Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
Sandro Cacchi* and Giancarlo Fabrizi
Dipartimento di Chimica e Technologie del Farmaco, Sapienza, Universita
di Roma, P.le A. Moro 5, 00185 Roma, Italy
Chem. Rev. 2011, 111, PR215–PR283 updated 2005, 105 (7), 2873-2920
Indole is the acronym from indigo (the natural dye) and oleum (used for the isolation)
Indole ring is a structural component of a vast number of biologically active natural and
synthetic compounds
Classical Indole Syntheses:
the Fischer indole synthesis
the Gassman indole synthesis
the Madelung synthesis
the Bischler indole synthesis
the Batcho-Leimgruber synthesis
the Bartoli indole synthesis
Classical Indole Syntheses
the Fischer indole synthesis
the Gassman indole synthesis
the Madelung cyclization
the Bischler indole synthesis,
the Batcho-Leimgruber synthesis of indoles
the Bartoli indole synthesis
Classical Indole Syntheses
the Fischer indole synthesis
the Gassman indole synthesis
the Madelung cyclization
the Bischler indole synthesis,
the Batcho-Leimgruber synthesis of indoles
the Bartoli indole synthesis
Richard F. Heck Ei-ichi Negishi
Akira Suzuki
El Premio Nobel de Química 2010 fue otorgado a los científicos Richard
F. Heck (EE.UU.), Ei-ichi Negishi (Japón), y Akira Suzuki (Japón), por
“las reacciones de acoplamiento cruzado catalizadas por paladio en síntesis
orgánica”
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
1. Construction of the pyrrole ring based on the utilization, as precursors, of
compounds containing nitrogen nucleophiles and carbon-carbon triple bonds
1.1. Cyclization of Alkynes: disconnection a
e
R
3
b
R
2
N
R
g
1
a
1.1. Cyclization of Alkynes
e
R
3
b
R
2
N
R
g
1
a
1.2. Disconnection a + g
e
R
3
b
R
2
N
R
1
a
g
?
N
N
N
N
H2N
N
H2N
1.3. Disconnection a + e + g
e
R
3
b
R
2
N
R
g
1.4.Disconnection a + b
1
a
c
d
1.5. Disconnection a + d
e
R
3
b
R
N
R
g
1
a
2
1.6. Disconnection a + e (SINTESIS DE LAROCK)
c
d
e
R
3
b
R
N
R
g
1
a
2
1.6. Disconnection a + e (SINTESIS DE LAROCK)
c
d
e
R
3
b
R
N
R
g
1
a
2
1.6. Disconnection a + e (SINTESIS DE LAROCK)
c
d
e
R
3
b
R
2
N
R
1
a
g
1.7. Disconnection c
1.8. Disconnection a + f
c
d
e
R
R
3
b
R
N
R
g
5
R 2 = C H ---- N u
2
f
1
a
GENERAL STRATEGIES
1. Construction of the pyrrole ring based on the utilization, as precursors, of
compounds containing nitrogen nucleophiles and carbon-carbon triple bonds
c
d
e
R
3
b
R
N
R
g
1
a
2
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
2. Construction of the pyrrole ring based on the utilization, as precursors, of
compounds containing nitrogen nucleophiles and carbon-carbon double bonds
2.1. Disconnection e
e
R
3
c
R
2
N
R
1
a
a + e
2.1. Disconnection e
e
R
3
c
R
2
N
R
1
a
a + e
2.2. Disconnection a + e
e
R
3
c
R
2
N
R
2.2. Disconnection a
1
a
a + e
2.3. Disconnection a
e
R
3
R 3 = C H 2 ---- N u
c
R
2
h
N
R
2.4. Disconnection c + h
1
a
a + e
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
2. Construction of the pyrrole ring based on the utilization, as precursors, of
compounds containing nitrogen nucleophiles and carbon-carbon double bonds
e
R
3
R 3 = C H 2 ---- N u
c
R
2
h
N
R
1
a
a + e
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
3. Construction of the pyrrole ring by C-N bond forming reactions
(Buchwald /Hartwig methodologies)
e
R
3.1. Disconnection g
3
b
R
2
N
R
g
1
a
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
3.1. Disconnection e + g
e
R
3
b
R
2
N
R
g
3.2. Disconnection a + g
1
a
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
3.3. Disconnection a + b
e
R
3
b
R
2
N
R
g
1
a
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
3.3. Disconnection a + e
e
R
3
b
R
2
N
R
g
1
a
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
3. Construction of the pyrrole ring by C-N bond forming reactions
e
R
3
b
R
2
N
R
g
1
a
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES
4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
Sandro Cacchi* and Giancarlo Fabrizi
Dipartimento di Chimica e Technologie del Farmaco, Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Roma, Italy
Chem. Rev. 2011, 111, PR215–PR28 updated 2005, 105 (7), 28732920
Classical Indole Syntheses
the Fischer indole synthesis
the Gassman indole synthesis
the Madelung cyclization
the Bischler indole synthesis,
the Batcho-Leimgruber synthesis of indoles
the Bartoli indole synthesis
Conclusion: “In general, it is apparent
from a synthetic perspective that the
application of palladiumbcatalysis to
indole
chemistry
has
had
a
considerable impact on the synthesis of
this important class of compounds. It is
used almost routinely in today’s
preparation of a vast number of indoles,
ranging from simple to complex
molecular targets.”