Biaryl Derivatives Research Articles

Caffeine and theophylline as sustainable, biosourced NHC ligand precursors for efficient palladium-catalyzed Suzuki–Miyaura cross-coupling reactions

• Caffeine and theophylline were used as biosourced NHC ligand precursors. • Three [PdX 2 (NHC)(Py)] complexes were synthesized and fully characterized. • These Pd-PEPPSI catalysts were tested in Suzuki–Miyaura cross-coupling reactions. • The reactions were successfully conducted in a green, water-based solvent mixture. • Only a low catalyst loading (0.25 mol%) and a weak inorganic base (K 2 CO 3 ) were required. The alkylation of caffeine with methyl iodide afforded 1,3,7,9-tetramethylxanthinium iodide, which was further reacted with PdCl 2 , KI, and K 2 CO 3 in neat pyridine to afford the [PdI 2 (NHC)(Py)] complex 1 in two steps and 73% overall yield. An intermediate anion exchange afforded the corresponding dichlorido complex 2 in 70% overall yield. Theophylline was successfully converted into a new xanthinium salt bearing an isobutyl group on its N7 atom, which was further employed to prepare the [PdCl 2 (NHC)(Py)] complex 3 . These three Pd-PEPPSI catalyst precursors were fully characterized and the molecular structure of complex 2 was determined. Complexes 1 – 3 displayed a high catalytic activity in the Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic acids. Aryl bromides and iodides bearing either electron-donating or withdrawing substituents afforded a wide range of biaryl derivatives that were isolated in 40–93% yields (30 examples). The reactions required only a low catalyst loading (0.25 mol%) and were carried out in a green, water-based solvent mixture using K 2 CO 3 as a base in the presence of air. Although less reactive, aryl chlorides were also successfully activated under more forcing conditions, provided that an electron-withdrawing group was present on their aromatic ring. The alkylation of caffeine with methyl iodide afforded 1,3,7,9-tetramethylxanthinium iodide, which was further reacted with PdCl 2 , KI, and K 2 CO 3 in neat pyridine to afford the [PdI 2 (NHC)(Py)] complex 1 in two steps and 73% overall yield. An intermediate anion exchange afforded the corresponding dichlorido complex 2 in 70% overall yield. Theophylline was successfully converted into a new xanthinium salt bearing an isobutyl group on its N7 atom, which was further employed to prepare the [PdCl 2 (NHC)(Py)] complex 3 . These three Pd-PEPPSI catalyst precursors were fully characterized and the molecular structure of complex 2 was determined. Complexes 1 – 3 displayed a high catalytic activity in the Suzuki–Miyaura cross-coupling of aryl halides with phenylboronic acids. Aryl bromides and iodides bearing either electron-donating or withdrawing substituents afforded a wide range of biaryl derivatives that were isolated in 40–93% yields (30 examples). The reactions required only a low catalyst loading (0.25 mol%) and were carried out in a green, water-based solvent mixture using K 2 CO 3 as a base in the presence of air. Although less reactive, aryl chlorides were also successfully activated under more forcing conditions, provided that an electron-withdrawing group was present on their aromatic ring.

Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp2/sp3γ‐C−H and sp2δ‐C−H Functionalization of Carboxamides

AbstractWe have shown our efforts toward expanding the utility of the relatively inexpensive pyridine‐N‐oxide directing group in the Pd(II)‐catalyzed site‐selective γ‐C(sp2)−H, γ‐C(sp3)−H and δ‐C(sp2)−H functionalization. The functionalization β−C−H bonds using bidentate directing group (DG) pyridine‐N‐oxide which operates through the N,O‐coordination mode has been well documented in the literature. However, there exist rare reports dealing with the functionalization of remote sp2/sp3 γ‐ and δ‐C−H bonds of carboxamides assisted by the bidentate directing groups operating via the N,O‐coordination. In this paper, the scope of pyridine‐N‐oxide DG was examined for accomplishing the site‐selective (mono) γ‐C(sp2)−H arylation in substrates containing competitive C(sp3)−H and C(sp2)−H bonds. The investigation has enabled to assemble a library of pyridine‐N‐oxide‐based biarylacetamides, heteroaryl‐based biaryl carboxamides, tricyclic quinolones, arylheteroarylmethanes, biaryl‐based aliphatic carboxamides and mono (ortho) arylated phenylglycine derivatives. In general, biaryl derivatives and in particular, arylacetamide, arylacetic acid derivatives and pyridine‐N‐oxide (2‐aminopyridyl) motifs are medicinally relevant classes of compounds. This work enabled the assembling of a library of the above‐mentioned types of compounds through the pyridine‐N‐oxide directing group‐aided site‐selective sp2/sp3 γ‐C−H and sp2 δ‐C−H functionalization of carboxamides.

