CuI-catalyzed and air promoted oxidative cyclization for one-pot synthesis of polyarylated oxazoles

Article abstract of DOI:10.1039/c3ob40657a

A facile CuI-catalyzed and air promoted oxidative cyclization was developed for the synthesis of polyarylated oxazoles. By virtue of this method, a variety of arylated oxazoles could be easily synthesized from readily available starting materials at room temperature in air. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40657a

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
CuI-catalyzed and air promoted oxidative cyclization
for one-pot synthesis of polyarylated oxazoles†
Cite this: DOI: 10.1039/c3ob40657a
Received 3rd April 2013,
Accepted 18th May 2013
Ping Hu, Qiang Wang, Yizhe Yan, Shuai Zhang, Baiqun Zhang and Zhiyong Wang*
DOI: 10.1039/c3ob40657a
www.rsc.org/obc
A facile CuI-catalyzed and air promoted oxidative cyclization was the Li group developed copper-catalyzed cross-dehydrogenative
developed for the synthesis of polyarylated oxazoles. By virtue of coupling (CDC) to construct C–C and C–N bonds.10 Nagasawa
this method, a variety of arylated oxazoles could be easily syn- reported a copper-catalyzed intramolecular oxidative C–O
thesized from readily available starting materials at room temp- coupling.11 The Jiao group also developed CDC for the for-
erature in air.
mation of N–N bonds.12 Since oxidations of aliphatic C–H
bonds are recently considered for being used in organic syn-
thesis,13 oxygen–copper systems in organic synthesis have
been more and more studied, mostly focusing on the oxidation
reactions of C–H bonds.9–12 There is no doubt that dehydro-
genation of aliphatic C–H bonds by atmospheric oxygen (O2)
offers one of the most environmentally benign and ideal oxi-
dation processes in organic synthesis.
We became interested in developing a one-pot, copper cata-
lyzed dehydrogenation domino process for the synthesis of ary-
lated oxazoles. This procedure was attractive due to its
intramolecular C–O bond formation, dehydrogenation by
atmospheric oxygen and rapid experimental procedure at
room temperature.
Initially, benzylamine (1a) and benzil (2a) were chosen as
model substrates to optimize the reaction conditions (Table 1).
Firstly, different copper salts (0.06 mmol) were examined
under the conditions of a typical procedure: 1a (0.2 mmol,
1 equiv.) and 2a (0.6 mmol, 3 equiv.) in 3 mL of DMA for 3 h at
60 °C. When copper(II) salts were used as the catalysts in the
reaction, 3a was detected in less than 5% yields by GC-MS (entries
1–4). Copper(I) salts provided much higher yields than copper(II)
salts (entries 5–7). Obviously, CuI was the most efficient
catalyst. The temperature had little influence on the reaction
and lower temperature favored the reaction (entries 7–9), so we
set the reaction temperature at room temperature. Among the
examined solvents (entries 10–14), DMA was the most effective
solvent for this oxidative cyclization process. Owing to the fact
that the benzylamine tended to be oxidized to phenylaldehyde
in this reaction system, the addition of benzylamine in two
portions was necessary. When 100 mg of 4 Å MS was added,
the yield of the reaction increased to 92% (entry 15). Other
metal salts, such as FeCl3, CoCl2, NiCl2 and ZnCl2, were also
examined. However, no product was detected when they were
examined in the reaction. Thus, the optimized conditions were
The importance of oxazoles in pharmaceuticals1 and func-
tional materials2d continues to inspire the development of new
synthetic approaches to this heterocyclic framework.3–7
Oxazole and its derivatives have attracted more and more inter-
est from both industry and academia over recent decades.2
Recently, arylated oxazoles were obtained through direct cross-
coupling arylation of simple oxazoles and cyclization of acyclic
precursors.3 For instance, Toshiaki Murai developed the
radical trap experiment on C–H bond arylation reaction of
simple oxazoles and obtained di- and triarylated oxazoles.4
The Jiao group reported the synthesis of 2,5-diarylated oxa-
zoles via copper-mediated aerobic oxidative dehydrogenation.5
Taking advantage of TBHP–I2-mediated oxidative cyclization,
our group also developed a series of methods in the synthesis
of oxazoles.6 Besides, the Jiang group also reported an elegant
one-pot protocol involving a TBHP–I2-mediated oxidative cycli-
zation for the synthesis of 2,4-diarylated oxazoles.7 Although
these methods are available for arylated oxazole synthesis,
using extra oxidants and harsh conditions limited their appli-
cations. Therefore, the development of efficient and economic
methods for the synthesis of polyarylated oxazoles is highly
desirable.
