Monodentate Transient Directing Group Assisted Pd-Catalyzed Direct Dehydrogenative Cross-Coupling of Benzaldehydes with Arenes toward 9-Fluorenones

Article abstract of DOI:10.1021/acs.joc.9b02139

Commercially available 3,5-bis(trifluoromethyl)aniline was found to be a highly efficient monodentate transient directing group (MonoTDG) for the palladium-catalyzed direct dehydrogenative cross-coupling of benzaldehydes with arenes. A diverse set of symm

Full text of DOI:10.1021/acs.joc.9b02139

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Article
Monodentate Transient Directing Group Assisted Pd-
Catalyzed Direct Dehydrogenative Cross-Coupling of
Benzaldehydes with Arenes toward 9-Fluorenones
Yi-Feng Wang, Wen-Gang Xu, Bing Sun, Qin-Qin Yu, Tuanjie Li, and Fang-Lin Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02139 • Publication Date (Web): 09 Sep 2019
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†
†
†
†
,‡
,†
Yi-Feng Wang, Wen-Gang Xu, Bing Sun, Qin-Qin Yu, Tuan-Jie Li,* and Fang-Lin Zhang*
†
School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, P.
R. China
‡
School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Ma-
terials, Jiangsu Normal University, Xuzhou 221116, P. R. China
Supporting Information Placeholder
ABSTRACT: Commercially available 3,5-bis(trifluoromethyl)aniline was found to be a highly efficient monodentate transi-
ent directing group (MonoTDG) for the palladium-catalyzed direct dehydrogenative cross-coupling of benzaldehydes with
arenes. A diverse set of symmetrical and unsymmetrical 9-fluorenones were readily obtained in yields of 32% to 72% along
with excellent regioselectivities and broad functional group compatibility as well as high atom economy under mild condi-
tions via dual carbon-hydrogen (C-H) bond activation sequence.
INTRODUCTION
optical and electronic properties (Figure 1).3
Fluorenone as a privileged core structure has abun-
dant existence in various important nature products and
Consequently, substantial attention has been drawn
from the chemical and material scientists and a variety of
synthetic methods has been hitherto established. In gen-
eral, there are two types of methodologies to construct the
fluorenone skeleton, which are classified as intramolecular
and intermolecular ways (Scheme 1a). On one hand, for the
intramolecular reaction, ortho carbonyl substituted bi-
1
drug molecules, which exhibit a broad spectrum of ex-
2
traordinary biological and pharmacological activities.
Meanwhile, fluorenone also represents a versatile synthon,
which has extensive applications in organic semiconductor
photoelectric polymer material science due to its pivotal
4
5
6
phenyls, benzophenones, ortho halogenated biphenyls
7
and triacetylenes are the four kinds of the most-widely
used precursors. On the other hand, for the intermolecular
fashion, ortho-halogenated benzaldehydes were selected
to react with various phenylboronic acids or in situ gener-
ated phenylenes through classical transition-metal-cata-
8
lyzed cross-coupling cascades.
Besides the above traditional synthetic approaches,
transition-metal-catalyzed C−H bond activation technol-
ogy also has been utilized in the construction of fluorenone
9
Figure 1. Selected examples of natural products, drugs and
polymers containing fluorenone as core structure.
framework. Taking advantage of the direct C−H bond ac-
tivation strategy, it does not need to prefunctionalize the
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coupling partnersanymore.10 Meantime, excellent regio-
specific control are achieved via the directing groups assis-
(MonoTDGs), and it simply restricts in aniline and its de-
2
2
rivatives. As part of our ongoing efforts to expand the syn-
thetic potential of MonoTDGs, herein, we demonstrate a
highly efficient Pd-catalyzed direct dehydrogenative cross
coupling of benzaldehydes with arenes to furnish diverse
symmetrical and unsymmetrical 9-fluorenones using com-
mercially available 3,5-bis(trifluoromethyl)aniline as
monodentate transient directing group (Scheme 1b).
10
tance to form cyclometalated intermediate. A number of
9
a-c
typical functional groups, including aldoxime ethers,
9
d,9i
9e
9f
9g
amide,
amine, nitrile, carboxylic acids, and alde-
hyde proved to be traceless directing groups to efficiently
construct fluorenone units in one-pot stepwise manner
9
h
(Scheme 1a).
