Diversity-oriented approach to CF3CHF-, CF3CFBr-, CF3CF2-, (CF3)2CH-, and CF3(SCF3)CH-substituted arenes from 1-(Diazo-2,2,2-trifluoroethyl)arenes

Article abstract of DOI:10.1021/ol5030184

Arenes substituted with perfluoroalkyl groups are attractive targets for drug and agrochemical development. Exploiting the carbenic character of donor/acceptor diazo compounds, a diversity-oriented synthesis of perfluoroalkylated arenes, for late stage fluorofunctionalization, is described. The reaction of 1-(diazo-2,2,2-trifluoroethyl)arenes with HF, F/Br, F₂, CF₃H, and CF₃SH sources give direct access to a variety of perfluoroalkyl-substituted arenes presenting with incremental fluorine content. The value of this approach is also demonstrated for radiochemistry and positron emission tomography with the [¹⁸F]-labeling of CF₃CHF-, CF₃CBrF-, and CF₃CF₂-arenes from [¹⁸F]fluoride.

Full text of DOI:10.1021/ol5030184

Letter
pubs.acs.org/OrgLett
Diversity-Oriented Approach to CF3CHF‑, CF3CFBr‑, CF3CF2‑,
(CF3)2CH‑, and CF3(SCF3)CH-Substituted Arenes from 1‑(Diazo-2,2,2-
trifluoroethyl)arenes
Enrico Emer,†,⊥ Jack Twilton,†,⊥ Matthew Tredwell,† Samuel Calderwood,† Thomas Lee Collier,§
Benoît Liegault,†,‡ Marc Taillefer,‡ and Veronique Gouverneur*,†
́
́
†Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, U.K.
‡Institut Charles Gerhardt Montpellier, UMR-CNRS 5253, AM2N, ENSCM 8, rue de l’Ecole Normale, 34296 Montpellier Cedex 5,
France
§Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, New York 14850 United States
S
* Supporting Information
ABSTRACT: Arenes substituted with perfluoroalkyl groups are attractive targets for drug
and agrochemical development. Exploiting the carbenic character of donor/acceptor diazo
compounds, a diversity-oriented synthesis of perfluoroalkylated arenes, for late stage
fluorofunctionalization, is described. The reaction of 1-(diazo-2,2,2-trifluoroethyl)arenes
with HF, F/Br, F2, CF3H, and CF3SH sources give direct access to a variety of
perfluoroalkyl-substituted arenes presenting with incremental fluorine content. The value of
this approach is also demonstrated for radiochemistry and positron emission tomography
with the [18F]-labeling of CF3CHF-, CF3CBrF-, and CF3CF2-arenes from [18F]fluoride.
luorine-containing arenes are an important class of
aromatic motifs found in pharmaceuticals. Fluorine
F
substitution affects docking interactions through contact with
the protein and allows control over drug conformation; the
presence of fluorine also influences physical and adsorption,
distribution, metabolism, and excretion properties of a lead
compound.1 Fluorine substitution is equally prominent in
agrochemicals that have progressed to the point where their
chemical structures, physical properties, and site-specific
binding make them difficult to distinguish from pharmaceutical
drugs.2 As a result, systematic fluorine scans emerge as a
promising strategy in drug and agrochemical discovery. To
date, most efforts have focused on late stage fluorination and
trifluoromethylation of arenes.3,4 Synthetic work leading to
higher-order perfluoroalkyl motifs for evaluation in the context
of drug and agrochemical performance is less documented. If
we consider the established therapeutic value of the CF3CF2-
containing drug Faslodex (fulvestrant), a selective estrogen
receptor down-regulator indicated for the treatment of
hormone receptor positive metastatic breast cancer.5 The
preparation of perfluoroalkyl-substituted arenes with incremen-
tal fluorine content for comparative studies of their biological
properties remains a laborious and time-consuming process
since no synthesis is available to synthesize CF3CHF-,
CF3CBrF-, CF3CF2-, (CF3)(CF3S)CH-, and (CF3)2CH-arenes
from a common precursor through late stage fluorofunction-
alization (Figure 1).
Figure 1. Branching pathway to perfluoroalkyl arenes: late stage
fluorofunctionalization of 1-(diazo-2,2,2-trifluoroethyl)arenes.
synthesis.6,7 1-(Diazo-2,2,2-trifluoroethyl)arenes emerged as
prime candidates for this purpose since these known
compounds are readily accessible from the parent trifluor-
omethylketones,8 via the corresponding tosylhydrazones,9 and
have been exploited in a range of transformations.10 The
absence of reports on fluorine incorporation prompted us to
interrogate the reactivity of 1-(diazo-2,2,2-trifluoroethyl)arenes
toward α,α-functionalization via net HF, F/Br, F2, CF3H, and
CF3SH addition. Successful implementation of this branching
pathway approach would offer a direct route to a range of aryl-
Rf motifs with precise control over incremental fluorine
substitution with the number of fluorine (n) into the products
varying from n = 4−6. Incidentally, the addition of H2 onto 1-
(diazo-2,2,2-trifluoroethyl)arenes readily expands the diversity
With these considerations in mind, we posited that a
diversity-oriented strategy exploiting the carbenic character of
donor/acceptor diazo compounds would be an attractive
alternative to conventional strategies for Rf-arene library
Received: October 14, 2014
© XXXX American Chemical Society
A
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Letter
scope to CF3CH2-substituted arenes (n = 3). An additional
motivation to study late stage fluorination of 1-(diazo-2,2,2-
trifluoroethyl)arenes for reactions using fluoride is to explore
[18F]-labeling and applications in positron emission tomog-
raphy. Successful [18F]-labeling could facilitate studies probing
the impact of higher-order fluorination of arenes on in vivo
biodistribution and in the broader context of drug and
agrochemical discovery.
