Rhodium-mediated 18F-oxyfluorination of diazoketones using a fluorine-18-containing hypervalent iodine reagent

Article abstract of DOI:10.1039/c9cc06905d

Geminal ¹⁸F-oxyfluorination of diazoketones was performed in the presence of rhodium mediators. The reactions were performed using a hypervalent iodine-based [¹⁸F]fluoro-benziodoxole reagent. By this methodology various α-[¹⁸

Full text of DOI:10.1039/c9cc06905d

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Rhodium-mediated F-oxyfluorination of
diazoketones using a fluorine-18-containing
hypervalent iodine reagent†
a
Cite this: Chem. Commun., 2019,
55, 13358
Received 4th September 2019,
Accepted 10th October 2019
Miguel A. Cortes Gonzalez,
Xingguo Jiang,a Patrik Nordeman,b Gunnar Antonib
´
´
a
and Kalman J. Szabo
*
´
´
´
DOI: 10.1039/c9cc06905d
rsc.li/chemcomm
Geminal 18F-oxyfluorination of diazoketones was performed in the by the half-life of fluorine-18 (109.7 minutes). A typical problem
presence of rhodium mediators. The reactions were performed with downscaling (see (i) above) of the reactions is that certain
using a hypervalent iodine-based [18F]fluoro-benziodoxole reagent. By side-reactions (leading to insignificant decrease of the yields in
this methodology various a-[18F]fluoro ethers were obtained in high stoichiometric fluorine-19 reactions) may prevail in the case
radiochemical yield (up to 98%) and molar activity (216 GBq lmolÀ1).
of using minute amounts of fluorine-18 reagents, completely
inhibiting the formation of the desired 18F-fluorinated products.
Organofluorine compounds have found a lot of recent applications Fluorine isotope exchange is, of course, not an issue in the
in the pharmaceutical1 and agrochemical industries2 as well as in development of new reactions with the natural fluorine isotope.
medical diagnostics.3 A high demand of structurally diverse However, exchange of fluorine-18 isotope with fluorine-19 (arising
organofluorine compounds in drug discovery1 and crop- from fluorinated reactants or ambient fluorine-19 sources) leads to
protection2b has led to a revolutionary development of new low molar activity of a 18F-labelled product limiting its use as a PET
methodologies in the synthesis of organofluorine compounds.4 tracer (see (ii) above).
In recent years this development has been focused on the use of
As a part of our organofluorine chemistry program,7 we have
new reagents and catalytic methods for the synthesis of organo- studied the use of the increasingly popular hypervalent iodine-
fluorines with high selectivity under mild reaction conditions.4 based fluorinating reagents8 for fluorine-18 labelling.7f [18F]Fluoro-
However, fluorine-18 labelling of organic compounds for Positron benziodoxole is a versatile electrophilic reagent, which can be
Emission Tomography (PET)3 (which is one of the most important easily generated (from [18F]Bu4NF) and purified in a standard
fields of organofluorine chemistry in medical diagnostics), has clinical environment.7f A particularly attractive feature of [18F]fluoro-
experienced less benefits of the development of synthetic organo- benziodoxole, [18F]1, is that it can be used for fluorine-18 labelling
fluorine chemistry than the other fields mentioned above. Indeed, with a remarkably high molar activity,7f which is several orders of
bridging the gap between recent advances in organofluorine magnitude higher than the molar activity reported for other electro-
chemistry and fluorine-18 labelling of PET tracers5 has become philic fluorinating reagents, such as [18F]F2 and related reagents.9
one of the greatest challenges in synthetic methodology.3a,6 The
In this paper we report our studies on geminal 18F-oxy-
main difficulty is to adapt the use of new reagents and catalysts to fluorination of diazocarbonyl compounds with [18F]fluoro-
the conditions of fluorine-18 labelling in a clinical environment. benziodoxole, [18F]1 (Fig. 1c). Previously, Gouverneur and
Some of the most important challenges of the adaptation co-workers reported a difluorination reaction of diazocompounds
(translation) of stoichiometric scale fluorine-19 chemistry to using [18F]Et4NF as a nucleophilic fluorine-18 source and pTolIF2 as
fluorine-18 labelling methods are: (i) downscaling the amounts an electrophilic fluorine-19 source (Fig. 1a).6b Subsequently, Doyle
of the fluorinating reagents to micromolar sometimes pico- and co-workers6d described a copper-catalysed asymmetric nucleo-
molar scale; (ii) requirement of very high fluorine-18 isotopic philic 18F-fluorination of diazocarbonyls (Fig. 1b) in good radio-
purity of the product (which is characterized by the molar chemical yields and molar activity. The methodology of using an
activity); and (iii) the brief timescale of the synthesis dictated electrophilic [18F]fluoro-benziodoxole reagent ([18F]1) is based on
our7c recent rhodium catalysed geminal oxyfluorination method.
