Stereoselective synthesis of cis- and trans-4-acyl-β-lactams from vicinal diketones and ketoaldehydes

Article abstract of DOI:10.1007/s11426-011-4372-1

4-Acyl-β-lactams are important synthetic intermediates in both pharmaceutical and organic chemistry. Cis- and trans-4-acyl-β-lactams were synthesized stereoselectively from vicinal diketones via the formation of bulky and less bulky diimines as key interm

Full text of DOI:10.1007/s11426-011-4372-1

SCIENCE CHINA
Chemistry
November 2011 Vol.54 No.11: 1711–1717
doi: 10.1007/s11426-011-4372-1
• ARTICLES •
Stereoselective synthesis of cis- and trans-4-acyl--lactams from
vicinal diketones and ketoaldehydes
WANG ZhiXin & XU JiaXi*
State Key Laboratory of Chemical Resource Engineering; Department of Organic Chemistry, Faculty of Science, Beijing University of
Chemical Technology, Beijing 100029, China
Received June 28, 2011; accepted July 12, 2011; published online August 25, 2011
4-Acyl--lactams are important synthetic intermediates in both pharmaceutical and organic chemistry. Cis- and trans-4-acyl--
lactams were synthesized stereoselectively from vicinal diketones via the formation of bulky and less bulky diimines as key
intermediates, respectively. The diimines reacted with acyl chloride in the presence of triethylamine to give rise to the corre-
sponding 4-imino--lactams, which were further hydrolyzed to afford 4-acyl--lactams. The cis- and trans selectivity is de-
pended on the steric hindrance of the imine N-substituents. A series of cis-4-acyl--lactams were synthesized from vicinal
ketoaldehydes via the formation of their monoimines and diimines as intermediates. Pyruvic aldehyde produced cis-4-acetyl--
lactams and cis-4-formyl--lactams, respectively, through the reactions of its monoimine and diimine with acyl chlorides.
Phenylglyoxal generated cis-4-benzoyl--lactams via its monoaldimine.
4-acyl--lactam, diimine, diketone, imine, ketoaldehyde, -lactam, stereoselectivity
yl)--lactams via periodinate oxidation [368]. However,
the above-mentioned methods can only be used for the syn-
thesis of cis-4-acyl--lactams. Trans--lactams have been
previously prepared from the 3-unsubstituted 4-hydro-
xymethyl--lactams via alkylation and the Swern oxidation
[39], or from N-2-oxoalkyl-2,3-epoxyalkanamides via an
intramolecular nucleophilic ring-open reaction of the
oxirane ring [40]. It is still in demand to develop efficient
methods to stereoselectively prepare both cis- and trans-4-
acyl--lactams with different acyl groups from simple
starting materials. Herein, we reported our preliminary work
on the stereoselective synthesis of both cis- and trans-4-
acyl--lactams with different acyl groups from vicinal
diketones and ketoaldehydes.
1 Introduction
4-Acyl--lactams are important synthetic intermediates in
both pharmaceutical and organic chemistry [1, 2]. They
have been widely used for the synthesis of -amino acid
derivatives [3, 4] and -amino acid derivatives [5, 6] via
ring-opening reactions. They have also been applied in the
preparation of heterocycles [718], polycyclic heterocyclic
compounds [1925], alkaloids [23, 26], antibiotics [2731],
and even more complex natural products [23, 32] via ring
enlargements. 4-Formyl--lactams have been prepared in
different ways, including the Swern oxidation from the cor-
responding 4-hydroxymethyl--lactams [33], ozonolysis
and reduction from 4-styryl--lactams [34], and acidic hy-
drolysis from 4-imino--lactams [35]. Additionally, opti-
cally pure 4-formyl--lactams were prepared from optically
pure 4-(1,3-dioxol-4-yl)--lactams or 4-(1,3-oxazolidin-4-
2 Experiments
2.1 Materials and measurements
*Corresponding author (email: jxxu@mail.buct.edu.cn)
All commercially available reagents and solvents were
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com www.springerlink.com

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Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
used without further purification unless otherwise noted.
Monoimines and diimines were prepared from diketones
and ketoaldehydes according to the previously reported
methods [41]. Reactions of propionyl chloride and imines
were carried out under nitrogen atmosphere in anhydrous
solvents. Melting points were measured on a melting point
2.3 Preparation of diimines (1d, e) of vicinal ketoalde-
hydes
N,N’-Bis(diphenylmethyl)-1,2-propanediimine (1d)
A round-bottom flask was charged with a solution of py-
ruvic aldehyde (14 mmol, 3.33 g of 30 % aqueous solution)
and diphenylmethylamine (5.34 g, 29 mmol) in diethyl ether
(30 mL). The mixture was stirred at room temperature for
24 h and filtered. The colorless crystals were further recrys-
tallized from ethanol and washed with n-hexane to afford
1d as colorless crystals (3.72 g, yield 66.2 %). m.p.
1
apparatus and are uncorrected. H NMR spectra were rec-
orded at 200, 300, or 400 MHz in CDCl3 with TMS as the
internal standard. 13C NMR spectra were recorded at 50.3,
75.5, or 100.6 MHz in CDCl3 with CDCl3 as the internal
standard at 77.0 ppm. IR spectra were determined directly.
HRMS spectra were performed on an LC/MSD TOF mass
spectrometer.
