In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better‐known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the author has been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy, the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.

In the intervening years since “The Chief” wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.

From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on even greater significance for the practice of chemical experimentation in the 21^st century.

Adams' description of the content of the intended chapters is still remarkably relevant today. The development of new chemical reactions over the past decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on the willingness of organic chemists to devote their time and efforts to the preparation of chapters. The fact that, at the dawn of the 21^st century, the series continues to thrive is fitting testimony to those chemists whose contributions serve as the foundation of this edifice. Chemists who are considering the preparation of a manuscript for submission to Organic Reactions are urged to contact the Editor‐in‐Chief.

Life isn't just addition and subtraction.

There is also the accumulation, the multiplication, of loss, of failure.

Julian Barnes, 2011

The Sense of an Ending

The two chapters in this volume of Organic Reactions reflect the notion of addition and subtraction, which are formally two sides of the same coin. For example, the addition of HX to an alkene gives a haloalkane with loss of the double bond, whereas the elimination of HX from a haloalkane does the converse. Indeed, this sentiment is the very cornerstone of designing a successful sequence of bond‐forming reactions that culminate in the conversion of one functional group into another in an orchestrated series of events to deliver a specific target with the desired properties. Hence, addition and subtraction are omnipresent in a particular sequence of reactions, irrespective of the nature and complexity of the transformations involved. The second line of the quote could pertain to the toil of discovery, in which the accumulation and multiplication of loss and failure are a prerequisite for the development of a new process. Indeed, any chemist can attest to the anguish and euphoria involved in developing a new transformation or synthetic route. Nevertheless, one critical facet of organic chemistry is the ability to convert failure into success and thus generate a body of work that disguises the many hours of loss and failure in the pursuit of success. A particularly attractive feature with the Organic Reactions series is the collation of this work in a single chapter to permit the chemist to compare and contrast these variations to provide confidence in selecting specific reaction conditions for a new application that mitigate the chances of failure. The two chapters in this volume focus on transformations connected by the addition and subtraction of functional groups that lead to more complex and valuable entities. The first chapter deals with the venerable hydroformylation reaction, and the second chapter delineates the Hauser–Kraus, Sammes, Staunton–Weinreb, and Tamura Annulations. Although both reactions involve olefin addition reactions, the latter is formally a cycloaddition of a 1,4‐dipole.

The first chapter by Toshiki Tazawa, Andreas Phanopoulos, and Kyoko Nozaki is an excellent treatise on the enantioselective hydroformylation reaction, which is the net addition of a formyl group and a hydrogen atom to an olefin catalyzed by a chiral late transition‐metal catalyst. Otto Roelen serendipitously discovered the hydroformylation reaction in 1938 during investigations of the Fischer‐Tropsch process. Remarkably, the reaction has become an important industrial process responsible for the annual global production of more than 10 million tons of so‐called “oxo” products. Although the reaction delivers both branched and linear aldehydes, it is the preparation of branched chiral nonracemic aldehydes that has recently attracted considerable attention, largely because chiral aldehydes are important intermediates for pharmaceuticals, agrochemicals, flavors, fragrances, and other fine chemicals. This chapter delineates the development of the enantioselective hydroformylation reaction from preliminary work with platinum catalysts to the more reactive rhodium variants, thereby complementing and updating an earlier chapter by Iwao Ojima, Chung‐Ying Tsai, Maria Tzamarioudaki, and Dominique Bonafoux (Volume 56, 2000) that primarily focused on the preparation of achiral linear aldehydes. The Mechanism and Stereochemistry section focuses entirely on the rhodium‐catalyzed reaction, providing an insightful account into the general catalytic cycle and the origin of regio‐ and enantioselectivity. For instance, the general catalytic cycle details Wilkinson's dissociative mechanism in the context of mono‐ and bidentate phosphine ligands, which includes different sources of hydrogen and carbon monoxide. The origin of regio‐ and enantioselectivity is discussed in the context of reaction conditions that render this process irreversible, namely pressure, temperature, etc., using the insight gleaned from both experimental and computational studies. The Scope and Limitations component is organized using the alkene as the primary rubric, namely vinyl arenes, aliphatic acyclic alkenes, heteroatom‐substituted acyclic alkenes, α,β‐unsaturated carbonyl compounds, allylic‐ and homoallylic‐substituted acyclic alkenes, conjugated dienes, and cyclic alkenes. The Applications to Synthesis section describes several applications to natural product syntheses, and the Comparison with Other Methods section provides a critical assessment of more classical methods that are commonly deployed for the construction of aldehydes bearing α‐ and β‐stereogenic centers. The Tabular Survey incorporates reactions reported up to June 2020 and mirrors the Scope and Limitations section to permit the reader to easily identify a specific reaction combination of interest. The authors have applied a lower limit of enantioselectivity to primarily focus on examples of practical interest while maintaining the necessary scholarship to define the limitations in a valuable and informative manner. Overall, this excellent chapter on a fundamentally important reaction, that continues to generate considerable interest provides a valuable resource for practicing synthetic chemists in both academia and industry.

