Metal-Free Oxidative [5+1] Cyclization of 1,5-Enynes for the Synthesis of Pyrazine 1-Oxide

Article abstract of DOI:10.1002/adsc.202000756

A chemo-selective nitrosylation of 1,5-enynes via a sequence of NO radical incorporation and intramolecular radical cyclization was reported. The formation of two C?N bonds and one C?O bond make this [5+1] cycloaddition reaction an efficient approach to synthesize pyrazine 1-oxides in moderate to good yields. Metal-free, short reaction time and mild conditions render this strategy more practical, eco-friendly and convenient. Synthetic utility of this protocol is highlighted by scaffolds diversification. (Figure presented.).

Full text of DOI:10.1002/adsc.202000756

Title: Metal-free oxidative [5+1] cyclization of 1,5-enynes for the
synthesis of pyrazine 1-oxide
Authors: Xiao-Feng Xia, Mingming Zhao, Wei He, Lianghua Zou,
Xinxin Sang, and Dawei Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000756
Link to VoR: https://doi.org/10.1002/adsc.202000756

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Oxidative [5+1] Cyclization of 1,5-Enynes for the
Synthesis of Pyrazine 1-Oxide
Xiao-Feng Xia, a* Mingming Zhao,a Wei He,a Lianghua Zou,b Xinxin Sanga and Dawei
Wang a
a
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material
Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China. E-mail:
xiaxf@jiangnan.edu.cn
b School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, 214122, People’s Republic of China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A chemo-selective nitrosylation of 1,5-enynes
Keywords: oxidative cyclization; 1,5-enynes; pyrazine 1-
via
a
sequence of NO radical incorporation and
oxide; metal-free; nitrosylation
intramolecular radical cyclization was reported. The
formation of two C-N bonds and one C-O bond make this
[5+1] cycloaddition reaction an efficient approach to
synthesize pyrazine 1-oxides in moderate to good yields.
Metal-free, short reaction time and mild conditions render
this strategy more practical, eco-friendly and convenient.
Synthetic utility of this protocol is highlighted by scaffolds
diversification.
generality of reaction, functional-group tolerance and
diversity, and green and sustainable chemistry.
Consequently, the development of green and
straightforward synthetic strategies to construct
multi-substituted pyrazine derivatives is of urgent
desire in synthetic chemistry.[3] Herein, we reported a
metal-free radical cyclization protocol for the
synthesis of pyrazine derivatives from 1,5-enynes and
tert-butyl nitrite (Scheme 1-b).
Introduction
The pyrazine unit is an important structural motif that
widely existed in many bioactive and nature
compounds.[1] The substituted pyrazines are widely
used in the fields of pharmaceuticals, materials,
flavours and fragrances.[1] For instance, 3,5-diaryl-2-
aminopyrazine series showed impressive in vitro
antiplasmodial activity against the K1 (multidrug
resistant) and NF54 (sensitive) strains of Plasmodium
falciparum, 6-arylpyrazine-2-carbox-amides can be
used
for
treatment
of
human
African
trypanosomiasis.[1a, 1c] Since the properties of these
compounds are in connection with different
substituents on the pyrazine rings, the invention of
methods enabling their rapid construction is a topic of
continuing scientific endeavour. The conventional
synthetic route to poly-substituted pyrazines often
occurred under the cyclocondensation condition of
ethylenediamine with diols or ketones, or via direct
substitution of pyrazine 1-oxides or pyrazines with
other functional groups (Scheme 1-a).[2] Although
these classical approaches are widely utilized but
there still exists a scope of improvement in terms of
Scheme 1. Different strategies for the construction of
pyrazine unit.
