Aziridinium ring opening

Synthesis of the phthalidylisoquinoline alkaloids cordrastine (82) and hydrastine (83) has been achieved by application of an aziridinium ring opening. A 2-methyl-3,4-dihydroisoquinolinium iodide was treated with 2-diazomethylbenzoate, in the hope of obtaining the rheadan or the phthalidylisoquinoline, as shown in Scheme 14. 

Aziridine adenylates 368 (Scheme 75) take part in MTase dependent DNA alkylations [261-263], where the aziridines are believed to undergo quar-ternization of the 5 -amine followed by MTase binding, delivery to the site of methylation, and subsequent aziridinium ring opening with concomitant substrate alkylation. 

Aziridinium ion-based click chemistry provides convenient access to pyrazolo[l,2-ajpyrazoles, active inhibitors of penicillin-binding proteins [58, 59]. Ring-opening of aziridinium ions 32 at the benzylic position with hydrazine, followed by intramolecular cyclization, gave pyrazolidin-3-ones 37 in excellent yields (Scheme 12.27). Heating of the hydrazides 37 with aromatic aldehydes at reflux in absolute... 

Scheme 1.30. Cationic cyclization/aziridinium ion formation/nucleophilic ring-opening procedure for the synthesis of pyrrolidines.

These findings can be interpreted in terms of a normal ring-opening mechanism of intermediate 325 with proton transfer favored by protic solvent, whilst in aprotic solvent cycloreversion of the unstable aziridinium grouping in 325 followed by ring expansion prevails. Likewise, 2,3-disubstituted aziridines follow this reaction pattern, while N-substituted aziridines do not225. ... 

Furthermore, triethylamine trisfhydrogen fluoride) is a highly versatile and easy-to-handle source of fluoride ions. Therefore, its use can be highly recommended for the ring-opening hydrofluorination of aziridines156 (or aziridinium ions166) see also refs 97 and 167. 

Nucleophilic Ring opening. Opening of the ethyleneimine ring with acid catalysis can generally be accomplished by the formation of an intermediate aziridinium salt, with subsequent nucleophilic substitution on the carbon atom which loses the amino group. In the following, R represents a Lewis acid, usually H + A = the nucleophile. 

Because of the rapid ring opening by the nucleophile, a ziridinium salts cannot usually be isolated. However, in a few cases it is possible to isolate such compounds (54), eg, at low temperatures, when the aziridinium salts are sparingly soluble or where there is steric hindrance to substitution. Stable ethyleneiminiiim salts can be prepared by reaction of ethyleneimine with acids not containing nucleophilic anions, for example HBF4 (55). 

Isomerization of the enantiopure hydroxylated azepane 42, after hydroxyl group activation, afforded either the ring-contracted piperidine derivative 45 (on O-mesylation to 43 followed by internal displacement to the aziridinium ion intermediate 44 and subsequent chloride ion induced ring opening) or the chiral ethylene-bridged morpholines 48 via 47 and an intramolecular Mitsunobu reaction of 46 (Scheme 4) <1996TL1613>. 

Several studies on the reactions and preparation of aziridines have been published. The ring opening of 2-substituted aziridines, accomplished by first converting them into aziridinium salts by reaction with a benzyl bromide and then attack of the bromide counter ion, gave only one bromide in a regio- and stereo-specific reaction.43 Since attack by the bromide ion of the aziridinium salt only occurred at the most substituted carbon with an inversion of stereochemistry, it was concluded the reaction occurred by an SN2 mechanism. This was supported by calculations at the MPWBlK/6-31+G(d) level of theory for reactions featuring two solvating acetonitrile molecules embedded in an acetonitrile matrix. 

The transition states for the ring opening reaction of an aziridinium ion by chloride ion were calculated using the IRC and QRC methods.56 Whereas the IRC method found only one transition state for the reaction, the QRC method suggested that there were two transition states that occurred sequentially along the reaction coordinate without an intervening intermediate. 

The amine product plays a critical role, as it deprotonates the H2 complex 18 to regenerate the catalytically active 17. This also prevents side reactions based on nucleophilic ring opening of the aziridinium cations by the amine products. Alkyl substituted aziridinium cations react via a classical SN2-mechanism. 

An organometallic reagent has also been used to ring-open an aziridinium ion (181), formed in situ by the treatment of the amino alcohol derivative 180 with lithium chloride. Subsequent addition of the aryl magnesium bromide 182 led to the formation of amine 183 in 95% overall yield <02TL6121>. 

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