devoted to the synthesis of chiral propargylamines. Many of these compounds possessing pharmaceutical properties have found applications in the treatment of diseases and can be considered among the most efficient building blocks for the synthesis N‐containing heterocycles.
The relevance of high atom efficiency and very limited waste production (high atom economy) is of paramount importance for the development of methodologies with industrial prospects. Reactions such as TM‐catalyzed asymmetric hydroamination, reductive amination, and hydroaminomethylation, reported in Chapter 5, meet these goals, an additional advantage being the simplicity and the easy availability of the starting materials, which is only partially counterbalanced by the complexity of the used ligands. Because of their relevance, these reactions are occasionally mentioned elsewhere in this book, although in the frame of different contexts, thus providing the reader with an exhaustive set of complementary information.
In the following chapters, metal‐free stereoselective catalytic methodologies at the service of amine synthesis, represented by organo‐ and biocatalysis, are treated with a greater focus on industrial applications reflecting the dynamic nature of these catalytic streams. The central goal of organocatalysis (Chapter 6) is herein addressed to the emerging utilization of this methodology as an exceedingly useful synthetic tool for the large‐scale preparation of active pharmaceutical ingredients (APIs) in industrial settings. An emphasis is placed on three case studied in which organocatalysis stands out with respect to other enantioselective strategies, for its versatility and potential for scale‐up. The revolutionary approach of enzyme engineering, in the context of oxidoreductase enzymes applied to the synthesis of N‐containing biologically relevant intermediates and products, is described in Chapter 7. The intrinsic selectivity of enzymes provides an obvious advantage in the key challenge of developing new synthetic platforms amenable to industrialization.
The following two chapters stand out for their uniqueness, targeting topics that were not even touched in the previous two books on amino chemistry but of exceptional prominence and timeliness. Chapter 8 deals with the use of amines in the synthesis, stabilization, and functionalization of organic–inorganic hybrid nanomaterials, highlighting through a large number of case studies the pivotal role played by the amino group to unlock practical applications in the fields of biology, medicine, and energy production. Conversely, the synthesis of a number of valuable amino compounds is reported in Chapter 9, from the transformation of renewable biomass resources that already incorporate the amino groups such as chitin, chitosan, and amino acids or by modifying bio‐based compounds, followed by amination. Rare aminosugars, precursors of medicinal compounds, and a wide range of heterocycles are obtained avoiding the use of fossil‐based feedstocks, thus providing a remarkable step forward in the ongoing shift from depleting to renewable resources.
The final Chapter 10 addresses current applications of TM‐catalyzed aromatic amination in industrial settings by discussing a large number of case studies related to the manufacturing process of pharmaceutical compounds. In addition, with reference to the seminal work by Ullmann, Buchwald, and Hartwig, this contribution points on new concepts still at academic level, but either further extending the applicability of new methodologies, or on the brink of being industrially used. Also approaches with a focus on process intensification and sustainability (flow chemistry and catalyst immobilization) are presented, together with a view of the accompanying questions when applying the methodology of aromatic amination in the pharmaceutical industry. To make aware the reader about these challenges, themes such as the control of elemental impurities, the TM accounting, and the metal recycling are treated as well. Besides being a highly useful and up‐to‐date source of information on the TM‐catalyzed aromatic amination in industry, this contribution will hopefully provide inspiration for academic research in developing new methodologies amenable to industrialization.
We warmly thank all the distinguished scientists and their coauthors for their rewarding and highly instructive contributions. Without their effort, even more valuable considering it partially coincided with a difficult period at the international level, this volume would have not been possible. Grateful acknowledgments are also addressed to the Wiley‐VCH editorial staff, and in particular to Anne Brennführer, Aruna Pragasam, Elke Maase, and Katherine Wong, who encouraged us at project outset and helped us in a very competent manner in all the phases of the preparation of this book.
Alfredo Ricci and Luca Bernardi
Bologna
07 April 2020
1 Substitution‐type Electrophilic Amination Using Hydroxylamine‐Derived Reagents
Zhe Zhouand László Kürti
Rice University, Department of Chemistry, 6500 Main Street, Houston, TX, 77030, USA
1.1 Introduction
Electrophilic amination is a class of organic reactions where C—N bonds are formed via the use of electrophilic aminating reagents [1–4]. Depending on the specific reaction pathway, electrophilic amination reactions can be classified either as substitution or addition. This chapter focuses on substitution reactions. Aminating reagents for the substitution‐type electrophilic aminations are essentially NR2+ synthons, and the electrophilicity on the nitrogen atom is generally achieved by attaching a more electronegative functionality (X) to the nitrogen atom that can serve as a leaving group. Common structural motifs for this class of reagents include chloramines, hydroxylamines, and oxaziridines (i.e. cyclic hydroxylamine derivatives). Because of the safety hazards associated with the use of chloramines, recent developments in this area have been focused on the use of more stable hydroxylamine‐type reagents (Scheme 1.1).
Substitution‐type electrophilic amination reactions can operate under either uncatalyzed or catalyzed conditions. The majority of catalytic substitution‐type electrophilic amination reactions are catalyzed by complexes of transition metals (TMs). In the uncatalyzed reactions, the carbon nucleophile directly attacks the electrophilic nitrogen atom and a new C—N bond is formed. In the TM‐catalyzed reactions, the transition metal first enters into the N—X bond via an oxidative addition, and the new C—N bond is formed after sequential ligand exchange and reductive elimination (Scheme 1.2). The major difference between TM‐catalyzed substitution‐type electrophilic amination reactions and TM‐catalyzed C–N cross‐coupling reactions (i.e. Buchwald–Hartwig coupling) is the role of the nitrogen source: it acts as an electrophile in the former while as a nucleophile in the latter.
The majority of the literature in this area concerns the TM‐catalyzed versions of substitution‐type electrophilic amination. Therefore, they will be discussed first in this chapter.
Scheme 1.1 General structure of electrophilic aminating reagent.
