Accepted Article

Title: Electrochemical synthesis of spiro[4.5]trienones through radical-

initiated dearomative spirocyclization

Authors: Jiawei Hua, Zheng Fang, Mixue Bian, Tao Ma, Man Yang, Jia
Xu, ChengKou Liu, Wei He, Ning Zhu, Zhao Yang, and Kai
Guo

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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
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.

To be cited as: ChemSusChem 10.1002/cssc.202000098

Link to VoR: http://dx.doi.org/10.1002/cssc.202000098

A Journal of

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ChemSusChem 10.1002/cssc.202000098

FULL PAPER
Electrochemical synthesis of spiro[4.5]trienones through radical-
initiated dearomative spirocyclization
Jiawei Hua,[a] Zheng Fang,[a] Mixue Bian,[a] Tao Ma,[a] Man Yang,[a] Jia Xu,[a] ChengKou Liu,[a] Wei He,[a]
Ning Zhu,[a] Zhao Yang,[b] Kai Guo*[a][c]
[a] J. Hua, J. Xu, J. Xu, B. Zhou, D. Zhang, Z. Yang, Prof. Z. Fang, and Prof. K. Guo
Department: College of Biotechnology and Pharmaceutical Engineering
Institution: Nanjing Tech University
Address 1: 30 Puzhu Rd S., Nanjing 211816, China
E-mail: guok@njtech.edu.cn
[b] Z. Yang
Department: College of Engineering

Accepted Manuscript
Institution: China Pharmaceutical University
Address 2: 24 Tongjiaxiang, Nanjing, 210003, China
[c] K. Guo
Department; State Key Laboratory of Materials-Oriented Chemical
Engineering
Institution: Nanjing Tech University
Address 3: 30 Puzhu Rd S., Nanjing 211816, China

Supporting information for this article is given via a link at the end of the document.

Abstract: A novel and green route has been developed for the
electrochemical synthesis of spiro[4.5]trienones through radical-
initiated dearomative spirocyclization of alkynes with diselenides.
This metal-free and oxidant-free electrosynthesis reaction was
performed in an undivided cell under mild conditions. And a variety
of selenation spiro[4.5]trienones products were prepared in
moderate to good yields bearing a broad scope and functional group
tolerance. Moreover, the continuous-flow system combined with
electrosynthesis possesses the potential to achieve scale-up
reaction, overcoming the low-efficiency of conventional
electrochemical scale-up reaction.
Introduction
Spirocarbocycles serve as one class of fundamental framework
widely found in numerous diverse natural products and
pharmacologically active molecules.[1] Among the various
spirocarbocycles, spiro[4.5]trienones draw continuous attention
from chemistry researchers due to the unique structural
characteristics and biological activities.[2] In particular,
dearomatization reactions are recognized as the common
strategy to construct different spiro[4.5]trienones from the
related functionalized phenols and alkoxyarenes. Several
examples reported valuable approaches to prepare the
spiro[4.5]trienones compounds by using electrophilic
halogenating reagents to achieve dearomative halo-
Despite the remarkable progress, these methods are always
restricted to take the expensive metal as the crucial catalyst.
Therefore, the development of green and efficient alternatives
for dearomative spirocyclization is highly desirable.
Organoselenium compounds are significant skeletons with
excellent biological and chemical properties, which are the key
intermediates in organic synthesis.[5] Additionally, the potential
application of organoselenium compounds in the field of
medicinal chemistry and material science has been
demonstrated. [6] Therefore, many efforts have been devoted for
the synthesis of more valuable organoselenides.[7] Particularly,
selenium-mediated radical cascade reactions with unsaturated
compounds (alkenes, alkynes or allenes) are common protocols
for preparing these compounds. [8] Similarly, the generation of
spiro[4.5]trienones involves multiple collaborative steps, which
could be initiated by radical cascade reaction and then undergo
concomitant dearomatization and spirocyclization. In this regard,
we proposed an assumption that spiro[4.5]trienones could be
formed through radical cascade reaction with diselenides as
selenium radical precursors.
Scheme 1. Electrochemical synthesis of spiro[4.5]trienones.

