Synthesis of arylated coumarins by Suzuki–Miyaura cross-coupling. Reactions and anti-HIV activity

Article abstract of DOI:10.1016/j.bmc.2016.08.029

Arylated coumarins were prepared by site-selective Suzuki–Miyaura cross-coupling reaction of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin. Triarylated coumarins were prepared by Suzuki–Miyaura cross-coupling reactions of 3-bromo-4-methyl-2-oxo-2H-c

Full text of DOI:10.1016/j.bmc.2016.08.029

Accepted Manuscript
Synthesis of arylated coumarins by Suzuki-Miyaura cross-coupling. Reactions
and anti-HIV activity
Aws M. Hamdy, Zien Khaddour, Najim A. Al-Masoudi, Qamar Rahman,
Christian Hering-Junghans, Alexander Villinger, Peter Langer
PII:
S0968-0896(16)30636-8
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.08.029
BMC 13212
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2016
28 July 2016
18 August 2016
Please cite this article as: Hamdy, A.M., Khaddour, Z., Al-Masoudi, N.A., Rahman, Q., Hering-Junghans, C.,
Villinger, A., Langer, P., Synthesis of arylated coumarins by Suzuki-Miyaura cross-coupling. Reactions and anti-
HIV activity, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.2016.08.029
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1
Synthesis of arylated coumarins by Suzuki-Miyaura cross-coupling.
Reactions and anti-HIV activity
Aws M. Hamdy,a,b Zien Khaddour,a Najim A. Al-Masoudi,c Qamar Rahman,a,d Christian Hering-
Junghans,a Alexander Villinger,a Peter Langer*,a,e
Abstract: Arylated coumarins were prepared by site-selective Suzuki-Miyauara cross-coupling
reaction of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin. Triarylated coumarins were
prepared by Suzuki-Miyauara cross-coupling reactions of 3-bromo-4-methyl-2-oxo-2H-chromene-
6,7-diylbis(trifluoromethanesulfonate). The in vitro anti-HIV activity of the products was
investigated. Two lead structures with considerable activities were identified.
Key words: Anti-HIV activity, Coumarins, Regioselective synthesis, Suzuki-Miyaura cross-coupling
reaction
1. Introduction
Coumarin and its derivatives are one of the important classes of heterocyclic compounds which
occur in many natural products with pharmacological activity.1-6 For example, wedelolactone 1,
isolated from Eclipta Elba, and ellagic acid 2 show a broad range of biological activities,7-10 while
other coumestans were isolated from the roots of Hedysarum multijugum,11 and exhibited anti-HCV
activity.12 Coumarin compounds are known to possess a wide range of biological activities, such as
antibacterial,13 anticancer,14,15 anticoagulant,16 anti-HIV protease inhibitory,17 anti-HIV
integrase,18,19 and serine protease inhibitory activity.20 They are inhibitors of steroid 5α-reductase,21
and of NO synthase inhibitors.22 Geiparvarin 3, a naturally occurring product bearing the coumarin
aInstitute für Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, College of Science, University of Mosul, Mosul, Iraq
c Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
d Amity University, Lucknow Campus, Viraj Khand-5, Gomti Nagar, Lucknow – 226010, India
e Leibniz-Institute für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059
Rostock, Germany.
† Electronic supplementary information (ESI) available. CCDC No.

2
residue, has been shown to possess a significant inhibitory activity against a variety of cell lines
including sarcoma 180, Lewis lung carcinoma, P-388 lymphocytic leukaemia, and Walker 256
carcinosarcoma.23 New furanocoumarines, such as japonagelol, have been prepared as novel
antiproliferative agents.24 In addition, coumarins are widely used as additives in food chemicals,
perfumes, agrochemicals, cosmetics, and dispersed fluorescent and laser dyes.1,25-27
Coumarins can be synthesized by various methods, such as Pechmann,28 Perkin,29 Knoevenagel,30
and Wittig31 reactions. Palladium-catalyzed site-selective cross-coupling reactions of 3-bromo-4-
trifluormethylsulfonyloxycoumarin or 3-bromo-4-tosyloxycoumarin provide an efficient and facile
route for the synthesis of 3,4-disubstituted coumarins.32,33 However, some recent reviews34,35 have
been reported covering scope and limitations as well as a range of previous applications of the
coupling reactions. Recently, we reported the synthesis of arylated coumarins by site-selective
Suzuki–Miyaura cross-coupling reactions of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin.36
Herein, we report full details of these studies. In addition to our short communication, we herein
report, for the first time, the synthesis of a series of triarylated coumarins starting from 3-bromo-4-
methyl-6,7-dihydroxycoumarin. In addition, the anti-HIV activity of a series of products has been
investigated.
Figure 1. Natural occurring coumarins
2. Result and Discussion
2.1. Synthesis
4-Methyl-6,7-dihydroxycoumarin (4) has been selected as a key intermediate for the synthesis
of new coumarin analogues. Thus, treatment of 4 with triflic anhydride (2.4 equiv) in the presence
o
of Et3N (4.0 equiv) at -78 C afforded the bis(triflate) 5 in 75% yield (Scheme 1). Reaction of 5
with arylboronic acids 6 (2.2 equiv.) via Suzuki-Miyaura reaction gave 4-methyl-6,7-
diarylcoumarines 7a-e in 70-88% yield (Scheme 2). Both electron-poor and electron-rich
arylboronic acids could be successfully employed. The best yields were obtained by using
Pd(PPh3)4 (6 mol-%) as a catalyst and K3PO4 (3.0 equiv) as a base in dioxane at 120 °C for 6 h
(Scheme 2, Table 1).

3
1
The structures of 5 and 7a-e were assigned on the basis of their H and 13C NMR and mass
spectra. In the 1H NMR spectra, H-3 of the coumarin ring appeared in the regions δ 6.37- 6.22 ppm
as a doublet (JCH3,H3 ~ 1.2 Hz), while methyl groups at C-4 resonated in the region δ 2.41-2.38 ppm
as a doublet as well. H-5 and H-8 protons appeared as broad singlets in the regions δ 7.53-7.41 and
δ 7.59-7.27 ppm, respectively. The other protons of aromatic, methoxy and other methyl groups
were fully analyzed (cf. Experimental section). The 13C NMR spectra of 5 and 7a-e contained
similar resonance signals of the coumarin carbons ring C-2 - C-8a. The higher-field signals between
δC 160.9 and 158.2 ppm were assigned to the carbonyl group of the benzopyran ring (C-2), while
the resonances in the regions of δC 115.1-112.4 ppm were assigned to C-3. The chemical shifts in
the regions δC 154.4-151.4 and 152.5-150.5 ppm were attributed to C-4 and C-8a, respectively. The
resonances at δC 141.7-137.1 and δC 118.5-110.9 ppm were assigned to the coumarin carbons C-7
and C-8, respectively. The C-4a carbon atom appeared between δC 120.1 and 117.6 ppm, except for
5, which resonated at δC 112.7 ppm. The resonances at the regions δC 126.4-125.1 ppm were
attributed to C-5, C-6 and carbons of the aromatic ring, whereas the methyl groups at C-4 appeared
in the range δC 20.3-17.6 ppm. The carbon atom of CF3 group of 5 appeared as a doublet at δC 117.9
ppm (JC,F = 317.0 Hz).
Scheme 1. Reagents and conditions: (i) Et3N, CH2Cl2, 20 °C, then Tf2O, -78 C to 20 °C, 6 h.

4
Figure 2. Molecular structure of 5
Scheme 2. Synthesis of 7a-e. Reagents and conditions: (i) K3PO4, Pd(PPh3)4, 1,4-dioxane, 120 °C,
6 h.
Table 1. Synthesis of 7a-e
7 (%)a
6,7
Ar
3,5-(Me)2C6H3
4-MeOC6H4
4-ClC6H4
75
83
83
70
88
a
b
c
C6H5
d
e
4-EtOC6H4
a Yields of isolated products
Treatment of 5 with arylboronic acids 6 (1.2 equiv.) via Suzuki-Miyaura reaction furnished 4-
methyl-7-aryl-6-trifluorosulfonyloxy-coumarins 8a-l in 70-90% yield with high site-selectivity
(Scheme 3, Table 2). During the optimization, it proved to be important to use 1.2 equiv. of the
arylboronic acid and to carry out the reaction at 70 oC instead of 120 °C to avoid double coupling.
Both electron-poor and electron-rich arylboronic acids were successfully used.
Scheme 3. Synthesis of 8a-l. Reagents and conditions: (i) K3PO4, Pd(PPh3)4, 1,4-dioxane,
70 °C, 6 h.
Table 2. Synthesis of 8a-m

5
8 (%)a
75
6,8
a
b
c
Ar
3,5-(Me)2C6H3
4-MeOC6H4
4-ClC6H4
80
85
C6H5
72
d
e
4-EtOC6H4
4-FC6H4
90
78
f
4-(F3C)C6H4
4-MeC6H4
3-MeC6H4
3-MeOC6H4
2,3,4-(MeO)3C6H2
4-tBuC6H4
83
g
h
i
75
80
70
j
90
k
l
77
a Yields of isolated products
The one-pot Suzuki-Miyaura reaction of bis-triflate 5 with two different arylboronic acids 6
(sequential addition of 1.2 equiv. of each boronic acid) was next studied. Firstly, 5 was treated with
4-methoxphenylboronic acid (6b) (1.2 equiv.), followed by further treatment with arylboronic acids
6c,g,j,a (1.2 equiv.) afforded the 4-methyl-6,7-diarylcoumarins 9a-d in 73-81% yields, respectively.
The reactions were carried out at 70 °C for the first step (to avoid double coupling) and at 120 °C in
the second step (Scheme 4, Table 3).
Scheme 4. Synthesis of 9a-d. Reagents and conditions: (i) 6b (1.2 equiv.), K3PO4 (1.5 equiv.),
Pd(PPh3)4 (3 mol-%), dioxane, 70 °C 6 h; (ii) Ar2B(OH)2 (1.2 equiv.), K3PO4 (1.5 equiv.),
Pd(PPh3)4 (3 mol-%), 1,4-dioxane, 120 °C, 6 h.
Table 3. Synthesis of 9a-d

6
9 (%)a
73
6
9
a
b
c
Ar2
4-ClC6H4
4-FC6H4
3-MeC6H4
3,5-(Me)2C6H3
b,c
b,g
b,j
b,a
78
75
81
d
a Yields of isolated products
Compounds 8a-l were identified from the 1H NMR and 13C NMR spectra, which showed almost
similar resonances of benzopyran ring atoms as those of 7a-e. H-3, and methyl group at C-4
appeared as two doublets with long range couplings in the regions δH 2.42-2.31 and 6.33-6.24 ppm,
respectively (JCH3,H3 ~ 1.3 Hz). H-5 and H-8 protons appeared as broad singlets in the regions δH
7.36-7.52 and 7.52-7.45 ppm, respectively. The aromatic protons resonated as multiplets or doublets
between δH 7.47 and 6.80 ppm, while the other alkyl protons were fully analyzed.
In the 13C-NMR spectra of 8a-l, the resonances at δH 163.9-158.4 ppm were attributed to the
carbonyl group (C-2). The carbon atoms C-3 and C-4 of the benzopyran ring resonated in the
regions δH 115.6-113.8 and 158.6-150.9 ppm, respectively, while C-4a and C-5 appeared in the
regions δ 119.5-115.5 and 117.5-115.1 ppm, respectively. C-6 - C-8a, aromatic and carbons of the
other substituents carbon atoms were fully assigned (cf. Experimental section). Compound 8b was
37
selected for further NMR studies. In the gradient-selected HMBC spectrum of 8b, the olefinic
proton (H-3) at δH 6.50 ppm showed two 2JC,H couplings: one to the carbonyl carbon atom of the the
coumarin ring (C-2) at δC 160.9 ppm and the other coupling was with C-4 at δC 151.3 ppm. A 3JC,H
between coupling between H-8 of coumarin ring at δH 6.60 ppm and aromatic carbon atom (C-1) at
δC 136.8 ppm was assigned. Furthermore, in the NOESY spectrum,38 a correlation between the
protons of methyl group at C-4 and H-3 as well as between H-8 of coumarin ring and the aromatic
protons H-2' and H-6' (Figure 3).
Figure 3. JC,H correlations in the HMBC (single head arrows), and NOESY (double head arrows)
correlations of 8b.
1
13
The H NMR and C NMR spectra of 9a-d were in agreement with the suggested structures.
The resonances of protons H-5 and H-8 appeared in the regions at δH 7.48-7.46 and 7.28-7.26 ppm,
respectively, which differ from those of analogues 8a,c,f,i, due to the substitution of the triflate

