Stereoselective synthesis of 3-alkylidene/alkylazetidin-2-ones from azetidin-2,3-diones

Article abstract of DOI:10.1016/j.tet.2006.12.010

Azetidin-2,3-diones have been used as synthons for the synthesis of C-3 alkylidene/alkylazetidin-2-ones. Some of the 3-alkylazetidin-2-ones are well known for their cholesterol absorption inhibitor activity. A regio and stereoselective Grignard reaction o

Full text of DOI:10.1016/j.tet.2006.12.010

Tetrahedron 63 (2007) 2524–2534
Stereoselective synthesis of 3-alkylidene/alkylazetidin-2-ones
from azetidin-2,3-diones
Dharmendra Kumar Tiwari, Ashif Y. Shaikh, Laxmikant S. Pavase, Vikas K. Gumaste
*
and Abdul Rakeeb A. S. Deshmukh
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, Maharashtra, India
Received 26 August 2006; revised 19 November 2006; accepted 7 December 2006
Available online 30 January 2007
Abstract—Azetidin-2,3-diones have been used as synthons for the synthesis of C-3 alkylidene/alkylazetidin-2-ones. Some of the 3-alkyl-
azetidin-2-ones are well known for their cholesterol absorption inhibitor activity. A regio and stereoselective Grignard reaction on a keto group
followed by dehydration using PPh3/CCl4 reagent is a key step in this synthesis. Hydrogenation of the 3-alkylideneazetidin-2-ones provided
stereoselectively cis-3-alkylazetidin-2-ones in very good yields.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
cholesterol absorption inhibitory property is normally asso-
ciated with trans-azetidin-2-ones,5 however, in some cases it
has also been shown that C-3-alkyl-substituted cis-azetidin-
2-ones are better cholesterol absorption inhibitors (Fig. 1).9
Although several syntheses are described in literature,7,8,10
there are very few reports wherein a suitably substituted
azetidin-2-one itself has been used as a synthon11 for the
preparation of desired C-3-substituted-b-lactams.
The b-lactam skeleton is the key structural unit of the most
widely employed class of antibacterial agents, the b-lactam
antibiotics.1 The constant need for new drugs displaying
broader antibacterial activity and the necessity for new
b-lactam antibiotics to combat the microorganisms that have
built up resistance against the most traditional drugs,2 have
maintained the interest of organic chemists in b-lactams
for decades. The major cause of bacterial resistance to
the antibiotics is a hydrolytic cleavage of the b-lactam ring
by b-lactamase enzyme. As a consequence, several stable
new b-lactams as well as b-lactamase inhibitors have been
developed. Apart from the antibacterial agents,1–3 b-lactams
are also being increasingly used as synthons for the
synthesis of a variety of pharmaceutically useful products.4
An important class of compounds, which act as hydrolytic
deactivators of b-lactamase enzyme, contains 3-alkylidene-
b-lactam subunit (1). Also, the discovery of cholesterol
absorption inhibition property associated with trans-3-alkyl-
azetidin-2-ones5 2 and 3 (Fig. 1) renewed the interest in the
synthesis of C-3-alkyl-substituted-b-lactams. Large number
of b-lactams has been synthesized to study the structure
activity relationship (SAR) in cholesterol absorption inhibi-
tors.6 In most of the synthesis, the azetidinone ring is con-
structed either by enolate–imine cyclocondensation5a,b,6a,7
of appropriately substituted esters and imines or by a
Staudinger ketene–imine cycloaddition reaction.7i,8 The
2. Results and discussion
As a part of our ongoing research program on the application
of azetidin-2-ones as synthons,12 we herein report the syn-
thesis of various 3-alkylidene/alkyl substituted azetidin-2-
ones from azetidin-2,3-diones, a common starting material.
In a recent publication13 we have shown that Grignard
reagent adds stereoselectively to a ketone in azetidin-2,3-di-
one (4) to give 3-alkyl-3-hydroxy-b-lactam. The approach of
the Grignard reagent is controlled by the C-4 substituent on
the ring, giving rise to trans stereochemistry in the product.
The reductive removal of the corresponding xanthate has
provided the cis-3-alkylazetidin-2-ones.
As a part of this project we were interested in developing a
simple synthetic protocol to make large number of 3-alkyl-
idene and 3-alkyl-b-lactams. Herein we report the syntheses
of 3-alkylidene and 3-alkylazetidin-2-ones from the azeti-
din-2,3-diones 4. The 3-alkyl-3-hydroxy-b-lactams (5),
which are readily obtained from the Grignard reaction on
azetidin-2,3-diones, could be easily converted to the corre-
sponding 3-alkyl-3-chloro-b-lactams (6). Further transfor-
mation of chloro-b-lactams 6 to a-alkylidene-b-lactams 7
and 8 via dehydrohalogenation or direct reductive removal
Keywords: Azetidin-2,3-diones; Azetidin-2-ones; b-Lactam; Grignard
reaction.
* Corresponding author. Tel.: +91 20 39821300; fax: +91 20 25902624;
e-mail addresses: Abdulrakeeb.Deshmukh@emcure.co.in; aras.deshmukh@
ncl.res.in
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.12.010

D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
2525
OMe
OH
OH
F
R2
O
R1
N
N
N
F
O
O
OMe
1, 3-Alkylidene
3, Sch 58235
2, Sch 48481
subunit
Figure 1. 3-Alkylidene/3-alkylazetidin-2-ones.
Table 1. 3-Alkyl-3-hydroxyazetidin-2-ones 5a–m
of the halogen would provide 3-alkyl-b-lactams 9. Similarly
catalytic hydrogenation of 7 and 8 would also provide
3-alkyl-b-lactams 9 (Scheme 1). With this idea in mind,
we prepared 3-alkyl-3-hydroxy-b-lactams (5) from azeti-
din-2,3-diones 4.
