Efficient synthesis of 3-alkoxy-4,4-difluoropiperidines

Article abstract of DOI:10.1055/s-0029-1217533

Fluorinated piperidines bearing an additional functional group at the heterocyclic ring are important building blocks for use in agrochemical or pharmaceutical chemistry. Therefore, for the first time 3-alkoxy-4,4- difluoropiperidines were synthesized by

Full text of DOI:10.1055/s-0029-1217533

LETTER
1933
Efficient Synthesis of 3-Alkoxy-4,4-difluoropiperidines
S
ynthesis of 3-A
l
i
koxy-4
c
,4-difluorop
c
iperidine
s
ardo Surmont,a,1 Guido Verniest,a Arvid De Weweire,a Jan Willem Thuring,b Gregor Macdonald,b Frederik
Deroose,b Norbert De Kimpe*a
a
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Gent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30,
2340 Beerse, Belgium
b
Received 23 March 2009
peridine ring, which is a promising feature for use in me-
dicinal chemistry. Three recent patents have been
published concerning 3-monosubstituted 4,4-difluoropip-
eridines (1 and 2), disclosing very promising anti-Alzhe-
Abstract: Fluorinated piperidines bearing an additional functional
group at the heterocyclic ring are important building blocks for use
in agrochemical or pharmaceutical chemistry. Therefore, for the
first time 3-alkoxy-4,4-difluoropiperidines were synthesized by
deoxofluorination of 3-alkoxy-4-piperidinones with morpholino- imer activities while 3-amino-4,4-difluoropiperidines 3
were reported as having anticancer activities (Figure 1).10
sulfur trifluoride and were selectively N- and O-deprotected. In
addition, the oxidation of 4,4-difluoro-3-hydroxy-1-trifluoro-
acetylpiperidine resulted in the interesting 4,4-difluoro-3,3-dihy-
droxypiperidine.
N
N
R
OH
O
Key words: piperidines, fluorine, ketones, deoxofluorination,
4,4-difluoropiperidines
N
Aryl
CF3
N
R
H
N
N
NEt2
COOH
NH2
The unique physical, chemical, and biological properties
of fluorine as a substituent in organic compounds and the
success of fluorinated compounds in medicinal chemistry
have resulted in an increasing interest for new fluorine-
containing building blocks for pharmaceuticals and agro-
chemicals with enhanced binding efficiencies and selec-
tivities.2 Until now, trifluoromethylated or ring-
fluorinated aromatics are amongst the most widely used
fluorinated physiologically active compounds. The use of
specifically fluorinated nonaromatic azaheterocycles,
however, is more limited, due to their often difficult syn-
thesis.3 This discrepancy results in a growing interest and
need for specifically fluorinated azaheterocycles. Recent-
ly, we published a new synthetic pathway towards valu-
able 2-substituted 3,3-difluoropiperidines,4 and now we
focus on substituted 4,4-difluoropiperidines. 4,4-Difluori-
nated piperidines have received most attention in the
patent literature thanks to the recent commercial availabil-
ity of 4,4-difluoropiperidine hydrochloride. This starting
material has been incorporated successfully in, for exam-
ple, antidiabetes,5 anticancer,6 antiinflamatory,7 and anti-
depressant compounds.8 Another strategy makes use of
the deoxofluorination reagent DAST [(diethylamino)sul-
fur trifluoride] at the end of the synthetic pathway to con-
vert N-alkyl- or N-aryl-4-piperidinones into 4,4-
difluoropiperidine derivatives in moderate to good
yields.9 In contrast, 3-substituted 4,4-difluoropiperidines
and in particular 3-heteroatom-substituted 4,4-difluoropi-
peridines are almost unknown in literature, although these
compounds enable the further functionalization of the pi-
F
F
F
F
O
F
F
3 (R = substituted
pyridine)
1 (R = 1H-indazole-
3-carboxamide)
2
Figure 1
Recently, a practical a-hydroxylation of ketones mediated
by iodine under basic conditions in MeOH was reported,
