Synthesis of 2-aryl-3-hydroxymethyl-5,5-difluoropiperidines

Article abstract of DOI:10.1016/j.tet.2012.08.049

A strategy toward the synthesis of functionalized 5,5-difluoropiperidines, a class of compounds with potential as building block in medicinal chemistry, was developed. In a three-step procedure 2,2-difluoroglutaric anhydride was synthesized starting from ethyl bromodifluoroacetate. This key intermediate reacts fluently with various imines to yield 5,5-difluoropiperidinone carboxylic acids. Subsequent esterification of the obtained carboxylic acids enabled the isolation of trans-substituted 5,5-difluoro-2-arylpiperidinone-3-carboxylates as the major isomers. Reduction of the difluorinated piperidinonecarboxylates using borane gave rise to new trans-2-aryl-1-benzyl-5,5-difluoro-3- hydroxymethylpiperidines in excellent yields.

Full text of DOI:10.1016/j.tet.2012.08.049

Tetrahedron 68 (2012) 9284e9288
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-aryl-3-hydroxymethyl-5,5-difluoropiperidines
,
Matthias Moens a, Guido Verniest a y, Matthias De Schrijver a, Peter ten Holte b, Jan-Willem Thuring b,
,
Frederik Deroose b, Norbert De Kimpe a
*
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2012
Received in revised form 9 August 2012
Accepted 16 August 2012
Available online 24 August 2012
A strategy toward the synthesis of functionalized 5,5-difluoropiperidines, a class of compounds with
potential as building block in medicinal chemistry, was developed. In a three-step procedure 2,2-
difluoroglutaric anhydride was synthesized starting from ethyl bromodifluoroacetate. This key in-
termediate reacts fluently with various imines to yield 5,5-difluoropiperidinone carboxylic acids. Sub-
sequent esterification of the obtained carboxylic acids enabled the isolation of trans-substituted 5,5-
difluoro-2-arylpiperidinone-3-carboxylates as the major isomers. Reduction of the difluorinated piper-
idinonecarboxylates using borane gave rise to new trans-2-aryl-1-benzyl-5,5-difluoro-3-
hydroxymethylpiperidines in excellent yields.
Keywords:
Fluorinated piperidines
2,2-Difluoroglutaric anhydride
Heterocycles
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
trifluoride (DAST) or (bis(2-methoxyethyl)amino)sulfur trifluoride
(DeoxofluorÒ).3,8 The major drawbacks of the latter reagents are their
Despite the low abundance of naturally occurring fluorinated
molecules, the interest in fluorine as a substituent in organic mol-
ecules has increased over the years.1 The numerous papers pub-
lished in this field confirm the importance of fluorinated compounds
in pharmaceutical sciences and agrochemistry.1,2 In particular,
fluorinated piperidines have proven their use in medicinal chemis-
try.3 For example, highly substituted 3,3-difluoropiperidines have
been used for the preparation of anti-Alzheimer’s agents and gly-
cosidase inhibitors, due to their similarity to iminosugars.4,5 Fur-
thermore, fluorinated hydroxymethylpiperidines have shown to
possess high potential for the treatment of metabolic syndrome,6
a combination of several risk factors linked to obesity.
The goal of this research is to develop a pathway toward novel 3-
hydroxymethyl-5,5-difluoropiperidines, starting from commer-
cially available ethyl bromodifluoroacetate. Despite the recently
developed routes toward valuable fluorinated piperidines,7,8 the
availability of synthetic pathways to substituted difluoropiper-
idines still remains limited.
