Cu-catalyzed oxidative C(sp2)-H cycloetherification of o-arylphenols for the preparation of dibenzofurans

Article abstract of DOI:10.1021/ol203442a

A new process involving copper-catalyzed aerobic C(sp²)-H activation, followed by cycloetherification, has been developed. This reaction serves as a direct method for the preparation of multisubstituted dibenzofurans starting with o-arylphenols. The presence of a strong para-electron-withdrawing group (e.g., NO₂) on the phenol is essential for the success of the reaction.

Full text of DOI:10.1021/ol203442a

ORGANIC
LETTERS
Cu-Catalyzed Oxidative C(sp2)ꢀH
Cycloetherification of o-Arylphenols for
the Preparation of Dibenzofurans
2012
Vol. 14, No. 4
1078–1081
Jiaji Zhao, Yong Wang, Yimiao He, Lanying Liu, and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China
zhu_qiang@gibh.ac.cn
Received December 24, 2011
ABSTRACT
A new process involving copper-catalyzed aerobic C(sp2)ꢀH activation, followed by cycloetherification, has been developed. This reaction serves
as a direct method for the preparation of multisubstituted dibenzofurans starting with o-arylphenols. The presence of a strong para-electron-
withdrawing group (e.g., NO2) on the phenol is essential for the success of the reaction.
Transition-metal-catalyzed CꢀH functionalization
serves as an atom-economical and environmentally benign
alternative for CꢀC and Cꢀheteroatom bond formation.
Substantial advances have been made during the past
decade in developing these processes.1 In most cases, the
requirement for a directing group in the substrate lessens
the advantageous impact of CꢀH functionalization pro-
cesses over other traditional methods that use prefunctio-
nalized Cꢀ(pseudo)halogen bond-containing substrates.
However, intramolecular CꢀH heterofunctionalization, in
which heteroatoms act as directing groups as well as
intramolecular nucleophiles, are ideal and atom-economical
processes that can be used for the construction of
heterocyclic architectures.2 Following the pioneering ef-
forts by Buchwald in 2005,3a this strategy has been applied
to the preparation of a variety of N-heterocycles,3 espe-
cially carbazoles.3aꢀf
In contrast, applications of a similar strategy to the
preparation of oxygen-containing heterocycles have been
less successful. In this regard, recent studies have revealed
that hydroxyl groups in carboxylic acids can be used as
nucleophiles in oxidative lactonization via Pt- or Pd-
catalyzed C(sp3)ꢀH activation.4 In 2008, Nagasawa et al.
developed a novel method for the synthesis of benzoxazole
derivatives based on intramolecular Cu-catalyzed CꢀO
(3) For examples of the synthesis of N-heterocycles via transition-
metal-catalyzed CꢀH functionalization, see: Carbazole: (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) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1115. (e) Youn, S. W.; Bihn, J. H.; Kim,
B. S. Org. Lett. 2011, 13, 3738. (f) Cho, S. H.; Yoo, J.; Chang, S. J. Am.
Chem. Soc. 2011, 133, 5996. Benzimidazole: (g) Brasche, G.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (h) Xiao, Q.; Wang, W.-H.;
Liu, G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Chem.ꢀEur. J.
2009, 15, 7292. Pyrido[1,2-a]benzimidazole: (i) Wang, H.; Wang, Y.;
Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217.
(j) Master, K. S.; Rauws, T. R. M.; Yadav, A. K.; Herrebout, W. A.; Van
der Veken, B.; Maes, B. U. W. Chem.ꢀEur. J. 2011, 17, 6315.
(1) For recent reviews of transition-metal-catalyzed CꢀH functiona-
€
lization, see: (a) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F.
Chem. Soc. Rev. 2011, 40, 4740. (b) Newhouse, T.; Baran, P. S. Angew.
Chem., Int. Ed. 2011, 50, 3362. (c) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (d) Daugulis, O.; D, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (e) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Rev. 2011, 111, 1293.
(2) For reviews of the synthesis of heterocycles via transition-metal-
catalyzed CꢀH functionalization, see: (a) Tansandote, P.; Lautens, M.
Chem.ꢀEur. J 2009, 15, 5874. (b) Stokes, B. J.; Driver, T. G. Eur. J. Org.
Chem. 2011, 4071. (c) Beccalli, E. M.; Broggini, G.; Fasana, A.;
Rigamonti, M. J. Organomet. Chem. 2011, 696, 277. (d) Zhang, M.
Adv. Synth. Catal. 2009, 351, 2243.
(4) (a) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc.
2001, 123, 8147. (b) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.;
White, M. C. J. Am. Chem. Soc. 2006, 128, 9032. (c) Lee, J. M.; Chang, S.
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r
10.1021/ol203442a
Published on Web 01/30/2012
2012 American Chemical Society

