NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides

Article abstract of DOI:10.1021/jacs.0c02637

[18F]-labeled aryl fluorides are widely used as radiotracers for positron emission tomography (PET) imaging. Aryl halides (ArX) are particularly attractive precursors to these radiotracers, as they are readily available, inexpensive, and stable. However, to date, the direct preparation of [18F]-aryl fluorides from aryl halides remains limited to SNAr reactions between highly activated ArX substrates and K18F. This report describes an aryl halide radiofluorination reaction in which the C(sp2)-18F bond is formed via a copper-mediated pathway. Copper N-heterocyclic carbene complexes serve as mediators for this transformation, using aryl halide substrates with directing groups at the ortho position. This reaction is applied to the radiofluorination of electronically diverse aryl halide derivatives, including the bioactive molecules vismodegib and PH089.

Full text of DOI:10.1021/jacs.0c02637

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Communication
NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides
Liam S. Sharninghausen, Allen F Brooks, Wade Winton, Katarina
J Makaravage, Peter J. H. Scott, and Melanie S. Sanford
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02637 • Publication Date (Web): 06 Apr 2020
Downloaded from pubs.acs.org on April 6, 2020
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NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl
Halides
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†
‡
‡
†
‡
Liam S. Sharninghausen, Allen F. Brooks, Wade Winton, Katarina J. Makaravage, Peter J. H. Scott*
†
and Melanie S. Sanford*
†
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United
States
‡
Department of Radiology, University of Michigan, 1301 Catherine, Ann Arbor, Michigan 48109, United States
Supporting Information Placeholder
1
8
fluorination of (hetero)aryl–halides and pseudohal-
ides.
ABSTRACT: [ F]-labeled aryl fluorides are widely used
as radiotracers for positron emission tomography (PET)
imaging. Aryl halides (ArX) are particularly attractive
precursors to these radiotracers, as they are readily
available, inexpensive, and stable. However, to date, the
8
,9
Scheme 1. Strategies for direct fluorination of aryl hal-
ides.
1
8
direct preparation of [ F]-aryl fluorides from aryl hal-
ides remains limited to S Ar reactions between highly
activated ArX substrates and K F. This report describes
an aryl halide radiofluorination reaction in which the
C(sp )– F bond is formed via a copper-mediated path-
way. Copper N-heterocyclic carbene complexes serve as
mediators for this transformation, using aryl halide sub-
strates with directing groups at the ortho position. This
reaction is applied to the radiofluorination of electroni-
cally diverse aryl halide derivatives, including the bioac-
tive molecules vismodegib and PH-089.
N
1
8
A. Radiofluorination of ArX via S
Ar pathway (ref. 3)
N
18F • modest yields
X
K18
F
•
limited to highly electron deficient ArX
Ar
Ar
2
18
• requires forcing conditions
B. Liu’s directed 19F-fluorination of ArBr via organometallic pathway (ref. 16)
Cu(CH CN) PF
6
3
4
N
equiv Ag19
N
• requires xs AgF
2
F
• scope limited to 2-arylpyridines
NBu PF
19F • not translatable to radiofluorination
Br
4
6
1
20 ºC, 8 h
Ar
Ar
C. Directed radiofluorination of ArX via organometallic pathway (this work)
N
N
N
N
DG
DG
R
R
R
R
+
K18
F
18F
X
Cu
OTf
Cu
18F
Late-stage methods for constructing 18F–(hetero)aryl
30 min
140 ºC
bonds are highly valued for the synthesis of positron
Our approach to this challenge has focused on devel-
oping Cu-mediated methods for C(sp )– F coupling re-
1
,2
emission tomography (PET) radiotracers. Historically,
2
18
1
8F-labeled aromatic substrates have most commonly
1,2b
actions.
such as Cu(OTf)
ophilic radiofluorination of aryl stannane, aryl boron,
Recent studies have shown that Cu salts
been prepared via S
ficient aryl halide precursors and K F (Scheme 1A).
N
Ar reactions between electron de-
2
and Cu(CH CN) PF mediate the nucle-
3
4
6
1
8
3,4
10
13
11
Aryl halides are particularly attractive radiofluorination
precursors because they are abundant, stable, and syn-
thetically accessible. However, the substrate scope of
12
18
diaryliodonium, and aryl C–H substrates with K F. In
these systems the key C(sp )– F bond is formed via re-
2
18
18
ductive elimination from an organometallic Cu(aryl)( F-
S
N
Ar (radio)fluorination reactions remains narrow, as
11f,14
fluoride) intermediate.
