BAKER’S YEAST CATALYZED AND ULTRASOUND ACCELERATED SYNTHESIS OF 2-AMINO-2-CHROMENES

In the present work, baker’s yeast catalyzed efficient synthesis of 2-amino-2-chromenes in methanol is presented. Here the ultrasonication has dual role i.e. as a source of energy for the reaction and tool for the disruption of the yeast cells. The cyclocondensation has been essentially carried under neutral conditions, thus reducing the

These synthetic methodologies which have been developed to accomplish the cyclocondensation reaction have their own merits and demerits. Some of the significant disadvantages associated with many of the existing synthetic protocols involve; prolonged reaction times, formation of side products resulting in lower yields, harsh reaction conditions, tedious work-up procedures and the use of expensive/ environmentally toxic catalysts.
Literature reveals that there is no report on the use of biocatalyst/ enzyme for accelerating the one pot multicomponent condensation leading to 2-amino-2-chromenes. Considering the above observations and in continuation of our work [43][44][45] towards the acceleration of synthetic protocols leading to bioactive molecules by employing biocatalysts/ biomimetic catalysts, it was thought worthwhile to study the catalytic role of baker's yeast for the synthesis of 2-amino-2-chromenes via three component reaction of aldehyde, malononitrile and 1-naphthol.
The application of ultrasonic waves is found to become more convenient to run organic synthesis [46]. Its development in the past few years has been considerably increased to know its mechanism of action inside the reaction flask [47]. Several applications in organic synthesis have made sonochemistry an attractive technique [48] and hence increasingly used in organic synthesis [49]. It has proved to be a great tool for improving yields and decreasing the reaction time [50] Considering all the above facts here in the present work objective was set to develop an efficient, cost effective and sustainable route for one pot three component cyclocondensations of aryl aldehydes, malononitrile and 1-naphthol in non-aqueous media (organic solvents) under relatively mild reaction conditions using an easily available, cheaper whole cell biocatalyst, active dry baker's yeast instead of the catalysts reported in the literature [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. The objective was also set in mind to use non-conventional energy source, ultrasonication for assisting the cyclocondensation.

Results and Discussion:-
The investigations were started with an optimization study of model reaction by allowing cyclocondensation of 4nitrobenzaldehyde (1g) malononitrile (2) and 1-naphthol (3) in the presence of baker's yeast (Scheme 2). To see the effect of reaction medium on the rate and yield of the reaction, the model reaction was carried in various solvents like water, chloroform, 1,4-dioxane, ethanol and methanol under stirring at room temperature (RT). NO 2 Scheme 2 Initially when the reaction was carried in water at room temperature (RT), it was found that the cyclocondensation gave low (33%) yield even after prolonged stirring at room temperature (36 h) ( Table 1, entry 1). The model reaction was then separately performed in organic solvents viz. chloroform, 1,4-dioxane, ethanol and methanol (Table 1). Comparatively better results were obtained when methanol was used as a solvent for the reaction (Table  1, entry 5). Hence methanol was selected as the reaction medium. In the further attempts to reduce reaction time and enhancing the yield of the product, the model reaction was performed in methanol under ultrasonication. This attempt was made because ultrasonication has been one of the most widely used laboratory methods for the disruption of the cells of baker's yeast for the fast release of enzymes [51]. Model reaction in methanol when performed under ultrasonication gave 87% yield within 2 h (Table 2, entry 3). Methanol US 2.5 nd b a Reaction conditions: 4-nitrobenzaldehyde (5 mmol), malononitrile (5 mmol), 1-naphthol (5 mmol), baker's yeast (2g) in methanol under ultrasonication. a Isolated yields. b Reaction without baker's yeast.
In view of these observations methanol was selected as the reaction medium to run baker's yeast catalyzed synthesis of 2-amino-2-chromene under ultrasonication. Subsequently the cyclocondensations of other substituted aryl aldehydes, malononitrile and 1-naphthol have been carried under the optimized reaction conditions and obtained the respective 2-amino-2-chromenes. The chromenes synthesized by this optimized novel protocol are already reported in literature [52] the physical parameters of the obtained products are in good agreement with those reported in the literature [27, 32,52]. The results are recorded in Table 3 (Scheme 2). From these results it seems that the baker's yeast is capable of catalyzing efficiently the present cyclocondensation. To investigate the role of baker's yeast in cyclocondensation the model reaction was run in the absence of baker's yeast, as a control reaction and formation of desired product was not observed (Table 2, entry 5).
Baker's yeast generates variety of enzymes which contains various amino acid residues. Among them, here in the present reaction it is proposed that Asp-His dyad present in the enzyme residues are active in catalyzing the cyclocondensation reaction.

Conclusion:-
In summary, baker's yeast has been used as whole cell biocatalyst to accelerate the one pot three component cyclocondensation of aryl aldehydes, malononitrile and 1-naphthol in methanol, to obtain 2-amino-2-chromenes. Ultrasonication as a non conventional energy source has been used for acceleration of synthetic route. The newly developed protocol has following advantages. 1. Baker's yeast is inexpensive and readily available biocatalyst. 2. The route is simple and user friendly. 193 3. Reaction time has been reduced appreciably due to use of ultrasonication as energy source.

Experimental section: General procedure for the synthesis of 2-amino-2-chromenes (4a-k):
To the round bottom flask containing methanol (25 ml), active dry baker's yeast (2 g) was added and sonicated for 10 min. After 10 min., aryl aldehyde (5 mmol) and malanonitrile (5 mmol) were added and further sonicated for 15 minutes. Then to this sonicated reaction mass 1-naphthol (5 mmol) was added and reaction was allowed to complete, under ultrasonication (20 KHz) at RT. The progress of the reaction was monitored by thin layer chromatography, using ethyl acetate: pet ether (2:8) as a solvent system. After two hours the reaction mass was filtered through the bed of celite (2 g). The solvent methanol was removed from filtrate under reduced pressure and the crude product obtained was crystallized from ethanol and obtained respective 2-amino-2-chromen (4a-k) (  248-250 a Reaction conditions: aldehyde (5 mmol), malononitrile (5 mmol), 1-naphthol (5 mmol), baker's yeast (2g) in methanol (25 ml) under ultrasonication. b Isolated yields. c The known 2-amino2-chromenes synthesized by this method are having their melting points in good agreement with those reported in the literature. [27,32,52]