Ketones Vilsmeier synthesis

The Gattermann-Koch reaction when appHed to alkenes or alkanes gives ketones or acids but not aldehydes. However, the Vilsmeier aldehyde synthesis can be appHed to aUphatic compounds. For example, 1,2-diaLkoxyethylenes react with /V-methy1foTmani1ide and POCl to give alkoxymalondialdehydes ... 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

Although the Vilsmeier reaction is known best in aromatic systems, aliphatic olefins also undergo formylation. Synthesis of forwocortal (257) involves such a step. Formation of the monoketal of 255 involves the 3-ketone function with the familiar concomitant shift of the double bond to C-5,6. 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

The synthesis of polymethines with dimethylene bridges starts with alicydic ketones (31), ketals (32), and enamines (X = NR2), or enol ethers (X = OR) (33). They possess two activated centers, methine or methylene groups, which react with Vilsmeiers reagent to produce the corresponding dyes. 

In their quest to synthesize quinolines without the need to involve metalated species as cross-coupling partners, Banwell and coworkers have devised a two-step procedure wherein the first step is the palladium[0]-mediated Ullmann cross-coupling of 1-bromo-2-nitroarenes (e.g. 173) with p-halo-cnals [74]. The resulting p-nitroaryl enal undergoes reductive cyclization, in the style of the Friedlander quinoline synthesis, to give the corresponding quinoline. A wide range of quinolines can be accessed by this method since many l-halo-2-nitroarenes are commercially available and p-halo-cnals such as 174 can be easily prepared by Vilsmeier haloformylation of the appropriate ketones. 

An early approach to the synthesis of cephalotaxine (Scheme 32) was reported by Dolby et al. (64) in 1972, shortly before Auerbach s and Wein-reb s report (22). The Vilsmeier-Haack condensation of piperonylamide 187 with pyrrole yielded ketone 188, which was successively reduced with sodium borohydride, hydrogenated, and acylated to give the precursory chloro amide 189. The photocyclization of 189 produced lactam 190, which, after reduction of the carbonyl with lithium aluminum hydride and subsequent oxidation with mercuric acetate, yielded the enamine 43. This mate-... 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Asokan et al. has developed a practical synthesis of 4-chloropyridines 1 from carbonyl compounds having two enolizable carbons adjacent to the carbonyl such as compound 2 <04T5069>. Ketone 2 was subjected to Vilsmeier-Haack reaction conditions leading to the... 

The failure of pentafluoroacetophenone to undergo the normal reaction of aryl alkyl ketones with Vilsmeier-Haack reagent (POCl -HCO-NMe2) (Vol. 1, p, 199) has been attributed to steric hindrance around the carbonyl group. This conclusion is supported by the normal behaviour of the vinjiogue, rrons-GiFs-CHtCH--COMe (obtained via a diethyl malonate synthesis from pentafluorocinnamoyl chloride), which on treatment with POCls-HCO-NMes and then aqueous per-... 

The methods of synthesis, properties, and reactions of j8-chloro-a/3-unsaturated aldehydes have been reviewed.In a recent innovation 8-chloro-a 8-unsaturated aldehydes are available through Vilsmeier formylation of ketones. ... 

With the above methodology in hand, a similar strategy was attenq)ted for the synthesis of the aryl acetic acid 7 (Scheme 7). The aniline 5 was treated with 2,5-dimethoxytetrahy ofuran in toluene and acetic acid to get the W-aryl pyrrole 28. The Vilsmeier/Triedel-Crafts acylation of 28 followed by decarbonylation afforded the keto ester 30. However, the reduction of the keto ester proved to be difficult. Most of the general methods employed for the reduction of ketones gave a mixture of products. However, a two step process involving the formation of the thioketal 31 followed by desulfurization with Ni proved to be successful. Although, the standard Wolff-Kishner conditions could not be employed in the system due to the susceptibility of the nitrile to hydrolysis, a modified Wolff-Kishner reduction (8) proved to be fruitful. 

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