Microwave-Assisted Improved Regioselective Synthesis of 12 H-Benzopyrano [ 3 , 2-c ] [ 1 ] benzopyran-5-ones by Radical Cyclisation

Two new effective methodologies have been adopted for the preparation of 4-(2′-bromobenzyloxy)benzopyran-7-ones 3(a–h). In the first methodology, 4-hydroxy[1]benzopyran-2-ones 1(a–d) was alkylated with 2-bromobenzyl bromide 2a or 2-bromo-5methoxy benzyl bromide 2b under phase transfer catalysis condition using lithium hydroxide/tetrabutyl ammonium bromide in N,N-dimethylformamide at 40–50◦C and in the second method the microwave irradiation protocol has been exploited by simply mixing of 4-hydroxy[1]benzopyran-2-ones 1(a–d) with 25% excess of 2-bromobenzyl bromide 2a or 2-bromo-5-methoxy benzyl bromide 2b. A catalytic amount of TBAB and potassium carbonate were added and irradiated in an open Erlenmeyer flask in a microwave oven for 4–10 min. The tributyltin-hydride-mediated radical cyclisation of 3(a–h) was carried out under microwave irradiation to generate 12H-benzopyrano[3,2-c][1]benzopyran-5-ones 4(a–h) in 78–88% yield and in this technique yields were significantly improved and reaction time was shortened compared to the previously reported conventional radical cyclisation method.


Introduction
In present time, the chemistry of radical cyclisation has been developed as a ripe field in all the aspects starting from polymers to synthesis of organic and inorganic compounds and such reactions have been applied to the synthesis of a number of natural products, pharmaceuticals, and others which mainly include heterocyclic compounds as a core structure [1].It is now well established that radical chemistry offers a wide array of useful transformations for efficiently constructing complex molecular architectures [2][3][4][5][6] and has become part of the repertoire of the synthetic organic chemist.Radical reactions are of vital importance in biology and medicine.The search for various heterocycles and many new methodologies has been a central goal for free-radical chemists in recent years.
Recently, microwave enhancement of organic reactions has attracted the chemists [20] as this technique is extremely useful in organic synthesis and the reactions can be performed with high reaction rates, low byproducts, high yields, and ease of experimental manipulations [21,22].It is now well established that microwave heating technique is extremely powerful tool to promote a variety of chemical reactions [23][24][25][26] and the beauty of such microwaveassisted reaction lies in its dramatically reducing reaction time or sintering time [27], increasing the overall yield and selectivity of the reaction, accelerating the rate of the reaction of various thermally conducted reactions, and the simple and easy work-up procedure.It is obvious that microwave-promoted organic synthesis is an efficient and environmentally friendly synthetic route in modern synthetic organic chemistry as well as in green chemistry and in particular microwave irradiation technique under solventfree conditions are extremely useful in offering reduced pollution compared to the traditional organic synthesis involving heating by conventional methods [23][24][25][26][27][28][29][30][31] and in the solvent-free reactions the absorption of microwave irradiation is restricted to the reacting species only [32].
In the conventional heating technique, reactants are slowly activated by a conventional external heat source and the heat penetrates first through the walls of the vessel for reaching the solvent and reactants and therefore is a slow and inefficient method for transferring energy into the reacting system.But, microwaves can create direct coupling with the molecules of the entire reaction mixture and the result is a rapid rise in temperature.There are many organic transformations proceeding through radical chemistry and chemists wonder if microwave irradiation can assist radical formation; microwave-promoted free-radical chemistry is increasingly being explored [33][34][35][36][37][38][39][40][41][42].
In spite of increasing interest of microwave irradiation technique, the use of this methodology in free-radical-based organic synthesis is less common [60][61][62][63][64].As a part of our recent research activity we became interested in building the 6-membered fused pyran ring by radical cyclisation exploiting microwave irradiation.It is well known that 4-hydroxycoumarins are a class of anticoagulant drug molecules derived from coumarin, and the importance of physiological activity [65,66] of coumarin and its derivatives motivated us to undertake the synthesis of 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by aryl radical cyclisation, and in this paper, we will highlight the microwaveassisted one pot facile method compared to our previously described conventional method [67].

