α-Fluorination of carbonyls with nucleophilic fluorine

Article abstract of DOI:10.1038/s41557-019-0215-z

Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C–H-fluorination of amides. Reduction of these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.

Full text of DOI:10.1038/s41557-019-0215-z

Articles
https://doi.org/10.1038/s41557-019-0215-z
α-Fluorination of carbonyls with nucleophilic
fluorine
PaulineAdler1,3, ChristopherJ.Teskeyꢀ ꢀ1,3, DanielKaiserꢀ ꢀ1, MarionHoly2, HaraldH.Sitteꢀ ꢀ2 and
NunoMaulideꢀ ꢀ1*
Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is
significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs.
State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can
be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolo-
nium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C–H-fluorination of amides. Reduction of
these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy prepara-
tion of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed anti-
depressant drug, is presented as an example of the preserved biological activity after fluorination.
ith a van der Waals radius of 1.47Å, fluorine is not sig- groups23–25. We have noted that there is a dearth of current methods
nificantly larger than hydrogen (1.2Å)1. It is therefore applicable to amide carbonyls. The ubiquity, ease of synthesis and
W
possible to replace a C–H bond with a C–F bond without range of further chemical transformations of amides would render
significantly distorting or altering the overall geometry of a mole- such a methodology extremely appealing, expanding the toolbox of
cule2. However, fluorineexertsconsiderableinfluenceontheelectron the synthetic chemist.
density distribution electronics of a molecule3, and this combina-
A further significant direct application of organofluorine com-
tion of properties has made fluorination an invaluable tool for drug pounds is that they can act as positron emitters when they carry
discovery, with more than 20% of new drugs containing at least the isotope 18F, which has a half-life of 109min (ref. 26). As an
one fluorine atom4,5. Promising candidates for medicinal chemistry established technique, positron-emission tomography (PET) is an
can often be enhanced by addition of a fluorine atom, which may extremely powerful method for the measurement of physiological,
ameliorate undesirable qualities without negatively impacting the biochemical and pharmacological function27. In this context, the
beneficial effects of a compound (Fig. 1a)6. For example, the intro- development of late-stage fluorination methods relying on nucleo-
duction of fluorine at the β-position of an amine lowers its basicity. philic fluorine is particularly critical due to the higher specific activ-
Although this can result in reduced binding affinity to a receptor, it ity associated with nucleophilic sources of 18F (refs. 28,29). To this end,
often leads to far improved bioavailability due to enhanced mem- we hypothesized that reversal of the natural polarity of a classically
brane permeation properties7,8. In addition, metabolic stability can nucleophilic species into an electrophile, enabling reaction with
be considerably increased by replacement of an easily oxidized C–H fluoride (F–), would represent a conceptual advance in the arena of
bond in a molecule with a C–F bond9. These benefits of fluorine organofluorine chemistry.
incorporation have been a major driving force for the booming
Our concept relies on chemoselective amide activation with
development of electrophilic ‘F+’ reagents in the last few decades10–13
.
triflic anhydride30–32 followed by addition of an oxidant, leading to
The premise of these pioneering efforts has been to facilitate the in situ generation of an ‘enolonium’ species33. Interception of this
introduction of fluorine into organic molecules where the reactive species with fluoride might then afford the α-fluorinated amide
partner has nucleophilic character14,15. State-of-the-art syntheses product, representing the first direct α-C–H fluorination of amides
of α-fluorinated carbonyls have thus, unsurprisingly, focused on (Fig. 1d). Furthermore, we expected functional group tolerance to
the reaction of a nucleophile (enolates or enamines) with electro- be orthogonal to that observed when a strong base is used to form
philic reagents such as NFSI (N-fluorobenzenesulfonimide) and a nucleophilic enolate34,35. However, the use of fluoride as a nucleo-
Selectfluor
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] phile in such a context is virtually unknown and we were quite
octane bis(tetrafluoroborate)). However, these methods are not uncertain whether its ‘hard’ nucleophilic character would be com-
generally applicable to amides (Fig. 1b)16–19. A number of elegant patible with the desired sense of reactivity towards the enolonium
routes to α-fluorinated amides have been developed by Lectka20 intermediate (Fig. 1d).
