Oxidative cyclization of 2-arylphenols to dibenzofurans under Pd(II)/peroxybenzoate catalysis

Article abstract of DOI:10.1021/ol202229w

2-Arylphenols undergo intramolecular C-H bond activation/C-O bond formation to afford dibenzofuran derivatives under palladium catalysis in the presence of tert-butyl peroxybenzoate as an oxidant. Kinetic isotope effect experiments indicated that C-H bond cleavage is the rate-limiting step of the reaction.

Full text of DOI:10.1021/ol202229w

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5504–5507
Oxidative Cyclization of 2-Arylphenols to
Dibenzofurans under Pd(II)/
Peroxybenzoate Catalysis
Ye Wei and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
Received August 17, 2011
ABSTRACT
2-Arylphenols undergo intramolecular CꢀH bond activation/CꢀO bond formation to afford dibenzofuran derivatives under palladium catalysis in
the presence of tert-butyl peroxybenzoate as an oxidant. Kinetic isotope effect experiments indicated that CꢀH bond cleavage is the rate-limiting
step of the reaction.
Intramolecularcarbonꢀheteroatom bondformationvia
transition-metal-catalyzed oxidative coupling of a CꢀH
bondand a heteroatom functionality has recently attracted
considerable interest from synthetic chemists, because it
offers a straightforward route to heterocyclic compounds.1
A series of this type of CꢀN bond-forming reaction has
been developed, allowing access to various azaheterocycles
such as carbazoles,2,3 indazoles,4 lactams,5 indolines,6
indoles,7 and benzimidazoles,8 where palladium catalysis
particularly plays a significant role. On the other hand,
a rather limited number of examples are known for
intramolecular CꢀO bond formation via oxidative cataly-
tic CꢀH functionalization, which leads to lactones,9
benzoxazoles,10 and dihydrobenzofurans.11,12 While this
manuscript was in preparation, Liu and co-workers re-
ported palladium-catalyzed cyclization of 2-arylphenols to
dibenzofuran derivatives using air as an oxidant (Scheme
1a).13 While the useof airisattractivefromeconomical and
environmental points of view, the method requires a rather
intricate combination of ligands (IPr and 4,5-diazafluoren-
9-one) and additives (MesCO2Na, K2CO3, and molecular
sieves). We report here that the same transformation can
be achieved by a simple alternative catalytic system con-
sisting of Pd(OAc)2, 3-nitropyridine as a ligand, and tert-
butyl peroxybenzoate (BzOOtBu) as an inexpensive oxi-
dant (Scheme 1b). The method allows facile synthesis of
dibenzofuran derivatives from a variety of 2-arylphenols
and may complement existing CꢀH activation/CꢀC bond
formation approaches to dibenzofurans.14 Kinetic iso-
tope effect (KIE) experiments indicated that our catalytic
(1) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874.
(2) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Tsang, W. C. P.; Munday, R. H.; Brasche, G.;
Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (c) Jordan-
Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 16184. (d) Cho, S. H.; Yoon, J.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 5996. (e) Youn, S. W.; Bihn, J. H.; Kim,
B. S. Org. Lett. 2011, 13, 3738.
(3) For metal-free reactions, see ref 2d and the following paper:
Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew.
Chem., Int. Ed. 2011, 50, 8605.
(4) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K.
Org. Lett. 2007, 9, 2931.
(5) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(6) (a) Mei, T.-S.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 10806. (b) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F.
Angew. Chem., Int. Ed. 2009, 48, 6892.
(7) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676.
(8) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int, Ed. 2008, 47,
1932. (b) Wang, H.-G.; Wang, Y.; Peng, C.-L.; Zhang, J.-C.; Zhu, Q.-A.
J. Am. Chem. Soc. 2010, 132, 13217.
(9) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001,
123, 8149.
(10) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
(11) Wang, X. S.; Lu, Y.; Dai, H. X.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 12203.
(12) For reactions mediated by a stoichiometric amount of FeCl3,
see: (a) Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao,
K. Org. Lett. 2009, 11, 4978. (b) Tang, L.; Pang, Y.; Yan, Q.; Shi, L.;
Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 2744.
(13) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu, J.;
Liu, L. J. Am. Chem. Soc. 2011, 133, 9250.
(14) (a) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou,
K. J. Org. Chem. 2008, 73, 5022. (b) Wang, C. Y.; Piel, I.; Glorius, F.
J. Am. Chem. Soc. 2009, 131, 4194.
r
10.1021/ol202229w
Published on Web 09/27/2011
2011 American Chemical Society

