The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process

Article abstract of DOI:10.1038/s41557-018-0197-2

Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalysed dearomatization–hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this dearomatization–hydrogenation process.

Full text of DOI:10.1038/s41557-018-0197-2

Articles
https://doi.org/10.1038/s41557-018-0197-2
The formation of all-cis-(multi)fluorinated
piperidines by a dearomatization–hydrogenation
process
ZackariaNairoukhꢀ ꢀ, MarcoWollenburg, ChristophSchlepphorst, KlausBergander
and FrankGloriusꢀ ꢀ*
Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals
and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous poten-
tial. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselec-
tive synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of
multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report,
we describe a straightforward process for the one-pot rhodium-catalysed dearomatization–hydrogenation of fluoropyridine
precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly
diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates
by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully
applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids
were obtained by this dearomatization–hydrogenation process.
he predictable and modular assembly of complex molecular
Current synthetic routes for the synthesis of relatively simple
structures is one of the main challenges in synthetic organic monofluorinated piperidine derivatives are usually based on elec-
chemistry, which therefore necessitates the development of trophilic fluorination and thus require the careful preparation of
T
1
–4
new synthetic strategies with improved selectivity and efficiency . pre-functionalized precursors. The diastereoselective synthesis of
Among the many elegant chemical transformations that have been substituted monofluorinated piperidines can be achieved by nucleo-
developed to meet this end, the metal-catalysed hydrogenation philic substitution (Fig. 1b). However, the difficult pre-decoration
1
7,18
of unsaturated compounds is arguably one of the most powerful of substrates with defined stereochemistry is required . Other
methods. However, there remain many unsolved challenges related synthetic routes based on radical intermediates have been reported
to reactivity and selectivity for the hydrogenation of simple planar recently, with a minor focus on the generation of fluorinated piperi-
5–8
19,20
aromatic ring systems .
dines . Furthermore, the preparation of multifluorinated piperi-
Saturated nitrogen heterocycles are among the most significant dines is rarely disclosed in the literature and often requires tedious
9
21
structural components of pharmaceuticals and natural products . multistep syntheses . It should also be noted that, to the best of our
To this end, a recent analysis of FDA-approved drugs revealed that knowledge, there are no known methods for the direct diastereose-
5
9% of small molecule drugs contain at least one N-heterocycle, lective synthesis of multifluorinated piperidines (Fig. 1c). In light
10
of which saturated piperidine is the most prevalent (Fig. 1a) . of the above, we considered that a more straightforward synthetic
In a similar fashion to N-heterocycles, fluorine substituents are route to access these motifs via the hydrogenation of fluoropyri-
frequently found in drugs, agrochemicals and materials science dine precursors would represent a significant synthetic advance-
(
Fig. 1a). Furthermore, the incorporation of fluorine into lead drug ment. However, this strategy would require several challenges to be
candidates has been recognized as a powerful strategy to improve overcome, such as avoiding catalyst deactivation by the Lewis-basic
7
their pharmacokinetic and physicochemical properties and hence heterocycles and the hydrodefluorination side reactions . Strategies
11–14
increase the likelihood of success in clinical trials . Therefore, it to circumvent catalyst poisoning by employing pyridinium salts
22,23
is not surprising that around 20% of all marketed drugs and 40% instead of pyridines are known . However, the extension of this
of the current top ten best-selling drugs today contain at least one method to fluorinated compounds has yet to be disclosed, presum-
15,16
24
fluorine substituent . With these considerations in mind, it seems ably due to competing hydrodefluorination side reactions . Thus, a
only logical to assume that the incorporation of fluorine into ali- direct synthetic protocol for the hydrogenation of fluorinated nitro-
phatic N-heterocycles is therefore of significant interest to the sci- gen-containing heteroarenes, in particular fluoropyridine deriva-
entific community (Fig. 1a). For instance, it was recently shown that tives, remains elusive.
the pK of a kinesin spindle protein (KSP) inhibitor could be altered
Herein, we describe a protocol for the highly selective one-
a
by the introduction of an axial or equatorial fluorine substituent pot dearomatization–hydrogenation (DAH) of fluorinated pyri-
16
into the piperidine core . From these studies, the axial diastereo- dines, providing convenient and diastereoselective access to cis-
mer (MK-0731) was selected for clinical trials over the equatorial fluorinated piperidine building blocks (Fig. 1d). Furthermore, this
homologue (Fig. 1a).