1
141.0142.5 °C. Lit. [41] m.p. 141–142 °C. H NMR (300
MHz, CDCl3) : 8.15 (s, 1H, CH=N), 7.23–7.37 (m, 20H,
ArH), 5.87 (s, 1H, CH), 5.56 (s, 1H, CH), 2.26 (s, 3H, CH3).
13C NMR (CDCl3). : 167.0, 164.5, 143.5, 143.3, 128.48,
128.45, 127.59, 127.53, 127.1, 126.9, 77.5, 68.8, 13.5. IR
(KBr):  (cm1) 1635 (C=N).
2.2 Preparation of diimines (1ac) of vicinal diketones
N,N’-Bis(diphenylmethyl)-2,3-butanediimine (1a)
Butanedione (0.86 g, 10 mmol) and diphenylmethyla-
mine (3.84 g, 21 mmol)) were dissolved in freshly distilled
anhydrous EtOH (15 mL). To the resulting solution were
added a drop of 98% formic acid and MgSO4 (2 g). The
mixture was stirred at room temperature for 24 h. Di-
chloromethane (20 mL) was added to fully dissolve the
product. After filtration and evaporation of the solvent un-
der reduced pressure, the residue was purified by recrystal-
lization in EtOH to afford 1a as colorless crystals (1.83 g,
yield 43.9 %). m.p. 185187 °C. Lit. [41] m.p. 185186 °C.
1H NMR (200 MHz, CDCl3) : 7.507.16 (m, 20H, ArH),
5.83 (s, 2H, 2CH), 2.31 (s, 6H, 2CH3).
N,N’- Bis(4-methoxyphenyl)-1,2-propanediimine (1e)
A round-bottom flask was charged with a solution of py-
ruvic aldehyde (7 mmol, 1.67 g of 30 % aqueous solution)
and 4-methoxyaniline (1.85 g, 15 mmol) in diethyl ether (20
mL). The mixture was stirred at 0 °C for 12 h. After remov-
al of the solvent under reduced pressure, the residue was
purified by crystallization in EtOH to afford 1e as yellow
crystals (1.01 g, yield 51.0 %). m.p. 108109 °C. Lit. [44]
1
m.p. 106108 °C. H NMR (200 MHz, CDCl3) : 8.29 (s,
1H, N=CH), 7.346.82 (m, 8H, ArH), 3.84 (s, 3H, CH3O),
3.83 (s, 3H, CH3O), 2.23 (s, 3H, CH3).
2.4 Preparation of ketoaldimines (1f, g) of vicinal ke-
toaldehydes
N,N’- Bis(4-methoxyphenyl)-2,3-butanediimine (1b)
An ethanolic solution (100 mL) of 4-methoxyaniline
(2.46 g, 20 mmol) was added dropwise to an ethanolic solu-
tion (100 mL) of 2,3-butanedione (0.86 g, 10 mmol). The
resulting solution was refluxed in a water bath for 8 h. The
yellow crystalline product was filtered, recrystallized from
ethanol, and washed with n-hexane to afford 1b as yellow
crystals (1.51 g, yield 50.6 %). m.p. 187188 °C. Lit. [42]
m.p. 185186 °C. 1H NMR (200 MHz, CDCl3) : 6.936.75
(m, 8H, ArH), 3.82 (s, 6H, 2OCH3), 2.17 (s, 6H, 2CH3).
1-(4-Methoxyphenylimino)propan-2-one (1f)
A round-bottom flask was charged with a solution of py-
ruvic aldehyde (28 mmol, 6.73 g of 30 % aqueous solution)
and 4-methoxyaniline (2.46 g, 20 mmol) in diethyl ether (20
mL). The mixture was stirred at 0 °C for 3 h and washed
with water. The organic phase was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The re-
sulting residue was purified via flash column chromatog-
raphy (silica gel, hexanes:EtOAc = 4:1, v/v) to afford 1f as
yellow crystals (0.9 g, yield 25.4 %). m.p. 70.072.0 oC. 1H
NMR (300 MHz, CDCl3) : 7.88 (m, 1H, CH=N), 7.34 (d, J
＝9.0 Hz, 2H, ArH), 6.94 (d, J＝9.0 Hz, 2H, ArH), 3.84
N,N’-Bis(4-methoxyphenyl)-1,2-diphenyl-1,2-ethanediimine
(1c)
An ethanolic solution (100 mL) of benzil (2.10 g, 10
mmol) and 4-methoxyaniline (2.46 g, 20 mmol) was re-
fluxed in a water bath for 24 h. The reaction mixture was
concentrated to one-third of its volume and kept overnight
in a sulfuric acid desiccator. The yellow crystalline prod-
uct was filtered, recrystallized from ethanol, and washed
with diethyl ether and hexane (1:1, v/v) to afford 1c as
yellow crystals (2.46 g, yield 58.6 %). m.p. 173174 °C.
Lit. [43] m.p. 171–172 °C. 1H NMR (200 MHz, CDCl3) :
7.88–7.31 (m, 12H, ArH), 6.65 (s, 6H, ArH), 3.72 (s, 6H,
2CH3O).
(s, 3H, OCH3), 2.52 (s, 3H, CH3). 13C NMR (CDCl3) :
200.1, 160.5, 154.0, 141.0, 123.9, 123.8, 114.5, 55.5, 24.6.
