4-Formylazetidin-2-ones, synthon for the facile synthesis of enantiopure 4-aminopiperidin-2-ones

Article abstract of DOI:10.1055/s-2003-40979

Enantiopure 4-formylazetidin-2-ones 1a-d have been used as building blocks for the synthesis of 4-aminopiperidin-2-ones 6a-d in 28-39% overall yields. The synthesis involves ring expansion of azetidinone 4a-d via methanolysis followed by a reductive cycli

Full text of DOI:10.1055/s-2003-40979

PAPER
1903
4-Formylazetidin-2-ones, Synthon for the Facile Synthesis of Enantiopure
4-Aminopiperidin-2-ones
4
-Formylazetidin-2
e
-ones, Syn
v
thon for
S
yn
a
thesis of 4-
n
A
minopiperi
a
din-2-one
s
than Krishnaswamy, Vidyesh V. Govande, Abdul Rakeeb A. S. Deshmukh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)5893153; E-mail: arasd@dalton.ncl.res.in
Received 31 March 2003; revised 26 May 2003
Dedicated to Dr. B. G. Hazra, Scientist, OCS, NCL, Pune, on his 60th birthday.
reduced to the corresponding 4-aminopiperidine deriva-
tives.9 One of these piperidine derivatives is a part struc-
ture of Cisapride,9b a useful drug for gastro-esophagal
reflux disease.
Abstract: Enantiopure 4-formylazetidin-2-ones 1a–d have been
used as building blocks for the synthesis of 4-aminopiperidin-2-
ones 6a–d in 28–39% overall yields. The synthesis involves ring ex-
pansion of azetidinone 4a–d via methanolysis followed by a reduc-
tive cyclization of the C-4 nitroethyl side chain with an ester group.
Although 4-aminopiperidin-2-ones are important inter-
mediates, there are very few syntheses reported so
far.6,8d,10 For the first time we report the synthesis of enan-
tiopure 4-aminopiperidin-2-ones from 4-formyl- -lac-
tam. We envisaged the introduction of an aminoethyl side
chain on C-4 of optically pure azetidin-2-one followed by
intra-molecular nucleophilic ring opening by the amino
group would give the required 4-aminopiperidin-2-one in
enantiomerically pure form (Scheme 1).
Key words: lactams, reductions , cyclizations, aldol reactions,
piperidines, esters
4-Formylazetidin-2-ones are useful building blocks for
the synthesis of monobactams, isocephams, carbapenams
and several other non- -lactam compounds like -hy-
droxyaspartate and hydroxybutanoic acids.1 The applica-
tion of 4-formylazetidin-2-ones as building blocks in
stereocontrolled synthesis has been reviewed recently.2
As a part of our research programmed on the asymmetric
synthesis of -lactams,3 we have developed an efficient
method for the synthesis of enantiomerically pure 4-
formylazetidin-2-ones from easily accessible (–)-diethyl
tartrate.4
The enantiopure 4-formyl- -lactams 1a–c were obtained
by our earlier reported method.4a The reaction of ni-
tromethane with cis-3-phenoxy-4-formyl- -lactam (1a) in
the presence of a catalytic amount of triethylamine gave a
diastereomeric mixture (80:20) of nitro-aldol product 2a.
The dehydration of nitro alcohol 2a under acidic as well
as basic reaction conditions did not give clean nitro olefin
3a. Therefore, the hydroxy group was acylated by acetic
anhydride in the presence of a catalytic amount of concen-
trated sulphuric acid at 0 ºC and the corresponding acetate
was refluxed with benzene for 5 hours in the presence of
sodium bicarbonate to give nitro olefin 3a in 70% yield.
There was no racemization of azetidin-2-one 2a and 3a
under the reaction conditions as the 1H NMR of the olefin
3a showed the presence of only a single isomer. The nitro
olefin 3a was reduced to nitro alkane 4a by stirring with
tributyltinhydride11 in dichloromethane for 24 hours at
room temperature (TLC). The reduction of nitro alkane 4a
or nitro alkene 3a with catalytic hydrogenation by Pd/C or
Raney Ni catalysts gave a complex mixture of products
In this publication we wish to report the application of 4-
formylazetidin-2-ones5 as a building block for the synthe-
sis of 4-aminopiperidin-2-ones, which are useful interme-
diates for biologically important compounds.
