LiAlH4-Promoted Tandem Reduction/Oxidation of Fluorenyl Derivatives under Air

Article abstract of DOI:10.1002/ejoc.201402642

The tandem reduction/oxidation of fluorenyl compounds was performed with LiAlH₄ under air to afford the corresponding 9-hydroxyfluorenyl derivatives in good yields. This methodology with LiAlH₄ is unprecedented and most likely proceeds by an organoaluminium intermediate, and in the proposed mechanism. The tandem reduction/oxidation of fluorenyl compounds with LiAlH₄ under air affords the corresponding 9-hydroxyfluorenyl derivatives in good yields.

Full text of DOI:10.1002/ejoc.201402642

FULL PAPER
DOI: 10.1002/ejoc.201402642
LiAlH4-Promoted Tandem Reduction/Oxidation of Fluorenyl Derivatives
under Air
Tetiana Matviiuk,[a,b] Christophe Menendez,[a,c] Chantal Carayon,[a,c] Nathalie Saffon,[d]
Zoia Voitenko,[b] Christian Lherbet,*[a,c] and Michel Baltas*[a,c]
Keywords: Synthetic methods / Tandem reactions / Oxidation / Alcohols / Polycycles
The tandem reduction/oxidation of fluorenyl compounds was
performed with LiAlH4 under air to afford the corresponding
ology with LiAlH4 is unprecedented and most likely proceeds
by an organoaluminium intermediate, and in the proposed
9-hydroxyfluorenyl derivatives in good yields. This method- mechanism.
Introduction
Direct C–H bond functionalizations have attracted much
interest in recent years. Among them, benzylic oxidation is
one of the most studied for the conversion of alkylarenes
into their corresponding carbonyl compounds. Several tran-
sition-metal-catalyzed reactions have been developed for
benzylic oxidations with various complexes of Mo,[1] Mn,[2]
Co,[3] Fe,[4] Cu,[5] Ru,[6] Rh,[7] Pd,[8] Au,[9] and Bi.[10] Metal-
free oxidation processes with iodine[11] or organocatalyst[12]
species have also been reported.
As part of our ongoing work on the synthesis of inhibi-
tors of enoyl-acyl carrier protein (enoyl-ACP) reductase, we
required a convenient access to 3-(9H-fluoren-9-yl)pyrrol-
idine derivatives.[13] The use of LiAlH4 led to the unexpec-
ted minor product 9-(pyrrolidin-3-yl)-9H-fluoren-9-ol (1b)
in 11% yield (Scheme 1). The structure was confirmed by
X-ray analysis, and a hydrogen-bonding interaction was ob-
served between the hydroxy group at the C-9 position of
the fluorenyl moiety and the carbonyl group of the pyrrol-
idinone moiety.[14] An investigation of the reactivity of these
fluorenyl compounds toward LiAlH4 seems interesting as
they could provide access to 9-hydroxyfluorenes.
Scheme 1. Tandem reaction observed for the reduction of suc-
cinimide.
[a] CNRS; Laboratoire de Synthèse et Physico-Chimie de
Molécules d’Intérêt Biologique, SPCMIB, UMR-5068,
118 Route de Narbonne, 31062 Toulouse cedex 9, France
E-mail: lherbet@chimie.ups-tlse.fr
Furthermore, fluorenyl derivatives are important build-
ing blocks in functional materials[15] and pharmaceuti-
cals.[16] For example, 9-hydroxyfluorenes are useful interme-
diates to 9,9-diarylfluorenes by BF3·Et2O-mediated Frie-
del–Crafts reactions.[17] 9-Hydroxyfluorenes, especially,
could be considered valuable building blocks for the devel-
opment of analogues of mazindol (obesity) or ciclazindol
(antidepressant)[18] or for the elaboration of thrombin in-
hibitors, as described by Stauffer et al. (Figure 1).[19] In this
latter case, the authors showed that the hydroxy group con-
baltas@chimie.ups-tlse.fr
[b] Taras Shevchenko National University of Kyiv, Department of
Chemistry,
64 str. Volodymyrska, Kyiv 01033, Ukraine
[c] Université de Toulouse; UPS, Laboratoire de Synthèse et
Physico-Chimie de Molécules d’Intérêt Biologique, SPCMIB,
118 route de Narbonne, 31062 Toulouse cedex 9, France
[d] Institut de Chimie de Toulouse, FR2599,
118 Route de Narbonne, 31062 Toulouse, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402642.
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Tandem Reduction/Oxidation of Fluorenyl Derivatives
tributed significantly to the backbone binding of the inhibi- ities in the parent 3-(9H-fluoren-9-yl) succinimide deriva-
tor to thrombin.
tives. All reactions are easily performed and proceed with
good efficiency under very simple and mild conditions
without any catalysts to afford moderate-to-good yields of
the products; thus, time-consuming, costly syntheses are
avoided.
Results and Discussion
We investigated the reduction of 3-(9H-fluoren-9-yl)-1-
phenethylpyrrolidine-2,5-dione (2a) under various condi-
tions. As shown in Table 1, the oxidation was initially con-
ducted with 8 equiv. of LiAlH4 at 70 °C; after 20 h of reac-
tion, the fully reduced 9-hydroxyfluorene derivative 2b was
Figure 1. Mazindol and ciclazindol as 9-hydroxyfluorene analogues
and a thrombin inhibitor.
