Synthesis of (3S,4R)-4-benzylamino-3-methoxypiperidine, an important intermediate for (3S,4R)-Cisapride

Article abstract of DOI:10.1016/j.tet.2008.05.090

An efficient synthesis of (3S,4R)-4-benzylamino-3-methoxypiperidine, an useful intermediate for the chiral synthesis of important drug molecule Cisapride and its analogs, from enantiopure 4-formylazetidin-2-one is described. Synthesis of trans as well as

Full text of DOI:10.1016/j.tet.2008.05.090

Tetrahedron 64 (2008) 7191–7198
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Synthesis of (3S,4R)-4-benzylamino-3-methoxypiperidine, an important
intermediate for (3S,4R)-Cisapride
,
Nilesh M. Shirode a, Anjali P. Likhite a, Vikas K. Gumaste a, Abdul Rakeeb A.S. Deshmukh b
*
a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
b Emcure Pharmaceuticals Limited, ARC-H, P-2, I.T.-B.T. Park, Phase-II, M.I.D.C., Hinjwadi, Pune 411057, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of (3S,4R)-4-benzylamino-3-methoxypiperidine, an useful intermediate for the
chiral synthesis of important drug molecule Cisapride and its analogs, from enantiopure 4-for-
mylazetidin-2-one is described. Synthesis of trans as well as cis isomers of 4-amino-3-methoxypiper-
idine from 4-formylazetidin-2-one is also achieved in good yield.
Received 20 February 2008
Received in revised form 17 May 2008
Accepted 19 May 2008
Available online 23 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective synthesis
Azetidin-2-ones
Cisapride
4-Aminopiperidine
Staudinger reaction
1. Introduction
Cisapride and its analogs, such as ATI 7505 (I), are safe and effective
for the treatment of various gastrointestinal disorders including,
The strain energy associated with the four-membered azetidin-
2-one ring makes it susceptible for nucleophilic ring cleavage. The
selective bond cleavage of the strained ring coupled with further
interesting transformations renders this fascinating molecule as
a powerful building block.1 One such synthon, 4-formylazetidin-2-
one, has wide applications as a building block for the synthesis of
gastroparesis, gastroesophageal reflux, emesis, dyspepsia, con-
stipation, intestinal pseudo-obstruction or postoperative ileus.12–14
Although a chiral version of Cisapride, which is obtained by
resolution of the racemic mixture12a–c is well known for its im-
proved activity. However, there are no reports on asymmetric
synthesis of this molecule. There are few reports on the synthesis of
racemic Cisapride and its analogs. Most of these syntheses are
reported from piperidine-4-one in 9–13 steps,15a–c with very poor
overall yields. A short synthesis by seven steps with an overall yield
of 4.5% has been reported.15d The racemic trans- and cis-4-amino-3-
methoxypiperidine is also used for the synthesis of Cisapride and
its analogs using a multi-step reaction sequence in very poor
overall yields.11 To the best of our knowledge, there is no report on
the synthesis of Cisapride or its analogs from azetidin-2-one. The
biological activity associated with Cisapride and its analogs, the
poor yield in the reported multi-step syntheses, and no reports on
the chiral synthesis, inspired us to design and develop a chiral
synthesis of this molecule from enantiopure azetidin-2-one. Based
on our experience in the asymmetric synthesis and application of
azetidin-2-ones in organic synthesis, we designed a retro-synthetic
strategy for the synthesis of Cisapride (Scheme 1). The key in-
termediate, 3-methoxy-4-aminopiperidine can be obtained from
corresponding 3-methoxypiperidine-2-one, which can be prepared
from 4-formylazetidin-2-one in five steps by a well established
reaction sequence. 3-Methoxy-4-aminopiperidine is also a core
monobactams, isocephams, carbapenems, and several other non-b-
lactam compounds like a-hydroxyaspartate and hydroxybutanoic
acids.2,3 Enantiomerically pure 4-formylazetidin-2-one can be
easily obtained from optically pure glyceraldehydes acetonide by
employing Staudinger’s ketene–imine cyclo-condensation re-
action.4–7 As a part of our research program on asymmetric syn-
thesis of
b-lactams and its applications for the preparation of
various biologically important compounds8,9 we have developed an
efficient method for enantiopure 4-formylazetidin-2-one from
easily accessible (ꢀ)-diethyl tartrate.
In continuation of our efforts toward the preparation of
substituted b
-lactams via the Staudinger reaction10 and their utility
as synthons6,8,9 for synthesizing various biologically important
compounds, we were interested in the chiral synthesis of an im-
portant drug molecule Cisapride (Fig. 1)11 from 4-formyl-
b-lactam.
* Corresponding author. Fax: þ91 20 25893153/25893355.
E-mail address: abdulrakeeb.deshmukh@emcure.co.in (A.R.A.S. Deshmukh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.090

7192
N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
R2
H2N
Cl
O
O
O
H
N
O
N
N
O
R1
N
F
Fentanyl derivatives
Cisapride
1: R1 = R2 = H
2: R1 = NCS, R2 = H
3: R1 = H, R2 = CH3 4: R1 = NCS, R2= CH3
H2N
Cl
O
O
O
H
N
N
N
O
ATI 7505
Figure 1. Cisapride, fentanyl derivatives, and analogs.
R1
H
R1
H
H2N
Cl
O
N
N
N
N
O
H
N
OCH3
O
OCH3
O
O
N
F
H
15
H
Cisapride
16
H
H
H
H
N
H
OCH3
NHR1
H3CO
CHO
H3CO
NO2
H3CO
NO2
N
R1
O
R1
O
H
O
14
10
13
a R1 = PMP
b R1 = PMB
c R1 = Bn
Scheme 1.
structure of fentanyl derivatives16 and ATI 7505 (Fig. 1). The retro-
synthesis is based on the well defined stereochemistry at both the
stereocenters of trans-3-methoxy-4-formylazetidin-2-one ring,
which is required for the synthesis of (3S,4R)-Cisapride and its
analogs.
cyclization gave 4-aminopiperidin-2-ones 6a,b in 60–70% yield.
The reduction of amide carbonyl of 6a,b with BH3/DMS afforded
cleanly (3S,4S)-4-amino-3-methoxypiperidines 7a,b in 50% yield
(Scheme 2).
(3S,4S)-4-Amino-3-methoxypiperidine 7a on alkylation with
bromo compound 17 in anhydrous DMF using Et3N gave N-alky-
lated aminopiperidine 8 in 35% yield (Scheme 3).11 The depro-
tection of 4-methoxy-phenyl (PMP) group is normally achieved by
2. Results and discussion
Initially we planned the synthesis of (3R,4R)-Cisapride as it can
be obtained from easily accessible (3R,4R)-cis-3-methoxy-4-for-
OH
H
H
N
H
H
N
H
H
N
H3CO
H3CO
CHO
H3CO
c)
b)
a)
NO2
mylazetidin-2-one. The enantiopure (3R,4R)-cis-4-formyl-b-lac-
NO2
tams 1a–c were either obtained from (ꢀ)-diethyl tartrate6 or from
O
R1
O
R1
O
R1
D
-glyceraldehyde acetonide using a reported procedure.4–6 The
3a-b
2a-b
1a-b
reaction of cis-3-methoxy-4-formyl-b-lactams 1a,b with nitro-
R1
H
methane in the presence of a catalytic amount of triethylamine
gave a 7:3 diastereomeric mixture of nitro-aldol products 2a,b in
quantitative yield. The hydroxy group of 2a,b was acetylated using
acetic anhydride8 in the presence of catalytic amount of concen-
trated sulfuric acid at 0 ꢁC to get a nitroacetate along with small
amount of nitroalkenes 3a,b. This crude mixture was refluxed in
benzene in the presence of sodium bicarbonate to afford crude
nitroalkenes, which were further purified by column chromatog-
raphy to get pure nitroalkenes 3a,b in 80–85% yield. The nitro-
alkenes 3a,b were reduced to nitroalkanes 4a,b with
N
N
H
OCH3
H
H
N
OCH3
O
H3CO
e)
H3CO
NO2
d)
NO2
H
NHR1
O
O
R1
H
6a-b
5a-b
4a-b
R1
H
N
OCH3
f)
N
H
7a-b
tributyltinhydride17 in 60–70% yield. The
b-lactam ring of the
a R1 = PMP
b R1 = PMB
nitroalkanes 4a,b was opened up by stirring with methanolic HCl
(20%) at room temperature for 12 h to get the nitroesters 5a,b in
nearly quantitative yield. The reduction of nitro group by transfer
hydrogenation18 using ammonium formate and Pd/C (10%) in
methanol at room temperature followed by in situ intramolecular
Scheme 2. Reagents and conditions: (a) CH3NO2, Et3N, 5 h, 97–98%; (b) (i)Ac2O, concd
H2SO4, 0 ꢁC, 1 h; (ii) NaHCO3, benzene, reflux, 4 h, 80–85% (overall yield); (c) Bu3SnH,
CH2Cl2/MeOH (10:1), rt, 3 h, 60–70%; (d) Methanolic HCl (20%), rt, 12 h, 90–95%; (e)
10% Pd/C, HCOONH4, MeOH, rt, 5 h, 60–70%; (f) BH3/DMS, toluene, reflux, 4 h, 50–51%.