Our interest in the synthesis of 4-aminopiperidin-2-ones
stems from their use as conformationally locked -amino
acid equivalents, peptide surrogates (homo-Friedinger
lactams)6 that can serve as peptidomimetics. They can
also be utilized as a monomer for more rigid peptide nu-
cleic acids (PNA), pseudopeptide mimic of natural nucle-
ic acids.7 Apart from their potential use as
peptidomimetics they are also part of the structure of
some natural products.8 4-Aminopiperidin-2-ones can be
Scheme 1
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 30 07 2003.
Art Id.1437-210X,E;2003,0,12,1903,1908,ftx,en;Z04603SS.pdf.
DOI: 10.1055/s-2003-40979
© Georg Thieme Verlag Stuttgart · New York

1904
D. Krishnaswamy et al.
PAPER
Erba, CHNS-O EA 1108 Elemental analyzer. Optical rotations were
recorded on a JASCO-181 digital Polarimeter under standard con-
ditions. Petroleum ether refers to the fraction with bp 60–80 ºC.
instead of either 4-aminopiperidin-2-one 6a or 4-aminoet-
hyl- -lactam. Therefore, the nitro- -lactam 4a was stirred
with methanolic HCl at room temperature for 24 hours
(TLC) to give -amino ester 5a in 82% yield. The reduc-
tion of the nitro group was successfully achieved by trans-
fer hydrogenation of -amino ester 5a using ammonium
formate and Pd/C (10%) in methanol at room temperature
for 3 hours (TLC). The lactamization occurred directly
during the transfer hydrogenation of nitro ester 5a to give
4-[(4-methoxyphenyl)amino]-3-phenoxypiperidin-2-one
(6a) in 80% yield (Scheme 2). A direct transfer hydroge-
nation of nitro alkene 3a or nitro alkane 4a with ammoni-
um formate and Pd/C also gave an inseparable complex
(3R,4S)-1-(4-Methoxyphenyl)-4-(2-nitrovinyl)-3-phenoxyazeti-
din-2-one (3a); Typical Procedure
To a solution of 1a (1.78 g, 6 mmol) in nitromethane (20 mL) was
added Et3N (0.1 gm, 1 mmol) at r.t. and the reaction mixture was
stirred for 4 h. The excess nitromethane was removed under reduced
pressure to afford a viscous oil of an inseparable diastereomeric
mixture (80:20) of nitro alcohols 2a. This mixture was dissolved in
acetic anhydride (20 mL) and cooled to 0 °C. A drop of concd
H2SO4 was added to the reaction mixture and stirred at 0 °C for 1 h.
After completion of the reaction (TLC), H2O (2 mL) was added at
0 °C and stirred for 30 min. It was extracted with EtOAc (2 × 15 ml)
mixture of products instead of the desired N-substituted 4- and the organic layer was washed with sat. aq NaHCO3 (3 × 10
mL), brine (15 mL) and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a diastereomeric mixture of nitro
acetates, which was refluxed with benzene (20 mL) in the presence
aminopiperidin-2-one 6a.
Several other 4-aminopiperidin-2-ones were prepared fol-
lowing the above synthetic scheme in 28–39% overall
yields (Table 1). The starting 3-unsubstituted 4-formyl-
azetidin-2-one 1d, required for the synthesis of 4-ami-
nopiperidin-2-one 6d, was prepared by a reported
procedure.12
of NaHCO3 (4.0 g) for 5 h. After completion of reaction (TLC), sol-
id was removed by filtration, and the solvent was removed from the
filtrate under reduced pressure to afford the crude nitro alkene 3a,
which was further purified by column chromatography (silica gel
60–120; petroleum ether–EtOAc, 75:25) to get pure nitro alkene 3a.
Yield: 1.42 g (70%); mp 116–118 °C; [ ]D28 +102.8 (c 1.05,
CHCl3).
IR (CHCl3): 1764, 1533, 1357 cm–1.
