Synthesis of piperidine derivatives by reduction of pyridinium salts

Article abstract of DOI:10.1080/00397910701483944

Piperidine derivatives 1a-e and 2a-f have been prepared by the reduction of 3-and 4-substituted pyridinium salts with NaBH4 in moderate to excellent yields. The reactions regioselectively give 1,2,5,6-tetrahydropyridines, and the yields depend greatly upon the nature of substituents on the phenyl ring and on the nitrogen atom, the nature and the position of the substituents on the pyridyl ring, and the chain length between the aryloxy and the pyridyl groups. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701483944

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Synthesis of Piperidine Derivatives by
Reduction of Pyridinium Salts
Zilong Tang a b , Joelle Mayrargue a & Mouad Alami a
a Faculty of Pharmacy, Department of Chemistry, University of Paris‐Sud,
Chatenay‐Malabry, Cedex, France
b School of Chemistry and Chemical Engineering, Hunan Provincial University
Key Laboratory of QSAR/QSPR, Hunan University of Science and Technology,
Xiangtan, P. R. China
Published online: 05 Oct 2007.
To cite this article: Zilong Tang , Joelle Mayrargue & Mouad Alami (2007): Synthesis of Piperidine
Derivatives by Reduction of Pyridinium Salts, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:19, 3367-3379
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Synthetic Communicationsw, 37: 3367–3379, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701483944
Synthesis of Piperidine Derivatives by
Reduction of Pyridinium Salts
Zilong Tang
Faculty of Pharmacy, Department of Chemistry, University of Paris-Sud,
Chatenay-Malabry, Cedex, France and School of Chemistry and
Chemical Engineering, Hunan Provincial University Key Laboratory of
QSAR/QSPR, Hunan University of Science and Technology, Xiangtan,
P. R. China
Joelle Mayrargue, and Mouad Alami
Faculty of Pharmacy, Department of Chemistry, University of Paris-Sud,
Chatenay-Malabry, Cedex, France
Abstract: Piperidine derivatives 1a–e and 2a–f have been prepared by the reduction
of 3- and 4-substituted pyridinium salts with NaBH4 in moderate to excellent yields.
The reactions regioselectively give 1,2,5,6-tetrahydropyridines, and the yields
depend greatly upon the nature of substituents on the phenyl ring and on the
nitrogen atom, the nature and the position of the substituents on the pyridyl ring,
and the chain length between the aryloxy and the pyridyl groups.
Keywords: peperidine, pyridinium salt, reduction, synthesis
Functionalized piperidines are common substructures found in natural
products, and many piperidine-containing compounds have bioactivity.[1] In
Received in P. R. China October 26, 2006
Address correspondence to Joelle Mayrargue, Faculty of Pharmacy, Department of
Chemistry, University of Paris-Sud, 5, rue Jean Baptiste Clement 92296, Chatenay-
Malabry, Cedex, France. E-mail: joelle.mayrargue@chimorg.upsud.fr or Zilong
Tang, Department of Chemistry, Faculty of Pharmacy, University of Paris-Sud, 5,
rue Jean-Baptiste Clement 92296, Chatenay-Malabry, Cedex, France and School of
Chemistry and Chemical Engineering, Hunan University of Science and Technology,
Xiangtan, 411201, P. R. China. E-mail: zltang67@yahoo.com.cn
3367

