Organic Synthesis

Cover
Half Title
Organic Synthesis
Copyright
Contents
About the Author
Preface to the Fifth Edition
Common Abbreviations
1. Retrosynthesis, Stereochemistry, and Conformations
	1.1 Introduction
	1.2 The Disconnection Protocol
	1.3 Bond Proximity and Implications for Chemical Reactions
	1.4 Stereochemistry
		1.4.1 Absolute Configuration in Chiral Nonracemic Molecules
		1.4.2 Diastereomers
		1.4.3 Chiral Molecules Without a Stereogenic Center (Molecules Containing a Chiral Axis)
		1.4.4 (E/Z) Isomers
		1.4.5 Prochiral Centers
		1.4.6 Definitions of Selectivity
	1.5 Conformations
		1.5.1 Conformations of Acyclic Molecules
			1.5.1.1 Conformations of Simple Alkanes
			1.5.1.2 The Boltzmann Distribution: Average Properties of Flexible Molecules
			1.5.1.3 Heteroatom Substituents
			1.5.1.4 Heteroatom–Heteroatom Bonds
			1.5.1.5 Bonds Connecting sp3 and sp2 Hybrids: Propene and But-1-ene
			1.5.1.6 Bonds Connecting sp2 Hybrids: Buta-1.3-diene and Styrene
		1.5.2 Conformations of Cyclic Molecules
		1.5.3 A1,3-Strain and G-Strain
		1.5.4 Conformations in Polycyclic Molecules
	1.6 Conclusion
2. Acids and Bases and Addition Reactions
	2.1 Introduction
	2.2 Brønsted-Lowry Acids and Bases
		2.2.1 Acidity in Organic Molecules
			2.2.1.1 Ka and pKa
			2.2.1.2 Inductive and Resonance Effects
		2.2.2 Basicity in Organic Molecules
	2.3 Lewis Acids
	2.4 Hard-Soft Acid-Base Theory
		2.4.1 Hard and Soft Acids and Bases
		2.4.2 HSAB and Molecular Orbital Theory
	2.5 Acid-Base Reactions of Alkenes and Alkynes (Addition Reactions)
		2.5.1 Alkenes and Alkynes as Brønsted-Lowry Bases
			2.5.1.1 Markovnikov Addition
			2.5.1.2 Rearrangement
			2.5.1.3 Radical Reactions With Alkenes or Alkynes
		2.5.2 π-Bonds as Lewis Bases: Oxymercuration
		2.5.3 π-Bonds as Lewis Bases: Reaction With Dihalogens and Related Reagents
	2.6 Conclusion
3. Functional Group Exchange Reactions: Aliphatic and Aromatic Substitution and Elimination Reactions
	3.1 Introduction
	3.2 Aliphatic Substitution Reactions
		3.2.1 Bimolecular Aliphatic Nucleophilic Substitution
		3.2.2 Unimolecular Nucleophilic Substitution: The SN1 Reaction
	3.3 Heteroatom-Stabilized Carbocations
	3.4 Substitution by Halogen
		3.4.1 Halogenation of Alcohols
		3.4.2 Allylic and Benzylic Halogenation
	3.5 Aromatic Substitution
		3.5.1 Defining Aromatic Substitution
		3.5.2 Electrophilic Aromatic Substitution: The SEAr Reaction
		3.5.3 SEAr Reactions of Substituted Benzenes
		3.5.4 SEAr Reactions in Polycyclic Aromatic Compounds
		3.5.5 Nucleophilic Aromatic Substitution: The SNAr Reaction
		3.5.6 Benzyne Derivatives
		3.5.7 SNAr Reactions of Aryl Diazonium Salts
	3.6 Elimination Reactions
		3.6.1 Bimolecular 1,2-Elimination: The E2 Reaction
		3.6.2 Unimolecular 1,2-Elimination: The E1 Reaction
	3.7 Characteristics of Substitution and Elimination Reactions
		3.7.1 The Solvent
		3.7.2 The Nucleophile Base
		3.7.3 The Substrate
		3.7.4 The Leaving Group
	3.8 SYN-Elimination Reactions
		3.8.1 Hofmann Elimination
		3.8.2 Amine Oxide Pyrolysis (Cope Elimination)
		3.8.3 Sulfoxide and Selenoxide Pyrolysis
		3.8.4 Burgess Reagent
		3.8.5 Ester Pyrolysis
	3.9 1,3-Elimination (Decarboxylation).