N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
7193
PMP
H
N
N
H3CO
H2N
H3CO
OCH3
Br
b)
H
a)
x
N
O
F
N
N
O
F
PMP
F
O
17
H
7a
9
8
Scheme 3. Reagents and conditions: (a) DMF, Et3N, 17, rt, 18 h, 35%; (b) CAN, CH3CN/H2O, 30 min.
ceric ammonium nitrate (CAN). However, in case of 8 the cleavage
of PMP group under various reaction conditions failed to give the
desired product 9.
The trans-4-formylazetidin-2-ones 10a–c were further con-
verted to (3S,4R)-cis-4-amino-3-methoxypiperidines 16a–c by fol-
lowing a well established synthetic sequence (Scheme 5) similar to
that shown in Scheme 2. The transformation of N-benzyl protected
aminopiperidine 16c into (3S,4R)-Cisapride can easily be achieved
by using a known synthetic protocol11 in just three steps (Scheme
6). Thus, the synthesis of (3S,4R)-4-benzylamino-3-methoxy-
piperidine, an important intermediate for (3S,4R)-Cisapride, was
achieved in six steps from trans-4-formylazetidin-2-one 10c with
12% overall yield.
Since the drug molecule Cisapride, fentanyl derivatives,16 and its
analogs with cis stereochemistry are more effective in potentiating
the contractile response of the ileum to coaxial stimulation.11
Therefore, we were also interested to get cis stereochemistry at C-3
and C-4 position of piperidine. To achieve cis stereochemistry at C-3
and C-4 position it is essential to start the synthesis from trans-4-
formylazetidin-2-ones 10a–c. This was achieved by epimerization
of cis-4-formylazetidin-2-one 1a by treatment with 40% dime-
thylamine to get trans-4-formylazetidin-2-one 10a in 50% yield. The
cis-4-formylazetidin-2-ones 1b,c can also be converted to trans-4-
formylazetidin-2-ones 10b,c by treatment with sodium carbonate
in acetonitrile/water (1:1) mixture in 65–70% yield (Scheme 4).19
3. Conclusion
In conclusion, we have accomplished the first chiral synthesis of
an important intermediate 16c of (3S,4R)-Cisapride. We have also
synthesized various cis and trans aminopiperidines, which can be
used for preparing analogs of Cisapride.
H
H
N
H
H
N
H3CO
CHO
R1
H3CO
CHO
R1
a)
O
O
4. Experimental
4.1. General
10a-c
1a-c
a
b
c
R1= PMP
R1= PMB
R1 = Bn
1H NMR and 13C NMR spectra were recorded in CDCl3 solutions
on Bru¨ker AV 200, AV 400 spectrometers, and chemical shifts are
reported in parts per million downfield from tetramethylsilane for
1H NMR. Infrared spectra were recorded on Perkin Elmer Infrared
Spectrophotometer, Model 599-B or Shimadzu FTIR-8400 using
sodium chloride optics. Melting points were determined on a Buchi
melting point apparatus and are uncorrected. The microanalyses
were performed on a Carlo-Erba CHNS-O EA 1108 elemental ana-
lyzer. Optical rotations were recorded on ADP 220 polarimeter
Bellinghamþ Stanley Ltd. under standard conditions. Mass spectra
were recorded on API QSTAR PULSAR using electron spray ioniza-
tion (ESI) method.
Scheme 4. Reagents and conditions: (a) dimethylamine 40%, benzene, rt, 24 h, 50%, 1a;
Na2CO3, CH3CN/H2O, (1:1) rt, 48 h, 65–70%, 1b,c.
OH
H
H
N
H
H
N
H
H
N
H3CO
H3CO
CHO
H3CO
b)
a)
NO2
H
NO2
R1
O
R1
O
R1
O
10a-c
12a-c
11a-c
R1
N
H
H
N
H
O
OCH3
H3CO
OCH3
O
e)
d)
NO2
c)
H3CO
NO2
R1
H
NHR1
O
N
H
13a-c
14a-c
15a-c
4.2. General procedure for the preparation of nitroalcohols
(2a,b)
R1
H
N
OCH3
To a solution of 4-formylazetidin-2-ones 1a,b (15 mmol) in ni-
tromethane (30 mL) was added Et3N (0.31 mL, 2.25 mmol) at room
temperature and the reaction mixture was stirred for 6 h. The ex-
cess nitromethane was removed under reduced pressure and the
residue was dissolved in CH2Cl2 (50 mL) and washed with water
(1ꢂ5 mL). The organic layer was dried over Na2SO4 and concen-
trated in vacuo to afford a 7:3 diastereomeric mixture of nitro-
alcohols 2a,b.
f)
a R1 = PMP
b R1 = PMB
c R1 = Bn
N
H
16a-c
Scheme 5. Reagents and conditions: (a) CH3NO2, Et3N, 5 h, 75–85%; (b) (i) Ac2O, concd
H2SO4, 0 ꢁC, 1 h; (ii) NaHCO3, benzene, reflux, 4 h, 75–87% (overall yield); (c) Bu3SnH,
CH2Cl2/MeOH (10:1), rt, 3 h, 50–62%; (d) methanolic HCl (20%), rt, 12 h, 94–98%; (e)
10% Pd/C, HCOONH4, MeOH, rt, 5 h, 55–67%; (f) BH3/DMS, toluene, reflux 4 h, 49–52%.
H
N
H2N
Cl
O
O
O
Ref11
OCH3
H
N
O
N
H
N
F
16c
(3S,4R)-Cisapride
Scheme 6.

7194
N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
4.2.1. (3R,4S)-4-(1-Hydroxy-2-nitro-ethyl)-3-methoxy-1-(4-
methoxy-phenyl)-azetidin-2-one (2a)
4.4. General procedure for the preparation of nitroalkanes
(4a,b)
Yield 98%; pale yellow solid; mp 97–101 ꢁC. [Found C, 52.93; H,
5.33; N, 9.43%. C13H16N2O6 requires C, 52.70; H, 5.44; N, 9.46%.] Rf
To a solution of nitroalkenes 3a,b (10.26 mmol) in anhydrous
CH2Cl2/MeOH (10:1, 30 mL), tributyltinhydride (3.30 mL,
11.29 mmol) was added at room temperature and the mixture was
stirred for 2 h. After completion of reaction (TLC), the solvent was
removed under reduced pressure and the crude product was pu-
rified by flash column chromatography on silica gel (EtOAc/pet.
ether 2:8 as eluent) to give pure nitroalkanes 4a,b.
30
(40% EtOAc/pet. ether) 0.20; [
a
]
þ77.8 (c 0.25, CHCl3); nmax
D
(CHCl3) 1751 cmꢀ1
;
dH (200 MHz, CDCl3) 3.04 (br s, 1H, –OH), 3.71
(s, 3H, –OCH3), 3.80 (s, 3H, Ar–OCH3), 4.39–4.44 (m, 1H, H-4), 4.50–
4.62 (m, 2H, H-5, H-3), 4.69–4.73 (m, 1H, Ha-6), 4.80–4.90 (m, 1H,
Hb-6), 6.85–6.92 (m, 2H, Ar), 7.36–7.40 (m, 2H, Ar); dC (125.76 MHz)
55.4, 58.1, 58.7, 59.6, 59.7, 67.1, 68.6, 77.5, 77.7, 82.4, 82.8, 114.4,
114.6, 119.4, 119.9, 129.7, 129.9, 157.0, 164.0, 164.5; MS (m/z): 297
(Mþ1).
