Mild and efficient organocatalytic method for the synthesis of flavones

Article abstract of DOI:10.1016/j.tetlet.2016.07.042

A convenient and efficient organocatalytic procedure for the selective cyclization of 1,3-diketones to give aromatic substituted 4H-chromen-4-ones under mild reaction conditions using N-triflyl phosphoramide is described. Application of the described conditions is presented in a formal synthesis of (S)-flavanone.

Full text of DOI:10.1016/j.tetlet.2016.07.042

Tetrahedron Letters 57 (2016) 3841–3843
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Tetrahedron Letters
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Mild and efficient organocatalytic method for the synthesis
of flavones
⇑
Filip Stanek, Maciej Stodulski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient organocatalytic procedure for the selective cyclization of 1,3-diketones to give
aromatic substituted 4H-chromen-4-ones under mild reaction conditions using N-triflyl phosphoramide
is described. Application of the described conditions is presented in a formal synthesis of (S)-flavanone.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 17 May 2016
Revised 29 June 2016
Accepted 12 July 2016
Available online 16 July 2016
Keywords:
Brønsted acid
Chromone
Flavone
N-Triflyl amide
Organocatalysis
Flavonoids are plant metabolites that constitute a broad range
of natural products (Fig. 1).1 In Nature flavonoids play many
important roles e.g., plant pigmentation, UV filtration, symbiotic
nitrogen fixation, floral pigmentation, and various physiological
regulations.2 Moreover, these compounds exhibit a broad range
of pharmacological activities including anticancer, antibacterial,
antiviral, antioxidant, antiinflammatory, antiallergic, and estro-
genic, or antiestrogenic properties.3 As a consequence of these
physiological activities, significant efforts have been devoted to
their isolation from plants and synthesis in the laboratory.4 The
chromone ring (4H-chromen-4-one) constitutes a core subunit of
flavones; therefore a broad range of studies have been related to
the synthesis of novel, more diverse and complex bioactive chro-
mone derivatives and the development of mild synthetic methods
that can be applied to the synthesis of chromone derivatives.5 Var-
ious derivatives have been characterized as potent anticancer
agents e.g., flavopirydol 4,6 or flavone-8-acetic acid 6.7 Cromolyn
5, and flavoxate 1 were already introduced for medicinal use
(Fig. 1).8,9
and are widely described.5 Historically, the most common method
for chromone preparation involves the Baker-Venkataraman rear-
rangement and is related to the cyclization of 1-(o-hydrox-
yphenyl)-1,3-diketones in the presence of strong acids,
anhydrides or bases.10
Other reagents have also been developed, e.g., CoIII(ligand)OH,11
FeCl3,12 Br2/CHCl3,13 or ionic liquids.14 Unfortunately, most of these
methods require harsh reaction conditions, high temperatures, or
stoichiometric use of reagents or metal catalysts. Despite the var-
ious methods reported, the efficient synthesis of chromone deriva-
tives with aromatic substituents at the C2 position under mild and
metal-free reaction conditions using the Baker-Venkataraman
rearrangement is limited.
As part of our efforts to develop a more practical catalytic sys-
tem for the intramolecular cyclization of aromatic 1-(o-hydrox-
yphenyl)-1,3 diketones to give chromones as a method to access
the flavone skeleton under mild and metal-free conditions; herein,
we present novel reaction conditions that facilitate cyclization
using catalytic N-triflyl phosphoramide.
The synthesis of the chromone skeleton and flavones possessing
substituents at the C2 position are broadly described in the litera-
ture. The main synthetic routes relate to the use of ortho-hydrox-
yarylketones through the Claisen, Baker-Venkataraman or
Kostanecki-Robinson cyclizations, benzopyrylium salts or the Vils-
meier–Haack reaction.5 Other methods have also been developed
With the goal to develop mild, organocatalytic conditions, we
developed a synthetic route utilizing aromatic diketones 8 as start-
ing materials, which were easily prepared according to literature
protocols11 (Scheme 1).
We began our study by testing various Brønsted acids with the
model substrate 8 (Table 1). We observed that treatment of com-
pound 8 with p-TsOH or diphenyl phosphate (DPP) led to the for-
mation of chromone 10a in 15% and 25%, respectively (Entries 3
and 4). It was noted, that the model reaction without catalyst gave
no product (Entries 1 and 2). However, reaction with N-triflyl phos-
⇑
Corresponding author. Tel.: +48 (22) 343 2130; fax: +48 (22) 632 6681.
E-mail address: maciej.stodulski@icho.edu.pl (M. Stodulski).
http://dx.doi.org/10.1016/j.tetlet.2016.07.042
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

