High regiocontrol in the nucleophilic ring opening of 1-aralkyl-3,4- epoxypiperidines with amines - A short-step synthesis of 4- fluorobenzyltrozamicol and novel anilidopiperidines

Article abstract of DOI:10.1016/j.tet.2011.03.045

Nucleophilic ring-opening reactions of three 1-aralkyl-3,4-epoxypiperidines with a series of aliphatic and aromatic amines have been investigated. Reactions in protic solvents, preferably 2-propanol, gave rise to 3-amino-piperidin-4-ols in ratios up to 20:1. Accordingly, 4- fluorobenzyltrozamicol, a highly potent ligand for the vesicular acetylcholine transporter was obtained directly from an epoxide ring opening in one step, without the need of chromatographic separation. Reactions in acetonitrile assisted by Li-salts, most suitable with LiBr, led regioselectively to trans-4-amino-piperidin-3-ols in high yields. N-Phenethyl substituted anilino-piperidinols as easily obtained by this method were converted into a series of new β-hydroxy substituted anilidopiperidines.

Full text of DOI:10.1016/j.tet.2011.03.045

Tetrahedron 67 (2011) 3448e3456
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
High regiocontrol in the nucleophilic ring opening of 1-aralkyl-
3,4-epoxypiperidines with aminesda short-step synthesis of
4-fluorobenzyltrozamicol and novel anilidopiperidines
,
b
a
a
Matthias Scheunemann a , Lothar Hennig , Uta Funke , Jorg Steinbach
*
€
a Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstr. 15, 04318 Leipzig, Germany
Universitat Leipzig, Institute of Organic Chemistry, Faculty of Chemistry and Mineralogy, Johannisalle 29, 04103 Leipzig, Germany
b
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Nucleophilic ring-opening reactions of three 1-aralkyl-3,4-epoxypiperidines with a series of aliphatic
and aromatic amines have been investigated. Reactions in protic solvents, preferably 2-propanol, gave
rise to 3-amino-piperidin-4-ols in ratios up to 20:1. Accordingly, 4-fluorobenzyltrozamicol, a highly
potent ligand for the vesicular acetylcholine transporter was obtained directly from an epoxide ring
opening in one step, without the need of chromatographic separation. Reactions in acetonitrile assisted
by Li-salts, most suitable with LiBr, led regioselectively to trans-4-amino-piperidin-3-ols in high yields.
N-Phenethyl substituted anilino-piperidinols as easily obtained by this method were converted into
Received 22 December 2010
Received in revised form 14 March 2011
Accepted 16 March 2011
Available online 23 March 2011
Keywords:
Trozamicol
VAChT
PET
a series of new b-hydroxy substituted anilidopiperidines.
Ó 2011 Elsevier Ltd. All rights reserved.
1-Aralkyl-3,4-epoxypiperidine
Nucleophilic ring opening
Anilidopiperidine
1. Introduction
4-Fluorobenzyltrozamicol (4-FBT) 3bb (Fig. 1), labelled with
fluorine-18, has been persistently used as radiotracer for imaging the
vesicular acetylcholine transporter (VAChT) with positron emission
tomography (PET).13 In contrast, compounds containing the vicinally
substituted 4-aminopiperidine motif appear to be more widespread
in pharmaceutical related research. Examples of such molecules
include the 4-anilidopiperidine analgesics 1b (ohmefentanyl),14a,b
1c14c and the cyclooctyl substituted J-113397 2,15 which was
The development of novel modular methodologies leading to
readily accessible synthetic templates is an area of intensive in-
vestigation in pharmaceutical and organic synthesis.1 Fragment
couplings as well as intramolecular pairing of functional groups for
diversity-oriented synthesis (DOS) strategies2 or combinatorial
chemistry in solution,3 require reliable and highly effective re-
actions.4 The trans-stereospecific course and facility of the nucle-
ophilic ring opening has made three-membered rings, such as
epoxides4a,5 and activated aziridines6 to favourable building blocks.
Recently, we have utilized a regioselective nucleophilic ring
opening on an epoxycyclohexane template for an exploratory li-
brary synthesis of cyclohexane-fused morpholin-3-ones.7 In this
paper, we describe full details on the ring opening of 1-aralkyl-3,4-
epoxypiperidines 7aec with aliphatic and aromatic amines by ap-
plying a Lewis acid or a non-Lewis acid promoted reaction.8
Polyfunctionalized piperidines are frequently found in natural
products and are common structural targets in pharmaceutical re-
search.9 3,4-Substituted piperidines10 containing a beta-amino al-
cohol or diol moiety are of interest as they form the core of naturally
occurring pseudodistomins11 and iminosugars,12 respectively.
* Corresponding
author.
E-mail
address:
m.scheunemann@hzdr.de
(M. Scheunemann).
Fig. 1. Examples of different 1,3,4-substituted piperidines.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.045

M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
3449
reported as first potent and highly selective nociceptin receptor
(NOP) antagonist. Prezamicol derivatives (4aa, 4bb) are of interest as
regioisomers with different binding properties to the VAChT.16
Amongst a couple of different methods to obtain these kinds of
structures, particularly the ring opening of 3,4-epoxypiperidines
appears to be an attractive key-step if aiming at an efficient library
synthesis17a and for involvement in stereocontrolled approaches17b
as well. However, in contrast to methodology, processing a com-
mon acyl16 or carbamoyl18 protective group at the piperidine nitro-
gen, we choose an aralkyl substitution. This conveniently allows the
combination of a suitable N-protection as well as the introduction of a
pharmacophoric element that is required for binding to a biological
target.
To our knowledge, highly regioselective conversions of these
types of 3,4-epoxypiperidines are rare and have been scarcely
published.19 The LiClO4-assisted ring opening of 7a (Scheme 1) with
a series of amines has been previously reported by Grishina and
co-workers19a,c to lead exclusively to trans-4-amino-piperidin-3-ols
(C4-product) with no detection of the opposite C3-regioisomer.20
convenient approach.23d Pyridine was reacted first with a series of
aralkyl halides (Scheme 1) either under solvent-free conditions (5a,
5b) or in refluxing xylene (5c) to form the corresponding pyr-
idinium salts. For the partial reduction we followed a modified
protocol according to Oediger and Joop.24 Sodium borohydride
(1.3e1.8 equiv) was gradually added to a solution of the N-
substituted pyridinium salt in ethanol at 0e20 ꢀC leading to a clean
reduction to the desired tetrahydropyridine.
Previous attempts to epoxidize the basic tetrahydropyridine 6a
with a standard oxidizing agent, such as m-chloroperoxybenzoic
acid (MCPBA) were not chemoselective and resulted in an over-
oxidation by formation of the amine-N-oxide as by-product.25 Thus,
a full protonation of the basic piperidine nitrogen with trifluoro-
acetic acid prior to the oxidation was regarded as necessary.26 By
using urea-hydrogen peroxide (UHP)27 in combination with tri-
fluoroacetic anhydride (TFAA) in dichloromethane (DCM) at 0e5 ꢀC
it was possible to epoxidize the amino-olefins in form of their tri-
fluoroacetate salts to obtain the epoxides 7aec in excellent yields
(Scheme 2). The N-ethoxycarbonyl substituted epoxide 7d, which
served as basis for a comparison, was prepared from 6a via in-
terchange of the N-benzyl group23d,25 with ethylchloroformate
(ECF) to obtain 6d followed by epoxidation with MCPBA (Scheme 1).
Scheme 2.
2.2. Regio-controlled ring opening of 1-aralkyl-
3,4-epoxypiperidinesdsynthesis of 4-FBT
Scheme 1. Synthesis of N-substituted 3,4-epoxypiperidines 7aed.
Concurrent to our work,8 a very recent letter describing a method
to yield and isolate highly enriched C4- and C3-products (up to
>20:1) from the same epoxide 7a by regioselective reactionwith five
different amines was published by Ikemoto and co-workers.21 This
report has prompted us to disclose our own results in this area in
obtaining pure trans-4-amino-piperidin-3-ols and trans-3-amino-
piperidin-4-ols.
