Oxidative fluorination of N-arylsulfonamides

Article abstract of DOI:10.1016/j.jfluchem.2015.07.030

We report a late stage oxidative nucleophilic fluorination of N-arylsulfonamides, a class of compounds so far not considered as precursors to 4-fluorophenyl sulfonamides. By installing a para-positioned tert-butyl substituent on the aniline, oxidative fluorination takes place regioselectively in the presence of HF·pyridine and PIDA. This methodology has been shown to give good yields for a variety of ortho- and meta-functionalised N-arylsulfonamides and has been adapted for radiofluorination to give 4-[¹⁸F]fluorophenyl sulfonamides under carrier added conditions.

Full text of DOI:10.1016/j.jfluchem.2015.07.030

Journal of Fluorine Chemistry 180 (2015) 33–39
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
Oxidative fluorination of N-arylsulfonamides
Faye Buckingham a,1, Samuel Calderwood a,1, Begon˜a Checa a, Thomas Keller a,
Matthew Tredwell a, Thomas Lee Collier b, Ian M. Newington c, Rajiv Bhalla c,
c
a,
*
´
Matthias Glaser , Veronique Gouverneur
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
b Advion BioSystems, Inc., 10 Brown Road, Ithaca, NY 14850, USA
c GE Healthcare, The Grove Centre, White Lion Road, Amersham HP7 9LL, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
We report a late stage oxidative nucleophilic fluorination of N-arylsulfonamides, a class of compounds
so far not considered as precursors to 4-fluorophenyl sulfonamides. By installing a para-positioned tert-
butyl substituent on the aniline, oxidative fluorination takes place regioselectively in the presence of
HFꢀpyridine and PIDA. This methodology has been shown to give good yields for a variety of ortho-
and meta-functionalised N-arylsulfonamides and has been adapted for radiofluorination to give
4-[18F]fluorophenyl sulfonamides under carrier added conditions.
Received 19 June 2015
Received in revised form 29 July 2015
Accepted 30 July 2015
Available online 6 August 2015
Keywords:
ß 2015 Elsevier B.V. All rights reserved.
Umpolung
Fluoride
Hypervalent iodine
18F-radiolabelling
N-Arylsulfonamide
1. Introduction
which become responsive to nucleophilic attack with [18F]fluoride
[10]. Herein, we report that this umpolung approach can be
Amongst the many functional groups frequently found in
pharmaceutical drugs, sulfonamides are well represented in a
number of antibacterial, anti-migraine, anti-inflammatory and
anti-diabetic agents as well as diuretics [1]. The benefits of fluorine
substitution in drug discovery [2] have encouraged the develop-
ment of methods to access fluorinated sulfonamide analogues. In
this context, methods to access N-arylsulfonamides with fluorine
substitution on the aryl sub-motif are in demand, especially
approaches that avoid sulfonyl chloride, which is known to be
genotoxic [3]. We opted for a synthesis based on late stage
fluorination with a fluoride source since this chemistry is attractive
for 18F-labelling and its application for Positron Emission
Tomography (PET) [4]. To date, 11C-labelled sulfonanilides have
been developed as potential PET agents for imaging of aromatase in
breast cancer [5]. Recently, our laboratory reported a method for
the oxidative 18F-fluorination of phenols mediated by hypervalent
iodine [6]. This metal free reaction, inspired by the seminal work of
Feiring [7], Yoneda [8] and Langlois et al. [9], employs PhI(OAc)2
(PIDA) to impose a reactivity switch on electron rich phenols,
successfully applied to N-arylsulfonamide precursors allowing
direct access to various fluorinated analogues. This advance is
significant since no example of direct fluorination of arylsulfona-
mides leading to 4-fluorophenyl sulfonamides is known; in fact, a
recent study conducted by Meng, Li and co-workers showed that
N-tosyl and N-mesylanilines are not suitable substrates for
oxidative fluorination with hypervalent iodine reagents [11].
2. Results and discussion
This work began with a study probing the effect on reactivity of
N-sulfonylation versus N-acylation with four representative
anilines (Table 1). Based on our previous success with the
oxidative fluorination of phenols [6], we selected the sulfonanilide
1a and the N-benzanilide 2a both substituted with a para-located
tert-butyl group on the aniline ring. The corresponding N-phenyl-4-
methylbenzenesulfonamide 3a and N-benzanilide 4a that are not
substituted at the para position were also subjected to oxidative
fluorination for comparison. The reaction was conducted using 1 eq.
of PIDA and 4 eq. of HFꢀpyridine in DCM for 15 min at room
temperature, followed by addition of trifluoroacetic acid (TFA).
Collectively, the data assembled in Table 1 demonstrate that the
presence of the tert-butyl group is critical for the oxidative
*
Corresponding author.
