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Article

TDAE Strategy in the Benzoxazolone Series: Synthesis and Reactivity of a New Benzoxazolinonic Anion

by
Aïda R. Nadji-Boukrouche
1,2,3,
Omar Khoumeri
3,
Thierry Terme
3,
Messaoud Liacha
2 and
Patrice Vanelle
3,*
1
Procédés, Université 8 mai 1945 Guelma, BP 401, Guelma 24000, Algeria
2
Laboratoire de Synthèse et de Biocatalyse Organique (LSBO), Faculté des Sciences, Université Badji Mokhtar-Annaba, BP 12 El-Hadjar, Annaba 23000, Algeria
3
Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Marseille 13385, France
*
Author to whom correspondence should be addressed.
Molecules 2015, 20(1), 1262-1276; https://doi.org/10.3390/molecules20011262
Submission received: 11 December 2014 / Accepted: 8 January 2015 / Published: 14 January 2015
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

:
We describe an original pathway to produce new 5-substituted 3-methyl-6-nitro-benzoxazolones by the reaction of aromatic carbonyl and α-carbonyl ester derivatives with a benzoxazolinonic anion formed exclusively via the TDAE strategy.

1. Introduction

Many benzoxazolinone derivatives have been described in therapeutics as possessing a wide variety of pharmacological activities [1,2,3,4,5,6,7,8,9,10]. Indeed, the clinical applications of this template are very broad, and range from analgesic anti-inflammatory compounds to antipsychotic and neuroprotective anticonvulsant compounds [11]. Several potentially useful drugs and pharmacological tools based on these pharmacophores have been developed in recent years [12,13,14,15,16].
Tetrakis(dimethylamino)ethylene (TDAE) is a reducing agent which reacts with halogenated derivatives to generate an anion under mild conditions via two sequential transfers of one electron [17,18,19]. Through this strategy, we have developed many reactions between nitrobenzylic substrates and a series of electrophiles such as aldehydes, ketones, α-ketoesters, α-ketolactams and ketomalonates leading to corresponding alcohol adducts [20,21,22,23]. This reactivity was recently extended using original heterocyclic carbaldehydes as electrophiles. The reactions led to the expected products, while at the same time bringing to light a new and original reactivity and enabling us to define some limitations of this strategy [24]. Moreover, we reported the reactions of dihalo- and trihalomethyl heterocyclic derivatives with aromatic aldehydes in the presence of TDAE, providing a mixture of cis/trans isomers of oxiranes and α-haloketone derivatives, respectively [25,26]. In the same context, the expected alcohols and oxiranes were obtained in good yields in the quinonic series [27].
In continuation of our research program centered on the design and synthesis of novel bioactive molecules [28,29,30,31,32], we report herein the preparation of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) and the study of their reactivity with various aromatic carbonyl and α-carbonyl ester derivatives using the TDAE methodology.

2. Results and Discussion

2.1. Synthesis of Mono and Dibromide Substrates

We prepared 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) [33] in four and five steps, respectively. The condensation of 2-amino-4-methylphenol with urea was inspired by a previously described method [34,35]. After methylation using dimethyl sulfate, the nitration of the obtained 3,5-dimethylbenzoxazolone by action of a mixture of nitric and sulfuric acids afforded 3,5-dimethyl-6-nitrobenzoxazolone (1) in 88% yield.
Molecules 20 01262 g001 550
Scheme 1. Synthesis of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3).
Scheme 1. Synthesis of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3).
Molecules 20 01262 g001
The bromination of 1 with 2 equivalents of N-bromosuccinimide in refluxing CCl4 for 8.5 h gave 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) in 61% yield, accompanied by 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) in 38% yield. However, the preparation of this latter compound was optimized (76%) using 6 equivalents of N-bromosuccinimide in refluxing CCl4 for 10 h (Scheme 1).

2.2. TDAE Reactivity of 5-(Bromomethyl)-3-methyl-6-nitrobenzoxazolone (2)

The reaction of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) with 3 equivalents of various aromatic carbonyl and α-carbonyl ester derivatives 4a–j in the presence of TDAE at −20 °C for 1 h, followed by 2 h at room temperature (r.t.) led to the corresponding alcohol derivatives 5a–j in moderate to good yields (31%–72%) as shown in Table 1 and Scheme 2.
Table
Table 1. Reaction of bromide 2 with aromatic carbonyl and α-carbonyl ester derivatives using TDAE a.
Table 1. Reaction of bromide 2 with aromatic carbonyl and α-carbonyl ester derivatives using TDAE a.
Entry aAromatic CarbonylR1R2Product NumberYield (%) b
14-Nitrobenzaldehyde4-NO2-C6H4H5a52
24-Bromobenzaldehyde4-Br-C6H4H5b49
34-Cyanobenzaldehyde4-CN-C6H4H5c31
42-Nitrobenzaldehyde2-NO2-C6H4H5d44
52-Bromobenzaldehyde2-Br-C6H4H5e49
63-Bromobenzaldehyde3-Br-C6H4H5f43
7Ethyl glyoxylateCO2C2H5H5g72
8Diethyl ketomalonateCO2C2H5CO2C2H55h62
Notes: a All the reactions were performed using 3 equivalents of aromatic carbonyl 4a–h, 1 equivalent of bromide 2 and 1 equivalent of TDAE in anhydrous DMF stirred at −20 °C for 1 h and then warmed to rt for 2 h; b % Yield relative to bromide 2.
Molecules 20 01262 g002 550
Scheme 2. TDAE reactivity of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) with aromatic carbonyl and some α-keto-ester derivatives 4a–h.
Scheme 2. TDAE reactivity of 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) with aromatic carbonyl and some α-keto-ester derivatives 4a–h.
Molecules 20 01262 g002
The reaction of substrate 2 with the aromatic aldehydes 4a–f under TDAE-initiated conditions furnished the expected alcohols 5a–f in moderate to good yields. The best yield (52%) was obtained with p-nitrobenzaldehyde (4a). Unexpectedly, o,p-bromobenzaldehyde (4e,4b) gave the same yield (49%), while o-nitrobenzaldehyde (4d) and m-bromobenzaldehyde (4f) gave approximately the same yield (44% and 43%, respectively). Notably, with p-nitrobenzaldehyde (4a) we observed 23% of the ester 6. According to a recent mechanistic study [36], the formation of the unexpected ester derivative 6 may be explained by an electron transfer in a primary step between 4-nitrobenzaldehyde (4a) as acceptor and TDAE as donor.
p-Cyanobenzaldehyde (4c) produced a moderate yield (31%). The formation of these alcohol derivatives may be explained by nucleophilic addition of benzazolinonic carbanions formed by the action of TDAE with 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) on the carbonyl group of the corresponding aldehyde. In summary, the difference in yields does not appear to be totally explained by electronic effects: the halogen groups furnished approximately the same yields in either position. With nitrobenzaldehydes, steric hindrance could explain the difference between o- and p-nitrobenzaldehyde yields (44% versus 52%).
It is important to note that in the reactions of substrate 2 with the electrophiles 4b–f, we observed the unavoidable formation of the reduction product 1 [37]. Extending the reaction times to 8 h at ambient temperature increases its percentage, but decreases the yield of alcohol. On the other hand, after 4 h of reaction, the percentage of reduction product decreases at the same time as that of the alcohol: in this case we also observed traces of the dimerization of substrate 2.
Moreover, after the reaction with aromatic aldehydes, we investigated the reaction of 2 with α-keto-ester derivatives such as ethyl glyoxylate (4g), diethyl ketomalonate (4h), acenaphtenedione (4i) and 1-methylisatin (4j) in the presence of TDAE. The reactions with these electrophiles furnished the corresponding hydroxyl derivatives 5i–j in good yields (59%–63%), as shown in Table 1 and Scheme 3.
Molecules 20 01262 g003 550
Scheme 3. TDAE reactivity of the 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and α-diketone and α-ketolactam derivatives 4i–j.
Scheme 3. TDAE reactivity of the 5-(bromomethyl)-3-methyl-6-nitrobenzoxazolone (2) and α-diketone and α-ketolactam derivatives 4i–j.
Molecules 20 01262 g003

