Littérature scientifique sur le sujet « Grignard reactions »

Reactions of a mixture of dimethyl polysulfides (DMPS, CH3SxCH3, x = 3 – 8) with methyl- and phenylmagnesium halides are described. The type of product obtained was dependent on the molar ratio of DMPS to Grignard reagent. When a 6:1 methyl-Grignard to DMPS ratio was used, methanethiol and dimethyl sulfide were the major products obtained after acidification of the reaction mixture. Lesser quantities of methyl-Grignard favored the formation of dimethyl sulfide, dimethyl disulfide, and H2S. Experiments with a 6:1 phenylmagnesium bromide to DMPS ratio produced benzenethiol and phenylmethyl sulfide as major products after acidification. No methanethiol was observed in these experiments. Mixtures of phenylmethyl mono-, di-, and trisulfides and H2S were obtained with a 3:1 Grignard/DMPS molar ratio. From a mechanistic viewpoint, product distributions obtained from reaction of Grignard reagents with DMPS can be explained by the formation of magnesium thiolates that are most readily stabilized by adjacent structures. Experiments using phenyl Grignard reagent in limited supply suggested that the internal sulfur atoms of the polysulfide chains were most reactive. Keywords: organic polysulfides, Grignard reagents.

Enantiomerically enriched α,β-unsaturated sulfinate esters of (–)-cholesterol undergo stereospecific substitutions at sulfur when treated in benzene at 6°C with Grignard reagents. Sulfoxides with ees of 85–99.5% are obtained when enantiopure sulfinates are used. The substitution reactions proceed with inversion of sulfur configuration. Enantiomerically pure cholesteryl (E)-2-carbomethoxyethenesulfinate is not a suitable reactant under the Grignard reaction conditions. It is suggested that the ester group induces unwanted reactions significantly lowering both the yield and sulfur stereogenicity.Key words: sulfinate, sulfoxide, Grignard reagents, stereospecific, unsaturated.

Without suffering from β-elimination, cobalt complexes allow cross-coupling reactions of alkyl halides with Grignard reagents. A combination of a cobalt complex and trimethylsilylmethyl Grignard reagent effects Mizoroki-Heck-type reaction of alkyl halide with styrene, which conventional palladium catalysts have never made possible. Cobalt exhibits intriguing catalytic activities on hydrophosphination and allylzincation of alkynes. Silylmethylcobalt reagent is a powerful tool for the synthesis of highly silylated ethenes.

Grignard reactions of N,N-bis(benzotriazolylmethyl)arylamines afford the corresponding N,N-dialkylarylamines in high yields. Electron-releasing substituents on the aryl ring facilitate the reaction. Arylamines are N,N-dialkylated with two different alkyl groups by a stepwise procedure: N-benzotriazolylmethylation of an amine followed by a Grignard reaction to introduce the first alkyl group, and repetition of the same procedure to introduce the second alkyl group. Grignard reagents derived from 1,4-dihalobutane, upon reaction with N,N-bis(benzotriazolylmethyl)arylamines, give the corresponding N-aryl-hexahydroazepines together with acyclic products. Keywords: azepine, tertiary arylamines.

This account reviews C-C bond formation reactions using alkyl fluorides mostly focusing on the transition-metal-catalyzed reactions. These reactions proceed efficiently under mild conditions by the combined use of Grignard reagents and transition-metal catalysts, such as Ni, Cu, and Zr. It is proposed that ate complex intermediates formed by the reaction of these transition metals with Grignard reagents play important roles as the active catalytic species. Organoaluminun reagents react directly with alkyl fluorides in nonpolar solvents at room temperature to form C-C bonds. These studies demonstrate the practical usefulness of alkyl fluorides in C-C bond formation reactions and provide a promising method for the construction of carbon frameworks employing alkyl fluorides. The scope and limitations, as well as reaction pathways, are discussed.

