Improvements of C-H Radio-Iodination of N-Acylsulfonamides toward Implementation in Clinics

Article abstract of DOI:10.1055/s-0037-1611884

An improved protocol to perform C-H radio-iodination is described. These new conditions allow rapid and clean formation of radio-iodinated N-acylsulfonamides using [¹²⁵ I]NIS and catalytic amounts of palladium acetate and para-toluenesulfonic a

Full text of DOI:10.1055/s-0037-1611884

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
special topic
A
en
E. Dubost et al.
Special Topic
Synthesis
Improvements of C–H Radio-Iodination of N-Acylsulfonamides
toward Implementation in Clinics
Emmanuelle Dubosta
Victor Babina
1) Pd(OAc)2 (cat.)
PTSA (cat.)
0.25 h
O
H
O
NHTs
NHTs
Florian Benoista
Alexandra Héberta
Gilbert Pigréeb
Jean-Philippe Bouillonc
Frédéric Fabisa
R
R
2) [125I]NIS, 0.25 h
125I
11 compounds RCC = 27–84%
Short reaction time
Catalytic
No side-products
Thomas Cailly*a,b,d
0
0
0
0-0
0
0
2-5
2
6
2-4
4
9
4
a Normandie Univ, UNICAEN, Centre d’Etudes et de Recherche
sur le Médicament de Normandie (CERMN), 14000 Caen,
France
b Normandie Univ, UNICAEN, IMOGERE, 14000 Caen, France
c Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA
(UMR 6014), 76000 Rouen, France
d Department of Nuclear Medicine, CHU Côte de Nacre, 14000 Caen, France
thomas.cailly@unicaen.fr
Published as part of the Special Topic Halogenation methods (with a view towards radioimaging applications)
Received: 29.05.2019
Accepted after revision: 18.06.2019
Published online: 09.07.2019
recently, some innovative methodologies using transition
metals have been described, however, they are still limited
by the synthesis of pre-functionalized precursors.6–11 Re-
cently, our group described a new approach to radio-iodin-
ate small molecules using palladium-mediated C–H activa-
tion (Scheme 1A).12 In this work, we used a crude pallada-
cycle solution as the precursor, taking advantage of the
functional groups present on the molecule to perform the
radio-iodination. This approach offers a new strategy to ra-
diolabel molecules of interest while avoiding the use of pre-
functionalized precursors. Nevertheless, in order to effi-
ciently transfer this technology to nuclear medicine facili-
ties, where the radiolabeling is usually achieved through
the use of radiopharmaceutical kits and automated sys-
tems, several problems had to be addressed. First, the for-
mer protocol used 1.05 equivalent of palladium acetate to
prepare the organometallic precursor. Due to the presence
of such an amount of precursor compared to the quantity of
iodine-125 in the reaction, many cold by-products were
generated. Second, formation of the palladacycle was
achieved within 24 hours prior to radiolabeling, thus con-
stituting a potential issue to further use in radiopharmacy.
In our efforts to provide a reliable methodology to radiola-
bel molecules on the basis of C–H activation, we have been
in search of improvements to our preliminary conditions
(Scheme 1A). From our point of view, decreasing the
amount of palladium should be beneficial for this method
in order to limit the formation of by-products and to allow
the transfer to automated synthesis systems (Scheme 1B).
Furthermore, modification of the reaction conditions to-
DOI: 10.1055/s-0037-1611884; Art ID: ss-2019-s0301-st
Abstract An improved protocol to perform C–H radio-iodination is de-
scribed. These new conditions allow rapid and clean formation of radio-
iodinated N-acylsulfonamides using [125I]NIS and catalytic amounts of
palladium acetate and para-toluenesulfonic acid. No pre-functionalized
precursors are required and the products are obtained with radiochem-
ical conversions (RCC) of 27–84%.
Key words radiochemistry, iodination, C–H activation, palladium,
iodine-125
Radiopharmaceuticals labelled with radioactive iodine
isotopes have always played a major role in nuclear medi-
cine and molecular imaging. Indeed, iodine presents 4 dif-
ferent isotopes that can be used for imaging or medical pur-
poses (123I for SPECT imaging, 124I for PET, 125I and 131I for ra-
diotherapy).1,2 However, compared to the radiochemistry of
other radio-elements such as 18F, 11C or 3H, inventive radio-
iodination for applications in either PET or SPECT imaging
has progressed slowly in recent decades. Most of the time,
typical procedures to prepare radiotracers are restricted to
nucleophilic aromatic substitution or iodo-demetallation of
arenes. The most used methodology is iodo-destannylation,
which leads to high radiochemical purity and specific activ-
ity, but stannylated precursors are reputed to be difficult to
purify and toxic.3 Isotopic exchange has been extensively
used in the past, but has led to poor specific activity and is
always performed under harsh reaction conditions.4,5 More
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Dubost et al.
Special Topic
Synthesis
ward an increase in the rate of palladacycle formation also
seemed to be a key implementation to provide a transfer-
able protocol to nuclear medicine facilities.
entry 1). Decreasing the amount of palladium acetate to 15
mol% slightly decreased the RCC to 81% (Table 1, entry 3).
