A Novel Route to 6-Substituted Piperidin-3-ols via Domino Cyclization of 2-Hydroxy-6-phosphinyl-5-hexenyl Tosylates with Primary Amines: Synthesis of (±)-Pseudoconhydrine and (±)- epi -Pseudoconhydrine

Article abstract of DOI:10.1055/s-0033-1338629

2-Hydroxy-6-phosphinyl-5-hexenyl tosylates, oxirane ring-opening products derived from glycidyl tosylates and phosphinyl-substituted allyl anions, undergo domino S_N2-Michael reactions with primary amines to give 6-phosphinylmethylpiperidin-3-ols. The phosphinyl unit can be used in Horner olefination reactions. This approach is applied to the synthesis of racemic pseudoconhydrine and its epimer.

Full text of DOI:10.1055/s-0033-1338629

2506▌
PAPER
paper
A Novel Route to 6-Substituted Piperidin-3-ols via Domino Cyclization of
2-Hydroxy-6-phosphinyl-5-hexenyl Tosylates with Primary Amines: Synthesis
of (±)-Pseudoconhydrine and (±)-epi-Pseudoconhydrine
A Novel Route to 6-Substituted Piperidin-3-ols
Cathrin Scherner,a Jens-Kerim Ergüden,a Gunadi Adiwidjaja,b Ernst Schaumann*a
a
Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722858; E-mail: ernst.schaumann@tu-clausthal.de
b
University of Hamburg, Mineralogisch-Petrographisches Institut, Grindelallee 46, 20146 Hamburg, Germany
Received: 02.03.2014; Accepted after revision: 04.04.2014
conveniently by a primary amine. In addition, a phos-
Abstract: 2-Hydroxy-6-phosphinyl-5-hexenyl tosylates, oxirane
phinyl moiety offers a handle for subsequent olefination
ring-opening products derived from glycidyl tosylates and phos-
chemistry (Scheme 1).
phinyl-substituted allyl anions, undergo domino SN2–Michael reac-
tions with primary amines to give 6-phosphinylmethylpiperidin-3-
ols. The phosphinyl unit can be used in Horner olefination reac-
tions. This approach is applied to the synthesis of racemic pseudo-
conhydrine and its epimer.
HO
HO
HO
HO
HO
HO
HO
N
H
(CH2)12COMe
N
H
8
Key words: phosphine oxides, domino reactions, cyclization,
piperidines, Horner olefination
O
1
2
OH
OH
OH
The piperidine ring represents an important structural mo-
tif in natural products making the synthesis of this hetero-
cycle the subject of continuing research.1–3 In particular,
substituted 3(5)-hydroxypiperidine units are present in
many alkaloids showing a broad spectrum of biological
and pharmacological properties.4,5 Typical examples in-
clude cassine (1),6 prosophylline (2),7 1-deoxyaltronojiri-
H
OH
N
H
N
Me
3
4
mycin
(3),8
(–)-5-hydroxysedamine
(4),9
and
pseudoconhydrine (5)10 (Figure 1). The 3-hydroxypiperi-
dine 5 is a well-known alkaloid first isolated in 1891 from
poison hemlock (Conium maculatum), along with four
other alkaloids.10 Various syntheses of racemic11 and of
enantiomerically pure12 pseudoconhydrine have been re-
ported. In the early syntheses, the substituted piperidine
was obtained by hydrogenation of the corresponding pyr-
idine,11a–c,12e but methods in which the piperidine ring is
elaborated indirectly into the target molecule also rely on
the parent pyridine.11e–g,i,k In asymmetric syntheses, the
piperidine ring is often formed by an SN reac-
tion11j,12a,b,d,f,g,l or by a cyclocondensation between an
amine unit and a carbonyl group.11d,12c,h,k,n,q Important
methods include ring enlargement of pyrrolidines,11h,12i
(cyclo)addition methods,12j,m,r a metathesis reaction,12o
and hydroformylation.12p If the source of the ring nitrogen
in the target molecule is not a pyridine nitrogen, then the
synthetic methodology often requires that the ring nitro-
gen be introduced in a higher oxidation state (nitro,11d hy-
droxylamine,11h,12h nitroso,12c or azide12d,f,j), or indirectly
as a nitrile group.11j We herein report a synthesis of 3-hy-
droxypiperidines in which the ring closure occurs in a
domino fashion and where the ring nitrogen is supplied
N
H
N
H
5
epi-5
Figure 1 Important types of naturally occurring 3(5)-hydroxypiper-
idines
HO
HO
O
P
TsO
a
N
R
Ph
O
Ph
P
Ph
Ph
b
6
NH2
R
Scheme 1 Domino process of nucleophilic attack (a) and Michael-
type addition (b) of a primary amine on 2-hydroxy-6-diphenyl-
phosphinyl-5-hexenyl tosylate (6)
The key intermediate is 2-hydroxy-6-diphenylphos-
phinyl-5-hexenyl tosylate (6). We had reported earlier that
this compound could be prepared conveniently by addi-
tion of tosylated glycidol to the anion of phosphine oxide
7 (Scheme 2).13 If toluene is employed as the solvent, the
reaction proceeds with high γ-selectivity, that is, at the un-
substituted terminus of the allyl system to create the elec-
tron-poor alkene double bond in 6.13 Thus, together with
SYNTHESIS 2014, 46, 2506–2514
Advanced online publication: 23.06.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338629; Art ID: ss-2014-t0154-op
© Georg Thieme Verlag Stuttgart · New York

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A Novel Route to 6-Substituted Piperidin-3-ols
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RNH2 (8), Et3N
O
1. n-BuLi, –78 °C
2.
EtOH, 60 °C
PPh2
6
O
α
γ
, BF ·OEt , –78 °C
OTs
3
2
7
HO
HO
HO
O
O
+
PPh2
PPh2
RHN
N
R
N
R
PPh2
O
9
cis-10
trans-10
8–10 see Table 1
Scheme 2 Formation of phosphine intermediate 6 and subsequent domino reactions with primary amines 8
the tosyloxy-substituted carbon, intermediate 6 represents
a dication equivalent. The reaction with primary amines,
which can act as bidentate nucleophiles, should allow the
domino process outlined in Scheme 1.
Table 1 Cyclization of Alkene 6 with Different Primary Amines 8
Amine
Product
Yield of Yield of
(total yield)
cis-10
trans-10
The reaction of 6 with model amine 8h turned out to be
rather slow. The optimum conditions involved heating the
reaction mixture at 60 °C in methanol or ethanol in the
presence of triethylamine for two days to give a 65–68%
yield of the cyclization product 10h (Scheme 2). In tert-
butyl alcohol as the solvent and using potassium tert-bu-
toxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tri-
ethylamine as the catalyst, the yields of piperidinol 10h
were only 25%, 29% and 40%, respectively. The use of
pyridine in ethanol as the solvent resulted in a 51% yield
of 10h. The reaction proceeded successfully with un-
branched primary amines 8a–c, as well as with amines
8f,g containing unsaturation and functionalized amines
8h,i (Table 1). However, under the standard reaction con-
ditions, the sterically hindered amine 8d and less nucleo-
philic aniline (8e) reacted via the SN2 process to yield
substitution products 9d,e (Table 1); more vigorous con-
ditions resulted in decomposition. It was not possible to
employ N-unsubstituted amides such as benzamide in the
tandem cyclization as only complex mixtures were ob-
tained. The formation of amines 9d,e indicates that the
successful domino cyclizations of the other amines 8 are
initiated by the substitution step, and that this is followed
by a Michael-type addition to the vinyl phosphine unit in
intermediates 9a–c,f–i, and not via the reverse sequence.
This reaction course is in line with the mechanism pro-
posed by Bunce et al. for the cyclization of ω-iodo-alke-
noates with benzylamine.14 The same should hold for a
mesylate substitution and Michael sequence of mesyloxy-
alkenoates.15
EtNH2 (8a)
10a (62%)
10b (87%)
10c (86%)
9d (73%)
9e (54%)
30%
31%
42%
–
29%
36%
28%
–
n-PrNH2 (8b)
BuNH2 (8c)
t-BuNH2 (8d)
PhNH2 (8e)
–
–
BnNH2 (8f)
10f (85%)
10g (73%)
10h (68%)
10i (78%)
36%
37%
34%
22%
48%
35%
34%
56%
allylNH2 (8g)
H2NCH2CH(OMe)2 (8h)
H2NCH2CH2OTBDMS (8i)
the cis- or trans-configuration to these diastereomers
based on the NMR coupling constants. After some exper-
imentation, we observed that a crystalline phenyl urethane
11 was formed from the predominating diastereomer of
piperidinol 10f and phenyl isocyanate (Scheme 3). An X-
ray structural investigation of a suitable crystal revealed
the trans-arrangement of the 5-carbamate and the 2-phos-
phinylmethyl substituents (Figure 2).16 Hence the starting
material was trans-10f, which is consequently the major
diastereomer and that which eluted second. Based on this
information, comparison of the NMR data of 10f with the
other piperidinols 10 allowed assignment of the configu-
rations of all products 10 (Table 1).
