Organic Synthesis

By Michael Smith

Organic Synthesis, Fourth Edition, provides a reaction-based approach to this important branch of organic chemistry. Updated and accessible, this eagerly-awaited revision offers a comprehensive foundation for graduate students coming from disparate backgrounds and knowledge levels, to provide them with critical working knowledge of basic reactions, stereochemistry and conformational principles. This reliable resource uniquely incorporates molecular modeling content, problems, and visualizations, and includes reaction examples and homework problems drawn from the latest in the current literature.

In the Fourth Edition, the organization of the book has been improved to better serve students and professors and accommodate important updates in the field. The first chapter reviews basic retrosynthesis, conformations and stereochemistry. The next three chapters provide an introduction to and a review of functional group exchange reactions; these are followed by chapters reviewing protecting groups, oxidation and reduction reactions and reagents, hydroboration, selectivity in reactions. A separate chapter discusses strategies of organic synthesis, and he book then delves deeper in teaching the reactions required to actually complete a synthesis. Carbon-carbon bond formation reactions using both nucleophilic carbon reactions are presented, and then electrophilic carbon reactions, followed by pericyclic reactions and radical and carbene reactions. The important organometallic reactions have been consolidated into a single chapter. Finally, the chapter on combinatorial chemistry has been removed from the strategies chapter and placed in a separate chapter, along with valuable and forward-looking content on green organic chemistry, process chemistry and continuous flow chemistry.

Throughout the text, Organic Synthesis, Fourth Edition utilizes Spartan-generated molecular models, class tested content, and useful pedagogical features to aid student study and retention, including Chapter Review Questions, and Homework Problems. A full Solutions Manual is also available online for qualified instructors, to support teaching.

• Winner, 2018 Textbook Excellence Award (Texty) from the Textbook and Academic Authors Association
• Fully revised and updated throughout, and organized into 19 chapters for a more cogent and versatile presentation of concepts
• Includes reaction examples taken from literature research reported between 2010-2015
• Features new full-color art and new chapter content on process chemistry and green organic chemistry
• Offers valuable study and teaching tools, including Chapter Review Questions and Homework Problems for students; Solutions Manual for qualified course instructors

• Language: English
• Publisher: Academic Press
• Release date: Nov 22, 2016
• ISBN: 9780128008072

Michael Smith

Professor Michael B. Smith received an A.A. from Ferrum College in 1967 and a BS in chemistry from Virginia Polytechnic Institute in 1969. After working for 3 years at the Newport News Shipbuilding and Dry Dock Co. in New- port News VA as an analytical chemist, he entered graduate school at Purdue University. He received a PhD in Organic Chemistry in 1977. He spent 1 year as a faculty research associate at the Arizona State University with Professor G. Robert Pettit, working on the isolation of cytotoxic principles from plants and sponges. He spent a second year of postdoctoral work with Professor Sidney M. Hecht at the Massachusetts Insti- tute of Technology, working on the synthesis of bleomycin A2.? Smith began his academic career at the University of Connecticut in 1979, where he is currently professor of chemistry.?In addition to this research, he is the author of the fifth, sixth, and seventh editions of March’s Advanced Organic Chemistry. He is also the author of an undergraduate textbook in organic chemistry titled Organic Chemistry. An Acid-Base Approach, now in its second edition. He is the editor of the Compendium of Organic Synthetic Methods, Volumes 6–13. He is the author of Organic Chemistry: Two Semesters, in its second edition, which is an outline of undergraduate organic chemistry to be used as a study guide for the first organic course. He has authored a research monograph titled Synthesis of Non-alpha Amino Acids, in its second edition.

Book preview

9780128008072_FC

Organic Synthesis

Fourth Edition

Michael B. Smith

Table of Contents

Cover image

Title page

Copyright

About the Author

Preface to the Fourth Edition

Preface to the Third Edition

Preface to the First Edition. Why I Wrote This Book!

Common Abbreviations

Chapter 1: Retrosynthesis, Stereochemistry, and Conformations

Abstract

1.1 Introduction

1.2 The Disconnection Protocol

1.3 Bond Proximity and Implications for Chemical Reactions

1.4 Stereochemistry

1.5 Conformations

1.6 Conclusion

Chapter 2: Acids, Bases, and Addition Reactions

Abstract

2.1 Introduction

2.2 Brønsted-Lowry Acids and Bases

2.3 Lewis Acids

2.4 Hard-Soft Acid-Base Theory

2.5 Acid-Base Reactions of Alkenes and Alkynes (Addition Reactions)

2.6 Conclusion

Chapter 3: Functional Group Exchange Reactions: Aliphatic and Aromatic Substitution and Elimination Reactions

Abstract

3.1 Introduction

3.2 Aliphatic Substitution Reactions

3.3 Heteroatom-Stabilized Carbocations

3.4 Substitution by Halogen

3.5 Elimination Reactions

3.6 Characteristics of Substitution and Elimination Reactions

3.7 Syn-Elimination Reactions

3.8 1,3-Elimination (Decarboxylation)

3.9 1,3-Elimination (Grob Fragmentation)

3.10 Aromatic Substitution

3.11 Conclusion

Chapter 4: Acids, Bases, and Functional Group Exchange Reactions: Acyl Addition and Acyl Substitution

Abstract

4.1 Introduction

4.2 Nucleophilic Acyl Addition and Substitution

4.3 Conjugate Addition

4.4 Functional Group Manipulation by Rearrangement

4.5 Macrocyclic Compounds

4.6 Conclusion

Chapter 5: Functional Group Exchange Reactions: Protecting Groups

Abstract

5.1 Introduction

5.2 When Are Protecting Groups Needed?

5.3 Protecting Groups for Alcohols, Carbonyls, and Amines

5.4 Conclusion

Chapter 6: Functional Group Exchange Reactions: Oxidations

Abstract

6.1 Introduction

6.2 Alcohols to Carbonyls (CH glyph_sbnd OH → C glyph_dbnd O)

6.3 Formation of Phenols and Quinones

6.4 Oxidation of Alkenes to Epoxides

6.5 Conversion of Alkenes to Diols (C glyph_dbnd C → CHOH glyph_sbnd CHOH)

6.6 Baeyer-Villiger Oxidation (RCOR′ → RCO2R′)

6.7 Oxidative Bond Cleavage (C glyph_dbnd C → C glyph_dbnd O + O glyph_dbnd C)

6.8 Oxidation of Alkyl or Alkenyl Fragments (CH → C glyph_dbnd O OR C glyph_sbnd OH)

6.9 Oxidation of Sulfur, Selenium, and Nitrogen

6.10 Conclusion

Chapter 7: Functional Group Exchange Reactions: Reductions

Abstract

7.1 Introduction

7.2 The Nature of Hydride Reducing Agents

7.3 Borane and Aluminum Hydride

7.4 Sodium Borohydride

7.5 Alternative Metal Borohydrides (Li, Zn, Ce)

7.6 Lithium Aluminum Hydride

7.7 Hydride Reducing Agents With Electron-Releasing Groups

7.8 Hydride Reducing Agents With Electron-Withdrawing Groups

7.9 Stereoselectivity in Reductions

7.10 Catalytic Hydrogenation

7.11 Dissolving Metal Reductions

7.12 Nonmetallic Reducing Agents

7.13 Conclusion

Chapter 8: Synthetic Strategies

Abstract

8.1 Introduction

8.2 Target Selection

8.3 Retrosynthesis

8.4 Synthetic Strategies

8.5 The Strategic Bond Approach

8.6 Strategic Bonds in Rings

8.7 Selected Synthetic Strategies: Maeocrystal V

8.8 Biomimetic Approach to Retrosynthesis

8.9 The Chiral Template Approach

8.10 Degradation Techniques as a Tool for Retrosynthesis

8.11 Computer Generated Strategies

8.12 Conclusion

Chapter 9: Functional Group Exchange Reactions: Hydroboration

Abstract

9.1 Introduction

9.2 Preparation of Alkyl Boranes

9.3 Preparation of Alkenylboranes

9.4 Formation of Oxygen-Containing Functional Groups

9.5 Other Functional Group Exchange Reactions

9.6 Conclusion

Chapter 10: Functional Group Exchange Reactions: Selectivity

Abstract

10.1 Introduction

10.2 Stereocontrol in Acyclic Systems

10.3 Stereocontrol in Cyclic Systems

10.4 Neighboring Group Effects and Chelation Effects

10.5 Acyclic Stereocontrol via Cyclic Precursors

10.6 Baldwin's Rules for Ring Closure

10.7 Conclusion

Chapter 11: Carbon-Carbon Bond-Forming Reactions: Cyanide, Alkyne Anions, Grignard Reagents, and Organolithium Reagents