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RESULTS AND DISCUSSION
Scheme 1. Synthetic Strategies toward 9-Fluorenones
The initial reactivity investigation commenced by
choosing 3-bromobenzaldehyde 1a and toluene 2a as
model substrates to screen suitable transient directing
groups. The results are summarized in scheme 2. Consid-
ering benzaldehyde derived oxime ethers have been suc-
cessfully employed in palladium-catalyzed synthesis of flu-
9
a
orenone via coupling with iodobezene, phenylboronic
9
b
9c
acid and arene respectively, o-methylhydroxylamine T1
was firstly tested to check whether it was possible to form
aldoxime ether in situ. Unfortunately, T1 failed to promote
the reaction, and no new spot was detected. Then two
amino acids (T2 and T3) as BiTDGs were examined, and
only T3 could give a low yield of a new product. The abso-
lute structure of the new product was unambiguously con-
firmed to be the desired 9-fluorenone 3a by X-ray crystal-
lographic diffraction (Scheme 3). This preliminary result
encouraged us to continue the reaction parameters optimi-
zation. As a consequence, a series of trifluoromethyl group
substituted anilines (T4 to T10) were further evaluated as
MonoTDGs with the wishes to improve the results. The po-
sition of trifluoromethyl group on the aniline significantly
influenced the reactivity. In case of ortho- and para- tri-
fluoromethyl group substituted anilines (T4 and T6), com-
parable yields were obtained, while meta-trifluoromethyl
group substituted aniline T5 provided dramatically higher
yield. Subsequently, several meta-trifluoromethyl group
substituted anilines bearing more substituents on the
However, the reported synthetic methods require ei-
ther excess steps to access prefunctionalized starting ma-
terials or are accompanied by generation of stoichiometric
amounts of waste, which significantly diminish the atom
and step economy. To circumvent these disadvantages, it
is therefore highly desirable to develop a new and practical
useful methodology to prepare this kind of valuable flu-
orenones starting from easily available inexpensive rea-
gents. Toward this end, we envisioned that the very re-
cently emerged transient directing groups (TDGs) strategy
would be an ideal alternative for direct C–H functionaliza-
tion of aldehydes through in situ reversible formation of
imine, avoiding the covalent installation and removal of
Scheme 2. Transient Directing Groups Screening for
a
Preparation of 9-Fluorenone
11
the stoichiometric directing groups. Nevertheless, biden-
tate transient directing groups (BiTDGs) currently domi-
nate this area, and a large number of bifunctional small or-
ganic molecules, such as natural and unnatural amino ac-
1
2
13
14,9h
15
ids, acetohydrazide, anthranilic acid,
orthanilic acid,
1
6
17
18
ortho-sulfinyl aniline, diamine, glyoxylic acid, alkyl ac-
etal, 2-hydroxynicotinaldehyde and salicylaldehyde
1
9
20
21
have been successfully developed as suitable BiTDGs to en-
able Pd-catalyzed various C−H functionalizations by our
and other groups. In contrast, only a few examples con-
cerned monodentate transient directing groups
aReaction conditions: 3-bromobenzaldehyde (0.2 mmol, 1.0
equiv.), toluene (5.0 equiv.), Pd(OAc)
2
(10 mol%), T (40 mol%),
2 2 8
K S O
(
(2.0 equiv.), HOAc (15.0 equiv.),TFA (8.0 equiv.), HFIP
4.0 mL) at 80 °C for 24 h. Isolated yields for all. No reaction.
b
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Scheme 3. Substrate Scope Investigation for Prepara-
tion of 9-Fluorenone
showed that all the reaction parameters, including palla-
dium catalyst, MonoTDG T10, oxidant and acid additive
were necessary for the successful transformation.
a
With the optimized conditions in hand, the generality
and limitation for the MonoTDG assisted palladium-cata-
lyzed tandem dual C-H functionalization was investigated,
and the results are presented in Scheme 3. First, a group of
substituted benzaldehydes were probed to afford the ex-
pected 9-fluorenone product in high efficiency. In general,
neither the electron properties nor steric hinderance had
significant influence on the process, and all the tested al-
dehydes could react smoothly with toluene to provide
moderate to good yields with excellent regioselectivity.
Halogenated benzaldehydes proved to be suitable sub-
strates for this reaction, and both chloride and bromide
atom (1a-1h) were well tolerated, which permit valuable
opportunities for further late-stage derivatizations via var-
ious classical transition-metal-mediated cross-couplings.
Moreover, a variety of disubstituted benzaldehydes (1c-1f)
were also compatible for this transformation to deliver the
desired fluorenones. Besides toluene, the substrate scope
could extend to anisole and chlorobenzene as well as bro-
mobenzene, furnishing the products in comparable good
outcomes. It is noteworthy that an interesting symmetrical
halogenated 9-fluorenone 3k could be readily constructed
in high efficiency via rational selection of starting materials.
It is worthy to note that benzene gave the highest yield of
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78% for 3q. Furthermore, both dimethyl and tert-butyl-
substituted arenes reacted well under the identical condi-
tions to generate satisfied yields (3r and 3s). Eventually, di-
phenyl ether and biphenyl were also tested. Although there
existed two possible reactive benzene rings in these sub-
strates, one mono fluorenone products were noticed. The
absolute structure of 3u was also determined by X-ray crys-
tallographic diffraction.
