Heterocyclic Chemistry. in Drag Discovery. Edited by. Jie Jack Li Bristol-Myers Squibb Company

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1 Heterocyclic Chemistry in Drag Discovery Edited by Jie Jack Li Bristol-Myers Squibb Company WlLEY A JOHN WILEY & SONS, INC., PUBLICATION

2 Detailed Table of Chapter 1 Introduction Nomenclature of Heterocycles Aromaticity of Heterocycles Importance of Heterocycles in Life Importance of Heterocycles in Drug Discovery Five-Membered Heterocycles with One Heteroatom Five-Membered Heterocycles with Two Heteroatoms Six-Membered Heterocycles with One Heteroatom Six-Membered Heterocycles with Two Heteroatoms 15 PART I FIVE-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 17 Chapter 2 Pyrroles Introduction Reactivity of the Pyrrole Ring Protonation C2 Electrophilic Substitution C3 Electrophilic Substitution Metalation Construction of the Pyrrole Rings Knorr Pyrrole Synthesis Paal-Knorr Pyrrole Synthesis Hantsch Pyrrole Synthesis Barton-Zard Reaction Palladium Chemistry of Pyrroles Possible Liabilities of Pyrrole-Containing Drugs Problems References 51 Chapter 3 Indoles Introduction Reactivity of the Indole Ring Protonation C3 Electrophilic Substitution C2 Electrophilic Substitution Metallation Construction of the Indole Rings Fischer Indole Synthesis Mori-Ban Indole Synthesis 67

3 X Larock Indole Synthesis Bischler-Möhlau Indole Synthesis Nenitzescu Indole Synthesis Bartoli Indole Synthesis Batcho-Leimgruber Indole Synthesis Gassman Indole Synthesis Cadogan-Sundberg Indole Synthesis Oxindole-containing Drug Synthesis Cross-coupling Reactions for Indoles Palladium-Catalyzed Oxidative Coupling Negishi Coupling Suzuki Coupling Sonogashira Coupling Heck Reaction Azaindoles Larock Reaction Bartoli Reaction Batcho-Leimgruber Reaction Cadogan-Sundberg Indole Synthesis Possible Liabilities ofdrugs Containing 3-Methylindole Problems References 113 Chapter 4 Furans, Benzofurans, Thiophenes, and Benzothiophenes Introduction Furans and Benzofurans Reactions of Furans and Benzofiirans Furan and Benzofuran Synthesis Synthesis of Furan-and Benzofuran-Containing Drugs Thiophenes and Benzothiophenes Reactions ofthiophene and Benzothiophene Synthesis ofthiophene and Benzothiophene Synthesis ofthiophene- and Benzothiophene- Containing Drugs Possible Liabilities of Furan- and Thiophene-Containing Drugs Problems References 191

4 xi PART II FIVE-MEMBERED HETEROCYCLES WITH TWO OR MORE HETEROATOMS 197 Chapter 5 Pyrazoles, Pyrazolones, and Indazoles Introduction Basicity and Acidity Tautomerization Reactivities of the Pyrazole Ring Alkylation of the Pyrazole Ring C4 Electrophilic Substitution C5-Metallation Construction of the Pyrazole and Indazole Rings Knorr Pyrazole Synthesis Variations of the Knorr Pyrazole Synthesis Pechmann Pyrazole Synthesis Pyrazolone-containing Drugs Indazole-containing Drugs Problems References 226 Chapter 6 Oxazoles, Benzoxazoles, and Isoxazoles Introduction Construction of the Heterocyclic Ring Construction of the Oxazole Ring Construction of the Benzoxazole Ring Construction of the Isoxazole Ring Reactivity Acid/Base Reactivity Electrophilic Substitution Metalation and Nucleophilic Substitution Pericyclic Reactions Cross-Coupling Reactions Preparation ofhalo-and Trifloyl Oxazoles Stille Coupling Suzuki Coupling Negishi Coupling Sonogashira Coupling Heck Coupling Selected Reactions of Isoxazoles Possible Liabilities of Oxazole-Containing Drugs Problems References 278

5 xii Chapter 7 Thiazoles and Benzothiazoles Introduction Basicity of Thiazoles Reactions of the Thiazole Ring Electrophilic Attack at Carbon C-Metalation Alkylation V-Oxidation Cycloaddition Palladium Chemistry Undergone by Thiazoles and Benzothiazoles Suzuki-Miyaura Reaction Negishi Coupling Heck Reaction Sonogashira Coupling Stille Coupling Construction of the Thiazole Ring Hantzsch Method Cook-Heilbron Synthesis of Thiazoles Gabriel Synthesis of Thiazoles Construction of the Benzothiazole Ring From 2-Aminobenzenethiols Hugerschoff Synthesis Jacobson Cyclization Miscellaneous Methods to Form Thiazole and Benzothiazole Possible Liabilities of Drugs Containing Thiazoles and Benzothiazoles Thiazoles and Benzothiazoles as Bioisosteres Problems References 328 Chapter 8 Imidazoles and Benzimidazoles Introduction to Imidazole Reactivity of the Imidazole Ring Nitrogen Alkylation Electrophilic C-Substitution Metallation and Direct Pd-Activation Construction of the Imidazole Ring Debus Weidenhagen Bredereck Radiszewski 344

