Pd-catalyzed Cross-coupling Research Articles

Pd-catalyzed cross-coupling of arabinogalactan propargyl ethers with 5-bromosalicylic acid

New salicylate derivatives of arabinogalactan have been synthesized in up to 90% yield by cross-coupling of propargyl ethers of arabinogalactan with 5-bromosalicylic acid salts. The reaction proceeds in the presence of the catalytic system Pd(PPh3)4/PPh3 with CuBr (CuI), and piperidine or 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) as a base in DMSO at 70–95 °С. The propargyl groups of the starting arabinogalactan ethers are converted into propinylsalicylate ones with 35 and 50% conversion depending on the nature of the base used. Degree of arabinogalactan substitution with propynyl salicylate fragments reaches 1.0 and 0.7 in the reactions with piperidine and DBU, respectively. In the case of piperidine, along with the main process, intensive unprecedented (for Sonogashira reaction) hydroamination of propargyl groups is also observed, followed by hydrolysis of unstable enamines. The products have been characterized by IR, 1Н and 13С NMR, UV spectroscopy as well as elemental analysis and gel permeation chromatography. Salicylate derivatives of arabinogalactan show high activity in prolonging the activated partial thromboplastin time (APTT), whereas neither the arabinogalactan nor propargyl ethers of arabinogalactan nor salicylic acid salts have obvious effects.

Cross-Coupling Reactions of Nitroarenes

Cross-coupling reactions are powerful synthetic tools to construct diverse chemical bonds often found in, for example, advanced materials and pharmaceuticals. Since their discovery, haloarenes have habitually been used as electrophilic coupling partners both in academic and industrial contexts. However, concerning the efficiency and the often-negative environmental impact of haloarene-based cross-coupling processes, more readily available, inexpensive, and environmentally friendly electrophiles have been explored.Nitroarenes, for example, are obtained from the facile nitration of aromatic compounds and, thus, represent one of the most easy-to-access feedstock electrophiles. Furthermore, their electron-deficient arene core can be functionalized easily and site-selectively through a wide variety of reactions. Yet, despite these advantages and even though the direct transformation of the NO2 group would be an attractive option in cross-coupling chemistry, it has so far remained difficult to convert nitroarenes via a cleavage of the Ar-NO2 bond given the inherent reactivity (or the lack thereof) of the nitro group. Such denitrative conversion has been performed by a conventional sequence of reduction, diazotization, and Sandmeyer reactions, which severely lacks efficiency and generality.This Account summarizes our recent research progress on cross-coupling reactions that employ nitroarenes as electrophiles. First, we developed the Suzuki-Miyaura coupling of nitroarenes using a palladium/BrettPhos catalyst. This reaction proceeds via an (at the time) unprecedented oxidative addition of the Ar-NO2 bond, which was supported by experimental results and theoretical calculations. A widely accepted catalytic cycle for Pd-catalyzed cross-couplings has since been extended to include nitroarenes as electrophiles, which significantly increases substrate generality. Second, this denitrative coupling protocol was applied to various bond-forming reactions, namely, Buchwald-Hartwig amination, etherification, and hydrogenation reactions. Such diversification has enhanced the utility of nitroarenes as cross-coupling partners. To develop each reaction, it was necessary to modify the reaction conditions as required to overcome the obstacles deriving from nitro functionality including transmetalation and side reactions, as well as oxidative addition. Third, we designed a new Pd/NHC catalyst that exhibits higher activity than Pd/BrettPhos. The improved performance of Pd/NHC system was supported by its strong electron-donicity and structural robustness, and it allows the reduction of the catalyst loading significantly, thus increasing the efficacy and practicality of this method.The field of nitroarene-based cross-coupling has just started to flourish. In addition to our original work, several research groups have already adopted Pd/BrettPhos or Pd/NHC catalysts to develop new denitrative functionalizations. The utility of nitroarenes in the context of organic synthesis should be now revisited.

Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source.

Catalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chemistry since the obtainable nitrogen-containing motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclinical candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepared independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, especially by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addition to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions.This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- versus outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temperature. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chemistry via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decomposition, thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chemical space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.

Palladium-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes: Switching Regioselectivity via Simple Hydrazones.

Conventional approaches for Pd-catalyzed ring-opening cross-couplings of gem-difluorocyclopropanes with nucleophiles predominantly deliver the β-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner-sphere 3,3'-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N-heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem-difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated α-fluorinated alkene motifs under mild conditions.

Mechanism and Selectivity Control in Ni- and Pd-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bond Activation.