low thermal stability, low functional group tolerance, and possible
release of HF. For those reasons, alternative pathways toward fluo-
rinated piperidines using a building block approach, starting from
commercially available fluorinated substrates gain popularity.7b,9
2. Results and discussions
This report focuses on the synthesis of new functionalized 5,5-
difluoropiperidines via reaction between 2,2-difluoroglutaric anhy-
dride 4 with suitably substituted imines. The synthesis of 2,2-
difluoroglutaric anhydride was accomplished via a three-step path-
way starting from commercially available ethyl bromodifluoroacetate
1 (Scheme 1).10e12 Ethyl 4-cyano-2,2-difluorobutanoate 2 was syn-
thesized starting from ethyl bromodifluoroacetate 1 and acrylonitrile
in the presence of copper in DMSO via a 1,4-addition reaction.10,11
Hydrolysis of ethyl 4-cyano-2,2-difluorobutanoate 2 using aq 5 M
NaOH provided 2,2-difluoroglutaric acid 3,11 which was ring closed to
2,2-difluoroglutaric anhydride 4 after reflux in acetic anhydride.12
This method was easily scaled up to several grams.
In the literature most difluoropiperidines are prepared by deox-
obisfluorinationofsuitablepiperidinonesusing(diethylamino)sulfur
Reaction of glutaric anhydride 4 with various imines in toluene or
xylene afforded 1-substituted 2-aryl-5,5-difluoropiperidine-6-one-
3-carboxylic acids 6 in moderate to good yields. The best results
were obtained when electron-rich imines were used as reaction
* Corresponding author. Tel.: þ32 (0)9 264 5951; fax: þ32 (0)9 264 6243;
e-mail addresses: matthias.moens@ugent.be (M. Moens), Norbert.dekimpe@
ugent.be (N. De Kimpe).
partners. Indeed, reaction of anhydride
4 with N-(4-nitro-
benzylidene)benzylamine or the N-benzylimine derived from
ethyl glyoxalate was sluggish and the degradation of anhydride 4
proceeded faster than the formation of the corresponding
y
Present address: Vrije Universiteit Brussel, Faculty of Science and
Bio-engineering Sciences, Department of Chemistry, Pleinlaan 2, B-1050 Brussel,
Belgium.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.049

M. Moens et al. / Tetrahedron 68 (2012) 9284e9288
9285
with H-2 and H-3 in the axial positions. This trans configuration was
confirmed by methyl ester 7b for which a small coupling constant of
Jtrans¼4.4 Hz was observed. This change in conformational equilib-
rium can be explained by a diaxial positioning of the substituents,
due to sterical hindrance. A coupling constant of Jcis¼5.5 Hz was
observed forall minor isomers 7a,cee. This indicates that H-2 and H-
3 occupy a pseudoaxialepseudoequatorial position, corresponding
tothe cis configuration.14 Theobtained diastereomeric ratio of trans-
and cis-substituted carboxylates 7 ranged from 3:1 to 1:0 depending
on the substrates used and the reaction temperature (Table 1).
O
2.2 equiv. Cu
O
2 equiv. CH2=CHCN
Br
CN
EtO
EtO
DMSO, 65°C, 6h
F
F
F
F
2
(59%)
1
5M NaOH
0°C->rt, 19h
O
O
O
O
O
F
Ac2O
h
HO
OH
Table 1
F
F
F
Influence of the imine substituents and the reaction temperature on the di-
astereomeric ratio of piperidinonecarboxylic acids 6
3
(95%)
4
(42%)
Entry
R1
H
R2
Product
Solvent
trans/cis
Scheme 1. Synthesis of 2,2-difluoroglutaric anhydride 4.10e12
1
2
3
4
5
6
7
8
Bn
6a
6a
6a
6b
6b
6c
6c
6d
6d
6e
6e
Tol
Xyl
Benzene
Tol
Xyl
Tol
Xyl
Tol
Xyl
5:1a
6:1a
10:1a
trans
trans
12:1b
4:1b
6:1b
3:1b
4:1b
3:1b
2-MeO
3-MeO
4-MeO
H
Bn
piperidinone-5-carboxylic acids. The enhanced reactivity of elec-
tron-rich imines with anhydride 4 can be explained by considering
a reaction mechanism in which the imine nitrogen serves as a nu-
cleophile as a first step in the reaction cascade.13 This nucleophilic
attack leads to the formation of a zwitterionic intermediate, which
suffers ring closure caused by addition of the enolate to the iminium
ion leading to the formation of piperidinone 6.13 In this way, mainly
trans-substituted isomers are formed, which is in agreement with
literature data on analogous non-fluorinated compounds.14 The
characterization of both diastereomers was based on the analysis of
H-2/H-3 coupling constants of methyl piperidinone-3-carboxylates
7 in 1H NMR spectroscopy, as these esters 7 were easily isolated and
analyzed (Scheme 2). The 1H NMR spectra of methyl esters 7 showed
Bn
Bn
9
10
11
4-MeOBn
Tol
Xyl
Ratio determined by 1H NMR based on the NCH-signal.
