Solid-phase synthesis of piperidines by N-acyliminium ion chemistry

Article abstract of DOI:10.1002/1099-0690(200209)2002:18<3133::AID-EJOC3133>3.0.CO;2-H

An efficient solid-phase procedure for the synthesis of a number of 2-substituted piperidines is reported. Starting from solid-supported carbamate -tethered δ-amino acetals, 2- benzotriazolyl- substituted (Bt-substituted) piperidines were obtained by acid-induced ring-closure followed by trapping of the transient N-acyliminium ions with benzotriazole. These 2-Bt-substituted piperidines were then used as precursors for the successful introduction of several C-nucleophiles by N-acyliminium ion chemistry. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:18<3133::AID-EJOC3133>3.0.CO;2-H

FULL PAPER
Solid-Phase Synthesis of Piperidines by N-Acyliminium Ion Chemistry
[a]
[a]
[b]
[b]
´
Johan J. N. Veerman, Jasper Klein, Rene W. M. Aben, Hans W. Scheeren,
Chris G. Kruse,[c] Jan H. van Maarseveen,[a] Floris P. J. T. Rutjes,*[a] and Henk Hiemstra*[a]
Keywords: N-Acyliminium ion / Benzotriazole / Cyclisation / Nitrogen heterocycles / Piperidines
An efficient solid-phase procedure for the synthesis of a
number of 2-substituted piperidines is reported. Starting
from solid-supported carbamate-tethered δ-amino acetals, 2-
benzotriazolyl-substituted (Bt-substituted) piperidines were
obtained by acid-induced ring-closure followed by trapping
of the transient N-acyliminium ions with benzotriazole.
These 2-Bt-substituted piperidines were then used as pre-
cursors for the successful introduction of several C-nucleo-
philes by N-acyliminium ion chemistry.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
would give facile access to libraries of piperidines by a sim-
ilar type of method would be highly desirable.[8,9] In a pro-
gram to develop N-acyliminium ion chemistry on solid sup-
ports, we have previously described the solid-phase syn-
thesis of several 2-substituted pyrrolidines, starting from
immobilised γ-amino acetals.[8e] These acetals were cyclised
under Lewis acidic conditions and coupled with suitable C-
nucleophiles in one-pot reactions, via N-acyliminium ion in-
termediates. Unfortunately, however, this one-pot procedure
did not work satisfactory for the homologous piperidine
analogues. Here we describe a modification of the initial
procedure, which has resulted in the successful synthesis of
a number of 2-substituted and 2,4-disubstituted piperidines.
The general strategy is outlined in Scheme 2.
Functionalised piperidines are frequently encountered
structural motifs in bioactive compounds and in natural
products.[1] The piperidine ring is often present as a sub-
structure in drug-like molecules.[2] A well-known example is
Ritalin (1, methyl α-phenyl-2-piperidinylacetate), used for
the treatment of attention deficiency/hyperactivity disorder
(ADHD) in children (Scheme 1).[3] Some other piperidine-
containing natural products that show interesting biological
activity are febrifugine (2)[4] and (Ϫ)-lobeline (3).[5]
Consequently, a plethora of synthetic routes affording
functionalised piperidines has been developed.[6] In many
groups, including ours, N-acyliminium ion pathways to-
wards these scaffolds have been developed over the years.[7]
In conjunction with this work, a solid-phase approach that
Scheme 1. Bioactive piperidines
[a]
Scheme 2. Retrosynthetic approach
Institute of Molecular Chemistry, University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The
Netherlands
Fax: (internat.) ϩ 31-20/525-5670,
E-mail: hiemstra@science.uva.nl
[b]
Rather than the one-pot cyclisation/coupling sequence,
we anticipated that it would be more favourable to generate
a stable intermediate aminal 6, which upon suitable activa-
tion would provide the targeted N-acylimium ion interme-
diate 5.[10] In order to do this, we decided to apply the
benzotriazole (Bt) group (6, LG ϭ Bt) developed by Ka-
tritzky[11] as a potentially good leaving group.
Department of Organic Chemistry, NSR Center, University of
Nijmegen,
Toernooiveld, 6525 ED Nijmegen, The Netherlands
Fax: (internat.) ϩ 31-24/365-3393,
E-mail: rutjes@sci.kun.nl
[c]
Solvay Pharmaceuticals,
P. O. Box 900, 1380 DA Weesp, The Netherlands
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2002, 3133Ϫ3139  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0918Ϫ3133 $ 20.00ϩ.50/0
3133

F. P. J. T. Rutjes, H. Hiemstra, et al.
FULL PAPER
Results and Discussion
Our synthetic work commenced with the coupling of the
amino acetals 9aϪf[12] to the sulfonylethoxycarbonyl-modi-
fied (SEC-modified) polystyrene resin 8 (Scheme 3).[8c,8e]
Scheme 4. (a) allyltrimethylsilane, BF3·OEt2, CH2Cl2, 0 °C to room
temp.; (b) pTSA (cat.), CH2Cl2, room temp.; (c) pTSA (cat.),
CH2Cl2/EtOH (2:1, v/v) room temp.; (d) pTSA (cat.), CH2Cl2, 15
min; then BtH, CH2Cl2, room temp.
Scheme 3. (a) DIPEA, THF, room temp.; (b) allyltrimethylsilane,
BF3·OEt2, CH2Cl2, 0 °C to room temp.; (c) 1  NaOMe, THF/
MeOH (2:1, v/v), room temp.; (d) Ac2O, pyridine, DMAP (cat.),
room temp.
improved this ratio to 6:1. However, compound 16 was
found to be rather unstable, since subjection to column
chromatography resulted largely in elimination to give en-
amide 17. To provide a more stable precursor, the acetal 13
was treated with catalytic pTSA, followed by addition of an
excess of 1H-benzotriazole, resulting in the 2-Bt-substituted
piperidine 18 as the sole product in 88% isolated yield.[13]
Subsequent treatment of this intermediate under identical
conditions as for 13 exclusively afforded the cyclic product
14 in an excellent yield of 93%.[14] In contrast, sequential
addition of pTSA and allyltrimethylsilane to compound 13
(not shown in Scheme 4) resulted in a low yield of product
14, due to the facile formation of the enamide 17 under
these conditions.[15]
Attempts to follow a one-pot procedure for the N-acylim-
inium ion mediated functionalisation (i.e., addition of a
Lewis acid and allyltrimethylsilane as the nucleophile) pro-
duced mixtures of cyclic and linear products. This became
apparent after sodium methoxide mediated cleavage and
acetylation of the nitrogen atom to afford piperidines 11a
(57%) and 11f (47%) and the linear side products 12a (4%)
and 12f (6%). The linear products are the result of direct
intermolecular attack of the allylsilane onto the oxycarben-
ium ion generated in situ, instead of intramolecular attack
by the carbamate nitrogen atom. Interestingly, this side re-
action was not observed in the pyrrolidine series, probably
due to a faster rate of cyclisation. As would be expected,
the ratio of cyclic to linear product is better for the 4-substi-
tuted piperidine 11a than for the unsubstituted analogue
11f. Sequential addition of the Lewis acid and the nucle-
ophile did not improve the situation, resulting in low yields
of the desired product. To suppress the side reaction the
concentration of allylsilane was lowered fourfold, which
should favour intramolecular attack of the carbamate moi-
ety. Although this did indeed result in the exclusive forma-
tion of the cyclised product in both cases, the yields were
significantly lower. More importantly, the high dilution fac-
tors render this approach unsuitable for possible application
in automated procedures.
