One-pot synthesis of 4H-Chromene and Dihydropyrano[3,2-c]chromene derivatives in hydroalcoholic media

ARTICLE

One-pot synthesis of 4H-Chromene and Dihydropyrano[3,2-c]chromene derivatives in hydroalcoholic media

Ramin Ghorbani-Vaghei^*; Zahra Toghraei-Semiromi; Rahman Karimi-Nami

Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65174 Hamedan, Iran

ABSTRACT

4H-Chromenes and dihydropyrano[3,2-c]chromenes are obtained in good to excellent yields by a simple, mild and efficient procedure using poly(N,N'-dibromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] and N,N,N',N'-tetrabromobenzene-1,3-disulfonamide [TBBDA ] as catalysts.

Keywords: 4H-chromenes, dihydropyrano[3,2-c]chromenes, TBBDA, PBBS

RESUMO

4H-Cromenos e diidropirano[3,2-c]cromenos são obtidos em rendimentos bons a excelentes através de um procedimento simples, brando e eficiente usando poli(N,N'-dibromo-N-etil-benzeno-1,3-dissulfonamida) [PBBS] e N,N,N',N'-tetrabromobenzeno-1,3-dissulfonamida [TBBDA] como catalisadores.

Introduction

The development of multi-component reactions (MCRs) has attracted much attention from the vantage point of combinatorial and medicinal chemistry.¹ Many important heterocycle syntheses are multi-component reactions. Recently, the synthesis of 4H-chromenes and dihydropyrano[3,2-c]chromenes derivatives have attracted great interest to their biological and pharmacological activities. The 4H-chromene derivatives show various pharmacological properties such as spasmolytic, diuretic, anticoagulant, anticancer, and antianaphylactic activities.² Substituted 4H-chromenes are particularly versatile compounds that bind Bcl-2 protein (B-cell lymphoma 2) and induce apoptosis in tumor cells. Specifically, Bcl-2 can contribute to neoplastic cell expansion by preventing normal cell turnover caused by physiological cell death mechanisms. High levels of the Bcl-2 gene expressions are found in a wide variety of human cancers and can lead to tumor cell resistance to conventional chemotherapy and radiotherapy. Thus, Bcl-2 protein binding compounds provide a promising lead for the development of potential anticancer agents and direct methods for their synthesis are highly desirable.^3-5 Dihydropyrano[3,2-c]chromenes are a class of important heterocycles that have been used as cognitive enhancers, for the treatment of neurodegenerative diseases, including Alzheimer^,s disease, amyotrophic lateral sclerosis, Parkinson^,s disease, Huntington^,s disease, AIDS associated dementia and Down^,s syndrome as well as for the treatment of schizophrenia and myoclonus.⁶ In addition, aminochromene derivatives exhibit a wide spectrum of biological activities including antihypertensive and anti-ischemic behavior.^7-9 Also, a number of 2-amino-4H-pyrans are useful as photoactive materials.¹⁰

4H-Chromenes have been prepared from salicylaldehydes and cyanoacetates in heterogeneous liquid phase catalysis using Al₂O₃^4,11 and molecular sieves.⁵ They are also synthesized in the presence of Zr(KPO₄)₂¹² and Amberlyst A21^®.¹³ Despite their importance from pharmacological, industrial and synthetic point of views, comparatively few methods for accessing pyrano[3,2-c]chromene derivatives have been reported.^14-16 2-Amino-4-aryl-5-oxo-4H, 5H-pyrano-[3,2-c]chromene-3-carbonitriles have already been prepared in the presence of organic bases like piperidine or pyridine in an organic solvent, i.e., ethanol and pyridine.¹⁴ They are also obtained in the presence of diammonium hydrogen phosphate,¹⁵ H₆P₂W₁₈O₆₂·18H₂O,¹⁶ DBU¹⁷ and K₂CO₃ under microwave irradiation.¹⁸

However, some of these protocols require long reaction times, multi-step reactions, complex synthetic pathways and afford products with only modest yields. Therefore, the introduction of milder, faster and more ecofriendly methods, accompanied with higher yields is needed.