Abstract

11.1 Introduction

11.2 Cyanide

11.3 Alkyne Anions (R glyph_sbnd C glyph_tbnd C:−)

11.4 Grignard Reagents (C glyph_sbnd Mg)

11.5 Grignard Reagents: Reduction, Organocerium Reagents, and Enolization

11.6 Organolithium Reagents (C glyph_sbnd Li)

11.7 Conclusion

Chapter 12: Carbon-Carbon Bond-Forming Reactions: Stabilized Carbanions, Organocuprates, and Ylids

Abstract

12.1 Introduction

12.2 Sulfur-Stabilized Carbanions and Umpolung

12.3 Organocopper Reagents (C glyph_sbnd Cu)

12.4 Phenolic Carbanions

12.5 Ylids

12.6 Transition Metal Olefination Reagents

12.7 Silane Reagents

12.8 Conclusion

Chapter 13: Nucleophilic Species That Form Carbon-Carbon Bonds: Enolate Anions

Abstract

13.1 Introduction

13.2 Formation of Enolate Anions

13.3 Reactions of Enolate Anions With Electrophiles

13.4 Enolate Condensation Reactions

13.5 Stereoselective Enolate Reactions

13.6 Enamines

13.7 Michael Addition and Related Reactions

13.8 Enolate Reactions of α-Halo Carbonyl Derivatives

13.9 Conclusion

Chapter 14: Pericyclic Reactions: The Diels-Alder Reaction

Abstract

14.1 Introduction

14.2 Frontier Molecular Orbital Theory

14.3 HOMO, LUMO Energies, and Orbital Coefficients

14.4 Allowed and Forbidden Reactions

14.5 [4+2]-Cycloadditions

14.6 Rate Enhancement in Diels-Alder Reactions

14.7 Intramolecular Diels-Alder Reactions

14.8 Inverse Electron Demand and the Retro-Diels-Alder Reactions

14.9 Heteroatom Diels-Alder Reactions

14.10 Enantioselective Diels-Alder Reactions

14.11 Conclusion

Chapter 15: Pericyclic Reactions: [m + n]-Cycloadditions, Sigmatropic Rearrangements, Electrocyclic, and Ene Reactions

Abstract

15.1 Introduction

15.2 [2 + 2]-Cycloaddition Reactions

15.3 Electrocyclic Reactions

15.4 [3 + 2]-Cycloaddition Reactions

15.5 Sigmatropic Rearrangements

15.6 The Ene Reaction

15.7 Conclusion

Chapter 16: Carbon-Carbon Bond-Forming Reactions: Carbocation and Oxocarbenium Ion Intermediates

Abstract

16.1 Introduction

16.2 Carbocations

16.3 Carbocations and Carbon-Carbon Bond-Forming Reactions

16.4 Friedel-Crafts Reactions

16.5 Friedel-Crafts Reactions: Formation of Heteroatom-Containing Derivatives

16.6 Conclusion

Chapter 17: Formation of Carbon-Carbon Bonds Via Radicals and Carbenes

Abstract

17.1 Introduction

17.2 Structure of Radicals

17.3 Formation of Radicals by Thermolysis

17.4 Photochemical Formation of Radicals

17.5 Reactions of Free Radicals

17.6 Intermolecular Radical Reactions

17.7 Intramolecular Radical Reactions (Radical Cyclization)

17.8 Metal-Induced Radical Reactions

17.9 Carbenes and Carbenoids

17.10 Conclusion

Chapter 18: Metal-Mediated, Carbon-Carbon Bond-Forming Reactions

Abstract

18.1 Introduction

18.2 Copper-Catalyzed Coupling Reactions

18.3 π-Allyl Palladium Complexes

18.4 Named Palladium-Catalyzed Coupling Reactions

18.5 π-Allyl Nickel Complexes

18.6 Metathesis Reactions

18.7 Pauson-Khand Reaction

18.8 Organometallic Compounds as Carbanionic Reagents

18.9 Electrophilic Iron Complexes

18.10 Conclusion

Chapter 19: Combinatorial and Process Chemistry

Abstract

19.1 Combinatorial Chemistry

19.2 Process Chemistry

19.3 Continuous-Flow Synthesis

19.4 Conclusion

Subject Index

Disconnection Index

Copyright

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About the Author

Professor Michael B. Smith was born in Detroit, Michigan in 1946 and moved to Madison Heights, Virginia in 1957, where he attended high school. He received an A.A. from Ferrum College in 1967 and a BS in chemistry from Virginia Polytechnic Institute in 1969. After working for 3 years at the Newport News Shipbuilding and Dry Dock Co. in Newport News VA as an analytical chemist, he entered graduate school at Purdue University. He received a PhD in Organic Chemistry in 1977, under the auspices of Professor Joe Wolinsky. He spent 1 year as a faculty research associate at the Arizona State University with Professor G. Robert Pettit, working on the isolation of cytotoxic principles from plants and sponges. He spent a second year of postdoctoral work with Professor Sidney M. Hecht at the Massachusetts Institute of Technology, working on the synthesis of bleomycin A2. Smith began his academic career at the University of Connecticut in 1979, where he is currently professor of chemistry. In 1986 he spent a sabbatical leave in the laboratories of Professor Leon Ghosez, at the Université Catholique de Louvain in Louvain-la-Neuve, Belgium, as a visiting professor.

Smith's research interests focus on (1) the synthesis and structure-proof of bioactive lipids obtained from the human dental pathogen Porphyromonas gingivalis. (2) The development of indocyanine-imidazole dye conjugates that show an affinity for cancerous hypoxic tumors, allowing imaging of the tumors using near-infrared fluorescence spectroscopy.

In addition to this research, he is the author of the fifth, sixth, and seventh editions of March's Advanced Organic Chemistry. He is also the author of an undergraduate textbook in organic chemistry titled Organic Chemistry. An Acid-Base Approach, now in its second edition. He is the editor of the Compendium of Organic Synthetic Methods, Volumes 6–13. He is the author of Organic Chemistry: Two Semesters, in its second edition, which is an outline of undergraduate organic chemistry to be used as a study guide for the first organic course. He has authored a research monograph titled Synthesis of Non-alpha Amino Acids, in its second edition.

Preface to the Fourth Edition

The fourth edition of Organic Synthesis has been revised, reorganized, and rewritten from front to back. I want to thank all who used the book in its first three editions. It is the same graduate level textbook that past users are familiar with, but specific examples have been updated and the book has been reorganized. Several long chapters have been split to make the concepts more focused. The chapter sequence has been reorganized, and a new chapter was created that will focus on organometallic chemistry. The molecular modeling problems that were prominent in the third edition have been removed. While I remain convinced that molecular modeling problems offer new insights into certain aspects of chemical reactivity, conformational analysis, and stereoselectivity, this feature in the third edition did not attract much interest and has been removed from the new edition. Many new examples of reactions have been added, specifically from the literature dating from 2008 to 2015. Apart from these changes, which will be described in detail below, the fourth edition remains what it was always intended to be. It is a graduate level textbook of organic chemical reactions, with a bias toward total synthesis, that targets first and second year graduate students. However, advanced undergraduate organic chemistry courses can certainly use the book.

