TDAE Strategy for the Synthesis of 2,3-Diaryl N-Tosylaziridines

We report herein an original and rapid synthesis of 2,3-diaryl N-tosylaziridines by TDAE strategy starting from ortho- or para-nitro(dichloromethyl)benzene derivatives and N-tosylimines. A mixture of cis/trans isomers was isolated from 1-(dichloromethyl)-4-nitrobenzene, whereas only trans-aziridines were obtained from ortho-nitro derivatives.

In order to extend this reactivity to the synthesis of aziridines, we explored the reaction of gem-dihalogenated derivatives with imines in the presence of TDAE. We chose the sulfonylaldimines for their ability to react, shown in fluorine chemistry [34] and, more recently, in anthraquinonic series [31] in the presence of TDAE. As part of our research program for new bioactive compounds [35][36][37][38], we report herein an original and efficient synthesis of 2,3-diaryl N-tosylaziridines using readily available N-tosylimines and nitro(dichloromethyl)benzene derivatives by the TDAE strategy.

Results and Discussion
The required starting materials 1-3 were prepared in good yields (76-87%) by chlorination of the corresponding aromatic benzaldehydes using SOCl 2 in DMF at 80 °C for 2 h (Scheme 1). Arylsubstituted N-tosylimines 4a-g were prepared by condensation of various benzaldehydes and p-toluenesulfonamide in the presence of AlCl 3 in a solvent-free procedure described by Sharghi [39].

Scheme 1. Synthesis of nitro(dichloromethyl)benzene derivatives 1-3.
The reaction of 1-(dichloromethyl)-4-nitrobenzene 1 with two equiv. of aromatic N-tosylimines 4a-g in the presence of TDAE at −20 °C for 1 h, followed by 2 h at rt, led to a mixture of cis/trans isomers of the corresponding aziridines 5a-g in good yields (70-81%) as shown in Scheme 2 and reported in Table 1. Both electron-withdrawing and electron-donating substituents on the phenyl ring of the N-tosylimines were suitable for this reaction. 1 H-NMR spectral studies identified the aziridines 5a-g as trans or cis isomers by their coupling constant. Two distinct doublets appeared in 3.39-4.60 ppm region with J = 4.3-4.7 Hz or J = 7.3-9.4 Hz, each of the signals corresponding to one proton. The low coupling constant here is consistent with a trans-isomer as reported in the literature [40], higher values being indicative of the cis-isomer of aziridine [41]. Scheme 2. TDAE-promoted reactivity of 1-(dichloromethyl)-4-nitrobenzene (1) and aromatic N-tosylimines 4a-g. 4-F 5g 84/16 80 a All the reactions were performed using two equiv. of sulfonimines 4a-g, one equiv. of dichloride 1 and one equiv. of TDAE in anhydrous THF at -20 °C for 1 h and then at rt for 2 h. b Determined by 1 H-NMR of the crude product. c All yields refer to chromatographically isolated pure products and are relative to dichloride 1.
The formation of these aziridines 5a-g may be explained by nucleophilic addition of α-chlorocarbanion, formed by TDAE acting with 1-(dichloromethyl)-4-nitrobenzene (1), on the C=N double-bond of N-tosylimines 4a-g followed by an intramolecular nucleophilic substitution. The greater stabilization of the cis isomer is explained by steric hindrance [15]: the largest group on the three-membered ring is the tosyl group and this will preferentially be anti to the other substituents to minimize 1,2-steric interactions, which forces the two remaining groups to be cis to each other.
The reaction of 1-(dichloromethyl)-2-nitrobenzene (2) and 1-(dichloromethyl)-4,5-dimethoxy-2nitrobenzene (3) with two equiv. of various N-tosylimines 4a-g in the presence of TDAE at -20 °C for 1 h followed by 2 h at rt led only to the corresponding trans-aziridines 6a-g and 7a-g in good yields (61-80%) as shown in Table 2 (Scheme 3). This total trans diastereoselectivy can be explained by analysing the relevant transition states (Scheme 4). The very high steric hindrance of the ortho-nitro subtituent of 2 and 3 with aromatic ring of sulfonimines has a significant effect. Clearly, transition state A is less sterically hindered than transition state B, which explains the preferential formation of the trans aziridines. To explain this total trans diastereoselectivity, a different coordination transition state could also be envisaged. In this hypothesis, the bis cation deriving from TDAE [42] coordinates both the TsN − anion and NO 2 group, thus stabilizing a transition state where TsN − anion and NO 2 group are on the same side like transition state C and increasing the formation of the trans aziridine that must be considered the cinetic compound. Table 2. Reaction of 1-(dichloromethyl)-2-nitrobenzene derivatives 2-3 with aromatic N-tosylimines 4a-g using TDAE strategy. a