synthetic protocol was successfully extended to multifluorinated
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany. *e-mail: glorius@uni-muenster.de
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

Articles
NATure CHemIsTry
a
b
X
R1
+
δ–
δ
Electrophilic fluorination
X = OH, H
N
C
F
Requires prefunctionalized
R
substrates
N
C–F bond is widely exploited in
agrochemical and
X
Common core in drugs
and natural products
R
F
F
pharmaceutical science
N
R
LG
Nucleophilic fluorination
R1
Requires defined
N
R
stereochemistry
Goal
R1
R1
Fn
N
R
N
R
Hydrogenation
F
Hydrodefluorination
– major pathway
R1
Incorporation of fluorine into
aliphatic heterocycles
N
‘
Underdeveloped’
Known example
F
OH
Ph
c
F
In trial
N
N
F
F
R =
F
F
δ–
MK-0731
5
steps
Separation
F
H
N
N
F δ–
O
+
N
≡
+
or
–
N
R
F
Deprotection
Cl
H
N
H
H
Unsuccessful
R
1,3-diaxial fluorine
F
4
KSP inhibitor
z
d
2D
3D
y
y
x
x
[
Rh–2]
[Rh–2]
Then
R–X
R1
R1
R1
R1
DippN
Fn
Fn
Fn
Fn
[Rh–2] =
HBpin
Rh
H2
N
N
N
N
or
H+
Rh
Cl
Bpin
Bpin
R/H
Rh
All-cis
Dearomatization
Hydrogenation
Fig. 1 | Preparation of all-cis-(multi)fluorinated piperidines by the dearomatization–hydrogenation process. a, Merging common elements of drugs.
The goal is the incorporation of fluorine into piperidine derivatives. The basicity of the KSP inhibitor was affected by the orientation of the fluorine atom.
The more basic axial isomer (MK-0731) was selected for clinical evaluation. b, Known retrosynthetic routes for the preparation of monofluorinated
piperidines. LG, leaving group. c, The multistep synthesis of cis-3,5-difluoropiperidine hydrochloride. A 1,3-diaxial behaviour of the fluorine atoms was observed.
d, Our proposed DAH process is a combined dearomatization and hydrogenation that gives access to all-cis-(multi)fluorinated piperidine building blocks.
pyridines to access the all-cis-multifluorinated piperidines with 3-fluoropyridine in THF at 25 °C. Indeed, the desired product was
excellent diastereoselectivity.
obtained in both good yield and chemoselectivity (Supplementary
Table 2). Other rhodium complexes were then examined, from
6
,28
ꢃesults and discussion
which the Rh–CAAC (ref. ) complex [Rh-2] was found to be
Our studies regarding the hydrogenation of fluoropyridines began optimal. The reaction conditions were further optimized utiliz-
by testing a variety of catalysts known to be capable of arene hydro- ing complex [Rh-2] by screening different solvents and concen-
6,7,25
genation for the reduction of 3-fluoro- and 3,5-difluoropyridine
.
trations. The influence of different hydride sources as well as the
However, these initial attempts were unsuccessful due to either cata- reaction pressure to ensure high efficiency were also investigated
lyst poisoning or uncontrolled hydrodefluorination side reactions (SupplementarySection3).Withtheoptimizedconditionsinhands,
(
Supplementary Section 3). We therefore tried to develop an effi- we began scoping studies for the hydrogenation of fluoropyridines
cient process that could both prevent catalyst poisoning and enable (Table 1). Notably, the substrates were obtained either from com-
fluoropyridine hydrogenation without the loss of the fluorine atoms. mercial sources or via a single-step synthesis following literature
Considering this, we envisioned that a borane reagent could be used procedures. On completion of the reactions, trifluoroacetic anhy-
to first dearomatize the pyridine ring system by forming a mixture dride was added as a trapping agent to prevent loss of the volatile
of dienes that could be more easily hydrogenated while also pre- fluorinated piperidine derivatives. For less reactive substrates, an
venting catalyst poisoning by protecting the Lewis-basic nitrogen.
increase in catalyst loading and/or reaction temperature improved
Initial studies towards our envisioned approach were conducted the yield of the final product. We also observed that, in some cases,
using 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin), a known an excess of pinacol borane could reduce the amount of the unde-
2
6,27
additive in the rhodium-catalysed dearomatization of pyridine
,
sired hydrodefluorinated side product. Generally, high yields and
and [Rh(COD)Cl] [Rh-1] as catalyst for the hydrogenation of excellent diastereomeric ratios were obtained. Furthermore, the
2
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

NATure CHemIsTry
Articles
Table 1 | Scope and conformational behaviour of all-cis-(multi)fluorinated piperidines
[
Rh–2] (0.5–2.0 mol%)
HBpin (2.0–4.0 equiv.)
