Dienamine Catalysis for Organic Synthesis

Kengadarane Anebouselvy, Dhevalapally B Ramachary, Indresh Kumar

• Publisher: Royal Society of Chemistry
• Year: 2018
• Edition: 1
• eBook ISBN:
  9781788014328
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

In the past decade a new era in asymmetric catalysis has been realised by the discovery of L-proline induced chiral enamines from carbonyls. Inspired by this, researchers have developed many other primary catalytic species in situ, more recently secondary catalytic species such as aminals have been identified for use in asymmetric synthesis.

High-yielding asymmetric synthesis of bioactive and natural products through mild catalysis is an efficient approach in reaction engineering. In the early days, synthetic chemists mainly focused on the synthesis of complex molecules, with less attention on the reaction efficiency and eco-friendly conditions. Recent investigations have been directed towards the development of atom economy, eco-friendly and enantioselective synthesis for more targeted and efficient synthesis.

Building on the momentum of this rapidly expanding research area, Dienamine Catalysis for Organic Synthesis will provide a comprehensive introduction, from the preformed species, in situ generation and onto their applications in the synthesis of bioactive molecules and natural products.

CHAPTER 1

Introduction to Dienamine Chemistry

KENGADARANE ANEBOUSELVY AND DHEVALAPALLY B. RAMACHARY^*

University of Hyderabad, School of Chemistry, Catalysis Laboratory, Hyderabad, 500 046, India

^*E-mail: [email protected], [email protected]

1.1 Origin of Dienamine Catalysis

Asymmetric catalysis is the most essential tool in organic chemistry as it assists chemists, biochemists and scientists in the construction of each and every complex chiral natural and non-natural product and drug substance. The third and recently unveiled pillar of support (the other two pillars being enzyme catalysis¹ and metal catalysis²) of asymmetric catalysis is “organocatalysis”. The realm of organocatalysis has grown swiftly in the last 15 years. Organocatalysis^3–5 possesses many advantages over metal and enzyme catalysis, such as operational simplicity, inexpensive and easily available catalysts, robustness, chemical efficiency, non-toxicity and atom economy, and is an environmentally benign, greener technology. As such, it has become a powerful and indispensable support for contemporary asymmetric catalysis research. The various activation methods in organocatalysis have facilitated numerous astoundingly elegant synthetic transformations, creating complex molecular architectures from rather simple starting materials. Since the evolution of asymmetric organocatalysis, with the use of small molecules like amino acids and chiral amines as catalysts for rate enhancement and chiral induction, there has been progressive growth in the field of asymmetric organic synthesis in terms of various enantioselective reactions and the synthesis of densely functionalized, complex natural products and drug molecules. One of the branches of organocatalysis, where chiral primary and secondary amines are utilized to catalyze asymmetric reactions, is termed “asymmetric aminocatalysis”.⁶

Carbonyl group activation of aldehydes and ketones with amines is essential in several important strategies for the synthesis of highly functionalized molecules. A covalent reaction takes place between the carbonyl and the amino group to generate enamine³ and iminium ion⁴ intermediates, which were found to undergo many reactions with suitable nucleophiles and electrophiles, respectively, as depicted in Figure 1.1(1) and (2). Employing the amine in catalytic quantities for plentiful transformations of carbonyl compounds has resulted in the development of this new branch of organocatalysis, called aminocatalysis.⁶ In the place of simple carbonyl compounds, when unsaturated carbonyl compounds were used, electron-rich dienamines were formed, which were found to create a wide variety of interesting reactivities.^4b,7 The phenomenal development in the field of dienamine catalysis has widened the horizons of an assortment of cycloaddition reactions,⁸ as well as many other synthetic organic transformations by allowing diverse functionalizations at various positions of the unsaturated carbonyl compounds.^3b,7

Figure 1.1 HOMO-activated enamine reactivity at the α-position of simple aldehydes and ketones (1); LUMO-activated iminium ion reactivity at the β-position of enals and enones (2).

Of the different modes of activation, the “highest occupied molecular orbital (HOMO) activation” mode observed in aminocatalysis has led to the development of a huge number of asymmetric α-functionalizations of aldehydes and ketones with various carbon-based, as well as heteroatom-based, electrophiles, as represented in Figure 1.1(1). In its infancy, organocatalysis encompassed a major portion of research work dealing with “enamine chemistry” and the scientific contributions made from several research groups were tremendously huge.³

Despite the fact that the reactive enamine intermediate was first prepared by Mannich and Davidsen in 1936,⁹ these intermediates only found widespread applications in the 1950s due to the seminal work of Stork and co-workers.¹⁰ First, in 1954, Stork reported alkylation of the pyrrolidine enamine of cyclohexanone using methyl iodide.^10a,b Preformed enamines were employed in the synthesis of many natural products, like vitamin-B₁₂. Synthesis of vitamin-B₁₂ by Woodward was based on a key reactive enamine intermediate.^10c Likewise, enamine chemistry found its applications in many other reactions, namely aldol, Mannich, Michael and Robinson annulation reactions, etc. In due course, researchers have also witnessed the emergence of a revolutionizing, brand new subdivision, named dienamine catalysis. The HOMO-raising principle observed in enamine-mediated reactions, when later applied to α,β-unsaturated aldehyde and α,β-unsaturated ketone starting materials, generated a particular mode of activation working through a dienamine intermediate species, thereby also providing activation of the γ-position of the original substrate toward various reactions.