		3-Oxopentanoic acid
		But-1-en-2-ol Butan-2-one
		OTBS
		CO2Me
		MeO2C
		CO2H
			130 °C , 3 h
			Quinoline
		(E)-2-(But-2-en-1-ylidene)- malonic acid
		(2Z,4E)-Hexa-2,4- dienoic acid
	3.10 1,3-Elimination (Grob Fragmentation)
	3.11 Conclusion
4. Acids, Bases, and Functional Group Exchange Reactions: Acyl Addition and Acyl Substitution
	4.1 Introduction
	4.2 Reactions of Carbonyl Compounds
	4.3 Nucleophilic Acyl Addition to Aldehydes and Ketones
	4.4 Nucleophilic Acyl Substitution of Acid Derivatives
	4.5 Conjugate Addition
	4.6 Functional Group Manipulation by Rearrangement
		4.6.1 Beckmann Rearrangement
		4.6.2 Schmidt Rearrangement
		4.6.3 Related Rearrangements
	4.7 Macrocyclic Compounds
	4.7.1 Macrocyclic Ring Closures
	4.7.2 Synthetic Approaches to Macrocyclic Lactones
	4.8 Conclusion
5. Functional Groups Exchange Reactions: Protecting Groups
	5.1 Introduction
	5.2 When Are Protecting Groups Needed?
	5.3 Protecting Groups for Alcohols, Carbonyls, and Amines
		5.3.1 Protection of Alcohols
			5.3.1.1 Ether and Acetal Protecting Groups
			5.3.1.2 Silyl Ether Protecting Groups
			5.3.1.3 Ester Protecting Groups
		5.3.2 Protection of Diols
		5.3.3 Protection of Aldehydes and Ketones
			5.3.3.1 Ketals and Acetals
			5.3.3.2 Dithioketals and Dithioacetals
		5.3.4 Protection of Amines
			5.3.4.1 N-Alkyl and N-Silyl Protecting Groups
			5.3.4.2 N-Acyl Protecting Groups
			5.3.4.3 N-Carbamate Protecting Groups
	5.4 Conclusion
6. Functional Group Exchange Reactions: Oxidations
	6.1 Introduction
	6.2 Alcohols to Carbonyls (CH—OH→C=O)
		6.2.1 Oxidation With Chromium (VI)
			6.2.1.1 The Reaction of Alcohols With Chromium (VI)
			6.2.1.2 Jones Oxidation
		6.2.2 Modified Chromium (VI) Oxidants
			6.2.2.1 Chromium Trioxide-Pyridine
			6.2.2.2 Pyridinium Chlorochromate and Pyridinium Dichromate
			6.2.2.3 Structurally Modified Chromium Reagents
		6.2.3 Oxidation With Dimethyl Sulfoxide-Based Reagents
			6.2.3.1 Swern Oxidation
			6.2.3.2 Moffatt Oxidation
			6.2.3.3 Other DMSO Oxidations
		6.2.4 Dess-Martin Periodinane Oxidation
		6.2.5 Oxidation With TEMPO and Oxammonium Salts
		6.2.6 Alternative Metal Compounds as Oxidizing Agents
			6.2.6.1 Tetrapropylammonium Perruthenate: Ley Oxidation
			6.2.6.2 Oppenauer Oxidation
			6.2.6.3 Oxidation with Manganese Dioxide
		6.2.7 Oxidations With Silver (Silver Carbonate and Silver Oxide)
			6.2.7.1 Silver Carbonate
			6.2.7.2 Silver (I) Oxide
			6.2.7.3 Silver (II) Oxide
		6.2.8 Other Transition Metal Oxidants
	6.3 Formation of Phenols and Quinones
		6.3.1 Quinones
		6.3.2 Phenols
	6.4 Oxidation of Alkenes to Epoxides
		6.4.1 Epoxides From Halohydrins
		6.4.2 Peroxide-Induced Epoxidation
			6.4.2.1 Hydrogen Peroxide
			6.4.2.2 Alkyl Hydroperoxides
			6.4.2.3 Juliá-Colonna Epoxidation
		6.4.3 Peroxycarboxylic Acids
		6.4.4 Asymmetric Epoxidation Reactions
			6.4.4.1 Sharpless Asymmetric Epoxidation
			6.4.4.2 Jacobsen-Katsuki Asymmetric Epoxidation
			6.4.4.3 Epoxidation With Dioxiranes
	6.5 Oxidation of Alkenes to Diols (C=C → CHOH-CHOH)
		6.5.1 Dihydroxylation With Potassium Permanganate
		6.5.2 Dihydroxylation With Osmium Tetroxide
			6.5.2.1 Dihydroxylation of Alkenes
