Visible-light-induced formation of thiavinyl 1,3-dipoles: A metal-free [3+2] oxidative cyclization with alkynes as easy access to thiophenes

Article abstract of DOI:10.1021/acs.orglett.1c00915

A visible-light-induced [3+2] oxidative cyclization of various alkynes with easily available ketene dithioacetals as the previously unknown thiavinyl 1,3-dipoles in the presence of an acridine photosensitizer is reported. A series of multisubstituted thiophenes were achieved regioselectively in ≤98% yields under very mild metal-free conditions without other additives. This reaction could tolerate a wide range of substrates and achieve good efficiency in large-scale syntheses. The reaction mechanism and their applications are described in detail to reveal the reactivity of the new 1,3-dipoles and the selectivity of the reactions.

Full text of DOI:10.1021/acs.orglett.1c00915

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Letter
Visible-Light-Induced Formation of Thiavinyl 1,3-Dipoles: A Metal-
Free [3+2] Oxidative Cyclization with Alkynes as Easy Access to
Thiophenes
Baihui Zheng, Xiaotong Li, Yang Song, Shuyang Meng, Yifei Li, Qun Liu, and Ling Pan*
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ABSTRACT: A visible-light-induced [3+2] oxidative cyclization of various alkynes with easily available ketene dithioacetals as the
previously unknown thiavinyl 1,3-dipoles in the presence of an acridine photosensitizer is reported. A series of multisubstituted
thiophenes were achieved regioselectively in ≤98% yields under very mild metal-free conditions without other additives. This
reaction could tolerate a wide range of substrates and achieve good efficiency in large-scale syntheses. The reaction mechanism and
their applications are described in detail to reveal the reactivity of the new 1,3-dipoles and the selectivity of the reactions.
could provide clean and inexpensive energy sources and green
catalytic environments.37,38 With the aid of photosensi-
tizers,39−41 the substrates could be easily activated to active
radical cations similar to the transformations under electrolysis
mentioned above,22−26 without additional oxidants. As part of
our continuous efforts in the construction of carbo/
heterocyclic compounds from easily available ketene dithioa-
cetals,42−46 we envisioned that visible-light-induced cycliza-
tions of ketene dithioacetals with alkynes would lead to the
novel [3+2] heterocyclization via the previously unknown
thiavinyl 1,3-dipoles (Scheme 1b). To the best of our
knowledge, there have been few studies on the photoredox
reactions of ketene dithioacetals and the studies have been
limited to the coupling reactions with aryldiazonium salts47 or
alkenes48 or need an other photo-redox-active reactant.49
There have been few reports about the visible-light-mediated
synthesis of thiophenes,13−17,50−54 with some syntheses of
benzothiophenes from alkynes with o-methylthio-arene diazo-
nium salts or 2-halothioanisoles.55−57 We are glad to see that
our proposed [3+2] oxidative cylization of ketene dithioacetals
eterocyclizations are powerful tools for the synthesis of
1−4
Hfive-membered heterocycles
that are often found in
natural products5,6 and synthetic pharmaceuticals7−9 and
widely used in material science and organic synthesis.10−17
Recent studies revealed that oxidative heterocyclizations18−21
could evoke novel and useful catalytic transformations, which
otherwise are difficult to achieve. For example, the cyclization
of ketene dithioacetals,22−26 a kind of electron-rich olefin,
under electrochemical conditions afforded the cyclic amino
acid derivatives (Scheme 1a, X = NH).24 Similarly,
(+)-nemorensic acid (Scheme 1a, X = O),26 the necic acid
portion of the macropyrrolizidine alkaloid nemorensine could
also be achieved efficiently with the oxidative intramolecular
cyclization mentioned above as the key step. In these
heterocyclizations, the electron-rich ketene dithioacetal moi-
eties of substrates were activated by losing an electron under
electrolysis to generate the corresponding electrophilic radical
cation, which further initiates the intramolecular cyclization.
Clearly, these transformations efficiently avoid using additional
oxidant or transition-metal catalysis, and more importantly, the
polarity of the α-carbon atom on the ketene dithioacetal
moiety can be reversed. However, considering the difficulty in
restraining side reactions, and the limitation of substrates,
more simple and efficient synthons and methods are strongly
desired for the heterocyclization reactions.
