Palladium-catalyzed heteroannulation of [60]fullerene with anilides via C-H bond activation

Article abstract of DOI:10.1021/ol901675t

The palladium-catalyzed reaction of [60]fullerene with a variety of readily available anilides, initiated by C-H bond activation and followed by cyclizatlon, afforded [60]fulleroindolines in a highly regloselectlve manner. A plausible reaction mechanism w

Full text of DOI:10.1021/ol901675t

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4334-4337
Palladium-Catalyzed Heteroannulation of
[60]Fullerene with Anilides via C-H
Bond Activation
Bo Zhu† and Guan-Wu Wang*,†,‡
Hefei National Laboratory for Physical Sciences at Microscale and Department
of Chemistry, UniVersity of Science and Technology of China, Hefei,
Anhui 230026, P. R. China, and State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou, Gansu 73000, P. R. China
gwang@ustc.edu.cn
Received July 22, 2009
ABSTRACT
The palladium-catalyzed reaction of [60]fullerene with a variety of readily available anilides, initiated by C-H bond activation and followed by
cyclization, afforded [60]fulleroindolines in a highly regioselective manner. A plausible reaction mechanism was proposed.
Fullerene chemistry has been extensively explored since the
1990s. Among the vast number of reactions discovered to
functionalize fullerenes,1 transition metal salt-mediated reac-
tions of fullerenes are much less investigated.2-11 Moreover,
only a few of them utilized palladium complexes, in which
a (sub)stoichiometric amount of palladium source was often
needed.3a-c Recently, Itami’s group reported the Pd-catalyzed
hydroarylation of C603d as well as the Pd-catalyzed allylation
and arylation of organo(hydro)fullerenes.3e More recently, we
achieved the first synthesis of [60]fulleroindolines through Pd-
catalyzed heteroannulation of C60 with o-iodoanilines.3f How-
ever, halide byproducts were produced, and quite a number of
o-iodoanilines as starting materials are expensive or difficult to
be prepared, thus limiting further application of this reaction.
Obviously, developing a more economic and efficient method
for the synthesis of fulleroindolines is highly desirable.
(2) Rh: (a) Becker, L.; Evans, T. P.; Bada, J. L. J. Org. Chem. 1993,
58, 7630. (b) Gonzalez, R.; Knight, B. W.; Wudl, F. J. Org. Chem. 1994,
59, 7949. (c) Pellicciari, R.; Annibali, D.; Costantino, G.; Marinozzi, M.;
Natalini, B. Synlett 1997, 1196. (d) Duczek, W.; Radeck, W.; Niclas, H.-
J.; Ramm, M.; Costisella, B. Tetrahedron Lett. 1997, 38, 6651. (e) Nair,
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1999, 40, 5087. (f) Muraoka, T.; Asaji, H.; Yamamoto, Y.; Matsuda, I.;
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10, 4609. (e) Nambo, M.; Itami, K. Chem.sEur. J. 2009, 15, 4760. (f)
Zhu, B.; Wang, G.-W. J. Org. Chem. 2009, 74, 4426.
† University of Science and Technology of China.
‡ Lanzhou University.
(1) For selected reviews, see: (a) Hirsch, A. Synthesis 1995, 895. (b)
Yurovskaya, M. A.; Trushkov, I. V. Russ. Chem. Bull. Int. Ed. 2002, 51,
367. (c) Thilgen, C.; Diederich, F. Chem. ReV. 2006, 106, 5049. For recent
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130, 15429. (g) Murata, M.; Maeda, S.; Morinaka, Y.; Murata, Y.; Komatsu,
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10.1021/ol901675t CCC: $40.75
Published on Web 09/04/2009
 2009 American Chemical Society

