Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-Fluoroamines

Article abstract of DOI:10.1021/jacs.8b12568

Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F

Full text of DOI:10.1021/jacs.8b12568

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Communication
Hydrogen Bonding Phase-Transfer Catalysis with Potassium
Fluoride: Enantioselective Synthesis of #-Fluoroamines
Gabriele Pupo, Anna Chiara Vicini, David M. H. Ascough, Francesco Ibba, Kirsten E.
Christensen, Amber L. Thompson, John M. Brown, Robert S. Paton, and Veronique Gouverneur
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12568 • Publication Date (Web): 28 Jan 2019
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Hydrogen Bonding Phase-Transfer Catalysis with Potassium
Fluoride: Enantioselective Synthesis of β-Fluoroamines
Gabriele Pupo,§,† Anna Chiara Vicini,§,† David M. H. Ascough,† Francesco Ibba,† Kirsten E.
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Christensen,† Amber L. Thompson,† John M. Brown,† Robert S. Paton,†,ƒ and Véronique Gouverneur†*
† University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK
ƒ Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
solid cesium fluoride, CsF(s) (lattice energy, 759 kJ/mol),13
into solution in the form of a hydrogen bonded fluoride
complex. This strategy afforded enantioenriched β-
ABSTRACT: Potassium fluoride (KF) is an ideal reagent for
fluorination because it is safe, easy to handle and low-cost.
However, poor solubility in organic solvents coupled with limited
fluorosulfides with a chiral N-alkyl bis-urea catalyst U*
(Fig. 1A), that adopts an anti-syn conformation and binds
fluoride as a tricoordinated hydrogen bonded complex. At
this stage, the prospect of using KF(s) under HB-PTC was
tantalizing considering the advantages of this reagent
compared to other fluorine sources (Fig. 1B).
Encouraged by initial calculations indicating that the
energy required to solubilize KF(s) in dichloromethane is
significantly reduced in the presence of bis-urea U* (see
SI), we envisioned that asymmetric HB-PTC may be
suitable for enantioselective fluorination with this more
demanding fluoride source (lattice energy, 829 kJ/mol).13
Precursors of meso aziridinium ions14 were selected as
substrates for this study because desymmetrization with KF
affords high value enantioenriched β-fluoroamines that are
of considerable interest for applications in medicinal
strategies to control its reactivity has discouraged its use for
asymmetric C–F bond formation. Here, we demonstrate that
hydrogen bonding phase transfer catalysis with KF provides
access to valuable β-fluoroamines in high yields and
enantioselectivities. This methodology employs a chiral N-ethyl
bis-urea catalyst that brings solid KF into solution as
a
tricoordinated urea-fluoride complex. This operationally simple
reaction affords enantioenriched fluoro-diphenidine (up to 50-g-
scale) using 0.5 mol% of recoverable bis-urea catalyst.
The benefits of fluorine incorporation in organic
molecules have been extensively studied and exploited in
the agrochemical and pharmaceutical industry.1 Fluorine
substituents can alter the pKa of neighboring groups, dipole
moment, and properties such as metabolic stability,
lipophilicity and bioavailability.2 In this context, the
demand for molecules featuring the fluorine substituent on
a stereogenic carbon has accelerated the development of
catalytic enantioselective fluorination methodologies.3
Electrophilic fluorine sources of tailored reactivity have
proved valuable for rapid advance of this field of research.4
Asymmetric catalysis towards C–F bond formation using
nucleophilic fluorine sources has progressed at a slower
pace in part due to the difficulties in controlling fluoride
reactivity.5 Fluoride is solvated and poorly reactive in
protic media, while unsolvated fluoride can react as a
BrØnsted base.6 These issues have led to the development
of reagents designed for in situ release of fluoride into
solution.5f, 7 Additional challenges for metal alkali fluorides
are their hygroscopicity and poor solubility in organic
solvents.6 These characteristics have discouraged the use of
potassium fluoride (KF) for asymmetric catalytic
fluorination, despite the fact that this reagent is low cost,
safe and easy to handle.8
chemistry, especially for central nervous system drug
16
discovery,15,
and catalyst design.17 Specifically, we
propose that a chiral bis-urea of type U* brings KF(s) into
solution as a tricoordinated hydrogen bonded complex; ion
pairing of this complex with in situ formed meso
aziridinium ion followed by fluorination delivers the
enantioenriched β-fluoroamine with release of the bis-urea
catalyst (Fig. 1C).