7
13
group at C-6 by the aryl moieties. In the C NMR spectra, carbon atoms C-5 and C-6 appeared in
the regions δC 130.5-129.7 and 135.4-131.0 ppm, respectively, whereas carbon atoms C-8 were
resonated in the region δC 117.8-117.1 ppm. Additional support of the proposed structures comes
from mass spectral data; mass spectra of the prepared compounds showed the correct molecular
ions as suggested by their molecular formulas. The structure of 8b was independently confirmed by
X-ray crystal structure analysis (Figure 4).
Figure 4. Molecular structure of 8b
Next, reaction of 4 with bromine afforded the brominated product 10 in 75% yield. The
structure of 10 was independently confirmed by 2D NMR (Figure 5). Compound 10 was converted
into bis-triflate 11. The structure of 11 was independently confirmed by X-ray crystal structure
analysis (Figure 6).

8
Scheme 5. Synthesis of 2. Reagents and conditions: (i) 4 (1.0 equiv), Br2 (2.0 equiv), AcOH, 30 C,
2 h; (ii) 10 (1.0 equiv), Et3N (4.0 equiv), CH2Cl2, 20 °C; then Tf2O (2.4 equiv), -78 C to 20 °C, 6
h.
Figure 5. 2D NMR studies of 10
Figure 6. Molecular structure of 11 in the crystal. Displacement ellipsoids are drawn at the 50 %
probability level.
Suzuki-Miyaura cross-coupling reaction of 11 with various arylboronic acids (3.1 equiv.)
afforded the 4-methyl-3,6,7-tris(aryl)coumarines 12a-c and 12e-p (Scheme 6, Table 4). Both
electron-rich and electron-poor arylboronic acid were successfully employed. The yields of the
products derived from arylboronic acids containing electron-withdrawing substituents, which are
less nucleophilic, were lower than the yields of products derived from arylboronic acid containing
electron-donating substituents. Unfortunately, all attempts to develop regioselective Suzuki-
Miyaura reactions failed. This result is surprising, as substrate 11 is structurally very similar to
substrate 5. Substrate 11 only contains an additional bromine atom at position 3. The failure of the
regioselective coupling can be explained by the fact that, in Suzuki-Miayaura reactions the bromine

9
atom is a better leaving group than the triflate. Thus, there is a competition between positions 3 and
7 which results in the formation of mixtures. Position 3 possesses a better leaving group, but is
sterically more hindered than position 7. Both positions 3 and 7 are more reactive than position 6.
However, due to the formation of complex mixtures, it was also not possible to selectively address
positions 3 and 7 by addition of two equivalents of a boronic acid.
Scheme 6. Synthesis of 12a-c and 12e-p. Reagents and conditions: (i) 6a-c, 6e-p (3.1 equiv.),
Pd(PPh3)4 (14 mg, 9 mol-%), K2CO3 (aq. solution, 2M), 1,4-dioxane, 120 °C, 10 h.
Table 4. Synthesis of 12a-c and 12e-p
Ar
12 (%)a
70
6,12
a
3,5-(Me)2C6H3
4-MeOC6H4
4-ClC6H4
80
b
c
60
4-EtOC6H4
4-FC6H4
84
e
70
f
4-(F3C)C6H4
4-MeC6H4
3-MeC6H4
3-MeOC6H4
2,3,4-(MeO)3C6H2
4-tBuC6H4
3,4-(Me)2C6H3
4-iPrC6H4
63
g
75
h
i
70
80
j
80
k
l
62
60
m
n
o
70
4-iProC6H4
77
4-EtC6H4
75
p
a Yields of isolated products

10
The conditions were optimized for synthesis of 12a using various bases, such as K2CO3, KF,
K3PO4 and NEt3, different solvents, like toluene, DMF, dioxane and THF, and Pd sources, such as
Pb(OAc)2 and Pd(PPh3)2Cl2 at various temperatures (65-130 °C) (Table 5).
Table 5. Optimization of synthesis of 12a
Entry
Base
K3PO4
K2CO3
KF
Solvent
Toluene
DMF
T (oC)
100
130
80
Catalyts
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
T (h) Yield (%)a
8
9
25
38
47
34
84
25
1
2
3
4
5
6
Dioxane
THF
10
7
NEt3
65
K2CO3
K2CO3
Dioxane
Toluene
120
90
10
9
a Yields of isolated products.
The structure of 12f was independently confirmed by 2D NMR (Figure 7), meanwhile the
structure of 12g was independently confirmed by X-ray crystal structure analysis (Figure 8).
Figure 7. JC,H correlations in the HMBC (single head arrow), and NOESY (double head arrow)
correlations of 12f.

11
Figure 8. Molecular structure of 12g in the crystal. Displacement ellipsoids are drawn at the 50 %
probability level.
2.2. In vitro anti-HIV activity
Compounds 5, 7a-e, 8a-l and 9a-d were tested for their in vitro anti-HIV-1 (strain IIIB) and
HIV-2 (strain ROD) activity in human (MT-4) cells based on an MTT assay (Table 6).39,40
Derivatives 12a-c and 12e-p showed a relatively low solubility and where, therefore, not tested. The
results are summarized in Table 6, in which the data for nevirapine (BOE/BIRG587)41 and
azidothymidine (DDN/AZT)42 are included for comparison purposes. Compound-induced
cytotoxicity was also measured in MT-4 cells parallel with the antiviral activity. Compounds 7a and
8i were found to be the only compounds from the series inhibiting HIV-1 replication in a cell
culture, which showed an IC50 of 4.57 μg mL-1 and 13.20 μg mL-1 with CC50 of 14.40 μg mL-1 and
61.34 μg mL-1, respectively, resulting in a selectivity index of 3 and 5. On the other hand, 8k, 9a,
and 9d showed some activity against HIV-1 (IIIB strain) with IC50 > 2.13, > 2.06 and > 2.08 μg
mL-1, respectively, but no selectivity was witnessed (SI < 1). However, implantation of methyl
groups in 3 and 5 positions of both phenyl groups at C-6 and C-7 of the coumarin ring (compound
7a) or methyl group in 3 position of phenyl residue at C-7 together with the triflate at C-6 of the
coumarin ring (compound 8i) considerably increased the anti-HIV activity, in comparison to the
effectiveness of other functional groups. In conclusion, the anti-HIV activity and the selectivity of
these compounds are too limited to perform extensive mode-of-action studies, and 7a and 8i might
be considered as a new lead in the development of antiviral agents as non-nucleoside reverse
transcriptase inhibitors.
Table 6. In vitro anti-HIV-1a and HIV-2b activity and cytotoxicity of some new coumarins
HIV-1 (IIIB)
IC50 (µg mL-1)c IC50 (µg mL-1)c
HIV-2 (ROD)
CC50
(µg mL-1)d
43.50
SIe
(IIIB)
<1
SIe
(ROD)
<1
Entry
>43.50
4.57
>43.50
>14.40
>11.00
>15.98
>13.78
>37.31
>33.10
>10.60
5
14.40
3
<1
7a
7b
7c
7d
7e
8a
8b
>11.00
>15.98
>13.78
>37.31
>33.10
>10.60
11.00
<1
<1
15.98
<1
<1
13.78
<1
<1
37.31
<1
<1
33.10
<1
<1
≥10.60
<orX1
<orX1

12
>30.65
>12.55
>27.20
>10.63
>80.33
>11.00
13.20
>35.65
>12.55
>27.20
>10.63
>80.33
>11.00
>61.34
>18.86
>2.13
35.65
12.55
≥27.20
10.63
80.33
11.00
61.34
18.86
2.13
<1
<1
<1
<1
8c
8d
<orX11
<1
<orX1
<1
8e
8f
<1
<1
8g
<1
<1
8h
5
<1
8i
>18.86
>2.13
<1
<1
8j
<1
<1
8k
>10.28
>2.06
>10.28
>2.06
10.28
2.06
<1
<1
8l
<1
<1
9a
9b
>10.92
>7.40
>10.92
>7.40
10.92
7.40
<1
<1
<1
<1
9c
>2.08
>2.08
2.08
<1
<1
9d
0.050
>4.00
>4.00
>25
>80
>11363
Nevirapine
AZT
<1
>26596
0.0022
0.00094
c
a Anti-HIV-1 activity measured with strain IIIB; b anti-HIV-2 activity measured with strain ROD;
compound concentration required to achieve 50% protection of MT-4 cells from the HIV-1 and
d
HIV-2-induced cytopathic effect; compound concentration that reduces the viability of mock-
infected MT-4 cells by 50 %; e SI: selectivity index (CC50/IC50).
3. Conclusion
In conclusion, we have reported a new synthesis of arylated coumarins by site-selective Suzuki-
Miyaura cross-coupling reactions. The synthesized compounds were evaluated for their in vitro
anti-HIV inihibitory activity. Two derivatives show considerable activities and can be regarded as
lead structures for further investigations. However, the selectivity and activity are so far not
sufficient to carry out mode-of-action studies which will be done in future studies along with
additional screening experiments.
4. Experimental
Melting points are uncorrected and were determined on a Micro heating table HMK 67/1825
Kuestner (Buchi Apparatus), and a Leitz Labolux 12 Pol with heating table Mettler FP 90. FT-IR
spectra were recorded on a Nicolet 205 FT-IR and Nicolet Prot´ege 460 FT-IR instruments using
1
the KBr technique. H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra were measured on

