A Mechanistic Study for Aziridination of Nitroalkenes Mediated by N-Chlorosuccinimide

A Mechanistic Study for Aziridination of Nitroalkenes Mediated by N-Chlorosuccinimide Kento Iwai, Khimiya Wada, Feiyue Hao, Haruyasu Asahara, and Nagatoshi Nishiwaki 1 School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, JAPAN 2 Research Center for Molecular Design, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, JAPAN 3 School of Pharmaceutical and Material Engineering, Taizhou University, Jiaojiang 318000, CHINA 4 Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, JAPAN

predominantly, and aprotic polar solvents such as THF, acetonitrile, and dichloromethane were found to be suitable for this aziridination 21 . Furthermore, using bulky bases such as DBU and tert-BuOK accelerated formation of imine 5 while Cs 2 CO 3 increased the yield of 4a R Pr up to 85 21 . On the other hand, the role of NCS in the reaction mechanism of Scheme 1 has not been fully understood. Therefore, in this paper, we discussed the reaction mode of the aziridination with focusing on the role of NCS.

General
The melting points were determined on SRS-Optimelt Automated Melting Point System and were uncorrected. All the reagents and solvents were commercially available and used as received. The 1 H NMR spectra were measured on a Bruker Ascend-400 and JEOL JMN-ECZ400S at 400 MHz with tetramethylsilane as an internal standard. The 13 C NMR spectra were measured on a Bruker Ascend-400 and JEOL JMN-ECZ400S at 100 MHz, and assignments of 13 C NMR spectra were performed by DEPT experiments.
The high-resolution mass spectra were measured on an AB SCIEX Triple TOF 4600. The IR spectra were recorded on a JASCO FT/IR-4200 spectrometer.

Chlorination of octylamine 2b
N-chloro-N-octylamine 8b : To a solution of octylamine 2b 129 mg, 1 mmol in THF 4 mL , NCS 133 mg, 1 mmol was added, and the resultant mixture was stirred at room temperature for 0.5 h. Hexane 10 mL was added, and precipitates were filtered off. The filtrate was concentrated to afford a mixture of chloramine 8b and dichlorinated product 85/15 as a colorless oil, in which 78 of 8b was contained. Despite various attempts, these products could not be separated. 1

Michael addition of amine 2a to nitrostyrene 3
To a solution of nitrostyrene 3 45 mg, 0.3 mmol in THF 3 mL , propylamine 2a 74 µL, 0.9 mmol was added. After stirring for 10 min., the resultant solution was concentrated under reduced pressure to afford yellow oil as a residue. The oil was confirmed to be a mixture of Michael adduct 7a 90 and nitrostyrene 3 10 by the 1 H NMR; however, further purification was not performed because of the instability of 7a. 1

N-Chlorination of Michael adduct 7a
To a solution of nitrostyrene 3 45 mg, 0.3 mmol in THF 3 mL , propylamine 2a 74 µL, 0.9 mmol was added. After stirring for 10 min., NCS 80 mg, 0.6 mmol was added and the resultant mixture was stirred for further 10 min. After removal of the solvent, a mixture of N-chlorinated product 10a 72 and nitrostyrene 3b 20 was obtained as a residual yellow oil; however, further purification was not performed because of the instability of 10a. 1