Fluoren-9-ol derivatives can be accessed in good yields isolated in 41% from a complex mixture of products
by the addition of a Grignard reagent to fluorenone or by (Table 1, Entry 1). The corresponding pyrrolidinone 2c was
a palladium-catalyzed ortho-arylation/ketone addition.[20] not identified. The amount of LiAlH4 had a clear effect on
The benzylic position can be readily oxidized under basic the yield of the reaction. Indeed, 2b was obtained in 79%
conditions through a carbanion mechanism proposed by yield or was present as traces with 4 or 2 equiv. LiAlH4,
Russell and Bemis.[21] A BuLi and O2 system, followed a respectively, under thermal conditions. In the latter case
reduction by NaBH4, can also afford the alcohols in two (2 equiv. LiAlH4; Table 1, Entry 3), a side product was ob-
steps.[22] More recently, the 9-position of fluorene was oxid- served and identified by NMR spectroscopy as the corre-
ized by KOH in tBuOH under an O2 atmosphere to afford sponding pyrrole derivative 2g along with the fully reduced
the corresponding alcohols in good yields.[23]
derivative 2d. In a similar way, Verniest and de Kimpe
Nowadays, tandem reactions in which several bonds are showed that succinimide derivatives could be reduced to
formed in sequence without the isolation of the different pyrrole by using 9-borabicyclo[3.3.1]nonane (9-BBN) as the
intermediates, the addition of reagents, or changes to the reducing agent.[24]
reaction conditions are very useful. In this paper, we de-
When the reaction was performed at room temperature,
scribe a tandem reaction that results in a new and unexpec- alcohol 2b was obtained in 33% yield after 26 h (Table 1,
ted oxidation to 9-hydroxyfluorene with LiAlH4 under an Entry 4). When the reaction was performed under nitrogen
air atmosphere during the reduction of carbonyl functional- and with heating, only trace amounts of the product were
Table 1. Reduction of succinimide 1a.
Entry
Conditions
Time [h]
Yield[a] [%]
1
2
3
4
5
6
7
8
LiAlH4 (8 equiv.), air, 4 °C to reflux
LiAlH4 (4 equiv.), air, 4 °C to reflux
LiAlH4 (2 equiv.), air, 4 °C to reflux
LiAlH4 (4 equiv.), air, 4 °C to room temp.
LiAlH4 (4 equiv.), N2, 4 °C to reflux
NaH (4 equiv.), air, 4 °C to reflux
NaH (1 equiv.), air, 4 °C to reflux
BH3·Me2S (5 equiv.), 4 °C to reflux
3
3
3
26
3
3
41 (2b)
79 (2b)
17 (fluorenone)/11 (2g)/15 (2d)
33 (2b)/mixture
Ͻ5 (2b)/75 (2d)
decomposition
n.r.[b]
3
1
59 (2e)/41 (2d)
[a] Isolated yields. [b] n.r.: no reaction.
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isolated; therefore, oxygen is essential for the reaction to was observed in the presence of 4 equiv. of NaH (Table 1,
occur (Table 1, Entry 5).[25] Control experiments showed Entries 6 and 7).
that no reaction occurred in the presence of 1 equiv. of
Finally, the reaction was performed in the presence of
NaH, and only the decomposition of the starting material BH3·Me2S to afford the corresponding mono- and di-
Table 2. Scope of the reaction.[a]
[a] Reaction conditions: fluorene derivative (0.27 mmol), LiAlH4 (1.08 mmol), tetrahydrofuran (THF); 4 °C, then reflux for 3 h. [b]
Isolated yields. [c] n.d.: not determined.
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Tandem Reduction/Oxidation of Fluorenyl Derivatives
reduced compounds 2e and 2d. No traces of oxidation were
1
observed (Table 1, Entry 8). The analysis of 2e by H and
13C NMR spectroscopy (multiplicity and chemical shifts of
the methylene groups) confirmed unambiguously that it was
the 2e regioisomer instead of the 2f, which has never been
detected.
To test the generality of the present method, various
fluorenyl compounds were investigated under our opti-
mized conditions (Table 2).
Fluorenyl compounds bearing substituted succinimide
moieties were totally reduced with concomitant oxidation
at the 9-position of the fluorenyl frame. The isolated prod-
uct yields were fairly good and varied between 45 and 79%,
except for those for the N-arylated compound 6a and the
fluorenyl succinimide derivative 1a. Only trace amounts of
6b were obtained, and 1b was isolated in 11% yield in a
complex mixture of unidentified compounds. Compounds
2e and 8a, obtained by reduction of the amide(s) bonds,
were also tested; the reactions in the presence of LiAlH4
(4 equiv.) afforded the 9-hydroxyfluorenyl compounds 2b
and 8b, respectively, in moderate yields (54 and 45%). The
structure of 8b was confirmed as an HCl salt by a single-
crystal X-ray diffraction analysis (Figure 2).
Finally, simple fluorenyl compounds were tested (9a–
11a). Under the studied conditions, the same fluorenyl di-
mer was isolated and identified, along with the hydroxyl-
ated fluorenyl compounds. The structure of this dimer was
confirmed by X-ray analysis and is comparable to the one
reported in the literature.[26] These dimeric molecules are
usually synthesized in two steps from 9-bromo-9H-fluor-
ene[17] or from 9-methyl-9H-fluorene with cobalt halide.[27]
Interestingly, 10a and 11a afforded the fluorenyl dimer with
complete reduction of the carboxylic and alcohol moieties,
respectively, to the corresponding methyl group.
