Pd-catalyzed multiple C-H functionalization to construct biologically active compounds from aryl aldoxime ethers with arenes

Article abstract of DOI:10.1002/chem.201102996

Functional fluorenones: Aromatic aldoxime ethers react with unactivated arenes catalyzed by palladium complexes to give biologically active fluoren-9-ones (see scheme). Multiple C-H bond activation and an oxidative cyclization are involved in the reaction.

Full text of DOI:10.1002/chem.201102996

COMMUNICATION
DOI: 10.1002/chem.201102996
À
Pd-Catalyzed Multiple C H Functionalization to Construct Biologically
Active Compounds from Aryl Aldoxime Ethers with Arenes
Vedhagiri S. Thirunavukkarasu and Chien-Hong Cheng*[a]
Fluorenones are an important structural scaffold found in
many natural products,[1] some antitumor drugs,[2] and com-
pounds for organic electronics.[3] In addition, fluorenone de-
rivatives are known to show various pharmaceutical proper-
ties that allows them to act as DNA G-Quadruplex-selective
binders or stabilizers, virus and enzyme inhibitors and recep-
tors.[4]
ed products has become very attractive recently.[10] Directing
groups such as anilides, pyridines, pyridine N-oxide, O-
phenyl carbamates, and imines have been used for this type
of biaryl synthesis.[11] Our continuous interest in metal-cata-
[12]
À
lyzed C H bond activation and cyclization reactions
prompted us to explore the reaction of Pd-catalyzed ortho-
À
directed multiple C H bond activation of aromatic aldox-
Several major synthetic methods for the preparation of
fluorenone derivatives have been reported including the oxi-
dation of fluorenol and fluorenes,[5a–b] Friedel–Crafts-type
ime ether with arenes. Herein, we disclose a complementary
method for the synthesis of fluorenone derivatives by using
this reaction. This reaction involves the formation of biaryls
cyclizations of biarylcarboxylic acid derivatives,[5c] C C
as the intermediates and requires a three-step C H bond ac-
À
À
bond formation under Pschorr cyclization reaction of 2-hal-
oarylketones to give fluorenones,[5d] transition-metal-cata-
lyzed cyclization of 2-haloarylketones,[5e] and the cyclocarbo-
nylation reaction of ortho-halobiaryls and benzyne.[5f–g] Pd-
tivation, however avoids the use of aryl halides or boronic
acids and expensive metal oxidant.
Initially, we chose benzaldehyde oxime ether (1a,
0.70 mmol) and benzene (2a, 2.0 mL) as model substrates
for the optimization studies. Oxime ether 1a was easily pre-
pared from the corresponding benzaldehyde and O-methyl
hydroxylamine hydrochloride. First, the reaction was carried
À
catalyzed directing-group-assisted C H bond activation is a
promising and efficient methodology for the synthesis of flu-
orenone derivatives (Scheme 1). First, Larock and co-work-
out using PdACTHUNRGTNEUNG(OAc)2 (10 mol%) as the catalyst in the pres-
ence of different silver salts such as Ag2O, Ag2CO3, or
AgOAc. However, no conversion was observed at 1208C for
36 h. Next, we tried other oxidants including Cu
ACHTUNGRTENN(UNG OAc)2, BQ,
and PhI(OAc)2, again no desired product was obtained.
AHCTUNGTRENNUNG
When we used oxone as the oxidant, the reaction afforded a
mixture of fluorenone oxime ether 3A in 15% and fluore-
none 3a in 22% isolated product yields. The mixture was
then hydrolyzed to give 3a in 32% yield. The replacement
of oxone by potassium persulfate (K2S2O8) afforded the de-
sired product 3a in 57% yield. As the catalyst loading was
increased to 20 mol%, compound 3a was obtained in 78%
yield. If both the amount of trifluoroacetic acid (TFA) and
oxidant increase, the yield of 3a decreases, but biphenyl
from oxidative coupling of benzene (2a) became the major
product. Controlled experiments revealed that no product
Scheme 1. Complementary method for the synthesis of fluorenones.
ers reported the synthesis of fluorenones from 2-iodophen-
yl(2-phenyl-benzylidene)amine by using a palladium migra-
tion method.[6] In 2008, Daugulis reported the synthesis of
fluorenones from simple aromatic amides and aryl halides.[7]
We also reported the synthesis of functionalized fluore-
nones from O-methyl benzaldehyde oxime ethers and aryl
halides catalyzed by a palladium complex[8] Later, Shi et al.
developed a Pd-catalyzed synthesis of fluorenones from O-
methyl benzaldehyde oxime ethers and aryl boronic acids.[9]
was observed in the absence of PdACTHNUTRGENUG(N OAc)2 or TFA.