To determine the synthetic scope of the procedure, the
resin-bound acetals 10aϪf were cyclised to give the 2-Bt
precursors 19aϪf (Scheme 5). In all cases complete ring-
closure was observed, as indicated by the disappearance of
the NH signal in the IR spectra.
Scheme 5. (a) pTSA (cat.), CH2Cl2, 30 min; then 1H-Bt, CH2Cl2,
room temp.; (b) nucleophile, BF3·OEt2, CH2Cl2, 0 °C to room
temp.; (c) 1  NaOMe, THF/MeOH (2:1, v/v), room temp.
To optimise the N-acyliminium ion mediated func-
tionalisation of piperidines at the 2-position from linear
precursors, further studies in solution were conducted first.
Subsequently, a number of nucleophiles were coupled un-
Consequently, amino acetal 9f was protected with a der these conditions and the products were cleaved from the
benzyloxycarbonyl group (Cbz) to afford the solution-phase resin (Table 1).
model system 13 (Scheme 4).
As expected, both allyl- and methallyltrimethylsilane
One-pot coupling of allyltrimethylsilane under identical could be coupled in high yield (Entries 1 and 2). Through
conditions as for resin 10f indeed afforded a 5:1 mixture of the use of a stoichiometric amount of camphorsulfonic
cyclic and linear products 14 and 15 in 95% yield. Alternat- acid,[16] a 2-furanyl substituent was coupled in reasonable
ively, 13 was cyclised to the corresponding N,O-acetal 16 yield (Entry 3). Finally, an ethyl chain was introduced, al-
by catalytic pTSA in CH2Cl2 (conditions b), but partial beit in a low yield, by the use of diethylzinc as the nucleoph-
formation of the undesired enamide 17 (1:2 ratio) could not ile (not optimised, Entry 4).[8b] Attempts to introduce a pro-
be prevented.[4] Use of slightly different conditions pargyl or an acetone moiety, with allenyltributyltin and iso-
[CH2Cl2/EtOH, 2:1, v/v mixture; conditions c)] drastically propenyl acetate, respectively, as the nucleophiles, failed.[17]
3134
Eur. J. Org. Chem. 2002, 3133Ϫ3139

Solid-Phase Synthesis of Piperidines by N-Acyliminium Ion Chemistry
Table 1. Synthesis of 2-substituted piperidines via 19aϪf
FULL PAPER
silane onto the analogous 4-alkyl-substituted oxycarben-
ium ions.[18]
Conclusions
In conclusion, a good method for the synthesis of 2-sub-
stituted and 2,4-disubstituted piperidines has been de-
veloped. Formation of linear side products was eliminated
by use of stable ring-closed 2-Bt-substituted piperidines de-
rived from linear acetals, which were used as precursors for
N-acyliminium ion chemistry. A small library of piperidines
was synthesised by this methodology, demonstrating the po-
tential for automated library synthesis.
Experimental Section
General Information: All reactions were carried out under dry nitro-
gen, unless stated otherwise. Standard syringe techniques were ap-
plied for transfer of air-sensitive reagents and dry solvents. Rf
values were obtained by thin layer chromatography (TLC) on silica
gel coated plastic sheets (Merck silica gel 60 F245) with the afore-
mentioned solvent (mixture) unless noted otherwise. Chromato-
graphic purification refers to flash chromatography[19] with the in-
dicated solvent (mixture) and ACROS silica gel (particle size 35Ϫ70
µm). Infrared spectra (IR) were recorded with a Bruker IFS 28
[a] Isolated yield over four steps from resin 8. [b] CSA (1 equiv.) was
[c]
used. Isolated as the HCl salt.
Next, the influence of the R substituent at the 4-position
in the piperidine ring was determined, with allyltrimethylsil-
ane as the nucleophile. In all cases, the product was ob-
tained in excellent yield and diastereoselectivity (Entries
5Ϫ9), except in the presence of a 4-furanyl substituent
(Entry 7), in which case an unidentifiable mixture of prod-
ucts was obtained.
spectrophotometer, and wavelengths [ν˜] are reported in cmϪ1
.
Infrared spectra of resins were measured in KBr using a DRIFT
module. 1H and 13C nuclear magnetic resonance (NMR) spectra
were obtained with a Bruker ARX 400 (400 MHz and 100 MHz,
respectively) unless indicated otherwise. Spectra are reported in
ppm on the δ scale. HRMS measurements were performed with a
JEOL JMS SX/SX102A four-sector mass spectrometer, coupled to
a JEOL MS-MP7000 data system. The solid-phase reaction mix-
tures were either gently stirred with a magnetic stirring bar or agit-
ated by rotation of the reaction vessel at an angle of 45° attached
to a rotary evaporator engine. The resins were washed according
to the indicated sequence. The resin was allowed to swell/shrink for
1 min before each filtration. ‘‘Drying’’ refers to drying in a vacuum
oven at 50 °C. Dry THF and Et2O were distilled from sodium
benzophenone ketyl prior to use. Dry CH2Cl2 was distilled from
1
Because of overlap of signals in the H NMR spectrum
it was not possible to assign the stereochemistry of the 2,4-
disubstituted piperidines directly. To effect splitting of the
signals, the amine group of product 20a was derivatised
with a strongly electron-withdrawing tosyl group to give pi-
peridine 24 in moderate yield (Scheme 6).
˚
CaH2 and stored over MS (4 A) under dry nitrogen. Diisopropyl-
Scheme 6. Stereochemistry
ethylamine was dried and distilled from KOH pellets. Reagents were
purchased at highest commercial quality and used without further
purification unless stated otherwise. Fluka Merrifield resin
(200Ϫ400 mesh, 1% DVB, 1.7 mmol Cl/g) was used. For an experi-
mental procedure for the synthesis of 9aϪe see the preceding art-
icle.[12]
Through the use of NOE difference measurements, a
clear NOE contact between the CH2 of the allyl group and
4-H of the piperidine ring was observed, indicating a cis
relationship between 4-H and the allyl function. In addi-
tion, no NOE enhancement between 2-H and 4-H of the
piperidine ring was observed, and the product was therefore 5,5-Diethoxy-3-phenylpentylamine (9a): 1H NMR (400 MHz,
CDCl3): δ ϭ 1.11 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.19 (t, J ϭ 7.0 Hz,
3 H, CH3), 1.30 (br. s, 2 H, NH2), 1.67Ϫ1.89 (m, 3 H), 1.93Ϫ2.00
(m, 1 H), 2.46Ϫ2.58 (m, 2 H, 1-H), 2.74Ϫ2.82 (m, 1 H, 3-H),
3.31Ϫ3.40 (m, 2 H, OCH2), 3.41Ϫ3.52 (m, 1 H, OCH2), 3.56Ϫ3.64
(m, 1 H, OCH2), 4.16 (dd, J ϭ 3.9, 8.0 Hz, 1 H, 5-H), 7.12Ϫ7.18
(m, 3 H, ArH), 7.20Ϫ7.30 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 15.3 (CH3), 39.5 (C-3), 40.2, 40.7, 40.9 (C-
1), 60.7 (OCH2), 61.4 (OCH2), 101.2 (C-5), 126.2 (ArCH), 127.6
(ArCH), 128.5 (ArCH), 144.5 (ArCq) ppm. IR (film): ν˜ ϭ 3310
(NH2), 1128, 1058. HRMS (C15H26NO2 [MHϩ]; FAB): calcd.
assigned as the trans diastereoisomer. This stereochemistry
can be explained by invoking the intermediate N-acylimin-
ium ion 25. The phenyl group adopts a pseudoequatorial
position, to minimise steric interactions. The nucleophile
then comes in axially to minimise steric interaction with the
axial proton at the C-3 position and to generate the product
with the lowest-energy conformation. This then results in
formation of the trans diastereoisomer. This stereochem-
istry is in good agreement with the results of Woerpel and
co-workers, who investigated the additions of allyltrimethyl- 252.1964; found 252.1965.