resulting in tert-butyl 3-hydroxy-4,4-dimethoxypiperi-
dine-1-carboxylate (5) starting from commercially avail-
able tert-butyl 4-oxopiperidine-1-carboxylate (4,
Scheme 1).11 After slight optimization of the latter de-
scribed synthesis, compound 5 was synthesized in 87%
yield from piperidinone 4 by the use of 1.3 equivalents of
iodine in the presence of KOH. The obtained 3-hydroxy-
piperidine 5 was used as the starting material for the syn-
thesis of various 3-alkoxy-4,4-difluoropiperidines. To
enable a high yielding deoxofluorination at the 4-position
of the piperidine ring, the hydroxy substituent of piperi-
dine 5 was O-protected by alkylation toward the corre-
sponding 3-alkoxy-4,4-dimethoxypiperidines
6
by
treatment with sodium hydride and reaction with benzyl
bromide. When THF was used as the solvent, the O-ben-
zylation proceeded slowly and resulted in only 91% con-
version after 96 hours. In contrast, when the reaction was
performed in DMF, a complete conversion of 5 to 3-(ben-
zyloxy)piperidine 6a was obtained after 7 hours at room
temperature. In this way, tert-butyl 3-alkoxy-4,4-
dimethoxy-1-piperidinecarboxylates 6a–c were synthe-
sized in 40–84% yield (Scheme 1). Despite the almost
quantitative conversion, attempts to further purify piperi-
dine 6a via flash silica gel chromatography always result-
ed in a considerable loss of material. To carry on the
SYNLETT 2009, No. 12, pp 1933–1936
x
x
.x
x
.2
0
0
9
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217533; Art ID: G09409ST
© Georg Thieme Verlag Stuttgart · New York

1934
R. Surmont et al.
LETTER
synthesis toward new difluorinated piperidines, it was de- were obtained when using Deoxofluor or Morph-DAST
cided to use these compounds 6 as such, without further as compared to DAST (79% and 73% vs. 57%).13 Analo-
purification (purity 89–95%).
gously, two more derivatives 9b and 9c, with different O-
substitution, were successfully prepared. 3-Benzyloxy-
4,4-difluoro-1-trifluoroacetylpiperidine 9a proved to be a
good substrate for further ring functionalization because
both the nitrogen and the oxygen atom can be selectively
deprotected. The N-trifluoroacetyl group of 9a was easily
removed by treatment with K2CO3 in a mixture of metha-
nol and water resulting in 3-benzyloxy-4,4-difluoropipe-
ridine 10 in quantitative yield (purity >92%).14 In
addition, the hydrogenolysis of the benzyloxy group of 9a
in ethyl acetate nicely gave 4,4-difluoro-3-hydroxy-1-tri-
fluoroacetylpiperidine (11) in 94% yield (Scheme 3).15
Boc
N
Boc
N
Boc
N
1) 1.5 equiv NaH
DMF, 0 °C,
0.5 h
2.4 equiv KOH
1.3 equiv I2
2) 1.05 equiv RBr
DMF, r.t., 7 h
MeOH, 0 °C
to r.t., 2.5 h
OR
OH
MeO OMe
MeO OMe
O
5 (87%)
4
6a R = Bn (84%)
6b R = Allyl (75%)
6c R = Pr (40%)
Scheme 1
The hydrolysis of dimethyl acetals 6a–c towards 3-
alkoxy-4-piperidinones 7a–c was investigated applying
different acidic conditions (Scheme 2). All hydrolytic
reaction conditions gave rise to the expected loss of the
N-Boc protecting group resulting in N-unsubstituted 3-
alkoxy-4-piperidinones 7a–c (Scheme 2). While the hy-
drolysis of 6a in a mixture of aqueous 2 M HCl and
dichloromethane (1:1) at room temperature proceeded
only slowly giving rise to 64% of conversion into 7a after
5 hours, and the use of mixtures of acetic acid and 2 M
HCl resulted in complex reaction mixtures, a clean and
complete conversion was obtained by the use of 1.1 equiv-
alents of water in trifluoroacetic acid. The synthesized N-
unsubstituted piperidines 7a–c were directly protected at
nitrogen using an excess trifluoroacetic anhydride in
dichloromethane, giving rise to stable 3-alkoxy-1-trifluo-
roacetyl-4-piperidinones 8a–c, which were easily purified
by column chromatography.
