(Radio)fluoroclick Reaction Enabled by a Hydrogen-Bonding Cluster

Article abstract of DOI:10.1002/anie.201711341

We have developed a widely applicable nucleophilic (radio)fluoroclick reaction of ynamides with readily available and easy-to-handle KF(¹⁸F). The reactions exhibited high functional-group tolerance and needed only an ambient atmosphere. This

Full text of DOI:10.1002/anie.201711341

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: (Radio)Fluoro-Click Reaction Enabled by a Hydrogen Bonding
Cluster
Authors: Gerald Hammond, Bo Xu, Xiaojun Zeng, Chin K Ng, and
Junling Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711341
Angew. Chem. 10.1002/ange.201711341
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10.1002/anie.201711341
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(Radio)Fluoro-Click Reaction Enabled by a Hydrogen Bonding
Cluster
Xiaojun Zeng,[a] Junling Li, [b] Chin K. Ng,[b] Gerald B. Hammond[c], * and Bo Xu[a],
*
Abstract: We have developed
a
widely applicable
additivity (hydrogen bond energy of a chain of H-bonds can be
greater than the total energies of the individual links),[9] strong
hydrogen bonding donors such as HFIP (hexafluoro-2-propanol)
could form a H-bond network or aggregation (Scheme 1c).[10]
This hydrogen-bonding network is a better H-bond donor than a
single HFIP, activating the electrophile via strong hydrogen
bonding interaction (Scheme 1c). Indeed, hydrogen bonding
donor solvents like HFIP have been shown to provide significant
rate enhancements in many reactions,[10a-c, 10f] and kinetic data
suggest that hydrogen-bonding solvent aggregates play an
important role.[10d]
nucleophilic (radio)fluoro-click reaction of ynamides with readily
available and easy handling KF(18F). The reactions exhibited
high functional group tolerance and needed only ambient
atmosphere. Most importantly, this is the first 18F addition
protocol to C-C unsaturated bonds with extraordinarily high
radiochemical yields.
Due to fluorine’s unique properties such as a small size and a
metabolically resistant C-F bond, the selective substitution of
hydrogen by fluorine constitutes a key strategy in drug discovery
and material research.[1],[2] More specifically, positron emission
tomography (PET) based on the radioactive fluorine isotope
(18F) has become increasingly important in diagnosis and drug
discovery.[3] But common fluorination reagents, including
nucleophilic fluorination reagents (e.g., HF-based reagents,
DAST) and electrophilic fluorination reagents (e.g., NFSI and
Selectfluor) are expensive, corrosive or toxic, and corresponding
fluorination processes often have very poor atom-economy.
Among fluorination reagents, alkali metal fluorides (MF), such as
KF, are inexpensive and easy to handle. Especially for
radioactive fluorine isotope introduction, the primary source of
18F is the alkali metal salt of 18F-. For the use of MF as
fluorination reagent,[4] especially in the introduction of 18F to
organic molecules,[5] the most common method is the
nucleophilic displacement of alkyl or aryl halides, pseudo halides,
ammonium or iodonium salts (Scheme 1a). In recent years,
there has been great progress in transition metal catalyzed
(radio)fluorinations using MF (Scheme 1b).[6], [7] However, these
metal catalyzed processes need more sophisticated conditions
and are usually limited to the synthesis of aryl fluorides. Clearly,
there is a need and a market for expanding the use of alkali
metal fluorides to other types of fluorination reactions, such as
addition reactions. We believe that the introduction of readily
available MF (18F) to an alkyne, under simple conditions and
with great efficiency, could pave the way to applications in
medicine and other fields in a manner not too dissimilar to the
click reaction (copper-catalyzed reaction of an organo azide with
an alkyne).[8] Thus, we have named this transformation a fluoro-
click reaction.
Scheme 1. Nucleophilic (radio)fluoro-click reaction using alkali fluorides.
Another problem of MF salts is their poor solubility in most
organic solvents. Since fluoride itself is a good hydrogen
bonding acceptor, a H-bond network could complex with MF and
make it highly soluble. Indeed, alkali fluorides such as KF have
good solubility in HFIP at room temperature. Also, it has been
reported that F- is a better nucleophile than other halides (Br-/I-)
in hydrogen-bonding donor solvents like t-BuOH, and t-BuOH
due to their positive effect on the ‘effective fluoride
nucleophilicity’.[11] Because HFIP is a stronger H-bond donor
than those alcohols, we expect it will have an even stronger
effect in the modulation of the nucleophilicity of fluoride. Lastly, a
H-bond network generated from HFIP could also act as a proton
source in hydrofluorination (Scheme 1c), as shown by Doyle and
coworkers in their copper-catalyzed H–F insertion into α-
diazocarbonyl compounds using HFIP as proton source.[12] We
are now glad to report the first 18F addition protocol to an alkyne
via a nucleophilic (radio)fluoro-click reaction, enabled by a
hydrogen bonding cluster and using the readily available KF(18F)
(Scheme 1d).
