Synthesis of fluorenones by using Pd(ii)/Mg-La mixed oxide catalyst

Article abstract of DOI:10.1039/c4cy01732c

Palladium(ii)/magnesium-lanthanum mixed oxide (Pd(ii)/Mg-La mixed oxide) catalyst was used in the dehydrogenative cyclization of benzophenones to afford fluorenones. This protocol represents a direct and facile approach to accessing a variety of fluorenone derivatives by means of C-H activation under heterogeneous conditions. The catalyst was recovered by centrifugation and used for three consecutive cycles with nearly consistent activity and selectivity.

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PAPER
Synthesis of fluorenones by using Pd(II)/Mg-La mixed oxide
catalyst
Ramineni Kishore,a Samudrala Shanthipriya,a Medak Sudhakar,a Boosa Venu,a
Akula Venugopal,*a Jagjit Yadav,b and Mannepalli Lakshmi Kantam*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Unfortunately, most of these methods involve multistep
procedures and requires prefunctionalization of substrate to
Palladium(II)/magnesium-lanthanum
(Pd(II)/Mg-La mixed oxide) catalyst was used in the
dehydrogenative cyclization of benzophenones to afford
mixed
oxide
obtain fluorenones. Hence,
a simple route to synthesize
50 fluorenones is highly desirable from the economical and
environmental point of view. In the present study, an efficient,
straightforward and highly atom economical method is
established over Pd(II)/Mg-La mixed oxide catalyst that afforded
excellent yields of fluorenone derivatives in a single step under
55 heterogeneous reaction conditions. The fresh and used Pd(II)/Mg-
La mixed oxide catalysts are characterized by XRD and TEM
analysis and a plausible reaction mechanism is proposed.
10 fluorenones. This protocol represents a direct and facile
approach for accessing a variety of fluorenone derivatives by
means of C-H activation under heterogeneous conditions. The
catalyst was recovered by centrifugation and used for three
consecutive cycles with nearly consistent activity and
15 selectivity.
1. Introduction
2. Results and Discussion
Fluorenones are found in many natural products and medicinally
relevant molecules. Generally fluorenone derivatives are known
20 to exhibit extraordinary biological and optical properties.1 Several
methods were developed for the synthesis of fluorenones e.g.
oxidation of fluorenol and fluorenes, Friedel-Crafts cyclization of
biaryl carboxylic acid derivatives, Pschorr cyclization reaction of
2-haloaryl ketones, cyclization of 2-haloaryl ketones and the
25 cyclocarbonylation of ortho-halo biaryls.2 However, these
methods have some disadvantages such as the use of strong acids,
strong bases, toxic CO gas and harsh reaction conditions. Larock
and coworkers reported the synthesis of fluorenones by an aryl to
imidoyl palladium migration process.3 Daugulis group and J. -C.
30 Hsieh have reported the synthesis of fluorenones from aromatic
amides and aryl halides.4,5 Synthesis of functionalized
fluorenones from aromatic aldoxime ethers, aryl halides and
benzophenones using Pd(OAc)2 is reported by Cheng and
Owing to the industrial prevalence of the heterogeneous catalytic
60 processes over the homogeneous catalytic processes, C-H
functionalization using a heterogeneous catalyst constitutes an
important area of research in view of its ease of handling, simple
workup and regenerability. Earlier, we have demonstrated the
catalytic activity of palladium impregnated magnesium
65 lanthanum mixed oxide in the chemoselective hydrogenation of
10
olefinic double bonds and also for the oxidative sp2 C-H bond
acylation with alcohols.11 Herein, we describe the use of
Pd(II)/Mg-La mixed oxide as an efficient heterogeneous and
reusable catalyst for dehydrogenative cyclization of readily
70 available benzophenones by dual C-H bond activation to produce
industrially important fluorenones (Scheme 1).
O
O
Pd (II)/Mg-La (30 mg, 5.3 mol % Pd)
7
coworkers.6, Shi et al and others have recently reported the
Ag O (1 mmol), TFA:H O (1:1, 1 mL)
2
2
75
35 synthesis of fluorenones through dehydrogenative coupling by
dual C-H functionalization of benzophenone derivatives using
homogeneous palladium acetate catalyst.8 They have also
reported Pd catalyzed synthesis of fluorenones from O-methyl
benzaldehyde oxime ethers and aryl boronic acids.9
o
130 C, 24 h
Scheme 1 Synthesis of fluorenones over Pd(II)/Mg-La mixed oxide.