4.4.1. (3R,4S)-3-Methoxy-1-(4-methoxy-phenyl)-4-(2-nitro-ethyl)-
azetidin-2-one (4a)
4.2.2. (3R,4S)-4-(1-Hydroxy-2-nitro-ethyl)-3-methoxy-1-(4-
methoxy-benzyl)-azetidin-2-one (2b)
Yield 70%; yellow solid; mp 140 ꢁC. [Found C, 55.92; H, 5.85; N,
10.23%. C14H16N2O5 requires C, 55.71; H, 5.75; N, 9.99%.] Rf (30%
30
Yield 97%; gummy compound. [Found C, 54.23; H, 5.77; N, 9.18%.
EtOAc/pet. ether) 0.27; [
a]
þ158.8 (c 1.02, CHCl3); nmax (CHCl3)
D
C
14H18N2O6 requires C, 54.18; H, 5.86; N, 9.03%.] Rf (50% EtOAc/pet.
1745 cmꢀ1
; dH (200 MHz, CDCl3) 2.35–2.49 (m, 1H, Ha-5), 2.66–2.79
30
ether) 0.26; [
a
]
þ57.7 (c 0.52, CHCl3); nmax (CHCl3) 1747 cmꢀ1
;
dH
(m, 1H, Hb-5), 3.68 (s, 3H, –OCH3), 3.81 (s, 3H, Ar–OCH3), 4.31–4.39
(m,1H, H-4), 4.51–4.58 (m, 2H, H-6), 4.65 (d, J¼5.1 Hz,1H, H-3), 6.91
(d, J¼8.8 Hz, 2H, Ar), 7.35 (d, J¼8.8 Hz, 2H, Ar); dC (125.76 MHz)
25.0, 53.9, 55.4, 59.2, 71.6, 82.7, 114.7, 118.6, 129.9, 156.7, 163.9; MS
(m/z): 281(Mþ1).
D
(200 MHz, CDCl3) 3.55–3.75 (m, 4H, –OCH3, H-4), 3.80 (s, 3H, Ar–
OCH3), 4.10–4.70 (m, 6H, H-3, H-5, H-6, –NCH2), 6.80–6.95 (m, 2H,
Ar), 7.15–7.25 (m, 2H, Ar); dC (125.76 MHz) 44.4, 44.9, 55.2, 57.4,
59.3, 59.6, 67.5, 68.9, 77.5, 77.9, 82.6, 83.7, 114.3, 126.6, 127.1, 129.7,
159.3, 159.4, 166.8, 167.2; MS (m/z): 311 (Mþ1).
4.4.2. (3R,4S)-3-Methoxy-1-(4-methoxy-benzyl)-4-(2-nitro-ethyl)-
azetidin-2-one (4b)
4.3. General procedure for the preparation of nitroalkenes
(3a,b)
Yield 67%; gummy compound. [Found C, 57.47; H, 6.40; N, 9.57%.
14H18N2O5 requires C, 57.12; H, 6.18; N, 9.52%.] Rf (50% EtOAc/pet.
C
30
ether) 0.31; [
a
]
þ81.2 (c 0.64, CHCl3); nmax (CHCl3) 1749 cmꢀ1
; dH
D
Diastereomeric mixture of nitroalcohols 2a,b (14 mmol) was
dissolved in acetic anhydride (30 mL) and cooled to 0 ꢁC. Three to
four drops of concentrated H2SO4 were added to the reaction
mixture and stirred for 1 h at 0 ꢁC. After completion of the re-
action (TLC), H2O (2 mL) was added at 0 ꢁC and the mixture was
stirred for 10 min. It was extracted with EtOAc (2ꢂ40 mL) and the
organic layer was washed with satd aq NaHCO3 (3ꢂ15 mL), brine
(15 mL), and dried (Na2SO4). The solvent was removed under
reduced pressure to afford nitroacetates 3a,b along with small
quantity of nitroalkene. This mixture was refluxed with benzene
(50 mL) in the presence of NaHCO3 (9.41 g, 112 mmol) for 6 h.
After completion of reaction (TLC), solid was removed by filtra-
tion, and the solvent was removed under reduced pressure to
afford the crude nitroalkenes 3a,b, which was further purified by
column chromatography on silica gel (EtOAc/pet. ether 3:7 as
eluent) to get pure 3a,b.
(200 MHz, CDCl3) 2.15–2.30 (m, 2H, H-5), 3.58 (s, 3H, –OCH3), 3.62–
3.73 (m, 1H, H-4), 3.80 (s, 3H, Ar–OCH3), 4.18 (d, J¼15.0 Hz, 1H,
–NCHaHb), 4.28–4.37 (m, 2H, –NCHaHb, H-3), 4.38–4.50 (m, 2H,
H-6), 6.87 (d, J¼8.8 Hz, 2H, Ar), 7.17 (d, J¼8.8 Hz, 2H, Ar); dC
(125.76 MHz) 25.9, 44.0, 54.3, 55.2, 59.1, 71.7, 83.5, 114.3, 127.0,
129.5, 159.4, 167.0; MS (m/z): 295 (Mþ1).
4.5. General procedure for the preparation of nitroesters
(5a,b)
A solution of nitroalkanes 4a,b (10 mmol) in methanolic HCl
(20%, 25 mL) was stirred at room temperature for 12 h. After
completion of the reaction (TLC), solvent was removed under re-
duced pressure and the residue was dissolved in CH2Cl2 (30 mL),
neutralized with solid NaHCO3, and filtered through Celite bed.
Filtrate was concentrated in vacuo to give nitroesters 5a,b.
4.3.1. (3R,4S)-3-Methoxy-1-(4-methoxy-phenyl)-4-(2-nitro-vinyl)-
azetidine-2-one (3a)
4.5.1. (2R,3S)-2-Methoxy-3-(4-methoxy-phenylamino)-5-nitro-
pentanoic acid methyl ester (5a)
Yield 80%; yellow crystalline solid; mp 119 ꢁC. [Found C, 56.43;
H, 5.18; N, 10.33%. C13H14N2O5 requires C, 56.11; H, 5.07; N, 10.07%.]
Yield 92%; viscous liquid. [Found C, 53.81; H, 6.63; N, 8.90%.
C14H20N2O6 requires C, 53.84; H, 6.45; N, 8.97%.] Rf (30% EtOAc/pet.
30
Rf (30% EtOAc/pet. ether) 0.25; [
a
]
þ177.4 (c 0.62, CHCl3); nmax
D
30
(CHCl3) 1757 cmꢀ1
;
dH (200 MHz, CDCl3) 3.57 (s, 3H, –OCH3), 3.80
ether) 0.32; [
a]
ꢀ27.7 (c 1.08, CHCl3); nmax (CHCl3) 1749 cmꢀ1
; dH
D
(s, 3H, Ar–OCH3), 4.83–4.92 (m, 2H, H-3, H-4), 6.88 (d, J¼8.9 Hz,
2H, Ar), 7.12–7.32 (m, 4H, Ar, H-5, H-6); dC (100.61 MHz) 55.2, 59.1,
85.3, 114.5, 118.3, 129.7, 135.5, 142.6, 156.8, 162.4; MS (m/z): 279
(Mþ1).
(200 MHz, CDCl3) 2.24–2.38 (m, 2H, H-4), 3.47 (s, 3H, –OCH3), 3.51
(s, 3H, –COOCH3), 3.73 (s, 3H, Ar–OCH3), 3.78–4.02 (m, 3H, –NH,
H-3, H-2), 4.51–4.61 (m, 2H, H-5), 6.60 (d, J¼9.0 Hz, 2H, Ar), 6.75 (d,
J¼9.0 Hz, 2H, Ar); dC (75.48 MHz) 29.9, 51.7, 54.5, 55.5, 58.8, 72.4,
81.0, 114.7, 115.6, 140.5, 152.7, 170.6; MS (m/z): 313 (Mþ1).
