Original Synthesis of Fluorenyl Alcohol Derivatives by Reductive Dehalogenation Initiated by TDAE

We report here a novel and easy-to-handle reductive dehalogenation of 9-bromofluorene in the presence of arylaldehydes and dicarbonyl derivatives to give the corresponding fluorenyl alcohol derivatives and Darzens epoxides as by-products in tetrakis(dimethylamino)ethylene (TDAE) reaction conditions. The reaction is believed to proceed via two successive single electron transfers to generate the fluorenyl anion which was able to react with different electrophiles. A mechanistic study was conducted to understand the formation of the epoxide derivatives.


Introduction
Fluorenyl derivatives have attracted interest from synthetic organic chemists due to their notable biological and pharmaceutical properties and applications. The literature reports that fluorenone Schiff base derivatives have a potential application and biological activity in therapeutic areas, such as antifungal agents [1,2]. The fluorene skeleton is found in numerous natural products. Dendroflorin and structurally-related nobilone displayed higher antioxidant activity than vitamin C in the ORAC assay [3]. Gramniphenols were isolated from the whole plant of Arundina gramnifolia by Yang and coworkers in 2012 and displayed anti-HIV-1 activity with therapeutic index values above 100:1 [4]. Many dermatological and photostable cosmetic compositions consist of lumefantrine, a 9-fluorenylidene derivative [5]. The fluorenyl core can be found in indecainide (Decabid ® ), which is a class Ic anti-arrhythmic agent [6].
In terms of non-steroidal anti-inflammatory agents (NSAIDs), this scaffold bearing an alkanoïc acid moiety gives cicloprofen. Paranyline is used in dispersible formulations of anti-inflammatory agents [7]. However, although these drugs are very effective and abundantly prescribed, they have revealed some gastric or intestinal adverse effect [8]. The representatives containing the fluorenyl scaffold cited above are shown in Figure 1.
A first attempt (entry 1) was carried out with 2 equiv. of 2a and 1 equiv. of RBr 1 to give 29% of the corresponding alcohol 4a. TDAE was added at −20 °C to maximize the charge transfer complex formation. Unfortunately, 1 H NMR spectra of the crude product showed a signal at δ 4.85 associated to the homo-coupling adduct of 9-bromofluorene (44%). To reduce the extent of dimer formation, 3 equiv. of 2a was employed (entry 2), giving 50% of 4a and the dimer was isolated with 8% yield (entry 2). The conversion to the 9,9′-bifluorenyl was not reduced by increasing the excess of aldehyde. The