1H NMR (CDCl3, 200 MHz): = 3.75 (s, 3 H), 5.10 (t, J = 5.8 Hz,
1 H), 5.60 (d, J = 4.9 Hz, 1 H), 6.90–7.50 (m, 11 H).
13C NMR (CDCl3, 50.3 MHz): = 53.3, 81.6, 114.7, 115.4, 118.4,
122.9, 129.7, 134.7, 142.9, 156.6, 157.0, 161.1.
MS: m/z = 340 (M+).
In summary, we have demonstrated the application of 4-
formylazetidin-2-ones 1a–d as building blocks for the
synthesis of 4-aminopiperidin-2-ones 6a–d via methanol-
ysis of the azetidinone ring followed by reductive cycliza-
tion.
1H NMR and 13C NMR Spectra were recorded in CDCl3 solution on
a Bruker AC 200 spectrometer and chemical shifts are reported in
ppm downfield from TMS for 1H NMR. IR spectra were recorded
on Shimadzu FTIR-8400 using sodium chloride optics. The MS
were recorded on a Finnigan Mat 1020 mass spectrometer at 70 eV.
Mps were determined on a Thermonik Campbell mp apparatus and
were uncorrected. The microanalyses were performed on a Carlo–
Anal. Calcd for C18H16N2O5: C, 63.52; H, 4.74; N, 8.23. Found: C,
63.45; H, 4.85; N, 8.01.
The nitro alkenes 3b–d were prepared following the above proce-
dure.
Scheme 2 Reagents and conditions: (a) CH3NO2, Et3N, r.t., 4 h (b) i) Ac2O, Concd H2SO4, 0 °C, 1 h; ii) NaHCO3, Benzene, reflux, 5 h
(c) Bu3SnH, CH2Cl2–MeOH (10:1), r.t., 3 to 24 h (d) 20% HCl/MeOH, r.t., 12 to 24 h (e) Pd/C, HCOONH4, MeOH, r.t., 2 to 16 h.
Synthesis 2003, No. 12, 1903–1908 © Thieme Stuttgart · New York

PAPER
4-Formylazetidin-2-ones, Synthon for the Synthesis of 4-Aminopiperidin-2-ones
1905
Table 1 Synthesis of Nitro Alkenes 3a–d, Nitro Alkanes 4a-d, Nitro Esters 5a–d and 4-Aminopiperidin-2-ones 6a–d
R1
R2
Mp (°C)
[ ]D
Yielda
(%)
28
Entry No.
Compound
No.
1
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
PhO
BnO
PhO
H
PMPc
PMP
Bn
116–118
137–138
95–97
+102.8 (c 1.05, CHCl3)
+99.2 (c 1, CHCl3)
70b
75 b
72 b
75 b
85
2
3
+53.8 (c 0.5, CHCl3)
+201.7 (c 1.15, CHCl3)
121.9 (c 1.05, CHCl3)
+98.6 (c 0.9, CHCl3)
+120.6 (c 0.9, CHCl3)
+66.5 (c 1.05, CHCl3)
–60.6 (c 1.1, CHCl3)
–11.9 (c 1, CHCl3)
4
PMP
PMP
PMP
Bn
viscous oil
108–110
viscous oil
viscous oil
78–80
5
PhO
BnO
PhO
H
6
73
7
65
8
PMP
PMP
PMP
Bn
75
9
PhO
BnO
PhO
H
98–100
82
10
viscous oil
viscous oil
viscous oil
73–75
91
11
–11.6 (c 1.1, CHCl3)
–37.9 (c 1, CHCl3)
91
12
PMP
PMP
PMP
Bn
90
13
PhO
BnO
PhO
H
+68.2 (c 1.1, CHCl3)
+43.1 (c 1.03, CHCl3)
+25.0 (c 1.1, CHCl3)
–9.9 (c 1.05, CHCl3)
80
14
140–141
130–132
144
66
15
62
16
PMP
73
a Isolated yields.
b Yield based on starting material 1.
c PMP = p-Methoxyphenyl.
(3R,4S)-1-(4-Methoxyphenyl)-4-(2-nitrovinyl)-3-benzyloxyaze-
tidin-2-one (3b)
(4R)-1-(4-Methoxyphenyl)-4-(2-nitrovinyl)azetidin-2-one (3d)
Yield: 75%; colourless oil; [ ]D28 +201.7 (c 1.15, CHCl3).