Furthermore, we found that under the same conditions it
was possible to reduce the quantity of palladium acetate to
2 mol% without affecting noticeably the RCC (Table 1, entry
4). Decreasing the reaction time to 5 minutes led to a lower
RCC of 69% (Table 1, entry 5). Mixing all the reagents at the
beginning of the reaction led to no conversion, showing
that the palladacycle cannot be formed in the presence of
A) Previous Work
O
O
1) Pd(OAc)2
(1.05 equiv) 24 h
NHTs
NHTs
125I
O
2) [125I]NIS, 0.25 h
H
O
B) This Work
1) Pd(OAc)2 (cat.)
PTSA (cat.)
0.25 h
[
125I]NaI and/or NCS (Table 1, entry 6). Repeating the condi-
NHTs
NHTs
125I
tions of entry 3 without PTSA led to a radiochemical con-
version of 58%, showing that the use of PTSA was crucial for
the reaction to be effective (Table 1, entry 7).
2) [125I]NIS, 0.25 h
H
Scheme 1 (A) C–H radio-iodination using a stoichiometric amount of
palladium.12 (B) C–H radio-iodination using a catalytic amount of palla-
dium.
Table 1 Optimization of C–H Radio-Iodination Using a Catalytic
Amount of Palladiuma
In the course of our optimization to find reaction condi-
tions able to increase the rate of the palladacycle formation,
we found that the use of a stoichiometric amount of para-
toluenesulfonic acid (PTSA) considerably shortened the re-
action time. For example, starting from 2-chloro-N-tosyl-
benzamide (1a) in the presence of 2 equivalents of PTSA
and 1 equivalent of Pd(OAc)2 in CD3OD, we were pleased to
observe after 1 hour a 20:80 (1a/1a-Pd) 1H NMR ratio
(Scheme 2, see the Supporting Information for details).
O
H
O
Cl
Cl
1) Pd(OAc)2, PTSA
MeOH, RT
NHTs
NHTs
2) [125I]NIS solution
TFA, RT, 0.25 h
125I
2a
1a
Entry
Pd(OAc)2 (mol%) PTSA (mol%)
Time (min)b RCCc
1
2
3
4
5
6
7
100
100
15
2
0
3
3
3
3
3
0
1440
15
15
15
5
71 ± 2
94 ± 0
81 ± 1
84 ± 3
69 ± 3
0d
O
O
Cl
Cl
Pd(OAc)2 (1 equiv)
PTSA (2 equiv)
Ts
NHTs
2
N
CD3OD, RT
Pd
H
L
2
0
1H NMR ratio:
30 min 30:70 (1a/1a-Pd)
60 min 20:80 (1a/1a-Pd)
L
1a
43 mM in CD3OD
2
15
58 ± 12
1a-Pd
crude palladacyle solution
a Reaction conditions: the palladacycle solution was prepared from 40 L of
0.16 M 1a solution in MeOH, 20 L of 8.8 mM PTSA solution in MeOH and
40 L of Pd(OAc)2 solution in DCM/MeOH (1:24). [125I]NIS solution was
generated from 95 L of NCS 16 mM in MeOH and 2–3 MBq of [125I]NaI in
5 L of H2O; 20 L of TFA was used.
Scheme 2 Formation of 1a-Pd in CD3OD
b Palladacycle preparation time.
From this preliminary observation, we decided to ex-
plore the influence of PTSA on C–H radio-iodination with
shorter reaction times (Table 1). For each reaction, the
crude palladacycle solutions were reacted with a solution of
c Radiochemical conversions (RCC) are given n = 2.
d n = 1.
[
125I]NIS prepared from [125I]NaI and NCS in 15 minutes.
The scope of the reaction was then evaluated toward a
panel of nine N-acylsulfonamides bearing electron-with-
drawing and electron-donating groups (Scheme 3). In each
case, the RCC was calculated as a mean of two experiments
(Scheme 3, conditions A) and compared with our previous
results using stoichiometric amounts of palladium (Scheme
3, conditions B).12 In most cases, similar to better RCC val-
ues were obtained for N-acylsulfonamides bearing an elec-
tron-donating group compared to our previous protocol.
Products bearing electron-withdrawing groups led to less
iodine-125 incorporation than the previous reported proto-
col. This result can be explained by the lower reaction rates
of substrates bearing these electron-withdrawing groups.
Therefore, in this study, the palladacycle solution was not
prepared 24 hours in advance as previously reported,12 but
directly in the glove box during the preparation of [125I]NIS.