bond forming reactions between carbonyl oxygens of the
anilide moiety and aromatic CꢀH bonds.5 In 2010, Yu
et al. described the first example of a dihydrobenzofuran syn-
thesis that involves a tertiary aliphatic alcohol-directed
cycloetherification process that is catalyzed by Pd(OAc)2
and PhI(OAc)2 as the oxidant.6 Despite the success of these
earlier studies and other oxidative CꢀO bond forming
cyclization reactions,7 CꢀH cycloetherification reactions
that employ phenols as nucleophiles remain underdeveloped.8
Reasons for this situation include the fact that (1) phenols
are prone to oxidation in the presence of strong oxidants
such as PhI(OAc)2, (2) homocoupling of phenols occurs
when transition metals such as Cu are present,9 and (3)
reductive elimination of CꢀO from the presumed Pd(II)
intermediates is a sluggish process that requires the assis-
tance of specially designed ligands to occur.10
Dibenzofuran is an important structural motif that
exists in a wide variety of biologically active compounds.11
Previously developed approaches for preparation of mem-
bers of this family include Pd- or Cu-catalyzed intramole-
cular O-arylation of 2-chlorobiphenyl-20-ols (path a,
Scheme 1),12 Pd-catalyzed cyclization of 1-halo-2-pheno-
xybenzenes,13 tandem decarboxylation/CꢀC coupling of
2-phenoxybenzoic acids,14 and oxidative CꢀC cyclization
of diphenylethers15 (path b, Scheme 1). Recently, Liu et al.
described a novel and elegant approach to the synthesis of
dibenzofurans that employs Pd-catalyzed CꢀH activation/
CꢀO cyclization reactions of o-arylphenols.8a Very
recently, Yoshikai et al. reported a similar Pd-catalyzed
process involving 3-nitropyridine as a ligand and tert-butyl
peroxybenzoate as an oxidant.8b
Scheme 1. Approaches toward Dibenzofurans
Inspired by the recent advantages of Cu-catalyzed CꢀH
functionalization processes,16 we hypothesized that inex-
pensive Cu catalysts should also be capable of promoting
CꢀO cyclization reactions of 2-arylphenols. Below, we
describe a new process for the preparation of multisubsti-
tuted dibenzofurans through aerobic C(sp2)ꢀH cycloe-
therification starting with o-arylphenols. The methodol-
ogy relies on a simple reaction system and inexpensive Cu
salts as catalysts.
Reactions using 2-phenylphenol as the substrate and
various Cu salts as catalysts under an air atmosphere were
not successful owing to the fact that the electron-rich
substrate is labile under these conditions. To overcome
this problem, reactions of 4-nitro-2-phenylphenol (1a), in
which the potential for oxidation is reduced significantly,
were explored (Table 1). No cyclization occurred even at
140 °C for 14 h when 20 mol % of Cu(OAc)2 were used
(1 equiv of PivOH, DMSO, 140 °C, under an air atmo-
sphere). To our delight, addition of various carbonate salts
to the reaction mixture leads to significantly improved
cyclization efficiencies (entries 2ꢀ5). Among the bases
screened, Cs2CO3 was observed to be the most effective,
producing 2a in 50% yield.17 Surprisingly, the reaction did
not take place when excess Cs2CO3 (2.0 equiv) was present
and the use of 0.25equiv ofCs2CO3 led toa 25% yield of 2a
(entries 6ꢀ7). Screening of other Cu sources resulted in the
identification of CuBr as the optimal catalyst (entries
8ꢀ12). The yield of 2a was further increased to 72% when
30 mol % of CuBr are used for the process. When CuBr
was absent or the Cu catalyst was replaced by Pd(OAc)2,
no product 2a was detected in both cases, indicating that
the reaction was indeed catalyzed by Cu (entries 14ꢀ15).
When the reaction was operated in argon, the cyclization
was considerablly less efficient, suggesting that O2 played a
vital role in the catalytic cycle (entry 16).
(5) (a) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
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The scope of substrates was probed under the optimized
reaction conditions (Scheme 2). Substrates with either
electron-donating or -withdrawing substituents in the
para-position were found to be reactive under these con-
ditions, giving the desired products 2bꢀ2g in 59ꢀ70%
(14) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
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Org. Lett., Vol. 14, No. 4, 2012
1079

