Palladium-catalyzed meta-C[sbnd]H bond iodination of arenes with I2

Article abstract of DOI:10.1016/j.cclet.2019.09.057

Palladium-catalyzed highly meta-selective C[sbnd]H iodination of phenylacetic acid, benzylphosphonate and benzylsulfonate scaffolds with molecular I₂ is developed using a pyridine-type template. The practical ester linkages enable the directing template easily installed and readily removed. The substrate scope is broad, and alkyl, methoxyl, trifluomethyl, and halo substituents are compatible with this reaction. Further transformations of ibuprofen iodide intermediates by Pd-catalyzed C[sbnd]C and C–heteroatom bond formation illustrate the broad utility of this method.

Full text of DOI:10.1016/j.cclet.2019.09.057

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CCLET 5263 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Palladium-catalyzed meta-CÀÀH bond iodination of arenes with I2
a,c,b,
Min Liua,c,b, Ling-Jun Lia,c,b, Jun Zhangd,b, Hui Xua,c,b, , Hui-Xiong Dai
*
*
a
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
University of Chinese Academy of Sciences, Beijing 100049, China
b
c
d
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Palladium-catalyzed highly meta-selective CÀÀH iodination of phenylacetic acid, benzylphosphonate and
benzylsulfonate scaffolds with molecular I2 is developed using a pyridine-type template. The practical
ester linkages enable the directing template easily installed and readily removed. The substrate scope is
broad, and alkyl, methoxyl, trifluomethyl, and halo substituents are compatible with this reaction.
Further transformations of ibuprofen iodide intermediates by Pd-catalyzed CÀÀC and C–heteroatom bond
formation illustrate the broad utility of this method.
Received 16 August 2019
Received in revised form 17 September 2019
Accepted 29 September 2019
Available online xxx
Keywords:
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Palladium catalysis
Meta-CÀÀH iodination
Pyridine-based template
Practical ester linkages
Molecular I2
Aryl iodides are widely utilized as important starting materials
in organic chemistry and pharmaceutical drug syntheses [1]. Many
synthetic methods have been developed for the construction of
aryl iodide, and metal-catalyzed CÀÀH iodination of arene is the
most straightforward way [2]. Assisted by a directing group, Pd [3],
Rh [4], Ru [5], Cu [6], Ni [7], and Co [8] have been adopted in the
ortho-CÀÀH iodination of arenes. Athough Pd-catalyzed meta-CÀÀH
chlorination using norbornene as the mediator and Ru-catalyzed
meta-CÀÀH bromination via electronic effects have been reported
[9,10], meta-CÀÀH iodination has been less explored. The rational
design of a directing group with proper distance and geometry
plays an important role to recognize the remote CÀÀH bonds
[11,12]. Recently, Yu elegantly designed pyridine-containing
templates and realized the palladium-catalyzed meta-CÀÀH
iodination of benzyl and phenyl ethyl alcohols by using 1,3-
diiodo-5,5-dimethylhydantoin (DIH) as the iodinating source [13]
(Scheme 1a). Due to the high importance of the phenylacetic acid
in organic synthesis and drug molecules, Yu subsequently applied
this strategy to phenylacetic acid with the template anchoring into
the substrates through an amide linkage [14] (Scheme 1b).
Using the inexpensive and milder molecular I2 as iodinating
reagent has become an attractable alternative in metal-catalyzed
CÀÀH iodination. In 2013, Yu reported the Pd-catalyzed ortho-CÀÀH
iodination of benzamides and phenylacetic amides using I2 as the
sole oxidant [3a]. Subsequently, Chatani and Koley realized the Ni-
catalyzed ortho-CÀÀH iodination of benzamides with molecular I2
[7]. Very recently, Chatani reported Co-catalyzed chelation-
assisted ortho-CÀÀH iodination of benzamides with molecular I2
as an iodinating reagent and Ag2CO3 as the oxidant [8]. Prompted
by these reports and our recent achievement in meta-CÀÀH
deuteration of arenes [15], we questioned whether we could
realize the meta-CÀÀH iodination by using molecular I2 as the
iodinating source. Herein, we reported the template-directed
meta-CÀÀH iodination of phenylacetic acid, benzylphosphonate,
and benzylsulfonate scaffolds by using molecular I2 (Scheme 1c).
Considering that the directing group should be easily installed and
readily removed for bioactive molecules, we anchored the
template into the substrates through a practical ester linkage.
We began our investigation by testing the meta-CÀÀH iodination of
phenylacetic acid containing a variety of 3-subsituted pyridine
based templates (Table 1). When simple pyridyl moiety in substrate
1issubjectedtometa-CÀÀHiodination,only<5%yieldsofiodination
product could be formed (entry 1). It was possible that the
coordination of pyridine with Pd(II) was too strong to form reactive
complex. Introduce a methyl group at 6 position could improve the
yields slightlyto25%(entry 2). Pyrimidine-based templatehas been
recently explored by Maiti in Pd-catalyzed meta-C–H functional-
izations [12]. When we change the heterocycle from pyridine to
pyrimidine, the yields improve to 60% with 54% mono and 6% di
(entry 3). Tuning the coordination ability by incorporation an
electron-withdrawing fluoro group at the C-2 and C-6 position of
* Corresponding authors at: Chinese Academy of Sciences Key Laboratory of
Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
E-mail addresses: xuhui2018@simm.ac.cn (H. Xu), hxdai@simm.ac.cn (H.-X. Dai).
https://doi.org/10.1016/j.cclet.2019.09.057
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: M. Liu, et al., Palladium-catalyzed meta-CÀÀH bond iodination of arenes with I2, Chin. Chem. Lett. (2019),
https://doi.org/10.1016/j.cclet.2019.09.057

