Metal-free chalcogenation of cycloketone oxime esters with dichalcogenides

Article abstract of DOI:10.1016/j.tetlet.2021.153202

We report the metal-free chalcogenation of cycloketone oxime esters with dichalcogenides via a radical process. Because of the metal-free condition and use of readily accessible dichalcogenides, this method is an effective and green strategy for the synthesis of chalcogen-substituted butyronitrile.

Full text of DOI:10.1016/j.tetlet.2021.153202

Tetrahedron Letters 75 (2021) 153202
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free chalcogenation of cycloketone oxime esters with
dichalcogenides
Liangshuo Ji a, Jiamin Qiao a, Junjie Liu a,b, Miaomiao Tian a, Kui Lu b, Xia Zhao a
a College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin 300387, China
b China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science &
Technology, Tianjin 300457, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the metal-free chalcogenation of cycloketone oxime esters with dichalcogenides via a radical
process. Because of the metal-free condition and use of readily accessible dichalcogenides, this method is
an effective and green strategy for the synthesis of chalcogen-substituted butyronitrile.
Ó 2021 Published by Elsevier Ltd.
Received 29 March 2021
Revised 15 May 2021
Accepted 20 May 2021
Available online 24 May 2021
Keywords:
Chalcogenation
Cycloketone oxime esters
Dichalcogenides
Metal-free protocols
Introduction
a nickel-catalysed thiolation/ and selenylation of cycloketone
oxime esters with thiosulfonate or selenium sulfonate [14].
Organochalcogen compounds have received continuous atten-
tion because of their extensive applications as pharmaceuticals,
drug candidates, agrochemicals, catalysis and functional materials
[1]. Some representative examples are shown in Fig. 1. Axtinib is an
anti-cancer drug [2]. Amenamevir is an anti-infective drug [3].
Compound 1 is a human breast cancer cell growth inhibitor [4].
Compound 2 is a retinoic acid receptor agonist [5]. Compound 3
is a fluorescence probe [6]. Hence, the formation of carbon-chalco-
gen bonds in an efficient manner is highly desirable.
Recently, we reported an ethanol/N,N-dimethylacetamide pro-
moted sp3 C-SCF3 coupling reaction between cycloketone oxime
esters and S-trifluoromethyl 4-methylbenzenesulfonothioate [15].
As a part of our on-going research to develop efficient methods
for carbon-chalcogen bond formation [16], we demonstrate herein
metal-free chalcogenation of cycloketone oxime esters with
dichalcogenides to form sp3 carbon chalcogen-bonds.
Results and discussion
In the past decade, cyclobutanone oxime esters have emerged
as versatile intermediates in organic synthesis as they can be con-
verted to functionalised nitriles via iminyl radicals. This type of
transformation involves the formation of new CAC, CAO, CAN,
and C–X bonds and is realised by transition-metal catalysis [7],
acid catalysis [8], microwave irradiation [9], photocatalysis [10]
and Lewis base activation [11]. However, carbon–chalcogen bond
formation via fragmentation of cycloketone oxime esters has not
been widely studied (Scheme 1). In 2005, Nishimura and Uemura
reported Ir-catalysed ring cleavage of cycloketone oxime esters
with diphenyl dichalcogenides to synthesize three phenyl alkyl
chalcogenides [12]. In 2019, Zhou and coworkers reported a photo-
catalytic sp3 CAS and C–Se bond formation through CAC bond
cleavage of cycloketone oxime esters [13]. Wang and Ji reported
Cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime (4a) was
treated with 1,2-di-p-tolyldisulfane (5a) in N,N-dimethylac-
etamide (DMA) at 120 °C [15]. Fortunately, the desired thiolation
product 6aa was obtained in 56% yield (Table 1, entry 1). To further
improve the yield, first, various solvents such as N,N-dimethylfor-
mamide (DMF), dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidi-
none (NMP), toluene, acetonitrile (MeCN), and butyronitrile (PrCN)
(Table 1, entries 2–7) were investigated, among which PrCN
afforded the highest yield. Next, the reaction temperature was
investigated. When the reaction temperature was decreased to
100 °C, no reaction took place. However, when the reaction tem-
perature was increased to 140 °C, the yield improved to 75% (en-
tries 8 and 9). Finally, the reaction concentration and the leaving
groups were studied. When the concentration of 4a was increased
from 0.1 to 0.2 M, the yield increased from 75% to 77% (entry 10).
E-mail address: hxxyzhx@mail.tjnu.edu.cn (X. Zhao)
https://doi.org/10.1016/j.tetlet.2021.153202
0040-4039/Ó 2021 Published by Elsevier Ltd.

