Preparation of the Serotonin Transporter PET Radiotracer 2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18 F]fluoroaniline (4-[18 F]ADAM): Probing Synthetic and Radiosynthetic Methods

Article abstract of DOI:10.1055/s-0039-1690522

Serotonin transporters (SERTs) are involved in regulating the concentration of synaptic serotonin and present a good target for many neurologic and psychiatric disorder drugs. Positron-emission tomography (PET) is a valuable tool in both diagnosis and mon

Full text of DOI:10.1055/s-0039-1690522

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
special topic
A
en
S. Milicevic Sephton et al.
Special Topic
Synthesis
Preparation of the Serotonin Transporter PET Radiotracer
2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline
(4-[18F]ADAM): Probing Synthetic and Radiosynthetic Methods
Selena Milicevic Sephton*
Xiaoyun Zhou
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0-0
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2-1
1
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5-6
7
2
6
NMe2
NMe2
NH2
NHBoc
S
S
18F–, Cu(OTf)2(py)4
Stephen Thompson
Franklin I. Aigbirhio
0
0
0
0-0
0
0
3-3
5
9
6-7
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2
O
18F
B
4-[18F]ADAM
4-[18F]2
29%
O
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging
Centre, Department of Clinical Neurosciences, University of Cam-
bridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK
sms96@cam.ac.uk
Published as part of the Special Topic Halogenation methods
(with a view towards radioimaging applications)
Received: 26.06.2019
Accepted after revision: 25.07.2019
Published online: 21.08.2019
brains affected by Parkinson’s disease.4–8 Owing to the role
SERT has in some neurologic and psychiatric disorders, sig-
nificant efforts have been made in developing PET radio-
tracers for non-invasive imaging of SERT in vivo.2 Of these
radiotracers the most widely applied is [11C]N,N-dimethyl-
2-(2-amino-4-cyanophenylthio)benzylamine ([11C]DASB,
[11C]1) (Scheme 1),9,10 which in human studies showed a di-
rect correlation between radioactivity uptake and the dis-
tribution of SERT. A study of patients with depression indi-
cated an 80% reduction in radioactivity uptake under block-
ing conditions with citalopram and fluoxetine.3 While
[11C]1 is a suitable radiotracer for the measurement of SERT
density showing favourable binding kinetics, a major disad-
vantage is due to its carbon-11 radiolabel with a short
physical half-life of 20 minutes. This in turn limits its appli-
cation to PET centres with an on-site cyclotron. To expand
the application, a fluorine-18 analogue with a physical half-
life of 110 minutes was sought.
DOI: 10.1055/s-0039-1690522; Art ID: ss-2019-c0355-st
Abstract Serotonin transporters (SERTs) are involved in regulating the
concentration of synaptic serotonin and present a good target for many
neurologic and psychiatric disorder drugs. Positron-emission tomogra-
phy (PET) is a valuable tool in both diagnosis and monitoring treatment
therapies, and hence much effort is being given to developing suitable
PET agents for imaging SERT. Our interest in applying the fluorine-18
analogue 4-[18F]ADAM for imaging SERT prompted the development of
an improved synthetic route to access unlabelled ADAM. This is
achieved using Pd-catalysed coupling with thiosalicylic acid and an
EDC/HOBt amide coupling in 36% yield over 4 steps. A novel radiolabel-
ling precursor, the pinacol-derived boronic ester, is prepared from the
bromide using the Miyaura borylation and is obtained in 27% yield over
6 steps. Pinacolate is then used for the radiolabelling of 4-[18F]ADAM
based on Cu-mediated nucleophilic fluorination in which the presence
of oxygen is critical for the reaction. A 1:1 substrate to copper ratio is
found to be optimal when the reaction is performed in dimethylacet-
amide at 85 °C. Using these conditions, 4-[18F]ADAM is prepared in 29 ±
10% (n = 6) radiochemical conversion after hydrolysis of the Boc group
with HCl. Furthermore, the method is successfully automated to afford
4-[18F]ADAM in 10% radiochemical conversion.
NMe2
NH2
S
Key words 4-[18F]ADAM, serotonin transporter, copper-mediated flu-
orination, 18F-radiolabelling, PET imaging
18F
11CH3
4-[18F]ADAM
18F]2
N
NH2
CH3
[
The serotonin transporter (SERT) is an oligomeric pro-
tein which controls the concentration of synaptic serotonin
by regulating reuptake of serotonin in the synaptic cleft.1
Deregulation of SERT function or expression consequently
leads to alterations in serotonergic neurotransmission,
which has been observed in some neurologic and psychiat-
ric disorders.2 For instance, depression is characterised by
the decrease of serotonergic neurotransmission.3 Similarly,
positron-emission tomography (PET) and single-photon
emission computed tomography (SPECT) studies have
shown a reduction in SERT density in monkey and human
S
Cu-mediated
fluorination
this work
NMe2
NC
[
11C]DASB
11C]1
NHPG
[
S
O
B
O
3
Scheme 1 Structures of SERT PET radiotracers: [11C]1 and 4-[18F]2 and
a novel radiolabelling precursor 3. PG = protecting group
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Milicevic Sephton et al.
Special Topic
Synthesis
Although several candidates were investigated11,12 in
vivo in human subjects, to date, no fluorine-18 PET radio-
tracer for imaging SERT has seen widespread use. This has
been due to various reasons, such as challenging chemistry
to synthesise the precursor and radiochemistry to incorpo-
rate the radioisotope.
yield. The same research group published the radiosynthe-
sis of 4-[18F]2 using an improved radiolabelling precursor 8
(Scheme 2) with 15% decay-corrected radiochemical yield
when radiosynthesis was performed manually.19 In an ef-
fort to reproduce the literature preparation of 2, we began
the synthesis using the same 4-fluorobromide 4 and thiosa-
licylic acid (10) instead of thiophenol 5, the latter being
commercially available only from specialised suppliers.
Thiosalicylic acid (10) has previously been used successful-
ly for the formation of the desired thioether13 and was
available commercially at a very low cost. In our hands the
substitution worked sluggishly and repeatedly gave insepa-
rable black tars. For this reason, we sought an improved
synthetic route and prepared 2 as depicted in Schemes 3
and 4.
An ongoing study in our laboratory required a SERT PET
imaging agent with a fluorine-18 radiolabel. Based on the
reports of rodent,1,8,13 non-human primate14 and initial hu-
man studies,11 we selected an analogue of 1, 2-({2-[(dime-
thylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline
(4-
[18F]ADAM, 4-[18F]2) as a potential PET radiotracer of inter-
est.
Herein, we report an improved synthesis of 2, as well as
the radiosynthesis of 4-[18F]2 based on a copper-mediated
method from the Gouverneur lab15,16 for the introduction of
CO2H
O
NMe2
fluorine-18 into the novel radiolabelling precursor
(Scheme 1).
3
NO2
NO2
HS
Br
S
10
The synthesis of 2 has been previously reported13,17 as
well as the radiolabelling to access 4-[18F]2 from either ni-
tro,17,18 bromo17 or trimethylammonium19 precursors 6, 7
or 8, respectively (Scheme 2).
a) Pd2(dba)3
NMP
R
R
4, R = F
11, R = F, 69%
12, R = Br, 99%
b) HNMe2
HOBt, EDC
9, R = Br
–
BH3·THF
O
NMe2
NaOMe
NMe2
BH3
NO2
NH2
NMe2
+
NMe2
Br HS
+
S
NO2
NO2
DMF
S
S
3 steps
15%17
F
F
+
4
5
2
R
R
14, R = F, traces
15, R = Br, 27%
13, R = F, 59%
7, R = Br, 41%
HCl
NMe2
O
NMe2
NO2
NO2
R = Br, 53%
S
S
Scheme 3 En route to compound 2: a reproducible synthetic route on
gram scale
R
Me3N
OTf
6, R = NO2
7, R = Br
8
2 steps
10%17
2 steps
15%19
[
18F]2
To form the thioether we employed the palladium-cata-
lysed coupling20 of 4-fluorobromide 4 with thiosalicylic
acid (10).
R = NO2
Scheme 2 Previously reported synthesis of 2 and radiosynthesis of
4-[18F]2 using nitro, bromo or trimethylammonium precursors 6, 7 and
8, respectively
Without purification the crude mixture was further re-
acted under amide coupling conditions using EDC/HOBt to
afford amide 11 in 69% yield over two steps. The amide
functionality in 11 was reduced with borane in 59% yield,
following the method from the Shiue group.17 An amine-
borane complex 14 was commonly isolated as a by-product
in agreement with the observations from the Shiue report.
Complex 14 could easily be converted into the desired
product, amine 13, by heating in 1 M aqueous hydrochloric
acid (HCl). The amount of isolated 14 after the borane re-
duction varied from batch to batch, and while extended
treatment with hot HCl prior to work-up showed a reduc-
tion in the isolated yield of 14, it did not eliminate the for-
mation of 14 completely (Scheme 3). In the final step, fluoro
analogue 2 was obtained in 89% yield after reduction of the
nitro group with SnCl2 (Scheme 4).
