Grignard reagents in synthesis

A5. R. C. Fuson, Advanced Organic Chemistry. Wiley, New York, 1950. See Chapter VII (pp. 154—176) on the uses of organometallic compounds (mainly Grignard reagents) in synthesis. 

A summary of the utility of Grignard reagents in synthesis is shown in Table 7.2. 

Grignard reagents in synthesis is less reactive than an acyl halide. However, the Grignard reagent is so reactive that it... 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

Of greater potential practical significance, however, are the note193 and full papers194,195 in which Fabre, Julia and Verpeaux describe a new stereoselective synthesis of trisubstituted alkenes in which vinyl sulphones are attacked by Grignard reagents in the presence of iron or nickel catalysts (equations 82-84). 

Aromatic and vinylic sulfides take part in cross-coupling reactions with Grignard reagents in the presence of Ni catalysts.336,337 This reaction has been applied to the enantioselective synthesis of binaphthyls using a standard chiral oxazoline ligand (Equation (25)) 338... 

Stereo- and regioselective synthesis of trienes and tetraenes has been reported by palladium-catalysed coupling of (E)- or (Z)-l-alkenyl boronates with (E)- or (Z)-2-bromo-1-phenylthio-l-alkenes followed by treatment with a Grignard reagent in the presence of a nickel catalyst (equation 146)259. 

Use of Amido Grignard Reagents in Inorganic Chemistry—Synthesis and Crystal Structure of Anti (Ragaini et al., 1997)... 

VII. APPLICATIONS OF IRON-CATALYZED REACTIONS OF GRIGNARD REAGENTS IN ORGANIC SYNTHESIS... 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmctrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolatc anions (generated from silyl cnol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

Trisubstituted alkenes.9 A stereoselective synthesis of trisubstituted alkenes uses (E)-alkenyl sulfoxides (1)>U as the starting material. These are reduced to the corresponding sulfides (2)," which undergo coupling with Grignard reagents in the presence of complexes of nickel chloride and phosphines as catalyst.12 The products (3) are obtained in steroisomeric purity of > 99%. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

A multistage synthesis which well illustrates the use of Grignard reagents in carbon-carbon formation is the synthesis of 7-acetoxyheptanal (7).15 Retro-synthetic analysis reveals the necessity of aldehyde group protection as a 1.3-dioxane (8) (see p. 624) prior to the reaction process. 

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