With the optimized conditions in hand, we next examined
the scope of the substrates. As shown in Table 1, the reac-
tion of electron-donating aryl aldoxime ethers such as 4-
methyl, 3-methyl and 4-tert-butyl benzaldehyde oxime
ethers 1b–1d with benzene proceeded smoothly to give the
corresponding substituted fluorenone derivatives in good
yields (Table 1, entries 2, 9, and 3). Interestingly, for sub-
À
The regioselective coupling of two arenes through C H
bond activation in both arenes to give biaryls or other relat-
[a] Dr. V. S. Thirunavukkarasu, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu, 30013 (Taiwan)
À
strate 1c, there are two possible sites at C2 and C6 for C H
Fax : (+886)35724698
E-mail: chcheng@mx.nthu.edu.tw
bond activation, but the reaction occurred only at C6, which
is most likely due to the steric effect of methyl group at C3.
The aromatic aldoxime ethers having an electron-withdraw-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102996.
Chem. Eur. J. 2011, 17, 14723 – 14726
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14723

Table 1. Results of the reaction of aromatic aldoxime ethers with arenes.[a]
Entry
1
2
Product 3
Yield [%][b] Entry
1
2
Product 3
Yield [%][b]
1
1a 2a
3a 78
12
13
1i
2a
3i
69
1m 2a
3m 49
2
3
4
5
R=Me
R=tBu
R=Cl
R=F
1b 2a
1d 2a
1e 2a
1h 2a
3b 62
3d 77
3e 82
3h 56[c]
14
15
16
17
1n 2a
1a 2b
1a 2c
1a 2d
3n 42
3o 51
3p 65
3q 39
6
R=CF3
1j 2a
3j 74[c]
18
1 f 2b
3r 73
7
8
R=Ph
1k 2a
1l 2a
3k 71
3l 53
19
20
1e 2b
3s 85[d]
R=NO2
1e 2c
3t
91[d]
9
1c 2a
3c 55[c]
21
22
1h 2b
3u 64[c]
10
11
1 f 2a
1g 2a
3 f 63
1k 2b
3v 69[d]
3g 71[c]
[a] Unless otherwise mentioned, all reactions were carried out using aldoxime ethers 1 (0.7 mmol), arenes 2 (2 mL), Pd
ACHTNUGTNERN(UNG OAc)2 (20 mol%), K2S2O8
(1.4 mmol) and TFA (7.0 mmol) at 1208C for 15 h. Following filtration, the filtrate was treated with an aqueous solution of HCl (8 molLÀ1, 2 mL),
1008C, 6–8 h. [b] Isolated product yields. [c] PdACTHUNTGRNNEGU(OAc)2 (20 mol%), K2S2O8 (2.8 mmol) and TFA (14.0 mmol) [d] PdAHCTUTGNERN(NUGN OAc)2 (20 mol%), K2S2O8
(3.5 mmol) and TFA (21.0 mmol).
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À
Pd-Catalyzed Multiple C H Functionalization
COMMUNICATION
ing group appear compatible with the present catalytic reac-
tions. Thus, the reaction of 4-chloro-, 3-chloro-, 2-chloro-, 3-
bromo-, and 4-trifluoromethyl-benzaldehyde oxime ethers
1e–j with 2a afforded the corresponding fluorenones 3e–3j
in 82–74% yields (Table 1, entries 4, 10, 11, 12, and 6). 4-
Phenyl and 4-nitro benzaldehyde oximes 1k–l were also effi-
ciently arylated under the reaction conditions (Table 1, en-
tries 7 and 8) to give the expected products 3k–l in good
yields. The reaction of 1-naphthyl and 2-naphthyl oxime
ethers with 2a also proceeded smoothly to give benzoan-
thracenone and benzofluorenone, in moderate yields
via PdIV.[13] In the second cycle, 7a is converted to fluore-
À
none oxime ether 3A catalyzed by the Pd complex with C
H bond activation and an insertion reaction as the key steps.
During the reaction, the Pd0 that is generated is reoxidized
to the active PdII by potassium persulfate.
