Metals Grignard reaction

Many organic halides do not react satisfactorily with lithium to form RLi ecMnpounds or with metallic magnesium to form Grignard reagents. The desired organolithium compound can often be prepared by a halogen-metal interconversion reaction ... 

By using a lOOX excess of the metal (less than lOO for experiments on a large scale) one can save much time. Some Grignard reactions, especially those with tertiary alkyl chlorides and cyclohexyl chloride, are not easily started and it seemed desirable, therefore, to inform the user of this book about our experiences. 

Alkynyl anions are more stable = 22) than the more saturated alkyl or alkenyl anions (p/Tj = 40-45). They may be obtained directly from terminal acetylenes by treatment with strong base, e.g. sodium amide (pA, of NH 35). Frequently magnesium acetylides are made in proton-metal exchange reactions with more reactive Grignard reagents. Copper and mercury acetylides are formed directly from the corresponding metal acetates and acetylenes under neutral conditions (G.E. Coates, 1977 R.P. Houghton, 1979). 

TT-Allylpalladium chloride (36) reacts with the nucleophiles, generating Pd(0). whereas tr-allylnickel chloride (37) and allylmagnesium bromide (38) reacts with electrophiles (carbonyl), generating Ni(II) and Mg(II). Therefore, it is understandable that the Grignard reaction cannot be carried out with a catalytic amount of Mg, whereas the catalytic reaction is possible with the regeneration of an active Pd(0) catalyst, Pd is a noble metal and Pd(0) is more stable than Pd(II). The carbon-metal bonds of some transition metals such as Ni and Co react with nucleophiles and their reactions can be carried out catalytic ally, but not always. In this respect, Pd is very unique. 

In Grignard reactions, Mg(0) metal reacts with organic halides of. sp carbons (alkyl halides) more easily than halides of sp carbons (aryl and alkenyl halides). On the other hand. Pd(0) complexes react more easily with halides of carbons. In other words, alkenyl and aryl halides undergo facile oxidative additions to Pd(0) to form complexes 1 which have a Pd—C tr-bond as an initial step. Then mainly two transformations of these intermediate complexes are possible insertion and transmetallation. Unsaturated compounds such as alkenes. conjugated dienes, alkynes, and CO insert into the Pd—C bond. The final step of the reactions is reductive elimination or elimination of /J-hydro-gen. At the same time, the Pd(0) catalytic species is regenerated to start a new catalytic cycle. The transmetallation takes place with organometallic compounds of Li, Mg, Zn, B, Al, Sn, Si, Hg, etc., and the reaction terminates by reductive elimination. 

Barbier reported (1) in 1899 that a mixture of methyl iodide, a methyl ketone, and magnesium metal in diethyl ether produced a tertiary alcohol. Detailed studies by his student Victor Grignard are documented in his now classical doctoral thesis, presented in 1901. Grignard estabUshed (2) that the reaction observed by Barbier could be separated into three distinct steps Grignard reagent formation, Grignard reaction, and hydrolysis. 

Phenyllithium can be used in Grignard-type reactions involving attachment of phenyl group, eg, in the preparation of analgesics and other chemotherapeutic agents (qv). It also may be used in metal—metal interconversion reactions leading, eg, to phenyl-substituted siUcon and tin organics. 

Historically, among the most important reactions of siUcon haUdes are those occurring with metal alkyls and metal alkyl haUdes. The Grignard reaction, for example, was the first commercial process for manufacturing organosiUcon compounds, which were later converted to siUcones (19). 

All lation. Thiophenes can be alkylated in the 2-position using alkyl halides, alcohols, and olefins. Choice of catalyst is important the weaker Friedel-Crafts catalysts, eg, ZnCl2 and SnCl, are preferred. It is often preferable to use the more readily accompHshed acylation reactions of thiophene to give the required alkyl derivatives on reduction. Alternatively, metalation or Grignard reactions, on halothiophenes or halomethylthiophenes, can be utilized. 

M. Kharasch and O. Reinmuth, Grignard Reactions ofNon-Metallic Substances, Prentice Hall, New York, 1954. 

Cesium forms simple alkyl and aryl compounds that are similar to those of the other alkah metals (6). They are colorless, sohd, amorphous, nonvolatile, and insoluble, except by decomposition, in most solvents except diethylzinc. As a result of exceptional reactivity, cesium aryls should be effective in alkylations wherever other alkaline alkyls or Grignard reagents have failed (see Grignard reactions). Cesium reacts with hydrocarbons in which the activity of a C—H link is increased by attachment to the carbon atom of doubly linked or aromatic radicals. A brown, sohd addition product is formed when cesium reacts with ethylene, and a very reactive dark red powder, triphenylmethylcesium [76-83-5] (C H )2CCs, is formed by the reaction of cesium amalgam and a solution of triphenylmethyl chloride in anhydrous ether. 

Several aEylation reactions are known, frequently using an organometaEic derivative of the compound being aEylated, or a strongly electropositive metal in conjunction with the reactants. Grignard reactions are in this group. 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

Many pharmacologically active compounds have been synthesized using 5-bromoisoquinoline or 5-bromo-8-nitroisoquinoline as building blocks.6 7 8 9 10 11 The haloaromatics participate in transition-metal couplings 81012 and Grignard reactions. The readily reduced nitro group of 5-bromo-8-nitroisoquinoline provides access to an aromatic amine, one of the most versatile functional groups. In addition to N-alkylation, TV-acylation and diazotiation, the amine may be utilized to direct electrophiles into the orthoposition. 

In some cases, the Grignard reaction can be performed intramolecularly. For example, treatment of 5-bromo-2-pentanone with magnesium and a small amount of mercuric chloride in THE produced 1-methyl-1-cyclobutanol in 60% yield. Other four- and five-membered ring compounds were also prepared by this procedure. Similar closing of five- and six-membered rings was achieved by treatment of a 6- or s-halocarbonyl compound, not with a metal, but with a dianion derived from nickel... 

However, none of these compounds can be easily resolved except TM (16) Itself. Me prefer to resolve as early as possible, (page T 94), so It is better to carry out the Diels-Alder reaction with acrylic acid and resolve acid (19) before adding the phenyl group by a Grignard reaction. The benzylic alcohol group in (20) can be taken out by metal-anunonia reduction. Syrithesis ... 

Mg powder can probably be activated for any subsequent Grignard reaction by treating the metal with MesSiCl 14 in either ether or THF, or entirely without solvent, followed by removal of unreacted MesSiCl 14 and HMDSO 7 and any ether or THF in vacuo before adding the halogen compound dissolved in ether or THF (Scheme 13.14). 

In liquid-solid processes reaction takes place between a liquid reactant and an insoluble or sparingly soluble solid which must be finely divided to speed up the process. Another measure to accelerate the process is to use an aqueous solution of a phase-transfer agent (typically a quaternary ammonium salt). The solid can also be a catalyst for reactions between liquid components, e.g. in acylations, carried out both conventionally in the presence of metal chlorides (mostly AICI3) or catalysed by zeolites and Grignard reactions. 

The formation of Grignard reagents takes place at the metal surface. Reaction commences with an electron transfer to the halide and decomposition of the radical ion, followed by rapid combination of the organic group with a magnesium ion.1 It... 

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