New syntheses of 3-aroylflavone derivatives; Knoevenagel condensation and oxidation versus one-pot synthesis

Article abstract of DOI:10.1055/s-0032-1317159

Two syntheses of 3-aroylflavones have been established. In the first synthesis the use of microwave irradiation led to an improvement in the yields of both the Knoevenagel condensation of β-diketones with aldehydes to afford 3-aroylflavanones and of their

Full text of DOI:10.1055/s-0032-1317159

LETTER
▌2353
lNetteerw Syntheses of 3-Aroylflavone Derivatives; Knoevenagel Condensation and
Oxidation versus One-Pot Synthesis
3-Aroylflavone Derivatives
Patrícia A. A. M. Vaz, Diana C. G. A. Pinto,* Djenisa H. A. Rocha, Artur M. S. Silva,* José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: diana@ua.pt; E-mail: artur.silva@ua.pt
Received: 17.06.2012; Accepted after revision: 30.07.2012
R
R
OMe
OMe
OMe
OMe
Abstract: Two syntheses of 3-aroylflavones have been established.
In the first synthesis the use of microwave irradiation led to an im-
provement in the yields of both the Knoevenagel condensation of
β-diketones with aldehydes to afford 3-aroylflavanones and of their
oxidation to 3-aroylflavones. In the second and more general syn-
thesis, a novel and efficient procedure for 3-aroylflavones involves
a one-pot reaction between 2-hydroxyacetophenones and aroyl
chlorides in the presence of lithium bis(trimethylsilyl)amide.
OH
O
O
OH
O
HO
O
1a R = H
1b R = OMe
OMe
MW
EtOH
H
piperidine
OMe
OMe
Key words: Claisen condensation, Knoevenagel condensation,
5'
OMe
lithium bis(trimethylsilyl)amide, microwaves
B
6'
R
O
OMe
8
R
4a O
2
3
A
C
OMe
O
2'
MW
O
4
Flavones constitute an important class of low molecular
weight molecules widely distributed in the plant kingdom,
where they impart interesting biological activities.1
Among the naturally occurring flavones and their synthet-
ic analogues, several compounds display anticancer,2 anti-
inflammatory3 and antioxidant4 activities, to mention a
few examples. The presence of substituents at the flavone
nucleus is considered to be an important structural feature.
For instance, a few years ago we reported that 3-alkyl-
flavones5 and 3-(3,4-dihydroxybenzoyl)-3′,4′,5,7-tetra-
hydroxyflavone5b are potent antioxidant agents.
6
O
8a
5
DMSO, I2
O 6''
D
2''
OMe
5''
OMe
OMe
OMe
2a R = H
2b R = OMe
3a R = H
3b R = OMe
Scheme 1
nones 2 were obtained in good yields (over 60%) (30 min
at 300 W),9–11 and their oxidation to 3-aroylflavones 3
were also performed in good yields (over 70%) (8 min at
500 W).12–14
Recent growing interest in 3-aroylflavones has focused on
other important pharmacological properties demonstrated
by some derivatives, in particular the moderate antitubulin
activity of 3-(3,4,5-trimethoxybenzoyl)-4′-methoxy-
flavone6 and the potent topoisomerase I inhibitory activity
We then studied the one-pot synthesis of 3-aroylflavones
by the reaction of 2′-hydroxyacetophenones with aroyl
chlorides in the presence of 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) as base.7 By treating acetophenone
(1 equiv) with aroyl chloride (3 equiv) and DBU (3
equiv), in anhydrous pyridine at 70–80 °C (12–24 h), fla-
vones were obtained as the main products (56–61%) and
3-aroylflavones as by-products (less than 5% yield).
of
3-(4-nitrobenzoyl)-7-benzoyloxy-4′-nitroflavone.7
Consequently, a search for new or improved routes to-
wards the synthesis of 3-aroylflavones is still a challenge.