We propose that a hydrogen-bonding network can activate
alkali metal fluorides such as KF. Due to σ-cooperativity or non-
[
]
a
X. Zeng, Dr. B. Xu
College of Chemistry, Chemical Engineering and Biotechnology
Donghua University, Shanghai 201620, China
Email: bo.xu@dhu.edu.cn
Dr. J. Li, Dr. C.K. Ng
Department of Diagnostic Radiology, University of Louisville,
Louisville, KY 40292 USA.
Dr. G. B. Hammond
Department of Chemistry, University of Louisville
Louisville, KY 40292 USA.
[b]
[b]
E-mail: gb.hammond@louisville.edu
We used the hydrofluorination of ynamide 1a as our model
reaction (Table 1). Ynamides are readily available compounds
that have found wide applications in organic synthesis.[13]
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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10.1002/anie.201711341
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Although the hydrofluorination of ynamides have been
reported,[14] these methods are based on hydrogen fluoride or
silver fluoride as fluorination reagents, all of which are not
We were quite pleased to find that our protocol could be
used in the radio fluorination of ynamides 1 (Table 3). In all
cases, we got excellent radiochemical yields (RCY). Various
functional groups, including halogen, ester, nitrile, and nitro did
not affect the efficiency of the reaction, and heterocycles such
as thiophene and pyridine were well tolerated. To demonstrate
the applicability of our method in biological applications, we
prepared ynamide 2x, an organoazide (Table 3, [F18]2aa) and a
biologically active compound (Table 3, [F18]2z) with great
efficiency. In principle, an activated ester could be tethered to
biomolecules such as peptides or proteins easily in
radiochemistry via formation of amide linkage.[15] And the azide
linker could be easily attached to bioactive compounds via click-
chemistry.[16] It should be noted that our method does not require
the use of expensive polycyclic multidentate cation ligands such
environmentally friendly. More importantly, the introduction of 18
F
is difficult using these methods. Initially, we chose HFIP as our
hydrogen bonding activator and proton source. Screening of
various alkali metal fluorides indicated that metal fluorides with
bulkier counterions gave better results (Table 1, entries 1-4,
efficiency LiF < NaF < KF ~ CsF). Because KF and CsF gave
similarly good results, and KF is more inexpensive, we chose KF
as our fluorination reagent. Also, a higher temperature promoted
the formation of HFIP addition by-product 2a’ (Table 1, entry 5).
We investigated the effect of solvents (Table 1, entries 5-7).
Reducing the amount of HFIP (Table 1, entry 6) or using the
weaker hydrogen-bonding donor solvent trifluoroethanol (TFE)
diminished the reactivity (Table 1, entry 7). The amount of HFIP
addition by-product 2a’ was effectively reduced by increasing
the number of equivalents of KF (Table 1, entry 8).
as K222
,
which has been commonly used in other
radiofluorination protocols to increase the nucleophilicity of 18F-.
Table 2. Scope for the synthesis of α-fluoroenamides 3.a
Table 1.Screening of reaction conditions.[a]
Yield (%)
2a:2a’:1a
Entry MF
Temp / oC
Solvent
1
2
3
4
5
6
7
8
LiF
NaF
KF
rt
HFIP
3/4/93
rt
HFIP
6/4/90
rt
HFIP
64/31/4
62/33/5
32/59/9
33/34/32
2/0/98
CsF
KF
rt
HFIP
70
70
rt
HFIP
KF
HFIP/DCE (1:1)
TFE
KF
KFc
rt
HFIP
84/14/1
[a] Reaction conditions: 1a (0.2 mmol), MF (0.6 mmol), solvent (0.4 mL), 8
h. [b] Determined by GC-MS analysis. [c] 6 equiv of KF was used.
Having found the optimized conditions, we then explored
the scope and functional group tolerance of our hydrofluorination
protocol (Table 2). First, we evaluated the effect of R2
substitution in ynamides 1 (Table 2, 2a-2g). The structure of R2
(alkyl groups, aryl groups and allyl group, benzyl group,
heterocyclic groups) played only a minor role good yields of 2
were obtained regardless (Table 2, 2a-2g). We evaluated the
effect of R1 substitution (Table 2, 2h-2u). When R1 was a
benzylic group, substitution patterns (ortho, meta, para) and the
presence of electron donating groups or electron withdrawing
groups on R1 exerted little influence on the efficiency of the
reaction (Table 2, 2h-2s). This reaction also tolerated a wide
variety of other R1 variations: simple alkyl group (Table 2, 2t),
fused aromatic (Table 2, 2u), or even heteroaromatics, such as
thiophene and pyridine (Table 2 , 2v-2w). To demonstrate the
applicability of our method, we synthesized ynamides tethered to
activated ester and azido functionalities (Table 2, 2x-2y) or
complex natural products (Table 2, 2z, 2aa); in all these cases
our reaction worked very well.
a Reaction conditions: 1 (0.2 mmol), KF (1.2 mmol), HFIP (0.5 mL), rt. All
yields are isolated yields. b Run at 60 oC.
