Direct Allylic C(sp3)?H and Vinylic C(sp2)?H Thiolation with Hydrogen Evolution by Quantum Dots and Visible Light

Article abstract of DOI:10.1002/anie.202101947

Direct allylic C?H thiolation is straightforward for allylic C(sp³)?S bond formation. However, strong interactions between thiol and transition metal catalysts lead to deactivation of the catalytic cycle or oxidation of sulfur atom under oxidative condition. Thus, direct allylic C(sp³)?H thiolation has proved difficult. Represented herein is an exceptional for direct, efficient, atom- and step-economic thiolation of allylic C(sp³)?H and thiol S?H under visible light irradiation. Radical trapping experiments and electron paramagnetic resonance (EPR) spectroscopy identified the allylic radical and thiyl radical generated on the surface of photocatalyst quantum dots (QDs). The C?S bond formation does not require external oxidants and radical initiators, and hydrogen (H₂) is produced as byproduct. When vinylic C(sp²)?H was used instead of allylic C(sp³)?H bond, the radical-radical cross-coupling of C(sp²)?H and S?H was achieved with liberation of H₂. Such a unique transformation opens up a door toward direct C?H and S?H coupling for valuable organosulfur chemistry.

Full text of DOI:10.1002/anie.202101947

Angewandte
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11779–11783
International Edition: doi.org/10.1002/anie.202101947
doi.org/10.1002/ange.202101947
Photocatalysis Very Important Paper
German Edition:
3
2
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Direct Allylic C(sp ) H and Vinylic C(sp ) H Thiolation with
Hydrogen Evolution by Quantum Dots and Visible Light
Cheng Huang+, Rui-Nan Ci+, Jia Qiao, Xu-Zhe Wang, Ke Feng, Bin Chen, Chen-Ho Tung, and
Li-Zhu Wu*
À
Abstract: Direct allylic C H thiolation is straightforward for
p-allyl metal intermediates, with the assistance of transition
metal catalyst. The p-allyl metal intermediates thus generated
can be intercepted by carbon, oxygen and nitrogen nucleo-
3
À
allylic C(sp ) S bond formation. However, strong interactions
between thiol and transition metal catalysts lead to deactivation
of the catalytic cycle or oxidation of sulfur atom under
oxidative condition. Thus, direct allylic C(sp ) H thiolation
has proved difficult. Represented herein is an exceptional for
3
À
philes leading to allylic C(sp ) H alkylation, oxidation and
3
amination[5] (Scheme 1A). Unfortunately, direct allylic C-
(sp ) H thiolation has not received the same level of success
because sulfur nucleophiles can poison the catalyst system by
precipitating the metals from the solution or tying up the
metal complex in solution in an unreactive form.[2a,6] Tran-
À
3
À
direct, efficient, atom- and step-economic thiolation of allylic
3
À
À
C(sp ) H and thiol S H under visible light irradiation.
Radical trapping experiments and electron paramagnetic
resonance (EPR) spectroscopy identified the allylic radical
and thiyl radical generated on the surface of photocatalyst
À
sition metal catalysed allylic C H functionalization reactions
involving radicals provide a powerful alternative,[7] however,
3
À
À
quantum dots (QDs). The C S bond formation does not
require external oxidants and radical initiators, and hydrogen
(H2) is produced as byproduct. When vinylic C(sp ) H was
used instead of allylic C(sp ) H bond, the radical-radical
direct allylic C(sp ) H thiolation with thiol via radical-radical
cross-coupling pathway remains elusive.
2
À
3
À
2
À
À
cross-coupling of C(sp ) H and S H was achieved with
liberation of H2. Such a unique transformation opens up
À
À
a door toward direct C H and S H coupling for valuable
organosulfur chemistry.
