Copper-Mediated Aminoquinoline-Directed Radiofluorination of Aromatic C?H Bonds with K18F

Article abstract of DOI:10.1002/anie.201812701

A Cu-mediated ortho-C?H radiofluorination of aromatic carboxylic acids that are protected as 8-aminoquinoline benzamides is described. The method uses K¹⁸F and is compatible with a wide range of functional groups. The reaction is showcased in t

Full text of DOI:10.1002/anie.201812701

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Accepted Article
Title: Cu-Mediated Aminoquinoline-Directed Radiofluorination of
Aromatic C–H Bonds with K¹⁸F
Authors: So Jeong Lee, Katarina J Makaravage, Allen F Brooks, Peter
Scott, and Melanie S Sanford
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812701
Angew. Chem. 10.1002/ange.201812701
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10.1002/anie.201812701
Angewandte Chemie International Edition
COMMUNICATION
Cu-Mediated Aminoquinoline-Directed Radiofluorination of
Aromatic C–H Bonds with K18F
So Jeong Lee,[a] Katarina J. Makaravage,[b] Allen F. Brooks,[a] Peter J. H. Scott,*[a] and Melanie S.
Sanford*[b]
Abstract: This communication describes a Cu-mediated ortho-C–H
radiofluorination of aromatic carboxylic acids that are protected as 8-
aminoquinoline benzamides. The method uses K18F and is compatible
with a wide range of functional groups. The reaction is showcased in
the high specific activity automated synthesis of the RARb2 agonist
[18F]AC261066.
demonstrated that 8-aminoquinoline directing groups enable Cu-
catalyzed ortho-C(sp2)–H activation/nucleophilic fluorination
reactions with AgF.12 The directing group is easily cleaved, thus
providing access to ortho-fluorinated carboxylic acids. This
communication describes translation of this method to
a
radiofluorination process. While AgF was required in Daugulis’
original transformation, our studies reveal that K18F is optimal for
radiofluorination. This nucleophilic radiofluorination of aromatic
C–H bonds is applied to a variety of carboxylic acid derivatives
and automated to access high specific activity radiotracers.
Aryl fluorides are widely prevalent in pharmaceuticals,1,2
and their 18F isotopologs are important for positron emission
tomography (PET) imaging.3,4 As such, there is significant interest
in methods for the late-stage 18F-fluorination of aromatic
scaffolds.5,6 The majority of existing methods for arene
radiofluorination require a prefunctionalized starting material. For
instance, hypervalent iodine reagents,6c organoborons,6d-f,j,k
organostannanes,6g Ni/Pd complexes,6a,b and phenols6h,i have
recently been introduced as precursors for nucleophilic
radiofluorination reactions. However, this requirement for pre-
installed functionality at the target site can be a roadblock for the
application of these methods to complex radiotracer targets.
Table 1. Optimization of C-H Radiofluorinationa
[Cu]
M18F/K2.2.2
additive (NMO and/or DBU)
N
N
HN
O
HN
18F
(118F)
O
DMF, 100 ºC, 30 min
H
(1H)
Me
Me
Entry
[Cu]
CuI
CuI
M18
F
NMO
✓
DBU
RCC (%)b
nd
A
complementary approach would involve the direct
radiofluorination of a C–H bond of an arene substrate. Several
strategies have been developed for the radiofluorination of
aliphatic7 and benzylic8 C–H bonds. However, analogous
transformations of C(sp2)–H substrates have proven considerably
more challenging. While C(sp2)–H radiofluorination can be
accomplished via electrophilic aromatic substitution (SEAr) with
[18F]F2 or [18F]Selectfluor,9 the generation and handling of these
reagents requires specialized equipment that is not widely
accessible. Additionally, the site- and chemoselectivities of SEAr
reactions are typically modest, and the final products generally
have low specific activity.10 In principle, these limitations could be
addressed through the development of nucleophilic (18F–) C(sp2)–
H radiofluorination methods. However, in practice, realization of
this approach has remained elusive due to the inertness of
C(sp2)–H bonds and the electronic mismatch between
nucleophilic 18F– and most arene substrates.11
1
2
Ag18
Ag18
Ag18
F
F
F
--
26 ± 1
29 ± 0
33 ± 0
31 ± 13
50 ± 2
✓
✓
3
(MeCN)4CuOTf
(MeCN)4CuOTf
(MeCN)4CuOTf
(MeCN)4CuOTf
✓
✓
--
--
✓
✓
✓
✓
4
K18
K18
K18
F
5
F
6c
F
[a] Conditions: 1H (20 µmol), Cu source (5 µmol), additives [NMO (90
µmol), K2.2.2 (1.33 µmol), DBU (20 µmol)], M18F (2500-3500 µCi), DMF (1000
µL). [b] RCC was determined by radio-TLC (n ≥ 3); nd = not detected. The
identity of 118F was confirmed by radio-HPLC. [c] NMM added (90 µmol).