This organometallic pathway
Ar reaction. As
resonance electron withdrawing substituents on the
aromatic ring are required to stabilize Meisenheimer-
type intermediates.1 Furthermore, even with such
is mechanistically distinct from an S
N
such, it enables the radiofluorination of a wide scope of
electronically diverse aryl groups.
,5
N
highly activated substrates, S Ar pathways often require
long reaction times and forcing conditions, which ren-
ders them ill-suited for many late-stage radiofluorina-
tion applications.6,7 As such, a key objective for the field
Despite this progress, analogous Cu mediators have
proven ineffective at engaging aryl halide substrates in
radiofluorination reactions. Two reports have docu-
1
9
mented the Cu-promoted nucleophilic F-fluorination
is to develop complementary methods for the radio-
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24
19
of aryl halides (e.g., the work of Liu in Scheme 1B).
Cu (CH
3
CN)
4
PF
6
/KF, CuF
2
, or AgF afforded ≤3% of 1- F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
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1
1
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2
2
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
However, both require superstoichiometric AgF as the
under otherwise identical conditions (Table S4). Fur-
thermore, no reaction was observed between the aryl
bromide substrate and K F under these conditions in
15,16
fluoride source,
and neither has proven translatable
to radiolabeling with 18F– (vide infra). This report de-
scribes the use of N-heterocyclic carbene (NHC) Cu
complexes as mediators for ligand-directed aryl halide
radiofluorination (Scheme 1C). The discovery of this
19
the absence of copper.
19
A time study with A- F shows that the fluorination
reaction is complete within 2 h at 140 °C and affords
40% yield after just 30 min (Scheme 2B). This suggests
the feasibility of achieving radiofluorination with this
system. Finally, a preliminary survey of substrates re-
1
9
transformation in the context of F-fluorination and its
subsequent translation to radiofluorination are de-
scribed in detail.
0
1
2
3
4
5
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0
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0
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0
Our initial studies attempted to translate Liu’s 19F-
fluorination of 2-(2-bromophenyl)pyridine (Scheme 1B)
to a radiolabeling protocol. However, as shown in eq. 1,
vealed that A- F-mediated fluorination has a signifi-
19
cantly enhanced scope versus that of Liu’s
I
19
3 4 6
Cu (CH CN) PF /Ag F system (Scheme 1B). For instance,
I
under the standard conditions (with Cu (CH
3
CN)
4
PF
6
,
the sterically hindered pyridine substrate 2-(2-
(bromo)phenyl)-6-methylpyridine was unreactive under
1
8
4 6 3
Ag F, and NBu PF in CH CN at 120 °C), no trace of
1
8
19
19
product 1- F was detected by radio-TLC or radio-HPLC
after 0.5 h. Furthermore, no improvement was ob-
served upon variation of the 18F source, solvent, addi-
tives, or temperature (Table S7). We note that, in con-
trast to the F-fluorination, the radiofluorination reac-
tion requires the use of Ag F as the limiting reagent at
Liu’s conditions, but affords 2- F in 34% yield with A- F
as the Cu mediator (Scheme 2C). Similarly, the oxazoline
and imine substrates were unreactive under Liu’s condi-
1
9
19
tions, but afford 30% and 37% yield of 3- F and 4- F,
respectively, using A- F.
1
9
19 25
1
8
Scheme 2. NHC-Cu-mediated 19F-fluorination of aryl
bromides
sub-micromolar concentrations. We hypothesize that
I
this renders Cu (CH
3
CN)
4
PF
6
-mediated radiofluorination
A. Synthesis and reactivity of A-19
F
prohibitively slow relative to the decay of the radionu-
clide (t1/2 ~110 min).
N
Br
N
N
N
N
Cu(CH CN) PF
R
R
R
R
N
3
4
6
K19
F
N
Ag18
F
N
Cu
Cu
19
F
not detected (1)
DMF, 30 min
140 ºC
DMF, 140 ºC
18F
1-18F)
Br
NBu PF6
4
OTf
19F
1
20 ºC, 30 min
(
i
i
R = 2,6-PrC H
R = 2,6-PrC H
6
3
6
3
1-19F)
(
(
A-OTf)
(A-19F)
Literature reports suggest that aryl-bromide bond
I
activation (via oxidative addition at Cu ) is likely the slow
B. Time study for A-19F-mediated fluorination
16,17
step in this transformation.
