CuI-mediated sequential iodination/cycloetherification of o-arylphenols: Synthesis of 2- or 4-iododibenzofurans and mechanistic studies

Article abstract of DOI:10.1021/ol302562a

An efficient synthesis of 2- or 4-iododibenzofurans through CuI-mediated sequential iodination/cycloetherification of two aromatic C-H bonds in o-arylphenols has been developed. Both the preexisting electron-withdrawing groups (NO₂, CN, and CHO) and the newly introduced iodide are readily modified for a focused dibenzofuran library synthesis. Mechanistic studies and DFT calculations suggest that a Cu(III)-mediated rate-limiting C-H activation step is involved in cycloetherification.

Full text of DOI:10.1021/ol302562a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
CuI-Mediated Sequential Iodination/
Cycloetherification of o‑Arylphenols:
Synthesis of 2- or 4‑Iododibenzofurans
and Mechanistic Studies
Jiaji Zhao,† Qi Zhang,‡ Lanying Liu,† Yimiao He,† Jing Li,† Juan Li,*,‡ and Qiang Zhu*,†
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530,
P. R. China, and Department of Chemistry, Jinan University, Huangpu Road West 601,
Guangzhou 510632, P. R. China
zhu_qiang@gibh.ac.cn; tchjli@jnu.edu.cn
Received September 18, 2012
ABSTRACT
An efficient synthesis of 2- or 4-iododibenzofurans through CuI-mediated sequential iodination/cycloetherification of two aromatic CꢀH bonds in
o-arylphenols has been developed. Both the preexisting electron-withdrawing groups (NO2, CN, and CHO) and the newly introduced iodide are
readily modified for a focused dibenzofuran library synthesis. Mechanistic studies and DFT calculations suggest that a Cu(III)-mediated rate-
limiting CꢀH activation step is involved in cycloetherification.
The copper-catalyzed/mediated annulation reaction via
CꢀH activation has been recognized as an atom-economic
and cost-effective alternative to classical coupling methods
using prefunctionalized substrates in the construction of
heterocycles.1 However, only one chemical bond, such
as a CꢀC,2 CꢀN,3 or CꢀO4 bond, is formed in most of
these processes. In contrast, domino reactions are highly
efficient in bond formation, in which multiple chemical
bonds are usually formed in one pot.5 Incorporation
of transition-metal-catalyzed CꢀH functionalization into
a domino reaction is arguably an ideal but challenging
strategy. Compared with Pd-catalyzed domino reactions
involving CꢀH activation,6 similar approaches catalyzed
† Guangzhou Institutes of Biomedicine and Health.
‡ Jinan University.
(1) For reviews on Cu-catalyzed/mediated CꢀH functionalizations,
see: (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int.
Ed. 2011, 50, 11062. (b) Zhang, M. Appl. Organometal. Chem. 2010, 24,
269.
(2) For Cu-catalyzed/mediated CꢀH activation/CꢀC annulation,
see: (a) Barbero, N.; SanMartin, R.; Domınguez, E. Org. Biomol. Chem.
´
2010, 8, 841. (b) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor,
R. J. K. Org. Lett. 2010, 12, 3446. (c) Bernini, R.; Fabrizi, G.; Sferrazza,
A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078.
(5) (a) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (b) Alba,
A.-N.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13,
1432.
(3) For Cu-catalyzed/mediated CꢀH activation/CꢀN annulation,
see: (a) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996. (b) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (c) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem.
Soc. 2010, 132, 13217. (d) Masters, 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. (e) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett.
2010, 12, 3682.
(4) For Cu-catalyzed/mediated CꢀH activation/CꢀO annulation,
see: (a) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47,
6411. (b) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272. (c) Guin,
S.; Ghosh, T.; Rout, S. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2011, 13,
5976. (d) Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2012, 14,
1078. (e) Zhao, J.; Wang, Y.; Zhu, Q. Synthesis 2012, 44, 1551.
(6) For recent examples of Pd-catalyzed domino reactions involving
CꢀH activation, see: (a) Lu, Z.; Cui, Y.; Jia, Y. Synthesis 2011, 2595.
(b) Chen, Z.; Zhu, J.; Xie, H. Adv. Synth. Catal. 2011, 353, 325. (c) Lu, Z.;
Hu, C.; Guo, J.; Li, J.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480.
(d) Ackermann, L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46,
1627. (e) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8,
4927. (f) Furuta, T.; Asakawa, T.; Linuma, M.; Fujii, S.; Tanaka, K.;
Kan, T. Chem. Commun. 2006, 3648. (g) Zhao, J.; Larock, C. Org. Lett.