We have proven that microwave irradiation can dramati-
cally improve the transformation of 2′,6′-bisaroyloxyaceto-
phenones into the corresponding 3-aroylflavones through
the Baker–Venkataraman rearrangement.8 It was also re-
ported that the Knoevenagel condensation of β-diketones
(which exist in equilibrium with their enolic form) with
aldehydes afforded 3-aroylflavanones, which were then
oxidized to 3-aroylflavones, although in low overall
yield.6
Next we considered the reaction of 2′-hydroxyaceto-
phenones with aroyl chlorides in the presence of LiHMDS
as base. This base was already used in the synthesis of
β-diketones, from ketones and aroyl chlorides,15 from
O-silyl-protected methyl salicylate with acetophenones,16
and also from hydroxylated 2′-hydroxyacetophenones
with acid chlorides.17 We started by investigating the re-
action of 2′-hydroxyacetophenone (4a) with benzoyl chlo-
ride (5a). Optimal conditions were established as the
reaction of 4a with 5a (3 equiv) and base LiHMDS (4
equiv), followed by treatment with hydrochloric acid
(20%),18 to give 3-aroylflavone 6a in good yield (67%).
With lower amounts of benzoyl chloride and/or base, 2-
acetylphenyl benzoate (7) was obtained as the major prod-
uct (72%; Scheme 2). These results contradict the results
Following our interest in these compounds, we initiated a
study on the synthesis of 3-aroylflavones and tried to im-
prove this methodology by using microwave irradiation as
an alternative source of energy (Scheme 1). 3-Aroylflava-
SYNLETT 2012, 23, 2353–2356
Advanced online publication: 14.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317159; Art ID: ST-2012-D0522-L
© Georg Thieme Verlag Stuttgart · New York

2354
P. A. A. M. Vaz et al.
LETTER
reported by Cushman and Nagarathnam,17 who reported The results indicate that both C- and O-aroylation may be
that C-2 aroylation of the acetophenone enolate took place occurring and an intermediate such as structure 10 can be
rather than O-aroylation. Next, our study was extended to formed (Scheme 3, path a). Compound 10 can be trans-
the use of p-nitro- and p-methoxybenzoyl chlorides (5b formed into 11 through a base-catalyzed Baker–
and 5c). In these cases, a larger amount of the aroyl chlo- Venkataraman rearrangement; although structure 11 can
ride derivative was necessary to obtain the desired 3-aro- also be obtained by bisaroylation of the C-2 acetophenone
ylflavones in good yields.18 With lower amounts of enolate (Scheme 3, path b). Finally, acid-catalyzed cycli-
LiHMDS or aroyl chloride, the (Z)-3-aryl-3-hydroxy-1- zation and water elimination leads to the expected 3-aroyl-
(2-hydroxyphenyl)prop-2-en-1-ones 8a and 8b were ob- flavones 6.
tained as the major products (48–52%; Scheme 2).
The next step in our synthetic strategy was to use other
Under the optimal conditions,18 4′-nitro-3-(4-nitrobenzo- 2′-hydroxyacetophenone derivatives 4b and 4c bearing
yl)flavone (6b) was obtained in very good yield,19 but in extra hydroxyl groups, which give rise to important 3-ar-
the reaction of 4a with p-methoxybenzoyl chloride (5c), oylflavones that are suitable for biological evaluations.
the 1H NMR spectrum of the obtained product showed, in The desired products 6d and 6e were obtained in good
addition to the 3-aroylflavone A, B and D ring proton res- yields (>50%), revealing the most challenging aspect of
onances, two singlets at δ = 6.65 and 16.69 ppm.20 The the work, which was the optimization of base and benzoyl
data indicate that we had not obtained the expected 3-aroyl- chloride amounts and the reaction time needed to accom-
flavone 6c, but, rather, the intermediate 2-hydroxy-3-(4- plish the synthesis. By this method it was possible to pre-
methoxybenzoyl)-2-(4-methoxyphenyl)chroman-4-one
pare polyhydroxy-3-aroylflavones without the need for
(9). The intramolecular hydrogen bond between the 2-hy- protection and deprotection steps and also without the use
droxyl proton and the 3-aroyl carbonyl group 9 deters wa- of 2′,6′-dihydroxyacetophenone, which proceed through a
ter elimination (9; Scheme 2).20 The referred singlets were bis-Baker–Venkataraman rearrangement.8
assigned to the H-3 and 2-OH proton resonances, respec-
tively.
OH
O
O
LiHMDS
To overcome this problem we used commercial hydro-
chloric acid (37%), because we considered that the final
acidification with 20% hydrochloric acid was not suffi-
cient to induce water elimination. Under these conditions
the desired 3-aroylflavone 6c was obtained in good yield
(72%), but only after stirring the reaction mixture at room
temperature for eight hours (TLC analysis).