3368
Z. Tang, J. Mayrargue, and M. Alami
a search for new ligands for the opioid receptor-like (ORL1) receptor that was
recently discovered, a fourth member of the classical m, d, and k opioid
receptor family,1f–1h we had to prepare key intermediate piperidines deriva-
tives 1 and 2. In the literature, there are various methods for the preparation
of six-membered nitrogen heterocycles.[2] Aza–Diels–Alder reaction is
often used to form six-membered nitrogen heterocycles and mostly applies
to the reactions of dienes with imines. Recently, ring-closing metathesis
(RCM)[2c] has provided a reliable synthetic method for the synthesis of unsa-
turated piperidines. However, examples of RCM where one of the olefins is
directly connected to the nitrogen atom are rare. In addition, the full
reduction of pyridines by hydrogenation and the partial reduction of
pyridines using NaBH4 provide direct and very useful synthetic tools for the
generation of piperidines.[2a] There were also a few reports on the reduction
pyridinium salts to tetrahedropyridines in the literature.[3] The advantage of
these sequences is that the heterocyclic ring is already present. However,
less attention has been paid to the position and the nature of substituents on
the pyridyl ring and the substituents on the nitrogen atom. We thus adopted
the reduction of 3- or 4-substituted N-alkylpyridinium salts with NaBH4 to
prepare piperidines derivatives 1 and 2 and investigated the effect of substitu-
ents on the reduction.
The synthetic route to unsaturated piperidines derivatives 1 is shown in
Scheme 1. Initially, intermediate pyridinium salts 3 were easily prepared in
48–99% yields (Table 1) by N-alkylation of the corresponding pyridines in
dichloromethane at room temperature. Then, the reduction of substituted pyr-
idinium salts 3 with NaBH4 was easily achieved in methanol to regioselectively
give 1,2,5,6-tetrahydropyridines 1a,[4] 1c, 1d,[5] and 1e[6] in moderate to
excellent yields. No other regioselective reduction products were found. It
can be seen from Table 1 that pyridinium salts with a substituent at position
4 gave relatively higher yield than those with a substituent at position 3. The
carbonyl groups in 3b and 3d were also reduced at the same time, whereas
the ester group in 3c remained unchangeable under the reaction conditions.
(For the preparation of ethyl 2-(yridine-3-yl) acetate, precursor to compound
3c, see Ref. 9.) However, the yield of the reduction of 3a giving compound
1a is higher than that of 3b with a carbonyl group (entries 1 vs. 2).
Scheme 1.

Synthesis of Piperidine Derivatives
3369
Table 1. Results of the alkyllation of pyridines and the reduction of pyridinium salts 3
Time
(h)a
Yield
(%)
Yield
(%)b
Entry
1
Pyridinium salt
Piperidine
12
90
83
2
3
4
48
12
48
48
85
99
65
58
88
5
24
92
90
aTime designed for the N-alkylation of pyridines.
bNaBH4 added at 08C, and reductions stirred in methanol at 08C for 1 h and at room
temperature (rt) for 2 h.
The sequence for the preparation of 3- or 4-aryloxyalkyl unsaturated
piperidines derivatives 2 is outlined in Scheme 2. The intermediate 3- or 4-ary-
loxyalkyl pyridines 6a–e were prepared by the Mitsunobu reaction[7] of sub-
stituted phenols 4a,[3e,8] 4b with pyridylalkyl alcohols 5a, 5b, and 5c[9] in the
presence of Ph3P and diethyl azodicarboxylate (DEAD) in dry dichloro-
methane at room temperature. It is seen clearly from Table 2 that the
reaction gave the desired ethers 6a–e in moderate to good yields, and the
Scheme 2.

3370
Z. Tang, J. Mayrargue, and M. Alami
Table 2. Results of Mitsunobu reactions of phenols 4a–b and alcohols 5a–c
Entry Phenols
Alcohols
Time (h)
8
Product
Yield (%)
58
1
4a
2
3
4
4b
4b
4a
5a
24
24
8
45
47
70
5
4a
5b
24
67
yields of 6a, 6d, 6e[3e] containing a methoxy group were higher than those of
6b and 6c (entries 1, 4 vs. 2, 3), probably because of the positive induction of
the methoxy group.
Similarly, pyridinium salts 7a–f were prepared in moderate to excellent
yields (Table 3) by N-alkylations of the obtained aryloxyalkyl pyridines 6a–e
at room temperature in dichloromethane.
Table 3. Results of N-alkylations of aryloxyalkyl pyridine 6a–e
Entry
1
Reactant
Time (h)
24
Product
Yield (%)
80
6a
2
3
4
5
6b
6b
6c
6d
24
48
24
16
74
62
85
90
6
6e
16
90

