Practical synthesis of naringenin

Article abstract of DOI:10.3184/174751915X14379994045537

Two routes for the synthesis of the flavanone naringenin are described. In the first, 3,5-dimethoxyphenol is converted to 2-hydroxy- 4,6-dimethoxyacetophenone and then by condensation with anisaldehyde to 2′-hydroxy-4,4′,6′-trimethoxychalcone. The chalcone is then cyclised with aqueous hydrochloric acid and demethylated with pyridine hydrochloride to form naringenin in 45% overall yield. The condensation of 2-hydroxy-4,6-dimethoxyacetophenone with anisaldehyde could also directly produce 4′,5,7-trimethoxyflavanone, which was then converted into naringenin in 60% overall yield. In the second route, a single step for the preparation of the chalcone is used in which 1,3,5-trimethoxybenzene is acylated with p-methoxycinnamic acid. Although the synthesis of naringenin is achieved in a lower overall yield of 29%, the process is simpler.

Full text of DOI:10.3184/174751915X14379994045537

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 AUGUST, 455–457
RESEARCH PAPER 455
Practical synthesis of naringenin
Qian Wanga, Jian Yanga*, Xiang-ming Zhangb,c, Lei Zhoub,c, Xia-li Liaoa and Bo Yanga
aFaculty of Life Science and Technology, Kunming University of Science and Technology, 727 South Jingming Road, Chenggong District, Kunming, Yunnan
Province 650500, P.R. China
bCollege of Pharmacy, Nankai University, 94 WeiJin Road, Nankai District, Tianjing 300071, P.R. China
cTianjin International Joint Academy of Biomedicine, 220 Dongting Road, Tianjin economic and technological development zone, Tianjin 300457, P.R. China
Two routes for the synthesis of the flavanone naringenin are described. In the first, 3,5-dimethoxyphenol is converted to 2-hydroxy-
4,6-dimethoxyacetophenone and then by condensation with anisaldehyde to 2′-hydroxy-4,4′,6′-trimethoxychalcone. The chalcone is
then cyclised with aqueous hydrochloric acid and demethylated with pyridine hydrochloride to form naringenin in 45% overall yield. The
condensation of 2-hydroxy-4,6-dimethoxyacetophenone with anisaldehyde could also directly produce 4′,5,7-trimethoxyflavanone, which
was then converted into naringenin in 60% overall yield. In the second route, a single step for the preparation of the chalcone is used in
which 1,3,5-trimethoxybenzene is acylated with p-methoxycinnamic acid. Although the synthesis of naringenin is achieved in a lower
overall yield of 29%, the process is simpler.
Keywords: naringenin, taxicatigenin, anisaldehyde, p-methoxycinnamic acid, chalcone
Flavanones, 2-phenylchroman-4-ones, belong to the family
of flavonoids, many of which are produced as secondary
metabolites in the plant kingdom1 and exhibit a broad spectrum
of interesting biological activities.2-5 Naringenin (5,7-dihydroxy-
2-(4-hydroxyphenyl)chroman-4-one, Fig. 1) is one of the most
abundant flavanones present in grapefruits and citrus fruits.6
It is well-known for its beneficial health-related properties,
including anti-oxidant, anti-cancer, anti-atherogenic, anti-
inflammatory and anti-proliferative activities.7,8 Naringenin
is reported to inhibit the assembly and long-term production
of infectious hepatitis C virus particles in a dose-dependent
manner.9 Furthermore, naringenin potentiates intracellular
signalling responses to low insulin doses, suggesting that
naringenin sensitises hepatocytes to insulin.10 Additionally,
naringenin was shown to traverse the blood–brain barrier and
exert a diverse array of neuronal effects through their ability to
interact with the protein kinase C (PKC) signalling pathways.11
