N-Heterocyclic Carbenes in Organocatalysis

Akkattu T. Biju

• Publisher: Wiley-VCH
• Year: 2019
• Print ISBN:
  9783527343102
• Edition: 1
• eBook ISBN:
  9783527809073
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

Summarizing the emerging field of N-heterocyclic carbenes used in organocatalysis, this is an excellent overview of the synthesis and applications of NHCs focusing on carbon-carbon and carbon-heteroatom bond formation. Alongside comprehensive coverage of the synthesis, characteristics and applications, this handbook and ready reference also includes chapters on NHCs for polymerization reactions and natural product synthesis.

1
An Overview of NHCs

Matthew N. Hopkinson¹ and Frank Glorius²

¹ Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany

² Westfälische Wilhelms‐Universität Münster, Organisch‐Chemisches Institut, Corrensstr. 40, 48149 Münster, Germany

Since the unambiguous isolation of the first free N‐heterocyclic carbene (NHC) IAd in 1991 by Arduengo et al. [1], these compounds have received a huge amount of attention from across the chemical community [2]. As stable examples of coordinatively unsaturated, electronically deficient carbene compounds, much of the earlier interest resulted from their status as academic curiosities. However, as studies were conducted on their properties and reactivity, the full potential of NHCs in many different areas of chemistry was revealed. As strong σ‐donors to metal centers, NHCs are nowadays widely used as ancillary ligands in organometallic chemistry including in industrially important catalytic transformations [3], rivaling phosphines, and cyclopentadienyls in this role. Many NHC–metal adducts are also attracting attention in materials science and as potential metallopharmaceuticals [4]. The strong binding properties and stabilizing features of NHCs have also led to many applications not involving metals. For example, boron–NHC adducts have been widely studied in a number of different contexts [5], whereas some classes of π‐accepting NHCs have been shown to activate small molecules such as ammonia [6]. It is the reactivity of NHCs as organocatalysts, however, that forms the basis of this book [7]. First observed by Ukai et al. in a thiazolium salt‐mediated benzoin condensation in 1943 [8], NHCs have proved efficient catalysts for umpolung reactions of aldehyde substrates, reacting via so‐called Breslow intermediates, which can be considered acyl anion equivalents [9]. Alongside these processes, alternative transformations involving a wide range of different reactivity modes with both aldehydes and other substrate classes are possible with the application of chiral NHCs often allowing for high levels of enantioselectivity [10]. The scope and diversity of NHC organocatalysis continue to expand at a rapid pace and detailed summaries highlighting that the major reaction classes and current research trends are to be found in the subsequent chapters of this book. In this introductory chapter, we instead provide a general overview of NHCs, highlighting their common structural features and properties and briefly summarizing some of their uses outside of organocatalysis. The major synthetic routes to commonly employed NHC organocatalysts are discussed while a particular focus is given to understanding and comparing the various electronic and steric properties of different classes of NHC.

1.1 General Structure of NHCs

1.1.1 Classes of NHCs and Related Stable Carbenes

The definition of what constitutes an NHC is often subject to different interpretations, and many classes of carbene compounds have been labeled NHCs in the literature. For the sake of clarity, we consider an NHC as any compound featuring a carbene center as part of a heterocyclic ring containing at least one nitrogen atom. Many different carbenes satisfy these criteria, and a selection of some of the most important classes of NHC is shown in Figure 1.1. The first reported compound IAd (1a), isolated by Arduengo et al. [1], is an example of an imidazolylidene NHC (1). The carbene center in this species is situated between the two nitrogen atoms in an aromatic imidazole heterocycle. Imidazolylidenes of this type were the focus of many of the early studies on NHCs, and they continue to find applications across many areas of chemistry. Derivatives featuring aromatic nitrogen substituents such as mesityl (IMes, 1b) and 2,6‐diisopropyl (IPr or IDipp, 1c) are particularly widely used as ligands for transition metals and feature in catalysts for cross‐coupling reactions and other important transformations. Related to imidazolylidenes but often displaying different reactivity are their saturated imidazolinylidene analogs 2. These species also feature two nitrogen atoms adjacent to the carbene center in a five‐membered heterocycle, yet are not aromatic. The first free imidazolinylidene NHC SIMes (2a) was prepared by Arduengo et al. [11], and this compound, which again features N‐mesityl substituents, has since found a widespread use as a ligand for ruthenium in Grubbs' second‐generation olefin metathesis catalysts [3f, u]. Benzimidazolylidenes 3 possess a benzene ring fused onto an imidazolylidene NHC while derivatives with larger ring sizes such as six‐membered tetrahydropyrimidinylidenes 4 or various ring‐sized N,N′‐diamidocarbenes (DACs, 5) have been prepared. These latter compounds, pioneered by Bielawski and coworkers, have been shown to activate small molecules such as ammonia and undergo insertion into alkenes in a similar manner to classical triplet carbenes [12].

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Table of contents

• Cover
• Table of Contents
• Preface
• Discovery of Catalysis by Nucleophilic Carbenes
• About the Editor
• 1 An Overview of NHCs
• 2 Benzoin Reaction
• 3 N‐Heterocyclic Carbene‐catalyzed Stetter Reaction and Related Chemistry
• 4 N‐Heterocyclic Carbene (NHC)‐Mediated Generation and Reactions of Homoenolates
• 5 Domino Processes in NHC Catalysis
• 6 N‐Heterocyclic Carbene Catalysis via the α,β‐Unsaturated Acyl Azolium
• 7 Recent Activation Modes in NHC Organocatalysis
• 8 N‐Heterocyclic Carbene‐Catalyzed Reactions via Azolium Enolates and Dienolates
• 9 N‐Heterocyclic Carbenes as Brønsted Base Catalysts
• 10 NHC‐Catalyzed Kinetic Resolution, Desymmetrization, and DKR Strategies
• 11 N‐Heterocyclic Carbenes for Organopolymerization: Metal‐Free Polymer Synthesis
• 12 N‐Heterocyclic Carbene Catalysis in Natural Product and Complex Target Synthesis
• Index
• End User License Agreement