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
Erick Iezzi @ Wipf Group 4 4/4/2005
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
Erick Iezzi @ Wipf Group 5 4/4/2005
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%
Erick Iezzi @ Wipf Group 6 4/4/2005
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
Erick Iezzi @ Wipf Group 7 4/4/2005
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
Erick Iezzi @ Wipf Group 8 4/4/2005
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
Erick Iezzi @ Wipf Group 9 4/4/2005
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)
Erick Iezzi @ Wipf Group 10 4/4/2005
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%
Erick Iezzi @ Wipf Group 11 4/4/2005
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