An experiment for a ring opening at the outset of our study is
depicted in Scheme 2. The reaction of 7a with 4-phenylpiperazine
(8a) in EtOH at 95 ꢀC in a closed tube resulted in the full conversion
of the starting epoxide within 6 h and in the predominant forma-
tion of the 4-hydroxypiperidinol derivative 3aa. A small amount of
a by-product was detected by TLC and identified as the regioisomer
4aa via comparison with an authentic sample. Removal of the
solvent and recrystallization of the solid residue from aqueous
MeOH afforded pure 3aa in 81% yield. From a subsequent ring
opening of 7b with 4-phenylpiperidine 8b we obtained in a similar
manner the desired 4-FBT 3bb in 78% yield.
Encouraged by these initial results and to estimate potential
solvent and chelation effects on the degree of regioselectivity, ad-
ditional protic solvents were tested as well as reactions in aceto-
nitrile (ACN) in the presence of a metal salt acting as a Lewis acid
catalyst. We investigated the ring opening of the epoxides 7a and
7b with two amines 8a and 8b. Table 1 summarizes the results of
both procedures. The relative ratios of isomers were determined by
comparing the peak areas of the individual regioisomers, detected
in the crude product mixtures by HPLC analysis (CS Multosorb
2. Results and discussion
Initially, we were interested in a convenient synthesis of tro-
zamicol analogues such as 3bb (Fig. 1).16 Recently, results were
published by Emond and co-workers, who disclosed members of
the regioisomeric 4-cycloamino-piperidin-3-ol series, as even more
favourable in terms of VAChT binding properties.22 However, these
comparisons were made with a series of structurally related pi-
perazines (Fig. 1, azaprezamicol 4aa with R¼N) instead of the
originally used piperidines (prezamicols, 4bb with R¼CH).16
Therefore, as part of our persistent efforts in the search for new
VAChT ligands for PET we elaborated a diversity-oriented short-
step preparation of both regioisomeric forms, which would obviate
the need for protection and deprotection steps.
RP18d7
mm, 250ꢁ4 mm).
In addition to EtOH, also other protic solvents, such as 2-prop-
anol (IPA) and 2,2,2-trifluoroethanol28 (TFE) were found to be well
suited for a reasonably rapid conversion of the starting epoxide at
95 ꢀC (Table 1, entries 1e3, 12 and 13). The best C3-regioselectiv-
ities20 were observed when IPA was used as the solvent, in spite of
resulting in a somewhat lower reaction rate (Table 1, entries 2 and
13). On the other hand, the shorter reaction time in TFE appeared to
2.1. Synthesis of 1-aralkyl 3,4-epoxypiperidines
Amongst a number of routes to 1-aralkyl tetrahydropyridines,
which were needed as starting materials,23 we regarded the bo-
rohydride reduction of an N-alkyl pyridinium salt as the most

3450
M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
Table 1
To further investigate the synthetic scope, a wider series of al-
iphatic and aromatic amines was applied in conversions with ep-
oxides 7aec. The entries of Table 2 clearly show that apart of
cycloamines (Table 2, entries 1, 4, 8 and 9), also small and bulky
aliphatic amines (Table 2, entries 3 and 2) may all be coupled using
this method.
Investigation of the conditions for the formation of aminoalcohols 3/4 from epoxide
7 and amine 8 produced via Scheme 2
Entry 7þ8a
1
2
3
4
5
6
7
Solvent (T [ꢀC]) Salt (mol %)b
t (h)c Ratio 3/4d
7aþ8a EtOH (95)
d
6
7
3aa/4aa 94:6
96:4
7aþ8a IPA (95)
d
7aþ8a TFE (95)
7aþ8a ACN (85)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7aþ8a ACN (rt)
7bþ8b EtOH (95)
7bþ8b IPA (95)
7bþ8b ACN (rt)
7bþ8b ACN (rt)
7dþ8a ACN (rt)
7dþ8a IPA (90)
d
4
92:8
d
96
12
40
12
40
20
240
12
4
93:7
9:91
46:54
4:96
9:91
10:90
43:57
39:61
Table 2
LiClO4 (120)
LiClO4 (20)
LiBr (120)
LiBr (20)
LiCl (120)
NaClO4 (120)
Mg(ClO4)2 (120)
d
Synthesis of trans-3-amino-piperidin-4-ols 3
8
9
10
11
12
13
14
15
16
17
3bb/4bb 92:8
94:6
d
6
LiBr (120)
LiClO4 (120)
LiClO4 (120)
d
12
12
18
18
5:95
7:93
3da/4da 37:63e
60:40e
,f
a
Solutions of 7 for salt-assisted [0.1e0.25 M] and for reactions without a salt
[0.5 M] were used; amine 8 was applied in a ratio of 1.08 to epoxide 7.
b
mol % relative to epoxide 7.
No starting epoxide was detected by TLC.
Relative ratios of products, which were not isolated, but determined by HPLC,
c
d
,
d
Entry Reactants Ratio 8/7 a Solvent (T [ꢀC])a t (h) Product 3 (yield %)c
unless otherwise noted (see Supplementary data; pairs of regioisomers, 3aa/4aa and
3bb/4bb have approximately equal UV response factors).
1
2
3
4
5
6
7
8
9
7bþ8b
7bþ8e
7aþ8f
7aþ8a
7aþ8g
7aþ8h
7cþ8h
7bþ8c
7bþ8d
1.04
5.0
6.1
1.01
1.12
2.0
1.9
1.02
1.05
IPA (95)
IPA (90)
6
3bb (80)
e
Determined by 1H NMR analysis.
18 3be (63)
f
Isolated yield of 3da: 25%, 4da: 22%.
EtOH (60)
IPA (95)
EtOH (90)
EtOH (85)
EtOH (85)
IPA (95)
18 3af (66)e
6
3aa (83)
48b 3ag (70)
20 3ah (71)
30 3ch (83)
be accompanied by a lower regioselectivity, which might be due to
the strong H-bond donating properties of TFE (Table 1, entry 3). The
time required for completion of the reaction in ACN as aprotic
solvent was significantly increased, with preservation of the C3-
regioselectivity (Table 1, entry 4).
As expected, the epoxide ring opening with an aliphatic amine
in ACN was accelerated in the presence of a metal salt and was
found to be completed at room temperature within up to 12 h. The
conversions resulted in a regioselectivity change to yield pre-
dominantly 3-hydroxypiperidinols, derived from a C4-attack on the
starting epoxide.
6
6
3bc (64)
3bd (71)
IPA (95)
a
b
c
Solutions of 7 [0.5e1.0 M] and 8 were reacted in a pressure tube.
The conversion in IPA needed 72 h (95 ꢀC) to go to completion.
Crystallized yield (free of C4-regioisomer, as detected by TLC and 1H NMR
analysis).
d
Isolated by evaporation of the reaction mixture and crystallization (see Exper-
imental): 3bb, 3aa, 3ch, 3bd (free base); 3be, 3bc (2HCl salt); 3ag (HCl salt) and 3ah
(hemioxalate salt).
e
Both regioisomers were separated by flash chromatography (see Supplementary
data), followed by crystallization as 2HBr salt: 3af (major isomer), as 2HCl salt: 4af
Among a series of alkali and earth alkali salts, which were tested
as activators for ring opening of 7a, 7b and 7d by cyclic amines,
(minor isomer, in 8% yield).
30
LiBr29 and LiClO4 gave the best results (Table 1, entries 5e8 and
14e16). Repeatedly, LiBr turned out to be slightly superior as ad-
ditive. Thus, a C4-/C3-product ratio of up to 96:4 could be observed
after reaction of epoxide (7a or 7b) in the presence of 120 mol % of
LiBr (Table 1, entries 7 and 14). By contrast lower ratios were
obtained with LiClO4 (Table 1, entries 5 and 15). The favourable
effect of LiBr compared to LiClO4y became more apparent when the
amount of the added salt was reduced to 20 mol % (Table 1, entry 6
vs entry 8).
In contrast to LiBr and LiClO4, the reaction in the presence of LiCl
proceeded slower and gave a slightly lower regioselectivity (Table 1,
entry 9). Interestingly, Mg(ClO4)2 shows good potential as activator,
however, with a very poor regioselectivity (Table 1, entry 11).
NaClO4, which was reported to be capable of activating the regio-
selective aminolysis of 3,4-epoxytetrahydropyran,30 was virtually
inactive in our approach (Table 1, entry 10).
In addition to aliphatic amines also weakly nucleophilic anilines
turned out as suitable substrates and gave the corresponding C3-
products as crystalline bases or salts without the need of chro-
matographic separation (Table 2, entries 5e7). However, due to the
reduced nucleophilicity compared to aliphatic cycloamines it was
found advisable for a shorter reaction time to work in EtOH (Table
2, entry 5) and apply a substantial excess of the aniline derivative,
which could be readily removed by distillation during the work-up
(Table 2, entries 6 and 7).
