Synthesis of Homoallylic Amines by Radical Allylation of Imines with Butadiene under Photoredox Catalysis.

Ionic (2 e−) nucleophilic addition of allylmetal regents to imines dominates the synthesis of homo‐allyl amine; however, single electron (1 e−) mediated imine allylation with feedstocks butadiene as an alternative allyl source remains unexplored. In this work, we report a conceptually different radical–radical cross‐coupling strategy for the synthesis of a homoallyl amine between an α‐amino alkyl radical and a transient allylic radical. This metal‐free method provided a novel approach for the synthesis of homoallylic amines (>80 examples) from readily available materials with excellent regioselectivity and exceptional broad functional group compatibility.

Single electron oxidation of amines provides an efficient way to access synthetically useful α-aminoalkyl radicals as reactive intermediates. After the single electron oxidation of amines, fragmentation of the resulting radical cations proceeds to give the α-aminoalkyl radicals along with generation of a proton. In the synthetic utilization of the α-aminoalkyl radicals, precise control of single electron transfer is essential, because further oxidation of the α-aminoalkyl radicals occurs more easily than the starting amines and the α-aminoalkyl radicals are converted into the corresponding iminium ions. As a result, photoinduced single electron transfer is quite attractive in the synthetic utilization of the α-aminoalkyl radicals. Recently, visible light-photoredox catalysis using transition metal-polypyridyl complexes and other dyes as catalysts has attracted considerable attention, where useful molecular transformations can be achieved through the single electron transfer process between the excited catalysts and substrates. In this context, MacMillan et al. ( Science 2011, 334 , 1114 , DOI: 10.1126/science.1213920 ) reported an aromatic substitution reaction of cyanoarenes with amines, where α-aminoalkyl radicals work as key reactive intermediates. Pandey and Reiser et al. ( Org. Lett. 2012 , 14 , 672 , DOI: 10.1021/ol202857t ) and our group ( Nishibayashi et al. J. Am. Chem. Soc. 2012 , 134 , 3338 , DOI: 10.1021/ja211770y ) independently reported reactions of amines with α,β-unsaturated carbonyl compounds, where addition of α-aminoalkyl radicals to alkenes is a key step. After these earliest examples, nowadays, a variety of transformations using the α-aminoalkyl radicals as reactive intermediates have been reported by many groups. The α-aminoalkyl radicals are usually produced from amines by single electron oxidation and the subsequent deprotonation of the C-H bond adjacent to the nitrogen atom. In addition, the α-aminoalkyl radicals are also produced from α-silylamines and α-amino acids in high efficiency through desilylation or decarboxylation after the single electron oxidation. The generated α-aminoalkyl radicals are utilized in a variety of reaction systems. In fact, reactions based on the addition of α-aminoalkyl radicals to alkenes and other unsaturated bonds have been extensively studied. Aromatic and other types of substitution reactions have also been investigated. Some of these transformations are achieved by combination of photoredox catalysts and other catalysts such as Brønsted and Lewis acids, organocatalysts, and transition metal catalysts. It is also noteworthy that the enantioselective reactions have been accomplished by combination of photoredox catalysts and chiral catalysts. The strategy for the generation of α-aminoalkyl radicals can be applied to utilize other types of alkyl radicals. In the generation of α-aminoalkyl radicals, the bond dissociation of the radical cations occurs at the α-position of amines. In relation to this process, synthetic utilization of other types of alkyl radicals generated by the bond dissociation of the radical cations at a remote position has been also investigated. These alkyl radicals have been applied to molecular transformations in a manner similar to the α-aminoalkyl radicals. Recently, organic synthesis using the α-aminoalkyl radicals and related alkyl radicals has been studied extensively. In this Account, we describe recent advances in photoredox-catalyzed synthetic utilization of these alkyl radicals.

Review: 68 refs.

General and Efficient C–P Bond Formation by Quantum Dots and Visible Light

Photochemistry usually functions on a one‐photon‐one‐electron basis, leading to unstable radical intermediates that must be intercepted rapidly to allow efficient product formation. This can render multi‐electron reductions and enantioselective reactions particularly challenging. In this minireview, we discuss recent advances in the area of photo‐driven multi‐electron transfer with a particular focus on our own work on reductive amination and the enantioselective synthesis of amines by combined photoredox and enzyme catalysis. Polarity‐matched hydrogen atom transfer (HAT) between photochemically‐generated α‐amino alkyl radicals and thiols is a key step in these reactions. A cyclic reaction network comprised of light‐driven imine reduction by an Ir‐photocatalyst and enantioselective amine oxidation by the enzyme monoamine oxidase (MAO‐N‐9) was used to obtain enantioenriched amines from imines.

