Preface

Although the major seminal discoveries in cross-coupling occurred during the 1970s, the importance of this technology has been realized only during the last two decades. Since then, the field has experienced rapid growth, ultimately leading to the award of the 2010 Nobel Prize in Chemistry.¹  The original pioneers may not have anticipated during that time that this area would become such a force in industry and academia, revolutionizing the way we think about organic synthesis, be it for a small molecule or a complex drug molecule or natural product. In fact, Prof. Heck in a BBC interview after he shared the 2010 Nobel Prize with Prof. Suzuki and Prof. Negishi, commented that he “did not make a dime out of this technology”, while Prof. Negishi commented that he was “lucky enough to be alive” to receive the award. I heard Prof. Suzuki speaking at a conference that he had difficulties in publishing his pioneering work in top-rated journals as the reviewers were “not so nice”. However, in the above-mentioned BBC interview, he joked that his hypertension is well controlled by one of the sartans developed using the Suzuki–Miyaura coupling technology – an ultimate satisfaction for any inventor to reach the climax.

I got into the area of cross-coupling accidentally when I joined Johnson Matthey in late 1995. I originally worked in the area of process chemistry and non-precious metal-based new product development, and in my spare time I started looking at the dppf ligand based on an inquiry. Although we developed a good process, the project died. Quite frustrated, I started to read about this ligand in a book titled Ferrocenes by Prof. Togni and Prof. Hayashi, where the importance of the bite angle was mentioned with respect to a Kumada–Corriu coupling involving a sec-alkyl Grignard reagent.²  Although we could not sell even gram quantities for 1–2 years, we pushed dppfPdCl₂ as a “magic catalyst” based on the description by Gan and Hor,²  in terms of its air stability and activity/selectivity in comparison with the air-sensitive Pd(PPh₃)₄. This was during the time that Prof. Hartwig started publishing several amination reactions, where the use of the dppf ligand in conjunction with Pd(dba)₂ or even the preformed catalyst was highlighted, while Prof. Buchwald was using a BINAP/Pd₂dba₃ combination for the same technology. We were the first group to develop a good process for both dppf and dppfPdCl₂ for multi-kilogram quantities for the industry. This helped us gain an early understanding of the importance of preformed catalysts versus in situ in terms of selectivity, activity, scalability and ease of handling, which has become a main theme today in the area of cross-coupling. Very soon, the field began to develop rapidly – 1998 was marked as an exciting year for cross-coupling. The first book on this topic was published by Prof. Diederich and Prof. Stang.³  Prof. Buchwald’s work⁴  using a novel electron-rich phosphine and Prof. Fu’s work⁵  on the use of the known “bulky electron-rich” P(t-Bu)₃ ligand, in conjunction with Pd, were other significant events in the new trends in cross-coupling with respect to C–C and C–N coupling, although Dr. Koie⁶  also reported related studies for C–N coupling. Continuing on the same theme, in subsequent years many modern ligands were developed by Prof. Buchwald (biaryl ligands – 1998),⁷  Prof. Nolan (N-heterocyclic carbenes – 1999),⁸  Prof. Hartwig (Q-Phos – 2000)⁹  and Prof. Beller (adamantyl-based ligands – 2000)¹⁰  to solve many problems in cross-coupling (see Chapters 2 and 4).

Making the catalyst technology accessible to fine chemical and pharmaceutical industries all over the world and also academia to meet their needs has been my primary concern in concert with understanding the structure–activity relationships of the catalysts and substrates. Several new preformed catalysts have been developed involving the following classes of compounds: L₂PdX₂, L₂Pd(0), (L–L)PdX₂ and precursors to LPd(0)-based catalysts, which indeed changed the landscape (Chapter 3).¹¹  New versions of the catalysts have emerged from time to time just as in the case of the iPhone™ technology, where the ever-increasing requirements of the customers such as air stability, low loading/high activity and selectivity, operating under mild reaction conditions, ease of handling, scalability of the catalyst and the coupling reactions, broader substrate scope and waste minimization have been addressed.

In spite of the new developments, demands continue to increase, broadening the scope of this technology. This was a significant driving force when I agreed to do this book, following an invitation from Dr Merlin Fox of the Royal Society of Chemistry. The initial feeling was overwhelming given my other responsibilities. Fortunately, I was very much aware of the academic push and industry expectations, and hence decided to create this book by providing the reader with a basic understanding about coupling, while discussing the modern trends from a technology and applied point of view. On behalf of the contributors, I hope that this book will serve as a textbook-cum-reference guide for both undergraduate and graduate students and also those who are experts in the area, irrespective of their academic or industrial background. It was designed to have contributions from both junior and senior authors, who are world leaders in their field, covering a wide range of topics in 16 chapters; including the logic behind choosing the ligand and catalyst, new reactions such as carboiodination, metal detection in the APIs, flow chemistry, API synthesis, reaction mechanisms, green chemistry, etc.

Because of my industry background, quality was one of my prime concerns, considering the size of the book. I was fortunate enough to be able to implement a peer review process for each chapter by at least two or three subject experts. With the reputation of Royal Society of Chemistry, I promised to maintain a high quality standard in terms of the book production.

I knew how busy each author was, considering their day-to-day responsibilities. A few had to go through some personal, unforeseen difficulties after they accepted the offer. I sincerely thank them all for putting their trust in me and completing the chapters with utmost sincerity. I am sure that their contributions in this book will stimulate the area further to grow at an advanced pace. I also personally acknowledge Johnson Matthey Catalysis and Chiral Technologies, the Royal Society of Chemistry and all the reviewers for their support and help in different capacities to make this project a success. My co-workers, Dr Carin Johansson Seechurn and Dr Andrew DeAngelis, are also thanked for their assistance.

Thomas J. Colacot