There are now 19 chapters in the new edition rather than the 14 in the third edition. The former Chapter 2 has been split into three chapters. In this new edition, Chapter 2 is now Acids and Bases and Addition Reactions. Chapter 3 is now Functional Group Exchange Reactions. Aliphatic and Aromatic Substitution, and Elimination Reactions. Chapter 4 is Acids, Bases, and Functional Group Exchange Reactions. Acyl Addition and Acyl Substitution. These changes were made to make this undergraduate organic chemistry review material more manageable. Chapter 7 in the third edition was the protecting groups chapter. Since most of that chemistry involves functional group exchange reactions, the protecting group discussion in the fourth edition is Chapter 5. Chapters 3 and 4 on oxidation and reduction from the third edition are retained as the new Chapters 6 and 7. The hydride reduction discussions in Chapter 7 have been reorganized to focus on borane and alane, and their structural modification that leads to new reagents. Catalytic hydrogenation and dissolving metal reductions follow. Note that the student syntheses for Chapter 14 in the 1st-3rd editions has been deleted in the fourth edition.

The synthetic strategy chapter has been moved to Chapter 8 in the fourth edition, but the section that introduced combinatorial chemistry has been removed, and is now part of the new Chapter 19. The synthetic strategy chapter is now followed by Chapter 9, Functional Group Exchange Reactions. Hydroboration, and Chapter 10, Functional Group Exchange Reactions. Selectivity. These discussions were Chapters 5 and 6, respectively in the first to third editions.

Chapter 8 in the third edition focused on Cd disconnections and carbanion reagents, whereas Chapter 9 in the third edition focused on enolate anion chemistry. The former Chapter 8 has been split into two chapters (Chapters 11 and 12) for the fourth edition: Chapter 11, Carbon-Carbon Bond-Forming Reactions. Cyanide, Alkyne Anions, Grignard Reagents, and Organolithium Reagents and Chapter 12, Carbon-Carbon Bond-Forming Reactions. Stabilized Carbanions and Ylids. Chapter 13 in the fourth edition is Nucleophilic Species That Form Carbon-Carbon Bonds. Enolate Anions. Chapter 11 in the third edition discussed all pericyclic reactions, which made for a very long chapter. In the fourth edition, these discussions have been split into two chapters (Chapters 14 and 15). Chapter 14 is Pericyclic Reactions. The Diels-Alder Reaction, and Chapter 15 is "Pericyclic Reactions: [m+ n]-Cycloadditions, Sigmatropic Rearrangements, Electrocyclic and Ene Reactions."

The discussion of carbocation-driven reactions in Chapter 12 of the third edition is now in Chapter 16 of the fourth edition. There is a significant change, however, because the discussion of organopalladium, organocopper, and other organometallic chemistry have been consolidated and moved to a new chapter, Chapter 18. The discussions of radical and carbene chemistry in Chapter 13 of the third edition are now found in Chapter 17 of the fourth edition. As noted, Chapter 18 is a new chapter in the fourth edition, Metal-Mediated, Carbon-Carbon Bond-Forming Reactions. This new chapter consolidates modern organometallic reactions from several chapters found in the third edition, primarily 8, 12, and 13, for a more focused presentation of this important area of chemistry.

Chapter 19, Combinatorial and Process Chemistry is new to the fourth edition. The discussion of combinatorial chemistry has been moved from the synthetic strategy chapter to this new chapter. In addition, a new section has been added on Process Chemistry, and a third new section added that discusses flow process chemistry.

Homework in each chapter has not been extensively revised. This decision was taken to minimize the introduction of errors by retaining most of the homework found in the third edition. Further, there has been extensive reorganization of the chapters but most homework problems were deemed completely suitable for the fourth edition. The answers to most problems are available in pdf format as an on-line Student Solutions Manual that is available from the Elsevier website for the book. Many of the homework problems that deal with synthesis do not contain leading references for the answers, but as in previous editions, leading references are provided for synthesis problems where it is appropriate. Note that the synthetic strategy chapter in particular, Chapter 8, does not offer specific answers but rather leading references. Students are encouraged to discuss their answers to any synthetic problem with their instructor as there are usually several correct approaches, especially for complex targets.

With the exception of a few scanned figures, all drawings in this book were prepared using ChemDraw Professional, version 15.0.0.106, provided by PerkinElmer. I thank Perkin-Elmer for this gift, and Ms. Julia Bracken in particular. All molecular model graphics are rendered with Spartan’10, version 1.0.1, provided by Wavefunction, Inc. I thank Warren Hehre and Sean Ohlinger for this gift, and for generously sharing their expertise over the years.

I express my gratitude to all of those who were kind enough to go through the first, second, and third editions and who supplied me with comments, corrections, and suggestions. I give special thanks to Peter Wuts, PhD (Kalexsyn) and Professor Tim Jamison (MIT) who reviewed the process chemistry and flow chemistry sections of Chapter 19, respectively, and who provided the inspiration for those new sections.

I thank my students, who provided the inspiration over many years for this book. They have also been my best sounding board, allowing me to test new ideas and organize the text as it now appears. I thank my friends and colleagues who have provided countless suggestions and encouragement over the years, particularly George Majetich (Georgia), Frederick Luzzio (Louisville), Spencer Knapp (Rutgers), and Phil Garner (Washington State). You have all helped more than you can possibly know, and I am most grateful.

A special thanks to my wife Sarah whose patience and understanding made the work possible, and to my son Steven.

Every effort has been made to keep the manuscript error free. Where there are errors, I offer my apologies and take complete responsibility. If there are corrections and/or suggestions, please let me know by Email or normal post. Any error list will be posted on the Elsevier website for this book.

I thank Ms. Jill Cetel for her work in the early days of this project, and especially Ms. Katey Birtcher, who worked to develop the manuscript in its present form, and Anitha Sivaraj, who made production of this book possible. A special thank you goes to Ms. Jeanette Stiefel, whose care and expertise ensured the highest quality of this book.

Thank you again for using this new edition. I hope that it is useful to you in your studies.

Michael B. Smith, University of Connecticut, Storrs, CT, United States

March, 2016

Preface to the Third Edition

The new edition of Organic Synthesis has been revised and rewritten from front to back. I want to thank all who used the book in its first and second editions. The book has been out of print for several years, but the collaboration of Warren Hehre and Wavefunction, Inc. made the third edition possible. It is the same graduate level textbook past users are familiar with, with two major exceptions. First, the book has been revised and updated. Second, molecular modeling problems are included in a manner that is not obtrusive to the theme of understanding reactions and synthesis. A total of 64 molecular modeling problems are incorporated into various discussions, spread throughout 11 of the 13 reactions-synthesis oriented chapters. Spartan models for each problem are provided on an accompanying CD, and Spartan Model is included. These features will allow the reader to manipulate each model and, in most cases, change or create model compounds of interest to the reader. It is our belief that the selected molecular modeling problems will offer new insights into certain aspects of chemical reactivity, conformational analysis, and stereoselectivity.

Updated examples are used throughout the new edition when possible, and new material is added that make this edition reflect current synthetic methodology. The text has been modified in countless places to improve readability and pedagogy. This new edition contains references taken from more than 6100 journal articles, books, and monographs. Of these references, more than 950 are new to this edition, all taken from the literature after 2002. More than 600 updated or new reactions have been added. There are several entirely new sections that discuss topics missing in the second edition. These include SN2 type reactions with epoxides; the Burgess Reagent; functional group rearrangements (Beckmann, Schmidt, Curtius, Hofmann, and Lossen); oxidation of allylic carbon with ruthenium compounds; a comparison of LUMO-mapping with the Cram model and Felkin-Anh models in Chapter 4; electrocyclic reactions; [2.3]-sigmatropic rearrangement (Wittig rearrangement); and consolidation of C glyph_sbnd C bond forming reactions of carbocations and nucleophiles into a new section.

Homework in each chapter has been extensively revised. There are more than 800 homework problems, and more than 300 of the homework problems are new. Most of the homework problems do not contain leading references for the answers. The answers to all problems from Chapters 1–9, and 11–13 are available in an on-line Student Solutions Manual for this book. As in previous edition, a few leading references are provided for the synthesis problems in Chapter 10. Although answers are given for homework that relates to all other chapters, in Chapter 10 most problems do not have answers. The student is encouraged to discuss any synthetic problem with their instructor.