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CCLET 5263 No. of Pages 4
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With the optimized reaction conditions in hand, we turned our
attention to investigate the phenylacetic acid scope (Scheme 2).
meta-CÀÀH iodination of phenylacetic acid provided the desired
products 2a in 81% isolated yields (62% mono and 19% di) with high
regioselectivity. Phenylacetic acid containing electron-donating
methyl, methoxyl group at the 2-, 3- or 4-position position could be
iodinated to give the corresponding products in moderate to good
yields with excellect meta ratio (2b, 2c, 2f, 2j). It is worth noting
that substrates containing electron-withdrawing fluoro, chloro,
iodo and even trifluoromethyl groups could react with I2, giving the
corresponding products with good to moderate yields (2d, 2e, 2g,
2i, 2k, 2l). The halide groups in products are useful handle for
further structural elaborations. For 2, 3- or 2, 4- disubstituted
phenylacetic acids, CÀÀH iodination occurred mainly at the less
hindered positions with moderate to good yields (2m-2o).
Furthermore, α-alkyl, cycloalkyl, heteroatom substituted phenyl-
acetic acids were also compatible in this reaction (2p-2s, 2w, 2x).
The versatility of this protocol was further validated by meta-CÀÀH
iodination of cyclic substrates (2u, 2v). Ibuprofen derivative can
also be meta-iodinated to give the corresponding mono iodinated
Scheme 1. Directed CÀÀH iodinaion.
Table 1
Optimization of the reaction conditions for meta-CÀÀH Iodination.
Entry
Template Ag salt Temp (oC) Yield (mono + di)a meta: othersb
1
2
3
4
5
6
7
8
T1
T2
T3
T4
T5
T6
T6
T6
T6
T6
T6
T6
AgOAc 70
AgOAc 70
AgOAc 70
AgOAc 70
AgOAc 70
AgOAc 70
5%<
–
25% (24 + 1)
60% (54 + 6)
61% (43 + 17)
20% (19 + 1)
85% (66 + 19)
82% (64 + 18)
73% (41 + 32)
31% (9 + 22)
27%
>20:1
12:1
>20:1
>20:1
>20:1
>20:1
>20:1
3:1
>20:1
>20:1
>20:1
Ag2O
70
Ag2CO3 70
Ag2SO4 70
AgOAc 40
AgOAc 50
AgOAc 60
9
10
11
12
40% (38 + 2)
67% (61 + 7)
Reaction conditions: 0.1 mmol 1, 0.4 mmol I2, 10 mol% Pd(OAc)2, 0.3 mmol Ag salt,
HFIP/AcOH = 4/1 (1 mL), 20 h.
a
Yields were determined by 1H NMR using CH2Br2 as internal standard.
Regioselectivity was determined by GC–MS.
b
the pyridine ring lead to improved yields, and 2-fluoro-3-pyridyl
template T6 showed the highest yield and meta-selectivity (entries
4–6). Among other silver salts, Ag2O showed comparable results to
AgOAc with 82% yields (entries 7–9). Lowering the reaction
temperature lead to the decreased yield of iodinated product
(entries 10–12).
Scheme 2. Scope of phenylacetic acids for meta-CÀÀH iodination. Reaction
conditions:1 (0.1 mmol), 0.4 mmol I2, 10 mol% Pd(OAc)2, 0.3 mmol AgOAc, HFIP/
AcOH = 4/1 (1 mL), 70 ꢀC, 20 h. Mono and di are showed in parenthesis.
a
b
c
d
Regioselectivity was determined GC–MS. 0.3 mmol I2. 80 ꢀC. 0.2 mmol I2.
e
f
20 mol% N-Ac-Gly-OH was added as ligands.
100 ꢀC. Regioselectivity was
determined LC–MS.
Please cite this article in press as: M. Liu, et al., Palladium-catalyzed meta-CÀÀH bond iodination of arenes with I2, Chin. Chem. Lett. (2019),
https://doi.org/10.1016/j.cclet.2019.09.057

