Diverse meta-C?H Functionalization of Arenes across Different Linker Lengths

Article abstract of DOI:10.1002/anie.201804043

Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta-position. Good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C?H bond and the coordinating heter

Full text of DOI:10.1002/anie.201804043

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Diverse Meta-C-H Functionalization of Arenes Across Different
Linker Lengths
Authors: Ramasamy Jayarajan, Jayabrata Das, Sukdev Bag, Rajdip
Chowdhury, and Debabrata Maiti
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804043
Angew. Chem. 10.1002/ange.201804043
Link to VoR: http://dx.doi.org/10.1002/anie.201804043
http://dx.doi.org/10.1002/ange.201804043

10.1002/anie.201804043
Angewandte Chemie International Edition
COMMUNICATION
Diverse Meta-CH Functionalization of Arenes Across Different
Linker Lengths
Ramasamy Jayarajan,* Jayabrata Das, Sukdev Bag, Rajdip Chowdhury and Debabrata Maiti*
Abstract: Conformationally flexible long-chain arenes have been
successfully functionalized at meta-position. Good to excellent meta-
selectivity has been achieved up to twenty atoms between the target
CH bond and the coordinating heteroatom of the directing group.
This palladium-catalyzed diverse functionalizations include alkylation,
cyanation, olefination and acetoxylation. Meta-selectivity is
exclusively governed by the design of flexible pyrimidine-based
scaffolds.
Activation of inert CH bonds of readily available starting
materials to incorporate functionalities has certainly emerged as
a key concept in order to elucidate the structure-reactivity
relationships in molecules of interest in pharmaceuticals,
industry and scientific research.[1] In the past few decades, ortho-
CH functionalization of arenes assisted by a native functionality
or an installed directing group in a molecule has substantially
thrived via five or six membered metallacycle.[2] In contrast,
selective meta- and para-C–H bond activation remain difficult
task owing to the formation of highly strained macrocyclic
transition state (TS).[3] Recent reports demonstrated the
significant efforts for directed distal CH bond functionalization
templates.[4,5]
Figure 1. Selective Meta-CH Functionalization of Conformationally Flexible
Long-Chain Arenes.
of
arenes
by
employing
nitrile-based
Functionalizations that are difficult to accomplish at the meta-
position of arenes using nitrile coordination, have been attained
by the judicious design of relatively stronger coordinating
directing groups.[6,7] However, the key to attain such selective
meta-activation relies solely on the rigidity of the cyclophane-like
TS, which might become fragile upon increase in the length of
the linker that bridges the directing group and the target site.
This has limited the application of such template-based
strategies to cases where meta-CH bonds are geometrically
The scope of this strategy has been demonstrated with a
series of arenes such as propyl to octylbenzene, decylbenzene,
ethyloxybenzene, hexyloxybenzene, benzyl alcohol and benzoic
acid that depicts the competence of the present scaffold in
enduring resistance to the entropic cost thus enabling the
required selectivity.
We began our investigation towards meta-CH
functionalization of propylbenzene scaffold as a model substrate.
Nitrile and heterocycle-based directing templates were tethered
to phenylpropyl alcohol (T1-T5) for meta-CH alkylation using 3-
buten-2-ol as the coupling partner (Table 1).[7a,9] Very less
conversion was observed with nitrile-based templates (T1-T3)
whereas heterocycle-based templates (T4 and T5) resulted in
the desired meta-alkylated product in improved yield.
Interestingly, both the scaffolds offered only mono alkylated (β-
aryl ketone) product.
accessible and proximate. Consequently,
a site selective
installation of useful functional groups into arenes that contain a
long alkyl chain is an extremely difficult task. In this context,
striking a proper balance between the number of atoms required
for maintaining the core metallacyclic TS and directing the
coordinating nitrile group to the target meta- site has been
identified to be crucial.[8] An increase in the number of involved
atoms in the metallacycle raises the entropic barrier that offsets
the situation of the catalyst at the optimum site for long-chain
containing systems. Further, scientists aimed for a template that
would facilitate a plethora of functionalization without any
compromise in selectivity.
Table 1: The Meta-Alkylation with Different Directing Templates.[10]
Herein, we disclose the use of an ether tethered
conformationally flexible pyrimidine-based template to achieve
diverse meta-functionalization of arenes (Figure 1) that is
insensitive towards the location of the directing group (DG) from
the target meta-CH bond. Four distinct functionalizations,
namely alkylation, cyanation, olefination and acetoxylation have
been successfully executed.
[*]
Dr. R. Jayarajan, J. Das, S. Bag, R. Chowdhury, Prof. Dr. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
The biphenyl pyrimidine-based template T5 has provided
better yield and excellent meta-selectivity compared to T4. The
observed high yield and regioselectivity can be explained by the
hydrogen bonding interaction of solvent 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP) with the pyrimidine-directing group
E-mail: dmaiti@chem.iitb.ac.in
Dr. R. Jayarajan
Department of Biosciences and Bioengineering
Indian Institute of Technology Bombay (India)
E-mail: rjayaraj7@gmail.com
This article is protected by copyright. All rights reserved.

