Hydroxylamines Vilsmeier-Haack reaction

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

The synthesis of 5- and 6-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34 and 35) has been described previously (Chapter 2). Using a Vilsmeier-Haack reaction, a formyl moiety was introduced on the 2-position of the thiophene ring.240 An excess of N-methylformanilide was used which could be easily removed by column chromatography. Reduction of the formaldehydes 65 and 68 with NaBFC yielded the hydroxymethyl compounds 66 and 69. From compound 65, the aldoxime 67 was synthesised, using hydroxylamine.HCl in ethanol and 5N NaOH-solution. 

The Vilsmeier-Haack reaction of electron-rich carbocyclic aromatic compounds (Ar—H) with chloromethyleneiminium salt (1) gives aldehyde derivatives (Ar—CHO), generally in good yield. The intermediate iminium salt (cf. salt 5 Scheme 1) can be treated with hydroxylamine to obtain nitrile derivatives (Ar—CN). Benzene and naphthalene are not sufTiciently electron rich to participate in the Vilsmeier-Haack reaction, but polycyclic hydrocarbons, such as anthracene, do react. Benzene and naphthalene derivatives that possess an electron-releasing substituent (—OMe,—SMe,—NMe2, etc.) af-... 

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