IR (CHCl3): 1745, 1529, 1380 cm–1.
1H NMR (CDCl3, 200 MHz): = 3.00 (dd, J = 3, 15.1 Hz, 1 H),
3.50 (dd, J = 5.8, 15.1 Hz, 1 H), 3.80 (s, 3 H), 4.65–4.80 (m, 1 H),
6.90 (d, J = 9.3 Hz, 2 H), 7.10–7.50 (m, 4 H).
13C NMR (CDCl3, 50.3 MHz): = 43.6, 47.6, 55.3, 114.46, 117.7,
130.4, 138.5, 141.1, 156.3, 161.8.
Yield: 75%; mp 137–138 °C ; [ ]D28 +99.2 (c 1, CHCl3).
IR (CHCl3): 1758, 1531, 1357 cm–1.
1H NMR (CDCl3, 200 MHz): = 3.8 (s, 3 H), 4.60 (d, J = 11.7 Hz,
1 H), 4.65–4.75 (m, 1 H), 4.90 (d, J = 11.2 Hz, 1 H), 5.05 (d, J = 5.4
Hz, 1 H), 6.9 (d, J = 8.8 Hz, 2 H), 7.00–7.50 (m, 9 H).
13C NMR (CDCl3, 50.3 MHz): = 55.4, 55.8, 74.2, 83.4, 114.6,
118.3, 128.1, 128.2, 128.7, 129.8, 135.5, 135.9, 142.3, 156.9, 162.5.
MS: m/z = 248 (M+).
MS: m/z = 354 (M+).
Anal. Calcd For C12H12N2O4: C, 58.04; H, 4.87; N, 11.28. Found:
C, 58.20; H, 4.68; N, 11.32.
Anal. Calcd for C19H18N2O5: C, 64.38; H, 5.12; N, 7.90. Found: C,
64.18; H, 4.96; N, 8.10.
(3R,4S)-1-(4-Methoxyphenyl)-4-(2-nitroethyl)-3-phenoxyazeti-
din-2-one (4a); Typical Procedure
(3R,4S)-1-Benzyl-4-(2-nitrovinyl)-3-phenoxyazetidin-2-one (3c)
Yield: 72%; mp 95–97 °C; [ ]D28 +53.8 (c 0.5, CHCl3).
IR (CHCl3): 1766, 1531, 1355 cm–1.
1H NMR (CDCl3, 200 MHz): = 4.30 (d, J = 14.7 Hz, 1 H), 4.45
(dd, J = 4.8, 8 Hz, 1 H), 4.70 (d, J = 14.7 Hz, 1 H), 5.50 (d, J = 4.8
Hz, 1 H), 6.90–7.50 (m, 12 H).
13C NMR (CDCl3, 50.3 MHz): = 45.2, 55.1, 82.2, 115.3, 122.7,
128.5, 129.0, 129.6, 133.9, 134.7, 142.5, 156.5, 164.2.
To a solution of 3a (1.130 g, 3.5 mmol) in anhyd CH2Cl2–MeOH
(10:1; 15 mL), tributyltin hydride (1.22 g, 4.2 mmol) was added at
r.t. and stirred for 24 h. After completion of reaction (TLC), the sol-
vent was removed under reduced pressure and the crude product
was purified by flash column chromatography to give pure nitro al-
kane 4a.
Yield: 0.960 g (85%); mp 108–110; [ ]D28 +121.9 (c 1.05, CHCl3).
IR (CHCl3): 1755, 1554, 1379 cm–1.
MS: m/z = 324 (M+).
1H NMR (CDCl3, 200 MHz): = 2.45–2.60 (m, 1 H), 2.75–2.90 (m,
1 H), 3.80 (s, 3 H), 4.40–4.60 (m, 3 H), 5.45 (d, J = 4.9 Hz, 1 H),
6.9 (d, J = 8.8 Hz, 2 H), 7.05–7.50 (m, 7 H).
Anal. Calcd For C18H16N2O4: C, 66.65; H, 4.97; N, 8.64. Found: C,
66.42; H, 4.73; N, 8.75.
