Ligand-Promoted Alkynylation of Aryl Ketones: A Practical Tool for Structural Diversity in Drugs and Natural Products

Article abstract of DOI:10.1021/acscatal.0c05372

Conversion of the numerous aryl ketones into aryl electrophiles via Ar-C(O) cleavage remains a challenging yet highly desirable transformation in Sonogashira-type coupling. Herein, we report a palladium-catalyzed ligand-promoted alkynylation of unstrained aryl ketones. The protocol allows the alkynylation to be carried out in a one-pot procedure with broad functional-group tolerance and substrate scope. The potential applications of this protocol in drug discovery and chemical biology are further demonstrated by late-stage diversification of a number of pharmaceuticals and natural products. More importantly, two different biologically important fragments derived from a pharmaceutical and natural product could be connected by the consecutive alkynylation of ketones. Distinct from aryl halides in conventional Sonogashira reactions, the protocol provides a practical tool for the 1,2-bifunctionalization of aryl ketone by merging ketone-directed ortho-C-H activation with ligand-promoted ipso-Ar-C(O) alkynylation.

Full text of DOI:10.1021/acscatal.0c05372

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Research Article
Ligand-Promoted Alkynylation of Aryl Ketones: A Practical Tool for
Structural Diversity in Drugs and Natural Products
Hui Xu,§ Biao Ma,§ Zunyun Fu,§ Han-Yuan Li, Xing Wang, Zhen-Yu Wang, Ling-Jun Li, Tai-Jin Cheng,
Mingyue Zheng,* and Hui-Xiong Dai*
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ABSTRACT: Conversion of the numerous aryl ketones into aryl
electrophiles via Ar−C(O) cleavage remains a challenging yet
highly desirable transformation in Sonogashira-type coupling.
Herein, we report a palladium-catalyzed ligand-promoted alkyny-
lation of unstrained aryl ketones. The protocol allows the
alkynylation to be carried out in a one-pot procedure with broad
functional-group tolerance and substrate scope. The potential
applications of this protocol in drug discovery and chemical
biology are further demonstrated by late-stage diversification of a
number of pharmaceuticals and natural products. More impor-
tantly, two different biologically important fragments derived from
a pharmaceutical and natural product could be connected by the consecutive alkynylation of ketones. Distinct from aryl halides in
conventional Sonogashira reactions, the protocol provides a practical tool for the 1,2-bifunctionalization of aryl ketone by merging
ketone-directed ortho-C−H activation with ligand-promoted ipso-Ar−C(O) alkynylation.
KEYWORDS: alkynylation, Ar−C(O) cleavage, ligand, palladium, late-stage diversification
important molecules. However, the oxidative addition of a
lkynes are important functional groups in organic
Achemistry commonly found in natural products, pharma- transition metal into the Ar−C(O) bond would lead to the
ceuticals, and organic materials.1 Alkyne moieties are often
employed as versatile synthons in organic synthesis.2 The
azide-alkyne click reaction, for example, is a powerful tool
employed in the material and pharmaceutical sciences.3 In the
past few decades, considerable attention has been directed to
the construction of C(sp2)−C(sp) bonds, with the transition-
metal-catalyzed Sonogashira-type cross coupling between aryl
(pseudo)halides and alkynes being one of the most important
methodologies.4 To expand the structural diversity of alkyne
products, the development of new electrophilic coupling
partners involving transition-metal-catalyzed C−O,5 C−P,6
C−N,7 C−C,8 and C−H9 bond activation has recently
attracted considerable interest.
Aryl ketones are ubiquitous structural motifs found in
pharmaceuticals, natural products, and fragrances, such as
fenbufen, iloperidone, tonalid, and androsin.10 Conversion of
the numerous aryl ketones as new electrophiles to couple with
alkynes is a highly desirable transformation. Additionally, the
ketone functional group is often employed as an efficient
directing group in transition-metal-catalyzed C−H bond
functionalization, including C−C and C-heteroatom (O, N,
Cl, Br, I) bond formation.11 Thus, the diversification of aryl
ketones in pharmaceuticals and natural products via ketone-
directed ortho-C−H activation and subsequent ipso-Ar−C(O)
alkynylation would allow for the facile synthesis of biologically
formation of two weak C−M bonds, which is thermodynami-
cally unfavorable.12 Thus, the cross coupling of aryl ketones
with alkynes still remains an underdeveloped research area.
