Synthesis of fluorine-containing prenylated benzophenones

Article abstract of DOI:10.1080/00397911.2020.1771597

In this study, an effective route to synthesize fluorine-containing prenylated benzophenones was developed. Friedel–Crafts acylation and electrophilic aromatic substitution reactions were the key reactions of this synthesis to achieve these fluorinated prenylated benzophenones. The use of DBU in the prenylation step achieved only the C-prenylated benzophenones, whereas K₂CO₃ produced the C- and O-prenylated benzophenones.

Full text of DOI:10.1080/00397911.2020.1771597

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of fluorine-containing prenylated
benzophenones
Vuyisa Mzozoyana & Fanie R. van Heerden
To cite this article: Vuyisa Mzozoyana & Fanie R. van Heerden (2020): Synthesis
of fluorine-containing prenylated benzophenones, Synthetic Communications, DOI:
10.1080/00397911.2020.1771597
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https://doi.org/10.1080/00397911.2020.1771597
Synthesis of fluorine-containing prenylated benzophenones
Vuyisa Mzozoyana and Fanie R. van Heerden
School of Chemistry and Physics, University of KwaZulu Natal, Pietermaritzburg, South Africa
ABSTRACT
ARTICLE HISTORY
Received 11 December 2019
In this study, an effective route to synthesize fluorine-containing pre-
nylated benzophenones was developed. Friedel–Crafts acylation and
electrophilic aromatic substitution reactions were the key reactions
of this synthesis to achieve these fluorinated prenylated benzophe-
nones. The use of DBU in the prenylation step achieved only the
C-prenylated benzophenones, whereas K2CO3 produced the C- and
O-prenylated benzophenones.
KEYWORDS
Benzophenone; fluorine;
Friedel–Crafts acylation;
prenylation
GRAPHICAL ABSTRACT
O
OR1
OH
R2
R'
R5O
OR3
HO
OH
R4
R' = H, 2-F, 3-F, 4-F
R1,R2,R3,R4,R5 = H
or
or
Introduction
Prenylated benzophenones and geranylated benzophenones have shown interesting bio-
logical activities such as anti-inflammation,[1] anticancer,[2] anti-HIV,[3–5] cholesterol
regulatory,[6] cytotoxic,[7] and antimicrobial activity.[8] These compounds belong to a
well-known class of natural compounds, benzophenones,[9,10] and are characterized by
two benzene rings linked by a carbonyl carbon. Vismiaphenone D (A), garciniaphenone
(B) and 4-geranyloxy-2,6-dihydroxybenzophenone (C) are examples of natural preny-
lated benzophenones and exhibit anti-HIV,[4] anti-cancer and antimicrobial[7] activities.
Over 150 types of fluorine-containing drugs have come onto the market, accounting
for about 20% of all pharmaceuticals.[11] The increasing prevalence and success of
fluorine-containing pharmaceuticals has stimulated further interest into the synthesis of
such compounds.
CONTACT Vuyisa Mozozoyana
mzozoyanav@ukzn.ac.za
School of Chemistry and Physics, University of KwaZulu
Natal, Pietermaritzburg, South Africa.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
V. MZOZOYANA AND F. R. VANHEERDEN
O
Cl
OMe
OH
K2CO3, MeI
Acetone
R
3a-d
AlCl3 DCM
99%
MeO
OMe
HO
OH
,
2
1
90-95%
O
OMe
O
OH
BBr3,DCM
98-99%
R
R
OMe
MeO
OH
HO
4a-d
5a-d
R=H; R=2-F; R=3-F; R=4-F
a
b
c
d
Scheme 1. Synthesis of arcylphloroglucinols 5a–d from phloroglucinol 1.
Despite the biological importance of prenylated benzophenones found in the litera-
ture, there has been a limited synthetic methods found in the literature to synthesize
them. Some prenylated benzophenones have been synthesized via the Friedel–Crafts
reaction but none of them contains fluorine.[12,13] In this paper, we report a convenient
way to synthesize prenylated benzophenones which involves the usage of mild condi-
tions and give good yields of the products.
Results and discussion
The aim of this study was to synthesize fluorine-containing prenylated benzophenones,
but no effective synthetic route could be found in the literature. However, we managed
to adopt the synthetic route we published in 2017,[14] to develop an effective synthetic
method to synthesize fluorine-containing prenylated benzophenones. The first step of
this synthesis was the methylation of phloroglucinol (1) to form 1,3,5-trimethoxyben-
zene (2).[15] This reaction was run under acetone reflux in the presence of potassium
carbonate. Compound 2 was found to react better than phlorogucinol in the subse-
quent step.
The second step of the reaction was the Friedel–Crafts acylation reaction.[13,14] This
reaction was carried out in dichloromethane and promoted by aluminum trichloride
(AlCl3) for an optimum yield of 4a–d (yield: 90 ꢀ 95%) as colorless crystals. Iron tri-
chloride (FeCl3) was also used in these reactions but yields were relatively low (yield:
48 ꢀ 61%) (Scheme 1).
The third step was the demethylation of the methoxy groups using a strong Lewis
acid (boron tribromide, BBr3).[14,16–18] The use of BBr3 for demethylation in this step
was preferred because the reactions proceeded under mild conditions. The reactions
were stirred at room temperature for 24 h for a complete demethylation.
The last step of the synthesis was the prenylation of benzophenones (5a was used as
a model reaction, Table 1, entry 1).[12,14] An aromatic proton is replaced by a prenyl
group under the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). These reactions took
place in THF at room temperature. Having successfully synthesized 7a, derivatives were

