ORIENTAL JOURNAL OF CHEMISTRY ISSN: 0970-020 X CODEN: OJCHEG An International Open Free Access, Peer Reviewed Research Journal 2013, Vol. 29, No. (4): Pg. 1475-1487 www.orientjchem.org

Synthesis of Flavone Skeleton by Different Methods

R.B. Kshatriya, Y.I. Shaikh and G.M. Nazeruddin*

Department of Chemistry (P.G. & Research Centre), Poona College ofArts, Science & Commerce, Pune, India. Corresponding author E-mail: [email protected]

http://dx.doi.org/10.13005/ojc/290425

(Received: October 01, 2013; Accepted: November 13, 2013)

Abstract

Flavones (flavus = yellow), are a class of flavonoids based on the backbone of 2-phenylchromen-4-one. Flavones are mainly found in cereals and herbs. Flavones are biologically active compounds. Therefore number of synthetic methods were developed. In this mini revive we have tried to cover various synthetic strategies for the synthesis of flavones. Some of the well known methods used for synthesis of flavones are Baker & Venkatraman synthesis and Claisen-Schmidt condensation.

Key words: Flavones, Biologically Active Compounds, Synthetic Methods

INTRODUCTION derived from 4-phenylcoumarine structure.The three flavonoid classes are all ketone-containing Flavones (flavus = yellow), are a compounds, and as such, are anthoxanthins class of flavonoids based on the backbone of (flavones and flavonols) 2-phenylchromen-4-one Apart from flavones other flavonoids are isoflavonoids, derived from Flavones are well known for their various 3-phenylchromen-4-one structure neoflavonoids, biological activities such as anticancer1 Anti

4' 1 5' 8 3' O O 1 1 8 8 7 O 2' O 7 7 2 2 1' 1' 6 3 3 5 4 6 6 2'' 4 4 5' 1' 5 5 O O 5' 3' 4' 2' 4' 3' Flavone Isoflavone Neoflavone Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1476

inflammatory2, anti-osteoporotic3, anti-diabetic4, benzoyl esters, followed by rearrangement in etc. some of the examples as shown as under. base to1,3diphenylpropane1,3diones which upon cyclization under acidic conditions furnishes flavones. Synthetic strategies of flaovones On the other hand hydroxychalcone synthesized Traditionally, flavones have been from 2hydroxyacetophenone anbenzaldehyde under prepared by BakerVenkatramanrearrangement ClaisenSchmidt conditions can undergo oxidative and Claisen-Schmidt condensation.which involves cyclization to furnish flavones ring. the conversion of 2hydroxyacetophenones into

Fig. 1: Basic reactions for the synthesis of flavones Basic schemes related to synthesis of flavones is mentioned below (Scheme 1-43),

I Pd(0),CO O R2 R1 R2 Base OAc O Scheme 1: Palladium catalysed synthesis is carried out in sence of basic environment by Hua & Yang9 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1477

R4 R3 R1 O O HO O HO OH R2 OEt R2 micro wave R1 R3 OH O OH R4

Scheme 2: Solvent free synthesiso f flavone is carrie out by Julia & co-workers10

I R2 R O 2 X TMS Pd2dba3 PA-Ph OH R R1 1 H microw wave,30 min. Pd2dba3 PA-Ph 1 atm.,CO O TBAF,DbU,DMF mw,30 min.

Scheme 3: Flavones via a Micro-Assisted, One-Pot Sonogashira”Carbonylation” Annulation Reactionis used by E.Awuah & A.Capretta11

R1 O O R2

R2 R3 O CH3CN X Cl R1 R3 Light R4 X R4 O Scheme 4: Photo cyclization of 2-Chloro-Substituted 1,3-Diarylpropan-1,3-diones to Flavones is invented by B.Kosmrrji & co-workers12

OH Si supported O R R

heteropoly acid O O O 10 minutes

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

O E O 1. TMP2Zn.2MgCl2.2LiCl

THF, -30 0C O O + 2. E E = allyl, acyl, aryl

Scheme 6: Alkene hydrogen is replaced by L.Klier & T.Bresser14 1478 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

