Vilsmeier reaction, intramolecular

Because isoquinolines are dealt with in more detail in Chapter 51, we will give just one important synthesis here. It is a synthesis of a dihydroisoquinoline by what amounts to an intramolecular Vilsmeier reaction in which the electrophile is made from an amide and POCI3. Since, to make the isoquinoline, two hydrogen atoms must be removed from carbon atoms it makes more sense to use a noble metal such as Pd(0) as the oxidizing agent rather than the reagents we used for pyridine synthesis. 

Conducted in an intramolecular sense, both Mannich and Vilsmeier reactions have been much used for the construction of tetrahydro-/3-carbolines (dihydro-/ -carbolines), such as are found in many indole alkaloids (/ -carboline is the widely-used, trivial name for the pyrido[3,4-Z>]indole). 

Isatins are indole derivatives with broad use in synthetic dye production and are intermediates in the synthesis of other heterocyclic molecules/ They also possess a variety of biological activities/ Aksenov et al. reported a one-pot synthesis of isatins using ethyl nitroacetate with substituted benzenes such as anisole (159) in polyphosphoric acid fScheme 5.38)/ The process for isatin formation likely includes a hybrid between the Nef and Vilsmeier reactions of anisole 159 and nitro ester 160 to form the oxime intermediate 161, which then undergoes a Beckmann rearrangement to give the anilide 162. Subsequent intramolecular acylation yields isatin 163. 

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. 

The Vilsmeier reaction is used to this day in largely the same way as it was originally conceived, though its substrate scope continues to expand. One important variation, known as the Bischler-Napieralski isoquinoline synthesis, involves an intramolecular Fiedel-Crafts acylation reaction where the acylating agent resembles a Vilsmeier electrophile. If the acylated phenethylamine substrate contains an a-hydroxyl group, a subsequent dehydration yields an isoquinoline. ... 

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 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),... 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

Thermolysis of the formamidrazone 590, obtained from the reaction of hydrazine 488 with Vilsmeier salt 589, at 200°C or on boiling in nitrobenzene led, by intramolecular transformation, to the triazolo[4,3-c]pyrimidine 591 (90T3897). Aryl isocyanide dichlorides reacted with 488 in the presence of Et2N to give 3-anilinotriazolopyrimidines (592) (Scheme 117). 

The well-known Bischler-Napieralski reaction, in effect an intramolecular Vilsmeier cyclization, is reviewed elsewhere.65... 

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