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Table 1. Synthesis of mono-C-prenylated benzophenonesa.
4''
O
OH
4'
2'
R
HO
or
O
OH
R'
Br
6
7a
O
OH
DBU,THF
20 °C
OH
4''
8''
R
OH
5'
HO
5a
2'
8'
R
HO
OH
8a
Entry
5
6
Product
Yieldb (%)
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5c
5d
5d
Prenyl-Br
Geranyl-Br
Prenyl-Br
Geranyl-Br
Prenyl-Br
Geranyl-Br
Prenyl-Br
Geranyl-Br
7a (R ¼ H)
62
42
0
8a (R ¼ H)
–
–
0
7c (R¼ 3-F)
8c (R¼ 3-F)
7d (R¼ 4-F)
8d (R¼ 4-F)
61
40
62
44
aAll reactions were run in THF (15 mL), 24 h.
bIsolated yields.
also synthesized in the same manner (Table 1) except the 2-fluoro derivative (7b). The
product that the 2-fluoro-benzophenone (5b) formed did not have characteristics of a
prenylated benzophenone, for example, the NMR data detected no fluorine in the struc-
ture. We tried the reaction in different conditions, such as low to high temperature
(0–60 ꢁC) and different solvents (DMF, ethyl acetate), but still it did not form a desired
product. After elucidating the structure of this product (7b), it was determined that a
prenylated xanthone is being formed instead and the fluorine gets eliminated in the
process. The mechanism and the structure of the prenylated xanthones that were
formed are not included in this paper.
NMR, IR and mass spectra were used to elucidate the structure to prove the success
1
of the prenylation reaction. H spectrum of 7a revealed two methyl peaks at 1.76 (doub-
let, J ¼ 1.1 Hz) and 1.80 ppm (singlet) corresponding to cis-allylic methyl-protons (H-4ʺ)
and trans-allylic protons (H-40), respectively.[19] A doublet peak, integrating for two
hydrogens, appears at dH 3.36 (J ¼ 7.0 Hz) and was assigned to H-10. A vinylic proton
peak (H-20) appeared as a multiplet at 5.26 ppm. The aromatic protons of the monosub-
stituted ring appeared at dH 7.64 (H-9,13), dH 7.51 (H-10,12) and dH 7.58 (H-11).
DEPT-135, HSQC and HMBC spectra were used for the assignment of 13C NMR peaks.
In the 13C NMR spectrum of 7a the prenyl carbons resonate upfield. The terminal
allylic carbons, C-40 and C-40’ resonate at dC 17.9 and dC 25.8, respectively,[20] whereas
the olefinic carbons (C-20 and C-30) resonate at dC 121.6 and dC 135.4, respectively. The
peak appearing downfield at dC 197.7 was assigned for the carbonyl carbon (C-7). The
quaternary carbon (C-8) and hydroxy carbons (C-2, C-4 and C-6) were deshielded and
appeared downfield at dC 140.0, dC 160.8, dC 162.6 and dC 159.4, respectively.

