Ubiquitous Functional Groups Research Articles

Organoboron catalysis for direct amide/peptide bond formation.

Amides and peptides are ubiquitous functional groups found in several natural and artificial materials, and they are essential for the advancement of life and material sciences. In particular, their relevance in clinical medicine and drug discovery has increased in recent years. Dehydrative condensation of readily available carboxylic acids with amines is the most "direct" method for amide synthesis; however, this methodology generally requires a stoichiometric amount of condensation agent (coupling reagent). Catalytic direct dehydrative amidation has become an "ideal" methodology for synthesizing amides from the perspective of green chemistry, with water as the only byproduct in principle, high atom efficiency, environmentally friendly, energy saving, and safety. Conversely, organoboron compounds, such as boronic acids, which are widely used in various industries as coupling reagents for Suzuki-Miyaura cross-coupling reactions or pharmaceutical structures, are environmentally friendly molecules that have low toxicity and are easy to handle. Based on the chemical properties of organoboron compounds, they have potential Lewis acidity and the ability to form reversible covalent bonds with dehydration, making them attractive as catalysts. This review explores studies on the development of direct dehydrative amide/peptide bond formation reactions from carboxylic acids using organoboron catalysis, classifying them based on chemical bonding and catalysis over approximately 25 years, from the early developmental days to 2023.

Fun With Unusual Functional Groups: Sulfamates, Phosphoramidates, and Di-tert-butyl Silanols.

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines, and amides, which serve as central "actors" in most organic reactions, sulfamates, phosphoramidates, and di-tert-butyl silanols have historically been viewed as "extras". Largely considered functional group curiosities rather than launch-points of vital reactivity, the chemistry of these moieties is under-developed. Our research program has uncovered new facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into truly general transformations, useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these "unusual" functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.

Ketone-Derived Pro-aromatic Reagents for Radical Group Transfer Reactions and Deconstructive Functionalizations

AbstractThe recent prominence of ketones as handles for sp3-rich radicals has expanded the paradigm of synthetic utility of ketones, putting the ubiquitous functional group once again into the spotlight in recent years. One emerging strategy arose through ketone-derived pro-aromatic reagents in the form of dihydrobenzothiazoline (BTZ), dihydroquinazolinone (DHQZ), dihydropyrazole (DHP), and dihydro-1,2,4-triazole (DHT) as key intermediates for aromaticity-promoted C–C bond homolytic fission. The formed sp3-radicals could then participate in various radical functionalizations, including alkylations, arylations, olefination, alkynylation, silylations, amination, thiolation, and deuteration, among others, either in photocatalytic, thermal, or oxidative conditions. In this review, we highlight the implications and recent advances in using these pro-aromatic reagents in radical group transfer reactions and deconstructive functionalization.1 Introduction2 Aromatization-Driven C–C Bond Scission of Ketones3 Photochemical Reactions of Ketone-Derived Pro-aromatic Reagents4 Non-photochemical Reactions of Ketone-Derived Pro-aromatic Reagents5 Conclusion and Future Outlook

Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

ConspectusConjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut-Currier (RC) and Morita-Baylis-Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the β-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position.Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted β-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

Direct Catalytic Amidations from Carboxylic Acid and Ester Derivatives: A Review

The prevalence of amides in biological systems and chemical fields such as polymers, materials and natural products drives continuous research on novel procedures to obtain these ubiquitous functional groups. Currently, efforts to this purpose are mainly focused around the discovery of direct and catalytic methods that are more atom economic, safe and practical for diversified applications (e.g., organic, medicinal and peptide chemistries, material and polymer purposes, etc.), in accordance with green chemistry principles. The field of amide synthesis has attained such a level of significance that the number of reviews and articles addressing it grown exponentially in the last decade. Rather than providing a general overview of amidation methods, which have been described broadly and well in recent literature, the purpose of this review is to highlight recent efforts in the catalytic formation of amide bonds from amines and carboxylic acids or esters. The goal is to emphasize mechanistic and catalytic aspects, but also to discuss substrate tolerance and racemization issues (when applicable).

One‐Electron Injection‐triggered Radical Reaction of Alkyl Benzoates Promoted by 1,4‐Bis(diphenylamino)benzene Photocatalysis

AbstractThe ester group is one of the most ubiquitous functional groups in natural products and synthetic organic molecules. Herein, we describe the photocatalytic generation of alkyl radicals from readily accessible alkyl benzoate esters. The excited organic photocatalyst 1,4‐bis(diphenylamino)benzene (BDB) plays a vital role as a one‐electron injector. The present photoredox‐catalytic system realizes the hydroxy‐1,1‐dialkylfluoroethylation of aromatic alkenes. Finally, a strategy is developed for generation of fluoroalkyl radicals from the corresponding readily available 2‐fluorinated 1,1‐dialkylethanols.