Scheme 3. Bromofluorination of 1-(Diazo-2,2,2-
trifluoroethyl)arenes 1a−i
We began by preparing a selection of 1-(diazo-2,2,2-
trifluoroethyl)arenes 1 applying an interrupted Bamford−
Stevens reaction to a range of tosyl hydrazones; these
precursors were obtained by reacting the corresponding aryl
trifluoromethylketones with tosylhydrazide (Scheme 1).11,12
a
b
19F NMR yield using fluorobenzene as internal reference. Reaction
run in Et2O with 2 equiv of NBS over 24 h.
Scheme 1. Preparation of 1-(Diazo-2,2,2-
trifluoroethyl)arenes 1
reaction was applied successfully to a series of substituted
arenes 3a−i in yields ranging from 54 to 81%.15
The late stage geminal difluorination of 1-(diazo-2,2,2-
trifluoroethyl)arenes as a route to pentafluoroethyl-substituted
arenes was considered next. Current methods to install the
CF3CF2 motif onto arenes rely on metal-catalyzed cross-
coupling methodologies and the use of perfluorinated building
blocks.16 These processes are not trivial to exploit for [18F]-
labeling. We were pleased to find that the difluorination of 1b
was successfully performed in a sealed tube by action of
(difluoroiodo)toluene (p-TolIF2)17 and 1 mol % of BF3·OEt2
(added as a stock solution in CH2Cl2) in chlorobenzene at 110
°C (Scheme 4).7g These reaction conditions provided 4b in
4-(1-Diazo-2,2,2-trifluoroethyl)-1,1′-biphenyl 1b served as a
model compound for validation of the various branching
pathways toward distinct perfluoroalkyl motifs. We focused at
first instance on hydrofluorination as a route to access 1,2,2,2-
tetrafluoroethyl-substituted arenes.13 Literature methods for the
preparation of these poorly explored target compounds are
scarce.14 One approach is the fluorination of α-trifluoromethyl
alcohols with diethylaminosulfur trifluoride, a reaction con-
ducted in DCM at −70 °C.14a An alternative strategy consists
of subjecting various (1-aryl-2,2,2-trifluoroethyl)hexyl sulfides
to oxidative fluorodesulfuration with Et3N·3HF and the oxidant
IF5.14b We found that the reaction of 1b with HF·Py (HF
∼70%, pyridine ∼30%) at 0 °C afforded 2b in 92% yield
(Scheme 2). This reaction was extended to a range of diazo
precursors leading to the hydrofluorinated products in yields
reaching 99%.
Scheme 4. Geminal Difluorination of 1-(Diazo-2,2,2-
trifluoroethyl)arenes 1b,d,f,i
Scheme 2. Hydrofluorination of 1-(Diazo-2,2,2-
trifluoroethyl)arenes 1a−k
52% isolated yield. The process was extended to diazo starting
materials 1d, 1f, and 1i, bearing electron-withdrawing or
electron-donating functional groups, producing the pentafluor-
oethylarene products in moderate to good yields.
Hydrotrifluoromethylation was successfully accomplished by
treating the model substrate 1b with trimethyl-
(trifluoromethyl)silane18 and CsF in the presence of CuI in
NMP/H2O (Scheme 5a).7h This reaction led to (1,1,1,3,3,3-
hexafluoropropan-2-yl)arenes 5b, 5f, 5h, and 5i in moderate to
very good yield. Using silver trifluoromethanethiolate
(AgSCF3) and CuCl instead of TMSCF3 and CuI,7j we
accessed (2,2,2-trifluoro-1-phenylethyl)(trifluoromethyl)sulfane
6b in 77% yield via net hydrotrifluoromethylthiolation (Scheme
5b).19 Following the same procedure, compounds 6h and 6i
were also obtained, albeit in lower yields.
For completeness, we also considered the conversion of 1-
(diazo-2,2,2-trifluoroethyl)arenes into CF3CH2-arenes.20 Hy-
drogenation of 1b was performed upon treatment with H2 (1
atm) in MeOH in the presence of 10% of Pd/C (10% w/w)
(Scheme 6). Under these conditions, 7b and 7f were isolated in
93 and 85% yield, respectively.
a
19F NMR yield using fluorobenzene as internal reference.
