Efficient Solution-Phase Parallel Synthesis of 4-Substituted N-Protected Piperidines

Article abstract of DOI:10.1002/ejoc.200300387

Practical conditions for the synthesis of 4-substituted N-protected piperidines through CuCN·2LiBr-catalyzed organozinc additions to 1-acylpyridinium salts and subsequent hydrogen-transfer hydrogenation have been established. The reaction sequence is performed at room temperature and provides 4-substituted N-protected piperidines in excellent overall yields without the isolation of intermediate dihydropyridines, In those cases in which the organozinc addition results in mixtures of 2- and 4-substituted dihydropyridines, the 2-substituted isomers are efficiently scavenged with maleic anhydride and subsequently removed by a mild extractive workup with NaHCO₃ (sat.). The N-acyl group can conveniently be exchanged from N-phenoxycarbonyl to N-tBoc, thus allowing orthogonal deprotection strategies. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300387

FULL PAPER
Efficient Solution-Phase Parallel Synthesis of 4-Substituted N-Protected
Piperidines
Xiaoyang Wang,[a] Anna M. Kauppi,[a] Roger Olsson,*[b] and Fredrik Almqvist*[a]
Keywords: Copper / Hydrogenations / Nitrogen heterocycles / Zinc / Parallel synthesis
Practical conditions for the synthesis of 4-substituted N-pro- results in mixtures of 2- and 4-substituted dihydropyridines,
tected piperidines through CuCN·2LiBr-catalyzed organo- the 2-substituted isomers are efficiently scavenged with ma-
zinc additions to 1-acylpyridinium salts and subsequent hy-
drogen-transfer hydrogenation have been established. The
reaction sequence is performed at room temperature and
provides 4-substituted N-protected piperidines in excellent
leic anhydride and subsequently removed by a mild extrac-
tive workup with NaHCO3 (sat.). The N-acyl group can con-
veniently be exchanged from N-phenoxycarbonyl to N-tBoc,
thus allowing orthogonal deprotection strategies.
overall yields without the isolation of intermediate dihy- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
dropyridines. In those cases in which the organozinc addition
Germany, 2003)
Introduction
ties of organozinc reagents Ϫ such as their compatibility
with a wide range of functional groups (e.g., chlorides, ni-
triles, esters, amides, and ketones) and the potential to per-
form the reactions at room temperature Ϫ makes their use
attractive in parallel synthesis.[17Ϫ20] Therefore, to improve
the regioselectivity it would be of great interest to investi-
gate the possibilities of the use of organozinc reagents in
combination with CuCN·2LiBr. A few scattered, individual
examples of the use of organozinc reagents in combination
with copper catalysis resulting in good regioselectivities
have been reported.[21Ϫ24] Further investigation of the scope
and limitations of these reactions is, however, necessary in
the context of developing a reliable method for parallel syn-
thesis. A practical Pd/C-catalyzed hydrogen-transfer re-
duction of the intermediate dihydropyridines, to provide the
substituted piperidines efficiently, was also investigated.
Here we report a practical and efficient procedure, also
amenable for parallel synthesis, for the synthesis of 4-substi-
tuted N-protected piperidines.
Substituted piperidines constitute one of the most stud-
ied heterocycles, owing to their ubiquitous nature in syn-
thetically challenging alkaloids as well as in pharmaceutical
research.[1Ϫ3] As a result, numerous methods for the syn-
thesis of piperidine derivatives have been reported.[4Ϫ6]
GoetzϪLuthy reported an attractive synthetic strategy that
takes advantage of the wealth of commercially available
pyridines as starting materials, dihydropyridines being syn-
thesized in low yields by direct alkylation of pyridines.[7]
Recent work by Comins et al., however, has shown that
activation of the pyridines through the formation of N-acyl
pyridinium derivatives prior to the nucleophilic addition
provides dihydropyridines in good yields and with good re-
gioselectivities.[8,9] A wide range of organometallic reagents
have also been used as nucleophiles in these reactions. Un-
catalyzed Grignard[10] and organotin[11] reagents favor the
formation of 2-substituted dihydropyridines, whereas the
use of organotitanium reagents[12,13] and lithium dialkylcu-
prates[14] mainly results in 4-substituted dihydropyridines,
which is also the case for Grignard reagents admixed with
copper iodide.[15] Organozinc reagents are reported to give
mainly mixtures of 4- and 2-substituted dihydropyri-
dines.[16] Although not synthetically useful, owing to the
formation of isomeric mixtures, the advantageous proper-
Results and Discussion
To study the regioselective alkylation, a set of commer-
cially available organozinc reagents, admixed with catalytic
amounts (5 mol %) of CuCN·2LiBr were added to pre-
formed N-acyl pyridinium salts (Table 1).
[a]
Both dialkylzinc reagents and secondary and primary
alkylzinc halides almost exclusively gave the 4-addition
products, with only trace amounts of the 2-substituted iso-
mers being detectable by NMR spectroscopy (Table 1, en-
tries 1Ϫ5). The tertiary alkylzinc nucleophile tert-butylzinc
bromide similarly afforded a high isomeric ratio of 98% of
the desired 4-substituted dihydropyridine 2, and only 2% of
˚
Organic Chemistry, Department of Chemistry, Umea
University,
˚
901 87 Umea, Sweden
E-mail: fredrik.almqvist@chem.umu.se
[b]
Discovery Chemistry, ACADIA Pharmaceuticals A/S,
Fabriksparken 58, 2600 Glostrup, Denmark
E-mail: roger@acadia-pharm.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300387
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Parallel Synthesis of 4-Substituted N-Protected Piperidines
Table 1. Conversion of pyridines into dihydropyridines 2 and 3
FULL PAPER
Entry
Pyridines
RZnX or R2Zn[a]
Yield[b] (%)
Ratio[c] (2/3)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
(CH3)2Zn
(CH3CH2)2Zn
96
97
91
95
92
90
72
84
94
95
92
90
90
0
Ͼ99:trace
Ͼ99:trace
Ͼ99:trace
Ͼ99:trace
Ͼ99:trace
98:2
65:35
75:25
Ͼ99:trace
Ͼ99:trace
Ͼ99:trace
92:8
CH3(CH2)3ZnBr
(CH2)4CHZnBr
(CH3)2CH(CH2)2ZnBr
(CH3)3CZnBr
2-methoxyphenylZnI
4-fluorophenylZnBr
3,5-difluorophenylZnBr
4-cyanophenylZnBr
2-methylphenylZnBr
2-methylphenylZnBr
(CH3CH2)2Zn
CH3(CH2)3ZnBr
2-methylphenylZnBr
(CH3CH2)2Zn
(CH3CH2)2Zn
CH3(CH2)3ZnBr
(CH3CH2)2Zn
pyridine
pyridine
pyridine
2-ethylpyridine
2-ethylpyridine
2-methoxypyridine
2-methoxypyridine
2-fluoropyridine
3-fluoropyridine
2,3,5-collidine
2,3,5-collidine
2,3,5-collidine
2,3,5-collidine
2,6-lutidine
2,6-lutidine
4-picoline
Ͼ99:trace
0
0
87
90
84
82
92
0
97:3
85:15
83:17
73:27
70:30
(CH3)3CZnBr
2-methylphenylZnBr
CH3(CH2)3ZnBr
(CH3CH2)2Zn
0
94
(CH3CH2)2Zn
trace:Ͼ99
[a]
[b]
[c]
1
Admixed with (5 mol%) CuCN·2LiBr. Isolated yield. Ratio determined by H NMR spectroscopy of the crude isolate.
