Modular Tandem Mizoroki-Heck/Reductive Heck Reactions to Construct Fluorenes from Cyclic Diaryliodoniums

Article abstract of DOI:10.1002/adsc.202001080

Starting from cyclic diaryliodoniums and terminal alkenes, a diverse set of fluorenes is conveniently constructed. The reactions catalyzed by palladium undergo one conventional Mizoroki-Heck reaction and one reductive Heck reaction. The scope of alkenes is general, leading to 29 fluorenes which would expand the structural diversity of fluorene reservoir. (Figure presented.).

Full text of DOI:10.1002/adsc.202001080

Title: Modular Tandem Mizoroki-Heck/Reductive Heck Reactions to
Construct Fluorenes from Cyclic Diaryliodoniums
Authors: xiaopeng peng, Yang Yang, Bingling Luo, Shijun Wen, and
Peng Huang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001080
Link to VoR: https://doi.org/10.1002/adsc.202001080

10.1002/adsc.202001080
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Modular Tandem Mizoroki-Heck/Reductive Heck Reactions to
Construct Fluorenes from Cyclic Diaryliodoniums
Xiaopeng Peng a,b, Yang Yang b,c, Bingling Luob, Shijun Wenb*, Peng Huangb
a
School of Pharmaceutical Sciences, Zhaoqing Medical College, Zhaoqing 526000, P. R. China
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative innovation
b
Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China. E-mail: wenshj@sysucc.org.cn
School of Pharmaceutical Science, Sun Yat-sen University
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Figure 1. Representative compounds containing fluorene.
Cyclic diaryliodoniums (CDAIs) can inhibit NADPH
oxidase and show promising anticancer activity in
vitro and in vivo.[13] Recently, they have been
extensively studied in the synthetic chemistry field.[14]
Now, CDAIs have emerged as important synthons to
construct diverse polycycles.[15]
Abstract. Starting from cyclic diaryliodoniums and
terminal alkenes, diverse set of fluorenes is
a
conveniently constructed. The reactions catalyzed by
palladium undergo one conventional Mizoroki-Heck
reaction and one reductive Heck reaction. The scope of
alkenes is general, leading to 29 fluorenes which would
expand the structural diversity of fluorene reservoir.
We previously demonstrated that either a three-
component reaction strategy or dual arylations of
dicarbonyls conveniently lead to the construction of
fluorenes from CDAIs (Scheme 1a, 1b).[16] Using
these two strategies, the diversity of fluorenes is still
Keywords: Cyclic diaryliodoniums; Terminal alkenes;
Fluorene; Heck reaction;
Fluorenes have attracted considerable attention in the
research community due to their potential
pharmacological activities [1] and unique functionality
in advanced materials.[2] For instance, TAS-103 1a
can inhibit topoisomerases and exhibits anti-cancer
activity (Figure 1).[3] Other examples are
antiarrhythmic 1b,[6] and a neuromuscular blocking
agent 1c.[7] Fluorene-based derivatives can also be
used as photocatalysts.[4] Recently, Chen and co-
workers reported that 9H-fluorene-based compound
1d acted as a photoredox catalyst for decarboxylative
arylation.[5] A variety of synthetic methods have been
reported to construct the fluorene scaffolding over the
past a few years,[8] including Freidel-Crafts reaction,[9]
the late-stage derivatization of existing fluorene
cores,[10] and miscellaneous methods.[11] However, the
present methods still suffer from limited substrate
scopes, poor accessibility of starting materials, or
harsh reaction conditions. In the past decades,
hypervalent diaryliodoniums have attracted research
interests for their important biological and chemical
activity.[12]
limited.
It was our envision that the careful
modulation of two tandem Heck reactions including
one conventional Mizoroki-Heck reaction and one
reductive Heck reaction between alkenes and CDAIs
could provide an alternative route to fluorenes. Herein,
we report a concise method to construct 9H-
subsituted fluorenes from CDAIs, catalyzed by
Pd(PPh3)4 (Scheme 1c).
Scheme 1. The strategies to build fluorenes with CDAIs.
To validate our hypothesis, CDAI 2a and methyl
acrylate 3a were initially employed to investigate a
possibility to access a known compound, methyl 2-
