Grignard methodology

The following undergraduate laboratory procedure for the synthesis of diphenylmethanol using the Grignard methodology (Box 4.1) according to Scheme 4.1 is given as an illustrative example where the above analysis is employed. 

Althou little studied, asymmetric copper-catalyzed substitution reactions of dialkylzinc [236] and Grignard reagents [237] vrith allylic substrates have been achieved vrith ferrocenylamidocopper and arenethiolatocopper catalysts, respec-tivdy. Good enantiosdectivity can be achieved vrith the zinc compounds (87% ee), but the method is limited to stericaUy hindered dialkylzinc reagents v/hile Grignard methodology gives only modest selectivities (18-50% ee). 

This consecutive Grignard methodology allows the synthesis of either enantiomer of the a-hydroxy aldehyde product, since its stereochemistry is determined only by the order of Grignard reactions. The preparation of natural products such as (+)- and (-)-fiontalin and malyngolide in high optical yield has been carried out, and demonstrates the synthetic utility of this chii auxiliary. The use of pyrrolidine-based chiral auxiliaries is reviewed by ElieP and Mukaiyama. ... 

The first definitive descriptions of organometallic divalent lanthanide complexes (Evans et al., 1970,1971) also alluded to applications similar to Grignard methodology [eq. (69)]. 

Titanium tetrakis(diethylamide) selectively adds to aldehydes in the presence of ketones and to the least hindered ketone in compounds containing more than one ketone. The protection is in situ, which thus avoids the usual protection-deprotec-tion sequence. Selective aldol and Grignard additions are readily performed employing this protection methodology. ... 

Scott was able to leverage the same type of methodology in an impressive display in which /V-methyltryptamine was dimerized directly to afford chimonanthine (7) (Scheme 9.2b) [9c]. Deprotonation of the indole 1H proton with methyl Grignard followed by treatment with FeCl3 accomplished the singleelectron oxidation and dimerization of the indole moiety. The racemic and meso stereoisomeric products were obtained as a mixture in 19 % and 7 % yields, respectively. Takayama later found hypervalent iodine to be a superior oxidant, affording yields of 17 % and 30 %, respectively [9j]. In both cases, however, as in the case of Hendrickson s example, stereocontrol could not be achieved. 

Iodopyrimidines 60 could be converted to their Grignard derivatives by the action of i-PrMgCl, which then react with various electrophiles <00T265>. Queguiner and co-workers reported the synthesis of pyrimidines 61 bearing alcohols, aldehydes, and esters through this methodology. 

Li and Wei have extended their Grignard-type methodology in water to the use of in. (////-generated imines from the corresponding aldehydes and arylamines, thus furnishing the corresponding propargylamines in a three-component one-pot procedure. 

Of all the palladium-catalyzed coupling reactions, the Kumada coupling has been applied least often in indole chemistry. However, this Grignard-Pd cross-coupling methodology has been used to couple l-methyl-2-indolylmagnesium bromide with iodobenzene and a-bromovinyltrimethylsilane to form l-methyl-2-phenylindole and l-methyl-2-(l-trimethyl-... 

Through known methodology, uridine was transformed into the aldehyde 88 (20) (Figure 14). Grignard reaction with allyl magnesium chloride gave a 7 1 mixture of C-5 Isomers and 90, with the crystalline C-5 (R) Isomer being preponderant. 

An enantioselective approach to both enantiomers of a-alkyl-a-methoxyarylacetic acid derivatives has been described from L-(- -)-tartaric acid. Key steps include stereoselective addition of Grignard reagents to 1,4-diketones derived from tartaric acid. This methodology has been applied in synthesizing the pine beetle pheromone frontalin. 

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