Entry
Compound
R
R1
Yieldb (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
n-Butyl
n-Butyl
n-Octyl
n-Octyl
n-Heptyl
n-Heptyl
n-Propyl
n-Propyl
iso-Propyl
iso-Propyl
3-Phenylpropyl
3-Phenylpropyl
Ph
PMPa
Ph
PMP
Ph
PMP
Ph
PMP
Ph
PMP
Ph
PMP
Ph
55
60
57
62
62
58
69
62
49
52
61
62
67
The starting azetidin-2,3-diones 4 could be easily obtained
in very good yields by oxidation of the corresponding
3-hydroxy-b-lactam 13, which in turn can be obtained from
3-acetoxy-b-lactams 12. Since enantiomerically pure 3-hy-
droxy-b-lactams are also available,14 the corresponding
azetidindiones can also be prepared by oxidation of the
hydroxyl group. However, to establish the synthetic protocol
we have used racemic b-lactams for our work.
9
10
11
12
13
5j
5k
5l
5m
PMP
a
PMP¼4-methoxyphenyl.
b
Isolated yields.
Staudinger cycloaddition of acetoxyacetyl chloride 10 with
imines 11 gave 3-acetoxy-azetidin-2-ones 12 in 62–65%
yields, which on careful hydrolysis with saturated sodium
bicarbonate in methanol gave the corresponding 3-hydr-
oxy-b-lactams 13 in quantitative yields. Oxidation of the
hydroxyl group was carried out by a known procedure using
phosphorous pentoxide and dimethyl sulfoxide15 to give the
desired azetidin-2,3-diones 4 (Scheme 2). The Grignard re-
agent, prepared from the corresponding alkyl or aryl halide,
on reaction with diones 4 gave the addition products 5 in
moderate to good yields (Table 1). A single isomer was
formed indicating that the addition occurred exclusively
from the side opposite to the C-4 substituent on the azetidi-
none ring. Slightly lower yields of the 3-isopropyl-3-hydr-
oxy-b-lactams were obtained with the bulkier Grignard
reagent i-PrMgBr.
3-Butyl-3-hydroxyazetidin-2-one (5a) on reaction with PPh3
in refluxing CCl4 did not give the expected 3-chloro-b-lac-
tam 6a. However, the dehydration occurred and a mixture
of E and Z-olefins 7a and 8a was obtained in very good yield
(Scheme 3). Although, dehydration of oximes,16 and other
intermolecular dehydration with the PPh3/CCl4 reagent are
well known,17 there are some examples of olefin formation
via an elimination of water from the corresponding hydroxy
compounds.18 The separation of both isomers from the mix-
ture was achieved by flash column chromatography. The
structure of the major compound was established as E-iso-
mer (7a) on the basis of 1H NMR spectrum. The downfield
chemical shift of vinyl proton (d 6.24, dt, J¼1.4 and
7.3 Hz, 1H) compared to the corresponding Z-isomer (8a)
R3
O
H
O
H
N
OHH
Cl H
H
N
H
N
O
O
PMP
R1
PMP
R1
PMP
R1
PMP
PMP
R1
R3
R
O
R
O
H
(a)
+
N
N
R1
4
5
6
7
8
H
H
N
PMP
PMP
R
O
dehalogenation
hydrogenation
9
Scheme 1. Reagents and conditions: (a) RMgBr, THF, 0 ꢀC to rt, 4 h.
H
H
O
HO
H
H
O
H
N
PMP
O
O
PMP
R1
O
PMP
R1
PMP
(c)
81-89%
O
O
(b)
(a)
Cl
+
N
N
N
CH3
O
86-88%
62-65%
CH3
R1
O
R1
10
11
12
13
4
Scheme 2. Reagents and conditions: (a) Et3N, CH2Cl2, 0 ꢀC to rt, 12 h; (b) NaHCO3, Na2CO3, MeOH/H2O, rt, 7 h; and (c) P2O5, DMSO, rt, 24 h.

2526
D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
R2
R3
R2
H
N
OHH
H
N
H
N
H
H
N
O
O
PMP
R1
PMP
R1
PMP
R1
PMP
PMP
R1
R
O
R3
R2
R3
(a)
(b)
(c)
+
49-67%
N
71-91%
91-97%
O
O
R1
O
8
9
7
4
5
4a, R1 = Ph, R2 = PMP
4b, R1 = R2 = PMP
Me
H
(δ 1.86-2.0)
(δ 5.49)
H
H
Cl H
H
H
PMP
PMP
Ph
PMP
PMP
PMP
H
Me
(δ 6.24)
H
N
H
N
N
(δ 2.37-2.55)
O
O
PMP
O
14
7a
8a
Scheme 3. Reagents and conditions: (a) RMgBr, THF, 0 ꢀC to rt, 4 h; (b) PPh3/CCl4, reflux, 12 h; and (c) H2, Pt/C (10%), EtOAc, 12 h.
Table 3. 3-Alkylazetidin-2-ones 9a–l
(d 5.49, dt, J¼1.0 and 7.8 Hz, 1H) was observed. This down-
Compound R1
R2
R3
Yielda (%) Cis/trans
field shift of the vinyl proton is due to an anisotropic de-
shielding effect of the b-lactam carbonyl group. A similar
deshielding effect was observed on the allylic methylene
protons in Z-isomer 8b (Z-isomer 8b, d 2.37–2.55, m, 2H;
E-isomer 8a, d 1.86–2.0, m, 2H). The generality of the
reaction was established by preparing several 3-alkylidene-
b-lactams (Table 2). Both the isomers were separated by
column chromatography and in all the cases E-isomer was
found to be the predominant product. Single pure com-
pounds (7i and 7j) were obtained by the dehydration of
3-isopropyl-3-hydroxyazetidin-2-ones (5i and 5j). 3-Phenyl-
3-hydroxyazetidin-2-one 5m under similar reaction condi-
tions gave 3-phenyl-3-chloro azetidin-2-one 14 in 92%
yield, as there was no b-H available in the side chain for
elimination reaction.
9a
9b
9c
9d
9e
9f
9g
9h
9i
PMP n-Propyl
H
H
H
H
H
H
H
H
92
95
94
91
94
95
97
94
98:2
96:4
97:3
97:3
97:3
98:2
96:4
95:5
95:5
97:3
97:3
96:4
Ph n-Propyl
PMP n-Heptyl
Ph n-Heptyl
PMP n-Hexyl
Ph n-Hexyl
PMP Ethyl
Ph Me
PMP Me
Ph Me
PMP 2-Phenylethyl
Ph 2-Phenylethyl
Me 92
Me 95
H
H
9j
9k
9l
94
95
a
Isolated yields.
