Regioselective synthesis of oxazole derivatives via palladium-catalyzed and copper-mediated cascade oxidative cyclization

Article abstract of DOI:10.1039/c3cc49788g

A novel Pd-catalyzed/Cu-mediated oxidative cyclization has been developed for the synthesis of trisubstituted oxazoles, which is thought to proceed through cascade formation of C-N and C-O bonds. In this protocol, four hydrogen atoms were removed and water was used as the oxygen atom source. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc49788g

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Regioselective synthesis of oxazole derivatives via
palladium-catalyzed and copper-mediated
cascade oxidative cyclization†
Cite this: Chem. Commun., 2014,
50, 3609
Received 26th December 2013,
Accepted 4th February 2014
Jia Zheng, Min Zhang, Liangbin Huang, Xiaohan Hu, Wanqing Wu, Huawen Huang
and Huangfeng Jiang*
DOI: 10.1039/c3cc49788g
www.rsc.org/chemcomm
A novel Pd-catalyzed/Cu-mediated oxidative cyclization has been
developed for the synthesis of trisubstituted oxazoles, which is
thought to proceed through cascade formation of C–N and C–O
bonds. In this protocol, four hydrogen atoms were removed and
water was used as the oxygen atom source.
Scheme 1 Bimetal-catalyzed formation of oxazoles.
Alkynes as available substrates have been used widely in
organic synthesis during the past decades.1 In particular, metal-catalyzed bimolecular annulation.10 The intramolecular
effective transformations of alkynes catalyzed by transition oxidative cyclization of precursors also provides a convenient
metals have been reported as powerful strategies to construct access.11 Some other methods, such as the intramolecular
C–C, C–O or C–N bonds.2 For example, Au has been reported to Wittig reaction,12 iodide-promoted oxidative coupling,13 and
be used in many efforts for the transformation of the C–C triple cyclization of propargylamides14 have been developed as well.
bond due to its powerful soft Lewis acidic nature.3 Moreover, Ag However, the development of simple and efficient methods for
and Cu have also been disclosed to activate alkynes to construct the preparation of trisubstituted oxazoles is still desirable. As
multiple bonds in a single process.4 In addition, besides part of our continuous interest in the oxidative functionaliza-
playing an important role in C–C cross-coupling reactions, Pd tion of alkynes and synthesis of heterocyclic compounds,6a–c
also exhibits significance in the activation of unsaturated C–C herein, we report a novel bimetal catalytic oxidative cyclization
bonds, which has drawn much attention in modern organic of propargyl esters and benzylamines to form oxazoles, with an
synthesis.5 Our group has focused on nucleopalladation pro- oxygen atom obtained from water. As accessible starting mate-
cesses, such as aminopalladation, halopalladation and oxy- rials, propargyl esters could be obtained from terminal
palladation, which are practical approaches to transfer alkenes alkynes.15 This transformation is supposed to go through the
and alkynes efficiently.6
cascade formation of C–N and C–O bonds, which affords an
On the other hand, the oxazole moiety, which has attracted efficient and regioselective protocol for the synthesis of
increasing attention, is a significant structure in numerous oxazoles.
bioactive natural products.7 Furthermore, a great number of
As the optimized conditions were established (see the ESI†
pharmacologically synthetic oxazole-containing molecules for details), we first investigated the scope of different benzyl-
show biological activities.8 Thus, various novel methods have amines. As shown in Table 1, both electron-withdrawing groups
been developed for the synthesis of this aromatic heterocycle (halogen or trifluoromethyl, 3ab–3ae) and electron-donating
(Scheme 1). Generally, they can be directly formed by the groups (methyl or methoxy, 3af–3ag) were well tolerated in the
oxidation of oxazolines.9 Another route to these structures is para-position which gave good to high yields. However, the
presence of meta- or ortho-substituents on the phenyl ring led
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn;
Fax: +86 20-87112906; Tel: +86 20-87112906
to moderate yields (3ah, 3ai–3ak). The naphthyl-substituted
amine also proceeded well with 1a to give the desired oxazole
3al in 72% yield. Besides, heterocyclic amines could be employed
as an amine component in the reaction. Thiophene-2-methyl-
amine and 2-pyridinemethanamine afforded the desired pro-
ducts 3am and 3an in 68% and 33% yields, respectively.
