Nucleophilic (Radio)Fluorination of α-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H-F Insertion

Article abstract of DOI:10.1021/jacs.6b06770

The copper-catalyzed H-F insertion into α-diazocarbonyl compounds is described using potassium fluoride (KF) and hexafluoroisopropanol. Access to complex α-fluorocarbonyl derivatives is achieved under mild conditions, and the method is readily adapted to

Full text of DOI:10.1021/jacs.6b06770

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Communication
Nucleophilic (Radio)Fluorination of #-Diazocarbonyl
Compounds Enabled by Copper-Catalyzed H–F Insertion
Erin E. Gray, Matthew K. Nielsen, Kimberly A. Choquette,
Julia Ann Kalow, Thomas J. A. Graham, and Abigail G. Doyle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06770 • Publication Date (Web): 08 Aug 2016
Downloaded from http://pubs.acs.org on August 8, 2016
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Nucleophilic (Radio)Fluorination of α-Diazocarbonyl Compounds
Enabled by Copper-Catalyzed H–F Insertion
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Erin E. Gray†, Matthew K. Nielsen†, Kimberly A. Choquette†, Julia A. Kalow†, Thomas J. A. Graham‡,
Abigail G. Doyle†,*
†Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
‡Translational Biomarkers, Merck Research Laboratories, West Point, Pennsylvania 19486, United States
Supporting Information Placeholder
α-[18F]fluorocarbonyl scaffold is featured heavily in PET tracers,
ABSTRACT: The copper-catalyzed H–F insertion into α-
in part as a tag for labeling biomolecules such as peptides, which
diazocarbonyl compounds is described using potassium
are desirable as PET probes due to their binding specificity.8 Typ-
ically, C–18F bonds are formed by nucleophilic substitution with
[18F]KF in the presence of phase transfer reagent Kryptofix 2.2.2.
(K222). While this approach takes advantage of nucleophilic fluo-
ride as a readily available, high specific activity source of fluo-
rine-18, the harsh conditions necessary for substitution (high tem-
peratures and basicity) are not suitable for the direct radiofluorina-
tion of most α-[18F]fluorocarbonyl targets.9 Instead, an indirect
method is pursued wherein fluorine-18 is first introduced into a
reactive precursor, such as activated ester [18F]NFP, and then into
the compound of interest (Figure 1B).2b This prosthetic group
strategy necessitates multiple radiochemical steps, highlighting
the limitations of classic nucleophilic substitution with [18F]KF.
fluoride (KF) and hexafluoroisopropanol. Access to
complex α-fluorocarbonyl derivatives is achieved under
mild conditions, and the method is readily adapted to
radiofluorination with [18F]KF. This late-stage strategy
provides an attractive route to 18F-labeled biomolecules.
Methods for the construction of C–F bonds are of high synthet-
ic value due to the broad applications of organofluorine com-
pounds as pharmaceuticals, agrochemicals, and materials.1 Addi-
tionally, strategies to incorporate fluorine-18 into organic mole-
cules are important for the synthesis of radiotracers for positron
emission tomography (PET), a minimally invasive molecular
imaging technology used in diagnostic medicine and clinical
pharmaceutical research.2 The demand for increasingly complex
radiotracers has stimulated the development of late-stage fluorina-
tion strategies.3 Although PET applications are frequently cited as
a rationale for the identification of these new fluorination tech-
niques, the successful translation of contemporary fluorination
approaches to practical and valuable radiofluorination protocols
remains a critical challenge.4 In addition to the inherent difficul-
ties associated with forming C–F bonds,5 several unique obstacles
must be addressed to translate a fluorination reaction to the 18F-
radionuclide counterpart. Methods must use fluoride as a limiting
reagent and take place rapidly, owing to the low available concen-
trations (nM to µM) of the short-lived 18F-radioisotope (half-life =
110 min).2 Additionally, the radiochemical protocol should pro-
ceed with high specific activity and be amenable to automation or
use by non-specialists.
