Fast and efficient synthesis of flavanones from cinnamic acids

Article abstract of DOI:10.1080/00397911.2016.1228110

A fast and efficient synthesis of flavanones from cinnamic acids in three steps has been developed. First, the cinnamic acid was converted to cinnamyol chlorides using SOCl₂. The acid chlorides were then treated with substituted phenols in BF₃· OEt₂to furnish corresponding chalcones in 42(75% yields. Base-catalyzed cyclization of the chalcones at room temperature afforded corresponding flavones in 85–95% yields. The conversion of the cinnamic acid derivatives to corresponding chalcones was found to be sensitive to the position and nature of the substituents on the aromatic rings.

Full text of DOI:10.1080/00397911.2016.1228110

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A Fast and Efficient Synthesis of Flavanones From
Cinnamic Acids
Kibrom Gebreheiwot Bedane, Runner R. T. Majinda & Ishmael B. Masesane
To cite this article: Kibrom Gebreheiwot Bedane, Runner R. T. Majinda & Ishmael B.
Masesane (2016): A Fast and Efficient Synthesis of Flavanones From Cinnamic Acids, Synthetic
Communications, DOI: 10.1080/00397911.2016.1228110
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Date: 08 September 2016, At: 00:20

A fast and efficient synthesis of flavanones from cinnamic acids
Kibrom Gebreheiwot Bedane1, Runner R. T. Majinda1, Ishmael B. Masesane1
1Department of Chemistry, University of Botswana, Gaborone, Botswana
Corresponding author Ishmael B. Masesane E-mail: masesane@mopipi.ub.bw
Abstract
A fast and efficient synthesis of flavanones from cinnamic acids in three steps has been
developed. First the cinnamic acid was converted to cinnamyol chlorides using SOCl2.
The acid chlorides were then treated with substituted phenols in BF3.OEt2 to furnish
corresponding chalcones in 42% 75% yields. Base catalyzed cyclization of the chalcones
at room temperature afforded corresponding flavones in 85% 95% yields. The
conversion of the cinnamic acid derivatives to corresponding chalcones was found to be
sensitive to the position and nature of the substituents on the aromatic rings.
Graphical Abstract
KEYWORDS: acylation; cinnamic acid; chalcone; flavanone
INTRODUCTION
Natural and synthetic flavanones attract the attention of researchers because of their
interesting biological activity including antioxidant,[1–4] antibacterial, antifungal,[5–7]
antivirial,[8] anti-inflammatory[9,10] and antihypertensive.[11,12] As part of our broader
1

interest on flavonoids, we have isolated a number of bioactive flavanones from Erythrina
livingstoniana.[13,14] In continuation of our interest in flavanones, we explored a simple
and easy synthetic method for the basic skeleton of these compounds starting with
cinnamic acid or its derivatives.
Most of the reported synthetic methods for the synthesis of flavanones involve the
preparation of the key intermediate 2’-hydroxychalcones of type 3 via the condensation
reaction of 2-hydroxyacetophenones of type 1 and aldehydes of type 2 in the presence of
a base. Subsequent cyclisation of intermediates of type 3 in either basic or acidic medium
afforded flavanones of type 4 in moderate to high yields, Scheme 1.[15–20]
It is important to note that the synthesis of the key 2’-hydroxychalcone of type 3 through
a Lewis acid catalysed aromatic acylation reaction is also possible and has been reported
for the synthesis of flavones.[21–23] In continuation of our interest on flavanones, we set
out to investigate the preparation of 2’-hydroxychalcone intermediate of type 3 from the
reaction of phenols with cinnamyol chloride and subsequent cyclisation of the
intermediate chalcones to give flavanones.
RESULT AND DISCUSSION
The first two steps were performed without the isolation of any intermediates. Thus, a
reaction of cinnamic acid 5 and SOCl2 under reflux for 2 hours to give intermediate acid
chloride 6. The progress of the reaction was monitored by TLC. Excess SOCl2 was then
removed under reduced pressure and resorcinol and BF3.OEt2 were added to the residue.
2

