Facile and selective aerobic oxidation of arylalkanes to aryl ketones using cesium carbonate

Article abstract of DOI:10.1055/s-2006-950189

Various arylalkanes such as fluorenes, xanthene, anthrone, 9,10-dihydroanthracene, and diphenylmethane are effectively transformed into the corresponding aryl ketones, while amino and aldehyde functionalities remain intact, under air in the presence of cesium carbonate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950189

PAPER
3617
Facile and Selective Aerobic Oxidation of Arylalkanes to Aryl Ketones Using
Cesium Carbonate
Aerobic
O
xidation
w
of Arylalkanesto
a
A
ryl
K
eton
n
es ghee Koh Park,*1 Lun K. Tsou, Andrew D. Hamilton*
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Fax +82(42)8218896 (Park); E-mail: khkoh@cnu.ac.kr (Park); fax +1(203)4323221 (Hamilton); E-mail: andrew.hamilton@yale.edu
(Hamilton)
Received 2 June 2006
Dedicated to Professor Marty Semmelhack on his 65th birthday
and open to air. After 3.5 hours, thin-layer chromatogra-
Abstract: Various arylalkanes such as fluorenes, xanthene, an-
phy showed quantitative conversion of fluorene into a sin-
gle product. Addition of water to the reaction mixture
throne, 9,10-dihydroanthracene, and diphenylmethane are effec-
tively transformed into the corresponding aryl ketones, while amino
resulted in precipitation of the product. Filtration of the
precipitates, washing with water, and then drying afforded
fluoren-9-one in an isolated yield of 96% without further
purification. This procedure is much superior to the previ-
ously reported methods4–9,11–14 in view of yield, cost, and
operational ease. Most noteworthy, the reaction is carried
out under open air, whereas the previously reported pro-
cedures require a molecular oxygen atmosphere of 1–3
atm.4–14
and aldehyde functionalities remain intact, under air in the presence
of cesium carbonate.
Key words: aerobic oxidation, oxygenation, arylalkanes, aryl ke-
tones, cesium carbonate
Alkanes are generally readily available and inexpensive
raw materials, and this makes the selective functionaliza-
tion of C–H bonds in alkanes an extremely important field
of chemistry.2 In particular, selective oxidation of alkanes
with molecular oxygen as oxidant is of great interest, due
to the fundamental and industrial aspects of the process as
well as the environmental advantages.3 Recently, oxygen-
ation of arylalkanes to give the corresponding carbonyl
compounds when using molecular oxygen has received
much interest.4–14 A number of reagents or catalysts such
as activated carbon,4 Ru(OH)x/Al2O3,5 N-hydroxyphthal-
imide,6–9 polyoxometalates,10–12 n-butyllithium,13 and
aqueous sodium hydroxide with phase-transfer catalyst14
have so far been reported for the oxygenation of arylal-
kanes with molecular oxygen. However, these all require
harsh reaction conditions and/or long reaction times,4–14
use catalysts that are not readily available,5,7–12 or give
only modest yields.4,6,8,9,11,12,14 Thus, development of an
alternative and convenient pathway for the transformation
is highly desirable. Herein we describe aerobic oxidation
of arylalkanes to aryl ketones in the presence of cesium
carbonate. Despite the many studies of benzylic C–H
bond oxygenation with molecular oxygen, the present
method is, to the best of our knowledge, unprecedented in
its convenience and effectiveness.
For comparison, the reaction was carried out in the pres-
ence of other metal carbonates and solvents, and different
amounts of cesium carbonate. The control reaction was
also carried out under nitrogen atmosphere. The results
are summarized in Table 1.
Table 1 Oxidation of Fluorene to Fluoren-9-one under Various
Conditionsa
O
Entry Base (base:fluorene) Solvent
Atmosphere Yieldb (%)
1
2
3
4
5
6
7
8
9
Cs2CO3 (1:1)
K2CO3 (1:1)
Na2CO3 (1:1)
Li2CO3 (1:1)
Cs2CO3 (1:1)
Cs2CO3 (1:1)
Cs2CO3 (2:1)
Cs2CO3 (3:1)
Cs2CO3 (3:1)
DMSO
DMSO
DMSO
DMSO
DMF
Air
Air
Air
Air
Air
Air
Air
Air
N2
78
71
0
0
67
0
THF
We initially studied the oxygenation of fluorene to fluo-
ren-9-one as a model reaction, since fluoren-9-one is use-
ful as an intermediate for various biologically active
compounds15,16 and this reaction has been most extensive-
ly studied.4–9,11–14
DMSO
DMSO
DMSO
90
>99
0
A mixture of fluorene and cesium carbonate (1:3 molar ra- a All the reactions were carried out at r.t. for 3.5 h.
