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Communication

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

by
Omar Khoumeri
,
Cédric Spitz
,
Thierry Terme
and
Patrice Vanelle
*
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Institut de Chimie Radicalaire ICR, Aix-Marseille Université, UMR CNRS 7273, 27 Boulevard Jean Moulin – CS 30064 – 13385 Marseille Cedex 05, France
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(7), 7364-7375; https://doi.org/10.3390/molecules18077364
Submission received: 27 May 2013 / Revised: 14 June 2013 / Accepted: 18 June 2013 / Published: 24 June 2013
(This article belongs to the Section Organic Chemistry)
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Abstract

:
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.

1. Introduction

Aziridines are found in a number of natural products exhibiting various biological properties, such as antitumor and antibiotic activities [1]. They are known to be valuable building blocks since they can undergo ring-opening reactions leading to a variety of amine products [2,3,4,5]. Therefore, the preparation of aziridines has received increasing attention in recent years. Various synthetic methods have been developed to prepare aziridines such as nitrene transfer to olefins [6,7,8,9,10,11], carbene addition to imines [12,13], aza-Darzens reaction [14], and ylide addition to imines [15,16].
Tetrakis(dimethylamino)ethylene (TDAE) is an organic reducing agent, which reacts with halogenated derivatives to generate a carbanion under mild conditions [17,18,19]. Since 2003, we have introduced a new program directed toward the development of original synthetic methods using TDAE methodology in medicinal chemistry [20,21,22,23,24,25,26,27].
In particular, we have shown that, from o- and p-nitrobenzyl chlorides, TDAE can generate a nitrobenzyl carbanion able to react with various electrophiles such as aromatic aldehydes, α-ketoester, ketomalonate, α-ketolactam, and sulfonimine derivatives [28,29,30,31].
Recently, we reported the reaction of 2-(dibromomethyl)quinoxaline and 2-(dibromomethyl)-1,4-dimethoxy-9,10-anthraquinone with aromatic aldehydes in the presence of TDAE, providing a mixture of cis/trans isomers of corresponding epoxides [32,33].
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.

2. Results and Discussion

The required starting materials 1–3 were prepared in good yields (76–87%) by chlorination of the corresponding aromatic benzaldehydes using SOCl2 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 AlCl3 in a solvent-free procedure described by Sharghi [39].
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. 1H-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].
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-2-nitrobenzene (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 NO2 group, thus stabilizing a transition state where TsN− anion and NO2 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.

3. Experimental

3.1. 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 1H- and 13C-NMR spectra were determined on a Bruker AC 200 spectrometer. The 1H- and the 13C- chemical shifts are reported from CDCl3 peaks: 1H (7.26 ppm) and 13C (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 F254 (Merck) in an appropriate solvent.

3.2. 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 H2O (3 × 100 mL) and dried over MgSO4. 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].
1-(Dichloromethyl)-4,5-dimethoxy-2-nitrobenzene (3). 76% yield; white solid; mp 110 °C; 1H-NMR (200 MHz, CDCl3) δH 3.98 (s, 3H), 4.05 (s, 3H), 7.54 (s, 1H), 7.56 (s, 1H), 7.73 (s, 1H); 13C-NMR (50 MHz, CDCl3) δC 56.6, 56.7, 66.4, 107.2, 110.8, 129.4, 149.8, 153.8. Anal. Calcd for C9H9Cl2NO4: C, 40.63; H, 3.41; N, 5.26. Found: C, 40.86; H, 3.26; N, 5.39.

