Aziridinium ions, formation

Scheme 1.30. Cationic cyclization/aziridinium ion formation/nucleophilic ring-opening procedure for the synthesis of pyrrolidines.

C to —10°C) followed by a Dess-Martin oxidation provided the necessary azidoaldehyde. An intramolecular Staudinger cyclization followed by reduction of the resultant amine provided azepine 364. Treatment of 364 with iodine induced an interesting double cyclization. Initial iodination of the double bond is followed by aziridinium ion formation 365. An intramolecular and stereospecific ring opening by the carboxylate provides the target (—)-stemospironine. 

Another interesting reaction is cyclization with halide elimination. The case of formation of aziridinium rings from A-(2-chloroethyl) derivatives (nitrogen mustards) has been reviewed in Sect. 11.4.2, as was sulfur mustard. The remainder of this subsection is devoted to comparable reactions in which the product is not a strongly electrophilic aziridinium ion, but another ring type. 

Neighboring group participation effects appear to play a crucial role in the nucleophilic substitution of chlorine in Michael adducts of 1-R, 2-R, 3-X. Thus, this substitution proceeds very easily in any of the adducts formed with an electron rich nitrogen, sulfur and oxygen Michael donor. For the adducts of nitrogen nucleophiles, the facile substitution of the chlorine has been suggested to occur via formation of intermediate aziridinium ions 103 [8] (Scheme 32), and this postulate was later supported by isolation of azaspiropentane derivatives under appropriate conditions in several reactions (see Sect. 3.2.2) [11b, 53,56]. It is most likely that alkylthio substituents in adducts of type 85 participate in the same way to first form spirocyclopropane-annelated thiiranium ion intermediates which are subsequently opened by attack of the incoming nucleophile. 

Piperidine ring-expansion methodology and aziridinium ion intermediate formation has been demonstrated to provide good regio- and stereochemical control in the synthesis of substituted azepanes. Reaction of 298 with azide ion afforded 300 from preferential attack from behind by the azide ion at the methine carbon in the intermediate 299 (Scheme 38) <2002J(P1)2080>. 

An Sn2 reaction with anchimeric assistance (via formation of a bicyclic aziridinium ion intermediate) has been proposed for the nucleophilic substitution of trans-2-substituted 3-piperidinol mesylates by nitrogen nucleophiles with retention of trans... 

This effect of solvent polarity on the product distribution is in agreement with the proposed reaction scheme. A solvent such as acetone favors a reaction involving charge destruction, such as the alkyl halide formation from the aziridinium ion with the counter ion. Thus acetone favors piperazine formation. A solvent of high polarity favors charge stabilization or charge transfer such as the polymerization steps. Therefore, polymer or piperazine derivatives can be prepared by the proper choice of solvent. 

An organometallic reagent has also been used to ring-open an aziridinium ion (181), formed in situ by the treatment of the amino alcohol derivative 180 with lithium chloride. Subsequent addition of the aryl magnesium bromide 182 led to the formation of amine 183 in 95% overall yield <02TL6121>. 

Copper triflate has been found to promote the [3+2] cycloaddition of iV-tosylaziridines with nitriles <2006TL5399>. Ghorai has found that aziridine 149 and a substituted benzonitrile were dissolved and added to a suspension of copper triflate, resulting in the formation of good yield of the imidazoline 150. The mechanism proposed involves the addition of the nitrogen atom of the nitrile to the presumed copper aziridinium ion formed with the triflate catalyst. Subsequently, the iV-Ts moiety attacks the electrophilic carbon of the nitrilium ion to form the imidazoline. 

An alternative mechanism for the formation of the substitution products 333 entails the intermediacy of an aziridinium ion (334). Curiously, reaction of these allyl halides (291,... 

Ring expansion reactions of 2-substituted pyrrolidines, with the intermediacy of a bicyclic aziridinium ion, has provided new piperidines. Treatment of the chiral olefmic imine 264 with Br2, followed by reduction of the resultant ion 265 results in the formation of a separable mixture of spiromethylpyrrolidines and a single spiropiperidine 266 (23% yield), a precursor of (-)-nitramine 267 (Scheme 80) <05SL1726>. 

Ring expansion reactions of 2-substituted pyrrolidines to piperidines have been useful in certain cases, particularly in the iminosugar area. A careful analysis of the formation and fate of the condensed aziridinium ion intermediate 191 was made for the Mitsunobu reaction of 192 to maximize formation of 193 relative to simple alkylation <04SL1711> (Scheme 71). The known conversion of chiral prolinol 194 to 195 was used in the synthesis of thymine PNA monomer 196 <04BMCL2147>. 

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