Remote and Selective C(sp2)-H Olefination for Sequential Regioselective Linkage of Phenanthrenes

Article abstract of DOI:10.1021/acs.orglett.0c01208

Biphenylcarboxylic acid with two competing C(sp²)-H sites was designed for site selective C(sp²)-H functionalization by developing carboxylic acids assisted remote and selective olefination via 7-membered palladacycle. Mechanism investigation and DFT calculations reveal a kinetics-determined process, which could be utilized to explore a variety of remote site selectivity. The practicability of this method was highlighted by the precise construction of phenathrene under sequential site selectivity.

Full text of DOI:10.1021/acs.orglett.0c01208

pubs.acs.org/OrgLett
Letter
Remote and Selective C(sp2)−H Olefination for Sequential
Regioselective Linkage of Phenanthrenes
Yi Wei,# Abing Duan,# Pan-Ting Tang, Jia-Wei Li, Rou-Ming Peng, Zheng-Xin Zhou, Xiao-Peng Luo,
Mohamedally Kurmoo, Yue-Jin Liu,* and Ming-Hua Zeng*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01208
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ABSTRACT: Biphenylcarboxylic acid with two competing C-
(sp2)-H sites was designed for site selective C(sp2)-H functional-
ization by developing carboxylic acids assisted remote and selective
olefination via 7-membered palladacycle. Mechanism investigation
and DFT calculations reveal a kinetics-determined process, which
could be utilized to explore a variety of remote site selectivity. The
practicability of this method was highlighted by the precise
construction of phenathrene under sequential site selectivity.
Scheme 1. Remote Functionalization of Carboxylic Acids via
he control of site selectivity is one of the ultimate goals
Tand challenges on the road to synthetic chemistry
progress.1 It is therefore highly desired to track the process
and analyze the mechanism for further understanding the
source of site selectivity governing the synthetic protocol.2,3
To control site selectivity in organic synthesis, introducing
directing groups is a common strategy,4 which has made much
progress for substrates with a single reaction site in the vicinity
of the directing group.5 However, it is still hard to control site
selectivity when two or more competitive reaction sites exist
near the directing group.6 Consequently, investigating the site-
selective methodology, mechanism, and source of multisite
competition assisted by the directing group still remains
challenging. When it comes to transition metal catalytic
directed C−H functionalization, there is a new opportunity for
the above challenge7,8 since cyclometalation reaction relatively
facilitates tracking the process and analyzing the mechanism to
understand whether kinetics or thermodynamicss controls the
reaction.9
Selective C(sp2)−H Activation
Among common substrate functional groups, carboxylic acid
has proved to be a highly effective directing group to assist the
transition metal and position it to break the C(sp2)−H bond
for cyclometalation.10,11 For aromatic carboxylic acid deriva-
tives with a single activation site, the ortho-C−H activation was
pioneered by Yu, Ackermann, Gooßen, and other groups
(Scheme 1a).12,13 Yu’s group further accounted for the source
of selectivity control, resulting from the 5-membered metal-
lacycle intermediate assisted by carboxyl coordination.12k
However, site-selective C−H bond functionalization for
carboxylic acid directed multisite activation is rarely inves-
tigated. Recently, Li’s group used the carboxylic-acid-assisted
κ2 coordination mode to form a U-shaped template to realize
meta-C(sp2)−H activation during competition of multiple C−
H bonds.14
Our group has been working on selective C−H cleavage
assisted by carboxylic acids. ortho-C−H alkynylation of
aromatic acid via a 5-palladacycle11a and 6-palladacycle10c
was included. Then, we found site-selective formation of
pyrano[4,3-b]indol-1(5H)-ones from indole-3-acids, and ole-
fins involve a 7-palladacycle as an intermediate during
Received: April 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01208
© XXXX American Chemical Society
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A

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a
Table 1. Reaction Optimizations
entry
ligand (20 mol %)
oxidant (x equiv)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
AgOAc (1.0)
BQ(1.0)
base (x equiv)
solvent
yield of 3 + 4 [%] (δ′: β)
1
2
3
5
6
7
8
9
---
---
---
---
---
---
---
---
---
---
---
---
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (1.5)
---
---
---
---
---
---
---
---
---
---
---
DMF
DCE
25 (1:1.0)
35 (1:1.2)
37(1:1.6)
30 (1:1.0)
41 (4.1:1)
33 (2.7:1)
47 (3.7:1)
trace
toluene
dioxane
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
10
11
12
13
14
15
16
17
18
Cu(OAc)2 (1.0)
AgCO2CF3 (1.0)
Ag2CO3 (1.0)
trace
49 (2.5:1)
47 (3.6:1)
48 (5.0:1)
67 (7.4:1)
62 (>20:1)
63 (>20:1)
86 (>20:1)
46 (1:1.4)
Ag2CO3 (2.0)
---
Ag2CO3 (2.0)/BQ (1.0)
Ag2CO3 (2.0)/BQ (1.0)
Ag2CO3 (2.0)/BQ (1.0)
Ag2CO3 (2.0)/BQ (1.0)
Ag2CO3 (2.0)/BQ (1.0)
b
AdCO2H
N-Ac-GIy-OH
N-Ac-AlaOH
N-Ac-Ala-OH
b
b
c
a
Conditions: 1a (0.1 mmol), 2a (5.0 equiv), Pd(OAc)2 (10 mol %), ligand (0.2 equiv), oxidant, base, solvent (0.5 mL), 100 °C, 12 h, air
b
c
atmosphere. NMR yield analyzed by CH2Br2 as an inner standard, δ′/β = (3aa + 3aa′)/4. 80 °C. 140 °C.
