Anhydrides, reaction with amide enolates

An alternative one-step polar cyclization procedure involves the condensation of n nucleophiles with amides to efficiently produce highly substituted pyridines <07JA10096>. As shown below, acetylenes 5 or enol ethers 6 react with electron-poor and electron-rich N-vinyl and A-aryl amides 7 that are activated with triflic anhydride in the presence of 2-chloropyridine. This novel method employs mild reaction conditions and provides rapid access to highly substituted pyridines 8 with good regiocontrol. 

Amides are converted to enamines by reaction with the Tebbe reagent (equation 24), whereas acyl halides lead to enolates (equation 25). Anhydrides lead to a combination of enolate formation, methyl-enation and enolization. ... 

Various preparation methods have been described. Wiley (1945, 1947) converted a-amino acids to acetdmido ketones by reaction with acetic anhydride in pyridine and obtained 2,5-dimethyl-4-substituted oxazoles after dehydration of the enol form of the intermediate. Theilig (1953) applied the reaction of a-bromoketones with the appropriate amides. 

Perhaps the most interesting developments in the area of selective lithiations to appear this year have been concerned with the control of absolute stereochemistry. The application of chiral amide bases to the enantioselective deprotonation of epoxides was first described some years ago by Whitesell and co-workers, but this year several groups have reported on other aspects of these useful reaqents. Symmetrically substituted ketones (5 R=Me, CH2Ph) have been shown by Simpkins to undergo an enantioselective deprotonation under kinetically controlled conditions to give, after reaction with an electrophile (iodomethane, allyl bromide or acetic anhydride), optically active ketones (6) or enol acetates (7) (Scheme 2). The ability of a number of bases to discriminate between the two prochiral protons present in (5) were evaluated and the most effective of those studied was the camphor derivative (8) deprotonation of (5 R=Me) proceeded in 74% enantiomeric excess... 

Since the discovery of Pd-catalyzed carbonylation of aryl, vinyl, and benzyl halides by Heck in 1974, this reaction has been used for the synthesis of ester, amide, acid, and acid anhydride. We can nse enol triflate, aryl Iriflate, aniUne derivatives, and vinyl silane as the pseudo aryl or vinyl halide. This reaction has now been further extended for the synthesis of aldehyde and ketone by combination with transmetalation. These reactions have widely been used in organic syntheses, especially the syntheses of biologically active substances in the field of fine chemistry and the syntheses of natural products. 

Aldehydes react with the lithio-derivatives of a-diazo-esters to give /3-hydr-oxy>a-diazo-esters, which in turn undergo rhodium(ii)-catalysed decomposition to give /3-keto-esters./3-Keto-amides are obtained in moderate to high yield from the acylation of amide enolates with mixed anhydrides. In a general reaction, orthoformates react with acidic methines to give /3-keto-aldehydes, isolated as their dialkyl acetals [equation (16)]. ... 

Miscellaneous Reactions. Pantothenic acid has been coupled to a long chain amine with reagent K (eq 8). This is another example of the nonreactivity of hydroxyl groups with the enol ester intermediate. Attempts to prepare this amide through the mixed anhydride procedure give low yields. 

Cyclobutanones (11, 560-561). Ketenimium salts are more reactive than ke-tenes in [2 + 2] cycloadditions with alkenes to prepare cyclobutanones. The salts are readily available by in situ reaction of tertiary amides with triflic anhydride and a base, generally 2,4,6-collidine. The cycloaddition proceeds satisfactorily with alkyl-substituted alkenes and alkynes, but not with enol ethers or enamines.1... 

A similar sequence was reported where the asymmetry was introduced by the reaction of weio-3-substituted glutanc anhydrides and (S)-methylbenzylamines to give diastereomeric hemiamides that could be separated by recrystallization The asymmetnc desymmetrization of certain 4-aryl substituted glutanmides has also been accomplished with high levels of selectivity (up to 97% ee) by enolization with a chiral bis-lithium amide base. The selectivity of the reaction was shown to be the result of asymmetric enolization, followed by a kinetic resolution." ... 

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary. The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configuration shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to the appropriate enolate is a widely used method for producing the enantiomers of a-alkyl substituted carboxylic acids...

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