In addition, to enhance the practical usage of this
newly developed methodology, an enlarged 8 mmol scale
reaction of 3k was performed, and comparably good yield
of 67% was obtained. Furthermore, classical palladium-
catalyzed Suzuki coupling of 3k with (4-(diphenyla-
mino)phenyl)boronic acid smoothly delivered donor-ac-
ceptor-donor (D-A-D) type molecule 4 in 86% yield under
mild conditions.
Scheme 4. Derivatization and Amplification Experi-
ments
aUnder the same conditions as in Scheme 2. Isolated yield.
benzene were examined. However, no better out comes
could be generated except for 3,5-bis(trifluoromethyl)ani-
line T10, which turned out to be optimal MonoTDG for the
catalytic dehydrogenative cross-coupling tandem reaction
in terms of yield and efficiency. Control experiment
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To gain deeper insights into the reaction mechanism
furnish the fluoren-9-amine G. Next, β-hydride elimina-
of this new direct dehydrogenative cross-coupling tandem
reaction, several control experiments were performed, and
the results are listed in Scheme 5. In the absence of acid
additive, only moderate yield of 27% for arylation product
tion delivers imine H, which affords the final fluorenone
product 3 via simple hydrolysis. Eventually, reductive elim-
ination of Pd(II)HX generates Pd(0), which is reoxidized to
2 2 8
the active catalyst Pd(II) species by K S O for next cata-
5
was generated (equation 1). When 5 was subjected to
lytic cycle.
standard reaction conditions, the intramolecular cycliza-
tion could occur smoothly to provide corresponding 9-flu-
orenone 3c (equation2). These experimental results indi-
cated that the dual C–H activation sequence may conduct
in a stepwise manner.
In conclusion, a simple and new synthetic route for
highly efficient construction of 9-fluorenone derivatives
was successfully developed via Pd-catalyzed dual C–H ac-
tivation. Commercially available 3,5-bis(trifluorome-
thyl)aniline was used as effective monodentate transient
directing group, and easily accessible inexpensive benzal-
dehydes with arenes were utilized as starting materials.
Moderate to good yields along with excellent regioselectiv-
ities and broad functional group compatibility as well as
high atom economy were achieved under mild conditions.
Only four hydrogen atoms in the starting materials were
eliminated to form two carbon-carbon bonds, constructing
the 9-fluorenone skeleton. Further development and appli-
cations of this new MonoTDGs strategy are underway in
our laboratory.
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Scheme 5. Control Experiments
In light of previous reports9c,9g-h and the above prelim-
inary experimental results, a plausible catalytic cycle was
proposed in Scheme 6. It is assumed that acid-promoted
reversible condensation of benzaldehyde 1 with T10 yields
EXPERIMENTAL SECTION
General Information Starting substrates 1 and 2, and
other reagents were all commercially available and were
used directly without further purification. Other reagents
were commercially available and were used directly with-
out further purification. Analytical thin layer chromatog-
raphy was performed on 0.25 mm silica gel 60-F254. Visu-
2
imine A firstly. Subsequent ortho-C(sp )-H activation of
imine A leads to the formation of the five-membered cy-
clopalladium intermediate B. By treatment with potassium
persulfate (K S O ), oxidation of intermediate B produces
2 2 8
the putative Pd(IV) species C, which is arylated by
arene2to afford intermediate D. Then, reductive elimina-
tion generates the ortho-arylated biphenyl product E,
whereas Pd(II) remains coordinating to the imine. The sec-
ond C−H palladation gives rise to the transient seven-
membered palladacycle F. Then ring-contraction through
intramolecular migratory insertion into the imine double
bonds constructs the second carbon−carbon bond to
1
alization was carried out with UV light. H NMR was rec-
orded on Bruker instrument (500MHz). Chemical shifts
were quoted in parts per million (ppm) referenced to 0.0
ppm for tetramethylsilane. The following abbreviations (or
combinations thereof) were used to explain multiplicities:
s = singlet, d = doublet, t = triplet, q =quartet, m = multiplet,
br = broad. Coupling constants, J, were reported in Hertz
1
3
unit (Hz). C NMR spectra were recorded on Bruker instru-
ment (126MHz) and were fully decoupled by broad band
proton decoupling. Chemical shifts were reported in ppm
referenced to either the center line of a triplet at 77.0 ppm
of chloroform-d or referenced to the center line of a septet
at 39.52 ppm of DMSO-d6. High-resolution mass spectra
Scheme 6. Plausible Mechanism
(HRMS) were recorded on an Agilent Mass spectrometer
using ESI-TOF (electrospray ionization-time of flight).
