Efficient synthesis of arylated coumarins by site-selective Suzuki-Miyaura cross-coupling reactions of the bis(triflate) of 4-methyl-5,7-dihydroxycoumarin

Article abstract of DOI:10.1055/s-0031-1290072

Arylated coumarins were prepared by site-selective Suzuki-Miyaura cross-coupling reactions of the bis(triflate) of 4-methyl-5,7-dihydroxycoumarin. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290072

LETTER
223
Efficient Synthesis of Arylated Coumarins by Site-Selective Suzuki–Miyaura
Cross-Coupling Reactions of the Bis(triflate) of 4-Methyl-5,7-dihydroxy-
coumarin
S
ynthesis of
Aryla
a
tedCoumar
d
ins i Eleya,a Zein Khaddour,a Tamás Patonay,b Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Department of Organic Chemistry, University of Debrecen, 4032 Debrecen, Egyetem tér 1, Hungary
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 13 October 2011
port a new and convenient synthesis of arylated coumarins
by site-selective18,19 Suzuki–Miyaura cross-coupling re-
actions of the bis(triflate) of 4-methyl-5,7-dihydroxycou-
marin. The products reported herein are not readily
available by other methods.
Abstract: Arylated coumarins were prepared by site-selective
Suzuki–Miyaura cross-coupling reactions of the bis(triflate) of 4-
methyl-5,7-dihydroxycoumarin.
Key words: cyclization, domino reaction, 4-chloro-3-formylcou-
marin, biaryl lactones, heterocycles
OH
OH
Coumarin and its derivatives are one of the important
classes of heterocyclic compounds which occur in many
natural products. For example, wedelolactone and other
coumarins were isolated from the roots of Hedysarum
multijugum, which is a plant in Hedysarum Linn. of the
family Leguminosae used as a folk herbal drug in north-
west China.1 Several types of coumarins were isolated
from plants, such as alternariol, umbelliferone (7-hydroxy-
coumarin), and others (Figure 1).2 Coumarin derivatives
are known to possess a wide range of biological activities,
such as anti-HIV, antibiotic, antifungal, antibacterial, an-
tiviral, anticancer, anticlotting, and anticoagulant activi-
ty.3 They are widely used as additives in food, perfumes,
agrochemicals, cosmetics, pharmaceuticals,4 and in the
preparations of insecticides, optical brightening agents,
and dispersed fluorescent and laser dyes.5
OMe
OH
O
OH
OH
HO
O
O
MeO
O
O
alternariol
wedelolactone
Figure 1 Natural products containing a benzo[c]chromen-6-one
subunit
5,7-Dihydroxy-4-methylcoumarin was prepared by
Pechman reaction of phloroglucinol (1,3,5-trihydroxy-
benzene) with ethyl acetoacetate in the presence of poly-
phosphoric acid.20 The reaction of 5,7-dihydroxy-4-
methylcoumarin (1) with triflic anhydride (2.4 equiv) af-
forded the bis(triflate) 2 in 75% yield (Scheme 1).21
OH Me
OTf Me
Coumarins can be synthesized by various methods, such
as Pechmann,6 Perkin,7 Knoevenagel,8 and Wittig reac-
tions.9 Because of its operational simplicity and relatively
inexpensive starting materials, the Pechmann reaction has
been widely used for the synthesis of coumarin and its de-
rivatives. This method involves the reaction of phenols
with b-keto esters in the presence of acidic catalysts.10–15
Transition-metal-catalyzed syntheses of coumarins have
also been reported. Yang et al. reported the synthesis of 4-
substituted coumarins by palladium-catalyzed cross-cou-
pling reactions of 4-tosylcoumarins with terminal acety-
lenes and organozinc reagents.16 A different approach to
substituted coumarins relies on site-selective palladium-
catalyzed cross-coupling reactions. Cross-coupling reac-
tions of 3-bromo-4-trifloxycoumarin or 3-bromo-4-tosyl-
oxycoumarin provide an efficient and facile route for the
synthesis of 3,4-disubstituted coumarins.17 Herein, we re-
i
HO
O
O
TfO
O
O
2 (75%)
1
Scheme 1 Synthesis of 2. Reagents and conditions: (i) 1) 1 (1.0
equiv), Et3N (4.0 equiv), CH2Cl2, 20 °C; 2) Tf2O (2.4 equiv), –78 °C
to 20 °C, 6 h.