spirocyclization.[3] However, these methods still suffer from some

obvious drawbacks, such as the harsh reaction conditions, the
safety and environmental issues caused by the demand of
oxidants and bases. Recently, gold catalysis has proven the
great capacity to build cyclic molecular skeletons including
spirocarbocycles. The groups of Hamada, You, Vadola and Patil
independently developed Au-catalyzed dearomatized
spirocyclization of phenols or p-methoxyaryl ring to the
spirocarbocycles compounds.[4a-e] Moreover, some significant
metals (Pd, Sn, Cu, Ag) have been demonstrated as efficient
protocols for constructing valuable spirocarbocycles.[4f-h]
In the recent years, organic electrochemistry has become a
research hotspot in the field of synthetic chemistry, [9] which is
accord with the development of current green chemistry. As a
reliable alternative for redox reagents, electrochemistry has
been recognized as an environmental friendly and economy tool,
employing electrons to promote chemical reactions. [10] According
to the slight parameter adjustment of applied electromotive force,
the reactivity of substrates could be precisely controlled.
Significant progress has been made by merging electrosynthesis

1
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ChemSusChem 10.1002/cssc.202000098

FULL PAPER

with radical cascade reactions and dehydrogenation cross
coupling reactions. [11] Inspired by this great breakthrough, the
spirocycle formation could be fulfilled in the electrochemical
environment. In our previous work,[12] ortho-cyclization of
alkynoates and alkynamides with diselenides has been
established under electrochemical oxidation conditions. It is
selectively switchable towards ipso-cyclization when substrates
bearing para-OMe substitutents on O-aryl or N-aryl ring were
employed. As a part of our continuous interest in the formation
of C-Se bond, herein, we report a direct selenation of alkynes to
achieve dearomative spirocyclization through electrochemical
oxidation under metal-free and oxidant-free conditions (Scheme
1).
graphite anode and a platinum cathode. Different solvents were
firstly examined with nBu4NPF6 (2) as the electrolyte at a
constant current of 15 mA, and 84% yield of the desired product
3a was obtained in CH3 CN/HFIP (v/v = 3/1) (Table 1, entry 5).
Inspired by the above phenomenon, a series of mixed solvents
were screened (Table S1, see supporting information). The
results disclosed that the cosolvent of CH3 CN/HFIP (v/v = 3/1)
might be a better choice. To some degree, HFIP could
effectively improve the stability of radical intermediates, which
