Synthesis Of Flavone Skeleton By Different Methods

Introduction

Flavones (flavus = yellow), are a class of flavonoids based on the backbone of 2-phenylchromen-4-one Apart from flavones other flavonoids are  isoflavonoids, derived from 3-phenylchromen-4-one  structure neoflavonoids, derived from 4-phenylcoumarine structure.The three flavonoid classes are all ketone-containing compounds, and as such, are anthoxanthins (flavones and flavonols)

 

Click here to View figure

 

Flavones are well known for their various biological activities such as anticancer¹ Anti inflammatory², anti-osteoporotic³, anti-diabetic⁴, etc. some of the examples as shown as under,

 

Table 1: Click here to View figure

 

Synthetic strategies of flaovones

Traditionally, flavones have been prepared by BakerVenkatramanrearrangement

and Claisen-Schmidt condensation.which involves the conversion of 2hydroxyacetophenones into benzoyl esters, followed by rearrangement in base to1,3diphenylpropane1,3diones which upon cyclization under acidic conditions furnishes flavones.On the other hand hydroxychalcone synthesized from 2hydroxyacetophenone anbenzaldehyde under ClaisenSchmidt conditions can undergo oxidative cyclization to furnish flavones ring.

 

Click here to View figure

 

Basic schemes related to synthesis of flavones is mentioned below (Scheme 1-43)

 

Scheme1  Click here to View figure

 

Solvent free synthesis of flavone is carried out by Julia & co-workers¹⁰

Scheme2

 

Schem2  Click here to View figure

 

Flavones via a Microwave-Assisted, One-Pot Sonogashira−Carbonylation−Annulation Reaction is used by E.Awuah & A.Capretta¹¹.

Scheme 3

 

Scheme3  Click here to View figure

 

Scheme 4: Photo cyclization  of 2-Chloro-Substituted 1,3-Diarylpropan-1,3-diones to Flavones is invented by B.Kosmrrji & co-workers¹².

 

Scheme 4 Click here to View figure

 

Scheme 5.Coversion of intermediate 1,3 dione is carried by G.Romanelli & co-workers¹³.

 

Scheme5.Coversion of intermediate 1,3 dione is carried by G.Romanelli & co-workers13.  Click here to View figure

 

Scheme 6. Alkene hydrogen is replaced by L.Klier & T.Bresser¹⁴.

 

Scheme 6. Alkene hydrogen is replaced by L.Klier & T.Bresser14.  Click here to View figure

 

Scheme 7: A Novel Synthesis of 4H-Chromen-4-ones via Intramolecular Wittig Reaction is used for the synthesis of flavones¹⁵.

 

A Novel Synthesis of 4H-Chromen-4-ones via Intramolecular Wittig Reaction is used for the synthesis of flavones15.  Click here to View figure

 

Scheme8.This invention converts 1,3 dione into flavones.Only base is used for this purpose¹⁶.

 

Scheme8.This invention converts 1,3 dione into flavones.Only base is used for this purpose16.  Click here to View figure

 

Scheme9.Koneni & his group first time invented flavones in which oxygen of flavone come from watr molecule¹⁷.

 

Scheme9.Koneni & his group first time invented flavones in which oxygen of flavone come from watr molecule17. Click here to View figure

 

Scheme10. A two step synthesis of flavones via Wacker oxidation is carried out in this process¹⁸.

 

Scheme10. A two step synthesis of flavones via Wacker oxidation is carried out in this process18.  Click here to View figure

 

Scheme11. G.Kabalka & A.Meredy carried microwave assisted synthesis of flavones.Copper chloride is used as a catalyst for this process¹⁹.

 

Scheme11. G.Kabalka & A.Meredy carried microwave assisted synthesis of flavones.Copper chloride is used as a catalyst for this process19. Click here to View figure

 

Scheme12. Photo-Wittig reaction is apllied for the synthesis of flavones²⁰.