On the other hand, the C-H functionalization approach
in organic synthesis has attracted great attention because of
its economic and environmentally benign features.12 Through
the ortho C-H bond activation, selective oxidative couplings
of anilides with alkyl halides,13a olefins,13b-d haloolefins,13e
trialkoxyarylsilanes,13f arylboronic acids,13g aryl iodides,13h
and simple arenes13i to construct C-C bonds have been
reported. The C-N,14a C-X (X ) Cl, Br),14b and C-O14c
bond formations of anilides have also been demonstrated.
However, to the best of our knowledge, the C-H bond
activation strategy has not been applied to fullerene chem-
istry. We surmised that the reaction of C60 with readily
available anilides, through C-C coupling initiated by C-H
bond activation and then C-N coupling to furnish the
cyclization, could be an alternative and more practical
pathway for the synthesis of fulleroindolines, as shown in
Scheme 1.
(0.05 mmol) and acetanilide 1a (5 equiv) was treated with
Pd(OAc)2 (50 mol %) and PTSA (1 equiv) in chlorobenzene
(8 mL) at 130 °C for 30 min, much to our delight, 35% of
the desired product 2a was obtained along with 60% of
recovered C60 (Scheme 2).
Scheme 2. Initial Result for the Synthesis of Product 2a
The initial success encouraged us to focus on developing
this reaction into a catalytic process. The loading of Pd(OAc)2
was reduced to 10 mol %, and various reaction conditions
including oxidants, acids, and solvent systems were screened.
Due to the usage of catalytic amount of Pd(OAc)2, an oxidant
should be required to fulfill the catalytic cycle for the reaction
of C60 and anilide 1a. Therefore, the effect of oxidants on
the reaction was first explored. The commonly used oxidants
Scheme 1
.
Design of the Alternative Pathway for the Synthesis
of [60]Fulleroindolines
including Cu(OAc)2,14a,b p-benzoquinone (BQ),13c,d,16 Ox-
14c,17a
one,17 and K2S2O8
for the Pd-catalyzed C-H activa-
tions of arenes were examined. Copper salt Cu(OAc)2·H2O
was found to afford product 2a, yet in only 9% yield (Table
1, entry 1). p-Benzoquinone and Oxone gave the desired
During the course of our work, a new Pd(II)-catalyzed
1,2-carboamination of electron-deficient dienes with N-aryl
ureas, initiated by a urea-directed C-H bond activation, was
reported.15 p-Toluenesulfonic acid (PTSA) proves to have a
large beneficial effect in the Pd-catalyzed C-H activa-
tion13c,d,15,16 and thus was utilized in our investigation.
Commercially available acetanilide 1a was first chosen as
the model substrate. At the onset, when a mixture of C60
Table 1. Screening of the Reaction Conditionsa
entry acid
oxidant
solvent (mL)
yield (%)b
(6) Cu: (a) Tsunenishi, Y.; Ishida, H.; Itoh, K.; Ohno, M. Synlett 2000,
1318. (b) Wang, G.-W.; Li, F.-B. Org. Biomol. Chem. 2005, 3, 794. (c)
For a review on the reactions of fullerenes involving organocopper reagents,
see: Matsuo, Y.; Nakamura, E. Chem. ReV. 2008, 108, 3016.
1
2
3
4
5
6
7
8
9
PTSA Cu(OAc)2·H2O PhCl (10)/CH3CN (0.5)
9 (82)
23 (88)
22 (88)
28 (85)
trace
15 (88)
<5%
PTSA BQ
PhCl (10)/CH3CN (0.5)
PhCl (10)/CH3CN (0.5)
PhCl (10)/CH3CN (0.5)
PhCl (10)/CH3CN (0.5)
PhCl (10)/CH3CN (0.5)
PhCl (10)/CH3CN (0.5)
PhCl (10)/THF (0.5)
PTSA Oxone
PTSA K2S2O8
none K2S2O8
CSA K2S2O8
PWA K2S2O8
PTSA K2S2O8
PTSA K2S2O8
(7) Ru, Fe, and Ce: (a) Gan, L.; Huang, S.; Zhang, X.; Zhang, A.; Cheng,
B.; Cheng, H.; Li, X.; Shang, G. J. Am. Chem. Soc. 2002, 124, 13384. (b)
Huang, S.; Xiao, Z.; Wang, F.; Gan, L.; Zhang, X.; Hu, X.; Zhang, S.; Lu,
M.; Pan, Q.; Xu, L. J. Org. Chem. 2004, 69, 2442. (c) Cheng, X.; Wang,
G.-W.; Murata, Y.; Komatsu, K. Chin. Chem. Lett. 2005, 16, 1327. (d)
Xiao, Z.; Wang, F.; Huang, S.; Gan, L.; Zhou, J.; Yuan, G.; Lu, M.; Pan,
J. J. Org. Chem. 2005, 70, 2060. (e) Wang, F.; Xiao, Z.; Yao, Z.; Jia, Z.;
Huang, S.; Gan, L.; Zhou, J.; Yuan, G.; Zhang, S. J. Org. Chem. 2006, 71,
4374. (f) Li, F.-B.; Liu, T.-X.; Wang, G.-W. J. Org. Chem. 2008, 73, 6417.
(8) Co: (a) Martin, N.; Altable, M.; Filippone, S.; Martin-Domenech,
A. Chem. Commun. 2004, 1338. (b) Martin, N.; Altable, M.; Filippone, S.;
Martin-Domenech, A.; Poater, A.; Sola, M. Chem.sEur. J. 2005, 11, 2716.
(9) Pb: (a) Chuang, S.-C.; Clemente, F. R.; Khan, S. I.; Houk, K. N.;
Rubin, Y. Org. Lett. 2006, 8, 4525. (b) Troshina, O. A.; Troshin, P. A.;
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(10) Mn :Wang, G.-W.; Li, F.-B. J. Nanosci. Nanotechnol. 2007, 7, 1162,
and references cited therein.
6 (86)
16 (70)
PhCl (10)/DMF (0.5)
10 PTSA K2S2O8
ODCB (4)/CH3CN (0.5) 39 (83)
a All the reactions were performed with 0.050 mmol of C60, 0.25 mmol
of 1a, 0.050 mmol of acid, 0.25 mmol of oxidant, and 0.0050 mmol of
Pd(OAc)2 in the indicated solvent at 130 °C for 24 h. b Isolated yield. Values
in parentheses were based on consumed C60.
product with acceptable yields of 23% and 22% (entries 2
and 3). Nevertheless, K2S2O8 provided a better result with a
yield of 28% (entry 4). The choice of acid proved very crucial
too. Without the addition of an acid, only a trace amount of
product 2a was obtained (entry 5). Other acids including
(11) W: (a) Tzirakis, M. D.; Orfanopoulos, M. Org. Lett. 2008, 10, 873.
(b) Tzirakis, M. D.; Orfanopoulos, M. J. Am. Chem. Soc. 2009, 131, 4063.
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174. (b) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069. (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (d) Li, C.-J. Acc. Chem.
Res. 2009, 42, 335.
Org. Lett., Vol. 11, No. 19, 2009
4335

