Palladium-Mediated Site-Selective C-H Radio-iodination

Article abstract of DOI:10.1021/acs.orglett.8b02819

The palladium-mediated C-H radio-iodination of arenes using sodium iodide as the primary isotopic source is reported and performed without chemical know-how in 30 min and applied to the synthesis of complex radio-iodinated compounds of biological interest.

Full text of DOI:10.1021/acs.orglett.8b02819

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Mediated Site-Selective C−H Radio-iodination
†
†
‡
†
Emmanuelle Dubost,†,∇ Victor Babin,†,∇ Florian Benoist, ⊥,A#lexandra Hebert, Pierre Barbey,
́
§
∥
§
́
́
́
́
Celine Chollet, Jean-Philippe Bouillon, Alain Manrique, Gregory Pieters, Frederic Fabis,
and Thomas Cailly*,†,#
†
́
Normandie Univ, UNICAEN, Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), 14000 Caen, France
‡Normandie Univ, UNICAEN, IMOGERE, 14000 Caen, France
§
́
SCBM, CEA, Universite Paris Saclay, 91191 Gif-sur-Yvette, France
∥Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
⊥
́
́
́
Signalisation, Electrophysiologie et Imagerie des Lesions d’Ischemie-Reperfusion Myocardique, Normandie Univ, UNICAEN,
14000 Caen, France
#
̂
Department of Nuclear Medicine, CHU Cote de Nacre, 14000 Caen, France
S
* Supporting Information
ABSTRACT: The palladium-mediated C−H radio-iodina-
tion of arenes using sodium iodide as the primary isotopic
source is reported and performed without chemical know-how
in 30 min and applied to the synthesis of complex radio-
iodinated compounds of biological interest.
uclear medicine using radionuclides has revolutionized
Nlife sciences since one of the first reports on the
successful treatment of thyroid cancer metastases using iodine-
131 in 1946.1 Since then, radionuclides have been extensively
used to improve healthcare through molecular imaging and
radiotherapy.2 Among the different radionuclides used in these
fields, iodine is undoubtedly one of the most relevant elements,
because of its widespread applications and versatility. Several
isotopes of iodine are available, allowing their use in different
areas of imaging and therapy: 123I for single-photon-emission
computed tomography (SPECT) imaging, 124I for positron
emission tomography (PET) imaging, 125I for biological
research (binding, radioimmunoassay, autoradiography, and
nuclear medicine) and 131I for radiotherapy and scintigraphy.3
Typical radio-iodination methods (see Figure 1A) are based on
the use of a prefunctionalized precursor, which has to be
synthesized, isolated, and purified before being introduced in
the radio-iodination step.4−6 Stannylated precursors are the
most widely used, and they are generally obtained from
halogenated compounds through Pd-catalyzed chemistry,
although their use remains limited, because of their difficult
synthesis and known toxicity.7 Electrophilic radio-iodination
(SEAr) of arenes does not require any precursor, but remains
limited to electron-rich arenes to be regioselective and/or
efficient. Aromatic nucleophilic substitution (SNAr) has also
been extensively used, either through isotopic exchange or
from a chemical precursor, but most often under harsh
conditions and/or leading to low specific activities. Recently,
several examples of transition-metal-mediated (MMed) radio-
iodination methods have been described, such as Ni-catalyzed
Br/I exchange at high temperature,8 Cu- or Au-catalyzed
B(OR)2/I exchange,9−11 or one-pot radio-iodination of
Figure 1. (A) State-of-the-art and (B) C−H radio-iodination
hypothesis. [Legend: FG, functional group; RI*, radio-iodination
reagent; SEAr, electrophilic aromatic substitution; SNAr, nucleophilic
aromatic substitution; MMed, transition-metal-mediated; DG, directing
group.]
diazonium derivatives.12 Although innovative and providing a
renewed interest for radio-iodination chemistry, these methods
are still based on and limited by the synthesis and purification
of prefunctionalized precursors. A breakthrough in the radio-
iodination field would be the direct and regioselective
introduction of iodine radioisotopes from a nonfunctionalized
C−H bond while taking advantage of chelating groups present
on the molecule (see Figure 1B).
