Synthesis of fluorenones from aromatic aldoxime ethers and aryl halides by palladium-catalyzed dual C-H activation and heck cyclization

Article abstract of DOI:10.1002/anie.200804153

(Chemical Equation Presented) Highway to Heck: An efficient new one-pot palladium-catalyzed synthesis is described which affords a wide range of 9-fluorenone derivatives in good to excellent yields. A mechanism for the two distinct catalytic steps, C-H bond activation followed by oxidative intramolecular Heck cyclization, is proposed and reaction intermediates supporting this mechanism have been isolated.

Full text of DOI:10.1002/anie.200804153

Communications
DOI: 10.1002/anie.200804153
Synthetic Methods
Synthesis of Fluorenones from Aromatic Aldoxime Ethers and Aryl
À
Halides by Palladium-Catalyzed Dual C H Activation and Heck
Cyclization**
Vedhagiri S. Thirunavukkarasu, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Recently, directing-group-assisted activation of ortho aro-
Herein, we report a new palladium-catalyzed synthesis of
functionalized 9-fluorenone derivatives from aromatic aldox-
À
À
matic C H bonds, and subsequent C C bond formation by
coupling with organic halides or organometallic reagents have
been reported.[1] A variety of directing groups, such as acetyl,
À
ime ethers and aryl iodides, with two distinct steps, C H
activation and oxidative Heck cyclization, in one pot.
acetamino, carboxylic acid, oxazolyl, pyridyl, and imino
Treatment of benzaldehyde oxime ether 1a and iodoben-
zene (2a) with Pd(OAc)2 (10 mol%) and Ag2O (1 equivalent)
in trifluoroacetic acid (TFA) at 1208C for 36 h afforded a
mixture of fluorenone oxime ether 3A and fluorenone 3a in a
78:22 ratio, in 95% combined yield. The mixture was then
hydrolyzed to give 3a in 90% yield (Table 1, entry 1).
[2]
À
moieties have been used for C H bond activation. Aside
from the above functional groups, a few examples have been
À
reported using oximes as directing groups for C H bond
activation. Thus, Bezsoudnova and Ryabov reported the
isolation of an ortho-palladated aryl oxime from benzalde-
hyde oximes and a palladium complex.[3] Sanford and co-
workers reported a palladium-catalyzed O-methyl oxime-
The presence of a silver salt was crucial to the reaction.
Various silver salts were examined to investigate the effect on
the product yield. Among them, Ag2O gave the best results,
and afforded 3a in 90% yield. Other silver salts including
AgOAc, Ag2CO3, Ag(O2CCF3) and AgOTf are less effective,
giving 3a in 53, 36, 27, and 18% yields, respectively.
Replacing the silver salt with NaOAc led to no formation of
the expected product 3a. The effect of solvents was also vital
to the catalytic reaction. Reaction in TFA gave the best
results, affording 3a in 90% yield. Acetic acid was also
effective, giving 3a in 53% yield. Other solvents, such as 1,2-
dichloroethane, dimethylsulfoxide, N,N-dimethylformamide,
and toluene, were totally ineffective for the catalytic reaction.
Under similar reaction conditions to those for the reaction
of 1a with 2a, various para-substituted aryl iodides 2b–d were
treated with aldoxime ether 1a, to give the corresponding
substituted fluorenone derivatives. 4-Iodotoluene (2b)
afforded 3b in 72% yield (Table 1, entry 2). Electron-with-
drawing aryl iodides, such as 4-nitroiodobenzene 2c and ethyl
4-iodobenzoate 2d, provided functionalized 9-fluorenones 3c
and 3d in 84 and 86% yields, respectively (Table 1, entries 3
and 4). Meta-substituted aryl iodides 2e and 2 f also reacted
smoothly with 1a, in a highly regioselective fashion, to give 3e
and 3 f, respectively, in slightly lower yields (Table 1, entries 5
and 6). Both of these reactions demonstrate interesting meta
2
3
À
directed activation of sp and sp C H bonds, followed by
oxygenation with ozone and PhI(OAc)2.[4a,b] In 2006, Che and
co-workers reported the ortho amidation of O-methyl oxime
[4c]
À
by palladium-catalyzed C H activation/nitrene insertion.
