Dual Catalysis Relay: Coupling of Aldehydes and Alkenes Enabled by Visible-Light and NHC-Catalyzed Cross-Double C-H Functionalizations

Article abstract of DOI:10.1021/acscatal.1c02890

Direct functionalizations of two distinct inert C-H bonds represent the most ideal ways to construct C-C bonds. Herein, we report an intermolecular vinylation of aldehydes using alkenes as the vinylating reagents through sequential two-fold C-H functionalizations. The merging of visible light and N-heterocyclic carbene catalysis allows for the coupling of alkenes with aldehydes through a dual catalysis relay enabled cross-dehydrogenative coupling mechanism. The use of diphenoquinone is essential for the success of this reaction, which plays an intriguing two-fold role in the reaction, as an electron acceptor as well as a radical reservoir for the radical coupling enabling the C-C forming process.

Full text of DOI:10.1021/acscatal.1c02890

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Letter
Dual Catalysis Relay: Coupling of Aldehydes and Alkenes Enabled by
Visible-Light and NHC-Catalyzed Cross-Double C−H
Functionalizations
Ming-Shang Liu, Lin Min, Bi-Hong Chen, and Wei Shu*
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ABSTRACT: Direct functionalizations of two distinct inert C−H
bonds represent the most ideal ways to construct C−C bonds.
Herein, we report an intermolecular vinylation of aldehydes using
alkenes as the vinylating reagents through sequential two-fold C−H
functionalizations. The merging of visible light and N-heterocyclic
carbene catalysis allows for the coupling of alkenes with aldehydes
through a dual catalysis relay enabled cross-dehydrogenative
coupling mechanism. The use of diphenoquinone is essential for the success of this reaction, which plays an intriguing two-fold
role in the reaction, as an electron acceptor as well as a radical reservoir for the radical coupling enabling the C−C forming process.
KEYWORDS: dual catalysis relay, cross-dehydrogenative coupling, NHC catalysis, visible-light catalysis, radical−radical coupling
Scheme 1. Impetus for Dual Catalysis Relay Enabled Two-
Fold C−H Functionalizations
arbon−carbon bonds represent one of the most
abundant and important chemical bonds in organic
C
compounds.1 Thus, the development of efficient construction
of C−C bonds has been a long-term interest in synthetic
chemistry and related areas.2 Conventional cross-coupling
reactions between C−X/C−X and C−H/C−X, where X =
(pseudo)halides or metals, to form C−C bonds rely heavily on
preinstallation of activated chemical handles for starting
materials.3 Although these reactions are highly powerful and
synthetically useful, the preactivation of substrates requires
additional steps to prepare and generate a stoichiometric
amount of metal salts as byproducts. For this reason, cross-
dehydrogenative coupling (CDC) represents an ideal alter-
native for C−C bond formation between two distinct C−H
bonds.4 The significant features of CDC reactions include the
following: (1) no prefunctionalization of substrates is required,
improving step- and atom-economy with reduced waste; (2)
direct C−H functionalizations are highly desirable for late-
stage functionalizations (Scheme 1a).5
On the other hand, N-heterocyclic carbene (NHC)
catalysis6 and visible-light catalysis7 have emerged as enabling
tools for organic synthesis over the past decades.8 Therefore,
merging visible-light catalysis and NHC catalysis for CDC
reactions is attractive yet challenging. Rovis’ group reported
the α-acylation of tertiary amines enabled by the visible-light
and NHC-catayzed cross-dehydrogenative coupling of alde-
hydes with the α-position of amines via ionic pathways
(Scheme 1b).9 The visible-light and NHC-catayzed cross-
dehydrogenative coupling via single electron pathways remains
underdeveloped. Recently, NHC-involved single electron
transfer reactions have emerged as novel and intriguing
reaction modes for bond-forming processes.10 Thus, combin-
Received: June 28, 2021
Revised: July 15, 2021
Published: July 19, 2021
https://doi.org/10.1021/acscatal.1c02890
© 2021 American Chemical Society
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Letter
ing a visible-light and NHC-catalyzed radical pathway offers
new opportunities for C−C/C−X coupling reactions.11
Recently, Ohmiya and Li et al. reported elegant examples of
NHC-catalyzed coupling of aldehydes with alkyl radicals in the
presence of redox-active esters or activated alkyl halides.12 In
these processes, a carbon electrophile (R−X species) couples
with Breslow intermediates from aldehydes to form a C−C
bond via a radical mechanism.13 To date, no report on the
