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Introduction to Strategies for Organic Synthesis

Introduction to Strategies for Organic Synthesis

Laurie S. Starkey

ISBN: 978-0-470-48409-8

Feb 2012

360 pages


The stepping-stone text for students with a preliminary knowledge of organic chemistry looking to move into organic synthesis research and graduate-level coursework

Organic synthesis is an advanced but important field of organic chemistry, however resources for advanced undergraduates and graduate students moving from introductory organic chemistry courses to organic synthesis research are scarce. Introduction to Strategies for Organic Synthesis is designed to fill this void, teaching practical skills for making logical retrosynthetic disconnections, while reviewing basic organic transformations, reactions, and reactivities.

Divided into seven parts that include sections on Retrosynthesis and Protective Groups; Overview of Organic Transformations; Synthesis of Monofunctional Target Molecules; Synthesis of Target Molecules with Two Functional Groups; Synthesis of Aromatic Target Molecules; Synthesis of Compounds Containing Rings; and Predicting and Controlling Stereochemistry, the book covers everything students need to successfully perform retrosynthetic analyses of target molecule synthesis.

Starting with a review of functional group transformations, reagents, and reaction mechanisms, the book demonstrates how to plan a synthesis, explaining functional group analysis and strategic disconnections. Incorporating a review of the organic reactions covered, it also demonstrates each reaction from a synthetic chemist's point of view, to provide students with a clearer understanding of how retrosynthetic disconnections are made.

Including detailed solutions to over 300 problems, worked-through examples and end-of-chapter comprehension problems, Introduction to Strategies for Organic Synthesis serves as a stepping stone for students with an introductory knowledge of organic chemistry looking to progress to more advanced synthetic concepts and methodologies.

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PART I Synthetic Toolbox 1: Retrosynthesis and Protective Groups 1