We initially examined the Cu-catalyzed radiofluorination of
aminoquinoline substrate 1H with Ag18F13 under conditions
closely analogous to those reported by Daugulis12 (1H (20 µmol),
CuI (5 µmol), N-methylmorpholine N-oxide (NMO, 90 µmol), K2.2.2
(1.33 µmol), Ag18F (2500-3500 µCi) in DMF). However, these
conditions did not afford detectable quantities of 118F as
determined by radio-TLC and radio-HPLC analysis (Table 1, entry
1). Notably, the Ag19F likely serves two roles in the original
Daugulis reaction. First, it acts as the nucleophile to install the
C(sp2)–F bond. Second, it serves as a base to sequester the
proton that is generated during C–H activation. Since Ag19F is
present in 3-4-fold excess relative to 1H, there is sufficient fluoride
available for both of these functions. In contrast, under the
radiofluorination conditions, the Ag18F is the limiting reagent. We
hypothesized that an exogeneous base might be needed to
sequester protons while preserving a reservoir of nucleophilic
fluoride for the desired C(sp2)–F coupling reaction. Consistent
An attractive strategy to address these challenges would be
to leverage modern advances in transition-metal catalyzed
C(sp2)–H functionalization. For example, recent work by Daugulis
[a]
[b]
Dr. S. J. Lee, Dr. A. F. Brooks, Prof. P. J. H. Scott
Department of Radiology
University of Michigan
1301 Catherine St, Ann Arbor, MI 48109, USA
E-mail: pjhscott@umich.edu
Ms. K. J. Makaravage, Prof. M. S. Sanford
Department of Chemistry
The University of Michigan
930 North University Ave, Ann Arbor, MI 48109, USA
Email: mssanfor@umich.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201812701
Angewandte Chemie International Edition
COMMUNICATION
Quin =
N
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
Quin
HN
O
O
O
O
O
O
O
O
O
O
O
18F
18F
18F
18F
18F
18F
18F
18F
18F
18F
Me
F
CF3
18F
CF3
OMe
(1118F)
10 ± 1% (n = 5)
Me
(118F)
Me
(318F)
F
CN
(518F)
NO2
(618F)
CO2Me
(718F)
CF3
(818F)
(218F)
(418F)
(918F)
35 ± 3% (n = 4)
(1018F)
41 ± 2% (n = 4)a
50 ± 2% (n = 5) 16 ± 2% (n = 5) 15 ± 1% (n = 5)a 62 ± 0% (n = 5)a 41 ± 5% (n = 4) 24 ± 1% (n = 4)a 29 ± 1% (n = 5)a 60 ± 4% (n = 5)
18F
O
18F
Quin
Quin
O
18F
O
Quin
O
HN
18F
Me
O
Quin
HN
O
18F
N
H
N
H
Quin
Me
F
N
O
H
18F
N
HN
F
H
O
N
N
18F
O
Quin
nPr
S
NH
N
S
N
N
N
O
O
O
N
BuO
nPr
Me
(1318F)
(1218F)
22 ± 2% (n = 5) 16 ± 1% (n = 5)
(1418F)
50 ± 1% (n = 5)
(1518F)
20 ± 2% (n = 5)a
(1618F)
13 ± 3% (n = 5)
(1718F)
22 ± 2% (n = 5)
(1818F)
37 ± 2% (n = 7)
Figure 1. Substrate Scope. Reported values indicate radiochemical conversion (RCC) determined by radio-TLC for n ≥ 4 runs. The identity of all products was
confirmed by radio-HPLC. General conditions: Substrate (20 µmol), (MeCN)4Cu(OTf) (5 µmol), NMM (90 µmol), K2.2.2 (1.33 µmol), DBU (20 µmol), K18F (2500-3500
µCi), DMF (1000 µL), 90-110 oC, 30 min. [a] in cases where other products were observed by radio-HPLC analysis, RCCs from radio-TLC analysis were corrected
as described in the Supporting Information.17
18F
18F
H
O
(MeCN)4Cu(OTf)
O
O
NMM, DBU, [18F]KF
Quin
4M NaOH
Quin
N
N
OH
H
DMF, 100 ºC, 30 min
100 ºC, 30 min
H
Me
Me
Me
(1H)
(118F)
(1918F)
Automated RCC: 28 ± 6% (n = 6)
Automated RCY: 9 ± 4% (n = 6)
>98% RCP, 6 ± 1 Ci/µmol SA
Automated RCC from 118F: 90 ± 2% (n = 3)
Overall automated RCC from [18F]F–: 21 ± 2% (n = 3)
18F
18F
H
O
O
O
Quin
Quin
N
N
OH
(MeCN)4Cu(OTf)
H
H
N
NMM, DBU, [18F]KF
N
N
4M NaOH
100 ºC, 30 min
O
O
O
DMF, 100 ºC, 30 min
S
S
S
BuO
BuO
BuO
Me
Me
(1818F)
Me
(18H)
(2018F)
Automated RCC: 12 ± 2% (n = 3)
Automated RCY: 3 ± 1% (n = 3)
