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Photoredox catalysis has revolutionized synthetic chemistry in recent decades. However, the field has traditionally used high-energy blue/ultraviolet light to activate chromophores. High-energy irradiation is associated with several drawbacks (e.g., activation of sensitive functional groups, undesired metal-ligand homolysis, background activation of molecules, and poor penetration), which has led researchers to develop alternative systems with lower energy deep red (DR) or near-infrared (NIR) light. This graphical review provides a concise overview of photophysical principles relevant to photoredox catalysis. Several applications that benefit from low-energy irradiation, such as large-scale batch reactions, photodynamic therapy, biological labeling, and multi-photon excitation are reviewed.

Aryl amination is an essential transformation for medicinal, process, and materials chemistry. In addition to classic Buchwald-Hartwig amination conditions, blue-light-driven metallaphotoredox catalysis has emerged as a valuable tool for C-N cross-coupling. However, blue light suffers from low penetration through reaction media, limiting its scalability for industrial purposes. In addition, blue light enhances unwanted side-product formation in metallaphotoredox catalysis, namely hydrodehalogenation. Low-energy light, such as deep red (DR) or near-infrared (NIR), offers a solution to this problem as it can provide enhanced penetration through reaction media as compared to higher-energy wavelengths. Herein, we show that low-energy light can also enhance the desired reactivity in metallaphotoredox catalysis by suppressing unwanted hydrodehalogenation. We hypothesize that the reduced side product is formed by direct photolysis of the aryl-nickel bond by the high-energy light, leading to the generation of aryl radicals. Using deep-red or near-infrared light and an osmium photocatalyst, we demonstrate an enhanced scope of (hetero)aryl bromides and amine-based nucleophiles with minimal formation of hydrodehalogenation byproducts.

The use of low-energy deep-red (DR) and near-infrared (NIR) light to excite chromophores enables catalysis to ensue across barriers such as materials and tissues. Herein, we report the detailed photophysical characterization of a library of OsII polypyridyl photosensitizers that absorb low-energy light. By tuning ligand scaffold and electron density, we access a range of synthetically useful excited state energies and redox potentials.1 Introduction1.1 Scope1.2 Measuring Ground-State Redox Potentials1.3 Measuring Photophysical Properties1.4 Synthesis of Osmium Complexes2 Properties of Osmium Complexes2.1 Redox Potentials of Os(L)2-Type Complexes2.2 Redox Potentials of Os(L)3-Type Complexes2.3 UV/Vis Absorption and Emission Spectroscopy3 Conclusions

A highly efficient and enantioselective asymmetric hydrogenation catalyzed by Ru-DTBM-segphos is reported for a broad range of pyridine-pyrroline tri-substituted alkenes. Kinetic, spectroscopic, and computational studies suggest that addition of H(2) is rate-determining and that alkene insertion is the enantio-determining step. These studies also reveal an intriguing Ru-catalyzed H/D exchange process that is facilitated by the substrate at room temperature and low pressure where hydrogenation activity is suppressed. These studies lead to a mechanistic proposal that further defines the roles of hydrogen gas, Ru-H species, and protic solvents in this catalytic system.

The cyclohexyl fragment 1 in BMS-986251 was synthesized starting from Hagemann’s ester 2 in 7 steps and 5 isolations. The route is highlighted by a dynamic kinetic resolution (DKR), a telescoped en...

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an

As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.

A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (1), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling...

Over the past decade, chemists have embraced visible-light photoredox catalysis due to its remarkable ability to activate small molecules. Broadly, these methods employ metal complexes or organic dyes to convert visible light into chemical energy. Unfortunately, the excitation of widely utilized Ru and Ir chromophores is energetically wasteful as ∼25% of light energy is lost thermally before being quenched productively. Hence, photoredox methodologies require high-energy, intense light to accommodate said catalytic inefficiency. Herein, we report photocatalysts which cleanly convert near-infrared (NIR) and deep red (DR) light into chemical energy with minimal energetic waste. We leverage the strong spin–orbit coupling (SOC) of Os(II) photosensitizers to directly access the excited triplet state (T1) with NIR or DR irradiation from the ground state singlet (S0). Through strategic catalyst design, we access a wide range of photoredox, photopolymerization, and metallaphotoredox reactions which usually require 15–50% higher excitation energy. Finally, we demonstrate superior light penetration and scalability of NIR photoredox catalysis through a mole-scale arene trifluoromethylation in a batch reactor., Os-based photocatalysts enable photoredox catalysis in the near-infrared region (NIR) which presents new opportunities for photoredox catalysis such as improved light penetration and scalability.