E-mail address: veronique.gouverneur@chem.ox.ac.uk (V. Gouverneur).
These authors contributed equally to this work.
1
http://dx.doi.org/10.1016/j.jfluchem.2015.07.030
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

34
F. Buckingham et al. / Journal of Fluorine Chemistry 180 (2015) 33–39
oxidative fluorination of 5a (19F NMR,
d
= ꢁ96.6 ppm). At first, we
Table 1
Fluorination of N-arylsulfonamides versus N-benzanilides.
employed 4 equivalents of HFꢀpyridine since the use of an excess
of the fluoride source was advantageous for the oxidative
fluorination of 4-tert-butylphenol (Table 2, entries 1–7) [6]. Yields
were comparable replacing PIDA with PhI(OPiv)2 but were lower
with PIFA (Table 2, entries 1–4). Dichloromethane and dichloro-
ethane emerged as the optimum solvents; tetrahydrofuran or
diethylether led to recovered starting material or very low
conversion of 1a into 6a (Table 2, entries 5–7). Only HF based
reagents were suitable (entry 10). In the absence of trifluoroacetic
acid (TFA), 3HF NEt3 did not allow for aromatisation of 6a (Table 2,
entries 8 and 9). Better results were obtained using only one
equivalent of HFꢀpyridine in the presence of TFA, which is in
contrast to the oxidative fluorination of 4-tert-butylphenol
(Table 2, 11–13). As expected, an excess of PIDA led mainly to
the difluorinated dienimine 7a resulting from further oxidative
fluorination of 5a (Table 2, entry 14) [12]. The addition of TFA
facilitates the conversion of the fluorinated dienimine 6a into 5a
(Table 2, entries 11–12). For this model substrate, the oxidative
fluorination is therefore best performed with 1 eq. of HFꢀpyridine
and 1 eq. of PIDA in DCM at room temperature followed by
treatment with TFA. Under these conditions, 5a was formed in 94%
yield (19F NMR) and isolated in 61% yield.
.
Entry
R
R0
Substrate
Product
Yield (%)a,b
1
2
3
4
Tos
t-Bu
t-Bu
H
1a
2a
3a
4a
5a
6a
5a
6a
46 (33)
66(69)
9 (0)
COPh
Tos
COPh
H
46
a
Determined by 19F NMR integration with 1-fluoro-3-nitrobenzene as internal
standard.
b
Values in parenthesis refer to yield of isolated product.
fluorination of sulfonamides to proceed. Pleasingly, the fluorination
of 1a was successful affording isolated 5a in 33% yield under
unoptimised reaction conditions (entry 1). When using N-phenyl-4-
methylbenzenesulfonamide 3a, the fluorinated sulfonanilide 5a was
detectable (<10%) prior to purification but could not be isolated (entry
3). In contrast, para-substitution with the tert-butyl group is not
essential for the fluorination of N-acylated anilines [11], although
beneficial based on comparative 19F NMR yields (entries 2 and 4).
Having established that the oxidative fluorination of the tert-
butylated sulfonanilide 1a is possible, further optimisation was
carried out (Table 2). Analysis of the crude reaction
mixture indicated that three fluorinated products were formed
upon fluorination of 1a: the dearomatised tert-butylated fluoro-
Various N-arylsulfonamides participated in the oxidative
fluorination effectively. In the first instance, we studied the
reactivity of substrates N-substituted with alkyl- and arylsulfonyl
groups (Scheme 1). All reactions were first conducted using our
intermediate 6a (19F NMR,
nilide 5a (19F NMR,
d
= ꢁ160.4 ppm), the desired sulfona-
d
= ꢁ116.6 ppm) and 7a resulting from further
Table 2
Oxidative fluorination of 1a: optimisation.
.
Entry
1
Fꢁ (eq.)
Ox. (eq.)
PIDA
Solvent
DCM
TFAa
Yield (%)b
(min)
6a, 5a, 7a
HF pyr (4.0)
–
0, 44, 20
(1.0)
2
HFꢀpyr (4.0)
HFꢀpyr (4.0)
HFꢀpyr (4.0)
HFꢀpyr (4.0)
HFꢀpyr (4.0)
HFꢀpyr (4.0)
3HF NEt3 (4.0)
3HF NEt3 (4.0)
TBAFꢀ3H2O (1.0)
HFꢀpyr (1.0)
HFꢀpyr (1.0)
HFꢀpyr (1.0)
HFꢀpyr (1.0)
PIDA (1.0)
PhI(OPiv)2 (1.0)
PIFA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PhI(OPiv)2 (1.0)
PIDA (2.0)
DCM
DCM
DCM
DCE
5
5
–
–
–
–
–
5
5
–
5
5
5
0, 46, 6
0, 52, 0
0, 34, 6
0, 43, 13
0, 0, 0
3
4
5
6
THF
7
Et2O
DCM
DCM
DCM
DCM
DCM
DCM
DCM
8, 0, 0
8
85, 0, 0
0, 42, 9
0, 12, 0
68, 19, 6
0, 94, 2
0, 92, 3
0, 0, 43
9
10
11
12
13
14
a
TFA added after 15 min.