Very recently, our group has realized the ligand-promoted C−
C borylation of aryl ketone oxime esters.13 However, the
synthesis of aryl ketone oxime esters from aryl ketones often
requires a multistep procedure (including oximation with
hydroxylamine and esterification with pentafluorobenzoyl
chloride) and further purification by column chromatography,
which would restrict its further application (Scheme 1a).
Considering the significance of alkyne scaffolds in organic
synthesis and drug discovery, we report herein a ligand-
promoted one-pot alkynylation of aryl ketones (Scheme 1b).
Our protocol has broad applicability and can facilitate the
diversification of pharmaceuticals and natural products.
Distinct from aryl halides in conventional Sonogashira
reactions, aryl ketones are facilely 1,2-bifunctionalized by
employing the ketone group as the directing group for ortho-
Received: December 7, 2020
Revised: January 13, 2021
Published: January 22, 2021
https://dx.doi.org/10.1021/acscatal.0c05372
© 2021 American Chemical Society
ACS Catal. 2021, 11, 1758−1764
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less than 11% yield. Other substituted 2,2′-bipyridine ligands
(L6-L10) and 1,10-phenanthroline (L11) were also inves-
tigated, and the desired product could be obtained in a slightly
improved yield of 52% when L6 was employed. Next, we
screened various pyridine-oxazoline-type ligands (L12−L37),
which have shown high reactivity in our previous work.13
When L16 was employed in the reaction, the yield could be
improved to 56%. Pyrimidine-oxazoline (L15) and quinoline-
oxazoline ligands (L12−L14) were also effective, giving the
desired product in 40−54% yields. Next, we investigated the
substituents on the pyridine moiety. Electron-donating
methyl-, methoxyl-, and phenyl-substituted pyridine-oxazoline
groups at the 3-, 4-, 5-, and 6-positions of the pyridine moiety
provided the desired product in 40−56% yields. Electron-
withdrawing halo and trifluromethyl groups in the pyridine
moiety were also investigated, and L31 gave the desired
product in 70% yield. Further substituent screening on the
oxazoline moiety (L32−L37) showed that the methyl-
substituted oxazoline ligand L32 could improve the product
yield to 74%. Different oxime ethers were also investigated,
with 1a’ providing the best result (see the Supporting
Information). To our delight, the reaction could be carried
out in a one-pot procedure, and the oxime ether 1a’ could be
generated in situ from the aryl ketone and commercially
available 2,4-dinitrophenylhydroxylamine, affording the desired
product 3l in 72% yield under the standard reaction
conditions.
Scheme 1. Transformation of Ketone to Alkyne
C−H alkylation and leaving group for Ar−C(O) alkynylation
(Scheme 1c).
Aryl ketone 1a could be straightforwardly converted to
oxime ether 1a’ with commercially available 2,4-dinitrophe-
nylhydroxylamine.14 Thus, we commenced our studies by
treating 1a’ and alkynylsilane 2l in the presence of 10 mol %
Pd(dba)2 and 2 equiv. of K2CO3 at 130 °C. However, the
desired product was not observed. To our delight, 3l could be
obtained in 14% yield by employing 2,2′-bipyridine (L5) as the
ligand. After screening various palladium catalysts, temper-
atures, solvents, additives, and reaction times, the yield could
be improved to 50% (see the Supporting Information). Given
that the ligand plays a crucial role in this reaction, we further
examined different ligands (Table 1). Phosphine ligands (L1,
L2) were inefficient for this reaction. When carbene ligands
(L3, L4) were employed, the desired product was obtained in
With the optimal ligand and reaction conditions in hand, we
began to explore the substrate scope. As shown in Table 2,
under the optimized conditions (10 mol % Pd(MeCN)2Cl2, 30
mol % L32, 20 mol % NaBArF (sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate), 2 equiv. of K2CO3, 5 mL
of DCE/butyronitrile (5:1), 140 °C), the alkyne substrate
scope was investigated by using ketone 1a as a coupling
partner (Table 2A). The protocol appeared to be quite general
a
Table 1. Screening of Ligands
a
Reaction conditions: 1a’ (0.1 mmol), 2l (3 equiv.), Pd(MeCN)2Cl2 (10 mol %), K2CO3 (2.0 equiv.), ligand (0.3 equiv.), NaBArF (20 mol %),
DCE/n-PrCN = 5:1 (5 mL), 140 °C, 6 h. Yield was determined by GC−MS using diphenylacetylene as the internal standard. DPPE: 1,2-
bis(diphenylphosphino)ethane. IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. IMes: 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
b
The reaction was performed in a one-pot fashion.
