BF 3 OEt 2 and MeSO 3 H-Promoted reactions of phenols and ethyl phenylpropiolate as a synthetic routes to neoflavones and a potential route to flavones

The BF 3 .OEt 2 and MeSO 3 H-promoted reactions of phenols and ethyl phenylpropiolate to give neoflavones in 17-96% and flavones in 0-25% yield are described. In general, phenols with activating substituents favor the formation of neoflavones under both BF 3 .OEt 2 and MeSO 3 H-promoted reaction conditions. Phenol and p - Chlorophenol reacted with ethyl phenylpropiolate under the MeSO 3 H-promoted reaction conditions to give close to 1:1 mixtures of the corresponding neoflavones and flavones.


Introduction
2][3][4] As part of a broader research project of drug discovery, the isolated compounds are supposed to be developed as lead compounds.However, the compounds are mostly isolated in minute quantities from medicinal plants and that has proved to be the bottleneck for the development of the compounds into lead compounds for the drug discovery.
Synthesis provides a possible route for accessing flavonoids in quantities that will allow their development into lead compounds for drug discovery.Our research group therefore initiated a research project on development of methods for the synthesis of flavonoids.A number of these methods have been reported in literature. 5,6 ere, we report the acid-promoted reactions of phenols and ethyl phenylpropiolate as a possible synthetic route to neoflavones or/and flavones.The theoretical basis of using the acid-mediated reaction of phenols and ethyl phenylpropiolate is summarized in scheme 1.It was anticipated that the synthetic process will proceed through a trans-esterification reaction of phenol 1 and propiolate 2 to give ester 3 which will in turn undergo an intramolecular electrophile aromatic substitution-Michael addition ring closure reaction to give coumarin 4. Alternatively, ester 3 will undergo a Fries rearrangement reaction to give intermediate 5 which can in turn undergo a ring closing Michael type reaction to give flavone 6.[9] Scheme 1. Acid-mediated reaction of Phenols and ethyl phenylpropiolate.

Results and Discussion
The model reaction of this study involved heating a mixture of phenol 1 and ethyl phenylpropiolate 2 in the presence of BF3.OEt2, Scheme 2. After 18 hours of heating, the reaction was quenched with distilled water and the organic components were extracted with chloroform.Purification of the organic extract using column chromatography gave neoflavone 4 in 15% yield together and flavone 6 in 5% yield.Addition of controlled amounts of DMF to the reaction mixture increased the yield of neoflavone 4 to 25% and that of the flavone 6 to 10% yield and reduced the reaction time to 3 hours.In a parallel reaction, a mixture of phenol 1, propiolate 2 and MeSO3H was stirred at room temperature for 2 hours to give neoflavone 4 in 23% yield and flavone 6 in 25% yield.
Encouraged by the results discussed above, we set out to investigate the effects of substituted phenols on the reaction.Interestingly, subjection of a mixture of resorcinol 7 and propiolate 2 to reaction conditions a) gave only neoflavone 8 in excellent yields of 90%, Scheme 3. The corresponding flavone was not detected.The reaction of 2 and 7 in the presence of MeSO3H also gave only neoflavone 8 in 96%.
The observation that the additional hydroxyl group of resorcinol 7 completely shuts down the Fries rearrangement and consequently the formation of the corresponding flavone was a striking aspect of the acidmediated reaction of phenols with propiolate 2. It was reasoned that groups that donate electrons to phenol less than the hydroxyl group will not stop the Fries rearrangement.Indeed, when a mixture of m-cresol 9, propiolate 2 and excess BF3.OEt2 in the presence of controlled amount of DMF was heated, neoflavone 10, flavones 11 and 12 were isolated in 20%, 4% and 6% respectively, Scheme 4, reagent and conditions a).On the other hand, exposure of a mixture of m-cresol 9 and propiolate 2 to the action of MeSO3H led to the formation of neoflavone 10 in 80% and flavone 11 in 15%, Scheme 4, reagents and conditions b).Flavone 12 was not detected under reaction conditions b).Scheme 4. Acid-mediated reaction of m-cresol and propiolate 2.
p-Cresol participated in the BF3.OEt2-mediated reaction with propiolate 2 to give neoflavone 14 in 35% yield and flavone 15 in 15%, Scheme 5, reagents and conditions a).The MeSO3H-promoted reaction of p-cresol 13 and propiolate 2 gave neoflavone 14 in 42% and flavone 15 in 12% yield scheme 5, reagents and conditions b).The low yield of this reaction can be attributed to non-cooperative directing effects of the methyl and hydroxyl groups of p-cresol 13.Scheme 5. Acid-mediated reaction of p-cresol and propiolate 2.
It was anticipated that deactivating groups on the phenol would stop both the Michael reaction which led to the formation of the neoflavone and the Fries rearrangement which gave the flavone.Indeed, when a mixture of 4-nitrophenol and propiolate 2 was subjected to either reaction conditions a) or b), none of the corresponding products were detected.However, p-chlorophenol 16 reacted with propiolate 2 under reaction conditions a) to give neoflavone 17 in 20% yields and flavone 18 in 8%.Under reaction conditions b) the reaction proceeded to give neoflavone 17 in 17% yield and flavone 18 in significantly increased yield of 13%.The increase in the proportion of flavone 18 when the reaction of 16 and 2 is performed under reaction conditions b) has potential for optimization to be a reliable route to flavones with amenable electron withdrawing groups on ring A. Scheme 6. Acid-promoted reaction of m-cresol 16 and propiolate 2.

Conclusions
In conclusion, the acid-promoted reaction of phenols and ethyl phenylpropiolate was described as a route to neoflavones and a potential route to flavones.Participation of phenols with activating substituents in the reaction were in general found to favour the formation of while phenols and p-chlorophenol gave to 1:1 ratio of the corresponding neoflavones and flavones.

Experimental Section
Typical procedure for BF3.OEt2-promoted reaction of phenols and ethyl phenylpropiolate A mixture of phenol 1 (0.50 g, 5.3 mmol) with ethyl phenylpropiolate 2 (0.93 g, 5.3 mmol) in the presence of excess BF3.OEt2 (3 mL, 24.3 mmol) and DMF (1.88 mL, 24.3 mmol) was refluxed for 3 h.The reaction was quenched with water and extracted with chloroform.The extract was concentrated using rotavapor and adsorbed silica before been subjected to column chromatography and eluted with n-hexane-ethyl acetate (8: 3) Typical procedures for MeSO3H-promoted reaction of phenols and ethyl phenylpropiolate A mixture of phenol 1 (0.5 g, 5.3 mmol) and ethyl phenylpropiolate 2 (0.93 g, 5.3 mmol) in the presence of excess methanesulfonic acid (3 mL, 46.2 mmol) was stirred at room temperature for 2 h.The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with chloroform.The extract was then concentrated using rotavapor and subjected to column chromatography eluting with n-hexane-ethyl acetate (8:3).