Deoxyfluorination with CuF2: Enabled by Using a Lewis Base Activating Group

Article abstract of DOI:10.1002/anie.202001015

Deoxyfluorination is a primary method for the formation of C?F bonds. Bespoke reagents are commonly used because of issues associated with the low reactivity of metal fluorides. Reported here is the development of a simple strategy for deoxyfluorination, using first-row transition-metal fluorides, and it overcomes these limitations. Using CuF₂ as an exemplar, activation of an O-alkylisourea adduct, formed in situ, allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF₂. The utility of the process in enabling ¹⁸F-radiolabeling is also presented.

Full text of DOI:10.1002/anie.202001015

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Deoxyfluorination using CuF2 enabled by a Lewis base activating
group strategy
Authors: Deepali Eilidh Sood, Sue Champion, Daniel Dawson, Sonia
Chabbra, Bela Bode, Andrew Sutherland, and Allan J. B.
Watson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001015
Angew. Chem. 10.1002/ange.202001015
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10.1002/anie.202001015
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Deoxyfluorination using CuF2 enabled by a Lewis base activating
group strategy
D. Eilidh Sood,[a] Sue Champion,[b] Daniel M. Dawson,[a] Sonia Chabbra,[a] Bela E. Bode,[a] Andrew
Sutherland,[c] and Allan J. B. Watson*[a]
Abstract: Deoxyfluorination is a primary method for the formation of
C–F bonds. Bespoke reagents are commonly used due to issues
associated with the low reactivity of metal fluorides. Here, we report
the development of a simple strategy for deoxyfluorination using first-
row transition metal fluorides that overcomes these limitations. Using
CuF2 as an exemplar, activation of an O-alkylisourea adduct formed
in situ allows effective nucleophilic fluoride transfer to a range of
primary and secondary alcohols. Spectroscopic investigations have
been used to probe the origin of the enhanced reactivity of CuF2. The
utility of the process towards enabling 18F-radiolabeling is also
presented.
reagents offer the combined advantages of in situ activation of the
alcohol, while simultaneously addressing the solubility and
reactivity problems of fluoride.
Overcoming the problems with the use of MFn salts remains a
major challenge in this field. There are limited examples of the
use of alkali metal fluorides for deoxyfluorination.[6] Recent
seminal studies by Gouverneur demonstrated that KF and CsF
can also be used within asymmetric processes.[7] With regards
transition metal (TM) fluorides, AgF and AgF2 are frequently used
as fluoride sources;[8] however, there are limited examples of
other TM salts in fluorination processes,[9,10] where they are more
commonly employed as bases.[11] Here we show the development
of a simple method for deoxyfluorination with typically unreactive
TM fluorides, using CuF2 as an example (Scheme 1b).
The installation of C–F bonds is a fundamental approach towards
the modulation of molecular properties within agrochemicals,
pharmaceuticals, and materials.[1] Electronic effects imparted by
fluorine have become integral within pharmaceutical and
agrochemical development, e.g., enhancing metabolic stability or
for radiolabeling applications. In addition, the well-known non-
covalent interactions introduced by C–F bonds (e.g., the gauche
effect),[2] provides conformational control in a variety of cyclic and
acyclic systems and, in turn, exploration of molecular space.
Accordingly, methods for C–F bond formation are highly valuable
and continue to be advanced.
(a) Previous work: Examples of deoxyfluorination reagents
AG
OH
AG
F
F–
SN
F
O
R
R
2
Activation
R
R'
R'
R'
iPr
iPr
F
S
F
Me
Me
N
N
F
N
F
F
N
SO2F
iPr
iPr
DAST
DuPont (1975)
PhenoFluorTM
Ritter (2011)
PyFluor
Doyle (2015)
Deoxyfluorination is one of the most widely used methods for
conversion of alkyl alcohols to the corresponding fluorides,
achieved by nucleophilic displacement of the activated alcohol by
F– (Scheme 1a).[3] This suggests that cheap, readily available
metal fluorides (MFn) would be the ideal reagent for
deoxyfluorination. However, the intrinsic properties of MFn have
meant that their direct use in these processes is underdeveloped.
These species are generally highly solvated, polymeric,
hygroscopic, basic, have high lattice energies, and are often
poorly soluble in organic solvents.[1d,3b,4] To circumvent these
issues, bespoke reagents have been developed for
deoxyfluorination,[3,5] including diethylaminosulfur trifluoride
(b) This work: Deoxyfluorination via O-alkylisoureas using CuF2
via:
iPr
LnCu
N
OH
CuCl (1 mol%), DIC
F
iPr
R
R
F
O
N
then CuF2, ∆
R'
R'
H
R
• Inexpensive bulk reagents • Atypical F– source
R'
• Stereospecific
Scheme 1. (a) Deoxyfluorination using bespoke reagents. (b) This work.
