Direct α-Acylation of Alkenes via N-Heterocyclic Carbene, Sulfinate, and Photoredox Cooperative Triple Catalysis

Article abstract of DOI:10.1021/jacs.1c01022

N-Heterocyclic carbene (NHC) catalysis has emerged as a versatile tool in modern synthetic chemistry. Further increasing the complexity, several processes have been introduced that proceed via dual catalysis, where the NHC organocatalyst operates in concert with a second catalytic moiety, significantly enlarging the reaction scope. In biological transformations, multiple catalysis is generally used to access complex natural products. Guided by that strategy, triple catalysis has been studied recently, where three different catalytic modes are merged in a single process. In this Communication, direct α-C-H acylation of various alkenes with aroyl fluorides using NHC, sulfinate, and photoredox cooperative triple catalysis is reported. The method allows the preparation of α-substituted vinyl ketones in moderate to high yields with excellent functional group tolerance. Mechanistic studies reveal that these cascades proceed through a sequential radical addition/coupling/elimination process. In contrast to known triple catalysis processes that operate via two sets of interwoven catalysis cycles, in the introduced process, all three cycles are interwoven.

Full text of DOI:10.1021/jacs.1c01022

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Direct α‑Acylation of Alkenes via N‑Heterocyclic Carbene, Sulfinate,
and Photoredox Cooperative Triple Catalysis
Kun Liu and Armido Studer*
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ABSTRACT: N-Heterocyclic carbene (NHC) catalysis has emerged as a versatile tool in modern synthetic chemistry. Further
increasing the complexity, several processes have been introduced that proceed via dual catalysis, where the NHC organocatalyst
operates in concert with a second catalytic moiety, significantly enlarging the reaction scope. In biological transformations, multiple
catalysis is generally used to access complex natural products. Guided by that strategy, triple catalysis has been studied recently,
where three different catalytic modes are merged in a single process. In this Communication, direct α-C−H acylation of various
alkenes with aroyl fluorides using NHC, sulfinate, and photoredox cooperative triple catalysis is reported. The method allows the
preparation of α-substituted vinyl ketones in moderate to high yields with excellent functional group tolerance. Mechanistic studies
reveal that these cascades proceed through a sequential radical addition/coupling/elimination process. In contrast to known triple
catalysis processes that operate via two sets of interwoven catalysis cycles, in the introduced process, all three cycles are interwoven.
catalysis cycles, all three cycles are interwoven, resulting in
three common intermediates (Figure 1D).
-Heterocyclic carbene (NHC) catalysis has drawn
1−8
Nconsiderable attention over the past decades.
For
example, umpolung of aldehydes via NHC catalysis to provide
acyl anion equivalents has led to the development of important
transformations,9−16 including the benzoin condensation17,18
and the Stetter reaction.19−22 Most of these reactions proceed
via a single catalysis cycle (Figure 1A), and there are
limitations associated with the use of single NHC cataly-
sis.23−25 In recent years, NHC catalysis has witnessed an
expansion by a move toward dual catalysis in which NHC
catalysis is merged with acid catalysis,26−33 hydrogen-bond
catalysis,34,35 transition-metal catalysis,36−43 or others44−49
(Figure 1B). In these processes, the NHC catalysis cycle is
interwoven with a second catalysis cycle, where the two cycles
have a common intermediate. The construction of complex
natural products in biological systems generally proceeds via a
multiple catalysis approach, and by following nature’s
strategies, multiple catalysis on the basis of combining three
or more distinct catalysts has emerged as an appealing
opportunity for the development of novel reactions.50,51
However, triple catalysis involving an NHC catalysis cycle is
still in its infancy. The challenges lie in the many compatibility
issues between catalysts and intermediates if two additional
catalysis cycles have to be considered along with the NHC
cycle. The few examples reported operate via two sets of
interwoven catalysis cycles with the first and second cycles
coupled and the second and third cycles coupled.52−54
However, the first and third cycles are not interwoven in
these systems, and overall, two common intermediates are
observed (Figure 1C).
The conceptual novel triple catalysis could be realized in a
direct α-C−H acylation of various alkenes with aroyl fluorides.