4.3.2. (3R,4S)-3-Methoxy-1-(4-methoxy-benzyl)-4-(2-nitro-vinyl)-
azetidine-2-one (3b)
4.5.2. (2R,3S)-2-Methoxy-3-(4-methoxy-benzylamino)-5-nitro-
pentanoic acid methyl ester (5b)
Yield 76%; gummy compound. [Found C, 57.73; H, 5.43; N, 9.76%.
C
14H16N2O5 requires C, 57.52; H, 5.53; N, 9.58%.] Rf (50% EtOAc/pet.
Yield 95%; viscous liquid. [Found C, 55.44; H, 6.83; N, 8.76%.
C15H22N2O6 requires C, 55.19; H, 6.81; N, 8.58%.] Rf (40% EtOAc/pet.
30
ether) 0.25; [
a
]
D
þ128.0 (c 0.5, CHCl3); nmax (CHCl3) 1763 cmꢀ1
;
dH
30
(200 MHz, CDCl3) 3.47 (s, 3H, –OCH3), 3.80 (s, 3H, Ar–OCH3), 4.10–
4.25 (m, 2H, –NCHaHb, H-4), 4.53 (d, J¼14.7 Hz, 1H, –NCHaHb), 4.67
(d, J¼4.5 Hz, 1H, H-3), 6.82–7.05 (m, 4H, Ar, H-5, H-6), 7.13 (d,
J¼8.7 Hz, 2H, Ar); dC (100.61 MHz) 44.5, 54.8, 55.3, 59.1, 85.9, 114.5,
126.1, 130.0, 135.6, 142.2, 159.7, 165.5; MS (m/z): 293 (Mþ1).
ether) 0.32; [
a
]
ꢀ2.8 (c 1, CHCl3); nmax (CHCl3) 1751 cmꢀ1
; dH
D
(200 MHz, CDCl3) 2.05–2.35 (m, 2H, H-4), 3.05–3.20 (m, 1H, H-3),
3.44 (s, 3H, –OCH3), 3.60–3.73 (m, 2H), 3.79 (s, 3H, –COOCH3), 3.80
(s, 3H, Ar–OCH3), 3.85 (d, J¼3.9 Hz, 1H, H-2), 4.51 (t, J¼6.8 Hz, 2H,
H-5), 6.86 (d, J¼8.7 Hz, 2H, Ar), 7.22 (d, J¼8.7 Hz, 2H, Ar); dC

N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
7195
(125.76 MHz) 29.2, 50.5, 52.1, 55.2, 55.9, 58.8, 72.6, 81.2, 113.8,
129.6, 158.9, 171.4; MS (m/z): 327 (Mþ1).
J¼7.8 Hz, 2H, Ar), 6.78 (m, 2H, Ar); dC (125.76 MHz) 25.8, 28.6, 50.4,
53.2, 55.4, 56.1, 56.8, 57.2, 60.4, 77.3, 79.6, 114.5, 114.7, 116.3, 140.5,
1
141.2, 152.1, 152.5; H NMR at 55 ꢁC dH (400 MHz, CDCl3, at 55 ꢁC)
4.6. General procedure for the preparation of 4-amino-
piperidin-2-ones (6a,b)
1.41–1.75 (m, 1H, H-5), 2.13–2.20 (m, 1H, H-5), 2.30–2.90 (m, 2H,
H-6), 2.95–3.35 (m, 3H, H-2, H-4), 3.44 (s, 3H, –OCH3), 3.47–3.65
(m, 1H, H-3), 3.75 (s, 3H, Ar–OCH3), 6.67 (d, J¼7.8 Hz, 2H, Ar), 6.78
(d, J¼7.8 Hz, 2H, Ar); MS (m/z): 237 (Mþ1).
To a solution of nitroesters 5a,b (10 mmol) in anhydrous MeOH
(40 mL), 10% Pd/C (600 mg) was added, followed by ammonium
formate (3.15 g, 50 mmol), and the reaction mixture was stirred at
room temperature under argon for 5 h. After completion of reaction
(TLC), the reaction mixture was filtered through a Celite bed and
the bed was washed with MeOH. The solvent from the filtrate was
removed under reduced pressure and the residue was dissolved in
CH2Cl2 (100 mL), washed with H2O (5 mL), brine (5 mL), and the
organic layer was dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure gave crude product, which was
purified by flash column chromatography (EtOAc/pet. ether 6:4 for
6a; acetone/pet. ether 6:4 for 6b) to get pure 6a,b.
4.7.2. (3S,4S)-3-Methoxy-4-(4-methoxy-benzylamino)-
piperidine (7b)
Yield 51%; viscous liquid. [Found C, 67.34; H, 8.92; N, 11.27%.
C
14H22N2O2 requires C, 67.17; H, 8.86; N, 11.19%.] Rf (80% acetone/
30
pet. ether) 0.30; [
a
]
þ33.3 (c 0.66, acetone); nmax (CHCl3) 3215,
D
3375 cmꢀ1
;
dH (200 MHz, CDCl3) 1.70–2.15 (m, 2H, H-5), 2.20–2.70
(m, 3H, H-6, –NH), 3.00–3.37 (m, 3H, H-2, H-4), 3.39 (s, 3H, –OCH3),
3.50–3.95 (m, 7H, H-3, –NCH2, Ar–OCH3, –NH), 6.86 (d, J¼8.5 Hz,
2H, Ar), 7.26 (d, J¼8.5 Hz, 2H, Ar); dC (125.76 MHz) 27.0, 50.4, 55.2,
56.7, 57.2, 58.6, 59.9, 72.1, 113.9, 129.5, 131.0, 158.8; MS (m/z): 251
(Mþ1).
4.6.1. (3R,4S)-3-Methoxy-4-(4-methoxy-phenylamino)-piperidine-
2-one (6a)
4.8. (3S,4S)-2-(3-(4-fluorophenoxy)propyl)-3-methoxy-N-
(4-methoxy-phenyl)piperidin-4-amine (8)
Yield 70%; white solid; mp 127–129 ꢁC. [Found C, 62.32; H, 7.33;
N, 11.47%. C13H18N2O3 requires C, 62.38; H, 7.25; N, 11.19%.] Rf (60%
30
EtOAc/pet. ether) 0.30; [
a
]
þ36.44 (c 1.18, CHCl3); nmax (CHCl3)
To a solution of 4-aminopiperidine 7a (0.236 mg, 1 mmol) in
anhydrous DMF (5 mL), Et3N (0.15 mL,1.1 mmol) was added and the
mixture was stirred for 10 min. To this solution, bromo compound
(0.256 g,1.1 mmol) in DMF (3 mL) was added dropwise and allowed
to stir for 12 h at room temperature. DMF was removed in vacuo at
30 ꢁC and the residue was purified by flash column chromatogra-
phy (CH2Cl2/MeOH 9:1 as eluent) to get pure 8 (0.155 g, 40%) as
a faint brown liquid. [Found C, 68.23; H, 7.27; N, 7.33. C22H29N2O3F
D
1649 cmꢀ1
;
dH (200 MHz, CDCl3) 1.89–2.09 (m, 1H, Ha-5), 2.34–2.51
(m, 1H, Hb-5), 3.62 (s, 3H, –OCH3), 3.64–3.74 (m, 3H, H-4, H-6), 3.76
(s, 3H, Ar–OCH3), 3.87 (d, J¼6.3 Hz, 1H, H-3), 6.76 (d, J¼9.2 Hz, 2H,
Ar), 6.82 (d, J¼9.2 Hz, 2H, Ar); dC (125.76 MHz) 24.1, 46.1, 52.3, 55.6,
59.2, 79.8, 114.9, 116.1, 139.9, 153.2, 163; MS (m/z): 251 (Mþ1).
