A two-step synthesis of 3,4-disubstituted piperidines from acyclic precursors through tetrahydropyridine intermediates

Article abstract of DOI:10.1055/s-0029-1218599

Cyclocondensation between acyclic 5-aminopent-2-enoate esters and aliphatic aldehydes containing an unsubstituted -methylene unit affords 1,2,3,4-tetrahydropyridine derivatives in good yields. The reaction has been applied to a range of aldehydes, showing good functional group tolerance. Chemoselective hydride reduction of the enamine double bond provides 3,4-disubstituted tertiary piperidine derivatives with acceptable to good diastereoselectivities, whereas catalytic hydrogenation of N-benzyl derivatives leads directly to the corresponding secondary piperidines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218599

PAPER
605
A Two-Step Synthesis of 3,4-Disubstituted Piperidines from Acyclic
Precursors through Tetrahydropyridine Intermediates
A
T
w
o-Ste
o
p
Synthesis
s
of 3,4-Dis
é
ubstituted Piperid
M
ines . Aurrecoechea,* José M. Gorgojo, Carlos Saornil
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Apartado 644, 48080 Bilbao, Spain
Fax +34(94)6013500; E-mail: jm.aurrecoechea@ehu.es
Received 10 July 2009; revised 29 October 2009
R2
Abstract: Cyclocondensation between acyclic 5-aminopent-2-
enoate esters and aliphatic aldehydes containing an unsubstituted a-
methylene unit affords 1,2,3,4-tetrahydropyridine derivatives in
good yields. The reaction has been applied to a range of aldehydes,
showing good functional group tolerance. Chemoselective hydride
reduction of the enamine double bond provides 3,4-disubstituted
tertiary piperidine derivatives with acceptable to good diastereose-
lectivities, whereas catalytic hydrogenation of N-benzyl derivatives
leads directly to the corresponding secondary piperidines.
N
R1
O
H
R2
N
R2
N
O
6
4
R1
H
R3
R3
R2
N
R1
EWG
EWG
R1
O
Key words: condensation, cyclizations, reductions, piperidines,
stereoselective synthesis
3
5
7
O
Scheme 1
The 1,2,3,4-tetrahydropyridine substructure 5 (Scheme 1)
is interesting because of its presence in alkaloids such as
cathenamine (1) and vallesiachotamine (2) and also as a
key functionality in synthetic schemes leading to several
natural products (Figure 1).1
control of the relative stereochemistry over three contigu-
ous stereogenic centers of 7 was easily attained.3
On the other hand, the application of this method to the
preparation of monocyclic enamines of type 9 (Scheme 2)
has been limited to N-benzyl-substituted examples (where
additionally R3 = H) derived from simple aliphatic un-
functionalized aldehydes 4,2 whereas studies devoted to
evaluate the generality and stereoselectivity of piperidine
synthesis using the strategy depicted in Scheme 2 are
lacking.5 In this paper we disclose the details of a study di-
rected at determining the practicality of the preparation of
substituted monocyclic piperidines 10 and 11 (Scheme 2)
from selected acyclic amines 8 and aldehydes 4 through
tetrahydropyridines 9.
N
N
N
H
N
H
H
H
CO2Me
CHO
vallesiachotamine (2)
H
H
O
MeO2C
cathenamine (1)
Figure 1
We have recently described the synthesis of 2-azabicyc-
lo[3.3.1]nonanes 62 and 3-hydroxypiperidine derivatives
73 using tetrahydropyridine precursors 5 (where R1,
R2 = alkyl). These applications took advantage of the abil-
ity of the enamine functionality to generate iminium ions
or undergo double bond hydrogenation, respectively. Cy-
clic enamines 5 were readily accessed by condensation of
the appropriate amine 3 and aldehyde 4 precursors
through presumed acyclic enamine intermediates.2–4 The
preparation of bicyclic piperidines 7 was studied in some
detail and found to be compatible with different substitu-
tion patterns at R2, as well as with the presence at R1 of
functionality, which proved useful for further transforma-
tions.3,4 Furthermore, in these rigid bicyclic systems good
R2
N
R2
N
R2
N
O
H
R3
R3
R3
H
4
H
R1
R1
R1
CO2Et
CO2Et
CO2Et
10 R2 = alkyl
11 R2 = H
8
9
Scheme 2
Specific target areas of study have included: 1. the scope
in the carbonyl component; 2. the determination of the ste-
reoselectivity of the cyclization and reduction steps in
these flexible systems (i.e., in the absence of the geomet-
rical constraints imposed by the rigidity of the bicyclic
systems 73); and 3. the possibility of extending this strate-
gy to the preparation of secondary piperidines 11 (R2 = H)
SYNTHESIS 2010, No. 4, pp 0605–0612
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x
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x
x
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0
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Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218599; Art ID: T13709SS
© Georg Thieme Verlag Stuttgart · New York

606
J. M. Aurrecoechea et al.
PAPER
by using appropriate R2 substituents in the secondary molecular sieves was beneficial in terms of yield when
amine cyclization precursors 8.
acetonitrile was used as the solvent (cf. entries 1 and 2),
but was not required in the case of ethanol (entries 13 and
14), a solvent that provided shorter reactions times. Both
linear and branched aldehydes worked well. One excep-
tion was phenylacetaldehyde, which reacted rapidly with
formation of a presumed acyclic enamine intermediate,3,8
but this material failed to cyclize to the desired tetrahydro-
pyridine. Likewise, ketones were found not to participate
in this reaction, in this case the starting materials were re-
covered after prolonged heating when 8a was treated with
cyclohexanone, acetophenone, or diethyl ketone. As
shown by entries 9–11 and 13–17, useful functionality,
both at the amine and aldehyde components, was allowed
in the preparation of 9. However, branching at the amine
a-position resulted in lower reactivity (entry 18) and, ad-
ditionally, this cyclization was only moderately diastereo-
selective.
Amines 8 were prepared by one of the two routes indicat-
ed in Scheme 3 that involved either zinc dienolate addi-
tion to an imine6 or Wittig-type homologation of
appropriate aldehydes. Amines 8a,b were selected to ex-
emplify the preparation of both tertiary (using 8b) and
secondary piperidines (using 8a7 with a subsequent de-
benzylation step), whereas the use of the a-substituted
amine 8c6a would provide a test of diastereoselectivity in
the formation of 9.
R2
N
N
R2
Ph
Bn
R3
N
P
H
+
a,b
H
c
ZnBr
(R3 = Ph)
(R3 = H)
O
+
CO2Et
Reduction of the enamine double bond afforded the corre-
sponding saturated piperidines in good yields with moder-
ate diastereoselectivity, the trans-isomer being formed
predominantly (Table 2). Hydride-based and catalytic hy-
drogenation methods were both found to be effective.
