Direct oxidative Heck cyclizations: intramolecular Fujiwara-Moritani arylations for the synthesis of functionalized benzofurans and dihydrobenzofurans.

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Direct Oxidative Heck Cyclizations: Intramolecular
Fujiwara-Moritani Arylations for the Synthesis of
Functionalized Benzofurans and Dihydrobenzofurans
by Zhang, H.; Ferreira, E. M.; Stoltz, B. M.
Angewandte Chemie International Edition
2004, 43, 6144-6148
Erick B. Iezzi
Current Literature
November 27, 2004
Erick Iezzi @ Wipf Group112/2/04

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Why is this Article Significant?
- Heck reaction is ubiquitous for the forming C-C bonds in synthetic
molecules
- uses halogenated arenes which requires an additional synthetic step
- a base is needed to remove the generated hydrohalic acid
- C-H activation of arenes eliminates the need for halogens
- Demonstrates the first use of catalytic Pd for oxidative intramolecular
C-H activation of arenes and the addition into unactivated olefins (Heck reaction)
- Illustrates that mechanism of cyclization follows the pathway of a
Fujiwara-Moritani/oxidative Heck cyclization
- Synthesize benzofuran and dihydrobenzofuran structures, which are
important components of numerous biologically active compounds
Erick Iezzi @ Wipf Group212/2/04

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Examples of Biologically Active Benzofurans
O
O
HN
O
O
N
RO-09-4609
- Antifungal activity against Candida albicans (a pathogenic fungi)
Masubuchi, et al. Bioorg. Med. Chem. 2003, 11, 4463
- An oxytocin antagonist
Wyatt, et al. Bioorg. Med. Chem. Lett. 2002, 12, 1405
O
O
H
N
O
N
O
O
N
H
(-) BPAP
- A serotonin release enhancer
Yoneda, et al. Bioorg. Med. Chem. 2001, 9, 1197
Erick Iezzi @ Wipf Group3 12/2/04

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Examples of Biologically Active Dihydrobenzofurans
O
- A tubulin polymerization inhibitor
(GI50 of <10 nM against some breast cancer cell lines)
Pieters, et al. J. Med. Chem. 1999, 42, 5475
O
OMe
OH
OH
OH
MeO
O
O
O
- An anti-inflammatory and analgesic drug
Janusz, et al. J. Med. Chem. 1998, 41, 1124
DHDMBF
O
NH
N
O
- An acyl-Co A: cholesterol acyltransferase inhibitor
Kataoka, et al. J. Med. Chem. 1996, 39, 1262
Erick Iezzi @ Wipf Group4 12/2/04

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Pd-Catalyzed Oxidative Heck Reaction
H
PdIICl2
HOAc
+
2
reflux
Fujiwara-Moritani arylation (1967)
Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 1119-1122
Catalytic intermolecular reaction with activated olefins
O
OEt
+
Pd(II)OAc
H
[Pd(II)OAc]+
O
OEt
Pd(OAc)2 (10 mol%)
heteropoly acid (2 mol%)
AcOH, 90 oC, O2 (1 atm)
Ishii, et al. J. Am. Chem. Soc. 2003, 125, 1476-1477
R
R
65-84%
R = H, Ph
Erick Iezzi @ Wipf Group512/2/04