Figure 2. Molecular view of (top) 9,9Ј-dimethyl-9H,9ЈH-9,9Ј-bi-
fluorene (fluorenyl dimer), (middle) the mixture of 9-[(9-methyl-
9H-fluoren-9-yl)methyl]-9H-fluoren-9-ol (9b) and 9-methyl-9H-
fluoren-9-ol (11b) as side products, and (bottom) 3-(9-hydroxy-9H-
fluoren-9-yl)-1-nonylpyrrolidinium chloride (8b·HCl). Thermal el-
Furthermore, the reaction with 11a afforded the fluor-
enyl dimer and a mixture of compounds. Two compounds
were eluted together from this mixture by flash column lipsoids are drawn at 50% probability, and hydrogen atoms are
omitted for clarity, except for H atoms bound to O or N (the crys-
tallographic data are provided in the Supporting information).
chromatography with silica and crystallized together to af-
ford the crystalline complex (9b + 11b), which was iden-
tified by X-ray analysis (Figure 2).[14] Interestingly, for 12a,
the corresponding diol 12b, of further interest to synthetic
and medicinal chemists, was isolated as the major product
in 57% yield and identified by analysis by mass spectrome-
1
try and H and 13C NMR spectroscopy.
Two dibenzylic systems were also investigated (7a and
13a). In contrast with the fluorenyl systems, neither of these
compounds was oxidized at the dibenzylic position. The
oxidation of diphenylmethylene derivatives 7a or 13a did
not occur mainly because of the difference of the pKa of
the hydrogen atom at the benzylic position.[28]
To probe the reaction mechanism, several experiments
were performed. Initially, the red coloration of the mixture
during the reaction (visible only during heating) suggests
the formation of an intermediate carbanion at C-9.[29] This
observation was confirmed by 13C NMR spectroscopy (Fig-
ure 3). The reaction was performed in an NMR tube with
Figure 3. 13C NMR spectra of the reaction performed in the pres-
9-methylfluorene in deuterated [D8]THF in the presence of
4 equiv. of LiAlH4. After 30 min, the 13C NMR spectrum ence of 9a in deuterated THF with 4 equiv. of LiAlH4.
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showed a chemical shift at δ = 87.1 ppm (δ = 86.9 ppm in mechanism with an intramolecular hydroalumination of the
ref.[30]), which is characteristic of a lithiated C-9 carbanion double bond. Furthermore, the two intermediates C1 and
species.
C2 could be considered in a mechanism similar to those
Further investigation revealed that an oxygen atmo- proposed for a Grignard reaction[32] or for the formation of
sphere facilitates the formation of the alcohol 9b (54%, dialkylaluminium alkoxide.[33] The last step is a hydrolysis
Scheme 2), and only traces of the dimer are observed. This reaction to afford the desired alcohol.
result is also to be compared with that obtained under air,
Considering the differences between 10a, 11a, and 12a, a
which afforded the dimer in 48% yield. In the presence of possible explanation could be the elimination reaction of
NaH (4 equiv.), instead of an aluminium species, the start- the alcohol formed from 10a or 11a to afford the dibenzo-
ing material was mainly recovered and isolated along with fulvene intermediate, which could be converted to anionic
the dimer (16%); compound 9b was not detected. Finally, 9a before dimerization. For 12a, the primary alcohol
under argon and in the presence of LiAlH4, the 9-methyl- formed cannot be eliminated; thus, it forms an Al complex
fluorene starting material was recovered in 71% yield along with the C-9 anionic form that leads to the diol 12b.
with the dimer (20% yield). The alcohol was mainly formed
The dimerization of 9a could be explained by a Wurtz-
in 7% yield during the reaction work-up (not detected by like coupling reaction.[34] Furthermore, Bradley et al. re-
thin-layer chromatography of the reaction mixture).
ported that the radical coupling of fluorene in the presence
of cobalt chloride afforded the fluorenyl dimer. It could be
interesting to obtain further insights into this reaction.[27]
Conclusions
A tandem reduction/oxidation reaction has been devel-
oped from an unexpected LiAlH4-mediated benzylic oxi-
dation in good yields. This method represents a straightfor-
ward and easy introduction of hydroxy groups at the C-9
position of fluorene with the tandem reduction of carbonyl
groups in the molecule. Efforts are underway to shed light
on the mechanism of LiAlH4-promoted oxidations, and we
are continuing to develop new transformations.
Scheme 2. Insights into the oxidation of fluorenyl derivatives.
Experimental Section
On the basis of the aforementioned results and previous
studies, a tentative mechanism for the reaction is proposed
with an initial formation of the carbanion A (Scheme 3).
Then, an organoaluminium intermediate (B) could be
formed and could be easily oxidized in the presence of oxy-
gen to form peroxide species (C1 and C2). There are pre-
cedents in the literature that support the viability of these
two steps. Csákÿ et al. showed the synthesis of 1,3-diols by
the reaction of α,β-unsaturated ketones with LiAlH4 in
General Information: All chemicals were obtained from Aldrich or
Acros Organics and used without further purification.
Caution: 9-Methylfluorene was purchased from Interchim and has
been shown to be mutagenic.[35]
Silica gel flash column chromatography was used to purify all of
the compounds. All of the reactions were monitored by TLC. Nu-
clear magnetic resonance spectra were recorded with a Bruker AC
300 spectrometer (1H and 13C NMR). H NMR spectra were re-
1
THF in a dry oxygen atmosphere.[31] They proposed a corded at 300 MHz by using CDCl3 (δ =7.26 ppm) as an internal
Scheme 3. Proposed mechanism for the oxidation of fluorenyl derivatives.