[5+1] Cycloaddition reaction represents one of the
most efficient and atom-economic ways to construct a
variety of structurally complicated heterocyclic
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
compounds without rigorous pre-functionalization of
the starting materials.[4] Over the past decades, [5+1]
cycloaddition strategies have been widely applied in
the synthesis of six-membered natural products,
temperature using trifluoroethanol as the solvent
(Table 1, entry 1). Under the same reaction
conditions, several organic solvents such as HFIP,
CH3CN, DCE, EtOAc, THF, DMSO, DMF,
chlorobenzene, toluene, and xylene were screened,
and DCE can give a higher yield (entry 4). The
reaction temperature played an important role in this
transformation, when the reaction was carried out in
biologically
active
compounds,
and
pharmaceuticals.[5] In previous reports, one-carbon
components were widely utilized in [5+1]
cycloaddition reactions,[4] however, one-nitrogen
components such as “NO” were rarely incorporated
into molecular scaffolds via [5+1] cycloaddition
strategy.[6] Recently, tert-butyl nitrite (TBN) has been
shown to be a very useful building block as the
source of NO and NO2 for the construction of
corresponding N-containing compounds under mild
conditions.[7] For instance, Jiao group recently
reported an efficient approach for the synthesis of
quinoxaline N-oxides via [5+1] radical cyclization
(Scheme 2-b).[6a, 6b] However, the direct construction
of six membered N-containing compounds from 1,5-
enynes by [5+1] radical cycloaddition reaction is still
a challenging task due to the manifold cyclization
modes.[8] Very recently, our group reported a metal-
o
60 C or 0 oC, a lower yield was observed (entries 12
and 13). It was worth mentioning that the
concentration of the reaction was very crucial for this
oxidative cyclization reaction, a better result was
obtained using a dilute system (entry 15 vs 4). In
order to further increase the efficiency of this
transformation, some additives such as TBAB, TBAI,
and TBAF were tried, but no better results were
found (entries 17-19). Control experiments
demonstrated that dioxygen was essential for this
transformation, and there is no reaction under argon
atmosphere (entry 21). Other oxidants such as
free oxidative annulation reaction of 1,6-enynes for tBuOOH, tBuOOtBu, and PhI(OAc)2 were also tried,
the synthesis of 4-carbonylquinolines using TBN as
the oxidant.[9] In this context, we hypothesized that if
1,5-enynes were introduced into this oxidative
systems, an intramolecular radical cyclization/NO
group insertion sequence could be realized (Scheme
2-c, path a). However, a different pathway via NO
but no target product was observed (entries 22-24). In
addition, the amount of the oxidant was crucial for
this oxidative cyclization reaction, a lower yield was
observed when 1.0 equiv. of TBN was used (entry
26).
radical
insertion/intramolecular
radical
Table 1. Optimization of reaction conditions a)
cyclization/oxygen atom insertion sequence occurred
(Scheme 2-c, path b), and multi-substituted pyrazine
derivatives were obtained using this inscrutable
approach.
Entry
Solvent
Temperature Yield
(℃)
(%)b)
1
2
3
4
5
6
7
8
CF3CH2OH (1 mL)
HFIP (1 mL)
CH3CN (1 mL)
DCE (1 mL)
EtOAc (1 mL)
THF (1 mL)
DMSO (1 mL)
DMF (1 mL)
PhCl (1 mL)
Toluene (1 mL)
Xylene (1 mL)
DCE (1 mL)
DCE (1 mL)
DCE (2 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
25
25
25
25
25
25
25
25
25
25
25
60
0
25
25
25
25
25
25
25
25
25
25
50
0
52
54
26
0
28
0
9
22
26
30
31
34
57
66
62
57
9
10
11
12
13
14
15
16c)
17d)
18e)
19f)
20g)
21h)
22i)
23j)
Scheme 2. Different strategies for [5+1] cycloaddition
reaction.
Results and Discussion
We initially commenced our investigation with our
previous reported reaction conditions[9] using ethyl 3-
phenyl-3-((3-phenylprop-2-yn-1-yl)-amino)-acrylate
1a and TBN as the model substrates. Gratifyingly, a
50% yield of 6-benzoyl-2-(ethoxycarbonyl)-3-
phenyl-pyrazine 1-oxide 2a was obtained at room
8
31
0
0
0
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
24k)
25l)
DCE (3 mL)
DCE (3 mL)
DCE (3 mL)
25
25
25
0
62
32
26m)
a)
Reaction conditions: 1a (0.1 mmol), TBN (2.0 eq.),
b)
solvent (1-3 mL), Time (30 min), O2 atmosphere.
