Palladium-Catalyzed meta-C-H Olefination of Arene-Tethered Diols Directed by Well-Designed Pyrimidine-Based Group

Article abstract of DOI:10.1021/acs.orglett.9b00433

The palladium-catalyzed meta-olefination of arene-tethered diols attached to a well-designed pyrimidine moiety is presented. Applications of the protocol are illustrated by the synthesis of various diol-based natural products, such as coumarins, phenylpropanoids, stilbenes, and chalcones. Advantages of this method are demonstrated through the easy removal of the template and a gram-scale olefination reaction. Finally, experimental verification, including ¹H NMR, ESI-MS and IR, and DFT studies are undertaken to elucidate the mechanistic complexity.

Full text of DOI:10.1021/acs.orglett.9b00433

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed meta-C−H Olefination of Arene-Tethered Diols
Directed by Well-Designed Pyrimidine-Based Group
Siqiang Fang, Xiaobing Wang,* Fucheng Yin, Pei Cai, Huali Yang, and Lingyi Kong*
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional
Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China
S
* Supporting Information
ABSTRACT: The palladium-catalyzed meta-olefination of arene-tethered diols attached to a well-designed pyrimidine moiety
is presented. Applications of the protocol are illustrated by the synthesis of various diol-based natural products, such as
coumarins, phenylpropanoids, stilbenes, and chalcones. Advantages of this method are demonstrated through the easy removal
of the template and a gram-scale olefination reaction. Finally, experimental verification, including 1H NMR, ESI-MS and IR, and
DFT studies are undertaken to elucidate the mechanistic complexity.
Scheme 1. Outline of the Research
ecently, carbon−hydrogen (C−H) functionalization has
Rshown great potential to dramatically streamline synthetic
efforts in total synthesis, semisynthesis, and the late-stage
diversification of natural products and pharmaceuticals.1
However, it is difficult to distinguish small differences in C−
H bonds in different locations and achieve specific selectivity.
With the introduction of a manifold of well-designed directing
groups (DGs) that can assist transition metals in differentiating
omnipresent C−H bonds, significant achievements were made
in transition-metal catalyzed C−H bond functionalization.2,3
Since carbonyl groups as DGs were presented,4,5 ortho-C−H
functionalization of arenes has gained momentum via steady
cyclometalation.6,7 Nevertheless, selective distal C−H bond
activation is still in its infancy owing to an unstable macrocyclic
transition state (TS) and intricate properties of substrates.
Despite undisputable achievements in the development of the
8,9
2
catalysis of remote Csp −H activation reactions,
the
Through the fine-tuning of DGs and reaction conditions, we
found Pd(OAc)2, Ac-Gly-OH, AgF, Na2CO3, and pyrimidine
as the DG were essential for achieving high yields and
selectivity (Tables S1−S5 from the SI). The subtle impact of
substrate chiralities on total yields was observed from Table S6
(SI). Next, the olefination of a variety of substituted arenes was
undertaken (Scheme 2). Exclusive meta-products were
founded for ortho-, meta-, and para-substituted substrates
with total isolated yields of 56−92% (1b−1r), and the reaction
showed good compatibility to electron-withdrawing groups as
well as electron-donating groups. For 1a, 1s, and 1t, which
have no substituted groups, some ortho- or para-products
efficiency and scope of those reactions via metal insertion
are far from enabling broad applications. In this domain, it is
crucial to strike a proper balance between the stability and
chelate ring size of a macrocyclic TS.10
Since the meta-olefination of alcohol compounds was
pioneered by Yu et al. using linear “end-on” coordinating
nitrile groups,11 the remote C−H functionalization of a variety
of alcohol has gradually evolved.12 Nevertheless, investigation
of the remote C−H functionalization of arene-tethered diols
has remained rare. Given the widespread occurrence of 1,2-diol
compounds in drug compounds and bioactive natural products
(Scheme 1a),13 the distal meta-C−H olefination of 3-
phenylpropane-1,2-diol has long been the focus of our
research. Initially, we envisioned that a template-based strategy
could potentially provide a route for our aim (Scheme 1b).
Received: February 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Functionalized Arenes and Olefin
Coupling Partners
Scheme 3. Utility of This Method
a b c
, ,
addition, to explore the elaboration of this approach, we used
the alkenylated product 3m or 3m′ as the reactant and thereby
achieved the synthesis of 5a, a coumarin analogue, by a ring-
closing reaction (Scheme 3b).
To elucidate the reaction mechanism, deuterium-labeling
experiments were performed. Two parallel experiments with 1a
and D-1a provided a kH/kD value of 1.17. Furthermore, an
intermolecular competition experiment was carried out and
gave a PH/PD value of 1.78 (Scheme 4a). This result suggests
that C−H activation is not the rate-limiting step, and the
mechanism may be related to radicals.14 Next, radical trapping
experiments were explored. The reaction still proceeded with
the addition of the radical scavengers TEMPO and BHT, and
there was no remarkable dropoff of the yield. These results
eliminate the possibility of a radical process (Scheme 4b). To
develop a better understanding of the reaction mechanism, the
reaction was monitored using real-time online 1H NMR.15 The
1H NMR analysis experiments were carried out in the same
clean NMR tube in a continuous sequence. For this
experiment, For-Gly-OH was used instead of Ac-Gly-OH. As
shown in Scheme 4c, upon the addition of the MPAA ligand