2.3. TDAE Reactivity of 5-(Dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3)

The optimized protocol of the dibromomethyl derivative 3, was defined with 3 equivalents of aromatic carbonyls 4a–h, 1 equivalent of 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) and 1.5 equivalents of TDAE in anhydrous DMF, for 1 h at −20 °C followed by 2 h at r.t. The reactions led to a mixture of cis/trans isomers of the corresponding oxiranes 7a–h in moderate to good yields as reported in Table 2 (Scheme 4). The formation of these oxiranes may be explained by nucleophilic addition of a α-bromocarbanion, formed by the action of TDAE with 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3), on the carbonyl group of aldehydes 4a–h followed by an intramolecular nucleophilic substitution [26].
In the case of the nitroaromatic aldehydes, steric hindrance could explain the yield difference between o- and p-nitrobenzaldehyde (46% and 63%). However, this effect disappears in the o-bromo-substituted aldehyde which gave 64% of the corresponding oxirane, the p- and m- substituted aldehydes with 55 and 48% yields respectively. p-Cyanobenzaldehyde gave the expected oxirane in good yield (72%).
Under the same experimental conditions, we studied the reaction of derivative 3 with α-keto-ester derivatives 4g–h as reported in Table 2 (Scheme 4). Only the trans isomers of the oxiranes 7g and 7h were obtained in 26% and 37% yields, respectively, with ethyl glyoxylate (4g) and diethyl ketomalonate (4h). Otherwise, acenaphtenedione (4i) and methyl isatin (4j) furnished mixtures of like/unlike original stereoisomers 7i and 7j, respectively, in good yields (Scheme 5). The diastereoisomers were separable, and their configuration was identified by NMR-analysis from the γ-left effect, as previously described [26,38].
Table
Table 2. Reaction of dibromide 3 with aromatic carbonyl and α-carbonyl ester derivatives using TDAE a.
Table 2. Reaction of dibromide 3 with aromatic carbonyl and α-carbonyl ester derivatives using TDAE a.
Entry aAromatic CarbonylR1R2OxiraneCis/Trans Isomers % bYield (%) c
14-Nitrobenzaldehyde4-NO2-C6H4H7a15/8563
24-Bromobenzaldehyde4-Br-C6H4H7b7/9355
34-Cyanobenzaldehyde4-CN-C6H4H7c15/8572
42-Nitrobenzaldehyde2-NO2-C6H4H7d32/6846
52-Bromobenzaldehyde2-Br-C6H4H7e19/8164
63-Bromobenzaldehyde3-Br-C6H4H7f7/9348
7Ethyl glyoxylateCO2C2H5H7g0/10026
8Diethyl ketomalonateCO2C2H5CO2C2H57h0/10037
Notes: a All the reactions were performed using 3 equivalents of aromatic carbonyl 4a–h, 1 equivalent of dibromide 3 and 1.5 equivalent of TDAE in anhydrous DMF stirred at −20 °C for 1 h and then warmed to r.t for 2 h; b % isomers determined on 1H-NMR measurements from the crude product; c % yield relative to dibromide 3.
Molecules 20 01262 g004 550
Scheme 4. TDAE reactivity of 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) with aromatic carbonyl and some α-keto-ester derivatives 4a–h.
Scheme 4. TDAE reactivity of 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) with aromatic carbonyl and some α-keto-ester derivatives 4a–h.
Molecules 20 01262 g004
Molecules 20 01262 g005 550
Scheme 5. TDAE reactivity of 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) and α-keto-ester derivatives 4i–j.
Scheme 5. TDAE reactivity of 5-(dibromomethyl)-3-methyl-6-nitrobenzoxazolone (3) and α-keto-ester derivatives 4i–j.
Molecules 20 01262 g005
The relative cis/trans percentages of oxirane isomers reported in Table 2 showed that the stereoselectivity of these reactions is not only sensitive to steric hindrance, but it also depends on the nature of the electrophile substituents. The reactions with bromo-substituted aldehydes in either position were more selective than with nitro-substituted aldehydes. The same percentages of cis/trans isomers were previously reported with p-nitro- and cyanobenzaldehyde. However, the reactions with ethyl glyoxylate and diethyl ketomalonate were the most selective. Moreover, stereoselectivity was recorded in the mixtures of like/unlike original stereoisomers with methyl isatin and acenaphtenedione.

3. Experimental Section

3.1. General Information

Melting points were determined on a Buchi capillary melting point apparatus and are uncorrected. Elemental analyses were performed by the Centre de Microanalyses of the University of Aix-Marseille. Both 1H- (200 MHz) and 13C-NMR (50 MHz) spectra were determined on a Bruker AC 200 spectrometer. The 1H chemical shifts are reported as parts per million downfield from tetramethylsilane (Me4Si), and the 13C chemical shifts were referenced to the solvent peaks: CDCl3 (76.9 ppm) or Me2SO-d6 (39.6 ppm). Absorptions are reported using the following notation: 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, Darmstadt, Germany, 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. 3,5-Dimethyl-6-nitrobenzoxazolone (1) was synthesized in three steps: condensation of 2-amino-4-methylphenol with urea [34], methylation using dimethyl sulfate and nitration by action of a mixture of nitric and sulfuric acids.

3.2. Synthesis of Substrates 1–3

3,5-Dimethyl-6-nitrobenzo[d]oxazol-2(3H)-one (1): yellow solid; mp 159 °C (EtOH); 1H-NMR (CDCl3): δ 2.70 (s, 3H, CH3), 3.45 (s, 3H, NCH3), 6.87 (s, 1H, CH), 7.95 (s, 1H, CH). 13C-NMR (CDCl3): δ 21.6 (CH3), 28.5 (NCH3), 107.3 (CH), 110.7 (CH), 132.2 (C), 135.7 (C), 140.2 (C), 143.5 (CNO2), 154.3 (CO). Anal. Calcld. for C9H8N2O4 (208.17): C, 51.93; H, 3.87; N; 13.46. Found: C, 52.34; H, 3.95; N, 13.40.
5-(Bromomethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (2) and 5-(dibromomethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (3) were prepared according to a previously described method [27].
5-(Bromomethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (2): yellow solid (EtOH); mp 120 °C; 1H-NMR (CDCl3): δ 3.49 (s, 3H, CH3), 4.91 (s, 2H, CH2Br), 7.14 (s, 1H, CH), 7.99 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.7 (NCH3), 29.3 (CH2Br), 108.0 (CH), 110.6 (CH), 131.1 (C), 136.1 (C), 141.7 (C), 142.6 (CNO2), 153.9 (CO). Anal. Calcld for C9H7BrN2O4 (287.07): C, 37.66; H, 2.46; N; 9.76. Found: C, 38.48; H, 2.58; N, 9.88.
5-(Dibromomethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (3): yellow solid (EtOH); mp 134 °C; 1H-NMR (CDCl3): δ 3.55 (s, 3H, NCH3), 7.55 (s, 1H, CHBr2), 7.75 (s, 1H, CH), 7.78 (s, 1H, CH). 13C-NMR (CDCl3): δ 29.0 (NCH3), 34.4 (CHBr2), 106.2 (CH), 110.7 (CH), 134.3 (C), 136.5 (C), 139.0 (C), 142.0 (CNO2), 153.6 (CO). Anal. Calcld for C9H7BrN2O4 (365.96): C, 29.54; H, 1.65; N; 7.65. Found: C, 29.59; H, 1.67; N, 7.69.