A.
C.
O
-fluoroamines
R1
NR'2
NR'2
N
H
HB
N
R
F
Cl
PTC
Medicinal chemistry
R"
R"
U*
H
N
H
N
R"
R"
KF
Catalyst design
R1
rac
ent
O
O
R'
R'
U*
*
B.
KF
N
N
H
N
KF(s)
F
H
Easy-to-handle
Safe F– source
Abundant
R
N
R"
insoluble
R"
ent
O
H
N
Low cost
O
O
R'
N
*
R'
N
N
H
*
R
N
N
H
Asymmetric
HB-PTC
H
Price ($/mol)
R"
N
R
K+
H
N
R"
KF
8
F
O
H
Nature has evolved a fluorinase enzyme that makes use
of a hydrogen bonded fluoride complex to enable C–F bond
formation.9 Inspired by this transformation, we prepared
fluoride complexes derived from alcohols and ureas to
study the effect of hydrogen bonding on fluoride
reactivity.10 These studies culminated with the discovery of
N
F
CsF
AgF
72
968
69
O
H
N
" F–
" F+
"
soluble chiral
F– reagent
TBAF
ion pairing
R'
R'
NFSI
111
407
R'
N
R'
N
"
hydrogen
bonding
Cl
Selectfluor
KCl(s)
Cl
R"
R"
rac
R"
R"
Figure 1 A. Tridentate bis-urea for HB-PTC. B.
Advantages of KF. C. Synthesis of enantioenriched β-
fluoroamines with KF(s), and proposed HB-PTC
mechanism.
hydrogen bonding phase-transfer catalysis (HB-PTC),11
a
new activation mode for PTC12 whereby a neutral hydrogen
bond donor urea catalyst acts as a transport agent to bring
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Most catalytic asymmetric methodologies towards β-
The reaction of rac-1a and KF (3 equiv) in
dichloromethane at rt with 5 mol% of urea (S)-3a afforded
β-fluoroamine 2a in >99% yield, but no control over
enantioselectivity was observed (e.r. = 55:45) (Table 1,
entry 1). This result however demonstrated that HB-PTC
enables fluorination with KF. The N-alkylated catalysts
3b–d capable of forming tricoordinated hydrogen bonded
complex with fluoride did improve enantiocontrol (Table 1,
entries 2–4, up to >99% yield and 86:14 e.r.). The e.r. (up
to 90.5:9.5) was increased with N-alkylated catalysts 3f and
3g featuring an extended poly-trifluoromethylated
terphenyl π-system (Table 1, entries 6–7). Further reaction
condition optimization (see SI for details) afforded 2a in
good yields and high enantioselectivity (71% yield of
isolated product, 95:5 e.r.). The optimized conditions
consist of treating rac-1a with KF (5 equiv.) and 3g (10
mol%) in CHCl3 at –15 °C for 72 h (Table 1, entry 11).
With the optimal reaction conditions in hand, we studied
the scope of the reaction (Scheme 2). Substrates with a
range of different amines were subjected to
enantioselective fluorination. The fluorinated analogue of
the analgesic lefetamine22 2b possessing two methyl groups
on nitrogen was obtained in 65% yield and 95:5 e.r..