(Fig. 1c) and Rovis21, among others22, but these methods still rely on
electrophilic fluorinating reagents and none begin directly from an Results and discussion
amide starting material.
At the outset, we focused on the use of commercial solutions of tetra-
Despite the notable successes of such an approach, it would N-butylammonium fluoride (TBAF) in THF as the source of nucleo-
appear that the use of nucleophilic ‘F–’ could hold a number of philic fluorine. In initial experiments, we were delighted to observe the
advantages, namely, the possibility to use reagents that are more formation of the α-fluorinated amide 2a in 54% NMR yield (Table 1,
abundant as well as typically more tolerant of other functional entry 1). A thorough screening of fluoride sources, bases and oxidants
1Institute of Organic Chemistry, University of Vienna, Vienna, Austria. 2Centre of Physiology and Pharmacology, Institute of Pharmacology, Medical
University of Vienna, Vienna, Austria. 3These authors contributed equally: Pauline Adler and Christopher J. Teskey. *e-mail: nuno.maulide@univie.ac.at
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a
b
O
O
CO2H
F
CO2H
O
O
Nucleophilic enolate
Electrophilic fluorinating agent
Poorly soluble
"F "
N
N
N
N
N
N
N
N
H
H
F
Strongly oxidizing
HN
HN
= EWG, SeR, SR, aryl — limited examples
= alkyl — few examples to date
Des-fluoro enoxacin
Enoxacin
Ph
Ph
c
OMe
N
N
N
F
N
N
N
N
N
O
N
N
O
NFSI
OCOPh
R
N
R
Nu
N
H
N
Then NuH
[M]
Cl
H
H
[M]
F
Hünig's Base
O
5HT1D agonist
Fluorinated 5HT1D agonist
R
58–91%
e.e. 94–99%
HO2C
HO2C
d
F
LG
Electrophilic enolonium
Nucleophilic
Tf2O
O
O
O
O
O
LG
O
δ-
fluorinating agent
Readily available
Easily tunable
N
N
N
δ+
Umpolung
event
OH
OH
F
OH
OH
Milder conditions
F
PGI2
7-F-PGI2
Fig. 1 | importance of fluorination in medicinal chemistry and approaches to α-fluorinated amides. a, Selected examples of improved biochemical
properties of fluorinated versus non-fluorinated compounds. Compared to the des-fluoro compounds, enoxacin possesses 15-fold greater gyrase activity,
the fluorinated 5HT1D (5-hydroxytryptamine receptor 1D) agonist shows a significant increase in bioavailability and 7-F-PGI2 (prostaglandin I2) has a
much longer chemical half-life. b, Previous approaches to direct fluorination of amides, using an electrophilic fluorinating agent. c, Synthesis of fluorinated
amides from acid chlorides. NFSI, N-fluorobenzenesulfonimide. d, Our novel proposed strategy using an amide umpolung approach, which, by reversing
the polarity of the α-position to be electrophilic, would allow use of nucleophilic fluorinating agents. Tf2O, trifluoromethanesulfonic anhydride.
details). We were pleased to note that a range of fluoride sources could
Table 1 | Selected optimization of fluorinating agents
be used for the transformation - including KF/Kryptofix® 222, which
gave the product in 64% yield (Table 1, entry 8).
2-I-pyr (2.2 equiv.),
Substrate scope. Turning our attention to the substrate scope
Tf2O (1.1 equiv.),
O
O
(Table 2), we initially probed variations of the carbon chain. The
reaction displayed good functional group tolerance, with reactive
handles such as alkenes 2b, alkynes 2c, esters 2d (also vide infra),
ketones 2e, halides 2f and nitriles 2g all tolerated under the reaction
conditions. β-Aryl amides could also be fluorinated to yield 2h and
2i. The amide derived from the natural product dehydrocholic acid
smoothly afforded 2p in good yield.
CH2Cl2, 0 °C, 15 min
Ph
Ph
N
N
LNO (1 equiv.), 5 min
F
F
(3 equiv.)