Eur. J. Org. Chem. 2002, 3133Ϫ3139
3135

F. P. J. T. Rutjes, H. Hiemstra, et al.
FULL PAPER
5,5-Diethoxy-3-(4-pyridyl)pentylamine (9b): 1H NMR (400 MHz,
CDCl3): δ ϭ 1.11 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.19 (t, J ϭ 7.0 Hz,
1
9f (1.1 g, 55%) as a colourless oil. H NMR (400 MHz, CDCl3,):
δ ϭ 1.19 (t, J ϭ 7.0 Hz, 6 H, CH3), 1.21 (br, 2 H, NH2), 1.35Ϫ1.47
3 H, CH3), 0.85Ϫ1.25 (br. s, 2 H, NH2), 1.68Ϫ1.89 (m, 3 H), (m, 4 H), 1.59Ϫ1.64 (m, 2 H), 2.68 (t, J ϭ 6.7 Hz, 2 H, 1-H),
1.97Ϫ2.03 (m, 1 H), 2.30Ϫ2.57 (m, 2 H, 1-H), 2.80Ϫ2.87 (m, 1 3.44Ϫ3.51 (dq, J ϭ 9.4, 7.0 Hz, 2 H, OCH2), 3.59Ϫ3.67 (dq, J ϭ
H, 3-H), 3.32Ϫ3.40 (m, 2 H, OCH2), 3.47Ϫ3.54 (m, 1 H, OCH2), 9.4, 7.0 Hz, 2 H, OCH2), 4.47 (t, J ϭ 5.7 Hz, 1 H, 5-H) ppm. 13C
3.56Ϫ3.65 (m, 1 H, OCH2), 4.17 (dd, J ϭ 4.1, 8.0 Hz, 1 H, 5-H), NMR (100 MHz, CDCl3): δ ϭ 15.1 (CH3), 21.8 (C-3), 33.0, 33.2,
7.11 (d, J ϭ 6.0 Hz, 2 H, ArH), 8.51 (d, J ϭ 6.1 Hz, 2 H, ArH)
41.7 (C-1), 60.8 (OCH2), 102.7 (C-5) ppm. IR (film): ν˜ ϭ 3325
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.2 (CH3), 39.0 (C-3), (NH2), 1573, 1127, 1062. HRMS (C9H22NO2 [MHϩ]; FAB): calcd.
39.8, 39.9, 40.0, 61.1 (OCH2), 61.4 (OCH2), 100.8 (C-5), 123.1
(ArCH), 149.9 (ArCH), 153.9 (ArCq) ppm. IR (film): ν˜ ϭ 3340
(NH2), 1599, 1486, 1127, 1058. HRMS (C14H25N2O2 [MHϩ];
FAB): calcd. 253.1916; found 253.1912.
176.1651; found 176.1636.
General Procedure A for Coupling the Amino Acetals to the Resin:
DIPEA (2 equiv.) and the appropriate amino acetal (2 equiv.) were
added to a 0.05 g/mL suspension of resin in dry THF, and the
suspension was swirled for 20 h. The resin was then filtered, washed
with CH2Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2, Et2O, CH2Cl2,
Et2O and CH2Cl2, and dried.
3-(4-Bromophenyl)-5,5-diethoxypentylamine (9c):
1H NMR
(400 MHz, CDCl3): δ ϭ 1.11 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.18 (t,
J ϭ 7.0 Hz, 3 H, CH3), 1.30 (br. s, 2 H, NH2), 1.63Ϫ1.83 (m, 3 H),
1.93Ϫ1.99 (m, 1 H), 2.48Ϫ2.55 (m, 1 H, 1-H), 2.74Ϫ2.81 (m, 1
H, 3-H), 3.31Ϫ3.38 (m, 2 H, OCH2), 3.48Ϫ3.53 (m, 1 H, OCH2),
3.56Ϫ3.64 (m, 1 H, OCH2), 4.15 (dd, J ϭ 3.9, 8.0 Hz, 1 H, 5-H),
7.05 (d, J ϭ 8.4 Hz, 2 H, ArH), 7.41 (d, J ϭ 8.4 Hz, 2 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.1 (CH3), 38.8 (C-3),
39.3, 39.7, 40.4, 60.7 (OCH2), 61.1 (OCH2), 100.8 (C-5), 119.7
(ArCq), 129.1 (ArCH), 131.3 (ArCH), 143.5 (ArCq) ppm. IR (film):
ν˜ ϭ 3370 (NH2), 1589, 1128, 1058. HRMS (C15H2579BrNO2
[MHϩ]; FAB): calcd. 330.1069; found 330.1066.
Resin 10a: IR: ν˜ ϭ 3356, 1726, 1512, 1120.
Resin 10b: IR: ν˜ ϭ 3342, 3203, 1729, 1519, 1124.
Resin 10c: IR: ν˜ ϭ 3340, 1732, 1513, 1124.
Resin 10d: IR: ν˜ ϭ 3346, 1730, 1493, 1125.
Resin 10e: IR: ν˜ ϭ 3344, 1731, 1511, 1121.
Resin 10f: IR: ν˜ ϭ 3360, 1728, 1518, 1126.
5,5-Diethoxy-3-(2-furanyl)pentylamine (9d): 1H NMR (400 MHz,
CDCl3): δ ϭ 1.05Ϫ1.35 [m, 8 H, (NH2 ϩ CH3)], 1.70Ϫ1.79 (m, 2
H), 1.82Ϫ1.97 (m, 2 H), 2.56Ϫ2.61 (m, 2 H, 1-H), 2.90Ϫ2.98 (m,
1 H, 3-H), 3.38Ϫ3.45 (m, 2 H, OCH2), 3.50Ϫ3.57 (m, 1 H, OCH2),
3.58Ϫ3.67 (m, 1 H, OCH2), 4.28 (dd, J ϭ 5.0, 9.0 Hz, 1 H, 5-H),
6.01 [s, 1 H, CHϪCHϭCH(C)O], 6.25 (s, 1 H, OCHϭCH), 7.29
(s, 1 H, OCHϭCH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.3
(CH3), 32.9 (C-3), 38.3, 38.5, 40.0 (C-1), 60.9 (OCH2), 61.7
(OCH2), 101.3 (C-5), 105.3 [CHCHϭC(C)O], 109.9 (OCHϭCH),
141.1 (OCHϭCH), 157.6 (ArCq) ppm. IR (film): ν˜ ϭ 3351 (NH2),
1576, 1127, 1059. HRMS (C13H24NO3 [MHϩ]; FAB): calcd.
242.1756; found 242.1748.
1-(2-Allyl-4-phenylpiperidin-1-yl)ethanone (11a) and N-(5-Ethoxy-3-
phenyloct-7-enyl)acetamide (12a): Allyltrimethylsilane (1.64 mL,
10.3 mmol) and BF3·OEt2 (0.39 mL, 3.08 mmol) were added at 0
°C to a suspension of resin 10a (1.00 g, 1.03 mmol) in dry CH2Cl2
(15 mL), and the reaction mixture was swirled for 20 h, thereby
allowing it to warm to room temperature, after which the resin was
filtered, washed with CH2Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2,
Et2O, CH2Cl2, Et2O and CH2Cl2, and dried. This resin (893 mg,
0.96 mmol) was suspended in 1  NaOMe in THF/MeOH (9 mL,
2:1, v/v) and stirred gently for 1 h. The resin was then filtered and
washed with CH2Cl2, MeOH, CH2Cl2, and MeOH, followed by
addition of 1  HCl in MeOH (20 mL) to the filtrate and evapora-
tion of the solvent. The residue was taken up in pyridine (5 mL),
and Ac2O (0.18 mL, 1.9 mmol) and DMAP (cat.) were added.