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a
Table 2. Substrates Scope
a
Reaction conditions: ketone 1 (0.1 mmol), 2,4-di-NO2-PhONH2 (1.1 equiv.), hydrochloric acid, and EtOH (2.5 mL) were used for the first step.
After solvent evaporation, 2 (3 equiv.), Pd(MeCN)2Cl2 (10 mol %), K2CO3 (2.0 equiv.), L32 (0.3 equiv.), NaBArF (20 mol %), and DCE/n-PrCN
b
c
= 5:1 (5 mL) were added and stirred at 140 °C for the second step. Me instead of n-Pr in ketone 1. The ketone oxime ether was employed as the
d
starting material. Bis(trimethylsilyl)acetylene (5 equiv.), Pd(OAc)2 (0.1 equiv.), 2-(3-methoxypyridin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (0.35
equiv.), NaBArF (20 mol %), DCE (5 mL), and n-PrCN (1 mL) were added and stirred at 120 °C for the second step. TABF (10 equiv.) was
added for the third step.
with respect to the substituents on the alkyne. Aryl alkynes 2
bearing electron-donating or -withdrawing groups (−Me,
−OMe, −NMe2, −OCF3, −Ph, −F, −Cl, −CN, −NO2,
−CF3) gave the desired products 3a−3p in 51−74% yields.
When a naphthyl alkyne was subjected to the standard
conditions, the cross coupling product 3q was obtained in 58%
yield. Pyridine- and thiophene-substituted alkyne substrates
were also tolerated, affording the corresponding products 3ah
and 3ai in moderate yields, respectively. Next, different aryl
ketones were examined under the standard conditions by using
alkynylsilane (2c) as the coupling partner (Table 2B). In
general, aryl ketones bearing different substituents at the para-,
meta-, and ortho-positions provided the corresponding
products (3r−3af) in moderate to good yields. Spice
muskolide was also a suitable substrate, giving the correspond-
ing product 3ag in 40% yield. By employing 2c as the
alkynylating reagents, aryl ketones bearing different alkyl
groups, including the methyl, ethyl, n-propyl, i-propyl, n-
butyl, and phenyl functionalities, were also investigated, and
the desired products 3c were obtained in 46−74% yields
(Table 2C). Significantly, our protocol shows high compati-
bility with various heteroaryl ketones, including furan, pyridine,
benzofuran, benzothiophene, indole, quinoline, triazole, and
benzothiazoles, furnishing the synthetically valuable alkyne
products 3aj−3aq in yields of 52−70% (Table 2D). Terminal
alkynes are versatile synthons in organic synthesis, especially
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a
Scheme 2. Late-Stage Diversification of Drugs and Natural Products
a
See the Supporting Information for detailed experiments.
for use in Sonogashira couplings, click reactions, and enyne
metathesis.1 However, only a moderate yield was obtained
under the optimal reaction conditions. After screening of
various ligands (see the Supporting Information), cross
coupling of (hetero)aryl ketones with bis(trimethylsilyl)-
acetylene afforded the corresponding terminal alkynes in
41−77% yields after desilication (Table 2E).
To demonstrate the synthetic robustness of this method, we
applied this protocol to the late-stage diversification of aryl
ketones derived from the medicinal drugs probenecid,
adapalene, and evodiamine and the natural product desoxy-
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Scheme 3. Mechanistic Studies
estrone (due to the low reactivity or poor solubility of some
ketone substrates, the corresponding oxime esters were
employed as the starting materials, see the Supporting
information) (Scheme 2). The corresponding alkyne products
were obtained in moderate to good yields (Scheme 2A). The
alkynylation of the natural product androsin 1bj and
subsequent downstream click reaction with tosyl azide could
conveniently introduce a 1,2,3-triazole group into the natural
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product (Scheme 2B). To further elaborate on the synthetic
utility of this protocol, consecutive alkynylations of ketone
substrates allowed for the connection (via a carbon−carbon
triple bond) of two different biologically important fragments
derived from a pharmaceutical compound and a natural
product, forming 5a and 5b in 63 and 48% yields, respectively
(Scheme 2C). Differing from aryl halides in conventional
Sonogashira reactions, by employing a ketone group as both
the directing group and leaving group, the natural product
deoxyestrone could be 1,2-bifunctionalized via ketone-directed
ortho-C−H alkylation and subsequent ligand-promoted ipso-
Ar−C(O) alkynylation (Scheme 2D).