40
2.1. Characterization
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad – 500607, India. E-mail: mlakshmi@iict.res.in
b Polymers and Functional Materials Division, Indian Institute of
Chemical Technology, Hyderabad – 500607, India
45 † Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/b000000x/
The Mg-La mixed oxide was synthesized by co-precipitation of
80 Mg- and La nitrates.12 The Pd-doped Mg-La mixed oxide catalyst
(Pd(II)/Mg-La mixed oxide) was prepared by impregnation
method (see experimental section, supporting information).The
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powder X-ray diffraction analysis of the fresh and used
Pd(II)/Mg-La mixed oxide catalysts revealed the presence of
both La2O2(CO3) and PdO phases (Figure 1). Diffraction lines
appeared at 2θ = 29.55, 22.84, 13.1 [ICDD # 23-0435] and
their corresponding ‘d’ values 0.302, 0.389 and 0.675 nm are
attributed to lanthanum oxide carbonate phase. The diffraction
peaks are observed due to PdO phase at 2θ = 31.7, 45.54,
27.33 with the corresponding ‘d’ values of 0.282, 0.199, 0.326
nm that are in good agreement with ICDD # 46-1211.
Table 1 Screening of reaction parameters for dehydrogenative
hydrogenation of benzophenone
55
Entry
1
2
3
4
5
6
7
8
Oxidant/Equiv. Solvent
Yield (%)a
46
60
82
-
-
-
-
5
10
15
20
TFA/H2O (1:1)
Ag2O/1
Ag2O/1.5
Ag2O/2
Cu(OAc)2/5
K2S2O8/5
Ag2O/2
Ag2O/2
Ag2O/2
Cu(OAc)2/5
Ag2O/2
Ag2O/2
-
TFA/H2O (1:1)
TFA/H2O (1:1)
TFA/H2O (1:1)
TFA/H2O (1:1)
H2O
Chlorobenzene
DMSO/TFA(1mmol)
DCE
DCE
AcOH
TFA/H2O (1:1)
TFA/H2O (1:1)
TFA/H2O (1:1)
TFA/H2O (1:1)
Trace
-
-
9
10
11
12
13
14
15
40
-
b
-
Ag2O/2
Ag2O/2
Ag2O/2
60c
55d
a
Benzophenone (0.5 mmol), Catalyst (30 mg, 5.3 mol % of Pd), TFA/water (1:1
v/v %) solvent (1 mL).
b Without Pd(II)/Mg-La mixed oxide catalyst.
c Using Pd(II)/MgO (5.3 mol % of Pd) .
60 d Using Pd(II)/La2O3 (5.3 mol % of Pd).
Fig. 1 XRD patterns of the Pd(II)/Mg-La mixed oxide: fresh and used
25 catalysts
equiv.) showed enhanced efficiency in terms of chemical yield
(Table 1, entries 1, 2 and 3). Other oxidants such as Cu(OAc)2
and K2S2O8 are inactive in the transformation of benzophenone to
65 fluorenone (Table 1, entries 4 and 5). As seen in Table 1, the
choice of solvent has a crucial role in the reaction outcome.
TFA/water showed excellent cyclization activity (Table 1, entries
7, 9 and 10). However, combination of DMSO and TFA solvents
afforded a trace amount of fluorenone. On the other hand, the use
70 of AcOH as a solvent resulted in only 40% yield of the product
(Table 1, entries 8 and 11). It is important to note that in the
absence of Pd(II)/Mg-La mixed oxide and Ag2O, the reaction
failed to produce any product (Table 1, entries 12 and 13). The
TON is found to be 15.4 which is slightly higher than the
75 earlier report.7 The dehydrogenative cyclization of
benzophenone is also performed using other heterogeneous
catalysts such as Pd(II)/MgO and Pd(II)/La2O3 under similar
experimental conditions (Table 1, entries 14 and 15). However,
both the catalysts afforded lower yields of the product than using
80 Pd(II)/Mg-La mixed oxide catalyst. Presence of higher number
of basic sites on Pd(II)/Mg-La mixed oxide measured by CO2
pulse chemisorption (Table S1 in SI), seems to increase the
electron density on metal sites. As a result of it the catalytic
activity of Pd(II)/Mg-La mixed oxide is higher compared to
85 Pd(II)/MgO and Pd(II)/La2O3 samples. Under the optimized
reaction conditions, the reactivity of different substituted
benzophenones are investigated on Pd(II)/Mg-La mixed oxide
catalyst and the results are summarized in Table 2.