Transition-metal-catalyzed C−H activation has emerged in
the past decade as a powerful methodology, allowing direct
functionalization of C(sp2)−H bonds. Starting from a
Received: September 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02819
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
compound bearing a directing group (DG), a wide panel of
C−C or C−heteroatom bonds can be obtained at the adjacent
C−H bond from the transient metallacycle formed as the key
intermediate in the catalytic process.13−15 Among them, C−
halogen bond formation has attracted much attention,16 as it
represents a nice way to selectively introduce halogen atoms
from an inactivated C−H bond, avoiding the synthesis of
precursors and using milder conditions than SEAr. Even though
C−H activation has been extensively described as a powerful
tool to synthesize halogenated compounds, to date, its use in
radiolabeling has only been reported for tritiation of arenes17,18
and radio-fluorination of aliphatic C−H bonds.19 Interestingly,
recent examples of radiochemistry performed from organo-
palladium intermediates have been described to promote 18F-
fluorination20 and 11C-cyanation.21 In these reports, palladium
complexes were obtained from precursors, through multistep
procedures in glovebox, requiring a high chemical expertise,
thus precluding the implementation of these methodologies in
health facilities for imaging applications. We report here a C−
H radio-iodination procedure avoiding the difficult isolation of
the palladacycle. This reaction proceeds under mild conditions
and has been applied to a wide variety of directing groups and
to pharmaceutically relevant molecules.
iodination and demonstrated that its formation was the rate-
limiting step of this process. C−H iodination has been first
investigated from 2-chloro-N-tosylbenzamide (1a) in order to
form 2-chloro-6-iodo-N-tosylbenzamide (2a) in a one-pot
procedure while avoiding isolation of the intermediate
organometallic species (see Figure 2B). A crude solution of
palladacycle (1a-Pd) was prepared using 1.05 equiv of
palladium acetate in methanol for 24 h at room temperature.
While mixing (1a-Pd) and a NIS solution (1 equiv in
methanol) compound (2a) was obtained in 15 min with 56%
1
1H NMR yield, using AcOH as an additive or 72% H NMR
yield with TFA (see Tables S1 and S2 in the Supporting
Information). Therefore, to perform radio-iodination, the
major difficulty to be solved was to adapt this process using
sodium iodide, the sole commercially available source of
radioactive iodine. In the literature, few examples of the
formation of NIS from NaI and N-chlorosuccinimide (NCS)
have been reported.23−25 Based on these results, we found that
[
125I]NIS can be formed using a mixture of NCS and [125I]NaI
in 15 min at room temperature in methanol. Compound 1a-Pd
was added to the resulting mixture with TFA or AcOH, leading
to the formation of the radio-iodinated compound [125I]2a
(see Figure 2C). During these investigations, it appeared that
the use of substoichiometric amount of NCS (0.48 equiv) was
mandatory to avoid side reactions, because of the presence of
unreacted NCS (methoxylation and/or chlorination) (Table
S4 in the Supporting Information). The best radiochemical
conversion (RCC) was obtained using a 30 mM solution of
NCS and a large excess of TFA leading to 82% RCC
(condition A). Replacing TFA by AcOH (condition B) or
using a lower amount of TFA with a more-diluted solution of
NCS (condition C) led to slightly lower RCCs of 76% and
71%, respectively. Two control experiments were performed
(without NCS and without Pd(OAc)2), where no reaction was
observed, clearly demonstrating the essential role of NCS in
the reaction and the C−H activation process occurring during
the radio-iodination.
In a previous work (see Figure 2A), our group has described
a room-temperature palladium-catalyzed C−H iodination from
The scope of the C−H radio-iodination was then evaluated
using various N-tosylbenzamides (1a−1l) bearing electron-
donating and electron-withdrawing groups (see Figure 3A). In
each of the cases, the palladacycle has been obtained using 1.05
equiv of palladium acetate in methanol at room temperature or
50 °C for up to 24 h. The amount of formed palladacycle was
estimated by 1H NMR while performing the reaction in
deuterated methanol (see Table S2 in the Supporting
Information). Substrate scope was investigated according to
conditions A, B, and C (see Table S5 in the Supporting
Information). The best results, depicted in Figure 3, revealed
that condition C was the most suitable, except for compound
1a (see Table S5). Starting from compounds 1d, 1e, 1f, and
1k, higher RCCs were obtained while preparing the pallada-
cycle crude solution in diluted conditions. Overall, the C−H
radio-iodination reaction is efficient with either electron-
donating or electron-withdrawing substituents in ortho, meta,
and para positions, leading to RCCs between 44% and 91%.