			6.5.2.2 Sharpless Asymmetric Dihydroxylation
		6.5.3 The Prévost Reaction
		6.5.4 Dihydroxylation of Aromatic Rings
		6.5.5 Aminohydroxylation
	6.6 Baeyer-Villiger Oxidation (RCOR’ → RCO2R’)
		6.6.1 Peroxide-Induced Baeyer-Villiger Oxidation
		6.6.2 Enzymatic Baeyer-Villiger Oxidation
	6.7 Oxidative Bond Cleavage (C=C → C=O + O=C)
		6.7.1 Cleavage of Alkenes by Transition Metals
			6.7.1.1 Potassium Permanganate
			6.7.1.2 Osmium Reagents
			6.7.1.3 Ruthenium Reagents
			6.7.1.4 Chromium Reagents
		6.7.2 Cleavage of Alkenes With Ozone
		6.7.3 Cleavage of 1,2-Diols
			6.7.3.1 Lead Tetraacetate
			6.7.3.2 Sodium Periodate
	6.8 Oxidation of Alkyl or Alkenyl Fragments (CH → C=O or C—OH)
		6.8.1 Selenium Dioxide
		6.8.2 Transition Metal CH oxidation
		6.8.3 Tamao-Fleming Oxidation
		6.8.4 Alkene Oxidation (C=C → C—C=O)
		6.8.5 Vilsmeier Formylation
	6.9 Oxidation of Sulfur, Selenium, and Nitrogen
		6.9.1 Oxidation of Sulfur Compounds
			6.9.1.1 Oxidation of Sulfides to Sulfoxides
			6.9.1.2 Preparation of Chiral Sulfoxides
			6.9.1.3 Oxidation of Sulfides or Sulfoxides to Sulfones and Oxidation of Selenium Compounds
		6.9.2 Oxidation of Amines
	6.10 Conclusion
7. Functional Group Exchange Reactions: Reductions
	7.1 Introduction
	7.2 The Nature of Hydride Reducing Agents
	7.3 Borane and Aluminum Hydride
		7.3.1 Borane
		7.3.2 Aluminum Hydride
	7.4 Sodium Borohydride
	7.5 Alternative Metal Borohydrides (Li, Zn, Ce)
	7.6 Lithium Aluminum Hydride
		7.6.1 Reduction of Carbonyl Compounds
		7.6.2 Reduction of Heteroatom Functional Groups Other Than Carbonyl
			7.6.2.1 Alkyl Halides (Hydrogenolysis)
			7.6.2.2 Sulfonate Esters
			7.6.2.3 Epoxides
			7.6.2.4 Alkyne-Alcohols
			7.6.2.5 Nitriles
			7.6.2.6 Azides
			7.6.2.7 Nitro Compounds
			7.6.2.8 Sulfonamides
			7.6.2.9 Ozonides
	7.7 Hydride Reducing Agents With Electron-Releasing Groups
		7.7.1 Borane and Alane Derivatives
			7.7.1.1 Alkylboranes
			7.7.1.2 Diisobutylaluminum Hydride (Diisobutylalane)
		7.7.2 Borohydride Derivatives
			7.7.2.1 Super-Hydride
			7.7.2.2 The Selectrides
		7.7.3 Alkylaluminum Hydrides
	7.8 Hydride Reducing Agents With Electron-Withdrawing Groups
		7.8.1 Alkoxyborohydrides
		7.8.2 Acyloxyborohydrides
		7.8.3 Sodium Cyanoborohydride
		7.8.4 Alkoxyaluminum Hydrides
	7.9 Stereoselectivity in Reductions
		7.9.1 Selectivity in the Reduction of Carbonyl Derivatives Containing a Stereogenic Carbon
		7.9.2 Controlling Stereoselectivity in the Reduction of Aldehydes and Ketones
		7.9.3 Chiral Additives in Acyclic Systems
		7.9.4 Selectivity in the Reduction of Monocyclic Molecules
		7.9.5 Stereoselectivity in the 1,2-Reduction of Cyclohexenone Derivatives
		7.9.6 Selectivity in the Reduction of Bicyclic and Polycyclic Derivatives
		7.9.7 Selectivity in Reduction in Synthesis
	7.10 Catalytic Hydrogenation
		7.10.1 Catalytic Activity and Reactivity
		7.10.2 Hydrogenation of Alkenes
		7.10.3 Hydrogenation of Alkynes
		7.10.4 Hydrogenation of Carbonyl Compounds
		7.10.5 Hydrogenation of Other Heteroatom Functional Groups
		7.10.6 Hydrogenolysis Reactions
		7.10.7 Hydrogenation of Aromatic and Heteroaromatic Hydrocarbons
		7.10.8 Asymmetric Catalytic Hydrogenation
	7.11 Dissolving Metal Reductions
