Greener route for the synthesis of chromone using Amberlyst®15 via enaminones

An efficient and novel methodology is reported for the synthesis of various 4H-chromene-4-ones via enamino ketone followed by cyclization with Amberlyst®15 was described. The Amberlyst®15 worked well as deaminating agent as well as enhances the efficiency of cyclization reaction for the synthesis of chromones. This method offers several advantages including mild reaction conditions, high yielding, catalyst reusability, lower the reaction toxicity, operational easiness and broad substrate scope.


Introduction
Chromone derivatives have a wide range of biological activities. 1 Chromone derivatives were shown to be tyrosine and protein kinase inhibitors, [2][3] anti-inflammatory, 4 antiviral, 5 antioxidant [6][7] and antihypertensive agents. 5Compounds containing chromone moiety are also active at benzodiazepine receptors, 8 on lipooxygenase and cyclooxygenase. 9In addition to this, they have shown to be anticancer agents 10 and in the treatment of cystic, as they activate the cystic fibrosis trans-membrane conductance regulator. 113] A variety of biologically active compounds synthesized from chromones have been found widespread use in medicinal chemistry (Figure 1). 14The chemistry of Amberlyst®15 is well known in the past decade. 15It is a heterogeneous macro reticular polystyrene-based ion exchange resin and contains strongly acidic sulfonic group functionality.Amberlyst®15 has many avantages viz.safe to use, easy to measure and easily separable at the end of reaction.] In general, synthesis of chromones has required acidic or basic conditions.One of the first methods for the synthesis of chromone was introduced by Heywang and Kostanecki which involved decarboxylation of chromone-2-carboxylic acid. 18The traditional 2,3-disubtituted benzopyranone were synthesized under acidic condition with 3-aryl-1-(2-hydroxyphenyl) propane-1,3-dione derivatives undergoing intramolecular condensation.Mostly, Claisen ester condensation and Bayer-Venkataraman rearrangement are commonly used for synthesis of 1,3-dione derivatives.Most of the synthesis was reported under acidic reaction conditions whereas by using basic reaction condition for ring closure required several hours.Gammill.0] Recently, Joussot and co-workers reported an efficient synthesis of 3-substituted chromones via enamino ketones. 21Synthesis of 3-benzylated chromones are also reported in the presence of NaI from enamino ketones and benzyl bromide. 22There are limited studies on the synthesis of 2, 3-unsubstitued chromones from enaminones, compared to 3-substituted chromones. 23For example, chromone 3a was synthesized by cyclization via deamination of enamino ketone 2a by using TMSCl/DMF.By using hydrochloric acid, Chromone synthesis was reported by Pleier A.K. et al, (Scheme 1, entry a). 25 Chromone-3-one was synthesized from enamino ketones (2a) using several sulfamoylating reagents was reported by Thiel Engelhart and Aldrich (Scheme 1, entry b). 263P was used for chromone synthesis under micro-wave reaction condition, reported by C. Balakrishna et al, (Scheme 1, entry c). 27Using mCPBA as an oxidative reagent was used for 3-Hydroxy Chromone synthesis reported by R. Gudipati et al. (Scheme 1, entry d). 28The reported method involves use of stringent reaction conditions like micro-wave, elevated temperature and not used environnemental compatibility solvents.To overcome all these limitations, the development of new methodologies for the synthesis of chromon-4-one is still required.Scheme 1. Synthetic approach of chromone using Ameberlyst®15.

