21 Introduction

Y. R. Mahajan and S. M. Weinreb

This volume covers the synthesis of compounds containing an amide moiety, including peptides and lactams. These compounds have been divided into groups depending on the type of amide and the nature of the substituents around the amide functionality. These groups are shown in ? Table 1, together with the sections in which they appear.

? Table 1 Classes of the Amide-Bond-Containing Compounds Covered in Volume 21

References to reviews on the different classes of compounds are given within each section. The discussion of each specific group is generally subdivided into methods that have been selected as the most useful for the preparation of the product class or subclass in question. Each method is presented separately as follows:

1. Introduction: comparison with other methods.
2. Presentation of the scope of the method including background, discussion of representative examples, safety, mechanistic information where relevant to the use of the method in synthesis, a table of examples (for selected methods), and reaction schemes.
3. Representative experimental procedures.

In some cases, methods are further subdivided into variations on a method, with each variation being presented according to the above format.

The coverage in this volume is not meant to be exhaustive, rather the most useful and reliable methods for the synthesis of each compound class have been selected by the respective authors. In some cases, methods that are apparently of only limited utility, or that have not yet been fully developed, are listed at the end of a section for reference. Tables and representative experimental procedures are given to illustrate the applicability of each approach.

It is important to note that amide polymers are not included, even though they certainly constitute an important class of amido compounds. This omission is mainly due to the fact that these macromolecules are not traditional targets for chemists working in the field of organic synthesis, and hence a thorough and comprehensive treatment of polymers is beyond the scope of the Science of Synthesis series.

This introduction outlines the individual product classes, together with highlighted synthetic methods.

The synthesis of simple amides (i.e., those without any other functional groups directly attached) is described in ? Section 21.1. The primary methods of amide synthesis discussed here are condensation processes and are classified depending on the nature of the precursor used: carbonic acids and derivatives, carboxylic acids and derivatives, aldehydes and ketones, and amines. Along with these sections, rearrangement reactions leading to amides are also discussed.

The synthesis of amides from carbonic acids and derivatives involves either a reduction or the formation of a C-C bond. Depending on the carbonic acid derivative, the synthesis may also involve the formation of a C-N bond. Phosgene and phosgene surrogates, chloroformates, carbonates, and carbon monoxide have been utilized for the simultaneous trapping of both a nitrogen and a carbon atom to afford amides. The preparation of amides from carbamates, carbamoyl chlorides, isocyanates, and urea derivatives involves the formation of a C-C bond. Generally, urea derivatives are not used in intermolecular amide synthesis due to the fact that the amide bond formed in this process is more reactive than the starting urea derivative, and thus can react further to form ketones. Hence, urea derivatives are mainly used in intramolecular reactions, as exemplified in ? Scheme 1 for the formation of amides 1.[1]

? Scheme 1 Synthesis of Amides from Urea Derivatives by Intramolecular Cyclization[1]

Formation of an amide bond by the coupling of carboxylic acids and derivatives with amines is one of the most popular methods in the synthesis of both amides and peptides. Owing to their wide application in peptide synthesis, methods employing carbodiimides, mixed anhydrides, and other condensation reagents are discussed in detail in Section

21.11. Along with carboxylic acids and derivatives, amides can also be prepared from thio-carboxylic acids and esters, nitriles, and imidates. Furthermore, significant progress has been made in the synthesis of amides from isocyanides via Ugi and Passerini multicomponent reactions.

In general, amides are prepared by the coupling of higher oxidation state compounds, such as carboxylic acid derivatives, with amines; however, synthetic methods starting with precursors in lower oxidation states, such as aldehydes, ketones, imines, and related compounds, are also available. As the products are therefore in a low oxidation state, an oxidation step must be included to obtain the desired amides. A variety of oxidizing agents such as N-bromosuccinimide, peroxides, sodium perborate, manganese(IV) oxide, and permanganate, as well as electrochemical techniques, have been employed to obtain the amides.

Rearrangement reactions comprise some of the most useful methods of converting non-nitrogenous compounds into amides. This reaction class contains very commonly used methods in amide and lactam synthesis, including the Beckmann and the Favorskii rearrangements, as well as the still-growing family of Schmidt reactions. These rearrangement reactions usually begin with ketones or ketone derivatives. As a-substituted ketones can be synthesized in enantiomerically pure form in numerous ways, and since most of these rearrangement reactions permit a migrating group bearing a stereogenic center to retain its stereochemical integrity, these reactions can also be employed for the asymmetric synthesis of amides, e.g. 2 (? Scheme 2).[2]

? Scheme 2 Asymmetric Amide Synthesis by an Intramolecular Schmidt Rearrangement[2]

The last part of ? Section 21.1 deals with substitution reactions and functional group manipulations of amide-containing compounds such as N-heteroatom-substituted alkanamides, formamides, diacyl- and triacylamines, ynamides, and enamides, without affecting the amide bond.

The synthesis of triacylamines, diacylamines, and related compounds is discussed in ? Section 21.2. More recently, imides have gained popularity as valuable synthetic intermediates due to their effectiveness as components of chiral auxiliaries such as Oppolzer's sultam and Evans' oxazolidines.[3,4] Furthermore, the utilization of amino acids and their derivatives as chiral templates, and their ready conversion into imides, has enabled the preparation of versatile chiral synthons for a number of applications. One of the reagents commonly used for N-phthaloyl protection of sensitive amino acids is N-(ethoxycarbonyl)phthalimide (ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate, 3; ? Scheme 3). This compound can be easily prepared either by treating phthalimide with ethyl chloroformate in the presence of triethylamine or by treating potassium phthalimide with ethyl chloroformate in dimethylformamide.[5]

? Scheme 3 Preparation and Application of N-(Ethoxycarbonyl)phthalimide[5]

The synthesis and applications of...