The proposed mechanism is strongly supported by the iso-
lation of a 5-membered palladacycle 4 (Scheme 2) and its re-
action with arenes under various conditions. Complex 4 was
prepared by the cyclometallation of 1a with PdACHTUNGTRENNUNG(OAc)2
(1 equiv) in TFA at 508C in 67% yield. The structure of 4
was confirmed by the single-crystal X-ray crystallographic
analysis. Notably, the Pd complex is dimeric in nature with
trifluoroacetate ligands bridging the two palladium metals.
À
(Table 1, entries 13 and 14). There are two possible C H
bond functionalization sites at C2 and C8 for substrate 1m,
but the C8-functionalized product 3m was observed exclu-
sively.
In addition, there is a weak interaction between the two pal-
[11f,g]
À
ladium nuclei with a Pd Pd distance of 2.882 ꢁ.
Next, we investigated the arylation of benzaldehyde
oxime ether 1a with various arenes. Benzaldehyde oxime
ether 1a reacted nicely with toluene and anisole as the cou-
pling partner to afford the regioselective fluoren-9-ones 3o
and 3p in good yields (Table 1, entries 15 and 16). The
transformation is highly site-selective at the 4-position and
then at 3-position of arenes. No other regioisomeric product
of 3o and 3p was observed indicating that the arylation step
does not occur at C2- or C3-position of the substituted
arene. The reaction of fluorobenzene 2d having an electron-
withdrawing fluoro group with 1a was less efficient and
gave fluorenone 3q in a lower yield (Table 1, entry 17). Fi-
nally, the coupling of aldoxime ether 1e having an electron-
withdrawing 4-chloro group with 2b and 2c afforded the
functionalized fluorenones 3r–3v in excellent yields
(Table 1, entries 18–22).
When complex 4 was treated with benzene and K2S2O8
(2 equiv) in TFA at 1208C for 15 h, the cyclization product
3a was produced in 83% yield (Scheme 3). If the same reac-
Scheme 3.
tion was carried out in the absence of K2S2O8 and TFA, no
desired product was observed. Similarly, no product 3A was
observed when 4 was treated with benzene and K2S2O8 in
the absence of TFA. These results show that both K2S2O8
and TFA are required for the transformations of complex 4
to product 3A via intermediate 6a. In the above reaction
(Scheme 3) or in the catalytic reactions (Table 1), no inter-
mediate product 6 was found in the product mixture. How-
ever, if the catalytic reaction of 1a with 2a was allowed for
only 25 min, product 6a was isolated in 7%. Whereas, with
a longer reaction time, this intermediate (6a) disappeared
completely. These observations, coupled with the fact that 4
can be easily generated at low temperature, suggest that the
arylation step, that is, the reaction of 4 with arene, is likely
to be the rate limiting step in the present catalytic reaction.
To further understand the nature of the catalytic reaction,
we next examined competition experiments using 4 as the
substrate. Treatment of 4 with 1:1 mixture of benzene and
anisole afforded products 3 A and 3P in a 1:2 ratio, indicat-
ing that the arylation is faster with electron-rich arene
(Scheme 4). This is in agreement with the results shown in
Table 1 that electron-rich arenes gave high yields of product
3 (Table 1, entries 15–17). Indeed, a catalytic competition
experiment of 1a with benzene and chlorobenzene
(Scheme 5) also supports the relative trends.
A plausible mechanism for the catalytic reaction of aldox-
ime ether 1a with arene 2a is proposed as shown in
Scheme 2, which is based on previously reported chelation-
À
assisted cross-couplings through C H bond functionaliza-
tion.[8,13] The catalytic reaction likely consists of two catalytic
cycles. The first one involves the formation of palladacycle
4, the oxidation of 4 by persulfate to give a PdIV intermedi-
ate 5 and arylation of 5 by benzene to afford 6. Then, reduc-
tive elimination leads to ortho-arylated product 7a and PdII.
It is known that acetoxylation and arylation of palladacycle
in the presence of strong oxidant were proposed to proceed
In conclusion, we have developed a useful and convenient
method for the synthesis of fluoren-9-one derivatives from
Scheme 2. Proposed mechanism (For clarity, some ligands on palladium
intermediates are omitted). X=OCOCF3.
Chem. Eur. J. 2011, 17, 14723 – 14726
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www.chemeurj.org
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C.-H. Cheng and V. S. Thirunavukkarasu
[3] a) H. Usta, A. Facchetti, J. T. Marks, Org. Lett. 2008, 10, 1385; b) K.
