Heterocyclic Chemistry

This book has so closely matched the requirements of its readership over the years that it has become the first choice for chemists worldwide.

Heterocyclic chemistry comprises at least half of all organic chemistry research worldwide. In particular, the vast majority of organic work done in the pharmaceutical and agrochemical industries is heterocyclic chemistry.

The fifth edition of Heterocyclic Chemistry maintains the principal objective of earlier editions – to teach the fundamentals of heterocyclic reactivity and synthesis in a way that is understandable to second- and third-year undergraduate chemistry students. The inclusion of more advanced and current material also makes the book a valuable reference text for postgraduate taught courses, postgraduate researchers, and chemists at all levels working with heterocyclic compounds in industry.

Fully updated and expanded to reflect important 21^st century advances, the fifth edition of this classic text includes the following innovations:

• Extensive use of colour to highlight changes in structure and bonding during reactions
• Entirely new chapters on organometallic heterocyclic chemistry, heterocyclic natural products, especially in biochemical processes, and heterocycles in medicine
• New sections focusing on heterocyclic fluorine compounds, isotopically labeled heterocycles, and solid-phase chemistry, microwave heating and flow reactors in the heterocyclic context

Essential teaching material in the early chapters is followed by short chapters throughout the text which capture the essence of heterocyclic reactivity in concise resumés suitable as introductions or summaries, for example for examination preparation. Detailed, systematic discussions cover the reactivity and synthesis of all the important heterocyclic systems. Original references and references to reviews are given throughout the text, vital for postgraduate teaching and for research scientists. Problems, divided into straightforward revision exercises, and more challenging questions (with solutions available online), help the reader to understand and apply the principles of heterocyclic reactivity and synthesis.

Preface to the Fifth Edition xix

P.1 Hazards xxi

P.2 How to Use This Textbook xxi

Acknowledgements xxii

References xxii

Web Site xxii

Biography xxiii

Definitions of Abbreviations xxv

1 Heterocyclic Nomenclature 1

2 Structures and Spectroscopic Properties of Aromatic Heterocycles 5

3 Substitutions of Aromatic Heterocycles 19

4 Organometallic Heterocyclic Chemistry 37

5 Methods in Heterocyclic Chemistry 97

6 Ring Synthesis of Aromatic Heterocycles 107

7 Typical Reactivity of Pyridines, Quinolines and Isoquinolines 115

8 Pyridines: Reactions and Synthesis 125

9 Quinolines and Isoquinolines: Reactions and Synthesis 177

10 Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones 205

11 Pyryliums, 2- and 4-Pyrones: Reactions and Synthesis 209

12 Benzopyryliums and Benzopyrones: Reactions and Synthesis 229

13 Typical Reactivity of the Diazine: Pyridazine, Pyrimidine and Pyrazine 249

14 The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions and Synthesis 253

15 Typical Reactivity of Pyrroles, Furans and Thiophenes 289

16 Pyrroles: Reactions and Synthesis 295

17 Thiophenes: Reactions and Synthesis 325

18 Furans: Reactions and Synthesis 347

19 Typical Reactivity of Indoles, Benzo[b]thiophenes, Benzo[b]furans, Isoindoles, Benzo[c]thiophenes and Isobenzofurans 369

20 Indoles: Reactions and Synthesis 373

21 Benzo[b]thiophenes and Benzo[b]furans: Reactions and Synthesis 433

22 Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions and Synthesis 447

23 Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and -1,2-Azoles 455

24 1,3-Azoles: Imidazoles, Thiazoles and Oxazoles: Reactions and Synthesis 461

25 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 485

26 Benzanellated Azoles: Reactions and Synthesis 503

27 Purines: Reactions and Synthesis 515

28 Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 539

29 Heterocycles Containing More Than Two Heteroatoms 557

30 Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis 587

31 Special Topics 609

32 Heterocycles in Biochemistry; Heterocyclic Natural Products 629

33 Heterocycles in Medicine 645

Index 665

“Overall, this book is recommended as a text for undergraduate and more advanced students on this pervasive, important, and underappreciated topic in chemistry.” (Journal of Chemical Education, 1 October 2012)

"This excellent book is well written, heavily referenced, and thoroughly indexed. Accordingly, it serves as both an instructional heterocyclic chemistry textbook and a portal to the primary synthetic chemistry literature." (Journal of Medicinal Chemistry, 2011)

"My favourite chapter is the organometallic chemistry that presents an up-to-date treatment of the topic and helps confirms a colleague's observation that ‘With today's techniques one can be convinced that a modern organic chemist can make any small molecule he or she desires.' I particularly like the treatment of the concatenation of five-membered ring systems, an increasingly important area in medicinal chemistry. This chapter proves a real ‘coup de grace'." (Reviews, December 2010)

"In summary, Heterocyclic Chemistry by Joule and Mills is in a class of its own and can be thoroughly recommended as supplementary reading for undergraduate courses and as a first port of call for researchers seeking a quick entry to the extensive heterocyclic literature." (Applied Organometallic Chemistry, 2010)

"My recommendation is, even if you already have the 4th edition, to buy the latest version. At only £39.95 for the paperback version this is outstanding value for money." (Organic Process Research & Development Journal, 2010)

John Joule is Emeritus Professor in the School of Chemistry, The University of Manchester, UK

Keith Mills spent 25 years in the Medicinal Chemistry and Development Chemistry departments at GlaxoSmithKline, Stevenage, UK, and is now an independent consultant.

Heterocyclic chemistry is a central part of organic chemistry and biochemistry. The term refers to a particular set of chemical structure characteristics, with many drugs and specialty chemicals, and most agrochemicals, containing these characteristics. Heterocyclic Chemistry by Joule & Mills has established itself as the premier textbook of heterocyclic chemistry, used by high level undergraduates, postgraduates and industrial researchers all over the world.

Heterocyclic Chemistry covers the fundamentals of heterocyclic reactivity and synthesis in a way that is understandable to second- and third-year undergraduate chemistry students. It also includes more advanced material, making the book appropriate for postgraduate taught courses and to researchers, either at postgraduate degree level or those working with heterocyclic compounds in industry. Essential teaching material is collected in specific introductory chapters, explaining the principles of heterocyclic reactivity in the simplest terms, suitable either as introductions or as summaries for examination preparation. These chapters are augmented by detailed, systematic discussions of the chemical reactivity of particular heterocyclic systems. References to both primary literature and reviews are given throughout the text, and whilst these are essential for postgraduate teaching and to research workers, they do not interfere with the readability of the text for undergraduate students.