Post on 28-Mar-2015
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
Sandro Cacchi* and Giancarlo FabriziDipartimento di Chimica e Technologie del Farmaco, Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Roma, ItalyChem. 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
¡Palladium-catalyzed reactions have deeply influenced the
strategies of indole synthesis in the last 30 years¡
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”
Ei-ichi NegishiAkira SuzukiRichard F. Heck
“Palladium-catalyzed reactions are in fact strongly dependent on a number of factors such as the nature of stabilizing ligands (as well as their presence or absence), bases, additives, the combination of them, solvents, and temperature. All of these factors combine to afford a toolbox of tunable reaction conditions that make palladium chemistry so flexible and, to some extent, unpredictable, leaving room for an uninterrupted discovery of new, exciting chemistry despite the vast amount of studies developed so far”
GENERAL STRATEGIES1. Construction of the pyrrole ring based on the utilization, as precursors, ofcompounds containing nitrogen nucleophiles and carbon-carbon triple bonds
1.1. Cyclization of Alkynes: disconnection a
N
R1
R2
R3
g
a
e
b
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
1.1. Cyclization of Alkynes
N
R1
R2
R3
g
a
e
b
1.2. Disconnection a + g
N
R1
R2
R3
g
a
e
b
N
NNH2
N N
NNH2
?
1.3. Disconnection a + e + g
1.4.Disconnection a + b
N
R1
R2
R3
g
a
e
b
1.5. Disconnection a + d
N
R1
R2
R3
ag
e
b
cd
1.6. Disconnection a + e (SINTESIS DE LAROCK)
N
R1
R2
R3
ag
e
b
cd
1.6. Disconnection a + e (SINTESIS DE LAROCK)
N
R1
R2
R3
ag
e
b
cd
1.6. Disconnection a + e (SINTESIS DE LAROCK)
N
R1
R2
R3
ag
e
b
cd
1.7. Disconnection c
1.8. Disconnection a + f
N
R1
R2
R3
ag
e
b
cd
R5
R2 = CH---- Nu
f
N
R1
R2
R3
ag
e
b
cd
GENERAL STRATEGIES1. Construction of the pyrrole ring based on the utilization, as precursors, ofcompounds containing nitrogen nucleophiles and carbon-carbon triple bonds
GENERAL STRATEGIES2. Construction of the pyrrole ring based on the utilization, as precursors, ofcompounds containing nitrogen nucleophiles and carbon-carbon double bonds
2.1. Disconnection e
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
c
a + e
2.1. Disconnection e
N
R1
R2
R3
a
e
c
a + e
2.2. Disconnection a + e
N
R1
R2
R3
a
e
c
a + e
2.2. Disconnection a
2.3. Disconnection a
2.4. Disconnection c + h
N
R1
R2
R3
a
e
c
a + e
R3 = CH2----Nu
h
GENERAL STRATEGIES2. Construction of the pyrrole ring based on the utilization, as precursors, ofcompounds containing nitrogen nucleophiles and carbon-carbon double bonds
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
c
a + e
R3 = CH2----Nu
h
GENERAL STRATEGIES3. Construction of the pyrrole ring by C-N bond forming reactions (Buchwald /Hartwig methodologies)
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
b
g
3.1. Disconnection g
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
b
g
3.1. Disconnection e + g
3.2. Disconnection a + g
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
b
g
3.3. Disconnection a + b
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
b
g
3.3. Disconnection a + e
GENERAL STRATEGIES3. Construction of the pyrrole ring by C-N bond forming reactions
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
N
R1
R2
R3
a
e
b
g
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
GENERAL STRATEGIES4. Functionalization of the preformed indole system
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions
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
¡Palladium-catalyzed reactions have deeply influenced the
strategies of indole synthesis in the last 30 years¡
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.”
Synthesis and Functionalization of Indoles Through Palladium-Catalyzed ReactionsSandro Cacchi* and Giancarlo FabriziDipartimento 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