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, and copies of 1H and 13C NMR spectra for
selected compounds. CCDC 982238. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc49788g
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Table 1 The reaction of different 2 with 1aa,b
the oxazole products. The electron-donating groups including
alkyl and methoxy also proceeded well with benzylamine to
form oxazoles in moderate to good yields (3da, 3ea and 3ga).
Only in the case of cyano-substituted ethyl phenylpropiolate,
45% yield of 3ha was obtained. Associated with the low yield of
the N-heterocyclic amine (Table 2, 3an), the N-containing group
had a negative effect on the reaction outcome. Besides, meta
methyl-, bromo- and 3,5-dichloro-substituted components
worked well as para substituents (3ia–3ka). Compared with
the meta-substituted group, ortho-substituted one offered rela-
tively low yield (3ia vs. 3ma). Furthermore, ethyl naphthylpro-
piolate could be smoothly transformed into the desired
products in high yield (3la). It is noteworthy that aliphatic
substituents were also tolerated in this protocol, which gave
the corresponding products 3na and 3pa in 58% and 51%
yields, respectively, suggesting that the transformation is
applicable to both aliphatic and aromatic propargyl esters.
When ethyl phenylpropiolate was switched with methyl phenyl-
propiolate, a close yield was obtained (3oa). To further confirm
the structure, X-ray crystallographic analysis of 3ka was given
(see the ESI† for details).16
a
Finally, some N-substituted benzylamines were subjected to
this transformation (Scheme 2). Desired product 3aa was
obtained in 63% and 41% yields, respectively, when using
N-methylbenzylamine and N,N-dibenzylamine as the sub-
strates. However, when the substituted group was changed to
t-Bu, no desired product was detected.
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), H2O (1.5 mmol),
Pd(CH3CN)2Cl2 b(5 mol%) and CuBr2 (2 equiv.) in 1.5 mL DMSO in air at
c
100 1C for 8 h. Isolated yield. The reaction was stirred for 15 h.
Table 2 The reaction of different 1 with 2aa,b
To gain a deeper insight into the mechanism of this cascade
oxidative cyclization, several control experiments were con-
ducted. The desired product was obtained only in very low
yield when TEMPO was added [Scheme 3, eqn (1)]. No desired
product 3aa was generated when benzonitrile 4 or benzamide 5
reacted with benzylamine 2a under the standard conditions,
which might exclude 4 or 5 being the intermediate in this
reaction [Scheme 3, eqn (2)]. Moreover, upon changing ethyl
phenylpropiolate (1a) to ethyl benzoylacetate, 53% yield of 3aa
was obtained [Scheme 3, eqn (3)]. Subsequently, we performed
18O-labled experiments to confirm the oxygen atom source. The
reaction of 1a and 2a generated 18O-labeled product [18O]-3aa in
74% yield when H218O was employed under the standard
conditions [Scheme 3, eqn (4)], which demonstrated that the
oxygen atom of the oxazole ring came from water.
On the basis of above-mentioned experimental results, a
plausible mechanism for this cascade oxidative cyclization is
proposed in Scheme 4. This reaction might be initiated by
hydration of 1a (path a), or oxypalladation of 1a followed by
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), H2O (1.5 mmol),
Pd(CH3CN)2Cl2 b(5 mol%) and CuBr2 (2 equiv.) in 1.5 mL DMSO in air at
100 1C for 8 h. Isolated yield.
Unfortunately, alkyl-substituted amines gave no desired product
3ao in this reaction.
The transformation was further expanded to various sub-
stituted ethyl phenylpropiolates (Table 2). Reactions with
electron-withdrawing groups, such as halogens or methoxy-
carbonyls (3ba, 3ca and 3fa) provided more than 80% yield of
Scheme 2 The scope of N-substituted benzylamines.
3610 | Chem. Commun., 2014, 50, 3609--3611
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S2012040007088), and the Fundamental Research Funds for
the Central Universities (2014ZP0004 and 2014ZZ0046) for
financial support.
