Synthesis of [18 F]-γ-Fluoro-α,β-unsaturated Esters and Ketones via Vinylogous 18 F-Fluorination of α-Diazoacetates with [18 F]AgF

Article abstract of DOI:10.1055/s-0039-1690012

This communication reports a method for the vinylogous radiofluorination of α-diazoacetates to generate [¹⁸ F]-γ-fluoro-α,β-unsaturated esters and ketones in moderate to good radiochemical yields. The method uses no-carrier-added [¹⁸ F]AgF and is compatible with aromatic and non-aromatic substrates and a number of different functional groups. The labeling method is showcased in the synthesis of a fluorinated cholest-5-en-3-one derivative as well as a difluorinated product pertinent to drug discovery.

Full text of DOI:10.1055/s-0039-1690012

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
special topic
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S. Thompson et al.
Special Topic
Synthesis
Synthesis of [18F]--Fluoro-,-unsaturated Esters and Ketones via
Vinylogous 18F-Fluorination of -Diazoacetates with [18F]AgF
Stephen Thompsona
So Jeong Leea
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Isaac M. Jacksona
Naoko Ichiishib
Allen F. Brooksa
Melanie S. Sanford*b
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Peter J. H. Scott*a
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a Department of Radiology, University of Michigan Medical
School, Ann Arbor, MI 48109, USA
pjhscott@umich.edu
b Department of Chemistry, University of Michigan, Ann Arbor,
MI 48109, USA
mssanfor@umich.edu
Published as part of the Special Topic Halogenation methods (with a view towards radioimaging applications)
Received: 01.07.2019
Accepted after revision: 16.07.2019
Published online: 30.07.2019
Incorporation of 18F at an sp3 carbon is one of the most
widely used labeling strategies. This is typically achieved
via nucleophilic displacement of an appropriate leaving
group with [18F]fluoride, such as in the production of 2-
[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) by the reaction of
mannose triflate with [18F]KF, one of the most commonly
used labeling reactions in PET radiochemistry.5 However,
this approach is not compatible with all substrates and new
methods for generating C(sp3)–F bonds are essential to sim-
plify production of diverse libraries of PET radiotracers for
preclinical and clinical evaluation.
DOI: 10.1055/s-0039-1690012; Art ID: ss-2019-c0373-st
Abstract This communication reports a method for the vinylogous ra-
diofluorination of -diazoacetates to generate [18F]--fluoro-,-unsat-
urated esters and ketones in moderate to good radiochemical yields.
The method uses no-carrier-added [18F]AgF and is compatible with aro-
matic and non-aromatic substrates and a number of different function-
al groups. The labeling method is showcased in the synthesis of a fluori-
nated cholest-5-en-3-one derivative as well as a difluorinated product
pertinent to drug discovery.
In recent years we, and others, have reported new reac-
tions for generating both C(sp2)–F and C(sp3)–F bonds that
have proven challenging using traditional nucleophilic sub-
stitution reactions with [18F]fluoride.4,6 Key to developing
such reactions has been our discovery that different forms
of [18F]fluoride (beyond traditional [18F]KF) are easily acces-
sible by simple adjustment of the solution used to elute
[18F]fluoride from the quaternary methylammonium (QMA)
cartridge employed to reprocess [18F]fluoride obtained from
cyclotron-irradiated [18O]H2O.6 For example, we recently re-
ported a new method for generating [18F]AgF6a and utilized
it in the C(sp3)–H radiofluorination of a series of 8-meth-
ylquinoline derivatives.6d This work demonstrated that new
fluorine-18 radiochemistry could be accessed using
[18F]AgF, and we were interested to explore whether we
could use [18F]AgF in the development of other novel radio-
fluorination methodology. In particular, vinylogous fluori-
nation is quite challenging, and we were particularly inter-
ested in the Ag-catalyzed vinylogous fluorination of -di-
azoacetates recently described by Davies and Qin (Scheme
1a).7 This paper describes our efforts towards translating
Ag-mediated vinylogous fluorination to radiofluorination
Key words fluorine-18, late-stage fluorination, PET radiochemistry,
diazo chemistry, positron emission tomography
Positron emission tomography (PET) is a functional im-
aging technique that is used for clinical diagnostic imaging
as well as research applications in academic medical cen-
ters and pharmaceutical companies.1,2 Fluorine-18 (18F) is
one of the most commonly used PET radionuclides because
of its useful half-life (110 min) and favorable imaging prop-
erties. Reflecting this, the development of new methods for
accessing novel radiotracer motifs using fluorine-18 is an
exciting area of research that has led to development of nu-
merous new methods for the fluorination of a diverse array
of substrates in recent years.3 New C–18F bond-forming re-
actions need to be compatible with the unique challenges
of working with 18F, such as short reaction times (usually
≤20 min), automated synthesis and purification, and cGMP
compliant dose-on-demand production. In this context,
transition-metal-mediated nucleophilic radiofluorination
methods have emerged as particularly practical approaches
for forming new C–18F bonds.4
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Thompson et al.
Special Topic
Synthesis
a. Ag-catalyzed vinylogous fluorination of a-diazo-b-unstaurated carbonyls
3HF•Et3N (5 equiv)
AgOAc (20 mol%)
R'
N2
R'
R''
F
R'''
R'''
R''
DCM, reflux, 2 h
O
O
Davies et al. Org. Lett., 2013, 15, 6152
b. Development of [18F]AgF and Ag-catalyzed vinylogous radiofluorination
18F
18F]AgF•K222•AgOTf
N2
[
AgOAc (1 equiv),
OMe
OMe
Im•HOTf (1 equiv), HOAc (3 equiv)
R
R
O
O
DCE (0.01 M)
100 °C, 30 min
This Work
Scheme 1 Strategies for (radio)fluorination of -diazoacetates and motivation for this work
using [18F]AgF (Scheme 1b). The transformation was partic-
ularly attractive as (1) gamma () functionalization of car-
bonyl compounds generally remains challenging,8 relying
primarily on SN2′ reactions with -substituted-,-unsatu-
rated esters, reaction of activated enol ethers with electro-
philes, or Wittig-type reactions with prefunctionalized re-
agents, all of which are challenging transformations to ac-
complish with [18F]fluoride; (2) while diazo compounds
have been demonstrated as useful precursors for radiofluo-
rination9 and related methods for allylic 18F-fluorination
have been reported,10 both remain unexploited as methods
for accessing candidate PET radiotracers and radioligands;
(3) the resultant -fluoro-,-unsaturated esters are useful
synthons for further reaction; and (4) difluorinated moi-
eties are attracting attention as bioisosteres and for the
synthesis of PET imaging agents.11,12
Initial examination of the reaction, as reported by
Davies and Qin,7 identified two parameters which could po-
tentially make such a reaction challenging to adapt for use
with fluorine-18. Firstly, the reaction requires the use of an
excess of fluoride (15 equivalents) with respect to the diazo
reagent. In PET radiochemistry, [18F]fluoride is produced in
pmol to nmol amounts and, under no-carrier-added condi-
tions, is always the limiting reagent, often by several orders
of magnitude. Secondly, the reaction requires a proton
source as the reaction involves the (formal) addition of HF
and in most cases, [18F]fluoride is used under basic condi-
tions.
