Synthesis and Reactivity of 18F-Labeled α,α-Difluoro-α-(aryloxy)acetic Acids

Article abstract of DOI:10.1021/acs.orglett.6b03730

In this work, we describe the ¹⁸F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-¹⁸F-fluorination functionalization. Protodecarboxylation offers a new entry to ¹⁸F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative ¹⁸F-labeled TRPV1 inhibitors and TRPV1 antagonists.

Full text of DOI:10.1021/acs.orglett.6b03730

Letter
pubs.acs.org/OrgLett
Synthesis and Reactivity of 18F‑Labeled α,α-Difluoro-α-(aryloxy)acetic
Acids
Tanatorn Khotavivattana,†,⊥ Samuel Calderwood,†,⊥ Stefan Verhoog,† Lukas Pfeifer,† Sean Preshlock,†
Neil Vasdev,§,# Thomas L. Collier,§,#,∧ and Veronique Gouverneur*,†
́
†Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
§Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston 02114, United States
#Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston 02114, United States
∧Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, New York 14850, United States
S
* Supporting Information
ABSTRACT: In this work, we describe the 18F-labeling of α,α-difluoro-α-
(aryloxy)acetic acid derivatives and demonstrate that these building blocks
are amenable to post-18F-fluorination functionalization. Protodecarboxyla-
tion offers a new entry to 18F-difluoromethoxyarene, and the value of this
approach is further demonstrated with coupling processes leading to
representative 18F-labeled TRPV1 inhibitors and TRPV1 antagonists.
Scheme 1. 18F-Labeling of ArOCF2 Motif
luorine-18 (18F) is one of the most commonly used
Fradionuclides for the production of positron emission
tomography (PET) radiotracers; PET is a noninvasive
molecular imaging modality that allows quantitative in vivo
observation of biochemical and physiological processes.1 This
technique is utilized as a tool for clinical diagnosis2 and to
facilitate drug development.3 To date, access to radiotracers has
relied mostly on radiosynthetic methodologies leading to
[18F]alkyl−F or [18F]aryl−F bond formation.4 With the aim
of expanding the chemical space available for radioligand
discovery, recent efforts have focused on the development of
innovative protocols for the 18F-labeling of perfluoroalkyl
substituents. In this context, molecules featuring the α,α-
difluorinated aryl ether motif (ArOCF2) are of interest because
of their increasing importance in medicinal chemistry (Scheme
1a).5 Difluoromethyl aryl ethers are prominent motifs in drug
development because the polarized C−H bond can act as a
hydrogen bond donor, a property that could enhance potency
without affecting microsomal stability.6,7 Moreover, the
replacement of OCH3 with OCHF2 does not increase P-gp
efflux liability, an advantage when designing neuro-PET
radioligands. As a result, methodologies for accessing 18F-
labeled ArOCF2H have recently appeared.8 Compounds
featuring a ArOCF2−C bond are also encountered in drug
discovery, for example, in studies aimed at developing TRPV1
antagonists9a and TRPV1 inhibitors.9b We noted that there is
no methodology available to date for the 18F-labeling of such a
motif.
functionalization; hence, we reasoned that [18F]α,α-difluoro-
α-(aryloxy)acetic acids ([18F]3) could serve as divergent
intermediates for the radiosynthesis of a range of 18F-labeled
difluoro-containing targets via post-18F-fluorination functional-
ization (Scheme 1b).
In this work, we opted for an 18F-labeling route leading to the
ArOCF2 motif with a diversity-oriented methodology in mind.
The carboxylic acid group is incredibly versatile for
Received: December 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03730
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In order to prepare [18F]3, we considered a two-step
procedure involving halogen exchange of ethyl α-bromo-α-
fluoro-α-(aryloxy)acetate (1) with cyclotron-produced [18F]-
fluoride to afford 18F-labeled ethyl α,α-difluoro-α-(aryloxy)-
acetates [18F]2. Hydrolysis of [18F]2 would then lead to [18F]3.
