Aryl Alkynes Research Articles

A Unified Continuous Flow Assembly‐Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines

AbstractA rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N‐alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst‐free conditions. This assembly‐line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four‐step, telescoped synthesis of measles therapeutic, AS‐136A, in a total residence time of 31.7 min (1.76 g h−1).

A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines.

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst free conditions. This assembly line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h-1).

Stable, Yet Highly Reactive Nonclassical Iron(II) Polyhydride Pincer Complexes: Z-Selective Dimerization and Hydroboration of Terminal Alkynes.

The synthesis, characterization, and catalytic activity of nonclassical iron(II) polyhydride complexes containing tridentate PNP pincer-type ligands is described. These compounds of the general formula [Fe(PNP)(H)2(η2-H2)] exhibit remarkable reactivity toward terminal alkynes. They efficiently promote the catalytic dimerization of aryl acetylenes giving the corresponding conjugated 1,3-enynes in excellent yields with low catalyst loadings. When the reaction is carried out in the presence of pinacolborane, vinyl boronates are obtained. Both reactions take place under mild conditions and are highly chemo-, regio-, and stereoselective with up to 99% Z-selectivity.

Photocatalyzed Facile Synthesis of α-Chloro Aryl Ketones with Polyaniline–g-C3N4–TiO2 Composite under Visible Light

PANI (polyaniline)–g-C3N4–TiO2 composite was prepared and utilized in the photocatalyzed synthesis of α-chloro aryl ketones via a radical-triggered domino process under oxygen atmosphere. This semiconductor photocatalyst showed good photocatalytic performance and chemoselectivity under visible light irradiation. A variety of aryl diazonium salts and aryl alkynes survived the reaction conditions well to afford the corresponding products in moderate to good yields. Scale-up (10 mmol) synthesis was also achieved. The recycle studies showed that the semiconductor composite could be readily recovered and reused for eight consecutive runs with a slight decrease in the catalytic activity. Control experiments were also performed, and a plausible catalytic mode was proposed.

Catalytic Anti-Markovnikov Hydroallylation of Terminal and Functionalized Internal Alkynes: Synthesis of Skipped Dienes and Trisubstituted Alkenes.

We have developed catalytic anti-Markovnikov hydroallylation of terminal and functionalized internal alkynes. In this article, we describe the development of the reaction, exploration of the substrate scope, and a study of the reaction mechanism. Synthesis of skipped dienes through the hydroallylation of terminal alkyl and aryl alkynes with simple allyl phosphates and 2-substituted allyl phosphates is described. The hydroallylation of functionalized internal alkynes leads to the formation of skipped dienes containing trisubstituted alkenes. We demonstrate that the hydroallylation of internal alkynes can be used in the regio- and diastereoselective synthesis of complex trisubstituted alkenes. A mechanism of the hydroallylation reaction is proposed, and experimental evidence is provided for the key steps of the catalytic cycle. Stoichiometric experiments demonstrate an unexpected role of lithium alkoxide in the carbon-carbon bond-forming step of the reaction. A study of the hydrocupration of internal alkynes provides new insight into the structure, stability, and reactivity of alkenyl copper intermediates, as well as insight into the source of the regioselectivity in reactions of internal alkynes.

Evaluation of guggulsterone derivatives as novel kidney cell protective agents against cisplatin-induced nephrotoxicity

Guggulsterone derivatives were prepared using [3+2] click chemistry with aryl and alkyl acetylene. The series of derivatives were evaluated for their cellular protective effects on cisplatin-treated cultured LLC-PK1 kidney epithelial cells. Among the guggulsterone-triazole derivatives, compound 6g, which contains a hydroxyl methyl group, was the most active of all the derivatives. In an additional study, we determined that inhibition of the mitogen-activated protein kinase/caspase-3 signaling cascade by 6g mediates its protective effects against cytotoxicity in cultured LLC-PK1 cells.

Aromatic PCN pincer palladium complexes: forming and breaking C[sbnd]C bonds

Through a salt metathesis reaction, (t−BuPCN)Pd-ONO2 (2) was prepared and used as a precursor for producing (t−BuPCN)Pd-OH (3) and (t−BuPCN)Pd-aryl acetylide complexes 4 (phenyl acetylide) and 5 (p-tolyl acetylide). The aryl acetylide complexes could also be prepared through another synthetic route: by condensation of 3 with the corresponding aryl acetylene. The reactivity of complexes 3 and 4 toward carbon dioxide was studied and it was found that both reactions give the hydrogen carbonate complex (6). The low reactivity of the Pd-acetylide bond was further confirmed by the fact that the propiolate complex undergoes decarboxylation to give 4. PCN palladium complexes are good catalysts for the decarboxylative cross coupling reactions between acetylene carboxylic acids and aryl halides. The yield of the cross coupling product was improved by adding a catalytic amount of CuI.