attribute to its special low-nucleophilicity and protic nature. [13]
Moreover, the effect of various electrolytes was also investigated.
However, the other electrolytes such as nBu4 NBF4, nBu4 NI,
n
Bu4NOAc, Et4NClO4, and NaI could not improve the yield of

Accepted Manuscript
product 3a (Table 1, entries 6-10). Either decreasing or
increasing the equivalent of nBu4NPF6 led to the lower
Results and Discussion transformation (Table 1, entries 11-14). Further exploration
focused on electrochemical parameters, the reaction failed to
proceed without the applied constant current (Table 1, entry 15).
[a]
Table 1. Optimization of reaction conditions . Compared to the reaction condition of 15 mA, the reaction
conditions of 5mA, 10mA and 20mA all resulted in a lower
conversion (Table 1, entries 16-18). Meanwhile, adjustment of
the equivalent of diphenyl diselenide 2a could not improve
reaction efficiency as well (Table 1, entries 19 and 20).
Furthermore, the substituent group on oxygen atom not merely
Entry Solvent Electrolyte I (mA) Yieldb limited to Methyl, the substrates (1b and 1c) with t-butyl and
(equiv.) (%) benzyl also performed well to give the product 3a in 80% and 76%
n
1 CH3CN Bu4NPF6 (2) 15 52 yields, respectively (Table 1, entries 21 and 22). Finally, the
n
2 DCE Bu4NPF6 (2) 15 21 molecular structure of 3a was identified by single crystal X-ray
n diffraction (CCDC 1971226, Figure S1, see supporting
3 DMF Bu4NPF6 (2) 15 18
n information).
4 HFIP Bu4NPF6 (2) 15 61
n
5 CH3CN/HFIP (3/1) Bu4NPF6 (2) 15 84
n
6 CH3CN/HFIP (3/1) Bu4NBF4 (2) 15 76
n Table 2. Substrate scope of electrochemical oxidative spirocyclization of
7 CH3CN/HFIP (3/1) Bu4NI (2) 15 0 alkynoates with diselenides and ditellurides
[a,b,c]
.
n
8 CH3CN/HFIP (3/1) Bu4NOAc (2) 15 0
9 CH3CN/HFIP (3/1) Et4NClO4 (2) 15 80
10 CH3CN/HFIP (3/1) NaI (2) 15 0
n
11 CH3CN/HFIP (3/1) Bu4NPF6 15 70
(0.5)
n
12 CH3CN/HFIP (3/1) Bu4NPF6 (1) 15 76
n
13 CH3CN/HFIP (3/1) Bu4NPF6 15 80
(1.5)
n
14 CH3CN/HFIP (3/1) Bu4NPF6 (3) 15 81
n
15 CH3CN/HFIP (3/1) Bu4NPF6 (2) 0 0
n
16 CH3CN/HFIP (3/1) Bu4NPF6 (2) 5 54
n
17 CH3CN/HFIP (3/1) Bu4NPF6 (2) 10 68
n
18 CH3CN/HFIP (3/1) Bu4NPF6 (2) 20 78
n
19 CH3CN/HFIP (3/1) Bu4NPF6 (2) 15 59c
n
20 CH3CN/HFIP (3/1) Bu4NPF6 (2) 15 77d
n
21 CH3CN/HFIP (3/1) Bu4NPF6 (2) 15 80e
n
22 CH3CN/HFIP (3/1) Bu4NPF6 (2) 15 76f
[a] Reaction conditions: Pt plate cathode (15 mm × 15 mm × 0.1 mm) cathode,
graphite rod anode (Φ 6 mm), 1a (0.5 mmol, R = Me), 2a (0.5 mmol), solvent
(10 mL), electrolyte, constant current, 2 h, room temperature, undivided cell.
[b] Isolated yield. [c] 0.5 equiv. of 2a. [d] 1.5 equiv. of 2a. [e] 1b (R= t-Bu). [f]
1c (R = Bn).