Results and Discussion
The role of NCS in this reaction was studied by 1 H NMR spectroscopy using CDCl 3 as the solvent. When NCS was added to a solution of nitrostyrene 3, no change in signals for either compound was observed; thus, the possibility of activation of 3 by NCS was quite less. On the other hand, a noticeable change in the signals was observed when propylamine 2a Fig. 1b was added to a solution of NCS Fig.  1a signals corresponding to 2a were shifted to the lower field, and a new singlet signal appeared at higher field, in addition to the signal of NCS Fig. 1c . This indicated the in situ formation of N-chloramine 8a and succinimide 25 27 . Indeed, comparison of the NMR data with those in the literature 27 indicated the formation of N-chloramine. N-Chloramines have been used in organic syntheses as N1 units possessing both nucleophilicity and electrophilicity. This helps them to bind to polar functional groups such as C N and C O, thus facilitating the construction of diaziridine 28 30 and oxaziridine 31 frameworks, respectively. For addition to a C C bond, anionic forms of N-chloramine that are stabilized by electron-withdrawing groups such as carbonyl 32 and sulfonyl 33 35 are often used. On the other hand, except for some examples of intramolecular addition 36,37 , the addition of N-alkylated chloramine to a C C bond has not been reported in the literature. This prompted us to study the reaction of 8 with nitrostyrene 3.
N-Chloro propyl amine 8a 28 derived from propylamine 2a cannot be isolated because of its low boiling point; accordingly, octylamine 2b was employed as the substrate.
After stirring a solution of 2b and NCS in THF at room temperature for 0.5 h, hexane was added to it, and succinimide precipitate formed was filtered. The filtrate contained chloro octyl amine 8b 78 yield and N,N-dichlorinated amine 9b 14 yield at a ratio of 85:15 Scheme 2a . After the solution was allowed to stand at room temperature for 2.5 h, the oily mixture solidified, and the ratio changed to 76:24. This indicated that chloro octyl amine 8b underwent gradual disproportionation at room temperature. When the mixture containing 8b was allowed to react with nitrostyrene 3 in the presence of Cs 2 CO 3 , aziridine 4b was obtained in only 5 yield. This indicated that 8b was not an actual active species for aziridination. Instead, Michael adducts 7b and 10b, derived from 3 and 8b, respectively, were mainly produced, suggesting that chloramine 10b was the precursor for the formation of aziridine 4b Scheme 2b . To confirm our hypothesis, the reaction was monitored by 1 H NMR spectroscopy. When propylamine 2a was added to a solution of nitrostyrene 3 in CDCl 3 , signals corresponding to olefinic protons disappeared, and signals from three protons appeared at a higher field, indicating the efficient formation of Michael adduct 7a Fig. 2a . The signals from 7a shifted to the lower field upon the addition of NCS, indicating the formation of chloro propyl amine 10a via Nchlorination Fig. 2b . During the reaction, the signals from nitrostyrene 3 increased, presumably because of the increased leaving ability of propylamine as a result of N-chlorination. Using 3.0 equiv. of propylamine 2a and 2.0 equiv. of NCS in THF effectively afforded 7a and 10a in 95 from 3 and 73 from 7a yields, respectively. Compound 10a was obtained in 72 yield from 3 via a one pot reaction Scheme 3a . Compound 10a was converted to aziridine 4a in 62 yield upon treatment with Cs 2 CO 3 Scheme 3b .
In contrast, using N-bromo-and N-iodosuccinimides NBS and NIS instead of NCS did not furnish aziridine 4a.
To study the differences in the reactivities, the above-mentioned NMR experiments were conducted using NBS. When NBS was added to a solution of propylamine 2a in CDCl 3 , the signals corresponding to 2a were shifted to the lower field in the 1 H NMR spectrum, confirming the formation of N-bromamine. However, when NBS was added to a solution of Michael adduct 7a in CDCl 3 , quantitative formation of N-propylimine 5a was observed instead of N-bromination, confirming that aziridination did not occur under these conditions. cis-Nitrostyrene3 38 was subjected to this reaction under the same conditions. The reactivity was similar to that of trans isomer 3, and trans-aziridine 4a was formed, indicating that this reaction proceeded in a stepwise manner via a common intermediate Schemes 4a and 4b .   A plausible reaction mechanism is shown in Scheme 5. This reaction is initiated by the Michael addition of amine 2a to the double bond of 3 to furnish 7a. Subsequent Nchlorination of 7a by NCS affords chloramine 10a path a . However, competitive C-C bond cleavage also occurs at this stage, furnishing imine 5a path b . Deprotonation of 10a by a base generates nitronate ion 11a, thereby eliminating the steric hindrance from the adjacent aryl group. Intramolecular substitution of nitronate ion 11a on the ni-trogen atom afforded aziridine 4a path c . Elimination of chloramine 8a from 11a regenerates nitrostyrene 3 path d .
Since bulkier base or NBS cannot approach 7a, N-halogenation does not occur. In this case, competitive C-C bond cleavage occurs predominantly to give imine 5a Scheme 5, path b . Another possibility is the α-bromination of the nitro group, which facilitates the elimination of bromo nitro methane, to give 5a. Scheme 3 One-pot synthesis of 10a and its aziridination.

Scheme 4 Aziridination of stereoisomers 3 and 3 .
Scheme 5 A plausible mechanism for the aziridination of 3.

Conclusion
A mechanistic study for diastereoselective aziridination of nitrostyrene 3 was performed. Amine 2 undergoes Michael addition to nitrostyrene 3. The amino group of the produced adduct 7 is chlorinated by NCS to afford 10, and trans-substituted aziridine 4 is formed by intramolecular nucleophilic substitution at the nitrogen atom by nitronate. The insights obtained here will be useful for researchers treating heterocyclic compounds, amines and halogenated compounds.