1
was detected from the H NMR spectrum. The biological
importance of both 3-alkylidene and 3-alkyl-b-lactams is
well known. 3-Alkylidene-b-lactams are known for the
b-lactamase inhibition activity, while 3-alkyl-b-lactams for
their cholesterol absorption inhibition activity.
A single product 9a was expected from the catalytic hydro-
genation of a mixture of olefins (7a and 8a) using Pd/C.
However, a partial isomerization of cis-b-lactam to a more
stable trans-isomer was observed (cis/trans¼70:30). The
isomerization phenomenon was considerably suppressed
(cis/trans¼97:3) when Pt/C catalyst was used, and a single
major cis-b-lactam 9a was obtained by the hydrogenation
of E/Z-mixture (7a and 8a). Several 3-alkylidene-b-lactams
were prepared (Table 2) and they were further hydrogenated
to the corresponding cis-3-alkyl-b-lactams using Pt/C as the
catalyst (Table 3). In most of the cases 3–5% of trans-isomer
3. Conclusion
In conclusion, a simple method for the synthesis of 3-alkyli-
dene/alkylazetidin-2-ones from azetidin-2,3-dione is devel-
oped. One of the 3-alkylazetidin-2-ones, 9k is well known
as cholesterol absorption inhibitor. A mild and an efficient
dehydration of 3-alkyl-3-hydroxyazetidin-2-ones by PPh3/
CCl4 reagent is a key step in this synthesis.
Table 2. 3-Alkylideneazetidin-2-ones 7a–l and 8a–l
Compounds
7 and 8
R1
R2
R3
Yielda
(%)
E/Z (7:8)
4. Experimental
4.1. General
a
b
c
d
e
f
g
h
i
PMP
Ph
PMP
Ph
PMP
Ph
PMP
Ph
PMP
Ph
PMP
Ph
n-Propyl
n-Propyl
n-Heptyl
n-Heptyl
n-Hexyl
n-Hexyl
Ethyl
Ethyl
Me
Me
2-Phenylethyl
2-Phenylethyl
H
H
H
H
H
H
H
H
90
90
89
88
94
89
85
86
71
70
91
89
72:28
71:29
71:29
66:34
71:29
69:31
72:28
69:31
—
1H NMR and 13C NMR spectra were recorded in CDCl3 so-
€
lutions on Bruker AC 200 and AV 400 spectrometers, and
chemical shifts are reported in parts per million downfield
1
from tetramethylsilane for H NMR. Infrared spectra were
Me
Me
H
j
k
l
—
70:30
70:30
recorded on Perkin–Elmer Infrared Spectrophotometer,
Model 599-B or Shimadzu FTIR-8400 using sodium chlo-
ride optics. Melting points were determined on a Thermonik
Campbell melting point apparatus and are uncorrected. The
H
a
Total yield.

D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
2527
microanalyses were performed on a Carlo-Erba, CHNS-O
EA 1108 elemental analyzer. Mass spectra were recorded
on API QSTAR PULSAR using electron spray ionization
(ESI) method.
1H, –OH), 3.76 (s, 3H, Ar–OCH3), 3.81 (s, 3H, Ar–
OCH3), 5.05 (d, J¼5.7 Hz, 1H, –C4H), 5.13 (d, J¼5.7 Hz,
1H, C3H), 6.70 (d, J¼9.4 Hz, 2H, Ar), 6.84 (d, J¼8.6 Hz,
2H, Ar), 7.15 (d, J¼8.5 Hz, 2H, Ar), 7.24 (d, J¼9.4 Hz,
2H, Ar); 13C NMR (50.3 MHz, CDCl3): d 55, 55.2, 61.7,
76.7, 113.6, 114.4, 118.2, 126.5, 129.3, 130.8, 155.5, 159,
166.4; MS (m/z): 300 (M+1).
4.1.1. 3-Acetoxy-1,4-bis-(4-methoxyphenyl)azetidin-2-
one (12a). A solution of acetoxyacetyl chloride (6.44 mL,
60 mmol) in anhydrous dichloromethane (20 mL) was
added slowly to a mixture of imine (9.64 g, 40 mmol) and
Et3N (19.44 mL, 140 mmol) in anhydrous dichloromethane
(60 mL) at 0 ꢀC. After completion of the addition, the reac-
tion mixture was allowed to warm up to room temperature
and stirred for additional 18 h. The reaction mixture was
then washed with water (3ꢁ75 mL), saturated NaHCO3
(3ꢁ75 mL), and brine (75 mL). The organic layer was sep-
arated, dried over anhydrous sodium sulfate, and concen-
trated under reduced pressure to give the crude product,
which was purified by column chromatography (silica gel
60–120 mesh) using Pet ether/ethyl acetate (83:17) to afford
compound 12a (8.49 g, 62%) as a white solid, mp 152–
154 ꢀC [Found: C, 66.93; H, 5.75; N, 4.08; C19H19NO5: re-
quires C, 66.85; H, 5.61; N, 4.10%]; Rf (18% EtOAc/Pet
4.1.4. 3-Hydroxy-1-(4-methoxyphenyl)-4-phenylazeti-
din-2-one (13b). Yield 88%; white solid, mp 215 ꢀC [Found:
C, 71.32; H, 5.80; N, 5.08; C16H15NO3: requires C, 71.36;
H, 5.61; N, 5.20%]; Rf (30% EtOAc/Pet ether) 0.4; nmax
1
(CHCl3) 3353, 1708 cmꢂ1; H NMR (200 MHz, DMSO-
d6): d 3.76 (s, 3H, Ar–OCH3), 4.50 (br s, 1H, –OH), 5.09
(d, J¼5.0 Hz, 1H, C4H), 5.12 (d, J¼5.0 Hz, 1H, C3H),
6.71 (d, J¼9.1 Hz, 2H, Ar), 7.19–7.39 (m, 7H, Ar); 13C
NMR (50.3 MHz, DMSO-d6): d 55.4, 62.1, 77.8, 114.6,
118.2, 127.9, 128.2, 128.4, 131.0, 135.1, 155.8, 166.4; MS
(m/z): 270 (M+1).
4.1.5. 1,4-Bis(4-methoxyphenyl)azetidin-2,3-dione (4a).