To do so, a solution of 2-chloro-N-tosylbenzamide (1a) in
methanol was mixed with solutions of PTSA in methanol
and palladium acetate in a mixture of DCM/MeOH (1:24) at
room temperature. Next, the desired quantity of palladacy-
cle solution was added to the solution of [125I]NIS, along
with TFA, and the resulting mixture was allowed to stir at
room temperature for 15 minutes. Using a stoichiometric
amount of palladium, a radiochemical conversion (RCC) of
94% was obtained (Table 1, entry 2), which showed a clear
improvement compared to our previous conditions (Table 1,
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
E. Dubost et al.
Special Topic
Synthesis
O
H
O
1) Pd(OAc)2 (2 mol%)
PTSA (3 mol%), RT, 0.25 h
NHTs
NHTs
125I
R
R
2) [125I]NIS solution
TFA, RT, 0.25 h
1a-i
[
125I]2a-i
O
O
O
OMe O
Cl
O
Me
O
O
O
F
O
Me
F3C
I
NHTs
125I
NHTs
NHTs
NHTs
NHTs
NHTs
125I
NHTs
NHTs
NHTs
Br
125I
125I]2h
125I
125I]2g
125I
125I
125I]2a
125I
125I]2d
125I
125I]2f
125I
125I]2b
[
[
[
125I]2c
[
[
125I]2e
[
[
[
[
125I]2i
84 3%, A
71 2%, B
80 0%, A
91 1%, B
76 5%, A
83 1%, B
57 2%, A
77 3%, B
84 4%, Aa
81 2%, Bb
72 1%, A
65 0%, Bb
31 2%, A
81 2%, B
68 3%, A
71 2%, B
27 2%, Aa
74 2%, B
Scheme 3 Scope of the palladium-catalyzed C–H radio-iodination of N-acylsulfonamides. Radiochemical conversions (RCC) are given n = 2. Reagents
and conditions: palladacycle solutions were prepared from 40 L of 0.16 M N-acylsulfonamide solution in MeOH. [125I]NIS solution was generated from
95 L of NCS 16 mM in MeOH and 2–3 MBq of [125I]NaI in 5 L of H2O; 20 L of TFA was used. A: Catalytic conditions: 20 L of 8.8 mM PTSA solution in
MeOH and 40 L of 2.5 mM Pd(OAc)2 solution in DCM/MeOH (1:24). B: Stoichiometric conditions: the palladacycle solution was prepared from an 80 mM
solution of Pd(OAc)2 at room temperature for 24 h.12 a The palladacycle solution was prepared from 40 L of 0.16 M N-acylsulfonamide solution in
DCM/MeOH (1:4). b The crude palladacycle solution was prepared from a 160 mM solution of Pd(OAc)2 in MeOH.
Due to the addition of PTSA to the reaction, the quantity
of palladium needed was drastically decreased. The addi-
tion of PTSA led to a faster formation of the palladacycle,
within a few minutes instead of several hours. Beyond the
gain in terms of reaction time with these new conditions,
we were also pleased to discover other advantages related
to this new protocol (Figure 1). In addition, cleaner UV
spectra were observed as, in most cases, we were only able
to observe the radio-iodinated product along with unreact-
ed starting material (Figure 1A). In our previous work, due
to the excess of palladium and extended reaction times,
both side chlorination and methoxylation were observed
with the radio-iodination (Figure 1B). Moreover, these con-
ditions also greatly improved the turbidity of our reactions
after the quench with aqueous sodium thiosulfate solutions
(Figure 2), a non-negligible advantage to adapt this protocol
toward an automated synthesis system.
We then applied these new conditions to the radiolabel-
ing of two molecules of interest presenting the N-acylsul-
fonamide group, LY3226213,14 and tasisulam.15 Following
our procedure, the expected radiolabeled compounds
Figure 1 UV spectra and radiochromatograms of [125I]2e in catalytic (A) and stoichiometric (B) conditions. Reagents and conditions: the palladacycle
solution was prepared from 40 L of a 0.16 M solution of 1e in DCM/MeOH (1:4). [125I]NIS solution was generated from 95 L of NCS 16 mM in MeOH
and 2–3 MBq of [125I]NaI in 5 L of H2O; 20 L of TFA were used. A: Catalytic conditions: 20 L of 8.8 mM PTSA solution in MeOH and 40 L of 2.5 mM
Pd(OAc)2 solution in DCM/MeOH (1:24). B: Stoichiometric conditions: the palladacycle solution was prepared from an 80 mM solution of Pd(OAc)2 at
room temperature for 24 h.12
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
E. Dubost et al.
Special Topic
Synthesis
groups that are able to perform efficiently C–H activation.
Now that the constraints related to reaction times and side-
products have been solved, we think that palladium-cata-
lyzed C–H radio-iodination will be truly beneficial to the
scientific community as complementary to other existing
radio-iodination methods.
Unless otherwise specified, all reagents and solvents were obtained
from commercial suppliers. Flash column chromatography was per-
formed over silica gel Macherey-Nagel C60 (40–60 m) or Biotage RP-
18 (50 m) using eluent systems as described for each experiment.
Melting points of solids were measured on a Stuart Automatic Melting
point SMP-50 apparatus. All NMR spectra were recorded on a Bruker
Avance III 400 spectrometer. 1H and 13C NMR spectra are reported as
chemical shifts () in parts per million (ppm). Coupling constants (J)
are reported in units of hertz (Hz). The following abbreviations are
used to describe multiplicities: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad).
Figure 2 C–H radio-iodination of 1a in catalytic (A) and stoichiometric
(B) conditions. Reagents and conditions: the palladacycle solutions were
prepared from 40 L of 0.16 M N-acylsulfonamide solution in MeOH.