After stirring at room temperature for 20 h, the reaction mixture
was concentrated to afford 11a (134 mg, 57%) as an oil after puri-
fication by chromatography (EtOAc). Rf ϭ 0.63. 1H NMR
(400 MHz, CDCl3, 1:1 mixture of rotamers): δ ϭ 1.54Ϫ1.82 (m, 2
H), 1.86Ϫ1.94 (m, 2 H), 2.12 (s, 1.5 H, CH3), 2.13 (s, 1.5 H, CH3),
2.35Ϫ2.53 (m, 1.5 H, CH2CHϭCH2), 2.57Ϫ2.64 (m, 0.5 H,
CH2CHϭCH2), 2.75Ϫ2.82 (m, 0.5 H), 2.91Ϫ2.99 (m, 1 H),
3.28Ϫ3.38 (m, 0.5 H), 3.72Ϫ3.77 (m, 0.5 H), 4.05Ϫ4.10 (m, 0.5 H),
4.70Ϫ4.74 (m, 0.5 H), 4.99Ϫ5.18 (m, 2.5 H), 5.70Ϫ5.83 (m, 1 H),
7.17Ϫ7.23 (m, 3 H, ArCH), 7.29Ϫ7.33 (m, 2 H, ArCH) ppm. 13C
NMR (100 MHz, CDCl3, 1:1 mixture of rotamers): δ ϭ 21.7 (CH3),
21.8, 32.6, 33.4, 34.5, 34.8, 35.0, 36.3, 36.4 (C-6), 36.5 (C-4), 36.6
5,5-Diethoxy-3-isopropylpentylamine (9e): 1H NMR (400 MHz,
CDCl3): δ ϭ 0.87 (t, J ϭ 11.0 Hz, 6 H, iPrϪCH3), 1.18 (t, J ϭ
9.0 Hz, 6 H, OCH2CH3), 1.30Ϫ1.36 (m, 1 H), 1.37Ϫ1.49 (m, 2 H),
1.59Ϫ1.63 (m, 1 H), 1.68Ϫ1.73 (m, 1 H), 2.63Ϫ2.71 (m, 2 H, 1-H),
3.44Ϫ3.51 (m, 2 H, OCH2), 3.57Ϫ3.70 (m, 2 H, OCH2), 4.52 (t,
J ϭ 6.0 Hz, 1 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
15.1 (OCH2CH3), 18.5 (iPrCH3), 18.7 (iPrCH3), 29.5 (iPrCH), 34.4,
34.8, 36.8 (C-3), 40.2 (C-1), 60.2 (OCH2), 61.2 (OCH2), 101.9 (C-
5) ppm. IR (film): ν˜ ϭ 3296 (NH2), 1582, 1124, 1061. HRMS
(C12H28NO2 [MHϩ]; FAB): calcd. 218.2120; found 218.2117.
5,5-Diethoxypentylamine (9f):[20] NaCN (2.7 g) and KI (1 mol %)
were added to a solution of 4-chloro-1,1-diethoxybutane (10 g,
55 mmol) in dry DMSO (50 mL), and the mixture was stirred at
100 °C for 20 h. The reaction mixture was then poured into water (C-4), 41.8 (C-6), 47.3 (C-2), 53.8 (C-2), 116.7 (CHϭCH2), 118.1
(500 mL) and extracted with Et2O (2ϫ150 mL). The combined
ether layers were washed with brine, dried with MgSO4, concen-
trated and further purified by bulb-to-bulb distillation (100 °C,
(CHϭCH2), 126.4 (ArCH), 126.6 (ArCH), 128.5 (ArCH), 134.0
(CHϭCH2), 135.1 (CHϭCH2), 145.0 (ArCq), 145.1 (ArCq), 169.0
(CϭO), 169.1 (CϭO). IR (film): ν˜ ϭ 1635 (CϭO). HRMS
1.5 mbar) to afford 6.68 g (39 mmol, 71%) of the corresponding (C16H22NO [MHϩ]; FAB): calcd. 244.1701; found 244.1684. Com-
1
cyanide as a clear oil. This oil (2.00 g, 11.7 mmol) was then dis-
solved in dry Et2O (30 mL) and cooled to 0 °C, and LiAlH4 (1.33 g,
35.1 mmol.) was added portionwise. After 15 min, the ice bath was
pound 12a (12 mg, 4%) was also obtained as an oil. Rf ϭ 0.45. H
NMR (400 MHz, CDCl3, 2:1 mixture, data of the major): δ ϭ 1.09
(t, J ϭ 7.0 Hz, 3 H), 1.83 (s, 3 H), 1.69Ϫ1.99 (m, 4 H), 2.14Ϫ2.29
removed and the mixture was stirred for 3 h. NaOH (2 ) was then (m, 2 H), 2.68Ϫ2.75 (m, 1 H), 2.96Ϫ3.06 (m, 1 H), 3.11Ϫ3.22 (m,
added slowly at 0 °C until a white precipitate was formed. The
1 H), 3.26Ϫ3.34 (m, 1 H), 3.39Ϫ3.47 (m, 1 H), 5.01Ϫ5.06 (m, 2
H), 5.28 (br. s, 1 H), 5.72Ϫ5.83 (m, 1 H), 7.13Ϫ7.31 (m, 5 H) ppm.
reaction mixture was filtered through Celite, concentrated and fur-
ther purified by bulb-to-bulb distillation (80 °C, 1.5 mbar) to afford 13C NMR (100 MHz, CDCl3, 2:1 mixture, data of the major): δ ϭ
3136
Eur. J. Org. Chem. 2002, 3133Ϫ3139

Solid-Phase Synthesis of Piperidines by N-Acyliminium Ion Chemistry
FULL PAPER
15.5, 23.2, 36.0, 38.0, 38.3, 40.5, 41.0, 63.9, 75.9, 117.0, 126.4,
18.7, 25.4, 27.6, 39.2, 50.4, 66.8, 116.8, 127.7, 127.8, 128.4, 135.2,
127.5, 128.6, 134.7, 144.7, 169.8 ppm. IR (film): ν˜ ϭ 3275, 1648. 137.0, 155.5 ppm. IR (film): ν˜ ϭ 2932, 1691, 1641, 1422, 1259.
HRMS (C18H28NO2 [MHϩ]; FAB): calcd. 290.2120; found HRMS (C16H22NO2, [MHϩ]; FAB): calcd. 260.1651; found
290.2134.
260.1660. 15 (12 mg, 16%) was also obtained as a clear oil. Rf ϭ
0.2. H NMR (400 MHz, CDCl3): δ ϭ 1.17 (t, J ϭ 7.0 Hz, 3 H),
1
1-(2-Allylpiperidin-1-yl)ethanone (11f) and N-(5-Ethoxyoct-7-enyl)-
acetamide (12f): Treatment of resin 10f (0.98 g, 1.1 mmol) according
to the procedure described above for resin 10a afforded 11f (85 mg,
47%) as an oil after purification by chromatography (EtOAc). Rf ϭ
1.25Ϫ1.35 (m, 1 H), 1.41Ϫ1.52 (m, 5 H), 2.19Ϫ2.29 (m, 2 H),
3.17Ϫ3.28 (m, 3 H), 3.35Ϫ3.41 (m, 1 H), 3.43Ϫ3.58 (m, 1 H), 4.75
(br. s, 1 H), 5.02Ϫ5.09 (m, 4 H), 5.77Ϫ5.85 (m, 1 H), 7.26Ϫ7.37
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.6, 22.6, 30.0,
33.6, 38.4, 41.0, 64.3, 66.6, 78.6, 116.8, 127.0, 128.1, 128.5, 135.0,
136.7, 156.4 ppm. IR (film): ν˜ ϭ 3417, 3332, 1701, 1640, 1250.