HO2CH2C
O
O
A. Targets:
N
H
O
NH
Bn
HN
O
O
F
NH
H
18F
N
NH2
NH
NH HN
N
H
O
3
Et
O
NH2
OH
O
4
N
NH
HO
MeO
O
CO
O
O
Me
HO
N
H
H2N
O
OH
18F
[
18F]FAO
ODC ligand
[
18F]Galacto-RGD
avb3 integrin ligand
IRAK4 inhibitor (Pfizer)
inflammatory disease
B. Prosthetic group strategy:
NO2
[
18F]KF
O
O
XH
O
Me
Me
18F
Me
18F
Y
X
O
Br
[
18F]NFP
multi-step radiosynthesis
radiotracer
To address these challenges, we sought to design a new catalyt-
ic method for the synthesis of α-fluorocarbonyl compounds that
would enable late-stage fluorination and translate readily to radio-
synthesis. Among medicinally relevant fluorinated molecules, the
α-fluorocarbonyl motif is prevalent and serves as a versatile build-
ing block for the construction of numerous aliphatic fluorine-
containing structures (Figure 1A).5 Many highly selective catalyt-
ic methods have been identified for the synthesis of α-
fluorocarbonyl derivatives using electrophilic fluorine sources.3,6
However, these strategies are not well suited for radiofluorination
in a clinical setting because electrophilic fluorination reagents
C. This work:
mild and functional
group tolerant
O
O
KF or [18F]KF
R
R
F/18
X
X
single-step, late-stage
(radio)fluorination
catalytic H–F
insertion
N2
F
Figure 1. (A) α-Fluorocarbonyl-containing bioactive targets. (B)
Multistep assembly of complex radiotracers using an α-fluoroacyl
prosthetic group. (C) Catalytic (radio)fluorination of α-diazocarbonyl
compounds.
generally
suffer
from
low
specific
activity.7
The
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Identification of catalytic schemes for α-fluorocarbonyl synthesis
1
2
3
4
that use nucleophilic fluoride, tolerate biologically relevant func-
tionality, and are amenable to radiofluorination would enable the
radiosynthesis of previously challenging or inaccessible PET trac-
ers in a single step. Furthermore, such methods could prove com-
plementary in scope to known electrophilic fluorination reactions.
Table 1. Reaction optimization.
O
[Cu(MeCN)4]PF6 (5 mol%)
O
O
Ph
(S,S)-t-BuBOX (7.5 mol%)
OMe
CF3
Ph
Ph
OMe
OMe
O
KF (3 equiv), HFIP (20 equiv)
DCE (0.1 M), 40 °C, 1 h
N2
1a
F
5
CF3
Here we report the development of a copper-catalyzed fluorina-
tion of α-diazocarbonyl compounds with KF (Figure 1C). This
reaction facilitates the direct installation of fluorine-19 and fluo-
rine-18 into advanced substrates under mild and functional group-
tolerant conditions. We chose to investigate α-diazocarbonyl
compounds as precursors to α-fluorocarbonyl derivatives since the
diazo functionality is known to react rapidly with transition metals
to form electrophilic metal carbenoids that can insert into carbon–
hydrogen, carbon–heteroatom, and heteroatom–hydrogen bonds
under mild conditions.10 Although this approach has become a
powerful tool to forge new C–X (X = C, Si, N, O, S) bonds regio-
and stereoselectively,11 the catalytic insertion into halogen–
hydrogen bonds has not been reported. The Davies group has
recently described a silver-catalyzed fluorination of vinyl diazo-
acetates with Et3NŸ3HF, but this transformation yields γ-fluoro-
α,β-unsaturated carbonyl compounds rather than fluorinating at
the carbenoid position.12 Direct fluorination of α-diazocarbonyl
substrates may be accomplished with highly reactive and acidic
HF-containing reagents.13-16 Only simple, unfunctionalized sub-
strates are tolerated, however, and translation to PET applications
is challenging.17
6
7
8
9
2a
3
Yield 2aa
Yield 3a
(%)
entry
conditions
(%)
68b
64c
1
2
standard conditions
2
1
10
11
12
13
14
15
16
17
18
19
20
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59
60
PhCOF (2 equiv), HFIP (4
equiv), DBN (20 mol%) instead
of KF/HFIP
3
4
no Cu or ligand
no HFIP
1
0
4
n/a
n/a
n/a
35
5
5
TFE instead of HFIP
phenol instead of HFIP
HFIP (3 equiv)
22
7
6
7
39
64
35d
57
53
8
HFIP (10 equiv)
9
ligand L2 instead of L1
ligand L3 instead of L1
15
10
4
10
11
[Rh(OAc)2]2 instead of
Cu/ligand
As an alternative to using stoichiometric HF or HF-containing
reagents, we envisioned accessing the reactive equivalent from the
combination of a mild fluoride reagent and proton source. Initial
experiments were conducted using diazoacetate 1a as a model
substrate with a copper (I) catalyst and a commercially available
bis(oxazoline) ligand L1 (Table 1). Previously, our laboratory
reported the enantioselective hydrofluorination of epoxides and
aziridines using benzoyl fluoride (PhCOF) and 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP) as a latent HF source.18 For the HF
insertion chemistry, this combination yielded the desired α-
fluoroester 2a (entry 2); however, since [18F]PhCOF is not readily
accessible, we evaluated other reagents that offer more convenient
sources of fluorine-18. Promisingly, the combination of KF and
HFIP provided the desired product in 68% yield (entry 1).