We reasoned that the
introduction of a strongly electron donating NHC ligand
I
18,19
at the Cu center would accelerate this key step.
Fur-
I
thermore, since (NHC)Cu (F) complexes can be generat-
ed directly from KF, this approach should eliminate the
requirement for excess AgF. Finally, sterically bulky NHC
ligands are known to stabilize Cu –fluoride complexes to
dimerization or disproportionation,1
2
0
I
9,21
which are likely
competing decomposition pathways for the Cu media-
2
2
tor.
C. Unoptimized yields of 19F fluorinated products with A-19F (after 21 h)
To test this hypothesis, we initially examined the reac-
I 19
tivity of a series of (NHC)Cu ( F) complexes with 2-(2-
Cy
bromophenyl)pyridine (Scheme 2A). As summarized in
O
N
N
N
H
N
1
9
Table S3, the yield of fluorinated product 1- F varied
19F
19F
19F
19F
from 3–65% as a function of the structure of the NHC
1
9,23
ligand,
with 1,3-bis-(2,6-diisopropylphenyl)imidazol-
1-19F)
5%
(2-19F)
(3-19F)
(4-19F)
(
2
-ylidine (IPr) affording the optimal result. Notably,
6
34%
30%
37%
I 19
19
(IPr)Cu ( F) (A- F) is available in nearly quantitative
I
19
(A) Conditions: A-OTf (0.006 mmol, 1 equiv), KF (1.5
equiv), DMF (0.01 M), 140 °C for 30 min, then aryl bro-
mide (0.006 mmol), 140 °C for 21 h. (B) Conditions: A-
yield from the reaction of (IPr)Cu (OTf) (A-OTf) with K F
2
0
(Scheme 2A), thus precluding the requirement for Ag
salts in this transformation. Importantly, control studies
revealed that other group 11 metal salts including
1
9
F (0.01 mmol, 1 equiv), aryl bromide (1 equiv), DMF
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9
(
0.015 M), 140 °C for 21 h. (C) Conditions: A- F (0.006
terns on the (hetero)arene ring were well tolerated,
affording compounds 10–16- F in RCCs ranging from
16–74%. An intramolecular competition reaction be-
1
2
3
4
5
6
7
8
9
18
mmol, 1 equiv), aryl bromide (1 equiv), DMF (0.01 M),
40 °C for 21 h. Yields determined by F NMR spectro-
19
1
scopic analysis of crude reaction mixtures.
tween an ortho-chloride and bromide resulted in selec-
tive radiofluorination of the bromide to form 13- F.
1
8
We next focused on translating these preliminary
results to radiofluorination. The reaction of (IPr)Cu (OTf)
I
This selectivity is consistent with that expected for a
2
29
1
8
metal-mediated activation of a C(sp )–X bond.
(A-OTf) with 2-(2-bromophenyl)pyridine and K F for 30
1
8
min at 140 °C in DMF afforded 1- F in 10% radiochemi-
Importantly, a variety of control reactions were con-
ducted in these systems. First, the 4-substituted aryl
bromides in the pyridine and cyclohexyl imine series
were subjected to the reaction conditions. These are
electronically similar, but do not benefit from the direct-
ing effect. As shown in Figure 1, these substrates did not
cal conversion (RCC) as determined by radio-TLC and
radio-HPLC (Table 1, entry 1).2
6,27
The reaction was op-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
timized by exploring additives that have been shown to
enhance yields in other Cu-mediated C(sp )– F cou-
2
18
pling reactions (e.g., phase transfer reagents, nitrogen
1,11a,13,28
18
18
heterocycles, Table 1, entries 2–5).
Of the sur-
afford detectable 17- F or 18- F under the optimized
3
0
veyed additives, 1 equiv of 4-dimethylaminopyridine
DMAP) relative to the aryl bromide precursor proved
conditions. In addition, all of these reactions were
conducted in the absence of Cu to test for background
(
1
8
optimal, affording 1- F in 65% RCC.
N
S Ar reactivity. As shown in Table S12, ≤1% of com-
1
8
pounds 1–16- F were detected under these conditions.
Table 1. Cu-mediated radiofluorination of aryl halides.