With the exception of scanned figures, all drawings in this book were prepared using ChemDraw, provided by CambridgeSoft, and all 3D graphics are rendered with Spartan, provided by Wavefunction, Inc. I thank both organizations for providing the software that made this project possible.

I express my gratitude to all of those who were kind enough to go through the first and second editions and supply me with comments, corrections, and suggestions.

For this new edition, special thanks and gratitude are given to Warren Hehre. Not only did he design the molecular modeling problems, but also included the CD with solutions to the problems and the accompanying software are provided by Warren. My thanks go deeper than that however. Warren, thorough Wavefunction, Inc., is publishing this edition and without his hard work and help this book would not have been possible. He has also helped me think about certain aspects of organic synthesis in a different way because of the modeling, and I believe this has greatly improved the book and the approaches presented in the book. Special thanks are also given to Ms. Pamela Ohsan, who converted the entire book into publishable form. Once again, without her extraordinary efforts, this third edition would not be possible.

Finally, I thank my students, who have provided the inspiration over the years for this book. They have also been my best sounding board, allowing me to test new ideas and organize the text as it now appears. I thank my friends and colleagues who have provided countless suggestions and encouragement over the years, particularly Spencer Knapp (Rutgers), George Majetich (Georgia), Frederick Luzzio (Louisville), and Phil Garner (Washington State). You have all helped more than you can possibly know, and I am most grateful.

A special thanks to my wife Sarah and son Steven, whose patience and understanding made the work possible.

Michael B. Smith, Storrs, Connecticut

April, 2010

Preface to the First Edition. Why I Wrote This Book!

A reactions oriented course is a staple of most graduate organic programs, and synthesis is taught either as a part of that course or as a special topic. Ideally, the incoming student is an organic major, who has a good working knowledge of basic reactions, stereochemistry, and conformational principles. In fact, however, many (often most) of the students in a first year graduate level organic course have deficiencies in their undergraduate work, are not organic majors and are not synthetically inclined. Does one simply tell the student to go away and read about it, giving a list of references, or does one take class time to fill in the deficits? The first option works well for highly motivated students with a good background, less well for those with a modest background. In many cases, the students spend so much time catching up that it is difficult to focus them on the cutting edge material we all want to teach. If one exercises the second option of filling in all the deficits, one never gets to the cutting edge material. This is especially punishing to the outstanding students and to the organic majors. A compromise would provide the student with a reliable and readily available source for background material that could be used as needed. The instructor could then feel comfortable that the proper foundations have been laid and push on to more interesting areas of organic chemistry.

Unfortunately, such a source of background material either is lacking altogether or consists of several books and dozens of review articles. I believe my teaching experience at UConn as just described is rather typical, with a mix of nonorganic majors, outstanding and well-motivated students, and many students with weak backgrounds who have the potential to go on to useful and productive careers if time is taken to help them. Over the years I have assigned what books were available in an attempt to address these problems, but found that graduate level textbooks left much to be desired. I assembled a large reading list and mountains of handouts and spent half of my life making up problems that would give my students a reasonable chance at practicing the principles we were discussing. I came to the conclusion that a single textbook was needed that would give me the flexibility I craved to present the course I wanted to teach, but yet would give the students the background they needed to succeed. As I tried different things in the classroom, I solicited the opinions of the graduate students who took the course and tried to develop an approach that worked for them and allowed me to present the information I wanted. The result is this book. I hope that it is readable, provides background information, and also provides the research-oriented information that is important for graduate organic students. I also hope it will be of benefit to instructors who face the same challenges I do. I hope this book will be a useful tool to the synthetic community and to graduate level education.

From talks with many people I know that courses for which this book is targeted can be for either one or two semesters. The course can focus only on functional groups, only on making carbon-carbon bonds, or some combination of both (like my course), or only on synthesis. I have tried to organize the book in such a way that one is not a slave to its organization. Every chapter is internally cross-referenced. If the course is to focus upon making carbon-carbon bonds, for example, there are unavoidable references to oxidation reagents, reducing agents, stereochemical principles, etc. When such a reaction or principle appears, the section and chapter where it is discussed elsewhere in the book is given in line so the student can easily find it. It is impossible to write each chapter so it will stand alone, but the chapters are reasonably independent in their presentations. I have organized the book so that functional groups are discussed in the first few chapters and carbon-carbon bond formation reactions are discussed in later chapters, making it easier to use the one book for two different courses or for a combined course. The middle chapters are used for review and to help the student make the transitions from functional group manipulations to applying reactions and principles and thence to actually building molecules. I believe that a course devoted to making carbon-carbon bonds could begin with Chapter 8, knowing that all pertinent peripheral material is in the book and readily available to the student. The ultimate goal of the book is to cut down on the mountains of handouts, provide homework to give the student proper practice, give many literature citations to tell the student exactly where to find more information, and allow the instructor to devote time to their particular focus.

This book obviously encompasses a wide range of organic chemistry. Is there a theme? Should there be? The beautiful and elegant total syntheses of interesting and important molecules published by synthetic organic chemists inspired me to become an organic chemist and I believe that synthesis focuses attention on the problems of organic chemistry in a unique way. To solve a synthetic problem, all elements of organic chemistry must be brought to bear: reactions, mechanism, stereochemistry, conformational control, and strategy. Synthesis therefore brings a perspective on all aspects of organic chemistry and provides a theme for understanding it. The theme of this book is therefore the presentation of reactions in the context of organic synthesis. Wherever possible, examples of a given reaction, process, or strategy are taken from a published total synthesis. The disconnection approach is presented in the first chapter, and as each new functional group transform and carbon-carbon bond forming reaction is discussed, the retrosynthetic analysis (the disconnect products for that reaction) is given. An entire chapter (Chapter 10) is devoted to synthetic strategies, and Chapter 14 provides examples of first year students' first syntheses. I believe that this theme is a reasonable and useful device for presenting advanced organic chemistry.

The text is fully referenced to facilitate further study, and (where feasible) the principal researcher who did the work is mentioned by name, so the student can follow that person's work in the literature and gain even more insight into a given area. As far as it is known to me, the pioneering work of the great chemists of the past has been referenced. Many of the named reactions are no longer referenced in journals, but when they are first mentioned in this book, the original references are given. I believe the early work should not be lost to a new generation of students.

In many cases I have used 3-D drawings to help illustrate stereochemical arguments for a given process. I give the structure of each reagent cited in the text, where that reagent is mentioned, so a beginning student does not have to stop and figure it out. This is probably unnecessary for many students, but it is there if needed.

This is a reaction-oriented book, but an attempt is made to give brief mechanistic discussions when appropriate. In addition, some physical organic chemistry is included to try to answer the obvious if unasked questions: why does that alkyl group move, why does that bond break, why is that steric interaction greater than the other one, or why is that reaction diastereoselective?

Most of all, a student needs to practice. Chapters 1–13 have end-of chapter problems that range from those requiring simple answers based on statements within the text to complex problems taken from research literature. In a large number of cases literature citations are provided so answers can be found.

The first part of the book (Chapters 1–4) is a review of functional group transforms and basic principles: retrosynthesis, stereochemistry, and conformations. Basic organic reactions are covered, including substitution reactions, addition reactions, elimination reactions, acid/base chemistry, oxidation, and reduction. The first two chapters are very loosely organized along the lines of an undergraduate book for presenting the functional group reactions (basic principles, substitution, elimination, addition, acyl addition, and aromatic chemistry). Chapter 1 begins with the disconnection approach. I have found that this focuses the students' attention on which reactions they can actually apply and instantly shows them why it is important to have a larger arsenal of reactions to solve a synthetic problem. This has been better than any other device I have tried and that is why it is placed first. Most of the students I see come into our program deficient in their understanding of stereochemistry and conformational control, and so those topics are presented next. Some of this information is remedial material and where unneeded can be skipped, but it is there for those who need it (even if they will not admit that they do). Chapter 2 presents a mini-review of undergraduate organic chemistry reactions and also introduces some modern reactions and applications. Chapter 3 is on oxidation and Chapter 4 is on reduction. Each chapter covers areas that are woefully under-emphasized in undergraduate textbooks.