12
62e
2
[Cu(OTf)]2ŸPhMe instead of
[Cu(MeCN)4]PF6
Me Me
Me Me
O
Me Me
O
O
O
O
O
N
N
N
N
N
N
Ph
Ph
t-Bu
t-Bu
L1
(S,S)-t-BuBOX
L2
L3
aDetermined by 19F NMR, 0.1 mmol scale using fluorobenzene as an
external standard. b9% ee, determined by chiral HPLC. c15% yield in
the absence of Cu and ligand. d23% ee. e31% ee.
With the optimized conditions in hand, we next explored the
scope of this transformation and found that a variety of aryldiazo-
acetate substrates perform well (Table 2). Substitution around the
aromatic ring is well tolerated (2b–d), including at the ortho posi-
tion, which suppresses substrate dimerization. High yields of the
desired products containing σ- and π-electron-withdrawing sub-
stituents (2e–k) are obtained, albeit with slightly longer reaction
Interestingly, HFIP is necessary for productive chemistry (entry
4). Deuterium-labeling experiments indicate the OH proton of
HFIP is incorporated into the product; however other proton
sources with similar pKas are inadequate substitutes (entries 5 and
6), suggesting an additional role for HFIP. Although HFIP is
considered a poor nucleophile,19 competitive O–H insertion (3) is
observed as the major side product, along with dimerization of the
diazo substrate.20 Counterintuitively, the yield and selectivity of
the reaction is significantly improved by increasing the equiva-
lents of HFIP (entries 7 and 8). We hypothesize that HFIP solv-
ates the otherwise insoluble KF and that increasing HFIP concen-
tration alters the solvent coordination environment of fluoride,
leading to a more reactive species. This finding appears related to
the influence of t-BuOH on reactions with TBAF and may prove
useful for enhancing the reactivity of other fluorination reactions
using KF.21 The reaction is less efficient with other commercial
bis(oxazoline) ligands such as L2 and achiral ligand L3 (entries 9
and 10). Evaluation of other transition metal catalysts proved
Cu(I) is most effective, as Rh2(OAc)2 delivered 2a in modest yield
times or higher temperatures (2g–i).
Electron-rich α-
diazocarbonyl substrates are less effective under the reaction con-
ditions; nevertheless, fluorinated products 2l, 2m, and 2o are fur-
nished in 30%, 46%, and 72% yields, respectively. Notably,
many valuable functional groups are tolerated in the reaction,
including azides (2k), silyl-protected alcohols (2n), and Lewis
basic functionality (2o, 2p). These results are significant as many
of these common functional groups are not compatible with cur-
rent electrophilic α-fluorination methods. Furthermore, this
straightforward protocol is readily scalable, as 2i was isolated in
89% yield in a multi-gram-scale reaction set up on the benchtop.22
The reaction is also generalizable to other α-diazocarbonyl pre-
cursors, including terminal diazoacetates (2q), diazoketones (2r),
and diazoacetamides (2s–2y). Acceptor/acceptor α-diazoester
compounds, however, are unreactive,16b and α-alkyl-α-
diazoacetates predominately undergo elimination to afford α,β-
unsaturated esters with only trace amounts of the desired fluor
inated products.22 To probe the scope of the reaction further, we
investigated the fluorination of α-diazo substrates derived
(entry 11).22
Although the optimal conditions with
[Cu(MeCN)4]PF6 and bis(oxazoline) L1 afford 2a in low ee, mod-
est asymmetric induction is achieved using [Cu(OTf)]2ŸPhMe
(31% ee, entry 12), demonstrating for the first time that enantiose-
lective halogen–hydrogen insertion is feasible using transition
metal catalysis.