In the report from the Shiue group,17 the synthesis of 2
commenced with the condensation of 4-fluorobromide 4
with thiophenol 5 to form the desired thioether in 58%
yield. This was followed by the borane reduction of the am-
ide group in 25% yield and subsequent quantitative reduc-
tion of the nitro group using SnCl2 to afford the desired
product 2 in 15% yield over three steps. In the same report,
the authors used both nitro (6) and bromo (7) precursors to
provide 4-[18F]2 in 5–10% radiochemical yield. The radiola-
belling process was also automated by the Shiue group;13,18
however, this did not have a beneficial effect on the radio-
chemical yield. Using precursor 6 in an automated protocol
afforded 4-[18F]2 in 1.7% decay-corrected radiochemical
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

C
S. Milicevic Sephton et al.
Special Topic
Synthesis
NMe2
NMe2
NMe2
NMe2
NO2
NH2
NO2
NO2
S
S
S
18F–
S
SnCl2
80 °C
R
R
Br
18F
DMF
120 °C
13, R = F
7, R = Br
2, R = F, 89%
7
[
18F]13
16, R = Br, 98%
Cu(OAc)2, NaBH4
4-[18F]2
a) Boc2O, THF
b) LiBr, MeCN
O
B
O
O
O
B
19
O
NMe2
O
NMe2
NO2
NO2
NMe2
NMe2
NHBoc
NHBoc
S
S
19
MeSO2CF3
S
S
Pd(dppf)Cl2
CH2Cl2
40 °C
R2N
MeI
Me3N
OTf
O
R = Br
R
87%
B
24, R = H, 48%
25, R = Me, 30%
8
O
3A
3A·HCl
17, R = F, 76%
18, R = Br, 96%
HCl
Me2NH⋅HCl, EDC, HOBt
Scheme 4 Completion of the gram-scale synthesis of 2 and prepara-
tion of radiolabelling precursor 3A
NO2
CO2H
NO2
10
S
Cl
CuBr, K2CO3
Our improved synthesis of 2 compared favourably with
the method published by the Shiue group, and gave an in-
creased overall yield of 36% despite an extra synthetic step.
With reference compound 2 in hand, we next turned our at-
tention to the preparation of an appropriate radiolabelling
precursor.
DMF
120 °C
R2N
R2N
22, R = H, 70%
23, R = Me, 72%
20, R = H
MeI, 56%
21, R = Me
Scheme 5 Attempted radiosynthesis of 4-[18F]2 using precursor 7 and
preparation of alternative precursor 8
Using our newly established synthetic route to 2, we be-
gan the analogous synthesis of bromo precursor 7 (Scheme
3). Bromo precursor 7 was chosen over the nitro precursor
6 for reasons of speculated poor selectivity between the
two nitro groups in 6 during the aromatic nucleophilic fluo-
rination. Furthermore, the nitro group at the ortho position
was more reactive as demonstrated by the higher radio-
chemical yield of the ortho analogue (3.9% vs 1.7% obtained
for 4-[18F]2) reported by the Shiue group.13 Analogous to
the synthesis of 2, bromobenzene 9 was coupled to thiosal-
icylic acid (10) in a palladium-catalysed reaction and the
crude mixture was similarly treated with EDC/HOBt to yield
99% of amide 12. Borane reduction of the amide in 12 af-
forded precursor 7 in 41% yield. In agreement with our pre-
vious observations, borane-amine complex 15 was isolated
in 27% yield and then converted into amine 7 with 53% yield
(Scheme 3).
Following the reported radiosynthesis conditions, aro-
matic nucleophilic substitution was attempted with bromo
precursor 7, only to fail to produce any of the desired fluori-
nated intermediate [18F]13 (Scheme 5), which would be
converted into 4-[18F]2 after reduction of the nitro group. A
change of the base from K2CO3 to Cs2CO3 and replacing the
reaction solvent with DMSO had no effect and none of the
nitro derivative [18F]13 was observed. The failure to radiola-
bel 4-[18F]2 using the bromo precursor 7 prompted us to at-
tempt the radiosynthesis with trimethylammonium pre-
cursor 8, which was reported to give a better radiochemical
yield.19 In our hands however, precursor 8 could not be
formed. Tertiary dimethylamine 25 was synthesised follow-
ing the modified method of Shiue and co-workers.19 Cop-
per-mediated coupling of thiosalicylic acid (10) and aniline
20 afforded thioether 22 in 70% yield. Acid 22 then under-
went EDC/HOBt amide coupling to yield 48% of amide 24,
which was subsequently methylated to give 25. Alternative-
ly, aniline 20 was methylated first to give 21 in 56% yield
and then coupled to afford 72% of thioether 23. This was fol-
lowed by amide coupling with dimethylamine to yield 25.
Numerous attempts to further methylate 25 with methyl
trifluoromethanesulfonate failed to yield any of the quater-
nary ammonium precursor 8. Instead, decomposition of the
starting material was observed.
Since established methods for the formation of 4-[18F]2
proved challenging, it was deemed beneficial to develop an
improved radiosynthesis. For this, we explored copper-me-
diated nucleophilic fluorination methodology from the
Gouverneur group.15 First published in 2014, the method
was based on fluorination of pinacol aryl boronic esters us-
ing nucleophilic [18F]fluoride in the presence of
Cu(OTf)2(py)4 and showed good functional group tolerabili-
ty as well as versatility towards both electron-poor and
electron-rich arenes. In the subsequent report,16 the Gou-
verneur group published an extension of the application of
the method to electron-deficient fluoroarenes and demon-
strated this on several previously low-yielding PET radio-
tracers (e.g., [18F]FPEB, [18F]flumazenil). The Gouverneur
method presented an appealing alternative for the radio-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

D
S. Milicevic Sephton et al.
Special Topic
Synthesis
synthesis of 4-[18F]2 and we envisaged boron pinacolate 3A
(Scheme 4) as a suitable radiolabelling precursor. Pinacolate
3A was easily accessible from bromide 7 in just three steps:
reduction of the nitro group with SnCl2 in 98% yield fol-
lowed by a one-pot, two-step method for the installation of
the Boc protecting group on the aniline to give a 96% yield
of 18. Finally, a palladium-catalysed Miyaura borylation re-
action afforded boron pinacolate 3A (Scheme 4). Pinacol bo-
ronic ester 3A was isolated as a colourless oil, and for the
ease of handling small amounts of this precursor, it was
converted into the HCl salt 3A·HCl. As an unlabelled refer-
ence, aniline 2 was also protected with Boc to give 17 in
76% yield.
Ph
Ph
18F–, K222, K2CO3
O
B
18F
Cu(OTf)2(py)4
21–55%
O
26
[
18F]27
NMe2
NHBoc
18F–, K222, K2CO3
Cu(OTf)2(py)4
S
3A·HCl
18F
[
18F]17
Scheme 6 The Gouverneur method for the radiosynthesis of [18F]27
and [18F]17
To establish the Gouverneur method in our hands, we
first performed the fluorination with biphenyl pinacol bo-
ronic ester 26 as a model reaction (Scheme 6) to obtain flu-
orinated [18F]27 with 21–55% radiochemical conversion
(RCC). When the same reaction conditions were applied to
pinacolate 3A·HCl, an ambiguous result was seen and the
radiolabelling product was detected, however, the HPLC co-
injection with reference 17 showed a mismatch. It was later
postulated that the product was likely the free amine with
the Boc group having been removed; however, showing a
different Rf to 2 due to coordination to copper.
tion of this effect. In the case of 3A·HCl the amount of Cu-
complex had very little effect (entries 1–3). Similarly, only
trace amounts of the desired product from the fluorination
of [18F]17 were observed when the solvent was changed
from DMA to DMF (entry 4). The application of the initial
Gouverneur conditions with Cu(OTf)2 as the catalyst in an
ester/Cu-complex ratio of 1:0.1 similarly resulted in no
product (entry 5). Finally, the reaction temperature was re-
duced to 80 °C (entry 6), but once again the procedure
failed to yield any [18F]17. Surprised by these results, but
encouraged that trace amounts of product did form, we
speculated that the difficulty in forming meaningful
amounts of the desired fluorinated product could arise
from the chemical form of the boronic ester which was a
solid HCl salt.
Table 1 Optimisation of the Reaction Conditions for the Radiolabelling
of 4-[18F]2 Based on the Gouverneur Copper-Mediated Nucleophilic
Fluorination Using 3A·HCl
18F–, K222, K2CO3
3A·HCl
[
18F]17
The next series of Cu-mediated nucleophilic fluorina-
tions was conducted with 3A as the free base (Table 2). Us-
ing the same conditions as with 3A·HCl (entry 1) no prod-
uct was observed. Similarly, application of Cu(OTf)2 as a Cu
source (entry 2) or portionwise addition of Cu(OTf)2(py)4
(entry 3) also failed to give the fluorinated product.