1a
2a
0 to r.t., 1 h
Entry
NMR yield (isolated)
F
1
2
3
4
5
6
7
8
TBAF (1 M in THF)
TBAT
54% (41–54%)
84% (83%)
56%
We then focused on the substitution patterns tolerated at the
amide nitrogen atom. Again, a broad variety of substrates were
cleanly α-fluorinated, including tertiary amides derived from pyr-
rolidine 2j, azetidine 2k, piperidine 2l, azepine 2m, morpholine 2n,
diallylamines 2o and 2t, dimethylamine 2q, diethylamine 2s
and diisobutylamine 2u. Non-symmetrical fluorinated amides
were also prepared, such as N-allyl-N-methylamine 2r, N-para-
methoxybenzyl-N-methylamine 2v, N-methyl-N-propargylamine
2w and tetrahydroisoquinoline 2x. A number of these amides bear
removable groups on nitrogen (2o, 2r, 2t, 2v).
TMAF
TBAF on silica
HF•pyridine
3HF•Et3N
KF
35%
0%
0%
0%
To demonstrate the utility of the carboxamide group of the fluo-
rinated products, we subjected 2a to electrophilic activation and
esterification to yield α-fluoro ester 3 (ref. 36). Selective reduction
of amide 2a to β-fluoro alcohol 4 could be achieved with a com-
bination of lithium aluminium hydride and sodium borohydride37.
Finally, azetidine amide 2k was transformed into α-fluorinated
KF/Kryptofix® 222
64%
2-I-pyr, 2-iodopyridine; Tf2O, trifluoromethanesulfonic anhydride; LNO, 2,6-lutidine N-oxide; TBAF,
tetra-N-butylammonium fluoride; TBAT, tetra-N-butylammonium difluorotriphenylsilicate; TMAF,
tetra-N-methylammonium fluoride.
ketone 5 in good yield following the procedure of ref. 38
.
ultimately yielded the product 2a in 84% yield using 3equiv. of tetra-
N-butylammonium difluorotriphenylsilicate (TBAT) as the fluoride Application of our methodology. At this juncture, we were eager
source (Table 1, entry 2, see Supplementary Tables 1–3 for further to apply this methodology to the synthesis of complex, fluorinated
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Table 2 | Scope of the α-fluorination of amides
O
2-I-pyr (2.2 equiv.), Tf2O (1.1 equiv.),
CH2Cl2, 0 °C, 15 min
O
F
Bu
Si
Bu
F
N
N
N
Bu
Then LNO (1 equiv.), 0 °C, 5 min
Then TBAT (3 equiv.), 0 to r.t., 1 h
Bu
F
Tetrabutylammonium
1a–1x
2a–2x
difluorotriphenylsilicate (TBAT)
O
O
O
O
O
O
O
O
Ph
Cl
N
N
N
MeO
N
Me
N
N
3
6
6
5
F
F
F
F
F
F
2a, 83%
2b, 72% (89% brsm)
2c, 46% (59% brsm)
2d, 77%
2e, 62% (78% brsm)
2f, 70% (84% brsm)
O
O
O
O
O
NC
C7H15
Ph
N
NMe2
Ph
NEt2
N
N
3
O
F
F
F
F
F
F
Br
Me
Me
N
O
H
2g, 64% (82% brsm)
2h, 78%
2i, 40%
2j, 42%
2k, 61%
H
Me
O
O
O
O
O
H
H
O
C7H15
C7H15
C7H15
N
MeO
N
N
N
O
5
H
F
F
F
O
F
2p, 62% (d.r. 2.2:1)a
2l, 52% (68% brsm)
2m, 70%
2n, 51% (76% brsm)
2o, 53%
O
O
O
O
O
O
O
O
O
C3H7
Me
NR2
MeO
NR2
MeO
N
MeO
N
MeO
N
5
5
5
5
F
F
F
PMB
F
Me
F
2v, 65%
2w, 46% (57% brsm)
2x, 63%
2q, R = Me, Me, 52%
2r, R = Me, allyl, 73%b
2s, R = Et, 80%
2t, R = Allyl, 48%
2u, R = i-Bu, 76%
2-I-pyr (3 eq.), Tf2O (1.3 eq.)
EtOH (12 eq.)
LiAlH4 (0.75 eq.)
O
O
NaBH4 (1.5 eq.)