To investigate the bromofluorination reaction,13 1b was
initially reacted with N-bromosuccinimide (2 equiv) and HF·Py
(8 equiv) in Et2O at 0 °C.7a Under these conditions, 50%
conversion to the desired bromofluorinated product 3b was
reached after 24 h (Scheme 3). Further optimization of the
reaction conditions led to the use of 4 equiv of NBS/HF·Py
(1:2) in CH2Cl2 at 0 °C for full conversion after 5 min, with a
yield of 81% of the isolated product 3b (Scheme 3). The
B
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Letter
but [18F]Et4NF was used in subsequent fluorinations as it was
found to give more consistent results. We next examined the
bromofluorination of 1b with NBS. Treatment of 1b (8 mg)
with [18F]Et4NF (∼30 MBq), NBS (12 mg), and HF·Py (1 μL)
in DCM (300 μL) at room temperature for 20 min gave [18F]
3b in 47 4% RCY (n = 4) in addition to [18F]2b in 12 2%
RCY. As observed for the hydrofluorination, no reaction
occurred in the absence of carrier-added HF·Py. The geminal
difluorination of 1b was carried out in the presence of p-TolIF2
(6 mg) and Sn(OTf)2 (1 mg) with [18F]Et4NF in DCM to give
Scheme 5. Copper-Mediated HCF3 and HSCF3 Addition
pentafluoroethyl arene [18F]4b in 16
3% RCY. The
hydrofluorinated product [18F]2b was formed as additional
separable labeled product in 7 1% RCY. No additional HF·Py
was required for this reaction to proceed.
In conclusion, a new strategy to generate ArCHFCF3,
ArCBrFCF3, ArCF2CF3, ArCH(CF3)2, and ArCH(CF3)(SCF3)
was developed through formal α,α-difunctionalization of 1-
Scheme 6. Palladium-Catalyzed Hydrogenation of 1-(Diazo-
2,2,2-trifluoroethyl)arenes 1b and 1f
−
(diazo-2,2,2-trifluoroethyl)arenes with nucleophilic F−, CF3 ,
and CF3S− sources. Several salient features of this new
approach include its diversity-oriented approach, simplicity of
operation, and good substrate scope. Easy access to the
unexploited or new motifs ArCHFCF3 and ArCH(CF3)(SCF3)
may encourage studies aimed at delineating the particularities
of these fluorinated groups, for example, through a combination
of bond vector analysis and/or polarity and lipophilicity
measurements. An additional feature of this diversity-oriented
strategy is its bespoke design for [18F]-labeling. We are aware
that the carrier-added nature of the protocols we have
developed may narrow the range of applications of this new
[18F] technology, but to the best of our knowledge, this is the
first report allowing for the labeling of CF2CF3 from
[18F]fluoride, not from [18F]F2. We also disclose the first
examples of [18F]-labeled ArCHFCF3 and ArCBrFCF3 motifs.
These merits should find useful applications especially in the
field of radiotracer development for clinical applications and for
drug discovery.
Our ongoing interest in carbene reactivity for [18F]
radiochemistry21 prompted us to investigate 1-(diazo-2,2,2-
trifluoroethyl)arenes as precursors to [18F]-labeled CF3CHF-,
CF3CBrF-, and CF3CF2-arenes using cyclotron-produced
[18F]fluoride (Scheme 7). To the best of our knowledge,
Scheme 7. [18F]-Labeling of CF3CHF-, CF3CBrF-, and
CF3CF2-Arenes from [18F]Fluoride
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: veronique.gouverneur@chem.ox.a.uk.
Author Contributions
there is no report in the literature on the labeling of these
aromatic motifs; the radiochemistry available to date to access
the nonaromatic CF3CF2-containing radiotracer EF5 does not
employ [18F]fluoride but requires [18F]F2 addition across the
corresponding trifluoroalkene.22
⊥E.E. and J. T. contributed equally.
Notes
The authors declare no competing financial interest.
The reaction of 1b (8 mg) with either [18F]KF/K222 or
[18F]Et4NF (∼30 MBq), in DCM (300 μL) at room
temperature for 20 min, gave none of the desired hydro-
fluorinated product, [18F]2b, the only radioactive component
present being unreacted [18F]fluoride. When the reaction was
performed using [18F]Et4NF in the presence of 1 μL of HF·Py,
[18F]2b was formed in 64 3% RCY (n = 4) as determined by
radio-TLC and HPLC. [18F]KF/K222 led to product formation,
ACKNOWLEDGMENTS
■
Financial support was provided by the EU (Marie Curie
Fellowship, E.E., PIEF-GA-2011-300774), the EPSRC/CRUK
(M.T., A16466), the MRC (S.C., DMC1M12), and Advion
(S.C.). V.G. is holding a Royal Society Wolfson Research Merit
Award. The authors thank Florence Hardy (University of
Oxford) for the synthesis of selected starting materials.
C
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5364−5367. (d) Wang, X.; Xu, Y.; Deng, Y.; Zhou, Y.; Feng, J.; Ji, G.;
Zhang, Y.; Wang, J. Chem.Eur. J. 2014, 961−965.
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