Important Synthons Research Articles

Highly Selective Boron-Wittig Reaction: A Practical Method to Synthesize Trans-Aryl Alkenes.

Olefins play an essential role in synthetic chemistry, serving not only as important synthons but also as key functional groups in numerous bio-active molecules. Consequently, there has been considerable interest in the development of more powerful methods for olefins. While the Wittig reaction stands as a prominent choice for olefin synthesis due to its simplicity and the ready availability of raw materials, its limitation lies in the challenge of controlling cis-trans selectivity, hampering its broader application. In this study, a novel Boron-Wittig reaction has been developed utilizing gem-bis(boryl)alkanes and aldehydes as starting materials. This method enables creating favourable intermediates, which possess less steric hindrance, and leading to trans-olefins via intramolecular O-B bonds elimination. Notably, synthesis studies have validated its good efficacy in modifying bioactive molecules and synthesizing drug molecules with great trans-selectivity. Furthermore, the reaction mechanism was elucidated based on intermediate trapping experiments, isotope labelling studies, and kinetic analyses.

Visible-Light-Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation.

Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur-containing heterocycles. This report presents a series of visible-light-driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non-nucleophilic carbon-based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.

Visible‐Light‐Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation

Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur‐containing heterocycles. This report presents a series of visible‐light‐driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non‐nucleophilic carbon‐based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.

Isolable Spirocyclic Silylone: π-Delocalized Spiro[3.3]heptasila-2,6-diylidone.

Strained cyclic tetrylones are important synthons due to various synthetic applications. Connecting two cyclic tetrylone rings through a single shared quaternary group 14 element atom to form a spirocyclic molecule has been unexplored both theoretically and experimentally. The formation of a spirocyclic motif has been a synthetic challenge. In contrast, the reaction of amidinato disilicon(I) 1, (Me3P)2SiCl4, and KC8 afforded π-delocalized spiro[3.3]heptasila-2,6-diylidone2 and tetrasilacyclobutadiene byproducts 3 and 4. Compound 2 is the smallest spirocyclic tetrylone derivative, which is composed of a σ-type lone pair and delocalized π bond in each all-silicon spirocyclic ring. The electronic property is supported by its coordination with a W(CO)5 moiety.

Recent Advances of 2‐Nitroglycals as Powerful Glycosyl Donors

Abstract2‐Nitroglycals are important synthons for biological active 2‐aminoglycosides, glycoconjugates and natural products synthesis. Herein, we summarized the recent advances of 2‐nitroglycals including its synthetic methods and its applications. Using 2‐nitroglycals, 2‐aminoglycosides, nitro‐polyol derivatives, sugar‐furan derivatives, sugar‐pyrrole molecules, 2,3‐diaminoglycosides and 2‐amino‐1,3‐dithioglycosides were obtained via Michael–type addition, retro‐Henry‐type reaction, C1/C3‐Ferrier rearrangement and [3+2] N‐heterocyclic addition. Most of these conversions are achieved via mild organo‐catalysis glycosylation methods.

Photocatalytic Boryl Radicals Triggered Sequential B─N/C─N Bond Formation to Assemble Boron-Handled Pyrazoles.

Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their C═C bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential B─N/C─N bond formation is described. The reaction starts with the addition of LBRs (Lewis base-boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron-handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.

Formal Deoxygenative Cross‐Coupling of Aldehydes to Ketones through α‐Haloboronates: A Route to Deoxygenative Hydroacylation of Aldehydes†

Comprehensive SummaryAldehydes are a kind of important synthons and reagents in organic synthesis. The efforts on transformations of aldehydes are highly rewarding and have always attracted considerable attention. Herein, a cross‐coupling of aldehydes with α‐haloboronates has been achieved under dual nickel/photoredox catalysis system. Considering the α‐haloboronates can be easily obtained from aldehydes with our deoxygenative difunctionalization of carbonyls (DODC) strategy, this protocol provides a formal deoxygenative cross‐coupling of aldehydes to one‐carbon‐prolonged ketone products. The mild conditions enabled good functional group tolerance and broad substrate applicability. The application of this method was presented via a tunable synthesis of two ketones with very similar skeletons from two same aldehydes.

DNA-Compatible Copper/TEMPO Oxidation for DNA-Encoded Libraries.