Isolated yield. c) 4Å MS was used as the additive. TBAB
d)
(10 mol%) was used as the additive. e) TBAI (10 mol%)
was used as the additive. f) TBAF (10 mol%) was used as
g)
h)
i)
the additive.
in air. Under Ar atmosphere. 2.0 eq.
j)
tBuOOH was used in Ar. 2.0 eq. tBuOOtBu was used in
Ar. k) 2.0 eq. PhI(OAc)2 was used in Ar. l) 3.0 eq. TBN was
used. m) 1.0 eq. TBN was used.
With the optimized conditions in hand (Table 1,
entry 15), the substrate scope of aryl propynyl amine
was first screened to probe the generality of this
radical cyclization protocol. As shown in scheme 3,
electron-donating substituents such as methyl,
methoxyl, tertiary butyl, and phenyl on the moiety of
alkyne arene were well tolerated under the oxidative
condition (2a-2e), and moderate yields (40-63%)
were separated. Aryl propynyl amines with electron-
withdrawing groups such as Cl, Br, F, CF3, Ac, and
COOMe at the para-position of alkyne arene were
also suitable, leading to the corresponding products
2f-2l in 52–71% yields.[10] It was worth mentioning
that acetyl protected active amino group can be
tolerated in this oxidative conditions, and a moderate
yield of product (2j) was isolated. To confirm further
the structural assignment of products in the present
radical oxidative cyclization, the structure of the
products 2a and 2h were unambiguously assigned by
X-ray crystallography.[11] In addition, the strong
electron-withdrawing groups such as CN and NO2
can be well tolerated in this oxidative condition (2m
and 2n), which can be easily transformed into other
groups. Products containing -F and -Me at the ortho-
and meta-positions (2o-2r) could be produced in
moderate yields. Naphthyl substitution also produced
the target product 2s in lower yield due to steric
hindrance. Notably, heteroaromatic groups such as 2-
pyridyl, 3-pyridyl, and thienyl were also compatible
with the reaction conditions, resulting in 35%-40%
yields (2t-2v). The group OH in the moiety of alkyne
aryl has been also tried, but no target product was
observed, the starting material decomposed in the
reaction system (not shown). In addition, the terminal
alkyne and alkyl substituted alkynes were not
tolerated in this transformation.
Scheme 3. Substrate scope for alkyne aryl
substituents.
The reaction efficiency of different substituents at
the α- and β-positions of the substituted enamines
was also investigated in Scheme 4. Electron-donating
groups (3a-3b) such as methyl, tertiary butyl and
electron-withdrawing groups such as fluoro, chloro,
bromo, trifluoromethyl, and acetyl in the moiety of
aryl (3c-3g) were well-tolerated in this radical
oxidative cyclization reaction, and moderate yields
(58-65%) were obtained. Notably, ortho- and meta-
substituted groups (-F) did not affect the radical
transformation, and delivered the target products 3i
and 3h in 53 % and 61% yields, respectively. In
addition, methyl ester substrate was suitable in this
transformation, giving a 64% yield of target product
3j. Importantly, except for ester substrates, benzoyl,
acetyl, amide, and cyano in R2 were also tolerated,
and moderate yields were obtained (3k-3n). However,
alkyl substituents in R1 were not suitable in this
reaction, and the substrates decomposed in this
transformation.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
radical scavengers, implying that some radical
species are involved in this transformation (Scheme
5-c).
Scheme 5. Mechanism studies.
It is noteworthy that a scale-up synthesis (2.0
mmol) could be easily realized using this strategy,
and a slight lower yield of product 2a was obtained
(Scheme 6-a). The product 2a could be easily
deoxidized into multi-substituted pyrazine derivative
4 under the reductive conditions in high yield
(Scheme 6-b).[7a] An interesting hydrolysis and
debenzoylation product 5 was obtained in high yield
under the basic and refluxing conditions, and the
corresponding product could be isolated through
direct filtration without further purification (Scheme
6-c).[6a] In addition, pyrazine derivative 4 could also
be easily transformed into product 6 under the same
basic reaction conditions in 83% yield (Scheme 6-d).
