One-pot synthesis of diarylmethylidenefluorenes and phenanthrenes by palladium-catalyzed multiple C-H bond functionalization

Article abstract of DOI:10.1002/chem.200902726

Chemical equation presented A palladium-catalyzed rapid synthesis of diarylmethylidenefluorenes and phenanthrenes by multiple C-H bond activation, C-C bond formation, and Heck-type cyclization is described (see scheme).

Full text of DOI:10.1002/chem.200902726

DOI: 10.1002/chem.200902726
One-Pot Synthesis of Diarylmethylidenefluorenes and Phenanthrenes by
À
Palladium-Catalyzed Multiple C H Bond Functionalization
Vedhagiri S. Thirunavukkarasu, Kanniyappan Parthasarathy, and Chien-Hong Cheng*[a]
À
À
Transition-metal-catalyzed C H bond functionalization
has become a most challenging method for organic synthe-
Devising C H bond activation reactions that achieve mul-
À
tiple C C bond formation in one operation has attracted
sis[1] in view of the large bond energy and the inertness of
C H bond. The sp and sp C H bond activation and subse-
quent C C bond formation reaction catalyzed by ruthenium,
rhodium, palladium, iridium, and other metal complexes
with or without directing groups have been demonstrated.[2]
In this context, we were particularly attracted by the PdII-
catalyzed directing-group-assisted ortho-functionalization of
considerable attention in metal-catalyzed organic synthe-
sis,[6] but there are only few methods known that can con-
struct complex molecules. Shi and co-workers reported the
2
3
À
À
À
synthesis of highly functionalized carbazoles by PdII-cata-
[7]
À
lyzed multiple C H activation of acetanilide with arenes.
Very recently, Lautens et al. reported a palladium-catalyzed
synthesis of tetrasubstituted helical alkenes by means of a
À
À
aromatic C H bond. Various directing groups have been
employed for the palladium-catalyzed arylation of ortho aro-
norbornene-mediated multiple C H bond activation of aryl
iodide with bromoalkyl aryl alkynes.[8] Our continued efforts
À
À
matic C H bonds leading to mono or diarylated products
in metal-catalyzed C H bond activation and cyclization re-
[Eq. (1)].[3a–f]
actions[9] prompted us to explore the reaction of aromatic
ketoxime ethers with aryl iodides. Herein, we wish to report
a rapid construction of diarylmethylidenefluorene and phen-
anthrene derivatives from these two reagents through a pal-
À
ladium-catalyzed multiple C H bond functionalization strat-
egy.
When we switched benzaldoxime ether to acetophenone
À
oxime ether in the Pd-catalyzed C H activation reaction
with iodobenzene,[5] the reaction gave a diarylmethylidene-
fluorene and a phenanthrene derivative instead of the fluo-
ren-9-one product. Thus, treatment of oxime ether 1a and
Apart from the above directing groups, only a few exam-
ples are known using oximes as a directing group for the ac-
aryl iodide 2a with 10 mol% of PdACHTNUTRGNEUNG(OAc)2 and one equiva-
À
tivation of aromatic or olefinic C H bonds. Thus, Sanford
and several other groups reported oxime-directed transfor-
lent of Ag2O in trifluoroacetic acid at 1208C for 15 h gave a
mixture of diphenylphenanthrene (3a) and diphenylmethyl-
À
À
mation of ortho-aromatic or olefinic C H bonds to C O,
ACHTUNGTRENiNUGN denefluorene (4a) in a 78:22 ratio in 78% combined yield
[4]
À
À
C X, and C N bonds catalyzed by palladium complexes.
Very recently, we reported a Pd-catalyzed synthesis of fluo-
ren-9-one derivatives from aldoxime ether and aryl iodides
(Scheme 1). Although products 3a and 4a could not be sep-
arated, the crystal structures of both compounds were deter-
mined by X-ray diffraction. The stoichiometry of these two
À
involving two distinct steps of C H activation and oxidative
Heck-type cyclization in one pot.[5]
[a] V. S. Thirunavukkarasu, Dr. K. Parthasarathy, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University, Hsinchu, 30043 (Taiwan)
Fax : (+886)35724698
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902726.
Scheme 1. The formation of diphenylmethylidenefluorene and diphenyl-
phenanthrene.
