LongLarf

The road less travelled: Select pyridinium reagents undergo an unprecedented heterolytic fragmentation upon single electron reduction to afford a synthetically viable N‐pyridyl radical cation. This reactive species was leveraged for the C−H amination of (hetero)arenes to furnish N‐aryl pyridinium products, which enable access to diverse nitrogen scaffolds.

Abstract

Electron‐transfer photocatalysis provides access to the elusive and unprecedented N‐pyridyl radical cation from selected N‐substituted pyridinium reagents. The resulting C(sp²)−H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin‐trapped N‐pyridyl radical adduct implicate SET‐triggered, pseudo‐mesolytic cleavage of the N−X pyridinium reagents mediated by visible light.

Crystallization and biocatalysis: In situ product crystallization is a powerful technique to overcome fundamental limitations in biocatalytic reactions, for example, unfavorable reaction equilibria or product inhibitions (see figure). This Minireview presents basic process considerations within (early) process development and illustrates the high potential of crystallization with selected examples.

Abstract

This Minireview highlights the application of crystallization as a very powerful in situ product removal (ISPR) technique in biocatalytic process design. Special emphasis is placed on its use for in situ product crystallization (ISPC) to overcome unfavorable thermodynamic reaction equilibria, inhibition, and undesired reactions. The combination of these unit operations requires an interdisciplinary perspective to find a holistic solution for the underlying bioprocess intensification approach. Representative examples of successful integrated process options are selected, presented, and assessed regarding their overall productivity and applicability. In addition, parallels to the use of adsorption as a very similar technique are drawn and similarities discussed.

Cyclic carbamates are core structures found in many pharmaceuticals. Their synthesis usually involves phosgene or other toxic and expensive reagents, which should be replaced with greener and equally efficient carbon dioxide‐based methods. This Minireview summarizes the major pathways from CO₂ to cyclic carbamates and recent developments on the topic.

As a versatile and sustainable C₁ source, carbon dioxide can substitute toxic reagents such as isocyanates and phosgene in many organic syntheses. In particular, it readily couples with amines to give various carbamate species. This reactivity can be exploited in the synthesis of cyclic carbamates, which are structural motifs found in many antibiotics and other pharmaceutically relevant or otherwise high value‐added compounds. In this Minireview, we explore the four major categories of carbon dioxide‐based syntheses of cyclic carbamates: cycloaddition of CO₂ into aziridines, epoxide‐based methods, cyclization of unsaturated compounds, and cyclization of amino alcohols.

Abstract

Cp*Ir (Cp*=pentamethylcyclopentadienyl) complexes with an N,N‐bidentate ligand such as 2,2′‐bipyridine serve as catalysts for both carbon dioxide (CO₂) hydrogenation to formate and formic acid dehydrogenation in water. Previously, it was shown that the introduction of an electron‐donating substituent on 2,2′‐bipyridine is an effective method to improve the catalytic activity. Especially, the highly electron‐donating hydroxyl (OH) substituent performs much better than other substituents such as methyl or methoxy under basic conditions. However, the introduction of an OH substituent on the ligand has been limited to six‐membered rings such as pyridine or pyrimidine. These results prompted us to develop a new ligand comprising a pyridyl‐pyrazole with an OH group on the pyrazole moiety for Cp*Ir‐catalyzed CO₂ hydrogenation and formic acid dehydrogenation. The resultant catalyst showed high catalytic activity in CO₂ hydrogenation and excellent robustness in formic acid dehydrogenation with a turnover number of 10 million.