PhNHCOO
PhNCO, 4-DMAP, Et2O
79%
O
trans-10f
PPh2
The Michael-type addition of the secondary amine unit in
9 may occur at the Re or Si face of the vinyl phosphine
moiety. In fact, piperidinols 10 were formed as mixtures
of diastereomers. The diastereoselectivity was moderate
(Table 1), but the two diastereomers could be separated
easily by column chromatography, with the minor diaste-
reomer being eluted first. We found it difficult to assign
N
Bn
11
Scheme 3 Addition of phenyl isocyanate to piperidinol trans-10f to
give carbamate 11
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2506–2514

2508
C. Scherner et al.
PAPER
To allow the use of a strong base in the olefination chem-
istry, the secondary alcohol functionality of diastereomer
trans-10f [isolated by column chromatography from the
reaction of 6 and benzylamine (see Scheme 3)] was pro-
tected by benzylation to give trans-12 (Scheme 4). Chain
elongation of the C-2 substituent was achieved by a two-
step Horner reaction using acetaldehyde as the carbonyl
component. The reaction first provided the α-hydroxy ad-
dition product, which was transformed into the alkene,
trans-13, using sodium hydride and N,N-dimethylform-
amide at 60 °C. The product was formed with moderate
Figure 2 X-ray crystal structure of trans-N-phenyl urethane deriva- trans-selectivity (E/Z = 67:33), which may reflect the
tive 11
similar steric requirements of the diphenylphosphinyl
group and the piperidine heterocycle in the Horner inter-
mediate. Reductive removal of the O- and N-benzyl pro-
tecting groups and simultaneous reduction of the double
bond was achieved by hydrogenation using palladium on
carbon as the catalyst to provide the target molecule, pseu-
doconhydrine (5). The structure of 5 was confirmed by
comparison of its NMR data,11h,12h and those of its hydro-
chloride salt (5·HCl)12r with literature values, which
proved to be identical.
In addition to the convenient one-step formation of piper-
idinols from a readily accessible precursor and different
amines as the nitrogen source, the presence of the phos-
phine oxide unit in 10 is an especially attractive feature for
subsequent Horner olefination chemistry. In this context,
an obvious target among naturally occurring piperidinols
was pseudoconhydrine (5; Figure 1). This synthesis would
require removal of the exocyclic substituent on nitrogen in
precursor 10, which should be possible, most convenient-
ly, with the benzyl residue in 10f. As this compound is
available in both its cis and trans forms, a synthesis of the
unnatural diastereomer, epi-pseudoconhydrine (epi-5),
can be envisaged using the same synthetic manipulations
starting from cis-10f (Scheme 4).
The synthesis of epi-5 was achieved along similar lines
(Scheme 4). In a modification, the reduction of alkene 13
into epi-5 was carried out in two steps, as the direct con-
version of trans-13 into 5 gave a rather modest yield. Ini-
tial exposure of cis-13 to an atmosphere of hydrogen in
the presence of Pearlman’s catalyst [Pd(OH)2/C] in eth-
anol–hydrochloric acid gave the partly cleaved and re-
duced product 14. As expected, in the presence of the
amine function,17 the O–Bn bond survived the reduction
reaction. In a second hydrogenation step using palladium
on charcoal (Pd/C) as the catalyst, epi-pseudoconhydrine
(epi-5) was formed. The structural assignment of epi-5
was based on the spectroscopic data, which were quite
similar to those of pseudoconhydrine (5).
BnO
O
a
b
trans-10f
PPh2
56%
57%
N
Bn
trans-12
BnO
c
5
In summary, we have presented a straightforward, amine-
induced domino cyclization of the phosphinyl-substituted
alcohol 6 to give 2-substituted piperidin-5-ols. Both dia-
stereomers could be isolated by chromatography. The
method was also applied to the synthesis of pseudoconhy-
drine (5) and epi-pseudoconhydrine (epi-5) in only three
or four additional steps following the cyclization. It
should be noted that the procedure may easily be utilized
for the synthesis of optically active 5 and epi-5 if the allyl
derivative 7 is reacted with an enantiomerically enriched
glycidol tosylate. This chiral substrate is readily available
by Sharpless epoxidation of allyl alcohol18 and subse-
quent tosylation.19
N
26%
Bn
trans-13
BnO
BnO
O
a
b
cis-10f
PPh2
61%
56%
N
N
Bn
Bn
cis-12
cis-13
BnO
c
d
epi-5
86%
56%
N
H
Pr
Reactions requiring anhydrous conditions were performed under ni-
trogen. The amines used in this research were purchased from com-
mercial sources, except for amine 8h.20 Column or flash column
chromatography was performed on Macherey–Nagel silica gel (60,
230–400 mesh). Petroleum ether (PE) refers to the fraction boiling
in the 60–70 °C range. Melting points were recorded using a Büchi
instrument according to Dr. Tottoli apparatus and are uncorrected.
FTIR spectra were measured on a Bruker Vektor 22 FT spectropho-
tometer. NMR spectra were measured at 400 MHz or 200 MHz
14
Scheme 4 Synthesis of pseudoconhydrine (5) and the unnatural di-
astereomer, epi-5. Reagents and conditions: (a) (1) NaH, THF, 0 °C
to r.t.; (2) BnBr, Bu4NI (0.2 equiv), 50 °C, 12 h; (b) (1) n-BuLi,
THF, –78 °C; (2) MeCHO, –78 °C → 0 °C; (3) NaH, DMF, 60 °C;
(c) H2, Pd/C, HCl, MeOH; (d) H2, Pd(OH)2/C, HCl, EtOH.
Synthesis 2014, 46, 2506–2514
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A Novel Route to 6-Substituted Piperidin-3-ols
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(1H), 100 or 50 MHz (13C) and 162 MHz (31P) on Bruker ARX-400
and DPX-200 instruments. Deuterated chloroform was used as the
solvent unless otherwise stated. Chemical shifts (δ) are reported rel-
ative to tetramethylsilane (δ = 0 ppm) as an internal standard for 1H
and 13C spectra in CDCl3, Me3SiCD2CD2COONa (δMe = 0 ppm) for
spectra in D2O, and external trimethyl phosphite (shifts corrected
for 80% aq H3PO4 with δ = 0 ppm) for 31P NMR spectra. MS spectra
were recorded using a Hewlett Packard HP 5989 B spectrometer.
High-resolution mass spectra (HRMS) were obtained using a VG
Autospec instrument at the Institut für Organische Chemie, Leibniz-
Universität Hannover. Elemental analyses were performed using a
Carlo Erba 1106 analyzer at the Institut für Pharmazeutische Che-
mie, TU Braunschweig.
cis-10b
Pale yellow solid; mp 38 °C.
IR (KBr): 3347, 3056, 2932, 1662, 1591, 1438, 1169, 1119, 719,
698 cm–1.
1H NMR (200 MHz, CDCl3): δ = 0.75 (t, J = 7.4 Hz, 3 H), 1.17–
3
1.82 (m, 6 H), 2.19–2.67 (m, 6 H), 2.59 (dd, 2J = 11.3 Hz, 3J = 3.8
Hz, 1 H), 3.09 (dddt, 3J = 8.7 Hz, 3J = 8.5 Hz, 3J = 4.0 Hz, 3JPH ≈ 2.0
Hz, 1 H), 3.72 (dddd, 3J = 8.0 Hz, 3J = 8.0 Hz, 3J = 4.0 Hz, 3J = 4.0
Hz, 1 H), 7.39–7.57 (m, 6 H), 7.68–7.83 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 11.7, 19.8, 26.6 (d, JPC = 69.5 Hz),
27.8, 29.1, 52.4, 55.1, 55.8, 66.3, 128.5, 128.8, 130.5, 130.7 (each
d, JPC = 9.2 Hz, 2 C), 131.69, 131.70 (each d, JPC = 2.4 Hz), 133.1
(d, JPC = 98.7 Hz), 133.8 (d, JPC = 99.1 Hz).
cis- and trans-1-Ethyl-6-(diphenylphosphinylmethyl)piperidin-
3-ol (10a); General Procedure
31P NMR (162 MHz, CDCl3): δ = 30.3.
A solution of alkene 613 (361 mg, 0.768 mmol), ethylamine (0.38
mL, 2 M in MeOH, 0.768 mmol) and anhydrous Et3N (0.118 mL,
0.845 mmol) in anhydrous EtOH (4.2 mL) was heated at 60 °C for
2.5 d. The mixture was allowed to cool and then concentrated in
vacuo. The residue was dissolved in a mixture of Et2O–CH2Cl2 (10
mL, 2:1). The organic layer was washed with 1 M NaOH (3 × 5 mL)
and brine (10 mL), dried (MgSO4) and concentrated in vacuo. The
crude mixture of isomeric products was purified by flash column
chromatography (EtOAc–EtOH–Et3N, 40:1:0.5) to give cis-10a (79
mg, 30%), a mixture of cis- and trans-10a (8 mg, 3%) and trans-10a
(77 mg, 29%); total yield: 164 mg (62%).
trans-10b
Pale yellow solid; mp 36 °C.
