Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation

Article abstract of DOI:10.1021/acscatal.0c03278

Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis-selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed.

Full text of DOI:10.1021/acscatal.0c03278

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Article
Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation
Tobias Wagener, Arne Heusler, Zackaria Nairoukh, Klaus
Bergander, Constantin G. G. Daniliuc, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c03278 • Publication Date (Web): 18 Sep 2020
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Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hy-
drogenation
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Tobias Wagener, Arne Heusler, Zackaria Nairoukh, Klaus Bergander, Constantin G. Daniliuc, and
Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany
hydrogenation • nitrogen heterocycles • fluorine • heterogeneous catalysis • palladium
ABSTRACT: Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general syn-
thetic access remains out of reach. Herein we describe a simple and robust cis-selective hydrogenation of abundant and cheap fluor-
opyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoro-
pyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated deriva-
tives of important drug compounds are prepared and a straightforward strategy for the synthesis of enantioenriched fluorinated piper-
idines is disclosed.
Fluorine has become recognized as a potent substituent in me-
dicinal, agricultural, and material science over the last dec-
ades.(1) Owing to their high polarity, carbon–fluorine bonds are
deliberately installed in drug candidates to optimize their physi-
cochemical properties.(2) Although fluorine is barely found in nat-
ural products, almost one quarter of all small-molecule drugs in
the market contain at least one fluorine atom.(3) For instance, flu-
orine’s strong preference for gauche orientation is widely utilized
to establish conformationally-defined building blocks.(4) Besides
fluorine, nitrogen-containing heterocycles are an outstandingly
important moiety commonly found in natural products and phar-
maceuticals.(5)
A recent investigation revealed that 59% of all small-molecule
drugs approved by the FDA contain at least one N-heterocycle.(6)
Undoubtedly, the combination of both, fluorine substituents and
N-heterocycles is of great interest to pharmaceutical and agricul-
tural researchers.(7) Although piperidine is the most abundant
heterocycle in pharmaceuticals, a straightforward and general
synthesis of fluorinated piperidines remains challenging.(8) Com-
mon synthetic fluorination pathways such as electrophilic and
nucleophilic substitution offer only limited access to fluorinated
piperidines.(9)
An alternative retrosynthetic strategy is the formation of piperi-
dines from fluorinated precursors.(10) Given the broad availability
of fluorinated pyridines, metal-catalyzed hydrogenation is recog-
nizable as a powerful tool to transform these to the desired sat-
urated building blocks (Figure 1a).(11) This synthetic approach,
however, is hampered by the competing hydrodefluorination
pathway, leading to undesired non-fluorinated piperidines.(12)
Table 1. Standard reaction conditions and selected devia-
tions.
Entry
Deviation
none
Yield B
88%
Conv. A
>99%
>99%
<5%
1
2
3
4
5
6
7
Rh/C (5 wt%)
Rh/Al2O3 (5 wt%)
Pt/C (5 wt%)
Ru/Al2O3 (5 wt%)
Pd/C (10 wt%)
no acid
53%
traces
6%
>99%
<5%
traces
83%
>99%
78%
17%
Figure 1. Synthetic strategies to access fluorinated piperidines.
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Chart 1. Substrate scope for the palladium-catalyzed hydrogenation of fluoropyridines. See Supporting Information for full
experimental details.
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To address this problem, our group recently reported the devel-
opment of a dearomatization-hydrogenation (DAH) process (Fig-
ure 1b).(13) Although this process allowed access to a series of
fluorinated piperidines for the first time, the synthetic utility is lim-
ited. Firstly, owing to the use of hydridic HBpin, polar and/or pro-
tic functional groups such as esters, amides, alcohols and free
amines are not tolerated under the reaction conditions.
Moreover, since rhodium is one of the most active transition met-
als for arene reduction, a general chemoselective hydrogenation
of pyridines over other (hetero)arenes such as benzene or imid-
azole was not possible.(14) Additionally, the reactivity of the DAH
process is highly dependent on the purity of reagents and sol-
vents applied.
To start our investigations, we studied the reduction of 3-fluoro-
pyridine in organic solvents using various heterogeneous cata-
lysts. Early experiments indicated that many catalysts are not
sufficiently active under these conditions. Thus, we tried to solve
both issues through protonation of both the substrate and prod-
uct with Brønsted acid.(16) To our delight, we found that the com-
bination of Pd(OH)2 on carbon (20 wt%) with aqueous HCl in
MeOH is a suitable and simple system for the hydrogenation of
fluorinated pyridines (Table 1, entry 1). In contrast, several com-
mon heterogeneous catalysts gave less or only traces of the de-
sired fluorinated product B (entries 2–6). Omitting the strong
Brønsted acid results in diminished conversion and formation of
the defluorinated side product C dominates (entry 7). Notably, no
special care was taken to exclude air and moisture during reac-
tion setup within this study – an attractive feature.