Deoxyfluorination using CuF2. AG, activating group; DIC, N,N’-
diisopropylcarbodiimide.
Our approach was based on the proposal that a group used
for activation of an alcohol could act as a coordinating group for
MFn. Variation of the activating group would provide a Lewis basic
site that could, in principle, be tuned for coordination to a specific
metal. This approach may assist in overcoming solubility and
hydration issues by providing a vector for chelate-directed F–
transfer, potentially offsetting the issues with F– reactivity when
used in an intermolecular process.
(DAST),[5c] PhenoFluorTM [5i] and PyFluor[5j] (Scheme 1a). These
,
[a]
D. E. Sood, D. M. Dawson, S. Chabbra, Dr B. E. Bode., Dr A. J. B.
Watson
EaStCHEM, School of Chemistry
University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST, U.K.
E-mail: aw260@st-andrews.ac.uk
Dr S. Champion
West of Scotland PET Centre
Greater Glasgow and Clyde NHS Trust
Glasgow, G12 OYN, U.K.
Dr A Sutherland
An initial screen of TM fluorides and alcohol activating groups
revealed CuF2 and DIC-derived O-alkylisourea as a promising
system for the deoxyfluorination of benchmark substrate 1a
(Table 1; see ESI for full details). Optimization delivered a system
where Cu(I)-catalyzed formation of O-alkylisourea[12] followed by
deoxyfluorination using CuF2 at 100 ºC gave 2a in 78% isolated
yield with clean SN2 (entry 1).
[b]
[c]
WestCHEM, School of Chemistry
University of Glasgow
Several optimization points are worth noting: (1) The reaction
required formation of the O-alkylisourea prior to addition of CuF2.
Reduced efficiency was observed in experiments where all
Glasgow, G12 8QQ, U.K.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202001015
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COMMUNICATION
reagents were combined from the outset (entry 2). (2) The
addition of H2O to anhydrous CuF2 was essential. Removal of H2O
or use of the dihydrate was less effective (entries 4 and 5; vide
infra). (3) Alternative activating groups were less effective (entries
6-10). (4) The urea byproduct was found to inhibit the reaction,
suggesting an absence of advantageous urea•F– H-bonding,[13]
and due to formation of Cu(II)•urea complexes (entry 10);[14] (5) It
was possible to use an exogenous fluoride (KF) with
stoichiometric Cu(OTf)2 (entry 11), providing utility within Positron
Emission Tomography (PET) radiolabeling (vide infra). This
process does not operate without Cu(OTf)2; however, attempts to
use catalytic Cu(OTf)2 were unsuccessful, possibly due to Cu(II)
inhibition as noted above.
The generality of the CuF2 process was assessed using a
range of alcohol substrates (Scheme 3).
CuCl (1 mol%), DIC (1 equiv), CPME, 60 °C, 1 h;
then CuF2 (2 equiv), H2O (1 equiv), 100 °C, 24 h
OH
F
R
R'
R
R'
1a-1ai
2a-2ak
(a) Primary alcohols
N
Me
S
MeO
MeO
F
F
F
O2N
Me
F
N
N
2b, 81%
2c, 76%
2d, 61%[a]
2e, 78%
O
F
F
O
F
F
N
O
O2N
NO2
Table 1. Reaction development.
Cl
2i, 42%
O
2f, 77%
2g, 52%
2h, 89%
CuCl (1 mol%), DIC (1 equiv), CPME, 60 °C, 1 h;
OH
Me
F
Ph
Ph
F
F
then CuF2 (2 equiv), H2O (1 equiv), 100 °C, 24 h
F
Ph
Ph
Me
F
2l, 50%
1a
‘optimized conditions’
2a
N
Br
HO
Bn
F
2n, 48%[a]
Entry
Deviation from ‘optimized’ conditions
Yield[a]
2j, 68%
2k, 60%
2m, 48%
(b) Secondary alcohols
78[b] (94% es)[c]
1
None
OBn
OH
F
F
F
O
F
21 (19)[d]
Ph
2
All reagents present from start
Second stage temperature = 80 ºC
No water
Me
BnO
OBn
N
34
22
27
0
N
Bn
Cbz
3
OBn
F
2p, 42%[a]
2q, 72%[a]
2r, 49%
2a, 78%
94% es
2o, 68%
21:79 ⍺:β
4
F
F
F
Me
N
F
OH
5
CuF2•2H2O
Ph
Ph
Me
Me
Me
Me
Ph
Cl
R
6
Activating group = acetate
Activating group = tosylate
Activating group = methyl xanthate
Activating group = trichloroacetimidate
N,N’-diisopropylurea (1 equiv) additive
R = H; 2u, 77%[a]
2s, 49%
2t, 78%
16:1 dr
2y, 13%
R = Me; 2v, 60%[a]
R = Cl; 2w, 44%[a]
16
0
7
R = CO2Me: 2x, 85%[a]
F
F
F
Br
Me
F
8
32
38
57
Ph
Ph
Br
9
2z, 78%[a]
2aa, 34%
2ab, 20%
2ac, 42%[a]
F
10
11
(c) Bioactive molecules
Cl
F
Cu(OTf)2 (1 equiv), KF (2 equiv), 18-
crown-6 (2 equiv), 110 ºC, 1 h
O
Me
H
N
Me
H
N
Cl
Reactions performed on 1 mmol scale. [a] Determined by 1H NMR using an
internal standard. [b] Isolated yield. [c] Determined by HPLC using a chiral
stationary phase. [d] 100 ºC from start. CPME, cyclopentyl methyl ether.