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Tandem Reduction/Oxidation of Fluorenyl Derivatives
1
standard. 13C NMR spectra were recorded at 75.0 MHz and are
referenced against the central line of the CDCl3 triplet at δ =
77.0 ppm. Coupling constants (J) are reported in Hertz and refer
to apparent peak multiplicities. The abbreviations s, d, t, q, and m
stand for singlet, doublet, triplet, quartet, and multiplet, respec-
tively. The mass spectrometry (MS) data were obtained with a
ThermoQuest TSQ 7000 spectrometer, and the high-resolution
mass spectra (HRMS) were data obtained with a ThermoFinnigan
MAT 95 XL spectrometer with electrospray ionization (ESI) meth-
ods. The melting points were recorded with a Mettler Toledo MP50
melting point system. The IR spectra were recorded with a
Thermo-Nicolet spectrometer equipped with a Diamond attenu-
ated total reflectance (ATR) accessory and a deuterated triglycine
sulfate (DTGS) detector. The data of the structures for 1b, 8b·HCl,
the fluorenyl dimer, and 9b/11b were collected with a Bruker-AXS
Quazar APEX II diffractometer by using a 30 W air-cooled micro-
focus source (ImS) with focusing multilayer optics (1b and 9b/11b)
and with a Bruker-AXS SMART APEX II diffractometer (8b·HCl
and dimer) at a temperature of 193(2)K with Mo-Kα radiation
(wavelength = 0.71073 Å) by using φ and ω scans. The data were
integrated with SAINT, and an empirical absorption correction
with SADABS was applied.[36] The structures were solved by direct
methods by using SHELXS-97[37] and refined by using the least-
squares method on F2.[37] All non-H atoms were treated anisotropi-
cally. All H atoms attached to C atoms were fixed geometrically
and treated as riding on their parent atoms with C–H = 0.95 (aro-
matic), 0.98 (CH3), 0.99 (CH2), or 1.0 Å (CH) and Uiso(H) =
1.2Ueq(CH, CH2) or Uiso(H) = 1.5Ueq(CH3). H atoms of O–H
groups (1b, 9b·HCl, and 10b/12b) were located in difference Fourier
maps.
3036, 2951, 1769, 1700, 1400, 1161 cm–1. H NMR (CDCl3): δ =
7.72 (t, J = 7.1 Hz, 2 H), 7.37 (m, 8 H), 6.87 (td, J = 7.6, 1.0 Hz,
2 H), 6.73 (d, J = 7.5 Hz, 1 H), 4.72 (d, J = 13.9 Hz, 1 H), 4.65 (d,
J = 3.6 Hz, 1 H), 4.61 (d, J = 13.9 Hz, 1 H), 3.65 (m, 1 H), 2.19
(dd, J = 18.6, 9.4 Hz, 1 H), 1.36 (dd, J = 18.6, 4.9 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 178.4, 175.6, 143.8, 141.9, 141.0, 140.8,
133.9, 133.88, 130.6, 128.7, 128.1, 127.9, 127.4, 127.2, 124.4, 123.5,
120.07, 120.05, 46.2, 42.6, 41.6, 29.1 ppm. HRMS [desorption
chemical ionization (DCI)]: calcd. for C24H18ClNO2 [M]+
388.1104; found 388.1096.
1-(2,2-Diphenylethyl)-3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione (7a):
White powder, yield (164 mg) 37%, m.p. 180.1 °C. IR (neat): ν =
˜
3066, 3029, 2921, 1598, 1494, 1403, 1152 cm–1. H NMR (CDCl3):
1
δ = 7.72 (m, 2 H), 7.35 (m, 14 H), 7.00 (td, J = 7.6, 1.1 Hz, 1 H),
6.79 (dd, J = 7.6, 0.7 Hz, 1 H), 4.78 (t, J = 8.3 Hz, 1 H), 4.65 (d,
J = 3.3 Hz, 1 H), 4.23 (m, 2 H), 3.51 (m, 1 H), 2.05 (dd, J = 18.3,
9.3 Hz, 1 H), 1.32 (dd, J = 18.4, 5.6 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 178.8, 176.2, 144.1, 141.8, 141.15, 141.07, 141.0,
128.61, 128.59, 128.2, 128.1, 128.0, 127.9, 127.6, 127.4, 127.0,
126.9, 124.3, 123.6, 120.12, 120.09, 48.0, 45.9, 43.3, 42.9, 29.0 ppm.
HRMS (DCI): calcd. for C31H25NO2 [M]+ 444.1964; found
444.1976.
1-(2,2-Diphenylethyl)pyrrolidine-2,5-dione (13a): Yellow powder,
yield (210 mg) 75%, m.p. 133.3 °C. IR (neat): ν = 3067, 3024, 2934,
˜
1693, 1409, 1165 cm–1. 1H NMR (CDCl3): δ = 7.20–7.29 (m, 10
H), 4.68 (t, J = 8.5 Hz, 1 H), 4.13 (d, J = 8.5 Hz, 2 H), 2.47 (s, 4
H) ppm. 13C NMR (CDCl3): δ = 176.9, 140.9, 128.5, 128.1, 126.9,
47.6, 43.0, 27.8 ppm. HRMS (TOF-MS, Cl+): calcd. for
C18H18NO2 [M + H]+ 280.1338; found 280.1331.