This chapter summarizes some important examples of carbon–carbon bond-forming reactions at the α-position of tertiary amines using photoredox catalysis. The photocatalytic single-electron oxidation of tertiary amines leads to the generation of an amine radical cation, from which two highly reactive and synthetically useful intermediates, iminium ions and α-aminoalkyl radicals, can be produced. Iminium ion intermediates, being electrophilic in nature, react with a range of carbon nucleophiles forming new carbon–carbon bonds. On the other hand, the α-aminoalkyl radical, an electron-rich radical, adds efficiently to electron-deficient unsaturated systems resulting in carbon–carbon bond-forming reactions. This chapter also highlights some examples of carbon–carbon bond-forming reaction by nucleophilic/radical addition to photocatalytically generated arene radical cations.

This chapter describes the procedure for the preparation of 1‐hydrosilatrane and explains its use in the highly practical synthesis of secondary and tertiary amines from aldehydes and ketones via direct reductive amination. The synthesis of amines is highly desired for their wide range of applications from pharmaceuticals to fine chemicals. This method is applicable to alkyl‐ and aryl‐ amines and shows broad functional group tolerance. The chapter presents some of the important points to be considered, the conditions that need to be maintained, characterization data, and the reagents required, as well as the techniques used and the equipment setup that are vital to carrying out the process. It also describes the hazards associated with working with chemicals and the ways to deal with these hazards.

The aminomethylation reaction, a fundamental and versatile organic transformation is extensively utilized to incorporate an aminomethyl group into target molecules and plays a significant role in the synthesis of natural products and functional molecules. In recent years, N-Aryl glycines and their analogues have been widely explored in visible-light-promoted photoredox reactions to install an aminomethyl moiety or construct various N-heterocycles under mild conditions. Their key reaction intermediates are α-aminoalkyl radicals, imines, or iminium ions. Recent advances in this field have been summarized into five categories according to the proposed reaction mechanisms: (i) radical addition initiated aminomethylation reactions, (ii) radical-radical cross coupling reactions, (iii) radical-triggered annulation reactions, (iv) transformations involving imines, and (v) metallophotoredox dual catalysis. We hope this review will give an overview of visible-light-promoted photoredox reactions of N-aryl glycines and their analogues and drive further research progress in this area.

Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

N-Containing Heterocycles on Demand by Merging Ni Catalysis and Photoredox PCET

Visible light-driven reduction of imines to enantioenriched amines in aqueous solution is demonstrated for the first time. Excitation of a new water-soluble variant of the widely used [Ir(ppy)3] (ppy = 2-phenylpyridine) photosensitizer in the presence of a cyclic imine affords a highly reactive α-amino alkyl radical that is intercepted by hydrogen atom transfer (HAT) from ascorbate or thiol donors to afford the corresponding amine. The enzyme monoamine oxidase (MAO-N-9) selectively catalyzes the oxidation of one of the enantiomers to the corresponding imine. Upon combining the photoredox and biocatalytic processes under continuous photo-irradiation, enantioenriched amines are obtained in excellent yields. To the best of our knowledge, this is the first demonstration of a concurrent photoredox- and enzymatic catalysis leading to a light-driven asymmetric synthesis of amines.

New reaction pathways by integrating chemo- and biocatalysis

The α-functionalisation of N-containing compounds is an area of broad interest in synthetic chemistry due to their presence in biologically active substances among others. Visible light-induced generation of nucleophilic α-aminoalkyl radicals as reactive intermediates that can be trapped by electron-deficient alkenes presents an attractive and mild approach to achieve said functionalisation. In this work, [Fe(iii)(phtmeimb)2]PF6 (phtmeimb = phenyl(tris(3-methylimidazol-2-ylidene))borate), an N-heterocyclic carbene (NHC) complex based on Earth-abundant iron, was used as photoredox catalyst to efficiently drive the formation of α-aminoalkyl radicals from a range of different α-trimethylsilylamines and their subsequent addition to a number of electron-deficient alkenes under green light irradiation. Mechanistic investigations elucidated the different reaction steps of the complete photocatalytic cycle. In terms of yields and substrate scope, we show that [Fe(iii)(phtmeimb)2]PF6 can compete with noble metal photoredox catalysts, for instance outcompeting archetypal [Ru(bpy)3]Cl2 under comparable reaction conditions, illustrating that iron photocatalysts can efficiently facilitate photoredox reactions of synthetic value.

Visible-light-mediated direct sp(3) C-H amination of benzocyclic amines via α-aminoalkyl radicals by using photoredox catalysts is described here. The obtained N,N-acetals were also successfully applied for carbon-carbon bond forming reactions with carbon nucleophiles. The procedure is suitable for a late-stage modification of C-H bonds to C-C bonds.

Controlling the cross‐coupling reaction between two different radicals is a long‐standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross‐coupling product. Generally, the cross‐coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross‐coupling of alkyl radicals with acyl radicals to construct C(sp2)−C(sp3) bonds, or with alkyl radicals to construct C(sp3)−C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2′ : 6′,2′′‐terpyridine) to enable radical cross‐coupling process to Ni‐mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)−C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late‐stage functionalization of natural‐occurring carboxylic acids and drugs.