Transition-metal-catalyzed C-O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C-O bond activation and functionalization methods.Toward the rational design of C-O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C(sp2)-O and C(sp3)-O bond activations. We found that the nickel catalyst cleaves the benzylic and allylic C(sp3)-O bonds via two general mechanisms: the stereoinvertive SN2 back-side attack model and the stereoretentive chelation-assisted model. These two models control the stereochemistry in a wide array of stereospecific Ni-catalyzed cross-coupling reactions with benzylic or allylic alcohol derivatives. Because of the catalyst distortion, the ligands can differentiate the competing stereospecific C(sp3)-O bond activations. The PCy3 ligand interacts with nickel mainly through σ-donation, and the Ni(PCy3) catalyst can undergo facile bending of the substrate-nickel-ligand angle, which favors the stereoretentive benzylic C-O bond activation. The N-heterocyclic carbene SIMes ligand has additional d(metal)-p(ligand) back-donation with nickel, which leads to an extra energy penalty for the same angle bending. This results in the preference of stereoinvertive benzylic C-O bond activation under Ni/SIMes catalysis. In addition to ligand control, a Lewis acid can increase the selectivity for stereoinvertive C(sp3)-O activation by stabilizing the SN2 back-side attack transition state. The oxygen leaving group complexes with the MgI2 Lewis acid in the stereoinvertive activation, leading to the exclusive stereoinvertive Kumada coupling of benzylic ethers. We also identified that the competing C(sp3)-O bond activation models have noticeable differences in charge separation. This leads to the solvent polarity control of the stereospecificity in C(sp3)-O activations. Low-polarity solvents favor the neutral stereoretentive C-O bond activation, while high-polarity solvents favor the zwitterionic stereoinvertive cleavage.In sharp contrast to the nickel catalysts, the C(sp2)-O bond activation under palladium catalysis mainly proceeds via the classic three-membered ring oxidative addition mechanism instead of the chelation-assisted mechanism. This is due to the lower oxophilicity of palladium, which disfavors the oxygen coordination in the chelation-assisted-type activation. The three-membered ring activation model selectively cleaves the weak C-O bond, resulting in the exclusive chemoselectivity of acyl C-O bond activation in Pd-catalyzed cross-coupling reactions with aryl carboxylic acid derivatives. This explains the overall acylation in the Pd-catalyzed Suzuki-Miyaura coupling with aryl esters. In collaboration with the Szostak group, we revealed that the three-membered ring model applies in the Pd-catalyzed C-O bond activation of carboxylic acid anhydride, which stimulated the development of a series of Pd-catalyzed decarbonylative functionalizations of aryl carboxylic acids.

Synthesis of Novel Methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates and Antitumor Activity Evaluation: Studies In Vitro and In Ovo Grafts of Chick Chorioallantoic Membrane (CAM) with a Triple Negative Breast Cancer Cell Line.

A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a–2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines—MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 μM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.

Macrocyclic Arenes-Based Conjugated Macrocycle Polymers for Highly Selective CO2 Capture and Iodine Adsorption.

Incorporating synthetic macrocycles with unique structures and distinct conformations into conjugated macrocycle polymers (CMPs) can endow the resulting materials with great potentials in gas uptake and pollutant adsorption. Here, four CMPs (CMP-n, n=1-4) capable of reversibly capturing iodine and efficiently separating carbon dioxide are constructed from per-triflate functionalized leaning tower[6]arene (LT6-OTf) and [2]biphenyl-extended pillar[6]arene (BpP6-OTf) via Pd-catalyzed Sonogashira-Hagihara cross-coupling reaction. Intriguingly, owing to the appropriate cavity size of LT6-OTf and the numerous aromatic rings in the framework, the newly designed CMP-4 possesses an outstanding I2 affinity with a large uptake capacity of 208 wt % in vapor and a great removal efficiency of 94 % in aqueous solutions. To our surprise, with no capacity to accommodate nitrogen, CMP-2 constructed from BpP6-OTf is able to specifically capture carbon dioxide at ambient conditions.

Iodo(III)-Meyer-Schuster Rearrangement of Propargylic Alcohols Promoted by Benziodoxole Triflate.

Benziodoxole triflate (BXT), a cyclic iodine(III) electrophile, has been found to promote a rearrangement of propargylic alcohols into α,β-unsaturated ketones bearing an α-λ3-iodanyl group. This iodo(III)-Meyer-Schuster rearrangement proceeds under mild conditions and tolerates a variety of functionalized propargylic alcohols, thus complementing previously reported halogen-intercepted Meyer-Schuster rearrangement. The α-λ3-iodanylenones can be utilized for facile Pd-catalyzed cross-coupling for the synthesis of multisubstituted enones.

Germatranes and carbagermatranes: (hetero)aryl and alkyl coupling partners in Pd-catalyzed cross-coupling reactions.