COCl
Ar
O
O
O
COCl
Ar
(a)
(b)
O
O
Ar
O
Ar
Ar
O
O
R3
O
O
Ar
O
O
O
R2
COCl
O
R2
R1
O
11
O
(i)
(ii)
HCl
O
10
+
H2O
R1
O
R3
OH
Ar
O
O
enolate
enolic form
R3
6b R1 = R2 = H; R3 = NO2
6c R1 = R2 = H; R3 = OMe
6d R1 = R3 = H; R2 = OH
6e R1 = R2 = OH; R3 = H
4a R1 = R2 = H
5a R3 = H
6a R1 = R2 = R3 = H
4b R1 = H; R2 = OH 5b R3 = NO2
O
Ar
4c R1 = R2 = OH
5c R3 = OMe
6
(i) LiHMDS in THF, toluene
0 °C to r.t.
Scheme 3
20 min to 12 h, under N2
(ii) HCl (20 or 37%), 1–12 h
In summary, we have established two successful method-
ologies to perform the synthesis of 3-aroylflavones. The
first involves a Knoevenagel condensation followed by
oxidation of the intermediate 3-aroylflavanones, under
microwave irradiation. This methodology provides facile
access to new derivatives in shorter reaction times and
higher yields, although it is necessary to protect the hy-
droxyl groups of the starting material 2′-hydroxy-
acetophenone. The second approach constitutes a new and
efficient one-pot synthesis of 3-aroylflavones, starting
from hydroxylated 2′-hydroxyacetophenones and aroyl
chlorides. To the best of our knowledge, this method rep-
R3
O
O
O
O
H
O
2
O
3
O
OH
HO
8a R3 = NO2
8b R3 = OMe
O
7
9
OMe
Scheme 2
Synlett 2012, 23, 2353–2356
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Aroylflavone Derivatives
2355
pH was adjusted to 2 with dilute HCl (10%). Finally, the
mixture was extracted with CHCl3 (3 × 20 mL), dried over
sodium sulfate, and evaporated to dryness. The obtained
residue was purified by column chromatography (EtOAc–
hexane, 1:1). After solvent evaporation, the obtained residue
was recrystallized from EtOH to give the expected
resents the most efficient route for the synthesis of 3-aroyl-
flavones. Application of this method in the synthesis of
other pharmaceutically useful compounds is being pur-
sued and the results will be disclosed in due course.
3-aroylflavanones 2a (134 mg, 60%) or 2b (163 mg, 68%).
(11) 3′,4′,7-Trimethoxy-3-(3,4-dimethoxyphenyl)flavanone
2b: Yellow solid; mp 140–142 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.82 (s, 3 H, 3′-OCH3), 3.84 (s, 3 H, 4′-OCH3),
3.85 (s, 3 H, 7-OCH3), 3.89 (s, 3 H, 3′′-OCH3), 3.91 (s, 3 H,
4′′-OCH3), 5.06 (d, J = 11.9 Hz, 1 H, H-3), 5.91 (d,
Acknowledgment
Thanks is due to the University of Aveiro, Fundação para a Ciência
e a Tecnologia (FCT) and FEDER for funding the Organic Chemi-
stry Research Unit (project PEst-C/QUI/UI0062/2011) and the Por-
tuguese National NMR Network (RNNMR). D.H.A. Rocha also
thanks FCT for her PhD grant (SFRH/BD/68991/2010).
J = 11.9 Hz, 1 H, H-2), 6.51 (d, J = 2.3 Hz, 1 H, H-8), 6.63
(dd, J = 2.3, 8.9 Hz, 1 H, H-6), 6.80 (d, J = 8.4 Hz, 1 H, H-
5′), 6.83 (d, J = 8.4 Hz, 1 H, H-5′′), 7.00 (br s, 1 H, H-2′),
7.02 (br d, J = 8.4 Hz, 1 H, H-6′), 7.40 (d, J = 1.9 Hz, 1 H,
H-2′′), 7.45 (dd, J = 1.9, 8.4 Hz, 1 H, H-6′′), 7.86 (d,
J = 8.9 Hz, 1 H, H-5). 13C NMR (75 MHz, CDCl3): δ = 55.6,
55.7, 55.8, 55.9, 56.0 (5 × OCH3), 58.7 (C-3), 82.2 (C-2),
100.8 (C-8), 109.9 (C-2′), 110.4 (C-5′′), 110.5 (C-5′), 110.6
(C-6), 111.0 (C-2′′), 114.4 (C-4a), 123.8 (C-6′′), 129.1 (C-5),
129.8 (C-1′), 131.1 (C-1′′), 148.9 (C-4′), 149.0 (C-3′′), 149.4
(C-3′), 157.7 (C-4′′), 163.2 (C-8a), 166.5 (C-7), 188.6 (C-4),
194.5 (C=O). Anal. Calcd for C27H26O8·1/2 H2O: C, 66.66;
H, 5.39. Found: C, 66.52; H, 5.46.
