Simple Alkynes Research Articles

An Organometallic Umpolung Approach for Iron‐Mediated Propargylic C–H Etherification

The synthesis of propargyl ethers is an efficient way to access a variety of pharmaceuticals and natural products. However, direct etherification of simple alkynes via propargylic C–H activation remains largely underreported, while propargylic substitution of prefunctionalized alkyne starting materials remains the dominant method for the synthesis of propargyl ethers. Herein, we report an organometallic umpolung approach for iron‐mediated C–H propargylic etherification. The stepwise iron‐mediated C–H activation followed by mild oxidative functionalization enables the first use of unadorned alkynes to preferentially couple with alcohols for the efficient synthesis of synthetically important propargylic ethers with excellent functional group compatibility, chemoselectivity and regioselectivity.

An Organometallic Umpolung Approach for Iron-Mediated Propargylic C-H Etherification.

The synthesis of propargyl ethers is an efficient way to access a variety of pharmaceuticals and natural products. However, direct etherification of simple alkynes via propargylic C-H activation remains largely underreported, while propargylic substitution of prefunctionalized alkyne starting materials remains the dominant method for the synthesis of propargyl ethers. Herein, we report an organometallic umpolung approach for iron-mediated C-H propargylic etherification. The stepwise iron-mediated C-H activation followed by mild oxidative functionalization enables the first use of unadorned alkynes to preferentially couple with alcohols for the efficient synthesis of synthetically important propargylic ethers with excellent functional group compatibility, chemoselectivity and regioselectivity.

Palladium‐Catalyzed Four‐Component Carbonylation Reactions of Acetylene: Synthesis of β‐Perfluoroalkyl Acrylamides

AbstractThe simplest alkyne, acetylene, is a suitable C2 linker synthon that enables the connection of organic molecules with different functional groups. However, reactions of acetylene with advanced organic building blocks are much less explored compared to substituted alkynes. In this article, we present a straightforward palladium‐catalyzed four‐component carbonylation reaction with acetylene, CO, amines, and perfluoroalkyl halides that enables the preparation of various β‐perfluoroalkyl acrylamides in one step. This protocol also provides a new strategy for the late‐stage modification of bioactive molecules, as demonstrated by the construction of β‐perfluoroalkyl ibrutinib derivatives.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

Copper-Catalyzed Enantioselective Radical Esterification of Propargylic C–H Bonds

AbstractThe copper-catalyzed enantioselective radical esterification of propargylic C–H bonds with tert-butyl peroxybenzoate (TBPB) as an oxidizing agent and an oxygenated nucleophile is reported. This variant of the Kharasch–Sosnovsky oxidation allows for the asymmetric esterification of open-chain carbon radicals without excessive amounts of alkyne substrates under mild reaction conditions, achieving a one-step conversion of simple alkynes into chiral propargylic esters.

Water-mediated one-pot multi-step synthesis of chiral 1,3-diarylpropan-1-ols by the asymmetric hydrofunctionalisation of simple alkynes

An enantioselective hydration–condensation-asymmetric transfer hydrogenation cascade process of simple alkynes and aldehydes in only water to prepare chiral 1,3-diarylpropan-1-ols has been developed.

Nickel-Catalyzed Hydroalkynylation of 1,3-Dienes with Simple Alkynes

AbstractA hydroalkynylation reaction of 1,3-dienes with simple alkynes, facilitated by an efficient nickel catalyst system with the 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) ligand, is presented. This reaction displays a broad substrate range for alkynes, encompassing both aryl alkynes and alkyl alkynes, thereby overcoming previous constraints in 1,3-diene hydroalkynylation. The method offers a convenient and direct means for obtaining allylic alkynes with high atom and step economy.

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes.

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.

Enantioselective De Novo Synthesis of α,α‐Diaryl Ketones from Alkynes

AbstractChiral α,α‐diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α‐diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α‐diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α‐diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α‐diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best‐selling anti‐breast cancer drugs, tamoxifen, are readily synthesized.

Asymmetric Allenylation of Alkynes mediated by Chiral Organoselenated Reagents under Oxidative Conditions.

The reactivity of novel chiral lactamide-substituted diselenide-based reagents under oxidative conditions was exploited to develop a metal-free method for the preparation of enantioenriched allenylamides from simple alkynes in good yields, and with enantiomeric excesses up to 99 %. The key of the success in this method is attributed to the hydrogen-bonded lactamide appendages that ensure configurational stability of chiral vinyl selenoxide intermediates for an optimal enantiotopic β-syn-elimination step.