Typical Procedure for the Synthesis of Pyrrolidine Derivatives with
BH3·Me2S: Compound 2a (100 mg, 0.27 mmol, 100 mol-%) was
dissolved in dry THF (15 mL), and the solution was cooled to 4 °C
with an ice bath. Thereafter, a solution of borane complex
(BH3·Me2S, 1.4 mmol, 0.14 mL, 10 m in THF) was added dropwise
in 10 min. Then, the mixture was heated to reflux for 1 h and
cooled to room temperature. The excess BH3 was eliminated by the
slow dropwise addition of MeOH (2–3 mL). Then, the solvent was
removed under reduced pressure. The residue was dissolved in
MeOH (8–10 mL), and hydrochloric acid was added (37% HCl,
3 mL). The resulting mixture was heated to reflux for 3 h, and the
solvent was then evaporated. The residue was slowly dissolved in a
saturated solution of sodium hydrogen carbonate (NaHCO3, 20–
30 mL) to low basic pH. The solution was extracted with EtOAc
(3ϫ 15 mL), and the combined organic layers were dried with
Na2SO4. After removal of the solvent under reduced pressure, the
crude product was purified by flash chromatography [petroleum
ether/ethyl acetate (PE/ethyl acetate)].
Procedure for the Synthesis of Succinimide Derivatives: The suc-
cinimide derivatives were prepared from the corresponding diacid
(1 mmol) according to a recently published procedure.[13] The ana-
lytical data for 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione (1a), 1-
benzyl-3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione (4a), and 1-(3,5-
dichlorophenyl)-3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione (6a) are
comparable to those previously reported.
3-(9H-Fluoren-9-yl)-1-phenethylpyrrolidine-2,5-dione (2a): White
powder, yield (232 mg) 63%, m.p. 130.9 °C. IR (neat): ν = 3038,
˜
2946, 1771, 1699, 1401, 1150 cm–1. 1H NMR (CDCl3): δ = 7.77 (d,
J = 7.6 Hz, 2 H), 7.49 (d, J = 7.4 Hz, 1 H), 7.22–7.45 (m, 8 H),
7.21 (m, 2 H), 4.77 (d, J = 3.6 Hz, 1 H), 3.88 (t, J = 7.8 Hz, 2 H),
3.69 (m, 1 H), 3.01 (m, 2 H), 2.21 (dd, J = 18.4, 9.1 Hz, 1 H), 1.43
(dd, J = 18.5, 5.2 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 178.7,
175.9, 144.1, 142.0, 141.2, 141.1, 137.6, 128.7, 128.5, 128.3, 127.9,
127.5, 127.4, 126.7, 124.5, 123.6, 120.3, 120.2, 46.1, 42.9, 40.0, 33.6,
29.2 ppm. HRMS (TOF-MS, Cl+): calcd. for C25H22NO2 [M +
H]+ 368.1651; found 368.1652.
3-(9H-Fluoren-9-yl)-1-phenethylpyrrolidine (4b): Colorless oil, yield
(47 mg) 59%. IR (neat): ν = 3061, 3026, 2924, 2852, 1449 cm–1. 1H
3-(9H-Fluoren-9-yl)-1-(4-methoxyphenethyl)pyrrolidine-2,5-dione
(3a): White powder, yield (183 mg) 46%, m.p. 142.7 °C. IR (neat):
˜
NMR (300 MHz, CDCl3): δ = 7.74–7.77 (m, 2 H), 7.52–7.60 (m, 2
H), 7.08–7.40 (m, 9 H), 4.05 (d, J = 5.4 Hz, 1 H), 2.58–3.00 (m, 7
H), 2.36–2.43 (m, 2 H), 1.92–2.05 (m, 1 H), 1.63–1.74 (m, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 146.3, 146.2, 141.53, 141.48,
140.8, 140.4, 128.8, 128.5, 127.33, 127.32, 127.0, 126.9, 126.2,
125.4, 125.1, 119.92, 119.88, 58.4, 57.9, 54.3, 50.1, 41.7, 35.5, 28.1
ppm. HRMS (TOF-MS, Cl+): calcd. for C25H26N [M + H]+
340.2065; found 340.2065.
ν = 3004, 2948, 1695, 1515, 1148 cm–1. 1H NMR (CDCl ): δ = 7.76
˜
3
(d, J = 7.6 Hz, 2 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.31–7.44 (m, 3 H),
7.18 (m, 4 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.71 (d, J = 3.6 Hz, 1 H),
3.81 (s, 3 H), 3.78 (t, J = 7.9 Hz, 2 H), 3.64 (m, 1 H), 2.88 (m, 2
H), 2.17 (dd, J = 18.5, 9.1 Hz, 1 H), 1.37 (dd, J = 18.5, 5.2 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = 178.9, 176.1, 158.5, 144.2, 142.2,
141.3, 141.2, 129.9, 129.8, 128.4, 128.0, 127.7, 127.6, 124.7, 123.8,
120.4, 120.3, 114.0, 55.3, 46.2, 43.1, 40.3, 32.8, 29.3 ppm. HRMS
(TOF-MS, Cl+): calcd. for C26H24NO3 [M + H]+ 398.1756; found
398.1754.