 

Scheme12. Photo-Wittig reaction is apllied for the synthesis of flavones20. Click here to View figure

 

Scheme13. Oxidative cyclisation of chalcone to flavone is carried out for the synthesis of flavones.Here n-tetrabutylammonium tribromide is used as a catalyst²¹.

 

Scheme13. Oxidative cyclisation of chalcone to flavone is carried out for the synthesis of flavones.Here n-tetrabutylammonium tribromide is used as a catalyst21.  Click here to View figure

 

Scheme14. 2’allyoxy chalcone undergoes oxidative coupling when treated with iodine & DMSO²².

 

Scheme14. 2’allyoxy chalcone undergoes oxidative coupling when treated with iodine & DMSO22. Click here to View figure

 

Scheme15.Palladium acetate   is used catalyst for the synthesis of flavones²³.

 

Scheme15.Palladium acetate   is used catalyst for the synthesis of flavones23.  Click here to View figure

 

Scheme16. Construction of flavones through regioselective carbonylative annulation of 2 bromo phenols & terminal alkynes is carried out²⁴.

 

Scheme16. Construction of flavones through regioselective carbonylative annulation of 2 bromo phenols & terminal alkynes is carried out24.  Click here to View figure

 

Scheme17. Ganguly’s synthesis includes synthesis of flavones using O-hydroxy acetophenone & acetyl chloride as a precursor²⁵.

 

Scheme17. Ganguly’s synthesis includes synthesis of flavones using O-hydroxy acetophenone & acetyl chloride as a precursor25.  Click here to View figure

 

Scheme18. One pot synthesis of flavones using ferric chloride is efficient method carrid out by Rajiv Karmarkar & co-worker²⁶.

 

Scheme18. One pot synthesis of flavones using ferric chloride is efficient method carrid out by Rajiv Karmarkar & co-worker26. Click here to View figure

 

Scheme19. Silica supported lewis acids indium chloride & indium bromide undergoes oxidative coupling to give flavones²⁷.

 

Scheme19. Silica supported lewis acids indium chloride & indium bromide undergoes oxidative coupling to give flavones27. Click here to View figure

 

Scheme20.Wet acetone is efficient catalyst for the one pot synthesis of flavones from 2-hydroxy acetophenone & acetyl chloride²⁸.

 

Scheme20.Wet acetone is efficient catalyst for the one pot synthesis of flavones from 2-hydroxy acetophenone & acetyl chloride28. Click here to View figure

 

Scheme21. Formation of 1,3 dione using LiHDMs followed by cyclisation using acid catalyst is achived²⁹.

 

Scheme21. Formation of 1,3 dione using LiHDMs followed by cyclisation using acid catalyst is achived29.  Click here to View figure

 

Scheme 22. Carbonylative couplig using Pd catalyst is invention of this method³⁰

 

Scheme 22. Carbonylative couplig using Pd catalyst is invention of this method30  Click here to View figure

 

Scheme 23. Daniel etal³¹suggested the following methodology consisting of five steps.

 

Scheme 23. Daniel etal31suggested the following methodology consisting of five steps.   Click here to View figure

 

Scheme 24. Iodo & bromo derivatives of flavones were synthesized by this method³².

 

Scheme 24. Iodo & bromo derivatives of flavones were synthesized by this method32. Click here to View figure

 

Scheme  25. Oxidative cyclisation followed by bromination is carried out by this process³³.

 

Scheme  25. Oxidative cyclisation followed by bromination is carried out by this process33. Click here to View figure

 

Scheme 26.Base is used for cyclisation of inermediate to flavone³⁴.

 

Scheme 26.Base is used for cyclisation of inermediate to flavone34.  Click here to View figure

 

Scheme 27. Wittig reaction is applied for the synthesis of flavones³⁵.