Results and Discussion

In continuation of our interest in the application of N,N,N',N'-tetrabromo benzene-1,3-disulfonamide [TBBDA] and poly(N,N'-dibromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS]^19-22 in organic synthesis, we report here a convenient method for the preparation of 4H-chromenes from salicylaldehydes and malononitrile or ethyl cyanoacetate in aqueous ethanol (H₂O:EtOH, (1:1)) at room temperature (Scheme 1 and Table 1).

Also the synthesis of dihydropyrano[3,2-c]chromenes was achieved by the three-component condensation of an aromatic aldehyde, malononitrile and 4-hydroxycoumarin in the presence of the catalysts. The reaction was carried out in aqueous ethanol at reflux using TBBDA and PBBS as catalysts to give products in good to high yields (Scheme 2 and Table 2).

The advantages of PBBS and TBBDA are: (i) ease of preparation; (ii) reagent stability under atmospheric conditions for two months; (iii) possibility of re-use.

In conclusion, we have developed an efficient procedure for the synthesis of 4H-chromenes and dihydropyrano[3,2-c]chromenes derivatives in aqueous media using [TBBDA] and [PBBS]. This method offers several advantages such as inexpensive catalysts, easy synthetic procedure, high yields, simple work-up procedure and easy product isolation.

Experimental

All commercially available chemicals were obtained from Merck and Fluka, and used without further purifications unless otherwise stated. ¹H NMR and ¹³C NMR spectra were recorded on a Jeol 90 MHz and a Bruker 300 MHz FT NMR spectrometers using TMS as internal standard and chemical shifts in δ (ppm). Infrared (IR) spectra were acquired on a Perkin Elmer GX FT-IR spectrometer. All yields refer to isolated products.

General procedure for the preparation of 4H-chromenes

A mixture of salicylaldehyde (5 mmol), malononitrile (1.2 mmol) and TBBDA (0.18 mmol) or PBBS (0.1 g) in H₂O (5 mL) and EtOH (5 mL) was stirred at room temperature for the appropriate time. After completion of the reaction, which was monitored by TLC, the solid product was collected by filtration, washed with water and aqueous ethanol and purified by recrystallization from ethanol.

General procedure for the preparation of 2-amino-5-oxo-dihydropyrano[3,2-c]chromenes

A mixture of aldehyde (10 mmol), malononitrile (1.2 mmol), 4-hydroxycoumarin (10 mmol) and TBBDA (0.18 mmol) or PBBS (0.1 g) in H₂O (5 mL) and EtOH (5 mL) was stirred under reflux for the appropriate time. After completion of the reaction, which was monitored by TLC, the mixture was monitored by TLC, the mixture was cooled to room temperature. The solid product was collected by filtration, washed with water and aqueous ethanol and purified by recrystallization from ethanol.

Recycling of the catalysts

The catalysts were recovered by evaporation of the solvent and washing of the solid with dichloromethane.

Supplementary Information

Supplementary characterization data and ¹H NMR spectra are available, free of charge at http://jbcs.sbq.org.br as a PDF file.

Acknowledgments

We are thankful to Bu-Ali Sina University, Center of Excellence in Development of Chemical Methods (CEDCM) for financial support.

References

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Submitted: September 20, 2010

Published online: February 3, 2011

Supplementary Information

Analytical data for selected compounds

2-Amino-3-cyano-4-(1,1-dicyanomethyl)-4H-chromene (Table 1, entry 1)

mp 147-148 ºC; IR (KBr) ν_max/cm^-1: 3486, 3386, 3181, 2201, 1643, 1600, 1568, 1408, 1236, 754, ¹H NMR (DMSO, 90 MHz), δ 4.82 (d, 1H, J 3.5 Hz, CH), 4.95 (d, 1H, J 3.60 Hz, CH), 6.69 (s, 2H, NH₂), 7.38 (m, 4H, aromatic).

2-Amino-8-methoxy-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 2)

mp 188-189 ºC; IR (KBr) ν_max/cm^-1: 3464, 3356, 2910, 2192, 1642, 1613, 1552, 1488, 1420, 1218, 750, ¹H NMR (DMSO, 90 MHz), δ 3.83 (s, 3H, CH₃), 4.53 (d, 1H, J 3.8 Hz, CH), 5.01 (d, 1H, J 3.90 Hz, CH), 7.07 (m, 3H, aromatic), 7.52 (s, 2H, NH₂).