the 2-isomer 3 was isolated from a total yield of 90% The presence of additional substituents in the ring, as exem-
(Table 1, entry 6). With the exceptions of the 2-meth- plified by 2,3,5-collidine, caused reduced regioselectivity;
oxyphenyl- and the 4-fluorophenylzinc halides (Table 1, en- when 2-methylphenylzinc bromide was used as nucleophile,
tries 7 and 8), high regioselectivities were observed for most for example, the 2/3 ratio went down to 70:30 (Table 1, en-
of the aromatic zinc halides tested (Table 1, entries 9Ϫ11). tries 18Ϫ21), although the yields remained high. As would
Reduced yields Ϫ of 72% and 84%, respectively Ϫ were also be expected, treatment of a 4-substituted pyridine with phe-
noticed in the two former cases, whereas the yields in all nyl chloroformate, Et2Zn, and CuCN·2LiBr resulted in ex-
the other examples were excellent (Ն 90%).
With these results in hand, the focus was turned to sub- 4,4Ј-disubstituted derivative 2 detectable (Table 1, entry 24).
stituted pyridines as starting materials. Since the activated Decomposition of the dihydropyridines occurred during
clusively the 2,4-disubstituted dihydropyridine 3, with no
species 1 has to be formed in order for the nucleophilic storage in the freezer. Consequently, to accomplish high
addition to proceed, the anticipation was that the presence overall yields, it was important to reduce the dihydropyri-
of substituents at the 2- and/or 6-positions in the pyridine dines quickly to the corresponding piperidines. Previously,
ring could be problematic. Surprisingly, 2-ethylpyridine these substrates had mostly been reduced by hydrogenation
worked equally well as pyridine itself, resulting in a 2/3 ratio with H2 gas as the hydrogen source in the presence of a
of 92:8 when 2-methylphenylzinc bromide was used catalyst[25Ϫ27] (e.g. 10% Pd/C, 45 psi, 8Ϫ10 h or PtO2, 6 h).
(Table 1, entry 12) and of Ͼ 99:1 in favor of the 4-substi- Since parallel synthesis with pressurized hydrogen gas de-
tuted product when diethylzinc was used (Table 1, entry 13). mands advanced equipment, the option to use a hydrogen-
On the other hand, if the pyridine was substituted in both transfer reduction would be particularly attractive. Advan-
the 2- and 6-positions, as in 2,6-lutidine, no reaction took tageously, both for avoiding the use of special equipment
place (Table 1, entries 22 and 23). 2-Methoxypyridine and and for the time-saving aspect in the reduced reaction times,
2-fluoropyridine also afforded no product under these con- ammonium formate in absolute methanol reduced the di-
ditions (Table 1, entries 14Ϫ16). The presence of a 3-fluoro hydropyridines to piperidines within one hour at room tem-
substituent, as in 3-fluoropyridine, gave excellent results in perature under Pd/C catalysis conditions (Table 2).[28,29] It
terms both of yield and of regioselectivity (Table 1, entry should be noted, though, that restricting the reaction tem-
17), affording mainly the 4-isomer (2/3, 97:3) in 87% yield. perature to room temperature meant that aromatic substi-
Eur. J. Org. Chem. 2003, 4586Ϫ4592
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4587

X. Wang, A. M. Kauppi, R. Olsson, F. Almqvist
Table 2. Conversion of 4-substituted dihydropyridines 2 into the corresponding piperidines 4
FULL PAPER
Entry
Product
R
RЈ
(Pd/C, equiv.)
Yield[a] (%)
1
2
3
4
5
6
7
8
9
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
CH3
CH3CH2
CH3(CH2)3
(CH3)3C
(CH3)2CH(CH2)2
CH3CH2
(CH2)4CH
3,5-difluorophenyl
2-methylphenyl
H
H
H
H
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.5
95
93
92
92
90
91[b]
90
90
92
H
2-CH2CH3
H
H
H
0.5
[a]
[b]
Isolated yield from pyridine. Ca. 1:1 mixture of cis and trans isomers.
tuted dihydropyridines required 10 times more Pd/C than
analogues with an aliphatic substituent (Table 2, entries 8
and 9). No reduction of the aromatic moiety was observed
and the yields were excellent in all cases.
Table 3. Synthesis of 4-substituted N-tBoc-protected piperidines 7
The outcome of the reduction of the 2,4-diethyl-1-acyl-
dihydropyridine was hard to foresee, due to the possibility
of forming a mixture of stereoisomers. The hydrogen-trans-
fer reduction proved to be synthetically limited to mono-
substituted dihydropyridines, since the reduction of 2.6 re-
sulted in an almost 1:1 mixture of the cis and trans isomers
Entry
Product
R
Yield[a] (%)
1
2
3
4
5
6
7
8
9
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
7.10
2-methylphenyl-
90
92
93
88
1
4.6 according to H NMR spectroscopy.
ϪCH(CH3)CH2CH3
ϪCH(CH2CH3)2
ϪCH2(CH2)3CH3
ϪCH(CH2CH3)(CH2)3CH3 91
ϪCH(CH2CH3)(CH2)2CH3 89
ϪC(CH3)2CH2CH3
ϪCH(CH2CH2CH3)2
ϪCH(CH3)(CH2)3CH3
ϪCH2CH(CH2CH3)2
Removal of the N-phenoxycarbonyl group was achieved
by treatment of the N-phenoxycarbonyl-protected piperi-
dines with a mixture of KOH and NH2NH2·H2O in ethyl-
ene glycol for one hour,[30] resulting in a series of 4-substi-
tuted piperidines 5.1Ϫ5.7 in 56Ϫ80% yield. Although this
deprotection method turned out to work conveniently, for
89
88
92
88
piperidines substituted either with aliphatic or with aro- 10
matic substituents, a milder procedure was preferable. N-
tBoc-protected piperidines can easily be deprotected by
[a]
Isolated yield from pyridine.
various mildly acidic methods and are therefore attractive
as target molecules. However, the organozinc addition is the final step, affording the desired 4-substituted N-tBoc-
not compatible with the use of tBocCl or tBoc anhydride protected piperidines 7.1Ϫ7.10 in excellent overall yields
as activating agents, as would be required for the pro- (88Ϫ93% in three steps, Table 3) and purities Ͼ 95%.