Synthesis of Piperidine Derivatives
3371
Using the method described previously, we first tried to reduce 3-aryloxy-
alkyl pyridinium salt 7a with NaBH4 in methanol. When NaBH4 was added at
room temperature and the reaction was stirred at the same temperature for 3 h,
compound 4a was obtained in 90% yield together with only a trace of the
expected product 1,2,5,6-tetrahydropyridines 2a. The yield of 4a decreased
to 58% when the reaction was carried out at 08C, and 2a was found in 10%
yield (entry 2, Table 4). The attempt to use NaBH3(CN) as a base failed to
improve the reaction. However, the reduction of 7b without a methoxy
group on the phenyl ring gave 2b in 32% yield (entry 3) at room temperature,
although compound 4b was isolated in 40% yield. While the reaction was
carried out at 08C, the yield of 2b was further raised to 36% (entry 4) and
the yield of 4b diminished to 29%. Furthermore, when the methyl group
connected to the nitrogen atom was replaced with a benzyl group, the yield
of the desired product 1,2,5,6-tetrahydropyridines 2c increased to 41%
(entry 5), albeit the decoupling compound 4b was still generated in 21%
yield. Interestingly, another decoupling product 8b (see Scheme 2) was also
obtained in 24% yield. When the aryloxyalkyl group on the pyridyl ring is
Table 4. Results of the reduction of aroxyalkyl pyridiniums 7a–e
Yielda
(%)
Compound 4
(yield, %)
Entry
1
Reactant
Product
7a
Traceb
4a (90)
2
3
7a
7b
2a
2b
10
4a (58)
4b (40)
32b
4
5
7b
7c
36
41
4b (29)
4b (24)
6
7
7d
7e
77
64
—
—
8
7f
75
—
aNaBH4 added at 08C, and reaction stirred in methanol at 08C for 1 h and at rt for 2 h.
bNaBH4 added at rt, and reaction carried out at rt for 3 h.

3372
Z. Tang, J. Mayrargue, and M. Alami
at position 4, the yields of the reduction were raised to 75–77% (entries 6, 8),
and no decoupling products 4a, or 4b were found. Likewise, when there are
two methylene groups between the aryloxy and the pyridyl groups, the yield
of the reduction of compound 7e was 64% (entry 7) without the formation
of compound 4a, although there is a methoxy group on the phenyl ring and
a substituent at position 3 of the pyridyl ring. Generally, the yields of all
the present cases are relatively lower than those of the reduction of the pyri-
dinium salts 3 with hydoxymethyl or carbonyl groups.
Alternatively, compound 2a was prepared in 37% yield by Mitsunobu
reaction of 4a with 1a.
To the best of our the knowledge, the decoupling reactions of 7a–c are
unprecedented. On the basis of these results, a plausible mechanism for the
decoupling reactions of 7a–c could be proposed and is shown in Scheme 3.
The reductionof7a–c byNaBH4 gaveintermediateA, which can betransformed
into B by resonation. A further reduction of the form B in methanol gave 1,2,3,6-
tetrahydropyridines 2a–c (route a). However, a decomposition of intermediate B
to C and iminium D could also operate (route b). Protonation of C in methanol
yielded 4a and b. Further reduction of the iminium D by NaBH4 afforded amino-
diene 8. The possibility of route b was justified by the isolation of aminodiene 8b.
Indeed, the decomposition of intermediate B competed with the reduction. The
reaction of B following route a or b depended on substitutents on the phenyl
ring and on the nitrogen atom, the chain length of the alkyl between the
aryloxy and the pyridyl ring, and the reaction temperature.
In conclusion, piperidines derivatives 1a–e and 2a–f were prepared by the
reduction of 3- or 4-substituted pyridinium salts with NaBH4 in moderate to
excellent yields. Thereactions regioselectivelygave1,2,5,6-tetrahydropyridines,
Scheme 3. Possible mechanism for the decoupling reactions of 7a–c.