The Wolff–Kishner reduction, discovered in the early 1910s, is a fundamental and effective tool to convert carbonyls into methylenes via deoxygenation under strongly basic conditions. For over a century, numerous valuable chemical products have been synthesized by this classical method. The reaction proceeds via the reversible formation of hydrazone followed by deprotonation with the strong base to give an N-anionic intermediate, which affords the deoxygenation product upon denitrogenation and protonation. By examining the mechanistic pathway of this century old classical carbonyl deoxygenation, we envisioned and subsequently developed two unprecedented new types of chemical transformations: a) alcohol deoxygenation and b) C–C bond formations with various electrophiles including Grignard-type reaction, conjugate addition, olefination, and diverse cross-coupling reactions.1 Introduction2 Background3 Alcohol Deoxygenation3.1 Ir-Catalyzed Alcohol Deoxygenation3.2 Ru-Catalyzed Alcohol Deoxygenation3.3 Mn-Catalyzed Alcohol Deoxygenation4 Grignard-Type Reactions4.1 Ru-Catalyzed Addition of Hydrazones with Aldehydes and Ketones4.2 Ru-Catalyzed Addition of Hydrazone with Imines4.3 Ru-Catalyzed Addition of Hydrazone with CO2 4.4 Fe-Catalyzed Addition of Hydrazones5 Conjugate Addition Reactions5.1 Ru-Catalyzed Conjugate Addition Reactions5.2 Fe-Catalyzed Conjugate Addition Reactions6 Cross-Coupling Reactions6.1 Ni-Catalyzed Negishi-type Coupling6.2 Pd-Catalyzed Tsuji–Trost Alkylation Reaction7 Other Reactions7.1 Olefination7.2 Heck-Type Reaction7.3 Ullmann-Type Reaction8 Conclusion and Outlook

The pure crystalline diastereomers (1R,2S,5R)-menthyl (R)- and (S)-2-methoxynaphthalene-1-sulfinate (1b) have been prepared and, by reaction with Grignard reagents (the Andersen procedure), converted into optically active alkyl and aryl 2-methoxynaphthyl sulfoxides in 67-77% yields. Use of an excess of Grignard reagent results in facile O-alkyl cleavage of the methoxy group to the corresponding naphthol or a competing loss of the alkyl- or aryl- sulfinyl group to form 2-methoxynaphthalene. Pure diastereomers of menthyl 2,7- dimethoxynaphthalene-1-sulfinate (2b) and menthyl 4-methoxynaphthalene-1-sulfinate (3b) have also been prepared and their reactions with Grignard reagents have been studied.

The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of C_α-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project. Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable C_α-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the "ate-complex" generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp²) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp³) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions. Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et₂O] was studied in order to predict the mechanism of this process in Et₂O solvent. Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1-magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies.
Ph. D.

Organometallic reactions, including allylation, alkylation, aldol and Reformatsky type reactions of carbonyl compounds in aqueous media mediated by Sn, Zn, Mn, and In were studied. The possible mechanism and stereochemistry of these reactions were investigated. The methodology has successfully been applied to the syntheses of 1,3-butadienes, vinyloxiranes, and methylenetetrahydrofurans; and the syntheses of natural product (+)-muscarine, (+)-epimuscarine, (+)-KDN and (+)-KDO.
A novel tellurium reagent, bis(triphenylstannyl)telluride, for organic synthesis was developed. Its application in the preparation of organotellurium compounds, reduction of vic-dihalides and $ alpha$-halo ketones, desulfurization of organic trisulfides and cleavage of organic disulfides was studied. All the reactions with this reagent proceeded under very mild conditions.