Yields determined by 19F NMR by integration relative to 1-fluoro-3-
b
nitrobenzene as the internal standard.
Scheme 1. Influence of the sulfonyl substituent on reactivity.

F. Buckingham et al. / Journal of Fluorine Chemistry 180 (2015) 33–39
35
standard reaction conditions and completed in less than
30 min. For some substrates, better yields were obtained with
4 eq. of HFꢀpyridine. The yields of isolated para-fluoroanilines 5a–g
were comparable ranging from 54% to 65%. This observation
suggests that the electronic profile of the N-sulfonyl substituent
remotely positioned from the aryl motif subjected to oxidative
fluorination, has little influence on the efficacy of the reaction.
However, the yield dropped for the sulfonamide 5h suggesting that
ortho-substitution of arylsulfonyl with the electron withdrawing
NO2 group impeded activation with PIDA. For this substrate, the
yield of fluorination did not exceed 40% despite using 4 eq. of
HFꢀpyridine. Advantageously, the cleavage of 2- or 4-nitrosulfo-
nylbenzene (nosyl) and mesylsulfonyl (mesyl) protecting groups is
known to occur under mild conditions when compared to the tosyl
protecting group [13].
Next, we examined how the substitution pattern of the N-aryl
sub-motif undergoing sequential oxidation–fluorination impacts
on reactivity (Scheme 2). For this study, we selected N-tosylated
aniline precursors. All reactions were performed using stoichio-
metric amount or an excess of HFꢀpyridine. The best yields were
obtained with an excess of fluoride, which is contrasting with the
optimisation performed on the model aniline 1a. The reaction was
tolerant to a selection of ortho or meta positioned functional groups
including alkyl, halogen and esters. Electron withdrawing groups
located ortho to the N-tosyl substituent have a detrimental effect
on the reaction due to lack of reactivity. This is illustrated with the
low isolated yield of the ester-substituted aniline 5n. Distancing
the ester functionality from the aniline ring was beneficial as
demonstrated with the successful synthesis of 5o. The reaction
led to the formation of the methoxy-substituted aniline 5p, but
with low conversion. The corresponding substrate, 2-methoxy-4-
tert-butyl-N-tosylaniline, is easier to oxidise than 4-tert-butyl-N-
tosylaniline 1a; however, it is possible that
a competitive
fluorination pathway occurs; fluoride attack on the oxidised
intermediate could indeed take place at the methoxy group with
concomitant release of methyl fluoride. The fluorination of 2-tert-
butyl-N-tosylaniline is chemoselective occurring exclusively at the
para position. For this substrate, the presence of the para located
tert-butyl group is not necessary to allow for oxidative fluorination.
The reaction gave aniline 5q (19F NMR,
was isolated in 39% yield. 2-Fluoro-N-tosylaniline (19F NMR,
d
= ꢁ115.7 ppm) that
19F NMR,
d
d
= ꢁ129.7 ppm) and 2.4-difluoro-N-tosylaniline
(
= ꢁ112.0 ppm and ꢁ123.4 ppm), both easily identifiable by 19F
NMR, could not be detected in the crude reaction mixture. Typically,
Scheme 2. Synthesis of N-tosylsulfonamides 5i–q.a

36
F. Buckingham et al. / Journal of Fluorine Chemistry 180 (2015) 33–39
Scheme 3. Mechanism of the fluorination of N-arylsulfonamides.
t-butyl group on the aniline. Using PIDA and an excess of
HFꢀpyridine, regioselective fluorination occurred by ipso substitu-
tion of the tert-butyl group. The reaction also allows access to a
representative fluorinated benzosultam. This study unveils an
important difference of reactivity for sulfonamides versus anilides
towards oxidative nucleophilic fluorination. Furthermore, we have
demonstrated that this methodology can be applied as a novel
route to the radiofluorination of N-arylsulfonamides, a useful
transformation in the production of PET tracers.
Scheme 4. Oxidative fluorination of benzosultams 8 and 9.
4. Experimental
4.1. General
All NMR spectra were recorded on Bruker AVIII400 and AVII500
spectrometers. Proton and carbon-13 NMR spectra are reported as
chemical shifts (d) in parts per million (ppm) relative to the solvent
peak using the Bruker internal referencing procedure (edlock).
