Original synthesis of fluorenyl alcohol derivatives by reductive dehalogenation initiated by TDAE

Article abstract of DOI:10.3390/molecules21101408

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.

Full text of DOI:10.3390/molecules21101408

molecules
Communication
Original Synthesis of Fluorenyl Alcohol Derivatives
by Reductive Dehalogenation Initiated by TDAE
Alain Gamal Giuglio-Tonolo, Thierry Terme and Patrice Vanelle *
Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de
Pharmaco-Chimie Radicalaire, Marseille 13385, France; gamal.giuglio-tonolo@univ-amu.fr (A.G.G.-T.);
thierry.terme@univ-amu.fr (T.T.)
* Correspondence: patrice.vanelle@univ-amu.fr; Tel.: +33-4-9183-5580; Fax: +33-4-9179-4677
Academic Editor: Derek J. McPhee
Received: 19 September 2016; Accepted: 19 October 2016; Published: 24 October 2016
Abstract: 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.
Keywords: tetrakis(dimethylamino)ethylene; reductive dehalogenation; single electron transfer
1. 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 [
Dendroflorin and structurally-related nobilone displayed higher antioxidant activity than vitamin C
in the ORAC assay [ ]. 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 [ ]. Many dermatological and photostable cosmetic compositions consist of lumefantrine,
a 9-fluorenylidene derivative [
]. The fluorenyl core can be found in indecainide (Decabid®), which is
1,2]. The fluorene skeleton is found in numerous natural products.
3
4
5
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.
Since 2003, our laboratory has been developing original synthetic methods based on neutral,
ground-state organic reducing agents [ 14], aimed at preparing new, potentially bioactive
compounds [ ]. Tetrakis(dimethylamino)ethylene (TDAE), as shown in Figure 1 [15 17], is a powerful
9–
9
–
tool in modern organic chemistry because it allows reduction under mild conditions. Reduction
can occur without the use of organometallics or reactive metals. TDAE shows a single, two-electron
oxidation peak at
as zinc metal [18
benzyl halides, to produce the corresponding carbanions [21
method to generate a 9-bromofluorenyl anion from fluorenyl bromide
series of carbonyl electrophiles affording the corresponding alcohol derivatives.
−
0.62 V vs. SCE in diméthylformamide (DMF) which means it is about as reducing
20]. TDAE can react with activated alkyl halides, such as CF3I, CF2Br2, and activated
30]. We report herein a valuable synthetic
and on its reaction with a
–
–
1
Molecules 2016, 21, 1408; doi:10.3390/molecules21101408
www.mdpi.com/journal/molecules

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Figure 1. Structures of biological active molecules and TDAE.
2. 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).
Scheme 1. Optimization of the reaction of fluorenyl bromide
1 with 4-chlorobenzaldehyde 2a
using TDAE.
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.
Table 1. Reactions of fluorenyl bromide 1 and aldehyde 2a with TDAE under various conditions.
Entry
Aldehyde 2a (eq.)
TDAE (eq.)
Solvent
Yield 1,2 of Dimer 3
Yield 1,2 of 4a
1
2
3
4
5
6
7
8
9
2
3
3
4
3
3
3
3
3
1
1
2
1
1
1
1
1
1
DMF
DMF
DMF
DMF
THF
44%
8%
10%
8%
12%
9%
16%
20%
11%
29%
50%
48%
46%
48%
56%
30%
12%
34%
DMF 3
CH3CN
DMSO
pyridine
1
Isolated yields; 2 Typical procedure: to a vigorously stirred solution of fluorenyl bromide
1
derivative in 4 mL
anhydrous solvent, at
in the reaction mixture and the reaction was run under air.
−
20 ◦C, under N2; 3 Moist DMF was used in the presence of a spatula of sodium sulfate
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
formation. Unfortunately, 1H NMR spectra of the crude product showed a signal at
to the homo-coupling adduct of 9-bromofluorene (44%). To reduce the extent of dimer formation,
−
20 ◦C to maximize the charge transfer complex
δ
4.85 associated

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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 9,90-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
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.
1 with various electrophiles was
,
,
,
,
Table 2. The scope of the reactivity of
1 in the presence of various electrophiles under TDAE
reaction conditions.