Experimental procedures, characterization of com-
pounds, NMR spectral data, and DFT calculations
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Mingyue Zheng − Drug Discovery and Design Center, State
Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, Shanghai
201203, China; orcid.org/0000-0002-3323-3092;
Email: myzheng@simm.ac.cn
Hui-Xiong Dai − Chinese Academy of Sciences Key Laboratory
of Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China; orcid.org/0000-0002-2937-6146; Email: hxdai@
simm.ac.cn
In order to gain a better insight into the reaction
mechanism, we carried out a number of control experiments
(Scheme 3A). Considering that oxime ether N−O bonds are
very weak (33−37 kcal/mol), they can easily generate N- and
O-centered radicals at moderate temperatures via homolytic
scission.14,15 However, the addition of the radical scavengers
TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) and BHT
(butylated hydroxytoluene) had a negligible impact on the
product yield, indicating that the reaction may not involve a
radical pathway (Scheme 3A-(1)). When pharmaceutical
fenbufen derivative 9 was subjected to the standard conditions,
the alkynylation product 3u and corresponding nitrile
compound 10 were obtained in 64 and 58% yields, respectively
(Scheme 3A-(2)). No desired product was detected when
amide 11 was employed under the standard conditions,
indicating that the 1,2-shift of the aryl group may not be
involved (Scheme 3A-(3)). Based on the above experiments
and a previous report,16 a plausible mechanism has been
proposed as shown in Scheme 3B. First, oxidative addition of
Pd(0) into the N−O bond of the oxime ether 1a’ gives the
palladium(II) intermediate I’, which can isomerize to
intermediate I. Computational studies showed that ligand-
promoted β-aryl elimination of I’ via transition state TS1 is
more favorable with a lower activation barrier (ΔG = 23.5
kcal/mol) than β-alkyl elimination via transition state TS1’
(ΔG = 35.9 kcal/mol) (Scheme 3C). Subsequent trans-
metallation of the aryl palladium species II with alkyne 2c gives
intermediate III. K2CO3 is assumed to promote the trans-
metallation process.4 Finally, palladium species III undergoes
reductive elimination to form the alkyne product 3c and
regenerate the Pd(0) species.
Authors
Hui Xu − Chinese Academy of Sciences Key Laboratory of
Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Biao Ma − Chinese Academy of Sciences Key Laboratory of
Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Zunyun Fu − School of Chinese Materia Medica, Nanjing
University Of Chinese Medicine, Nanjing, Jiangsu 210023,
China
Han-Yuan Li − Chinese Academy of Sciences Key Laboratory
of Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Xing Wang − Chinese Academy of Sciences Key Laboratory of
Receptor Researc, Shanghai Institute of Materia Medicah,
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
Ling-Jun Li − Chinese Academy of Sciences Key Laboratory of
Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China
In summary, we have developed a palladium-catalyzed
pyridine-oxazoline-promoted alkynylation of unstrained aryl
ketones via Ar−C(O)bond cleavage. A variety of alkyne
products were synthesized with excellent functional-group
tolerance and heterocyclic compatibility. Late-stage diversifi-
cation of a number of pharmaceuticals and natural products
demonstrates the synthetic practicality of this methodology
and its potential application in drug discovery. 1,2-Bifunction-
alization of the natural product deoxyestrone was accom-
plished via ketone-directed ortho-C−H alkylation and ligand-
promoted ipso-Ar−C(O) alkynylation. Further applications of
this protocol to unstrained alkenyl and alkyl ketones are
currently ongoing in our laboratory.
Tai-Jin Cheng − Chinese Academy of Sciences Key Laboratory
of Receptor Researc, Shanghai Institute of Materia Medicah,
University of Chinese Academy of Sciences, Shanghai 201203,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05372
Author Contributions
§H.X., B.M., and Z.F. contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Shanghai Institute of Materia
Medica, the Chinese Academy of Sciences, the NSFC
(21772211, 21920102003), the Youth Innovation Promotion
Association CAS (Nos. 2014229 and 2018293), the Science
and Technology Commission of Shanghai Municipality
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05372.
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