Tetrahedron xxx (2012) 1e16
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tetrahedron report number XXX
Chemistry of biologically important flavonesq
Alok K. Verma, Ram Pratap *
Division of Medicinal & Process Chemistry, Central Drug Research Institute (CSIR), Lucknow 226001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2012
Available online xxx
The syntheses of flavones with biologically important functional groups like C-glycoside, isoprenyl, and
hydroxy functionalities at different positions available to medicinal chemists for SAR studies are reviewed. Some rearrangements and transformations facilitating the functionalization of flavones are also
discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cannflavin
Flavone
Flavopiridol
Flavone-8-acetic acid
C-Glycosylation
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Synthetic protocols for flavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reactions of flavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Degradation in presence of base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Reduction reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Oxidation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Rearrangement reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
Substitution reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.
Addition/condensation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.
Reactions with organometallic reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Flavones are natural products of the benzopyran class constituting an important group of oxygen heterocycles, ubiquitously
present in fruits and vegetables. We inadvertently consume them in
our daily diet and they have a positive impact on our health.
Quercetin is well known for its antioxidant activity while the
rohitukine 2 has anti-inflammatory and immunomodulatory
q CDRI manuscript number: 197/2010.
* Corresponding author. Tel./fax: þ91 522 2623405; e-mail address: r_pratap@
cdri.res.in (R. Pratap).
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activities.1 Rohitukine was later modified into flavopiridol 1, an
anticancer agent presently in clinical trials.2
The various biological activities exhibited by the flavones are
dependent on the nature and position of the substituents on the
flavone skeleton. They have attracted significant attention of
chemists to develop various synthetic strategies. As the chemistry
of the flavones has not been discussed in depth, the synthetic
protocols and transformational chemistry of flavones, will be surveyed in this report.
The flavones exhibit a great diversity in their biological activities
due to their unique ability to modulate various enzyme systems.3
Some of the important natural and synthetic flavones 1e12 of
pharmacological importance have been shown in Fig. 1. The
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.097
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
Fig. 1. Some important flavonoids of pharmacological significance.
flavones are active against metabolic and infectious diseases and
demonstrate anti-inflammatory, anti-estrogenic, antimicrobial,4
anti-allergic, antioxidant,5 vascular, antitumor, and cytotoxic6
activities.
2. Synthetic protocols for flavones
A number of methods for the synthesis of various flavones are
available, which broadly can be categorized into two groups involving b-diketones and chalcones as penultimate intermediates
derived from o-hydroxyacetophenones.
Most of the current syntheses of flavonoids are based on
b-diketones emanating from the pioneering work of Robinson7 and
Venkataraman.8 In spite of the number of steps involved in both the
methods, they constitute the most popular strategies for flavone
syntheses. All of these methods involve the formation of a b-diketone intermediate through a base-catalyzed acylation of acetophenone followed by an acid-catalyzed cyclodehydration.
The BakereVenkataraman rearrangement is one of the fundamental reactions that involves conversion of o-hydroxyacetophenone 13 into phenolic ester 14, which undergoes an
intramolecular Claisen condensation in the presence of a base to
form b-diketone 15 (Scheme 1).9
The rearrangement proceeds via the formation of an enolate 14a
followed by an intramolecular acyl transfer (Scheme 2). A wide
range of bases have been employed in the formation of b-diketones.
The b-diketones thus formed are cyclized to flavones under relatively harsh acidic conditions, e.g., heating with concentrated sulfuric acid in glacial acetic acid.
Allan and Robinson7 synthesized flavones through the reaction
of o-hydroxyacetophenone with aromatic acid anhydrides and sodium salts of aryl acids used in the anhydrides. This led to the
formation of two products 16 and 20. The formation of these
products was explained through a hemiketal intermediate 17.
The hemiketal 17 under basic conditions gave the flavone 16,
but the hemiketal 17 also opens to form u-benzoyl-o-hydroxyacetophenone 15, which has an acidic proton and further reacts
with the acid anhydride to form a triketone 18 leading to hemiketal
19, which undergoes dehydration to yield 3-benzoyl-flavone (20)
(Scheme 3).10 The formation of 3-benzoyl-flavone was avoided by
heating 2-benzoyloxy-acetophenone (14) in anhydrous glycerol.11
Scheme 1. Typical synthesis of flavones via b-diketone intermediate.
O
O
O
O
O
O
14a
Scheme 2. BakereVenkataraman rearrangement.
When there are electron withdrawing groups on the ring A,
a milder base is required for the b-diketone formation. Thus, Tang
et al. synthesized 6-nitroflavones by utilizing potassium carbonate
followed by 5% KOH in ethanol for the b-diketone formation.12
Further, Saxena et al. used potassium carbonate under phasetransfer-catalyzed (PTC) conditions for the synthesis of b-diketone intermediates and p-toluenesulphonic acid for the cyclodehydration step.13 The reaction failed to get satisfactory results
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
OBz
O
O
OH
O
Ph
O
14
O
16
17
O
OH
OH
Ph
OH
O
Ph
Ph
Bz
Bz
Bz
Bz
O
O
O
19
18
15
Bz
O
20
Scheme 3. Formation of flavones and 3-benzoylflavones.
when unprotected polyhydroxyacetophenones were used as
starting materials. Later, Jain et al. improved the process by using
aqueous K2CO3 followed by passing a stream of CO2 in the cyclodehydration step.14 Similarly, metabolites of nobiletin were prepared using potassium t-butoxide for the BakereVenkataraman
rearrangement.15 Natural flavones, baicalein and scutellarein, were
synthesized via a BakereVenkataraman rearrangement using
sodamide for the formation of b-diketones and cyclodehydration
with fused sodium acetate in glacial acetic acid.16 vonKostanecki
used metallic sodium for the synthesis of b-diketone intermediates
from o-methoxy-acetophenone and arylacid esters. Treatment of
the b-diketone with HI led to demethylation and subsequent
cyclodehydration to flavones.17,18
The synthesis of flavones with carbon substituents on ring A
through b-diketones has been exemplified with the synthesis of the
anticancer agents flavopiridol 1, where the carbon substituent has
been introduced at the initial stage. Thus, 1,3,5-trimethoxybenzene
21 was reacted with N-methylpiperidone under acidic conditions to
give the alkene 22, which on hydroboration with diborane (generated in situ from NaBH4 and BF3.Et2O) followed by treatment with
alkaline hydrogen peroxide formed the hydroxy compound 23 as
the trans isomer. It was then converted into the cis isomer 25
by Swern oxidation followed by reduction of 24 with NaBH4.