I
II
Finally, substituting simple Cu or Cu salts for
K18
F
I
N
N
Ar
Ar
(IPr)Cu (OTf) afforded yields of ≤5% for representative
additive (1 equiv)
N
N
+
Cu
OTf
(A-OTf)
DMF
40 ºC, 30 min
substrates (Table S11), underscoring the central role of
the NHC ligand in these transformations.
18F
Br
1
Figure 1. Substrate scope of Cu-mediated radiofluorina-
tion of aryl halides.
entry
Additive
none
RCC (%)
1
2
3
4
5
10
26
23
30
65
Kryptofix
pyridine
DBU
DMAP
Conditions: aryl bromide (0.005 mmol, 1 equiv), A-OTf
18
(
1 equiv), additive (1 equiv), K F, DMF (0.015 M), N
2
27
atmosphere, 140 °C, 30 min. RCC determined by radio-
TLC (n ≥ 2).
With these optimized conditions in hand, we next
explored the scope of the A-OTf-mediated radiofluori-
nation of aryl halides. As shown in Figure 1, the chloro-,
bromo-, and iodo-2-phenylpyridine precursors all react-
1
8
ed to afford 1- F in RCCs ranging from 10–65%. In con-
1
9
18
19
trast, no F/ F exchange was detected with 1- F under
these conditions. It is currently unclear why 1-I affords
lower yield than 1-Br; however, this observation is in
19
line with Liu’s results for the Cu-catalyzed [ F]-
16
fluorination of halophenylpyridines. Substitution on
either the pyridine or aryl ring was tolerated to afford
1
8
18
18
products such as 2- F, 6- F, and 7- F. Other nitrogen-
donors, including oxazoline, pyrazole, cyclohexyl imine,
and mesityl imine, served as effective directing groups,
1
8
18
18
18
affording 3- F, 8- F, 4- F, and 9- F, respectively. The
scope of cyclohexyl imine derivatives was most thor-
oughly explored, as this directing group is straightfor-
ward to install and remove starting from readily availa-
ble benzyaldehyde derivatives. Various substitution pat-
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DG
DG
N
N
DMAP, K18
DMF
Ar
Ar
F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
18F
N
X
+
Cu
Cu complex A-OTf
N
18F
DMAP, K18
F
1
40 ºC, 30 min
OTf
Cl
O
Br
i
X = Cl, Br, I
DMF
40 ºC, 30 min
Ar = 2,6-PrC6H3
Cl
O
N
H
1
O
N
H
O S
O
(19-18F)
N
N
N
N
O
S
vismodegib analogue
basal cell carcinoma treatment)
9±1% (n=4)
18F
18F
18F
18F
F
(
(
1-18F)
(2-18F)
(6-18F)
(7-18F)
MeO
O
O
X = Br: 65 ± 7% (n=18)
X = I: 30 ± 8% (n=3) X = Br: 84 ± 2%
X = Cl: 10 ± 2% (n=3)
X = F: 0% (n=1)
HN
HN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
X = Br: 38 ± 2%
X = Br: 30 ± 8%
(n=3)
Cu complex A-OTf
a
DMAP, K18
(n=3)
(n=4)
F
N
H
N
H
DMF
60 ºC, 30 min
N
N
1
Cy
N
Mes
Cl
18F
O
N
N
H
H
N
N
18F
18F
18F
(4-18F)
18F
(9-18F)
(20-18
F)
3-18F)
(8-18F)
(
18F- PH-089 (MK-2 inhibitor)
X=Cl: 5±1% (n=3)
X = Br: 53 ± 10% (n=8)
X = I: 57 ± 8% (n=4)
X = Cl: 6 ±2% (n=3)a
X = F: 0% (n=1)
Cy
X = Br: 54 ± 6%
n=3)
X = Br: 11 ± 4%
(n=3)
X = Br: 36 ± 8%
(n=5)
(
A final set of studies focused on automating the radi-
osynthesis of 1- F using a TRACERLab FXFN synthesis
module. Initial automated studies using 241.1 mCi (8.93
Cy
Cy
Cy
18
H
N
H
N
H
N
H
N
18F
18F
18F
18F
(13-18F)
Cl
9
18
(12-18F)
OMe
X = Br: 32 ± 3% X = Br: 50 ± 4%
x 10 Bq) of K F gave 57 ± 8 % radiochemical yield (RCY;
n = 2), demonstrating the compatibility of the method
with automation. Further investigations coupled auto-
mated synthesis with semi-preparative HPLC purifica-
tion to afford 1- F in 14.3 ± 3.2% RCY (decay-corrected;
119.9 mCi ± 28; n = 2) with good molar activity (1614 ±
353 Ci/mmol; n = 2) and radiochemical purity. While
unoptimized, this result demonstrates the potential of
this method for PET applications.
