Angewandte
Chemie
DOI: 10.1002/anie.201305326
Heterocycle Synthesis
Palladium-Catalyzed Synthesis of Benzofurans and Coumarins from
Phenols and Olefins**
Upendra Sharma, Togati Naveen, Arun Maji, Srimanta Manna, and Debabrata Maiti*
Benzofuran derivatives are ubiquitous in natural products,[1]
agrochemicals,[2] pharmaceuticals,[3,4] and organic materials.[5]
Particularly, 2-arylbenzofurans are widely distributed in
nature,[6] and possess a number of biological activities.[4b,7]
Over the years, several effective strategies involving transi-
tion-metal-catalyzed[8] inter[9]/intramolecular[10] heteroannu-
lation reactions have been reported for synthesizing benzo-
furan scaffolds.[11] However, synthesis of 2-substituted benzo-
furan[12] by simply reacting phenol and an unactivated olefin
has yet to be reported (Scheme 1).
À
Scheme 2. Synthesis of coumarins by C H functionalization (select
examples). EDG=electron-donating group, EWG=electron-withdraw-
ing group.
(10 mol%), 1,10-phenanthroline (20 mol%), Cu(OAc)2
(1 equiv), and NaOAc (3 equiv) in ClCH2CH2Cl at 1108C
for 24 hours.[17,18] Without NaOAc, the yield of the benzo-
furan decreases to 43%. First we tested electron-deficient
phenols since the synthesis of 2-arylbenzofurans bearing
strong-electron withdrawing groups, such as NO2, CN, CHO,
À
Scheme 1. Synthesis of 2-arylbenzofurans via C H activation (select
examples).
and COCH3, on the benzenoid portion remain intangible.[12a–l]
Styrenes having either a meta or para substituent reacted
successfully with 4-nitrophenol to produce the desired
Another “privileged scaffold”,[13] coumarin, possesses
various interesting biological activities.[14] The most common
approach for their synthesis is the Pechmann condensation
wherein phenol is reacted with a b-ketoester or acid under
strongly acidic conditions.[15] Despite having a number of
effective alternative methods (mainly for electron-rich phe-
nols),[16] the synthesis of coumarins from phenol and methyl
acrylate remains attractive (Scheme 2). Herein, we report
product in 55–92% yield (3a–d; Table 1). Switching to 4-
cyanophenol from 4-nitrophenol did not affect the outcome of
the reaction (3e–j), and sterically demanding ortho-substi-
tuted styrenes also produced the expected product in
synthetically useful yields (3 f and 3o). Halogen-substituted
phenols or styrene gave the benzofuran derivative in good
yield without any dehalogenation (3d, 3h, 3j, and 3n), and
carbonyl groups, such as CHO and COCH3, on either
coupling partner remained intact under the reaction con-
ditions (3i, 3k, and 3l). Unfortunately, only 30% yield of 2-
phenylbenzofuran (3m) was obtained under the optimized
reaction conditions. In the case of 3-chloro and 3-triflorome-
thylphenol two regioisomers were formed (3q and 3r). A
derivative of vitamin E was also converted into the desired
benzofuran product 3zb. A gram-scale reaction was carried
out successfully in 85% yield (3a).[17]
Next, we focused on the synthesis of naphthofuran since
they are found in natural products and in pharmacologically
relevant molecules.[19] As expected, 6-bromo-2-phenylnaph-
thofuran (3z; 89%, Table 1) was obtained in excellent yield
from the corresponding 6-bromo-2-naphthol. 2-Naphthol also
provided naphthofuran in high yield (3za; 82%). In spite of
possibility of forming regioisomers in both these cases, only
one product was exclusively generated.
À
À
a palladium-catalyzed C O/C C bond formation sequence
between phenol and an olefin for the convenient synthesis of
benzofurans and coumarins.
Initial studies revealed that the benzofuran moiety can be
synthesized efficiently (94%) from 4-nitrophenol and styrene
by
a palladium-catalyzed method involving Pd(OAc)2
[*] Dr. U. Sharma, T. Naveen, A. Maji, S. Manna, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
E-mail: dmaiti@chem.iitb.ac.in
[**] This activity is supported by BRNS, India. Financial support received
from DST under the Fast Track Scheme (U.S.), CSIR-India (fellow-
ship to T.N. and A.M.) is gratefully acknowledged. XPS study was
carried out at ESCA, IIT Bombay. We thank Mr. Arijit Mallick (NCL
Pune) for XPS data analysis. Palladium catalysts were obtained as
a gift from Johnson Matthey Chemicals, MIDC Taloja (India).
After evaluating the scope with styrene derivatives,
different terminal and internal aliphatic olefins were tested
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 12669 –12673
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12669