Received: March 16, 2021
Published: April 21, 2021
In recent years, visible-light-promoted transformations
proved to be efficient in organic synthesis27−36 because they
https://doi.org/10.1021/acs.orglett.1c00915
© 2021 American Chemical Society
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a
Scheme 1. Oxidative Cyclizations
Table 1. Optimization of Reaction Conditions
b
entry
1a:2a
catalyst (mol %)
solvent
t (h) yield (%)
1
2
3
4
5
6
7
8
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
2:1
Ps-A (3)
Ps-B (3)
Ps-C (3)
Ru(bpy)3Cl2 (3)
Ir(ppy)3 (3)
Ps-B (5)
Ps-B (5)
Ps-B (5)
Ps-B (5)
Ps-B (5)
Ps-B (5)
Ps-B (5)
Ps-B (5)
−
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
THF
EtOH
DCE
DCE
DCE
24
24
24
24
24
24
24
24
24
36
36
36
36
36
36
36
45
58
12
c
NR
NR
c
70
84
90
64
94
2.5:1
1:2
9
10
11
12
13
14
2.5:1
2.5:1
2.5:1
2.5:1
2.5:1
2.5:1
2.5:1
49
14
trace
trace
and alkynes (Scheme 1b) could proceed smoothly under
extremely simple and mild reaction conditions without using
base, acid or oxidants.58−60 Clearly, α-acyl ketene dithioacetals
were activated by visible light to form a previously unknown
thiavinyl 1,3-dipole intermediate that thus initiates this [3+2]
cyclization.
d
c
15
16
Ps-B (5)
Ps-B (5)
NR
e
f
NO
a
Reaction conditions: 1a or 2a (0.3 mmol scale), solvent (2 mL).
b
c
d
e
Isolated yields. No reaction was observed. Without light. TEMPO
f
(1.0 equiv) was added. No 3a was observed.
First, the catalytic construction of multisubstituted thio-
phenes was investigated by the reaction of α,α′-diacetyl ketene
dithioacetal 1a with phenylacetylene 2a in the presence of an
acridine photosensitizer without any other additives under blue
light-emitting diode (LED) irradiation (Table 1). Multi-
substituted thiophene 3a (see the single-crystal analysis of 3a
in the Supporting Information) was obtained in 45% isolated
ketene dithioacetal 1a with various alkynes 2 showed excellent
tolerance to alkynes. The reactions of para-substituted arynes 2
bearing either electron-donating (2b−g) or electron-with-
drawing substituents (2h−j) on the benzene ring afforded
thiophenes 3b−j in good to excellent yields. Moreover, 4-
trifluoromethyl-substituted aryne 2k could also give the desired
3k. In addition, ortho-, meta-, or disubstituted arynes 2l−p
reacted smoothly to furnish thiophenes 3l−p, respectively. The
reaction of 3,5-dimethoxy-substituted aryne 2q delivered the
desired product 3q in 14% yield. Furthermore, alkynes 2r−u
proved to be the suitable substrates for the [3+2] cyclization.
All of these reactions showed high regioselectivity for the
formation of multisubstituted thiophenes.
It was noticed that the reaction of 1,4-diethynylbenzene 2v
with 1a afforded the corresponding thiophene 3v in 45% yield
with one alkynyl group remaining even when 10 equiv of 2v
was added. The borate moiety and silyl substitution on the
benzene ring in 2w and 2x were tolerant to this reaction, giving
more opportunities for further transformations. Reactions of
enynes 2y and 2z and aliphilic alkyne 2aa with 1a could also
give the desired thiophenes 3y, 3z, and 3aa, respectively,
showing the broad tolerance of this [3+2] heterocyclization to
a wide variety of alkynes.
yield in the presence of Acr+-Mes ClO4 (Ps-A, 3 mol %) in
−
1,2-dichloroethane (DCE) at room temperature (entry 1). The
yield of 3a was increased to 58% when Acr+-Mes-Ph BF4− (Ps-
B, 3 mol %) was used as the photosensitizer (entry 2). An
obvious decrease in the yield of 3a was observed with Acr+-
Mes-Ph Cl− (Ps-C) as the photosensitizer (entry 3). No 3a
was observed when a photosensitizer like Ru(bpy)3Cl2 or
Ir(ppy)3 was applied (entry 4 or 5, respectively). 3a was
formed in a higher yield when the amount of Ps-B was
increased to 5 mol % (entry 6 vs entry 2). Then, the 1a/2a
ratio was investigated with 5 mol % Ps-B in DCE (entries 7−
9). With a 2.5/1 1a/2a ratio, 3a was obtained in 90% yield
(entry 8). We are glad to see that the yield of 3a was increased
to 94% when the reaction was performed for 36 h (entry 10).
The effect of solvents was also examined, and DCE proved to
be the optimal choice (entries 10−13). Furthermore, control
experiments showed that nearly no the desired product was
observed without the photosensitizer or in the dark (entries 14
and 15). When 1.0 equiv of TEMPO was added, product 3a
was not observed at all (entry 16).
