Selectivity aziridination

Reaction of 7V-benzylidine-o-anisidine with ethyl diazoacetate as the carbene-donor fragment in the presence of SnCU as the catalyst (5 mol %) gives the cw-aziridine selectively as the catalyst in reasonable yields (Eq. 65) [98], In the presence of SnCU no reaction occurs. This imine-SnC intermediate gives important information about the reaction course for the Lewis acid-catalyzed aziridination of imines. 

With respect to the C H functionalization/aziridination selectivity challenge. White and coworkers recently reported a significant advance [49]. Utilizing a hetero bimetallic Pd/Cr(salen)Cl catalyst system, a wide variety of alpha olefins were... 

Carbon-based nucleophiles continue to be examined in ring-opening reactions of aziridines. Select examples from the year 2014 include employment of indole derivatives in Friedel-Crafts-type reactions (14T4512, 14MI16478), utilization of malonate-type nucleophiles (14JA9190, 14EJ0767), and arylation reactions involving the use of N-heterocyclic... 

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... 

The reaction of a hydroperoxide with 2-methylaziridine [75-55-8] has been described (94). The reaction of ethyleneknine with phenols (95) and carboxyHc acids (96,97) produces ethylamine ethers and esters, respectively. However, these reactions frequentiy yield product mixtures which contain polyaminoalkylated oxygen nucleophiles and polymers, in addition to the desked products (1). The selectivity of the reaction can often be improved by using less than the stoichiometric amount of the aziridine component (98,99). 

Under conditions similar to those already outlined, stable aziridin imine derivatives, e.g. (422) and (423), can be prepared in excellent yields (70-80%) by treating the appropriate a-bromoamidines (easily accessible from the amide precursor) with potassium t-butoxide in ether <70AG(E)38l). At low temperatures the elimination proceeds with high regio- and stereo-selectivity at -40 °C (421) yields predominantly (422). 

Aziridines can best be obtained by ring closure of amine derivatives which contain a tm 5-oriented leaving group at the -position, see (89). The variable conformational and steric influences in the steroid skeleton limit the generality of a particular synthetic method and necessitate a selection of reagents based on the position of fusion of the aziridine ring. 

The formation of the tran -aziridine 281 as the major product of the conjugated addition of benzylamine to the furanone 280 was rationalized in terms of selective facial protonation of the initially formed enol 284 (Scheme 75) (00TL3061). 

Saito has recently reported high yields and enantioselectivities in aziridine synthesis through reactions between aryl- or vinyl-substituted N-sulfonyl imines and aryl bromides in the presence of base and mediated by a chiral sulfide 122 (Scheme 1.41) [66]. Aryl substituents with electron-withdrawing and -donating groups gave modest transxis selectivities (around 3 1) with high enantioselectiv-... 

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

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 ... 

The BF3 Et20-catalyzed aziridination of compounds 47 (Scheme 3.15) with a diazo ester derived from (R)-pantolacetone gave aziridine-2-carboxylates 48 [59]. The reaction exhibited both high cis selectivity (>95 <5) and excellent diastereose-lectivity. Treatment of a-amino nitrile 49 (Scheme 3.16) with ethyl diazoacetate in the presence of 0.5 equivalent of SnCl4 afforded aziridines 50 and 51 in 39% yield in a ratio of 75 25 [60]. 

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. 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

The reaction is somewhat selective for the cis diastereomer. The use of chiral additives in this reaction leads to aziridines enantioselectively. 

Aziridines are versatile intermediates in organic synthesis and commonly found in bioactive molecules. The transition metal-catalyzed nitrene transfer to alkenes is an attractive method for the synthesis of aziridines [7]. In 1984, Mansuy and coworkers reported the first example of an iron-catalyzed alkene aziridination in which iron porphyrin [Fe(TTP)Cl] was used as catalyst and PhINTs was used as nitrene source [30]. Subsequently, the same authors demonstrated that [Fe(TDCPP) (CIO4)] is a more efficient and selective catalyst than [Fe(TTP)Cl] (Scheme 20). 