Synthesis of Piperidine Derivatives
3373
and the yields depended greatly upon the nature of substituents on the phenyl ring
and on the nitrogen atom, the nature and the position of substituents on the
pyridyl ring, the chain length between the aryloxy and the pyridyl groups. For
pyridinium salts with an aryloxyalkyl at position 4 of the pyridyl ring, the
reaction gave relatively higher yield than those with an aryloxyalkyl at
position 3. Likewise, when there are two methylene groups between the
aryloxy and the pyridyl groups, the reduction gave good yields even if there is
a methoxy group on the phenyl ring and an aryloxyalkyl at position 3 of the
pyridyl ring. A possible mechanism for the unprecedented decoupling
reactions of 7a–c was also proposed. Apparently, the advantage of this
sequence is that the heterocyclic ring is already present, and the C55C double
bond in the piperidine ring can be further functionalized.
The Mitsunobu reaction of 1a–e and cyclization of 2a–f to heterocycles,
as well as the bioactivity of the heterocycles, will be reported latter.
EXPERIMENTAL
General Information
All reactions requiring anhydrous or inert conditions were carried out under an
atmosphere of dried argon in flame-dried glassware. All solvents were dried by
standard procedure and freshly distilled. Infrared spectra were recorded on a
1
Bruker Vector22 with Golden Gate. H NMR spectra were recorded on a
Bruker ARX 200-MHz sonde QNP (H, C, F, P) and Avance 400-MHz sonde
H-BB with gradient Z. 13C NMR spectra were recorded at 50 and 100 MHz.
Chemical shifts (d) are given relative to Me4Si (0 ppm, 1H) or CDCl3
(77.0 ppm, 13C). Mass spectra were recorded on Varian MAT-44 or Finnigan
MAT-TSQ 70 spectrometers. Thin-layer chromatographic (TLC) analyses
were performed on Merck 60 F254 silica-gel plates (coated on aluminium).
Flash chromatograph separations were performed using Merck 60 40 to 63-
mm silica. Compound 4a was prepared according to Refs. 3e and 8 and ethyl
2-(pyridine-3-yl) acetate and compound 5c according to Ref. 9.
Synthesis of Piperidine Derivatives 1a–e
General Procedure for the Preparation of 3a–e
To a 250-ml flask with a stirring bar, 3.0 g of 3-hydroxymethylpyridine
(27 mmol), 8.6 mL of MeI (140 mmol), and 100 mL of CH2Cl2 were added.
The mixture was stirred at room temperature for 12 h until the disappearance
of 3-hydroxymethylpyridine, checked by TLC. The solid formed was filtered
and washed with dichloromethane. The crude product was recrystallized with
MeOH/petroleum ether to give the pure product 3a (yield: 90%).