IR (KBr): 3375, 3057, 2963, 2930, 2872, 1656, 1591, 1438, 1160,
1120, 699 cm–1.
1H NMR (200 MHz, CDCl3): δ = 0.77 (t, J = 7.3 Hz, 3 H), 1.07–
3
1.78 (m, 6 H), 2.14–2.54 (m, 5 H), 2.75 (dd, 2J = 11.9 Hz, 3J = 2.1
Hz, 1 H), 3.10–3.26 (m, 1 H), 3.73–3.84 (m, 1 H), 4.70 (br s, 1 H,
OH), 7.39–7.58 (m, 6 H), 7.61–7.85 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 11.6, 19.6, 25.2 (d, JPC = 69.2 Hz),
25.9, 27.8, 53.0, 54.2, 55.7, 64.9, 128.6, 128.8, 130.5 (d, JPC = 10.2
Hz, 2 C), 130.7 (d, JPC = 9.2 Hz, 2 C), 131.8 (d, JPC = 3.1 Hz, 2 C),
132.6 (d, JPC = 98.7 Hz), 133.5 (d, JPC = 99.7 Hz).
cis-10a
Yellow solid; mp 43 °C.
IR (KBr): 3412, 3055, 2929, 1655, 1591, 1438, 1162, 1119, 696 cm–1.
31P NMR (162 MHz, CDCl3): δ = 30.5.
3
1H NMR (200 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H), 1.38–
HRMS (EI): m/z [M]+ calcd for C21H28NO2P: 357.1858; found:
1.82 (m, 4 H), 2.39–2.73 (m, 6 H), 2.97–3.36 (m, 2 H, CH, OH),
3.70–3.87 (m, 1 H), 7.39–7.58 (m, 6 H), 7.67–7.85 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 10.3, 26.5, 29.0, 29.3 (d, JPC = 69.2
Hz), 47.5, 54.2, 54.9, 64.6, 128.8, 128.9, 130.6, 130.6 (d, JPC = 9.2
Hz, 2 C), 132.0 (d, JPC = 3.1 Hz, 2 C), 132.6 (d, JPC = 100.7 Hz),
132.9 (d, JPC = 99.7 Hz).
31P NMR (162 MHz, CDCl3): δ = 30.0.
HRMS (EI): m/z [M]+ calcd for C20H26NO2P: 343.1701; found:
357.1858.
cis- and trans-1-Butyl-6-(diphenylphosphinylmethyl)piperidin-
3-ol (10c)
Reaction of alkene 6 (354 mg, 0.75 mmol) and n-butylamine (0.07
mL, 0.75 mmol) using the general procedure, and purification by
flash column chromatography (EtOAc–EtOH–Et3N, 40:1:0.5) gave
cis-10c (117 mg, 42%), a mixture of cis- and trans-10c (43 mg,
15.5%) and trans-10c (79 mg, 28.4%); total yield: 239 mg (85.9%).
343.1701.
cis-10c
Pale yellow solid; mp 42 °C.
trans-10a
IR (KBr): 3385, 3057, 2930, 2869, 1657, 1591, 1438, 1163, 1119,
695 cm–1.
Yellow solid; mp 45 °C.
IR (KBr): 3383, 3058, 2964, 2932, 2857, 1652, 1591, 1439, 1178,
1119, 697 cm–1.
1H NMR (200 MHz, CDCl3): δ = 0.80 (t, J = 7.3 Hz, 3 H), 1.06–
3
1.82 (m, 8 H), 2.16–2.52 (m, 6 H), 2.59 (dd, 2J = 11.3 Hz, 3J = 3.5
Hz, 1 H), 3.08 (dddt, 3J = 8.7 Hz, 3J = 8.5 Hz, 3J = 4.3 Hz, 3JPH ≈ 2.5
Hz, 1 H), 3.72 (dddd, 3J = 8.0 Hz, 3J = 8.0 Hz, 3J = 4.0 Hz, 3J = 4.0
Hz, 1 H), 7.38–7.58 (m, 6 H), 7.67–7.84 (m, 4 H).
1H NMR (200 MHz, CDCl3): δ = 0.90 (t, J = 7.2 Hz, 3 H), 1.34–
3
1.83 (m, 4 H), 2.30–2.58 (m, 5 H), 2.74 (dd, 2J = 11.9 Hz, 3J = 2.4
Hz, 1 H), 3.04–3.22 (m, 1 H), 3.69 (br s, 1 H, OH), 3.72–3.84 (m, 1
H), 7.39–7.58 (m, 6 H), 7.69–7.83 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 13.9, 20.4, 27.2 (d, JPC = 70.0 Hz),
28.3 (d, JPC = 1.5 Hz), 28.8, 29.3, 52.5, 53.6, 55.3, 66.4, 128.5,
128.8 (each d, JPC = 1.5 Hz, 2 C), 130.5, 130.7 (each d, JPC = 9.2 Hz,
2 C), 131.70, 131.71 (each d, JPC = 2.4 Hz, 2 C), 133.2, 133.9 (d,
JPC = 98.7 Hz).
31P NMR (162 MHz, CDCl3): δ = 30.2.
HRMS (EI): m/z [M]+ calcd for C22H30NO2P: 371.2014; found:
13C NMR (50 MHz, CDCl3): δ = 11.3, 26.1 (d, JPC = 69.2 Hz), 26.5,
28.5, 47.6, 52.9, 54.2, 64.9, 128.7, 128.8, 130.5, 130.7 (each d,
JPC = 9.2 Hz, 2 C), 131.9 (d, JPC = 2.0 Hz, 2 C), 132.6, 133.4 (each
d, JPC = 99.7 Hz).
31P NMR (162 MHz, CDCl3): δ = 30.3.
HRMS (EI): m/z [M]+ calcd for C20H26NO2P: 343.1701; found:
343.1701.
371.2014.
cis- and trans-1-Propyl-6-(diphenylphosphinylmethyl)piperi-
din-3-ol (10b)
trans-10c
Pale yellow solid; mp 33 °C.
Reaction of alkene 6 (470 mg, 1 mmol) and n-propylamine (0.083
mL, 1 mmol) using the general procedure, and purification by flash
column chromatography (EtOAc–EtOH–Et3N, 40:1:0.5) gave cis-
10b (109 mg, 31%), a mixture of cis- and trans-10b (70 mg, 20%)
and trans-10b (129 mg, 36%); total yield: 308 mg (87%).
IR (KBr): 3355, 3057, 2933, 2870, 1660, 1591, 1438, 1181, 1120,
698 cm–1.
1H NMR (200 MHz, CDCl3): δ = 0.80 (t, J = 7.2 Hz, 3 H), 1.07–
3
1.73 (m, 8 H), 2.18–2.51 (m, 5 H), 2.67 (dd, 2J = 11.8 Hz, 3J = 2.0
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2506–2514

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C. Scherner et al.
PAPER
Hz, 1 H), 3.04 (br s, 1 H, OH), 3.10–3.30 (m, 1 H), 3.70–3.81 (m, 1
H), 7.39–7.59 (m, 6 H), 7.68–7.84 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 13.8, 20.3, 24.4 (d, JPC = 69.5 Hz),
25.7, 27.5, 28.9, 52.6, 53.7, 54.0, 65.1, 128.6, 128.8 (each 2 C),
130.5, 130.8 (each d, JPC = 9.2 Hz, 2 C), 131.8 (d, JPC = 2.4 Hz, 2
C), 132.8, 133.8 (each d, JPC = 99.1 Hz).
13C NMR (50 MHz, CDCl3): δ = 27.1 (d, JPC = 69.3 Hz), 28.1, 29.1,
53.4, 54.5, 58.4, 66.5, 127.0, 128.4, 128.2 (each 2 C), 128.7 (d,
JPC = 11.5 Hz, 4 C), 130.5 (d, JPC = 9.2 Hz), 130.7 (d, JPC = 9.0 Hz),
131.7 (d, JPC = 3.0 Hz), 132.9 (d, JPC = 98.4 Hz), 133.9 (d,
JPC = 98.4 Hz), 138.8.
31P NMR (162 MHz, CDCl3): δ = 30.3.
31P NMR (162 MHz, CDCl3): δ = 30.5.
Anal. Calcd for C25H28NO2P: C, 74.05; H, 6.96; N, 3.45. Found: C,
73.61; H, 6.94; N, 3.17.
Anal. Calcd for C22H30NO2P: C, 71.14; H, 8.14; N, 3.77. Found: C,
71.45; H, 8.35; N, 3.63.
trans-10f
Pale yellow solid; mp 56 °C.