A number of syntheses of 1 have been reported because of
its attractive biological characteristics. In 2006, Selenski et
al.12 described a synthesis of naringenin in three steps using
tris-o-Boc salicylaldehyde as the starting material. However,
whereas the key starting material tris-o-Boc salicylaldehyde
could not be prepared easily and the yield was relatively low
(32.5%). In 2009, Hamilton and coworkers13 reported another
route to naringenin in seven steps using phloroglucinol as the
starting material. However, the route did not have the potential
for industrial production on account of the complicated process,
the presence of a side product and the low overall yield.
Naringenin has also been prepared by others,14-16 but most of
these methods consist of long reaction times, low yields of the
products, harsh reaction conditions, and the use of expensive
and environmentally toxic reagents. As a result, there is a need
for a more straightforward and cost-effective procedure for the
synthesis of naringenin.
We have reported the synthesis of naringenin in five steps
from 1,3,5-trimethoxybenzene or phloroglucinol with
a
moderate overall yield.17 As a continuation of our investigations
on the synthesis of the bioactive natural flavonoids and their
biological activity,17,18-25 we have carried out further studies
and we now report the preparation of 1 using commercially
available starting materials, and by an improved procedure with
satisfactory yields.
Results and discussion
As shown in Schemes 1 and 2, the last two steps of the routes
involved cyclisation of the key intermediate 4 and demethylation
of the precursor 5. The first approach gave 1 in four steps. The
remaining two pathways involve just three steps.
As shown in Scheme 1, the first step started with the acylation
of 2 by acetic acid under the ZnCl2 as a catalyst (145 °C, 2 h) to
give acetophenone 3 in good yield (79%). Aldol condensation
of 3 with anisaldehyde (KOH, r.t., 80 h) gave the chalcone 4 in
decent yield (86%). Conversion of 4 to 5 was performed by 10%
aqueous HCl (room temperature, r.t., 50 h), and the resulting
product 5 (74%) was demethylated with pyridine hydrochloride
under an N2 atmosphere (180 °C, 6 h) to give the target natural
product 1 in commendable yield (90%). Alternatively, in light
of the report by Cui et al.,17 a one-pot reaction directly produced
a compound 5 (85%) via a Claisen–Schmidt condensation of
compound 3 with anisaldehyde (KOH, r.t., 72 h) by increasing
the concentration of KOH, which was subsequently converted
into naringenin (r.t., 72 h) in good yield (90%).
Although compound 1 was prepared in a fairly good overall
yield from taxicatigenin, we decided to improve the strategy
by further shortening the total time of the synthesis of 1. This
was fulfilled by a single step via the treatment of the readily
available 1,3,5-trimethoxybenzene 6 and p-methoxycinnamic
acid 7 in BF3–Et2O (100 °C, 5 h) to give chalcone 4 (step f)
in moderate yield (44%). Then, the following two steps were
performed under identical conditions as same as above.
Although this synthetic pathway gave a lower yield of 1 (29%),
the reaction time was shorter and the workup was simplified.
In summary, two novel routes which used commercially
available starting materials and reagents for the synthesis
of naringenin have been described. The former improved
procedures had better yields and the latter shortened the
reaction time. Moreover, each step gave the product easily.
OH
HO
O
O
OH
Fig. 1. Structure of naringenin.
* Correspondent. E-mail:trueyangjian@163.com