Deconstructive diversification of cyclic amines

Deconstructive diversification of cyclic amines, Published online: 31 October 2018; doi:10.1038/s41586-018-0700-3

Deconstructive diversification of cyclic amines

Exploration of intermediates that enable chemoselective cycloaddition reactions and expeditious construction of fused- or bridged-ring systems is a continuous challenge for organic synthesis. As an intermediate of interest, the oxyallyl cation has been harnessed to synthesize architectures containing seven-membered rings via (4+3) cycloaddition. However, its potential to access five-membered skeletons is underdeveloped, largely due to the thermally forbidden (3+2) pathway. Here, the combination of a tailored precursor and a Pd(0) catalyst generates a Pd-oxyallyl intermediate that cyclizes with conjugated dienes to produce a diverse array of tetrahydrofuran skeletons. The cycloaddition overrides conventional (4+3) selectivity by proceeding through a stepwise pathway involving a Pd-allyl transfer and ring closure sequence. Subsequent treatment of the (3+2) adducts with a palladium catalyst converts the heterocycles to the carbocyclic cyclopentanones.

Facile functionalization: Combining the chemical transformation of carbon dioxide with C−H bond functionalization is of great importance in the synthesis of carboxylic acids and their derivatives. Herein, a comprehensive review of these processes is presented. Transition‐metal‐free, organocatalytic, electrochemical, and light‐driven methods are also highlighted.

Abstract

Carbon dioxide is a nontoxic, renewable, and abundant C₁ source, whereas C−H bond functionalization represents one of the most important approaches to the construction of carbon–carbon bonds and carbon–heteroatom bonds in an atom‐ and step‐economical manner. Combining the chemical transformation of CO₂ with C−H bond functionalization is of great importance in the synthesis of carboxylic acids and their derivatives. The contents of this Review are organized according to the type of C−H bond involved in carboxylation. The primary types of C−H bonds are as follows: C(sp)−H bonds of terminal alkynes, C(sp²)−H bonds of (hetero)arenes, vinylic C(sp²)−H bonds, the ipso‐C(sp²)−H bonds of the diazo group, aldehyde C(sp²)−H bonds, α‐C(sp³)−H bonds of the carbonyl group, γ‐C(sp³)−H bonds of the carbonyl group, C(sp³)−H bonds adjacent to nitrogen atoms, C(sp³)−H bonds of o‐alkyl phenyl ketones, allylic C(sp³)−H bonds, C(sp³)−H bonds of methane, and C(sp³)−H bonds of halogenated aliphatic hydrocarbons. In addition, multicomponent reactions, tandem reactions, and key theoretical studies related to the carboxylation of C−H bonds are briefly summarized. Transition‐metal‐free, organocatalytic, electrochemical, and light‐driven methods are highlighted.

Easy as Py: A three‐component reductive arylation of amides with stable reactants (iPrOH and arylboronate esters) in the presence of a 2‐pyridinyl (Py) directing group (DG) is described. The N‐Py‐amide substrates are readily prepared from carboxylic acids, and the resulting N‐Py‐1‐arylalkanamine products are transformed into the corresponding chlorides by substitution of the HN‐Py group with HCl.

Abstract

A new three‐component reductive arylation of amides with stable reactants (iPrOH and arylboronate esters), making use of a 2‐pyridinyl (Py) directing group, is described. The N‐Py‐amide substrates are readily prepared from carboxylic acids and PyNH₂, and the resulting N‐Py‐1‐arylalkanamine reaction products are easily transformed into the corresponding chlorides by substitution of the HN‐Py group with HCl. The 1‐aryl‐1‐chloroalkane products allow substitution and cross‐coupling reactions. Therefore, a general protocol for the transformation of carboxylic acids into a variety of functionalities is obtained. The Py‐NH₂ by‐product can be recycled.

