Other Isoxazoles

The main psychedelic component of these mushrooms appears to be muscimole (5-aminomethyl-3-OH-isoxazole), which is active in an oral dose of about 10 mg. See HCA 48,920( 1965) for extraction of muscimole from the fungus. 

The value of muscimole as a psychedelic is diminished by the dizziness and muscle twitching which seem to occur (at least in some people), but a smcdl dose in conjunction with another psychedelic should be very interesting. Ibotenic acid also occurs in Amanita, and though not itself a desirable psychedelic, it can be converted to muscimole by dissolving in dimethylsulfoxide or refluxing in water. 

Dissolve 100 g l-CI-3-Butanone (JACS 75,5438(1953)) in 300 ml dimethylformamide stir and add 77.5 g NaNOj with cooling. Stir five hours and let stand twelve hours. Add 300 ml water extract with ether and dry, evaporate in vacuum the extract (can distill residue 86/2) to get 50 g l-NOj-3-butanone (1). Dissolve 18 g (1) in 90 ml 48% HBr and reflux ten minutes. Add 100 ml water and steam distill. Dry, extract with ether and dry, evaporate in vacuum the extract (can distill 67-8/18) to get 4.8 g 3-Br-5-methyl-isoxazole 

Test for psychedelic activity. Dissolve 4 g (VII) and 2.5 g KOH in 12 ml ethanol and reflux eight hours. Dissolve in 20 ml water, acidify with dilute HCI and evaporate to dryness. Dissolve residue in hot ethanol and evaporate to get 3 g 5-aminomethyl-3-methoxy-isoxazole (Vlll). Test for activity. 1 g (VIII) in 10 ml glacial acetic acid and 4.5 g HBr and reflux one hour. Evaporate in vacuum to get muscimole. 

Pass chlorine gas into an ice cold, well-stirred solution of 5 ml acetylketene in 30 ml CCl until there is a 4.5 g increase in weight (solution is slightly yellow). Pour slowly into excess methanol or ethanol at 0° and distill at 118/17 to get 6 ml methyl (or ethyl)-4-Cl-acetoacetate (1). To 2.7 ml methanol saturated with dry HCI at 0°, add a mixture of 10 g (I), 20 g methyl orthoformate (trimethoxy-methane) and 13 g methanol and reflux four hours. Pour hot into 200 ml ice water and adjust pH to 8 with 30% NaOH. Extract four times with ether and evaporate and distill to get methyl (or ethyl)-4-Cl-3,3-dimethoxy-butyrate (II). Dissolve 40 g (11) in 20 ml methanol and add hydroxylamine.HCI in methanol. After ninety-six hours at room temperature (under Nj if possible), evaporate in vacuum. Qan purify the residue by dissolving in water and put on anionic column wash column to neutrality and elute with 2N acetic acid just before the acid elutes, the alkaline fraction giving a positive FeClj test appears evaporate in vacuum this fraction below 40° and dry at 40/0.5 for twelve hours. Dissolve 5 g product in 130 ml glacial acetic acid and saturate at room temperature, then at 0° with dry HCI. Let stand sixteen hours at room temperature and evaporate in vacuum at 40°. Dilute with water and evaporate three times. Extract with 2X130 ml hot ether and filter, evaporate in vacuum to get 3-Cl-methyl-5-OH-isoxazole (111) (recrystallize-acetone). Heat (111) sixteen hours at 90° in concentrated NH OH in autoclave and evaporate to get muscimole. 

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A variety of other isoxazole aldehydes has also been reported (62HC(17)l, p. 77). 

Some hydroxamic acids of the isoxazole series also display a marked antituberculosis activity. The penicillin derivatives, acylated with isoxazole carboxylic acids possess an antibacterial activity similar to that of penicillin, against resistant species.Among other isoxazole derivatives possessing activity one should especially mention the sulfonamides of this series, and 4-hydroxyiminoisoxazol-5-... 

After an incident involving the violent decomposition of hot 3-methyl-5-amino-isoxazole, the thermal stability of 7 other isoxazole derivatives was studied by DSC, TGA and ARC. Only 4-amino-3-isoxazolidinone decomposed exothermally in an open crucible, but all did so in sealed capsules, evolving much gas. The results below give isoxazole derivative, ARC onset temperature of decomposition (°C)/adiabatic exotherm (°C)/max. pressure (bar) and DSC heat of decomposition (kJ/g), respectively for all 9 compounds. 

The Amanita muscaria mushroom from which muscarine is isolated is also psychoactive. It was believed at first that muscarine was the primary CNS agent. However, more detailed research indicated that muscarine only constituted 0.003% of the fungus. Other species of Inocybe and Clitocybe have more muscarine than muscaria. Other isoxazole components of the muscaria mushroom, such as ibotenic acid and its metabolites, are the main causes of amanita intoxication. This mushroom is believed to have been involved in ancient rituals of the Old World, especially in the Ayrian culture which lived in Siberia around 2000 B.C. This rite worshipped a god called Soma whose presence on earth occurred in the mushroom. Amanita muscaria. Rituals involved brewing a juice with the mushrooms which was consumed by priests. Their urine (isoxazole metabolites) was collected and drunk by others. This ceremony could involve many people and several metabolic rounds until everyone was intoxicated. 

