Palladium-Catalyzed meta-Selective C-H Functionalization by Noncovalent H-Bonding Interaction

Article abstract of DOI:10.1021/acscatal.1c02974

Controlling positional selectivity represents one of the most important aspects in transition-metal-catalyzed C-H bond functionalization. However, the conventional directing template strategies via a covalent binding to the substrates are always hindered by prior stoichiometric installation and removal of the directing groups. Herein, we report a palladium-catalyzed meta-selective C-H olefination of aromatic carbonyl compounds by noncovalent hydrogen-bonding interaction. N,N′-Substituted ureas were engineered to serve as a H-bonding donor for binding to the substrates and, meanwhile, achieve site-selective control by the integrated directing group.

Full text of DOI:10.1021/acscatal.1c02974

pubs.acs.org/acscatalysis
Letter
Palladium-Catalyzed meta-Selective C−H Functionalization by
Noncovalent H‑Bonding Interaction
Guoshuai Li, Yifei Yan, Pengfei Zhang, Xiaohua Xu,* and Zhong Jin*
Cite This: ACS Catal. 2021, 11, 10460−10466
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Controlling positional selectivity represents one of
the most important aspects in transition-metal-catalyzed C−H
bond functionalization. However, the conventional directing
template strategies via a covalent binding to the substrates are
always hindered by prior stoichiometric installation and removal of
the directing groups. Herein, we report a palladium-catalyzed meta-
selective C−H olefination of aromatic carbonyl compounds by
noncovalent hydrogen-bonding interaction. N,N′-Substituted ureas
were engineered to serve as a H-bonding donor for binding to the
substrates and, meanwhile, achieve site-selective control by the
integrated directing group.
KEYWORDS: palladium, noncovalent H-bonding interaction, C−H activation, olefination, urea
ransition-metal-catalyzed remote meta- or para-C−H
Scheme 1. Noncovalent Bonding Strategies for Pd-
Catalyzed Distal C−H Functionalization
T
bond functionalization of arenes1,2 has attracted the
extensive interest from both chemical and medicinal
communities in recent years owing to its vast potentials for
step- and atom-economic synthesis of active pharmacophores,
as well as late-stage diversification of pharmaceuticals. To
render the catalyst proximal to the distal C−H bond efficiently,
the C−H activation process frequently requires the partic-
ipation of a deliberated σ-bonding directing group (DG) in the
formation of a metal-embedded macrocyclic transition state.
However, the stoichiometric installation and removal of a DG
consistently influence the synthetic efficacy of the C−H
functionalization strategy.3,4 Moreover, some kinds of sub-
strates such as aromatic aldehydes/ketones and esters, among
others, are incompatible with the DG’s methodology because
they lack a site for the installation of DG. In contrast, the
employment of noncovalent bonding interactions to direct
transition-metal-catalyzed C−H functionalization remarkably
solves these irreconcilable conflicts. For instance, through
various noncovalent bonding interactions,5−8 iridium-catalyzed
meta-C−H borylation of arenes has been successfully achieved
by several research groups to date.
Relative to the high reactivity of iridium catalysts, palladium-
catalyzed remote C−H activation based on noncovalent
bonding interactions still remains extremely challenging to
date. In 2017, a class of bifunctional directing templates based
on noncovalent Lewis acid/base coordination was elegantly
designed by the Yu group for Pd-catalyzed distal C−H
alkenylation of heteroarenes,9 for example, quinolines (Scheme
1a). In such a template, one palladium atom fixed in the
template central scaffold is in charge of reversibly anchoring
substrates by heteroatom coordination, and the other
regioselectively cleaves the distal C−H bonds by coordination
to the DG. Subsequently, through utilizing symmetrically
bidentate nitrile templates (Scheme 1a), the Maiti group also
realized Pd-catalyzed distal C−H alkenylation and alkylation in
the same heteroarenes based on the template designed by Yu’s
group.10 To date, the intermolecular hydrogen-bonding
approach to achieve the palladium-catalyzed remote C−H
Received: July 2, 2021
Revised: July 26, 2021
https://doi.org/10.1021/acscatal.1c02974
© XXXX American Chemical Society
ACS Catal. 2021, 11, 10460−10466
10460

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
activation of arenes is yet to be exploited probably because of
the perceived lower reactivity. To address this, we sought to
investigate aromatic carbonyl compounds in palladium-
catalyzed remote meta-C−H activation, envisaging that the
carbonyl group serving as a hydrogen-bond acceptor would be
able to pair with a hydrogen-bond donor bearing a suitable
directing template. N,N′-Substituted ureas behave as the
strong double hydrogen-bond donors, shown thus far to be
capable of assembling a lot of guest acceptor molecules
including aldehydes, ketones, esters, imines, N-acyliminium
ions, and nitro compounds.11 Herein, we report that the N,N′-
substituted urea scaffold is highly proficient as a hydrogen-
bond donor to direct palladium-catalyzed C−H functionaliza-
tion to the meta position in a series of arene substrates bearing
the carbonyl group as hydrogen-bond acceptors.
