Direct aziridination

Notwithstanding the drawbacks to the method, the addition of nitrenes to alkenes is a well studied classical method for direct aziridination. The original reactions (often involving alkoxycarbonylnitrenes) employed harsh conditions, resulting in nonstereoselective transformations. In these pioneering reports, the requi-... 

The direct aziridination of nitroalkanes has been reported for the first time. Treatment of nitroalkene with an excess of CaO and NsONHC02Et (Ns = 4-nitrobenzenesulfonyl) gives the a-nitroaziridine in good yields (Eq. 10.70).101 The reaction proceeds via aza-Michael reaction followed by a ring closure. 

A general method for direct aziridination of alkenes, discovered nearly thirty years ago, involved oxidation of a number of A-aminoheterocyclic compounds, such as 240, with lead tetraacetate (LTA) in the presence of the alkene to give 241 375. The intermediates in these aziridinations were originally believed to be the corresponding TV-nitrenes but have recently been shown to be (at least for A-aminoquinazolinone 240 and A-aminophthalimide) the corresponding A-acetoxyamino compounds 242375. 

One more method which we would like to mention is the direct aziridination of unsaturated ketones using aminoimides 40 obtained in the reaction of N,N-dimethylhydrazine 38 with methyl oxirane 39 [57] (Scheme 1.11) ... 

The direct aziridination of alkenes can be accomplished by several methods which involve the in situ generation of the epiminating intermediate from a variety of precursors. 

Other less important methods for the direct aziridination of alkenes include the reaction of pentafluoronitrosobenzene with triethyl phosphite, and the base-induced a-elimination of ethyl 4-nitrophenylsulfonylcarbamate, performed in the presence of the alkene. These methods were examined in parallel with the methods employing the corresponding azides, hence direct comparison is possible, since the same aziridines are produced (Section 7.2.9). 

Dauban and coworkers published a detailed study on the reactivity of 2,3-epimino-2,3-dideoxy-D-lyxono-1,4-lactone derivatives 370, 380 with both soft (RSH, AcOH, LiBr) and hard (ROH, BnNH2) nucleophiles. Reactions of the epimines with soft nucleophiles proceeded by direct aziridine-ring cleavage to give predominantly C-2 regioisomers. 

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. 

Trichloroethylsulfamate ester has a potential to be a useful nitrogen source for aziridination because it is readily available, and the trichloroethoxysulfonyl group can be removed from the product under mild conditions. Guthikonda and Du Bois reported that tetratrifiuoroacetamide rhodium-catalyst, Rh2(tfacam)4 (tfacam = CF3CONH), was effective for the direct aziridination of various types of alkenes using sulfa-mate ester 19 and PhI(OAc)2 (Scheme 2.25) [38]. The results of the reactions of tmns- and di-(3-methylstyrene, and trans-and cw-decene indicated that the aziridination proceeded in a stereospecific manner via an electrophilic Rh-nitrene transfer. 

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... 

This chapter will deal exclusively with three-membered rings containing the hetero atoms O, S and N, and fused to the steroid skeleton. Because of the conformational requirements in steroids, not all of the usual methods of synthesis of three-membered rings are applicable to the fused ring system. For the synthesis of steroids to which an aziridine, oxirane or thiirane is attached either in the side chain or at a ring position but not directly fused to the nucleus, the methods discussed in this chapter, as well as others, are applicable. 

Thus, in contrast to benzothiepins, dibenzo compounds can be synthesized by direct acid-catalyzed elimination of water from hydroxy derivatives, or of amines from amino derivatives, at elevated temperatures due to their thermal stability. As in the case of benzothiepins, dibenzo derivatives can also be prepared by base-catalyzed elimination from the corresponding halo derivatives however, the yields are somewhat lower compared to the acid-catalyzed reactions. As a special case, an aziridine derivative was deaminated by palladium-catalyzed hydrogenation to afford the corresponding dibenzothiepin.69... 

This is by far the most versatile route to the synthesis of ester-substituted aziridines, especially as the benzhydryl group can easily be cleaved by hydrogenolysis. Wulff has applied this methodology to a short asymmetric synthesis of the antibiotic (-)-chloramphenicol in four steps from p-nitrobenzaldehyde (Scheme 1.34) [61]. In this case it was found that treatment of the aziridine 111 with excess dichloroacetic acid gave the hydroxy acetamide directly, so no separate deprotection step was required. 