Synthesis 2003, No. 12, 1903–1908 © Thieme Stuttgart · New York

1906
D. Krishnaswamy et al.
PAPER
13C NMR (CDCl3, 50.3 MHz): = 24.9, 54.2, 55.3, 71.3, 79.3, 79.7,
114.6, 115.6, 118.6, 122.6, 129.6, 156.8, 157.0, 159.5, 162.1.
MS: m/z = 342 (M+).
NaHCO3 (10 mL), brine (10 mL), and dried (Na2SO4). The solvent
was removed under reduced pressure to get the crude nitro ester,
which was purified by column chromatography (silica gel 60–120;
petroleum ether–EtOAc, 80:20) to afford the pure nitro ester 5a.
Yield: 0.910 g (82%); mp 98–100 °C; [ ]D28 –60.6 (c 1.1, CHCl3).
IR (CHCl3): 3382, 1751, 1552, 1377 cm–1.
Anal. Calcd for C18H18N2O5: C, 63.15; H, 5.29; N, 8.18. Found: C,
63.22; H, 5.44; N, 8.27.
(3R,4S)-1-(4-Methoxyphenyl)-4-(2-nitroethyl)-3-benzyloxyaze-
tidin-2-one (4b)
Following the typical procedure, nitro alkene 3b (1.240 g, 3.5
mmol) was treated with tributyltin hydride (1.22 g, 4.2 mmol) at r.t.
for 24 h to give the nitro alkane 4b.
1H NMR (CDCl3, 200 MHz): = 2.25–2.55 (m, 2 H), 3.50 (s, 3 H),
3.76 (s, 3 H), 4.16–4.23 (m, 1 H), 4.50–4.70 (m, 3 H), 4.75 (d,
J = 2.4 Hz, 1 H), 6.65–7.35 (m, 9 H).
13C NMR (CDCl3, 50.3 MHz): = 30.0, 52.0, 54.5, 55.4, 72.2, 76.8,
114.7, 114.9, 115.8, 122.1, 129.5, 140.2, 152.9, 157.2, 169.7.
Yield: 1.030 g (73%); colourless oil.
IR (CHCl3): 1758, 1554, 1380 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.35–2.55 (m, 1 H), 2.60–2.80 (m,
1 H), 3.80 (s, 3 H), 4.30–4.40 (m, 1 H), 4.45–4.60 (m, 2 H), 4.75 (d,
J = 11.7 Hz, 1 H), 4.85 (d, J = 5.4 Hz, 1 H), 5.05 (d, J = 11.7 Hz, 1
H), 6.90 (d, J = 9.3 Hz, 2 H), 7.25–7.50 (m, 7 H).
13C NMR (CDCl3, 50.3 MHz): = 25.1, 54.1, 55.3, 71.5, 73.2, 80.5,
114.64, 118.5, 127.9, 128.9, 128.5, 129.9, 136.6, 156.7, 163.9.
MS: m/z = 356 (M+).
MS: m/z = 374 (M+).
Anal. Calcd for C19H22N2O6: C, 60.95; H, 5.92; N, 7.48. Found: C,
60.75; H, 6.08; N, 7.31.
Methyl (2R,3S)-3-[(4-Methoxyphenyl)amino]-5-nitro-2-benzyl-
oxypentanoate (5b)
Following the typical procedure, nitro alkane 4b (1.060 g, 3 mmol)
was stirred in methanolic HCl (20%) for 12 h (TLC) to give the nitro
ester 5b.
Yield: 1.100 g (91%); pale yellow oil; [ ]D28 –11.9 (c 1, CHCl3).
IR (neat): 3373, 1747, 1550, 1380 cm–1.
Anal. Calcd for C19H20N2O5: C, 64.02; H, 5.66; N, 7.86. Found: C,
64.16; H, 5.52; N, 7.65.
1H NMR (CDCl3, 200 MHz): = 2.15–2.35 (m, 2 H), 3.50 (s, 3 H),
3.75 (s, 3 H), 3.80–4.55 (m, 6 H), 4.90 (d, J = 11.7 Hz, 1 H), 6.55
(d, J = 8.8 Hz, 2 H), 6.75 (d, J = 8.8 Hz, 2 H), 7.25–7.45 (m, 5 H).
