Ketones acyl substitution

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

This method accommodates aryl aldehydes with both electron-deficient and electron-rich aryl substitutents. Acetaldehyde is also a competent couphng partner, providing the corresponding amido ketone in 62% yield. Acyl substitution of the tosyl amide varies to include hydrogen, methyl, tert-butoxy, and phenyl producing the desired a-amido ketones in moderate to high yields. Expansion of this methodology to synthesize di- and tri-substituted imidazoles was reported by Murry and co-workers (Scheme 7) [54]. 

Russian authors investigated this important reaction type to prepare a wide range of aryl-, alkyl-, and acyl-substituted imidazo[2,l-ft]thiazoles (70KGS508, 70KGS512 71KGS389). Several 2-mercaptoimidazoles react with a-halo ketones in one step directly to the bicyclic products 35 under reflux in butanol or ethanol followed by basification. Yields vary between 52 and 99%, but the two-step cyclization route requires isolation of the intermediates 34 and subsequent heating in phosphorus oxychloride. 

In analogy with iron-catalyzed Barbier-type reactions with Sml2 (cf. Scheme 8.5), intramolecular nucleophilic acyl substitutions (SNt) can be used to prepare cyclic ketones from esters [50]. An illustrative example is shown in Scheme 8.13 [51], Again, tris(l,3-diphenyl-l,3-propanedionato)iron(III) [Fe(dbm)3] is used as the catalyst. Compound 40 is obtained as one racemic diastereoisomer. 

In 1993 Murai et al. [16] reported a rare example of the catalytic C-C bond formation between aromatic ketones or acyl-substituted heteroaromatics and cy-cloalkenes via activation of the C-H bond in the ortho position to the ketone functionality. These reactions are described in the chapter Activation of Inert C-H Bonds . 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

Ketones, aldehydes, and carboxylic acids all contain the carbonyl group, yet the reactions of acids are quite different from those of ketones and aldehydes. Ketones and aldehydes commonly react by nucleophilic addition to the carbonyl group but carboxylic acids (and their derivatives) more commonly react by nucleophilic acyl substitution, where one nucleophile replaces another on the acyl (C=0) carbon atom. 

Crossed Claisen condensations between ketones and esters are also possible. Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation. The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution and thereby acylates the ketone. 

As the imidazole nucleus does not undergo Friedel-Crafts acylation, ketone substituents must be introduced indirectly, either before the ring is formed34,41,210,275,435 or by modification of existing substituents.210 Roe210 prepared 2-acetylimidazole (92) by oxidation of l-(imidazol-2 -yl)ethanol (91) with chromic oxide in pyridine. The acyl-substituted imidazoles have distinctive infrared and ultraviolet... 

Alkenyl, Alkynyl, Aryl and Related Acids. Vinylphosphonates are an important group of compounds that have found use in organic transformations. They are also useful reagents for the synthesis of biologically active systems. The synthesis of vinylphosphonates is varied. However additional convenient routes to them are always welcome. Four recent reports demonstrated that zirco-nacycles (180), readily available from diethyl 1-alkynylphosphonates, are very useful precursors of different vinylphosphonates. They react with alkynes, aldehydes, ketones acyl chlorides and nitriles to produce, in a highly stereo- and regio-selective manner, substituted vinylphosphonates (181), (182), (183) (184) and (185) respectively (Scheme 46). 

Gomtsyan, A. Org. Lett. 2000, 2, 11. For a reaction with methyl esters with an excess of vinylmagnesium halide and a copper catalyst to give a 3-butenyl ketone by a similar acyl substitution-Michael addition route, see Hansford, K.A. Dettwiler, J.E. Lubell, W.D. Org. Lett. 2003, 5, 4887. Gomtsyan, A. Koenig, R.J. Lee, C.-H. J. Org. Chem. 2001, 66, 3613. 

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