L. Ji, J. Qiao, J. Liu et al.
Tetrahedron Letters 75 (2021) 153202
zoic ester was employed, trace product and 72% yield of the pro-
duct was obtained respectively. Thus, the optimised reaction
conditions for thiolation of 4a were as follows: 4a (0.30 mmol),
5a (0.36 mmol), and PrCN (1.5 mL) at 140 °C.
With the optimised reaction conditions in hand, the reaction
scope was investigated with various disulfides and 4a; the results
are presented in Scheme 2. Phenyl disulfide bearing electron-
donating or electron-withdrawing substituents in para-, meta-, or
ortho-positions were well tolerated and afforded the desired prod-
ucts (6ab–6ak). Moreover, 1,2-di(naphthalen-2-yl)disulfane (5 l)
and 1,2-di(thiophen-2-yl)disulfane (5 m) could afford the respec-
tive products 6al and 6am in good yields.
Next, a series of cycloketone oxime esters and aryl disulfides
were tested under the optimised conditions. The results are sum-
marised in Scheme 3. 3-Phenyl cyclobutanone oxime ester (4b)
and 3-aryl cyclobutanone oxime esters with para- or meta-substi-
tution on the phenyl ring (4c–4f) were compatible with this trans-
formation and furnished the desired products (6ba–6fa). In
addition, 3-ethoxycarbonyl-, 3-((tert-butoxycarbonyl)amino)-, 3-
benzyloxy-, and 3-methyl-3-phenyl-substituted cyclobutanone
oxime esters (4g–4j) as well as Boc-protected 7-azaspiro[3.5]
nonan-2-one oxime ester (4k), Boc-protected azetidin-3-one
oxime ester (4l), and oxetan-3-one oxime ester (4m) were treated
with 5a and were found to afford the desired products (6ga–6ma)
in moderate to good yields. Notably, when 2-benzyl-substituted
cyclobutanone oxime was used, its perfluorobenzoic ester instead
of 4-(trifluoromethyl)benzoic ester was employed, which afforded
the desired product (6na) in 41% yield. Moreover, other function-
alised nitriles (6bh–6lh) could be prepared from the corresponding
cycloketone oxime esters and aryl disulfides under the optimised
reaction conditions. However, when cyclopentanone O-(4-(trifluo-
romethyl)benzoyl) oxime was employed as substrate, the desired
product 6oa was obtained in low yield.
Fig. 1. Representative organochalcogen compounds with diverse functions.
n-PrCN
To further broaden the substrate scope of this reaction, cycloke-
tone oxime esters (4a, 4b, 4c, 4e, 4h, 4i, 4k, and 4m) were coupled
with aryl diselenides (7a–7f) and phenyl ditelluride (7g). The
results are shown in Scheme 4. In all cases, the desired phenyl alkyl
selenides (8aa–8af) and phenyl alkyl tellurides (8ag–8eg) were
obtained in moderate to good yields.
Scheme 1. Carbon-chalcogen bonds formation via fragmentation of cycloketone
oxime esters.
A plausible mechanism for chalcogenation is proposed on the
basis of the aforementioned results and related literature [9]
(Scheme 5). Initially, pyrolysis of cyclobutanone oxime esters 4a
However, further increasing the reaction concentration decreased
the yield (entry 11). Notably, when 3, 5-(ditrifluoromethyl)benzoic
ester and perfluorobenzoic ester instead of 4-(trifluoromethyl)ben-
Table 1
Reaction Optimizationa.
Entry
Solvent (mL)
Temperature (°C)
Reaction time (h)
Yield (%)
1
2
3
4
5
6
7
8
DMA (3.0 mL)
DMF (3.0 mL)
DMSO (3.0 mL)
NMP (3.0 mL)
Toluene (3.0 mL))
MeCN (3.0 mL)
PrCN (3.0 mL)
PrCN (3.0 mL)
PrCN (3.0 mL)
n-PrCN (1.5 mL)
PrCN (0.5 mL)
PrCN (0.5 mL)
PrCN (0.5 mL)
120
120
120
120
120
120
120
100
140
140
140
140
140
12
12
12
12
12
12
12
19
19
19
19
19
19
56
39
trace
trace
trace
58
72
N.R.
75
9
10
11
12
13
77
68
traceb
72c
a
b
c
Reaction conditions: 4a (0.30 mmol), 5a (0.36 mmol) in solvent (0.5–3.0 mL) at indicated temperature for 12–19 h, Ar = 4-(trifluoromethyl)phenyl.
Ar = 3, 5-(di trifluoromethyl)phenyl.
Ar = perfluorophenyl.
2