Ratio determined by 1H NMR based on the OMe-signal.
a
b
It was observed that the diastereomeric ratio of the obtained
trans- and cis-piperidones 6 could be improved by performing the
reaction at lower temperature of reflux, i.e., in toluene instead of
xylene. However, when using benzene, only small amounts of
piperidinones 6 were obtained, which is in accordance to literature
data on related non-fluorinated analogues.14
two sets of doublets, close to
d
¼4.9 ppm, corresponding with the H-
2 protons of the trans- and cis-diastereomer, from which the di-
astereomeric ratio could be measured. The largest coupling con-
stants were observed for the major diastereomers 7 (Jtransꢀ6.1 Hz),
which indicates that methyl esters 7 have the trans configuration,
A much larger effect on the diastereomeric ratio was observed
when the position of the substituent at the aromatic imine was
R2
R1
N
R1
R1
R1
Recryst.
Petroleum ether /
Diethyl ether
(5:1)
H
R2
N
R2
N
R2
N
CH2N2, Et2O
rt, on
O
O
O
F
O
F
F
O
F
F
O
F
5
MeO
MeO
HO
F
solvent
6h
F
O
O
4
O
trans-7a R1 = H, R2 = Bn (73%)
trans-7b R1 = 2-MeO, R2 = Bn (25%)
trans-7c R1 = 3-MeO, R2 = Bn (40%)
trans-7d R1 = 4-MeO, R2 = Bn (13%)
trans-7e R1 = H, R2 = 4-MeOC6H4CH2
(31%)
7a-e
6
a R1 = H, R2 = Bn
b R1 = 2-MeO, R2 = Bn
c R1 = 3-MeO, R2 = Bn
d R1 = 4-MeO, R2 = Bn
e R1 = H, R2 = 4-MeOC6H4CH2
5 equiv BH3SMe2
CH2Cl2, on
R1
R2
N
8a R1 = H, R2 = Bn (86%)
8b R1 = 2-MeO, R2 = Bn (75%)
8c R1 = 3-MeO, R2 = Bn (80%)
8d R1 = 4-MeO, R2 = Bn (70%)
8e R1 = H, R2 = 4-MeOC6H4CH2 (97%)
F
F
OH
Scheme 2. Overview of the synthesis of trans-2-aryl-3-hydroxymethyl-5,5-difluoropiperidines.

9286
M. Moens et al. / Tetrahedron 68 (2012) 9284e9288
changed. An excellent diastereomeric ratio of 12:1 (trans/cis) was
obtained for the 3-MeO derivative (6c). The closer the substituent
was positioned to the imine functionality, the higher the trans/cis
ratio was (Table 1, entries 4e9). In the case of the 2-MeO derivative
(6b) only the trans-isomer was formed. (Table 1, entries 4 and 5).
The obtained mixtures of trans- and cis-2-aryl-5,5-
difluoropiperidine-6-one-3-carboxylates 7aee were subjected to
chromatographic separation on silica gel. Subsequent re-
crystallization in petroleum ether/diethyl ether (5:1) resulted in the
isolation of the trans-isomers as pure compounds. In order to
synthesize the envisaged new difluoropiperidines 8, trans-methyl
carboxylates 7aee were reduced by using 5 equiv of BH3$SMe2 in
dichloromethane under reflux overnight. The trans-2-aryl-1-
benzyl-5,5-difluoro-3-hydroxymethylpiperidines 8aee were ob-
tained in 70e97% yield. Attempts to perform a selective reduction
of the piperidinone without reducing the methyl ester moiety using
either borane reagents (BH3$SMe2, BH3$THF), or monochloroalane,
failed. It was observed that even at room temperature, reduction of
the ester moiety already took place in an early stage.