Various N-heterocycles were tolerated including motifs
frequently encountered in FDA approved drugs (e.g.
piperidine, piperazine, pyrrolidine, morpholine);23 this is
demonstrated with the synthesis of β-fluoroamines 2c–i that
were obtained in good yields and high enantioselectivities
(up to 94% yield and 96:4 e.r.). Within this series,
asymmetric HB-PTC gave access to fluorinated analogues
of NMDA receptor antagonists 2e (MT-45)24a and 2g
(diphenedine) in high enantioselectivity.24b-d The reaction is
highly effective for substrates possessing two different N-
substituents that may lead to two diastereomeric meso
aziridinium ions as exemplified with the synthesis of 2i, 2j
and 2k that were obtained with e.r. reaching 96:4. Various
substituents on the phenyl ring of the substrates are
compatible including electron-donating and electron-
withdrawing groups. β-Fluoroamines 2l–2s were
synthesized in good yields and e.r. (up to 87% yield and
96:4 e.r.). A study comparing KF and CsF indicates that
comparable yields could be obtained by simply increasing
the excess of KF (5 vs. 3 equiv.), and the reaction
concentration (0.5 vs. 0.25 M). The enantiomeric ratios
were unaffected by the nature of the alkali fluoride.
Departing from diaryl-based substrates, six- and five-
membered cyclic meso aziridinium precursors were also
evaluated. Asymmetric catalytic fluorination occurred
smoothly at room temperature in -trifluorotoluene,
and afforded the cyclic β-fluoroamines 2t-v in good yields
and with moderate enantioselectivity.
fluoroamines require fluorinated building blocks,18 but
strategies featuring late stage enantioselective fluorination
have been disclosed. Enamine catalysis and anionic phase
transfer catalysis have been successfully applied using
1
2
3
4
5
6
7
8
electrophilic
fluorination
reagents.19
Catalytic
enantioselective nucleophilic fluorinations towards β-
fluoroamines have also appeared, but these reactions
typically require hazardous HF reagents, or rely on in situ
fluoride release from reagents of reduced atom economy.20
These examples highlight the progress made toward
accessing enantioenriched β-fluoroamines, and underline
the demand for asymmetric catalytic methods for their
synthesis using safe and readily available fluoride sources
such as KF(s).
Preliminary studies identified the stilbene-derived β-
chloro-N-diallylamine 1a as a suitable aziridinium ion
precursor for the proposed enantioselective fluorination
towards β-fluoroamine (Table 1) (see SI for details). This
substrate features a tertiary amine rarely encountered in the
context of late stage asymmetric fluorination,3 and the
product of fluorination belongs to the 1,2-
9
10
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12
13
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diphenylethylamine
family
of
NMDA
receptor
antagonists.21 We opted for N-allyl substitution to allow
release of the primary amine via Pd-catalyzed deallylation
post-fluorination.22
Table 1. Optimization of Reaction Conditions.
NAllyl2
Cl
NAllyl2
KF (3 equiv.)
(S)-3a–g (5 mol%)
F
Ph
Ph
Solvent (0.25 M), 24 h
Ph
rac-1a
Ph
2a
CF3
F3C
CF3
CF3
CF3
O
O
N
H
N
N
R
N
R
F3C
F3C
H
H
N
H
N
H
N
H
N
CF3
CF3
O
O
CF3
(S)-3a: R=H
(S)-3b: R=Me
(S)-3c: R=Et
(S)-3d: R=iPr
F3C
(S)-3e:
(S)-3f:
(S)-3g:
R = H
R = Me
R = Et
CF3
Entry
1
2
3
4
Cat.
Solvent
T (°C)
rt
rt
rt
rt
rt
rt
rt
0
Yielda
>99%
98%
>99%
83%
77%
72%
80%
80%
90%
58%
71%e
e.r.b
3a
3b
3c
3d
3e
3f
3g
3g
3g
3g
3g
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
55:45
85:15
86:14
86:14
55:45
88:12
90.5:9.5
93:7
5
6
7
8c
9c
10c
11c
d
0
0
–15
93.5:6.5
94:6
95:5
1,2-DFB
d
CHCl3
The catalyst loading was reduced to 3 mol% for the
reaction on a 1.1 g scale of 1a. This fluorination was
performed at 5 °C, and afforded 2a in 76% yield and 93:7
e.r. (Scheme 3A). N-Deprotection of β-fluoroamine 2a
under Pd(0) catalysis21 afforded β-fluoroamine 4 in 72%
yield with no erosion of e.r.. A single recrystallization gave
4 in high enantiopurity (99.8:0.2 e.r.). Reductive amination
of 4 with acetaldehyde yielded fluorinated ephenidine 5 as
a single enantiomer,24e an additional NMDA receptor
antagonist of the 1,2-diphenylethylamine family.