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Table 2. Scope of fluorination.a
[Cu(MeCN)4]PF6 (5 mol%)
(S,S)-t-BuBOX (7.5 mol%)
O
O
R
R
X
X
4
5
6
7
KF (3 equiv), HFIP (20 equiv)
DCE (0.1 M), 40 °C, 1–5 h
N2
1a–y
F
2a–y
Me
Me
F
Br
O
O
O
O
O
O
8
OMe
Me
OMe
OMe
OMe
OMe
OMe
9
F
F
F
F
F
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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58
59
60
2a
67% yield
2b
59% yield
2c
61% yield
2d
71% yield
2e
72% yield
2f
81% yield
F3C
O2N
MeO
O
O
O
O
O
O
O2N
OMe
MeO
OMe
N3
OMe
OMe
OMe
OMe
F
F
F
F
F
F
2i
2h
81% yieldb
2l
2g
78% yield
2j
66% yield
2k
71% yield
91% yieldc
30% yieldd
O
OTIPS
O
S
O
O
O
O
O
O
O
O
OMe
O
F
F
F
N
NHBn
OBn
Ph
OMe
OMe
F
N
OMe
F
i-Pr
O
CF3
F
F
2m
46% yield
2n
60% yield
2o
72% yield
2p
63% yield
2q
14% yield
2r
23% yield
2s
49% yield
OBz
O
O
Ph
O
O
O
O
H
F
BzO
BzO
O
F
N
H
F
N
F
N
N
H
OBn
Me
OH
N
H
F
NEt2
HN
NHBoc
N
H
OBz
MeO
O
O
NH2
O
O
Ot-Bu
Me
F
2u
22% yield
2v
74% yield
2w
38% yield
2x
77% yield
2y
47% yield
2t
50% yield
aYields are the average of two runs, 0.18-0.5 mmol scale. bReaction run at 50 °C for 24 h. cReaction run at 45 °C. dReaction run at rt.
from biologically relevant structures. Importantly, this approach
provides access to fluorinated amino acid derivatives (2v, 2w),
peptides (2x), and glycosides (2y) bearing unprotected, protic
amines (2u) and alcohols (2w). The exceptional functional group
tolerance of these examples highlights the mildness of the reaction
conditions and the potential for late-stage fluorination
ble 3). Thus for applications requiring high specific activity,
[Cu(MeCN)4]ClO4 should be used in place of [Cu(MeCN)4]PF6.
Based on these results and with insights gained from the 19F-
catalytic system, we interrogated the generality of the
α-radiofluorination. Complex α-diazocarbonyl substrates were
subjected to the procedure with [18F]KF-K222, and trends in the
functional group tolerance of the 19F-conditions were recapitulat-
ed in the radiofluorination (Table 3). Diazo esters and amides are
competent in the reaction, and Lewis basic ([18F]2o, [18F]2t) as
well as protic functionality on peptides ([18F]2x) and glycosides
([18F]2y) is compatible. Moreover, known radiotracer N5-
[18F]FAO ([18F]2v)24 is readily accessible using this practical
approach, as is the homologue of PET probe [18F]FPDA
([18F]2t).25 Notably, the one-step copper-catalyzed radiofluorina-
tion is significantly higher yielding than the synthetic sequences
previously reported in the literature: whereas [18F]FPDA required
installation of a prosthetic group over four radiochemical steps
with 3% overall RCY, [18F]2t can be generated in 45% RCC in a
single step. Likewise, N5-[18F]FAO, which was previously pre-
pared by SN2 displacement of bromide with 8% RCY, can be
labeled under our conditions in 38% RCC. This method estab-
lishes a strategic alternative for the radiofluorination of complex
biomolecules via their diazoacetylated precursors.26
We then sought to demonstrate the utility of this transformation
by identifying a practical radiochemical protocol. By designing
our reaction with KF, we envisioned this method would be readily
adaptable to the direct, late-stage radiofluorination of
α-diazocarbonyl compounds simply by applying [18F]KF and K222
to our standard reaction conditions. Typically, radiochemical
protocols differ substantially from their synthetic counterparts,
and most syntheses employing [18F]KF require high temperatures
(>100 °C) for reactivity. Therefore, we were pleased to find that
substrate 1a underwent radiofluorination in excellent radiochemi-
cal conversion (80% RCC) using the combination of [18F]KF-K222
and HFIP at 50 °C (Table 3). Control experiments without copper
or HFIP delivered no significant radiochemical conversion, and
the reaction conditions are remarkably similar to the 19F-protocol.