Fluorine-19 NMR spectra are referenced relative to CFCl3 in
CDCl3. Coupling constants (J) are reported in units of hertz (Hz) to
the nearest 0.1 Hz. The following abbreviations are used to
describe multiplicities – s (singlet), d (doublet), t (triplet), q
(quartet), quin (quintet), sept (septet), m (multiplet), brs (broad
singlet). High resolution mass spectra (HRMS, m/z) were recorded
Scheme 5. Oxidative fluorination with [18F]fluoride. n = number of experiments.
the outcome of these reactions correlates well with the ability of the
substrates to undergo oxidation [14].
on
a Bruker MicroTOF spectrometer using positive/negative
Mechanistically [15], this reaction transits via an aryl-stabilised
N-sulfonylnitrenium [16] amenable to nucleophilic fluorination.
Addition of TFA facilitates aromatisation of the resulting fluor-
odienimine with concomitant loss of the tert-butyl carbocation
(Scheme 3).
electrospray ionisation (ESI) or on a Micromass GCT spectrometer
using field ionisation (FI+). Infrared spectra were recorded either as
the neat compound or in a solution using a Bruker Tensor 27 FT-IR
spectrometer. Absorptions are reported in wavenumbers (cmꢁ1
)
and only peaks of interest are reported. Melting points of solids
were measured on a Gryphon apparatus and are uncorrected. All
reaction solvents were dried on a column of alumina prior to use.
Flash column chromatography was performed over Merck silica gel
Pleasingly, 3.4-dihydro-2.1-benzothiazine 2.2-dioxide 9 acti-
vated with the tert-butyl group at C-6 underwent fluorination with
PIDA and 4 eq. of HFꢀpyridine. This reaction gave 10 in 52% yield. A
control experiment performed with the unsubstituted benzosul-
tam 8 confirmed that the presence of the tert-butyl group on the
substrate is advantageous for reactivity. In its absence, conversion
remained low even after extended reaction time (Scheme 4).
As late-stage radiofluorination reactions are favoured for the
synthesis of PET tracers, extension of this methodology to employ
C60 (40–60
mm). Chemicals were purchased from Acros, Alfa
Aesar, Fisher Scientific, Fluorochem and Sigma–Aldrich and used as
received. Reactions were monitored by thin-layer chromatography
(TLC) carried out on Merck Kiesegel 60 F254 plates.
4.2. General procedure for oxidative fluorination reaction
[
18F]fluoride was highly desirable. In the first instance, conditions
from previous work from our research group on the oxidative
18F-fluorination of phenols [6] were adapted for this system, using
[
substrate 1a. However, under these conditions only low yields of
4-[18F]fluoro-N-tosylaniline ([18F]5a) were observed (RCY = 2 ꢂ 1%
(n = 4)) (Scheme 5). The addition of HFꢀpyridine (1.0 eq.) as the acid
was more successful, leading to the synthesis [18F]5a in good yields
(RCY = 52 ꢂ 6% (n = 4)). This carrier added approach is however
unfavourable in terms of specific activity and work is ongoing to find
suitable alternative conditions.
To a solution of N-arylsulfonamide (1.0 eq.) in DCM (0.5 M) in
a Falcon tube was added HFꢀpyridine (70%) (1.0/4.0 eq.) followed
by PIDA (1.0 eq.). The reaction was stirred at room temperature
for 15 min before the addition of TFA (1.0 mL). After stirring for a
further 5 min the reaction was quenched with saturated
aqueous sodium bicarbonate and extracted into DCM. The
combined organic phases were washed with brine, dried over
magnesium sulphate and the solvent removed under reduced
pressure. Purification was performed by flash chromatography
on silica gel.
18F]NEt4F as the [18F]fluoride source, and applied to the model
To obtain 19F NMR yields, the reaction was performed on a
0.50 mmol scale. The crude residue was fully dissolved in CDCl3
3. Conclusions
before the addition of 1-fluoro-3-nitrobenzene (53
mL, 0.50 mmol,
In summary, we have developed a direct method for the
fluorination of N-arylsulfonamides that are para substituted with a
1.0 eq.) as an internal standard. An aliquot of the resulting solution
was taken for NMR analysis.

F. Buckingham et al. / Journal of Fluorine Chemistry 180 (2015) 33–39
37
N-(4-Fluorophenyl)-4-methylbenzenesulfonamide
(5a). Purification by flash chromatography on silica gel (SiO2,
petroleum ether 30–40:EtOAc 9:1–4:1) afforded the title compound
as a white solid (162 mg, 0.61 mmol, 61% yield). Data consistent
with literature [17].