2-(4-Methoxyphenylimino)-1-phenylethanone (1g)
A mixture of phenylglyoxal hydrate (1.13 g, 7.46 mmol),
4-methoxyaniline (0.97 g, 7.40 mmol), and anhydrous
magnesium sulfate (2 g) in dichloromethane (25 mL) was
stirred at 0 °C for 1 h, warmed to rt, filtered through Celite,
and concentrated under reduced pressure. The resulting res-
idue was purified via flash column chromatography (silica

Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
1713
gel, hexanes:EtOAc = 8:1, v/v) to afford 1g as an orange oil
(1.0 g, yield 60 %). 1H NMR (400 MHz, CDCl3) : 8.38 (s,
1H, CH), 8.336.98 (m, 9H, 2CH), 3.871 (s, 3H, OCH3).
156.3, 156.0, 142.5, 139.6, 135.5, 130.7, 128.5, 128.4,
127.9, 127.8, 127.4, 122.1, 121.5, 113.8, 113.5, 73.5, 60.4,
55.2, 12.3. IR (KBr):  (cm1) 1747 (C=O), 1626 (C=N).
HRMS (ESI) calcd for C31H29N2O3 [M+H]+ m/z: 477.2173,
found 477.2173.
2.5 General procedure for the reaction of propionyl
chloride and imines
Cis-1-diphenylmethyl-4-[(E)-(diphenylmethylimino)methyl]-
3,4-dimethylazetidin-2-one (2d)
A solution of propionyl chloride (111 mg, 1.2 mmol) in
anhydrous benzene (5 mL) was added dropwise to a solu-
tion of imine (1 mmol) and triethylamine (0.152 g, 1.5
mmol) in toluene (10 mL). The resulting mixture was stirred
at 80 °C under nitrogen for 416 h (monitoried by TLC),
diluted with CH2C12 (20 mL), and washed with saturated
aqueous NaHCO3 solution (20 mL) and brine (2 x 10 mL).
The organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The resulting residue
was purified via recrystallization in a mixture of EtOAc and
hexanes (for crystalline products) or via flash column
chromatography (silica gel, a mixture of hexanes and
EtOAc as eluent) (for liquid products) to afford the prod-
ucts.
Colorless crystals 0.339 g, yield 74.1 %, m.p. 113.0
115.0 °C. 1H NMR (200MHz, CDCl3) : 7.62 (s, 1H, CHN),
7.26–7.20 (m, 20H, ArH), 5.55 (s, 1H, ArCH), 5.28 (s, 1H,
ArCH), 3.10 (q, J =7.6 Hz, 1H, CH), 1.50 (s, 3H, CH3),
1.04 (d, J =7.6 Hz, 3H, CH3). 13C NMR (CDCl3) : 169.4,
163.9, 143.2, 143.1, 140.0, 128.43, 128.39, 128.30, 128.27,
127.5, 127.4, 127.3, 127.3, 127.0, 77.6, 63.9, 61.7, 55.7,
21.4, 9.9. IR (KBr):  (cm1) 1748 (C=O), 1653(C=N).
HRMS calcd for C32H31N2O [M+H]+ m/z: 459.2431, found
459.2440.
Cis-1-(4-methoxyphenyl)-4-[(E)-(4-methoxyphenylimino)-
methyl]-3,4-dimethylazetidin-2-one (2e)
1
Yellow oil 0.260 g, yield 76.9 %. H NMR (200 MHz,
Cis-1-diphenylmethyl-4-[(E)-1-(diphenylmethylimino)ethyl]-
3,4-dimethylazetidin-2-one (2a)
CDCl3) : 7.99 (s, 1H, CH=N), 7.306.72 (m, 8H, ArH),
3.70 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.21 (q, J=7.6 Hz,
1H, CH), 1.76 (s, 3H, CH3), 1.21 (d, J=7.6 Hz, 3H, CH3).
13C NMR (CDCl3) : 167.0, 162.4, 158.5, 155.9, 143.5,
130.6, 121.9, 118.3, 114.3, 114.2, 63.7, 56.6, 55.3, 55.2,
19.9, 9.9. IR (KBr):  (cm1) 1742 (C=O), 1644 (C=N).
HRMS (ESI) calcd for C20H23N2O3 [M+H]+ m/z: 339.1703,
found 339.1709.
Colorless crystals 0.200 g, yield 42.3%, m.p. 164.0
1
166.0 °C. H NMR (200 MHz, CDCl3) : 7.467.18 (m,
20H, ArH), 5.70 (s, 1H, CH), 5.67 (s, 1H, CH), 2.95 (q, J
= 7.5 Hz, 1H, CH), 1.84 (s, 3H, CH3), 1.40 (s, 3H, CH3),
1.05 (d, J = 7.5 Hz, 3H, CH3). 13C NMR (CDCl3) : 168.9,
167.5, 144.0, 143.9, 141.9, 140.0, 128.8, 128.5, 128.4,
128.33, 128.27, 127.8, 127.4, 127.34, 127.28, 126.85,
126.79, 126.7, 68.4, 68.0, 62.9, 54.8, 22.8, 16.7, 10.6. IR
(KBr):  (cm1) 1743 (C=O), 1653 (C=N). HRMS (ESI)
calcd for C33H33N2O [M+H]+ m/z: 473.2587, found
473.2591.
