Carbamoyl isoxazoles

Azole approach. Hofmann degradation of isoxazole-4,5-dicarboxamide goes faster for the 4-substituent, which is converted- into an isocyanate group. The latter reacts with the remaining carbamoyl substituent to form the fused uracil (42) (67T675). 

Isoxazoles bearing alkyl or carbamoyl groups were transformed into the corresponding pyrazoles in high yields by treatment with hydrazine in methanol in the presence of a hydrogenation catalyst such as Raney nickel, at room temperature <07T12195>. 

Amino-3-(pyrrol-2-yl)isoxazoles 348 were selectively prepared by treatment of cyano-ethylthio-ethenylpyrroles 347 with hydroxylamine in methanol, probably through replacement of their SEt group with a hydroxylamino moiety. With carbamoyl derivatives 347 (R = CONH2), minor amounts of regioisomers 349 were also isolated and their formation was increased (12-48%) operating in the presence of aqueous NaOH (Scheme 84) <2005T4841>. 

Under similar conditions, with 2-(l-ethylthio-2-carbamoyl-2-cyanovinyl)pyr-roles, which exist exclusively as isomers with the cw-disposition of carbamoyl and NH-pyrrole groups, the reaction chemoselectivity breaks [582] along with major 5-amino-3-(pyrrol-2-yl)isoxazoles (the content in the reaction mixture is 95%-97%), their structural isomers, 3-amino-5-(pyrrol-2-yl)isoxazoles, are also formed (Schane 2.112, Table 2.13). 

SCHEME 2.114 Selective synthesis of 3-amino-5-(pyrrol-2-yl)isoxazoles from 2-(l-eth-ylthio-2-carbamoyl-2-cyanovinyl)pyrroles and hydroxylamine in the presence of NaOH in MeOH. 

In this case, 3-aminoisoxazoles are likely formed due to the opening of the pyr-rolizine ring that leads to 2-(l-ethylthio-2-carbamoyl-2-cyanovinyl)pyrroles with the di-configuration of nitrile and NH groups and (after reaction with hydroxylamine) intermediates B, which further cyclize to the isoxazoles (Scheme 2.116). 

As mentioned so far, methylnitroisoxazolone 10 serves as a precursor of carbamoylnitrile oxide 6 upon treatment with only water under mild conditions, in which any special reagents, conditions, and manipulations are not necessary. The nitrile oxide 6 reacts with alkynes 15, alkenes 17, nitriles 29, and 1,3-dicarbonyl compounds 34 to afford corresponding carbamoyl-substituted isoxazoles 16, isoxazolines 18, 1,2,4-oxadiazoles 28, and isoxazoles 33, respectively (Scheme 9.17). The electron-withdrawing carbamoyl group realizes the cycloaddition with electron-rich dipolarophiles, which is inverse electron-demand 1,3-dipolar cycloaddition. Furthermore, the carbamoyl group also plays a role of an activator of the dipolarophile. This mefliodology will be useful for the construction of a new library of functionalized compounds. 

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