Copper-mediated Reaction Research Articles

Copper-mediated reaction of 2-halopyridines with ethyl bromodifluoroacetate

A facile process for the preparation of substituted ethyl 2′-pyridyldifluoroacetates 3 is described starting from readily available ethyl bromodifluoroacetate 2 and substituted 2-bromo or 2-chloropyridines 1 . This process features a copper-mediated cross-coupling reaction in DMSO and is the first to utilise pyridylbromides or chlorides with ethyl bromodifluoroacetate 2 in this reaction.

The First Efficient Synthesis and Optical Resolution of Monosubstituted Cyclotribenzylenes

A new and high yielding synthetic route to monosubsti- tuted cyclotribenzylenes 6 via the cyclocondensation of benzene with a suitably monosubstituted diol 20, obtained from ozonolysis of the corresponding dibenzosuberene precursor 19, was developed for the first time! The dibenzosuberene itself could be readily pre- pared in large quantities from inexpensive starting materials in five steps. Using this synthetic approach, a mono bromosubstituted cy- clotribenzylene 12a was synthesized on large scale. Another four monosubstituted cyclotribenzylenes 21 24 were also prepared ei- ther via bromine/lithium exchange followed by subsequent quench- ing with external electrophiles or a copper mediated reaction with cyanide. These molecules adopt a rigid crown conformation as shown by X-ray analysis and temperature dependent NMR studies. The barrier to inversion is quite high, requiring temperatures well above 120 °C before inversion takes place. Futhermore, such mono- substituted cyclotribenzylenes are planar chiral and after optical resolution, using HPLC, we were able to obtain the first planar chiral C1-symmetric cyclotribenzylenes in form of the optically pure enantiomers of 12a, the CD spectra of which are exact mirror images over the entire spectral range.

ChemInform Abstract: The Synthesis of Stable 1,3,4-Triphenylphospholes.

The first syntheses of 1,3,4-triphenylphosphole, 2-bromo-1,3,4-phenylphosphole and 2,5-dibromo-1,3,4-triphenylphosphole are described. These phospholes, unlike most of the known derivatives, are difficult to oxidise and they and their corresponding oxides show little tendency to dimerise. The NBS mediated bromination of 1,3,4-triphenyl-2,5-dihydrophosphole oxide led to the desired precursors of the corresponding phospholes and in one case unexpectedly yielded a phosphole oxide directly. Some reactions including the formation of organolithium reagents and their derivatisation are reported. McMurry reactions of derived formylphospholes to give coupled products are described and some copper mediated reactions are also discussed.

The synthesis of stable 1,3,4-triphenylphospholes

The first syntheses of 1,3,4-triphenylphosphole, 2-bromo-1,3,4-phenylphosphole and 2,5-dibromo-1,3,4-triphenylphosphole are described. These phospholes, unlike most of the known derivatives, are difficult to oxidise and they and their corresponding oxides show little tendency to dimerise. The NBS mediated bromination of 1,3,4-triphenyl-2,5-dihydrophosphole oxide led to the desired precursors of the corresponding phospholes and in one case unexpectedly yielded a phosphole oxide directly. Some reactions including the formation of organolithium reagents and their derivatisation are reported. McMurry reactions of derived formylphospholes to give coupled products are described and some copper mediated reactions are also discussed.

Copper-ligand interactions and physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry In Vitro

With a view to the possible use of copper(II)-·OH inactivating ligand (OIL) complexes as regulators of inflammation, the reactivity of the copper(II)-ascorbate system with hydrogen peroxide has been investigated in the presence of three key substances: histidine (the main copper(II) low molecular mass ligand in extracellular fluid), salicylic acid (the well-known non-steroidal antiinflammatory drug, previously shown to be potentiated by copper(II) in animal models of inflammation), and anthranilic acid (an inactive substance by itself, known to be activated by copper(II) in the same models) at physiological pH (7.4) and inflammatory pH (5.5).Such substances may affect the amount of TBARS detected in solution following copper-mediated Fenton-like reactions through three distinct mechanisms: (i) by decreasing the Cu(II)/Cu(I) redox potential, i.e. at the expense of ·OH radical production, (ii) by scavenging ·OH radicals in the body of the solution, and/or (iii) by acting as a true OIL, i.e. at the expense of ·OH detection. Redox potential measurements of initial solutions have been performed in parallel to TBARS determinations to help discriminate between different ligand influences. Computer-aided speciation has been used to understand the role of copper(II) distribution on the ligand effects characterised.Contrary to previous interpretations, histidine has been found to mainly affect ·OH production by lowering the redox potential of the Cu(II)/Cu(I) couple. Salicylate, which has no effect on ·OH production, has been confirmed to mainly scavenge ·OH radicals in the body of the solution. Anthranilate, which both increases ·OH production and decreases ·OH detection, behaves as a potential OIL.These results tend to confirm our previous hypothesis that copper potentiation of antiinflammatory substances is indirect, i.e. independent of any interaction between metal and drug, whereas copper activation of substances that are inactive by themselves results from specific metal-substance interactions taking place at inflammatory sites.