However, the exsitence of a methyl group in the ortho-
position completely hampers the cyclization (result not
shown). Replacement of the para-NO2 by cyano and
formyl groups leads to substrates that undergo reaction
to form the corresponding products in respective 64% and
44% yields. When other substituents are present adjacent
to the phenolic hydroxyl group, cyclization reactions take
place with comparable efficiencies (2lꢀ2m). In addition, in
the cases of 2n and 4a where bulky iodo and phenyl groups
are present, a change in the catalyst from CuBr to Cu-
(OAc)2 is necessary to avoid the formation of unidentified
byproducts.
For the purpose of gaining insight into the mechan-
ism of the CꢀH cycloetherification reaction, the di-
phenyl substrate 3a-d5 bearing one fully deuterated
phenyl ring was prepared and subjected to the reac-
tion conditions described for 4a in Scheme 2. 1H NMR
analysis of the isolated product mixture generated
after 4 h demonstrated that the process displayed a
large kinetic isotope effect (KIE) of 4.5.18 In addition,
this analysis showed that proton scrambling did not
take place in the recovered starting material 3a-d5,
indicating that the CꢀH activation process is irrevers-
ible (Scheme 3).
Table 1. Optimization of Reaction Conditionsa
catalyst
time
yield
(%)b
entry
(20 mol %)
base
(h)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(TFA)2
Cu(OTf)2
CuI
ꢀ
14
14
14
14
14
14
14
24
24
22
15
21
14
17
17
14
0
2
Li2CO3
Na2CO3
K2CO3
36
36
41
50
0c
25d
50
48
53
55
63
72
0
3
4
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6
7
8
9
10
11
12
13
14
15
16
CuCl
CuBr
CuBre
ꢀ
f
Pd(OAc)2
0
CuBr g
28
a All reactions were carried out at 0.2 mmol scale, with Cu catalyst
(20 mol %), PivOH (1 equiv), base (0.5 equiv), in DMSO (1 mL),
at 140 °C, in air. b Isolated yield. c 2 equiv of Cs2CO3 were used. d 0.25
equiv of Cs2CO3 was used. e 30 mol % CuBr was used. f 10 mol %.
g In argon.
Scheme 3. Intramolecular Kinetic Isotope Effect Study
Scheme 2. Scope of the Catalytic CꢀH Cycloetherificationa
To obtain further information about the mechanism for
CꢀH activation, intramolecular competition experiments
were carried out using the unsymmetrical 2,6-diaryl-4-
nitrophenols (3bꢀe), which possess one electron biased
aryl ring (Table 2). To determine the ratio of the two
regioisomers formed in each reaction, the possible regioi-
someric products 4bꢀe and 5bꢀe were synthesized by
using Suzuki coupling reactions of the iodinated dibenzo-
furan 2n and corresponding arylboronic acids (see Sup-
porting Information). As the results in Table 2 indicate,
CꢀH bonds in electron-deficient aromatic rings are more
easily cleaved (entries 3ꢀ4), although the reactivity trend
for the electron-rich arene ring containing substrates
3b and 3c is not clear. This finding suggests that a
concerted-metalation-deprotonation (CMD)19 rather
thanelectrophilic metalation process is likely occurring.3g,5
Furthermore, the addition of TEMPO, a radical scavenger,
a All reactions were carried out at 0.2 mmol scale, with CuBr (30 mol %),
PivOH (1 equiv), Cs2CO3 (0.5 equiv), in DMSO (1 mL), at 140 °C
under air, isolated yield. bRegioisomers (para/ortho = 20:1, by 1H
NMR) were obtained. 30 mol % of Cu(OAc)2 were used instead of
CuBr.
c
yields. It is notable that the bromine-containing substrate
reacts to yield the corresponding cyclization product 2g,
which along with the corresponding methoxylated prod-
uct 2c can serve as a suitable intermediate for further
modification of the dibenzofuran skeleton. The reactions
of the meta-substitued reactants generate the sterically
favored products 2h and 2i with a ca. 20:1 selectivity.
(18) Gomez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.
Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Soc. Chem. 2010, 132, 5837.
Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581.
(19) For a review of mechanistic work on the CMD pathway, see:
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
1080
Org. Lett., Vol. 14, No. 4, 2012