Electrophiles
R1
Yield 1,2 of 4
Yield 1,2 of 5
Entry
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
4-ClC6H4
C6H5
H
H
H
H
H
H
H
H
H
56% (4a)
57% (4b)
75% (4c)
34% (4d)
54% (4e)
41% (4f)
24% (4g)
14% (5a)
17% (5b)
10% (5c)
4-BrC6H4
4-OMeC6H4
4-FC6H4
4-CNC6H4
4-MeC6H4
4-(NO2)C6H4
4-CF3 C6H4
2-furyl
4-pyridinyl
3-pyridinyl
Me
CF3
H
CO2Et
C6H5
30% (5f)
17% (5h)
6% (5i)
19% (5j)
11% (5k)
49% (4i)
28% (4j)
42% (4k)
19% (4l)
47% (4m)
41% (4n)
25% (4o)
70% (4p)
H
H
H
CO2Et
CO2Me
CO2Et
CO2Et
Et
1
Isolated yields; 2 Typical procedure: to a vigorously-stirred solution of 9-bromofluorene
1
in 4 mL moist DMF
with a spatula of sodium sulfate, under air, TDAE was slowly added at
1 h at this temperature followed by 2 h at ambient temperature.
−
20 ◦C. The solution was then stirred
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 10–12). 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 poor yield

Molecules 2016, 21, 1408
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(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
1,10-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).
Scheme 3. Reactivity of 9-bromofluorene and 4-cyanobenzaldehyde in the presence of trimethylamine.
Another compound had been observed by 1H-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

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1
the presence of cyclohexene [32]. The 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.
3. Materials and Methods
3.1. 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 1H- and 13C-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 1H- and
1
the 13C-chemical shifts are reported from CDCl3 peaks: H (7.26 ppm) and 13C (77 ppm) or Me2SO-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
aluminum plates coated with silica gel 60 F254 (Merck) in an appropriate solvent.
×
10 cm
3.2. Typical Procedure
◦
The TDAE (0.14 mL, 0.6 mmol) was slowly added, with a syringe, at
stirred solution of fluorenyl bromide
−
20 C to a vigorously
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 MgSO4. 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.
×
×
3.3. Compound Characterizations
0
0
◦ ◦
3
(9%); yellow powder; m.p. 216–217 C (Lit.: 237–239 C). 1H-NMR (200 MHz)
9H,9 H-9,9 -Bifluorene:
(CDCl3) 7.66 (d, J = 7.51 Hz, 4H); 7.33–7.26 (m, 4H); 7.15–7.07 (m, 4H); 6.97 (d, J = 7.34 Hz, 4H); 4.85
(s, 2H). 13C-NMR (50 MHz) (CDCl3) 144.6 (4CIV); 141.5 (4CIV); 127.3 (4CHar); 126.7 (4CHar); 124.0
(4CHar); 119.6 (4CHar); 49.8 (2CH). Physical and spectroscopic data agree with those reported in the
literature [33,34].
(4-Chlorophenyl)(9H-fluoren-9-yl)methanol: 4a (56%); yellow powder; m.p. 142–143 ◦C (Lit.: 126.5 ◦C).
1H-NMR (200 MHz) (CDCl3): 7.70 (d, J = 7.5 Hz, 2H); 7.40–7.17 (m, 10H); 5.15 (d, J = 5.7 Hz, 1H); 4.37
(d, J = 5.7 Hz, 1H); 1.90 (bs, OH). 13C-NMR (50 MHz) (CDCl3): 143.0 (CIV); 142.9 (2CIV); 141.7 (CIV);
140.2 (2CIV); 128.1 (2CHar); 127.7 (2CHar); 126.7 (2CHar); 125.9 (2CHar); 125.5 (2CHar); 119.8 (2CHar);
75.6 (CH); 56.4 (CH). HRMS (ESI+): m/z [M + Na]+ calculated for C20H15OClNa+: 329.0704 Da; found:
329.0704 Da. Physical data agree with those reported in the literature [35].
◦
1
30-(4-Chlorophenyl)spiro(fluorene-9,20-oxirane): 5a (14%) yellow powder; m.p. 63–64 C. H-NMR
(200 MHz) (CDCl3) 7.76–7.68 (m, 2H); 7.51–7.29 (m, 8H); 7.02–6.94 (dd, J = 1 and 7.6 Hz, 1H); 6.50
(d, J = 7.6 Hz, 1H); 4.91 (s, 1H). 13C-NMR (50 MHz) (CDCl3) 141.6 (CIV); 141.4 (CIV); 140.6 (CIV);
138.4 (CIV); 134.0 (CIV); 133.7 (CIV); 129.4 (CHar); 129.3 (CHar); 128.6 (2CHar); 128.3 (2CHar); 127.6

Molecules 2016, 21, 1408
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(2CHar); 127.0 (CHar); 123.9 (CHar); 121.6 (CHar); 120.1 (CHar); 67.6 (CIV); 59.1 (CH). HRMS (ESI+):
m/z [M + H]+ calculated for C20H14OCl+: 305.0728 Da; found: 305.0728 Da.
