Alkynylation Reaction Research Articles

Double 1,2-Migration of Bromine and Silicon in Directed C–H Alkynylation Reactions with Silyl-Substituted Alkynyl Bromides through an Iridium Vinylidene Intermediate

The iridium(III)-catalyzed C–H alkynylation of 2-acylimidazoles with alkynyl bromides, which was recently developed by our group, provides an efficient strategy for the construction of both C(sp)–C(sp2) and C(sp)–C(sp3) bonds. The mechanism for this reaction was extensively studied using density functional theory (DFT) calculations. The computed catalytic cycle is initiated by C–H activation, and the formed iridacycle undergoes a strain-controlled regioselective migratory insertion of an alkynyl bromide. The resulting α-bromovinyl iridium species is rapidly converted into a more stable iridium vinylidene intermediate by a 1,2-bromine migration, and the adjacent silyl group subsequently migrates to furnish a C–H-alkynylated product. The origin of the unique difference in reactivity with respect to the substituent on the alkynyl bromide is the 1,2-migration step, in which a silyl group can highly stabilize the transition state by the β-silicon effect.

Reaction of Alkynyl- and Alkenyltrifluoroborates with Propargyldicobalt Cations: Alkynylation, Alkenylation, and Cyclopropanation Product Pathways.

The Lewis acid-mediated Nicholas reactions of propargyl acetate-Co2(CO)6 complexes with a series of potassium alkynyltrifluoroborates and potassium alkenyltrifluoroborates are described. Alkynyltrifluoroborates directly alkynylate the intermediate propargyldicobalt cations. In contrast, alkenyltrifluoroborates proceed through one of the three modes of dominant reactivity: C-2-substituted alkenyltrifluorobrates directly alkenylate, predominantly with the retention of stereochemistry. C-1-substituted alkenyltrifluoroborates alkenylate at C-2. Potassium vinyltrifluoroborate incorporates a cyclopropane at the site propargyl to alkynedicobalt. Computational analysis of these systems explains the differential modes of reactivity of alkenyltrifluoroborates and outlines the probable mechanisms for the formation of each product.

The Preparation and Application of Diaryliodonium Salts Derived from Gemfibrozil and Gemfibrozil Methyl Ester

AbstractThe diaryliodonium salts derived from gemfibrozil and gemfibrozil methyl ester were synthesized from ArI(OH)OTs or bis(4-methoxyphenyl)iodonium diacetate with good regioselectivity. These iodonium salts were successfully used in the derivatization of gemfibrozil or gemfibrozil methyl ester, including fluorination, alkynylation, aryl­ation, etherification, esterification, and iodination reactions.

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry.

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl3 ⋅ 6H2 O, FeCl3 , and Fe(OTf)3 showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.

Synthesis of 6-Alkynyl-6-hydroxyindoloquinazolinone Scaffolds via Copper-Catalyzed Alkynylation of Tryptanthrins

AbstractWe report a copper-catalyzed direct alkynylation reaction of tryptanthrins with terminal alkynes under mild reaction conditions. The developed method provides an array of synthetic building blocks of 6-alkynyl-6-hydroxyindoloquinazolinone compounds in moderate to good yields with varied functional group compatibility. Furthermore, the obtained adducts can be smoothly converted into versatile building blocks via hydrogenation, hydration, and further Sonogashira coupling transformations.

Xantphos‐coordinated palladium dithiolates: Highly efficient catalyst for decarboxylative Sonogashira reaction into corresponding alkynes

This work reports Xantphos‐coordinated palladium dithiolate complexes as catalysts for decarboxylative Sonogashira coupling reaction of phenyl propiolic acid and 2‐butynoic acid with various iodoarenes. These palladium aryl dithiolate complexes were synthesized and characterized by 1H and 31P nuclear magnetic resonance (NMR) spectroscopy, melting point, and elemental analysis (CHNS). Synthetic utility for the reported protocol is explored for the effect of various functional groups on the yield of corresponding heteroaryl alkynes. The current protocol showed excellent catalytic activity towards decarboxylative alkynylation reaction with high turn‐over number (TON) up to 105 and turn‐over frequency (TOF) up to 104 h−1. The catalyst could be recycled up to six recycles without losing its catalytic activity. The in situ generation of palladium nanoparticles (PdNPs) was observed after the third recycle, and the amount was significant after the sixth recycle, which were confirmed and characterized by powder X‐ray diffraction (XRD), scanning electron microscope (SEM), and energy‐dispersive X‐ray (EDX) analysis and high‐resolution transmission electron microscopy (HR‐TEM). The catalytic activity of the reaction is attributed to the formation of PdNPs.

Preparation and Synthetic Application of Naproxen-Containing Diaryliodonium Salts.