Photocatalysis driven by visible and ultraviolet irradiation is a fundamental tool for synthetic chemists. Recently, expansion of this tool to near-infrared (NIR) light has gained in popularity. Herein, we report the detailed photophysical characterization of a library of OsII polypyridyl photosensitizers that absorb NIR irradiation. By tuning ligand scaffold and electron density, we access a range of synthetically useful excited state energies and redox potentials.

As sp

The palladium-catalyzed, α-selective hydroarylation of acrylates and acrylamides is reported. Under optimized conditions, this method is highly tolerant of a wide range of substrates including those with base sensitive functional groups and/or multiple enolizable carbonyl groups. A detailed mechanistic study was undertaken, and the high selectivity of this transformation was shown to be enabled by the formation of an [PdII(Ar)(H)] intermediate, which performs selective hydride insertion into the β-position of α,β-unsaturated carbonyl compounds.

We describe a new family of catalysts that undergo direct ground state singlet to excited state triplet excitation with IR light, leading to photoredox catalysis without the energy waste associated with intersystem crossing. The finding allows a mole scale reaction in batch using infrared irradiation.

Herein we report acid-directed β-C(sp3 )-H arylation of α-amino acids enabled by pyridine-type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc-protected unnatural amino acids in three steps. The pyridine-type ligands are crucial for the development of this new C(sp3 )-H arylation.

Using nickel and photoredox catalysis, the direct functionalization of C(sp(3))-H bonds of N-aryl amines by acyl electrophiles is described. The method affords a diverse range of α-amino ketones at room temperature and is amenable to late-stage coupling of complex and biologically relevant groups. C(sp(3))-H activation occurs by photoredox-mediated oxidation to generate α-amino radicals which are intercepted by nickel in catalytic C(sp(3))-C coupling. The merger of these two modes of catalysis leverages nickel's unique properties in alkyl cross-coupling while avoiding limitations commonly associated with transition-metal-mediated C(sp(3))-H activation, including requirements for chelating directing groups and high reaction temperatures.

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp(3))–H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp(3))–H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively mono-selectivity in the presence of multiple β-C–H bonds. The product γ-lactone can be readily opened to give either the highly valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

Variable temperature NMR spectroscopy is used to determine the ΔH° and ΔS° of hydrogen bond formation in a simple diamide. In this two- or three-day experiment, students synthesize N,N′-dimethylmalonamide, dimethylsuccinamide, dimethylglutaramide, or dimethyladipamide from methylamine and the corresponding diester (typically in 50% recrystallized yield) and record NMR spectra at temperatures between 200 and 313 K. Solutions of N-methylacetamide in concentrations between 1.00 mM and 13.1 M (neat) are prepared and their NMR spectra recorded to determine the chemical shift of the amide proton in the hydrogen-bonded (δB) and nonbonded (δN) limits. By using these data, the equilibrium constants, ΔH°, and ΔS° for the conversion of an open-chain diamide to a cyclic structure with an intramolecular hydrogen bond are determined.

In hydroformylation, phosphorus-based directing groups have been consistently successful at placing the aldehyde on the carbon proximal to the directing group. The design and synthesis of a novel catalytic directing group are reported that promotes aldehyde formation on the carbon distal relative to the directing functionality. This scaffolding ligand, which operates through a reversible covalent bond to the substrate, has been applied to the diastereoselective hydroformylation of homoallylic alcohols to afford δ-lactones selectively. Altering the distance between the alcohol and the olefin revealed that homoallylic alcohols gives the distal lactone with the highest levels of regioselectivity.