carboxylic acid 6. To an ice cooled solution of carboxylic acid 6
(1.0 equiv) in dry diethyl ether, diazomethane15 (5 equiv) in diethyl
ether was carefully added at 0 ꢂC and the reaction mixture was then
stirred overnight at room temperature. The solvent was evaporated
in vacuo to yield trans- and cis-methyl 2-aryl-1-benzyl-5,5-
difluoro-6-oxopiperidine-3-carboxylate 7. The diastereomers were
purified via column chromatography on silicagel (petroleum ether/
EtOAc). Subsequent recrystallization in petroleum ether/diethyl
ether (5:1) afforded the major trans-diastereomer.
4.2.1. trans-Methyl-1-benzyl-5,5-difluoro-6-oxo-2-phenylpiperidine-
3-carboxylate (7a). Yield: 73%. White crystals. Mp: 139.0e140.5 ꢂC.
Flash chromatography (petroleum ether/EtOAc 4:1, Rf¼0.16). 1H
NMR (300 MHz, CDCl3):
d
2.56 (2H, td, J¼13.6, 6.6 Hz), 3.08 (1H, q,
J¼6.6 Hz), 3.49 (1H, d, J¼15.4 Hz), 3.53 (3H, s), 4.84 (1H, d,
J¼6.1 Hz), 5.41 (1H, d, J¼14.9 Hz), 7.13e7.38 (10H, m). 13C NMR
(75 MHz, CDCl3):
d
31.9 (t, J¼24.2 Hz), 44.0 (t, J¼5.2 Hz), 48.1, 52.6,
61.1, 111.4 (t, J¼224.6 Hz), 127.1, 128.0, 128.7, 128.9, 129.0, 129.4,
135.2, 137.7, 161.8 (t, J¼30 Hz), 170.6. 19F NMR (282 MHz, CDCl3):
d
ꢃ98.84 (1F, dt, J¼284.1, 13.2 Hz), ꢃ100.0 (1F, dt, J¼284.1, 13.2 Hz).
3. Conclusion
IR (ATR, cmꢃ1): nC
]O 1729,1676; nmax 1350,1199,1095, 746, 707. MS
(ESþ): m/z (%): 360 (Mþ1, 100). Anal. Calcd for C20H19F2NO3: C,
In conclusion, a strategy toward substituted 3-hydroxymethyl-
5,5-difluoropiperidines, a new class of compounds with potential
as building block in medicinal chemistry, was developed. The key
step in the synthesis includes a cyclocondensation reaction of im-
ines with 2,2-difluoroglutaric anhydride, which is easily available
from ethyl bromodifluoroacetate in three steps. This reaction yiel-
ded mainly trans-substituted piperidinones, which were isolated
after methylation to methyl piperidinone-3-carboxylates. The ob-
tained methyl piperidinonecarboxylates were subsequently used as
substrates for the synthesis of new N-protected difluorinated bi-
functional building blocks. Hydroxymethylated difluoropiperidines
were obtained in high yield by reduction of piperidinone-3-
carboxylates using borane in dichloromethane.
66.84; H, 5.33; N, 3.90. Found: C, 66.66; H, 5.24; N, 3.95.
4.2.2. trans-Methyl-1-benzyl-5,5-difluoro-6-oxo-2-(2-methoxyphenyl)
piperidine-3-carboxylate (7b). Yield: 25%. White crystals. Mp:
118.3e120.3 ꢂC. Flash chromatography (hexane/EtOAc 3:1, Rf¼0.20).