formal Heck reaction of aldehydes with alkenes by
dehydrogenation has been successful. During the preparation
of this paper, Studer reported an elegant example of coupling
of acyl fluorides with alkenes enabled by triple catalysis
(Scheme 1c).14a More recently, Ohmiya developed the NHC-
catalyzed two-component or three-component reaction using
aryl iodides as the aryl radical precursors.14b As part of our
continuous interest in visible-light catalysis and NHC
catalysis,15 we herein report the cross-dehydrogenative C−C
bond-forming process from aldehydes and alkenes enabled by a
dual-catalyzed radical relay (Scheme 1d). The use of a visible-
light and NHC catalysis strategy allows for the direct
dehydrogenative vinylation of aldehydes with alkenes.16
We commenced to investigate the reaction using 4-
methylbenzaldehyde 1a and 4-methoxystyrene 2a as the
prototype substrates. After extensive optimization of the
reaction parameters, we define the use of Ru(bpy)3Cl2·6H2O
(2 mol %) and NHC-1 (10 mol %) as catalysts, potassium
carbonate (1.0 equiv) as base, sodium benzenesulfinate (1.9
equiv) as additive, and TTBDPB (3,3′,5,5′-tetra-tert-butyldi-
phenoquinone, 1.9 equiv) as oxidant in DMSO (0.1 M) under
irradiation of 30 W blue LEDs at room temperature as the
optimal conditions, affording desired vinylaryl ketone 3a in
81% isolated yield (Table 1 and Tables S1−S8).17 The use of
another NHC catalyst could also mediate the transformation,
albeit in lower conversions and yields (Table 1, entries 2 and 3,
and Table S2). Other photocatalysts with reasonable oxidative
potential proved efficient for this reaction (Table 1, entries 4−
6, and Table S3). The use of other bases to replace potassium
carbonate resulted in lower yields of 3a (Table S4). TTBDPB
is essential for the success of this two-fold C−H functionaliza-
tion reaction. The use of 1,4-benzoquinone, DDQ, or
potassium persulfate led to low efficiency of this reaction
(Table 1, entries 7−9, and Table S6). Many other sulfinate
derivatives could mediate the reaction (Table S7), among
which sodium benzenesulfinate furnished the best result of 3a.
Control experiments revealed that both the NHC catalyst and
photocatalyst were essential for the desired reaction (Table 1,
entries 10 and 11). No desired product 3a was formed in the
absence of NHC catalyst, whereas the reaction delivered 3a in
15% yield without photocatalyst, probably due to the
formation of weak EDA complexes between sulfinate and
oxidant. No light irradiation led to no formation of 3a (Table
1, entry 12), proving that the use of visible light is critical to
the success of this transformation. No 3a was detected in the
absence of sulfinate or oxidant (Table 1, entries 13 and 14).
With the optimized conditions in hand, we evaluated the
scope of this reaction. The mild conditions tolerated a wide
variety of functional groups and substitution patterns in terms
of aldehydes and alkenes for this dual-catalyzed vinylation
reaction of aldehydes (Table 2). First, the scope of aldehydes
was evaluated. Electron-withdrawing and electron-donating
substituted aromatic aldehydes were well-tolerated under the
reaction conditions, giving the corresponding vinylphenylke-
tones in 50−86% yields (3b−3q). Various para-substituted
Table 1. Condition Evaluation for the Direct Coupling of
Aldehydes with Alkenes
a
b
entry
variation from standard conditions
yield of 3a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
none
83% (81%)
64%
72%
58%
61%
76%
7%
trace
ND
ND
NHC-2 instead of NHC-1
NHC-3 instead of NHC-1
4Cz-IPN as PC
Ru(bpz)3(PF6)2 as PC
[Ir(ppy)2(dtbbpy)]PF6 as PC
1,4-benzoquinone as oxidant
DDQ as oxidant
K2S2O8 as oxidant
no NHC
no Ru(bpy)3Cl2·6H2O
no light
no PhSO2Na
15%
ND
ND
no TTBDPB
trace
a
The reaction was conducted using 1a (0.2 mmol), 2a (0.1 mmol),
b
with 30 W blue LEDs under indicated conditions. Yield was
determined by H NMR of the crude mixture of the reaction using
1
mesitylene as internal standard. Number in the parentheses is the
yield after flash chromatography. PC = photocatalyst. ND = not
detected.
aromatic aldehydes were all good substrates for this reaction,
affording the desired C−C coupling products in 50−86%
yields (3b−3j). Notably, fluoro-, chloro-, bromo-, and iodo-
substituted aldehydes were successfully transformed into the
desired products in 50−72% yields (3f−3i), leaving a chemical
handle for further elaboration. meta-Substituted aromatic
aldehyde could be converted to the desired product 3k in
82% yield. Naphthyl aldehyde could be coupled with 2a to give
the desired product 3l in 65% yield. ortho-Substituted aldehyde
could be tolerated to give the desired product 3m in 69% yield.