Compound 25 was then acylated using BF3.Et2O to yield
substituted acetophenone 26, which was reacted with methyl
2-chlorobenzoate using NaH to b-diketone intermediate, which
was demethylated with HCl gas and neutralized with Na2CO3 to get
flavone 27. The flavone 27 on demethylation using pyridine
hydrochloride at 180 C gave the desired flavone 1 (Scheme 4).19
3-Hydroxyflavones (also known as flavonols) are conventionally
prepared from a-methoxy- or benzyloxy-o-hydroxyacetophenone
via BakereVenkataraman rearrangement forming the b-diketones,
which undergo cyclization.20,21 Tanaka et al. synthesized kaempferol analogs from phloroglucinol 28. It was reacted with benzyloxyacetonitrile under acidic conditions to give corresponding
a-benzyloxy-o-hydroxyacetophenone 29. The acetophenone 29
was suitably protected with TBDPS chloride to 30, which was
treated with benzoic acid using 1-(3-dimethyl-aminopropyl)-3ethylcarbodiimide (EDCI), dimethylamino-pyridine (DMAP) and
p-toluenesulphonic acid (TsOH) as a catalyst to give ester 31 followed by treatment with K2CO3 in pyridine to provide the cyclized
product 32. The hydrogenation of 32 gave the desired product 33
(Scheme 5).22
Ganguly et al. prepared 3-acylflavones through a modified
BakereVenkataraman rearrangement using DBU and pyridine via
a triketo intermediate.23 These 3-acylflavones were then converted
into flavones by refluxing with aqueous K2CO3 (Scheme 6).
Similarly, Pinto et al. used K2CO3-pyridine under microwave
assisted conditions to prepare b-diketone intermediates, which
were cyclized to give 3-aroylflavones.24 Nagarathnam and Cushmann utilized LiHMDS, a non-protic base of high pKa, for the formation of b-diketone 35 from 34 followed by acid-catalyzed
cyclization to form flavone 36.25 The method does not involve
BakereVenkataraman rearrangement, but instead involves lithiated polyanions to yield b-diketones directly (Scheme 7). In addition, the method avoids the formation of 3-aroylflavones and needs
no prior protection of phenolic groups. The success of the flavone
synthesis utilizing intermediates susceptible to generate polyanions without protection led to the synthesis of carboxyl
substituted flavones. Cushman et al. also prepared 3-carboxylated
flavones from methyl-3-(2-hydroxyphenyl)-3-oxo-propanoate
obtained by the reaction of hydroxyeacetophenones with LiHMDS
and dimethyl carbonate.26 The carboxylated acetophenones were
then reacted with MgeEtOH followed by treatment with acid
chlorides to finally yield the flavone-3-methyl-carboxylate.
Further, 6-carboxyflavone 39 has been prepared via
a BakereVenkataraman rearrangement from 3-acyl-4-hydroxy-
OMe
N-methypiperidone,
1.BF3-OEt2, NaBH4
0
OMe diglyme, 50 C
MeO
MeCO2H, HCl (g)
Me
N
Me
N
Me
N
MeO
3
HO
DMSO,
MeO
O
MeO
OMe
2. NaOH, H2O2
OMe
OMe
OMe
OMe
22
21
24
23
NaBH4
ethanol
Me
N
Me
N
CO2Me
Me
N
HO
pyridine HCl,
HO
O
o
180 C
1
O
Me
N
HO
Cl
HO
MeO
OMe
BF3-OEt2,
HO
MeO
O
Cl
OH
OMe
oxalyl chloride
Cl
(i) NaH, dry DMF
(ii) HCl (g)
(iii) Na2CO3
Ac2O, CH2Cl2
MeO
OMe O
OMe O
27
OMe
OMe
26
Scheme 4. Synthesis of anticancer flavone, flavopiridol (1).
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
Scheme 5. Synthesis of 3-hydroxyflavone derivatives.
Scheme 6. Synthesis of 3-acylflavones via triketo intermediate.
Scheme 8. Synthesis of 6-carboxyflavone.
OH
HO
Cl
OH
+
HO
Me
O
O
O
LiHMDS,THF
34
conc. H2SO4 ,
glac. AcOH
HO
O
35
-78oC
O
O
36
Scheme 7. Flavone synthesis by Cushman method.
methyl-benzoate (37) and 2-benzyloxy-methyl-benzoate. The intermediate b-diketone 38 was then cyclized by refluxing with
formic acid (Scheme 8).27 8-Carboxyflavones having leukotriene
inhibitory action were also prepared using a similar method.28
A synthesis of flavones from o-methoxyacetophenones via
a two-step process, which utilizes only 1 equiv of LDA to form the
lithium enolate has also been reported. The enolate is reacted with
benzoyl cyanide to give the b-diketone, which on treatment with HI
yields the flavone.29
iso-Prenylflavones, routinely isolated from plants, possess
strong antioxidant properties and hence their efficient synthesis is
needed for SAR studies. The synthesis of natural cannflavin B (11)
and its unnatural regioisomer, cannflavin A (46), having the isoprenyl unit in ring A, with COX inhibiting activity, was reported by
Minassi et al.30 The iso-prenyl group was introduced at a very early
stage from 40 by a Mitsonbu reaction followed by a CopeeClaisen
rearrangement to form acetophenone 41. In order to achieve
regioselectivity, the pivaloyl group in 42 is utilized as a protecting
group and chemoselective o-desilylation with TFA in THF/water led
the formation of 43. The reaction of 43 with benzoyl chloride 44
gave the b-diketone 45. The regioisomeric diketones 45 and 46
were cyclized using a Lewis acid (CuCl2) and TMS chloride to result
in the formation of 11 and 47 (Scheme 9).