4
V. MZOZOYANA AND F. R. VANHEERDEN
O
O
OH
O
OH
H
O
HO
HO
OCH3
A
B
O
OH
HO
O
C
Figure 1. Structures of some bioactive benzophenones.
The 1H NMR spectrum of 8a showed the appearance of the geranyl protons confirms
the incorporation of a geranyl group. Geranyl protons including the terminal allylic pro-
tons (H-4ʺ, H-8ʺ and H-8ʺ), non-terminal allylic protons (H-10, H-40 and H-50) and ole-
finic protons (H-20 and H-60) are shown in the experimental section as well as in the
1H NMR spectrum (supplementary data).[21,22] The DEPT-135, HSQC and HMBC spec-
tra were used to assign the signals in the 13C NMR spectrum.
Derivatives of Vismiaphenone D (Fig. 1), characterized by two prenyl groups
bonded to the aromatic ring, were also synthesized in this study. This was achieved
by increasing the temperature of the prenylation reaction to 45 ꢁC as well as double
the equivalence of the prenyl bromide and DBU (Table 2). At this temperature,
both mono-prenylated and di-prenylated benzophenones were isolated. The further
increase in the temperature of the reaction had no effect on the relative yields of
the mono- and di-prenylated benzophenone. Fluorinated derivatives of di-prenylated
benzophenones were also synthesized in the same conditions as shown in Table 2.
The isolation of mono-prenylated and di-prenylated benzophenones was achieved
using rotatory thin-layer chromatotron with high ratio of non-polar-to-polar solvent
as eluent (e.g., hexane:ethylacetate, 4:1). The results above clearly show that DBU is
a good base to be used for C-prenylation and C-geranylation reactions of trihydroxy-
benzophenones as there were no O-prenylated benzophenone isolated. DBU can
selectively mono-prenylate or di-prenylate benzophenones depending on the reac-
tion conditions.
Since the use of DBU restrict the reaction to C-prenylation only, we chose to use
a harder base to achieve an O-prenylation.[23,24] For O-prenylation reactions, a
mono-prenylated benzophenone 7c was reacted with 1.2 equivalence of prenyl brom-
ide (6) in the presence of K2CO3 under acetone-reflux (Table 3, entry 1). This reac-
tion resulted in the formation of two products (11c and 12c). The structure
elucidation of compound 12c clearly indicated that both C- and O-prenylation had
taken place during the reaction. A geranylation reaction of 8d under the same con-
ditions formed a similar type of products (11d0 and 12d0) (Table 3, entry 3). These
geranylated benzophenones were isolated by rotatory thin-layer chromatotron using
solvent system that is dominated by non-polar solvent as eluent (e.g.,

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Table 2. Synthesis of di-C-prenylated benzophenonesa.
O
OH
R
R'
Br
HO
OH
6
O
OH
7a
DBU,THF
45 °C
+
R
HO
OH
O
OH
5a
R
HO
9a
OH
Entry
5
6
Product
Yieldb (%)
1
5a
Prenyl-Br
7a (R ¼ H)
9a (R ¼ H)
13
48
16
46
5
16
18
47
7
2
3
4
5
5c
5c
5d
5d
Prenyl-Br
7c (R¼ 3-F)
9c (R¼ 3-F)
8c (R¼ 3-F)
10c (R¼ 3-F)
7d (R¼ 4-F)
9d (R¼ 4-F)
8d (R¼ 4-F)
10d (R¼ 4-F)
Geranyl-Br
Prenyl-Br
Geranyl-Br
16
aAll reactions were run in THF (10 mL), 24 h.
bIsolated yields.
Table 3. O-prenylation reactions of mono-prenylated benzophenonesa.
O
OH
R
F
O
O
R
O
OH
R
11c
R
K2CO3,Acetone
Reflux
R
Br
+
+
F
HO
OH
6
7c
O
O
OH
R
F
O
R
R
R = H or
R
12c
Entry
7/8
6
R
Products (Yieldb)
1
2
3
7c (3-F)
7d (4-F)
8d (4-F)
Prenyl-Br
Prenyl-Br
Geranyl-Br
H
H
11c (82%) þ 12c (18%)
11d (81%) þ 12d (19%)
11d’ (83%) þ 12d’ (13%)
Prenyl
aAll reactions were run at 1:1.2 ratio of 7:6, acetone (10 mL), 2 h.
bRelative yields at 100% conversion of the starting material.