The novel catalytic directing group (CDG) operates by means of a reversible covalent bond to the substrate and promotes aldehyde formation on the carbon distal to the directing functionality.

The synthesis of β-amino-aldehydes has been achieved through enantioselective hydroformylation of PMP-protected allylic amines. The reaction is accomplished by using a scalemic scaffolding ligand that covalently and reversibly binds to the substrate. These ligands behave like chiral auxiliaries because they are covalently attached to the substrate during hydroformylation; however, similar to traditional asymmetric ligands, they can be used in catalytic quantities. The directed hydroformylation of disubstituted olefins occurs under mild conditions (35 °C and 50 psi CO/H(2)), and Z-olefins afford excellent enantioselectivities (up to 93% ee).

[1253288-75-3] C22H28NOP (MW 353.44) InChI = 1S/C22H28NOP/c1-15(2)19-14-13-17-9-8-12-20-21(17)23(19)22(24-16(3)4)25(20)18-10-6-5-7-11-18/h5-12,15-16,19,22H,13-14H2,1-4H3/t19-,22+,25-/m0/s1 InChIKey = MGLYEMMYHPZSOT-SWHJIRTISA-N (enantiopure scaffolding ligand applied to regio- and enantioselective hydroformylation of allylic aniline derivatives) Physical Data: colorless crystals. Solubility: soluble in benzene, tetrahydrofuran, methanol, and isopropanol. Form supplied in: colorless solid. Analysis of Reagent Purity: purity is analyzed by 31P NMR (C6D6, 202 MHz) δ −22.0. Purification: crystallized from pentane at −37 °C in a glovebox. More material can be recrystallized from the mother liquor. Handing, Storage, and Precautions: moisture sensitive; readily ionizes the NO acetal functionality and forms phosphine oxide in the presence of water. It should be stored in a glovebox, and should be used only in the presence of dry, degassed solvents.

Natural photosynthesis harvests the energy in solar light to power chemical reactions and uses CO2 as the carbon source. Because light as an energy source is free and abundant, chemical reactions similar to photosynthesis have major fundamental and practical implications.[1-2] Indeed, significant efforts have been attracted to this research goal. The majority of attention for photochemical reactions that transform CO2 have focused primarily on conversion into fuels.[3-4] How to learn from photosynthesis and devise reaction routes for the synthesis of useful organic compounds receives relatively underwhelmed considerations.[5] Drawing inspiration from the mechanisms found in dark reactions of photosynthesis and using p-type Si nanowires as a photocathode, here we show that highly specific reactions can be readily carried out to produce α-hydroxy acids by photoreduction of aromatic ketones, followed by CO2 fixation. Powered by solar light, this reaction is in close resemblance to natural photosynthesis, and different from its electrochemical analogues. The carboxylation products of two of the substrates examined in this communication serve as precursors to nonsteroidal anti inflammatory drugs (NSAID), ibuprofen and naproxen.[6]

We have developed a ligand that reversibly binds to aniline substrates, allowing for the control of regioselectivity and enantioselectivity in hydroformylation. In this paper we address how the electronics of the aniline ring affect both the binding of the substrate to the ligand and the enantioselectivity in this reaction.

We have developed a ligand that reversibly binds to aniline substrates, allowing for the control of regioselectivity and enantioselectivity in hydroformylation. In this paper we address how the electronics of the aniline ring affect both the binding of the substrate to the ligand and the enantioselectivity in this reaction.

The synthesis of β-amino-aldehydes has been achieved through enantioselective hydroformylation of PMP-protected allylic amines. The reaction is accomplished by using a scalemic scaffolding ligand that covalently and reversibly binds to the substrate. These ligands behave like chiral auxiliaries because they are covalently attached to the substrate during hydroformylation; however, similar to traditional asymmetric ligands, they can be used in catalytic quantities. The directed hydroformylation of disubstituted olefins occurs under mild conditions (35 °C and 50 psi CO/H2), and Z-olefins afford excellent enantioselectivities (up to 93% ee).