Our system was also extended to iodofluorinations[14a]
(Table 4). When the iodination reagent NIS was incorporated to
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COMMUNICATION
our fluorination system (KF/HFIP), we obtained the
iodofluorination product 3 (Table 4a). The yields were only
moderate, possibly due to the relatively instability of the resulting
vinyl-iodides. To our delight, the corresponding radio-
iodofluorination was very efficient: close to 80% RCY yield was
obtained (Table 4b).
Our methodology is scalable (Scheme 2a) and the reaction
products could be further utilized in transition metal catalyzed
cross-coupling reactions. As shown in Scheme 2b and 2c, the
Suzuki coupling of 2m with phenyl boronic acid gave moderate
yield of the coupling product 4a, and the Sonogashira coupling
of 2m only furnished the aromatic substitution product 4b.
The proposed mechanism is shown in Scheme 3. The
hydrogen-bonding network generated from HFIP facilitates the
rate-determining proton transfer step, which produces the key
intermediate--keteniminium A.[17] Keteniminium A possesses a
linear geometry,[17] with its upper face being sterically hindered
by the R1 group, thus favoring the nucleophile (fluoride) syn
approach (formation of the syn-addition product) (Scheme 3,
top).[18] On the other hand, in the presence of NIS, an iododium
B forms instead because NIS is a strong electrophile; ring-
opening of B by fluoride yields the anti-addition product 3
(Scheme 3, bottom).
Table 3. Radio fluorination of ynamides 1.a
H
18F
EWG
R2
HFIP (0.5 mL), K18
60 oC, 1.0 h
F
R1
N
R1
N
EWG
R2
1
[F18]2
I
Ms
N
Ts
Ms
N
Ph
H
N
Ph
N
18F
18F
18F
H
[F18]2m
H
2b
[F18]
[F18]2w
RCY 99 ± 1% (n = 3)
isolated yield 96 ± 1%
(n = 3)
RCY 99 ± 1% (n = 3)
isolated yield 97 ± 1%
(n = 3)
RCY 89 ± 3% (n = 3)
isolated yield 76 ± 13%
(n = 3)
18F
Ms
N
H
18F
H
O
N
Ms
O
O
N3
[F18]2y
[F18]2aa
RCY 99 ± 1% (n = 3)
isolated yield 97 ± 1%
(n = 3)
RCY 88 ± 12% (n = 3)
isolated yield 82 ± 12%
(n = 3)
a
Reaction conditions: 1 (0.015 mmol) in HFIP (100 µl) was mixed with
18F (~ 0.3 mCi, in 50 µL HFIP), 60 oC, 1 h. Reactions were performed 3
times; radiochemical yields were determined by radio-HPLC and are
given in the form mean ± standard deviation.
Table 4. Iodofluorinationa and radio iodofluorinationb of ynamides 1.
Scheme 2. Gram scale reaction and further synthetic manipulations.
Scheme 3. Proposed mechanism.
a Reaction conditions: 1 (0.2 mmol), KF (1.2 mmol), NIS (0.24 mmol)
HFIP (0.4 mL), DCM (0.1 mL), rt, 8 h. b Reaction conditions: 1 (0.015
mmol),NIS (2.7mg) in HFIP (100 µl) was mixed with 18F (~ 0.3 mCi, in 50
µl HFIP), 60 oC, 1 h. Reactions were performed 3 times; radiochemical
yields were determined by radio-HPLC and are given in the form mean ±
standard deviation.
In summary, we have developed a widely applicable
synthesis of α-fluoroenamides using KF(18F). The reactions
exhibited high functional groups tolerance and needed only
ambient atmosphere. Most importantly, this is the first 18F
addition protocol to C-C unsaturated bonds with extraordinary
high radiochemical yields. Other (radio)fluorination systems
based on KF/HFIP system are currently being investigated in our
laboratories.
We also investigated the serum stability of our synthesized
18F-tracer in fetal bovine serum (incubated at 37 oC for 2 h, see
section 7 of SI). Our results, based on three radiotracers (2b,
2w, 2y) showed that they were stable for up to 2 h in serum.
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Acknowledgements
We are grateful to the National Science Foundation of
China (NSFC-21672035) and China Recruitment Program of
Global Experts for financial support. G.B.H. is grateful to the
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10.1002/anie.201711341
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
We developed a widely
applicable nucleophilic
(radio)fluoro-click
Xiaojun Zeng, Junling Li,
Chin K. Ng, Gerald B.
Hammond,* and Bo Xu*
reaction of ynamides
using readily available
KF(18F). This is also
the first 18F addition
protocol to C-C
Page No. – Page No.
(Radio)Fluoro-Click
Reaction Enabled by a
Hydrogen Bonding
Cluster
unsaturated bonds.
This article is protected by copyright. All rights reserved.