6-Formyl-2- reaction with hydroxylamine

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

Compound 63, the 2-formyl derivative of compound 61, undergoes a series of side-chain reactions at the carbonyl group including reduction with sodium borohydride and condensation reactions with hydroxylamine or malononitrile. The reactions afford the appropriately 2-substituted products in excellent yields <2004CHE1477>. 

Five-membered heterocycles have been used as substitutes for the y-lactone ring of cardenolides. Thus, the 17 -(5 -isoxazolyl)- and 17)8-(3 -pyrazolyl)-cardenolides (526) and (527) have been prepared from 20-ethoxy-21-formyl-3 -acetoxy-17)8-pregna-5,14,20-triene (528) by reaction with hydroxylamine and hydrazine hydrate, respectively. The isomeric 14a,15a- and 14) ,15/S-epoxides (529) and (530) in both series were then obtained by peracid treatment or alkaline cyclization of the respective 14,15-bromohydrin. 

Fused Heterocycles The /8-dicarbonyl system in the formyl derivative of 17-methyltestosterone shows much the same reactivity as the same array in simpler compounds. Thus, reaction of the formyl derivative 17-1 with hydrazine fuses apyrazolering onto the steroid at positions 2,3 (21-1) (Scheme 5.21). This compound, stanazol, is one of the more frequently abused anabolic agents. Reaction of the same formyl derivative with hydroxylamine goes on to add an isoxazole ring to give danazol (21-2). 

The synthesis of this series involved the reaction of disubstituted or benzo fused 6-keto(formyl)-2-cyclohexenones with hydroxylamine (Scheme 176), Base degradation gave a-cyanoketones which can be further degraded to diacids (67AHC(8)277, 80IJC(B)406). 

The classical method for preparing isoxazole involves the condensation of 1,3-dicarbonyl compounds with hydroxylamine, a reagent that contains the preformed N—O bond. The regiochemistry of the reactions can usually be rationalized by assuming that the first step involves imine bond formation at the more reactive carbonyl group. Thus, reaction of formyl ketone (44-1) with hydroxylamine gives... 

Reaction of 2-formyl-3-thiopheneboronic acid with hydroxylamine yields 4-hydroxy-4,5-boroxazothieno[2,3-c]pyridine (414) in 31% yield (equation 49) as a stable substance with m.p. 144-146.5 °C (65ACS1271). 

A number of syntheses of compounds having nitrogen on a carbon attached to 2-pyrazolin-5-one rings have already been mentioned, but several others are known. The most important of these is the reaction of 4-formyl- or 4-acyl-2-pyrazolin-5-ones with hydroxylamine, hydrazines, semicarbazide and similar chemicals.559 1841 These compounds can also be obtained by direct synthesis from an appropriate /3-ketoester or derivative and a hydrazine (eq. 50).138 512-1100 An interesting syn-... 

Condensation reactions can be grouped into two categories. The first category involves pyrazol-3-ones with formyl, acyl, nitroso, a,jS-unsaturated oxo, 3-oxo-2-azobutyric acid ethyl ester or acetonitrile substituents at position 4 or formyl substituents at position 5 and their reaction with carbanions, heterocyclic methylcarbenium salts, primary and secondary amines, diamines, heterocyclic perchlorates, hydroxylamine, hydrazines, urea or thiosemicarbazide. The second category involves pyrazol-3-ones with amino, hydrazino, heteroaromatic amino, acetyl or acetonitiilo groups at position 4 and their reaction with aryl or heteroaromatic aldehydes or cyclic ketones. 

The structures of the di-isoxazoles obtained from the di-a-formyl ketones (241) depended upon the reaction conditions hydroxylamine hydrochloride afforded the di-isoxazole (257) whilst hydroxylamine hydrate gave (242 X = O). Similarly, the unsaturated dichlorodialdehyde (258) gave (259) with hydroxylamine hydrochloride and (244 X = O) with the hydrate. 

A number of nitrogen heterocycles have been prepared from solasod-4-en-3-one (8) in a search for new physiologically active steroids. Reaction of (8) with ethyl formate and sodium hydride gave the formyl derivative (9), which cyclized with methylhydrazine, phenylhydrazine, and p-nitrophenylhydrazine to give the pyrazoles (11), (12), and (13), respectively. Similarly, (8) was condensed with ethyl trifluoroacetate to give (10), which reacted with hydrazine and with hydroxylamine to give pyrazole (14) and isoxazole (16), respectively. Heterocycles (15) and (17)... 

The 2 -formyl derivative 57 was further subjected to functional group interconversions, leading to a series of a new 2 -substituted m-terphenyls. Wittig reaction on 57 provided the alkenyl derivative 61 in 58% yield [21], The oxime 62 was obtained in 62% yield by treatment with hydroxylamine hydrochloride. 

As in 0-52 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 351). Imidates RC(=NH)OR give amidines RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 8-amino esters in an internal example of this reaction. Isopropenyl formate is a useful compound for the formylation of primary and secondary amines,897... 

To a solution of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-l,4-dihydropyridine- 3-carboxylic acid (4.5 g) in acetic acid (35 ml) were added hydroxylamine hydrochloride (0.97 g) and sodium acetate (1.43 g), and the mixture was stirred at ambient temperature for 2.5 hours. After acetic anhydride (4.14 g) was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and at 95-100°C for additional 4 hours. The acetic acid and the excess of acetic anhydride were removed in vacuum, followed by adding water to the residue and it was neutralized with a saturated aqueous solution of sodium bicarbonate. This aqueous suspension was extracted twice with ethyl acetate, and the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a reddish-brown oil (4.88 g), which was chromatographed over silica gel (150 g) with a mixture of... 

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