Alkenes aziridine precursors

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... 

The anti-SN2 substitution of allylic aziridines (see Section 10.5.2.1.3.2) has been extended to the synthesis of the methyl-substituted D-Ala-Ala alkene isostere 153 (Scheme 33)J91 For the corresponding (trifluoromethyl) alkene isostere, the aziridine precursor could not be formed. Instead, allylic SN2 displacement (see Section 10.5.2.1.3.1) of the mesylate 154 occurred readily to provide the Ala-D-Ala isostere 155. 

In addition to alkenes, imines are tremendously popular aziridine precursors via an aza-Darzens approach. For example, a stereoselective synthesis of C-sulfonylated aziridines was reported via an aza-Darzens approach employing bromomethyl phenyl sulfbne, NaHMDS, and a series of N-tert-butanesulfinyl imines (14MI969). Likewise as shown below, chiral tert-butane- and mesitylsulfinimines were subjected to an aza-Darzens reaction with substituted 2-bromoesters to provide a host of aziridines in good yield with excellent stereocontrol (14OL6920). In turn, these aziridines could be subsequently converted to chiral A/-H aziridines in a total of three steps starting with a wide range of commercially available aldehydes. 

When unacylated azides are used as nitrene precursors, the first reaction with an alkene is a cydoaddition, generating the corresponding 1,2,3-triazoline, which often eliminates N2 under the fierce reaction conditions to give an aziridine product (Scheme 4.9 ). 

Since alkenes are relatively impotent precursors to aziridines, especially with regard to stereoselective reactions, substantially greater advances have been made in this field by means of the addition reactions between imines and a range of car-bene equivalents. 

Aziridines are important compounds due to their versatility as synthetic intermediates. In addition, aziridine rings are present in innumerable natural products and biologically active compounds. Nitrene addition to alkenes is one of the most well established methods for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the A-sulfonyloxy precursor. 

Interestingly, sulfonium ylides generated from electrophilic carbene complexes and sulfides can react with carbonyl compounds, imines, or acceptor-substituted alkenes to yield oxiranes [1320-1325], aziridines [1321,1326,1327] or cyclopropanes [1328,1329], respectively. In all these transformations the thioether used to form the sulfonium ylide is regenerated and so, catalytic amounts of thioether can be sufficient for complete conversion of a given carbene precursor into the... 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The thermolytic preparation by De Shong et al. (74) of azomethine ylides from aziridines and their intermolecular reactions are the first examples of singly stabilized ylides of this type. However, the protocol has been further extended to include intramolecular processes. Aziridines tethered to both activated and unactivated alkenes were subjected to flash vacuum thermolysis generating cycloadducts in moderate-to-excellent yields. While previously singly activated alkenes had furnished low material yields via an intermolecular process, the intramolecular analogue represents a major improvement. Typically, treatment of 222 under standard conditions led to the formation of 223 in 80% yield as a single cis isomer. Similarly, the cis precursor furnished adduct 224 in 52% yield, although as a 1 1 diastereomeric mixture (Scheme 3.77). 

Garner et al. (90,320) used aziridines substituted with Oppolzer s sultam as azomethine ylide precursors. The azomethine ylide generated from 206 added to various electron-dehcient alkenes, such as dimethyl maleate, A-phenylmalei-mide, and methyl acrylate, giving the 1,3-dipolar cycloaddition product in good yields and up to 82% de (for A-phenylmaleimide). They also used familiar azomethine ylides formed by imine tautomerization (320). Aziridines such as 207 have also been used as precursors for the chiral azomethine ylides, but in reactions with vinylene carbonates, relatively low de values were obtained (Scheme 12.59) (92). 

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. 

A -Phthalimidonitrene was thought to be the common intermediate5 in the thermal decomposition of sulfimide l6 and aziridines 27, 3a48 and 3b8. Similarly, the aziridines 4 and 5, more readily available than 3, are precursors of nitrenes, since their thermal decomposition in the presence of cyclohexene or (Z)-4-methyl-2-pentene produces new aziridines, e.g., 68. However, these nitrene exchange methods have limited synthetic utility for the supplementary steps required for the preparation of the nitrene precursors, but can be utilized for the aziridination of alkenes sensitive to oxidants, acids or UV light, conditions that are required by other aziridination methods. 

R1 R2 Config. Nitrene Precursor Conditions Solvent Alkene Cone (%) Aziridine Ref... 

The transition metal-mediated nitrenoid transfer to olefins represents a very concise route to the aziridine structure very often, however, an excess of the olefinic substrate is required for preparatively useful yields. In this arena, Andersson and co-workers have studied the copper-catalyzed aziridination of olefins using [A -(arenesulfonyl)imino]phenyliodinanes 446 as nitrene precursors, and have reported on conditions which give good to excellent yields of aziridines 447 without the constraint of having to use an excess of alkene (Scheme 116). 

An even more recent approach uses A -tosyloxycarbamates as the nitrene precursor species <2005JA14198>. It is interesting to note that this method is very stereospecific with complete retention of the alkene being observed in the product aziridine. The yields are comparable to both the thermal method as well as the PhIO route. Attempts to aziridinate A -tosyloxycarbamates derived from homoallylic alcohols gave no aziridine products (Equation 30). 

From aziridines. N-Tosylaziridines, easily obtained by aziridination of the corresponding alkenes, can be opened by selenolate reagents and furnish, after straightforward N-alkylation, radical precursors suitable for the preparation of pyrrolidine derivatives [12]. The preparation of octahydro-lff-indole 24 is shown in Eq. (4). A competing process involving radical azi-doselenenylation of alkenes has also been developed and will be discussed later (Sect. 5.2). 

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