13C NMR (CDCl3, 50.3 MHz): = 29.9, 51.6, 54.6, 55.5, 72.4, 72.7,
77.7, 114.8, 115.7, 128.2, 128.4, 136.8, 140.5, 152.8, 170.7.
(3R,4S)-1-Benzyl-4-(2-nitroethyl)-3-phenoxyazetidin-2-one (4c)
Following the typical procedure, nitro alkene 3c (1.130g, 3.5 mmol)
was treated with tributyltin hydride (1.22 g, 4.2 mmol) at r.t. for 24
h to give the nitro alkane 4c.
Yield: 0.750 g (65%); colourless oil; [ ]D28 +120.6 (c 0.9, CHCl3).
IR (CHCl3): 1758, 1554, 1384 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.30–2.40 (m, 2 H), 3.85–3.95 (m,
1 H), 4.30–4.40 (m, 3 H), 4.60 (d, J = 15.2 Hz, 1 H), 5.25 (d, J = 4.9
Hz, 1 H), 6.95–7.50 (m, 10 H).
13C NMR (CDCl3, 50.3 MHz): = 26.0, 44.9, 54.9, 71.6, 80.6,
115.52, 122.6, 128.2, 129.0, 129.7, 134.8, 157.0, 165.4.
MS: m/z = 388 (M+).
Anal. Calcd for C20H24N2O6: C, 61.83; H, 6.23; N, 7.21. Found: C,
61.62; H, 6.40; N, 7.38.
Methyl (2R,3S)-3-(Benzylamino)-5-nitro-2-phenoxypentanoate
(5c)
Following the typical procedure, nitro alkane 4c (0.970 g, 3 mmol)
was stirred in methanolic HCl (20%) for 24 h (TLC) to give the nitro
ester 5c.
Yield: 0.975 g (91%); pale yellow oil; [ ]D28 –11.6 (c 1.1, CHCl3).
MS: m/z = 326 (M+).
Anal. Calcd for C18H18N2O4: C, 66.23; H, 5.56; N, 8.58. Found: C,
66.35; H, 5.44; N, 8.70.
IR (neat): 3348, 1753, 1550, 1379 cm–1.
(4S)-1-(4-Methoxyphenyl)-4-(2-nitroethyl)azetidin-2-one (4d)
Following the typical procedure, nitro alkene 3d (0.870 g, 3.5
mmol) was treated with tributyltin hydride (1.22 g, 4.2 mmol) at r.t.
for 3 h to give the nitro alkane 4d.
Yield: 0.654 g (75%); mp 78–80 °C; [ ]D28 +66.5 (c 1.05, CHCl3).
IR (CHCl3): 1743, 1554, 1388 cm–1.
1H NMR (CDCl3, 200 MHz): = 2.10–2.35 (m, 1 H), 2.75 (dd,
J = 2.1, 14.9 Hz, 1 H), 2.75–2.95 (m, 1 H), 3.25 (dd, J = 5.1, 14.9
Hz, 1 H), 3.80 (s, 3 H), 4.10–4.25 (m, 1 H), 4.40–4.55 (m, 2 H), 6.0
(d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H).
13C NMR (CDCl3, 50.3 MHz): = 29.2, 41.5, 47.9, 55.1, 71.3,
114.3, 118.2, 130.1, 156.1, 162.7.
1H NMR (CDCl3, 200 MHz): = 2.10–2.50 (m, 3 H), 3.25–3.40 (m,
1 H), 3.70–4.00 (m, 2 H), 3.81 (s, 3 H), 4.50–4.65 (m, 2 H), 4.75 (d,
J = 3.4 Hz, 1 H), 6.80–7.50 (m, 10 H).
13C NMR (CDCl3, 50.3 MHz): = 29.3, 51.0, 52.2, 56.3, 72.5, 77.1,
115.0, 122.0, 127.1, 128.1, 128.3, 129.6, 139.7, 157.3, 170.4.
MS: m/z = 358 (M+).
Anal. Calcd for C19H22N2O5: C, 63.66; H, 6.19; N, 7.82. Found: C,
63.52; H, 6.05; N, 7.66.