Scheme 2. Evaluation of Hydrogen-Bonding Donors for Pd-
Catalyzed meta-C−H Olefination
a
Based on the Yu’s pioneering work3a on remote meta-
selective C−H functionalization directed by a covalently U-
shaped template, a range of DGs for transition-metal-catalyzed
distal C−H functionalization have been developed since then.
Over the past few years, We,12 Yu,13 Maiti,14 and others15 have
identified a substituted salicylonitrile moiety as the versatile
template to direct palladium-catalyzed meta-C−H functional-
ization in various arene derivatives. In approaching the
development of an efficient hydrogen-bonding donor template,
we began by elaborating an appropriate N,N′-substituted urea
framework for Pd-catalyzed remote C−H functionalization of
arenes, according to the experimental and computational
results established for the covalently binding template-
s.12a,13b,16 By integrating a salicylonitrile-bearing tether into
the urea backbone, a powerful double hydrogen-bonding
interaction appears plausible with an aromatic carbonyl
substrate promoting C−H activation at the meta position of
the phenyl ring. Therefore, we first synthesized a series of N-
cyclohexyl ureas, L1−L5, containing an additional directing
functional group on the other nitrogen atom (Scheme 2).
Using acetophenone as a model substrate, C−H olefination
only gave the poor reactivity with a mixture of o-, m-, and p-
products (o/m/p = 1/0.8/0.2) in the absence of a hydrogen-
bonding donor. The major o-olefinated product obtained is
probably attributed to the natively Pd-catalyzed carbonyl-
directed ortho-C−H activation.17 While an equivalent H-
bonding donor (L2−L4) bearing a meta-selective DG was
added into the reaction, the desired products were afforded
with significantly improved regioselectivity, albeit in just a
slightly higher yield. By modifying the salicylonitrile moiety in
hydrogen-bonding donors (L5), C−H olefination achieved the
m-product in up to 48% yield with a regioselectivity of o/m/p =
1.0/3.1/1.2. Pleasingly, replacing the cyclohexyl group in the
urea with a 3,5-(bis)trifluoromethyl phenyl group led to a
dramatic improvement in both reactivity and regioselectivity
(L6−L10). Hydrogen-bonding donor L9 was the most effective,
affording the olefinated products at 69% yield with a
regioselectivity of o/m/p = 1.0/4.0/1.0. A possible explanation
for the enhanced reactivity of hydrogen-bonding donors (L6−
L10) is that a very weak, not detectable by routine
spectroscopic and crystallographic methods, intramolecular
C−H--O interaction between the weakly acidic ortho-C−H
proton and the urea carbonyl group takes place,11a−c which
drastically increases the binding potential of hydrogen-bonding
donors to guest molecules. The dimethoxy substituent on the
nitrile template (L9) affords improved reactivity and
regioselectivity, probably because of the enhanced electron
density of the phenyl ring which prompts the metal binding of
a
NMR yield, and regioselectivity was determined by 1H NMR
b
analysis with reference to an internal standard. C−H olefination
occurring in the template was also observed. n.d.: regioselectivity not
detected, n.r.: no reaction.
the cyano group.18 The use of symmetrical N,N′-dicyclohexyl,
N,N′-diaryl ureas (L11 and L13), or unsymmetrical urea (L12)
only provided comparable yields to the blank experiment but
with slightly higher meta regioselectivities. C−H olefination in
the presence of thiourea (L14) failed to give the desired
products, which is certainly due to the poisoning deactivation
of Pd catalysts by the coordination of sulfur atoms in the
thiourea molecules. As the control experiments, removal of the
nitrile group in the hydrogen-bonding donor (L15 vs L6) led to
a significant decline in both reactivity and regioselectivity,
indicating the essential directing effect of the nitrile group.