◦
◦
(9H-Fluoren-9-yl)(phenyl)methanol: 4b (57%); yellow powder; m.p. 116–117 C (Lit.: 120–121 C).
1H-NMR (200 MHz) (CDCl3) 7.64–7.60 (m, 2H); 7.31–7.24 (m, 7H); 7.16–7.06 (m, 3H); 6.97 (d, J = 6.9 Hz,
1H); 5.09 (d, J = 6.1 Hz, 1H); 4.40 (d, J = 6.1 Hz, 1H); 1.68 (bs, OH). 13C-NMR (50 MHz) (CDCl3) 143.6
(CIV); 143.3 (CIV); 142.1 (CIV); 141.8 (CIV); 141.7 (CIV); 128.1 (2CHar); 127.8 (CHar); 127.6 (CHar);
126.8 (2CHar); 126.7 (CHar); 126.6 (CHar); 126.6 (CHar);126.2 (CHar); 125.5 (CHar); 119.8 (CHar) ; 119.7
(CHar); 76.3 (CH); 54.7 (CH). HRMS (ESI+): m/z [M + Na]+ calculated for C20H16ONa+: 295.1093 Da;
found: 295.1093 Da. Physical and spectroscopic data agree with those reported in the literature [34,36].
◦
◦
30-Phenylspiro(fluorene-9,20-oxirane): 5b (17%); yellow powder; m.p. 119–120 C (Lit.: 130–131 C).
1H-NMR (200 MHz) (CDCl3) 7.76–7.67 (m, 2H); 7.50–7.30 (m, 9H); 6.93 (dt, J = 7.6 and 0.9 Hz, 1H);
6.50 (d, J = 7.6 Hz, 1H); 4.97 (s,1H). 13C-NMR (50 MHz) (CDCl3) 141.7 (CIV); 141.5 (CIV); 140.6 (CIV);
138.7 (CIV); 135.2 (CIV); 129.3 (CHar); 129.1 (CHar); 128.3 (2CHar); 128.1 (CHar); 127.6 (CHar); 127.0
(CHar); 126.8 (2CHar); 124.1 (CIV); 121.6 (CHar); 120.2 (CHar); 120.1 (CHar); 67.6 (CIV); 65.7 (CH).
HRMS (ESI+): m/z [M + Na]+ calculated for C20H14ONa+: 293.0937 Da; found: 293.0936 Da. Physical
and spectroscopic data agree with those reported in the literature [37].
◦
1
(4-Bromophenyl)(9H-fluoren-9-yl)methanol: 4c (75%); yellow powder; m.p. 129–130 C. H-NMR
(200 MHz) (CDCl3) 7.70 (d, J = 7.4 Hz, 2H); 7.43–7.34 (m, 4H); 7.30–7.20 (m, 4H); 7.15 (d, J = 8.4 Hz, 2H);
5.15 (d, J = 5.5 Hz, 1H); 4.38 (d, J = 5.5 Hz, 1H). 13C-NMR (50 MHz) (CDCl3) 143.0 (2CIV); 142.9 (CIV);
141.8 (CIV); 140.8 (2CIV); 131.1 (2CHar); 128.4 (2CHar); 127.7 (CHar); 126.8 (CHar); 126.7 (CHar); 125.9
(CHar); 125.5 (CHar); 121.5 (CHar); 119.9 (CHar); 119.8 (CHar); 75.7 (CH), 54.6 (CH). HRMS (ESI+):
m/z [M + Na]+ calculated for C20H15OBrNa+: 373.0198 Da; found: 373.0198 Da.