		7.11.1 Reduction With Alkali Metals
		7.11.2 Reduction of Carbonyl Compounds
		7.11.3 Reduction of Alkynes
		7.11.4 Hydrogenolysis
		7.11.5 Birch Reduction
		7.11.6 Reduction With Zinc
		7.11.7 Reduction With Tin and Tin Compounds
		7.11.8 Reduction With Aluminum and Aluminum Compounds
		7.11.9 Electrolytic Reductions
	7.12 Nonmetallic Reducing Agents
		7.12.1 Reduction With Hydrazine (Wolff-Kishner)
		7.12.2 Reduction With Diimide
		7.12.3 Reduction With Silanes (Hydrosilylation)
		7.12.4 Reduction With Formic Acid
		7.12.5 Photoreduction
		7.12.6 Enzymatic Reductions
	7.13 Conclusion
8. Synthetic Strategies
	8.1 Introduction
	8.2 Target Selection
		8.2.1 The Rationale for Total Synthesis
		8.2.2 Structural Verification
		8.2.3 Biological Activity
		8.2.4 Analog Studies
		8.2.5 Structural Challenges
		8.2.6 New Reactions and New Reagents
	8.3 Retrosynthesis
		8.3.1 The Disconnection Approach
		8.3.2 The Problem of Complex Targets
		8.3.3 Consecutive Versus Convergent Syntheses
	8.4 Synthetic Strategies
		8.4.1 Defining Strategic Approaches
		8.4.2 LHASA
	8.5 The Strategic Bond Approach
		8.5.1 The Preliminary Scan
			8.5.1.1 Is There Symmetry or Near Symmetry in Two Parts of the Molecule?
			8.5.1.2 Is the Problem Like One Already Solved?
			8.5.1.3 Is the Molecule a String of Available or at Least Simple Pieces?.
		8.5.2 Criteria for Disconnection of Strategic Bonds
	8.6 Strategic Bonds in Rings
		8.6.1 Carbocyclic Rings
		8.6.2 Heterocyclic Rings
	8.7 Selected Synthetic Strategies: Merrilactone A
	8.8 Biomimetic Approach to Retrosynthesis
		8.8.1 Polyene Cyclization
		8.8.2 Sparteine
		8.8.3 Deoxyerythronolide B
	8.9 The Chiral Template Approach
	8.10 Degradation Techniques as a Tool for Retrosynthesis
		8.10.1 Chemical Degradation
		8.10.2 Retro-Mass Spectral Degradation
	8.11 Computer-Generated Strategies
		8.11.1 Hendrickson’s SYNGEN Approach
		8.11.2 Barone’s MARSEIL/SOS System
	8.12 Conclusion
9. Functional Group Exchange Reactions: Hydroboration
	9.1 Introduction
	9.2 Preparation of Alkyl Boranes
		9.2.1 The Reactions of Alkenes and Boranes
		9.2.2 Regioselectivity and Diastereoselectivity
		9.2.3 Isomerization of Alkylboranes
		9.2.4 Hydroboration of Heteroatom-Containing Alkenes and Dienes
	9.3 Preparation of Alkenylboranes
	9.4 Formation of Oxygen-Containing Functional Groups
		9.4.1 Oxidation of Organoboranes to Alcohols
		9.4.2 Asymmetric Hydroboration
	9.5 Other Functional Group Exchange Reactions
		9.5.1 Protonolysis
		9.5.2 Halogenation
		9.5.3 Alkene, Diene, and Alkyne Synthesis
		9.5.4 Coupling, Isomerization, and Displacement
		9.5.5 Addition of Allylboranes to Carbonyl Compounds
		9.5.6 Oxidation to Aldehydes and Ketones
		9.5.7 Carbonylation: Formation of Alcohols, Aldehydes, and Ketones
		9.5.8 Conjugate Addition
		9.5.9 Amines and Sulfides via Hydroboration
			9.5.9.1 Nitrogen-Containing Compounds
			9.5.9.2 Sulfur
	9.6 Conclusion
10. Functional Group Exchange Reactions: Selectivity
	10.1 Introduction
	10.2 Stereocontrol in Acyclic Systems
		10.2.1 Regioselectivity
		10.2.2 Retention Versus Inversion of Configuration
		10.2.3 cis-trans Selectivity
		10.2.4 syn-anti Selectivity
