Vilsmeier reactions

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). 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

Pyrrolo[2,3-d]pyrimidine, 5-cyano-bromination, 4, 506 Pyrrolo[2,3-d]pyrimidine, 5-nitroso-nucleophilic reactions, 4, 507 Pyrrolo[l, 2- c]pyrimidine-3-carboxylic acids methyl ester synthesis, 4, 293 Pyrrolopyrimidine-2,4-diones Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolopyrimidines synthesis, 4, 514, 517, 524, 527 Pyrrolopyrimidines, chloro-nucleophilic attack, S, 312 Pyrrolo[2,3-d]pyrimidines NMR, 4, 500... 

Sydnone, 3-p-nitrophenyl-4-phenyl-mass spectra, 6, 370 Sydnone, 3-phenyl-acetylation, 5, 58 6, 373 carbonylation, 6, 373 dipole moments, 6, 368 nitration, 6, 372 reduction, 6, 371 Vilsmeier reaction, 6, 373 Sydnone, 4-phenyl-3-p-tolyl-photolysis, 6, 374 Sydnone, 3-(3-pyridyl)-photolysis, 6, 375 Sydnone, 3-p-tolyl-dipole moments, 6, 368 Sydnones... 

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). 

Perumal investigated a novel variation that involved the combination of a Vilsmeier reaction with a Paal-Knorr condensation. Reaction of 3-benzoylpropionic acid (87) under Vilsmeier conditions furnished chloroformylfuran 88 in 75% yield, while reaction of acetonylacetone (89) provided formylfuran 90 in 60% yield." ... 

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

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 ... 

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. ... 

Direct Vilsmeier reaction can also be applied to chlorins as in the porphyrin scries32k (see Section 1.1.2.3.). An interesting extension to this approach is the vinylogous Vilsmeier reaction with / -(dimethylamino)acrylaldehyde.24 The products, e.g. 19, can be further used for instance in the transformation of nickel(II) octaethylchlorin 18 into isobacteriochlorins. 

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... 

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. 

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... 

Cinnamic acid esters can be converted to dienals via Grignard addition and Vilsmeier reaction (equation 184)306. 

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>. 

Convert indole to indolyl-3-methyl-ketone (I) by treating indolyl-Mg-Br (preparation already described) with acetyl-Cl, by treating indole in POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole with diketene (ACS 22,1064(1968)). 15.9 g (1) in 50 ml methanol cool, stir and add dropwise 16 g Br2. Reflux 1 Vi hours on water bath cool, filter, wash with ether and recrystallize-methanol to get 18 g indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (II) in 60 ml warm isopropanol and add 11 g 3 8% aqueous DMA (or equimoiar amount other amine) reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g indolyl-3-dimethylamino-methyl ketone (III). Add 4.6 g (0.02 M) (III) in 30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml tetrahydrofuran, stir one-half hour at room temperature and reflux two hours. Add a little water dropwise and extract the precipitate with acetone. Dry, evaporate in vacuum the combined organic phases to get an oil which will precipitate with ether-petroleum ether to give DMT. (Ill) should be tested for psychedelic activity. Dialkyltryptamines BCSJ 11,221 (1936), BSC 2291 (1966)... 

A Vilsmeier reaction of pyridine-2-carbonitriles 126 was found to produce mixtures of l-formyl-2-dimethyl-amino[l,5-4]pyridines with a chlorine atom 127 or a hydrogen 128 at the C-7 position < 1998J(P 1 )3851 >. When extended to isoquinoline-1 -carbonitriles such as 129, this reaction gave in modest yield compounds 130 (Scheme 40). Later on, it was demonstrated that this reaction leads to imidazo[l,5- ]pyridinium chlorides when A,A-dimethylbenzamides were used instead of dimethylformamide (DMF) <1999H(50)887>. 

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