The reaction of bis(triflate) 2 with two equivalents of aryl-
boronic acids 3a–g afforded the 5,7-diarylcoumarins 4a–
g in 70–86% yield (Scheme 2, Table 1).22,23 The yields of
the products derived from electron-rich boronic acids
were higher than the yields of the products derived from
electron-poor boronic acids.
The reaction of 2 with one equivalent of arylboronic acids
3a–e,h afforded the 7-aryl-5-(trifluoromethylsulfonyl-
oxy)coumarins 5a–f in 60–80% yield (Scheme 3,
Table 2).22,24 The reactions proceeded with very good site-
selectivity in favor of position 7. The yields of products
derived from electron-rich boronic acids were again high-
SYNLETT 2012, 23, 223–226
x
x.
x
x.
2
0
1
2
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290072; Art ID: B55111ST
© Georg Thieme Verlag Stuttgart · New York

224
N. Eleya et al.
LETTER
and H-8 with the ortho protons of the 3,5-dimethylphenyl
group was observed (Figure 2).
Ar
Me
O
OTf Me
ArB(OH)2
3a–g
i
Ar
O
OTf CH3
TfO
O
O
2
4a–g
Scheme 2 Synthesis of 4a–g. Reagents and conditions: (i) 2 (1.0
equiv), 3a–g (2.0 equiv), K3PO4 (3.0 equiv), Pd(PPh3)4 (6 mol%),
toluene–1,4-dioxane (1:1), 105 °C, 8 h.
H3C
O
O
CH3
Table 1 Synthesis of 4a–g
Figure 2 Important HMBC (single head arrows) and NOESY
(double head arrows) correlations of 5b
Entry
3
4
Ar
Yield of 4 (%)a
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4-MeC6H4
3,5-MeC6H3
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-F3CC6H4
Ph
86
81
83
77
74
70
79
The one-pot reaction of 2 with two different arylboronic
acids (sequential addition) afforded the 5,7-diarylcou-
marins 6a–d in 60–75% yield (Scheme 4, Table 3).22,25
The first attack occurred at position 7. During the optimi-
zation it proved to be again important to carry out the first
step at 70 °C to induce a good site-selectivity.
Ar2 Me
OTf Me
1) Ar1B(OH)2
2) Ar2B(OH)2
3g
a Yields of isolated products.
i
Ar1
O
O
TfO
O
O
2
6a–d
er than the yields of the products derived from electron-
poor boronic acids. During the optimization, it proved to
be important to carry out the reaction at 70 °C instead of
105 °C (as for products 4a–g). In some cases, a small
amount of biscoupled product could be detected in the
product mixture by TLC which could be easily separated
by chromatography.
Scheme 4 Synthesis of 6a–d. Reagents and conditions: (i) 2 (1.0
equiv), 1) Ar1B(OH)2 (1.0 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (3
mol%), toluene, 70 °C, 8 h; 2) Ar2B(OH)2 (1.0 equiv), K3PO4 (1.5
equiv), Pd(PPh3)4 (3 mol%), 1,4-dioxane, 105 °C, 8 h.
Table 3 Synthesis of 6a–d
Entry
3
6
Ar1
Ar2
Yield of 6
The structure of product 5b was elucidated by 2D NMR
spectroscopy (NOESY, COSY, HMBC, HSQC). A diag-
nostic NOESY correlation between hydrogen atoms H-6
(%)a
1
2
3
4
3b,a
3b,c
3a,d
3c,a
6a
6b
6c
6d
3,5-Me2C6H3
3,5-Me2C6H3
4-MeC6H4
4-MeC6H4 70
4-FC6H4
60
62
OTf Me
OTf Me
ArB(OH)2
4-ClC6H4
3a–e,h
4-MeOC6H4
4-MeC6H4 75
i
Ar
O
O
TfO
O
O
2
5a–f
a Yields of isolated products.
