Dicarbonyl compounds reaction with hydroxylamine

The standard syntheses for pyrazoles (17) and isoxazoles (19) involve the reactions of (3-dicarbonyl compounds (18) with hydrazines and hydroxylamine, respectively. These reactions take place under mild conditions and are of very wide applicability the substituents Y can be H, R, Ar, CN, C02Et, etc. 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

In the case of NH2OH with a sharp difference in the nucleophilicity of the two functions, the primary amino group reacts with the carbocation C-1 center. For example, the reaction of l-alkylaminoalk-l-en-3-ynes with hydroxylamine leads to selective synthesis of alkylisoxazoles (69ZOR1179). A preparative value of this method is evident because the use of dicarbonyl compounds as starting materials for the synthesis of alkylisoxazoles results in a mixture of isomers. 

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... 

Dicarbonyl compounds with a double bond in the 2,3-position condense with hydrazine to give pyridazines (e.g. 91 — 92). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group, then reactions with hydrazines or hydroxylamine lead to pyridazinones or 1,2-oxazinones (e.g. 93 — 94 Z = NH, NPh, O). Similarly a cyano group leads to an amino or imino product. 

Reviews have appeared that in part cover recent advances in the ring-chain tautomerism of the nitrogen-containing derivatives of 1,3-dicarbonyl compounds (95ZOB705) of the reaction products of alkenals, alkenones, and alkane-1,3-diones with hydrazines and hydroxylamines (950PP519) and of other compounds [95H(41)1805 95H(41 )2057]. 

Azine approach. Cyclization of the oxime (48) (73G219) corresponds to a common method for the preparation of isoxazoles, viz. the reaction between 1,3-dicarbonyl compounds and hydroxylamine. Similarly a cyano group reacts with hydroxylamine to form an N-hydroxyamidine which can be cyclized to an isoxazole if the vicinal carbon is activated and carries a leaving group. The 5-cyanopyrimidine (49) perhaps behaves unexpectedly in that it is a trichloromethyl substituent which is the leaving group in the cyclization (79JHC11-09). This behavior may be attributed to its location in the activated pyrimidine 4-position. 

This reaction was extended to other (i-dicarbonyl compounds containing a nitro group [474 176], The mechanism of the reaction of hydrazine with 1,3-dicarbonyl compounds is still largely unclear. Nevertheless, important evidence was obtained to indicate that a dihydroxypyrazolidine intermediate is formed in this reaction [477], If hydroxylamine is used instead of free hydrazine in the reaction with nitromalonaldehyde, the product is 4-nitroisoxazole [471], When a mixture of nitrocyanoacetic ester with one equivalent of hydrazine hydrate and a small amount of water is boiled, 5-amino-4-nitro-3-pyrazolone is formed [478],... 

The oxidants dimethyl sulfoxide and nitroso compounds react easily with oL-bromo ketones and convert them into a-dicarbonyl compounds. The reaction with nitroso compounds is usually carried out in the presence of pyridine and proceeds through a nitrone stage. Phenacyl bromide (a-bromoacetophenone) is thus transformed first into phenacylpyridinium bromide and further, with nitrosobenzene, into a-ketoaldonitrone, which is subsequently treated with hydroxylamine to give phenylglyoxal monoxime or with phenylhydrazine to give phenylglyoxal osazone [985] (equation 411). 

The reaction of 1,3-dicarbonyl compounds with hydroxylamine, usually as the hydrochloride, is widely used for the synthesis of isoxazoles. The reaction is... 

Direct IV-oxidation of these heterocycles invariably fails (see Section 3.02.7.2.8), making ring synthetic methods the only viable alternative <93CHE127>. Although there has been considerable interest in the chemistry of compounds of this type, there are no new synthetic approaches of a general nature. The most common approach is to react a-oximinoketones with aldehydes and primary amines. With formaldehyde, however, the 2-unsubstituted 1-oxides rearrange to 2-imi-dazolones. Variations on this theme allow synthesis of 1-hydroxyimidazole 3-oxides. Thus, treatment of an a-dicarbonyl compound with an aldehyde and hydroxylamine, or reaction of the aldehyde oxime or aldehyde with a 1,2-dioxime are common approaches <898773 >. Similarly, a-hydroxyamino-... 

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). 

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