Cu-source
Conditions (see Table)
Entry 3A·HCl Cu source
3A·HCl/Cu Solvent Temp Time
(°C) (min) (% RCC)
[
18F]17
(mg)
1
2
3
4
5
6
10
10
10
10
5
Cu(OTf)2(py)4 1:1.5
Cu(OTf)2(py)4 1:1
Cu(OTf)2(py)4 1:0.5
Cu(OTf)2(py)4 1:1
DMA
DMA
DMA
DMF
DMA
DMA
115
30
30
30
40
50
50
<1
<1
<1
<1
0
In order to confirm product formation under non-radio-
active conditions, 3A was treated with KF in a model reac-
tion under Gouverneur conditions, and the reaction prog-
115
115
115
115
80
1
ress followed by H NMR and LCMS. While a product was
Cu(OTf)2
1:0.1
not observed by NMR analysis, LCMS showed a mass ion
corresponding to the desired product, thus suggesting the
presence of trace amounts of 17 in the reaction mixture.
With the aim of achieving higher yields, we needed to
consider the mechanism of the reaction. While the mecha-
nism of the radioactive reaction has not been studied, the
method was based on the known Chan–Lam coupling.22 For
the reductive elimination to occur, the Cu(II) complex
formed after the transmetalation and ligand exchange must
be oxidised to Cu(III), for which the presence of oxygen is
needed. It is possible that the reductive elimination occurs
from a Cu(II) complex by reducing it to Cu(0), however, this
is energetically more demanding. Thus the presence of oxy-
gen in the reaction mixture makes the reaction more facile,
and hence the reaction mixtures were sparged with air pri-
5
Cu(OTf)2(py)4 1:1
0
It has been established that in the presence of Cu(OTf)2,
the aniline Boc-protecting group can become labile.21
In an effort to understand the outcome of the initial ra-
diolabelling reaction with 3A·HCl, we conducted a series of
manual reactions in order to optimise the reaction condi-
tions (Table 1). Gouverneur and co-workers found the
Cu(OTf)2(py)4 complex to be the highest yielding. They also
determined that a ratio of pinacol boronic ester to Cu-com-
plex of at least 10:1 is required for a successful reaction.15
However, subsequently16 the effect of the ratio of ester to
Cu-complex was shown to be substrate dependent, thus
further directing our investigation towards the determina-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

E
S. Milicevic Sephton et al.
Special Topic
Synthesis
or to heating. Further to the requirement of an oxidant in
the reaction mixture, the Chan–Lam coupling was com-
monly performed at ambient temperature. Taking this into
consideration, the reaction was attempted with reduced
temperatures compared to the initial 115 °C (Table 2).
These modifications led to a 43% RCC to [18F]17 when
the reaction was performed at 85 °C (Table 2, entry 4).
When DMF was used instead of DMA the RCC decreased to
11% (entry 5). Using Cu(OTf)2 as a source of copper with
added pyridine as a ligand, an 11% RCC was observed (entry
6). Reducing the reaction temperature to 70 °C or 40 °C (en-
tries 7 and 9) resulted in reduced RCCs of 22% and 1%, re-
spectively. Similarly using only 1 mg of 3A afforded only
trace amounts of [18F]17 (entry 8).
Encouraged by the reproducibility of the method we
next sought to translate the radiosynthesis of 4-[18F]2 onto
an automated synthesiser. For this purpose, we employed a
GE Tracerlab FXFN (see the Supporting information) as a
modular platform. While keeping the amounts of required
fluoride drying reagents (e.g., K222 and K2CO3) the same as
those used in manual radiosynthetic runs, the amounts of
precursor and Cu source were doubled. Although the reac-
tion concentration changed, the ratio of 3A to Cu source
was preserved, thus affording 4-[18F]2 in 10% RCC after
semi-preparative purification. The concentration of cold
ADAM in the sample was 32 g/mL in agreement with other
similar radioactive fluorinations on this scale in our labora-
tory.
In conclusion, we have optimised the synthesis of unla-
belled reference compound 2 (ADAM) and obtained it with
an overall yield higher than that previously reported. We
have successfully optimised the radiochemical reaction
conditions to reproducibly prepare 4-[18F]2 in good RCC
from the boron pinacolate 3A based on a new application of
the method developed by the Gouverneur group15,16 using
copper-mediated nucleophilic fluorination of arenes. As a
proof-of-principle, we have also demonstrated the prepara-
tion of 4-[18F]2 on an automated radiosynthesiser using our
optimised reaction conditions. This represents an improve-
ment over the pre-existing radiolabelling methods, which
use bromo or trimethylammonium precursors 7 or 8, re-
spectively, and which in our hands proved challenging. Fur-
ther efforts in translating this method to a good manufac-
turing practice (GMP)-compliant platform are underway in
our laboratory.
To complete the radiosynthesis of 4-[18F]2, Boc-protect-
ed [18F]17 was hydrolysed using 4 M HCl at 85 °C for 10
minutes with 90% RCC (Table 2).
Table 2 Optimisation of the Reaction Conditions for the Radiolabelling
of 4-[18F]2 Based on the Gouverneur Copper-Mediated Nucleophilic
Fluorination Using Free Base 3A
18F–, K222, K2CO3
HCl
3A
[
18F]17
4-[18F]2
Cu-source
Conditions (see Table)
Entry 3A
Cu source
3A/Cu
Solvent Temp Time
(°C)a (min) (% RCC)
[
18F]17
(mg)
1
2
3
4
5
6
7
8
9
10
10
5
Cu(OTf)2(py)4
Cu(OTf)2
1:1.5
1:0.1
DMA
DMA
115
115
115
85
30
50
50
50
50
50
30
30
30
0
0
Cu(OTf)2(py)4
Cu(OTf)2(py)4
Cu(OTf)2(py)4
Cu(OTf)2, py
Cu(OTf)2(py)4
Cu(OTf)2(py)4
Cu(OTf)2(py)4
1:0.5:0.5c DMA
0
5
1:1
DMA
DMF
DMF
DMA
DMA
DMA
43
11b
11b
22
<1
<1
5
1:1
85
All reactions requiring anhydrous conditions were conducted in
oven-dried glass apparatus under an atmosphere of inert gas. All
chemicals and anhydrous solvents were purchased from Aldrich or
Alfa Aesar and used as received unless otherwise noted. Triethyl-
amine was distilled over P2O5 and then stored over KOH prior to use.
Reported density values are for ambient temperature. Purity of com-
pounds was ≥95% as determined by analytical HPLC on a Thermo Di-
onex 3000 HPLC system. Preparative chromatographic separations
were performed on Material Harvest silica gel 60 (35–75 m) and re-
actions were followed by TLC analysis using Sigma-Aldrich silica gel
60 plates (2–25 m) with fluorescent indicator (254 nm), and visual-
ised with UV or potassium permanganate. 1H NMR spectra were re-
corded in Fourier transform mode at the field strength specified on
Bruker Avance III FT-NMR spectrometers (300 MHz). Spectra were
obtained from the specified deuterated solvents in 5 mm diameter
tubes. Chemical shifts in ppm are quoted relative to residual solvent
signals calibrated as follows: CDCl3, H (CHCl3) = 7.26, C = 77.2. Multi-
plicities in the 1H NMR spectra are described as: s = singlet,
d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet,
br = broad; coupling constants are reported in Hz. Numbers in paren-
theses following carbon atom chemical shifts refer to the number of
attached hydrogen atoms as revealed by the DEPT/HSQC spectral edit-
ing technique. LRMS mass spectra as well as HRMS were obtained
from the EPSRC Mass Spectrometry Service at the University of Swan-
sea. Ion mass/charge (m/z) ratios are reported as values in atomic
5
1:1:2d
1:1
85
5
70
1
1:1
70
5
1:1
40
a For temperatures below 100 °C a variation of ca. 5 °C was observed.
b The identity of the product could not be determined.
c overall ratio 3A/Cu was 1:1, but the addition of the Cu-complex was done
in two equal portions.
d The ratio depicted is 3A:Cu:py.
Further to co-injection of the product with the reference
material, confirmation of product formation was warranted
when the hydrolysis was performed under analogous non-
radioactive reaction conditions and the progress followed
by 1H NMR and LCMS to show complete consumption of 17.
With these optimised conditions in hand, radiolabelling us-
ing novel pinacolate precursor 3A was repeated and afford-
ed the desired fluorinated product 4-[18F]2 with 29 ± 10%
(n = 6) RCC.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

F
S. Milicevic Sephton et al.
Special Topic
Synthesis
mass units. The radio-TLC was performed on DC-Fertigfolien ALU-
GRAM® SIL G/UV254 (Macherey-Nagel, Germany) plates with a speci-
fied mobile phase. Plate analysis was carried out using an image plate
scanner (DÜRR MEDICAL - CR 35 BIO, Germany). The automated ra-
diosynthesis was performed on a GE Healthcare FXFN TRACERlab.