General Procedure for the Synthesis of 9-Fluorenone
from Benzaldehyde
A sealed tube with magnetic stir bar was charged with
1
(0.2 mmol), 2 (1.0 mmol), Pd(OAc)
2
(0.02 mmol, 4.5 mg),
2 2 8
K S O
(0.4 mmol, 108.0 mg), followed by HFIP (2.0 mL),
T10(0.08 mmol, 18.3 mg), TFA(1.6 mmol, 182.4 mg),
AcOH(3.0 mmol, 180.1 mg) in air,. The reaction mixture
o
was stirred at 80 C in an oil bath for 24 hours. Upon com-
pletion, the reaction mixture was cooled to room temper-
ature. Next the reaction mixture was quenched by sat. Na-
HCO (aq) 10 mL and extracted with CH2Cl2 for 3 times.
3
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The combined organic layers were washed with water 15
mL, dried over anhydrous Na SO , and concentrated in
vacuo. The crude residue was purified by column chroma-
tography on silica gel using petroleum ether/DCM as elu-
ent to afford the desired products.
vacuo. The crude residue was purified by column chroma-
tography on silica gel using petroleum ether/DCM as elu-
ent to afford the desired products 5 (14.3 mg, 27%).
2
4
A sealed tube with magnetic stir bar was charged with 5
(0.2 mmol, 53.o mg), Pd(OAc)2, (0.02 mmol, 4.5 mg),
Gram-Scale Preparation of 3k
K S O (0.4 mmol, 108.0 mg), followed by HFIP (2.0 mL),
2 2 8
T10 (0.08 mmol, 18.3 mg), TFA (1.6 mmol, 182.4 mg), AcOH
The 3-bromobenzaldehyde 1a (8.0 mmol, 1.48 g, 1.0
equiv.), bromobenzene 2c (40.0 mmol, 6.28 g, 5.0 equiv.),
(3.0 mmol, 180.1 mg) in air. The reaction mixture was
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stirred at 80 C for 24 hours. Upon completion, the reaction
Pd(OAc)2 (0.8 mmol, 0.18 g, 0.1 equiv.), K
.32 g, 2.0 equiv.) were taken in a sealed tube with mag-
netic stir bar. Then HFIP (60 mL) T10 (3.2 mmol, 732 mg,
.4 equiv.), TFA (64.0 mmol, 7.296 g, 8.0 equiv.) and AcOH
2 2 8
S O (16.0 mmol,
mixture was cooled to room temperature. Next the reac-
tion mixture was quenched by sat. NaHCO (aq) 10 mL and
3
extracted with CH2Cl2 for 3 times. The combined organic
layers were washed with water 15 mL, dried over anhydrous
2 4
Na SO , and concentrated in vacuo. The crude residue was
purified by column chromatography on silica gel using pe-
troleum ether/DCM as eluent to afford the desired prod-
ucts 3c (44.7 mg, 85%).
4
0
(
120.0 mmol, 7.2 g, 15 equiv.) was added with a syringe and
o
the resulting mixture was heated in an oil bath at 80 C for
48 h. After completion of the reaction (TLC monitored), it
was cooled to room temperature and diluted with water
and CH2Cl2. The mixture was extracted with CH2Cl2 50 ml,
three times. The organic layer was dried over anhydrous
Na SO . The solvent was evaporated to dryness and the re-
2 4
sulting residue was purified by silica gel column chroma-
2-bromo-7-methyl-9H-fluoren-9-one (3a)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (30.6 mg, 56 %, mp = 136 - 138 C). H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.47
(s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.30
tography to provide pure product 3k (1.81 g, 67%).
Synthesis of 2,7-Bis[4-(diphenylamino)phenyl]-9H-
2
3
13
1
fluoren-9-one 4
(d, J = 7.6 Hz, 1H), 2.37 (s, 3H). C{ H} NMR (126 MHz,
CDCl3) δ 192.7, 143.2, 141.1, 139.8, 137.0, 135.9, 135.5, 134.0,
127.5, 125.3, 122.4, 121.4, 120.3, 21.4. HRMS (ESI) m/z: M+
calcd for C14H9BrO 271.9837, found 271.9828.
Following a previously reported procedure, 2,7-Di-
bromo-9-fluorenone (1.0 mmol, 337.9 mg), 4-boronic acid-
triphenylamine (2.5 mmol, 722.8 mg), Trans-Dichloro-
bis(triphenyl-phosphine)Palladium(II) (0.1 mmol, 70.2 mg)
Anhydrous potassium carbonate (4.0 mmol, 552.8 mg) was
added to the flask, nitrogen was introduced three times,
and 7.5 ml of toluene, 2.5 ml of methanol and 2 ml of water
were added under nitrogen, and reacted at room tempera-
ture for 36 hours. Through TCL detection to completion of
reaction. After that, the reaction mixture was quenched
with water. The aqueous layer was extracted three times
with 20 ml DCM. The combined organic layers were dried
2-chloro-7-methyl-9H-fluoren-9-one (3b)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (23.8 mg, 52%, mp = 131 - 133 C). H NMR (500 MHz,
CDCl3) δ 7.57 (d, J = 1.7 Hz, 1H), 7.46 (s, 1H), 7.42 – 7.40 (m,
1
H), 7.39 – 7.35 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H).