Very recently, we reported a rhodium-catalyzed chelation-
À
assisted C H activation of a,b-unsaturated ketoxime and the
reaction with alkynes, which afforded substituted pyridine
derivatives in good-to-excellent yields.[5]
The oxidative Heck cyclization is a synthetically useful
carbon–carbon bond-forming reaction catalyzed by transi-
tion-metal complexes.[6] Moritani and Fujiwara first reported
an intermolecular oxidative Heck cyclization reaction of
benzene with activated olefins.[7] In 2004, Stoltz and co-
workers reported a palladium-catalyzed synthesis of func-
tionalized benzofurans and dihydrobenzofurans by direct
intramolecular oxidative Heck cyclization of allyl phenyl
ether.[8] Recently, Tanaka and co-workers developed a
palladium-catalyzed Heck-type cyclization of oxime ethers
that leads to the formation of 3-indolinone derivatives.[9] In
this context, an intermolecular version of Heck cyclization
reactions of carbon–nitrogen double bonds is extremely
À
limited. Our continued efforts in metal-catalyzed C H bond
activation and cyclization reactions[10] prompted us to explore
the reaction of aromatic aldoxime ethers with aryl iodides.
À
substitution effects. There are two possible C H bond
activation sites, at C2 and C6 of 3-iodotoluene (2e) and 3-
iodonitrobenzene (2 f), but only the products resulting from
À
[*] V. S. Thirunavukkarasu, K. Parthasarathy, Prof. Dr. C.-H. Cheng
Department of Chemistry
C H bond activation at C6 were formed. The steric effect of
À
the meta substituent for the C H bond activation at C2 likely
National Tsing Hua University
Hsinchu, 30043 Taiwan
Fax: (+886)35724698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/~chcheng/
accounts for the absence of the other regioisomer in both of
these cases. 4-Methylbenzaldehyde oxime ether (1b) reacted
with 2a and 2b to give 3e and 3g in 77 and 73% yield,
respectively (Table 1, entries 7 and 8). The present catalytic
reaction is also compatible with nitro, chloro, and fluoro
substituents on the aromatic ring of oxime ethers 1. Thus, the
reaction of 4-nitro-, 4-chloro-, and 4-fluorobenzaldehyde
oxime ethers (1c–e) with 2a gave substituted fluorenones
[**] We thank the National Science Council of Republic of China
(NSC 96-2113M-007-020-MY3) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804153.
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Chemie
Table 1: (Continued)
Table 1: Results of the reaction of aromatic aldoxime ethers with aryl
halides.[a]
Entry
1[b]
2
Product 3
Yield
[%][c]
13
1e 2a
1e 2d
1 f 2a
3k 72
14
3l 78
3m 74
15
Entry
1[b]
2
Product 3
Yield
[%][c]
16
1g 2a
3n 73
1
2
3
4
1a 2a
1a 2b
1a 2c
1a 2d
3a 90
17
18
1h 2a
1i 2a
3o 79
3p 76
3b 72
3c 84
3d 86
[a] Reaction conditions unless otherwise stated: aldoxime ether 1
(1.0 mmol), aryl iodide 2 (5-6 equiv), Pd(OAc)2 (10 mol%), Ag2O
(1.0 mmol) and CF3CO2H (2.0 mL), 1208C, 36 h. Following filtration,
the filtrate was treated with concentrated HCl (2.0 mL), 1008C, 8 h.
[b] E/Z ratio ꢀ95:5. [c] Yield of isolated product.
5
6
1a 2e
1a 2 f
3e 65
3 f 63
3 f, 3h, and 3k in 72–82% yield (Table 1, entries 9, 10, and 13).
The reaction of 4-chloro- and 4-fluorobenzaldehyde oxime
ether with other aryl iodides also proceeded smoothly to give
the corresponding substituted fluorenones in good yield
(Table 1, entries 11, 12, and 14). Interestingly, the ortho-
substituted substrate 2-fluorobenzaldehyde oxime ether 1 f
also reacted smoothly with 2a to give product 3m in 74%
yield (Table 1, entry 15). For 3-bromobenzaldehyde oxime
ether (1g), the reaction with 2a proceeded in a regioselective
manner, to give 3n in 73% yield (Table 1, entry 16). Oxime
ether 1h, bearing a phenyl substituent, is also compatible with
the reaction with 2a, providing 3o in 79% yield (Table 1,
entry 17). Finally, the reaction of 2-naphthaldehyde oxime
ether (1i) with 2a afforded benzofluorenone 3p in 76% yield.
7
8
1b 2a
1b 2b
3e 77
3g 73
9
10
11
12
1c 2a
1d 2a
1d 2b
1d 2d
3 f 82
3h 78
3i 71
3j 80
À
In this reaction, there are two possible C H bond activation
sites at C2 and C6 of 1g. However, activation occurs only at
C6, most likely owing to the steric effect of the fused aromatic
ring.
Based on known metal-catalyzed directing-group-assisted
[1,4,7,8]
À
C H bond activation and Heck cyclization reactions,
a
mechanism for the present palladium-catalyzed cyclization of
aldoxime ether 1a with iodobenzene 2a has been proposed,
involving two different catalytic cycles (Scheme 1). In the first
cycle, coordination of 1a to the PdII species is followed by an
À
ortho C H bond activation to form a five-membered pallada-
cycle 4 and the release of a proton. Oxidative addition of
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indicate that both palladium acetate and silver
oxide are required for the conversion of intermedi-
ate 6 into product 3, and also that silver(I) acts as an
oxidant to regenerate the PdII active catalyst.