Semi-preparative purification of radiolabelled material was per-
formed on a Merck-Hitachi L6200A system equipped with a Knauer
variable wavelength detector and an Eberline radiation detector. Ana-
lytical HPLC samples were analysed with a ThermoFisher Scientific
Dionex 3000 HPLC system equipped with a UV multi-wavelength de-
tector and a Bioscan standard radiation detector. The calculation of
the radiochemical conversion (RCC) was performed as follows: for
manual reactions for which radioTLC or analytical HPLC was used, the
RCC represents the percentage of the peak area of the product ob-
served over the total peak area of all radioactive peaks present, in-
cluding unreacted fluoride and any other observed radioactive spe-
cies. This value was not decay-corrected. For the automated radiosyn-
thesis the RCC was calculated in the same way, only this time the
value was obtained from the semi-preparative HPLC trace. The mate-
rial was not formulated. The manual reactions were performed in
small reaction vessels and the [18F]fluoride absorbed onto the reac-
tion vessel was under the detectable levels.
1H NMR (300 MHz, CDCl3):  = 7.94–7.86 (m, 1 H), 7.62–7.37 (m, 4 H),
7.18–7.08 (m, 1 H), 7.00–6.90 (m, 1 H), 3.04 (s, 3 H), 2.85 (s, 3 H).
The data are in complete agreement with those previously pub-
lished.13,23
2-[(4-Bromo-2-nitrophenyl)thio]-N,N-dimethylbenzamide (12)
An oven-dried one-neck flask was allowed to cool to ambient tem-
perature under vacuum and backfilled with nitrogen. At ambient
temperature under nitrogen, it was then charged with 1,4-dibromo-
2-nitrobenzene (9) (500 mg, 1.77 mmol, 1 equiv) and anhydrous 1-
methyl-2-pyrrolidinone (15 mL) was added. The obtained brown
solution was treated with triethylamine (2.0 mL, 1.44 g, 14.2 mmol, 8
equiv, d = 0.726) in one portion and then tris(dibenzylideneace-
tone)dipalladium(0) (49 mg, 0.05 mmol, 0.03 equiv) was added fol-
lowed by 1,1′-bis(diphenylphosphino)ferrocene (118 mg, 0.21 mmol,
0.12 equiv) and the resulting brown heterogeneous mixture was
sparged with nitrogen over 30 min. After this time, thiosalicylic acid
(10) (2.2 g, 14.2 mmol, 8 equiv) was added in a single portion and the
brown mixture heated (oil bath temperature: 85 °C) for 21 h. After
this time, the mixture was allowed to cool to ambient temperature
and then diluted with H2O (100 mL) and EtOAc (80 mL). The two lay-
ers were well-shaken, separated and the aqueous phase was extracted
with EtOAc (2 × 80 mL). The combined organic extracts were washed
with H2O (5 × 60 mL), brine (1 × 60 mL), dried (MgSO4) and concen-
trated in vacuo to give a crude oily residue (630 mg, 1.8 mmol, quant.)
that was used without purification in the next step.
2-[(4-Fluoro-2-nitrophenyl)thio]-N,N-dimethylbenzamide (11)
An oven-dried one-neck flask was allowed to cool to ambient tem-
perature under vacuum and backfilled with nitrogen. At ambient
temperature under nitrogen, it was then charged with 1-bromo-4-
fluoro-2-nitrobenzene (4) (500 mg, 2.27 mmol, 1 equiv) and anhy-
drous 1-methyl-2-pyrrolidinone (19 mL) was added. The obtained
brown solution was treated with triethylamine (2.5 mL, 1.80 g, 18.2
mmol, 8 equiv, d = 0.726) in one portion and then tris(dibenzylidene-
acetone)dipalladium(0) (62 mg, 0.07 mmol, 0.03 equiv) was added
followed by 1,1′-bis(diphenylphosphino)ferrocene (151 mg, 0.27
mmol, 0.12 equiv) and the resulting brown heterogeneous mixture
was sparged with nitrogen over 40 min. After this time, thiosalicylic
acid (10) (2.8 g, 18.2 mmol, 8 equiv) was added in a single portion and
the brown mixture heated (oil bath temperature: 85 °C) for 28 h. After
this time, the mixture was allowed to cool to ambient temperature
and then diluted with H2O (100 mL) and EtOAc (80 mL). The two lay-
ers were well-shaken, separated and the aqueous phase extracted
with EtOAc (2 × 80 mL). The combined organic extracts were washed
with H2O (5 × 80 mL), brine (80 mL), dried (MgSO4) and concentrated
in vacuo to give a crude oily residue (665 mg, 2.3 mmol, quant.) that
was used without purification in the next step.
To the crude residue (630 mg, 1.8 mmol, 1 equiv) was added anhy-
drous tetrahydrofuran (33 mL) and the mixture was cooled to 0 °C (ice
bath) and then treated with dimethylamine hydrochloride salt (160
mg, 1.96 mmol, 1.1 equiv). Next, 1-hydroxybenzonitrile (308 mg, 86%
pure, 1.96 mmol, 1.1 equiv) was added followed by EDC (682 mg, 3.56
mmol, 2 equiv) and finally triethylamine (1.0 mL, 719 mg, 7.12 mmol,
4 equiv, d = 0.726) was added via syringe, and the resulting green–
brown heterogeneous mixture was allowed to stir under nitrogen at
ambient temperature over 30 h. After this time, the crude mixture
was diluted with EtOAc (60 mL), filtered through a Celite pad (using a
Hirsch funnel) and the filter cake was rinsed with EtOAc (2 × 60 mL).
The combined filtrates were washed with 1 M aq HCl (2 × 60 mL), H2O
(2 × 80 mL), brine (1 × 80 mL), dried (MgSO4) and concentrated in vac-
uo to give a brown oily residue that was purified by column chroma-
tography on a silica gel column (gradient elution: 100% CH2Cl2 to 10%
EtOAc in CH2Cl2) to afford the title compound (673 mg, 1.76 mmol,
99%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 8.31 (d, J = 2.2 Hz, 1 H), 7.62–7.54 (m, 2
To the crude residue (665 mg, 2.3 mmol, 1 equiv) was added anhy-
drous tetrahydrofuran (42 mL) and the mixture was cooled to 0 °C (ice
bath) and then treated with dimethylamine hydrochloride salt (203
mg, 2.5 mmol, 1.1 equiv). Next, 1-hydroxybenzonitrile (392 mg, 86%
pure, 2.5 mmol, 1.1 equiv) was added followed by 1-ethyl-3-(3-dime-
thylaminopropyl)carbodiimide hydrochloride (EDC) (870 mg, 4.54
mmol, 2 equiv) and finally triethylamine (1.3 mL, 917 mg, 9.08 mmol,
4 equiv, d = 0.726) was added via syringe, and the resulting green–
brown heterogeneous mixture was allowed to stir under nitrogen at
ambient temperature over 30 h. After this time, the crude mixture
was diluted with EtOAc (100 mL), filtered through a Celite pad (using
a Hirsch funnel) and the filter cake was rinsed with EtOAc (2 × 80 mL).
The combined filtrates were washed with 1 M aq HCl (2 × 80 mL), H2O
(2 × 80 mL), brine (1 × 80 mL), dried (MgSO4) and concentrated in vac-
uo to give a brown oily residue that was purified by column chroma-
tography on a silica gel column (gradient elution: 100% CH2Cl2 to 5%
EtOAc in CH2Cl2) to afford the title compound (502.6 mg, 1.57 mmol,
69%) as a pale yellow oil.
H), 7.52–7.40 (m, 3 H), 6.81 (d, J = 8.8 Hz, 1 H), 3.04 (s, 3 H), 2.85 (s, 3
H).
MS (ES+): m/z = 381 (79Br) [M + H]+, 383 (81Br) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H14BrN2O3S: 380.9903; found:
380.9906.
The data are in complete agreement with those previously pub-
lished.23
1-{2-[(4-Fluoro-2-nitrophenyl)thio]phenyl}-N,N-dimethylmeth-
anamine (13) and 1-{2-[(4-Fluoro-2-nitrophenyl)thio]phenyl}-
N,N-dimethylmethanamine Borane Complex (14)
At ambient temperature under a nitrogen atmosphere, a one-neck
round-bottom flask was charged with 2-[(4-fluoro-2-nitrophe-
nyl)thio]-N,N-dimethylbenzamide (11) (502 mg, 1.57 mmol, 1 equiv)
and anhydrous tetrahydrofuran (8.7 mL) was added. The resulting yel-
low solution was allowed to cool to 0 °C (ice bath) and borane tetrahy-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

G
S. Milicevic Sephton et al.
Special Topic
Synthesis
drofuran complex (4.7 mL, 4.71 mmol, 3 equiv, c = 1 M) was added
dropwise over 1 min and the yellow homogeneous mixture was heat-
ed (oil bath temperature: 80 °C) and stirred under nitrogen for 2 h.