duction of tBoc-protected piperidines. We therefore treated
Another problem was the occasional occurrence of iso-
the N-phenoxycarbonyl derivatives 2 with KOtBu, resulting meric mixtures of the 2- and 4-substituted dihydropyridines.
in high yields of the N-tBoc-protected dihydropyridines 6 Even if excellent regioselectivities were observed in most of
(Table 3).[31,32]
the examples, the exclusive isolation of the 4-substituted
For the development of a procedure amenable for high- piperidine as the end product is necessary to make this pro-
throughput organic synthesis it was necessary to perform cedure useful. Therefore, to avoid any substrate dependency,
the reactions without cumbersome purification steps. Re- a scavenger step was added, demonstrated here by the 2-
ducing the number of time-consuming purification steps methoxyphenyl and the 4-fluorophenyl derivatives, in which
was achieved without complications, thanks to the fact that the most pronounced mixtures of 4- and 2-isomers (65:35
all reaction steps had been high-yielding and had delivered and 75:25, respectively) had been formed (Table 1, entry 7
fairly pure crude products. Thus, conversion of the pyri- and 8). Maleic anhydride was added to remove the conju-
dines into a variety of N-tBoc-protected piperidines was gated 2-substituted dihydropyridines 3.7 and 3.8 in a [4ϩ2]
performed with only quick aqueous washings of intermedi- reaction, followed by washing with NaHCO3 (sat.)
ates 2 and 6, followed by a simple silica gel filtration after (Scheme 1). Although no experimental details had been re-
4588
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Eur. J. Org. Chem. 2003, 4586Ϫ4592

Parallel Synthesis of 4-Substituted N-Protected Piperidines
FULL PAPER
ported, this methodology had previously been used to re-
move unsubstituted conjugated dihydropyridines.[33] Owing
to the more sterically demanding substituents in the current
examples, heating of the reaction mixture at reflux for 10 h
with 4 equivalents of maleic anhydride was initially tried.
This long reaction time turned out to be detrimental for
the outcomes of the reactions, giving low yields of the 4-
substituted piperidines. A reduction of the reaction time to
2 h and an increase in the amount of maleic anhydride to
10 equivalents, however, afforded isomerically pure 4-sub-
stituted piperidines in excellent overall yields (Scheme 1).
For the fluorine-containing derivative, 19F NMR spec-
troscopy was used to monitor the disappearance of the 2-
isomer.
Experimental Section
General: All reactions were carried out under inert atmospheres
with dry solvents under anhydrous conditions, unless otherwise
stated. Pyridine was distilled before use. Methanol and ethylene
˚
glycol were dried over molecular sieves (3 A) in a flask. THF was
distilled from potassium. All the other chemicals were purchased
from Aldrich and were used as received (it should be noted that
some of the aliphatic zinc reagents contained traces of regioiso-
mers, which was confirmed by treatment with benzoyl chloride fol-
lowed by analysis by LCMS and NMR spectroscopy). TLC was
performed on 60 F254 silica gel (Merck) with detection by UV light
and by staining with solutions of potassium permanganate (3 g),
potassium carbonate (20 g), 5% aqueous sodium hydroxide (5 mL)
in water (300 mL), or of 2% Ninhydrin in EtOH 95%. Flash col-
umn chromatography (eluents given in brackets) was performed on
1
˚
silica gel (Matrex, 60 A, 35Ϫ70 µm, Grace Amicon). The H and
13C NMR spectra were recorded on a Bruker DRX 400 instrument
on solutions in CDCl3 [residual CHCl3 (δH ϭ 7.26 ppm) or CDCl3
(δC ϭ 77.00 ppm) as internal standard] or in [D6]DMSO {residual
[D5]DMSO (δH ϭ 2.50 ppm) or [D6]DMSO (δC ϭ 40.0 ppm) as
internal standard} at 298 K. First-order chemical shifts and coup-
ling constants were obtained from one-dimensional spectra. Proton
and carbon resonances were assigned from appropriate combi-
nations of COSY and 1H-13C HMQC. IR spectra were recorded
on an ATI Mattson Genesis Series FTIRTM spectrometer. LCMS
analysis was performed with a Waters micromass ZQ spectrometer
[ES], and high-resolution mass spectra [EI or FAB] were recorded
on a Jeol JMS-SX 102 spectrometer. All organic extracts were dried
with solid Na2SO4 unless otherwise stated.
General Procedure for the Preparation of Substituted Phenyl Di-
hydropyridine-1-carboxylates 2 and 3: Pyridine (0.6 mL, 7.5 mmol),
CuCN (45 mg, 0.5 mmol), and LiBr (86 mg, 1 mmol) were dis-
solved in THF (20 mL) at room temperature, which resulted in a
yellow-green solution. Upon the dropwise addition of phenyl
chloroformate (0.63 mL, 5 mmol) the color changed to orange-red
and a lot of solid was formed. The zinc reagent was then added
dropwise at room temperature. After one hour at room tempera-
ture, aqueous NH4Cl (20%, 25 mL) and Et2O (50 mL) were added.
The water layer was separated and reextracted with Et2O (2 ϫ
7 mL). The organic layers were combined and washed with aqueous
NH4Cl (20%)/NH4OH (20%) (1:1, 10 mL), water (2 ϫ 10 mL), HCl
(10% aq., 2 ϫ 10 mL), water (2 ϫ 10 mL), and brine (2 ϫ 10 mL)
and dried. Concentration at reduced pressure gave the crude prod-
ucts 2 and 3. (See Table 1 for isolated yields).
Scheme 1. Synthesis of isomerically pure 4-substituted piperidines
7.11 and 7.12 by scavenging of the 2-substituted isomer by a [4ϩ2]
cycloaddition reaction with maleic anhydride followed by washing
with NaHCO3 (sat.)
Conclusions
General Procedure for the Synthesis of 4-Substituted Phenyl Piperi-
dine-1-carboxylates by Removal of Undesired 2-Isomers by a [4؉2]
Cycloaddition with Maleic Anhydride: A mixture of the 2- and 4-
substituted dihydropyridine (0.5 mmol) was added to a solution of
maleic anhydride (490 mg, 5 mmol) in THF (1.5 mL). After the
mixture had been heated at reflux for two hours, saturated aqueous
NaHCO3 (5 mL) was added. Et2O (15 mL) was then added, and
the water layer was separated and reextracted with Et2O (2 ϫ
5 mL). The organic layers were combined, washed with brine (2 ϫ
5 mL), and dried. Concentration at reduced pressure gave the crude
4-substituted dihydropyridine, which was used immediately in the
next step without further purification.
A practical method suitable for the parallel synthesis of
4-substituted N-protected piperidines has been developed.
Even though the substituted dihydropyridines were formed
in high diastereomeric ratios, the developed strategy in-
cludes the option to remove undesired 2-substituted di-
hydropyridine to provide isomerically pure products. Fur-
thermore, conditions for exchange of the N-phenoxycar-
bonyl to the N-tBoc protecting groups, which can be con-
sidered as orthogonal protecting groups, have been
established. The high regioselectivities and yields achieved
in the reaction, together with the practical synthetic and
purification procedures, make this procedure attractive for
library synthesis. The incorporation of these building
blocks into more complex derivatives in a parallel manner
will be reported in due course.