1H NMR (300 MHz, CDCl3):
d 2.38e2.72 (2H, m), 3.19 (1H, m), 3.54
(3H, s), 3.58 (1H, d, J¼14.3 Hz), 3.77 (3H, s), 5.19 (1H, d, J¼4.4 Hz),
5.33 (1H, d, J¼14.3 Hz), 6.89e7.39 (9H, m). 13C NMR (75 MHz,
CDCl3):
d
31.5 (t, J¼24.2 Hz), 40.9, 48.7, 52.4, 55.3, 56.9, 111.1, 111.4
(t, J¼244.0 Hz), 120.9, 124.7, 127.7, 127.9, 128.4, 128.8, 130.0, 135.4,
156.8, 162.2 (t, J¼30 Hz), 171.1. 19F NMR (282 MHz, CDCl3):
d
ꢃ97.17
(1F, d, J¼286.8 Hz), ꢃ100.44 (1F, d, J¼286.8 Hz). IR (ATR, cmꢃ1):
nC
]
1742, 1685; nmax 1600, 1487, 1456, 1362, 1239, 1197, 1101,
O
1101, 940, 756, 698. MS (ESþ): m/z (%): 389 (Mþ1, 100). Anal. Calcd
for C21H21F2NO4: C, 64.77; H, 5.44; N, 3.60. Found: C, 64.38; H, 5.44;
N, 3.63.
4. Experimental section
4.1. General
4.2.3. trans-Methyl-1-benzyl-5,5-difluoro-6-oxo-2-(3-methoxyphe-
nyl)piperidine-3-carboxylate (7c). Yield: 40%. White crystals. Mp:
71.7e73.7 ꢂC. Flash chromatography (hexane/EtOAc 3:1, Rf¼0.18).
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSEþ)
with CDCl3 as solvent and TMS as a reference. 13C NMR spectra were
recorded at 75 MHz (JEOL ECLIPSEþ) with CDCl3 as solvent and TMS
as reference. 19F NMR spectra were recorded at 282 MHz (JEOL
ECLIPSEþ) with CDCl3 as solvent and CFCl3 as reference. Electron
spray (ES) mass spectra were obtained with an Agilent 1100 Series
MS (ES, 4000 V) mass spectrometer. IR spectra were measured with
a Spectrum One FT-IR spectrophotometer. Diethyl ether, benzene,
toluene, and xylene were dried over sodium benzophenone ketyl.
Dichloromethane was dried over CaH2. Other solvents and reagents
were used as received from the supplier. Melting points of crys-
1H NMR (300 MHz, CDCl3):
d
2.57 (2H, td, J¼13.6, 6.6 Hz), 3.09 (1H,
q, J¼6.6 Hz), 3.53 (1H, d, J¼14.6 Hz), 3.55 (3H, s), 3.79 (3H, s), 4.80
(1H, d, J¼6.1 Hz), 5.41 (1H, d, J¼14.6 Hz), 6.66e7.39 (9H, m). 13C
NMR (75 MHz, CDCl3):
d
32.0 (t, J¼24.2 Hz), 44.4 (t, J¼4.6 Hz), 48.1,
52.6, 55.4, 61.0, 111.4 (t, J¼244.6 Hz), 113.0, 114.2, 119.3, 128.1, 128.7,
128.9, 130.5, 135.3, 139.4, 160.4, 161.8 (t, J¼30 Hz), 170.7. 19F NMR
(282 MHz, CDCl3):
d
ꢃ98.91 (1F, dt, J¼284.1, 13.2 Hz), ꢃ100.05 (1F,
dt, J¼284.1, 13.2 Hz). IR (ATR, cmꢃ1): nC
] 1745, 1672; nmax 1600,
O
1364, 1284, 1210, 1096, 922, 792, 745, 701. MS (ESþ): m/z (%): 390
(Mþ1, 100). Anal. Calcd for C21H21F2NO4: C, 64.77; H, 5.44; N, 3.60.
Found: C, 65.35; H, 5.47; N, 3.66.
€
talline compounds were measured with a Buchi 540 apparatus.
Elemental analyses were obtained using a Perkin Elmer 2400 Series
II Apparatus.