◦
1
30-(4-Bromophenyl)spiro(fluorene-9,20-oxirane) 5c (10%) yellow powder; m.p. 122–123 C. H-NMR
(200 MHz) (CDCl3) 7.76–7.69 (m, 2H); 7.57–7.54 (m, 2H); 7.51–7.28 (m, 6H); 7.02–6.96 (m, 1H); 7.51
(d, J = 7.7 Hz, 1H); 4.86 (s, 1H). 13C-NMR (50 MHz) (CDCl3) 141.6 (CIV); 141.3 (CIV); 140.6 (CIV);
138.2 (CIV); 134.2 (CIV); 131.6 (2CHar); 129.5 (CHar); 129.3 (CHar); 128.6 (2CHar); 127.7 (CHar); 127.1
(CHar); 123.9 (CHar); 122.2 (CIV); 121.6 (CHar); 120.2 (2CHar); 67.6 (CIV); 65.1 (CH). HRMS (ESI+):
m/z [M + H]+ calculated for C20H14OBr+: 349.0223 Da; found: 349.0150 Da.
(9H-Fluoren-9-yl)(4-methoxyphenyl)methanol: 4d (34%); white powder; m.p. = 115–116 ◦C (Lit.:
◦
1
122–123 C)3; H-NMR (200 MHz) (CDCl3) 7.74–7.70 (dd, J = 7.6 and 3.3 Hz, 2H); 7.46–7.32 (m,
3H); 7.27–7.15 (m, 4H); 7.03 (d, J = 7.6 Hz, 1H); 6.88 (d, J = 8.8 Hz, 2H); 4.97 (d, J = 6.5 Hz, 1H); 4.38
(d, J = 6.5 Hz, 1H); 3.83 (s, 3H) 1.96 (bs, OH). 13C-NMR (50 MHz) (CDCl3) 159.1 (CIV); 143.9 (CIV);
143.3 (CIV); 141.8 (CIV); 141.6 (CIV); 134.4 (CIV); 128.0 (2CHar); 127.6 (CHar); 127.5 (CHar); 126.6
(CHar); 126.5 (CHar); 126.3 (CHar); 125.7 (CHar); 119.8 (CHar); 119.7 (CHar); 113.5 (2CHar); 76.1 (CH);
55.2 (CH); 54.7 (CH3). HRMS (ESI+): m/z [M + Na]+ calculated for C21H18O2Na+: 325.1199 Da; found:
325.1200 Da.
(9H-Fluoren-9-yl)(4-fluorophenyl)methanol: 4e (54%); white powder; m.p. 120–121 ◦C; 1H-NMR
(200 MHz) (CDCl3) 7.70 (d, J = 7.4 Hz, 2H); 7.41–7.33 (m, 3H); 7.26–7.14 (m, 5H); 7.01–6.95 (m, 2H); 5.11
(d, J = 5.6 Hz, 1H); 4.37 (d, J = 5.6 Hz, 1H); 2.01 (bs, OH). 13C-NMR (50 MHz) (CDCl3) 160.5 (CIV); 143.5
(CIV); 143.2 (CIV); 142.0 (CIV); 141.9 (CIV); 134.8 (CIV); 128.5 (CHar); 128.4 (CHar); 127.7 (2CHar);
126.7 (2CHar); 126.0 (CHar); 125.7 (CHar); 119.9 (CHar) ; 119.8 (CHar); 115.0 (CHar); 114.7 (CHar);
75.9 (CIV); 54.9 (CH). HRMS (ESI+): m/z [M + Na]+ calculated for C20H15OFNa+: 313.0999 Da; found:
313.0999 Da.
4-((9H-Fluoren-9-yl)(hydroxy)methyl)benzonitrile: 4f (41%); white powder; m.p. 169–170 ◦C; 1H-NMR
(200 MHz) (CDCl3) 7.68 (d, J = 7.7 Hz, 2H); 7.52 (d, J = 8.2 Hz, 2H); 7.41–7.18 (m, 8H); 5.36 (d, J = 4.7 Hz,
1H); 4.42 (d, J = 4.7 Hz, 1H); 2.07 (bs, 1H). 13C-NMR (50 MHz) (CDCl3) 146.7 (CIV); 142.5 (CIV); 142.3
(CIV); 141.8 (2CIV); 131.6 (2CHar); 128.0 (2CHar); 127.3 (2CHar); 127.0 (CHar); 126.8 (CHar); 125.5

Molecules 2016, 21, 1408
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(CHar); 125.4 (CHar); 120.1 (CHar); 120.0 (CHar); 118.8 (CIV); 111.3 (CIV); 75.5 (CH), 54.5 (CH). HRMS
(ESI+): m/z [M + H]+ calculated for C21H16NO+: 298.1154 Da; found: 298.1154 Da.
