Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling

Article abstract of DOI:10.1021/acs.orglett.5b02640

The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of [¹⁸F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of α-diazocyclohexenones with Selectfluor and Et₃N·3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and rapidly. To adapt this chemistry to ¹⁸F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophenol via an α-bromo-α-fluoroketone intermediate in lower but still reasonable yields.

Full text of DOI:10.1021/acs.orglett.5b02640

Letter
pubs.acs.org/OrgLett
Preparation of o‑Fluorophenols from Nonaromatic Precursors:
Mechanistic Considerations for Adaptation to Fluorine-18
Radiolabeling
Norio Yasui,† Christopher G. Mayne,§ and John A. Katzenellenbogen*,†
†Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United
States
§Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana−Champaign, 405 North Mathews Avenue,
Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of
[18F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of α-diazocyclohexenones
with Selectfluor and Et3N·3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and
rapidly. To adapt this chemistry to 18F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophenol
via an α-bromo-α-fluoroketone intermediate in lower but still reasonable yields.
any phenolic functions in drugs are substituted with
indirect routes are often inefficient and time-consuming (see
Mfluorine, particularly at the ortho position, because this Scheme 1).5 Direct fluorination of phenols with electrophilic
often enhances in vivo potency by increasing receptor target
binding affinity and/or retarding metabolism.1 An interesting
example is 2-fluoroestradiol, whose fluorine-18 radiolabeled
version has the potential to be a better radiotracer for positron
emission tomographic (PET) imaging than widely used 16α-
[18F]fluoroestradiol (FES) due to its enhanced binding to a
serum steroid carrier protein. In any case, fluorine substitution is
either beneficial to bioactivity or, in the worst case, is generally
well tolerated and thus potentially suitable for radiolabeling with
18F.
Scheme 1. 2-Fluoroestradiol and Its Indirect Radiosynthesis
Curiously, conventional fluorination methods of phenols have
limited efficiency and selectivity. Common electrophilic
fluorinating agents, such as N-fluoropyridinium and N-
fluoroammonium compounds, provide poor regioselectivity
and require harsh conditions. For instance, electrophilic
fluorination of estradiol produces a mixture of 2- and 4-estradiol,
and Selectfluor affords ipso-fluoroestradiol as the major
product.2−4
Nucleophilic substitution on aromatic rings has been studied
extensively for 18F radiolabeling of PET radiotracers. There are
many methods for labeling small molecules with 18F on electron-
deficient aromatic rings, but until recently, there were no reliable
and practical methods to label electron-rich aromatic rings, such
as phenols, with 18F at high specific activity (SA, i.e., radioactivity
per molar mass). Most approaches for 18F labeling of phenols
involve labeling electron-poor precursor arenes by nucleophilic
aromatic substitution, followed by conversion to phenols; these
fluorinating agents is not optimal for 18F labeling because, when
labeled with 18F, such reagents can only be produced using 19F as
the carrier, which results in greatly lowered SA.
Recently, transition-metal-mediated fluorination of arenes
used PdII-mediated aromatic fluorination by reductive elimi-
nation from Ar−PdII-F intermediates.6 Subsequently, Ar−F
bond formation methods using highly oxidized palladium
complexes were reported;7,8 this was followed by a Ni-mediated
Received: September 11, 2015
© XXXX American Chemical Society
A
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Organic Letters
Letter
aryl fluorination method.9 The preparation of the precursors for
these methods, however, is troublesome. Recent work has
focused on hypervalent iodine compounds (Ar−I+-Ar′) as
precursors for 18F radiolabeling of arenes, but directing
[18F]fluoride attack on the proper arene ring is often problem-
atic, although Cu-mediated regioselective fluorination using
Mes-I+-Ar as precursor gives minimum formation of the Mes-F
byproduct.10,11
(80% overall yield). The substrate scope is shown in Table 1. o-
and m-butyl-α-diazocyclohexenone also produced the corre-
sponding o-fluorophenols as well.
Table 1. Substrate Scope for o-Fluorophenol Synthesis from
a
α-Diazoketones Using Selectfluor
Rotstein and co-workers’ discovery of spirocyclic iodonium
ylides as stable precursors appears to be a more practical
approach for 18F radiolabeling on aromatic rings.12 However, this
method still requires prior phenol protection and then
deprotection to obtain the o-fluorophenol; acid-sensitive func-
tional groups are not stable under most deprotection conditions.
Thus, novel approaches to produce fluorophenols efficiently,
rapidly, conveniently, and adaptable to 18F labeling, are still
needed.