4.2.4. trans-Methyl-1-benzyl-5,5-difluoro-6-oxo-2-(4-methoxyphe-
nyl)piperidine-2-carboxylate (7d). Yield: 13%. White crystals. Mp:
104.4e106.6 ꢂC. Flash chromatography (hexane/EtOAc 3:1,
4.2. General procedure
To
a
solution of N-(benzylidene)benzylamine (3.33 mmol,
Rf¼0.15). 1H NMR (300 MHz, CDCl3):
d 2.43e2.64 (2H, m), 3.04e3.11
1.0 equiv) in dry toluene (7 mL), 2,2-difluoroglutaric anhydride 4
(3.33 mmol, 1.0 equiv) was added. The reaction mixture was
refluxed for 6 h. After cooling, the reaction mixture was extracted
with sodium bicarbonate (3ꢁ10 mL) and the aqueous layer was
acidified with 3 M HCl to pH¼1. The acidic aqueous layer was
extracted with EtOAc (3ꢁ25 mL). The organic phase was dried over
MgSO4 and evaporated under reduced pressure, yielding the crude
trans- and cis-2-aryl-1-benzyl-5,5-difluoro-6-oxopiperidine-3-
(1H, m), 3.49 (1H, d, J¼14.9 Hz), 3.54 (3H, s), 3.84 (3H, s), 4.73 (1H,
d, J¼7.2 Hz), 5.40 (1H, d, J¼14.9 Hz), 6.90e7.31 (9H, m). 13C NMR
(75 MHz, CDCl3):
d
32.2 (t, J¼24.2 Hz), 44.4 (t, J¼4.6 Hz), 47.8, 52.6,
55.4, 60.7, 111.5 (t, J¼243.5 Hz), 114.7, 128.0, 128.5, 128.7, 128.8,
129.4, 135.3, 160.0, 161.7 (t, J¼30 Hz), 170.8. 19F NMR (282 MHz,
CDCl3):
d
ꢃ98.92 (1F, dt, J¼282.8, 11.8 Hz), ꢃ100.6 (1F, dt, J¼282.8,
11.8 Hz). IR (ATR, cmꢃ1): nC
] 1747, 1667; nmax 1610, 1515, 1426,
O
1284, 1251, 1146, 1023, 835, 747, 701. MS (ESþ): m/z (%): 390 (Mþ1,

M. Moens et al. / Tetrahedron 68 (2012) 9284e9288
9287
100). Anal. Calcd for C21H21F2NO4: C, 64.77; H, 5.44; N, 3.60. Found:
C, 64.84; H, 5.11; N, 3.59.
2.10e2.30 (3H, m), 2.88 (1H, d, J¼13.2 Hz), 3.11e3.64 (4H, m), 3.76
(1H, d, J¼13.2 Hz), 3.80 (3H, s), 6.83 (1H, d, J¼8.3, 1.7 Hz), 7.00e7.03
(2H, m), 7.17e7.30 (6H, m). 13C NMR (75 MHz, CDCl3):
d 35.6 (dd,
4.2.5. trans-Methyl-1-(4-methoxybenzyl)-5,5-difluoro-6-oxo-2-
phenylpiperidine-3-carboxylate (7e). Yield: 31%. White crystals. Mp:
115.5e118.5 ꢂC. Flash chromatography (petroleum ether/EtOAc 3:1,
J¼25.4, 21.9 Hz), 43.4 (d, J¼10.0 Hz), 55.2, 56.9 (dd, J¼31.2, 24.2 Hz),
58.6, 63.6, 68.8, 113.3, 133.5, 120.2 (t, J¼240.0 Hz), 120.7, 127.0,
128.3, 128.4, 129.8, 138.2, 142.6, 160.0. 19F NMR (282 MHz, CDCl3):
Rf¼0.21). 1H NMR (300 MHz, CDCl3):
d
2.49e2.68 (2H, td, J¼13.5,
d
ꢃ98.0 (1F, d, J¼239.4 Hz), ꢃ103.1 (1F, dtt, J¼239.4, 32.9, 10.5 Hz).
6.6 Hz), 3.08 (1H, q, J¼6.6 Hz), 3.43 (1H, d, J¼14.6 Hz), 3.55 (3H, s),
3.79 (3H, s), 4.82 (1H, d, J¼6.6 Hz), 5.36 (1H, d, J¼14.6 Hz), 6.82 (2H,
d, J¼8.8 Hz), 7.04 (2H, d, J¼8.8 Hz), 7.15 (2H, m), 7.37e7.44 (3H, m).