The mixture was then refluxed for 30 minutes to give chalcone 7 in 72% yield together
with coumarin 8 in 4%, Scheme 2. The two products were easily separable by column
chromatography. Having achieved the expedient synthesis of chalcone intermediate 7, we
were in a position to address its cyclisation to the corresponding flavanone. Although it is
conceivable that chalcone 7 could cyclized to the corresponding flavanone under acidic
conditions, all attempts at the use of H3PO4 acid under a variety of conditions failed to
give the flavanone. Attention was then turned to bases and Na2CO3 failed under different
reaction conditions to facilitate the cyclisation of chalcone intermediate 7. Gratifyingly,
when a solution of chalcone 7 in methanol was stirred in the presence of KOH at room
temperature for four hours, flavanone 9 was isolated in 95% yield[24] (Scheme 2).
Both chalcone 7 and flavanone 9 were characterized using NMR spectroscopy and mass
spectrometry. The 1H NMR spectral features worth mentioning are signal for a chelated
proton at δC 13.44 in chalcone 7’s spectrum and the ring C protons signals at δH 2.77,
3.05 and 5.59 for the spectrum of flavanone 9.
Next, a more reactive phenol, phloroglucinol, was used in the preparation of the
intermediate chalcone instead of resorcinol. In the event, cinnamic acid was treated with
SOCl2 as described above to give the acid chloride. Once excess SOCl2 was removed, the
reaction mixture was treated with phloroglucinol and BF3.OEt2 and refluxed for 2 hours
to give chalcone 10 in 63% yield together with coumarin 11 in 6% yield, Scheme 3.
Subjection of chalcone 10 to the KOH-mediated cyclisation conditions gave flavanone 12
in 90% yield.
3

The reactions that were described thus far involved phenols that we activated towards
electrophilic substitution reactions in the synthesis of the chalcone intermediates. It was
therefore of interest to investigate if less active phenols would participate in the reaction.
Thus, treatment of the acid chloride that was prepared by reaction of cinnamic acid with
SOCl2 with phenol and BF3.OEt2 and refluxing for 2 hours gave chalcone intermediate 13
in 55% yield. Surprisingly, attempts to cyclise chalcone 13 in the presence of NaOH were
not successful. However, subjection of chalcone 13 to a stronger base NaOMe led to its
cyclisation to give flavanone 14 in 87% yield, Scheme 4.
In a parallel sequence of reactions, a mixture cinnamic acid and SOCl2 was refluxed for 4
hours and then treated with 4-bromophenol in the presence of BF3.OEt2. The mixture was
further refluxed for 2 hours and chalcone intermediate 15 was isolated in 42% yield.
Subsequent treatment of chalcone 15 with NaOMe gave flavanone 16 in 85% yield,
Scheme 5. It is important to note that the aromatic acylation reaction failed when 4-
nitrophenol was used instead of 4-bromophenol. This was not surprising bearing in mind
that the nitro group withdraws electrons from the aromatic by both resonance and
inductive effect thereby making the ring less nucleophilic and less reactive to the acyl
group. The bromo substituent on the other hand only withdraws electrons from the
aromatic ring by inductive effect.
Lastly, the effects of electron donating and electron withdrawing substituents attached to
cinnamic acid on the yields of reactions involved in this procedure were investigated. To
this end, 3-methoxycinnamic acid 17 and 3-nitrocinnamic acid 19 were converted to their
4

acid chlorides using SOCl2 and reacted with resorcinol in the presence of BF3.OEt2 to
give chalcones 22 and 24 in 75% and 66% yields respectively, Scheme 6. Consequent
cyclization of chalcones 22 and 24 afforded flavanones 27 and 28 in 92% and 90%
respectively. Interestingly, 4-methoxy and 4-nitrocinnamic acids 18 and 20 under the
described conditions failed to undergo the aromatic acylation reaction and only the
corresponding esters where detected in the reaction mixture. However, 4-chlorocinnamic
acid 21 was successively converted to its acid chloride and reacted with resorcinol to give
chalcone 26 in 44% yield. Chalcone 26 was thereafter subjected to the cyclisation
conditions to give flavanone 29 in 93% yield.
It is instructive to draw attention to the fact that the aromatic acylation reaction is
dependent on the position and nature of the substituent on the cinnamic acid. While C-4
attached substituents that either withdraw or donate electrons by resonance (-OMe and –
NO2) shut down the aromatic acylation reaction, a C-4 attached substituent that
withdraws electrons by inductive effect (-Cl) allows the reaction to proceed. The logical
explanation for the similar effect of 4-OMe and 4-NO2 groups is that BF3.OEt2
coordinates with the oxygen atom of the methoxy group and turns it into an electron
withdrawing group. The effect is less pronounced for 3-OMe and 3-NO2 substituted
cinnamic acid substrates because of lack of conjugation between the substituents and the
acid carbonyl group.
EXPERIMENTAL
5

