Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions Sandro Cacchi* and...

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

http://www.google.es/imgres?imgurl=http://upload.wikimedia.org/wikipedia/commons/3/35/Indole_structure.png&imgrefurl=http://commons.wikimedia.org/wiki/File:Indole_structure.png&usg=__CB8TlgQYOR3nFvqi4FonBG_vroY=&h=863&w=901&sz=4&hl=es&start=1&zoom=1&tbnid=hEzbAKAg-tEEvM:&tbnh=140&tbnw=146&ei=tZReUY-QDseVswb2noCIAQ&prev=/search%3Fq%3Dindole%2Bstructure%26um%3D1%26hl%3Des%26sa%3DN%26gbv%3D2%26tbm%3Disch&um=1&itbs=1&sa=X&ved=0CCwQrQMwAA

Classical Indole Syntheses



the Madelung cyclization

the Bischler indole synthesis,

the Batcho-Leimgruber synthesis of indoles


http://en.wikipedia.org/wiki/File:Gassman_Indole_Synthesis_Summary.png

http://en.wikipedia.org/wiki/File:Madelung_Synthesis_Scheme.png

http://en.wikipedia.org/wiki/File:Bischler-Mohlau_Indole_Synthesis.png

http://en.wikipedia.org/wiki/File:Leimgruber-Batcho_Indole_Scheme.png

http://en.wikipedia.org/wiki/File:Bartoli_Indole_Synthesis_Scheme.png









¡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


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

1.7. 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


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


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)


N

R1

R2

R3

a

e

b

g

3.1. Disconnection g


N

R1

R2

R3

a

e

b

g

3.1. Disconnection e + g

3.2. Disconnection a + g


N

R1

R2

R3

a

e

b

g

3.3. Disconnection a + b


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


N

R1

R2

R3

a

e

b

g

GENERAL STRATEGIES4. Functionalization of the preformed indole system









¡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


Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions Sandro Cacchi* and...

Documents

Transcript of Synthesis and Functionalization of Indoles Through Palladium-Catalyzed Reactions Sandro Cacchi* and...