The 4-tert-butyl aryl substituted ester 1a was chosen as a model
substrate to validate this strategy and optimize the reaction
conditions (Table 1).
instead a protocol involving in situ hydrolysis by introducing
the base as an additive in the 18F-fluorination step. A mixture of
[18F]2a and [18F]3a was obtained when the reaction was
performed in the presence of various bases with the best result
observed with K2CO3 (Table 1, entries 8−12). A decrease in
RCC of [18F]3a was observed when the amount of K2CO3 was
doubled (Table 1, entry 13). It is known that certain crown
ethers and cryptands can serve as a chelator for potassium ion,
hence enhancing the solubility of the base.10 Although the
addition of 18-crown-6 (2.4 equiv) did not lead to a significant
improvement (Table 1, entry 14), the RCC of [18F]3a was
dramatically increased to 80% when the reaction was performed
in the presence of Kryptofix-2.2.2 (K2.2.2) (2.4 equiv) as an
additional additive (Table 1, entry 15). A solvent screen (Table
1, entries 16−19) revealed that the reaction was most efficient
in acetone at 50 °C, affording [18F]3a in 83% RCC (Table 1,
entry 19) (see Table S2 for full data).
Table 1. Optimization for the 18F-Fluorination of the
a
Brominated Precursor 1a
b
b
[18F]2a RCC
[18F]3a RCC
entry
solvent
additive (equiv)
(%)
(%)
With the optimized reaction conditions in hand, the scope of
18F-fluorination with in situ hydrolysis was investigated with a
range of brominated precursors containing various functional
groups on the arene (Scheme 2). Substrates containing electron
c
,
d
1
2
3
4
5
6
MeCN
DMF
<1
<1
0
c
,
d
,
e
0
d
d
,
f
MeCN
MeCN
MeCN
MeCN
28
57 15
70
2
0
0
0
6
Scheme 2. Substrate Scope for the 18F-Labeling of α,α-
1 M HNO3
19 18
22 14
a
Difluoro-α-(aryloxy)acetic Acids [18F]3
g
(10.0)
g
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
1 M NaOH (5.0)
Bu4NOH (1.4)
LiOH (1.4)
0
26
1
0
20
9
0
0
4
21
16
36
1
5
0
10
11
12
13
14
15
16
17
18
CsOH·H2O (1.4)
Cs2CO3 (1.4)
K2CO3 (1.4)
K2CO3 (2.8)
K2CO3 (1.4)
K2CO3 (1.4)
K2CO3 (1.4)
K2CO3 (1.4)
31 21
15
24 21
22
1
40 18
14
38 18
6
2
h
i
34 13
<1
80
2
4
i
<1
1
i
<1
60 11
45 10
i
t-BuOH K2CO3 (1.4)
<1
i j
19 ,
acetone K2CO3 (1.4)
<1
83
2
a
b
1a (0.01 mmol), solvent (600 μL). Radiochemical conversions
c
determined by radio-TLC and radio-HPLC (n = 2). [18F](Et4N)F
d
e
was used. 1a (0.03 mmol), MeCN (300 μL). Temperature = 150 °C.
f
g
Reaction time = 10 min. The additive was added after the reaction
h
and then stirred at 80 °C for another 20 min. The reaction was
performed in the presence of 2.4 equiv of 18-crown-6. The reaction
i
was performed in the presence of 2.4 equiv of Kryptofix-2.2.2.
j
Acetone (200 μL), 50 °C.
a
1 (0.01 mmol), K2CO3 (0.014 mmol), K2.2.2 (0.024 mmol), acetone
Preliminary optimization investigating the source of 18F-
fluoride revealed that [18F]Et4NF was not efficient for this
transformation even with a reaction temperature as high as 150
°C (Table 1, entries 1 and 2). However, [18F]2a was detected
in 28% radiochemical conversion (RCC) when 1a was treated
with [18F]KF/K2.2.2 in MeCN at 80 °C for 10 min (Table 1,
entry 3). The reaction finished in 20 min with the RCC of [18F]
2a increasing to 57% (Table 1, entry 4). After the amount of
precursor and solvent was optimized, the RCC was further
improved to 70% (Table 1, entry 5) (see Table S1). The
subsequent hydrolysis of [18F]2a was examined by addition of 1
M HNO3 or 1 M NaOH to the crude mixture of the optimized
conditions then stirred at 80 °C for 20 min (Table 1, entries 6
and 7). Under acidic conditions, a mixture of [18F]2a and [18F]
3a was obtained. The labeled ester [18F]2a was fully consumed
under basic conditions, but the desired carboxylic acid [18F]3a
was obtained in 26% RCC only. Therefore, we considered
(200 μL), 50 °C, 20 min; RCCs determined by radio-TLC and radio-
b
HPLC (n = 4). Along with 28
8% of radiolabeled byproduct
resulting from the partial hydrolysis of the phthalimide group. Phth =
phthalimide.