2-Amino-6-methoxy-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 3)

mp 184-185 ºC; IR (KBr) ν_max/cm^-1: 3402, 3342, 3218, 2185, 1659, 1587, 1426, 1217, 1037, 820, ¹H NMR (DMSO, 90 MHz), δ 3.73 (s, 3H, CH₃), 4.54 (s, 1H, CH), 5.09 (s, 1H, CH), 7.02 (s, 3H, aromatic), 7.41 (s, 2H, NH₂). ¹³C NMR [DMSO-d₆, 300 MHz]: δ 164.1, 156.3, 144.0, 120.0, 119.1, 118.4, 117.7, 116.3, 113.6, 113.4, 113.4, 56.0, 48.79, 38.0. Anal. Calc. C, 63.15; H, 3.79; N, 21.04%. Found: C, 62.90; H, 3.51; N, 20.65%. m/z 266.

2-Amino-6-nitro-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 4)

mp 180-181 ºC; IR (KBr) ν_max/cm^-1: 3408, 3319, 3074, 2199, 1659, 1608, 1526, 1352, 1262, 748, ¹H NMR (DMSO, 90 MHz), δ 4.76 (d, 2H, J 3.7 Hz, CH), 5.18 (d, 2H, J 3.7 Hz, CH), 7.32-7.42 (m, 1H, aromatic), 7.77 (s, 2H, NH₂), 8.23-8.50 (m, 2H, aromatic).

2-Amino-6-bromo-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 5)

mp 163-164 ºC; IR (KBr) ν_max/cm^-1: 3471, 3349, 2885, 2189, 1635, 1597, 1596, 1426, 1228, 817, ¹H NMR (DMSO, 90 MHz), δ 4.76 (d, 2H, J 3.5 Hz, CH), 5.19 (d, 2H, J 3.5 Hz, CH), 7.72-7.96 (m, 5H, aromatic and NH₂).

2-Amino-6, 8-dibromo-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 6)

mp 182-183 ºC; IR (KBr) ν_max/cm^-1: 3414, 3332, 2885, 2197, 1655, 1600, 1562, 1457, 1433, 871, ¹H NMR (DMSO, 90 MHz), δ 4.76 (d, 2H, J 3.6 Hz, CH), 5.17 (d, 2H, J 3.6 Hz, CH), 7.74-7.96 (m, 4H, aromatic and NH₂).

2-Amino-6-chloro-3-cyano-4-(1,1-dicyanomethyl)-4Hchromene (Table 1, entry 7)

mp 151-154 ºC; IR (KBr) ν_max/cm^-1: 3445, 3337, 2862, 2194, 1644, 1600, 1572, 1457, 1483, 819, ¹H NMR (DMSO, 90 MHz), δ 4.62 (d, 1H, J 3.8 Hz, CH), 5.14 (d, 1H, J 3.8 Hz, CH), 7.10-7.57 (m, 5H, aromatic and NH₂), ¹³C NMR [DMSO-d6, 300 MHz]: δ 163.7, 149.0, 130.5, 129.0, 128.9, 120.3, 119.6, 119.2, 118.8, 113.4, 113.2, 48.9, 37.3. Anal. Calc. C, 57.69; H, 2.61; N, 20.07%. Found: C, 57.53; H, 2.36; N, 19.94%. m/z 270.

2-Amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 2, entry 1)

mp 260-264 ºC; IR (KBr) ν_max/cm^-1: 3379, 3305, 2196, 1713, 1676, 1637, ¹H NMR (DMSO, 90 MHz), δ 4.45 (s, 1H, CH), 7.28-7.86 (m, 11H, aromatic and NH₂).

2-Amino-4-(4-chlorophenyl)-5-oxo-4,5-dihydropyrano[ 3,2-c]chromene-3-carbonitrile (Table 2, entry 2)

mp 265-267 ºC;IR (KBr) ν_max/cm^-1: 3380, 3291, 3189, 2191, 1713, 1676, ¹H NMR (DMSO, 90 MHz), δ 4.72 (s, 1H, CH), 7.40-8.13 (m, 10H, aromatic and NH₂).

2-Amino-4-(4-methoxyphenyl)-5-oxo-4,5-dihydropyrano[ 3,2-c]chromene-3-carbonitrile (Table 2, entry 3)

mp 246-249 ºC; IR (KBr) ν_max/cm^-1: 3500, 3450, 3350, 2208, 1647,1174, ¹H NMR (DMSO, 90 MHz), δ 3.71 (s, 3H, CH₃), 4.39 (s, 1H, CH), 6.81-7.85 (m, 10H, aromatic and NH₂).

