Halogen-Adjusted Chemoselective Synthesis of Fluorene Derivatives with Position-Controlled Substituents

Article abstract of DOI:10.1002/asia.201501135

Fluorenes have been synthesized through an efficient novel Pd-catalyzed tandem cross-coupling reaction; these substrates are fascinating building blocks found in organic photoelectric materials. The position of the substituent on fluorenes could be conveniently tuned by changing the halogen in the ortho-halobenzyl bromide substrates when coupled with various arylboronic acids. This newly developed synthetic approach could achieve the potential diversity in fluorene-based molecular architectures.

Full text of DOI:10.1002/asia.201501135

DOI: 10.1002/asia.201501135
Communication
CÀH Functionalization
Halogen-Adjusted Chemoselective Synthesis of Fluorene
Derivatives with Position-Controlled Substituents
Juan Song,*[a] Wei Sun,[a] Yali Li,[a] Fuliang Wei,[a] Chao Liu,*[b] Yan Qian,[a] and Shufen Chen[a]
of fluorenes by transition-metal-mediated cyclizations through
Abstract: Fluorenes have been synthesized through an ef-
ficient novel Pd-catalyzed tandem cross-coupling reaction;
a CÀH bond activation protocol is more attractive.[5] A chemical
bond can be formed through an intramolecular cyclization by
these substrates are fascinating building blocks found in
Pd catalysis, as demonstrated by the research groups of Chang
organic photoelectric materials. The position of the sub-
and Wu, who showed that intramolecular CÀH benzylation and
stituent on fluorenes could be conveniently tuned by
intramolecular benzylic CÀH arylation could be achieved, re-
changing the halogen in the ortho-halobenzyl bromide
spectively.[6] In comparison, the direct intermolecular reaction
substrates when coupled with various arylboronic acids.
that allows construction of two single bonds of the central five
This newly developed synthetic approach could achieve
membered ring would be more appealing. The tandem-type
the potential diversity in fluorene-based molecular archi-
coupling reaction has several advantages over the intramolec-
tectures.
ular cyclization, such as readily commercially available sub-
strates, step economy, increase of molecular complexity with
minimized isolation and so forth. Hu and co-workers have re-
Fluorene is a non-alternant polycyclic aromatic hydrocarbon
(PAH) that is an important building block in material science.
Owing to the additional methylene carbon that prevents for-
mation of an aromatic system, fluorene can facilely be func-
tionalized with different side groups at its 9-position[1] or copo-
lymerized with other conjugated units in the aromatic ring.[2]
Therefore, providing more opportunities to adjust the optoe-
lectronic performances. Its derivatives, including polymers and
oligomers, have been widely used in organic light-emitting
diodes (OLEDs), polymer light-emitting diodes (PLEDs), solar
cells, fuel cells, memory devices and so on.[3] In this context,
the fundamental synthesis of the fluorene skeleton is impor-
tant for the development of more structure-diversified fluo-
rene-containing materials.
ported a tandem-type coupling reaction of 1,2-dihalobenzenes
with 2,6-dimethylphenylmagnesium bromide[7] or 2-tolylboron-
ic acid[8] in which benzylic CÀH bond activation is the key
point for the successful cyclization (Scheme 1). In Hu’s ap-
proach, 1,2-dihalobenzenes acted as the electrophile, which
Scheme 1. Design for the construction of fluorene.
The classic synthetic methods for fluorene compounds
mainly rely on the reduction of fluoren-9-ones, which are usu-
ally obtained through the traditional Friedel–Crafts acylation
reaction under excess amounts of Lewis acid.[4] However, the
ring-closure strategy to construct the key five-membered ring
contained two electrophilic reaction sites on aromatic rings
and correspondingly, ortho-methyl substituted organometallic
compounds as the nucleophile that provided two nucleophilic
sites (aryl carbon-metal bond and benzylic CÀH bond). First,
the 2-methyl-2’-palladabiphenyl intermediate was formed, and
this then underwent cyclization through benzylic CÀH bond
activation. Alternatively, we supposed whether we can switch
the nucleophilic sites and the electrophilic sites by using o-hal-
obenzyl bromide as the electrophile, arylboronic acid as the
nucleophile for a tandem-type coupling reaction for the prepa-
ration of fluorenes. o-Halobenzyl bromide and arylboronic acid
were easily obtained compounds and we expected to obtain
different fluorenes by adjusting the halogen. In this case, as
the benzylic CÀX and the aromatic CÀX have obviously differ-
ent reactivity, we envisioned that the chemoselectivity can be
easily controlled by adjusting the halogens. Herein, we report
our newly developed, halogen-adjusted chemoselective syn-
[a] Dr. J. Song, W. Sun, Y. Li, F. Wei, Dr. Y. Qian, Prof. S. Chen
Key Laboratory for Organic Electronics and Information Displays
Institute of Advanced Materials
Nanjing University of Posts and Telecommunications
Nanjing, 210023 (P. R. China)
E-mail: iamjsong@njupt.edu.cn
[b] Prof. C. Liu
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Suzhou Research Institute of LICP
Lanzhou Institute of Chemical Physics (LICP)
Chinese Academy of Sciences
Lanzhou, 730000 (P. R. China)
E-mail: chaoliu@licp.cas.cn
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/asia.201501135.
