Aziridination, intramolecular

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

Intramolecular alkylnitrene addition to an alkenic moiety situated S,e to the electron deficient center has been utilized for the preparation of bi- and tri-cyclic aziridines (Scheme 11) (68JA1650). Oxidation of the primary alkylamine can be effected cleanly with NCS, LTA or mercury(II) oxide. 

An intramolecular trapping variant of the Hoch-Campbell aziridine synthesis was reported by Taguchi et When 2-(l-p-chlorophenylcyclohexyl)cyclohexanone (16)... 

A related aziridine synthesis is the Gabriel reaction (a.k.a. Gabriel-Cromwell reaction), which involves an intramolecular Sn2 reaction of a P-amino halide. However, the reaction has become so common that the name Gabriel is not tightly related to the transformation. 

The mechanism for the Wenker aziridine synthesis is very straightforward. As depicted by conversion 2—>3, the transformation is a simple case of intramolecular Sn2 displacement process, in which the sulfate ester is the leaving group. 

There is only one report in the literature of a [3-1-3] cycloaddition involving TMM and activated aziridines to give the corresponding piperidine (124) [44]. The formation of the six-membered ring adduct is presumed to proceed via the ringopening of the aziridine by the attack of TMM complex (2) on the least hindered carbon, which is then followed by an intramolecular cyclization (Scheme 2.34). 

Ring-opening of diastereomerically pure vinylaziridine 131, prepared by azir-idination of butadiene with 3-acetoxyaminoquinazolinone 130 [52], yielded acetate 132 with inversion of configuration, together with amino alcohol 133 with retention (Scheme 2.34) [53]. The formation of 133 can be explained by assuming participation by the quinazolinone carbonyl oxygen, which produces an intramolecular reaction with the aziridine carbon with retention of configuration. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Recently, Lee and co-workers reported an efficient method for the preparation of enantiomerically pure oxazolidin-2-ones from aziridine-2-carboxylates 186 (Scheme 3.68) [128]. This one-pot aziridine ring-opening and subsequent intramolecular cyclization process was highly regio- and stereoselective, affording 187 in high yield. 

When aziridine 194 (Scheme 3.71) was treated with a catalytic amount of NaOEt in ethanol it underwent an intramolecular ring-expansion to pyrrolidinone 195 in 88% yield [130]. The ring-opening took place via an internal SN2 reaction, which was confirmed by an X-ray analysis of the product 195. It is interesting to note that under similar reaction conditions 196 (Scheme 3.72) afforded P-lactam product 197 [130]. 

Intramolecular and intermolecular 1,3-dipolar cycloadditions of aziridine-2-car-boxylic esters with alkenes and alkynes have been investigated [131, 132]. Upon heating, aziridine-2-carboxylates undergo C-2-C-3 bond cleavage to form azome-... 

Dipolar cycloaddition of azides with olefins provides a convenient access to triazolines, cyclic imines, and aziridines and hence is a valuable technique in heterocyclic synthesis. For instance, tricyclic -lactams 273 - 276 have been synthesized using the intramolecular azide-olefin cycloaddition (lAOC) methodology (Scheme 30) [71]. 

An intramolecular ring expansion of aziridine esters can be accomplished by installing an appropriate nucleophilic entity in these substrates. Conversion of the ester moiety into carboxamides derived from aminomalonate ester gives compounds 44 containing the requisite nucleophilic site in the malonate moiety (Scheme 35). 

A deviant reaction was observed when the AT-Boc-aziridinecarboxamide 44b was treated with LDA in THF as the base. Under these kinetically controlled conditions an intramolecular reaction of the amide nitrogen with the Boc group takes place leading to the bicyclic product 46 in which the aziridine ring is retained (Scheme 36) [45]. 

The 8-methyl-8,14-cycloberbine 364, derived from the protoberberine 324 via the betaine 363, was reduced with sodium borohydride or lithium aluminum tri-tert-butoxyhydride to give a diastereoisomeric mixture of cis-and trans-alcohols (7.8 1 or 1 7.8, respectively) (Scheme 64).t)n exposure to formaldehyde the mixture underwent N-hydroxymethylation and subsequent intramolecular substitution on the aziridine ring to give the oxazolidine 365. Removal of the hydroxyl group in 365 was accomplished by chlorination followed by hydrogenolysis with tributyltin hydride. Reductive opening of the oxazolidine 366 with sodium cyanoborohydride afforded ( )-raddeanamine (360), which has already been converted to ochotensimine (282) by dehydration. 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

Intramolecular hydrogen abstraction leading to the aziridine 344 has been proposed to account for the unexpected conversion of the /f-amino vinyl phenyl ketones 345 into the pyrroles 346.286... 

Intermolecular addition of photochemically generated nitrenes and in particular acylnitrenes to alkenes provides a useful and widely applied route to aziridines.385 An analogous intramolecular photoreaction is thought to be involved in the conversion of the o-azidophenylethylfuran 461 into the pyrrolo[l,2-a]quinoline 462 as outlined in Scheme 13,386 and intramolecular addition to an azo group has been observed in the 8-azido-1-arylazonaphthalenes 463.387... 

While nitrogen sources such as chloramine-T and PhI=NTs have been used for aziridination reactions, TsNC12 has not been explored until now. The reaction of TsNCL, with Pd(OAc)2 and K2C03 provides the expected N-tosyl aziridines in good yields <06TL7225>. This reaction presumably proceeds through an initial amidohalogenation reaction catalyzed by palladium. The chloroamide is then converted to the aziridine via an intramolecular substitution reaction. 

The intramolecular addition of sulfur ylides to imines (e.g. 72) has proven to be an excellent route to fused-ring aziridines (e.g. 73) <06AG(I)7066>. The addition of a sulfonamide to a vinylsulfonium salt leads to the formation of the sulfur ylide 72. The ylide then undergoes an intramolecular addition to form the product fused-ring aziridine 73. This method has also been used for the synthesis of fused-ring epoxides. 

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICH2C1 with MeLi generates a chloromethyllithium reagent, which then adds to the inline 74. A subsequent intramolecular /V-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene. 

Typically in ring-opening reactions of aziridines, the amine functional group is retained in the product molecule. An example of such a reaction where the amine group has been lost has recently been reported <06TL977>. An intramolecular Friedel-Craft reaction of aziridine 91 leads to the expected product as an intermediate. Under the rather drastic reaction conditions, the sulfonamide is lost leading to formation of the naphthalene ring. 

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