Using this methodology a biologically relevant a-fluoro ether motif2a
can be introduced in a single reaction step in a multicomponent
a Department of Organic Chemistry, Stockholm University, SE-106 91, Sweden.
E-mail: kalman.j.szabo@su.se; Web: http://www.organ.su.se/ks/
process (Fig. 1c).
b Department of Medicinal Chemistry, Uppsala University, SE-751 23, Sweden
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data and radiochemistry. See DOI: 10.1039/c9cc06905d
As mentioned above stoichiometric amounts of diazocarbonyl
compounds (2), alcohols and fluoro-benziodoxole (1) react readily
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Table 1 Deviation of reaction conditionsa
Entry
Deviation
RCYb (%)
1
2
3
4
5
6
7
8
9
None
98 Æ 1 (n = 2)
0 (n = 2)
Methanol instead of 3
Benzyl alcohol instead of 3
DCM/3 1 : 1
2 Æ 2 (n = 2)c
0 (n = 2)
Rh2(OAc)4 instead of Rh2(OPiv)4
Rh2(esp)2 instead of Rh2(OPiv)4
Rh2(TPA)4 instead of Rh2(OPiv)4
No Rh
90 Æ 2 (n = 2)
21 Æ 1 (n = 2)
26 Æ 9 (n = 2)
0 (n = 2)
Fig. 1 18F-Fluorination of diazo compounds.
[
18F]Bu4NF instead of [18F]1
0 (n = 2)
a
Unless otherwise stated, to a mixture of Rh2(OPiv)4 (0.5 mg, 0.8 mmol)
and [18F]1 was added a solution of 2a (2 mg, 14 mmol) in 3 (500 mL)
before stirring at room temperature for 10 minutes. RCY was estimated
b
by radio-HPLC analysis of the crude reaction mixture. N.B. Previously, this
value was referred as radiochemical conversion (RCC).10 c The corres-
ponding benzyloxylated product was formed.
Fig. 2 Geminal oxyfluorination of diazoketones with stoichiometric
amounts of fluoro-benziodoxole 1.7c
was used, formation of [18F]4a was not observed (entry 4).
This emphasizes the importance of using 3 as solvent for the
reaction. We have also tested different rhodium complexes in
the reaction (entries 5–7). Application of Rh2(OAc)4 instead of
Rh2(OPiv)4 (entry 5) led to a slight decrease of the RCY (90%),
probably because of the lower solubility of Rh2(OAc)4 in 3. When
we switched to Rh2(esp)2 or Rh2(TPA)4 the RCY values were
substantially decreased (entries 6 and 7). The presence of
a rhodium complex, such as Rh2(OPiv)4 is essential for the
Fig. 3 Attempted 18F-labelling of diazoketones using alcohols as nucleo-
philes.