Reaction conditions: 0.05 mmol of 1a, 0.25 M, (S)-3a–g
(5 mol%), stirring at 1200 rpm for 24 h. a Determined by
b
19F-NMR using 4-fluoroanisole as internal standard;
e.r. = enantiomeric ratio determined by HPLC; c 0.5 M, 5
d
equiv. of KF, 10 mol% of 3g; CHCl3 was filtered on
basic alumina to remove residual HCl; e Yield of isolated
product after 72 h.
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optimized the process (Scheme 3B, see SI for details).
Multigram quantities of substrate rac-1g were prepared via
Scheme 2. Substrate scope with KF and CsF .
(s)
(s)
CF3
1
2
3
4
5
6
7
8
F3C
CF3
a
chromatography-free
epoxidation/ring-
commercially
O
O
R
R
R
R
opening/chlorination sequence
from
(S)-3g (5–10 mol%)
KF (5 equiv.) or CsF (3 equiv.)
N
N
N
N
F3C
F3C
H
X
F
Et
H
available cis-stilbene (48% yield over three steps). The
fluorination of rac-1g was performed at room temperature
on a 50-g-scale using a smaller excess of KF (3 equiv.), and
0.5 mol% of catalyst (S)-3g for 72h; this was made possible
by increasing the concentration to 2 M and replacing
chloroform with dichloromethane. The catalyst (S)-3g was
separated from the product 2g via acid/base work-up, and
R'
R'
H
N
CHCl3 (0.25 or 0.5 M)
N
R'
R'
-20 – +10 °C, 24–72
h
rac-1
(S,S)-2a–v
CF3
(0.2 mmol)
(S)-3g
F3C
X = -Cl 1a–s
X = -Br 1t–v
CF3
Fluorinated
Lefetamine
O
9
N
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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45
46
47
48
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50
51
52
53
54
55
56
57
58
59
60
F
F
F
F
the crude product was purified with
a
single
recrystallization in MeOH to afford 2g in 66% yield and
97:3 e.r.. The catalyst was quantitatively recovered and
recycled without loss of efficiency with respect to both
yield and enantioselectivity. Noteworthy, the reaction set-
up is operationally simple, does not require dry solvents, is
carried out under air, and KF is used without any pre-
treatment.
2a
2b
2c
2d
A: 71% yield, 95:5 e.r.
B: 95% yield, 95:5 e.r.
A: 65% yield, 95:5 e.r.
B: 85% yield, 97:3 e.r.
A: 92% yield,95:5 e.r.
B: 90% yield, 97:3 e.r.
A: 81% yield, 94:6 e.r.[a]
B: 75% yield,94.5:5.5 e.r.
Fluorinated
MT-45
Fluorinated
Diphenidine
Ph
N
Cy
N
N
N
N
F
F
F
Scheme 3. A. Gram scale fluorination of 1a enabling
access to enantiopure fluorinated ephenidine. B. 50-g-scale
reaction for the synthesis of fluorinated diphenidine.
2e
2f
2g
A: 90% yield, 94:6 e.r.
B: 94% yield,94:6 e.r.
A: 69% yield, 95:5 e.r.
B: 84% yield,95.5:4.5 e.r.
A: 56% yield, 96:4 e.r.
B: 90% yield, 95:5 e.r.
N
N
N
N
F
F
F
F
2h
2i
2j
2k
A: 76% yield, 92:8 e.r.
B: 61% yield, 93:7 e.r.
A: 91% yield, 96:4 e.r.
B: 96% yield, 96:4 e.r.
A: 89% yield, 95.5:4.5 e.r.
B: 72% yield,95.5:4.5 e.r.