6
V. MZOZOYANA AND F. R. VANHEERDEN
a
Table 4. Prenylation of benzophenones under K2CO3 .
O
OR1
R2
O
OH
K2CO3,Acetone
Reflux
Br
F
R5O
OR3
+
Br
or
F
R4
HO
OH
5c
6
Other products
13c
14c
+
+
Entry
5
6
Products (Yieldb)
13c (R1¼R2¼R4¼H, R3¼R5¼prenyl)
14c (R2¼R4¼H, R1¼R3¼R5¼prenyl)
1
5c (3-F)
5d (4-F)
5d (4-F)
Prenyl-Br
Prenyl-Br
Geranyl-Br
þ
þ 11c þ 12c
2
3
13d (R1¼R2¼R4¼H, R3¼R5¼prenyl)
þ
14d (R1¼R2¼H, R3¼R4¼R5¼prenyl)
þ 11d þ 12d
13d’ (R1¼R2¼R4¼H, R3¼R5¼geranyl)
þ
14d’ (R2¼R4¼H, R1¼R3¼R5¼geranyl)
þ 11d’ þ 12d’
aAll reactions were run at 1:1.5 ratio of 5:6, acetone (10 mL), 2 h.
bRelative yields at 100% conversion of the starting material.
hexane:ethylacetate, 5:1). NMR and mass spectra were used to elucidate the structure
of the O-prenylated benzophenones (spectral data found in the supplementary file).
When a non-prenylated benzophenone 5c was subjected to a prenylation reaction
under K2CO3, four products (11c, 12c, 13c and 14c) were isolated (Table 4, entry 1).
The structure of these compounds were elucidated and the findings showed that the
reaction underwent both O-prenylation and C-prenylation. A 4-fluoro benzophenone
derivative (5d) was also prenylated under similar conditions and four products were iso-
lated (Table 4, entry 2). Geranylation of 5d under similar conditions resulted in the iso-
lation of four compounds (Table 4, entry 3).
Conclusion
In conclusion, we have developed an effective route to synthesize fluorine-containing
prenylated benzophenones. This method does not involve harsh conditions and gives
the products in moderate yields and is expected to be a useful synthetic method for a
wide range of novel compounds. The key reaction steps of this synthesis were the
Friedel–Crafts acylation and prenylation steps. In general, C-prenylation of the benzo-
phenones was obtained when DBU was used as a base, whereas the use of K2CO3 as a
base resulted in O-prenylation.
Experimental
General
Qualitative thin-layer chromatography (TLC) was used to monitor reactions. TLC plates
(Merck Kieselgel 60254 aluminum backed) were bought ready for use. Visualization of