O SiMe 3 O R1 OTBDMS R R Ph3P OCOR1 O Scheme 7: A Novel Synthesis of 4H-Chromen-4-ones via Intramolecular Wittig Reaction is used for the synthesis of flavones15

O O 20 mole % K CO 2 3 O

R1 R1 OA DMF,N2 A = Et,Me,Ph O

Scheme 8: This invention converts 1,3 dione into flavones.Only base is used for this purpose16

KOH R OH O 2 EtOH OH I2 R R R R R1 1 H 2 1 2 Heat DMSO O O O O

Scheme 9: Koneni & his group first time invented flavones in which oxygen of flavone come from watr molecule17

Na2PdCl4.3H2O,NaOAc R2 OH HOAc , tBuOH.3H2O O R R1 R2 1 tBuOOH , 700C O O

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

OH CuCl2 O R2 R1 R1 R2 MW O O O Scheme 11: G.Kabalka & A.Meredy carried microwave assisted synthesis of flavones.Copper chloride is used as a catalyst for this process19 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1479

OH CuCl2 O R2 R1 R1 R2 MW O O O Scheme 12: Photo-Wittig reaction is apllied for the synthesis of flavones20

O O R PPh Br 1 3 R1 H2O/Et3N/hv R O 2 R2 O O R3

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

R2 R1 R3 R2

R5 OH R1 R3 1. TBATB,CH2Cl2 R5 O R4 2. Et3N,K2CO3 R6 R4 R6 O 3. 0.1M,NaOMe,NaOH O

Scheme 14: 2’allyoxy chalcone undergoes oxidative coupling when treated with iodine & DMSO22

R2

R3 O R2 I2, DMSO R3 O R1 1300C,30 min. R4 R1 R4 O O

Scheme 15: Palladiumacetate is used catalyst for the synthesis of flavones23

O O Ar-H, Pd(OAc)2,AgOAC

O PivOH ,CsOPiv,1100C O

Scheme16: Construction of flavones through regioselective carbonylative annulation of 2 bromo phenols &terminal alkynes is carried out24 1480 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

O PdCl ,PPh /L Br 2 3 R2 CO R1 R1 + + nPr2NH OH O R2

Scheme 17. Ganguly’s synthesis includes synthesis of flavones using O-hydroxy acetophenone & acetyl chloride as a precursor25

R1 O R3 R1 OH O R1 O R3 + R3 R3 Cl R2 R2 O O R2 O O

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

O O Ar H FeCl3(10 mole %) R1 + R Ar 1 OH Piperidine (20 mole %) Toluene, 6-12 Hrs. Reflux O

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

R2 OH Silica Supported InCl3 O R 1 R2 R1 45 min.130 0C O O Scheme 20: Wet acetone is efficient catalyst for the one pot synthesis of flavones from 2-hydroxy acetophenone & acetyl chloride28

R4 R4 R1 O R1 OH pR4C6H4COCl R1 O + O R2 R2 K2CO3,wet acetone R3 O R3 O Reflux R2 O Minor Major R4

Scheme 21: Formation of 1,3 dione using LiHDMs followed by cyclisation using acid catalyst is achived29 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1481

R5 R6 R1 R5 R1 R5 R1 R OH R 2 6 LiHDMS R2 OH R6 R2 O AcOH R7 Cl R THF 3 R7 R3 R7 H2SO4 R3 R O 4 O R4 O O R4 O

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

I O R R Pd Catalyst 2 2 + R1 + CO R1 OH 20 atm. O

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

HOOC

O2N Cl CHO O + OH NH2 O

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

X O R OBn O R I2 / Br2 & DMSO I2 / Br2 & DMSO X R One Equivalent Cat. Amount OH O OH O OH O

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

R R6 6 R R5 5 X R O R1 OH 1 R R4 4 1. V O ,H O /NH Br 2 5 2 2 4 R R3 Y 3 CH Cl ,0-50C 2 2 R O R2 O 2 2.0.2M KOH,EtOH.H2O(4:1)