Replacement of two hydrogen atoms on the urea N−H bonds
by two methyl groups (L16) also afforded a diminished yield
and meta selectivity. As observed in the previous reports,19 as a
solvent hexafluoroisopropanol (HFIP) shows a significant
influence on the yield and regioselectivity of C−H olefination
(for details, see Supporting Information).
It is well-established that N,N′-disubstituted ureas as
hydrogen-bond donors may associate with guest molecules,
such as triphenylphosphine oxide (TPPO), dimethyl sulfoxide
(DMSO), and benzophenone,11b to form 1:1 complexes
through double hydrogen bonds. The solution NMR and IR
analyses proved to be particularly useful for hydrogen-bonding
interaction. As compared with L9 (5.81 ppm, 7.62 ppm) in d-
chloroform solution, the chemical shifts of two urea N−H
protons move downfield to 6.62 ppm, 9.18 ppm in L9/TPPO
1:1 complex and 6.70 ppm, 9.45 ppm in d6-DMSO solution,
respectively (Figure 1), consistent with the previous
10461
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Figure 1. Chemical shift variations of urea L9 N−H protons resulted
from intermolecular H-bonding interaction.
Figure 3. IR spectra of 1:1 cocrystals of L9 and aromatic aldehyde,
observation by Kuninobu and Kanai.5a The 31P chemical shift
of TPPO also moves downfield by 2.32 ppm in the complex,
which is obviously resulted from deshielding by hydrogen-
bonding interactions. Carbonyl stretching frequencies for L9
are highly sensitive to hydrogen bonding, varying from 1658
cm−1 in L9 to 1712 cm−1 in both 1:1 complexes of L9 with
TPPO and benzophenone (Figure 2). The high-frequency
ester, and amide.
Scheme 3. Pd-Catalyzed meta-C−H Olefination of Aromatic
Ketones and Aldehydes
a
Figure 2. IR analyses of intermolecular H-bonding interaction.
bands occur in both complexes where the PO or carbonyl
oxygen forms two strong hydrogen bonds to the N−H protons
of urea L9. Meanwhile, the carbonyl stretching frequency of
benzophenone varies from 1651 to 1528 cm−1 in L9/
benzophenone 1:1 complex. Similarly, urea carbonyl stretching
frequencies in 1:1 cocrystals of L9 and aromatic aldehyde, ester
and amide also vary from 1658 cm−1 in L9 to 1712 cm−1
(Figure 3). All IR and NMR data unambiguously supports the
occurrence of hydrogen-bonding interaction between L9 and
hydrogen-bond acceptors.
Next, we investigate the application of hydrogen-bond donor
L9 in Pd-catalyzed meta-C−H olefination of aromatic carbonyl
derivatives. For acetophenones and benzaldehydes (Scheme
3), the methoxyl substituents on the ortho, para positions of
the phenyl ring were well tolerated, giving similar yields and
excellent meta selectivities (3b, 3c, 3m, 4b, and 4c). Substrates
a
Isolated yield.
bearing electron-withdrawing fluorine, chlorine, and trifluor-
omethoxyl groups on the para position of the phenyl ring are
compatible with the protocol, affording the meta products in
yields of 52%−65% with regioselectivities of up to >20/1 (3e−
3h, 4d, and 4e). C−H olefination proceeds smoothly with the
substrates owning difluoro or dichloro groups in different
substitution patterns to provide the desired meta products in
10462
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
52%−66% yields (3i−3k, 4g, and 4h). Compared with 2,4-
dichloro benzophenone (3j), 2,4-difluoro benzophenone (3i)
gave rise to a decreased meta selectivity. Notably, N-methyl 2-
acetyl pyrrole (3n) is also compatible with the protocol,
providing the olefinated product in 50% yield with a
regioselectivity of C4/C3 = 3/1. In general, a meta group on
the phenyl ring led to the drastic decrease of meta selectivity in
the C−H olefination process. This phenomenon was
previously observed in template-enabled meta-C−H olefination
of 3-arylpyridines by Yu,9 probably attributed to the meta
substitution in substrates interfering with the optimal
conformational orientation because of steric repulsion. Besides
acetophenones, other aromatic ketones, such as 3f and 3m, are
also suitable substrates for the present protocol. The presence
of a bulky substituent liking the methyl (3d) and iso-butyl (3l)
group led to the obvious decline of product regioselectivity due
to the steric effect. Owing to the enhanced electron-deficient
nature, the substrates bearing an additionally electron-with-
drawing group such as NO2, CF3, and ester group only
provided a trace amount of olefinated products.
protocol, giving rise to the desired olefinated products in
60%−67% yields with regioselectivities of 8/1 to >20/1 (7h−
7j and 8d−8g). In addition to methyl ester, other alkyl esters
are also suitable substrates in C−H olefination, albeit in
decreased meta selectivity (7l). For benzamide substrates (8a),
in the absence of L9, ortho-olefinated product was obtained as
the major product (o/m = 7.5/1) due to the proximal σ-
chelation of the amide group. In contrast, regioselectivity of
C−H olefination was improved to o/m = 1/1.2 with L9 as a
hydrogen-bond donor.