A: 73% yield, 94:6 e.r.
B: 69% yield, 94:6 e.r.
N
N
N
N
Me
F
F
F
Cl
F
MeO
F
Me
F
Cl
OMe
2l
2m
2n
A: 77% yield, 96:4 e.r.
2o
A: 86% yield, 95:5 e.r.
A: 87% yield, 96:4 e.r. A: 73% yield, 94:6 e.r.
B: 83% yield,96:4 e.r.
B: 70% yield, 95.5:4.5 e.r. B: 76% yield,97.5:2.5 e.r. B: 97% yield, 97.5:2.5 e.r.
Reaction conditions: i) Thiosalicyclic acid (2.5 equiv.), Pd(dba)2 (10
mol%), dppb (10 mol%), THF, 60 °C, 12 h; ii) CH3CHO (5 equiv),
NaBH(OAc)3 (3 equiv.), MeOH (0.2 M), rt, 3 h (1 mmol scale).
Derivatization of 4 confirmed its (S,S) absolute configuration (see SI).5g
N
N
N
N
Me
F
F
F
F
Me
F
Br
Me
Me
Me
The reaction was investigated computationally by
molecular dynamics (MD) simulations, and density
functional theory (DFT) calculations (see SI for full
details).25 MD simulations in chloroform confirmed that N-
alkylated catalyst 3g forms a stable and persistent tridentate
fluoride complex, with the alkylated urea in an anti-syn
conformation.26 MD was further used for conformational
sampling for DFT calculations,11,27 resulting in 15 DFT
optimized transition structures (TSs) for ring-opening.
A Boltzmann ensemble of competing TSs predicted
preferential (S,S) product formation from catalyst (S)-3g
(supported by single-crystal x-ray diffraction of (S,S)-2g).
Further, the computed selectivity of 95:5 e.r. at 278.15 K
compares favorably with experimental values. The most
stable competing TSs contributing towards major and
minor product formation are shown in Figure 2A. The N-
substituents of the aziridinium ion are pointing away from
Me
F
Br
2p
2q
2r
2s
A: 58% yield, 90:10 e.r.
B: 85% yield,91:9 e.r.
A: 71% yield, 95:5 e.r.
B: 74% yield,95:5 e.r.
A: 67% yield, 95:5 e.r.
B: 80% yield,95:5 e.r.
A: 71% yield, 91:9 e.r.
B: 73% yield, 90.5:9.5 e.r.
Ph Ph
Ph Ph
N
N
N
F
F
OMe
MeO
F
2t
2u
2v
A: 69% yield, 85.5:14.5 e.r.[b]
B: 60% yield, 85:15 e.r.[b]
A: 63% yield, 84:16 e.r.[b]
B: 52% yield, 85.5:14.5 e.r. [a,b]
A: 71% yield, 74.5:25.5 e.r.[b]
B: 68% yield, 75:25 e.r.[b]
Conditions A: 1 (0.2 mmol), KF (5 equiv.), (S)-3g (5–10 mol%), CHCl3
(0.5 M). Conditions B: 1 (0.2 mmol), CsF (3 equiv.), (S)-3g (5-10 mol%),
CHCl3 (0.25 M). a15 mol% of catalyst used. bReaction performed in
-trifluorotoluene. Structure of (S,S)-2g determined by single-crystal
x-ray diffraction. Absolute configuration of all products assigned by
analogy with (S,S)-2g.
In order to demonstrate the applicability of the
methodology to multidecagram synthesis, we further
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Journal of the American Chemical Society
the catalytic pocket, into solvent, explaining wide
substituent tolerance in these positions (Fig. 2Bi). In both
TSs, the aziridinium ion docks with the catalyst backbone -
favorable cation– interactions between naphthyl ring and
aziridinium C-H protons are present (Fig. 2Bii).28
We used various energy decomposition analyses to
rationalize the origins of enantioselectivity.29-31 The cation–
 interaction is stronger in the major TS based on truncated
models - in the absence of this interaction the selectivity is
Page 4 of 8
reduced by 1.5 kJ/mol. Steric crowding in the minor TS
also leads to unfavorable geometric distortion (Fig. 2Biii).