Table 2. Intramolecular Competition Studya
Scheme 4. Proposed Reaction Mechanism
ratio
of 4/5b
yield of
4þ5 (%)c
entry
substrate
1
2
3
4
3b R = Me
3c R = OMe
3d R = Cl
3e R = F
1:1
80
96
71
84
1:0.9
1:0.66
1:0.88
a All reactions were carried outin0.2 mmolscale, Cu(OAc)2 (30 mol%),
PivOH (1 equiv), Cs2CO3 (0.5 equiv), in DMSO (1 mL), at 140 °C
under air. b The ratios were determined by 1H NMR analysis.
c Isolated yield.
In conclusion, a Cu-catalyzed process for the synthesis of a
variety of dibenzofuran derivatives has been developed. A
catalytic amount of Cu can promote the cycloetherification
reaction when 0.5 equiv of Cs2CO3 and 1.0 equiv of PivOH are
employed as additives under an air atmosphere. Although an
electron-withdrawing group prelocated at the para-position
relative to the phenolic OH is essential to prevent direct
oxidation of the substrate, these electron-withdrawing groups
(NO2, CN, CHO) may serve as versatile functionalities for
further transformations. The new methodology not only
serves as an alternative approach for the synthesis of dibenzo-
furans but also broadens the application of Cu-catalyzed
CꢀH activation reactions in the preparation of oxygen-con-
taining heterocycles. The results of mechanistic studies suggest
that an irreversible, rate-limiting CMD step is most likely
involved in the mechanistic pathway for CꢀH activation.
However, detailed studies are needed to gain deeper insight
into the mechanism of the process, especially for elucidating
the valence of Cu involved in the CꢀH activation step.
Acknowledgment. We are grateful to the National
Science Foundation of China (21072190) for financial
support of this work.
has no influence on the product formation, which rules out
the possibility of a radical mechanism.
Based on the results of the mechanistic studies described
above, two pathways for the cycloetherification reaction
displayed in Scheme 4 are plausible. In path a, initial
coordination of Cu(II) species with the phenolic hydroxyl
group forms intermediate A, which undergoes rate-limiting,
irreversible ligand assisted CMD through intermediate
B. Subsequent reductive elimination gives the cyclized
product with concurrent formation of Cu(0), which is then
oxidized by O2 in the presence of acid. Alternatively,
activation of the aromatic ring by Cu(II) can take place
via the η2 π complex D.3j Nucleophilic attack of the
phenolic OH on the activated arene results in production
of the cyclized intermediate E, which then undergoes cis
hydride elimination to generate the product and Cu(0).
Considering the severe influence of the ortho-methyl group
on product formation, path a involving a coplanar transi-
tion state is more likely followed in this process. However,
a possible Cu(I) to Cu(III) cycle cannot be ruled out at the
current time.20
Supporting Information Available. Experimental pro-
cedure, and characterization data for all new compounds.
This material is free of charge via the Internet at http://
pubs.acs.org.
(20) (a) Huffman, L. M.; Casitas, A.; Font, M.; Canta, M.; Costas,
M.; Ribas, X.; Stahl, S. S. Chem.;Eur. J 2011, 17, 10643. (b) Chen, B.;
Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc. 2011, 133, 7668 and
references cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1081