The scope of C−H olefination was further studied using
different olefin partners with acetophenone 1b (Scheme 5). To
a
Scheme 5. Scope of the Olefins
Besides ketones and aldehydes, we also examined the
generality of hydrogen-bond donor L9 in Pd-catalyzed meta-
C−H olefination of benzoate esters and benzamides (Scheme
4). Similar to ketones and aldehydes, the methoxyl group at
either ortho or para position of the phenyl ring was reactive to
provide the olefination products in more than 70% isolated
yields and excellent regioselectivities (7b, 7c, and 8b).
Substrates incorporating difluoro or dichloro groups in
different substitution patterns are compatible with the
Scheme 4. Pd-Catalyzed meta-C−H Olefination of Benzoate
a
Esters and Benzamides
a
Isolated yield.
our delight, in the presence of hydrogen-bond donor L9, meta-
selective C−H olefination was shown to be compatible with a
diverse set of olefins containing ketones (9a and 9l), esters
(9c), aldehydes (9f), amides (9g), multiple-fluoro substituted
aryl and alkyl (9e, 9h, and 9i) functional groups. The diverse
olefins derived from naturally occurring terpenes were also well
tolerated in the protocol (9j−9n).
To elucidate the roles of hydrogen-bond donors in the
reaction, we further carried out three sets of parallel
experiments (Figure 4). In the absence of hydrogen-bond
donor L9, the olefination reaction gave no more than 20% of
the olefinated products 3a after 20 h, while under the same
conditions, close to 65% of the products were obtained with
1.0 equiv of L9. Both the reactivity and meta selectivity (53%
yield, o/m/p = 1/3.3/1) declined obviously when reducing the
loadings of hydrogen-bond donor L9 to 0.5 equiv. It was found
that with a loading of 0.5 equiv L9, C−H olefination products
were provided in slightly higher yield (58% yield) when further
extending the reaction time to 48 h. In regard to meta-C−H
olefination products, kinetic isotope effect (KIE) was also
measured, and the value of kH/kD was 3.93 (Scheme 6),
indicating that C−H-bond cleavage is probably the rate-
determining step as observed in the previous reports.12,13b
a
Isolated yield.
10463
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
AUTHOR INFORMATION
Corresponding Authors
■
Zhong Jin − State Key Laboratory of Elementoorganic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China; Laboratory of Xinjiang Native Medicinal
and Edible Plant Resource Chemistry, College of Chemistry
and Enviromental Science, Kashi University, Kashgar
844007, China; orcid.org/0000-0001-5722-7175;
Email: zjin@nankai.edu.cn
Xiaohua Xu − State Key Laboratory of Elementoorganic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China; Email: xiaohuaxu@nankai.edu.cn
Authors
Guoshuai Li − State Key Laboratory of Elementoorganic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Yifei Yan − State Key Laboratory of Elementoorganic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Pengfei Zhang − State Key Laboratory of Elementoorganic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Figure 4. Effect of H-bonding interaction on C−H olefination.
Scheme 6. KIE Experiment
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02974
Finally, hydrogen-bonding donor enabled C−H olefination
was carried out on a 3 mmol scale to provide the meta-
olefinated product 3b in 64% isolated yield, accompanied by
82% recovery of hydrogen-bond donor L9 from the reaction
(Scheme 7).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 32072440, 21672116, 21172111)
for financial support.
Scheme 7. Up-Scaled Reaction and Recovery of H-Bonding
Donor
DEDICATION
■
Dedicated to the 100th anniversary of chemistry at Nankai
University and 60th anniversary of Kashi University.
