Florencio Zaragoza D�rwald

Side Reactions in Organic Synthesis

Side Reactions in Organic Synthesis. Florencio Zaragoza D�rwaldCopyright � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31021-5

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Florencio Zaragoza D�rwald

Side Reactions in Organic Synthesis

A Guide to Successful Synthesis Design

Author

Dr. Florencio Zaragoza D�rwaldMedicinal ChemistryNovo Nordisk A/SNovo Nordisk Park2760 M=løvDenmark

& All books published by Wiley-VCH are carefully pro-duced. Nevertheless, authors, editors, and publisherdo not warrant the information contained in thesebooks, including this book, to be free of errors.Readers are advised to keep in mind that statements,data, illustrations, procedural details or other itemsmay inadvertently be inaccurate.

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� 2005 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim

All rights reserved (including those of translationinto other languages). No part of this book may bereproduced in any form – nor transmitted or trans-lated into machine language without written permis-sion from the publishers. Registered names, trade-marks, etc. used in this book, even when notspecifically marked as such, are not to be consideredunprotected by law.

Printed in the Federal Republic of Germany.

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ISBN 3-527-31021-5

V

Preface IX

Glossary and Abbreviations XI

1 Organic Synthesis: General Remarks 1

1.1 Introduction 1

1.2 Synthesis Design 2

1.2.1 Convergent vs Linear Syntheses 2

1.2.2 Retrosynthetic Analysis 3

1.3 Hard and Soft Acids and Bases 9

1.4 The Curtin–Hammett Principle 13

2 Stereoelectronic Effects and Reactivity 17

2.1 Hyperconjugation with r Bonds 17

2.2 Hyperconjugation with Lone Electron Pairs 19

2.2.1 Effects on Conformation 19

2.2.2 The Anomeric Effect 20

2.2.3 Effects on Spectra and Structure 21

2.3 Hyperconjugation and Reactivity 23

2.3.1 Basicity and Nucleophilicity 23

2.3.2 Rates of Oxidation 25

2.3.3 Rates of Deprotonation 26

2.3.4 Other Reactions 27

2.4 Conclusion 30

3 The Stability of Organic Compounds 35

3.1 Introduction 35

3.2 Strained Bonds 35

3.3 Incompatible Functional Groups 41

3.4 Conjugation and Hyperconjugation of Incompatible FunctionalGroups 42

3.5 Stability Toward Oxygen 45

3.5.1 Hydrogen Abstraction 45

Contents

Side Reactions in Organic Synthesis. Florencio Zaragoza D�rwaldCopyright � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31021-5

