Vilsmeier-Haack aldehyde synthesis

Iminium chlorides have become valuable synthetic tools, as evidenced by the work of Zollinger and his colleagues in Switzerland, Arnold and his co-workers in Czechoslovakia, and Eilingsfeld et al. in Germany. The intermediacy of iminium chlorides in the Vilsmeier-Haack aldehyde synthesis is well established. 

If the self-condensation of the iminium chlorides is minimized by suitable substitution, reaction with other reactive substrates is readily accomplished. Perhaps the best-known example of this type of reaction is the Vilsmeier-Haack aldehyde synthesis (121,285,286 general review of this reaction can be found in Houben-Weyl ( ). 

The Vilsmeier-Haack aldehyde synthesis is especially useful for the synthesis of heterocyclic aldehydes. Thus, formylation of pyrroles (112,220.240,246 tetrahydroquinolines indoles (25o,306 naph-thostyryl carbazoles (82.84.238 benzazepines thiophenes (S i 181,236,301,302j 2,2 -bithenyl ( ), thionaphthenes thiazines di-... 

Vilsmeier-Haack formylation Synthesis of substituted benzaldehydes and heteroaromatic aldehydes using chloromethyliminium salts. 468... 

The 5//-pyrido[4,3-f ]benzo[/]indole ring system (e.g., 192) represents another type of isoellipticine, and its synthesis has been explored by Bisagni and co-workers (95) (Scheme 33). Azaindole 188 was elaborated by means of conventional lithiation methodology to alcohol 189. A sequence of dehydration, hydrogenation, and chlorination gave 190. Either Vilsmeier-Haack conversion to aldehyde 191 and polyphosphoric acid (PPA) cyclization to the desired ring system 192 or direct cyclization to 192 completed the synthesis. The side chain amines were introduced by heating the components neat to provide 193-195. The methoxyl derivatives 196 and 197 were also synthesized (95). 

There are several methods for the direct introduction of an aldehyde group into an aromatic compound. In the Vilsmeier-Haack reaction, activated aromatic systems such as aryl ethers and dialkylanilines are formylated by a mixture of dimethylformamide, HCONMe2, and phosphorus oxychloride, POCL, (Scheme 6.4). The process involves elec-trophilic attack by a chloroiminium ion, Me2N=CHCl, formed by interaction of dimethylformamide and phosphorus oxychloride. Hydrolysis of the dimethyl imine completes the synthesis. 

In a related reaction, the Gattermann aldehyde synthesis, the carbon monoxide of the previous reaction is replaced by hydrogen cyanide (Scheme 6.6). This reaction gives poor yields with benzene itself, but is successful with activated species such as aryl ethers and phenols. The reaction proceeds via an aryl imine and the mechanism is not dissimilar to that of the Vilsmeier-Haack reaction. 

Another acylation procedure uses iminium salts rather than acyl halides. The Vilsmeier-Haack reaction is a well-known process illustrated by reaction of pyrrole with the POCI3 complex of N,N-dimethylacetamide (207, which can decompose to a chloroiminium salt). The acylation reaction gave 208, which was converted to 2-acetylpyrrole by hydrolysis with aqueous sodium acetate.A synthetic example is taken from Lai s synthesis of indole analogs of mycophenolic acid,l in which 209 reacted with POCI3 and DMF to give a 77% yield of the aldehyde 210. 

Vilsmeier-Haack Formylation with N,N-Dimethylformamide. In the presence of phosphorus oxychloride (POCI3), the—CHO group of N,N-dimethylformamide can be attached to the pyrrole ring (Scheme 7.7). This is a highly useful process for the synthesis of pyrrole aldehydes, which are precursors of pyrrole acids by oxidation, of pyrryl carbinols by reductions with LiAHtj, and of other products (Scheme 7.7). 

This reaction is related to the Friedel-Crafts Acylation, Reimer-Tiemann Reaction, Houben-Hoesch Reaction, Gatterman Aldehyde Synthesis, and Vilsmeier-Haack Formylation. 

As our final example of the use of phosphorus in organic synthesis, we will choose the Vilsmeier-Haack reaction, the classic method for electrophilic formylation (addition of an aldehyde functionality) of aromatic rings with POCI3 and dimethylformamide (DMF, HCONMc2). 

A novel synthesis of isoselenazoles (150), using bromoseleno-intermediates in the final cyclization stage, comprises the successive treatment, at -80 C, of selenoethers of type (148), e.g. cis-/3-methylseleno-2-propenal, with bromine and ammonia it generally affords the desired heterocycles in very good yield. The precursors (148) are ultimately derived from the appropriate ketones (146), which are first converted into the chloro-aldehydes (147) by the Vilsmeier-Haack reaction, and then treated with methaneselenol in pyridine-triethylamine. They arise as mixtures of cis- and trans-isomers, separable by spinning-band fractional distillation. The u.v. and n.m.r. spectra of the isoselenazoles were recorded and discussed. ... 

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