Results and Discussion
It was anticipated that fluorenyl bromide 1 could be a good electron-acceptor, because of its large π-conjugated system. Initially, the reaction of 9-bromofluorene 1 and 4-chlorobenzaldehyde 2a was investigated as the model system (Scheme 1).
A first attempt (entry 1) was carried out with 2 equiv. of 2a and 1 equiv. of RBr 1 to give 29% of the corresponding alcohol 4a. TDAE was added at −20 °C to maximize the charge transfer complex formation. Unfortunately, 1 H NMR spectra of the crude product showed a signal at δ 4.85 associated to the homo-coupling adduct of 9-bromofluorene (44%). To reduce the extent of dimer formation, 3 equiv. of 2a was employed (entry 2), giving 50% of 4a and the dimer was isolated with 8% yield (entry 2). The conversion to the 9,9′-bifluorenyl was not reduced by increasing the excess of aldehyde. The We performed the reactions using various aprotic polar solvents. The influence of the quantity of aldehyde 2a and TDAE was also studied. The results are summarized in Table 1. A first attempt (entry 1) was carried out with 2 equiv. of 2a and 1 equiv. of RBr 1 to give 29% of the corresponding alcohol 4a. TDAE was added at −20 • C to maximize the charge transfer complex formation. Unfortunately, 1 H NMR spectra of the crude product showed a signal at δ 4.85 associated to the homo-coupling adduct of 9-bromofluorene (44%). To reduce the extent of dimer formation, 3 equiv. of 2a was employed (entry 2), giving 50% of 4a and the dimer was isolated with 8% yield (entry 2). The conversion to the 9,9 -bifluorenyl was not reduced by increasing the excess of aldehyde. The optimized protocol of 9-bromofluorene 1 was defined with 3 equiv. of aldehyde 2a, 1 equiv. of TDAE in DMF, for 1 h at −20 • C followed by 2 h at room temperature. The reactions led to the corresponding alcohol 4a with 56% yield (Table 1, entry 6). The 9-Bromofluorene was found to be a good substrate in such TDAE-mediated carbon-carbon coupling reactions. This methodology was then applied to other electrophiles. The TDAE-initiated reaction of 1 with various electrophiles was investigated according to the optimal procedure cited above and the results are summarized in Table 2.
The expected corresponding alcohols 4a, 4b, 4e, 4f, 4i were isolated in moderate to good yields, from 41% to 75% with aldehydes bearing an electron-withdrawing group. optimized protocol of 9-bromofluorene 1 was defined with 3 equiv. of aldehyde 2a, 1 equiv. of TDAE in DMF, for 1 h at −20 °C followed by 2 h at room temperature. The reactions led to the corresponding alcohol 4a with 56% yield (Table 1, entry 6). The 9-Bromofluorene was found to be a good substrate in such TDAE-mediated carbon-carbon coupling reactions. This methodology was then applied to other electrophiles. The TDAE-initiated reaction of 1 with various electrophiles was investigated according to the optimal procedure cited above and the results are summarized in Table 2. The expected corresponding alcohols 4a, 4b, 4e, 4f, 4i were isolated in moderate to good yields, from 41% to 75% with aldehydes bearing an electron-withdrawing group.
For 4-nitrobenzaldehyde 2h, no alcohol product was isolated. Its strong electrophilic character, has already led to unexpected reactivity in these reaction conditions, as cited in our previous work [11]. With methylbenzaldehyde 2g and 4-methoxybenzaldehyde 2d, the conversions were lower with, respectively, 24% and 34% yields. This may be explained by their weak electrophilic character compared to the other aldehydes. Competitive epoxide formation was observed, which was obtained in low yield (from 6% to 30%, Table 2, entries 1-9). Subsequently, the methodology was generalized to heteroaromatic aldehydes (entries [10][11][12]. When pyridine-4-carbaldehyde 2k was employed, 42% of the corresponding alcohol 4k was obtained. With pyridine-3-carbaldehyde 2l, the yield reported was lower (19%). The scope of this original reactivity was extended to pyruvates, ethyl glyoxylate, methyl 3,3,3-trifluoropyruvate, and diethylketomalonate (entries 13-16). The best result was achieved with diethylketomalonate affording the corresponding fluorenyl alcohol 4p in 70% yield (entry 16). This can, no doubt, be attributed to the stronger electrophilic character of its carbonyl function. It should be noted that we never observed the reaction of the fluorenyl anion with ester moiety. The For 4-nitrobenzaldehyde 2h, no alcohol product was isolated. Its strong electrophilic character, has already led to unexpected reactivity in these reaction conditions, as cited in our previous work [11]. With methylbenzaldehyde 2g and 4-methoxybenzaldehyde 2d, the conversions were lower with, respectively, 24% and 34% yields. This may be explained by their weak electrophilic character compared to the other aldehydes. Competitive epoxide formation was observed, which was obtained in low yield (from 6% to 30%, Table 2, entries 1-9). Subsequently, the methodology was generalized to heteroaromatic aldehydes (entries [10][11][12]. When pyridine-4-carbaldehyde 2k was employed, 42% of the corresponding alcohol 4k was obtained. With pyridine-3-carbaldehyde 2l, the yield reported was lower (19%). The scope of this original reactivity was extended to pyruvates, ethyl glyoxylate, methyl 3,3,3-trifluoropyruvate, and diethylketomalonate (entries [13][14][15][16]. The best result was achieved with diethylketomalonate affording the corresponding fluorenyl alcohol 4p in 70% yield (entry 16). This can, no doubt, be attributed to the stronger electrophilic character of its carbonyl function. It should be noted that we never observed the reaction of the fluorenyl anion with ester moiety. The poor yield (19%) observed with ethyl glyoxylate 2o could be due to a polymerization reaction of the aldehyde. With propriophenone 2q, only starting materials were recovered (entry 17), which could be attributed to the acidity of the protons adjacent to the carbonyl function.
In order to extend the substrate scope of TDAE-initiated reactions, an attempt had been run with 1,1 -bromobiphenylmethane, but no alcohol adduct was formed. The corresponding dimer product was obtained with 74% yield. This difference in reactivity can be attributed to the better stabilization of the corresponding 9-fluorenyl aromatic anion.
The formation of the alcohol product can be conceived to proceed via two successive single electron transfers (Scheme 2). The first reduction leads to the cleavage of the C-Br bond to form the 9-fluorenyl radical and the bromide anion. A subsequent SET (single monoelectronic transfer) gave the fluorenyl anion A, which is aromatic and has an intense orange color, from the corresponding radical. An alcoholate was successively obtained by the nucleophilic addition of the fluorenyl anion A on the aldehyde which gave the corresponding alcohol after hydrolysis. As cited above, 9-bromofluorene 1 can react under our conditions with aromatic aldehydes, yielding epoxy products. Our hypothesis is that 9-bromofluorenyl anion B could be formed after deprotonation of 1 by the above alcoholate. The reaction of B with the aldehyde gave the epoxide derivatives via Darzen reaction. Our hypothesis is supported by literature data [31]. poor yield (19%) observed with ethyl glyoxylate 2o could be due to a polymerization reaction of the aldehyde. With propriophenone 2q, only starting materials were recovered (entry 17), which could be attributed to the acidity of the protons adjacent to the carbonyl function.
In order to extend the substrate scope of TDAE-initiated reactions, an attempt had been run with 1,1′-bromobiphenylmethane, but no alcohol adduct was formed. The corresponding dimer product was obtained with 74% yield. This difference in reactivity can be attributed to the better stabilization of the corresponding 9-fluorenyl aromatic anion.
The formation of the alcohol product can be conceived to proceed via two successive single electron transfers (Scheme 2). The first reduction leads to the cleavage of the C-Br bond to form the 9-fluorenyl radical and the bromide anion. A subsequent SET (single monoelectronic transfer) gave the fluorenyl anion A, which is aromatic and has an intense orange color, from the corresponding radical. An alcoholate was successively obtained by the nucleophilic addition of the fluorenyl anion A on the aldehyde which gave the corresponding alcohol after hydrolysis. As cited above, 9-bromofluorene 1 can react under our conditions with aromatic aldehydes, yielding epoxy products. Our hypothesis is that 9-bromofluorenyl anion B could be formed after deprotonation of 1 by the above alcoholate. The reaction of B with the aldehyde gave the epoxide derivatives via Darzen reaction. Our hypothesis is supported by literature data [31].