Conditions based on sodium cyanoborohydride/zinc chlo-
ride (Method A, entries 1, 2, 4, and 5) followed those pre-
viously described for 10a (entry 1),2 while initial
protonation of the enamine, followed by sodium borohy-
dride reduction, proved also effective in the single case
tried (Method B, entry 3). Standard catalytic hydrogena-
tion conditions provided yields and diastereoselectivities
in line with those obtained in the hydride reductions
(Method C, entries 6 and 7; see also Scheme 5). However,
in comparison with the similar double bond reductions
previously described leading to the more rigid bicyclic
piperidines 7,3 the greater conformational flexibility of
tetrahydropyridines 9 resulted in lower diastereoselectivi-
ties. Nevertheless, useful isolated overall yields for the
major isomers were realized in all cases. The cis/trans rel-
ative configurations of piperidines 10 and 11 were as-
signed by analogy with the known product 10a.9 In
support of these assignments, the expected g-gauche ef-
fects were observed in the 13C NMR resonances of the pi-
peridine ring C3 and C4, which were deshielded in the
trans-isomers relative to the more congested cis counter-
parts.7,10–13
CO2Et
Ph3P=CHCO2Et
8a R2 = Bn, R3 = H
8b R2 = 2-(3,4-dimethoxyphenyl)ethyl, R3 = H
8c R2 = Bn, R3 = Ph
Scheme 3
The previously unknown 8b was prepared starting from
3,4-dimethoxyphenethylamine according to Scheme 4.
Thus, initial conjugate addition to ethyl acrylate was fol-
lowed by amine protection and carbonyl reduction to af-
ford aldehyde 14. Wittig reaction and acidic removal of
the Boc-protecting group provided the desired 8b.
ArCH2CH2
N
ArCH2CH2
N
(a)
(c)
Boc
P
ArCH2CH2NH2
CHO
CO2Et
(Ar = 3,4-dimethoxyphenyl)
(b)
14 (61%)
12 P = H (100%)
13 P = Boc (91%)
ArCH2CH2
N
(d)
P
15 P = Boc (83%)
8b P = H (100%)
(e)
CO2Et
Bn
N
H
N
Scheme 4 Reagents and conditions: (a) ethyl acrylate, EtOH, r.t.;
(b) (Boc)2O, EtOAc, 0 °C to r.t.; (c) DIBAL-H, toluene, –78 °C; (d)
Ph3P=CHCO2Et, CH2Cl2, r.t.; (e) TFA, CH2Cl2, 0 °C.
H2, Pd/C
EtOH
R1
R1
Tetrahydropyridines 9 were then obtained by stirring un-
der reflux equimolar amounts of amine 8 and aldehyde 4
in the appropriate solvent. Results are collected in
Table 1, which also includes previously reported data (en-
tries 3, 6, and 8) to enable appropriate comparisons. Ace-
tonitrile and ethanol proved to be adequate solvents in this
condensation, but benzene failed to give the desired prod-
ucts even with Dean–Stark removal of water. The use of
CO2Et
CO2Et
9c R1 = i-Pr
9f R1 = (CH2)3CO2Et
11c (65%, cis/trans = 26:74)
11f (68%, cis/trans = 30:70)
Scheme 5
Synthetic advantage can be also taken from the choice be-
tween two alternative reducing methods for the enamine
double bond. For example, the hydride method allowed
Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York

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A Two-Step Synthesis of 3,4-Disubstituted Piperidines
607
Table 1 Preparation of Tetrahydropyridines 9 from Amines 8 and Aldehydes 4
R2
N
R2
N
R3
R3
O
H
H
solvent
reflux
+
R1
R1
CO2Et
CO2Et
8
4
9
Entry
1
Substrate
8a
R1
Et
Et
Et
Bu
Solvent
MeCN
MeCNb
EtOH
Time (h)
Product
9a
9a
9a
9b
9c
Yielda (%)
9
14
5.5
7
52
71
77c
80
70
67c
79
75c
81
64
77
0e
2
8a
3
8a
4
8a
EtOHb
MeCNb
EtOHb
MeCNb
EtOHb
MeCNb
MeCNb
MeCNb
MeCNb
EtOH
5
8a
i-Pr
19
3
6
8a
i-Pr
9c
7
8a
Bn
15
3
9d
9d
9e
8
8a
Bn
9
8a
CH2Ard
(CH2)3CO2Et
12
20
14
3
10
11
12
13
14
15
16
17
18
8a
9f
8a
(CH2)2CH=CHCO2Et
9g
–
8a
Ph
8b
8b
8b
8b
8b
8c
Et
2
9h
9h
9i
77
75
77
86
69
59f
Et
EtOHb
EtOH
1.5
2.5
2
n-C9H19
Bn
EtOH
9j
(CH2)3CO2Et
Bn
EtOH
3
9k
9l
EtOH
24
a Yield of chromatographically purified products.
b Addition of 4 Å MS.
c Ref. 2.
d Ar = 3,4-dimethoxyphenyl.
e See text.
f dr = 63:37.
chemoselective enamine reduction in the presence of a electron-deficient double bond, condense effectively with
second C=C bond (entry 5), whereas hydrogenation con- a range of aldehydes to afford substituted tetrahydropy-
ditions applied to benzyl-protected enamines 9 (R2 = Bn) ridines, which undergo chemoselective enamine reduc-
resulted in both double bond reduction and debenzylation tion to yield tertiary piperidine derivatives with
leading to formation of secondary piperidines 11 acceptable to good diastereoselectivities. In the case of N-
(Scheme 5). Interestingly, under these conditions reduc- benzyl-substituted tetrahydropyridines, under catalytic
tion of the enamine double bond was observed to take hydrogenation conditions enamine double bond reduction
place rapidly, as evidenced by TLC monitoring of the re- is followed by debenzylation and this gives alternative ac-
action, and was then followed by slower removal of the cess to the corresponding secondary piperidines.
benzyl group. In any case, two-step preparation of second-
All reactions involving air- and moisture-sensitive materials were
performed under an atmosphere of dry argon. CH2Cl2, toluene, and
MeCN were freshly distilled from CaH2. Et2O was freshly distilled
ary piperidines 11 from amines 8 and aldehydes 4 is readi-
ly available.
from Na/benzophenone. EtOH and MeOH were dried with Mg/I2.