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Scheme 2. A new palladium-catalyzed tandem-type coupling reaction designed for the preparation of fluorenes.
thesis of fluorene derivatives with position-controlled substitu-
Table 1. Palladium-catalyzed tandem cross-coupling reaction of o-bromo-
benzyl bromide with 4-fluorophenylboronic acid.[a]
ents.
In our design, o-halobenzyl bromide was employed as the
electrophilic coupling partner with two reactive sites and
simple, readily commercially available arylboronic acid as the
nucleophile (Scheme 2). The challenge in this tandem reaction
lies in that both the arylic CÀX bond and benzylic CÀBr bond
are reactive chemical bonds in Pd-catalyzed reactions that
might form two different intermediates such as benzylpalladi-
um intermediate (Scheme 2I) or arylpalladium intermediate
(Scheme 2II). These two intermediates lead to different cycliza-
tion products through a CÀH activation process (Scheme 2,
path A and path B), or cross-coupling with arylboronic acid to
afford a double coupling product. This indicates that, firstly, we
should develop a new catalyst system with not only high cata-
lyst activity but also selectivity and, it is also an opportunity
that, by changing the reactivity of arylic CÀX, we may realize
the synthesis of fluorene derivatives with position-controlled
substituents (Scheme 2).
Entry
Base
Additives
Solvent
T [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
K2CO3/PivOH
K2CO3/PivOH
K2CO3/PivOH
Cs2CO3/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
N/A
N/A
N/A
N/A
N/A
N/A
N/A
KBr
KI
KCl
LiCl
LiCl
DMA
NMP
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
120
120
120
120
120
80
trace
trace
44
25
61
50
46
65
42
59
69
73
88 (86[e]
)
60
120
120
120
120
120
120
9
In our initial investigations, o-bromobenzyl bromide (1) and
4-fluorophenyl-boronic acid (2a) were selected as the model
substrates. Solvent screening experiments were firstly carried
out (Table 1, entries 1–3) at 1208C, together with Pd(OAc)2 as
the catalyst, PCy3 as the ligand and K2CO3/PivOH as the base.
Interestingly, the corresponding fluorofluorene 3a was indeed
obtained as the desired product with THF as the solvent
(44%), and only a trace amount of the diarylation coupling
product was observed together with a significant amount of
side product 4. As shown in Scheme 2, two isomers 2-fluoro-
fluorene or 3-fluorofluorene could be formed in the reaction.
2-Fluorofluorene and 3-fluorofluorene are known compounds
and were easily identified with 13C NMR spectroscopy. In the
13C NMR spectrum of 2-fluorofluorene, the 9-methylene peak
at the meta-position to the fluorine split into a doublet. While,
in 3-fluorofluorene, the 9-methylene at the para-position of
the fluorine exhibited a singlet. By carefully analyzing the
13C NMR spectrum of compound 3a, it was determined to be
2-fluorofluorene, as an obvious doublet peak at 37.0 ppm with
a coupling constant of 2.5 Hz was observed, which is consis-
tent with the reported data.[6] The formation of 2-fluorofluor-
10
11
12[c]
13[c,d]
LiCl/4 Š MS
[a] Reaction conditions:
1
(0.3 mmol, 1.0 equiv), 2a (0.45 mmol,
1.5 equiv), Pd(OAc)2 (3 mol%), PCy3 (6 mol%), base (1.8 mmol, 6.0 equiv),
PivOH (0.3 mmol, 1.0 equiv), additive (0.45 mmol, 1.5 equiv), solvent
(2 mL). [b] Yields were determined by 1H NMR spectroscopy. [c] PivOH
(0.24 mmol, 0.8 equiv). [d] 4 Š MS (200 mg), THF (5 mL). [e] Yield of isolat-
ed product. [f] DMA=N,N-Dimethylacetamide, NMP=1-Methyl-2-pyrroli-
dinone, THF=Tetrahydrofuran.