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7
the TLC plates was achieved using an iodine tank and/or fluorescence on exposure to
short wavelength ultraviolet light (254 nm). For purification, centrifugal chromatography
was conducted on a Harrison Research Chromatotron model 7924 T on glass plates
coated with Merck silica gel (particle size 0.040–0.063 mm), 1–4 mm thick.
Melting points (mp) were determined using a Stuart melting point apparatus with
open-ended capillary tubes and are uncorrected. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker 400 MHz UltraShield spectrometer at frequencies of
399.995 MHz and 100.4296 MHz for proton (1H) and carbon (13C), respectively.
Infrared (IR) 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.
Synthesis
Phenyl(2,4,6-trimethoxyphenyl)methanone (4a)
Benzoyl chloride (1.1 g, 7.8 mmol) was added dropwise to an ice-cooled stirred mixture
of AlCl3 (1.0 g, 7.8 mmol) in DCM (20 mL). After being stirred at 0 ꢁC for 1 h, the reac-
tion mixture was added slowly to a solution of 1,3,5-trimethoxybenzene (0.5 g,
7.8 mmol) in DCM (15 mL) at 0 ꢁC. The reaction mixture was allowed to reach room
temperature and stirred for further 12 h. An ice-cooled 6 mol/L HCl (20 mL) was poured
slowly into the reaction mixture and DCM (20 mL) was also added into the mixture.
The organic layer was separated and washed with saturated NaHCO3 solution (15 mL),
water (20 mL) and brine (15 mL) and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure. The resulting product was purified by silica gel col-
umn chromatography (hexanes:EtOAc, 7:3) to give 4a as a white solid (1.9 g, 7.0 mmol,
90%). After recrystallization (Hexanes:EtOAc, 9:1), 4a was obtained as colorless crystals,
mp 113–115 ꢁC (lit.[15] 113–114 ꢁC); TLC Rf 0.35 (Hexanes:EtOAc, 7:3); 1H NMR
(400 MHz, CDCl3): d 3.66 (6H, s), 3.84 (3H, s), 6.16 (2H, s), 7.39 (2H, t, J ¼ 7.9 Hz),
7.50 (1H, tt, J ¼ 7.9, 1.3 Hz), 7.82 (2H, dd, J ¼ 7.9, 1.3 Hz). 13C NMR (100 MHz,
CDCl3): d 55.7, 56.1 (2ꢂ), 91.0 (2ꢂ), 111.3, 128.5 (2ꢂ), 129.6 (2ꢂ), 133.1, 138.5, 159.0
(2ꢂ), 162.7, 195.2; HRMS (ESIþ): Found [M þ Na]þ 295.0945, Calc. for C16H16NaO4
295.0946; IR (neat) ꢀmax (cmꢀ1) 3053, 2949, 1660, 1599, 1583, 1453, 1123.
Phenyl(2,4,6-trihydroxyphenyl)methanone (5a)
To a stirring solution of phenyl(2,4,6-trimethoxyphenyl)methanone (1.6 g, 6.0 mmol) in
DCM (30 ml) at –78 ꢁC was added boron tribromide (3 ml). The temperature of the
reaction mixture was allowed to reach the room temperature slowly. After being stirred
for 24 h at room temperature, the reaction mixture was cooled to 0 ꢁC and quenched
with water. DCM (15 ml) was added into a stirring mixture. A clear liquid was decanted
off the mixture and the residue was washed with EtOAc. The organic layer was dried
over anhydrous MgSO4 and the solvent was removed in vacuo. The resulting yellow
product was purified by silica gel column chromatography with 40% EtOAc in hexanes
as eluent and 5a was obtained a light yellow crystalline solid (1.4 g, 5.9 mmol, 99%), mp
1
168–170 ꢁC (lit.[12] 168–170 ꢁC); TLC Rf 0.52 (Hexanes:EtOAc, 3:2); H NMR (400 MHz,
DMSO-d6): d 5.84 (2H, s), 7.43 (2H, t, J ¼ 7.9), 7.53 (1H, tt, J ¼ 7.9, 1.3), 7.62 (2H, dd,