[
125I]NIS solution was generated from 95 L of NCS 16 mM in MeOH
and 2–3 MBq of [125I]NaI in 5 L of H2O; 20 L of TFA were used. A: Cat-
alytic conditions: 20 L of 8.8 mM PTSA solution in MeOH and 40 L of
2.5 mM Pd(OAc)2 solution in DCM/MeOH (1:24); quench, Na2S2O3 (0.05
M in H2O, 200 L) followed by H2O (550 L) and MeOH (550 L). B: Stoi-
chiometric conditions: the palladacycle solution was prepared from an
80 mM solution of Pd(OAc)2 at room temperature for 24 h; quench,
Na2S2O3 (0.05 M in H2O, 200 L) followed by H2O (1 mL).12
C–H Radio-Iodination; Typical Procedure
In a V-vial equipped with a stirrer bar, N-chlorosuccinimide (0.016 M
in MeOH, 95 L) was added to an aqueous solution of [125I]sodium io-
dide (5L, 2–3 MBq). The resulting mixture was stirred for 15 min at
room temperature. In parallel, in another V-vial, the starting N-acyl-
sulfonamide (0.16 M in MeOH, 40 L), PTSA (8.8 mM in MeOH, 20L)
and palladium acetate [2.5 mM in DCM/MeOH (1:24), 40L)] were
mixed together for 15 min at room temperature. A 50 L aliquot of
the obtained mixture was added to the [125I]NIS solution, along with
20 L of pure TFA. The resulting mixture was stirred for 15 min at
room temperature and then quenched with a solution of sodium thio-
sulfate (0.05 M in H2O, 200 L) and diluted with H2O (550 L) and
MeOH (550 L).
[
125I]2j and [125I]2k were obtained with RCC values of 27 ±
2% and 48 ± 4%, respectively (Scheme 4), demonstrating the
ability of this process to be applied to radiotracers.
O
Cl
O
O
O
Cl
O
O
S
S
N
N
H
H
1) Pd(OAc)2 (2 mol%)
PTSA (3 mol%),
RT, 0.25 h
Cl
or
Cl
Cl
H
125I
1j
[
125I]2j
RCC = 27 2%
LY32262
or
2) [125I]NIS solution
TFA, RT, 0.25 h
Cl
O
Cl
O
O
O
S
O
O
S
S
S
N
N
Br
Br
H
H
H
Cl
125I
1k
tasisulam
[
125I]2k
N-Tosylbenzamides 1a,b,e,g–i; General Procedure (G1)
RCC = 48 4%
A round-bottom flask was filled with p-toluenesulfonamide (1 equiv),
EtOAc (2 mL/mmol), Et3N (2.5 equiv) and DMAP (0.5 mol%) under N2.
A solution of acyl chloride (1.1 equiv) in dried toluene (0.8 mL/mmol)
was added via a syringe over 15 min at room temperature. The mix-
ture was stirred for 3 h at 55 °C, cooled to room temperature and
quenched with 0.5 M aqueous HCl solution (3 mL/mmol). The result-
ing mixture was extracted with EtOAc (3 times). The combined or-
ganic layers were dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure. The crude residue was purified by sili-
ca gel chromatography using AcOH/EtOAc/cyclohexane (5:15:85) as
eluent.
Scheme 4 C–H radio-iodination of 1j and 1k. Reagents and conditions:
the palladacycle solutions were prepared from 40 L of 0.16 M N-acyl-
sulfonamide solution in MeOH. [125I]NIS solution was generated from
95 L of NCS 16 mM in MeOH and 2–3 MBq of [125I]NaI in 5 L of H2O;
20 L of TFA were used. Catalytic conditions: 20 L of 8.8 mM PTSA solu-
tion in MeOH and 40 L of 2.5 mM Pd(OAc)2 solution in DCM/MeOH
(1:24).
In conclusion, we have developed a new protocol to ra-
diolabel N-acylsulfonamides using palladium catalyzed C–H
activation thanks to the use of PTSA for the preparation of
the palladacycle solution. This protocol is faster and the ob-
tained crude mixture is cleaner than with previous report-
ed conditions, leading to easier purification for radiotrac-
ers. This new protocol has been successfully applied to a
representative panel of molecules with good to excellent
RCC values being obtained. Medium RCC values were ob-
tained using substrates with electron-withdrawing groups,
but with no or minor production of hot and cold by-prod-
ucts, leading to a simple purification. From our point of
view, this new approach could be applied to other directing
N-Tosylbenzamides 1c,f; General Procedure (G2)
To a round-bottom flask were introduced the carboxylic acid (1
equiv) in dry THF (8 mL/mmol), a catalytic amount of DMF and oxalyl
chloride (2 equiv) under N2. The resulting mixture was stirred over-
night at room temperature. The reaction mixture was concentrated
under reduced pressure, placed under nitrogen and solubilized in
dried toluene (0.8 mL/mmol). This solution was added via a syringe
over 15 min to a mixture of p-toluenesulfonamide (1 equiv), Et3N (2.5
equiv) and DMAP (0.5 mol%) in EtOAc (2 mL/mmol) under nitrogen.
The resulting mixture was stirred for 3 h at 55 °C, cooled to room
temperature and quenched with 0.5 M aqueous HCl solution (3
mL/mmol). The resulting mixture was extracted with EtOAc (3 times).
The combined organic layers were dried over anhydrous MgSO4, fil-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
E. Dubost et al.
Special Topic
Synthesis
tered and concentrated under reduced pressure. The crude residue
was purified by silica gel chromatography using AcOH/EtOAc/cyclo-
hexane (5:15:85) as eluent.
1H NMR (400 MHz, CDCl3):  = 9.42 (br s, 1 H), 8.15 (t, J = 1.8 Hz, 1 H),
8.04 (d, J = 8.3 Hz, 2 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H),
7.35 (d, J = 8.1 Hz, 2 H), 7.15 (t, J = 7.9 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.0, 145.5, 142.2, 136.9, 135.2,
133.0, 130.5, 129.7 (2 C), 128.7 (2 C), 126.9, 94.3, 21.8.