◦
1
4-(Spiro(fluorene-9,20-oxiran)-30-yl)benzonitrile: 5f (30%) white powder; m.p. 139–140 C; H-NMR
(200 MHz) (CDCl3) 7.69–7.60 (m, 4H); 7.55–7.52 (m, 2H); 7.47–7.23 (m, 4H); 6.92–6.85 (m, 1H); 6.33
(d, J = 7.7 Hz, 1H); 4.86 (s,1H). 13C-NMR (50 MHz) (CDCl3) 141.1 (CIV); 141.0 (CIV); 140.7 (CIV); 140.6
(CIV); 132.2 (2CHar); 130.5 (CHar); 129.7 (CHar); 129.6 (CHar); 129.1 (CIV); 128.6 (CIV); 127.8 (2CHar);
127.1 (CHar); 123.7 (CHar); 121.6 (CHar); 120.8 (CIV); 120.4 (CHar); 120.3 (CHar); 65.0 (CIV); 60.3 (CH).
HRMS (ESI+): m/z [M + Na]+ calculated for C21H13NONa+: 318.0889 Da; found: 318.0889 Da.
◦
(9H-Fluoren-9-yl)(p-tolyl)methanol 4g (24%); yellow powder; m.p. 86–87 C; 1H-NMR (200 MHz) (CDCl3)
7.72 (d, J = 7.7 Hz, 1H); 7.41–7.04 (m, 11H); 5.02 (d, J = 5.0 Hz, 1H); 4.39 (d, J = 5.0 Hz, 1H); 2.38 (s, 3H).
13C-NMR (50 MHz) (CDCl3) 143.7 (CIV); 143.4 (CIV); 141.8 (CIV); 141.7 (CIV); 139.2 (CIV); 137.5 (CIV);
128.9 (2CHar); 127.6 (CHar); 127.5 (CHar); 126.7 (2CHar); 126.6 (2CHar); 126.3 (CHar); 125.6 (CHar);
119.8 (CHar); 119.7 (CHar); 76.2 (CH); 54.7 (CH); 21.2 (CH3). HRMS (ESI+): m/z [M + Na]+ calculated
for C21H18ONa+: 309.1250 Da; found: 309.1249 Da.
◦
1
30-(4-Nitrophenyl)spiro(fluorene-9,20-oxirane) 5h (17%); yellow powder; m.p. 152–153 C; H-NMR
(200 MHz) (CDCl3) 8.30 (dd, J = 8.6 and 2.4 Hz, 2H); 7.77–7.66 (m, 4H); 7.52–7.31 (m, 4H); 6.97–6.94
(m, 1H); 6.45 (d, J = 7.7 Hz, 1H); 4.99 (s, 1H). 13C-NMR (50 MHz) (CDCl3) 147.8 (CIV); 142.4 (CIV); 141.7
(CIV); 140.8 (CIV); 140.6 (CIV); 137.6 (CIV); 129.8 (CHar); 129.6 (CHar); 127.9 (2CHar); 127.8 (CHar);
127.1 (CHar); 123.7 (2CHar); 123.5 (CHar); 121.6 (CHar); 120.5 (CHar); 120.3 (CHar); 68.0 (CIV); 64.9
(CH). HRMS (ESI+): m/z [M + H]+ calculated for C20H14NO3+: 315.0895 Da; found: 315.0895 Da.
◦
(9H-Fluoren-9-yl)(4-(trifluoromethyl)phenyl)methanol 4i (49%); white powder; m.p. 149–150 C. 1H-NMR
(200 MHz) (CDCl3) 7.72 (d, J = 7.6 Hz, 2H); 7.56 (d, J = 8.3 Hz, 2H); 7.42–7.21 (m, 8H); 5.31 (d, J = 5.3 Hz,
1H); 4.43 (d, J = 5.3 Hz, 1H). 13C-NMR (50 MHz) (CDCl3) 145.7 (CIV); 142.8 (CIV); 141.6 (2CIV); 141.8
(2CIV); 127.8 (2CHar); 127.0 (2CHar); 126.9 (CHar); 126.7 (CHar); 125.8 (CHar); 125.3 (CHar); 125.0
(CHar); 124.9 (CHar); 124.8 (CIV); 120.0 (CHar); 119.9 (CHar); 75.6 (CH); 54.6 (CH). HRMS (ESI+):
m/z [M + Na]+ calculated for C21H15OF3Na+: 363.0967 Da; found: 363.0969 Da.