in the presence of a rhodium catalyst to give geminal oxyfluori- 18F-oxyfluorination reaction, as in the absence of rhodium
nated products 4 (Fig. 2).7c However, repeating the reaction with [18F]4a was not formed (entry 8). In addition, the oxyfluorination
minute amounts of [18F]1, formation of oxyfluorinated products process requires the presence of an electrophilic fluorinating
[18F]4 could not be detected (Fig. 3). Variation of the reaction reagent, such as [18F]1. Thus formation of [18F]4a was not
conditions and application of different alcohols was not helpful. observed when [18F]1 was replaced by a nucleophilic fluorine-
We hypothesized that an unfavourable downscaling effect (see 18 source [18F]Bu4NF (entry 9). Probably due to steric reasons,
problem (i) above) prevented the formation of the expected trimethyl orthoformate 3 is a much weaker nucleophile than
oxyfluorinated products [18F]4. As 1 is an electrophilic reagent, MeOH. This is beneficial for the present fluorine-18 labelling
it readily reacts with nucleophiles. The reaction of 1 with stoi- method, as, unlike MeOH, 3 did not solvolyse the micromolar
chiometric amounts of alcohols is very slow at room temperature. amounts of [18F]1 (compare entries 1 and 2). However, using
However, micromolar amounts of [18F]1 probably reacted com- orthoformates instead of alcohols as nucleophiles in this multi-
pletely with the enormous excess of the alcohol component component reaction imposes some limitations as well. For
instead of the vinyl-ether intermediate (see below) of the desired example, application of triethyl orthoformate (instead of 3) did
reaction. In order to avoid this side reaction, we employed not result in a-[18F]fluoro ether product. This can be explained by
trimethyl orthoformate 3 as a nucleophile.
the increase of the steric hindrance in triethyl orthoformate
After optimization of the reaction conditions, we found that leading to further lowering of the nucleophilicity of the reagent
conducting the reaction of diazoketone 2a with [18F]1 in the compared to MeOH or trimethyl orthoformate (see mechanistic
presence of Rh2(OPiv)4 in neat 3, 18F-oxyfluorinated product discussion below, Fig. 6).
[
18F]4a was obtained in excellent (98%) RCY (Table 1, entry 1).
With the optimized conditions in hand, we sought to explore
Deviations from these conditions led to a decreased amount of the substrate scope of this labelling reaction (Fig. 4) using
18F]4a or lack of 18F-oxyfluorination reaction. When methanol different diazocarbonyl compounds (2). Under these conditions
[
was used as a solvent instead of 3, formation of [18F]4a was not diazoketone 2b, bearing a naphthyl substituent, gave about as
observed (entry 2), which is consistent with the above-mentioned high RCY (94%) as 2a (98%). Diazoketones with electron-
findings (Fig. 3). Interestingly, traces (2%) of fluorine-18 labelled withdrawing halogen substituents, such as bromine and fluorine,
benzyloxylated product were formed using benzyl alcohol instead reacted smoothly, and products [18F]4c and [18F]4d were obtained
of 3 (entry 3). When a 1 : 1 mixture of DCM and orthoformate 3 in 91% and 96% RCY respectively. However, in the presence of a
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Fig. 5 Isolation and molar activity determination of [18F]4c.
[18F]4c in 38% RCY. After isolation by semi-preparative HPLC we
obtained 253 MBq of purified [18F]4c (AY = 9% with respect to
[
18F]1) with a radiochemical purity (RCP) of 89%. This activity
of purified [18F]4c corresponds to a molar activity (Am) of
216 GBq mmol-1, determined 110 minutes after the end of the
bombardment (Fig. 5). This value is in the range of our7f previously
reported value for labelling with [18F]1 and it is orders of
magnitude higher than those obtained using electrophilic
18F-fluorination reagents derived from [18F]F2.9b,d,f
Based on our previous experimental7c,11 and DFT modelling12
studies on the rhodium catalysed oxyfluorination of diazocarbonyl
compounds with alcohols, we propose a catalytic cycle for using
trimethyl orthoformate as a nucleophile (Fig. 6).
The initial step of the above oxyfluorination reaction is most
probably the formation of rhodium carbene B from Rh2(OPiv)4
and diazoketone 2 via intermediate A.13 Alcohols and ethers
readily form onium ylides with electrophilic rhodium carbenes
(such as B).14 Thus, nucleophilic attack of trimethyl orthoformate
Fig. 4 Substrate scope in Rh-mediated electrophilic 18F-labelling of diazo-
ketones. RCY estimated by radio-HPLC analysis of the crude reaction
mixture starting from [18F]1. a The reaction was performed at 90 1C.
nitro group in the diazoketone substrate, the RCY dropped
considerably for the formation of [18F]4e (26%). The reaction
also proceeded with good to excellent RCY in the presence of
electron-donating substituents in the aromatic ring of the diazo-
ketone. Thus, 4-methyl-substituted diazoketone 2f reacted to give
[18F]4f in excellent (98%) RCY, whereas its isomer 2g afforded
[18F]4g in 67% RCY. Diazoketone 2h, bearing a 4-methoxy sub-
stituent, afforded the corresponding product [18F]4h in 79% RCY.
