Pd Reagent Research Articles

Palladium-Mediated Incorporation of Carboranes into Small Molecules, Peptides, and Proteins.

Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report a strategy based on palladium-mediated C-X (X = C, S, and N) bond formation for the installation of carborane-containing moieties onto small molecules and peptides. We demonstrate the ability of Pd-based reagents with appropriate ligands to overcome the high hydrophobicity of the carborane group and enable chemoselective conjugation of cysteine residues at room temperature in aqueous buffer. Accordingly, carboranes can be efficiently installed on proteins by employing a combination of a bis-sulfonated biarylphosphine-ligated Pd reagent in an aqueous histidine buffer. This method is successfully employed on nanobodies, a fully synthetic affibody, and the antibody therapeutics trastuzumab and cetuximab. The conjugates of the affibody ZHER2 and the trastuzumab antibody retained binding to their target antigens. Conjugated proteins maintain their activity in cell-based functional assays in HER2-positive BT-474 cell lines. This approach enables the rapid incorporation of carborane moieties into small molecules, peptides, and proteins for further exploration in boron neutron capture therapy, which requires the targeted delivery of boron-dense groups.

Rationally Designing Regiodivergent Dipolar Cycloadditions: Frontier Orbitals Show How To Switch between [5 + 3] and [4 + 2] Cycloadditions

A pyridinium zwitterion substrate is employed with two different types of transition metal catalysts to develop a regiodivergent cycloaddition. The pyridinium zwitterion is a highly reactive dipolar substrate that can undergo a dipolar cycloaddition with various reactants. It has multiple reaction sites, and the chemoselectivity is determined by the electronic demand of the catalyst–substrate complex. The reaction with nucleophilic Pd reagents affords fused N-heterocyclic compounds via regioselective [4 + 2] cycloaddition. The origin of the site selectivity and the mechanism of this reaction are investigated in this combined experimental and computational study. We found that the pyridinium zwitterion plays a completely different role in the palladium(0)-catalyzed [4 + 2] cycloaddition reaction and in the rhodium(II)-catalyzed [5 + 3] cycloaddition, which was examined experimentally in a previous study. The frontier molecular orbitals of the pyridinium substrate and activated catalyst complex reveal that ...

Biaryl Coupling Reactions of 3‐Methoxy‐N‐(2‐iodophenyl)‐N‐methylbenzamide and 3‐Methoxycarbonyl‐N‐(2‐Iodophenyl)‐N‐methylbenzamide Using Palladium Reagent.

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Studies toward the Synthesis of Toddaquinoline by Intramolecular Cyclization

In connection with studies on the total synthesis of toddaquinoline (1), the synthesis of [l,3]dioxolo[4',5':4,5]benzo[h]quinoline (la), which is the tetracyclic core of 1, was investigated. Intramolecular benzene-pyridine coupling reactions of the monobromide (9) and dibromide (10), using a Pd reagent and Cu reagent, were evaluated to produce la in poor to moderate yields.

Synthetic Studies on Aromatic Heterocyclic Compounds

This review covers the concise synthesis of simple coumarin with salicyl aldehydes and Wittig reagent, and a convenient synthesis of polycyclic aromatic heterocyclic compounds using the aryl-aryl coupling reaction of aryl benzamides and aryl benzoates with a Pd reagent is presented. In the first section, the reactions of salicyl aldehydes with OMe, OH, Br, CO(2)Me, and NO(2) groups with carbethoxymethylenetriphenylphophorane are described. Specifically, the reaction of 3-nitrosalicylaldehyde with amines gave benzoxazoles in moderate yield. In the second section, the syntheses of benzo[c]phenanthridine alkaloids, quinazoline alkaloids, and graphislactones in the Pd-mediated biaryl coupling reaction are described. Moreover, the synthesis of benzonaphthazepine and pyrrolophenanthridine alkaloids utilizing regioselective C-H activation with intramolecular coordination of a benzylamine to Pd is described, and the effects of oxygen substituents in the benzoyl part of benzanilides on the coupling position in its biaryl coupling reaction are presented. An effective Pd reagent for the coupling reaction of aryl tolyflate and arene was developed.

