Organic Synthons Research Articles

N-Fluorosulfurylamidines Enable Modular Synthesis of 1,5-Disubstituted Tetrazoles.

Here we report the modular synthesis of 1,5-disubstituted tetrazoles using two highly chemoselective reactions, ligations of N-fluorosulfurylamidines with amines and diazotransfer reactions between FSO2N3 and N-monosubstituted amidines, respectively. Enabled by sulfur(VI) fluoride exchange (SuFEx) click chemistry, we have successfully synthesized a series of N-fluorosulfurylamidines and identified them as stable and scalable organic synthons. We then discover that N-fluorosulfurylamidines react selectively toward a series of aliphatic amines, resulting in the formation of N-monosubstituted amidines that can react further with FSO2N3 to deliver 1,5-disubstituted tetrazoles. Our work provides a new platform for generating a library of 1,5-disubstituted tetrazoles with diverse structures, which is unprecedented.

Modular Synthesis of Azines Bearing a Guanidine Core from N-Heterocyclic Carbene (NHC)-Derived Selenoureas and Diazo Reagents.

N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.

Cobalt catalyzed practical hydroboration of terminal alkynes with time-dependent stereoselectivity

Stereodefined vinylboron compounds are important organic synthons. The synthesis of E−1-vinylboron compounds typically involves the addition of a B-H bond to terminal alkynes. The selective generation of the thermodynamically unfavorable Z-isomers remains challenging, necessitating improved methods. Here, such a proficient and cost-effective catalytic system is introduced, comprising a cobalt salt and a readily accessible air-stable CNC pincer ligand. This system enables the transformation of terminal alkynes, even in the presence of bulky substituents, with excellent Z-selectivity. High turnover numbers (>1,600) and turnover frequencies (>132,000 h−1) are achieved at room temperature, and the reaction can be scaled up to 30 mmol smoothly. Kinetic studies reveal a formal second-order dependence on cobalt concentration. Mechanistic investigations indicate that the alkynes exhibit a higher affinity for the catalyst than the alkene products, resulting in exceptional Z-selective performance. Furthermore, a rare time-dependent stereoselectivity is observed, allowing for quantitative conversion of Z-vinylboronate esters to the E-isomers.

C-H functionalization enabled by multiple isocyanides.

Past decades have witnessed significant advance of isocyanides as a class of versatile organic synthons as well as their broad applications in multi-component reactions (MCRs) and other tandem reactions. Reactions involving multiple isocyanides allow the construction of molecules with further diversification and complexity, while C-H functionalization emphasizes the advantages of high atom economy, broad substrate availability and great synthetic efficiency. This promising synergistic strategy of C-H functionalization involving multiple isocyanides provides a variety of valuable synthetic methods for organic chemists' toolbox and offers considerable potential in pharmaceutical chemistry and materials science as well. The present review outlines in detail various reaction types of C-H functionalization enabled by multiple isocyanides, and the relevant mechanistic rationale is discussed.

Construction of stable porous organic cages: from the perspective of chemical bonds.

Porous organic cages (POCs) are constructed from purely organic synthons by covalent linkages with intrinsic cavities and have shown potential applications in many areas. However, the majority of POC synthesis methods reported thus far have relied on dynamically reversible imine linkages, which can be metastable and unstable under humid or harsh chemical conditions. This instability significantly hampers their research prospects and practical applications. Consequently, strategies to enhance the chemical stability of POCs by modifying imine bonds and developing robust covalent linkages are imperative for realizing the full potential of these materials. In this review, we aim to highlight recent advancements in synthesizing chemical-stable POCs through these approaches and their associated applications. Additionally, we propose further strategies for creating stable POCs and discuss future opportunities for practical applications.

