Copper powder catalyzed direct ring-opening arylation of benzazoles with aryl iodides in polyethylene glycol

Article abstract of DOI:10.1002/ejoc.201201166

The expedient and efficient copper powder catalyzed direct ring-opening arylation of benzazoles with aryl iodides in polyethylene glycol that proceeds in the absence of an added ligand has been developed. The protocol provides facile access to 2-(arylthio)anilines and 2-phenoxyanilines in high yields with a wide tolerance of functional groups. Transmission electron microscopy confirmed that the active catalyst results from the in situ generation of copper nanoparticles under standard reaction conditions, which is an alternative avenue to develop a highly effective metallic copper catalyst. Moreover, the catalytic system can be recycled up to six times. Copyright

Full text of DOI:10.1002/ejoc.201201166

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201166
Copper Powder Catalyzed Direct Ring-Opening Arylation of Benzazoles with
Aryl Iodides in Polyethylene Glycol
Lifang Yao,[a] Qing Zhou,[a] Wei Han,*[a] and Shaohua Wei[a]
Dedicated to the 110th anniversary of Nanjing Normal University
Keywords: Copper / Nanostructures / Cross-coupling / Sustainable chemistry / Arenes
The expedient and efficient copper powder catalyzed direct
ring-opening arylation of benzazoles with aryl iodides in
polyethylene glycol that proceeds in the absence of an added
ligand has been developed. The protocol provides facile ac-
cess to 2-(arylthio)anilines and 2-phenoxyanilines in high
mission electron microscopy confirmed that the active cata-
lyst results from the in situ generation of copper nanopar-
ticles under standard reaction conditions, which is an alter-
native avenue to develop a highly effective metallic copper
catalyst. Moreover, the catalytic system can be recycled up
yields with a wide tolerance of functional groups. Trans- to six times.
Introduction
highly selective and direct coupling reaction for 2-(phen-
2-(Arylthio)aniline and 2-aryloxyaniline are privileged
scaffolds of various compounds that exhibit unique bio-
logical and pharmaceutical properties, including antifungal,
anticancer, and antiviral activities and caspase-1 inhibitors,
and have attracted considerable interest from chemistry and
biology to medicine.[1] Generally, the methods for the syn-
thesis of 2-(arylthio)anilines and 2-(aryloxy)anilines mainly
rely on transition-metal-catalyzed C–S[2] and C–O[3] cross-
coupling reactions with aryl halides, respectively. In these
reactions involving aromatic –NH2 and aromatic –SH (and/
or aromatic –OH) active groups, site-specific selectivity is
difficult, particularly in the preparation of 2-(aryloxy)-
anilines.[4] Moreover, those methods also suffer from the
need to prepare easily oxidized 2-aminothiophenols and 2-
aminophenols as starting materials.
To address these problems, a two-step procedure was re-
ported: a nitroaryl substrate was used for the cross-coupling
reaction and then the nitro group was reduced.[5] Although
this process can give excellent selectivity, two steps are re-
quired, which leads to the formation of much more waste.
Recently, Duan and co-workers reported that the reduction
of the nitro group and C–S cross-coupling can occur con-
currently in a one-pot reaction.[6] However, only strongly
electron-deficient coupling partners could undergo this
transformation smoothly. Alternatively, Li developed a
ylthio)aniline with 2,2Ј-disulfanediyldianiline and phenyltri-
methoxysilane in the presence of an air-sensitive and toxic
phosphane ligand.[7] To date, it is still a challenge to develop
an efficient and environmentally benign catalytic system for
the synthesis of 2-(arylthio)anilines and 2-(aryloxy)anilines.
During our research, Xu et al. demonstrated the CuCl-
catalyzed cross-coupling reactions of benzothiazole with
aryl iodides to form 2-(arylthio)anilines in water,[8] but this
approach is strictly limited to a single heterocyclic substrate,
benzothiazole, and more inexpensive metallic copper is an
ineffective catalyst in the system.[9]
Metallic copper is cheap, nontoxic, and readily available.