The reaction design and mechanistic rationality are depicted in
Scheme 1. The sulfinate catalysis cycle starts with single
electron transfer (SET) oxidation of an aryl sulfinate by an
excited photoredox catalyst *PCn to give an aryl sulfonyl
radical along with a PCn−1 complex.55−60 Radical addition of
the sulfonyl radical to substrate alkene 1 leads to adduct radical
A. On the other hand, the reaction between aroyl fluoride 2
and the NHC catalyst gives acyl azolium ion B, which
undergoes SET reduction with the reduced photoredox
catalyst (PCn−1 complex) to generate ketyl-type radical C
and the starting PCn complex, thereby closing the photoredox
cycle.61−63 Radical/radical cross-coupling between C and C
radical A followed by NHC fragmentation leads to
intermediate D, closing the NHC catalysis cycle. Such
radical/radical cross-couplings are steered by the persistent
radical effect64,65 and have recently been successfully used by
Ohmiya,66−68 Scheidt,69 other groups,70−75 and us63 in NHC-
catalyzed radical processes. Base-mediated elimination of the
aryl sulfinate eventually delivers α-acylated alkene 3, closing
the sulfinate catalysis cycle.76 Notably, acylation of substituted
alkenes with acyl electrophiles usually affords the correspond-
ing β-acylation products.77−81
Received: January 27, 2021
Published: March 24, 2021
Herein we present an unprecedented mode of NHC triple
catalysis in which NHC catalysis is merged with cooperative
sulfinate and photoredox catalysis. In contrast to known triple
catalysis processes that operate via two sets of interwoven
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a
Table 1. Reaction Optimization
yield of 3a
b
c
entry
PC
NHC
sulfinate
base (equiv)
(%)
1
2
3
4
PC-I
PC-I
PC-I
PC-I
A
A
A
A
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
Cs2CO3 (2)
KOtBu (2)
DBU (2)
Cs2CO3 (1) + KOtBu trace
(1)
n.d.
n.d.
n.d.
5
6
PC-I
PC-I
PC-I
PC-I
PC-I
PC-II
A
A
B
C
D
B
B
B
B
B
B
B
B
B
B
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
PhSO2Na
Cs2CO3 (1) + DBU
(1)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
Cs2CO3 (0.5) +
MTBD (1.3)
8
26
7
39
8
17
9
22
10
11
12
13
14
15
16
17
18
19
43
PC-
III
PC-
IV
28
35
PC-V
PC-II
PC-II
PC-II
PC-II
PC-II
PC-II
n.d.
10
4-OMe-
PhSO2Na
4-Cl-
PhSO2Na
4-CN-
PhSO2Na
MeSO2Na
56
48
Figure 1. General representation of NHC-catalyzed transformations
proceeding via single, double, and triple catalysis.
4
Scheme 1. Reaction Design and Proposed Mechanism
d
4-Cl-
PhSO2Na
4-Cl-
PhSO2Na
81 (78)
e
n.d.
a
Reaction conditions: 1a (0.15 mmol), 2a (0.3 mmol), NHC (15 mol
%), photoredox catalyst (1.5 mol %), PhSO2Na (25 mol %), base (2.0
equiv), and MeCN (1.5 mL) under irradiation with a 23 W CFL for
b
24 h. Photoredox catalysts and NHCs:
c
GC yields using biphenyl as an internal standard. The yield of the
d
isolated product is given in parentheses. 20 mol % NHC, 30 mol %
4-Cl-PhSO2Na, and 2.5 equiv of 2a were applied. Without
e
photoredox catalyst, NHC, sulfinate, or irradiation.
On the basis of our design, we began the investigations with
4-methylstyrene (1a) and benzoyl fluoride (2a) as the model
substrates. PhSO2Na was chosen as the sulfinate catalyst (25
mol %) in combination with [Ir(ppy)2(dtbbpy)]PF6 (1.5 mol
%) as the photoredox catalyst. Triazolium salt A was selected
as the NHC precatalyst (15 mol %) for initial base screening.
Experiments were conducted in acetonitrile at room temper-
ature under irradiation with a compact fluorescent lamp
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a
Scheme 2. Substrate Scope for the α-Acylation of Various Substituted Alkenes
a
b
c
Reactions were conducted on a 0.15 mmol scale. Yields are of the isolated materials after purification, Bz = benzoyl. 4-CF3-PhSO2Na. 4-CN-
d
e
f
g
PhSO2Na. trans-Anethole. cis-Anethole. Half of 2a and MTBD were added at the beginning, and the rest was added after 12 h. Cs2CO3 (0.8
equiv).
(CFL). Disappointingly, with Cs2CO3, KOtBu, or DBU (2
equiv), the target 3a was not formed (Table 1, entries 1−3). A
small amount of side product 4, corresponding to intermediate
D (see Scheme 1), was identified in the presence of Cs2CO3. It
is obvious that the base plays a crucial role.
