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

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.


OPEN ACCESS
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].
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.
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%).
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.

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 1 H-(200 MHz) and 13 C-NMR (50 MHz) spectra were determined on a Bruker AC 200 spectrometer. The 1 H chemical shifts are reported as parts per million downfield from tetramethylsilane (Me4Si), and the 13 C 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) were prepared according to a previously described method [27]. (2)

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.

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.      13

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.