neutral and bromine substituents gave the desired 18F-
fluorinated acids [18F]3a−f in RCCs ranging from 35% to
84%. The lower RCC of the o-bromo substrate ([18F]3f) could
be accounted for by evoking steric hindrance. The reaction
tolerates a wide range of functional groups such as fluoro, ester,
ketone, nitrile, trifluoromethyl, and protected amine ([18F]3g-
l); for these functionalized products, the RCCs ranged from
36% to 65%.11
The radiosyntheses of [18F]3a and [18F]3k were performed
using a higher amount of [18F]fluoride (∼4 GBq) (Scheme 3,
eq 1). In these processes, the addition of K2CO3 and K2.2.2 as
additives was not necessary since they were used in the eluent
B
DOI: 10.1021/acs.orglett.6b03730
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Isolation of [18F]3a and [18F]3k and the
Preparation of TRPV1 Antagonist [18F]4 and TRPV1
Inhibitor [18F]5
Table 2. Optimization of Conditions for the Decarboxylation
of 3a
a
b
b
conv of 3a
yield of 6
entry
additive (equiv)
KOH (1.5)
(%)
(%)
c
1
0
91
0
2
3
AgNO3 (1.0), K2S2O8 (2.0)
AgNO3 (1.0), K2S2O8 (4.0)
AgNO3 (1.0), K2S2O8 (4.0)
AgNO3 (1.0), K2S2O8 (4.0)
30
d
>99
82
53 (50)
47
e
4
f
g
5
96
4
6
7
8
9
AgNO3 (1.0), K2S2O8 (4.0), A
62
25
8
(1.0)
AgNO3 (1.0), K2S2O8 (4.0), B
(1.0)
9
34
84
AgNO3 (1.0), K2S2O8 (4.0), C
(1.0)
1
AgNO3 (1.0), K2S2O8 (4.0), D
(1.0)
53
h
10
AgNO3 (1.0), K2S2O8 (4.0)
AgNO3 (1.0), (NH4)2S2O8 (4.0)
Ag(II) picolinate (1.0)
22
>99
55
4
41
0
11
12
system during the drying process of [18F]fluoride. After the
reactions, the products were isolated by solid-phase extraction
(C-18 SepPak), affording [18F]3a and [18F]3k in 36% and 31%
radiochemical yields (RCYs) with specific activities (SA) of
0.37 GBq/μmol and 0.51 GBq/μmol, respectively.
a
b
3a (0.1 mmol), acetone/H2O (1:1) (400 μL). Yields determined by
19F NMR using Ph−CF3 as an internal standard; isolated yield of a 2.0
c
mmol scale reaction in parentheses. In diglyme at 200 °C.
d
Compounds 6, 7, 8, and 9 were separated and isolated in 50%, 3%,
The isolated 18F-labeled carboxylic acids can be used as
starting materials for subsequent radiochemical reactions. The
amide coupling of [18F]3a with the corresponding amine using
4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium
chloride (DMTMM) as a coupling reagent led to the formation
of [18F]4, an 18F-labeled TRPV1 antagonist,9a in 18% RCC
(Scheme 3, eq 2) (see Table S3 for the results of other coupling
reagents). In addition, we demonstrated that the reaction of
[18F]3k with 3′,4′-diamino-N,N-dimethyl[1,1′-biphenyl]-2-sul-
fonamide in 6 M HCl at 110 °C gave 16% RCC of
benzimidazole [18F]5, a known TRPV1 inhibitor (Scheme 3,
eq 3).9b
e
f
4%, and 4% yield, respectively. In acetone/D2O (1:1). In acetone-d6/
H2O. 5% of deuterated 6 observed. The reaction was performed at
room temperature.
g
h
at room temperature (Table 2, entry 10), and the yield was not
improved by using either an alternative oxidant or silver(II) salt
(Table 2, entries 11 and 12).