Aldehydes are important synthons for DNA-encoded library (DEL) construction, but the development of a DNA-compatible method for the oxidation of alcohols to aldehydes remains a significant challenge in the field of DEL chemistry. We report that a copper/TEMPO catalyst system enables the solution-phase DNA-compatible oxidation of DNA-linked primary activated alcohols to aldehydes. The semiaqueous, room-temperature reaction conditions afford oxidation of benzylic, heterobenzylic, and allylic alcohols in high yield, with DNA compatibility verified by mass spectrometry, qPCR, Sanger sequencing, and ligation assays. Subsequent transformations of the resulting aldehydes demonstrate the potential of this method for robust library diversification.

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes.

This review presents a comprehensive overview of transition-metal-catalyzed domino reactions of strained bicyclic alkenes, including both homo- and heterobicyclic alkenes. These compounds are important synthons in organic synthesis, providing an important platform for the construction of biologically/medicinally significant compounds which bear multiple stereocenters. The review has been divided according to the metal used in the reaction. An overview of the substrate scope, reaction conditions, and their potential applications in organic synthesis is discussed. A comprehensive outlook on the reactivity paradigms of homo- and heterobicyclic alkenes is discussed and should shed light on future directions for further development in this field.

Take Advantage of the N‐Nucleophilicity of Imine in Catalytic Cyclization Reactions

AbstractImines, or Schiff bases are basic and important synthons in modern chemical synthesis, which are widely used in methodological studies, synthesis of natural products or pharmaceutical agents, construction of organic porous materials and relative late‐stage modifications. In most cases, the imines often act as “electrophilic reagents” in reactions on the basis of their C‐electrophilicity owing to the dipole effect of the C=N bond. However, on the other hand, reactions initiated by the N‐nucleophilicity of imine, draw relatively less attentions. In this concept article, we try to give a concise summary of the reactions, especially the cyclization reaction that are initiated by the N‐nucleophilicity of imine. The basic measurement data and discussions of the N‐nucleophilicity of different imines, relative possible mechanisms, catalytic strategies, and reaction types in this context are briefly discussed. We hope the imines, as one of the basic chemical synthons in organic synthesis, will be utilized in broader scope in the future by taking advantage of their N‐nucleophilicity.

Baylis–Hillmanadducts as an important synthon for the synthesis of α‐carbolinone and α‐carboline derivatives

AbstractBaylis–Hillman adducts were conveniently transformed into α‐carbolinone and α‐carboline derivatives by monoalkylation of 2‐nitrobenzylcyanide, imide formation/Friedel–Crafts cyclization, and treatment with Fe/AcOH in simple process is described.

Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes.

An efficient method for the direct C(sp)-H difluoromethylation of terminal alkynes and the desilylation-difluoromethylation of (trimethylsilyl)acetylenes is disclosed. The copper-catalyzed transformation provides access to a wide range of structurally diverse CF2H alkynes in good yields, utilizing a (difluoromethyl)zinc reagent and an organic oxidant. The difluoromethylation of important synthons and API's is showcased. The synthetic utility of these (difluoromethyl)alkynes is demonstrated by selected cycloaddition reactions. Additionally, a slight modification to the reaction conditions allowed the selective preparation of a 2-difluoromethylindole.

Studies on the [4 + 2] cycloaddition and allylic substitution of indole-fused zwitterionic π-allylpalladium.

The zwitterionic π-allylpalladium species, also known as dipoles, are important synthons widely used in various reactions including cycloaddition and allylic substitution. This study reported the development of a new indole-fused zwitterionic π-allylpalladium precursor compound and its application in [4 + 2] cycloaddition and allylic substitution reactions. As a result, the synthesis of pyrrolo[3,2,1-ij]quinazolin-3-one and 7-vinyl indole compounds was achieved with moderate to good yields. Notably, the allylic substitution reaction exhibited excellent regio- and stereoselectivity.

Cu(OTf)2/NBS Promoted Cyclization of 1‐Cinnamyl Alcohol‐o‐Carboranes: An Efficient Approach for Synthesis ofo‐Carboranes Substituted Oxetanes

AbstractThe Cu(OTf)2/NBS promoted cyclization of 1‐cinnamyl alcohol‐o‐carboranes for synthesis ofo‐carborane substituted oxetanes has been developed. A series of substituted oxetanes has been synthesized with moderate to good yields, which would be an important synthon for design novel reactions in oxetane chemistry as well as carborane chemistry.