Scheme 3 Synthesis of 5a–f. Reagents and conditions: (i) 2 (1.0
equiv), 3a–e,h (1.0 equiv), K3PO4 (1.0 equiv), Pd(PPh3)4 (3 mol%),
toluene, 70 °C, 8 h.
The site-selective formation of products 5 and 6 can be ex-
plained by steric effects. The first attack occurs at the ster-
ically less hindered position 7 (Figure 3). Position 5 and 7
can be considered similar with regard to their electron
density. Therefore, electronic factors are unlikely to play
a role.
Table 2 Synthesis of 5a–f
Entry
3
5
Ar
Yield of 5 (%)a
1
2
3
4
5
6
3a
3b
3c
3d
3e
3h
5a
5b
5c
5d
5e
5f
4-MeC6H4
3,5-MeC6H3
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-EtC6H4
80
77
75
60
63
70
sterically
more hindered
OTf Me
TfO
O
O
2
sterically
less hindered
Figure 3 Possible explanation for the site-selectivity of the Suzuki
reactions of 2
a Yields of isolated products.
Synlett 2012, 23, 223–226
© Thieme Stuttgart · New York

LETTER
Synthesis of Arylated Coumarins
225
(19) For Suzuki–Miyaura reactions of bis(triflates) of benzene
derivatives and other arenes, see for example: (a) Takeuchi,
M.; Tuihiji, T.; Nishimura, J. J. Org. Chem. 1993, 58, 7388.
(b) Sugiura, H.; Nigorikawa, Y.; Saiki, Y.; Nakamura, K.;
Yamaguchi, M. J. Am. Chem. Soc. 2004, 126, 14858.
(c) Akimoto, K.; Suzuki, H.; Kondo, Y.; Endo, K.; Akiba,
U.; Aoyama, Y.; Hamada, F. Tetrahedron 2007, 63, 6887.
(d) Akimoto, K.; Kondo, Y.; Endo, K.; Yamada, M.;
Aoyama, Y.; Hamada, F. Tetrahedron Lett. 2008, 49, 7361.
(e) Hosokawa, S.; Fumiyama, H.; Fukuda, H.; Fukuda, T.;
Seki, M.; Tatsuta, K. Tetrahedron Lett. 2007, 48, 7305.
(f) Nawaz, M.; Adeel, M.; Ibad, M. F.; Langer, P. Synlett
2009, 2154. (g) Mahal, A.; Villinger, A.; Langer, P. Synlett
2010, 1085. (h) Abid, O.-U.-R.; Ibad, M. F.; Nawaz, M.; Ali,
A.; Sher, M.; Rama, N. H.; Villinger, A.; Langer, P.
Tetrahedron Lett. 2010, 51, 1541. (i) Akrawi, O. A.;
Hussain, M.; Langer, P. Tetrahedron Lett. 2011, 52, 1093.
(j) Nawaz, M.; Khera, R. A.; Malik, I.; Ibad, F. A.; Villinger,
A. M.; Langer, P. Synlett 2010, 979.
In conclusion, we have reported a convenient synthesis of
arylated coumarins by site-selective Suzuki–Miyaura
cross-coupling reactions of the bis(triflate) of 4-methyl-
5,7-dihydroxycoumarin. The selectivity is controlled by
steric effects.
Acknowledgment
Financial support by the DAAD (scholarship for N.E.) and by the
State of Mecklenburg-Vorpommern is gratefully acknowledged.
References and Notes
(1) Wang, W.; Zhao, Y. Y.; Liang, H.; Jia, Q.; Chen, H. B.
J. Nat. Prod. 2006, 69, 876.
(2) (a) Raistrick, H.; Stilkings, C. E.; Thomas, R. Biochemistry
1953, 55, 421. (b) Abaul, J.; Philogene, E.; Bourgeois, P.
J. Nat. Prod. 1994, 57, 846.
(20) Kapil, R. S.; Joshi, S. S. J. Indian Chem. Soc. 1959, 36, 596.