Cross coupling-conjugate addition reaction of zirconacyclopentadienes with 3-iodopropenoates

Copper-mediated reaction of zirconacyclopentadienes with iodopropenoates afforded penta- and hexasubstituted cyclopentadienes.

Synthesis of Primary sec-alkylamines via nucleophilic ring-opening of N-phosphorylated aziridines

Abstract The novel ring-opening reaction of various 2-alkyl- and 2,2-dimethyl-N-(diethoxyphosphoryl)aziridines (1) and (10) with copper-modified Grignard reagents proceeds regiospecifically at the less hindered carbon. The diethyl N-sec-alkylphosphoramidates (2) thus obtained may efficiently be converted to primary sec-alkylamine hydrochlorides (3) by refluxing with 20% hydrochloric acid. 2,3-Disubstituted N-phosphorylated aziridines except N-phosphorylated cyclohexenimine (4) do not react under the described conditions. Copper-mediated reaction of 2-phenyl-N-(diethoxyphosphoryl)aziridine (7) with Grignard reagents affords a mixture of regioisomers (8) and (9) but still with the preference of ring-opening at the carbon of lesser substitution.

Candidate Trail Attractants ofReticultermes lucifugus: Stereoselective Syntheses of (3Z, 6E, BE)-(3Z, 6E, 8Z)-and (3Z, 6Z, 8Z)-3,6,8 -Dodecatrien-1-OL1

Abstract Stereoselective syntheses on a gram scale of (3Z,6E,8E)-, (3Z,6E,8Z)-and (3Z,6Z,8Z)-3,6,8-dodecatrien-1-ol, 8, 9 and 10, respectively, are described. A key step of the synthesis of 8 consisted of a copper-mediated coupling reaction between 4-(2-tetrahydropyranyloxy)-1-butynylmagnesium bromide (15) and the mesyl ester of (2E,4E)-2,4-octadien-1-ol (14). A similar copper-mediated reaction between 15 and the mesyl ester of (E)-2-octen-4-yn-1-ol (19) was used to construct the C-12 carbon skeleton of 9. On the other hand, the synthesis of 10 was based on a palladium-promoted reaction between (Z)-1-bromo-1-pentene (23) and the organozinc bromide derived from 3,6-heptadiyn-1-yl acetate (27).

Acylation of oxazoles by the copper-mediated reaction of oxazol-2-ylzinc chloride derivatives

C-2 acylation of oxazole derivatives is accomplished by reaction of oxazol-2-ylzinc chloride reagents with acid chlorides in the presence of cuprous iodide. O-acylated vinylisonitriles, which are the sole product from the corresponding reaction employing lithiooxazole, are not observed. The method accommodates substituted and unsubstituted oxazoles with a variety of acid chlorides.

Copper(I) salt-mediated arylation of phosphinyl-stabilized carbanions and synthetic application to heterocyclic compounds

The copper-mediated reaction of phosphinyl-stabilized carbanions 2a-c with aryl halides 1a-i in DMF or HMPA produced (arylmethyl)phosphonates 3-11 in good yields. Similar treatment of N-(2-iodophenyl)- and N-(2-iodophenyl)-N-methyl-α-(diethoxyphosphinyl)acetamides (12 and 14) led to 2-[(diethoxyphosphinyl)methyl]benzoxazole (13) and 1-methyl-3-(diethoxyphosphinyl)oxindole (15) in 71 and 85% yields, respectively. 4-(Ethorycarbonyl)-3,4-dihydroisoquinoline N-oxide (33) was synthesized by the reaction of ethyl α-(o-formylphenyl)acrylate (31), derived from 6 and paraformaldehyde, with hydrorylamine. The cycloaddition of 33 to olefins such as dimethyl maleate, methyl acrylate, and styrene was studied

Metal-mediated reduction of cytochrome c by thioglycolic acid

The reduction of cytochrome c by thioglycolic acid was found to be extremely sensitive to metal catalysis. The rate of the uncatalyzed reaction was negligible in comparison with rates obtained from reactions supplemented with catalytic amounts of copper or iron. Both the catalyzed and uncatalyzed reactions were independent of pH (near neutrality) but when o-phenanthroline was included in the reaction mixture, a pH dependence was induced. This pH dependence is the result of an interference of oxygen with the metal complexes. A comparison of the rate constants at zero ionic strenght, which were obtained from the application of the Debye-Hückel theory for the ionic strength dependence, demonstrated that copper complexes are superior catalysts as compared with iron complexes. Our results suggest that in the copper-mediated reaction, the catalyst is a cupric thioglycolate complex with a net charge of −2. The addition of o-phenanthroline to the reaction mixture results in a tenfold decrease in the catalytic activity and in a change in the net charge of the catalyst to −1. At pH 8 the iron-mediated reduction is catalyzed by a ferric thioglycolate complex, whereas at pH 7 a ferrothioglycolate complex provides the catalytic activity. Both complexes have a net negative charge of −2. At both pH's the catalytic activity is completely abolished by the addition of o-phenanthroline. The results demonstrate the effectiveness by which metal-sulfur complexes can facilitate one-electron transfer reactions and could there-fore serve as a model in the study of various biological oxidations.