4.6.2. (3R,4S)-3-Methoxy-4-(4-methoxy-benzylamino)-piperidine-
2-one (6b)
requires C, 68.02; H, 7.52; N, 7.21%.] Rf (10% MeOH/CH2Cl2) 0.15;
30
Yield 62%; gummy compound. [Found C, 63.83; H, 7.69; N,
[a
]
þ11.1 (c 0.36, CHCl3); nmax (CHCl3) 3369 cmꢀ1
; dH (200 MHz,
D
10.74%. C14H20N2O3 requires C, 63.60; H, 7.64; N, 10.60%.] Rf (80%
CDCl3) 2.05–2.45 (m, 4H, H-5, H-8), 3.05–3.40 (m, 2H, H-6), 3.44 (s,
3H, –OCH3), 3.46–3.70 (m, 3H, H-7, Ha-2), 3.71 (s, 3H, Ar–OCH3),
3.72–3.92 (m, 3H, Hb-2, H-4, H-3), 4.02 (t, J¼6.2 Hz, 2H, H-9), 6.73–
7.00 (m, 8H, Ar); dC (100.61 MHz) 22.9, 24.8, 52.1, 55.7, 58.3, 62.2,
63.7, 65.6, 65.9, 76.9, 114.8, 115.4, 115.6, 115.9, 141.1, 152.5; MS (m/z):
389 (Mþ1).
30
acetone/pet. ether) 0.32; [
a]
þ70.0 (c 0.60, CHCl3); nmax (CHCl3)
D
1651 cmꢀ1
;
dH (200 MHz, CDCl3) 1.75–1.95 (m, 1H, H-5), 2.20–2.40
(m, 1H, H-5), 3.00–3.10 (m, 1H, H-4), 3.47–3.71 (m, 5H, H-6, –OCH3),
3.73–3.82 (m, 2H, –NCHaHb, H-3), 3.72–3.82 (m, 3H, –NCHaHb), 3.84
(s, 3H, Ar–OCH3), 3.91 (d, J¼12.9 Hz, 1H, –NCHaHb), 4.40 (br s, 2H,
–NH), 6.91 (d, J¼8.7 Hz, 2H, Ar), 7.28 (d, J¼8.7 Hz, 2H, Ar); dC
(125.76 MHz) 24.1, 46.2, 50.4, 55.0, 55.3, 59.9, 80.1, 114.0, 129.5,
130.7, 159.0, 164.0; MS (m/z): 265 (Mþ1).
4.9. (3R,4S)-3-Methoxy-1-(4-methoxy-phenyl)-4-
oxo-azetidin-2-carbaldehyde (10a)
4.7. General procedure for the preparation of 4-amino-
piperidines (7a,b)
To a stirred solution of cis-4-formylazetidin-2-one 1a (0.940 g,
4 mmol) in benzene (40 mL), dimethylamine (40% aq, 4.0 mL) was
added and the reaction mixture was stirred at room temperature
for 24 h. After completion of reaction (TLC), organic layer was
separated, concentrated in vacuo, and further purified by flash
column chromatography (EtOAc/pet. ether 25:75 as eluent) to get
trans-4-formylazetidin-2-one 10a as viscous liquid (0.470 g, 50%).
To a solution of 4-aminopiperidin-2-ones 6a,b (10 mmol) in dry
toluene (30 mL) BH3/DMS (10.0 mM,1.10 mL 10% excess) was added
dropwise under nitrogen at 0 ꢁC. The reaction mixture was stirred
at this temperature for 15 min and then refluxed for 3 h. The re-
action was quenched by adding 15 mL of 10% aq Na2CO3 at 20 ꢁC,
stirred for 3 h at 20 ꢁC. The toluene layer was separated and dried
over anhydrous Na2SO4. The solvent was removed and the crude
piperidine was purified by flash column chromatography (EtOAc/
pet. ether 8:2 for 7a; 9:1 for 7b) to get pure 4-aminopiperidines
7a,b.
[Found C, 61.34; H, 5.66; N, 5.87%. C12H13NO4 requires C, 61.27; H,
30
5.57; N, 5.95%.] Rf (25% EtOAc/pet. ether) 0.15; [
a]
ꢀ51.2 (c 0.82,
D
CHCl3); nmax (CHCl3) 1747 cmꢀ1
;
dH (200 MHz, CDCl3) 3.56 (s, 3H,
–OCH3), 3.78 (s, 3H, Ar–OCH3), 4.47 (dd, J¼1.8, 3.2 Hz, 1H, H-4), 4.69
(d, J¼1.8 Hz, 1H, H-3), 6.86 (d, J¼9.0 Hz, 2H, Ar), 7.24 (d, J¼9.0 Hz,
2H, Ar), 9.81 (d, J¼3.2 Hz,1H, –CHO); dC (50.32 MHz) 55.4, 58.1, 65.1,
85.0, 114.6, 118.3, 130.2, 156.9, 161.8, 197.1; MS (m/z): 236 (Mþ1).
4.7.1. (3S,4S)-3-Methoxy-4-(4-methoxy-phenylamino)-
piperidine (7a)
4.10. (3R,4S)-3-Methoxy-1-(4-methoxy-benzyl)-4-
Yield 50%; viscous liquid. [Found C, 66.24; H, 8.47; N, 12.03%.
oxo-azetidin-2-carbaldehyde (10b)
C
13H20N2O2 requires C, 66.07; H, 8.53; N, 11.85%.] Rf (60% EtOAc/pet.
30
ether) 0.27;
[
a
]
þ12.9 (c 0.7, CHCl3); nmax (CHCl3) 3215,
To a stirred solution of cis-4-formylazetidin-2-one 1b (5 g,
17.79 mmol) in acetonitrile and water (1:1, 602 mL), Na2CO3 (3.77 g,
35.58 mmol) was added and stirred at room temperature for 48 h.
Acetonitrile was removed under reduced pressure and the aqueous
layer was extracted with EtOAc (5ꢂ75 mL). Organic layer was dried
D
3375 cmꢀ1
;
dH (400 MHz, CDCl3, at room temperature) 1.35–1.44
(m, 0.6H, H-5), 1.68–1.85 (m, 0.4H, H-5), 2.17–2.20 (m, 1H, H-5),
2.45–2.60 (m, 1H, H-6) 2.86–3.37 (m, 4H, 1ꢂH-6, H-2, H-4), 3.44 (s,
3H, –OCH3), 3.46–3.73 (m, 1H, H-3), 3.75 (s, 3H, Ar–OCH3), 6.67 (dd,

7196
N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
30
over anhydrous Na2SO4, concentrated in vacuo to get crude 10b,
which was purified by flash column chromatography on silica gel
(EtOAc/pet. ether 7:3 as eluent) to afford pure trans-4-for-
mylazetidin-2-one 10b as a gummy compound (3.5 g, 70%). [Found
[
a
]
þ51.4 (c 0.7, CHCl3); nmax (CHCl3) 1751 cmꢀ1
; dH (200 MHz,
D
CDCl3) 3.42–3.64 (m, 4H, –OCH3, H-5), 4.31–4.77 (m, 6H, –NCH2, H-
4, H-3, H-6), 7.25–7.46 (m, 5H, Ar); dC (125.76 MHz) 44.5, 45.6, 57.8,
57.9, 60.0, 60.2, 64.7, 69.1, 77.5, 77.7, 82.7, 84.3, 128.1, 128.2, 129.0,
129.2, 134.6, 135.0, 166.8, 167.0; MS (m/z): 281 (Mþ1).
C, 59.44; H, 5.94; N, 10.68%. C13H15NO4 requires C, 59.30; H, 5.75; N,
30
10.64%.] Rf (70% EtOAc/pet. ether) 0.20; [
a
]
þ42.8 (c 0.5, CHCl3);
D
nmax (CHCl3) 1747 cmꢀ1
;
dH (200 MHz, CDCl3) 3.48 (s, 3H, –OCH3),
4.11.4. (3R,4R)-3-Methoxy-1-(4-methoxy-phenyl)-4-
(2-nitro-vinyl)-azetidine-2-one (12a)
Following the general procedure, as for 3a,b, 12a was obtained
as a oil in 87% yield. [Found C, 56.27; H, 5.15; N, 10.22%. C13H14N2O5
3.80 (s, 3H, Ar–OCH3), 3.94 (t, 1H, H-4), 4.24 (d, J¼14.6 Hz, 1H,
–NCHaHb), 4.55 (d, J¼1.5 Hz, 1H, H-3), 4.68 (d, J¼14.6 Hz, 1H,
–NCHaHb), 6.86 (d, J¼8.7 Hz, 2H, Ar), 7.15 (d, J¼8.7 Hz, 2H, Ar), 9.54
(d, J¼3.2 Hz, 1H, –CHO); dC (125.76 MHz) 45.2, 55.2, 57.8, 64.5, 85.4,
114.4, 126.2, 130.0, 159.5, 164.9, 196.9; MS (m/z): 250 (Mþ1).
requires C, 56.11; H, 5.07; N, 10.07%.] Rf (40% EtOAc/pet. ether) 0.34;
30
[a
]
ꢀ162.0 (c 0.5, CHCl3); nmax (CHCl3) 1764 cmꢀ1
; dH (200 MHz,
D
CDCl3) 3.64 (s, 3H, –OCH3), 3.84 (s, 3H, Ar–OCH3), 4.60–4.70 (m, 2H,
H-4, H-3), 6.94 (d, J¼9.0 Hz, 2H, Ar), 7.17 (d, J¼13.5 Hz,1H, H-6), 7.30
(d, J¼9.0 Hz, 2H, Ar), 7.44 (dd, J¼6.7, 13.5 Hz, 1H, H-5); dC
(50.32 MHz) 55.5, 56.6, 58.4, 89.0, 114.7, 118.6, 129.4, 136.6, 141.5,
157.0, 161.7; MS (m/z): 279 (Mþ1).