a
Scheme 2. Scope of Selective δ′-C(sp2)−H Olefination Reaction via Palladacycle 7
a
Conditions: 1 (0.1 mmol, 1.0 equiv), 2 (5.0 equiv), Pd(OAc)2 (10 mol %), N-Ac-Ala-OH (0.2 equiv), Ag2CO3 (2.0 equiv), benzoquinone (1.0
b
c
equiv), HFIP (0.5 mL), 80 °C, 12 h, air atmosphere; yields of monoalkenylated product; [ ] yields of dialkenylated product. 60 °C, 24 h. Without
benzoquinone. AgOAc (2.0 equiv), t-amylOH (0.5 mL), 60 °C.
d
B
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competition between 7-palladacycle and 6-palladacycle.11b
Based on our past research, we rationally design biaryl
carboxylic acids with competing C−H sites in adjacent
aromatic rings. Here, we aim to explore the selectivity and
origin of carboxylic acid coordination to form a conventional
5-membered metallacycle intermediate or unusual 7-mem-
bered metallacycle intermediate for further site selectivity
control and theoretical calculation analysis, which offer
examples for studying thermodynamics and kinetic control in
cyclometalation (Scheme 1b). Considering the remote
selectivity achieved, it is convenient to sequentially control
the site selectivity for the transformation to phenanthrene15
through decarboxylative C−H functionalization, namely, that
the remote C−H bond could be transformed into the C−C
bond under sequential control, which offers a new opportunity
for the construction of the valuable aromatic polycyclic
compounds (Scheme 1c).
Based on previous studies, we speculate that the selective δ′-
C(sp2)−H functionalization of carboxylic acid will be achieved
by rational optimizations of the reaction conditions (Table 1).
When the reaction was carried out with 1a and methyl acrylate
2a in the presence of 10 mol % of Pd(OAc)2, 1.0 equiv of
AgOAc, and 0.5 equiv of NaOAc, at 100 °C under air in DMF
(0.5 mL) for 12 h, both remote δ′-C−H olefinic product 3aa
via 7-membered palladacycle and ortho-β-C−H olefination and
annulation product 4 via 5-membered palladacycle were
obtained in 25% yield with low site selectivity (δ′/β = 1:1).
To realize the high selectivity of δ′-C−H functionalization, the
reaction was extensively investigated. (For details see
Supporting Information.) Among the diverse solvents used,
the hexafluoroisopropanol (HFIP) exerts a slight improvement
in the site selectivity (δ′/β = 4.1:1), which is associated with its
acidic nature being favorable for electron-rich δ′-C−H
activation via the electrophilic metalation process (entry 6).
Next, we investigated the effect of base on the selectivity of the
reaction, given that it promotes concerted metalation
dehydrogenation during transition-metal-catalyzed C−H acti-
vation. As expected, the δ′-olefinated product 3aa could further
increase in the absence of base (entry 8). Considering that
oxidants are essential to this oxidative Heck reaction, different
oxidants were investigated. The combination of Ag2CO3 and
1,4-benzoquinone gave the remote δ′-C(sp2)−H alkenylated
products in 59% yield and the ortho-β-C−H-functionalized
product 4 in 8% yield (entry 14). To our delight, the δ′-
selectivity could be further improved (>20:1) when the
reaction was conducted at 80 °C. Lastly, various amino acids
as auxiliary ligands were tested and found to improve the yield
(entries 15−17). Although most of the acids had a positive
effect on the yield, N-acetyl-protected alanine was most
effective, delivering the high yield (86%) including mono-
olefinated product (64%) with diolefinated product (22%) and
site selectivity (δ′: β > 20:1, entry 17). However, low yield and
selectivity were observed when the reaction was conducted at a
higher temperature (entry 18).
over, multisubstituted substrates, such as 3,4-disubstituted
biaryl carboxylic acids (3oa), successfully gave the desired δ′-
C(sp2)−H alkenylated products in moderate yields. Moreover,
the biaryl carboxylic acids containing heteroarenes such as
thiophene and furan could also give the site-selective δ′-
functionalized products but in reduced yields (3ra and 3sa).