Phase-Transfer Reduction: The crude 4-substituted dihydropyri-
dine, together with dry ammonium formate (20 mol equiv.), dis-
solved in a solution of absolute methanol/THF (11 mL, 10:1), were
added to a slurry of activated 10% Pd/C (30 mg) in absolute meth-
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4589

X. Wang, A. M. Kauppi, R. Olsson, F. Almqvist
FULL PAPER
anol (1 mL).[34] The resulting mixture was stirred at room tempera-
ture for half to one hour until all the starting material had been
consumed (indicated by TLC, n-heptane/EtOAc, 6:1). The slurry
was filtered through Celite and the Celite was thoroughly washed
with Et2O. The resulting organic solution was washed with water
and brine to remove the residual ammonium formate and dried.
Concentration at reduced pressure gave the crude product, which
was purified by short silica gel flash chromatography (n-heptane/
EtOAc, 6:1) to provide pure 4-substituted 1-(phenyloxycarbonyl)pi-
peridine 4.10 (total yield 56%) and 4.11 (total yield 65%).
H), 1.06Ϫ1.93 (m, 1 H), 0.92Ϫ0.78 (m, 12 H) ppm. 1H NMR
(400 MHz, [D6]DMSO, 408 K), 2nd isomer: δ ϭ 7.39Ϫ7.02 (m, 10
H), 4.24 (m, 1 H), 4.05 (m, 1 H), 3.85 (t, 1 H), 3.80Ϫ3.70 (m, 1
H), 3.31Ϫ3.19 (m, 1 H), 3.97 (t, 1 H), 1.97Ϫ1.81 (m, 2 H),
1.81Ϫ1.67 (m, 4 H), 1.67Ϫ1.43 (4 H), 1.43Ϫ1.42 (m, 2 H),
1.32Ϫ1.17 (m, 5 H), 1.17Ϫ1.10 (m, 1 H), 0.97Ϫ0.83 (m, 12 H)
ppm. IR (neat): ν˜ ϭ 2960, 2923, 2873, 1712 (CϭO), 1594, 1494,
1415 (CϭC), 1373, 1201(CϪO), 1149, 1058, 744, 690 cmϪ1. MS
(EI): 262 (M), 168 (100%), 140, 112, 94, 77, 65.
Phenyl 4-(Cyclopentyl)piperidine-1-carboxylate (4.7): Purification
by short flash chromatography on silica (n-heptane/EtOAc, 3:1)
Phenyl 4-Methylpiperidine-1-carboxylate (4.1): Purification by
short flash chromatography on silica (n-heptane/EtOAc, 9:1) gave
4.1 as a white solid (yield, 95%). m.p. 61Ϫ63 °C. Commercially
available, registry number: 333444Ϫ36Ϫ3.
1
gave 4.7 as a white solid (yield, 90%). m.p.: 60Ϫ61 °C, H NMR
(400 MHz, CDCl3): δ ϭ 7.43Ϫ7.07 (m, 5 H), 4.39Ϫ4.07 (br. m, 2
H), 3.09Ϫ2.73 (br. m, 2 H), 1.94Ϫ1.48 (m, 10 H), 1.32Ϫ1.07 (m, 4
H) ppm. 13C NMR: δ ϭ 153.47, 151.42, 128.97, 124.85, 121.57,
45.72, 44.72, 44.39, 41.52, 31.20, 30.80, 30.20, 25.01 ppm. IR
(neat): ν˜ ϭ 3056, 2939, 2863, 1710 (CϭO), 1590, 1494, 1417 (Cϭ
C), 1259, 1197 (CϪO), 1162, 742, 688 cmϪ1. MS (EI): 273 (M),
204, 180 (100%), 95, 77, 67, 65.
Phenyl 4-Ethylpiperidine-1-carboxylate (4.2): Purification by short
flash chromatography on silica (n-heptane/EtOAc, 9:1) gave 4.2 as
a colorless oil (yield, 93%). 1H NMR (400 MHz, CDCl3): δ ϭ
7.37Ϫ7.08 (m, 5 H), 4.35Ϫ4.19 (br. m, 2 H), 3.03Ϫ2.72 (br. m, 2
H), 1.75 (m, 2 H), 1.40 (m, 3 H), 1.20 (m, 2 H), 0.95 (t, 3 H) ppm.
13C NMR: δ ϭ 153.65, 151.55, 129.12, 125.00, 121.72, 44.83, 44.50,
37.51, 31.93, 31.52, 29.07, 11.13 ppm. IR (neat): ν˜ ϭ 3041, 2956,
2925, 2856, 1670 (CϭO), 1425 (CϭC), 1205 cmϪ1. MS (EI): 234
[M ϩ 1], 233 [M], 140 (100%), 112, 94, 77, 65.
Phenyl 4-(3Ј,5Ј-Difluorophenyl)piperidine-1-carboxylate (4.8): Puri-
fication by short flash chromatography on silica (n-heptane/EtOAc,
5:2) gave 4.8 as a white solid (yield, 90%). m.p.: 88Ϫ89 °C. 1H
NMR (400 MHz, CDCl3): δ ϭ 7.42Ϫ6.63 (m, 8 H), 4.53Ϫ4.34 (br.
m, 2 H), 3.14Ϫ2.84 (br. m, 2 H), 2.71 (tt, 1 H, J ϭ 12.08 Hz,
3.75 Hz), 1.89 (d, 2 H), 1.72 (dddd, 2 H, J ϭ 38.24 Hz, 25.25 Hz,
12.62 Hz, 4.12 Hz) ppm. 13C NMR: δ ϭ 163.91 (dd, J ϭ 248.25 Hz,
12.80 Hz), 153.39, 151.26, 149.16 (t, J ϭ 8.76 Hz), 129.04, 125.04,
121.54, 109.44 (dd, J ϭ 18.19 Hz, 6.40 Hz), 101.61 (t, J ϭ
25.60 Hz), 44.60, 44.25, 41.93, 32.64, 32.23 ppm. 19F NMR: δ
Ϫ110.35 ppm. IR (neat): ν˜ ϭ 3095, 3060, 3005, 2933, 2902, 2867,
1702(CϭO), 1625, 1594, 1496, 1452, 1421(CϭC), 1290,
1197(CϪO), 1110, 1047, 960, 856, 748, 682 cmϪ1. MS (EI): 317
(M), 267, 224 (100%), 182, 153, 127, 112, 94, 77, 65.