Scheme 26: Base is used for cyclisation of inermediate to flavone34 1482 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

Br Br MeO OH Ar MeO OH Ar MeO O Ar 4.0 eqv.BDMS Br0.2M KOH Br DCM,RT EtOH.H2O OMe O OMe O OMe O

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

O O R3 PPh3 R3 1. RCOCl,Pyridine R2 OH R2 O R R1 2. MeONa/MeOH R1

Scheme 28: Frédéric et al36 suggested

R1 COMe R1 Br COMe SEt R OH R3 O 3 R2 R3 O K2CO3 R2 + AlCl CN NC SEt 3 R1 CN DMSO Heat,PhNO R R4 2 2 R4 O R4 O

Scheme 29: Dhanapalan N37 et al and Scheme30. Yoshida et al38 suggested the following methodologies respectively

R4 R3 R4 OSi R3 O LiHDMS,THF R + 2 OMe R1 R2 H2SO4,AcOH O O R1 O

Scheme 30:

R 1 R1 R OH 2 DMAP 10 mole % R2 O R

R 0 3 R DMF,30 C R3 R O 4 R4 O

Scheme 31: Hydrogen peroxide is used as catalyst for this one pot method39 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1483

MeO OH 1. ArCHO MeO O

2. H2O2 O O

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

R OH O FeCl3.6H2O R MeOH,Reflux O 8-10 Hrs. OH O

Scheme 33: Zanwar,M. R41suggested the following methodology

R1 O O NO2 O R + Et3N,R2OH R OR2 R1 OH O O Scheme 34: Yitterbium triflate is ude for the one pot synthesi of flavones in this paper42

O R O O Yb(OTf) 3 1 X + X OH O O

Me OMe O

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

X MeO OH MeO O X X MeO OH DCM,DMAP AlCl3 NaO + O X MeO X H HO O MeO MeO OMe CH2Cl2,DMF Cl(CH ) Cl THF OMe 2 2 OMe O X

R1 MeO O Cl R R1 2 + MeO O MeO Pd(PPh3)4,10 mole % R2 B(OH)2 OMe O K2CO3,Dioxane MeO 68-70% OMe O

Scheme 36: Zambre& Sangshetti used oxalic acid for oxidative coupling method44 1484 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

R R OH 2 O 2 NaOH OH Oxalic acid + R R1 2 R R1 H EtOH 1 EtOH,Reflux O O O O

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

R R2 OH OH 2 O I I2 / Al2O3 + R 2 R R1 2 H R1 1 mw Al2O3/NaOH O O O O mw Scheme 38: Bosale & Sarda used ionic liquid for the synthesis of flavones from dione intermediate46

R2 bmim BF O R 4 1 R2 R1 1000C,45 min. O O O Scheme 39: Jae In Lee et al47suggested the following methodology

R5 R OH R1 OH R 1 4 OMe 1.3 eq. CH3Li,THF + OH N 1. 2 eq.LiN(iPr) 2 R + 4 2.H2O 2. H2O R2 O R2 O R3 O

R4 R3 R5

R R O 1 1 R H2SO4,CH3CN 6

R2 O O R2 O

Scheme 40: Sodium tellurim oxide is used for the oxidativ coupling method by the author KumarS& Sharma D48

R3 R4 R3 R1 OH R4 R O Na2TeO3 1

R DMSO 2 R2 O O

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 solvents49 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013) 1485

R OH HPA,Reflux O 2 R 1 R2 R1 Solvent or O solvent free O

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

OH R2 1.CuI,10 mole % O R 1 R2 R1 2.solvent,heat air O O

OH R2 1.CuI,10 mole % O R 1 R2 R1 0 2. Bmim NTf2,50 C O O O2,1 atm.