Our initial investigations focused on the radiofluorina-
tion of model -diazoacetate substrate 1N2 using the previ-
ously-described preparation of [18F]AgF, with kryptofix-222
(K222) as a phase transfer catalyst (Table 1).6d Early experi-
ments focused on the reaction of [18F]AgF·K222·AgOTf with
1N2 at 40 °C in dichloromethane in the dark, using a proto-
col similar to that described by Davies and Qin.7 Under
these conditions, radiochemical yields (RCY)13 of [18F]1F
were found to be ≤0.5% (Table 1, entry 1), which was not
unexpected considering the lack of a proton source in this
system. Screening of protic additives in the reaction identi-
fied imidazolium triflate (Im·HOTf) as an additive that led
to improved RCYs (Table 1, entry 2). RCYs were further in-
creased to 23 ± 11% (n = 7) upon addition of 3 equivalents of
acetic acid (Table 1, entry 3). Further optimization of the re-
action revealed that higher temperatures [which necessitat-
ed changing the reaction solvent from DCM to dichlo-
roethane (DCE)] also led to improved yields. At 40 °C in DCE
in the presence of Im·HOTf and HOAc, [18F]1F was produced
in 12 ± 6% RCY (n = 4) (Table 1, entry 4), which was lower
than the observed RCY in DCM at that temperature. Howev-
er, increasing the temperature of the reaction to 100 °C in-
creased the RCY of [18F]1F to 40 ± 12% (n = 26) (Table 1, en-
try 5). Further increases in temperature under these condi-
tions led to erosion of the observed RCY. Interestingly, RCYs
for the transformation when [18F]KF·K222·KOTf was used as a
source of [18F]fluoride are similar to those observed when
using [18F]AgF·K222·AgOTf (Table 1, entries 5 and 6). Since
the transformation using [18F]AgF·K222·AgOTf requires
1 equivalent of AgOAc for the reaction to proceed, it is per-
haps not surprising that the reaction proceeds equally well
with [18F]AgF and [18F]KF. Omitting AgOAc from the reac-
tion greatly suppressed RCY, regardless of whether [18F]AgF
or [18F]KF was used as the [18F]fluoride source (Table 1, en-
tries 7 and 8). Ultimately however, in order to maintain a
common counterion, we elected to move forward with
[18F]AgF·K222·AgOTf for further development of this meth-
odology. Other variables, including the identity and loading
of a variety of silver and imidazolium salts, and weak acids
as well as the concentration of 1N2 and AgOAc were opti-
mized for their effect on the reaction (see Supporting Infor-
mation). Ultimately, the optimal conditions for the conver-
sion of 1N2 to [18F]1F were as follows: 1N2 (10 mol), AgOAc
(10 mol), Im·HOTf (10 mol), HOAc (30 mol),
[18F]AgF·K222·AgOTf in DCE (100 L, 100–1000 Ci) in a total
volume of 1 mL DCE, heated to 100 °C for 30 minutes. These
optimal
conditions
generated
[18F]1F
RCY
of
40 ± 12% (n = 26) (Table 1, entry 5). Analysis of a typical ra-
diosynthesis employing 328 μCi of [18F]fluoride provided
151 μCi of [18F]1F (46% RCY) with a molar activity of 0.5
Ci/mmol (typical for a lower activity synthesis run in our
laboratory6d).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

C
S. Thompson et al.
Special Topic
Synthesis
Table 1 Optimization of Radiofluorination of -Diazoacetates Using
18F]AgFa
Following optimization of the reaction conditions using
simple unsubstituted arene substrate 1N2, the substrate
scope of the reaction was explored using a series of substi-
tuted arene precursors without further optimization of the
reaction conditions (Scheme 2). Electron-deficient ([18F]2F)
and electron-neutral arenes [18F]3F–[18F]6F were well toler-
ated in the reaction. Contrastingly, electron-rich arenes,
such as anisoles [18F]7F and N,N-dimethylanilines [18F]8F,
proved poor substrates presumably due to instability of the
18F-fluorinated product, which is implied by the in situ
analysis of such substrates in the original reaction.7,14 While
most substrates tested contained para-substituents, the re-
action was also tolerant of ortho- and meta-substituents on
the phenyl ring. RCYs of the para- [18F]4F, meta- [18F]5F,
and ortho-bromo-substituted [18F]6F products were com-
parable, with the slightly lower RCYs of the ortho- and
meta-substituted products likely attributable to steric ef-
fects. Using a fluorovinyl--diazo precursor 9N2, it was
found that the difluorinated product [18F]9F could be ob-
tained in 45 ± 5% (n = 4) RCY, suggesting that this transfor-
mation may be useful for the synthesis of [18F]CF2 groups
which is of interest as the CF2 motif is being explored for
PET imaging and as a bioisostere in drug design.11,12 Finally,
it was demonstrated that this method was suitable for ra-
diolabeling non-aromatic precursors, whereby 4-diazo-
[
[
18F]MF•K222•MOTf
AgOAc (1 equiv)
18F
N2
OMe
OMe
additive (1 equiv)
acid (3 equiv)
O
O
solvent (0.01 M)
temperature, 30 min
Entry
M
Additive
–
Acid
Solvent
Temp RCYb (%)13
1
Ag
–
–
DCM
DCM
DCM
DCE
DCE
DCE
DCE
DCE
40
0.5 ± 0.1 (n = 3)
8 ± 3 (n = 3)
2
Ag Im·HOTf
Ag Im·HOTf
Ag Im·HOTf
Ag Im·HOTf
40
3
HOAc
40
23 ± 11 (n = 7)
12 ± 6 (n = 4)
40 ± 12 (n = 26)
40 ± 3 (n = 3)
3 ± 2 (n = 3)
4
HOAc
HOAc
HOAc
HOAc
HOAc
40
5
100
100
100
100
6
K
Im·HOTf
Ag Im·HOTf
Im·HOTf
7c
8c
K
1 ± 0 (n = 3)
a Conditions: 1N2 (10 mol), AgOAc (10 mol), additive (10 mol), acid (30
mol), [18F]MF·K222·MOTf in solvent (100 L, 100–1000 Ci) in a total vol-
ume of 1 mL solvent, heat, 30 min.