		10.2.5 Heteroatom Chelation
	10.3 Stereocontrol in Cyclic Systems
		10.3.1 Regioselectivity
		10.3.2 Bredt’s Rule
		10.3.3 Diastereoselectivity
	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
11. Carbon-Carbon Bond-Forming Reactions: Cyanide, Alkyne Anions, Grignard Reagents, and Organolithium Reagents
	11.1 Introduction
	11.2 Cyanide
		11.2.1 Formation of Nitriles
		11.2.2 Isonitriles: Formation and Reactions
		11.2.3 Other Nitrile-Forming Reactions
	11.3 Alkyne Anions (R-C≡C:−)
		11.3.1 Preparation of Alkynes
		11.3.2 Acidity of Terminal Alkynes
		11.3.3 Reactions of Alkyne Anions
	11.4 Grignard Reagents (C—Mg)
		11.4.1 Preparation and Properties of Grignard Reagents
		11.4.2 The Reaction With Alkyl and Aryl Halides
			11.4.2.1 The Kharasch Reaction
			11.4.2.2 Reaction With α-Halocarbonyls
		11.4.3 Reactions With Carbonyl Derivatives
			11.4.3.1 Acyl Addition
			11.4.3.2 Acyl Substitution
			11.4.3.3 Reaction With Nitriles
			11.4.3.4 Reaction With Carbon Dioxide
		11.4.4 Conjugate Addition
		11.4.5 Reaction With Epoxides
		11.4.6 Stereochemical Stability of Grignard Reagents
		11.4.7 Stereoselectivity of Grignard Reactions
	11.5 Grignard Reagents: Reduction, Organocerium Reagents, and Enolization
		11.5.1 Reduction With Grignard Reagents
		11.5.2 Organocerium Reagents
		11.5.3 Enolization
	11.6 Organolithium Reagents (C—Li)
		11.6.1 Preparation, Structure, and Stability
		11.6.2 Metal-Halogen Exchange
		11.6.3 Wurtz Coupling
		11.6.4 Reactions With Aldehydes and Ketones
		11.6.5 Stereoselectivity in Organolithium Reactions
			11.6.5.1 Configurational Stability
			11.6.5.2 Diastereoselective Acyl Addition Reactions
		11.6.6 Reactions of Organolithium Reagents With Other Functional Groups
		11.6.7 Directed Ortho Metalation
		11.6.8 Addition to Epoxides, Alkenes, and Alkynes
			11.6.8.1 Reactions With Epoxides
			11.6.8.2 Intramolecular Addition to Alkenes and Alkynes
		11.6.9 Basicity: Metal-Hydrogen Exchange
	11.7 Conclusion
12. Carbon-Carbon Bond-Forming Reactions: Stabilized Carbanions and Ylids
	12.1 Introduction
	12.2 Sulfur-Stabilized Carbanions and Umpolung
		12.2.1 Sulfur-Stabilized Organolithium Reagents
		12.2.2 Umpolung
			12.2.2.1 Acyl Anion Equivalents
			12.2.2.2 Other Umpolung Equivalents
	12.3 Organocopper Reagents (C—Cu)
		12.3.1 Organocuprates
			12.3.1.1 Preparation of Gilman Reagents
			12.3.1.2 Higher Order Organocuprates
		12.3.2 Reactions of Organocuprates
			12.3.2.1 Alkyl Coupling Reactions
			12.3.2.2 Conjugate Addition
			12.3.2.3 Reaction with Epoxides
			12.3.2.4 Reaction with Acid Chlorides
			12.3.2.5 Reaction with Aldehydes and Ketones
		12.3.3 Asymmetric Induction
	12.4 Phenolic Carbanions
	12.5 YLIDS
		12.5.1 Phosphorus Ylids
			12.5.1.1 Wittig Reagents
			12.5.1.2 (E/Z) Isomers in Wittig Reactions
			12.5.1.3 Phosphine Oxides and Phosphonate Esters
			12.5.1.4 Alkenylphosphonium Salts
		12.5.2 Sulfur Ylids
			12.5.2.1 Sulfonium and Sulfoxonium Ylids
			12.5.2.2 Diphenylcyclopropylsulfonium Derivatives
		12.5.3 Nitrogen Ylids
			12.5.3.1 Formation of Nitrogen Ylids
			12.5.3.2 The Stevens’ Rearrangement and the Sommelet Rearrangement
	12.6 Transition Metal Olefination Reagents
