1.3- Diketones, reaction with hydroxylamine

In 1888 Claisen (1888CB1149) first recognized a general synthesis of isoxazoles (283) by the condensation-cyclization of 1,3-diketones (280) with hydroxylamine. It is now generally accepted that the monoxime (281) of the 1,3-diketone and the subsequent 5-hydroxy-isoxazoline (282) are the intermediate products of the reaction. The isolation of the monoxime (281) and 5-hydroxyisoxazoline (282), which were both readily converted into the isoxazole (283) by treatment with acid or base, has been reported (62HC(17)l). 

Trialkylisoxazoles have been prepared by the condensation of primary nitroalkanes under the influence of basic reagents (40JA2604). They can also be obtained from the reaction of a 1,3-diketone RCOCHRCOR with hydroxylamine hydrochloride <62HC(17)l, p. 54). 

The reaction of appropriate 1,3-diketones (302) with hydroxylamine hydrochloride in pyridine (79MI41601) has been reported to result in a regiospecific synthesis of 3-alkyl-5-arylisoxazoles, as has the reaction of an a -bromoenone (307) with hydroxylamine hydrochloride in ethanol in the presence of potassium carbonate (81H(16)145). Regiospecific syntheses of 5-alkyl-3-phenylisoxazoles also result from the reaction of an a-bromoenone (307) with hydroxylamine in the presence of sodium ethoxide (81H(16)145). 3-Aryl-5-methylisoxazoles were prepared from phosphonium salts (304) and hydroxylamine (80CB2852). 

Synthesis of 3,5-diarylisoxazoles 200 and 201 (overall yield up to 85%) by the reaction of asymmetrically substituted -diketones (199) with hydroxylamine was investigated (equation 87). It has been found that the reaction occurs with a low degree of site selectivity unless steric effects are operating. The isoxazole that has the more electron-deficient aryl group in position 3 is formed preferably when the reaction is performed with hydrox-ylamine hydrochloride. When the reaction is carried ont in a nentral medium, a reversed site stereoselectivity is observed. Similar cycUzation occurred using / -dioximes as starting material . 

The structure of /8-diketones of the selenophene series was found by physical129 (UV, IR, and NMR spectra) and chemical75,98 99 (reaction with hydroxylamine) methods. 

All unsymmetrical diketones can exist in two cis-enolic forms. A possible insight into the structures is given by the reaction with hydroxylamine. This involves the assumption, however, that the enolic form of the /3-diketone reacts at its carbonyl group to form the monooxime which is then cyclized to the isoxazole. The structures of isoxazoles thus obtained were corroborated by their independent synthesis and, for comparison, the synthesis of their isomers. The enolization of /3-diketones has also been discussed in Section V, C. 

The cyclocondensation proceeds according to the retroanalytical prognosis via the isolable intermediates of a monoxime 5 and a 5-hydroxy-4,5-dihydrooxazole 6. In the case of unsymmetrically substituted y -diketones, it is still possible to control the regioselectivity by using variable carbonyl electro-philicity and observing strict reaction conditions. a-Hydroxymethylene ketones, the corresponding enol ethers and ethynyl ketones also yield isoxazoles by reaction with hydroxylamine. 

Scheme 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylamine gives, via the isolable monoxime (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-metrical 1,3-diketones result in both possible isomers (110) and (111), but the ratio of the isomeric products can be controlled by the right combination of the 1,3-dicarbonyl component and the reaction conditions used. These important considerations are described in Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed to yield diverse substituents in the resultant isoxazole. 

It was soon found that the reaction of unsymmetrtcal 1,3-diketones (290) or their derivatives with hydroxylamine results in both possible isomeric isoxazoles (291) and (292), a complication which not only reduces the yield of desired product but also often leads to separation problems, particularly when R and R are similar. However, the reaction does give one isomer, or predominantly one isomer, if the right combination of the CCC... 

Alkyl-5-arylisoxazoles (303) were prepared by the regiospecific reaction of appropriate 1,3-diketones (302) (R = alkyl or perfluoroalkyl) with hydroxylamine hydrochloride in pyridine (79MI41601). 