However, the ideal catalyst frequently exhibits poor per-
formance in cross-coupling reactions.[10] Recently, Ranu
and co-workers reported the direct use of metallic copper
powder as a catalyst for C–S bond-formation reactions that
showed far lower activity than copper nanoparticles pre-
prepared by a routine procedure.[11] Therefore, it is highly
desirable to find a way to directly use metallic copper as an
effective catalyst.
On the basis of previous studies in cross-coupling reac-
tions in polyethylene glycol (PEG),[12] we report herein a
novel ligandless and efficient protocol for preparing 2-(aryl-
thio)anilines and 2-phenoxyaniline from the reactions of
[a] Jiangsu Key Laboratory of Biofunctional Materials, Key Labo-
ratory of Applied Photochemistry, School of Chemistry and
Materials Science, Nanjing Normal University,
Nanjing 210023, China
Fax: +86-25-8589-1455
E-mail: whhanwei@yahoo.com.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201166.
Scheme 1. Copper-catalyzed reactions of benzazoles with aryl iod-
ides.
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Cu Powder Catalyzed Direct Ring-Opening Arylation of Benzazoles
benzazoles with aryl iodides by directly using copper pow- zoles and aryl iodides were evaluated (Table 2). The reac-
der as the catalyst in PEG-600 (Scheme 1).
tions with aryl iodides bearing either electron-rich or elec-
tron-deficient substituents at the phenyl moiety proceeded
efficiently to afford the desired products (i.e., 3aa–3da) in
excellent yields in short times. The reaction times were ob-
served to be only loosely correlated with the electronic na-
ture of the aryl iodides. This protocol could tolerate halides
such as F and Br, which can be used for further functionali-
zation. The structure of 3ce was confirmed by single-crystal
X-ray diffraction (see Supporting Information).[15] In ad-
dition, a free amino group was also tolerated under normal
conditions. Recently, Liu and co-workers disclosed that the
nitro group could be reduced in PEG-600.[6] Interestingly,
in our case, the nitro group did not disturb the high selectiv-
ity and remained intact in PEG-600. Sterically hindered
iodo-2-methylbenzene was a good substrate and provided
the corresponding products in high yields (i.e., 3ab and
3cb). Moreover, a doubly functionalized product could be
Results and Discussion
Initially, the cross-coupling of benzothiazole with iodo-
benzene was chosen to optimize the reaction parameters
(Table 1). When the reaction was performed in the presence
of copper powder as the catalyst and Cs2CO3 as the base
in EG (ethylene glycol),[13] an acceptable yield was obtained
in 6 h (Table 1, entry 1). Gratifyingly, under otherwise iden-
tical conditions, reactions that were performed in solvents
containing long alkyl chains, for example, PEG-400 and
PEG-600,[14] went to completion to afford desired product
3aa in 94 and 96% yield, respectively (Table 1, entries 2 and
3), whereas PEG-2000 and PEG-6000 with far longer alkyl
chains resulted in critically low yields (Table 1, entries 4 and
5). Various other copper catalysts were tested: CuCl and
CuI showed good catalytic activity (Table 1, entries 13 and
15), whereas CuBr and Cu2O gave product 3aa in moderate
yields (Table 1, entries 14 and 16). The base also heavily af-
fected the transformation: relative to the reaction per-
formed with Cs2CO3 (the best), K2CO3 and K3PO4·3H2O
required much longer times to reach completion (Table 1,
entries 6 and 7), and CH3COOK, KF, Na2CO3, and
NaHCO3 were completely ineffective (Table 1, entries 8–
11).
Table 2. Copper-catalyzed reactions of benzazoles with aryl iod-
ides.[a,b]
Table 1. Effect of reaction conditions.[a]
Entry Cat.