10.1002/anie.201804043
Angewandte Chemie International Edition
COMMUNICATION
(DG) which decreases the basicity of DG and concurrently
increases the -acidity towards the palladium center.[11] The
NMR studies reveal the existence of strong hydrogen bonding
between pyrimidine DG and HFIP solvent (see Supporting
Information).[7b]
phenol-based scaffold (1p and 1q) provided meta-coupled β-aryl
keto product in good yield and selectivity. The practicality of this
transformation was tested by a large-scale reaction (10 mmol
scale, 2.9 g) which afforded the desired meta-alkylated product
1a in 61% yield (Scheme 1).[10]
A control experiment without using the directing template
did not produce any alkylated product (Table 1).[10] These
findings indicate that the flexibility of the ether tethered
pyrimidine-based template would be significant to encourage the
formation of macrocyclic TS for the remote palladium-catalyzed
C−H bond activation.
Arylnitrile is a key structural motif in natural products,
pharmaceuticals and transformation of nitrile to other
functionalities provide the precursor for several valuable
compounds.[12] Our recent effort towards meta-selective
cyanation led us to install a nitrile group in arenes possessing
various lengths of alkyl chains which were previously
inaccessible.[7b] Our initial attempt with propylbenzene scaffold
provided a moderate yield and excellent meta-selectivity. After
optimizing different parameters, it was observed that the yield
and meta-selectivity remarkably increased when copper(I)
cyanide was used as a cyanide source in the presence of silver
carbonate and copper(I) oxide.[10, 13]
Scheme 1. Meta-Alkylation of Long-Chain Tethered Arenes.[10]
In order to achieve the highest synthetic yield of meta-
alkylation product, the reaction condition was extensively
optimized.[10] A wide range of functional arenes possessing
variable alkyl backbone has been subjected to the optimal meta-
alkylation reaction conditions (Scheme 1). Arenes with variable
linker length such as propyl (1a), butyl (1b), pentyl (1c), hexyl
(1d), octyl (1e) and decyl (1f) were alkylated selectively at the
meta-position. Exclusive mono selectivity was observed for all
the scaffolds under the present reaction conditions. Scope of the
reaction was explored using various alkenyl alcohols (1g-1j) and
arenes containing different substitution (1k-1n). Mono product
was observed with 3,3-diphenyl scaffold (1o) where one of the
aryl rings was alkylated with good meta-selectivity. Remarkably,
Scheme 2. Meta-Cyanation of Long-Chain Tethered Arenes.[10]
With optimized reaction conditions in hand, we have
probed various scaffolds having elongated alkyl backbones
(Scheme 2). We were delighted to find that the present reaction
protocol provides selective mono-cyanation product. Almost
similar reactivity pattern (yield and selectivity) was observed with
propyl to octyl arene scaffolds (2a-2f) as noticed for alkylation.
Meta-cyanation product for phenol-based hexyloxybenzene (2g)
and benzyl alcohol-based scaffold 2h was also obtained. The
structure of 2g was confirmed by X-ray crystallography. Further,
the compatibility of substituents on aromatic ring has been
examined with electron donating (2i), electron withdrawing (2l,
2m and 2n) and sterically encumbered α-methyl propylbenzene
This article is protected by copyright. All rights reserved.