13
Bruker AC 250, Bruker ARX 300 and Bruker ARX 500 instruments in DMSO-d6 as a solvent.
Mass spectra (MS) were run on AMD MS40, Varian MATCH 7, MAT 731 (EI, 70 eV), Intecta
AMD 402, (EI, 70 eV and CI), and Finnigan MAT 95 (CI, 200 eV) spectrometers. High-resolution
mass spectrometry (HRMS) was performed on Varian MAT 311 and Intecta AMD 402 instruments.
The X-ray crystal structure analyses were deposited at the CCDC.46
4.1. Chemistry
4.1.1. 6,7-Bis(trifluoromethanesulphonyl)-4-methyl-2H-chromen-2-one (5)
To a solution of 4-methyl-6,7-dihydroxycoumarin (4) (0.50 g, 2.60 mmol) in CH2Cl2 (30 mL) was
added Et3N (0.36 mL, 10.4 mmol) at room temperature under an argon atmosphere. After 10 min,
Tf2O (1.0 mL, 6.20 mmol) was added at -78 °C. The mixture was allowed to warm to 20 °C and
stirred for 6 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (flash silica gel, heptane / EtOAc = 4 :1) without aqueous
work up to give 5 as a white solid (0.90 g, 75%); mp: 125-127 °C. IR (KBr, cm-1): v 3124, 3053,
1
2964, 2926 (w), 1740 (s), 1673, 1625, 1613, 1570 (w), 1498 (m). H NMR (300 MHz, CDCl3) δ:
2.41 (d, JCH3,H3 = 1.5 Hz, CH3), 6.37 (d, 1H, H-3), 7.41 (br s., 1H, H-5), 7.59 (br s., 1H, H-8). 13C
NMR (75.46 MHz, CDCl3) δ: 18.6 (CH3), 110.9 (C-8), 112.7 (C-3 + C-4a), 113.1 (C-5), 117.9 (d,
JC,F = 317.0 Hz, CF3), 136.4 (C-6), 141.7 (C-7), 150.5 (C-8a), 152.6 (C-4), 158.2 (CO). 19F NMR
(282.4, MHz) δ: - 72.8, - 72.7. GC-MS (EI, 70 eV): m/z (%) = 456 ([M]+, 100), 324 (10), 323 (84),
232 (10), 203 (33), 162 (13), 134 (26), 69 (55). HRMS (EI, 70 eV) calcd for C12H6F6O8S2 ([M]+):
455.94028; found: 455.94130.
4.1.2. General procedure for the preparation of 6,7-bis(aryl)-4-methyl-2H-chromen-2-one
(7a-e)
To a dioxane suspension (3 mL) of bis(triflate) analogue 5 (70 mg, 0.15 mmol), Pd(PPh3)4 (11 mg,
6 mol -%, 0.0092 mmol), and arylboronic acids 6 (0.34 mmol) was added K3PO4 (98 mg, 0.46
o
mmol). The mixture was heated at 120 C under Argon atmosphere for 6 h. The reaction mixture
was diluted with water and extracted with CH2Cl2 (3x25 mL). The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by
flash chromatography (silica gel, EtOAc / heptane).
4.1.2.1. 6,7-Bis(3,5-dimethylphenyl)-4-methyl-2H-chromen-2-one (7a)
From 3,5-dimethylphenylboronic acid (6a) (51 mg). Yield: 42 mg (75%) as a white solid, mp: 121-
122 °C. IR (KBr, cm-1): v 3015, 3082, 3066, 2868, 2732, 2645 (w), 1722 (s), 1618, 1607 (m), 1573,

14
1
1537, 1516, 1485 (w). H NMR (300 MHz, CDCl3) δ: 2.13 (s, 6H, 2xCH3), 2.14 (s, 6H, 2xCH3),
2.39 (d, 3H, JCH3,H3 = 1.3 Hz, CH3), 6.24 (d, 1H, H-3), 6.67-6.80 (m, 6H, ArH), 7.30 (br s., 1H, H-
8), 7.49 (br s., 1H, H-5). 13C NMR (75.46 MHz, CDCl3) δ: 17.6 (2xCH3), 20.1 (2xCH3), 26.1 (CH3),
113.9 (C-3), 117.7 (C-8), 120.1 (C-4a), 125.1, 126.4, 126.6, 127.4, 127.9 (Carom + C-5 + C-6),
136.3 (C-7), 138.5, 139.1 (Carom), 151.2 (C-8a), 154.4 (C-4), 160.9 (CO). GC-MS (EI, 70 eV): m/z
(%) = 368 ([M]+, 100), 353 (12), 338 (10). HRMS (EI, 70 eV) calcd for C26H24O2:368.17708 [M]+;
found: 368.17685.
4.1.2.2. 6,7-Bis(4-methoxyphenyl)-4-methyl-2H-chromen-2-one (7b)
From 4-methoxyphenylboronic acid (6b) (52 mg). Yield: 47 mg (83%) as a white solid, mp: 103-
105 °C. IR (KBr, cm-1): v 3115, 3092, 3076, 2968, 2932, 2845 (w), 1732 (s), 1628, 1607 (m), 1583,
1547, 1526, 1495 (w). 1H NMR (300 MHz, CDCl3) δ: 2.38 (d, 3H, JCH3,H3 = 1.2 Hz, CH3), 3.72 (s,
6H, 2xOCH3), 6.23 (d, 1H, H-3), 6.69-6.74 (m, 4H, ArH), 6.97-7.01 (m, 4H, ArH), 7.27 (br s., 1H,
H-8), 7.47 (br s., 1H, H-5). 13C NMR (75.46 MHz, CDCl3) δ: 18.6 (CH3), 55.2 (2xOMe), 113.6 (C-
3), 114.8 (Carom), 118.2 (C-8), 118.6 (C-4a), 126.3, 130.7, 130.8, 132.1, 132.7 (Carom + C-5 + C-6),
136.6 (C-7), 152.1 (C-8a), 152.5 (C-4), 158.6, 158.8 (2xCarom-OMe), 160.9 (CO). GC-MS (EI, 70
e): m/z (%) = 372 ([M]+, 100), 357 (12), 341 (11), 229 (10). HRMS (EI, 70 eV) calcd for C24H20O4:
372.13561 [M]+; found: 372.13535.
4.1.2.3. 6,7-Bis(4-chlorophenyl)-4-methyl-2H-chromen-2-one (7c)
From 4-chlorophenylboronic acid (6c) (53 mg). Yield: 49 mg (83%) as a white solid, mp: 221-222
°C. IR (KBr, cm-1): v 3065, 2959, 2922, 2852 (w), 1727, 1715 (s), 1621, 1614 (m), 1594, 1573,
1
1568, 1543, 1510, 1505, 1479 (w). H NMR (300 MHz, CDCl3) δ: 2.40 (d, 3H, JCH3,H3= 1.3 Hz,
CH3), 6.27 (d,1H, H-3), 6.97-6.99 (m, 4H, ArH), 7.15-7.19 (m, 4H, ArH), 7.28 (br s., 1H, H-8),
7.48 (br s., 1H, H-5). 13C NMR (75.46 MHz, CDCl3) δ: 17.6 (CH3), 114.5 (C-3), 117.5 (C-8), 118.3
(C-4a), 125.4, 127.4, 127.5, 129.8, 130.0, 132.4, 132.9, 134.7 (Carom + C-5 + C-6), 136.7 (C-7),
137.2, 142.0 (Carom), 150.8 (C-8a), 151.8 (C-4), 159.4 (CO). GC-MS (EI, 70 eV): m/z (%) = 380
([M]+, [Cl] 35, [Cl] 35, 100), 352 (11), 252 (18), 253 (13). HRMS (EI, 70 eV) calcd for
C22H14Cl2O2[Cl]35, [Cl] 35): 380.03654 ([M]+; found: 380.03632.
4.1.2.4. 4-Methyl-6,7-diphenyl-2H-chromen-2-one (7d)
From phenylboronic acid (6d) (42 mg). Yield: 34 mg (70%) as a white solid, mp: 163-165 °C. IR
(KBr, cm-1): v 3110, 3087, 3071, 2963, 2927, 2840 (w), 1727 (s), 1623, 1602 (m), 1578, 1542,
1521, 1490 (w). 1H NMR (300 MHz, CDCl3) δ: 2.40 (d, 3H, JCH3,H3 = 1.1 Hz, CH3), 6.25 (d,1H, H-
3), 7.04-7.07 (m, 4H, ArH), 7.16-7.18 (m, 6H, ArH), 7.33 (br s., 1H, H-8), 7.53 (br s., 1H, H-5). 13C

15
NMR (75.46 MHz, CDCl3) δ:18.6 (CH3), 115.1 (C-3), 118.5 (C-4a + C-8), 126.4, 126.9, 127.4,
128.1, 129.6, 129.8 (Carom + C-5 + C-6), 137.1 (C-7), 139.6, 144.4 (Carom), 152.1 (C-8a), 153.6 (C-
4), 160.8 (CO). GC-MS (EI, 70 eV): m/z (%) = 312 ([M]+, 100), 311 (12), 284 (11), 283 (15), 252
(10), 239 (17). HRMS (EI, 70 eV) calcd for C22H16O2: 312.11448 [M]+; found: 312.11468.
4.1.2.5. 6,7-Bis(4-ethoxyphenyl)-4-methyl-2H-chromen-2-one (7e)
From 4-ethoxyphenylboronic acid (6e) (57 mg). Yield: 54 mg (88%) as a white solid, mp: 188-190
°C. IR (KBr, cm-1): v 3118, 3093, 3079, 2971, 2935, 2848 (w), 1735 (s), 1631, 1609 (m), 1585,
1549, 1528, 1497 (w). 1H NMR (300 MHz, CDCl3) δ: 1.33 (t, 6H, J = 6.5 Hz, 6H, 2xCH2CH3), 2.38
(d, 3H, JCH3,H3 = 1.2 Hz, CH3), 3.94 (q, 4H, J = 6.9 Hz, 2xCH2CH3), 6.22 (d,1H, H-3), 6.68-6.72
(m, 4H, ArH), 6.95-6.90 (m, 4H, ArH), 7.27 (br s., 1H, H-8), 7.46 (br s., 1H, H-5). 13C NMR (75.46
MHz, CDCl3) δ:13.8, 17.6 (2xCH2CH3), 20.3 (CH3), 62.3 (2xCH2CH3), 113.2 (C-3), 113.8, 114.4
(Carom), 117.2 (C-8), 117.6 (C-4a), 125.2, 129.7, 129.8, 130.9, 131.6 (Carom + C-5+ C-6) , 135.7 (C-
7), 151.2 (C-8a), 151.5 (C-4), 157.0, 157.3 (2xC4arom-OEt), 160.9 (CO). GC-MS (EI,70 eV): m/z
(%) = 400 ([M]+, 100), 344 (15). HRMS (EI, 70 eV) calcd for C26H24O4: 400.16691 [M]+; found:
400.16654.
4.1.3. General procedure for the preparation of 7-aryl-4-methyl-6-O-trifluoromethane
sulphonyl-2H-chromen-2-one (8a-l)
Method was analogous to the procedure for preparation of 7a-e, using instead arylboronic acid 6a-l
(1.2 equiv., 0.18 mmol), Pd(PPh3)4 (5 mg, 3 mol -%, 0.005 mmol) and K3PO4 (49 mg, 0.23 mmol).
4.1.3.1. 7-(3,4-Dimethylphenyl)-4-methyl-6-O-trifluoromethanesulphonyl-2H-chromen-2-one
(8a)
From 3,5-dimethylphenylboronic acid (6a) (27 mg). Yield: 47 mg (75%) as a white solid, mp: 165-
167 °C. IR (KBr, cm-1): v 3057, 2950, 2910, 2838 (w), 1721 (s), 1611, 1606 (m), 1538 (w), 1509,
1491 (m). 1H NMR (300 MHz, CDCl3) δ: 1.45 (s, 6H, 2xCH3), 2.31 (d, 3H, JCH3,H3 = 1.4 Hz, CH3),
13
6.31 (d, 1H, H-3 ), 7.17 (m., 3H, ArH), 7.33 (d, 1H, H-5), 7.48 (br s., 1H, H-8). C NMR (75.47
MHz, CDCl3) δ: 17.6 (2xCH3), 20.1 (CH3), 113.9 (C-3), 115.2 (C-5), 118.7 (C-4a), 125.4 (q, JC,F =
320.4 Hz, CF3), 126.4 (C-8), 127.9 (C-7), 129.8, 132.8, 136.3, 137.3, 138.4 (Carom), 141.5 (C-8a),
149.8 (C-6), 151.3 (C-4), 160.1 (CO). 19F NMR (282.4, MHz) δ: - 73.8. GC-MS (EI, 70 eV): m/z
(%) = 412 ([M]+, 100), 280 (20), 279 (30), 264 (12), 235 (11). HRMS (EI, 70 eV) calcd for
C19H15F3O5S: 412.05868 [M]+; found: 412.05840.

