Cu-Mediated C-H 18F-Fluorination of Electron-Rich (Hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.7b01902

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp²)-H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt

Full text of DOI:10.1021/acs.orglett.7b01902

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Letter
pubs.acs.org/OrgLett
18
Cu-Mediated C−H F‑Fluorination of Electron-Rich (Hetero)arenes
Matthew S. McCammant,† Stephen Thompson,‡ Allen F. Brooks,‡ Shane W. Krska,§
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
§Chemistry Capabilities and Screening, Merck Sharp & Dohme, Kenilworth, New Jersey 07033, United States
S
* Supporting Information
ABSTRACT: This communication describes a method for
the nucleophilic radiofluorination of electron-rich arenes. The
reaction involves the initial C(sp2)−H functionalization of an
electron-rich arene with MesI(OH)OTs to form a (mesityl)-
(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated
radiofluorination with [18F]KF. This approach leverages the
stability and availability of electron-rich arene starting materials
to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination
has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 700 Ci/mmol) specific
activity.
Scheme 1. Strategies for the C−H Radiofluorination of
Electron-Rich Arenes
he development of methods for the nucleophilic radio-
Tfluorination of electron-rich (hetero)arene precursors
represents a long-standing challenge for the radiochemistry
community.1−3 Most existing routes to 18F-labeled electron-rich
aromatics are limited by the requirement for prefunctionali-
zation of the labeling site with, for example, a boron, tin,
hypervalent iodine, or transition-metal substituent.3,4 These
prefunctionalized precursors are often not commercially avail-
able and must be accessed via multistep synthesis and purifica-
tion sequences.3a−c,e−k Furthermore, a number of radio-
fluorination precursors (e.g., hypervalent iodine reagents and
Ni/Pd complexes) have limited shelf lives, which precludes
widespread clinical applications.5 Overall, methods for the
direct nucleophilic radiofluorination of arene C−H bonds
would help to address these challenges.6
Several methods have been reported for the electrophilic
C−H radiofluorination of electron-rich arenes (Scheme 1A).1c,f
These involve the initial generation of an 18F+ source (e.g.,
[18F]F2 or [18F]Selectfluor) and subsequent electrophilic aro-
matic substitution (SEAr) between the 18F+ reagent and the
arene substrate. This approach eliminates the need for prefunc-
tionalization. However, the requirement for 18F+ reagents leads
to three key limitations. First, 18F+ reagents afford radio-
fluorinated products with low specific activity due to the need
to use carrier [19F]F2 gas for their synthesis.7 Second, the
production of 18F+ sources requires specialized facilities.8 Third,
the high reactivity of electrophilic fluorinating reagents often
results in poor site and chemoselectivity.9
the electronic mismatch between nucleophilic [18F]KF and
the nucleophilic electron-rich arene substrate (Ar−H). We
hypothesized that this could be overcome via an umpolung
strategy that would invert the polarity of the arene substrate
(Scheme 1C). Specifically, an initial SEAr reaction with an
electrophile (E+) would functionalize the C−H bond and
generate an electrophilic coupling partner (Ar−E).10 Ar−E
could then undergo in situ nucleophilic radiofluorination
with [18F]KF. We demonstrate herein the realization of this
approach using IIII-based electrophiles. This enables the
These limitations could be addressed through the develop-
ment of a nucleophilic radiofluorination of (hetero)aryl C−H
bonds (Scheme 1B), as this would enable the use of easily
accessible bench-stable precursors in combination with high
specific activity [18F]KF. The key challenge for this approach is
Received: June 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01902
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Letter
selective radiofluorination of electron-rich aromatics, including
toluene, anisole, aniline, pyrrole, and thiophene derivatives.
Furthermore, it can be scaled to automated radiosynthesis
modules and used to access high specific activity 18F-labeled
products.
The approach in Scheme 1C is predicated on the iden-
tification of an electrophile (E+) that (i) undergoes site-
selective SEAr with diverse electron-rich (hetero)arenes and
(ii) generates an intermediate (Ar−E) that can participate in a
nucleophilic radiofluorination. Notably, it is not critical that
Ar−E be stable; indeed, a key advantage of this approach
is that Ar−E will be used in situ, thus precluding the need
for isolation/storage of this intermediate. On the basis of
these considerations, we selected IIII reagents as E+. As shown
in Scheme 2, ArIIIIX2 salts are known to participate in
electrophile and activator for this one-pot radiofluorination.
First, these reagents should not contain nucleophilic counter-
ions (Y) (e.g., carboxylates), as these are susceptible to
undesired coupling reactions with the diaryliodonium inter-
mediate 2 (eq 1).18 Second, their byproducts should be
compatible with the Cu-mediated radiofluorination step.
