4-Aziridine analogs

CuOTf to ll-pregnene-3,20-dione provided the Ses-protected aziridinosteroid 25 in 53% yield (Equation 8). Deprotection of the Ses-aziridine resulted in a 77% yield of the deprotected aziridine. The aziridination reaction of 1 Tpregnene-3,20-dione provided only the 11,12-a aziridine analog of the steroid. 

R. erythropolis (previously R. rhodochrous) AJ270, which has been utilized in many enantioselective transformations of nitriles such as cyclopropane, oxirane, and aziridine analogs [10, 12], was recently proved to catalyze the enantioselective hydrolysis of azetidine-2-carbonitriles [13] and P-lactam carbonitriles also [14] (Figure 11.2). Carboxylic acids and carboxamides were also obtained with significant enantiomeric excesses from 3-hydroxy-4-aryloxybutanenitriles and 3-hydroxy-3-arylpropanenitriles (Figure 11.3) using R. rhodochrous ATCC BAA-870 [15], which is more elaborately discussed in Chapter 14. 

Polyurethanes can also be obtained via copolymerization of cyclic amines such as aziridines (analogous to epoxides) and azetidines (analogous to oxetanes) with CO2, according to Scheme 6.26 [190, 191]. 

Aziridines react with alkyleneamines iu an analogous fashion to epoxides (10,11). Product distribution is controlled by the alkyleneainine-to-aziridine mole ratio. 

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

Azomethine ylides are also frequently obtained by ring opening of aziridines, and the analogous carbonyl ylides from oxiranes. These aspects are dealt with in Section 3.03.5.1. A variety of five-membered heterocycles can also function as masked 1,3-dipoles and this aspect is considered in Section 3.03.5.2. 

Certain bifunctional nucleophiles allow cyclization after ring opening. The formation of 2-thiazolium salts (71JHC40S) and the analogous production of 2-amino-2-thiazolines (191) from aziridines and thiocyanic acid fall into this category (72JOC4401). 

The most useful reactions combine carbanion nucleophiles with activated aziridines. For example, the ring expansion which occurs on treatment of aziridines (219) with malonate salts typifies the heterocyclic synthesis possible. The conversion is quite general since many analogous transformations have been observed in which different carbanion stabilizing substituents were employed (73S546). 

One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

Iodine azide, on the other hand, forms pure adducts with A -, A - and A -steroids by a mechanism analogous to that proposed for iodine isocyanate additions. Reduction of such adducts can lead to aziridines. However, most reducing agents effect elimination of the elements of iodine azide from the /mwj -diaxial adducts of the A - and A -olefins rather than reduction of the azide function to the iodo amine. Thus, this sequence appears to be of little value for the synthesis of A-, B- or C-ring aziridines. It is worthy to note that based on experience with nonsteroidal systems the application of electrophilic reducing agents such as diborane or lithium aluminum hydride-aluminum chloride may yet prove effective for the desired reduction. Lithium aluminum hydride accomplishes aziridine formation from the A -adducts, Le., 16 -azido-17a-iodoandrostanes (97) in a one-step reaction. The scope of this addition has been considerably enhanced by the recent... 

Asymmetric transformation of imines into chiral aziridines remains less well developed than the analogous transformation of aldehydes into epoxides [49, 50, 51]. The reported methods can be divided into three conceptual categories involving... 

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. 

Thus, the key reason for the paucity of methods available by analogy with epox-idation methods is the comparative inertness of N-O and N-N bonds relative to the peroxide bond. This means that the synthetic methods that have been developed for preparation of aziridines are distinct from those that have evolved for epoxide synthesis. 

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],... 

O Brien et al. provided the first examples of olefin formation by reductive alkylation of aziridines [97]. Treatment of aziridine 267 with s-BuLi gave olefin 270 in 76% yield (Scheme 5.68). For the formation of olefin 270 they suggest a reaction pathway that proceeds in a manner analogous to that proposed for epoxides [36] namely, nucleophilic attack of s-BuLi on lithiated aziridine 268 to form dilithiated species 269, which eliminates Li2NTs (TsNH2 was observed as a product of this reaction) to yield olefin 270. 

When a better leaving group than LiNSC R (e.g., OMe) is present at the a-position, retention of the potentially useful sulfonamide moiety occurs (e. g., in the conversion of aziridine 271 into the highly functionalized amino ether 272 Scheme 5.69) [98]. It should be noted that the analogous chemistry with epoxides of allylic diethers failed this could again (see above) be possibly due to the higher pKa of the epoxide proton relative to the aziridine proton. 

The (3-elimination of epoxides to allylic alcohols on treatment with strong base is a well studied reaction [la]. Metalated epoxides can also rearrange to allylic alcohols via (3-C-H insertion, but this is not a synthetically useful process since it is usually accompanied by competing a-C-H insertion, resulting in ketone enolates. In contrast, aziridine 277 gave allylic amine 279 on treatment with s-BuLi/(-)-spar-teine (Scheme 5.71) [97]. By analogy with what is known about reactions of epoxides with organolithiums, this presumably proceeds via the a-metalated aziridine 278 [101]. 

It should be noted that the sense of asymmetric induction in the lithiation/ rearrangement of aziridines 274, 276, and 279 by treatment with s-butyllithium/ (-)-sparteine is opposite to that observed for the corresponding epoxides (i.e. removal of the proton occurs at the (S)-stereocenter) [102], If one accepts the proposed model to explain the selective abstraction of the proton at the (R) -stereo-center of an epoxide (Figure 5.1), then, from the large difference in steric bulk (and Lewis basicity) between an oxygen atom and a tosyl-protected nitrogen atom, it is obvious that this model cannot be applied to the analogous aziridines. 

Bei der Reduktion konnen sich neben den sek. Aminen auch Aziridine Widen13. O-Alkyl-14 und O-Acyl-oxime15 mit analoger Struktur werden durch Lithiumalanat ahnlich umgelagert. Durch Zugabe von Tit-an(lV)- Oder Eisen(III)-chlorid kann die Umlagerung zum sek. Amin unterdriickt werden16. 

This reaction is analogous to 10-7. It may be acid (including Lewis acids),base, or alumina catalyzed, occur with electrolysis, and may occur by either an SnI or Sn2 mechanism. Many of the P-hydroxy ethers produced in this way are valuable solvents, for example, diethylene glycol, Cellosolve, and so on. Reaction with thiols leads to hydroxy thioethers. Aziridines can similarly be converted to P-amino ethers. 

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." ... 

A new type of mechanism-based enzyme-inactivators, which are related to conduritol epoxides with respect to activation at the active site, was introduced by Tong and Ganem, " who prepared the aziridine 37 from the o-galacto analog of 1-deoxynojirimycin. Compound 37 proved to be a pp-... 

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