Scheme 2. Proposed mechanism.
When 9-bromofluorene 1 was treated with 3 equiv. of triethylamine in the presence of 4-cyanobenzaldehyde 2f under classical TDAE conditions, the corresponding Darzens condensation product 5f was afforded in low yields (7%) (Scheme 3). Another compound had been observed by 1 H-NMR corresponding to 4-((9H-fluoren-9-ylidene) methyl)benzonitrile 6f with 15% yield. However, another multistep pathway involving a carbenelike intermediate cannot be excluded. To verify this hypothesis, we examined the reaction of 1 in the presence of cyclohexene [32]. The 1 H-NMR spectrum of the crude mixture showed no signal attributable to a cyclopropane adduct that could formed by carbene insertion to the cyclohexene Scheme 2. Proposed mechanism. When 9-bromofluorene 1 was treated with 3 equiv. of triethylamine in the presence of 4-cyanobenzaldehyde 2f under classical TDAE conditions, the corresponding Darzens condensation product 5f was afforded in low yields (7%) (Scheme 3). poor yield (19%) observed with ethyl glyoxylate 2o could be due to a polymerization reaction of the aldehyde. With propriophenone 2q, only starting materials were recovered (entry 17), which could be attributed to the acidity of the protons adjacent to the carbonyl function. In order to extend the substrate scope of TDAE-initiated reactions, an attempt had been run with 1,1′-bromobiphenylmethane, but no alcohol adduct was formed. The corresponding dimer product was obtained with 74% yield. This difference in reactivity can be attributed to the better stabilization of the corresponding 9-fluorenyl aromatic anion.
The formation of the alcohol product can be conceived to proceed via two successive single electron transfers (Scheme 2). The first reduction leads to the cleavage of the C-Br bond to form the 9-fluorenyl radical and the bromide anion. A subsequent SET (single monoelectronic transfer) gave the fluorenyl anion A, which is aromatic and has an intense orange color, from the corresponding radical. An alcoholate was successively obtained by the nucleophilic addition of the fluorenyl anion A on the aldehyde which gave the corresponding alcohol after hydrolysis. As cited above, 9-bromofluorene 1 can react under our conditions with aromatic aldehydes, yielding epoxy products. Our hypothesis is that 9-bromofluorenyl anion B could be formed after deprotonation of 1 by the above alcoholate. The reaction of B with the aldehyde gave the epoxide derivatives via Darzen reaction. Our hypothesis is supported by literature data [31].

