Grignaid reagents

The main synthetic application of Grignaid reagents is their reaction with certain caibonyl-containing compounds to produce alcohols. Caibon-caibon bond fonnation is rapid and exothennic when a Grignaid reagent reacts with an aldehyde or ketone. 

An ability to fonn caibon-caibon bonds is fundamental to organic synthesis. The addition of Grignaid reagents to aldehydes and ketones is one of the most frequently used reactions in synthetic organic chemistry. Not only does it pennit the extension of caibon chains, but because the product is an alcohol, a wide variety of subsequent functional group transformations is possible. 

Acetylenic Grignaid reagents of the type RC CMgBr aie prepaied, not from an acetylenic halide, but by an acid-base reaction in which a Grignaid reagent abstracts a proton from a tenninal alkyne. 

Often the precursor is not defined completely, but rather its chemical nature is emphasized by writing it as a species to which it is equivalent for synthetic purposes. Thus, a Grignaid reagent or an organolithium reagent might be considered synthetically equivalent to a caibanion ... 

Step 4 Since a Grignaid reagent may be considered as synthetically equivalent to a caibanion, this suggests the synthesis shown. 

Secondaiy alcohols may be prepaied by two different combinations of Grignaid reagent and aldehyde ... 

Grignaid reagents, and so it is not nonnally possible to intenupt the reaction at the ketone stage even if only one equivalent of the Grignaid reagent is used. 

Two of the groups bonded to the hydroxyl-beaiing caibon of the alcohol aie the same because they aie derived from the Grignaid reagent. For example,... 

Grignaid reagents react with ethylene oxide to yield primary alcohols containing two more carbon atoms than the alkyl halide from which the organometallic compound was prepared. 

In contrast to alcohols with their- rich chemical reactivity, ethers (compounds containing a C—O—C unit) undergo relatively few chemical reactions. As you saw when we discussed Grignaid reagents in Chapter 14 and lithium aluminum hydride reductions in Chapter 15, this lack of reactivity of ethers makes them valuable as solvents in a number of synthetically important transfonnations. In the present chapter you will leain of the conditions in which an ether linkage acts as a functional group, as well as the methods by which ethers are prepared. 

The reaction of Grignaid reagents with epoxides is regioselective in the sane sense. Attack occurs at the less substituted carbon of the ring. 

The major limitation to this procedure is that the alkyl or aiyl halide must not beai substituents that aie incompatible with Grignaid reagents, such as OH, NH, SH, or... 

You have already had considerable experience with caibanionic compounds and their- applications in synthetic organic chemistry. The first was acetylide ion in Chapter 9, followed in Chapter 14 by organometallic compounds—Grignaid reagents, for exanple—that act as sources of negatively polarized car bon. In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic, and that this property can be used to advantage as a method for carbon-carbon bond formation. 

The reaction proceeds by fonnation of the Grignaid reagent from o-bromofluorobenzene. Because the order of reactivity of magnesium with aiyl halides is Arl > ArBr > ArCl > ArF, the Grignaid reagent has the structure shown and fonns benzyne by loss of the salt FMgBr ... 

Benzyne is a reactive dienophile and gives Diels-Alder products when generated in the presence of dienes. In these cases it is convenient to fonn benzyne by dissociation of the Grignaid reagent of o-bromofluoro-benzene. 

Figure 5.11 Crystal structures of adducts of Grignaid reagents.

Similarly, aromadc Grignaid reagents undeiga free-radical self-coupling reactions when treated with MCI2 (M=Cr, Mn, Ft, Co, Ni), e.g. ... 

Alkenea can be synthesized from aUehydes or ketones using the Grignaid reagent derived from CH]Br2 ... 

Fmlfaerexamplesof the ingenious use of Grignaid reagents will be found in many books on synthetic organic chemistry and much recent work in this area was reviewed in a special edition of Bull. Soc. Chim. Franct, 1972, 2127-86, which commemorated the centenary of Victor Grignaid s biith. 

Very recently, Cinquini and Cozzi (120,121) described an interesting synthesis of chiral sulfmamides starting from (-)-(5 -45. They found that treatment of (-)-(5)-45 with imino-Grignaid reagents results in the formation of the corresponding optically active N-alkylidenesulfinamides 82 which, in turn, were converted into a mixture of the diastereomeric sulfmamides 83 upon reduction by... 

Geranyl acetones also reacts with vinyl Grignaid reagent to produce nerolidol direcdy (192). 

This general strategy has also successfully been exploited for the formation of carbon-carbon bonds. Compound (38) underwent ring expansion with concomitant formation of two new carbon-carbon bonds when treated sequentially with Grignaid reagents as depicted in equation (25). Similarly, treatment of cyclic ketoxime methanesulfonates with trimethylaluminum in dichloromethane gave cyclic imines, the... 

Poliak, I. U. and Grillot, G. F., The reaction of Grignaid reagents with arylthiomethylary-lamines and with tristphcnylthiomethylF amine.s, J. Org. Chem., 32, 2892, 1967. 

The 1,5-diketone foimation by the Michael addition of allylsilane (48) to a, -unsaturated ketones was applied to the synthesis of (-i-)-nootkatone." Reaction of the keto group of keto aldehyde (58) with allyl Grignaid reagent and dehydration gave the diene aldehyde (59). The selective oxidation of the terminal double bond afforded the 1,5-dicarbonyl compound (60), which is not stable and converted directly to pyridines and phenols (Scheme 18)." ... 

Cydohexene oxide yields on treatment with methylmagnesiiuu iodide and several other Grignaid reagents (Eq. B62) the oorrespoiMling alkyl < clopenty) earbinds. tuid In certain coses some imtts-2-haln-cyclohexanols as well, - um, i< 7. it ... 

Clemmensen reduction, 537 with Grignaid reagents, 537 by Meerwein-Pondorf procedure, 537 Thiazol-2-yllithium, preparation, 119 Thiazol-2-ytaiagnesiura bromide, preparation, 119... 

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