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

O Conclusion

O R CsF-CaO O R In conclusion I try to give most of the schems related to flavones.This review provides 0 O 240 C ready data for the people working in this field. O

References

1. Liu, H. L.; Jiang, W. B.; Xie, M. X. Recent Iwasaki, N.; Ikeda, M.; Ito, A.; Sashida, Pat. Anti-Cancer Drug Discovery 5: 152-164 Y.; Mimaki, Y.; Yano, M.; Sato, M.; Igarashi, (2010). Y.; Oikawa, T. Bioorg Med. Chem. Lett. 19: 2. Manthey, J. A.; Grohmann, K.; Montanari, 2062-2064 (2009). A.; Ash, K.; Manthey, C. L. J. Nat Prod., 62: 5. Gabrielska, J.; SoczyDska-Kordala, M.; 441-444 (1999). Przestalski, S. J. Agric. Food Chem. 53: 76-83 3. Maurya, R.; Rawat, P.; Sharan, K.; Siddiqui, J. (2005). A.; Swarnkar, G.; Mishra, G.; Manickavasagam, 6. Martens, S.; Mithofer, A. Phytochemistry, 66: K.; Arya, R.; Chattopadhyay, N. World Pat. 2399-2407 (2005). 110003 (2009). 7. Halliwell, B.; Aeshbach, R.; Loliger, J.; 4. Kunimasa, K.; Kuranuki, S.; Matsuura, N.; Aruoma, O. I.; Food Chem. Toxicol. 33: 601- 1486 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

