Esters Grignard reagent transformation

Grignard reagents transform esters into alcohols... 

An interesting appetite suppressant very distantly related to hexahydroamphetamines is somanta-dine (24). The reported synthesis starts with conversion of 1-adamantanecarboxylic acid (20) via the usual steps to the ester, reduction to the alcohol, transformation to the bromide (21), conversion of the latter to a Grignard reagent with magnesium metal, and transformation to tertiary alcohol 22 by reaction with acetone. Displacement to the fomiamide (23) and hydrolysis to the tertiary amine (24) completes the preparation of somantadine [6]. 

Amidation-the Bodroux reaction Finally, amidahon of methyl ester 33 was required to complete the process. To accomplish this transformation, we turned to a reaction first reported in 1904 by Bodroux [12]. The reaction involves activation of an amine by conversion to the magnesium amide using a Grignard reagent. Subsequent reaction of the magnesium amide with the ester produces the carboxamide. 

Grignard reaction and similar transformations allow C-C bond formation without a palladium catalyst. Grignard reagents and organolithium compounds are very versatile carbanion sources used in the synthesis of acyclic, heterocychc and carbo-cychc compounds. The esters, ketones and aldehydes are more stable when the reaction takes place on solid supports than in the hquid-phase, because this immo-bihzed components are not so sensitive towards water or oxygen. In the total synthesis of (S)-zearalenone (155) on solid supports the Grignard reaction is one of the key steps (Scheme 3.16) [120]. 

Compared with aldehydes, ketones and esters are less reactive electrophiles in the addition of dialkylzincs. This makes it possible to perform a unique reaction that cannot be done with alkyllithium or Grignard reagents, which are too reactive nucleophiles. For example, Watanabe and Soai reported enantio- and chemoselective addition of dialkylzincs to ketoaldehydes and formylesters using chiral catalysts, affording enantiomerically enriched hydroxyketones 30 (equation 12)43 and hydroxyesters 31 in 91-96% , respectively (equation 13). The latter are readily transformed into chiral lactones 3244. 

A variety of functional transformations occurring far from the SMA framework have been described. Acylation of a silyl ether, sodium borohydride or LAH reduction of an ester into a carbinol, oxidation of a carbinol into an aldehyde or a ketone, and the addition of Grignard reagents to a carbonyl are some examples.95,168,255... 

Thiazolines activated with an equivalent of BF3 readily react with a wide range of organometals, giving tranj-4,5-disubstituted thiazoles stereoselectively. Alkyllithiums, Grignard reagents, lidiium alkynides, nitronates, ester and ketone enolates have been employed as the nucleophile. Stereocontrolled construction of three contiguous asymmetric centers is performed with a lithiated isothiocyanatoacetate, and the product is successfully transformed to (+)-biotin (Scheme 27), ° ... 

Some transformations constitute examples of more than one of these classes. For example, the reaction of esters with Grignard reagents gives alcohols in what is a substitution and an addition reaction. Remember that classification schemes are created by people. A compound does not stop and worry about whether a particular reaction fits within the boundaries of human classification schemes before it undergoes the reaction. 

This section covers the formation of cyclopropanes via cyclization of reactive allylic intermediates (cations, anions, radicals). Included are those transformations of allylic functional derivatives (e.g. allylic halides, alcohols, aldehydes, ketones, acids, esters, boronates, Grignard reagents) to cyclopropyl derivatives that do not actually proceed via allylic reactive intermediates, but which are not covered by other sections of this volume. Additionally, this section will cover methods for the formation of cyclopropanes by pericyclic reactions. 

Titanocene dichloride catalyzes the reduction of alkyl, aryl, and vinyl bromides, aryl chlorides, alkoxy- and halosilanes ketones, esters, and carboxylic acids with alkyl Grignard reagents. This Cp2TiCl2/RMgX system can also be used for the hydromagnesation of alkynes, dienes, and alkenes (Section 3.2.5). Kambe et al. have reported a new type of titanocene-catalyzed transformation with vinyl Grignard reagents and chlorosilanes to furnish l,4-disilyl-2-butenes, as shown in Scheme 3.43 [31]. 

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