To anhydrous P2O5 (0.98 g, 3.5 mmol calculated for
P4O10) was added dry dimethyl sulfoxide (15 mL) at room
temperature. The suspension was stirred for 5 min at the
same temperature and then the corresponding 3-hydroxy-
b-lactam (1.5 g, 5 mmol) was added in one portion with
vigorous stirring. The reaction mixture was then stirred for
additional 24 h. After the reaction was over, the mixture
was slowly poured into cold aqueous NaHCO3 (50 mL) and
extracted with ethyl acetate. The organic layer was washed
with brine (3ꢁ50 mL) and dried over sodium sulfate. Evapo-
ration of the solvent under reduced pressure and then column
chromatography (60–120 mesh silica gel, 20% ethyl acetate/
Pet ether) provided the corresponding 3-keto-b-lactam
(1.32 g, 89%); yellow solid, mp 144 ꢀC [Found: C, 68.85;
H, 5.13; N, 4.67; C17H15NO4: requires C, 68.68; H, 5.08;
N, 4.71%]; Rf (20% EtOAc/Pet ether) 0.5; nmax (CHCl3)
1
ether) 0.4; nmax (CHCl3) 1753 cmꢂ1; H NMR (200 MHz,
CDCl3): d 1.73 (s, 3H, CO–CH3), 3.75 (s, 3H, Ar–OCH3),
3.80 (s, 3H, Ar–OCH3), 5.27 (d, J¼5.1 Hz, 1H, C4H), 5.87
(d, J¼5.1 Hz, 1H, C3H), 6.77 (d, J¼9.0 Hz, 2H, Ar), 6.86
(d, J¼9.0 Hz, 1H, Ar), 7.22 (d, J¼9.0 Hz, 2H, Ar), 7.25 (d,
J¼8.5 Hz, 2H, Ar); 13C NMR (50.3 MHz, CDCl3): d 19.8,
55.2, 55.3, 61.01, 76.8, 113.8, 114.3, 118.8, 123.9, 129.2,
130.2, 156.5, 159.8, 161.3, 169.2; MS (m/z): 342 (M+1).
4.1.2. 3-Acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-
2-one (12b). Yield 65%; white solid, mp 164–166 ꢀC
[Found: C, 69.53; H, 5.45; N, 4.48; C18H17NO4: requires
C, 69.44; H, 5.50; N, 4.50%]; Rf (18% EtOAc/Pet ether)
0.5; nmax (CHCl3) 1751 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 1.68 (s, 3H, COCH3), 3.76 (s, 3H, Ar–OCH3),
5.35 (d, J¼5.1 Hz, 1H, C4H), 5.95 (d, J¼5.1 Hz, 1H,
C3H), 6.82 (d, J¼9.00 Hz, 2H, Ar), 7.28–7.35 (m, 7H,
Ar); 13C NMR (50.3 MHz, CDCl3): d 20.3, 55.9, 61.9,
76.3, 114.9, 119.3, 128.9, 129.3, 130.8, 132.8, 157.1,
161.8, 169.7; MS (m/z): 312 (M+1).
1832, 1809, 1753 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d 3.79 (s, 3H, Ar–OCH3), 3.80 (s, 3H), 3.75 (s, 3H, Ar–
OCH3), 5.52 (s, 1H, C4H), 6.90 (d, J¼9.0 Hz, 2H, Ar), 7.20
(d, J¼8.6 Hz, 2H, Ar), 7.25 (d, J¼8.6 Hz, 2H, Ar), 7.46 (d,
J¼9.0 Hz, 2H, Ar); 13C NMR (50.3 MHz, CDCl3): d 55.3,
55.4, 74.4, 114.6, 114.9, 119.7, 123.5, 127.7, 129.8, 157.8,
160.1, 160.4, 191.2; MS (m/z): 298 (M+1).
4.1.3. 3-Hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-
one (13a). To a solution of 3-acetoxy-b-lactam 12a
(12.3 g, 36 mmol) in methanol (105 mL) was added a satu-
rated solution of sodium bicarbonate (53 mL) followed by
solid sodium carbonate (1.93 g, 18.25 mmol). The reaction
mixture was stirred at room temperature for 12 h. After the
reaction was complete (monitored by TLC), methanol was
evaporated under reduced pressure and the residue was
diluted with dichloromethane. The organic layer was sepa-
rated and the aqueous layer was washed with CH2Cl2
(3ꢁ50 mL). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo to
furnish the crude reaction mixture, which on purification
by silica gel column chromatography (60–120 mesh) using
30% ethyl acetate/Pet ether yielded 3-hydroxy-1-(4-meth-
oxyphenyl)-4-phenylazetidin-2-one 13a (10.6 g, 86%) as a
white solid, mp 146–149 ꢀC [Found: C, 68.32; H, 5.80; N,
4.61; C17H17NO4: requires C, 68.22; H, 5.73; N, 4.68%];
Rf (40% EtOAc/Pet ether) 0.5; nmax (CHCl3) 3353,
4.1.6. 1-(4-Methoxyphenyl)-4-phenylazetidin-2,3-dione
(4b). Yield 81%; yellow solid, mp 127 ꢀC [Found: C,
71.86; H, 5.11; N, 5.27; C16H13NO3: requires C, 71.90; H,
4.90; N, 5.24%]; Rf (40% EtOAc/Pet ether) 0.5; nmax
(CHCl3) 1832, 1809, 1753 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): d 3.75 (s, 3H, Ar–OCH3), 5.52 (s, 1H, C4H), 6.90
(d, J¼9.0 Hz, 2H, Ar), 7.24–7.38 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 55.3, 74.4, 114.6, 114.8, 119.7,
123.5, 127.8, 129.9, 157.8, 160.4, 191.2; MS (m/z): 268
(M+1).