3.3. 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 (CH2Cl2) clearly showed that compound (1–3) was totally consumed. The solution was filtered (to remove the octamethyl-oxamidinium dichloride) and hydrolyzed with H2O (70 mL). The aqueous solution was extracted with chloroform (3 × 40 mL), the combined organic layers washed with H2O (2 × 40 mL) and dried over MgSO4. Evaporation of the solvent furnished an orange viscous liquid as crude product. Purification by silica gel chromatography (CH2Cl2/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].
2-(4-Nitrophenyl)-3-o-tolyl-1-tosylaziridine (5b). cis-isomer; white solid; mp 202 °C; 1H-NMR (200 MHz, CDCl3) δH 2.13 (s, 3H), 2.45 (s, 3H), 4.28 (d, 1H, J = 7.3 Hz), 4.33 (d, 1H, J = 7.3 Hz), 6.91–7.14 (m, 4H), 7.22 (d, 2H, J = 8.6 Hz), 7.38 (d, 2H, J = 7.8 Hz), 7.87–7.99 (m, 4H). 13C-NMR (50 MHz, CDCl3) δC 21.6, 21.7, 45.6, 47.9, 123.0, 125.6, 127.9, 128.0, 128.2, 129.7, 129.8, 130.0, 131.5, 134.4, 134.5, 135.9, 139.6, 145.2. trans-isomer; white solid; mp 161 °C; 1H-NMR (200 MHz, CDCl3) δH 2.38 (s, 3H), 2.41 (s, 3H), 4.20 (d, 1H, J = 4.7 Hz), 4.35 (d, 1H, J = 4.7 Hz), 7.17–7.28 (m, 6H), 7.59–7.66 (m, 4H), 8.21 (d, 2H, J = 8.7 Hz). 13C-NMR (50 MHz, CDCl3) δC 18.8, 21.6, 45.6, 47.8, 123.0, 125.6, 127.9, 128.0, 128.1, 128.1, 129.0, 129.7, 129.9, 134.3, 135.9, 139.5, 145.2, 147.3. Anal. Calcd for C22H20N2O4S: C, 64.69; H, 4.94; N, 6.86; S, 7.85. Found: C, 64.79; H, 4.97; N, 6.85; S, 7.92.
2-(2-Chlorophenyl)-3-(4-nitrophenyl)-1-tosylaziridine (5c). cis-isomer; white solid; mp 193 °C; 1H-NMR (200 MHz, CDCl3) δH 2.45 (s, 3H), 3.39 (d, 1H, J = 7.6 Hz), 3.46 (d, 1H, J = 7.6 Hz), 7.04–7.20 (m, 4H), 7.26 (d, 2H, J = 8.6 Hz), 7.38 (d, 2H, J = 8.2 Hz), 7.93 (d, 2H, J = 8.6 Hz), 7.97 (d, 2H, J = 8.2 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 46.0, 46.9, 123.1, 126.5, 128.0, 128.3, 129.0, 129.3, 129.4, 129.5, 130.0, 133.2, 134.1, 139.1, 145.3, 147.4. trans-isomer; white solid; mp 185 °C; 1H-NMR (200 MHz, CDCl3) δH 2.42 (s, 3H), 4.10 (d, 1H, J = 4.5 Hz), 4.56 (d, 1H, J = 4.5 Hz), 7.22–7.41 (m, 6H), 7.69 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 8.23 (d, 2H, J = 8.7 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 47.2, 49.8, 123.5, 127.0, 127.7, 128.4, 129.4, 129.6, 130.0, 130.0, 131.2, 134.5, 136.1, 139.5, 144.8, 148.1. Anal. Calcd for C21H17ClN2O4S: C, 58.81; H, 4.00; N, 6.53; S, 7.48. Found: C, 58.88; H, 3.99; N, 6.43; S, 7.49.
