Novel Approach toward 3,3-Difluoropiperidines from Easily Available Starting Materials and Synthesis of a New Phosphodiesterase Inhibitor

Article abstract of DOI:10.1055/s-0036-1588313

A novel methodology for the synthesis of 3,3-difluoropiperidines has been developed. The target compounds are prepared in three steps using a robust protocol and simple starting materials. The incorporation of the fluorine is achieved by using the cheap and easily available ethyl 2-bromo-2,2-difluoroacetate as building block. Using this methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) inhibitor containing the functionalized fluorinated piperidine scaffold has been prepared.

Full text of DOI:10.1055/s-0036-1588313

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
J. Giacoboni et al.
Letter
Synlett
Novel Approach toward 3,3-Difluoropiperidines from Easily Avail-
able Starting Materials and Synthesis of a New Phosphodiesterase
Inhibitor
Jessica Giacobonia,b
Rasmus P. Clausenb
Mauro Marigo*a
HN
3 steps
EtO2C
Br
aliphatic
aromatic
R
Li
CN
R
F
F
heteroaromatic
F
F
easily available starting materials
R = Me, aryl, heteroaryl
a Department of Discovery Chemistry & DMPK, H. Lundbeck
A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark
maum@lundbeck.com
b Department of Drug Design and Pharmacology, Faculty of
Health and Medical Sciences, University of Copenhagen,
2 Universitetsparken, DK-2100 Copenhagen, Denmark
3,3-difluoro-
piperidines
Received: 12.07.2016
Accepted after revision: 25.08.2016
Published online: 12.09.2016
starting from the commercially available ethyl 2-bromo-
2,2-difluoroacetate (1) and acrylonitrile (2, Scheme 1). In
our hands, the reaction proceeded well under mild condi-
tions and in multigram scale.
DOI: 10.1055/s-0036-1588313; Art ID: st-2016-b0451-l
Abstract A novel methodology for the synthesis of 3,3-difluoropiperi-
dines has been developed. The target compounds are prepared in three
steps using a robust protocol and simple starting materials. The incor-
poration of the fluorine is achieved by using the cheap and easily avail-
able ethyl 2-bromo-2,2-difluoroacetate as building block. Using this
methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) in-
hibitor containing the functionalized fluorinated piperidine scaffold has
been prepared.
Cu (2.1 equiv)
TMEDA (0.5 equiv)
O
O
Br
CN
CN
+
EtO
EtO
AcOH (0.9 equiv), THF
91%
F
F
F
F
1
2
3
Scheme 1 Multigram synthesis of building block 3
Key words fluorine, piperidine, ethyl 2-bromo-2,2-difluoroacetate,
reductive amination, phosphodiesterase
This common intermediate 3 was easily functionalized
and 4,4-difluoro-5-oxo-5-phenylpentanenitrile (5a) was
obtained by addition of phenyl lithium 4a (Scheme 2). Us-
ing 1.1 equivalents of the organolithium reagent in THF at
–78 °C only minor amounts of diarylated products were ob-
served resulting in a very satisfactory 89% yield. On the con-
trary, the reaction with the Grignard reagent phenyl mag-
nesium bromide 4b resulted in a lower conversion, and it
was affected by the formation of other side products.
While fluorine-containing natural products are rare,1
synthetic fluorinated compounds are widely used in a vari-
ety of fields due to the fact that molecules containing fluo-
rinated groups often display unique properties that cannot
be accomplished using other elements. Carbon–fluorine
bonds have been incorporated in pharmaceuticals,2–5 agro-
chemicals,6,7 materials,8,9 and tracers for positron emission
tomography.10,11 The introduction of fluorine into biologi-
cally active molecules can make them more bioavailable,
improve metabolic stability, change the pKa, and increase
the strength of a compound’s interaction with a target pro-
tein. At the same time, functionalized piperidines are com-
mon scaffolds in medicinal chemistry and they are present
in many natural occurring and synthetic biologically active
compounds.5
In this context, we here disclose a novel methodology
for the synthesis of 3,3-difluoro-2-substitued-piperidines12
that proceeds in good yields and that avoids the use of reac-
tive fluorine sources.