IR (ATR, cmꢃ1): nOH 3422; nmax 1586, 1437, 1312, 1287, 1264, 1131,
1014, 973, 783, 754. MS (ESþ): m/z (%): 348 (Mþ1, 100).
13C NMR (75 MHz, CDCl3):
d
32.0 (t, J¼24.2 Hz), 44.3 (d, J¼5.7 Hz),
4.3.4. trans-1-Benzyl-5,5-difluoro-3-hydroxymethyl-2-(4-methoxy-
phenyl) piperidine (8d). Yield: 70%. Colorless oil. Flash chromatog-
raphy (petroleum ether/EtOAc 4:1, Rf¼0.14). 1H NMR (300 MHz,
47.3, 52.6, 55.3, 60.8, 111.4 (t, J¼244.6 Hz), 114.1, 127.1, 127.2, 128.9,
129.4, 130.3, 137.8, 159.4, 161.7 (t, J¼30 Hz), 170.7. 19F NMR
(282 MHz, CDCl3):
d
ꢃ99.1 (1F, dt, J¼284.1, 13.2 Hz), ꢃ100.4 (1F, dt,
CDCl3):
d
1.20 (1H, br s), 1.89 (1H, dtd, J¼33.3, 13.1, 5.5 Hz),
J¼284.1, 13.2 Hz). IR (ATR, cmꢃ1): nC
]O 1749, 1669; nmax 1612, 1511,
2.07e2.36 (3H, m), 2.85 (1H, d, J¼13.8 Hz), 3.10e3.37 (4H, m), 3.75
(1H, d, J¼13.8 Hz), 3.79 (3H, s), 6.90 (2H, d, J¼8.8, 1.7 Hz), 7.18e7.29
1356, 1242, 1195, 1174, 1093, 1033, 941, 808, 758, 709. MS (ESþ): m/z
(%): 390 (Mþ1, 100). Anal. Calcd for C21H21F2NO4: C, 64.77; H, 5.44;
N, 3.60. Found: C, 64.54; H, 5.36; N, 3.42.
(5H, m), 7.35 (2H, d, J¼8.8 Hz). 13C NMR (75 MHz, CDCl3):
d 35.6 (dd,
J¼24.2, 22.0 Hz), 43.1 (d, J¼10.4 Hz), 55.3, 57.0 (dd, J¼31.2, 24.2 Hz),
58.4, 63.8, 68.1, 114.3, 120.3 (t, J¼240.0 Hz), 127.0, 128.3, 128.4,
4.3. General procedure
129.2, 132.7, 138.2, 159.2. 19F NMR (282 MHz, CDCl3):
d
ꢃ98.1 (1F, d,
J¼239.2 Hz), ꢃ103.1 (1F, dt, J¼239.2, 30.9, 10.5 Hz). IR (ATR, cmꢃ1):
nOH 3401; nmax 1610, 1511, 1297, 1242, 1133, 1060, 1014, 908, 829,
730, 689. MS (ESþ): m/z (%): 348 (Mþ1, 100).
To a solution of trans-methyl-2-aryl-1-benzyl-5,5-difluoro-6-
oxopiperidine-3-carboxylate
7
(0.26 mmol, 1 equiv) in dry
dichloromethane (5 mL), BH3SMe2 (5 equiv) was added under N2
atmosphere, and the mixture was refluxed overnight. The reaction
was quenched by careful addition of aq methanol (1:1) at 0 ꢂC. The
mixture was extracted with dichloromethane (3ꢁ10 mL), dried over
MgSO4, and evaporated. The product was dissolved in MeOH and
stirred overnight on Pd/C and filtered over CeliteÒ. Final purification
was performed by flash chromatography, utilizing petroleum ether/
EtOAc(4:1) on silica gel. After which the corresponding trans-2-aryl-
1-benzyl-5,5-difluoro-3-hydroxymethylpiperidine was obtained as
a pure compound.