References and Notes
(1) Verma, A. K.; Pratap, R. Nat. Prod. Rep. 2010, 27, 1571.
(2) (a) Lin, Y.-P.; Hsu, F.-L.; Chen, C.-S.; Chern, J.-W.; Lee,
M.-H. Phytochemistry 2007, 68, 1189. (b) Zhu, J. T. T.;
Choi, R. C. Y.; Chu, G. K. Y.; Cheung, A. W. H.; Gao, Q.
T.; Li, J.; Jiang, Z. Y.; Dong, T. T. X.; Tsim, K. W. K.
J. Agric. Food Chem. 2007, 55, 2438.
(3) (a) Nagaoka, T.; Banskota, A. H.; Tezuka, Y.; Midorikawa,
K.; Matsushige, K.; Kadota, S. Biol. Pharm. Bull. 2003, 26,
487. (b) Moscatelli, V.; Hnatyszyn, O.; Acevedo, C.;
Megias, J.; Alcaraz, M. J.; Ferrana, G. Planta Med. 2006, 72,
72.
(12) The optimal conditions were established after a complete
study of the reaction conditions. The amount of iodine was
optimized in order to prevent the formation of iodinated
derivatives. MW irradiation power was optimized to 500 W;
with less power, a longer reaction time (30 min) was needed
to perform the complete oxidation into flavones, without
improvement in the obtained yields, and with higher power
there was more degradation and consequently a lower yield
(40–56%).
(13) Optimized Experimental Procedure for the Synthesis of
3-Aroylflavones 3a and 3b: Iodine (5 mg, 0.02 mmol) was
added to a solution of the appropriate 3′,4′-dimethoxy-3-
(3,4-dimethoxybenzoyl)flavanone 2a and 2b (0.2 mmol) in
DMSO (5 mL). The mixture was poured into a two-necked
glassware apparatus equipped with a magnetic stirring bar,
fibre-optic temperature control and reflux condenser, and
was then irradiated in an Ethos SYNTH microwave
(4) (a) Beyer, G.; Melzig, M. F. Planta Med. 2003, 69, 1125.
(b) Vaya, J.; Mahmood, S.; Goldblum, A.; Aviram, M.;
Volkova, N.; Shaalan, A.; Musa, R.; Tamir, S.
Phytochemistry 2003, 62, 89.
(5) (a) Filipe, P.; Silva, A. M. S.; Seixas, R. S. G. R.; Pinto, D.
C. G. A.; Santos, A.; Patterson, L. K.; Silva, J. N.; Cavaleiro,
J. A. S.; Freitas, J. P.; Mazière, J.-C.; Santus, R.; Morlière,
P. Biochem. Pharmacol. 2009, 77, 957. (b) Gomes, A.;
Neuwirth, O.; Freitas, M.; Couto, D.; Ribeiro, D.;
Figueiredo, A. G. P. R.; Silva, A. M. S.; Seixas, R. S. G. R.;
Pinto, D. C. G. A.; Tomé, A. C.; Cavaleiro, J. A. S.;
Fernandes, E.; Lima, J. L. F. Bioorg. Med. Chem. 2009, 17,
7218.
(6) Quintin, J.; Roullier, C.; Thoret, S.; Lewin, G. Tetrahedron
2006, 62, 4038.
(Milestone Inc.) at 500 W constant power for 8 min. After
that period, the reaction mixture was poured into a mixture
of ice (10 g) and water (20 mL), and Na2S2O3·5H2O was
added. Finally, the mixture was extracted with CHCl3
(3 × 20 mL), dried over sodium sulfate, and the organic
solvent was evaporated to dryness. The residue was purified
by preparative TLC (EtOAc–hexane, 1:1), affording
3-aroylflavones 3a (70 mg, 78%) or 3b (71 mg, 75%).