Phenyl 4-Butylpiperidine-1-carboxylate (4.3): Purification by short
flash chromatography on silica (n-heptane/EtOAc, 6:1) gave 4.3 as
a colorless oil (yield, 92%). 1H NMR (400 MHz, CDCl3): δ ϭ
7.39Ϫ7.07 (m, 5 H), 4.34Ϫ4.17 (br. m, 2 H), 3.03Ϫ2.72 (m, 2 H),
1.75Ϫ1.10 (m, 11 H), 0.91 (t, J ϭ 6.68 Hz, 3 H) ppm. 13C NMR:
δ 153.55, 151.46, 129.03, 124.91, 121.63, 44.76, 44.41, 36.01, 35.70,
32.24, 31.82, 28.71, 22.72, 13.95 ppm. IR (neat): ν˜ ϭ 2929, 2856,
1722 (CϭO), 1423, 1199 cmϪ1. MS (EI): 261 [M], 204, 168 (100%),
140, 112, 77, 65.
Phenyl 4-tert-Butylpiperidine-1-carboxylate (4.4): Purification by
short flash chromatography on silica (n-heptane/EtOAc, 8:1) gave
4.4 as a white solid (yield, 92%). m.p.: 83Ϫ84 °C. 1H NMR
(400 MHz, CDCl3): δ ϭ 7.38Ϫ7.08 (m, 5 H), 4.43Ϫ4.26 (br. m, 2
H), 3.01Ϫ2.72 (br. m, 2 H), 1.74 (d, 2 H), 1.36Ϫ1.14 (m, 3 H), 0.89
(s, 9 H) ppm. 13C NMR: δ ϭ 153.58, 151.55, 129.15, 125.03, 121.73,
46.55, 45.30, 45.01, 32.25, 27.25, 26.96, 26.56 ppm. IR (neat): ν˜ ϭ
3052, 2948, 2921, 2861, 1710 (CϭO), 1592, 1492, 1419, 1378, 1313,
1199, 1182, 1035, 740, 688 cmϪ1. MS (EI): 261 (M), 204, 168
(100%), 113, 94, 77.
Phenyl 4-(2Ј-Methylphenyl)piperidine-1-carboxylate (4.9): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
8:1) gave 4.9 as a colorless oil (yield, 92%). H NMR (400 MHz,
1
CDCl3): δ ϭ 7.43Ϫ7.10 (m, 9 H), 4.54Ϫ4.39 (br. m, 2 H),
3.18Ϫ2.94 (br. m, 3 H), 2.39 (s, 3 H), 1.90Ϫ1.68 (m, 4 H) ppm. 13
C
NMR: δ ϭ 153.72, 151.44, 143.14, 135.02, 130.45, 129.19, 126.35,
126.13, 125.35, 125.16, 121.72, 45.37, 45.05, 38.12, 32.49, 32.11,
19.32 ppm. IR (neat): ν˜ ϭ 3045, 3018, 2937, 2854, 1716 (CϭO),
1425(CϭC), 1201(CϪO), 1012, 750 cmϪ1. MS (FAB): 296 [M ϩ 1].
Phenyl 4-(2Ј-Methoxyphenyl)piperidine-1-carboxylate (4.10): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
Phenyl 4-(3Ј-Methylbutyl)piperidine-1-carboxylate (4.5): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
5:1) gave 4.5 as a white solid (yield, 90%). m.p. 42Ϫ43 °C. 1H NMR
(400 MHz, CDCl3): δ ϭ 7.37Ϫ7.07 (m, 5 H), 4.34Ϫ4.16 (br. m, 2
H), 3.02Ϫ2.73 (br. m, 2 H), 1.75 (d, 2 H), 1.55 (m, 1 H), 1.45 (m,
1 H), 1.40Ϫ1.20 (m, 6 H), 0.91 (d, J ϭ 6.68 Hz, 6 H) ppm. 13C
NMR: δ ϭ 153.58, 151.49, 129.06, 124.93, 121.65, 44.80, 44.46,
36.04, 35.81, 34.08, 32.32, 31.91, 28.06, 22.53 ppm. IR (neat): ν˜ ϭ
3066, 3014, 2950, 2925, 2900, 2867, 2846, 1704 (CϭO), 1592, 1417
(CϭC), 1367, 1274, 1240, 1191, 740 cmϪ1. MS (EI): 275 (M), 182
(100%), 162, 126, 94, 77, 65.
1
9:1) gave 4.10 as a colorless oil (yield, 56%). H NMR (400 MHz,
CDCl3): δ ϭ 7.40Ϫ6.85 (m, 9 H), 4.50Ϫ4.36 (br. m, 2 H), 3.85 (s,
3 H), 3.19 (tt, 1 H, J ϭ 12.08 Hz, 3.57 Hz), 3.06Ϫ2.93 (br. m, 2
H), 1.90 (d, 2 H), 1.75 (m, 2 H) ppm. 13C NMR: δ ϭ 156.72,
153.76, 151.55, 133.42, 129.20, 127.21, 126.47, 125.11, 121.77,
120.68, 110.39, 55.29, 45.42, 45.08, 35.23, 31.95, 31.47 ppm. IR
(neat): ν˜ ϭ 3012, 2939, 2854, 1718(CϭO), 1596, 1492, 1427, 1238,
1203 (CϪO), 752 cmϪ1. MS (EI): 312 [M ϩ 1] (100%), 218, 175,
154, 77.
Phenyl 4-(4Ј-Fluorophenyl)piperidine-1-carboxylate (4.11): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
Phenyl 2,4-Diethylpiperidine-1-carboxylate (4.6): Purification by
short flash chromatography on silica (n-heptane/EtOAc, 5:1) gave 9:1) gave 4.10 as a white solid (yield, 65%). m.p. 80Ϫ82 °C. 1H
4.6 as a colorless oil (yield, 91%). 1H NMR (400 MHz, [D6]DMSO,
298 K): two isomers (1:1), 1st isomer: δ ϭ 7.40Ϫ7.27 (m, 10 H),
4.30Ϫ4.08 (m, 1 H), 4.08Ϫ3.89 (m, 1 H), 3.78 (t, 1 H), 3.75Ϫ3.67
NMR (400 MHz, CDCl3): δ ϭ 7.42Ϫ7.06 (m, 9 H), 4.53Ϫ4.38 (br.
m, 2 H), 3.21Ϫ1.85 (br. m, 2 H), 2.73 (tt, 1 H, J ϭ 12.17 Hz,
3.57 Hz), 1.91 (d, 2 H), 1.72 (m, 2 H) ppm. 13C NMR: δ ϭ 161.38
(m, 1 H), 3.22Ϫ3.11 (m, 1 H), 3.08Ϫ2.80 (m, 1 H), 1.91Ϫ1.62 (m, (d, J ϭ 244.21 Hz), 153.61, 151.40, 140.95 (d, J ϭ 3.37 Hz), 129.16,
6 H), 1.57Ϫ1.37 (m, 4 H), 1.37Ϫ1.26 (m, 2 H), 1.26Ϫ1.11 (m, 5 128.02 (d, J ϭ 7.75 Hz), 125.12, 121.66, 115.20 (d, J ϭ 20.88 Hz),
4590
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4586Ϫ4592

Parallel Synthesis of 4-Substituted N-Protected Piperidines
FULL PAPER
45.01, 44.68, 41.69, 33.43, 32.91 ppm. 19F NMR: δ ϭ Ϫ117.12 tert-Butyl 4-(1Ј-Methylpropyl)piperidine-1-carboxylate (7.2): Purifi-
ppm. IR (neat): ν˜ ϭ 3073, 2996, 2950, 2919, 2850, 1716(CϭO), cation by short flash chromatography on silica (n-heptane/EtOAc,
1
1598, 1508, 1425(CϭC), 1274, 1193(CϪO), 1160, 1112, 1047, 829, 6:1) gave 7.2 as a colorless oil (yield, 92%). H NMR (400 MHz,
744 cmϪ1. MS (FAB): 300[M ϩ 1].