3.3. General Procedure for the Reaction of 2 and Aromatic Carbonyl Derivatives 4a–f, α-Carbonyl Ester 4g, Ketomalonate 4h, Acenaphtenedione 4i and Ketolactam 4j Using TDAE

A solution of 2 (0.5,1.74 mmol) in anhydrous DMF (10 mL) and the corresponding carbonyl derivative 4a–j (5.22 mmol, 3 equivalents) were placed under nitrogen at −20 °C in a two-necked flask equipped with a silica-gel drying tube and a nitrogen inlet. The solution was stirred and maintained at this temperature for 30 min and then the TDAE (0.41 mL, 1.74 mmol, 1 equivalent) was added dropwise via a syringe. A red color immediately developed with the formation of a fine white precipitate. The solution was vigorously stirred at −20 °C for 1 h and then warmed to r.t. for 2 h. After this time TLC analysis (dichloromethane) clearly showed that 2 was totally consumed. The orange-red turbid solution was filtered (to remove the octamethyloxamidinium dibromide) and hydrolyzed with 80 mL of H2O. The aqueous solution was extracted with toluene (3 × 40 mL), the combined organic layers washed with H2O (3 × 40 mL) and dried over MgSO4. Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica gel chromatography and recrystallization in ethyl alcohol gave the corresponding products.
5-(2-Hydroxy-2-(4-nitrophenyl)ethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5a): Brown solid; mp 233 °C; 1H-NMR (DMSO-d6): δ 3.37 (s, 3H, NCH3), 3.17–3.33 (m, 2H, 2 × CH), 4.92–5.01 (m, 1H, 1H, CH), 5.67 (bs, 1H, OH), 7.33 (s, 1H, CH), 7.61 (d, J = 8,5 Hz, 2H, 2 × CH), 8.00 (s, 1H, CH), 8.21 (d, J = 8.5 Hz, 2H, 2 × CH). 13C-NMR (DMSO-d6): δ 28.9 (NCH3), 42.2 (CH2), 72.1 (CH), 106.7 (CH), 112.5 (CH), 123.6 (2 × CH), 127.0 (2 × CH), 131.2 (C), 135.8 (C), 140.2 (C), 144.1 (C), 146.7 (C), 153.2 (C), 154.3 (CO). HRMS (EI): calcd for C16H13N3O7 (M+) 337.1092, found 337.1092.
5-(2-(4-Bromophenyl)-2-hydroxyethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5b): Brown solid; mp 213 °C; 1H-NMR (CDCl3): δ 2.13 (d, J = 3.2 Hz, 1H, OH), 3.13 (dd, J = 13.7 Hz, J = 9.1 Hz, 1H, CH), 3.43 (s, 3H, NCH3), 3.50 (dd, J = 13.7 Hz, J = 3.7 Hz, 1H, CH), 5.06 (dd, J = 9.1 Hz, J = 3.7 Hz, 1H, CH), 6.85 (s, 1H, CH), 7.33 (d, J = 8.4 Hz, 2H, 2 × CH), 7.52 (d, J = 8.4 Hz, 2H, 2 × CH), 7.94 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.6 (NCH3), 43.7 (CH2), 73.5 (CH), 107.5 (CH), 111.9 (CH), 121.7 (C), 127.3 (2 × CH), 131.7 (2 × CH), 135.6 (C), 140.8 (C), 142.7 (CH), 144.0 (C), 154.3 (CO). C-NO2 was not observed under these experimental conditions. Anal. Calcld for C16H13BrN2O5 (393.19) C, 48.88; H, 3.33; N; 7.12. Found: C, 48.91; H, 3.39; N, 7.19.
4-(1-Hydroxy-2-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)ethyl)benzonitrile (5c): Yellow solid; mp 213 °C; 1H-NMR (CDCl3): δ 2.27 (d, J = 3.0 Hz, 1H, OH), 3.05 (dd, J = 13.5 Hz, J = 9.4 Hz, 1H, CH), 3.46 (s, 3H, NCH3), 3.57 (dd, J = 13.5 Hz, J = 2.6 Hz, 1H, CH), 5,15 (dd, J = 9.4 Hz, J = 2.6 HZ, 1H, CH), 6.93 (s, 1H, CH), 7.61 (d, J = 8.3 Hz, 2H, 2 × CH), 7.70 (d, J = 8.3 Hz, 2H, 2 × CH); 7.98 (s,1H, CH). 13C-NMR (CDCl3): δ 28.6 (NCH3), 43.8 (CH2), 73.3 (CH), 107.6 (CH), 111.7 (C), 112.0 (CH), 118.7 (C), 126.3 (2 × CH), 131.5 (C), 132.5 (2 × CH), 135.7 (C), 140.9 (C), 149.0 (C), 154.2 (CO). C-NO2 was not observed under these experimental conditions. HRMS (EI): calcd for C17H13N3O5 (M+) 357.1193, found 357.1194.
5-(2-Hydroxy-2-(2-nitrophenyl)ethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5d): Brown solid; mp 130 °C; 1H-NMR (CDCl3): δ 3.36 (dd, J = 13.8 Hz, J = 8.8 Hz, 1H, CH), 3.41 (s, 3H, NCH3), 3.56 (dd, J = 13.8 Hz, J = 3.2 Hz, 1H, CH), 5.47 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H, CH), 7.05 (s, 1H, CH), 7.44 (t, J = 7.0 Hz, 1H, CH), 7.65 (t, J = 7.6 Hz, 1H, CH), 7.73 (s, 1H, CH), 7.80 (d, J = 7.0 Hz, 1H, CH), 7.89 (d, J = 7.6 Hz, 1H, CH). 13C-NMR (CDCl3): δ 28.5 (NCH3), 40.6 (CH2), 70.4 (CH), 107.1 (CH), 111.0 (CH), 124.5 (CH), 128.4 (CH), 128.6 (CH), 131.1 (C), 133.9 (CH), 135.5 (C), 139.1 (C), 140.5 (C), 144.8 (C), 147.4 (C), 154.3 (CO). HRMS (EI): calcd for C16H13N3O7 (M+) 337.1092, found 337.1092.
5-(2-(2-Bromophenyl)-2-hydroxyethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5e): Yellow solid; mp 159 °C; 1H-NMR (DMSO-d6): δ 3.29 (s, 3H, NCH3), 3.30–3.33 (m, 2H, CH2), 5.51 (bs, 1H, CH), 7.15 (s, 1H, CH), 7.21 (d, J = 7.3 Hz, 1H, CH), 7.40 (t, J = 7.7 Hz, 1H, CH), 7.51–7.54 (m, 2H, 2 × CH), 7.95 (s, 1H, CH). 13C-NMR (DMSO-d6): δ 28.6 (NCH3), 40.5 (CH2), 71.35 (CH), 106.6 (CH), 111.9 (CH), 121.4 (C), 128.1 (CH), 128.3 (CH), 129.3 (C), 130.5 (CH), 132.3 (CH), 135.4 (C), 140.1 (C), 143.8 (C), 144.7 (C), 154.3 (CO). HRMS (EI): calcd for C16H13BrN2O5 (M+) 410.0346, found 410.0347.