The lipase-catalyzed resolution of (2/ , 35 )-3-methyl-3-phenyl-2-aziridine-methanol ( )-H by using the low-temperature method gave synthetically useful (2/ ,35 )-ll and its acetate (2S, iR)- a with (25 )-selectivity E = 55 at —40°C), while a similar reaction of (2/ , 3f )-3-methyl-3-phenyl-2-aziridinemethanol ( )-12 gave (25,35 )-12 and its acetate (2/ ,3/ )-12a with (2/ )-selectivity E = 73 at —20°C) (Scheme 2). Compound ( )-ll was prepared conveniently via diastereos-elective addition of MeMgBr to t-butyl 3-phenyl-2//-azirine-2-carboxylate, which was successfully prepared by the Neber reaction of oxime tosylate of t-butyl... 

In the presence of magnesium bromide etherate, yields of the a-allylpyrrolidines could be considerably improved. If instead of the quinazolinone aziridine the phthalimido aziri-dine was selected, the reaction proceeded better in the absence of magnesium bromide. 

The concept for the synthesis of4-hydroxy-4,5-dihydroisoxazoles by Righi and coworkers was discussed earlier, in Chapter 7. Here, an extension of this methodology by utilizing polymer-bound nitroacetate (hydroxylated Merrifield resin) is described [10], Thus, the one-pot domino oxidation/nitroaldol cyclization of aziridine 10-28 with immobilized nitroacetate 10-29 furnished 10-30 which, after detachment from the resin, led to the desired product 10-31 in good yield and excellent trans-selectivity (Scheme 10.7). 

Kim et al. have reported that the copper complex bearing the unique dinitrogen ligand (51) catalyzes the aziridination of conjugated as well as nonconjugated olefins with good enantio-selectivity (Scheme 37).159... 

Typically, the stereospecific formation of quaternary centers is as problematic as selective nucleophilic attack at the more substituted carbon of aziridines. Interestingly, a copper mediated methodology has been reported that does both <060L5105>. Although N-tosyl aziridines show favorable results, A-nosyl aziridines gave the best results. The reaction of 89 with a variety of phenols yielded 90 in moderate yields. 

Another problem with the reaction of phenols with aziridines is the selectivity between O-alkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B selects for C-alkylation <06OL2627>. Most of the examples reported in this paper showed less than 5% of the O-alkylation product. What is interesting about this report is the stereochemistry of the product. While the mechanism is not known, the product is formally an SNl type product. Generally less than 5% was the product of inversion of configuration (the Sn2 product). In addition to the A-tosyl, both the A-Cbz and A-Dpp aziridines gave excellent yields of aziridine-opened product. 

A novel C-3 functionalization of methylene aziridines has also been reported <06T8447>. Selective deprotonation of 98 to form 99 and the reaction 99 with an electrophile yielded 100 in good yields. In this way, a variety of alkyl groups could be selectively placed on the aziridine. These researchers also found that (S)-a-methylbenzyl substituted methylene aziridines, 101, when deprotonated and reacted with a variety of electrophiles gave 102 in moderate yields and with good diastereoselectivity. 

In the reaction of fused aziridines with alkene dipolarophiles, the opportunity for stereoselectivity as well as facial selectivity arises since exo- or entfo-isomers can be formed (Scheme 10). In practice, maleic anhydride 6, A-methyl maleimide and JV-phenyl maleimide each reacted exo-stereoselectively with TV-benzyl aziridine 69 to form adducts of type 71 (Scheme 10b), the stereochemistries of which were confirmed by NOE measurement between Hb and He. Similar reaction of the Y-phenyl aziridine 67 with N-Ph maleimide gave a 1 1 mixture of endo-adduct 72 and exo-adduct 73 (Scheme 10c). Adducts 68, 71-73 all exhibited a low-field methano-bridge proton (Ha) in the range 5 3.06-3.60 confirming the syn-facial stereochemistry of the two bridges. 

Halides in heterocyclic compounds can also be reduced selectively by tin hydrides. For example, the more reactive chlorine in a fluorinated aziridine can be reduced readily using very mild conditions and without a catalyst75. Again, the more reactive chlorine is reduced preferentially (equation 67). 

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