Synthesis of Fluorenes Starting from 2-Iodobiphenyls and CH2Br2 through Palladium-Catalyzed Dual C-C Bond Formation

Article abstract of DOI:10.1021/acs.orglett.6b01300

A facile and efficient approach is developed for the synthesis of fluorene and its derivatives starting from 2-iodobiphenyls and CH₂Br₂. A range of fluorene derivatives can be synthesized under relatively mild conditions. The reaction proceeds via a tandem palladium-catalyzed dual C-C bond formation sequence through the key dibenzopalladacyclopentadiene intermediates, which are obtained from 2-iodobiphenyls through palladium-catalyzed C-H activation.

Full text of DOI:10.1021/acs.orglett.6b01300

Letter
pubs.acs.org/OrgLett
Synthesis of Fluorenes Starting from 2‑Iodobiphenyls and CH2Br2
through Palladium-Catalyzed Dual C−C Bond Formation
Guangfa Shi, Dushen Chen, Hang Jiang, Yu Zhang, and Yanghui Zhang*
Department of Chemistry, Shanghai Key Laboratory of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road,
Shanghai 200092, China
S
* Supporting Information
ABSTRACT: A facile and efficient approach is developed for the synthesis of
fluorene and its derivatives starting from 2-iodobiphenyls and CH2Br2. A range of
fluorene derivatives can be synthesized under relatively mild conditions. The
reaction proceeds via a tandem palladium-catalyzed dual C−C bond formation
sequence through the key dibenzopalladacyclopentadiene intermediates, which are
obtained from 2-iodobiphenyls through palladium-catalyzed C−H activation.
Table 1. Optimization of the Reaction Conditions for the
Synthesis of Fluorene from 2-Iodobiphenyl and CH2Br2
luorene is one of the simplest motifs in polycyclic aromatic
Fhydrocarbons, and its derivatives have found broad
applications in materials science,1 pharmaceutical chemistry,2
and organic synthesis.3 While traditional methods for the
synthesis of fluorenes suffer from harsh conditions or
complicated procedures,4 an efficient strategy via C−H
functionalization has gained considerable interest. This novel
strategy involves transition-metal-mediated C−H activation and
subsequent cyclization. Currently, a variety of great reactions of
this type have been developed.5 All the reactions rely on the use
of substrates in which the methylene carbon is preinstalled
(Figure 1).
Metallacycles are one of the most popular classes of
organometallic compounds and have been extensively inves-
tigated over the past several years.6 Dibenzometallacyclopenta-
diene (metal 2,2′-biphenyl complex) (Figure 1, DBM), a
particularly intriguing metallacycle, remains comparatively
underexploited.7 Recently, we initiated a program to exploit
the unique reactivity of DBM, aiming to develop novel organic
reactions and shed light on the mechanism of reactions
a
entry
base (equiv)
solvent (mL)
DMF (1.2)
yield/%
1
2
3
4
5
6
K2CO3/KOAc (5/6)
KHCO3/KOAc (5/6)
KHCO3/KOAc (5/6)
KHCO3/KOAc (5/6)
KHCO3/KOAc (3/4)
KHCO3/KOAc (8/9)
KHCO3/KOAc (8/9)
KHCO3/KOAc (8/9)
KHCO3/KOAc (8/9)
KHCO3/KOAc (8/9)
KHCO3/KOAc (5/6)
KHCO3/KOAc (8/9)
KHCO3/KOAc (5/6)
KHCO3/KOAc (8/9)
52
60
63
73
57
DMF (1.2)
DMF/DMA (1.2/0.4)
b
DMF/DMA/H2O
b
DMF/DMA/H2O
b
c
DMF/DMA/H2O
85 (81 )
d
b
7
DMF/DMA/H2O
71
60
75
22
57
81
−
e
b
8
DMF/DMA/H2O
f
b
9
DMF/DMA/H2O
g
b
10
DMF/DMA/H2O
h
b
11
DMF/DMA/H2O
i
b
12
DMF/DMA/H2O
j
b
13
DMF/DMA/H2O
k
c
14
DMF/DMA/H2O (12/4/2)
78
a
1
The yields were determined by H NMR analysis of crude reaction
b
mixture using CHCl2CHCl2 as the internal standard. DMF/DMA/
H2O (1.2 mL/0.4 mL/0.2 mL). Isolated yield. 2 equiv of MeOH
were used instead of i-PrOH. No i-PrOH. 4 equiv of CH2Br2.