Ni/g‐C3N4 Photocatalysis: Aerobic Oxidative Coupling Reaction Leading to Amidation of Aldehydes with Amines and C−N, C−O, and C−C Cross‐Coupling Reaction

AbstractDual nickel/carbon nitride (Ni/g‐C3N4) photocatalyst was employed for the synthesis a wide range of amide derivatives by cross‐coupling reaction of benzamides with aryl halides. Also, oxidative amidation of aromatic and aliphatic aldehydes with primary and secondary amines has been investigated. The synthesis of various derivatives of esters was performed based on the cross‐coupling reaction between carboxylic acids with aryl halides. Surprisingly, decarboxylation of carboxylic acid derivatives occurred under ambient conditions for the synthesis of biaryl derivatives. The reactions were run solvent‐free or in environmental benignant solvents, with recyclable photocatalysts under irradiation.

Chiral Selenide/Achiral Sulfonic Acid Cocatalyzed Atroposelective Sulfenylation of Biaryl Phenols via a Desymmetrization/Kinetic Resolution Sequence.

Enantioselective synthesis of axially chiral sulfur-containing biaryl derivatives through the electrophilic sulfenylation of biaryl phenols has been achieved for the first time. This catalytic asymmetric system, which involves sequential desymmetrization and kinetic resolution, is enabled by a combination of a novel 3,3'-disubstituted BINOL-derived selenide catalyst and an achiral sulfonic acid. Control experiments and computational studies suggest that multiple noncovalent interactions between the cocatalysts and substrate, especially a network of hydrogen bond interactions, play a crucial role in determining the enantioselectivity and reactivity.

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Synthesis and Biological Evaluation of Trehalose-Based Bi-Aryl Derivatives as C-Type Lectin Ligands

Synthesis and Biological Evaluation of Trehalose-Based Bi-Aryl Derivatives as C-Type Lectin Ligands

Preparation and characterization of a Cu complex based on 2,2′-bipyrimidine as a recyclable metal-organic framework for Suzuki coupling

A Cu complex based on 2,2′-bipyrimidine ([CuBpm·2H2O]n) as a recyclable metal-organic framework (MOF) was used for the synthesis of biaryl derivatives by the Suzuki coupling reaction. The Suzuki reaction was performed with mixing of aryl halides with arylboronic acids in DMSO. The prepared catalyst was characterized by FT-IR, XRD, SEM, EDX, BET, BJH and ICP-AES analysis. [CuBpm·2H2O]n as catalyst demonstrated good to excellent yields for Suzuki reaction in comparison with other catalysts. The catalyst was recovered by a simple filtration and retained its activity even after several cycles.

PdII on Guanidine-Functionalized Fe3O4 Nanoparticles as an Efficient Heterogeneous Catalyst for Suzuki-Miyaura Cross-Coupling and Reduction of Nitroarenes in Aqueous Media.

This paper presents guanidine-functionalized Fe3O4 magnetic nanoparticle-supported palladium (II) (Fe3O4@Guanidine-Pd) as an effective catalyst for Suzuki–Miyaura cross-coupling of aryl halides using phenylboronic acids and also for selective reduction of nitroarenes to their corresponding amines. Fe3O4@Guanidine-Pd synthesized is well characterized using FT-IR spectroscopy, XRD, SEM, TEM, EDX, thermal gravimetric analysis, XPS, inductively coupled plasma-optical emission spectroscopy, and vibrating sample magnetometry analysis. The prepared Fe3O4@Guanidine-Pd showed effective catalytic performance in the Suzuki–Miyaura coupling reactions by converting aryl halides to their corresponding biaryl derivatives in an aqueous environment in a shorter reaction time and with a meagerly small amount of catalyst (0.22 mol %). Also, the prepared Fe3O4@Guanidine-Pd effectively reduced nitroarenes to their corresponding amino derivatives in aqueous media at room temperature with a high turnover number and turnover frequency with the least amount of catalyst (0.13 mol %). The most prominent feature of Fe3O4@Guanidine-Pd as a catalyst is the ease of separation of the catalyst from the reaction mixture after the reaction with the help of an external magnet with good recovery yield and also reuse of the recovered catalyst for a few cycles without significant loss in its catalytic activity.