Gothelf et al. described a unique method to prepare b-diketones
via an isoxazole intermediate, which was ultimately cyclized to
flavone 54.31 The precursor arylisoxazole 50 was prepared by
a 1,3-dipolar cycloaddition reaction of an aryl nitrile oxide generated from benzaldoxime 48 by reaction with N-chlorosuccinimide
(NCS) with tributylstannylacetylene 49. The Heck coupling reaction
of stannyl-iso-oxazole 50 with iodophloroglucinol 51 gave isoxazole 52. The isoxazole 52 was then converted into b-diketone 53
by reductive ring cleavage and subsequently cyclized to flavone 54
(Scheme 10).
In order to introduce a substituent at the 3-position, Lӧwe and
Matzanke opened the activated C-ring of 56, which was prepared
from dihydroflavone 55, by reaction with benzylamine to yield
enaminone 57, which reacted with chlorosulphonyl urea to yield
flavone-3-sulphonylurea 58 with elimination of benzylamine hydrochloride (Scheme 11).32
PhotoeFries rearrangement of phenyl-epoxy-cinnamates leads
to the formation of epoxyechalcones, which on photolysis give
b-diketones.33
Like the variety of bases used in the synthesis of b-diketones,
a large number of reagents and conditions have also been tried for
the cyclodehydration step. Mavel et al. prepared styrylchromones
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
5
Scheme 9. Synthesis of iso-prenylflavones.
OH
HO
OH
Bu3Sn
OH
HO
OH
HO
O
+
H -AcOH
HO
I
i. NCS
ii. KHCO3-EtOAc
OH
Ra-Ni, H2
PdCl2, dioxane
O N
50
OH
OH
O N
OH
MeOH, H2O
52
OH
O
O
53
OH O
54
OH
51
OH
+ Bu3Sn
HO
N
48
49
Scheme 10. Synthesis of flavones via isoxazoles.
utilizing Amberlyst, an acidic cation-exchange resin, for the cyclodehydration step in refluxing propan-2-ol34 while Varma et al.
cyclodehydrated b-diketones to flavones on a clay surface using
microwave irradiation.35,36 Miyake et al. reported the formation of
Scheme 11. Synthesis of flavone-3-sulphonylurea.
3-bromoflavones from b-diketones utilizing CuBr2.37 Similarly, Su
et al. carried out the cyclodehydration of b-diketones under VilsmeiereHaack conditions using bis-(trichloromethyl)carbonate and
dimethylformamide (BTC/DMF).38 The protocol is advantageous as
the presence of electron-withdrawing or -donating groups on the
aromatic ring does not affect the reaction significantly, either the
yield or the rate.
Besides these conditions, strong acids like HCl, HBr or HI, catalysts like NaHSO4/SiO2,39 H3PMo12O40.2H2O/SiO2,40,41 Co(III)(salpr)
OH,42 EtOH/HCl43 or H2SO4 under microwave irradiation,44 nonaqueous cation-exchange resins like Dowex,45 Lewis acids like
Ga(OTf)345 and ionic liquids35,36 have also been demonstrated to
drive the cyclodehydration. Mentzer and Pillion reported a onestep process for the synthesis of flavones by reaction of phenol
with b-ketoesters under heating.46 However, the reaction has a serious drawback of having extremely low yields. Seijas et al. reported
the one-step synthesis of flavone 60 under microwave conditions.
Irradiation of b-ketoester 59 gave a-oxoketene 61. Nucleophilic
addition of phloroglucinol 28 to a-oxoketene followed by thermal
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
Scheme 12. Microwave-assisted synthesis of flavone.
Fries rearrangement gave the b-diketone, which was subsequently
cyclized (Scheme 12).47
Chalcones being natural precursors are obviously important
intermediates for the synthesis of flavones. They are easily prepared by ClaiseneSchmidt reaction of acetophenones with benzaldehydes. Chalcones are converted into the corresponding
flavones either directly or through flavanones. The most conventional and common method for the cyclization is through an oxidative ring closure with bromine and a base (Scheme 13)48 or by
the lowest.57 Recently, Kumar and Perumal demonstrated the use of
ferric chloride in the oxidative cyclization of o-hydroxychalcones to
flavones.58
Kasahara et al. cyclized o-hydroxychalcone 65 to flavone 68
using lithium chloropalladate for the activation of the olefinic
bond.59 Reaction of the chalcone 65 with a palladium(II) salt under
basic conditions involves an intramolecular trans-phenoxypalladation, followed by cis elimination of palladium(II) hydride.
The reaction is accompanied by a small amount of flavanone formation via base-catalyzed cyclization of the chalcone (Scheme 14).
Scheme 13. Oxidative cyclization of 2-hydroxychalcone.
