Cover Page

Advisory Board

John E. Baldwin

Peter Beak

Dale L. Boger

André B. Charette

Engelbert Ciganek

Dennis Curran

Samuel Danishefsky

Huw M. L. Davies

John Fried

Jacquelyn Gervay-Hague

Heinz W. Gschwend

Stephen Hanessian

Louis Hegedus

Paul J. Hergenrother

Robert C. Kelly

Andrew S. Kende

Laura Kiessling

Steven V. Ley

James A. Marshall

Michael J. Martinelli

Stuart W. McCombie

Jerrold Meinwald

Scott J. Miller

Larry E. Overman

Leo A. Paquette

Gary H. Posner

T. V. RajanBabu

Hans J. Reich

James H. Rigby

William R. Roush

Scott D. Rychnovsky

Martin Semmelhack

Charles Sih

Amos B. Smith, III

Barry M. Trost

James D. White

Peter Wipf

Former Members of the Board Now Deceased

Roger Adams

Homer Adkins

Werner E. Bachmann

A. H. Blatt

Robert Bittman

Virgil Boekelheide

George A. Boswell, Jr.

Theodore L. Cairns

Arthur C. Cope

Donald J. Cram

David Y. Curtin

William G. Dauben

Richard F. Heck

Louis F. Fieser

Ralph F. Hirshmann

Herbert O. House

John R. Johnson

Robert M. Joyce

Willy Leimgruber

Frank C. McGrew

Blaine C. McKusick

Carl Niemann

Harold R. Snyder

Milán Uskokovic

Boris Weinstein

Organic Reactions

Volume 94

Editorial Board

Scott E. Denmark, Editor-in-Chief

Jeffrey Aubé

David B. Berkowitz

Carl Busacca

Jin K. Cha

P. Andrew Evans

Paul L. Feldman

Dennis G. Hall

Donna M. Huryn

Marisa C. Kozlowski

Gary A. Molander

John Montgomery

Albert Padwa

Tomislav Rovis

Steven M. Weinreb

Robert M. Coates, Secretary University of Illinois at Urbana-Champaign, Urbana, Illinois

Jeffery B. Press, Secretary Press Consulting Partners, Brewster, New York

Danielle Soenen, Editorial Coordinator

Landy K. Blasdel, Editorial Assistant

Dena Lindsay, Editorial Assistant

Linda S. Press, Editorial Consultant

Engelbert Ciganek, Editorial Advisor

Associate Editors

Alberto Brandi

Francesca Cardona

Stefano Cicchi

Franca M. Cordero

Andrea Goti

Wiley Logo

Introduction to the Series Roger Adams, 1942

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.

Introduction to the Series Scott E. Denmark, 2008

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 21st 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 21st 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.

Preface to Volume 94

If we take into account the close relationship between carboxylic acids and nitronic acids, we shall come to the following comparison of the corresponding C and N compounds. The designation “nitrone” for the compounds of the type R1R2=N=O becomes readily comprehensible..”

P. Pfeiffer, Annalen 1916, 411, 72

The 76-year history of the Organic Reactions series serves not only as a treasure trove of knowledge but also as a chronicle of the progress of synthetic organic chemistry. In our current state of oversaturation and obsession with the latest report or incremental advance, we become immune to the realization of how much progress has been made in such a short period of time. Casual perusal of the more than 200 chapters in the series reveals the incredible structure of vertical science, a perspective difficult to perceive in a culture wherein “scholarly” outlets compete for immediate attention.

One of the most compelling illustrations of the progress of this discipline can be seen in the evolution of various reactions that have been documented several times in our history. Compare for example the chapter on the “Aldol Condensation” in Volume 16 (1968) with that on “Catalytic, Enantioselective Aldol Reactions” in Volume 67 (2006) or even more dramatically, the chapter on the “Schmidt Reaction” in Volume 3 (1946) and the update by the same name in Volume 78 (2012). Reading these chapters provides a welcome calibration on the health and power of synthesis and also invites the unavoidable question, “quo vadis” what will chemists be able to accomplish 50 years hence?

The single chapter in Volume 94 provides another such landmark, and one that is all the more remarkable because it provides an update on an even more recent chapter than those mentioned above. The combination of Rolf Huisgen's early studies on reactions of dipoles, along with the brilliant insights of Woodward and Hoffmann on the foundational theory of pericyclic reactions, has led to a universe of powerful transformations belonging the family of dipolar cycloadditions. One of the most synthetically useful members of this family is the [3+2] cycloaddition of nitrones which was the topic of a definitive chapter in Volume 36 (1988) authored by Pat Confalone and Edward Huie. Now, nearly 30 years later, this reaction has grown to be so valuable in organic synthesis that a similarly comprehensive treatment has become impossible. Nevertheless, we are extremely fortunate that one of the world's leading experts in this reaction, Professor Alberto Brandi and his team at the University of Florence (in the charmingly named “Dipartimento Ugo Schiff”) agreed to compose an update focused solely on the reactions of cyclic nitrones with alkenes. Even with this limited scope, this chapter constitutes the entire contents of Volume 94.

“[3+2] Dipolar Cycloadditions of Cyclic Nitrones with Alkenes” by Alberto Brandi, Francesca Cardona, Stefano Cicchi, Franca M. Cordero, and Andrea Goti is a masterful treatment of both the inter- and intramolecular variants of this tremendously important reaction. The chapter is systematically organized by ring size of the nitrone in the intermolecular manifold and then again by tether length in the intramolecular manifold. The critical features of regioselectivity and stereoselectivity characteristic of all cycloaddition reactions are expertly presented such that readers can understand the key controlling components and are thus well positioned to design synthetic sequences with predictable outcomes. Of course, the product isoxazolidines are rarely found in target structures, so the authors have described the most common unmasking strategies to reveal the 1,3-amino alcohol subunit in a wide range of structural settings. Not surprisingly, a reaction capable of increasing molecular complexity with predictable regio- and stereoselectivity has found widespread application in synthetic endeavors, and the authors provide many illustrations that are bound to inspire readers to employ this useful technology. Finally, as is characteristic of organic reactions developed in the past 30 years, the [3+2] cycloaddition is susceptible to catalysis, and the most recent advances in this aspect are thoroughly treated as well. The Tabular Survey comprises 13 tables organized by both nitrone ring size and then connecting tether length to allow readers to easily identify the kinds of precursor structure that could be employed in their own synthetic programs.

Volume 94 represents the fifteenth single chapter volume to be produced in our 76-year history (eighth in the past fifteen volumes!). Such single-chapter volumes represent definitive treatises on extremely important chemical transformations. The organic chemistry community owes an enormous debt of gratitude to the authors of such chapters for the generous contribution of their time, effort, and insights on reactions that we clearly value. The completion of this chapter in just over four years after being commissioned is fitting testimony to the dedication and efforts of this highly talented and motivated Italian team.

It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular Steven Weinreb who shepherded this chapter to completion. The contributions of the author, editors, and the publisher were expertly coordinated by the board secretary, Robert M. Coates. In addition, the Organic Reactions enterprise could not maintain the quality of production without the dedicated efforts of its editorial staff, Dr. Danielle Soenen, Dr. Jeffery Press, Dr. Linda S. Press, Dr. Dena Lindsey, and Dr. Landy Blasdel. Insofar as the essence of Organic Reactions chapters resides in the massive tables of examples, the authors' and editorial coordinators' painstaking efforts are highly prized.

Scott E. Denmark
Urbana, Illinois