However, as for 2-(furan-2-yl)biaryl carboxylic acids (3ta),
there is no desired alkenylated product. We speculate it is a
consequence of the more stable palladium complex formation
due to palladium ion coordination to the carboxylic group and
oxygen of furan. Furthermore, this reaction is also effective for
other types of acid substrate such as arylacrylic acid, generating
the δ′-C(sp2)−H-alkenylated product in good yields (3ua and
3va).
After simple optimization of reaction conditions, less acidic
solvent (t-AmylOH) and AgOAc as oxidant are used. This
reaction can also be applied to 2-alkenyl benzoic acid. Cyclic
olefin substrates can afford a site-selective conjugated diene
product in acceptable yields (3wa−3ya), and chain olefinic
benzoic acid gave the mixture of Z- and E-type products in
good yields (3za). Unfortunately, this reaction is not suitable
for substrates bearing monosubstituted olefins and disubsti-
tuted olefins.
Then, we investigated the scope of olefin reactants. Various
acrylates (2b−2i) underwent a facile reaction with 1a to afford
the corresponding δ′-C(sp2)−H mono-(3aa−3ae) in good
yields (62%−71% total). However, tert-butyl acrylate (2h) had
no activity under the reaction conditions, possibly due to steric
effects of the tert-butyl group. In addition to acrylates, phenyl
sulfone was suitable for this protocol, giving the corresponding
product 3ai in 51% yield. Unfortunately, styrene and alkyl
olefins proved no activities.
To prove the practicability of this reaction, the scale-up
reactions were conducted under standard reaction conditions
first (Scheme 3). Most of the large-scale reactions (2−4 mmol)
of aromatic acids 1 and olefins 2 proceeded smoothly under
standard conditions, delivering the desired δ′-C−H olefinated
products in moderate to good yields, which provided sufficient
feedstock for subsequent diverse conversion of products.
a
Scheme 3. Large-Scale Reaction
Having identified the optimal conditions, the scope of biaryl-
2-carboxylic acids was first investigated (Scheme 2). Aromatic
acids with either electron-donating or electron-withdrawing
groups were smoothly alkenylated to afford the site-selective
δ′-C(sp2)−H olefinic products with excellent site selectivity
(3ba−3la). The structure of 3fa was determined by X-ray
analyses. Notably, various halogens, even the Br substituent,
were tolerated under optimized conditions, generating the
remote δ′-C−H alkenylated products in good yields. More-
a
Conditions: 1 (2 or 4 mmol), methyl acrylate 2 (5.0 equiv),
Pd(OAc)2 (10 mol %), N-Ac-Ala-OH (0.2 equiv), BQ (1.0 equiv),
and Ag2CO3 (2.0 equiv) at 80 °C in HFIP for 12 h. Isolated yield.
C
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Having the unique δ′-C(sp2)−H olefinated products in
hand, we were inspired by decarboxylative C−H functionaliza-
tion and utilized them in the syntheses of phenanthrenes which
are valuable skeletons found in numerous functional materials
and medicinal compounds.16 A series of substituted methyl
phenates were prepared simply and efficiently from olefinated
products 3 via decarboxylative C−H functionalization reaction
(Scheme 4). It is noteworthy that the δ′-substituent could
Scheme 5. Mechanistic Studies
Scheme 4. Synthesis of Phenanthrenes from δ′-Olefinated
a
Carboxylic Acids
activation step proceeds via a facile base-assisted internal
substitution-type C−H activation process (Scheme 5b).
Moreover, one-pot competitive reaction between 1a and
d5−1a proves the significant kinetic isotope effect, which
indicates that the δ′-C(sp2)−H bond cleavage may be the
limiting step (Scheme 5c).
