Formamides, and phosphorus oxychloride

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),... 

The Vilsmeier reaction has been applied to indolizines to yield a variety of products. The normal reaction conditions with jV,jV-dimethyl-formamide and phosphorus oxychloride can give the indolizine-1-aldehyde,168 e.g., with 6-ethyl-2,3-dimethylindolizine. However, N,N-dimethylacetamide with 5-methyl-2-phenylindolizine gave a mixture of isomers, 105 and 106, with the former predominating.165 Hydrolysis of 105 gave enamine 107 instead of the acetyl compound. 

Vilsmeier-Haack reaction. Formulation of activated aromatic or heterocyclic compounds with disubstituted formamides and phosphorus oxychloride. 

An attractive novel preparation of isoquinolones proceeds through reaction of a homophthalic acid with dimethyl formamide and phosphorus oxychloride, as described in Scheme 3.1. The alkaloid doryanine was prepared in good yield by this method. ... 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

C. a-Tosylbenzyl isocyanide (3) (Note 9). A 1-L, three-necked, round-bottomed flask fitted with an overhead stirrer, a 100-mL addition funnel and a temperature probe is charged with 200 mL of tetrahydrofuran (THF) (Note 10) and 27.6 g (94.8 mmol) of N-(a-tosylbenzyl)formamide (2). Phosphorus oxychloride (17.7 mL, 190 mmol) (Notes... 

The acaricidal properties of N,N-dimethyl-N -(4-chloro-2-methylphenyl) form-amidine (chlorphenamidine, 13) have been described by Dittrich (1966). The compound is prepared by the condensation of 4-chIoro-2-methylaniiine and dimethyl formamide with phosphorus oxychloride (Arndt and Steinhausen, 1963). 

Although Vilsmeier and Haack in 1927 were the first who recognized the general applicability of this method, Dimroth and Zoeppritz in 1902 had obtained dihydroxybenzaldehyde from resorcinol, formanilide, and phosphorus oxychloride. The modern mechanistic interpretation of this reaction was advanced by Arnold and Sorm Jutz and Bosshard and Zollinger (, 43 example, when a suitable substrate, such as N,N-dimethylaniline, is treated with the phosphorus oxychloride complex of a N,N-disubstituted formamide, the intermediate iminium chloride... 

Phosphorus oxychloride, dehydration of formamides with, 41, 13, 101 removal from reaction of cyanoacetic acid and phosphorus pentachlo-ride, 41,5,7... 

Anthrapyrimidine and its substituted derivatives are obtained by condensation of 1-aminoanthraquinone (or its derivatives) with formamide or aqueous form-aldehyde/ammonia in the presence of an oxidant, such as ammonium vanadate or m-nitrobenzosulfonic acid. A newly developed, more simple route proceeds via formamidinium chloride, which is prepared from 1-aminoanthraquinone with di-methylformamide and thionyl chloride or phosphorus oxychloride. Cyclization in a solvent in the presence of ammonium acetate affords the desired product ... 

Fused cyclic system 340 can be obtained by type (i) reaction through the reduction of the nitro aldehyde intermediate 339 and its sequential cyclization in acetic acid. Alternate type (iii) process starts from the corresponding formamide 341 that can be cyclized with phosphorus oxychloride by a Bischler-Napieralski reaction (Scheme 72 (1994JHC1033)). 

The starting material (48-1) for a pyrrazolopyridazine can be obtained by treating the corresponding enol, which is simply the condensation product of methylmaleic anhydride and hydrazine, with phosphorus oxychloride. Reaction with piperazine leads to the displacement of the sterically more accessible chlorine to afford the alkylation product (48-2). Treatment with hydrazine leads to the replacement of the remaining halogen and the formation of (48-3). The missing carbon is, in this case, supplied by formamide to afford zindotrine (48-4) [51], a compound that shows activity as a bronchodilator. 

The of N-[2-(4-bromophenyl)-2-oxoethyl]-[[(2,4-dioxo-l-imidazolidinyl) imino]methyl]formamide (22.0 g, 0.061 mole) was combined with phosphorus oxychloride (310 ml) and the mixture was stirred and refluxed for 7 h. The solid was filtered off and stirred into an ice and water mixture (1 L). The 15.0 g (70%) of l-[[[5-(4-bromophenyl)-2-oxazolyl]methylene]amino]-2,4-imidazolidinedione was collected by filtration, melting point 290°-292°C (recrystallization from 700 ml acetic acid). 

Successive reduction of l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]-thiophen-4-one (Section III,C) with sodium borohydride and dehydration of the resulting alcohol with polyphosphoric acid gives the unstable 1,3-dimethyl derivative [(18) R = H] in excellent yield,35 and successive treatment of the same ketone with methylmagnesium iodide and acid gives the 1,3,7-trimethyl derivative [(18) R=Me] (Table IV) and a second compound which is reported to be a dimer. 36 When l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one is treated with a mixture of phosphorus oxychloride and dimethyl-formamide (Vilsmeier-Haack formylation), it gives compound 19, which yields 20 on being treated successively with thioglycolic acid... 

Selenophene and its homologs are easily formylated by dimethyl-formamide in the presence of phosphorus oxychloride as usual the formyl group always enters the a position.70 Methyl selenophenes are formylated under milder conditions than is the unsubstituted selenophene.71 2-Methylselenophene gives the 5-formyl,71 and 3-methyl-selenophene the 2-formyl derivative.55... 

Other variations include formamide (57JA6421), sodium dithioformate or phosphorus oxychloride-DMF (69RTC1263), a thioamide (78MI41000) and acetylacetone (77JHC813). Reduction of 2,6-dibenzamido-3-(2-butoxypyrid-5-ylazo)pyridine with iron and hydrochloric acid resulted in ring closure to 5-benzamido-2-phenylimidazo[4,5-f>]pyridine (60AC(R)125). 

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