b RCY is the non-isolated yield estimated by radioTLC and reported as mean
± standard deviation for n runs.
c Reactions run without any AgOAc.
[
18F]AgF•K222•AgOTf
AgOAc (1 equiv)
18F
R'
N2
Im•HOTf (1 equiv), HOAc (3 equiv)
DCE (0.01 M), 100 °C, 30 min
R'
R''
R''
R
R
O
O
18F
18F
18F
OMe
OMe
OMe
OMe
OEt
O
O
O
O
O
H
F3C
Ph
[
18F]2F
26 6 (n = 4)
[
18F]3F
[
18F]1F
44 14 (n = 4)
40 12 (n = 26)
18F
18F
Br 18F
OMe
OMe
Br
OMe
OMe
O
O
O
O
Br
[
18F]6F
[
18F]4F
[
18F]5F
29 8 (n = 4)
26 4 (n = 3)
35 7 (n = 5)
18F
18F
18F
F
MeO
N
[
18F]7F
1 (n = 4)
[
18F]8F
2 (n = 4)
[
18F]9F
45 5 (n = 4)
2
3
H
H
H
18F]10F
15 8 (n = 4)
O
[
18F
Scheme 2 Substrate scope of AgOAc-mediated radiofluorination of -diazoacetates using [18F]AgF. Reagents and conditions: 1N2–10N2 (10 mol),
AgOAc (10 mol), Im·HOTf (10 mol), HOAc (30 mol), [18F]AgF·K222·AgOTf in DCE (100 L, 100–1000 Ci) in a total volume of 1 mL DCE, 100 °C, 30
min. Non-isolated RCYs were estimated by radioTLC and product identities were confirmed by radioHPLC.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

D
S. Thompson et al.
Special Topic
Synthesis
functionalized cholest-5-en-3-one was successfully radio-
fluorinated using [18F]AgF·K222·AgOTf to generate [18F]10F in
modest radiochemical yield (15 ± 8%, n = 4). The latter com-
pound is of interest for our program radiolabeling steroid
derivatives for applications, such as use of PET to quantify
cholesterol metabolism.6e,15
In conclusion, we have developed a simple method for
the vinylogous radiofluorination of substituted -diazoace-
tates in moderate to good radiochemical yield using
[18F]AgF. This method provides access to [18F]--fluoro-,-
unsaturated esters which are useful synthons for further
elaboration. These labeled substrates are challenging to ac-
cess via traditional radiochemistry, and this method has po-
tential for labeling drug molecules and preparing new PET
radiotracers. In the latter case, we are in the process of us-
ing the new methodology to label steroids such as [18F]10F
for pre-clinical PET imaging and anticipated translation into
clinical trials.
up in dry MeCN and added to the suspension dropwise over 10 min.
The total volume of MeCN used gave a final concentration of the ester
of 0.25 M; two thirds of the total volume of MeCN was used to dis-
solve the ester/ketone, and the remaining third used for the DBU. The
suspension was stirred at 0 °C for a further 30 min, and at r.t. for a
further 30–60 min until the reaction was found to be complete by
TLC. The deep orange solution was concentrated, and the residue was
taken up into DCM, and dry loaded onto silica gel, before being passed
through a short (5 cm) silica plug, eluting with 20% EtOAc/hexanes.
The product was further purified by automated silica gel chromatog-
raphy (hexane/EtOAc gradient) to yield the corresponding diazo ester.
The isolated diazo products are unstable at r.t., and are best stored at
–20 °C in the dark. Prolonged storage under vacuum (i.e., to remove
residual solvents) was found to accelerate decomposition. If stored for
long periods (>1–2 months), diazo precursors should be re-purified
before use. The 13C NMR signal for the diazo carbon is not observed,
due to the long T1 for such carbons.
Methyl (E)-2-Diazo-4-phenylbut-3-enoate (1N2)
Synthesized according to the general procedure to yield 1N2 (766 mg,
83%) as an orange-red oil that solidified upon storage at –20 °C.
1H NMR (399.7 MHz, CDCl3):  = 7.36–7.29 (m, 4 H, ArH), 7.22–7.17
(m, 1 H, ArH), 6.48 (d, J = 16.3 Hz, 1 H, ArCH=CH), 6.19 (d, J = 16.3 Hz,
1 H, ArCH=CH), 3.85 (s, 3 H, COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 165.7, 136.9, 128.8, 127.2, 126.0,
123.1, 111.3, 52.5.
Reagents were purchased from Sigma Aldrich, Alfa Aesar, Oakwood,
Fisher Scientific, EMD Millipore Corporation and Acros Organics. 1H
NMR spectra were obtained on a Varian 400 MHz MR NMR (399.7
MHz for 1H, 100.5 MHz for 13C and 376.1 MHz for 19F) and Varian 500
MHz VNMRS (499.5 MHz for 1H, 125.6 MHz for 13C) spectrometers.
Spectra were referenced to TMS as an internal standard (1H:  = 0.00)
or residual solvent peak (CDCl3: 1H:  = 7.26, 13C:  = 77.16). 19F NMR
spectra are referenced to an external standard CFCl3 (CFCl3:  = 0.00
for 19F). NMR spectra were recorded at r.t. HRMS were recorded on a
Micromass AutoSpec Ultima Magnetic Sector mass spectrometer.