Next, the reactivity of selected ketene dithioacetals 1 as the
thiavinyl 1,3-dipoles was investigated (Scheme 3). As a result,
phenylacetylene 2a could react with a wide variety of ketene
dithioacetals 1 under the optimal reaction conditions.
Multisubstituted thiophene 4c could be obtained in 90%
With the optimal reaction conditions (Table 1, entry 10) in
hand, the generality of this catalytic [3+2] oxidative cyclization
was investigated. As shown in Scheme 2, the reactions of
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bearing para-, meta-, ortho-, and multisubstituted aroyls (1b,
1c, 1e−m) furnished thiophenes 4a, 4b, 4d−l, respectively, in
good to excellent yields. Reactions of 2a with heteroaroyl- and
2-naphthoyl-substituted ketene dithioacetals (1n−p) proved to
be efficient in affording the desired products 4m−o in high
yields. It was observed that various R1 or R2 groups on ketene
dithioacetals were tolerant to this reaction, and multi-
substituted thiophenes 4p−t were produced smoothly from
the reaction of α-symmetrically- or unsymmetrically sub-
stituted ketene dithioacetals 1 with 2a. The structures of
products 4b, 4c, 4e, 4m, 4s, and 4t were further confirmed by
HMBC analysis (see the Supporting Information). It was
deduced that the acetyl group is easier to transfer than the
benzoyl group to the sulfur atom, and both of them are faster
than the ester group. 3-Cyano-substituted thiophene 4u (see
the single-crystal analysis of 4u in the Supporting Information)
could also be obtained in 52% yield, although 10 equiv of 1v
was required. Fortunately, the trifluoromethyl group, which
often shows special properties in organic reactions, could also
be tolerant to this reaction, providing trifluoromethylated
thiophene 4v in 59% yield.
Scheme 2. Synthesis of Multisubstituted Thiophenes from
Ketene Dithioacetal 1a and Alkynes 2
To verify the practicality of this novel [3+2] oxidative
cyclization, the scaled-up synthesis of 3n was run (Scheme 4).
Scheme 4. Scaled-Up Synthesis of Polysubstituted
Thiophenes 3n
a
b
With 10 mol % Ps-B. With 3 equiv of 2aa.
Scheme 3. Synthesis of Multisubstituted Thiophenes from
Ketene Dithioacetals 1 and Phenylacetylene 2a
It was proved that 2.63 g of 3n was obtained in 86% yield on a
10 mmol scale of 1a with 2n. Considering the efficiency of the
solar synthesis, this catalytic transformation was also
performed under natural sunlight irradiation. As a result, 3n
was also obtained in 55% yield after reaction for 12 days.
To shed light on the reaction mechanism, a series of control
experiments were investigated (Figure 1; for details, see the
Supporting Information). First, the reactions of 1a and 2a were
investigated with the light off/on over a period of time under
the optimal reaction conditions. The reaction proceeded well
under visible light irradiation, but no further transformation
was observed without light irradiation (Figure 1a), indicating
the continuous irradiation of visible light is essential for this
catalytic reaction.61,62 Furthermore, the UV−vis absorption
spectra (Figure 1b) confirmed that Acr+-Mes-Ph BF4 (Ps-B)
−
is the best photosensitizer as the sole catalyst tested in this
[3+2] oxidative cyclization. The Stern−Volmer emission
quenching studies (Figure 1c) determined that polarized
ketene dithioacetals 1 more easily quench the excited
photosensitizer than alkynes do.
Furthermore, the resulting gaseous phases of the reactions
for 2a with ketene dithioacetals 1x−z bearing different 1,3-
dithiolane moieties were analyzed by GC-MS. To our delight,
propene, 2-butene, and styrene were clearly observed from the
related GC-MS spectra (see the Supporting Information),
a
With 10 equiv of ketene dithioacetal 1v.
yield from the reaction of α-benzoyl-α′-acetyl ketene
dithioacetal 1d with 2a. α-Aroyl-α′-acetyl ketene dithioacetals
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elucidate the proposed mechanism, the catching experiment
for intermediate I was performed by the addition of CuBr2 (1.0
equiv) under otherwise standard reaction conditions (Table 1,
entry 10). 2-Bromoethylthio-substituted thiophene 5 was
obtained in 47% yield, providing strong support for the
proposed catalytic [3+2] cyclization with ketene dithioacetals
1 as the previously unknown thiavinyl 1,3-dipoles (Scheme 5).
Then, the practicality of this catalytic synthesis of multi-
substituted thiophenes was further elucidated by the reaction
of 1a with alkyne-containing natural products. The reaction of
estrone 665,66 with 1a gave thiophene 7 in 69% yield with the
estrone moiety intact (Scheme 6a). The reaction of N-
Scheme 6. Applications for the Facile Synthesis of
Thiophenes
Figure 1. Mechanistic investigations. The yields in panel a were
1
calculated from the H NMR monitors with CH2Br2 as the internal
standard.
elucidating the release of one molecule of alkene from C(sp3)−
S bond cleavage during the transformations, which may
facilitate the final generation of the products.