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128, 9048.
r
10.1021/ol302562a
XXXX American Chemical Society

or mediated by Cu are underdeveloped.7 In addition to
atom economy and bond-forming efficiency, the feasibility
of further modification on the heterocyclic scaffold thus
formed is particularly important in medicinal chemistry.
Considering the versatility of organic iodides in chemi-
cal transformations, a domino iodination/annulation
reaction via CꢀH activation is of great interest.8 Herein,
we report a CuI-mediated sequential iodination/cycloether-
ification of o-arylphenols for the synthesis 2- or 4-iododi-
benzofurans, in which CuI acts as both an iodinating
reagent under aerobic conditions and a promotor in CꢀH
cycloetherification.
The dibenzofuran skeleton exists in a wide range of
biologically active compounds.9 Methods leading to
the construction of this scaffold are mainly based on
Pd- or Cu-catalyzed intramolecular O-arylation of
2-chlorobiphenyl-20-ols,10 Pd-catalyzed cyclization of
1-halo-2-phenoxybenzenes,11 tandem decarboxyla-
tion/CꢀC coupling of 2-phenoxybenzoic acids,12 and
oxidative CꢀC cyclization of diphenylethers.13 Inde-
pendently, Liu and Yoshikai reported concise ap-
proaches to construct the dibenzofuran scaffold from
2-arylphenols through Pd-catalyzed intramolecular
CꢀH activation CꢀO bond formation.14 We also dis-
closed a similar strategy for the synthesis of electron-
deficient dibenzofurans using inexpensive CuBr and
Cu(OAc)2 as catalysts.4d,e
Table 1. Optimization of Reaction Conditionsa
CuI
additive
(equiv)
yield (%)b
entry
(equiv)
2a
1
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
55
63
63
60
9
2
3
4c
5d
6
AcOH (1.0)
PivOH (1.0)
PivOH (2.0)
79
82
82
7
8
a The reactions were carried out at 0.2 mmol scale in 1 mL of DMSO.
b Isolated yield. c The reaction was performed under O2 (1 atm).
d The reaction was performed under Ar (1 atm).
argon atmosphere deteriorated the reaction dramati-
cally, indicating a vital role played by O2 (entries 4ꢀ5).
Efforts toward using a catalytic amount of CuI along
with a stoichiometric amount of other iodide sources
were unsuccessful (see Supporting Information (SI)).
Screening of additives revealed that the presence of
PivOH (1 equiv) could enhance the yield of 2a signifi-
cantly to 82%.15
To determine the sequence of CꢀI and CꢀO bond
formation in 2a, 2-nitrodibenzofuran 34d was subjected
to the conditions described in entry 7, Table 1. Compound
3 was totally stable under the reaction conditions, which
suggested that iodination took place prior to cycloether-
ification (eq 1, Scheme 1). The conclusion was further
confirmed by the fact that when the reaction of 1a was
performed at 60 °C for 40 h, the reaction stopped at the
stage of iodination (eq 2). The isolated uncyclized iodide 1b
could be further cyclized at a higher temperature (140 °C)
with the aid of an excess amount of CuI, indicating that the
active copper species cannot be regenerated (eq 3). It is
notable that although there are many methods available
for iodination of phenols,16 to the best of our knowledge,
this is the first example of using CuI as an iodinating
reagent.
During the course of catalyst optimization in CꢀH
cycloetherification using 2-phenyl-4-nitrophenol 1a as
a substrate, an unexpected iodinated cyclization pro-
duct, 4-iodo-2-nitrodibenzofuran 2a, was produced in
55% yield when 1 equiv of CuI was employed (entry 1,
Table 1). The yield of 2a was maximized to 63% as the
loading of CuI increased (entries 2ꢀ3). The reaction
efficiency diminished slightly when the reaction was
performed under a dioxygen atmosphere, while an inert
(7) (a) Liao, Q.; Zhang, L.; Li, S.; Xi, C. Org. Lett. 2011, 13, 228.
(b) Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R. J. Am. Chem.
Soc. 2012, 134, 12149.
(8) (a) Wei, H.-L.; Piou, T.; Dufour, J.; Neuville, L.; Zhu, J. Org.
Lett. 2011, 13, 2244. (b) For recent reported Cu-catalyzed halocycliza-
tions that do not involve a CꢀH activation step, see: (b) Brotherton,
W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77, 6443. (c) Yin, B.;
Huang, L.; Zhang, X.; Ji, F.; Jiang, H. J. Org. Chem. 2012, 77, 6365.
