Carbonyl compounds Grignard additions

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. 

In addition to reacting with aldehydes and ketones—Class II carbonyl compounds— Grignard reagents react with Class I carbonyl compounds—carbonyl compounds that have groups that can be replaced by another group. 

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 with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

Few a-ketosulphoxides 123 were prepared by trapping the enolate anions 124, which are generated by the Michael addition of Grignard reagents to easily available a, jS-unsaturated carbonyl compounds 125, with methanesulphinyl chloride174 (equation 65). 

Addition of TCS 14 to Cu-catalyzed 1,4-additions of Grignard reagents of Li alkyls to a/yS-unsaturated carbonyl compounds has recently been repeatedly reviewed [42-44 a] and is thus not treated here. 

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. 

One of the important new directions in the study of addition reactions of organozinc compounds to aldehydes is the use of ionic liquids. Usually, application of these compounds in reactions with common organometallic reagents has a serious problem ionic solvents are usually reactive toward them, particularly Grignard and organolithium derivatives. It has been recently reported that carbonyl compounds react with allylzinc bromide formed in situ from allyl bromide and zinc in the ionic liquid 3-butyl-l-methylimidazolium tetrafluoroborate, [bmim][BF4].285 Another important finding is that the more reactive ZnEt2 alkylates aldehydes in a number of ionic liquids at room temperature.286 The best yields (up to 96%) were obtained in A-butylpyridinium tetrafluoroborate, [bpy][BF4] (Scheme 107). 

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