3374
Z. Tang, J. Mayrargue, and M. Alami
General Procedure for the Preparation of 1a–e by Reduction of 3a–e
Compound 3a (6.05 g, 24 mmol) was dissolved in 20 mL of MeOH, then
3.65 g of sodium borohydride (96 mmol) was added portionwise at 08C.
The mixture was continued to stir at 08C for 1 h and then at room temperature
for 2 h. The solvent was evaporated under reduced pressure, then 5 mL water
was added, and the mixture was extracted with CH2Cl2 (3 ꢀ 10 mL). The
combined organic phases were dried over Na2SO4 and evaporated. The
residue was purified by flash chromatograph to afford 2.53 g of product 1a.
Data
(5-Hydroxymethyl)-1-methyl-1,2,5,6-tetrahydropyridine 1a
1
Viscous oil, 83%. H NMR (200 MHz, CDCl3): 5.61–5.69 (m, 1H, 55CH),
3.97 (s, 2H, OCH2), 3.61 (s (br), 1H, OH), 2.93 (s, 2H), 2.47 (t, J ¼ 5.9 Hz,
2H), 2.34 (s, 3H, NMe), 2.15–2.25 (m, 2H). 13C NMR (50 MHz, CDCl3):
137.05 (55C), 118.84 (55CH), 63.76 (OCH2), 54.66, 51.68, 45.11 (NMe),
25.34; IR: 3193, 2097, 2841, 2789, 1460, 12888, 1261, 1115, 1014,
831 cm21. MS (EI, 70 eV): 127 [M]þ.
Ethyl 2-(1-Methyl-1,2,5,6-tetrahydropyridin-5-yl) Acetate 1c
1
Viscous oil, 58%. H NMR (200 MHz, CDCl3): 5.58–5.60 (m, 1H), 4.00
(q, J ¼ 6 Hz, 2H, OCH2), 2.81 (s, 2H), 2.78 (s, 2H), 2.30 (t, J ¼ 4.5 Hz,
2H), 2.20 (s, 3H, NMe), 2.07–2.09 (m, 2H), 1.13 (t, J ¼ 6 Hz, 3H, Me).
13C NMR (50 MHz, CDCl3): 170.89 (C55O), 129.23 (55C), 123.12 (55CH),
60.29, 56.81, 51.14, 45.41 (NMe), 40.99, 25.79, 13.94 (Me). MS (EI, 70
eV): 183 [M]þ. HRMS-EI: calculated for C10H17NO2: 183.1259; found:
183.1263.
1-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl) Ethanol 1d
1
Viscous oil, 88%. H NMR (200 MHz, CDCl3): 5.64–5.70 (m, 1H), 4.12–
4.24 (m, 1H, CHO), 2.89 (s, 2H), 2.30 (t, J ¼ 5.0 Hz, 2H), 2.35 (s, 3H,
NMe), 2.16–2.53 (m, 2H), 1.25 (d, J ¼ 6.4 Hz, 3H, Me). 13C NMR
(50 MHz, CDCl3): 140.04 (55C), 118.35 (55CH), 69.47 (OCH), 52.83,
51.66, 45.42 (NMe), 25.21, 21.54. MS (EI, 70 eV): 141 [M]þ.
(1-Benzyl-1,2,5,6-tetrahedropyridin-4-yl)-methanol 1e
1
Viscous oil, 90%. H NMR (200 MHz, CDCl3): 7.25–7.41 (m, 5H), 5.59–
5.66 (m, 1H), 4.01 (s, 2H, OCH2), 3.60 (s, 2H, NCH2), 2.95–3.02 (m, 2H),
2.61 (t, J ¼ 5.8 Hz, 2H), 2.36 (s (br), 1H, OH), 2.10–2.21 (m, 2H). 13C

Synthesis of Piperidine Derivatives
3375
NMR (50 MHz, CDCl3): 137.64, 136.41, 129.29 (2C), 128.15 (2C), 127.08,
119.44, 65.75, 62.64, 52.32, 49.53, 26.21. MS (EI, 70 eV): 203 [M]þ.
General Procedure for the Synthesis of 6
Compounds 6a, 6b, 6c, 6d, 6e were prepared according to the reference (7). To
a 100-mL, three-neck flask with a stirring bar, 0.5 g of 2-iodo-6-methoxyphe-
nol (2 mmol), 0.58 g of PPh3 (2.2 mmol), 0.24 g of 3-hydroxy pyridine
(2.2 mmol), and 10 mL, of dry CH2Cl2 were added under argon. Then, a
solution of DEAD (0.38 g, 2.2 mmol) in 5 mL of CH2Cl2 was added
dropwise at room temperature. After the addition was completed, the
mixture was stirred for an additional 8 h at the same temperature. The
solvent was removed under reduced pressure, and the residue was chromato-
graphied to afford 6a in 58% yield.
General Procedure for the Synthesis of Aryloxylalkyl Piperidines
2a–f
To a 250-mL flask with a stirring bar, 1.34 g of 6c (4.3 mmol), 1.54 mL of MeI
(2.21 g, 12.9 mmol), and 50 mL of CH2Cl2 were added. The mixture was
stirred at room temperature for 24 h until the disappearance of 6c as shown
by TLC. The solid was filtered and washed with dichloromethane. The
product was dried, and the yield of the product 7d was 85%.
Then, 0.45 g of sodium borohydride (12 mmol) was added portionwise to
1.15 g of 7d (2.4 mmol) in 10 mL of MeOH at 08C. The mixture continued to
stir at 08C for 1 h and then at room temperature for 2 h. The solvent was evap-
orated under the reduced pressure, 5 mL of water was added, and the mixture
was extracted with CH2Cl2 (3 ꢀ 10 mL). The combined organic phases were
dried over Na2SO4 and evaporated. The residue was purified by flash chro-
matograph to afford 0.75 g of 2d (77%).
Data
5-[(2-Iodo-6-methoxyphenoxy)methyl]-1-methyl-1,2,5,6-
tetrahedropyridine 2a
Viscous oil, 10%. 1H NMR (200 MHz, CDCl3): 7.35 (dd, J ¼ 7.7, 1.8 Hz, 1H,
ArH), 6.89 (dd, J ¼ 8.1, 1.8 Hz, 1H, ArH), 6.81 (t, J ¼ 7.7 Hz, 1H, ArH),
5.89–5.95 (m, 1H), 4.48 (s, 2H), 3.84 (s, 3H, OMe), 3.25 (s, 2H), 2.73
(t, J ¼ 7.5 Hz, 2H), 2.55 (s, 3H, NMe), 2.35–2.43 (m, 2H). 13C NMR
(50 MHz, CDCl3): 152.70, 147.70, 132.32, 130.54, 125.77, 124.04, 112.74,
92.70 (55C-I), 75.04 (OCH2), 55.88, 55.33, 51.24, 45.39 (NMe), 25.29. MS