Flash column chromatography was conducted using a Biotage Isolera
Prime system with SNAP KP-Sil column cartridges (10 g or 25 g).
HRMS (ESI+): m/z [M + H]+ calcd for C11H11O2N2: 203.0815; found:
203.0813.
Methyl (E)-2-Diazo-4-[4-(trifluoromethyl)phenyl]but-3-enoate
(2N2)
Synthesized according to the general procedure to yield 2N2 (184 mg,
83%) as an orange solid.
1H NMR (399.7 MHz, CDCl3):  = 7.55 (app. d, J = 8.3 Hz, 2 H, ArH),
7.43 (app. d, J = 8.3 Hz, 2 H, ArH), 6.61 (d, J = 16.3 Hz, 1 H, ArCH=CH),
6.22 (d, J = 16.3 Hz, 1 H, ArCH=CH), 3.87 (s, 3 H, COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 165.1, 140.2 (q, J = 1.5 Hz), 128.6 (q,
J = 32.5 Hz), 125.8, 125.6 (q, J = 3.8 Hz), 124.2 (q, J = 271.8 Hz), 121.2,
114.4, 52.5.
Ultrapure water was obtained from a Millipore MilliQ Gradient A10
system. Sterile vials were purchased from Hollister-Stier.
QMA-light Sep-Paks were purchased form Waters Corporation, and
were preconditioned with EtOH (10 mL), followed by water (10 mL),
followed by 0.5 M aq KOTf (10 mL), followed by water (10 mL) before
use.
19F NMR (376.1 MHz, CDCl3):  = –62.46 (s, 3 F, CF3).
HRMS (ESI+): m/z [M + H]+ calcd for C12H10O2F3N2: 271.0689; found:
Glass-backed TLC plates coated with silica gel 60F254 were used for
TLC and radioTLC analysis and were purchased from EMD-Millipore.
TLC plates were visualized with KMnO4 or anisaldehyde stain. RadioTLC
analysis was performed using a Bioscan AR 2000 RadioTLC scanner
(Ekert and Ziegler).
271.0687.
Methyl (E)-4-(Biphenyl-4-yl)-2-diazobut-3-enoate (3N2)
Activity in vials was counted using a CRC-15 (Capintec) detector, cali-
brated for fluorine-18.
Synthesized according to the general procedure to yield 3N2 (107 mg,
65%) as an orange solid.
HPLC was performed using
a Shimadzu LC-2010A HT system
1H NMR (399.7 MHz, CDCl3):  = 7.61–7.55 (m, 4 H, ArH), 7.46–7.42
(m, 4 H, ArH), 7.36–7.32 (m, 1 H, ArH), 6.52 (d, J = 16.3 Hz, 1 H,
ArCH=CH), 6.24 (d, J = 16.3 Hz, 1 H, ArCH=CH), 3.87 (s, 3 H, COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 165.7, 140.7, 140.0, 135.9, 128.9,
127.5, 127.4, 127.0, 126.4, 122.7, 111.4, 52.0.
equipped with a Bioscan B-FC-1000 radiation detector in series. A 0.2
min offset was applied to all traces below to account for the detectors
being in series. Specific HPLC conditions are specified in the Support-
ing Information.
HRMS (ESI+): m/z [M + H]+ calcd for C17H15O2: 279.1128; found:
279.1127.
Synthesis of -Diazoacetate Substrates 1N2–10N2; General Proce-
dure for Diazo Transfer
-Diazoacetate substrates 1N2–10N2 were prepared through adapta-
tion of literature methods reported by Davies and Qin.7 Briefly, the
ester (1 equiv, see precursors S1–S10 in Supporting Information) and
p-acetamidobenzenesulfonyl azide (1.1 equiv) were taken up in dry
MeCN and the suspension cooled to 0 °C. DBU (1.1 equiv) was taken
Methyl (E)-4-(4-Bromophenyl)-2-diazobut-3-enoate (4N2)
Synthesized according to the general procedure to yield 4N2 (134 mg,
61%) as an orange-red oil that solidified upon storage at –20 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

E
S. Thompson et al.
Special Topic
Synthesis
1H NMR (399.7 MHz, CDCl3):  = 7.44–7.41 (m, 2 H, ArH), 7.22–7.20
(m, 2 H, ArH), 6.48 (d, J = 16.3 Hz, 1 H, ArCH=CH), 6.13 (d, J = 16.3 Hz,
1 H, ArCH=CH), 3.85 (s, 3 H, COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 165.4, 135.7, 131.8, 127.3, 121.6,
120.7, 112.3, 52.4.
Ethyl (Z)-2-Diazo-4-fluoro-4-phenylbut-3-enoate (9N2)
Synthesized according to the general procedure to yield 9N2 (102 mg,
93%) as a pale orange solid.
1H NMR (399.7 MHz, CDCl3):  = 7.48–7.46 (m, 2 H, ArH), 7.38–7.34
(m, 2 H, ArH), 7.29–7.25 (m, 1 H, ArH), 5.71 (d, J = 37.2 Hz, 1 H, CF-
CHCN2), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 1.32 (t, J = 7.1 Hz, 3 H,
CH2CH3).
HRMS (EI+): m/z [M]+ calcd for C11H9O2N279Br: 279.9847; found:
279.9847.
13C NMR (100.5 MHz, CDCl3):  = 165.7, 131.8 (d, J = 26.4 Hz), 128.7 (d,
J = 2.4 Hz), 128.6, 123.5 (d, J = 7.3 Hz), 89.9 (d, J = 12.0 Hz), 61.7, 14.6;
note: CF resonance as well as CN2 resonance not observed.
Methyl (E)-4-(3-Bromophenyl)-2-diazobut-3-enoate (5N2)
Synthesized according to the general procedure to yield 5N2 (206 mg,
75%) as an orange-red oil that solidified upon standing.
19F NMR (376.1 MHz, CDCl3):  = –117.77 (br s, 1 F, CFCHCN2).
1H NMR (399.7 MHz, CDCl3):  = 7.49–7.47 (m, 1 H, ArH), 7.31–7.29
(m, 1 H, ArH), 7.25–7.23 (m, 1 H, ArH), 7.17–7.13 (m, 1 H, ArH), 6.41
(d, J = 16.3 Hz, 1 H, ArCH=CH), 6.11 (d, J = 16.3 Hz, 1 H, ArCH=CH),
3.85 (s, 3 H, COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 165.3, 139.0, 130.2, 129.9, 128.7,
124.5, 123.0, 121.4, 113.2, 52.5.