Chapter 5 covers hydroboration, an area that is discussed in several books and reviews. I thought it useful to combine this material into a tightly focused presentation which (1) introduces several novel functional group transforms that appear nowhere else and (2) gives a useful review of many topics introduced in Chapters 1–4. Chapter 6 reviews the basic principles that chemists use to control a reaction rather than be controlled by it. It shows the techniques chemists use to fix the stereochemistry, if possible, when the reaction does not do what it is supposed to. It shows how stereochemical principles guide a synthesis. An alternative would be to separate stereochemistry into a chapter that discusses all stereochemical principles. However, the theme is synthesis, and stereochemical considerations are as important a part of a synthesis as the reagents being chosen. For that reason, stereochemistry is presented with the reactions in each chapter. Chapter 6 simply ties together the basic principles. This chapter also includes the basics of ring-forming reactions. Chapter 7 completes the first part of the book and gives a brief overview of what protecting groups are and when to use them.

The second half of the book focuses on making carbon-carbon bonds. It is organized fundamentally by the disconnection approach. In Chapter 1, breaking a carbon-carbon bond generated a disconnect product that was labeled as Cd (a nucleophilic species), Ca (an electrophilic species), or Cradical (a radical intermediate). In some cases, multiple bonds were disconnected, and many of these disconnections involved pericyclic reactions to reassemble the target. The nucleophilic regents that are equivalent to Cd disconnect products are covered in Chapters 8 and 9, with the very important enolate anion chemistry separated into Chapter 9. Chapter 10 presents various synthetic strategies that a student may apply to a given synthetic problem. This information needs to be introduced as soon as possible, but until the student knows some chemistry, it cannot really be applied. Placement of synthetic strategies after functional group transforms and nucleophilic methods for making carbon-carbon bonds is a reasonable compromise. Chapter 11 introduces the important Diels-Alder cyclization, as well as dipolar cycloadditions and sigmatropic rearrangements that are critically important to synthesis. Chapter 12 explores electrophilic carbons (Ca), including organometallics that generally react with nucleophilic species. Chapter 13 introduces radical and carbene chemistry. Chapter 14 is included to give the student a taste of a first-time student proposal and some of the common mistakes. The point is not to reiterate the chemistry but to show how strategic shortsightedness, poor drawings, and deficiencies in overall presentation can influence how the proposal is viewed. It is mainly intended to show some common mistakes and also some good things to do in presenting a synthesis. It is not meant to supersede the detailed discussions of how and why a completed elegant synthesis is done but to assist the first-time student in preparing a proposal.

The goal of this work is to produce a graduate level textbook, and it does not assume that a student should already know the information, before the course. I hope that it will be useful to students and to the synthetic community. Every effort has been made to keep the manuscript error-free. Where there are errors, I take full responsibility and encourage those who find them to contact me directly, at the address given below, with corrections. Suggestions for improving the text, including additions and general comments about the book are also welcome. My goal is to incorporate such changes in future editions of this work. If anyone wishes to contribute homework problems to future editions, please send them to me and I will, of course, give full credit for any I use.

I must begin my thank yous with the graduate students at UConn, who inspired this work and worked with me through several years to develop the pedagogy of the text. I must also thank Dr. Chris Lipinski and Dr. David Burnett of Pfizer Central Research (Groton, CT) who organized a reactions/synthesis course for their research assistants. This allowed me to test this book upon an outside and highly trained audience. I am indebted to them for their suggestions and their help.

There are many other people to thank. Professor Janet Carlson (Macalester College) reviewed a primeval version of this book and made many useful comments. Professors Al Sneden and Suzanne Ruder (Virginia Commonwealth University) classroom tested an early version of this text and both made many comments and suggestions that assisted me in putting together the final form of this book. Of the early reviewers of this book I would particularly like to thank Professor Brad Mundy (Colby College) and Professor Marye Anne Fox (University of Texas, Austin), who made insightful and highly useful suggestions that were important for shaping the focus of the book.

Along the way, many people have helped me with portions or sections of the book. Professor Barry Sharpless (Scripps) reviewed the oxidation chapter and also provided many useful insights into his asymmetric epoxidation procedures. Dr. Peter Wuts (Upjohn) was kind enough to review the protecting group chapter (Chapter 7) and helped me focus it in the proper way. Professor Ken Houk (UCLA), Professor Stephen Hanessian (Université de Montréal), Professor Larry Weiler (U. of British Columbia), Professor James Hendrickson (Brandeis), Professor Tomas Hudlicky (U. Florida), and Professor Michael Taschner (U. of Akron) reviewed portions of work that applied to their areas of research and I am grateful for their help.

Several people provided original copies of figures or useful reprints or comments. These include Professor Dieter Seebach (ETH), Professor Paul Williard (Brown), Professor E.J. Corey (Harvard), Dr. Frank Urban (Pfizer Central Research), Professor Rene Barone (Université de Marseilles), and Professor Wilhelm Meier (Essen).

Two professors reviewed portions of the final manuscript and not only pointed out errors but made enormously helpful suggestions that were important for completing the book: Professor Fred Ziegler (Yale) and Professor Douglass Taber (U. of Delaware). I thank both of them very much.

There were many other people who reviewed portions of the book and their reviews were very important in shaping my own perception of the book, what was needed and what needed to be changed. These include: Professor Winfield M. Baldwin, Jr. (U. of Georgia), Professor Albert W. Burgstahler (U. of Kansas), Professor George B. Clemens (Bowling Green State University), Professor Ishan Erden (San Francisco State University), Professor Raymond C. Fort, Jr. (U. of Maine), Professor John F. Helling (U. of Florida), Professor R. Daniel Little (U. of California), Professor Gary W. Morrow (U. of Dayton), Professor Michael Rathke (Michigan State University), Professor Bryan W. Roberts (U. of Pennsylvania), Professor James E. Van Verth (Canisius College), Professor Frederick G. West (U. of Utah), and Professor Kang Zhao (New York University). I thank all of them.

I must also thank the many people who have indulged me at meetings, at Gordon conferences, and as visitors to UConn and who discussed their thoughts, needs, and wants in graduate level education. These discussions helped shape the way I put the book together.

Finally, but by no means last in my thoughts, I am indebted to Professors Joe Wolinsky and Jim Brewster of Purdue University. Their dedication and skill taught me how to teach. Thank you!

I particularly want to thank my wife Sarah and son Steven. They endured the many days and nights of my being in the library and the endless hours on the computer with patience and understanding. My family provided the love, the help, and the fulfillment required for me to keep going and helped me to put this project into its proper perspective. They helped me in ways that are too numerous to mention. I thank them and I dedicate this work to them.

Michael B. Smith

Common Abbreviations

Ac acetyl fm01-9780128007204

acac acetylacetonate

AIBN azobisisobutyronitrile

All allyl

Am amyl ( glyph_sbnd CH2 (CH2)3CH3)

aq aqueous

Ar aryl

ax axial

fm02-9780128007204  9-borabicyclo[3.3.1]nonylboryl

9-BBN 9-borabicyclo[3.3.1]nonane

BINAP (2R,3S)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl

BINOL 1,1′-bi-2-naphthol

Bn benzyl ( glyph_sbnd CH2Ph)

Boc tert-butoxycarbonyl fm03-9780128007204

Bom benzyloxymethyl

Bpy 2,2′-bipyridyl, 2,2′-bipyridine

Bu n-butyl ( glyph_sbnd CH2CH2CH2CH3)

Bz benzoyl

CAN ceric ammonium nitrate ((NH4)2Ce(NO3)6)

c- cyclo-

cat catalytic

Cbz carbobenzyloxy fm04-9780128007204

Chap chapter(s)

Chirald (2S,3R)-(+)-4-dimethylamino-1,2-diphenyl-3-methylbutan-2-ol

CIP Cahn-Ingold-Prelog

cod 1,5-cyclooctadiene

cot 1,3,5-cyclooctatriene

Cp cyclopentadienyl

CSA camphorsulfonic acid

CTAB cetyltrimethylammonium bromide (C16H33NMe3+ Br−)