On the basis of the above results and previous
reports,[6a,9,12] a tentative mechanism is depicted in
Scheme 7. The first step of this transformation is the
formation of the tert-butoxy radical and NO radical
generated by homolysis of TBN.[7,6a] Then, H
abstraction of the N-H bond by tert-butoxy radical
occurs to generate radical intermediate A, which can
be stabilized by electron-withdrawing group (COOEt).
The intermediate A undergoes radical coupling with
the NO radical to afford the nitroso intermediate B.
The nitroso intermediate B further undergoes H
abstraction by tert-butoxy radical to give radical
intermediate C, where the carbon radical was
delocalized by NO group. The delocalized nitroso
radical can easily attack the electron-rich alkyne via a
Scheme 4. Substrate scope for substituted enamines. a The
b
o
reaction was carried out at 0 C for 30 min. N.D. = not
detected.
To gain more insights into the mechanism, some
isotope labelling experiments and radical quenching
experiments were carried out (Scheme 5). First, in
order to clarify the origin of the oxygen atom of
ketone products, isotopic labelling experiments with
18O2 and H218O were studied. When the reaction was
carried out under 18O-labelled dioxygen atmosphere,
the 18O-labelled product 2f was not observed by
HRMS (Scheme 5-a). When 2.0 equiv. of 18O-
18
labelled H2 O was added into the standard conditions,
the 18O-labelled product 2f can be obtained with part
un-labelled product 2f (Scheme 5-b). These
phenomenons clearly showed that the oxygen atom of
ketone in product was from water in this
transformation. Then, some radical quenching
experiments were conducted. The oxidative
cyclization reaction was found to be completely
inhibited using 2.0 equiv. of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy), BHT (2,6-di-tert-
butyl-4-methylphenol) or 1,1-diphenylethylene as the
6-exo-dig intramolecular radical cyclization to give
6b]
the cyclic intermediate D,[6a,
which then goes
through further oxidation to give intermediate E.
Water is captured by intermediate E to produce
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
intermediate F,[9,13] which finally undergoes oxidative
aromatization to give the final product 2a.
General Procedure
The mixture of ethyl (Z)-3-phenyl-3-((3-phenylprop-2-yn-
1-yl)-amino)-acrylate (0.20 mmol) and TBN (0.40 mmol),
were combined in DCE (6.0 mL) at room temperature for
30 min under 1 atm dioxygen atmosphere. After the
reaction, 6 mL water was added to quench the reaction,
and the resulting mixture was extracted twice with DCM.
The combined organic extracts were washed with brine,
dried over Na2SO4 and concentrated. Purification of the
crude product by flash column chromatography afforded
the desired product 2a (petroleum ether/ethyl acetate as
eluent (8:1-6:1)).
Acknowledgements
We thank the National Science Foundation of China NSF
21402066 and the Natural Science Foundation of Jiangsu
Province (BK20140139) for financial support. Financial support
from MOE&SAFEA for the 111 project (B13025) is also
gratefully acknowledged. We thank central laboratory, school of
chemical and material engineering, Jiangnan University for
characterization analysis.
References
Scheme 6. Scale-up reaction and further transformations.
[1] a) R. Rahmani, K. Ban, A. J. Jones, L. Ferrins, D.
Ganame, M. L. Sykes, V. M. Avery, K. L. White, E.
Ryan, M. Kaiser, S. A. Charman, J. B. Baell, J. Med.
Chem. 2015, 58, 6753; b) Y.-K. Zhang, J. J. Plattner, E.