After this time, the crude mixture was allowed to cool to ambient
temperature and then further to 0 °C (ice bath). It was then quenched
with 1 M aq HCl which was added until the pH of the mixture reached
1. The crude mixture was concentrated in vacuo, diluted with H2O (15
mL) and then allowed to stand at ambient temperature for 21 h. After
this time, the mixture was heated (oil bath temperature: 100 °C) for
1.5 h. Once the mixture had cooled to ambient temperature, saturated
aq NaHCO3 was added to adjust the pH to 8 and the mixture was then
extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo to give a crude mix-
ture as a yellow oil, purification of which by chromatography on a sil-
ica gel column (gradient elution: 20% to 80% EtOAc in petrol) afforded
the title compound 13 (284 mg, 0.93 mmol, 59%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.96 (dm, J = 8.4 Hz, 1 H), 7.66 (br d,
J = 7.4 Hz, 1 H), 7.58–7.46 (m, 2 H), 7.35 (br t, J = 7.4 Hz, 1 H), 7.12–
7.03 (m, 1 H), 6.74–6.65 (m, 1 H), 3.54 (br s, 2 H), 2.19 (br d, J = 1.5 Hz,
6 H).
MS (ES+): m/z = 307 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H16FN2O2S: 307.0911; found:
Borane complex 15 (167 mg, 0.44 mmol, 27%) was also isolated.
1H NMR (300 MHz, CDCl3):  = 8.40 (br d, J = 2.2 Hz, 1 H), 7.77 (dd,
J = 7.5, 1.7 Hz, 1 H), 3.65–3.47 (m, 3 H), 7.42 (dd, J = 8.7, 2.2 Hz, 1 H),
6.37 (d, J = 8.7 Hz, 1 H), 4.19 (s, 2 H), 2.60 (s, 6 H).
MS (ES+): m/z = 398 (79Br) [M + NH4]+, 400 (81Br) [M + NH4]+.
HRMS (ESI): m/z [M + NH4]+ calcd for C15H22BBrN3O2S: 398.0704;
found: 398.0702.
The data are in complete agreement with those previously pub-
lished.23
1-{2-[(4-Bromo-2-nitrophenyl)thio]phenyl}-N,N-dimethylmeth-
anamine (7)
At ambient temperature under a nitrogen atmosphere, a one-neck
round-bottom flask was charged with 1-{2-[(4-bromo-2-nitrophe-
nyl)thio]phenyl}-N,N-dimethylmethanamine borane complex (15)
(167 mg, 0.44 mmol, 1 equiv) and a solution hydrogen chloride in
methanol (3.5 mL, c = 1.25 M) and the resulting yellow homogeneous
mixture was heated (oil bath temperature: 90 °C) and stirred for 19 h.
After this time, the mixture was allowed to cool to ambient tempera-
ture and then concentrated in vacuo. The yellow residue was diluted
with H2O (10 mL) and the pH of the mixture was adjusted to 8 using
saturated aq NaHCO3. The aqueous phase was extracted with CH2Cl2
(3 × 25 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to give a yellow oily residue which was purified
by chromatography on a silica gel column (50% EtOAc/petrol) to afford
the title compound (85.1 mg, 0.23 mmol, 53%).
307.0910.
The data were in complete agreement with those previously pub-
lished.23 Borane complex 14 was in this instance isolated in trace
amounts only.
1-{2-[(4-Bromo-2-nitrophenyl)thio]phenyl}-N,N-dimethylmeth-
anamine (7) and 1-{2-[(4-Bromo-2-nitrophenyl)thio]phenyl}-N,N-
dimethylmethanamine Borane Complex (15)
2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-fluoroaniline (2)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 1-{2-[(4-fluoro-2-nitrophenyl)thio]phenyl}-
N,N-dimethylmethanamine (13) (284 mg, 0.93 mmol, 1 equiv) and
ethanol (12.4 mL). The resulting bright yellow solution was further
treated with tin(II)chloride dihydrate (2.1 g, 9.3 mmol, 10 equiv) in
one portion and the heterogeneous mixture was heated (oil bath tem-
perature: 80 °C) and stirred under nitrogen over 2.5 h. After this time,
the mixture was allowed to cool to ambient temperature and then
concentrated in vacuo to give an oily residue. The residue was cooled
to 0 °C (ice bath) and then treated with 5% aq NaOH (32 mL) and the
resulting white heterogeneous mixture was allowed to stir open to
the air for 7 h. The mixture was then diluted with H2O (90 mL) and
EtOAc (90 mL) and the two layers were well shaken and separated.
The aqueous phase was extracted with EtOAc (2 × 90 mL). The com-
bined organic extracts were washed with brine (1 × 90 mL), dried
(MgSO4) and concentrated in vacuo to give a pale brown oily residue
(229.1 mg, 0.83 mmol, 89%) which was used for the next step without
purification.
At ambient temperature under a nitrogen atmosphere, a one-neck
round-bottom flask was charged with 2-[(4-bromo-2-nitrophe-
nyl)thio]-N,N-dimethylbenzamide (12) (609 mg, 1.6 mmol, 1 equiv)
and anhydrous tetrahydrofuran (9.0 mL) was added. The resulting yel-
low solution was allowed to cool to 0 °C (ice bath) and borane tetrahy-
drofuran complex (4.8 mL, 4.8 mmol, 3 equiv, c = 1 M) was added
dropwise over 1 min and the yellow homogeneous mixture was heat-
ed (oil bath temperature: 80 °C) and stirred under nitrogen for 2 h.
After this time, the crude mixture was allowed to cool to ambient
temperature and then further to 0 °C (ice bath). It was then quenched
with 1 M aq HCl which was added until the pH of the mixture reached
1. The crude mixture was concentrated in vacuo, diluted with H2O (15
mL) and then allowed to stand at ambient temperature for 40 h. After
this time, the mixture was heated (oil bath temperature: 110 °C) for 1
h. Once the mixture had cooled to ambient temperature, saturated aq
NaHCO3 was added to adjust the pH to 8 and the mixture was then
extracted with CH2Cl2 (3 × 35 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo to give a crude mix-
ture as a yellow oil, purification of which by chromatography on a sil-
ica gel column (gradient elution: 20% EtOAc in petrol to 100% EtOAc)
afforded the title compound 7 (242 mg, 0.66 mmol, 41%) as a pale yel-
low oil.
MS (ES+): m/z = 277 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H18FN2S: 277.1169; found:
277.1171.
Note: For the purposes of material storage, 2 was converted into 2·HCl
to give a crystalline solid.
1H NMR (300 MHz, CDCl3):  = 12.36 (br s, 1 H), 7.80–7.70 (m, 1 H),
7.35–7.20 (m, 2 H), 6.85–6.79 (m, 1 H), 6.56–6.39 (m, 3 H), 4.36 (s, 2
H), 2.89 (s, 6 H).
1H NMR (300 MHz, CDCl3):  = 8.37 (d, J = 2.2 Hz, 1 H), 7.67 (br d,
J = 7.4 Hz, 1 H), 7.57–7.47 (m, 2 H), 7.41–7.32 (m, 2 H), 6.55 (d, J = 8.7
Hz, 1 H), 3.54 (s, 2 H), 2.20 (s, 6 H).
MS (ES+): m/z = 367 (79Br) [M + H]+, 369 (81Br) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H16BrN2O2S: 367.0110; found:
5-Bromo-2-({2-[(dimethylamino)methyl]phenyl}thio)aniline (16)
367.0114.
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 1-{2-[(4-bromo-2-nitrophenyl)thio]phenyl}-
N,N-dimethylmethanamine (7) (75 mg, 0.20 mmol, 1 equiv) and etha-
The data are in complete agreement with those previously pub-
lished.23
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

H
S. Milicevic Sephton et al.
Special Topic
Synthesis
nol (2.7 mL). The resulting bright yellow solution was further treated
with tin(II)chloride dihydrate (461 mg, 2.0 mmol, 10 equiv) in one
portion and the heterogeneous mixture was heated (oil bath tem-
perature: 80 °C) and stirred under nitrogen over 2 h. After this time,
the mixture was allowed to cool to ambient temperature and then
concentrated in vacuo to give an oily residue. The residue was cooled
to 0 °C (ice bath) and then treated with 5% aq NaOH (6.8 mL) and the
resulting white heterogeneous mixture was allowed to stir open to
the air for 3 h. The mixture was then diluted with H2O (25 mL) and
EtOAc (25 mL) and the two layers were well shaken and separated.