Flash column chromatography was performed on silica gel (230–
In conclusion, secondary N-alkyl- and N-benzyl-substi-
tuted acyclic amines, containing a suitably positioned
Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York

608
J. M. Aurrecoechea et al.
PAPER
Table 2 Reduction of Enamines 9a
R2
N
R2
N
conditions
R1
R1
A, B or C
CO2Et
CO2Et
10
9
Entry
Substrate
R1
R2
Method
Product
10a
Yieldb (%) (ratio cis/trans)
79 (30:70)c
1
2
3
4
5
6
7
9a
9c
9d
9e
9g
9h
9j
Et
Bn
A
A
B
A
A
C
C
i-Pr
Bn
Bn
10c
89 (18:82)
Bn
10d
10e
76 (25:75)
CH2Ard
Bn
91 (13:87)
(CH2)2CH=CHCO2Et
Bn
10g
73 (26:74)
Et
(CH2)2Ard
(CH2)2Ard
10h
10j
82 (37:63)
Bn
95 (22:78)
a Method A: NaBH3CN, ZnCl2, MeOH, r.t.; B: 1. TFA, Et2O, 0 °C; 2. evaporate; 3. NaBH4, EtOH, 0 °C to r.t.; C: Pd/C, H2.
b Yield of isolated pure product.
c Ref. 2.
d Ar = 3,4-dimethoxyphenyl.
400 mesh). NMR spectra were obtained at 250 MHz for 1H and 62.9
1H NMR: d = 1.24 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 2.52–2.54 (br,
MHz for 13C with CDCl3 as solvent and internal reference [d = 7.26
2 H), 2.74–2.76 (br, 2 H), 3.38–3.40 (br, 4 H), 3.85 (s, 3 H), 3.86 (s,
(1H), d = 77.0 (13C)]. The DEPT sequence was routinely used for 13
C
3 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.67–6.81 (m, 3 H).
multiplicity assignment. IR data include only characteristic absorp-
tions. Mass spectra were obtained at 70 eV. The following com-
pounds have been previously reported: 8a,7 8c,6a 9a,2 9c,2 9d,2,7 9e,7
and 10a.9
13C NMR: d = 14.0, 28.2, 33.3, 33.9, 34.7, 43.5, 43.7, 49.7, 49.9,
55.5, 55.6, 60.3, 79.3, 79.4, 111.0, 111.8, 120.5, 131.5, 147.3,
148.6, 154.9, 171.7, 171.9.
Anal. Calcd for C20H31NO6: C, 62.96; H, 8.20; N, 3.67. Found: C,
62.80; H, 8.26; N, 3.51.
Ethyl 3-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}propanoate
(12)
Ethyl acrylate (19.3 mL, 0.178 mol) was added to a soln of 2-(3,4-
dimethoxyphenyl)ethylamine (30.7 mL, 0.178 mol) in anhyd EtOH
(135 mL) at r.t. The resulting mixture was stirred for 25 h and evap-
orated under reduced pressure to afford 12 (50.1 g, quantitative) as
an orange oil.
tert-Butyl [2-(3,4-Dimethoxyphenyl)ethyl](3-oxopropyl)car-
bamate (14)
A 1 M soln of DIBAL-H in hexanes (3.3 mL, 3.3 mmol) was added
dropwise to a soln of 13 (1.0 g, 2.6 mmol) in toluene (8 mL) at –78
°C under argon. The resulting mixture was stirred for 10 min and
anhyd EtOH (0.13 mL) was added dropwise, followed by
Na2SO4·10 H2O (200 mg). The mixture was then allowed to warm
to r.t. and it was filtered over Celite. The solid was washed with
EtOAc (150 mL) and the combined filtrate and washings were
evaporated to dryness. The crude product was purified by flash
chromatography (hexanes–EtOAc, 72:28) to yield 14 (0.55 g, 61%)
as a colorless oil as a rotamer mixture.
IR (neat): 1725 (CHO), 1695 cm–1 (NCO).
1H NMR: d = 1.40 (br s, 9 H), 2.61–2.71 (br, 4 H), 3.38 (br, 4 H),
3.82 (s, 3 H), 3.83 (s, 3 H), 6.65–6.78 (m, 3 H), 9.73 (s, 1 H).
13C NMR: d = 28.2, 34.0, 34.7, 41.4, 43.2, 43.6, 49.7, 50.0, 55.7,
55.7, 79.6, 79.9, 111.1, 111.8, 120.6, 131.5, 147.4, 148.7, 154.9,
155.2, 200.7, 201.1.
IR (neat): 3320 (N–H), 1735 cm–1 (C=O).
1H NMR: d = 1.07 (t, J = 7.1 Hz, 3 H), 1.19 (br s, 1 H), 2.33 (t,
J = 6.5 Hz, 2 H), 2.55–2.61 (m, 2 H), 2.68–2.77 (m, 4 H), 3.68 (s, 3
H), 3.71 (s, 3 H), 3.95 (q, J = 7.1 Hz, 2 H), 6.57–6.66 (m, 3 H).
13C NMR: d = 13.7, 34.3, 35.4, 44.5, 50.7, 55.2, 55.3, 59.8, 110.7,
111.4, 120.0, 132.0, 146.8, 148.3, 172.1.
HRMS: m/z [M]+ calcd for C15H23NO4: 281.1627; found: 281.1637.
Ethyl 3-{(tert-Butoxycarbonyl)[2-(3,4-dimethoxyphenyl)eth-
yl]amino}propanoate (13)
(Boc)2O (0.34 mL, 1.47 mmol) was added to a soln of 12 (412 mg,
1.47 mmol) in EtOAc (1 mL) at 0 °C. The resulting mixture was al-
lowed to warm to r.t. and stirred for 20 h. After dilution with EtOAc
(9 mL) the soln was washed successively with 1 M HCl (5 mL), sat.
NaHCO3 (5 mL), and brine (5 mL) and dried (Na2SO4). After evap-
oration, the crude product was purified by flash chromatography
(hexanes–EtOAc, 80:20) to yield 13 (510 mg, 91%) as a pale yellow
oil as a rotamer mixture.
HRMS: m/z [M]+ calcd for C18H27NO5: 337.1889; found: 337.1890.
Ethyl 5-{(tert-Butoxycarbonyl)[2-(3,4-dimethoxyphenyl)eth-
yl]amino}pent-2-enoate (15)
A soln of Ph3P=CHCO2Et (661 mg, 1.8 mmol) and 14 (552 mg, 1.6
mmol) in CH2Cl2 (6 mL) was stirred at r.t. for 11 h and then it was
evaporated under reduced pressure. The residue was purified by
flash chromatography (hexanes–EtOAc, 80:20) to yield (Z)-15 (21
IR (neat): 1740 (C=O), 1700 cm–1 (NCO).
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PAPER
A Two-Step Synthesis of 3,4-Disubstituted Piperidines
609
mg, 3%) and (E)-15 (548 mg, 83%) as rotamer mixtures; ratio Z/E
4:96.
