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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
Entry Pyridine ligand pKa(pyrH+) conversion (%)
1 4-OMe 6.47 3
2 4-t-Bu 5.99 1
3 unsub. 5.25 23
4 4-CO2Et 3.45 52
* 5 3-CO2Et 3.35 76
6 3-COCH3 3.18 58
7 3-F 2.97 64
8 3-CN 1.39 55
9 3,5-di-Cl 0.90 22
Best result: 40 mol% ethyl nicotinate*, 0.1M tert-amyl alcohol/AcOH (4:1), 99% conversion, 82% isolated yield
Erick Iezzi @ Wipf Group 10 12/2/04
Screening of Oxidants for the CatalyticIntramolecular Oxidative Heck Cyclization
Pd(OAc)2 (10 mol%), oxidant,
ethyl nicotinate (40 mol%),
t-AmOH:AcOH (4:1), 24 h, 80 oC
Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, 6144-6148
Entry Oxidant [1 equiv.] Yield [%] by GC 1 O2 56 2 benzoquinone 62 3 Cu(OAc)2 31 4 AgOAc 29 5 Tl(OCOCF3)3 <10 6 K2S2O8 30 7 H2NC(S)NH2 <10 8 PhCO3tBu 42
OMeO
OMe
MeO
OMe
O MeO
OMe
O
Erick Iezzi @ Wipf Group 11 12/2/04
Examples of Oxidative Benzofuran Synthesis
Pd(OAc)2 (10 mol%), NaOAc (20 mol%),
ethyl nicotinate (20 mol%),
benzoquinone (1 equiv.),
0.1M t-AmOH:AcOH (4:1), 100 oC
Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, 6144-6148
OMeO
OMe
Me MeO
OMe
O
Me
Me
77%
OMeO
OMe
Me
Ph
MeO
OMe
O
Me 61%
Ph
OMeO
OMe
Et
O Et
Me
MeO
OMe
O
Et
Me
79%
Me
O
Et
Me
O
O
O
O
conditions above
conditions above
conditions above52%
Erick Iezzi @ Wipf Group 12 12/2/04
Synthesis of Quaternary Carbon-Containing Dihydrobenzofurans via Oxidative Cyclization
Pd(OAc)2 (10 mol%), NaOAc (20 mol%),
ethyl nicotinate (20 mol%),
benzoquinone (1 equiv.),
0.1M t-AmOH:AcOH (4:1), 100 oC
Stoltz, et al. Angew. Chem. Int. Ed. 2004, 43, 6144-6148
OMeO
OMe
MeO
OMe
O
74%
OMeO
OMe
MeO
OMe
O
55%
OMeO
OMe
MeO
OMe
O
80%
conditions above
conditions above
OMeO
OMe
MeO
OMe
O
74%conditions above
2.3:1 diastereomers
Erick Iezzi @ Wipf Group 13 12/2/04
Mechanistic Probe for the Oxidative Heck Cyclization
OMeO
OMe
MeO
OMe
OMeO
OMe
O
OBn OBnOBn
OMeO
OMeMe
OBn
H
PdLn(OAc)2
OMeO
OMe
OBn
Pd(OAc)2 (10 mol%),
NaOAc (20 mol%),
ethyl nicotinate (20 mol%),
benzoquinone (1 equiv.),
t-AmOH:AcOH (4:1), 100 oC
+
not observed 60% yield
OMeO
OMe
OBn
PdLn(OAc)2
olefinactivation
arenepalladation
PdLn(OAc)2
PdLn(OAc)
antinucleophilicattack
MeO
OMe
O
OBn
PdLn(OAc)
H
Me
1 2
1 not observed
HPdLn(OAc)
PdLn(OAc)2
MeO
OMe
O
OBn
synolefininsertion
2 60% yield
PdLn(OAc)
H
Me
synB-hydrideelimination
synB-hydrideelimination
Erick Iezzi @ Wipf Group 14 12/2/04
Future Work
- Develop catalysts to facilitate oxidative C-H activation of electron-poor arenes
- Develop method of synthesizing ether rings of six-members and greater
Erick Iezzi @ Wipf Group 15 12/2/04
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