Cis-4-acetyl-1-(4-methoxyphenyl)-3-methylazetidin-2-one (3f)
Colorless crystals 0.268 g, yield 76.6 %, m.p. 118.0
1
120.0 °C. H NMR (300 MHz, CDCl3) : 7.20 (d, J = 9.0
Hz, 2H, ArH), 6.85 (d, J = 9.0 Hz, 2H, ArH), 4.62 (d, J =
6.4 Hz, 1H, NCH), 3.77 (s, 3H, OCH3), 3.72-3.65 (dq, J =
6.4, 7.6 Hz 1H, CH), 2.21 (s, 3H, CH3), 1.23 (d, J = 7.6 Hz,
3H, CH3). 13C NMR (75 MHz, CDCl3) : 204.8, 166.0,
156.4, 131.1, 117.9, 114.5, 61.6, 55.5, 47.7, 28.2, 9.5. IR
(KBr):  (cm1) 1715 (C=O), 1743 (C=O, in amide). HRMS
(ESI) calcd for C13H16NO3 [M+H]+ m/z: 234.1125, found
234.1129.
Trans-1-(4-methoxyphenyl)-4-[(E)-1-(4-methoxyphenylimino)
ethyl]-3,4-dimethylazetidin-2-one (2b)
Colorless crystals 0.249 g, yield 70.7 %, m.p.
1
188.0190.0 °C. H NMR (300 MHz, CDCl3) : 7.416.63
(m, 8H, ArH), 3.79 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.33
(q, J =7.5 Hz, 1H, CH), 1.88 (s, 3H, CH3), 1.85 (s, 3H, CH3),
1.32 (d, J = 7.6 Hz, 3H, CH3). 13C NMR (CDCl3) : 170.7,
166.8, 156.1, 155.9, 143.8, 131.0, 120.0, 118.7, 114.3,
114.2, 67.5, 56.5, 55.4, 21.7, 17.9, 9.3. IR (KBr):  (cm1)
1742 (C=O), 1652 (C=N). HRMS (ESI) calcd for
C21H25N2O3 [M+H]+ m/z: 353.1860, found 353.1864.
Cis-4-benzoyl-1-(4-methoxyphenyl)-3-methylazetidin-2-one
(3g)
Colorless crystals 0.293 g, yield 80 %, m.p. 160.0
162.0 °C. 1H NMR (400 MHz, CDCl3) : 7.986.81 (m, 9H,
ArH), 5.54 (d, J = 6.2 Hz, 1H, CH), 3.83 (dq, J = 6.2, 7.4
Hz, 1H, CH), 3.76 (s, 3H, OCH3), 1.11 (d, J = 7.4 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3) : 193.9, 165.7, 156.2,
135.2, 134.3, 131.3, 129.2, 128.2, 118.4, 114.3, 59.1, 55.5,
48.4, 10.0. IR (KBr)  (cm1): 1699 (C=O), 1746 (C=O in
amide). HRMS (ESI) calcd for C18H18NO3 [M+H]+ m/z:
296.1281, found 296.1277.
Trans-1-(4-methoxyphenyl)-4-[(E)-(4-methoxyphenylimino)
(phenyl)methyl]-3-methyl-4-phenylazetidin-2-one (2c)
1
Yellow oil 0.239 g, yield 50.3 %. H NMR (300 MHz,
CDCl3) : 7.506.59 (m, 18H, ArH), 3.88 (q, J =7.5 Hz, 1H,
CH), 3.71 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 1.59 (d, J
=7.4 Hz, 3H, CH3). 13C NMR (CDCl3) : 168.5, 166.5,

1714
Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
(ESI) calcd for C19H20NO2 [M+H]+ m/z: 294.1489, found
294.1492.
2.6 General procedure for hydrolysis of 4-imino--
lactams
A round-bottom flask was charged with a solution of
4-imino--lactams (30 mg) and 1 mol/L aqueous HCl (6 mL)
in THF (6 mL). The mixture was stirred at reflux for 3 h.
After removal of solvent under reduced pressure, the resi-
due was diluted with CH2C12 (10 mL) and subsequently
washed with 1 mol/L aqueous HCl (6 mL) and water (6 mL).
The organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to afford the desired
products.
Trans-1-(4-methoxyphenyl)-2,3-dimethylazetidin-2-one-4-c
arbaldehyde (3e)
1
Yellowish oil 18.6 mg, yield 90 %. H NMR (400 MHz,
CDCl3) : 9.83 (s, 1H, CHO), 7.16 (d, J = 9.0 Hz, 2H, ArH),
6.78 (d, J = 9.0 Hz, 2H, ArH), 3.70 (s, 3H, OCH3), 3.19 (q,
J = 7.7 Hz, 1H, CH), 1.60 (s, 3H, CH3), 1.22 (d, J = 7.7 Hz,
3H, CH3). 13C NMR (100 MHz, CDCl3) : 202.1, 166.4,
156.5, 130.0, 118.6, 114.6, 66.8, 56.3, 55.5, 17.0, 9.5. IR
(KBr):  (cm1) 1658 (C=O), 1741 (C=O in amide). HRMS
(ESI) calcd for C13H16NO3 [M+H]+ m/z: 234.1125, found
234.1140.
Cis-4-acetyl-1-diphenylmethyl-3,4-dimethylazetidin-2-one (3a)
1
Yellowish oil 17.9 mg, yield 92 %. H NMR (400 MHz,
CDCl3) : 7.447.25 (m, 10H, ArH), 5.46 (s, 1H, NCH),
3.05 (q, J = 7.5 Hz, 1H, CH), 2.09 (s, 3H, COCH3), 1.43 (s,
3H, CH3), 1.20 (d, J = 7.6 Hz, 3H, CH3). 13C NMR (100
MHz, CDCl3) : 207.4, 168.2, 140.4, 139.1, 128.6, 128.3,
128.2, 127.6, 127.4, 69.9, 62.9, 55.1, 27.8, 21.2, 10.3. IR
(KBr):  (cm1) 1711 (C=O), 1742 (C=O, in amide). HRMS
(ESI) calcd for C20H22NO2 [M+H]+ m/z: 308.1645, found
308.1649.