The aqueous phase was extracted with EtOAc (2 × 25 mL). The com-
bined organic extracts were washed with brine (1 × 20 mL), dried
(MgSO4) and concentrated in vacuo to give a pale brown oily residue
(67.9 mg, 0.20 mmol, 98%) which was used for the next step without
purification.
tert-Butyl [5-Bromo-2-({2-[(dimethylamino)methyl]phe-
nyl}thio)phenyl]carbamate (18)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 5-bromo-2-({2-[(dimethylamino)methyl]phe-
nyl}thio)aniline (16) (67 mg, 0.2 mmol, 1 equiv) and anhydrous tetra-
hydrofuran (1.0 mL). The resulting pale yellow solution was treated
with 4-dimethylaminopyridine (2.4 mg, 0.02 mmol, 0.1 equiv) in one
portion followed by di-tert-butyldicarbonate (130 mg, 0.60 mmol, 3
equiv) and the brown heterogeneous mixture was heated (oil bath
temperature: 40 °C) and stirred for 16 h. The mixture was allowed to
cool to ambient temperature and then concentrated in vacuo. The oily
residue was diluted with anhydrous acetonitrile (2.0 mL) and treated
with lithium bromide (54 mg, 0.62 mmol, 3.1 equiv) and the resulting
brown heterogeneous mixture was heated (oil bath temperature:
65 °C) and stirred under nitrogen for 10 h. After this time, the mixture
was allowed to cool to ambient temperature and then concentrated to
give a crude mixture which was purified by chromatography on a sili-
ca gel column (gradient elution: 20% to 40% EtOAc in petrol with 0.1%
Et3N) to afford the title compound (83.4 mg, 0.19 mmol, 96%) as a pale
yellow oil.
MS (ES+): m/z = 337 (79Br) [M + H]+, 339 (81Br) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H18BrN2S: 337.0369; found:
337.0371.
Note: For the purposes of material storage 16, was converted into
16·HCl to give a crystalline solid.
1H NMR (300 MHz, CDCl3):  = 12.48 (br s, 1 H), 7.82–7.70 (m, 1 H),
7.30–7.23 (m, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.00 (d, J = 1.6 Hz, 1 H),
6.92–6.84 (m, 3 H), 4.36 (s, 2 H), 2.88 (s, 6 H).
1H NMR (300 MHz, CDCl3):  = 8.45 (d, J = 2.1 Hz, 1 H), 7.86 (s, 1 H),
7.37 (d, J = 8.2 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.17–7.05 (m, 3 H), 6.80
(dd, J = 7.1, 2.0 Hz, 1 H), 3.56 (s, 2 H), 2.31 (s, 6 H), 1.46 (s, 9 H).
MS (ES+): m/z = 437 (79Br) [M + H]+, 439 (81Br) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H26BrN2O2S: 437.0893; found:
437.0894.
tert-Butyl [2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-fluoro-
phenyl]carbamate (17)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 2-({2-[(dimethylamino)methyl]phenyl}thio)-
5-fluoroaniline (2) (50.5 mg, 0.18 mmol, 1 equiv) and anhydrous tet-
rahydrofuran (0.9 mL). The resulting pale yellow solution was treated
with 4-dimethylaminopyridine (2.2 mg, 0.02 mmol, 0.1 equiv) in one
portion followed by di-tert-butyldicarbonate (120 mg, 0.55 mmol, 3
equiv) and the brown heterogeneous mixture was heated (oil bath
temperature: 40 °C) and stirred for 15.5 h. The mixture was allowed
to cool to ambient temperature and then concentrated in vacuo. The
oily residue was diluted with anhydrous acetonitrile (1.8 mL), treated
with lithium bromide (49 mg, 0.57 mmol, 3.1 equiv) and the resulting
brown heterogeneous mixture was heated (oil bath temperature:
65 °C) and stirred under nitrogen for 8.5 h. After this time, the mix-
ture was allowed to cool to ambient temperature and then concen-
trated to give a crude mixture which was purified by chromatography
on a silica gel column (gradient elution: 20% to 40% EtOAc in petrol
with 0.1% Et3N) to afford the title compound (52.5 mg, 0.14 mmol,
76%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 8.07 (dd, J = 11.7, 2.8 Hz, 1 H), 7.97 (s, 1
H), 7.52 (dd, J = 8.5, 6.4 Hz, 1 H), 7.31–7.24 (m, 1 H), 7.16–7.04 (m, 2
H), 6.78–6.70 (m, 2 H), 3.58 (s, 2 H), 2.33 (s, 6 H), 1.46 (s, 9 H).
13C NMR (75 MHz, CDCl3):  = 164.4 (0, d, J = 246 Hz), 152.6 (0), 142.9
(0, d, J = 12.5 Hz), 138.8 (1, d, J = 9.7 Hz), 137.0 (0), 137.0 (0), 130.6
(1), 128.4 (1), 127.8 (1), 126.0 (1), 115.0 (0, d, J = 3.3 Hz), 110.1 (1, d,
J = 22.2 Hz), 107.0 (1, d, J = 28.6 Hz), 81.3 (0), 62.6 (2), 45.3 (3, 2 C),
28.4 (3, 3 C).
tert-Butyl [2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate
(3A)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with tert-butyl [5-bromo-2-({2-[(dimethylami-
no)methyl]phenyl}thio)phenyl]carbamate (18) (93 mg, 0.21 mmol, 1
equiv) and 1,4-dioxane (6.8 mL). The resulting colourless solution was
treated with potassium acetate (63 mg, 0.64 mmol, 3 equiv) followed
by [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31
mg, 0.04 mmol, 0.2 equiv) and 1,1′-bis(diphenylphosphino)ferrocene
(47 mg, 0.85 mmol, 0.4 equiv) and the obtained orange coloured mix-
ture was sparged with nitrogen for 1 h. After this time, bis(pinacola-
to)diboron 19 (324 mg, 1.28 mmol, 6 equiv) was added and the re-
sulting brown heterogeneous mixture was heated (oil bath tempera-
ture: 100 °C) and stirred under nitrogen for 23.5 h. After this time, the
obtained black mixture was allowed to cool to ambient temperature
and then diluted with H2O (100 mL) and EtOAc (100 mL), and the two
layers were well shaken and separated. The aqueous phase was ex-
tracted with EtOAc (2 × 100 mL). The combined organic extracts were
washed with H2O (3 × 100 mL), brine (1 × 100 mL), dried (MgSO4) and
concentrated in vacuo to give a crude mixture as a brown oily residue.
The residue was purified by chromatography on a silica gel column
(gradient elution: 20% to 40% EtOAc in petrol with 0.1% Et3N) to afford
the title compound (90.5 mg, 0.19 mmol, 87%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 8.49 (br s, 1 H), 7.56 (s, 1 H), 7.45–7.44
(m, 1 H), 7.44 (d, J = 1.1 Hz, 1 H), 7.29 (dd, J = 7.6, 1.5 Hz, 1 H), 7.12 (td,
J = 7.3, 1.4 Hz, 1 H), 7.05 (td, J = 7.7, 1.8 Hz, 1 H), 6.81 (dd, J = 7.6, 1.3
Hz, 1 H), 3.56 (s, 2 H), 2.30 (s, 6 H), 1.44 (s, 9 H), 1.33 (s, 12 H).
MS (ES+): m/z = 377 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H26FN2O2S: 377.1694; found:
377.1692.
13C NMR (75 MHz, CDCl3):  = 152.9 (0), 139.8 (0), 137.8 (0), 136.4 (0,
d, J = 0.02 Hz), 135.6 (1), 130.4 (1), 129.5 (1), 128.9 (1), 128.3 (1),
126.2 (1), 125.9 (1), 124.8 (0, d, J = 0.01 Hz), 84.2 (0), 83.7 (0), 80.6 (0),
62.6 (2), 45.4 (3, 2 C), 28.5 (3, 2 C), 25.2 (3, 2 C), 25.1 (3, 3 C); the car-
bon attached to boron was not observed.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

I
S. Milicevic Sephton et al.
Special Topic
Synthesis
MS (ES+): m/z = 485 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H38BN2O4S: 484.2676; found:
was insufficiently pure so a second column was performed (eluting
with 10% CH2Cl2 in EtOAc with 0.1% HCO2H) to afford the title com-
pound (1.82 g, 6.3 mmol, 70%). The product could not be isolated in
pure form even after several attempted crystallisations. 1H NMR data
were in complete agreement with those previously published.19
484.2669.
tert-Butyl [2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl]carbamate
Hydrochloric Salt (3A·HCl)
2-{[4-(Dimethylamino)-2-nitrophenyl]thio}benzoic Acid (23)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 4-chloro-N,N-dimethyl-3-nitroaniline (112
mg, 0.56 mmol, 1 equiv) (21) and anhydrous N,N′-dimethylforma-
mide (2 mL). The resulting orange solution was treated with potassi-
um carbonate (169 mg, 1.22 mmol, 2.2 equiv) followed by thiosalicyl-
ic acid (10) (86 mg, 0.56 mmol, 1 equiv) and copper(I) bromide (80
mg, 0.56 mmol, 1 equiv). The obtained black heterogeneous mixture
was heated (oil bath temperature: 120 °C) and stirred for 24.5 h. After
this time, the resulting green coloured mixture was allowed to cool to
ambient temperature, diluted with ice-cold H2O (25 mL) and then fil-
tered through a Celite pad (using a Hirsch funnel). The pH of the fil-
trate was adjusted to 2 by adding 2 M aq HCl and the aqueous phase
was extracted with EtOAc (3 × 40 mL). The combined organic extracts
were washed with H2O (5 × 25 mL), brine (1 × 30 mL), dried (MgSO4)
and concentrated in vacuo to give an orange solid residue (128.1 mg,
0.40 mmol, 72%). The crude mixture was used for the next step with-
out further purification.