N-(4-Fluorophenyl)-2-nitrobenzenesulfonamide (5h). Puri-
fication by flash chromatography on silica gel (SiO2, petroleum
ether 30–40:EtOAc 17:3–7:3) afforded the title compound as a
yellow solid (118 mg, 0.40 mmol, 40% yield). Data consistent with
literature [21].
N-(4-Fluorophenyl)benzamide (6a). Purification by flash
chromatography on silica gel (SiO2, petroleum ether 30–40:EtOAc
19:1–9:1) afforded the title compound as a white solid (148 mg,
0.69 mmol, 69% yield). Data consistent with literature [18].
N-(4-Fluorophenyl)methanesulfonamide (5b). Purification
by flash chromatography on silica gel (SiO2, petroleum ether
30–40:EtOAc 4:1) afforded the title compound as an off-white
solid (102 mg, 0.54 mmol, 54% yield). Data consistent with
literature [19].
N-(4-Fluoro-2-methylphenyl)-4-methylbenzenesulfona-
mide (5i). Purification by flash chromatography on silica gel (SiO2,
petroleum ether 30–40:EtOAc 17:3) afforded the title compound
as an off-white solid (100 mg, 0.36 mmol, 60% yield). MP: 95–
96 8C; IR (
n
, cmꢁ1): 3270 (w, NH), 1497 (m, C55CAr), 1329 (m, S55O),
= 1.99
1161 (s, S55O), 1092 (w, C–F); 1H NMR (400 MHz, CDCl3):
d
(3H, s), 2.41 (3H, s), 6.65 (1H, brs), 6.81 (1H, d, J = 8.8 Hz), 6.82–6.85
(1H, m), 7.18–7.23 (1H, m), 7.24 (2H, d, J = 8.2 Hz), 7.60 (2H, d,
J = 8.2 Hz); 13C NMR (101 MHz, CDCl3):
d = 17.8, 21.6, 113.5 (d,
N-(4-Fluorophenyl)propane-2-sulfonamide (5c). Purification
by flash chromatography on silica gel (SiO2, petroleum ether 30–
40:EtOAc 17:3) afforded the title compound as a pale orange solid
J = 22.3 Hz), 117.3 (d, J = 22.3 Hz), 127.2, 127.7 (d, J = 9.5 Hz), 129.7,
130.2 (d, J = 3.2 Hz), 135.6 (d, J = 7.9 Hz), 136.5, 143.9, 161.0 (d,
J = 246.4 Hz); 19F NMR (377 MHz, CDCl3)
d
= ꢁ115.5; HRMS (ESI+,
(125 mg, 0.57 mmol, 57% yield). MP: 74–76 8C; IR (
(w, NH), 1506 (s, C55CAr), 1322 (m, S55O), 1140 (s, S55O), 1099 (w, C–
F); 1H NMR (400 MHz, CDCl3):
= 1.40 (6H, d, J = 6.8 Hz), 3.27
(1H, sept., J = 6.8 Hz), 6.60 (1H, brs), 7.00–7.08 (2H, m), 7.21–7.27
(2H, m); 13C NMR (101 MHz, CDCl3):
= 16.5, 52.5, 116.4 (d,
n
, cmꢁ1): 3257
m/z): [C14H14FNNaO2S]+ (M+Na)+ calcd. 302.0621, found 302.0620.
N-(2-Bromo-4-fluorophenyl)-4-methylbenzenesulfonamide
(5j). Purification by flash chromatography on silica gel (SiO2,
petroleum ether 30–40:EtOAc 19:1–9:1) afforded the title
compound as a pale orange solid (179 mg, 0.52 mmol, 52% yield).
d
d
J = 22.3 Hz), 123.1 (d, J = 9.5 Hz), 132.8 (d, J = 3.2 Hz), 160.3 (d,
MP: 92–93 8C; IR (
(m, S55O), 1161 (s, S55O), 1090 (m, C–F); 1H NMR (400 MHz, CDCl3):
= 2.39 (3 H, s), 6.80 (1H, brs), 7.03 (1H, ddd, J = 8.9 Hz, J = 7.9 Hz,
n
, cmꢁ1): 3260 (w, NH), 1486 (s, C55CAr), 1334
J = 244.8 Hz); 19F NMR (377 MHz, CDCl3)
d
= ꢁ117.1; HRMS (ESI+,
m/z): [C9H12FNNaO2S]+ (M+Na)+ calcd. 240.0465, found 240.0474.
