Grignard, ketone from amide chloride

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. ... 

It is possible that the ketone product formed by reaction of a Grignard with an acid chloride or anhydride is. css reactive than those starting materials. If so, significant amounts of the ketone product can be isolated, but the yields are often low. With esters and amides, the ketone product is usually more reactive, very little ketone 1 isolated from the reaction mixture, and the ketone reacts further to form a tertiary alcohol. If a large excess... 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

Ketone syntheses. Acyl derivatives that favor the arrestment of Grignard reactions beyond the first round include A-acylpyrazoles, acyl hemiacetals, and acyl tributylphosphonium chlorides (generated in situ from RCOCl and Bu,P). The protocol involving Al-methoxy-Al-methyl carboxamides has been extended to the preparation of a-chloro ketones, a-keto amides, and a-diketones (the last two from the oxalyl diamides). Symmetrical diketones are obtained by the Grignard reaction of bis(benzimidazole) methiodides. Note that an analogous reaction of 1,3-disubstituted benzimidazolium salts furnishes aldehydes. ... 

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