(14) 3′,4′-Dimethoxy-3-(3,4-dimethoxyphenyl)flavone (3a):
Orange solid; mp 150–152 °C. 1H NMR (300 MHz, CDCl3):
δ = 3.73 (s, 3 H, 3′-OCH3), 3.89 (s, 3 H, 4′-OCH3), 3.90 (s,
3 H, 4′′-OCH3), 3.92 (s, 3 H, 3′′-OCH3), 6.80 (d, J = 8.4 Hz,
1 H, H-5′′), 6.84 (d, J = 8.4 Hz, 1 H, H-5′), 7.19 (d,
(7) Maicheen, C.; Jittikoon, J.; Ungwitayatorn, J. Meeting in
Advances in Synthetic and Medicinal Chemistry, St.
Petersburg, Russia, August 21–25, 2011, P103, 216.
(8) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett
2007, 1897.
(9) The optimal conditions were established after a study of the
reaction times, ranging from 5 to 30 minutes, and microwave
(MW) irradiation power, ranging from 200 to 500 W. The
obtained results indicate that higher MW irradiation power
gave lower yields (40–50%) and more degradation even
when shorter reaction times were used. When using MW
irradiation power lower than 300 W with shorter reaction
times the starting β-diketones 1a and 1b were recovered
(depending on the time and power 10–25%).
(10) Optimized Experimental Procedure for the Synthesis of
Flavanones 2a and 2b: A mixture of the appropriate
1-(2-hydroxyaryl)-3-(3,4-dimethoxyphenyl)propan-1,3-
dione 1a,b (0.5 mmol), 3,4-dimethoxybenzaldehyde (0.25 g,
1.5 mmol) and piperidine (0.4 mmol) in EtOH (15 mL), was
poured in a two-necked glassware apparatus equipped with
a magnetic stirring bar, fibre-optic temperature control and
reflux condenser, and was then irradiated in an Ethos
SYNTH microwave (Milestone Inc.) at 300 W constant
power for 30 min. After that period, the reaction mixture was
poured into a mixture of ice (10 g) and water (30 mL) and the
J = 2.0 Hz, 1 H, H-2′), 7.34 (dd, J = 2.0, 8.4 Hz, 1 H, H-6′),
7.44 (br d, J = 7.0, 8.0 Hz, 1 H, H-6), 7.48 (dd, J = 2.0,
8.4 Hz, 1 H, H-6′′), 7.60 (br d, J = 8.0 Hz, 1 H, H-8), 7.62 (d,
J = 2.0 Hz, 1 H, H-2′′), 7.75 (ddd, J = 1.7, 7.0, 8.0 Hz, 1 H,
H-7), 8.24 (dd, J = 1.7, 8.0 Hz, 1 H, H-5). 13C NMR (75
MHz, CDCl3): δ = 55.7, 55.9, 56.0 (4 × OCH3), 110.2 (C-
5′′), 110.3 (C-2′′), 110.9 (C-5′), 111.2 (C-2′), 118.0 (C-8),
121.7 (C-1′), 122.1 (C-6′), 123.2 (C-3), 124.1 (C-4a), 125.3
(C-6′′), 125.4 (C-6), 126.0 (C-5), 130.4 (C-1′′), 134.1 (C-7),
148.8 (C-3′′), 149.3 (C-3′), 151.6 (C-4′), 153.9 (C-4′′), 155.9
(C-8a), 161.6 (C-2), 176.5 (C-4), 192.4 (C=O). Anal. Calcd
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2353–2356

2356
P. A. A. M. Vaz et al.
LETTER
for C26H22O7·1/2 H2O: C, 68.56; H, 5.09. Found: C, 68.43;
H, 5.10.
(15) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675.
(16) Nagarathnam, D.; Cushman, M. Tetrahedron 1991, 47,
5971.