Results and Discussion
Previously we prepared [67] 4-(2 -bromobenzyloxy)benzopyran-7-ones 3(a-h) by refluxing 4-hydroxy [1]benzopyran-2ones with either 2-bromobenzyl bromide 2a or 2-bromo-5-methoxy benzyl bromide 2b in dry acetone in the presence of anhydrous potassium carbonate.Herein, we have established two new more effective methodologies for the preparation of 4-(2 -bromobenzyloxy)benzopyran-7-ones 3(a-h).In the first methodology, 4-hydroxy [1]benzopyran-2-ones 1(a-d) can be successfully alkylated with 2bromobenzyl bromide 2a or 2-bromo-5-methoxy benzyl bromide 2b under phase transfer catalysis condition using lithium hydroxide/tetrabutyl ammonium bromide in N,Ndimethylformamide at 40-50 • C with a shorter reaction time than the conventional acetone-potassium carbonate method (Scheme 1 and Table 1).This new protocol involving reagents (LiOH, TBAB, and DMF) which are apparently little expensive than the previous one, but considering the shorter reaction time and higher yield this new technique is considered to be more effective and energy saving too.In this case, addition of less expensive sodium hydroxide in place of lithium hydroxide would break the lactone ring of the coumarin moiety and thus will be avoided.However, by using less basic LiOH at around 40-50 • C, the products 3(a-h) were obtained in very good yield.
Additionally, we have also exploited the microwave irradiation protocol in synthesising the radical precursor 3(a-h) under solvent free condition.The syntheses were carried out by simply mixing of 4-hydroxy [1]benzopyran-2-ones 1(a-d) with 25% excess of 2-bromobenzyl bromide 2a or 2-bromo-5-methoxy benzyl bromide 2b and a catalytic amount Product 4 (yield) mp of tetrabutylammonium bromide (TBAB) (Scheme 1 and Table 1).The mixtures were adsorbed on potassium carbonate and irradiated in an open Erlenmeyer flask in a microwave oven for 4-10 min (optimized time).The crude reaction mixture after usual workup was purified by column chromatography.Elution of the column with an appropriate mixture of ethyl acetate and petroleum ether gave the required product 3.
We found that the above alkylation reaction using microwave irradiation (MWI) has advantages over conventional conditions [68] in several aspects including shorter reaction times, cleaner products, and simpler work-up procedures.
Previously we reported [67] the radical cyclisation mediated by tributyltin chloride and sodium cyanoborohydride, which was carried out initially under refluxing benzene conditions, in the reaction mixture maintained by the addition of this reagent via a syringe pump.The reaction furnished 12H-benzopyrano [3,2-c][1]benzopyran-5-ones (70-85%), respectively.Performing the cyclisation under microwave heating in an open vessel resulted in some shortening of the reaction time (1 h instead of 3-4 h for complete consumption of starting material, as detected by TLC), but, the important factor is that yields were significantly improved to 78-88% (Scheme 2).
In summary, this paper describes new and efficient methodologies involving microwave irradiation to synthesise 12H-benzopyrano [3,2-c][1]benzopyran-5-ones via radical cyclisation pathway and the mechanism of all the reactions is already well established [67].This microwave-assisted free radical cyclisation is proved to be extremely powerful synthetic tool and the beauty of such reactions is improved reaction yields, shortening of reaction time, and being environment friendly.The methodology described here is very simple and general one.

Experimental
All the reagents were obtained from commercial sources and used as received.Except methanol (which was HPLC grade), the remaining solvents were dried and distilled before use.Elemental analyses and mass spectra (ESI+) were performed at the Indian Institute of Chemical Biology, Kolkata.UV absorption spectra were recorded in EtOH on a Shimadzu UV-2401 PC spectrophotometer (λ max in nm) and IR spectra on KBr discs on a Perkin Elmer L 120-000A apparatus (ν max in cm −1 ).Routine 1 H and 13 C{ 1 H} NMR spectra were recorded with a Bruker DPX-300 MHz instrument and Varian VRX-500 MHz instruments at 298 K.The chemical shifts (δ) are given in ppm and the coupling constants (J) in Hz.In all cases, the solvent for the NMR experiments was CDCl 3 (99.9%)and the references were SiMe 4 (for 1 H and 13 C { 1 H} NMR experiments).Silica gel ((60-120, 230-400 mesh), SRL, India) was used for chromatographic separation.Silica gel G (E-Merck (India)) and Silica gel 60F 254 (E-Merck (Germany)) were used for TLC.Petroleum ether refers to the fraction boiling between 60 and 80 • C. Reaction mixture was irradiated in the CEM Discover microwave synthesis system.
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Cl 2 (2 × 50 mL) and washed with water and then with brine and dried (Na 2 SO 4 ).After removal of dichloromethane solvent, the crude reaction mixture was purified by flash chromatography.Elution of the column with an appropriate mixture of ethyl acetate and petroleum ether gave the required products 3 in excellent yield.