REFERENCES
■
(1) (a) Julia-Hernandez, F.; Simonetti, M.; Larrosa, I. Metalation
dictates remote regioselectivity: Ruthenium-catalyzed functionaliza-
tion of meta CAr−H bonds. Angew. Chem., Int. Ed. 2013, 52, 11458−
11460. (b) Ye, J.; Lautens, M. Palladium-catalysed norbornene-
mediated C−H functionalization of arenes. Nat. Chem. 2015, 7, 863−
870. (c) Li, J.; De Sarkar, S.; Ackermann, L. meta- and para-Selective
C−H functionalization by C−H activation. Top. Organomet. Chem.
2015, 55, 217−258. (d) Mihai, M. T.; Genov, G. R.; Phipps, R. J.
Acess to the meta position of arenes through transition metal
catalysed C−H bond functionalisation: a focus on metals other than
palladium. Chem. Soc. Rev. 2018, 47, 149−171. (e) Dey, A.; Sinha, S.
K.; Achar, T. K.; Maiti, D. Accessing remore meta- and para-C(sp2)-H
bonds with covalently attached directing groups. Angew. Chem., Int.
Ed. 2019, 58, 10820−10843. (f) Meng, G.; Lam, N. Y. S.; Lucas, E. L.;
Saint-Denis, T. G.; Verma, P.; Chekshin, N.; Yu, J.-Q. Achieving site-
selectivity for C−H activation processes based on distance and
geometry: A carpenter’s approach. J. Am. Chem. Soc. 2020, 142,
10571−10591. (g) Ali, W.; Prakash, G.; Maiti, D. Recent develop-
ment in transition metal-catalysed C−H olefination. Chem. Sci. 2021,
12, 2735−2759. (h) Dutta, U.; Maiti, S.; Bhattacharya, T.; Maiti, D.
Arene diversification through distal C(sp2)−H functionalization.
Science 2021, 372, eabd5992.
In conclusion, we have described the first example of Pd-
catalyzed meta-selective C−H functionalization of aromatic
carbonyl compounds through noncovalent hydrogen-bonding
interaction. The N,N′-substituted ureas as hydrogen-bond
donors were demonstrated to be capable of forming the double
hydrogen bonds with aromatic ketones, aldehydes, benzoate
esters, and benzamides, thereby achieving C−H functionaliza-
tion on the meta position of the phenyl ring by an embedded
nitrile directing group. We believe that the present noncovalent
hydrogen-bonding strategy for Pd-catalyzed distal C−H bond
functionalization will prove to be applicable in other types of
substrates and/or reactions.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02974.
(2) (a) Dey, A.; Maity, S.; Maiti, D. Reaching the south: metal
catalyzed transformation of the aromatic para-position. Chem.
Commun. 2016, 52, 12398−12414. (b) Sasmal, S.; Dutta, U.;
Lahiri, G. K.; Maiti, D. Transition metals and transition metals/
General information, experimental procedures, analytical
data, and NMR spectra for products (PDF)
10464
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Lewis acid cooperative catalysis for directing group assisted para-C−
H functionalization. Chem. Lett. 2020, 49, 1406−1420.
borylation of aromatic amides. Angew. Chem., Int. Ed. 2018, 57,
15762−15766.
(7) (a) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion pair-directed
regiocontrol in transition-metal catalysis: A meta-selective C−H
borylation of aromatic quaternary ammonium salts. J. Am. Chem. Soc.
2016, 138, 12759−12762. (b) Mihai, M. T.; Phipps, R. J. Ion-pair-
directed meta-selecitve C−H borylation of aromatic quaternary
ammonium salts. Synlett 2017, 28, 1011−1017. (c) Mihai, M. T.;
Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion pair-directed C−H
activation on flexible ammonium salts: meta-Selective borylation of
quaternized phenethylamines and phenylpropylamines. ACS Catal.
2018, 8, 3764−3769. (d) Lee, B.; Mihai, M. T.; Stojalnikova, V.;
Phipps, R. J. Ion-pair-directed borylation of aromatic phosphonium
salts. J. Org. Chem. 2019, 84, 13124−13134. (e) Genov, G. R.;
Douthwaite, J. L.; Lahdenpera, A. S. K.; Gibson, D. C.; Phipps, R. J.
Enantioselective remote C−H activation directed by a chiral cation.
Science 2020, 367, 1246−1251.
