Tricyclic aziridines, formation

One of the features of a,/3-unsaturated ketones is the presence of two electrophilic centers. Because of this feature, reactions with binucleophiles can proceed as a 1,2-addition or as a 1,4-addition. Regarding three-membered nitrogen-containing heterocycles formed from a,/3-unsaturated ketones and their derivatives, the unsaturated ketone acts either as a 1,2-bielectrophile (substituted ethylene), which leads to the formation of ethyleneimines, or as a 1,4-bielectrophile, giving rise to either bi- or tricyclic aziridines. Hence, the present chapter is divided into two parts, one which is entirely dedicated to aziridinyl ketones and the other to bi- and tricyclic aziridines. 

The first chapter is devoted to the formation and subsequent modification of three-membered heterocycles—aziridines. Synthesis and properties of aziridinyl ketones, bi- and tricyclic aziridine derivatives, cycloaddition and photochemical reactions are described. The second chapter deals with... 

The formation of a nitrene adjacent to a double bond can be used in the synthesis of novel heterocyclic systems. For example, the azide 721 converts smoothly into the tricyclic product 722 on irradiation and the same modus operandi is used for the synthesis of pyrrolo[2,3-J]pyrimidines from substituted 4-azidopyrimidines . Aziridine formation is also encountered in the cyclization of 723 to the tetrahydroquinoline derivatives 724 . Other cyclizations provide routes to imidazoindoles 725 " or thienopyrroles 726 . ... 

Some of the most synthetically useful reactions are intramolecular cycloadditions. An intramolecular cyclopentenone cycloaddition led to the formation of the tricyclic aziridine 54, an intermediate for the preparation of the alkaloid ( )-cephalotaxine, in good yield (Scheme 6.25). The intermediate triazoline was not detected. A related synthesis of the aziridine 55 was used as a step in a synthesis of the alkaloid ( )-aspidospermidine. °... 

Vinyltriazolines are unique thermolysis leads to high yields of 1-vinylaziridines. This is true of fused-ring tetracyclic (Scheme 40)199,201 and tricyclic triazolines (Schemes 42 and 43)200 204 with vinylic substitution in the 1-position. 1-Vinyltriazoline with no substituents on the ring carbons furnishes 1-vinylaziridine without formation of pyrrolines.378 Thermal decomposition of vinyl azides in acrylic acid derivatives is a synthetic route for 2-substituted 1-vinylaziridines.470 Similarly, aziridine 1-oximes are the only products of thermolysis of triazoline 1-oximes.107... 

As with the mitomycins, general routes to the synthesis of FR900482 and analogs have evolved. A very straightforward approach is the formation of the aziridine ring late in the synthesis using an intramolecular N-alkylation. A second is the incorporation of an intact monocyclic aziridine as part of the formation of the tricyclic ring system. 

An interesting intramolecular cycloaddition reaction of indoles with azides has also been reported. Heating solutions of l-(D-azidoalkylindoles 199, which bear an electron-attracting substituent (e.g., CHO, COMe, C02Me, CN) at C-3, has led to the formation of tricyclic indoles 201 as products [87] (Scheme 55). The authors suggest that after the initial 1,3-dipolar cycloaddition, the intermediate triazoline 200 loses nitrogen (perhaps via an aziridine intermediate) to produce the tricyclic products 201. 

Chlorosulfonyl isocyanate and 3-phenyl-2/f-aziridine undergo a [2 -H 2 -H 2] cycloaddition at room temperature to yield a mixture of separable tricyclic adducts (140) and (141), which on hydrolysis undergo ring expansion to give either the l,3,6-triazocin-2-one (24) or l,3,6-oxadiazocin-2-one (34) (Scheme 29) <93SC2151>. The formation of the oxadiazocin-2-one (34) is accompanied by a second product identified as 2,5-diphenylpyrazine. 

Recently, in 2008, Dixon and co-workers [96] developed highly efficient enantioselective a-alkylation of cyclic p-ketoesters with o-(trifiuoromethane)benzene-sulfonyl aziridine 39 under phase-transfer catalysis with (9-adamantoyl derivative LII (up to 85% yield and 97% ee). Moreover, the corresponding products 40 were obtained with high diastereoselectivity when PTC aziridine ring-opening of single enantiomeric aziridines was performed. In this work, also formation of diastereomerically pure tricyclic compounds via one-pot alkylation/desulfonation/ cyclization sequence was described. 

Rearomatization is much more common in bi- and tricyclic azides than ring expansion although ring expansion may be achieved employing sodium methoxide in methanol-dioxan as solvent. This dichotomy again may be resolved by invoking an aziridine intermediate vide supra). The formation of aminoketals from 2-azidoanthracene and 48 is of particular interest as similar products are commonly formed from aliphatic azirines on treatment with mildly basic methanol. At the moment, the intermediacy of benzazirine in phenyl azide photolysis at room temperature cannot be ruled out. In the case of bi- and tricyclic aromatic azides and azidouracil decompositions the nature of the products strongly supports azirine involvement. Only further experimental work will resolve this mechanistic dilemma. With this in mind, benzazirine intermediacy will be assumed for the purposes of this discussion. 

The formation of stabilized imino-iodanes as nitrene precursors has been exploited widely in aziridination of alkenes. Traditionally, isolated iminoiodanes have been the preferred route toward transition metal mediated or catalyzed aziridination or C-H amination chemistry [33]. Despite the great success in this field, some reports have become available on the corresponding transition metal-free variants. For example, Padwa reported an iodine(lll)-mediated aziridination of some carbamates 43 from allylic alcohols that in situ formed the corresponding imino-iodanes. Unexpectedly, these compounds underwent direct aziridination to the putative tricyclic compound 44, which was subsequently opened by addition of suitable nucleophiles to arrive at the 1,2-difunctionalized product 45 in a completely stereoselective manner (Scheme 11) [34]. This transformation constituted the proof of concept that iodine(lll)-mediated aziridination does not necessarily require metal promoters. 

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