The synthesis of naproxen-containing diaryliodonium salts has been realized from naproxen methyl ester and ArI(OH)OTs activated by trimethylsilyl trifluoromethanesulfonate (TMSOTf) in a solvent mixture comprising dichloromethane and 2,2,2-trifluoroethanol (TFE). Those iodonium salts have been successfully used in the functionalization of an aromatic ring of naproxen methyl ester, including fluorination, iodination, alkynylation, arylation, thiophenolation, and amination and esterification reactions. Moreover, further hydrolysis of the obtained 5-iodo-naproxen methyl ester afforded 5-iodo-naproxen.

SYNTHESIS OF AROMATIC ACETYLENE ALCOHOLS USING COMPLEX CATALYTIC SYSTEMS

Some cyclic ketones (cyclopentanone, cyclohexanone, 2-methylcyclohexanone, menthol, camphor and adamantanone) enantioselective alkynylation reactions with phenylacetylene have been studied in the presence of complex catalytic systems - Zn(OTf)2/NЕt3/MeCN, 3,3′-Ph2BINOL-2Li/TGF and BuLi/KOtBu/TGF. Synthesis were performed new aromatic acetylene alcohols – 1-(2-phenylathinyl) cyclopentanol (1), 1-(2-phenylethinyl)cyclohexanol (2), 2-methyl-1-(2-phenylethinyl)cyclohexanol (3), 2-isopropyl-5-methyl-1-(2-phenylethinyl)cyclohexanol (4), 1,7,7,-trimethyl-2-(2-phenylethinyl)bicyclo [2.2.1] heptanol-2 (5) and 2-phenylethinyltricyclo [3,3,1.03,7]nonanol-2 (6). Synthesis reactions of aromatic acetylene alcohols, activation energies were determined, kinetics of chemical changes were analyzed, reaction mechanisms were proposed. The course of the reactions and the effect of the selected ketone molecule size, structure and number of rings on the product yield were analyzed. A series of catalytic activity of the applied complex catalytic systems has been developed.

Consecutive O-S/N-S Bond Cleavage in Gold-Catalyzed Rearrangement Reactions of Alkynyl N-Sulfinylimines.

Gold-catalyzed reactions of alkynyl N-sulfinylimines were used to produce the corresponding 2H-azirines possessing sulfenyl and acyl groups at the 3-position of the azirine ring in good to excellent yields. These reactions involved internal transfer of the sulfinyl oxygen atom to form a thiooxime intermediate tethered to an α-oxo gold carbene moiety. Subsequent insertion of the carbene into the N-S bond resulted in ring construction.

Consecutive O−S/N−S Bond Cleavage in Gold‐Catalyzed Rearrangement Reactions of Alkynyl N‐Sulfinylimines

AbstractGold‐catalyzed reactions of alkynyl N‐sulfinylimines were used to produce the corresponding 2H‐azirines possessing sulfenyl and acyl groups at the 3‐position of the azirine ring in good to excellent yields. These reactions involved internal transfer of the sulfinyl oxygen atom to form a thiooxime intermediate tethered to an α‐oxo gold carbene moiety. Subsequent insertion of the carbene into the N−S bond resulted in ring construction.

Cover Picture: Consecutive O−S/N−S Bond Cleavage in Gold‐Catalyzed Rearrangement Reactions of Alkynyl N‐Sulfinylimines (Angew. Chem. Int. Ed. 22/2021)

A gold catalyst promotes the sequential cleavage of the S−O and N−S bonds of a sulfinyl group, leading to S-functionalized azirines. As Itaru Nakamura et al. illustrate in their Communication on page 12248, the transformation is like making plastic models: A golden diagonal plier cuts these bonds, and the cut out parts are assembled into the product using an alkyne triple bond unit. Substituents in the product can be chosen from the kit as desired.

Alkynyl-functionalization of carbon nanotubes to promote anchoring potential in glycidyl azide polymer-based binders via Huisgen reaction for solid propellant application

Triazole curing systems based on glycidyl azide polymer (GAP) have been widely used as the binders of solid propellant systems due to moisture insensitivity, high energy density, and room temperature curing. However, the low-flexible molecular structure of GAP usually causes low mechanical properties, and reinforcement fillers may not be suitable in the binder system of propellants because they probably diffuse into other parts of propellants. Thus, we anchored a strong nanomaterial, carbon nanotube (CNT), on GAP to prevent the CNT from diffusing uncontrollably. The anchoring process was based on the alkynylation reaction and the Huisgen reaction, which was confirmed by tests on chemical structure. The reaction process was further adjusted to introduce CNT into the triazole crosslinked network, leading to a 23.6% increase in the elongation at break of the binder. The high rigidity of CNT also improved the Young’s modulus and tensile strength of the binder increased by 107.7% and 199.0%, respectively. Furthermore, the high thermal conductivity of CNT could reduce the thermal resistance index of the binders from 160.4 °C to 151.2 °C, and decrease the carbon residue rate from 17.8% to 10.5%. Such an anchoring modification can thus target the reinforcement region in multi-component systems, which can be used not only in solid propellants, but also in ablative materials.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

SOMOphilic alkynylation using acetylenic sulfones as functional reagents

Recent advancements in SOMOphilic alkynylation reactions by using acetylenic sulfones as functional reagents are summarized.