Base
Solvent
t [h] Yield[b] [%]
1
2
3
4
5
6
7
8
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4·3H2O PEG-600
CH3COOK PEG-600
KF
EG
6
6
6
6
72
94
96
9
PEG-400
PEG-600
PEG-2000
PEG-6000
PEG-600
6
6
24
15
6
6
6
6
6
6
6
94
96
–
0
0
9
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
10
11
12[c]
13
14
15
16
17[d]
Na2CO3
NaHCO3
Cs2CO3
0
65
89
72
87
70
86
CuCl Cs2CO3
CuBr Cs2CO3
CuI
Cu2O Cs2CO3
Cu Cs2CO3
Cs2CO3
6
6
6
[a] Reaction conditions: benzothiazole (0.5 mmol), iodobenzene
(1.0 mmol), base (1.0 mmol), solvent (2.0 g), 140 °C, N2 atmo-
sphere. [b] Yield of isolated product after column chromatography
on silica gel. [c] Air atmosphere. [d] Loading of copper was de-
creased to 5 mol-%.
[a] Reaction conditions: benzothiazole (0.5 mmol), iodobenzene
(1.0 mmol), base (1.0 mmol), solvent (2.0 g), 140 °C, N2 atmo-
sphere. [b] Yield of isolated product after column chromatography
With the above-optimized reaction conditions (10 mol-%
Cu, 2.0 equiv. Cs2CO3, PEG-600, N2), a series of benza- on silica gel.
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L. Yao, Q. Zhou, W. Han, S. Wei
SHORT COMMUNICATION
obtained in good yield under analogous reaction conditions
when 1,4-diiodobenzene was used as the aryl iodide
[Eq. (1)]. Notably, complicated aryl iodide 2i was quite ef-
fective in the reaction with benzothiazole and furnished de-
sired product 3ai in 91% yield [Eq. (2)], which is potentially
useful for the synthesis of biologically important natural
products and pharmaceuticals.[16]
Figure 1. TEM image of copper nanoparticles.
To gain preliminary insight into the process of the trans-
formation, control experiments were performed.[19] In 2007,
Ranu and co-workers reported copper nanoparticle cata-
lyzed C–S bond formation from the cross-coupling of thio-
phenols with aryl halides and proposed a radical mecha-
nism.[11] To check this mechanism in our case, 2,2,6,6-tet-
ramethylpiperidine N-oxide (TEMPO, 1.0 equiv. relative to
the benzothiazole), a radical scavenger, was added to the
model reaction under otherwise identical reaction condi-
tions. The reaction was not affected at all by the presence
of TEMPO, which suggested a radical pathway was not in
operation. Earlier works have indicated that azoles possess
acidic C–H protons and that they can be ring opened upon
deprotonation.[20] In our case, the reactivity is proportional
to the C–H acidity at C2 of the benzothiazoles (Table 2),
which supports a deprotonation pathway. Moreover, the re-
action between 2-aminothiophenol and iodobenzene pro-
ceeded smoothly to afford 3aa in 94% yield within 1 h
[Eq. (3)]. These findings imply that a deprotonation-in-
duced ring-opening step may be present.
(1)
(2)
Diverse benzazoles were tested in this transformation.
Benzothiazoles having electron-rich and electron-deficient
groups worked well under the optimized reaction condi-
tions (Table 2). The reactivities of the electron-deficient
benzothiazoles were higher than those of the electron-rich
benzothiazoles, which was found to be proportional to the
C–H acidity at C2 of the benzothiazole. Notably, benzo-
xazole also underwent the transformation successfully to
give product 3da in 93% within 3 h. However, the desired
products were not obtained when thiazole and N-methyl-
benzimidazole were used as substrates.
During the reaction between benzothiazole and iodo-
benzene under the standard conditions, the copper catalyst
was examined by transmission electron microscopy (TEM).
(3)
Although the detailed mechanism for the copper-cata-
The in situ generated copper nanoparticles had an average lyzed ring-opening arylation reaction remains to be eluci-
size of 3 nm (Figure 1). This is an alternative to the conven- dated, a possible catalytic cycle is proposed. As shown in
tional protocol used to prepare metal nanoparticles, which Figure 2, ring-opened intermediate A is formed by depro-
leads to problems of waste formation and environmental tonation of a benzazole under the assistance of base and
pollution.[17] The use of copper nanoparticles as a highly subsequently is hydrolyzed to intermediate B. The catalytic
efficient catalyst in C–S bond-formation reactions has been cycle is initiated by oxidative addition of the aryl iodide to
reported.[11,18] Gratifyingly, the in situ formed catalyst can the copper nanoparticles to generate intermediate C, fol-
be recycled up to six times by using the model reaction to lowed by attack of intermediate B to give key intermediate
afford the corresponding product in 96, 95, 95, 94, 90, and D. Finally, reductive elimination of intermediate D fur-
55% yield, respectively.
nishes the desired product and regenerates the catalyst.