O
CF3
O
CF3
3 equiv
O
N
SF3
N
N
CH2Cl2
–78 °C to r.t., 2 h
OR
OR
F
F
O
9a R = Bn (73%)
9b R = Allyl (57%)
9c R = Pr (50%)
8a–c
H2, 25% Pd/C, 4.9 bar
EtOAc, r.t., 15 h (9a)
3 equiv K2CO3
MeOH–H2O (2:1)
r.t., 12 h (9a)
O
CF3
H
N
N
OH
OBn
F
F
F
F
11 (94%)
10 (100%)
Scheme 3
O
CF3
Having in hand a good procedure for the preparation of
3-hydroxy-4,4-difluoropiperidine 11, the further transfor-
mation of the latter compound into a variety of interesting
new piperidines was investigated. It was proposed that pi-
peridines bearing a nitrile function at the 3-position could
serve as precursors to valuable 4,4-difluoropiperidine-3-
carboxylic acids. To synthesize these compounds, the hy-
droxyl function of piperidine 11 was first transformed into
its tosylate, triflate, or mesylate derivative 12a–c using
standard reaction conditions (Scheme 4). Surprisingly, all
these compounds proved to be very resistant towards sub-
stitution with KCN or NaCN, even after 3 days reaction in
DMF or DMSO at 100 °C. Instead of further exploring the
synthetic potential of derivatives 12a–c, we next turned
our attention to 4,4-difluoro-3-piperidinone 15 as an inter-
esting target compound in order to achieve further func-
tionalization at the 3-position. Treatment of 4,4-difluoro-
3-hydroxypiperidine 11 with pyridinium chlorochromate
or SO3·pyridine complex did not result in any oxidation
into 3,3-dihydroxypiperidine 14 or piperidinone 15. How-
ever, when Dess–Martin periodinane was used, a com-
plete oxidation was obtained towards the corresponding
piperidinone, which occurred as a hydrate after aqueous
workup.16 Although the resulting hydrate 14 could be par-
tially dehydrated with phosphorus pentoxide (57% con-
TFAA/
CH2Cl2
(1:1)
Boc
N
1.1 equiv
H2O
H
N
N
r.t., 4 h
TFA
r.t., 5 h
OR
OR
OR
MeO OMe
O
O
6a–c
7a–c
8a R = Bn (74%)
8b R = Allyl (89%)
8c R = Pr (65%)
Scheme 2
The use of the N-trifluoroacetyl protecting group has the
advantage that it can be removed easily under very mild
alkaline conditions. Moreover, the electron-withdrawing
property of this functional group reduces the nucleophilic-
ity of the nitrogen and its reactivity toward deoxofluorina-
tion reagents. The fluorination of N-protected 3-alkoxy-4-
piperidinones 8 into 4,4-difluoropiperidines 9 was evalu-
ated using commercially available deoxofluorinating re-
agents. Because of the thermal instability of DAST, it was
preferred to use the more stable and safer Deoxo-fluor
{[bis(2-methoxyethyl)amino]sulfur trifluoride} and
Morph-DAST
(morpholinosulfur
trifluoride,
Scheme 3).12 Indeed, after evaluation of various deoxoflu-
orination conditions using 8a as the substrate, it was ob-
served that higher yields of 4,4-difluoropiperidine 9a
Synlett 2009, No. 12, 1933–1936 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Alkoxy-4,4-difluoropiperidines
1935
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purification. It is known that a,a-difluorination of ketones
increases the electrophilicity of the carbonyl group signif-
icantly, resulting in the formation of stable hydrates.17
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O
CF3
O
CF3
O
CF3
MsCl
or Tf2O
or TsCl
KCN
or NaCN
X
N
N
N
OH
OZ
CN
F
F
F
F
F
F
11
12a Z = Ms (79%)
12b Z = Tf (51%)
12c Z = Ts (59%)
13
O
CF3
O
CF3
2 equiv
Dess–Martin
periodinane
10 equiv
P2O5
N
N
OH
OH
CH2Cl2
r.t., 15 h
Et2O
r.t., 15 h
O
F
F
F
F
slow conversion
(57%)
14 (60%)
15 (not isolated)
H2O (fast)
Scheme 4
In conclusion, new 3-alkoxy-4,4-difluoropiperidines were
synthesized via deoxofluorination of suitable 4-piperidin-
inones and were selectively O- or N-deprotected enabling
further functionalization. In addition, 4,4-difluoro-3-hy-
droxypiperidine 11 was successfully oxidized toward the
corresponding hydrate providing new entries for further
functionalization. These 3-substituted 4,4-difluoropipe-
ridines form an interesting class of compounds with prom-
ising potential in medicinal chemistry.
Acknowledgment
The authors are indebted to the Research Foundation – Flanders
(FWO – Flanders), Ghent University (GOA), and Janssen Pharma-
ceutica (Johnson & Johnson) for financial support.