10.1002/anie.201804043
Angewandte Chemie International Edition
COMMUNICATION
(2j). The structure of product 2i was confirmed by X-ray
afford corresponding meta-functionalized 3-phenylpropanol (5a)
crystallography (Scheme 2).
(Scheme 5).
Scheme 4. Meta-Acetoxylation of Long-Chain Tethered Arenes.[10]
Scheme 5. Template Removal.[10]
Figure 2. a) Rate of meta-alkylation with propyl (1a), pentyl (1c) and decyl (1f)
scaffolds was measured by initial rate (i.e., slope of the plots). b)
Concentration effect on yield and selectivity; Data points of both the plots
represent the NMR yields and values in parentheses represents meta:others
selectivity.[10]
To rationalize the effect of different linker lengths (propyl,
pentyl and decyl), we further studied the rate of the reaction and
concentration effect on yield and selectivity (Figure 2).[10] We
performed three parallel sets of meta-alkylation reactions over
8 h, quenching them in 1 h interval and monitored the
conversion by 1H NMR spectroscopy of the crude reaction
mixture (Figure 2a). The observed initial rate reveals that rate of
the reaction drops down when linker length increases. Further,
an effect of concentration on yield and selectivity was tested.
Decrease in yields has been observed from optimum to lower or
Scheme 3. Meta-Olefination with Diverse Scaffolds.[10]
After successful implementation of cyanation reaction, we
have examined meta-CH olefination with a wide variety of
scaffolds (Scheme 3). The protocol is compatible with different
alkyl benzenes (3a-3d), various activated olefins like acrylates
(3e, 3l and 3m), vinylketone (3g), sulfone (3h-3i) and amide (3k).
Interestingly, acrolein as a coupling partner yielded the alkenyl
aldehyde (3j). Electron donating (3p) and withdrawing (3q)
substituent on the arenes are also well tolerated. Substituted
benzoic acid (3o) produced meta-olefinated product in
synthetically useful yield and its structure was confirmed by X-
ray crystallography (Scheme 3).
The meta-acetoxylation reaction was also found to be
feasible with long-chain containing arenes (Scheme 4). Arenes
with different chain lengths (4a, 4b and 4c) and substitution
patterns (4d, 4e and 4f) have been acetoxylated under
optimized reaction conditions. All scaffolds afforded mono
acetoxylated product in synthetically useful yields and selectivity.
Finally, removal of the directing template was
accomplished by oxidative cleavage of olefinated product 3a
using ceric ammonium nitrate (CAN) at room temperature to
higher concentration. However, only
a slight change in
regioselectivity was observed with the change in concentration
(Figure 2b).
A plausible catalytic cycle is depicted in Scheme 6 for the
formation of meta-alkylation with long-chain arenes.[7a] The
target meta-CH bond of flexible arene might be selectively
activated by conformationally well-defined reactive pyrimidine
coordinated Pd-mono-N-protected amino acid species (I). The
ESI-MS studies of individual reaction mixtures of propyl, pentyl
and decyl scaffolds in the absence of alkyl coupling partner also
suggested the formation of a macrocyclic palladacycle (I).
Coordination followed by 1,2-migratory insertion of the allyl
alcohol would give intermediate II. Thermodynamically stable -
hydride (Hs) elimination may lead to the formation of
This article is protected by copyright. All rights reserved.