3 Results and discussion
3.1 Synthesis of cis- and trans-4-acyl--lactams from
symmetric vicinal diketones
Although it is an economic and convenient route to prepare
4-acyl--lactams from vicinal diketones and acyl chlorides
in the presence of tertiary amine via monoimine derivatives
of diketones, the reaction of diketones and amines, even in a
molar ratio of 1:1, generally produces a mixture of mo-
noimine and diimine derivatives of diketones that are diffi-
cult to separate due to their similar polarity and unstability
in a silica gel column. Thus, it is more practical to prepare
4-acyl--lactams from vicinal diketones and acyl chlorides
via diimines of diketones followed by subsequent hydroly-
sis. According to our proposal on the stereocontrol in the
synthesis of -lactams [45, 46], we hoped to synthesize the
cis- and trans-4-acyl--lactams via the diketone diimines
with bulky and less steric N-substituents, respectively.
First, 2,3-butanedione reacted with diphenylmethylamine
and p-methoxyaniline to prepare the corresponding diimines
1a and 1b, respectively. Diimines 1a and 1b reacted with
propionyl chloride in the presence of triethylamine in di-
chloromethane to give rise to the cis- and trans-4-imino--
lactams 2a and 2b, respectively, which were further hydro-
lyzed to produce the cis- and trans-4-acetyl--lactams 3a
and 3b. Similarly, the trans-4-benzoyl--lactam 3c was
synthesized from 1,2-diphenyl-1,2-ethanedione. The stereo-
structures of products 2 and 3 were identified on the basis of
their NOESY spectra [45]. For example, the correlation
between the C3 proton and the C4 methyl group of
-lactams was observed in 2a, but not in 2b. Unfortunately,
the reaction of 1,2-diphenyl-1,2-ethanedione and bulky di-
phenylmethylamine did not occur (Scheme 1).
Trans-4-acetyl-1-(4-methoxyphenyl)-3,4-dimethylazetidin-2-
one (3b)
1
Yellowish oil 19.7 mg, yield 94 %. H NMR (400 MHz,
CDCl3) : 7.28 (d, J = 9.1 Hz, 2H, ArH), 6.87 (d, J = 9.1
Hz, 2H, ArH), 3.78 (s, 3H, OCH3), 3.24 (q, J = 7.6 Hz, 1H,
CH), 2.24 (s, 3H, COCH3), 1.77 (s, 3H, CH3), 1.23 (d, J =
7.6 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) : 210.7,
166.2, 156.2, 130.3, 118.7, 114.5, 69.5, 56.2, 55.4, 28.0,
19.8, 9.4. IR (KBr):  (cm1) 1715 (C=O), 1743 (C=O, in
amide). HRMS (ESI) calcd for C14H18NO3 [M+H]+ m/z:
248.1281, found 248.1276.
Trans-4-benzoyl-1-(4-methoxyphenyl)-3-methyl-4-phenylaze
tidin-2-one (3c)
1
Yellow oil 19.3 mg, yield 94%. H NMR (300 MHz,
CDCl3) : 7.506.59 (m, 14H, ArH), 4.14 (q, J =7.4 Hz, 1H,
CH), 3.71 (s, 3H, OCH3), 1.24 (d, J =7.4 Hz, 3H, CH3). IR
(KBr):  (cm1) 1686 (C=O), 1747 (C=O in amide). HRMS
(ESI) calcd for C24H22NO3 [M+H]+ m/z: 372.1594, found
372.1591.
Cis-1-diphenylmethyl-2,3-dimethylazetidin-2-one-4-carbald
ehyde (3d)
Yellowish oil 18.2 mg，yield 91 %. 1H NMR (400 MHz,
CDCl3) : 9.37 (s, 1H, CHO), 7.367.25 (m, 10H, ArH),
5.79 (s, 1H, NCH), 3.16 (q, J = 7.7 Hz, 1H, CH), 1.39 (s,
3H, CH3), 1.21 (d, J = 7.7 Hz, 3H, CH3). 13C NMR (100
MHz, CDCl3) : 201.1, 169.1, 138.9, 138.6, 128.9, 128.8,
128.6, 128.3, 128.0 127.8, 67.6, 61.7, 55.6, 18.4, 9.4. IR
(KBr):  (cm1) 1659 (C=O), 1742 (C=O in amide). HRMS
3.2 Synthesis of cis-4-acyl--lactams from unsymmet-
ric vicinal ketoaldehydes
Pyruvic aldehyde reacted with amines in different molar
ratios to generate diimines 1d, 1e, and ketoaldimine 1f, re-

Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
1715
spectively, because the ketone and aldehyde groups showed
obviously different reactivity with amines. The diimines 1d
and 1e reacted with propionyl chloride in the presence of
triethylamine to give rise to the cis-4-aldimino--lactams 2d
and 2e, respectively. Their stereostructures were identified
on the basis of the NOESY spectra. Lactams 2d and 2e were
further hydrolyzed to produce cis-4-formyl--lactams 3d
and 3e. As comparison, the ketoaldimine 1f reacted with
propionyl chloride to afford cis-4-acetyl--lactam 3f direct-
ly (Scheme 2). This is because ketimines reacted more pre-
dominantly with the acyl chloride than aldimines due to
their higher electron density and less steric hindrance in the
attacking of imines to ketenes generated from propionyl
chloride in the presence of triethylamine. Similarly, cis-4-
benzoyl--lactam 3g was synthesized from ketoaldimine 1g
generated from phenylglyoxal with 4-methoxyaniline
(Scheme 2). The stereostructures of products 3f and 3g were
identified on the basis of the coupling constants between the
C3 protons and C4 protons of -lactams (6.4 and 6.2 Hz,
respectively) because the coupling constant of cis-protons
ranges from 4 to 6 Hz, while that for trans-protons is less
than 4 Hz [45]. Unfortunately, attempts to prepare the phe-
nylglyoxal-derived diimines failed.