0
0
◦
3 -(4-(Trifluoromethyl)phenyl)spiro[fluorene-9,2 -oxirane] 5i (6%); yellow powder; m.p. 75–76 C. 1H-NMR
(200 MHz) (CDCl3) 7.67–7.16 (m, 10H); 6.90–6.63 (m, 1H); 6.39–6.35 (dd, J = 6.4 et 1.4 Hz, 1H); 4.87
(s, 1H). 13C-NMR (50 MHz) (CDCl3) 145.3 (CIV); 144.2 (CIV); 141.3 (CIV); 140.2 (CIV); 140.0 (CIV);
129.7 (CHar); 129.4 (CHar); 127.6 (CIV); 127.5 (2CHar); 127.4 (2CHar); 125.5 (CHar); 124.1 (CHar); 123.7
(CHar); 123.6 (CHar); 120.1 (CHar); 120.0 (CIV); 84.7 (CIV); 78.9 (CH). HRMS (ESI−): m/z [M
−
H]−
calculated for C21H12OF3−: 337.0846 Da; found: 337.0846 Da.
◦
(9H-Fluoren-9-yl)(furan-2-yl)methanol 4j (28%); brown powder; m.p. 91–92 C. 1H-NMR (200 MHz)
(CDCl3) 7.75 (d, J = 7.7 Hz, 2H); 7.50–7.20 (m, 6H); 7.05 (d, J = 7.6 Hz, 1H); 6.40–6.39 (m, 1H); 6.15–6.14
(m, 1H); 5.03 (d, J = 6.2 Hz, 1H); 4.56 (d, J = 6.2 Hz, 1H). 13C-NMR (50 MHz) (CDCl3) 154.9 (CIV);
143.1 (CIV); 143.0 (CIV); 141.7 (2CIV); 127.7 (2CHar); 127.0 (2CHar); 126.0 (2CHar); 124.9 (CHar); 119.7
(2CHar); 110.5 (CHar); 107.4 (CHar); 70.3 (CH); 52.4 (CH). HRMS (ESI+): m/z [M + Na]+ calculated for
C18H14O2Na+: 285.0886 Da; found: 285.0884 Da.
0
0
◦
3 -(Furan-2-yl)spiro(fluorene-9,2 -oxirane) 5j (19%); brown crystals; m.p. 135–136 C. 1H-NMR (200 MHz)
(CDCl3) 8.70–8.63 (m, 2H); 8.45–8.41 (m, 1H); 7.83–7.50 (m, 7H); 6.78–6.70 (m, 2H). 13C-NMR (50 MHz)
(CDCl3) 148.7 (CIV); 148.3 (CIV); 143.4 (CHar); 131.6 (CIV); 131.4 (CIV); 128.0 (CHar); 127.1 (CHar);
126.7 (CHar); 126.4 (CIV); 124.9 (CHar); 124.8 (CHar); 124.3 (CHar); 123.5 (CHar); 122.7 (CHar); 122.5
(CHar); 111.8 (CHar); 111.4 (CHar); 106.5 (CIV).
◦
(9H-Fluoren-9-yl)(pyridin-4-yl)methanol: 4k (42%); orange powder; m.p. 235–236 C; 1H-NMR (200 MHz)
(DMSO-d6) 8.08 (d, J = 6.0 Hz, 2H); 7.96–7.92 (m, 2H); 7.87–7.83 (m, 2H); 7.44–7.36 (m, 4H); 6.74
(d, J = 4.6 Hz, 1H); 6.68 (d, J = 6.0 Hz, 2H); 5.50 (d, J = 4.6 Hz, 1H). 13C-NMR (50 MHz) (DMSO-d6) 150.2
(CIV); 147.0 (2CHar); 143.2 (2CIV); 140.8 (2CIV); 127.2 (2CHar); 126.9 (2CHar); 125.8 (2CHar); 122.1

Molecules 2016, 21, 1408
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−
−
(2CHar); 118.9 (2CHar); 73.0 (CH); 63.73 (CH). HRMS (ESI+): m/z [M
272.1081 Da; found: 272.1081 Da.
−
H] calculated for C19H14NO :
◦
1
4-(Spiro(fluorene-9,20-oxiran)-30-yl)pyridine: 5k (11%); Yellow powder; m.p. 197–198 C H-NMR
(200 MHz) (DMSO-d6) 8.13 (d, J = 8.0 Hz, 1H); 7.88 (d, J = 7.0 Hz, 2H); 7.36–7.18 (m, 4H); 6.50
(d, J = 7.0 Hz, 2H); 6.22 (d, J = 5.9 Hz, 1H); 5.83 (d, J = 5.9 Hz, 1H). 13C-NMR (50 MHz) (DMSO-d6)
147.7 (2CHar); 144.4 (2CIV); 143.5 (2CIV); 139.0 (CIV); 129.3 (CHar); 129.2 (CHar); 127.5 (CHar); 127.3
(CHar); 126.7 (CHar); 125.1 (CHar); 122.4 (2CHar); 119.8 (CHar); 119.6 (CHar); 76.9 (CH); 75.6 (CH).