1436
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1436 – 1440

COMMUNICATION
Table 1. Synthesis of diphenylphenanthrene derivatives.[a]
products shows that the catalytic reaction requires a mole-
cule of oxime ether 1a and three molecules of aryl iodide
2a for the formation of each 3a or 4a molecule. To the best
À
of our knowledge, this is the first example of multiple C H
À
functionalization, C C bond formation, and a cyclization in
one pot. It is worth noting that other directing groups gener-
ally gave only mono- or diarylated products at the ortho-po-
sition [Eq. (1)].
Under similar conditions, 1a also reacted with 4-iodo
ACHTUNGTNERtNUNG ol-
ACHTUNGTRENNUNGuene (2b) smoothly, but gave only the corresponding phen-
1
2
Product 3
Yield[%][b]
anthrene 3b in 76% yield (entry 1, Table 1). There was no
methylidenefluorene species observed. Similarly, various
acetophenone oxime ethers 1b–f reacted with 2b to afford
substituted 9,10-ditolylphenanthrenes 3c–g (Table 1). Thus,
treatment of 4-methyl acetophenone oxime ether 1b with
2b gave 3c in 69% yield (entry 2). Both 2- and 4-chloroace-
1
2
3
1a
2b
3b
3c
3d
76
tophenone oxime ethers (1c) and ACHTUNTRGNEUNG(1d) reacted smoothly
with 2b to give 3d and 3e in 74 and 71% yields, respectively
(entries 3 and 4). In a similar manner, 4-fluoro- and 4-phe-
nylacetophenone oxime ethers (1e and 1 f) performed well
with 2b to give 3 f and 3g, respectively, in good yields (en-
tries 5, 6).
To our surprise, 3-iodotoluene (2c) reacted with 1d under
the present reaction conditions to afford the corresponding
methylidenefluorene species 4b in 58% yield (Table 2,
entry 1), instead of the expected phenanthrene derivative.
When aryl iodide 2 contained a strong electron-donating
1b
1c
2b
2b
69
74
À
group, like 4-iodoanisole, it was inactive for the multiple C
H functionalization giving no desired compound 3 or 4. In
addition, 2-iodotoluene also did not undergo the reaction
with 1d to provide phenanthrene or methylidenefluorene
product. The steric repulsion of methyl group at ortho-posi-
tion likely accounts for the failure of the reaction.
4
5
6
1d
1e
1 f
2b
2b
2b
3e
3 f
3g
71
62
58
This Pd-catalyzed formation of methylidenefluorene de-
rivative was successfully extended to a range of aryl iodides
with an electron-withdrawing substituent (2d–f) with oxime
ethers 1a. As shown in Table 2, ethyl 4-iodobenzoate (2d)
afforded 4c in 80% yield (entry 2), 4-nitroiodobenzene (2e)
provided 4d in 76% yield (entry 3) and 4-bromoiodoben-
zene (2e) gave a chemoselective product 4e in which the
À
C Br bonds remain intact in 70% yield (entry 4). In a simi-
lar manner, aromatic oxime ether with different substituents
on the phenyl ring (1b–f) also reacted with 2d to give the
corresponding diphenylmethylidenefluorenes derivatives
4 f–j in good yields (entries 4–9). However, the present reac-
tion is limited by the use of acetophenone-type oxime ether.
If the methyl group in acetophenone was changed to ethyl
group or other longer-chain alkyl group, no similar type of
methylidenefluorene or phenanthrene product was found.
A plausible mechanism to account for the present palladi-
um-catalyzed formation of product 4a from aromatic ketox-
ime ether 1a and iodobenzene 2a is proposed in
(Scheme 2). The initial several steps are similar to the palla-
dium-catalyzed synthesis of fluoren-9-one derivatives from
the substituted benzaldehyde oxime ethers with aryl halides
until the reaction steps after intermediate 9.[5] Protonation
of 9 followed by demethoxyamination gives 10 and PdII.
[a] Unless otherwise mentioned, all reactions were carried out using
oxime ethers (1.0 mmol), aryl iodide (5–6 equiv), Pd(OAc)2
(10 mol%), Ag2O (1.0 mmol) and CF3CO2H (2.0 mL) at 1208C for 8 h.
1
2
ACHTUNGTRENNUNG
[b] Isolated yields.
À
Two consecutive arylation of the vinyl C H bonds in 10 by
aryl iodide then proceed to give product 4a.
To support the proposed mechanism, we tried to isolate
intermediate 5 shown in Scheme 2. Thus, heating 1a in the
presence of one equivalent of PdACTHNUTRGEN(UNG OAc)2 and Ag2O in tri-
Chem. Eur. J. 2010, 16, 1436 – 1440
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1437

C.-H. Cheng et al.