Whereas the role of silver oxide is not entirely
clear, it seems to perform three separate functions
in the present catalytic reaction. In addition to its
status as an oxidant, oxidizing Pd0 to PdII, it acts as a
halide scavenger, removing iodide from palla-
dium(IV) complex 5, facilitating reductive elimina-
tion.[13] Thirdly, it acts as a base to remove protons
released from the reaction. In addition, the use of
Ag+ as an oxidant for the oxidation of Pd0 species is
known.[14]
In summary, we have successfully developed a
new efficient palladium-catalyzed synthesis of 9-
Scheme 1. Proposed mechanism for the reaction of benzaldoxime ethers with aryl
iodides Some ligands on palladium intermediates are omitted for clarity.
iodobenzene to 4 gives palladium(IV) intermediate 5. Sub-
sequent reductive elimination leads to ortho-arylated product
6a and PdII. In the second catalytic cycle, the coordination of
À
6a to palladium(II) followed by C H bond activation gives
seven-membered palladacycle 7. Subsequent intramolecular
=
insertion of the C N group into the Pd–aryl bond to produce
intermediate 8,[11] followed by b-H elimination affords com-
pound 3A and Pd0. The latter is reoxidized to PdII by silver
ions in the solution.
The proposed mechanism is supported by the isolation of
intermediate 4. Heating of 1a in the presence of one
equivalent of Pd(OAc)2 and Ag2O in TFA led to the
formation of the anionic palladacycle 4 in 77% yield. This
1
complex was characterized by H NMR, 13C NMR, and IR
spectroscopy. In addition, the structure was further elucidated
by single-crystal X-ray diffraction (Figure 1). The reaction of
4 with iodobenzene in TFA at 1208C for 3 h afforded the
fluorenone oxime ether 3A in 83% yield [Eq. (1)].
Figure 1. ORTEP representation of palladacycle 4. Thermal ellipsoids
are set at 50% probability.
Further evidence supporting the proposed mechanism for
the catalytic reaction was the isolation of 2-(4-nitrophenyl)-
benzaldehyde O-methyl oxime (6c) in 52% yield from the
reaction of 1a and 2c, under the standard catalytic reaction
conditions shown in Table 1, except that the solution was
heated for only six hours. To further prove that compound 6 is
an intermediate in the catalytic reaction, 6a was prepared
separately,[12] and examined under various conditions. Firstly,
6a was treated with palladium acetate (10 mol%) and
silver(I) oxide (1 equivalent) in TFA at 1208C for 18 h,
affording Heck cyclization product 3A in 87% yield
[Eq. (2)]. The same reaction, carried out in the absence of
silver oxide, afforded 3A in 8% yield. Product 3A was not
formed by treatment of 6a with one equivalent of silver oxide
in the absence of palladium acetate in TFA. The above results
fluorenone derivatives, from the reaction of substituted
benzaldehyde oxime ethers with aryl halides. This trans-
À
formation involves an unprecedented one-pot dual C H
activation and oxidative Heck cyclization. The proposed
mechanism is strongly supported by the isolation of an anionic
palladacycle 4 and an intermediate organic compound 6c.
Experimental Section
General procedure for the palladium-catalyzed synthesis of 9-
fluorenone derivatives: In a sealed tube under a N2 atmosphere,
trifluoroacetic acid (2.0 mL), aldoxime ether 1 (1.00 mmol), and aryl
iodide
2 (5–6 equivalents) were added to Pd(OAc)2 (22 mg,
0.010 mmol) and silver(I) oxide (231 mg, 1.00 mmol), and the reaction
mixture was stirred at 1208C for 36 h. The mixture was filtered
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Chemie
through a short celite pad, which was washed with dichloromethane
several times. The filtrate was concentrated in vacuo. Concentrated
hydrochloric acid (2.0 mL) was added to the residue and the resultant
mixture was kept at 1008C for 8 h. After completion of the reaction,
the mixture was cooled, diluted with dichloromethane (80 mL),
filtered to remove solids, and then concentrated in vacuo. Purification
by column chromatograph on silica gel (eluent: hexane/EtOAc 9:1)
gave the corresponding pure 9-fluorenone product 3a–p.
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Received: August 22, 2008
Published online: October 31, 2008
À
Keywords: C H activation · cyclization · Heck reaction · oximes ·
palladium
.
À
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Pfeffer, Chem. Rev. 2002, 102, 1731; b) C.-H. Jun, C. W. Moon,
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[3] E. Y. Bezsoudnova, A. D. Ryabov, J. Organomet. Chem. 2001,
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[4] Palladium-catalyzed O-methyl oxime as a directing group see:
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