The results indicate that both cis- and trans-4-acyl-
lactams were prepared from 2,3-butanedione via its
diimines with more or less bulky N-substituents (Scheme 1).
However, only cis-4-formyl--lactams were prepared from
diimines generated from pyruvic aldehyde no matter
whether they possess bulky or less bulky N-substituents.
This is because the ketimine moiety in the diimines pre-
dominately reacted with the acyl chloride due to its higher
electron density. It is also because the generated zwitterion-
ic intermediates prefer to direct ring closure due to their
iminium moiety with electron-withdrawing aldimine sub-
stituents. Although only cis-4-acyl--lactams were obtained
from pyruvic aldehyde, both cis-4-acetyl--lactams and
cis-4-formyl--lactams were synthesized via its monoimine
and diimine derivatives, respectively. The diastereoselectiv-
ity follows our previous proposal on the stereoselectivity of
the Staudinger reaction [47, 48]. That is, the diastereoselec-
tivity is a result of the competition between the direct
conrotatory ring closure and the isomerization of the imin-
ium moiety in the zwitterionic intermediates generated from
ketenes and imines (Scheme 3). Strong electron-donating
ketene substituents, strong electron-withdrawing imine
C-substituents, and bulky imine N-substituents prefer the
formation of cis--lactams, while weak electron-donating
and electron-withdrawing ketene substituents dominate the
formation of trans--lactams.
Scheme 1 Synthesis of cis- and trans-4-acyl--lactams 3 from vicinal
diketones.
4 Conclusions
Scheme 2 Synthesis of cis-4-acyl--lactams 3 from vicinal ketoalde-
hydes.
Cis- and trans-4-acyl--lactams were stereoselectively syn-

1716
Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
Scheme 3 Selectivity in synthesis of cis- and trans-4-acyl--lactams 3 from vicinal diketones and ketoaldehydes.
lactones from azetidin-2-ones. Synlett, 2005: 2370–2372
thesized from vicinal diketones while cis-4-acyl--lactams
were synthesized from ketoaldehydes. Diketones and ke-
toaldehydes reacted with amines to afford diimines. The
diimines reacted with propionyl chloride in the presence of
triethylamine to give rise to the corresponding 4-imino--
lactams, which were further hydrolyzed to afford 4-acyl--
lactams. Cis- and trans- selectivity depends on the steric
hindrance of the imine N-substituents and on the electronic
property of the imine C-substituents. Pyruvic aldehyde
produced cis-4-acetyl--lactams and cis-4-formyl--lactams,
respectively, through the reactions of its monoimines and
diimines with propionyl chlorides. Phenylglyoxal generated
cis-4-benzoyl--lactams via its monoaldimines.
8
9
J Alcaide B, Martın-Cantalejo Y, Rodrıguez-Lopez J, Sierra MA.
New reactivity patterns of the β-lactam ring: tandem C3–C4 bond
breakage-rearrangement of 4-acyl- or 4-imino-3,3-dimethoxy-2-
azetidinones promoted by stannous chloride (SnCl2-2H2O). J Org
Chem, 1993, 581: 4767–4770
Alcaide B, Domınguez G, Martın-Domenech A, Plumet J, Monge A,
Perez-Garcıa V. Ring expansion of 4-benzoyl-β-lactams. Heterocy-
cles, 1987, 26: 1461–1466
10 Alcaide B, Almendros P, Cabrero G, Ruiz MP. Organocatalytic ring
expansion of β-lactams to γ-lactams through a novel N1-C4 bond
cleavage. Direct synthesis of enantiopure succinimide derivatives.
Org Lett, 2005, 7: 3981–3984
11 Alcaide B, Almendros P, Cabreroa G, Ruiza MP. Direct organocata-
lytic synthesis of enantiopure succinimides from β-lactam aldehydes
through ring expansion promoted by azolium salt precatalysts. Chem
Commun, 2007: 4788–4790
12 Li GQ, Li Y, Dai LX, You SL. N-heterocyclic carbene catalyzed ring
expansion of 4-formyl-beta-lactams: Synthesis of succinimide deriv-
atives. Org Lett, 2007, 9: 3519–3521
13 Domingo LR, Aurell MJ, Arno M. Understanding the mechanism of
the N-heterocyclic carbene-catalyzed ring-expansion of 4-formyl-β-
lactams to succinimide derivatives. Tetrahedron, 2009, 65: 3432–
3440
The authors express their thanks to the support from the National Natural
Science Foundation of China (20972013 and 20772005), Beijing Natural
Science Foundation (2092022), the Fundamental Research Funds for the
Central Universities (ZZ1020). and the Doctoral Fund of Ministry of Edu-
cation of China (200800100010).