Metal‐Free Electrocatalytic Diacetoxylation of Alkenes

Abstract1,2‐Dioxygenation of alkenes leads to a structural motif ubiquitous in organic synthons, natural products and active pharmaceutical ingredients. Straightforward and green synthesis protocols starting from abundant raw materials are required for facile and sustainable access to these crucial moieties. Especially industrially abundant aliphatic alkenes have proven to be arduous substrates in sustainable 1,2‐dioxygenation methods. Here, we report a highly efficient electrocatalytic diacetoxylation of alkenes under ambient conditions using a simple iodobenzene mediator and acetic acid as both the solvent and an atom‐efficient reactant. This transition metal‐free method is applicable to a wide range of alkenes, even challenging feedstock alkenes such as ethylene and propylene, with a broad functional group tolerance and excellent faradaic efficiencies up to 87 %. In addition, this protocol can be extrapolated to alkenoic acids, resulting in cyclization of the starting materials to valuable lactone derivatives. With aromatic alkenes, a competing mechanism of direct anodic oxidation exists which enables reaction under catalyst‐free conditions. The synthetic method is extensively investigated with cyclic voltammetry.

Metal-Free Electrocatalytic Diacetoxylation of Alkenes.

1,2-Dioxygenation of alkenes leads to a structural motif ubiquitous in organic synthons, natural products and active pharmaceutical ingredients. Straightforward and green synthesis protocols starting from abundant raw materials are required for facile and sustainable access to these crucial moieties. Especially industrially abundant aliphatic alkenes have proven to be arduous substrates in sustainable 1,2-dioxygenation methods. Here, we report a highly efficient electrocatalytic diacetoxylation of alkenes under ambient conditions using a simple iodobenzene mediator and acetic acid as both the solvent and an atom-efficient reactant. This transition metal-free method is applicable to a wide range of alkenes, even challenging feedstock alkenes such as ethylene and propylene, with a broad functional group tolerance and excellent faradaic efficiencies up to 87 %. In addition, this protocol can be extrapolated to alkenoic acids, resulting in cyclization of the starting materials to valuable lactone derivatives. With aromatic alkenes, a competing mechanism of direct anodic oxidation exists which enables reaction under catalyst-free conditions. The synthetic method is extensively investigated with cyclic voltammetry.

C‐Heteroatom Bond Formation via a Highly C2‐Site Selective Functionalization of Quinone Imine Ketals

AbstractQuinone imine ketals (QIKs), as a kind of functionalized organic synthons, have attracted considerable attention in organic synthesis during recent years. In this paper, acetyl chloride, acetyl bromide, H‐phosphonate and thiophenol were used as nucleophiles to react with QIKs, providing a series of C2‐site functionalization molecules via an efficient C−Cl/C−Br/C−P/C−S bond formation with high yields and excellent selectivity under mild conditions.

Metalo Hydrogen-Bonded Organic Frameworks Self-Assembled by Charge-Assisted Synthons for Ultrahigh Proton Conduction

Hydrogen-bonded organic frameworks (HOFs) have been well recognized for constructing solid-state proton-conducting materials due to their inherent well-defined H-bonded networks; however, the design and synthesis of stable HOFs showing ultrahigh superprotonic conductivity is still challenging. Herein, we reported a facile and effective synthetic strategy to build high proton-conducting metalo hydrogen-bonded organic–inorganic frameworks (MHOFs) through charge-assisted inorganic and organic synthons. The supramolecular self-assembly of simple metal salts and tetra-carboxylic acids gives rise to two hydrogen-bonded frameworks, [M(H2O)6][H2tcba] (M = Zn2+, Ni2+; H4tcba = 1,2,4,5-benzenetetracarboxylic acid). X-ray crystallography and gas adsorption confirmed the nonporous nature of the HOIFs. Variable-temperature single-crystal and powder X-ray diffraction experiments reveal the thermal and water stability of the supramolecular structures sustained by exclusively charge-assisted hydrogen bonds. The high density of carboxylic acid groups and coordinated water molecules provide ample protons and hydrophilic environments for efficient proton transport; therefore, variable-temperature and -humidity electrochemical impedance spectroscopy revealed that MHOFs are good supramolecular proton conductors with conductivities up to 1.1 × 10–2 and 2.1 × 10–2 S·cm–1 for 1 and 2, respectively, at 80 °C under 97% RH. Our study demonstrates great potential of charge-assisted inorganic and organic synthons in the design and construction of proton-conducting HOIFs.