2-Amino-5-oxo-4-p-tolyl-4,5-dihydropyrano[3,2-c] chromene-3-carbonitrile (Table 2, entry 4)

mp 252-254 ºC; IR (KBr) ν_max/cm^-1: 3388, 3311, 3189, 2194, 1713, 1676, 1637, ¹H NMR (DMSO, 90 MHz), δ 2.25 (s, 3H, CH₃), 4.40 (s, 1H, CH), 7.12-7.93 (m, 10H, aromatic and NH₂).

2-Amino-4-(4-nitrophenyl )-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 5)

mp 255-258 ºC; IR (KBr) ν_max/cm^-1: 3482, 3370, 3071, 2196, 1718, 1673, 1606, 1505,1373, 1348, 766. ¹H NMR (DMSO, 90 MHz), δ 4.66 (s, 1H, CH), 7.47-8.21 (m, 10H, aromatic and NH₂).

2-Amino-4-(3-nitrophenyl )-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 6)

mp 256-259 ºC; IR (KBr) ν_max/cm^-1: 3408, 3324, 3192, 2194, 1710, 1677, 1608, 1528,1380, 1347, 764. ¹H NMR (DMSO, 90 MHz), δ 4.72 (s, 1H, CH), 7.54-8.12 (m, 10H, aromatic and NH₂).

2-Amino-4-(4-bromophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 7)

mp 255-257 ºC; IR (KBr) ν_max/cm^-1: 3387, 3309, 3188, 2181, 1710, 1677, 1602, 1577,1062, 758. ¹H NMR (DMSO, 90 MHz), δ 4.46 (s, 1H, CH), 7.19-7.84 (m, 10H, aromatic and NH₂).

2-Amino-4-(2,4-dichlorophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 8)

mp 255-258 ºC; IR (KBr) ν_max/cm^-1: 3459, 3290, 3163, 2199, 1716, 1673, 1630, 1589,1061, 761. ¹H NMR (DMSO, 90 MHz), δ 4.94 (s, 1H, CH), 7.34-7.92 (m, 9H, aromatic and NH₂).

2-Amino-4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 9)

mp 273-276 ºC; IR (KBr) ν_max/cm^-1: 3405, 3305, 3181, 2199, 1711, 1674, 1602, 1492,1062, 764. ¹H NMR (DMSO, 90 MHz), δ 5.07 (s, 1H, CH), 7.33-7.96 (m, 9H, aromatic and NH₂).

2-Amino-4-(2,6-dichlorophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, entry 10)

mp 274-277 ºC; IR (KBr) ν_max/cm^-1: 3419, 3277, 3173, 2200, 1707, 1673, 1633, 1599,1379, 758. ¹H NMR (DMSO, 90 MHz), δ 5.51 (s, 1H, CH), 7.35-7.92 (m, 9H, aromatic and NH₂)

2-Amino-5-oxo-4-(3,4,5-trimethoxyphenyl)-4,5-dihydropyrano[ 3,2-c]chromene-3-carbonitrile (Table 2, entry 11)

mp 224-226 ºC; IR (KBr) ν_max/cm^-1: 3425, 3321, 2191, 1672, 1595, 1375, 1154, ¹H NMR (DMSO, 90 MHz), δ 3.63 (s, 3H, CH₃), 3.71 (s, 6H, CH₃), 4.43(s, 1H, H), 6.52 (s, 2H, NH₂), 7.36-7.93 (m, 6H, aromatic), ¹³C NMR [DMSO-d6, 300 MHz]: δ 160.1, 158.5, 154.0, 153.3, 152.6, 139.4, 137.1, 133.3, 125.1, 123.0, 119.7, 117.0, 113.6, 105.4, 104.1, 60.4, 58., 56., 37.7. Anal. Calc. C, 65.02; H, 4.46; N, 6.89%. Found: C, 65.0; H, 4.27; N, 6.93%. m/z 404.

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Publication Dates

• Publication in this collection
  16 May 2011
• Date of issue
  May 2011

History

• Received
  20 Sept 2010
• Accepted
  03 Feb 2011