HRMS (C18H28NO3, [MHϩ]; FAB): calcd. 306.2069; found
306.2057.
1
0.52. H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers): δ ϭ
1.32Ϫ1.43 (m, 1 H), 1.54Ϫ1.66 (m, 5 H), 2.03 (s, 1.5 H, CH3), 2.05
(s, 1.5 H, CH3), 2.20Ϫ2.39 (m, 1.5 H, CH2CHϭCH2), 2.43Ϫ2.50
(m, 0.5 H, CH2CHϭCH2), 2.54Ϫ2.60 (m, 0.5 H), 3.04Ϫ3.11 (m,
0.5 H), 3.54Ϫ3.57 (m, 0.5 H), 3.89 (br. m, 0.5 H), 4.50Ϫ4.54 (0.5
H), 4.81Ϫ4.86 (m, 0.5 H), 4.96Ϫ5.10 (m, 2 H, CHϭCH2),
5.64Ϫ5.74 (m, 1 H, CHϭCH2) ppm. 13C NMR (100 MHz, CDCl3,
1:1 mixture of rotamers): δ ϭ 18.7, 18.8, 21.6 (CH3), 21.8 (CH3),
25.2, 26.0, 27.1, 28.5, 34.1, 34.6, 36.3 (C-6), 41.8 (C-6), 47.1 (C-2),
53.7 (C-2), 116.5 (CHϭCH2), 117.8 (CHϭCH2), 134.3 (CHϭCH2),
135.3 (CHϭCH2), 169.1 (CϭO), 169.2 (CϭO) ppm. IR (film): ν˜ ϭ
1641 (CϭO), 1424. 12f (14 mg, 6%) was also obtained as an oil.
Benzyl 2-Benzotriazolylpiperidine-1-carboxylate (18): A catalytic
amount of pTSA (10 mol %) was added to a solution of acetal
13 (93 mg, 0.3 mmol) in dry CH2Cl2 (6 mL). After 15 min, 1H-
benzotriazole (357 mg, 3 mmol) was added and the reaction mix-
ture was stirred at room temperature for 5 h. The reaction mixture
was then poured into saturated aqueous K2CO3 (10 mL), the layers
were separated, and the organic layer was washed with aqueous
saturated K2CO3 (10 mL) and brine (10 mL), dried with MgSO4
and concentrated to afford 18 (89 mg, 88%) as an oil after purifica-
tion by chromatography (pentane/Et2O, 5:6). Rf ϭ 0.5. 1H NMR
(400 MHz, CDCl3, 3:1 mixture, data of the major): δ ϭ 1.49Ϫ1.72
(m, 2 H), 1.75Ϫ1.86 (m, 2 H), 2.04Ϫ2.27 (m, 1 H), 2.38Ϫ2.59 (m,
2 H), 3.01Ϫ3.11 (m, 1 H), 4.00Ϫ4.15 (m, 1 H), 5.14 (d, J ϭ
12.2 Hz, 1 H), 5.19 (d, J ϭ 12.2 Hz, 1 H), 6.85Ϫ6.98 (m, 1 H),
7.12Ϫ7.43, (m, 7 H), 8.04 (d, J ϭ 8.7 Hz, 1 H) ppm. IR (film):
ν˜ ϭ 1701. HRMS (C19H21N4O2, [MHϩ]; FAB): calcd. 337.1665;
found 337.1643.
1
Rf ϭ 0.33. H NMR (400 MHz, CDCl3): δ ϭ 1.18 (t, J ϭ 7.0 Hz,
3 H), 1.32Ϫ1.37 (m, 1 H), 1.44Ϫ1.55 (m, 5 H), 1.97 (s, 3 H),
2.19Ϫ2.29 (m, 2 H), 3.21Ϫ3.29 (m, 3 H), 3.41Ϫ3.47 (m, 1 H),
3.52Ϫ3.59 (m, 1 H), 5.02Ϫ5.09 (m, 2 H), 5.55 (br. s, 1 H),
5.75Ϫ5.83 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 15.5,
22.8, 23.3, 29.5, 33.5, 38.4, 39.6, 64.3, 78.6, 116.8, 134.9, 170.1 ppm.
IR (film): ν˜ ϭ 3294, 1638. HRMS (C12H24NO2 [MHϩ]; FAB):
calcd. 214.1807; found 214.1816.
Benzyl 5,5-Diethoxypentylcarbamate (13): DIPEA (0.31 mL) and
benzyl cyanoformate (0.23 mL) were added to a solution of 5,5-
diethoxypentylamine (9f, 286 mg, 1.63 mmol) in dry CH2Cl2
(5 mL), and the mixture was stirred at room temperature for 5 h.
The reaction mixture was then poured into saturated aqueous
NaHCO3 (10 mL) and extracted with CH2Cl2 (2ϫ10 mL). The
combined CH2Cl2 layers were washed with brine, dried with
MgSO4 and concentrated to afford 13 (440 mg, 87%) as a clear oil
Benzyl 2-Allylpiperidine-1-carboxylate (14) from 18: Allyltrimethyl-
silane (0.34 mL) and BF3·OEt2 (0.08 mL) were added at 0 °C to a
solution of 18 (71 mg, 0.21 mmol) in dry CH2Cl2 (5 mL). After
stirring for 1 h at 0 °C, the mixture was allowed to warm to room
temperature and stirred for another 3 h. The reaction mixture was
then poured into saturated aqueous K2CO3 (10 mL), the layers
were separated, and the water layer was extracted with CH2Cl2
(5 mL). The combined CH2Cl2 layers were washed with brine, dried
with MgSO4 and concentrated to afford 14 (51 mg, 93%) as a clear
oil after purification by chromatography.
after purification by chromatography (pentane/Et2O, 2:3). Rf
ϭ
0.46. 1H NMR (400 MHz, C6D6): δ ϭ 1.12 (t, J ϭ 7.1 Hz, 6 H,
CH3), 1.15Ϫ1.21 (m, 4 H), 1.52Ϫ1.57 (m, 2 H), 2.93Ϫ2.96 (m, 2
H, 1-H), 3.30Ϫ3.38 (dq, J ϭ 9.3, 7.1 Hz, 2 H, OCH2CH3),
3.48Ϫ3.55 (dq, J ϭ 9.3, 7.1 Hz, 2 H, OCH2CH3), 4.10 (br. s, 1 H,
NH), 4.36 (t, J ϭ 5.6 Hz, 1 H, 5-H), 5.10 (s, 2 H, OCH2Ph),
7.04Ϫ7.28 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, C6D6): δ ϭ
16.3 (CH3), 22.8, 30.7, 34.2, 41.8 (C-1), 61.5, 67.2, 103.6 (C-5),
127.6 (ArCH), 128.0 (ArCH), 129.1 (ArCH), 129.3 (ArCq), 156.9
(CϭO) ppm. IR (film): ν˜ ϭ 3341, 1726, 1704.
General Procedure B for the Formation of the Bt Intermediates: A
catalytic amount of pTSA (10 mol %) was added to a 0.05 g/mL
suspension of resin in dry CH2Cl2, and the suspension was swirled
for 30 min. 1H-Benzotriazole (10 equiv.) was then added, and the
mixture was swirled for another 5 h. Subsequently, the resin was
filtered, washed with CH2Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2,
Et2O, CH2Cl2, Et2O and CH2Cl2, and dried.