It should be noted that any attempt to analyze mixtures of 3ag/
4ag (Table 2, entry 5) by TLC failed. The 1HNMR analysis of the crude
reaction mixture revealed a ratio of 93:7 (see Supplementary data).
A second series of ring-opening reactions was carried out under
metal-assisted conditions in ACN, by using either LiBr or LiClO4. The
desired C4-aminoalcohols were efficiently prepared and isolated as
free bases (Table 3).
The obtained yields appeared to benefit from the use of LiBr as
additive in direct comparison with LiClO4 (Table 3, entries 1e8),
thus confirming aforementioned results (see Table 1).
Next, we were interested to compare aliphatic and aromatic
amines, which have been found to create high regioselectivity in
both types of ring openings of 7aec with 4-thiocresol (8s) as
a sulfur nucleophile. As depicted in Scheme 3, a reaction of 8s with
epoxide 7a, carried out in EtOH at 60 ꢀC, was judged as being
completed by TLC after 6 h. However, a mixture of 3as/4as was
1-Ethoxycarbonyl-3,4-epoxypiperidine 7d was similarly reacted
in two experiments with 8a. As expected, regioselectivity was low
in both conversions (Table 1, entries 16 and 17). The results indicate
that the existence of a localized nitrogen lone pair in 1-aralkyl-3,4-
epoxypiperidines, such as 7a or 7b, unlike 7d, is supposed to be
required for achieving high regioselectivity.
y
In organic solvents lithium perchlorate is a potential explosive hazard. It must
be handled in small amounts and with appropriate care.

M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
3451
Table 3
As expected, the Li-assisted reaction led to a full conversion of
7a within 10 h at 22 ꢀC and to a high predominance of the C4-
product 4as, which was isolated in 89% yield.19c
Synthesis of trans-4-amino-piperidin-3-ols 4
2.3. NMRdstructural correlations
The structure of trans-3-amino-4-hydroxy- and trans-4-amino-
3-hydroxy piperidines, obtained by C3- and C4-ring opening of
epoxides 7aed was confirmed by NMR measurements in CDCl3 (1H,
13C, 19F, APT, COSY, HSQC, and HMBC at 22 ꢀC). With combination of
these methods it was possible to assign unambiguously almost all
the signals for protons, carbons and fluorines as well.
b
Entry
Reactants
Li-salta
Ratio 8/7
t (h)
Product 4 (yield %)c
1
2
3
4
5
6
7
8
7bþ8b
7bþ8b
7bþ8e
7bþ8e
7aþ8f
7aþ8f
7aþ8a
7aþ8a
7aþ8g
7aþ8h
7cþ8h
LiClO4
LiBr
LiClO4
LiBr
LiClO4
LiBr
LiClO4
LiBr
1.04
1.04
1.3
1.3
4.2
12
12
24
24
12
12
12
12
24
24
24
4bb (79)
4bb (82)
4be (76)
4be (82)
4af (80)
4af (91)
4aa (70)
4aa (85)
4ag (96)
4ah (92)
4ch (86)
Regarding the 13C-APT signals associated to the piperidin-3/-4-
ol ring carbons, the secondary 5-C could be observed as signal in
the range of 20e38 ppm. In case of products derived from a C4-ring
opening, the piperidine 5-C is vicinal to a primary or secondary
amino group (or thioether) and frequently gave an isolated signal,
4.5
1.07
1.07
1.05
1.25
1.25
9
10
11
LiBr
LiBr
LiBr
which is caused by stronger shielding (
d<30 ppm) relative to the
corresponding 5-C in C3-products ( >30 ppm), which is neigh-
d
a
120 mol % relative to epoxide.
boured to the tertiary hydroxymethylene (4eC) carbon. Only one
exceptional case was found in the 3be/4be pair of regioisomers. As
expected, a reverse shift was consistently observed also for the
piperidin-3/-4-ol 2-C resonances.
b
c
No starting epoxide was detected by TLC.
Crystallized yield (free of C3-regioisomer, as detected by TLC or H NMR analy-
sis); Isolated after aqueous work-up followed by evaporation and crystallization (for
further details see Experimental part and Supplementary data): 4bb, 4aa, 4ag, 4ah,
4be (free base); 4af (2HCl salt); 4ch (HCl salt).
2.4. Steric effects on regioselectivity
formed in a ratio of approximately 1:2 as determined by 1H NMR
analysis. Both regioisomers were readily separated by medium
pressure chromatography (MPLC). A slight modification, by using
1,1,3,3-tetramethylguanidine (TMG) as strong base to deprotonate
8s allows to reduce the reaction temperature to 40 ꢀC, but the
product distribution was found to be displaced now even further
towards the regioisomer 4as, derived from the cleavage of the ep-
oxy C4-bond.
Because of the structural resemblance of 1-benzyl-3,4-epoxy-
piperidine 7a with epoxycyclohexane its conformation could be
regarded ashalf-chair witha quasi-axialand quasi-equatorialH-atom
at 2-C and 5-C as well.31 In contrast to the latter one, which rapidly
equilibrate between two enantiomeric conformations,31b 3,4-epoxy-
piperidine may similarly switch its conformation, however, into
forms, which appear to be energetically unequal (Scheme 4, con-
formers A and B). Due to mutual repulsion of one of the two O-lone
pairs with the localized lone pair of the piperidine nitrogen in A, the
prevalence of B as energetically favoured conformer is more likely.32
A small amine nucleophile (Nu1), intended to react axially and
33
€
in accordance with the FurstePlattner rule with the epoxide
electrophile in B (Scheme 4, B2), may preferentially attack at the 3-
C epoxy carbon due to the sterically unfavourable interaction (of
the lone pair in Nu1) with the bonding pair of the H-atom in quasi-
axial position on 5-C, located at the same side.34
Regarding the different regioselectivity of the thiolysis reaction
in EtOH (Scheme 3) it appears that the attack of thiol 8s on con-
formation A becomes more decisive (Scheme 4, Nu2 on A1). Due to
its character as a softer Lewis base a repulsive force between the
more spacious lone pairs on the thiol S-atom and the lone pair of
Scheme 3. Thiolysis of 7a by 4-thiocresol 8s under different conditions.
Scheme 4. Rationalization of the regiocontrol in the course of the nucleophilic ring opening of 7a.

3452
M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
Scheme 5. Synthesis of hexahydro-pyrido oxazin-ones 12 and 13.
the piperidine nitrogen as depicted in B1 (Scheme 4) might take
place. A similar regioselectivity has been reported in ring-opening
reactions of 3,4-epoxytetrahydropyran.30
applying tuned experimental protocols resulting in a high regiose-
lection. Thus, avoiding a deprotection step and a time consuming
chromatographic separation it was possible to obtain 4-FBT in an
overall yield of up to 51% (3-pot/4-step¼68%þ93%þ80%), starting
from simple starting materials. The high regioselectivity observed
appears to be induced mainly by steric reasons.
In case of the nucleophilic ring-opening reactions assisted by
aLiesalt,themetal-ionappearstobechelatedbothwiththeepoxyO-
and the piperidine N atom. Primarily, there is an electronic activation
both on 3-C and 4-C through the epoxide oxygen, which is co-
ordinated to the lithium cation. In addition a ‘frozen’ conformation C
is more likely, which will be attacked by the nucleophile Nu (Nu1 or
Nu2) preferentially at the 4-C epoxy carbon from steric reasons,
which are quite similar to the non-chelate case (Scheme 4, C1).
4. Experimental part
4.1. General
NMR spectra were recorded using Varian spectrometers (Varian
Gemini, Varian Mercury). Mass spectra were recorded on an FT-ICR
APEX II (Bruker Daltonics) and a Mariner Biospectrometry Work-
station (Applied Biosystems). Analytical TLC was performed on
silica gel coated sheets (MachereyeNagel 60 F254, 0.25 mm thick-
ness) with the following mixtures of solvents: Sm2 (CHCl3, MeOH,
NH3; 10:1:0.1); sm4 (CHCl3, MeOH; 12:1). Organic solvents were
purified by standard procedures. Starting amines (8aeh) were
commercial products.