Our synthetic strategy started from ethyl 4-cyano-2,2-
difluorobutanoate (3), a versatile building block that can be
prepared using the methodology reported by Lee et al.13,14
Li
O
O
4a
CN
CN
EtO
THF, –78 °C
89%
F
F
F
F
3
5a
Scheme 2 Functionalization of intermediate 3 with organolithium re-
agent 4a
The last step in the synthesis of fluorinated piperidines
was a one-pot reduction of the nitrile group and subse-
quent reductive amination to form 3,3-difluoro-2-phen-
ylpiperidine 7a (Table 1). Initial attempts to reduce the ni-
trile in the H-Cube using Pd/C or PtO2 did not yield any
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
J. Giacoboni et al.
Letter
Synlett
product (Table 1, entries 1 and 2) while Raney nickel was
quickly identified as a more promising catalytic system. Us-
ing methanol as solvent, at 50 °C and 50 bar of hydrogen,
slow conversion of the nitrile into the amine 6a and sub-
stantial formation of several defluorinated species were ob-
served. After adding NaBH4 to the crude reaction mixture,
the desired product 7a was finally isolated. However, the
poor conversion and the concomitant formation of the un-
desired 3-fluoro-2-phenylpiperidine (8) and 2-phen-
ylpiperidine (9) limited the yield to only 30% (Table 1, entry
3).15 The yield of the hydrogenation from 5a to intermediate
6a could not be improved by extending the reaction time
because the higher conversion was negatively compensated
by a more extensive formation of the defluorinated side
products. Using a mixture of acetic acid/methanol and low-
ering the flow to 0.2 mL/min to increase the residence time
on the catalyst led to the formation of the difluorinated
piperidine 7a in good chemical yield (Table 1, entry 4). In
order to accelerate the overall reaction and minimize the
formation of the undesired defluorinated piperidines, ace-
tic acid was tested as a solvent. In this reaction media, using
a flow of 1 mL/min under 5 bar of hydrogen the product 7a
was obtained in 86% yield (Table 1, entry 5).
whether the reduction could be performed also in batch
mode. Using the Raney nickel catalyst in acetic acid under 5
bar of hydrogen in the autoclave, the desired product was
isolated in 45% yield after one hour at room temperature.
Although the yield is only moderate, it is a viable alterna-
tive to the use of the H-Cube.
Finally, we tested the scope of this two-step transforma-
tion and a diverse series of 3,3-difluoropiperidines could be
prepared (Table 2). The various organolithium reagents
were purchased as a solution from commercial suppliers or
prepared in situ from the corresponding brominated aro-
matics and heteroaromatics.17 The addition of (4-fluoro-
phenyl)lithium proceeded very well (81% yield), and the in-
termediate 5b was hydrogenated to produce the corre-
sponding difluorinated piperidine 7b in 68% yield (Table 2,
entry 2). An electron-donating group such as 4-benzyloxy
did not have a negative effect on the reaction, and the inter-
mediate 5c could be obtained in good yield under the same
reaction conditions. During the hydrogenation, the benzyl
protecting group was also cleaved and the 4-(3,3-difluoro-
piperidin-2-yl)phenol (7c) was isolated in 79% yield (Table
2, entry 3).18 Notably, this approach works efficiently also
for the preparation of heteroaryl-substituted piperidines.
Table 1 Screening of Hydrogenation Conditions at the H-Cube for the
One-Pot Reduction–Reductive Amination Reactiona
Table 2 Scope of the Two-Step Preparation of 3,3-Difluoropiperidines
from the Common Intermediate 319,20
HN
H2
Raney Ni
O
O
HN
R
Li
CN
CN
O
F
F
EtO
R
R
N
CN
F
F
F
F
7a
F
F
+
3
5a–g
7a–g
F
F
F
F
HN
5a
6a
Entry
1
R
Product, yield (%)a,c
Product, yield (%)b,c
R
8 (R = F)
9 (R = H)
5a, 89
7a, 86
Entry Catalyst
Solvent
T
(°C)
P
Flow
Yield
(bar) (mL/min) (%)b
2
3
5b, 81
7b, 68
F
1
2
3
4
5
Pd/C (10%) MeOH
70
21
50
21
50
50
10
50
1
1
–
PtO2
MeOH
1
–
5c (R2 = Bn), 72
7c (R2 = H), 79
R2
Raney Ni
Raney Ni
Raney Ni
MeOH
1
30c,d
70d
86
O
R2 = Bn
MeOH–AcOH (1:1)
AcOH
0.2
1
5
4
5
N
N
5d, 64d
5e, –e
7d, 89
7e, 40f
a Reaction conditions: reaction performed using H-Cube continuous-flow
hydrogenation, with sealed disposable cartridges, 5a [0.01 M].
b Isolated yield after column chromatography.