4.1.7. 3-Butyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azeti-
din-2-one (5a). To a solution of dione 4a (0.891 g,
3 mmol) in dry THF (10 mL) was added a solution of n-butyl
magnesium bromide (3.9 mmol) in dry THF at 0 ꢀC. The
mixture was stirred for 4 h at room temperature. Saturated
aqueous NH4Cl was then added and the reaction mixture
was extracted with ethyl acetate (3ꢁ15 mL). The combined
1
1708 cmꢂ1; H NMR (200 MHz, DMSO-d6): d 2.15 (br s,

2528
D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was puri-
fied by flash column chromatography (230–400 mesh silica
gel) using 15% ethyl acetate/Pet ether to furnish compound
5a (0.59 g, 55%) as brownish oil [Found: C, 70.98; H, 7.16;
N, 3.89; C21H25NO4: requires C, 70.96; H, 7.09; N, 3.94%];
Rf (15% EtOAc/Pet ether) 0.5; nmax (CHCl3) 1728 cmꢂ1; 1H
NMR (200 MHz, CDCl3): d 0.96 (t, J¼6.9 Hz, 3H,
CH3(CH2)2CH2), 1.30–1.73 (m, 4H, CH3(CH2)2–CH2),
1.96–2.09 (m, 2H, CH3(CH2)2CH2), 3.76 (s, 3H, Ar–
OCH3), 3.81 (s, 3H, Ar–OCH3), 4.98 (s, 1H, C4H), 6.79
(d, J¼9.1 Hz, 2H, Ar), 6.82 (d, J¼8.7 Hz, 2H, Ar), 7.22
(d, J¼8.7 Hz, 2H, Ar), 7.29 (d, J¼8.9 Hz, 2H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 13.9, 22.9, 25.6, 35.1, 55.2,
55.4, 66.9, 85.9, 114.3, 114.5, 118.8, 125.7, 128.4, 130.6,
156.2, 159.9, 168; MS (m/z): 356 (M+1).
72.78; H, 7.96; N, 3.68; C24H31NO4: requires C, 72.52; H,
7.86; N, 3.52%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
(CHCl3) 3388, 1745, 1731 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): d 0.86 (t, J¼6.4 Hz, 3H, CH3(CH2)5CH2), 1.20–
1.54 (m, 10H, CH3(CH2)5–CH2), 1.89–2.02 (m, 2H,
CH3(CH2)5CH2), 3.73 (s, 3H, Ar–OCH3), 3.78 (s, 3H, Ar–
OCH3), 4.94 (s, 1H, C4H), 6.76 (d, J¼9.1 Hz, 2H, Ar),
6.80 (d, J¼8.9 Hz, 2H, Ar), 7.23 (d, J¼8.6 Hz, 2H, Ar),
7.28 (d, J¼9.0 Hz, 2H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 14.0, 22.5, 28.7, 29.2, 29.7, 31.5, 35.3, 55.2,
55.3, 66.7, 85.8, 114.3, 114.5, 118.1, 125.7, 128.5, 130.7,
156.2, 159.8, 168.2; MS (m/z): 398 (M+1).
4.1.12. 3-Heptyl-3-hydroxy-1-(4-methoxyphenyl)-4-phe-
nylazetidin-2-one (5f). Yield 58%; thick oil [Found: C,
75.26; H, 7.56; N, 3.76; C23H29NO3: requires C, 75.17; H,
7.95; N, 3.81%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
1
Following a similar procedure other 3-alkyl-3-Hydroxy-b-
lactams 5b–m, were synthesized.
(CHCl3) 3390, 1747 cmꢂ1; H NMR (200 MHz, CDCl3):
d 0.89 (t, J¼6.8 Hz, 3H, CH3(CH2)5CH2), 1.25–1.82 (m,
10H, CH3(CH2)5CH2), 1.87–2.03 (m, 2H, CH3(CH2)5CH2),
3.76 (s, 3H, Ar–OCH3), 5.01 (s, 1H, C4H), 6.81 (d,
J¼9.1 Hz, 2H, Ar), 7.27–7.39 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 14.3, 22.9, 23.8, 29.3, 30.1, 31.9,
35.7, 55.6, 67.5, 86.4, 114.6, 119.1, 127.4, 129.3, 130.9,
134.3, 156.5, 168.1; MS (m/z): 368 (M+1).
4.1.8. 3-Butyl-3-hydroxy-1-(4-Methoxyphenyl)-4-phe-
nylazetidin-2-one (5b). Yield 55%; brownish oil [Found:
C, 73.50; H, 7.26; N, 4.45; C20H23NO3: requires C, 73.82;
H, 7.12; N, 4.30%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
1
(CHCl3) 3388, 1737 cmꢂ1; H NMR (200 MHz, CDCl3):
d 0.83 (t, J¼6.9 Hz, 3H, CH3(CH2)2CH2), 1.25–1.76 (m,
4H, CH2(CH2)2CH3), 1.85–1.96 (m, 2H, CH3(CH2)2CH2),
3.63 (s, 3H, Ar–OCH3), 4.90 (s, 1H, C4H), 6.79 (d,
J¼9.0 Hz, 2H, Ar), 7.22–7.37 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 13.9, 22.9, 25.6, 35.1, 55.2, 55.4,
66.9, 85.9, 114.3, 118.8, 127.2, 128.6, 129, 130.6, 134,
156.3, 167.9; MS (m/z): 326 (M+1).
4.1.13. 3-Propyl-3-hydroxy-1,4-bis(4-methoxyphenyl)-
azetidin-2-one (5g). Yield 59%; thick oil [Found: C, 70.19;
H, 6.87; N, 3.98; C20H23NO4: requires C, 70.36; H, 6.79; N,
4.10%]; Rf (15% EtOAc/Pet ether) 0.5; nmax (CHCl3)
1739 cmꢂ1
;
1H NMR (200 MHz, CDCl3): d 0.98 (t,
J¼7.2 Hz, 3H, CH3(CH2)2), 1.53–1.62 (m, 2H, CH3(CH2)–
CH2), 1.90–1.98 (m, 2H, CH3CH2CH2), 3.72 (s, 3H, Ar–
OCH3), 3.77 (s, 3H, Ar–OCH3), 4.94 (s, 1H, C4H), 6.75
(d, J¼9.1 Hz, 2H, Ar), 6.79 (d, J¼8.7 Hz, 2H, Ar), 7.21
(d, J¼8.7 Hz, 2H, Ar), 7.28 (d, J¼9.1 Hz, 2H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 14.3, 17.1, 37.5, 55.2, 55.4,
66.9, 85.9, 114.3, 114.5, 118.8, 125.7, 128.4, 130.6, 156.2,
159.9, 167.9; MS (m/z): 342 (M+1).
