Mizoroki-Heck Reaction of Unstrained Aryl Ketones via Ligand-Promoted C-C Bond Olefination

Article abstract of DOI:10.1021/acs.orglett.1c00296

Mizoroki-Heck reaction of unstrained aryl ketone with acrylate/styrene is accomplished via palladium-catalyzed ligand-promoted C-C bond cleavage. Various (hetero)aryl ketones are compatible in the reaction, affording the alkene product in good to excellent yields. Further applications in the late-stage olefination of some drugs, natural products, and fragrance-derived aryl ketones demonstrate the synthetic utility of this protocol. By employing ketone as both the directing group and the leaving group, 1,2-bifunctionalization is achieved via sequential ortho-C-H alkylation/ipso-Heck olefination.

Full text of DOI:10.1021/acs.orglett.1c00296

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Letter
Mizoroki−Heck Reaction of Unstrained Aryl Ketones via Ligand-
Promoted C−C Bond Olefination
Mei-Ling Wang, Hui Xu, Han-Yuan Li, Biao Ma, Zhen-Yu Wang, Xing Wang, and Hui-Xiong Dai*
Cite This: Org. Lett. 2021, 23, 2147−2152
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ABSTRACT: Mizoroki−Heck reaction of unstrained aryl ketone with acrylate/styrene is accomplished via palladium-catalyzed
ligand-promoted C−C bond cleavage. Various (hetero)aryl ketones are compatible in the reaction, affording the alkene product in
good to excellent yields. Further applications in the late-stage olefination of some drugs, natural products, and fragrance-derived aryl
ketones demonstrate the synthetic utility of this protocol. By employing ketone as both the directing group and the leaving group,
1,2-bifunctionalization is achieved via sequential ortho-C−H alkylation/ipso-Heck olefination.
Scheme 1. Transition-Metal-Catalyzed C−C Olefination
ince the original report in the 1970s, the palladium-
catalyzed Mizoroki−Heck coupling between the alkene
S
and aryl electrophile has emerged as the most powerful tool for
the C−C bond formation1 and found wide applications in the
synthesis of pharmaceuticals, organic material, and natural
products.2 Besides olefination of aryl (pseudo)halides,2,3
various aryl electrophiles have been developed over the past
few decades via transition-metal-catalyzed C−O,3 C−N,4 C−
S,5 C−P,6 and C−H7 bond activation. C−C bonds are the
main constituents in the organic compound. To broaden the
substrate scope, transformation of simple organic compounds
into high-valued olefin product via transition-metal-catalyzed
C−C bond cleavage and reconstruction would be highly
appealing. Decarbonylative and decyanative Heck-type cou-
plings of aryl carboxylic acid derivatives,8−12 aldehydes,13 and
cyanides14 with terminal alkenes have been reported by de
Vries, Gooβen, Szostak, Miura, Li, and Morandi et al. (Scheme
1a). In recent years, chelation-assisted C−C bond activation
has emerged as a powerful tool for the generation of aryl
electrophiles (Scheme 1b).15 In 2011, Shi reported the
Rh(III)-catalyzed pyridinyl-directed alkenylation of secondary
arylmethanols via β-carbon elimination.16 Subsequently,
Johnson synthesized the aryl alkenes via the Rh(I)-catalyzed
olefination of aryl quinolinyl ketones.17 Very recently, Kakiuchi
achieved Rh(III)-catalyzed chelation-assisted olefination of
allylbenzenes and styrenes.18 Despite undisputable achieve-
ments, successful examples are limited to the substrates bearing
a nonremovable directing group.
Received: January 26, 2021
Published: March 4, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00296
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2147−2152
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b
c
Scheme 2. Screening of Ligands
Scheme 3. Substrate Scope
a
b
Isolated yield in the parentheses. Reaction conditions: 1a (0.1
mmol), 2a (0.2 mmol), Pd(MeCN)4(OTf)2 (10 mol %), ligand (35
mol %), Ag2CO3 (20 mol %), Na2CO3 (0.1 mmol), DCE (5.0 mL),
1
N2, 130 °C, 12 h. Yields were determined by H NMR spectroscopy.