Then, density functional theory (DFT) was performed to
further understand the unconventional δ′-selectivity. First, two
possible pathways were proposed to reveal the origin of
selectivity (Figure 1). The activation free energy (AFE) of δ′-
C−H bond cleavage assisted by the carboxylic acid is 24.4
kcal/mol, lower than that of the β-C−H metalation pathway
(30.7 kcal/mol). This implies that the formation of the 7-
membered palladacycle is a kinetic favorable process, which is
consistent with the selectivity of experimental results. Second,
a
Conditions: 3 (0.1 mmol), NIS (0.4 mmol), and K2CO3 (0.1 mmol)
at 100 °C in 0.5 mL of CH3CN for 12 h. Isolated yields.
suppress this transformation, probably due to a strong steric
effect of the δ′-substituent, giving the desired methyl phenates
(7b) in 27% yield. This transformation offers a new protocol
for the preparation of multisubstituent phenanthrenes, with
much more available aromatic carboxylic acids and olefins as
starting materials.
To investigate high site selectivity for the δ′-C(sp2)−H
bond, a combination of different techniques was conducted.
First, H/D exchange experiments were performed in heavy
water, D2O. The deuteration reaction of 1a mainly occurs at
the δ′-C(sp2)−H bond (D, 20%), while a trace amount of
deuterated product was detected at the β-position (D, <5%)
(Scheme 5a). This result showed that under our optimized
reaction conditions the activation process of the δ′-C(sp2)−H
bond is favorable and faster over that of the β-C(sp2)−H bond.
This is consistent with the selectivity of δ′-C−H metalation
and functionalization because of the more electron-rich δ′-C
center. Furthermore, an intermolecular competition experi-
ment was conducted to examine the electron-rich substrate 1i
and its electron-deficient counterpart 1j. The higher yield for
1i than for 1j highlights the fact that electron-rich substrates
are inherently more reactive, implying that the δ′-C−H
Figure 1. DFT-computed relative Gibbs free energy profiles of C−H
functionalization step transition states.
D
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the AFE of the δ′-C−H bond cleavage is the highest, implying
the δ′-C−H activation is the rate-determining step in this
transformation, which is in agreement with the experimental
results (Scheme S6).
Abing Duan − College of Environmental Science and
Engineering, Hunan University, Changsha 410082, China
Pan-Ting Tang − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China
Jia-Wei Li − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China
Rou-Ming Peng − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China
Zheng-Xin Zhou − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China
Xiao-Peng Luo − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China
Mohamedally Kurmoo − Institut de Chimie de Strasbourg,
In conclusion, we have realized carboxylic acid remote C−H
functionalization to obtain δ′-olefinated carboxylic acids by
rational design of biphenylcarboxylic acid with two competing
C(sp2)−H sites. Moreover, the reaction has the advantages of
broad substrates, good functional group tolerance, and
excellent regioselectivity. The principle of using acidic
conditions to promote the electrophilicity of palladium catalyst
is the key to achieve high regioselectivity of this reaction.
Mechanism investigation and DFT calculations clarify the
remote site selectivity, originating from a kinetically favorable
seven-membered palladacycle. More interestingly, under
sequential site selectivity control, it is convenient to transform
to phenanthrene through decarboxylative C−H transforma-
tion, which offers a new strategy for sequential construction of
multisubstituted aromatic polycyclic compounds commonly
found in natural products.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01208.
Detailed experimental procedures and compound
characterization data (PDF)
́
CNRS-UMR7177, Universite de Strasbourg, Strasbourg 67070,
Accession Codes
France; orcid.org/0000-0002-5205-8410
CCDC 1981706 and 1981722 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01208
Author Contributions
#Y.W. and A.D. contributed equally.
Notes
AUTHOR INFORMATION
■
The authors declare no competing financial interest.
Corresponding Authors
Yue-Jin Liu − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China;
orcid.org/0000-0003-4226-0890; Email: liuyuejin@
hubu.edu.cn
Ming-Hua Zeng − Hubei Collaborative Innovation Center for
Advanced Chemical Materials, Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules and College of Chemistry and Chemical
Engineering, Hubei University, Wuhan 430062, China;
Department of Key Laboratory for the Chemistry and Molecular
Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin
541004, China; orcid.org/0000-0002-7227-7688;
Email: zmh@mailbox.gxnu.edu.cn
ACKNOWLEDGMENTS
■
We thank the National NSF of China (Grant 21525101), the
NSF of Hubei Province (Grants 2018CFB156 and
2017CFA006), the Program of Ministry of Education Key
Laboratory for the Synthesis and Application of Organic
Functional Molecules (Grant KLSAOFM1702), and the
BAGUI talent program and the NSFGX (Grants
2019AC26001 and 2017GXNSFDA198040) for their financial
support. M.K. is funded by the CNRS-France.
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