2.52–2.81 (m, 4 H), 3.91 (s, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 5.81 (s,
1 H), 7.22–7.35 (m, 5 H).
13C NMR: d = 14.0, 14.2, 22.4, 27.4, 30.3, 30.8, 32.4, 39.7, 43.3,
E-Isomer (E)-15
Colorless oil.
IR (neat): 1720 (C=O), 1695 (NCO), 1655 cm–1 (C=C).
59.6, 60.2, 111.1, 127.0, 128.2, 128.3, 132.4, 138.5, 173.2.
HRMS: m/z [M]+ calcd for C20H29NO2: 315.2198; found: 315.2198.
1H NMR: d = 1.27 (t, J = 7.1 Hz, 3 H), 1.45 (br s, 9 H), 2.36 (br, 2
H), 2.75 (br, 2 H), 3.22–3.33 (br, 4 H), 3.85 (s, 3 H), 3.86 (s, 3 H),
4.17 (q, J = 7.1 Hz, 2 H), 5.81 (d, J = 15.5 Hz, 1 H), 6.66–6.94 (m,
4 H).
13C NMR: d = 14.1, 28.2, 31.2, 31.8, 34.0, 34.7, 46.1, 46.4, 49.3,
49.7, 55.7, 55.7, 60.1, 79.5, 111.1, 111.8, 120.6, 122.8, 131.5,
145.5, 147.3, 148.7, 155.1, 166.1.
Ethyl {1-Benzyl-5-[3-(ethoxycarbonyl)propyl]-1,2,3,4-tetrahy-
dropyridin-4-yl}acetate (9f)
Chromatography: hexanes–Et3N, 98:2; yellowish oil.
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.23 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H),
1.60–1.94 (m, 5 H), 2.00–2.10 (m, 2 H), 2.17–2.34 (m, 2 H), 2.49–
2.57 (m, 2 H), 2.64–2.80 (m, 2 H), 3.91 (s, 2 H), 4.10 (q, J = 7.1 Hz,
2 H), 4.11 (q, J = 7.1 Hz, 2 H), 5.81 (s, 1 H), 7.20–7.34 (m, 5 H).
13C NMR: d = 14.2, 23.8, 27.3, 29.9, 32.0, 33.6, 39.6, 43.1, 59.5,
60.1, 60.1, 109.1, 127.0, 128.0, 128.2, 133.2, 138.3, 172.9, 173.8.
Anal. Calcd for C22H33NO6: C, 64.83; H, 8.17; N, 3.44. Found: C,
64.54; H, 8.33; N, 3.75.
Z-Isomer (Z)-15
Colorless oil.
HRMS: m/z [M]+ calcd for C22H31NO4: 373.2253; found: 373.2245.
IR (neat): 1720 (C=O), 1695 (NCO), 1645 cm–1 (C=C).
Ethyl {(E)-1-Benzyl-5-[4-(ethoxycarbonyl)but-3-enyl]-1,2,3,4-
tetrahydropyridin-4-yl}acetate (9g)
Chromatography: hexanes–Et3N, 98:2; yellowish oil.
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.24 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H),
1.60–1.70 (m, 1 H), 1.81–2.44 (m, 6 H), 2.47–2.58 (m, 2 H), 2.58–
2.82 (m, 2 H), 3.92 (s, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 4.18 (q,
J = 7.1 Hz, 2 H), 5.81 (dt, J = 15.7, 1.4 Hz, 1 H), 5.82 (s, 1 H), 6.96
(dt, J = 15.6, 6.6 Hz, 1 H), 7.01–7.35 (m, 5 H).
13C NMR: d = 14.3, 27.4, 30.2, 31.3, 31.6, 39.7, 43.1, 59.5, 60.1,
60.3, 108.6, 121.3, 127.1, 128.1, 128.3, 133.3, 138.4, 149.0, 166.7,
172.9.
1H NMR: d = 1.26 (t, J = 7.1 Hz, 3 H), 1.43 (br s, 9 H), 2.74–2.88
(br, 4 H), 3.25–3.35 (br, 4 H), 3.84 (s, 3 H), 3.86 (s, 3 H), 4.14 (q,
J = 7.1 Hz, 2 H), 5.81 (d, J = 11.5 Hz, 1 H), 6.20 (br, 1 H), 6.70–
6.80 (br, 3 H).
13C NMR: d = 14.1, 27.9, 28.2, 33.9, 34.6, 45.8, 46.5, 48.9, 55.6,
55.7, 59.7, 79.2, 111.0, 111.8, 120.6, 121.1, 131.7, 146.2, 146.5,
147.2, 148.6, 155.3, 166.0.
Anal. Calcd for C22H33NO6: C, 64.83; H, 8.17; N, 3.44. Found: C,
64.75; H, 8.31; N, 3.30.
Ethyl (E)-5-[2-(3,4-Dimethoxyphenyl)ethylamino]pent-2-
enoate (8b)
HRMS: m/z [M]+ calcd for C23H31NO4: 385.2253; found: 373.2258.
TFA (1.5 mL) was added dropwise to a soln of (E)-15 (458 mg, 1.10
mmol) in anhyd CH2Cl2 (8.4 mL) at 0 °C under argon. The mixture
was allowed to warm to r.t. and then stirred for 3 h. After evapora-
tion, the residue was dissolved in EtOAc (20 mL) and the soln was
washed with sat. NaHCO3 (20 mL) and dried (Na2SO4). Solvent
evaporation afforded 8b (346 mg, quantitative yield) as a pale yel-
low oil, which was used without further purification.
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-ethyl-1,2,3,4-tet-
rahydropyridin-4-yl}acetate (9h)
Chromatography: hexanes–EtOAc–Et3N, 90:8:2; pale yellow oil.
IR (neat): 1735 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 0.97 (t, J = 7.4 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H),
1.64–1.74 (m, 1 H), 1.84–1.97 (m, 3 H), 2.09 (dd, J = 15.6, 11.2 Hz,
1 H), 2.53–2.60 (m, 2 H), 2.65–2.78 (m, 2 H), 2.81–2.93 (m, 2 H),
2.97–3.03 (m, 2 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.14 (q, J = 7.1 Hz,
2 H), 5.67 (s, 1 H), 6.70–6.81 (m, 3 H).
IR (neat): 3310 (N–H), 1720 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.28 (t, J = 7.1 Hz, 3 H), 1.72 (br s, 1 H), 2.35–2.42
(m, 2 H), 2.72–2.89 (m, 6 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.17 (q,
J = 7.1 Hz, 2 H), 5.84 (d, J = 15.7 Hz, 1 H), 6.72–6.96 (m, 4 H).