16
4.1.3.2.
7-(4-Methoxyphenyl)-4-methyl-6-O-trifluoromethanesulphonyl-2H-chromen-2-one
(8b)
From 4-methoxyphenylboronic acid (6b) (27 mg). Yield: 50 mg (80%) as a white solid, mp: 134-
136 °C. IR (KBr, cm-1): v 3112, 3089, 3074, 2965, 2929, 2841 (w), 1729 (s), 1621, 1605 (m), 1576,
1543, 1520, 1491 (w). 1H NMR (300 MHz, CDCl3) δ: 2.39 (d, 3H, JCH3,H3 = 1.2 Hz, CH3), 3.80 (s,
3H, OMe), 6.30 (d, 1H, H-3), 6.93 (d, 2H, J3,5 = 8.9 Hz, ArH3,5), 7.33-7.37 (m, 3H, ArH + H-5),
7.48 (br s., 1H, H-8). 13C NMR (75.46 MHz, CDCl3) δ: 18.5 (CH3), 55.3 (OMe), 114.3 (C-3), 116.1
(C-5), 118.4 (Carom), 119.1 (q, JC,F = 320.1 Hz, CF3), 119.5 (C-4a), 120.4 (C-8), 126.3 (C-7), 130.6,
19
138.8 (Carom), 142.6 (C-8a), 150.9 (C-4), 152.4 (C-6), 159.7 (Carom-OMe), 160.9 (CO). F NMR
(282 MHz, CDCl3) δ: - 73.6. GC-MS (EI, 70 eV): m/z (%) = 414 ([M]+, 100), 282 (20), 281 (30).
HRMS (EI, 70 eV) calcd for C18H13F3O6S: 414.03794 [M]+; found: 414.03813.
4.1.3.3. 7-(4-Chlorophenyl)-4-methyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8c)
From 4-chlorophenylboronic acid (6c) (28 mg). Yield: 55 mg (85%) as a white solid, mp: 124-125
°C. IR (KBr, cm-1): v 3080, 3065, 2921, 2850 (w), 1738, 1732, 1615 (s), 1592, 1574, 1538 (w),
1505 (m), 1477 (m). 1H NMR (300 MHz, CDCl3) δ: 2.40 (d, 3H, JCH3,H3 = 1.1 Hz, CH3), 6.33 (d,
1H, H-3), 6.96-7.42 (m, 6H, ArH). 13C NMR (62.9 MHz, CDCl3) δ:17.6 (CH3), 115.6 (C-3 + C-5),
117.5 (q, JC,F = 320.3 Hz, CF3), 119.3 (C-4a), 128.1 (C-8), 129.4 (C-7), 129.6, 131.4, 134.6, 136.7,
141.3 (Carom), 144.7 (C-8a), 150.0 (C-6), 151.3 (C-4), 158.4 (CO). 19F NMR (282.4 MHz) δ: - 73.5.
GC-MS (EI, 70 eV): m/z (%) = 418 ([M]+, [ 35Cl], 100), 287 (34), 285 (20), 251 (10), 222 (41), 165
35
(25). HRMS (EI, 70 eV) calcd for C17H10O5 ClF3S: 417.98841 [M]+; found: 417.98743.
4.1.3.4. 4-Methyl-7-phenyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8d)
From phenylboronic acid (6d) (22 mg). Yield: 42 mg (72%) as a white solid, mp: 95-96 °C. IR
(KBr, cm-1): v 3090, 2981, 2941, 2869 (w), 2981 (s), 2925, 2875 (m), 1568 (w), 1529, 1496 (m).
1H NMR (300 MHz, CDCl3) δ: 2.40 (s, 3H, CH3), 6.26 (s, 1H, H-3), 7.07-7.18 (m, 5H, ArH + H-5),
7.53 (br s., 1H, H-8). 13C NMR (75.47 MHz, CDCl3) δ: 17.6 (CH3), 114.2 (C-3), 117.5 (C-5 + C-
4a), 117.7 (q, JC,F = 320.2 Hz, CF3), 125.4 (C-8), 126.4 (C-7), 127.7 128.2, 128.8, 136.1, 138.6,
19
139.2 (Carom), 143.4 (C-8a), 151.1 (C-6), 151.7 (C-4), 159.8 (CO). F NMR (282.4, MHz) δ: -
73.7. GC-MS (EI, 70 eV): m/z (%) = 384 ([M]+, 100), 252 (18), 251 (30), 195 (19), 152 (13).
HRMS (EI, 70 eV) calcd for C17H11F3O5S [M]+: 384.02738; found: 384.02760.
4.1.3.5. 7-(4-Ethoxyphenyl)-4-methyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8e)
From 4-ethoxyphenylboronic acid (6e) (30 mg). Yield: 59 mg (90%) as a white solid, mp: 122-124
°C. IR (KBr, cm-1): v 3119, 3081, 2988, 2923, 2852 (w), 1728 (s), 1660 (w), 1607 (m), 1576, 1542,

17
1
1522, 1496 (w). H NMR (300 MHz, CDCl3) δ: 1.48 (t, 3H, J = 6.9 Hz, CH2CH3), 2.39 (s, 3H,
JCH3,H3 = 1.6 Hz, CH3), 4.03 (q, 2H, J = 6.9 Hz, CH2CH3), 6.29 (d, 1H, J = 1.6 Hz , H-3), 6.92 (d,
2H, J = 8.8 Hz, ArH3,5), 7.29-7.39 (m, 3H, ArH + H-5), 7.48 (br s., 1H, H-8). 13C NMR (75.46
MHz, CDCl3) δ: 18.4 (CH2CH3), 18.6 (CH3), 63.5 (CH2CH3), 114.7 (C-3 + Carom), 116.0 (C-5),
117.3 (C-4a), 118.2 (q, JC,F = 320.0 Hz, CF3), 119.5 (C-8), 127.3 (C-7), 130.5, 138.8 (Carom), 142.6
(C-8a), 151.9 (C-4), 152.5 (C-6), 158.2 (Carom-OEt), 159.8 (CO). 19F NMR (282 MHz, CDCl3) δ: -
73.7. GC-MS (EI, 70 eV): m/z (%) = 428 ([M]+, 100), 296 (19), 295 (30), 267 (69). HRMS (EI, 70
eV) calcd for C19H15F3O6S: 428.05359 [M]+; found: 428.05397.
4.1.3.6. 7-(4-Fluorophenyl)-4-methyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8f)
From 4-fluorophenylboronic acid (6f) (25 mg). Yield: 48 mg (78%) as a white solid, mp: 111-112
°C. IR (KBr, cm-1): v 3022, 2961, 2918, 2851 (w), 1731, 1715 (s), 1651 (w), 1621, 1610 (m), 1573,
1
1568, 1543, 1519, 1514, 1485 (w). H NMR (300 MHz, CDCl3) δ: 2.38 (d, 3H, JCH3,H3 = 1.3 Hz,
CH3), 6.23 (d, 1H, H-3), 6.94-6.98 (m, 4H, ArH), 7.29 (br s., 1H, H-5), 7.49 (br s., 1H, H-8). 13C
NMR (75.46 MHz, CDCl3) δ: 17.6 (CH3), 114.1 (C-3), 117.4 (C-5), 117.8 (C-4a + C-8), 118.8 (q,
JC,F = 320.1 Hz, CF3), 127.8, 128.6 (2xd, J = 21.6, 8.2 Hz, Carom-F + C-7), 136.0 (d, J = 3.3 Hz,
19
C1arom-F), 143.4 (C-8a), 146.8 (d, JC,F = 248.9 Hz, Carom-F), 151.7 (C-4 + C-6), 159.9 (CO). F
NMR (282 MHz, CDCl3) δ: - 112.4, -73.8. GC-MS (EI, 70 eV): m/z (%) = 402 ([M]+, 100), 270
(17), 269 (30), 165 (12). HRMS (EI, 70 eV) calcd for C17H10F4O5S: 402.01796 [M]+; found:
402.01766.
4.1.3.7. 4-Methyl-7-(4-(trifluoromethanephenyl)-6-trifluoromethanesulphonyl-2H-chromen-
2-one (8g)
From 4-trifluoromethanephenylboronic acid (6g) (34 mg). Yield: 58 mg (83%) as a white solid, mp:
101-102 °C. IR (KBr, cm-1): v 3053, 2961, 2905, 2854 (w), 1723, 1614 (s), 1574, 1547, 1488 (w).
1H NMR (300 MHz, CDCl3) δ: 2.42 (d, 3H, JCH3,H3 = 1.3 Hz, CH3), 6.30 (d, 1H, H-3), 7.17 (d, 2H,
J2,6 = 8.1 Hz, ArH2,6), 7.33 (br s., 1H, H-5), 7.46 (d, 2H, J3,5 = 8.1 Hz, ArH3,5), 7.54 (br s., 1H, H-8).
13C NMR (75.46 MHz, CDCl3) δ: 17.6 (CH3), 114.9 (C-3), 117.8 (C-5), 118.8 (C-4a + C-8), 122.2
(q, JC,F = 320.4 Hz, SO2CF3), 124.3 (d, JCarom,F = 21.6 Hz, C3arom), 125.7 (d, JCarom,F = 8.2 Hz, C3
arom
+ C-7), 135.6 (d, JCarom,F = 32.6 Hz, C4arom-CF3), 135.8, 136.4 (Carom), 143.4 (C-8a), 146.8 (d, JC,F
= 248.9 Hz, CF3), 151.7 (C-6), 152.1 (C-4), 159.9 (CO). 19F NMR (282 MHz, CDCl3) δ: -112.4, -
62.6. GC-MS (EI, 70 eV): m/z (%) = 452 ([M]+, 100), 270 (17), 269 (30), 165 (12). HRMS (EI, 70
eV) calcd for C18H10F6O5S: 452.01476 [M]+; found: 452.12567.
4.1.3.8. 4-Methyl-7-(4-methylphenyl)-6-trifluoromethanesulphonyl-2H-chromen-2-one (8h)

