3- aziridine 2254 Transformation

The reaction of chloroform with imidazoles > benzimidazoles and secondary amines (especially alicyclic amines) in the presence of alkoxides or hydroxides, as well as the reaction of chlorodifluoro-methane with sodium N-alkyl-iV-arylamides furnishes trisaminomethanes (525) and (526) (Scheme 95), respectively. Aziridine transforms fluorodialkyl sulfide (527) to the orthoamide (528 equation... 

The two-bond disconnection (re/ro-cycloaddition) approach also often works very well if the target molecule contains three-, four-, or five-membered rings (see section 1.13 and 2.5). The following tricyclic aziridine can be transformed by one step into a monocyclic amine (W. Nagata, 1968). In synthesis one would have to convert the amine into a nitrene, which-would add spontcaneously to a C—C double bond in the vicinity. 

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). 

Oxime 26 was prepared from 5,ll-dihydro-dibenzo[a,d]cyclohepten-10-one. The Hoch-Campbell reaction of 26 with 3-dimethylaminopropylmagnesium bromide produced aziridine 27 in 46% yield after acidic workup. Extension of the Hoch-Campbell reaction to steroids has also been reported. Thus, treatment of 3(3-hydroxy-5-pregnen-20-one oxime (28) with methylmagnesium iodide furnished a mixture of diastereomers, 20ot/20P,21-imino-20-methyl-5-pregnen-3P-ol (29) in a 50% combined yield and a 3 1 ratio. On the other hand, homo-adamantan-4-one oxime (30) was transformed to homo-adamantano[4,5-b]-2 -ethylaziridine (31) in 76% yield upon the action of... 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

A related aziridine synthesis is the Gabriel reaction (a.k.a. Gabriel-Cromwell reaction), which involves an intramolecular Sn2 reaction of a P-amino halide. However, the reaction has become so common that the name Gabriel is not tightly related to the transformation. 

The mechanism for the Wenker aziridine synthesis is very straightforward. As depicted by conversion 2—>3, the transformation is a simple case of intramolecular Sn2 displacement process, in which the sulfate ester is the leaving group. 

Mesylates and tosylates may be used as variants of the 0-sulfate ester. For instance, 55% of aziridine 7 was obtained from base-mediated cyclization of amino mesylate 6. In comparison, the classic Wenker protocol only gave 3% of 7. In another instance, A-tosyl amino alcohol 8 was tosylated to give 9, which was transformed to aziridine 10 in 64% yield, along with 29% of the P-elimination product due to the presence of the ester moiety. Likewise, aziridine 12 was assembled from tosylate 11 in two steps and 60% yield. ... 

Due to the abundance of epoxides, they are ideal precursors for the preparation of P-amino alcohols. In one case, ring-opening of 2-methyl-oxirane (18) with methylamine resulted in l-methylamino-propan-2-ol (19), which was transformed to 1,2-dimethyl-aziridine (20) in 30-35% yield using the Wenker protocol. Interestingly, l-amino-3-buten-2-ol sulfate ester (23) was prepared from l-amino-3-buten-2-ol (22, a product of ammonia ring-opening of vinyl epoxide 21) and chlorosulfonic acid. Treatment of sulfate ester 23 with NaOH then led to aziridine 24. ... 

Enantioselective synthesis and transformations of oxirane and aziridine derivatives 99PAC423. 

Benzodiazcpine 4-oxides are also produced from 2-(chloromethyl)-l,2-dihydroquin-azoline 3-oxides 11. Thus, the action of potassium /< )7-butoxide on compound 11a gives the fused aziridine 12a, which readily isomerizes to the 5H-], 4-benzodiazepine 4-oxidc 13a on heating. The homolog lib similarly affords the 5//-benzodiazepine oxide 13b on treatment with potassium rerr-butoxide via the aziridine 12b, which, however, could not be isolated. Under different conditions, i.e. with aqueous ethanolic sodium hydroxide, compound 11b is transformed into the tautomeric 3//-1,4-benzodiazepine 4-oxide 14.222... 