VI

3.5.2 Oxidation by SET 48

3.5.3 Addition of Oxygen to C–C Double Bonds 51

3.6 Detonations 52

4 Aliphatic Nucleophilic Substitutions: Problematic Electrophiles 59

4.1 Mechanisms of Nucleophilic Substitution 59

4.2 Structure of the Leaving Group 62

4.2.1 Good and Poor Leaving Groups 62

4.2.2 Nucleophilic Substitution of Fluoride 66

4.2.3 Nucleophilic Substitution of Sulfonates 70

4.3 Structure of the Electrophile 72

4.3.1 Steric Effects 72

4.3.2 Conjugation 75

4.3.3 Electrophiles with a-Heteroatoms 79

4.3.4 Electrophiles with b-Heteroatoms 84

4.3.5 Electrophiles with a-Electron-withdrawing Groups 86

4.3.6 Neighboring-group Participation 90

4.3.7 Allylic and Propargylic Electrophiles 93

4.3.8 Epoxides 97

5 The Alkylation of Carbanions 143

5.1 Introduction 143

5.2 The Kinetics of Deprotonations 144

5.3 Regioselectivity of Deprotonations and Alkylations 146

5.3.1 Introduction 146

5.3.2 Kinetic/Thermodynamic Enolate Formation 148

5.3.3 Allylic and Propargylic Carbanions 150

5.3.4 Succinic Acid Derivatives and Amide-derived Carbanions 155

5.3.5 Bridgehead Carbanions 157

5.3.6 Dianions 158

5.3.7 a-Heteroatom Carbanions 161

5.3.8 Vinylic Carbanions 171

5.3.9 Acyl, Imidoyl, and Related Carbanions 173

5.3.10 Aromatic Carbanions 175

5.3.11 Aromatic vs Benzylic Deprotonation 180

5.4 The Stability of Carbanions 182

5.4.1 Introduction 182

5.4.2 a-Elimination 183

5.4.3 b-Elimination 184

5.4.4 Cyclization 190

5.4.5 Rearrangement 193

5.4.6 Oxidation 195

5.4.7 Other Factors which Influence the Stability of Carbanions 196

5.4.8 Configurational Stability of Carbanions 197

Contents

VII

6 The Alkylation of Heteroatoms 229

6.1 Alkylation of Fluoride 229

6.2 Alkylation of Aliphatic Amines 231

6.3 Alkylation of Anilines 234

6.4 Alkylation of Alcohols 239

6.5 Alkylation of Phenols 241

6.6 Alkylation of Amides 243

6.7 Alkylation of Carbamates and Ureas 248

6.8 Alkylation of Amidines and Guanidines 250

6.9 Alkylation of Carboxylates 251

7 The Acylation of Heteroatoms 261

7.1 Problematic Carboxylic Acids 261

7.1.1 Sterically Demanding Carboxylic Acids 261

7.1.2 Unprotected Amino and Hydroxy Carboxylic Acids 262

7.1.3 Carboxylic Acids with Additional Electrophilic Groups 265

7.2 Problematic Amines 267

7.2.1 Sterically or Electronically Deactivated Amines 267

7.2.2 Amino Acids 269

7.2.3 Amines with Additional Nucleophilic Groups 270

7.3 Problematic Alcohols 271

7.3.1 Sterically Deactivated and Base-labile Alcohols 271

7.3.2 Alcohols with Additional Nucleophilic Groups 273

8 Palladium-catalyzed C–C Bond Formation 279

8.1 Introduction 279

8.2 Chemical Properties of Organopalladium Compounds 279

8.3 Mechanisms of Pd-catalyzed C–C Bond Formation 282

8.3.1 Cross-coupling 282

8.3.2 The Heck Reaction 285

8.4 Homocoupling and Reduction of the Organyl Halide 287

8.5 Homocoupling and Oxidation of the Carbon Nucleophile 291

8.6 Transfer of Aryl Groups from the Phosphine Ligand 293

8.7 ipso- vs cine-Substitution at Vinylboron and Vinyltin Derivatives 294

8.8 Allylic Arylation and Hydrogenation as Side Reactions of the HeckReaction 295

8.9 Protodemetalation of the Carbon Nucleophile 296

8.10 Sterically Hindered Substrates 296

8.11 Cyclometalation 298

8.12 Chelate Formation 300

9 Cyclizations 309

9.1 Introduction 309

9.2 Baldwins Cyclization Rules 309

9.3 Structural Features of the Chain 315

Contents

9.4 Ring Size 319

9.4.1 Formation of Cyclopropanes 321

9.4.2 Formation of Cyclobutanes 325

9.5 Heterocycles 327

10 Monofunctionalization of Symmetric Difunctional Substrates 333

10.1 Introduction 333

10.2 Monofunctionalization of Dicarboxylic Acids 334

10.3 Monofunctionalization of Diols 336

10.4 Monofunctionalization of Diamines 342

10.5 Monoalkylation of C,H-Acidic Compounds 346

10.6 Monoderivatization of Dihalides 348

Index 355

ContentsVIII

IX

Most non-chemists would probably be horrified if they were to learn how manyattempted syntheses fail, and how inefficient research chemists are. The ratio of suc-cessful to unsuccessful chemical experiments in a normal research laboratory is farbelow unity, and synthetic research chemists, in the same way as most scientists,spend most of their time working out what went wrong, and why.

Despite the many pitfalls lurking in organic synthesis, most organic chemistrytextbooks and research articles do give the impression that organic reactions justproceed smoothly and that the total synthesis of complex natural products, forinstance, is maybe a labor-intensive but otherwise undemanding task. In fact, mostsyntheses of structurally complex natural products are the result of several years ofhard work by a team of chemists, with almost every step requiring careful optimiza-tion. The final synthesis usually looks quite different from that originally planned,because of unexpected difficulties encountered in the initially chosen syntheticsequence. Only the seasoned practitioner who has experienced for himself the manyfailures and frustrations which the development (sometimes even the repetition) ofa synthesis usually implies will be able to appraise such work.