18
From 4-methylphenylboronic acid (6h) (25 mg). Yield: (46 mg (75%) as a white solid, mp: 135-136
°C.IR (KBr, cm-1): v 3067, 2960, 2920, 2848 (w), 1731 (s), 1621, 1606 (m), 1548 (w), 1519, 1491
(m). 1H NMR (300 MHz, CDCl3) δ: 2.25 (s, 3H, CH3), 2.40 (d, 1H, JCH3,H3 = 1.3 Hz, 3H, CH3), 6.32
(d, 1H, H-3), 7.11 (d, 2H, J3,5 = 8.2 Hz, ArH3,5), 7.32 (br s., 1H, H-5), 7.47 (d, 2H. J2,6 = 8.3 Hz,
ArH2,6), 7.50 (br s., 1H, H-8). 13C NMR (75.47 MHz, CDCl3) δ: 17.5, 17.6 (2xCH3), 114.8 (C-3),
115.1 (C-5), 115.5 (C-4a), 117.2 (C-8), 118.5 (q, JC,F = 319.4 Hz, CF3), 130.3 (C-7 + Carom), 136.9 ,
141.4 (Carom), 149.7 (C-8a), 151.3 (C-4 + C-6), 162.9 (CO). 19F NMR (282 MHz, CDCl3) δ: - 73.5.
GC-MS (EI, 70 eV): m/z (%) = 398 ([M]+, 100), 265 (16), 238 (17), 237 (85), 209 (34), 165 (32).
HRMS (EI, 70 eV) calcd for C18H13F3O5S: 398.04303 [M]+; found: 398.04309.
4.1.3.9. 4-Methyl-7-(3-methylphenyl)-6-trifluoromethanesulphonyl-2H-chromen-2-one (8i)
From 3-methylphenylboronic acid (6i) (25 mg). Yield: 48 mg (80%) as a white solid, mp: 85-86 °C.
IR (KBr, cm-1): v 3070, 2961, 2921, 2849 (w), 2961 (s), 2905, 2855 (m), 1548 (w), 1519, 1491 (m).
1H NMR (300 MHz, CDCl3) δ: 2.20 (s, 3H, CH3), 2.39 (d, 3H, JCH3,H3 = 1.2 Hz, CH3), 6.24 (d, 1H,
H-3), 6.80 (d, 2H, J = 8.3 Hz, ArH), 7.01-7.03 (m, 2H, ArH), 7.31 (br s., 1H, H-5), 7.50 (br s., 1H,
H-8). 13C NMR (75.47 MHz, CDCl3) δ: 17.5, 17.6 (2xCH3), 114.8 (C-3), 115.1 (C-5), 115.5 (C-4a),
118.5 (C-8), 118.7 (q, JC,F = 319.4 Hz, CF3), 130.3 (C-7 + Carom), 136.9, 141.4 (Carom), 151.3 (C-8a),
19
151.5 (C-6), 152.6 (C-4), 163.9 (CO). F NMR (282.4, MHz) δ: - 73.7. GC-MS (EI, 70 eV): m/z
(%) = 398 ([M]+, 100), 266 (18), 265 (30), 209 (11). HRMS (EI, 70 eV) calcd for C18H13F3O5S:
398.04303 [M]+; found: 398.04297.
4.1.3.10. 7-(3-Methoxyphenyl)-4-methyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8j)
From 3-methoxyphenylboronic acid (6j) (27 mg). Yield: 44 mg (70%) as a white solid, mp: 112-
114 °C. IR (KBr, cm-1): v 3112, 3089, 3074, 2965, 2929, 2841 (w), 1731 (s), 1621, 1600, 1582 (m),
1547, 1506, 1482, 1468 (w). 1H NMR (300 MHz, CDCl3) δ: 2.40 (d, 3H, JCH3,H3 = 1.3 Hz, CH3),
3.78 (s, 3H, OMe), 6.32 (d, 1H, H-3), 6.91-6.93 (m, 2H, ArH), 6.95 (d, 1H, J = 8.8 Hz, ArH), 7.30
13
(d, 1H, J = 8.8 Hz 1H, ArH), 7.36 (br s., 1H, H-5), 7.49 (br s., 1H, H-8). C NMR (75.46 MHz,
CDCl3) δ: 17.5 (CH3), 54.3 (OMe), 113.8 (C-3), 115.1 (C-5), 115.4 (C-4a), 118.8 (C-8), 119.1 (q,
JC,F = 320.1 Hz, CF3), 128.8 (C-7 + Carom), 134.2, 137.9, 141.5 (Carom), 151.3 (C-8a), 158.6 (C-4 +
C-6), 159.1 (Carom-OMe), 160.9 (CO). 19F NMR (282 MHz, CDCl3) δ: - 73.7. GC-MS (EI, 70 eV):
m/z (%) = 414 ([M]+, 100), 282 (18), 281 (40), 67 (18). HRMS (EI, 70 eV) calcd for C18H13F3O6S:
414.03794 [M]+; found: 414.03799.
4.1.3.11. 4-Methyl-7-(2,3,4-trimethoxyphenyl)-6-trifluoromethanesulphonyl-2H-chromen-2-
one (8k)

19
From 2,3,4-trimethoxyphenylboronic acid (6k) (38 mg). Yield: 65 mg (90%) as a white solid, mp:
155-157 °C. IR (KBr, cm-1): v 3110, 3087, 3072, 2963, 2927, 2839 (w), 1727 (s), 1619, 1603 (m),
1
1574, 1541, 1520, 1492 (w). H NMR (300 MHz, CDCl3) δ: 2.39 (d, 3H, JCH3,H3 = 1.2 Hz, CH3),
3.78 (s, 3H, OMe), 3.84 (2xs, 6H, 2xOCH3 ), 6.31 (d, 1H, H-3), 6.68 (d, J = 8.4 Hz, 1H, ArH), 6.89
13
(d, J5,6 = 8.3 Hz, 1H, ArH5,6), 7.31 (br s., 1H, H-5), 7.45 (br s., 1H, H-8). C NMR (75.46 MHz,
CDCl3) δ: 17.4 (CH3), 55.0, 59.8, 59.9 (3xOMe), 106.1 (C5arom), 115.1 (C-3), 116.1 (C-4a), 118.8
(C-8), 119.5 (q, JC,F = 319.1 Hz, CF3), 119.6 (C1arom), 124.4 (C-7), 135.2 (Carom), 142.5 (C-8a),
149.9, 150.3, 151.0 (Carom-OMe), 154.0 (C-4 + C-6), 158.8 (CO). 19F NMR (282 MHz, CDCl3) δ: -
73.9. GC-MS (EI, 70 eV): m/z (%) = 474 ([M]+,100), 341 (22), 310 (30), 295 (12). HRMS (EI, 70
eV) calcd for C20H17F3O8S: 474.05907 [M]+; found: 474.05931.
4.1.3.12. 7-(4-tert-Butylphenyl)-4-methyl-6-trifluoromethanesulphonyl-2H-chromen-2-one (8l)
From 4-tert-butyl-phenylboronic acid (6l) (32 mg). Yield: 52 mg (77%) as a white solid, mp: 131-
133 °C. IR (KBr, cm-1): v 3070, 2963, 2923, 2851 (w), 1734 (s), 1624, 1609 (m), 1551 (w), 1521,
1494 (m). 1H NMR (300 MHz, CDCl3) δ: 1.23 (s, 9H, 3xCH3), 2.40 (d, 3H, JCH3,H3 = 1.2 Hz, CH3),
6.31 (d, 1H, H-3), 7.34 (m, 3H, ArH), 7.44 (m., 2H, ArH + H-5), 7.50 (br s., 1H, H-8). 13C NMR
(75.47 MHz, CDCl3) δ: 17.5 (CH3), 30.2 (3xCH3), 115.2 (C-3), 117.1 (C-5), 118.7 (C-4a + C-8),
119.9 (q, JC,F 320.4 Hz, CF3), 124.7, 125.1 (C-7 + Carom), 138.0 (C1arom), 141.7 (C-8a), 149.9
=
(C4arom-CMe3), 151.3 (C-6), 151.6 (C-4), 158.7 (CO). 19F NMR (282.4, MHz) δ: -73.7. GC-MS (EI,
70 eV): m/z (%) = 440 ([M]+, 100), 265 (16),238 (17), 237(85), 209 (34), 165 (32). HRMS (EI,70
eV) calcd for C21H19F3O5S: 440.08998 [M]+; found: 440.04309.
4.1.4. General procedure of 6-aryl-7-(4-methoxyphenyl)4-methyl-2H-chromen-2-one
derivatives (9a-d)
To a dioxane suspension (3 mL) of bis(triflate) analogue 5 (70 mg, 0.15 mmol), Pd(PPh3) (5 mg, 3
mol -%, 0.005 mmol), and 4-methoxyphenylboronic acid (6b) )28 mg, 0.15 mmol), K3PO4 (49 mg,
0.23 mmol) was added. The mixture was heated at 70oC under Argon atmosphere. After 6 h, a
dioxan (3 mL) suspension of arylboronic acid 6c,g,j,a (0.15 mmol), Pd(PPh3)4 (5 mg, 3 mol-%,
o
0.005 mmol), K3PO4 (49 mg, 0.23 mmol) was added. The mixture was heated at 120 C under
Argon atmosphere for 6 h. The reaction mixture was worked up as experiments 7a-e.
4.1.4.1. 6-(4-Chlorophenyl)-7-(4-methoxyphenyl)-4-methyl-2H-chromen-2-one (9a)
From 4-chlorophenylboronic acid (6c) (28 mg). Yield: 42 mg (73%) as a white solid, mp: 172-174
°C. IR (KBr, cm-1): v 3115, 3092, 3076, 2966, 2932, 2845 (w), 1731 (s), 1620, 1600 (m), 1580,
1540, 1522, 1493 (w). 1H NMR (300 MHz, CDCl3) δ: 2.39 (d, 3H, JCH3,H3 = 1.1 Hz, CH3), 3.73 (s,

20
3H, OMe), 6.24 (d, 1H, H-3), 6.72 (d, 2H, J = 8.1 Hz, ArH), 6.95-6.99 (m, 4H, ArH), 7.26 (m, 2H,
ArH + H-8), 7.46 (br s., 1H, H-5). 13C NMR (75.46 MHz, CDCl3) δ: 17.6 (CH3), 54.2 (OMe), 112.7
(C-3), 114.1 (Carom), 117.4 (C-8), 117.8 (C-4a), 125.3, 127.4, 129.8, 130.0 (Carom), 130.5 (C-5),
132.0 (C-6), 134.7 (Carom-Cl), 137.8, 143.1 (C-7 + Carom), 151.0 (C-8a), 151.9 (C-4), 158.1 (Carom
-
OMe), 159.7 (CO). GC-MS (EI, 70 eV): m/z (%) = 376 ([M]+, [35Cl], 100), 348 (13). HRMS (EI, 70
eV) calcd for C23H1735ClO3: 376.08607 ([M]+); found 367.08589.
4.1.4.2. 6-(4-Fluorophenyl)-7-(4-methoxyphenyl)-4-methyl-2H-chromen-2-one (9b)
From 4-fluorophenylboronic acid (6f) (25 mg). Yield: 43 mg (78%) as a white solid, mp: 192-194
°C. IR (KBr, cm-1): v 3115, 3092, 3076, 2966, 2932, 2845 (w), 1731 (s), 1620, 1600 (m), 1580,
1540, 1522, 1493 (w). 1H NMR (300 MHz, CDCl3) δ: 2.39 (d, 3H, JCH3,H3 = 1.3 Hz, CH3), 3.72 (s,
3H, OMe), 6.24 (d, 1H, H-3), 6.70 (d, 2H, J = 8.4 Hz, ArH), 6.88-7.03 (m, 6H, ArH), 7.28 (br s.,
13
1H, H-8), 7.46 (br s., 1H, H-5). C NMR (75.46 MHz, CDCl3) δ: 17.6 (CH3), 54.2 (OMe), 112.7
(C-3), 114.2 (Carom) 117.3 (C-8 + C-4a), 117.7 (d, J = 8.2 Hz, Carom), 125.3 (Carom), 129.8 (C-5),
130.6 (d, J = 21.6 Hz, Carom), 134.9 (C-7), 135.4 (C-6), 143.1 (Carom), 151.0 (C-8a), 151.8 (C-4),
158.7 (q, JC,F = 273.1 Hz, Carom-F), 159.8 (Carom-OMe), 162.5 (CO). 19F NMR (282 MHz, CDCl3) δ:-
115.3. GC-MS (EI,70 eV): m/z (%) = 360 ([M]+, 100), 348 (13). HRMS (EI, 70 eV) calcd for
C23H17FO3: 360.11562 [M]+; found: 360.11580.
4.1.4.3. 7-(4-Methoxyphenyl)-4-methyl-6-(3-methylphenyl)-2H-chromen-2-one (9c)
From 3-methylphenylboronic acid (6i) (25 mg). Yield: 41 mg (75%) as a white solid, mp 209-211
°C. IR (KBr, cm-1): v 3111, 3094, 3077, 2967, 2931, 2846 (w), 1732 (s),1624, 1606 (m), 1583,1547,
1
1526, 1495 (w). H NMR (300 MHz, CDCl3) δ: 2.21 (s, 3H, CH3), 2.37 (d, 3H, JCH3,H3 = 1.2 Hz,
CH3), 3.69 (s, 3H, OMe), 6.21 (d, 1H, H-3), 6.70 (d, 2H, J = 8.4 Hz, ArH), 6.81 (d, 2H, J = 8.9 Hz,
ArH), 6.93-7.06 (m, 3H, ArH), 7.27 (br s., 1H, H-8), 7.48 (br s., 1H, H-5). 13C NMR (75.46 MHz,
CDCl3) δ: 17.6, 20.3 (2xCH3), 54.1 (OMe), 112.5 (C-3), 113.8 (Carom), 117.1 (C-8), 117.6 (C4a),
125.9, 126.6, 126.9, 129.3 (Carom), 129.7 (C-5), 131.0 (C-6), 136.8 (C-7), 139.3, 143.1 (Carom), 151.2
(C-8a), 151.6 (C-4), 158.0 (Carom-OMe), 159.9 (CO). GC-MS (EI, 70 eV): m/z (%) = 356 ([M]+,
100), 341(10). HRMS (EI, 70 eV) calcd for C24H20O3: 356.14070 [M]+; found: 356.14106.
4.1.4.4. 6-(3,5-Dimethlyphenyl)-7-(4-methoxyphenyl)-4-methyl-2H-chromen-2-one (9d)
From 3,5-dimethylphenylboronic acid (6a) (28 mg). Yield: 46 mg (81%) as a white solid, mp:
203-205 °C. IR (KBr, cm-1): v 3117, 3094, 3078, 2969, 2934, 2847 (w), 1734 (s), 1627, 1609 (m),
1
1585, 1549, 1528, 1497 (w). H NMR (300 MHz, CDCl3) δ: 2.15 (6H, 2xCH3), 2.38 (d, 3H,
JCH3,H3 = 1.4 Hz, CH3), 3.71 (s, 3H, OMe), 6.22 (d, 1H, H-3), 6.67-6.79 (m, 5H, ArH), 6.99 (d,