5-(2-(3-Bromophenyl)-2-hydroxyethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5f): Yellow solid; mp 154 °C; 1H-NMR (CDCl3): δ 2.15 (d, J = 2.9 Hz, 1H, OH), 3.13 (dd, J = 13.6 Hz, J = 9.0 Hz, 1H, CH), 3.44 (s, 3H, NCH3), 3.53 (dd, J = 13.6 Hz, J = 3.4 Hz, 1H, CH), 5.08 (dd, J = 9.0 Hz, J = 3.4 Hz, 1H, CH), 6.87 (s, 1H, CH), 7.29 (s, 1H, CH), 7.35–7.48 (m, 2H, 2 × CH), 7.61–7.63 (m, 1H, CH), 7.95 (s,1H, CH). 13C-NMR (CDCl3): δ 28.5 (NCH3), 43.7 (CH2), 73.4 (CH), 107.5 (CH), 111.9 (CH), 122.8 (C), 124.3 (CH), 128.7 (CH), 130.2 (CH), 131.0 (CH), 131.7 (C), 135.6 (C), 140.8 (C), 144.0 (C), 146.1 (C), 154.3 (CO). Anal. Calcld for C16H13BrN2O5 (393.19) C, 48.88; H, 3.33; N, 7.12. Found: C, 49.11; H, 3.46; N, 7.28.
Ethyl 2-hydroxy-3-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)propanoate (5g): Yellow solid; mp 136 °C; 1H-NMR (CDCl3): δ 1.32 (t, J = 7.1 Hz, 3H, CH3), 2.99 (d, J = 5.3 Hz, 1H, OH), 3.17 (dd, J = 13.9 Hz, J = 8.8 Hz, 1H, CH), 3.46 (s, 3H, NCH3), 3.68 (dd, J = 13.9 Hz, J = 3.7 Hz, 1H, CH), 4.28 (q, J = 7.1 Hz 2H, CH2), 4.50–4.55 (m, 1H, CH), 7.02 (s, 1H, CH), 7.91 (s, 1H, CH). 13C-NMR (CDCl3): δ 14.1 (CH3), 28.6 (NCH3), 37.9 (CH2), 62.4 (CH2), 70.1 (CH), 107.4 (CH), 111.6 (CH), 130.3 (CH), 135.5 (CH), 140.8 (CH), 144.2 (CH), 154.2 (CO), 173.9 (CO). Anal. Calcld for C13H14N2O7 (310.26) C, 50.33; H, 4.55; N, 9.03. Found: C, 50.28; H, 4.54; N, 8.91
Diethyl 2-hydroxy-2-((3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)malonate (5h): Yellow solid; mp 111 °C; 1H-NMR (CDCl3): δ 1.27 (t, J = 7.1 Hz, 6H, 2xCH3), 3.43 (s, 3H, NCH3), 3.85 (bs, 1H, OH), 3.88 (s, 2H, CH2), 4.11–4.34 (m, 4H, CH2), 7.14 (s, 1H, CH), 7.75 (s, 1H, CH). 13C-NMR (CDCl3): δ 13.9 (2 × CH3), 28.5 (NCH3), 35.5 (2 × CH2), 63.1 (CH2), 78.4 (C-OH), 107.2 (CH), 111.8 (CH), 127.1 (C), 134.8 (C), 140.8 (C), 145.6 (C), 154.2 (CO), 169.4 (2 × CO). Anal. Calcld for C16H18N2O9 (382.32) C, 50.26, H, 4.75, N, 7.33. Found: C, 50.25, H, 4.83, N, 7.18.
5-((1-Hydroxy-2-oxo-1,2-dihydroacenaphthylen-1-yl)methyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5i): Green solid; mp 204 °C; 1H-NMR (CDCl3): δ 3.45 (s, 3H, NCH3), 3.64 (d, J = 14.0 Hz, 1H, CH), 3.84 (d, J = 14.0 Hz, 1H, CH), 7.12 (s, 1H, CH), 7.27 (d, J = 7.3 Hz, 1H, CH), 7.61 (dd, J = 8.0 Hz, J = 7.3 Hz,1H, CH), 7.77 (dd, J = 7.8 Hz, J = 7.3 Hz, 1H, CH), 7.88 (s, 1H, CH), 7.89–7.98 (m, 2H, 2 × CH), 8.15 (d, J = 8.0 Hz, 1H, CH). 13C-NMR (CDCl3): δ 28.6 (NCH3), 40.9 (CH2), 79.8 (C-OH), 107.5 (CH), 112.4 (CH), 120.3 (CH), 122.7 (CH), 125.9 (CH), 128.6 (CH), 128.7 (CH+C), 130.1 (C), 130.7 (C), 132.4 (CH), 135.3 (C), 138.7 (C), 140.7 (C), 141.0 (C), 144.5 (C), 154.3 (CO); 203.8 (CO). Anal. Calcld for C21H14N2O6 (390.35) C, 64.62, H, 3.62, N, 7.18. Found: C, 64.15, H, 3.72, N, 7.05.
5-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)methyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (5j): Yellow solid; mp 253 °C; 1H-NMR (DMSO-d6): δ 3.03 (s, 3H, NCH3), 3.31 (s, 3H, NCH3), 3.36 (d, J = 13.7 Hz, 1H, CH), 3.66 (d, J = 13.7 Hz, 1H, CH), 6.19 (s, 1H, CH), 6.78 (d, J = 6.8 Hz, 1H, CH), 6.91–6.95 (m, 2H, 2 × CH), 7.13 (s, 1H, CH), 7.24–7.31 (m, 1H, CH). 13C-NMR (DMSO-d6): δ 26.0 (NCH3); 28.5 (NCH3), 75.4 (C-OH), 106.7 (CH), 108.6 (CH), 112.9 (CH), 122.3 (CH), 123.9 (CH), 127.6 (C), 129.4 (CH), 130.5 (C), 135.0 (C), 140.3 (C), 142.8 (C), 144.7 (C), 154.3 (CO), 176.8 (CO). C-NO2 was not observed under these experimental conditions. Anal. Calcld for C18H15N3O6 (369.33) C, 58.54, H, 4.09, N, 11.38. Found: C, 58.26, H, 4.25, N, 11.01.
1-(3-Methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-2-(4-nitrophenyl)ethyl 4-nitrobenzoate (6): Yellow solid; mp 305 °C; 1H-NMR (CDCl3): δ 3.35 (s, 3H, NCH3), 3.73 (d, J = 6.2 Hz, 2H, CH2), 6.44 (t, J = 6.2 Hz, 1H, CH), 6.84 (s, 1H, CH), 7.68 (d, J = 8.5 Hz, 2H, 2 × CH), 7.97 (s, 1H, CH), 8.17 (d, J = 8.8 Hz, 2H, 2 × CH), 8.28 (d, J = 8.5 Hz, 1H, 2 × CH), 8.32 (d, J = 8.5 Hz, 1H, 2 × CH). 13C-NMR (CDCl3): δ 28.5 (NCH3), 40.8 (CH2), 76.4 (CH), 108.1 (CH), 110.7 (CH), 114.1 (C), 123.8 (2 × CH), 124.3 (2 × CH), 127.1 (2 × CH), 129.6 (C), 130.7 (2 × CH), 134.4 (C), 135.9 (C), 141.2 (C), 145.9 (C), 148.1 (C), 150.9 (C), 153.8 (CO). HRMS (EI): calcd for C23H16N4O10 (M+) 526.1205, found 526.1209.