2.5. Synthesis of hexahydro-pyrido oxazin-ones
Intrigued by the opportunity of achieving an efficient dual
regiocontrol we sought to further develop this method to obtain
two potential new molecular entities (NMEs). Thus, starting either
from ring opened product 4ch or 3ch a simple two-step access to
conformationally rigid fluorinated anilidopiperidine analogues 12
and 13 was conceived. Both pathways and the synthesis of new 3-
hydroxyfentanyl derivatives 10a and 10b as well are depicted in
Scheme 5.
4.2. Preparation of N-aralkyl-1,2,3,6-tetrahydropyridines
Due to the steric demand and reduced nucleophilicity of the
phenylamino group in addition to the competing vicinal OH-group
a selective and efficient N-acylation was anticipated to be difficult.
While the fluoroacetyl derivative 10b was obtained under standard
conditions in only 47% yield, the conversions of 9a and 9c in toluene
at 130 ꢀC without an added base gave an improvement to gain 10a
and 10c in reasonable yields. The hexahydro-1H-pyrido[3,4-b][1,4]
oxazin-2(3H)-one 12 was finally obtained from 10c applying an
approved ring-closure protocol.7
We next examined the conversion of 3ch into the expected
lactame 13 by the corresponding pathway. The initial N-chlor-
oacetylation to form 11c was found to proceed smoothly, but for its
subsequent ring closure under similar conditions as described for
12, we were faced with a greater extent of hydrolysis back to the
anilinoalcohol 3ch. Therefore, a modified protocol with a THF so-
lution of potassium tert-butanolate at ꢂ12 ꢀC for 1 h was adapted to
obtain hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one 13 after
removal of 3ch by flash chromatography.
The required 1,2,3,6-tetrahydropyridines 6a,23d and 6c35 were
prepared according to an approved protocol.24 The preparation of
6b outlined below represents a typical procedure.
4.2.1. Representative procedure of 1-(4-fluorobenzyl)-1,2,3,6-tetra-
hydropyridine (6b). A mixture of pyridine (2.0 g, 25.2 mmol) and 4-
fluorobenzylchloride (3.62 g, 25 mmol) was stirred at 22 ꢀC for 24 h.
The resulting highly viscous material was heated to w130 ꢀC for 1 h
while the pyridinium salt solidified as a reddish mass. It was crushed,
dissolved by stirring in EtOH (20 mL), and NaBH4 (1.22 g, 32 mmol)
was gradually added at 0e3 ꢀC within 6 h. The resulting mixture was
stirred for 14 h at 10e20 ꢀC, H2O (15 mL) and Celite (1 g) were added
and stirring was continued for 5 h. The solid was filtered off, washed
with EtOH (3ꢁ3 mL) and the filtrate was concentrated to a volume of
w15 mL. After addition of aqueous NaOH (0.25 M, 15 mL), the two-
phase mixture was extracted with MTBE (4x15 mL). The combined
organic phase was washed with brine (15%, 15 mL), dried (Na2CO3),
filtered and evaporated. The residualorange oil (5.1 g)waspurified by
distillation to provide 6b (3.25 g, 68%), as a slightly yellowish oil,
bp(12 mbar) 114e116 ꢀC; 1H NMR (300.1 MHz, CDCl3): dH 2.12e2.20 (m,
2H, 3-H2), 2.54 (t-like, J¼5.5 Hz, 2H, 2-H2), 2.95 (m, 2H, 6-H2), 3.54 (s,
2H, ArCH2N), 5.62e5.69 (m, 1H, 4-H), 5.72e5.80 (m, 1H, 5-H),
6.95e7.04(m, 2H, Ar:30-H, 50-H), 7.28e7.35(m, 2H, Ar:20-H, 60-H);13C
NMR (75.4 MHz, CDCl3): dC 26.28 (3-C), 49.70 (2-C), 52.85 (6-C), 62.26
(ArCH2N), 115.09 (d, J¼21.01 Hz, 2CAr, 30-C, 50-C), 125.38 (4-C), 125.42
3. Conclusion
Insummary, wepresent anefficient3-pot/4-stepapproachforthe
preparation of 3-amino-4-hydroxypiperidines and its regioisomers.
In contrast to former methodology, processing a common N-acyl or
N-carbamoyl protective group at the 3,4-epoxypiperidine, which
exclusivelyledto a low regioselectivity, the 1-aralkyl group allowsfor

M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
3453
(5-C),130.70 (d, J¼7.74 Hz, 2CAr, 20-C, 60-C),134.23 (d, J¼2.21 Hz,1CAr,
10-C), 162.11 (d, J¼244.4 Hz, 1CAr, 40-C); 19F NMR (282.3 MHz, CDCl3):
dF ꢂ116.46 (m,1FAr, 40-F); LRMS (ESI) m/z¼192.12 (MHþ,100%); HRMS
(ESI) calcd for C12H14FN [MþH]þ: 192.11830; found: 192.11830.
completion of the reaction, as indicated by TLC analysis (sm2). The
solvent was evaporated and the viscous residue was dissolved in
CHCl3 (5 mL), filtered through a plug of silica gel 60 (40e63 mm,
w0.6 g) and evaporated. The solid was recrystallized from MeOH/
H2O (4:1, 1.5 mL) to yield 3bb (0.171 g, 80%), as white crystals, mp
144e146 ꢀC; Rf¼0.50 (sm2); 1H NMR (300.1 MHz, CDCl3): dH 1.61 (m,
1H, 5-Ha), 1.63e2.02 (m, 6H, 2-Ha, 6-Ha, 30-H2, 50-H2), 2.04 (ddd,
J¼11.7, 4.7, 2.3 Hz, 1H, 5-Hb), 2.26 (dt-like, J¼11.7, 2.3 Hz, 1H, 20-Ha),
2.46 (tt-like, J¼11.7, 4.1 Hz,1H, 40-H), 2.54 (dt-like, J¼10.5, 3.5 Hz,1H,
3-H), 2.72 (m, 1H, 60-Ha), 2.79e2.88 (m [br], 2H, 6-Hb, 60-Hb),
2.96e3.06 (m, 2H, 2-Hb, 20-Hb), 3.46 (ddd, J¼10.5, 10.0, 4.7 Hz,1H, 4-
H), 3.50 (AB, J¼13.5 Hz, 2H, ArCH2N), 3.70 (s [br], 1H, OH), 7.01 (m,
2HAr, 300-H, 500-H), 7.16e7.34 (m, 7HAr, 200-H, 600-H, 2000-H, 6000-H); 13C
NMR (75.449 MHz, CDCl3): dC 32.38 (1Csec, 5-C), 34.24 (1Csec, 30-C [or
50-C]), 34.46 (1Csec, 50-C [or 30-C]), 43.06 (1Ctert, 40-C), 46.10 (1Csec, 20-
4.3. Epoxidation of 1-aralkyl-1,2,3,6-tetrahydropyridines
4.3.1. Representative procedure of 1-(4-fluorobenzyl)-3,4-epox-
ypiperidine (7b). A mixture of UHP (1.85 g, 19.6 mmol) in dry DCM
(16 mL) was stirred at 5 ꢀC while a solution of TFAA (4.12 g, 2.74 mL,
19.6 mmol) in DCM (8 mL) was gradually added within 15 min. The
resulting mixture was stirred at 0e2 ꢀC for 1 h. A cold solution pre-
pared from 6b (2.68 g, 14 mmol) and trifluoroacetic acid (TFA, 2.08 g,
18.2 mmol) in DCM (10 mL) was added at 2e6 ꢀC within 5 min. After
stirring at 0e3 ꢀC for 20 min, the temperature was reduced to ꢂ15 to
ꢂ10 ꢀC. A solution of Na2SO3 (1.52 g, 12 mmol) and K2CO3 (3.46 g,
25 mmol) in H2O (18 mL) was carefully added to the vigorously stirred
mixture without allowing the temperature to raise above 10 ꢀC. After
addition, the mixture was stirred for 2 min and a test of the aqueous
(upper) layer with KI-starch paper displayed a negative result for the
presence of peroxide. The organic phase was separated and the aque-
ous layer was extracted with DCM (2ꢁ10 mL). The combined organic
phase was washed with NaHCO3 (7.5%, 8 mL), dried (Na2CO3), filtered
and evaporated. The residue (3.6 g) was dissolved in MTBE (12 mL),
C), 50.17 (1Csec, 2-C), 51.66 (1Csec, 6-C), 53.76 (1Csec, 60-C), 62.36 (1Csec
,
ArCH2N), 67.61 (1Ctert, 4-C), 68.21 (1Ctert, 3-C), 115.56 (d, J¼22.1 Hz,
2CAr, 300-C, 500-C), 126.31 (1CAr, 4000-C), 126.91 (2CAr, 2000-C, 6000-C),
128.56 (2CAr, 3000-C, 5000-C),130.47 (d, J¼7.7 Hz, 2CAr, 200-C, 600-C),134.18
(d, J¼3.3 Hz, 1CAr, 100-C), 146.28 (1CAr, 1000-C), 162.13 (d, J¼245.5 Hz,
1CAr, 400-C); 19F NMR (282.3 MHz, CDCl3): dF ꢂ116.25 (m, 1FAr, 400-F);
LRMS (ESI) m/z¼369.25 (MHþ,100%). Anal. Calcd for C23H29FN2O (%):
C, 74.97; H, 7.93; N, 7.60. Found: C, 74.95; H, 8.02; N, 7.56.