E. Easom, R. T. Jacobs, D. Guo, V. Sanders, Y. R.
Freund, B. Campo, P. J. Rosenthal, W. Bu, F.-J. Gamo,
L. M. Sanz, M. Ge, L. Li, J. Ding, Y. Yang, J. Med.
Chem. 2015, 58, 5344; c) J. D. Osborne, T. P.
Matthews, T. McHardy, N. Proisy, K.-M. J. Cheung, M.
Lainchbury, N. Brown, M. I. Walton, P. D. Eve, K. J.
Boxall, A. Hayes, A. T. Henley, M. R. Valenti, A. K.
De Haven Brandon, G. Box, Y. Jamin, S. P. Robinson,
I. M. Westwood, R. L. M. van Montfort, P. M. Leonard,
M. B. A. C. Lamers, J. C. Reader, G. W. Aherne, F. I.
Raynaud, S. A. Eccles, M. D. Garrett, I. Collins, J. Med.
Chem. 2016, 59, 5221; d) K. Nakahara, K. Fuchino, K.
Komano, N. Asada, G. Tadano, T. Hasegawa, T.
Yamamoto, Y. Sako, M. Ogawa, C. Unemura, M.
Hosono, H. Ito, G. Sakaguchi, S. Ando, S. Ohnishi, Y.
Kido, T. Fukushima, D. Dhuyvetter, H. Borghys, H. J.
M. Gijsen, Y. Yamano, Y. Iso, K. Kusakabe, J. Med.
Chem. 2018, 61, 5525; e) H. Wang, Y. Wen, X. Yang,
Y. Wang, W. Zhou, S. Zhang, X. Zhan, Y. Liu, Z.
Shuai, D. Zhu, ACS Appl. Mater. Interfaces, 2009, 1,
1122; f) B. R. Jones, P. A. Varughese, I. Olejniczak, J.
M. Pigos, J. L. Musfeldt, C. P. Landee, M. M. Turnbull,
G. L. Carr, Chem. Mater. 2001, 13, 2127; g) Y. Masaki,
T. Inde, A. Maruyama, K. Seio, Org. Biomol. Chem.
2019, 17, 859; h) Q. Sun, X. Li, Q. Lin, M. Lu, Org.
Biomol. Chem. 2018, 16, 8034.
Scheme 7. Proposed mechanism.
Conclusion
In conclusion, we have developed an efficient
oxidative [5+1] cyclization of 1,5-enynes for the
construction of multi-substituted pyrazine N-oxides
through NO radical incorporation/intramolecular
radical cyclization and oxygen atom insertion. Facile
operation, metal-free, and mild conditions at room
temperature offer a particularly practical and
attractive protocol for the synthesis of pyrazine
derivatives. The produced pyrazine N-oxides can be
easily transformed into other substituted pyrazine
derivatives in high yields. This strategy using
molecular oxygen as the oxidant and water as the
oxygen source under mild reaction conditions makes
this protocol particularly sustainable and eco-friendly.
[2] a) F. Zaragoza, A. Gantenbein, Org. Process Res. Dev.
2017, 21, 448; b) H. Andersson, R. Olsson, F. Almqvist,
Org. Biomol. Chem. 2011, 9, 337; c) B. Klein, J.
Berkowitz, Bernard Klein and Judith Berkowitz, 1959,
81, 5160; d) N. Sato, Y. Shimomura, Y. Ohwaki, R.
Takeuchi, J. Chem. Soc. Perkin Trans. 1 1991, 2877; e)
Experimental Section
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
N. Sato, K. Kawahara, N. Morii, J. Chem. Soc. Perkin
Huang, H. Liang, Chin. J. Org. Chem. 2017, 37, 1916;
l) W.-T. Wei, W.-W. Ying, W.-H. Bao, L.-H. Gao, X.-
D. Xu, Y.-N. Wang, X.-X. Meng, G.-P. Chen, Q. Li,
ACS Sustainable Chem. Eng. 2018, 6, 15301; m) M. Hu,
B. Liu, X.-H. Ouyang, R.-J. Song, J.-H. Li, Adv. Synth.
Catal. 2015, 357, 3332; n) X.-H. Hao, P. Gao, X.-R.