4-Chloro-N-(4-fluorophenyl)benzenesulfonamide (5d). Puri-
fication by flash chromatography on silica gel (SiO2, petroleum
ether 30–40:EtOAc 9:1–7:3) afforded the title compound as an off-
d
J = 2.9 Hz), 7.16 (1H, dd, J = 7.7 Hz, J = 2.8 Hz), 7.22 (2H, d,
J = 8.3 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.68 (1H, dd, J = 9.0 Hz,
J = 5.4 Hz); 13C NMR (101 MHz, CDCl3):
d = 21.8, 115.9 (d,
white solid (166 mg, 0.58 mmol, 58% yield). MP: 106–108 8C; IR (
n
,
J = 22.3 Hz), 117.1 (d, J = 9.5 Hz), 119.8 (d, J = 25.4 Hz), 125.2 (d,
J = 8.7 Hz), 127.5, 129.9, 131.3 (d, J = 3.2 Hz), 135.8, 144.5, 160.0 (d,
cmꢁ1): 3261 (w, NH), 1507 (s, C55CAr), 1332 (m, S55O), 1163 (s,
S55O), 1094 (m, C–F), 755 (s, C–Cl); 1H NMR (400 MHz, DMSO-d6):
J = 249.5 Hz); 19F NMR (377 MHz, CDCl3)
d
= ꢁ114.2; HRMS (ESI+,
d
= 7.04–7.15 (4H, m), 7.61–7.66 (2H, m), 7.67–7.74 (2H, m), 10.31
(1H, brs); 13C NMR (126 MHz, DMSO-d6):
= 116.0 (d, J = 21.9 Hz),
123.2 (d, J = 8.6 Hz), 128.6, 129.4, 133.5 (d, J = 2.9 Hz), 137.8, 138.0,
m/z): [C13H1179BrFNNaO2S]+ (M+Na)+ calcd. 365.9570, found
365.9570.
d
N-(2-Chloro-4-fluorophenyl)-4-methylbenzenesulfonamide
(5k). Purification by flash chromatography on silica gel (SiO2,
hexane:EtOAc 9:1–4:1) afforded the title compound as a pale
orange solid (162 mg, 0.54 mmol, 54% yield). MP: 102–103 8C; IR
159.3 (d, J = 242.2 Hz); 19F NMR (471 MHz, DMSO-d6)
d
= ꢁ115.5;
HRMS (ESI+, m/z): [C12H9ClFNNaO2S]+ (M+Na)+ calcd. 307.9199,
found 307.9906.
N-(4-Fluorophenyl)-4-methoxybenzenesulfonamide
(5e).
(n
, cmꢁ1): 3250 (m, NH), 1490 (s, C55CAr), 1339 (m, S55O), 1165 (s,
Purification by flash chromatography on silica gel (SiO2, petroleum
ether 30–40:EtOAc 17:3–7:3) afforded the title compound as a
S55O), 1091 (m, C–F), 729 (s, C–Cl); 1H NMR (400 MHz, CDCl3):
= 2.38 (3H, s), 6.89 (1H, brs), 6.95–7.02 (1H, m), 7.22 (1H, d,
J = 8.1 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.66 (1H,
dd, J = 9.1 Hz, J = 5.4 Hz); 13C NMR (101 MHz, CDCl3):
= 21.7,
d
white solid (176 mg, 0.59 mmol, 59% yield). MP: 72–74 8C; IR (
cmꢁ1): 3246 (m, NH), 1449 (w, C55CAr), 1333 (m, S55O), 1149 (s,
S55O), 1090 (m, C–F); 1H NMR (400 MHz, CDCl3):
= 3.84 (3H, s),
n,
d
d
115.2 (d, J = 22.3 Hz), 116.7 (d, J = 26.2 Hz), 125.2 (d, J = 8.7 Hz),
127.0 (d, J = 10.3 Hz), 127.4, 129.7, 129.9 (d, J = 3.2 Hz), 135.8,
144.5, 159.7 (d, J = 249.5 Hz); 19F NMR (377 MHz, CDCl3):
6.58 (1H, brs), 6.90 (2H, d, J = 8.8 Hz), 6.92–6.97 (2H, m), 7.01–7.06
(2H, m), 7.66 (1H, d, J = 8.8 Hz); 13C NMR (101 MHz, CDCl3):
d
= 51.2, 109.9, 111.7 (d, J = 24.0 Hz), 120.1 (d, J = 9.6 Hz), 125.1,
d
= ꢁ114.2; HRMS (ESI+, m/z): [C13H11ClFNNaO2S]+ (M+Na)+ calcd.
125.7, 128.1 (d, J = 3.2 Hz), 156.2 (d, J = 244.5 Hz), 158.8; 19F NMR
322.0075, found 322.0075.
(471 MHz, CDCl3)
(M+Na)+ calcd. 304.0414, found 304.0403.
d
= ꢁ116.6; HRMS (ESI+, m/z): [C13H12FNNaO3S]+
N-(2.4-Difluorophenyl)-4-methylbenzenesulfonamide (5l).