In recent years, despite the large amount of novel and clinically validated targets identified from the human genome project, the number of new drug launched on the market is decreasing and the overall costs for the development of a drug are rising significantly. Pharmaceutical and biotechnology companies are under a strong pressure to produce a steady stream of innovative, well-differentiated drugs with a reduced cost both for discovery and development. Currently it takes an estimated 10-14 years to develop and market a drug at a cost that exceeds 1 billion dollars. With the aim at increasing the productivity of original and highly pure molecules as potential modulators of therapeutic targets, different and novel technologies, related to synthesis, work-up and isolation, were developed. In particular the so called “Enabling Techniques” have emerged and were studied in a large extent in Academia. Among these new technologies continuous flow organic synthesis is now being investigated widely in fine chemistry and, with the advent of commercially available microreactors, also in pharmaceutical industry. In the framework of my PhD thesis exploring the application of the so called “Enabling Techniques” in a medicinal chemistry laboratory, my efforts were devoted to the evaluation of the benefits that continuous flow chemistry could provide in Drug Discovery programs and in the synthesis of natural products in comparison with traditional synthetic techniques. Flow technologies have recently received a great deal of attention and a fair number of scientific publications have demonstrated their potential for improving productivity in organic synthesis. Established continuous flow chemistry advantages include precise control of temperature, pressure, concentration, residence time and heat transfer. All these aspects significantly affect the reaction outcome improving yield and selectivity. Within my thesis, continuous flow chemistry was firstly applied to the synthesis of hydroxamic acids, a class of well known inhibitors of important biological targets such as metalloproteinases and histone deacetylases. As a part of a medicinal chemistry project, a simple conversion of ester into hydroxamic acids (Scheme 1) was envisaged as a suitable and convenient synthetic method for the preparation of a collection of compounds featuring such privileged substructure. The effects of flow rate, reactor volume and temperature were examined and the optimized reaction conditions were then successfully applied for the preparation of a small collection of ten hydroxamic acids featuring a range of functional groups. Good yields, purity and high reproducibility were observed using this simple protocol. R = Aryl, Alkyl, Heteroaryl, Aminoalkyl; R' = Me, Et Scheme 1. Synthesis of Hydroxamic Acids No racemisation occurred when the reaction was performed on protected amino acids. The yields were comparable and, in some cases, even better than what reported in literature where the same transformation was performed by MW irradiation. Even if the reaction time is relatively longer than with MW, no limitation in scale-up is present using flow chemistry. Based on the good results obtained in the development of the continuous flow synthesis of hydroxamic acids this new methodology was applied to the synthesis of SAHA (suberoylanilide hydroxamic acid). Our two-step sequence entails the conversion of the commercially available methyl suberoyl chloride into methyl suberanilate under Schotten-Baumann conditions, followed by the transformation of ester by aqueous hydroxylamine in presence of sodium methoxide (Scheme 2). Scheme 2. Synthesis of SAHA (suberoylanilide hydroxamic acid) To avoid a time consuming work-up procedure and extensive manual purification of the final compound, an integrated sequential flow synthetic pathway was set-up employing immobilized scavenger. The reaction stream was directly passed through a short packed column containing silica supported quaternary amine for the selective removal of the carboxylic acid by-product. The solution containing the product and traces of the starting material was collected and, after solvent evaporation, crystallization from MeOH afforded SAHA in 84% yield and 99% purity (80% yield over two steps). With the aim at studying the applicability of flow technique also to the synthesis of a natural compound, the continuous flow multi-step synthesis of Dumetorine was undertaken. (+)-Dumetorine, isolated in 1985 from the tubers of Dioscorea dumetorum Pax, shows a notable use in folk medicine and arrow poisons. Its total batch-synthesis was recently published by our group (Scheme 3). Scheme 3. Batch-Total synthesis of Dumetorine The planned synthetic route envisaged a flow process where the synthetic steps were combined into only one continuous sequence minimizing work up and purifications. The reaction crudes had to be processed through packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents. In this way the improvements gained through the precise control of reaction conditions and the reduction in manual handling could be easily evaluated. To synthesize this natural alkaloid, new protocols had to be developed for performing classical reactions under continuous flow conditions. With this aim the flow addition of Grignard reagent to carbonyl compounds was the first reaction that we broadly investigated. In fact, despite many classes of reaction was successfully transferred to continuous flow approach, the addition of Grignard reagents to aldehydes and ketones under flow conditions is up-to-date poorly exemplified in the literature. The optimization of the experimental parameters was investigated by varying the temperature of the stored solution, the residence time and the number of Grignard equivalents. A short column containing polymer