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with tert-butyl [2-({2-[(dimethylamino)meth-
yl]phenyl}thio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]carbamate (189 mg, 0.39 mmol, 1 equiv) (3A) and methanol (2.3
mL). The resulting brown solution was treated with a solution of hy-
drogen chloride in methanol (0.31 mL, 0.39 mmol, 1 equiv, c = 1.25 M)
dropwise over 1 min and then stirred for 30 min. After this time, the
crude mixture was concentrated in vacuo and the brown residue was
further diluted with Et2O and allowed to crystallise. The crystals were
filtered, washed with ice-cold Et2O and dried in air to afford the title
compound (64.8 mg, 0.12 mmol, 32%) as needle-like crystals.
1H NMR (300 MHz, CDCl3):  = 12.68 (s, 1 H), 8.25 (d, J = 1.0 Hz, 1 H),
8.21 (br d, J = 6.6 Hz, 1 H), 7.46 (dd, J = 7.8, 1.0 Hz, 1 H), 7.48–7.41 (m,
1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.14 (dd, J = 7.9, 0.9 Hz, 1 H), 7.09 (d,
J = 7.8 Hz, 1 H), 6.89 (br s, 1 H), 4.40 (d, J = 3.4 Hz, 2 H), 2.77 (d, J = 2.8
Hz, 6 H), 1.48 (s, 9 H), 1.33 (s, 12 H).
4-Chloro-N,N-dimethyl-3-nitroaniline (21)
2-[(4-Amino-2-nitrophenyl)thio]-N,N-dimethylbenzamide (24)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 4-chloro-3-nitroaniline (172 mg, 1 mmol, 1
equiv) and anhydrous N,N′-dimethylformamide (20 mL). The result-
ing brown solution was treated with potassium carbonate (3.6 g, 26
mmol, 26 equiv) and then methyl iodide (0.75 mL, 1.7 g, 12 mmol, 12
equiv, d = 2.28) was added dropwise over 1 min and the mixture was
heated (oil bath temperature: 120 °C) for 24 h. After this time, the
crude mixture was allowed to cool to ambient temperature, poured
into H2O (50 mL) and diluted with CH2Cl2 (40 mL). The two layers
were well shaken, separated and the aqueous phase was extracted
with CH2Cl2 (2 × 40 mL). The combined organic extracts were washed
with H2O (5 × 30 mL), brine (1 × 40 mL), dried (MgSO4) and concen-
trated in vacuo to give a crude oily residue. The crude residue was pu-
rified by chromatography on a silica gel column (eluting with 50%
CH2Cl2/petrol) to afford the title compound (112.1 mg, 0.56 mmol,
56%) as a pale yellow oil.
To the crude residue 22 (100 mg, 0.34 mmol, 1 equiv) was added an-
hydrous tetrahydrofuran (6.0 mL) and the mixture was allowed to
cool to 0 °C (ice bath) and then treated with dimethylamine hydro-
chloride salt (31 mg, 0.38 mmol, 1.1 equiv). Next, 1-hydroxybenzoni-
trile (60 mg, 86% pure, 0.38 mmol, 1.1 equiv) and EDC (132 mg, 0.69
mmol, 2 equiv) were added. Triethylamine (0.19 mL, 139 mg, 1.38
mmol, 4 equiv, d = 0.726) was added via syringe and the resulting
green–brown heterogeneous mixture was allowed to stir under nitro-
gen at ambient temperature over 20.5 h. After this time, the crude
mixture was diluted with EtOAc (20 mL), filtered through a Celite pad
(using a Hirsch funnel) and the filter cake was rinsed with EtOAc
(2 × 20 mL). The combined filtrates were washed with 1 M aq HCl
(2 × 20 mL), H2O (2 × 20 mL), brine (1 × 25 mL), dried (MgSO4) and
concentrated in vacuo to give a brown oily residue which was purified
by column chromatography on a silica gel column (gradient elution:
100% CH2Cl2 to 90% EtOAc in CH2Cl2) to afford the title compound
(52.9 mg, 0.17 mmol, 48%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.30 (d, J = 9.0 Hz, 1 H), 7.09 (d, J = 3.0
Hz, 1 H), 6.77 (dd, J = 9.0, 3.0 Hz, 1 H), 3.00 (s, 6 H).
1H NMR (300 MHz, CDCl3):  = 7.54–7.29 (m, 5 H), 6.90 (d, J = 8.7 Hz, 1
H), 6.74 (dd, J = 8.5, 2.5 Hz, 1 H), 3.05 (s, 3 H), 2.85 (s, 3 H).
2-[(4-Amino-2-nitrophenyl)thio]benzoic Acid (22)
The data are in complete agreement with those previously pub-
lished.19
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 4-chloro-3-nitroaniline (1.53 g, 8.9 mmol, 1
equiv) and anhydrous N,N′-dimethylformamide (33 mL). The result-
ing brown solution was treated with potassium carbonate (2.7 g, 19.5
mmol, 2.2 equiv) followed by thiosalicylic acid (10) (1.4 g, 8.9 mmol, 1
equiv) and copper(I) bromide (1.3 g, 8.9 mmol, 1 equiv). The obtained
black heterogeneous mixture was heated (oil bath temperature:
120 °C) and stirred for 24 h. After this time, the mixture was allowed
to cool to ambient temperature, diluted with ice-cold H2O (100 mL)
and then filtered through a Celite pad (using a Hirsch funnel). The pH
of the filtrate was adjusted to 2 by adding 2 M aq HCl and the aqueous
phase was extracted with EtOAc (3 × 150 mL). The combined organic
extracts were washed with H2O (5 × 100 mL), brine (1 × 100 mL),
dried (MgSO4) and concentrated in vacuo to give a crude orange solid
residue. The residue was purified by chromatography on a silica gel
column (eluting with 20% CH2Cl2 in EtOAc). The obtained material
2-{[4-(Dimethylamino)-2-nitrophenyl]thio}-N,N-dimethylben-
zamide (25)
To the crude residue 23 (128 mg, 0.40 mmol, 1 equiv) was added an-
hydrous tetrahydrofuran (7.4 mL) and the mixture was allowed to
cool to 0 °C (ice bath) and then treated with dimethylamine hydro-
chloride salt (36.1 mg, 0.44 mmol, 1.1 equiv). Next, 1-hydroxybenzo-
nitrile (70 mg, 86% pure, 0.44 mmol, 1.1 equiv) and EDC (154 mg, 0.8
mmol, 2 equiv) were added. Triethylamine (0.22 mL, 163 mg, 1.6
mmol, 4 equiv, d = 0.726) was added via syringe and the resulting
green–brown heterogeneous mixture was allowed to stir under nitro-
gen at ambient temperature over 22 h. After this time, the crude mix-
ture was diluted with EtOAc (10 mL), filtered through a Celite pad (us-
ing a Hirsch funnel) and the filter cake was rinsed with EtOAc (3 × 10
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

J
S. Milicevic Sephton et al.
Special Topic
Synthesis
mL). The combined filtrates were washed with 1 M aq HCl (2 × 20
mL), H2O (2 × 20 mL), brine (1 × 20 mL), dried (MgSO4) and concen-
trated in vacuo to give a brown oily residue which was purified by
column chromatography on a silica gel column (gradient elution:
100% CH2Cl2 to 10% EtOAc in CH2Cl2) to afford the title compound (42
mg, 0.12 mmol, 30%) as a pale yellow oil.
was taken and added to a 1.5 mL reaction vial containing a magnetic
stir bar and precursor 26 (6 mg, 0.02 mmol) dissolved in dimethylac-
etamide (300 L) in the presence of Cu(OTf)2(py)4 (14 mg, 0.02
mmol). Air (10 mL) was bubbled through the reaction mixture after
which the reaction vial was sealed and heated at 115 °C for 20 min.
The reaction mixture was analysed by HPLC analysis using an Ultra-
Core 2.5 Å, Super C18, 50 × 4.6 mm column (gradient elution: 5% to
95% aqueous MeCN).