H
N
S
Cl
Cl
F
F
H
N(nBu)2
Finally, while CuF2 was selected as an exemplar system, the
same process allows deoxyfluorination using a range of other first
row TM fluorides (e.g., Scheme 2).
2ad, 55%
(from Lumefantrine)
2ae, 69%
>20:1 d.r.
2af, 60%[a]
(from Perphenazine)
(d) Specific limitations
F
F
MeN
O
O
F
O
F
CO2Me
NPhth
2a (%)[a]
MFn
Me
Me
F
CuCl (1 mol%), DIC (1 equiv)
CPME, 60 °C, 1 h;
Ph
Ar
OMe
Ph
MnF3
FeF3
CoF3
NiF2
31
52
23
9
OH
Me
F
MeO
2ag, 0%
(75% elim.)
2ah, 0%
(58% elim.)
2ai, 0%
2ak, 0%
(36% elim.)
Ar = p-BrC6H4
2aj, 0%
(71% elim.)
then MFn (2 equiv)
H2O (1 equiv), 100 °C, 24 h
Ph
Ph
Me
(47% elim.)
1a
2a
ZnF2
28
Scheme 3. Example scope. Isolated yields unless noted. [a] Determined by NMR
using an internal standard.
[a]
Scheme 2. Use of other MFn. Reactions performed on 1 mmol scale.
Determined by 1H NMR using an internal standard.
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Primary alcohols were broadly accommodated in good yield
(Scheme 3a). A variety of common functional groups were
tolerated including aryl halides, heterocycles, and amine
protecting groups. The reaction was selective for SN2 vs. potential
SN2’ in systems where this is possible (2l, 2m). Similarly, the
reaction was effective for secondary alcohols (Scheme 3b). In
addition, the reaction demonstrated high stereospecificity across
several substrate types, including simple alcohols (2a, 94% es)
and aminoalcohols (2t, 16:1 dr), with good diastereoselection also
displayed for exemplar sugar substrate 2o (21:79 a:b). In addition,
the reaction was selective for displacement of the O-alkylisourea
vs. alkyl bromides (2aa), consistent with the experimental design.
Substrates inclined to SN1 pathways delivered product but in low
yield (2y). Specific substrates were noted to undergo efficient
fluorination (as determined by 19F NMR of the crude reaction) but
were prone to elimination on silica, leading to low yield (e.g., 2ab,
2ac). The reaction was chemoselective for primary alcohols in the
presence of phenols (2n) and secondary alcohols (2r), and
selective for secondary alcohols over tertiary (2s) except for a
specific 1,3-diol where unexpected selectivity was observed (see
ESI). More complex substrates also delivered the expected
products in good yield (Scheme 3c). Finally, specific limitations
(Scheme 3d) were observed with substrates liable to elimination
(2ag-2ak). Experiments to probe whether the approach would
operate for other common deoxyfluorination substrates (epoxides,
ketones) were unsuccessful, consistent with the activation
strategy.
NMR investigations. However, engagement of the O-alkylisourea
intermediate by Cu(II) was demonstrated by EPR (see ESI).
In terms of the engagement/activation of CuF2, we were
intrigued by the results which showed a critical dependence on
H2O: addition of 1 equiv H2O to anhydrous CuF2 was essential,
with both an anhydrous reaction and use of the dihydrate
significantly less effective (Table 1: entry 1 vs. entries 4 and 5). It
should be noted that commercial “anhydrous” CuF2 can contain
variable quantities of the dihydrate, which can affect reaction
efficiency. Accordingly, we sought to interrogate the nature of the
copper species generated using a combination of EPR, solid-
state NMR, and powder XRD. It was not possible to directly study
anhydrous CuF2 + H2O due to heterogeneity within the sample;
however, “aged” anhydrous CuF2 (stored on benchtop under air)
offered similar performance to anhydrous CuF2 + 1 equiv H2O.
We therefore used the aged sample for analysis. EPR proved
uninformative due to a lack of resolution of the hyperfine coupling
(see ESI). While greater insight was obtained through ssNMR and
powder XRD (see ESI), these only demonstrated that the aged
sample is essentially a superposition of the two pure phases,
suggesting either
a
unique phase somewhere between
anhydrous and dihydrate or mixture of phases.