Scheme 2. Proposed mechanism.
When 9-bromofluorene 1 was treated with 3 equiv. of triethylamine in the presence of 4-cyanobenzaldehyde 2f under classical TDAE conditions, the corresponding Darzens condensation product 5f was afforded in low yields (7%) (Scheme 3). Another compound had been observed by 1 H-NMR corresponding to 4-((9H-fluoren-9-ylidene) methyl)benzonitrile 6f with 15% yield. However, another multistep pathway involving a carbenelike intermediate cannot be excluded. To verify this hypothesis, we examined the reaction of 1 in the presence of cyclohexene [32]. The 1 H-NMR spectrum of the crude mixture showed no signal attributable to a cyclopropane adduct that could formed by carbene insertion to the cyclohexene Another compound had been observed by 1 H-NMR corresponding to 4-((9H-fluoren-9-ylidene) methyl)benzonitrile 6f with 15% yield. However, another multistep pathway involving a carbene-like intermediate cannot be excluded. To verify this hypothesis, we examined the reaction of 1 in the presence of cyclohexene [32]. The 1 H-NMR spectrum of the crude mixture showed no signal attributable to a cyclopropane adduct that could formed by carbene insertion to the cyclohexene double bond: only peaks due to dimer 3 were found. These findings indicate that the epoxide derivative could be formed through the 9-bromofluorenyl anion sequence.

General Information
Melting points were determined on a Büchi melting point B-540 apparatus (BÜCHI Labortechnik AG, Flawil, Switzerland) and are uncorrected. Element analyses were performed on a Thermo Finnigan EA1112 (San Jose, CA, USA) at the spectropole of the Aix-Marseille University. Both 1 H-and 13 C-NMR spectra were determined on a Bruker Avance 250 spectrometer (Wissembourg, France) at the Service de RMN de la Faculté de Pharmacie de Marseille of the Aix-Marseille University and on a Bruker Avance III NanoBay 300 MHz spectrometer at the spectropole of Aix-Marseille University. The 1 H-and the 13 C-chemical shifts are reported from CDCl 3 peaks: 1 H (7.26 ppm) and 13 C (77 ppm) or Me 2 SO-d6 (39.6 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, (Merck, Darmstadt, Germany). Thin Layer Chromatography (TLC) was performed on 5 cm × 10 cm aluminum plates coated with silica gel 60 F254 (Merck) in an appropriate solvent.

Typical Procedure
The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at −20 • C to a vigorously stirred solution of fluorenyl bromide 1 (150 mg, 0.6 mmol) with the appropriate aldehyde (1.8 mmol, 3 equivalents) and a spatula of sodium sulfate in 4 mL of DMF, under air. A red color was immediately developed with the formation of a fine white precipitate. The mixture was then stirred at −20 • C for 1 h and warmed to room temperature over a period of 2 h. Then 0.5 mL of water was added to quench the reaction. The solution was extracted with dichloromethane (3 × 30 mL), the combined organic layers were washed with brine (3 × 40 mL), and dried over MgSO 4 . The crude product was then obtained after evaporation of the solvent under reduced pressure. Purification by silica gel chromatographic column (dichloromethane: methanol) gave the corresponding fluorenyl derivatives.

Conclusions
This strategy afforded a novel and convenient synthesis of various 9-fluorenylidene derivatives under mild reaction conditions. TDAE was used to generate the fluorenyl anion in situ and under practical conditions, which could be extended to electrophiles. In this study, TDAE, or another base present in the reaction mixture, was also able to promote the formation of epoxide derivatives. Moreover, because of their structural analogy with recently reported compounds, the anti-nociceptive properties of all intermediates are under active investigation.