Laboratory grade chemicals and solvents were procured from Sigma-Aldrich and used
without any further purification. Reactions were monitored by TLC, which was carried
out on 0.25 mm layer of Merck silica gel 60 F254 pre-coated on aluminium sheets.
Melting points measurements were determined on a Stuart melting point apparatus SMP1
(UK) and are uncorrected. Infra-red spectra were recorded neat on a Perkins Elmer FT-IR
spectrophotometer. Mass spectra were recorded on a GCT Premier spectrometer (Waters)
and an ionization energy of 70 eV. NMR spectra were recorded on a Bruker Avance DPX
300 spectrometer using standard pulse sequences and referenced to residual solvent
signals.
Typical Procedure For The Synthesis Of Chalcone Intermediates
Cinnamic acid 1 (1.48 g, 10 mmol) was suspended in SOCl2 (2 ml) and refluxed for 2
hours and monitored by TLC. Excess SOCl2 was then removed under pressure and to the
remaining residue was added resorcinol (1.0 g, 9 mmol) and BF3.OEt2 (2.0 ml). The
mixture was refluxed for 4 hours, and then quenched with water (25 ml) and extracted
three times with ethyl acetate (25 ml x 2). The organic layers were combined and dried
under pressure. The residue was subjected to column chromatography eluting with
petroleum ether:ethyl acetate (8:2) to give chalcone 3 in 72% yield and coumarin 4 in
4%.
2',4'-dihydroxychalcone (3): yellow solid, 72% yield, mp 156-158 C; IR (neat) ν: 3248,
1610, 1552, 1587 cm-1; 1H NMR (300 MHz, acetone-d6): δ 7.46-7.49 (3H, m, H-3,4,5),
7.84-7.88 (2H, m, H-2,6), 6.43 (1H, d, 2.5 Hz, H- 3'), 6.52 (1H, dd, 8.5, 2.5 Hz, H- 5'),
6

8.18 (1H, d, 8.5 Hz, H- 6'), 7.90 (1H, d, 15.6 Hz, H-α), 7.96 (1H, d, 15.6 Hz, H-β). 13C
NMR (75 MHz, acetone-d6): δ 135.0 (C-1), 128.7 (C-2 and 6), 128.9 (C-3 and 5), 130.5
(C-4), 113.6 (C-1'), 165.9 (C-2'), 103.9 (C-3'), 167.7 (C-4'), 108.0 (C-5'), 132.7 (C-6'),
192.0 (C=O), 120.8 (C-α), 143.9 (C-β). HRMS-ES (m/z) calcd for [C15H12O3 + H]:
241.0865; found, 241.0872.
Typical Procedure For The Synthesis Of Flavanones
Chalcone 3 (0.24 g, 1.0 mmol) was dissolved in a solution of KOH (0.24 g, 1.0 mmol) in
methanol (25 ml) and the mixture was stirred at room temperature. The reaction mixture
was then acidified with HCl (2 M) and then extracted three times with ethyl acetate. The
organic extracts were combined and concentrated under pressure to give flavanone 5 in
95% yield.
7-hydroxyflavanone (5): yellow solid, 95% yield, mp 180-182 C; IR (neat) ν: 3675,
1
2988, 2905, 1656, 1601, 1552 cm-1; H NMR (300 MHz, acetone-d6): δ 5.58 (1H, dd,
12.8, 3.0 Hz, H-2), 2.77 (1H, dd, 16.7, 3.0 Hz, H-3eq), 3.05 (1H, dd, 16.7, 12.8 Hz, H-
3ax), 7.77 (1H, d, 8.7 Hz, H-5), 6.62 (1H, dd, 8.7, 2.3 Hz, H-6), 6.49 (1H, d, 2.3 Hz, H-8),
7.65 (1H, m, H-2', 6'), 7.40-7.50 (3H, m, H-3', 4', 5'). 13C NMR (75 MHz, acetone-d6): δ
79.7 (C-2), 43.9 (C-3), 189.3 (C-4), 128.7 (C-5), 110.5 (C-6), 163.5 (C-7), 102.9 (C-8),
164.4 (C-9), 114.4 (C-10), 139.6 (C-1', 6'), 126.3 (C-2', 5'), 128.5 (C-3'), 128.3 (C-4').
HRMS-ES (m/z) calcd for [C15H12O3 + H]: 241.0865, found, 241.0862
7

The following chalcones and flavanones that were prepared are known compounds and
were characterised on the basis of data that matched literature data: Chalcones 3[25], 6[26]
,
10[27], 12[28], 19[29], 21[30] and 23[31]; Flavanones 5[32], 8[33], 11[34,35], 13[36], and 25[37]
.
CONCLUSION
In conclusion, a convenient straightforward and efficient synthesis of flavanones starting
from cinnamic acid in three steps has been developed. The first two steps were performed
without solvents and without purification of intermediates. In the final step base-
catalysed cyclisation of the 2’-hydroxychalcones at room temperature afforded the
flavanones in consistent yields of over 85%. The aromatic acylation reaction was found
to be highly sensitive to the type and position of the substituents on both phenol and
cinnamic acid.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed from the publisher’s website.
ACKNOWLEDGEMENTS
Kibrom G. Bedane gratefully acknowledges German Academic Exchange Service
(DAAD) for a doctorial scholarship through NAPRECA. We thank Mr S. M. Marape
(University of Botswana) for NMR experiments.
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Scheme 1.
13

Scheme 2.
14

Scheme 3.
15

Scheme 4.
16

Scheme 5.
17

Scheme 6.
18