C{ H} NMR (126 MHz, CDCl3) δ 192.7, 142.8, 141.1, 139.6,
13
1
135.8, 135.5, 134.6, 134.2, 134.1, 125.3, 124.6, 121.0, 120.3, 21.4.
HRMS (ESI) m/z: M+ calcd for C14H9ClO 228.0342, found
228.0339.
2 4
with anhydrous Na SO , filtered. The solvent was evapo-
rated under reduced pressure and the crude mixture was
purified by silica gel column chromatography for pure
product 4 as a Red solid (573.5 mg, 86 %).
1,2-dichloro-7-methyl-9H-fluoren-9-one(3c)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (32.1 mg, 61%, mp = 132 - 134 C). H NMR (500 MHz,
General Procedure for Control Experiments
CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 7.6
13
1
A sealed tube with magnetic stir bar was charged with
Hz, 1H), 7.33 – 7.30 (m, 2H), 2.39 (s, 3H). C{ H} NMR (126
MHz, CDCl3) δ 190.1, 144.9, 140.2, 139.2, 135.5, 135.3, 134.0,
1c(0.2 mmol, 35 mg), 2a(1.0 mmol, 92 mg), Pd(OAc)2, (0.02
1
33.8, 131.2, 131.1, 125.4, 120.3, 118.8, 21.4. HRMS (ESI) m/z:
mmol, 4.5 mg), K (0.4 mmol, 108.0 mg), followed by
2 2 8
S O
M+ calcd for C14H8Cl2O 261.9952, found 261.9943.
HFIP (2.0 mL), T10 (0.08 mmol, 18.3 mg), in air,. The reac-
o
tion mixture was stirred at 80 C for 24 hours. Upon com-
2,3-dichloro-7-methyl-9H-fluoren-9-one (3d)
pletion, the reaction mixture was cooled to room temper-
ature. Next the reaction mixture was quenched by sat. Na-
Eluent: petroleum ether/dichloromethane (10:1). Yellow
HCO
The com-bined organic layers were washed with water 15
mL, dried over anhydrous Na SO , and concentrated in
3 2 2
(aq) 10 mL and extracted with CH Cl for 3 times.
o
1
solid (16.8 mg, 32%, mp = 125 - 127 C). H NMR (500 MHz,
CDCl3) δ 7.68 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.38 (d, J =
2
4
13
1
7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H). C{ H} NMR
(126 MHz, CDCl3) δ 191.6, 143.8, 140.4, 140.1, 138.6, 135.6,
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134.4, 133.7, 132.6, 126.1, 125.5, 122.1, 120.5, 21.4. HRMS (ESI)
m/z: M+ calcd for C14H8Cl2O 261.9947; Found 261.9938.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (41.1 mg, 70%, mp = 170 - 172 C). H NMR (500 MHz,
CDCl3) δ 7.78 (d, J = 1.7 Hz, 1H), 7.65 – 7.61 (m, 2H), 7.48 –
7.46 (m, 1.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9
1,3-dichloro-7-methyl-9H-fluoren-9-one (3e)
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1
Hz, 1H). C{ H} NMR (126 MHz, CDCl3) δ 191.0, 142.3, 141.8,
37.5, 135.6, 135.5, 135.2, 134.6, 127.9, 125.0, 123.2, 121.8, 121.5.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
1
o
1
solid (32.6 mg, 62%, mp = 129 - 131 C). H NMR (500 MHz,
HRMS (ESI) m/z: M+ calcd for C13H6BrClO 291.9291,
found 291.9303.
CDCl3) δ 7.51 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H),
13
1
7
(
1
.33 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 2.40 (s, 3H). C{ H} NMR
126 MHz, CDCl3) δ 189.8, 147.9, 141.0, 140.9, 138.9, 135.3,
34.5, 133.2, 129.9, 128.1, 125.3, 120.5, 119.2, 21.5. HRMS (ESI)
m/z: M+ calcd for C14H8Cl2O 261.9947; Found 261.9937.
0
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7
8
9
0
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2
3
4
5
6
7
8
9
0
2,7-dibromo-9H-fluoren-9-one (3k)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (48,7 mg, 72%, mp = 203 - 205 C). H NMR (400 MHz,
3-chloro-1,7-dimethyl-9H-fluoren-9-one (3f)
CDCl3) δ 7.77 (s, 2H), 7.64 (d, J = 7.9 Hz, 2H), 7.40 (d, J =
13
1
7
1
.9 Hz, 2H). C{ H} NMR (101 MHz, CDCl3) δ 201.1, 166.4,
42.3, 137.5, 127.9, 121.9, 100.0. HRMS (ESI) m/z: M+ calcd
for C13H6Br2O 335.8785, found 335.8777.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (16.5 mg, 34%, mp = 141 - 143 C). H NMR (500 MHz,
CDCl3) δ 7.45 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 6.1
1
3
1
Hz, 2H), 7.01 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H). C{ H} NMR
126 MHz, CDCl3) δ 194.0, 146.8, 140.8, 140.0, 140.0, 139.9,
34.9, 134.9, 130.8, 129.4, 124.7, 120.1, 118.2, 21.4, 17.6. HRMS
ESI) m/z: M+ calcd for C15H11ClO 242.0498, found
42.0493.