Because of its low price, slight toxicity and environmentally
benign features among transition metals, copper is a very
important catalyst in organic synthesis,8 especially in recent
copper-catalyzed oxidative C–H bond activation.9 For example,
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of
Soft Matter Chemistry and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, P. R. China. E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185
†Electronic supplementary information (ESI) available: Experiment procedure
and NMR data. See DOI: 10.1039/c3ob40657a
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
Table 2 The scope of various benzylaminesa
Entry
Copper salts
Solvents
Temp. (°C)
Yieldc(%)
1
2
3
4
5
6
7
8
Cu(OAc)2
CuSO4
CuBr2
CuCl2
CuBr
CuCl
Cul
Cul
Cul
Cul
Cul
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
CH3CN
DMSO
NMP
DMF
60
60
60
60
60
60
60
40
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
<5
<5
<5
<5
35
20
80
86
89
<5
12
70
66
<5
92
9
10
11
12
13
14
15b
Cul
Cul
Cul
Cul
Dioxane
DMA
a Reaction conditions: 1a (0.6 mmol, added in two portions), 2a
(0.2 mmol), copper salts (0.06 mmol), and solvents (3 mL). The
reaction was performed for 3 h. b Addition of 100 mg of powder 4 Å
molecular sieve. c Determined by GC-MS with 1,3,5-trimethylbenzene
as an internal standard.
a Standard reaction conditions: 2a (0.2 mmol), 1 (0.6 mmol, added in
two portions), CuI (0.06 mmol), 100 mg 4 Å MS and DMA (3 mL), r.t.,
exposed to air. The isolated yield based on 2a.
obtained as follows: benzil derivatives (0.2 mmol), benzyl-
amine derivatives (0.6 mmol in two portions), CuI
(0.06 mmol), and 4 Å MS (100 mg) in DMA (3 mL) were
exposed to air.
influence on the reaction (Table 3, 3n and 3s–3t), and 1,2-bis-
To evaluate the influence of the functional groups in the (2-chloro-phenyl)ethane-1,2-dione gave the lowest reaction
reaction, we investigated the substrate scope of the reaction yield (Table 3, 3t). Heterocyclic substrates afforded the corres-
under typical conditions. Firstly, the scope of a one-pot syn- ponding oxazoles with moderate to good yields (Table 3, 3v
thesis of triaryl oxazoles was explored by using a series of ben- and 3u). As expected, 1-phenylpropane-1,2-dione gave the
zylamine derivatives and benzil as the substrates. As shown in single product in good yield (Table 3, 3w). However, two pro-
Table 2, most of the benzylamine, regardless of their electronic ducts were obtained when unsymmetrical benzil derivatives
or steric properties, proceeded smoothly to afford the expected were employed in this reaction; the carbonyl group neighbor-
triaryl oxazoles with moderate to good yields (56–90%). Gener- ing the relatively electro-deficient phenyl showed a better reac-
ally, higher yields were obtained with electron-rich substitu- tivity in the first step of the reaction, which determined the
ents on the aromatic ring, while the electron-deficient final product (Table 3, 3x and 3y).