(9H-fluoren-9-yl) acetate 4a. To our satisfaction, a
trace of 4a was observed with Pd(OAc)2 as a catalyst
and Na2CO3 as the base in DMF under argon
atmosphere at 120°C (entry 1, Table 1). To further
1
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10.1002/adsc.202001080
Advanced Synthesis & Catalysis
optimize the reaction conditions, other palladium
With the optimal reaction condition in hand, a
species were examined (entries 2−4). The observation variety of alkenes
3 with different electron-
indicated that all the palladium species mediated the withdrawing groups (EWG) were investigated to react
transformation albeit at low yields. After a further with CDAI 2a (Scheme 2). The desired fluorenes
base screening (entries 5−8), triethylamine was found were successfully obtained at modest to good yields
to be the best, likely because triethylamine had a while alkyls in acrylate esters were varied (4a-4e).
reducing potential to enhance the reductive Heck Other important substrates acrolein and acrylamides
reaction. Next, the addition of HCOONa further were also suitable to give modest to good yields (4f-
increased the reaction yield (entries 9-10). Thus, the 4i). Acrylonitrile provided fluorenes 4j that could
Et3N/HCOONa system was selected for further undergo further transformations to build complex
condition optimization (entry 10). The following molecular scaffolds. Sulfonyl group was tolerated in
screening of solvents found that 1,2-dichloroethane the formation of fluorene 4k. 2-Methyl substituted
(DCE) provided 4a at good yield (entries 11-14). It is acrolein also provided the expected product 4l in good
worth mentioning that 4a was not observed in NMP yield. Our results demonstrated a broad substrate
and the only uncyclized compound, methyl 3-([1,1'- generality of alkenes, and a variety of 9H-fluorenes
biphenyl]-2-yl) acrylate was gained (entry 13). could be quickly obtained.
Finally, we investigated the effect of temperature on
the reaction. The best yield was obtained when the
reaction took place at 100°C (entries 15-18). Thus,
our final optimal reaction condition was set for
Pd(PPh3)4 as catalyst and Et3N/HCOONa as
base/reducing agent system in 1,2-dichloroethane at
100°C.
Table 1. Reaction Condition Optimizationa
Yield
Entry Catalyst
Base
Solvent
Temp
b
1
2
Pd(OAc)2
Na2CO3
Na2CO3
DMF
DMF
120
120
5
9
Pd(OAc)2/
PPh3
3
4
PdCl2(PPh3)2 Na2CO3
DMF
DMF
120
120
12
14
Pd(PPh3)4
Na2CO3
5
6
Pd(PPh3)4
Pd(PPh3)4
K2CO3
DMF
DMF
120
120
13
18
NaHCO3
7
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Et3N
DMF
DMF
DMF
120
120
120
ND
35
8
Scheme 2. The scope of α, β-unsaturated alkenes.
Conditions: 2a (0.2 mmol, 1.0 equiv), alkene 3 (2.0 equiv),
Pd(PPh3)4 (0.1 equiv), Et3N (3.0 equiv), HCOONa (2.0
equiv), DCE (3.0 mL), 100 °C, 15h, Ar.
9c
Et3N/
33
CH3COONa
10c
11c
12c
13c
14c
15c
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Et3N/HCOONa DMF
Et3N/HCOONa DMSO
Et3N/HCOONa Toluene
Et3N/HCOONa NMP
Et3N/HCOONa DCE
120
120
120
120
120
100
46
21
45
Other types of alkenes including styrene and alkyl
alkene were further investigated to explore the
synthetic versatility of this method (Scheme 3). The
styrenes with different substituents performed well
(4m-4p). Notably, halogens (F, Cl) were tolerable in
the current conditions (4o, 4p). Synthetically, both
fluorinated and chlorinated fluorenes 4o and 4p could
undergo further modifications to broaden the
structural complexity. To our satisfaction, even
pyridine- substituted alkene also underwent the
reaction smoothly (4q). The pyridine motif is
frequently found in polycyclic heteroarenes. More
strikingly, the more inert alkyl alkenes also worked
well and provided the expected desired products
under our condition (4r, 4s). Notably, the terminal
ND
67
Et3N/
HCOONa
DCE
78
16c
17c
18c
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Et3N/HCOONa DCE
Et3N/HCOONa DCE
Et3N/HCOONa DCE
80
60
rt
53
21
ND
a Unless otherwise stated, 2a (0.2 mmol, 1.0 equiv), 3a (2.0
equiv), catalyst (0.1 equiv), base (3.0 equiv), 15h, Ar.
HPLC yield. Et3N (3.0 equiv), HCOONa (2.0 equiv).
Note: NMP, N-Methyl pyrrolidone; DCE, 1,2-
b
c
dichloroethane.
2
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10.1002/adsc.202001080