21
2H, J = 8.4 Hz, ArH), 7.28 (br s., 1H, H-8), 7.47 (br s., 1H, H-5). 13C NMR (75.46 MHz, CDCl3)
δ: 17.6 (2xCH3), 21.6 (CH3), 54.2 (OMe), 113.8 (C-3), 114.1 (Carom), 117.1 (C-8), 117.5 (C-4a),
125.3, 126.4, 126.6, 127.5 (Carom), 129.7 (C-5), 131.0 (C-6), 136.2 (C-7), 136.5, 136.6, 139.2,
143.1 (Carom), 151.2 (C-8a), 151.6 (C-4), 157.9 (Carom-OMe), 159.9 (CO). GC-MS (EI, 70 eV):
m/z (%) = 370 ([M]+,100), 355 (12), 300 (11). HRMS (EI, 70 eV) calcd for C25H22O3: 370.15635
[M]+; found: 370.15622.
4.1.5. 3-Bromo-6,7-dihydroxy-4-methyl-2H-chromen-2-one (10)
To a solution of 4-methyl-6,7-dihydroxycoumarin (4) (1.0 equiv., 0.003 mol, 0.50 g) in glacial
acetic acid (20 mL) bromine (2.0 equiv., 0.005 mol, 0.80 g) were added dropwise under argon
atmosphere, the reaction mixture was stirred at 30 °C for 2 h, the reaction monitored by TLC
(heptane / EtOAc = 9.5 : 0.5). The reaction mixture poured onto ice-cold water (250 mL), stirred
with a solution of sodium hydrogen sulphite till the yellow color disappeared, filtered and the
residue was purified by column chromatography (silica gel, heptane / EtOAc = 10 : 1) to give 10 as
o
a yellow solid (0.52 g, 75%), mp: 181-183 C. NMR (300 MHz, CDCl3) δ: 2.50 (s, 3H, CH3), 6.77
(s, 1H, ArH), 7.09 (s, 1H, ArH), 9.80 (s, 1H, OH), 10.30 (s, 1H, OH). 13C NMR (75.4 MHz, CDCl3)
δ: 19.4 (CH3), 102.4 (CH), 107.6 (C), 109.9 (CH), 111.2, 143.3, 146.1, 150.5 (C), 161.3 (CO). IR
(KBr, cm-1): v 3057, 2995, 2950, 2930, 2831 (w), 1599 (s), 1574, 1551 (w). GC-MS (EI, 70 eV):
m/z (%) 272 ([M+H]+, [81Br], 100), 271 ([M]+, [81Br], 26), 270 ([M+H]+, [79Br], 99), 269 ([M]+,
[79Br], 10), 244 (20), 242 (22), 192 (12), 191 (17),164 (58), 89 (16). HRMS (EI, 70 eV) calcd for
81
79
C10H8 BrO4 [M+H]+: 272.9581, found: 272.9574, C10H8 BrO4 [M+H]+: 270.96005; found:
270.95949.
4.1.6. 3-Bromo-4-methyl-2-oxo-2H-chromene-6,7-diyl bis-(trifluoromethanesulfonate) (11)
To a solution of 10 (0.50 g, 2.60 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.36 mL, 10.4
mmol) at room temperature under an argon atmosphere. After 10 min, Tf2O (1.0 mL, 6.20 mmol)
was added at -78°C. The mixture was allowed to warm to 20 °C and stirred for 6 h. The reaction
mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by
chromatography (flash silica gel, heptane / EtOAc = 4 : 1) without aqueous work up to give 11 as a
white solid (0.90 g, 75%), mp: 125-27 °C. 1H NMR (300 MHz, CDCl3) δ: 2.58 (CH3), 7.45 (s , 1H,
ArH), 7.79 (s, 1H, ArH). 13C NMR (75.46 MHz, CDCl3) δ: 18.80 (CH3), 111.6 (CH), 115.2 (C),
115.5 (q, JF,C = 316.0 Hz, CF3), 118.9 (C), 119.2 (CH), 120.3 (q, JF,C = 316.0 Hz, CF3), 135.9, 140.6,
147.6, 149.7 (C), 153.9 (CO). 19F NMR (282.4, MHz) δ: -72.7, -72.9 (3F, CF3). IR (KBr, cm-1): v
3123, 3051, 2962, 2925 (w), 1742 (s), 1670, 1621, 1612, 1571 (w), 1492 (m). GC-MS (EI, 70 eV):
m/z (%) = 535 ([M]+, [81Br], 19), 533 ([M]+, [79Br], 17), 403 (27), 401 (24), 311 (28), 281 (11), 309

22
81
(29), 202 (13), 77 (25). HRMS (EI, 70 eV) calcd for C12H5O8 BrF6S2 [M]+: 535.84875; found:
79
535.84860, C12H5O8 BrF6S2 [M]+: 533.85079; found: 533.85079.
4.1.7. General procedure for synthesis of 3,6,7-tris(aryl)-4-methyl-2H-chromen-2-one
derivatives (12a-c and 12e-p)
The reactions were carried out in a pressure tube. A 1,4-dioxane solution (4 mL) of 11 (70 mg, 0.13
mmol), arylboronic acid (3.1 equiv., 0.41 mmol), aqueous K2CO3 (2 M, 2 mL), and Pd(PPh3)4 (14
mg, 9 mol-%, 0.012 mmol) was heated at 120 °C for 10 h under argon atmosphere. After cooling to
20 °C, water was added and the reaction mixture was extracted with CH2Cl2 (3 x 25 mL). The
organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, heptane/EtOAc = 9:1).
4.1.7.1. 3,6,7-Tris(3,5-dimethylphenyl)-4-methyl-2H-chromen-2-one (12a)
From 3,5-dimethylphenylboronic acid (6a) (61 mg). Yield: 43 mg (70%) as a white solid, mp: 190-
o
1
192 C. H NMR (300 MHz, CDCl3) δ: 2.13 (s, 6H, 2xCH3), 2.14 (s, 6H, 2xCH3), 2.24 (s, 3H,
CH3), 2.28 (s, 6H, 2xCH3), 6.68 - 6.69 (m, 5H, ArH), 6.79 - 6.84 (m, 5H, ArH), 6.94 (d, J = 8.6,
13
Hz, 1H, ArH), 7.32 (s, 1H, ArH). 7.55 (br. s, 2H, ArH). C NMR (75.4 MHz, CDCl3) δ: 15.5
(2xCH3), 20.2 (2xCH3), 20.3 (2xCH3), 28.6 (CH3), 116.9 (CH), 118.3 (C), 125.6, 126.4, 126.5,
126.6, 127.3, 127.8, 127.9 (CH), 133.4, 136.3, 136.3, 136.8, 138.6, 139.3, 143.1, 143.1, 143.2,
146.3, 147.4, 150.6, 154.2 (C),161.2 (CO). IR (KBr, cm-1): v 3012, 2955 (w), 2919 (m), 2853 (w),
1707 (s), 1610, 1597 (m), 1552, 1495 (w). GC - MS (EI, 70 eV): m/z (%) = 472 ([M]+, 100), 444
(15), 429 (12), 214 (14), 179 (10). HRMS (EI, 70 eV) calcd for C34H32O2 [M]+: 472.240; found:
472.24014.
4.1.7.2. 3,6,7-Tris(4-methoxyphenyl)-4-methyl-2H-chromen-2-one (12b)
From 4-methoxyphenylboronic acid (6b) (61 mg). Yield: (50 mg, 80%) as a white solid, mp: 169-
170 oC. 1H NMR (300 MHz, CDCl3) δ: 2.28 (s, 3H, CH3), 3.72 (s, 6H, 2xOMe), 3.78 (s, 3H, OMe),
6.73 (dd, J = 1.7, 8.3 Hz, 4H, ArH), 6.93 (d, J = 8.6, Hz, 2H, ArH), 6.99 (dd, J = 1.6, 8.6 Hz, 4H,
13
ArH), 7.23 (d, J = 8.6, Hz, 2H, ArH), 7.30 (s, 1H, ArH), 7.53 (s, 1H, ArH). C NMR (75.4 MHz,
CDCl3) δ: 16.6 (CH3), 55.2, 55.3, 55.5 (OMe), 113.6, 113.8, 117.9, 119.4, 126.6 (CH), 126.7, 126.9
(C), 130.8, 130.9, 131.3, 131.6 (CH),132.2, 132.9, 136.6, 143.4, 147.1, 151.6, 158.6, 158.9, 159.4
(C), 161.3 (CO). IR (KBr, cm-1): v 3059, 2993, 2952, 2931, 2834 (w), 1715, 1599 (s), 1574, 1551
(w). GC-MS (EI, 70 eV): m/z (%) = 478 ([M]+, 100), 450 (14), 207 (13). HRMS (EI, 70 eV) calcd
for C31H26O5 [M]+: 478.53514; found: 478.53412.
4.1.7.3. 3,6,7-Tris(4-chlorophenyl)-4-methyl-2H-chromen-2-one (12c)