With these drawbacks in mind, we were searching for a direct
hydrogenation without the need for a dearomatizing agent to cir-
cumvent the functional group incompatibility and sensitivity prob-
lems affiliated with the DAH process (Figure 1c).(15)
A recently described reaction-condition-based sensitivity screen
revealed, that our procedure is insensitive towards small devia-
tions of concentration, pressure, temperature and the presence
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of oxygen or moisture (see Supporting Information for further de-
tails).(17)
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Having optimized reaction conditions in hand, we then investi-
gated the substrate scope of the protocol (Chart 1). Since purifi-
cation of volatile, unprotected fluorinated piperidines is challeng-
ing, we investigated the trapping with different protecting groups.
Fluorinated piperidines 1 and 2 were isolated in high yields after
in situ benzyloxycarbonyl (Cbz) protection. Performing the syn-
thesis of piperidine 2 in a gram-scale reaction afforded the de-
sired product in 67% yield. Likewise, Fmoc-protected fluorinated
piperidine 3 was obtained in good yield and excellent diastere-
oselectivity after in situ trapping.
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Further, amide- (4) and sulfonamide-protecting groups (5) could
also be employed and in both cases the products were isolated
in good yield and excellent diastereoselectivity. Difluorinated pi-
peridine 6 was isolated in 30% yield after Cbz protection, owing
to significant formation of single- and double-defluorinated side
products.
In contrast to our previous study,(13) free hydroxy groups were
tolerated under the reaction conditions and led to the isolation of
valuable δ-lactam products 7 and 8 in good yields, respectively.
Our catalytic system facilitated the cis-selective reduction of
fluoropyridines over benzene rings and enabled the synthesis of
5-fluoro-2-phenylpiperidine (9) in good diastereoselectivity.(18)
A
series of multi-fluorinated 2-aryl-5-fluoropiperidines 10–13 were
synthesized in good to moderate yields and high diastereoselec-
tivities.
Scheme 1. Synthesis of fluorinated methylphenidate (a), bu-
pivacaine (b), ropivacaine (c), and enantioenriched 3-fluor-
opiperidine (d).
Moreover, aryl- and alkyl ether substituted aryl-fluoropiperidines
14–16 and ester substituted piperidine 17 were synthesized in
good yield and excellent diastereoselectivity, respectively. Fur-
thermore, multifluorinated 4-aryl-3-fluoropiperidines 18 and 19
were synthesized in THF/H2O while not-fully reduced fluorinated
tetrahydropyridine 20 was obtained in moderate yield when
changing the solvent to MeOH. To our delight, 2-aryl-3,5-dilfluor-
opiperidine 21 was synthesized after elongated reaction time in
good yield and diastereoselectivity.
Fluorinated, unnatural amino acids are of high interest, but syn-
thetic access remains difficult.(19) Our protocol allows the isola-
tion of 22 after a single reaction step from a commercially avail-
able starting material in 62% yield. Moreover, this method re-
veals access to β-amino acid 23 and tetrahydropyridine γ-amino
acid 24. Besides esters, a series of amide-substituted fluorinated
piperidines 25–30 was synthesized. 2-Phenylacetamide substi-
tuted piperidine 31 was isolated in 52% yield and only two dia-
stereomers in a 71:29 ratio were observed. NMR and X-ray anal-
yses revealed cis-configuration for both isolated isomers with the
erythro isomer as the main component.
To further investigate the selective reduction of fluorinated pyri-
dines over other (hetero)arenes, we tested the hydrogenation of
various imidazo[1,2-a]pyridines. To our delight, 6-fluoro-5,6,7,8-
tetrahydroimidazo[1,2-a]pyridine (32) was isolated without re-
duction of the imidazole ring being observed. A series of 2-sub-
stituted (multi)fluorinated tetrahydroimidazo[1,2-a]pyridines 33–
37 were synthesized in good yields tolerating alkyl, aryl, trifluo-
romethyl and ester substituents.
Many of the products listed in Chart 1 were isolated in diminished
yields and accompanied with non-fluorinated piperidines. This is
due to remaining hydrodefluorination reactions, which are not
completely suppressed by our new catalytic system.
Preliminary mechanistic investigations indicate that hydro-
defluorination occurs on dearomatized intermediates (see Sup-
porting Information for further details). The beneficial role of the
Brønsted acid on reactivity towards hydrogenation has been in-
vestigated in the literature(20) yet the influence on hydrodefluori-
nation remains unclear. Further mechanistic investigations are
ongoing but beyond the scope of this study.
The conformational behavior of fluorinated piperidines aroused
the interest of physical-organic chemists.(21) A recent, detailed
study investigated the fundamental interactions of fluorinated pi-
peridines.(22) NMR analysis of the free NH piperidines synthe-
sized in this study proved the gauche conformation of the prod-
ucts in CDCl3.
To further show the utility of our developed method, several fluor-
inated drug derivates have been prepared (Scheme 1). Fluori-
nated methylphenidate (Ritalin©, Concerta©) 38 was obtained in
89% yield from 31 after stirring in MeOH in the presence of
H2SO4. Free NH piperidines 26 and 28 were prepared applying
our new protocol and were transformed into fluorinated deriva-
tives of bupivacaine 39 and ropivacaine 40, respectively.