DippN
Then
R1
Fn
R1
Fn
[Rh–2] =
TFAA
N
4 Å MS (50 mg)
N
Rh
Cl
THF (1 M), H2 (50 bar)
TFA
2
5–40 °C, 24 h
TFA-analogues
HCl-analoguesa
TFA-analogues
HCl-analoguesa
F
F
F
H
N
F
F
H
N
F
TFA
F
F
F
N
TFA
≡
≡
N
N
H
N
H
TFA
TFA
, 81% (92%)b
2, 70%
b
4, 95%, d.r. >99:1
1
3, 79% (95%) , d.r. >99:1
Gram-scale, 1.57 g, 72%, d.r. >99:1
Me
Me
F
H
N
F
H
TFA
F
N
F
TFA
≡
Me
≡
N
N
Me
H
Me
N
Me
H
F
N
F
TFA
TFA
b
5
, 81% (97%) , d.r. 90:10
6, 89%, d.r. >99:1
7, 90%, d.r. 95:5
8, 99%, d.r. >99:1
F
F
TFA
TFA
N
H
N
F
H
F
F
≡
≡
NH
NH
N
Me
F
Me
Me
N
Me
Me
Me
Me
TFA
TFA
b
b
9
, 77% (89%) , d.r. 95:5
10, 99%, d.r. >99:1
11, 84% (95%) , d.r. 90:10
12, 99%, d.r. >99:1
Me
F
TFA
F
N
F
H
Me
F
Me
F
H
N
F
≡
≡
TFA
NH
CF3
N
F3C
N
Me
Me
H
CF3
N
TFA
TFA
b
1
3, 79% (93%) , d.r. 93:7
14, 80%, d.r. >99:1
15, 70%, d.r. 95:5:0
16, 99%, d.r. 95:5:0
Me
F
F
F
F
H
N
F
F
≡
TFA
N
Me
Me
H
N
TFA
1
7, 72%, d.r. 97:2:1
18, 97%, d.r. 99:1:0
Reactions were carried out on a 0.25–10.0ꢀmmol scale. Yields were determined after column chromatography (TFA-analogues) or precipitation (HCl-analogues). d.r. values were determined by 19F NMR
or gas chromatography (GC) analysis before purification. The conformational behaviour was determined by NMR studies. For details concerning catalyst loading, amount of HBpin and temperature, see
a
Supplementary Section 4. The given yields correspond to the deprotection step of the TFA-fluoropiperidines to generate the fluoropiperidine HCl-analogues, see general procedure B in Supplementary
b
19
Section 4 for more details. NMR yields are provided in parentheses and were determined by F NMR spectroscopy with hexafluorobenzene as internal standard before the addition of TFAA. HBpin,
,4,5,5-tetramethyl-1,3,2-dioxaborolane; Dipp, 2,6-diisopropylphenyl; THF, tetrahydrofuran; TFAA, trifluoroacetic anhydride; TFA, trifluoroacetyl; MS, molecular sieves; Me, methyl.
4
isolation of the major diastereomer by standard column chroma- of TFA-analogue 3. This reaction was also readily carried out on a
tography was often possible. Deprotection of the TFA-analogues gram scale, affording 1.57 g of 3 in good yield and with excellent
afforded the piperidine hydrochlorides almost quantitatively. diastereoselectivity (72%, d.r. >99:1, Sigma-Aldrich product no.
Accordingly, the cis-3,5-difluoropiperidine hydrochloride (4), pre- 903817).Thecis-selectivityaswellasthe1,3-diaxialbehaviourofthe
2
1
viously requiring a six-step synthesis , is now obtained in a two- fluorine atoms in 4 was confirmed by NMR studies and was consis-
step process as a single diastereomer (d.r. >99:1) after deprotection tent with previously published reports (Supplementary Section 4).
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

Articles
NATure CHemIsTry
a
b
d
[
Rh–2], HBpin, 4 Å MS
THF, H2, 40 °C, 24 h
[Rh–2], HBpin (1 mmol)
Complete
+
HBpin
hydrodefluorination
N
F
N
N
4 Å MS, THF, H , 40 °C
N
Then TFAA
2
(25% NMR yield)
TFA
0.5 mmol
24 h
Bpin
>99% conversion
>99% conversion
c
F
(
1) [Rh–2], HBpin, 4 Å MS
F
D
F
F
THF, D2, 40 °C, 24 h
NH2
D
8
[
Rh–2], 4 Å MS
H
00%
D
H–Bpin
D–Bpin
(45% D incorporation)
1
3%
Then TFAA
D
THF, D2, 40 °C, 24 h
N
D
59%
(
2) Deprotection
D
D
5
50%
8%
4-D, 65% (overall)
d.r. >99:1
Fig. 2 | Selected mechanistic experiments for the Dꢁꢅ process. a, Complete hydrodefluorination of 2-fluoropydrine was observed. b, The amount
of HBpin was determined after the reaction by NMR analysis using benzene as the internal standard. c, Deuterium scrambling was observed by
employing molecular deuterium. The structure of 4-D was confirmed by NMR and electrospray ionization mass spectrometry (ESI–MS) studies.
d, D-incorporation for HBpin was observed under the reaction conditions. For more details concerning additional mechanistic studies,
see Supplementary Section 6.