b Fluoren-9-one yields were determined by integration of the 1H NMR
spectra of the precipitates obtained when H2O was added to the reac-
tion mixtures. The precipitates contained only fluorene and fluoren-
9-one, and the combined yield of fluorene and fluoren-9-one was
>95%.
tio) in dimethyl sulfoxide was stirred at room temperature
SYNTHESIS 2006, No. 21, pp 3617–3620
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950189; Art ID: Z11306SS
© Georg Thieme Verlag Stuttgart · New York

3618
K. K. Park et al.
PAPER
Table 1 shows that sodium carbonate and lithium carbon- of a methylene into a carbonyl functionality without con-
ate are not effective at all for the oxygenation reaction (en- current oxidation of an amino group in the same molecule.
tries 3 and 4), and potassium carbonate is less effective The reaction in entry 2 provides a convenient route to ami-
than cesium carbonate (compare entries 1 and 2). Chang- no-substituted fluoren-9-ones that have been prepared
ing the solvent from dimethyl sulfoxide to tetrahydrofuran previously either by oxidation of an amino-group-protect-
or N,N-dimethylformamide resulted in either no reaction ed fluorene4 or reduction of nitrofluoren-9-ones.15,16,19
(in THF, entry 6) or lower yield (in DMF, compare entries
The detailed mechanism for the transformation of the
1 and 5). A detailed clarification of the origin of the de-
methylene into a carbonyl group when using molecular
pendence of the reactivity on the nature of the alkaline
oxygen and cesium carbonate is not clear at this point, but
metal carbonate and solvent is beyond the scope of this
it possibly involves the pathway shown in Scheme 1.13
work. However, it is likely that the optimal effect of di-
The involvement of anionic intermediates is supported by
methyl sulfoxide arises from the better solubility of cesi-
the observation that electron-withdrawing groups in the
um carbonate in this solvent,17 and the enhanced
aryl ring facilitate the reaction (compare reaction times of
nucleophilicity of anions (see Scheme 1) in dimethyl sulf-
entries 1–3 in Table 2). Similarly, the requirement for the
oxide over other solvents.18 Greater amounts of cesium
bridged methylene group to be flanked by two aryl rings
carbonate, up to a threefold molar ratio, gave better yields
presumably derives from its greater acidity compared to
of the product (compare entries 1, 7, and 8). That no reac-
the single benzylic methylene group.
tion takes place under a nitrogen atmosphere (entry 9)
Scheme 1 shows carbanion A reacting with molecular
oxygen to produce the peroxy anion B. This can give the
final ketone product either directly through intramolecu-
clearly indicates that the oxidizing agent is molecular ox-
ygen in the air.
The remarkably simple and convenient reaction condi-
lar abstraction of a proton from the benzylic site by the
tions, easy workup procedure, and high yield for the trans-
peroxy anion with concomitant loss of hydroxide ion
(route a) or via intermediate C (route b). Proton removal
from the benzylic site of B to give C could occur by the
peroxy anion and/or cesium carbonate.
formation of fluorene to fluoren-9-one prompted us to
attempt to extend the scope of this methodology to the
oxygenation of other arylalkanes. Table 2 shows that the
methylene groups bridging two aryl groups, as in various
fluorene derivatives (entries 1–4), xanthene (entry 5), an-
H
H
H
O
throne (entry 6), diphenylmethane (entry 7), and 9,10-di-
hydroanthracene (entry 8), are efficiently transformed
into carbonyl groups under air in the presence of cesium
carbonate. Except for fluorene-2-carboxaldehyde (entry
4) and 9,10-dihydroanthracene (entry 8), the starting ma-
terial was completely converted into a single product, as
shown by thin-layer chromatography and 1H NMR spec-
troscopy. In the case of fluorene-2-carboxaldehyde, the
starting material disappeared within 10 minutes after stir-
ring in dimethyl sulfoxide to give a complex mixture of
products. We did not attempt to identify the products,
which may arise from the vulnerability of the aldehyde to
various anionic intermediates. We changed the solvent
from dimethyl sulfoxide to N,N-dimethylformamide to in-
vestigate the effect of lower reaction temperatures. Stir-
ring the reaction mixture in N,N-dimethylformamide at
0 °C for 1.5 hours and then at room temperature for 1 hour
afforded 9-oxofluorene-2-carbaldehyde in 72% yield after
column chromatography. Further lowering of the reaction
temperature to –40 °C gave a similar result. In the case of
9,10-dihydroanthracene, the reaction went to completion,
but two oxygenated products, anthraquinone and an-
thracene-9,10-diol were obtained in 4:1 ratio. A com-
pound containing a methylene group connected to only
one aromatic ring remained unchanged after prolonged re-
Cs2CO3
O2
H
O
Ar
C Ar
Ar
C Ar
Ar
C Ar
A
b
O
H
O
Ar
C
Ar
OH
O
B
Ar
C
Ar
a
b
C
O
C
Ar
Ar
Scheme 1 Proposed mechanism for the transformation of a methyl-
ene group into a carbonyl group in the presence of molecular oxygen
and cesium carbonate.