Scheme 14. Oxidative cyclization of chalcones using lithium chloropalladate(II).
refluxing with SeO2 in dioxane.49 In the reaction of chalcone 63
with bromine, besides bromine addition to the olefinic bond, nuclear bromination at position 50 also occurs resulting in the bromoflavone.50 Chalcone dibromide 64 is converted into flavone by
the action of pyridine.51 Several studies have been performed on
the types of reagents utilized for the cyclization of chalcones to
flavones. Ray and Dutta converted chalcone dibromide 64 into the
corresponding flavone 16 by heating above the melting point.52 Rao
et al. studied the cyclization of chalcones with DDQ and found that
even a slight variation in reaction conditions led to the formation of
a mixture of flavones and flavanones.53 Yao et al.54 synthesized
nitroeflavones through regioselective nitration of chalcones followed by cyclization catalyzed by I2-DMSO. Huang et al. improved
the total synthesis of baicalein, wogonin, and oroxylin from chalcones using I2-DMSO as the cyclizing agent55 and Lokhande et al.
also cyclized 2-allyloxychalcones to flavones using I2-DMSO.56
Alam studied the conversion of methylenedioxyechalcones utilizing diphenyl sulphide, I2-DMSO or DDQ and found that cyclization
with I2-DMSO led to the best yields, while diphenyl sulphide gave
Kumazawa et al. prepared a naturally occurring 6-C-glucosylated derivative (isoorientin, 75) and the 8-C-glucosylated compound (orientin, 12) via the cyclization of chalcones.60,61 The
suitably substituted chalcone precursors were synthesized via
a regioselective rearrangement of the glucosyl moiety from O to C
using BF3.Et2O.62 For the synthesis of the 6-C-glucosyl isomer 75,
2-benzyloxy-4-(2-methyl)-benzyloxy-6-hydroxy-acetophenone 69
was subjected to regioselective glucosylation using BF3.Et2O to
form acetophenone 71. Compound 71 was then subjected to protection of the free hydroxy group with 2-methylbenzyl chloride.
The resulting glucosyl-acetophenone 72 was selectively debenzylated with PdeC/H2 in EtOAc to give the glucosylated acetophenone
73. The acetophenone 73 was then condensed with 3,4dibenzyloxy-benzaldehyde to form chalcone 74, which was
cyclized using I2-DMSO to the protected flavone. Debenzylation of
the protected flavone with PdeC/H2 in EtOAceEtOH furnished
isoorientin 75 (Scheme 15).
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
7
Scheme 15. Synthesis of C-glucoside, isoorientin (75).
Prenylated flavones, isolated from various natural sources, play
significant role in enhancing the antioxidant properties of the
flavones. Gula’csi et al. reported the synthesis of a natural prenylated flavone, kanzonol D 78, through the chalcone 76. Cyclodehydrogenation of the prenylated o-hydroxychalcone 76 in the
presence of phenyliodine(III) diacetate (PIDA)/KOH in methanol
furnished the required product without affecting the prenyl group
during cyclization (Scheme 16).63 The prenylated benzaldehyde
used for the chalcone was prepared using the KOH-prenyl bromide
method.64
ethanolic NaOH or silver acetate in acetic acid or I2eAl2O3.74 Oxalic
acid has been reported as a catalyst for the intramolecular cyclization of o-hydroxychalcones to flavones in good yields.75
3-Hydroxyflavones are predominantly isolated from natural
sources, but are also synthesized from chalcones. In one of the
conventional methods, o-hydroxychalcone 79 is subjected to basecatalyzed epoxidation of the conjugated double bond (Algar-FlynnOyamada, AFO) oxidation followed by ring closure and aromatization to yield flavonol 80 (Scheme 17).44
OBn
OBn
OBn
OH
OBn
O
H2O2, NaOH
O
OH
O
79
80
Scheme 17. Synthesis of 3-hydroxyflavone via AFO oxidation.
Scheme 16. Cyclization of prenylated chalcones.
Flavanones are converted into flavones by bromination at C3
with subsequent dehydrobromination.65 Bromination is accomplished either by NBS or pyridinium perbromide.66 When NBS is
used only partial dehydrohalogenation occurs yielding a mixture of
flavone and 3-bromoflavanone.67 They are converted into flavones
using NBS under microwave conditions.68 The 40 -O-alkyl-derivatives of 5,7-dihydroxy-flavones were prepared by cyclization of
the corresponding chalcones with sodium acetate followed by oxidation of the crude intermediates (flavanones) with a catalytic
amount of iodine in pyridine.69
Takeno et al. demonstrated the utility of 2-pyrrolidone hydrotribromide (PHT) in DMSO in the formation of flavones from flavanones.70 The low concentration of the enolic form consumes the
bromine as soon as it is liberated to form 3-bromoflavanones in
THF. Flavone is directly formed when DMSO is used as the solvent,
as it is an effective dehydrobrominating solvent.71 The presence of
electron releasing groups led to a reduction in the yields, due to the
formation of 2,3-dibromoflavanones as intermediates. Flavanones
are dehydrogenated to flavones with PCl5 in benzene.72 They are
formed from chalcones via oxidative transformation of 2-phenyl2H-1-benzopyrans with KMnO4 in acetone.73 Flavones are reported
to be formed from chalcones by treatment with iodine monochloride (ICl) in acetic acid followed by treatment with pyridine,
Another synthesis of 3-hydroxyflavones has been reported
through a-oximation of flavanone 82 prepared from chalcone 81
followed by hydrolysis of the resulting oximino ketone 83 to
an a-diketo intermediate 84, which subsequently enolizes to
3-hydroxyflavone (Scheme 18).76
Scheme 18. 3-Hydroxyflavone synthesis through a-oximation of flavanone.
Usually, 3-benzylflavones 88 are obtained by the isomerization
of 3-benzylidineflavanones 87 synthesized by the condensation of
o-hydroxyacetophenones 85 and the appropriate benzaldehyde.77
Dong et al. proposed a one-pot synthesis of 3-benzylflavones 88
from o-hydroxyacetophenones 85 and benzaldehydes through the
intermediacy of chalcone 86 (Scheme 19).78 A sufficient quantity of
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
reaction works well with aurones having ring A derived from resorcinol, but fails with aurones having ring A derived from
phlorogucinol.83
Flavones are formed via Wittig-type reactions also. Kumar and
Bodas reported a simple route to prepare flavones 98 via intramolecular ester carbonyl olefination using (trimethylsilyl)-methylenetriphenylphosphorane 97 (Scheme 23).84 The mechanism
involves acylation of (trimethylsilyl)-methylenetriphenylphosphorane 97 by 96 to form the phosphonium salt 99 followed by a migration of the trimethylsilyl group from C to O, and extrusion of silyl
ether forming 100. This subsequently undergoes ring closure via an
intramolecular Wittig reaction on the ester carbonyl to afford flavones 98.