(21) 4-Methyl-2-oxo-2H-chromene-5,7-diyl Bis(trifluoro-
methanesulfonate) (2)
(3) (a) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.;
Furukawa, H.; Takahashi, D.; Koshimizu, K.; Ohigashi, H.
Bioorg. Med. Chem. Lett. 2000, 10, 59. (b) Xia, Y.; Yang,
Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.;
Lee, K.-H. J. Med. Chem. 2001, 44, 3932. (c) Itoigawa, M.;
Ito, C.; Tan, H. T.-W.; Kuchide, M.; Tokuda, H.; Nishino,
H.; Furukawa, H. Cancer Lett. 2001, 169, 15.
(d) Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M.
Tetrahedron Lett. 2006, 47, 3755. (e) Yamamoto, Y.;
Kurazono, M. Bioorg. Med. Chem. Lett. 2007, 17, 1626.
(f) Kayser, O.; Kolodziej, H. Planta Med. 1997, 63, 508.
(g) Wang, C. J.; Hsieh, Y. J.; Chu, C. Y.; Lin, Y. L.; Tseng,
T. H. Cancer Lett. 2002, 183, 163.
(4) O’Kennedy, R.; Thornes, R. D. Coumarins: Biology,
Applications, and Mode of Action; John Wiley and Sons:
Chichester, 1997.
(5) Murray, R. D. H.; Méndez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry, and Biochemistry;
Wiley: New York, 1982.
To a solution of 5,7-dihydroxycoumarin (1, 0.5 g, 2.60
mmol) in CH2Cl2 (30 mL) was added Et3N (0.36 mL, 10.4
mmol) at r.t. under an argon atmosphere. After 10 min, Tf2O
(1.0 mL, 6.2 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, heptanes–EtOAc = 10:1) without aqueous workup
to give 2 as a colourless solid (0.9 g, 75%), mp 131–132 °C.
1H NMR (300 MHz, CDCl3): d = 2.56 (d, J = 1.3 Hz, CH3),
6.32 (d, J = 1.3 Hz, 1 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.28 (d,
J = 2.5 Hz, 1 H). 13C NMR (75.46 MHz, CDCl3): d = 21.9
(CH3), 110.0, 110.6 (CH), 113.1 (C), 117.3 (q, JF,C = 320.0
Hz, CF3), 117.6 (q, JF,C = 320.0 Hz, CF3), 118.1 (CH), 144.8,
147.9, 148.5, 154.5 (C), 156.4 (CO). 19F NMR (282.4,
MHz): d = –72.6, –72.2. IR (KBr): n = 3181, 3111, 3084,
3065, 3020, 2935, 1795 (w), 1728, 1615 (s), 1566, 1547,
1530, 1476, 1454 (w), 1434, 1415 (s), 1379, 1359 (m), 1326,
1285 (w), 1244, 1235, 1218, 1202, 1132, 1124 (s), 1071 (m),
1052, 1006, 993 (s), 898, 878, 870 (m), 834, 796 (s), 771 (w),
759, 730, 707, 659 (m), 610, 589, 579 (s), 550, 538 (w) cm–1.
GC-MS (EI, 70 eV): m/z (%) = 456 (100) [M]+, 323 (25),
295 (79), 231 (47), 203 (22), 162 (30), 134 (37). HRMS (EI,
70 eV): m/z calcd for C12H6F6O8S2 [M]+: 455.94028; found:
455.941352.
(6) Sethna, S. M.; Phadke, R. Org. React. 1953, 7, 1.
(7) Donnelly, B. J.; Donnelly, D. M. X.; Sullivan, A. M. O.
Tetrahedron 1968, 24, 2617.
(8) (a) Jones, G. Org. React. 1967, 15, 204. (b) Bigi, F.;
Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999, 64,
1033.
(9) Yavari, I.; Hekmat-Shoar, R.; Zonuzi, A. Tetrahedron Lett.
1998, 39, 2391.
(10) Nadkarni, A. J.; Kudav, N. A. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1981, 20, 719.
(11) Bose, D. S.; Rudradas, A. P.; Babu, M. H. Tetrahedron Lett.