2-Chloro-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1a)16
Starting from 2-chlorobenzoyl chloride (4.2 mL, 33.0 mmol), using
the general procedure (G1), work-up and column chromatography af-
forded 1a.
3-(Trifluoromethyl)-N-(4-methylbenzenesulfonyl)benzenecar-
boxamide (1g)16
Starting from 3-(trifluoromethyl)benzoyl chloride (1.0 mL, 7.3
mmol), using the general procedure (G1), work-up and column chro-
matography afforded 1g.
Yield: 9.4 g (93%); white solid; mp 115–116 °C.
1H NMR (400 MHz, CDCl3):  = 8.89 (br s, 1 H), 8.04 (d, J = 8.3 Hz, 2 H),
7.72 (dd, J = 1.6, 7.8 Hz, 1 H), 7.46–7.32 (m, 5 H), 2.45 (s, 3 H).
Yield: 0.7 g (37%); white solid; mp 160–162 °C.
13C NMR (100 MHz, CDCl3):  = 163.1, 145.4, 135.2, 133.2, 131.5,
131.2, 130.9, 130.6, 129.6 (2 C), 128.7 (2 C), 127.5, 21.8.
1H NMR (400 MHz, CDCl3):  = 9.18 (br s, 1 H), 8.08 (s, 1 H), 8.05 (d, J =
8.6 Hz, 2 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.60 (t, J =
7.8 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2 H), 2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.9, 145.6, 135.0, 132.1, 131.5 (q, J =
31 Hz), 130.9, 129.9 (q, J = 4 Hz), 129.7 (2 C), 129.6, 128.8 (2 C), 125.0
(q, J = 4 Hz), 121.1 (q, J = 263 Hz), 21.8.
2-Fluoro-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1b)17
Starting from 2-fluorobenzoyl chloride (4.0 mL, 34.0 mmol), using the
general procedure (G1), work-up and column chromatography afford-
ed 1b.
3-Methyl-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1h)16
Yield: 7.1 g (83%); white solid; mp 137–138 °C.
Starting from 3-methylbenzoyl chloride (1.7 mL, 12.9 mmol), using
the general procedure (G1), work-up and column chromatography af-
forded 1h.
1H NMR (400 MHz, CDCl3):  = 8.99 (br s, 1 H), 8.05 (d, J = 8.4 Hz, 2 H),
8.00 (td, J = 1.8, 8.0 Hz, 1 H), 7.59–7.53 (m, 1 H), 7.36 (d, J = 8.2 Hz, 2
H), 7.26 (td, J = 0.9, 7.6 Hz, 1 H), 7.19–7.14 (m, 1 H), 2.44 (s, 3 H).
Yield: 3.0 g (90%), white solid; mp 132–134 °C.
1H NMR (400 MHz, CDCl3):  = 8.96 (br s, 1 H), 8.05 (d, J = 8.4 Hz, 2 H),
7.60–7.56 (m, 2 H), 7.38–7.30 (m, 4 H), 2.44 (s, 3 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 160.8 (d, J = 249 Hz), 160.2 (d, J = 3
Hz), 145.3, 135.6 (d, J = 10 Hz), 135.4, 132.4, 129.6 (2 C), 128.8 (2 C),
125.4 (d, J = 3 Hz), 118.5 (d, J = 11 Hz), 116.4 (d, J = 24 Hz), 21.8.
13C NMR (100 MHz, CDCl3):  = 164.2, 145.2, 139.0, 135.5, 134.3,
131.2, 129.6 (2 C), 128.9, 128.7 (2 C), 128.3, 124.7, 21.7, 21.3.
2-Methyl-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1c)16
Starting from 2-methylbenzoic acid (1.0 g, 7.3 mmol), using the gen-
eral procedure (G2), work-up and column chromatography afforded
4-Bromo-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1i)16
1c.
Starting from 4-bromobenzoyl chloride (1.8 g, 8.3 mmol), using the
general procedure (G1), work-up and column chromatography afford-
ed 1i.
Yield: 1.6 g (90%); white solid; mp 114–116 °C.
1H NMR (400 MHz, CDCl3):  = 8.72 (br s, 1 H), 8.00 (d, J = 8.4 Hz, 2 H),
7.49–7.30 (m, 4 H), 7.18 (t, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 2.34 (s, 3 H).
Yield: 1.5 g (73%), white solid; mp 199–201 °C.
13C NMR (100 MHz, CDCl3):  = 166.2, 145.2, 138.0, 135.5, 132.1,
131.8, 131.7, 129.6 (2 C), 128.5 (2 C), 127.3, 126.0, 21.7, 20.1.
1H NMR (400 MHz, CDCl3):  = 9.06 (br s, 1 H), 8.04 (d, J = 4.7 Hz, 2 H),
7.67 (d, J = 6.6 Hz, 2 H), 7.57 (d, J = 6.6 Hz, 2 H), 7.37 (d, J = 4.4 Hz, 2 H),
2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.4, 163.3, 145.5, 135.2, 132.3 (2 C),
130.0, 129.7 (2 C), 129.3 (2 C), 128.7 (2 C), 21.8.