filtered through a plug of silica gel 60 (40e63
m
m, w2 g) and evapo-
4.4.2. (3SR,4SR)-1-Benzyl-4-(4-phenylpiperazin-1-yl)piperidin-3-ol
(3aa). According to representative procedure in Section 4.4.1, col-
ourless powder, yield: 83%; mp 123e125 ꢀC [MeOH/H2O (5:1)] (lit.22
mp 131e132 ꢀC); Rf¼0.39 (sm2); 1H NMR (300.1 MHz, CDCl3): dH
1.62 (m,1H, 5-Ha),1.96 (m,1H, 2-Ha),1.98 (m,1H, 6-Ha), 2.06 (m,1H, 5-
Hb), 2.59 (dt-like, J¼10.0, 3.5 Hz, 1H, 3-H), 2.64 (m, 2H, 20-Ha, 60-Ha),
2.87(m [overlapped],1H, 6-Hb), 2.93 (m, 2H, 20-Hb, 60-Hb), 3.04 (m,1H,
2-Hb), 3.17(m, 4H, 30-H2, 50-H2), 3.48(m,1H, 4-H),3.54(s,2H, PhCH2N),
3.59(s[br],1H, OH),6.84e6.94 (m, 3HAr, 6000-H, 2000-H, 4000-H), 7.22e7.38
(m, 7HAr, 3000-H, 5000-H, 200-H, 600-H); 13C_APTNMR(75.4 MHz,CDCl3): dC
32.34 (1Csec, 5-C), 48.78 (2Csec, 30-C, 50-C), 50.13 (2Csec, 20-C, 60-C), 50.16
(1Csec, 2-C), 51.67 (1Csec, 6-C), 63.19 (1Csec, ArCH2N), 67.57 (1Ctert, 4-C),
67.79 (1Ctert, 3-C),116.39 (2CAr, 2000-C, 6000-C),120.05 (1CAr, 4000-C),127.24
(1CAr, 400-C), 128.39 (2CAr, 300-C, 500-C), 129.11 (2CAr, 200-C, 600-C), 129.22
(2CAr, 3000-C, 5000-C), 138.22 (1CAr, 100-C), 151.41 (1CAr, 1000-C); LRMS (ESI)
m/z¼352.26 (MHþ, 100%). Anal. Calcd for C22H29N3O (%): C, 75.18; H,
8.32; N, 11.96. Found: C, 75.35; H, 8.63; N, 11.79.
rated to leave a product (2.82 g, 97%), which turned out to be pure
enough for subsequent transformations. The product was further pu-
rified by bulb-to-bulb distillation in vacuo (1e2 mbar) at 130e150 ꢀC
(air-bath temperature) to yield 7b (2.70 g, 93%), as a colourless oil; 1H
NMR (400.0 MHz, CDCl3): dH 1.91e2.00 (2 m, 2H, 5-H2), 2.18 (ddd,
J¼11.7, 9.4, 4.7 Hz,1H, 6-Ha), 2.29 (m, 1H, 6-Hb), 2.66 (d, J¼13.3 Hz, 1H,
2-Ha), 2.97 (ddd, J¼13.3, 3.9,1.6 Hz,1H, 2-Hb), 3.18e3.24 (m, 2H, 3-H, 4-
H), 3.40 (s, 2H, PhCH2N), 6.98 (m, 2HAr, 30-H, 50-H), 7.24 (m, 2HAr, 20-H,
60-H); 13C NMR (100.0 MHz, CDCl3): dC 25.66(1Csec, 5-C), 45.87 (1Csec,6-
C), 50.73 (1Ctert, 3-C {or 4-C}), 51.35 (1Ctert, 4-C {or 3-C}), 52.38 (1Csec, 2-
C), 61.59 (1Csec, 4F-PhCH2N), 115.12 (d, J¼22.1 Hz, 2CAr, 30-C, 50-C),
130.55 (d, J¼8.8 Hz, 2CAr, 20-C, 60-C), 133.79 (d, J¼4.4 Hz, 1CAr, 10-C),
162.12 (d, J¼246.2 Hz, 1CAr, 40-C); 19F NMR (376.4 MHz, CDCl3): dF
ꢂ116.18 (m, 1FAr, 40-F); LRMS (ESI) m/z¼208.12 (MHþ, 100%); HRMS
(ESI) calcd for C12H14FNO [MþH]þ: 208.11322; found: 208.11322.
4.3.2. 1-Phenethyl-3,4-epoxypiperidine (7c). Following the repre-
sentative procedure in Section 4.3.1, by using 6c (3.75 g, 20 mmol),
UHP (2.65 g, 28 mmol) and TFAA (5.9 g, 3.93 mL, 28 mmol) to
provide 7c (3.74 g, 92%), as a slightly yellowish oil. A sample
(625 mg) was further purified by isocratic MPLC using MTBE with
1% additive of 32% solution of trimethylamine in IPA to obtain 7c
(562 mg, 83%), as a colourless oil; 1H NMR (300.1 MHz, CDCl3): dH
1.97e2.17 (m, 2H, 5-H2), 2.32 (ddd, J¼11.7, 8.8, 4.7 Hz, 1H, 6-Ha),
2.39 (m, 1H, 6-Hb), 2.54e2.61 (m, 2H, PhCH2eCH2N), 2.75e2.83 (m,
3H, 2-Ha, PhCH2eCH2N), 3.09 (ddd [br], J¼13.5, 4.1, 1.2 Hz, 1H, 2-
Hb), 3.24e3.28 (m [br], 2H, 3-H, 4-H), 7.12e7.32 (2 m, 5HAr, ArH);
4.4.3. (3SR,4SR)-3-(4-Fluorophenylamino)-1-phenethylpiperidin-4-
ol (3ch). According to representative procedure in Section 4.4.1,
white powder, yield: 83%; mp 131e132 ꢀC (MeOH); Rf¼0.42 (sm2);
1H NMR (400.0 MHz, CDCl3): dH 1.71 (m, 1H, 5-Ha), 2.01 (m [br], 1H,
2-Ha), 2.06 (m,1H, 5-Hb), 2.26 (dt-like, J¼11.7, 3.1 Hz,1H, 6-Ha), 2.44
(br, 1H, OH), 2.61 (A-part of AA’BB0, 2H, PhCH2CH2N), 2.78 (B-part of
AA’BB0, 2H, PhCH2CH2N), 2.87 (m, 1H, 6-Hb), 3.09 (dd, J¼11.7, 2.3 Hz,
2-Hb), 3.36 (br, 1H, 3-H), 3.46e3.59 (m [br], 2H, 4-H, NH), 6.62 (A-
part of AA’MM0X, 2HAr, 30-H, 50-H), 6.89 (M-part of AA’MM0X, 2HAr
20-H, 60-H), 7.20 (m, 3HAr, 200-H, 400-H, 600-H), 7.29 (m, 2HAr, 300-H, 500-
H); 13C NMR (100.6 MHz, CDCl3): dC 31.79 (1Csec, 5-C), 33.78 (1Csec
,
,
13C NMR (75.4 MHz, CDCl3): dC 25.66 (1Csec
,
5-C), 33.64
(PhCH2CH2N), 46.34 (1Csec, 6-C), 50.63 (1Ctert, 3-C [or 4-C]), 51.38
(1Ctert, 4-C [or 3-C]), 52.37 (1Csec, 2-C), 59.98 (PhCH2CH2N), 126.15
(1CAr, 40-C), 128.49 (2CAr, 30-C, 50-C), 128.74 (2CAr, 20-C, 60-C), 140.27
(1CAr, 10-C); LRMS (ESI) m/z¼204.08 (MHþ, 100%); HRMS (ESI) calcd
for C13H17NO [MþH]þ: 204.13829; found: 204.13829.