(19) 4′-Nitro-3-(4-nitrophenyl)flavone (6b): Yellow solid; 1H
NMR (500 MHz, CDCl3): δ = 7.46 (ddd, J = 0.7, 7.2, 7.9 Hz,
1 H, H-6), 7.64 (br d, J = 7.9 Hz, 1 H, H-8), 7.81 (d,
J = 7.0 Hz, 2 H, H-2′′, H-6′′), 7.85 (ddd, J = 1.6, 7.2, 7.9 Hz,
1 H, H-7), 8.08 (d, J = 7.0 Hz, 2 H, H-2′,6′), 8.24 (dd,
J = 1.6, 7.9 Hz, 1 H, H-5), 8.27 (d, J = 7.0 Hz, 2 H, H-3′′5′′),
8.30 (d, J = 7.0 Hz, 2 H, H-3′,5′). 13C NMR (75 MHz,
CDCl3): δ = 118.3 (C-8), 123.1 (C-4a), 123.2 (C-3), 124.1
(C-3′′,5′′), 124.2.0 (C-3′,5′), 126.2 (C-6), 126.6 (C-5), 129.7
(C-2′′,6′′), 130.2 (C-2′,6′), 135.3 (C-7), 137.1 (C-1′), 141.0
(C-1′′), 149.4 (C-4′′), 150.8 (C-4′), 156.0 (C-8a), 161.3 (C-
2), 176.0 (C-4), 191.6 (C=O). MS (ESI+): m/z (%) = 439
(100) [M + Na]+. Anal. Calcd for C22H12N2O7: C, 63.47; H,
2.91; N, 6.73; Found: C, 63.60; H, 3.19; N, 6.27.
(20) 2-Hydroxy-4′-methoxy-3-(4-methoxyphenyl)flavanone
(9): Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 3.84 (s,
3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.65 (s, 1 H, H-3), 6.80 (d,
J = 8.3 Hz, 2 H, H-3′′,5′′), 6.98 (d, J = 8.8 Hz, 2 H, H-3′,5′),
7.29 (dd, J = 1.3, 7.9 Hz, 1 H, H-8), 7.39 (ddd, J = 1.3, 7.6,
7.7 Hz, 1 H, H-6), 7.56 (ddd, J = 1.8, 7.6, 7.9 Hz, 1 H, H-7),
7.67 (d, J = 8.3 Hz, 1 H, H-2′′,6′′), 7.93 (dd, J = 1.8, 7.7 Hz,
1 H, H-5), 8.20 (d, 8.8 Hz, 2 H, H-2′,6′), 16.69 (1 H, 2-OH).
13C NMR (75 MHz, CDCl3): δ = 55.4 (OCH3), 55.5 (OCH3),
96.4 (C-3), 105.0 (C-2), 113.7 (C-3′′,5′′), 114. 0 (C-3′,5′),
121.5 (C-1′), 123.9 (C-8), 126.2 (C-6), 127.9 (C-1′′), 129.3
(C-2′′,6′′), 129.5 (C-4a), 129.8 (C-5), 132.5 (C-2′,6′), 149.0
(C-8a), 163.1 (C-4′′), 164.1 (C-4′), 182.4 (C-4), 186.2
(C=O). MS (ESI+): m/z (%) = 427 (100) [M + Na]+. Anal.
Calcd for C24H10O6: C, 71.28; H, 4.98; Found: C, 70.95; H,
4.99.
(17) Cushman, M.; Nagarathnam, D. Tetrahedron Lett. 1990, 31,
6497.
(18) Optimized Procedure for the Synthesis of
3-Aroylflavones 6a–e: The appropriate acetophenone 4a–c
(1 mmol) was dissolved in toluene (5 mL) in a screw cap vial
equipped with a magnetic stirring bar and sealed with a
septum. The solution was cooled at 0 °C under nitrogen and
LiHMDS (4.2 mL in THF, 4.2 mmol) was quickly added by
using a syringe. The solution was stirred for approximately
5 min before the addition of aroyl chlorides 5a–c (4 mmol)
in one portion. The solution was then removed from the ice
bath and stirred at room temperature [20 min (6a,b), 8 h (6c)
and 12 h (6d,e)]. After that period, HCl (4 mL) [20% (6a,b)
or 37% (6c–e)] was added and the resulting solution was
stirred for 1 h (6a,b) or 8 h (6d,e) and then extracted with
CH2Cl2 (3 × 15 mL). The organic layer was then washed
with brine, dried over sodium sulfate, and evaporated under
reduced pressure. The resulting residue was purified by
column chromatography (4:1, hexane–EtOAc; in the case of
6d,e the eluent was CH2Cl2). After solvent evaporation and
residue crystallization from EtOH, the expected
3-aroylflavones 6a–e were obtained (6a: 218 mg, 67%; 6b:
287 mg, 69%; 6c: 278 mg, 72%; 6d: 195 mg, 57%; 6e: 183
mg, 51%).
Synlett 2012, 23, 2353–2356
© Georg Thieme Verlag Stuttgart · New York