Chemoselective Suzuki-Miyaura reactions of 4-trifluoromethylsulfonyloxy-6- bromocoumarin

Article abstract of DOI:10.1016/j.tetlet.2012.03.108

Suzuki-Miyaura reactions of 4-trifluoromethylsulfonyloxy-6-bromocoumarin provide a convenient access to arylated coumarins. The reactions proceed with excellent chemoselectivity in favour of position 4.

Full text of DOI:10.1016/j.tetlet.2012.03.108

Tetrahedron Letters 53 (2012) 3206–3209
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Tetrahedron Letters
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Chemoselective Suzuki–Miyaura reactions of 4-trifluoromethylsulfonyloxy-6-
bromocoumarin
a
⇑
Omer A. Akrawi , Gergo Z. Nagy a,b, Tamás Patonay b, Alexander Villinger a, Peter Langer a,c,
}
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1, Hungary
c Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Suzuki–Miyaura reactions of 4-trifluoromethylsulfonyloxy-6-bromocoumarin provide a convenient access
to arylated coumarins. The reactions proceed with excellent chemoselectivity in favour of position 4.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 March 2012
Revised 22 March 2012
Accepted 26 March 2012
Available online 20 April 2012
Keywords:
Coumarins
Chemoselectivity
Palladium
Catalysis
Suzuki–Miyaura reaction
Coumarin (2H-1-benzopyran-2-one) represents a privileged
oxygen heterocycle which is widely distributed throughout the
plant kingdom.1 Among naturally occurring coumarins, 4-aryl-
coumarins (neoflavones) constitute a subgroup of flavonoids found
in plants of the families Guttiferae, Passifloraceae, Leguminosae and
Rubiaceae (1a) (Scheme 1).2–4 Since natural and synthetic neoflav-
ones exhibit a broad range of pharmacological activities5, much
effort has been devoted to their synthesis6 and isolation.7 4-Aryl-
coumarins have been reported to show anti-HIV,8 anti-HCV (hepa-
titis C virus),9 antimalarial,10 antibacterial,11 and cytotoxic activity.
Examples include both natural products (e.g., 1b)12 and synthetic
molecules (e.g., 1c,d).13 4-Arylcoumarin analogues of the stilbene
combretastatin A-4 (2) have been reported to exhibit potent cyto-
toxic activity against human leukemia CEM cell lines. Recently, 6-
arylcoumarins received considerable attention, because of their
pharmacological and photophysical properties. Some derivatives
have been used as fluorescent sensors (e.g., 3)14 and others exhibit
potent progesterone antagonist activity (e.g., 4).15
phoranylidene)acetate18 or by cyclization of phenyl 3-arylpropio-
nates in the presence of HSO3F or AlBr3.19 4-Arylcoumarins have
R1
MeO
R2
O
O
MeO
MeO
OMe
OMe
OH
R3
OMe
OMe
1a R1 = OH, R2 = R3 = H Exostemin
1b R1 = R2 = R3 = H
2
1c R1 = R2 = H, R3 = OH
1
2
3
,
1d R = H, R = OMe, R = OH
NC
Me
Classically, 4-arylcoumarins have been prepared from phenols
by condensation with carbonyl compounds (Pechmann or Perkin
reactions)16 or by Kostanecki acylation of 2-hydroxybenzophenon-
es with acid anhydrides or chlorides followed by base-induced
ring-closure.17 In addition, 4-arylcoumarins are available by Wittig
olefination of 2-hydroxybenzophenone with ethyl (triphenylphos-
O
O
N
X
N
O
O
N
O
O
X= H,OH,NH2
4
3
⇑
Corresponding author. Fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Pharmacologically relevant arylated coumarins 1, 3, and 4 and stilbene
combretastatin A-4 (2).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.108

O. A. Akrawi et al. / Tetrahedron Letters 53 (2012) 3206–3209
3207
been synthesized by palladium, nickel or rhodium catalyzed reac-
tions of 4-tosyloxy-, 4-trifluormethanesulfonyloxy-, and 4-(dieth-
ylphosphonyloxy)coumarins or of 4-(coumarinyl)zinc bromide.20–
25 Other methods have been also reported to introduce aryl groups
at position 4 of coumarins. This includes a domino Heck-cycliza-
tion process between cinnamates with aryl halides26 or the Cu-cat-
alyzed hydroarylation of phenylpropiolates with arylboronic
acids.27
1).34,35 Both electron rich and poor arylboronic acids could be suc-
cessfully employed.
