Synthesis of 3-geranyl- and 3-prenyl-2,4,6-trihydroxybenzophenone

Article abstract of DOI:10.1080/00397911.2016.1276603

Biologically active phenyl[3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl]methanone (2) and phenyl[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]methanone (3) were synthesized by an efficient and convenient synthetic sequence. The reaction steps of this synthesis included methylation, Friedel-Crafts acylation, demethylation and geranylation steps.

Full text of DOI:10.1080/00397911.2016.1276603

Synthesis of 3-geranyl- and 3-prenyl-2,4,6-trihydroxybenzophenone
Vuyisa Mzozoyana1, Fanie R. van Heerden1
1School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville,
Pietermaritzburg, South Africa
Corresponding Author: Fanie R. van Heerden, School of Chemistry and Physics,
University of KwaZulu-Natal, Private Bag X01, Scottsville, 3209 Pietermaritzburg,
South Africa. Email: vanheerdenf@ukzn.ac.za
Graphical Abstract:
OH
O
OH
O
OH
HO
OH
HO
OH
HO
OH
3-Geranyl benzophenone 2
Phloroglucinol
3-Prenyl benzophenone 3
INTRODUCTION
Prenylated and geranylated benzophenones have interesting biological activities such as
anti-inflammatory,[1] anticancer,[2] anti-HIV,[3-5] cholesterol regulatory,[6] cytotoxic[7] and
antimicrobial activity.[8] These compounds fall under the well-known class of
benzophenones with general structure 1. This is a large class of compounds with various
applications, but in this context, we will narrow our focus to the prenylated and
geranylated benzophenones. Most of these compounds are naturally occurring and are
extracted from various plant species. Benzophenones with interesting bioactivity have
been isolated from the Hypericaceae and Clusiaceae plant families, for example
phenyl[3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl]methanone (2), which
was isolated from Hypericum roeperianum,[9] Tovomita longifolia[7] and Garcinia
vieillardii,[10] has an inhibitory effect against Mycobacterium smegmatis (IC50 = 50
µg/ml) and other microbes.[7] Compounds 2 and 3 can also serve as precursors in the
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synthesis of more complex benzophenones, for example, in the synthesis of
isovismiaphenone B.[11]
Despite the biological importance of prenylated and geranylated benzophenones and their
role as precursors in the synthesis of more complex products, optimized methods for their
preparation have not received much attention. Lee et al.[11] reported the synthesis of
phenyl[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]methanone (3), but the yield was
relatively low (about 40%). These authors acylated phloroglucinol without protecting the
phenolic groups which may result in the competing O-acylation as well. Compound 3
was also synthesized by Brajeul et al.[12] who used Hunig’s base and prenyl in the form of
the sulfonium salt to prenylate benzophenones. A number of palladium-catalyzed
reactions for the C-prenylation of aromatic systems have been reported recently. Starting
from aryl chlorides and a homoallyl alcohol, Iwasaki et al.[13] used a palladium-catalyzed
retro-allylation reaction to prepare prenylated aryls. High yields were obtained with
electron-deficient aryl chlorides. Farmer et al. described a variant of the Suzuki-Miyaura
reaction.[14] Starting with an aryl iodide and a prenylboronic ester in the presence of
palladium catalyst with PEPPI-Ipent as ligand, high yields of the prenylated products
were obtained. Yang and Buchwald also reported the prenylation of aryls by a Suzuki-
Miyaura cross-coupling between aryl halides and allylboronates.[15] By using specific
ligands, either the α product (prenyl) or the isomeric γ product (1,1-dimethylprop-2-enyl)
could be obtained in high yield. A similar approach was followed by Thomas et al.[16]
These reactions are a valuable addition to the arsenal of C-prenylation reaction. However,
some of the ligands used are not easy to prepare and/or are expensive to obtain
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commercially. Futhermore, phloroglucinol derivatives are notorious difficult substrates
for many reactions because of the high electron density on the aromatic ring and standard
reactions often do not give high yields.
In this paper, we report an optimized route to synthesize prenylated benzophenones
which involves the usage of mild conditions and readily available reagents and give good
yields of the products.
DISCUSSION
The retrosynthetic analysis in Scheme 1 outlines the synthetic approach to prepare the
prenylated benzophenones. It was envisaged that benzoylphloroglucinol (4) could be
formed via the acylation of phloroglucinol (7).[17] The hydroxy groups in the aromatic
ring are ortho directing, making prenylation of benzophenone via electrophilic aromatic
substitution feasible to form C-prenylated benzophenones (2).
The first step of our synthesis (Scheme 2) was the methylation of phloroglucinol (7) to
form 1,3,5-trimethoxybenzene (8) as adapted from Mondal et al.[17] The second step of
the reaction was the Friedel-Crafts acylation reaction.[12] Compound 8 was found to give
a better yield in the acylation step than phloroglucinol, an electron-rich aromatic
compound, which lead to the formation of the mixture of C-acyl and O-acyl products,
which are difficult to separate. This reaction was carried out in dichloromethane and
catalyzed with aluminum trichloride (AlCl3) for an optimum yield of 9 (90%) as
colourless crystals. The third step was the demethylation of the methoxy groups of the
3

