Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

Summary The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring opening followed by cyclization of the resulting haloalkoxy amine.

Recently we have reported the visible light-mediated ring opening of aziridines by a number of nucleophiles, such as LiBr, NaN 3 and alcohols [24]. As a part of an ongoing program on the ring opening of aziridines [25][26][27][28][29][30][31], we have developed an  efficient method for the synthesis of 2-substituted and 2,3disubstituted morpholines from aziridines utilizing a simple and inexpensive ammonium persulfate salt as the oxidant at room temperature (Scheme 1b) [32,33].

Results and Discussion
Our investigation started with the treatment of 2-phenyl-Ntosylaziridine (1a) with 2-chloroethanol in the presence of sodium persulfate at room temperature for 13 h (Table 1). To our delight, NMR studies showed that chloroethoxyamine 2a is observed as the only ring-opening product. After screening different persulfates, in concordance with Zeng [32], we found that ammonium persulfate ((NH 4 ) 2 S 2 O 8 ) is superior to Na 2 S 2 O 8 and K 2 S 2 O 8 in the transformation, leading to chloroethoxyamine 2a in an excellent yield (93%) in short time. Encouraged by the result that treatment of 2a with KOH at room temperature in THF led to morpholine 3a in 90% yield, we performed the reaction by addition of KOH to the mixture of 1a and (NH 4 ) 2 S 2 O 8 in 2-chloroethanol after the reaction and hoped to prepare 3a in one pot. Gratifyingly the reaction proceeded smoothly to furnish 3a in 93% yield (Scheme 2). To investigate the scope of this methodology, various substituted aziridines were prepared from the corresponding alkenes and submitted them to the reaction conditions. As shown in Table 2, both electron-deficient and electron-rich 2-aryl-substi-tuted aziridines 1a-j were well tolerated and the desired morpholines 3a-j were obtained in good yields ( Table 2, entries 1-10). N-Tosylaziridine 1k was also a viable substrate for the reaction leading to the corresponding bicyclic morpholine 3k in Scheme 3: Metal-free one-pot synthesis of optically pure morpholine derivatives from chiral aziridines.
95% yield ( Table 2, entry 11). In addition, the reaction of 2,3disubstituted aziridines (acyclic and/or cyclic ones), separable mixtures of regioisomers 3l,m and 4l,m were obtained arising from isomeric ring opening (Table 2, entries 12 and 13). We speculated that the observed regioselectivity might depend on the combined action of electronic effects and the position of substitution [31]. Under identical reaction conditions, the separable 2-butylmorpholine 3n and 3-butylmorpholine 4n could be easily prepared from aziridine 1n ( Table 2, entry 14).
To further investigate the applicability of this strategy in organic synthesis, we next performed a series of experiments to determine the potential of the straightforward synthesis of optically pure morpholines from chiral aziridines. The initial investigation was carried out by the replacement of racemic 2-phenyl-N-tosylaziridine (1a) with optically pure (S)-2-phenyl-1-tosylaziridine under the standard reaction conditions. To our delight, (R)-3a was obtained in 93% yield and 70% ee (Scheme 3). For optically pure (S)-2-alkyl-substituted aziridines 1p,q, separable (R)-2-alkylmorpholines 3p,q and (S)-3-alkylmorpholines 4p,q were prepared in pure forms (95-99% ee) and low to moderate overall yields. Furthermore, the enantiospecific synthesis of seven and eight-membered homologues of morpholine was also conducted to extend the potential application of the strategy. For example, when 2-chloroethanol was replaced by 3-bromopropanol, the seven-membered product (R)-3ab was obtained in 72% yield and 84% ee. Similarly, reaction of (R)-2-phenyl-N-tosylazetidine (1o) with 2-bromoethanol and/or 3-bromopropanol under the one-pot reaction conditions, afforded the seven-membered product (S)-3o and the eight-membered compound (S)-3ob in 65% and 60% yield with 52% and 67% ee, respectively.
Based on the above results, a viable mechanism was proposed as shown in Scheme 4. Initially, aziridine 1a might participate in single-electron transfer (SET) with the persulfate anion to render the radical cation A [32,34]. Concerted ring opening and nucleophilic addition leads to amino radical intermediate B, which is converted to the haloalkoxy amine intermediate 2a after abstraction of one hydrogen atom from alcohol. Finally, an intramolecular ring closure affords the morpholine product 3a in the presence of KOH [21].

Conclusion
In conclusion, we have developed a simple and practicable metal-free protocol for the synthesis of 2-substituted and 2,3disubstituted morpholines. Compared with the previous procedure, this reaction is conducted with a simple and inexpensive ammonium persulfate salt as the oxidant to realize the ring opening of aziridines for the reaction with haloalcohols through a radical cation intermediate pathway. Furthermore, a range of optically pure morpholines could be achieved by the use of chiral aziridines.

Experimental
General procedure for the one-pot synthesis of morpholines: A 10 mL round bottom flask equipped with a magnetic stirring bar was charged with aziridine/azetidine 1 (0.3 mmol, 1 equiv), (NH 4 ) 2 S 2 O 8 (137 mg, 0.6 mmol, 2 equiv) and haloalcohol (10 equiv). The mixture was stirred at rt for the appropriate time until the starting material disappeared completely (monitored by TLC). Then, 5.0 mL THF and excess KOH (12 equiv) were added to the reaction mixture and the mixture was stirred at rt. After the reaction was completed, the resulting suspension was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. Solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane mixtures to afford the pure products.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data and copies of 1 H and 13 C NMR spectra for products.