Results and Discussion
In our continued ongoing efforts to produce innovative synthetic methodologies [29][30][31][32][33][34] for the synthesis of Chromone-4-one analogues.We envisioned that Amberlyst-15 can be used for the cyclization of enamino ketone to prepare the chromone-4-one by taking advantage of suitable position of the hydroxyl group in the aromatic ring.Herein, we have described the synthesis of chromone-4-one derivatives by using Amberlyst®15.We have introduced first time, Amberlyst-15 as deamination reagent for the synthesis of chromone derivatives.Scheme 2. Preparation of Chromone Using Ameberlyst®15.
Initially, 1-(2-hydroxyphenyl) ethanone 1a was treated with N, N-Dimethylformamide dimethyl acetal under microwave irradiation to synthesized enaminone 2a, 32 was analyzed by LCMS and 1 H-NMR data.The peak at 8.2 ppm in 1 H-NMR Spectrum shows the olefinic proton which was close to the nitrogen.The conversion of enaminoketone (2a) to chromone (3a) was executed by using Amberlyst®15 at room temperature.Thus the model reaction was conducted by treating enaminone (2a, 1 mmol) in Toluene solvent with Amberlyst 15 (40% w/w) at ambient temperature.We are pleased to find that this reaction condition worked well for synthesis of chromone with the good yield.(Table 1, Entry 4).To optimize the reaction conditions, we have screened several réaction conditions (Table 1).Initially, we have performed the reaction without Ameberlyst-15 at room temperature and observed no product formation (entry 1) then we have introduced the Amberlyst-15 and monitored the reaction and showed 46% conversion of desired chromone product, further we have continued the reaction at room temperature for 12 h and observed 95% conversion of desired chromone product (entry 2 to 4).In order to reduce the reaction time, we have performed the reaction under micro-wave irradiation at 100 °C however, not observed much promising conversion of chromone (entry 5).
To validate further we have changed the solvents like acetone, dimethyl carbonate, acetonitrile and DCM.However, these solvents not shown the good conversion compared to toluene and in DCM conversion was observed 89% (entry 6 to 9).In addition, we have performed controlled experiment by a decrease in the amount to 25% w/w of Amberlyst-15, resulted 43% conversion of chromone (entry 10).These experiments showed that the optimized reaction conditions were 40 wt% Amberlyst-15 in toluene at room temperature for 12 h to obtain an 95% yield of 3a (entry 4, Table 1).The work-up procedure also simplified by filtering the Amberlyst-15 and evaporated the reaction mixture under reduced pressure to get pure chromone product.We did not used any toxic solvents or reagents.
We have examined the recyclability of Amberlyst-15 ion-exchange resin up to five cycles.In the first and second cycle, we have observed the 95% yield of chromone (3a) consistantly.From third to five cycles yields are 88%, 84% and 75% respectively.We have activated the recycled catalyst Amberlyst-15 using aqueous HCl follwed by water and methanol.When we have used recovered catalyst as such without activation, the reaction was unsuccessful.
Thus, a series of enaminones 2a-p were taken for the reaction to prove this method applicability.Excellent yield of the intended chromone derivatives 3a-p (Table 2) was obtained in each case under the optimum reaction conditions.This methodology was tolerant of various halides (Cl, Br, and F) and aryl halides.Both electon rich and deficient aromatic rings showed reactivity similar under this optimal conditions.In Table 2, synthesized Chromones 3a 27 , 3e 35 , 3k 36 , 3n 27 , 3o 37 and 3p 38 are reported in the literature, 3b, 3c, 3d, 3f, 3g, 3h, 3i, 3j, 3i and 3m are unknown compounds.A one-pot chromone synthesis was also tried, o-hydroxy acetophenone (1a) and DMF-DMA in toluene with amberlyst®15 at RT for 12 hours, chromone 3a was not formed, instead we have observed the formation of compound 2a which was confirmed by LCMS data.

Conclusions
In summary, we have developed an efficient and novel methodology, simply reproducible of substituted chromone derivatives by using an excellent Heterogeneous catalyst as amberlyst®15.This method offers an effective alternative to the mild acidic conditions that are required generally for this conversion.The reaction conditions are easy and sufficiently mild to tolerate various functionalities which will function the potential for further functionalization of the chromone products.We anticipate that this method is going to be find widespread application in preparation of chromone derivatives.This methodology can also be used to synthesize chromones on a gram scale.
General procedure for the synthesis of chromen-4-one derivatives.To a stirred solution of compound Enaminone 2 (1 mmol) was dissolved in toluene (4 ml), was added amberlyst-15 (40% w/w) and the reaction mixture was stirred at RT for 12 h.The progress of the reaction was monitored by TLC (30% Ethyl acetate & Pet ether).After completion of the reaction, the reaction mixture was filtered through celite pad and washed with toluene.The filtrate was evaporated under reduced pressure to obtained crude compound 3, which was further triturated with n-pentane to get pure compond 3 as off white solid.4H-Chromen-4-one (3a).The title compund was prepared following general procedure compound 3a was off white solid in 95% yield.