The same behaviour was also observed for the hydrochloride
Table 2 | Scope and conformational behaviour of all-cis-4-
(
HCl)-analogue of 1. Observation of the large axial preference for
fluoropiperidines
3
-fluoro- and 3,5-difluoropiperidine hydrochloride ring systems
was first discussed by Lankin and colleagues and was rationalized
F
F
+
21,29
[
Rh–2] (1.0–2.0 mol%)
by the occurrence of charge dipole interactions (C–F···HN )
.
HBpin (4.0 equiv.)
Then
As our protocol provides access to a variety of new substituted
fluorinated piperidines, we wondered whether the axial prefer-
ence will also be preserved in the presence of bulky substituents
on the piperidine ring system (Table 1). Comprehensive NMR
studies (including nuclear Overhauser effect (NOE), HetNOE,
high and low temperature experiments) for the TFA-analogues
as well as the HCl-analogues revealed that in most cases the
axial preference is preserved (see Supplementary Section 4 for
more details). Interestingly, even in highly crowded ring systems
(15–18), fluorine atoms still prefer occupying axial positions
(Table 1). However, when the TFA-analogue of the piperidine
ring system contains a substituent adjacent to the nitrogen, the
conformers favour equatorial fluorine (9, 11 and 13), in sharp
contrast to the conformational behaviour of their HCl-analogues
R1
R1
TFAA
N
4 Å MS (50 mg)
N
THF (1 M), H2 (50 bar)
0 °C, 24 h
TFA
4
TFA-analogues
HCl-analoguesa
F
TFA
N
H
N
≡
F
H
N
F
TFA
1
9, 20%
20, 93%
(
10, 12 and 14). Notably, in both the TFA- and HCl-analogues of
cis-3-fluoro-5-methylpiperidine (5 and 6), the equatorial orienta-
3
F
tion is dominant. It should be noted that the vicinal J(F,H) cou-
H
Me
N
TFA
pling constants provide useful insight into the conformational
Me
N
3
≡
Me
H
structure, as large values of J(F,H ) indicate axial preference and
a
3
N
F
small values of J(F,H ) indicate equatorial preference (for more
a
F
3
0
TFA
details, see Supplementary Section 4) .
Despite the generality of the reaction, we also discovered some
limitations. For example, while 2- and 4-fluoropyridine derivatives
readily underwent hydrogenation, the hydrodefluorinated products
were identified as the major species, presumably due to unavoidable
defluorination of the unstable conjugated intermediates. Further
optimization of 4-fluoropyridine precursors allowed access to a
variety of all-cis-4-fluoropiperidine derivatives (19–24) with high
diastereoselective ratios but in reduced yields. Their conformation
was also determined by comprehensive NMR studies for both TFA-
and HCl-analogues (Table 2). Interestingly, in most cases the axial
orientation is dominant.
2
1, 31%, d.r. 97:3
22, 99%, d.r. 97:3
F
TFA
N
H
≡
NH
Me
F
N
Me
F
Me
TFA
2
3, 23%, d.r. 92:8
24, 99%, d.r. 92:8
We next sought to demonstrate the utility of this methodol-
ogy for the preparation of highly valuable and versatile fluorinated
building blocks, and at the same time to demonstrate the mild
nature of the conditions employed (Table 3). A variety of functional
groups, which allow further elaboration of the molecular struc-
ture, were well-tolerated. Among these are tert-butyl(dimethyl)silyl
Reactions were carried out on a 0.5–1.0ꢀmmol scale. Yields were determined after column
chromatography (TFA-analogues) or precipitation (HCl-analogues). d.r. values were determined
1
9
by F NMR or GC analysis before purification. The conformational behaviour was determined
by NMR studies. For details concerning catalyst loading, see Supplementary Section 4.
a
The given yields correspond to the deprotection step of the TFA-fluoropiperidines to generate
the fluoropiperidine HCl-analogues, see general procedure B in Supplementary Section 4 for
more details.
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

NATure CHemIsTry
Articles
Table 3 | Scope of all-cis-(multi)fluorinated piperidine building blocks
[
Rh–2] (0.5–2.0 mol%)
HBpin (2.0–4.0 equiv.)