PhCH2CH2N), 50.92 (1Csec, 6-C), 56.19 (1Csec, 2-C), 57.41 (1Ctert, 3-C),
59.89 (1Csec, PhCH2CH2N), 71.28 (1Ctert, 4-C), 114.95 (d, J¼7.3 Hz,
2CAr, 20-C, 60-C), 115.98 (d, J¼22.1 Hz, 2CAr, 30-C, 50-C), 126.20 (1CAr
,
400-C), 128.51 (2CAr, 300-C, 500-C), 128.81 (2CAr, 200-C, 600-C), 140.30
(1CAr, 100-C), 143.55 (d, J¼2.2 Hz, 1CAr, 10-C), 156.28 (d, J¼235.9 Hz,
1CAr, 40-C); 19F NMR (376.4 MHz, CDCl3): dF ꢂ127.32 (s, 1FAr, 400-F);
ESI-MS: m/z¼315.08 (MHþ, 100%). Anal. Calcd for C19H23FN2O (%):
C, 72.58; H, 7.37; N, 8.91. Found: C, 72.35; H, 7.44; N, 8.86.
4.4. Non-Lewis acid-catalysed epoxide ring opening of 7aec
4.4.1. Representative procedure of (3SR,4SR)-1-(4-fluorobenzyl)-3-
(4-phenylpiperidin-1-yl)piperidin-4-ol (3bb). A mixture of epoxide
7b (0.12 g, 0.58 mmol) and 4-phenylpiperidine (8b, 0.097 g,
0.6 mmol) in IPA (0.8 mL) was stirred in a closed reaction vial (4 mL
volume) and heated to 95e98 ꢀC (bath temperature) for 6 h, till the
4.5. LiBr-assisted epoxide ring opening of 7aec
4.5.1. Representative procedure of (3SR,4SR)-1-(4-fluorobenzyl)-4-(4-
phenylpiperidin-1-yl)piperidin-3-ol (4bb). LiBr (0.185 g, 2.1 mmol),

3454
M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
which was dried by heating under a stream of dry argon, was dis-
solved in anhydrous ACN (2 mL). A solution of epoxide 7b (0.248 g,
1.195 mmol) in ACN (1 mL) was added and the resulting mixture
was stirred for 5 min followed by the addition of a solution of 4-
phenylpiperidine (8b, 0.195 g, 1.21 mmol) in ACN (0.5 mL). The re-
action mixture was stirred at 22 ꢀC for 12 h. Compound 7b was
completely consumed as detected by TLC (sm2, Rf[7b]¼0.65) and
a single product appeared (sm2, Rf¼0.54). The solvent was evapo-
rated and H2O (10 mL) was added to the residue. The heteroge-
neous mixture was extracted with CHCl3 (1ꢁ10, 2ꢁ5 mL) and the
combined organic phases were dried (Na2CO3), filtered and evap-
orated to leave a yellowish viscous residue (410 mg). After tritura-
tion with MeOH (1 mL) a crystalline product was formed. The solid
was filtered off, washed with MeOH/H2O (4:1) and dried to obtain
4bb (0.287 g). A second crop (0.074 g) was isolated from the filtrate
after evaporation and trituration in a similar way to yield in total
0.361 g (82%), as a colourless solid, mp 120.5e124 ꢀC; 1H NMR
(300.1 MHz, CDCl3): dH, 1.56 (dddd, J¼12.3, 12.3, 12.3, 4.1 Hz, 1H, 5-
Ha), 1.62e1.92 (m, 6H, 5-Hb, 2-Ha, 30-H2, 50-H2), 2.00 (dt-like, J¼11.7,
2.9 Hz, 1H, 6-Ha), 2.25 (m, 2H, 4-H, 20-Ha), 2.50 (tt-like, J¼12.0,
3.7 Hz, 1H, 40-H), 2.73 (m, 2H, 60-H2), 2.96 (m, 2H, 6-Hb, 20-Hb), 3.21
(ddd, J¼10.0, 4.6, 1.8 Hz, 1H, 2-Hb), 3.51 (AB, J¼13.3 Hz, 2H,
ArCH2N), 3.62 (s [br], 1H, OH overlapped with ddd, J¼10.0, 10.0,
4.7 Hz, 1H, 3-H), 7.00 (m, 2HAr, 300-H, 500-H), 7.17e7.33 (m, 7HAr, 200-
2.83 (m [overlapped], 1H, 6-Hb), w3.1 (br, 1H, NH), 3.12 (m [br,
overlapped],1H, 4-H), 3.15 (m [br, overlapped],1H, 2-Hb), 3.60 (ddd,
J¼8.2, 8.2, 4.1 Hz, 1H, 3-H), 6.64 (A-part of AA0MM0X, 2HAr, 30-H, 50-
H), 6.90 (M-part of AA’MM0X, 2HAr, 20-H, 60-H), 7.17e7.33 (m, 5HAr
,
200-H, 600-H); 13C NMR (75.4 MHz, CDCl3): dC 29.91 (1Csec, 5-C), 33.79
(1Csec, PhCH2CH2N), 52.01 (1Csec, 6-C), 58.21 (2C [not resolved]:
1Ctert, 4-C; 1Csec, 2-C), 60.07 (1Csec, PhCH2CH2N), 70.98 (1Ctert, 3-C),
115.30 (d, J¼7.2 Hz, 2CAr, 20-C, 60-C), 115.93 (d, J¼22.6 Hz, 2CAr, 30-C,
50-C), 126.25 (1CAr, 400-C), 128.56 (2CAr, 300-C, 500-C), 128.81 (2CAr, 200-
C, 600-C), 140.24 (1CAr, 100-C), 143.72 (d, J¼1.7 Hz, 1CAr, 10-C), 156.40
(d, J¼236.7 Hz, 1CAr, 40-C); 19F NMR (376.4 MHz, CDCl3): dF ꢂ127.13
(s, 1FAr, 400-F); LRMS (ESI) m/z¼315.12 (MHþ, 100%). Anal. Calcd for
C19H23FN2O$HCl$¼EtOH$¼MTBE (%): C, 64.83; H, 7.47; N, 7.29.
Found: C, 64.83; H, 7.71; N, 7.12.
4.6. Two-step synthesis of hexahydro-pyrido oxazin-ones 12
and 13
4.6.1. 2-Chloro-N-(4-fluorophenyl)-N-((3RS,4RS)-3-hydroxy-1-phe-
nethylpiperidin-4-yl)acetamide (10c). Compound 4ch$HCl (0.105 g,
0.3 mmol) was stirred in toluene (1.6 mL) at 60 ꢀC, and 9c (0.09 g,
0.8 mmol) was added in one portion. The resulting mixture was
stirred at 130 ꢀC for 2 h, while a finely dispersed solid precipitated.