CDCl3): δ ϭ 4.15Ϫ3.96 (br. s, 2 H), 2.64Ϫ2.47 (br. s, 2 H), 1.48
(d, 2 H), 1.38 (s, 9 H), 1.35 (m, 1 H), 1.29Ϫ1.00 (m, 5 H), 0.84Ϫ0.72
(m, 6 H) ppm. 13C NMR: δ ϭ 154.68, 78.88, 44.20(br. s), 40.65,
38.89, 29.59, 27.95, 28.32, 26.24, 15.43, 11.53 ppm. IR (neat): ν˜ ϭ
General Procedure for the Preparation of 4-Substituted Piperidines
(5): A mixture of phenyl piperidine-1-carboxylate 4 (1.5 mmol),
KOH (2.1 g, 38 mmol), and 100% NH2NH2·H2O (0.52 mL) in eth-
ylene glycol (20 mL) was heated at reflux for 1 hour. The mixture
was poured into water and extracted with CH2Cl2 (3 ϫ 15). The
organic solution was washed with NaOH (30%, aq.) and dried.
Concentration at reduced pressure and purification by flash chro-
matography on silica gel (Et2O:isopropylamine, 9:1) gave pure com-
pound.
2962, 2931, 2856, 1695 (CϭO), 1421, 1365, 1282, 1234, 1174 cmϪ1
MS (EI): 242 [M ϩ 1], 241, 186 (100%), 168, 140, 84.
.
tert-Butyl 4-(1Ј-Ethylpropyl)piperidine-1-carboxylate (7.3): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
6:1) gave 7.3 as a colorless oil (yield, 93%). H NMR (400 MHz,
CDCl3): δ ϭ 4.21Ϫ3.89 (br. s, 2 H), 2.65Ϫ2.43 (br. s, 2 H), 1.46
(d, 2 H), 1.38 (m, 10 H), 1.36 (m, 2 H), 1.21Ϫ1.03 (m, 4 H), 0.91
(m, 1 H), 0.83Ϫ0.72 (m, 6 H) ppm. 13C NMR: δ ϭ 154.64, 78.83,
45.54, 44.34 (br. s), 37.88, 28.94, 28.30, 22.15, 11.58 ppm. IR (neat):
ν˜ ϭ 2962 cmϪ1, 2931, 2873, 1697 (CϭO), 1423, 1366, 1234, 1174
cmϪ1. MS (EI): 255 [M], 200 (100%), 182, 126, 84, 71.
4-Methylpiperidine (5.1): Yield 56% Commercially available,
registry number: 626Ϫ58Ϫ4.
4-Ethylpiperidine (5.2): Yield 60% Commercially available, registry
number: 3230Ϫ23Ϫ7.[35,36]
4-Butylpiperidine (5.3): Yield 72% Spectral data as published.[35Ϫ37]
tert-Butyl 4-Pentylpiperidine-1-carboxylate (7.4): Purification by
short flash chromatography on silica (n-heptane/EtOAc, 6:1) gave
7.4 as a colorless oil (yield, 88%). 1H NMR (400 MHz, CDCl3):
δ ϭ 4.14Ϫ3.88 (br. s, 2 H), 2.69Ϫ2.52 (br. s, 2 H), 1.58 (d, 2 H),
1.40 (s, 9 H), 1.32Ϫ1.10 (m, 9 H), 1.08Ϫ0.93 (m, 2 H), 0.83 (t, 3
H) ppm. 13C NMR: δ ϭ 154.67, 78.86, 43.87 (br. s), 36.42, 35.90,
32.16, 31.94, 28.36, 26.18, 22.53, 13.94 ppm. IR (neat): ν˜ ϭ 2956,
2925, 2856, 1698 (CϭO), 1421, 1365, 1278, 1245, 1172 cmϪ1. MS
(EI): 255 [M], 200 (100%), 182, 154, 140, 126, 84.
4-tert-Butylpiperidine (5.4): Yield 75% Commercially available,
registry number: 1882Ϫ42Ϫ4.[35]
4-(3-Methylbutyl)piperidine (5.5): Yield 76% Commercially avail-
able, registry number: 372196Ϫ26Ϫ4.[38]
4-(2Ј-Methylphenyl)piperidine (5.6): Mixture of solid and oil. Yield
80% 1H NMR (400 MHz, CDCl3): δ ϭ 7.28Ϫ7.07 (m, 4 H), 3.2
(d, 2 H), 2.89Ϫ2.73 (m, 3 H), 2.35 (s, 3 H), 2.13 (s, 1 H), 1.77 (d,
2 H), 1.66 (m, 2 H) ppm. 13C NMR: δ ϭ 144.40, 134.91, 130.19,
126.16, 125.66, 125.44, 47.31, 38.57, 33.58, 19.22 ppm. IR (neat):
ν˜ ϭ 3060, 3018, 2931, 2846, 2807, 2732, 1604, 1556, 1490, 1461,
1317, 1282, 1243, 752 cmϪ1. MS (EI): 175 [M] (100%), 160, 117,
91, 83.
tert-Butyl 4-(2Ј-Ethylhexyl)piperidine-1-carboxylate (7.5): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
6:1) gave 7.5 as a colorless oil (yield, 91%). H NMR (400 MHz,
CDCl3), δ ϭ 4.14Ϫ3.86 (br. s, 2 H), 2.70Ϫ2.51 (br. s, 2 H), 1.55
(d, 2 H), 1.39 (s, 9 H), 1.38(m, 1 H), 1.30Ϫ1.11 (m, 9 H), 1.09Ϫ0.91
(m, 4 H), 0.83 (t, J ϭ 7.04 Hz, 3 H), 0.77 (t, J ϭ 7.41 Hz, 3 H)
ppm. 13C NMR: δ ϭ 154.71, 78.89, 43.87(br. s), 40.64, 35.22, 33.31,
32.91, 32.55, 32.44, 28.65, 28.33, 25.87, 23.00, 14.01, 10.46 ppm.
IR (neat): ν˜ ϭ 2958, 2921, 2858, 1697 (CϭO), 1465, 1421, 1365,
1278, 1243, 1172, 1151 cmϪ1. MS (EI): 297 [M], 242 (100%), 224,
196, 168, 129, 84.
