By the Vilsmeier reaction

Reaction of 3-methyl-6-methylaminouracil 494 with 495, obtained by the Vilsmeier reaction of ethyl acetoacetate and ethyl benzoylacetate, or with vinyl ketones 496 under a modified procedure previously described <1984CPB1699, 2002H(57)491>, afforded the pyrido[2,3-,71pyrimidine derivatives 497-500 (Scheme 21) <2004H(63)1393>. 

This compound has a -CH-CHC -OH group attached to pyrrole at position 2. The best method of achieving this is by the Vilsmeier reaction to form pyrrole-2-carbaldehyde, followed by the Reformatsky reaction to form the given product ... 

Bu, -BrCgH, 4-HOCgHjj, 4-MeOCgHjj, R =Me,PhCH, R =CHO) are prepared from the parent compounds (95 R =H) by the Vilsmeier reaction. 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

Vinylogous forma mides have been obtained by double Vilsmeier reactions of methyl ketones (53,54), 4-methylpyridine (53,54), and olefinic (55) compounds. The dienamine intermediates were demonstrated in the latter cases. 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

In the Meth-Cohn quinoline synthesis, the acetanilide becomes a nucleophile and provides the framework of the quinoline (nitrogen and the 2,3-carbons) and the 4-carbon is derived from the Vilsmeier reagent. The reaction mechanism involves the initial conversion of an acylanilide 1 into an a-iminochloride 11 by the action of POCI3. The a-chloroenamine tautomer 12 is subsequently C-formylated by the Vilsmeier reagent 13 derived from POCI3 and DMF. In examples where acetanilides 1 (r = H) are employed, a second C-formylation of 14 occurs to afford 15 subsequent cyclisation and... 

An elegant application of the Vilsmeier reaction is the synthesis of substituted biphenyls as reported by Rao and RaoJ Starting with homoallylic alcohol 8, the biphenyl derivative 9 was obtained from a one-pot reaction in 80% yield ... 

Benzoisobacteriochlorin 14 can be prepared from nickel(II) chlorin 12 by vinylogous Vilsmeier reaction to give 13 and subsequent acid-induced cyclization.22 The chlorin 12 is, as expected, alkylated in a meso position adjacent to the reduced pyrrole ring. 

Acid-induced cyclization of the appropriate (hydroxypropenyl)pyrroles 30, which can be easily derived from a-unsubstituted pyrroles by vinylogous Vilsmeier reaction followed by reduction of the formyl function, yields the corresponding expanded porphyrinogens 31. The... 

Reaction of 256 with phosphorous oxychloride and DMF involves first formylation at the 6-position opening of the ketal to the enol ether by the HC1 produced in the Vilsmeier reaction would afford a hydroxyethyl side chain at C-3. This is no doubt converted to a chloroethyl group by excess oxychloride. There is thus obtained the antiinflammatory agent formocortal (257). 77... 

The formyl group is generally introduced via the Vilsmeier reaction by dimethylformamide in the presence of phosphorus oxychloride, by the Sommelet reaction via the corresponding chloromethyl derivative, or by treating the lithio compound with dimethylformamide.87... 

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>. 

Similarly, aminopyrimidine 67 was treated with a-bromoketone 68 to produce 69, an intermediate used by Laneri and co-workers in subsequent studies of the Vilsmeier reaction in the synthesis of various imidazopyrimidines <00JHC1265>. 

When DMF and phosphorus oxychloride are reacted together in the Vilsmeier reaction, the A,A-dimethylamino(chloro)methyleniminium cation is generated, and this reacts with indole at 5 °C to give 3-(A,A-dimethylaminomethylene)indolenine (see Section 6.1.2). When hydrolysed by treatment with dilute sodium hydroxide, this gives an excellent yield of 3-formylindole (Scheme 7.5). 

Compound 246 was prepared by a Vilsmeier reaction analogous to that shown in Scheme 16 for the synthesis of 196 <1972CPB1325>. The halogenation and subsequent elimination of HCl from 251-253 is made possible by the ester substituent at the 3-position (Scheme 40) <1973J(P1)1321>. 

Shkurko and Mamaev50,408 have studied the l//-benzothieno[3,2-6]-pyrrole system 391 extensively. Electrophilic substitution (e.g., Mannich reaction, acetylation, diazonium coupling) takes place at C-2, as predicted by MO calculations.4080 If position 2 is occupied, substitution occurs at C-3.44 The Vilsmeier reaction on the 2-aryl derivative gave the expected product, but bromination of the parent system 391 failed. A 3-bromo derivative was successfully obtained from the N-methyl compound 392 with bromine in chloroform.44... 

In structural and synthetic chemistry, we also find instances of reconsideration 3-(3-methoxyphenoxy)-2-butanone gives by ringclosing dehydration a mixture of 2,3-dimethyl-4-methoxybenzofuran and 2,3-dimethyl-6-methoxybenzofuran,101 not just the 6-derivative.102 2-Ethyl-7-methoxybenzofuran is not formylated in position 3 by the Vilsmeier-Haack reaction, but in position 4.10,103... 

Acylpyrroles can also be prepared by using the Vilsmeier reaction with various amides. Excellent yields of 2-aroylpyrroles were obtained using morpholides instead of the more common N,N- dimethylamides (equation 178) (77JOC4248). Similarly, a variety of 3-acylin-doles have been prepared using the Vilsmeier-Haack reaction (79HC(25-3)357). 

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