2-(3-Fluorophenyl)-3-(4-nitrophenyl)-1-tosylaziridine (5e). cis-isomer; white solid; mp 108 °C; 1H-NMR (200 MHz, CDCl3) δH 2.47 (s, 3H), 4.22 (d, 1H, J = 9.4Hz), 4.32 (d, 1H, J = 9.4Hz), 6.69–6.88 (m, 3H), 7.04–7.16 (m, 1H), 7.23 (d, 2H, J = 8.3 Hz), 7.39 (d, 2H, J = 8.3 Hz), 7.96 (d, 2H, J = 8.3 Hz) 7.99 (d, 2H, J = 8.3 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.7, 46.3, 47.1 (d, J = 2.6 Hz), 114.5 (d, J = 22.7 Hz), 115.2 (d, J = 21.1 Hz) 123.2 (d, J = 2.9 Hz), 123.3, 128.0, 128.5, 129.9, 130.1, 133.7 (d, J = 8.0 Hz), 134.2, 139.1, 145.4, 147.6, 162.4 (d, J = 247.0 Hz). trans-isomer; white solid; mp 143 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 4.22 (d, 1H, J = 4.4 Hz), 4.26 (d, 1H, J = 4.4 Hz), 7.70 (d, 2H, J = 8.8 Hz), 7.24–7.41 (m, 4H), 7.60 (d, 2H, J = 8.8 Hz), 7.67 (d, 2H, J = 8.2 Hz), 8.21 (d, 2H, J = 8.8 Hz). 13C NMR (50 MHz, CDCl3) δC 21.6, 49.0, 50.1 (d, J = 2.2 Hz), 115.2 (d, J = 22.7 Hz), 116.1 (d, J = 21.2 Hz), 123.7, 124.0 (d, J = 2.9 Hz), 127.5, 129.2, 129.7, 130.0, 134.7 (d, J = 7.7 Hz), 136.4, 140.2, 144.7, 148.1, 162.7 (d, J = 247.4Hz). Anal. Calcd for C21H17FN2O4S: C, 61.16; H, 4.15; N, 6.79; S, 7.77. Found: C, 60.51; H, 4.19; N, 6.62; S, 7.66.
2-(4-Nitrophenyl)-3-(3-(trifluoromethyl)phenyl)-1-tosyl-aziridine (5f). cis-isomer; white solid; mp 63 °C; 1H-NMR (200 MHz, CDCl3) δH 2.44 (s, 3H), 4.30 (d, 1H, J = 7.7 Hz), 4.34 (d, 1H, J = 7.7 Hz), 7.21–7.41 (m, 8H), 7.95 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 8.4 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 46.4, 46.9, 123.3, 124.4 (q, J = 4.0 Hz), 125.0 (q, J = 4.0 Hz), 128.0, 128.5, 128.8, 130.0, 130.5 (q, J = 33.0 Hz), 130.7, 132.3, 133.9, 138.9, 142.5 (q, J = 238.9 Hz), 145.6, 147.5. trans-isomer; white solid; mp 164 °C; 1H-NMR (200 MHz, CDCl3) δH 2.40 (s, 3H), 4.25 (d, 1H, J = 4.3 Hz), 4.35 (d, 1H, J = 4.3 Hz), 7.20–7.25 (m, 4H), 7.54–7.65 (m, 4H), 7.97 (d, 2H, J = 8.8 Hz), 8.20 (d, 2H, J = 8.8 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.5, 48.5, 50.1, 123.7, 125.3 (q, J = 3.7Hz), 125.8 (q, J = 3.7 Hz), 127.5, 129.1, 129.7, 130.1, 130.9 (q, J = 32.6 Hz), 131.6, 133.1, 136.1, 140.1, 140.5 (q, J = 238.1 Hz), 144.9, 148.1. Anal. Calcd for C22H17F3N2O4S: C, 57.14; H, 3.71; N, 6.06; S, 6.93. Found: C, 55.46; H, 3.74; N, 5.92; S, 6.71.
trans-2-(2-Nitrophenyl)-3-o-tolyl-1-tosylaziridine (6b). White solid; mp 160 °C; 1H-NMR (200 MHz, CDCl3) δH 2.27 (s, 3H), 2.41 (s, 3H), 3.87 (d, 1H, J = 4.8 Hz), 5.16 (d, 1H, J = 4.8 Hz), 7.16–7.20 (m, 4H), 7.26–7.32 (m, 1H), 7.48–7.77 (m, 6H), 8.15 (dd, 1H, J = 8.1, 1.1 Hz). 13C-NMR (50 MHz, CDCl3) δC 19.3, 21.5, 43.6, 51.9, 124.9, 125.7, 127.9, 128.5, 128.6, 129.1, 129.2, 129.4, 129.7, 129.8, 131.4, 134.2, 135.4, 139.6, 144.3, 148.1. Anal. Calcd for C22H20N2O4S: C, 64.69; H, 4.94; N, 6.86; S, 7.85. Found: C, 64.81; H, 4.96; N, 6.82; S, 7.57.