Abstract

The development of hydrogen bond donors (HBDs) as catalytic moieties in the cycloaddition of carbon dioxide to epoxides is an active field of research to access efficient, inexpensive and sustainable metal‐free systems for the conversion of carbon dioxide to useful chemicals. Thus far, no systematic attempt to correlate the activity of a diverse selection of HBDs to their physico‐chemical properties has been undertaken. In this work, we investigate factors influencing the catalytic activity of hydroxyl HBDs from different chemical families under ambient conditions by considering the HBDs Brønsted acidity (expressed as pK_a), the number of hydroxyls and structural aspects. As an effect, this study highlights the crucial role of the hydroxyl protons’ Brønsted acidity in determining the catalytic activity of the HBDs, identifies an ideal range for the hydroxyl HBDs proton acidity (9 <pK_a <11) and leads to a revaluation of phenol and to the discovery of a simple ascorbic acid derivative as efficient HBDs for the title cycloaddition reaction. Density functional theory (DFT) calculations show mild reactions barriers for the reaction catalysed by phenol and suggest the occurrence of aggregation between molecules of ascorbic acid as a further factor affecting catalytic activity.

From alkylarenes to anilines via site-directed carbon–carbon amination

From alkylarenes to anilines via site-directed carbon–carbon amination, Published online: 29 October 2018; doi:10.1038/s41557-018-0156-y

Limitations associated with the primary amination of aryl C–H bonds include the poor control of regioselectivity with electron-rich substrates and the challenging nature of the reaction in the case of electron-deficient arenes. Now, site-directed C–C bond primary amination of simple alkylarenes and benzyl alcohols provides a route for the direct and efficient preparation of anilines.

“Mn” of action: A general and efficient dual‐deoxygenative coupling of primary alcohols with 2‐arylethanols, catalyzed by a well‐defined manganese/PNP pincer complex, is reported. Mechanistic studies indicate that this transformation undergoes a reaction process involving catalytic dehydrogenation, aldol condensation, and base‐promoted deformylation.

Abstract

Reported herein is a general and efficient dual‐deoxygenative coupling of primary alcohols with 2‐arylethanols catalyzed by a well‐defined Mn/PNP pincer complex. This reaction is the first example of the catalytic dual‐deoxygenation of alcohols using a non‐noble‐metal catalyst. Both deoxygenative homocoupling of 2‐arylethanols (17 examples) and their deoxygenative cross‐coupling with other primary alcohols (20 examples) proceeded smoothly to form the corresponding alkenes by a dehydrogenation and deformylation reaction sequence.

Base-free nickel-catalysed decarbonylative Suzuki–Miyaura coupling of acid fluorides

Base-free nickel-catalysed decarbonylative Suzuki–Miyaura coupling of acid fluorides, Published online: 24 October 2018; doi:10.1038/s41586-018-0628-7

This nickel-catalysed Suzuki–Miyaura coupling of aryl boronic acids with in-situ-generated acid fluorides does not require an exogenous base and is applicable to a range of base-sensitive boronic acids and bioactive carboxylic acids.

Primary amines are essential constituents of biologically active molecules and versatile intermediates in the synthesis of drugs and agrochemicals. However, their preparation from easily accessible alkenes remains challenging. Here, we report a general strategy to access primary amines from alkenes through an operationally simple iron-catalyzed aminochlorination reaction. A stable hydroxylamine derivative and benign sodium chloride act as the respective nitrogen and chlorine sources. The reaction proceeds at room temperature under air; tolerates a large scope of aliphatic and conjugated alkenes, including densely functionalized substrates; and provides excellent anti-Markovnikov regioselectivity with respect to the amino group. The reactivity of the 2-chloroalkylamine products, an understudied class of amphoteric molecules, enables facile access to linear or branched aliphatic amines, aziridines, aminonitriles, azido amines, and homoallylic amines.

Drink of water: A general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids has been developed with D₂O as an inexpensive deuterium source (see scheme). The transformation, enabled by synergistic photoredox catalysis, thiol catalysis, and phosphoranyl radical chemistry, shows broad scope and good functional‐group tolerance and can be used for late‐stage deoxygenative deuteration.

Abstract

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D₂O as an inexpensive deuterium source. The use of Ph₃P as an O‐atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph₂POEt is a better O‐atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late‐stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.