system involves CꢀH bond cleavage as the rate-limiting
step and is mechanistically distinct from Liu’s system,
where CꢀO bond formation is rate-limiting.
Table 1. Screening Conditions for Pd-Catalyzed Cyclization of
2-Phenylphenol to Dibenzofurana
entry
oxidant
ligand
solventb
yield (%)c
1
BzOOtBu
tBuOOtBu
tBuOOH
Cu(OAc)2
PhI(OAc)2
Air
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
none
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6/DMI
C6F6
72
0
Scheme 1
2
3
0
4
0
5
0
6
0
7
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
BzOOtBu
49
30
11
31
43
39
38
50
47
57
8
pyridine
2,20-bipyridine
9d
10
11
12
13
14
15
16
PPh3
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
3-nitropyridine
PhCl
toluene
DMI
NMP
C6F6/NMP
a Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol %), ligand
(5 mol %), oxidant (2 equiv), solvent (0.5 mL), 90 °C, 2 h. b The ratio
of the mixed solvents was 3:2. c Isolated yields. d 2.5 mol % of 2,
20-bipyridine was used.
After considerable experimentation on the reaction of
2-phenylphenol 1a, we found that it underwent complete
conversion in the presence of Pd(OAc)2 (5 mol %), 3-ni-
tropyridine (5 mol %), and BzOOtBu (2 equiv) at 90 °C in
C6F6/DMI (N,N0-dimethylimidazolidinone) within 2 h to
afford dibenzofuran 2a in 72% yield (Scheme 1b). The rest
of the starting material decomposed into unidentified
compounds, and efforts to further improve the product
yield have not yet met with success.
Table 1 summarizes the key results obtained during the
optimization process. The choice of the oxidant was the
most critical. Common oxidants in palladium catalysis
other than BzOOtBu, such as tBuOOtBu, tBuOOH, Cu-
(OAc)2, PhI(OAc)2, and air, did not promote the reaction
at all, but 2-phenylphenol was either partially (entries 2ꢀ4
and 6) or totally (entry 5) decomposed . The reaction took
place in the absence of ligand but afforded 2a in a lower
yield (entry 7). Among the various ligands examined,
3-nitropyridine performed the best,15 while most of them
(e.g., pyridine, 2,20-bipyridine, and PPh3) showed detri-
mental effects (entries 8ꢀ10). The addition of bases such as
alkalimetalcarbonates(M2CO3; M= Li, Na, K) provided
2a in poor yields (data not shown). While aromatic
solvents such as C6F6, PhCl, toluene, and Lewis basic
solvents such as DMI and NMP by themselves gave
modest yields of 40ꢀ50% (entries 11ꢀ15), a mixture of
aromatic and Lewis basic solvents improved the reaction
(entries 1 and 16). Note that, in the absence of Pd(OAc)2,
1a decomposed and did not give any 2a.
formation took place exclusively at the less hindered position.
A substituent on the 20-position slowed down the reaction,
presumably because of steric hindrance (2e and 2h). A styryl
group tolerated the oxidative conditions (2j). Aromatic
carbonꢀhalogen (Br, Cl, F) bonds remained intact, while
the yields of the desired dibenzofurans 2kꢀ2m were modest.
Other tolerable functional groups include ketone (2n), ester
(2o), and acetal (2p). A brief examination of the variation of
the phenol moiety successfully afforded dibenzofurans 2q
and 2r in moderate yields, while naphthalene-2-ol turned out
to be an inferior substrate for the present cyclization reaction
(2s). Note that, even when the product yield was low (e.g., 2e,
2m, and 2s), we did not recover the starting material but
observed its decomposition to intractable products due to
the background reaction with peroxybenzoate (vide infra).
To gain insight into the reaction mechanism, we per-
formed a series of KIE experiments. First, cyclization of the
monodeuterated substrate 1a-d under the standard condi-
tions for 5 min afforded a mixture of 2a-d and 2a in a ratio of
3.8 (eq 1), the magnitude of which is in line with H/D KIEs
typically observed for the concerted metalationꢀdeprotonation
mechanism of aromatic CꢀH bond activation.16,17 This is in
stark contrast to the result of a similar experiment per-
formed with Liu’s catalytic system (Scheme 1a), where no
isotope effect was observed.13,18 Next, an intermolecular
competition reaction using an equimolar mixture of 1a
and 1a-d5 afforded a mixture of 2a and 2a-d4 in a ratio of
With the optimized catalytic system in hand, we explored
the scope of 2-arylphenol derivatives for dibenzofuran
synthesis (Scheme 2). 2-Arylphenols bearing electron-
neutral or -donating substituents (i.e., Ph, Me, OMe, SiMe3)
on the 30- or 40-position of the aryl ring afforded the
corresponding dibenzofurans (2bꢀ2d, 2f, 2g, and 2i) in
49ꢀ76% yield. For 30-substituted substrates, CꢀO bond
(16) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
(17) (a) Chiong, H. A.; Pham, Q. N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879. (b) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.;
Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230. (c) Li, J. J.; Giri, R.;
Yu, J.-Q. Tetrahedron 2008, 64, 6979. (d) Potavathri, S.; Pereira, K. C.;
Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc.
2010, 132, 14676. (d) Pintori, D. G.; Greaney, M. F. J. Am. Chem. Soc.
2011, 133, 1209.
(15) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
Org. Lett., Vol. 13, No. 20, 2011
5505