(E)-[5-Hydroxy-6-(tert-butylamino)-1-hexenyl]diphenylphos-
phine Oxide (9d)
Reaction of alkene 6 (470 mg, 1.0 mmol) and tert-butylamine (0.11
mL, 1.0 mmol) using the general procedure gave the crude product
9d (272 mg, 73%) as an orange viscous oil, which was characterized
without further purification.
1H NMR (200 MHz, CDCl3): δ = 1.11 (s, 9 H), 1.52–1.66 (m, 2 H),
2.36 (dd, 2J = 11.8 Hz, 3J = 9.0 Hz, 1 H), 2.42–2.64 (m, 2 H), 2.73
(dd, 2J = 11.8 Hz, 3J = 3.0 Hz, 1 H), 2.83 (br s, 2 H), 3.46–3.61 (m,
1 H), 6.27 (ddt, 3J = 17.0 Hz, 4J = 1.5 Hz, 2JPH = 24.4 Hz, 1 H), 6.74
(ddt, 3J = 17.0 Hz, 3J = 6.4 Hz, 3JPH = 19.5 Hz, 1 H), 7.37–7.57 (m,
6 H), 7.60–7.75 (m, 4 H).
IR (KBr): 3354, 3056, 3026, 2932, 2859, 2798, 1661, 1591, 1437,
1181, 1119, 742, 696 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.48–1.86 (m, 3 H), 1.95–2.17 (m,
1 H), 2.37 (dd, 2J = 12.0 Hz, 3J = 4.4 Hz, 1 H), 2.51 (dd, 2J = 12.6
3
2
3
Hz, J = 6.6 Hz, 2 H), 2.69 (dd, J = 12.0 Hz, J = 2.0 Hz, 1 H),
3.15–3.32 (m, 1 H), 3.38 (d, 2J = 13.6 Hz, 1 H), 3.54 (d, J = 13.2
2
Hz, 1 H), 3.72 (mc, 1 H), 7.14–7.34 (m, 5 H), 7.38–7.58 (m, 6 H),
7.67–7.79 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 25.1 (d, JPC = 68.8 Hz), 25.8, 27.4,
53.4, 54.5, 58.6, 65.2, 127.2, 128.4, 128.6 (2 C), 128.70, 128.73 (d,
J
PC = 11.6 Hz, 2 C), 130.5, 130.8 (d, JPC = 9.2 Hz, 2 C), 131.7 (d,
J
PC = 2.0 Hz), 131.8 (d, JPC = 3.0 Hz), 132.6 (d, JPC = 99.6 Hz),
(E)-[5-Hydroxy-6-(phenylamino)-1-hexenyl]diphenylphos-
phine Oxide (9e)
Reaction of alkene 6 (595 mg, 1.27 mmol) and aniline (0.12 mL,
1.27 mmol) using the general procedure, and purification by flash
column chromatography (EtOAc–EtOH–Et3N, 50:1:0.5) gave 9e
(269 mg, 54%).
133.9 (d, JPC = 99.6 Hz), 138.3.
31P NMR (162 MHz, CDCl3): δ = 30.3.
Anal. Calcd for C25H28NO2P: C, 74.05; H, 6.96; N, 3.45. Found: C,
73.45; H, 7.07; N, 3.43.
Pale orange solid; mp 38 °C.
cis- and trans-1-Allyl-6-(diphenylphosphinylmethyl)piperidin-
3-ol (10g)
IR (KBr): 3352, 3054, 3023, 2927, 1635, 1603, 1437, 1173, 1121,
1102, 997, 809, 753, 722, 694 cm–1.
Reaction of alkene 6 (715 mg, 1.52 mmol) and allylamine (0.114
mL, 1.52 mmol) using the general procedure, and purification by
flash column chromatography (EtOAc–EtOH–Et3N, 40:1:0.5) gave
cis-10g (199 mg, 37%), a mixture of cis- and trans-10g (4 mg, 1%),
and trans-10g (188 mg, 35%); total yield: 391 mg (73%).
1H NMR (200 MHz, CDCl3): δ = 1.60–1.78 (m, 2 H), 2.28–2.63 (m,
2 H), 3.00 (dd, 2J = 12.7 Hz, 3J = 8.2 Hz, 1 H), 3.20 (dd, 2J = 12.7
Hz, 3J = 3.4 Hz, 1 H), 3.74–3.92 (m, 1 H), 6.26 (ddt, 3J = 17.1 Hz,
2
4J = 1.5 Hz, JPH = 24.4 Hz, 1 H), 6.25–6.76 (m, 3 H), 6.74 (ddt,
3J = 17.1 Hz, 3J = 6.4 Hz, 3JPH = 19.8 Hz, 1 H), 7.07–7.20 (m, 2 H),
cis-10g
Pale yellow solid; mp 41 °C.
7.35–7.57 (m, 6 H), 7.58–7.75 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 30.7 (d, JPC = 17.0 Hz, 1 C), 33.1,
50.2, 69.2, 113.1 (2 C), 117.6, 121.9 (d, JPC = 103.0 Hz, 1 C), 128.6
(d, JPC = 12.2 Hz, 4 C), 129.2 (2 C), 131.2 (d, JPC = 10.2 Hz, 4 C),
131.8 (d, JPC = 2.9 Hz, 2 C), 132.8 (d, JPC = 105.5 Hz, 2 C), 148.3,
152.2 (d, JPC = 2.4 Hz, 1 C).
31P NMR (162 MHz, CDCl3): δ = 23.5.
HRMS (EI): m/z [M]+ calcd for C24H26NO2P: 391.1701; found:
IR (KBr): 3348, 3077, 3058, 2935, 2869, 2805, 1643, 1591, 1438,
1178, 1120, 751, 699 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.40–1.83 (m, 4 H), 2.37–2.67 (m,
4 H), 2.94, 3.10 (each ddt, 2J = 14.0 Hz, 3J = 6.4 Hz, 4J = 1.4 Hz, 1
H), 2.95–3.13 (m, 1 H), 3.73 (dddd, 3J = 7.6 Hz, 3J = 7.6 Hz,
3J = 3.8 Hz, 3J = 3.8 Hz, 1 H), 4.99–5.13 (m, 2 H), 5.66 (ddt,
3
3J = 17.0 Hz, J = 10.2 Hz, 3J = 6.4 Hz, 1 H), 7.39–7.57 (m, 6 H),
7.67–7.83 (m, 4 H).
391.1701.
13C NMR (50 MHz, CDCl3): δ = 27.8 (d, JPC = 69.4 Hz), 27.8 (d,
JPC = 2.0 Hz), 29.4, 53.3, 55.1, 57.2, 66.2, 117.5, 128.5, 128.8 (each
2 C), 130.5 (d, JPC = 9.7 Hz, 2 C), 130.7 (d, JPC = 9.2 Hz, 2 C), 131.7
(d, JPC = 2.4 Hz, 2 C), 133.2 (d, JPC = 98.2 Hz), 133.9 (d, JPC = 99.1
Hz), 135.1.
31P NMR (162 MHz, CDCl3): δ = 30.1.
HRMS (EI): m/z [M]+ calcd for C21H26NO2P: 355.1701; found:
cis- and trans-1-Benzyl-6-(diphenylphosphinylmethyl)piperi-
din-3-ol (10f)
Reaction of alkene 6 (5.283 g, 11.238 mmol) and benzylamine
(1.226 mL, 11.238 mmol) using the general procedure, and purifi-
cation by flash column chromatography (EtOAc–EtOH–Et3N,
30:1:0.5) gave cis-10f (1.279 g, 28.1%), a mixture of cis- and trans-
10f (ratio 1:5, 2.234 g, 49.1%) and trans-10f (0.33 g, 7.3%); total
yield: 3.846 g (85%).
355.1701.
cis-10f
trans-10g
Pale yellow solid; mp 48 °C.
Pale yellow solid; mp 58 °C.
IR (KBr): 3333, 3059, 3027, 2936, 2867, 2802, 1665, 1591, 1438,
1177, 1120, 695 cm–1.
IR (KBr): 3339, 3077, 3058, 2935, 2862, 2806, 1641, 1591, 1438,
1183, 1120, 751, 698 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.40–1.88 (m, 4 H), 2.04 (br s, 1
H, OH), 2.40 (dd, 2J = 11.6 Hz, 3J = 8.0 Hz, 1 H), 2.46–2.61 (m, 3
H), 3.17 (dddt, 3J = 8.8 Hz, 3J = 8.8 Hz, 3J = 4.4 Hz, JPH = 2.5 Hz, 1
H), 3.36, 3.64 (each d, 2J = 13.6 Hz, 1 H), 3.69 (dddd, 3J = 8.0 Hz,
1H NMR (200 MHz, CDCl3): δ = 1.37–1.77 (m, 3 H), 1.95–2.10 (m,
1 H), 2.33–2.49 (m, 2 H), 2.42 (dd, 2J = 12.6 Hz, 3J = 8.8 Hz, 1 H),
2
3
2.70 (dd, J = 12.0 Hz, J = 2.4 Hz, 1 H), 2.89, 3.04 (each ddt,
2J = 14.0 Hz, J = 6.4 Hz, J = 1.4 Hz, 1 H), 3.08–3.30 (m, 1 H),
3
4
3J = 8.0 Hz, J = 4.0 Hz, J = 4.0 Hz, 1 H), 7.15–7.29 (m, 5 H),
3.73 (dddd, 3J = 5.2 Hz, 3J = 5.2 Hz, 3J = 2.6 Hz, 3J = 2.6 Hz, 1 H),
3
3
7.37–7.57 (m, 6 H), 7.62–7.81 (m, 4 H).