3842
F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843
O
O
OH
O
O
OH
O
O
OH
O
glucose
OH
OH
OH
HO
HO
CO2R
1
2
3
Flavoxate
Quercetin
OH
Kampferol-3- O-glucoside
O
OH
O
O
O
O
O
O
HO
HO
O
H
HO2C
O
CO2H
CO2H
Cl
N
4
5
6
Flavone-8-acetic acid
Flavopirydol
Cromolyn
Figure 1. Representative examples of natural and synthetic products containing the chromone framework.
O
1. ArCO2H, DCC,
DCM, DMAP,
rt, 24 h
PhO
PhO
F
O
S
O
P
F
O
O
O
O
O
HN
9
R2
Ar
F
R2
Ar
R2
OH
8
2. tBuONa, DMF,
rt, 1 h
Ar = Ph, 4-MePh, 4-OMePh,
4-ClPh, 4-CF3Ph, 1-Naphthyl
R1 = Cl, Br, OMe
OH
R1
R1
R1
7
10
up to 89% yield
42-68% yield
R
2 = H, Me, CH2Ph
Scheme 1. Synthesis of ring substituted flavones.
Table 1
To examine the scope of the methodology, various starting
materials (Table 2, entries 1–16) were used. This revealed that a
broad spectrum of substrates containing electron donating or elec-
tron withdrawing groups can be used. Substituents in the meta-
position or more sterically demanding groups such as 1-naphthyl-
were successful in this transformation. The reactivity of 8 was
slightly dependent on the substituent in the para-position of the
aromatic ring. Strongly electron withdrawing groups such as CF3
led to lower yields than other functional groups. Cyclization of
Optimization of the reaction conditionsa
O
O
O
O
Cat., solvent, 40 °C
sealed tube
OH
8
10a
Entry
Cat.
Solvent
Temp. (°C)
Yield (%)
1
2
3
4
5
6
7
8
—
—
DCM
DCM
DCM
DCM
DCM
THF
Dioxane
Toluene
MeCN
AcOEt
MeOH
rt
0
0
40
40
40
40
40
40
40
40
40
40
p-TsOH (20 mol %)
DPP (20 mol %)
9 (20 mol %)
9 (20 mol %)
9 (20 mol %)
9 (20 mol %)
9 (20 mol %)
9 (20 mol %)
9 (20 mol %)
15
25
76
13
16
18
67
22
85
Table 2
Substrate scope
R5
R2
O
R5
O
O
conditionsa
R4
R3
R6
R1
R4
R3
R1
R6
OH
9
10
11
O
R2
8
10a-j
a
8 0.20 mmol, solvent (2 mL), 16 h, isolated yields; DPP: diphenyl phosphate.
Entry Product
R1
R2 R3
R4
R5
R6
Yield
10
(%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
H
MeO
MeO
H
H
H
H
H
H
H
Me
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
85
86
86
79
77
89
68
67
79
71
60
61
55
phoramide afforded the desired flavone in 76% yield (Entry 5).
These results were strongly correlated with the pKa of the Brønsted
acids, where the stronger acid gave higher yields. Further opti-
mization and solvent screening revealed that the best results were
obtained in methanol using 5 mol % catalyst. In this case chromone
10a was obtained in 85% yield. Polar protic solvents favor forma-
tion of the chromone scaffold due to solvatation and stabilization
of the forming ions.
These experiments showed that N-triflyl phosphoroamide 9
actively promoted the cyclization reaction and constitutes an
excellent alternative to known methods which give poor results
in the case of aromatic substituted diketones. Moreover, it should
be stressed that the reaction conditions are much milder than
known acidic procedures where heating in a mixture of concen-
trated AcOH/HCl is required.10
4-ClPh
3-ClPh
1-Naphtyl
3-MeOPh
4-MeOPh
4-CF3Ph
Ph
Ph
Ph
Ph
Ph
3,4-
MeOPh
Ph
Ph
Ph
9
10
11
12
13
j
k
l
m
14
15
16
n
o
p
H
H
H
H
H
H
H
H
Br
H
H
H
Me
CH2Ph 16
Me
20
8
a 8 0.20 mmol, 9 (20 mol%), MeOH (2 mL), 40 °C, 16 h, sealed tube, isolated yields.

