Practical approach for synthesis of 2-amino-benzoxazole in water

Article abstract of DOI:10.1080/00397911.2015.1015035

A practical copper-catalyzed amination of benzoxazole with secondary amine in water has been developed. This reaction has proved to be effective to some cyclic amines, and the substituted group of nitrogen has a great impact on the amination reaction. A copper-catalyzed/amine-induced ring opening of the benzoxazole and recyclization/oxidation mechanism was also proposed.

Full text of DOI:10.1080/00397911.2015.1015035

This article was downloaded by: [University of Georgia]
On: 21 February 2015, At: 20:05
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Practical Approach for Synthesis of 2-Amino-
Benzoxazole in Water
a
a
a
Ke Cao , Jia-Ling Wang & Lin-Hui Wang
a
State Key Laboratory Cultivation Base for Nonmetal Composite and Functional Materials
&
School of Materials Science and Engineering, Southwest University of Science and
Technology, Mianyang, P. R. China
Accepted author version posted online: 09 Feb 2015.
Click for updates
To cite this article: Ke Cao, Jia-Ling Wang & Lin-Hui Wang (2015): A Practical Approach for Synthesis of 2-Amino-Benzoxazole
in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1015035
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1015035
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

A practical approach for synthesis of 2-amino-benzoxazole in water
1
1
1
Ke Cao , Jia-Ling Wang , Lin-Hui Wang
1
State Key Laboratory Cultivation Base for Nonmetal Composite and Functional Materials
&
School of Materials Science and Engineering, Southwest University of Science and
Technology, Mianyang, P. R. China
Corresponding author Ke Cao State Key Laboratory Cultivation Base for Nonmetal
Composite and Functional Materials & School of Materials Science and Engineering,
Southwest University of Science and Technology, Mianyang, 621010, P. R. China E-mail:
caoke@swust.edu.cn
Abstract
A practical copper catalyzed amination of benzoxazole with secondary amine in water
has been developed. This reaction has proved to be effective to some cyclic amines, and
the substituted group of nitrogen has a great impact on the amination reaction. A
copper-catalyzed/ amine-induced ring-opening of the benzoxazole and re-cyclization
/
oxidation mechanism was also proposed.
KEYWORDS: amination ; benzoxazole; water; oxidation; copper
INTRODUCTION
1

The development of novel methodologies to construction of C-N bond is a very important
and prosperous area due the nitrogen-containing compounds are a class of important motifs
[
1]
in biologically active natural products and materials science. To facilitate this
transformation, pioneering works focus on transition metal catalyzed C-H amination have
been well developed, especially copper catalyzed aerobic oxidation to construction C-N
[
2]
bond represents the most economic and highly efficient strategy.
For organic reactions, water would be an ideal medium due to its safety and
environmentally friendly character. Therefore, the development of organic transformation
in water has been attracting many research interests from chemists in academic as well as
[
3]
industry areas. However, due the interaction (hydrogen bonding, polarity etc.) of water
with substrates and the moisture sensitive characteristic of transition metal catalysts, which
largely limited the application of water as reaction medium for construction of C-X bonds
(X = N, O etc.). Therefore, development of novel method and further expand the substrate
scope to construction of C-X bond in water medium is desired and still a challenge.
The benzoxazole moiety is the key structure feature of a large number of biologically
[4]
active natural products and pharmaceutical compounds. The functionalization of
2
-position of benzoxazole has attracted many interests from chemists and has been well
developed. Among them, the amination of benzoxazole displayed more challenge and still
exist some drawbacks have not been addressed. Such as high reaction temperature,
2

[
5]
stoichiometric or sub-stoichiometric metal reagents and strong oxidants etc.. In
[6]
connection with our continued interest in construction of C-C and C-N bonds, we
recently found the amination of benzoxazole could proceeds in water with relatively mild
conditions. Herein, we are pleased to represent our preliminary results.
RESULTS AND DISCUSSION
To initial our research, we choose benzoxazole and morpholine as substrate to screen
conditions and the results were summarized in Table 1. To our delight, the amination could
o
proceed at 60 C with 10 mmol % of CuBr and 2 equivalent of acetic acid under O
2
2
atmosphere, the desired coupling product was obtained only with 10% yield, and along
with a large amount of decomposed product 4 (entry 1). When benzoic acid was used
instead of acetic acid, the 4 was afforded as major product and only gave trace amount of
the expected amination product (entry 2). With Cu(OAc) as catalyst, the result was similar
2
to that of entry 2 (entry 3). Next, we intended to examine the effect of oxidant, when the
o
reaction was conducted with I at 25 C, the corresponding product was afforded with 13%
2
yield (entry 4). Furthermore, the yields were enhanced to 30% and 35% when the reaction
was carried with 2 equivalents of Na S O and K S O , respectively (entries 5-6). The
2
2
8
2
2
8
yield was further increased to 45% when K S O was reduced to 1 equivalent (entry 7).
2
2
8
Fortunately, When 20 mmol % of PPh was added, the expected product was given in 55%
3
yield (entry 9). Other additive such as bipyridine and tetrabutylammonium bromide could
3