The C−H radio-iodination reaction was then evaluated on
biologically relevant N-acylsulfonamides (see Figure 4).
Among the molecules described in the literature exhibiting
this functional group, LY32262 (1m),26,27 Tasisulam (1n),28
and the Bcl-xL/Mcl-1 dual inhibitor (1o)29 were selected and
successfully radiolabeled within high RCCs using condition C.
Starting from an activity of 31.9 MBq, [125I]2m was isolated
with a radiochemical yield (RCY) of 42% (see Table S6 in the
Figure 2. C−H radio-iodination optimization: (A) previous work of
22
́
Peron et al., (B) C−H iodination proof of concept, and (C) C−H
radio-iodination optimal conditions and control experiments.
[Legend: RCC, radiochemical conversion; equiv, equivalent; rt,
room temperature; NIS, N-iodosuccinimide; NCS, N-chlorosuccini-
mide; TFA, trifluoroacetic acid; and NMR, nuclear magnetic
resonance. The asterisk symbol (*) denotes that the reaction was
performed from 1a without Pd(OAc)2.]
N-acylsulfonamides in methanol using either IOAc or N-
iodosuccinimide (NIS)/trifluoroacetic acid (TFA) as the
iodination reagents.22 Mechanistic investigations of this
reaction led to isolation and characterization of the
intermediate palladacycle through ligand exchanges with
acetonitrile. Reactivity of the latter was also evaluated toward
B
DOI: 10.1021/acs.orglett.8b02819
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Scope of the N-acylsulfonamide C−H radio-iodination: (A)
C−H radio-iodination from N-acylsulfonamides and (B) C−H radio-
iodination applied to pharmaceutically N-acylsulfonamides. Radio-
chemical conversions are shown, n = 2. Condition A is defined as
125I]NIS generated from 50 μL of NCS at 30 mM and 2−3 MBq of
125I]NaI, and 50 μL of TFA were used. Condition B is defined as
125I]NIS generated from 50 μL of NCS at 30 mM and 2−3 MBq of
125I]NaI, and 50 μL of AcOH were used. Condition C is defined as
125I]NIS generated from 95 μL of NCS at 16 mM and 2−3 MBq of
125I]NaI, and 20 μL of TFA were used. Superscript “1” indicates that
Figure 4. C−H radio-iodination directing group scope. Radio-
chemical conversions are shown, n = 2. Palladation conditions: I,
Pd(OAc)2 1.05 equiv, CD3OD or MeOH, rt, 24 h; II, Pd(OAc)2 1.05
equiv, TsOH 2 equiv, CD3OD or MeOH, rt, 24 h; III, PdCl2 1.05
equiv, CD3CN or MeCN, 80 °C, 24 h; IV, Pd(OAc)2 1.05 equiv,
TsOH 2 equiv, CDCl3 or CHCl3, 60 °C, 24 h. Condition C is applied
for C−H radio-iodination: [125I]NIS was generated from 95 μL of
NCS at 16 mM and 2−3 MBq of [125I]NaI, and 20 μL of TFA were
used. Superscript “1” indicates that radiochemical conversions are
shown for n = 3; superscript “2” indicates that palladacycle crude
solution was prepared at room temperature; superscript “3” indicates
that radiochemical conversion is shown for n = 1; and superscript “4”
indicates that a complex mixture of radio-iodinated molecules was
observed. [Legend: equiv, equivalent; rt, room temperature; NIS, N-
iodosuccinimide; NCS, N-chlorosuccinimide; and TFA, trifluoro-
acetic acid.]
[
[
[
[
[
[
palladacycle crude solution was prepared from a 160 mM solution of
Pd(OAc)2 in MeOH; superscript “2” indicates that palladacycle crude
solution was prepared from a 80 mM solution of Pd(OAc)2 in
MeOH; and superscript “3” indicates palladacycle crude solution was
prepared in 7 h. [Legend: equiv, equivalent; rt, room temperature;
NIS, N-iodosuccinimide; NCS, N-chlorosuccinimide; TFA, trifluoro-
acetic acid.]
