Ligand-Free, Cu- and Fe-Catalyzed Selective Ring-Opening Arylations of Benzoxazoles with Aryl Iodides

Article abstract of DOI:10.1002/asia.201600252

Cu- or Fe-based catalyst systems have been reported to selectively catalyze the N,N-diarylation or N-monoarylation of benzoxazoles ring-opening with aryl iodides in the absence of additional added ligand in polyethylene glycol under an inert atmosphere. Two types of coupling products (triphenylamines and diphenylamines) have been examined and the reaction routes can be simply controlled by changing the metal salts (Cu or Fe) as catalyst. A range of substrates have been investigated for the diverse reactions, and the corresponding arylation products were achieved in good to high yields. This selective, low-cost, and environmentally friendly protocol displays great potential for replacing existing methodologies as well as extending the synthetic applications of benzoxazoles.

Full text of DOI:10.1002/asia.201600252

DOI: 10.1002/asia.201600252
Communication
Arylation
Ligand-Free, Cu- and Fe-Catalyzed Selective Ring-Opening
Arylations of Benzoxazoles with Aryl Iodides
Yue He,[a] Jincheng Mao,*[a, b] Guangwei Rong,[a] Hong Yan,[a] and Guoqi Zhang*[c]
narrow range of substrates, relatively low yields, and stoichio-
Abstract: Cu- or Fe-based catalyst systems have been re-
ported to selectively catalyze the N,N-diarylation or N-
monoarylation of benzoxazoles ring-opening with aryl io-
dides in the absence of additional added ligand in poly-
ethylene glycol under an inert atmosphere. Two types of
coupling products (triphenylamines and diphenylamines)
have been examined and the reaction routes can be
simply controlled by changing the metal salts (Cu or Fe)
as catalyst. A range of substrates have been investigated
for the diverse reactions, and the corresponding arylation
products were achieved in good to high yields. This selec-
tive, low-cost, and environmentally friendly protocol dis-
plays great potential for replacing existing methodologies
as well as extending the synthetic applications of benzox-
azoles.
metric amounts of copper reagent of which most are poorly
soluble in organic solvents.[3] Thereafter, to solve these prob-
lems, Buchwald and Hartwig devised a new protocol that used
palladium-catalyzed amination of aryl halides, namely, the
Buchwald–Hartwig reaction.[4] Although significant improve-
ments such as higher efficiency and milder reaction conditions
have been achieved through the Buchwald–Hartwig method,
there are still limitations, for instance, the high cost and poten-
tial environmental toxicity of palladium. Subsequently, im-
proved Ullmann-type N-arylations have been studied, where
anilines,[5] amides,[6] imidazoles,[7] nitrogen heterocycles,[8] and
hydrazides[9] have been used as nitrogen-containing substrates
under milder conditions. Recently, copper-based catalyst sys-
tems with the right choice of chelating ligands have been de-
veloped for the formation of CÀN bonds, namely, post-Ullmann
reactions.[10]
In the last decade, the direct arylation at the C-2 position of
benzothiazoles or benzoxazoles through CÀH functionalization
with aryl iodides has been extensively explored and transition
metals such as palladium,[11] nickel,[12] or copper[13] have been
generally employed as catalysts. In contrast, the ring-opening
arylation of benzothiazoles or benzoxazoles that is assumed to
be in competition with direct arylation at the C-2 position is
a more challenging process, as the active hydroxy (or sulfenyl)
and amine groups might be generated during the reaction,
causing side-reaction problems.[6b] In 2012, Han and co-work-
ers[14] reported a copper nanoparticle catalyzed ring-opening
O-arylation of benzoxazoles by using polyethylene glycol
(PEG)-600 as a solvent under basic conditions (cesium carbon-
ate was proposed to open the benzoxazole ring first)
[Scheme 1, Eq. (1)]. Very recently, Kim and co-workers[15] devel-
oped a new protocol for the selective, copper-catalyzed ring-
opening N,N-diarylation and direct arylation at the C-2 position
of benzoxazole with aryl iodides and the type of product was
controlled by the choice of reaction vessel [Scheme 1, Eq. (2)].
While this observation represents the first example of the ring-
opening N,N-diarylation of benzoxazoles with aryl iodides, rela-
tively expensive solvent, pivalonitrile, and an additional phos-
phorous ligand were required. Besides these studies, very little
is known about the benzoxazole ring-opening reactions that
lead to N,N-diarylation or N-monoarylation by using inexpen-
sive, less toxic, and earth abundant metal catalysts such as Cu
or Fe. Herein, we wish to report our recent success in the
facile, ligand-free catalytic ring-opening N-arylation reactions
of benzoxazoles with aryl iodides by common copper and iron
It is well known that diphenylamines and triphenylamines are
prevalent structural units in a large number of compounds in-
cluding some biologically active molecules, agrochemicals, HIV-
1 protease inhibitors, and photofunctional materials.[1] In view
of their widespread applications, over the past decade, several
protocols have emerged to synthesize di- or tri-aryl amines
through the CÀN bond formation, and the classic Ullmann cou-
pling method provides one of the most useful and practical
methods for the synthesis of these compounds.[2] However, the
Ullmann coupling reaction suffers from high temperature,
[a] Y. He, Prof. Dr. J. Mao, G. Rong, H. Yan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry
Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (P. R. China)
Fax: (+86)512-65880403
E-mail: jcmao@suda.edu.cn
[b] Prof. Dr. J. Mao
State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation
Southwest Petroleum University
Chengdu 610500 (P. R. China)
[c] Prof. Dr. G. Zhang
Department of Sciences
John Jay College and The Graduate Center
The City University of New York
New York, NY 10019 (USA)
E-mail: guzhang@jjay.cuny.edu
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600252.
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we conducted a thorough screening of other condi-
tions including the catalyst loading, reaction times,
solvents, and temperature, however, no further im-
provement in the yield for the desired product was
obtained (details for the optimization of reaction con-
ditions can be found in the Supporting Information).
The base additive proved to be critical for the forma-
tion of 3a as only a trace amount of 3a and <10%
4a were detected when the reaction was conducted
in the absence of Cs2CO3 (Table 1, entry 21), which is
consistent with the previous assumption that Cs2CO3
plays a key role in the initial ring-opening step of
benzoxazole.
During the above-mentioned screening of reaction
conditions for the synthesis of 3a, we noticed that
the diphenylamine 4a was frequently observed,
albeit in low yields. We were, therefore, also interest-
ed to investigate whether or not the yield of 4a
Scheme 1. Different strategies for ring-opening arylation reactions of benzoxazole and its
analogues.
salts, when PEG-400 was used as a green solvent [Scheme 1,
Eq. (3)]. It was also interesting to observe that the nature of
the reaction pathway was controlled by the choice of copper
or iron as a catalyst, as both the di- and tri-phenylamine prod-
ucts[16] were obtained in good yields through N,N-diarylation or
N-monoarylation, respectively, by simply switching the metal
salts. This represents a novel example of catalytically selective
ring-opening arylations of benzoxazoles.
could be improved by modifying the reaction conditions and/
or catalysts, while inhibiting the formation of 3a. Indeed, after
a brief catalyst screening and optimization of conditions (see
Table 1. Optimized reaction conditions for the selective synthesis of di-
and triphenylamines.[a]
Initially, we used benzoxazole (1a) with iodobenzene (2a) as
the starting materials for the metal-catalyzed ring-opening ary-
lation, and then the reaction conditions were optimized. The
results are summarized in Table 1. To our delight, the desired
triphenylamine, 2-(diphenylamino)phenol (3a) was afforded in
59% yield with CuCl (10 mol%) as a catalyst, PEG-400 as the
solvent, and potassium carbonate (K2CO3) as the base at 1308C
for 18 h under an atmosphere of argon. However, the diphe-
nylamine product, 2-(phenylamino)phenol (4a) was also isolat-
ed in 14% yield (Table 1, entry 1). Further screening was carried
out by altering the CuI salts and it was revealed that while
CuCN led to slightly improved yields (3a; 66%) under the
same reaction conditions (Table 1, entry 2), other CuI halides
showed similar catalytic activity to CuCl, except in the case of
CuBr, where the formation of 4a was partially suppressed
(Table 1, entries 3 and 4). In contrast, CuII salts were found to
be less active catalysts for the reaction (Table 1, entries 5–9), al-
though both 3a and 4a were obtained in each case. It was no-
ticed that a significantly lower yield was observed when the re-
action was performed under an atmosphere of air (Table 1,
entry 10 vs entry 3). To further improve the efficiency for the
conversion of benzoxazole, we then tested the reaction with
three equivalents of iodobenzene. Indeed, higher conversion
(83%) was revealed and 3a was isolated in 71% yield as
a major product (Table 1, entry 11). Furthermore, a variety of
bases was screened, and it was found that cesium carbonate
(Cs2CO3) gave the best result, affording 3a in 80% yield, while
other bases were much less effective (Table 1, entries 12–17).
Finally, increasing the amount of Cs2CO3 (0.75 mmol) resulted
in a slightly improved yield of 3a (84%), together with com-
plete suppression of 4a (Table 1, entries 18–20). In addition,
Entry 1a:2a Catalyst
Base
T [oC] Yield[f] (3a) Yield[f] (4a)
1
2
3
4
5
6
7
8
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:3
1:3
1:3
1:3
1:3
1:3
1:3
CuCl
CuCN
CuBr
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
130 59
130 66
130 61
130 53
130 35
130 40
130 43
130 38
130 39
130 42
130 71
130 22
130 36
14
10
<5
16
23
19
15
21
18
11
12
trace
22
CuSO4
.
CuCl2 2H2O
Cu2O
CuCl2
Cu(OAc)2 H2O K2CO3
CuBr
.
9
10
11
12
13
14
15
16
17
K2CO3
K2CO3
Na2CO3
K3PO4
CH3COONa 130
CsF 130 14
CH3CH2ONa 130 20
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
<10
trace
trace
32
130 80
130 84
130 78
130 77
130 trace
<5
trace
trace
trace
<10
73
18[b] 1:3
19[c] 1:3
20[d] 1:3
21
1:3
22[e] 1:2
FeSO4 7H2O
Cs2CO3
130
<5
.
[a] Reaction conditions: benzoxazole 1a (0.3 mmol), iodobenzene 1a
(0.9 mmol), copper cyanide (0.03 mmol), potassium carbonate
(0.60 mmol), PEG-400 (2.0 mL), Ar, 18 h, 1308C; [b] cesium carbonate
(0.75 mmol). [c] cesium carbonate (0.90 mmol). [d] cesium carbonate
(1.05 mmol). [e] Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol),
FeSO4·7H2O (0.03 mmol), cesium carbonate (0.60 mmol), PEG-400
(2.0 mL), Ar, 12 h, 1308C. [f] All yields are for isolated products.
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the Supporting Information), we were delighted to find that 2-
(phenylamino)phenol (4a) could be isolated in 73% yield
when the reaction of benzoxazole (1.0 equiv) with iodoben-
zene (2.0 equiv) was conducted at 1308C in PEG-400 using
FeSO4·7H2O as a catalyst in the presence of Cs2CO3 (Table 1,
entry 22). It is worth mentioning that although the arylation of
benzoxazole was previously established by Cu-based catalysts,
iron was unknown for these reactions and the selective di- or
mono-arylation after ring-opening of benzoxazole by simply
switching Cu or Fe salts as catalysts is unprecedented.
Table 2. Cu-catalyzed synthesis of triphenylamines.[a]
Having established the optimized reaction conditions for the
synthesis of 3a and 4a, we next focused on the extension of
the substrate scope for the two reactions. First, we examined
the CuI-catalyzed ring-opening N,N-diarylation reactions for the
selective synthesis of triphenylamines by introducing a variety
of aryl iodides, and the results are summarized in Table 2. It
was revealed that aryl iodides containing either electron-do-
nating or electron-withdrawing groups on their aromatic rings
could be smoothly transformed into the desired products. Spe-
cifically, halo substituents (Br, Cl, and F) at the para-position of
aryl iodides did not affect the efficiency and the corresponding
products were all obtained in high yields with interesting che-
moselectivity, proceeding CÀN coupling exclusively at the posi-
tion with an iodo group (3b–3d). It was further observed that
even in the presence of a strongly electron-withdrawing tri-
fluoromethyl group at different positions (para- or meta-) of
the benzene ring, the corresponding triphenylamines were all
obtained in moderate yields (3e and 3 f). Gratifyingly, methyl
and methoxy substituents at different positions (para-
or meta-) of the benzene ring did not affect the efficiency and
the corresponding triphenylamines were obtained in good-to-
excellent yields (3h–3k). Moreover, aryl iodides with ortho-sub-
stituents, which usually require rigorous conditions, were cou-
pled with the ring-opening intermediate of benzoxazole to
afford the desired products in moderate or high yields (3g and
3l), indicating that steric hindrance does not have a significant
influence on the arylation process. In addition, the reactions in-
volving iodonaphthalene also proceeded well to give the ex-
pected product in 74% yield (3m). With regard to other ben-
zoxazoles, 5-methylbenzoxazole and 5-chlorobenzoxazole were
tested in the reactions with three different aryl iodides and
they showed almost the same reactivity as benzoxazole, lead-
ing to the desired products (3n–3r) with 71–85% yields
(Table 2).
Subsequently, the substrate scope for the FeII-catalyzed ring-
opening N-monoarylation of benzoxazoles for the selective
synthesis of diphenylamines was explored and the results are
summarized in Table 3. Specifically, while 4-iodoanisole as
a substrate provided diphenylamine product 4b in only mod-
erate yield, 3-iodoanisole was found to be better suited to the
reaction, and thus 4c was isolated in 78% yield. Substrates
bearing a methyl group at the meta- or para-position of aryl
iodides participated in the reactions with benzoxazole to give
the corresponding products (4d and 4e) in good yields. It is
noteworthy that 1-iodo-3,5-dimethylbenzene was also coupled
with benzoxazole for the targeted reaction with good efficien-
cy (4 f). However, exceptions were with iodobenzene sub-
[a] Reaction conditions: benzoxazole (0.3 mmol), aryl iodide (0.9 mmol),
cuprous cyanide (0.03 mmol), cesium carbonate (0.75 mmol), PEG-400
(2.0 mL), Ar, 18 h, 1308C. [b] Reaction conditions: benzoxazole (0.3 mmol),
aryl iodides (0.9 mmol), cuprous cyanide (0.03 mmol), cesium carbonate
(0.75 mmol), PEG-400 (2.0 mL), Ar, 24 h, 1308C. [c] Reaction condition:
benzoxazole (0.3 mmol), aryl iodides (1.2 mmol), cuprous cyanide
(0.03 mmol), cesium carbonate (0.75 mmol), PEG-400 (2.0 mL), Ar, 24 h,
1308C. [d] All yields are for isolated products.
strates bearing electron-withdrawing halo groups and iodo-
naphthalene, in which cases the corresponding diphenyla-
mines (4g–4i) were obtained in relatively low yields, even
though the loading of both iron catalyst and the base was in-
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Table 3. FeII-catalyzed synthesis of diphenylamines through ring-opening
arylation.[a]
[a] Reaction conditions: benzoxazole (0.3 mmol), aryl iodide (0.6 mmol),
FeSO4·7H2O (0.03 mmol), cesium carbonate (0.6 mmol), PEG-400 (2.0 mL),
Ar, 12 h, 1308C. [b] Reaction conditions: benzoxazole (0.3 mmol), aryl io-
dides (0.6 mmol), FeSO4·7H2O (0.03 mmol), cesium carbonate (0.75 mmol),
PEG-400 (2.0 mL), Ar, 12 h, 1308C. [c] Reaction condition: benzoxazole
(0.3 mmol), aryl iodides (0.6 mmol), FeSO4·7H2O (0.06 mmol), cesium car-
bonate (0.75 mmol), PEG-400 (2.0 mL), Ar, 12 h, 1308C. [d] All yields are
for isolated products.
Scheme 2. Additional experiments performed to understand the reaction
mechanisms.
the exact reaction details are unknown at this stage. Based on
the literature reports and our own results, we assume that the
CuCN-catalyzed arylation was likely to occur through a two-step
reaction route, that is, the ring-opening of benzoxazole followed
by an Ullmann-type coupling, however, the FeSO4-catalyzed re-
action probably underwent a concerted ring-opening/coupling
in one step, and in the process the presence of a benzoxazole
precursor was necessary.
creased. This is in contrast to the results described above re-
garding the CuI-catalyzed synthesis of triphenylamines.
To gain some insights into the reaction details, several addi-
tional experiments were conducted (Scheme 2). First, we exam-
ined the reaction of benzoxazole with iodobenzene in the pres-
ence of Cs2CO3 (2.5 equiv) under standard conditions without
the use of a metal catalyst, and the results showed that diphe-
nylamine product 4a was isolated in 39% yield, whereas only
a trace amount of 3a was observed [Eq. (1), Scheme 1]. We
have previously discussed the critical role of the base additive in
promoting the ring-opening process of benzoxazole (Table 1,
entry 21). Herein, we performed more control experiments to
further understand this process. Heating benzoxazole alone
with the standard CuCN- or FeSO4-catalyst systems led to the
formation of a ring-opened intermediate 2-aminophenol in 40%
and 15% yield, respectively. However, the same reaction in the
absence of CuCN afforded only a small amount of 2-aminophe-
nol [5%, Eq. (2) and (3), Scheme 2]. These findings indicate that
the presence of a transition metal (Cu or Fe) remarkably acceler-
ated the process of the initial ring-opening of benzoxazole
during the reaction, although the base was required. Next, we
used 2-aminophenol to replace benzoxazole as the starting ma-
terial for the Cu- and Fe-catalyzed reactions under standard con-
ditions [Eq. (4) and (5), Scheme 2]. The results reveal that while
both 3a and 4a were obtained in moderate yields (33% and
54%, respectively) under the Cu-catalyzed conditions, the iron
catalyst system was essentially nonreactive for the CÀN coupling
step. This led us to propose that two different reaction mecha-
nisms should be responsible for the arylations of benzoxazoles
depending on the Cu or Fe catalyst system applied, although
In summary, we have successfully developed a selective,
non-precious metal catalyzed ring-opening arylation of ben-
zoxazoles with aryl iodides promoted by copper and iron cata-
lysts. Triphenylamines or diphenylamines resulting from N,N-di-
arylation or N-monoarylation processes, can be subtly con-
trolled by switching the copper or iron catalyst, respectively.
The present copper and iron catalysis systems are suitable for
the ring-opening coupling reactions between a range of ben-
zoxazole and aryl iodide substrates, allowing access to a variety
of di- or tri-phenylamines in moderate-to-good yields. The use
of inexpensive, abundant, and non-toxic iron or copper as
a catalyst and PEG-400 as a green solvent, as well as the
ligand-free conditions make this method attractive and promis-
ing for industrial applications. Further studies of relevant reac-
tion mechanisms and the exploration of further applications of
this method are underway in our laboratory.
Experimental Section
General experimental: All the reactions were carried out under an
atmosphere of argon. Solvents were dried and degassed by stan-
dard methods and benzoxazole, iodobenzene, and cesium carbon-
ate were commercially available. Other benzoxazoles and iodoben-
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2008, 56, 5247; j) L. Naya, M. Larrosa, R. Rodriguez, J. Cruces, Tetrahe-
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matography was performed using silica gel (300–400 mesh). Ana-
lytical thin-layer chromatography was performed using glass plates
pre-coated with 200–400 mesh silica gel impregnated with a fluo-
rescent indicator (254 nm). NMR spectra were measured in CDCl3
on a 400 MHz or 300 MHz NMR spectrometer with TMS as an inter-
nal reference. Products were characterized by comparison of
1H NMR, 13C NMR, and LC-MS.
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General Procedure for the N,N-arylation Reaction between Ben-
zoxazole and Iodobenzene: benzoxazole (0.3 mmol), iodobenzene
(0.9 mmol), cuprous cyanide (10 mol%), cesium carbonate
(0.75 mmol), and PEG-400 (2 mL) were added to a Schlenk tube
equipped with a magnetic stir bar under an atmosphere of argon.
The resulting reaction mixture was kept stirring at 1308C for 18 h.
At the end of the reaction, the reaction mixture was poured into
a saturated aqueous NaCl solution (20 mL) and extracted with
ethyl acetate (3”15 mL). The organic phases were combined, and
the volatile components were evaporated under reduced pressure.
The crude product was purified by column chromatography on
silica gel using ethyl acetate/petroleum ether (1:50) to afford the
desired product in high purity.
General Procedure for the N-arylation Reaction between Ben-
zoxazole and Iodobenzene: benzoxazole (0.3 mmol), iodobenzene
(0.6 mmol), FeSO4·7H2O (10 mol%), cesium carbonate (0.60 mmol),
and PEG-400 (2 mL) were added to a Schlenk tube equipped with
a magnetic stir bar under an atmosphere of argon. The resulting
reaction mixture was kept stirring at 1308C for 12 h. At the end of
the reaction, the reaction mixture was poured into a saturated
aqueous NaCl solution (20 mL) and extracted with ethyl acetate
(3”15 mL). The organic phases were combined, and the volatile
components were evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel
using ethyl acetate/petroleum ether (1:20) to afford the desired
product in high purity.
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Acknowledgements
The research is supported by Open Fund (PLN1409) of State
Key Laboratory of Oil and Gas Reservoir Geology and Exploita-
tion (Southwest Petroleum University), the Major Program of
the National Natural Science Foundation of China (51490653)
and 973 Program (2013CB228004). We are grateful to the
grants from the Scientific Research Foundation for the Re-
turned Overseas Chinese Scholars, State Education Ministry
and the Key Laboratory of Organic Synthesis of Jiangsu Prov-
ince. GZ acknowledges the donors of the American Chemical
Society Petroleum Research Fund for partial support of this re-
search (#54247-UNI3).
Keywords: arylation · catalysis · copper · iron · ligand-free
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Manuscript received: February 26, 2016
Accepted Article published: March 30, 2016
Final Article published: May 11, 2016
Chem. Asian J. 2016, 11, 1672 – 1676
www.chemasianj.org
1676
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