Yield [%][b]
Table 2. Synthesis of diphenylphenanthrene derivatives.[a]
Table 2. (Continued)
1
2
Product 4
5
6
7
1b
2d
4 f
4g
4h
72
66
73
1c
1d
2d
2d
1
2
Product 4
Yield [%][b]
1
1d
2c
4b
58
2
3
4
1a
1a
1a
2d
2e
2 f
4c
4d
4e
80
76
70
8
9
1e
1 f
2d
2d
4i
4j
65
63
[a] Unless otherwise mentioned, all reactions were carried out using
oxime ethers (1.0 mmol), aryl iodide (5–6 equiv), Pd(OAc)2
1
2
ACHTUNGTRENNUNG
(10 mol%), Ag2O (1.0 mmol) and CF3CO2H (2.0 mL) at 1208C for 15 h.
[b] Isolated yields.
1
were characterized by H NMR, 13C NMR, and IR spectros-
copy. In addition, the structure of 5a was determined by
single-crystal X-ray diffraction. Interestingly, the reaction of
5a with 4-iodotoluene (2b) in TFA at 1208C for 4 h gave 3b
in 73% yield [Eq. (2)]. On the other hand, treatment of 5g
with 4-iodobenzoate (2d) in TFA for 8 h gave 4g in 76%
yield [Eq. (3)].
Scheme 2. Proposed mechanism for the formation of product 4.
fluoroacetic acid (TFA) led to
the isolation of an anionic pal-
ladacycle 5a in 93% yield. Sim-
ilarly, we isolated intermediate
5g from 1c. These complexes
1438
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1436 – 1440

À
C H Activation
COMMUNICATION
We were unable to detect or isolate intermediate 10 in
the reaction. However, when 1c and 2b was heated under
standard conditions for 0.2 h, we observed intermediate 11c
in 68% isolated yield [Eq. (4)].
Scheme 3. Possible pathway for the rearrangement of 4a to 3a.
palladium complex 6 to facilitate reductive elimination to
give 7, is an oxidizing agent to oxidize Pd0 to PdII, and is a
base to remove protons released from the reaction. The re-
moval of iodide ligand from PdIV to facilitate reductive eli-
To further prove that compound 10 is an intermediate in
the present catalytic reaction, 10 was synthesized by a re-
ported method[10] and was examined under standard condi-
tions. When 10 was heated with 2d in the presence of
10 mol% of palladium acetate and one equivalent of Ag2O
in TFA at 1208C for 4 h, product 4k was obtained in 64%
yield [Eq. (5)]
AHCTUNGTRENNUNG
mination was reported previously.[12] In addition, the use of
Ag+ as an oxidant for the oxidation of Pd0 species is
known.[13]
In conclusion, we have successfully developed a palladi-
À
um-catalyzed multiple C H functionalization of aromatic
ketoxime ethers with aryl iodides to afford diarylmethylid-
AHCTUNGTREGeNNNU nefluorenes or phenanthrenes in good to excellent yields.
The reaction requires one molecule of ketoxime ether and
three molecules of aryl iodide for each molecule of products
À
À
formed. Multiple C H activation, C C bond formation and
extensive bond rearrangement and breaking are involved in
the reaction. Several experimental evidences were provided
À
to support the proposed multiple C H functionalization
pathways. The detailed mechanistic investigations are in
progress.
The mechanism for the arylation of 10 is not clear. One
À
possible route is through two C H activations of the vinyl
protons of intermediate 10 by PdII to give alkenylpalladi-
ACHTUNGTRENNUNG
um(II),[11] followed by oxidative addition of PhI to the alk-
A
E
Experimental Section
tion of the resulting PdIV species. Alternatively, the arylation
may take place by the Mizoroki–Heck reaction, which re-
quires the presence of a Pd0 species for the oxidative addi-
tion of aryl iodide. A drawback of this mechanism is that
the reaction is performed in the presence of high concentra-
tion of silver ion that is known to oxidize Pd0 to PdII readily.