23
From 4-chlorophenylboronic acid (6c) (61 mg). Yield: 39 mg (61%) as a white solid, mp: 200-201
oC. 1H NMR (300 MHz, CDCl3) δ: 2.28 (s, 3H, CH3), 6.97 - 7.02 (m, 3H, ArH), 7.14 - 7.21 (m, 5H,
ArH), 7.27 - 7.40 (m, 6H, ArH) .13C NMR (75.4 MHz, CDCl3) δ: 16.6 (CH3), 114.1, 114.2, 114.3,
115.2, 117.8, 119.3 (CH), 124.4 (C), 124.7, 124.8 (CH), 128.7, 128.8, 130.3, 132.0, 132.8, 134.6,
143.4, 145.2, 150.5, 151.5, 156.9 (C), 160.4 (CO). IR (KBr, cm-1): v 3067, 3032, 2979, 2927, 2918,
2888, 2839 (w), 1715, 1599 (s), 1572, 1548, 1519 (w), 1512 (m). GC-MS (EI, 70 eV): m/z (%) =
GC - MS (EI, 70 eV): m/z (%) = 490 ([M]+, 3×[35Cl], 99), 345 (45), 270 (15). HRMS (EI, 70 eV)
calcd for C28H1735Cl3O2 [M]+: 490.02886; found: 490.02834.
4.1.7.4. 3,6,7-Tris(4-ethoxyphenyl)-4-methyl-2H-chromen-2-one (12e)
From 4-ethoxyphenylboronic acid (6e) (68 mg). Yield: 57 mg (84%) as a white solid (57 mg, 84
%), mp: 179-180 oC. 1H NMR (300 MHz, CDCl3) δ: 1.30 - 1.35 (m, 9H, 3xCH3), 2.26 (s, 3H, CH3),
3.91 - 3.98 (m, 6H, 3xOCH2), 6.67 - 6.72 (m, 4H, ArH), 6.88 (d, J = 8.6, Hz, 2H, ArH), 6.97 (dd, J
13
= 1.9, 8.6 Hz, 4H, ArH), 7.15 (d, J = 8.6, Hz, 3H, ArH), 7.53 (s, 1H, ArH). C NMR (75.4 MHz,
CDCl3) δ: 14.7, 14.8, 14.9, 16.6 (CH3), 63.4, 63.5, 63.6 (OCH2), 113.1, 113.2, 113.3, 114.2, 116.8,
118.3 (CH), 125.4 (C), 125.7, 125.8 (CH), 129.7, 129.8, 130.3, 131.0, 131.8, 135.6, 142.4, 146.2,
150.5, 150.5, 156.9 (C), 160.4 (CO). IR (KBr, cm-1): v 3066, 3031, 2978, 2928, 2919, 2887, 2849
(w), 1716, 1599 (s), 1573, 1548, 1519 (w), 1510 (m). GC-MS (EI, 70 eV): m/z (%) = 520 ([M]+,
100), 492 (14), 209 (13). HRMS (EI, 70 eV) calcd for C34H32O5 [M]+: 520.22497; found:
520.22478.
4.1.7.5. 3,6,7-Tris(4-fluorophenyl)-4-methyl-2H-chromen-2-one (12f)
From 4-fluorophenylboronic acid (6f) (59 mg). Yield: 40 mg (70%) as a white solid, mp: 222-
224°C. 1H NMR (300 MHz, CDCl3) δ: 2.28 (s, 3H, CH3) , 6.86 - 6.92 (m, 4H, ArH), 7.00 - 7.04 (m,
4H, ArH), 7.12 (d, J = 8.52 Hz, 2H, ArH), 7.21 - 7.26 (m, 2H, ArH), 7.32 (s, 1H, ArH), 7.56 (s, 1H,
ArH). 13C NMR (62.9 MHz, CDCl3) δ: 15.6 (CH3), 114.1 (d, JF,C = 21.4 Hz), 114.4 (d, JF,C = 21.4
Hz), 115.6 (d, JF,C = 21.4 Hz), 117.2 (CH), 118.6, 125.6 (C), 126.0 (CH), 129.1 (d, JF,C = 3.5 Hz)
(C), 130.2, 130.3 (CH), 130.4 (C), 130.8 (d, JF,C = 1.7 Hz) (CH), 142.0, 146.5, 150,9, 159.3, 159.6,
159.7 (C), 159.9 (d, JF,C = 246.9 Hz)(CF), 162.6 (d, JF,C = 246.0 Hz) (CF), 162.9 (d, JF,C = 247.4
19
Hz)(CF), 163.2 (CO). F NMR (282.4, MHz) δ: -113.1, -144.8, -114.9 (ArF). IR (KBr, cm-1): v
3038, 2929, 2859, 1892 (w), 1604 (m), 1558 (w), 1507 (s), 1490 (m). GC-MS (EI, 70 eV): m/z (%)
= 442 ([M]+, 100), 441 (21), 415 (10), 414 (38), 413 (20). HRMS (EST-TOF/MS): calcd for.
C28H17O2F3 [M]+ : 442.11752; found: 442.11697.
4.1.7.6. 4-Methyl-3,6,7-tris[4-(trifluoromethyl)phenyl]-2H-chromen-2-one (12g)

24
From 4-(trifluoromethyl)phenylboronic acid (6g) (77 mg). Yield: 49 mg (63%) as a white solid, mp:
1
188-189 °C. H NMR (300 MHz, CDCl3) δ: 2.30 (s, 3H, CH3) , 6.52 - 6.59 (m, 5H, ArH), 7.00 -
7.06 (m, 3H, ArH), 7.14 (d, J = 8.52 Hz, 2H, ArH), 7.23 - 7.27 (m, 2H, ArH), 7.30 (s, 1H, ArH),
7.53 (s, 1H, ArH). 13C NMR (62.9 MHz, CDCl3) δ: 16.6 (CH3), 115.1 (d, J F,C = 21.4 Hz), 115.4 (d,
J F,C = 21.4 Hz), 115.6 (d, J F,C = 21.4 Hz), 117.3 (CH), 118.7, 125.8 (C), 126.2 (CH), 129.4 (d, J F,C
= 3.5 Hz) (C), 130.1, 130.3 (CH), 130.4 (C), 130.9 (d, J F,C = 1.7 Hz) (CH), 133.2 (d, J F,C = 3.6 Hz),
142.1, 146.6 (d, J F,C = 3.3 Hz), 150. 9, 159.2, 159.5, 159.6, 159.8 (C), 159.9 (d, J F,C = 246.9 Hz)
(CF3), 162.7 (d, J F,C = 246.0 Hz) (CF3), 162.9 (d, J F,C = 247.4 Hz) (CF3), 163.3 (CO). 19F NMR
(282.4, MHz) δ: - 62.5, - 62.6, - 62.7(3F,CF3). IR (KBr, cm-1): v 3069, 2959, 2921, 2850 (w), 1721
(s), 1650, 1645, 1615, 1575, 1556, 1486, 1463, 1455 (w) . GC-MS (EI, 70 eV): m/z (%) = 592
([M]+, 100), 591 (45), 573 (13), 565 (11), 564 (37), 563 (18), 419 (15). HRMS (EST-TOF/MS):
calcd for. C31H17O2F9 [M]+: 592.10794; found: 592.10714.
4.1.7.7. 4-Methyl-3,6,7-tri-p-tolyl-2H-chromen-2-one (12h)
From 4-methylphenylboronic acid (6h) (55 mg). Yield: 42 mg (75%) as a white solid, mp: 163-165
oC. 1H NMR (300 MHz, CDCl3) δ: 2.09 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.32 (s,
3H, CH3), 6.99 (br. s, 1H, ArH) 7.12 (d, J = 8.3, Hz, 2H, ArH), 7.18 - 7.23 (m, 5H, ArH), 7.28 -
7.34 (m, 2H, ArH), 7.55 (s, 2H, ArH), 7.64 (br. s, 2H, ArH). 13C NMR (75.4 MHz, CDCl3) δ: 15.2,
16.3, 20.1, 20.3 (CH3), 28.5 (C), 117.2, 118.1, 118.2 (CH), 118.5 (C), 125.6, 125.9, 126.1, 126.4,
126.3 (CH), 129.4, 133.2, 136.1, 136.3, 137.0, 138.5, 139.4, 143.2, 146.2, 150.6 (C), 160.3 (CO).
IR (KBr, cm-1): v = 2962, 2923, 2854 (w), 1715 (s), 1608 (m), 1586, 1551, 1479 (w). GC-MS (EI,
70 eV): m/z (%) = 430 ([M]+, 100), 420 (22), 413 (13), 186 (18). HRMS (EI, 70 eV) calcd for
C31H26O2 [M]+: 430.19328; found: 430.19355.
4.1.7.8. 4-Methyl-3,6,7-tri-m-tolyl-2H-chromen-2-one (12i)
From 3-methylphenylboronic acid (6i) (55 mg). Yield: 39 mg, 70%) as a white solid, mp: 143-145
oC. 1H NMR (300 MHz, CDCl3) δ: 2.20 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.34 (s,
3H, CH3), 6.83 (br. s, 2H, ArH) 6.94 - 7.06 (m, 6H, ArH), 7.15 (t, J = 7.3, Hz, 2H, ArH), 7.25 (t, J
= 7.2, Hz, 2H, ArH), 7.35 (s, 1H, ArH), 7.58 (br. s, 1H, ArH). 13C NMR (75.4 MHz, CDCl3) δ: =
15.6, 16.6, 20.4, 20.5 (CH3), 28.6 (C), 117.1, 118.2, 118.3 (CH), 118.4 (C), 125.8, 125.9, 126.0,
126.5, 126.6, 126,8, 127.0, 127.3, 127.9, 129.3, 129.4 (CH),129.5, 133.4, 136.2, 136.6, 137.0,
138.6, 139.3, 143.1, 146.3, 150.7 (C), 160.2 (CO). IR (KBr, cm-1): v = 2961, 2920, 2853 (w), 1711
(s), 1607 (m), 1585, 1552, 1478 (w). GC-MS (EI, 70 eV): m/z (%) = 430 ([M]+, 100), 429 (21), 415
(10), 402 (18), 186 (10). HRMS (EI, 70 eV) calcd for C31H26O2 [M]+: 430.19328; found:
430.19373.

25
4.1.7.9. 3,6,7-Tris(3-methoxyphenyl)-4-methyl-2H-chromen-2-one (12j)
From 3-methoxyphenylphenylboronic acid (6j) (62 mg). Yield: 50 mg (80%) as a white solid, mp:
101-103 oC. 1H NMR (300 MHz, CDCl3) δ: 2.27 (s, 3H, CH3), 3.57 (s, 6H, 2x OCH3), 3.76 (s, 3H,
OCH3), 6.60 - 6.62 (m, 3H, ArH), 6.68 - 6.74 (m, 3H, ArH), 6.78 - 6.81(m, 3H, ArH), 7.10 (d, J =
8.6, Hz, 1H, ArH), 7.17 (d, J = 8.4, Hz, 1H, ArH), 7.28 - 7.37 (m, 2H, ArH), 7.61 (s, 1H, ArH). 13C
NMR (75.4 MHz, CDCl3) δ: 16.6 (CH3), 55.1, 55.2, 55.3 (OCH3), 112.7, 113.5, 113.7, 115.0,
115.4, 115.7, 118.1 (CH), 119.6 (C), 122.0, 122.2, 122.3, 126.9 (CH), 127.7 (C), 129.2, 129.3,
129.5 (CH), 136.4, 136.9, 141.4, 141.7, 143.8, 147.5, 151.9, 159.2, 159.3, 159.5 (C), 160.8 (CO).
IR (KBr, cm-1): v 3054, 2998, 2952, 2934, 2823 (w), 1712, 1598, 1575, (s), 1556 (m),1477 (w). GC
- MS (EI, 70 eV): m/z (%) = 478 ([M]+, 100), 477 (22), 207 (13). HRMS (EI, 70 eV) calcd for
C31H26O5 [M]+ : 478.17748; found: 478.17709.
4.1.7.10. 4-Methyl-3,6,7-tris(2,3,4-trimethoxyphenyl)-2H-chromen-2-one (12k)
From 2,3,4-trimethoxyphenylboronic acid (6k) (86 mg). Yield: 69 mg (80%) as a white solid, mp:
1
110-112 oC. H NMR (300 MHz, CDCl3) δ: 2.20 (s, 3H, CH3), 3.63 (s, 9H, 3xOCH3), 3.66 (s, 9H,
3xOCH3), 3.85 (s, 9H, 3xOCH3), 6.99 (dd, J = 1.9, 8.4 Hz, 2H, ArH), 6.62 - 6.70 (m, 3H, ArH),
6.18 (d, J = 8.3 Hz, 1H, ArH), 7.34 (s, 1H, ArH), 7.59 (s, 1H, ArH). 13C NMR (75.4 MHz, CDCl3)
δ: 15.5 (CH3), 28.6 (3xOCH3), 54.9 (3xOCH3), 55.0 (3xOCH3), 105.3, 105.4, 106.3, 108.3, 108.4,
112.2, 112.4, 117.2 (CH), 120.3, 122.7, 124.2, 124.3, 124.7, 125.7, 126.0, 133.3, 140.5, 140.8,
140.9, 141.3, 147.8, 150.1, 150.3, 150.9, 152.0, 152.2, 153.0 (C), 160.2 (CO). IR (KBr, cm-1) : v
3065, 3034 (w), 2971 (m), 2931, 2920, 2881, 1887 (w), 1721, 1600 (s), 1573, 1557, 1552, 1518,
1506, 1485 (w). GC-MS (EI, 70 eV): m/z (%) = 658 ([M]+, 100), 620 (10), 577 (20), 438 (17), 411
(25), 207 (14). HRMS (EI, 70 eV) calcd for C37H38O11 [M]+: 658.24141; found: 658.24135.
4.1.7.11. 3,6,7-Tris(4-tert-butylphenyl)-4-methyl-2H-chromen-2-one (12l)
From 4-tert-butylphenylboronic acid (6l) (72 mg). Yield: 45 mg (62%) as a white solid, mp: 150-
o
1
152 C. H NMR (300 MHz, CDCl3) δ: 1.22 (s, 9H, 3xCH3), 1.23 (s, 9H, 3xCH3), 1.28 (s, 9H,
3xCH3), 2.27 (s, 3H, CH3), 7.01 (d, J = 8.3, Hz , 4H, ArH), 7.16 - 7.20 (m, 7H, ArH), 7.38 (t, J =
13
7.2, Hz, 3H, ArH). C NMR (75.4 MHz, CDCl3) δ: 15.7 (CH3), 30.2 (3xCH3), 30.3 (3xCH3), 30.4
(3xCH3), 33.4, 33.5, 33.6, 117.0 (C), 118.4, 123.8, 123.8, 124.2 (CH), 125.9, 126.1 (C), 128.3,
128.4, 128.7 130.4 (CH),135.7, 136.0, 136.5, 142.9, 146.3, 148.8, 149.3, 149.9, 150.6 (C), 160.2
(CO). IR (KBr, cm-1): v 3030 (w), 2959 (s), 2903, 2865 (w), 1719 (s), 1609, 1604, 1564, 1557,
1547, 1505 (w). GC-MS (EI, 70 eV): m/z (%) = 556 ([M]+, 100), 542 (18), 541 (49), 385 (11), 251

