ABSTRACT
Low-toxicity chromium(II) chloride catalyzes at 25 °C within minutes the coupling reactions of various (hetero)arylmagnesium reagents with N-heterocyclic halides, aromatic halogenated ketones or imines, and alkenyl iodides. Remarkably, much lower amounts of homo-coupling side products are obtained compared to related iron, cobalt, or manganese cross-couplings.
Subject(s)
Chlorides/chemistry , Chromium Compounds/chemistry , Catalysis , Molecular Structure , Organometallic Compounds/chemistryABSTRACT
The total synthesis of protoporphyrin IX and its disodium salt using a new alternative method to the classical MacDonald condensation is reported. The key step is the reaction of the new unsymmetrical diiodo dipyrrylmethane 1 with the known dipyrrylmethane 2. Coupling of the two fragments leads directly to porphyrin 3 without the need of an oxidizing agent. The new methodology is well suited for the synthesis of protoporphyrin IX derivatives on a multi-100 g scale in good quality without the need for chromatography. Furthermore, these preparations are completely free of any contaminant of animal origin, which represents a real improvement in the manufacturing of protoporphyrin IX derivatives.
Subject(s)
Hematoporphyrins/chemical synthesis , Protoporphyrins/chemical synthesis , Sodium/chemistry , Molecular StructureSubject(s)
Cobalt/chemistry , Iron/chemistry , Ligands , Catalysis , Cyclization , Isoquinolines/chemistry , Magnesium , Quinolines/chemistry , Transition Elements/chemistryABSTRACT
A simple, practical iron salt catalyzed procedure allows fast cross-couplings of N-heterocyclic chlorides and bromides with various electron-rich and -poor arylmagnesium reagents. A solvent mixture of THF and tBuOMe is found to be essential for achieving high yields mainly by avoiding homocoupling side reactions.
Subject(s)
Boron Compounds/chemistry , Boronic Acids/chemistry , Hydrocarbons, Brominated/chemistry , Hydrocarbons, Chlorinated/chemistry , Iron/chemistry , Magnesium/chemistry , Organometallic Compounds/chemistry , Catalysis , Hydrocarbons, Brominated/chemical synthesis , Hydrocarbons, Chlorinated/chemical synthesis , Indicators and Reagents , Molecular StructureABSTRACT
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