Itami, K. Tonogaki, T. Nokami, Y. Ohashi, J.-I. Yoshida, Angew.
Chem. 2006, 118, 2464; Angew. Chem. Int. Ed. 2006, 45, 2404;
c) D. A. Shultz, J. C. Sloop, G. Washington, J. Org. Chem. 2006, 71,
9104; d) F. Cariati, U. Caruso, R. Centore, A. De Maria, M. Fusco,
B. Panunzi, A. Roviello, A. Tuzi, Opt. Mater. 2004, 27, 91.
[4] I.-J. Kang, L.-W. Wang, S.-J. Hsu, C.-C. Lee, Y.-C. Lee, Y.-S. Wu, A.
Yueh, J.-C. Wang, T.-A. Hsu, Y.-S. Chao, J.-H. Chern, Bioorg. Med.
Chem. Lett. 2009, 19, 6063.
Scheme 4.
[5] a) W. Qian, E. Jin, W. Bao, Y. Zhang, Angew. Chem. 2005, 117, 974;
Angew. Chem. Int. Ed. 2005, 44, 952; b) A. Dhakshinamoorthy, M.
Alvaro, H. Garcia, J. Catal. 2009, 267, 1; c) S. Reim, M. Lau, P.
Langer, Tetrahedron Lett. 2006, 47, 6903; d) J. N. Moorthy, S. Saman-
ta, J. Org. Chem. 2007, 72, 9786; e) G. Qabaja, G. B. Jones, J. Org.
Chem. 2000, 65, 7187; f) M. A. Campo, R. C. Larock, Org. Lett.
2000, 2, 3675; g) N. Chatani, A. Kamitani, M. Oshita, Y. Fukumoto,
S. Murai, J. Am. Chem. Soc. 2001, 123, 12686.
[6] J. Zhao, D. Yue, M. A. Campo, R. C. Larock, J. Am. Chem. Soc.
2007, 129, 5288.
Scheme 5.
[7] D. Shabashov, J. R. M. Maldonado, O. Daugulis, J. Org. Chem. 2008,
73, 7818.
[8] V. S. Thirunavukkarasu, K. Parthasarathy, C.-H. Cheng, Angew.
Chem. 2008, 120, 9604; Angew. Chem. Int. Ed. 2008, 47, 9462.
[9] C.-L. Sun, N. Liu, B.-J. Li, D.-G. Yu, Y. Wang, Z.-J. Shi, Org. Lett.
2010, 12, 184.
[10] a) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009,
121, 6161; Angew. Chem. Int. Ed. 2009, 48, 9792; b) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147; c) X. Chen, K. M. Engle,
D. H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem.
Int. Ed. 2009, 48, 5094; d) D. R. Stuart, K. Fagnou, Science 2007,
316, 1172; e) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn, B.
DeBoef, Org. Lett. 2007, 9, 3137; f) P. Xi, F. Yang, S. Qin, D. Zhao,
J. Lan, G. Gao, C. Hu, J. You, J. Am. Chem. Soc. 2010, 132, 1822;
g) Y. Wei, W. Su, J. Am. Chem. Soc. 2010, 132, 16377.
substituted benzaldehyde oxime ethers with simple arenes.
In addition, this methodology provides synthesis of fluoren-
9-one that avoids the use of aryl halides, aryl boronic acids,
and expensive metal oxidants. The proposed mechanism is
supported by the isolation of a dimeric cyclopalladacycle 4
and its reaction with arenes.
Experimental Section
General procedure for the synthesis of fluoren-9-one derivatives: A
sealed tube (15 mL) (initially fitted with a septum) containing PdACTHNUTRGNE(NUG OAc)2
[11] a) G. Brasche, J. Garcıa-Fortanet, S. L. Buchwald, Org. Lett. 2008,
10, 2207; b) B.-J. Li, S.-L. Tian, Z. Fang, Z.-J. Shi, Angew. Chem.