The transmission electron microscope (TEM) images of fresh and
used (after 1st cycle) Pd(II)/Mg-La mixed oxide catalysts are
reported in Figure 1a and Figure 1b. The average Pd particle size
is measured from TEM images (Figure 2) and found to be 38 and
30 43 nm for fresh and used catalysts respectively. The shapes of
palladium particles are spherical in both fresh and used samples.
35
40
Fig. 2 TEM images of the Pd (II)/Mg-La mixed oxide: [a] fresh and [b]
used catalyst (recovered after 1st cycle).
2.2. Dehydrogenative cyclization of benzophenones
45 In order to optimize the reaction conditions benzophenone was
chosen as a model substrate. The reaction of benzophenone using
Pd(II)/Mg-La mixed oxide (5.3 mol % of Pd), Ag2O (1 equiv)
and TFA/H2O (1:1 vol %, 1 mL) at 130 °C for 24 h gave the
desired cyclization product i.e. fluorenone with 46% isolated
50 yield (Table 1, entry 1). Encouraged by this result, several
optimization studies were conducted by altering the oxidant and
solvents. Increasing the quantity of oxidant (Ag2O, up to 2
2.3. Substrate scope
90 Benzophenones substituted with 4- and/or 3-methyl groups gave
the corresponding fluorenone derivatives in 72 and 70% yields
respectively [Table 2, entries 2 and 3]. However, the 2-substituted
benzophenone resulted in a moderate yield~50% [Table 2, entry
2
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4]. Similarly, 4-methoxy and 4.4ʹ-dimethoxy substituted
benzophenones have afforded the corresponding fluorenone
Reaction conditions: aSubstrate (0.5 mmol), Pd(II)/Mg-La mixed oxide
catalyst (30 mg, 5.3 mol % of Pd), Ag2O (2 equiv., 1mmol), TFA/Water
products of about 66 and 72% yields within 22 h [Table 2, entries 55 (1:1 v/v %, 1 mL) at 130 °C. bGC yields.
5 and 12]. It is interesting to note that the Pd(II)/Mg-La mixed
5
oxide is also compatible with chloro and fluoro substituted
benzophenones [Table 2, entries 6 and 7].
The 4-phenyl and 4, 4ʹ-difluoro substituted benzophenones
afforded fluorenones with 77 and 70% yields respectively [Table
2, entries 8 and 13]. The 3, 4-dimethyl and 4, 4ʹ-dimethyl
substituted benzophenones are also examined under the standard
60 reaction conditions which gave fluorenones yields of about 60
and 72% respectively [Table 2, entries 10 and 11]. Under the
optimized reaction conditions 2-benzonapthanone is also
transformed to benzofluorenone with 50% yield [Table 2, entry
9]. Apart from benzophenone, the benzophenone imine also
65 afforded the desired cyclization product of about 50% yield
[Table 2, entry 14]. All the products were carefully characterized
by 1H and 13C NMR spectroscopy.
Table 2 Dehydrogenative cyclization of different benzophenone
derivatives.
Yield (%)
82
Time (h)
24
Entry
1
Substrate
O
Product
O
O
O
O
10
15
20
25
30
35
40
45
50
2
72
20
O
O
22
40
70
3
4
2.4. Recyclability
The recyclability of the catalyst was examined using
70 benzophenone at 130 °C using 1:1 v/v % of TFA/water as solvent
and the results are shown in Figure 3. The activity graph
illustrates that the catalyst can be used for 3 consecutive cycles.
O
50b
O
O
O
5
6
22
24
66
85
MeO
Cl
MeO
Cl
100
75
O
O
80
60
40
20
O
7
8
24
22
60
77
80
F
0
F
Cycle 1
Cycle 2
Cycle 3
O
O
No of cycles
Fig. 3 Recyclability of catalyst.
O
O
O
O
In the recyclability studies, catalyst was recovered by simple
centrifugation method. The recovered catalyst was washed with
85 alkali and distilled water, air-dried and reused directly for the
next cycle without any further purification. The ICP-MS analysis
showed that the Pd content in the fresh and the used catalysts
were about 9.6% and 9.0% respectively.