Ph
Ph
Ph
CH2Cl2, 0 °C to r.t., 20 h
THF, 0 °C, 30 min.
N
OEt
OH
F
F
F
2a
3, 48% (72% brsm)
α-fluoro ester
4, 52%
β-fluoro alcohol
MeLi (3 eq.), THF
0 °C, 30 min.
O
O
Ph
Ph
N
Me
F
F
2k
5, 61%
α-fluoro ketone
All reactions were performed on a 0.2ꢀmmol scale. For each compound the isolated yield is given in percent. aThe d.r. was determined by 1H NMR analysis of the crude material. bRun on 2ꢀmmol scale. b.r.s.m.,
based on recovered starting material.
targets that may lie beyond the reach of previously described meth- unknown fluoro-citalopram 9 (Fig. 2a), in the hope of investigat-
ods. Particularly interesting were studies that document the posi- ing what effects placing a fluorine at the β-position to the tertiary
tive impact of fluorine when located at the β-position of an amine6, amine would have on the efficacy of the drug. In the event, amide 7
as we recognized that such amines should be easily accessible via is easily prepared in one high-yielding step from commercial start-
reduction of an α-fluoro amide.
ing material 6 on a multigram scale. The fluorination step yielded 8
Depression affects hundreds of millions of people around the in good yield as a mixture of diastereomers, and the yield remained
world. Very recently, a large study has confirmed that antidepres- high even on a 10g scale, demonstrating that our nucleophilic fluo-
sants are an effective tool for treating major depressive disorder39,40
Selective serotonin reuptake inhibitors are currently the gold stan- (avoiding competitive reduction of the nitrile group), fluoro-citalo-
dard of antidepressant therapies41, and citalopram is one of the most pram 9 was isolated in good yield. Biological testing revealed that,
successfully applied compounds of that class42. We targeted the as a mixture of the four stereoisomers, fluoro-citalopram 9 blocked
.
rination is amenable to scaling up. After chemoselective reduction
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a
b
120
100
80
60
40
20
0
120
100
80
NC
NC
O
NaH (0.2 equiv.)
DMF, 23 °C, 16 h
O
O
+
60
NMe2
(1.0 equiv.)
Me
Me
40
N
(R *,S *)-9
F-Citalopram
Paroxetine
Citalopram
(S,S)-9
(R,R)-9
20
O
(S,S)-9
F
F
(S *,R *)-9
0
6
7, 82% (>10 g scale)
Log([dose] (M))
Log([dose] (M))
2-I-pyr (2.2 equiv.), Tf2O (1.1 equiv.)
CH2Cl2, 0 °C, 15 min
c
Then LNO (1 equiv.), 0 °C, 5 min
Then TBAT (3 equiv.), 0 to r.t., 12 h
N
NC
NC
O
H2PtCl6.6H2O (1 mol%)
Me
N
TMDS (2.5 eq.)
O
O
F
F
Toluene, 75 °C, 3 h
Me
F
Me
Me
Me
Me
N
N
O
F
F
F
(S,S)-9
Fluoro-citalopram
8, 66% (on 10 g scale)
9, 51%
d.r. 1.7:1
Cl
d
Cl
TBDPSO
TBDPSO
2-I-pyr (2.2 equiv.), Tf2O (1.1 equiv.)
CH2Cl2, 0 °C, 15 min
O
O
O
3 steps
F
O
N
Me
N
Me
Then LNO (1 equiv.), 0 °C, 5 min
Then TBAT (3 equiv.), 0 to r.t., 1 h
F
N
Me
11, 37%
10
Fluoro-piperalin
12, 34% (3 steps)
Prepared in two steps
e
Ph
O
Ph
O
N
N
2-I-pyr (2.2 equiv.), Tf2O (1.1 equiv.)