3376
Z. Tang, J. Mayrargue, and M. Alami
(EI, 70 eV): 359 [M]þ. HRMS-EI calculated for C14H18INO: 359.0382; found:
359.0376.
5-[(2-Iodophenoxy)methyl]-1-methyl-1,2,5,6-tetrahedropyridine 2b
1
Viscous oil, 36%. H NMR (200 MHz, CDCl3): 7.69 (dd, J ¼ 7.8, 1.6 Hz,
1H), 7.19 (td, J ¼ 8.9, 1.6 Hz, 1H), 6.74 (dd, J ¼ 9.5, 1.1 Hz, 1H), 6.62 (td,
J ¼ 7.7, 1.4 Hz, 1H), 5.80–5.87 (m, 1H), 4.40 (s, 2H), 2.98 (s, 2H), 2.46
(t, J ¼ 5.8 Hz, 2H), 2.33 (s, 3H, NMe), 2.14–2.24 (m, 2H). 13C NMR
(50 MHz, CDCl3): 157.09, 139.34, 131.86, 129.24, 123.35, 122.52, 112.37,
86.63 (55C-I), 71.55, 54.96, 51.57, 45.75 (NMe), 25.73. MS (EI, 70 eV):
329 [M]þ. HRMS-EI calculated for C13H16INO: 329.0277; found: 329.0272.
1-Benzyl-5-[(2-iodophenoxy)methyl]-1,2,5,6-tetrahedropyridine 2c
Viscous oil, 41%. 1H NMR (200 MHz, CDCl3): 76 (dd, J ¼ 7.7, 1.5 Hz, 1H),
7.22–7.41 (m, 6H), 6.79 (dd, J ¼ 8.2, 1.3 Hz, 1H), 6.7 (td, J ¼ 7.4, 7.7,
1.4 Hz, 1H), 5.90–5.95 (m, 1H), 4.44 (s, 2H), 3.66 (s, 2H), 3.13 (dd,
J ¼ 6.0, 2.0 Hz, 2H), 2.61 (t, J ¼ 5.7 Hz, 2H), 2.20–2.28 (m, 2H). 13C
NMR (50 MHz, CDCl3): 157.14, 139.34, 138.15, 131.99, 129.21 (2C),
128.22 (3C), 127.01, 123.68, 122.56, 112.41, 86.79 (55C-I), 71.64, 62.68,
53.20, 49.47, 25.69. MS (EI, 70 eV): 405 [M]þ. HRMS-EI calculated for
C19H20INO: 405.0590; found: 405.0594.
Compound 8b
1
Yield 24%. H NMR (200 MHz, CDCl3): 7.29–7.37 (m, 5H, ArH), 6.24 (dt,
J ¼ 9.7, 2.1 Hz, 1H), 5.77–5.87 (m, 1H), 4.87 (s, 1H), 4.78 (s, 1H), 3.64
(s, 2H), 3.23 (t, J ¼ 1.1 Hz, 2H), 3.07–3.14 (m, 2H). 13C NMR (50 MHz,
CDCl3): 140.37, 137.85, 129.18 (2C), 128.23 (2C), 127.82, 127.62, 127.12,
110.76 (55CH2), 61.82, 55.86, 52.14. MS (EI, 70 eV): 185 [M]þ. HRMS-EI
calculated for C13H15N: 185.1204; found: 185.1210.
1-Benzyl-4-[(2-iodophenoxy)methyl]-1,2,5,6-pyridine 2d
1
Viscous oil, 77%. H NMR (200 MHz, CDCl3): 7.77 (dd, J ¼ 7.8, 1.6 Hz,
1H), 7.23–7.38 (m, 6H, ArH), 6.82 (dd, J ¼ 8.3, 1.3 Hz, 1H), 6.70 (td,
J ¼ 7.5, 1.4 Hz, 1H), 5.82–5.88 (m, 1H), 4.47 (s, broad, 2H), 3.62 (s, 2H),
3.02–3.08 (m, 2H), 2.66 (t, J ¼ 5.8 Hz, 2H), 2.26–2.35 (m, 2H). 13C NMR
(50 MHz, CDCl3): 157.19, 139.37, 138.17, 131.801, 129.32, 129.13 (2C),
128.20 (2C), 127.04, 122.87, 122.52, 112.44, 86.69 (55C-I), 72.17, 62.59,
52.40, 49.44, 26.53. MS (EI, 70 eV): 405 [M]þ. HRMS-EI calculated for
C19H20INO: 405.0590; found: 405.0585.