3-(9H-Fluorene-9-yl)-1-phenethyl-2-pyrrolidin-2-one (5b): White
amorphous solid, yield (39 mg) 41%, m.p. 138.1 °C. IR (neat): ν =
˜
1
3057, 3032, 2933, 1685, 1268 cm–1. H NMR (300 MHz, CDCl3):
1-(4-Chlorobenzyl)-3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione (5a): δ = 7.73–7.76 (m, 2 H), 7.19–7.50 (m, 11 H), 4.66 (d, J = 3.6 Hz,
Yellow powder, yield (268 mg) 69%, m.p. 167.7 °C. IR (neat): ν = 1 H), 3.56–3.74 (m, 2 H), 3.37 (td, J = 3.6, 9.0, 12.6 Hz, 1 H), 2.82–
˜
Eur. J. Org. Chem. 2014, 6538–6546
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6543

C. Lherbet, M. Baltas, et al.
FULL PAPER
3.07 (m, 3 H), 2.74 (td, J = 3.3, 9.3, 12.6 Hz, 1 H), 1.41–1.52 (m,
7.57 (d, J = 7.4 Hz, 2 H), 7.50 (d, J = 7.4 Hz, 1 H), 7.44 (d, J =
1 H), 0.70–0.83 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 7.5 Hz, 1 H), 7.34 (t, J = 7.4 Hz, 2 H), 7.24 (t, J = 7.5 Hz, 2 H),
175.3, 145.9, 143.6, 142.2, 141.4, 138.8, 128.8, 128.7, 127.6, 127.4,
127.3, 127.2, 126.6, 125.6, 123.9, 119.9, 119.8, 47.1, 46.0, 45.5, 44.4,
34.0, 18.7 ppm. HRMS (TOF–MS, Cl+): calcd. for C25H24NO [M
+ H]+ 354.1858; found 354.1842.
7.05 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 3.76 (s, 3 H),
3.63 (m, 1 H), 2.68–3.12 (m, 8 H), 2.51 (m, 1 H), 1.89 (m, 2 H)
ppm. 13C NMR (CDCl3): δ = 158.3, 147.9, 147.6, 139.5, 139.4,
129.5, 129.2, 127.9, 127.8, 124.3, 124.0, 120.0, 114.0, 82.2, 57.5,
55.22, 55.20, 53.8, 46.3, 32.3, 25.2 ppm. HRMS (DCI): calcd. for
C26H28NO2 [M + H]+ 386.2120; found 386.2112.
3-(9H-Fluoren-9-yl)-1-nonylpyrrolidine (8a): Flash chromatography
(PE/Et O = 8:2). Brown oil, yield (53 mg) 54%. IR (neat): ν = 3059,
˜
2
3033, 2956, 2923, 2850, 2793, 1447 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.65 (d, J = 7.2 Hz, 2 H), 7.43–7.51 (m, 2 H), 7.16–
7.29 (m, 4 H), 3.93 (d, J = 5.1 Hz, 1 H), 2.65–2.84 (m, 3 H), 2.15–
2.35 (m, 4 H), 1.80–1.92 (m, 1 H), 1.50–1.62 (m, 1 H), 1.30–1.40
(m, 2 H), 1.13–1.23 (m, 12 H), 0.79 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 146.4, 146.2, 141.5, 141.4, 127.2,
127.1, 126.9, 126.8, 125.4, 125.1, 119.8, 119.7, 57.9, 56.8, 54.2, 50.2,
41.6, 32.0, 29.7, 29.6, 29.4, 28.9, 28.1, 27.7, 22.8, 14.2 ppm. HRMS
(DCI): calcd. for C26H36N [M]+ 362.2848; found 362.2838.
9-(1-Benzylpyrrolidin-3-yl)-9H-fluoren-9-ol (4b): Yellow powder,
yield (43 mg) 46%, m.p. 72.3 °C. IR (neat): ν = 3297, 3060, 2921,
˜
1
1611, 1513, 1448, 1247 cm–1. H NMR (CDCl3): δ = 7.59 (d, J =
7.5 Hz, 2 H), 7.49 (t, J = 6.5 Hz, 2 H), 7.35 (tt, J = 7.5, 1.3 Hz, 2
H), 7.22–7.29 (m, 7 H), 3.61 (d, J = 12.9 Hz, 1 H), 3.44 (d, J =
12.9 Hz, 1 H), 2.91 (m, 1 H), 2.63 (m, 3 H), 2.35 (m, 1 H), 1.70
(m, 2 H) ppm. 13C NMR (CDCl3): δ = 148.7, 148.1, 139.7, 139.6,
138.1, 128.95, 128.91, 128.86, 128.2, 127.8, 127.6, 127.1, 124.8,
124.1, 119.8, 119.7, 83.3, 59.9, 55.2, 53.6, 46.3, 25.8 ppm. HRMS
(DCI): calcd. for C24H24NO [M + H]+ 342.1858; found 342.1857.
Typical Procedure for the Oxidation of Fluorenyl Derivatives 1a–
13a, 5b with LiAlH4: Pyrrolidine-2,5-dione (100 mg, 0.27 mmol,
100 mol-%) was added to a cooled solution of LiAlH4 (100–
400 mol-%, see Table 1) in anhydrous THF (5 mL). Then, the re-
sulting slurry was heated to reflux for 3 h. The resulting mixture
was cooled to room temperature, and wet THF was added slowly.
The solvent was removed under reduced pressure. Purification of
the product by flash chromatography (gradient, CH2Cl2/MeOH
100:0 to 80:20) provided the desired compounds.