Suzuki−Miyaura coupling and O−arylation reactions catalysed by palladium(II) complexes of bulky ligands bearing naphthalene core, Schiff base functionality and biarylphosphine moiety

Schiff bases L1 [i.e., 2-(diphenylphosphino)-N-(naphthalen-1-ylmethylene)ethanamine], L2 [i.e., 2- (diphenylphosphino)-N-(naphthalen-2-ylmethylene)ethanamine], L3 [i.e., 2-(1-(2-(diphenylphosphino)ethylim- ino)ethyl)naphthalen-1-ol] and L4 [i.e., 2-((2-(diphenylphosphino)ethylimino)methyl)naphthalen-1-ol] have been synthesized using a straightforward methodology which involves a condensation reaction between H 2 N−CH 2 −CH 2 −PPh 2 and appropriate carbonyl compound. Due to the presence of diphenylphosphine (−PPh 2 ) moiety and >C = N− functionality, these compounds behave as ligands and undergo complexation reaction with palladium on treatment with Na 2 PdCl 4 to yield the palladium(II) complexes ( 1–4 ). Ligands as well as complexes have been characterized using standard NMR spectroscopic techniques. ESI−MS and single crystal X−ray diffraction studies corroborate the structures of complexes. Crystal structures of complexes 1−3 reveal clearly that the geometry around Pd centre is distorted square planar. Ligands L1 and L2 are coordinated to Pd centre in bidentate (P, N type) mode, however, L3 and L4 act as a tridentate (P,N,O type) ligand and bind with metal in anionic mode. The Pd P and Pd N bond distances in complexes 1−3 are in the ranges 2.204−2.212 Å and 2.023−2.072 Å, respectively. Complex 3 [i.e., PdCl( L3 −H)] also has a Pd-O bond, the length of which is found to be 2.009(3) Å. All the complexes have potential for catalysing O-arylation (C-O coupling) of phenol and Suzuki-Miyaura coupling (SMC) reactions. Both bromoarenes and chloroarenes can be used as substrates in Suzuki coupling and converted into biaryl derivatives. For O-arylation reactions of phenol, bromoarenes are used as arylating agents. For catalysis of such reactions (i.e., C-O coupling), high (0.1 mol%) catalyst loading is required. However, Suzuki reactions require low (0.001 mol%) loading of catalysts to occur with bromoarenes and give the products. The high potential of the complexes is also evident from the fact that they also convert different aryl chlorides into the coupled products in Suzuki coupling. 31 P{ 1 H} NMR data reveal that the electronic environments of nuclei of phosphorous donors are closely similar in all the four ligands. Similar magnitude of deshielding of the 31 P{ 1 H} signals in all the complexes indicate that, while forming the dative bond, the P donor of all the ligands transfer the electron density to the palladium to a similar extent. Hence, the electronic effects created by the ligands through the phosphorous donor are similar in all the complexes. Therefore, it is inferred that variation in their catalytic performance is because of difference in the binding mode of the ligand and/or minor alteration in the architecture of organic ligand. Amongst them, complex 2 shows the highest catalytic activity, and the least active catalyst is complex 3 for C-C coupling reactions. For C-O coupling reactions, the efficiencies of complexes 1 and 2 are slightly higher than those of complexes 3 and 4 .

Preparation and characterization of Cu based on 2-(5-Aminopyrimidin-2-yl)pyrimidin-5-amine as novel recyclable metal–organic frameworks for Suzuki reaction

• In this work, a new, heterogeneous and recyclable catalyst was designed using immobilizing Cu on 2-(5-Aminopyrimidin-2-yl)pyrimidin-5-amine ( [ CuAPPA·2H 2 O ] n ) named metal–organic frameworks (MOFs). • This catalyst was used for the synthesis of biaryl derivatives by Suzuki reaction. • The prepared catalyst was characterized with different analytical techniques such as FT-IR, XRD, SEM, EDX, BET and ICP-AES analysis. • The recoverability and reusability related to this catalyst was checked by a simple filtration with reserving its activity even after several cycles. For first time, in this work, a new, heterogeneous and recyclable catalyst was designed using immobilizing Cu on 2-(5-Aminopyrimidin-2-yl)pyrimidin-5-amine ( [ CuAPPA·2H 2 O ] n ) named metal–organic frameworks (MOFs). This catalyst was used for the synthesis of biaryl derivatives by Suzuki reaction. Suzuki reaction performed with mixing of the aryl halides with arylboronic acids in the DMF solvent conditions. Also, the prepared catalyst was characterized with different analytical techniques such as FT-IR, XRD, SEM, EDX, BET and ICP-AES analysis. [ CuAPPA·2H 2 O ] n catalyst displayed good to excellent yields catalytic efficiency for Suzuki reaction in comparison with to other catalysts. Also, the recoverability and reusability related to this catalyst was checked by a simple filtration with reserving its activity even after several cycles.

Water-Dispersible Pd–N-Heterocyclic Carbene Complex Immobilized on Magnetic Nanoparticles as a New Heterogeneous Catalyst for Fluoride-Free Hiyama, Suzuki–Miyaura and Cyanation Reactions in Aqueous Media

Pd–N-heterocyclic carbine complex immobilized on magnetic nanoparticles is synthesized and characterized by different techniques such as FT-IR, XPS, TEM, EDX, FESEM, VSM, TGA, and ICP. The synthesized catalyst was used as a new water dispersible heterogeneous catalyst in the fluoride-free Hiyama, Suzuki–Miyaura and cyanation reactions in pure water. By this method, different types of biaryls and aryl nitriles were synthesized in good to high yields by the reaction of a variety of aryl iodides, bromides and chlorides with triethoxyphenylsilane, phenylboronic acid and K4[Fe(CN)6]·3H2O, respectively. The presence of sulfonates as hydrophilic groups on the surface of the catalyst confers a highly water dispersible, active and yet magnetically recoverable Pd catalyst. The possibility to perform the reaction in water as a green medium, ease of the catalyst recovery and reuse by magnetic separation, and the absence of any additives or co-solvents make this method as an eco-friendly and economical protocol for the synthesis of biaryl derivatives and aryl nitriles. A new water dispersible heterogeneous Pd–N-heterocyclic carbene for the efficient fluoride-free Hiyama, Suzuki–Miyaura and cyanation reactions in pure water is developed.

Palladium-Catalyzed Arylation of C(sp2)-H Bonds with 2-(1-Methylhydrazinyl)pyridine as the Bidentate Directing Group.

Palladium-catalyzed C(sp2)–H arylation of ortho C–H bonds involving 2-(1-methylhydrazinyl)pyridine (MHP) as the directing group has been investigated. The reaction proceeds smoothly under an air atmosphere to generate biaryl derivatives in an environmentally friendly manner while tolerating a wide range of functional groups. Notably, the directing group present in the product could be easily removed under mild reductive conditions.

Modeling environmental effects in two-photon circular dichroism calculations

Accounting for solvent effects in theoretical predictions of spectroscopic properties may be of significant importance since a solvent—and on a more general basis any environment—may influence key spectroscopic parameters in nontrivial ways—especially in relation to calculation of nonlinear optical properties. At the simplest level, solvent effects may be included into quantum chemistry calculations by use of a dielectric continuum approach; however, such a description may fail in addressing correctly environment anisotropies as well as specific interactions such as hydrogen bonding. On the other hand, discrete embedding methods allow for a more correct description of an environment since such methods keep the atomistic nature of the environment intact. In this paper, two-photon circular dichroism (TPCD) spectra will be calculated for two different biaryl derivatives introducing solvent effects by two different discrete embedding schemes, i.e., polarizable embedding based on induced dipoles (PE) or the fluctuating charge (FQ) model. While we find inclusion of solvent effects on this molecular property to be important, we conclude at the same time that the influence of the solvent on the TPCD rotatory strength is accounted for in an overall rather equivalent manner by either embedding methods.

Synthesis of N-Arylcytisine Derivatives Using the Copper-Catalyzed Chan-Lam Coupling.

N-Arylcytisine derivatives are quite rare. We report here a practical methodology to obtain these compounds. Using the copper-catalyzed Chan-Lam coupling, we synthesized new N-arylcytisine derivatives at room temperature, in air and using inexpensive phenylboronic acids. Cytisine and 3,5-dihalocytisines can act as substrates, and among the products, the p-Br-derivative 2r was used as a substrate to obtain biaryl derivatives under Pd-coupling conditions; ester 2j was converted into its acid and amide derivatives using classical carbodiimide conditions. This shows that the Chan-Lam cross-coupling reaction can be included as a versatile synthetic tool in the derivatization of natural products.

Palladium Nanoparticles on Covalent Organic Framework Supports as Catalysts for Suzuki–Miyaura Cross-Coupling Reactions

Suzuki–Miyaura cross-coupling (SMC) reaction by palladium (Pd) catalysis is widely used in cross-coupling chemistry synthesis for C—C bond formation, yet the biaryl products are generally lacking halo substituents due to highly active palladium species. Suitable catalysts according to this property for the region-selective SMC synthesis of biaryl derivatives with halo substituents did not receive due and sufficient attention. Here, we report the facile synthesis of a covalent organic frameworks (COFs)-supported nanoparticles Pd catalyst that can region-selectively catalyze the SMC reaction of aryl boronic acids and aryl halides, especially with halogenated aryl boronic acids. The methodology exhibits mild operating conditions, broad functional group tolerance, and environmental friendliness and can be strategically applied for cross-coupling scenarios governed by sequential transition metal catalysts to build with or without a halo-substituted moiety. The Pd/COF-SMC nanoparticles catalysts are stable and reusable and succeed in synthesizing halo-substituted biaryl products in excellent yield, which avoids the homocoupling of halogenated aryl boronic acid. The most outstanding advantage is the precise regulation of nanoparticles Pd activity with the well-designed COF ligand.

Design and synthesis of new indole containing biaryl derivatives as potent antiproliferative agents

A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 µM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.

Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors

A structure-activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.

One‐pot Suzuki Coupling‐Knoevenagel Condensation Tandem Reaction Catalyzed by a Recyclable Magnetic Bifunctional Catalyst

AbstractA novel magnetic nanoparticle‐supported bifunctional catalyst NH−Pd(0)@MNP was prepared and its activity was evaluated in one‐pot Suzuki coupling‐Knoevenagel condensation tandem reaction. A series of biaryl derivatives were synthesized via sequential Suzuki coupling‐Knoevenagel condensation in ethanol/water medium under phosphine‐free conditions. Meanwhile, the catalyst could be easily separated by an external magnetic field, and could be reused several times without remarkable loss of catalytic activity.

Ultrasound assisted synthesis of Pd NPs decorated chitosan-starch functionalized Fe3O4 nanocomposite catalyst towards Suzuki-Miyaura coupling and reduction of 4-nitrophenol

In recent days the nanomagnetic biocomposites have been evolved as sustainable green catalysts. In that context, we are prompted to design and synthesize a novel Pd NP adorned chitosan-starch dual biopolymer encapsulated core-shell type magnetic nanocomposite (Fe3O4@CS-Starch/Pd) in an eco-friendly pathway applying ultrasound irradiations. The morphological and physicochemical features of the material were determined using several advanced techniques like FT-IR, FESEM, HRTEM, EDX, atomic mapping, VSM, XRD and ICP-OES. Catalytic efficiency of the material was investigated in the ultrasound assisted classical Suzuki-Miyaura coupling towards the synthesis of diverse range of biaryl derivatives and in the catalytic reduction of 4-Nitrophenol.In both the protocols the catalyst exhibited excellent performances. Sonication had a significant role in enhancing the catalytic performances in both the reactions as compared to conventional heating. Due to super-paramagnetism, the catalyst was easily magnetically isolable and reused in 11cycles without considerable leaching and change in reactivity.

Magnetic covalently immobilized nickel complex: A new and efficient method for the Suzuki cross‐coupling reaction

In this study, an efficient procedure was reported to prepare Fe3O4@SiO2magnetic nanoparticles (MNPs) with immobilized nickel NPs. In order to increase the activity of this catalyst, creatine as a ligand with high content of nitrogen atoms was linked onto the magnetic core–shell structure. Then, Ni(II) ions were coordinated on the surface of the silica‐coated MNPs and reduced to Ni(0) NPs to obtain the final catalyst. The catalytic activity of the prepared catalyst was studied for the synthesis of biaryl derivatives via the Suzuki–Miyaura cross‐coupling reaction in high yields. The catalyst could also be recovered and reused with no loss of activity over five successful runs.