(9) (a) De Lombaert, S.; Blanchard, L.; Stamfold, L. B.; Tan, J.;
Wallace, E. M.; Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.;
Moliterni, J.; Marcopoulos, N.; Savage, P.; Chou, M.; Trapani, A. J.;
Jeng, A. Y. J. Med. Chem. 2000, 43, 488. (b) Kaul, R.; Deechongkit, S.;
Kelly, J. W. J. Am. Chem. Soc. 2002, 124, 11900. (c) Carney, J. R.;
Krenisky, J. M.; Williamson, R. T.; Luo, J. J. Nat. Prod. 2002, 65, 203.
(10) (a) Kawaguchi, K.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007,
72, 5119. (b) Liu, J.; Fitzgerald, A. E.; Mani, N. S. J. Org. Chem. 2008,
73, 2951.
Having identified the optimized conditions, we next
explored the substrate scope of this sequential iodina-
tion/CꢀH cycloetherification reaction. It was found
that, in some cases, the desired iodinated dibenzofurans
were contaminated with noniodinated cyclization
products as a result of competitive cyclization of the
starting phenols. To solve this problem, the reactions
(11) (a) Ames, D. E.; Opalko, A. Synthesis 1983, 234. (b) Campeau,
L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
581. (c) Xu, H.; Fan, L.-L. Chem. Pharm. Bull. 2008, 56, 1496. (d) Liu, Z.;
Larock, R. C. Tetrahedron 2007, 63, 347. (e) Liu, Z.; Larock, R. C. Org.
Lett. 2004, 6, 3739.
(12) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(13) (a) Shiotani, A.; Itatani, H. Angew. Chem., Int. Ed. 1974, 13, 471.
(b) Hellwinkel, D.; Kistenmacher, T. Liebigs Ann. Chem. 1989, 945.
(15) Ackermann, L. Chem. Rev. 2011, 111, 1315.
ꢀ
(c) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
(16) For selected examples, see: (a) Bovonsombat, P.; Leykajarakul,
J.; Khan, C.; Pla-on, K.; Krause, M. M.; Khanthapura, P.; Ali, R.;
Doowa, N. Tetrahedron Lett. 2009, 50, 2664. (b) Joshi, S. N.; Vyas,
S. M.; Wu, H.; Duffel, M. W.; Parkin, S.; Lehmler, H.-J. Tetrahedron
2011, 67, 7461.
J. Org. Chem. 2008, 73, 5022.
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J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250. (b) Wei, Y.; Yoshikai, N.
Org. Lett. 2011, 13, 5504.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Verification of the Reaction Sequence
Scheme 3. Diversification of 2a
yields. Regioselectivities were excellent to good for
meta methyl and methoxy substituted phenols (2iꢀ2j).
The presence of a methyl group on the ortho position
seriously retarded the cyclization due to steric effects
(2k). The para nitro on the phenol ring could be re-
placed by other electron-withdrawing groups (EWG),
such as CF3, CN, and CHO, albeit in reduced yields
(2lꢀ2n). A dual chelation effect was observed in the
preparation of 2o, where the benzylic alcohol acted as
an additional directing group besides the phenolic OH
to activate the sterically more hindered CꢀH bond
preferentially.4e In this case, the reaction tempera-
ture should be kept under 80 °C to avoid oxidation of
the benzyl alcohol. For substrates bearing a nitro group
on the ortho position, corresponding 2-iodo-4-nitrodi-
benzofuran derivatives were obtained in moderate
to good yields (2qꢀ2v). In addition, when CuBr was
used in place of CuI, a sequential bromination/CꢀH
cycloetherification reaction took place, leading to
4-bromo-2-nitrodibenzofuran 2p in 63% yield. Unfor-
tunately, substrates without an EWG group on the
phenolic ring quickly decomposed under the reaction
conditions.
were performed first at lower temperature (110 °C) for
complete iodination and then at elevated tempera-
ture (140 °C) to promote the cyclization. For other
substrates, this kind of operation was not necessary
probably because the iodination step was relatively
fast. Investigation on the substitution effect on the
nonphenolic ring disclosed that the reaction was
not sensitive to the electronic properties of the substi-
tuents (Scheme 2). Substrates containing both electron-
donating (Me, OMe) and -withdrawing (F, Cl, CF3,
NO2) groups on the para position produced the corre-
sponding 4-iodo-2-nitrodibenzofurans 2bꢀ2h in good
Scheme 2. Substrate Scopea
The feasibility of diversifying the dibenzofuran scaffold
was demonstrated by using 2a as an example (Scheme 3).
The C-4 of 2acan be modified smoothly witha phenyl ring,
an imidazole heterocycle, and an acetylene by Suzuki,
Ullmann, and Sonogashira couplings, respectively. In
addition, the preexisting nitro group could be reduced
selectively to NH2 with the iodide intact.
