Palladium-catalyzed cross-coupling reactions of 4-tosylcoumarin and arylboronic acids: Synthesis of 4-arylcoumarin compounds

Article abstract of DOI:10.1016/S0040-4039(02)00718-9

The palladium-catalyzed reaction between 4-tosylatecoumarin and arylboronic acids was investigated. This reaction provides an efficient approach to synthesize diversified 4-arylcoumarins in good yields.

Full text of DOI:10.1016/S0040-4039(02)00718-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4395–4397
Palladium-catalyzed cross-coupling reactions of 4-tosylcoumarin
and arylboronic acids: synthesis of 4-arylcoumarin compounds
Jie Wu,† Lisha Wang,† Reza Fathi*,‡ and Zhen Yang*,‡
Harvard Institute of Chemistry and Cell Biology (ICCB), Harvard University, 250 Longwood Avenue, SGM 604, Boston,
MA 02115, USA
Received 25 February 2002; accepted 8 April 2002
Abstract—The palladium-catalyzed reaction between 4-tosylatecoumarin and arylboronic acids was investigated. This reaction
provides an efficient approach to synthesize diversified 4-arylcoumarins in good yields. © 2002 Elsevier Science Ltd. All rights
reserved.
The prominence of coumarin in natural products and
biologically active molecules1 has promoted consider-
able efforts toward their synthesis.2 As a ‘privileged’
scaffold, 4-substituted coumarin shows interesting bio-
logical properties, especially for their anti-HIV and
antibiotic activities.3 Our continued interest to build-up
a coumarin based combinatorial library led us to
devote our efforts to develop efficient methods for the
synthesis of diversified coumarin molecules.
preparation comparing to its corresponding triflate.
These advantages inspired us to look for other applica-
tions of 4-tosylcoumarins, such as the Suzuki-type
cross-coupling reaction.5
From a synthetic point of view, the use of aryl sul-
fonates (in particular tosylates) as electrophiles for the
Suzuki-type cross-coupling is a very attractive alterna-
tive due to their unique characteristics aforementioned.
There are some interesting reports related to utilizing
arene sulfonates as electrophiles in the Suzuki cou-
plings, but most of them utilized organo-nickels as
catalysts. High loading catalysts (up to 10%) and harsh
reaction conditions (130°C for 10–60 h) had to be
utilized in order to achieve the respective yields.6
In our previous paper,4 we discussed a chemistry of the
palladium-catalyzed cross-coupling reactions of substi-
tuted 4-tosylcoumarins with acetylenes or zinc reagents
under very mild conditions with satisfactory yields. We
fortunately identified the 4-tosylcoumarin as an ideal
synthon for synthesizing 4-substituted coumarin in
terms of its stability, cost-effective issues and easy
We assumed that the 4-tosyl group attached to the
electron-withdrawing a,b-unsaturated double bond in
4-tosylcoumarins would definitely increase its capability
to oxidatively add to the transition metals, therefore,
the rate limited step in this 4-tosylcoumarin based
Suzuki reaction would be significantly improved as
comparing with other aryl or vinyl sulfonates species.
OTs
O
Ar
O
ArB(OH)2, PdCl2(PPh3)2 (5 mol%)
Na2CO3 (2M in water), THF, 60οC
R
R
O
O
1
2
1a: R = H; 1b: R = 7-OMe;
1c: R = 6-Me; 1d: R = 6-OMe.
Initially, we selected 4-tosylcoumarin as a substrate to
react with 2-methoxyphenylboronic acids in the pres-
ence of nickel catalysts (NiCl2(dppe), NiCl2(dppf)), and
a complicated mixture was generated, even though a
variety of reaction conditions were tested. We thought
that the nickel catalysts maybe so active to cause the
substrates decomposition. We therefore focused our
attention to the palladium-catalyzed cross-coupling
reaction with the hope of finding a less reactive catalyst,
which may give a better selectivity. Primarily, when
Scheme 1.
* Corresponding authors. E-mail: z.yang@vivoquest.com
† Current address: The Aaron Diamond AIDS Research Center
(ADARC), Rockefeller University, 455 First Avenue, NY 10016,
USA.
‡ Current address: VivoQuest, Inc., 711 Executive Blvd., Valley Cot-
tage, NY 10989, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00718-9

4396
J. Wu et al. / Tetrahedron Letters 43 (2002) 4395–4397
Pd(PPh3)4 was employed to mediate the cross-coupling
reaction between 4-tosylcoumarin and 2-
boronic acids with electron-donating group gave better
yields.
methoxyphenyl-boronic acid in the presence of potas-
sium carbonate as the base, the reaction indeed
proceeded albeit in 32% yield. After systematic investi-
gation by studying a variety of combination, such as
the amount of different catalysts (PdCl2(PPh3)2,
Pd(OAc)2, Pd(PPh3)4), the solvents (THF, DCM,
CH3CN, DMF, dioxane), and the bases (Na2CO3,
Cs2CO3, K2CO3, K3PO4), an optimal condition for the
coupling of 4-tosylcoumarin with 2-methoxyphenyl-
boronic acid was selected. The best catalyzed reaction
was employed by using PdCl2(PPh3)2 in THF at 60°C in
the presence of Na2CO3 and the results are depicted
below in Scheme 1.
In a typical experimental procedure, 4-tosylatecoumarin
(0.25 mmol), arylboronic acid (0.50 mmol) and
PdCl2(PPh3)2 (9 mg, 5 mol%) was dissolved in THF (2.0
mL) under argon atmosphere, and then an aqueous
sodium carbonate solution (2 M, 2.0 mL) was added.
The reaction mixture was stirred at 60°C for 12 h
(completion of a reaction was monitored by TLC). The
reaction mixture was cooled, and extracted with ethyl
acetate (2×20 mL). The organic phase was washed
successively with water (5.0 mL), brine (5.0 mL), and
dried over Na2SO4. The solvent was removed under
vacuum and the residue was purified by silica gel chro-
matography to give the corresponding product.
As is demonstrated in Table 1, all the reactions pro-
ceeded smoothly under the selected condition and
afforded the corresponding products in good to excel-
lent yields. Synthetically, all these cross-coupling reac-
tions illustrated in Table 1 went to completion at 60°C
in less than 12 h, regardless of different substitution
patterns on these substrates. Therefore, diversified sub-
stitutions on both coumarin and boronic acids were
tolerated under the reaction conditions, and indeed
In summary, the cross-coupling reactions between 4-
tosylcoumarins and boronic acids have been investi-
gated. The chemistry described above illustrates
4-tosylcoumarin as an alternative for the palladium-cat-
alyzed Suzuki reaction. The superiority of 4-tosylcou-
marin versus its corresponding triflate in terms of its
stability, the synthetic reagent cost, and easy prepara-
tion should make it an ideal synthon for combinatorial
Table 1.

J. Wu et al. / Tetrahedron Letters 43 (2002) 4395–4397
4397
synthesis of coumarin on solid support. Application of
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Merck & Co. grant (c: MCI97MITC804) and Merck
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