Classical Indole Syntheses: the Fischer indole synthesis 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 2

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¡ 3

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” “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”

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

1.1. Cyclization of Alkynes

1.2. Disconnection a + g

1.3. Disconnection a + e + g 1.4.Disconnection a + b

1.5. Disconnection a + d

1.6. Disconnection a + e (SINTESIS DE LAROCK)

1.6. Disconnection a + e (SINTESIS DE LAROCK)

1.6. Disconnection a + e (SINTESIS DE LAROCK) 1.7. Disconnection c

1.8. Disconnection a + f

GENERAL STRATEGIES 1. Construction of the pyrrole ring based on the utilization, as precursors, of compounds containing nitrogen nucleophiles and carbon-carbon triple bonds

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

2.1. Disconnection e

2.2. Disconnection a + e 2.2. Disconnection a

2.3. Disconnection a 2.4. Disconnection c + h

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

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) 3.1. Disconnection g

Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions 3.1. Disconnection e + g 3.2. Disconnection a + g

Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions 3.3. Disconnection a + b

Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions 3.3. Disconnection 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

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 ¡Palladium-catalyzed reactions have deeply influenced the strategies of indole synthesis in the last 30 years¡ 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.” 31