With these criteria in mind, we first examined the use of
TsOH as the activator. The two-step procedure involved
(1) stirring 1a, MesI(OH)OTs, and TsOH (10 μmol) in CH2Cl2
for 18 h at 25 °C and then (2) adding the reaction mixture to a
solution of (MeCN)4CuOTf and [18F]KF·18-crown-6 in DMF
and heating at 85 °C for 20 min. The reactions were assayed
using radio-TLC and radio-HPLC, and these initial condi-
tions afforded a 27% radiochemical conversion (RCC) to
4-[18F]fluoroanisole (3a) (Table 1, entry 1).3a We hypothe-
sized that the addition of a base in step 2 would quench the
residual acid from the diaryliodonium formation step. This was
expected to enhance the radiofluorination yield, as Cu-catalyzed
nucleophilic fluorinations are known to be acid-sensitive.19
Scheme 2. Proposed Use of Hypervalent Iodine Reagents as
E+
i
Indeed, a screen of bases revealed that Pr2NEt (20 μmol)
increased the RCC to 61 8% (n = 9, entry 2).20,21
Trimethylsilyl trifluoromethanesulfonate (TMSOTf) also
proved to be an effective activator for the SEAr reaction. The
site-selective SEAr reactions with electron-rich (hetero)arenes.11−13
Furthermore, these transformations yield diaryliodonium salts,
which we have shown to undergo Cu-catalyzed radiofluo-
rination with [18F]KF.3a,14 While electron-rich diaryliodonium
salts are notoriously unstable,5a,15 this approach offers the
advantage that they are generated in situ from stable and readily
available C−H starting materials.
Our initial investigations focused on the reaction of anisole
(1a) with MesI(OH)OTs (Table 1). These partners were
selected because they are well-known to undergo SEAr in the
presence of Lewis or Brønsted acid activators16 (MY or HY,
respectively, in eq 1) to form a single isomeric product,
[4-MeOC6H4-I-Mes]+ (2a). Furthermore, 2a is known to
undergo Cu-catalyzed radiofluorination with [18F]KF.3a,13,14,17
There were two key considerations for our choice of aryliodonium
i
use of this activator in step 1 coupled with Pr2NEt (20 μmol)
in step 2 delivered 4-[18F]fluoroanisole (3a) in 78 4% RCC
(n = 3, entry 5). Finally, the evaluation of different additives
revealed that the addition of quinaldic acid (10 μmol) to the
Cu-mediated radiofluorination under otherwise identical
conditions resulted in a RCC of 87 4% (n = 13, entry 6).22
Notably, the RCC of this transformation of 1a to 3a (87%) is
comparable to that reported using isolated [4-MeOC6H4-I-Mes]+
as the substrate for Cu-catalyzed radiofluorination (79%).3a
The site-selectivity of the reaction of anisole was determined
by radio-HPLC analysis23 via comparison to authentic
standards of the three possible isomers (see the Supporting
Information for complete details). The 18F-fluorination pro-
ceeded to afford the para-isomer with >99:1 selectivity.12,13a−d
This high selectivity is fully consistent with that reported for
SEAr reactions between hypervalent iodine reagents and related
electron-rich arene substrates.12 Importantly, <2% of [18F]-
fluoromesitylene was detected under any of the conditions
examined.
a
Table 1. Optimization of the Radiofluorination of Anisole
We next evaluated the scope of this C−H radiofluorination
(Figure 1).24 A series of anisoles (3a−f), protected anilines
(3g−i), and toluene (3j,k) derivatives reacted under the
standard conditions to form 18F-labeled arenes in >80% RCC.
The transformation was tolerant of aryl halides (3c and 3o),
esters and tertiary amides (3d, 3g, and 3m), sulfonamides (3h,
3o, and 3q), and nitro groups (3q) as well as substitution
adjacent to the site of fluorination (3e). Protic functional
groups (e.g., alcohols, amines, and amides) were not com-
patible and were thus protected prior to the reaction.27 The
radiofluorination of heterocycles, including thiophene, pyrrole,
and uracil, required elevated temperature (105 °C) to afford
3l−n. Notably, the radiofluorination of these heterocycles
proceeded with lower selectivity, and significant quantities of
[18F]fluoromesitylene were observed in these systems. How-
ever, in all cases, this byproduct was readily separable by
b
entry
activator
base
RCC 3a (%)
1
2
3
4
5
TsOH·H2O
TsOH·H2O
TMSOTf
TMSOTf
TMSOTf
TMSOTf
27 4 (n = 4)
61 8 (n = 9)
iPr2NEt (20 μmol)
5
2 (n = 5)
iPr2NEt (10 μmol)
iPr2NEt (20 μmol)
iPr2NEt (20 μmol)
58 0.4 (n = 3)
78 4 (n = 3)
87 4 (n = 13)
c,d
6
a
Conditions: (1) 1a (10 μmol), MesI(OH)OTs (10 μmol), activator
(10 μmol), CH2Cl2 (40 μL); (2) (MeCN)4CuOTf (10 μmol),
[18F]KF·18-crown-6·K2CO3 complex in DMF (100 μL, 80−
b
1200 μCi), total volume 1.0 mL. RCC was determined by radio-
TLC (average of n runs). The identity of 3a was confirmed by HPLC.
