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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


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


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


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


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


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%


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


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%


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


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


Examples of Oxidative Benzofuran Synthesis

Pd(OAc)2 (10 mol%), NaOAc (20 mol%),


benzoquinone (1 equiv.),

0.1M t-AmOH:AcOH (4:1), 100 oC


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%


Synthesis of Quaternary Carbon-Containing Dihydrobenzofurans via Oxidative Cyclization

Pd(OAc)2 (10 mol%), NaOAc (20 mol%),



0.1M t-AmOH:AcOH (4:1), 100 oC


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


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%),



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


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


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