CH2Cl2, 0 °C, 15 min
Me
Me
F
Then LNO (1 equiv.), 0 °C, 5 min
Then TBAT (3 equiv.), 0 to r.t., 1 h
N
N
Ph
Ph
Fentanyl
Fluoro-fentanyl
13, 40%
Fig. 2 | Preparation of fluorinated analogues of pharmaceutical and agrochemical compounds. a, The synthesis of fluoro-citalopram. TMDS,
1,1,3,3-tetramethyldisiloxane. b, Left, Pharmacological profile of F-citalopram 9 in comparison to citalopram, paroxetine and (S,S)-9. Uptake of the indicated
tritiated 5-HT into HEK293 cells expressing human SERT was determined in the presence of increasing concentrations of F-citalopram, citalopram and
paroxetine. The following numbers indicate the number of individual experiments performed in triplicate: nꢀ=ꢀ11, racemic F-citalopram; nꢀ=ꢀ3, (S,S)-9; nꢀ=ꢀ4,
citalopram; nꢀ=ꢀ9, paroxetine. Symbols represent means and error bars indicate s.d. See Supplementary Figs 1–3 for full details. Right, a pharmacological
profile of the four stereoisomers of fluoro-citalopram. Uptake of the indicated tritiated 5-HT into HEK293 cells expressing human SERT was determined in
the presence of increasing concentrations of enantiomer-pure preparations of F-citalopram. All individual experiments were performed in triplicate in three
independent experiments. All symbols represent meanꢀ ꢀs.d. c, The most active stereoisomer (S,S)-9 and image of the isomer docked in the human SERT
crystal structure, as optimized using LigandScout. d, Synthesis of fluoro-piperalin. TBDPS, tert-butyldiphenylsilyl. e, Late-stage fluorination of fentanyl with
yield determined by NMR analysis using an internal standard.
the uptake of [3H]5-HT (tritium labelled 5-hydroxytryptamine) at 83.0 12nM (mean s.e.m.) (Fig. 2b left; citalopram is denoted
a half-maximum inhibitory concentration (IC50) of 655.1 37nM by blue circles). Higher affinities can be reached with paroxetine,
(mean s.e.m.) (Fig. 2b left; racemic fluoro-citalopram 9 is denoted which yields approximately 47.1 17nM (mean s.e.m.) (Fig. 2b
by black triangles, enantiopure (S,S)-9 by red squares). In com- left; paroxetine is denoted by green triangles). Fluoro-citalopram
parison, the parent compound citalopram blocked serotonin trans- thus retains activity at citalopram’s clinical target, SERT, and there-
porter (SERT)-mediated uptake of [3H]5-HT at an IC50 value of fore may serve as a proof of principle for the use of fluorine in this
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context. As one of the major drawbacks in antidepressant therapy is widespread use in radiolabelling and in medicinal pharmacy, sus-
the considerably delayed onset of activity and the lack of response taining the everlasting quest to create better tools for the benefit of
in a considerable cohort of depressed patients (30%), the poten- medicine and healthcare.
tial benefits that fluorination may offer in terms of bioavailability
open up perspectives for investigating the in vivo efficiency of this Reporting summary. Further information on research design is
compound43,44
.
available in the Nature Research Reporting Summary linked to this
Having carried out the synthesis of the fluorinated-citalopram article.
analogue 9 on a larger scale, we were intrigued to investigate the
individual activity of all four stereoisomers. Following separation Data availability
The data that support the findings of this study are available from the
corresponding author upon request.
by preparative HPLC (see Supplementary Section 6.1 for details),
the same biological study was carried out individually on each of the
four compounds. Our results showed that isomer (S,S)-9 (Fig. 2b
right, red squares) is the most active, with an IC50 of 467.8 108nM.
Isomer (R*,S*)-9 (Fig. 2b right, grey hexagons) has an IC50 of
3.2 1µM; the less potent isomers are (R,R)-9 (Fig. 2b right, blue
open circles) and (S*,R*)-9 (Fig. 2b right, brown diamonds), which
have IC50 values of 32.0 3µM and 21.5 5µM, respectively.
Received: 26 March 2018; Accepted: 7 January 2019;
Published: xx xx xxxx
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Academy of Sciences (DOC-fellowship to D.K.) is acknowledged.
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Authors contributions
P.A., C.J.T and D.K. performed and analysed the chemical experiments. P.A., C.J.T and
N.M. co-wrote the manuscript. M.H and H.H.S. performed the biological testing. N.M.
directed the project.
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Competing interests
The authors declare no competing interests.
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Reprints and permissions information is available at www.nature.com/reprints.
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