Aryl ketones are useful intermediates in organic synthesis
and are commonly found in pharmaceuticals, natural products,
and organic materials.19 Conversion of aryl ketones into aryl
electrophiles to couple with alkene would significantly broaden
the scope of the olefin product. However, the cleavage of the
unstrained Ar−C(O) bond of aryl ketone often required a
directing group to enhance the reactivity.15 Recently, we
demonstrated that aryl ketone could be transformed to aryl
borates and aryl alkyne via palladium-catalyzed ligand-
promoted Ar−C(O) cleavage (Scheme 1c).20 To further
explore the potential application of this protocol, we report
herein the palladium-catalyzed pyridine-oxazoline-promoted
olefination of aryl ketone derivatives (Scheme 1d). Our
protocol shows good functional group tolerance and high
compatibility with various heterocycles. Late-stage diversifica-
tion of some natural products and pharmaceuticals further
demonstrated the broad utility of this protocol.
Aryl ketones could be facilely activated to ketone oxime
esters, which are important building blocks in organic
synthesis.21 Previously, we have paved an avenue from aryl
ketone to aryl palladium species via palladium-catalyzed β-aryl
elimination of oxime esters.20 The employment of an
appropriate ligand is the key to the success of the
transformation. Thus, after screening various palladium
catalysts, additives, bases, solvents, and temperatures, we
turned our attention to screening various ligands by treating
oxime ester 1a and methyl acrylate 2a in the presence of 10
mol % of Pd(MeCN)4(OTf)2, 20 mol % of Ag2CO3, and 1
equiv of Na2CO3 at 130 °C (Scheme 2, see the Supporting
Information for details). No desired product was detected
without the ligand. When phosphine ligands (L1−L3) were
a
b
c
Me instead of n-Pr. 2 (1.2 equiv). Reaction conditions: 1 (0.1
mmol), 2 (0.2 mmol), Pd(MeCN)4(OTf)2 (10 mol %), L26 (35 mol
%), Ag2CO3 (20 mol %), Na2CO3 (0.1 mmol), DCE (5.0 mL), N2,
130 °C, 12 h.
employed, the yields were improved to 7%. Carbene ligands
(L4, L5) and pyridine ligands (L6−L8) were also effective
compared to the ligand-free conditions. To our delight, N,N-
bidentate ligands (L9−L14) significantly increased the yields.
When 2,2′-bipyridine ligand L11 was employed, 3a was
obtained in 76% yield. Pyridine-oxazoline ligand L15, which
was the optimal ligand in our previous work,20a gave the
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a
Scheme 4. Late-Stage Diversification of Drugs and Natural Products
a
See the Supporting Information for detailed experiments.
Having identified the optimal ligands and the reaction
Scheme 5. Mechanistic Studies
conditions, we next explored the scope of aryl ketone
derivatives (Scheme 3). To our delight, an array of substituted
aryl ketones bearing both eletron-donating and -withdrawing
groups were all demonstrated to be suitable substrates, giving
the desired products 3a−3u in moderate to excellent yields
(Scheme 3a). A variety of functional groups, including methyl,
methoxyl, trifluoromethoxyl, fluoride, chloride, trifluoromethyl,
carboxylic ester, and alkene, could be well accommodated
under the optimal reaction conditions. When naphthyl ketone
substrates were employed, the coupling products 3v and 3w
were obtained in 93% and 62% yields, respectively. Next, we
investigated the alkyl groups in aryl ketones, including methyl,
ethyl, n-propyl, i-propyl, n-butyl, and arylethyl groups, giving
the desired products 3a in 60−96% yields (Scheme 3b).
Remarkably, diverse heteroaryl ketones containing thiophene,
pyridine, benzofuran, benzothiophene, quinoline, benzothia-
zoles, furan, and triazole proceeded smoothly, delivering the
corresponding olefination products 3x−3ah in 50−94% yields
(Scheme 3c). Next, we proceeded to examine the substrate
scope of olefin coupling partners (Scheme 3d). A range of α,β-
unsaturated olefins, including various acrylic esters, ketones,
phosphonates, and sulfones, were shown to be competent
substrates, delivering the desired products in moderate to good
yields (3ba−3bj). When styrenes were used as the substrates,
1,1-diphenylethylenes were often observed in previous Rh-
catalyzed decarbonylative Heck olefination.11 To our delight,
Scheme 6. Gram-Scale Synthesis
desired product in 74% yield. To further evaluate the
electronic and steric effects of the substituents in the ligands,
modifications in both pyridine and oxazoline moieties were
investigated (L16−L28). Comparably, substituents in oxazo-
line moieties have little influence on the yields, affording 3a in
51−75% yields (L16−L20). To our delight, ligands containing
a trifluoromethyl group in the 5-position of the pyridine
moiety (L26) provided almost quantitative yields with 96%
isolated yield. Sterically hindered ligands significantly de-
creased the yields (L27, L28).