Notes and references
1 (a) L. A. Paquette, Organic Reactions, Wiley, Hoboken, 1994, vol. 46;
(b) H. Takaya and R. Noyori, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991; (c) K. Gilmore
and I. V. Alabugin, Chem. Rev., 2011, 111, 6513.
2 (a) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874; (b) F. Alonso,
I. P. Beletskaya and M. Yus, Chem. Rev., 2004, 104, 3079; (c) I. Beletskaya
and C. Moberg, Chem. Rev., 2006, 106, 2320; (d) M. C. Willis, Chem. Rev.,
2010, 110, 725; (e) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108, 3395.
3 (a) L. Ye, L. Cui, G. Zhang and L. Zhang, J. Am. Chem. Soc., 2010, 132, 3258;
(b) H. Yeom, J. Lee and S. Shin, Angew. Chem., Int. Ed., 2008, 47, 7040;
(c) N. D. Shapiro and F. D. Toste, J. Am. Chem. Soc., 2007, 129, 4160.
4 (a) T. Shen, T. Wang, C. Qin and N. Jiao, Angew. Chem., Int. Ed., 2013,
52, 6677; (b) J. Liu, Z. Fang, Q. Zhang, Q. Liu and X. Bi, Angew. Chem.,
Int. Ed., 2013, 52, 6953; (c) R. Zhu, J. Wei and Z. Shi, Chem. Sci., 2013,
4, 3706; (d) Z.-F. Xu, C.-X. Cai and J.-T. Liu, Org. Lett., 2013, 15, 2096.
´
´
5 (a) M. Garcıa-Melchor, A. A. C. Braga, A. Lledos, G. Ujaque and
F. Maseras, Acc. Chem. Res., 2013, 46, 2626; (b) G. Zeni and R. C.
Larock, Chem. Rev., 2004, 104, 2285; (c) G. Zeni and R. C. Larock,
Chem. Rev., 2006, 106, 4644.
Scheme 3 Control experiments.
6 (a) W. Wu and H. Jiang, Acc. Chem. Res., 2012, 45, 1736; (b) B. Liu, H. Gao,
Y. Yu, W. Wu and H. Jiang, J. Org. Chem., 2013, 78, 10319; (c) Q. Wang,
L. Huang, X. Wu and H. Jiang, Org. Lett., 2013, 15, 5094; (d) X. Ji,
H. Huang, W. Wu and H. Jiang, J. Am. Chem. Soc., 2013, 135, 5286.
7 (a) A. S. Kende, K. Kawamura and R. J. DeVita, J. Am. Chem. Soc.,
1990, 112, 4070; (b) M. Debono, R. M. Molloy, J. L. Occolowitz,
J. W. Paschal, A. H. Hunt, K. H. Michel and J. W. Martin, J. Org.
Chem., 1992, 57, 5200; (c) K. C. Nicolaou, M. Bella, D. Y.-K. Chen,
X. Huang, T. Ling and S. A. Snyder, Angew. Chem., Int. Ed., 2002,
41, 3495; (d) 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;
(e) G. Fontana, Curr. Bioact. Compd., 2010, 6, 284.
8 (a) P. Wipf, Chem. Rev., 1995, 95, 2115; (b) W. Wang, D. Yao, M. Gu,
M. Fan, J. Li, Y. Xing and F. Nan, Bioorg. Med. Chem. Lett., 2005,
15, 5284; (c) S. Heng, K. R. Gryncel and E. R. Kantrowitz, Bioorg. Med.
Chem., 2009, 17, 3916; (d) N. Desroy, F. Moreau, S. Briet, G. Le
Fralliec, S. Floquet, L. Durant, V. Vongsouthi, V. Gerusz, A. Denis
and S. Escaich, Bioorg. Med. Chem., 2009, 17, 1276.
Scheme 4 Possible mechanism for this cascade oxidative cyclization.