The reaction could also be applied to heterocyclic diazoketones,
such as furane (2i) and thiophene (2j) derivatives. Thus, labelled
compound [18F]4i was obtained in excellent (95%) RCY, while
thiophene containing product [18F]4j was only obtained in 49%
RCY. Not only diazoketones but diazoamide derivative 2k can
also be used as a substrate. Thus, [18F]4k could be obtained in
16% RCY, when the reaction was performed at 90 1C (instead of
room temperature, which was typically used). The low RCY and
the high temperature required for the reaction indicates a lower
reactivity for the diazoamide substrates compared to the diazo-
ketones. Fluorine-18 labelling of aliphatic diazoketones was not
successful. For example, we were not able to obtain [18F]4l. This
result was surprising as the reaction with the natural fluorine
isotope using equimolar amounts of 1 and 2l in trimethyl
orthoformate gave 4l. Most probably, a so far unknown side
reaction prevented formation of [18F]4l.
The optimized procedure was employed to determine the
activity yield (AY) and molar activity (Am) of an isolated labelled
compound.10 These studies were performed with diazoketone 2c
bearing an aromatic bromine substituent. The aromatic bromide
functionality in product [18F]4c can be used in subsequent Suzuki–
Miyaura coupling as a prosthetic group.3b,6i For determination of
the AY and Am, 2.70 GBq of [18F]1 was reacted with 2c affording
Fig. 6 Suggested mechanism for 18F-fluorination of diazoketones.
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3 on rhodium carbene B leads to the formation of rhodium ylide
C. Obviously, 3 is more sterically hindered, and thus a weaker
nucleophile than the corresponding alcohols, which were used in
our previous studies7c for oxyfluorination with the natural isotope
in 1. Formation of ylide C is affected by the lower nucleophilicity
of trimethyl orthoformate 3 vs. MeOH or other alcohols. Our DFT
modelling studies have shown that rhodium ylides,12 such as C,
readily rearrange to vinyl ethers, such as E. The key step of the
oxyfluorination reaction12a is the electrophilic addition of [18F]1
to vinyl ether E to form intermediate F. As mentioned above, a
possible reason for the unsuccessful oxyfluorination of 2 with
MeOH (Fig. 3) is that the micromolar amounts of [18F]1 reacted
with the large excess of MeOH instead of vinyl ether E. After
rhodium migration and isomerization of the I–F bond to form
intermediate G, C–F bond formation by displacement of the
hypervalent iodine gives H.12a Finally, dissociation of rhodium
gives the final oxyfluorinated product [18F]4.
In summary, we have presented an efficient fluorine-18
labelling method for the one-step synthesis of the biologically
relevant a-[18F]fluoro ether motif.2a The reaction is based on the
downscaling/translation of our rhodium-catalysed oxyfluorination
of diazoketones. The key reagent is [18F]fluoro-benziodoxole,
[18F]1, which is an electrophilic 18F-fluorinating reagent generated
in an operationally simple process from [18F]Bu4NF in the standard
clinical environment. The fluorine-18 oxyfluorination reactions
were performed rapidly typically under mild reaction conditions,
affording fluorine-18 labelled compounds in up to 98% RCY. A
preparative 18F-oxyfluorination experiment gave the a-[18F]fluoro
ether product with a molar activity of 216 GBq mmolÀ1, which is a
higher value compared to typical molar activities reported for
fluorine-18 products obtained using other electrophilic fluor-
inating reagents. We hope that this study contributes to the
application of electrophilic fluorinating reagent [18F]1 extending
the reagent scope of fluorine-18 labelling of PET tracers to
hypervalent iodines.
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We thank the Knut och Alice Wallenbergs Foundation (Dnr:
2018.0066) and Swedish Research Council (VR) for financial
support and Carl Tryggers Foundation (CTS 17:458) for a
postdoctoral fellowship to X. J.
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