O
wing to the importance of allylic sulfides in pharmaceut-
icals, agrochemicals and organic synthesis,[1] the construction
3
À
of allylic C(sp ) S bond has received extensively attention
and a great progress has been made by transition metal
catalysis.[2] For example, transition metal catalyzed allylic
3
À
substitution reaction enables construction of allylic C(sp ) S
bond in organic synthesis.[3] However, leaving group such as
ester, carbonate and halide at the allylic position is always
required, which put limits on the substrate scope and lead to
tedious reaction steps for prefunctionalization and defunc-
À
tionalization. Recent interest in allylic C H bond activation
3
À
has triggered the synthetic transformation for C(sp ) X (X =
C, O, N) bond formation.[4] Common to these C H bonds
functionalization is the formation of high-active electrophiles,
À
À
À
Scheme 1. Direct allylic C H bond activation for C S bond formation.
[*] C. Huang,[+] R.-N. Ci,[+] J. Qiao, X.-Z. Wang, Dr. K. Feng,
Prof. Dr. B. Chen, Prof. Dr. C.-H. Tung, Prof. Dr. L.-Z. Wu
Key Laboratory of Photochemical Conversion and Optoelectronic
Materials, Technical Institute of Physics and Chemistry & University
of Chinese Academy of Sciences, Chinese Academy of Sciences
Beijing 100190 (P. R. China)
3
À
Herein, we report the first allylic C(sp ) H thiolation via
cross-coupling of allylic radical and thiyl radical, i.e., irradi-
ation of a photocatalyst, quantum dots (QDs), by visible light
results in direct allylic C(sp ) H thiolation at extremely mild
3
À
reaction condition (Scheme 1B). The protocol presented here
does not require pre-functionalization of both the coupling
partners and any external oxidant or radical initiator, and
produces hydrogen (H2) as byproduct. Benefiting from the
quantum confinement effects, rich surface-binding properties,
broad and intense absorption spectra in the visible region,[8]
QDs offer new and versatile ways to serve as photocatalysts
for chemical transformation.[9] In this contribution, we found
and
School of Future Technology, University of Chinese Academy of
Sciences
Beijing 100049 (P. R. China)
E-mail: lzwu@mail.ipc.ac.cn
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101947.
[10]
À
that QDs can activate allylic C H bond
to form allylic
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À
Table 1: Optimization of allylic C H thiolation.
radical under visible light irradiation, and the hydrogen atom
À
eliminated from the allylic C H bond can be reduced for
hydrogen evolution. Along with the previous works on the
thiol activation to produce thiyl radicals on the surface of
QDs,[11] we envision that the allylic radical generated from
Entry
Modification of reaction conditions[a]
Yield[b] [%]
À
allylic C H bond might be captured by thiyl radical on the
1
2
3
4
5
6
7
8
9
None
75
74
55
43
44
87
81
n.d.
n.d.
89
surface of QDs to achieve radical-radical cross-coupling for
Acetone instead of CH3CN
DMF instead of CH3CN
DMSO instead of CH3CN
H2O instead of CH3CN
1.4ꢀ10À14 M CdSe QDs
In the air, 1.4ꢀ10À4 M CdSe QDs
Without CdSe QDs
3
À
allylic C(sp ) S bond formation. To our delight, this is indeed
the case. Irradiation of the reaction mixture containing CdSe
QDs, thiol and alkenes with blue LEDs (l = 450 nm) resulted
3
À
in the desired allylic C(sp ) H thiolation product in excellent
yield. Such a transformation facilitates the activation of allylic
3
À
À
C(sp ) H and thiol S H bond without introducing extraneous
functional groups and external oxidants or radical initiator.
Our initial study chose 4-methoxybenzenthiol 1a and
cyclohexene 2a as model substrates in the presence of CdSe
QDs in CH3CN at room temperature. Upon visible light
Without light
1a, 0.05 mmol
2.0 equiv TEMPO
10
11
n.d.
[a] Reaction condition: 0.1 mmol 1a, 5 mmol 2a, and CdSe QDs
(8.0ꢀ10À5 M) which was dispersed by 4 mL CH3CN were added into
10 mL reaction tube under room temperature. The solution was strictly
deaerated and irradiated for 20 h by blue LEDs (l=450 nm). [b] Yields
detected by H NMR using diphenylacetonitrile as an internal standard
based on 1a. n.d.=no detected. H2 was determined by GC-TCE.