HRMS (ESI+): m/z [M – N2 + H]+ calcd for C12H12FO2: 207.0816; found:
207.0815.
4-Diazocholest-4-en-3-one (10N2)
Cholest-5-en-3-one (100 mg, 0.25 mmol, 1 equiv) and p-acetamido-
benzenesulfonyl azide (70 mg, 0.29 mmol, 1.1 equiv) were taken up in
dry MeCN (4 mL) and the suspension cooled to 0 °C. DBU (43 L, 0.29
mmol, 1.1 equiv) was taken up in dry MeCN (1 mL), and added to the
suspension dropwise over 10 min. The suspension was stirred at 0 °C
for a further 30 min, and at r.t. for a further 90 min, until the reaction
was found to be complete by TLC. The deep orange solution was con-
centrated, and the residue was taken up into DCM, and dry loaded
onto silica gel, before being passed through a short (5 cm) silica plug,
eluting with 20% EtOAc/hexanes. The product was further purified by
automated silica gel chromatography (hexane/EtOAc acetate gradi-
ent) to give 10N2 (13.7 mg, 13%) as a yellow oil.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10O2N279Br: 280.9920; found:
280.9918.
Methyl (E)-4-(2-Bromophenyl)-2-diazobut-3-enoate (6N2)
Synthesized according to the general procedure to yield 6N2 (150 mg,
68%) as an orange-red oil.
1H NMR (399.7 MHz, CDCl3):  = 7.54–7.51 (m, 2 H, ArH), 7.28–7.23
(m, 1 H, ArH), 7.07–7.03 (m, 1 H, ArH), 6.55 (d, J = 16.3 Hz, 1 H,
ArCH=CH), 6.47 (d, J = 16.3 Hz, 1 H, ArCH=CH), 3.85 (s, 3 H, COOCH3).
13C NMR (126 MHz, CDCl3):  = 165.4, 136.6, 133.2, 128.4, 127.8,
126.6, 123.3, 121.5, 114.7, 52.6.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10O2N279Br: 280.9920; found:
280.9921.
1H NMR (399.7 MHz, CDCl3):  = 5.18 (dd, J = 4.9, 2.8 Hz, 1 H), 2.47–
2.44 (m, 2 H), 2.23 (dt, J = 18.0, 5.2 Hz, 1 H), 2.05 (dt, J = 12.6, 3.3 Hz, 1
H), 2.00–1.95 (m, 1 H), 1.90–1.82 (m, 1 H), 1.79–0.96 (m, 23 H), 0.92
(d, J = 6.5 Hz, 3 H), 0.87 (dd, J = 6.6, 1.7 Hz, 6 H), 0.72 (s, 3 H).
13C NMR (100.5 MHz, CDCl3):  = 192.90, 129.42, 114.87, 56.6, 56.0,
48.3, 42.4, 39.5, 39.5, 36.1, 35.8, 35.4, 33.4, 32.4, 31.5, 31.3, 28.2, 28.0,
24.2, 23.8, 22.8, 22.6, 21.2, 19.4, 18.7, 11.9.
Methyl (E)-2-Diazo-4-(4-methoxyphenyl)but-3-enoate (7N2)
Synthesized according to the general procedure to yield 7N2 (59 mg,
49%) as an orange-red oil that solidified upon storage at –20 °C.
HRMS (ESI+): m/z [M – N2 + H]+ calcd for C27H43O: 383.3308; found:
1H NMR (399.7 MHz, CDCl3):  = 7.30–7.28 (m, 2 H, ArH), 6.87–6.85
(m, 2 H, ArH), 6.30 (d, J = 16.3 Hz, 1 H, ArCH=CH), 6.14 (d, J = 16.3 Hz,
1 H, ArCH=CH), 3.85 (s, 3 H, COOCH3), 3.81 (s, 3 H, ArOCH3).
383.3308.
Synthesis of Fluorinated Reference Standards; General Proce-
dure14
13C NMR (100.5 MHz, CDCl3):  = 165.9, 158.9, 129.7, 127.0, 122.8,
AgOAc (0.2 equiv) was placed in a flame dried, foil-covered flask, and
the flask evacuated and filled with argon (3 ×). Dry DCM (final con-
centration 0.075 M) was added to the flask under argon, and 3HF·Et3N
was added to the suspension. The suspension was heated to reflux be-
fore the -diazoacetate substrate [1 equiv, in DCM (ca. 1 mL)] was
added to the refluxing suspension by syringe pump over 1 h. After ad-
dition was complete, a further aliquot of DCM (1 mL) was taken up
into the syringe, and this added in one portion to the suspension. The
mixture was refluxed for a further 3 h. The reaction was cooled, the
foil removed, and the reaction quenched with sat. aq NaHCO3
(10 × the volume of 3HF·Et3N used), and the resultant mixture stirred
for 30 min. The mixture was diluted with water (10 mL), then the re-
sultant biphasic mixture was separated and the aqueous phase ex-
tracted with DCM (3 × 30 mL). The organic extracts were combined,
dried (Na2SO4), filtered, and concentrated. The residue was taken up
into DCM, dry loaded onto silica gel, and purified by automated silica
gel chromatography (hexane/EtOAc gradient) to yield the correspond-
ing fluorinated product.
114.3, 108.7, 55.3, 52.3.
HRMS (ESI+): m/z [M + H]+ calcd for C12H13O3N2: 233.0921; found:
233.0914.
Methyl (E)-2-Diazo-4-[4-(dimethylamino)phenyl]but-3-enoate
(8N2)
Synthesized according to the general procedure to yield 8N2 (44 mg,
85%) as an orange-red oil that solidified upon standing.
1H NMR (399.7 MHz, CDCl3):  = 7.27–7.24 (m, 2 H, ArH), 6.69–6.67
(m, 2 H, ArH), 6.19 (d, J = 16.3 Hz, 1 H, ArCH=CH), 6.11 (d, J = 16.3. Hz,
1 H, ArCH=CH), 3.84 (s, 3 H, COOCH3), 2.96 [s, 6 H, ArN(CH3)2].
13C NMR (100.5 MHz, CDCl3):  = 149.9, 127.0, 125.5, 123.7, 112.6,
105.9, 52.4, 40.6; (C=O not observed).