Then
DippN
R1
Fn
R1
Fn
[
Rh–2] =
N
+
N
4
Å MS (50 mg)
H
or TFAA
Rh Cl
THF (1 M), H2 (50 bar)
or (Boc)2O
PG
2
5–40°C,24h
PG = H, TFA, Boc
OTBS
F
F
F
F
F
OTBS
TBSO
NHBoc
BocHN
N
N
N
N
N
Boc
Boc
PG
PG
Boc
2
5, 84%
26, 94%
d.r. 97:3
27, 85%
d.r. 95:5
28, PG = Boc, 88%, d.r. 99:1
29, PG = TFA, 24%, d.r. 99:1
30, PG = Boc, 75%, d.r. 97:3
31, PG = TFA, 61% (95%) , d.r. 97:3
a
d.r. 99:1
Bu
NHBoc
OMe
F
Cl NH3
F
F
F
F
TBSO
N
N
N
N
N
Cl
H
Boc
TFA
Boc
TFA
H
3
2, 92%
33, 80%
d.r. 99:1
34, 94%
d.r. 97:3
35
99%b
d.r. 97:3
36, 70%
d.r. 99:1
,
d.r. 95:5
OTBS
OTBS
Bpin
SiMe3
F
F
F
F
Me
F
F
F
OTBS
N
N
N
N
N
PG
Boc
TFA
Boc
Boc
3
7, 73%
38, 71% (83%)a
d.r. >99:1
39, 64% (91%)a
d.r. 93:7:0
40, 80%
d.r. 90:10:0
41, PG = Boc, 80%, d.r. 99:1:0
42, PG = H, 46%, d.r. 99:1:0
d.r. 96:4
SPh
F
F
F
F
TFA
Boc
F
F
N
N
OH
NHBoc
N
N
Me
N
H
F
N
N
H
H Cl
Boc
F
TFA
TFA
3, 99%b
d.r. 99:1:0
44, 60%
d.r. 99:1:0
45, 44% (91%)a
d.r. 86:14:0
46, 41%c
47, 91%
48, 78%
4
Reactions were carried out on a 0.25–0.5ꢀmmol scale. Yields were determined after column chromatography (TFA- or Boc-analogues) or precipitation (HCl-analogues). d.r. values were determined by
1
9
F NMR or GC analysis before purification. The conformational behaviour was determined by NMR studies. For details concerning catalyst loading, amount of HBpin and temperature, see Supplementary
a
19
b
Section 4. NMR yields are provided in parentheses and were determined by F NMR spectroscopy with hexafluorobenzene as internal standard before addition of the trapping agent. See general
procedure C in Supplementary Section 4 for the deprotection of Boc-fluoropiperidines to generate the fluoropiperidine HCl-analogues. 60% conversion. PG, protecting group; (Boc)
c
2
O, di-tert-butyl
dicarbonate; Boc, tert-butyloxycarbonyl; TBS, tert-butyl(dimethyl)silyl; Bpin, 4,4,5,5-tetramethyl-1,3,2-dioxaboroyl; Bu, n-butyl; Ph, phenyl.
(
TBS)-protected alcohols (25–27), tert-butyloxycarbonyl (Boc)- consistent with the simplified substitution analogues in Table 1
protected amines (28–31), methoxy (36), pinacol boronic ester (37) (Supplementary Section 4). The cis-selectivity and equatorial pref-
and trimethylsilyl groups (38). Different trapping agents, such erence of the fluorine in 29 were also confirmed by X-ray crystal-
as TFAA and (Boc) O, or simple addition of MeOH, were cho- lographic analysis. Orthogonally protected building blocks can
2
sen to ensure straightforward isolation of the final products. The be obtained through our strategy, albeit in low yields due to the
fluorinated analogues of the (Boc)-protected 4-aminopiperidine deprotection of the Boc group upon addition of TFAA (29,31). The
(
34) and its HCl-analogue (35), a common core in pharmaceuti- multi-substituted monofluorinated piperidine (39) as well as multi-
cals, were also obtained in high yields and diastereoselectivities. fluorinated moieties bearing additional functional groups (40–44)
The conformational behaviour in solution of the new fluorinated were all obtained in a highly diastereoselective manner. In all of
building blocks was determined by NMR and was found to be these cases, the axial orientation of the fluorine atoms is dominant.