Benzyl 2-Allylpiperidine-1-carboxylate (14)[21] and Benzyl (5-Ethoxy-
oct-7-enyl)carbamate (15): Allyltrimethylsilane (0.4 mL) and
BF3·OEt2 (0.1 mL) were added at 0 °C to a solution of 13 (77 mg,
0.25 mmol) in dry CH2Cl2 (4 mL). After stirring for 1 h at 0 °C,
the mixture was allowed to warm to room temperature and stirred
for another 3 h. The reaction mixture was then poured into satur-
ated aqueous NaHCO3 (10 mL), the layers were separated, and the
water layer was extracted with CH2Cl2 (5 mL). The combined
CH2Cl2 layers were washed with brine, dried with MgSO4 and con-
centrated to afford 14 (51 mg, 79%) as a clear oil after purification
by chromatography (pentane/Et2O, 2:1 Ǟ 1:1). Rf ϭ 0.4. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.35Ϫ1.45 (m, 1 H), 1.47Ϫ1.60 (m, 5 H),
Resin 19a: IR: ν˜ ϭ 1713, 1494, 1122.
Resin 19b: IR: ν˜ ϭ 1722, 1494, 1121.
Resin 19c: IR: ν˜ ϭ 1713, 1492, 1125.
Resin 19d: IR: ν˜ ϭ 1701, 1492, 1117.
Resin 19e: IR: ν˜ ϭ 1722, 1493, 1125.
Resin 19f: IR: ν˜ ϭ 1714, 1493, 1126.
General Procedure C for the N-Acyliminium Ion Reactions and
2.22Ϫ2.29 (m, 1 H), 2.39Ϫ2.46 (m, 1 H), 2.81Ϫ2.89 (m, 1 H), Cleavage: The nucleophile (5 equiv.) and BF3·OEt2 (3 equiv.) were
4.04Ϫ4.07 (m, 1 H), 4.38 (br. m, 1 H), 4.98Ϫ5.07 (m, 2 H), 5.11 added at 0 °C to a suspension of 200 mg of resin in 5 mL of dry
(d, J ϭ 12.5 Hz, 1 H), 5.14 (d, J ϭ 12.5 Hz, 1 H), 5.65Ϫ5.73 (m, CH2Cl2, and the reaction mixture was swirled for 20 h, thereby al-
1 H), 7.29Ϫ7.38 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ lowing it to warm to room temperature, after which the resin was
Eur. J. Org. Chem. 2002, 3133Ϫ3139
3137

F. P. J. T. Rutjes, H. Hiemstra, et al.
FULL PAPER
filtered, washed with CH2Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2,
Et2O, CH2Cl2, Et2O and CH2Cl2, and dried. The resin was sus-
pended in 1  NaOMe in THF/MeOH (2 mL, 2:1, v/v) and gently
stirred for 1 h, after which it was filtered and washed with CH2Cl2,
MeOH, CH2Cl2 and MeOH. The filtrate was concentrated, and the
residue was diluted with a 2  solution of NaOH (5 mL) and a
saturated NaCl solution (5 mL). The aqueous layer was extracted
with EtOAc (2ϫ 5 mL), the combined organic layers were dried
with MgSO4 and filtered, and the solvent was removed.
ppm. IR (film): ν˜ ϭ 3296 (NH), 2925, 1666, 1452. HRMS
(C15H18NO [MHϩ]; FAB): calcd. 228.1388; found 228.1400.
trans-2-Ethyl-4-phenylpiperidine (23a): Treatment of resin 19a and
diethylzinc according to General Procedure C afforded 23a (5 mg,
14%) as a yellow oil after purification by chromatography (CH2Cl2/
3.5  NH3 in MeOH, 9:1). Rf ϭ 0.21. 1H NMR (400 MHz, CDCl3):
δ ϭ 0.94 (t, J ϭ 7.5 Hz, 3 H, CH2CH3), 1.54Ϫ1.63 (m, 1 H),
1.65Ϫ1.81 (m, 3 H), 1.83Ϫ1.83 (m, 1 H), 1.93Ϫ2.00 (m, 2 H),
2.87Ϫ3.00 (m, 4 H), 7.18Ϫ7.19 (m, 1 H, ArH), 7.21Ϫ7.33 (m, 4 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 10.9 (CH3), 24.3
(CH2CH3), 32.2 (C-3), 35.4 (C-5), 36.0 (C-4), 40.3 (C-6), 53.9 (C-
2), 126.2 (ArCH), 127.0 (ArCH), 128.5 (ArCH), 145.3 (ArCq) ppm.
IR (film): ν˜ ϭ 3304 (NH), 2927, 1452. HRMS (C13H20N [MHϩ];
FAB): calcd. 190.1596; found 190.1594.
General Procedure D for the N-Acyliminium Ion Reactions and
Cleavage: This was identical to General Procedure C, except that,
after cleavage, 1  HCl in MeOH (4 mL) was added to the filtrate
and the solvents were evaporated. The residue was extracted with
iPrOH (2 mL), filtered and concentrated to afford the products as
their HCl salts.
trans-2-Allyl-4-(4-pyridinyl)piperidine (20b): Treatment of resin 19b
and allyltrimethylsilane according to General Procedure C afforded
20b (29 mg, 71%) as a yellow oil after purification by chromato-
graphy (CH2Cl2/3.5  NH3 in MeOH, 9:1). Rf ϭ 0.58. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.72Ϫ1.78 (m, 1 H), 1.80Ϫ1.92 (m, 2 H),
1.93Ϫ2.02 (m, 1 H), 2.20 (br, 1 H, NH), 2.23Ϫ2.29 (m, 1 H,
CH2CHϭCH2), 2.39Ϫ2.46 (m, 1 H, CH2ϪCHϭCH2), 2.84Ϫ2.90
(m, 1 H, 4-H), 2.92Ϫ3.00 (m, 2 H, 6-H), 3.02Ϫ3.08 (m, 1 H, 2-H),
5.10Ϫ5.15 (m, 2 H, CHϭCH2), 5.71Ϫ5.82 (m, 1 H, CHϭCH2),
7.17 (d, J ϭ 5.6 Hz, 2 H, ArH), 8.51 (d, J ϭ 5.9 Hz, 2 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 31.5 (C-3), 35.6 (C-5),
35.9 (C-4), 37.1 (CH2CHϭCH2), 40.4 (C-6), 51.3 (C-2), 117.7
(CHϭCH2), 122.6 (ArCH), 135.5 (CHϭCH2), 149.8 (ArCH), 154.4
(ArCq) ppm. IR (film): ν˜ ϭ 3281 (NH), 1598, 1413. HRMS
(C13H19N2 [MHϩ]; FAB): calcd. 203.1548; found 203.1549.
trans-2-Allyl-4-phenylpiperidine (20a): Treatment of resin 19a and
allyltrimethylsilane according to General Procedure C afforded 20a
(32 mg, 80%) as a yellow oil after purification by chromatography
(CH2Cl2/3.5  NH3 in MeOH, 9:1). Rf ϭ 0.3. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.74Ϫ1.91 (m, 4 H), 1.96Ϫ2.01 (m, 1 H), 2.24Ϫ2.30
(m, 1 H, CH2CHϭCH2), 2.44Ϫ2.50 (m, 1 H, CH2CHϭCH2),
2.87Ϫ3.00 (m, 3 H, 6-H ϩ 4-H), 3.07Ϫ3.12 (m, 1 H, 2-H),
5.09Ϫ5.15 (m, 2 H, CHϭCH2), 5.74Ϫ5.83 (m, 1 H, CHϭCH2),
7.18Ϫ7.21 (m, 2 H, ArH), 7.21Ϫ7.33 (m, 3 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 33.0 (C-3), 36.7 (C-4), 36.9, 37.0,
40.6 (C-6), 51.5 (C-2), 117.1 (CHϭCH2), 125.9 (ArCH), 127.1
(ArCH), 128.4 (ArCH), 136.0 (CHϭCH2), 146.0 (ArCq) ppm. IR
(film): ν˜ ϭ 3280 (NH), 3030, 1440. HRMS (C14H20N [MHϩ];
FAB): calcd. 202.1596; found 202.1602.