At the outset of our study, the electrochemical oxidative

spirocyclization of 4-methoxyphenyl 3-phenylpropiolate 1a and
diphenyl diselenide 2a was chosen as the model reaction to
generate 3-selenated spiro[4.5]trienones 3a by utilizing a

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ChemSusChem
FULL PAPER
[a] Reaction conditions: Pt plate cathode (15 mm × 15 mm × 0.1 mm) cathode,
n
graphite rod anode (Φ 6 mm), 1 (0.5 mmol), 2 (0.5 mmol), Bu4NPF6 (1 mmol),
CH3CN/HFIP (v/v = 3/1, 10 mL), constant current = 15mA, 2 h (2.2 F/mol),
room temperature, undivided cell. [b] Isolated yield. [c] CH3CN/HFIP (v/v = 1/1,
10 mL).
With the optimal reaction conditions in hand, the substrate scope
and generality of dearomative spirocyclization of alkynoates 1
with diselenides 2 was investigated (Table 2). To our delight, the
reaction of 4-methoxy alkynoates 1 bearing both ortho-
substituents (Me, t-Bu, Cl, Br Ac) and meta-substituents (OMe, F,
Cl, Br) proceeded smoothly under the standard electrochemical
reaction conditions (Table 2, 3b-3j). Next, the substrates with
electron-donating or electron-withdrawing substituents attached
on the alkyne showed great compatibility to prepare the
corresponding products in high yields ranging from 74% to 85%
(Table 2, 3l-3t). However, the substrate 1k containing terminal
alkyne failed to produce the desired product 3k under the
optimized reaction conditions. A variety of diselenides including
alkyl diselenides and aryl diselenides tolerated well to give the
spirocyclization products in 77-85% yields (Table 2, 3u-3z, 3aa-
3ab). Similarly reaction works for 1-naphthyl alkynoates to
generate the product 3ac in 81% yields. Notably, diphenyl
ditelluride was successfully suitable for this strategy to afford the
tellurium- substituted spiro[4.5]trienones (Table 2, 3ad).
Unfortunately, no desired product was detected when diphenyl
disulfide reacted with 1a (Table 2, 3ae).
Table 3. Substrate scope of electrochemical oxidative spirocyclization of
[a,b]
alkynamides with diselenides and ditellurides .
[a] Pt plate cathode (15 mm × 15 mm × 0.1 mm) cathode, graphite rod anode
n
(Φ 6 mm), 4 (0.5 mmol), 2 (0.5 mmol), Bu4NPF6 (1 mmol), CH3CN/HFIP (v/v =
3/1, 10 mL), constant current = 15mA, 2 h (2.2 F/mol), room temperature,
undivided cell. [b] Isolated yield.
This article is protected by copyright. All rights reserved.
10.1002/cssc.202000098
Subsequently, we turned our attention to explore the substrate
scope of electrochemical spirocyclization of alkynamides 4. As
shown in Table 3, the N-methyl, N-phenyl, N-benzyl and N-H
substituted alkynamides showed great tolerance to offer the
products in moderate to good yields ranging from 50% to 86%
yields (Table 3, 5a-5d). The substrates which contain
substituents attached to alkynes all worked well except 4e under
the optimized reaction conditions (Table 3, 5e-5m). Besides,
both dialkyl diselenides and diaryl diselenides were subjected to
the standard conditions, affording the expected
azaspiro[4,5]trienones products in reasonable yields (Table 3,
5n-5s). The reaction of alkynamide with ditelluride was also
tested, which is suitable for this electrochemical transformation
Accepted Manuscript
to provide the product 5t in 61% yield.
In order to evaluate the practical application of this
electrochemical dearomative spirocyclization, the scale-up
reactions in batch were completed. As shown in Figure 1, the
results of scale-up reactions were unsatisfactory. Only 49% and
44% yields of product 3a were obtained in the case of 5mmol
and 10mmol scale-up reaction, which totally consumed 8h and
16h, respectively. Moreover, extending reaction time or
increasing current intensity would result in the consumption of
substrates and products. Electrochemical continuous flow
system could solve the above problem well, because of some
benefits such as the small interelectrode gap, the large electrode
surface to reactor volume ratio and the efficient mass transfer. [14]
Meanwhile, electrochemical continuous flow system is capable
to realize precise control and keep reaction system stable, which
is easy to perform scale-up reaction through prolonging reaction
time and the parallel amplification without changing the
parameters. Therefore, the attempt of oxidative spirocyclization
was treated in a flow electrochemistry system (the Asia Flux
module). And the screening of reaction conditions was
summarized in Table S2 (see supporting information). Due to
the fixed size and channel of the commercially available flow cell
and the restriction of flow rate and residence time, the optimized
results of 0.5 mmol scale reaction in flow cell were slightly
inferior to batch reactor (Figure 1). However, the great
performance of scale-up reaction in electrochemical continuous
flow system is still worthy of expectation. And 2.87g of product
3a was obtained in 73% yield consuming nearly 15h on the
10mmol scale, which is superior to the batch reactor.
Furthermore, the derivatization of product 3a was also
conducted (Scheme 2). The product 3a was oxidized to
generate selenoxides 6a in the presence of m-CPBA.
To further understand the mechanism of this method, the control
experiments were subsquently carried out (Scheme 3). The
reaction of 1a were performed under the standard conditions in
the absence of 2a, but the spirocyclization product 7 were not
detected (Scheme 3a). The result indicated that the compound 7
might not be the pivotal intermediate in this reaction system.
Moreover, no desired product was observed by adding 3 equiv.
radical scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
and 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 3b). In
addition, cyclic voltammetry (CV) experiments were carried out
to analyze the redox potential of the substrates. As depicted in
Figure 2, the obvious oxidation peaks of diphenyl diselenide,
diphenyl disulfide and diphenyl ditelluride were appeared at
1.95V, 1.68V and 0.92V, respectively, while the oxidation peak
of substrate 1a was appeared at 2.10 V. This phenomenon
ChemSusChem 10.1002/cssc.202000098

FULL PAPER

declared that diphenyl diselenide, diphenyl disulfide and

diphenyl ditelluride are oxidized preferentially at the anode.

Accepted Manuscript
100
in batch
84 in flow
80
72 73
Yield of 3a (%)