In the past few decades, palladium-catalyzed cross-coupling reactions have taken root in the construction of a complex synthetic community. The development of organometallics has been an important objective in this field. Our group has focused on exploiting new germanium-based reagents and the corresponding catalytic processes. In the past three years, we have established new methods for the synthesis of structure-modified (hetero)aryl germatranes and alkyl carbagermatranes. Particularly for alkyl carbagermatranes, the stability to be compatible with various derivatization reactions and the high activity for transmetallation (e.g. base/additive-free for primary alkyl carbagermatranes) distinguish them from many reported nucleophiles. In this article, we would introduce (1) the development process of organogermanium reagents in palladium-catalyzed cross-couplings; (2) the history of germatrane-type systems and the breakthrough we have made in the field; (3) the outlook for (carba)germatranes and alkyl-GeMe3.

B-N bond formation through palladium-catalyzed, microwave-assisted cross-coupling of nitrogen compounds with iodo-dodecaborate.

Substituted undecahydrido-closo-dodecaborates [B12H11NR2]2- have potential use in materials and drugs, but have presented a synthetic challenge. Microwave-assisted palladium-catalyzed amination of iodo-dodecaborate [B12H11I]2- allows mild and reproducible formation of B-N bonds with aromatic amines, HN-containing heteroaromatics, and amides. The reaction allows general access to amides, reproducible reactions to dodecaborate-substituted anilines, and, for the first time, the substitution of dodecaborate with HN-containing heterocycles.

A mechanistic investigation of the Pd-catalyzed cross-coupling between N-tosylhydrazones and aryl halides.

The cross-coupling of N-tosylhydrazones and aryl halides forms carbon-carbon bonds, producing 1,1-disubstituted alkenes. Though it has proven extremely useful in several fields of chemistry, its mechanism remains experimentally unexplored. Combining benchtop NMR and real-time mass spectrometry afforded the ability to monitor the catalytic intermediates as well as the rate of product formation.

Highlights: Multilingual Safety Resources, Pd-Catalyzed Cross-Coupling Reactions, Ethylene Glycol Purification, and More

Highlights: Multilingual Safety Resources, Pd-Catalyzed Cross-Coupling Reactions, Ethylene Glycol Purification, and More

Organogermanes as Orthogonal Coupling Partners in Synthesis and Catalysis.

Since the advent of metal-catalyzed cross-coupling technology more than 40 years ago, the field has grown to be ever-increasingly enabling, yet the employed coupling partners are largely still those that were originally employed in the context of Pd-catalyzed cross-coupling, namely, arylboronic esters/acids, aryl silanes, aryl stannanes, or organometallic reagents (RMgX, RZnX). Aryl germanes have little precedent in the literature; they were historically explored in the context of Pd0/PdII-catalyzed cross-coupling reactions but were found to be much less reactive than the already established reagents. Consequently, few efforts were made by the community on their further mechanistic or synthetic exploration.In 2019, our group described trialkyl aryl germanes as robust, convenient, and nontoxic reagents. Although structurally similar to trialkyl aryl stannanes or silanes, the GeEt3 site does not engage in the traditional transmetalation mode of PdII complexes. Our studies instead provided strong support for an unprecedented and orthogonal reactivity of organogermanes that follows electrophilic aromatic substitution (SEAr)-type reactivity. This mode of bond activation allowed us to devise a number of synthetic strategies in which the Ge functionality was for the first time more reactive and exclusively functionalized in preference over several of the established coupling partners (e.g., silanes, boronic acids/esters, halogens).Within the past year we have showcased the unique reactivity of organogermanes in C-C and C-X bond-forming transformations. Because of the exquisite mode of bond activation, the new strategies offer access to complementary chemical transformations, tolerating other cross-coupling enabling functionalities, and allow for their further downstream diversification. We have for instance demonstrated that organogermanes can be coupled efficiently with aryl halides under Pd nanoparticle conditions with tolerance of all other established cross-coupling partners, while under homogeneous Pd0/PdII catalysis all of the other established groups can be functionalized preferentially over the Ge functionality. We similarly were able to harness this orthogonal reactivity mode in oxidative gold catalysis, where organogermanes proved to be more reactive than the established silanes or boronic esters. We have also developed an orthogonal approach for metal-free halogenation of organogermanes with convenient halogenation agents, offering access to the chemo- and regioselective installation of valuable halide motifs in the presence of alternative groups that can also engage in electrophilic halogenations.In this Account, we wish to provide an overview of (i) the historic versus current reactivity findings and synthetic utility of organogermanes, (ii) the current state of mechanistic understanding of their reactivity, and (iii) the synthetic repertoire and ease of installing the germanium functionality in organic molecules.

Synthetic Studies towards the Total Synthesis of Indole Alkaloids Containing Indolyl Lactam Frameworks

AbstractIn this account, recent progress on the synthetic studies of several monoterpene indole alkaloids, (±)-mersicarpine, misassigned (±)-tronoharine, and (±)-leuconodines D and E, is summarized. Specifically, the rationale for the design and development of the Lewis acid catalyzed SN1-type substitution and formal [3+3] cycloaddition reaction of indol-2-yl carbinols, and the Pd-catalyzed aerobic oxidative intramolecular Heck cross-coupling of indolyl amides tethered with a terminal olefin functionality, are emphasized. These key reactions set the basis for the rapid construction of the fused ring skeleton containing an all-carbon quaternary center at the indol-2-yl position.1 Introduction2 Synthetic Study of (±)-Mersicarpine3 Synthetic Study of the Misassigned (±)-Tronoharine4 Study of the Asymmetric Reaction of Indol-2-yl Carbinols5 Synthetic Study of (±)-Leuconodines D and E6 Conclusion

An efficient Pd-catalyzed intramolecular cyclization reaction followed by formation of benzimidazole derivatives: Synthesis of novel quinolin-fused benzo[d] azeto[1,2-a]benzimidazole analogues

Novel quinolin-fused benzo[d]azeto[1,2-a]benzimidazole analogues have been synthesized from o-phenylene diamine and various substituted 2-chloro-5-(2-methylquinoline-4-yl) benzaldehyde through Pd-mediated simultaneous CH–NH and CH–CX bond activation via intramolecular cyclization reaction followed by formation of benzimidazole derivatives. Developed two step, one pot route for quinoline fused four membered azeto[1,2-a] benzimidazole derivatives through Pd-catalyzed cross coupling reaction. The synthesis was carried out by using Pd2(dba)3 as a catalyst, Xphos as a ligand, Cs2CO3 as a base and toluene as a solvent and developed its mechanistic pathway.

One-Pot Alkene Hydroboration/Palladium-Catalyzed Migratory Suzuki–Miyaura Cross-Coupling

Chain-walking is a powerful approach towards the functionalization of C–H bonds remote to a functional group. Whereas various Pd-catalyzed migratory cross-couplings have been developed in the past ...

Decarbonylative Suzuki-Miyaura Cross-Coupling of Aroyl Chlorides.

Herein, we report a catalyst system for Pd-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of aroyl chlorides with boronic acids to furnish biaryls. This strategy is suitable for a broad range of common aroyl chlorides and boronic acids. The synthetic utility is highlighted in the direct late-stage functionalization of pharmaceuticals and natural products capitalizing on the presence of carboxylic acid moiety. Extensive mechanistic and DFT studies provide key insight into the reaction mechanism and high decarbonylative cross-coupling selectivity.

Total Synthesis and Structure–Activity Relationship Studies of Phelligridins C and D, and Phellifuropyranone A

Abstract α-Pyrone polyphenols, phelligridins C and D (meshimakobnols B and A), and phellifuropyranone A, isolated from a Japanese mushroom, are growth inhibitors of cancer cells. Herein, we report full details of the total synthesis of phelligridins C and D. The key reactions of the synthetic pathways were Pd catalyzed cross-coupling and aldol-type condensation. This strategy also enabled the total synthesis of phellifuropyranone A and artificial analogs of phelligridins. Subsequent biological evaluation of these compounds clarified that the whole skeleton of phelligridin C and the catechol group of the left hand side are essential for the cytotoxicity.

Selective Arylation of 2-Bromo-4-chlorophenyl-2-bromobutanoate via a Pd-Catalyzed Suzuki Cross-Coupling Reaction and Its Electronic and Non-Linear Optical (NLO) Properties via DFT Studies.

In the present study, 2-bromo-4-chlorophenyl-2-bromobutanoate (3) was synthesized via the reaction of 2-bromo-4-chlorophenol with 2-bromobutanoyl bromide in the presence of pyridine. A variety of 2-bromo-4-chlorophenyl-2-bromobutanoate derivatives (5a–f) were synthesized with moderate to good yields via a Pd-catalyzed Suzuki cross-coupling reaction. To find out the reactivity and electronic properties of the compounds, Frontier molecular orbital analysis, non-linear optical properties, and molecular electrostatic potential studies were performed.

Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates.

Carboxylate esters have many desirable features as electrophiles for catalytic cross-coupling: they are easy to access, robust during multistep synthesis, and mass-efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non-aromatic electrophiles, remain difficult to functionalize through cross-coupling. We demonstrate that Pd catalysis is effective for coupling electron-deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C-O bond activation. A Pd0/II catalytic cycle is viable when using a Pd0 precatalyst, with turnover-limiting C-O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β-carboxyl elimination is proposed for PdII precatalysts. This work provides a clear path toward engaging myriad oxygen-based electrophiles in Pd-catalyzed cross-coupling.