One-Pot Synthesis of 4 H-Chromene and Dihydropyrano [ 3 , 2-c ] chromene Derivatives in Hydroalcoholic Media

The development of multi-component reactions (MCRs) has attracted much attention from the vantage point of combinatorial and medicinal chemistry. 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. 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. 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 Alzheimers disease, amyotrophic lateral sclerosis, Parkinsons disease, Huntingtons disease, AIDS associated dementia and Downs syndrome as well as for the treatment of schizophrenia and myoclonus. In addition, aminochromene derivatives exhibit a wide spectrum of biological activities including antihypertensive and anti-ischemic behavior. Also, a number of 2-amino-4H-pyrans are useful as photoactive materials. 4H-Chromenes have been prepared from salicylaldehydes and cyanoacetates in heterogeneous liquid phase catalysis using Al2O3 4,11 and molecular sieves. They are also synthesized in the presence of Zr(KPO4)2 12 and Amberlyst A21. 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. 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. They are also obtained in the presence of diammonium hydrogen phosphate, H6P2W18O62•18H2O, 16 DBU and K2CO3 under microwave irradiation. 18


Introduction
The development of multi-component reactions (MCRs) has attracted much attention from the vantage point of combinatorial and medicinal chemistry. 1Many 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.4][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. 68][9] Also, a number of 2-amino-4H-pyrans are useful as photoactive materials. 10H-Chromenes have been prepared from salicylaldehydes and cyanoacetates in heterogeneous liquid phase catalysis using Al 2 O 3 4,11 and molecular sieves. 5They are also synthesized in the presence of Zr(KPO 4 ) 2 12 and Amberlyst A21 ® . 135][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. 14hey are also obtained in the presence of diammonium hydrogen phosphate, 15 H 6 P 2 W 18 O 62 • 18H 2 O, 16 DBU 17 and K 2 CO 3 under microwave irradiation. 18owever, 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.
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. 1 H NMR and 13 C 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 d (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 H 2 O (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-oxodihydropyrano[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 H 2 O (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.

Table 1 .
Synthesis of various 4H-chromenes using TBBDA and PBBS at room temperature a Products were characterized from their physical properties, by comparison with authentic samples, and by spectroscopic methods.b Without using the catalysts.

Table 2 .
Synthesis of various dihydropyrano[3,2-c]chromenes using TBBDA and PBBS under refluxing H 2 O:EtOH (1:1) a Products were characterized from their physical properties, by comparison with authentic samples, and by spectroscopic methods.b Without using the catalysts.