Formamides, and phosphorus

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. ... 

Amino-pyridazines and -pyridazinones react with monomethyl- or iV,A-dimethyl-formamide and other aliphatic amides in the presence of phosphorus trichloride, thionyl chloride, phosgene or benzenesuUonyl chloride to give mono- or di-alkylaminomethyl-eneamino derivatives. The same compounds can be prepared conveniently with A,iV-dimethylformamide dimethyl acetal in high yield (Scheme 50). 

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) ... 

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

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... 

Synthesis of 2-unsubstituted 1,3-selenazoles 24 has been reported by reactions of selenoformamides with a-bromoketones. Selenoformamides are prepared by the reaction of formamide with phosphorus selenide using ultrasound. Because of the unstable nature and volatility of 2-unsubstituted 1,3-selenazoles, the yields are relatively low, 6-28%. The cyclizations were achieved in the presence of either pyridine or an acidic ion exchange resin. The absence of base or the use of sodium acetate resulted in formation of considerable amounts of diphenacyl selenides (ArCOCH2)2Se (Scheme 6) <2005EJO3637>. 

Adjacent ketone and nitrile groups are annulated by heating the compound with formamide and either phosphorus oxychloride or (often for a higher yield) ammonia. 

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). 

N.Q.R. The C1 n.q.r. spectra of cyclic 1,3,2-/i -diazaphosphorines correlate with parameters estimated by CNDO/2 calculations. The structures of the intermediates produced in the reactions of formamides and acetamides with phosphorus pentachloride and phosphoryl trichloride have been studied by n.q.r. spectroscopy. The stereochemistry of dichlorodiazadiphosphetane has been studied, and evidence on the polarity of radial chloride atoms in chlorophosphoranes discussed. ... 

Tetrachloropyrimidine is formed in quantitative yield by the cyclization (with FeCla, at 200 °C) of perchloro-l-cyano-3-azabutadiene (Cl2C=N—CC1=CC1CN), itself formed by successive treatment of cyanoethyl)formamide with phosphorus pentachloride and chlorine. j8-Iminoyl-enamines (222), prepared by the reaction of the appropriate anils with nitriles, condense with ethyl chloroformate and carbon disulphide to give excellent yields of 2-oxo- and 2-thioxo-pyrimidines (223 X = O or S). Aldehydes, acetals, and ketals (but not ketones) also react with these enamines (222) to give 1,2-dihydropyrimidines (224) (70—93%). In similar fashion, malondiamidines condense with a large variety of aromatic aldehydes to give 2-aryl-5-arylmethyl-4,6-diaminopyrimidines. °... 

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... 

A mixture of the formamide 1637 (7.81 g, 25 mmol) and phosphorus penta-chloride (5.21 g, 25 mmol) in anhydrous tetrachloromethane (50 mL) was stirred at 50 °C for 30 min. The solvent was then evaporated under reduced pressure and the residue was redissolved in absolute Et20 (200 mL). The solution was stirred at 0-5 °C, and triethylamine (6.07 g, 60 mmol) was very slowly added dropwise. After standing overnight in a refrigerator, the EtaN HCl deposited was filtered off, the solvent was evaporated from the filtrate, and the residue was chromatographed on a silica gel column (EtOAc) yield 83%. 

Anhydride Formation. Among other anhydride-forming reagents, including Acetic Anhydride, Trifluoroacetic Anhydride, and Phosphorus(V) Oxide, DCC is one of the simplest, mildest, and most effective reagents for the preparation of symmetrical anhydrides, including formic anhydride, which is useful in the preparation of formamides (eq 2). 

The development of a brown color indicates that sufl cient phosphorus oxytrichloride has been added. If the mixture remains colorless, the final product is likely to be contaminated with unreacted iV-( -tolylsulfonylmethyl)formamide. It is therefore advantageous to add more phosphorus oxjrtrichloride and continue stirring until the brown color is obtained. 

Triazole has been prepared by the oxidation of substituted 1,2,4-triazoles, by the treatment of urazole with phosphorus pentasulfide, by heating equimolar quantities of formyl-hydrazine and formamide, by removal of the amino function of 4-amino-l,2,4-triazole, by oxidation of l,2,4-triazole-3(5)-thiol with hydrogen peroxide, by decarboxylation of 1,2,4-triazole-3(5)-carboxylic acid, by heating hydrazine salts with form-amide,by rapidly distilling hydrazine hydrate mixed with two molar equivalents of formamide, i by heating N,N -diformyl-hydrazine with excess ammonia in an autoclave at 200° for 24 hours, and by the reaction of 1,3,5-triazine and hydrazine monohydrochloride. ... 

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