trans-2-Allyl-4-(4-bromophenyl)piperidine (20c): Treatment of resin
19c and allyltrimethylsilane according to General Procedure C af-
forded 20c (39 mg, 85%) as a yellow oil after purification by chro-
matography (CH2Cl2/3.5  NH3 in MeOH, 9:1). Rf ϭ 0.36. 1H
NMR (400 MHz, CDCl3): δ ϭ 1.71Ϫ1.82 (m, 2 H, 5-H), 1.84Ϫ1.90
(m, 1 H, 3-H), 1.91Ϫ1.99 (m, 1 H, 3-H), 2.15 (br, 1 H, NH),
trans-2-Methallyl-4-phenylpiperidine (21a): Treatment of resin 19a
and 2-methallyltrimethylsilane according to General Procedure C
afforded 21a (33 mg, 76%) as a yellow oil after purification by chro-
matography (CH2Cl2/3.5  NH3 in MeOH, 9:1). Rf ϭ 0.46. 1H
NMR (400 MHz, CDCl3): δ ϭ 1.74 (s, 3 H, CH3), 1.71Ϫ1.91 (m,
3 H), 1.97Ϫ2.04 (m, 1 H), 2.16 [dd, J ϭ 14.0, 5.5 Hz, 1 H,
CH2C(CH3)ϭCH2], 2.52 (dd, J ϭ 16.2, 9.2 Hz, 1 H, CH2C(CH3)ϭ
CH2), 2.86Ϫ3.03 (m, 3 H, 4-H ϩ 6-H), 3.20Ϫ3.26 (m, 1 H, 2-H),
4.79 [d, J ϭ 0.9 Hz, 1 H, CH2C(CH3)ϭCH2], 4.86 [t, J ϭ 1.7 Hz,
1 H, CH2C(CH3)ϭCH2], 7.18Ϫ7.22 (m, 2 H, ArH), 7.25Ϫ7.33 (m,
3 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 22.1 (CH3),
29.7 (C-3), 31.5 (C-5), 35.4 [CH2C(CH3)ϭCH2], 35.9 (C-4), 40.1
(C-6), 49.6 (C-2), 113.6 [CH2C(CH3)ϭCH2], 126.3 (ArCH), 127.0
(ArCH), 128.5 (ArCH), 142.0 [CH2C(CH3)ϭCH2], 145.0 (ArCq)
ppm. IR (film): ν˜ ϭ 3330 (NH), 2850, 1450. HRMS (C15H22N
[MHϩ]; FAB): calcd. 216.1752; found 216.1759.
2.22Ϫ2.32 (m,
1 H, CH2CHϭCH2), 2.41Ϫ2.50 (m, 1 H,
CH2ϪCHϭCH2), 2.84Ϫ3.00 (m, 3 H, 6-H ϩ 4-H), 3.08Ϫ3.13 (m,
1 H, 2-H), 5.07Ϫ5.13 (m, 2 H, CHϭCH2), 5.70Ϫ5.79 (m, 1 H,
CHϭCH2), 7.12 (d, J ϭ 1 0.0 Hz, 2 H, ArH), 7.39 (d, J ϭ 1 0.0 Hz,
2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 29.7 (C-3),
31.9 (C-5), 35.8 (C-4), 36.2 (CH2CHϭCH2), 40.1 (C-6), 51.4 (C-2),
117.8 (CHϭCH2), 119.8 (ArCq), 128.8 (ArCH), 131.5 (ArCH),
135.0 (CHϭCH2), 144.3 (ArCq) ppm. IR (film): ν˜ ϭ 3356 (NH),
2849, 1489. HRMS (C13H1979BrN [MHϩ]; FAB): calcd. 280.0701;
found 280.0698.
trans-2-Allyl-4-(2-propyl)piperidine HCl Salt (20e): Treatment of
resin 19f and allyltrimethylsilane according to General Procedure
D afforded 20e (37 mg, 86%) as its HCl salt. H NMR (400 MHz,
trans-2-(2-Furanyl)-4-phenylpiperidine (22a): CSA (1.1 equiv.) was
added to a suspension of 200 mg of resin 19a in furan (5 mL). The
reaction mixture was swirled for 20 h, filtered, washed with
CH2Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2, Et2O, CH2Cl2, Et2O
and CH2Cl2, and dried. The product was then cleaved from the
resin by General Procedure C to afford 22a (25 mg, 54%) as a yel-
low oil after purification by chromatography (CH2Cl2/3.5  NH3
in MeOH, 9:1). Rf ϭ 0.38. 1H NMR (400 MHz, CDCl3): δ ϭ
1.75Ϫ1.86 (m, 2 H, 5-H), 2.05 (br. s, 1 H, NH), 2.09Ϫ2.17 (m, 1
H, 3-H), 2.28Ϫ2.33 (m, 1 H, 3-H), 2.86Ϫ3.01 (m, 3 H, 4-H ϩ 6-
H), 4.37 (d, J ϭ 3.4 Hz, 1 H, 2-H), 6.27 (dd, J ϭ 2.0, 0.9 Hz, 1 H),
6.38 (dd, J ϭ 3.1, 1.8 Hz, 1 H), 7.19Ϫ7.34 (m, 5 H, ArH), 7.41 (d,
J ϭ 0.9 Hz, 1 H, OCHϭCH) ppm. 13C NMR (125 MHz, CDCl3):
1
D2O): δ ϭ 0.90 (d, J ϭ 6.2 Hz, 6 H, CH3), 1.53Ϫ1.69 (m, 3 H),
1.72Ϫ1.79 (m, 2 H), 1.83Ϫ1.89 (m, 1 H), 2.47Ϫ2.51 (m, 2 H,
CH2CHϭCH2), 3.17Ϫ3.20 (m, 2 H, 6-H), 3.53Ϫ3.56 (m, 1 H, 2-
H), 5.25Ϫ5.30 (m, 2 H, CHϭCH2), 5.78Ϫ5.84 (m, 1 H, CHϭCH2)
ppm. 13C NMR (125 MHz, D2O): δ ϭ 19.5 (CH3), 19.6 (CH3),
25.1 (C-5), 29.7, 34.9, 35.2, 39.7 (C-6), 51.9 (C-2), 120.1 (CHϭ
CH2), 132.5 (CHϭCH2) ppm. HRMS (C11H21N [Mϩ]; EI): calcd.
167.1674; found 167.1640.
