Cis-aziridines

Jorgensen has recently reported similar enantioselective reactions between N-tosylimines 107 and trimethylsilyldiazomethane (TMSD) catalyzed by chiral Lewis acid complexes (Scheme 1.32) [57, 53]. The cis-aziridine could be obtained in 72% ee with use of a BINAP-copper(i) catalyst, but when a bisoxazoline-copper(i) complex was used the corresponding trans isomer was fonned in 69% ee but with very poor diastereoselectivity. 

Entry R Catalyst ligand Yield of cis-aziridines (%) ee of cis-aziridine (%) cis trans aziridine... 

Entry R Yield of trans aziridines (%) trans cis aziridine... 

Aziridines not substituted on the nitrogen atom react with nitrous acid to produce olefins.324 An N-nitroso compound is an intermediate (2-51) other reagents that produce such intermediates also give olefins. The reaction is stereospecific cis aziridines give cis olefins and trans aziridines give trans olefins.325 Aziridines carrying N-alkyl substituents can be converted to olefins by treatment with ferrous iodide326 or with m-chloroperbenzoic acid.327 An N-oxide intermediate (9-28) is presumably involved in the latter case. 

The conrotatory stereochemistry fits the Woodward-Hoffmann rule, illustrated 4.81 as [dashed lines could equally have been drawn to make it [02a+w2J. 

Aziridines can be obtained by Bi(OTf)3- or Sc(OTf)3-catalyzed reaction of aldi-mines with ethyl diazoacetate in ionic liquid [139]. Ethyl diazoacetate adds to the imine leading to intermediate 150 which cyclizes to give the aziridine 151. In most cases the reaction is highly stereoselective affording cis-aziridines predominantly (Scheme 8.63). 

For many years16 activated acetylenes have been known to undergo Diels-Alder reactions, which take place8,9 by concerted processes. The stereochemistry of the pyrazoline 9, obtained as sole product from the cis-aziridine 7 by heating in the presence of DMAD, can only be accounted for if opening of the ring to the ylid 8 is followed by a concerted, or extremely rapid, combination with the acetylene.16... 

To explain the enantioselectivity obtained with semi-stabilized ylides (e.g., benzyl-substituted ylides), the same factors as for the epoxidation reactions discussed earlier should be considered (see Section 10.2.1.10). The enantioselectivity is controlled in the initial, non-reversible, betaine formation step. As before, controlling which lone pair reacts with the metallocarbene and which conformer of the ylide forms are the first two requirements. The transition state for antibetaine formation arises via a head-on or cisoid approach and, as in epoxidation, face selectivity is well controlled. The syn-betaine is predicted to be formed via a head-to-tail or transoid approach in which Coulombic interactions play no part. Enantioselectivity in cis-aziridine formation was more varied. Formation of the minor enantiomer in both cases is attributed to a lack of complete control of the conformation of the ylide rather than to poor facial control for imine approach. For stabilized ylides (e.g., ester-stabilized ylides), the enantioselectivity is controlled in the ring-closure step and moderate enantioselectivities have been achieved thus far. Due to differences in the stereocontrolling step for different types of ylides, it is likely that different sulfides will need to be designed to achieve high stereocontrol for the different types of ylides. 

The aziridination works for both aromatic and aliphatic olefins, including less active linear terminal olefins. Most reactions proceed in good yield at room temperature. The use of ci.v-stilbene at 0°C gives predominately cis aziridine product in about 90 10 cis trails ratio (Table 6.1). The conservation of cis structure suggests that a discrete silver nitrene intermediate is involved in the reaction path. Because of the unique disilver structure and unlikely formation of a silver(III) species, the authors suspect that a bridged nitrene intermediate between the two silver atoms may be responsible for this transformation in which each silver atom donates one electron to the nitrenoid. However, further research is necessary to prove this hypothesis and a fast radical reaction mechanism cannot be eliminated on the basis of current evidence. 

In contrast, the aziridination of c/s-(J-methylstyrene was not observed at 0°C in spite of the presence of pyridine A-oxide. At room temperature, in the absence of the /V-oxide, the cis-aziridine was obtained in a poor yield and with a low ee value (Table 6.4). The addition of the JV-oxide improved the yield of the product, but did not cause a dramatic change in the ee value. 

Finally, analogous to the epoxides, aziridines can also be prepared by the addition of carbenoid centers to a carbon-nitrogen double bond. In this arena, Aggarwal and co-workers have reported a highly diastereoselective aziridination of imines with trimethylsilyldiazo-methane (TMSD). Thus, tosylimine 146 was converted to the cis aziridine 147 in 65% yield <02JOC2335>. 