60
49 Scheme 4. Plausible mechanism.
44
40

20
Based on the above results and previous literature, [15] a possible
0
0.5 2 5 10 0.5
reaction mechanism for the electrochemical transformation is
Scale (mmol) proposed in Scheme 4. Diphenyl diselenide 2a is firstly oxidized
to give the cationic radical intermediate A, which is later
decomposed to generate phenylselenium radical B and phenyl
Figure 1. Comparison of yields of 3a in batch and flow.
selenium cation C. Then phenylselenium radical B reacts with
1a to produce vinyl radical D via radical addition of the C–C
triple bond. Due to the relative stability of the resonant free
radical and the five-membered ring structure, vinyl radical D
tends to perform the intramolecular spirocyclization to provide E,
which is obviously different from our earlier work. [12] And
intermediate E undergoes further oxidation at the anode to
Scheme 2. Derivatization of product 3a. afford oxygenium cation intermediate F. Finally, the product 3a
was generated through the demethylation of cation F and the
dearomatization of aromatic ring (path a). Alternatively, we
cannot rule out the possibility that phenyl selenium cation C
reacts with 1a to form the intermediate G. Subsequently,
intramolecular nucleophilic attack of electron-rich aromatic ring
on the cyclic selenium cation to give intermediate F, which
undergo the demethylation to generate the product 3a (path b).

Conclusion
Scheme 3. Control experiments.
In summary, we have developed a practical and green
dearomative spirocyclization of alkynes with diselenides through
a direct constant current electrolysis under metal-free and
Blank
oxidant-free conditions. A series of selenation
0.00002
1a
PhSeSePh
spiro[4.5]trienones were provided in moderate to good yields,
0.00000
PhTeTePh
PhSSPh which shows great universality and compatibility of this method.
-0.00002
Moreover, with the help of electrochemical continuous flow
-0.00004
system, the scale up reaction was successfully conducted,
-0.00006
Current (A)

proving the bright future of the combination electrochemistry and

-0.00008
flow chemistry. Further research about electrochemical oxidative
-0.00010
cyclization combining continuous flow system is undergoing in
-0.00012
our laboratory.
-0.00014

-0.00016

-0.00018
0.0 0.5 1.0 1.5 2.0 2.5 Experimental Section
Potential (V)

General procedure for the synthesis of product 3

Figure 2. Cyclic voltammograms of substrates.
4

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ChemSusChem
FULL PAPER
A 50 mL vial was charged with substrate 1 (0.5 mmol), 2 (0.5 mmol,
1.0equiv.), nBu4NPF6 (1.0 mmol, 2equiv.), CH3CN/HFIP (10 mL, v/v =
3/1) and a magnetic stir bar. The vial was equipped with platinum
electrodes (1.5 cm×1.5 cm×0.1 mm) as cathode, graphite rod (Φ 6 mm)
as the anode. The whole cell was undivided cell. The reaction mixture
was stirred and electrolyzed at a constant current of 15mA at room
temperature for 2 hours (2.2 F). After completing reaction, it was
monitored with TLC. The solvent was removed with a rotary evaporator.
The pure product 3 was obtained by flash chromatography on silica gel
using petroleum ether and ethyl acetate as the eluent.
General procedure for the synthesis of product 5
A 50 mL vial was charged with substrate 4 (0.5 mmol), 2 (0.5 mmol,
1.0equiv.), nBu4NPF6 (1.0 mmol, 2equiv.), CH3CN/HFIP (10 mL, v/v =
3/1) and a magnetic stir bar. The vial was equipped with platinum
electrodes (1.5 cm×1.5 cm×0.1 mm) as cathode, graphite rod (Φ 6 mm)
as the anode. The whole cell was undivided cell. The reaction mixture
was stirred and electrolyzed at a constant current of 15mA at room
temperature for 2 hours (2.2 F). After completing reaction, it was
monitored with TLC. The solvent was removed with a rotary evaporator.
The pure product 5 was obtained by flash chromatography on silica gel
using petroleum ether and ethyl acetate as the eluent.
Acknowledgements
The research was supported by the National Key Research and
Development Program of China (2016YFB0301501), the
National Science Foundation of China (Grant No. 21776130 &
21878145), the Jiangsu Synergetic Innovation Center for
Advanced Bio-Manufacture (No. X1821 and X1802) and
Postgraduate Research & Practice Innovation Program of
Jiangsu Province.
Keywords: Electrochemical • spiro[4.5]trienones • dearomative
spirocyclization • metal-free • oxidant-free
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Entry for the Table of Contents

A direct selenation of alkynes to achieve dearomative spirocyclization through electrochemical oxidation under metal-free and
oxidant-free conditions has been developed. A series of selenation spiro[4.5]trienones were provided in moderate to good yields,
which shows great universality and compatibility of this method. Moreover, the continuous-flow system combined with

Accepted Manuscript
electrosynthesis possesses the potential to achieve scale-up reaction, overcoming the low-efficiency of conventional electrochemical
scale-up reaction.

7
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