8
V. MZOZOYANA AND F. R. VANHEERDEN
J ¼ 7.9, 1.3), 9.82 (1H, bs), 10.08 (2H, bs). 13C NMR (100 MHz, DMSO-d6): d 94.8
(2ꢂ), 106.0, 128.6 (2ꢂ), 128.9 (2ꢂ), 132.1, 140.2, 159.8 (2ꢂ), 162.3, 196.9; HRMS
(ESI–): Found [M – H]– 229.0497, Calc. for C13H9O4 229.0501; IR (neat) ꢀmax (cmꢀ1):
3621, 1625, 1598, 1543, 1319.
Phenyl[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl] methanone (7a)
To a mixture of phenyl(2,4,6-trihydroxyphenyl)methanone (0.276 g, 1.2 mmol) and
DBU (0.183 g, 1.2 mmol) in dry THF (15 ml) was added a prenyl bromide (0.179 g,
1.2 mmol) in small increments. The mixture was stirred at room temperature for
24 h. After addition of 2 M HCl (30 ml), the mixture was stirred for a further 15 min
and extracted with EtOAc (4 ꢂ 20 ml), washed with brine (30 ml) and dried over
anhydrous MgSO4. The removal of the solvent in vavuo resulted in a light orange
product. After purification by the silica gel column chromatography (Hexanes:EtOAc,
4:1), 7a was obtained as a light orange semisolid (0.222 g, 0.744 mmol, 62%); TLC Rf
1
0.54 (Hexanes:EtOAc, 4:1); H NMR (400 MHz, CDCl3): d 1.76 (3H, d, J ¼ 1.1), 1.80
(3H, s), 3.36 (2H, d, J ¼ 7.0), 5.26 (1H, m), 5.93 (2H, s), 6.15 (1H, bs), 7.51 (2H,
dd, J ¼ 8.1, 7.5), 7.58 (1H, tt, J ¼ 7.5, 1.5), 7.64 (2H, dd, J ¼ 8.1,1.5), 10.29 (1H, bs).
13C NMR (100 MHz, CDCl3): d 17.9, 21.7, 25.8, 96.2, 104.6, 106.6, 121.6, 127.8
(2ꢂ), 129.2 (2ꢂ), 132.2, 135.4, 140.0, 159.4, 160.8, 162.6, 197.7; HRMS (ESI–):
Found [M – H]– 297.1130, Calc. for C18H17O4 297.1127; IR (neat) ꢀmax (cmꢀ1):
3523, 3023, 2953, 1652, 1594, 1577, 1420, 1111.
Phenyl[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]methanone (9a)
To a mixture of phenyl(2,4,6-trihydroxyphenyl)methanone (0.276 g, 1.2 mmol) and DBU
(0.366 g, 2.4 mmol) in dry THF (15 ml) was added a prenyl bromide (0.358 g, 2.4 mmol)
in small increments. The temperature of the reaction mixture was increased to 45 ꢁC
and stirred for 24 h. After the temperature of the mixture was reduced to room tem-
perature, a 2 M HCl (20 mL) was added to the mixture, it was stirred for a further
15 min and extracted with EtOAc (4 ꢂ 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 silica gel column chromatography (Hexanes:EtOAc, 4:1),
9a was obtained as a light orange semisolid (48%); TLC Rf 0.85 (Hexanes:EtOAc, 4:1);
1H NMR (400 MHz, CDCl3): d 1.74 (6H, d, J ¼ 1.1), 1.79 (6H, s), 3.34 (4H, d, J ¼ 7.1),
5.22 (2H, m), 6.35 (1H, bs), 7.50 (2H, dd, J ¼ 8.0, 7.7), 7.57 (1H, tt, J ¼ 7.7, 1.5), 7.64
(2H, dd, J ¼ 8.0, 1.5), 8.91 (2H, bs). 13C NMR (100 MHz, CDCl3): d 17.6 (2ꢂ), 21.8
(2ꢂ), 26.0 (2ꢂ), 104.6, 106.3 (2ꢂ), 121.9 (2ꢂ),127.8 (2ꢂ), 129.2 (2ꢂ), 132.2, 135.4
(2ꢂ), 140.0, 157.5 (2ꢂ), 161.0, 198.0; HRMS (ESIþ): Found [M þ Na]þ 389.1723, Calc.
for C23H26NaO4 389.1729; IR (neat) ꢀmax (cmꢀ1): 3512, 3023, 2942, 1632, 1586, 1566,
1443, 1121.
Full experimental detail, characterization data for all compounds and 1H and 13C
NMR spectra. This material can be found via the “Supplementary materail” section of
this article’s webpage.

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Funding
We gratefully acknowledge National Research Foundation (South Africa) and the University of
KwaZulu-Natal (SA) for financial assistance.
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