	12.7 Silane Reagents
		12.7.1 Allylsilane Reagents
		12.7.2 Silane Carbanions
	12.8 Conclusion
13. Nucleophilic Species That Form Carbon-Carbon Bonds: Enolate Anions
	13.1 Introduction
	13.2 Formation of Enolate Anions
		13.2.1 Preparation and Properties
		13.2.2 Nonnucleophilic Bases
		13.2.3 (E/Z) Geometry in Enolate Formation
		13.2.4 Structure and Aggregation State of Enolate Anions
		13.2.5 Kinetic Versus Thermodynamic Control
	13.3 Reactions of Enolate Anions With Electrophiles
		13.3.1 Enolate Alkylation
		13.3.2 O- Versus C-Alkylation of Enolate Anions
		13.3.3 Enolate Anion Reactions With Noncarbonyl Electrophiles
	13.4 Enolate Condensation Reactions
		13.4.1 The Aldol Condensation
			13.4.1.1 Intermolecular Reactions
			13.4.1.2 Intramolecular Aldol Reactions
		13.4.2 Condensation Reactions of Acid Derivatives
			13.4.2.1 The Claisen Condensation
			13.4.2.2 The Dieckmann Condensation
			13.4.2.3 The Knoevenagel Condensation
			13.4.2.4 Nitrile Enolate Anions
			13.4.2.5 The Stobbe Condensation
			13.4.2.6 The Darzens’ Glycidic Ester Condensation
			13.4.2.7 Acid Dianions
		13.4.3 The Mukaiyama Aldol Reaction
		13.4.4 Boronic Esters (Boron Enolates)
		13.4.5 The Meyers Aldehyde Synthesis
		13.4.6 Imine and Hydrazone Carbanions
			13.4.6.1 Imine Carbanions
			13.4.6.2 Hydrazone Carbanions
		13.4.7 Nozaki-Hiyama-Kishi Coupling
	13.5 Stereoselective Enolate Reactions
		13.5.1 Simple Diastereoselection
			13.5.1.1 Alkylation
			13.5.1.2 Diastereoselectivity in the Aldol Condensation
			13.5.1.3 The Zimmerman-Traxler Model
			13.5.1.4 The Evans Model
			13.5.1.5 The Noyori Open-Chain Model
			13.5.1.6 Isomerization in the Aldol Condensation
		13.5.2 Selectivity With Chiral Nonracemic Reactants
			13.5.2.1 Diastereoface Selectivity
			13.5.2.2 Double Stereodifferentiation
		13.5.3 Chelation Control
		13.5.4 Diastereoselectivity in Alkylidene Enolates
	13.6 Enamines
		13.6.1 The Stork Enamine Synthesis
		13.6.2 Reactions of Enamines
		13.6.3 Asymmetric Enamine Syntheses
	13.7 Michael Addition and Related Reactions
		13.7.1 Michael Addition
		13.7.2 Baylis-Hillman Reaction
		13.7.3 Robinson Annulation
		13.7.4 Selectivity in the Robinson Annulation
	13.8 Enolate Reactions of α-Halo Carbonyl Derivatives
		13.8.1 α-Halogenation
		13.8.2 The Reformatsky Reaction
		13.8.3 The Favorskii Rearrangement
	13.9 Conclusion
14. Pericyclic Reactions: The Diels-Alder Reaction
	14.1 Introduction
	14.2 Frontier Molecular Orbital Theory
	14.3 Homo and Lumo Energies and Orbital Coefficients
	14.4 Allowed and Forbidden Reactions
	14.5 [4 + 2]-Cycloadditions
		14.5.1 The Diels-Alder Reaction
		14.5.2 Reactivity in the Diels-Alder Reaction
		14.5.3 Selectivity in the Diels-Alder Reaction
			14.5.3.1 Endo-Selectivity
			14.5.3.2 Cis-Trans Selectivity
			14.5.3.3 Regioselectivity of Cycloaddition Reactions
	14.6 Rate Enhancement in Diels-Alder Reactions
		14.6.1 Catalysis by Lewis Acids
		14.6.2 Rate Enhancement in Aqueous Media
		14.6.3 Rate Enhancement under High-Pressure Conditions
	14.7 Intramolecular Diels-Alder Reactions
	14.8 Inverse Electron Demand and the Retro-Diels-Alder Reactions
		14.8.1 Inverse Electron Demand Diels-Alder Reactions
