NIS-TBHP promoted oxidative coupling of C–N and C–O bonds: A metal-free approach to polysubstituted oxazoles

Article abstract of DOI:10.1016/j.tetlet.2020.151846

A metal-free approach to polysubstituted oxazoles via the oxidative coupling of readily available benzylamines and 1,3-dicarbonyl derivatives in the presence of an external base has been developed. A variety of functional groups on both of the starting materials are tolerated using this method, affording the corresponding oxazoles in moderate to good yields. Iodination was proposed as the initiation step of the reaction and a plausible mechanism has been proposed to explain the reaction pathway.

Full text of DOI:10.1016/j.tetlet.2020.151846

Tetrahedron Letters 61 (2020) 151846
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NIS-TBHP promoted oxidative coupling of CAN and CAO bonds: A metal-
free approach to polysubstituted oxazoles
Shengxiang Yang a,b, Yuzhu Yang a,b, , Fei Li a,b, Xiaolan Liu a,b
⇑
a State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China
b The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal-free approach to polysubstituted oxazoles via the oxidative coupling of readily available benzy-
lamines and 1,3-dicarbonyl derivatives in the presence of an external base has been developed. A variety
of functional groups on both of the starting materials are tolerated using this method, affording the cor-
responding oxazoles in moderate to good yields. Iodination was proposed as the initiation step of the
reaction and a plausible mechanism has been proposed to explain the reaction pathway.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 20 January 2020
Revised 10 March 2020
Accepted 13 March 2020
Available online 16 March 2020
Keywords:
Oxazoles
Oxidative coupling
Metal-free
Iodination
Introduction
chemical procedure which does not require any transition metal
catalyst or oxidant compared with the traditional thermo-chemical
Oxazoles are one of the most widely found motifs in biologically
active compounds, synthetic intermediates, and pharmaceuticals
[1]. In particular, 2,5-disubstituted and 2,4,5-trisubstituted oxa-
zoles are found in numerous natural products and pharmacologi-
cally active compounds such as the antimycobacterial natural
product texaline [2], the antipancreatic cancer agent PC-046 [3],
and the antidiabetic agent AD-5061 [4] (Fig. 1). Therefore, contin-
uing efforts have been devoted to the development of concise and
efficient methods for the construction of substituted oxazoles.
There are three typical methods for the preparation of oxazoles:
the cyclization of acyclic precursors [5], the coupling of prefunc-
tionalized oxazoles with organometallic reagents [6], and the oxi-
dation of oxazolines [7]. However, the development of single step
reactions which proceed with operational simplicity for the syn-
thesis of oxazoles from readily available starting materials is still
of great demand.
methods (Scheme 1b) [10]. Xie and co-workers reported a Bu4NI/
TBHP promoted system in which the hypoiodite or iodite anion
plays an important role for the assembly of oxazoles (Scheme 1c)
[11]. Herein, we report the NIS (N-iodosuccinimide)-TBHP (tert-
butyl hydroperoxide) promoted oxidative reaction of benzylami-
nes and 1,3-dicarbonyl derivatives in the presence of an external
base for the synthesis of oxazoles (Scheme 1d).
The model coupling reaction of benzylamine 1a and ethyl 3-
oxo-3-phenylpropanoate 2a was performed for the optimization
study (Table 1). The combination of NIS, TBHP and Na2CO3 in
DMA (dimethylacetamide) at 50 °C for 16 h afforded the highest
yield (85%) of the desired product 3aa (Entry 1). No reaction
occurred in the absence of NIS (Entry 2). The yield dropped to
32% without the addition of TBHP (Entry 3). An external base Na2-
CO3 increased the yield from 72% to 85% (Entry 4). When the
amount of NIS or TBHP was increased, the yield decreased (Entries
5–6). The addition of iodine instead of NIS gave product 3aa in only
62% yield (Entry 7). When tetrabutylammonium iodide replaced
NIS in this reaction, the yield dropped to 36% (Entry 8). Besides
TBHP, DTBP (di-tert-butyl peroxide) was also tested as an oxidant,
but the yield decreased dramatically to 25% (Entry 9). Other exter-
nal bases such as Li2CO3 and K2CO3 gave lower yields than Na2CO3
(Entries 10–11). Screening of other solvents such as DMSO
(dimethyl sulfoxide), DCE (dichloroethane), MeCN (acetonitrile),
THF (tetrahydrofuran) and EtOAc (ethyl acetate) indicated that
A copper catalysed oxidative system was utilized by Wang’s
group [8] and Chen’s group [9] for the preparation of polysubsti-
tuted oxazoles from benzylamines and b-diketone derivatives
(Scheme 1a). Yuan and co-workers reported an alternative electro-
⇑
Corresponding author at: State Key Laboratory of Functions and Applications of
Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014,
PR China.
E-mail address: yangyuzhu15@126.com (Y. Yang).
https://doi.org/10.1016/j.tetlet.2020.151846
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
S. Yang et al. / Tetrahedron Letters 61 (2020) 151846
the best solvent was DMA (Entries 12–16). Finally, the reaction
temperature was optimized and the results showed running the
reaction at 50 °C gave the highest yield of product 3aa (Entries
17–18).
With the optimal reaction conditions in hand, we extended the
substrate scope with respect to the benzylamine (Scheme 2). (4-
Ethoxyphenyl)methanamine and naphthalen-1-ylmethanamine
gave the desired products 3ab in 77% yield and 3ac in 70% yield,
respectively. A steric effect was observed with para-substituted
product 3ad (73%), meta-substituted product 3ae (64%) and
ortho-substituted product 3af (62%). Inductive electron-withdraw-
ing groups such as fluoro, chloro and bromo were tolerated in this
reaction (3ag 76%, 3ah 69% and 3ai 81%). Conjugative electron-
withdrawing groups such as cyano and methyl carboxylate also
gave the corresponding products 3aj in 55% yield and 3ak in 54%
yield, respectively. In addition to the phenyl ring, thiophene- and
furan-containing products could also be obtained in 74–87% yield
(3al, 3am and 3an).
Fig 1. Bioactive oxazole derivatives.
Next 1,3-dicarbonyl derivatives with different aryl and alkyl
substituents were investigated as shown in Scheme 3. 1,3-Dicar-
bonyl derivatives with electron-withdrawing groups such as -CF3,
-Br, -Cl, and -F on the phenyl ring gave the desired products in
48–68% yield. Ethyl 3-(benzo[d][1,3]dioxol-5-yl)-3-oxopropanoate
with an electron-donating group gave the expected product 3bg in
47% yield. Other b-ketoesters with heterocycles such as tetrahy-
drofuran, N-methyl pyrrole, pyridine, thiophene and furan were
also suitable substrates. Furthermore, 1,3-dicarbonyl derivatives
such as ethyl 3-oxobutanoate, ethyl 4,4-dimethyl-3-oxopen-
tanoate and pentane-2,4-dione were compatible and gave the cor-
responding products in 64–80% yield.
A control experiment was performed to determine the possible
reaction pathway. Ethyl 3-oxo-3-phenylpropanoate (2a) was con-
verted to ethyl 2-iodo-3-oxo-3-phenylpropanoate (4a) in 95% yield
in the presence of 1.1 equiv. NIS.[12] When intermediate 4a was
subjected to the reaction conditions (without the addition of
NIS), the desired product 3aa was isolated in 83% yield (Scheme 4).
These results suggested that the first step of this transformation
Scheme 1. Selected annulation approaches to multisubstituted oxazoles.
Table 1
a
Optimization of the reaction conditions.a Reagents and conditions: 1a (0.3 mmol), 2a (0.2 mmol), NIS (0.2 mmol),
TBHP (0.6 mmol), Na2CO3 (0.4 mmol), DMA (2 mL), 50 °C, 16 h. Isolated yield.
Entry
Deviation from the standard conditions
Yield 3aa (%)
1
2
No change
Without NIS
85
0
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Without TBHP
Without Na2CO3
2 equiv. NIS
5 equiv. TBHP
32
72
53
69
62
36
25
68
27
61
37
54
0
I2 instead of NIS
Bu4NI instead of NIS
DTBP instead of TBHP
Li2CO3 instead of Na2CO3
K2CO3 instead of Na2CO3
DMSO instead of DMA
DCE instead of DMA
MeCN instead of DMA
THF instead of DMA
EtOAc instead of DMA
30 °C instead of 50 °C
70 °C instead of 50 °C
45
56
75