irradiation of the reaction mixture (l = 450 nm) in argon
3
À
atmosphere for 20 h, the desired allylic C(sp ) H thiolation
1
product 3a and hydrogen (H2) were obtained, respectively
(Table 1, entry 1). Examination of a range of solvents includ-
ing CH3CN, acetone, DMF, DMSO, H2O showed that CH3CN
was the best (entries 1–5). Increasing the amount of CdSe
QDs from 8.0 ꢀ 10À5 M to 1.4 ꢀ 10À4 M improved the desired
thiolation with thiol proceeded under optimized condition,
that is, irradiation of 4.0 mL degassed CH3CN solution of
0.05 mmol 4-methoxybenzenthiol 1a, 2.5 mmol cyclohexene
2a and 8.0 ꢀ 10À5 M CdSe QDs by blue LED (l = 450 nm).
Encouraged by the important result, we attempted to
identify the reaction intermediates of the transformation.
When a well-known radical scavenger, 2,2,6,6-tetramethyl-1-
product 3a to 87% yield (entry 6). Even under aerobic
3
À
condition, the photocatalytic allylic C(sp ) H thiolation could
proceed in 81% yield (entry 7). Both QDs and visible light
were necessary for successful implementation of the reaction
(entries 8 and 9). A higher yield (89%) could be achieved
when thiol substrate 1a was reduced to 0.05 mmol (entry 10).
Even though 50 equiv of alkene was used, the low yield of
piperidinyloxy (TEMPO), was added into the reaction
system, the desired allylic C(sp ) H thiolation was greatly
3
À
homocoupling product of 2a (1.4%) obtained in the cross-
3
À
coupling of allylic C(sp ) H thiolation indicated that the QDs
suppressed, suggesting radicals involved in this transforma-
tion (entry 11). In order to further identify the radical
intermediates formed in situ, we performed electron para-
magnetic resonance (EPR) spectroscopy experiments. As
shown in Scheme 2A, no spectral signal was detected when
reaction is in fact a surface reaction so that a large ratio of
alkenes is to guarantee the interaction of QDs and substrates,
3
À
and thereby realizing the allylic C(sp ) H thiolation with
3
À
higher efficiency. To summarize, the direct allylic C(sp ) H
Scheme 2. Mechanistic studies. A) Electron paramagnetic resonance spectroscopy experiments. (i), A solution containing CdSe QDs (dispersed by
CH3CN) and DMPO (0.2 M) was irradiated for 10 s with blue LEDs (l=450 nm) under argon atmosphere. (ii), 4-methoxybenzenthiol 1a was
added into the solution containing CdSe QDs (dispersed by CH3CN) and DMPO (0.2 M) under the irradiation of blue LEDs (l=450 nm). (iii),
Cyclohexene 2a was added into the solution containing CdSe QDs (dispersed by CH3CN) and DMPO (0.2 M) under the irradiation of blue LEDs
(l=450 nm). (iv), 1,1-diphenylethylene 4a was added into the solution containing CdSe QDs (dispersed by CH3CN) and DMPO (0.2 M) under
the irradiation of blue LEDs (l=450 nm). B) Control experiments.
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À
À
a mixture of CdSe QDs and DMPO (5,5-dimethyl-1-pyrroline
N-oxide) was irradiated with blue LEDs (l = 450 nm) for
10 seconds under argon atmosphere (i). When 4-methoxy-
benzenthiol 1a was presented into the mixture of CdSe QDs
and DMPO, however, the thiyl radical signal was detected
with coupling constants of aN = 13.38; aH = 15.68[12] (ii).
On the other hand, the addition of cyclohexene 2a into
the solution of CdSe QDs and DMPO immediately led to new
peaks, assigned to the typical spin adduct of allylic radicals
C H thiolation at relatively weak C H bond position (3aa–
3ab).