Synthesis 2014, 46, 2506–2514
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Novel Route to 6-Substituted Piperidin-3-ols
2511
3
3
3
4.98–5.11 (m, 2 H), 5.67 (ddt, J = 17.6 Hz, J = 9.6 Hz, J = 6.4
(dddd, 3J = 8.0 Hz, 3J = 8.0 Hz, 3J = 4.0 Hz, 3J = 4.0 Hz, 1 H), 7.46
Hz, 1 H), 7.39–7.57 (m, 6 H), 7.68–7.82 (m, 4 H).
(mc, 6 H), 7.74 (mc, 4 H).
13C NMR (50 MHz, CDCl3): δ = 25.7 (d, JPC = 69.7 Hz), 26.4, 28.2,
53.3, 54.2, 57.3, 65.4, 117.7, 128.6, 128.8 (each 2 C), 130.5 (d,
JPC = 9.2 Hz, 2 C), 130.8 (d, JPC = 9.2 Hz, 2 C), 131.8 (d, JPC = 2.4
Hz, 2 C), 132.8 (d, JPC = 98.2 Hz), 133.8 (d, JPC = 99.6 Hz), 135.1.
31P NMR (162 MHz, CDCl3): δ = 30.4.
HRMS (EI): m/z [M]+ calcd for C21H26NO2P: 355.1701; found:
13C NMR (101 MHz, CDCl3): δ = –5.38, –5.36, 18.2, 25.9, 27.8 (d,
JPC = 2.0 Hz), 27.9 (d, JPC = 69.9 Hz), 29.1, 53.5, 56.1 (2 C), 61.4,
66.1, 128.6 (d, JPC = 11.9 Hz, 4 C), 130.5, 130.7 (each d, JPC = 9.3
Hz, 2 C), 131.7 (d, JPC = 2.8 Hz, 2 C), 133.0 (d, JPC = 98.9 Hz),
133.8 (d, JPC = 99.3 Hz).
31P NMR (162 MHz, CDCl3): δ = 30.7.
355.1701.
Anal. Calcd for C26H40NO3PSi: C, 65.93; H, 8.51; N, 2.96. Found:
C, 65.13; H, 8.63; N, 2.84.
cis- and trans-1-(2,2-Dimethoxyethyl)-6-(diphenylphosphinyl-
methyl)piperidin-3-ol (10h)
trans-10i
Orange viscous oil.
IR (film): 3356, 3057, 2929, 2856, 1591, 1438, 1254, 1183, 836 cm–1.
Reaction of alkene 6 (1.88 g, 4 mmol) and 2,2-dimethoxyethan-
amine (0.436 mL, 4 mmol) using the general procedure, and purifi-
cation by flash column chromatography (EtOAc–EtOH–Et3N,
30:1:0.5) gave the diastereomers of 10h in equal amounts; total
yield: 1.097 g (68%).
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.85 (s, 9 H), 1.46–
1.68 (m, 3 H), 2.02 (m, 1 H), 2.34–2.55 (m, 6 H), 2.77 (dd, 2J = 11.9
Hz, 3J = 2.1 Hz, 1 H), 3.16 (mc, 1 H), 3.51 (t, 3J = 6.2 Hz, 2 H), 3.73
(mc, 1 H), 7.48 (m, 6 H), 7.76 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = –5.4, 18.2, 25.5 (d, JPC = 69.0
Hz), 25.6, 25.9, 27.4, 53.5, 54.4, 56.2, 61.2, 65.1, 128.68, 128.70
(each d, JPC = 11.9 Hz, 2 C), 130.5, 130.8 (each d, JPC = 9.2 Hz, 2
C), 131.76, 131.78 (each d, JPC = 2.8 Hz, 2 C), 132.8 (d, JPC = 99.1
Hz), 133.8 (d, JPC = 99.9 Hz).
cis-10h
Orange oil.
IR (film): 3347, 3056, 2937, 1438, 1175, 750, 720, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.47 (mc, 1 H), 1.66 (mc, 1 H),
1.76 (mc, 2 H), 2.44–2.62 (m, 6 H), 2.73 (dd, 2J = 11.6 Hz, 3J = 4.0
Hz, 1 H), 3.13 (mc, 1 H), 3.25, 3.29 (each s, 3 H), 3.71 (ddd,
3J = 12.4 Hz, 3J = 8.0 Hz, 3J = 4.0 Hz, 1 H), 4.27 (t, 3J = 5.2 Hz, 1
H), 7.47 (mc, 6 H), 7.75 (mc, 4 H).
31P NMR (162 MHz, CDCl3): δ = 31.0.
Anal. Calcd for C26H40NO3PSi: C, 65.93; H, 8.51; N, 2.96. Found:
C, 65.47; H, 8.56; N, 2.74.
13C NMR (101 MHz, CDCl3): δ = 27.0 (d, JPC = 69.5 Hz), 27.4 (d,
JPC = 2.0 Hz), 28.8, 53.1, 53.7, 53.8, 55.7, 55.9, 66.1, 128.6 (d,
J
PC = 11.7 Hz, 4 C), 103.3, 130.4, 130.7 (each d, JPC = 9.2 Hz, 2 C),
trans-1-Benzyl-6-(diphenylphosphinylmethyl)piperidin-3-yl N-
Phenylcarbamate (11)
131.7 (d, JPC = 2.4 Hz, 2 C), 132.8 (d, JPC = 99.1 Hz), 133.7 (d,
To a vigorously stirred suspension of trans-10f (202.5 mg, 0.5
mmol) in Et2O (1 mL) was added phenyl isocyanate (0.054 mL, 0.5
mmol) and Et3N (1 drop). After 24 h without significant reaction,
DMAP (6.1 mg, 0.05 mmol) was added. Stirring was continued for
another 12 h. The mixture was triturated with PE (4 mL), and the re-
maining solid removed by filtration and then washed with PE (3 × 1
mL). Crystallization from benzene–PE gave the desired product
(206 mg, 79%).
J
PC = 98.7 Hz).
Anal. Calcd for C22H30NO4P: C, 65.49; H, 7.49; N, 3.47. Found: C,
65.11; H, 7.35; N, 3.38.
trans-10h
Orange oil.
IR (film): 3355, 3056, 2934, 2831, 1591, 1438, 1184, 750, 664 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.46–1.68 (m, 3 H), 2.04 (mc, 1
H), 2.36–2.51 (m, 4 H), 2.53 (dd, J = 12.3 Hz, J = 4.0 Hz, 1 H),
2.82 (br s, 1 H, OH), 2.81 (dd, 2J = 12.3 Hz, 3J = 2.0 Hz, 1 H), 3.19
(mc, 1 H), 3.24, 3.30 (each s, 3 H), 3.74 (mc, 1 H), 4.26 (t, 3J = 5.4
Hz, 1 H), 7.44–7.56 (m, 6 H), 7.76 (mc, 4 H).
13C NMR (101 MHz, CDCl3): δ = 25.5 (d, JPC = 70.5 Hz), 25.6,
27.2, 53.7, 53.8, 54.7, 55.6, 55.7, 65.1, 103.2, 128.69, 128.72 (each
d, JPC = 11.6 Hz, 2 C), 130.5, 130.8 (each d, JPC = 9.5 Hz, 2 C),
131.8 (d, JPC = 2.8 Hz, 2 C), 132.8 (d, JPC = 98.5 Hz), 133.8 (d,
Pale yellow solid; mp 152–154 °C.
2
3
IR (KBr): 3326, 3287, 3238, 3192, 3128, 3058, 3035, 2951, 2867,
2802, 1720, 1548, 1597, 1444, 1230, 1176, 1157, 1120, 694 cm–1.
1H NMR (200 MHz, CD3OD): δ = 1.48–1.68, 1.84–2.26 (each m, 2
2
3
H), 2.50 (dd, J = 13.0 Hz, J = 5.3 Hz, 1 H), 2.58–2.92 (m, 2 H),
2.83 (dd, 2J = 12.8 Hz, 3J = 2.5 Hz, 1 H), 3.06–3.26 (m, 1 H), 3.44,
3.73 (each d, 2J = 13.8 Hz, 1 H), 4.68–4.80 (m, 1 H), 6.94–7.06 (m,
2 H), 7.11–7.65 (m, 14 H), 7.73–7.90 (m, 4 H).
13C NMR (50 MHz, CD3OD): δ = 26.7, 26.9 (d, JPC = 69.0 Hz),
27.5, 52.0, 55.0, 59.4, 70.3, 120.4, 123.9 (d, JPC = 6.3 Hz), 128.0,
129.3 (2 C), 129.6, 129.7 (each 2 C), 129.9, 130.0 (d, JPC = 11.7 Hz,
4 C), 131.7 (d, JPC = 9.7 Hz, 2 C), 131.8 (d, JPC = 9.7 Hz, 2 C), 133.3
(d, JPC = 2.9 Hz, 2 C), 133.4 (d, JPC = 99.6 Hz), 134.5 (d,
J
PC = 100.1 Hz).