Scheme 2. Scope of Dibenzofuran Synthesis from 2-Arylphenol
Derivativesa
The above KIE experiments clearly demonstrated that
the present catalytic system is mechanistically distinct
from Liu’s system, in which a Pd(II)/Pd(0) catalytic cycle
involving rate-limiting CꢀO reductive elimination was
proposed.13 In addition, a stoichiometric reaction of 1a with
Pd(OAc)2 in the absence of BzOOtBu did not afford 2a at
all, indicating that the Pd(II)/Pd(0) mechanism is unlikely in
the present case.20 Given this and the stronger oxidizing
power of BzOOtBu compared with molecular oxygen, we
suggest a catalytic cycle involving a high-oxidation-state
palladium species,21,22 as proposed by Yu et al. for Pd-
catalyzed CꢀH activation/CꢀO cyclization directed by an
aliphatic alcohol (Scheme 3).11 Thus, the reaction is initiated
by phenol-directed, rate-limiting CꢀH bond cleavage with a
Pd(II) species.23 The resulting pallada(II)cycle intermediate
is oxidized to a higher oxidation state (e.g., Pd(IV)), from
which CꢀO bond-forming reductive elimination takes place
to afford the dibenzofuran product.
Scheme 3. Possible Catalytic Cycle
a Reaction was performed on a 0.2 mmol scale. Yields refer to isolated
yields.
4.4 (eq 2), which is of similar magnitude to the product ratio
of the intramolecular competition (eq 1). These two experi-
ments strongly suggest that CꢀH bond cleavage is the first
irreversible step of the reaction.19 Finally, we compared
individual reactions of 1a and 1a-d5 and determined the KIE
to be ca. 2 (eq 3), which indicates that CꢀH bond cleavage is
also the rate-limiting step of the reaction.
In summary, we have developed a Pd(II)-catalyzed
oxidative cyclization reaction of a 2-arylphenol to a
(18) The absence of intramolecular KIEs in Liu’s system may reflect
an electrophilic palladation process: (a) Park, C.-H.; Ryabova, V.;
Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159.
(b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050.
(19) Note that KIEs determined for competition reactions reflect the
catalytic step in which the substrate is irreversibly consumed, but not
necessarily the rate-limiting step: (a) Vo, L. K.; Singleton, D. A. Org.
Lett. 2004, 6, 2469. (b) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 15258.
(20) For a Pd(II)/Pd(0) catalytic cycle involving BzOOtBu as an
oxidant, see: Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2005, 44, 3125.
(21) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 7420.
~
(22) For recent reviews, see: (a) Muniz, K. Angew. Chem., Int. Ed.
2009, 48, 9412. (b) Lyons, T.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(23) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740. (b) Miura, M.; Tsuda, T.; Satoh, T.;
Nomura, M. Chem. Lett. 1997, 1103. (c) Satoh, T.; Inoh, J.-i.; Kawamura,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239.
5506
Org. Lett., Vol. 13, No. 20, 2011

dibenzofuran derivative. The catalytic system features a
simple combination of a palladium(II) salt and a pyridine
ligand and the use of peroxybenzoate as an inexpensive
and convenient oxidant. Mechanistic experiments suggest
that the reaction involves Pd(II)-mediated CꢀH bond
cleavage as the rate-limiting step, which is followed by
oxidation to a high-oxidation-state palladium species
and subsequent CꢀO bond-forming reductive elimination.
Acknowledgment. We thank the Singapore National
Research Foundation (NRF-RF-2009-05) and Nanyang
Technological University for financial support.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 20, 2011
5507