After cooling, the solvent and surplus of acid chloride were evap-
orated to leave a colourless solid, which was stirred with aqueous
NaHCO3 (7.5%, 4 mL) and extracted with DCM (2ꢁ5 mL). The or-
ganic phase was dried (Na2SO4), filtered and evaporated to give
a residue, which was slurried with MTBE/PE40e60 and filtered to
yield 10c (0.075 g, 64%), as a colourless powder; The isolated
compound was found to be pure by TLC; Rf¼0.44 (sm4); mp
186.5e188 ꢀC; 1H NMR (400.0 MHz, CDCl3): dH 1.40 (dddd, J¼12.5,
12.5, 12.5, 4.7 Hz, 1H, 5-Ha), 1.78 (m, 1H, 5-Hb), 2.09 (dd, 10.9,
10.2 Hz, 1H, 2-Ha), 2.18 (m [br], 1H, 6-Ha), 2.61 (A of AA’BB0, 2H,
PhCH2CH2N), 2.73 (B of AA’BB0, 2H, PhCH2CH2N), 2.93 (m [br],1H, 6-
Hb), 3.26 (m [br], 1H, 2-Hb), 3.45 (m [br], 1H, 3-H), 3.78 (AB,
H, 600-H, 2000-H, 6000-H); 13C NMR (75.4 MHz, CDCl3): dC 21.71 (1Csec
,
5-C), 34.07 (1Csec, 30-C [or 50-C]), 34.46 (1Csec, 50-C [or 30-C]), 43.09
(1Ctert, 40-C), 45.86 (1Csec, 20-C), 53.19 (1Csec, 6-C), 53.61 (1Csec, 60-C),
58.97 (1Csec, 2-C), 62.04 (1Csec, ArCH2N), 66.21 (1Ctert, 3-C), 69.70
(1Ctert, 4-C), 115.12 (d, J¼21.0 Hz, 2CAr, 300-C, 500-C), 126.30 (1CAr
,
4000,0-C), 126.94 (2CAr, 2000-C, 6000-C), 128.56 (2CAr, 3000-C, 5000-C),
130.68 (d, J¼7.7 Hz, 2CAr, 200-C, 600-C), 133.99 (d, J¼3.3 Hz,1CAr, 100-C),
146.36 (1CAr, 1000-C), 162.16 (d, J¼245.5 Hz, 1CAr, 400-C); 19F NMR
(282.3 MHz, CDCl3): dF ꢂ116.29 (m, 1FAr, 400-F); LRMS (ESI) m/
z¼369.25 (MHþ, 100%). Anal. Calcd for C23H29FN2O (%): C, 74.97; H,
7.93; N, 7.60. Found: C, 75.26; H, 8.10; N, 7.59.
2JHH¼13.3 Hz, 2H, ClCH2C]O), 4.59 (m,1H, 4-H), 7.11e7.21 (m, 6HAr
,
4.5.2. (3SR,4SR)-1-Benzyl-4-(4-phenylpiperazin-1-yl)piperidin-3-ol
(4aa). According to representative procedure in Section 4.5.1, col-
ourless solid, yield: 85%; mp 121e123 ꢀC (MeOH), (lit.22 mp
120e121 ꢀC); 1H NMR (400.0 MHz, CDCl3): dH 1.58 (dddd, J¼12.5,
12.5, 11.7, 3.9 Hz, 1H, 5-Ha), 1.76 (ddd, J¼12.5, 6.3, 3.1 Hz, 1H, 5-Hb),
1.92 (t-like, J¼10.2 Hz, 1H, 2-Ha), 2.02 (dt-like, J¼11.7, 2.3 Hz, 1H, 6-
Ha), 2.29 (ddd, J¼12.5, 10.2, 3.9 Hz, 1H, 4-H), 2.60 (ddd, J¼10.2, 6.3,
3.1 Hz, 2H, 20-Ha, 60-Ha), 2.91 (m, 2H, 20-Hb, 60-Hb), 2.96 (m, 1H, 6-
Hb), 3.19 (m, 4H, 30-H2, 50-H2), 3.25 (m, 1H, 2-Hb), 3.49 (s [br], 1H,
OH), 3.56 (AB, J¼13.3 Hz, PhCH2N), 3.65 (ddd, J¼10.2, 10.2, 4.7 Hz,
1H, 3-H), 6.85e6.95 (m, 3HAr, 6000-H, 2000-H, 4000-H), 7.23e7.36 (m,
7HAr, 3000-H, 5000-H, 200-H, 600-H); 13C_APT NMR (100.6 MHz, CDCl3):
dC 21.88 (1Csec, 5-C), 48.69 (2Csec, 30-C, 50-C), 50.09 (2Csec, 30-C, 50-C),
53.16 (1Csec, 6-C), 59.08 (1Csec, 2-C), 62.95 (1Csec, ArCH2N), 66.30
(1Ctert, 3-C), 69.37 (1Ctert, 4-C), 116.43 (2CAr, 2000-C, 6000-C), 120.10
(1CAr, 4000-C),127.36 (1CAr, 400-C), 128.47 (2CAr, 300-C, 500-C), 129.35
(2CAr, 200-C, 600-C), 129.37 (2CAr, 3000-C, 5000-C), 138.26 (1CAr, 100-C),
151.54 (1CAr, 1000-C); LRMS (ESI) m/z¼352.21 (MHþ, 100%). Anal.
Calcd for C22H29N3O (%): C, 75.18; H, 8.32; N, 11.96. Found: C, 75.31;
H, 8.62; N, 11.83.
30-H, 50-H, 60-H, 200-H, 400-H, 600-H), 7.26 (m, 2HAr, 300-H, 500-H), 7.48
(m [br], 1HAr, 20-H); 13C NMR (100.6 MHz, CDCl3): dC 28.73 (1Csec, 5-
C), 33.80 (1Csec, PhCH2CH2N), 42.64 (1Csec, ClCH2C]O), 52.38 (1Csec
,
6-C), 59.69 (1Ctert, 4-C), 59.89 (1Csec, PhCH2CH2N), 60.39 (1Csec, 2-C),
68.72 (1Ctert, 3-C), 116.70 (d, 2JCF¼22.1 Hz, 1CAr, 50-C [or 30-C]), 117.14
2
(d, JCF¼22.1 Hz, 1CAr, 30-C [or 50-C]), 126.27 (1CAr, 400-C), 128.56
3
(2CAr, 300-C, 500-C), 128.74 (2CAr, 200-C, 600-C), 132.15 (d, JCF¼8.8 Hz,
3
1CAr, 60-C [or 20-C]), 132.33 (d, JCF¼8.8 Hz, 1CAr, 20-C [or 60-C]),
4
132.71 (d, JCF¼4.4 Hz, 1CAr, 10-C), 140.02 (1CAr, 100-C), 162.98 (d,
1JCF¼250.6 Hz, 1CAr, 40-C), 168.55 (1Csec, ClCH2C]O); 19F NMR
(376.4 MHz, CDCl3): dF ꢂ111.27 (s, 1FAr, 40-F); ESI-MS: m/z¼391.04
(MHþ, 100%). Anal. Calcd for C21H24ClFN2O2 (%): C, 64.53; H, 6.19; N,
7.17. Found: C, 64.55; H, 6.02; N, 7.24.
4.6.2. (4aRS,8aRS)-1-(4-Fluorophenyl)-hexahydro-6-phenethyl-1H-
pyrido[3,4-b][1,4]oxazin-2(3H)-one (12). A stock solution of 2-
PrONa (3.39%, w/w) was prepared by dissolving sodium metal
(0.038 g, 1.653 mmol) in hot IPA (4.5 mL) and filling up with fresh
IPA to a final weight of 4 g. A mixture of 10c (0.096 g, 0.245 mmol)
in THF (3 mL) and IPA (1.5 mL) was stirred at 0e2 ꢀC, while a solu-
tion of 2-PrONa in IPA (3.39%, w/w, 0.665 g, 0.275 mmol) was added
at once. A finely dispersed precipitate (NaCl) was formed after 20 s.
The suspension was stirred at 0e2 ꢀC for 6 h. The reaction mixture
was acidified with aqueous citric acid (1%, 0.5 mL) and evaporated.
