21, 413.

[6] 6. Suarez, M.; Molero, D.; Salfran, E.; Rodriguez, H.; Coro, J.; Saez, E.; Martinez-Alvarez, R.; Martin, N.; J. Braz. Chem. Soc. 2010 (in press).

[7] 7. Baskovc, J.; Bevk, D.; Stanovnik, B.; Svete, J.; J. Comb. Chem. 2009, 11, 500.

[8] 8. Zhu, X. Q.; Liu, Y.; Zhao, B. J.; Cheng, J. P.; J. Org. Chem. 2001, 66, 370.

[9] 9. Daryabari, N.; Akbarzadeh, T.; Amini, M.; Miri, R.; Mirkhani, H.; Shafiee, A.; J. Iran. Chem. Soc. 2007, 4, 30.

[10] 10. Shan, R.; Velazquez, C.; Knaus, E. E.; J. Med. Chem. 2004, 47, 254.

[11] 11. Suarez, M.; Verdecia, Y.; Illescas, B.; Martinez-Alvarez, R.; Avarez, A.; Ochoa, E.; Seoane, C.; Kayali, N.; Martin, N.; Tetrahedron 2003, 59, 9179.

[12] 12. Zarghi, A.; Sadeghi, H.; Fassihi, A.; Faizi, M.; Shafiee, A.; Il Farmaco 2003, 58, 1077.

[13] 13. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.; Tetrahedron Lett. 2003, 44, 4129.

[14] 14. Simon, C.; Constantieux, T.; Rodriguez, J.; Eur. J. Org. Chem. 2004, 4957.

[15] 15. Sabitha, G.; Arundhathi, K.; Sudhakar, K.; Sastry, B. S.; Yadav, J. S.; Synth. Commun. 2009, 39, 2843.

[16] 16. Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Sadeghi, A.; J. Iran. Chem. Soc. 2009, 6, 317.

[17] 17. Rafiee, E.; Eavani, S.; Rashidzadeh, S.; Joshaghani, M.; Inorg. Chim. Acta 2009, 362, 3555.

[18] 18. Kumar, A.; Maurya, R. A.; Tetrahedron 2008, 64, 3477.

[19] 19. Ghorbani-Choghamarani, A.; Zolfigol, M. A.; Salehi, P.; Ghaemi, E.; Madrakian, E.; Nasr-Isfahanid, H.; Shahamirian, M.; Acta Chim. Slov. 2008, 55, 644.

[20] 20. Wu, L. Q.; Yang, C. G.; Yang, L. M.; Yang, L. J.; Heterocycles 2009, 78, 977.

[21] 21. Veitch, G. E.; Bridgwood, K. L.; Rands-Trevor, K.; Ley, S. V.; Synlett 2008, 2597.

[22] 22. Bridgwood, K. L.; Veitch, G. E.; Ley, S. V.; Org. Lett. 2008, 10, 3627.

[23] 23. Wang, G. W.; Xia, J. J.; Miao, C. B.; Wu, X. L.; Bull. Chem. Soc. Jpn. 2006, 79, 454.

[24] 24. Zolfigol, M.A.; Safaiee, M.; Synlett 2004, 827.

[25] 25. Hernandez-Gallegos, Z.; Lehmann, P. A.; Hong, E.; Posadas, F.; Hernandez-Gallegos, E.; Eur. J. Med. Chem. 1995, 30, 355.

[26] 26. Sivamurugan, V.; Vinu, A.; Palanichamy, M.; Murugesan V.; Heteroat. Chem. 2006, 17, 267.

Brasil

Brasil

Nano aluminium nitride as a solid source of ammonia for the preparation of hantzsch 1,4-dihydropyridines and bis-(1,4-dihydropyridines) in water via one pot multicomponent reaction

Abstracts

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