3.4. General Procedure for the Reaction of 3 and Aromatic Carbonyl Derivatives 4a–f, α-Carbonyl Ester 4g, Ketomalonate 4h, Acenaphtenedione 4i and Keto-lactam 4j Using TDAE

A solution of 3 (0.5 g, 1.36 mmol) in anhydrous DMF (10 mL) and the corresponding carbonyl derivative 4a–j (4.098 mmol, 3 equivalents) were placed under nitrogen at −20 °C in a two-necked flask equipped with a silica-gel drying tube and a nitrogen inlet. The solution was stirred and maintained at this temperature for 30 min and then the TDAE (0.48 mL, 2.049 mmol, 1.5 equivalent) was added dropwise via a syringe. A red color immediately developed with the formation of a fine white precipitate. The solution was vigorously stirred at −20 °C for 1 h and then warmed to rt for 2 h. After this time TLC analysis (dichloromethane) clearly showed that 3 was totally consumed. The orange-red turbid solution was filtered (to remove the octamethyloxamidinium dibromide) and hydrolyzed with 80 mL of H2O. The aqueous solution was extracted with toluene (3 × 40 mL), the combined organic layers washed with H2O (3 × 40 mL) and dried over MgSO4. Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica gel chromatography and recrystallization in ethyl alcohol solvent gave the corresponding oxiranes 7a–j.
3-Methyl-6-nitro-5-(3-(4-nitrophenyl)oxiran-2-yl)benzo[d]oxazol-2(3H)-one (7a) trans-isomer: Yellow solid; mp 224 °C; 1H-NMR (CDCl3): δ 3.52 (s, 3H, NCH3), 3.92 (d, J = 1.9 Hz, 1H, CH), 4.54 (d, J = 1.9 Hz, 1H, CH), 7.33 (s, H, CH), 7.60 (d, J = 8.7 Hz, 2H, 2 × CH), 8.13 (s, 1H, CH), 8.30 (d, J = 8.7 Hz, 2H, 2 × CH). 13C-NMR (CDCl3): δ 28.8 (NCH3), 61.0 (CH), 61.1 (CH), 105.7 (CH), 107.4 (CH), 124.0 (2 × CH), 126.6 (2 × CH), 131.8 (C), 137.28 (C), 141.6 (C), 142.1 (C), 143.0 (C), 148.2 (CO). C-NO2 was not observed under these experimental conditions. HRMS (EI): calcd for C16H11N3O7 (M+) 375.0935, found 375.0943.
5-(3-(4-Bromophenyl)oxiran-2-yl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (7b) trans-isomer: Yellow solid; mp 209 °C; 1H-NMR (CDCl3): δ 3.51 (s, 3H, NCH3), 3.77 (d, J = 1.9 Hz, 1H, CH), 3.54 (d, J = 1.9 Hz, 1H, CH), 7.28 (d, J = 8.4 Hz, 2H, 2 × CH), 7.31 (s, 1H, CH), 7.54 (d, J = 8.4 Hz, 2H, 2 × CH), 8.11 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.7 (NCH3), 60.5 (CH), 61.7 (CH), 105.6 (CH), 107.3 (CH), 122.8 (C), 127.5 (2 × CH), 131.9 (2 × CH), 132.5 (C), 134.8 (C), 137.0 (C), 141.3 (C), 154.1 (CO). Anal. Calcld for C16H11BrN2O5 (391.17) C, 49.13; H, 2.83; N, 7.16. Found: C, 49.27; H, 2.92; N, 7.85.
4-(3-(3-Methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxiran-2-yl)benzonitrile (7c) trans-isomer: Yellow solid; mp 213 °C; 1H-NMR (CDCl3): δ 3.51 (s, 3H, NCH3), 3.86 (d, J = 1.8 Hz, H, CH), 4.52 (d, J = 1.8 Hz, H, CH), 7.32 (s, 1H, CH), 7.53 (d, J = 8.3 Hz, 2H, 2 × CH), 7.72 (d, J = 8.3 Hz, 2H, 2 × CH), 8.12 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.7(NCH3), 61.0 (CH), 61.2 (CH), 105.7 (CH), 107.3 (CH), 112.6 (C), 118.5 (C), 126.5 (2 × CH), 131.9 (C), 132.5 (2 × CH), 137.1(C), 141.1 (C), 141.5 (C), 142.1(C); 154.1 (CO). HRMS (EI): calcd for C17H11N3O5 (M+) 355.1037, found 355.1036.
3-Methyl-6-nitro-5-(3-(2-nitrophenyl)oxiran-2-yl)benzo[d]oxazol-2(3H)-one (7d) trans-isomer: yellow solid; mp 215 °C; 1H-NMR (CDCl3): δ 3.52 (s, 3H, NCH3), 4.54 (d, J = 2.0 Hz, 1H, CH), 4.60 (d, J = 2.0 Hz, 1H, CH), 7.36 (s, 1H, CH), 7.52–7.61 (m, 1H, CH), 7.75–7.77 (m, 2H, 2 × CH), 8.14 (s, 1H, CH), 8.23 (d, J = 8.0 Hz, 1H, CH). 13C-NMR (CDCl3): δ 28.7 (NCH3), 59.9 (CH), 60.0 (CH), 105.5 (CH), 107.6 (CH), 125.2 (CH), 126.9 (CH), 129.2 (C), 131.8 (CH), 132.5 (C), 134.4 (CH), 137.0 (C), 141.5 (C), 142.6 (C), 147.9 (C), 154.2 (CO). HRMS (EI): calcd for C16H11N3O7 (M+) 375.0935, found 375.0940.
3-Methyl-6-nitro-5-(3-(2-nitrophenyl)oxiran-2-yl)benzo[d]oxazol-2(3H)-one (7d) cis-isomer: Beige solid; mp 166 °C; 1H-NMR (CDCl3): δ 3.38 (s, 3H, NCH3), 5.14 (d, J = 4.9 Hz, 1H, CH), 5.17 (d, J = 4.9 Hz, 1H, CH), 7.03 (s, 1H, CH), 7.30–7.40 (m, 1H, CH), 7.44–7.46 (m, 2H, 2 × CH), 7.86–7.90 (m, 2H, 2 × CH). 13C-NMR (CDCl3): δ 28.6 (NCH3), 59.0 (2 × CH), 107.3 (CH), 107.4 (CH), 124.7 (CH), 128.8 (CH), 128.9 (C), 129.2 (CH), 129.4 (C), 132.7 (CH), 135.9 (C), 141.2 (C), 148.5 (C), 153.9 (CO). Anal. Calcld for C16H11N3O7 (357.27) C, 53.79; H, 3.10; N, 11.76. Found: C, 53.48; H, 3.30; N, 11.44.
5-(3-(2-Bromophenyl)oxiran-2-yl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (7e) trans-isomer: Green solid; mp 203 °C; 1H-NMR (CDCl3): δ 3.52 (s, 3H, NCH3), 4.09 (d, J = 1.9 Hz, 1H, CH), 4.57 (d, J = 1.9 Hz, 1H, CH), 7.20–7.29 (m, 1H, CH), 7.36 (s, 1H, CH), 7.38–7.47 (m, 2H, 2 × CH), 7.60 (d, J = 7.5 Hz, 1H, CH), 8.12 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.7 (NCH3), 60.1 (CH), 62.0 (CH), 105.6 (CH), 107.4 (CH), 123.1 (C), 126.1 (CH), 127.8 (CH), 130.0 (CH), 132.2 (C), 132.7 (CH), 135.2 (C), 137.0 (C), 141.4 (C), 142.4 (C), 154.2 (CO). Anal. Calcld for C16H11BrN2O5 (391.17) C, 49.13; H, 2.83; N, 7.16. Found: C, 49.27; H, 2.93; N, 7.17.