		14.8.2 Retro-Diels-Alder Reactions
	14.9 Heteroatom Diels-Alder Reactions
		14.9.1 Aldehydes and Ketones
		14.9.2 Conjugated Aldehydes and Ketones
		14.9.3 Amino- and Amidodienes
		14.9.4 Azadienes
		14.9.5 Imines
		14.9.6 Nitroso-Type Compounds
	14.10 Enantioselective Diels-Alder Reactions
		14.10.1 Chiral Auxiliaries
		14.10.2 Chiral Additives and Chiral Catalysts
		14.10.3 Chiral Templates
	14.11 Enzymatic Diels-Alder Reactions
	14.12 Conclusion
15. Pericyclic Reactions: [m+n]-Cycloadditions, Sigmatropic Rearrangements, Electrocyclic, and Ene Reactions
	15.1 Introduction
	15.2 [2+2]-Cycloaddition Reactions
		15.2.1 Thermal [2+2]-Cycloadditions
		15.2.2 General Principles of Photochemistry
		15.2.3 Photochemical [2+2]-Cycloadditions
		15.2.4 The Paternò–Büchi Reaction
		15.2.5 [2+2]-Cycloreversion Reactions
	15.3 Electrocyclic Reactions
		15.3.1 Cyclobutene Ring Opening
		15.3.2 Hexatriene Derivatives and Related Compounds
	15.4 [3+2]-Cycloaddition Reactions
		15.4.1 Dipoles and Dipolarophiles
		15.4.2 Nitrile Ylids
		15.4.3 Nitrile Oxides
		15.4.4 Nitrones
		15.4.5 Diazoalkanes
		15.4.6 Azomethine Ylids
		15.4.7 Azomethine Imines
		15.4.8 Alkyl Azides
		15.4.9 Carbonyl Ylids
	15.5 Other Cycloaddition Reactions
	15.6 Sigmatropic Rearrangements
		15.6.1 [ m, n]-Sigmatropic Shifts
		15.6.2 The Vinylcyclopropane Rearrangement
		15.6.3 [2.3]-Sigmatropic Rearrangement (Wittig Rearrangement)
		15.6.4 The Cope Rearrangement
			15.6.4.1 The Classical Cope Rearrangement
			15.6.4.2 Oxy-Cope Rearrangement
			15.6.4.3 The Aza-Cope Rearrangement
		15.6.5 The Claisen Rearrangement
			15.6.5.1 Allyl-Vinyl Ether Rearrangements
			15.6.5.2 Variants of the Claisen Rearrangement
			15.6.5.3 Thio-Claisen and Aza-Claisen Rearrangements
	15.7 The Ene Reaction
		15.7.1 Enes and Enophiles
		15.7.2 Ene Reactions of 1,7-Dienes
		15.7.3 Carbonyl and Imino Ene Reactions
		15.7.4 Chiral Ene Reactions
	15.8 Conclusion
16. Carbon-Carbon Bond-Forming Reactions: Carbocation and Oxocarbenium Ion Intermediates
	16.1 Introduction
	16.2 Carbocations
		16.2.1 Cation Stability
		16.2.2 Configurational Instability
		16.2.3 Carbocation Rearrangements
		16.2.4 The Pinacol Rearrangement
	16.3 Carbocations and Carbon-Carbon Bond-Forming Reactions
		16.3.1 Carbocation Reactions With Alkene Nucleophiles
		16.3.2 Koch–Haaf Carbonylation
		16.3.3 Nazarov Cyclization
		16.3.4 The Prins Reaction
	16.4 Friedel–Crafts Reactions
		16.4.1 Electrophilic Aromatic Substitution
		16.4.2 Friedel–Crafts Alkylation
			16.4.2.1 Alkyl Carbocations and Regioselectivity
			16.4.2.2 Isomerization, Polyalkylation, and Deactivation
			16.4.2.3 Influence of the Catalyst
		16.4.3 Friedel–Crafts Alkylation Reactions From Alkene and Alcohol Substrates
		16.4.4 Friedel–Crafts Acylation
		16.4.5 Synthesis of Polycyclic Aromatics That Do Not Contain Nitrogen
	16.5 Friedel–Crafts Reactions: Formation of Heteroatom-Containing Derivatives
		16.5.1 Synthesis of Quinoline Derivatives
		16.5.2 Synthesis of Isoquinoline Derivatives
		16.5.3 Synthesis of Acridines, Carbazoles, and Phenanthridines
		16.5.4 Synthesis of Oxygenated Aromatic Derivatives
		16.5.5 Synthesis of Indoles
	16.6 Conclusion