followed by the addition of substrate 1a, the absolute integral
of the acetyl (-Ac) peak gradually decreased and inversely the
acetic acid (AcOH) peak increased, which indicates the release
of the acetyl group from Pd(OAc)2 and then the formation of
the acetic acid. These results suggest the process from the
intermediate II′ to the intermediate III′. Meanwhile, this
process was also confirmed by the ESI-MS (Scheme 4d). In
addition, the formation of the interaction between the
palladium and substrate 1a was also proved by IR analysis
(see Figure S4 from the SI).
According to the above mechanistic studies and related
reports,16 a detailed description of our proposed mechanism
for this reaction is outlined in Scheme 5. Under standard
conditions, the interaction of Pd(OAc)2, HFIP, and Ac-Gly-
OH forms intermediate II. In the presence of 1a, the
intermediate II undergoes substrate binding to form
intermediate III, which leads to the formation of intermediate
IV, a 13-membered palladacycle. Subsequently, olefin coordi-
nation, 1,2-migratory insertion, β-hydride elimination, and
finally reductive elimination produce desired meta-olefinated
products, which may generate the hydroxylated compound
a
b
meta-C−H Olefinations were all undertaken on 0.1 mmol. Data
c
were reported as isolated yields. Others refer to ortho- or para-
products, and m/others values were determined by H NMR.
1
emerged. Next, a gram-scale experiment was performed to
demonstrate the utility of this protocol. With 1i of 1g, the
reaction was scalable in normal reaction equipment and gave
the olefinated products with a total yield of 66%. Gratifyingly,
the pyrimidine template was also available for the meta-C−H
olefination of 1s and 1t with different chain lengths, although
decreasing the aliphatic chain length distinctly reduced the
yield, possibly due to an increase in steric hindrance. In
addition, we further investigated whether the protocol could be
applied to a wide range of olefin coupling partners. As
expected, butyl acrylate, ketone, amide, and phosphonate (3aa,
3ac, 3ad, and 3ae, respectively) could all be effectively
tolerated with moderate to good yields. This reaction was also
suitable for the 1,2-disubstituted olefin (3ab). Notably, phenyl
vinyl sulfone, cyclohexene, phenyl ketene, and styrene gave no
hydrolysis products (3af−3ai). It might be attributed to spatial
or electronic effects.
Next, as shown in Scheme 3a, another major advantage of
this method is the easy removal of the template by a hydrolysis
step. Substrate 3a was readily converted to meta-olefinated free
benzyl diol 3a′ in 90% yield under acidic conditions. In
B
DOI: 10.1021/acs.orglett.9b00433
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Organic Letters
Letter
Scheme 4. Mechanistic Studies
Scheme 5. A Plausible Mechanistic Cycle
Scheme 6. Free Energy Profile for the Mechanistic Cycle
Scheme 4c and Scheme 4d can also lay a solid foundation for
HFIP intervention. Obviously, the deprotonation of 1a by the
amide of Ac-Gly-OH as an intramolecular base is significantly
endergonic,17 which illuminates why lower temperatures do
not enable this reaction to proceed. Notably, C−H activation
may occur through the concerted-metalation-deprotonation
(CMD) pathway.18
In conclusion, we have disclosed the PdII-catalyzed meta-C−
H olefination of arene-tethered diols attached to a pyrimidine
template. Electron-withdrawing and electron-donating groups
are tolerated at all positions on the 3-phenylpropane-1,2-diol
framework. The site-selective olefination of arene-tethered
diols across different linker lengths and a broad coupling
partner scope can enable the rapid adoption of this
methodology in the pursuit of bioactive natural products
including phenylpropanoids, stilbenes, chalcones, and coumar-
ins. Easy removal of the template and gram-scale reaction
demonstrated the utility of this protocol. Finally, experimental
and computational studies provide the basis of the reaction
mechanism. Further applications of this protocol to natural
compounds are underway.
through acid catalyzed hydrolysis in the case of HFIP.
Meanwhile, the Pd0 intermediate regenerates PdII by
reoxidation, which completes the mechanistic cycle.
To further illuminate this mechanism, DFT studies were
carried out (Scheme 6). The proposed initiation of the
mechanism is the formation of the monomeric Pd-Gly complex
I. At the same time, bidentate coordination between Ac-Gly-
OH and palladium may facilitate ligand exchange of the acetate
with HFIP. As shown in Scheme 6, the change from
intermediate I to II is exergonic, which indicates that HFIP
may act as an active ligand leading to coordination of the
substrate 1a. The 1H NMR and ESI-MS experiments shown in
C
DOI: 10.1021/acs.orglett.9b00433
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00433.
■
S
Detailed experimental and computational procedures
and compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cpu_lykong@126.com.
*E-mail: xbwang@cpu.edu.cn.
ORCID
Xiaobing Wang: 0000-0001-5044-3721
Lingyi Kong: 0000-0001-9712-2618
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Tanaka, K.; Chen, Q.-H.; Pissarnitski, N.; Streckfuss, E.; Yu, J.-Q. ACS
Cent. Sci. 2015, 1, 394−399.
This work was funded by grants from the National Natural
Science Foundation of China (81573313), the Six Talent
Peaks Project of Jiangsu Province (X.B.W., SWYY-107), the
Qing Lan Project of Jiangsu Province (X.B.W.), the Jiangsu
Province “333” Project (X.B.W.), the “111 Center” from the
Ministry of Education of China and the State Administration
of Foreign Export Affairs of China (No. B18056), and the
Innovative Research Team in University (IRT_15R63).
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DOI: 10.1021/acs.orglett.9b00433
Org. Lett. XXXX, XXX, XXX−XXX