13C NMR: d = 13.3, 14.1, 25.4, 27.5, 30.2, 33.6, 39.6, 43.2, 55.6,
55.7, 57.3, 60.0, 111.0, 111.8, 111.9, 120.4, 130.9, 132.4, 147.1,
148.6, 173.0.
13C NMR: d = 13.9, 32.4, 35.5, 47.6, 50.8, 55.4, 55.5, 59.9, 110.9,
111.5, 120.2, 122.4, 132.0, 146.2, 147.1, 148.5, 166.0.
HRMS: m/z [M]+ calcd for C17H25NO4: 307.1784; found: 307.1790.
HRMS: m/z [M]+ calcd for C21H31NO4: 361.2253; found: 361.2272.
Tetrahydropyridines 9; General Procedure
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-nonyl-1,2,3,4-tet-
rahydropyridin-4-yl}acetate (9i)
Chromatography: hexanes–EtOAc–Et3N, 90:8:2; yellowish oil.
IR (neat): 1735 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 0.87 (t, J = 6.3 Hz, 3 H), 1.26–1.30 (m, 17 H), 1.65–
1.95 (m, 4 H), 2.08 (dd, J = 15.8, 11.5 Hz, 1 H), 2.54–2.60 (m, 2 H),
2.67–2.75 (m, 2 H), 2.86–2.90 (m, 2 H), 2.99 (t, J = 7.7 Hz, 2 H),
3.86 (2 s, 6 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.68 (s, 1 H), 6.70–6.81
(m, 3 H).
13C NMR: d = 14.1, 14.2, 22.6, 27.6, 28.7, 29.3, 29.6, 30.2, 31.9,
32.7, 33.6, 39.7, 43.3, 55.7, 55.8, 57.4, 60.2, 110.7, 111.0, 111.9,
120.5, 131.8, 132.5, 147.2, 148.6, 173.1.
A mixture of amine 8 (1.9 mmol) and aldehyde 4 (1.9 mmol) in an-
hyd solvent (26 mL) was refluxed for the time indicated in Table 1.
Where appropriate (Table 1), 4 Å MS (4.8 g) was also used. After
cooling, the mixture was filtered over Celite and the solvents were
evaporated under reduced pressure. The crude product was purified
by flash chromatography (silica gel saturated with Et3N). Purifica-
tion details and characterization data are provided below for the in-
dividual cases.
Ethyl (1-Benzyl-5-butyl-1,2,3,4-tetrahydropyridin-4-yl)acetate
(9b)
Chromatography: hexanes–Et3N, 98:2; yellowish oil.
IR (neat): 1740 (C=O), 1680 cm–1 (C=C).
1H NMR: d = 0.89 (t, J = 6.9 Hz, 3 H), 1.22–1.45 (m, 7 H), 1.59–
1.69 (m, 1 H), 1.78–2.00 (m, 3 H), 2.06 (dd, J = 15.7, 11.3 Hz, 1 H),
HRMS: m/z [M]+ calcd for C28H45NO4: 459.3349; found: 459.3338.
Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York

610
J. M. Aurrecoechea et al.
PAPER
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-benzyl-1,2,3,4-tet-
rahydropyridin-4-yl}acetate (9j)
product was purified by flash chromatography (silica gel saturated
with Et3N).
Chromatography: hexanes–EtOAc–Et3N, 86:12:2; orange oil.
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
Method C: A deoxygenated mixture of 9 (1.0 mmol), 10% Pd/C (14
mg), and abs EtOH (12 mL) was treated with H2 (1 atm) for 2 h. The
resulting mixture was filtered over Celite, and the solid was washed
with EtOAc (50 mL). The combined filtrate and washings were
evaporated under reduced pressure and the residue after evaporation
was purified by flash chromatography (silica gel saturated with
Et3N). Purification details and characterization data are provided
below for the individual cases.
1H NMR: d = 1.23 (t, J = 7.1 Hz, 3 H), 1.63–1.73 (m, 1 H), 1.77–
1.90 (m, 1 H), 2.10 (dd, J = 14.5, 10.1 Hz, 1 H), 2.38–2.47 (m, 1 H),
2.53 (dd, J = 14.5, 3.5 Hz, 1 H), 2.63–2.81 (m, 2 H), 2.93 (dd,
J = 7.5, 3.9 Hz, 2 H), 3.05 (t, J = 7.6 Hz, 2 H), 3.20 and 3.24 (AB q,
J = 15.3 Hz, 2 H), 3.87 (s, 3 H), 3.87 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2
H), 5.74 (s, 1 H), 6.70–6.82 (m, 3 H), 7.14–7.30 (m, 5 H).
13C NMR: d = 14.2, 27.3, 30.1, 33.8, 39.4, 39.6, 42.8, 55.7, 55.8,
57.2, 60.1, 108.8, 111.1, 111.9, 120.5, 125.7, 128.1, 128.5, 132.4,
133.7, 141.2, 147.2, 148.7, 172.8.
Ethyl (1-Benzyl-3-isopropylpiperidin-4-yl)acetate (10c)
Chromatography: hexanes–Et3N, 99:1; colorless oil; ratio cis/trans
19:81.
IR (neat): 1740 cm–1 (C=O).
HRMS: m/z [M]+ calcd for C26H33NO4: 423.2410; found: 423.2405.
1H NMR: d = 0.79 (d, J = 7.0 Hz, 3 H, trans), 0.87 (d, J = 6.3 Hz, 6
H, cis), 0.90 (d, J = 7.0 Hz, 3 H, trans), 1.24 (t, J = 7.1 Hz, 3 H),
1.22–1.60 (m, 2 H), 1.67–2.39 (m, 6 H), 2.54 (dd, J = 14.7, 4.1 Hz,
1 H), 2.61–2.84 (m, 2 H), 3.40 and 3.56 (AB q, J = 13.1 Hz, 2 H,
trans), 3.43 and 3.57 (AB q, J = 13.1 Hz, 2 H, cis), 4.12 (q, J = 7.1
Hz, 2 H), 7.20–7.34 (m, 5 H).
13C NMR: d = 14.0, 16.1, 20.3 (cis), 21.0, 26.1, 27.2 (cis), 29.2
(cis), 30.1 (cis), 30.6 (cis), 31.4, 34.6, 38.0, 45.4 (trans), 45.7 (cis),
47.6 (cis), 52.8, 52.9, 59.8, 59.9 (cis), 63.3, 126.6, 127.8, 128.7,
138.2, 172.9 (trans), 173.2 (cis).
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-[3-(ethoxycarbon-
yl)propyl]-1,2,3,4-tetrahydropyridin-4-yl}acetate (9k)
Chromatography: hexanes–EtOAc–Et3N, 84:14:2; yellow oil.