Next, radiolabeled [18F]3a was subjected to protodecarbox-
ylation using AgNO3 (1 equiv) and K2S2O8 (4 equiv) in
acetone/H2O (1:1) at 50 °C for 20 min. After purification by
semipreparative HPLC, [18F]6 was successfully isolated in 22%
RCY with a SA of 0.30 GBq/μmol (Scheme 4).
Next, we envisaged that [18F]3 could serve as a precursor for
18F-labeled ArOCF2H [18F]6 via protodecarboxylation. Since
this transformation has never been reported in the literature on
this motif,12 we first investigated this process using nonlabeled
3a as a model substrate (Table 2). No reaction was observed
when 3a was treated with KOH even at 200 °C (Table 2, entry
1).13 Pleasingly, 3a underwent silver-mediated oxidative
decarboxylation at 50 °C using K2S2O8 to give 6 in 30%
yield (Table 2, entry 2).14 The yield was improved to 53% with
full conversion of 3a using 4 equiv of K2S2O8 (Table 2, entry
3). When the reaction was performed on a 2.0 mmol scale, 3a
was isolated in 50% yield along with three minor side products
identified as 7−9. Deuterium-labeling experiments revealed that
acetone is the source of hydrogen in this process (Table 2,
entries 4 and 5). The yield was not improved upon addition of
hydrogen sources such as Hantzsch ester A, 1,3-cyclohexadiene
B, silane C, or 2,4-dimethyl-3-pentanone D (Table 2, entries
6−9) (see Table S4 for full data). The reaction was inefficient
Scheme 4. Radiosynthesis and Isolation of [18F]6
In summary, we have successfully developed a mild and
efficient protocol for the preparation of 18F-labeled α,α-
difluoro-α-(aryloxy)acetic acids applying a halogen-exchange
18F-fluorination of the brominated ester precursors with in situ
hydrolysis. The reaction tolerates a wide range of substituents,
and the subsequent postfunctionalization of the acid was
demonstrated with the preparation of an amide-containing
TRPV1 antagonist and a benzimidazole-containing TRPV1
C
DOI: 10.1021/acs.orglett.6b03730
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Han, Y. T.; Yang, S.-M.; Wang, X.-Y.; Li, F.-N. Arch. Pharm.
Res. 2014, 37, 440−451. (b) Cheung, W. S.; Parks, D. J.; Parsons, W.
H.; Patel, S.; Player, M. R. US2008/146637 A1, 2008.
inhibitor. Moreover, the protodecarboxylation to form the
arylOCF2H [18F]6 was also successfully implemented.
(10) (a) Down, J. L.; Lewis, J.; Moore, B.; Wilkinson, G. J. Chem. Soc.
1959, 3767−3773. (b) Landini, D.; Maia, A.; Montanari, F.; Tundo, P.
J. Am. Chem. Soc. 1979, 101, 2526−2530.
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) We experienced difficulties in preparing substrates with
electron-donating substituents such as a methoxy group due to the
formation of byproducts resulting from aromatic bromination.
(12) The formation of the protodecarboxylated product (ArOCF2H)
was reported as a side reaction in the fluorodecarboxylation of
ArOCF2CO2H; see: Zhou, M.; Ni, C.; He, Z.; Hu, J. Org. Lett. 2016,
18, 3754−3757.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03730.
1
Experimental procedures, characterization data, and H,
19F, and 13C NMR spectra for all new compounds and
optimization tables (PDF)
(13) Huang, C. G.; Rozov, L. A.; Halpern, D. F.; Vernice, G. G. J.
Org. Chem. 1993, 58, 7382−7387.
AUTHOR INFORMATION
(14) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92,
1651−1659. (b) Gong, Y.; Lin, L. Molecules 2011, 16, 2714−2727.
■
Corresponding Author
*E-mail: veronique.gouverneur@chem.ox.a.uk.
ORCID
Veronique Gouverneur: 0000-0001-8638-5308
́
Author Contributions
⊥T.K. and S.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Royal Thai
Government (T.K.), SCI (T.K.), the MRC (S.C.), Advion
(S.C.) the EPSRC (S.V., S.P.), the CRUK (S.V.), GSK (S.V.),
and the EU (FP7-PEOPLE-2012-ITN-RADIOMI-316882 to
L.P.). V.G. thanks the Royal Society for a Wolfson Research
Merit Award (2013-2018).
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DOI: 10.1021/acs.orglett.6b03730
Org. Lett. XXXX, XXX, XXX−XXX