F. Stanek, M. Stodulski / Tetrahedron Letters 57 (2016) 3841–3843
3843
Table 3
References and notes
Comparison to literature methods
1. (a) McNaught, A. D.; Wilkinson, A. IUPAC. Compendium of Chemical Terminology,
2nd ed. (the ‘Gold Book’); Wiley Blackwell; 2nd Revised edition edition.; (b)
Grotewold, E. The Science of Flavonoids; Springer Science + Business Media:
New York, 2006.
2. Galeotti, F.; Barile, E.; Curir, P.; Dolci, M.; Lanzotti, V. Phytochem. Lett. 2008, 1,
44.
3. (a) Hollman, P. C. H.; Hertog, M. G. L.; Katan, M. B. Biochem. Soc. Trans. 1996, 24,
785; (b) Rice-Evans, C. A.; Miller, N. J. Biochem. Soc. Trans. 1996, 24, 790; (c)
Manthey, J. A.; Guthrie, N.; Grohmann, K. Curr. Med. Chem. 2001, 8, 135; (d)
Prasad, S.; Phromnoi, K.; Yadav, V. R.; Chaturvedi, M. M.; Aggarwal, B. B. Planta
Med. 2010, 76, 1044.
Entry
Conditions
Yield of 10a (%)
Ref.
1
2
3
4
5
6
7
8
N-Tf-phosphoroamide (5 mol %), 40 °C
AcOH/H2SO4, 100 °C
KHSO4, 120 °C
Gallium(III) triflate, MeCN, 80 °C
CuBr2, CHCl3, AcOEt, reflux
CuCl2, EtOH, 80 °C, MW
Co(III)salen(OH), 60 °C
[EtNH3]NO3, MW
85
76
98
97
79
98
94
81
10a
10o
10p
10q
10r
11
14
4. (a) Tanaka, K.; Sugino, T. Green Chem. 2001, 3, 133; (b) Saravanamurugan, S.;
Palanichamy, M.; Arabindoo, B.; Murugesan, V. J. Mol. Catal. A: Chem. 2004, 218,
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Nibbs, A. E.; Scheidt, K. A. Eur. J. Org. Chem. 2012, 2012, 449.
O
O
5. (a) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014,
114, 4960; (b) Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G. Eur. J. Med.
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ref. 15
O
89%
78% ee
O
Scheme 2. Formal synthesis of (S)-flavone.
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Kaye, S. B. Br. J. Cancer 1989, 60, 104; (b) Bauvois, B.; Puiffe, M. L.; Bongui, J. B.;
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diketones 8 containing additional substituents (methyl and benzyl)
on the methylene group between the two ketones were also inves-
tigated (Entries 14–16). Unfortunately, in these cases the desired
chromones were only obtained in 8–20% yield.
In comparison to other reports in the literature for the construc-
tion of related chromone derivatives using the Baker-Venkatara-
man rearrangement, the proposed procedure can be considered
as particularly convenient in terms of mild, organocatalytic reac-
tion conditions and efficiency for the synthesis of chromones 10
containing aromatic substituents (Table 3).
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Floor Dysfunct. 1999, 10, 91.
Moreover, the presented protocol can be applied to the formal
synthesis of (S)-flavone, which has been described by Glorious
and co-workers (Scheme 2).15 This sequence involves stereoselec-
tive reduction of the double bond and oxidation of the hydroxyl
10. (a) Banerji, A.; Goomer, N. C. Synthesis 1980, 874; (b) Hoshino, Y.; Takeno, N.
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group. Additional functionalization of the double bond in the
a-
position to the carbonyl group also can be applied to the synthesis
of various oxygen-substituted flavone analogues.5
In conclusion, we report an efficient approach for the
organocatalytic dehydrative cyclization of 1,3-diaryl diketones to
give a variety of substituted flavones. The simple and straightfor-
ward cyclization can be performed under mild, metal-free, mois-
ture, and air tolerant conditions. Taking into account the mild
conditions and simple steps that do not require special preparative
procedures, the presented methodology offers advantages over
literature procedures. In most cases the flavones containing aro-
matic substituents were obtained in good yields in the presence
of catalytic N-triflyl phosphoramide.
11. Nishinaga, A.; Ando, H.; Maruyama, K.; Mashino, T. Synthesis 1992, 839.
12. Zubaidha, P. K.; Hashmi, A. M.; Bhosale, R. S. Heterocycl. Commun. 2005, 11, 97.
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Acknowledgment
The authors gratefully acknowledge financial support from the
Polish National Science Centre (DEC-2012/07/D/ST5/02313).
15. Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 8454.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.07.
042.