With Formamide

In 1895, Niementowski discovered the reaction that still bears his name the condensation of 2-aminobenzoic acid (anthranilic acid) with formamide to give quinazolin-4-one. He used two molecular equivalents of formamide and heated at 125°C for 3 hr.279 The yield is excellent, even on the 500 g scale.280 The reaction also goes well when the benzene ring is substituted, whether by electron-attracting or electron-releasing substituents.1 The course of the reaction is as follows.281,282 Ammonium-2-formamidobenzoic acid is first formed and can be isolated when the reaction is run at a lower temperature. At 130°C, this salt is dehydrated to 2-formamidobenzamide (163), which slowly cyclizes to quinazolin-4-one. 

Attempts have been made to improve yields by (a) starting with the preformed ammonium salt,283 (b) doubling the proportion of formamide,282 or (c) running the reaction at a low and then a higher temperature.282,284 Seventeen C-substituted anthranilic acids were converted to quinazolin-4-ones by heating at 130°C for 45 min, then at 175°C for 75 min, and the yields were excellent.284 

Whether annelated pyrimidin-4-ones should be made from oaminoamides or from oamino acids depends on the availability of each. The former gives a wider variety of reactions, and the reactions common to both host molecules seem to proceed faster and cleaner with the amides. However, if the amide 

The Niementowski reaction has not been widely used for heterocyclic host molecules. The following examples comprise most of what has been done, mainly at 170°C for 2 hr (good yields) pyrido[2,3-d]pyrimidin-4-one (see 3) from 2-aminopyridine-3-carboxylic acid285,286 pyrido[3,2-d]-pyrimidin-4-one (see 6) from 3-aminopyridine-2-carboxylic acid216,287 and pyrido[3,4-d ]pyrimidin-4-one (see 4) from 3-aminopyridine-4-carboxylic acid.288 289 

N-Methylformamide converted 2-aminopyridine-3-carboxylic acid to 3-methylpyrido[2,3-d]pyrimidin-4-one (5 hr at 180°C) in good yield.290 The same reagent also made 3-methyl-6-nitroquinazolin-4-one from 2-amino-5-nitrobenzoic acid in excellent yield some slowly reacting 2-aminobenzoic acids were assisted with phosphoryl chloride.291 A moderate yield of 3-phenylquinazolin-4-one was obtained from the action of formani-lide on 2-aminobenzoic acid (90 min at 140°C).282 

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The conversion of an aldehyde or ketone into the corresponding amine by heating with ammonium formate or with formamide and formic acid at about... 

In unalloyed steel containers formamide discolors slowly during shipment and storage. Both copper and brass are also subject to corrosion, particularly in the presence of water. Lead is less readily attacked. Aluminum and stainless steel are resistant to attack by formamide and should be used for shipping and storage containers where the color of the product is important or when metallic impurities must be minimized. Formamide attacks natural mbber but not neoprene. As a result of the solvent action of formamide, most protective paints and finishes are unsatisfactory when in contact with formamide. Therefore, formamide is best shipped in containers made of stainless steel or in dmms made of, or coated with, polyethylene. Formamide supphed by BASF is packed in Lupolen dmms (230 kg) or Lupolen canisters (60 kg) both in continental Europe and overseas. 

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). 

Halomycins. The halomycins are a group of four antibiotics produced by M.icromonospora halophjtica and separated by partition chromatography on Chromosorb W coated with formamide (19). Further purification was accompHshed using preparative dc (212). 

Partially reduced derivatives have been obtained from o-aminopyridinemethanors (218 219) (75JAP(K)75157394), and partially reduced pyridines e.g. 220) have also furnished this type of derivative in reactions with formamide, guanidine and imidates <72JHC1113, 72JHC1123, 78CB2297). 

Once again, frequency shifts provide a good way of examining the solvent effect. The highly polar solvent produces about the same shift for each compound with the exception of fortnamide, where it is quite a bit greater, the result of combining the polar solvent with formamide s rather large dipole moment. ... 

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

When o-aminobenzophenone is heated with formamide in the presence of formic acid at 150°C for 20 min, a quantitative yield of 4-phenylquinazoline is obtained. In the absence of formic acid longer heating is necessary. Although this reaction does not proceed with o-acylamidobenzophenones, its extension to other o-acylanilines with aliphatic amides may prove fruitful. 

Pyrido[4,3-rf]pyrimidin-4(3/7)-oiie (138) was prepared from either ethyl 4-aminonicotinate or from 4-aminomcotinamide by fusion with formamide. A parallel to the pyrido[3,2-d]pyrimidines (cf. Section II,B, la) was demonstrated in the conversion of 2-methyl-pyrido[4,3-d][l,3]oxa7in-4-ones (139, Ri = Me) into the corresponding pyrido[4,3-d]pyrimidin-4(377)-ones (142) on treatment with a number of amines.There were certain limitations to the method in this series, however, and the intermediate diamides (140) were more conveniently prepared from the appropriate 4-amidonicotinate (141) and. .Ri... 

D. Reactions with Formamide, Guanidine, and Thiocai bamide. 199... 

Alkylpyrimidines were obtained in 59-70% yield from higher 1-dimethyl-amino- and l-methoxyalk-l-en-3-ynes (R = Me, Et, -Pr) by their reaction with formamide (70ZOR2374). The exception was l-methoxy-5,5-dimethylhex-l-en-3-yne, from which the pyrimidine was obtained in 45% yield only, which is related to steiic hindrance for the attack at the acetylene bond. 

In a departure from the prototype molecule, the benzylpiperi-done is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone... 

Condensation of hydrazine with ethoxymethylenemalononitrile (22) gives 3-amino-4-cyanopyrazole (23). Hydrolysis with sulfuric acid leads to the amide, 24 heating with formamide inserts... 

Properties. It can be stored at low temps in the absence of air or w, and is described as a powerful oxidant which is insensitive to shock, but explds on contact with eth, and flames on contact with formamide or dimethyl formamide (Ref 3)... 

Arenediazoisocyanides (Ar —N2NC) were synthesized by Ignasiak et al. (1975) by reaction of arenediazonium ions with formamide and dehydration of the resulting l-aryl-3-formyltriazene with thionyl chloride (Scheme 6-19). These compounds are interesting in the context of the (Z)/( )-isomerism of diazocyanides (see Sec. 6.6). 

Non-aqueous microemulsions have been prepared by replacing water with formamide, a highly structured polar solvent [71]. Formamide enhances the solubility of organic compounds and is also used as a reactant. 

Microwave irradiation of a mixture of substituted anthranilic acid 224 with formamide (5 equiv) at 150 °C for 5 min gave quinazoUnones 225 in good yields (Scheme 82). This microwave version of the Niementowski reaction [ 143] showed significantly improved yields compared to the conventional reaction conditions [144]. 

A similar rotational analysis has been done with formamide derivatives. It is known that thioformamide has a larger rotational barrier than formamide, which can... 

Formylation of aromatic rings with formamides and POCI3... 

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