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

Articles
NATure CHemIsTry
a
O
O
Cl
Me
O
Me
F
O
F
BuO
O
N
F
BuO
N
NEt3, MeCN
F
O , HCl (37%)
49, 84%
52, 74%
F-Melperone analogue
F-Dyclonine analogue
R1
F
–
+
N
Cl
H
H
O
(1)
,
O
Ph
Ph
O
Me
HO
Ph
Ph
F
Cl
HO
HCl (37%), 53%
F
N
Ph
HO
Ph
N
NaHCO3, NaI, DMF
F
(2)
MgCl , ZnCl2
5, 26%
51, 59%
F
5
F2-Diphenidol analogue
F2-Cycrimine analogue
b
O
Ph
O
F
Ph
O
F
N
N
Me
N
Ph
HO
Ph
N
F
F
Et
F
Cl
57, F-Cloperastine analogue
Cl
50, F-Diphenidol analogue
53, F-Eperisone analogue
59, F2-Cloperastine analogue
c
(
1) K2CO3, MeCN
F
F
F
F
F
–
Br
O
(1) NEt3, THF
(2)
+
N
P
N
+
N
–
X
O
(2) (R)-BINOL-PCl, THF
(3) LiTFSI or AgOTf
Cl
H
H
F
60, 65% (overall)
61, X = TFSI, 50% (overall)
62, X = OTF, 40% (overall)
4, d.r. >99:1
[
[
F2-AAPip]TFSI
F2-AAPip]OTf
(
R,R,S)-(–)-F2PipPhos
Fig. 3 | ꢁpplication of the all-cis-(multi)fluorinated piperidine building blocks. a, Preparation of fluorinated analogues of commercial drugs starting from
fluoropiperidine hydrochloride derivatives. b, Fluorinated analogues of additional commercial drugs. For reaction conditions, see Supplementary Section 7.
c, Preparation of fluorinated analogues of PipPhos and ionic liquids. For detailed reaction conditions see Supplementary Section 7. NEt , triethylamine;
3
MeCN, acetonitrile; DMF, dimethylformamide; (R)-BINOL-PCl, (R)-1,1′-binaphthyl-2,2′-dioxychlorophosphine; LiTFSI, bis(trifluoromethane)sulfonimide
lithium salt; AgOTf, silver trifluoromethanesulfonate.
The scope of this reaction was also extended to other heterocycles
To illustrate the utility of our method and further demonstrate
(
45–48). Interestingly, we could even selectively reduce the pyridine the value of the prepared building blocks, we synthesized several
ring system in the presence of other phenyl rings (46–48).
fluorinated analogues of commercially available drugs, the PipPhos
Preliminary mechanistic experiments were performed to gain a ligand and ionic liquids (Fig. 3a–c). The monofluorinated analogue
better understanding of the DAH process (Fig. 2). In the absence of Melperone (49) as well as mono- and difluorinated analogues of
of pinacol borane, no product was detected (Supplementary Diphenidol (50,51) were prepared using the corresponding piperi-
Section 3). Traces of the proposed borylated-dearomatized inter- dinium salts by nucleophilic substitution. The monofluorinated
1
19
mediates could be observed by H and F NMR studies of the crude analogues of Dyclonine (52), Eperisone (53) and Cycrimine (55)
reaction mixture of 3,5-difluoropyridine after 5h. However, our were all prepared starting from fluorinated piperidine hydro-
attempts to isolate the intermediates were unsuccessful, presumably chloride derivatives utilizing a modified Mannich reaction with
due to their rapid hydrogenation. On the other hand, NMR analysis 1,3-dioxolane. Moreover, the synthesis of mono- and difluorinated
of the crude reaction showed that HBpin was consumed during the analogues of Cloperastine (57,59) were also achieved (Fig. 3a,b; see
reaction (Fig. 2b), suggesting that it has a crucial role in the DAH Supplementary Section 7 for more details). Additionally, the difluo-
process. Hydrogenation of 3,5-difluoropyridine using molecular rinated phosphoramidite analogue of PipPhos (60) was accessed
deuterium was also performed generating the isotopologues of the starting from 3,5-difluoropiperidine hydrochloride (4) in a one-pot
3
,5-difluoropiperidine 4-D (Fig. 2c). Deuterium scrambling can be process (Fig. 3c). Interestingly, NMR analysis of 60 revealed that
rationalized due to the formation of imine-enamine intermediates the fluorine atoms adopt the equatorial orientation in polar and
as well as the D-incorporation into HBpin that was also observed non-polar solvents. However, X-ray crystallographic analysis of
under our reaction conditions (Fig. 2d).
F -PipPhos (60) showed that the 1,3-diaxial behaviour is dominant
2
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry

NATure CHemIsTry
Articles
1
1
2. Shah, P. & Westwell, A. D. ꢀe role of ꢂuorine in medicinal chemistry.
in the solid state. In materials science, fluorinated ionic liquids (FILs)
31
J. Enzyme Inhib. Med. Chem. 22, 527–540 (2007).
are gaining attention due to their unique physical properties .
Therefore, we incorporated our new building blocks into analogues
of previously known ionic liquids (61,62) (Fig. 3c).
3. O’Hagan, D. Understanding organoꢂuorine chemistry. An introduction to the
C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).
14. ꢀiehoꢅ, C., Rey, Y. P. & Gilmour, R. ꢀe ꢂuorine gauche eꢅect: a brief
history. Isr. J. Chem. 57, 92–100 (2017).