K3PO4 was superior to K2CO3 and Cs2CO3 (Table 1, entries 3–5).
Additionally, using K3PO4/PivOH as the base, the reaction was
obviously sluggish at a lower temperature (Table 1, entries 5–
7). We reasoned that K3PO4 was not strong enough efficiently
promote the nucleophilic substitution by pivalate and thus im-
prove the efficacy of CÀH activation.[8] Unfortunately, no satis-
fied result was observed in the further efforts to optimize the
reaction conditions and the formation of trimethylacetate 4 in
the reaction was the primary cause of these moderate yields. It
ene showed that the aromatic CÀBr bond coupled with the CÀ was obvious that the active benzylic CÀBr bond was suscepti-
B bond in this case.
ble to nucleophilic attack by PivOÀ under alkaline conditions.
We found that the addition of LiCl together with a reduction
in PivOH to 0.8 equivalents could improve the yield of product
Further optimization showed that when K2CO3 was replaced
by K3PO4 or Cs2CO3 in the reaction system, it was found that
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3a to 73% and minimized the formation of the byproduct 4
(Table 1, entry 12). Moreover, the yield of the desired product
3a was remarkably improved to 88% when 4 Š molecular
sieves (MS) were introduced to the reaction system (Table 1,
entry 13). Based on the above results, the optimal reaction
conditions were concluded as follows: Pd(OAc)2 (3 mol%), PCy3
(6 mol%), bromobenzyl bromide (1.0 equiv), 4-fluorophenyl-
boronic acid (1.5 equiv), K3PO4 (6 equiv), PivOH (0.8 equiv), LiCl
(1.5 equiv) and 4 Š MS (200 mg) in THF (5 mL) at 1208C for
12 h.
higher than those with electron-donating groups (3c, 3d and
3e); this indicated a weak electronic effect in the reaction.
When o-substituted arylboronic acids were employed in the re-
action, 4-substituted fluorenes were obtained accordingly and
the yield of the products were slightly lower (3g and 3h) be-
cause of the steric hindrance. However, when m-substituted ar-
ylboronic acids were used, a mixture of two regioisomers (1-
and 3-substituted fluorenes) was observed that were difficult
to separate (3i and 3j). However, it is interesting to note that
by using 3,5-difluorophenylboronic acid as a substrate, 1,3-di-
fluorofluorene was synthesized in excellent yield of 98% (3k).
In the cross-coupling reaction, coupling a thiophene boronic
acid/ester with an aryl bromide was always thought to be
a challenge. In this palladium-catalyzed tandem coupling reac-
tion, 3-thiophene-boronic acid was chosen to react with o-bro-
mobenzylic bromide and the reaction smoothly proceeded to
give the product 3m in 69% yield, but under the same reac-
tion conditions, almost no desired product (3l) was detected
when 2-thiophene-boronic acid was employed (Scheme 3).
Obviously, when o-bromobenzyl bromide was employed as
the substrate, based on the position of substituents in the final
products, a putative reaction mechanism could be depicted in
Scheme 4. The cross-coupling reaction of aromatic CÀBr bond
with arylboronic acid took place first and generated 2-arylben-
zyl bromide, followed by an oxidative addition of benzylic CÀ
Br bond to form intermediate C. At the last stage, intermediate
C underwent a cyclization proceeding through a CÀH activa-
tion process to afford the desired product (Scheme 4, path A).
According to this proposal, it can be concluded that the cou-
pling of the aromatic CÀBr bond was more reactive than that
of benzylic CÀBr bond in the current tandem coupling reac-
tion. With this consideration, we wondered whether using the
less-active aromatic CÀCl bond could favor the Suzuki coupling
reaction of benzylic CÀBr. If this postulation was feasible, we
could then deduce that the reaction would be initiated by an
oxidative addition of the benzylic CÀBr bond into the Pd0
center to generate an intermediate B, which can couple with
the arylboronic acid to form the diarylmethane intermediate.
