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We report how the rearrangement of highly reactive nitrile imines derived from N-2-nitrophenyl hydrazonyl bromides can be harnessed for the facile construction of amide bonds. This amidation reaction was found to be widely applicable to the synthesis of primary, secondary, and tertiary amides and was used as the key step in the synthesis of the lipid-lowering agent bezafibrate. The orthogonality and functional group tolerance of this approach was exemplified by the N-acylation of unprotected amino acids.

We report the use of

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters., Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.

Nitrilium betaine 1,3-dipoles are ubiquitous reagents in organic chemistry, with applications ranging from natural product synthesis to materials science. Given the high reactivity of these zwitterionic motifs, they are invariably generated in situ from a suitable precursor, prior to use. This short review summarises the recent progress in the development of modern approaches towards the formation of these 1,3-dipoles, and their applications within a diverse range of fields.1 Introduction2 Nitrile Ylides2.1 2H-Azirine Rearrangement2.2 Addition of Nitriles to Carbenes3 Nitrile Imines3.1 2,5-Tetrazole Thermolysis3.2 2,5-Tetrazole Photolysis3.3 Diaryl Sydnone Photolysis4 Nitrile Oxides4.1 Hypervalent Iodine4.2 The Nitroso Radical4.3 Green Chemistry Approaches4.4 Other Approaches5 Conclusions

An operationally simple E → Z isomerization of activated dienes, based on the β-ionyl motif intrinsic to retinal, is reported using inexpensive (−)-riboflavin (vitamin B2) under irradiation at 402 nm. Selective energy transfer from photoexcited (−)-riboflavin to the starting E-isomer enables geometrical isomerization. Since the analogous process with the Z-isomer is inefficient, microscopic reversibility is circumvented, thereby enabling a directional isomerization to generate the contra-thermodynamic product (up to 99% yield, up to 99:1 Z/E). Prudent choice of photocatalyst enables chemoselective isomerization to be achieved in both inter- and intramolecular systems. The principles established from this study, together with a molecular editing approach, have facilitated the development of a regioselective isomerization of a truncated triene based on the retinal scaffold.

The challenges of developing sustainable methods of carbon-carbon bond formation remains a topic of considerable importance in synthetic chemistry. Capitalizing on the highly reactive nature of the nitrile imine 1,3-dipole, we have developed a novel metal-free coupling of this species with aryl boronic acids. Photochemical generation of a nitrile imine intermediate and trapping with a palette of boronic acids enabled rapid and facile access to a broad library of more than 25 hydrazone derivatives in up to 92 % yield, forming a carbon-carbon bond in a metal free fashion. This represents the first reported example of direct reaction between boronic acids and a 1,3-dipole.

A range of 1,3,4‐oxadiazoles have been synthesized using a UV‐B activated flow approach starting from carboxylic acids and 5‐substituted tetrazoles. The application of UV light represents an attractive alternative to the traditional thermolytic approach and has demonstrated comparable efficiency and versatility, with a diverse substrate scope, including the incorporation of highly substituted amino acids., A photochemical, flow‐based Huisgen synthesis of 1,3,4‐oxadiazoles from 5‐substituted tetrazoles and carboxylic acids has been developed. This has enabled the expedient and facile synthesis of a broad palette of heterocyclic derivatives which are of direct relevance to a range of applications including pharmaceuticals and materials science (see scheme).

The need for alternative, complementary approaches to enable C−C bond formation within organic chemistry is an on‐going challenge in the area. Of particular relevance are transformations that proceed in the absence of transition‐metal reagents. In the current study, we report a comprehensive investigation of the coupling of nitrile imines and aryl boronic acids as an approach towards sustainable C−C bond formation. In situ generation of the highly reactive 1,3‐dipole facilitates a Petasis–Mannich‐type coupling via a nucleophilic boronate complex. The introduction of hydrazonyl chlorides as a complementary nitrile imine source to the 2,5‐tetrazoles previously reported by our laboratory further broadens the scope of the approach. Additionally, we exemplify for the first time the extension of this protocol into another 1,3‐dipole, through the synthesis of aryl ketone oximes from aryl boronic acids and nitrile N‐oxides., A scalable and metal‐free approach to carbon–carbon bond formation using 1,3‐dipole systems generated from hydrazonyl chloride or hydroxamoyl chloride precursors and aryl boronic acid derivatives is reported. Generation of the 1,3‐dipole results in activation of the boronic acid, with migration of the pendant aryl group to forge a new C−C bond in yields up to 80 % (see scheme).

2,5-Diaryltetrazoles are a diverse range of compounds of considerable interest within the field of photochemistry as a valuable precursor of the nitrile imine 1,3-dipole. Current literature approaches toward this heterocycle remain unsuitable for the practical synthesis of a library of these derivatives. Herein, we disclose the development of a modular approach toward 2,5-diaryltetrazoles compatible with an array-type protocol, facilitated by a tandem Suzuki-hydrogenolysis approach.

One of the most unique properties of nitrile imines in comparison to other 1,3-dipoles is their diverse reactivity profile with a number of distinct substrates. This chapter aims to categorise the different transformations of the dipole that have been reported in the literature over the past 60 years. Of particular utility is the conventional 1,3-dipolar cycloaddition reaction between the nitrile imine and unsaturated carbon-carbon bonds. While further research is required to fully comprehend the factors determining the rate and regioselectivity of such reactions, these aspects are also discussed. Nitrile imines also exhibit substantial reactivity with a number of nucleophiles, particularly softer examples such as carboxylic acids and thiols. In the absence of any reaction partners, certain species of nitrile imine are also labile to undergo intramolecular rearrangement, dimerisation, or decomposition.

Owing to the promiscuous reactivity profile of the nitrile imine, the species is normally generated as an intermediate during the desired reaction. This requires the selection of a precursor that is able to furnish the desired moiety when exposed to appropriate conditions. This chapter discusses a library of different molecules that have previously been employed as sources of nitrile imines. Of particular importance within this field are the hydrazonyl halides and the 2,5-tetrazoles, which have risen to prominence as the two most common methods of nitrile imine generation within the literature. The methods employed in the liberation of the dipole are also explored, with a broad scope of different reaction conditions available, including photolytic generation via UV light.

Nitrile imines have been employed in a diverse range of fields relating to the chemical sciences. This likely originates from the pleiotropic reactivity of the dipole, coupled with the diverse range of methods available for their generation. The overwhelming majority of these applications utilise the facile and often orthogonal 1,3-dipolar cycloaddition between nitrile imines and electronically- or strain-activated alkenes. More recent reports have also explored the introduction of hydrazide synthesis through the combination of the dipole with carboxylic acids. In addition to the adaption of nitrile imines within traditional chemical synthesis, the dipole has also demonstrated widespread application in both bioorthogonal chemistry and materials science as a ligation agent.

This chapter introduces the nitrile imine 1,3-dipole, examining the history behind its discovery and the core spectroscopic characteristics associated with the species. The different resonance forms available to nitrile imines can often complicate their characterisation, however appropriate interrogation of data such as UV-Vis, IR and NMR spectra may elucidate the core properties of the dipole. Substitution on either terminus of this typically highly reactive intermediate can also improve stability, enabling the isolation of some nitrile imines at room temperature.

An operationally simple

A procedure for the formation of aryl amides through the palladium-catalyzed coupling of nitriles and aryl bromides, via the formation of intermediary silanoate derived imidate species is reported. Optimization was undertaken and examples of the process are described that furnish the products in up to 86% isolated yield.

The starting amide salts are prepared by reaction of appropriate nitriles with Tms—OK according to a known procedure.