Grignard reagents, reaction with acid chlorides

Reaction of Acid Chlorides with Organometallic Reagents Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same. 

Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same. The mechanism of the reaction is similar to that of L1A1H4 reduction. The first equivalent of Grignard reagent adds to the acid chloride, loss of Cl from the tetrahedral intermediate delds a ketone, and a second equivalent of Grignard reagent immediately adds to the ketone to produce an alcohol. 

The reactions of Grignard reagents with aldehydes and ketones give alcohols, reaction with acid chlorides and esters give tertiary alcohols, reaction with carbon dioxide to give carboxylic acids, reaction with nitriles give ketones, and reaction with epoxides give alcohols. 

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... 

The reactions of Grignard reagents with a range of substrates are summarized in Table 14.3 the reactions with acid chlorides and esters are included for completeness, and we will look at them in detail in the next chapter. 

Ullmann condensation of the sodium salt of p-chlorothiophe-nol (31) with 2-iodobenzoic (32) acid gives 33. Cyclization by means of sulfuric acid affords the thioxanthone, 34. Reaction with the Grignard reagent from 3-dimethylaminopropyl chloride affords the tertiary carbinol (35). Dehydration by means of acetic anhydride affords chlorprothixene as a mixture of geometric isomers, 36. (Subsequent work showed the Z isomer-chlorine and amine on the same side—to be the more potent compound.) Chlorprothixene is said to cause less sedation than the phenothiazines. ... 

Reduction is also observed in the reaction of acid chlorides with Grignard reagents Whitmore, F.C., Whitaker, J.S., Mosher, W.A., Brevick, O.N., Wheeler,... 

Synthesis of ketones by reaction of Grignard reagents with acid chlorides bearing substituents susceptible to side reactions (COOCHj, Cl) is possible if.the reaction is conducted at —70° in T1IF.2... 

X-5 The reaction of a cadmium Grignard reagent (R2Cd) with an acid chloride. This reaction requires the formation or a cadmium Grignard which can be formed as shown below... 

Ultraviolet spectral data have been reported for a few organocopper compounds 36, 77, 253, 303). Methyl(triphenylphosphine)copper complexes were decomposed by UV light 310). The reaction of Grignard reagents with acid chlorides in the presence of copper(I) chloride, in which free radicals are supposedly formed via organocopper compounds, was also promoted by UV light 103). 

Fig. 4. Ionic and radical mechanisms in the syntheses of hindered ketones from the copper-catalyzed reaction of Grignard reagents with acid chlorides.

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