The second chapter by Charles B. de Koning, Kathy Hadje Georgiou, Joseph P. Michael, and Amanda L. Rousseau delineates the development of the Hauser–Kraus, Sammes, Staunton–Weinreb, and Tamura Annulations. These annulations are all closely related and date back to Schmid's early work in the mid‐1960s, which employed an ester‐stabilizing group to generate the enolate using sodium in ethanol. Further studies in the late 1970s and early 1980s initiated a series of adaptations that permit access to similar annulated products, albeit with the newly formed ring at different oxidation states. This class of annulation reactions is based on the addition of a 1,4‐dipole equivalent to a Michael acceptor with a concomitant Dieckmann or Claisen condensation to complete the annulation. The chapter independently catalogs the development of each of these variants, which provides a versatile strategy for constructing annulated six‐membered rings. The Mechanism section outlines the two most common mechanistic scenarios for this type of process, which either proceed through the stepwise addition of the formal 1,4‐dipole or a [4+2] cycloaddition of the dienolate mesomer with the requisite electrophilic acceptor. The section delineates the oxidation‐state differences in the products, which is primarily derived from the differences in C3 substitution in the 1,4‐dipole/1,3‐diene component. There is also evidence for one mechanism over the alternative in some cases. The Scope and Limitations section details each annulation separately, which permits the direct comparison to provide context for which version might prove superior for a particular application. The authors have described the preparation of the 1,4‐dipole equivalents in specific cases, which include variations in the nucleophilic phthalide and homophthalide components and their reactions with a variety of acyclic and cyclic Michael acceptors (enones, cyclohexadienes, quinones, and arynes). A particularly notable feature of this section is the discussion of the knowledge gaps in each of the four processes, which enable future areas of investigation to be easily identified. The Applications to Synthesis section describes an expansive array of applications to the construction of particularly challenging and important natural products, which certainly highlights the utility of this approach as an enabling transformation. The targets illustrate why this process has become so important for preparing complex bioactive agents. The section on Comparison with Other Methods is primarily focused on the examination of other cycloaddition and annulation reactions that deliver similar adducts. The Tabular Survey organization follows the Scope and Limitations, wherein the specific type of annulation is listed separately to permit the reader to compare and contrast the kind of annulation of interest. A particularly interesting facet of this chapter is that one of the variants is named after our esteemed colleague, Dr. Steven M. Weinreb, who ironically served as the Responsible Editor for this chapter. Overall, this is an outstanding chapter on a particularly important and useful process that will be a valuable resource to the synthetic community.

This volume of Organic Reactions is dedicated to Dr. Debra D. Dolliver, who sadly passed away in January of this year. Debra joined Organic Reactions as a Processing Editor in 2018 and worked on many important chapters, including the Nozaki chapter in this volume. She quickly learned the organization's nuances and contributed to several of the previous volumes that have been published in recent years. We acknowledge her contributions to the series in her short tenure, and we offer our deepest condolences to her husband, Dr. Artie McKim. A more detailed obituary is included at the beginning of this volume written by Arty McKim and Kevin H. Shaughnessy. The obituary paints a picture of a talented and deeply caring individual. I was unaware that Debra was also an artist and specialized in watercolors. If you are interested, I recommend visiting her website, where there are some beautiful examples of landscapes, still life subjects, and her dogs (dolliverart.com). I also selected the quotation with the loss of Debra in mind, which is meant to pertain to the life cycle and the pain of losing individuals. The events of 2020 have brought the value of human life and the expectation of its longevity to the fore. We therefore honor Dr. Debra D. Dolliver in this volume and recognize her contributions to our profession; she is sadly missed.

I would be remiss if I did not acknowledge the entire Organic Reactions Editorial Board for their collective efforts in steering this volume through the various stages of the editorial process. I want to thank Donna M. Huryn (Chapter 1) and Steven M. Weinreb (Chapter 2), who served as the Responsible Editors to marshal the chapters through the various phases of development. I am also deeply indebted to Dr. Danielle Soenen for her continued and heroic efforts as the Editorial Coordinator; her knowledge of Organic Reactions is critical to maintaining consistency in the series. Dr. Dena Lindsay (Secretary to the Editorial Board) is thanked for coordinating the contributions of the authors, editors, and publisher. In addition, the Organic Reactions enterprise could not maintain the quality of production without the efforts of Dr. Steven M. Weinreb (Executive Editor), Dr. Engelbert Ciganek (Editorial Advisor), Dr. Landy Blasdel (Processing Editor), and the late Dr. Debra Dolliver (Processing Editor). I would also like to acknowledge Dr. Barry B. Snider (Secretary) for keeping everyone on task and Dr. Jeffery Press (Treasurer) for making sure that we are fiscally solvent!

I am also indebted to past and present members of the Board of Editors and Board of Directors for ensuring the enduring quality of Organic Reactions. The unique format of the chapters, in conjunction with the collated tables of examples, makes this series of reviews both unique and exceptionally valuable to the practicing synthetic organic chemist.