Under these standard conditions, however, [18F]2a was ob-
tained in poor specific activity (24 mCi/µmol) suggesting that at
least one reagent other than KF contains labile fluoride. Con-
sistent with previous reports,23 we found that HFIP is not a signif-
icant fluoride source; yet, in the absence of KF, the hexafluoro-
phosphate anion of the copper catalyst generates small amounts of
product.22 Replacing hexafluorophosphate with a perchlorate ani-
on restores specific activity to 1300 mCi/µmol, a value consistent
with other no-carrier-added radiofluorinations (Catalyst B in Ta-
This work introduces a new method for catalytic C–F/18F bond
formation enabled by copper catalysis and the use of KF-HFIP as
a reactive fluoride source. The approach generates useful
α-fluorocarbonyl derivatives under mild reaction conditions and is
compatible with a variety of valuable functional groups. Fur-
thermore, by considering translation to fluorine-18 in our design
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ly drying reagents.
1
2
3
4
5
6
7
8
Table 3. Radiofluorination using [18F]KF.a
Catalyst A: [Cu(MeCN)4]PF6 or
Catalyst B: [Cu(MeCN)4]ClO4
(S,S)-t-BuBOX
O
O
R
R
X
X
N2
18F
2a–y
[
18F]KF-K222, HFIP
DCE, 50 °C, 10 min
1a–y
O
9
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18F
NEt2
OMe
O
OMe
N
H
18F
N
18F
18F]2a
i-Pr
O
[
[
18F]2o
[
18F]2t
A: 80 ±7% RCCb (n = 3) A: 64 ±6% RCC (n = 3)
B: 74 ±16% RCCc (n = 3) B: 88 ±2% RCC (n = 3)
A: 32 ±9% RCC (n = 4)
B: 45 ±5% RCC (n = 3)
OBz
O
Ph
O
O
O
18F
H
N
O
BzO
BzO
N
H
18F
N
H
OBn
OBz
Me
HN
NHBoc
O
O
Ot-Bu
Me
18F
[
18F]2y
[
18F]2v
A: 38 ±11% RCC (n = 4) A: 53 ±25% RCC (n = 3)
B: 25 ±1% RCC (n = 2) B: 16 ±3% RCC (n = 3)
[
18F]2x
A: 36 ±9% RCC (n = 3)
B: 53 ±2% RCC (n = 3)
aRCC determined by radio-TLC and corrected for insoluble activity;
identity of product confirmed by radio-HPLC. bSpecific activity:
24 mCi/µmol EOB. cSpecific activity: 1300 mCi/µmol EOB.
and employing commonly used [18F]KF-K222, we are able to ef-
fect the one-step radiofluorination of biomolecules under opera-
tionally convenient conditions.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, additional reaction optimization, and
spectroscopic data for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
agdoyle@princeton.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Dr. Eric Hostetler (Merck & Co., Inc., West Point, PA)
for providing access to radiosynthesis facilities and Ivanny
Jacome Ottati for substrate synthesis. Financial support from
Janssen Research & Development LLC and NSF (CHE-1565983)
is gratefully acknowledged. This material is based upon work
supported by the National Science Foundation Graduate Research
Fellowship under Grant No. DGE-1148900 (E. E. G.) and a F32
Ruth L. Kirschtein NRSA Fellowship under award No.
GM108291 (K. A. C.).
(21) Engle, K. M.; Pfiefer, L.; Pidgeon, G. W.; Giufreddi, G. T.;
Thompson, A. L.; Paton, R. S.; Brown, J. M.; Gouverneur, V. Chem.
Sci. 2015, 6, 5293.
(22) See SI for details.
(23) Revunonv, E.; Zhuravlev, F. J. Fluorine Chem. 2013, 156,
130.
REFERENCES
(24) Turkman, N.; Gelovani, J. G.; Alauddin, M. M. J. Label
Compd. Radiopharm. 2011, 53, 33.
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(25) Liu, H.; Liu, S.; Miao, Z.; Jiang, H.; Deng, Z.; Hong, X.;
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