7
-bromo-1,2-dimethyl-9H-fluoren-9-one (3l)
(
1
(
2
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (27.0 mg, 47%, mp = 147 - 149 C). H NMR (500 MHz,
CDCl3) δ 7.70 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.32
(
d, J = 7.9 Hz, 1H), 7.23 (s, 2H), 2.58 (s, 3H), 2.28 (s, 3H).
13
1
1,2-dichloro-7-methoxy-9H-fluoren-9-one (3g)
C{ H} NMR (126 MHz, CDCl3) δ 193.9, 142.4, 141.9, 139.7,
1
39.2, 136.7, 136.2, 135.2, 130.7, 127.1, 122.2, 121.1, 117.7, 19.3, 13.5.
HRMS (ESI) m/z: M+ calcd for C15H11BrO 285.9993, found
85.9989.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (22.9 mg, 41%, mp = 124 - 126 C). H NMR (500 MHz,
2
CDCl3) δ 7.48 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H),
7
.23 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.99 (d, J =
7-bromo-1,2-dichloro-9H-fluoren-9-one (3m)
13
1
5
.8 Hz, 1H), 3.86 (s, 3H). C{ H} NMR (126 MHz, CDCl3) δ
1
1
89.7, 161.4, 145.2, 135.6, 135.5, 134.3, 133.0, 131.2, 131.1, 121.6,
20.8, 118.4, 109.6, 55.8. HRMS (ESI) m/z: M+ calcd for
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (43.9 mg, 67%, mp = 187 - 189 C). H NMR (500 MHz,
CDCl3) δ 7.66 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H),
7.50 – 7.48 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9
C14H8Cl2O2 277.9901, found 277.9910.
1-bromo-7-methoxy-9H-fluoren-9-one (3h)
13
1
Hz, 1H). C{ H} NMR (126 MHz, CDCl3) δ 188.5, 143.9, 140.0,
136.0, 135.7, 135.2, 134.7, 134.6, 131.6, 130.9, 125.1, 121.5, 119.2.
HRMS (ESI) m/z: M+ calcd for C13H5BrCl2O 325.8901,
found 325.8894.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (21.4 mg, 37%, mp = 118 - 120 C). H NMR (500 MHz,
CDCl3) δ 7.41 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.31
(
d, J = 8.0 Hz, 1H), 7.26 (d, J = 3.3 Hz, 1H), 7.21 (s, 1H), 7.01
7-chloro-1-methyl-9H-fluoren-9-one (3n)
1
3
1
(d, J = 5.8 Hz, 1H), 3.87 (s, 3H). C{ H} NMR (126 MHz,
CDCl3) δ 191.0, 161.3, 147.4, 135.7, 135.4, 134.9, 132.9, 131.4,
21.4, 120.6, 120.4, 118.5, 109.3, 55.8. HRMS (ESI) m/z: M+
calcd for C14H9BrO2 287.9786, found 287.9793.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
1
solid (17.8 mg, 39%, mp = 135 - 137 C). H NMR (500 MHz,
CDCl3) δ 7.58 (s, 1H), 7.46 – 7.41 (m, 2H), 7.38 – 7.32 (m,
13
1
2
H), 7.07 (d, J = 6.8 Hz, 1H), 2.62 (s, 3H). C{ H} NMR (126
MHz, CDCl3) δ 193.5, 193.4, 144.0, 142.0, 139.9, 135.9, 134.9,
34.3, 133.8, 132.1, 130.8, 124.2, 121.1, 118., 17.8. HRMS (ESI)
m/z: M+ calcd for C14H9ClO 228.0342, found 228.0331.
7
-bromo-1-methyl-9H-fluoren-9-one (3i)
1
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (24.0 mg, 44%, mp = 152 - 154 C). H NMR (500 MHz,
CDCl3) δ 7.73 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.9
7
-chloro-1,2-dimethyl-9H-fluoren-9-one (3o)
1
Hz, 1H), 7.36 – 7.32 (m, 2H), 7.08 (d, J = 5.9 Hz, H), 2.62 (s,
13
3H). C{1H} NMR (126 MHz, CDCl3) δ 193.4, 144.1, 142.5,
139.9, 136.8, 136.0, 134.3, 132.2, 130.6, 127.1, 122.7, 121.5, 118.0,
17.8. HRMS (ESI) m/z: M+ calcd for C14H9BrO 271.9837,
found 271.9830.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (19.9 mg, 41%, mp = 141 - 143 C). H NMR (500 MHz,
CDCl3) δ 7.55 (d, J = 1.5 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.38 (d,
13
1
J = 7.9 Hz, 1H), 7.23 (s, 2H), 2.58 (s, 3H), 2.29 (s, 3H). C{ H}
NMR (126 MHz, CDCl3) δ 194.0, 142.0, 141.9, 139.5, 139.2,
136.0, 135.2, 134.4, 133.8, 130.9, 124.2, 120.7, 117.6, 19.3, 13.5.