(13) 3-Benzyloxy-4,4-difluoro-1-(trifluoroacetyl)piperidine
(9a)
References and Notes
In a 25 mL flask, 3-benzyloxy-1-(trifluoroacetyl)-4-
piperidinone (8a, 0.30 g, 1.00 mmol) was dissolved in anhyd
CH2Cl2 (10 mL). The solution was cooled to –78 °C under
nitrogen atmosphere and morpholinosulfur trifluoride
(Morph-DAST; 0.53 g, 3.00 mmol, 3 equiv, 0.37 mL) was
added dropwise. The reaction mixture was allowed to warm
to r.t. over 1 h and was stirred for 2 h at the same
temperature. The mixture was poured in CH2Cl2 (10 mL)
and H2O (10 mL). The separated aqueous phase was
extracted twice with CH2Cl2 (10 mL), and the combined
organic phases were dried over MgSO4. After filtration, the
solvent was evaporated in vacuo, and the concentrate was
purified via flash chromatography over silica gel (hexane–
EtOAc = 83:17, Rf = 0.29) yielding 0.24 g of piperidine 9a
(0.73 mmol, 73%). Ratio of rotamers = 3:2; colorless oil. 1H
NMR (300 MHz, CDCl3): dmajor = 1.88–2.05 (1 H, m,
NCH2CHaHb), 2.17–2.43 (1 H, m, NCH2CHaHb), 3.21 (1 H,
br d, J = 14.9 Hz, NCHaHbCH), 3.37 (1 H, ddd, J = 14.5,
(1) Aspirant of the Research Foundation – Flanders (FWO-
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Delpon, D. J. Fluorine Chem. 2006, 127, 992. (g) Kirk,
K. L. J. Fluorine Chem. 2006, 127, 1013.
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522085.
Synlett 2009, No. 12, 1933–1936 © Thieme Stuttgart · New York

1936
R. Surmont et al.
LETTER
11.4, 3.2 Hz, NCHaHbCH2), 3.55–3.73 (1 H, m, OCH), 3.80–
3.93 (1 H, m, NCHaHbCH2), 4.44–4.53 (1 H, m,
hydrogen pressure of 4.75 bar. The mixture was filtered over
Celite®, and the filtrate was evaporated in vacuo to yield
0.75 g of pure piperidine 11 (3.20 mmol, 94%). Ratio of
rotamers = 53:47; yellow oil. 1H NMR (300 MHz, CDCl3):
NCHaHbCH), 4.63 (1 H, d, J = 11.8 Hz, CHaHbPh), 4.71 (1
H, d, J = 11.8 Hz, CHaHbPh), 7.21–7.44 (5 H, m, 5 × CHar);
dminor = 1.88–2.05 (1 H, m, NCH2CHaHb), 2.17–2.43 (1 H, m,
dmajor = 1.93–2.11 (1 H, m, NCH2CHaHb), 2.18–2.48 (1 H, m,
NCH2CHaHb), 3.27 (1 H, ddd, J = 14.0, 10.5, 3.4 Hz,
NCHaHbCH2), 3.48 (1 H, br d, J = 14.3 Hz, NCHaHbCH),
3.55–3.73 (1 H, m, OCH), 3.80–3.93 (1 H, m, NCHaHbCH),
4.10–4.21 (1 H, m, NCHaHbCH2), 4.64 (1 H, d, J = 11.6 Hz,
CHaHbPh), 4.74 (1 H, d, J = 11.6 Hz, CHaHbPh), 7.21–7.44
(5 H, m, 5 × CHar). 19F NMR (282 MHz, CDCl3): d = –67.8
and –68.8 (3 F, s, CF3), –107.4 (1 F, dd, J = 247.6, 24.3 Hz,
CFaFb,rotamer1), –107.6 (1 F, br d, J = 247.6 Hz, CFaFb,rotamer2),
–108.5 (1 F, br d, J = 247.6 Hz, CFaFb,rotamer1), –109.2 (1 F,
br d, J = 247.6 Hz, CFaFb,rotamer2). 13C NMR (75 MHz,
CDCl3): d = 30.3 and 31.1 (t, J = 22.8 Hz), 40.1 and 42.3,
44.1 and 47.0, 72.5 and 73.4, 73.1 and 73.5 (t, J = 20.5 Hz),
116.5 (q, J = 288.2 Hz), 120.0 (t, J = 246.9 Hz) and 120.6
(dd, J = 250.4, 244.6 Hz), 128.0, 128.1, 128.2, 128.4, 128.7,
136.9 and 137.1, 156.4 and 156.5 (q, J = 36.2 Hz). IR
(NaCl): n = 1699, 1203, 1116 cm–1. GC-MS (EI): m/z (%) =
NCH2CHaHb), 2.60–3.10 (1 H, br s, OH), 3.47 (1 H, d × m,
J = 13.8 Hz, NCHaHbCH), 3.46–3.54 (1 H, m,
NCHaHbCH2), 3.81–3.95 (1 H, m, NCHaHbCH2), 3.97–4.05
(1 H, m, OCH), 4.28 (1 H, d × m, J = 13.8 Hz, NCHaHbCH);
dminor = 1.93–2.11 (1 H, m, NCH2CHaHb), 2.18–2.48 (1 H, m,
NCH2CHaHb), 2.60–3.10 (1 H, br s, OH), 3.41 (1 H, ddd,
J = 13.8, 10.0, 3.7 Hz, NCHaHbCH2), 3.65 (1 H, d, J =
13.8 Hz, NCHaHbCH), 3.81–3.95 (2 H, m, OCH and
NCHaHbCH), 4.14 (1 H, dt, J = 13.8, 4.8 Hz, NCHaHbCH2).