6 xiii van Leusen Use of a-amido-ketones Use of DAMN Reagent Fused-lmidazole Rings Miscellaneous Imidazole Ring Construction Conversion of Imidazolines to Imidazoles Possible Liabilities of Imidazole-Containing Drugs Introduction to Benzimidazole Synthesis of Benzimidazoles: Classical Approaches Construction of the Benzimidazole Core Using Transition Metal- Mediated Approaches C-N Bond Formation from Aryl Halide C-H Functionalization Alternative Cyclization Approach Toward Benzimidazoles: Process Route Toward BYK Problems References 370 Chapter 9 Triazoles and Tetrazoles Introduction Reactivity of the Triazole and Tetrazole Ring Substitution of the 1,2,3-Triazole Substitution of the 1,2,4-Triazole Alkylation of Triazole Substitution of the Tetrazole Reactions of 1,2,3-Triazoles and Tetrazoles Construction of the Triazole Ring Construction of the 1,2,3-Triazole Ring Construction of the 1,2,4-Triazole Ring Construction of the Tetrazole Ring Possible Liabilities oftriazole-containing Drugs Problems References 394 part III SIX-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 397 Chapter 10 Pyridines Introduction Pyridine-Containing Drugs Potential Liabilities for Pyridine-Containing Drugs Reactivity of the Pyridine Ring 404

7 xiv Electrophilic Attack at Nitrogen of the Pyridine Ring C-C/C-N Cross-Coupling Reactions with Organometallic Reagents Construction of the Pyridine Ring Synthesis via Condensation Reactions Synthesis via Cycloaddition Reactions Synthesis via Rearrangement Reactions Synthesis via Transformation of Another Heterocycle Problems References 459 Chapter 11 Quinolines and Isoquinolines Introduction Reactivity of the Quinoline and Isoquinoline Ring Protonation Electrophilic Addition to the Nitrogen Atom Electrophilic Substitution at Carbon Atom Nucleophilic Substitution Amphiphilic Character of Quinoline-A^-Oxides Metallation of Quinolines and Isoquinolines Palladium-Catalyzed Oxidative Coupling Cross-Coupling Reactions Construction of Quinoline Core Camps Quinoline Synthesis Combes Quinoline Synthesis Conrad-Limpach and Knorr Reactions Friedlander and Pfitzinger Syntheses Gould-Jacobs Reaction Meth-Cohn Quinoline Synthesis Skraup/Doebner-von Miller Reaction Modern Methods Construction of Isoquinoline Core Bischler-Napieralski Reaction Pictet-Spengler Reaction Pictet-Gams Isoquinoline Synthesis Pomeranz-Eritsch Reaction Gabriel-Colman Rearrangement Modern Methods Possible Liabilities of Drugs Containing Quinoline and Isoquinoline Rings Problems References 528

8 xv PART IV SIX-MEMBERED HETEROCYCLES WITH TWO HETEROATOMS 535 Chapter 12 Pyrazines and Quinoxalines Introduction Formation ofdiazines Reactivity of the Molecules Reactivity of the Nitrogen Reactivity of the Diazine Ring Metallation of the Diazine Ring Coupling Reactions Transition-metal Coupling Reactions Palladium-catalyzed Reactions Problems References 565 Chapter 13 Pyrimidines Introduction Construction of the Pyrimidine Ring Synthesis Involving Formation of Two Bonds Synthesis Involving Formation ofthree or More Bonds Synthesis of Pyrimidine-Fused Systems Synthesis of Pyrimidine-Containing Drugs Allopurinol Trimethoprim Imatinib Bosentan Erlotinib Rosuvastatin Sildenafil Problems References 611 Chapter 14 Quinazolines and Quinazolones Introduction Reactions of Quinazolines and Quinazolinones Reactions at C Reactions at C Metal-Mediated Substitution Reactions Quinazoline and Quinazolinone Synthesis Bischler Reaction Niementowski Reaction 626

9 xvi Cyclization and Rearrangement Approaches Transition Metal-Promoted Reactions Synthesis of Quinazoline-and Quinazolinone-Containing Drugs Quinazoline-Containing Drugs Quinazolinone-Containing Drugs Problems References 644 Subject Index 647