3
À
In spite of elegant protocol for allylic C(sp ) H activation
by HAT with the generated thiyl radical,[7c] our approach is
3
À
À
the direct cross-coupling of allylic C(sp ) H and S H bond
with hydrogen evolution. Strikingly, a facile thiyl radical
addition to olefins[14] is negligible. To examine the possibility
2
À
for such an addition process, we introduced vinylic C(sp ) H
to replace allylic C(sp ) H for the thiolation. To our surprise,
when vinylic C(sp ) H was added into the mixture of CdSe
3
À
2
with DMPO of aN = 14.64 and aH = 19.93[13] (iii). Compared to
À
3
previous reported system,[6b] where allylic C(sp ) H bond was
QDs and DMPO, a typical set of vinyl radical signals was
À
activated with the aid of disulfide as HAT reagent to form
C(sp ) S bond via ionic coupling process under air condition,
our photochemical reaction realizes direct allylic C H and S
H bonds activation to yield allylic radical and thiyl radical
without external oxidants or radical initiators. More impor-
tantly, the allylic radical and thiyl radical thus generated can
observed with coupling constants of aN = 14.64; aH = 19.42[13]
3
À
(Scheme 2, iv). On the basis of the result, we explored vinylic
C(sp ) H thiolation by irradiation of the reaction mixture
2
À
À
À
containing CdSe QDs, 4-methoxythiophenol 1a and 1,1-
diphenylethylene 4a. The cross-coupling product 5, a signifi-
cant scaffold found in natural products and pharmaceutical
molecules,[15] was exclusively obtained (Scheme 2B). Differ-
ent from vinyl sulfides, which are typically prepared via the
addition reaction of thiols to alkynes and cross-coupling
undergo radical-radical coupling on the surface of QDs for
3
À
allylic (Csp ) S bond construction. In contrast to a molecular
photocatalyst that can only be coordinated by one substrate at
a time, the QD photocatalyst can bind multiple substrates to
reactions of vinyl halides with thiols,[2a,16] the protocol
presented constructs vinylic C(sp ) S bond via direct radi-
cal-radical cross-coupling of C H and S H (see details for
reaction optimization in Supporting Information). As shown
in Scheme 3, a wide range of thiol and vinylic C(sp ) H
participated in the reaction, providing vinyl sulfides with high
efficiency. Thiophenol substrates bearing alkoxy, methylthio,
alkyl, aryl and F group furnished the desired vinylic C(sp ) H
thiolation products in yields ranging from 61–89% (5a–5l).
Heterocyclic thiols, prevalent in natural products and phar-
maceuticals, were also effective (5m). When thiolactic acid
was employed as a coupling partner, the corresponding
product with decarboxylation was obtained in 90% yield
(5n). Also, alkyl thiols 8-mercaptomaleone was successfully
coupled to vinylic C(sp ) H bonds to afford the vinyl sulfides
in moderate yields (5o). On the other hand, the scope of 1,1-
diarylethylene substrates 4 for the vinyl C(sp ) H thiolation
protocol was examined. A range of 1,1-diarylethylene deriv-
atives bearing OMe, Me, tBu, F, Cl, and NMe2 groups
produced the desired thiolation products in moderate to
good yields (5p–5u). Although styrene failed to yield the
cross-coupling product (see details in Supporting Informa-
tion), unsymmetrical substituted 1,1-diarylethylene substrates
enable to couple with 4-methoxythiophenol to afford the
corresponding product in excellent yields (5v–5x).
2
À
À
À
simultaneously dictate C H and S H substrate activation for
subsequent transformation.
À
À
To highlight the unique ability of QDs for photocatalytic
3
2
À
À
allylic C(sp ) H bond activation, we monitored the cross-
coupling reaction of 1a and 2a shown in Figure S5. At the
beginning of the reaction, a very small amounts of disulfides
1aa were formed and then quickly consumed in 30 minutes. In
the absence of the thiol coupling partner, homocoupling
2
À
product 2aa was formed (Scheme 2), indicating the activation
3
À
of allylic C(sp ) H bond by the QDs rather than by thiyl
radical mediated HAT process. In addition, when disulfide
1aa was used as substrate instead of thiol 1a, the desired
allylic sulfide 3a was obtained smoothly in 74% yield under
standard condition.