Biaryl Coupling Reactions of 3-Methoxy-N-(2-iodophenyl)-N-methylbenzamide and 3-Methoxycarbonyl-N-(2-iodophenyl)-N-methylbenzamide Using Palladium Reagent

We examined palladium-assisted biaryl coupling reactions of 3-methoxy and 3-methoxycarbonyl benzanilides, and propose an aspect of the mechanism involved in forming a biaryl bond using Pd reagent.

Palladium-assisted Biaryl Coupling Reaction of 1-(2-Iodobenzoyl)-1,2,3,4-tetrahydroquinoline

The biaryl coupling reaction of 1-(2-iodobenzoyl)-1,2,3,4-tetrahydroquinoline using Pd reagent was examined. The reaction proceeded smoothly to produce 5,6-dihydro-4H,8H-pyrido‖3,2,1-de]phenanthridin-8-one in excellent yield.

Use of Polymer‐Supported Pd Reagents for Rapid and Efficient Suzuki Reactions Using Microwave Heating.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Novel Synthesis of a New Skeletal Compound Benzonaphthazepine by Regioselective C—H Activation Utilizing the Intramolecular Coordination of an Amine to Pd.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Benzo[c]Phenanthridine Alkaloids, Using a Novel Palladium-Phosphine Combination System - Pd(OAc)2, DPPP, and Bu3P

Total synthesis of several benzo[c]phenanthridine alkaloids was accomplished via an aryl-aryl coupling reaction using a novel Pd reagent prepared from Pd(OAc) 2 , DPPP, and Bu 3 P. This is a versatile method for the coupling reactions of not only aryl triflates and arenes hut also aryl halides and arenes.

Use of polymer-supported Pd reagents for rapid and efficient Suzuki reactions using microwave heating.

A rapid and efficient Suzuki coupling protocol has been developed utilizing polymer-supported palladium catalysts and microwave irradiation. It is also shown that solid-phase extraction of excess boronic acids can be rapidly and conveniently accomplished by utilization of a silica-supported carbonate base. [reaction: see text]

Novel Synthesis of a New Skeletal Compound Benzonaphthazepine by Regioselective C-H Activation Utilizing the Intramolecular Coordination of an Amine to Pd

The novel synthesis of a new skeletal compound, benzonaphthazepine, from N-bromobenzylnaphthylamine using a Pd reagent is described. In the biaryl coupling reaction of N-bromobenzylnaphthylamine using a Pd reagent, the intramolecular coordination of the benzylamino group to Pd causes regioselective C-H activation at the peri position relative to the amine group on the naphthalene ring, producing benzonaphthazepine in good to excellent yield. The bulkiness of the substituent at C7 on the naphthalene ring affects the regioselectivity of the biaryl coupling reaction.

Synthetic Studies on Pyrrolophenanthridone Skeleton from 1-Benzoyl-7-iododihydroindole Derivatives Using Palladium-assisted Biaryl Coupling Reactions

The biaryl coupling reaction of 1-benzoyl-7-iododihydroindole derivatives using Pd reagent was examined. 1-[(1,3-Benzodioxol-5-yl)carbonyl]-7-iodo-2,3-dihydroindole gave 4,5-dihydro-7H-[1,3]dioxolo[4,5-k]pyrrolo[3,2,1-de]phenanthridin-7-one, which was formed by connection to a more hindered carbon, as a major product. 1-(3,4-Dimethoxybenzoyl)-7-iodo-2,3-dihydroindole gave oxoassoanine and 10,11-dimethoxy-4,5-dihydropyrrolo[3,2,1-de]-phenanthridin-7-one in an almost equal ratio.