camphorsulfonic acid (CSA) and 12-phosphotungstic acid
(PWA) were less effective, giving 2a in 15% and <5% yields,
respectively (entries 6 and 7). The critical role played by
TsOH was believed to be the in situ formation of a more
reactive mono- or bistosylate species from the Pd(OAc)2
precatalyst,15 thus promoting the current heteroannulation
of C60. The effect of solvents was also vital to the catalytic
reaction. Notably, replacing CH3CN with THF or DMF as
the cosolvent led to an obvious decrease in the yield of
product 2a (entry 4 vs entries 8 and 9). It was reported that
solvents showed drastic effects on palladium-mediated C-H
functionalizations.13a,b,14b,c The poor results for THF and
DMF relative to that of CH3CN as the cosolvent might be
due to their stronger coordination to the Pd catalyst, and
hence hampering the catalytic reaction. To our satisfaction,
the highest yield was achieved by decreasing the volume of
the solvent to increase the reaction concentration. With a
mixture of ODCB (4 mL) and CH3CN (0.5 mL) as the
solvent, product 2a was obtained in 39% yield (entry 10). It
should be noted that acetonitrile was added in the above
conditions to increase the solubility of the employed
inorganic salts.
Table 2. Results for the Pd-Catalyzed Reaction of C60 with
Anilides 1a-ia
With the optimal conditions in hand, the scope of this
annulation was explored by using a variety of substrates as
illustrated in Table 2. We were pleased to find that a wide
variety of anilides could be employed and furnished the
desired C60-fused indoline derivatives 2a-i in synthetically
valuable yields. Substrates bearing electron-donating groups
(1b, 1c) and weak electron-withdrawing group (1d) on the
para position of the phenyl ring afforded products 2b-d in
good yields comparable to that of anilide 1a (Table 2, entries
2-4 vs entry 1). However, substrate 1e substituted with an
electron-withdrawing ketone group on the para position of
the phenyl ring retarded the reaction obviously, giving the
corresponding product 2e only in 20% yield even by
increasing the Pd(OAc)2 loading to 50 mol % (Table 2, entry
5). It is known that ortho substitution inhibits15 or
hampers13c,d the Pd-catalyzed ortho C-H insertions. There-
fore, it was not surprising that the o-methyl substitution on
substrate 1f greatly reduced the reaction yield and selectivity
under standard reaction conditions. Fortunately, the corre-
sponding product 2f could be obtained in good yield utilizing
50 mol % of Pd(OAc)2 only after 0.5 h (Table 2, entry 6).
When anilides were substituted at the meta position, products
resulting from the reactions at the less sterically hindered
positions were regioselectively obtained in good yields (Table
2, entries 7 and 8). Interestingly, N-benzoylated aniline 1i
was found to be also an effective substrate and showed higher
reactivity than acetanilide 1a (Table 2, entry 9). Compared
to our previous method3f for the synthesis of fulleroindolines,
the present reaction allowed the synthesis of diverse fulle-
roindolines utilizing a wide variety of commercially available
anilides as substrates and lower catalyst loading (down to
10 mol % Pd(OAc)2 in most cases). In addition, functional
groups such as Cl, CH3CO, and CH3O could be tolerated
and did not alter the reaction site for the C-H bond
activation.
a Unless otherwise specified, all the reactions were performed with 0.050
mmol of C60, 0.25 mmol of 1, 0.050 mmol of PTSA, 0.25 mmol of K2S2O8,
and 0.0050 mmol of Pd(OAc)2 in ODCB (4 mL)/CH3CN (0.5 mL) at 130
°C for 24 h. b Isolated yield. Values in parentheses were based on consumed
C60. c The reaction was performed with 0.050 mmol of C60, 0.25 mmol of
1d, 0.025 mmol of Pd(OAc)2, and 0.050 mmol of PTSA in chlorobenzene
(8 mL) at 130 °C for 1.5 h. d The reaction was performed with 0.050 mmol
of C60, 0.25 mmol of 1f, 0.025 mmol of Pd(OAc)2, and 0.050 mmol of
PTSA in chlorobenzene (8 mL) at 130 °C for 0.5 h.
4336
Org. Lett., Vol. 11, No. 19, 2009