22
50
9
O
24
22
60
72
10
11
O
3. Plausible reaction mechanism
90 A plausible reaction mechanism is proposed and reported in
Scheme 2 in conjugation with earlier reports.[6,7] In the first step
Pd particle activates the ortho-C-H of benzophenones to form (I).
In the next step, the activated hydrogen is replaced by
trifluoroacetate group which would form (II) as it is expected to
95 be in equilibrium with palladium aryl s-complex in (III).
Subsequently the six membered palladium complex (IV) may be
formed by activating the second hydrogen of benzophenone.
Reductive elimination of (IV) produces Pd(0) and fluorenone.
Finally Pd(0) species reacts with Ag(I) to regenerate the active
100 Pd(II) species for further cycles. The XRD analysis Pd(II)/Mg-La
mixed oxide also confirmed the presence of PdO phase in used
catalyst.
O
O
22
24
72
70
12
13
MeO
MeO
OMe
OMe
O
O
F
F
F
F
NH
NH
14
40
50b
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Page 4 of 4
1
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4. Conclusions
55
60
In summary, we have developed a simple and effective route for
the synthesis of various fluorenone derivatives using
a
heterogeneous reusable Pd(II)/Mg-La mixed oxide catalyst.
Utilization of inexpensive, readily available starting materials,
low catalyst loading, H2O as a solvent, short reaction time and
avoiding the use of base are significant advantages in this
investigation. Both electron rich and electron poor substrates
have been screened in this study and obtained good to excellent
5
10 yields towards various fluorenones.
65 2 (a) R. A. Fernandes and P. Kumar, Tetrahedron Lett., 2003, 44,
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H
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15
PdO
PdO PdO
Mg-La
PdO PdO
Mg-La
PdO
O
OOCCF3
(I)
PdO PdO PdO
Mg-La
Ag(0)
Ag(I)
20
(II)
Pd
Mg-La
Pd
Pd
O
OOCCF3
PdO
25
PdO PdO
Mg-La
O
O
(III)
PdO
PdO
PdO
Mg-La
3
4
5
J. Zhao, D. Yue, M. A. Campo and R. C. Larock, J. Am. Chem. Soc.
2007, 129, 5288-529.
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2008, 73, 7818-7821.
J. -C. Wan, J. -M. Huang, Y. -H. Jhan and J. -C. Hsieh, Org. Lett.,
2013, 15, 2742-2745.
CF3COOH
30
(IV)
Scheme 2 Plausible reaction mechanism of Pd(II)/Mg-La mixed
oxide catalyzed synthesis of fluorenones.
95 6 V. S. Thirunavukkarasu, K. Parthasarathy and C. -H. Cheng, Angew.
Chem., 2008, 120, 9604-9607.
7
8
9
P. Gandeepan, C. -H. Hung and C. -H. Cheng, Chem. Commun.,
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Acknowledgements
100
RK and MS thank the CSIR, New Delhi for the award of Senior
35 Research Fellowship. BV thank UGC for Junior Research
Fellowship, SSP thank the RMIT for financial support.
10 M. L. Kantam, R. Kishore, J. Yadav, M. Sudhakar and A. Venugopal,
Adv. Synth. Catal., 2012, 354, 663-669.
105 11 R. Kishore, M. L. Kantam, J. Yadav, M. Sudhakar, S. Laha and A.
Venugopal, J. Mol. Catal. A: Chem., 2013, 379, 213-218.
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Notes and references
‡ Typical procedure for synthesis of fluorenones by using Pd(II)/Mg-La
mixed oxide catalyst: A 10 mL round bottom flask was charged with
40 benzophenone (91.1 mg, 0.5 mmol), Pd(II)/Mg-La mixed oxide (30 mg,
5.3 mol % of Pd), Ag2O (231.7 mb, 2 equiv., 1mmol) and TFA/H2O (1:1
o
v/v %, 1 mL). The round bottom flask was kept stirring at 130 C for 24
h. After the completion of the reaction, as monitored by TLC, the catalyst
was separated by simple centrifugation, washed with distilled water for 5
45 times times, dried at 100 ºC and directly used for the next cycle without
any further purification. The reaction mixture was cooled and extracted
with dichloromethane (3x5 mL). The combined filtrate was dried with
Na2SO4 then concentrated and separated on a silica gel column using
hexane/EtOAc (15:1) as eluent gave the corresponding pure fluorenone
50 product with 82% yield.
References
4
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