1
1
1
5. Wang, J. et al. Fluorine in pharmaceutical industry: ꢂuorine-containing drugs
introduced to the market in the last decade (2001−2011). Chem. Rev. 114,
Conclusions
In conclusion, we have developed a straightforward strategy to
access all-cis-(multi)fluorinated piperidines from the correspond-
ing fluoropyridine precursors in a highly diastereoselective manner.
This process proceeds via a rhodium-catalysed pyridine dearomati-
zation event followed by complete saturation of the resulting inter-
mediates by hydrogenation. We envision that the newly developed
methodology will be of immediate interest in medicinal, agrochem-
ical and materials science.
2
432–2506 (2014).
6. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A.
Applications of ꢂuorine in medicinal chemistry. J. Med. Chem. 58,
8315–8359 (2015).
7. Li, X. et al. Process development for scale-up of a novel 3,5-substituted
thiazolidine-2,4-dione compound as a potent inhibitor for estrogen-related
receptor 1. Org. Process Res. Dev. 18, 321–330 (2014).
1
1
2
8. Goldberg, N. W., Shen, X., Li, J. & Ritter, T. AlkylFluor: deoxyꢂuorination of
alcohols. Org. Lett. 18, 6102–6104 (2016).
9. Liu, W. et al. Oxidative aliphatic C–H ꢂuorination with ꢂuoride ion catalyzed
by a manganese porphyrin. Science 337, 1322–1325 (2012).
0. Ventre, S., Petronijevic, F. R. & MacMillan, D. W. C. Decarboxylative
ꢂuorination of aliphatic carboxylic acids via photoredox catalysis. J. Am.
Chem. Soc. 137, 5654–5657 (2015).
Methods
General procedure for DAH of ꢀuoropyridine derivatives. An oven-dried reaction
vessel (4 or 9ml screw-cap vial) equipped with a stirring bar was allowed to cool to
room temperature under vacuum. Activated 4Å molecular sieves (crushed, 50mg),
2
1. Snyder, J. P., Chandrakumar, N. S., Sato, H. & Lankin, D. C. ꢀe unexpected
diaxial orientation of cis-3,5-diꢂuoropiperidine in water: a potent CF- - -NH
charge-dipole eꢅect. J. Am. Chem. Soc. 122, 544–545 (2000).
2. Glorius, F., Spielkamp, N., Holle, S., Goddard, R. & Lehmann, C. W. Eꢄcient
asymmetric hydrogenation of pyridines. Angew. Chem. Int. Ed. 43,
[
Rh-2] (and solid substrates, 1.0 equiv.), were added under air. ꢀe vial was then
depressurized and pressurized with argon gas three times before the addition of dry
2
THF (1M) (and liquid substrates, distilled over CaH , 1.0equiv.). Following the addition
of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0–4.0equiv. as indicated), the glass
vial was placed in a 150ml stainless-steel autoclave under an argon atmosphere.
2
2
850–2852 (2004).
ꢀ
e autoclave was pressurized and depressurized with hydrogen gas three times before
2
2
2
2
2
3. Zhou, Y.-G. Asymmetric hydrogenation of heteroaromatic compounds.
Acc. Chem. Res. 40, 1357–1366 (2007).
the indicated pressure was set. ꢀe reaction mixture was stirred at 25–40°C for 24h.
Aꢁer the autoclave was carefully depressurized, triꢂuoroacetic anhydride (3.0equiv.)
4. Whittlesey, M. K. & Peris, E. Catalytic hydrodeꢂuorination with late
transition metal complexes. ACS Catal. 4, 3152–3159 (2014).
5. Dyson, P. J. Arene hydrogenation by homogeneous catalysts: fact or ꢃction?
Dalton Trans. 2003, 2964–2974 (2003).
2 2
and CH Cl (0.5ml) were added to the crude mixture and stirring was continued
for 10min at room temperature. Alternatively, di-tert-butyl dicarbonate (3.0equiv.),
2 2
triethyl amine (3.0equiv.) and CH Cl (0.5ml) were added to the reaction mixture
and stirring was continued for 2h at room temperature. ꢀe crude was then ꢃltered
6. Park, S. & Chang, S. Catalytic dearomatization of N-heteroarenes with silicon
and boron compounds. Angew. Chem. Int. Ed. 56, 7720–7738 (2017).
7. Oshima, K., Ohmura, T. & Suginome, M. Regioselective synthesis of
over fritted funnel and the remaining solid was washed with ethyl acetate (2×5ml).
ꢀ
e combined solution was concentrated under reduced pressure and submitted to
column chromatography (pentane/ethyl acetate or pentane/dichloromethane) to
obtain the ꢃnal product. ꢀe indicated diastereoselectivities were determined by GC
1
,2-dihydropyridines by rhodium-catalyzed hydroboration of pyridines.