5-(3-(2-Bromophenyl)oxiran-2-yl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (7e) cis-isomer: Green solid; mp 151 °C; 1H-NMR (CDCl3): δ 3.42 (s, 3H, NCH3), 4.71 (d, J = 4.4 Hz, 1H, CH), 5.17 (d, J = 4.4 Hz, 1H, CH), 6.98–7.14 (m, 3H, 3 × CH), 7.16 (s, 1H, CH), 7.36–7.42 (m, 1H, CH), 7.93 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.6 (NCH3), 59.3 (CH), 61.0 (CH), 107.3 (CH), 107.9 (CH), 122.5 (C), 126.4 (CH), 128.0 (CH), 129.4 (C), 129.6 (CH), 132.7 (CH), 132.9 (C), 135.8 (C), 141.1 (C), 142.5 (C), 154.0 (CO). Anal. Calcld for C16H11BrN2O5 (391.17) C, 49.13; H, 2.83; N, 7.16. Found: C, 49.42; H, 3.02; N, 7.28.
5-(3-(3-Bromophenyl)oxiran-2-yl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (7f) trans-isomer: Beige solid; mp 165 °C; 1H-NMR (CDCl3): δ 3.51 (s, 3H, 3H, NCH3), 3.77 (d, J = 1.9 Hz, 1H, CH), 4.55 (d, J = 1.9 Hz, 1H, CH), 7.24–7.28 (m, 1H, CH), 7.32 (s, 1H, CH), 7.33–7.38 (m, 1H, CH), 7.49–7.54 (m, 2H, 2 × CH), 8.11 (s, 1H, CH). 13C-NMR (CDCl3): δ 28.7 (NCH3), 60.6 (CH), 61.4 (CH), 105.7 (CH), 107.3 (CH), 122.8 (C), 124.6 (CH), 128.7 (CH), 130.2 (CH), 131.9 (CH), 132.3 (C), 137.0 (C), 138.1 (C), 141.4 (C), 142.1 (C), 154.1 (CO). Anal. Calcld for C16H11BrN2O5 (391.17) C, 49.13; H, 2.83; N, 7.16. Found: C, 49.30; H, 2.97; N, 7.10.
Ethyl 3-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxirane-2-carboxylate (7g) trans-isomer: Light yellow needles; mp 199 °C; 1H-NMR (CDCl3): δ 1.36 (t, J = 7.2 Hz, H, CH); 3.38 (d, J = 1.9 Hz, 3H, CH); 3.48 (s, 3H, NCH3); 4,35 (q, J = 7.2 Hz, 2H, CH2); 4,75 (d, J = 1.9 Hz, 1H, CH); 7.19 (s, 1H, CH); 8.12 (s, 1H, CH). 13C-NMR (CDCl3): δ 14.1 (CH3), 28.8 (NCH3), 56.0 (CH), 56.6 (CH), 62.2 (CH2), 105.8 (CH), 107.4 (CH), 130.9 (C), 137.0 (C), 141.6 (C), 142.2 (C), 154.0 (CO), 167.2 (CO). HRMS (EI): calcd for C13H12N2O7 (M+) 309.0717, found 309.0713.
Diethyl 3-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)oxirane-2,2-dicarboxylate (7h) trans-isomer: Dark brown; mp 118 °C; 1H-NMR (CDCl3): δ 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3), 3.48 (s, 3H, NCH3), 3.98 (q, J = 7.2 Hz, 2H, CH2), 4.39 (q, J = 7.2 Hz, 2H, CH2), 5.14 (s, 1H, CH), 7.24 (s, 1H, CH), 8.12 (s, 1H, CH). 13C-NMR (CDCl3): δ 13.8 (CH3), 14.0 (CH3), 28.9 (NCH3), 61.2 (CH), 62.2 (CH2), 63.3 (CH2), 107.2 (CH), 107.4 (CH), 127.9 (C), 136.7 (C), 141.9 (C), 142.3 (C), 153.9 (C), 163.3 (CO), 164.6 (CO). Anal. Calcld for C16H16N2O9 (380.31) C, 50.53; H, 4.24; N, 7.37. Found: C, 50.96; H, 4.54; N, 7.25.
3-Methyl-6-nitro-5-(2-oxo-2H-spiro[acenaphthylene-1,2'-oxiran]-3'-yl)benzo[d]oxazol-2(3H)-one (7i) like-isomer: Yellow solid; mp 235 °C; 1H-NMR (CDCl3): δ 3.59 (s, 3H, NCH3), 5.29 (s, 1H, CH), 7.62 (d, J = 6.8 Hz, 1H, CH2), 7.74 (s, 2H, 2 × CH); 7.77–7.80 (m, 1H, CH), 7.85 (d, J = 6.7 Hz, 1H, CH2), 8.01 (d, J = 8.4 Hz, 1H, CH2), 8.06 (s, 1H, CH), 8.19 (d, J = 8.1 Hz, 1H, CH). 13C-NMR (CDCl3): δ 28.9 (NCH3), 65.8 (CH), 67.1 (C), 106.8 (CH), 108.9 (CH), 118.9 (CH), 122.1 (CH), 126.5 (CH), 128.3 (CH), 128.7 (CH), 129.2 (C), 130.4 (C), 131.2 (C), 132.1 (C), 132.3 (CH), 136.5 (C), 141.4 (C), 141.7 (C), 142.5 (C), 154.2 (CO), 196.0 (CO). Anal. Calcld for C21H12N2O6 (388.33) C, 64.95; H, 3.11; N, 7.21. Found: C, 64.08; H, 3.26; N, 6.85.
3-Methyl-6-nitro-5-(2-oxo-2H-spiro[acenaphthylene-1,2'-oxiran]-3'-yl)benzo[d]oxazol-2(3H)-one (7i) unlike-isomer: Beige solid; mp 201 °C; 1H-NMR (CDCl3): δ 3.63 (s, 3H, NCH3), 5.30 (s, 1H, CH), 6.34 (d, J = 6.8 Hz, 1H, CH2), 7.32 (d, J = 6,7 Hz, 1H, CH), 7.67 (s, 1H, CH), 7.77–7.88 (m, 2H, 2 × CH), 8.07 (s, 1H, CH), 8.12 (d, J = 1.7 Hz,1H, CH), CH), 8.16 (d, J = 3.2 Hz,1H, CH). 13C-NMR (CDCl3): δ 29.0 (NCH3), 64.7 (CH), 66.5 (C); 107.3 (CH), 107.7 (CH), 119.1 (CH), 122.7 (CH), 126.8 (CH), 127.8 (CH), 128.5 (CH), 129.7 (C), 130.2 (C), 130.5 (C), 130.6 (C), 132.3 (CH), 136.9 (C), 141.9 (C), 143.2 (C), 154.0 (C), 196.3 (CO). C-NO2 was not observed under these experimental conditions. HRMS (EI): calcd for C21H12N2O6 (M+) 389.0768, found 389.0768.
1-Methyl-3'-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)spiro[indoline-3,2'-oxiran]-2-one (7j) like-isomer: Beige solid; mp 190 °C; 1H-NMR (CDCl3): δ 3.13 (s, 3H, NCH3), 3.54 (s, 3H, NCH3), 5.15 (s, 1H, CH), 6.93 (dd, J = 7.8 Hz, J = 0.7 Hz,1H, CH), 7.17 (td, J = 7.5 Hz, J = 0.7 Hz,1H, CH), 7.32 (dd, J = 7.3 Hz, J = 0.7 Hz, 1H, CH), 7.44 (td, J = 7.3 Hz, J = 1.4 Hz, 1H, CH), 7.62 (s, 1H, CH), 8.08 (s, 1H, CH). 13C-NMR (CDCl3): δ 26.5 (NCH3), 28.8(NCH3), 62.7 (CH), 65.0 (C), 106.8 (CH), 108.9 (CH), 109.0 (CH), 122.2 (CH), 122.3 (C), 123.2 (CH), 128.8 (C), 130.8 (CH), 136.4 (C), 141.5 (C), 141.7 (C), 144.8 (CH), 154.2 (CO), 169.6 (CO). Anal. Calcld for C18H13N3O6 (367.31) C, 58.86; H, 3.57; N, 11.44. Found: C, 58.85; H, 3.71; N, 11.31.
1-Methyl-3'-(3-methyl-6-nitro-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)spiro[indoline-3,2'-oxiran]-2-one (7j) unlike-isomer: Beige solid; mp 211 °C; 1H-NMR (CDCl3): δ 3.33 (s, 3H, NCH3), 3.59 (s, 3H, NCH3), 5.18 (s, 1H, CH), 6.01 (d, J = 7.5 Hz, 1H, CH), 6.71 (t, J = 7.5 Hz, 1H, CH), 6.88 (d, J = 7.7 Hz, 1H, CH), 7.32 (d, J = 7.7 Hz, 1H, CH), 7.57 (s, 1H, CH), 8.08 (s, 1H, CH). 13C-NMR (CDCl3): δ 26.8 (NCH3), 29.0 (NCH3), 62.2 (CH), 64.4 (C), 107.3 (CH), 107.8 (CH), 109.2 (CH), 119.8 (C), 122.0 (CH), 122.4 (CH), 129.4 (C), 130.9 (CH), 137.0 (C), 141.8 (C), 141.9 (C), 145.6 (C), 154.0 (CO), 170.6 (CO). HRMS (EI): calcd for C18H13N3O6 (M+) 368.0877, found 368.0876.