S. Yang et al. / Tetrahedron Letters 61 (2020) 151846
3
Scheme 5. Plausible mechanism.
Scheme 6. Gram-scale synthesis.
could be the iodination process. Based on the above results and
previous reports,[13] a plausible mechanism has been proposed
in Scheme 5. Firstly, the NIS-mediated iodination process forms
4a, which undergoes coupling with benzylamine in the presence
of base to generate intermediate A. Further oxidation gives imine
intermediate B. In the presence of base, cyclization generates inter-
mediate C, which undergoes deprotonation and dehydrogenative
aromatization to give the final product 3aa.
Scheme 2. Scope of the amines for the synthesis of oxazoles.
A gram-scale reaction was performed to demonstrate the prac-
ticality of our protocol. The reaction of benzylamine with ethyl 3-
oxo-3-phenylpropanoate (2a) on a 5 mmol scale using the opti-
mized conditions provided the oxazole product 3aa in 72% yield
(Scheme 6).
In summary, we have developed a metal-free approach to 2,4,5-
trisubstituted oxazoles via NIS-TBHP promoted oxidative coupling
in the presence of an external base using readily available starting
materials. This facile and efficient protocol tolerates a variety of
functional groups on the 1,3-dicarbonyl derivatives. Further inves-
tigations and the application of this methodology to other useful
heterocycles are currently ongoing in our laboratory.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Scheme 3. Scope of the 1,3-dicarbonyls for the synthesis of oxazoles.
Acknowledgments
Financial support from the Natural Science Foundation of Guiz-
hou Province, China (QKHJC[2017]1117, QKHJC[2018]1109,
QKHPTRC[2017]5718) and West Light Foundation of The Chinese
Academy of Sciences is acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151846. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
Scheme 4. Control experiment.

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S. Yang et al. / Tetrahedron Letters 61 (2020) 151846
H.; Fei, Z.; Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; She, N.-F.; Wu, A.-X.
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