Only in a few instances, where both phenyl groups were sufficiently different in their substitution patterns, were 3,5-diarylisoxazoles prepared regiospecifically by the reaction of 1,3-diketones (302) (R = substituted phenyl) with hydroxylamine (45JA134). Accordingly, other CCC component synthons have been employed for the regiospecific synthesis of 3,5-diarylisoxazoles. 

Diethyl 4-hydroxyisoxazole-3,5-dicarboxylate (334) was prepared by the reaction of acetonedicarboxylic acid ester with nitrosyl chloride (78JHC1519). Other 4-hydroxyisoxazoles have been prepared by the reaction of 2-hydroxy (or acetoxy)-1,3-diketones with hydroxylamine (34JA2190, 62HC(i7)i, p. 149), and by hydrolysis of 4-isoxazolediazonium salts (62HC(17)1, p. 149). The parent 4-hydroxyisoxazole has not yet been reported. 

The reaction of /3-diketones with hydroxylamine can generate a variety of products besides the 2-isoxazolin-5-ol and includes dioximes and monooximes 69JOC3248, 69CC1062, 75GEP2424691, 80CB1507, 72USP3629245). 

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. °... 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

A number of recent papers have described the use of new types of /3-diketone derivatives to synthesize isoxazoles. We must first mention 1,1,3,3-tetraalkoxypropanes which are now manufactured on a large scale. Condensation of these derivatives with hydroxylamine has made readily available the parent compound, unsubstituted isoxazole itself (4). " This type of reaction using tetraalkoxypropane... 

The five-coordinate complexes Ir(CO)(PPh3)2L, where HL = /3-diketone, A-benzoyl-A-phenyl-hydroxylamine, salicylaldehyde, 8-hydroxyquinoline, 2-hydroxybenzophenone, 2-hydroxy-8-methoxybenzophenone, were prepared from [Ir(CO)(PPh3)2Cl].632 The resulting compounds all underwent oxidative addition reactions with Br2. Reaction of [(cod)2IrCl]2 with N-substituted 3-hydroxy-2-methyl-4-pyridine gives the bichelated complex (389). 33... 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Diketones are synthetically quite versatile, but they have found only modest use in the syntheses of heterophanes. When 1,3-cyclohexadecanedione (53) is treated with hydrazine hydrate or phenylhydrazine, pyrazolophane (54) or (55), respectively, is obtained (78TL2821). Reaction of dione (56) with hydroxylamine, followed by acid-catalyzed cyclization of the intermediate monoxime, gives the [3,5]isoxazolophane (57) (79TL1875). 

On treatment with concentrated hydrochloric acid and aluminum amalgam, l-telluracyclohexane-3,5-diones decompose with elimination of tellurium. Their chemical behavior is determined by the presence of the dicoordinate tellurium center and two carbonyl groups in their molecules. As cyclic diketones, compounds 12 readily form oximes and dioximes under treatment with hydroxylamine. The former reaction is preferably carried out in dilute acetic acid solution, whereas the latter is carried out in basic... 

As explained in chapter 21, vinyl ketones such as 57 are unstable and we often prefer to use the Mannich base instead. This example works spectacularly well. Heating the Mannich base 58 with cyclohexanone gives the 1,5-diketone 55 that combines with hydroxylamine to give the pyridine 54 both reactions giving excellent yield.10... 

The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. 

Reaction of a 1,3-diketone with hydroxylamine gives an isoxazole 50 via the isolable monoxime 48 and 5-hydroxydihydroisoxazole 49 (Scheme 34). Various modifications of this procedure involving other 1,3-dielectrophiles are known the examples can be represented by the reaction of alkynyl ketone 51 with hydroxylamine hydrochloride leading to the 3-substituted isoxazole 52 (Scheme 35) <2000J(P1)2311 >, and the electrophilic cyclization of O-methyl oximes 53 allowing access to a variety of 3,5-disubstituted-4-halo- or -4-selenoisoxazoles 54 under mild reaction conditions (Scheme 36) <20050L5203>. 

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