Methyl (3S)-3-[4-(Methoxyphenyl)amino]-5-nitropentanoate
(5d)
Following the typical procedure, nitro alkane 4d (0.750 g, 3 mmol)
was stirred in methanolic HCl (20%) for 24 h (TLC) to give the nitro
ester 5d.
Yield: 0.766 g (91%); pale yellow oil; [ ]D28 –37.9 (c 1, CHCl3).
MS: m/z = 250 (M+).
Anal. Calcd for C12H14N2O4: C, 57.57; H, 5.64; N, 11.19. Found: C,
57.45; H, 5.80; N, 11.34.
IR (neat): 3365, 1730, 1550, 1380 cm–1.
Methyl (2R,3S)-3-[(4-Methoxyphenyl)amino]-5-nitro-2-phen-
oxypentanoate (5a); Typical Procedure
A solution of nitro alkane 4a (1.020 g, 3 mmol) in methanolic HCl
(20%; 10 mL) was stirred at r.t. for 24 h. After completion of the re-
action (TLC), solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2 (20 mL), washed with sat. aq
1H NMR (CDCl3, 200 MHz): = 2.10–2.60 (m, 4 H), 3.70 (s, 3 H),
3.80 (s, 3 H), 4.50–4.65 (m, 2 H), 6.65 (d, J = 9.3 Hz, 2 H), 6.80 (d,
J = 9.3 Hz, 2 H).
13C NMR (CDCl3, 50.3 MHz): = 31.9, 38.1, 49.3, 57.4, 55.3, 72.5,
114.7, 115.6, 140.2, 152.6, 171.5.
Synthesis 2003, No. 12, 1903–1908 © Thieme Stuttgart · New York

PAPER
4-Formylazetidin-2-ones, Synthon for the Synthesis of 4-Aminopiperidin-2-ones
1907
MS: m/z = 282 (M+).
MS: m/z = 296 (M+).
Anal. Calcd for C13H18N2O5: C, 55.29; H, 6.43; N, 9.93. Found: C,
55.42; H, 6.25; N, 9.75.
Anal. Calcd for C18H20N2O2: C, 72.93; H, 6.80; N, 9.45. Found: C,
73.10; H, 6.64; N, 9.56.
(3R,4S)-4-[(4-Methoxyphenyl)amino]-3-phenoxypiperidin-2-
one (6a); Typical Procedure
(4S)-4-[(4-Methoxyphenyl)amino]piperidin-2-one (6d)
Following the typical procedure, the nitro ester 5d (0.450 g, 1.6
mmol) was treated with 10% Pd/C (0.100 g) and ammonium for-
mate (0.500 g, 8 mmol) at r.t. for 2 h to give the 4-aminopiperidin-
2-one 6d.
Yield: 0.260 g (73%); mp 144 °C; [ ]D28 –9.9 (c 1.05, CHCl3).
IR (CHCl3): 3336, 1633 cm–1.
1H NMR (CDCl3, 200MHz): = 1.90–3.00 (m, 4 H), 3.50–4.00 (m,
4 H), 3.75 (s, 3 H), 5.5 (br s, 1 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.85,
(d, J = 8.8 Hz, 2 H).
13C NMR (CDCl3, 50.3 MHz): = 27.9, 37.3, 46.2, 48.4, 55.7,
115.1, 116.5, 138.5, 153.7, 163.1
To a solution of nitro ester 5a (0.598 g, 1.6 mmol) in anhyd MeOH
(10 mL), 10% Pd/C (100 mg) was added, followed by ammonium
formate (0.500 g, 8 mmol), and the reaction mixture was stirred at
r.t. under argon for 2 h. After completion of reaction (TLC), the re-
action mixture was filtered through a Celite bed and the bed was
washed with MeOH. The solvent from the filtrate was removed un-
der reduced pressure and the residue was dissolved in CH2Cl2 (20
mL), washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4).
Removal of solvent under reduced pressure gave crude product
which was purified by column chromatography (silica gel 60–120;
petroleum ether–EtOAc, 60:40) to afford pure 4-aminopiperidin-2-
one 6a.
MS: m/z = 220 (M+).
Yield: 0.400 g (80%); mp 73–75 °C ; [ ]D28 +68.2 (c 1.1, CHCl3).