14 Alcaide B, Aly M, Rodrıguez C, Rodrıguez-Vicente A. Base-
promoted isomerization of cis-4-formyl-2-azetidinones: chemoselec-
tive C4-epimerization vs rearrangement to cyclic enaminones. J Org
Chem, 2000, 65: 3453–3459
15 Krishnaswamy D, Govande VV, Deshmukh ARAS. 4-Formylazet-
idin-2-ones, synthon for the facile synthesis of enantiopure
4-aminopiperidin-2-one. Synthesis, 2003: 1903–1908
16 Bailey PD, Millwood PA, Smith PD. Asymmetric routes to substi-
tuted piperidines. Chem Commun, 1998: 633–640
17 Parr IB, Horenstein BA. New electronic analogs of the sialyl cation:
N-functionalized 4-acetamido-2,4-dihydroxypiperidines. Inhibition of
bacterial sialidases. J Org Chem, 1997, 62: 7489–7494
1
2
3
Alcaide B, Almendros P. 4-Oxoazetidine-2-carbaldehydes as useful
building blocks in stereocontrolled synthesis. Chem Soc Rev, 2001,
30: 226–240
Alcaide B, Almendros P, Aragoncillo C. -Lactams: Versatile build-
ing blocks for the stereoselective synthesis of non--lactam products.
Chem Rev, 2007, 107: 4437–4492
Palomo C, Aizpurua CJM, Ganboa I, Carreaux F, Cuevas C, Maneiro
E, Ontoria JM. New synthesis of -amino acid N-carboxy anhydrides
through Baeyer-Villiger oxidation of -keto--lactams. J Org Chem,
1994, 59: 3123–3130
4
Palomo C, Aizpurua CJM, Ganboa I, Odriozola B, Urchegui R, Gorls
H. Concise synthesis of -alkyl--amino acids and their incorpora-
tion into peptides via -lactam-derived -amino acid N-carboxy an-
hydrides. Chem Commun, 1996: 1269–1270
18 Alcaide B, Almendros P, Cabrero G, Ruiz MP. Stereocontrolled ac-
cess to orthogonally protected anti,anti-4-aminopiperidine-3,5-diols
through chemoselective reduction of enantiopure β-lactam cyanohy-
drins. J Org Chem, 2007, 72 : 7980–7991
5
6
Robinson RP, Donahue KM. Synthesis of a peptidyl difluoro ketone
bearing the aspartic acid side chain: An inhibitor of interleukin-1
converting enzyme. J Org Chem, 1992, 57: 7309–7314
Palomo C, Arrieta A, Cossío FP, Aizpurua JM, Mielgo A, Aurre-
koetxea N. Highly stereoselective synthesis of -hydroxy--amino
acids through -lactams: application to the synthesis of the taxol and
bestatin side chains and related systems. Tetrahedron Lett, 1990, 31:
6429–6432
19 Kale AS, Puranik VG, Rakeeb A, Deshmukh AS. A practical formal
synthesis of D-(+)-biotin from 4-formylazetidin-2-one. Synthesis,
2007, 17: 1159–1164
20 Alcaide B, Almendros P, Alonso JM.
A practical ruthenium-
catalyzed cleavage of the allyl protecting group in amides, lactams,
imides, and congeners. Chem Eur J, 2006, 12: 2874–2879
21 Buttero PD, Molteni G, Papagnib A, Pilati T. The intramolecular
aromatic nucleophilic substitution as a route to tricyclic β-lactams.
Synthesis of the novel 4-oxa-7-azabicyclo[4.2.0]octane skeleton.
7
Kale AS, Deshmukh ARAS. An efficient synthesis of 2,3-aziridino-γ-