We next explored mixed-base systems by combining Cs2CO3
with KOtBu or DBU, where the second base was expected to
facilitate the elimination of the aryl sulfinate (Table 1, entries 4
and 5). Gratifyingly, the Cs2CO3/DBU couple provided
ketone 3a in an encouraging 8% yield, whereas the Cs2CO3/
KOtBu mixture was not efficient. The base system containing
0.5 equiv of Cs2CO3 and 1.3 equiv of 7-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene (MTBD) led to an improved
yield (26%; Table 1, entry 6). Without base, this cascade did
not proceed (not shown). Optimization was continued by
screening of different NHCs. The steric and electronic nature
of the NHCs showed a measurable effect, and the use of B as
the precatalyst provided an improved 39% yield, whereas the
NHCs derived from C and D led to lower yields (Table 1,
entries 7−9). Next, different photocatalysts were investigated,
and Ru(bpy)3(PF6)2 afforded an improved yield (Table 1,
entry 10). [Ir[dF(CF3)ppy]2(dtbbpy)]PF6 gave a worse result,
and no product was identified with Ir(ppy)3 (Table 1, entries
11 and 13). Replacing the Ru photocatalyst with 4-CzIPN led
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Scheme 3. Product Transformations
Scheme 4. Mechanistic Studies
to a slightly lower yield (Table 1, entry 12). Knowing that
electron-poor aryl sulfinates show better leaving group ability
in elimination reactions, we also varied the sulfinate. p-
Methoxyphenyl sulfinate showed decreased efficiency com-
pared with PhSO2Na (Table 1, entry 14). Pleasingly, a 56%
yield of the target 3a was obtained with p-chlorophenyl
sulfinate (Table 1, entry 15). The more electron-deficient p-
cyanophenyl sulfinate gave a minor improvement (Table 1,
entry 16). Of note, an aliphatic sulfinate was not an efficient
cocatalyst (Table 1, entry 17). Some styrene remained
unreacted in the best run (Table 1, entry 15), and we
therefore increased the amount of NHC, sulfinate, and benzoyl
fluoride. A significant improvement was achieved with 2.5
equiv of 2a, 20 mol % NHC, and 30 mol % sulfinate, which
provided 3a in 78% yield (Table 1, entry 18). Control
experiments revealed that the photoredox catalyst, NHC,
sulfinate, and irradiation are all indispensable (Table 1, entry
19).
Under the optimized conditions, we explored the generality
of the protocol by first varying the alkene component while
keeping fluoride 2a as the acylation reagent (Scheme 2). The
effect of substituents on the benzene ring in various styrenes
was investigated. Acceptors bearing a halogen atom or
electron-donating groups at the para position reacted smoothly
to afford the products 3a−f in good yields (65−78%). Lower
reaction efficiency was noted for the p-CF3- and p-EtO2C-
substituted congeners (3g and 3h), where a significant amount
of the alkene remained unreacted. The radical α-acylation also
worked with ortho- and meta-substituted styrenes, and 3i−l
were isolated in 60−73% yield. Ester and amide functionalities
were tolerated, as documented by the preparation of 3m
(85%) and 3n (68%). The fluoroalkylamine entity and a base-
sensitive primary alkyl chloride were tolerated (3o and 3p).
For substrates containing both an aryl alkene and a terminal
aliphatic alkene moiety, the reaction occurred at the activated
aryl alkene position (3q). Alkenes substituted with biologically
important heteroarenes such as thiazole, benzothiophene,
benzofuran, indole, and carbazole engaged in the α-
benzoylation, and ketones 3r−x were obtained in 55−76%
yield. Along with terminal alkenes, internal alkenes like 1,2-
dihydronaphthalenes were α-acylated with complete regiose-
lectivity (3z−aa, 76−81%). For the noncyclic system 3y, good
E/Z selectivity (6.7:1) was obtained from trans-anethole when
p-cyanophenyl sulfinate was used as the cocatalyst. A similar
result was obtained with cis-anethole. With regard to aliphatic
alkenes, only a trace amount of product was detected when the
standard conditions were applied. We assumed that a more
electron-deficient sulfinate catalyst might facilitate the radical
addition and elimination steps. Indeed, when p-cyanophenyl
sulfinate was used instead of p-chlorophenyl sulfinate,
allylbenzene and 1-octene reacted to give the α-alkylated
vinyl ketones (3ba and 3ca), albeit in lower yields. Next, the
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Communication
aroyl fluoride component was varied using 4-methylstyrene as
the coupling partner. Electron-rich (3ab and 3ah) and
electron-poor (3ac, 3ai, and 3aj) aroyl fluorides reacted well,
and the product ketones were obtained in 51−75% yield.