Metallapentalenofurans and Lactone-Fused Metallapentalynes.

Metalla-aromatics are attractive species because they exhibit the properties of both organometallics and aromatics. Reported metal-bridged polycyclic aromatic complexes, as well as Möbius aromatic species, are still rare. Herein, we present the construction of two new metal-bridged polycyclic aromatic frameworks, α-metallapentalenofurans and lactone-fused metallapentalynes, by the reactions of osmapentalyne with terminal aryl alkynes in the presence of H2 O or HBF4 /H2 O, respectively. DFT calculations show that the α-metallapentalenofurans possess rare planar Craig-type Möbius aromaticity derived from the 11-center-12-electron dπ -pπ π-conjugation. This study offers a new route for the construction of polycyclic metalla-aromatics as well as planar Möbius aromatic species.

Implications of the final ring closure to 10b-aza-10c-borapyrene for aryl–alkyne ring-closing mechanisms

Through a combined computational and isotopic labeling study, it has been observed that the activation energy for the aryl–alkyne ring closure of the azaborine containing 4-ethynyl-4a-aza-4b-boraphenanthrene is dramatically lower, and it appears to proceed via an alternate mechanism than that of its hydrocarbon analog. This catalyst-free reaction proceeds at modest reaction conditions compared with traditional pyrolytic synthetic methods and holds promise for the efficient construction of fused ring systems containing azaborine functional groups that may not be accessible in the purely hydrocarbon form.

Copper-Catalyzed Arylation with Diaryliodonium Salts

The unique reactivity of diaryliodonium salts with copper complexes has been applied to a variety of synthetic organic transformations. These hypervalent iodine compounds have been used for diverse copper-catalyzed cross-coupling reactions including C–H functionalizations, enantioselective C–C bond formation, cascade reactions and different heteroatom arylation processes. This review provides a summary of recent developments on this topic and discusses both the synthetic utility and mechanisms of these transformations. 1 Introduction 2 Historical Background 3 Arylation of Carbon Nucleophiles 3.1 Arylation of Organometallic Compounds 3.2 Arylation of Heteroarenes 3.3 Arylation of Arenes 3.4 Arylation of Alkenes 3.5 Arylation of Alkynes 4 Nitrogen Arylation 4.1 Arylation of Acyclic Amine Derivatives 4.2 Arylation of Cyclic Amine Derivatives 4.3 Arylation of Nitriles 4.4 Arylation of Azides 5 Oxygen Arylation 6 Arylation of Other Heteroatoms 6.1 Fluorine Arylation 6.2 Sulfur Arylation 6.3 Phosphorus Arylation 6.4 Iodine Arylation 7 Summary and Conclusions

Green Hydroselenation of Aryl Alkynes: Divinyl Selenides as a Precursor of Resveratrol.

A simple and efficient protocol to prepare divinyl selenides has been developed by the regio- and stereoselective addition of sodium selenide species to aryl alkynes. The nucleophilic species was generates in situ, from the reaction of elemental selenium with NaBH4, utilizing PEG-400 as the solvent. Several divinyl selenides were obtained in moderate to excellent yields with selectivity for the (Z,Z)-isomer by a one-step procedure that was carried out at 60 °C in short reaction times. The methodology was extended to tellurium, giving the desired divinyl tellurides in good yields. Furthermore, the Fe-catalyzed cross-coupling reaction of bis(3,5-dimethoxystyryl) selenide 3f with (4-methoxyphenyl)magnesium bromide 5 afforded resveratrol trimethyl ether 6 in 57% yield.

Modular Assembly of Spirocarbocyclic Scaffolds through Pd0‐Catalyzed Intermolecular Dearomatizing [2+2+1] Annulation of Bromonaphthols with Aryl Iodides and Alkynes

AbstractA novel palladium(0)‐catalyzed dearomatizing [2+2+1] spiroannulation of 1‐bromo‐2‐naphthols with aryl iodides and alkynes was developed for the rapid assembly of spiro[indene‐1,1′‐naphthalen]‐2′‐ones. This three‐component cascade reaction was realized through consecutive Catellani‐type C−H activation, unsymmetrical biaryl coupling, alkyne migratory insertion, and arene dearomatization. The potential utility of our method is illustrated by the one‐step construction of the polycyclic skeletons of dalesconols A and B from alkyne‐tethered aryl iodides and 1‐bromo‐2‐naphthol.

Modular Assembly of Spirocarbocyclic Scaffolds through Pd0 -Catalyzed Intermolecular Dearomatizing [2+2+1] Annulation of Bromonaphthols with Aryl Iodides and Alkynes.