1H NMR (300 MHz, CDCl3):  = 7.42–7.27 (m, 5 H), 7.03 (d, J = 9.0 Hz, 1
H), 6.77 (dd, J = 9.0, 2.9 Hz, 1 H), 3.06 (s, 3 H), 2.98 (s, 6 H), 2.86 (s, 3
H).
tert-Butyl (2-{[2-(dimethylamino)methyl]phenyl}thio)-5-
The data are in complete agreement with those previously pub-
lished.19
([18F]fluorophenyl)carbamate (4-[18F]17)
[
18F]Fluoride ions were produced by the 18O(p,n)18F nuclear reaction
using a GE PETtrace cyclotron (GE Healthcare, Sweden). [18F]fluoride
(0.7–2 GBq) in [18O]H2O (2 mL) was passed through a QMA cartridge
(Waters, Sep-pak Light in carbonate form). The trapped [18F]fluoride
was eluted with an eluent (0.8 mL) containing Kryptofix 222 (K222) (12
mg) and K2CO3 (2.4 mg) dissolved in H2O/MeCN (1:4, v/v) in a 5 mL V-
vial. The solution was dried at 120 °C under a N2 flow. The [18F]KF/K222
complex was dried two more times with anhydrous MeCN (2 × 1 mL).
The complex was then re-dissolved in anhydrous MeCN to reach an
activity concentration of 3 MBq/L. An aliquot of this solution (20 L)
was taken and added to a 1.5 mL reaction vial containing a magnetic
stir bar and precursor 3A·HCl or 3A (5–10 mg, 0.01–0.02 mmol) dis-
solved in dimethylacetamide (300 L) in the presence of
Cu(OTf)2(Py)4 (7–14 mg 0.01–0.02 mmol). Air (10 mL) was bubbled
through the reaction mixture after which the reaction vial was sealed
and heated at 85–115 °C for up to 50 min. Aliquots were collected and
analysed to obtain the radiochemical conversion by radio-TLC (mobile
phase: 40% EtOAc/hexane with 0.2% Et3N).
2-{[4-(Dimethylamino)-2-nitrophenyl]thio}-N,N-dimethylben-
zamide (25)
At ambient temperature under a nitrogen atmosphere, a one-neck
flask was charged with 2-[(4-amino-2-nitrophenyl)thio]-N,N-di-
methylbenzamide (24) (52 mg, 0.16 mmol, 1 equiv) and anhydrous
N,N′-dimethylformamide (3.2 mL). The resulting mixture was treated
with potassium carbonate (589 mg, 4.26 mmol, 26 equiv) followed by
methyl iodide (0.12 mL, 279 mg, 1.97 mmol, 12 equiv, d = 2.28) and
the resulting red heterogeneous mixture was heated (oil bath tem-
perature: 120 °C) and stirred for 37 h. After this time, the mixture was
allowed to cool to ambient temperature and then diluted with H2O
(10 mL) and EtOAc (15 mL) and the two layers were well shaken and
separated. The aqueous phase was extracted with EtOAc (2 × 15 mL).
The combined organic extracts were washed with H2O (5 × 10 mL),
brine (1 × 15 mL), dried (MgSO4) and concentrated in vacuo to give a
crude mixture which was purified by chromatography on a silica gel
column (gradient elution: 100% CH2Cl2 to 20% EtOAc in CH2Cl2) to af-
ford the title compound (29.7 mg, 0.08 mmol, 52%).
2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline
(4-[18F]2)
tert-Butyl [2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-fluoro-
phenyl]carbamate (17)
[
18F]Fluoride ions were produced by the 18O(p,n)18F nuclear reaction
using a GE PETtrace cyclotron (GE Healthcare, Sweden). [18F]fluoride
(0.7–2 GBq) in [18O]H2O (2 mL) was passed through a QMA cartridge
(Waters, Sep-pak Light in carbonate form). The trapped [18F]fluoride
was eluted with an eluent (0.8 mL) containing Kryptofix 222 (K222) (12
mg) and K2CO3 (2.4 mg) and dissolved in H2O/MeCN (1:4, v/v) in a 5
mL V-vial. The solution was dried at 120 °C under a N2 flow. The
At ambient temperature open to air, a one-neck flask was charged
with
tert-butyl
[2-({2-[(dimethylamino)methyl]phenyl}thio)-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3A)
(8.8 mg, 0.018 mmol, 1 equiv) and Kryptofix (13.7 mg, 0.036 mmol, 2
equiv), followed by potassium fluoride (spray-dried, 2 mg, 0.036
mmol, 2 equiv) and anhydrous N,N′-dimethylformamide (0.5 mL). The
resulting brown heterogeneous reaction mixture was heated (oil bath
temperature: 110 °C) and stirred over 15 h. After this time, the reac-
tion mixture was allowed to cool to ambient temperature and then
diluted with H2O (10 mL) and EtOAc (10 mL) and the two layers were
well shaken and separated. The aqueous phase was extracted with
EtOAc (2 × 10 mL) and the combined organic extracts were washed
with H2O (5 × 8 mL), brine (1 × 10 mL), dried (MgSO4) and concentrat-
ed in vacuo to give a crude mixture as a yellow oily residue. The resi-
due was analysed by 1H NMR and LCMS.
[
18F]KF/K222 complex was dried two more times with anhydrous
MeCN (2 × 1 mL). The complex was then re-dissolved in anhydrous
MeCN to reach an activity concentration of 3 MBq/L. An aliquot of
this solution (20 L) was taken and added to a 1.5 mL reaction vial
containing a magnetic stir bar and precursor 3A (5 mg, 0.01 mmol)
dissolved in dimethylacetamide (300 L) in the presence of
Cu(OTf)2(Py)4 (7 mg, 0.01 mmol). Air (10 mL) was bubbled through
the reaction mixture after which the reaction vial was sealed and
heated at 85 °C for 10 min. Upon completion of the reaction, to the
mixture was added 4 M HCl (60 L) and the temperature maintained
at 85 °C for another 10 min, which was followed by neutralisation
with 4 M NaOH (60 L). Aliquots were collected for analysis of the ra-
diochemical conversion by radio-TLC (mobile phase: 40% EtOAc/hex-
ane with 0.2% Et3N) as well as by HPLC. For the latter, the crude mix-
ture was diluted with H2O (2 equiv) and filtered through a 0.02 m
filter (Anotop 10, GE Healthcare, Germany) before the injection. The
HPLC analysis was conducted using an analytical HPLC column (ACE
UltraCore 2.5 Å Super C18, 2.5 m, 4.6 × 50 mm) at a flow rate of 1
mL/min using the following gradient: 80% 100 mM NH4CO2H in
MeCN, 0–4 min; 60% 100 mM NH4CO2H in MeCN, 5–7 min; 30% 100
mM NH4CO2H in MeCN, 8–10 min; 80% 100 mM NH4CO2H in MeCN,
11 min.
MS (ES+): m/z = 377 [M + H]+.
4-[18F]Fluoro-1,1′-biphenyl ([18F]27)
[
18F]Fluoride ions were produced by the 18O(p,n)18F nuclear reaction
using a GE PETtrace cyclotron (GE Healthcare, Sweden). [18F]fluoride
(0.7 GBq) in [18O]H2O (2 mL) was passed through a QMA cartridge
(Waters, Sep-pak Light in carbonate form). The trapped [18F]fluoride
was eluted with an eluent (0.8 mL) containing Kryptofix 222 (K222) (12
mg) and K2CO3 (2.4 mg) dissolved in H2O/MeCN (1:4, v/v) in a 5 mL V-
vial. The solution was dried at 120 °C under a N2 flow. The [18F]KF/K222
complex was dried two more times with anhydrous MeCN (2 × 1 mL).
The complex was then re-dissolved in anhydrous MeCN to reach an
activity concentration of 3 MBq/L. An aliquot of this solution (20 L)
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K

K
S. Milicevic Sephton et al.
Special Topic
Synthesis
Automated Radiosynthesis of 2-({2-[(Dimethylamino)methyl]phe-
nyl}thio)-5-[18F]fluoroaniline (4-[18F]2)
References
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[
18F]Fluoride ions were produced by the 18O(p,n)18F nuclear reaction
using a GE PETtrace cyclotron (GE Healthcare, Sweden). [18F]fluoride
(5.09 GBq) in [18O]H2O (2.5 mL) was transferred into the receiving
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4 mL/min; column: ACE C18, 5 m, 10 × 100 mm.
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reactor, each solution was sparged with air by bubbling air through
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was continued for another 10 min. The mixture was allowed to cool
to 50 °C and then neutralised with the base/eluent mixture from V6.
The crude mixture was injected into the semi-preparative column
and the resulting chromatogram showed a 10% radiochemical yield
for 4-[18F]2. The identity of the product was confirmed by co-injec-
tion on the analytical HPLC. The concentration of cold ADAM in the
sample was determined from the calibration curve.
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Funding Information
This work was in part funded by an internal grant from the Be-
havioural and Clinical Neuroscience Institute (BCNI), University of
Cambridge.()
Acknowledgment
Dr. Lindsay McMurray (WBIC) is acknowledged for many useful dis-
cussions on the non-radioactive synthesis of ADAM. Dr. Bianca Jupp
(BCNI) is acknowledged for suggesting the [18F]ADAM radiotracer for
application in drug addiction in vivo studies. Dr. Mark Sephton (CRL)
is acknowledged for proofreading the manuscript.
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Isot 2009, 67, 1063.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690522.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–K