4-Cyclopentylpiperidine (5.7): Yield 63% Commercially available,
registry number: 123812Ϫ47Ϫ5.[39]
General Procedure for the Preparation of 4-Substituted tert-Butyl
Piperidine-1-carboxylates (7): Crude 4 (5 mmol) was added drop-
wise at Ϫ40 °C to a solution of KOtBu (1.4 g, 12.5 mmol) in THF
(15 mL), resulting in a red solution. The mixture was kept for one
hour at Ϫ40 °C and then for 30 min at room temperature. Water
(30 mL) was added, and the resulting mixture was extracted with
Et2O (3 ϫ 25 mL). The organic layers were combined, washed with
water (2 ϫ 15 mL) and brine (2 ϫ 15 mL), and dried. Concen-
tration at reduced pressure and purification by short flash chroma-
tography on silica gel (n-heptane/EtOAc, 6:1) gave 7.11 (87%, from
4.10) and 7.12 (85%, from 4.11). Compounds 6.1Ϫ6.10 were pre-
pared by the same procedure, starting from the corresponding 4-
substituted 1-phenyloxycarbonyl-dihydropyridine (2). These were
reduced without prior purification, by the phase-transfer hydrogen-
ation described above, to 4-substituted 1-tert-butoxycarbonylpiper-
idines 7.1Ϫ7.10.
tert-Butyl 4-(1Ј-Ethylbutyl)piperidine-1-carboxylate (7.6): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
6:1) gave 7.6 as a colorless oil (yield, 89%). H NMR (400 MHz,
CDCl3): δ ϭ 4.21Ϫ3.88 (br. s, 2 H), 2.67Ϫ2.42 (br. s, 2 H),
1.50Ϫ0.90 (m, 21 H), 0.89Ϫ0.64 (m, 6 H) ppm. 13C NMR: δ ϭ
154.52, 78.72, 44.33 (br. s), 43.62, 38.14, 32.15, 28.85, 28.72, 28.21,
22.67, 20.37, 14.23, 11.51 ppm. IR (neat): ν˜ ϭ 2958, 2931, 2869,
1697 (CϭO), 1465, 1423, 1365, 1236, 1174, 1145 cmϪ1. MS (EI):
269 [M], 213 (100%), 196, 168, 129, 126, 84.
tert-Butyl 4-(1Ј,1Ј-Dimethylpropyl)piperidine-1-carboxylate (7.7):
Purification by short flash chromatography on silica (n-heptane/
EtOAc, 6:1) gave 7.7 as a colorless oil (yield, 89%). 1H NMR
(400 MHz, CDCl3): δ ϭ 4.18Ϫ3.82 (br. s, 2 H), 2.58Ϫ2.29 (br. s, 2
H), 1.55Ϫ1.20 (m, 11 H), 1.20Ϫ0.86 (m, 5 H), 0.81Ϫ0.47 (m, 9 H)
ppm. 13C NMR: δ ϭ 154.44, 78.71, 44.35 (br. s), 43.85, 34.17,
32.10, 28.20, 26.18, 23.74, 7.78 ppm. IR (neat): ν˜ ϭ 2962, 2858,
1695 (CϭO), 1465, 1448, 1423, 1365, 1241, 1162, 1116 cmϪ1. MS
(EI): 255 [M], 200 (100%), 182, 129, 126, 84, 71.
tert-Butyl 4-(2Ј-Methylphenyl)piperidine-1-carboxylate (7.1): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
6:1) gave 7.1 as a colorless oil (yield, 90%). H NMR (400 MHz,
CDCl3), δ ϭ 7.20Ϫ7.09 (m, 4 H), 4.31Ϫ4.17 (br. s, 2 H), 2.92Ϫ2.75
(m, 3 H), 2.36 (s, 3 H), 1.76 (d, 2 H), 1.63 (m, 2 H), 1.51 (s, 9 H)
ppm. 13C NMR: δ ϭ 154.76, 143.51, 134.95, 130.31, 126.21, 125.91,
125.29, 79.28, 44.31 (br. s), 38.26, 32.31, 28.40, 19.24 ppm. IR
(neat): ν˜ ϭ 3006, 2973, 2937, 2852, 1695 (CϭO), 1423, 1365 (Cϭ
tert-Butyl 4-(1Ј-Propylbutyl)piperidine-1-carboxylate (7.8): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
C), 1280, 1232, 1170 (CϪO), 1114, 752 cmϪ1. MS (EI): 275 (M), 6:1) gave 7.8 as a colorless oil (yield, 88%). H NMR (400 MHz,
219 (100%), 204, 160, 117, 105, 91, 70.
CDCl3): δ ϭ 4.21Ϫ3.87 (br. s, 2 H), 2.67Ϫ2.37 (br. s, 2 H),
4591
Eur. J. Org. Chem. 2003, 4586Ϫ4592
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

X. Wang, A. M. Kauppi, R. Olsson, F. Almqvist
FULL PAPER
[2]
[3]
[4]
[5]
[6]
[7]
[8]
1.51Ϫ1.27 (m, 12 H), 1.27Ϫ0.96 (m, 11 H), 0.79 (t, 6 H) ppm. 13C
NMR: δ ϭ 154.62, 78.83, 44.41 (br. s), 41.82, 38.56, 32.80, 28.75,
28.25, 20.42, 14.28 ppm. IR (neat): ν˜ ϭ 2956, 2929, 2861, 1693
(CϭO), 1454, 1423, 1365, 1234, 1172 (CϪO), 1145. MS (EI): 283
[M], 227 (100%), 210, 182, 14o, 129, 84.
P. S. Watson, B. Jiang, B. Scott, Org. Lett. 2000, 2, 3679Ϫ3681.
D. O’Hagan, Nat. Prod. Rep. 2000, 17, 435Ϫ446.
D. M. Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223Ϫ243.
S. Laschat, T. Dickner, Synthesis 2000, 1781Ϫ1813.
R. Lavilla, J. Chem. Soc., Perkin Trans. 1 2002, 1141Ϫ1156.
N. Goetz-Luthy, J. Am. Chem. Soc. 1949, 71, 2254Ϫ2255.
D. L. Comins, S. O’Connor, Adv. Heterocycl. Chem. 1988, 44,
199Ϫ267.
D. L. Comins, G. Chung, M. A. Foley, Heterocycles 1994, 37,
1121Ϫ1135.
R. Yamaguchi, Y. Nakazono, M. Kawanisi, Tetrahedron Lett.
1983, 24, 1801Ϫ1804.
R. Yamaguchi, M. Moriyasu, M. Yoshioka, M. Kawanisi, J.
Org. Chem. 1988, 53, 3507Ϫ3512.
D. L. Comins, J. D. Brown, Tetrahedron Lett. 1984, 25,
3297Ϫ3300.
L.-L. Gundersen, F. Rise, K. Undheim, Tetrahedron 1992, 48,
5647Ϫ5656.