Products 2a3f and 2h3f are known compounds, and their
identities were confirmed by comparison of their spectral
data with those reported previously by us. New compounds
2b-g and 2i were unambiguously characterized by their
anilides to afford intermediate A, followed by insertion of
C60 into the arylpalladium bond to yield intermediate B.
Subsequent reductive elimination of intermediate B generates
fulleroindolines and Pd(0). The latter is reoxidized to Pd(II)
by the oxidant to complete the catalytic cycle. The suggested
ortho C-H insertion/carbopalladation/cyclization sequence
for the Pd(II)-catalyzed 1,2-carboamination of dienes with
N-aryl ureas15 further supports our proposed reaction mech-
anism.
In conclusion, we have successfully accomplished the
synthesis of a wide variety of fulleroindolines in a highly
regioselective manner via Pd-catalyzed annulation of C60 with
readily available anilides instead of o-iodoanilines. Impor-
tantly, we have demonstrated the first example of exploiting
the C-H bond activation strategy to functionalize fullerenes.
A possible reaction mechanism was proposed to explain the
formation of fulleroindolines.
1
HRMS, H NMR, 13C NMR, FT-IR, and UV-vis spectral
data. All of the MALDI or ESI FT-ICR mass spectra of these
fulleroindoline products gave the correct molecular ion peaks.
The 13C NMR spectra of fulleroindolines 2b-g and 2i clearly
exhibited less than 30 peaks with two half-intensity ones in
the range of 134-153 ppm for the sp2-carbons of the
fullerene cage and two peaks at 86-87 and 70-72 ppm for
the two sp3-carbons of the fullerene skeleton, consistent with
the Cs symmetry of their molecular structures. The chemical
shifts for the two C60 sp3-carbons of fulleroindolines 2b-g
and 2i are close to those of fullerene derivatives with the
nitrogen atom1j,3f,18 and sp2-carbon atom3f,18 attached to the
C60 skeleton, respectively. The typical chemical shifts at
167-172 ppm in the 13C NMR spectra and the absorptions
at 1661-1678 cm-1 in the IR spectra of 2b-g and 2i
indicated the presence of an amide moiety. Their UV-vis
spectra displayed a characteristic peak at 427-429 nm, which
is a diagnostic absorption for the 1,2-adduct of C60.1j,3f,18
On the basis of the above reaction results and previous
acetamino-assisted Pd-catalyzed C-H bond functionaliza-
tions,13,14 a plausible mechanism is shown in Scheme 3. The
Acknowledgment. The authors are grateful for the finan-
cial support from the National Natural Science Foundation
of China (Nos. 20572105 and 20621061) and the National
Basic Research Program of China (2006CB922003).
Supporting Information Available: Detailed experimen-
1
tal procedures and characterization data, as well as the H
NMR and 13C NMR spectra of 2b-g and 2i. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901675T
Scheme 3. Proposed Reaction Mechanism
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