3,4-Unsubstituted 2-tert-Butyl-pyrrolidine-1-oxyls with Hydrophilic Functional Groups in the Side Chains

Abstract

Pyrrolidine nitroxides with four bulky alkyl substituents adjacent to N–O group are known for their high resistance to bioreduction. The 3,4-unsubstituted 2-tert-butyl-2-ethylpyrrolidine-1-oxyls were prepared from the corresponding 2-tert-butyl-1-pyrroline-1-oxides via either the addition of ethinylmagnesium bromide with subsequent hydrogenation or via treatment with ethyllithium. The new nitroxides showed excellent stability to reduction with ascorbate with no evidence for additional large hyperfine couplings in the EPR spectra.

Synthesis of Sterically Shielded Nitroxides Using the Reaction of Nitrones with Alkynylmagnesium Bromides

“…The synthesis of nitroxides via reaction of 1-pyrroline 1-oxides with alkynylmagnesium halides was earlier investigated by K. Hideg et al [ 34 , 35 , 36 ]. Recently, we suggested using this reaction for the preparation of sterically shielded 2,2,5,5-tetraalkylpyrrolidine nitroxides [ 8 , 21 ]. In this paper, we showed how these reagents could be applied for the preparation of various highly strained nitroxides of pyrrolidine, imidazolidine and 2,5-dihydroimidazole series.…”

“…However, sterically hindered 1-pyrroline 1-oxides are not prone to the addition of EtMgBr [ 8 , 17 ], presumably due to metalation [ 18 ]. These nitrones, nevertheless, readily react with vinylmagnesium [ 19 ], allylmagnesium [ 20 ] or ethynylmagnesium halides [ 8 , 21 ], which are known to show lower basicity than EtMgBr, affording corresponding nitroxides in good yields. The terminal vinyl or ethynyl groups can then be converted into ethyl ones via hydrogenation.…”

“…Although the nitroxide group is reduced to hydroxylamine, it can be easily recovered via oxidation. This technique of indirect introduction of the ethyl group allowed us to prepare highly resistant to reduction nitroxides [ 8 , 19 , 21 ].…”

2,5-Di-tert-butyl-2,5-diethylpyrrolidine-1-oxyls: Where Is a Reasonable Limit of Sterical Loading for Higher Resistance to Reduction?

“…This reaction was used to prepare highly strained, stable nitroxides with β-hydrogen [32]. In our studies of this reaction, we have developed a convenient procedure for the synthesis of strained pyrrolidines with three large alkyl substituents at positions 2 and 5, which can be used for preparation of various sterically shielded nitroxides of pyrrolidine series [16,[33][34][35][36]. It should be noted that even highly strained 2-tert-butyl-substituted nitroxides 1a,b (Figure 1) can be prepared with much higher overall yields than nitroxides 2-4 prepared via alternative methods [33,36].…”

“…In our studies of this reaction, we have developed a convenient procedure for the synthesis of strained pyrrolidines with three large alkyl substituents at positions 2 and 5, which can be used for preparation of various sterically shielded nitroxides of pyrrolidine series [16,[33][34][35][36]. It should be noted that even highly strained 2-tert-butyl-substituted nitroxides 1a,b (Figure 1) can be prepared with much higher overall yields than nitroxides 2-4 prepared via alternative methods [33,36]. For example, 2-(tert-butyl)-2-butyl-5,5-diethyl-3,4-bis(hydroxymethyl)pyrrolidin-1-oxyl (1b) was prepared from tert-leucine, 3-pentanone and dimethyl fumarate in four steps with the overall yield 36% [33].…”