Cy (c-C6H11) cyclohexyl fm05-9780128007204

°C temperature in degrees Celsius

DABCO 1,4-diazabicyclo[2.2.2]octane

d day(s)

dba dibenzylideneacetone

DBE 1,2-dibromoethane (BrCH2CH2Br)

DBN 1,5-diazabicyclo[4.3.0]non-5-ene

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC 1,3-dicyclohexylcarbodiimide (c-C6H11 glyph_sbnd N glyph_dbnd C glyph_dbnd N glyph_sbnd c-C6H11)

DCE 1,2-dichloroethane (ClCH2CH2Cl)

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

% de % diastereomeric excess

DEA diethylamine (HN(CH2CH3)2)

DEAD diethyl azodicarboxylate (EtO2C glyph_sbnd N glyph_dbnd NCO2Et)

DET diethyl tartrate

(DHQD)2PHAL) 1,4-dichlorophthalazine adduct with dihydroquinidine

(DHQ)2PHAL) 1,4-dichlorophthalazine adduct with dihydroquinone

DHP dihydropyran

DIAD diisopropyl azodicarboxylate

dibal diisobutylaluminum hydride ((Me2CHCH2)2AlH)

DIPEA diisopropylethylamine

diphos (dppe) 1,2-bis(diphenylphosphino)ethane (Ph2PCH2CH2PPh2)

diphos-4 (dppb) 1,4-bis(diphenylphosphino)butane (Ph2P(CH2)4PPh2)

DIPT diisopropyl tartrate

DMA dimethylacetamide

DMAP 4-(N,N-dimethylamino)pyridine

DMB 3,4-dimethoxybenzyl ether

DMDO 3,3-dimethyldioxirane

DME dimethoxyethane (MeOCH2CH2OMe)

DMF N,N′-dimethylformamide fm06-9780128007204

DMS dimethyl sulfide

DMSO (solvent) dimethyl sulfoxide

dmso (ligand) dimethyl sulfoxide

dppb 1,4-bis(diphenylphosphino)butane (Ph2P(CH2)4PPh2)

dppe 1,2-bis(diphenylphosphino)ethane (Ph2PCH2CH2PPh2)

dppf (1,1′-bis(diphenylphosphino)ferrocene)

dppp 1,3-bis(diphenylphosphino)propane (Ph2P(CH2)3PPh2)

dr diastereomeric ratio

dvb divinylbenzene

e− electron transfer

EA electron affinity

% ee % enantiomeric excess

EE 1-ethoxyethoxy (EtO(Me)CH glyph_sbnd )

er enantiomeric ratio

Et ethyl ( glyph_sbnd CH2CH3)

EDA ethylenediamine (H2NCH2CH2NH2)

EDTA ethylenediaminetetraacetic acid

equiv equivalent(s)

ESR electron spin resonance

FMO frontier molecular orbital

fod tris-(6,6,7,7,8,8,8)-heptafluoro-2,2-dimethyl-3,5-octanedionate

Fp cyclopentadienylbis(carbonyl iron) (ferrocene)

FVP flash vacuum pyrolysis

GC gas chromatography

gl glacial

¹H NMR proton nuclear magnetic resonance

h hour (hour)

hν irradiation with light

1,5-HD 1,5-hexadienyl

HMDS hexamethyldisilazide

HMPA hexamethylphosphoramide ((Me2N)3P glyph_dbnd O)

HMPT hexamethylphosphorus triamide ((Me2N)3P)

HOMO highest occupied molecular orbital

HPLC high performance liquid chromatography

HSAB Hard-Soft Acid-Base

IP ionization potential

Ipc2BH diisopinocampheylborane

i-Pr isopropyl ( glyph_sbnd CH(Me)2)

IR infrared

IUPAC International Union of Pure and Applied Chemistry

LICA (LIPCA) lithium isopropylcyclohexylamine

LDA lithium diisopropylamide (LiN(i-Pr)2)

LHASA logic and heuristics applied to synthetic analysis

LHMDS lithium hexamethyldisilazide (LiN(SiMe3)2)

LTMP lithium 2,2,6,6-tetramethylpiperidide

LUMO lowest unoccupied molecular orbital

mcpba meta-chloroperoxybenzoic acid

Me methyl ( glyph_sbnd CH3 or Me)

MEM β-methoxyethoxymethyl (MeOCH2CH2OCH2 glyph_sbnd )

Mes mesityl (2,4,6-tri-Me-C6H2)

min minutes

MOM methoxymethyl (MeOCH2 glyph_sbnd )

Ms methanesulfonyl (MeSO2 glyph_sbnd )

MS molecular sieves (3 or 4 Å)

MTM methylthiomethyl

MVK methyl vinyl ketone (MeSCH2 glyph_sbnd )

NAD nicotinamide adenine dinucleotide

NADP nicotinamide adenine dinucleotide phosphate

NADPH reduced nicotinamide adenine dinucleotide phosphate

NAP 2-napthylmethyl

napth napthyl (C10H8)

NBD norbornadiene

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NIS N-iodosuccinimide

Ni(R) Raney nickel

NMO N-methylmorpholine N-oxide

N.R. no reaction

Nu (Nuc) nucleophile

OBs O-benzenesulfonate

Oxone 2 KHSO5 · KHSO4 · K2SO4

fm07-9780128007204  polymeric backbone

PCC pyridinium chlorochromate

PDC pyridinium dichromate

PEG poly(ethylene glycol)

pet petroleum

Ph phenyl fm08-9780128007204

PhH benzene

PhMe toluene

phen 1,10-phenanthroline

Phth phthaloyl

Pip piperidino fm09-9780128007204

Piv pivaloyl

PMB p-methoxybenzyl

PMP p-methoxyphenyl

PPA polyphosphoric acid

PPTS p-toluenesulfonic acid

Pr n-propyl ( glyph_sbnd CH2CH2CH3)

Py pyridine fm10-9780128007204

PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

quant quantitative yield

Red-Al [(MeOCH2CH2O)2AlH2]Na

rt room temperature

sBu sec-butyl (CH3CH2CH(CH3))

sBuLi sec-butyllithium (CH3CH2CH(Li)CH3)

s second

salen bis(salicylidene)ethylenediamine

SEM 2-(trimethylsilyl)ethoxymethyl

SET single electron transfer

Siamyl sec-isoamyl ((CH3)2CHCH(CH3) glyph_sbnd )

(Sia)2BH disiamylborane

SOMO singly occupied molecular orbital

TASF tris-(diethylamino)sulfonium difluorotrimethyl silicate

TBAF tetrabutylammonium fluoride (n-Bu4N+ F−)

TBDMS or TBS tert-butyldimethylsilyl (t-BuMe2Si)

TBDPS tert-butyldiphenylsilyl ( glyph_sbnd BuPh2Si)

TBHP (t-BuOOH) tert-butylhydroperoxide (Me3COOH)

TES triethylsilyl

t-Bu tert-butyl ( glyph_sbnd CMe3)

TEBA triethylbenzylammonium (Bn(Et3)3N+)

TEMPO tetramethylpiperidinyloxy free radical

Tf (OTf) triflate ( glyph_sbnd SO2CF3 ( glyph_sbnd OSO2CF3))

TFA trifluoroacetic acid (CF3COOH)

TFAA trifluoroacetic anhydride ((CF3CO)2O)

ThexBH2 thexylborane (tert-hexylborane)

THF (solvent) tetrahydrofuran

Thf (ligand) tetrahydrofuran

THP tetrahydropyranyl

TIPS triisopropylsilyl

TMEDA N,N,N′,N′-tetramethylethylenediamine (Me2NCH2CH2NMe2)

TMS trimethylsilyl ( glyph_sbnd Si(CH3)3)

TMP 2,2,6,6-tetramethylpiperidine

Tol tolyl (4-(Me)C6H4)

TPAP tetrapropylammonium perruthenate

Tr trityl ( glyph_sbnd CPh3)

TRIS triisopropylphenylsulfonyl

Ts(Tos) tosyl = p-toluenesulfonyl (4-(Me)C6H4SO2)

UV ultraviolet

VSEPR valence shell electron pair repulsion

Xc chiral auxiliary

Other, less common abbreviations are given in the text when the term is used.