2-Methoxy-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(1e)16
Starting from 2-methoxybenzoyl chloride (4.0 mL, 23 mmol), using
the general procedure (G1), work-up and column chromatography af-
forded 1e.
2,4-Dichloro-N-(benzenesulfonyl)benzenecarboxamide (1j)12
In a round-bottom flask under N2 were introduced respectively 2,4-
dichlorobenzoic acid (1.0 g, 5.3 mmol), anhydrous THF (100 mL), DMF
(4 drops) and oxalyl chloride (0.92 mL, 11.0 mmol). The reaction mix-
ture was stirred for 2 h at room temperature and then concentrated
under reduced pressure, placed under nitrogen and diluted with dried
toluene (7 mL). This solution was added via a syringe over 15 min to a
mixture of benzenesulfonamide (0.99 g, 6.3 mmol), EtOAc (15 mL),
Et3N (1.5 mL, 13 mmol) and DMAP (6 mg, 0.05 mmol) placed under
nitrogen. The mixture was stirred for 3 h at 55 °C, cooled to room
temperature and quenched with 0.5 M aqueous HCl solution (60 mL).
The resulting mixture was extracted with EtOAc (3 × 100 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude residue was pu-
rified by silica gel chromatography using DCM as the eluent to afford
1j.
Yield: 6.6 g (92%); white solid; mp 128–130 °C.
1H NMR (400 MHz, CDCl3):  = 10.37 (br s, 1 H), 8.09–8.03 (m, 3 H),
7.52 (td, J = 1.8, 7.8 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.06 (t, J = 7.6 Hz,
1 H), 7.00 (d, J = 8.5 Hz, 1 H), 4.05 (s, 3 H), 2.43 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 157.8, 144.8, 136.0, 135.1,
132.8, 129.5 (2 C), 128.7 (2 C), 121.8, 118.8, 111.7, 56.5, 21.7.
3-Iodo-N-(4-methylbenzenesulfonyl)benzenecarboxamide (1f)12
Starting from 3-iodobenzoic acid (1.0 g, 3.3 mmol), using the general
procedure (G2), work-up and column chromatography afforded 1f.
Yield: 1.0 g (78%); white solid; mp 146–148 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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E. Dubost et al.
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Synthesis
Yield: 0.90 g (52%); white solid; mp 125–127 °C.
2-Fluoro-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarboxam-
ide (2b)17
1H NMR (400 MHz, CDCl3):  = 8.94 (br s, 1 H), 8.16–8.13 (m, 2 H),
7.68 (d, J = 8.4 Hz, 2 H), 7.58 (t, J = 8.0 Hz, 2 H), 7.42 (d, J = 2.0 Hz, 1 H),
7.33 (dd, J = 2.0 Hz, 8.4 Hz, 1 H).
Starting from 1b (180 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using Et2O/cyclohexane (4:6) as eluent to afford 2b.
13C NMR (100 MHz, CDCl3):  = 162.2, 139.1, 138.1, 134.4, 132.4,
Yield: 170 mg (68%); white solid; mp 158–160 °C.
131.8, 130.5, 129.7, 129.1, 128.7 (2 C), 128.1 (2 C).
1H NMR (400 MHz, CDCl3):  = 8.50 (br s, 1 H), 8.01 (d, J = 8.3 Hz, 2 H),
7.60 (dd, J = 6.8, 1.9 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 2 H), 7.15–7.05 (m, 2
H), 2.47 (s, 3 H).
2,4-Dichloro-N-[(5-bromo-2-thienyl)sulfonyl]benzenecarboxam-
ide (1k)12
13C NMR (100 MHz, CDCl3):  = 161.9, 158.7 (d, J = 255 Hz), 145.6,
135.2 (d, J = 4 Hz), 134.9, 133.2 (d, J = 9 Hz), 129.6 (2 C), 128.8 (2 C),
128.1 (d, J = 20 Hz), 115.9 (d, J = 21 Hz), 92.4 (d, J = 2 Hz), 21.9.
In a round-bottom flask under N2 were introduced respectively 2,4-
dichlorobenzoic acid (270 mg, 1.4 mmol), anhydrous THF (30 mL),
DMF (4 drops) and oxalyl chloride (470 L, 5.6 mmol). The reaction
mixture was stirred overnight at room temperature and then concen-
trated under reduced pressure. In a round-bottom flask under N2
were introduced respectively 5-bromothiophene-2-sulfonamide (300
mg, 1.2 mmol), EtOAc (10 mL), Et3N (300 L, 3.2 mmol) and DMAP (2
mg, 0.02 mmol). A solution of 2,4-dichlorobenzoyl chloride, previous-
ly prepared in dried toluene (10 mL), was added via a syringe over 15
min. The mixture was stirred for 5 h at 55 °C under N2, cooled to room
temperature and quenched with 0.5 M aqueous HCl solution (40 mL).
The resulting mixture was extracted with EtOAc (3 × 600 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude residue was pu-
rified by silica gel chromatography using DCM as eluent to afford 1k.
2-Methyl-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarbox-
amide (2c)17
Starting from 1c (173 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using Et2O/cyclohexane (4:6) as eluent to afford 2c.
Yield: 190 mg (76%); white solid; mp 176–178 °C.