With the optimized reaction conditions in hand, a variety of
arylboronic acids were tested. As shown in Scheme 3, the aryl
boronic acids bearing a substituent group at the 4-position
proceeded smoothly and afforded 2-substituted fluorenes in
good-to-excellent yields (3a, 3c–3 f). The yields of products
with electron-withdrawing groups (3a and 3 f) were slightly
Scheme 3. Pd-catalyzed tandem cross-coupling reactions of o-bromobenzyl
bromide with aryl boronic acid. Reaction conditions: 1 (0.3 mmol), 2a–m
(0.45 mmol), Pd(OAc)2 (3 mol%), PCy3 (6 mol%), K3PO4 (1.8 mmol), PivOH
(0.24 mmol), LiCl (0.45 mmol), 4 Š MS (200 mg), THF (5 mL). Yield of isolated
product.
Scheme 4. The postulated reaction mechanism.
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Further transformations would yield the product of fluorene
with a substituent in a different position (Scheme 4, path B).
This approach not only could tune the position of substituents
on fluorenes conveniently by changing the halogen in o-halo-
benzyl bromide substrates in the reaction with the same aryl-
boronic acid, but also compensate for the deficiency in the re-
action of o-bromobenzyl bromid coupling with m-substituted
arylboronic acid to synthesize 1-substituted or 3-substituted
fluorenes.
Table 2. Palladium-catalyzed cross-coupling reaction of o-chlorobenzyl
bromide with 4-fluoro boronic acid.[a]
To verify the proposal, we then examined the coupling reac-
tion of 2-chlorobenzyl bromide (5) with 4-fluorophenylboronic
acid (2a) under the previous standard reaction conditions.
Indeed, 3-fluorofluorene (6a) was obtained albeit in low yield
(Table 2, entry 1) (the position of the CÀF substituent was also
determined by 13C NMR spectroscopy). In contrast to the re-
sults obtained previously for the investigation of reactions
with o-bromobenzyl bromide, the main by-product was 1-
chloro-2-(4-fluorobenzyl)benzene (7) and only a trace amount
of benzyl trimethylacetate was found in the reaction system.
This result indicated that, owing to the less reactivity of arylic
CÀCl bond in the coupling reaction, the benzylic CÀBr bond
could be firstly and quickly inserted by Pd0 species and LiCl
and 4 Š MS might be not necessary in this case. Intriguingly,
the yield of 6a was improved to 44% without LiCl and 4 Š MS
(Table 2, entry 2). The influence of base was also reinvestigated
and K2CO3 gave a slight higher yield of 48% (Table 2, entry 3),
while the reaction with Cs2CO3 was almost inhibited (Table 2,
entry 4). Furthermore, various solvents were investigated and
the results are outlined in Table 2. Again, THF was also superior
to 1,4-dioxane and toluene (Table 2, entries 5 and 6). The reac-
tion in MeTHF provided a comparable result to that of THF
(Table 2, entry 7), but a slightly higher yield (56%) was ob-
tained (Table 2, entry 8) when the reaction temperature was
elevated to 1308C; this indicated that a higher temperature fa-
cilitated the reaction. Finally, in the consideration of inferior re-
activity of aromatic CÀCl, no further attempt on the optimiza-
tion of reaction conditions was conducted. Hence, based on
the above reaction condition screening results, the optimal
conditions for the reaction of 2-chlorobenzyl bromide 5 are as
Entry
Base
Solvent
T [oC]
Yield [%][b]
1[c]
2
3
4
5
6
7
8
K3PO4/PivOH
K3PO4/PivOH
K3PO4/PivOH
Cs2CO3/PivOH
K2CO3/PivOH
K2CO3/PivOH
K2CO3/PivOH
K2CO3/PivOH
THF
THF
THF
THF
Dioxane
Toluene
MeTHF
MeTHF
120
120
120
120
120
120
120
130
32
44
48
trace
30
40
50
56 (53[d]
)
[a] Reaction conditions:
1
(0.3 mmol, 1.0 equiv), 2a (0.33 mmol,
1.1 equiv), Pd(OAc)2 (3 mol%), PCy3-HBF4 (6 mol%), base (1.8 mmol,
6.0 equiv), PivOH (0.3 mmol, 1.0 equiv), solvent (2 mL). [b] Yields were de-
termined by 1H NMR spectroscopy. [c] LiCl (0.45 mmol), and 4 Š MS
(200 mg) were added. [d] Yield of isolated product. [e] THF=Tetrahydro-
furan, MeTHF=2-Methyltetrahydrofuran.
follows: Pd(OAc)2 (3 mol%), PCy3-HBF4 (6 mol%), 2-chloroben-
zyl bromide 5 (1.0 equiv), 4-fluorophenyl-boronic acid 2a
(1.1 equiv), K2CO3 (6 equiv), PivOH (1.0 equiv) in MeTHF (2 mL)
at 1308C for 12 h.