Scheme 19. Pyrrolidine-catalyzed synthesis of 3-benzylflavones.
O
pyrrolidine is necessary, indicating a requirement of the basic
conditions in the reaction.
Zheng et al. prepared flavones using a slightly modified
protocol. Reaction of phloroglucinol or resorcinol with chloroacetonitrile under HoubeneHoesch conditions provided
u-chloro-o-hydroxyacetophenone 89, which on condensation
with a,a,a-trifluoromethyl-p-tolualdehyde in the presence of
aqueous NaOHeEtOH followed by elimination of HCl from the
3-chloroflavanone intermediate in a basic medium yielded flavones like 90 (Scheme 20).79
R1
Ph3P-CH-SiMe3
97
O
R
O
OTBDMS
O
98
O
96
O
O
R1
Ph3P-CH-SiMe3
O
R
R
OTBDMS
PPh3
SiMe3
TBDMS
O
O
96
99
O
R
R1
R1
O
+
R
O
98
Flavones have been also synthesized via cross-coupling reactions. Liang et al. reported a synthesis of flavones by sequential
carbonylative coupling (Sonogashira coupling) of o-iodophenols 91
with terminal acetylenes 92 to form a,b-unsaturated ketones, followed by intramolecular cyclization to afford flavones 93 in a onepot procedure (Scheme 21).80 Some minor modifications like the
use of ionic liquids81 or microwaves82 have been reported recently.
R1
O
O
Scheme 20. One-step synthesis of flavones.
R1
R
TMS-O-TBDMS
PPh3
O
100
Scheme 23. Wittig-like synthesis of flavones.
Auwers et al. reported the synthesis of 3-hydroxyflavone 103
from aurone 101 via a series of reactions commonly known as the
Auwers synthesis.85 Bromination of the alkene yields a dibromo
adduct 102, which rearranges to flavonol by treatment with KOH
involving the intermediates 104e107 (Scheme 24).
Scheme 21. Flavone synthesis by cross coupling.
Aurone 94 is rearranged to flavone 95 by reaction with KCN
(Scheme 22). The mechanism of the transformation involves nucleophilic attack of cyanide anion on the methylene carbon, which
rearranges to flavone. The method has limited application, as the
Scheme 24. Synthesis of 3-hydroxyflavone from aurone.
Scheme 22. Conversion of aurone into flavone.
The synthesis of an antiangiogenic agent, flavone-8-acetic acid
113, with substitution on rings A and C of the flavone skeleton has
been reported where the suitable substituents have been introduced in the starting material itself. The starting 2-hydroxy-3allyl-benzaldehyde 108 was synthesized from salicylaldehyde
via a Claisen rearrangement followed by concerted Michael
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
condensation with 109 to give nitroecarbinol 110 followed by the
oxidation to yield nitroeketone 111. The acetic acid moiety was
later generated from allyl 112 by Sharpless oxidation using ruthenium(III) chloride and sodium metaperiodate (Scheme 25).86
9
OH
b
O
15
O
16
O
O
OH
+
a
Me
OH
OH
O
O
OH
O
+
O
HO
Me
15
O
O
Scheme 27. Alkaline degradation of flavone.
Scheme 25. Synthesis of antiangiogenic, 3-nitroflavone-8-acetic acid.
Diastereomeric dihydroflavonols 117 have been prepared via an
chiral epoxidation of chalcone 114 to 115 by AFO oxidation followed
by epoxide opening with benzylmercaptan to yield 116, which was
cyclized using a Lewis acid, SnCl4 (Scheme 26).87
MeO
MeO
H2O2 / NaOH
OMe poly-L- or
poly-D-alanine
OMOM
OMOM
O
OMe
OMe O
114
OMe
reduction reactions of the double bond as well as of the carbonyl
group. When flavones are heated with tetralin and PdeC, ring fission is accompanied by the reduction.92 On hydrogenation with
Adam’s catalyst, the 2,3-olefinic bond of 118 is reduced to yield
flavanone 119.93 High pressure hydrogenation of flavones yields
flavan-4-ols, flaven-4-ols and flavanones. When hydrogenation of
5-hydroxy-, 7-hydroxy- or 5,7-dihydroxy-flavones 120 are interrupted after 3 mol of hydrogen absorption, ring B is reduced to form
121 (Scheme 28).94
OMe
OMe O
115
OH
OH
BnSH/ SnCl4
OH
OMe
MeO
HO
O
OMe
AgBF4
MeO
OH
OH
OH
OMe O
117
O
OMe
OMe O
HO
OMe
SBn
OH
O
O
Adam's
cat.
OH
116
HO
O
3. Reactions of flavones
The chemistry of flavones is quite simple and a variety of reactions occur depending on the reagents used and the functional
groups present. In general, they possess three functional groups viz.
hydroxy, carbonyl, and conjugated double bond; hence they give
characteristic reactions of all three functional groups. Flavones are
colorless-to-yellow crystalline substances, soluble in water and
ethanol. They are moderate-to-strong oxygen bases and are soluble
in acids due to the formation of oxonium salts.88 They also dissolve
in alkali to give yellow solutions.89
3.1. Degradation in presence of base
The structure of flavones is determined mainly by identification
of alkaline degradation products. Both in acidic and alkaline solutions, there exists equilibrium between the flavone and b-diketone.