substituents decreased the reaction yields (Table 2, 3a–3h). It
To explore the reaction mechanism, several control experi-
is noted that there is a slight influence when substituents are ments were performed. The reaction gave racemic 1,2-di-
presented on the para, meta, and ortho positions of the benzyl- phenyl-2-(1-phenylethylimino)ethanone as the product (72%)
amines such as 1b, 1c and 1d. Then some heterocyclic amines, when (R)-1-phenylethanamine and benzil were employed
naphthalen-2-ylmethanamine and prop-2-en-1-amine, were under the standard conditions (Scheme 1, A). Also, no corres-
employed as the reaction substrates and still afforded the ponding product was obtained when the typical reaction was
corresponding oxazoles (Table 2, 3i–3k). However, the desired carried out in a nitrogen atmosphere (Scheme 1, B).
product was not detected with pyridin-2-ylmethanamine as the
substrate (Table 2, 3l).
On the basis of the experimental results and the previous
reports,14 a plausible mechanism of the present reaction could
Furthermore, various benzil derivatives were employed to be described as follows (Scheme 2): First, 1a and O2 activate
examine the scope of the reaction substrates (Table 3). Gener- the formation of [Cu] and then A is formed after the addition
ally, electron-withdrawing substituents on the aromatic ring of benzil; its enolizational isomer coordination of copper ions
were more beneficial for this transformation, while the elec- provides B. B undergoes an intramolecular cyclization via an
tron-donating group decreased the reaction yields (Table 3, oxygen atom attacking the double bonds and gives the inter-
3m–3r). However, 1,2-bis(4-(trifluoromethyl)phenyl)ethane-1,2- mediate C. After an intramolecular hydrogen transfer, D is
dione gave a lower yield (Table 3, 3o). Steric effect had a great formed. And then the reaction proceeds via the copper-
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 3 The scope of various benzil derivativesa
Scheme 1 Control experiments.
Scheme 2 A plausible reaction mechanism.
with the removal of aliphatic hydrogen atoms. Furthermore,
the transformation can occur at room temperature and
afforded moderate to good yields, which makes the method
more economical. Therefore, this method is an attractive
alternative method for the synthesis of polyarylated oxazoles.
We are grateful to the Natural Science Foundation of China
(no. 21272222, 21172205, 20932002, 20972144, 91213303,
J1030412) for support.
Notes and references
1 (a) N. Desroy, F. Moreau, S. Briet, G. L. Fralliec, S. Floquet,
L. Durant, V. Vongsouthi, V. Gerusz, A. Denis and S. Escaich,
Bioorg. Med. Chem., 2009, 17, 1276; (b) S. Heng,
K. R. Gryncel and E. R. Kantrowitz, Bioorg. Med. Chem.,
2009, 17, 3916; (c) B. R. Copp, Nat. Prod. Rep., 2003, 20, 535;
(d) N. A. Lack, P. Axerio-Cilies, P. Tavassoli, F. Q. Han,
K. H. Chan, C. Feau, E. LeBlanc, E. T. Guns, R. K. Guy,
P. S. Rennie and A. Cherkasov, J. Med. Chem., 2011, 54, 8563.
2 (a) Z. Jin, Nat. Prod. Rep., 2009, 26, 382; (b) K. C. Nicolaou,
M. Bella, D. Y. K. Chen, X. H. Huang, T. T. Ling and
S. A. Snyder, Angew. Chem., Int. Ed., 2002, 41, 3495;
(c) G. Pattenden, N. J. Ashweek, C. A. G. Baker-Glenn,
G. M. Walker and J. G. K. Yee, Angew. Chem., Int. Ed., 2007,
46, 4359; (d) B. Champagne and B. Kirtman, in Handbook
of Advanced Electronic and Photonic Materials and Devices,
Academic Press, 2000.
a Standard reaction condition: 2 (0.2 mmol), 1a (0.6 mmol, added in
two portions), CuI (0.06 mmol), 100 mg 4 Å MS and DMA (3 mL), r.t.,
exposed to air. Isolated yield based on 2.
catalyzed generation of a possible imine-type intermediate E
with half of an oxygen molecule.15 Further dehydration of E
affords the product 3a.
