Carboxylic acid amides Grignard synthesis

Conductivity measurements have revealed that DMF and carboxylic acid chlorides form salt-like adducts (22) in an equilibrium reaction (equation 12). Such adducts can be prepared either from DMF and acid halides (chlorides and bromides) or from chloromethyleneiminium salts and salts of carboxylic acids. Acyloxyiminium salts (23) can be prepared in the pure state by reacting acid amides with carboxylic acid chlorides in the presence of silver trifluoromethanesulfonate (equation 13). Salts of type (24 equation 14) are regarded as being intermediates in the synthesis of ketones from carboxylic acids and Grignard reagents in the presence of a-chloroenamines as well as in the preparation of acyl halides (F, Cl, Br, I) by action of a-haloenamines on carboxylic acids. ... 

Carboxylic acid amides by Grignard synthesis with addition of 1 C-atom from halides... 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmctrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolatc anions (generated from silyl cnol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

Acid-catalyzed iminium ion 57 fonnation is followed by isocyanide 54 addition and capture of the remaining nitrilium ion 58 by the carboxylate of 56 to generate compound 59. A rapid O N acyl transfer takes then place in order to obtain dipeptide 60 as a mixture of epimers at C4. Although the control of the stereochanistry of the newly formed stereocenter still remains a problan of the Ugi reaction, it nicely demonstrates the force of the Ugi MCR, as all of the carbon atoms needed are successively assanbled in a single step [22], Mannich-type 4CR are often used for the synthesis of natural products. One example is the synthesis of the alkaloid ( )-roelactamine 65 (Scheme 6.6). The reaction of piperonal 61 with methylamine, Grignard reagent 62, and acid chloride 63 results in the formation of amide 64, which... 

Mukaiyama T, Iwasawa N. A facile asymmetric synthesis of P-substituted alkanoic acid the highly stereoselective Michael addition of Grignard reagents to a,p-unsaturated carboxylic amides derived from L-ephedrine. Chem. Lett. 1981 10 913-916. 

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