In conclusion, under air in the presence of cesium carbon-
ate, the bridging methylene group between two aryl rings
can be selectively oxidized to give the corresponding car-
bonyl group in high yield. This approach has advantages
over previously reported methods in terms of yield, cost,
and operational ease.
All the reagents and solvents were commercially available from ei-
ther Aldrich or J. T. Chemical Co., and were used without further
action time at high temperature, despite the presence of an purification. 1H NMR and 13C NMR spectra were recorded at 400
adjacent electronegative oxygen atom (entry 9).
and 100 MHz, respectively, in DMSO-d6, on a Bruker DPX 400
spectrometer. Chemical shifts are given in ppm. TLC was conduct-
ed with pre-coated silica gel glass plates with fluorescent indicator
It is noteworthy that easily oxidizable functionalities such
as amino (Table 2, entry 2) and aldehyde (entry 4) groups
remain intact under these reaction conditions. To our
knowledge, this is the first example of the transformation
active at UV light of 254 nm. Purification by column chromatogra-
phy was carried out on silica gel (230–450 mesh size).
Synthesis 2006, No. 21, 3617–3620 © Thieme Stuttgart · New York

PAPER
Aerobic Oxidation of Arylalkanes to Aryl Ketones
3619
Table 2 Aerobic Oxidation of Various Arylalkanes to Aryl Ketones in the Presence of Cesium Carbonatea
Entry
1
Starting material
Reaction conditions
r.t., 3.5 h
Product
Yieldb (%)
96
O
2
r.t., 16 h
96
NH2
NH2
H2N
H2N
O
3
4
5
6
r.t., 3 h
98
72c
97
94
Br
Br
O
0 °C, 1.5 h, then r.t., 1 h
CHO
CHO
O
O
r.t., 24 h
O
O
O
O
r.t., 16 h
O
7
8
80–90 °C, 48 h
r.t., 48 h
91
O
O
95d
OH
OH
+
O
9
80–90 °C, 72 h
No reactione
0
O
a In DMSO; Cs2CO3:arylalkane = 3.0:1 (except for entries 4 and 8).
b Isolated yields.
c In DMF; Cs2CO3:arylalkane = 1.1:1.
d Cs2CO3:arylalkane = 4.0:1; anthraquinone:anthracene-9,10-diol = ca. 4:1 (by 1H NMR integration data).
e Starting material recovered: 95%.
Oxidation of Arylalkanes (Table 2, entries 1–3, and 5–8);
General Procedure
which was a mixture of two oxidation products, anthraquinone and
anthracene-9,10-diol.
A mixture of arylalkane (1.5 mmol) and Cs2CO3 (1.466 g, 4.5
mmol) in DMSO (7 mL) was stirred under an atmosphere of air.
When TLC showed that no starting material remained (for appropri-
ate reaction times, see Table 2), H2O (25 mL) was added to the re-
action mixture to give precipitates (except in the case of entry 7, see
below). The precipitate was collected by suction filtration, washed
with H2O (3 × 5 mL), and then dried under vacuum to give the prod-
uct, which required no further purification, with the exception of the
reaction product of 9,10-dihydroanthracene (Table 2, entry 8),
In case of diphenylmethane (Table 2, entry 7), the reaction mixture
was extracted with CH2Cl2 (3 × 30 mL) after the addition of H2O.
The organic layers were combined, dried (anhyd Na2SO4), concen-
trated, and then dried under vacuum to give the desired product.