Our method can be further expanded to the synthesis of enanti-
oenriched fluorinated piperidines. Adopting a strategy which was
previously established in our lab,(23) oxazolidine-substituted pyr-
idine 41 was prepared. Under acidic conditions, pyridine 41 was
hydrogenated to the corresponding oxazolidine-substituted pi-
peridine in a diastereoselective fashion. In situ cleavage of the
auxiliary followed by reduction of the imine intermediate gave the
enantioenriched piperidine 42 in 55% yield and 95:5 e.r. after
Cbz protection. After the protecting group was removed, the ab-
solute configuration of 3-fluoropiperidine·HCl was determined
using X-Ray analysis.
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In summary, we have developed a new method to access highly
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valuable fluorinated piperidines based on a palladium-catalyzed
hydrogenation. This protocol enables the transformation of
cheap and abundant fluoropyridines to sought-after fluorinated
piperidines in a robust and simple manner. Using a common het-
erogeneous palladium catalyst, a selective reduction of fluoro-
pyridines over benzene and imidazole systems was established.
The robustness of our method was demonstrated by applying a
reaction-condition based sensitivity assessment, revealing high
tolerance for the presence of air and moisture. The products are
obtained in good yields and high diastereoselectivities and the
synthetic utility was highlighted by the synthesis of fluorinated
drug derivatives. Furthermore, this method was expanded to the
synthesis of highly enantioenriched fluorinated piperidines in a
straightforward fashion.
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AUTHOR INFORMATION
Corresponding Author
Frank Glorius – Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster, Münster 48149, Germany
orcid.org/0000-0002-0648-956X;
Email:glorius@uni-muenster.de
Present Addresses
Zackaria Nairoukh – The Institute of Chemistry, The Hebrew Uni-
versity of Jerusalem, 9190401 Israel
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pyridine, piperidine and tropane alkaloids. Nat. Prod. Rep. 2000,
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Rings in Drugs. J. Med. Chem. 2014, 57, 5845–5859.
(6) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Struc-
tural Diversity, Subsitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J.
Med. Chem. 2014, 57, 10257–10274.
orcid.org/0000-0001-8443-4292
Notes
The authors declare no competing financial interests.
(7) For a hydrogenation of trifluoromethylated pyridines, see: (a)
Zhang, X.; Ling, L.; Luo, M.; Zeng, X. Accessing Difluorometh-
ylated and Trifluoromethylated cis-Cycloalkanes and Saturated
Heterocycles: Preferential Hydrogen Addition to the Substitution
Sites for Dearomatization. Angew. Chem., Int. Ed. 2019, 58,
16785–16789. For a hydrogenation of fluorinated isoquinolines,
see: (b) Guo, R.-N.; Cai, X.-F.; Shi, L.; Ye, Z.-S.; Chen, M.-W.;
Zhou, Y.-G. An efficient route to chiral N-heterocycles bearing a
C–F stereogenic center via asymmetric hydrogenation of fluori-
nated isoquinolines. Chem. Commun. 2013, 49, 8537–8539. (c)
Chen, M.-W.; Ji, Y.; Wang, J.; Chen, Q.-A.; Shi, L.; Zhou, Y.-G.
Asymmetric Hydrogenation of Isoquinolines and Pyridines Us-
ing Hydrogen Halide Generated in Situ as Activator. Org. Lett.
2017, 19, 4988–4991.
(8) For selected examples, see ref. 13 and: (a) Kajimoto, T.; Liu, K.
K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J. A. Jr.;
Wong, C.-H. Enzyme-Catalyzed Aldol Condensation for Asym-
metric Synthesis of Azasugars: Synthesis, Evaluation, and Mod-
eling of Glycosidae Inhibitors. J. Am. Chem. Soc. 1991, 113,
6187–6196. (b) Yang, Y.; Zheng, F.; Bols, M.; Marinescu, L. G.;
Qing, F.-L. Synthesis of monofluorinated isofagomine analogues
and evaluation as glycosidase inhibitors. J. Fluor. Chem. 2011,
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J.; Kawade, S.; Doshi, P. J.; Dhavale, D. D. Fluorinated piperi-
dine iminosugars and their N-alkylated derivatives: Synthesis,
conformational analysis, immunosuppressive and glycosidase in-
hibitory activity studies. Tetrahedron 2018, 74, 852–858. (d)
Sarver, P. J.; Bacauanu, V.; Schultz, D. M.; DiRocco, D. A.; Lam,
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website.
X-ray crystallographic data for compounds 7 (CCDC Nr.:
1999050), 8 (CCDC Nr.: 1999051), 13 (CCDC Nr.: 1999052), 27
(CCDC Nr.: 1999053), 31 (CCDC Nr.: 1999054), 32 (CCDC Nr.:
1999055), and 43 (CCDC Nr.: 2026631) can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENT
The authors acknowledge financial support from the European Re-
search Council (ERC Advanced Grant Agreement No. 788558), the
Deutsche Forschungsgemeinschaft (Leibniz Award), and the Al-
fred Krupp von Bohlen und Halbach Foundation. The authors also
thank Toryn Dalton, Daniel Moock, J. Luca Schwarz, and Marco
Wollenburg for many helpful discussions.
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