Chapter 1

Retrosynthesis, Stereochemistry, and Conformations

Abstract

The total synthesis of complex molecules demands a thorough knowledge of reactions that form carbon-carbon bonds, as well as those that change one functional group into another. The largest number of chemical reactions used in a synthesis involve the manipulation of functional groups. Further, the synthesis of a molecule is rarely successful unless all aspects of chemical reactivity, functional group interactions, conformations, and stereochemistry are well understood.

Keywords

Disconnection; Stereochemistry; Absolute configuration; Cahn-Ingold-Prelog rules; Enantiomers; Diastereomers; Chirality; Selectivity; Conformation; Pseudorotation; Steric strain; Chiral axis

1.1 Introduction

The total synthesis of complex molecules demands a thorough knowledge of reactions that form carbon-carbon bonds, as well as those that change one functional group into another. The largest number of chemical reactions used in a synthesis involve the manipulation of functional groups. Further, the synthesis of a molecule is rarely successful unless all aspects of chemical reactivity, functional group interactions, conformations, and stereochemistry are well understood.

Today the term organic synthesis encompasses an enormous variety of chemical reactions. Planning and using organic transformation to put together a molecule is certainly an important aspect of organic synthesis. A thorough understanding of the many organic reactions, reagents, and chemical transformations that are now known is required to accomplish this goal. As noted, the practice of organic synthesis requires an understanding of chirality and the stereochemistry of molecules, both for developing a synthetic strategy and for the choice of reactions and reagents used for various chemical transformations. Conformational analysis of each molecule, from starting material to final product, must be understood because chemical reactivity and stereochemistry are often influenced by the conformation.

Perhaps the most important component of planning an organic synthesis is a thorough and intimate knowledge of chemical reactions and reagents. If one knows only one reagent to convert an alcohol to a ketone, and if that reagent does not work for a given system, there is no alternative. On the other hand, if one knows 30 different reagents for that transformation, there are many alternatives if one of them does not work. Perhaps more importantly, understanding the 30 reagents allows one to better plan a synthesis to use a certain reagent that will maximize the chance that the synthetic sequence will go as planned. The same comment applies to making carbon-carbon bonds. Presumably, a synthesis begins with a starting material of a few carbon atoms, and reactions will add carbon fragments to increase the complexity of the molecules as it is transformed in many steps to the final target. Understanding different reactions and reagents that form different types of carbon-carbon bonds is therefore essential.

This book has the title Organic Synthesis, but from the preceding paragraph it is clear that organic synthesis begins and ends with reactions. The goal of this text is to explain and provide examples of the many reactions that manipulate functional groups (functional group exchange reactions), as well as those that form carbon-carbon bonds. Examples of various reactions are provided, taken from published organic syntheses, to provide an example and also to show the context of how they are used.

Before discussing these reactions, it is important to present a brief overview of structural features that are important in planning a synthesis. A full discussion of strategies for total synthesis will be introduced in Chapter 8. Reviews of stereochemistry and conformational analysis are provided in this chapter for the same reason. The operating paradigm is that these concepts are an important part of chemical reactivity with respect to why some reactions work better than others, and why some reagents are better suited for a given application.

Changing one functional group into another is defined as a functional group interchange (FGI). Simple examples are the SN2 reaction of 3-bromopentane with the nucleophilic cyanide ion of NaCN to form 2-ethylbutanenitrle, and the E2 reaction of 2-bromo-2-methylpentane via reaction with the basic KOH to yield 2-methylpent-2-ene. The first transformation changes a halide to a cyano group (alkyl halide to nitrile), whereas the second transformation changes a halide to an alkene (alkyl halide to alkene). Such functional group exchange reactions are important because they incorporate key functionality into the final target, but they are also used to set up the molecule for making a carbon-carbon bond (DMF = N,N-dimethylformamide).

u01-01-9780128007204

A reaction that brings reactive fragments together to form a new bond between two carbon atoms is classified as a carbon-carbon bond-forming reaction, and it is clear that such reactions are used to increase the size of a molecule. Such reactions are obviously critical to total synthesis. An example is the reaction of a carbon nucleophile with an alkyl halide in an SN2 reaction. The conjugate base formed when prop-1-yne reacts with a strong base (e.g., sodium amide) is an alkyne anion. Under SN2 reaction conditions (Section 3.2.1), this alkyne anion is a carbon nucleophile that reacts with (2S)-bromobutane with inversion to yield (4R)-methylhex-2-yne. Note that a new carbon-carbon bond has been formed, that the new alkyne product has more carbon atoms, and it is more complex than either prop-1-yne or (2S)-bromobutane. (4R)-Methylhex-2-yne has a stereogenic carbon atom and the SN2 reaction has proceeded with 100% inversion of configuration, so there is chirality transfer from the enantiopure (2S)-bromobutane to (4R)-methylhex-2-yne. With respect to synthetic planning, the carbon-carbon bond-forming reaction was chosen to control stereochemistry in the product. This example was chosen to show why it is important to understand a given reaction, the reactivity of the chosen reagent with the substrate, and possible stereochemical consequences before choosing that chemical reaction (THF = tetrahydrofuran, solvent).

u01-02-9780128007204

Today, the relationship of two molecules in a synthesis is commonly shown using a device known as a transform, defined by Corey and Cheng¹ as: the exact reverse of a synthetic reaction to a target structure. Using the conversion of prop-1-yne to (4R)-methylhex-2-yne, the target structure is (4R)-methylhex-2-yne (Fig. 1.1), and it is the molecule that is the object of the synthesis. The transform for this synthetic step is, therefore, (4R)-methylhex-2-yne ⇒ prop-1-yne, which requires that one mentally break the highlighted bond (bond a) in (4R)-methylhex-2-yne (represented by the dashed line) leads to fragments prop-1-yne and (2S)-bromobutane and in this process bond a is said to be disconnected. The backward arrow (⇒) is used to indicate that prop-1-yne is the starting material for the preparation of (4R)-methylhex-2-yne.

f01-01-9780128007204

Fig. 1.1 Transform versus synthesis.

How is the disconnection approach useful in planning a synthesis? In part, this statement suggests that it is important to understand why bond a in Fig. 1.1 was chosen for the disconnection. The choice of bond a is based on a thorough knowledge of the chemical properties of (4R)-methylhex-2-yne. When bond a was disconnected, it is with the understanding that bond a will be made during the synthesis by a specific chemical reaction. To understand the structural characteristics of (4R)-methylhex-2-yne that led to the disconnection of bond a, the chemical reaction(s) required to form that bond must be known and understood.

Disconnection of a bond in the target leads to so-called disconnection fragments or disconnection products, which are not real compounds. Disconnection of bond a in (4R)-metylhex-2-yne, for example, does not lead directly to real molecules, but to fragments 1 and 2. These disconnection fragments are intended to point the chemist toward a chemical reaction between two reactive partners. The structures of 1 and 2 allow certain assumptions to be made that will correlate any disconnection fragment with a real molecule

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To convert 1 and 2 to real fragments, another operation is required that correlates each disconnect fragment with what is known as a synthetic equivalent. The process used for this correlation is discussed in Section 1.2. Once actual molecules have been identified as capable of undergoing a chemical reaction that will make the target, in this case (4R)-methylhex-2-yne, the synthesis can proceed. In effect, disconnection of the target to yield fragments works backward to discover the starting materials that are required to make the target. Working backward in this manner is termed retrosynthetic analysis or retrosynthesis,² defined by Corey² as a problem-solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simple materials along a pathway that ultimately leads to a simple or commercially available starting material for chemical synthesis. In principle, the synthesis is the reverse of the disconnection. The use of a backward arrow (⇒) indicates disconnection of the target to give disconnect fragments. This individual disconnection is usually referred to as a transform. The retrosynthesis shown is a single disconnection that points to a single reaction, but to complete a real synthesis starting from a given target, reagents must be provided. In this case, the alkyne is treated with a suitable base to generate the corresponding alkyne anion, which subsequently reacts with the chiral alkyl halide.