IR (neat): 1735 (C=O), 1655 cm–1 (C=C).
1H NMR: d = 1.21–1.28 (m, 6 H), 1.55–1.90 (m, 5 H), 1.92–2.13
(m, 2 H), 2.22–2.32 (m, 2 H), 2.50–2.58 (m, 2 H), 2.63–2.75 (m, 2
H), 2.86–2.90 (m, 2 H), 2.99 (t, J = 7.7 Hz, 2 H), 3.84, 3.85, 3.86 (3
s, 6 H), 4.06–4.17 (m, 4 H), 5.68 (s, 1 H), 6.69–6.80 (m, 3 H).
13C NMR: d = 14.2, 23.8, 27.5, 29.9, 32.0, 33.6, 33.7, 39.6, 43.1,
55.7, 55.8, 57.3, 60.1, 60.2, 108.6, 111.1, 111.9, 120.5, 132.4,
132.6, 147.2, 148.7, 173.0, 173.8.
HRMS: m/z [M]+ calcd for C19H29NO2: 303.2198; found: 303.2195.
HRMS: m/z [M]+ calcd for C25H37NO6: 447.2621; found: 447.2681.
Ethyl (1,3-Dibenzylpiperidin-4-yl)acetate (10d)
Chromatography: hexanes–Et3N, 98:2; pale yellow oils.
Ethyl (1,5-Dibenzyl-2-phenyl-1,2,3,4-tetrahydropyridin-4-
yl)acetate (9l)
Chromatography: hexanes–Et3N, 98:2; orange oil; dr 63:37.
trans-Isomer
IR (neat): 1730 cm–1 (C=O).
1H NMR: d = 1.27 (t, J = 7.1 Hz, 3 H), 1.38–1.47 (m, 1 H), 1.66–
1.85 (m, 4 H), 1.95 (td, J = 11.3, 2.5 Hz, 1 H), 2.21 (dd, J = 14.9,
7.9 Hz, 1 H), 2.34 (dd, J = 13.6, 8.2 Hz, 1 H), 2.65–2.76 (m, 3 H),
2.94 (dd, J = 13.6, 2.1 Hz, 1 H), 3.28 and 3.53 (AB q, J = 13.1 Hz,
2 H), 4.15 (q, J = 7.1 Hz, 2 H), 7.12–7.30 (m, 10 H).
13C NMR: d = 14.2, 31.2, 37.5, 38.0, 38.7, 42.0, 52.4, 58.5, 60.2,
63.1, 125.8, 126.8, 128.0, 128.2, 129.0, 129.0, 138.2, 140.2, 173.0.
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.14 and 1.18 (2 t, J = 7.1 Hz, 3 H), 1.77–2.15 (m, 3
H), 2.40–2.57 and 2.69–2.72 (2 m, 2 H), 3.21–3.35 (m, 2 H), 3.63
and 3.66 (2 d, J = 14.6 Hz, 1 H), 3.84 (td, J = 10.7, 3.1 Hz, 1 H),
3.91–4.08 (m, 3 H), 5.99 (s, 1 H), 7.04–7.39 (m, 15 H).
13C NMR: d = 14.1, 14.2, 30.6, 31.5, 37.4, 37.9, 38.5, 39.5, 39.7,
39.9, 55.6, 55.7, 60.1, 60.2, 110.3, 110.5, 125.8, 125.9, 127.1,
127.2, 127.2, 127.3, 128.2, 128.2, 128.2, 128.4, 128.5, 128.5, 128.6,
128.6, 128.7, 134.2, 135.1, 137.7, 137.8, 140.6, 141.1, 142.9, 143.0,
172.6, 172.8.
Anal. Calcd for C23H29NO2: C, 78.58; H, 8.32; N, 3.99. Found: C,
78.26; H, 8.42; N, 3.86.
cis-Isomer
HRMS: m/z [M]+ calcd for C29H31NO2: 425.2355; found: 425.2353.
IR (neat): 1740 cm–1 (C=O).
1H NMR: d = 1.30 (t, J = 7.1 Hz, 3 H), 1.53–1.72 (m, 2 H), 1.89–
2.25 (m, 4 H), 2.33–2.62 (m, 4 H), 2.80–2.92 (m, 2 H), 3.38 and
3.46 (AB q, J = 13.0 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 7.05–7.37
(m, 10 H).
13C NMR: d = 14.3, 28.2, 32.4 (br), 36.0 (br), 37.5 (br), 40.4, 53.2
(br), 55.5, 60.2, 63.2, 125.5, 126.8, 128.1, 129.2, 138.9, 141.4,
172.9.
Piperidines 10; General Procedures
Method A: 0.5 M ZnCl2 in THF (4.1 mL, 2.05 mmol) was added to
a suspension of NaBH3CN (0.268 g, 4.20 mmol) in MeOH (2.9 mL)
under argon, and the mixture was stirred at r.t. for 1 h and then add-
ed to a soln of 9 (2.02 mmol) in MeOH (4.4 mL). The soln was
stirred further 2 h and poured over 1 M NaOH (50 mL). The mixture
was extracted with EtOAc (3 × 50 mL) and the combined organic
layers were dried (Na2SO4). After evaporation, the residue was pu-
rified by flash chromatography (silica gel saturated with Et3N).
Anal. Calcd for C23H29NO2: C, 78.58; H, 8.32; N, 3.99. Found: C,
78.25; H, 8.47; N, 3.86.
Method B: TFA (2.57 mmol) was added dropwise to a soln of 9
(1.85 mmol) in Et2O (28 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 30 min, allowed to warm to r.t. and evaporated
under reduced pressure. The residue was dissolved in anhyd EtOH
(7 mL) and to the cool soln (0 °C) NaBH4 (3.80 mmol) was added.
The resulting mixture was allowed to warm to r.t. and evaporated
under reduced pressure. After addition of 1 M KOH (25 mL), the
soln was extracted with CH2Cl2 (3 × 25 mL), and the combined or-
ganic extracts were dried (Na2SO4). After evaporation, the crude
Ethyl [1-Benzyl-3-(3,4-dimethoxybenzyl)piperidin-4-yl]acetate
(10e)
Chromatography: hexanes–EtOAc–Et3N, 86:12:2; light yellow oils.
trans-Isomer
IR (neat): 1730 cm–1 (C=O).
