Isoxazole
Isoxazole (1,2-oxazole) contains a pyridine-like N-atom, but differs from oxazole by the pres- ence of an N-0 bond. The bond energy of such a cr-bond amounts only to 200 kJ moF, much
lower than that of N-C or O-C bonds. The univalent radical is known as isoxazolyl.
The isoxazole molecule is planar (see Fig. 5.11). Again, it is evident that the heteroatoms impair the derealization of the ^-electrons. This is more pronounced than in oxazole, as can be deduced from a comparison of the bond lengths between ring atoms 3 and 4.
142.5
Fig. 5.11 Structure of isoxazole
(bond lengths in pm, bond angles in degrees)
The ionization energy of isoxazole is 10.17 eV and its dipole moment of 2.75 D is greater than that of oxazole. Isoxazole, like oxazole, has a very short-wave UV absorption. The chemical shifts in the NMR spectrum are found in the region typical for benzenoid compounds.
Isoxazole is aromatic like its structural isomer oxazole. It is a ^--excessive heterocycle. The following ^--electron densities have been calculated:
1.753
Therefore, electrophilic substitutions occur at the 4-position, whereas nucleophiles prefer the 3-position. The following reactions are typical for isoxazoles.
Salt formation
Isoxazoles are very weak bases. The pKa of isoxazole is -2.97. Protonation occurs at the N-atom.
Reactions with electrophilic reagents
Isoxazoles are quaternized by iodoalkanes or dialkyl sulfates. Electrophilic substitutions such as halo-genation, nitration, sulfonation, Vilsmeier-Haack formylation and acetoxymercuration, occur at the 4-position, provided this position is unsubstituted. As with oxazole, the pyridine-like N-atom impedes electrophilic substitution, so that isoxazoles are less reactive than furans but more reactive than benzene.
Reactions with nucleophilic reagents
Nucleophiles react with isoxazoles and even faster with isoxazolium salts, but differently in each case and usually with ring cleavage. A special and synthetically useful reaction of isoxazoles unsubstituted in the 3-position is the ring-opening by bases, e.g.:
HOI'
The base does not attack at the C-3 atom but at the H-atom. Via an E2-type mechanism, facilitated by the weak N-0 bond, a (Z)-cyano enolate is formed leading to an a-cyano ketone.
Reductive ring opening
On catalytic hydrogenation, isoxazoles give rise to enamino ketones, which can be hydrolysed to produce 1,3-diketones:
Isoxazoles are reduced by sodium in liquid ammonia in the presence of tert-butanol to yield /?-amino ketones, which are converted on heating or by acid into ^^-unsaturated ketones:
The reactions of isoxazoles differ considerably from those of oxazoles, although both systems are aromatic. The reason for this lies in the relatively weak N-0 bond in the isoxazole molecule, which is cleaved in all ring-opening reactions. Moreover isoxazoles, unlike oxazoles, do not react with dieno-philes to form Diels-Alder adducts [82].
^ For the retrosynthesis of the isoxazole system (see Fig. 5.12), it is essential that the heterocycle - possesses the functionality of an oxime and of an enol ether, and that C-3/C-5 are at the oxidation level of a carbonyl function. Therefore, a logical retrosynthetic route (a - c) leads by way of the monoxime 2 to the 1,3-diketone and hydroxylamine. If the retrosynthetic operation a to d is generalized, one arrives at the 4,5-dihydroisoxazole 1. Its analysis, according to a retroanalytically permitted cycloreversion, leads to an alkene unsubstituted by a leaving group and to a nitrile oxide 3. These fragments represent the two components of a 1,3-dipolar cycloaddition.
Retrosynthesis of isoxazole
These two synthetic principles proved of advantage in the synthesis of isoxazoles.
(1) /?-Diketones yield 3,5-disubstituted isoxazoles 4 with hydroxylamine (Claisen synthesis):
- + h2n-oh
-2H20
-H20
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 /?-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.
(2) Nitrile oxides 7 react as 1,3-dipoles with alkynes in a [3+2] cycloaddition to give isoxazoles (Quilico synthesis). The nitrile oxides are generated in situ. They are obtained, for instance, by dehy-drohalogenation of hydroxamic acid chlorides (a-chloraldoximes) with triethylamine:
One of the resonance structures of the nitrile oxides is represented by a 1,3-dipole. With alkynes as dipolarophiles, a concerted [3+2] cycloaddition occurs to give isoxazoles 8:
The regioselectivity depends on the nature of the substituents present. Alkynes with a terminal triple bond yield 3,5-disubstituted isoxazoles (8, R2 = H).
The 1,3-dipolar cycloaddition of nitrile oxides to alkenes furnishes 2,3-dihydroisoxazoles (see p 144), which can be converted into isoxazoles with suitable oxidizing agents.
Isoxazole is a colourless liquid of a pyridine-like odour, bp 94.5°C. It is soluble at room temperature in six times its volume of water.
A few oxazoles occur in nature, e.g. muscimol 9, a CNS depressant in the fly agaric (Amanita muscaria) [83]. The compound acts as an antagonist of the neurotransmitter 4-aminobutyric acid.
Among the isoxazoles, many biologically active compounds are found. Some of them are important as drugs or biocides, e.g. the long-acting sulfonamide sulfamethoxazole 10, the anti-inflammatory isoxi-cam 11, the antiarthritic and antirheumatic leflunomide 12 and the fungicide 3-hydroxy-5-methylisoxazole.
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