Rh(II)-catalyzed cyclopropanation-ring expansion of 7-azaindoles with halodiazoacetates and indoles with halodiazophosphonates

Up until now, the antibacterial 8-azaquinolones have been prepared using various ring-closing reactions. This work demonstrates the attempted synthesis of 8-azaquinolone antibacterial agents using a synthetic route that involves a reaction recently developed in our group. The reaction is considered the key step of the synthesis and allows for the transformation of 7-azaindoles to 8-azaquinoline-3-carboxylates via a Rh(II)-catalyzed cyclopropanation-ring expansion reaction with ethyl halodiazoacetates. No 8-azaquinolone antibacterial agent was successfully synthesized from 7-azaindoles using this reaction due to decomposition of an intermediate product. The majority of the time was spent on optimization of the reaction conditions as the major product turned out to be the undesired N-H-insertion product. With the new, optimized conditions, reproducibility was seemingly an issue. Even so, some already reported and some novel 8-azaquinolines were successfully synthesized in modest to good yields. The chemistry and transformations of halodiazophosphonates have not been extensively investigated. For that reason, it was of large interest to investigate if they could participate in the same cyclopropanation-ring expansion reactions as the halodiazoacetates, and further be used in synthesis towards a bioisoster of a (fluoro)quinolone antibacterial agent. In this part of the work, the successful generation and isolation of diethyl halodiazophosphonates, and the generation of quinolinyl-3-phosphonates from indoles and diethyl halodiazophosphonates is described. The reaction was investigated for a series of indole derivatives with substituents in selected positions. The majority of the reactions afforded the desired product in modest to good yields. Except for one product, the 3-quinolinyl-phosphonates described are synthesized and isolated here for the first time. Purification and isolation of these compounds on silica gel proved to be troublesome due to tailing of the products and traces of several byproducts. No bioisoster of a (fluoro)quinolone was successfully synthesized as the investigation of the indole series revealed that the reaction was not compatible with the required substitution pattern. Both diazo compounds used throughout this work were halogenated according to a procedure developed in our group. The successful quantification of the halogenated ethyl halodiazoacetates where excellent yields were afforded is also described in this work. The same success was not obtained in the quantitative analysis of the halogenated diazophosphonates due to a large degree of varying yields

A Mechanistic Study of the Cu-catalyzed N-arylation of Hydantoin with Aryl(TMP)iodonium Salts

The use of diaryliodonium salts in organic reactions has rapidly increased in the last decade because of their efficiency in arylation reactions. Despite this, mechanistic investigations are still scarce, particularly for copper catalyzed N-arylation reactions. Recently, we published the use of the unsymmetrical aryl(TMP)iodonium salts (TMP=2,4,6-trimethoxyphenyl) for the selective Cu-catalyzed N-arylation of hydantoins. In this work, the mechanism of this reaction has been studied by DFT methods, and our results have been compared with previous and new experimental data. In contrast to the mechanism proposed for C−H arylation reactions, our results suggest that deprotonation of hydantoin precedes the oxidative addition of aryl(TMP)iodonium salt, with the oxidative addition to a Cu(I) imido intermediate and ligand rearrangements being the rate-limiting steps. This mechanism agrees with the species observed by NMR spectroscopy, kinetic isotope experiments, and the product yields observed using aryl(TMP)iodonium salts with different steric and electronic properties. In addition, it gives some hints for increasing the efficiency of arylation reactions by tuning the diaryliodonium salt

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

We present a short and efficient way of synthesizing two synthetically versatile 4-quinolone-3-carboxylate building blocks by cyclopropanation-ring expansion of 3-chloroindoles with α-halodiazoacetates as the key step. This novel transformation was applied towards the synthesis of the antibiotic drug norfloxacin

Cu-catalyzed N-3-Arylation of Hydantoins Using Diaryliodonium Salts

A general Cu-catalyzed, regioselective method for the N-3-arylation of hydantoins is described. The protocol utilizes aryl(trimethoxyphenyl)iodonium tosylate as the arylating agent in the presence of triethylamine and a catalytic amount of a simple Cu-salt. The method is compatible with structurally diverse hydantoins and operates well with neutral aryl groups or aryl groups bearing weakly donating/withdrawing elements. It is also applicable for the rapid diversification of pharmaceutically relevant hydantoins