HRMS (ESI+): m/z [M + H]+ calcd for C13H16O2N3: 246.1237; found:
246.1236.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

F
S. Thompson et al.
Special Topic
Synthesis
Methyl (E)-4-Fluoro-4-phenylbut-2-enoate (1F)
13C NMR (100.5 MHz, CDCl3):  = 166.2, 143.8 (d, J = 21.9 Hz), 135.8 (d,
J = 20.5 Hz), 132.2, 128.4 (d, J = 5.7 Hz), 123.6 (d, J = 3.0 Hz), 121.6 (d,
J = 10.2 Hz), 91.2 (d, J = 176.1 Hz), 52.1.
Synthesized according to the general procedure to yield 1F (27 mg,
36%) as a colorless oil.
19F NMR (376.1 MHz, CDCl3):  = –174.13 (dd, J = 46.8, 19.0 Hz, 1 F,
CHFCHCH).
HRMS (ESI+): m/z [M + H]+ calcd for C11H11O2F79Br: 272.9921; found:
1H NMR (399.7 MHz, CDCl3):  = 7.43–7.26 (m, 5 H, ArH), 7.06 (ddd,
J = 19.2, 15.7, 4.4 Hz, 1 H, ArCHFCH=CH), 6.19 (ddd, J = 15.7, 1.6, 1.6
Hz, 1 H, ArCHFCH=CH), 6.02 (ddd, J = 47.0, 19.2, 1.6 Hz, 1 H, ArCH-
FCH=CH), 3.76 (s, 3 H, COOCH3).
272.9916.
13C NMR (100.5 MHz, CDCl3):  = 166.4, 144.5 (d, J = 22.0 Hz), 136.8 (d,
J = 20.0 Hz), 129.4 (d, J = 2.4 Hz), 129.0, 126.8 (d, J = 5.7 Hz), 121.1 (d,
J = 10.2 Hz), 91.9 (d, J = 175.3 Hz), 52.0.
Methyl (E)-4-(3-Bromophenyl)-4-fluorobut-2-enoate (5F)
Synthesized according to the general procedure to yield 5F (15 mg,
30%) as a colorless oil.
19F NMR (376.1 MHz, CDCl3):  = –173.50 (dd, J = 47.0, 19.2 Hz, 1 F,
1H NMR (399.7 MHz, CDCl3):  = 7.52–7.50 (m, 2 H, ArH), 7.29–7.27
(m, 2 H, ArH), 7.00 (ddd, J = 19.0, 15.7, 4.5 Hz, 1 H, ArCHFCH=CH), 6.19
(ddd, J = 15.7, 1.6, 1.6 Hz, 1 H, ArCHFCH=CH), 5.98 (ddd, J = 46.9, 4.4,
1.6 Hz, 1 H, ArCHFCH=CH), 3.77 (s, 3 H, COOCH3).
CHFCHCH).
HRMS (ESI+): m/z [M + H]+ calcd for C11H12O2F: 195.0816; found:
195.0811.
Methyl (E)-4-Fluoro-4-[4-(trifluoromethyl)phenyl]but-2-enoate
(2F)
13C NMR (100.5 MHz, CDCl3):  = 166.2, 143.6 (d, J = 21.6 Hz), 139.00
(d, J = 20.4 Hz), 132.5, 130.6, 129.7 (d, J = 6.2 Hz), 125.2 (d, J = 5.8 Hz),
121.8 (d, J = 10.4 Hz), 91.0 (d, J = 177.1 Hz), 52.1.
Synthesized according to the general procedure to yield 2F (4.7 mg,
16%) as a colorless oil.
19F NMR (376.1 MHz, CDCl3):  = –175.29 (dd, J = 46.9, 19.0 Hz, 1 F,
1H NMR (399.7 MHz, CDCl3):  = 7.67 (d, J = 8.0 Hz, 2 H, ArH), 7.48 (d,
J = 8.0 Hz, 2 H, ArH), 7.02 (ddd, J = 18.8, 15.7, 4.6 Hz, 1 H, ArCH-
FCH=CH), 6.20 (ddd, J = 15.7, 1.7, 1.7 Hz, 1 H, ArCHFCH=CH), 6.15–
6.02 (m, 1 H, ArCHFCH=CH), 3.77 (s, 3 H, COOCH3).
CHFCHCH).
HRMS (ESI+): m/z [M + H]+ calcd for C11H11O2F79Br: 272.9921; found:
272.9918.
13C NMR (100.5 MHz, CDCl3):  = 166.1, 143.3 (d, J = 21.2 Hz), 127.3
(app. d, J = 32.5 Hz), 126.8 (d, J = 6.2 Hz), 126.0 (q, J = 3.8 Hz), 122.0 (d,
J = 10.5 Hz), 91.1 (d, J = 177.0 Hz), 52.1; note: quartets for C-CF3 and C-
CF3 carbons were not observed due to the low mass of material isolat-
ed.
19F NMR (376.1 MHz, CDCl3):  = –177.30 (dd, J = 46.7, 18.8 Hz, 1 F,
CHFCHCH), –62.80 (s, 3 F, CF3).
Methyl (E)-4-(2-Bromophenyl)-4-fluorobut-2-enoate (6F)
Synthesized according to the general procedure to yield 6F (16 mg,
55%) as a pale yellow solid.
1H NMR (499 MHz, CDCl3):  = 7.58 (dt, J = 8.1, 1.2 Hz, 1 H, ArH), 7.45
(dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.38 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.26–
7.21 (m, 1 H, ArH), 7.04 (ddd, J = 19.0, 15.7, 4.3 Hz, 1 H, ArCHFCH=CH),
6.42 (ddd, J = 45.7, 4.3, 1.8 Hz, 1 H, ArCHFCH=CH), 6.22 (dt, J = 15.7,
1.7 Hz, 1 H, ArCH-CH=CH), 3.76 (s, 3 H, COOCH3).
HRMS (ESI+): m/z [M + H]+ calcd for C12H11O2F4: 263.0690; found:
13C NMR (126 MHz, CDCl3):  = 166.4, 143 (d, J = 21.9 Hz), 136.5 (d,
J = 21.5 Hz), 133.1, 131.7, 130.6 (d, J = 1.9 Hz), 127.9 (d, J = 8.3 Hz),
121.6 (d, J = 10.4 Hz), 90.5 (d, J = 176.5 Hz), 52.1.
