Aziridine amides

Amidation of 520 with propionic anhydride provides in 91% yield the aziridine amide 521. Deprotonation at the amide (X-CR2 position occurs at — 78 °C with lithium bis-(trimethylsilyl)amide. Subsequent treatment of the anion with benzyl bromide results in a-alkylation to furnish in 79% yield the single diastereomer 522. On the other hand, if this anion is treated with benzaldehyde at —78 °C, the aldol reaction proceeds with high 5y -selectivity... 

A solution of 5 mmol 2-phenyl-5-ethoxyoxazole-4-carboxylic acid chloride in 20 mL benzene was added to a solution of 5 mmol aziridine and 0.5 g triethylamine (5 mmol) in 40 mL benzene at 0°C. The mixture was then stirred for 3 h at room temperature, filtered, washed with water, and dried over MgSOa. Upon removal of benzene by evaporation, the resulting amides were recrystallized several times from petroleum ether (b.p. 60-70°C) to give 80% of 2-phenyl-5-ethoxyoxazole-4-carboxy-aziridine amide, m.p. 82-83°C. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Alternative degradation pathways are operative when the initial aziridines bear (3-hydrogen atoms. In these instances a,(3- unsaturated amides (322) (from aziridinones) and amidines, e.g. (320), from aziridinimines are frequently isolated as the major products. 

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). 

The commonest of these for oxirane opening are amines and azide ion [amide ions promote isomerization to allylic alcohols (Section 5.05.3.2.2)]. Reaction with azide can be used in a sequence for converting oxiranes into aziridines (Scheme 49) and this has been employed in the synthesis of the heteroannulenes (57) and (58) (80CB3127, 79AG(E)962). 

The present authors have found that the preparation of 7V-acetyl aziridine derivates provides the most secure method of differentiating aziridines from primary amines which are alternate reaction products in a number of cases. The infrared spectra of the former derivatives show only a peak at 1690 cm" for a tertiary amide peaks at ca. 3440 and 1530 cm" indicative of a secondary amide are absent. Acetylation also shifts the aziridine ring protons to a lower field in the NMR by ca. 1 ppm relative to the parent aziridine. The A"-acetyl aziridines are hydrolyzed with 3% methanolic potassium hydroxide. " Published NMR spectra of several 16j5,17j -aziridines reveal resonance patterns resembling those of the respective epoxides. " ... 

For most common amides cleavage is quite difficult, but in the case of an aziridine (which exhibited reduced participation significantly in amide resonance because of the nonplanar amide moiety ) hydrolysis is much simpler, as shown in the following illustration ... 

Sml2, DMPU, 50-97% yield. " The reaction works well for alkyl-substituted aziridines benzenesulfonamides react faster than tosyl amides. 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

Aziridines Bearing Electron-withdrawing Croups Esters and Amides 1.3.1.1 Aza-Darzens Route... 

S,3R)-Aziridine-2-carboxylic amide 258 (Scheme 3.95) has been used in the synthesis of the cyclic guanidino amino acid, L-epicapreomycidine (260) [145]. Treatment of 258 with saturated ammonia in methanol at 30 °C for 4 days in a pressure bottle resulted in the aziridine ring-opening product, which afforded 259 in 52 % yield after removal of the Cbz protecting group. 

Another conceptually unique approach in alkene aziridination has come from Johnston s labs. These workers shrewdly identified organic azides as nitrene equivalents when these compounds are in the amide anion/diazonium resonance form. Thus, when a range of azides were treated with triflic acid and methyl vinyl ketone at 0 °C, the corresponding aziridines were obtained, in synthetically useful yields. In the absence of the Bronsted acid catalyst, cycloaddition is observed, producing triazolines. The method may also be adapted, through the use of unsaturated imi-des as substrates, to give anti-aminooxazolidinones (Scheme 4.25) [32]. 

A deviant reaction was observed when the AT-Boc-aziridinecarboxamide 44b was treated with LDA in THF as the base. Under these kinetically controlled conditions an intramolecular reaction of the amide nitrogen with the Boc group takes place leading to the bicyclic product 46 in which the aziridine ring is retained (Scheme 36) [45]. 

This reaction to bicyclic compounds containing the aziridine group was also observed for other amides, viz., 44c-f, when treated with a catalytic amount of f-BuOK in THF or MeONa in methanol. LDA treatment of the tosyl-activated substrate 44 a gave the five-membered ring product albeit in a low yield (31 %). Remarkably, the carboxamide derived from the cz5-aziridine failed to react with base, probably due to steric hindrance. 

For further dehydration, for example, of aldoximes and amides to nitriles, of alcohols to olefines, as well as the synthesis of heterocycles like oxiranes and aziridines see Section 18.5. 

Che et al. have reported that chiral Ru11(salen)s (54a) and (54b) are efficient catalysts for aziridination of alkenes (up to 83% ee) and amidation of silyl enol ethers (up to 97% ee), respectively (Scheme 39).163... 

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