The products of hydrolysis depend on the nature of the substituents
present and the hydrolyzing agents.90 Anhydrous ethanolic KOH
causes fission via path ‘a’, whereas aqueous KOH cleaves via path ‘b’
(Scheme 27). Introduction of a substituent at C5 slows the fission
while 7-acetoxy- and 5,7-diacetoxy-flavones are resistant to alkaline hydrolysis.91
O
eriodictyol 119
luteolin 118
Scheme 26. Synthesis of dihydroflavonols via epoxide.
OH
HO
O
Pt
H2 (3 mols)
HO
OH
O
HO
OH
120
O
121
Scheme 28. Hydrogenation reactions of flavones.
Uncontrolled reductions of 122 and 125 occur with lithium
aluminum hydride (LAH) to yield mixtures of flavenes 123 and 126
and ring-opened products 124 (Scheme 29).95 Sodium amalgam
reduces flavones to 4-hydroxyflavans, as well as the corresponding
chalcones and other products.93
5,7-Dihydroxyflavone 127 undergoes selective nuclear deoxygenation of the 7-hydroxy group via the formation of the 7-O-
3.2. Reduction reactions
Flavones possess an a,b-unsaturated carbonyl group, which is in
conjugation with rings A and B having hydroxy groups. They exhibit
Scheme 29. Reductions of flavones with lithium aluminum hydride.
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
ether with 5-chloro-1-phenyl-triazole 128 followed by hydrogenolysis with formic acid and PdeC (Scheme 30).96
When 30 ,40 ,5,60 ,7-pentamethoxyflavone 133 is oxidized with
silver oxide and nitric acid, only the methoxy groups at 1,4 orientations are oxidized, leading to the formation of a quinone intermediate 134, which furnished a typical DielseAlder adduct 135
with butadiene (Scheme 32).108
Scheme 30. Selective deoxygenation of flavone.
5,7-Dihydroxyflavones undergo reductive amination of the hydroxyl group via triflate formation. The reaction of 130 with aniline
triflamide gave 131, which on reaction with benzylamine under
micro-wave irradiation yielded 132. The reaction has been generalized for nucleophilic amines and, in the case of anilines, addition
of triethylamine enhances the reactivity of the flavones. The
reaction has an additional advantage of not using costly palladium
catalysts (Scheme 31).97
OMe
OMe
BnO
BnO
O
O
OBn
OBn
PhNTf2, NaHMDS
OH
OTf
O
130
O
131
mW
benzylamine, NMP
BnO
O
Scheme 32. Silver oxide-nitric acid oxidation of flavone.
3.4. Rearrangement reactions
The WesselyeMoser rearrangement involves the conversion of
5,7,8-trimethoxyflavone 136 into 5,6,7-trihydroxyflavone 120 during a demethylation reaction catalyzed with mineral acids like HCl,
HBr or HI.109 A three-step mechanistic sequence of the rearrangement reaction has been proposed to explain the conversion and it
involves: (I) acid-catalyzed ring opening to diketone 138, (II) bond
rotation with the formation of a favorable acetylacetone-like phenyleketone interaction followed by demethylation in 137, and (III)
ring closure concomitant with the hydrolysis of two methoxy
groups (Scheme 33).110 The application of the WesselyeMoser
OMe
OMe
Me O
O
Ph
OBn
HI
HO
O
Ph
HO
NH
O
OMe
O
120
136
132
Scheme 31. Reductive amination of flavone.
O Me
MeO
OH
MeO
OH
Ph
3.3. Oxidation reactions
Ph
MeO
O Me O
The C2eC3 double bond of flavones is unreactive toward classical
oxidants, such as H2O2/OH-,98 KMnO4,73,99b NiO2,100 SeO2,101 and
Tl(OAc)3.102 However, under strictly neutral conditions, it reacts
with dimethyldioxirane (DMD)103 or methyl (trifluoromethyl)dioxirane104 to form the corresponding epoxide.105 Chu et al. studied
the application of DMD in the synthesis of 3-substituted flavones in
detail and observed that, when permethoxykaemferol is subjected
to epoxidation using DMD in an acidic (2 M HCl) medium, the epoxidation is followed by nuclear halogenations. When ring A has
a free 5-hydroxy group, reaction of flavone with dioxirane leads to
nuclear hydroxylation at C8 to form 8-hydroxyflavone.106 Flavones
with a protected 5-hydroxy group, form 3-hydroxyflavones via epoxidation. Thus, tetramethylluteolin gave tetramethylquercetin.
Further, acylation of 5,7-hydroxy groups favors mainly the
2,3-epoxidation reaction.107
OH
O
O
138
OH
O
O
137
Scheme 33. WesselyeMoser rearrangement.
rearrangement has been extended for the synthesis of 6alkylamino-5,7-dihydroxyflavones 140 from 8-alkylamino isomer
139 (Scheme 34).111
The synthesis of prenylated flavones has been of significant
importance and Daskiewicz et al. attempted the synthesis of
C-prenylated chrysin 145 through a double Claisen rearrangement
in N,N-dimethylaniline. The selective hydroxyl protection in 60
gave 141 on prenylation at free hydroxyl gave 142, which after
double sigmatropic rearrangement involving intermediates 143
and 144 ultimately yielded prenylated flavone 145. It was
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
H
N
11
MeO
HO
O
O
HO
R
R
R
R
O
O
O
O
O
OH
K2CO3
Conc. HCl
OH
HN
OMe O
139
146
OH O
140
R
O
O
O
147 H
O
R
Me
O
OH
Scheme 34. Extension of WesselyeMoser rearrangement.
O
O
O H
OH
O
O
H
O
O
O
O
MEMO
R
O
O
O
O
MEM chloride
OH
O
OH O
141
60
t
Bu4N OH
200oC
O
R1 X
O
O
H
R
R
R1 X
R1 O
O
R1
R'
OR1 O
O
H
151
Scheme 36. Formation of 3-alkylflavones.