Me
c The reduction stops at intermediate 6a. Yield determined after reduction
with NaBH4 (see Supporting Information).
a General reaction conditions for the addition of the organolithium re-
agents: 3 (1 equiv, 0.3 M) in Et2O, RLi (1.5 equiv) at –78 °C.
b Reaction performed using H-Cube continuous-flow hydrogenation, Raney
Ni, 5a–e [0.01 M] in AcOH, 1 mL/min, 5 bar, 50 °C.
d Formation of defluorinated piperidines 8 and 9 observed in the crude mix-
ture.
c Isolated yield after column chromatography.
d Organolithium reagent prepared and added at –95 °C.
e Intermediate 5c not purified due to the low boiling point.
f Overall yield for the transformation from 3 to 7e. The crude piperidine was
Boc-protected in situ and purified by flash chromatography; 7e was isolat-
ed as HCl salt after deprotection.
A drawback of using acetic acid is that the catalyst car-
tridge of the H-Cube deteriorates over time limiting the
chance of upscaling the reaction.16 Therefore, to further ex-
tend the applicability of this methodology we investigated
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
J. Giacoboni et al.
Letter
Synlett
Intermediate 5d with a methylpyrazole functionality was
efficiently ring-closed in high yield (Table 2, entry 4). The
protocol is also applicable to the preparation of piperidines
with alkyl side chains. The more volatile 4,4-difluoro-5-oxo-
nitrile (5e) was not purified but after aqueous workup was
directly reduced in the H-Cube (Table 2, entry 5).
HN
HN
F
F
F
HO
F
K2CO3
O
7c
Cl
DMSO, 120 °C, 1 h
47%
N
N
Cl
N
A slightly modified procedure was applied in the pres-
ence of more sensitive heteroaromatic functionalities (Ta-
ble 3). The addition of thiophen-2-yllithium to the ester 3
worked very well (87% yield). However, the final product 7f
could not be obtained using the standard conditions due to
the reduction of the thiophene ring.21 To minimize the un-
desired side reaction, the hydrogenation in the H-Cube was
conducted at 20 °C (rather than the standard 50 °C). Under
these milder conditions the nitrile group is reduced, but the
reductive amination on the ketone does not occur. To com-
plete the synthesis of the piperidine products, the reduc-
tion of the imine intermediate was obtained using NaBH4 in
methanol. With this updated protocol (no further optimisa-
tion was pursued), the final product 7f could be obtained in
30% yield (Table 3, entry 1) and the racemic fluorinated an-
alogue of the naturally occurring alkaloid anabasine 7g was
also isolated in 52% yield (Table 3, entry 2).
Cl
N
N
N
N
(
)-11
N
PDE2A IC50 = 3 nM
10
Scheme 3 Incorporation of the piperidine 7c into biologically active
compounds; synthesis of potent in vitro PDE2A inhibitors
In conclusion, we developed a novel methodology for
the preparation of functionalized 3,3-difluoropiperidines.
Although this is a small study it demonstrates that the pro-
tocol is tolerant to a diverse range of substituents that have
general application in drug discovery and the target mole-
cules are prepared using easily available starting materials.
Acknowledgment
The work was financially supported by The Ministry of Higher Educa-
tion and Science and H. Lundbeck A/S. We thank Christoffersen, C.T.
for the determination of the IC50 of compound 11.
Table 3 Scope of the Three-Step Preparation of 3,3-Difluoropiperi-
dines from the Common Intermediate 3
1. H2, Raney Ni
2. NaBH4
O
O
HN
R
Li
Supporting Information
CN
CN
EtO
R
R
F
F
F
F
F
F
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588313.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
3
5f–g
7f–g
Entry
1
R
Product, yield (%)a,b
Product, yield (%)c,b
References and Notes
S
5f, 87
7f, 30
(1) O’Hagan, D.; Harper, B. J. Fluorine Chem. 1999, 100, 127.
(2) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(3) Wang, J.; Sanchez-Rosell, M.; Acena, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432.
2
5g, 71d
7g, 52
N
a General reaction conditions for the addition of the organolithium re-
agents: 3 (1 equiv, 0.3 M) in Et2O, RLi (1.5 equiv) at –78 °C.
b Isolated yield after column chromatography.
(4) (a) Bégué, J. P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127,
992. (b) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
(5) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422.
(6) Fujiwara, T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16.