This book attempts to highlight the competing processes and limitations of someof the most common and important reactions used in organic synthesis. Awarenessof these limitations and problem areas is important for the design of syntheses, andmight also aid elucidation of the structure of unexpected products. Two chapters ofthis book cover the structure–reactivity relationship of organic compounds, andshould also aid the design of better syntheses.

Chemists tend not to publish negative results, because these are, as opposed topositive results, never definite (and far too copious). Nevertheless, I have venturedto describe some reactions as difficult or impossible. A talented chemist might, how-ever, succeed in performing such reactions anyway, for what I congratulate him inadvance. The aim of this book is not to stop the reader from doing bold experiments,but to help him recognize his experiment as bold, to draw his attention to potentialproblems, and to inspire, challenge, and motivate.

Preface

Side Reactions in Organic Synthesis. Florencio Zaragoza D�rwaldCopyright � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31021-5

X

I wish to express my thanks to Ullrich Sensfuss, Bernd Peschke, and Kilian W.Conde-Frieboes for the many helpful discussions and for proofreading parts of themanuscript, and to Jesper Lau (my boss) for his support.

Smørum, Denmark Florencio Zaragoza D�rwaldMay 2004

Preface

XI

Ac acetyl, MeCOacac pentane-2,4-dioneAIBN azobis(isobutyronitrile)All allylAlloc allyloxycarbonylAmberlyst 15 strongly acidic, macroporous ion exchange resinaq aqueousAr undefined aryl group9-BBN 9-borabicyclo[3.3.1]nonaneBHT 2,6-di-tert-butyl-4-methylphenolbimim N-butyl-N¢-methylimidazoliumBINAP 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthylBn benzylBoc tert-butyloxycarbonylBom benzyloxymethylBs 4-bromobenzenesulfonylBSA N,O-bis(trimethylsilyl)acetimidateBt 1-benzotriazolylBu butylBz benzoylCAN ceric ammonium nitrate, (NH4)2Ce(NO3)6

cat catalyst or catalytic amountCbz Z, benzyloxycarbonyl, PhCH2OCOCDI carbonyldiimidazolecelite silica-based filter agentCOD 1,5-cyclooctadienecoll collidine, 2,4,6-trimethylpyridineconc concentratedCp cyclopentadienylCSA 10-camphorsulfonic acid

Glossary and Abbreviations

Side Reactions in Organic Synthesis. Florencio Zaragoza D�rwaldCopyright � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31021-5

Glossary and Abbreviations

Cy cyclohexylD bond dissociation enthalpyDABCO 1,4-diazabicyclo[2.2.2]octaneDAST (diethylamino)sulfur trifluoridedba 1,5-diphenyl-1,4-pentadien-3-oneDBN 1,5-diazabicyclo[4.3.0]non-5-eneDBU 1,8-diazabicyclo[5.4.0]undec-5-eneDCC N,N¢-dicyclohexylcarbodiimideDCE 1,2-dichloroethaneDCP 1,2-dichloropropaneDDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinonede diastereomeric excessDEAD diethyl azodicarboxylate, EtO2C–N=N–CO2EtDec decylDIAD diisopropyl azodicarboxylate, iPrO2C–N=N–CO2iPrDIBAH diisobutylaluminum hydrideDIC diisopropylcarbodiimidediglyme bis(2-methoxyethyl) etherdipamp 1,2-bis[phenyl(2-methoxyphenyl)phosphino]ethaneDIPEA diisopropylethylamineDMA N,N-dimethylacetamideDMAD dimethyl acetylenedicarboxylate, MeO2C–C”C–CO2MeDMAP 4-(dimethylamino)pyridineDME 1,2-dimethoxyethane, glymeDMF N,N-dimethylformamideDMI 1,3-dimethylimidazolidin-2-oneDMPU 1,3-dimethyltetrahydropyrimidin-2-oneDMSO dimethyl sulfoxideDMT 4,4¢-dimethoxytritylDNA deoxyribonucleic acidDnp 2,4-dinitrophenylDPPA diphenylphosphoryl azide, (PhO)2P(O)N3

dppb 1,2-bis(diphenylphosphino)butanedppe 1,2-bis(diphenylphosphino)ethanedppf 1,1¢-bis(diphenylphosphino)ferrocenedppp 1,3-bis(diphenylphosphino)propanedr diastereomeric ratioE undefined electrophileEDC N-ethyl-N¢-[3-(dimethylamino)propyl]carbodiimide hydrochlorideEDT 1,2-ethanedithiolee enantiomeric excessEEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolineeq equivalenter enantiomeric ratioEt ethyl