As a control, it is known that heating CuF2•2H2O to the
threshold temperature of 132 ºC will produce a Cu(OH)F•CuF2
species with the release of HF and H2O (eqn 1).[18]
132 ºC
(eqn 1)
2 CuF2●2H2O
Cu(OH)F●CuF2
+
HF
+
3 H2O
As noted in Table 1 (entry 11), the deoxyfluorination can be
achieved using Cu(OTf)2 + KF. Based on this, it was envisioned
that this method could be readily adapted for radiofluorination.[15]
Radiochemical protocols often differ substantially from the
corresponding non-radioactive counterpart, mainly due to the
requirement of [18F]fluoride as the limiting reagent. However, a
proof of concept study with benchmark substrate 1a showed that
this process could be easily adapted for 18F radiolabeling
(Scheme 4). From initial radiochemistry experiments, only
increased CuCl catalyst loading (from 1 to 3 mol%) was required
for optimization of the radiochemical yield (RCY).[16] Use of the
standard reaction conditions from the 19F-protocol and [18F]F-
/K222 gave 18F-labeled product 2a’ in 54 ± 6% RCY (n = 2). While
radiofluorination can be performed with sulfonate activated
secondary alcohols, these are often accompanied with elimination
by-products.[15b,17] Using the controlled reactivity of the directed
copper-mediated [18F]fluoride displacement of the O-alkylisourea
adduct in this method allows clean formation of the
radiofluorinated product, directly from the alcohol substrate.
It is therefore plausible that HF could be produced in small
quantities in the present system, which posed the question
whether the observed reactivity was due to formation of HF in situ.
A series of control reactions were therefore conducted to explore
the possibility of CuF2 acting as a masked HF source including
treatment of the O-alkylisourea with HF and the use of acid- or
fluoride-sensitive additives to probe for the generation of HF in
situ (see ESI). Ultimately, while the generation of HF cannot be
ruled out conclusively, the totality of the current data suggests that,
if present, this contribution appears to be minimal.
In summary, a simple method for deoxyfluorination using first-
row transition metal fluorides has been developed and
exemplified using CuF2. The process is based on a proposed
chelate-driven fluoride transfer that effectively overcomes the
reactivity issues associated with these fluoride sources. Control
experiments and spectroscopic data suggest Cu(II) activation of
an O-alkylisourea with fluoride transfer from a hydrated Cu(II)F
species. The process can also be leveraged to allow effective 18
installation.
F
18F
CuCl (3 mol%), DIC (1 equiv), 60 °C, 1 h;
Cu(OTf)2 (1 equiv),
18F]F–/K222/K2CO3, MeCN, 110 °C, 1 h
OH
Me
[
Ph
Ph
Me
Acknowledgements
1a
2a’
54 ± 6% RCY
(n = 2)
We thank the University of St Andrews for PhD studentships
(D.E.S and S.C.), GlaxoSmithKline and the University of Glasgow
for financial support. We thank Dr Yuri G. Andreev (St. Andrews)
for assistance with powder XRD analysis, Dr Helen F. Sneddon
(GlaxoSmithKline) for useful discussions, Dr James W. B. Fyfe for
assistance with data analysis, and Mr Amand W. Connor for
assistance with sample preparation.
Scheme 4. Installation of 18F.
Efforts to understand the operation of the process were
difficult based on the heterogeneity of the system and the
stoichiometry of Cu(II), precluding in situ monitoring or meaningful
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10.1002/anie.202001015
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COMMUNICATION
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Keywords: copper • deoxyfluorination • fluorine • PET •
radiolabeling
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[16] During this proof of concept study, the use of more forcing conditions was
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10.1002/anie.202001015
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
D. Eilidh Sood, Sue Champion, Daniel
M. Dawson, Sonia Chabbra, Bela E.
Bode, Andrew Sutherland, and Allan J.
B. Watson*
via:
OH
CuCl (1 mol%), DIC
F
iPr
LnCu
N
R
R
then CuF2, ∆
R'
R'
iPr
F
O
N
H
>30 examples
• Stereospecific
R
• Inexpensive bulk reagents • Atypical F– source
R'
Page No. – Page No.
Deoxyfluorination using CuF2
enabled by a Lewis base activating
group strategy
A Lewis base activating group strategy enables deoxyfluorination using first-row
transition metal fluorides. Using CuF2 as an exemplar, activation of an O-alkylisourea
adduct formed in situ allows effective nucleophilic fluoride transfer to a range of
primary and secondary alcohols. Spectroscopic investigations have been used to
probe the origin of the enhanced reactivity of CuF2. The method is also amenable to
18F-radiolabeling.
This article is protected by copyright. All rights reserved.