Although Cu-catalyzed bromination and chlorina-
tion of electron-rich arenes and heterocycles have been
reported in literature,1a,17,18 CuI-mediated iodination of
phenols has not been documented. In the current pro-
tocol, the phenol substrates were most likely iodinated
by molecular I2 which was formed by cooperative oxi-
dation of O2 and Cu. Actually, the nonpolar I2 with its
distinctive purple color was observed during column
chromatography of the reaction mixture using only
petroleum ether as an eluent.
a All reactions were carried out at 0.2 mmol scale, CuI (1.5 equiv),
PivOH (1.0 equiv) in 1 mL of DMSO, under air, isolated yield. b 110 °C
for 10 h and 140 °C for 10 h (for 2k, 26 h). c140 °C for 10 h (for 2qꢀ2v,
1H NMR analysis. e 60 °C for 90 h and 80 °C for 40 h. f CuBr (1.5 equiv)
was used instead of CuI, 100 °C for 24 h and 140 °C for 10 h.
(17) (a) Menimeni, L.; Gusevskaya, E. V. Chem. Commun. 2006, 209.
(b) Menimeni, L.; Gusevskaya, E. V. Appl. Catal., A 2006, 309, 122.
(c) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
d
24 h). The ratio of para/ortho in the parentheses was determined by
(18) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 6460.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Isotope Labeling Experiments
Scheme 5. Proposed Mechanism
To gain insight into the mechanism of the CꢀH
cycloetherification step, isotope labeling experiments
were performed (Scheme 4). When a 1:1 mixture of 1a
and 1a-D5 was subjected to the standard conditions for 3
h, a 5:1 mixture of 2a and 2a-D4 was isolated in 38%
total yield. In parallel reactions using 1a and 1a-D5 as
substrates respectively, a significant kH/kD (4.1) was
also observed by comparing the rate of product forma-
tion (see SI).19 No deuterium scrambling was observed
in the recovered 1a-D5. These results confirmed that an
irreversible rate-limiting CꢀH cleavage was involved in
cyclization. Therefore, a mechanism of concerted meta-
lationꢀdeprotonation (CMD) rather than electrophilic
aromatic substitution (SEAr) or single-electron transfer
(SET) is more likely involved in the step of CꢀH
activation.20
The oxidation state of Cu involved in the CꢀH
activation step is still a question to be answered.
Density functional theory (DFT) calculations were
carried out for both Cu(III)- and Cu(II)-mediated
CMD mechanisms. The overall free energy barrier for
the Cu(III)-mediated CMD process is 21.9 kcal/mol as
shown in Figure 1. In contrast, the CMD mechanism
for Cu(II) species needs to overcome an energy barrier of
27.1 kcal/mol. Being consistent with the experimental
results, data of DFT calculations suggest that mechanisms
of both SET (37.8 kcal/mol) and SEAr (25.8 kcal/mol) are
less favorable.21
Based on the investigations described above, we
propose the reaction mechanism in Scheme 5. Initial
oxidation of the iodide anion by a Cu(II) species forms
I2 which serves as an iodinating reagent to iodinate
1a to 1b. Coordination of 1b with a pivalate coordi-
nated Cu(III) species formed by either disproportiona-
tion or aerobic oxidation of Cu(II) and the following
pivalate assisted CMD yield the intermediate B via A.
Subsequent reductive elimination leads to the cyclized
product and concurrent formation of a Cu(I) species. It
is noteworthy that CMD is very rare for Cu-catalyzed
CꢀH activation reactions.4d
In conclusion, we have developed a one-pot sequen-
tial iodination/CꢀH cycloetherification of electron-
deficient 2-arylphenols for the synthesis of electron-
withdrawing group substituted 2- or 4-iododibenzofurans.
The reaction is mediated by 1.5 equiv of CuI which serves
as aniodinating reagent first and thena promoter for CꢀH
cycloetherification. Both the preexisting EWGs (NO2,
CN, and CHO) and thenewlyintroducediodidearereadily
transferred to diversify the dibenzofuran skeleton. Deuter-
ium labeling experiments suggest that an irreversible rate-
limiting CꢀH cleavage step is involved. Results of DFT
calculations prefer Cu(III) rather than Cu(II) species in the
pivalate-assisted CMD process.
Acknowledgment. We are grateful to the National
Science Foundation of China (21072190 and 21103072)
and Fundamental Research Funds for the Central Uni-
versities (Grant No. 21612404) for financial support of this
work.
Supporting Information Available. Experimental pro-
cedure and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(20) For a review of mechanistic work on the CMD pathway, see:
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
(21) DFT calculations are detailed in the SI.
Figure 1. Energy profiles of the CMD mechanism for the CꢀH
cycloetherification step with a Cu(III) catalyst. The calculated
relative free energies and electronic energies (in parentheses) are
given in kcal/mol. Selected bond distances (A) calculated for
species are shown in blue.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX