Palladium-catalyzed Coupling Research Articles

Ring-Enlargement of in Situ Generated Cyclopropanones by the Reaction with Sulfonium Ylides: One-Pot Synthesis of Cyclobutanones.

In this report, we describe a simple method for the synthesis of 2-aryl-2-vinyl-cyclobutanones through the reaction of in situ generated cyclopropanones and cinnamylsulfonium ylides, representing an example of a formal carbene insertion into these three-membered rings. The cyclobutanones thus obtained are ideal substrates for palladium-catalyzed coupling reactions upon enol triflate formation, thereby providing access to densely functionalized cyclobutenes. A mechanistic proposal for the ring-enlargement is presented based on experimental evidence.

Synthesis of Indole- and Benzofuran-Based Benzylic Sulfones by Palladium-Catalyzed Sulfonylation of ortho-Iodoaryl Allenes.

A highly efficient palladium-catalyzed domino coupling reaction of ortho-iodoaryl allene with sodium sulfonates under mild conditions is described. This novel method provides a practical protocol to access diverse indole- and benzofuran-containing sulfones by simultaneous construction of C(sp2)-C(sp2) bond and a C(sp3)-S bonds in one pot. The salient features of this transformation include simple operations, broad substrate scope, and good functional group tolerance.

C-C Coupling in sterically demanding porphyrin environments.

Unlike their planar counterparts, classic synthetic protocols for C-C bond forming reactions on nonplanar porphyrins are underdeveloped. The development of C-C bond forming reactions on nonplanar porphyrins is critical in advancing this field of study for more complex porphyrin architectures, which could be used in supramolecular assemblies, catalysis, or sensing. In this work a library of arm-extended dodecasubstituted porphyrins was synthesized through the optimization of the classic Suzuki-Miyaura coupling of peripheral haloaryl substituents with a range of boronic acids. We report on palladium-catalyzed coupling attempts on the ortho-, meta-, and para-meso-phenyl position of sterically demanding dodecasubstituted saddle-shaped porphyrins. While para- and meta-substitutions could be achieved, ortho-functionalization in these systems remains elusive. Furthermore, borylation of a dodecasubstituted porphyrin's meso-phenyl position was explored and a subsequent C-C coupling showed the polarity of the reaction can be reversed resulting in higher yields. X-ray analysis of the target compounds revealed the formation of supramolecular assemblies, capable of accommodating substrates in their void.

Exploring C2 and N6 Substituent Effects on Truncated 4'-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands.

Based on high binding affinity of truncated 2-hexynyl-4'-thioadenosine (3a) at both A2A adenosine receptor (AR) and A3 AR, we explored structure-activity relationship (SAR) of the C2-substitution by altering chain length of the 2-hexynyl moiety, thereby evaluating the hydrophobic pocket size. A series of truncated N6-substituted 4'-thioadenosine derivatives with C2-alkynyl substitution were successfully synthesized from D-mannose, using a palladium-catalyzed Sonogashira coupling reaction as the key step, whose structures were confirmed by the X-ray crystal structure of 4h. As the size of the alkynyl group at the C2-position increased, the binding affinity improved; however, when the substituted group was larger than hexynyl, the binding affinity decreased. The introduction of a bulky hydrophobic group such as 3-halobenzyl group at the free N6-amino group decreased the binding affinity at hA2AAR. These results confirm our previous findings that a free amino group at N6-position and longer hydrophobic chain at C2-position are essential for hA2A AR binding affinity. The introduction of a bulky hydrophobic group at free N6-amino group maintained the binding affinity at hA3 AR. The binding mode of truncated 2-substituted-4'-thioadenosine derivatives to hA2A and hA3 AR were predicted by a molecular docking study.

Thienothiophene and benzothiadiazole based conjugated donor-acceptor polymers; synthesis, photophysical properties and organic field effect transistor applications

Novel conjugated donor-acceptor (D-A) type polymers (P1-P3) possessing thieno[3,2-b]thiophenes (TT) as donors having different functional groups and 2,1,3-benzothiadiazole (BT) as an acceptor were designed and synthesized via palladium-catalyzed Sonogashira coupling reaction. Their electronic and optical properties were investigated by UV–Vis and fluorescence spectroscopies and cylic voltammetry analysis. Organic field-effect transistor (OFET) of the polymers were fabricated using biodegradable and environmental-friendly khaya gum as a high dielectric layer to investigate their charge transport characteristics were at low voltage. All the polymers displayed a p-type field-effect behaviour, among which alkyl chain (C9H19) substituted P2 exhibited the highest average saturated hole mobility, μsat, 0.086 cm2 V−1 s−1, on/off current ratio, Ion/Ioff = 1.0 × 103, and subthreshold swing, SS, 425 mV dec−1. The results presented in this work corroborate that the three novel TT-BT polymers have promising potential for electronic and optoelectronic applications, in particular, where tunability of the field-effect behaviour is essential for performance.

Palladium-Catalyzed Cross-Electrophile Couplings of Aryl Thianthrenium Salts with Aryl Bromides via C-S Bond Activation.

We report here a step-economic and cost-effective cross-electrophile coupling of aryl thianthrenium salts with widely available aryl bromides, which proceeded effectively via C-S bond activation at ambient temperature in THF in the presence of a palladium catalyst, magnesium turnings, and lithium chloride to enable the facile assembly of a wide array of structurally diverse biaryls in modest to good yields with good functional group compatibility. In addition, the gram-scale reaction could also be realized.

A novel propiolate-enabled deaminative hiyama coupling of aryl silanes and propargylamines

The development of general approaches for the regioselective construction of propargylic derivatives from propargylic electrophiles remains a formidable challenge in synthetic chemistry. Enabled by the newly developed propiolate-enabled C−N activation, we disclosed an efficient palladium-catalyzed deaminative Hiyama coupling of propargylamines with aryl silanes under microwave irradiation. Various structurally diverse propargyl derivatives are produced in good to excellent yields, utilizing propargylamines as propargylic electrophiles in which C−N bond was activated by in situ formed propargylic ammonium salts. The salient features of this protocol include readily or easily available feedstock, broad substrate scope, single-step preparation, and high regioselectivity.

Palladium-catalyzed desymmetric coupling reaction between silacyclobutanes and terminal alkynes for the synthesis of silicon-stereogenic allyl vinylsilanes

A palladium/TADDOL-derived phosphonate catalyzed desymmetric ring-opening coupling bewteen prochiral silacyclobutanes and alkyl terminal alkynes was developed. This catalytic system facilitates the formation of optically active allyl vinylsilane compounds featuring a quaternary silicon-stereogenic center, achieving good to high yields and moderate to good enantiomeric ratios. This approach significantly broaden the scope of ring-opening desymmetrization reactions involving silacyclobutanes under transition metal catalysis.

Iron-catalyzed synthesis of substituted 3-arylquinolin-2(1H)-ones via an intramolecular dehydrogenative coupling of amido-alcohols.

Here we report an iron-complex-catalyzed synthesis of various mono- and di-substituted quinolin-2(1H)-ones achieved via the intramolecular acceptorless dehydrogenative cyclization of amido-alcohols. This approach for the synthesis of N-heterocycles has provided access to underdescribed disubstituted quinolinones and represents an alternative to the well-known palladium-catalyzed coupling reactions.

Palladium-Catalyzed Hiyama-Type Coupling of Thianthrenium and Phenoxathiinium Salts.

Here, we demonstrate palladium-catalyzed Hiyama-type cross-coupling reactions of aryl thianthrenium or phenoxathiinium salts. By employing stable and inexpensive organosilanes, the arylation, alkenylation, and alkynylation were realized in high efficiency using commercially available Pd(tBu3P)2 as the catalyst, thus providing a reliable method for preparation of biaryls, styrenes, and aryl acetylenes with a broad functional group tolerance under mild conditions. Given the accessibility of aryl thianthrenium or phenoxathiinium salts from simple arenes in a remarkable regioselective fashion, this protocol also provides an attractive approach for the late-stage modification of complex bioactive scaffolds.

Synthesis and photodynamic activity of new 5-[(E)-2-(3-alkoxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-2-phenyl-3H-indoles.

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.

Design and synthesis of new nicotinamide derivatives generated via Suzuki Miyaura coupling as potential anticancer hits targeting pancreatic cancer cell line MIA PaCa-2

Pancreatic cancer is one of the most fatal malignancies with low survival rate and spreads asymptomatically due to the intensive involvement and expression of PARP1 protein. Nicotinamide is recognised as an efficient ring system in the treatment of pancreatic cancer because of its uses in both cellular and biological processes. In this investigation, 3-methoxyphenyl nicotinamide derivatives were synthesised utilizing a palladium-catalysed Suzuki-Miyaura coupling, and their confirmation has been identified by spectroscopic techniques (HRMS, 1H NMR & 13C NMR). The confirmed compounds (5a-f) were introduced to in-vitro cytotoxic studies using the MTT assay, which demonstrated that 5d and 5f were potent against MIA PaCa-2 cell line with IC50 values of 26±1.21µM and 18.61±0.20µM. The compounds 5d and 5f were also examined against HEK 293 cells, which exhibited a diminished antiproliferative effect with an IC50 values of 82.6µM and 138.07µM, respectively. Consequently, 5d and 5f were found to be safer with reduced antiproliferative effect. The MTT assay results were validated by the molecular docking and ADMET studies, which revealed the binding affinities of compounds 5d and 5f are -9.1 and -9.4 Kcal/mol. Overall, the designed and synthesised conjugates 5d and 5f demonstrated a viable lead for the investigation of new chemotherapeutic drugs against pancreatic cancer in this study.

Phase transfer catalysts shift the pathway to transmetalation in biphasic Suzuki-Miyaura cross-couplings

The Suzuki-Miyaura coupling is a widely used C-C bond forming reaction. Numerous mechanistic studies have enabled the use of low catalyst loadings and broad functional group tolerance. However, the dominant mode of transmetalation remains controversial and likely depends on the conditions employed. Herein we detail a mechanistic study of the palladium-catalyzed Suzuki-Miyaura coupling under biphasic conditions. The use of phase transfer catalysts results in a remarkable 12-fold rate enhancement in the targeted system. A shift from an oxo-palladium based transmetalation to a boronate-based pathway lies at the root of this activity. Furthermore, a study of the impact of different water loadings reveals reducing the proportion of the aqueous phase increases the reaction rate, contrary to reaction conditions typically employed in the literature. The importance of these findings is highlighted by achieving an exceptionally broad substrate scope with benzylic electrophiles using a 10-fold reduction in catalyst loading relative to literature precedent.

P,N-Coordinating Ylide-Functionalized Phosphines (NYPhos): A Ligand Platform for the Selective Monoarylation of Small Nucleophiles.

Palladium-catalyzed coupling reactions of small nucleophiles are of great interest, but challenging due to difficulties in selectivity control. Herein, we report the development of a new platform of P,N-ligands consisting of ylide-functionalized phosphines with aminophosphonium groups (NYPhos) to address this challenge. These phosphine ligands are easily accessible in a wide structural diversity with highly modular electronic and steric properties. Based on a family of 14 ligands the selective monoarylation of acetone as well as other challenging ketones and amides was accomplished with record-setting activities even for aryl chlorides at room temperature including late-stage functionalizations of drug molecules. Moreover, ammonia and other small primary amines could be coupled at mild conditions. Isolation and structure analyses of palladium complexes within the catalytic cycle confirmed that the P,N-coordination mode is necessary to achieve the observed selectivities. It also demonstrated the facile adjustability of the N-donor strength, which is beneficial for the targeted design of tailored P,N-ligands for future applications.

5-Trifluoromethoxy-substituted Nicotinic Acid, Nicotinamide and Related Compounds

A practical and convenient method for synthesizing nicotinic acid and nicotinamide with the trifluoromethoxy group in position 5 of the ring has been developed. A series of related compounds, for example, nicotinic aldehyde and nicotinic alcohol, have been synthesized. It has been shown that 3-bromo-5-trifluoromethoxypyridine is a convenient and efficient synthon for palladium-catalyzed coupling reactions. The trifluoromethoxy group has been found to be remarkably stable against hydroiodic acid in contrast to the methoxy group.

Synthesis of Unsymmetrically Condensed Benzo- and Thienotriazologermoles.

Germoles and siloles unsymmetrically condensed with heteroaromatic units are attracting much interest. In this study, compounds containing a triazologermole core unit condensed with a benzene or thiophene ring were prepared. Thienotriazologermole was subjected to bromination to obtain the bromide, which underwent transformation via the palladium-catalyzed Stille coupling reaction to form triphenylamine-substituted thienotriazolegermole, with an effective extension of conjugation. The electronic states and properties of these triazologermole derivatives are discussed on the basis of optical and electrochemical measurements and density functional theory calculations. Triphenylamine-substituted thienotriazolegermole showed clear solvatochromic properties in photoluminescence measurements, suggesting that intramolecular charge transfer occurs at the photo-excited state. This clearly indicates that the triazologermole unit is useful as an acceptor of donor-acceptor compounds. The potential application of triphenylamine-substituted thienotriazolegermole as a sensing material was also explored.

Recyclable Palladium-Catalyzed Carbonylative Coupling of Aryl Halides and Organoaluminum Compounds with tert-Butyl Iso­cyanide as CO Equivalent Leading to 1,2-Diketones

AbstractAn efficient heterogeneous palladium-catalyzed carbonylative coupling of aryl halides and organoaluminum compounds has been developed using tert-butyl isocyanide as CO equivalent. The carbonylation reaction proceeds smoothly in toluene with KOtBu as a base at 100 °C by using 10 mol% of an SBA-15-anchored bidentate phosphine palladium(0) complex [2P-SBA-15-Pd(0)] as the catalyst and provides a general and practical approach for the assembly of 1,2-diketones in good to excellent yields. This heterogenized palladium catalyst can be readily separated and recovered via a simple centrifugation process and reused for more than seven cycles with almost consistent catalytic efficiency.

Stereoselective Synthesis of C-Aryl Glycosides via Palladium-Catalyzed Heck Coupling

Stereoselective Synthesis of C-Aryl Glycosides via Palladium-Catalyzed Heck Coupling

Synthesis and Evaluation of diaryl ether modulators of the leukotriene A4 hydrolase aminopeptidase activity

Activation of the aminopeptidase (AP) activity of leukotriene A4 hydrolase (LTA4H) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC50 of 0.12 μM. An X-ray crystal structure of LTA4H in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTA4H, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B4 (LTB4) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.

Photoinduced Palladium-Catalyzed Radical Heck-Type Coupling of Cyclobutanone Oxime Esters with Vinyl Arenes.

A palladium-catalyzed radical Heck-type coupling reaction of cyclobutanone oxime esters with olefins under visible-light irradiation has been developed. The cyanoalkyl/Pd(I) hybrid species generated by selected ring-opening C-C bond cleavage of imino/Pd(I) species reacted smoothly with vinyl arenes, delivering the cyanoalkylation olefins under mild conditions. This elegant strategy has a broad scope and functional group tolerance. Subsequently, late-stage functionalization of bioactive molecules and synthetic transformations of the product further confirm the practicality.