Synthesis of azaheterocycles from oxime derivatives*

Electrophilic amination of Grignard reagents has been accomplished by using O-sulfonyloximes as amination reagents. Benzophenone O-sulfonyloxime derivatives react with Grignard reagents on sp2 nitrogen, yielding primary amines by successive hydrolysis of the resulting N-alkylimines. Various cyclic imines are synthesized by Pd-catalyzed reaction from olefinic oxime derivatives. That is, treatment of O-pentafluorobenzoyloximes of olefinic ketones with a catalytic amount of Pd(PPh3)4 and triethylamine affords nitrogen-containing heterocycles, such as pyrroles, pyridines, isoquinolines, spiro-imines, and aza-azulenes. This reaction proceeds via the initial formation of alkylideneaminopalladium(II) species generated by oxidative addition of the oximes to the Pd(0) complex, and the following intramolecular amination on the olefinic moiety. Cyclic imines are prepared from γ,δ-unsaturated O-acetyloximes by treatment with acetic acid and 1,4-cyclohexadiene in the presence of a catalytic amount of 1,5-naphthalenediol. γ,δ-Unsaturated ketone O-methoxycarbonyloximes are transformed to 2-bromomethyl3,4-dihydro-2H-pyrroles by the action of a catalytic amount of Cu(I) bromide dimethyl sulfide complex and lithium bromide. INTRODUCTION During the course of study on the catalytic Beckmann rearrangement of oximes by the use of tetrabutylammonium perrhenate and trifluoromethanesulfonic acid [1], we found that SN2-type substitution proceeded on the nitrogen atom of phenethyl ketone oximes in a nonpolar solvent instead of the Beckmann reaction (eq. 1) [2]. In addition, SN2-type cyclization was observed in the reaction of O-sulfonyloxime having an active methine group at γor δ-position with DBU as shown in the following equation [3]. This reaction proceeded in a stereospecific manner: The anti oximes cyclized to fiveand six-membered cyclic imines (eq. 2), while the syn isomers did not give any such cyclization products [4]. *Lecture presented at the 14th International Conference on Organic Synthesis (ICOS-14), Christchurch, New Zealand, 14–18 July 2002. Other presentations are published in this issue, pp. 1–70. (1) On the contrary, it was found that both of the syn and anti isomers cyclized into cyclic imines when γ,δ-unsaturated ketone O-2,4-dinitrophenyloximes were treated with reducing agents in the presence of radical trapping reagents [5]. The reaction proceeded via one-electron reduction of O-2,4-dinitrophenyloximes with sodium hydride and 3,4-methylenedioxyphenol, followed by radical cyclization with eliminating 2,4-dinitrophenoxide (Scheme 1). These results imply that oxime derivatives could be utilized for amination reagents. However, the above procedures have some drawbacks as synthetic methods. Due to the stereospecificity of the SN2-type cyclization, only the anti isomer can be employed for the intramolecular reaction. In the electron-transfer reaction, it is needed to use large excess amounts of sodium hydride and to introduce a bulky leaving group such as 2,4-dinitrophenoxy group. Hence, we have been studying the improvement of the above carbon–nitrogen bond-forming reactions for the synthesis of nitrogen-containing compounds. The following points should be realized to use oxime derivatives for amination reactions: (1) suppressing the Beckmann reaction, (2) overcoming syn/anti stereospecificity of the SN2-type reaction, (3) use of simple oxime derivatives, and (4) designing catalytic process. PREPARATION OF PRIMARY AMINES FROM O-SULFONYLOXIMES AND GRIGNARD REAGENTS In general, primary amines are prepared by the reduction of the compounds bearing a nitrogen function such as nitro and azide groups or the Gabriel-type nucleophilic amination reactions. Although electrophilic amination is another method to prepare primary amines, it has been rarely employed in organic synthesis [6]. As mentioned in the above SN2-type reaction, oxime derivatives were found to behave as electrophilic amination reagents. On the basis of the findings, the reaction of oxime derivatives and organometallic reagents was examined. There have been reported reactions of this type. Hagopian prepared primary arylamines by the reaction of tetraphenylcyclopentadienone O-sulfonyloxime with large K. NARASAKA © 2003 IUPAC, Pure and Applied Chemistry 75, 19–28 20