Fast highly efficient ‘on - solvent’ non -catalytic cascade transformation of benz-aldehydes and 4-hydroxycoumarin into bis(4-hydroxycoumarinyl)arylmethanes

Non-catalytic cascade reaction of benzaldehydes and two equivalents of 4-hydroxycoumarin initiated by reflux in propanol results in the fast (15 min) and efficient formation of substituted tetrahydro-1 H -xanthen-1-ones in 93 – 98% yields. The developed fast cascade approach to the substituted bis(4-hydroxycoumarinyl)arylmethanes, which are known as medicinally relevant substances with anti-HIV, antibiotic, anti-inflammatory and anti-cancer activity, is beneficial from the viewpoint of diversity-oriented large-scale processes and represents fast, efficient and environmentally benign synthetic concept for cascade reactions strategy.


Introduction
Cascade reactions are known as powerful method to construct molecular complexity from readily available starting materials by combining two or more reactions into a single transformation. 1,2Cascade reactions forming a number of bonds by one operation are useful for the creation of polycyclic and spirocyclic compounds. 3Thus, cascade reactions are of increasing importance in modern organic chemistry.This is not only due to the need for the more efficient and less labour-intense methodologies for the synthesis of pharmaceuticals and other fine chemicals, but also because of the increasing importance of the environmental considerations. 4,5oumarins or benzopyran-2-ones, are one of the most known oxygen heterocyclic compounds which are efficiently studied from their discovery up to our days. 6The great interest to these compounds is due to their known anti-cancer, 7,8 anti-inflammatory, 9 antihyperlipidemic 10 anticholinesterase, 11 antinociceptive, 12 antidiabetic and antidepressant 13 activities.
4-Hydroxycoumarins are important class of biologically active substances in nature and in medicine.They exhibit sufficient anticoagulant activity and among them, there are some drugs -Warfarin and Acenocoumarol.Many of them display important pharmacological effects, as anti-inflammatory 14 , anticancer, 15 anti-HIV and antiviral 16 agents.
Although all this procedures for the synthesis of corresponding dicoumarols have their merits, but all of them suffer from some drawbacks, such as unsufficient yields, prolonged reaction times, the use of costly reagents or catalysts.The recovery of the catalyst and the procedure of isolation pure dicoumarols may also be complicated in many cases.
5][36][37][38] Considering our results on the non-catalytic multicomponent and cascade transformation of C-H acids and carbonylcompounds [34][35][36][37][38] as well as the certain biomedical application of bis(4hydroxycoumarinyl)arylmethanes mentioned above, we were prompted to design a convenient fast and facile non-catalytic methodology for the fast efficient cascade synthesis of substituted bis(4hydroxycoumarinyl)arylmethanes based on cascade reaction of of benzaldehydes and 4-hydroxycoumarin.
The most interesting was the fact that just the same yield (75%) was obtained in ethanol without any catalyst (entry 3, Table 1).Somewhat lower yields 70% were found when reaction time was shortened to 15 min.

Conclusions
The very simple and fast (15 min.)non-catalytic procedure can produce an efficient and selective transformation of benzaldehyde, and 4-hydroxycoumarin into substituted 3,3'-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) in excellent 93-98% yields.This new non-catalytic cascade process opens an efficient and convenient way to substituted 3,3'-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones), the pharmacologically active substances with known anti-HIV, antibiotic, anti-inflammatory, anti-cancer activity and promising compounds for different biomedical applications.This non-catalytic cascade procedure utilizes simple equipment; it is easily carried out and is valuable from the viewpoint of environmentally benign diversityoriented large-scale processes.

Experimental Section
General.All melting points were measured with a Gallenkamp melting-point apparatus and are uncorrected. 1H spectra were recorded in CDCl3 with a Bruker Avance II 300 spectrometer at ambient temperature.Chemical shift values are relative to Me4Si.All chemicals used in this study were commercially available.General procedure.A mixture of 4-hydroxycoumarin (1.62 g, 10 mmol) and benzaldehyde (5 mmol) in 1 mL of n-PrOH was heated under stirring at 97 °C for 15 min.Then the precipitated product was filtered off, rinsed with an ice-cold ethanol (1 mL) and dried under reduced pressure.