Organic Synthesis on Solid Phase. (Supports, Linkers, Reactions)

Organic synthesis on solid supports is a rapidly developing methodology, which offers several advantages if compared to traditional synthesis in solution. In recent years the number of substance classes that can be synthesised on solid phase has quickly increased, and solid-phase synthesis is becoming a valuable alternative to traditional synthesis - in particular when large numbers of different compounds in small quantities are needed for screening.

This exhaustive and systematically organised reference work gives an in-depth view on organic syntheses on insoluble polymers from the basic principles to the newest developments. The work quickly guides the reader to any particular type of reaction and to the best method for preparing a given class of compounds on solid support.

Many tables with clear preseantation collect valuable information about the feasibility of a given reaction on solid support, and a wealth of information is opened up to the reader through a thoroughly worked out and comprehensive reference list. This makes the book the first stop when it comes to synthesising your compounds on solid support.

• General Techniques and Analytical Tools for Solid-Phase Organic Synthesis
• Supports for Solid-Phase Organic Synthesis
• Linkers for Solid-Phase Organic Synthesis
• Preparation of Organometallic Compounds
• Preparation of Hydrocarbons
• Preparation of Alkyl and Aryl Halides
• Preparation of Alcohols and Ethers
• Preparation of Sulfur Compounds
• Preparation of Organoselenium Compounds
• Preparation of Nitrogen Compounds
• Preparation of Phosphorus Compounds
• Preparation of Aldehydes and Ketones
• Preparation of Carboxylic Acid Derivatives
• Preparation of Carbonic Acid Derivatives
• Preparation of Heterocycles
• Preparation of Oligomeric Compounds
• Index

Table of Contens:

 Glossary and Abbreviations  XIV

 Experimental Procedures  XX

1

General Techniques and Analytical Tools for Solid-Phase Organic Synthesis  1

1.1

General Techniques for Performing Syntheses on Insoluble Supports  1

1.2

Strategies for Parallel Synthesis  3

1.3

Analytical Methods for Support-bound Intermediates  5

1.3.1

 Combustion Analysis  5

1.3.2

 Colorimetric Assays  5

1.3.3

 Infrared Spectroscopy  7

1.3.4

 Mass Spectrometry  7

1.3.5

 Nuclear Magnetic Resonance Spectroscopy  7

1.4

Strategies for the Selection of Reactions and Reagents for Parallel Solid-Phase Synthesis  8