XII

Glossary and Abbreviations

Fmoc 9-fluorenylmethyloxycarbonylFVP flash vacuum pyrolysisHal undefined halogenHep heptylHex hexylHMPA hexamethylphosphoric triamide, (Me2N)3POhm lightHOAt 3-hydroxy-3H-[1,2,3]triazolo[4,5-b]pyridine,

4-aza-3-hydroxybenzotriazoleHOBt 1-hydroxybenzotriazoleHOSu N-hydroxysuccinimideHPLC high pressure liquid chromatographyHSAB hard and soft acids and basesiPr isopropylIR infraredL undefined ligandLDA lithium diisopropylamideM molar, mol/l; undefined metalMCPBA 3-chloroperbenzoic acidMe methylMEK 2-butanoneMES 2-(4-morpholino)ethanesulfonic acidMMT monomethoxytritylMOM methoxymethylMos 4-methoxybenzenesulfonylmp melting pointMs methanesulfonylMS molecular sievesnbd norbornadieneNBS N-bromosuccinimideNCS N-chlorosuccinimideNIS N-iodosuccinimideNMM N-methylmorpholineNMO N-methylmorpholine-N-oxideNMP N-methyl-2-pyrrolidinoneNMR nuclear magnetic resonanceNos nosyl, 4-nitrobenzenesulfonylNu undefined nucleophileOct octyloxone� 2 KHSO5·KHSO4·K2SO4, potassium peroxymonosulfatePEG poly(ethylene glycol)Pent pentylPG protective groupPh phenylPht phthaloyl

XIII

Glossary and Abbreviations

Piv pivaloyl, 2,2-dimethylpropanoylPMDTA N,N,N¢,N†,N†-pentamethyldiethylenetriaminePNB 4-nitrobenzoylPol undefined polymeric supportPPTS pyridinium tosylatePr propylPTC phase transfer catalysisPTFE poly(tetrafluoroethylene)R undefined alkyl groupRed-Al� sodium bis(2-methoxyethoxy)aluminum hydridesatd saturatedsec secondaryL-Selectride� lithium tri(2-butyl)borohydrideSET single electron transferSn1 monomolecular nucleophilic substitutionSn2 bimolecular nucleophilic substitutionSnR1 monomolecular radical nucleophilic substitutionst. mat. starting materialSu N-succinimidylTBAF tetrabutylammonium fluorideTBDPS tert-butyldiphenylsilylTBS tert-butyldimethylsilyltBu tert-butylTentagel� PEG-grafted cross-linked polystyrenetert tertiaryTeoc 2-(trimethylsilyl)ethoxycarbonylTf trifluoromethanesulfonylTFA trifluoroacetic acidTfOH triflic acid, trifluoromethanesulfonic acidthd 2,2,6,6-tetramethyl-3,5-heptanedioneTHF tetrahydrofuranTHP 2-tetrahydropyranylTIPS triisopropylsilylTMAD N,N,N¢,N¢-tetramethyl azodicarboxamideTMEDA N,N,N¢,N¢-tetramethylethylenediamineTMG N,N,N¢,N¢-tetramethylguanidineTMP 2,2,6,6-tetramethylpiperidin-1-ylTMPP tris(2,4,6-trimethoxyphenyl)phosphineTMS trimethylsilyl, Me3SiTol 4-tolyl, 4-methylphenylTr tritylTriton� X-100 polyoxyethylene isooctylcyclohexyl etherTs tosyl, p-toluenesulfonylTyr tyrosineUV ultraviolet

XIV

Glossary and Abbreviations

Wang resin cross-linked polystyrene with 4-benzyloxybenzyl alcohol linkerX undefined leaving group for nucleophilic displacementX, Y undefined heteroatoms with unshared electron pairZ Cbz, benzyloxycarbonyl; undefined electron-withdrawing group

XV