Vilsmeier reagent, reaction with ketones

Vilsmeier reagent, reaction with ketones to form 0-chloro- ,3-unsaturated aldehydes, 46,19... 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Benzofuran-3(2/f)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2-acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[6]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3-substituted benzo[6]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. 

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. 

Vilsmeier reactions on 1,3-diketones, 1,4-diketones, and conjugated enones give cyclic products as shown by the reactions of compounds 86 (Eq. 81), 87 (Eq. 82), and 88 (Eq. 83). The reaction of the Vilsmeier reagent with a,jS-epoxy ketones also gives benzaldehydes or 1,3-phthalaldehydes (Eq. 83a) ... 

Chromones. 3-Substituted chromones, including isoflavones (3-arylchro-niones), can be prepared in fair to excellent yields by treatment of 2-hydroxy-phcnyl alkyl (arylalkyl) ketones (I) with BF3 etherate (exothermic reaction) in DMF. Metlianesulfonyl chloride in DMF (Vilsmeier reagent) is then added at 52 and (he reaction is warmed on a steam bath (90 minutes). Chromones (2) arc obtained in 65 96% yield. The function of BF , etherate is to deactivate the hydroxylalcd aromatic ring hy complex formation and thus prevent ring lormylalion. 

The formylation of polyene aldehydes and o,jS-unsubstituted ketones with the Vilsmeier reagent (DMF-POCI3) has been reported recently. For example, reaction of the ketones XXIV with the Vilsmeier reagent produces the iminium salts XXV, which are hydrolyzed to the aldehydes XXVI. The latter compounds form the conjugated ene-yne derivatives XXVII upon addition of their dioxane solution to dilute sodium hydroxide at 80-90°C... 

However, the reactions of most non-aromatic n nucleophiles with Vilsmeier reagents yield more complicated products." The reaction of the following ketone, via its enol tautomer, is illustrative. ... 

The Bishler-Napieralski reaction, described above, is a named reaction in which Vilsmeier formylation results in a molecule that can participate in a subsequent cyclization reaction, resulting in a net annulation. There are numerous other examples of similar tandem sequences, most of which are not named reactions, and they generally give only modest yields. For instance, when ketone 25 is treated with a Vilsmeier reagent, isoflavone 26 is produced in nearly quantitative yield. ... 

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-... 

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