The observation of two distinct products 3 and 4 that
depend greatly on the aryl iodide used from the present Pd-
catalyzed reaction is extremely intriguing in terms of the
mechanism of the reaction. We suspect that product 3 is
from an acid-catalyzed rearrangement of the corresponding
compound 4. This notion is supported by the fact that fur-
ther heating of 4a in TFA at 1208C for 5 h led to complete
conversion of 4a to 3a. A possible pathway for the re-
General procedure for the palladium-catalyzed synthesis of diarylmethy-
lidenefluorenes or phenanthrenes: A 15 mL screw-cap seal tube initially
fitted with septum containing PdACTHUNTRGNE(UNG OAc)2 (22 mg, 0.01 mmol) and silver(I)
oxide (231 mg, 1.00 mmol) was evacuated and purged with nitrogen gas
three times. Then trifluoroacetic acid (2.0 mL), acetophenone oxime
ether 1 (1.00 mmol) and aryl iodide (5–6 equiv) were added to the system
and the reaction mixture was stirred at 1208C for 8–15 h. The mixture
was filtered through a short Celite pad and the Celite pad was washed
with dichloromethane several times. The filtrate was concentrated by
vacuum and the residue was purified on a silica gel column using hexane/
EtOAc as eluent to afford the desired product 3 or 4.
ACHTUNGTRENNUNGarrangement is presented in (Scheme 3). It is worth noting
that six-membered-ring product 3 is more stable than the
corresponding five-membered-ring product 4 because the
latter has less aromatic resonance stabilization energy, but
has relative high angle strain due to the small average angle
of 1088 for the sp2 carbons in the five-membered ring.
Acknowledgements
We thank the National Science Council of Republic of China (NSC 96-
2113M-007-020-MY3) for support of this research.
À
À
While the role of silver oxide in the present catalytic reac-
tion is not entirely clear, we think it can remove iodide from
Keywords: C H activation
methylidenefluorene · palladium · phenanthrene
·
C H functionalization
·
Chem. Eur. J. 2010, 16, 1436 – 1440
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1439

C.-H. Cheng et al.
À
[4] Palladium-catalyzed oxime assisted C H activation see: a) E. Y.
Bezsoudnoba, A. D. Ryabov, J. Organom. Chem. 2001, 38, 622;
b) L. V. Desai, L. K. Hull, S. M. Sanford, J. Am. Chem. Soc. 2004,
126, 9542; c) L. V. Desai, H. A. Malik, S. M. Sanford, Org. Lett.
2006, 8, 1141; d) H.-Y. Thu, W.-Y. Yu, C.-M. Che, J. Am. Chem. Soc.
2006, 128, 9048; e) W.-Y. Yu, W.-N. Sit, K.-M. Lai, Z. Zhou, A. S. C.
Chan, J. Am. Chem. Soc. 2008, 130, 3304; f) L. V. Desai, K. J. Stow-
ers, S. M. Sanford, J. Am. Chem. Soc. 2008, 130, 13285; g) J. M. Ra-
cowski, A. R. Dick, S. M. Sanford, J. Am. Chem. Soc. 2009, 131,
10974.
À
[1] Some recent reviews on C H activations, see a) G. Dyker, Angew.
Chem. 1999, 111, 1808; Angew. Chem. Int. Ed. 1999, 38, 1698; b) F.
Kakiuchi, S. Murai, Acc. Chem. Res. 2002, 35, 826; c) V. Ritleng, C.
Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731; d) C.-H. Jun, C. W.
Moon, D.-Y. Lee, Chem. Eur. J. 2002, 8, 2423; e) A. R. Dick, M. S.
Sanford, Tetrahedron 2006, 62, 2439; f) C. G. Jia, T. Kitamura, Y. Fu-
jiwara, Acc. Chem. Res. 2001, 34, 633; g) D. Alberico, M. E. Scott,
M. Lautens, Chem. Rev. 2007, 107, 174; h) D. R. Stuart, K. Fagnou,
Science 2007, 316, 1172; i) L. Ackermann, A. Althammer, Angew.
Chem. 2007, 119, 1652; Angew. Chem. Int. Ed. 2007, 46, 1627.
[2] a) F. Kakiuchi, S. Kan, K. Igi, N. Chatani, S. Murai, J. Am. Chem.
Soc. 2003, 125, 1698; b) H. Ihara, M. Suginome, J. Am. Chem. Soc.
2009, 131, 7502; c) H. He, W.-B. Liu, L.-X. Dai, S. L. You, J. Am.
Chem. Soc. 2009, 131, 8346; d) S.-G. Lim, J.-A. Ahn, C.-H. Jun, Org.