Quinaldic acid (10 μmol) was included in step 2. 98:2 selectivity
(3a/[18F]fluoromesitylene) detected by radio-HPLC.
c
d
B
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Letter
Figure 1. Cu-mediated C(sp2)−H radiofluorination of electron-rich arenes. Conditions: (1) 1 (10 μmol), MesI(OH)OTs (10 μmol), TMSOTf
(10 μmol), CH2Cl2 (40 μL); (2) (MeCN)4CuOTf (10 μmol), quinaldic acid (10 μmol), iPr2NEt (20 μmol), [18F]KF·18-crown-6·K2CO3 complex
in DMF (100 μL, 80−1200 μCi), total volume 1.0 mL. Reported radiochemical conversions were measured by radio-TLC (average of n runs) and
were corrected for presence of 4 (ratio of 3/4 determined by radio-HPLC). The identity of each product was confirmed by radio-HPLC. Key:
(a) 105 °C; (b) TMSOTf (5 μmol).25,26
HPLC.25,26 The formation of 2-[18F]fluoro-3-methylthiophene
(3l) in 25% RCC is particularly noteworthy, as thiophenes are
particularly challenging to radiofluorinate using other meth-
ods.1d−f,28 Indeed, thiophene is typically used as the inert ligand
on diaryliodonium salts to direct radiofluorination to the other
arene ligand.1d−f,29
We next examined the late-stage C−H radiofluorination of
fragments that appear in pharmaceuticals. In one example, the
dibenzothiazepine fragment of tianeptine (Coaxil), underwent
radiofluorination to yield 3o in 18% RCC. Additionally, both
stability and availability of electron-rich aromatic substrates.
O-Bn-protected propofol (an anesthetic and sedative) and
Current efforts are focused on the application of this C(sp2)−H
N-Bn-protected nimesulide (a nonsteroidal anti-inflammatory)
to C−18F radiofluorination chemistry to clinically relevant
targets.
reacted under our standard conditions to yield 18F-analogues
3p and 3q in 87% and 81% RCC, respectively.
A final set of experiments focused on automation of this
reaction on a TRACERLab FXFN radiosynthesis module used
for the preparation of clinical radiotracers.2b Initial auto-
mated studies were conducted for anisole (1a) using ∼1.5
Ci of [18F]fluoride ([18F]KF·18-crown-6·KOTf) and afforded
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01902.
■
S
4-[18F]fluoroanisole (3a) in 56
activity of 2700
4% RCC and a specific
Experimental and spectral data for all new compounds
and all reactions (PDF)
1900 Ci/mmol (n = 4).20,30 We also
automated the radiofluorination of N-Bn-protected nimesulide
without any further optimization. Radiolabeling was conducted
using ∼1.5 Ci of [18F]fluoride, and the product was purified via
semipreparative HPLC to yield a formulated 41 31 mCi dose
of 3q in 2.8 1.9% non-decay-corrected radiochemical yield
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pjhscott@umich.edu.
*E-mail: mssanfor@umich.edu.
(RCY) with 2800
700 Ci/mmol specific activity (n = 3,
ORCID
eq 2). This proof-of-concept demonstration provides a founda-
tion for the application of this method to the synthesis of other
radiotracer targets.
In summary, this report describes a method for the nucleo-
philic radiofluorination of electron-rich arene C−H bonds that
enables the late-stage C−H functionalization of (hetero)aromatic
scaffolds. This approach eliminates the need to isolate/store
prefunctionalized starting materials, instead leveraging the bench
Stephen Thompson: 0000-0003-3596-7812
Allen F. Brooks: 0000-0003-3773-3024
Peter J. H. Scott: 0000-0002-6505-0450
Melanie S. Sanford: 0000-0001-9342-9436
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b01902
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (b) Merritt, E. A.;
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ACKNOWLEDGMENTS
■
This work was supported by Merck Sharp & Dohme, NIH
(R01EB021155) and DOE (DE-SC0012484). We thank
Drs. Idriss Bennacef, Thomas Graham, Eric Hostetler, Wenping
Li, James Mulhearn, and Petr Vachal from Merck for helpful
discussions.
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