Catalytic Cross Coupling Reactions in Aromatic and Heteroaromatic Synthesis

Aim of the Course

a) to provide a conceptual framework for the multitude of reactions currently emanating from the impact of transition metal catalysis on the field of aromatic and heteroaromatic synthesis and to place it into practical
perspective;
b) to present a systematic picture of C-C bond coupling methods (Suzuki-Miyaura, Negishi, Kumada-Corriu, Stille, and, most recently, Hiyama) according to hybridization format, e.g. sp2-sp2, sp2-sp3, inter alia
c) to survey other rapidly evolving synthetically promising catalytic processes (Buchwald- Hartwig, Heck, Ullmann, Sonogashira, Grubbs) in a systematic manner using C-N, C-O, C-S formalism;
d) to connect directed ortho metalation(DoM) strategies to these blossoming areas of transition metal catalysed
processes;
e) to contrast and compare the above modern processes with classical but still useful synthetic methods.
The desired consequence is the facility(both on paper and in the lab!) to use these modern strategies for the regiospecific construction of polysubstituted aromatic/
heteroaromatic systems and for the rational assemblage of complex bioactive molecules and natural products. Normal synthetic and mechanistic organic knowledge will be assumed. Retrosynthetic analysis, specific mechanistic features of old and new reactions, and theoretical basis of synthetic principles will guide the presentation, discussion and problem solving sessions.

Course Outline

1.0 C-C CROSS COUPLING REACTIONS (C-C XCOUPL)
1.1 Historical
Aryl-Aryl Cross Coupling (X-Coupl) Grid
Name XCOUPL Reactions: Reviews and
Historical Origins

1.2 Mechanism. General Considerations
General Catalytic Pathway for Pd Catalyzed Reactions
Monophosphine and Diphosphine Ligands: step by step analysis of mechanism

1.3 Kumada - Corriu - Tamao Cross Coupling Reaction Mechanism
Methodology and Scope

1.4 The Negishi Cross Coupling Reaction
Negishi/Sonogoshira Comparison
Methodology and Scope

1.5 The Suzuki-Miyaura Cross Coupling Reaction
Alkyl Boranes. Mechanism
Advantages/Disadvantages
Methodology and Scope

1.6 The Stille Cross Coupling Reaction Mechanism
Hiyama Modification
Methodology and Scope

1.7 The Hiyama Cross Coupling Reaction
Mechanism and Stereochemistry
Silanols, Hypervalent Siloxane
Methodology and Scope

1.8 a-Enolate Cross Coupling
Mechanism
Methodology and Scope

1.9 C-C Cross Coupling Comparisons
Mg-Ni/Mg/Pd vs. Zn-Ni, Zn-Pd vs. B-Pd
Steric Considerations
Methodology and Scope

2.0 C-N CROSS COUPLING REACTIONS
The Catalytic Cycle
ArX + Amine. Copper Catalysis in Air
ArX + Amine. Pd Catalysis
ArX + HetcycleArB(OH)2 + Amine, Phenol
ArB(OH)2 + Hetcycle
ArX +Imine: N-Arylation. An Ammonia
Equivalent
Classical and Modern Ullmann Comparisons

3.0 C-O CROSS COUPLING
Cu Catalysis
Cu Catalysis. B(OH)2 + Phenols
Cu Catalyst: Solid Phase Ullmann
Pd Catalysis
Intermolecular Alkyl-Aryl Ether Ullmann
Intramolecular Alkyl-Aryl Ether Ullmann

4.0 C-S AND C-P CROSS COUPLING REACTIONS
Mechanism
Substrates

5.0 CROSS COUPLING STRATEGIES IN BIOACTIVE MOLECULE CONSTRUCTION
A selection of structures in modern med. chem. Indications, e.g. antihypertensive,
antitumour, antiviral

6.0 CROSS COUPLING STRATEGIES IN NATURAL PRODUCT CONSTRUCTION
A selection of aromatics and heteroaromatics derived from terrestrial, marine and fungal sources.

7.0 THE DoM/CROSS COUPLING NEXUS
The DoM-Suzuki XCoupl
The O-Aryl Carbamate - Grignard XCoupl
Aryl S-Thiocarbamate - Grignard Cross
Coupling Reaction
The DoM - Negishi XCoupl
Comparisons of ArMgX, ArZnX, ArB(OH)2 +
ArOTf Efficacies
The Arsulfonamides + Grignard XCoupl
Applications

8.0THE HECK CROSS COUPLING REACTION
Mechanism
Polymer Supported Catalysis
Heck versus Suzuki
Domino-Heck
Asymmetric Induction
Applications

9.0 THE SONOGOSHIRA - HAGIHARA CROS COUPLING REACTION
Catalytic Cycle
Comparison with Zn,Sn, Mg Equivalents
Applications

10.0 THE GRUBBS METATHESIS REACTION
Mechanistic considerations
The catalysts (1st, 2nd generation and beyond)
Alkyne metathesis
Applications

11.0 Pd-CATALYSIS IN HETEROCYCLIC RING CONSTRUCTION
Indoles by Sequential Sonogashira-Base-
Catalyzed Heteroannelation
2-Substituted Indoles via α-Enolate Coupling
Condensed Indoles via d-Catalyzed C-H
Functionalization
Benzofuran by Suzuki-Base Catalyzed
Heteroannulation
Benzofurans by Sonogashira Castro-Stephens
Heteroannulation. With Subsequent RCM
Heteroannelated Quinolines by Heck
Miscellaneous Heterocycles
C-N Coupling Route to Indoloindazoles