2
À
With understanding the reaction mechanism, we inves-
3
2
À
À
tigated the generality of allylic C(sp ) H thiolation. As shown
in Scheme 3, a wide variety of thiophenols substrates reacted
smoothly with cyclohexene to afford allylic C(sp ) H thio-
3
À
lation products in good to excellent yields (3a–3v). Thiophe-
nols bearing alkyl, alkoxy and methylthiol group could be
transformed into the corresponding products in yields of 61–
89% (3a–3l). Ortho-substituted thiophenols did not lead to
an obvious difference in reactivity as compared to unsubsti-
tuted variants (3a–3c). Halogenated thiophenols were com-
patible with the catalytic system, providing opportunities to
further functionalize the formed allylic sulfide using the
radical-radical cross-coupling chemistry (3m–3o). Notably,
À
To evaluate the scalability of this C S bonds forming
protocol, we used 4-methoxythiophenol 1a and 1,1-diaryl-
ethylene 4u to perform a large-scale reaction, and obtained
0.74 g (91% yield) of the cross-coupling product 5u under the
standard conditions. Under sunlight irradiation, the direct
allylic C(sp ) H thiolation and vinylic C(sp ) H thiolation
could also be achieved in 77% and 95% yields, respectively
(3a and 5u), demonstrating the practical potential for
thiophenol containing free hydroxyl and amine group were
3
À
well tolerated under our allylic C(sp ) H thiolation condition,
3
2
À
À
eliminating the need for protecting groups (3q–3v). Next,
a variety of alkene 2, including cyclic, linear, and heterocyclic
alkenes were examined. Unfunctionalized cyclic alkenes
À
(five-, seven- and eight-membered rings) readily reacted
construction of C S bonds using solar energy.
3
À
with 4-methoxybenzenthiol to afford the allylic C(sp ) H
In summary, a general, efficient and selective allylic
3
2
À
À
thiolation product in moderate yields (3w–3y), so did linear
C(sp ) H or vinylic C(sp ) H thiolation with thiol via radical-
radical cross-coupling has been established for the first time.
Mechanistic studies revealed the allylic radical (or vinylic
radical) and thiyl radical generated on the surface of QDs
3
À
alkene (3z). Heterocyclic alkenes with allylic C(sp ) H bond
3
À
and a-oxy C(sp ) H bond were suitable for selective allylic
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Scheme 3. Substrate scope. [a] Standard conditions: 0.05 mmol of thiophenol 1 (1.0 equiv), 2.5 mmol of alkenes 2 (50.0 equiv), CdSe QDs
(8.0ꢀ10À5 M), in 4 mL of CH3CN under Ar, irradiation with blue LEDs (l=450 nm) for 20 h at room temperature; Isolated yield; H2 was
determined by GC-TCE. [b] Sun light instead of blue LEDs (l=450 nm), see details in Supporting information. [c] Reaction conditions: 0.1 mmol
of thiophenol 1 (1.0 equiv), 0.3 mmol of alkene 4 (3.0 equiv), DMAP (1.0 equiv), CdSe QDs (1.2ꢀ10À4 M) in 4 mL of CH3CN under Ar, irradiation
with blue LEDs (l=450 nm) for 12 h at room temperature; Isolated yield; H2 was determined by GC-TCE. [d] Reaction was performed on a large
1
scale, see details in Supporting Information [e] Ratio of isomers was determined by H NMR analysis.
Acknowledgements
upon irradiation by visible light, which enable direct radical-
3
2
À
À
radical cross-coupling for allylic C(sp ) H or vinylic C(sp )
H thiolation at extremely mild condition. The atom- and step-
economic protocol bypasses external oxidants or radical
initiators and pre-functionalization of both the coupling
partners, employs readily available chemical feedstocks and
compatible with a variety of functional groups, and produces
hydrogen (H2) as the byproduct. All of the features highlight
the photocatalysis with QDs and visible light promising in
both academic and industrial settings.
We are grateful for financial support from the National
Natural Science Foundation of China (22088102, 21933007
and 21861132004), the Ministry of Science and Technology of
China (2017YFA0206903), the Strategic Priority Research
Program of the Chinese Academy of Science
(XDB17000000), the Key Research Program of Frontier
Sciences of the Chinese Academy of Science (QYZDY-SSW-
JSC029), and K. C. Wong Education Foundation.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: allylic C(sp3)-H thiolation · C-S bond formation ·
quantum dots · solar energy conversion · visible light catalysis
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Manuscript received: February 7, 2021
Accepted manuscript online: March 4, 2021
Version of record online: April 14, 2021
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