aromatic ring using a strong Lewis acid (boron tribromide, BBr3) (99% yield).[18-19] The
use of BBr3[20] for aryl deprotection in this research was preferred over the other methods
because the reaction proceeds under mild conditions.
The last step of the synthesis was the C-geranylation of benzophenone 4. During this
electrophilic aromatic substitution, an aromatic proton is displaced by a geranyl group by
the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) base. This geranylation method
was preferred over other methods because it gave better yield (63%) and does not require
harsh conditions. In the reaction, only C-alkylation was observed and the products from
the competing O-alkylation were not detected. Reaction with a base such as potassium
carbonate resulted in a mixture of products. The spectroscopic data of benzophenone 2
was in agreement with those of the natural product.[9] This report presents the first total
synthesis of phenyl[3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl]methanone
(3-geranyl-2,4,6-trihydroxybenzophenone) (2).
Having successfully synthesized 2, compound 3 with a prenyl group was also
synthesized in a similar sequence of reactions (Scheme 3). The spectroscopic data of
benzophenone 3 are in agreement with the published data.[21-22]
In conclusion, phenyl[3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-
trihydroxyphenyl]methanone (2) and phenyl[2,4,6-trihydroxy-3-(3-methyl-2-
butenyl)phenyl]methanone (3) were successfully synthesized by an efficient and
convenient synthetic sequence. Although this is a three-step procedure, the methods do
4

not involve harsh conditions and competing reactions are minimized. The two
compounds prepared here can be used as starting material for the synthesis of a wide
range of biologically active compounds.
EXPERIMENTAL
General
Qualitative thin-layer chromatography (TLC, silica gel 60254, aluminum backed) was
used to monitor reactions and to determine the purity of compounds. Visualization of the
TLC plates was achieved using an iodine tank and/or fluorescence on exposure to short
wavelength ultraviolet light (254 nm). For purification, column chromatography (silica
gel 60, 0.040-0.063 mm) or centrifugal chromatography conducted on a Harrison
Research Chromatotron model 7924T (glass plates coated with silica gel 60 PF254
containing gypsum, 2 and 4 mm thick layer) was used. Melting points were determined
using a Stuart melting point apparatus with open-ended capillary tubes and are
uncorrected. Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz
UltraShield spectrometer at frequencies of 399.995 MHz and 100.4296 MHz for 1H and
13C, respectively. Infrared spectra were recorded on a Perkin Elmer spectrometer (FTIR
Spectrum 100) as neat solid or liquid samples. High-resolution mass spectrometry
(HRMS) was performed on a Waters LCT Premier time-of-flight mass spectrometer.
Phenyl[3-(3,7-Dimethyl-2,6-Octadienyl)-2,4,6-Trihydroxyphenyl]Methanone (2)
To a mixture of phenyl(2,4,6-trihydroxyphenyl)methanone (0.28 g, 1.2 mmol) and DBU
(0.18 g, 1.2 mmol) in dry THF (15 ml) was added geranyl bromide (0.26 g, 1.2 mmol) in
5

small amounts. The mixture was stirred at room temperature for 24 h. After addition of 2
M HCl (20 ml), the mixture was stirred for a further 15 min and extracted with EtOAc (4
x 20 ml), washed with brine (20 ml) and dried over anhydrous MgSO4. The removal of
the solvent in vacuo resulted in a light orange product. After purification by the column
chromatography (hexanes-EtOAc, 8:2), 2 was obtained as a light orange semisolid (0.28
g, 0.76 mmol, 63%); TLC Rf 0.46 (hexanes-EtOAc, 8:2). 1H NMR (400 MHz, CDCl3) δH
1.59 (3H, d, J = 1.1), 1.66 (3H, s), 1.79 (3H, s), 2.02-2.16 (4H, m), 3.37 (2H, d, J = 7.0),
5.05 (1H, t, J = 6.6), 5.27 (1H, t, J = 6.8), 5.93 (1H, s), 6.27 (1H, bs), 7.47-7.66 (5H, m),
10.28 (1H, bs). 13C NMR (100 MHz, CDCl3) δC 16.2, 17.7, 21.7, 25.7, 26.3, 39.7, 96.3,
104.6, 106.5, 121.5, 123.7, 127.8, 129.1, 123.1, 132.2, 139.3, 140.1, 159.4, 160.8, 162.6,
197.8. HRMS (ESI+): Found [M+Na]+ 389.1721, Calc. for C23H26NaO4 389.1729. IR
(neat) νmax (cm-1): 3533, 3073, 2943, 1656, 1595, 1569, 1444, 1161.
ACKNOWLEDGEMENTS
We gratefully acknowledge National Research Foundation (South Africa) (Grant No:
98345, 2016) and the University of KwaZulu-Natal for financial assistance.
SUPPORTING INFORMATION
Full experimental details, 1H, 13C NMR and HRMS spectra can be found via the
“Supplementary Content” section of this article’s webpage.
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Figure 1. Structures of the benzophenones 1 – 3.
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Scheme 1. Retrosynthetic analysis of geranylated benzophenone (2)
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Scheme 2. Synthesis of geranylated benzophenone (2)
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Scheme 3. Synthesis of prenylated benzophenone (3)
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