1.2 Various Types of Dienamine Intermediates

As the name dienamine suggests, the species encompasses a diene moiety substituted with an amino group. Based on the generation technique of the dienamine species, it is mainly classified broadly into “stoichiometric preformed dienamines” and “in situ formed catalytic dienamines”. The dienamines can be further divided depending upon the position of the amino group on the generated diene moiety into “2-amino-1,3-butadiene” and “1-amino-1,3-butadiene” species, which are generated from α,β-unsaturated ketone and α,β-unsaturated aldehyde substrates, respectively,^11a as depicted in Scheme 1.1. When there is an additional electron-withdrawing group present at the 4-position of the 1-amino-1,3-butadiene species, it is categorized as a push–pull dienamine. Furthermore, as it is extended to ynone substrates, novel dienamine species (“aminoenynes”) are generated. A dienamine species differs from a simple enamine based on the following three aspects: (1) the presence of an additional nucleophilic site at the δ-position and an electrophilic site at the γ-position for 1-amino-1,3-butadienes, (2) the presence of three types of reactivity modes (diene reactivity and vinylogous reactivity, in addition to enamine reactivity), and (3) the capacity to act as an electron-rich olefin source in inverse-electron-demand [4 + 2]-cycloadditions by increasing the energy of the HOMO of the olefin.

Scheme 1.1 Different reactivities arising from the dienamine intermediate at various positions of enals and enones.

1.3 Significance of Dienamine Intermediates in Diels–Alder Type Reactions

During the last 15 years, dienamine catalysis has proven its importance by exhibiting multiple modes of activation, with very good substrate tolerance and high chemo-, regio- and stereo-selectivity. The power and potential of dienamine catalysis has been highlighted in the pioneering work of many scientists, who have contributed to a variety of asymmetric C–C bond-forming reactions and complex natural product and drug molecule syntheses. The dienamines were usually prepared from α,β-unsaturated aldehydes or ketones under conditions comparable to those used for the preparation of simple enamines. One of the modes of activation of dienamine catalysis that is most frequently encountered is the HOMO-activation concept, wherein α,β-unsaturated aldehydes, α,β-unsaturated ketones and ynones after condensation with the aminocatalyst generate the dienamine species, which is capable of undergoing stereoselective [4 + 2]-cycloadditions. The dienamines, which are very closely related to enamines, were also reported by Mannich in 1936.^11b Nevertheless, Snyder first utilized these dienamines in 1939 as a diene source in [4 + 2]-cycloadditions.¹²

In organic synthesis one of the most significant, straightforward, rapid, efficient, atom-economic and multiple-bond-forming reactions is indisputably the cycloaddition reaction. No chemist would deny the fact that the most revered asymmetric [4 + 2]-cycloaddition is a highly powerful tool for the synthesis of highly functionalized, complex organic molecules containing six-membered carbo- or hetero-cycles, with hi...

Table of contents

• Cover
• Title
• Copyright Page
• Preface
• Dedication
• Contents
• Chapter 1 Introduction to Dienamine Chemistry
• Chapter 2 Synthesis and Applications of Preformed Dienamines
• Chapter 3 Barbas Dienamines (2-Aminobuta-1,3-Dienes): Scope and Applications
• Chapter 4 Ramachary’s Dienamines (Push–Pull Dienamines): In situ Generation and Applications
• Chapter 5 Serebryakov–Jørgensen Dienamines (1-Aminobuta-1,3-Dienes): Different In situ Generation Methods and Applications in [4+2]-Cycloadditions
• Chapter 6 Serebryakov–Jørgensen Dienamines (1-Aminobuta-1,3-Dienes): Different In situ Generation Methods and Applications in [2+2], [3+2] and a Few Other Cycloadditions
• Chapter 7 Asymmetric α-Selective and Remote γ-Selective Functionalization of Enals and Enones Through Serebryakov–Jørgensen Dienamines (1-Aminobuta-1,3-Dienes)
• Chapter 8 Applications of Serebryakov–Jørgensen Dienamines (1-Aminobuta-1,3-Dienes) in Domino or Cascade Reactions
• Chapter 9 Aminoenyne (2-Aminobuta-1,3-Enyne) Catalysis: In situ Generation and Synthetic Applications in Organic Reactions
• Chapter 10 Trienamine-catalyzed Stereoselective Cycloadditions and Other Remote Functionalizations of Polyconjugated Enals/Enones
• Chapter 11 Tetraenamine-catalyzed Stereoselective Cycloadditions of Polyunsaturated Carbonyl Compounds
• Subject Index