The Suzuki–Miyaura reaction of 2 with one equivalent of
arylboronic acids afforded the 4-aryl-6-bromocoumarins 5a–g in
60–88% yield (Scheme 4, Table 2).36,37 The reaction proceeds by
Table 2
The synthesis of 6-arylated coumarins has only been scarcely
reported. Examples include classic transformations28–30 and palla-
dium-catalyzed cross coupling reactions.14,31,32 Herein, we report a
new and convenient synthesis of arylated coumarins (neoflavones)
by what are, to the best of our knowledge, the first Suzuki–Miyaura
reactions of 4-trifluoromethylsulfonyloxy-6-bromocoumarin. The
reactions proceed with excellent chemoselectivity in favour of po-
sition 4.
Synthesis of 5a–g
3
5
Ar
% (5)a
a
c
d
e
f
a
b
c
d
e
f
4-(MeO)C6H4
4-tBuC6H4
3,5-Me2C6H3
4-ClC6H4
4-FC6H4
2-(MeO)C6H4
3-ClC6H4
87
95
81
77
70
79
83
g
h
g
The reaction of 4-hydroxy-6-bromocoumarin (1) with triflic
anhydride afforded the triflate 2 (Scheme 2).33
a
Yields of isolated compounds.
The Suzuki–Miyaura reaction of 4-trifluoromethyl-sulfonyloxy-
6-bromocoumarin (2) with arylboronic acids 3a–f (2.2 equiv) affor-
ded the 4,6-diarylcoumarins 4a–f in 60–88% yield (Scheme 3, Table
OTf
OH
Br
Br
i
O
O
O
O
2
1
Scheme 2. Synthesis of
2
Reagents and Conditions: (i),
1
(1.0 equiv), Tf2O
(1.3 equiv), Et3N (2.0 equiv), CH2Cl2, À15 °C, 2 h.
Ar
OTf
ArB(OH)2
3a-f
Ar
Br
i
O
O
O
O
Figure 1. Crystal structure of compound 5b.
4a-f
2
Scheme 3. Synthesis of 4a–f. Reagents and Conditions: (i), 2 (1.0 equiv), ArB(OH)2
(2.2 equiv), Pd(PPh3)4 (6 mol %), K3PO4 (3.0 equiv), dioxane, 90 °C, 10 h.
Table 1
Synthesis of 4,6-diarylcoumarins 4a–f
3,4
Ar
% (4)a
a
b
c
d
e
f
4-(MeO)C6H4
4-EtC6H4
4-tBuC6H4
3,5-Me2C6H3
4-ClC6H4
86
88
60
75
82
71
4-FC6H4
a
Yields of isolated compounds.
OTf
O
Ar
ArB(OH)2
3a,c-h
Br
Br
i
O
O
O
2
5a-g
Scheme 4. Synthesis of 5a–g. Reagents and Conditions: (i) 2 (1.0 equiv), ArB(OH)2
(1.1 equiv), Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), toluene/dioxane (9:1), 65 °C, 5 h.
Figure 2. Crystal structure of compound 5c.

3208
O. A. Akrawi et al. / Tetrahedron Letters 53 (2012) 3206–3209
chemoselective attack onto the triflate group, despite the fact that
it is known that usually bromides are more reactive than triflates
in the Suzuki reaction, due to the formation of a stable boron-bro-
mide bond. The selectivity can be explained by the highly electron
deficient character of position 4 of the coumarin moiety. During
the optimization, it proved to be important to carry out the reac-
tion at lower temperature (65 °C) as compared to the synthesis
of the diarylated coumarins. In addition, the employment of a sol-
vent mixture of toluene and dioxane (instead of pure dioxane)
proved to be advantageous. Again, both electron rich and poor aryl-
boronic acids gave very good yields. The structures of 5b and 5c
were independently confirmed by X-ray crystal structure analyses
(Figs. 1 and 2).38
chemoselective attack onto the triflate group. Both electron rich
and poor arylboronic acids could be successfully employed in the
first or in the second step of the one-pot reaction. During the opti-
mization it again proved to be important to carry out the first step
at 65 instead of 90 °C. A fresh portion of the catalyst had to be
added in the second step in order to obtain good yields. The struc-
ture of 6b was independently confirmed by X-ray crystal structure
analysis (Fig. 3).38
In conclusion, we have reported the first Suzuki–Miyaura reac-
tions of 4-trifluoromethylsulfonyloxy-6-bromo-coumarin. These
reactions provide a convenient access to arylated coumarins. The
reactions proceed with excellent chemoselectivity in favour of po-
sition 4.