4.3.5. trans-1-(4-methoxybenzyl)-5,5-difluoro-3-hydroxymethyl-2-
phenylpiperidine (8e). Yield: 97%. Colorless oil. Flash chromatog-
raphy (petroleum ether/EtOAc 4:1, Rf¼0.16). 1H NMR (300 MHz,
CDCl3):
d
1.38 (1H, br s), 1.90 (1H, dtd, J¼33.6, 13.2, 5.0 Hz),
2.08e2.36 (3H, m), 2.82 (1H, d, J¼13.2 Hz), 3.11e3.35 (4H, m), 3.66
(1H, d, J¼13.2 Hz), 3.79 (3H, s), 6.81 (2H, d, J¼8.8,1.7 Hz), 7.13 (2H, d,
J¼8.8 Hz), 7.23e7.46 (5H, m), 13C NMR (75 MHz, CDCl3):
d 35.6 (dd,
J¼24.2, 22.0 Hz), 43.1 (d, J¼10.4 Hz), 55.2, 56.7 (dd, J¼31.2, 24.2 Hz),
57.9, 63.7, 68.7, 113.7, 120.3 (t, J¼240.0 Hz), 127.9, 128.2, 128.9, 129.6,
139.9, 141.0, 158.7. 19F NMR (282 MHz, CDCl3):
d
ꢃ98.0 (1F, d,
4.3.1. trans-1-Benzyl-5,5-difluoro-3-hydroxymethyl-2-phenylpiperi-
dine (8a). Yield: 86%. Colorless oil. Flash chromatography (petro-
J¼239.4 Hz), ꢃ100.4 (1F, dtt, J¼239.4, 32.9, 10.5 Hz). IR (ATR, cmꢃ1):
nOH 3421; nmax 1611, 1510, 1301, 1248, 1132, 1060, 1012, 909, 818,
760, 732, 702. MS (ESþ): m/z (%): 348 (Mþ1, 100).
leum ether/EtOAc 4:1, Rf¼0.20). 1H NMR (300 MHz, CDCl3):
d 1.16
(1H, br s) 1.91 (1H, dtd, J¼33.6, 13.0, 5.5 Hz), 2.1e2.37 (3H, m), 2.90
(1H, d, J¼13.8 Hz), 3.12e3.24 (3H, m), 3.33 (1H, dd, J¼10.7, 3.0 Hz),
3.74 (1H, d, J¼13.8 Hz), 7.20e7.46 (10H, m). 13C NMR (75 MHz,
Acknowledgements
CDCl3):
d
35.7 (dd, J¼31.7, 22.0 Hz), 43.1 (d, J¼10.4 Hz), 57.0 (dd,
The authors are indebted to Ghent University (GOA) and Janssen
Research and Development, a division of Janssen Pharmaceutical
NV, for financial support.
J¼24.8, 6.9 Hz), 58.7, 63.8, 68.9, 114.1, 120.4 (t, J¼240.0 Hz),
127.1e129.0, 138.2, 141.0. 19F NMR (282 MHz, CDCl3):
d
ꢃ98.0 (1F, d,
J¼239.4 Hz), ꢃ103.2 (1F, dtt, J¼239.4, 30.9, 10.5 Hz). IR (ATR, cmꢃ1):
nOH 3387; nmax 1452, 1310, 1133, 1060, 908, 763, 731, 699. MS (ESþ):
m/z (%): 317 (Mþ1, 100).
Supplementary data
Copies of NMR spectra of all newly synthesized products. Sup-
plementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.08.049.
4.3.2. trans-1-Benzyl-5,5-difluoro-3-hydroxymethyl-2-(2-methoxy-
phenyl) piperidine (8b). Yield: 75%. White crystals. Mp:
117.0e119.0 ꢂC. Flash chromatography (petroleum ether/EtOAc 4:1,
Rf¼0.19). 1H NMR (300 MHz, CDCl3):
d 1.70 (1H, br s),1.95e2.36 (4H,
References and notes
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