Anal. Calcd for C22H30NO4P: C, 65.49; H, 7.49; N, 3.47. Found: C,
65.30; H, 7.79; N, 3.60.
cis- and trans-1-[2-(tert-Butyldimethylsilyloxy)ethyl]-6-(diphe-
nylphosphinylmethyl)piperidin-3-ol (10i)
J
PC = 100.1 Hz), 140.0, 140.2, 155.5.
Reaction of alkene 6 (230 mg, 0.49 mmol) and 2-(tert-butyldimeth-
ylsiloxy)ethylamine (86 mg, 0.49 mmol) using the general proce-
dure, and purification by flash column chromatography (EtOAc–
EtOH–Et3N, 30:1:0.5) gave cis-10i (50 mg, 22%), and trans-10i
(131 mg, 56%); total yield: 181 mg (78%).
31P NMR (162 MHz, CD3OD): δ = 37.1.
Anal. Calcd for C32H33N2O3P: C, 73.27; H, 6.34; N, 5.34. Found: C,
72.49; H, 6.21; N, 5.64.
cis-1-Benzyl-2-(diphenylphosphinylmethyl)-5-(benzyloxy)pi-
peridine (cis-12)
cis-10i
Orange viscous oil.
A solution of cis-10f (2.385 g, 5.89 mmol) in anhydrous THF (74
mL) was cooled to 0 °C and NaH (339.2 mg, 7.07 mmol) was added
in small portions. The mixture was allowed to warm to r.t. and
stirred for 30 min. Bu4NI (435 mg, 1.178 mmol) and BnBr (0.77
mL, 6.479 mmol) were added and the resulting mixture was heated
at 50 °C for 2 h. The mixture was hydrolyzed with H2O (4.5 mL),
extracted with a mixture of Et2O–CH2Cl2 (2:1, 3 × 5 mL), dried
(MgSO4) and concentrated in vacuo. Purification by flash column
IR (film): 3347, 3057, 2930, 2856, 1591, 1438, 1254, 1180, 1118,
836 cm–1.
1H NMR (400 MHz, CDCl3): δ = –0.01 (s, 6 H), 0.84 (s, 9 H), 1.45,
1.62 (each mc, 1 H), 1.71 (mc, 2 H), 2.35–2.60 (m, 6 H), 2.65 (dd,
2J = 12.0 Hz, 3J = 3.6 Hz, 1 H), 3.04 (dddt, 3J = 8.4 Hz, 3J = 8.0 Hz,
3
3J = 4.0 Hz, JPC = 2.5 Hz, 1 H), 3.50 (t, J = 6.6 Hz, 2 H), 3.69
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2506–2514

2512
C. Scherner et al.
PAPER
chromatography (EtOAc–PE–Et3N, 2:1:2 v/v) afforded the title
product (1.784 g, 61%).
ed with Et2O (5 × 176 mL). The combined organic layer was dried
(MgSO4) and evaporated. The residue was purified by flash column
chromatography (PE–EtOAc–Et3N, 25:1:10 v/v) to give cis-13 (401
mg, 56%) as a 55:45 mixture of Z*/E-isomers.
Colorless needles; mp 107 °C.
IR (KBr): 3050, 3025, 2945, 2868, 1591, 1495, 1439, 1355, 1180,
1121, 1107, 906, 739, 695 cm–1.
Pale yellow oil.
IR (film): 3062, 3027, 2937, 2854, 1604, 1494, 1452, 1102, 1067,
735, 697 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.40–2.04 (m, 4 H), 2.33 (dd,
2J = 11.4 Hz, 3J = 9.8 Hz, 1 H), 2.45 (ddd, 2J = 12.2 Hz, 3J = 2.4 Hz,
JPH = 14.8 Hz, 1 H), 2.62 (ddd, 2J = 12.8 Hz, 3J = 10.0 Hz,
1H NMR (200 MHz, CDCl3): δ (55:45 mixture of Z*/E-
isomers) = 1.51–1.86 (m, each 4 H), 1.61 (dd, 3J = 6.6 Hz, 4J = 1.6
Hz, 3 H), 1.71* (dd, 3J = 6.2 Hz, 4J = 1.4 Hz, 3 H), 2.25, 2.28* (each
dd, 2J = 12.0 Hz, 3J = 3.6 Hz, 1 H), 2.78 (dd, 2J = 12.0 Hz, 3J = 6.0
Hz, 1 H), 2.82*–2.90 (m, 2 H), 3.20 (ddd, 3J = 10.8 Hz, 3J = 8.0 Hz,
3J = 3.2 Hz, 1 H), 3.275*, 3.279 (each d, 2J = 13.6 Hz, 1 H), 3.47–
3.55 (m, each 1 H), 3.97, 3.89* (each d, 2J = 13.6 Hz, 1 H), 4.417,
J
PH = 14.8 Hz, 1 H), 2.74 (dd, 2J = 11.6 Hz, 3J = 4.4 Hz, 1 H), 3.27–
3.54 (m, 2 H), 3.49 (s, 2 H), 4.41, 4.49 (each d, 2J = 11.8 Hz, 1 H),
7.12–7.33 (m, 10 H), 7.35–7.55 (m, 6 H), 7.64–7.82 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 24.8 (d, JPC = 68.9 Hz), 25.7, 27.7
(d, JPC = 1.6 Hz), 50.3, 52.3, 58.6, 70.2, 73.9, 126.9, 127.4 (2 C),
127.5 (2 C), 128.2 (2 C), 128.3 (4 C), 128.6 (d, JPC = 11.9 Hz, 2 C),
130.5, 130.7 (d, JPC = 9.2 Hz, 2 C), 131.6 (d, JPC = 2.4 Hz, 2 C),
132.9 (d, JPC = 98.0 Hz), 134.2 (d, JPC = 100.8 Hz), 138.6, 138.9.
2
4.419*, 4.473, 4.477* (each d, J = 12.4 Hz, 1 H), 5.52–5.73 (m,
each 2 H), 7.19–7.35 (m, each 10 H).
13C NMR (50 MHz, CDCl3): δ (55:45 mixture of Z*/E-
isomers) = 13.3*, 18.0, 27.6, 27.6*, 28.1*, 29.0, 53.1, 53.4*, 56.7*,
59.1*, 59.2, 62.8, 69.8*, 69.8, 72.6*, 72.9, 125.4*, 126.6, 126.7,
127.3, 127.5, 127.5, 128.0, 128.0, 128.2, 128.9, 129.0, 131.5*,
131.7, 139.0, 139.4*.
31P NMR (162 MHz, CDCl3): δ = 30.5.
Anal. Calcd for C32H34NO2P: C, 77.55; H, 6.91; N, 2.83. Found: C,
77.47; H, 6.99; N, 2.73.
trans-1-Benzyl-2-(diphenylphosphinylmethyl)-5-(benzyloxy)pi-
peridine (trans-12)
MS (Z-isomer) (EI, 70 eV): m/z (%) = 280 (2) [M – C3H5]+, 230 (3)
In an analogous manner to that described for the synthesis of cis-12,
trans-12 was prepared from trans-10f (1.450 g, 3.58 mmol) using
NaH (206 mg, 4.296 mmol), Bu4NI (264.5 mg, 0.716 mmol) and
BnBr (0.468 mL, 3.938 mmol) in THF (45 mL). Purification by
flash column chromatography (EtOAc–PE–Et3N, 2:1:2 v/v) gave
the title product (0.991 g, 56%).
[M – C7H7]+, 215 (7), 186 (7), 160 (7), 124 (9), 91 (100) [C7H7]+.
MS (E-isomer) (EI, 70 eV): m/z (%) = 322 (1) [M + H]+, 321 (1)
[M]+, 280 (5) [M – C3H5]+, 230 (7) [M – C7H7]+, 215 (18), 200 (8),
186 (13), 160 (15), 124 (13), 91 (100) [C7H7]+.
trans-1-Benzyl-2-(1-propenyl)-5-(benzyloxy)piperidine (trans-
13)
Yellow solid; mp 121 °C.