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... 

A novel guanidinium ylide-mediated procedure has recently been reported by Ishi-kawa [62]. Though not an imine transformation, it does employ an imine precursor in the fonn of an aldehyde. Guanidinium ylides react with aldehydes to form aziridines (Scheme 1.35). The mechanism for the formation of the aziridine is believed to involve [3+2] cycloaddition between the guanidinium ylide 112 and the aldehyde, followed by stereospecific extrusion of the urea with concomitant aziridine formation. 

Another example is indium(0)-induced electron transfer to aziridines 270 incorporating allyl iodide moieties (Scheme 2.66). Treatment with indium(O) in MeOH at reflux gave the corresponding chiral (E)-dienylamines 271 in excellent yields [98]. It should be noted that indium was found to be more effective for this transformation than other metals such as zinc, samarium, and yttrium. 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

More recently, Tardella and co-workers reported that treatment of 2-trifluorome-thyl acrylate 36 (Scheme 3.12) with the anion generated from nosyloxycarbamate 37 gave rise to aziridine-2-carboxylate 38 in 96% yield and 72% de with undetermined stereochemistry [40]. Aza-MIRC (Michael-initiated ring closure) was used to account for this transformation. A number of other hydroxylamine derivatives have been employed successfully in this type of aziridination reaction, includ-... 

Aziridine lactone 235 (Scheme 3.87) underwent ring-opening with allyl alcohol to give a 53% yield of a-amino lactone 236, which was successfully transformed to the unnatural enantiomer of polyoxamic acid (—)-237 [32],... 

One of the key steps in the synthesis of actinomycin D (241 Scheme 3.88) and its serine analogue involved the regio- and stereoselective ring-opening of aziridine 238 with the acid 239 [138, 139]. This transformation took place in methylene... 

Treatment of aziridine-2-carboxylic ester 251 (Scheme 3.93) with benzyl mercaptan in the presence of boron trifluoride etherate afforded 252 in 71% yield [142]. Compound 252 has been transformed into peptide 253, an analogue of a penicillin precursor. 

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-... 

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. 

Within the biooxidation of disulfides, chiral thiosulfinates become available. Tert-Butyl tert-butanethiosulfinate represents a particularly valuable chiral auxiliary for the preparation of several chiral sulfoxides and sulfinimines, which can be subsequently transformed into branched amine compounds, P-aminoacids, and chiral aziridines. This product is accessible readily by mediated biooxidation of tert-butyl... 

Certain reagents promote ring opening and subsequent cyclization to give other heterocycles. For example, di-tert-butyl dicarbonate induces the stereoselective ring transformation of N-alkyl aziridines 159 into oxazolidin-2-ones 160 <96TET2097>. 

Oxazolines have also been obtained from aziridines and carboxylic imidazolides via iV-acylaziridinesJ1271 Isomerization of the Af-acylaziridines can be achieved by heating with a catalytic amount of tetrabutylammonium iodide or bromide. The transformation can be carried out as a one-pot reaction in quantitative yield (solvents THF, CHC13, benzene) with a wide spectrum of substituents R (R = H, alkyl, c-C6Hi i, C6H5,3-pyridyl). 

The research groups of Mariano and West developed a photoinduced electrocydi-zation/nucleophilic addition sequence. Thus, irradiation of N-alkylpyridinium perchlorates as 5-19 in an aqueous solution led to the aziridine cations 5-20, which react in a nucleophilic addition with OH to give the isolable azabicyclo[3.1.0]hex-2-enols 5-21. These can be further transformed by a nucleophilic ring-opening of the aziridine moiety under acidic conditions to lead to useful unsymmetrically trans,trans-trisubstituted cyclopentenes 5-22 (Scheme 5.5) [10]. 

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