(3) (a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Activation of remote
meta-C−H bonds assisted by an end-on template. Nature 2012, 486,
518−522. (b) Hofmann, N.; Ackermann, L. meta-Selective C−H
bond alkylation with secondary alkyl halides. J. Am. Chem. Soc. 2013,
135, 5877−5884. (c) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.;
Li, S.; Engle, K. M.; Yu, J.-Q. Ligand-enabled meta-C−H activation
using a transient mediator. Nature 2015, 519, 334−338. (d) Dong, Z.;
Wang, J.; Dong, G. Simple amine-directed meta-selecitve C−H
arylation via Pd/norbornene catalysis. J. Am. Chem. Soc. 2015, 137,
5887−5890. (e) Chu, L.; Shang, M.; Tanaka, K.; Chen, Q.;
Pissarnitski, N.; Streckfuss, E.; Yu, J.-Q. Remote meta-C−H activation
using a pyridine-based template: Achieving site-selectivity via the
recognition of distance and geometry. ACS Cent. Sci. 2015, 1, 394−
399. (f) Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-
X.; Yu, J.-Q. Ligand-promoted meta-C−H amination and alkynylation.
J. Am. Chem. Soc. 2016, 138, 14092−14099. (g) Bag, S.; Jayarajan, R.;
Mondal, R.; Maiti, D. Template-assisted meta-C−H alkylation and
alkenylation of arenes. Angew. Chem., Int. Ed. 2017, 56, 3182−3186.
(h) Achar, T. K.; Zhang, X.; Mondal, R.; Shanavas, M. S.; Maiti, S.;
Maity, S.; Pal, N.; Paton, R. S.; Maiti, D. Palladium-catalyzed directed
meta-selective C−H allylation of arenes: Unactivated internal olefins
as allyl surrogates. Angew. Chem., Int. Ed. 2019, 58, 10353−10360.
(i) Shi, H.; Herron, A. N.; Shao, Y.; Shao, Q.; Yu, J.-Q.
Enantioselective remote meta-C−H arylation and alkylation via a
chiral transient mediator. Nature 2018, 558, 581−585. (j) Li, S.;
Wang, H.; Weng, Y.; Li, G. Carboxy group as a remote and selective
chelating group for C−H activation of arenes. Angew. Chem., Int. Ed.
2019, 58, 18502−18507. (k) Bag, S.; K, S.; Mondal, A.; Jayarajan, R.;
Dutta, U.; Porey, S.; Sunoj, R. B.; Maiti, D. Palladium-catalyzed meta-
C−H allylation of arenes: A unique combination of a pyrimidine-
based template and hexafluoroisopropanol. J. Am. Chem. Soc. 2020,
142, 12453−12466.
(8) (a) Bisht, R.; Chattopadhyay, B. Formal Ir-catalyzed ligand-
enabled ortho and meta borylation of aromatic aldehydes via in situ-
generated imines. J. Am. Chem. Soc. 2016, 138, 84−87. (b) Yang, L.;
Uemura, N.; Nakao, Y. meta-Selective C−H borylation of benzamides
and pyridines by an iridium-Lewis acid bifunctional catalyst. J. Am.
Chem. Soc. 2019, 141, 7972−7979.
(9) Zhang, Z.; Tanaka, K.; Yu, J.-Q. Remote site-selective C−H
activation directed by a catalytic bifunctional template. Nature 2017,
543, 538−542.
(10) (a) Achar, T. K.; Ramakrishna, K.; Pal, T.; Porey, S.; Dolui, P.;
Biswas, J. P.; Maiti, D. Regiocontrolled remoted C−H olefination of
samll heterocycles. Chem. - Eur. J. 2018, 24, 17906−17910.
(b) Ramakrishna, K.; Biswas, J. P.; Jana, S.; Achar, T. K.; Porey, S.;
Maiti, D. Coordination assisted distal C−H alkylation of fused
heterocycles. Angew. Chem., Int. Ed. 2019, 58, 13808−13812.
(11) (a) Etter, M. C.; Panunto, T. W. 1,3-Bis(m-nitrophenyl)urea:
An exceptionally good complexing agent for proton acceptors. J. Am.
Chem. Soc. 1988, 110, 5896−5897. (b) Etter, M. C.; Urbanczyk-
Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T. W. Hydrogen bond
directed cocrystallization and molecular recognition properties of
diarylureas. J. Am. Chem. Soc. 1990, 112, 8415−8426. (c) Etter, M. C.
Encoding and decoding hydrogen-bond patterns of organic
compounds. Acc. Chem. Res. 1990, 23, 120−126. (d) Taylor, M. S.;
Jacobsen, E. N. Asymmetric catalysis by chiral hydrogen-bond donors.
Angew. Chem., Int. Ed. 2006, 45, 1520−1543. (e) Volz, N.; Clayden, J.