Halogen substituents were tolerated (3ad−ag), and aroyl
fluorides bearing an extended π system or heteroarenes like
thiophene and furan reacted to afford ketones 3ak−am in 52−
70% yield. Of note, no product was identified with benzoyl
chloride or benzoyl bromide instead of benzoyl fluoride. The
potential of the process was further documented by late-stage
functionalization of more complex activated alkenes. For
example, alkenes derived from D-phenylalanine, hormone,
natural product, and marketed drugs bearing an indole ring or
functional groups such as ketone, amide, halide, and ester
could all be aroylated at the α-position (3da−ha). Thus, our
process offers a good platform to access more complex α-
substituted vinyl ketones.
To illustrate the synthetic value of these α-substituted vinyl
ketones, a gram-scale reaction of 1m was conducted with
reduced amounts of the catalysts, and a comparable yield was
obtained (Scheme 3a). Furthermore, [3 + 2] annulation82 of
vinyl ketone 3a with an N-acylhydrazone provided dihydro-
1H-pyrazole 5 in 75% yield (Scheme 3b). Photoredox-
catalyzed hydroacylation of 3al with α-oxocarboxylic acid
gave 1,4-diketone 6 (Scheme 3c),83 and epoxidation of enone
3z afforded oxirane 7 in 71% yield (Scheme 3d).
To support the mechanism suggested in Scheme 1,
additional experiments were conducted. With acyl azolium
ion 8 as the substrate in the absence of the NHC, 4-
methylstyrene reacted in 51% yield to give vinyl ketone 3a,
indicating that acyl azoliums B (see Scheme 1) are competent
intermediates (Scheme 4a). The reaction between α-
methylstyrene and benzoyl fluoride with 1 equiv of p-
chlorophenyl sulfinate furnished the three-component coupling
product 9 in 48% yield (Scheme 4b). The absence of an acidic
proton at the position β to the sulfone moiety prevents the
sulfinate elimination, showing that three-component products
of type D are intermediates in these cascades.
cycles are interwoven. Along with the carbene, a photoredox
catalyst and a sulfinate catalyst are used for α-acylation of
alkenes with acyl fluorides to access α-substituted vinyl
ketones. The cascade exhibits high functional group tolerance.
Successful late-stage modification shows the potential of the
method, and useful follow-up chemistry on the product
ketones further documents the value of the process. Notably,
existing methods for acylation of aryl alkenes usually afford the
β-acylation products. Mechanistic studies indicate that the
reaction proceeds through a radical addition/coupling/
elimination cascade. We are confident that multiple catalysis
proceeding through NHC-catalyzed radical transformations
will enable the discovery of other novel transformations in the
future.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01022.
■
sı
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Armido Studer − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität, 48149 Munster, Germany;
̈
orcid.org/0000-0002-1706-513X; Email: studer@uni-
muenster.de
Author
Kun Liu − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität, 48149 Munster, Germany
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01022
Notes
The authors declare no competing financial interest.
Furthermore, to investigate the sulfinate elimination from D,
a parallel kinetic isotope effect (KIE) experiment was carried
out using 1z and [D]-1z as substrates (Scheme 4c). The two
reactions were stopped after 40 min, and on the basis of the
individual conversions, a KIE value of 2.8 was calculated. A
competition KIE experiment using equal amounts of 1z and
[D]-1z (0.5 equiv each) was stopped after 40 min, and analysis
of the unreacted starting alkene revealed a KIE value of 2.2
(Scheme 4d). These results indicate that the deprotonation
process might be involved in the rate-determining step.
Moreover, when the model reaction was conducted in the
presence of 2 equiv of 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO), the α-acylation was not observed. Instead,
benzoyl-TEMPO adduct 10 was isolated in 19% yield,
suggesting ketyl radical C as an intermediate (Scheme 4e).
On the other hand, the formation of adduct radical A was
supported by a radical probe experiment using styrene 11 as
the acceptor to give ring-opening product 12 (44% yield;
Scheme 4f). Finally, fluorescence quenching experiments
revealed that only sodium sulfinates quench the excited state
of Ru*(II) (see Figure S2 for details), supporting the reductive
quenching pathway. Thus, all of these experiments are in line
with our suggested mechanism.
ACKNOWLEDGMENTS
We thank the European Research Council (Advanced Grant
Agreement 692640) for supporting this work.
■
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