2008, 120, 1131; Angew. Chem. Int. Ed. 2008, 47, 1115; c) K. L. Hull,
M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904; d) K. L. Hull,
M. S. Sanford, J. Am. Chem. Soc. 2009, 131, 9651; e) S. H. Cho, S. J.
Hwang, S. Chang, J. Am. Chem. Soc. 2008, 130, 9254; f) X. Zhao,
C. S. Yeung, V .M. Dong, J. Am. Chem. Soc. 2010, 132, 5837; g) C. S.
Yeung, X. Zhao, N. Borduas, V. M. Dong, Chem. Sci. 2010, 1, 331;
h) M. J. Tredwell, M. Gulias, N. G. Bremeyer, C. C. C. Johansson,
B. S. L. Collins, M. J. Gaunt, Angew. Chem. Int. Ed. 2011, 50, 1076;
i) S. J. Hwang, H. J. Kim, S. Chang, Org. Lett. 2009, 11, 4588; j) C.-L.
Sun, B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677.
(46 mg, 0.020 mmol) and potassium persulfate (560 mg, 2.00 mmol) was
evacuated and purged with nitrogen gas three times. Arenes (4 mL), tri-
fluoroacetic acid (1.18 g, 10.0 mmol), and aldoxime ether 1 (1.00 mmol)
were added to the system and the reaction mixture was stirred at 1208C
for 12–15 h until complete consumption of 1 (based on TLC monitoring).
Then, an aqueous solution of HCl (8 molLÀ1, 2 mL) was added to the
tube for hydrolysis at 1008C for 6–8 h. After completion of reaction, the
mixture was cooled, diluted with dichloromethane, filtered and then con-
centrated. Separation on a silica gel column using n-hexane/EtOAc as
eluent gave the corresponding pure fluoren-9-one product.
[12] a) V. S. Thirunavukkarasu, K. Parthasarathy, C.-H. Cheng, Chem.
Eur. J. 2010, 16, 1436; b) P. Gandeepan, K. Parthasarathy, C.-H.
Cheng, J. Am. Chem. Soc. 2010, 132, 8569; c) K. Muralirajan, K. Par-
thasarathy, C.-H. Cheng, Angew. Chem. 2011, 123, 4255; Angew.
Chem. Int. Ed. 2011, 50, 4169; d) T. T. Jayanth, C.-H. Cheng, Chem.
Commun. 2006, 894; e) P. Shukla, C.-H. Cheng, Org. Lett. 2006, 8,
2867; f) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org. Lett.
2008, 10, 325.
[13] a) L. V. Desai, H. A. Malik, M. S. Sanford, Org. Lett. 2006, 8, 1141;
b) G.-W. Wang, T.-T. Yuan, X.-L. Wu, J. Org. Chem. 2008, 73, 4717;
c) K. L. Hull, E. L. Lanni, M. S. Sanford, J. Am. Chem. Soc. 2006,
128, 14047; d) C. F. Rosewall, P. A. Sibbald, D. V. Liskin, F. E. Mi-
chael, J. Am. Chem. Soc. 2009, 131, 9488; e) P. A. Sibbald, C. F.
Rosewall, R. D. Swartz, F. E. Michael, J. Am. Chem. Soc. 2009, 131,
15945; f) J. Karthikeyan, C.-H. Cheng, Angew. Chem. 2011, 123,
10054; Angew. Chem. Int. Ed. 2011, 50, 9880; g) L.-M. Xu, B.-J. Li,
Z. Yang, Z.-J. Shi, Chem. Soc. Rev. 2010, 39, 712.
Acknowledgements
We thank the National Science Council of the Republic of China (NSC
99–2119-M-007–010) for support of this research.
À
Keywords: C H activation · cyclization · fluorenone · oxime
ether · palladium
[1] a) R. K. Arafa, T. Wenzler, F. A. Taniou, W. D. Stephens, C. E.
Wilson, D. W. Boykin, J. Med. Chem. 2005, 48, 5480; b) W. Zeng,
T. E. Ballard, A. G. Tkachenko, V. A. Burns, D. L. Feldheim, C.
Melander, Bioorg. Med. Chem. Lett. 2006, 16, 5148.
[2] a) E. Gonzꢂlez-Cantalapiedra, ꢃ. de Frutos, C. Atienza, C. Mateo,
A. M. Echavarren, Eur. J. Org. Chem. 2006, 1430; b) J.-M. Fu, B.-P.
Zhao, M. J. Sharp, V. Snieckus, Can. J. Chem. 1994, 72, 227; c) W.
Wang, V. Snieckus, J. Org. Chem. 1992, 57, 424; d) M. V. Sargent, J.
Chem. Soc. Perkin Trans. 1 1987, 2553.
Received: September 23, 2011
Published online: December 6, 2011
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Chem. Eur. J. 2011, 17, 14723 – 14726