2

Supports for Solid-Phase Organic Synthesis  13

2.1

Polystyrene  14

2.1.1

 Microporous Styrene--Divinylbenzene Copolymers  14

2.1.1.1

 Swelling Behavior  15

2.1.1.2

 Chemical Stability  17

2.1.1.3

Functionalization  17

2.1.2

 Macroporous Styrene--Divinylbenzene Copolymers  19

2.1.3

 Miscellaneous Polystyrenes  20

2.2

Poly(ethylene glycol)--Polystyrene Graft Polymers  21

2.3

Poly(ethylene glycol)  22

2.4

Polyacrylamides  22

2.5

Polyacrylamide--PEG Copolymers  24

2.6

Silica  25

2.7

Polysaccharides  26

2.8

Miscellaneous Supports  27

3

Linkers for Solid-Phase Organic Synthesis  33

3.1

Linkers for Carboxylic Acids  35

3.1.1

 Linkers for Acids Cleavable by Acids or Other Electrophiles  35

3.1.1.1

 Benzyl Alcohol Linkers  35

3.1.1.2

 Diarylmethanol (Benzhydrol) Linkers  37

3.1.1.3

 Trityl Alcohol Linkers  37

3.1.1.4

 Non-Benzylic Alcohol Linkers  38

3.1.2

 Linkers for Acids Cleavable by Bases or Nucleophiles  39

3.1.2.1

 Benzyl Alcohol Linkers  40

3.1.2.2

 Non-Benzylic Alcohol Linkers  40

3.1.2.3

 Miscellaneous Linkers Cleavable by Bases or Nucleophiles  43

3.1.3

 Photocleavable Linkers for Carboxylic Acids  45

3.1.4

 Linkers for Acids Cleavable by Transition Metal Catalysis  47

3.1.5

 Linkers for Acids Cleavable by Enzymes  49

3.2

Linkers for Thiocarboxylic Acids  50

3.3

Linkers for Amides, Sulfonamides, Carbamates, and Ureas  50

3.3.1

 Benzylamine Linkers  51

3.3.2

 (Diarylmethyl)amine and Tritylamine Linkers  55

3.3.3

 Linkers for Amides Cleavable by Nucleophiles  59

3.3.3.1

 Nucleophilic Cleavage of Alkyl Esters  59

3.3.3.2

 Nucleophilic Cleavage of Aryl Esters  61

3.3.3.3

 Nucleophilic Cleavage of Oxime and Related Esters  63

3.3.3.4

 Nucleophilic Cleavage of Amides and Carbamates  63

3.4

Linkers for Hydroxamic Acids and Hydrazides  63

3.5

Linkers for Carboxylic Esters  67

3.5.1

 Linkers for Esters Cleavable by Nucleophiles  67

3.5.2

 Linkers for Lactones Cleavable by Electrophiles or Oxidants  70

3.6

Linkers for Primary and Secondary Aliphatic Amines  71

3.6.1

 Benzylamine, (Diarylmethyl)amine, and Tritylamine Linkers  72

3.6.2

 Carbamate Attachment  74

3.6.3

 Miscellaneous Linkers for Aliphatic Amines  76

3.7

Linkers for Tertiary Amines  77

3.8

Linkers for Aryl- and Heteroarylamines  79

3.9

Linkers for Guanidines and Amidines  81

3.10

Linkers for Pyrroles, Imidazoles, Triazoles, and Tetrazoles  84

3.11

Linkers for Alcohols and Phenols  85

3.11.1

 Attachment as Ethers  85

3.11.2

 Attachment as Silyl Ethers  89

3.11.3

Attachment as Acetal  91

3.11.4

 Attachment as Esters  91

3.11.5

 Miscellaneous Linkers for Alcohols and Phenols  94

3.12

Linkers for Thiols  96

3.13

Linkers for Alkyl and Aryl Halides  99

3.14

Linkers for Aldehydes and Ketones  99

3.14.1

 Attachment as Enol Ethers, Enamines, and Imines  100

3.14.2

 Attachment of Carbonyl Compounds as Acetals  100

3.14.3

 Miscellaneous Linkers for Aldehydes and Ketones  103

3.15

Linkers for Olefins  103

3.15.1

 Linkers for Olefins Cleavable by b-Elimination  104

3.15.2

 Linkers for Olefins Cleavable by Olefin Metathesis  108

3.16

Linkers for Alkanes and Arenes  110

3.16.1

 Cleavage followed by Decarboxylation  110

3.16.2

 Cleavage of Silanes and related Compounds  111

3.16.3

 Reductive Cleavage of Carbon--Oxygen and Carbon--Nitrogen Bonds  114

3.16.4

 Reductive Cleavage of Carbon--Phosphorus, Carbon--Sulfur, and Carbon--Selenium Bonds  116