Purification by flash chromatography on silica gel (SiO2, hex-
ane:EtOAc 9:1) afforded the title compound as an orange solid
N-(4-Fluorophenyl)benzenesulfonamide (5f). Purification by
flash chromatography on silica gel (SiO2, petroleum ether 30–
40:EtOAc 9:1) afforded the title compound as a white solid
(77 mg, 0.27 mmol, 45% yield). MP: 102–103 8C; IR (
(w, NH), 1506 (s, C55CAr), 1335 (m, S55O), 1160 (s, S55O), 1092 (m, C–
F); 1H NMR (400 MHz, CDCl3):
= 2.39 (3H, s), 6.71 (1H, ddd,
n
, cmꢁ1): 3250
(151 mg, 0.60 mmol, 60% yield). MP: 106–108 8C; IR (
3259 (w, NH), 1507 (s, C55CAr), 1328 (m, S55O), 1157 (s, S55O), 1091
(m, C–F); 1H NMR (400 MHz, CDCl3):
= 6.87–6.99 (2H, m), 7.03–
7.11 (2H, m), 7.19 (1H, brs), 7.40–7.51 (2H, m), 7.52–7.60 (1H, m),
7.75–7.79 (2H, m); 13C NMR (101 MHz, CDCl3):
= 116.1 (d,
n
, cmꢁ1):
d
J = 10.2 Hz, J = 8.3 Hz, J = 2.8 Hz), 6.81–6.88 (2H, m), 7.23 (2H, d,
J = 8.2 Hz), 7.56 (1H, td, J = 9.0 Hz, J = 5.8 Hz), 7.63 (2H, d,
d
J = 8.2 Hz); 13C NMR (101 MHz, CDCl3):
d = 21.7, 104.2 (dd,
d
J = 27.0 Hz, J = 23.8 Hz), 111.9 (dd, J = 22.3 Hz, J = 4.8 Hz), 120.8
(dd, J = 12.7 Hz, J = 4.0 Hz), 126.1 (dd, J = 9.5 Hz, J = 1.6 Hz), 127.3,
129.9, 135.8, 144.4, 155.0 (dd, J = 248.8 Hz, J = 11.9 Hz), 160.2 (dd,
J = 22.3 Hz), 124.7 (d, J = 9.5 Hz), 127.3, 129.1, 132.1 (d, J = 3.2 Hz),
133.2, 138.6, 160.7 (d, J = 246.4 Hz); 19F NMR (471 MHz, CDCl3)
d
= ꢁ116.1; HRMS (ESI+, m/z): [C12H10FNNaO2S]+ (M+Na)+ calcd.
J = 248.8 Hz, J = 11.1 Hz; 19F NMR (377 MHz, CDCl3):
d
= ꢁ123.4
274.0308, found 274.0302.
(1F, d, J = 5.7 Hz), ꢁ112.0 (1F, d, J = 5.7 Hz); HRMS (ESI+, m/z):
[C13H11F2NNaO2S]+ (M+Na)+ calcd. 306.0371, found 306.0368.
N-(3-Chloro-4-fluorophenyl)-4-methylbenzenesulfonamide
(5m). Purification by flash chromatography on silica gel (SiO2,
hexane:EtOAc 9:1–4:1) afforded the title compound as an orange
N-(4-Fluorophenyl)-4-nitrobenzenesulfonamide (5g). Purifi-
cation by flash chromatography on silica gel (SiO2, petroleum ether
30–40:EtOAc 17:3–7:3) afforded the title compound as a yellow
solid (193 mg, 0.65 mmol, 65% yield). Data consistent with
literature [20].
solid (91 mg, 0.30 mmol, 61% yield). MP: 110–112 8C; IR (n
, cmꢁ1):

38
F. Buckingham et al. / Journal of Fluorine Chemistry 180 (2015) 33–39
3251 (m, NH), 1499 (s, C55CAr), 1326 (m, S55O), 1161 (s, S55O), 1091
(m, C–F), 669 (m, C–Cl); 1H NMR (400 MHz, CDCl3):
= 2.41 (3H, s),
6.94–7.03 (2H, m), 7.15 (1H, brs), 7.19 (1H, dd, J = 6.3 Hz,
J = 2.5 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz); 13C
4.3. Radiochemistry
d
Procedure for [18F]fluorination reactions: [18F]fluoride was
trapped on an anion exchange cartridge, released with 6 ꢃ 100
mL
NMR (101 MHz, CDCl3):
d
= 21.6, 117.0 (d, J = 22.3 Hz), 121.6
of a solution of NEt4HCO3 in MeCN:H2O (7 mg in 1 mL (4:1)) and
azeotropically dried with MeCN. Dried [18F]fluoride was resolu-
(d, 19.1 Hz), 121.9 (d, J = 7.2 Hz), 124.3, 127.3, 129.2, 133.1 (d,
J = 3.4 Hz), 135.4, 144.4, 156.0 (d, J = 247.8 Hz); 19F NMR (377 MHz,
bilised in anhydrous DCM (1000
18F]NEt4F. This was used to dispense [18F]NEt4F (15–30 MBq) into
a v-vial containing a stirrer bar and 1a (12 mg, 40 mol, 1.0 eq.).