Automated RCC from 1818F: 98 ± 1% RCC (n = 5)
Automated RCY from [18F]F–: 2 ± 1% ( n = 3)
>98% RCP, 0.80 ± 0.25 Ci/µmol SA
Scheme 1. Automated C(sp2)-H Radiofluorination
with
this
hypothesis,
the
addition
of
1,8-
methylmorpholine (NMM), the base counterpart of NMO,
resulted in enhanced reproducibility as well as an improved
RCC of 50 ± 2% (Table 1, entry 6).
diazabicyclo(5.4.0)undec-7-ene (DBU) (20 µmol, 1 equiv
relative to 1H) led to the formation of the desired product 118F
in 26 ± 1% RCC as determined by radio-TLC and confirmed by
radio-HPLC (Table 1, entry 2).14 Further optimization revealed
that switching from CuI to more soluble (MeCN)4CuOTf
resulted in a slightly improved RCC (29 ± 0%; Table 1, entry
3). Under these conditions, the [18F]fluoride source could be
changed to readily accessible K18F3 to afford 33 ± 0% RCC of
118F (Table 1, entry 4).
We next examined whether NMO is necessary for this
transformation. In the Ag19F reaction (which is conducted
under inert atmosphere), NMO acts as the terminal oxidant for
Cu. However, the radiochemical reactions are conducted
under ambient air, which could directly oxidize the Cu. Indeed,
excluding NMO from the Ag18F reaction under otherwise
identical conditions resulted in a comparable RCC (31 ± 13%,
entry 5),15 although it did negatively impact the run-to-run
reproducibility. We evaluated a number of additives to address
this latter issue and found that the use of 90 µmol of N-
The scope of this reaction was examined using
aminoquinolines derived from a variety of substituted benzoic
acids.16 As shown in Figure 1, electron-neutral (118F-418F), -
withdrawing (518F-1018F),17 and -donating (1118F) substituents
were tolerated on the arene ring. Many functional groups,
including benzylic C–H bonds, trifluoromethyl, cyano, nitro,
ester, amide, and sulfonamide substituents, were compatible.
This C(sp2)–H radiofluorination was also effective on pyridine-
and indole-derived substrates, providing 1218F and 1318F in
moderate RCC. A substrate containing a fluorine substituent at
the activated 4-position on the quinoline reacted to afford the
ortho-18F-labelled product 1418F in 50% RCC.18 This method
was applied to the late-stage radiofluorination of a series of
biologically relevant molecules. Four carboxylic acid-
containing drugs, probenecid, ataluren, tamibarotene, and
AC261066, were converted to the corresponding 8-
aminoquinoline benzamides and then subjected to the optimal
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10.1002/anie.201812701
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COMMUNICATION
conditions. The [18F]fluorinated analogues (1518F-1818F,
respectively) were obtained in 13-37% RCC.19
Keywords: C-H functionalization • PET radiochemistry •
Fluorine-18 • Late-stage Fluorination • C-H Fluorination
A final set of experiments involved automation of this
reaction on a TRACERLab FXFN synthesis module and
hydrolysis of the aminoquinoline protecting group (Scheme 1).
Initial automated studies were conducted with 1H, and afforded
118F in 28 ± 6% (n = 6) automated RCC or, by incorporating
semi-preparative HPLC purification, 9 ± 4% (n = 6) isolated
decay-corrected radiochemical yield (RCY) and >98%
radiochemical purity (RCP). Starting with 1.7 Ci of [18F]fluoride
118F was obtained in 42 ± 3 mCi (n = 3) with high specific
activity (6 ± 1 Ci/µmol). Hydrolysis of the aminoquinoline
protecting group was then achieved with 4 M NaOH to afford
1918F in 90 ± 2% RCC from 118F (n = 3) and 21 ± 2% RCC
based upon starting [18F]fluoride.