O
O
O
143
O
142
[3,3] sigmatropic shift
H
MEMO
O
O
H R1
K2CO3
prenyl bromide
MEMO
[3,3] sigmatropic
shift
O
O
H
O
O
MEMO
O
-H2O
O
R
O
O
H R1
H
DIPEA, dry DMF
O 150
R = OMe
R
OH
HO
O
148
H
concluded that the rearrangement is dependent on solvent and
choice of protecting groups on the hydroxyl function. Out of MEM,
MOM, TBDPS, and benzoyl esters, MEM was found to be the most
compatible protecting group (Scheme 35).112
149
H
R = CF3, OCF2H
O
O
O
O
O
O
144
MEMO
O
OH
O
145
Scheme 35. 8-Isoprenyl-chrysin via double Claisen rearrangement.
there have been reports of the synthesis of 3-bromoflavone 153
with reagents like Br2epyridine or pyridine hydrobromide perbromide (PHPB) without using mercury salts (Scheme 37).120 With
milder reagents, like 2,4,4,6-tetrabromo-2,5-cyclohexadienone, the
formation of side products was minimized.121 The presence of
hydroxyl groups on the ring A drives the regioselectivity in the reaction of flavones with bromine. The reaction of chrysin
60 (5,7-dihydroxyflavone) with Br2/H2O gave 6,8-dibromo-5,7dihydroxyflavone 154 while bromination of 5,7-dimethoxyflavone
155 with N-bromosuccinimide (NBS) gave 8-bromo-5-hydroxy7-methoxyflavone 156 (Scheme 37).122 Iodination of 5,7dimethoxyflavone with iodine monochloride (ICl) in acetic acid and
The reaction of 5,7-dihydroxyflavones 146 with alkyl halides in
the presence of K2CO3 as base gave unexpected 3-alkylated-flavones 151 and the formation was explained through a ringopening and -closure mechanism involving intermediates 147
and 150 (Scheme 36). The key step in the rearrangement is the
‘switching’ of the 5-hydroxy proton between two oxygen atoms at
C4 and C5, generating a pyrilium ion, which undergoes nucleophilic ring opening and cyclization to give the rearranged product.
When the 40 -position has eOMe group, OH attacks at C2 in 148,
while in the presence of groups like CF3 or OCF2H, it attacks at C2
as in 149.113
Me
O
O
PHPB
Br
O
152
O
153
Br
O
HO
HO
3.5. Substitution reactions
The electrophilic substitution mainly occurs on the ring B but in
the presence of hydroxyl groups it can also take place on the ring
A.114 When nitrated, 5-hydroxyflavone gave 5-hydroxy-6-nitro- or
5-hydroxy-8-nitro-flavone.115 7-Hydroxyflavone gave 7-hydroxy8-nitro- and 7-hydroxy-6-nitro-flavone.116 Monobromination of
5-hydroxyflavone yielded 5-hydroxy-8-bromoflavone. When the
flavones are boiled with thionyl chloride, 3-chloroflavones are
obtained,117 while sulfuryl chloride gave 2, 3, 3-trichloroflavanones.118
3-Bromoflavones are important intermediates in the synthesis of
3-substituted flavones. The 3-bromoflavones are generally prepared
using Br2eAcOH in the presence of mercuric acetate.119 Recently,
Me
Br2, H2O
OH
O
Br
O
OH
60
O
154
Br
MeO
O
MeO
O
NBS
OMe O
OH
155
O
156
Scheme 37. Bromination reactions of flavones.
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
DMSO gives 5, 7-dimethoxy-8-iodoflavone. Zhang and Li studied the
reaction of flavones with iodineecerium(IV) ammonium nitrate
(I2/CAN) and proposed the formation of 3-iodoflavones.123 When
chrysin was reacted with I2/CAN in acetonitrile, a nonseparable mixture was obtained by Zheng et al., but when the reaction was performed in acetic acid, 5,7-dihydroxy-8-nitroflavone was obtained.
Further, 5,7-dimethoxyflavone with I2/CAN in acetic acid gave 8-iodo5-hydroxy-7-methoxy-6-nitroflavone.122 Thus, the free hydroxyl
groups on ring A have a directive influence on the substitution
reactions.
7-O-Alkyl derivatives of flavones have been prepared by
various workers. Babu et al. prepared 7-O-alkylated derivatives
of chrysin having antibacterial activity using alkyl halides and
K2CO3.124 Shin et al. also attempted to synthesize regioselective
7-O-alkyl derivatives of chrysin using K2CO3 or KHCO3, but to
obtain a mixture of mono- and di-O-alkylated products.125 They
successfully tried to form 7-O-esters using DCC and DMAP. It
was concluded that esterification occur primarily at C7 because
of the shielding of the 5-hydroxy by the 4-keto group. Jain et al.
also attempted nuclear iso-prenylation of chrysin by refluxing it
with prenyl bromide in the presence of NaOMeeMeOH, but
the results were not satisfactory due to poor yields.126
Comte et al. prepared C-prenylated flavones in low yields by
microwave irradiation on a solution of chrysin and tetramethylammonium hydroxide in methanol containing tetraethylammonium iodide.127
Scheme 39. 1,3-Dipolar addition to flavones.
Scheme 40. Grignard reaction on flavone.
3.6. Addition/condensation reactions
In general, the carbonyl group of flavone is inert, but it forms
the hydrazone with 2,4-dinitrophenylhydrazine. Flavones react
with p-tosylhydrazine in an acid medium to give the p-tosylhydrazones. Flavones on reaction with hydroxylamine yield phenyleisoxazoles instead of the expected oximes (Scheme 38).128 The
formation of phenyleisoxazole instead of flavone oximes has been
explained by a mesomeric effect of the phenyl group on the C2
atom as well as the existence of non-canonical resonance forms.