Anal. Calcd for C12H16N2O2: C, 65.42; H, 7.32; N, 12.72 Found: C,
65.55; H, 7.43; N, 12.85.
IR (CHCl3): 3336, 1654 cm–1.
1H NMR (CDCl3, 200MHz): = 1.85–2.00 (m, 1 H), 2.30–2.55 (m,
1 H), 3.60–3.90 (m, 4 H), 3.75 (s, 3 H), 4.75 (d, J = 5.8 Hz, 1 H),
6.60–7.40 (m, 10 H).
Acknowledgement
13C NMR (CDCl3, 50.3 MHz): = 24.3, 46.8, 52.6, 55.9, 78.2,
115.2, 116.4, 116.8, 122.4, 129.7, 140.2, 153.4, 158.6, 163.2.
The authors (DK and VVG) thank CSIR for the financial support.
MS: m/z = 312 (M+).
References
Anal. Calcd for C18H20N2O3: C, 69.19; H, 6.45; N, 8.97 Found: C,
69.39; H, 6.33; N, 8.85.
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Bhawal, B. M.; Deshmukh, A. R. A. S. Synlett 2002, 1455.
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52, 8989.
(3R,4S)-4-[(4-Methoxyphenyl)amino]-3-benzyloxypiperidin-2-
one (6b)
Following the above procedure, the nitro ester 5b (0.622 g, 1.6
mmol) was treated with 10% Pd/C (0.100 g) and ammonium for-
mate (0.500 g, 8 mmol) at r.t. for 6 h to give the 4-aminopiperidin-
2-one 6b.
Yield: 0.345 g (66%); mp 140–141 °C; [ ]28D +43.1(c 1.03, CHCl3).
IR (CHCl3): 3352, 1633 cm–1.
1H NMR (CDCl3, 200MHz): = 1.75–2.00 (m, 1 H), 2.35–2.55 (m,
1 H), 3.50–3.80 (m, 4 H), 3.75 (s, 3 H), 4.00 (d, J = 5.3 Hz, 1 H),
4.75 (d, J = 11.7 Hz, 1 H), 5.00 (d, J = 11.7 Hz, 1 H), 6.50 (d,
J = 8.3 Hz, 2 H), 6.75 (d, J = 8.3 Hz, 2 H), 7.20–7.50 (m, 6 H).
13C NMR (CDCl3, 50.3 MHz): = 24.4, 45.6, 53.2, 55.7, 73.5, 76.8,
115.0, 116.2, 128.1, 128.5, 137.5, 139.7, 153.4, 163.4.
MS: m/z = 326 (M+).
Anal. Calcd for C19H22N2O3: C, 69.90; H, 6.79; N, 8.58. Found: C,
69.73; H, 6.74; N, 8.70.
(3R,4S)-4-Benzylamino-3-phenoxypiperidin-2-one (6c)
Following the typical procedure, the nitro ester 5c (0.574 g, 1.6
mmol) was treated with 10% Pd/C (0.100 g) and ammonium for-
mate (0.500 g, 8 mmol) at r.t. for 16 h to give the 4- aminopiperidin-
2-one 6c.
Yield: 0.292 g (62%); mp 130–132 °C; [ ]D28 +25.0 (c 1.1, CHCl3).
IR (CHCl3): 3330, 1662 cm–1.
1H NMR (CDCl3, 200 MHz): = 1.70–1.90 (m, 1 H), 2.20–2.35 (m,
1 H), 3.10–3.20 (m, 1 H), 3.35–3.90 (m, 4 H), 4.60 (d, J = 7.3 Hz, 1
H), 5.10 (br s, 2 H), 6.80–7.35 (m, 10 H).
13C NMR (CDCl3, 50.3 MHz): = 24.3, 46.2, 51.0, 55.2, 77.7,
116.4, 122.1, 127.4, 128.0, 128.6, 129.4, 139.3, 158.7, 163.0.
Synthesis 2003, No. 12, 1903–1908 © Thieme Stuttgart · New York

1908
D. Krishnaswamy et al.
PAPER
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Synthesis 2003, No. 12, 1903–1908 © Thieme Stuttgart · New York