The urea renaissance. Angew. Chem., Int. Ed. 2011, 50, 12148−12155.
(12) (a) Zhang, L.; Zhao, C.; Liu, Y.; Xu, J.; Xu, X.; Jin, Z. Activation
of remote meta-C−H bonds in arenes with tethered alcohols: A
salicylonitrile template. Angew. Chem., Int. Ed. 2017, 56, 12245−
12249. (b) Wang, B.; Zhou, Y.; Xu, N.; Xu, X.; Xu, X.; Jin, Z.
Palladium(II)-catalyzed remote meta-C−H functionalization of
aromatic tertiary amines. Org. Lett. 2019, 21, 1885−1889. (c) Xie,
S.; Li, S.; Ma, W.; Xu, X.; Jin, Z. Chelation-directed remote meta-C−
H functionalization of aromatic aldehydes and ketones. Chem.
Commun. 2019, 55, 12408−12411.
(13) (a) Tang, R.-Y.; Li, G.; Yu, J.-Q. Conformation-induced remote
meta-C−H activation of amines. Nature 2014, 507, 215−220.
(b) Fang, L.; Saint-Denis, T. G.; Taylor, B. L. H.; Ahlquist, S.;
Hong, K.; Liu, S.; Han, L.; Houk, K. N.; Yu, J.-Q. Experimental and
computational development of a conformationally flexible template
for the meta-C−H functionalization of benzoic acids. J. Am. Chem. Soc.
2017, 139, 10702−10714.
(14) (a) Bera, M.; Modak, A.; Patra, T.; Maji, A.; Maiti, D. meta-
Selective arene C−H bond olefination of arylacetic acid using a
nitrile-based directing group. Org. Lett. 2014, 16, 5760−5763.
(b) Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D. Palladium(II)-catalyzed
meta-C−H olefination: Constructing multisubstituted arenes through
homo-diolefination and sequential hetero-diolefination. Angew. Chem.,
Int. Ed. 2015, 54, 8515−8519. (c) Maji, A.; Bhaskararao, B.; Singha,
S.; Sunoj, R. B.; Maiti, D. Directing group assisted meta-hydroxylation
by C−H activation. Chem. Sci. 2016, 7, 3147−3153. (d) Bera, M.;
Sahoo, S. K.; Maiti, D. Room-temperature meta-functionalization:
(4) (a) Bag, S.; Patra, T.; Modak, A.; Deb, A.; Maity, S.; Dutta, U.;
Dey, A.; Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D.
Remote para-C−H functionalization of arenes by a D-shaped
biphenyl templated-based assembly. J. Am. Chem. Soc. 2015, 137,
11888−11891. (b) Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey,
A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D. Palladium-catalyzed
directed para-C−H functionalization of phenols. Angew. Chem., Int.
Ed. 2016, 55, 7751−7755. (c) Yang, L.; Semba, K.; Nakao, Y. para-
Selective C−H borylation of (hetero)arenes by cooperative iridium/
aluminum catalysis. Angew. Chem., Int. Ed. 2017, 56, 4853−4857.
(d) Maji, A.; Dahiya, A.; Lu, G.; Bhattacharya, T.; Brochetta, M.;
Zanoni, G.; Liu, P.; Maiti, D. H-Bonded reusable template assisted
para-selective ketonisation using soft electrophilic vinyl ethers. Nat.
Commun. 2018, 9, 3582−3592. (e) Li, M.; Shang, M.; Xu, H.; Wang,
X.; Dai, H.-X.; Yu, J.-Q. Remote para-C−H acetoxylation of electron-
deficient arenes. Org. Lett. 2019, 21, 540−544. (f) Chen, X.; Fan, S.;
Zhang, M.; Gao, Y.; Li, S.; Li, G. Palladium-catalyzed remote para-C−
H activation of arenes assisted by a recyclable pyridine-based
template. Chem. Sci. 2021, 12, 4126−4131.
(5) For review, see: (a) Pandit, S.; Maiti, S.; Maiti, D. Noncovalent
interactions in Ir-catalyzed remote C−H borylation: a recent update.
Org. Chem. Front. 2021, 8, 4349. (b) Kuninobu, Y.; Ida, H.; Nishi, M.;
Kanai, M. A meta-selective C−H borylation directed by a secondary
interaction between ligand and substrate. Nat. Chem. 2015, 7, 712−
717. (c) Davis, H. J.; Genov, G. R.; Phipps, R. J. meta-Selective C−H
borylation of benzylamine, phenethylamine-, and phenylpropylamine-
derived amides enbaled by a single anionic ligand. Angew. Chem., Int.