4.1.9. 3-Octyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azeti-
din-2-one (5c). Yield 57%; oil [Found: C, 72.96; H, 8.08;
N, 3.40; requires: C, 72.98; H, 7.96; N, 3.78. C25H33NO4:
requires C, 72.96; H, 8.08; N, 3.40%]; Rf (15% EtOAc/
1
Pet ether) 0.4; nmax (CHCl3) 3390, 1747, 1730 cmꢂ1; H
NMR (200 MHz, CDCl3): d 0.92 (t, J¼6.4 Hz, 3H,
CH3(CH2)6CH2), 1.31–1.46 (m, 12H, CH3(CH2)6–CH2),
2.01–2.08 (m, 2H, CH3(CH2)6CH2), 3.79 (s, 3H, Ar–
OCH3), 3.84 (s, 3H, Ar–OCH3), 5.00 (s, 1H, C4H), 6.79
(d, J¼9.1 Hz, 2H, Ar), 6.97 (d, J¼8.9 Hz, 2H, Ar), 7.25 (d,
J¼8.7 Hz, 2H, Ar), 7.32 (d, J¼9.0 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 14.0, 22.6, 23.6, 29.2, 29.8, 31.8,
35.3, 55.2, 55.4, 66.9, 85.9, 114.3, 114.5, 118.8, 125.7,
128.5, 130.7, 156.2, 159.8, 168.1; MS (m/z): 412 (M+1).
4.1.14. 3-Propyl-3-hydroxy-1-(4-methoxyphenyl)-4-phe-
nylazetidin-2-one (5h). Yield 62%; white solid, mp 144–
146 ꢀC [Found: C, 73.18; H, 6.76; N, 4.38; C19H21NO3:
requires C, 73.28; H, 6.85; N, 4.50%]; Rf (15% EtOAc/
1
Pet ether) 0.5; nmax (CHCl3): 3461, 1739 cmꢂ1; H NMR
(200 MHz, CDCl3): d 1.03 (t, J¼6.5 Hz, 3H, CH3(CH2)2),
1.58–1.68 (m, 2H, CH3CH2CH2), 1.96–2.07 (m, 2H,
CH3CH2CH2), 3.76 (s, 3H, Ar–OCH3), 5.03 (s, 1H, C4H),
6.81 (d, J¼9.1 Hz, 2H, Ar), 7.14–7.31 (m, 7H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 14.3, 17.1, 37.6, 55.4, 67.3,
86.2, 114.3, 118.8, 127.2, 128.6, 129, 130.6, 134, 156.3,
167.9; MS (m/z): 312 (M+1).
4.1.10. 3-Octyl-3-hydroxy-1-(4-methoxyphenyl)-4-phe-
nylazetidin-2-one (5d). Yield 62%; oil [Found: C, 75.62;
H, 8.16; N, 3.75; C24H31NO3: requires C, 75.56; H, 8.19;
N, 3.67%]; Rf (15% EtOAc/Pet ether) 0.5; nmax (CHCl3)
1
3384, 1730 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.91 (t,
J¼6.7 Hz, 3H, CH3(CH2)6–CH2), 1.25–1.72 (m, 12H,
CH3(CH2)6–CH2), 1.96–2.13 (m, 2H, CH3(CH2)6CH2),
3.78 (s, 3H, Ar–OCH3), 5.04 (s, 1H, C4H), 6.81 (d,
J¼8.9 Hz, 2H, Ar), 7.28–7.45 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 14.1, 22.7, 23.7, 25.8, 29.3, 29.9,
31.9, 35.6, 55.4, 66.4, 86.2, 114.4, 118.9, 127.2, 128.7,
129.1, 130.7, 134.1, 156.4, 168; MS (m/z): 382 (M+1).
4.1.15. 3-Hydroxy-3-isopropyl-1,4-bis(4-methoxyphe-
nyl)azetidin-2-one (5i). Yield 49%; thick oil [Found: C,
70.38; H, 6.86; N, 3.89; C20H23NO4: requires C, 70.36; H,
6.79; N, 4.10%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
1
(CHCl3) 3488, 1735 cmꢂ1; H NMR (200 MHz, CDCl3):
d 1.12 (d, J¼7.0 Hz, 3H, aCH3–CH–bCH3), 1.20 (d,
a
J¼6.9 Hz, 3H, CH3–CH–bCH3), 3.76 (s, 3H, Ar–OCH3),
3.81 (s, 3H, Ar–OCH3), 4.99 (s, 1H, C4H), 6.72 (d,
J¼9.1 Hz, 2H, Ar), 6.81 (d, J¼8.9 Hz, 2H, Ar), 7.23 (d,
J¼8.6 Hz, 2H, Ar), 7.30 (d, J¼9.2 Hz, 2H, Ar); 13C NMR
4.1.11. 3-Heptyl-3-hydroxy-1,4-bis(4-methoxyphenyl)-
azetidin-2-one (5e). Yield 62%; colorless oil [Found: C,

D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
2529
(50.3 MHz, CDCl3): d 16.7, 17.1, 33.2, 55.3, 55.5, 64.9,
88.8, 114.3, 114.5, 118.8, 125.7, 128.4, 130.6, 156.2,
159.9, 167.8; MS (m/z): 342 (M+1).
concentrated under reduced pressure to afford the crude
product (0.67 g, 90%). The H NMR of the crude product
showed it to be a mixture of 3-alkylidene-b-lactams 7a
and 8a (E and Z isomers 72:28), which were separated by
flash column chromatography (Pet ether/ethyl acetate 9:1).