(22) General Procedure for Suzuki–Miyaura Reactions
A solution of K3PO4 (1.5 equiv per cross-coupling),
Pd(PPh3)4 (3 mol% per cross-coupling step), and arylboronic
acid 3 (1.1 equiv per cross-coupling) in the solvent indicated
was stirred at the indicated temperature and for the indicated
time. After cooling to 20 °C, distilled H2O was added. The
organic and the aqueous layers were separated, and the latter
was extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (flash silica gel, heptanes–EtOAc).
(23) 5,7-Bis(4-methoxyphenyl)-4-methyl-2H-chromen-2-one
(4c)
2002, 43, 9195.
(12) Smitha, G.; Reddy, C. S. Synth. Commun. 2004, 34, 3997.
(13) Wang, L.; Xia, J.; Tian, H.; Qian, C.; Ma, Y. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2003, 42,
2097.
(14) Woods, L. L.; Sapp, J. J. Org. Chem. 1962, 27, 3703.
(15) Zagotto, G.; Gia, O.; Baccichetti, F.; Uriarte, E.; Palumbo,
M. Photochem. Photobiol. 1993, 58, 486.
(16) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642.
(17) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72,
7279.
(18) For reviews of site-selective, palladium(0)-catalyzed cross-
coupling reactions, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Schnürch, M.; Flasik, R.;
Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
J. Org. Chem. 2006, 3283. (c) Wang, R.; Manabe, K.
Synthesis 2009, 1405.
Starting with 2 (80 mg, 0.18 mmol), 3c (48 mg, 0.35 mmol),
Pd(PPh3)4 (6 mg, 3 mol%, 0.005 mmol), K3PO4 (111 mg,
0.525 mmol), and a toluene–1,4-dioxane mixture (1:1, 4
mL), 4c was isolated by chromatography (flash silica gel,
heptanes–EtOAc = 10:1) as a colourless solid (54 mg, 83%),
mp 132–134 °C. 1H NMR (300 MHz, CDCl3): d = 1.71 (d,
J = 1.2 Hz, 3 H, CH3), 3.76 (s, 3 H, OCH3), 3.79 (s, 3 H,
© Thieme Stuttgart · New York
Synlett 2012, 23, 223–226

226
N. Eleya et al.
LETTER
OCH3), 6.05 (d, J = 1.2 Hz, 1 H), 6.88 (m, 4 H), 7.14 (d,
J = 8.7 Hz, 2 H), 7.22 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 2.0
Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H). 13C NMR (75.46 MHz,
CDCl3): d = 24.0 (CH3), 55.3, 55.4 (OCH3), 113.4, 113.7,
114.5, 116.1 (CH), 117.0 (C), 126.2, 128.2, 130.3 (CH),
130.9, 134.3, 141.7, 142.5 153.9, 155.0, 159.4, 160.1 (C),
160.6 (CO). IR (KBr): n = 3040, 2998, 2964, 2931, 2906,
2834, 1900, 1864, 1790 (w), 1722, 1715, 1597 (s), 1557,
1538 (m), 1514 (s), 1462, 1435 (m), 1514 (s), 1462, 1435
(m), 1393, 1378, 1351, 1309 (m), 1292, 1240 (s), 1195,
1177, 1138, 1110 (m), 1085 (w), 1032 (s), 1019 (m), 965,
942, 914, 894, 873, 849 (w), 830 (s), 793, 774, 738, 730, 718
(w), 706 (m), 672, 649, 629, 612, 603, 585, 546 (w). GC-MS
(EI, 70 eV): m/z (%) = 372 (100) [M]+, 371 (13), 344 (17),
329 (12). HRMS (EI, 70 eV): m/z calcd for C24H20O4 [M]+:
372.13561; found: 372.135278.
1206, 1179, 1133 (s), 1089 (m), 1039, 926, 880, 869, 813,
787, 764, 758 (s), 735, 712, 703, 690 (w), 656 (m), 640, 633,
617 (w), 601, 574 (m), 548, 539 (w) cm–1. GC-MS (EI, 70
eV): m/z (%) = 398 (100) [M]+, 265 (16), 238 (17), 237 (85),
209 (34), 165 (32). HRMS (EI, 70 eV): m/z calcd for
C18H13F3O5S [M]+: 398.04303; found: 398.04309.