1H NMR (400 MHz, CDCl3):  = 8.03 (d, J = 8.2 Hz, 2 H), 7.56 (d, J = 7.9
Hz, 1 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 7.6 Hz, 1 H), 6.97 (t, J = 7.8
Hz, 1 H), 2.46 (s, 3 H), 2.27 (s, 3 H). The NH signal is not observed.
13C NMR (100 MHz, CDCl3):  = 166.7, 145.4, 139.9, 137.0, 136.5,
Yield: 300 mg (59%); yellow solid; mp 114–116 °C.
134.9, 131.4, 130.1, 129.5 (2 C), 128.9 (2 C), 91.1, 21.8, 19.6.
1H NMR (400 MHz, CDCl3):  = 9.07 (br s, 1 H), 7.74 (d, J = 6.0 Hz, 1 H),
7.73 (d, J = 1.6 Hz, 1 H), 7.45 (d, J = 1.9 Hz, 1 H), 7.36 (dd, J = 8.4, 2.0 Hz,
1 H), 7.13 (d, J = 4.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 162.2, 139.5, 138.6, 136.0, 132.5,
131.9, 130.7, 130.5, 129.3, 128.2, 123.3.
2-Iodo-N-(4-methylbenzenesulfonyl)benzenecarboxamide (2d)12
Starting from 1d (500 mg, 1.88 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using EtOAc/Cyclohexane (2:8) as eluent to afford 2d.
Yield: 610 mg (97%); yellow solid; mp 144–145 °C.
2-Iodo-N-tosylbenzamides 2a–k: ‘Cold References’; General Proce-
dure (G3)
1H NMR (400 MHz, CDCl3):  = 8.86 (br s, 1 H), 7.99 (d, J = 8.4 Hz, 2 H),
7.78 (d, J = 8.0 Hz, 1 H), 7.42–7.28 (m, 4 H), 7.08 (td, J = 7.6, 1.9 Hz, 1
H), 2.44 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.9, 145.4, 140.3, 138.5, 135.0,
132.5, 129.6, 128.9, 128.8, 128.3, 91.7, 21.8.
A round-bottom flask was filled with N-tosylbenzamide 1 (1 equiv),
MeOH (13 mL/mmol) and Pd(OAc)2 (1.1 equiv). The reaction mixture
was stirred for 24 h at room temperature. Acetic acid (1 equiv), NIS (1
equiv) and MeOH (3 mL/mmol) were added and the reaction mixture
was stirred for 30 min at room temperature. The resulting mixture
was diluted with water, quenched with saturated aqueous Na2S2O3
solution and extracted with ethyl acetate. The combined organic lay-
ers were dried over anhydrous MgSO4, filtered and concentrated un-
der reduced pressure.
2-Methoxy-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarbox-
amide (2e)12
Starting from 1e (173 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by reverse-phase gel
chromatography using H2O/CH3CN (80:20 to 50:50) as eluent to af-
ford 2e.
2-Chloro-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarboxam-
ide (2a)17
Yield: 190 mg (76%); white solid; mp 86–88 °C.
Starting from 1a (190 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using Et2O/cyclohexane (4:6) as eluent to afford 2a.
1H NMR (400 MHz, CDCl3):  = 8.56 (br s, 1 H), 7.98 (d, J = 8.3 Hz, 2 H),
7.33 (dd, J = 8.3, 8.2 Hz, 3 H), 7.01 (t, J = 8.2 Hz, 1 H), 6.84 (d, J = 8.2 Hz,
1 H), 3.73 (s, 3 H), 2.44 (s, 3 H).
Yield: 130 mg, (50%); white solid; mp 85–86 °C.
13C NMR (100 MHz, CDCl3):  = 164.6, 157.0, 145.2, 135.3, 132.7,
131.6, 129.5 (2 C), 128.9, 128.8 (2 C), 111.0, 93.0, 56.2, 21.9.
1H NMR (400 MHz, CDCl3):  = 8.62 (br s, 1 H), 8.02 (d, J = 7.7 Hz, 2 H),
7.66 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 1 H),
7.02 (t, J = 8.0 Hz, 1 H), 2.47 (s, 3 H).
3,6-Diiodo-N-(4-methylbenzenesulfonyl)benzenecarboxamide
(2f)12
13C NMR (100 MHz, CDCl3):  = 163.7, 145.6, 138.9, 137.7, 134.7,
Starting from 1f (240 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using EtOAc/cyclohexane (2:8) as eluent to afford 2f.
132.3, 131.2, 129.6 (2 C), 129.4, 128.9 (2 C), 92.0, 21.8.
Yield: 120 mg (38%); white solid; mp 202–204 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

G
E. Dubost et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.59 (br s, 1 H), 8.02 (d, J = 8.4 Hz, 2 H),
7.65 (d, J = 2.1 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 1 H), 7.42 (dd, J = 8.3, 2.1 Hz,
1 H), 7.38 (d, J = 8.1 Hz, 2 H), 2.46 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.1, 145.6, 141.7, 141.4, 140.4,
137.4, 134.9, 129.7 (2 C), 128.9 (2 C), 93.5, 90.8, 21.8.