trans-2-(2-Chlorophenyl)-3-(2-nitrophenyl)-1-tosyl-aziridine (6c). White solid; mp 153 °C; 1H-NMR (200 MHz, CDCl3) δH 2.42 (s, 3H), 4.25 (d, 1H, J = 4.8 Hz), 5.04 (d, 1H, J = 4.8 Hz), 7.21–7.35 (m, 5H), 7.51–7.72 (m, 5H), 7.87 (d, 1H, J = 7.6 Hz), 8.20 (d, 1H, J = 7.6 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 46.0, 49.3, 125.0, 126.4, 127.8, 129.1, 129.5, 129.6, 129.9, 130.0, 130.1, 130.2, 130.3, 134.2, 135.7, 136.0, 144.6, 148.5. Anal. Calcd for C21H17ClN2O4S: C, 58.81; H, 4.00; N, 6.53; S, 7.48. Found: C, 58.72; H, 3.99; N, 6.50; S, 7.46.
trans-2-(2-Bromophenyl)-3-(2-nitrophenyl)-1-tosyl-aziridine (6d). White solid; mp 153 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 4.26 (d, 1H, J = 4.9 Hz), 5.00 (d, 1H, J = 4.9 Hz), 7.21–7.26 (m, 2H), 7.29–7.42 (m, 2H), 7.51–7.72 (m, 6H), 7.89–7.92 (m, 1H), 8.18 (dd, 1H, J = 8.1 Hz, J = 1.0 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.5, 46.4, 51.1, 125.0, 127.3, 127.8, 128.1, 129.4, 129.6, 129.7, 129.8, 130.0, 130.3, 131.3, 132.3, 134.1, 135.6, 144.6, 148.5. Anal. Calcd for C21H17BrN2O4S: C, 53.29; H, 3.62; N, 5.92; S, 6.77. Found: C, 53.36; H, 3.66; N, 5.96; S, 6.78.
trans-2-(3-Fluorophenyl)-3-(2-nitrophenyl)-1-tosyl-aziridine (6e). White solid; mp 154 °C; 1H-NMR (200 MHz, CDCl3) δH 2.42 (s, 3H), 3.91 (d, 1H, J = 4.6 Hz), 5.03 (d, 1H, J = 4.6 Hz), 7.01–7.26 (m, 4H), 7.31–7.36 (m, 2H), 7.48–7.69 (m, 5H), 8.17 (d, 1H, J = 7.9 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 45.5, 51.6 (d, J = 2.2 Hz), 116.1 (d, J = 20.8 Hz), 116.5 (d, J = 22.7 Hz), 125.0, 125.3 (d, J = 2.9 Hz), 127.8, 129.4, 129.5, 129.8, 129.9, 130.5, 133.1 (d, J = 8.0 Hz), 134.2, 135.8, 144.6, 148.2, 162.4 (d, J = 246.6 Hz). Anal. Calcd for C21H17FN2O4S: C, 61.16; H, 4.15; N, 6.79; S, 7.77. Found: C, 61.29; H, 4.20; N, 6.75; S, 7.72.
trans-2-(2-Nitrophenyl)-3-(3-(trifluoromethyl)phenyl)-aziridine (6f). White solid; mp 145 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 3.91 (d, 1H, J = 4.5 Hz), 5.13 (d, 1H, J = 4.5 Hz), 7.21 (d, 2H, J = 8.1 Hz), 7.49–7.84 (m, 9H), 8.18 (d, 1H, J = 8.4 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.5, 44.9, 51.6, 121.5 (q, J = 272.2 Hz), 125.0, 125.8 (q, J = 3.7 Hz), 126.8 (q, J = 3.7 Hz), 127.7, 128.9, 129.5, 129.6, 129.8, 130.4 (q, J = 32.2 Hz), 130.6, 131.5, 132.8, 134.3, 135.5, 144.8, 148.1. Anal. Calcd for C22H17F3N2O4S: C, 57.14; H, 3.71; N, 6.06; S, 6.93. Found: C, 56.96; H, 3.72; N, 6.11; S, 6.72.
