Pd-catalyzed double C-H bond activation of diaryl ketones for the synthesis of fluorenones

Article abstract of DOI:10.1039/c2cc34344d

An efficient synthesis of fluorenones from diaryl ketones by Pd-catalyzed oxidative cyclization is described. A possible mechanism involving a carbonyl group assisted ortho-C-H activation and cyclometalation followed by a second C-H activation to form a six-membered palladacycle and reductive elimination is proposed.

Full text of DOI:10.1039/c2cc34344d

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Pd-Catalyzed Double CH Bond Activations of Diaryl Ketones for the
Synthesis of Fluorenones
Parthasarathy Gandeepan, Chen-Hsun Hung and Chien-Hong Cheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient synthesis of fluorenones from diaryl ketones by
Pd-catalyzed oxidative cyclization is described. A possible
mechanism involving a carbonyl group assisted ortho-CH
activation and cyclometalation followed by a second CH
activation to form a six-membered palladacycle and reductive
elimination is proposed.
biaryl carboxylic acids, Pschorr cyclization reaction and
transitionmetalcatalyzed cyclization of 2-haloarylketones and
6
cyclocarbonylation reaction of ortho-halobiaryls are known. Our
40
group has developed a convenient method to access a variety of
fluorenone derivatives from O-methyl aryl aldoxime ethers and
aryl iodides or from simple arenes using Pd-catalyzed multiple
1
0
7
CH activation reactions. Apart from us, other research groups
Transitionmetalcatalyzed oxidative CH coupling is an
also applied the CH activation methodologies to fluorenone
8
attractive method for the synthesis of biaryls. Utilization of no 45 synthesis. As a continuation of our earlier success of ortho-CH
9
pre-functionalized two CH bonds as the coupling partners for
the biaryl synthesis avoids the steps for installation of pre-
activated functional groups. In recent years, a number of effective
functionalization of aryl ketones, we wish to report an effective
method for the synthesis of fluorenones from diaryl ketones via
Pd-catalyzed oxidative cyclization.
1
2
2
3
5
0
5
0
1
The attempt to transform diaryl ketones to the corresponding
By contrast, intramolecular CC bond formations through 50 fluorenones was initiated by heating benzophenone 1a in the
intermolecular oxidative CH couplings have been developed.
oxidative CH couplings are not widely examined. In an early
example, synthesis of dibenzofurans from diaryl ethers were
attained by oxidative CC bond formation using stoichiometric or
presence of a Pd(II) catalyst. Since the combination of Pd(OAc)
and Ag O is known to be an effective catalyst system for ortho-
CH functionalization of ketones, we employed this system for
the oxidative cyclization of benzophenone (1a) to screen solvents
for this transformation. Heating 1a in CH COOH at 130 °C for
3
12 h with Pd(OAc) (10 mol%) and Ag O (1 equiv) gave
2 2
2
2
9
2
catalytic amount of Pd complexes. Afterwards, various research
5
6
6
7
7
5
0
5
0
5
groups extended this methodology to the synthesis of carbazole
3
and indole derivatives from diaryl amines and enaminones. This
strategy was also used to form five-, six-, seven- and eight-
fluorenone 2a in 15% yield (Table 1, entry 1). When
trifluoroacetic acid (TFA) was used as the solvent, the yield of 2a
was increased in 60% yield (entry 2). The choice of solvent is
crucial for this transformation. Other solvents including pivalic
acid (PivOH), 1,2-dichloroethane (DCE), toluene, 1,4-dioxane, n-
butanol, DMF and DMSO were all not effective except PivOH
which gave fluorenone 2a in 34% yield (entries 3-9). We then
focused on the oxidant for this transformation. Several other
oxidants K S O , oxone, Cu(OAc) , benzoquinone and oxygen
4
member rings by intramolecular oxidative cyclization. However,
so far this type of reactions has only been applied to electron rich
substrates. With this contrast, we wish to explore the possibility
of oxidative cyclization of electron deficient diaryl ketones to
form fluorenone derivatives (Scheme 1).
2
2
8
2
(
O ) were used as the oxidant for the transformation and no
2
desired product 2a was observed (entries 10-14). Later, we
examined the reaction time of the reaction in entry 2. As the
reaction time was extended to 24 h using Ag O as an oxidant, the
2
yield of 2a was increased to 85% (entry 15). Other silver salts
such as AgOAc, Ag CO are also effective in this transformation
2
3
to produce 2a in 70 and 74% respectively (entries 16-17). When
the amount of Ag O was increased to 1.5 equiv, the yield of 2a
2
was increased to 93%. Without an oxidant, only 6% of product 2a
Scheme 1
was observed. These results reveal the importance of Ag O in this
2
transformation (entry 20). Finally, in the absence of Pd(OAc)2,
The fluorenone structure is an important moiety in many
natural products, drugs and organic light emitting materials.
Ag O alone gave no reaction product 2a (entry 21).
5
2
3
5
Various synthetic methods towards the synthesis of fluorenones
including oxidation of fluorenol, FriedalCraft cyclization of
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[journal], [year], [vol], 00–00 | 1