1
4.1.16. 3-Hydroxy-3-isopropyl-1-(4-methoxyphenyl)-4-
phenylazetidin-2-one (5j). Yield 51%; white solid, mp
114–116 ꢀC [Found: C, 73.18; H, 6.76; N, 4.38;
C19H21NO3: requires C, 73.33; H, 6.81; N, 4.50%]; Rf (35%
4.2.1. E-1,4-Bis-(4-methoxyphenyl)-3-butylideneazeti-
din-2-one (7a). Yield 72%; white solid, mp 88–89 ꢀC
[Found: C, 74.68; H, 6.88; N, 4.29; C21H23NO3: requires
C, 74.75; H, 6.87; N, 4.15%]; Rf (7% EtOAc/Pet ether)
1
EtOAc/Pet ether) 0.5; nmax (CHCl3): 3388, 1735 cmꢂ1. H
a
NMR (200 MHz, CDCl3): d 1.12 (d, J¼7.0 Hz, 3H, CH3–
CH–bCH3), 1.20 (d, J¼6.9 Hz, 3H, aCH3–CH–bCH3),
2.18–2.32 (m, 1H, aCH3–CH–bCH3), 3.81 (s, 3H, Ar–
OCH3), 5.01 (s, 1H, C4H), 6.72 (d, J¼9.1 Hz, 2H, Ar),
7.19–7.56 (m, 7H, Ar); 13C NMR (50.3 MHz, CDCl3):
d 14.3, 17.1, 37.6, 55.4, 67.3, 86.2, 114.3, 118.8, 127.2,
128.6, 129, 130.6, 134, 156.3, 167.9; MS (m/z): 312 (M+1).
0.3; nmax (CHCl3) 1745 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): d 0.75 (t, J¼7.3 Hz, 3H, ]CH–CH2CH2CH3),
1.24–1.37 (m, 2H, ]CH–CH2CH2CH3), 1.86–1.99 (m,
2H, ]CH–CH2CH2CH3), 3.77 (s, 3H, Ar–OCH3), 3.84 (s,
3H, Ar–OCH3), 5.38 (d, J¼1.4 Hz, 1H, C4H), 6.25 (dt,
J¼1.4, 7.3 Hz, 1H, ]CH(CH2)2CH3), 6.83 (d, J¼9.1 Hz,
2H, Ar), 6.93 (d, J¼8.7 Hz, 2H, Ar), 7.29 (d, J¼9.1 Hz,
2H, Ar), 7.40 (d, J¼8.7 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 13.4, 21.6, 29.6, 55.3, 55.4, 62.6,
114.3, 114.4, 118.1, 127.6, 128.3, 128.8, 131.4, 142.3,
155.8, 159.8, 161.3; MS (m/z): 338 (M+1).
4.1.17. 3-Hydroxy-1,4-bis-(4-methoxyphenyl)-3-(3-phe-
nylpropyl)azetidin-2-one (5k). Yield 61%; thick oil
[Found: C, 75.02; H, 6.32; N, 3.55; C26H27NO4: requires
C, 74.80; H, 6.52; N, 3.36%]; Rf (15% EtOAc/Pet ether)
1
0.5; nmax (CHCl3) 3384, 1731 cmꢂ1; H NMR (200 MHz,
CDCl3): d 1.97–2.14 (m, 4H, PhCH2(CH2)2), 2.72 (t,
J¼6.9 Hz, 2H, PhCH2(CH2)2), 3.80 (s, 3H, Ar–OCH3),
3.85 (s, 3H, Ar–OCH3), 4.98 (s, 1H, C4H), 6.81 (d,
J¼9.1 Hz, 2H, Ar), 6.94 (d, J¼8.6 Hz, 2H, Ar), 7.17–7.37
(m, 9H, Ar); 13C NMR (50.3 MHz, CDCl3): d 25.2, 34.9,
35.9, 55.2, 55.3, 67, 85.8, 114.3, 114.5, 118.9, 125.6,
125.7, 128.3, 128.5, 130.6, 141.8, 156.3, 159.9, 168; MS
(m/z): 418 (M+1).
4.2.2. Z-1,4-Bis-(4-methoxyphenyl)-3-butylideneazeti-
din-2-one (8a). Yield 28%; yellow oil [Found: C, 74.65; H,
6.98; N, 4.19; C21H23NO3: requires C, 74.75; H, 6.87; N,
4.15%]; Rf (7% EtOAc/Pet ether) 0.5; nmax (CHCl3)
1
1734 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.96 (t, J¼
7.8 Hz, 3H, ]CH–CH2CH2CH3), 1.40–1.58 (m, 2H, ]CH–
CH2CH2CH3), 2.44–2.66 (m, 2H, ]CH–CH2CH2CH3), 3.76
(s, 3H, Ar–OCH3), 3.82 (s, 3H, Ar–OCH3), 5.20 (d,
J¼1.0 Hz, 1H, C4H), 5.56 (t, J¼1.0, 7.8 Hz, 1H,
]CH(CH2)2CH3), 6.82 (d, J¼9.1 Hz, 2H, Ar), 6.92 (d, J¼
8.7 Hz, 2H, Ar), 7.28 (d, J¼9.1 Hz, 2H, Ar), 7.32 (d,
J¼8.7 Hz, 2H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.5,
22.4, 30.6, 55.2, 55.4, 62.5, 114.3, 114.4, 118.1, 128,
129.3, 131.3, 131.6, 142, 155.9, 159.7, 161.5; MS (m/z):
338 (M+1).
4.1.18. 3-Hydroxy-1-(4-methoxyphenyl)-4-phenyl-3-(3-
phenylpropyl)azetidin-2-one (5l). Yield 62%; thick oil
[Found: C, 77.32; H, 6.52; N, 3.55; C25H25NO3: requires
C, 77.49; H, 6.50; N, 3.61%]; Rf (13% EtOAc/Pet ether)
1
0.4; nmax (CHCl3): 3369, 1731 cmꢂ1; H NMR (200 MHz,
CDCl3): d 1.81–2.01 (m, 4H, PhCH2(CH2)2), 2.67 (t,
J¼7.1 Hz, 2H, PhCH2(CH2)2), 3.71 (s, 3H, Ar–OCH3),
4.93 (s, 1H, C4H), 6.75 (d, J¼9.0 Hz, 2H, Ar), 7.18–7.40
(m, 12H, Ar); 13C NMR (50.3 MHz, CDCl3): d 25.2, 35,
35.7, 55.2, 66.99, 85.76, 114.3, 118.8, 127.2, 128.6, 129,
130.6, 134, 156.3, 167.9; MS (m/z): 388 (M+1).
Following a similar procedure other 3-alkylidene-b-lactams
7b–l and 8b–l were also synthesized.