trans-2-(4-Fluorophenyl)-3-(2-nitrophenyl)-1-tosylaziridine (6g). White solid; mp 135 °C; 1H-NMR (200 MHz, CDCl3) δH 2.42 (s, 3H), 3.86 (d, 1H, J = 4.6 Hz), 5.10 (d, 1H, J = 4.6 Hz), 7.04 (t, 2H, J = 8.4 Hz), 7.23 (t, 2H, J = 8.4 Hz), 7.47–7.63 (m, 7H), 8.15 (d, 1H, J = 7.8 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.6, 44.9, 52.4, 115.3 (d, J = 21.6 Hz), 125.0, 126.2 (d, J = 3.3 Hz), 127.7, 129.3, 129.5, 129.6, 131.1, 131.7 (d, J = 8.4 Hz), 134.3, 136.0, 144.5, 148.1, 162.5 (d, J = 248.4 Hz). Anal. Calcd for C21H17FN2O4S: C, 61.16; H, 4.15; N, 6.79; S, 7.77. Found: C, 61.31; H, 4.20; N, 6.79; S, 7.71.
trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-phenyl-1-tosylaziridine (7a). White solid; mp 154 °C; 1H-NMR (200 MHz, CDCl3) δH 2.39 (s, 3H), 3.74 (s, 3H), 3.88 (d, 1H, J = 4.4 Hz), 3.94 (s, 3H), 5.15 (d, 1H, J = 4.4 Hz), 6.91 (s, 1H), 7.19–7.23 (m, 2H), 7.34–7.37 (m, 3H), 7.59–7.63 (m, 4H), 7.71 (s, 1H). 13C-NMR (50 MHz, CDCl3) δC 21.5, 45.3, 53.7, 56.1, 56.4, 107.8, 110.6, 126.1, 127.8, 128.2, 129.0, 129.5, 129.9, 130.2, 136.5, 140.3, 144.2, 148.5, 153.7. Anal. Calcd for C23H22N2O6S: C, 60.78; H, 4.88; N, 6.16; S, 7.06. Found: C, 60.80; H, 4.92; N, 6.20; S, 7.03.
trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-o-tolyl-1-tosylaziridine (7b). White solid; mp 167 °C; 1H-NMR (200 MHz, CDCl3) δH 2.38 (s, 6H), 3.76 (s, 3H), 3.82 (d, 1H, J = 4.8 Hz), 3.93 (s, 3H), 5.18 (d, 1H, J = 4.8 Hz), 6.98 (s, 1H), 7.18 (d, 4H, J = 7.3 Hz), 7.24–7.32 (m, 2H), 7.56 (d, 1H, J = 8.2 Hz), 7.65 (d, 1H, J = 7.3 Hz), 7.70 (s, 1H). 13C-NMR (50 MHz, CDCl3) δC 19.4, 21.4, 44.3, 52.5, 56.1, 56.4, 107.8, 110.7, 125.7, 126.4, 127.9, 128.5, 128.7, 129.2, 129.4, 129.8, 135.9, 139.9, 140.2, 144.2, 148.4, 153.7. Anal. Calcd for C24H24N2O6S: C, 61.52; H, 5.16; N, 5.98; S, 6.84. Found: C, 61.86; H, 5.21; N, 5.98; S, 6.78.
trans-2-(2-Chlorophenyl)-3-(4,5-dimethoxy-2-nitrophenyl)-1-tosylaziridine (7c). White solid; mp 144 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 3.83 (s, 3H), 3.95 (s, 3H), 4.17 (d, 1H, J = 4.9 Hz), 5.07 (d, 1H, J = 4.9 Hz), 7.09 (s, 1H), 7.24 (d, 2H, J = 8.2 Hz), 7.29–7.40 (m, 3H), 7.65 (d, 2H, J = 8.2 Hz), 7.72–7.76 (m, 2H).13C-NMR (50 MHz, CDCl3) δC 21.5, 46.3, 50.0, 56.2, 56.4, 107.9, 111.3, 125.0, 126.8, 127.9, 129.1, 129.4, 129.5, 130.1, 130.3, 136.0, 136.4, 140.8, 144.5, 148.8, 153.6. Anal. Calcd for C23H21ClN2O6S: C, 56.50; H, 4.33; N, 5.73; S, 6.56. Found: C, 56.44; H, 4.33; N, 5.71; S, 6.57.
