Ketones reactions with organometallics

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Scheme 152. C-C Bond Formation by (a) Heck Reaction, (b) Tandem Cyclization—Coupling Reaction, (c) Cross-Coupling Reaction with Organometallics, and (d) a-Arylation of Ketones and Amides...

Acid chlorides are prepared by standard methods and undergo the usual acid chloride reactions. They have found important applications as substrates in the syntheses of ketones by transition metal-catalyzed coupling reactions with organometallics (Section 6.02.5.5.14). Acid chlorides (424) are also good substrates for the preparation of ketones (425) using organomanganese(II) iodide, especially for the preparation of alkyl pyrimidinyl ketones <86ACS(B)764>. 

In a number of reactions, such as those leading to amidines and the formation of ketones by reaction with organometallic reagents, the cyanopyridines behave normally, and these call for no comment. The simultaneous attack of propyl magnesium bromide on the cyano group and C(4) in nicotinonitrile has been mentioned (p. 200). 

The oxidation of alcohols to aldehydes and ketones by chromium(VI) reagents opens up important synthetic possibilities based on further reactions with organometallic reagents. 

Two other acid derivatives may also be converted to ketones by reaction with organometallic compounds. Grignard reagents add to nitriles to give imine salts (Section 14.4.3), which are hydrolyzed to ketones in the reaction work-up. In Figure 19.27, again the disconnected bond is highlighted in red. Remember than many aliphatic nitriles are readily prepared by displacement... 

Diphenylphosphinic mixed anhydrides have been utilized to form peptide bonds. Peptides are easier to isolate by this method than by employing 1,3-Dicyclohexylcarbodiimide. These anhydrides are the method of choice for the formation of amides of 2-alkenoic acids (eq 1 ). Carbodiimide and acyl carbonate methods proved to be inferior. Primary amines result in better yields than secondary amines. This activation protocol can be employed to form thiol esters (eq 2) p-Amino acids are readily converted to p-lactams with chlorodiphenylphosphine oxide (eq 3). Secondary amines work best. This activation protocol has been utilized to convert acids to amines via a Curtius rearrangement. Phenols have been generated from diene acids, presumably via base-induced elimination of diphenylphosphinic acid from the mixed anhydrides to form ketenes which spontaneously cyclize. Acids have been converted to ketones via activation followed by reaction with organometallic reagents (eq 4)."... 

The most general synthetic route to ketones uses the reaction of carboxylic acids (or their derivatives) or nitriles with organometallic compounds (M.J. Jorgenson, 1970). Lithium car-boxylates react with organolithium compounds to give stable gem-diolates, which are decom-... 

Ketones can be prepared by trapping (transmetallation) the acyl palladium intermediate 402 with organometallic reagents. The allylic chloride 400 is car-bonylated to give the mixed diallylic ketone 403 in the presence of allyltri-butylstannane (401) in moderate yields[256]. Alkenyl- and arylstannanes are also used for ketone synthesis from allylic chlorides[257,258]. Total syntheses of dendrolasin (404)f258] and manoalide[259] have been carried out employing this reaction. Similarly, formation of the ketone 406 takes place with the alkylzinc reagent 405[260],... 

Organohthium and organomagnesium compounds find their chief use m the prepa ration of alcohols by reaction with aldehydes and ketones Before discussing these reac tions let us first examine the reactions of these organometallic compounds with proton donors... 

Zirconium tetrachloride is instantly hydrolyzed in water to zirconium oxide dichloride octahydrate [13520-92-8]. Zirconium tetrachloride exchanges chlorine for 0x0 bonds in the reaction with hydroxylic ligands, forming alkoxides from alcohols (see Alkoxides, METAl). Zirconium tetrachloride combines with many Lewis bases such as dimethyl sulfoxide, phosphoms oxychloride and amines including ammonia, ethers, and ketones. The zirconium organometalLic compounds ate all derived from zirconium tetrachloride. 

Reaction of organometallic compounds with enamine salts have been successfully used for the synthesis of some natural products (256). Thus reaction of the immonium salt of 0-alkylated enamino ketone 122 with isobutyllithium affords the compound 169. 

The presence of unsaturation in the side chain is also compatible with antihistaminic activity. Mannich condensation of p-chloroacetophenone with formaldehyde and pyrollidine affords the amino ketone, 109. Reaction with an organometallic reagent from 2-bromopyridine gives 110. Dehydration leads to triproli-dine (111). ... 

Reaction of Nitriles with Organometallic Reagents Grignard reagents add to a nitrile to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone. 

Reaction with an organometallic reagent to yield a ketone or an alcohol... 

The initial formation of an ate complex by attack of the nucleophile on the aluminum reagent, followed by reaction with the ketone, is unlikely since treatment of the ketone with a mixture of MAD and the organometallic reagent gave results comparable to those obtained with the organometallic reagent in the absence of MAD. 

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