Original TDAE reactivity in benzoxa-and benzothiazolone series

We present herein an extension of the TDAE strategy using original heterocyclic carbaldehyde as electrophiles. We also evaluate the influence of the presence of nitro group on the reactivity. The TDAE-initiated reactions of various halomethyl and gem -dihalomethyl derivatives with non-nitrated carbaldehyde 1 or 2 formed the expected products accompagnied by original rearranged products while the presence of a nitro group just like the carbaldehyde 21 furnished only the expected products in good yields.

Due to the importance of benzoxazolone building block in medicinal chemistry and in continuation of our research program directed toward the development of original synthetic methods, 14 we report herein the study of the behavior of 2(3H)-benzoxazolone and 2(3H)benzothiazolone carbaldehyde derivatives with various carbanions which are formed via the TDAE strategy.
Table 1.TDAE-initiated reactions of halomethyl derivatives 3a-c and 4 with heterocyclic aldehyde 1 or a All the reactions were performed using 3 equiv of aldehyde 1 or 2, 1 equiv of halomethyl derivative 3a-c and 4 and 1 equiv of TDAE in anhydrous DMF, 1 h at -20 °C followed by 24 h at r.t. for 3a and 3b or 2 h for 3c and 4. % All yields refer to chromatographically isolated pure products and are relative to halomethyl derivatives 3a-c and 4.
The reaction time at r.t. has been optimized according to the corresponding halomethyl derivatives i.e. 24 h for derivatives 3a and 3b and 2 h for derivatives 3c and 4. Increasing time for compounds 3c and 4 for 24h at r.t.caused to decrease the yield of product.The reason of this phenomenon was not clear to us but maybe arose from the low stability of the corresponding carbanions.
We have continued our study by using gem-dibromomethyl derivatives such as 2-(dibromomethyl)-1,4-dimethoxy-anthracene-9,10-dione 9 and 2-(dibromomethyl)quinoxaline 12. Surprisingly, the reaction of 1 or 2 with these two dibromomethyl substrates 9, 12 under TDAEinitiated conditions produced original compounds.The reactions of 9 with 1 or 2 led to the formation of observed alcohol 7 or 8 and ketone 10 or 11.The yield of compounds 7, 8, 10 and 11 were 44, 50, 12 and 15% respectively (Scheme 1).The formation of alcohol derivatives 7 and 8 may be explained by the reduction of dibromomethyl substrate 9 by the TDAE in the monobromomethyl derivative 4 which reacts under TDAE conditions with 1 or 2. The formation of the ketone derivatives 10-11 could be explain by the rearrangement of the expected oxirane during the purification process. 17Effectively, in the 1 H-NMR spectra of the crude product we have observed the alcohol and the signal of oxirane but after purification by column chromatography (silica gel) we have obtained these original ketone products.The position of the carbonyl group in 10 and 11, between the two aromatic rings, has been determined after comparison of NMR spectra with those of the ketones formed by oxidation of 7 or 8.For example, the oxidation of 7 using CrO3/H2SO4 in acetone led to a new ketone with a CH2 signal at 4.41 ppm while the CH2 signal appears at 4.35 ppm for the ketone 10.In the reaction of 2-(dibromomethyl)-quinoxaline 12 with 1 or 2, we have observed the expected cis-trans mixture of oxirane 13 or 14 in respectively 7 or 57% and an original dimeric compound 15 or 16 in respectively 41 and 30% yields (Scheme 2).This difference of reactivity could be explained by a stronger unstability of oxiranes in benzoxazolone series.Formation of compounds 15 and 16 arises from the dimer of ketone analogs, this dimerization could occurs during the rearrangement of oxirane.12e This versatile reactivity observed with these two heterocyclic carbaldehydes could be explained by the low electrophilicity of carbonyl allowing the development of side reactions.In order to activate the carbonyl group of these heterocyclic carbaldehydes, we have used an analog of these carbaldehydes containing an electron withdrawing group such as the nitro group.