Herein, we report a novel and rapid method to prepare o-
fluorophenols regioselectively with minimum transformation
after fluorine incorporation using α-diazocyclohexenones as
precursors. Diazo compounds are known to react with various
electrophiles, including N-bromosuccinimide (NBS) and HF-
pyridine,13,14 PhSeX15 and PhIX2,14,16 forming C−F bonds α to
the carbonyl group. Therefore, by starting from α-diazocyclo-
hexenone, we thought that halofluorination would afford an α-
halo-α-fluoroketone that would undergo hydrohalide elimina-
tion followed by tautomerization to produce the fluorinated
electron-rich arene o-fluorophenol (Scheme 2). Notably, even
a
Conditions: Selectfluor (1.2 equiv), Et3N·3HF (2 equiv), CH3CN
b
(0.1 M), rt, 5 min; DBU (1.5 equiv), rt, 25 min. Yields determined by
c
1H and 19F NMR; isolated yields are in parentheses. Without Et3N·
3HF.
2-Fluoroestradiol could also be prepared from the correspond-
ing diazoketone efficiently and selectively (Scheme 4). 3-
Scheme 4. Synthesis of 2-Fluoroestradiol
Scheme 2. Strategy for o-Fluorophenol Preparation from an
α-Diazoketone
though the starting material is a nonaromatic precursor, the
oxidation state of the α-diazocyclohexenone is the same as o-
fluorophenol, so these transformations involve no oxidation or
reduction. Thus, the overall reaction conditions are potentially
mild with a likelihood of good functional group tolerance.
We chose α-diazocyclohexenone 4a as a model substrate
because it mimics the AB ring system of estradiol and can be
readily prepared by Robinson annulation of cyclohexanone with
methyl vinyl ketone, followed by α-activation with a trifluor-
oacetyl group and diazo transfer from methanesulfonyl azide (see
the Supporting Information).17 This substrate turned out to be
stable for at least 6 months at low temperature in the dark.
Diazoketone 4a reacted with Selectfluor in the presence of
Et3N·3HF, producing α,α-difluoroketone 5a followed by HF
elimination promoted by DBU to produce o-fluorotetralol 6a in a
good yield (Scheme 3). This sequence of two reactions
proceeded rapidly (5 and 25 min, respectively) and efficiently
Methylestradiol 7 underwent Birch reduction to 1,4-diene, and
acid hydrolysis/isomerization gave α,β-unsaturated ketone 8.
After protection of the C-17 OH as the THP ether the diazo
function was introduced as previously described.
The resulting diazoketone precursor 10 was readily converted
by Selectfluor to the corresponding α,α-difluoroketone, and
following DBU treatment and a rapid acidic deprotection of the
THP group, 2-fluoroestradiol was obtained in a good yield. It is
notable that because the diazo function directs the site of
reaction, this method produces no other isomers whereas
conventional electrophilic fluorination methods give in many
cases mixtures of regioisomers that are troublesome to separate.
Our ultimate application is to develop an 18F-labeling method
suitable for the preparation of o-[18F]fluorophenols at high SA,
Scheme 3. o-Fluorophenol from an α-Diazoketone
B
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Letter
and for this purpose, it is not suitable to use fluorine electrophiles
due to their low SA, mentioned previously. Thus, in our search
for nonfluorine-containing electrophiles that could ultimately be
partnered with [18F]fluoride ion, we investigated the electrophile
scope of this reaction, focusing on those containing bromine,
chlorine, and iodine (Table 2; see also Table S1). For these
studies, the halofluorination and elimination reactions were done
in one pot.
radiolabeling in which only a trace amount of radiofluoride ion is
used together with a large excess amount of substrate and
reagents (entry 8). (It is of note that entry 3 of Table 1 shows that
o-fluorophenol was formed even without added fluoride, Et3N·
3HF. In this case, the o-fluorophenol was formed directly, not via
the α,α-difluoroketone, as is discussed in detail later in this paper
(Scheme 6, path B).)
Formation of the bromophenol side product was thought to
arise from elimination of HF instead of HBr. To investigate this,
we tried to isolate the bromofluorination α-bromo-α-fluoroke-
tone intermediates; however, they proved to be very unstable.
Nevertheless, we could quantify the formation of two presumed
epimeric intermediates, R and S, indirectly by 19F NMR using an
internal standard. (We are illustrating only one enantiomeric
series of the racemic epimers.) These are shown in half-chair
conformations, and based on their H−F coupling constants, the
one with the larger coupling (S, having F axially disposed) is
more abundant (19%), and the one with the smaller coupling (R,
having F disposed equatorially) is less abundant (11%) (Scheme
5).