10.1002/anie.201804043
Angewandte Chemie International Edition
COMMUNICATION
2014, 356, 1461; f) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2014, 136,
898; g) H. Kinuta, M. Tobisu, N. Chatani, J. Am. Chem. Soc. 2015, 137,
1593; h) D. Zhao, V.-S. Cespedes, F. Glorius, Angew. Chem. Int. Ed.
2015, 54, 1657.
intermediate III. Next, double bond isomerization (IV) and keto-
enol tautomerization provides the desired meta-alkylated
product (1). However, the formation of a bimetallic Pd-Ag adduct
with substrate could facilitate the meta-functionalization with
[3]
a) Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
5072; b) N. Hofmann, L. Ackermann, J. Am. Chem. Soc. 2013, 135,
5877; c) Y. Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015, 7,
712; d) J. Li, S. Warratz, D. Zell, S. De Sarkar, E. E. Ishikawa, L.
Ackermann, J. Am. Chem. Soc. 2015, 137, 13894; e) N. Y. P. Kumar, A.
Bechtoldt, K. Raghuvanshi, L. Ackermann, Angew. Chem. Int. Ed. 2016,
55, 6929; f) R. Bisht, B. Chattopadhyay, J. Am. Chem. Soc. 2016, 138,
84; g) P. Wang, M. E. Farmer, X. Huo, P. Jain, P.-X. Shen, M. Ishoey, J.
E. Bradner, S. R. Wisniewski, M. E. Eastgate, J.-Q. Yu, J. Am. Chem.
Soc. 2016, 138, 9269; h) H. P. L. Gemoets, G. Laudadio, K. Verstraete,
V. Hessel, T. Noel, Angew. Chem. Int. Ed. 2017, 56, 7161; i) M. E.
Hoque, R. Bisht, C. Haldar, B. Chattopadhyay, J. Am. Chem. Soc. 2017,
139, 7745; j) J. Li, K. Korvorapun, S. De Sarkar, T. Rogge, D. J. Burns,
S. Warratz, L. Ackermann, Nat. Commun. 2017, 8, 15430. k) Z. Zhang,
K. Tanaka, J.-Q. Yu, Nature 2017, 543, 538.
long chain scaffolds as proposed in recent reports.[8,10]
A
detailed mechanistic understanding remains our study of interest.
[4]
a) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature 2012, 486, 518; b) G.
Yang, P. Lindovska, D. Zhu, J. Kim, P. Wang, R.-Y. Tang, M.
Movassaghi, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 10807; c) S. Li, H.
Ji, L. Cai, G. Li, Chem. Sci. 2015, 6, 5595; d) Y. Deng, J.-Q. Yu, Angew.
Chem. Int. Ed. 2015, 54, 888; e) M. Bera, A. Maji, S. K. Sahoo, D. Maiti,
Angew. Chem. Int. Ed. 2015, 54, 8515; f) S. Li, L. Cai, H. Ji, L. Yang, G.
Li, Nat. Commun. 2016, 7, 10443; g) H.-J. Xu, Y. Lu, M. E. Farmer, H.-
W. Wang, D. Zhao, Y.-S. Kang, W.-Y. Sun, J.-Q. Yu, J. Am. Chem. Soc.
2017, 139, 2200. h) G. Yang, D. Zhu, P. Wang, R.-Y. Tang, J.-Q. Yu,
Chem. Eur. J. 2018, 24, 3434.
[5]
a) S. Bag, T. Patra, A. Modak, A. Deb, S. Maity, U. Dutta, A. Dey, R.
Kancherla, A. Maji, A. Hazra, M. Bera, D. Maiti, J. Am. Chem. Soc.
2015, 137, 11888; b) T. Patra, S. Bag, R. Kancherla, A. Mondal, A. Dey,
S. Pimparkar, S. Agasti, A. Modak, D. Maiti, Angew. Chem. Int. Ed.
2016, 55, 7751; c) A. Maji, S. Guin, S. Feng, A. Dahiya, V. K. Singh, P.
Liu, D. Maiti, Angew. Chem. Int. Ed. 2017, 56, 14903.
Scheme 6. Plausible Mechanistic Cycle for meta-CH Alkylation.[10]
In conclusion, we have demonstrated Pd(II)-catalyzed
diverse meta-CH functionalization of long-chain arenes, where
more conformational degrees of freedom make the CH bond
cleavage step entropically unfavourable. Alkylation, cyanation,
olefination and acetoxylation have been accomplished at remote
meta-position of arenes across different linker lengths.
[6] a) L. Chu, M. Shang, K. Tanaka, Q. Chen, N. Pissarnitski, E. Streckfuss,
J.-Q. Yu, ACS Cent. Sci. 2015, 1, 394; b) U. Dutta, A. Modak, B.
Bhaskararao, M. Bera, S. Bag, A. Mondal, D. W. Lupton, R. B. Sunoj, D.