not facilitate the transformation effectively (entries 10-11). The yield was further increased
to 75% when 20 mmol % of CuBr was used (entry 12).
2
Following the optimized conditions (Table 1, entry12), we then examined the scope of the
reaction, and the results were summarized in Table 2. Surprisingly, when piperidine and
pyrrole were subjected to the standard conditions, the desired product was afforded with
only 34% and 41% yield, respectively, accompanied with large amount of 4. Furthermore,
when N-methylbenzylamine was used, the 4 was isolated as the main product, and the
corresponding coupling product 3d was only given with 15% yield. However, when
diethylamine was used, we have not obtained the desired coupling product, and only 4 can
be isolated. We considered this result might arouse from the hydrolysis of the ring-opening
product of benzoxazole with diethylamine (see B in Scheme 1). So, we first mixed
o
benzoxazole and diethylamine and stirred under 40 C for 1h, then H O, CuBr , PPh ,
2
2
3
AcOH and K S O was sequentially added and continue stirred for 6h. With this method,
2
2
8
the expected product 3e could be isolated with 35% yield. Other amines such as
phenylethylamine, diisopropylamine, N-methylaniline, tetrahydroisoquinoline, piperazine
derivatives etc. are not compatible with this transformation, and only 4 were isolated as the
sole product.
For benzoxazoles, both 5-methylbenzoxazole and 5-chlorobenzoxazole could facilitate
this transformation and gave the desired product with 72% and 52% yield, respectively.
4

This result demonstrated the electronic effect has distinct influence on the reaction
efficiency. However, when benzothiazole and benzimidazole was used, this reaction
proceeded very sluggish, and could not give the expected products.
Based on the experiment results, the mechanism for the amination was also proposed and
showed in Scheme 1. First, coordinating of copper with nitrogen of benzoxazole to form A.
Then, o-hydroxyamidine B was formed via the ring-opening of benzoxazole by
morpholine. Subsequently, acetic acid promoted intramolecular cyclization to give the
intermediate C. Meanwhile, if the B is not stable enough, which would hydrolysis to 4, that
is to say, the forming of C and 4 is a competed process, and the substituted group of
nitrogen has an important influence in this stage. At last, the oxidative dehydrogenation of
C gave the product 3a and releases the copper to the next cycle.
EXPERIMENTAL
General Procedure For Synthesis Of 3a-3d And 3f-3g
To a 10mL flask were sequentially added benzoxazole (60mg, 0.5mmol), amine (0.6mmol),
H O (1mL), CuBr (22.4mg, 0.1mmol), PPh (26.2mg, 0.1mmol), K S O (135mg,
2
2
3
2
2
8
0
.5mmol) and AcOH (0.057mL, 1mmol) under air atmosphere. After the reaction mixture
o
was stirred at 40 C until the substrate was consumed completely (about 6h), the reaction
mixture was quenched with NaHSO (aq.) and cooled to room temperature. Then extracted
3
with AcOEt (3x15mL), washed with NaHCO (aq.) (3x5mL), brine (3x10mL) and dried
3
5

over anhydrous sodium sulfate. After evaporation of the solvent under vaccum, the residue
was purified by column chromatography.
CONCLUSION
In summary, we have developed a copper catalyzed amination of benzoxazole with
secondary amine as nitrogen source in water for the first time. This method facilitated the
amination of benzoxazole with mild and green conditions, and a series of
amino-substituted benzoxazole have been synthesized from simple and readily available
starting materials. Further studies toward synthetic application are currently ongoing in our
group.
SUPPORTING INFORMATION
1
13
Full experimental detail, H and C NMR spectra, MS data for this article can be accessed
on the publisher’s website.
ACKNOWLEDGEMENT
This work is supported by Scientific Reserch Fund of Sichuan Provincial Education
Department (13ZB0173, 13TD0022), Applied Technology and Development Fund of
Science and Technology Bureau of Mianyang (12G031-3) and Sichuan’s Undergraduate
Innovative and Entrepreneurship Training Program (201310619031) for Miss J.-L. Wang
and L.-H. Wang.
6