supported benzaldehyde was used for the scavenging of the excess of Grignard reagent. The optimized conditions (room teperature; 1.2 Grignard eq; residence time 33 minutes) were successfully applied on different aldehydes and ketones (arylic, heteroarylic, alkylic etc.) for the preparation of a small collection of alcohols (Scheme 5). Good yields (ranging from 88% to 96%), purity and high reproducibility were observed. Scheme4. Flow Grignard addition to carbonyl compounds The protocol was applied to the synthesis of Tramadol, a well known centrally active analgesic used for treating moderate to severe pain (Yield 96%). The developed conditions also allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function (Scheme 5). Scheme5. Flow Grignard addition to carbonyl compounds in presence of nitriles. In the light of the interesting results concerning the flow addition of Grignard reagent to carbonyl compounds, we started to perform the five-step continuous flow synthesis of (+) Dumetorine reported below (Scheme 6). Scheme 6. Flow-Total synthesis of (+)Dumetorine This synthesis entailed IBX oxidation of primary alcohol, Grignard addition on carbonyl compounds, acylation, ring closing metathesis and Eschweiler-Clarke reductive amination. In the second step the flow addition of suitable Grignard reagent to aldehyde (2) was performed under the previously optimized conditions. The yield of the isolated compound was 90% with a remarkable improvement respect to the batch process. This result is a direct consequence of the efficient mixing and heat dispersion due to the high surface area-to-volume ratios in the PTFE tubing that keeps the temperature constant minimizing the occurrence of side reactions. Compound (5) presents the structural features for ring-closing metathesis and this type of reaction was performed in batch using 2nd generation Grubbs catalyst in good yield. The same result was obtained flowing for short time (less than 20 min) the starting material in presence of dissolved catalyst (both 1st and 2nd generation catalysts were tested) but, in this way, the problem of the final purification by flash chromatography was still present. After a few failing attempts using not commercially available supported Grubbs catalysts of 1st (a) and 2nd (b) generation (Figure 1) , we evaluated the application to flow chemistry of a homogeneous PEG supported Grubbs catalyst in order to increase the performance in RCM maintaining the possibility of a simple catalyst recovery. Figure 1. Supported Grubbs Catalysts prepared A newly synthesized PEG- Supported Hoveyda catalyst (8) was prepared (Scheme 5) in collaboration with Prof. M. Benaglia and Dr. A. Caselli (Università degli Studi di Milano). Using this PEG-supported catalyst, the flow RCM was successfully and we observed the total conversion of (5) in (6). The pure compound (6) was simply obtained by evaporation of the solvent after the precipitation of the catalyst in presence of Et2O. The catalyst easily recovered can be recycled for RCM reactions. Scheme 5. Synthesis of PEG-supported Hoveyda catalyst The Dumetorine batch synthesis was affected by a low yielding acid catalyzed cleavage of Boc protecting group due to a Michael side reaction of the secondary amine on the α-β unsaturated lactone ring. As a consequence, the reductive amination resulted not an easy task to be managed. In order to overcome these problems, we performed the unprecedented flow Eschweiler-Clarke reaction, a particular amination reduction. Under optimized continuous flow conditions, we assessed the concomitant BOC deprotection and N-methylation. The solutions of starting materials and reagents were pumped in the PTFE tubing reactor and then through a column containing SCX cartridge (catch and release purification) obtaining (+)-Dumetorine in high purity and good yield (Overall yield: 29% (65% diastereoisomeric mixture); obtained (+)-Dumetorine amount: 227 mg). So, a flow-based synthesis of (+)-Dumetorine was accomplished; remarkable results were obtained in the Grignard reaction, performed in an efficient and safe manner at room temperature avoiding cryogenic temperature; in the RCM reaction, carried out with a newly synthesised PEG-supported Hoveyda catalyst and finally in the unprecedented flow Eschweiler-Clarke reaction with concomitant BOC deprotection and N-methylation in high yield. This flow total synthesis represents a significant improvement over the existing protocol characterized by lower yield and more steps and the synthetic route was also tested for the preparation of additional analogue derivatives. In fact on the basis of the results that we obtained in the synthesis of (+)-Dumetorine, we applied flow technology to the preparation of its simplified natural congeners (+)-Sedridine (9) and (-)-Sedamine (10). The synthesis of the two natural alkaloids was assessed with good results using protocols (Grignard addition, Eschweiler Clarke reaction) optimized for the preparation of (+)-Dumetorine. Figure 2. (+)-Sedridine (9) and (-)-Sedamine (10) All the results that were assessed in this PhD thesis clearly demonstrate how flow chemistry shows great potentiality in the Medicinal Chemistry field and how that this technique is of great advantage in the assembly of challenging molecules, as natural products, in terms of overall yield reaction time and limitation of handling and purification.

The synthesis of a novel class of antioxidants, namely pyridine annulated heterocyclic nitroxides has been investigated. Two analogues were developed that differed in the structure around the free radical nitroxide. The isolation and characterisation of several side products formed in the reactions gave insight into the reaction mechanism. These findings were exploited in order to improve the overall synthetic yield of the reaction.