2-bromo-7-chloro-9H-fluoren-9-one (3j)
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HRMS (ESI) m/z: M+ calcd for C15H11ClO 242.0498, found
242.0487.
1,2-dichloro-7-phenyl-9H-fluoren-9-one (3u)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1,2,7-trichloro-9H-fluoren-9-one (3p)
solid (42.3 mg, 65%, mp = 121 - 123 C). 1H NMR (500 MHz,
CDCl3) δ 7.87 (d, J = 1.5 Hz, 1H), 7.73 – 7.71 (m, 1H), 7.61 –
7.57 (m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H),
7.46 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.36 (d, J =
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (35.2 mg, 62%, mp = 193 - 195 C). H NMR (500 MHz,
13
1
CDCl3) δ 7.64 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H),
7.9 Hz, 1H). C{ H} NMR (126 MHz, CDCl3) δ 189.7, 144.5,
143.1, 140.5, 139.4, 135.5, 134.5, 134.3, 133.5, 131.3, 131.2, 129.0,
128.2, 126.8, 123.3, 120.8, 119.1. HRMS (ESI) m/z: M+ calcd
for C19H10Cl2O 324.0109, found 324.0098.
7
.50 – 7.48 (m, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
Hz, 1H). C{ H} NMR (126 MHz, CDCl3) δ 188.5, 143.9, 134.0,
36.0, 135.7, 135.2, 134.7, 134.6, 131.6, 130.9, 125.1, 121.5, 119.2.
HRMS (ESI) m/z: M+ calcd for C13H5Cl3O 281.9400; Found
61.9391.
1
2
2,7-bis[4-(diphenylamino)phenyl]-9H-fluoren-9-one
(
4)
1,2-dichloro-9H-fluoren-9-one (3q)
Eluent: petroleum ether/dichloromethane (2:1). Red solid
o
1
Eluent: petroleum ether/dichloromethane (10:1). Yellow
(573.5 mg, 86%, mp = 254 - 256 C). H NMR (500 MHz,
o
1
solid (38.8 mg, 78%, mp = 157 - 159 C). H NMR (500 MHz,
CDCl3) δ 7.87 (d, J = 1.5 Hz, 2H), 7.68 – 7.66 (m, 2H), 7.52
CDCl3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H),
(d, J = 7.8 Hz, 2H), 7.48 (d, J = 8.7 Hz, 4H), 7.29 – 7.25 (m,
7
.54 – 7.50 (m, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.36 – 7.33 (m,
13
1
8H), 7.14 – 7.13 (m, 12H), 7.05 (t, J = 7.3 Hz, 4H). C{ H}
NMR (126 MHz, CDCl3) δ 194.0, 147.8, 147.5, 142.6, 141.5,
135.2, 133.4, 132.6, 129.4, 127.4, 124.7, 123.5, 123.2, 122.4, 120.7.
HRMS (ESI) m/z: M+ calcd for C49H34N2O 666.2666;
Found 666.2619.
13
1
1
1
H). C{ H} NMR (126 MHz, CDCl3) δ 189.8, 144.7, 141.8,
35.4, 135.0, 134.4, 133.7, 131.3, 131.1, 129.8, 124.8, 120.4, 119.1.
HRMS (ESI) m/z: M+ calcd for C13H6Cl2O 247.9796, found
47.9802.
2
1,2-dichloro-5,7-dimethyl-9H-fluoren-9-one (3r)
3,4-dichloro-4'-methyl-[1,1'-biphenyl]-2-carbaldehyde
(
5)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (37.1 mg, 67 %, mp = 144 - 146 C). H NMR (500 MHz,
Eluent: petroleum ether/dichloromethane (10:1). White
o
1
CDCl3) δ 7.52 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H),
solid (14.3 mg, 27%, mp = 71 - 73 C). H NMR (500 MHz,
13
1
7
.35 (s, 1H), 7.09 (s, 1H), 2.52 (s, 3H), 2.35 (s, 3H). C{ H}
NMR (126 MHz, CDCl3) δ 190.5, 145.9, 139.9, 138.3, 137.0,
35.1, 134.6, 133.5, 133.3, 131.4, 131.1, 123.1, 121.6, 21.1, 20.2.