17. Formation of Carbon-Carbon Bonds via Radicals and Carbenes
	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
		17.5.1 Coupling
		17.5.2 Addition Reactions
		17.5.3 Substitution Reactions
		17.5.4 Reduction by Atom Transfer
		17.5.5 Fragmentation
		17.5.6 Rearrangement and Hydrogen Atom Abstraction
	17.6 Intermolecular Radical Reactions
	17.7 Intramolecular Radical Reactions (Radical Cyclization)
		17.7.1 Carbocyclic Ring Systems
		17.7.2 Heteroatom Ring Systems
		17.7.3 Cyclization of •C—X Radicals and Cyclization of Heteroatom Radicals
		17.7.4 Bergman Cyclization
	17.8 Metal-Induced Radical Reactions
		17.8.1 General Principles
		17.8.2 Phenolic Oxidative Coupling
		17.8.3 Pinacol Coupling
		17.8.4 The Acyloin Condensation
		17.8.5 McMurry Olefination
	17.9 Carbenes and Carbenoids
		17.9.1 Definition of a Carbene
		17.9.2 Preparation of Carbenes
			17.9.2.1 Diazomethane
			17.9.2.2 Diazoalkanes
			17.9.2.3 α-Diazocarbonyl Compounds
			17.9.2.4 Photolysis of Cyclopropanes
			17.9.2.5 The Bamford-Stevens Reaction
			17.9.2.6 Photolysis of Carbonyls
			17.9.2.7 Halocarbenes
		17.9.3 N-Heterocyclic Carbenes
		17.9.4 Reactions of Diazomethane
		17.9.5 Carbene Reactions of Diazoalkanes
		17.9.6 Carbenoids
	17.10 Conclusion
18. Metal-Mediated, Carbon-Carbon Bond-Forming Reactions
	18.1 Introduction
	18.2 Copper-Catalyzed Coupling Reactions
		18.2.1 Aryl Coupling Reactions
		18.2.2 Alkyne-Coupling Reactions
		18.2.3 Stephens-Castro and Sonogashira Coupling
	18.3 π-Allyl Palladium Complexes
		18.3.1 The Wacker Process
		18.3.2 Formation of π-Allyl Palladium Complexes
		18.3.3 Reactions of π-Allyl Palladium Complexes
		18.3.4 Catalytic π-Allyl Palladium Reactions
			18.3.4.1 Reactions With Nucleophiles
			18.3.4.2 Palladium-Mediated Cyclization Reactions
			18.3.4.3 Palladium-Mediated Arylation Reactions
			18.3.4.4 Trimethylenemethane Equivalents
	18.4 Named Palladium-Catalyzed Coupling Reactions
		18.4.1 The Mizoroki-Heck Reaction
		18.4.2 Stille Coupling
		18.4.3 Suzuki-Miyaura Coupling
	18.5 π-Allyl Nickel Complexes
	18.6 Metathesis Reactions
	18.7 Pauson-Khand Reaction
	18.8 Organometallic Compounds as Carbanionic Reagents
		18.8.1 Allyltin Reagents
		18.8.2 Alkyltitanium Reagents
		18.8.3 Organoaluminum Compounds
		18.8.4 Organochromium Reagents
		18.8.5 Organoiron Compounds
			18.8.5.1 Formation and Stability
			18.8.5.2 Cyclopentadienylirondicarbonyl (Fp) Compounds
			18.8.5.3 Sodium Tetracarbonyl Ferrate
	18.9 Electrophilic Iron Complexes
		18.9.1 Alkene and Diene Iron Complexes
		18.9.2 Reactions of Iron Complexes With Nucleophiles
		18.9.3 Chiral Organoiron Species
	18.10 Conclusion
19. Combinatorial and Process Chemistry and Flow Synthesis
	19.1 Combinatorial Chemistry
		19.1.1 Combinatorial Techniques for Synthesis
		19.1.2 Deconvolution
		19.1.3 Product Identification
		19.1.4 Synthesis Using Combinatorial Techniques
	19.2 Process Chemistry
		19.2.1 Principles of Green Chemistry
		19.2.2 Scale-up Problems and Safety Issues
		19.2.3 Removal of Metals
		19.2.4 Modification of Synthetic Routes
		19.2.5 Scale-up and Optimization
	19.3 Continuous Flow Synthesis
	19.4 Conclusion
Subject Index
Disconnection Index