(7) Jeschke, P. Pest. Manage. Sci. 2010, 66, 10.
c Reduction to the imine using H-Cube continuous-flow hydrogenation,
Raney Ni, 5f–g [0.01 M] in AcOH, 1 mL/min, 5 bar, 20 °C. After evaporation
of the solvent, the crude intermediate was reduced with NaBH4 (2 equiv) at
0 °C in MeOH.
d Organolithium reagent prepared and added at –95 °C.
(8) Barnes, N. A.; Brisdon, A. K.; Ellis, M. J.; Pritchard, R. G. J. Fluorine
Chem. 2001, 112, 35.
(9) Brisdon, A. K.; Ali Ghaba, H.; Beutel, B.; Egjandi, A.; Addaraidi,
A.; Pritchard, R. G. Dalton Trans. 2015, 44, 19717.
(10) Couturier, O.; Luxen, A.; Chatal, J. F.; Vuillez, J. P.; Rigo, P.;
Hustinx, R. Eur. J. Nucl. Med. Mol. Imaging 2004, 31, 1182.
(11) Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sanford, M. S.; Scott,
P. J. H. Chem. Sci. 2014, 5, 4545.
As an example of the potential application of the 3,3 di-
fluoropiperidines in drug discovery, the phenoxy-substitut-
ed product 7c was easily incorporated in the structure of a
novel nanomolar inhibitor of the phosphodiesterase
PDE2A.22,23 The new inhibitor 11 was obtained by nucleop-
hilic aromatic substitution reaction of 7c with 6-chloro-3-
(2-chlorophenyl)-[1,2,4]triazolo[3,4-a]phthalazine (10, Scheme
3) and the IC50 was determined20 to be fivefold more potent
if compared with the nonfluorinated analogue.
(12) Verniest, G.; Surmont, R.; Hende, E. V.; Deweweire, A.; Deroose,
F.; Thuring, J. W.; De Kimpe, N. J. Org. Chem. 2008, 73, 5458.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
J. Giacoboni et al.
Letter
Synlett
(13) (a) Kim, B. C.; Park, A.; An, J. E.; Lee, W. K.; Lee, H. B.; Shin, H.
Synthesis 2012, 44, 3165. For earlier reports on the addition of 1
to Michael acceptors, see: (b) Sato, K.; Tamura, M.; Tamoto, K.;
Omote, M.; Ando, A.; Kumadaki, I. Chem. Pharm. Bull. 2000, 48,
1023. (c) Sato, K.; Nakazato, S.; Enko, H.; Tsujita, H.; Fujita, K.;
Yamamoto, T.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine
Chem. 2003, 121, 105. (d) Sato, K.; Omote, M.; Ando, A.;
Kumadaki, I. J. Fluorine Chem. 2004, 125, 509.
(14) For examples of synthesis of fluorinated piperidines starting
from 2-bromo-2,2-difluoroacetate, see: (a) Surmont, R.;
Verniest, G.; Thuring, J. W.; Macdonald, G.; Deroose, F.; De
Kimpe, N. J. Org. Chem. 2010, 75, 929. (b) Moens, M.; Verniest,
G.; De Schrijver, M.; ten Holte, P.; Thuring, J. W.; Deroose, F.; De
Kimpe, N. Tetrahedron 2012, 68, 9284.
(600 MHz, CDCl3): δ = 8.17–8.12 (2 H, m), 7.69–7.66 (1 H, m),
7.54–7.51 (2 H, m), 2.71–2.68 (2 H, m), 2.66–2.58 (2 H, m). 19F
NMR (471 MHz, CDCl3): δ = –101.1 (t, J = 16.0 Hz). 13C NMR (151
MHz, CDCl3): δ = 187.8 (C, t, J = 31.6 Hz), 135.0 (CH, s), 131.4 (C,
t, J = 3.32 Hz), 130.4 (CH, t, J= 3.4 Hz), 128.9 (CH, s), 118.1 (C, s),
120.0–116.0 (CF2, t, J = 255.8 Hz), 30.0–29.6 (CH2, t, J = 23.5 Hz),
10.7–10.5 (CH2, t, J = 6.71 Hz).
(20) General Experimental Procedures for the Reduction–Reduc-
tive Amination Reaction
A solution of 5 in acetic acid (0.01 M) was reduced using H-
Cube Pro® (ThalesNano) continuous-flow hydrogenation
system; CartCart Raney nickel THS01112; Temperature T = 50
°C and the flow rate of 1 mL/min. After full conversion of the
starting material (reaction followed by LC–MS), the solvent was
removed in vacuo, and the product was purified by flash
column chromatography.
