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 Group 1 12/2/04
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Direct Oxidative Heck Cyclizations: IntramolecularFujiwara-Moritani Arylations for the Synthesis of
Functionalized Benzofurans and Dihydrobenzofurans
by Zhang, H.; Ferreira, E. M.; Stoltz, B. M.
Angewandte Chemie International Edition2004, 43, 6144-6148
Erick B. IezziCurrent Literature
November 27, 2004
Erick Iezzi @ Wipf Group 1 12/2/04
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 Group 2 12/2/04
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 HN
O
N
O
O
NH
(-) BPAP
- A serotonin release enhancer
Yoneda, et al. Bioorg. Med. Chem. 2001, 9, 1197
Erick Iezzi @ Wipf Group 3 12/2/04
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 Group 4 12/2/04
Pd-Catalyzed Oxidative Heck Reaction
HPdIICl2
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)OAcH[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 Group 5 12/2/04
Mechanism of Arene Insertion into Activated Esters and Reoxidation of Catalyst
[O] / Pd(II)Pd(OAc)2
[PdOAc]+
-OAc
Ar-PdOAcR'
CO2R
R' CO2R
Ar PdOAcH H
R' CO2R
Ar H
Pd(0)
Ar-H
Erick Iezzi @ Wipf Group 6 12/2/04
Pd-Catalyzed Reactions of Arenes with Alkynes
X OPd(OAc)2 (10 mol%)
TFA/CH2Cl2 (1:1)
Fujiwara, et al. Acc. Chem. Res. 2001, 34, 633-639
R'
R
X = O, NH, S
X O
R
R'
+ CO2Et
Pd / [O]
TFA
CO2Et
Pd(OAc)2 TFA, RT
Ar CO2EtAr
CO2Et
Ar
Ar CO2Et+ +
72% 6% 5%
50-91%
Erick Iezzi @ Wipf Group 7 12/2/04
Carboxylation of Arenes and Ru-Catalyzed Oxidative Heck Reactions
+ CO
CO2H10% Pd(OAc)2K2S2O4 / TFART, 20h ~100%
B(OH)2 O
OBu+
2.5 mol% Ru-cat. (1)
2.5 equiv. Cu(OAc)2Et3N, CH2Cl2, RT
O
OBu
* need prefunctionalized arene to facilitate reaction Ru
Cl
Cl
98% GC, 60% isolated
Fujiwara, et al. Acc. Chem. Res. 2001, 34, 633-639
Brown, et al. Angew. Chem. Int. Ed. 2002, 41, 169-171
1
Erick Iezzi @ Wipf Group 8 12/2/04
Palladium-Promoted Oxidative Heck Cyclization in Total Synthesis
Corey, et al. J. Am. Chem. Soc. 2003, 125, 5628-5629
NH
MeO2C
N
Me Me
O
FmocHN
H
H
N
MeMe
NH
MeO2CN O
FmocHN
H
H
N
MeMe
MeMe
1 equiv. Pd(OAc)2,
AcOH:dioxane:H2O
1 atm O2, 25 oC, 16h
NH
NO
N
H
H
N
MeMe
MeMe
O
HOH
Okaramine N
44%
Erick Iezzi @ Wipf Group 9 12/2/04
First Example of Pd-Catalyzed Oxidative Annulations of Indoles
NMe
Pd(OAc)2 (10 mol%), O2 (1 atm)
pyridine ligand (40 mol%),
0.1 M solvent, 24 h, 80 oC NMe
NMe
Pd
Ln
olefin insertion
NMe LnPd
H
palladationB-hydride elimination
Stoltz, et al. J. Am. Chem. Soc. 2003, 125, 9578-9579