Wang ZX, et al. Sci China Chem November (2011) Vol.54 No.11
1717
Tetrahedron, 2003, 59: 5259–5263
5042–5047
22 Alcaide B, Almendros P, Alonso JM, Aly MF. Useful dual Diels-
Alder behavior of 2-azetidinone-tethered aryl imines as azadieno-
philes or azadienes: A β-lactam-based stereocontrolled access to op-
tically pure highly functionalized indolizidine systems. Chem Eur J,
2003, 9: 3415–3426
23 Alcaide B, Almendros P, Alonso JM, Aly MF. 1,3-Dipolar cycload-
dition of 2-azetidinone-tethered azomethine ylides. application to the
rapid, stereocontrolled synthesis of optically pure highly functional-
ized pyrrolizidine systems. Chem Commun, 2000: 485–486
24 Alcaide B, Almendros P, Alonso JM, Aly MF. Rapid and stereocon-
trolled synthesis of racemic and optically pure highly functionalized
pyrrolizidine systems via rearrangement of 1,3-dipolar cycloadducts
derived from 2-azetidinone-tethered azomethine ylides. J Org Chem,
2001, 66: 1351–1358
25 Alcaide B, Polanco C, Sierra MA. Alkyne-Co2(CO)6 complexes in
the synthesis of fused tricyclic β-lactam and azetidine system. J Org
Chem, 1998, 63: 6786–6796
26 Ojima I, Lin S, Inoue T. Miller ML, Borella CP, Geng X, Walsh JJ.
Macrocycle formation by ring-closing metathesis. Application to the
syntheses of novel macrocyclic taxoids. J Am Chem Soc, 2000, 122:
5343–5353
27 Hart DJ, Lee CS. Asymmetric synthesis of β-lactams and the car-
bapenem antibiotic (+)-PS-5. J Am Chem Soc, 1986, 108: 6054–6056
28 Georg GI, Kant J, Gill HS. Symmetric synthesis of (1'R,3R,4R)-4-
acetoxy-3-[1'-((tert-butyldimethylsilyl)oxy)ethyl]-2-azetidinone and
other 3-(1'-hydroxyethyl)-2-azetidinones from (S)-(+)-ethyl 3-hy-
droxybutanoate: formal total synthesis of (+)-thienamycin. J Am
Chem Soc, 1987, 109: 1129–1135
29 Evans DA, Sjogren EB. The asymmetric synthesis of -lactam anti-
biotics II The first enantioselective synthesis of the carbacepha-
loporin nucleus. Tetrahedron Lett, 1985, 26, 3783–3787
35 Alcaide B, Yolanda MC, Javier PC, Julih RL, Miguel AS. The stere-
oselective preparation of mono- and bis--lactams by the 1,4-diaza-
l,3-diene-acid chloride condensation: scope and synthetic applications.
J Org Chem, 1992, 57: 5921–5931
36 Evans DA, Williams JM. The asymmetric synthesis of -lactam anti-
biotics-V application of chiral ,β-epoxyimines in ketene-imine cy-
cloaddition reactions leading to homochiral 3-aminoazetidinones
Tetrahedron Lett, 1988, 29: 5065–5068
37 Jayaraman M, Deshmukh AR, Bhawal BM. Application of
(+)-(1S,2S)-2-amino-1-phenylpropan-1,3-diol in the formal total syn-
thesis of carbapenems, novel 4-cyano--lactams and -hydroxy as-
partates. Tetrahedron, 1996, 52: 8989–9004
38 Shirode NM, Rakeeb A, Deshmukh AS. 4-Formylazetidin-2-ones,
synthon for the synthesis of (2R,3S) and (2S,3R)-3-amino-2-
hydroxydecanoic acid (AHDA) Tetrahedron, 2006, 62: 4615–4621
39 Cundy DJ, Donohue AC, McCarthy TD. An asymmetric synthesis of
ADDA and ADDA-glycine dipeptide using the -lactam synthon
method. J Chem Soc Perkin Trans 1, 1999, 5: 559–568
40 Laurent M, Cérésiat M, Marchand-Brynaert J. Synthesis of
(1R,3S,4S)-3-[1-(tert-butyldimethylsilyloxy)ethyl]-4-(cyclopropylcar
bonyloxy)azetidin-2-one. Eur J Org Chem, 2006: 3755–376
41 Pansuriya PB, Patel MN. Synthesis, spectral, thermal, DNA I nterac-
tion and antimicrobial properties of novel Cu(II) heterochelates. Appl
Organomet Chem, 2007, 21: 739–749
42 Lemp E, Zanocco AL, Guenther G, Pizarro N. Solvent effect on the
sensitized photooxygenation of cyclic and acyclic -diimines Tetra-
hedron, 2006, 62: 10734–10746
43 Jin W, Makioka Y, Kitamura T, Fujiwara Y. A novel reductive di-
merization/oxidative dehydrogenation of aldimines mediated by lan-
thanoid metals. J Org Chem, 2001, 66: 514–520
44 Jose B, Fernando A, Ramon L. Oxidative aminomercuration of
prop-2-ynol. Syntheses of substituted propane-1,2-diimines and
2-aminopropionamidines. J Chem Soc Chem Comm, 1981, 22: 1181–
1182
30 Fujisawa T, Shibuya A, Sato D, Shimizu M. Stereoselective synthesis
of monocyclic -lactam related to a carmonam precursor via ke-
tene-imine reaction. Synlett, 1995, 39: 1067–1068
31 Tsubouchi H, Tsuji K, Yusumura K, Tada N, Nishitani S, Mina-
mikawa J, Ishikawa H. A convenient one pot asymmetric synthesis of
cis--lactams: Key precursors for optically active 2-oxaisocephems.
Tetrahedron: Asymmetry, 1994, 5: 441–452
32 Broady SD, Rexhausen JE, Thomas EJ. Total synthesis of AI-77-B:
Stereoselective hydroxylation of 4-alkenylazetidinones. J Chem Soc,
Perkin Trans 1, 1999:1083–1094
33 Myers AG, Zhong B, Movassaghi M, Kung DW, Lanman BA, Kwon
S. Synthesis of highly epimerizable N-protected α-amino aldehydes
of high enantiomeric excess. Tetrahedron Lett, 2000, 41, 1359–1362
34 Garcia-Martin M, Violante de Paz Banez M, Garcia-Alvarez M,
Munoz-Guerra S, Galbis JA. Synthesis and structural studies of
2,3-disubstituted poly(β-peptide)s. Macromolecules, 2001, 34:
45 Liang Y, Jiao L, Zhang SW, Yu ZX, Xu JX. New insights into the
torquoselectivity of the Staudinger reaction. J Am Chem Soc, 2009,
131: 1542–1549
46 Li BN, Wang YK, Du DM, Xu JX. Notable and obvious ketene sub-
stituent-dependent effect of temperature on the stereoselectivity in the
Staudinger reaction. J Org Chem, 2007, 72: 990–997
47 Jiao L, Liang Y, Xu JX. Origin of the relative stereoselectivity of the
β-lactam formation in the Staudinger Reaction. J Am Chem Soc, 2006,
128: 6060–6069
48 Qi HZ, Li XY, Xu JX. Stereoselective control in the Staudinger reac-
tions involving monosubstituted ketenes with electron acceptor sub-
stituents: Experimental investigation and theoretical rationalization.
Org Biomol Chem, 2011, 9: 2702–2714