Recent Advances in Radical-Involved Alkynylation of Unactivated C(sp3)–H Bonds by Hydrogen Atom Abstraction

AbstractThe direct C(sp3)–H functionalization is one of the major research topics in synthetic chemistry since C(sp3)–H bonds are ubiquitous in every aspect of chemistry. Despite impressive advances in transition-metal-catalyzed C(sp3)–H activation, the radical-initiated process via hydrogen atom abstraction (HAA) of C(sp3)–H bonds represents a more appealing strategy owing to the mild reaction conditions and good regioselectivity. Given the importance of alkynes as versatile synthons in organic synthesis and key structural motifs in drug discovery, great efforts have been made toward their synthesis via the combination of HAA and alkynylation process in recent years. This review summarizes the recent progress in radical-initiated C(sp3)–H alkynylation reactions with emphasis on the alkynylating reagents and mechanistic discussion.1 Introduction2 Alkynylation of C(sp3)–H via Intermolecular Hydrogen Atom Abstraction3 Alkynylation of C(sp3)–H via Intramolecular Hydrogen Atom Abstraction4 Conclusion

Boryl Radical‐Mediated C−H Activation of Inactivated Alkanes for the Synthesis of Internal Alkynes

AbstractAn intriguing pyridine‐boryl radical‐mediated C−H alkynylation reaction of inactivated alkanes was described. The reaction features mild operation condition and wide substrate scope, and affords the corresponding products in moderate to good yields. Notably, The presence of 4‐cyanopyride N‐oxide was key to the success of the reaction. Cyclohexane are more easily to be functionalized in this reaction than toluene, which could be rationally explained by polarity‐match principle.magnified image

Syntheses of 2-Iminoindolin-3-ones and 2-Alknyl-2,3-dihydroquinazolin-4(1H)-ones from 3-Diazoindolin-2-imines.

3-Diazoindolin-2-imines reacted with nitrones to furnish 2-iminoindolin-3-ones through a Au(I)-catalyzed cascade oxygen transfer/imine exchange process. The prepared 2-iminoindolin-3-ones could be further transformed into 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones through a Ag(I)-catalyzed reaction with terminal alkynes. A MeOH-triggered ring expansion mechanism involving cyclic iminium formation and nucleophilic addition is proposed for this novel alkynylation reaction. This two-step procedure provides a general and convenient approach to 2-alknyl-2,3-dihydroquinazolin-4(1H)-ones, which are privileged structures in medicinal chemistry.

Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels–Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.

Asymmetric Alkynylation of Cyclic N‐Sulfonyl Imines using Synergistic Chiral Phosphoric Acid/Copper Catalysis

AbstractThe catalytic enantioselective alkynylation of six‐membered cyclic N‐sulfonyl imines was achieved using a cooperative chiral phosphoric acid and Cu(I) catalyst. This alkynylation reaction displays a broad substrate scope for both terminal alkynes and benzoxathiazine 2,2‐dioxides and provides a highly efficient method for the synthesis of chiral propargylic sulfamidates in up to 95% yield and 99% enantiomeric excess.magnified image

A Review on Metal-Free Oxidative α-Cyanation and Alkynylation of N-Substituted Tetrahydroisoquinolines as a Rapid Route for the Synthesis of Isoquinoline Alkaloids

As a fast-growing research field in modern organic chemistry, the crossdehydrogenative coupling (CDC) has seen considerable development in its scope of application, uptake into industry, and understanding of its mechanism to functionalize the tetrahydroisoquinoline (THIQ) scaffold. Among the vast number of possibilities offered by the CDC coupling, the metal-free oxidative α-cyanation and alkynylation reactions have emerged as powerful strategies in the synthesis of diverse and potentially bioactive THIQs. Even though transition-metal catalyzed CDC reactions have undoubtedly made significant progress in THIQ chemistry, general and selective protocols for the metal-free oxidative α-cyanation and alkynylation reactions of THIQs are urgently needed. Thereby, this critical discussion is aimed to highlight the recent progress in this field of CDC reactions where Csp3-H bonds are activated without metal catalysts to introduce the CN and the alkynyl groups into the THIQ core.