Transition‐Metal‐Catalyzed Remote C(sp3)−H Functionalization Of Carboxylic Acid And Its Derivatives

AbstractCarboxylic acids are ubiquitous functional groups present in many bio‐relevant molecules, including drugs and amino acids. In general, α‐ and β−C(sp3)−H bonds of carboxylic acids are easy to functionalize, contrary to remote (γ‐ and δ) C−H bonds which are difficult due to the distal location of these C−H bonds from the functional group. On the other hand, functionalizing an inert C(sp3)−H bond is another critical challenge in synthetic chemistry due to its lower acidity and reactivity. Nevertheless, the last decade has witnessed tremendous development in remote sp3‐C−H bond functionalization of carboxylic acid and its derivatives. Here, in this review, we have delineated recent progress in remote γ‐ and δ‐C−H bond functionalization of aliphatic carboxylic acids/amino acids and their derivatives. This review is further subdivided based on the type of functionalization reaction. Finally, we have presented some applications of these methodologies, such as total synthesis of hibispeptin A, etc.

Enantio‐, Diastereo‐ and Regioselective Synthesis of Chiral Cyclic and Acyclic gem‐Difluoromethylenes by Palladium‐Catalyzed [4+2] Cycloaddition

Abstractgem‐Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd‐catalyzed asymmetric [4+2] cycloaddition between substituted‐2‐alkylidenetrimethylene carbonates and gem‐difluoroalkyl ketones, we were able to easily access chiral 1,3‐dioxanes that contain a tetrasubstituted difluoroalkyl stereogenic center in cyclic and acyclic skeletons. A novel phosphoramidite ligand, which contains a bulky 1,1‐dinaphthylmethanamino moiety, was developed to provide the products in high yield with excellent enantio‐, diastereo‐, and regioselectivity. Strikingly, the gem‐difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α‐difluorinated β‐ketoester, and a β‐ketosulfone are suitable substrates for this method.

Enantio-, Diastereo- and Regioselective Synthesis of Chiral Cyclic and Acyclic gem-Difluoromethylenes by Palladium-Catalyzed [4+2] Cycloaddition.

gem-Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd-catalyzed asymmetric [4+2] cycloaddition between substituted-2-alkylidenetrimethylene carbonates and gem-difluoroalkyl ketones, we were able to easily access chiral 1,3-dioxanes that contain a tetrasubstituted difluoroalkyl stereogenic center in cyclic and acyclic skeletons. A novel phosphoramidite ligand, which contains a bulky 1,1-dinaphthylmethanamino moiety, was developed to provide the products in high yield with excellent enantio-, diastereo-, and regioselectivity. Strikingly, the gem-difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α-difluorinated β-ketoester, and a β-ketosulfone are suitable substrates for this method.

18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Recent Developments in Hydrodecyanation and Decyanative Functionalization Reactions

AbstractNitrile is one of the ubiquitous functional groups in natural products and polymer industry. It is often used as a versatile building block in synthetic chemistry. Classically, nitrile group is used for alpha functionalization, ortho−C−H activation and as a precursor for amine or carbonyl functionalities. With the development of various transition metal catalyzed methods, in the last two decades, nitrile group has emerged as a source of carbon synthons through C−CN bond activation despite of its high bond energy. In this review we have summarized all recent developments involving the carbon synthons arising from the cleavage of C−CN bonds. Depending on the fate of the carbon center after cleavage, all the reactions are classified in two major categories for the ease of discussion: 1) decyanation (removal of the nitrile group) and 2) decyanative functionalization (replacement of the nitrile group). Finally, current limitations in C−CN bond activation strategies and future prospects are discussed.

Cu catalysts do chiral amide synthesis

A pair of copper catalysts can create chiral amides in a new, light-driven process, offering a useful alternative to the standard method for making these staples of medicinal chemistry ( Nature 2021, DOI: 10.1038/s41586-021-03730-w ). “Amides are ubiquitous functional groups in bioactive molecules, such as peptides,” says Gregory C. Fu , a chemist at the California Institute of Technology who co-led the work. The conventional route to chiral amides involves producing a single enantiomer of an amine and then reacting it with a carboxylic acid derivative. In contrast, the Caltech team’s method needs only a single step and controls the stereochemistry of the amide as it forms. The reaction relies on two different Cu catalysts and combines an amide with an alkyl bromide to form a chiral secondary amide—where the nitrogen atom is bonded to a hydrogen and two carbons, one of which is chiral. The first catalyst is a

Copper-Catalyzed Asymmetric Borylacylation of Styrene and Indene Derivatives.

The enantioselective copper-catalyzed borylacylation of aryl olefins with acyl chlorides and bis-(pinacolato)diboron is reported. This three-component reaction involves an enantioselective syn-borylcupration of the aryl olefin, followed by a nucleophilic attack on the acyl chloride. This reaction proceeds with a 2 mol % catalyst loading and is generally completed within 30 min at room temperature. Because the boron moiety can be converted into versatile functional groups and the carbonyl group is a ubiquitous functional group, the resulting chiral β-borylated ketones are versatile intermediates in organic synthesis.