Lett. 2004, 6, 4687; e) A. Lazareva, O. Daugulis, Org. Lett. 2006, 8,
5211; f) S. J. Tremont, H. Rahman, J. Am. Chem. Soc. 1984, 106,
5759; g) V. G. Zaitsev, O. Daugulis, J. Am. Chem. Soc. 2005, 127,
4156; h) D. Kalyani, N. R. Deprez, L. V. Desai, M. S Sanford, J. Am.
Chem. Soc. 2005, 127, 7330; i) A. R. Dick, K. L. Hull, M. S. Sanford,
J. Am. Chem. Soc. 2004, 126, 2300; j) R. Giri, X. Chen, J.-Q. Yu,
Angew. Chem. 2005, 117, 2150; Angew. Chem. Int. Ed. 2005, 44,
2112; k) S. Yanagisawa, T. Sudo, R. Noyori, K. Itami, J. Am. Chem.
Soc. 2006, 128, 11748.
[5] V. S. Thirunavukkarasu, K. Parthasarathy, C.-H. Cheng, Angew.
Chem. 2008, 120, 9604; Angew. Chem. Int. Ed. 2008, 47, 9462, and
references therein.
[6] a) M. Catellani, Top. Organomet. Chem. 2005, 8, 21; b) M. Catellani,
E. Motti, N. D. Ca, Acc. Chem. Res. 2008, 41, 1512.
[7] B.-J. Li, S.-L. Tian, Z. Fang, Z.-J. Shi, Angew. Chem. 2008, 120, 1131;
Angew. Chem. Int. Ed. 2008, 47, 1115.
[8] K. M. Gericke, D. I. Chai, N. Bieler, M. Lautens, Angew. Chem.
2009, 121, 1475; Angew. Chem. Int. Ed. 2009, 48, 1447.
[9] a) S. Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Org. Lett. 2006,
8, 5581; b) T. T. Jayanth, C.-H. Cheng, Chem. Commun. 2006, 894;
c) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org. Lett. 2008,
10, 325; d) K. Parthasarathy, C.-H. Cheng, Synthesis 2009, 1400.
[10] N. Lebrasseur, I. Larrosa, J. Am. Chem. Soc. 2008, 130, 2926, and
references therein.
[11] a) L.-C. Chapeau, M. Parisien, M. Leblanc, K. Fagnou, J. Am.
Chem. Soc. 2004, 126, 9186; b) L.-C. Chapeau, M. Parisien, A. Jean,
K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581; c) Y.-H. Yu, J. Lu, T.-
P. Loh, J. Am. Chem. Soc. 2009, 131, 1372.
[12] N. Tamaki, T. Kazuyuki, Y. Tohru, O. Yoshio, J. Am. Chem. Soc.
2001, 123, 9182.
[13] a) S. H. Cho, S. J. Hwang, S. Chang, J. Am. Chem. Soc. 2008, 130,
9254; b) X. Chen, C. E. Googhue, J. Q. Yu, J. Am. Chem. Soc. 2006,
128, 12634.
[3] a) N. Gꢁrbꢁz, I. Ozdemir, B. Cetinkaya, Tetrahedron Lett. 2005, 46,
2273; b) Y. Terao, Y. Kametani, Y. Wakui, H. Satoh, T. Miura, M.
Nomura, Tetrahedron 2001, 57, 5967; c) Y. Kametani, T. Satoh, M.
Miura, M. Nomura, Tetrahedron Lett. 2000, 41, 2655; d) D. Shaba-
shov, O. Daugulis, Org. Lett. 2005, 7, 3657; e) V. G. Zaitsev, D. Sha-
bashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154; f) O. Dau-
gulis, V. G. Zaitsev, Angew. Chem. 2005, 117, 4114; Angew. Chem.
Int. Ed. 2005, 44, 4046; g) X. Chen, C. E. Goodhue, J.-Q. Yu, J. Am.
Chem. Soc. 2006, 128, 12634; h) K. L. Hull, M. S. Sanford, J. Am.
Chem. Soc. 2007, 129, 11904; i) S. Yang, B. Li, X. Wan, Z. Shi, J.
Am. Chem. Soc. 2007, 129, 6066; j) Z. Shi, B. Li, X. Wan, J. Cheng,
Z. Fang, B. Cao, C. Qin, Y. Wang, Angew. Chem. 2007, 119, 5650;
Angew. Chem. Int. Ed. 2007, 46, 5554; k) D. H. Wang, T. S. Mei, J.-
Q. Yu, J. Am. Chem. Soc. 2008, 130, 17676.
Received: October 28, 2009
Published online: December 29, 2009
1440
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1436 – 1440