General
Melting points were determined on a Büchi melting point B-540 apparatus and are uncorrected. Element analyses were performed on a Thermo Finnigan EA1112 at the spectropole of the Aix-Marseille University. Both 1 H-and 13 C-NMR spectra were determined on a Bruker AC 200 spectrometer. The 1 H-and the 13 C-chemical shifts are reported from CDCl 3 peaks: 1 H (7.26 ppm) and 13 C (76.9 ppm). Multiplicities are represented by the following notations: s, singlet; d, doublet; t, triplet; q, quartet; m, a more complex multiplet or overlapping multiplets. The following adsorbents were used for column chromatography: silica gel 60 (Merck, particle size 0.063-0.200 mm, 70-230 mesh ASTM). TLC was performed on 5 cm × 10 cm aluminium plates coated with silica gel 60 F 254 (Merck) in an appropriate solvent.

General Procedure for the Preparation of 1-3
Benzaldehyde derivative (13 mmol) was dissolved in thionyl chloride (10 mL), and then to the mixture was added 1 mL of DMF. The reaction mixture was stirred for 2 h at 80 °C. Then, the solvent was removed under vacuum. The residue was dissolved in dichloromethane (100 mL), washed with H 2 O (3 × 100 mL) and dried over MgSO 4 . After evaporation, the crude product was purified by silica gel chromatography with dichloromethane: petroleum ether (1:1) to give the corresponding dichlorobenzene derivatives 1-3. Analyses for compounds 1 and 2 are in agreement with those reported in the literature [43,44].

General Procedure for TDAE Reaction
Into a two-necked flask equipped with a drying tube (silica gel) and a nitrogen inlet was added 15 mL of an anhydrous THF solution of dichloride derivative 1-3 (1 equiv.) and N-tosylimine 4a-g (2 equiv.). The solution was cooled to −20 °C, maintained at this temperature for 30 min and then was added dropwise (via a syringe) the TDAE (1 equiv.). The solution was vigorously stirred at −20 °C for 1 h and then maintained at rt for 2 h. After this time, TLC analysis (CH 2 Cl 2 ) clearly showed that compound (1-3) was totally consumed. The solution was filtered (to remove the octamethyl-oxamidinium dichloride) and hydrolyzed with H 2 O (70 mL). The aqueous solution was extracted with chloroform (3 × 40 mL), the combined organic layers washed with H 2 O (2 × 40 mL) and dried over MgSO 4 . Evaporation of the solvent furnished an orange viscous liquid as crude product. Purification by silica gel chromatography (CH 2 Cl 2 /petroleum ether: 70/30) and recrystallization from isopropanol gave corresponding aziridines (5-7). Analyses for compounds 5a, 5d, 5g and 6a are in agreement with those reported in the literature [45].     43.6, 51.9, 124.9, 125.7, 127.9, 128.5, 128.6, 129.1, 129.2, 129.4, 129.7, 129.8

Conclusions
TDAE methodology is extended here to the reaction of ortho-or para-nitro dichloromethylbenzene derivatives 1-3 with various aromatic N-tosylimines 4a-g, leading to the corresponding aziridines 5-7 in good yields (61-81%). The diastereoselectivity of the reaction is shown to be sensitive to steric hindrance. Further research is in progress to extent this method to other dichloride derivatives and to explore the ring opening reactions of the aziridines.