The one-pot reaction of 2 with two different arylboronic acids
(sequential addition) afforded the diarylated coumarins 6a–e in
60–88% yield (Scheme 5, Table 3).39,40 The reaction proceeds by
Acknowledgments
Financial support by the DAAD (scholarship for O.A.), by the
DAAD Ostpartnerschaften program (scholarship for G.Z.N.) and by
the State of Mecklenburg-Vorpommern is gratefully acknowledged.
1) Ar1B(OH)2
Ar1
2) Ar2B(OH)2
OTf
Ar2
References and notes
Br
3a,d,e,h,i
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O
O
O
O
2
6a-e
Scheme 5. Synthesis of 6a–e. Reagents and Conditions: (i), 2 (1.0 equiv), Ar1B(OH)2
(1.0 equiv), Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), dioxane/toluene (9:1), 65 °C, 8 h;
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Table 3
Synthesis of 6a–e
3
6
Ar1
Ar2
% (6)a
a,e
a,h
d,a
e,a
e,i
a
b
c
d
e
4-(MeO)C6H4
4-(MeO)C6H4
3,5-Me2C6H3
4-ClC6H4
4-ClC6H4
3-ClC6H4
4-(MeO)C6H4
4-(MeO)C6H4
3-FC6H4
78
81
70
63
85
4-ClC6H4
a
Yields of isolated compounds.
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Figure 3. Crystal structure of 6b.

O. A. Akrawi et al. / Tetrahedron Letters 53 (2012) 3206–3209
3209
33. Synthesis of 6-bromo-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (2). Tf2O
solution of (0.45 g,
162 °C. Reaction temperature: 65 °C for 5 h. 1H NMR (300 MHz, CDCl3): d = 1.32
(s, 9H, 3CH3), 6.31 (s, 1H, C@CH), 7.21 (d, 1H, J = 8.7 Hz, ArH), 7.30 (d, 2H,
J = 8.4 Hz, ArH), 7.48 (d, 2H, J = 8.5 Hz, ArH), 7.55 (dd, 1H, J = 2.3, 8.7 Hz, ArH),
7.59 (d, 1H, J = 2.3 Hz, ArH). 13C NMR (62.9 MHz, CDCl3): d = 31.2 (3CH3), 34.9
(C), 115.8 (CH), 116.9 (C), 119.0 (CH), 120.7 (C), 126.1, 128.1, 129.4 (CH), 131.5
(C), 134.6 (CH), 153.1, 153.4, 154.5 (C), 160.1 (CO). IR (KBr): v = 3117, 3084,
3068, 3055, 2961, 2901, 2866, 1926 (w), 1721 (s), 1612, 1593, 1551, 1510 (m),
1501 (w), 1467, 1462, 1406 (m), 1305 (w), 1259 (m), 1246, 1199 (s), 1174,
1130, 1104, 1071, 1020, 952, 944 (w) 931 (s), 888, 870, 847 (m), 832, 826 (s),
799, 757, 746, 734, 710, 666, 659, 626 (w), 603 (s), 563, 545, 530 (w) cmÀ1. GC–
MS (EI, 70 eV): m/z (%) = 358 ([M, 81Br]+, 37), 356 ([M, 79Br]+, 37), 343 (98), 341
(99), 315 (15), 313 (14), 281 (10), 253 (09), 234 (13), 208 (21), 207 (100), 191
(0.41 mL, 2.43 mmol) was added at À15 °C to
a
1
1.87 mmol) and triethylamine (0.5 mL, 3.74 mmol) in CH2Cl2 (15 mL) and the
reaction mixture was stirred at the same temperature under argon atmosphere
for 2 h. To the reaction mixture was added toluene (10 mL) and the solution
was concentrated in vacuo. The residue was chromatographed (EtOAc/
Heptanes: 9/300) without aqueous work up to yield
2 as a white solid
(0.42 g, 60%), mp 110–112 °C. 1H NMR (300 MHz, CDCl3): d = 6.47 (s, 1H,
C@CH), 7.25 (d, 1H, J = 8.9 Hz, ArH), 7.69–7.73 (m, 2H, ArH). 19F NMR
(282.4 MHz, CDCl3): d = À72.5. 13C NMR (75.5 MHz, CDCl3): d = 105.5 (CH),
114.4, 117.1 (C), 118.1 (CH), 118.3 (q, JC,F = 320.6 Hz, CF3), 124.0, 136.0 (CH),
151.2, 154.8, (C), 157.8 (CO). IR (KBr): v = 3119, 3087, 3054, 2918, (w), 1727 (s),
1628, 1599, 1562, 1473 (m), 1436, 1418, 1349 (s), 1307, 1266 (w), 1250 (m),
1213, 1184 (s), 1170 (m), 1041 (s), 937 (w), 876, 852, 825, 826, 808, 788, 759
(m), 741, 712, 696, 653, 633 (w) cmÀ1. GC–MS (EI, 70 eV): m/z (%) = 374 ([M,
81Br]+, 100), 372 ([M, 79Br]+, 97), 282 (29), 280 (29), 213 (51), 211 (53). HRMS
(EI, 70 eV): calcd for C10H4BrF3O5S [M, 79Br]+: 371.89094; found 371.89097,
calcd for C10H4BrF3O5S ([M, 81Br]+: 373.88890; found 373.88890.