Table 2. o-Fluorophenol Synthesis from an α-Diazoketone
Precursor
Scheme 5. Proposed Stereochemistry of Bromofluoroketone
Epimers, S and R, Revealed by 19F NMR
a
yield (%)
entry
E+ (X)
NBA
fluoride
6a
11
12
59
1
2
3
4
5
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Pyr·9HF
17
14
0
4
DBDMH
NCS
5
100
43
66
0
NIS
0
11
0
I2
0
100
20
b
6
NBA
14
27
18
29
0
68
68
82
15
trace
nd
b
7
DBDMH
DBDMH
NBA
Pyr·9HF
Pyr·9HF
5
b
c
8
0
d
9
Et3N·3HF
42
e
10
DBDMH
TBAF
trace
nd
f
11
DBDMH
TBAF
6
a
b
Yields were determined by 1H and 19F NMR. Electrophile and
c
We expected that elimination of hydrogen halide from these
epimeric bromofluoroketones would proceed by an E2 process,
following strict antiperiplanar geometry, with R losing HBr and S
losing HF. Consequently, we anticipated that the yield of the
fluorophenol could not exceed that of epimer R having bromine
axially disposed (namely 11%). The fact that the fluorophenol is
obtained in 25% yield, which is 14% greater than the amount of
epimer R present, indicates, surprisingly, that a substantial
amount of product is coming from the S epimer. Thus, it appears
that the more abundant epimer (S) is able to access an alternate,
half-twist chair conformer in which H and Br approach an
antiperiplanar geometry.
We explored this possibility through careful energy calcu-
lations of both the half-chair and half-twist chair conformations
of both the R and S epimers (see details in SI). Indeed, the
energies of the half-chair and twist-chair conformers of the S
epimer differ by less than 1 kcal/mol and are separated by a
conformational energy barrier of ca. 9 kcal/mol, suggesting that
elimination of HBr from this epimer is indeed feasible. By
contrast, the twist-chair conformer of the R epimer (which would
lose HF by an E2 elimination) is ca. 3 kcal/mol higher in energy
than the half-chair conformer, making it an unlikely participant in
the elimination.
fluoride source were mixed before substrate addition. 0.9 equiv of
d
fluoride was used. Electrophile was added portionwise at 0 °C.
e
f
Trihydrate was used without drying. TBAF was dried azeotropically
with CH3CN and t-BuOH. nd = not determined.
Bromine electrophiles, such as 1,3-dibromo-5,5-dimethylhy-
dantoin (DBDMH) and N-bromoacetamide (NBA) (entries 1
and 2), gave moderate yields of the desired o-fluorophenol, using
Et3N·3HF as fluoride source. Chlorine or iodine electrophiles did
not produce the fluorophenol, giving only other undesired o-
halophenols byproducts (entries 3−5). As a fluoride source, Pyr·
9HF gave similar product yields (entries 6 and 7). However,
other fluoride sources typically used in 18F radiolabeling, such as
CsF or KF/Kryptofix 222, did not produce any fluoride-
containing products (see the SI). Although TBAF·3H2O
interfered with reaction of the diazoketone with the electrophile
(no N2 release observed, unreacted starting material recovered)
(entry 10), after azeotropic drying, fluorine incorporation was
observed. Among the solvents tested, best yields were obtained
in CH2Cl2 or Et2O; polar solvents were unsuitable for the
formation of the o-fluorophenol (see also Table S1). The highest
yield was obtained by lowering the reaction temperature and/or
portionwise addition of electrophile. Substoichiometric levels of
fluoride ion still produced o-fluorophenol in comparable yields,
which bodes favorably for the effectiveness of this reaction in 18F
These findings also indicate that HF elimination from the
bromofluoroketone intermediates is not the major route for
C
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Letter
forming the o-bromophenol (Scheme 6). In fact, the o-
bromophenol had already been formed at the bromofluorination
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02640.
Scheme 6. Proposed Mechanism for Halofluorination/
Elimination
Complete experimental details and relevant spectra for all
important compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jkatzene@illinois.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for support of this work through research grants
from the Department of Energy (DOE DE-SC0005434) and the
National Institutes of Health (PHS 5R01CA025836) to J.A.K.
N.Y. was supported by a training grant from the Department of
Energy (DOE DE-SC0008432). C.M. is supported by the Center
for Macromolecular Modeling and Bioinformatics (NIH P41-
GM104601). We thank Kurt Brorsen for advice on quantum
mechanical calculations.
step, though no o-fluorophenol had yet been produced (see the
SI). Thus, the sequence of reactions appears to be somewhat
complex: The first step is the attack of Br+ on the diazo group,
giving a highly reactive α-bromo-α-diazonium intermediate that
then rapidly partitions, either with fluoride displacing the
diazonium group, giving the epimeric bromofluoroketone
intermediates S and R, or alternatively, by deprotonation at the
β position, leading directly to the bromophenol. Further
bromination forms dibromophenol 12, presumably by a
conventional electrophilic aromatic bromination. This sequence
of events also explains why no bromofluorophenol was observed,
and in the reactions with Selectfluor, the o-fluorophenol was
formed without added fluoride ion, as noted earlier (entry 3,
Table 1).
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Org. Lett. XXXX, XXX, XXX−XXX