The Role of Solvent Hydroxyl Functional Groups on the Interaction Energy and Growth of Form I Paracetamol Crystal Facets

The morphology of a crystal grown in a solvent can change depending on the solvent used during the crystallization process. Modification of the morphology of a crystal can be engineered based on information conferred by the functional groups of the facets of interest and the functional groups of the solvent. This study aims to predict the effect of the alcoholic functional group of amyl alcohol, benzyl alcohol, and phenol on the {002}, {011}, and {110} facets of Form I paracetamol. Prediction and simulation studies were carried out using an embedded tool available in Material Studio. The interaction between the solvents (phenol, benzyl alcohol, and amyl alcohol) and the surfaces used in this study revealed that the {011} facet had the most negative nonbonded energy, followed by the {110} and {002} facets. Overall, the nonbonded interactions between the solvents and the facets were dominated by Coulombic interactions, accounting for more than 90% of the energies, which is within the range from −2566 to −3613 kcal/mol. The binding energy for amyl and benzyl alcohols on the facets of the crystal, ranked from the strongest to the weakest, was in the order {002} > {110} > {011}, while for phenol, the rank was {002} > {011} > {110}. This result is in line with the observed crystal morphology of Form I paracetamol crystallized in a polar protic solvent, in which the most favorable solvent binding on the {002} facets delayed the growth of the elongated hexagonal morphology along the c-axis and formed prismatic-like morphology. Using benzyl alcohol as a case study, an assessment of synthon formation on facets {002} and {011} showed that synthon B is an important synthon for the growth of units of these facets, while synthon F is an important building block synthon for the {110} facet.

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Cobalt(II)-Catalyzed C-H and N-H Functionalization of 1-Arylpyrazolidinones with Dioxazolones as Bifunctional Synthons.

Dioxazolone has been attractive as an important synthon for a direct C-H amidation through a nitrene intermediate or Curtius rearrangement to form the isocyanate. However, the combination of two reaction models of dioxazolone has not been reported. Herein, a cobalt-catalyzed C-H and N-H functionalization of 1-arylpyrazolidinones with dioxazolones was developed. The dioxazolones acted as an amidated and carboxamidated reagent. Three C-N bonds were formed in a "one-pot" manner, which promoted the requirement of synthetic diversity.

Selective hydroboration of terminal alkynes catalyzed by heterometallic clusters with uranium–metal triple bonds

Selective hydroboration of terminal alkynes catalyzed by heterometallic clusters with uranium–metal triple bonds

Functionalization of DNA-Tagged Alkenes with Diazo Compounds via Photocatalysis.

To explore potential chemical space using DNA-encoded library (DEL) technology, the development of various types of robust DNA-compatible reactions is urgently needed. Diazo compounds, which serve as valuable building blocks and important synthons in synthetic chemistry, have been rarely applied in DEL synthesis, probably because of their potential modifications of the bases and phosphate backbone of DNA. Herein we report two cases of DNA-compatible reactions with alkenes and diazo compounds, providing corresponding hydroalkylation and cyclopropanation products in moderate to excellent yields. Notably, these transformations not only provide new access to C(sp3)-C(sp3) bond formation in DELs with excellent functional group tolerance but also represent practical ligation methods to introduce functionalized molecules into DNA.

Versatile and Facile One-Pot Biosynthesis for Amides and Carboxylic Acids in E. coli by Engineering Auxin Pathways of Plant Microbiomes

The development of enzymatic routes toward amide and carboxylic acid bond formation in bioactive molecular scaffolds using aqueous conditions is a major challenge for biopharmaceutical and fine chemical industrial sectors. We report biocatalytic and kinetic characterization of two indole-3-acetamide (IAM) pathway enzymes, tryptophan-2-monooxygenase (iaaM) and indole-3-acetamide hydrolase (iaaH), present in plant microbiomes that produce indole-3-acetic acid (IAA). In this pathway, tryptophan is converted to indole-3-acetamide by the monooxygenase activity of iaaM, followed by its hydrolysis to form carboxylic acid by iaaH enzyme. Since IAA or auxin is an essential natural plant hormone and an important synthon for fine chemicals, the developed monooxygenase-based bioconversion route has a wider scope compared to currently available synthetic and biocatalytic methods to produce synthetic auxins and a range of amides and carboxylic acids for agrochemical and pharmaceutical applications. To display this, one-pot multienzyme biosynthetic cascades for preparative-scale production of IAA derivatives were performed by incorporating tryptophan synthase and tryptophan halogenase enzymes. We also report the creation of an efficient de novo biosynthesis for IAA and its derivatives from glucose or indoles via a reconstructed IAM pathway in Escherichia coli.