Asymmetric Allenylation of Alkynes mediated by Chiral Organoselenated Reagents under Oxidative Conditions

AbstractThe reactivity of novel chiral lactamide‐substituted diselenide‐based reagents under oxidative conditions was exploited to develop a metal‐free method for the preparation of enantioenriched allenylamides from simple alkynes in good yields, and with enantiomeric excesses up to 99 %. The key of the success in this method is attributed to the hydrogen‐bonded lactamide appendages that ensure configurational stability of chiral vinyl selenoxide intermediates for an optimal enantiotopic β‐syn‐elimination step.

Synthesis, structure characterization, DFT calculations, and computational anticancer activity investigations of 1-phenyl ethanol derivatives

1-Phenyl ethanol derivatives are well-known classes of drug molecules that play an important role as effective substitute analogs to anticancer and antiviral agents. In this work, phenylacetylene was selected as a simple alkyne in the presence of iron (II) phthalocyanine with NaBH4 as a catalyst. This reaction has been proven that it is a significantly efficient catalyzed conversion of terminal and internal alkynes to 1-phenyl ethanol derivatives as secondary alcohols followed by the addition and elimination mechanism. However, such drug design by compiling the redox reaction and its sequence essentially requires exact stoichiometry of iron phthalocyanine to alkynes. The products were characterized using flash column chromatography with an eluent ratio of PE: EA (5: 1 / V: V), gas chromatography, 1H, and 13C NMR spectroscopy. The potential of the synthesized compounds to bind to protein kinase B was investigated through molecular docking to dig out their probable anticancer activity. Compound 7 (1-(4-bromophenyl) ethan-1-ol) exhibited the highest binding potential. However, the binding potential of all the compounds was less than the standard parent compound. In addition, the density functional theory (DFT) studies of the compounds were also applied which revealed that compound 1 might have the highest chemical stability.

1,3-Butadiynamides the Ethynylogous Ynamides: Synthesis, Properties and Applications in Heterocyclic Chemistry.

1,3-butadiynamides-the ethynylogous variants of ynamides-receive considerable attention as precursors of complex molecular scaffolds for organic and heterocyclic chemistry. The synthetic potential of these C4-building blocks reveals itself in sophisticated transition-metal catalyzed annulation reactions and in metal-free or silver-mediated HDDA (Hexa-dehydro-Diels-Alder) cycloadditions. 1,3-Butadiynamides also gain significance as optoelectronic materials and in less explored views on their unique helical twisted frontier molecular orbitals (Hel-FMOs). The present account summarizes different methodologies for the synthesis of 1,3-butadiynamides followed by the description of their molecular structure and electronic properties. Finally, the surprisingly rich chemistry of 1,3-butadiynamides as versatile C4-building blocks in heterocyclic chemistry is reviewed by compiling their exciting reactivity, specificity and opportunities for organic synthesis. Besides chemical transformations and use in synthesis, a focus is set on the mechanistic understanding of the chemistry of 1,3-butadiynamides-suggesting that 1,3-butadiynamides are not just simple alkynes. These ethynylogous variants of ynamides have their own molecular character and chemical reactivity and reflect a new class of remarkably useful compounds.

Thiol-Yne click chemistry of acetylene-enabled macrocyclization

Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological research. However, the efficient preparation of macrocycles remains an ongoing research challenge in organic synthesis because of the high entropic penalty involved in the ring-closing process. Herein we report a photocatalyzed thiol-yne click reaction to forge diverse sulfur-containing macrocycles (up to 35-membered ring) and linear C2-linked 1,2-(S-S/S-P/S-N) functionalized molecules, starting from the simplest alkyne, acetylene. Preliminary mechanistic experiments support a visible light-mediated radical-polar crossover dihydrothiolation process. This operationally straightforward reaction is also amenable to the synthesis of organometallic complexes, bis-sulfoxide ligand and a pleuromutilin antibiotic drug Tiamulin, which provides a practical route to synthesize highly valued compounds from the feedstock acetylene gas.

Synthesis of (E)‐β‐Iodovinyl Sulfones via Photoredox Catalyzed Difunctionalization of Terminal Alkynes

AbstractA photoredox mediated approach enabling the synthesis of (E)‐β‐iodovinyl sulfones at room temperature using simple alkynes and thiols as the coupling partners in the presence of TBAI as iodine source is reported. The direct conversion of thiols into sulfones following the tandem introduction of C−I and C−S bonds is achieved using SeO2 as an oxidizing agent. The method is viable with a wide range of alkynes and thiols at room temperature, employs mild conditions, and has good yields. Besides, we could also use β‐iodovinyl sulfones as the starting material to access different β‐functionalized sulfone derivatives.