E. Piers, M. Soucy, Can. J. Chem. 1974, 52, 3563Ϫ3564.
D. L. Comins, A. H. Abdullah, J. Org. Chem. 1982, 47,
4315Ϫ4319.
D. L. Comins, S. O’Connor, Tetrahedron Lett. 1987, 28,
1843Ϫ1846.
tert-Butyl 4-(1Ј-Methylpentyl)piperidine-1-carboxylate (7.9): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
[9]
1
6:1) gave 7.9 as a colorless oil (yield, 92%). H NMR (400 MHz,
CDCl3): δ ϭ 4.15Ϫ3.95 (br. s, 2 H), 2.65Ϫ2.41 (br. s, 2 H),
1.55Ϫ1.31 (m, 11 H), 1.31Ϫ0.94 (m, 10 H), 0.87Ϫ0.68 (m, 6 H)
ppm. 13C NMR: δ ϭ 154.64, 78.84, 44.24 (br. s), 41.03, 37.17,
33.42, 29.58, 29.42, 28.32, 27.91, 22.86, 15.93, 13.96 ppm. IR
(neat): ν˜ ϭ 2956, 2929, 2856, 1697 (CϭO), 1465, 1421, 1365, 1280,
1234, 1174 (CϪO), 1145 cmϪ1. MS (EI): 269 [M], 214 (100%), 196,
128, 84.
[10]
[11]
[12]
[13]
[14]
[15]
tert-Butyl 4-(2Ј-Ethylbutyl)piperidine-1-carboxylate (7.10): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
1
6:1) gave 7.10 as a colorless oil (yield, 88%). H NMR (400 MHz,
[16]
[17]
CDCl3): δ ϭ 4.13Ϫ3.84 (br. s, 2 H), 2.71Ϫ2.45 (br. s, 2 H),
1.61Ϫ1.43 (br. s, 2 H), 1.43Ϫ1.26 (br. s, 10 H), 1.26Ϫ1.09 (m, 5
H), 1.09Ϫ0.84 (m, 4 H), 0.84Ϫ0.60 (br. s, 6 H) ppm. 13C NMR:
δ ϭ 154.62, 78.80, 43.83 (br. s), 40.11, 36.65, 33.26, 32.46, 28.29,
25.34, 10.48 ppm. IR (neat): ν˜ ϭ 2962, 2917, 2859, 1693 (CϭO),
1421, 1365, 1278, 1243, 1172 (CϪO), 1151 cmϪ1. MS (EI): 269 [M],
213 (100%), 196, 184, 140, 129, 84.
L. Zhu, R. M. Wehmeyer, R. D. Rieke, J. Org. Chem. 1991,
56, 1445Ϫ1453.
R. D. Rieke, M. V. Hanson, Tetrahedron 1997, 53, 1925Ϫ1956.
P. Knochel, J. J. Almena Perea, P. Jones, Tetrahedron 1998,
54, 8275Ϫ8319.
A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem.
Int. Ed. 2000, 39, 4414Ϫ4435.
[18]
[19]
[20]
[21]
[22]
tert-Butyl 4-(2Ј-Methoxyphenyl)piperidine-1-carboxylate (7.11):
Purification by short flash chromatography on silica (n-heptane/
EtOAc, 5:1) gave 7.11 as a colorless oil (yield, 87%). 1H NMR
(400 MHz, CDCl3): δ ϭ 7.22Ϫ7.11 (m, 2 H), 6.96Ϫ6.83 (m, 2 H),
4.33Ϫ4.12 (br. s, 2 H), 3.83 (s, 3 H), 3.09 (tt, 1 H, J ϭ 12.26 Hz,
3.57 Hz), 2.82 (bt, 2 H, J ϭ 12.62 Hz), 1.76 (d, 2 H), 1.58 (m, 2
H), 1.48 (s, 9 H) ppm. 13C NMR: δ ϭ 156.72, 154.93, 133.87,
127.03, 126.48, 120.62, 110.34, 79.27, 55.28, 44.46 (br. s), 35.32,
31.81, 28.49 ppm. IR (neat): ν˜ ϭ 3004, 2960, 2933, 2852, 1693 (Cϭ
O), 1492, 1423, 1365, 1236, 1170 (CϪO), 1016, 752 cmϪ1. MS
(FAB): 292 [M ϩ 1].
W.-L. Chia, M.-J. Shiao, Tetrahedron Lett. 1991, 32,
2033Ϫ2034.
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[23]
[24]
[25]
[26]
[27]
tert-Butyl 4-(4Ј-Fluorophenyl)piperidine-1-carboxylate (7.12): Purifi-
cation by short flash chromatography on silica (n-heptane/EtOAc,
[28]
[29]
1
9:1) gave 7.12 as a colorless oil (yield, 85%). H NMR (400 MHz,
CDCl3), δ ϭ 7.18Ϫ7.11 (m, 2 H), 7.07Ϫ6.94 (m, 2 H), 4.32Ϫ4.14
(br. s, 2 H), 2.78 (br. m, 2 H), 2.62 (tt, 1 H, J ϭ 12.26 Hz, 3.75 Hz),
1.79 (d, 2 H), 1.64Ϫ1.51 (m, 2 H), 1.48 (s, 9 H) ppm. 13C NMR:
δ ϭ 161.32 (d, J ϭ 244 Hz), 154.83, 141.44 (d, J ϭ 3.37 Hz), 128.07
(d, J ϭ 7.75 Hz), 115.21 (d, J ϭ 21.22 Hz), 78.48, 44.35 (br. s),
42.00, 33.35, 28.47 ppm. 19F NMR: δ Ϫ117.51 ppm. IR (neat): ν˜ ϭ
3008, 2975, 2933, 2852, 1693 (CϭO), 1511, 1425, 1365, 1280, 1228,
1168 (CϪO), 1122 cmϪ1. MS (EI): 280 [M], 224 (100%), 154, 136,
107, 77.
[30]
[31]
[32]
[33]
[34]
Supporting Information Available: 13C NMR spectra of all purified
compounds (see also the footnote on the first page of this article).
[35]
[36]
[37]
[38]
[39]
Acknowledgments
We are grateful to the Swedish Natural Science Research Council,
the Knut and Alice Wallenberg Foundation, and the foundation
˚
for technology transfer in Umea for financial support, and to Dr.
C. A. Andersson, B. M. Friberg, N. Skjaerbaek, T. Spalding,
A. K. Uldam, PCT Int. Appl. 2001, 84 pp.
P. Traxler, W. Kump, K. Mueller, W. Tosch, J. Med. Chem.
1990, 33(2), 552Ϫ560.
Nicholas M. Kelly for valuable comments on the manuscript.
[1]
C. H. Hansen, R. Olsson, G. Croston, C.-M. Andersson, Bio-
org. Med. Chem. Lett. 2000, 10, 2435Ϫ2439.
Received June 26, 2003
4592
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4586Ϫ4592