9-[1-(4-Chlorobenzyl)pyrrolidin-3-yl]-9H-fluoren-9-ol (5b): Yellow
powder, yield (67 mg) 66%. IR (neat): ν = 3062, 2958, 2920, 2803,
˜
1491, 1448, 736 cm–1. 1H NMR (CDCl3): δ = 7.58 (dd, J = 7.3,
2.7 Hz, 2 H), 7.48 (d, J = 7.3 Hz, 2 H), 7.35 (tdd, J = 7.4, 3.5,
1.1 Hz, 2 H), 7.21–7.29 (m, 4 H), 7.10 (d, J = 8.4 Hz, 2 H), 3.50
(d, J = 13.1 Hz, 1 H), 3.32 (d, J = 13.1 Hz, 1 H), 2.89 (m, 1 H),
2.58 (br s, 1 H), 2.49 (m, 3 H), 2.28 (m, 1 H), 1.68 (m, 2 H) ppm.
13C NMR (CDCl3): δ = 148.6, 148.2, 139.72, 139.66, 137.4, 132.5,
130.0, 128.9, 128.8, 128.2, 127.8, 127.6, 125.5, 124.7, 124.2, 119.74,
119.70, 83.4, 59.3, 55.3, 53.9, 46.3, 25.9 ppm. HRMS (DCI): calcd.
for C24H22NOCl [M]+ 375.1390; found 375.1387.
The 1H and 13C NMR spectroscopic data for the fluorenyl dimer[26]
and 9b[29] matched those previously reported.
3-(9-Hydroxy-9H-fluoren-9-yl)pyrrolidin-2-one (1b): Yellow solid,
9-[1-(2,2-Diphenylethyl)pyrrolidin-3-yl]-9H-fluoren-9-ol (7b): Brown
m.p. 122–124 °C (dec.), yield (8 mg) 11%. IR (neat): ν = 3389,
˜
3195, 2901, 1671, 1449, 1297 cm–1. 1H NMR (CDCl3): δ = 7.54–
7.64 (m, 4 H), 7.23–7.40 (m, 4 H), 6.20 (br s, 1 H), 6.17 (br s, 1
H), 3.31 (t, J = 9.5 Hz, 1 H), 3.14 (m, 1 H), 2.88 (td, J = 9.4,
2.2 Hz, 1 H), 1.66 (m, 1 H), 1.00 (m, 1 H) ppm. 13C NMR (CDCl3):
δ = 179.8, 146.6, 146.0, 140.8, 139.9, 129.4, 129.3, 128.4, 128.3,
123.8, 120.1, 119.9, 82.8, 47.6, 40.1, 22.8 ppm. HRMS (DCI):
calcd. for C17H15NO2 [M]+ 265.1103; found 265.1104.
gummy solid, yield (67 mg) 58%. IR (neat): ν = 3271, 3060, 3027,
˜
258, 2926, 2792, 1734, 1449, 1243 cm–1. 1H NMR (CDCl3): δ =
7.56 (m, 2 H), 7.15–7.39 (m, 15 H), 7.12 (td, J = 7.5, 1.1 Hz, 1 H),
4.25 (m, 1 H), 3.17 (m, 1 H), 3.02 (m, 1 H), 2.82 (m, 2 H), 2.47–
2.64 (m, 3 H), 1.67 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 148.6,
147.8, 139.5, 128.88, 128.85, 128.50, 128.48, 128.1, 127.9, 127.67,
127.65, 126.4, 124.8, 124.0, 119.8, 119.7, 83.1, 61.2, 55.9, 54.6, 49.9,
46.2, 25.5 ppm. HRMS (DCI): calcd. for C31H30NO [M + H]+
432.2327; found 432.2334.
9-(1-Phenethylpyrrolidin-3-yl)-9H-fluoren-9-ol (2b): Gummy solid,
yield (76 mg) 79% from 1a, 54% from 1g. IR (neat): ν = 3235,
˜
3058, 2924, 2805, 1673, 1448 cm–1. 1H NMR (CDCl3): δ = 7.57 (d,
J = 7.3 Hz, 2 H), 7.52 (d, J = 7.5 Hz, 1 H), 7.47 (d, J = 7.4 Hz, 1
H), 7.33 (t, J = 7.3 Hz, 2 H), 7.16–7.29 (m, 5 H), 7.13 (d, J =
7.5 Hz, 2 H), 3.95 (br s, 1 H), 2.70 (m, 4 H), 2.54 (m, 3 H), 2.21
(m, 1 H), 1.71 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 148.7, 148.4,
139.8, 139.55, 139.52, 128.85, 128.83, 128.5, 128.3, 127.7, 127.6,
126.0, 124.5, 124.1, 119.8, 119.7, 82.7, 57.7, 55.4, 53.9, 46.3, 34.5,
25.5 ppm. HRMS (DCI): calcd. for C25H26NO [M+ H]+ 356.2014;
found 356.2027.
9-(1-Nonylpyrrolidin-3-yl)-9H-fluoren-9-ol (8b): Gummy solid, yield
(46 mg) 45%. IR (neat): ν = 3220, 2926, 2853, 1449 cm–1. 1H NMR
˜
(CDCl3): δ = 7.57 (d, J = 7.4 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 2 H),
7.34 (t, J = 7.5 Hz, 2 H), 7.24 (t, J = 7.4 Hz, 2 H), 3.22 (t, J =
8.6 Hz, 1 H), 3.08 (m, 1 H), 2.95 (m, 1 H), 2.78 (t, J = 10.0 Hz, 1
H), 2.56 (m, 3 H), 1.90 (m, 2 H), 1.55 (m, 2 H), 1.21 (m, 12 H),
0.86 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 147.8, 147.4,
139.4, 139.3, 129.3, 129.2, 127.9, 127.8, 124.3, 123.9, 120.1, 120.0,
82.0, 55.7, 54.8, 53.3, 46.2, 31.7, 29.3, 29.1, 29.0, 26.9, 26.1, 25.0,
22.6, 14.0 ppm. HRMS (DCI): calcd. for C26H36NO [M + H]+
378.2797; found 378.2794.