equiv of CH2Cl2 were used instead of CH2Br2. Under an air
c
d
e
f
g
7
h
i
j
k
atmosphere. 3 mol % Pd(OAc)2. No Pd(OAc)2. 2.0 mmol of 1.
involving other metallacycles.8 We found that DBM exhibited
novel reactivity that is distinct from that of other common
arylmetal complexes. DBM can selectively react with alkyl
halides,9 which are not reactive toward open-chain arylmetal
complexes.8a Furthermore, one of the advantages of DBM is
that the presence of two carbon−metal bonds in the complex
Received: May 4, 2016
Figure 1. Synthesis of fluorenes via C−H functionalization.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01300
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Letter
Scheme 1. Substrate Scope for Pd-Catalyzed Coupling of 2-Iodophenyls and CH2Br2
a
b
c
Isolated yield. 3 mol % Pd(OAc)2. 90 °C.
Scheme 2. Mechanistic Studies for the Dual Alkylation of 2-
Iodobiphenyl with CH2Br2
Figure 2. Proposed mechanism for the dual alkylation of 2-
iodobiphenyl with CH2Br2.
offers opportunities to difunctionalize biphenyl at the 2- and 2′-
positions. Inspired by this advantage and their unique reactivity
toward alkyl halides, we envisioned that the reaction of DBM
with dihaloalkanes would offer efficient access to dibenzocy-
cloalkanes via a tandem palladium-catalyzed dual C−C bond-
forming reaction.
Herein, we report the Pd-catalyzed coupling reaction of 2-
iodobiphenyls with dibromomethane, which provides a
convenient and efficient method for the synthesis of fluorenes
starting from substrates without a preinstalled methylene group.
B
DOI: 10.1021/acs.orglett.6b01300
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Letter
examined. A variety of symmetrically or asymmetrically
substituted 2-iodobiphenyls were found to be compatible
with the reaction conditions, affording multiply functionalized
fluorenes as the products. Notably, for several representative
substrates, the yield was the same or only slightly diminished
when the catalyst loading was lowered to 3 mol % Pd(OAc)2.
To gain insight into the mechanism involved in the
formation of fluorene, additional experiments were conducted
(Scheme 2). The formation of fluorene could involve
intermediate 29, which is formed via the reaction of complex
A and CH2Br2 (Figure 2, dashed arrows). To rule out this
possible pathway, we subjected 29 to the standard reaction
conditions. Only a negligible amount of fluorene was observed,
and 29 was converted into its acetoxy analogue in 91% yield.
Furthermore, when 0.5 equiv of 29 was added into the reaction
mixture of 0.5 equiv of 5, fluorene was not observed, and the
fluorene derivative 5a was formed in 72% yield. Based on these
experimental outcomes, the pathway involving 29 can be ruled
out. Therefore, a mechanism involving the dibenzometalla-
cyclopentadiene complex appears plausible. As shown in Figure
2, the catalytic cycle starts with the oxidative addition of 2-
iodobiphenyl to Pd(0). The resulting Pd(II) species A cleaves
the 2′-C−H bond to form the key palladacycle B. The oxidative
addition of the CH2Br2 to the Pd(II) in B forms Pd(IV)
complex C, which then undergoes reductive elimination to
afford intermediate D. It should be mentioned that a metathesis
Scheme 3. Kinetic Isotope Effect Studies for the Dual
Alkylation of 2-Iodobiphenyl with CH2Br2
The research was commenced by investigating the reaction
of 2-iodobiphenyl with CH2Br2. Gratefully, the reaction formed
the desired fluorene product 1a in 52% yield in the presence of
10 mol % Pd(OAc)2, 5 equiv of K2CO3, 6 equiv of KOAc, and
2 equiv of i-PrOH (Table 1, entry 1). The yield further
increased to 60% in the presence of a mixture of KHCO3 and
KOAc (entry 2) and was improved to 73% when the reaction
was carried out in a mixture of DMF, DMA, and H2O (entry 4).