Treatment of cyclic vinylaziridine 105 with organocuprates of the R2CuLi type proceeds in a highly syn-selective manner (Scheme 2.29) [46], The syn stereochemistry of the reaction reflects the effect of the acetonide group, which directs the nucleophilic attack to the less hindered a-face. The formation of SN2 products 109 from the cyclic (chlorovinyl)aziridine 107 can be explained by assuming a syn-SN2 ... 

In 1999, Bob Atkinson wrote [1] that aziridination reactions were epoxida-tion s poor relation , and this was undoubtedly true at that time the scope of the synthetic methods available for preparation of aziridines was rather narrow when compared to the diversity of the procedures used for the preparation of the analogous oxygenated heterocycles. The preparation of aziridines has formed the basis of several reviews [2] and the reader is directed towards those works for a comprehensive analysis of the area this chapter presents a concise overview of classical methods and focuses on modern advances in the area of aziridine synthesis, with particular attention to stereoselective reactions between nitrenes and al-kenes on the one hand, and carbenes and imines on the other. 

Since the mid-1990s, synthetic attention has been directed more towards the use of metal-stabilized nitrenes as synthetic effectors of alkene aziridination. In 1969 it was reported that Cu(i) salts were capable of mediating alkene aziridination when treated with tosyl azide, but the method was limited in scope and was not adopted as a general method for the synthesis of aziridines [12]. Metaloporphyrins [13] were shown to be catalysts for the aziridination of alkenes in the presence of the nitrene precursor N-tosyliminophenyliodinane [14] in the early 1980s, but the reaction did... 

Other reactions adapted from asymmetric aldol reactions suffer in comparison from the fact that (probably due to the strength of the boron-nitrogen bond) boron-mediated processes generally yield the intermediate 2-halo-3-aminoester products rather than aziridine products directly [51]. 

Direct deprotonation/electrophile trapping of simple aziridines is also possible. Treatment of a range of N-Bus-protected terminal aziridines 265 with LTMP in the presence ofMe3SiCl in THF at-78 °C stereospecifically gave trans-a, 3-aziridinylsi-lanes 266 (Scheme 5.67) [96]. By increasing the reaction temperature (to 0 °C) it was also possible to a-silylate a (3-disubstituted aziridine one should note that attempted silylation of the analogous epoxide did not provide any of the desired product [81],... 

In direct contrast with the chemistry of epoxides [81], trapping of the intermediate lithiated aziridine was possible with external electrophiles (which would... 

Two methods that are particularly convenient for large-scale synthesis of aziridines are discussed below. Both utilize readily available chloramine salts, such as chloramine-T, as sources of nitrogen. The first method involves direct olefin azir-idination catalyzed by phenyltrimethylammonium tribromide (PhNMe3+Br3 PTAB) [42]. In the second method, 1,2-hydroxysulfonamides, conveniently obtained by osmium-catalyzed aminohydroxylation of olefins, are converted into aziridines by one-pot cyclodehydration. 

The commercially available chloramine-T trihydrate (TsNNaCl 3H20) could also be used directly as the oxidant, although slightly more dilute concentrations (0.2 m vs. 0.5 m) had to be employed to ensure comparable yields. The applicability of this trihydrate version to large-scale syntheses was demonstrated by the aziridination of cyclopentene on a 0,5 mol scale reaction, providing 6-tosylazabicyclo-[3.1.0]hexane in 80% isolated yield (Scheme 12.14). 

It is possible to prepare aziridines, which are synthetically important molecules, directly from the corresponding epoxide. Reaction of Ph3P=NPh with an epoxide in the presence of ZnCl2 gives the N-phenyl aziridine. ... 

Aziridines can be prepared directly from double-bond compounds by photolysis or thermolysis of a mixture of the substrate and an azide. The reaction has been carried out with R = aryl, cyano, EtOOC, and RSO2, as well as other groups. The reaction can take place by at least two pathways. In one, the azide is converted to a nitrene, which adds to the double bond in a manner analogous to that of carbene addition (15-62). Reaction of NsONHC02Et/ CuO [Ns = A(/7-toluenesulfonyl-inimo)] and a conjugated ketone, for example, leads to the A-carboethoxy aziridine derivative.Calcium oxide has also been used to generate the nitrene.Other specialized reagents have also been used." ... 

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