263.0696.
Methyl (E)-4-Fluoro-4-(biphenyl-4-yl)but-2-enoate (3F)
19F NMR (470 MHz, CDCl3):  = –180.58 (dd, J = 19.3 Hz, 1 F,
Synthesized according to the general procedure to yield 3F (15 mg,
30%) as a colorless oil.
CHFCHCH).
1H NMR (399.7 MHz, CDCl3):  = 7.64–7.57 (m, 4 H, ArH), 7.47–7.41
(m, 4 H, ArH), 7.39–7.35 (m, 1 H, ArH), 7.09 (ddd, J = 19.0, 15.7, 4.4 Hz,
1 H, ArCHFCH=CH), 6.22 (ddd, J = 15.7, 1.6, 1.6 Hz, 1 H, ArCHFCH=CH),
6.07 (ddd, J = 47.0, 4.3, 1.6 Hz, 1 H, ArCHFCH=CH), 3.77 (s, 3 H,
COOCH3).
13C NMR (100.5 MHz, CDCl3):  = 166.4, 144.4 (d, J = 22.1 Hz), 142.44,
140.5, 135.7 (d, J = 20.1 Hz), 129.0, 127.8 (d, J = 6.5 Hz), 127.8, 127.3
(d, J = 5.5 Hz), 127.3, 121.3 (d, J = 10.0 Hz), 91.8 (d, J = 175.2 Hz), 52.0.
19F NMR (376.1 MHz, CDCl3):  = –172.96 (dd, J = 47.0, 19.0 Hz, 1 F,
CHFCHCH).
HRMS (ESI+): m/z [M + Na]+ calcd for C17H16O2F: 293.0948; found:
293.0946.
HRMS (ESI+): m/z [M]+ calcd for C11H1079BrFO2: 271.9848; found:
271.9853.
Ethyl (E)-4,4-Difluoro-4-phenylbut-2-enoate (9F)
Synthesized according to the general procedure to yield 9F (14 mg,
48%) as a colorless oil.
1H NMR (399.7 MHz, CDCl3):  = 7.51–7.43 (m, 5 H, ArH), 7.01 (dt,
J = 15.7, 10.5 Hz, 1 H, CF2CH=CH), 6.26 (dt, J = 15.7, 2.3 Hz, 1 H,
CF2CH=CH), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 1.32 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13C NMR (100.5 MHz, CDCl3):  = 165.2, 140.1 (t, J = 30.7 Hz), 135.3 (t,
J = 27.1 Hz), 130.6 (t, J = 1.7 Hz), 128.8, 125.4 (t, J = 5.8 Hz), 124.9 (t,
J = 8.2 Hz), 118.5 (t, J = 240.4 Hz), 61.4, 14.3.
Methyl (E)-4-(4-Bromophenyl)-4-fluorobut-2-enoate (4F)
19F NMR (376.1 MHz, CDCl3):  = –117.77 (br s, 1 F, CF2CHCH).
Synthesized according to the general procedure to yield 4F (15 mg,
30%) as a colorless oil.
1H NMR (399.7 MHz, CDCl3):  = 7.54 (d, J = 8.3 Hz, 2 H, ArH), 7.22 (d,
J = 8.3 Hz, 2 H, ArH), 7.00 (ddd, J = 19.0, 15.7, 3.9 Hz, 1 H, ArCH-
FCH=CH), 6.19–6.15 (m, 1 H, ArCHFCH=CH), 6.04–5.92 (m, 1 H, ArCH-
FCH=CH), 3.77 (s, 3 H, COOCH3).
HRMS (ESI+): m/z [M + H]+ calcd for C12H13F2O2: 227.0878; found:
227.0875.
(6R)-6-Fluorocholest-4-en-3-one (10F)
Synthesized according to the general procedure, replacing AgOAc
with AgOTf, and using 3HF·Et3N (10 equiv), to yield 10F (14 mg, 30%)
as a colorless solid, as a single diastereomer.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

G
S. Thompson et al.
Special Topic
Synthesis
1H NMR (399.7 MHz, CDCl3):  = 5.87 (d, J = 4.9 Hz, 1 H), 4.99 (ddd,
J = 49.2, 2.5, 2.5 Hz, 1 H), 2.55 (ddd, J = 16.8, 15.1, 4.9 Hz, 1 H), 2.40
(ddd, J = 16.8, 3.3, 3.3 Hz, 1 H), 2.25–2.16 (m, 2 H), 1.91–1.81 (m, 2 H),
1.73 (td, J = 14.3, 14.3, 4.4 Hz, 1 H), 1.65–0.94 (m, 22 H), 0.92 (d, J = 6.5
Hz, 3 H), 0.87 (dd, J = 6.6, 1.7 Hz, 6 H), 0.74 (s, 3 H).
13C NMR (100.5 MHz, CDCl3):  = 200.2, 162.3 (d, J = 12.3 Hz), 128.4 (d,
J = 9.1 Hz), 93.7 (d, J = 166.0 Hz), 56.2, 55.9, 53.4, 42.7, 39.6, 38.0, 37.6,
37.4, 37.0, 36.3, 35.9, 34.4, 30.1, 28.3, 28.2, 24.2, 24.0, 23.0, 22.7, 21.0,
18.8, 18.5 (d, J = 0.9 Hz), 12.1.
(3) For recent reviews of new fluorine-18 radiochemistry, see:
(a) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem. Int.
Ed. 2008, 47, 8998. (b) Cai, L.; Lu, S.; Pike, V. W. Eur. J. Org. Chem.
2008, 2853. (c) Tredwell, M.; Gouverneur, V. Angew. Chem. Int.
Ed. 2012, 51, 11426. (d) Brooks, A. F.; Topczewski, J. J.; Ichiishi,
N.; Sanford, M. S.; Scott, P. J. H. Chem. Sci. 2014, 5, 4545.
(e) Jacobson, O.; Kiesewetter, D. O.; Chen, X. Bioconjugate Chem.