HRMS (ESI+): m/z [M + Na]+ calculated for C19H13NONa+: 294.0889 Da; found: 294.0891 Da.
(9H-Fluoren-9-yl)(pyridin-3-yl)methanol 4l (19%); white powder; m.p. 253–254 ◦C. 1H-NMR (200 MHz)
(DMSO-d6) 8.16–8.14 (dd, J = 4.7 et 1.7 Hz, 1H); 7.88 (d, J = 1.9 Hz, 1H); 7.76–7.73 (m, 1H); 7.56–7.45
(m, 3H); 7.34–7.26 (m, 4H); 7.08–7.04 (dt, J = 7.9 et 1.9, 1H); 6.95–6.90 (dd, J = 7.7 ou 7.9 et 4.7 Hz,
1H); 6.03 (s, OH); 5.83 (d, J = 3.7 Hz, 1H); 5.17 (d, J = 3.7 Hz, 1H). 13C-NMR (50 MHz) (DMSO-d6)
148.4 (CHar); 147.3 (CHar); 146.3 (2CIV); 139.8 (2CIV); 134.2 (CHar); 128.2 (CHar); 128.1 (CHar); 126.7
(2CHar); 126.6 (CIV); 125.6 (CHar); 124.5 (CHar); 121.4 (CHar); 119.2 (CHar); 119.0 (CHar); 83.71 (CH);
76.3 (CH). HRMS (ESI+): m/z [M + H]+ calculated for C19H16NO+: 274.1226 Da; found: 274.1226 Da.
1
Ethyl 2-(9H-fluoren-9-yl)-2-hydroxypropanoate 4m (47%): orange oil. H-NMR (200 MHz) (CDCl3) 7.73
(d, J = 7.3 Hz, 2H); 7.63–7.54 (m, 2H); 7.39–7.35 (m, 4H); 4.31 (s, 1H); 4.05 (q, J = 7.1 Hz, 2H); 1.60
(s, 3H); 1.04 (t, J = 7.1 Hz, 3H). 13C-NMR (50 MHz) (CDCl3) 175.3 (CIV); 143.0 (CIV); 142.6 (CIV); 142.2
(CIV); 141.8 (CIV); 127.9 (CHar); 127.7 (CHar); 126.7 (2CHar); 126.0 (CHar); 125.7 (CHar); 119.7 (CHar);
119.6 (CHar); 77.2 (CIV); 61.7 (CH2); 56.0 (CH); 23.9 (CH3); 13.7 (CH3). HRMS (ESI+): m/z [M + NH4]+
calculated for C18H22NO3+: 300.1594 Da; found: 300.1592 Da.
Methyl 2-(9H-fluoren-9-yl)-3,3,3-trifluoro-2-hydroxypropanoate 4n (41%); yellow powder; m.p. 94–95 ◦C.
1H-NMR (200 MHz) (CDCl3) 7.77–7.71 (m, 3H); 7.45–7.39 (m, 2H); 7.33–7.25 (m, 3H); 4.61 (s, 1H); 3.70
(s, 3H). 13C-NMR (50 MHz) (CDCl3) 169.2 (CIV); 142.7 (CIV); 142.1 (CIV); 140.1 (CIV); 139.8 (CIV);
128.5 (CHar); 128.3 (CHar); 126.7 (CHar); 126.8 (2CHar); 125.5 (CHar); 119.8 (CHar); 119.6 (CHar); 80.0
+
(CIV); 79.5 (CIV); 53.8 (CH); 50.2 (CH3). HRMS (ESI+): m/z [M + NH4]+ calculated for C17H17NO3F3
:
340.1155 Da; found: 340.1157 Da.
1
Ethyl 2-(9H-fluoren-9-yl)-2-hydroxyacetate 4o (25%): yellow powder; m.p. 135–136 ◦C. H-NMR
(200 MHz) (CDCl3) 7.75 (d, J = 7.1 Hz, 2H); 7.65 (m, 1H); 7.43–7.26 (m; 5H); 4.94 (d, J = 2.7 Hz,
1H); 4.43 (d, J = 2.7 Hz, 1H); 4.08 (q, J = 7.1 Hz, 2H); 1.03 (t, J = 7.1 Hz, 3H). 13C-NMR (50 MHz) (CDCl3)
173.2 (CIV); 143.3 (2CIV); 142.2 (2CIV); 127.8 (CHar); 127.7 (CHar); 127.2 (CHar); 127.0 (CHar); 124.7
(CHar); 124.5 (CHar); 119.9 (CIV); 119.8 (CHar); 72.6 (CH); 61.6 (CH); 48.31 (CH2); 13.7 (CH3). HRMS
(ESI+): m/z [M + H]+ calculated for C17H17O3+: 269.1172 Da; found: 269.1171 Da.
◦
1
Diethyl 2-(9H-fluoren-9-yl)-2-hydroxymalonate 4p (70%): white powder; m.p. 75–76 C. H-NMR
(200 MHz) (CDCl3) 7.74 (d, J = 7.4 Hz, 2H); 7.49 (d, J = 7.4 Hz, 2H); 7.43–7.36 (m, 2H); 7.30–7.22
(m, 2H); 4.93 (s, 1H); 4.25 (q, J = 7.2 Hz, 4H); 3.88 (bs, 1H); 1.19 (t, J = 7.2 Hz, 6H). 13C-NMR (50 MHz)
(CDCl3) 169.5 (2CIV); 142.1 (2CIV); 141.6 (2CIV); 128.0 (2CHar); 127.0 (2CHar); 125.3 (2CHar); 119.7
(2CHar); 81.3 (CIV); 62.6 (2CH2); 54.6 (CH); 13.7 (2CH3). HRMS (ESI–): m/z [M + H]+ calculated for
C20H21O5+: 341.1384 Da; found: 340.1311 Da.
3.4. Reactivity of 9-Bromofluorene and 4-Cyanobenzaldehyde in the Presence of Triethylamine
Triethylamine (150 mg, 1.2 mmol) was added to a stirred solution of fluorenyl bromide
0.5 mmol) with the 4-cyanobenzaldehyde (160 mg, 1.2 mmol) and a spatula of sodium sulfate in 4 mL
of DMF, under air. The mixture was then stirred at
20 ◦C for 1 h and warmed to room temperature
over a period of 24 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 MgSO4. The crude product was then obtained after evaporation of the
1 (100 mg,
−
×
×

Molecules 2016, 21, 1408
9 of 11
solvent under reduced pressure. Purification by silica gel chromatographic column (dichloromethane:
methanol) gave the 20% of the unreacted 9-bromofluorene with 15% yield of the 4-((9H-fluoren-9-
ylidene)methyl)benzo-nitrile 8c and 7% yield of the 4-(spiro(fluorene-9,20-oxiran)-30-yl)benzonitrile 5f
gave the unreacted 9-bromofluorene (20%) with 4-((9H-fluoren-9-ylidene)methyl)benzonitrile 6f (15%)
and 4-(spiro(fluorene-9,20-oxiran)-30-yl)benzonitrile 5f (7%).
4-((9H-Fluoren-9-ylidene)methyl)benzonitrile: 6f (15%) yellow powder; m.p. 149–150 ◦C (Lit.: 150–151).
1H-NMR (200 MHz) (CDCl3) 7.97–7.94 (m, 1H); 7.75–7.73 (m, 1H); 7.41–7.30 (m, 6H); 7.12 (d, J = 8.3 Hz,
2H); 7.12 (d, J = 8.3 Hz, 2H); 6.80 (bs, 1H). Physical and spectroscopic data agree with those reported in
the literature [38].
4. 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.
Acknowledgments: This work is supported by the Centre National de la Recherche Scientifique. We express our
thanks to V. Remusat for 1H- and 13C-NMR spectra recording and Valérie Monnier for measured HRMS.
Author Contributions: A.G.G.-T., T.T. and P.V. conceived and designed the study. A.G.G.-T. and T.T. designed the
experiments and interpreted the results. A.G.G.-T., T.T. and P.V. wrote the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 4a
–4g; 4i–4p and 5a–5c; 5f–5k; 6f are available from the authors.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).