456 JOURNAL OF CHEMICAL RESEARCH 2015
OH
OH
3
O
O
OH
O
O
a
b
O
O
O
O
O
O
2
4
c
d
OH
O
O
HO
O
e
O
O
OH
O
1
5
Scheme 1 Reagents and conditions: (a) ZnCl2, CH COOH, 145 °C, 2 h, 79%; (b) anisaldehyde, KOH, r.t., 80 h, 86%; (c) 10% aqueous HCl, ethanol,
r.t., 50 h, 74%; (d) anisaldehyde3, 40% aqueous KOH, methanol, r.t., 72 h, 85%; (e) Py·HCl, 180 °C, 6 h, 90%.
OH
O
O
O
COOH
f
+
O
O
O
O
O
4
6
7
O
OH
O
O
HO
O
e
c
O
O
OH
O
5
1
Scheme 2 Reagents and conditions: (f) p-methoxycinnamic acid, BF –Et2O, 100 °C, 5 h, 44%; (c) 10% aqueous HCl, ethanol, room temperature,
50 h, 74%; (e) Py·3HCl, 180 °C, 6 h, 90%.
2-Hydroxy-4,6-dimethoxyacetophenone (3): A mixture of fused
ZnCl2 (13.6 g, 0.1 mol) and acetic acid (6 ml, 0.1 mol) was heated
slowly with stirring till the solution became homogeneous. Compound
2 (15.4 g, 0.1 mol) was added and the reaction mixture was kept for
about 2 h at 145 °C. The reaction mixture was cooled, poured over
crushed ice containing hydrochloric acid (1:1). The solid that separated
out was filtered and washed separately with water and sodium
bicarbonate solution. The crude product was purified using column
chromatography over silica gel. Elution with a gradient solvent system
of petroleum ether/ethyl acetate gave compound 4 as white powdery
(15.5 g, yield 79%); m.p. 80–82 °C (lit.26 82–83 °C); IR νmax (KBr/
cm−1): 3448 (OH), 1613 (C=O); 1H NMR (400 MHz, CDCl3): δ 13.88
(s, 1H, OH), 6.12 (s, 1H), 5.97 (s, 1H), 3.82 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 2.60 (s, 3H, COCH3); MS (m/z): 197 [M+H]+.
2′-Hydroxy-4,4′,6′-trimethoxychalcone (4); (Step b): Potassium
hydroxide (11.2 g, 0.2 mol) was added to methanol (80 mL). After it
had cooled to ambient temperature, compound 3 (2.0 g, 0.01 mol)
and anisaldehyde (1.5 g, 0.011 mol) were added to the solution. It was
stirred for 80 h at room temperature. Then the mixture was neutralised
to pH 5–6 by adding 5% aqueous HCl. The precipitate was filtered off,
Compared to previous works of our team, we decreased the
reaction procedures and raised the yield at the same time. Taken
together, these advances significantly enhance opportunities for
potential industrial scale-up of this important natural compound
and could be a useful addition to the reported methods for the
preparation of the flavanone.
Experimental
All glassware was thoroughly washed and dried in an oven at 120 °C.
Teflon-coated magnetic stirring bars were washed with acetone and
dried. All reactions were monitored, and the purity of the products
was checked by TLC performed on GF-254 silica gel plates with
visualisation by UV light. IR spectra were recorded on Impact 400 FT-
IR instrument. Melting points were measured on a YRT-3 temperature
1
apparatus, H NMR spectral data were recorded on a Bruker Avance
400 NMR spectrometer or a Bruker DRX 500 NMR spectrometer,
chemical shifts were reported in parts per million (ppm) against internal
tetramethylsilane. Mass spectra were determined on VG Auto Spec-
3000 spectrometer and reported as m/z. All reagents were purchased
from Tansoole reagent, China, and used without further purification.

JOURNAL OF CHEMICAL RESEARCH 2015 457
washed with water and recrystallised from ethanol to give compound 4
as yellow crystals. (2.7g, yield 86%).
and Technology (no. 20150728). This support is gratefully
acknowledged.
(Step f): A mixture of 1,3,5-trimethoxybenzene (6) (1.7 g, 0.01
mol) and p-methoxycinnamic acid (7) (2.7 g, 0.015 mol) in BF3-
Et2O (30 mL) was stirred at 100 °C for 5 h. The solution was left
overnight and the red solid was filtered and dried to give red needles.
A suspension of the needles in alcohol was refluxed for 2 h to give a
clear orange solution. After being decolourised with active charcoal
and cooled to 0 °C, the yellow crystals of compound 4 were filtered
and dried to give 1.4 g (44%); m.p. 114–115 °C (lit.27 113–114 °C); IR
Received 29 June 2015; accepted 7 July 2015
Paper 1503452 doi: 10.3184/174751915X14379994045537
Published online: 7 August 2015
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This work was funded by the National Natural Science
Foundation of China (NSFC) (no. 21062009) and Analysis
and Testing Foundation of Kunming University of Science