9 (a) A. I. Meyers and F. X. Tavares, J. Org. Chem., 1996, 61, 8207;
(b) A. J. Y. Uto, P. Wipf, M. J. Reno and D. R. Williams, Org. Lett.,
2000, 2, 1165; (c) D. R. Williams, D. P. Lowder, G. Y. Gu and
D. A. Brooks, Tetrahedron Lett., 1997, 38, 331.
protonolysis (path b), to generate intermediate A. Next, inter-
mediate B was formed by the reaction of intermediate A and
benzylamine 2a via oxidative amination.17 Afterward, inter-
mediate B was oxidized by O2 and CuII to give intermediate C.
Then intermediate D was obtained by nucleophilic addition.
Finally, the oxidation of intermediate D afforded the desired
product 3aa.
´
´
10 (a) I. Cano, E. Alvarez, M. C. Nicasio and P. J. Perez, J. Am. Chem. Soc.,
2011, 133, 191; (b) B. Shi, A. J. Blake, W. Lewis, I. B. Campbell,
B. D. Judkins and C. J. Moody, J. Org. Chem., 2010, 75, 152; (c) C. Wan,
J. Zhang, S. Wang, J. Fan and Z. Wang, Org. Lett., 2010, 12, 2338;
(d) Y. Luo, K. Ji, Y. Li and L. Zhang, J. Am. Chem. Soc., 2012,
134, 17412; (e) Y. Odabachian, S. Tong, Q. Wang, M. Wang and
J. Zhu, Angew. Chem., Int. Ed., 2013, 52, 10878; ( f ) Z. Xu, C. Zhang and
N. Jiao, Angew. Chem., Int. Ed., 2012, 51, 11367; (g) X. Li, L. Huang,
H. Chen, W. Wu, H. Huang and H. Jiang, Chem. Sci., 2012, 3, 3463.
In summary, we have developed a novel and efficient
approach to forge C–N and C–O bonds in one process for the 11 (a) Y. Zheng, X. Li, C. Ren, D. Zhang-Negrerie, Y. Du and K. Zhao,
J. Org. Chem., 2012, 77, 10353; (b) W. Zhou, C. Xie, J. Han and Y. Pan,
Org. Lett., 2012, 14, 4766; (c) A. E. Wendlandt and S. S. Stahl, Org.
Biomol. Chem., 2012, 10, 3866; (d) C. W. Cheung and S. L. Buchwald,
synthesis of trisubstituted oxazole derivatives. Products with
great regioselectivity could be obtained in this bimetal catalytic
transformation. Moreover, in this protocol four hydrogen
atoms were removed and one oxygen atom was obtained from
water, which exhibited high atom economy. The mechanism
and synthetic applications of this reaction are under further
studies in our laboratory and the results will be reported in due
course.
The authors thank the National Natural Science Foundation
of China (21172076 and 21202046), the National Basic Research
Program of China (973 Program) (2011CB808600), the Guang-
dong Natural Science Foundation (10351064101000000 and
J. Org. Chem., 2012, 77, 7526.
12 Y.-L. Tsai, Y.-S. Fan, C.-J. Lee, C.-H. Huang, U. Das and W. Lin,
Chem. Commun., 2013, 49, 10266.
13 W.-J. Xue, Q. Li, Y.-P. Zhu, J.-G. Wang and A.-X. Wu, Chem. Commun.,
2012, 48, 3485.
14 (a) Y. Hu, R. Yi, F. Wu and B. Wan, J. Org. Chem., 2013, 78, 7714;
(b) Y. Pan, F. Zheng, H. Lin and Z. Zhan, J. Org. Chem., 2009, 74, 3148.
15 (a) D. Yu and Y. Zhang, PNAS, 2010, 107, 20184; (b) S. T. Gadge and
B. M. Bhanage, Synlett, 2013, 0981; (c) C. Pan, F. Luo, W. Wang, Z. Ye
and J. Cheng, Tetrahedron Lett., 2009, 50, 5044.
16 The CCDC number of compound 3ka is 982238.
17 R. W. Evans, J. R. Zbieg, S. Zhu, W. Li and D. W. C. MacMillan, J. Am.
Chem. Soc., 2013, 135, 16074.
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Chem. Commun., 2014, 50, 3609--3611 | 3611