4.11. (3R,4S)-1-Benzyl-3-methoxy-4-oxo-azetidin-2-
carbaldehyde (10c)
To a stirred solution of cis-4-formylazetidin-2-one 1c (5 g,
22.83 mmol) in acetonitrile and water (1:1, 684 mL), Na2CO3
(4.84 g, 45.66 mmol) was added and stirred at room temperature
for 48 h. Acetonitrile was removed under reduced pressure and the
aqueous layer was extracted with EtOAc (5ꢂ80 mL). Organic layer
was dried over anhydrous Na2SO4, concentrated in vacuo to give
crude 10c, which was purified by flash column chromatography on
silica gel (EtOAc/pet. ether 8:2 as eluent) to get pure trans-4-for-
mylazetidin-2-one 10c as a viscous liquid (3.2 g, 64%). [Found C,
4.11.5. (3R,4R)-3-Methoxy-1-(4-methoxy-benzyl)-4-
(2-nitro-vinyl)-azetidine-2-one (12b)
Following the general procedure, as for 3a,b, 12b was obtained
as pale yellow oil in 81% yield. [Found C, 57.73; H, 5.43; N, 9.76%.
14H16N2O5 requires C, 57.52; H, 5.53; N, 9.58%.] Rf (35% EtOAc/pet.
ether) 0.23; [
(200 MHz, CDCl3) 3.49 (s, 3H, –OCH3), 3.80 (s, 3H, Ar–OCH3), 3.98
(dd, J¼1.5, 7.2 Hz, 1H, H-4), 4.08 (d, J¼14.8 Hz, 1H, –NCHaHb), 4.43
(d, J¼1.5 Hz, 1H, H-3), 4.63 (d, J¼14.8 Hz, 1H, –NCHaHb), 6.85–7.20
(m, 6H, Ar, H-5, H-6); dC (100.61 MHz) 44.7, 55.3, 55.9, 58.2,
89.2, 114.5, 125.9, 129.9, 136.9, 141.1, 159.6, 165.2; MS (m/z): 293
(Mþ1).
C
30
a]
ꢀ23.3 (c 1.2, CHCl3); nmax (CHCl3) 1763 cmꢀ1
; dH
D
65.65; H, 6.14; N, 6.47%. C12H13NO3 requires C, 65.74; H, 5.98; N,
30
6.39%.] Rf (80% EtOAc/pet. ether) 0.22; [
a]
þ20.4 (c 0.44, CHCl3);
D
nmax (CHCl3) 1755 cmꢀ1
;
dH (200 MHz, CDCl3) 3.50 (s, 3H, –OCH3),
3.98–4.00 (m, 1H, H-4), 4.28 (d, J¼14.8 Hz, 1H, –NCHaHb), 4.57 (d,
J¼1.9 Hz, 1H, H-3), 4.77 (d, J¼14.8 Hz, 1H, –NCHaHb), 7.24–7.38 (m,
5H, Ar), 9.58 (d, J¼1.9 Hz, 1H, –CHO); dC (125.76 MHz) 45.8, 57.8,
64.5, 85.5, 128.3, 128.6, 129.1, 134.2, 165.0, 196.7; MS (m/z): 220
(Mþ1).
4.11.6. (3R,4R)-1-Benzyl-3-methoxy-4-(2-nitro-vinyl)-azetidine-
2-one (12c)
Following the general procedure, as for 3a,b, 12c was obtained
as pale yellow viscous liquid in 75% yield. [Found C, 59.75; H, 5.41;
4.11.1. (3R,4R)-4-(1-Hydroxy-2-nitro-ethyl)-3-methoxy-1-
(4-methoxy-phenyl)-azetidin-2-one (11a)
Following the general procedure, as for 2a,b, inseparable di-
astereomeric mixture of 11a was obtained in 3:2 ratio as a viscous
liquid in 77% yield. [Found C, 52.84; H, 5.57; N, 9.43%. C13H16N2O6
N, 10.55%. C13H14N2O4 requires C, 59.54; H, 5.38; N, 10.68%.] Rf (40%
30
EtOAc/pet. ether) 0.30; [
a
]
D
ꢀ53.3 (c 0.6, CHCl3); nmax (CHCl3)
1767 cmꢀ1
;
dH (200 MHz, CDCl3) 3.50 (s, 3H, –OCH3), 4.02 (dd, J¼1.5,
7.2 Hz, 1H, H-4), 4.13 (d, J¼14.8 Hz, 1H, –NCHaHb), 4.46 (d, J¼1.5 Hz,
1H, H-3) 4.70 (d, J¼14.8 Hz, 1H, –NCHaHb), 6.92–7.42 (m, 7H, Ar, H-
5, H-6); dC (100.61 MHz) 45.2, 56.0, 58.2, 89.4, 128.4, 128.5, 129.1,
134.0, 136.8, 141.2, 165.2; MS (m/z): 263 (Mþ1).
requires C, 52.70; H, 5.44; N, 9.46%.] Rf (40% EtOAc/pet. ether) 0.24;
30
[
a]
ꢀ2.9 (c 0.70, CHCl3); nmax (CHCl3) 1751 cmꢀ1
; dH (200 MHz,
D
CDCl3) 3.57 (s, 3H, –OCH3), 3.80 (s, 3H, Ar–OCH3), 4.00–4.20 (m, 1H,
H-4), 4.43–4.60 (m, 2H, H-3, H-5), 4.69–4.98 (m, 2H, H-6), 6.87–6.93
(m, 2H, Ar), 7.30–7.35 (m, 2H, Ar); dC (50.32 MHz) 55.5, 58.2, 60.6,
61.0, 63.0, 63.4, 64.3, 67.9, 77.2, 82.4, 83.9, 114.6, 114.8, 119.6, 120.6,
129.1, 157.1, 163.5; MS (m/z): 297 (Mþ1).
4.11.7. (3R,4R)-3-Methoxy-1-(4-methoxy-phenyl)-4-
(2-nitro-ethyl)-azetidin-2-one (13a)
Following the general procedure, as for 4a,b, 13a was prepared
in 60% yield as gummy compound. [Found C, 55.92; H, 5.85; N,
4.11.2. (3R,4R)-4-(1-Hydroxy-2-nitro-ethyl)-3-methoxy-1-
(4-methoxy-benzyl)-azetidin-2-one (11b)
Following the general procedure, as for 2a,b, inseparable di-
astereomeric mixture of 11b was obtained in 3:2 ratio as a viscous
liquid in 82% yield. [Found C, 54.23; H, 5.77; N, 9.18%. C14H18N2O6
10.23%. C13H16N2O5 requires C, 55.71; H, 5.75; N, 9.99%.] Rf (30%
30
EtOAc/pet. ether) 0.23; [
a
]
þ14.9 (c 1.34, CHCl3); nmax (CHCl3)
D
1754 cmꢀ1
; dH (200 MHz, CDCl3) 2.09–2.32 (m, 1H, Ha-5), 2.74–2.90
(m, 1H, Hb-5), 3.57 (s, 3H, –OCH3), 3.80 (s, 3H, Ar–OCH3), 4.03–4.11
(m, 1H, H-4), 4.35 (d, J¼1.6 Hz, 1H, H-3), 4.49–4.58 (m, 2H), 6.91 (d,
J¼9.0 Hz, 2H, Ar), 7.29 (d, J¼9.0 Hz, 2H, Ar); dC (50.32 MHz) 27.3,
55.3, 56.7, 57.7, 71.2, 87.0, 114.5, 119.2, 129.0, 156.7, 162.6; MS (m/z):
281 (Mþ1).
