Vilsmeier reaction, aliphatic

Although limited to electron-rich aromatic compounds and alkenes, the Vilsmeier reaction is an important formylation method. When yV,A-dimethylformamide is used in excess, the use of an additional solvent is not necessary. In other cases toluene, dichlorobenzene or a chlorinated aliphatic hydrocarbon is used as solvent. ... 

Formylation of alkenes can be accomplished with N-disubstituted formamides and POCl3. ° This is an aliphatic Vilsmeier reaction (see 11-15). Vilsmeier formylation can also be performed on the ot position of acetals and ketals, so that hydrolysis of the products gives keto aldehydes or dialdehydes ... 

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. 

There is now general agreement that Vilsmeier reactions with acetals, ketals, and the corresponding thio derivatives proceed by loss of a molecule of alcohol or thiol to give the reactive unsaturated ether or thioether with cyclic ketals the alcohol remains tethered, and may be chlorinated. The acetals and ketals are often more readily available than the unsaturated ethers, and yields of products are similar. A wide range of aliphatic and alicyclic acetals and ketals has been formylated the reaction can tolerate bulky groups at either end of the double bond, as is shown for compound 64 (Eq. 51). Products are isolated as iminium sails... 

Much of the research on Vilsmeier reactions in the past 50 years has focused on expanding the scope of this transformation. Whereas the reaction was once limited to electron-rich aromatics and heteroaromatics, aliphatic substrates have increasingly been found to react with Vilsmeier reagents. Furthermore, alternate transformations of the iminium intermediate to form products with functional groups other than aldehyde have been developed. Finally, access to a diverse range of heterocycles is now possible due to discovery of substrate classes that are capable of undergoing intramolecular annulation reactions on the iminium intermediate. 

It is apparent that the formation of the furo[2,3-l>]quinoxalin-2-one derivative 108 proceeds via the initial formation of compound A according to the first stage of the aliphatic Vilsmeier reaction, performed on the methylene group of the substituent at position 3 of quinoxalin-2(lfl)-one 103. The latter undergoes intramolecular cyclization with the subsequent elimination of EtOH and HCl results in the final product 108 (Scheme 6.36). 

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. ... 

Preparation.—From Alcohols or other Halides. Factors affecting the formation of isomerically and optically pure alkyl halides from saturated aliphatic alcohols have been discussed by Hudson and co-workers. - Reactions with thionyl chloride give reduced amounts of rearrangement products if pyridine hydrochloride is added, and isomerically pure chlorides RCl from almost all alcohols ROH if HMPT or DMF is the solvent. In the latter medium (58) is a presumed intermediate, as is the case in the reaction of alcohols with Vilsmeier reagents (59, X = Cl or Br). Such species produce halides via inversion of configuration from secondary alcohols, presumably according to Scheme 24. In the related reaction of PCI3 with unhindered primary alcohols in DMF to produce alkyl... 

Aryl ketones are frequently prepared by Friedel-Crafts reactions an aliphatic version is known but is much less common. Examples are given in Figure 19.29. It is also possible to substitute an aldehyde group directly onto an aryl ring (Figure 19.30). The first reaction is the one that we already know—the Gattermann-Koch process. The other is the Vilsmeier-Haack reaction—which is... 

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