4. Conclusions

In conclusion, we have investigated the reactivity of some new benzoxazolone derivatives formed via the TDAE strategy. This is the first example of the use of the TDAE strategy to generate a benzoxazolinonic anion, which cannot be formed via the standard organometallic strategy. This study brought to light a new and original reactivity and we have defined some limitations of the TDAE strategy. We show that 5-(bromomethyl)-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (2), in addition to providing the expected alcohols 5a–i in moderate to good yields, furnished an unexpected ester 6 formed in 23% yield, particularly with the p-nitrobenzaldehyde. The reactions of 5-(dibromomethyl)-3-methyl-6-nitro-benzo[d]oxazol-2(3H)-one (3) led to the expected oxiranes 7a–j and mixtures of original stereoisomers 7i–j in good yields. All these synthesized products are currently undergoing pharmacological evaluation.

Acknowledgments

This work was supported by the Centre National de la Recherche Scientifique. We express our thanks to V. Remusat for 1H- and 13C-NMR spectra recording. A. R. Nadji Boukrouche thanks the Ministère de l’Enseignement Supérieur et de la Recherche for financial support.

Author Contributions

A.R.N.B., M.L., O.K., T.T. and P.V. conceived of and designed the study. A.R.N.B. and O.K. designed the experiments and interpreted the results.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lesieur, D.; Carato, P.; Bonte, J.-P.; Depreux, P.; Caignard, D.-H.; Millan, M.; Newman-Tancredi, A.; Renard, P.; Rettori, M.-C. Preparation of Piperazinylmethylbenzothiazolinones, -Benzoxazolinones, -Benzoxazinones, and Related Compounds as Central Nervous System Agents. EP 841330, 13 May 1998. [Google Scholar]
  2. Fukaya, T.; Ishiyama, T.; Baba, S.; Masumoto, S. Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand. J. Med. Chem. 2013, 56, 8191–8195. [Google Scholar] [CrossRef] [PubMed]
  3. Aichaoui, H.; Poupaert, J.H.; Lesieur, D.; Henichart, J.-P. Regioselectivity in the C-acylation of 2(3H)-benzoxazolones. Tetrahedron 1991, 47, 6649–6654. [Google Scholar] [CrossRef]
  4. Moussavi, Z.; Depreux, P.; Lesieur, D.; Cotelle, N.; Sauzieres, J.; Plancke, M.O.; Fruchart, J.C. Pharmacomodulation of 7-(2-methylenebutyryl)-2,3-dihydrobenzoxazin-[1,4]-3-one structure and normolipemic activity. Farmaco 1991, 46, 339–355. [Google Scholar] [PubMed]
  5. Ucar, H.; van derpoorten, K.; Cacciaguerra, S.; Spampinato, S.; Stables, J.P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge, J.; Poupaert, J.H. Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives. J. Med. Chem. 1998, 41, 1138–1145. [Google Scholar] [CrossRef] [PubMed]
  6. Courtois, M.; Mincheva, Z.; Andreu, F.; Rideau, M.; Viaud-Massuard, M.C. Synthesis and biological evaluation with plant cells of new fosmidomycin analogues containing a benzoxazolone or oxazolopyridinone ring. J. Enzym. Inhib. Med. Chem. 2004, 19, 559–565. [Google Scholar] [CrossRef]
  7. Raju, B.G.; Ciabatti, R.; Maffioli, S.I.; Singh, U.; Romano, G.; Micheluucci, E.; Tiseni, P.S.; Candiani, G.; Kim, B.; O’Dowd, H. Ramoplanin Derivatives Possessing Antibacterial Activity. US 0211603, 21 September 2006. [Google Scholar]
  8. Jadhav, J.S.; Chatpalliwar, V.A.; Khadse, S.C.; Patil, R.R. Synthesis and screening of some new 2-(3H)-benzoxazolone derivatives for analgesic, antiinflammatory, and skeletal muscle relaxant activity. Indian J. Heterocycl. Chem. 2008, 17, 343–346. [Google Scholar]
  9. Köksal, M.; Kelekci, N.G.; Mercanoglu, G.O.; Erdoğan, H. Synthesis and evaluation of analgesic, anti-inflammatory and antioxidant activities of new 6-acyl-3-alkyl-5-methyl-2(3H)-benzoxazolones. Arzneim. Forsch. 2008, 58, 398–404. [Google Scholar]
  10. Mésangeau, C.; Narayanan, S.; Green, A.M.; Shaikh, J.; Kaushal, N.; Viard, E.; Xu, Y.; Fishback, J.A.; Poupaert, J.H.; Matsumoto, R.R.; et al. Conversion of a highly selective sigma-1 receptor-ligand to sigma-2 receptor preferring ligands with anticocaine activity. J. Med. Chem. 2008, 51, 1482–1486. [Google Scholar] [CrossRef] [PubMed]
  11. Poupaert, J.H.; Carato, P.; Colacino, E. 2(3H)-benzoxazolone and bioisosters as “privileged scaffold” in the design of pharmacological probes. Curr. Med. Chem. 2005, 12, 877–885. [Google Scholar] [CrossRef] [PubMed]
  12. Diouf, O.; Carato, P.; Depreux, P.; Bonte, J.P.; Caignard, D.H.; Guardiola-Lemaître, B.; Rettori, M.C.; Belzung, C.; Lesieur, D. 5-HT1A and 5-HT2A ligands with anxiolytic and antipanic-like properties. Bioorg. Med. Chem. Lett. 1997, 7, 2579–2584. [Google Scholar] [CrossRef]
  13. Diouf, O.; Carato, P.; Lesieur, I.; Rettori, M.C.; Caignard, D.H. Synthesis and pharmacological evaluation of novel 4-(4-fluorobenzoyl)piperidine derivatives as mixed 5-HT1A/5-HT2A/D2 receptor ligands. Eur. J. Med. Chem. 1999, 34, 69–73. [Google Scholar] [CrossRef]
  14. Carato, P.; Depreux, D.; Lesieur, D.; Millan, M.; Newman-Tancredi, A.; Rettori, M.C.; Caignard, D.H. Synthesis and binding studies on a new series of arylpiperazino benzazol-2-one and benzoxazin-3-one derivatives as selective D4 ligands. Drug Des. Discov. 2000, 17, 173–181. [Google Scholar] [PubMed]
  15. Lesieur, D.; Delmas, E.; Yous, S.; Depreux, P.; Guillaumet, G.; Dacquet, C.; Levens, N.; Boutin, J.; Bennejean, C.; Renard, P. Preparation of Novel Heterocyclic Derivatives and Pharmaceutical Composition Containing Them as Hypoglycemic Agents. FR 2804431, 3 August 2001. [Google Scholar]
  16. Lesieur, D.; Blanc-Delmas, E.; Bennejean, C.; Chavatte, P.; Guillaumet, G.; Dacquet, C.; Levens, N.; Boutin, J.; Renard, P. Preparation of Azolylalkylphenylalkylindolinones as Hypoglycemic Andhypolipidemic Agents. FR 2830012, 28 March 2003. [Google Scholar]
  17. Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W.R., Jr. Nucleophilic trifluoromethylation of acyl chlorides using the trifluoromethyl iodide/TDAE reagent. Tetrahedron Lett. 2002, 43, 4317–4319. [Google Scholar] [CrossRef]