Song, Y.-F. Qiu, D.-P. Jin, X.-Y. Liu, Y.-M. Liang,
Chem. Commun. 2015, 51, 6839; o) S. Mai, C. Rao, M.
Chen, J. Su, J. Du, Q. Song, Chem. Commun. 2017, 53,
10366; p) D. Wang, F. Zhang, F. Xiao, G.-J. Deng, Org.
Biomol. Chem. 2019, 17, 9163; q) Y. Wu, Y. Zhang, Z.
Yang, J. Jiao, X. Zheng, W. Feng, M. Zhang, H. Cheng,
L. Tang, Chem. Sus. Chem. 2019, 12, 3960.
Trans. 1 1993, 15; f) J. Hu, G. Zhou, Y. Tian, X. Zhao,
Org. Biomol. Chem. 2019, 17, 6342; g) K. S. Kumar, M.
S. Ramulu, B. Rajesham, N. P. Kumar, V. Voorab, R.
K. Kancha, Org. Biomol. Chem. 2017, 15, 4468.
[3] a) S. Okumura, Y. Takeda, K. Kiyokawaa, S. Minakata,
Chem. Commun. 2013, 49, 9266; b) Y.-X. Jiao, L.-S.
Wei, C.-Y. Zhao, K. Wei, D.-L. Mo, C.-X. Pan, G. -F.
Su, Adv. Synth.Catal. 2018, 360, 4446.
[4] a) J. Nan, Y. Hu, P. Chen, Y. Ma, Org. Lett. 2019, 21,
1984; b) R. Kuppusamy, K. Muralirajan, C.-H. Cheng,
ACS Catal. 2016, 6, 3909; c) X. Li, W. Song, W. Tang,
J. Am. Chem. Soc. 2013, 135, 16797; d) G.-J. Jiang, X.-
F. Fu, Q. Li, Z.-X. Yu, Org. Lett. 2012, 14, 692; e) S.
Zhao, J.-B. Lin, Y.-Y. Zhao, Y.-M. Liang, P.-F. Xu,
Org. Lett. 2014, 16, 1802; f) F. Xu, W.-F. Kang, Y.
Wang, C.-S. Liu, J.-Y. Tian, R.-R. Zhao, M. Du, Org.
Lett. 2018, 20, 3245; g) D. Shu, X. Li, M. Zhang, P. J.
Robichaux, W. Tang, Angew. Chem., Int. Ed. 2011, 50,
1346; h) L.-J. Wu, R.-J. Song, S. Luo, J.-H. Li, Angew.
Chem., Int. Ed. 2018, 57, 13308; i) D. Shu, X. Li, M.
Zhang, P. J. Robichaux, I. A. Guzei, W. Tang, J. Org.
Chem. 2012, 77, 6463; j) W. Xu, J. Zhao, X. Li, Y. Liu,
J. Org. Chem. 2018, 83, 15470.
[8] a) X. Xin, D. Wang, F. Wu, X. Li, B. Wan, J. Org.
Chem. 2013, 78, 4065; b) S. Cacchi, G. Fabrizi, E.
Filisti, Org. Lett. 2008, 10, 2629; c) M. Zora, S.
Karabiyikoglu, Abstracts of Papers, 243th National
Meeting of American Chemical Society, San Diego,
California; March 25−29, 2012; American Chemical
Society: Washington, DC, 2012; ORGN 844; d) A.
Saito, T. Konishi, Y. Hanzawa, Org. Lett. 2010, 12,
372; e) X. Y. Xin, D. P. Wang, X. C. Li, B. S. Wan,
Angew. Chem., Int. Ed. 2012, 51, 1693; f) X. Xin, H.
Wang, X. Li, D. Wang, B. Wan, Org. Lett. 2015, 17,
3944; g) X. Xin, D. Wang, F. Wu, C. Wang, H. Wang,
X. Li, B. Wan, Org. Lett. 2013, 15, 4512; h) K. K. Toh,
Y.-F. Wang, E. P. J. Ng, S. Chiba, J. Am. Chem. Soc.