The yield was optimized to 85% by increasing the amounts of
KHCO3 and KOAc (entry 6). The use of CH3OH as the
reductant led to a lower yield (entry 7), and the yield decreased
to 60% in the absence of an alcohol (entry 8), demonstrating
the positive effect of an alcohol on the reaction. The reaction
afforded the desired product in good yield even when the
amount of CH2Br2 was reduced to 4 equiv (entry 9). CH2Cl2
was also reactive, albeit in a far lower yield (entry 10). When
the reaction was carried out under an atmosphere of air, 1a was
formed in a lower yield (entry 11). One possible explanation
for this observation is that O2 could oxidize catalytically active
Pd(0) and thereby suppress the reaction. Notably, the yield
remained almost unchanged when the amount of Pd(OAc)2
was reduced from 10 to 3 mol % (entry 12). A control
experiment in the absence of Pd(OAc)2 confirmed that it was
necessary for formation of 1a (entry 13). Notably, the product
could be obtained in 78% yield even on 2.0 mmol scale (entry
14), demonstrating the practical utility of this method.
Having developed an efficient protocol for palladium-
catalyzed coupling of 2-iodobiphenyl with CH2Br2, we next
investigated the substrate scope of this transformation. We first
examined the compatibility of different functional groups on
the phenyl ring opposite to the iodo group. As shown in
Scheme 1, substrates bearing a substituent (either methoxy or
methyl group) at the 2′, 3′, or 4′ positions underwent the
coupling reaction with CH2Br2 efficiently under the optimal
conditions. Both fluoro and chloro groups were similarly well-
tolerated in the reaction, giving the desired fluorene derivatives
in moderate to high yields. A range of other common functional
groups were compatible, including phenyl, acetylamino,
alkoxycarbonyl, and acetyl groups. 2-Iodobiphenyl substrates
bearing two substituents were also reacitve, albeit in a poor
yield for 3′,4′-difluoro-2-iodobiphenyl. Next, we investigated
the coupling reaction of 2-iodobiphenyl derivatives with a
subtituent on the phenyl ring containing the iodo group. 2-
Iodobiphenyls substituted at 4 or 5 positions were transformed
into corresponding fluorenes in high yields. Finally, the
reactivity of multiply substituted 2-iodobiphenyls was also
pathway cannot be ruled out for the formation of D.10
D
undergoes intramolecular oxidative addition to give E, and the
subsequent reductive elimination affords fluorene as the final
product. Likewise, a metathesis pathway cannot be excluded.
In addition, the kinetic isotope effect in the reaction was
investigated. Therefore, a mixture of 1 and 2′,3′,4′,5′,6′-
pentadeutero-2-iodo-biphenyl (1-D5) (1:1) or 2′-deutero-2-
iodobiphenyl (1-D) was subjected to the standard conditions
(Scheme 3). Intriguingly, whereas the intermolecular KIE was 1
to 1, the intramolecular KIE was 3 to 1. These results are
consistent with a mechanism in which the first oxidative
addition of the aryl iodide to Pd(0) or reduction of Pd(II) to
Pd(0) is the slowest step. Subsequently, after complex A is
formed C−H activation is the next slowest step, and
subsequent steps should be comparatively fast.
In conclusion, we have developed a facile and efficient
approach for the synthesis of fluorene and its derivatives
starting from 2-iodobiphenyls and CH2Br2. This strategy
represents the first synthesis of fluorenes via C−H activation
utilizing substrates without a preinstalled methylene group and
provides convenient access to a variety of fluorene derivatives.
Mechanistic studies provided evidence to support the
intermediacy of a dibenzopalladacyclopentadiene in the
reaction, and the reaction proceeds via a tandem Pd-catalyzed
dual C−C bond formation sequence.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01300.
Detailed experimental procedures, spectroscopic data
and characterization of starting materials and products
(PDF)
C
DOI: 10.1021/acs.orglett.6b01300
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Organic Letters
Letter
(9) For selected examples of Pd-catalyzed C−H alkylations with alkyl
halides, see: (a) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-
Q. J. Am. Chem. Soc. 2015, 137, 11574. (b) Chen, K.; Shi, B.-F. Angew.
Chem., Int. Ed. 2014, 53, 11950. (c) Zhang, S.-Y.; Li, Q.; He, G.; Nack,
W. A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135. (d) Zhang, S.-Y.;
He, G.; Nack, W. A.; Zhao, Y.-S.; Li, Q.; Chen, G. J. Am. Chem. Soc.
2013, 135, 2124. (e) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem.
Sci. 2013, 4, 3906. (f) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhangyanghui@tongji.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097.
This work was supported by the National Natural Science
Foundation of China (21372176), Tongji University 985 Phase
III funds, the Program for Prof. of Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher Learning,
and the Shanghai Science and Technology Commission
(14DZ2261100).
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