2015, 26, 1. (f) Preshlock, S.; Tredwell, M.; Gouverneur, V. Chem.
Rev. 2016, 116, 719. (g) Deng, X.; Rong, J.; Wang, L.; Vadev, N.;
Josephson, L.; Liang, S. H. Angew. Chem. Int. Ed. 2019, 58, 2580.
(4) Sanford, M. S.; Scott, P. J. H. ACS Cent. Sci. 2016, 2, 128.
(5) For, a recent example.; see:, Langstrom. B.; Blom, E. WO
2008106442 A1, 2008.
19F NMR (376.1 MHz, CDCl3):  = –165.07 to –165.58 (m, 1 F, CCF-
HCH2).
HRMS (ESI+): m/z [M + H]+ calcd for C27H44FO: 404.3371; found:
404.3375.
(6) (a) Scott, P. J. H.; Brooks, A. F.; Ichiishi, N.; Sanford, M. S. US
20160317682 A1, 2016. (b) Mossine, A. V.; Brooks, A. F.; Ichiishi,
N.; Makaravage, K. J.; Sanford, M. S.; Scott, P. J. H. Sci. Rep. 2017,
7, 233. (c) Mossine, A. V.; Brooks, A. F.; Bernard-Gauthier, V.;
Bailey, J.; Ichiishi, N.; Schirrmacher, R.; Sanford, M. S.; Scott, P. J.
H. J. Labelled Compd. Radiopharm. 2018, 61, 228. (d) Lee, S. J.;
Brooks, A. F.; Ichiishi, N.; Makaravage, K. J.; Mossine, A. V.;
Sanford, M. S.; Scott, P. J. H. Chem. Commun. 2019, 55, 2976.
(e) Lee, S. J.; Makaravage, K. J.; Brooks, A. F.; Scott, P. J. H.;
Sanford, M. S. Angew. Chem. Int. Ed. 2019, 58, 3119. (f) Verhoog,
S.; Brooks, A. F.; Winton, W. P.; Viglianti, B. L.; Sanford, M. S.;
Scott, P. J. H. Chem. Commun. 2019, 55, 6361.
Davies and Qin report the isolation of a single diastereomer with con-
figuration as shown above.7 Data are in agreement with the reported
data.
Radiochemistry
General Procedure for Vinylogous 18F-Fluorination
To a 4-mL vial were added AgOAc (1.6 mg, 10 mol, 1.0 equiv) and
imidazolium triflate (2.2 mg, 10 mol, 1.0 equiv), followed by anhy-
drous DCE (700 L) and HOAc solution [100 L of a stock solution in
DCE (18 L HOAc/1 mL DCE), 30 mol, 3 equiv) The solution was
briefly vortexed. The reaction vial was capped with a PTFE/Silicone
septum cap and a 100 L aliquot of [18F]AgF·K222·AgOTf complex in
DCE (typically 60–1000 Ci; see Supporting Information) was added
to the reaction vial by syringe. Finally the diazo compound (10 mol
in 100 L DCE) was added by syringe. The mixture was heated in an
aluminum block at 100 °C for 30 min with the exclusion of light.16 Af-
ter 30 min, the reaction was removed from the heat and allowed to
cool to r.t. before analysis by radioTLC and radioHPLC to confirm RCY
and identity, respectively.
(7) Qin, C.; Davies, H. M. L. Org. Lett. 2013, 15, 6152.
(8) Glasspoole, B. W.; Crudden, C. M. Nat. Chem. 2011, 3, 912.
(9) Gray, E. E.; Nielsen, M. K.; Choquette, K. A.; Kalow, J. A.; Graham,
T. J. A.; Doyle, A. G. J. Am. Chem. Soc. 2016, 138, 10802.
(10) (a) Hollingworth, C.; Hazari, A.; Hopkinson, M. N.; Tredwell, M.;
Benedetto, E.; Huiban, M.; Gee, A.; Brown, J. M.; Gouverneur, V.
Angew. Chem. Int. Ed. 2011, 50, 2613. (b) Topczewski, J. J.;
Tewson, T. J.; Nguyen, H. M. J. Am. Chem. Soc. 2011, 133, 19318.
(c) Benedetto,
E.;
Tredwell,
M.;
Hollingworth,
C.;
Khotavivattana, T.; Brown, J. M.; Gouverneur, V. Chem. Sci. 2013,
4, 89.
(11) Carbonnel, E.; Poisson, T.; Jubault, P.; Pannecoucke, X.; Besset, T.
Front. Chem. 2019, 7, 111; DOI: 10.3389/fchem.2019.00111.
(12) (a) Frost, A. B.; Brambilla, M.; Exner, R. M.; Tredwell, M. Angew.
Chem. Int. Ed. 2019, 58, 472. (b) Tredwell, M. Synlett 2019, 30,
1371.
(13) Radiochemical yields (RCY) are nonisolated and were calculated
by % integrated area of the 18F-labelled product versus [18F]fluo-
ride in a radio-TLC trace. Product identities were confirmed by
radio-HPLC.
(14) In addition to low RCYs, we were not able to synthesize refer-
ence standards to confirm the identity of [18F]7F and [18F]8F
because of stability issues, which is consistent with Davies’
results. For example, they reported an NMR yield for the OMe
product, but did not isolate it, suggesting that the compound is
unstable.7
Funding Information
We acknowledge U.S. Department of Energy/National Institute of Bio-
medical Imaging and Bioengineering (NIBIB) (DE-SC0012484 to
P.J.H.S.) and National Institutes of Health (R01EB021155 to M.S.S. and
P.J.H.S.) for financial support.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690012.
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References
(15) Winton, W.; Brooks, A. F.; Wong, K. K.; Scott, P. J. H.; Viglianti, B.
L. SynOpen 2019, 3, 55.
(16) Lights in the fume hood where the reactions occurred were
turned off as a general precaution. However, ambient laboratory
lighting was left on and we do not believe the chemistry is light
sensitive.
(1) For a general overview of PET, see: Ametamey, S. M.; Honer, M.;
Schubiger, P. A. Chem. Rev. 2008, 108, 1501.
(2) For an introduction to the use of PET in drug development, see:
Elsinga, P. H.; Waarde, A. V.; Paans, A. M. J.; Dierckx, R. A. J. O.
Trends on the Role of PET in Drug Development 2012.
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