Part‐per‐million catalysis of azide‐alkyne cycloaddition reaction in water using a new ferromagnetic μ1,1‐N3 bridged dinuclear Cu(II) complex

An original copper(II) dimeric compound formulated as [Cu2(μ1,1‐N3)2L2(N3)2].2CHCl3 (1), with L = 2,6‐pyridinedicarboxaldehydebis(p‐iodophenyl‐imine), has been synthesized and characterized. Single crystal X‐ray structural characterization revealed that this complex displays a centrosymmetric dinuclear structure in which the two Cu(II) centers are connected by double symmetric μ1,1 (end‐on, EO) azido bridges, generating distorted octahedral CuN6 coordination geometry. Magnetic susceptibility measurements indicate a ferromagnetic Cu···Cu coupling with J = 26.7 cm−1 (J being the parameter of the exchange Hamiltonian H = −2JS1S2). The catalytic properties of complex 1 have been evaluated in the one‐pot azide‐alkyne cycloaddition reaction in water without any additional reducing agents or bases. As expected, the absence of any catalyst did not lead to product formation, whereas when complex 1 was introduced as catalyst, the reaction led to the desired product with different chemical yields (10–98%), for which the highest one (98%) corresponds to the reaction performed in the presence of 125 ppm of 1 in water at 90 C. These optimized parameters have been then taken into account to extend the initial reaction based on benzyl chloride and simple alkyne to different substituted benzyl chloride and alkyne molecules.

Copper-Mediated Three-Component Reaction for the Synthesis of N-Acylsulfonamide on DNA.

The DNA-encoded library (DEL) technology is a new method for discovering hit compounds for target proteins in the pharmaceutical industry. The N-acylsulfonamide functional group has been reported to exhibit various pharmacological activities, and based on this, the demand for a method that allows its introduction into the DEL platform has increased. In this report, a procedure for synthesizing N-acylsulfonamide functional groups applicable to DEL construction was developed in the presence of a copper reagent and water as a nucleophile from simple alkynes or sulfonyl azides, which are widely commercially available. Furthermore, we prove that a new alternative procedure can be used to construct a DNA-encoded library.

Base/B2pin2-Mediated Iodofluoroalkylation of Alkynes and Alkenes

AbstractA base/B2pin2-mediated iodofluoroalkylation of alkynes and a part of alkenes, using ethyl difluoroiodoacetate (ICF2CO2Et) or ICnF2n+1 (n = 3, 4, 6) as difluoroacetylating or perfluoroalkylating reagent, is disclosed. The reaction proceeds under mild conditions, and iododifluoroalkylation, hydrodifluoroalkylation and several perfluoroalkylation products were generated from alkynes or alkenes. Notably, this methodology provides a simple access to difluoroalkylated and perfluoroalkylated organic compounds starting from simple alkynes or alkenes.

2,2,2-Trifluoroethanol-mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes.

A new mild and practically simple alkyne hydroarylation protocol for the synthesis of 3-(indol-3-yl)-3-(trifluoromethyl)acrylic acid esters by the reaction of indole derivatives with ethyl/methyl 4,4,4-trifluoro-3-(indol-3-yl)but-2-enoates in trifluoroethanol was developed. This method has the following advantages: no catalyst, atom economy, high yields, broad substrate scope, and large-scale synthesis. The potential application of this protocol was further demonstrated by the synthesis of a variety of CF3 -substituted synthons and a new class of (un)symmetrical 3,3'-diindolylmethanes with a quaternary carbon core that might be biologically active.

Diverse synthesis of C2-linked functionalized molecules via molecular glue strategy with acetylene

As the simplest alkyne and an abundant chemical feedstock, acetylene is an ideal two-carbon building block. However, in contrast to substituted alkynes, catalytic methods to incorporate acetylene into fine chemicals are quite limited. Herein, we developed a photoredox-catalyzed synthetic protocol for diverse C2-linked molecules via a molecular glue strategy using gaseous acetylene under mild conditions. Initiated by addition of an acyl radical to acetylene, two cascade transformations follow. One involves a double addition for the formation of 1,4-diketones and the other where the intermediate vinyl ketone is intercepted by a radical formed from a heterocycle. In addition to making two new C-C bonds, two C-H bonds are also created in two mechanistically distinct ways: one via a C-H abstraction and the other via protonation. This system offers a reliable and safe way to incorporate gaseous acetylene into fine chemicals and expands the utility of acetylene in organic synthesis.