Metalation of the phenyl-substituted cis-aziridine 25 followed by methyl iodide quench afforded the tricyclic isothiazole 1,1-dioxide 26 as a single diastereoisomer in 75% yield. The reaction was proposed to proceed via metalation of the benzylic position of the aziridine, rather than the position a to the silicon. Subsequent intramolecular attack of the benzylic anion 27 at the tosyl group ortho to the sulfonyl group gave 28 which was trapped with Mel to give the single diastereoisomer 26, whose structure was confirmed by X-ray analysis <02JOC2335>. 

Similar examples of de-aromatizing anionic cyclization reactions have also been described by other authors. Aggarwal and Ferrara have reported that cis-aziridine 254, on treatment with BuLi followed by quenching with iodomethane, gives the tricyclic aziridine 255 as a single diastereoisomer. This product probably arises from deprotonation of the benzylic carbon followed by intramolecular nucleophilic addition of the anion on the tosyl ring and subsequent methylation (Scheme 67)117. 

Among ions, the opening of a cyclopropyl anion is exemplified by the reactions of the trans and cis aziridines 6.55 and 6.58, which are isoelectronic with the cyclopropyl anion. They open in the conrotatory sense to give the W- and sickle-shaped ylids 6.56 and 6.59, respectively, which are isoelectronic with the corresponding allyl anions. This step is an unfavourable equilibrium, which can be detected by the 1,3-dipolar cycloaddition of the ylids to dimethyl acetylenedicarboxylate, which takes place suprafacially on both components to give the cis and trans dihydropyrroles 6.57 and 6.60. The conrotatory closing of a pentadienyl cation can be followed in the NMR spectra of the ions 6.61 and 6.62, and the disrotatory closing of a pentadienyl anion can be seen in what is probably the oldest known pericyclic reaction, the formation of amarine 6.64 from the anion 6.63. 

Interestingly, both cis and trans aziridine isomers gave the same azirine ester 68, surprising as the C2 proton is more acidic than the C3 proton and would also result in conjugation with the ester functionality. The intermediate 69 is shown for the cis aziridine. R groups included alkyl chains and phenyl substituents and yields varied from 54% to 86% with higher yields obtained via the trans aziridines. 

From Aziridines. Further aspects of the old established synthesis of thiazolidines from aziridines have been carefully studied. The use of cis- and rra/i5-2,3-dialkylaziridines (273) in conjuction with carbon disulphide affords 30—80% yields of 4,5-disubstituted thiazolidine-2-thiones (274) of opposite geometrical configuration, as indicated by the results of n.m.r. and mass spectrometric studies. The reaction is stereospecific for cis-aziridines, but only stereoselective for rmns-aziridines. A proposed mechanism accounts for the observations. 2-Alkylaziridines produce 4-alkylthiazolidine-2-thiones (274 R = H) in this reaction. ... 

Azomethine Ylides. Various azomethine ylides, generated by different methods, can be trapped by 1 to give spirocyclic 1,3-thiazolidines. Thermolysis of cis aziridines of type 37 in the presence of 1 occurs stereoselectively to give frans configured cycloadducts (38) (eq 16). Reactions carried out with trans-aziridines lead to as-substituted 1,3-thiazolidines. 

The reaction is cis-steieospecific when esters of acetic acid are used while, in the case of a-bromopropionic esters, a mixture of cis-trans aziridines is formed. The cu-selectivity shown by esters of acetic acid is not surprising. In fact, it may be explained by assuming an E geometry for both the enolate and the imine and a closed chair-like Zimmerman-Traxler transition state in which the imine side chain is in an axial position while the halogen atom is in an equatorial location. The subsequent nucleophilic di lacement oi the halogen atom in the resulting intermediate teads directly to the formation of the cis-aziridine (Scheme 19). 

PROBLEM 10.62 What does the formation of only cis aziridine (2) from irradiation of azide (1) in c -2-butene tell you about the nature of the reacting species in Problem 10.61 ... 

In 2004, Hossain and Redlich reported the synthesis of a series of iron-pybox complexes and their employment in the catalytic asymmetric aziridine forming reaction with imine (109a) and ethyl diazoacetate (10) (Scheme 16.31) [35]. When combined with AgSbFe, the isopropyl- and tert-butyl-pybox complexes (112a) and (112b) produce 47% of the cis-aziridine (110) in moderate enantiomeric excesses. The best overall results came when the tert-butyl pybox catalyst was used, although results obtained with the isopropyl pybox catalyst are very similar. 

In 1998, Hossain et al. reported the catalytic synthesis of aziridines, using an achiral iron Lewis acid-THF adduct, [CpFe(CO)2(THF)]+[BF4] (108). The reaction was generally ds-aziridine selective. With this approach, cis selectivity is now known to be typical, since most catalytic reactions mainly yield ds-aziridine. In 2001, they continuously reported the reason for the apparent cis-aziridine selectivity in the reaction of ethyl diazoacetate (10) with JV-benzylidene aniline (109a), catalyzed by (108) [36]. The catalytic reaction produces both cis- and trans-aziridines. Once... 

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