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Table 1 Optimization studies for Pd-catalyzed oxidative cyclization of
diaryl ketone
Table 2 Optimization studies for Pd-catalyzed oxidative cyclization of
diaryl ketone
a
a
Time
h/Temp ºC
Yield
(%)
Yield
(%)
Entry
Oxidant/equiv
Solvent
AcOH
TFA
b
Entry
1
Diaryl Ketone 1
Time h
24
Product 2
b
1
2
Ag
2
2
O/1
O/1
12/130
15
88
86
81
Ag
12/130
60
1
1
a
2a
3
4
5
6
7
8
9
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
O/1
O/1
O/1
O/1
O/1
O/1
O/1
PivOH
DCE
toluene
dioxane
butanol
DMF
DMSO
TFA
12/130
12/130
12/130
12/130
12/130
12/130
12/130
12/130
12/130
12/130
12/130
12/130
24/130
24/130
24/130
24/130
24/130
24/130
24/130
24/120
34
-
2
3
24
24
-
b
2
b
-
-
-
1c
2
c
-
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
K
2
S
2
O
8
/2
Oxone/2
Cu(OAc) /2
-
TFA
-
1
1
4
5
6
7
8
1d: R = OMe
24
30
30
36
36
2d: R = OMe
83
71
63
91
90
1
1
1e: R = Cl
2e: R = Cl
2
TFA
-
1
1
1f: R = F
2f: R = F
1
1
O
2
TFA
-
1g: R = C(CH
3
)
3
2g: R = C(CH
3
)
3
1
1
1h: R = Ph
2h: R = Ph
BQ
Ag O/1
AgOAc/2
Ag CO /1
Ag O/2
TFA
-
2
TFA
85
70
74
96
93
6
TFA
1
2
1
2
9
1i: R = R = Me
2i: R = R = Me
88
74
2
3
TFA
1
2
1
2
1
0
1j: R = R = OMe
24
36
2j: R = R = OMe
2
TFA
Ag
2
O/1.5
TFA
1
1
79
-
TFA
1
k
2
k
c
2
1
Ag
2
2
O/1.5
O/1.5
TFA
-
2
2
Ag
TFA
81
1
2
36
72
a
All reactions were carried out using benzophenone 1a (1.0 mmol),
Pd(OAc) (10 mol %), oxidant (1-2 equiv) and solvent (2.0 mL) at 130 ºC
for 12-24 h. Yields of 2a were measured by H NMR, using mesitylene
1
l
2l
5
0
5
0
5
2
b
1
c
2
as an internal standard. No Pd(OAc) was used.
With the optimized reaction conditions in hand, we next
examined the scope of diaryl ketones for the formation of
fluorenone derivatives (Table 2). Thus, by using the reaction
1
2
1
2
1
1
15
3
4
1m: R = 2-F; R = H
1n: R = 2-F; R = Me
1o: R = 3-F; R = H
30
30
30
2m: R = 2-F; R = H
68
1
2
1
2
2n: R = 2-F; R = Me 76
1
2
1 2
1
1
2
2
2o: R = 3-F; R = H
71
conditions Pd(OAc)2 (10 mol %), Ag O (1.5 equiv) in
a
2
All reactions were carried out using diaryl ketone 1 (1.0 mmol),
Pd(OAc) (10 mol %), Ag O (1.5 equiv) and TFA (2.0 mL) at 130 ºC for
24-36 h. Isolated yield.
trifluoroacetic acid for 24-36 h at 130 °C, simple benzophenone
3
0
2
b
2
1
1
a afforded fluorenone 2a in 88% isolated yield (Table 2, entry
). The product was carefully characterized by H, C and mass
1
13
benzophenones 1e and 1f also reacted smoothly, but with
extended reaction time to produce the corresponding fluorenone
derivatives 2e and 2f in 71 and 63% yields, respectively (entries 5
and 6). 4-tert-Butyl, 4-phenyl substituted benzophenone 1g and
spectral data. Phenyl(p-tolyl)methanone 1b and phenyl(m-
tolyl)methanone 1c gave the corresponding fluorenone
derivatives 2b and 2c in 86 and 81% yield, respectively (entries
35
2
-3). For 3-methyl benzophenone, the reaction proceeded in an
1
h afforded fluorenone derivatives 2g and 2h in 91 and 90%
excellent regioselective manner providing only one regioisomer
2c. This presumably is due to the steric effect of methyl
substituent (entry 3) preventing CH bond activation at the
carbon ortho to the keto and the methyl group. Similarly, 4-
OMe-substituted benzophenone 1d offered the corresponding
fluorenone derivative product 2d in 83% yield (entry 4).