2,4-Dichloro-6-iodo-N-[(5-bromo-2-thienyl)sulfonyl]benzenecar-
boxamide (2k)12
To a round-bottom flask were introduced respectively 1k (100 mg,
0.24 mmol), MeOH (5 mL) and Pd(OAc)2 (60 mg, 0.26 mmol). The re-
action mixture was stirred for 24 h at room temperature and then
acetic acid (14 L, 0.24 mmol), NIS (54 mg, 0.24 mmol) and MeOH (1
mL) were added. The reaction mixture was stirred for 30 min at room
temperature and the resulting mixture was diluted with H2O (2 mL),
quenched with saturated aqueous Na2S2O3 solution (4 mL) and ex-
tracted with EtOAc (3 × 6 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated under re-
duced pressure. The crude residue was purified by reverse-phase gel
chromatography using HCOOH/H2O/CH3CN as eluent (0.1:95:5 to
0.1:5:95) to afford 2k.
3-(Trifluoromethyl)-6-iodo-N-(4-methylbenzenesulfonyl)benzen-
ecarboxamide (2g)16
Starting from 1g (206 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using EtOAc/cyclohexane (2:8) as eluent to afford 2g.
Yield: 90 mg (32%), white solid; mp 210–212 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.81 (br s, 1 H), 8.10 (d, J = 8.2 Hz,
1 H), 7.88 (d, J = 8.1 Hz, 2 H), 7.69 (s, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.43
(d, J = 8.1 Hz, 2 H), 2.40 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 166.8, 144.1, 141.5, 140.9, 137.1,
129.6 (2 C), 128.7 (q, J = 33 Hz), 127.9 (3 C), 124.9, 123.8 (q, J = 271
Hz), 99.0, 21.2.
Yield: 62 mg (47%); brown powder; mp 70–72 °C.
1H NMR (400 MHz, CDCl3):  = 8.88 (br s, 1 H), 7.74 (d, J = 4.0 Hz, 1 H),
7.68 (d, J = 1.8 Hz, 1 H), 7.36 (d, J = 1.8 Hz, 1 H), 7.15 (d, J = 4.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 163.3, 137.9, 137.4, 137.4, 137.1,
136.3, 131.7, 130.7, 129.5, 123.3, 92.0.
3-Methyl-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarbox-
amide (2h)16
Funding Information
Starting from 1h (173 mg, 0.60 mmol), using the general procedure
(G3), the obtained crude residue was purified by silica gel chromatog-
raphy using TFA/toluene (2:98) as eluent to afford 2h.
The authors are grateful for financial support provided by the Region-
al Council of Normandy, FEDER, Crunch Network, la Ligue Contre le
Cancer, The ARC foundation, the University of Caen, Tremplin Carnot
I2C and the French Ministry of Research.()
Yield: 40 mg (16%); white solid; mp 77–78 °C.
1H NMR (400 MHz, CDCl3):  = 8.39 (br s, 1 H), 8.05 (d, J = 8.3 Hz, 2 H),
7.69 (d, J = 8.1 Hz, 1 H), 7.38 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 1.6 Hz, 1 H),
6.96 (dd, J = 8.1, 1.7 Hz, 1 H), 2.46 (s, 3 H), 2.30 (s, 3 H).
Supporting Information
13C NMR (100 MHz, CDCl3):  = 165.5, 145.4, 140.1, 138.9, 138.3,
135.1, 133.6, 129.6 (2 C), 128.9 (2 C), 87.3, 21.8, 20.8.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611884.
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4-Bromo-6-iodo-N-(4-methylbenzenesulfonyl)benzenecarboxam-
ide (2i)12
References
Starting from 1i (212 mg, 0.60 mmol), using the general procedure
(G3), the crude residue was purified by reverse-phase gel chromatog-
raphy using H2O/CH3CN (80:20 to 50:50) as eluent to afford 2i.
(1) Adam, M. J.; Wilbur, D. S. Chem. Soc. Rev. 2005, 34, 153.
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Yield: 110 mg (38%); white solid; mp 82–84 °C.
1H NMR (400 MHz, CDCl3):  = 8.92 (br s, 1 H), 8.00 (d, J = 8.4 Hz, 2 H),
7.97 (d, J = 1.8 Hz, 1 H), 7.49 (dd, J = 8.2, 1.8 Hz, 1 H), 7.36 (d, J = 8.1 Hz,
2 H), 7.26 (d, J = 8.2 Hz, 1 H), 2.46 (s, 3 H).
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(2j)12
To a round-bottom flask were introduced respectively 1j (100 mg, 0.3
mmol), MeOH (4 mL), TFA (230 L, 3.0 mmol), NIS (81 mg, 0.4 mmol)
and Pd(OAc)2 (7 mg, 0.03 mmol). The reaction mixture was stirred for
48 h at room temperature and then diluted with EtOAc (6 mL), filtered
through a pad of Celite and concentrated under reduced pressure. The
crude residue was purified by silica gel chromatography using EtO-
Ac/cyclohexane (10:90) as eluent to afford 2j.
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Yield: 50 mg (37%); brown solid; mp 178–180 °C.
1H NMR (400 MHz, CDCl3):  = 8.16 (d, J = 7.8 Hz, 3 H), 7.74–7.65 (m, 2
H), 7.59 (dd, J = 8.5, 7.1 Hz, 2 H), 7.38 (d, J = 1.8 Hz, 1 H).
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134.5, 131.6, 129.5, 129.0 (2 C), 128.8 (2 C), 92.0.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
E. Dubost et al.
Special Topic
Synthesis
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H