Reduction and Grignard reactions

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

Unusual selectivity, however, is observed in the reduction (and Grignard reaction) of 6-phenyl- (e.g., 337a) and l,3-dibromothieno[c]tropylium salts which are exclusively attacked at C-4 or C-6, respectively (74YZ1452). In the tricyclic series, pyrrole 647 (Scheme 173) is reported to give a single reduction product [94JCS(P1)2579] whereas furoditropylium salt 260 forms... 

Among the important reactions ofaitriles are hydrolysis.reduction, and Grignard reaction U> yield ketones tPigure 21.11k... 

Among the important reactions of nitriles are hydrolysis, reduction, and Grignard reaction to yield ketones (Figure 21.11). 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

The new 23-hydroxy-epimers of cholesterol have been prepared by boro-hydride reduction of the 23-ketone, and Grignard reactions on the cyanohydrin of pregnenolone acetate have been used to prepare both epimers of 20a,22-dihydroxycholesterol. Using optically pure half-esters of methyl succinic acid in Kolbe electrolytic coupling reactions with various bile acids the corresponding 25-d- and 25-L-cholestanoic acids have been prepared. ... 

Phosphorinanones have been utilized as substrates for the preparation of alkenes/ amines,indoles, - and in the synthesis of a series of secondary and tertiary alcohols via reduction,and by reaction with Grignard and Refor-matsky - reagents. Phosphorinanones have also been used as precursors to a series of 1,4-disubstituted phosphor ins. The use of 4-amino-l,2,5,6-tetrahydro-l-phenylphosphorin-3-carbonitrile for the direct formation of phosphorino-[4,3-< ] pyrimidines has been reported. ... 

Chiral cyanohydrins serve as the alcohol moieties of several commercial pyre-throid insecticides (see below) [1527]. Hydrolysis or alcoholysis of the nitrile group affords chiral a-hydroxyacids or -esters and Grignard reactions provide acyloins [1528], which in turn can be reduced to give vicinal diols [1529], Alternatively, the cyanohydrins can be subjected to reductive amination to afford chiral ethanol-amines [1530]. a-Aminonitriles as well as aziridines are obtained via the corresponding a-sulfonyloxy nitriles [1531]. 

The opening of 9a jlOce -oxides by Grignard reagents (Scheme 74) and the Michael reaction with 17a-ketones (Schemes 104 and 105) have been used to an extremely limited extent. The passage from estrogens to 10-methylsteroids has been effected in low yield by Birch reduction and subsequent reaction with carbenes (Scheme 39). The Reimer—Tiemann reaction has been used for the same purpose [53] with the reaction (70) (71)... 

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. 

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. 

In equation 1, the Grignard reagent, C H MgBr, plays a dual role as reducing agent and the source of the arene compound (see Grignard reaction). The Cr(CO)g is recovered from an apparent phenyl chromium intermediate by the addition of water (19,20). Other routes to chromium hexacarbonyl are possible, and an excellent summary of chromium carbonyl and derivatives can be found in reference 2. The only access to the less stable Cr(—II) and Cr(—I) oxidation states is by reduction of Cr(CO)g. 

Aryl and alkyl trimethylsilyl ethers can often be cleaved by refluxing in aqueous methanol, an advantage for acid- or base-sensitive substrates. The ethers are stable to Grignard and Wittig reactions and to reduction with lithium aluminum hydride at —15°. Aryl -butyldimethylsilyl ethers and other sterically more demanding silyl ethers require acid- or fluoride ion-catalyzed hydrolysis for removal. Increased steric bulk also improves their stability to a much harsher set of conditions. An excellent review of the selective deprotection of alkyl silyl ethers and aryl silyl ethers has been published. ... 

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