The present review offers an overview of nonclassical (e.g., with no pre- or in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines (section 2); the use of carboxylic acid surrogates (section 3); and the use of amine surrogates (section 4). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5.

Nonclassical Routes for Amide Bond Formation

Radical cyclizations and multicomponent radical cascades in solution were studied, which are initiated by intermolecular radical addition to C-C triple bond in alkynes as well as to related C?N triple bonds in nitriles and isonitriles. The reactions were arranged according to the atom that carries the unpaired electron in the attacking radical and cover main group IV-VI elements. The initial radical addition is highly regioselective and in reactions with substrates possessing several π systems, the alkyne moiety is usually attacked with high preference. This selectivity can be rationalized by the reversibility with which the initial radicaladdition occurs in many cases, in particular with Sn- and S centered radicals. Due to their high reactivity, vinyl radicals that are formed through radical attack at the alkyne moiety in enynes. Alkyl radicals resulting from radical addition to an alkene are far less reactive so that the competing dissociation and regeneration of the starting materials is often faster than the forward reaction steps.

Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems

It is shown for the first time that N-sulfonyl amides can be efficiently prepared by an unconventional approach of the hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of copper catalyst and amine base under very mild conditions. The present route is quite general, and a wide range of alkynes and sulfonyl azides are readily coupled catalytically with water to furnish amides in high yields. A variety of labile functional groups are tolerated under the conditions, and the reaction is regioselective in that only terminal alkynes react while double or internal triple bonds are intact. The reaction can be readily scaled up and is also adaptable to a solid-phase procedure with high efficiency.

Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water.

Photochemistry has ushered in a new era in the development of chemistry, and photoredox catalysis has become a hot topic, especially over the last five years, with the combination of visible-light photoredox catalysis and radical reactions. A novel, simple, and efficient radical oxidative decarboxylative coupling with the assistant of the photocatalyst [Ru(phen)3 ]Cl2 is described. Various functional groups are well-tolerated in this reaction and thus provides a new approach to developing advanced methods for aerobic oxidative decarboxylation. The preliminary mechanistic studies revealed that: 1) an SET process between [Ru(phen)3 ](2+) * and aniline play an important role; 2) O2 activation might be the rate-determining step; and 3) the decarboxylation step is an irreversible and fast process.

Visible‐Light‐Mediated Decarboxylation/Oxidative Amidation of α‐Keto Acids with Amines under Mild Reaction Conditions Using O2

A mild and efficient copper-catalyzed oxidative amidation of aldehydes was developed using amine HCl salts and tert-butyl hydroperoxide as an oxidant.

Highly Efficient Oxidative Amidation of Aldehydes with Amine Hydrochloride Salts

Radical chain reactions using THP as a solvent

The carbonylation of alkanes 1 under radical-reaction conditions was examined by using ethynyl triflone A as the unimolecular chain-transfer (UMCT) reagent. Good to moderate yields of ethynyl ketones 2 were prepared by means of this three-component coupling reaction. Higher CO pressures as well as lower concentrations of triflone A improved the efficiency of the reaction over the direct addition, the latter leading to alkylated ethynes 3. In contrast to the reaction with A, the reaction of cyclohexane (1a) with allyl triflone B (= ethyl 2-methylene-3-[(trifluoromethyl)sulfonyl]propanoate) in the presence of CO gave a mixture of carbonylation products, including 8a formed from two molecules each of cyclohexane, CO, and allyl triflone B.

Trifluoromethyl-Radical-Mediated Carbonylation of Alkanes Leading to Ethynyl Ketones

Figure 1. Concept of ketenyl radical trapping Radical carbonylation reactions are becoming a powerful tool for the introduction of carbon monoxide into organic molecules. We have previously reported that free-radical mediated stannylcarbonylation of alkynes provides a useful entry to α,βunsaturated acyl radicals, which are likely to exist in an equilibrium with α-ketenyl radicals. Intraand intermolecular trapping attempts of α,β-unsaturated acyl radicals/α-ketenyl radicals led us to postulate that ketenyl carbonyl has an electrophilic nature sufficient enough to allow for the attack of nitrogen nucleophiles, such as imines, oxazolines, and amines. While stannylcarbonylation of amino-substituted alkynes gave lactams, we were curious at knowing if the stannylcarbonylation of hydroxy-substituted alkynes would give the corresponding lactones or not, since nucleophilicity of alcohols is not so strong as that of amines. We report herein the results of the free-radical mediated stannylcarbonylation reaction of 5-hydroxyalkynes, which gave cyclized carbonylated products, lactols, as principal carbonylated products. Interestingly recent work of Nishii, Tanabe, and coworkers reported that lactols can be formed by radical carbonylation of cyclopropyl radicals, through the trapping of intermediary acyl radicals by an internal hydroxyl group. Choosing 4-pentyn-1-ol (1a), as a model compound, we examined AIBN-initiated stannylcarbonylation reaction. As shown in Scheme 1, the reaction gave cyclized carbonylated products, unsaturated lactone 3a and lactol 4a, whereas lactone 2a was formed in only a trace amount. The formation of lactol 4a presumably requires two equivalents of tributyltin hydride. In consistent with this, the reaction using 1.3 equiv of tributyltin hydride caused the shortage of tin hydride resulting in the recovery of 1a. With 3.1 equivalents of tin hydride, the yield of 4a increased up to 46%. We also examined stannylcarbonylation of 3-butyn-1-ol (1b) and 5-hexyn-1-ol (1c). These results are shown in Scheme 2.

/pdf/stannylcarbonylation-of-hydroxy-substituted-alkynes-pz9g7kh3uh.pdf

Stannylcarbonylation of Hydroxy-substituted Alkynes. Intramoleuclar Trapping of α-Ketenyl Radicals by a Hydroxy Group Leading to Lactols † †

THP (tetrahydropyran) has been found to show an excellent stability towards autooxidation, compared with THF. Tributyltin hydride mediated radical cyclization, when conducted in THF as a solvent, suffers from competition of hydrogen abstraction from the solvent, whereas the use of THP resulted in the course to negligible degree. Tributyltin hydride, TTMSS, and hexanethiol mediated radical reactions were carried out successfully using THP as a solvent.

Radical Chain Reactions Using THP as a Solvent.

The tin hydride mediated radical carbonylation of hydroxy-substituted alkynes leads to lactols as principal products.

Stannylcarbonylation of Hydroxy‐Substituted Alkynes. Intramolecular Trapping of α‐Ketenyl Radicals by a Hydroxy Group Leading to Lactols.

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