CDCl3) δ 10.00 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.25 – 7.23
13
1
(m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H). C{ H} NMR
126 MHz, CDCl3) δ 190.7, 144.5, 138.6, 134.0, 133.9, 133.6,
1
(
HRMS (ESI) m/z: M+ calcd for C15H10Cl2O 276.0109,
found 276.0097.
133.1, 132.2, 129.9, 129.5, 129.3, 21.2. HRMS (ESI) m/z:
[M+Na]+ calcd for C14H10Cl2ONa 287.0001; Found
286.9979.
7-(tert-butyl)-1,2-dichloro-9H-fluoren-9-one (3s)
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (43.3 mg, 71%, mp = 112 - 114 C). H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 1.7 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.42 (d,
13
1
J = 7.8 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 1.35 (s, 9H). C{ H}
NMR (126 MHz, CDCl3) δ 190.3, 153.8, 144.8, 139.2, 135.3,
The Supporting Information (SI) is available free of charge via
the Internet at http://pubs.acs.org.
Conditional screening, spectral data, X-ray data (PDF)
1
33.9, 133.8, 131.9, 131.4, 131.1, 122.0, 120.2, 118.9, 35.2, 31.2.
HRMS (ESI) m/z: M+ calcd for C17H14Cl2O 304.0422,
found 304.0414.
Crystallographic data (CIF)
1,2-dichloro-7-phenoxy-9H-fluoren-9-one (3t)
CCDC 1923373 1942120 1941843 contains the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge via www.ccdc.cam.ac.uk/data_re-
quest/cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Eluent: petroleum ether/dichloromethane (10:1). Yellow
o
1
solid (38.6 mg, 58%, mp = 96 - 98 C). H NMR (500 MHz,
CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.38
(t, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.18
(t, J = 7.4 Hz, 1H), 7.14 – 7.12 (m, 1H), 7.05 (d, J = 7.7 Hz, 2H).
13
1
C{ H} NMR (126 MHz, CDCl3) δ 189.2, 159.5, 156.0, 144.7,
1
1
36.2, 135.7, 135.6, 133.6, 131.3, 131.3, 130.2, 130.1, 124.4, 124.2,
21.7, 119.5, 119.2, 118.7, 114.6. HRMS (ESI) m/z: M+ calcd for
C19H10Cl2O2 340.0058, found 340.0047.
*Email: fanglinzhang@whut.edu.cn (F.Z.)
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*Email: ltj2008@jsnu.edu.cn (T.L.)
(5) (a) Li, H.; Zhu, R.; Shi, W.; He, K.; Shi, Z. Synthesis of Flu-
orenone Derivatives through Pd-Catalyzed Dehydrogenative Cy-
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C.; Cheng, C. Pd-catalyzed double C-H bond activation of diaryl
ketones for the synthesis of fluorenones. Chem. Commun. 2012, 48,
The authors declare no competing financial interest.
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379–9381. (c) Kishore, R.; Priya, S. S.; Sudhakar, M.; Venu, B.;
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (no. 21772070),
Natural Science Foundation of Hubei Province (2018CFB505).
Venugopal, A.; Yadav, J.; Kantam, M. L. Synthesis of fluorenones
by using Pd(II)/Mg-La mixed oxide catalyst. Catal. Sci. Technol.
2015, 5, 3363–3367. (d) Moorthy, J. N.; Samanta, S. Photoinduced
C-Br Homolysis of 2-Bromobenzophenones and Pschorr Ring Clo-
sure of 2-Aroylaryl Radicals to Fluorenones. J. Org. Chem. 2007,
0
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2, 9786–9789. (e) Haggam, R. A. Cu(I)-catalyzed intramolecular
(
1) Shi, Y.; Gao, S. Recent advances of synthesis of fluorenone
and fluorene containing natural products. Tetrahedron 2016, 72,
717–1735.
2) (a) Robarge, M. J.; Husbands, S. M.; Kieltyka, A.; Brodbeck,
R.; Thurkauf, A.; Newman, A. H. Design and synthesis of [(2,3-
dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as
cyclizations of substituted 2-iodobenzophenones under thermal
and microwave conditions. Tetrahedron 2013, 69, 6488–6494. (f)
Lockner, J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Practical
Radical Cyclizations with Arylboronic Acids and Trifluoroborates.
Org. Lett. 2011, 13, 5628–5631. (g) Seo, S.; Slater, M.; Greaney, M. F.
Decarboxylative C-H arylation of benzoic acids under radical con-
ditions. Org. Lett. 2012, 14, 2650–2653.
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(
novel ligands selective for the dopamine D3 receptor subtype. J.
Med. Chem.2001, 44, 3175–3186. (b) Krueger, R. F.; Mayer, G. D.
Tilorone hydrochloride: an orally active antiviral agent. Science
(6) (a) Campo, M. A.; Larock, R. C. Synthesis of Fluoren-9-ones
via Palladium-Catalyzed Cyclocarbonylation of o-Halobiaryls.
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