(25) 7-(4-Methoxyphenyl)-4-methyl-5-(p-tolyl)-2H-chromen-
2-one (6c)
The reaction was carried out in a one-pot procedure with
sequential addition of the boronic acids. Catalyst and base
had to be added two times. Starting with 2 (80 mg, 0.175
mmol), 3c (20 mg, 0.175 mmol), Pd(PPh3)4 (6 mg, 3 mol%,
0.005 mmol), K3PO4 (55 mg, 0.26 mmol), and then followed
by toluene (3 mL), 3a (23 mg, 0.18 mmol), Pd(PPh3)4 (6 mg,
3 mol%, 0.005 mmol), K3PO4 (55 mg, 0.26 mmol), and
dioxane (3 mL), 6c was isolated by chromatography (flash
silica gel, heptanes–EtOAc = 10:1) as a colorless solid (47
mg, 75%), mp 256–258 °C. 1H NMR (300 MHz, CDCl3):
d = 1.73 (d, J = 1.2 Hz, 3 H, CH3), 2.32 (s, 3 H, CH3), 3.80
(s, 3 H, OCH3), 6.09 (d, J = 1.2 Hz, 1 H), 6.88 (d, J = 8.7 Hz,
2 H), 7.15–7.20 (m, 4 H), 7.26 (d, J = 2.0 Hz, 1 H), 7.45–
7.49 (m, 3 H). 13C NMR (75.47 MHz, CDCl3): d = 21.1, 24.1
(CH3), 55.3 (OCH3), 113.4, 114.1, 116.3 (CH3), 117.3 (C),
126.5, 126.9, 129.7, 130.3 (CH), 134.3, 135.6, 138.6, 141.7,
142.8, 153.9, 154.9, 159.4 (C), 160.5 (CO). IR (KBr):
n = 3029, 2927, 2852, 2836 (w), 1725 (s), 1642 (w), 1599
(s), 1574, 1536 (w), 1510 (s), 1464, 1439, 1391, 1379, 1354,
1286 (m), 1243 (s), 1191, 1176, 1137 (s), 1108, 1084 (w),
1032 (s), 1017 (w), 963 (s), 893, 875, 853, 834 (w), 816 (s),
795, 778, 726, 714, 672, 648 (w), 613, 582, 555 (w) cm–1.
GC-MS (EI, 70 eV): m/z (%) = 356 (100) [M]+, 355 (11),
328 (26). HRMS (EI, 70 eV): m/z calcd for C24H20O3 [M]+:
356.14070; found: 356.140927.
(24) 4-Methyl-2-oxo-7-(p-tolyl)-2H-chromen-5-yl
Trifluoromethanesulfonate (4a)
Starting with 2 (80 mg, 0.18 mmol), 3a (24 mg, 0.18 mmol),
Pd(PPh3)4 (6 mg, 3 mol%, 0.005 mmol), K3PO4 (55 mg, 0.26
mL), and toluene (3 mL), 4a was isolated by chromatog-
raphy (flash silica gel, heptanes–EtOAc = 10:1) as a
colourless solid (55 mg, 80%), mp 135–136 °C. 1H NMR
(300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.56 (d, J = 1.2
Hz, 3 H, CH3), 6.24 (d, J = 1.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz,
2 H), 7.41 (d, J = 1.8 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.49
(d, J = 1.8 Hz, 1 H). 13C NMR (75.47 MHz, CDCl3):
d = 21.2, 22.9 (CH3), 112.3 (C), 115.0, 116.0, 117.7 (CH),
118.4 (q, JF,C = 318.8 Hz, CF3), 126.8, 130.1 (CH), 134.2,
139.8, 144.8, 145.7, 149.6, 155.3 (C), 159.0 (CO). 19F NMR
(282.4, MHz): d = –72.6. IR (KBr): n = 3071, 3053, 3033,
2923, 2852, 1914, 1803 (w), 1735, 1613 (s), 1577, 1529,
1482, 1452 (w), 1424 (m), 1398 (s), 1386, 1364, 1292 (m),
Synlett 2012, 23, 223–226
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