CHAPTER 1.1 Retrosynthetic Analysis 3

Retrosynthesis by Functional Group Interconversion (FGI) 4

Retrosynthesis by Making a Disconnection 6

CHAPTER 1.2 Protective Groups 11

Protection of Ketones and Aldehydes 12

Protection of Alcohols 12

Protection of Carboxylic Acids 16

Protection of Amines 17

Part I Problems Protective Groups 19

PART II Synthetic Toolbox 2: Overview of Organic Transformations 21

CHAPTER 2.1 Nucleophiles and Electrophiles 23

Common Nucleophiles 23

Common Electrophiles 26

CHAPTER 2.2 Oxidation and Reduction Reactions 27

Overview of Oxidations and Reductions 27

Common Oxidation Reactions and Oxidizing Agents 29

Common Reduction Reactions and Reducing Agents 35

Part II Problems Nucleophiles, Electrophiles, and Redox 41

PART III Synthesis of Monofunctional Target Molecules (1-FG TMs) 45

CHAPTER 3.1 Synthesis of Alcohols (ROH) 47

Synthesis of Alcohols by Functional Group Interconversion (FGI) 48

Synthesis of Alcohols by the Grignard Reaction 50

Synthesis of Propargylic Alcohols (RC=CCH2OH) 56

Synthesis of Phenol Derivatives (ArOH) 57

Example: Alcohol TM 58

CHAPTER 3.2 Synthesis of Alkyl (RX) and Aryl Halides (ArX) 61

Synthesis of Alkyl Halides via Free-Radical Halogenation 61

Synthesis of Alkyl Halides via FGI 62

Retrosynthesis of Alkyl Halides 63

Synthesis of Aryl Halides (ArX) 63

Example: Alkyl Halide TM 64

CHAPTER 3.3 Synthesis of Ethers (ROR') 67

Williamson Ether Synthesis (RX + R'O- ? ROR') 67

Alternate Ether Preparations 68

Synthesis of Epoxides 69

Retrosynthesis of Ethers 70

Example: Ether TM 71

CHAPTER 3.4 Synthesis of Thiols (RSH) and Thioethers (RSR') 73

Example: Thioether TM 75

CHAPTER 3.5 Synthesis of Amines (RNH2) and Anilines (ArNH2) 77

Synthetic Equivalents of NH3 (RX ? RNH2) 78

Synthesis of Amines via Reduction Reactions 80

Retrosynthesis of Amines 82

Synthesis of Aniline Derivatives (ArNH2) 82

Example: Amine TM 83

CHAPTER 3.6 Synthesis of Alkenes (R2C=CR2) 85

Synthesis of Alkenes via FGI 85

Synthesis of Alkenes via the Wittig Reaction 88

Example: Alkene TM 90

CHAPTER 3.7 Synthesis of Alkynes (RC=CR') 93

Synthesis of Alkynes via FGI 93

Synthesis of Alkynes from Other Alkynes (RC=CH ? RC=CR') 94

Example 1: Alkyne TM 95

Example 2: Alkyne TM 95

CHAPTER 3.8 Synthesis of Alkanes (RH) 97

Synthesis of Alkanes via FGI 97

Synthesis of Alkanes via C-C Bond Formation 99

Retrosynthesis of Alkanes 101

Example: Alkane TM 102

CHAPTER 3.9 Synthesis of Aldehydes and Ketones (RCHO, R2C=O) 105

Synthesis of Aldehydes/Ketones via FGI 105

Synthesis of Aldehydes/Ketones via Acyl Substitutions 107

Synthesis of Ketones via a-Alkylation 109

Example: Ketone TM 113

CHAPTER 3.10 Synthesis of Carboxylic Acids (RCO2H) 115

Synthesis of Carboxylic Acids via FGI 115

Synthesis of Carboxylic Acids via Grignard (RMgBr + CO2 ? RCO2H) 116

Carboxylic Acids via a-Alkylation: Malonic Ester Synthesis 117

Example: Carboxylic Acid TM 119

CHAPTER 3.11 Synthesis of Carboxylic Acid Derivatives 121

Relative Reactivities of Carboxylic Acid Derivatives (RCOLG) 121

Synthesis of Acid Chlorides (RCOCl) 123

Synthesis of Anhydrides (RCO2COR) 124

Synthesis of Esters (RCO2R) 124

Synthesis of Amides (RCONH2) 128

Synthesis of Nitriles (RC=N) 131

Example: Carboxylic Acid Derivative 132

Part III Problems Monofunctional Target Molecules (1-FG TMs) 135

PART IV Synthesis of Target Molecules with Two Functional Groups (2-FG TMs) 139

CHAPTER 4.1 Synthesis of ß-Hydroxy Carbonyls and a,ß-Unsaturated Carbonyls 141

The Aldol Reaction 141

Synthesis of a,ß-Unsaturated Esters Using the Wittig Reaction 149

Example: a,ß-Unsaturated Carbonyl 150

CHAPTER 4.2 More Enolate Reactions: Synthesis of 1,3-Dicarbonyls, 1,5-Dicarbonyls, and Cyclohexenones 153

The Claisen Condensation 153

The Michael Reaction 157

Summary of Enolate Syntheses 161

Robinson Annulation 162

CHAPTER 4.3 "Illogical" Disconnections: Umpolung (Polarity Reversal) 165

Synthesis of TMs with a 1,2-Dioxygenated Pattern 165

Synthesis of TMs with a 1,4-Dioxygenated Pattern 171

Synthesis of TMs with a 1,6-Dicarbonyl Pattern 175

Part IV Problems Target Molecules with Two Functional Groups (2-FG TMs) 177

PART V Synthesis of Aromatic Target Molecules 181

CHAPTER 5.1 Electrophilic Aromatic Substitution (ArH + E+ ? ArE) 183

Mechanism of the Electrophilic Aromatic Substitution 183

Electrophiles for the Electrophilic Aromatic Substitution 183

Electrophilic Aromatic Substitution on Substituted Benzenes 185

Retrosynthesis of Aromatic TMs (Electrophilic Aromatic Substitution) 191

Example: Aromatic TM 1 193

CHAPTER 5.2 Synthesis of Aromatic TMs via Diazonium Salts (ArN2+ + Nu ? ArNu) 195