In summary, we have developed a facile type of one-pot, air
promoted oxidative dehydrogenation domino process for the
synthesis of polyarylated oxazoles. This transformation can be
realized from facile benzylamine and benzil derivatives, invol-
ving a tandem oxidative cyclization. In contrast to the tra-
ditional synthetic methods for oxazoles, additional oxidants
are not necessary and the transformation is highly efficient
3 (a) F. Shibahara, E. Yamaguchi and T. Murai, Chem.
Commun., 2010, 46, 2471; (b) J. C. Lee, J. Seo and
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
J. W. Baek, Synth. Commun., 2007, 37, 2159; (c) G. L. Young,
S. A. Smith and R. J. K. Taylor, Tetrahedron Lett., 2004, 45,
3797; (d) M. V. Marques, M. M. Ruthner, L. A. M. Fontoura
and D. Russowsky, J. Braz. Chem. Soc., 2012, 23, 171;
(e) W. W. Pei, S. H. Li, X. P. Nie, Y. W. Li, J. Pei, B. Z. Chen,
J. Wu and X. L. Ye, Synthesis, 1998, 1298; (f) M. Keni and
J.-J. Tepe, J. Org. Chem., 2005, 70, 4211.
9 (a) F. Z. Yang, Z. Q. Xu, Z. Wang, Z. K. Yu and R. Wang,
Chem.–Eur. J., 2011, 17, 6321; (b) G. S. Yellol, C. T. Chou,
W. J. Chang, B. Maiti and C. M. Sun, Adv. Synth. Catal.,
2012, 354, 187; (c) J. Y. Lu, Y. B. Jin, H. X. Liu, Y. Y. Jiang
and H. Fu, Org. Lett., 2011, 13, 3694; (d) X. Q. Wang,
Y. H. Jin, Y. F. Zhao, L. Zhu and H. Fu, Org. Lett., 2012, 14,
452; (e) G. S. Kumar, C. U. Maheswari, R. A. Kumar,
M. L. Kantam and K. R. Reddy, Angew. Chem., Int. Ed.,
2011, 50, 11748.
4 F. Shibahara, E. Yamaguchi and T. Murai, J. Org. Chem.,
2011, 76, 2680.
5 Z.-J. Xu, C. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2012, 10 (a) C. A. Correia and C.-J. Li, Adv. Synth. Catal., 2010, 352,
51, 11367.
1446; (b) O. Basle, N. Borduas, P. Dubois, J. M. Chapuzet,
T. Chan, J. Lessard and C.-J. Li, Chem.–Eur. J., 2010, 16,
8162.
6 (a) C. F. Wan, J. T. Zhang, S. J. Wang, J. M. Fan and
Z. Y. Wang, Org. Lett., 2010, 12, 2338; (b) C. F. Wan,
L. F. Gao, Q. Wang, J. T. Zhang and Z. Y. Wang, Org. Lett., 11 S. Ueda and H. Nagasawa, Angew. Chem., Int. Ed., 2008, 47,
2010, 12, 3902. 6411.
7 H. F. Jiang, H. W. Huang, H. Cao and C. R. Qi, Org. Lett., 12 C. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2010, 49,
2010, 12, 5561. 6174.
8 (a) E. S. Sherman, S. R. Chemler, T.-B. Tan and O. Gerlits, 13 M. C. White, Science, 2012, 355, 807.
Org. Lett., 2004, 6, 1573; (b) T. P. Zabawa, D. Kasi and 14 (a) M. Y. Niu, Z. M. Yin, H. Fu and Y. F. Zhao, J. Org. Chem.,
S. R. Chemler, J. Am. Chem. Soc., 2005, 127, 11250;
(c) L. A. Adrio and K. K. Hii, Chem. Commun., 2008, 2325;
2008, 73, 3961; (b) O. Basle and C.-J. Li, Green Chem., 2007,
9, 1047.
(d) Y. Ohta, S. Oishi, N. Fujii and H. Ohno, Chem. 15 S. I. Murahashi, N. Komiya, H. Terai and T. Nakae, J. Am.
Commun., 2008, 835.
Chem. Soc., 2003, 125, 15312.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013