DABCO Catalyzed Synthesis of Xanthene Derivatives in Aqueous Media

The reaction of 5,5-dimethylcyclohexane-1,3-dione with various heteroarylaldehydes afforded the corresponding heteroaryl substituted xanthene derivatives 1(a–f). The reaction proceeds via the initial Knoevenagel, subsequent Michael, and final heterocyclization reactions using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst in aqueous media. The synthesized heteroaryl substituted xanthenes 1(a–f) reacted with malononitrile to obtain different alkylidenes 2(a–f). Short reaction time, environmentally friendly procedure, avoiding of cumbersome apparatus, and excellent yields are the main advantages of this procedure which makes it more economic than the other conventional methods.


Introduction
In the past few decades, the synthesis of new heterocyclic compounds has been a subject of great interest due to their wide applicability. The importance of multicomponent reactions in organic synthesis has been recognized, and considerable efforts have been focused on the design and development of one-pot procedures for the generation of libraries of heterocyclic compounds [1,2]. Multicomponent reactions (MCRs) have emerged as an important tool for building of diverse and complex organic molecules through carbon-carbon and carbon-heteroatom bond formations taking place in tandem manner [3]. Particularly, in the last three decades a number of three-and four-component reactions have been developed [4][5][6].
Xanthene derivatives are very important heterocyclic compounds and have been widely used as dyes [7] and fluorescent materials for visualization of biomolecules and in laser technologies [8]. They have also been reported for their agricultural bactericide activity [9] and anti-inflammatory [10] and antiviral activity [11]. These compounds are also utilized as antagonists for paralyzing action of zoxazolamine and in photodynamic therapy [12]. Due to their wide range of applications, these compounds have received a great deal of attention in connection with their synthesis. A wide variety of methods for the preparation of the xanthenes have been reported [13][14][15][16][17][18][19]. However, many of these methods are associated with several shortcomings such as long reaction times (16 h to 5 days), expensive reagents, harsh conditions, low product yields, and use of toxic organic solvents. Diazabicyclo[2.2.2]octane (DABCO) is an inexpensive, nontoxic, and commercially available catalyst that can be used in laboratory without special precautions [20][21][22]. But, it has not been used as a catalyst in xanthene synthesis; only a few reports are therein the literature [23][24][25]. This prompted us to develop a new synthetic method for heteroaryl substituted xanthenes using DABCO as a catalyst (see Scheme 1).
With our continued interest in the synthesis of heterocyclic systems [26] and application of DABCO as a catalyst in organic synthesis [27] herein, we wish to report a facile condensation of heteroarylaldehyde, 5,5 -dimethyl-1,3-cyclohexanedione (dimedone), in the presence of catalytic amount of DABCO to produce a variety of 1,8-dioxooctahydroxanthenes derivatives 1(a-f) (Scheme 2).

Results and Discussion
In order to optimize the reaction conditions, the synthesis of compound 1d was used as a model reaction. Therefore, a mixture of 3-methyl thienaldehyde (1 mmol), 5,5-dimethyl cyclohexane-1,3-dione ( an appropriate time as indicated by TLC using different amounts of DABCO ( Table 1). The efficiency of the reaction is mainly affected by the amount of the catalyst. Traces of the product could be detected in the absence of this catalyst (entry 1), while good results were obtained in the presence of DABCO. The optimal amount of the catalyst was 10 mmol% (entry 6); the higher amount of the catalyst did not increase the yield noticeably (entry 7). The synthesized products 1(a-f) in Scheme 2 were further treated with malononitrile to obtain corresponding alkylidenes 2(a-f) by the Knoevenagel reaction. The reaction involves the attack of malononitrile on two carbonyl groups (C=O) of xanthene derivatives to form alkylidene malononitrile within 60 min. using DABCO as an organic catalyst (Scheme 3).
In order to extend the range of substrates, we employed a wide range of aldehydes in the presence of 10 mmol% DABCO under similar conditions. It was found that this method is effective with a variety of substituted heteroarylaldehydes independent of the nature of the substituent on the heteroaromatic ring and obtained satisfactory results ( Table 2).
The formation of the products 1(a-f) was assumed to proceed via formation of a Knoevenagel product which on addition of 2nd molecule to give the Michael adduct intermediate was followed by cyclization reaction (Scheme 4). An , -bis(arylidene)cycloalkanone A was first condensed with dimedone to afford the B on addition of 2nd molecule of dimedone; this step can be regarded as a Michael addition reaction. The intermediate B was cyclized by nucleophilic attack of the OH group on the C=C moiety and gave the expected products 1(a-f).

Conclusion
In summary, we have reported an efficient, simple, convenient, and straightforward practical one-pot procedure for the synthesis of 1(a-f) in aqueous media. Reaction of malononitrile on the synthesized products 1(a-f) gave corresponding alkylidene derivatives 2(a-f) in good yields. All starting materials are readily available from commercial sources. Moreover, there is no need for dry solvents or protecting gas atmospheres. Using DABCO as a catalyst offers advantages including simplicity of operation, easy workup, time minimizing, and high yields of products. The procedure is very simple and can be used as an alternative to the existing procedures.  1(a-f). A mixture of 5-membered, heteroarylaldehyde (1 mmol), 5,5-dimethylcyclohexane-1,3-dione (2 mmol), and DABCO (10 mmol%) in H 2 O (20 mL) was refluxed for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature, and the solid was filtered off and washed with H 2 O. The crude product was purified by recrystallization from 95% ethanol.  was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature and the solid was filtered off and washed with H 2 O. The crude product was purified by column chromatographic technique using hexane: ethyl acetate. 3,6,6-tetramethyl-3,4,5,6,7,9-    3,3,6,6-Tetramethyl-9-(1H-pyrrol-2-yl) -3,4,5,6,7,9-