3-(9H-Fluoren-9-yl)-1-phenethyl-1H-pyrrole (7b): Colorless oil,
1
yield (10 mg) 11%. IR (neat): ν = 3062, 2924, 1497, 1449 cm–1. H
˜
9-(2-Hydroxyethyl)-9H-fluoren-9-ol (12b): Yellow oil, yield (35 mg)
NMR (CDCl3): δ = 7.77 (d, J = 7.3 Hz, 2 H), 7.44 (d, J = 7.6 Hz,
2 H), 7.36 (t, J = 7.5 Hz, 2 H), 7.22–7.30 (m, 5 H), 7.04 (dd, J =
7.3, 2.1 Hz, 2 H), 6.53 (t, J = 2.4 Hz, 1 H), 6.37 (m, 1 H), 5.95 (m,
1 H), 4.99 (s, 1 H), 4.01 (t, J = 7.3 Hz, 2 H), 3.00 (t, J = 7.4 Hz, 2
H) ppm. 13C NMR (CDCl3): δ = 148.3, 140.6, 138.5, 128.7, 128.5,
127.0, 126.8, 126.5, 125.2, 122.6, 120.6, 119.7, 118.5, 107.8, 51.2,
47.0, 38.3 ppm. HRMS (DCI): calcd. for C25H21N [M]+ 335.1674;
found 335.1339.
57%. IR (neat): ν = 3332, 3064, 2927, 1477 cm–1. 1H NMR
˜
(CDCl3): δ = 7.62 (d, J = 7.6 Hz, 2 H), 7.57 (d, J = 7.5 Hz, 2 H),
7.37 (td, J = 7.4, 1.3 Hz, 2 H), 7.31 (td, J = 7.4, 1.4 Hz, 2 H), 3.72
(t, J = 6.0 Hz, 2 H), 2.53 (br s, 2ϫ1 H), 2.23 (t, J = 6.0 Hz, 2 H)
ppm. 13C NMR (CDCl3): δ = 148.4, 139.0, 129.1, 128.0, 124.0,
120.1, 82.5, 60.1, 41.0 ppm. HRMS (DCI): calcd. for C15H14O2
[M]+ 226.0984; found 226.0984.
9-[1-(4-Methoxyphenethyl)pyrrolidin-3-yl]-9H-fluoren-9-ol
(3b):
1-(2,2-Diphenylethyl)pyrrolidine (13b): Brownish gummy solid, yield
Brown powder, yield (77 mg) 74%, m.p. 115.2 °C. IR (neat): ν =
(68 mg) 91%. IR (neat): ν = 3060, 3025, 2961, 2926, 2784, 1493,
˜
˜
1
1
3292, 3039, 2925, 1611, 1448, 1247 cm–1. H NMR (CDCl3): δ = 1451 cm–1. H NMR (CDCl3): δ = 7.20–7.34 (m, 10 H), 4.26 (t, J
6544
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6538–6546

Tandem Reduction/Oxidation of Fluorenyl Derivatives
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CCDC-988728 (for 1b), -988729 (for 8b·HCl), -988728 (for di-
mer), and -988731 (for 9b/11b) contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
= 7.5 Hz, 2 H), 3.18 (d, J = 7.5 Hz, 2 H), 2.55 (m, 4 H), 1.73 (m,
4 H) ppm. 13C NMR (CDCl3): δ = 143.8, 128.4, 128.0, 126.2, 61.7,
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Detection of Carbanion Intermediate by 13C NMR Spectroscopy: A
solution of 9-methyl-9H-fluorene (50 mg, 0.28 mmol) in [D8]THF
(500 μL) was introduced into an NMR tube and cooled to 4 °C.
Then, LiAlH4 (21 mg, 200 mol-%) was added slowly. The NMR
tube was heated to 50 °C until the appearance of a red color and
then cooled to room temperature. The carbanion intermediate was
observed by 13C NMR spectroscopy.
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Oxidation of 9-Methyl-9H-fluorene (9a) with O2 and LiAlH4: 9-
Methyl-9H-fluorene (53 mg, 0.29 mmol, 100 mol-%) was added to
a cooled solution of LiAlH4 (200 mol-%) and (2,2,6,6-tetrameth-
ylpiperidin-1-yl)oxidanyl (TEMPO, 120 mol-%) in anhydrous THF
(5 mL). The resulting slurry was heated for 10 min until the appear-
ance of a red color. Then, oxygen (balloon) was bubbled directly
into the reaction mixture for 5 min until the red color changed to
grey. The resulting mixture was cooled to room temperature, and
wet THF was added slowly. The solvent was removed under re-
duced pressure. Purification of the product by flash chromatog-
raphy (gradient, CH2Cl2/MeOH 100:0 to 80:20) provided the de-
sired compounds.
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Acknowledgments
The authors are grateful to the Ministère de l’Enseignement et de
la Recherche Scientifique and the Centre National de la Recherche
Scientifique (CNRS) for financial support. T. M. was supported by
the French Embassy in Kiev, Ukraine. The investigations have been
performed within the framework of the Groupement Franco-
Ukrainien en Chimie Moléculaire (GDRI) between UPS, Toulouse
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