J. Am. Chem. Soc. 134, 3699–3702 (2012).
19
analysis or from the F NMR spectrum immediately aꢁer the reaction. NMR yield
was calculated using hexaꢂuorobenzene (20μl, 0.173mmol) as internal standard.
2
8. Jazzar, R. et al. Intramolecular ‘hydroiminiumation’ of alkenes: application to
the synthesis of conjugate acids of cyclic alkyl amino carbenes (CAACs).
Angew. Chem. Int. Ed. 46, 2899–2902 (2007).
Data availability
29. Lankin, D. C., Chandrakumar, N. S., Rao, S. N., Spangler, D. P. & Snyder, J. P.
Protonated 3-ꢂuoropiperidines: an unusual ꢂuoro directing eꢅect and a test for
quantitative theories of solvation. J. Am. Chem. Soc. 115, 3356–3357 (1993).
30. Silla, J. M. et al. Gauche preference of β-ꢂuoroalkyl ammonium salts.
J. Phys. Chem. A 118, 503–507 (2014).
Crystallographic data for the structures reported in this Article have been deposited
at the Cambridge Crystallographic Data Centre under deposition numbers CCDC
1
845054 (29) and 1845055 (60). Copies of the data can be obtained free of charge
via https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings
of this study are available within the Article and its Supplementary Information, or
from the corresponding author upon reasonable request.
31. Pereiro, A. B. et al. Fluorinated ionic liquids: properties and applications.
ACS Sustain. Chem. Eng. 1, 427–439 (2013).
Received: 20 June 2018; Accepted: 26 November 2018;
Published: xx xx xxxx
ꢁcknowledgements
The authors acknowledge financial support from the Hans-Jensen-Minerva Foundation
(Z.N.), the Deutsche Forschungsgemeinschaft IRTG 2027 (M.W.) and the European
Research Council (ERC Advanced Grant Agreement no. 788558). The authors thank
M.P. Wiesenfeldt, M. Teders, M.J. James and M. van Gemmeren for helpful
discussions. C.G. Daniliuc is acknowledged for X-ray crystallographic analysis.
ꢃeferences
1.
Trost, B. M. Selectivity: a key to synthetic eꢄciency. Science 219, 245–250 (1983).
Baran, P. S., Maimone, T. J. & Richter, J. M. Total synthesis of marine natural
products without using protecting groups. Nature 446, 404–408 (2007).
Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity
for invention. Nat. Chem. 1, 193–205 (2009).
2
3
4
5
6
.
.
.
.
.
1-(cis-3,5-difluoropiperidin-1-yl)-2,2,2-trifluoroethan-1-one (3) is available from
Sigma-Aldrich (product no. 903817).
ꢁ
uthor contributions
Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460,
Z.N., M.W., C.S. and F.G. designed, performed and analysed experiments. K.B. performed
and analysed NMR data. Z.N. and F.G. prepared the manuscript with contributions from
all authors.
197–201 (2009).
Zhao, D., Candish, L., Paul, D. & Glorius, F. N-Heterocyclic carbenes in
asymmetric hydrogenation. ACS Catal. 6, 5978–5988 (2016).
Wei, Y., Rao, B., Cong, X. & Zeng, X. Highly selective hydrogenation of
aromatic ketones and phenols enabled by cyclic (amino)(alkyl)carbene
rhodium complexes. J. Am. Chem. Soc. 137, 9250–9253 (2015).
Wiesenfeldt, M. P., Nairoukh, Z., Li, W. & Glorius, F. Hydrogenation of
ꢂuoroarenes: direct access to all-cis-(multi)ꢂuorinated cycloalkanes. Science
Competing interests
Z.N., C.S. and F.G. are inventors on German patent application DE 10 2018 104 201.9
held by WWU Muenster, which covers the DAH process for the synthesis of all-cis-
(multi)fluorinated aliphatic heterocycles.
7.
3
57, 908–912 (2017).
8.
Wiesenfeldt, M. P., Knecht, T., Schlepphorst, C. & Glorius, F. Silylarene
hydrogenation: a strategic approach enabling direct access to versatile silylated
saturated carbo- and heterocycles. Angew. Chem. Int. Ed. 57, 8297–8300 (2018).
O’Hagan, D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids.
Nat. Prod. Rep. 17, 435–446 (2000).
ꢁ
dditional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-018-0197-2.
9
1
.
Reprints and permissions information is available at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to F.G.
0. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity,
substitution patterns, and frequency of nitrogen heterocycles among US FDA
approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
1. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: Looking
beyond intuition. Science 317, 1881–1886 (2007).
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1
© The Author(s), under exclusive licence to Springer Nature Limited 2019
NꢁTꢂꢃꢄ CꢅꢄMꢆSTꢃꢇ | www.nature.com/naturechemistry