Maiti, ACS Catal. 2017, 7, 3162; d) Z. Jin, L. Chu, Y.-Q. Chen, J.-Q. Yu,
Org. Lett. 2018, 20, 425.
[7]
a) S. Bag, R. Jayarajan, R. Mondal, D. Maiti, Angew. Chem. Int. Ed.
2017, 56, 3182; b) S. Bag, R. Jayarajan, U. Dutta, R. Chowdhury, R.
Mondal, D. Maiti, Angew. Chem. Int. Ed. 2017, 56, 12538.
a) L. Zhang, C. Zhao, L. Liu, J. Xu, X. Xu, Z. Jin, Angew. Chem. Int. Ed.
2017, 56, 12245; b) L. Fang, T. G. Saint-Denis, B. L. H. Taylor, S.
Ahlquist, K. Hong, S. Liu, L. Han, K. N. Houk, J.–Q. Yu, J. Am. Chem.
Soc. 2017, 139, 10702.
Acknowledgements
This research activity was supported by DST Nano Mission
(SR/NM/NS-1065/2015), India. R.J. thanks DST-India for Fast
Track Scheme (YSS/2014/000530). CSIR-India (J. D.) and
UGC-India (S. B.) is gratefully acknowledged. D.M. sincerely
thanks Prof. Samir K. Maji (BSBE, IITB) for insightful discussions.
[8]
[9]
a) Z. Shi, M. B. Arapinis, F. Glorius, Chem. Commun. 2013, 49, 6489;
b) J. Fournier, O. Lozano, C. Menozzi, S. Arseniyadis, J. Cossy, Angew.
Chem. Int. Ed. 2013, 52, 1257; c) R. Manoharan, M. Jeganmohan,
Chem. Commun. 2015, 51, 2929.
Keywords: • long-chain arenes • conformational flexibility •
meta-functionalizations • palladium
[10] See the Supporting Information for a detailed description.
[11] a) C. M. Glinkerman, D. L. Boger, J. Am. Chem. Soc. 2016, 138,
12408; b) Y. Wang, V. Gevorgyan, Angew. Chem. Int. Ed. 2017, 56,
3191.
[1]
a) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed.
2012, 51, 8960; b) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F.
Glorius, Angew. Chem. Int. Ed. 2012, 51, 10236; c) M. Tobisu, N.
Chatani, Science 2014, 343, 850; d) K. Takamatsu, K. Hirano, M. Miura,
Angew. Chem. Int. Ed. 2017, 56, 5353; e) H. P. L. Gemoets, I. Kalvet, A.
V. Nyuchev, N. Erdmann, V. Hessel, F. Schoenebeck, T. Noel, Chem.
Sci. 2017, 8, 1046.
[12] (a) J. Zanon, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
2890; b) W. Zhou, L. Zhang, N. Jiao, Angew. Chem. Int. Ed. 2009, 48,
7094; c) S. Ding, N. Jiao, J. Am. Chem. Soc. 2011, 133, 12374; d) T. D.
Senecal, W. Shu, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52,
10035; e) Y. Yang, S. L. Buchwald, Angew. Chem. Int. Ed. 2014, 53,
8677; f) Y. Yang, P. Liu, ACS. Catal. 2015, 5, 2944.
[2] a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda,
N. Chatani, Nature 1993, 366, 529; b) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; c) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48,
9792; d) L. Ackermann, Acc. Chem. Res. 2014, 47, 281; e) S. De
Sarkar, W. Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal.
[13] S. Gronowitz, P. Bjork, J. Malm, A.-B. Hornfeldt, J. Organomet. Chem.
1993, 460, 127.
This article is protected by copyright. All rights reserved.

10.1002/anie.201804043
Angewandte Chemie International Edition
COMMUNICATION
Table of Contents
COMMUNICATION
Palladium-catalyzed diverse
meta-CH functionalization
of arenes that are located
Dr. R. Jayarajan,* J. Das, S.
Bag, R. Chowdhury and Prof.
Dr. Maiti*
remotely
methylene spaces) from a
removable ether-tethered
pyrimidine-based template
have been described. This
method is unique compared
to classical cyclometallation
due to its insensitivity of
location of the DG from
target CH bond.
(up
to
10
Page No. – Page No.
Diverse Meta-CH
Functionalization of Arenes
Across Different Linker
Lengths
This article is protected by copyright. All rights reserved.