9-Oxofluorene-2-carboxaldehyde (Table 2, entry 4)
A soln of fluorene-2-carboxaldehyde (0.194 g, 1.0 mmol) in DMF
(5 mL) was added slowly to a suspension of Cs2CO3 (0.358 g, 1.1
mmol) in DMF (20 mL) at 0 °C under dry air. After the mixture had
Synthesis 2006, No. 21, 3617–3620 © Thieme Stuttgart · New York

3620
K. K. Park et al.
PAPER
Martell, A. E.; Sawyer, D. T., Eds.; Plenum: New York,
1993. (c) Weissermel, K.; Arpe, H.-J. Industrial Organic
Chemistry; VCH: New York, 1997.
been stirred at 0 °C for 1.5 h, the temperature was raised to r.t. and
stirring was continued for 1 h. H2O (50 mL) was added to the mix-
ture, which was extracted with CH2Cl2 (3 × 30 mL). The organic
layers were combined, dried (anhyd Na2SO4), concentrated, and
then purified by column chromatography (silica gel, CH2Cl2); this
gave 9-oxofluorene-2-carboxaldehyde; yield: 0.149 g (72%).
(4) Kawabata, H.; Hayashi, M. Tetrahedron Lett. 2004, 45,
5457; and references cited therein.
(5) Kamata, K.; Kasai, J.; Yamaguchi, K.; Mizuno, N. Org. Lett.
2004, 6, 3577.
(6) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.;
Iwahama, T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934.
(7) Wang, J.-R.; Liu, L.; Wang, Y.-F.; Zhang, Y.; Deng, W.;
Guo, Q.-X. Tetrahedron Lett. 2005, 46, 4647.
(8) Yang, G.; Zhang, Q.; Miano, H.; Tong, X.; Xu, J. Org. Lett.
2005, 7, 263.
(9) Nechab, M.; Einhorn, C.; Einhorn, J. Chem. Commun. 2004,
1500.
(10) Khenkin, A. M.; Weiner, L.; Wang, Y.; Neumann, R. J. Am.
Chem. Soc. 2001, 123, 8531.
(11) Yamaguchi, K.; Mizuno, N. New J. Chem. 2002, 26, 972.
(12) Lykakis, I. N.; Orfanopoulos, M. Tetrahedron Lett. 2004,
45, 7645.
(13) Harvey, R. G.; Abu-shqara, E.; Yang, C. X. J. Org. Chem.
1992, 57, 6313.
All products are known and available. The identities of the products
were confirmed by comparison of their spectroscopic and physical
data with those of authentic samples either commercially available
from Aldrich Chemical Co. (Table 2, entries 1, 3–8) or previously
reported (entry 2).15,20
2,7-Diaminofluoren-9-one (Table 2, entry 2)
Mp 276–278 °C (Lit.15 278–279 °C).
1H NMR15 (400 MHz, DMSO-d6): d = 5.30 (s, 4 H, NH2), 6.58 (dd,
J = 8, 2 Hz, 2 H, H-3,6), 6.70 (d, J = 2 Hz, 2 H, H-1,8), 7.09 (d, J =
8 Hz, 2 H, H-4,5).
13C NMR20 (100 MHz, DMSO-d6): d = 194.8, 148.1, 134.5, 133.2,
119.8, 118.5, 109.6.
Acknowledgment
(14) Mori, H. JP 2002212126, 2002; Chem. Abstr. 2002, 137,
124994.
This work was supported by the National Institutes of Health
(GM35208). K. K. Park is a recipient of a grant from the Internatio-
nal Visiting and Cooperative Research Program (2006) of Chung-
nam National University, Republic of Korea.
(15) Perry, P. J.; Read, M. A.; Davies, R. T.; Gowan, S. M.;
Reszka, A. P.; Wood, A. A.; Kelland, L. R.; Neidle, S. J.
Med. Chem. 1999, 42, 2679.
(16) Arafa, R. K.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson,
W. D.; Stephens, C. E.; Boykin, D. W. J. Med. Chem. 2005,
48, 5480.
(17) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis,
Vol. 7; Wiley: New York, 1979, 57.
(18) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry.
Part A; Kluwer: New York, 2000, 237–243.
(19) Yamashina, K.; Namimatsu, K.; Chiba, N. JP 9,031,036,
1997; Chem. Abstr. 1997, 126, 231517.
References
(1) On leave from the Department of Chemistry, Chungnam
National University, Daejeon 305-764, South Korea.
(2) (a) Sen, A. Acc. Chem. Res. 1998, 31, 550. (b) Shilov, A.
E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879.
(3) (a) Olah, G. A.; Molnár, A. Hydrocarbon Chemistry; Wiley:
New York, 1995. (b) The Activation of Dioxygen and
Homogeneous Catalytic Oxidation; Barton, D. H. R.;
(20) Hauser, A.; Thurner, J.-U.; Hinzmann, B. J. Prakt. Chem.
1988, 330, 367.
Synthesis 2006, No. 21, 3617–3620 © Thieme Stuttgart · New York