REFERENCE
[
1] a) Sànchez, C.; Mèndez, C.; Salas, J. A. Sagai. Nat. Prod. Rep. 2006, 23, 1007-1045; b)
Surry, D. S.; Buchwald, S. L. Sagai. Angew.Chem. Int. Ed. 2008, 47, 6338-6361; c) Lyons,
T. W.; Sanford, M. S. Sagai. Chem. Rev. 2010, 110, 1147-1169; d) Collet, F.; Dodd, R. H.;
Dauban, P. Sagai. Chem. Commun. 2009, 5061-5074; e) Li, C.-J. Sagai. Acc. Chem. Res.
2
008, 42, 335-344. f) Thansandote, P.; Lautens, M. Sagai. Chem. Eur. J. 2009, 15,
5
874-5883.
[
2] a) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Sagai. Chem. Rev. 2004, 104,
105-4123; b) Beller, M. Sagai. Adv. Synth. Catal. 2004, 346, 107-108; c) Wendlandt, A. E.;
4
Suess, A. M.; Stahl, S. S. Sagai. Angew. Chem. Int. Ed. 2011, 50, 11062-11087; d) Allen, S.
E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Sagai. Chem. Rev. 2013, 113,
6
234-6458.
[
3] a) Organic Reactions in Water (Ed: U. Marcus Lindström, Blackwell Publishing, 2007).
b) Li, C.-J. Chem. Rev. 2005, 105, 3095-3165. c) Lipshutz, B. H.; Isley, N. A.; Fennewald,
J. C.; Slack, E. D. Angew. Chem. Int. Ed. 2013, 52, 10952-10958.
[
[
4] Viirre, R. D.; Evindar, G.; Batey, R. A. Sagai. J. Org. Chem. 2008, 73, 3452-3459.
5] a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Sagai. Org. Lett. 2009, 11,
1
607-1610; b) Wang, Q.; Schreiber, S. L. Sagai. Org. Lett. 2009, 11, 5178-5180; c) Cho, S.
H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Sagai. Angew. Chem., Int. Ed. 2009, 48, 9127-9130; d)
Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Sagai. Angew. Chem., Int. Ed. 2010, 49,
7

9
2
8
2
899-9903; e) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Sagai. Chem. Commun.
011, 47, 3652–3654; e) Joseph, J.; Kim, J. Y.; Chang, S. Sagai. Chem. Eur. J. 2011, 17,
294-8298; f) Li, Y.; Xie, Y.; Zhang, R.; Jin, K.; Wang, X.; Duan, C. Sagai. J. Org. Chem.
011, 76, 5444-5449.
[
6] Cao, K.; Zhang, F.-M.; Tu, Y.-Q.; Zhuo, X.-T.; Fan, C.-A. Sagai. Chem. Eur. J. 2009, 15,
6
332-6334; b) Cao, K,; Tu, Y.-Q.; Zhang, F.-M. Sagai. Sci China Chem 2010, 53, 130-134.
8

a
Table 1 Optimization of reaction conditions for amination of benzoxazole in water
o
b
entry catalyst
acid/oxidant/temp( C) % yield
1
2
3
4
5
6
7
8
9
1
1
CuBr2
CuBr2
Cu(OAc)2
CuBr2
CuBr2
CuBr2
CuBr2
AcOH/O /60
10
2
PhCOOH/O /60
trace
trace
13
2
AcOH/O /60
2
AcOH/I /25
2
AcOH/Na S O /25
30
2
2
8
AcOH/K S O /25
35
2
2
8
c
AcOH/K S O /25
45
2
2
8
c
CuSO ·5H O AcOH/K S O /40
41
4
2
2
2
8
c,d
CuBr2
AcOH/K S O /40
55
2
2
8
c,e,g
0
1
2
CuBr2
CuBr2
CuBr2
AcOH/K S O /40
trace
2
2
8
c,f,g
AcOH/K S O /40
45
75
2
2
8
c,d,g
1
AcOH/K S O /40
2 2 8
a
Reaction condition: benzoxazole (0.5 mmol), morpholine (0.6 mmol), catalyst (0.05
mmol), acid (1 mmol), oxidant (1 mmol except entries 1-3) and 1 mL of water under air
atmosphere for 6h.
b
Isolated yields based on benzoxazole.
9

c
d
e
f
with 0.5 mmol K S O ,
2
2
8
added 0.1mmol PPh3.
added 0.1mmol bipyridine.
added 0.1mmol tetrabutylammonium bromide.
with 0.1 mmol of CuBr2
g
10

a,b
Table 2. The copper-catalyzed amination of benzoxazole with secondary amine in water
a
Reaction conditions: benzoxazole (0.5 mmol), amine (0.6 mmol), CuBr (0.1 mmol),
2
o
PPh (0.1 mmol), K S O (0.5 mmol), AcOH (1 mmol), H O (1 mL), 40 C.
3
2
2
8
2
b
Isolated yield.
11

Scheme 1. Proposed mechanism for the amination of benzoxazole in water
12