With these optimized reaction conditions, some other aryl-
boronic acids were employed to investigate the scope of this
new catalytic system (Scheme 5). Arylboronic acids bearing
electron-withdrawing groups (6a, 6 f) and electron-donating
groups (6c–6e, 6g, 6h) worked well and afforded the corre-
sponding fluorene product in moderate yields (38–63%). The
reason for the moderate yields could be ascribed to the re-
duced reactivity of the arylic CÀCl bond in the cyclization pro-
ceeding through a CÀH activation process.
Scheme 5. Tandem cross-coupling reactions of 2-chlorobenzyl bromide with phenylboronic acids. Reaction conditions: 5 (0.3 mmol), 6a–f (0.45 mmol),
Pd(OAc)2 (3 mol%), PCy3-HBF4 (6 mol%), K2CO3 (1.8 mmol), PivOH (0.3 mmol), MeTHF (2 mL). Yield of isolated product.
Chem. Asian J. 2016, 11, 211 – 215
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In summary, we have successfully developed an efficient Pd-
catalyzed tandem cross-coupling reaction for the synthesis of
fluorenes. With this newly developed synthetic method, vari-
ous fluorene compounds were conveniently obtained in mod-
erate-to-good yields. Changing the halogen substituent in the
substrate of the o-halobenzyl bromide, which reacted with the
same arylboronic acid, could fulfill the different exclusive selec-
tivity of substituted fluorenes. This approach could be used to
afford diverse fluorene-based molecular architectures, and
therefore would provide more opportunities to research the
properties of these materials. Further investigations into the
application of this chemistry are currently underway in our lab-
oratory.
Synergistic Innovation Center for Advanced Materials (SICAM),
Priority Academic Program Development (PAPD) of Jiangsu
Higher Education Institutions, the Foundation for Incubation
Project of Nanjing University of Posts and Telecommunicaitons
(NY214085).
Keywords: CÀH functionalization · chemoselectivity · cross-
coupling · fluorenes · Palladium
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Experimental Section
General procedure for the Pd-catalyzed cross-coupling reactions
of arylboronic acids with 2-bromobenzyl bromide: THF (5 mL)
was added to a sealed tube containing bromobenzyl bromide
(0.3 mmol), arylboronic acid (0.45 mmol), K3PO4 (1.8 mmol),
Pd(OAc)2 (0.009 mmol), PCy3 (0.018 mmol), and PivOH (0.24 mmol).
The mixture was allowed to stir at 1208C for 12 h before it was
cooled down to room temperature and quenched by water. The
solution was extracted with ethyl acetate (3”15 mL). The organic
layers were combined, washed with brine, dried by Na2SO4, and fil-
tered. The solvent was removed under reduced pressure. The resi-
due was subjected to column chromatography on silica gel, elut-
ing with petroleum ether to afford the desired products.
General procedure for Pd-catalyzed cross-coupling reactions of
arylboronic acids with 2-chlorobenzyl bromide: MeTHF (2 mL)
was added to a sealed tube containing 2-chlorobenzyl bromide
(0.3 mmol), arylboronic acid (0.33 mmol), K2CO3 (1.8 mmol),
Pd(OAc)2 (0.009 mmol), PCy3-HBF4 (0.018 mmol), and PivOH
(0.3 mmol). The mixture was allowed to stir at 1308C for 12 h
before it was cooled down to room temperature and quenched by
water. The solution was extracted with ethyl acetate (3”15 mL).
The organic layers were combined, washed with brine, dried by
Na2SO4, and filtered. The solvent was removed under reduced pres-
sure. The residue was subjected to column chromatography on
silica gel, eluting with petroleum ether to afford the desired prod-
ucts.
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Acknowledgements
Manuscript received: October 15, 2015
Accepted Article published: October 21, 2015
Final Article published: November 9, 2015
This work was supported by the National Natural Science
Foundation of China (61274065, 21373114, 21302148), National
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