A Mild and Regioselective Ring-Opening of Aziridines with Acid Anhydride Using TBD or PS-TBD as a Catalyst

The ring-opening of N-tosylaziridines with various acid anhydrides catalyzed by 5 mol % of 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) afforded the corresponding β-amino esters in excellent yields under mild reaction conditions. Polymer-supported catalyst, PS-TBD also acts as a good catalyst for this reaction. PS-TBD was easily recovered and reused with minimal loss of activity.


Results and Discussion
Initially, the ring-opening reaction of N-tosylaziridine 1a with acetic anhydride was examined. The reaction was carried out by adding the 1a and acetic anhydride in the presence of 5 mol % of TBD in DMF at 50 °C. The reaction was monitored by TLC. Hydrolytic work up with saturated NH4Cl at room temperature followed by flash column chromatography afforded the ring-opened products. The product was obtained at 78% yield in 24 h along with 18% of the starting material. Although the reaction was performed for 48 h, the starting material did not disappear. Then the reaction was examined at elevated temperature (80 °C), and the reaction proceeded smoothly. The desired product was obtained at 94% yield in 4 h ( Table 1, entry 2). This reaction also proceeded smoothly when 2 mol % of TBD was used (Table 1, entry 3). Among the screened solvents, DMF has proved to be the most effective for this reaction ( Table 1, entries 1 vs. [4][5][6]. The product was obtained in lower yield when other bases, such as DBU, TMG, TTMPP and DMAP ( Figure 1) were used instead of TBD (Table 1, entries 1 vs. 7-10). An approximately comparable yield was observed when MTBD was used as a catalyst (Table 1,   To clarify the scope of this reaction, several N-tosylaziridines and acid anhydrides were examined in the presence of 5 mol % TBD. In all cases, reactions were very clean and the desired products were afforded in good to excellent yields. Almost complete regioselectivity was observed when using alkyl-N-tosyl aziridines as substrates, and reaction on the less-substituted aziridine carbon was observed ( Table 2, entries 7-10). For aryl-N-tosyl aziridines, in the case of a Lewis acid catalyzed reaction, selectivity demonstrated an opposite trend with alkyl-N-tosyl aziridines due to an electronic effect. Thus, the attack of the nucleophile at the benzylic position of aziridine occurred. However, in this Lewis base catalyzed reaction, the selectivity demonstrated the same trend: the reaction occurred on the less-substituted aziridine carbon (Table 2, entries [11][12][13][14]. Reaction of propionic anhydride and benzoic anhydride also proceeded smoothly to afford the corresponding β-amino acetals in high yield. When propionic anhydride was used, regioselectivity was slightly higher than the reaction using acetic anhydride. In addition, cycloalkyl-N-tosyl aziridines also worked well. Unfortunately, no reaction occurred when non-acitivated aziridine such as N-benzylcyclohexylaziridine was employed. Furthermore, we applied a polymer-supported TBD, PS-TBD [50][51][52][53] to this reaction. Polymer-supported catalysts have attracted significant attention in recent decades due to their inherent advantages in synthetic chemistry, e.g., simplification of reaction procedures including easy recovery of the catalyst by filtration, application to automated systems, and recycling of the catalyst [54][55][56][57][58][59]. Some unique reactions have been reported using TBD as an organocatalyst [31,[60][61][62][63][64][65]. Thus, we examined the ring-opening reaction of N-tosylaziridine 1a with acetic anhydride in the presence of 10 mol % of PS-TBD. As shown in Table 3, the reaction proceeded smoothly and the desired product was obtained at 85% yield in 10 h at 80 °C in DMF. A variety of N-tosylaziridines reacted well with acetic anhydrides to give β-amino acetates. The reaction also occurred on the less substituted aziridine carbon regardless of the type of aziridine. In addition, the recovery and reuse of PS-TBD for the reaction of N-tosylaziridine 1a with acetic anhydrides also examined. After the reaction was completed, ethyl acetate was added to the reaction mixture and the catalyst was recovered by filtration. The recovered catalyst was washed, dried and then reused. The catalyst was reused, maintaining its catalytic activity after 4 uses ( Table 3, entries 1-4).  A possible mechanism is illustrated in Scheme 1. First, TBD activated the anhydride to form Next, this intermediate immediately reacts with aziridines to give the ring-opening product B. Finally, acylation occurs to give the N-acylated adduct with regeneration of TBD.
In this transition state, a steric effect has greater priority over the electronic effect (Scheme 2). Therefore, in this Lewis base catalyzed reaction, selectivity is not dependent on a substituent. The reaction occurred on the less-substituted aziridine carbon even in the case of phenyl substituted aziridine 1e.

General
All reactions were performed under an argon atmosphere using oven-dried glassware. Flash column chromatography was performed using silica gel Wakogel C-200 (Wako Chemical, Osaka, Japan). Preparative thin-layer chromatography was carried out on silica gel Wakogel B-5F (Wako Chemical). Dehydrate DMF, THF, toluene and CH3CN were purchased from Wako Chemical. Other commercially available reagent was used as received without further purification. The aziridines were prepared according to literature procedure [66]. Yields refer to isolated compounds estimated to be >95% pure, as determined by 1 H-NMR spectroscopy. IR spectra were recorded on a JUSCO FT/IR-430 spectrometer (JASCO Corporation, Tokyo, Japan). 1 H-and 13 C-NMR spectra were determined for solutions in CDCl3 with Me4Si as internal standard on a Bruker Avance III instrument (Bruker Corporation, Billerica, MA, USA). HRMS data were measured on a JEOL JMS-700 mass spectrometer (JEOL Ltd., Tokyo, Japan).

General Procedure for TBD-Catalyzed Ring-Opening of Aziridines with Acid Anhydride
To a solution of TBD (0.05 mmol) in DMF (1 mL) was added aziridine (1.0 mmol) and acid anhydride (1.25 mmol) at room temperature. After the reaction was complete (as determinedby TLC), the reaction mixture was washed with saturated NH4Cl and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc:hexane = 1:3) to give the corresponding product.

General Procedure for PS-TBD Catalyzed Ring-Opening of Aziridines with Acid Anhydride
To a solution of PS-TBD (0.10 mmol) in DMF (1 mL) was added aziridine (1.0 mmol) and acid anhydride (1.25 mmol) at room temperature. After the reaction was complete (as determined by TLC), EtOAc (5 mL) was added to the mixture and PS-TBD was separated by filtration. The filtrate was washed with saturated NH4Cl, dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel (EtOAc:hexane = 1:3) to give the corresponding product. The recovered catalyst is reusable after washing (acetone and water) and drying in vacuo.    [23]. Colorless oil; yield: 253 mg (85%); IR (neat) : 3278, 2925, 1732, 1455, 1326, 1158, 1092    Copies of 1 H-and 13 C-NMR Spectra of products 2a-2f, 2aʹ-2fʹ, 2aʹʹ, and 2cʹʹ could be found in the supplementary materials.

Conclusions
In conclusion, we have demonstrated TBD catalyzed ring-opening reactions of N-tosylaziridine with acid anhydrides. A broad range of N-tosylaziridine and acid anhydrides could be applied using 5 mol % TBD. Furthermore, polymer-supported catalyst, PS-TBD also act as a good catalyst for this reaction. PS-TBD was easily recovered and reused with minimal loss of activity. These reactions provide a simple and convenient method for the synthesis of highly functionalized β-amino alcohols.

Author Contributions
S.M. conceived the ideas, analyzed the data, and wrote the paper; Y.M. performed the experiments, analyzed the data; All authors read and approved the final manuscript.