Preparation of Diazonium Salts (ArNH2 ? ArN2+) 195

Use of Diazonium Salts (ArN2+ + Nu ? ArNu) 195

Retrosynthesis of Aromatic TMs (via Diazonium Salts) 196

Example: Aromatic TM 2 197

CHAPTER 5.3 Nucleophilic Aromatic Substitution (ArX + Nu: ? ArNu) 199

Mechanism of Nucleophilic Aromatic Substitution (SNAr) 199

Retrosynthesis of Aromatic TMs (SNAr) 200

Example: Aromatic TM 3 201

Part V Problems Aromatic TMs 203

PART VI Synthesis of Compounds Containing Rings 207

CHAPTER 6.1 Synthesis of Cyclopropanes 209

Retrosynthesis of Cyclopropane TMs 210

CHAPTER 6.2 Synthesis of Cyclobutanes 213

Retrosynthesis of Cyclobutane TMs 213

CHAPTER 6.3 Synthesis of Five-Membered Rings (Radical Cyclization Reactions) 215

Baldwin's Rules 216

Retrosynthesis of Methylcyclopentane TMs 216

Example: Methylcyclopentane TM 217

CHAPTER 6.4 Synthesis of Six-Membered Rings (Diels–Alder Reaction) 219

The Dienophile (E+) 220

The Diene (Nu:) 221

Regiochemistry of the Diels-Alder 223

Retrosynthesis of Cyclohexenes (Diels-Alder) 225

Retrosynthesis of 1,4-Cyclohexadienes 226

Part VI Problems Cyclic TMs 229

PART VII Predicting and Controlling Stereochemistry 233

CHAPTER 7.1 Reactions That Form Racemates 235

Formation of New Chiral Carbons 235

Loss of a Group from a Chiral Carbon: Racemization 238

CHAPTER 7.2 SN2 Mechanism: Backside Attack 241

CHAPTER 7.3 Elimination Mechanisms 243

E2 Elimination (Anti) 243

Cope Elimination (Syn) 244

CHAPTER 7.4 Additions to Alkenes and Alkynes 245

Syn Additions 245

Anti Additions 246

CHAPTER 7.5 Additions to Carbonyls 249

Diastereoselectivity in Acyclic Systems: Cram's Rule, Felkin-Ahn Model 249

Chelation Control by Neighboring Groups 251

Addition to Cyclohexanones 252

CHAPTER 7.6 Additions to Enolates: Aldol Stereochemistry 253

Formation of (E) and (Z) Enolates 253

Aldol Reaction with (E) and (Z) Enolates 254

Examples: Predicting Aldol Stereochemistry 255

CHAPTER 7.7 Enantioselectivity and Asymmetric Syntheses 257

Prochiral Environments 257

Enantioselective Techniques 259

Part VII Problems Stereochemistry 263

Solutions to Problems 267

Solutions to Part I: Protective Groups 267

Solutions to Part II: Nucleophiles, Electrophiles, and Redox 270

Solutions to Part III: Monofunctional Target Molecules (1-FG TMs) 274

Solutions to Part IV: Difunctional Target Molecules (2-FG TMs) 286

Solutions to Part V: Aromatic TMs 303

Solutions to Part VI: Cyclic TMs 310

Solutions to Part VII: Stereochemistry 320

Index 331

“Finally, my overall impression of the book is that it will serve well as a quick reference or starting point for an undergraduate researcher or new PhD student in organic synthesis. It is essentially a back-to-basics textbook and there may even be something there for the odd academic who needs some inspiration when handed a new teaching assignment in an undergraduate subject in organic synthesis.”  (Angewandte Chemie, 1 September 2012) 

“I will certainly be recommending it to my own students.”  (ChemMedChem, 1 January 2013)

“Summing Up: Recommended.  Lower-and upper-division undergraduates.”  (Choice, 1 November 2012)