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Cu Powder Catalyzed Direct Ring-Opening Arylation of Benzazoles
by column chromatography on silica gel (petroleum ether/diethyl
ether/triethylamine = 30:1:1).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, 1H NMR and
13C NMR spectra of the products, and X-ray data for compound
3ce.
Acknowledgments
The work was sponsored by the Natural Science Foundation of
Jiangsu Provincial Colleges and Universities (12KJB150014), the
Scientific Research Start-up Foundation of Nanjing Normal Uni-
versity (2011103XGQ0250), and the Priority Academic Program
Development of Jiangsu Higher Education Institutions. We thank
Prof. Min Fang and Dr. Min Han for assistance with X-ray struc-
ture analysis and TEM analysis, respectively.
[1] a) G. P. Sarmiento, R. G. Vitale, J. Afeltra, G. Y. Moltrasio,
A. G. Moglioni, Eur. J. Med. Chem. 2011, 46, 101–105; b) H.
Prinz, B. Chamasmani, K. Vogel, K. J. Böhm, B. Aicher, M.
Gerlach, E. G. Günther, P. Amon, I. Ivanov, K. Müller, J. Med.
Chem. 2011, 54, 4247–4263; c) J. Raval, K. K. Desai, ARKI-
VOC 2005, xiii, 21–28; d) A. B. Shahripour, M. S. Plummer,
E. A. Lunney, T. K. Sawyer, C. J. Stankovic, M. K. Connolly,
J. R. Rubin, N. P. C. Walker, K. D. Brady, H. J. Allen, R. V.
Talanian, W. W. Wong, C. Humblet, Bioorg. Med. Chem. Lett.
2001, 11, 2779–2782.
[2] For reviews on transition-metal-catalyzed C–S coupling reac-
tions, see: a) T. Kondo, T. Mitsudo, Chem. Rev. 2000, 100,
3205–3220; b) S. V. Ley, A. W. Thomas, Angew. Chem. 2003,
115, 5558–5607; Angew. Chem. Int. Ed. 2003, 42, 5400–5449.
[3] For reviews on transition-metal-catalyzed C–O coupling reac-
tions, see: a) J. F. Hartwig, Angew. Chem. 1998, 110, 2154–
2177; Angew. Chem. Int. Ed. 1998, 37, 2046–2067; b) A. R.
Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131–209; c)
F. Theil, Angew. Chem. 1999, 111, 2493–2495; Angew. Chem.
Int. Ed. 1999, 38, 2345–2347; d) F. Monnier, M. Taillefer, An-
gew. Chem. 2009, 121, 7088–7105; Angew. Chem. Int. Ed. 2009,
48, 6954–6971; e) J. S. Sawyer, Tetrahedron 2000, 56, 5045–
5065.
Figure 2. A possible catalytic loop for the reaction of benzazoles
with aryl iodides.
Conclusions
In conclusion, a simple, practical, recyclable, and envi-
ronmentally benign protocol has been developed for the di-
rect synthesis of pivotal 2-(arylthio)aniline and 2-phen-
oxyaniline intermediates through the in situ generated cop-
per nanoparticle catalyzed ring-opening arylation of benza-
zoles with aryl iodides in PEG-600. The approach over-
comes the disadvantages of classic coupling reactions that
involve the use of substrates that can be readily oxidized
and that suffer from selectivity problems. Various benz-
azoles were treated with aryl iodides to afford the desired
products in high yields with a remarkable compatibility of
functional groups. The starting materials are readily avail-
able and stable and can be used to prepare more reactive
products with free amino groups that have been widely used
in the synthesis of drug-like and/or pharmaceutically rel-
evant molecules. Further work will be dedicated to the ap-
plication of the present system for the construction of com-
plex molecules and to the investigation of the detailed
mechanism.
[4] a) Y. M. Li, H. F. Wang, L. L. Jiang, F. F. Sun, X. M. Fu, C. Y.