3.17

Non-Covalent Linkers  118

3.17.1

 Ion-Exchange Resins  118

3.17.2

 Transition Metal Complexes  118

3.17.3

 Miscellaneous Non-Covalent Linkers  119

4

Preparation of Organometallic Compounds  133

4.1

Group I and II Organometallic Compounds  133

4.2

Group III Organometallic Compounds  136

4.3

Group IV Organometallic Compounds  137

4.4

Transition Metal Complexes  138

5

Preparation of Hydrocarbons  143

5.1

Preparation of Alkanes  143

5.1.1

 Preparation of Alkanes by Hydrolysis of Organometallic Compounds  143

5.1.2

 Preparation of Alkanes by Hydrogenation and Reduction  143

5.1.3

 Preparation of Alkanes by Carbon--Carbon Bond Formation  145

5.1.3.1

 Coupling Reactions with Group I Organometallic Compounds  145

5.1.3.2

 Coupling Reactions with Group II Organometallic Compounds  146

5.1.3.3

 Coupling Reactions with Boranes  147

5.1.3.4

 Coupling Reactions with Arylpalladium Compounds  148

5.1.3.5

 Alkylations with Alkyl Radicals  149

5.1.3.6

 Preparation of Cycloalkanes  150

5.2

Preparation of Alkenes  151

5.2.1

 Preparation of Alkenes by b-Elimination and Reduction  151

5.2.2

 Preparation of Alkenes by Carbonyl Olefination  152

5.2.2.1

 By Wittig Reaction  152

5.2.2.2

 By Aldol and Related Condensations  155

5.2.2.3

 By Other Carbonyl Olefinations  156

5.2.3

 Preparation of Alkenes by Olefin Metathesis  156

5.2.4

 Preparation of Alkenes by C-Vinylation  159

5.2.5

 Preparation of Cycloalkenes by Cycloaddition  163

5.3

Preparation of Alkynes  165

5.4

Preparation of Biaryls  168

6

Preparation of Alkyl and Aryl Halides  177

6.1

Preparation of Alkyl Halides  177

6.2

Preparation of Aryl and Heteroaryl Halides  181

7

Preparation of Alcohols and Ethers  185

7.1

Preparation of Alcohols  186

7.1.1

 Reduction of Carbonyl Compounds  186

7.1.2

 Addition of Carbon Nucleophiles to C--O Double Bonds  187

7.1.3

 Miscellaneous Preparations of Alcohols  191

7.1.4

 Protective Groups for Alcohols  193

7.1.4.1

 Protective Groups Cleavable by Acids  193

7.1.4.2

 Protective Groups Cleavable by Nucleophiles  195

7.2

Preparation of Ethers  197

7.2.1

 Preparation of Dialkyl Ethers  197

7.2.2

 Preparation of Alkyl Aryl Ethers  200

7.2.3

 Preparation of Diaryl Ethers  204

8

Preparation of Sulfur Compounds  209

8.1

Preparation of Thiols  209

8.2

Preparation of Thioethers  211

8.3

Preparation of Sulfoxides and Sulfones  215

8.4

Preparation of Sulfonamides  216

8.5

Preparation of Sulfonic Esters  221

9

Preparation of Organoselenium Compounds  227

10

Preparation of Nitrogen Compounds  229

10.1

Preparation of Amines  229

10.1.1

 Preparation of Amines by Aliphatic Nucleophilic Substitution  229

10.1.1.1

 With Support-Bound Alkylating Agents  229

10.1.1.2

 By Alkylation of Support-Bound Amines  233

10.1.2

 Preparation of Amines by Aromatic Nucleophilic Substitution  233

10.1.2.1

 With Support-Bound Arylating Agents  233

10.1.2.2

 By Arylation of Support-Bound Amines  237

10.1.3

 Preparation of Amines by Addition of Amines to C--C Double Bonds  239

10.1.4

 Preparation of Amines by Reduction of Imines  239

10.1.5

 Preparation of Amines by Reaction of Carbon Nucleophiles with Imines or Aminals  242