 

Scheme 27. Wittig reaction is applied for the synthesis of flavones35.  Click here to View figure

 

Scheme 28. Frédéric etal³⁶suggested

 

Scheme 28. Frédéric etal36suggested  Click here to View figure

 

Scheme 29 30.  Dhanapalan N³⁷ etal and Scheme30. Yoshida etal³⁸ suggested the following methodologies respectively

 

Scheme 29 30 Click here to View figure

 

Scheme31.Hydrogen peroxide is used as catalyst for this one pot method³⁹.

 

Scheme31.Hydrogen peroxide is used as catalyst for this one pot method39.  Click here to View figure

 

Scheme  32.Lewis acid ferric chloride is capplied for the synthesis of flavones  via oxidative coupling by Kumar & Perumal⁴⁰.

 

Scheme  32.Lewis acid ferric chloride is capplied for the synthesis of flavones  via oxidative coupling by Kumar & Perumal40.  Click here to View figure

 

Scheme 33 Zanwar,M. R⁴¹suggested the following methodology.

 

Scheme 33 Zanwar,M. R41suggested the following methodology. Click here to View figure

 

Scheme 34.Yitterbium triflate is ude for the one pot synthesis of flavones in this paper⁴².

 

Scheme 34.Yitterbium triflate is ude for the one pot synthesis of flavones in this paper42.  Click here to View figure

 

Scheme 35.Suzuki-Miyaura coupling used for the synthesis of flavone by Kraus & Gupta⁴³.

 

Scheme 35.Suzuki-Miyaura coupling used for the synthesis of flavone by Kraus & Gupta43. Click here to View figure

 

Scheme 36.Zambre& Sangshetti used oxalic acid for oxidative coupling method⁴⁴.

 

Scheme 36.Zambre& Sangshetti used oxalic acid for oxidative coupling method44. Click here to View figure

 

Scheme  37. Iodine is used as catalyst for both Clause-Schmit condensation and oxidative coupling⁴⁵.

 

Scheme  37. Iodine is used as catalyst for both Clause-Schmit condensation and oxidative coupling45. Click here to View figure

 

Scheme 38. Bosale & Sarda used ionic liquid for the synthesis of flavones from dione intermediate⁴⁶.

 

Scheme 38. Bosale & Sarda used ionic liquid for the synthesis of flavones from dione intermediate46.  Click here to View figure

 

Scheme 39.Jae In Lee etal⁴⁷suggested the following methodology.

 

Scheme 39.Jae In Lee etal47suggested the following methodology.  Click here to View figure

 

Scheme 40.  Sodium tellurim oxide is used for the oxidativ coupling method by the author KumarS& Sharma D. ⁴⁸

 

Scheme 40.  Sodium tellurim oxide is used for the oxidativ coupling method by the author KumarS& Sharma D. 48  Click here to View figure

 

Scheme 41.New catalyst at present is use of hetro polyacid is used for the synthesis of flavones.This solvent free synthesis avoids excess loss of solvents. ⁴⁹

 

Scheme 41.New catalyst at present is use of hetro polyacid is used for the synthesis of flavones.This solvent free synthesis avoids excess loss of solvents. 49  Click here to View figure

 

Scheme 42. CuI is another important catalyst invented by  Zhiyun, Du & Huifen N..This method gives new catalyst for oxidative coupling of flavones⁵⁰.

 

Scheme 42. CuI is another important catalyst invented by  Zhiyun, Du & Huifen N..This method gives new catalyst for oxidative coupling of flavones50. Click here to View figure

 

Scheme 43.Ortho acetyl acetophenone get converted to flavone directly without conversion to 1,3 dione intermediate⁵¹.

 

Scheme 43.Ortho acetyl acetophenone get converted to flavone directly without conversion to 1,3 dione intermediate51. Click here to View figure

 

Conclusion

In conclusion I try to give most of the schemes related to flavones. This review provides ready data for researchers  working in this field and skeleton flavone can be taileored to various novel Pharmacophore asper the need.

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