Duan, Eur. J. Org. Chem. 2010, 6967–6973; b) D. Maiti, S. L.
Buchwald, J. Am. Chem. Soc. 2009, 131, 17423–17429.
[5] a) N. Jarkas, J. McConathy, R. J. Voll, M. M. Goodman, J.
Med. Chem. 2005, 48, 4254–4265; b) Z. Wrobel, Tetrahedron
2003, 59, 101–110.
[6] Z. Duan, S. Ranjit, X. Liu, Org. Lett. 2010, 12, 2430–2433.
[7] P.-S. Luo, M. Yu, R.-Y. Tang, P. Zhong, J.-H. Li, Tetrahedron
Lett. 2009, 50, 1066–1070.
[8] Y.-S. Feng, H.-X. Qi, W.-C. Wang, Y.-F. Liang, H.-J. Xu, Tetra-
hedron Lett. 2012, 53, 2914–2917.
[9] Copper powder is an ineffective catalyst for ring-opening aryl-
ation of benzothiazole with iodobenzene under Xu’s conditions
(see ref.[8]).
Experimental Section
[10] a) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359–1469; b) G. Evano, N. Blanchard,
M. Toumi, Chem. Rev. 2008, 108, 3054–3131.
General Procedure for the Copper Powder Catalyzed Cross-Coupling
of Benzazole with Aryl Iodides: A 25-mL flask was charged with
copper (10 mol-%, 3.2 mg), Cs2CO3 (1.0 mmol, 330 mg), and PEG-
600 (2.0 g) before standard cycles of evacuation and back-filling
with dry and pure N2. Benzazole (0.5 mmol) and the aryl iodide
(2 equiv., 1.0 mmol) were then added successively. The mixture was
stirred at 140 °C for the indicated time. At the end of the reaction,
the reaction mixture was poured into a saturated aqueous NaCl
solution (20 mL) and extracted with ethyl acetate (3ϫ 15 mL). The
organic phases were combined, and the volatile components were
evaporated under reduced pressure. The crude product was purified
[11] B. C. Ranu, A. Saha, R. Jana, Adv. Synth. Catal. 2007, 349,
2690–2696.
[12] a) W. Han, C. Liu, Z.-L. Jin, Adv. Synth. Catal. 2008, 350, 501–
508; b) W. Han, C. Liu, Z.-L. Jin, Org. Lett. 2007, 9, 4005–
4007; c) W. Han, N. Liu, C. Liu, Z.-L. Jin, Chin. Chem. Lett.
2010, 21, 1411–1414.
[13] H. R. Yue, Y. J. Zhao, X. B. Ma, J. L. Gong, Chem. Soc. Rev.
2012, 41, 4218–4244.
[14] J. Chen, S. K. Spear, J. G. Huddleston, R. D. Rogers, Green
Chem. 2005, 7, 64–82.
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L. Yao, Q. Zhou, W. Han, S. Wei
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[15] CCDC number 893598 (for 3ce) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[16] E. Riego, D. Hernández, F. Álbericio, M. Alvarez, Synthesis
2005, 1907–1922.
[17] B. C. Ranu, R. Dey, T. Chatterjee, S. Ahammed, ChemSus-
Chem 2012, 5, 22–44.
[18] B. C. Ranu, K. Chattopadhyay, L. Adak, A. Saha, S. Bhadra,
R. Dey, D. Saha, Pure Appl. Chem. 2009, 81, 2337–2354.
[19] Copper nanoparticles as a substitute for copper powder was
used to catalyze the model reaction under identical conditions,
and the same result as that obtained for the in situ generated
copper nanoparticles was observed.
[20] a) C. Hilf, F. Bosold, K. Harms, M. Marsch, G. Boche, Chem.
Ber./Recueil 1997, 130, 1213–1221; b) R. S. Sánchez, F. A. Zhu-
ravlev, J. Am. Chem. Soc. 2007, 129, 5824–5825; c) F. A. Zhu-
ravlev, Tetrahedron Lett. 2006, 47, 2929–2932.
Received: August 30, 2012
Published Online: November 6, 2012
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