Novel Synthesis of NaphthobenzazepinesfromN-Bromobenzylnaphthyl­aminesby Regioselective C-H Activation Utilizing the Intramolecular Coordinationof an Amine to Pd

In a biaryl coupling reaction of N-bromobenzylnaphthylamine using Pd reagent, the intramolecular coordination of the benzylamino group to Pd causes the regioselective C-H activation at the peri-position to the amine groupon the naphthalene ring to produce a new skeletal compound, naphthobenzazepine, in good to excellent yield.

Aryl—Aryl Coupling Reaction Using a Novel and Highly Active Palladium Reagent Prepared from Pd(OAc)2, 1,3‐Bis[diphenylphosphino]propane (DPPP), and Bu3P.

A palladium-assisted coupling reaction of aryl triflate with arene was investigated, and a novel Pd reagent prepared from equimolar Pd(OAc)2, 1,3-Bis[diphenylphosphino]propane (DPPP), and Bu3P was developed. This method is useful for intramolecular biaryl coupling reactions, not only between aryl triflate and arene (triflate-amide), but also between aryl halide and arene (halo-amide).

Aryl-aryl coupling reaction using a novel and highly active palladium reagent prepared from Pd(OAc)2, 1,3-bis[diphenylphosphino]propane (DPPP), and Bu3P.

A palladium-assisted coupling reaction of aryl triflate with arene was investigated, and a novel Pd reagent prepared from equimolar Pd(OAc)2, 1,3-Bis[diphenylphosphino]propane (DPPP), and Bu3P was developed. This method is useful for intramolecular biaryl coupling reactions, not only between aryl triflate and arene (triflate-amide), but also between aryl halide and arene (halo-amide).

Determination of Enantiomer Purity ofβ- andγ-Amino Acids by NMR Analysis of Diastereoisomeric Palladium Complexes

Like α-amino acids, β- and γ-amino acids form spirobicyclic complexes (see 2 and 3) by reaction with the chiral di-μ-chlorobis{2-[1-dimethylamino-ϰN)-ethyl]phenyl-ϰC}dipalladium complexes 1 under basic conditions (Scheme 1 and X-ray structures in Fig. 1). The diastereoisomeric complexes formed with mixtures of enantiomers of either the amino acids or the dichloro-dipalladium complexes give rise to marked chemical-shift differences in the 1H- and 13C-NMR spectra (Figs. 2 – 4) to allow determination of the enantiomer purities. A simple procedure is described by which β- and γ-amino acids (which may be generated in situ from Boc- or Fmoc-protected precursors) are converted to the Pd complexes and subjected to NMR measurements. The effects of solvent, temperature, and variation of the aryl group in the chiral derivatizing Pd reagent are described (Figs. 4 and 5). The methyl esters of β-amino acids can also be employed, forming diastereoisomeric chloro[(amino-ϰN)aryl-ϰC][(amino-ϰN)alkanoate]palladium complexes 6 for determining enantiomer ratios (Scheme 6). The new method has great scope, as demonstrated for β2-, β3-, β2,3-, β2,2,3-, γ2-, γ3-, γ4-, and γ2,3,4-amino acid derivatives.

Internal Aryl-Aryl Coupling Reaction Using a Novel and Highly Active Palladium Reagent Prepared from Pd(OAc)2, DPPP, and Bu3P.

A novel Pd reagent prepared from equimolar Pd(OAc)2, DPPP, and Bu3P (method B) was useful for the internal biaryl coupling reaction of not only triflate-amide but also halo-amide.

Synthesis of the pentacyclic intermediate for dynemicin a and unusual formation of spiro-oxindole ring

A pentacyclic compound was synthesized as an important intermediate of antitumor antibiotic dynemicins. The key step was the intramolecular Heck reaction using catalytic Pd reagent. During the course of the synthetic studies, an unusual spiro ring compound was found to be produced via intramolecular conjugate addition.