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trans-stilbenes with single olefin isomers were obtained in 58−
97% yields (4a−4m).
AUTHOR INFORMATION
Corresponding Author
■
The promising functional group tolerance and heterocyclic
compatibility of the protocol promoted us to explore the
synthetic applications in the late-stage modification of
biologically important molecules (Scheme 4). Aryl ketones
derived from the medicinal drugs probenecid, adapalene, and
evodiamine, fragrance celestolide, and natural product
desoxyestrone proceeded smoothly, furnishing the correspond-
ing alkene products (5a−5h) in 50−81% yields (Scheme 4a).
Moreover, natural-product-derived acrylates were well suited
under the standard reaction conditions, giving the products
(5i−5l) in moderate to good yields (Scheme 4b). To further
highlight the synthetic practicability, cholesterol-derived
acrylate was facilely introduced to evodiamine and probene-
cid-derived ketone moieties, delivering the corresponding
products 5m and 5n in 50% and 70% yields, respectively
(Scheme 4c). To differentiate aryl ketone from aryl halide in
traditional Heck cross coupling, 1,2-bifunctionalization of
desoxyestrone ketone was accomplished by employing the
ketone group as a directing group for ortho-C−H alkylation
and a leaving group for C−C olefination (Scheme 4d).
To gain some insight into the mechanism, some control
experiments were carried out (Scheme 5). When butylated
hydroxytoluene (BHT) and 1,1-diphenyleylene (DPE) were
employed as radical scavengers, the cross-coupling proceeded
smoothly, which indicated that single electron transfer
processes might not be involved in the reaction. However,
the addition of 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO) completely inhibited the reaction, possibly due to
its oxidative capacity (Scheme 5 (1)). When 1a-1 was
employed, the olefin product 3ai and nitrile compound 3a-1
were obtained in 58% and 66% yield, indicating the aryl
palladium species were generated via the β-aryl elimination
process (Scheme 5 (2)).22
Hui-Xiong Dai − Chinese Academy of Sciences Key Laboratory
of Receptor Research, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Shanghai 201203,
China; University of Chinese Academy of Sciences, Beijing
100049, China; orcid.org/0000-0002-2937-6146;
Email: hxdai@simm.ac.cn
Authors
Mei-Ling Wang − Nano Science and Technology Institute,
University of Science and Technology of China, Suzhou,
Jiangsu 215123, China
Hui Xu − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Han-Yuan Li − Chinese Academy of Sciences Key Laboratory
of Receptor Research, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Biao Ma − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Zhen-Yu Wang − School of Chinese Materia Medica, Nanjing
University of Chinese Medicine, Nanjing, Jiangsu 210023,
China
Xing Wang − Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00296
Notes
To further demonstrate the feasibility of this transformation
for the gram-scale reaction, one-pot olefination of aryl ketone
1a′ with 2a on a 7.8 mmol scale was carried out, affording the
desired product 3a in 77% isolated yield (Scheme 6).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Shanghai Institute of Materia
Medica, the Chinese Academy of Sciences, the National
Natural Science Foundation of China (21772211,
21920102003), the Youth Innovation Promotion Association
CAS (No. 2014229 and 2018293), Institutes for Drug
Discovery and Development, Chinese Academy of Sciences
(No. CASIMM0120163006), the Science and Technology
Commission of Shanghai Municipality (17JC1405000 and
18431907100), the Program of Shanghai Academic Research
Leader (19XD1424600), and the National Science &
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2018ZX09711002-006), for
financial support.
In summary, we have developed an efficient protocol for the
palladium-catalyzed ligand-promoted Mizoroki−Heck reaction
of unstrained aryl ketones. Our protocol proceeded smoothly
in the absence of the chelation assistance, affording the olefin
products in good-to-excellent yields. The key to the success for
this strategy is the employment of a pyridine-oxazoline ligand.
The excellent functional group tolerance and heterocyclic
compatibility for both coupling partners made this protocol
attractive for the synthesis and modification of biologically
important molecules. Further exploration of this protocol in
the olefination of unstrained alkyl ketones and asymmetric
Heck reaction is currently ongoing in our laboratory.
REFERENCES
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ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00296.
Experimental procedures, characterizations of new
compounds, and NMR spectral data (PDF)
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