Electron-withdrawing halogens like 4-Cl, 4-F substituted
yield, respectively. Di(p-tolyl)methanone (1i) and bis(4-
methoxyphenyl)methanone (1j) were also treated under the
standard reaction conditions to give fluorenones 2i and 2j in 88
and 74% yield respectively. 2-Naphthyl benzophenone 1k was
also transformed to benzofluorenone 2k in 79% under the
standared reaction conditions. In this reaction, there are two CH
activation sites at C2 and C6 of 1k. However, the activation
40
2
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occurs only at C6, owing to to the steric effect of the fused
aromatic ring. Similarly, 1-benzoyl naphthalene 1l underwent the
transformation to afford benzoanthracenone 2l in 72% yield
entry 12). There are two possible CH functionalization sites at
3
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1
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(
5
0
5
0
C2 and C8 for substrate 1l, but the C8 functionalized product 2l
was observed exclusively. The regioselectivity is surprising, but
the reason for the observed selectivity is not clear. The product
structure was assigned based on comparison of the NMR data
1
0
with those reported previously. The oxidative cyclization of 2-F
and 3-F substituted benzophenones 1m-1o also proceeded
smoothly to give the corresponding fluorenones 2m-2o in good
yields (entries 13-15).
5
022; (i) W. C. P. Tsang, N. Zheng and S. L. Buchwald, J. Am.
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[
1-4],[9]
Based on our observation and earlier literatures,
a
possible mechanism for this fluorenone formation is outlined in
Scheme 2. Initially, the ketone group of 1a is coordinated to
Pd(II) and the consecutive ortho-CH bond activation leads to the
formation of palladacycle A which is expected to be in
equilibrium with its palladium aryl -complex B. A second CH
bond activation in B takes place to form the six membered
palladium complex C and its reductive elimination gives the
fluorenone product and Pd(0) species. Oxidization of the Pd(0)
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70
species by Ag O to Pd(II) restarts the next catalytic cycle.
2
7
8
8
9
9
5
0
5
0
5
6
(a) R. A. Fernandes and Pradeep Kumar. Tetrahedron Lett., 2003, 44,
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2
5
In summary, we have developed an efficient approach to the
synthesis of fluorenones by Pd-catalyzed oxidative cyclization of
diaryl ketones. This simple method offers an alternative and
complimentary way to other fluorenone synthesis.
We thank the National Science Council of Republic of China
(NSC-100-2119-M-007-002) for support of this research.
3
0
7
8
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Notes and references
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*
3
Department of Chemistry, National Tsing Hua University, Hsinchu
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chcheng@mx.nthu.edu.tw
3
5
Electronic Supplementary Information (ESI) available: [Experimental
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procedures, compound characterizations, and the copies of H NMR and
1
3
C NMR spectra.]. See DOI: 10.1039/b000000x/
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