Moreover, the reaction was compatible with highly function-
alized aldehydes. Various sensitive functional groups, such as
amides with free N−H, alkenes, and alkynes, were well-
tolerated in the reaction, delivering the two-fold C−H
functionalization products in 66−84% yields (3n−3p). The
structure of the products was unambiguously assigned by the
X-ray diffraction analysis of 3n. Furthermore, heteroaromatic
aldehydes containing triazoles, pyridines, quinolines, furans,
benzathiophenes, and thiophenes were all good substrates for
this transformation, affording corresponding heteroarylvinyl
ketones in 56−92% yields (3q−3w). Unfortunately, aliphatic
aldehydes led to no formation of desired enones. Next, the
scope of alkenes was tested. Aromatic alkenes with para-
substitutents, such as thioethers, halides, and esters, could be
converted to the desired vinylketones in 52−85% yields (4a−
4i). The practicality of this reaction was showcased by the
gram-scale synthesis of 4c without erasing the efficiency of this
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†
Table 2. Scope for the Double C−H Functionalization Reaction with Respect to Aldehydes and Alkenes
†
a
b
Standard conditions; see Table 1 for details. The reaction was conducted on 5.0 mmol scale. Cs2CO3 was used as base, and sodium 4-
chlorophenylsulfinate was used as sulfinate. See Supporting Information for details.
reaction. Under the standard conditions, 5.0 mmol of 4-tert-
butylstyrene was successfully coupled with 1a to afford 1.04 g
of vinylarylketone 4c in 75% yield. Alkenes with meta- and
ortho-substituents could be converted to the desired vinyl-
ketones in 65−79% yields (4j−4l). Multisubstituted aromatic
alkene was successfully involved in the reaction, giving the
desired acylated product 4m in 81% yield. Fused aromatic
alkene was converted to 4n in 86% yield. Moreover, alkenes
bearing alkynes and amides were good substrates for the
reaction, furnishing acylated alkenes in 50−76% yields (4o−
4q).
Notably, heteroaryl alkenes, such as benzothiophene-,
quinoline-, and carbazole-containing alkenes, proceeded
smoothly to give corresponding heteroaryl vinyl ketones in
65−90% yields (4r−4t). Internal alkenes could undergo
regioselective acylation with aldehydes to give corresponding
arylvinyl ketone 4u in 65% yield. Unfortunately, aliphatic
alkenes did not deliver desired enone products. To further
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Scheme 2. Mechanistic Investigations of the Reaction
demonstrate the synthetic potential of this mild protocol, the
reaction was applied to late-stage functionalization of natural
products. Oleanic acid-derived aldehyde and estrone-derived
alkene were both successfully involved in this two-fold C−H
functionalization process to deliver corresponding vinyl-
arylketones (5a and 5b) in 61% and 93% yields, respectively.
To gain insight into the mechanism of this reaction, we set
up experiments to shed light on the reaction mechanism
(Scheme 2). First, the reaction of aldehyde 1a with cyclopropyl
styrene 6 was carried out under standard conditions. Ring
opening of cyclopropane was observed, with the formation of 7
in 9% yield and 8 in 38% yield (Scheme 2a). This result
suggested the reaction proceeded via the radical intermediate
[6−1], followed by radical ring opening of cyclopropane to
give radical intermediate [6−2]. Second, the reaction of
aldehyde 1a with alkene 2a under standard conditions was
conducted for 40 min. Intriguingly, the adduct 9 was formed in
61% yield from the addition of phenylsulfonate with quinone
and alkene 2a (Scheme 2b). The structure of 9 was further
confirmed by the X-ray diffraction analysis. Compound 9 was
further submitted to the reaction with 1a in the presence of
sodium benzenesulfinate (0.9 equiv) under otherwise identical
standard conditions, delivering the vinylation product of
aldehyde 3a in 78% yield along with the formation of biphenol
10 in 85% yield (Scheme 2c). These results indicated the
adduct 9 could be the intermediate of this dual C−H bond
functionalization process of aldehydes and alkenes. Next, a
light on−off experiment was carried out with aldehyde 1a and
alkene 2a (Scheme 2d). The light on−off results indicated the
reaction underwent a catalytic radical reaction instead of a
radical chain pathway.15 Then luminescence quenching
experiments were examined with different components
(Scheme 2e).7a None of aldehyde 1a, alkene 2a, the mixture
of NHC-1 catalyst with potassium carbonate, or intermediate 9
showed a significant luminescence quenching effect to the
excited state of the photocatalyst (Ru(II)*). In contrast,
sodium benzenesulfinate as well as the combination of
aldehyde 1a with NHC-1 in the presence of potassium
carbonate showed a very strong quenching effect on the
excited photocatalyst. These observations provided evidence
that either sodium benzenesulfinate or the combination of
aldehyde 1a with NHC-1 in the presence of potassium
carbonate could quench Ru(II)* to give Ru(I) via single
electron transfer.