Supporting Information) and its molar specific activity was
found to be 32.9 GBq/μmol (see Table S7 in the Supporting
Information), validating the potential of this C−H radio-
iodination approach toward applications in the field of nuclear
medicine and imaging.
radio-iodination was then evaluated for each case where a
consumption of the starting material appeared. Thus, N-
tosylbenzamide (3a) was radio-iodinated using either con-
dition I or condition II (Pd(OAc)2 and para-toluene sulfonic
acid (TsOH) in MeOH at rt). Acetanilide and anilide
derivatives such as pyrrolidinone, boc-aniline, and urea (3b−
3g) were radio-iodinated within good RCCs using either
condition II or condition IV (Pd(OAc)2 and TsOH in CHCl3
at 60 °C). Closely related directing groups such as acetate and
methylacetamide (3h and 3i) were unable to promote any
palladation reaction under the investigated conditions.
Benzamide derivatives (3j−3l) were all radio-iodinated
efficiently using condition II. Using carboxylic acid as the
directing group, we found that benzoic acid was unable to
promote C−H activation while the corresponding sodium
carboxylate (3m) could be radiolabeled using either condition
III (PdCl2 in MeCN at 80 °C) or condition IV. If conditions
Finally, the C−H radio-iodination was extended to the use
of other directing groups (see Figure 4). During our
investigations, the palladation conditions discovered for the
C−H radio-iodination of N-acylsulfonamides (condition I)
rapidly appeared limited and the directing groups were
evaluated using three other palladation conditions (II, III,
and IV). In order to quickly assess if a directing group was able
to direct C−H activation, and taking into account the very
1
different nature of the palladacycles, a H NMR investigation
was performed (see Table S3 in the Supporting Information).
In all cases, while performing the palladation in deuterated
solvent, the amount of starting material was monitored,
showing either the consumption (Figure 4, green tick) or the
total recovery of the substrate (Figure 4, red cross). The C−H
C
DOI: 10.1021/acs.orglett.8b02819
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) Wager, K. M.; Jones, G. B. Curr. Radiopharm. 2010, 3 (1), 37−
III and IV were found to be efficient, starting from sodium
phenyl acetate (3n), radio-iodination was only observed from
condition III. Starting from sodium phenylpropanoate (3o), no
palladation was observed. Using nitriles as the directing group
(3p−3q), radio-labeling was observed using condition II
within moderate RCCs, because of the formation of the
corresponding amide as a side product. Using a ketone (3r) or
methylsulfonamide (3s) as the directing group did not provide
any C−H activation. Finally, radio-iodination of 1-phenyl-1H-
pyrazole (3t) was possible using conditions I or III, while 2-
phenylthiophene (3u) was unable to promote C−H activation.
In summary, we described the first example of radio-
iodination using a C−H activation approach. This general
strategy, which is applicable to 15 different directing groups,
allows rapid and efficient access to radio-iodinated molecules
that possess high specific activities without using chemical
precursors. Moreover, this new radio-iodination method can be
applied under mild conditions without specific chemical
expertise or equipment and therefore possesses great potential
in terms of implementation in health or imaging facilities.
Considering the large panel of chelating groups present in
biologically relevant molecules and the possibility of
introducing other atoms or group of atoms through C−H
activation processes, we expect that this new approach could
be applied to other radionuclides and/or directing groups and
thus accelerate the discovery process in radiolabeling problem-
atics.
45.
(6) Mushtaq, S.; Jeon, J.; Shaheen, A.; Jang, B. S.; Park, S. H. J.
Radioanal. Nucl. Chem. 2016, 309, 859−889.
(7) Boyer, I. J. Toxicology 1989, 55, 253−298.
(8) Cant, A. a.; Champion, S.; Bhalla, R.; Pimlott, S. L.; Sutherland,
A. Angew. Chem., Int. Ed. 2013, 52, 7829−7832.
(9) Wilson, T. C.; McSweeney, G.; Preshlock, S.; Verhoog, S.;
Tredwell, M.; Cailly, T.; Gouverneur, V. Chem. Commun. 2016, 52,
13277−13280.
(10) Zhang, P.; Zhuang, R.; Guo, Z.; Su, X.; Chen, X.; Zhang, X.
Chem. - Eur. J. 2016, 22, 16783−16786.