Oximes and methyloximes of hydroxyflavones have also been
prepared after the transient protection of 3-hydroxyflavone,
7-hydoxyflavone, and 6-hydroxyflavone with haloacetone under
basic conditions followed by treatment with NH2OH or
NH2OMe.129 Mannich reactions of flavones yield 8-aminomethyl
derivatives.130
Flavone 16 condenses with 9-fluorenyl-sodium 159 to give
the 1,4-addition product, 2-hydroxy-b-fluorenylidene-b-phenylpropiophenone (160) (Scheme 39).131 Similarly, guanidine reacts
with flavones to give 1,3-dipolar addition to 2-aminopyrimidines.132
Flavone 161 reacts with Grignard reagent to give the 1,2addition product, chromen-4-ol 162, which has been converted
into the benzopyrilium salt 163 (Scheme 40).133
Scheme 38. Isoxazole formation from flavones.
3.7. Reactions with organometallic reagents
Various cross-coupling reactions of flavones are also known.134
Palladium-catalyzed Stille reactions of flavone triflates 164 with
tetravinyltin give vinylflavones 165, whereas the reactions with
benzophenone imine, followed by hydrolysis, afford aminoflavones
167 (Scheme 41).135
Zheng et al. performed Suzuki cross coupling on apigenin using
difluoromethyl as the hydroxyl protecting group. The key intermediate, 6-iodoflavone 171 prepared from 168 through the intermediates 169 and 170, was regioselectively synthesized with
AgOAc/I2 under mild conditions. Flavone-30 -boronate 173 prepared
from iodoflavone 172 was then coupled with 6-iodoflavone 171
using tetrakis(triphenylphosphine)palladium(0) (Scheme 42).136
7-Carboxylflavone 176 has also been prepared using a crosscoupling strategy starting from 7-hydroxyflavone via the flavone
triflate. The 5-hydroxy group was protected as the pivaloyl ester
and the intermediate 175 was subjected to palladium acetatecatalyzed cross coupling in the presence of CO gas (Scheme 43).137
4. Summary
Flavones constitute a major portion of natural products present
in fruit and vegetables of biological importance. They possess significant pharmacological activities like antioxidant, anticancer,
antiviral, antibacterial, anti-allergic, anti-osteoporotic etc. Due to
their diverse pharmacological profile, they have attracted the attention of medicinal chemists. There are a number of processes
available for the synthesis of flavones generally involving simple
organic molecules as starting materials. On the basis of the intermediate involved in the preparation of flavones, these preparations fall into two major groups involving b-diketones and
chalcones as intermediates. Studies have led to the realization that
no process is absolute and that they may be modified according to
the need. Syntheses of ring A modified flavones in the majority of
cases require prior synthesis of the appropriate acetophenones and
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
13
R3
HO
O
R3
TfO
R2
R2
pyridine
R1
OH
O
Tf2O
O
R1
(Ph3P)4Pd,
tetravinyltin
R1= H, OMe
R2, R3= H, OBzI
OH
164
O
Ac2O, pyridine
LiCl, BHT
R3
R3
TfO
O
O
R2
R2
R1
R1
OH
OAc
O
165
Cs2 CO3, Ph C
NH ,
2
Pd(OAc)2,
BINAP
R3
H2N
O
R2
R1
OH
O
cyclohexene
Pd(OH)2
N
O
R1
OH
167
R2
Ph
EtOH, reflux
O
R3
Ph
O
166
Scheme 41. Cross-coupling reactions of flavone triflates.
Scheme 42. Suzuki coupling of iodoflavone to form biflavones.
the B ring modified flavones require prior modification of benzaldehydes. The C-ring modified flavones at the C3 position can be
prepared either through u-substituted acetophenones, which are
prepared through the HoubeneHoesch method or epoxy chalcones.
Flavones exhibit chemical reactions of the double bond and the
carbonyl group as well as the hydroxyl groups. The regioselectivity
in most of the reactions on flavones is determined by the presence
and positioning of the hydroxyl groups (either free or protected) on
the ring A. Some reactions like the WesselyeMoser rearrangement
can be utilized for shifting of the substituent from the C8 to the C6
position and double sigmatropic rearrangement for the synthesis of
C8 prenylflavones.
Acknowledgements
Scheme 43. Synthesis of 7-carboxyflavone through cross coupling.
A.V. is grateful to CSIR, New Delhi for the award of a Senior
Research Fellowship.
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
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A.K. Verma, R. Pratap / Tetrahedron xxx (2012) 1e16
Biographical sketch
Dr. Ram Pratap is Chief Scientist at Central Drug Research Institute, Lucknow, India. He
received his M.Sc. and Ph. D. degrees from Banaras Hindu University, Varanasi. He
worked with Dr Nitya Anand, former CDRI Director for his doctorate degree. Later,
he did his post-doctoral studies with Prof. Raymond Castle, Editor J. Heterocyclic
Chemistry on the synthesis and mutagenic activity of polyaromatic thiophenes present
in coal liquids. He is a Medicinal Chemist and has worked for the technology development of drugs as well as design & synthesis of molecules for metabolic and infectious
diseases. To mention some significant technologies developed by him, are quinidine
from quinine to avoid deforestation, guggulsterone, acyclovir, and primaquine diphosphate. Dr Ram Pratap was involved in the development of Bulaquine, an antimalarial
drug safer as compared to primaquine, which was later marketed. He has discovered
several new chemical entities for drug development that are presently in the R&D
pipeline. He has to his credit eight US patents and sixty six publications in peerreviewed journals. He was given CSIR Technology Award 2008 for his work on guggulsterone and related molecules.
Alok K. Verma was born in 1981 in Faizabad, India. He graduated from the University
of Allahabad in 20 01 and worked as a Lecturer in Bundelkhand University
(2002e2004) before joining as junior research fellow (CSIR) in the group of Dr. Ram
Pratap at Central Drug Research Institute, Lucknow. His research work was focused
on the design and synthesis of antihyperglycemic and antihyperlipidemic agents.
Please cite this article in press as: Verma, A. K.; Pratap, R., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.06.097