Metalation | EPFL Graph Search

Metalation (Alt. spelling: Metallation) is a chemical reaction that forms a bond to a metal. This reaction usually refers to the replacement of a halogen atom in an organic molecule with a metal atom, resulting in an organometallic compound. In the laboratory, metalation is commonly used to activate organic molecules during the formation of C—X bonds (where X is typically carbon, oxygen, or nitrogen), which are necessary for the synthesis of many organic molecules. In synthesis, metallated reagents are typically involved in nucleophilic substitution, single-electron-transfer (SET), and redox chemistry with functional groups on other molecules (including but not limited to ketones, aldehydes and alkyl halides). Metallated molecules may also participate in acid-base chemistry, with one organometallic reagent deprotonating an organic molecule to create a new organometallic reagent. The most common classes of metallated compounds are organolithium reagents and Grignard reagents. However,

Endeavors in synthetically oriented organometallic chemistry

Giuseppe Mangano

This thesis work aimed to show the potentialities of the organometallic approach and, in particular, the organoalkali one, in Organic Synthesis (whose possibilities cannot be underestimated). A wide opening on the big landscape of possibilities has been reached by the study of functionalization of minimally acidic hydrocarbons with the Schlosser LICKOR superbase. This has allowed selective functionalization of a biphenylic system with different functional groups and the preparation of molecules of interest in catalysis. The study of the organometallic approach in organic synthesis continued with the functionalization of the virtually "no-cost" substrate 1-fluoronaphthalene with a big variety of functional groups like phosphinic, aldehydic, carboxylic, halides etc.. This preliminary study was useful in order to develop a strategy in the preparation of binaphthylic systems, obtained by a method that uses copper (II) as an arene coupling agent. This method was developed in the laboratories of Prof. Schlosser's Group and gave good results in the preparation of molecules that can be used as ligands in Asymmetric Catalysis. A complementary study was done on the possibility of using chloride as a protecting group in metalation to have also access to the functionalization of 1-fluoronaphthalene in positions different from the 2-position derived from an ortho-metalation. The preparation of hydrazines using organoalkali reagents was the other target studied because hydrazines are useful starting materials for Pharmaceuticals. A preliminary study was done using the addition of organolithium reagents to azobisformamides. At the end, after the encouraging results obtained, an unexpected result was obtained on the reactivity of azobisformamides. Pyrazoles are an important class of heterocycles, widely used as drugs for the therapy of various diseases. In particular, the trifluoromethylpyrazoles are a class of substances that show some activity as antiinflammatory drugs or as selective insecticides. The organometallic approach in preparation and functionalization of these substrates again showed its power.

EPFL2004

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

Assunta Ginanneschi

The use of organometallic reagents for functionalization of arenes and heterocycles has recently been renewed by our group. The use of bulky trialkylsilyl groups allows one to shield an acidic position by steric hindrance and the introduction of a chlorine atom permits the activation of the nearby site. The organometallic methods were applied to fluorinated indoles, taking into account the growing attention toward halogen as a key factor for improving drug activity. Only few commercial fluoroindoles are inexpensive. Therefore it was necessary to find a method allowing an efficient preparation of the staring material. Many methods have been developed to synthesize halogenated indoles. The more common ways implies electrophilic cyclization. Once obtained the starting material, all four fluoroindoles were subjected to exhaustive functionalization by organometallic reagents, using either bromine/metal permutation or direct metalation in conjunction with chlorine or triisopropylsilyl residues as protecting groups. Once protected position 2 by steric shielding, the metalation occurs at the position next to the fluorine. In the case of 4 and 7-fluoroindoles there is no ambiguity, but for the 4 and 6 isomers we were obliged to play with bases in order to achieve a good regioselectivity. The use of chlorine was necessary to reach the meta position to the fluorine. Only a few derivatives of fluoroindoles are known in literature. However one could expect such compounds to be versatile building blocks for the synthesis of biologically active compound, due to the presence of fluorine or trifluoromethyl group, helping to fine-tune the lipophilicity of a molecule or to protect against metabolic oxidation. This thesis work aimed to fill the gaps in this field by elaborating methods to efficiently and easily prepare functionalized derivatives of fluoroindoles and in particular all twelve possible regioisomeric fluoroindole carboxylic acids.

EPFL2005

In search of simplicity and flexibility: a rational access to twelve fluoroindolecarboxylic acids

Assunta Ginanneschi

All twelve indolecarboxylic acids carrying both a fluorine substituent and a carboxy group at the benzo ring have been prepd. either directly from the corresponding fluoroindoles or from the chlorinated derivs. by hydrogen/metal permutation ("metalation"), or from the bromo- or iodofluoroindoles by halogen/metal permutation, the organometallic intermediate being each time trapped with carbon dioxide. In most, though not all cases, the nitrogen atom in the five-membered ring had to be protected by a trialkylsilyl group. Some of the bromo- or iodofluoroindoles were successfully subjected to a basicity gradient-driven selective migration of the heavy halogen. An unexpected finding on the way to the target compds. were the rigorously site-selective metalation of the 5-fluoro-N-(trialkylsilyl)indole (exclusive deprotonation of the 4-position). The fluoroindoles, although previously known, were accessed more conveniently from suitably substituted nitrobenzenes using the Bartoli or the Leimgruber-Batcho method. A new and very attractive indole synthesis was elaborated consisting of the ortho-lithiation of an N-acyl-protected aniline followed by ortho-formylation, Wittig chloromethylenation and base-catalyzed cyclization accompanied by dehydrochlorination. These five consecutive steps can be contracted to a convenient one-pot protocol. [on SciFinder (R)]

2006

Endeavors in synthetically oriented organometallic chemistry

Giuseppe Mangano

EPFL2004

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

Assunta Ginanneschi

EPFL2005