Addition of Grignard reagents

Addition of Grignard reagents to aldehydes is the most important method of preparing of alcohols. The product of these reactions is a kind of alkoxide. This alkoxide hydrolyses in the presence of acid and forms an alcohol. 

You may remember that to prepare primary alcohols by this method we should start with formaldehyde, and to prepare secondary alcohols we should start with higher aldehydes. 

Generally, sodium hydrogensulfite addition products of higher molar mass aldehydes can be precipitated easily. Hence NaHS03 is often used to separate aldehydes from mixtures. 

Write out the addition reactions of acetaldehyde with the following substances under suitable conditions. 

Aldehydes undergo polymerization reactions under certain conditions. In these reactions, as the aldehyde molecules react with different functional groups to form polymers. 

The addition of Grignard reagents to x,jS-unsaturated ketones gives mixtures resulting from 1,2-addition and 1,4-addition. In the presence of cuprous salts, however, the conjugate (1,4) addition is enhanced to the extent that the reaction becomes synthetically useful (11). Two examples of this procedure are given. 

By a procedure analogous to that described in the preceding experiment, octalone-2 (12 g, 0.08 mole, Chapter 9, Section III) in ether is added to methylmagnesium iodide in the presence of cuprous bromide (0.2 g). After decomposition with ice-acetic acid, extraction with ether, and washing of the ether extract, the ethereal solution is shaken with an equal volume (50-60 ml) of saturated aqueous sodium bisulfite for 3 hours. The mixture is filtered and the filtrate is reserved. The crystals are washed with ether. The filtrate is separated and the aqueous phase is combined with the filtered solid. The combination is acidified (dilute hydrochloric acid) and heated under reflux for 30 minutes. The product thus liberated is extracted into ether, the ether is washed with bicarbonate, then with saturated aqueous sodium chloride solution, and then dried and evaporated. The residual oil is the desired product, bp 250-254°. 

In a related study, the factors affecting the steric outcome of reaction of 

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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 ... 

An ability to form carbon-carbon bonds is fundamental to organic synthesis The addition of Grignard reagents to aldehydes and ketones is one of the most frequently used reactions m synthetic organic chemistry Not only does it permit the extension of carbon chains but because the product is an alcohol a wide variety of subsequent func tional group transformations is possible... 

Addition of Grignard reagents and organolithium compounds (Sections 14 6-14 7) Aldehydes are converted to secondary alcohols and ketones to tertiary alcohols... 

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially... 

Addition of Grignard reagents to ketones and aldehydes was one of the reactions which led to the formulation of Cram s rule. Many ketones and aldehydes have subsequently been examined to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 8.2. 

A mechanism of the 1,2-addition of Grignard reagents to ketones has been suggested by Swain involving a six-membered cyclic transition state. Ashby proposed a detailed mechanism as shown in (l)-(2). 

Kharasch has shown that the presence of a small amount of cuprous chloride favored the conjugate addition of Grignard reagents to a, -un-saturated ketones rather than 1,2-addition. 

Cyclic enamines with an isomeric position of the double bond have been obtained by the addition of Grignard reagents to five- (78-81), six- (82-86), seven- (87-90), and thirteen- (89-91) membered lactams, whereas other medium-sized (92,93) lactams furnished amino ketones. The reaction has been extended to substituted lactams (94-98), and iminoethers (99,100). 

Grignard reagents do not add directly to enamines, but their reactions with the corresponding imonium salts readily furnish tertiary amines (225,526). The reductive removal of halogen has been observed in the addition of Grignard reagents to a-bromoimonium salts (527). 

Use of the imonium group for protection of enones was explored. Stability to peracids, lead tetraacetate, bromine, and acetic anhydride was claimed (727). The usual resistance of enamines (but not their salts) to additions of Grignard reagents was used for selective addition to a 3,17-diketosteroid by formation of the usual 3-monoenamine 728). 

Direct addition of Grignard reagents to Zincke-derived chiral pyridinium salts such as 99, meanwhile, allowed subsequent reduction to 1,2,3,6-tetrahydropyridines (e.g., 100, Scheme 8.4.32). This strategy provided entry to asymmetric syntheses of (-)-lupetidin and (+)-solenopsin. Tetrahydropyridines prepared by reduction of chiral... 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

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). 

Reductive Dimerization2 5,6 can be competitive with the addition of Grignard reagents to the C —N double bond of nonenolizable imines, especially with increasing size and branching of the carbanion,... 

Enantiomerically pure of-dibenzylamino-/V-tosylimines 2 arc accessible from amino acids. Since they are not suitable for storage it is advantageous to prepare them in situ from the corresponding aldehydes 1 and A-sulfmyl-4-toluenesulfonamide immediately before use. Addition of Grignard reagents affords the protected 1,2-diamines 3 in good yields (57-95%) and diastereoselectivities (d.r. 85 15 >95 5)8. Deprotection is achieved without racenuzation by reductive methods, see 4-6. 

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

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