ISSN 1551-7012
Page 362  ARKAT USA, Inc.The reaction of aldehyde 21 with mono-and bis-halomethyl substrates 3a-c, 4 and 9, 12 under TDAE-initiated conditions furnished the expected alcohols 22a-c, 23 (Scheme 4) and oxiranes 24, 25 (Scheme 5), in good yields.In order to optimize reaction conditions, we have studied the influence of the chloride/aldehyde/TDAE ratio and the reaction time.The best reaction conditions for the halomethyl derivatives 3a-c, 4 have been found with 3 equiv of aldehyde 21, 1 equiv of halomethyl derivatives 3a-c, 4 and 1 equiv of TDAE in anhydrous DMF, 1h at -20 °C followed by 2 h at r.t.(Scheme 5).The corresponding alcohols have been isolated.
Concerning the formation of oxiranes via the reaction of the dibromomethyl derivatives 9, 12 with 21 under TDAE conditions, the optimized protocol was defined with 3 equiv of aldehyde 21, 1 equiv of dibromomethyl derivatives 9, 12 and 1.5 equiv of TDAE in anhydrous DMF, 1h at -20 °C followed by 2 h at r.t.(Scheme 6).Only the trans isomers of the oxiranes 24 and 25 have been obtained in respectively 73 and 72% yields.This stereoselectivity is in agreement with the previous results in which the dibromomethyl derivative 9 furnished only the trans isomer of corresponding oxirane with o-nitro and o-bromo-benzaldehydes.14g

Conclusions
We present herein an extension of the TDAE strategy using original heterocyclic carbaldehydes with great biological interest.This method furnished two series of new benzoxazolone and benzothiazolone derivatives.This study allowed us to discover new original reactivity and to define some limits of the TDAE strategy.We have shown the importance of the electrophily of carbaldehyde to obtain classical TDAE reactivity and to limit the development of secondary reactions.Moreover, as observed in our previous studies, 14e we have shown the unstability of some diaromatic oxiranes.In continuation of our program directed toward the preparation of new bioactive compounds as anti-infectious agents, the pharmacological evaluation of all these synthesized compounds is under active investigation in this area.

Experimental Section
General.Melting points were determined on a Buchi capillary melting point apparatus and are uncorrected.Elemental analyses were by the Centre de Microanalyses of the spectropole (Aix-Marseille University).Both 1 H and 13 C NMR spectra were determined on a Brucker 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 solvents peaks: CDCl3 (76.9 ppm) or Me2SO-d6 (39.6 ppm).Absorptions are reported with the following notations: s, singulet; d, doublet; t, triplet; q, quartet; m, a more complex multiplet or overlapping multiplets.The solid-state 13 C NMR spectrum was obtained on a Bruker Avance-400 MHz NMR spectrometer operating at a 13 C resonance frequency of 106 MHz and using a commercial Bruker double-bearing probe.The following adsorbents were used for column chromatography: silica gel 60 (Merck, particule size 0.063-0.200mm, 70-230 mesh ASTM).TLC were performed on 5 cm x 10 cm aluminium plates coated with silica gel 60 F-254 (Merck) in an appropriate solvent.The following materials were prepared and purified according to reported procedures: 15,16  General procedure for the reaction of halomethyl or dihalomethyl derivatives (3a-c, 4, 9, 12) and carbaldehydes (1, 2) using TDAE Into a two-necked flask equipped with a drying tube (silica gel) and a nitrogen inlet was added 10 mL of anhydrous DMF solution of halomethyl (dihalomethyl) derivative 3a-c, 4, 9, 12 (1 mmol) and carbaldehyde 1, 2 (3 mmol).The solution was stirred and maintained at this temperature for 30 min and then was added dropwise (via a syringe) the TDAE (1 mmol).A red color immediately developed with the formation of a white fine precipitate.The solution was vigorously stirred at -20 °C for 1 h and then warmed up to r.t. for 24 h 3a, 3b or for 2 h 3c, 4, 9, 12.After this time TLC analysis (CH2Cl2) clearly showed that compound 3a-c, 4, 9, 12 was totally consumed.The solution was filtered (to remove the octamethyl-oxamidinium dihalide) and hydrolyzed with 80 mL of H2O.The aqueous solution was extracted with chloroform (3x40 mL), the combined organic layers washed with H2O (2x40 mL) and dried over MgSO4.Evaporation of the solvent left an orange viscous liquid as crude product.Purification by silica gel chromatography and recrystallization from appropriate solvent gave corresponding products.