1H NMR: d = 1.24 (t, J = 7.1 Hz, 3 H), 1.35–1.45 (m, 1 H), 1.64–
1.79 (m, 4 H), 1.93 (td, J = 11.3, 2.5 Hz, 1 H), 2.17 (dd, J = 14.9,
7.9 Hz, 1 H), 2.26 (dd, J = 13.8, 8.1 Hz, 1 H), 2.62–2.75 (m, 3 H),
Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York

PAPER
A Two-Step Synthesis of 3,4-Disubstituted Piperidines
611
2.86 (dd, J = 13.7, 2.0 Hz, 1 H), 3.30 and 3.50 (AB q, J = 13.1 Hz,
2 H), 3.84 (s, 6 H), 4.12 (q, J = 7.1 Hz, 2 H), 6.62–6.66 (m, 2 H),
6.74 (d, J = 8.7 Hz, 1 H), 7.19–7.25 (m, 5 H).
13C NMR: d = 14.2, 31.3, 37.5, 37.6, 38.7, 42.0, 52.5, 55.7, 55.8,
58.5, 60.2, 63.2, 111.0, 112.0, 120.9, 126.8, 128.0, 129.0, 132.7,
138.1, 147.1, 148.6, 173.0.
13C NMR: d = 10.5 (trans), 11.5 (cis), 13.8, 20.0 (br, cis), 23.2,
28.2, 31.3, 32.8, 32.9, 34.0 (br, cis), 34.6 (br, cis), 36.7 (trans), 38.0,
39.4 (cis), 41.4 (trans), 51.5 (br, cis), 53.0, 54.7, 55.1, 55.2, 58.0,
59.6, 60.5, 60.6, 110.6 (cis), 110.6 (trans), 111.4, 119.9, 132.6
(trans), 132.7 (cis), 146.6 (cis), 146.7 (trans), 148.2 (cis), 148.2
(trans), 172.5 (trans), 172.6 (cis).
HRMS: m/z [M]+ calcd for C21H33NO4: 363.2410; found: 363.2408.
Anal. Calcd for C25H33NO4: C, 72.95; H, 8.09; N, 3.41. Found: C,
73.07; H, 8.17; N, 3.30.
Ethyl {3-Benzyl-1-[2-(3,4-dimethoxyphenyl)ethyl]piperidin-4-
yl}acetate (10j)
Chromatography: hexanes–EtOAc–Et3N, 78:20:2; colorless oil;
ratio cis/trans 22:78.
cis-Isomer
IR (neat): 1740 cm–1 (C=O).
1H NMR: d = 1.26 (t, J = 7.1 Hz, 3 H), 1.52–1.68 (m, 2 H), 1.87–
1.93 (m, 1 H), 2.02–2.22 (m, 3 H), 2.30–2.48 (m, 2 H), 2.53 (dd,
J = 13.0, 3.9 Hz, 2 H), 2.74–2.84 (m, 2 H), 3.40 (s, 2 H), 3.77 (s, 3
H), 3.82 (s, 3 H), 4.15 (q, J = 7.1 Hz, 2 H), 6.58 (dd, J = 8.1, 1.9 Hz,
1 H), 6.66 (d, J = 1.9 Hz, 1 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.19–7.34
(m, 5 H).
IR (neat): 1730 cm–1 (C=O).
1H NMR: d = 1.26 (t, J = 7.1 Hz, 3 H), 1.41–1.51 (m, 1 H), 1.63–
1.72 (m, 3 H), 1.81–1.87 (m, 1 H), 1.95–2.04 (m, 1 H), 2.15–2.31
(m, 2 H), 2.37–2.78 (m, 6 H), 2.92–2.99 (m, 2 H), 3.81–3.85 (m, 6
H), 4.10–4.19 (m, 2 H), 6.63–6.79 (m, 3 H), 7.07–7.28 (m, 5 H).
13C NMR: d = 14.2, 28.1, 32.1 (br), 35.6 (br), 37.2 (br), 40.3, 52.8
(br), 55.6, 55.6, 55.7, 60.1, 63.0, 110.9, 112.2, 121.0, 126.7, 128.0,
128.9, 133.8, 138.8, 146.8, 148.5, 172.8.
13C NMR: d = 14.1, 28.2 (cis), 31.5, 33.1, 35.5 (cis), 36.7 (trans),
37.7 (trans), 37.8, 38.6, 40.1 (cis), 42.0 (trans), 53.0, 55.1 (cis),
55.5, 55.7, 55.7 (cis), 58.5, 60.2, 60.7, 110.9, 111.6 (trans), 111.8
(cis), 120.2 (trans), 120.4 (cis), 125.6 (cis), 125.8 (trans), 128.0
(cis), 128.1 (trans), 128.8 (trans), 129.0 (cis), 132.8 (trans), 133.2
(cis), 139.9 (trans), 141.1 (cis), 147.0, 148.5, 172.8 (cis), 172.8
(trans).
HRMS: m/z [M]+ calcd for C25H33NO4: 411.2410; found: 411.2409.
Ethyl {1-Benzyl-3-[3-(ethoxycarbonyl)but-3-enyl]piperidin-4-
yl}acetate (10g)
Chromatography: hexanes–EtOAc–Et3N, 96:2:2; pale yellow oils.
HRMS: m/z [M]+ calcd for C26H35NO4: 425.2566; found: 425.2572.
trans-Isomer
Debenzylated Piperidines 11; General Procedure
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
A deoxygenated mixture of 9 (1.5 mmol), 10% Pd/C (22 mg), and
EtOH (7 mL) was treated with H2 (3.45 bar) at r.t. for 48 h. The mix-
ture was filtered through Celite, which was washed with CH2Cl2
(100 mL). The combined filtrate and washings were evaporated un-
der reduced pressure and the residue was purified by flash chroma-
tography (silica gel saturated with Et2NH). Purification details and
characterization data are provided below for the individual cases.
1H NMR: d = 1.24 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H),
1.32–1.45 (m, 3 H), 1.46–1.77 (m, 4 H), 1.98–2.25 (m, 4 H), 2.52
(dd, J = 15.0, 4.3 Hz, 1 H), 2.76–2.81 (m, 1 H), 2.83–2.88 (m, 1 H),
3.45 and 3.51 (AB q, J = 13.2 Hz, 2 H), 4.07–4.21 (m, 4 H), 5.75
(dt, J = 15.6, 1.4 Hz, 1 H), 6.89 (dt, J = 15.6, 6.9 Hz, 1 H), 7.20–
7.37 (m, 5 H).
13C NMR: d = 14.2, 29.2, 29.5, 31.3, 37.1, 38.4, 39.8, 53.1, 58.0,
60.1, 60.3, 63.2, 121.4, 126.9, 128.1, 129.0, 138.2, 148.7, 166.5,
173.0.
Ethyl (3-Isopropylpiperidin-4-yl)acetate (11c)
Chromatography: EtOAc–Et2NH, 98:2; colorless oil; ratio cis/trans
26:74.
IR (neat): 3300 (N–H), 1735 cm–1 (C=O).