26
(18), 149 (18), 71 (10). HRMS (EI, 70 eV) calcd for C40H44O2 [M]+: 556.33358; found:
556.33339.
4.1.7.12. 3,6,7-Tris(3,4-dimethylphenyl)-4-methyl-2H-chromen-2-one (12m)
From 3,4-dimethylphenylboronic acid (6m) (61 mg). Yield: 37 g (60%) as a white solid, mp: 171-
o
1
172 C. H NMR (300 MHz, CDCl3) δ: 2.11 (s, 3H, CH3), 2.13 (s, 6H, 2xCH3), 2.16 (s, 6H,
2xCH3), 2.23 (s, 6H, 2xCH3), 6.75 (br. s, 2H, ArH) 6.87 - 7.01 (m, 5H, ArH), 7.16 (t, J = 7.4, Hz,
13
2H, ArH), 7.31 (s, 1H, ArH), 7.53 (s, 1H, ArH). C NMR (75.4 MHz, CDCl3) δ: 15.5 (2xCH3),
18.3 (2xCH3), 18.6 (2xCH3), 18.7 (CH3), 28.6 (C), 117.1 (CH), 118.3 (C), 125.9, 126.1, 126.2,
126.3, 126.4, 128.2, 128.6, 129.7, 129.8, 1390.0 (CH), 131.2, 134.1, 134.6, 135.2, 135.3, 135.5,
135.6, 136.0, 126.3, 137.1, 142.9, 146.2, 149.5 (C), 160.3 (CO). IR (KBr, cm-1): v 2961, 2919, 2854
(w), 1713 (s), 1609 (m), 1573, 1568, 1549, 1503, 1484 (w). GC-MS (EI, 70 eV): m/z (%) = 472
([M]+, 100), 471 (26), 457 (10), 445 (17), 443 (11), 429 (13), 414 (11), 207 (16). HRMS (EI, 70
eV) calcd for C34H32O2 [M]+: 472.23968; found: 472.23921.
4.1.7.13. 3,6,7-Tris(4-isopropylphenyl)-4-methyl-2H-chromen-2-one (12n)
From 4-isopropylphenylboronic acid (6n) (66 mg). Yield: 47 mg (70%) as a white solid, mp: 120-
o
1
122 C. H NMR (300 MHz, CDCl3) δ: 1.14 (s, 6H, 2xCH3), 1.16 (s, 6H, 2xCH3), 1.22 (s, 6H,
2xCH3), 2.25 (s, H, CH3), 2.27 - 2.91 (m, 3H, 3xCH), 6.96 - 7.01 (m, 8H, ArH), 7.15 (d, J = 8.4,
Hz, 2H, ArH), 7.24 (d, J = 8.2, Hz, 2H, ArH), 7.33 (s, 1H, ArH), 7.56 (s, 1H, ArH).13C NMR (75.4
MHz, CDCl3) δ: 15.6 (2xCH3), 22.8 (2xCH3), 22.9 (2xCH3), 24.7 (CH3), 32.6, 32.7, 32,9 (CH),
117.0 (C), 118.4, 124.7 (CH), 125.0, 125.4 (C), 126.0, 126.1, 128.3, 128.5, 128.9, 130.7 (CH)
136.1, 136.2, 136.9, 142.9, 146.3, 146.5, 147.1, 147.6, 150.6 (C), 160.3 (CO). IR (KBr, cm-1): v
3064, 3041, 3024 (w), 2957 (s), 2924, 2865 (w), 1724 (s), 1613, 1604 (m), 1568, 1551, 1510, 1506,
1484 (w). GC-MS (EI, 70 eV): m/z (%) = 514 ([M]+, 100), 500 (10), 499 (17),
4.1.7.14. 3,6,7-Tris(4-isopropoxyphenyl)-4-methyl-2H-chromen-2-one (12o)
From 4-isopropoxyphenylboronic acid (6o) (73 mg). Yield: 57 mg (77%) as a white solid, mp: 210-
211 oC. 1H NMR (300 MHz, CDCl3) δ: 1.28 (q, J = 7.4 Hz, 18H, 6xCH3), 2.28 (s, 3H, CH3), 4.38 -
4.59 (m, 3H, 3xOCH), 6.64 - 6.72 (m, 4H, ArH), 6.97 (d, J = 8.4 Hz, 3H, ArH), 6.99 (dd, J = 1.7,
13
8.2 Hz, 4H, ArH), 7.18 (d, J = 8.3 Hz, 2H, ArH), 7.30 (s, 1H, ArH). C NMR (75.4 MHz, CDCl3)
δ: 15.6 (2xCH3), 21.0 (2xCH3), 21.1 (2xCH3), 23.7 (CH3), 67.2, 68.8, 68.8 (OCH), 114.4, 114.5,
114.6, 116.8, 118.3 (CH), 125.3, 125.7 (C), 129.8, 129.9, 130.4 (CH), 130.9, 131.7, 135.6, 142.4,
146.1, 150.5, 150.6, 155.8, 156.2, 156.7 (C), 160.4 (CO). IR (KBr, cm-1) : v 3062, 3030, 2970,

27
2920, 2851 (w), 1721 (s), 1650, 1644, 1633 (w), 1599 (m), 1573 (w), 1518, 1506, 1484, 1463, 1455
(w). GC-MS (EI, 70 eV): m/z (%) = 562 ([M]+, 100), 520 (10), 478 (10), 473 (27), 436 (93), 435
(19), 408 (24), 407 (14). HRMS (EI, 70 eV) calcd for C37H38O2 [M]+: 562.27138; found:
562.27101.
4.1.7.15. 3,6,7-Tris(4-ethylphenyl)-4-methyl-2H-chromen-2-one (12p)
From 4-ethylphenylboronic acid (6p) (61 mg). Yield: 46 mg (75%) as a white solid, mp: 134-135
oC.1H NMR (300 MHz, CDCl3) δ: 1.11 - 1.23 (m, 9H, 3xCH3), 2.26 (s, 3H, CH3), 2.50 - 2.61 (m,
6H, 3xCH2), 6.68 - 6.71 (m, 4H, ArH), 6.77 (d, J = 8.6, Hz, 2H, ArH), 6.87 (dd, J = 1.6, 8.6 Hz,
4H, ArH), 7.13 (d, J = 8.6, Hz, 3H, ArH), 7.51 (s, 1H, ArH). 13C NMR (75.4 MHz, CDCl3) δ: 15.3,
15.4, 15.5, 16.6 (CH3), 28.4, 28.6, 28.7 (CH2), 118.1, 119.5, 127.1 (CH), 127.2, 127.6 (C), 127.9,
129.6, 129.7, 130.1, 131.7 (CH), 137.0, 137.1, 137.8, 142.9, 143.4, 143.9, 144.2, 147.3, 151.7,
152.8, (C), 161.2 (CO). IR (KBr, cm-1): v 3407, 3071, 3024, 2962, 2927, 2871, 2854 (w), 1722 (s),
1613, 1604 (m), 1573, 1568, 1556, 1552 (w). GC-MS (EI, 70 eV): m/z (%) = 472 ([M]+, 100), 444
(13), 443 (12). HRMS (EI, 70 eV) calcd for C34H32O2 [M]+: 472.23968; found: 472.23912.
4.2. Crystal structure determination of 5, 7e and 8b. Data were collected on a Bruker APEX II
Duo diffractometer.The structure was solved by Direct Methods andrefined by full-matrix least-
squares procedures on F2 withthe SHELXTL software package [-]. Hydrogen atoms wereplaced in
idealized positions and included as constrainedinto the refinement while all other atoms were
refined withanisotropic displacement parameters.
4.3. In vitro anti-HIV assay. Evaluation of the antiviral activity of the compounds 6-15 and 16-19
against HIV-1 strain IIIB and HIV-2 strain (ROD) in MT-4 cells was performed using the MTT
assay as previously described39,40. Briefly, stock solutions (10 x final concentration) of test
compounds were added in 25 µL volumes to two series of triplicate wells so as to allow
simultaneous evaluation of their effects on mock-and HIV-infected cells at the beginning of each
experiment. Serial 5-fold dilutions of test compounds were made directly in flat-bottomed 96-well
microtiter trays using a Biomek 3000 robot (Beckman instruments). Untreated control HIV-and
mock-infected cell samples were included for each sample. HIV-1(IIIB)43 or HIV-2 (ROD)44 stock
(50 µL) at 100-300 CCID50 (50% cell culture infectious dose) or culture medium was added to
either the infected or mock-infected wells of the microtiter tray. Mock-infected cells were used to
evaluate the effect of test compound on uninfected cells in order to assess the cytotoxicity of the test
compound. Exponentially growing MT-4 cells45 were centrifuged for 5 min at 1,000 rpm and the
supernatant was discarded. The MT-4 cells were resuspended at 6 x 105 cells/mL and 50 µL

28
volumes were transferred to the microtiter tray wells. Five days after infection, the viability of
mock-and HIV-infected cells was examined spectrophotometrically by the MTT assay.
Acknowledgements
We thank Prof. C. Pannecouque of Rega Institute for Medical Research, Katholieke Universiteit,
Leuven, Belgium, for the anti-HIV screening. Financial support by the DAAD (scholarships for A.
M. H.) and by the State of Iraq is gratefully acknowledged.
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