Intoxication produced by Amanita muscaria and related Amanita species arises from the neurologic and hallucinogenic properties of muscimol, ibotenic acid, and other isoxazole derivatives that stimulate excitatory and inhibitory amino acid receptors. Symptoms range from irritability, restlessness, ataxia, hallucinations, and delirium to drowsiness and sedation. Treatment is mainly supportive benzodiazepines are indicated when excitation predominates atropine often exacerbates the delirium. 

There are several examples of the formation of pyridazines from other heterocycles, such as azirines, furans, pyrroles, isoxazoles, pyrazoles or pyrans and by ring contraction of 1,2-diazepines. Their formation is mentioned in Section 2.12.6.3.2. 

For isoxazoles the first step is the fission of the weak N—O bond to give the diradical (51) which is in equilibrium with the vinylnitrene (52). Recyclization now gives the substituted 2//-azirine (53) which via the carbonyl-stabilized nitrile ylide (54) can give the oxazole (55). In some cases the 2H-azirine, which is formed both photochemically and thermally, has been isolated in other cases it is transformed quickly into the oxazole (79AHC(2.5)U7). 

Neutral azoles are readily C-lithiated by K-butyllithium provided they do not contain a free NH group (Table 6). Derivatives with two heteroatoms in the 1,3-orientation undergo lithiation preferentially at the 2-position other compounds are lithiated at the 5-position. Attempted metallation of isoxazoles usually causes ring opening via proton loss at the 3-or 5-position (Section 4.02.2.1.7.5) however, if both of these positions are substituted, normal lithiation occurs at the 4-position (Scheme 21). 

A number of general reviews related to the topics covered in this chapter have appeared (Table 1) and others will be discussed in the section dealing with synthetic aspects (Section 4.04.3.1). The Sokolov review is particularly noteworthy since it is quite recent and complete, containing 304 references to pyrazoles and isoxazoles. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

A Hiickel model used for calculating aromaticity indicated that the isoxazole nucleus is considerably less aromatic than other five-membered heterocycles, including oxazole and furan. SCF calculations predicted that isoxazole is similar to oxazole. Experimental findings are somewhat difficult to correlate with calculations (79AHC(25)147). PRDDO calculations were compared with ab initio values and good agreement for the MO values was reported... 

A number of studies on the NMR spectra of isoxazole has been compiled and this list includes the coupling constants in various solvents as well as the neat liquid. The N signal for isoxazole appears at 339.6 p.p.m. relative to TTAI and is at much lower field than in other azoles. Reports of spectra of substituted isoxazoles also abound (79AhC(25)147, p. 201). 

Prototropic tautomerism of isoxazole derivatives has been well studied over a number of years and has recently been reviewed in context with similar behavior in other five-membered heterocycles (70C134, 76AHC(Sl)l, 79AHC(25)147, p. 202). Several generalizations are summarized below. 

With 3- and 4-substituted isoxazoles the tautomeric form normally present is the XH tautomer, (13 X = O) and (14 X = O, N) respectively. However, other influences need to be considered as in cycloserine (IS), which exists as a zwitterion, as does 5-amino-3-hydroxy-isoxazole (16). 

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

The iso)tazole ring is rather resistant to sulfonation. However, on prolonged heating with chlorosulfonic acid, 5-methyl-, 3-methyl- and 3,5-diraethyl-isoxazoles are converted into a mixture of the sulfonic acid and the corresponding sulfonyl chloride. The sulfonic acid group enters the 4-position even when other positions are available for substitution. The sulfonation of the parent isoxazole occurs only under more drastic conditions (20% oleum) than that of alkyl isoxazoles isoxazole-4-sulfonic acid is obtained in 17% yield. In the case of 5-phenylisoxazole (64), only the phenyl nucleus is sulfonated to yield a mixture of m-and p-arenesulfonic acid chlorides (65) and (66) in a 2 1 ratio (63AHC(2)365). 

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

Isoxazoles are stable toward peracids and are fairly stable to other acidic oxidizing agents such as chromic and nitric acids, and acidic permanganate. 3-Substituted isoxazoles are... 

The action of nucleophilic reagents with isoxazoles can take a number of courses involving (i) nucleophilic addition to the ring (ii) nucleophilic replacement of a substituent and (iii) deprotonation. Other processes such as thermal or photochemical reactions may precede reaction with a nucleophile (see Section 4.16.3.1.2). 

The importance of this group of reactions to the chemistry of isoxazoles is shown by the considerable amount of effort expended on this topic (63AHC(2)365,79AHC(25)147). The lability of the isoxazole nucleus towards nucleophiles and bases distinguishes this heterocycle from other azoles. The conditions which lead to ring cleavage are quite varied and depend on the position and the nature of the substituents. 

Other amino substituted isoxazoles undergo ring-opening reactions on treatment with base. Thus the amidine derivative (249) gave the triazole (250) (64TL149), while the triazene (251) on reaction with ammonia gave the tetrazole (252) (64X461). 

Most reactions leading to isoxazoles must involve at some stage cyclization of an intermediate which contains all five atoms of the isoxazole ring. In some cases the acyclic intermediates are short-lived and unisolable, in others they are stable and able to be isolated. In this section we discuss reactions which involve an isolable acyclic precursor. These reactions mostly utilize (CCCNO) synthons although a few examples of (OCCCN), (CCCON) and (CONCC) synthons are encountered. We are unaware of examples involving (CNOCC) synthons. 

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