L. Ji, J. Qiao, J. Liu et al.
Tetrahedron Letters 75 (2021) 153202
n-PrCN
Scheme 2. Substrate Scope for thiolation of 4a.
n-PrCN
n-PrCN
Scheme 4. Scope for chalcogenation of cyclobutanone oxime esters.
Scheme 5. Plausible mechanism for chalcogenation of cyclobutanone oxime esters.
n-PrCN
Scheme 3. Scope for thiolation of cyclobutanone oxime esters.
Scheme 6. Scale up of the thiolation reaction.
(Scheme 6). To our delight, the desired product 6aa was obtained
in 66% yield.
leads to the generation of 4-(trifluoromethyl)benzoate radical 9
and iminyl radical 10, which is converted to cyanoalkyl radical
11 via
a ring-opening process. Intermediate 11 reacts with
dichalcogenide 12 to afford the chalcogenation product (13) and
sulfur radical (14). Finally, single electron transfer between 14
and 8 affords salt 15.
Finally, to illustrate the possible practical application of this
transformation, a gram-scale thiolation of 4a was conducted
Conclusion
We conducted the metal-free chalcogenation of cycloketone
oxime esters with dichalcogenides via a radical process for the first
time. The metal-free condition and the readily accessible
3

L. Ji, J. Qiao, J. Liu et al.
Tetrahedron Letters 75 (2021) 153202
[7] (a) Y. Wei, N. Yoshikai For selected examples J. Am. Chem. Soc. 135 (2013)
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dichalcogenides make this method an alternative and green strat-
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synthesis of other chalcogen-substituted allyl nitriles from
cycloketone oxime esters by this strategy is underway in our labo-
ratory, and the results will be reported in due time.
(b) H.M. Ko, G. Dong, Nat. Chem. 6 (2014) 739–744;
(c) F. Juliá-Hernández, A. Ziadi, A. Nishimura, R. Martin, Angew. Chem. Int. Ed.
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Declaration of Competing Interest
(h) J.-F. Zhao, X.-H. Duan, Y.-R. Gu, P. Gao, L.-N. Guo, Org. Lett. 20 (2018) 4614–
4617;
(i) X.-Y. Yu, J. Chen, H.-W. Chen, W.-J. Xiao, J.-R. Chen, Org. Lett. 22 (2020)
2333–2338.
We declare that we have no financial and personal relationships
with other people or organizations that can inappropriately influ-
ence our work. There is no professional or other personal interest
of any nature or kind in any product, service and/or company that
could be construed as influencing the position presented in, or the
review of, the manuscript entitled.
[8] Z. Yin, J. Rabeah, A. Brückner, X.-F. Zhiping Yin Zhiping Yin Leibniz-Institut für
Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059
Rostock, Germany. Wu, ACS Catal. 8 (2018) 10926-12930.
[9] M.M. Jackman, S. Im, S.R. Bohman, C.C.L. Lo, A.L. Garrity, S.L. Castle, Chem.–Eur.
J. 24 (2018) 594–598.
[10] (a) L. Li, H. Chen, M. Mei, L. Zhou For selected examples Chem. Commun. 53
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Acknowledgements
(b) S. Yao, K. Zhang, Q.-Q. Zhou, Y. Zhao, D.-Q. Shi, W.-J. Xiao, Chem. Commun.
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(c) P.-Z. Wang, X.-Y. Yu, C.-Y. Li, B.-Q. He, J.-R. Chen, W.-J. Xiao, Chem.
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(d) X.-Y. Yu, P.-Z. Wang, D.-M. Yan, B. Lu, J.-R. Chen, W.-J. Xiao, Adv. Synth.
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The authors sincerely thank the financial support from National
Natural Science Foundation of China (Grant 22077095) and Natural
Science Foundation of Tianjin City (Grant 18JCQNJC76600).
(e) X.-Y. Yu, J.-R. Chen, P.-Z. Wang, M.-N. Yang, D. Liang, W.-J. Xiao, Angew.
Chem. Int. Ed. 57 (2018) 738–743;
(f) B. Zhao, C. Chen, J. Lv, Z. Li, Y. Yuan, Z. Shi, Org. Chem. Front. 5 (2018) 2719–
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(g) X. Shen, J.-J. Zhao, S. Yu, Org. Lett. 20 (2018) 5523–5527;
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153202.
[11] J.-J. Zhang, X.-H. Duan, Y. Wu, J.-C. Yang, L.-N. Guo, Chem. Sci. 10 (2019) 161–
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