2011, 133, 13942.
[5] a) M. Zhang, W. Tang, Org. Lett. 2012, 14, 3756; b)
L.-N. Wang, Q. Cui, Z.-X. Yu, J. Org. Chem. 2016, 81,
10165.
[9] X.-F. Xia, W. He, D. Wang, Adv. Synth. Catal. 2019,
361, 2959.
[6] a) J. Pan, X. Li, F. Lin, J. Liu, N. Jiao, Chem. 2018, 4,
1427; b) F. Chen, X. Huang, X. Li, T. Shen, M. Zou, N.
Jiao, Angew. Chem., Int. Ed. 2014, 53, 10495; c) L. A.
Combee, S. L. Johnson, J. E. Laudenschlager, M. K.
Hilinski, Org. Lett. 2019, 21, 2307.
[10] Because the starting materials were not stable under
the oxidative conditions, after the reaction, we found
that the decomposed ethyl 3-oxo-3-arylpropanoates
were observed in some cases. So, only moderate yield
was obtained.
[7] a) G. C. Senadi, J.-Q. Wang, B. S. Gore, J.-J. Wang,
Adv. Synth. Catal. 2017, 359, 2747; b) B. A. Mir, S. J.
Singh, R. Kumar, B. K. Patel, Adv. Synth. Catal. 2018,
360, 3801; c) J. Yang, Y.-Y. Liu, R.-J. Song, Z.-H.
Peng, J.-H. Li, Adv. Synth. Catal. 2016, 358, 2286; d) T.
Feng, Y. He, X. Zhang, X. Fan, Adv. Synth. Catal. 2019,
361, 1271; e) Y. Liu, J.-L. Zhang, R.-J. Song, P.-C.
Qian, J.-H. Li, Angew. Chem., Int. Ed. 2014, 53, 9017;
f) K. Qiao, X. Yuan, L. Wan, M.-W. Zheng, D. Zhang,
B.-B. Fan, Z.-C. Di, Z. Fang, K. Guo, Green Chem.
2017, 19, 5789; g) X. Jia, P. Li, Y. Shao, Y. Yuan, H.
Ji, W. Hou, X. Liu, X. Zhang, Green Chem. 2017, 19,
5568; h) B. Wang, L. Tang, L. Liu, Y. Li, Y. Yang, Z.
Wang, Green Chem. 2017, 19, 5794; i) K. He, P. Li, S.
Zhang, Q. Chen, H. Ji, Y. Yuan, X. Jia, Chem.
Commun. 2018, 54, 13232; j) T.-S. Zhang, R. Wang,
P.-J. Cai, W.-J. Hao, S.-J. Tu, B. Jiang, Org. Chem.
Front. 2019, 6, 2968; k) W. Wei, W. Zhu, Y. Wu, Y.
[11] CCDC 1955747 (2a) and 1941858 (2h) contains the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
[12] a) R.-L. Yan, H. Yan, C. Ma, Z.-Y. Ren, X.-A. Gao,
G.-S. Huang, Y.-M. Liang, J. Org. Chem. 2012, 77,
2024; b) R.-L. Yan, J. Luo, C.-X. Wang, C.-W. Ma, G.-
S. Huang, Y.-M. Liang, J. Org. Chem. 2010, 75, 5395.
c) B. Yuan, F. Zhang, Z. Li, S. Yang, R. Yan, Org. Lett.
2016, 18, 5928.
[13] W. Wu, S. Yi, W. Huang, D. Luo, H. Jiang, Org. Lett.
2017, 19, 2825.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000756
Advanced Synthesis & Catalysis
FULL PAPER
Metal-free oxidative [5+1] cyclization of1,5-
enynes for the synthesis of pyrazine 1-oxide
Adv. Synth. Catal. Year, Volume, Page – Page
Xiao-Feng Xia,a* Mingming Zhao,a Wei He,a
Lianghua Zou,b Xinxin Sang a and DaweiWang a
7
This article is protected by copyright. All rights reserved.