Several routes have been developed for the syntheses of aziridines (aziridination).
Cyclization of haloamines and amino alcoholsedit
An amine functional group displaces the adjacent halide in an intramolecularnucleophilic substitution reaction to generate an aziridine. The parent aziridine is produced industrially from aminoethanol via two related routes. The Nippon Shokubai process requires an oxide catalyst and high temperatures to effect the dehydration. In the Wenker synthesis, the aminoethanol is converted to the sulfate ester, which undergoes base-induced sulfate elimination.[6]
Aziridines are obtained by treating a mono-, di-, tri- or tetra-substituted alkene (olefin) with O-(2,4-dinitrophenyl)hydroxylamine (DPH) [de] in the presence of rhodium catalysts.
For instance, Ph-Aziridine-Me can be synthesized by this method and then converted by ring opening reaction to (D)- and (L)-amphetamine (the two active ingredients in Adderall).[11]
Aziridines are reactive substrates in ring-opening reactions with many nucleophiles due to their ring strain. Alcoholysis and aminolysis are basically the reverse reactions of the cyclizations. Carbon nucleophiles such as organolithium reagents and organocuprates are also effective.[16][17]
Lewis acids, such as B(C 6F 5) 3, can induce decomposition of the ring to a carbocation and linear azanide, which then attack unsaturated moieties in tandem.[24] Oxidation to the N-oxide instead induces nitroso compound extrusion, leaving an olefin.[25]
Safetyedit
As electrophiles, aziridines are subject to attack and ring-opening by endogenous nucleophiles such as nitrogenous bases in DNA base pairs, resulting in potential mutagenicity.[26][27][28]
The International Agency for Research on Cancer (IARC) classifies aziridine compounds as possibly carcinogenic to humans (IARC Group 2B).[29] In making the overall evaluation, the IARC Working Group took into consideration that aziridine is a direct-acting alkylating agent, which is mutagenic in a wide range of test systems and forms DNA adducts that are promutagenic. The features that are responsible for their mutagenicity are relevant to their beneficial medicinal properties.[5]
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