(15) Formation of side products with mass corresponding to 8 and 9
was detected by LC–MS.
(16) Incompatibility of the catalyst cartridge with acetic acid as
solvent is reported in the user manuals for H-Cube.
(17) For a detailed description of the preparation of the organolith-
ium reagents, see Supporting Information.
(18) The hydrogenation of 5c could also be conducted in batch mode
using an autoclave. The benzyl protecting group was stable
under these reaction conditions (see Supporting Information)
and the fluorinated piperidine 7h (R2 = Bn) was isolated in 42%
yield.
(19) General Experimental Procedures for the Addition of the
Organolithium Reagents to 4-Cyano-2,2-difluorobutanoate
(3)
3,3-Difluoro-2-phenylpiperidine (7a)
The title compound 7a (81 mg, 0.411 mmol, 86% yield) was
obtained according to the general procedure starting from a
solution of 5a in AcOH (100.0 mg, 0.478 mmol, 0.01 M). 1H NMR
(600 MHz, CDCl3): δ = 7.46–7.43 (2 H, m), 7.38–7.32 (3 H, m),
3.89–3.84 (1 H, d, J = 23.2 Hz), 3.25–3.19 (1 H, m), 2.83–2.75 (1
H, m), 2.59 (1 H, br s), 2.35–2.25 (1 H, m), 1.95–1.80 (3 H, m). 19
F
NMR (471 MHz, CDCl3): δ = –99.5 (d, J = 240.7 Hz), –117.5 (m).
13C NMR (151 MHz, CDCl3): δ = 135.9 (C, s), 128.8 (CH, s), 128.3
(CH, s), 128.1 (CH, s), 121.1–117.8 (CF2, dd, J = 244.9, 248.0 Hz),
66.0–65.4 (CH, dd, J = 26.5, 22.0 Hz), 45.9 (CH2, s), 33.8–33.4
(CH2, dd, J = 25.9, 21.7 Hz), 24.0–23.9 (CH2, d, J = 9.9 Hz). ESI-
To a solution of ethyl 4-cyano-2,2-difluorobutanoate (3, 1 equiv,
0.3 M) in Et2O was added dropwise a solution of commercially
available organolithium (1.1 equiv) at –78 °C. After 2 h the reac-
tion was quenched with an aq sat. solution of NH4Cl, EtOAc was
added, and the phases were separated. The aqueous phase was
further extracted twice with EtOAc. The combined organic
phases were dried over MgSO4, filtered, concentrated in vacuo,
and purified using silica gel chromatography to provide the
desired product.
HRMS: m/z calcd for C
11H13F2N [MH+]: 198.1089; found:
198.1090.
(21) Formation of a product with mass corresponding to 2-butyl-
3,3-difluoropiperidine was observed by LC–MS.
(22) For the determination of the PDE2A activity, see: Redrobe, J. P.;
Jørgensen, M.; Christoffersen, C. T.; Montezinho, L. P.; Bastlund,
J. F.; Carnerup, M.; Bundgaard, C.; Lerdrup, L.; Plath, N. Psycho-
pharmacology 2014, 231, 3151.
(23) For selected references on PDE2A as a potential therapeutic
target, see: (a) Gomez, L.; Breitenbucher, J. G. Bioorg. Med. Chem.
Lett. 2013, 23, 6522. (b) Buijnsters, P.; De Angelis, M.; Langlois,
X.; Rombouts, F. J. R.; Sanderson, W.; Tresadern, G.; Ritchie, A.;
Trabanco, A. A.; VanHoof, G.; Roosbroeck, Y. V.; Andrés, J. I. ACS
Med. Chem. Lett. 2014, 5, 1049. (c) Lueptow, L. M.; Zhan, C.;
O’Donnel, J. M. Psycopharmacology 2016, 233, 447.
4,4-Difluoro-5-oxo-5-phenylpentanenitrile (5a)
The title compound 5a (1.51 g, 5.02 mmol, 89% yield) was
obtained according to the general procedure starting from a
solution of ethyl 4-cyano-2,2-difluorobutanoate (3) in Et2O
(5.56 mmol, 0.3 M) and a commercially available 1.8 M solution
of 4a in n-dibutyl ether (3.45 mL, 6.21 mmol) at –78 °C. 1H NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D