trans-2-(2-Bromophenyl)-3-(4,5-dimethoxy-2-nitrophenyl)-1-tosylaziridine (7d). White solid; mp 164 °C; 1H-NMR (200 MHz, CDCl3) δH 2.40 (s, 3H), 3.85 (s, 3H), 3.94 (s, 3H), 4.19 (d, 1H, J = 4.8 Hz), 5.02 (d, 1H, J = 4.8 Hz), 7.14 (s, 1H), 7.21–7.25 (m, 3H), 7.34 (t, 2H, J = 7.3 Hz), 7.53–7.72 (m, 3H), 7.74 (s, 1H). 13C-NMR (50 MHz, CDCl3) δC 21.5, 47.0, 51.7, 56.3, 56.4, 107.9, 111.6, 124.6, 126.3, 127.4, 127.9, 129.5, 130.1, 130.4, 131.2, 132.3, 135.9, 140.9, 144.5, 148.8, 153.4. Anal. Calcd for C23H21BrN2O6S: C, 51.79; H, 3.97; N, 5.25; S, 6.01. Found: C, 51.77; H, 3.93; N, 5.22; S, 5.88.
trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-(3-fluorophenyl)-1-tosylaziridine (7e). White solid; mp 161 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 3.75 (s, 3H), 3.84 (d, 1H, J = 4.4 Hz), 3.95 (s, 3H), 5.08 (d, 1H, J = 4.4 Hz), 6.91 (s, 1H), 7.03–7.12 (m, 1H), 7.23–7.29 (m, 3H), 7.33–7.45 (m, 2H), 7.65 (d, 2H, J = 8.3 Hz), 7.72 (s, 1H). 13C-NMR (50 MHz, CDCl3) δC 21.6, 45.7, 52.7, 56.2, 56.5, 107.9, 110.7, 116.2 (d, J = 20.8 Hz), 116.9 (d, J = 22.7 Hz), 125.7, 127.9, 129.5, 129.6, 129.8 (d, J = 8.0 Hz), 132.9 (d, J = 8.0 Hz), 136.3, 144.6, 148.7, 153.8, 160.0, 162.5 (d, J = 248.6 Hz). Anal. Calcd for C23H21FN2O6S: C, 58.47; H, 4.48; N, 5.93; S, 6.79. Found: C, 58.55; H, 4.54; N, 5.92; S, 6.76.
trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-(3-(trifluoromethyl)phenyl)-1-tosylaziridine (7f). White solid; mp 163 °C; 1H-NMR (200 MHz, CDCl3) δH 2.39 (s, 3H), 2.76 (s, 3H), 3.85 (d, 1H, J = 4.5 Hz), 3.93 (s, 3H), 5.14 (d, 1H, J = 4.5 Hz), 6.94 (s, 1H), 7.21 (d, 2H, J = 8.1 Hz), 7.48–7.68 (m, 5H), 7.71 (s, 1H), 7.88 (d, 1H, J = 7.4 Hz). 13C-NMR (50 MHz, CDCl3) δC 21.4, 45.3, 52.3, 56.2, 56.4, 107.8, 110.6, 125.5 (q, J = 272.6 Hz), 125.8 (q, J = 3.7 Hz), 126.9 (q, J = 4.0 Hz), 127.7, 128.8, 128.8, 129.6, 130.4 (q, J = 32.6 Hz), 131.3, 133.1, 135.9, 140.2, 144.7, 148.7, 153.8. Anal. Calcd for C24H21F3N2O6S: C, 55.17; H, 4.05; N, 5.36; S, 6.14. Found: C, 55.21; H, 4.19; N, 5.41; S, 6.05.
trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-(4-fluorophenyl)-1-tosylaziridine (7g). White solid; mp 158 °C; 1H-NMR (200 MHz, CDCl3) δH 2.41 (s, 3H), 3.72 (s, 3H), 3.82 (d, 1H, J = 4.4 Hz), 3.90 (s, 3H), 5.13 (d, 1H, J = 4.4 Hz), 6.86 (s, 1H), 7.06 (t, 2H, J = 8.6 Hz), 7.23–7.28 (m, 2H), 7.58–7.78 (m, 5H). 13C-NMR (50 MHz, CDCl3) δC 21.5, 45.5, 53.1, 56.1, 56.4, 107.9, 110.5, 115.3 (d, J = 21.6 Hz), 126.1 (d, J = 2.2 Hz), 126.2, 127.8, 129.6, 131.9 (d, J = 8.4 Hz), 136.6, 140.3, 144.4, 148.6, 153.8, 162.8 (d, J = 248.8 Hz). Anal. Calcd for C23H21FN2O6S: C, 58.47; H, 4.48; N, 5.93; S, 6.79. Found: C, 58.53; H, 4.51; N, 5.90; S, 6.62.

