Direct C-Arylation of Free (NH)-Indoles and PyrrolesCatalyzed by Ar–Rh(III) Complexes Assembled In Situ

by Wang, X; Lane, B. S.; Sames, D.

Journal of the American Chemical Society2005, ASAP (Communication)

Erick B. IezziCurrent Literature

April 2, 2005

Erick Iezzi @ Wipf Group 1 4/4/2005

Why is this paper significant?

Heteroaromatics are important structural units found in natural products, pharmaceuticals and numerous functional synthetics

C–H bond activation represents a chemical process of broad synthetic scope:

- ability to selectively and/or systematically functionalize a heteroaromatic molecule - selectively functionalize sp2 and sp3 carbon atoms

Direct C-arylation of free (NH)-azoles eliminates the need for introducing protecting groups and reactive functionalities prior to C–C formation (i.e., halogenation or stoichiometric metalation prior to C–C coupling)

Free pyrroles, indoles and imidazoles are unreactive under known arylation conditions, yielding little or no C-arylated products

Erick Iezzi @ Wipf Group 2 4/4/2005

Common Methods for Synthesizing Substituted Indoles

NH NH2Ph

O

CH3

+Polyphosphoric acid

NH

Ph

NO2

EtO

O

O

OEt+

Fisher indole synthesis

Reissert indole synthesis

1) KOEt, Et2O; HOAc

NH

CO2Et

2) H2/Pt, HOAc

heat

64-66%

76%

I

NH2

R

Sonagashira coupling/base-mediated cyclization

H Ph,

PdCl2(PPh3)2,

CuI, Et3N; MsCl,

pyridine

NHMs

R

Ph

NH

PhR

TBAF (2 equiv.)

THF, reflux

94%

Sakamoto, et al. J. Chem. Soc., Perkin Trans. 1, 1999, 529-534

Erick Iezzi @ Wipf Group 3 4/4/2005

Classical Methods for Synthesizing Substituted Pyrroles

NHOO

NH3, HOAc

Paal-Knorr Synthesis

Hantzsch Synthesis

R1

O

X +

O R2

CO2Et

+ NH2

R3 NR2R1 N

R2+

R3R3

CO2Et CO2EtR1

Knorr Synthesis

R1 O

NH2

+

O R3

CO2Et

R2NH

R3R2

CO2EtR1

-H2O

-H2O

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Electrophilic Aromatic Substitution of Indoles and Pyrroles

NH

NH

N

EH

H

3-position(lower energy)

N

H

E

H

2-position

vs.

Mannich Reaction

CH2O, HNMe2

HOAc NH

NMe2

Houben-Hoesh Reaction

R C N, HCl

NH O

RN

H

E

H

N

H

E

H

N

H

E

H

- Indole favors C-3 substitution

- Pyrrole favors C-2 substitution

N

SO2Ph

N

SO2Ph

Friedel-Crafts Acylation with Protected Pyrrole

NH

NaH, PhSO2Cl RCOCl, AlCl3

O

R

Anderson, et al. Tetrahedron Lett. 1981, 22, 4899-4900

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N-Arylation of Azoles

MeO

Br

NH

+N

OMe

Pd2(dba)3,

P(t-Bu)3, Cs2CO3,

Toluene, 100 oC, 6h

NPd2(dba)3,

P(t-Bu)3, Cs2CO3,

NH

Br

+

Hartwig, et al. J. Org. Chem. 1999, 64, 5575-5580.

83%

Toluene, 100 oC, 6h

77%

NH

I

+N

CuI (1 mol%), Ligand,

K3PO4, 110 oC, 24h,

Dioxane

Buchwald, et al. J. Am. Chem. Soc. 2001, 123, 7727-7729.