Synthesis of Piperidine Derivatives
3377
5-[2-(2-Iodo-6-methoxyphenoxy)ethyl]-1-methyl-1,2,5,6-
tetrahedropyridine 2e
1
Viscous oil, 64%. H NMR (200 MHz, CDCl3): 7.34 (dd, J ¼ 7.7, 1.6 Hz,
1H), 6.89 (dd, J ¼ 8.2, 1.6 Hz, 1H), 6.78 (t, J ¼ 7.8 Hz, 1H), 5.62–5.69
(m, 1H), 4.05 (t, J ¼ 7.0 Hz, 2H), 3.85 (s, 3H, OMe), 3.14 (s, 2H), 2.66
(t, J ¼ 5.9 Hz, 2H), 2.54 (t, J ¼ 7.0 Hz, 2H), 2.48 (s, 3H, NMe), 2.23–2.34
(m, 2H). 13C NMR (50 MHz, CDCl3): 152.75, 148.05, 132.09, 130.51,
125.67, 120.64, 112.69, 92.94 (55C-I), 71.54, 57.06, 55.87 (OMe), 51.37,
45.25 (NMe), 35.78, 25.33. MS (EI, 70 eV): 373 [M]þ. HRMS-EI calculated
for C15H20INO2: 373.0539; found: 373.0546.
1-Benzyl-4-((2-iodo-6-methoxyphenoxy)methyl)-1,2,5,6-
tetrahydropyridine 2f
Viscous oil, 75%. 1H NMR (200 MHz, CDCl3): 7.25–7.41 (m, 6H, ArH), 6.88
(dd, J ¼ 8.2, 7.8 Hz, 1H, ArH), 6.8 (t, J ¼ 7.8 Hz, 1H, ArH), 5.80–5.88
(m, 1H), 4.39 (s, 2H), 3.83 (s, 3H, OMe), 3.62 (s, 2H), 2.99–3.10 (m, 2H),
2.67 (t, J ¼ 5.9 Hz, 2H), 2.40–2.49 (m, 2H). 13C NMR (50 MHz, CDCl3):
152.89, 147.90, 138.42, 132.99, 130.66, 129.09 (2C), 128.16 (2C), 126.96,
125.73, 123.77, 112.80, 92.82 (55C-I), 75.84, 62.62, 55.92 (OMe), 52.57,
49.66, 22.17. MS (EI, 70 eV): 435.30 [M]þ. HRMS-EI calculated for
C20H22INO2: 435.0695; found: 435.0687.
ACKNOWLEDGMENT
We thank the EGIDE for financial support.
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