requires C, 54.18; H, 5.86; N, 9.03%.] Rf (60% EtOAc/pet. ether) 0.33;
30
[
a]
þ50.0 (c 1.0, CHCl3); nmax (CHCl3) 1751 cmꢀ1
; dH (200 MHz,
D
CDCl3) 3.38–3.65 (m, 4H, –OCH3, H-5), 3.79 (s, 3H, Ar–OCH3), 4.08–
4.72 (m, 6H, H-3, H-4, –NCH2, H-6), 6.84–6.94 (m, 2H, Ar), 7.16–7.26
(m, 2H, Ar); dC (125.76 MHz) 44.0, 45.0, 55.2, 57.7, 57.9, 59.9, 60.2,
64.9, 69.1, 77.5, 77.7, 82.6, 84.3, 114.4, 114.5, 126.6, 126.9, 129.5,
129.6, 159.3, 166.7, 166.9; MS (m/z): 311 (Mþ1).
4.11.8. (3R,4R)-3-Methoxy-1-(4-methoxy-benzyl)-4-
(2-nitro-ethyl)-azetidin-2-one (13b)
Following the general procedure, as for 4a,b, 13b was prepared
in 62% yield as gummy compound. [Found C, 57.47; H, 6.40; N,
4.11.3. (3R,4R)-4-(1-Hydroxy-2-nitro-ethyl)-3-methoxy-1-
(4-methoxy-benzyl)-azetidin-2-one (11c)
Following the general procedure, as for 2a,b, inseparable di-
astereomeric mixture of 11c was obtained in 3:2 ratio as a viscous
liquid in 85% yield. [Found C, 55.56; H, 6.03; N, 10.11%. C13H16N2O5
requires C, 55.71; H, 5.75; N, 9.99%.] Rf (60% EtOAc/pet. ether) 0.32;
9.57%. C14H18N2O5 requires C, 57.12; H, 6.18; N, 9.52%.] Rf (40%
30
EtOAc/pet. ether) 0.18; [
a
]
þ63.3 (c 0.60, CHCl3); nmax (CHCl3)
D
1757 cmꢀ1
; dH (200 MHz, CDCl3) 2.04–2.45 (m, 2H, H-5), 3.40–3.60
(m, 4H, H-4, –OCH3), 3.81 (s, 3H, Ar–OCH3), 4.15 (d, J¼15.2 Hz, 1H,
–NCHaHb), 4.20–4.36 (m, 3H, H-3, H-6), 4.55 (d, J¼15.2 Hz, 1H,
–NCHaHb), 6.89 (d, J¼8.5 Hz, 2H), 7.19 (d, J¼8.5 Hz, 2H); dC

N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
7197
(125.76 MHz) 28.5, 44.0, 55.3, 56.6, 57.9, 71.6, 87.5, 114.4, 126.8,
129.5, 159.4, 166.1; MS (m/z): 295 (Mþ1).
4.11.14. (3R,4R)-3-Methoxy-4-(4-methoxy-benzylamino)-
piperidine-2-one (15b)
Following the general procedure, as for 6a,-b, 15b was obtained
4.11.9. (3R,4R)-1-benzyl-3-methoxy-4-(2-nitro-ethyl)-azetidin-2-
one (13c)
Following the general procedure, as for 4a,b, 13c was prepared
in 50% yield as a pale yellow viscous liquid. [Found C, 58.87; H, 6.32;
in 61% yield as a gummy compound. [Found C, 63.85; H, 7.77; N,
10.55%. C14H20N2O3 requires C, 63.60; H, 7.64; N, 10.60%.] Rf (60%
30
acetone/pet. ether) 0.16; [
a
]
D
þ48.0 (c 0.50, CHCl3); nmax (CHCl3)
1650 cmꢀ1
;
dH (200 MHz, CDCl3) 1.84–2.02 (m, 1H, Ha-5), 2.04–2.24
N, 10.42%. C13H16N2O4 requires C, 59.08; H, 6.10; N, 10.60%.] Rf (40%
(m, 1H, Hb-5), 3.07–3.17 (m, 1H, H-4), 3.46–3.52 (m, 1H, H-6), 3.55
(s, 3H, –OCH3), 3.67–3.79 (m, 3H, H-6, –NCH2), 3.80 (s, 3H, Ar–
OCH3), 3.87 (d, J¼3.5 Hz, 1H, H-3), 3.95–4.15 (br s, 2H, 2ꢂN–H), 6.87
(d, J¼8.6 Hz, 2H, Ar), 7.24 (d, J¼8.6 Hz, 2H, Ar); dC (50.32 MHz) 23.3,
46.0, 49.9, 53.1, 55.3, 59.3, 77.3, 113.9, 129.3, 131.4, 158.8, 164.3; MS
(m/z): 265 (Mþ1).
30
EtOAc/pet. ether) 0.18; [
a
]
þ70.0 (c 0.80, CHCl3); nmax (CHCl3)
D
1759 cmꢀ1
;
dH (200 MHz, CDCl3) 2.07–2.39 (m, 2H, H-5), 3.45–3.51
(m, 4H, –OCH3, H-4), 4.18–4.35 (m, 4H, H-3, H-6, –NCHaHb), 4.61 (d,
J¼15.1 Hz, 1H, –NCHaHb), 7.23–7.40 (m, 5H, Ar); dC (125.76 MHz)
28.4, 44.6, 56.8, 57.9, 71.5, 87.6, 128.1, 128.2, 129.1, 134.8, 166.1; MS
(m/z): 265 (Mþ1).
4.11.15. (3R,4R)-4-Benzylamino-3-methoxypiperidine-2-one (15c)
Following the general procedure, as for 6a,b,15c was obtained in
55% yield as a gummy compound. [Found C, 66.53; H, 7.92; N,
4.11.10. (2R,3R)-2-Methoxy-3-(4-methoxy-phenylamino)-5-nitro-
pentanoic acid methyl ester (14a)
Following the general procedure, as for 5a,b, 14a was obtained
as a yellow viscous liquid in 95% yield. [Found C, 53.81; H, 6.63; N,
11.67%. C13H18N2O2 requires C, 66.64; H, 7.74; N, 11.96%.] Rf (70%
30
acetone/pet. ether) 0.32; [
a
]
þ36.8 (c 0.68, MeOH); nmax (CHCl3)
D
8.90%. C14H20N2O6 requires C, 53.84; H, 6.45; N, 8.97%.] Rf (30%
1655 cmꢀ1
; dH (200 MHz, CDCl3) 2.02–2.33 (m, 2H, H-5), 3.22–3.30
30
EtOAc/pet. ether) 0.28; [
a
]
D
þ19.2 (c 0.52, CHCl3); nmax (CHCl3)
(m, 1H, H-4), 3.53 (s, 3H, –OCH3), 3.64–3.80 (m, 2H, H-6), 3.90–4.09
(m, 3H, H-3, –NCH2), 7.28–7.40 (m, 5H, Ar), 7.50 (br s, 1H, –CONH);
dC (50.32 MHz) 22.2, 47.0, 49.6, 52.7, 59.3, 76.3, 128.3, 128.8, 128.9,
135.3, 163.0; MS (m/z): 235 (Mþ1).
1749 cmꢀ1
;
dH (200 MHz, CDCl3) 2.10–2.23 (m, 2H, H-4), 3.40 (s, 3H,
–OCH3), 3.77 (s, 3H, –COOCH3), 3.79 (s, 3H, Ar–OCH3), 3.79–3.95 (m,
1H, H-3), 3.97 (d, J¼3.1 Hz, 1H, H-2), 4.45–4.72 (m, 2H, H-5), 6.70 (d,
J¼9.0 Hz, 2H, Ar), 6.82 (d, J¼9.0 Hz, 2H, Ar); dC (75.48 MHz) 27.6,
51.9, 54.7, 55.4, 59.0, 72.4, 79.9, 115.0, 116.6, 139.9, 153.3, 171.2; MS
(m/z): 313 (Mþ1).