19F NMR (282 MHz, CDCl3): d = –67.8 and –68.9 (3 F, s,
CF3), –110.1 (1 F, dd, J = 246.0, 21.1 Hz, CFaFb,rotamer1),
–110.4 (1 F, dd, J = 246.0, 23.7 Hz, CFaFb,rotamer2), –111.2 (1
F, br d, J = 246.0 Hz, CFaFb,rotamer1), –111.6 (1 F, br d,
J = 246.0 Hz, CFaFb,rotamer2). 13C NMR (75 MHz, CDCl3):
d = 29.7 and 30.7 (t, J = 23.1 Hz), 40.2 (t, J = 5.2 Hz), 42.3
(d, J = 3.5 Hz), 46.3 (t, J = 3.5 Hz), 47.9 (d, J = 2.3 Hz), 67.5
(t, J = 26.5 Hz), 67.7 (t, J = 27.1 Hz), 116.3 (q, J = 287.7
Hz), 119.9 and 120.1 (t, J = 246.3 Hz), 156.7 (q, J = 36.5
Hz). IR (ATR): n = 3444, 1683, 1464, 1185, 1111, 967
+
323 (22) [M+], 107 (71) [C7H9O+], 91 (100) [C7H7 ]. Anal.
Calcd: C, 52.02; H, 4.37; N, 4.33. Found: C, 51.76; H, 4.11;
N, 4.01.
+
(14) 3-Benzyloxy-4,4-difluoropiperidine (10)
cm–1. MS (ES+): m/z (%) = 251 (100) [M + NH4 ]. Anal.
In a 25 mL flask, 3-benzyloxy-4,4-difluoro-1-(trifluoro-
acetyl)piperidine (9a, 0.50 g, 1.55 mmol) was dissolved in
MeOH (6 mL). A solution of K2CO3 (0.64 g, 4.64 mmol, 3
equiv) in H2O (3 mL) was added, and the mixture was stirred
for 12 h at r.t. After completion of the reaction, the solvent
was evaporated in vacuo, and the residue was dissolved in
CH2Cl2 (20 mL) and H2O (20 mL). The separated aqueous
phase was extracted twice with CH2Cl2 (20 mL) and the
combined organic phases dried over MgSO4. After filtration,
the solvent was evaporated in vacuo, yielding 0.35 g of
piperidine 10 (1.55 mmol, 100%, purity >92%). For
analytical purposes a 50 mg sample of the compound was
subjected to an acid–base extraction (30% yield), excluding
the necessity of flash chromatography to yield pure
compound 10 as a yellow oil. 1H NMR (300 MHz, CDCl3):
d = 1.48–1.72 (1 H, br s, NH), 1.87 (1 H, dddt, J = 24.7, 13.0,
4.0, 1.3 Hz, CHaHb), 2.12 (1 H, dddd, J = 35.4, 13.0, 10.2,
5.0 Hz, CHaHb), 2.73–2.91 (2 H, m, NCH2CH2), 2.91–3.10
(2 H, m, NCH2CH), 3.45–3.54 (1 H, m, OCH), 4.63 (1 H, d,
J = 11.8 Hz, OCHaHb), 4.80 (1 H, d, J = 11.8 Hz, OCHaHb),
7.27–7.38 (5 H, m, 5 × CHar). 19F NMR (282 MHz, CDCl3):
d = –104.9 (1 F, br s),–105.7 (1 F, br s). 13C NMR (75 MHz,
CDCl3): d = 32.5 (t, J = 20.8 Hz), 42.8 (t, J = 4.0 Hz), 48.4
(t, J = 2.3 Hz), 72.8, 74.7 (t, J = 24.8 Hz), 121.6 (t, J = 247.5
Hz), 127.8, 127.9, 128.4, 137.7. IR (ATR): n = 3324, 3032,
2930, 1454, 1351, 1200, 1111, 967, 737, 698 cm–1. MS
(ES+): m/z (%) = 228 (100) [M + H+]. Anal. Calcd: C, 63.42;
H, 6.65; N, 6.13. Found: C, 63.08; H, 6.01; N, 5.95.