An analogous method was applied to the synthesis of
[18F]AC261066 (2018F), a RARb2 agonist (Scheme 1).20
Subjecting 18H to the C–H radiofluorination conditions
afforded 1818F in 12 ± 2% automated RCC (n = 3). Starting
with 1.7 Ci of [18F]fluoride, 1818F was obtained in 36 ± 8 mCi (n
= 3) after sep-pak purification, corresponding to 3 ± 1%
isolated decay-corrected RCY. Manual hydrolysis of the amide
with 4 M NaOH formed [18F]AC261066 (2018F) in 98 ± 1% RCC
from 1818F (n = 5, determined by radio-TLC). Overall, the
isolated decay-corrected RCY of 2018F was 9 ± 7 mCi (2 ± 1%
based upon starting [18F]fluoride, n = 3). The product was
obtained in high chemical and radiochemical (>98%) purity and
high specific activity (0.80 ± 0.25 Ci/µmol).21
In summary, we describe the Cu-catalyzed,
aminoquinoline-directed C(sp2)–H radiofluorination of arene
C(sp2)–H bonds with K18F.22 The method has been applied to
a variety of substrates, including the active pharmaceutical
ingredients of probenecid, ataluren, and tamibarotene. In
addition, it has been translated to an automated synthesis of
high specific activity doses of RARb2 agonist [18F]AC261066.
We note that the automated radiochemical yields and directing
group cleavage procedures will require additional optimization
before they can be applied in routine radiosyntheses. In
addition, future work should target the use of more practical
directing groups as well as non-directed approaches to C–H
radiofluorination. However, overall this operationally simple
procedure demonstrates proof-of-concept that metal-catalyzed
nucleophilic C(sp2)–H radiofluorination is feasible, and that this
approach shows promise for the late-stage radiofluorination of
bioactive molecules.
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Experimental Section
Detailed experimental details are provided in the supporting information.
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Acknowledgements
[14] Other bases were also compatible (e.g. comparable RCCs could be
obtained using 1,5-diazabicyclo[4.3.0]non-5-ene; see Supporting
Information).
This work was supported by NIH (R01EB021155) and DOE
(DE-SC0012484).
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[15] When Table 1, entry 5 was set up in a glovebox and kept under an
inert atmosphere the RCC dropped prohibitively (to 6 ± 4%), further
consistent with the role of air as the oxidant.
amide groups). Small impurity peaks were detected in the crude
radio-HPLC traces of these products; however, 1518F-1818F were the
major products in each case, and they appear to be readily separable
from the side products formed in the reaction.
[16] Product identities were confirmed by radio-HPLC. To further confirm
that radiofluorination occurred at the expected ortho-site (rather than
on the quinoline ring) we conducted control experiments and
demonstrated baseline separation of regioisomeric products by
HPLC (see Supporting Information).
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[21] These unoptimized automation results demonstrate that this method
can be used to prepare sufficient amounts of radiotracers for pre-
clinical evaluation in rodents and non-human primates. We expect
that yields can be further improved through careful optimization of the
automated method. This work is currently underway, along with
qualification of a synthesis and formulation of 2018F for preclinical use.
[22] Radioiodination of this scaffold has been reported. See: L. W. Deady,
J. Desneves, L. M. A. Tilley, J. Labelled Compd. Radiopharm., 2000,
43, 977.
[17] Some arenes bearing electron-withdrawing substituents give rise to
minor side products. We ruled out the formation of side products
derived from competing SNAr reactions (see Supporting Information),
but have not been able to positively identity the side products to date.
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[19] Products 15–18 contain functional groups that could potentially direct
C-H fluorination elsewhere in the molecule (e.g. 17H contains 2
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Entry for the Table of Contents
COMMUNICATION
Author(s), Corresponding Author(s)*
18F
O
Page No. – Page No.
20 mol % [Cu]
OH
NMM, DBU
N
N
K2.2.2, M18
F
Title
N
HN
O
HN
O
O
DMF, 90-110 ºC, 30 min
S
18F
H
BuO
18F]AC261066
Me
[
R
R
This communication reports a method for the Cu-mediated
ortho-C(sp2)-H radiofluorination of aromatic carboxylic acids
that are protected as 8-aminoquinoline benzamides with K18F.
Fluorination of 18 examples in up to 62% RCC and high specific
activity is reported, including the automated synthesis of
[18F]AC261066 (after removal of 8-aminoquinoline auxiliary).
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