PIDA (13 mg, 40 mol, 1.0 eq.) in DCM (150 L) was added,
followed by the acid (HFꢀpyridine (1 L, 40 mol, 1.0 eq.) or TFA
(12 L, 160 mol, 4.0 eq.)) in DCM (50 L). The reaction mixture
was stirred for 15 min before TFA (22 L) was added and left for a
mL) to give a stock solution of
CDCl3):
d
= ꢁ118.9; HRMS (ESI+, m/z): [C13H11ClFNNaO2S]+
[
(M+Na)+ calcd. 322.0075, found 322.0075.
m
Methyl 5-fluoro-2-(4-methylphenylsulfonamido)benzoate
(5n). Purification by flash chromatography on silica gel (SiO2,
hexane:EtOAc 9:1–4:1) afforded the title compound as a white
m
m
m
m
m
m
m
solid (52 mg, 0.16 mmol, 21% yield). MP: 65–67 8C; IR (
n
, cmꢁ1):
m
3184 (w, NH), 1691 (m, C55O), 1494 (m, C55CAr), 1342 (m, S55O),
1229 (m, C–O), 1162 (s, S=O), 1121 (m, C–O), 1090 (w, C–F); 1H
further 10 minutes prior to radioHPLC and radioTLC analysis.
NMR (400 MHz, CDCl3): d = 2.37 (3H, s), 3.87 (3H, s), 7.16–7.22 (1H,
Acknowledgements
m), 7.22 (2H, d, J = 8.1 Hz), 7.58 (1H, dd, J = 9.0 Hz, J = 3.2 Hz), 7.68
(2H, d, J = 8.3 Hz), 7.72 (1H, dd, J = 9.2 Hz, J = 4.8 Hz), 10.28
We gratefully acknowledge the BBSRC and GE Healthcare (FB),
the MRC and Advion (SC), the EU (Grant PIEF-GA-2011-301342 to
BC), and the EPSRC and CRUK (MT) for generous funding.
(1H, brs); 13C NMR (101 MHz, CDCl3):
d = 21.5, 52.9, 117.3 (d,
J = 25.4 Hz), 117.5 (d, J = 6.4 Hz), 121.9 (d, J = 22.3 Hz), 122.0 (d,
J = 4.8 Hz), 127.4, 129.8, 136.3, 136.8 (d, J = 3.2 Hz), 144.2, 158.0 (d,
J = 246.4 Hz), 167.3 (d, J = 3.2 Hz); 19F NMR (377 MHz, CDCl3):
Appendix A. Supplementary data
d
= ꢁ118.3; HRMS (ESI+, m/z): [C15H14FNNaO4S]+ (M+Na)+ calcd.
346.0520, found 346.0513.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.07.
030.
(E)-Methyl 3-(5-fluoro-2-(4-methylphenylsulfonamido)phe-
nyl)acrylate (5o). Purification by flash chromatography on silica
gel (SiO2, petroleum ether 30–40:EtOAc 17:3) afforded the title
compound as a white solid (80 mg, 0.23 mmol, 52% yield). MP:
152–155 8C; IR (
C55C), 1490 (m, C55CAr), 1328 (m, S55O), 1161 (s, S55O), 1092 (w, C–
F); 1H NMR (400 MHz, CDCl3):
= 2.37 (3H, s), 3.79 (3H, s), 6.08
n
, cmꢁ1): 3244 (w, NH), 1700 (m, C55O), 1632 (w,
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(101 MHz, CDCl3):
d = 21.5, 52.0, 113.3 (d, J = 23.8 Hz), 117.9 (d,
J = 22.3 Hz), 121.1, 127.4, 129.7, 130.6 (d, J = 3.2 Hz), 130.7 (d,
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J = 8.3 Hz); 13C NMR (101 MHz, CDCl3):
d = 21.7, 30.9, 34.9, 113.4
(d, J = 22.3 Hz), 114.6 (d, J = 23.8 Hz), 126.0 (d, J = 8.7 Hz), 127.5,
129.8, 130.9 (d, J = 2.4 Hz), 137.4, 144.1, 145.2 (d, J = 7.2 Hz), 160.5
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2.2-dioxide
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