A copper catalyzed Doyle–Kirmse reaction for the concise and effective preparation of multifunctional 3-allyl-3-(thio) succinimides

A highly efficient Doyle–Kirmse reaction between alpha-arylidene diazosuccinimides and allyl thioethers in the presence of a cheaply and easily available copper catalyst for the concise and effective preparation of multifunctional 3-allyl-3-(thio) succinimides and 3-allenyl-3-(thio) succinimides in excellent yields (up to 90%) under mild conditions within a few hours has been developed. The target multifunctional succinimides may boast potential biological activities for the succinimide scaffold, and may be also used as potential new organic synthon for the preparations of new chemical and pharmaceutical entities or sulfoxide-olefin ligands. Afurther successful scale-uppreparationhas demonstrated the feasibility of the Doyle–Kirmse rearrangement and our new protocol.

A new entrant in ketene family: Generation of 2‐(3‐Oxo‐allyl)‐isoindole‐1,3‐dione and their [4+2] Cycloadditions with 1,3‐Diazabuta‐1,3‐dienes

AbstractThe manuscript describes a synthetic route for the formation of 5‐(methylisoindole‐1,3‐dione) pyrimidinones by [4+2] cycloaddition reactions of functionalized 1,3‐diazabuta‐1,3‐dienes with 2‐(3‐Oxo‐allyl)‐isoindole‐1,3‐dione generated in situ from phthaloylalanine and tosyl chloride using triethylamine as a base. The functionalized 5‐(methylisoindole‐1,3‐dione) pyrimidinones were further explored in the deprotection of amines to afford a variety of 5‐methylamino pyrimidinones. The synthesis of such functionalized pyrimidinones is significant as they have a wide range of pharmacological profiles and are valuable as organic synthons. Mechanistic insights are also proposed for the given synthetic methodology.

Synthesis of pyrimidines from dinitrogen and carbon.

The element nitrogen and nitrogenous compounds are vital to life. The synthesis of nitrogen-containing compounds using dinitrogen as the nitrogen source, not through ammonia, is of great interest and great value but remains a grand challenge. Herein, we describe a strategy to realize this transformation by combining the heterogeneous approach with the homogeneous methodology. The N2 molecule was first fixed with carbon and LiH through a one-pot heterogeneous process, forming Li2CN2 as an 'activated' nitrogen source with high efficiency. Then subsequent homogeneous treatments of Li2CN2 to construct the organic synthon carbodiimide and the RNA/DNA building block pyrimidines were fulfilled. By using 15N2 as the feedstock, their corresponding 15N-labeled carbodiimide and pyrimidines were readily obtained. This homogeneous-heterogeneous synergy strategy will open a new chapter for N2 transformation.

Nickel catalyzed multicomponent stereodivergent synthesis of olefins enabled by electrochemistry, photocatalysis and photo-electrochemistry

Trisubstituted alkenes are important organic synthons and have broad applications in the synthesis of many pharmaceuticals and materials. The stereoselective synthesis of such compounds has long been a research focus for organic researchers. Herein, we report a three-component, reductive cascade, cross-coupling reaction for the arylalkylation of alkynes. A wide range of trisubstituted alkenes are obtained in good to high yields with excellent chemo- and stereoselectivity by switching between electrochemistry and photocatalysis. The E isomer of the product is obtained exclusively when the reaction is conducted with electricity and nickel, while the Z isomer is generated with high stereoselectivity when photo- and nickel dual catalysts are used. Moreover, photo-assisted electrochemically enabled nickel catalyzed protocol is demonstrated to selectively deliver Z-trisubstituted alkenes without the addition of photocatalysts.

Copper(II) NHC Catalyst for the Formation of Phenol from Arylboronic Acid.

Arylboronic acids are commonly used in modern organic chemistry to form new C-C and C-heteroatom bonds. These activated organic synthons show reactivity with heteroatoms in a range of substrates under ambient oxidative conditions. This broad reactivity has limited their use in protic, renewable solvents like water, ethanol, and methanol. Here, we report our efforts to study and optimize the activation of arylboronic acids by a copper(II) N-heterocyclic carbene (NHC) complex in aqueous solution and in a range of alcohols to generate phenol and aryl ethers, respectively. The optimized reactivity showcases the ability to make targeted C-O bonds, but also identifies conditions where water and alcohol activation could be limiting for C-C and C-heteroatom bond-forming reactions. This copper(II) complex shows strong reactivity toward arylboronic acid activation in aqueous medium at ambient temperature. The relationship between product formation and temperature and catalyst loading are described. Additionally, the effects of buffer, pH, base, and co-solvent are explored with respect to phenol and ether generation reactions. Characterization of the new copper(II) NCN-pincer complex by X-ray crystallography, HR-MS, cyclic voltammetry, FT-IR and UV-Vis spectral studies is reported.