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3
Meta-CÀÀH iodinated products are versatile step stone for
further functionalization at meta positions of arenes. For example,
iodinated ibuprofen derivative 2t could be converted to a diverse
range of meta-substituted ibuprofen ester by alcoholysis and
subsequently Pd-catalyzed cross-coupling reactions, illustrating
the broad utility of this methodology (Scheme 5).
Finally, the template could be easily removed by hydrolysis of
2c at room temperature by using LiOH in THF/H2O, giving the meta-
iodinated phenylacetic acids 8 in good yields (Scheme 6).
In summary, we developed Pd-catalyzed highly meta-selective
CÀÀH iodination of phenylacetic acid, benzylphosphonate, and
benzylsulfonate scaffolds using a pyridine-type template. The
directing template was anchored to the substrates via the practical
ester linkage. A variety of phenylacetic acids containing electron-
withdrawing and electron-donating substituents are compatible
with these reactions. Further transformations of ibuprofen iodide
intermediates by Pd-catalyzed CÀÀC and C–heteroatom bond
formation demonstrated the importance of this methodology in
organic synthesis and drug discovery.
Scheme 3. meta-CÀÀH iodination of benzylphosphonate and benzylsulfonate.
Declaration of competing interest
Scheme 4. Gram-scale reaction.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
We gratefullyacknowledgeShanghai Institute ofMateriaMedica,
Chinese Academy of Sciences, National Natural Science Foundation
of China (No. 21772211), Youth Innovation Promotion Association
CAS (Nos. 2014229 and 2018293), Institutes for Drug Discovery and
Development,
Chinese
Academy
of
Sciences
(No.
CASIMM0120163006), Science and Technology Commission of
Shanghai Municipality (No. 17JC1405000), Program of Shanghai
Academic Research Leader (No. 19XD1424600), National Science &
Technology Major Project “Key New Drug Creation and Manufactur-
ing Program”, China (No. 2018ZX09711002-006), and the State Key
Laboratory of Natural and Biomimetic Drugs for financial support.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.09.057.
Scheme 5. Transformation of iodinated ibuprofen derivative 2t.
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Please cite this article in press as: M. Liu, et al., Palladium-catalyzed meta-CÀÀH bond iodination of arenes with I2, Chin. Chem. Lett. (2019),
https://doi.org/10.1016/j.cclet.2019.09.057