CuI (1 mol%), Ligand,

K3PO4, 110 oC, 24h,

Dioxane

N

N

OMe

NH

N+

I

OMe

91%

100%

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Metalation as N-Protection and Activation of Heteroarenes

- this process suffers from considerable moisture sensitivity and limited functional group scope

Sames, et al. J. Am. Chem. Soc. 2003, 125, 5274-5275

NH

Pd(OAc)2 (5 mol%),

PPh3 (20 mol%), MgO

(1.2 equiv.), dioxane/

DMF, 150 oC, 18 h

NH

Ph +NPh

Base (1.2 equiv.) Isolated yield (A / B)

LiOH or NaOMe 0 / 0%

K3PO4 or KOAc 0 / 0%

Cs2CO3 0 / 5%

MgO 53 / 0%

EtMgBr 65 / 0%

ZnO 44 / 0%

A B

RI

NH

NH

R R = H (84%), Me (81%),

F (74%), CF3 (75%),

OMe (87%), COMe (79%)

Ar-Pd-X(L2)

from ArX, Pd(0), L

same conditions

NH

Me

+

NH

Me

39% 12%I

Me

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Mechanistic Explanations for C-2 and C-3 Arylation of N-Metalated Indole

N

MgOH

Ar-Pd-(L2)

Ar-Pd-X(L2)

N

MgOH

Ar

PdX

H

H

N

MgOH

MgO

MgOH

N

MgOH

Pd(0)

NH

Me

X

Pd-ArH

Pd-Ar

N

MgOH

Ar

H

XPd

Pd(0) + X

MgO

MgOH

NH

MeC-3 C-2

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Selectivity in C-Arylation of In Situ N-Metalated Azoles

Arylation of Imidazole: Complete Orthogonality

Sames, et al. J. Am. Chem. Soc. 2003, 125, 5274-5275

NH

Ph-I (1.2 equiv.)

Pd(OAc)2 (5 mol%),

PPh3 (20 mol%), MgO

(1.2 equiv.), dioxane,

150 oC, 12-15 h

NH

Ph 86%

N

NH

N

NH

72%

N

NH

N

NH

Ph83%

Phconditions above

conditions above

+ CuI (2 equiv.)

N

NH

N

NH

Ar-I

Pd/Ph3P/MgO

ArN

NH

N

N

C-4

Ar

Ar-I

Pd/Ph3P/MgO

+ CuI

C-2

Ar-I N-1

Ar

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Direct C-Arylation of Free (NH)-Azoles by a Rh(III) Catalyst: Evaluation of Substrates and Functional Groups

Sames, et al. J. Am. Chem. Soc. 2005, ASAP.

NH

Ar-Rh-(OPiv)2(L)2

from ArX, Rh(I), L, CsOPiv NH

Ar

NH

Azole Product Isolated yield

NH

Ph 82%

NH

HN

NH

HN

Piv Piv 78%

NH

HN

Boc

NH

HN

BocPh 59%

NH

NHTosyl

NH

NHTosyl

Ph65%

HN

HN

p-Tol 81%

HNN H

NN

Ph 0%

Reaction conditions:

Azole (1 equiv.), ArI (1.2 equiv.),

CsOPiv (1.4 equiv.), [Rh(coe)2Cl]2 (1 mol%),

[p-(CF3)-C6H4]3P (15 mol%), Dioxane,

120 oC, 18-36 h.

NH

MeO2C

NH

MeO2C

59%Br

N

MgBr

RMgX Ar-Pd-X(L2)

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Synthesis and Reactivity of Rh(III) Catalyst

- CsOPiv and 4-Tol-I serve as trapping agents to prevent decomposition of Rh(I)- Carbonates and phosphates of alkali metals as well as amines were ineffective as bases- CsOAc gave 45% product, versus 82% for CsOPiv

RhPh

PivO

OPiv

L

L

[Rh(coe)2Cl]2

L = [p-(CF3)C6H4]3P, Ar = Ph, 4-Tol

+ indole (20 equiv.)

NH

Ph

65%

dioxane, 120 oC

Ar-I, CsOPiv

120 oC,

120 min.

(25 mM)

+ CsOPiv

+ CsOPiv, Tol-I

81%

98%

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Proposed Catalytic Cycle

NH NH

H

RhPh

PivO

OPiv

L

NH

NH

Rh

L

Ph

OPiv

Ar

RhPh

PivO

OPiv

L

L

HOPiv

RhL2(OPiv)

Ph-ICsOPiv

Ph-ICsOPiv

L

[Rh(COE)2Cl2]2

L = [p-(CF3)C6H4]3P

slow

(resting state)

L

Erick Iezzi @ Wipf Group 12 4/4/2005

Future Work

Taylor catalyst to work with basic amine substrates (i.e., 7-azaindole)

Clearify mechanistic details of C-H metalation via the Rh(III) catalyst

Erick Iezzi @ Wipf Group 13 4/4/2005