  18. Pooput, C.; Médebielle, M.; Dolbier, W.F., Jr. A New and efficient method for the synthesis of trifluoromethylthio- and selenoethers. Org. Lett. 2004, 6, 301–303. [Google Scholar] [CrossRef] [PubMed]
  19. Pooput, C.; Dolbier, W.F., Jr.; Médebielle, M. Nucleophilic perfluoroalkylation of aldehydes, ketones, imines, disulfides, and diselenides. J. Org. Chem. 2006, 71, 3564–3568. [Google Scholar] [CrossRef] [PubMed]
  20. Giuglio-Tonolo, G.; Terme, T.; Médebielle, M.; Vanelle, P. Original reaction of p-nitrobenzyl chloride with aldehydes using tetrakis(dimethylamino)ethylene (TDAE). Tetrahedron Lett. 2003, 44, 6433–6435. [Google Scholar] [CrossRef]
  21. Giuglio-Tonolo, G.; Terme, T.; Médebielle, M.; Vanelle, P. Nitrobenzylation of α-carbonyl ester derivatives using TDAE approach. Tetrahedron Lett. 2004, 45, 5121–5124. [Google Scholar] [CrossRef]
  22. Amiri-Attou, O.; Terme, T.; Vanelle, P. Functionalization of 6-nitrobenzo[1,3]dioxole with carbonyl compounds via TDAE methodology. Molecules 2005, 10, 545–551. [Google Scholar] [CrossRef] [PubMed]
  23. Montana, M.; Crozet, M.D.; Castera-Ducros, C.; Terme, T.; Vanelle, P. Rapid synthesis of new azaheterocyclic hydroxymalonate derivatives using TDAE approach. Heterocycles 2008, 75, 925–932. [Google Scholar] [CrossRef]
  24. Nadji-Boukrouche, A.R.; Khoumeri, O.; Terme, T.; Liacha, M.; Vanelle, P. Original TDAE reactivity in benzoxa- and benzothiazolone series. ARKIVOC 2010, 10, 358–370. [Google Scholar] [CrossRef]
  25. Montana, M.; Terme, T.; Vanelle, P. Original synthesis of oxiranes via TDAE methodology: reaction of 2-(dibromomethyl)quinoxaline with aromatic aldehydes. Tetrahedron Lett. 2005, 46, 8373–8376. [Google Scholar] [CrossRef]
  26. Montana, M.; Terme, T.; Vanelle, P. Original synthesis of α-chloro ketones in aza heterocyclic series using TDAE approach. Tetrahedron Lett. 2006, 47, 6573–6576. [Google Scholar] [CrossRef]
  27. Khoumeri, O.; Montana, M.; Terme, T.; Vanelle, P. First TDAE approach in quinonic series: Synthesis of new 2-substituted 1,4-dimethoxy-9,10-anthraquinones. Tetrahedron 2008, 64, 11237–11242. [Google Scholar] [CrossRef]
  28. Vanelle, P.; Maldonado, J.; Madadi, N.; Gueiffier, A.; Chapat, J.-P.; Crozet, M.P. SRN1 reactions in imidazo[1,2-a]pyridine series. Tetrahedron Lett. 1990, 31, 3013–3016. [Google Scholar] [CrossRef]
  29. Delmas, F.; Gasquet, M.; Timon-David, P.; Madadi, N.; Vanelle, P.; Vaille, A.; Maldonado, J. Synthesis and in vitro anti-protozoan activity of new 5-nitrothiophene oxime ether derivatives. Eur. J. Med. Chem. 1993, 28, 23–27. [Google Scholar] [CrossRef]
  30. Gellis, A.; Vanelle, P.; Kaafarani, M.; Benakli, K.; Crozet, M.P. Synthesis and SRN1 reactions of nitrothiazoles. Tetrahedron 1997, 53, 5471–5484. [Google Scholar] [CrossRef]
  31. Crozet, M.D.; Botta, C.; Gasquet, M.; Curti, C.; Remusat, V.; Hutter, S.; Chapelle, O.; Azas, N.; de Méo, M.; Vanelle, P. Lowering of 5-nitroimidazole’s mutagenicity: Towards optimal antiparasitic pharmacophore. Eur. J. Med. Chem. 2009, 44, 653–659. [Google Scholar] [CrossRef] [PubMed]
  32. Dunn, L.A.; Burgess, A.G.; Krauer, K.G.; Eckmann, L.; Vanelle, P.; Crozet, M.D.; Gillin, F.D.; Upcroft, P.; Upcroft, J.A. A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro. Int. J. Antimicrob. Agents 2010, 36, 37–42. [Google Scholar] [CrossRef] [PubMed]
  33. Khoumeri, O.; Crozet, M.D.; Terme, T.; Vanelle, P. Original TDAE application: Synthesis of 2-substituted-4,11-dimethoxy-anthra[2,3-b]furan-5,10-diones via intramolecular Buchwald reaction. Tetrahedron Lett. 2009, 50, 6372–6376. [Google Scholar] [CrossRef]
  34. Suzuki, F.; Trenbeath, S.; Gleim, R.D.; Sih, C.S. Total synthesis of anthracyclinones via intramolecular base-catalyzed cyclizations. J. Org. Chem. 1978, 43, 4159–4169. [Google Scholar] [CrossRef]
  35. Gökhan, N.; Köksal, M.; Küpeli, E.; Yeşilada, E.; Erdoğan, H. Some new Mannich bases of 5-methyl-2-benzoxazolinones with analgesic and anti-inflammatory activities. Turk. J. Chem. 2005, 29, 445–454. [Google Scholar]
  36. Amiri-Attou, O.; Terme, T.; Médebielle, M.; Vanelle, P. Original formation of benzyl benzoates by TDAE strategy. Tetrahedron Lett. 2008, 49, 1016–1020. [Google Scholar] [CrossRef]
  37. Juspin, T.; Laget, M.; Terme, T.; Azas, N.; Vanelle, P. TDAE assisted synthesis of new imidazo[2,1-b]thiazole derivatives as anti-infectious agents. Eur. J. Med. Chem. 2010, 45, 840–845. [Google Scholar] [CrossRef] [PubMed]
  38. Montana, M.; Correard, F.; Khoumeri, O.; Esteve, M.-A.; Terme, T.; Vanelle, P. Synthesis of new quinoxalines containing an oxirane ring by the TDAE strategy and in vitro evaluation in neuroblastoma cell lines. Molecules 2014, 19, 14987–14998. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: Samples of the compounds 1, 2, 3, 5a–j, 6 and 7a–j are available from the authors.

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MDPI and ACS Style

Nadji-Boukrouche, A.R.; Khoumeri, O.; Terme, T.; Liacha, M.; Vanelle, P. TDAE Strategy in the Benzoxazolone Series: Synthesis and Reactivity of a New Benzoxazolinonic Anion. Molecules 2015, 20, 1262-1276. https://doi.org/10.3390/molecules20011262

AMA Style

Nadji-Boukrouche AR, Khoumeri O, Terme T, Liacha M, Vanelle P. TDAE Strategy in the Benzoxazolone Series: Synthesis and Reactivity of a New Benzoxazolinonic Anion. Molecules. 2015; 20(1):1262-1276. https://doi.org/10.3390/molecules20011262

Chicago/Turabian Style

Nadji-Boukrouche, Aïda R., Omar Khoumeri, Thierry Terme, Messaoud Liacha, and Patrice Vanelle. 2015. "TDAE Strategy in the Benzoxazolone Series: Synthesis and Reactivity of a New Benzoxazolinonic Anion" Molecules 20, no. 1: 1262-1276. https://doi.org/10.3390/molecules20011262

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