(17), 189 (17). HRMS (ESI-TOF/MS): calcd for
C
19H18BrO2 [M+H, 79Br]+:
357.04847; found 357.04926, calcd for C19H18BrO2 [M+H, 81Br]+: 359.04663;
found 359.04746.
38. CCDC 875642–875644 contains all crystallographic details of this publication
and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
can be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax: +44 1223 336 033; or
deposit@ccdc.cam.ac.uk.
34. General procedure A for the synthesis of 4a–f: A 1,4-dioxane solution (2 mL) of 2
(0.13 mmol), arylboronic acid (2.2 equiv), K3PO4 (3.0 equiv) and Pd(PPh3)4
(6 mol %) was heated at 90 °C for 10 h under argon atmosphere. After cooling to
20 °C, H2O was added and the reaction mixture was extracted with CH2Cl2
(3 Â 25 mL). The organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. The residue was purified by column chromatography (EtOAc/
Heptanes: 6/300).
39. General procedure C for one-pot unsymmetrical 4,6-diarylcoumarins 6a–e. A
toluene/1,4-dioxane solution (9:1: 2 mL) of 6-bromo-2-oxo-2H-chromen-4-yl
trifluoromethanesulfonate
2
(0.134 mmol), Ar1B(OH)2 (1.0 equiv), K3PO4
(1.5 equiv) and Pd(PPh3)4 (3 mol %) was heated at 65 °C for 8 h under argon
atmosphere. After cooling to 20 °C, Ar2B(OH)2 (1.3 equiv), Pd(PPh3)4 (6 mol %),
dioxane (1 mL) were added and reaction mixture was heated at 90°C for
further 14 h. Reaction mixture was cooled again to 20 °C, H2O was added and
the reaction mixture was extracted with CH2Cl2 (3 Â 25 mL), organic layers
were dried (Na2SO4), filtered and then concentrated in vacuo. The residue was
purified by column chromatography (EtOAc/Heptanes: 6:300).
35. 4,6-Bis(4-ethylphenyl)-2H-chromen-2-one (4b). Starting with
2
(50 mg,
0.134 mmol), arylboronic acid (44 mg, 0.29 mmol), K3PO4 (85 mg, 0.4 mmol)
and Pd(PPh3)4 (9 mg, 6 mol %), 6b was prepared as a yellow highly viscous oil
(42 mg, 88%): Reaction temperature: 90 °C for 10 h. 1H NMR (300 MHz, CDCl3):
d = 1.18 (t, 3H, J = 7.6 Hz, CH3), 1.24 (t, 3H, J = 7.6 Hz, CH3), 2.60 (q, 2H,
J = 7.6 Hz, CH2), 2.67 (q, 2H, J = 7.6 Hz, CH2), 6.32 (s, 1H, C@CH), 7.16–7.19 (m,
2H, ArH), 7.27–7.35 (m, 6H, ArH), 7.38 (d, 1H, J = 8.5 Hz, ArH), 7.63 (d, 1H, J =
2.1 Hz, ArH), 7.66 (dd, 1H, J = 2.1, 8.5 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
d = 15.3, 15.6 (CH3), 28.5, 28.7 (CH2), 115.2, 117.6 (CH), 119.2 (C), 125.1, 127.1,
128.2, 128.4, 128.5, 130.7 (CH), 132.7, 137.1, 137.5, 143.9, 146.2, 153.5, 155.8
(C), 160.9 (CO). IR (KBr): v = 3024, 2962, 2928, 2871 (w), 1721 (s), 1613, 1569,
1558, 1509, 1481 (m), 1454 (w), 1428, 1413 (m), 1400 (w), 1360, 1266, 1257,
1177 (m), 1141 (w), 1121 (m), 1060, 1050, 1018, 953 (w), 929 (m), 901, 869
(w), 818 (s), 773, 759, 736, 710, 683, 634, 614, 600, 539, 537 (w) cmÀ1. GC–MS
(EI, 70 eV): m/z (%) = 354 ([M]+, 100), 339 (33), 325 (13), 311 (24), 296 (10), 252
(07). HRMS (EI, 70 eV): calcd for C25H22O2 [M]+: 354.16143; found 354.16181.