It is important to point out that a retrosynthetic analysis rarely correlates with the exact reverse track with simple reagents to synthesize the target. For molecules with multiple functionality, particularly complex natural products, the idea of doing a retrosynthetic analysis and simply providing reagents for each disconnection to convert the starting material to the target is usually problematic. A given disconnection may not be possible unless a functional group is changed or modified. Commonly, there are steps that simply do not work using available reagents or those suggested by literature precedent. In addition, reactions may give poor yields or the wrong stereochemistry. There may also be unanticipated interactions of functional groups and unexpected requirements for protecting groups (see Chapter 5). In short, the approach shown here is a first step, intended to begin the retrosynthesis process, and to think about what reactions may be appropriate to put them together again. The discussion given here is intended to show the importance of a basic understanding of organic chemistry. Other important concepts in organic chemistry must be brought to bear, including stereochemistry and conformational theory.

The issues of stereochemistry and conformation with respect to organic reactions can be illustrated by the simple transform (2R)-(hydroxymethyl)cyclohexan-(1S)-ol ⇒ (2R)-(hydroxymethyl)cyclohexan-1-one, which is arguably a single chemical reaction (a reduction, see Section 7.5). This disconnection demands the use of a reaction that will provide the relative stereochemistry (trans) shown in (2R)-(hydroxymethyl)cyclohexan-(1S)-ol. This demand cannot be satisfied unless the proper spatial relationship of the functional groups in the target is known prior to making the choice for a chemical reaction. That relationship is the conformation of the cyclohexanone starting material (see Section 1.5.2), which can be difficult to see using the two-dimensional (2D) structures shown. The molecular model shown for (2R)-(hydroxymethyl)cyclohexan-1-one provides a better perspective of the relative positions of all atoms in the molecule (the stereochemical and conformational relationships; see Sections 1.4 and 1.5). In this case, the molecular model shows that the hydroxyl group is positioned on one side of the molecule, relative to the carbonyl group. If a chelating metal is used in a hydride reduction reagent (e.g., zinc borohydride; see Section 7.5), coordination with the hydroxyl group (3) will deliver the hydride primarily from the same face as the CH2OH unit, leading to the observed trans stereochemistry in (2R)-(hydroxymethyl)cyclohexan-(1S)-ol. In this example, the conformation of the molecule provides a model that helps to plan a desired stereochemical outcome of the reaction.

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Three important factors will be reviewed in this chapter: (1) disconnection and retrosynthesis, (2) stereochemistry, (3) conformational analysis. This review will not formally introduce synthesis (synthetic strategies will be presented in Chapter 8),³ so the goal is to understand concepts that place the use of reactions in proper context.

1.2 The Disconnection Protocol

When retrosynthetic theory is introduced as part of a course, it is easy to become concerned about making the correct disconnection rather than focusing on the chemical reactions and concepts required to form the disconnected bond in the synthesis. In reality, the choice of a disconnection is usually dictated by the ability to form a given bond, in the context of stereochemistry and selectivity, and not the other way around. The synthesis of organic molecules dates to the nineteenth century, but the work of Perkin, Robinson, and others in the early twentieth century demonstrated the importance of synthetic planning.¹ In the 1940s and 1950s, Woodward, Robinson, Eschenmoser, Stork, and others clearly showed how molecules could be synthesized in a logical and elegant manner. In the 1960s, Corey identified the rationale behind his syntheses, and such logical synthetic plans (termed retrosynthetic analyses) are now a common feature of the synthetic literature.² The disconnection approach is now used to teach synthesis, and Warren⁴ has several books that describe this approach in great detail. There are several other books that describe syntheses and approaches to total synthesis.⁵ Several different strategies for the synthesis of organic molecules are available (see Chapter 8) and all are useful. All disconnection approaches assign priorities to bonds in a molecule and disconnect those bonds with the highest priorities, as with Corey's strategic bond analysis (see Section 8.5).¹,³ Smith⁶ described a simple method where the priorities are based only on the relative ability to chemically form the bond broken in the disconnection, based on known reactions. When these strategies are applied to a first synthesis in an introductory course, the first issue raised after a disconnection is what to do with the disconnect products.

In a typical introductory organic chemistry course, there are two fundamental types of synthesis problems. In the first, both the starting material and the target are specified. In the second, only the final target is given and the synthetic chemist must deduce the starting material. This latter case usually poses a more difficult problem. The fundamentals of a retrosynthetic analysis will be illustrated with the first type of problem, and a discussion of the second type will be delayed until Chapter 8.

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In the disconnection of 2,6-dimethylheptan-3-one ⇒ 2-methylprop-1-ene (isobutene), the alkene is the designated starting material. Since the starting material is specified, the disconnections are limited to those that will lead back to isobutene. Therefore, the four carbon atoms of the alkene must be located in 2,6-dimethylheptan-3-one, which will define the carbon-carbon bonds that must be disconnected for the retrosynthesis. The presence of two methyl groups in isobutene limits the carbon atoms that correlate with the target, but there are two different locations where the four carbons may be found in the target (see 4A and 4B). If the pattern shown in 4A is chosen, C glyph_sbnd C bond a must be disconnected. If the pattern in 4B is chosen, then the C glyph_sbnd C bond b must be disconnected. Disconnection of bond a in 4A leads to two fragments (disconnect products), 5 and 6. Similarly, disconnection of bond b in 4B leads to disconnect products 7 and 8. Both disconnections must be considered, but structures 5–8 are not real molecules, so the relative merit of each disconnection cannot be properly evaluated using these fragments. Only real molecules can be correlated with the viability of a real reaction. To assist in this process, two assumptions will be made: (1) The key carbon-carbon bonds will be formed by a small subset of reactions and (2) the bonds will be made by reactions involving polarized or ionic intermediates.

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The first assumption that key carbon-carbon bonds will be formed by a small subset of reactions is based on those reactions that are usually presented in a typical sophomore organic chemistry course. Examples are the carbon-carbon bond-forming reactions shown in Table 1.1.⁶a The second assumption that bonds will be made by reactions involving polarized or ionic intermediates is based on the observation that all reactions in Table 1.1 except entry 10 (the Diels-Alder reaction, see Section 14.5.1) involve highly polarized or ionic intermediates.

Table 1.1

Carbon-Carbon Bond-Forming Reactions

Reprinted with permission from Smith, M.B. J. Chem. Educ. 1990, 67, 848. Copyright © 1990 American Chemical Society.

Based on these two assumptions, it is reasonable to conclude that the disconnection of bond a or b in 2,6-dimethylheptan-3-one will lead to ionic or polarized precursors, and the requisite carbon-carbon bond will be formed using one of the reactions found in Table 1.1. In other words, fragments 5–8 should be polarized if possible, and then correlated with a polarized or ionic real molecule.

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The concept of nucleophilic and electrophilic atoms in ionic and polarized intermediates is well known. Polarized bond notation (e.g., Cδ + glyph_sbnd Brδ − and Cδ − glyph_sbnd Liδ +) is commonly used in describing the polarization of such bonds, and such polarization commonly correlates with the reactivity of these bonds. Using these observations, Seebach⁷ used structure 9 to formalize a bond-polarization model. The sites marked d in 9 represent donor sites or nucleophilic atoms. The sites marked a are acceptor sites and correspond to electrophilic atoms.

Bond polarization induced by the heteroatom extends down the carbon chain, due to the usual inductive effects that are a combination of through-space and through-bond inductive effects.⁸ The X moiety is typically a functional group or an electron-withdrawing atom (e.g., oxygen or a halogen). The electrophilic carbon adjacent to X is designated Ca (an acceptor atom) since proximity to the δ− electronegative atom (X) induces the opposite polarity. Similarly, C2 is a donor atom (Cd), but less polarized than X (this carbon is further away from the