These combined effects contribute approximately half of
ΔΔG‡. The remainder is due to substrate conformation (Fig.
2Biv), favoring conjugation of the phenyl ring with the
forming and breaking bonds (benzylic SN2). On the basis of
dihedral angles, the minor TS is 20° further from
conjugation than the major (see SI for more details of this
analysis).32
1
2
3
4
5
6
7
8
9
10
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42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
Figure 2 Computed lowest energy TSs to major and minor product at the ωB97X-D3/(ma)-def2-TZVPP/COSMO(CHCl3)//
M06-2X/def2-SVP(TZVPPD)/CPCM(CHCl3) level of theory, with highlights rationalizing substituent tolerance and origins
of enantioselectivity.
In summary, we have shown that asymmetric HB-PTC
enables enantioselective fluorination of racemic β-
chloroamines with KF, an ideal fluoride source based on
safety, availability and cost. The resulting β-fluoroamines
are obtained in high yields and enantiomeric ratios. This
reaction uses a novel N-ethylated bis-urea catalyst that
transports KF in solution as a chiral tricoordinated bis-
urea/fluoride complex. Subsequent ion-pairing with in situ
formed meso aziridinium ion enables enantioselective C–F
bond formation. The method stands out as it is
operationally simple, can be performed in an open vessel,
and does not require dry solvents or pre-treatment of KF. A
50-g-scale reaction was performed for the synthesis of an
enantioenriched fluorinated analogue of diphenidine, an
NMDA receptor antagonist. We anticipate that the
advantages of this novel HB-PTC process will offer new
prospects in fluorination chemistry both in academia and
industry.
ASSOCIATED CONTENT
Supporting Information
Data and materials availability: Additional optimization and
mechanistic data are provided in the Supporting Information.
Computational methods, energies and coordinates are provided in
the Supporting Information. Crystallographic data are available
free of charge from the Cambridge Crystallographic Data Centre
under references CCDC 1880527-1880530. The Supporting
Information is available free of charge on the ACS Publications
website.
AUTHOR INFORMATION
Corresponding Author
veronique.gouverneur@chem.ox.ac.uk
Author Contributions
§ These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
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Fluorination: Ring Opening of Oxabicyclic Alkenes” Angew. Chem.
Int. Ed. 2012, 51, 12353. (d) Katcher, M. H.; Doyle, A. G.
“Palladium-catalyzed asymmetric synthesis of allylic fluorides” J.
Am. Chem. Soc. 2010, 132, 17402. (e) Katcher, M. H.; Sha, A.;
Doyle, A. G. “Palladium-catalyzed regio- and enantioselective
fluorination of acyclic allylic halides” J. Am. Chem. Soc. 2011, 133,
15902; (f) Kalow, J. A.; Doyle, A. G. “Enantioselective Ring
ACKNOWLEDGMENT
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We thank Dr P. Ricci for preliminary experiments. This work was
supported by the EU Horizon 2020 Research and Innovation
Programme (Marie Skłodowska-Curie agreements 675071 and
789553), and the EPSRC (EP/R010064, SBM-CDT
EP/L015838/1). We acknowledge the University of Oxford
Advanced
facility (http://dx.doi.org/10.5281/zenodo.22558)
Extreme Science and Engineering Discovery Environment
Research
Computing
and the
(XSEDE) through
CHE180056.
allocation TG-CHE180006
and
TG-
Opening of Epoxides by Fluoride Anion Promoted by
a
9
Cooperative Dual-Catalyst System” J. Am. Chem. Soc. 2010, 132,
3268; (g) Kalow, J. A.; Doyle, A. G. “Enantioselective fluoride ring
opening of aziridines enabled by cooperative Lewis acid
catalysis” Tetrahedron 2013, 69, 5702.
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dihedral in the major TS, is approximately 7° from optimum, and in
the minor, 27° (Fig. S13).
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