Moreover, monitoring the profile for the reaction of
aldehyde 1a and alkene 2a under standard conditions was
conducted and shown in Figure 1. The results showed that
alkene 2a was quickly consumed in the first 40 min of the
reaction with little formation of coupling product 3a. Instead,
the yield of 9 increased dramatically. After 40 min, the yield of
3a increased with the consumption of 9. 3a was formed in 78%
yield with full conversion of 9 in 4 h. These results further
confirmed that this double C−H cross-functionalization of
aldehydes with alkenes proceeded stepwisely via a photo-
catalytic radical relay process and further proved that 9 was the
intermediate of this reaction.
Based on the above-mentioned mechanistic results and
literature, a plausible mechanism for this transformation is
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been demonstrated for the first time. The reaction was enabled
by site- and regioselective two-fold sequential C−H cross-
functionalization. Mechanistic investigations reveal the reac-
tion features a dual catalysis relay with two independent
radical−radical coupling processes. Diphenoquinone has a
two-fold role in the reaction, acting as an oxidant and a
reservoir for radical intermediates. The reaction tolerates a
wide range of aldehydes and alkenes with good functional
group compatibility. We anticipate the dual catalysis relay
strategy will open an avenue for visible-light and NHC-
catalyzed carbon−carbon and carbon−heteroatom bond-
forming processes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02890.
■
sı
Figure 1. Reaction profile of the reaction of 1a with 2a.
depicted in Scheme 3. First, Ru(II)* was formed via
photoexcitation of the Ru(II)-based photocatalyst, which was
Experimental procedures, characterization of all new
compounds and X-ray data for compounds 3n (CCDC
2079915) and 9 (CCDC 2077990) (PDF)
Scheme 3. Proposed Mechanism for the Reaction
AUTHOR INFORMATION
Corresponding Author
■
Wei Shu − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055 Guangdong, P.R. China; orcid.org/
0000-0003-0890-2634; Email: shuw@sustech.edu.cn
Authors
Ming-Shang Liu − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055 Guangdong, P.R. China
Lin Min − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055 Guangdong, P.R. China
Bi-Hong Chen − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055 Guangdong, P.R. China
quenched by phenylsulfinate to give the Ru(I) species as well
as phenyl sulfonyl radical M1. Ru(II) could be regenerated by
single electron oxidation of oxidant (TTBDBB) with the
formation of radical anion intermediate M2. In the presence of
alkene, M1 would undergo radical addition to alkene to give
carbon-centered radical M3, which rebounded with M2 via
radical−radical coupling followed by protonation to give M4.
Meanwhile, the radical addition of M3 to TTBDPB,
followed by single electron reduction by Ru(I) to give Ru(II)
and M4, is also possible. Aldehyde 1 condensed with nitrogen
heterocyclic carbene (NHC) catalyst to generate correspond-
ing Breslow intermediate M5 with the assistance of a base,18
which could quench the excited photocatalyst (Ru(II)*) by
single electron transfer to form radical cationic intermediate
M6 and Ru(I) species.19 The reduced photocatalyst Ru(I)
could reduce M4 to regenerate radical intermediate M3 and
Ru(II) by single electron transfer. Intermediates M3 and M6
could undergo radical−radical coupling to deliver M7 via C−C
bond formation. M7 was transformed to M8 upon releasing
the NHC catalyst. Final product was formed by elimination of
phenylsulfinate in the presence of a base.11b,20
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02890
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to the 10th anniversary of the
Chemistry Department at SUSTech. We sincerely thank NSFC
(21971101 and 21801126), Guangdong Basic and Applied
Basic Research Foundation (2019A1515011976), The Pearl
River Talent Recruitment Program (2019QN01Y261), Thou-
sand Talents Program for Young Scholars, The Stable Support
Plan Program of Shenzhen Natural Science Fund (No.
20200925152608001), and Guangdong Provincial Key Labo-
ratory of Catalysis (No. 2020B121201002) for financial
support. We acknowledge the assistance of SUSTech Core
In summary, a visible-light and NHC-catalyzed vinylation of
aldehydes from alkenes and aldehydes at room temperature has
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Research Facilities. We thank Dr. Xiaoyong Chang (SUSTech)
for X-ray crystallographic analysis of 3n (CCDC 2079915) and
10 (CCDC 2077990), and Dr. Yi-Dan Du (SUSTech) and Si-
Fan Li (SUSTech) for reproducing the results of 3h, 4a, 5h,
and 6b.
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