(11) Webster, S.; O’Rourke, K. M.; Fletcher, C.; Pimlott, S. L.;
Sutherland, A.; Lee, A. Chem. - Eur. J. 2018, 24, 937−943.
(12) Sloan, N. L.; Luthra, S. K.; McRobbie, G.; Pimlott, S. L.;
Sutherland, A. Chem. Commun. 2017, 53, 11008−11011.
(13) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S.
W. Chem. Soc. Rev. 2016, 45, 546−576.
(14) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J.
Chem. Soc. Rev. 2016, 45, 2900−2936.
(15) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−
1169.
(16) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116,
8003−8104.
(17) Yang, H.; Dormer, P. G.; Rivera, N. R.; Hoover, A. J. Angew.
Chem., Int. Ed. 2018, 57, 1883−1887.
(18) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C−H. Angew.
Chem., Int. Ed. 2018, 57, 3022−3047.
(19) Liu, W.; Huang, X.; Placzek, M. S.; Krska, S. W.; McQuade, P.;
Hooker, J. M.; Groves, J. T. Chem. Sci. 2018, 9, 1168−1172.
(20) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.;
Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T.
Science 2011, 334, 639−642.
ASSOCIATED CONTENT
* Supporting Information
■
S
(21) Zhao, W.; Lee, H. G.; Buchwald, S. L.; Hooker, J. M. J. Am.
Chem. Soc. 2017, 139, 7152−7155.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02819.
́
(22) Peron, F.; Fossey, C.; Sopkova-de Oliveira Santos, J.; Cailly, T.;
Fabis, F. Chem. - Eur. J. 2014, 20, 7507−7513.
̈
(23) Youfeng, H.; Coenen, H. H.; Petzold, G.; Stocklin, G. J.
Detailed experimental procedures and spectroscopic
data for all new compounds (PDF)
Labelled Compd. Radiopharm. 1982, 19, 807−819.
(24) Vankar, Y. D.; Kumaravel, G. N. Tetrahedron Lett. 1984, 25,
233−236.
AUTHOR INFORMATION
(25) Racys, D. T.; Sharif, S. A. I.; Pimlott, S. L.; Sutherland, A. J. Org.
Chem. 2016, 81, 772−780.
■
Corresponding Author
*E-mail: thomas.cailly@unicaen.fr.
ORCID
(26) Corbett, T. H.; White, K.; Polin, L.; Kushner, J.; Paluch, J.;
Shih, C.; Grossman, C. S. Invest. New Drugs 2003, 21, 33−45.
(27) Lobb, K. L.; Hipskind, P. A.; Aikins, J. A.; Alvarez, E.; Cheung,
Y.; Considine, E. L.; De Dios, A.; Durst, G. L.; Ferritto, R.; Grossman,
C. S.; et al. J. Med. Chem. 2004, 47, 5367−5380.
Thomas Cailly: 0000-0002-5262-4494
Author Contributions
∇These authors contributed equally.
(28) Meier, T.; Uhlik, M.; Chintharlapalli, S.; Dowless, M.; Van
Horn, R.; Stewart, J.; Blosser, W.; Cook, J.; Young, D.; Ye, X.; et al.
Mol. Cancer Ther. 2011, 10, 2168−2178.
(29) Rega, M. F.; Wu, B.; Wei, J.; Zhang, Z.; Cellitti, J. F.; Pellecchia,
M. J. Med. Chem. 2011, 54, 6000−6013.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support provided by the
Regional Council of Normandy, FEDER, Crunch Network, la
Ligue Contre le Cancer, la Fondation ARC pour la Recherche
Contre le Cancer, the University of Caen, Tremplin Carnot
I2C, the French Ministry of Research and Bernard Rousseau
from SCBM (CEA Saclay, France) for helpful advices.
REFERENCES
■
847.
(1) Seidlin, S. M.; Marinelli, L. D.; Oshry, E. JAMA 1946, 132, 838−
(2) Pimlott, S. L.; Sutherland, A. Chem. Soc. Rev. 2011, 40, 149−162.
(3) Adam, M. J.; Wilbur, D. S. Chem. Soc. Rev. 2005, 34, 153−163.
(4) Seevers, R. H.; Counsell, R. E. Chem. Rev. 1982, 82, 575−590.
D
DOI: 10.1021/acs.orglett.8b02819
Org. Lett. XXXX, XXX, XXX−XXX