Grignard addition to carbonyl

Another isohypsic transformation of special significance involves elimination of H-X elements from allylic derivatives to form 1,3-dienes. Besides being extremely important compounds as monomers, 1,3-dienes occupy a unique position in synthetic practice as components in the Diels-Alder reaction. One of the common routes of synthesis of 1,3-dienes also employs a vinyl Grignard addition to carbonyl compounds as the initial step (Scheme 2.55). Allylic alcohols thus formed can easily undergo 1,2-elimination (in some cases it is preferable first to transform the alcohols into their respective acetates). 

Grignard additions to carbonyl compounds are especially useful because they can be used to prepare primary, secondary, or tertiary alcohols ... 

The main use of organocadmium compounds is for the preparation of ketones and keto-esters, and their special merit lies in the fact that they react vigorously with acid chlorides of all types but add sluggishly or not at all to multiple bonds (compare addition of Grignard reagents to carbonyl groups). Some t3rpical syntheses are ... 

Addition to Carbonyl Compounds. Unlike Grignard and alkykitliium compounds, trialkylboranes are inert to carbonyl compounds. The air-catalyzed addition to formaldehyde is exceptional (373). Alkylborates are more reactive and can transfer alkyl groups to acyl halides. The reaction provides a highly chemoselective method for the synthesis of ketones (374). 

Grignard and alkyl lithium reagents were found to add to the carbonyl group of a tricyclic vinylogous amide. However, the same compound underwent the usual vinylogous reduction with lithium aluminum hydride (712). Grignard additions to di- and trichloroenamines gave a-chloro- and dichloroketones (713). 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

As examples of their addition to carbonyl compounds, Grignard reagents react with formaldehyde, H2C = 0, to give primary alcohols, with aldehydes to give secondary alcohols, and with ketones to give tertiary alcohols. 

The Grignard addition to unsymmelrica] cyclic imides proceeds with high rcgioselectivity with preferential addition to the less hindered carbonyl group50 54. 

The development of the Grignard-type addition to carbonyl compounds mediated by transition metals would be of interest as the compatibility with a variety of functionality would be expected under the reaction conditions employed. One example has been reported on the addition of allyl halides to aldehydes in the presence of cobalt or nickel metal however, yields were low (up to 22%). Benzylic nickel halides prepared in situ by the oxidative addition of benzyl halides to metallic nickel were found to add to benzil and give the corresponding 3-hydroxyketones in high yields(46). The reaction appears to be quite general and will tolerate a wide range of functionality. 

An organocerium reagent gave better yields than either the lithium or Grignard reagents in addition to carbonyl at the 17-position on steroids.156... 

Since aluminium alkyls are easily available from inexpensive starting materials, their addition to carbonyl compounds could constitute a cheap alternative to the more expensive Grignard reagents or alkyllithium compounds. Unfortunately, this addition is only clean for aluminium alkyls without /1-hydrogens [16, 19], which are precisely those not accessible via the convenient... 

Cobalt hydrocarbonyl, diborane, and aluminum hydrides add, I think, to all of these carbonyl compounds. Of course, there is the well known Grignard reagent and the alkyllithium additions to carbonyl compounds. Aluminum alkyls add, and we could have listed all the other alkali metal alkyls. Recent work has shown that the tin alkoxides add readily to all these derivatives, and similarly, a tin amide adds to most of these carbonyl compounds. 

C. Additions of Grignard Reagents to Carbonyl Compounds without... 

SCHEME 2. A termolecular mechanism for Grignard reagent addition to carbonyl compounds via... 

Electronic and conformational effects on jt-facial stereoselectivity in nucleophilic additions to carbonyl compounds have been studied by the use of RHF/3-21G and RHF/6-31G methods ". Figure 10 shows a comparison of predicted and experimental selectivities for methyl Grignard additions. Satisfactory agreement of the ratios of anti and equatorial attacks of MeMgX on the carbonyl carbon atoms was reported. 

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