Water (10 mL) was added to the residue and it was made alkaline
with aqueous K2CO3 and extracted with MTBE (3x6 mL). The or-
ganic phases were combined, dried (Na2SO4), filtered and reduced
to a volume of w1 mL. The crystalline precipitate was filtered,
washed (MTBE/PE40e60) and dried to obtain 0.072 g. The product
was recrystallized from a mixture of IPA (1 mL) and MTBE (3 mL),
4.5.3. (3SR,4SR)-4-(4-Fluorophenylamino)-1-phenethylpiperidin-3-
ol (4ch). According to representative procedure in Section 4.5.1,
slowly crystallizing compound, which was converted into the
monohydrochloride of 4ch; colourless solid, yield: 86%; mp
124.5e127 ꢀC (EtOH/MTBE); Rf¼0.38 (sm2); For NMR, the base was
liberated with aqueous K2CO3; 1H NMR (300.1 MHz, CDCl3): dH 1.44
(m, 1H, 5-Ha), 2.10 (ddd, J¼12.3, 7.0, 4.1 Hz, 1H, 5-Hb), 2.21 (m
[overlapped], 1H, 2-Ha), 2.24 (m [overlapped], 1H, 6-Ha), 2.65 (m,
2H, PhCH2CH2N), w2.7 (m [br], 1H, OH), 2.80 (m, 2H, PhCH2CH2N),

M. Scheunemann et al. / Tetrahedron 67 (2011) 3448e3456
3455
followed by the addition of PE40e60 (2 mL) to yield 12 (0.061 g,
70%); as a colourless crystalline product, which was pure by TLC;
Rf¼0.41 (sm4), mp 156e157 ꢀC; 1H NMR (300.1 MHz, CDCl3): dH
1.40 (dddd, J¼12.3, 12.0, 11.7, 4.1 Hz, 1H, 8-Ha), 1.51 (m, 1H, 8-Hb),
2.03 (dt-like, J¼12.3, 2.9 Hz, 1H, 7-Ha), 2.14 (t-like, J¼10.0 Hz, 1H, 5-
Ha), 2.67 (A of AA’BB0, 2H, PhCH2CH2N), 2.79 (B of AA’BB0, 2H,
PhCH2CH2N), 2.91 (m, 1H, 7-Hb), 3.28 (ddd, J¼10.5, 4.1, 1.8 Hz, 1H, 5-
Hb), 3.54 (ddd, J¼11.7, 8.8, 4.7 Hz, 1H, 8a-H), 3.72 (ddd, J¼10.0, 10.0,
4.1 Hz, 1H, 4a-H), 4.45 (AB, J¼16.4 Hz, 2H, 3-H2), 7.08e7.33 (m,
9HAr); 13C_APT NMR (75.4 MHz, CDCl3): dC 29.05 (1Csec, 8-C), 33.82
(1Csec, PhCH2CH2N), 51.54 (1Csec, 7-C), 55.73 (1Csec, 5-C), 59.63
(1Csec, PhCH2CH2N), 60.73 (1Ctert, 8a-C), 68.94 (1Csec, 3-C), 76.06
applying a mixture of CHCl3 (150 mL)/MeOH (30 mL)/30% NH3
(4 mL) as eluent. The fraction eluted first was evaporated and the
residue (0.11 g) was triturated with MTBE/PE40e60 to yield 13
(0.072 g, 51%), as colourless crystals; Rf¼0.60 (sm2); mp
125e126 ꢀC; 1H NMR (400.0 MHz, CDCl3): dH 1.81 (dddd, J¼12.5,
12.5, 12.5, 4.7 Hz, 1H, 8-Ha), 1.83 (t-like [overlapped], J¼10.9 Hz, 1H,
5-Ha), 2.05 (m,1H, 8-Hb), 2.18 (dt-like, J¼12.5, 3.1 Hz,1H, 7-Ha), 2.56
(m, 2H, PhCH2CH2N), 2.63 (m, 3H, PhCH2CH2N, 5-Hb), 3.06 (m,1H, 7-
Hb), 3.49 (m,1H, 8a-H), 3.76 (ddd, J¼10.9, 9.4, 3.9 Hz,1H, 4a-H), 4.43
(AB, J¼16.4 Hz, 2H, 2-H2), 7.09e7.20 (m, 7HAr, 200-H, 400-H, 600-H, 20-H,
30-H, 50-H, 60-H), 7.24 (m, 2HAr, 300-H, 500-H); 13C_APT NMR
(100.6 MHz, CDCl3): dC 29.86 (1Csec, 8-C), 33.78 (1Csec, PhCH2CH2N),
(1Ctert, 4a-C), 116.43 (d, 2JCF¼22.6 Hz, 2CAr, 30-C, 50-C), 126.30 (1CAr
,
51.15 (1Csec, 7-C), 55.56 (1Csec, 5-C), 59.38 (1Ctert, 4a-C), 59.44 (1Csec,
400-C), 128.55 (2CAr, 300-C, 500-C), 128.75 (2CAr, 200-C, 600-C), 129.75 (d,
PhCH2CH2N), 69.04 (1Csec, 2-C), 78.03 (1Ctert, 8a-C), 116.46 (d,
2JCF¼22.8 Hz, 2CAr, 30-C, 50-C),126.26 (1CAr, 400-C),128.50 (2CAr, 300-C,
500-C), 128.64 (2CAr, 200-C, 600-C), 129.46 (d, 3JCF¼8.9 Hz, 2CAr, 60-C, 20-
3JCF¼8.3 Hz, 2CAr, 60-C, 20-C), 133.39 (d, JCF¼3.3 Hz, 1CAr, 10-C),
4
140.00 (1CAr,100-C),161.92 (d, 1JCF¼247.1 Hz,1CAr, 40-C),167.74 (1Csec
,
C]O [2-C]); 19F NMR (282.3 MHz, CDCl3): dF ꢂ113.98 (m, 1FAr, 40-F);
ESI-MS: m/z¼355.08 (MHþ, 100%). Anal. Calcd for C21H23FN2O2 (%):
C, 71.17; H, 6.54; N, 7.90. Found: C, 70.92; H, 6.58; N, 7.96.
C), 133.22 (d, JCF¼3.0 Hz, 1CAr, 10-C), 139.00 (1CAr, 100-C), 161.90 (d,
4
1JCF¼247.7 Hz, 1CAr, 40-C), 167.83 (1Csec, C]O [3-C]); 19F NMR
(376.4 MHz, CDCl3): dF ꢂ113.81 (t-like, 1FAr, 40-F); ESI-MS: m/
z¼355.16 (MHþ, 100%). Anal. Calcd for C21H23FN2O2 (%): C, 71.17; H,
6.54; N, 7.90. Found: C, 70.85; H, 6.68; N, 7.86.
4.6.3. 2-Chloro-N-(4-fluorophenyl)-N-((3RS,4RS)-4-hydroxy-1-phe-
nethylpiperidin-3-yl)acetamide (11c). Triethylamine (TEA, 0.292 g,
2.88 mmol) was added to a solution of 3ch (0.38 g,1.2 mmol) in DCM
(18 mL). The mixture was cooled to 0 ꢀC, while a solution of chlor-
oacetyl chloride (9c, 0.237 g, 2.1 mmol) in DCM (3.0 mL) was grad-
ually added. The reaction mixture was stirred at 0e3 ꢀC for 2 h. The
starting aniline (sm2, Rf¼0.43) was completely consumed as
detected by TLC and a product appeared (sm2, Rf¼0.37). The reaction
mixture was stirred with aqueous NaHCO3 (5%, 15 mL), dried
(Na2SO4), filtered and evaporated. The residue (0.657 g) was dis-
solved in MeOH (5 mL). After the addition of aqueous K2CO3 (3%,
6 mL) the mixture was stirred at 22 ꢀC, and a solid precipitated
within 3 h. The product was filtered, washed (MeOH/H2O) and dried
to give 11c (0.434 g, 88%), as a colourless solid, which was pure by
TLC; Rf¼0.30 (sm4); mp 119.5e120 ꢀC; 1H NMR (300.1 MHz, CDCl3):
dH 1.72e1.94 (m, 3H, 5-Ha, 2-Ha, 6-Ha), 2.00e2.06 (m [br], 2H, 5-Hb,
OH), 2.58 (A of AA’BB0, 2H, PhCH2CH2N), 2.76 (B of AA’BB0, 2H,
PhCH2CH2N), 2.91 (m [br], 1H, 6-Hb), 3.04 (ddd, J¼10.5, 3.6, 2.1 Hz,
1H, 2-Hb), 3.33 (ddd, J¼10.8, 10.8, 5.1 Hz, 1H, 4-H), 3.76 (AB,
2JHH¼13.5 Hz, 2H, ClH2C[C]O]N), 4.70 (ddd, J¼10.8, 10.8, 4.3 Hz, 3-
H), 7.12e7.22 (m, 6HAr, 30-H, 50-H, 60-H, 200-H, 400-H, 600-H), 7.25e7.28
(m, 2HAr, 300-H, 500-H), 7.53 (m [br],1HAr, 20-H); 13C NMR (75.46 MHz,
Supplementary data
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet.2011.03.045. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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CDCl3): dC 34.02 (1Csec, PhCH2CH2N), 34.32 (1Csec, 5-C), 42.74 (1Csec
,
ClH2C[C]O]N), 51.89 (1Csec, 6-C), 55.36 (1Csec, 2-C), 59.31 (1Ctert, 3-
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solved], JCF¼23.8 Hz, 2CAr, 50-C, 30-C), 126.24 (1CAr, 400-C), 128.55
3
(2CAr, 300-C, 500-C), 128.77 (2CAr, 200-C, 600-C), 131.77 (d, JCF¼8.8 Hz,
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