2-Allylpiperidine HCl Salt (20f):[22] Treatment of resin 19f and allyl-
trimethylsilane according to General Procedure D afforded 20f
δ ϭ 33.0 (C-5), 34.2 (C-3), 37.6 (C-4), 41.5 (C-6), 50.5 (C-2), 106.8 (29 mg, 78%) as its HCl salt. 1H NMR (400 MHz, D2O): δ ϭ
(CHϭC(CH)O), 110.2 (OCHϭCH), 125.9 (ArCH), 126.9 (ArCH), 1.45Ϫ1.71 (m, 3 H), 1.89Ϫ1.93 (m, 2 H), 2.01Ϫ2.04 (m, 1 H),
128.1 (ArCH), 141.5 (OCHϭCH), 145.8 (ArCqPh), 155.7 (ArCqFur
)
2.36Ϫ2.52 (m, 2 H, CH2CHϭCH2), 2.96Ϫ3.02 (m, 1 H, 6-H),
3138
Eur. J. Org. Chem. 2002, 3133Ϫ3139

Solid-Phase Synthesis of Piperidines by N-Acyliminium Ion Chemistry
FULL PAPER
Trost, I. Fleming, C. H. Heathcock), Pergamon, Oxford, 1991,
3.20Ϫ3.23 (m, 1 H, 6-H), 3.39Ϫ3.44 (m, 1 H, 2-H), 5.25Ϫ5.30 (m,
2 H, CHϭCH2), 5.80Ϫ5.90 (m, 1 H, CHϭCH2) ppm. 13C NMR
(100 MHz, D2O): δ ϭ 23.6 (C-5), 23.8 (C-4), 30.2 (C-3), 39.7
(CH2CHϭCH2), 46.8 (C-6), 58.1 (C-2), 122.1 (CHϭCH2), 123.9
(CHϭCH2). HRMS (C8H16N [MHϩ]; FAB): calcd. 126.1283;
found 126.1245.
vol. 2, p. 1047. [7d] R. A. Volkmann, In Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming, C. H. Heathcock),
[7e]
Pergamon, Oxford, 1991, vol. 1, p. 355.
W. N. Speckamp,
H. Hiemstra, Tetrahedron 1985, 41, 4367.
For examples of N-acyliminium ion chemistry on resin, see: [8a]
[8]
M. G. Valverde, D. Dallinger, C. O. Kappe, Synlett 2001, 6,
[8b]
741.
C. Vanier, A. Wagner, C. Mioskowski, Chem. Eur. J.
trans-2-Allyl-4-phenyl-1-(4-tolylsulfonyl)piperidine (24): p-Tolu-
enesulfonyl chloride (72 mg, 0.38 mmol) was added to a solution
of 20a (32 mg, 0.16 mmol) in pyridine (2 mL) and the mixture was
stirred for 20 h. The reaction mixture was concentrated, and the
residue was taken up in CH2Cl2 (10 mL) and extracted with satur-
ated aqueous NaHCO3 (10 mL), aqueous saturated CuSO4 (10 mL)
and brine (10 mL), dried with Na2SO4 and concentrated to afford
24 (37 mg, 65%) after purification by chromatography (PE/EtOAc,
[8c]
2001, 7, 2318.
J. H. van Maarseveen, W. J. N. Meester, J. J.
N. Veerman, C. G. Kruse, P. H. H. Hermkens, F. P. J. T. Rutjes,
[8d]
H. Hiemstra, J. Chem. Soc., Perkin Trans. 1 2001, 994.
H.
Wang, A. Ganessian, Org. Lett. 1999, 1, 1647. [8e] J. J. N. Veer-
man, F. P. J. T. Rutjes, J. H. van Maarseveen, H. Hiemstra,
Tetrahedron Lett. 1999, 40, 6079.
T. Rutjes, P. H. H. Hermkens, H. Hiemstra, Tetrahedron Lett.
[8f]
W. J. N. Meester, F. P. J.
[8g]
1999, 40, 1601.
M. Eguchi, M. S. Lee, H. Nakanishi, M.
1
Stasiak, S. Lovell, M. Kahn, J. Am. Chem. Soc. 1999, 121,
7:1). Rf ϭ 0.21. H NMR (400 MHz, CDCl3): δ ϭ 1.43Ϫ1.63 (m,
[8h]
´
´
T. Vojkovsky, A. Weichsel, M. Patek, J. Org. Chem.
12204.
2 H), 1.69Ϫ1.72 (m, 1 H), 1.76Ϫ1.80 (m, 1 H), 2.38Ϫ2.42 (m, 2 H,
CH2CHϭCH2), 2.44 (s, 3 H, CH3), 2.77Ϫ2.85 (m, 1 H, 4-H), 3.14
(dt, J ϭ 2.7, 13.5 Hz, 1 H, 6-H), 3.91Ϫ3.95 (m, 1 H, 6-H),
1998, 63, 3162.
[9]
For additions to resin-bound N-acylimines, see: S. Schunk, D.
Enders, Org. Lett. 2001, 3, 3177.
For a stable intermediate, see also ref.[8b]
[10]
[11]
4.24Ϫ4.29 (m, 1 H, 2-H), 5.03Ϫ5.11 (m, 2 H, CHϭCH2),
5.66Ϫ5.77 (m, 1 H, CHϭCH2), 7.02 (d, J ϭ 8.4 Hz, 2 H, TsCH),
7.16Ϫ7.32 (m, 5 H, ArCH), 7.36 (d, J ϭ 8.4 Hz, 2 H, TsCH) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 21.5 (CH3), 31.9, 34.3, 34.4,
36.0 (C-4), 40.9 (C-6), 52.8 (C-2), 117.4 (CHϭCH2), 126.5 (ArCH),
126.6 (ArCH), 127.1 (ArCH), 128.5 (ArCH), 129.7 (ArCH), 134.7
(CHϭCH2), 138.6 (ArCq), 143.1 (ArCq), 145.1 (ArCq) ppm. IR
(film): ν˜ ϭ 1638, 1307, 1155. HRMS (C21H26NO2S [MHϩ]; FAB:
calcd. 356.1684; found 356.1687.
A. R. Katritzky, X. Lan, J. Z. Yang, O. V. Denisko, Chem. Rev.
1998, 98, 409.
[12]
Details on the synthesis of amino acetals 9aϪe are published
in the preceding article: R. W. M. Aben, H. W. Scheeren, Eur.
J. Org. Chem. 2002, 0000Ϫ0000. ((O02200))
For a 2-Bt-substituted pyrrolidine see: A. R. Katritzky, Z. S.
Luo, Y. F. Fang, Tetrahedron Lett. 2000, 41, 9691.
[13]
[14] [14a] For benzotriazole as a leaving group in N-acyliminium ion
chemistry, see: A. R. Katritzky, Y. Fang, A. Silina, J. Org.
[14b]
Chem. 1999, 64, 7622.
A. R. Katrizky, A. V. Ignatchenko,
H. Lang, J. Org. Chem. 1995, 60, 4002.
Acknowledgments
[15]
Direct conversion of enamide 17 to product 14 was not pos-
sible. Compound 13 was stirred in CH2Cl2 in the presence of
pTSA (cat.) for 15 min to provide a mixture of 16 and 17. Allyl-
trimethylsilane was then added, and the mixture was stirred at
room temperature for 20 h. This yielded a mixture consisting
mainly of 16 and 17 and a small amount of product 14. Pre-
sumably, allyltrimethylsilane is not stable to protic acids, mak-
ing this an ineffective procedure. This result corresponds well
with the findings of Shono et al. who observed the same when
trying to couple a silyl enol ether to an enamide precursor us-
ing a protic acid: T. Shono, Y. Matsumura, K. Tsubata, J. Am.
Chem. Soc. 1981, 103, 1172.
These investigations are supported (in part) by the Netherlands Re-
search Council for Chemical Sciences (CW) with financial aid from
the Netherlands Technology Foundation (STW). J. A. J. Geenev-
asen and A. M. van den Burg are gratefully acknowledged for per-
forming the NOE experiments.
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H. de Koning, W. N. Speckamp, Methods Org. Chem. (Houben-
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H. Hiemstra, W. N.
Received April 10, 2002
[O02201]
Eur. J. Org. Chem. 2002, 3133Ϫ3139
3139