(
(11-18F)
F
10-18F) MeO
X = Br: 28 ± 9%
X = Br: 74 ± 3%
(n=3)
(
n=4)
(n=3)
(n=4)
Cy
N
Cy
N
Cy
N
1
8
H
H
H
18F
18F
18F
O
(14-18F)
N
(15-18F)
(16-18F)
S
Pr2N
Br
O
X = Br: 33 ± 8%
(n=3)
X = Br: 16 ± 7%
(n=8)
X = Br: 49 ± 9%
(n=3)
In conclusion, we have developed a Cu-mediated pro-
Cy
N
19
18
tocol for the F- and F-fluorination of diverse aryl hal-
ide substrates. Strategic design of the Cu mediator was
necessary to achieve the reaction rates/yields required
for efficient radiofluorination, and an NHC-ligated Cu
complex ultimately proved optimal in this system. A
wide scope of nitrogen-containing directing groups and
N
H
17-18F)
(18-18F)
(
18F
18F
X = Br: 0%
n=1)
X = Br: 0%
(n=2)
(
1
8
control substrates
substituted aryl halide derivatives underwent F-
fluorination, and the reaction proved effective for the
synthesis of biologically relevant molecules such as 19-
Conditions: aryl halide (0.005 mmol, 1 equiv), A-OTf (1
equiv), DMAP (1 equiv), K F, DMF (0.015 M), N atmos-
2
phere, 140 °C for 30 min. RCC determined by radio-
1
8
18
18
F and 20- F. More broadly, this work demonstrates
2
7
2
that NHC-type ligands enable new C(sp )–F coupling
reactions at Cu. As such, this work opens up opportuni-
ties for designing next-generation Cu mediators for the
radiofluorination of currently inert substrates (e.g., aryl
halides that lack a directing group).
a
TLC (n ≥ 3). Reaction conducted at 160 °C.
18F-analogues of several bioactive molecules could
also be accessed using this approach. In a first example,
the bromide analogue of vismodegib (19-Br), a basal
cell carcinoma treatment, underwent radiofluorina-
tion to afford 19- F (Scheme 3). In a second example,
F-labeled PH-089 (20- F in Scheme 3), an MK-2 inhib-
itor, was synthesized in 5% RCC from the chloride pre-
cursor.
31
1
8
ASSOCIATED CONTENT. Supporting Information. A list-
ing of the contents of each file supplied as Supporting
Information should be included.
1
8
18
3
2
Scheme 3. Radiofluorination of bioactive molecules.
AUTHOR INFORMATION
Corresponding Author
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*
*
Peter J. H. Scott. E-mail: pjhscott@umich.edu.
Melanie S. Sanford. e-mail: mssanfor@umich.edu.
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ACKNOWLEDGMENT
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(
a) Terrier, F. Modern Nucleophilic Aromatic Substitution; Wiley-
This work was supported by the NIH [award number
F32GM136022 (LSS) and award number R01EB021155
(MSS and PJHS)]. We acknowledge Dr. Devin M. Fergu-
son, Isaac M. Blythe, Dr. Yiyang See, Dr. Sean M.
Preshlock, Dr. Jay S. Wright and Pronay Roy for helpful
discussions. We also acknowledge Dr. Rachel S. Plumb
for assistance with data processing.
VCH, Weinheim, 2013, p. 236-268. (b) Cole, E. L.; Stewart, M. N.;
Littich, R.; Hoareau, R.; Scott, P. J. H. Radiosyntheses using Fluorine-
1
8: the Art and Science of Late Stage Fluorination. Curr. Top. Med.
Chem. 2014, 14, 875–900. (c) Jacobson, O.; Kiesewetter, D. O.;
Chen, X. Fluorine-18 Radiochemistry, Labeling Strategies and Syn-
thetic Routes.ꢀBioconjugate Chem. 2015, 26, 1−18.
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In many cases, radiofluorination of simple building blocks followed
by subsequent synthetic steps is required. See: (a) Krüll, J.; Heinrich,
18
M. R. [ F]Fluorine-Labeled Pharmaceuticals: Direct Aromatic Fluori-
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