On the basis of the experimental results, mechanistic studies
mentioned above (Schemes 2−4, Figure 1, and Table 1), and
related reports,63,64 a plausible catalytic mechanism for this
visible-light-induced synthesis of multisubstituted thiophenes 3
and 4 is proposed with the formation of 3a as an example
(Scheme 5). The photosensitizer is excited at first under blue
Scheme 5. Proposed Reaction Mechanism
protected erlotinib 867 with 1a could also proceed smoothly
using 10 mol % Ps-B under 40 W blue LED irradiation
(Scheme 6b). Furthermore, the transformations of the
multisubstituted thiophenes were tested. In the presence of
TiCl4 and Zn, the reduction of thiophene 3a gave 2,4-
disubstituted thiophenes 10, instead of the expected McMurry
cyclization product.68−70 In addition, thieno[2,3-b]thiophene
11 was achieved when 3a was treated with ethyl diazoacetate in
the presence of Cu(OTf)2 (Scheme 6c).14
In conclusion, a visible-light-induced catalytic [3+2]
oxidative cyclization of alkynes with ketene dithioacetals
under very mild metal-free conditions without using a base
or an oxidant was developed. We found that the easily available
ketene dithioacetals can be activated to form a thiavinyl 1,3-
dipole equivalent. The previously unknown thiavinyl 1,3-
dipole-triggered highly regioselective [3+2] cyclization pro-
vides a new access to multisubstituted thiophenes in ≤98%
yields. The reaction shows a wide tolerance to both ketene
dithioacetals and alkynes, including natural products. The
catalytic reaction mechanism is described in detail to reveal the
reactivity of the new 1,3-dipoles and the selectivity of the
reactions. Further investigation of the thiavinyl 1,3-dipole is in
progress.
LED (or sunlight) irradiation. Then, single-electron transfer
(SET) from ketene dithioacetal 1a to the excited state of the
photosensitizer leads to the formation of radical cation
intermediate 1a* acting as the electrophilic thiavinyl 1,3-
dipole equivalent, which undergoes [3+2] cyclization with
alkynes 2a to afford cyclic intermediate I in a regioselective
manner. The subsequent SET process between I and the
photosensitizer facilitates the cleavage of the C(sp3)−S bond
to form intermediate II, which releases a relatively stable small
molecule (ethylene) to form intermediate III. Finally, III
undergoes a sequential intramolecular nucleophilic acyl
transfer driven by aromatization to afford 3a. To further
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
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Corresponding Author
Ling Pan − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China; orcid.org/0000-0003-0654-9216;
Email: panl948@nenu.edu.cn
Authors
Baihui Zheng − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China
Xiaotong Li − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China
Yang Song − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China
Shuyang Meng − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China
Yifei Li − Jilin Province Key Laboratory of Organic Functional
Molecular, Design & Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China;
orcid.org/0000-0002-3167-7175
Qun Liu − Jilin Province Key Laboratory of Organic
Functional Molecular, Design & Synthesis, Department of
Chemistry, Northeast Normal University, Changchun
130024, China
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Pyrrole via Amine-Initiated (3 + 2) Annulation and Aromatization
Cascade Reaction of β′-Acetoxyallenoate and 1,2-Bisnucleophile. Org.
Lett. 2016, 18, 2240−2243.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00915
Notes
(17) Kurandina, D.; Gevorgyan, V. Rhodium Thiavinyl Carbenes
from 1,2,3-Thiadiazoles Enable Modular Synthesis of Multisubstituted
Thiophenes. Org. Lett. 2016, 18, 1804−1807.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(18) Wei, B.-Y.; Xie, D.-T.; Lai, S.-Q.; Jiang, Y.; Fu, H.; Wei, D.;
Han, B. Electrochemically Tuned Oxidative [4 + 2] Annulation and
Dioxygenation of Olefins with Hydroxamic Acids. Angew. Chem., Int.
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(19) Song, C.; Dong, X.; Wang, Z.; Liu, K.; Chiang, C.-W.; Lei, A.
Visible-Light-Induced [4 + 2] Annulation of Thiophenes and Alkynes
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Azabicyclic Olefins through Twofold C−H Activation. Angew.
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■
Financial support of this research by the National Natural
Science Foundation of China (21971033) and the Funda-
mental Research Funds for the Central Universities
(2412019FZ016 and 2412019FZ013) is gratefully acknowl-
edged.
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