Microwave-assisted regioselective ring opening of non-activated aziridines by lithium aluminium hydride

Abstract

-A new synthetic protocol for the LiAlH 4 -promoted reduction of non-activated aziridines under microwave conditions was developed. Thus, ring opening of 2-(acetoxymethyl)aziridines provided the corresponding β-amino alcohols, which were then used as eligible substrates in the synthesis of 5-methylmorpholin-2-ones via condensation with glyoxal in THF. The same procedure was applied for the preparation of novel 5(R)-and 5(S)-methylmorpholin-2-ones starting from the corresponding enantiopure 2-(hydroxymethyl)aziridines. Additionally, 2-(methoxymethyl)-and 2-(phenoxymethyl)aziridines were treated with LiAlH 4 under microwave irradiation, giving rise to either isopropylamines or 1-methoxypropan-2-amines depending on the reaction conditions.

Regioselectivity in the ring opening of non-activated aziridines

“…35 Recently, the same conclusion on the regioselectivity has been deduced in the ring opening of 2-(bromomethyl)aziridines 78 using LiAlH 4 . 36 The suggested mechanistic pathway for this transformation consists of an initial reductive debromination of the starting aziridines 78 toward 2-methylaziridines 79, which subsequently suffered from reductive ring opening by a hydride ion to yield isopropylamines 80 (Scheme 26). Apparently, the reducing agent acts both as the activator of the aziridine ring (through coordination of aluminium with nitrogen), and as the provider of the nucleophile (hydride) which opens up the ring at the less hindered position.…”

“…In addition, 2-(acetoxymethyl)-, 2-(methoxymethyl)and 2-(phenoxymethyl)aziridines were treated with LiAlH 4 under microwave irradiation, giving rise to either b-amino alcohols, isopropylamines or 1-methoxypropan-2-amines depending on the reaction conditions. 36 However, Uneyama and coworkers 37 have reported the unsuccessful transformation of chiral 2-(trifluoromethyl)aziridines 81 toward ring-opened products by using Lewis acids as catalysts and aliphatic amines as nucleophiles (Scheme 27). In this case, the reduced basicity of the aziridine nitrogen atom due to the strong electron-withdrawing effect of the CF 3 group clearly hampered the formation of aziridiniumlike intermediates.…”

LiAlH4‐Induced Thia‐Aza‐Payne Rearrangement of Functionalized 2‐(Thiocyanatomethyl)aziridines into 2‐(Aminomethyl)thiiranes as an Entry to 5‐(Chloromethyl)thiazolidin‐2‐ones

“…The in situ formed sulfide anion effects intramolecular aziridine ring opening, and this results in 2‐(aminomethyl)thiirane 6a after aqueous workup. Although nonactivated aziridines generally require activation of the ring system prior to ring opening (in contrast to activated aziridines), the ring opening of 1‐benzylaziridine 5a can be attributed to the Lewis acid activity of LiAlH 4 (through coordination of aluminum with nitrogen) . Subsequent treatment of obtained 2‐(aminomethyl)thiirane 6a with triphosgene resulted in N‐acylation to give carbamate 8a , and this was followed by regioselective chloride‐induced ring opening of the thiirane core at the less‐substituted carbon atom[7d], and ring transformation into corresponding 5‐(chloromethyl)thiazolidin‐2‐one 7a .…”

Advances in the Synthesis of Morpholin-3-ones and Morpholin-2-ones

“…99 Enantiopure 5-substituted morpholin-2-ones 185 (Table 15), 186 (Table 16) and 188 (Table 17) are mainly synthesized by the reaction of enantiomers of 2-substituted 2aminoethanols 47 and 50 with alkyl 2-bromoacetates 183 24,98,[101][102][103][104][105][106] or glyoxal 187. [107][108][109][110][111] They are valuable chiral substrates in the asymmetric synthesis of α-amino acids and other natural products.…”