Formylation using Vilsmeier reagent

Substituted acetophenones were irradiated in a domestic microwave oven with P0Cl3-DMF/Si02 to give /J-chlorovinylaldehydes in 2 min with yields of 75-88%. Under the same conditions, conventional heating lead to only 30-40% (Eq. 52). 

The specific microwave effect can be attributed to two different facts  

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Vilsmeier reagent The reagent obtained from POCI3 mixed with either N,N-dimethyl-formamide or N-methylformanilide. Used for introducing the methanoyl (formyl) (-CHO) group into activated aromatic substrates. 

Scheme 11.5 gives some examples of these acylation reactions. Entry 1 is an example of a chloromethylation reaction. Entry 2 is a formylation using carbon monoxide. Entry 3 is an example of formylation via to-chloromethyl ether. A cautionary note on this procedure is the potent carcinogenicity of this reagent. Entries 4 and 5 are examples of formylation and acetylation, using HCN and acetonitrile, respectively. Entries 6 to 8 are examples of Vilsmeier-Haack reactions, all of which are conducted on strongly activated aromatics. 

Vilsmeier formylation has attracted much attention as a route to cyclazines (see Section III,B,6). Jessep and Leaver have obtained the Vilsmeier salt 263 from 1 by using dimethylformamide and phosphoryl chloride at — 65°C, but the formylpyrrolizine was very unstable, and a second Vilsmeier reaction has not been achieved.128 The salt 263 could be converted to the 3,5-bisaldehyde equivalent 264a by treatment with dimethylthioformamide and acetic anhydride. Flitsch et al. prepared l-chloro-3H-pyrrolizine and treated it in situ at — 60°C with the Vilsmeier reagent to obtain the chloro derivative 259 of compound 263. 7 They also obtained the bis(dimethylaminomethylene) derivative 264b and, at room temperature, the tris(dimethylaminomethylene) derivative 265, which was hydrolyzed to give the dialdehyde 266. Reactions... 

Formylation.2 Dimethylformamide and trifluoromethanesulfonic anhydride form an iminium salt (1) that is more reactive than that formed from dimethylformamide and POCl3, which is generally used for formylation (Vilsmeier reagent). Although the Vilsmeier reagent does not react with naphthalene or phenanthrene, reactions with 1 results in 1-naphthalenacarbaldehyde in 50% yield and in 3-phenanthrenecarbaldehyde in 25% yield. 

An W-formylated dibenzodiazocine was isolated in some cases in very poor yield <1998J(P1)1257>. Using the same synthetic approach, a series of fused diazocines were obtained. Thus, the action of bis-Vilsmeier reagents derived from W,W -dimethyl-W,W -diformyl-4-phenylenediamine with 4-substituted AUV-dimethylanilines, the diben-zo[ ]benzo[l,2-/4,5-/]bis-l,5-diazocines were obtained <2000S640>. Benzo[2,3]pyrido[6,7-A]-l,5-diazocines were synthesized from a Vilsmeier reagent derived from 4-W-(methylformamido)pyridine reacting with 4-substituted... 

The most useful acylation reaction of azaindoles, as with indoles, is 3-formylation. This is carried out conveniently with the Vilsmeier reagent (phosphoryl chloride in dimethylformamide). 

Formylation of Hmoneae. (-i-)-(4R)-Limonene (1) is formylated by the Vilsmeier reagent (2) stereoselectively to give mainly the (E)-of,)3-unsaturated aldehyde 3. The product was used tor the synthesis of (4R),(E)-a-atlantone (5), a sesquiterpene from Cedrus oils. 

Paul, S., Gupta, M., Gupta, R. Vilsmeier reagent for formylation in solvent-free conditions using microwaves. Synlett 2000,1115-1118. 

Substituted 3-pyridinecarboxaldehydes can be prepared by Vilsmeier for-mylation of dihydropyridine intermediates. Various 3-substituted pyridines (161) can be transformed into 3-substituted l-(phenoxycarbonyl)-1,2-dihydro-pyridines (162) using NaBH4 and phenyl chloroformate in methanol. Treatment of these 1,2-dihydropyridines with Vilsmeier reagent (POCIj/DMF) gives 3-substituted 5-formyI-1 -(phenoxycarbonyl)-1,2-dihydropyridines (163), which are aromatized with sulfur to provide 5-substituted 3-pyridinecarboxaldehydes (164). The formylation of 4-substituted 1-(phenoxycarbonyl)-1,4-dihydropyridines 165 and subsequent aromatization give 3-pyridinecarboxaldehydes 166(87H2159). 

Usefully functionalised quinolines are easily accessible from anilines the iV-acetyl derivative is simply reacted with the Vilsmeier reagent and a 2-chloro-3-formyl-quinoline results. One may speculate that a... 

Formylation of trienes. Formylation of alkenes and dienes with the Vilsmeier reagent has been of limited value, but Dutch chemists find that formylation of trienes can be useful. Formylation occurs mainly at Ci (equation I) the reaction has been used for synthesis of dehydrocitral from 2,6-dimethyl-2,5-heptadienone (equation II). ... 

The Vilsmeier reagent prepared by treating DMF with COCI2 is a useful reagent in nudeic add chemistry, e.g. for chlorination and formylation of nucleosides, and in the synthesis of oligonucleotides [1315]. 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

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),... 

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