Protocol for Palladium/N-Heterocyclic Carbene-Catalyzed Suzuki–Miyaura Cross-Coupling of Amides by N–C(O) Activation

AbstractAmides are among the most important and ubiquitous functional groups in organic chemistry and process development. In this Practical Synthetic Procedure, a protocol for the Suzuki–Miyaura cross-coupling of amides by selective N–C(O) bond activation catalyzed by commercially available, air- and moisture-stable palladium/N-heterocyclic carbene (NHC) complexes is described. The procedure described involves [Pd(IPr)(cin)Cl] [IPr = 2,6-(diisopropylphenyl)imidazol-2-ylidene, cin = cinnamyl] at 0.10 mol% at room temperature and is performed on decagram scale. Furthermore, a procedure for the synthesis of amide starting materials is accomplished via selective N-tert-butoxycarbonylation, which is the preferred method over N-acylation. The present protocol carries advantages of operational simplicity, commercial availability of catalysts, and excellent conversions at low catalyst loadings. The method is generally useful for activation of N–C(O) amide bonds in a broad spectrum of amide precursors. The protocol should facilitate the implementation of amide cross-coupling reactions.

Copper‐Catalyzed Carbonylative Hydroamidation of Styrenes to Branched Amides

AbstractAmides are one of the most ubiquitous functional groups in synthetic and medicinal chemistry. Novel and rapid synthesis of amides remains in high demand. In this communication, a general and efficient procedure for branch‐selective hydroamidation of vinylarenes with hydroxyamine derivatives enabled by copper catalysis has been developed for the first time. The reaction proceeds under mild conditions and tolerates a broad range of functional groups. Applying a chiral phosphine ligand, an enantioselective variant of this transformation was achieved, affording a variety of chiral α‐amides with excellent enantioselectivities (up to 99 % ee) and high yields.

Copper-Catalyzed Carbonylative Hydroamidation of Styrenes to Branched Amides.

Amides are one of the most ubiquitous functional groups in synthetic and medicinal chemistry. Novel and rapid synthesis of amides remains in high demand. In this communication, a general and efficient procedure for branch-selective hydroamidation of vinylarenes with hydroxyamine derivatives enabled by copper catalysis has been developed for the first time. The reaction proceeds under mild conditions and tolerates a broad range of functional groups. Applying a chiral phosphine ligand, an enantioselective variant of this transformation was achieved, affording a variety of chiral α-amides with excellent enantioselectivities (up to 99 % ee) and high yields.

Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products

The tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meant—in the past—that selective manipulation of this motif remaine...

Gold-Carbon Contacts from Oxidative Addition of Aryl Iodides.

Aryl halides are ubiquitous functional groups in organic chemistry, yet despite their obvious appeal as surface-binding linkers and as precursors for controlled graphene nanoribbon synthesis, they have seldom been used as such in molecular electronics. The confusion regarding the bonding of aryl iodides to Au electrodes is a case in point, with ambiguous reports of both dative Au-I and covalent Au-C contacts. Here we form single-molecule junctions with a series of oligophenylene molecular wires terminated asymmetrically with iodine and thiomethyl to show that the dative Au-I contact has a lower conductance than the covalent Au-C interaction, which we propose occurs via an in situ oxidative addition reaction at the Au surface. Furthermore, we confirm the formation of the Au-C bond by measuring an analogous series of molecules prepared ex situ with the complex AuI(PPh3) in place of the iodide. Density functional theory-based transport calculations support our experimental observations that Au-C linkages have higher conductance than Au-I linkages. Finally, we demonstrate selective promotion of the Au-C bond formation by controlling the bias applied across the junction. In addition to establishing the different binding modes of aryl iodides, our results chart a path to actively controlling oxidative addition on an Au surface using an applied bias.

Generation of Phosphoranyl Radicals via Photoredox Catalysis Enables Voltage-Independent Activation of Strong C-O Bonds.

Despite the prevalence of alcohols and carboxylic acids as functional groups in organic molecules and the potential to serve as radical precursors, C-O bonds remain difficult to activate. We report a synthetic strategy for direct access to both alkyl and acyl radicals from these ubiquitous functional groups via photoredox catalysis. This method exploits the unique reactivity of phosphoranyl radicals, generated from a polar/SET crossover between a phosphine radical cation and an oxygen-centered nucleophile. We show the desired reactivity in the reduction of benzylic alcohols to the corresponding benzyl radicals with terminal H atom trapping to afford the deoxygenated products. Using the same method, we demonstrate access to synthetically versatile acyl radicals, which enables the reduction of aromatic and aliphatic carboxylic acids to the corresponding aldehydes with exceptional chemoselectivity. This protocol also transforms carboxylic acids to heterocycles and cyclic ketones via intramolecular acyl radical cyclizations to forge C-O, C-N, and C-C bonds in a single step.

Gold‐Catalyzed C−H Imidation of Polycyclic Aromatic Hydrocarbons

AbstractAmino group is one of the most ubiquitous functional groups, and therefore the direct introduction of amino groups into arenes has gained much attention. Methods for installing amino groups into organic molecules are highly sought after. Herein, a direct C−H imidation under gold(I) chloride catalysis has been developed with N‐fluorobenzenesulfonimide as the imine source. The choice of ligand plays an important role where 2,2′‐biquinoline was found to be most efficient. Various polycyclic aromatic hydrocarbons were directly imidated under the newly established protocol.