In an analogous manner to that described for the synthesis of cis-13,
trans-13 was prepared from trans-12 (495 mg, 1 mmol) using n-
BuLi (0.689 mL, 1.6 M solution in n-hexane, 1.1 mmol), acetalde-
hyde (0.062 mL, 1.1 mmol) in THF (10 mL), and NaH (57.6 mg, 1.2
mmol) in DMF (40 mL). Purification by flash column chromatog-
raphy (PE–EtOAc–Et3N, 25:1:10 v/v) gave the title product (182
mg, 57%) as a 55:45 mixture of E/Z*-isomers.
IR (KBr): 3080, 3058, 3030, 2941, 1591, 1437, 1183, 1121, 1105,
741, 696 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.24–1.58 (m, 2 H), 1.84–1.98 (m,
2
3
1 H), 2.19 (dd and m, J = 11.8 Hz, J = 8.0 Hz, 2 H), 2.34 (ddd,
2J = 12.6 Hz, 3J = 9.8 Hz, JPH = 15.0 Hz, 1 H), 2.71 (ddd, 2J = 12.4
3
Hz, J = 2.6 Hz, JPH = 15.0 Hz, 1 H), 2.82–2.96 (m, 2 H), 3.29 (d,
2J = 14.0 Hz, 1 H), 3.35–3.50 (m, 1 H), 3.84 (d, 2J = 13.8 Hz, 1 H),
4.37, 4.43 (each d, 2J = 12.0 Hz, 1 H), 7.17–7.34 (m, 10 H), 7.38–
7.52 (m, 6 H), 7.65–7.80 (m, 4 H).
Colorless oil.
IR (film): 3063, 3028, 2936, 2856, 2795, 1604, 1495, 1453, 1098,
736, 697 cm–1.
13C NMR (50 MHz, CDCl3): δ = 28.4, 29.1, 31.4 (d, JPC = 70.4 Hz,
1 C), 54.5, 55.4, 58.2, 70.0, 73.1, 126.9, 127.3, 127.4, 128.2 (4 C),
128.5, 128.6 (d, JPC = 11.8 Hz), 128.7 (d, JPC = 11.8 Hz), 130.5,
130.7 (each d, JPC = 9.2 Hz), 131.6, 131.7 (each d, JPC = 2.4 Hz),
133.0 (d, JPC = 98.7 Hz), 134.0 (d, JPC = 99.8 Hz), 138.7, 139.2.
1H NMR (400 MHz, C6D6):
isomers) = 1.17–1.68 (m, each 3 H), 1.51*, 1.52 (each d, J = 5.1
δ (55:45 mixture of E/Z*-
3
Hz, 3 H), 1.92 (mc, 2 × each 1 H), 2.00 (mc, 2 × each 1 H), 2.51
3
3
3
(ddd, J = 10.4 Hz, J = 7.6 Hz, J = 2.8 Hz, 1 H), 2.91* (ddd,
3J = 10.6 Hz, J = 7.8 Hz, J = 2.8 Hz, 1 H), 2.94, 2.96* (each d,
2J = 13.6 Hz, 1 H), 3.28–3.36 (m, each 1 H), 3.37–3.47 (m, each 1
H), 4.17*, 4.22 (each d, 2J = 13.6 Hz, 1 H), 4.21 (each d, 2J = 11.9
3
3
31P NMR (162 MHz, CDCl3): δ = 30.0.
MS (EI, 70 eV): m/z (%) = 496 (2) [M + H]+, 405 (5) [M + H –
C7H7]+, 404 (16) [M – C7H7]+, 294 (14) [M – Ph2PO]+, 202 (10)
[Ph2POH]+, 201 (28) [Ph2PO]+, 91 (100) [C7H7]+.
2
Hz, 1 H), 4.25, 4.26* (each d, J = 11.9 Hz, 1 H), 5.40–5.54 (m,
each 2 H), 7.03–7.24 (m, each 8 H), 7.33–7.40 (m, each 2 H).
13C NMR (50 MHz, CDCl3): δ (55:45 mixture of E/Z*-
isomers) = 13.5*, 17.9, 30.6*, 30.7*, 30.7, 31.9, 56.7, 56.8*, 58.7*,
59.2*, 59.3, 65.2, 70.3, 70.3*, 74.7, 74.8*, 125.6*, 126.7, 126.7*,
127.3, 127.4, 127.6, 128.1, 128.3, 129.0, 129.2, 133.9*, 134.7,
138.7, 139.2*.
HRMS (EI): m/z [M]+ calcd for C22H27NO: 321.2093; found:
321.2092.
Anal. Calcd for C32H34NO2P: C, 77.55; H, 6.91; N, 2.83. Found: C,
77.31; H, 6.99; N, 2.78.
cis-1-Benzyl-2-(1-propenyl)-5-(benzyloxy)piperidine (cis-13)
A solution of cis-12 (1.10 g, 2.22 mmol) in anhydrous THF (23 mL)
was cooled to –78 °C. n-BuLi (1.53 mL, 1.6 M solution in hexane,
2.442 mmol) was added and the mixture stirred at –78 °C for 15
min. Acetaldehyde (0.138 mL, 2.442 mmol) in anhydrous THF (2
mL) was added slowly. The solution was stirred for 30 min, allowed
to warm to 0 °C and then quenched with brine (50 mL). The aq layer
was extracted with CH2Cl2 (5 × 44 mL) and the combined organic
layer dried (MgSO4) and concentrated in vacuo. The crude product
was dissolved in anhydrous DMF (89 mL) and NaH (128 mg, 2.664
mmol) was added in small portions. The mixture was heated at
60 °C for 2.5 h. After dissolving the dark brown solution in Et2O
(264 mL), it was washed with 1 M NaOH (3 × 44 mL). The organic
layer was extracted with 4% HCl (5 × 88 mL) and the combined aq
layer was made alkaline with 2 M NaOH. The aq layer was extract-
cis-2-Propyl-5-(benzyloxy)piperidine (14)
Under a H2 atm, a solution of cis-13 (161 mg, 0.5 mmol) in EtOH
(1 mL) was added to a suspension of Pd(OH)2/C (20 wt%) in EtOH
(4 mL). 2 M HCl (5.8 equiv, 1.4 mL) was added slowly and the mix-
ture was stirred for 5 d. After filtration, the catalyst was washed with
EtOH. The filtrate was neutralized with 2 M NaOH and evaporated.
The residue was taken up in brine (8.5 mL) and the aq layer extract-
ed with CHCl3 (4 × 5 mL). The combined organic layer was dried
(MgSO4) and the solvents evaporated. Purification by flash column
Synthesis 2014, 46, 2506–2514
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Novel Route to 6-Substituted Piperidin-3-ols
2513
chromatography (PE–EtOAc–Et3N, 25:1:10) gave the title product
(65 mg, 56%) as a yellow oil.
13C NMR (100 MHz, CDCl3): δ = 14.2, 18.9, 27.0, 31.1, 39.1, 52.6,
56.5, 64.4.
IR (NaCl): 3301, 3064, 3031, 2955, 2930, 2869, 1561, 1544, 1497,
1454, 1093, 1070, 736, 699 cm–1.
References
3
1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H), 1.24–
1.60 (m, 7 H), 2.06 (ddddd, 2J = 13.8 Hz, 3J = 6.0 Hz, 3J = 3.0 Hz,
3J = 3.0 Hz, 4J = 0.6 Hz, 1 H), 2.28 (br s, 1 H), 2.52 (dddd, 3J = 9.6
Hz, 3J = 9.6 Hz, 3J = 3.2 Hz, 3J = 3.2 Hz, 1 H), 2.73 (dd, 2J = 13.6
(1) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D.
R. Tetrahedron 2003, 59, 2953.
(2) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
(3) (a) De Risi, C.; Fanton, G.; Pollini, G. P.; Trapella, C.;
Valente, F.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19,
131. (b) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633. (c) Laschat, S.; Dickner, T. Synthesis
2000, 1781. (d) Cossy, J. Chem. Rec. 2005, 5, 70.
(4) Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J.
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3
2
3
Hz, J = 1.6 Hz, 1 H), 3.20 (dt, J = 13.6 Hz, J = 2.4 Hz, 1 H),
2
3.42–3.47 (m, 1 H), 4.52, 4.56 (each d, J = 12.0 Hz, 1 H), 7.25–
7.38 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 19.1, 27.4, 28.0, 38.9, 49.3,
55.7, 69.9, 71.1, 127.4, 127.5, 128.3, 138.9
HRMS (EI): m/z [M]+ calcd for C15H23NO: 233.1780; found:
233.1780.
(5) Wijdeven, M. A.; van Delft, F. L.; Rutjes, F. P. J. T.
Tetrahedron 2010, 66, 5623.
trans-5-Hydroxy-2-propylpiperidine (Pseudoconhydrine, 5)
10% Pd/C (15 mg, 17 wt%) was dissolved in anhydrous MeOH (5
mL) and prehydrogenated for 30 min. A solution of trans-13 (86
mg, 0.267 mmol) in anhydrous MeOH (3 mL) and 2 M HCl (1.5
equiv) were added slowly. The mixture was stirred for 4 d at r.t. un-
der H2. After filtration, the filtrate was neutralized with 2 M NaOH
and concentrated in vacuo. Brine (3 mL) was added and the aq layer
extracted with CHCl3 (4 × 5 mL). The combined organic layer was
dried (MgSO4) and evaporated carefully. Sublimation11a,j gave
pseudoconhydrine (29 mg, 26%).