10.1.6

 Preparation of Amines by Reduction of Amides and Carbamates  245

10.1.7

 Preparation of Amines by Reduction of Nitro Compounds  246

10.1.8

 Preparation of Amines by Reduction of Azides  247

10.1.9

 Miscellaneous Preparations of Amines  248

10.1.10

 Protective Groups for Amines  249

10.1.10.1

 Carbamates  250

10.1.10.2

 Amides  256

10.1.10.3

 Cyclic Imides  257

10.1.10.4

 Enamines  258

10.1.10.5

 Imines  259

10.1.10.6

 N-Alkyl and N-Aryl Derivatives  259

10.1.10.7

 N-Sulfenyl and N-Sulfonyl Derivatives  260

10.2

Preparation of Quaternary Ammonium Salts  261

10.3

Preparation of Hydrazines and Hydroxylamines  262

10.4

Preparation of Azides  263

10.5

Preparation of Diazo Compounds  264

10.6

Preparation of Nitro Compounds  265

11

Preparation of Phosphorus Compounds  274

11.1

Phosphonic Acid Derivatives  274

12

Preparation of Aldehydes and Ketones  275

12.1

Preparation of Aldehydes and Ketones by C-Acylation  275

12.2

Preparation of Aldehydes and Ketones by Oxidation  277

12.3

Miscellaneous Preparations of Aldehydes and Ketones  278

13

Preparation of Carboxylic Acid Derivatives  285

13.1

Preparation of Amides  285

13.1.1

 Preparation of Amides by Acylation of Amines with Isolated Acylating Agents  285

13.1.2

 Acylation of Amines with Acylating Reagents Formed In Situ  288

13.1.2.1

 Activation of Acids with Carbodiimides  290

13.1.2.2

 Activation of Acids with Phosphonium Salts  294

13.1.2.3

 Activation of Acids with Uronium Salts  296

13.1.3

 Miscellaneous Preparations of Amides  298

13.1.4

 Preparation of Amides by C-Alkylation of Other Amides  300

13.1.5

 Preparation of Amides by N-Alkylation of Other Amides  301

13.2

Preparation of Hydroxamic Acids and Hydrazides  302

13.3

Preparation of Carboxylic Acids  303

13.4

Preparation of Carboxylic Esters  304

13.4.1

 Preparation of Esters from Support-Bound Alcohols  304

13.4.1.1

 Esterification of Support-bound Alcohols with N-Protected a-Amino Acids  309

13.4.2

 Preparation of Esters from Support-Bound Alkylating Agents  311

13.4.3

 Preparation of Esters from Support-Bound Carboxylic Acids  313

13.4.4

 Preparation of Esters by Chemical Modification of Other Esters  315

13.5

Preparation of Thiol Esters  315

13.6

Preparation of Amidines and Imino Ethers  315

13.7

Preparation of Nitriles and Isonitriles  318

13.8

Preparation of Imides  319

13.9

Preparation of Thioamides  321

14

Preparation of Carbonic Acid Derivatives  327

14.1

Preparation of Carbodiimides  327

14.2

Preparation of Isocyanates and Isothiocyanates  328

14.3

Preparation of Guanidines  329

14.4

Preparation of Ureas  331

14.5

Preparation of Thioureas and Isothioureas  334

14.6

Preparation of Carbamates  335

14.7

Preparation of Carbonates and Miscellaneous Carbonic Acid Derivatives  338

15

Preparation of Heterocycles  343

15.1

Preparation of Epoxides and Aziridines  343

15.2

Preparation of Azetidines and Thiazetidines  344

15.3

Preparation of Pyrroles and Pyrrolidines  345

15.4

Preparation of Indoles and Indolines  350

15.5

Preparation of Furans and Tetrahydrofurans  354

15.6

Preparation of Benzofurans and Dihydrobenzofurans  356

15.7

Preparation of Thiophenes  358

15.8

Preparation of Imidazoles  361

15.9

Preparation of Hydantoins (2,4-Imidazolidinediones) and Thiohydantoins  363

15.10

Preparation of Benzimidazoles  367

15.11

Preparation of Isoxazoles  369

15.12

Preparation of Oxazoles and Oxazolidines  373

15.13

Preparation of Thiazoles and Thiazolidines  373

15.14

Preparation of Pyrazoles  374

15.15

Preparation of Triazoles, Tetrazoles, Oxadiazoles, and Thiadiazoles  376

15.16

Preparation of Pyridines and Dihydropyridines  378

15.17

Preparation of Tetrahydropyridines and Piperidines  380

15.18

Preparation of Fused Pyridines  382

15.19

Preparation of Pyridazines (1,2-Diazines)  387

15.20

Preparation of Pyrimidines (1,3-Diazines)  389

15.21

Preparation of Quinazolines  391

15.22

Preparation of Pyrazines and Piperazines (1,4-Diazines), and Fused Derivatives thereof  394

15.22.1

 Preparation of Diketopiperazines  394

15.22.2

 Preparation of Miscellaneous 1,4-Diazines and Quinoxalines  397

15.23

Preparation of Triazines  398

15.24

Preparation of Pyrans and Benzopyrans  399

15.25

Preparation of Oxazines and Thiazines  400

15.26

Preparation of Azepines and Larger Heterocycles with one Nitrogen Atom  402

15.27

Preparation of Diazepines, Thiazepines, and larger Heterocycles with more than one Het eroatom  404

16

Preparation of Oligomeric Compounds  413

16.1

Peptides  414

16.1.1

 Merrifield\9s Peptide Synthesis  414

16.1.2

 The Boc Strategy  415

16.1.3

 The Fmoc Strategy  417

16.1.4

 Side-Chain Protection  419

16.1.5

 Backbone Protection  420

16.1.6

 Cyclic Peptides  421

16.2

Oligonucleotides  422

16.2.1

 Historical Overview  422

16.2.2

 The Phosphotriester Method  424

16.2.3

 The Phosphoramidite and H-Phosphonate Methods  425

16.2.4

 Oligonucleotide Analogs  428

16.3

Oligosaccharides  428

16.3.1

 Glycosylation with Glycosyl Bromides  429

16.3.2

 Glycosylation with Glycosyl Sulfoxides  430

16.3.3

 Glycosylation with Glycosyl Thioethers  431

16.3.4

 Glycosylation with Miscellaneous Glycosyl Donors  431

16.4

Miscellaneous Oligomeric Compounds  433

16.4.1

 Oligoamides  433

16.4.1.1

 Oligoglycines  434

16.4.1.2

 Peptide Nucleic Acids (PNA)  434

16.4.2

 Oligoesters  436

16.4.3

 Oligoureas and Oligothioureas  436

16.4.4

 Oligocarbamates  437

16.4.5

 Oligosulfonamides  438

16.4.6

 Oligomeric Phosphoric Acid Derivatives  438

16.4.7

 Peptide-Derived Oligomeric Compounds  439

16.4.8

 Oligomers Prepared by C--C Bond Formation  439

16.4.9

 Dendrimers  441

17

Index  449

*Editor's Note: The brief summary and the contents of the books are reported as provided by the author or the publishers. Authors and publishers are encouraged to send review copies of their recent books of potential interest to readers of Molecules to the Editor-in-Chief (Dr. Shu-Kun Lin, MDPI, Saengergasse 25, CH-4054 Basel, Switzerland. Tel. +41 79 322 3379, Fax +41 61 302 8918, E-mail: [email protected]). Some books will be offered to the scholarly community for the purpose of preparing full-length reviews.