4. 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.

Acknowledgments

This work was supported by the Centre National de la Recherche Scientifique. We express our thanks to V. Remusat for recording the 1H and 13C-NMR spectra.

Conflict of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 5a–g, 6a–g and 7a–g, are available from the authors.
Molecules 18 07364 sch001 550
Scheme 1. Synthesis of nitro(dichloromethyl)benzene derivatives 1–3.
Scheme 1. Synthesis of nitro(dichloromethyl)benzene derivatives 1–3.
Molecules 18 07364 sch001
Molecules 18 07364 sch002 550
Scheme 2. TDAE-promoted reactivity of 1-(dichloromethyl)-4-nitrobenzene (1) and aromatic N-tosylimines 4a–g.
Scheme 2. TDAE-promoted reactivity of 1-(dichloromethyl)-4-nitrobenzene (1) and aromatic N-tosylimines 4a–g.
Molecules 18 07364 sch002
Molecules 18 07364 sch003 550
Scheme 3. TDAE-promoted reactivity 1-(dichloromethyl)-2-nitrobenzene derivatives 2–3 and aromatic N-tosylimines 4a–g.
Scheme 3. TDAE-promoted reactivity 1-(dichloromethyl)-2-nitrobenzene derivatives 2–3 and aromatic N-tosylimines 4a–g.
Molecules 18 07364 sch003
Molecules 18 07364 sch004 550
Scheme 4. Diastereoselectivity of the aziridine formation.
Scheme 4. Diastereoselectivity of the aziridine formation.
Molecules 18 07364 sch004
Table
Table 1. Reaction of 1-(dichloromethyl)-4-nitrobenzene (1) with aromatic N-tosylimines 4a–g using TDAE strategy. a
Table 1. Reaction of 1-(dichloromethyl)-4-nitrobenzene (1) with aromatic N-tosylimines 4a–g using TDAE strategy. a
EntryXAziridinecis/trans isomers b (%)Yieldc (%)
1H5a86/1481
22-Me5b67/3374
32-Cl5c74/2670
42-Br5d68/3272
53-F5e86/1471
63-CF35f75/2573
74-F5g84/1680
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 1H-NMR of the crude product. c All yields refer to chromatographically isolated pure products and are relative to dichloride 1.
Table
Table 2. Reaction of 1-(dichloromethyl)-2-nitrobenzene derivatives 2–3 with aromatic N-tosylimines 4a–g using TDAE strategy. a
Table 2. Reaction of 1-(dichloromethyl)-2-nitrobenzene derivatives 2–3 with aromatic N-tosylimines 4a–g using TDAE strategy. a
EntrySubstrateXtrans-Aziridine bYield c (%)
12H6a70
222-Me6b62
322-Cl6c80
422-Br6d70
523-F6e75
623-CF36f63
724-F6g79
83H7a73
932-Me7b70
1032-Cl7c61
1132-Br7d74
1233-F7e68
1333-CF37f75
1434-F7g64
a All the reactions were performed using 2 equiv of sulfonimines 4a–g, 1 equiv of dichloride 2–3 and 1 equiv of TDAE in anhydrous THF at –20 °C for 1 h and then at rt for 2 h. b Determined by 1H-NMR of the crude product. c All yields refer to chromatographically isolated pure products and are relative to dichloride 2–3.

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Khoumeri, O.; Spitz, C.; Terme, T.; Vanelle, P. TDAE Strategy for the Synthesis of 2,3-Diaryl N-Tosylaziridines. Molecules 2013, 18, 7364-7375. https://doi.org/10.3390/molecules18077364

AMA Style

Khoumeri O, Spitz C, Terme T, Vanelle P. TDAE Strategy for the Synthesis of 2,3-Diaryl N-Tosylaziridines. Molecules. 2013; 18(7):7364-7375. https://doi.org/10.3390/molecules18077364

Chicago/Turabian Style

Khoumeri, Omar, Cédric Spitz, Thierry Terme, and Patrice Vanelle. 2013. "TDAE Strategy for the Synthesis of 2,3-Diaryl N-Tosylaziridines" Molecules 18, no. 7: 7364-7375. https://doi.org/10.3390/molecules18077364

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