(6) (a) Christofidis, I.; Welter, A.; Jadot, J. Tetrahedron 1977,
33, 977. (b) Hasseberg, H.-A.; Gerlach, H. Liebigs Ann.
Chem. 1989, 255. (c) Makabe, H.; Kong, L. K.; Mitsuru, H.
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J. Org. Chem. 1999, 64, 4914. (b) Kim, I. S.; Ryu, C. B.; Li,
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(9) Ibekeke-Bomangwa, W.; Hootelé, C. Tetrahedron 1987, 43,
935.
(10) Ladenburg, A.; Adam, G. Ber. Dtsch. Chem. Ges. 1891, 24,
1671.
Colorless solid; mp 87–89 °C (Lit.11a 91.5–92 °C).
IR (KBr): 3292, 3126, 2955, 2921, 2854, 2828, 1449, 1050 cm–1.
3
1H NMR (400 MHz, D2O): δ = 0.85 (br t, J = 7.2 Hz, 3 H), 1.10
(11) (a) Marion, L.; Cockburn, W. F. J. Am. Chem. Soc. 1949, 71,
3402. (b) Gruber, W.; Schlögl, K. Monatsh. Chem. 1949, 80,
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Tetrahedron 1973, 29, 455. (e) Enders, D.; Hassel, T.;
Pieter, R.; Renger, B.; Seebach, D. Synthesis 1976, 548.
(f) Renger, B.; Kalinowski, H.-O.; Seebach, D. Chem. Ber.
1977, 110, 1866. (g) Shono, T.; Matsumura, Y.; Onomura,
O. Chem. Lett. 1984, 1101. (h) Harding, K. E.; Burks, S. R.
J. Org. Chem. 1984, 49, 40. (i) Plehiers, M.; Hootelé, C.
Tetrahedron Lett. 1993, 34, 7569. (j) Fry, D. F.; Brown, M.;
McDonald, J. C. Tetrahedron Lett. 1996, 37, 6227.
(k) Plehiers, M.; Hootelé, C. Can. J. Chem. 1996, 74, 2444.
(12) (a) Tadano, K.; Iimura, Y.; Suami, T. J. Carbohydr. Chem.
1985, 4, 129. (b) Takahata, H.; Inose, K.; Momose, T.
Heterocycles 1994, 38, 269. (c) Oppolzer, W.; Bochet, C. G.
Tetrahedron Lett. 1995, 36, 2959. (d) Herdeis, C.; Held, W.
A.; Kirfel, A.; Schwabenländer, F. Liebigs Ann. 1995, 1295.
(e) Sakagami, H.; Kamikubo, T.; Ogasawara, K. Chem.
Commun. 1996, 1433. (f) Hirai, Y.; Shibuya, K.; Fukuda, Y.;
Yokoyama, H.; Yamaguchi, S. Chem. Lett. 1997, 221.
(g) Dockner, M.; Sasaki, N. A.; Riche, C.; Potier, P. Liebigs
Ann. Recl. 1997, 1267. (h) Moody, C. J.; Lightfoot, A. P.;
Gallagher, P. T. J. Org. Chem. 1997, 62, 746. (i) Cossy, J.;
Dumas, C.; Pardo, D. G. Synlett 1997, 905. (j) Herdeis, C.;
Schiffer, T. Synthesis 1997, 1405. (k) Agami, C.; Couty, F.;
Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783.
(l) Löfstedt, J.; Pettersson-Fasth, H.; Bäckvall, J.-E.
Tetrahedron 2000, 56, 2225. (m) Hedley, S. J.; Moran, W.
J.; Prenzel, A. H. G. P.; Price, D. A.; Harrity, J. P. A. Synlett
2001, 1596. (n) Liu, G.; Meng, J.; Feng, C.-G.; Huang, P.-Q.
Tetrahedron: Asymmetry 2008, 19, 1297. (o) Satyalakshmi,
G.; Suneel, K.; Shinde, D. B.; Das, B. Tetrahedron:
Asymmetry 2011, 22, 1000. (p) Bates, R. W.; Sivarajan, K.;
Straub, B. F. J. Org. Chem. 2011, 76, 6844.
(dddd, 2J = 13.4 Hz, 3J = 11.2 Hz, 3J = 11.2 Hz, 3J = 3.6 Hz, 1 H),
1.23–1.35 (m, 5 H), 1.78 (dq, 2J = 13.4 Hz, 3J = 3.4 Hz, 1 H), 1.99
(br d, J = 12.0 Hz, 1 H), 2.34 (dd, 2J = 11.6 Hz, 3J = 10.6 Hz, 1 H),
2
3
4
2.40–2.49 (m, 1 H), 3.06 (ddd, J = 11.2 Hz, J = 4.2 Hz, J = 2.2
Hz, 1 H), 3.60 (dddd, 3J = 11.2 Hz, 3J = 11.2 Hz, 3J = 4.2 Hz,
3J = 4.2 Hz, 1 H).
13C NMR (100 MHz, D2O): δ = 13.8, 19.1, 30.3, 32.9, 37.7, 52.0,
55.0, 67.8.
trans-5-Hydroxy-2-propylpiperidine Hydrochloride (5·HCl)
Anhydrous HCl gas was bubbled through a solution of 5 (10 mg,
0.07 mmol) in CHCl3 (3 mL) for 10 min. The solvent was evaporat-
ed and the residue, a pale yellow solid, was crystallized from anhy-
drous acetone to give 5·HCl (5 mg, 40%).
Colorless solid; mp 182 °C (Lit.12p 185–185.5 °C).
IR (KBr): 3374, 2960, 2939, 2873, 2807, 2508, 1104.
1H NMR (400 MHz, D2O): δ = 0.84 (t, 3J = 7.4 Hz, 3 H), 1.27–1.56
(m, 6 H), 1.97–2.10 (m, 2 H), 2.68 (dd, 2J = 12.0 Hz, 3J = 10.8 Hz,
2
3
1 H), 2.98–3.10 (m, 1 H), 3.33 (ddd, J = 12.0 Hz, J = 4.6 Hz,
4J = 1.8 Hz, 1 H), 3.78–3.88 (m, 1 H).
13C NMR (101 MHz, D2O, with DMSO as an internal standard at
δ = 39.51): δ = 13.3, 18.4, 26.4, 30.6, 34.6, 48.6, 56.0, 64.3.
cis-5-Hydroxy-2-propylpiperidine (epi-5)
In an analogous manner to that described for the synthesis of pseu-
doconhydrine (5), compound 14 (42 mg, 0.18 mmol) was deprotect-
ed under a H2 atm using 10% Pd/C (6.3 mg) as the catalyst, MeOH
(3 mL) and 2 M HCl (0.13 mL, 0.27 mmol). The reaction time was
4 d. The crude product (22 mg, 86%) was characterized spectro-
scopically without further purification.
IR (film): 3288, 2930, 1440, 1106, 980 cm–1.
3
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H), 1.28–
1.59 (m, 7 H), 1.79–1.91 (m, 1 H), 2.35 (br s, 2 H), 2.44–2.63 (m, 1
H), 2.77 (dd, 2J = 12.0 Hz, 3J = 1.6 Hz, 1 H), 3.01 (dt, 2J = 12.0 Hz,
3J = 2.8 Hz, 1 H), 3.81–3.90 (m, 1 H).
(q) Higashiyama, K.; Matsumura, M.; Kurita, E.; Yamauchi,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2506–2514

2514
C. Scherner et al.
PAPER
charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(17) (a) Czech, B.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076.
(b) Sajiki, H.; Kuno, H.; Hirota, K. Tetrahedron Lett. 1998,
39, 7127.
T. Heterocycles 2012, 86, 371. (r) Lovick, H. M.; Michael,
F. E. J. Am. Chem. Soc. 2010, 132, 1249.
(13) Ergüden, J.-K.; Schaumann, E. Synthesis 1996, 707.
(14) Bunce, R. A.; Peeples, C. J.; Jones, P. B. J. Org. Chem. 1992,
57, 1727.
(15) Bryson, T. A.; Smith, D. C.; Krueger, S. A. Tetrahedron
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Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
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(19) Nakabayashi, N.; Masuhara, E.; Iwakura, Y. Bull. Chem.
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(16) Unit cell parameters: a = 1145.5(1) pm, b = 851.1(1) pm,
c = 3014.2(1) pm, β = 102.49(1)°, V = 2869·106 pm3, Z = 4,
monoclinic, space group P21/c, R = 0.059, Rw = 0.147.
CCDC 799120 contains the supplementary crystallographic
data for this compound. These data can be obtained free of
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Synthesis 2014, 46, 2506–2514
© Georg Thieme Verlag Stuttgart · New York