Advanced Synthesis & Catalysis
tethered hydroxyl group was compatible and could
provide opportunities for further transformation.
Finally, to further verify the synthetic generality of
this transformation, symmetrical and unsymmetrical
diaryliodoniums were also investigated (Scheme 4).
Scheme 4. The scope of cyclic iodoniums. Conditions:
CDAIs 2 (1.0 equiv), alkene 3 (2.0 equiv), Pd(PPh3)4 (0.1
equiv), Et3N (3.0 equiv), HCOONa (2.0 equiv), DCE (3.0
mL), 100 °C, 15h, Ar.
Scheme 3. The scope of terminal arylalkenes and
alkylalkenes. Conditions: CDAI 2a (0.2 mmol, 1.0 equiv),
alkene 3 (2.0 equiv), Pd(PPh3)4 (0.1 equiv), Et3N (3.0
equiv), HCOONa (2.0 equiv), DCE (3.0 mL), 100 °C, 15h,
Ar.
To gain more knowledge of this reaction, several
additional experiments were performed (Scheme 5).
First, one gram of cyclic diaryliodonium salt 2a was
employed, and the reaction yield was not
compromised (Scheme 5a). Second, a control
experiment was performed for a short time in the
absence of HCOONa (Scheme 5b). Only a trace of
the expected fluorene 4a was observed, and the major
products were uncyclized 6a and unwanted fluorene
6b. Finally, 4a could be obtained after 6a was
subjected to our standard condition (Scheme 5c).
Both tert-butyl acrylate and acrylonitrile were used as
alkene substrates since the attached t-butyl and
nitriles could be further transformed. Under the
standard reaction conditions, both CDAIs and
heterocyclic iodoniums provided the expected
fluorenes at modest to good yields. Unsymmetrical
CDAIs with either electron-donating groups or
electron-withdrawing groups underwent the
transformation smoothly (5a-5g). The steric effect of
the substituents was minimal (5b, 5f and 5g). The
CDAI with CF3 gave 5e in relatively low yield.
Subsequently, symmetrical CDAI was examined and
it was also transformed to the desired fluorene 5h at
modest yield. Polycyclic heteroarenes compounds
often demonstrate important biological properties, and
their construction is demanded. In our current method,
heterocyclic iodoniums worked smoothly and
conveniently provided TAS-1036-like compounds (5i,
5j) that may have potential anticancer activity [3]
.
Scheme 5. Scale-up reaction and control experiments.
Based on our results and control experiments, a
possible reaction mechanism was proposed (Scheme
6). Initated by palladium (0), cyclic iodoniums 2a
could undergo oxidative addition and subsequential
insertion into alkenes 3, and final -H elimination to
form a key intermediate C, finishing the first cycle of
conventional Mizoroki-Heck reaction. Then,
C
underwent a further cyclization to give palladium
species E. Subsequently, E could undergo a -H
3
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10.1002/adsc.202001080
Advanced Synthesis & Catalysis
This work was supported by National Natural Science Foundation
of China (81672952), Guangzhou Science and Technology
Program (201807010041), Guangdong Provincial Department of
Education
Youth
Innovation
Talents
Project
(No.
2017GkQNCX099), China; Guangdong Medical Research Fund
Project (No. A2018497), China.
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Scheme 6. Proposed mechanism.
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Experimental Section
To a reaction tube, was added cyclic diaryliodonium
salt 2a (0.2 mmol), alkenes 3 (0.4 mmol), Pd(PPh3)4
(0.1 equiv), Et3N (0.6 mmol), HCOONa (0.4 mmol),
1,2-dichloroethane (3.0 mL). Then, the tube was
sealed, degassed and recharged with argon. The
o
reaction proceeded at 100 C for 15 h under argon
atmosphere. Finally, dichloromethane (20 mL) was
added to dilute the reaction mixture. The diluted
mixture was washed with H2O (2 mL x 3) and brine
(2 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was
purified by column chromatography on a silica gel
(petroleum/EtOAc = 50/1-20/1) to provide 4.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.202001080
Advanced Synthesis & Catalysis
COMMUNICATION
Modular Tandem Mizoroki-Heck/reductive Heck
reactions to construct fluorenes from cyclic
diaryliodoniums
Adv. Synth. Catal. Year, Volume, Page – Page
Xiaopeng Peng, Yang Yang, Bingling Luo, Shijun
Wen*, Peng Huang
6
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