36. General procedure B for the synthesis of 5a–g. A toluene/1,4-dioxane solution
(9:1, 2 mL) of 2 (0.13 mmol), arylboronic acid (1.1 equiv), K3PO4 (1.5 equiv) and
Pd(PPh3)4 (3 mol %) was heated at 65 °C for 5 h under argon atmosphere. After
cooling to 20 °C, CH2Cl2 (20 mL) was added and the mixture was filtered and
the filtrate was concentrated in vacuo. The residue was purified by column
chromatography (EtOAc/Heptanes: 3:300).
40. 6-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2H-chromen-2-one (6a) Starting with
2 (50 mg, 0.13 mmol), 4-methoxyphenylboronic acid as Ar1B(OH)2 (20 mg,
0.13 mmol), K3PO4 (43 mg, 0.2 mmol), Pd(PPh3)4 (4.5 mg, 3 mol %) and 4-
chlorophenylboronic acid as Ar2B(OH)2 (27 mg, 0.17 mmol), 6b was prepared
according to general procedure C as an off-white solid (38 mg, 78%), mp 154–
156 °C. Conditions: 65 °C for 8 h (first step) and 90 °C for 14 h (second step). 1
H
NMR (300 MHz, CDCl3): d = 3.82 (s, 3H, OCH3), 6.31 (s, 1H, C@CH), 6.98 (d, 2H,
J = 8.8 Hz, ArH), 7.30–7.33 (m, 4H, ArH), 7.35–7.42 (m, 3H, ArH), 7.61–7.66 (m,
2H, ArH). 13C NMR (75.5 MHz, CDCl3): d = 55.5 (OCH3), 114.5, 115.1, 117.9 (CH),
119.5 (C), 125.2 (CH), 127.3 (C), 128.3, 129.1, 129.9, 130.5 (CH), 133.8, 136.2,
138.2, 153.8, 155.2, 160.7 (C), 161.0 (CO). IR (KBr): v = 3116, 3096, 2964, 2928,
2897, 2834, 1947, 1887, 1855 (w), 1730 (s), 1605 (m), 1573, 1564, 1557 (w),
1512, 1477, 1460, 1424 (m), 1389 (w), 1358, 1305, 1290 (m), 1259, 1247, 1181,
1173 (s), 1140, 1123, 1114, 1091 (w), 1031, 1008 (m), 974, 948 (w), 925, 893
(m), 840 (s), 824, 815 (w), 800 (s), 781, 758, 736, 729, 706, 674, 649, 636, 626
(w), 603, 584 (m), 567 (w), 547 (m). cmÀ1. GC–MS (EI, 70 eV): m/z (%) = 364
([M, 37Cl]+, 40), 362 ([M, 35Cl]+, 100), 336 (16), 334 (50), 321 (12), 319 (28), 228
(15), 226 (24). HRMS (EI, 70 eV): calcd for C22H15ClO3 [M, 35Cl]+: 362.07042;
found 362.07013, calcd for C22H15ClO3 [M, 37Cl]+:.364.06747; found 364.06794.
37. 6-Bromo-4-(4-(tert-butyl) phenyl)-2H-chromen-2-one (5b). Starting with
2
(50 mg, 0.134 mmol), 5b was prepared as a white solid (45 mg, 95%), mp