(15) 4,4-Difluoro-3-hydroxy-1-(trifluoroacetyl)piperidine
(11)
Calcd: C, 36.06; H, 3.46; N, 6.01. Found: C, 35.79; H, 3.09;
N, 5.88.
(16) 4,4-Difluoro-3,3-dihydroxy-1-(trifluoroacetyl)piper-
idine (14)
In a 10 mL flask, 4,4-difluoro-3-hydroxy-1-(trifluoro-
acetyl)piperidine (11, 0.10 g 0.43 mmol) was dissolved in
anhyd CH2Cl2 (5 mL). After adding Dess–Martin
periodinane (0.36 g, 0.86 mmol, 2.0 equiv), the solution was
stirred for 15 h at r.t. The mixture was diluted with Et2O (30
mL), and the organic phase was washed three times with a
sat. aq NaHCO3 solution (20 mL). The organic phase was
dried over MgSO4, and after filtration the solvent was
evaporated in vacuo. The concentrate was dissolved in Et2O
(5 mL) and cooled to –40 °C to crystallize residues of the
Dess–Martin periodinane reagent. After filtration of the
solids, the filtrate was evaporated in vacuo to yield 0.06 g of
piperidine 14 (0.26 mmol, 60%). Ratio of rotamers = 2:1;
colorless oil. 1H NMR (300 MHz, CDCl3): dmajor = 2.11–2.31
(2 H, m, NCH2CH2), 3.71 (2 H, t, J = 6.1 Hz, NCH2CH2),
3.83 [2 H, s, NCH2C(OH)2], 5.52 (2 H, br s, 2 × OH);
dminor = 2.11–2.31 (2 H, m, NCH2CH2), 3.67 [2 H, s,
NCH2C(OH)2], 3.78 (2 H, t, J = 6.1 Hz, NCH2CH2), 5.52 (2
H, br s, 2 × OH). 19F NMR (282 MHz, CDCl3): d = –67.2 and
–68.9 (3 F, s, CF3), –119.6 (2 F, t, J = 13.2 Hz, CF2,rotamer1),
–119.7 (2 F, t, J = 13.2 Hz, CF2,rotamer2). 13C NMR (75 MHz,
CDCl3): dmajor = 31.6 and 30.2 (t, J = 23.1 Hz), 40.2 (t,
J = 4.6 Hz), 42.6 (m), 49.9 and 51.6, 90.8 and 91.5 (t,
J = 24.2 Hz), 116.3 and 116.3 (q, J = 287.3 Hz), 118.7 and
119.0 (t, J = 250.9 Hz), 156.6 and 156.8 (q, J = 36.5 Hz). IR
(ATR,): n = 3410, 1685, 1461, 1187, 1112, 964 cm–1. MS
(ES+): m/z (%) = 267 (100)[M + NH4 ]. Anal. Calcd: C,
+
In a dry pressure vessel, 3-benzyloxy-4,4-difluoro-1-
(trifluoroacetyl)piperidine (9a, 1.10 g, 3.40 mmol) was
dissolved in EtOAc (10 mL). After adding 10% Pd/C (0.22
g) at 0 °C, the mixture was stirred during 15 h at r.t. under
33.75; H, 3.24; N, 5.62. Found: C, 33.41; H, 3.49; N, 5.43.
(17) Bégué, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991, 47,
3207.
Synlett 2009, No. 12, 1933–1936 © Thieme Stuttgart · New York

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