Oxa-Michael Addition Reactions of 3-hydroxy-2-azetidinones: Synthesis of 1, 3, 4-Trisubstituted-2-Azetidinones

Abstract:The manuscript describes a facile and an efficient methodology for the synthesis of 1, 3, 4 trisubstituted-β-lactams by base mediated oxa-Michael addition reactions of 3-hydroxy-2- azetidinones with acetylenic esters under different reaction conditions. These functionalized 1, 3, 4-trisubstituted-azetidin-2-ones are useful organic synthons for the synthesis of various heterocyclic compounds having diverse pharmacological applications.

Mild, metal-free synthesis of 2-substituted quinazolinones from imidates and methyl 2-aminobenzoates or 2-aminobenzamides

In the present work, we developed a mild, metal-free method for synthesizing 2-substituted quinazolinones in good to excellent yields (50%–99%) from methyl 2-aminobenzoates or 2-aminobenzamides using 2,2,2-trichloroethyl imidates hydrochloride as the organic synthon. A cheap, readily available base (NaOAc) was used for this transformation. The reaction has a broad substrate scope and can be performed on a gram scale.

Transition-metal-free azide insertion of N-triftosylhydrazones using a non-metallic azide source.

Benzylic azides, an important class of active organic synthons, were synthesized in high yields from the easily accessible N-triftosylhydrazones with stable TMSN3 under mild conditions. The reaction features high efficiency and excellent functional group tolerance, as illustrated by gram-scale synthesis and the synthesis of drug-like molecules. Mechanistic studies reveal that azidation occurs at the electron-deficient diazo-carbon via the elimination of N2 by an azide ion.

Reactions of Sulfoxides with Benzynes

AbstractSulfoxides are important organic synthons that have been used in a variety of transformations. In this account, we focus on advances in the reaction of sulfoxides with benzynes, which can be divided into two types: benzyne ortho-difunctionalization and benzyne multifunctionalization.1 Introduction2 Benzyne ortho-Difunctionalization3 Benzyne Multifunctionalization4 Conclusion

Photochemical Radical C-H Halogenation of Benzyl N-Methyliminodiacetyl (MIDA) Boronates: Synthesis of α-Functionalized Alkyl Boronates.

α-Haloboronates are useful organic synthons that can be converted to a diverse array of α-substituted alkyl borons. Methods to α-haloboronates are limiting and often suffer from harsh reaction conditions. Reported herein is a photochemical radical C-H halogenation of benzyl N-methyliminodiacetyl (MIDA) boronates. Fluorination, chlorination, and bromination reactions were effective by using this protocol. Upon reaction with different nucleophiles, the C-Br bond in the brominated product could be readily transformed to a series of C-C, C-O, C-N, C-S, C-P, and C-I bonds, some of which are difficult to forge with α-halo sp2 -B boronate esters. An activation effect of B(MIDA) moiety was found.

Photochemical Radical C–H Halogenation of Benzyl N‐Methyliminodiacetyl (MIDA) Boronates: Synthesis of α‐Functionalized Alkyl Boronates

Abstractα‐Haloboronates are useful organic synthons that can be converted to a diverse array of α‐substituted alkyl borons. Methods to α‐haloboronates are limiting and often suffer from harsh reaction conditions. Reported herein is a photochemical radical C‐H halogenation of benzyl N‐methyliminodiacetyl (MIDA) boronates. Fluorination, chlorination, and bromination reactions were effective by using this protocol. Upon reaction with different nucleophiles, the C−Br bond in the brominated product could be readily transformed to a series of C−C, C−O, C−N, C−S, C−P, and C−I bonds, some of which are difficult to forge with α‐halo sp2‐B boronate esters. An activation effect of B(MIDA) moiety was found.