617 (1995). Tetrahedron Letters, 46(2):253-256 (2005. 8. Ammar, N. M.; El-Diwany, A. I. J. Islamic Acad. 28. Chin Fei Chee, Michael J.C. Buckle, Sci.1: 72-73 (1988). Noorsaadah Abd. Rahman Tetrahedron 9. Hua M.; Zhen Y. Org. Lett., 2(12): 1765–1768 Letters, 52(24): 3120-3123 (2011). (2000). 29. Mark Cushman, Dhanapalan Nagarathnam 10. Julio A. S.; Pilar V.T.; Raquel C.R., J. Org. Tetrahedron Letters 31: 6497-6500 (1990). Chem., 70(7): 2855–2858 (2005). 30. V.N. Kalinin, M.V. Shostakovsky, A.B. 11. Emelia A. ; Alfredo C., Org. Lett., 11(15): Ponomaryov Tetrahedron Letters,31: 4073- 3210–3213 (2009). 4076 (1990). 12. Berta K.;Boris Š. Org. Lett., 9(20): 3993–3996 31. Daniel ,D.; Laetitia, M. Tetrahedron Letters,36: (2007) 1845-1848 (1995). 13. Gustavo P. R.; Virla,E.G.; Duchowicz,P.R. Ana, 32. Pinto,D.; Silva,A.S.; Cavaleiro,J.S. L. G.; Diego M. R.; Daniel O. B., Erlinda del V. TetrahedronLetters, 35: 9459-9460 (1994). O. ; Autino, J.C. J. Agric. Food Chem., 58(10): 33. Khan,A.T.; Goswami,P. Tetrahedron Letters, 6290–6295 (2010). 46: 4937-4940 (2005). 14. Lydia, K.; Tomke, B.; Tobias, A.; Nigst, K.; 34. Abu T. Khan, Abhik Choudhury, Shahzad Ali, Knochel,K J. Am. Chem. Soc., 134(33): Md. Musawwer Khan Tetrahedron Letters, 53: 13584-13587 (2012). 4852-4857 (2012). 15. Kumar,K.; Bodas M. S. Org. Lett., 2(24): 35. yves Le, F.;Martine L. Tetrahedron Letters, 3821–3823 (2000). 27: 5503-5504 (1986). 16. Jie, Z.; Yufen,Z.; Hua, F. Org. Lett., 14 (11): 36. Frédéric Lassagne, Francis Pochat Tetrahedron 2710-2713 (2012). Letters, 44(22): 9283-9285 (2003). 17. Sashidhara,K.V. ;Kumar,M.; Kumar,A. 37. Dhanapalan N., Mark C. Tetrahedron, 47: Tetrahedron Letters, 53(18): 2355-2359 5071-5076 (1991 ). (2012). 38. yoshida, Y.F.; Koya S.; Takayuki, D. Tetrahedron, 18. Michael, L.; Kabir,M.S.; Cook,J.M. Tetrahedron 67(23): 9993-9997 (2011). Letters, 51(7): 1095-1098 (2010). 39. Francesco F.; Giosanna P.; Oriana P.; 19. Kabalka,G.W. Mereddy,A.R. Tetrahedron Ferdinando P. Tetrahedron 50(39): 11499- Letters, 46(37): 6315-6317 (2005). 11508 (1994). 20. Das,J.; Ghosh,S. Tetrahedron Letters, 52(52): 40. Kumar,K.H.; Perumal,P.T. Tetrahedron, 63(38): 7189-7194 (2011). 9531-9535 (2007). 21. Bose,G.; Mondal,E.; Khan,A.T. ; Bordoloi,M. 41. Zanwar,M. R.; Raihan,M. J.; Gawande,S.D; J. Tetrahedron Letters, 42(50): 8907-8909 Kavala,V; Janreddy, V.;Chun-Wei K.; Ambre,R. (2001). ; Ching-Fa,Y. J. Org. Chem., 77: 495-6504 22. Lokhande,P.D.; Sakate,S.S.;Taksande, K. N.; (2012). Navghare,B.Tetrahedron Letters, 46(9): 1573- 42. Eric F.; Dumas,A. M.; Kuropatwa, B. A.; 1574 (2005). Malhotra,N.R.; Sitler, T. C. J. Org. Chem., 71: 23. Kim,K.H.; Lee,H.S.; Kim,S.H. ;Kim,J.S. 409–412 (2006). Tetrahedron Letters, 22(53): 2761-2764 43. Kraus, G.A.; Gupta, V. Org. Lett. 12: 5278– (2012). 5280 (2010). 24. Jianming, L.; Muwen, L.;Yuanyuan ,Y.; Ningfei, 44. Zambare,A. S.; Sangshetti ,J. N. ; Kokare,N. Z.; Yuanli, Z.; Kelei, Z. Tetrahedron Letters, D.; Shinde ,D. B. Chinese Chemical Letters 54(14): 1802-1807 (2013). 20: 171–174 (2009). 25. Ganguly,A.K. ; Kaur,S.; Mahata,P.K. ; Biswas, 45. Sarda, S.R.;Jadhav,W. N. ; Pawar,R. P. D.; Pramanik,B.N. ; Chan,T.M. Tetrahedron International Journal of ChemTech Research Letters, 46(23): 4119-4121 (2005). 3: 539-543 (2009). 26. Maiti,M.; Karmakar,R.; Bhattacharya,R.N.; 46. Bhosalea,R.S. ; Sardaa,S.R.; Girama, Kayal,K. Tetrahedron Letters, 52(43): 5610- R.P.; Rauta,D.S; Parwea, S.P.; Ardhapurea, 5612 (2011). S.S.Pawarb,R.P. J.Iran.Chem.Soc., 6: 519- 27. Naseem Ahmed, Hasrat Ali, Johan E. van Lier 512 (2009). 1487 Kshatriya et al., Orient. J. Chem., Vol. 29(4), 1475-1487 (2013)

47. Jae In Lee, Hwa Soo Son, Hyun Park Bull. 210–216 (2010. Korean Chem. Soc. 25: 1945 (2004). 50. Zhiyun, Du; Huifen N; Kun, Zhang; Zengb,H; 48. Kumar,S; Sharma ,D. Oriental Journal of Wang, J. Org. Biomol. Chem., 9: 6930 Chemistry,27: 761-763 (2011). (2011). 49. Jahangir,G.M. ; Roshani, J.; Scheeren,W. 51. Didier, V.; Messaoud, H. React. Kinet. Catal. Bulgarian Chemical Communications 2(3): Lett., 72: 3-10 (2001).