Ed. 2017, 56, 13351−13355. (d) Lu, X.; Yoshigoe, Y.; Ida, H.; Nishi,
M.; Kanai, M.; Kuninobu, Y. Hydrogen bond-accelerated meta-
selective C−H borylation of aromatic compounds and expression of
functional group and substrate specificities. ACS Catal. 2019, 9,
1705−1709.
(6) Bisht, R.; Hoque, M. E.; Chattopadhyay, B. Amide effects in C−
H activation: Noncovalent interactions with L-shaped ligand for meta
10465
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Pd(II)-catalyzed synthesis of 1,3,5-trialkenyl arene and meta-
hydroxylated olefin. ACS Catal. 2016, 6, 3575−3579. (e) Casali, E.;
Kalra, P.; Brochetta, M.; Borsari, T.; Gandini, A.; Patra, T.; Zanoni,
G.; Maiti, D. Overriding ortho selectivity by template assisted meta-
C−H activation of benzophenones. Chem. Commun. 2020, 56, 7281−
7284.
(15) Williams, A. F.; White, A. J. P.; Spivey, A. C.; Cordier, C. J.
meta-Selective C−H functionalisation of aryl boronic acids directed
by a MIDA-derived boronate ester. Chem. Sci. 2020, 11, 3301−3306.
(16) Yang, Y.-F.; Cheng, G.-J.; Liu, P.; Leow, D.; Sun, T.-Y.; Chen,
P.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D.; Houk, K. N. Palladium-catalyzed
meta-selective C−H bond activation with a nitrile-containing
template: Computational study on mechanism and origins of
selectivity. J. Am. Chem. Soc. 2014, 136, 344−355.
(17) (a) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. Palladium-
catalyzed intermolecular directed C−H amidation of aromatic
ketones. J. Am. Chem. Soc. 2011, 133, 1466−1474. (b) Shan, G.;
Yang, X.; Ma, L.; Rao, Y. Pd-catalyzed C−H oxygenation with TFA/
TFAA: Expedient access to oxygen-containing heterocycles and late-
stage drug modification. Angew. Chem., Int. Ed. 2012, 51, 13070−
13074. (c) Mo, F.; Trzepkowski, L. J.; Dong, G. Synthesis of ortho-
acyphenols through the palladium-catalyzed ketone-directed hydrox-
ylation of arenes. Angew. Chem., Int. Ed. 2012, 51, 13075−13079.
(d) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Regio- and chemoselective C−
H chlorination/bromination of electron-deficient arenes by weak
coordination and study of relative directing-group abilities. Angew.
Chem., Int. Ed. 2013, 52, 4440−4444. (e) Choy, P. Y.; Kwong, F. Y.
Palladium-catalyzed ortho-CH-bond oxygenation of aromatic ketones.
Org. Lett. 2013, 15, 270−273.
(18) (a) Maji, A.; Guin, S.; Feng, S.; Dahiya, A.; Singh, V. K.; Liu, P.;
Maiti, D. Experimental and computational exploration of para-
selective silylation with a hydrogen-bonded template. Angew. Chem.,
Int. Ed. 2017, 56, 14903−14907. (b) Dutta, U.; Maiti, S.; Pimparkar,
S.; Maiti, S.; Gahan, L. R.; Krenske, E. H.; Lupton, D. W.; Maiti, D.
Rhodium catalyzed template-assisted distal para C-H olefination.
Chem. Sci. 2019, 10, 7426−7432. (c) Pimparkar, S.; Bhattacharya, T.;
Maji, A.; Saha, A.; Jayarajan, R.; Dutta, U.; Lu, G.; Lupton, D. W.;
Maiti, D. para-Selective cyanation of arenes by H-bonded template.
Chem. - Eur. J. 2020, 26, 11558−11564.
(19) (a) Sinha, S. K.; Bhattacharya, T.; Maiti, D. Role of
hexafluoroisopropanol in C−H activation. React. Chem. Eng. 2019,
4, 244−253. (b) Bhattacharya, T.; Ghosh, A.; Maiti, D. Hexafluor-
oisopropanol: the magical solvent for Pd-catalyzed C−H activation.
Chem. Sci. 2021, 12, 3857−3870.
10466
https://doi.org/10.1021/acscatal.1c02974
ACS Catal. 2021, 11, 10460−10466