HRMS: m/z [M]+ calcd for C23H33NO4: 387.2410; found: 387.2406.
1H NMR: d = 0.78 (d, J = 7.1 Hz, 3 H, trans), 0.88 (d, J = 6.0 Hz, 6
H, cis), 0.92 (d, J = 7.0 Hz, 3 H, trans), 1.09–1.30 (m, 5 H), 1.23 (t,
J = 7.1 Hz, included in m at d = 1.09–1.30), 1.57–2.05 (m, 4 H),
2.21–3.02 (m, 6 H), 4.10 (q, J = 7.1 Hz, 2 H).
13C NMR: d = 14.1, 15.9, 20.0, 21.0, 21.1, 26.1, 27.3, 30.7, 32.9,
35.4, 38.5, 40.7, 45.2, 45.5, 46.5, 47.0, 47.2, 60.0, 60.1, 173.1,
173.5.
cis-Isomer
IR (neat): 1730 (C=O), 1660 cm–1 (C=C).
1H NMR: d = 1.22 (t, J = 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H),
1.19–1.36 (m, 1 H), 1.51–1.62 (m, 4 H), 1.85–2.27 (m, 5 H), 2.22
(d, J = 7.6 Hz, 2 H), 2.46 (br, 1 H), 2.64 (br, 1 H), 3.30 and 3.51 (AB
q, J = 13.1 Hz, 2 H), 4.05–4.19 (m, 4 H), 5.72 (d, J = 15.6 Hz, 1 H),
6.89 (dt, J = 15.4, 7.0 Hz, 1 H), 7.17–7.32 (m, 5 H).
13C NMR: d = 14.1, 24.8 (br), 28.2, 29.7, 35.2 (br), 36.3 (br), 37.1,
52.9 (br), 55.1, 60.0, 60.1, 63.0, 121.2, 126.8, 128.0, 128.7, 138.8,
149.0, 166.5, 172.8.
HRMS: m/z [M]+ calcd for C12H23NO2: 213.1729; found: 213.1723.
Ethyl {3-[3-(Ethoxycarbonyl)propyl]piperidin-4-yl}acetate
(11f)
Chromatography: EtOAc–Et2NH, 98:2 EtOAc–Et2NH; pale yellow
oil; ratio cis/trans 30:70.
Anal. Calcd for C23H33NO4: C, 71.27; H, 8.59; N, 3.62. Found: C,
71.43; H, 8.61; N, 3.31.
IR (neat): 3340 (N–H), 1740 cm–1 (C=O).
Ethyl {1-[2-(3,4-Dimethoxyphenyl)ethyl]-3-ethylpiperidin-4-
yl}acetate (10h)
Chromatography: hexanes–EtOAc–Et3N, 84:14:2; pale yellow oil;
1H NMR: d = 1.07–1.25 (m, 2 H), 1.22 (t, J = 7.1 Hz, 6 H), 1.27–
1.76 (m, 7 H), 2.02 (dd, J = 14.8, 8.9 Hz, 1 H, trans), 2.14–2.31 (m,
3 H), 2.49–3.12 (m, 4 H), 4.09 (q, J = 7.1 Hz, 4 H).
ratio cis/trans 37:63.
IR (neat): 1730 cm–1 (C=O).
13C NMR: d = 14.1, 21.9, 22.7, 26.1, 29.0, 30.4, 32.6, 34.3, 34.4,
35.2, 35.9, 37.8, 38.1, 38.8, 41.3, 44.7, 46.3, 48.4, 51.3, 60.1, 173.0,
173.4, 173.4.
1H NMR: d = 0.86–0.94 (m, 3 H), 1.05–1.46 (m, 6 H), 1.26 (t,
J = 7.1 Hz, included in m at d = 1.05–1.46), 1.51–1.81 (m, 3 H),
1.93–2.08 (m, 1 H), 2.17–2.64 (m, 6 H), 2.67–2.79 (m, 2 H), 2.95–
3.04 (m, 1 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.13 (q, J = 7.1 Hz, 2 H),
6.72–6.81 (m, 3 H).
HRMS: m/z [M]+ calcd for C15H27NO4: 285.1940; found: 285.1938.
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J. M. Aurrecoechea et al.
PAPER
(7) Aurrecoechea, J. M.; Fernandez, A.; Gorgojo, J. M.; Saornil,
C. Tetrahedron 1999, 55, 7345.
Acknowledgment
(8) This was indicated by the presence in the crude 1H NMR
spectrum of new doublets at ca. d = 5.3 and 6.8 ppm
replacing the characteristic phenylacetaldehyde signals.
(9) Bonjoch, J.; Linares, A.; Guardià, M.; Bosch, J.
Heterocycles 1987, 26, 2165.
Financial support by Janssen-Cilag is gratefully acknowledged.
References
(1) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org.
Chem. 1994, 59, 3939.
(2) Aurrecoechea, J. M.; Gorgojo, J. M.; Saornil, C. J. Org.
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(10) Whitesell, J. K.; Minton, M. A. Stereochemical Analysis of
Alicyclic Compounds by C-13 NMR Spectroscopy; Chapman
and Hall: London, 1987.
(11) Yadav, V.; Fallis, A. G. Can. J. Chem. 1991, 69, 779.
(12) Stereochemical elucidation based on NOE measurements
was impractical in this case due to signal overlap. In
previous work, we have confirmed the validity of
assignments based on the observation of g-gauche effects
using NOE studies on related piperidine derivatives (see ref.
3).
(13) Also characteristic of the cis-isomers was the room
temperature broadening of some of the 13C NMR
resonances, because of conformational interconversion
between two equatorial/axial conformers, whereas the
corresponding signals in the diequatorial trans-isomers were
sharp.
(3) Aurrecoechea, J. M.; Suero, R.; de Torres, E. J. Org. Chem.
2006, 71, 8767.
(4) Aurrecoechea, J. M.; Coy, C. A.; Patino, O. J. J. Org. Chem.
2008, 73, 5194.
(5) For reviews on synthetic approaches to piperidines, see:
Hopper, D. W.; Kutterer, K. M. K.; Crombie, A. L.;
Clemens, J. J. In Progress in Heterocyclic Chemistry, Vol.
20; Gribble, G. W.; Joule, J. A., Eds.; Elsevier: Oxford,
2009, 289–332; and previous volumes in the series.
(6) (a) Bustos, F.; Gorgojo, J. M.; Suero, R.; Aurrecoechea, J.
M. Tetrahedron 2002, 58, 6837. (b) Aurrecoechea, J. M.;
Fernandez, A.; Gorgojo, J. M.; Suero, R. Synth. Commun.
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Synthesis 2010, No. 4, 605–612 © Thieme Stuttgart · New York