A novel palladium(0)-catalyzed dearomatizing [2+2+1] spiroannulation of 1-bromo-2-naphthols with aryl iodides and alkynes was developed for the rapid assembly of spiro[indene-1,1'-naphthalen]-2'-ones. This three-component cascade reaction was realized through consecutive Catellani-type C-H activation, unsymmetrical biaryl coupling, alkyne migratory insertion, and arene dearomatization. The potential utility of our method is illustrated by the one-step construction of the polycyclic skeletons of dalesconols A and B from alkyne-tethered aryl iodides and 1-bromo-2-naphthol.

Theoretical elucidation of the potential possibility of synthesizing arylboronic acids via Rh-catalytic borylations of aryl acetylene and aryl ethylene

As a new type of catalytic borylations, the Rh-catalytic borylation reaction of aryl cyanides has been reported experimentally (Tobisu et al. J. Am. Soc. Chem. 2012, 134, 115). Here, to aid experimental designs of the novel type of borylation reactions, we theoretically predict Rh-catalytic borylations of two alternative substrates of aryl cyanides, i.e. aryl acetylene and aryl ethylene. Both borylation and diborylation pathways have been calculated in details for each substrate. It is found that aryl ethylene prefers to the borylation product via the β-H elimination mechanism, in contrast, aryl acetylene favors the diborylation product by inserting the CC bond into the RhB bond. The theoretical results are expected to be helpful for the preparation of organoboron compounds.

Green protocol for sp-sp2 coupling of aryl iodide and alkynes using copper carbonate: Facile synthesis of aryl alkynes

Green protocol for sp-sp² coupling of aryl iodide and alkynes using copper carbonate: Facile synthesis of aryl alkynes

Glaser-Hay hetero-coupling in a bimetallic regime: a Ni(ii)/Ag(i) assisted base, ligand and additive free route to selective unsymmetrical 1,3-diynes.

A Ni(OAc)2/Ag(OTf) catalysed coupling of aryl alkynes and propargylic alcohol/ether/ester gave the corresponding unsymmetrical 1,3-diynes in good to excellent yields. The reaction does not require bases, ligands or additives and shows excellent hetero-selectivity, thereby addressing the current challenges in the field of coupling of two different terminal alkynes.

Selective hydration of asymmetric internal aryl alkynes without directing groups to α-aryl ketones over Cu-based catalyst

The catalyst enlarges the uniqueness of the electron population on the two triple-bond carbon atoms, resulting in highly regioselective hydration.

Cu-Catalyzed electrophilic amination of internal alkynes via hydroalumination.

A straightforward and efficient method for the synthesis of 1,2-diaryl-substituted enamines through the Cu-catalyzed electrophilic amination reaction of O-benzoyl hydroxylamines with vinylaluminum reagents generated in situ from the Ni-catalyzed hydroalumination of readily accessible internal aryl acetylenes is described. The amination is catalyzed by 1 mol% CuCl without any additive at ambient temperature to afford new versatile enamines in good yield (61-91%) with high selectivity (>98% E-enamine).

Novel 2,3-Dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones: Synthesis and Biological Evaluation.

Herein we describe the synthesis and evaluation of a series of novel 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones for in vitro cytotoxicity against three human cancer cell lines as well as for potential antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The title compounds were prepared via PdCl2-mediated endo-dig cyclization of 2-aryl-8-(arylethynyl)-6-bromo-2,3-dihydroquinazolin-4(1H)-ones. The latter were prepared, in turn, via initial Sonogashira cross-coupling of 2-amino-5-bromo-3-iodobenzamide with aryl acetylenes followed by boric acid-mediated cyclocondensation of the intermediate 2-amino-3-(arylethynyl)-5-bromobenzamides with benzaldehyde derivatives. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–k were evaluated for potential in vitro cytotoxicity against the breast (MCF-7), melanoma (B16) and endothelioma (sEnd.2) cell lines. All of the compounds except 4h and 4i were found to be inactive against the three cancer cell lines. Compound 4h substituted with a 4-methoxyphenyl and 4-fluorophenyl groups at the 3- and 5-positions was found to exhibit significant cytotoxicity against the three cancer cell lines. The presence of phenyl and 3-chlorophenyl groups at the 3- and 5-posiitons of the pyrroloquinazolinone 4i, on the other hand, resulted in significant cytotoxicity against vascular tumour endothelial cells (sEnd.2), but reduced activity against the melanoma (B16) and breast cancer (MCF-7) cells except at higher concentrations. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–l were found to be inactive against the chloroquine sensitive 3D7 strain of Plasmodium falciparum.

Synthesis of Quinolines through Three-Component Cascade Annulation of Aryl Diazonium Salts, Nitriles, and Alkynes.

An efficient and rapid synthesis of multiply substituted quinolines is described. This method is enabled by a three-component cascade annulation of readily available aryl diazonium salts, nitriles, and alkynes. This reaction is catalyst- and additive-free. Various aryl diazonium salts, nitriles, and alkynes can participate in this transformation, and the yields are up to 83%.