4.11.16. (3S,4R)-3-Methoxy-4-(4-methoxy-phenylamino)-
piperidine (16a)
Following the general procedure, as for 7a,b,16a was obtained in
52% yield as a viscous liquid. [Found C, 66.24; H, 8.47; N, 12.03%.
4.11.11. (2R,3R)-2-Methoxy-3-(4-methoxy-benzylamino)-5-nitro-
pentanoic acid methyl ester (14b)
Following the general procedure, as for 5a,b, 14b was obtained
as yellow viscous liquid in 94% yield. [Found C, 55.44; H, 6.83; N,
C
13H20N2O2 requires C, 66.07; H, 8.53; N, 11.85%.] Rf (60% EtOAc/pet.
30
ether) 0.28; [
a
]
þ12.5 (c 0.72, CHCl3); nmax (CHCl3) 3215,
D
3368 cmꢀ1
;
dH (200 MHz, CDCl3) 1.72–2.04 (m, 2H, H-5), 2.69–2.85
8.76%. C15H22N2O6 requires C, 55.19; H, 6.81; N, 8.58%.] Rf (30%
(m, 2H, H-6), 3.25–3.45 (m, 5H, H-2, –OCH3), 3.57–3.70 (m, 2H, H-4,
H-3), 3.74 (s, 3H, Ar–OCH3), 6.62 (d, J¼7.8 Hz, 2H, Ar), 6.78 (d,
J¼7.8 Hz, 2H, Ar), 7.63 (br s, 1H, Ar–NH); dC (125.76 MHz) 25.6, 52.9,
55.6, 55.9, 56.9, 57.0, 76.0, 114.9, 116.3, 140.2, 152.9; MS (m/z): 237
(Mþ1).
30
EtOAc/pet. ether) 0.27; [
a
]
þ42.9 (c 0.7, CHCl3); nmax (CHCl3)
D
1747 cmꢀ1
;
dH (200 MHz, CDCl3) 1.94–2.06 (m, 2H, H-4), 2.92–3.02
(m, 1H, H-3), 3.45 (s, 3H, –OCH3), 3.63 (d, J¼12.9 Hz, 1H, –NCHaHb),
3.75–3.87 (m, 7H, –NCHaHb, –COOCH3, Ar–OCH3), 4.06 (d,
J¼3.3 Hz, 1H, H-2), 4.40–4.62 (m, 2H, H-5), 6.87 (d, J¼8.6 Hz, 2H,
Ar), 7.24 (d, J¼8.6 Hz, 2H, Ar); dC (125.76 MHz) 27.9, 50.5, 52.1,
55.3, 56.4, 59.1, 72.8, 79.4, 113.8, 129.2, 131.8, 158.8, 171.8; MS
(m/z): 327 (Mþ1).
4.11.17. (3S,4R)-3-Methoxy-4-(4-methoxy-benzylamino)-
piperidine (16b)
Following the general procedure, as for 7a,b, 16b was prepared
in 50% yield as a viscous liquid. [Found C, 67.34; H, 8.92; N, 11.27%.
4.11.12. (2R,3R)-3-Benzylamino-2-methoxy-5-nitro-pentanoic acid
methyl ester (14c)
Following the general procedure, as for 5a,b, 14c was obtained
as yellow viscous liquid in 98% yield. [Found C, 56.83; H, 6.92; N,
C14H22N2O2 requires C, 67.17; H, 8.86; N, 11.19%.] Rf (70% acetone/
30
pet. ether) 0.18; [
a
]
þ18.0 (c 0.5, CHCl3); nmax (CHCl3) 3257,
D
3328 cmꢀ1
;
dH (200 MHz, CDCl3) 1.60–1.99 (m, 3H, H-5, Ha-2), 2.05
(br s, 1H, –NH), 2.40–2.78 (m, 3H, H-6, H-2), 3.18–3.26 (m, 1H, H-4),
3.36 (br s, 1H, –NH), 3.42 (s, 3H, –OCH3), 3.47–3.58 (m, 1H, H-3),
3.73–3.87 (m, 5H, Ar–OCH3, –NCH2), 6.88 (d, J¼8.7 Hz, 2H, Ar), 7.26
(d, J¼8.7 Hz, 2H, Ar); dC (100.61 MHz) 26.5, 49.1, 52.1, 53.4, 54.3,
55.3, 57.5, 73.9, 114.0, 129.5, 130.5, 159.0; MS (m/z): 251 (Mþ1).
9.63%. C14H20N2O5 requires C, 56.75; H, 6.80; N, 9.45%.] Rf (30%
30
EtOAc/pet. ether) 0.26; [
a
]
D
þ42.5 (c 0.8, CHCl3); nmax (CHCl3)
1743 cmꢀ1
;
dH (200 MHz, CDCl3) 1.98–2.08 (m, 2H, H-4), 2.31 (br s,
1H, –NH) 2.97–3.06 (m, 1H, H-3), 3.45 (s, 3H, –OCH3), 3.69–3.79 (m,
4H, –NCHaHbPh, –COOCH3), 3.90 (d, J¼13.1 Hz, –NCHaHbPh), 4.08
(d, J¼3.1 Hz, 1H, H-2), 4.44–4.61 (m, 2H, H-5), 7.26–7.37 (m, 5H, Ar);
dC (50.32 MHz) 27.8, 51.1, 52.1, 56.5, 59.1, 72.7, 79.3, 127.4, 128.2,
128.5, 139.3, 171.6; MS (m/z): 297 (Mþ1).
4.11.18. (3S,4R)-4-Benzylamino-3-methoxypiperidine (16c)
Following the general procedure, as for 7a,b,16c was obtained in
49% yield as a gummy compound. [Found C, 71.12; H, 9.32; N,
12.95%. C13H20N2O requires C, 70.87; H, 9.15; N, 12.72%.] Rf (70%
30
4.11.13. (3R,4R)-3-Methoxy-4-(4-methoxy-phenylamino)-
piperidine-2-one (15a)
acetone/pet. ether) 0.25; [
a
]
D
þ11.2 (c 0.72, CHCl3); nmax (CHCl3)
3211, 3319 cmꢀ1
;
dH (200 MHz, CDCl3) 1.65–1.95 (m, 2H, H-5), 2.35–
Following the general procedure, as for 6a,b, 15a was prepared
in 67% as a gummy compound. [Found C, 62.32; H, 7.33; N, 11.47%.
2.70 (m, 2H, H-6), 2.80–3.45 (m, 6H, H-2, –NH, –OCH3), 3.50–3.90
(m, 4H, H-4, H-3, –NCH2), 4.34 (br s,1H, –NH), 7.20–7.33 (m, 5H, Ar);
dC (100.61 MHz) 26.6, 50.3, 55.0, 56.5, 56.9, 57.4, 75.9, 127.1, 128.1,
128.4, 139.6; MS (m/z): 221 (Mþ1).
C
13H18N2O3 requires C, 62.38; H, 7.25; N, 11.19%.] Rf (60% EtOAc/pet.
30
ether) 0.33; [
a
]
þ38.2 (c 0.55, CHCl3); nmax (CHCl3) 1651 cmꢀ1
; dH
D
(200 MHz, CDCl3) 2.00–2.28 (m, 2H, H-5), 3.56 (s, 3H, –OCH3), 3.58–
3.73 (m, 3H, H-4, H-6), 3.75 (s, 3H, Ar–OCH3), 3.90 (d, J¼3.5 Hz, 1H,
H-3), 6.65 (d, J¼9.0 Hz, 2H, Ar), 6.80 (d, J¼9.0 Hz, 2H, Ar); dC
(50.32 MHz) 23.3, 47.2, 51.7, 55.6, 59.3, 77.3, 114.9, 116.2, 139.5,
153.1, 162.9; MS (m/z): 251 (Mþ1).
Acknowledgements
Authors thank DST, New Delhi, for financial support and N.M.S.
thanks UGC, New Delhi, for research fellowship. We would like to

7198
N.M. Shirode et al. / Tetrahedron 64 (2008) 7191–7198
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thank Dr. P. R. Rajmohanan of our NMR-group for useful
discussions.
Supplementary data
Supplementary data for compound 7a is available online. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.05.090.
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