4.2.3. E-1-(Methoxyphenyl)-3-butylidene-4-phenylazeti-
din-2-one (7b). Yield 71%; white solid, mp 104–105 ꢀC
[Found: C, 78.34; H, 6.56; N, 4.63; C20H21NO2: requires
C, 78.15; H, 6.89; N, 4.56%]; Rf (8% EtOAc/Pet ether)
4.1.19. 3-Hydroxy-1,4-bis-(4-methoxyphenyl)-3-phenyl-
azetidin-2-one (5m). Yield 67%; white solid, mp 144–
146 ꢀC [Found: C, 73.69; H, 5.62; N, 3.85; C23H21NO4: re-
quires C, 73.58; H, 5.64; N, 3.73%]; Rf (14% EtOAc/Pet
0.3; nmax (CHCl3) 1732 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 0.73 (t, J¼7.4 Hz, 3H, ]CH–CH2CH2CH3),
1.26–1.33 (m, 2H, ]CH–CH2CH2CH3), 1.81–1.99 (m,
2H, ]CH–CH2CH2CH3), 3.78 (s, 3H, Ar–OCH3), 5.43
(d, J¼1.4 Hz, 1H, C4H), 6.28 (dt, J¼1.4, 7.6 Hz, 1H,
]CH(CH2)2CH3), 6.73 (d, J¼9.1 Hz, 2H, Ar), 7.16–7.35
(m, 7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.5, 22.4,
30.6, 55.3, 62.7, 114.3, 118.1, 126.5, 127.8, 128.4, 131.5,
137.4, 141.6, 155.8, 161.3; MS (m/z): 308 (M+1).
1
ether) 0.4; nmax (CHCl3) 1739 cmꢂ1; H NMR (200 MHz,
CDCl3): d 2.74 (br s, 1H, OH), 3.77 (s, 3H, Ar–OCH3), 3.83
(s, 3H, Ar–OCH3), 5.17 (s, 1H, C4H), 6.83 (d, J¼8.7 Hz, 2H,
Ar), 6.94 (d, J¼8.6 Hz, 2H, Ar), 7.17–7.37 (m, 9H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 55.2, 55.3, 70.1, 86.6, 114.2,
114.4, 119.1, 124.9, 125.4, 128.4, 128.7, 128.8, 130.2,
138.8, 156.3, 160.0, 166.5; MS (m/z): 376 (M+1).
4.2. General procedure for dehydration of 3-butyl-3-
hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-ones
(7a and 8a)
4.2.4. Z-1-(Methoxyphenyl)-3-butylidene-4-phenylazeti-
din-2-one (8b). Yield 29%; mp 106 ꢀC [Found: C, 78.41;
H, 6.99; N, 4.78; C20H21NO2: requires C, 78.15; H,
6.89; N, 4.56%]; Rf (8% EtOAc/Pet ether) 0.5; nmax
1
A solution of alcohol 5a (0.78 g, 2.19 mmol) and triphenyl-
phosphine (1.14 g, 4.38 mmol) in anhydrous carbon tetra-
chloride (10 mL) was refluxed for 12 h. The reaction
mixture was then filtered through a small pad of Celite and
(CHCl3) 1735 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.94
(t, J¼7.5 Hz, 3H, ]CH–CH2CH2CH3), 1.41–1.52 (m,
2H, ]CHCH2CH2CH3), 2.41–2.64 (m, 2H, ]CH–
CH2CH2CH3), 3.75 (s, 3H, Ar–OCH3), 5.27 (d, J¼1.2 Hz,

2530
D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
1H, C4H), 5.56 (dt, J¼1.2, 7.9 Hz, 1H, ]CH(CH2)2CH3),
6.79 (d, J¼9.1 Hz, 2H, Ar), 7.25–7.39 (m, 7H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 13.3, 21.6, 29.8, 55.4, 63,
114.3, 118.2, 127.1, 128.6, 128.9, 131.4, 137, 142.1,
155.9, 161.2; MS (m/z): 308 (M+1).
(m, 7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.8, 22.2,
27.4, 28.1, 28.5, 31.3, 55.2, 62.4, 114, 117.8, 127.6, 128.1,
128.5, 129.5, 131.1, 141.8, 155.5, 161; MS (m/z): 364
(M+1).
4.2.9. E-1,4-Bis-(4-methoxyphenyl)-3-heptylideneazeti-
din-2-one (7e). Yield 71%; white solid, mp 65–66 ꢀC
[Found: C, 75.88; H, 7.88 N, 3.68; C24H29NO3: requires C,
75.96; H, 7.70; N, 3.69%]; Rf (5% EtOAc/Pet ether) 0.3;
4.2.5. E-1,4-Bis-(4-methoxyphenyl)-3-octylideneazeti-
din-2-one (7c). Yield 71%; colorless oil [Found: C, 76.38;
H, 7.96; N, 3.68; C25H31NO3: requires C, 76.30; H, 7.94;
N, 3.56%]; Rf (5% EtOAc/Pet ether) 0.3; nmax (CHCl3)
nmax (CHCl3) 1737 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
1
1740, 1612 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.89 (t,
d 0.86 (t, J¼6.7 Hz, 3H, ]CH–CH2(CH2)4CH3), 1.22–
1.38 (m, 8H, ]CH–CH2(CH2)4CH3), 1.87–2.01 (m, 2H,
]CH–CH2(CH2)4CH3), 3.76 (s, 3H, Ar–OCH3), 3.83 (s,
3H, Ar–OCH3), 5.37 (d, J¼1.4 Hz, 1H, C4H), 5.24 (dt,
J¼1.4, 7.4 Hz, 1H, ]CH(CH2)5CH3), 6.81 (d, J¼9.1 Hz,
2H, Ar), 6.92 (d, J¼8.7 Hz, 2H, Ar), 7.31 (d, J¼9.1 Hz,
2H, Ar), 7.38 (d, J¼8.7 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 13.9, 22.4, 27.7, 28.3, 28.5, 31.3,
55.1, 55.3, 62.6, 114.3, 118.1, 127.9, 128.30, 128.8, 131.4,
142.1, 155.8, 159.8, 161.3; MS (m/z): 380 (M+1).
J¼6.7 Hz, 3H, ]CH–CH2(CH2)5CH3), 1.13–1.28 (m,
10H, ]CH–CH2(CH2)5CH3), 1.87–2.01 (m, 2H, ]CH–
CH2(CH2)5CH3), 3.77 (s, 3H, Ar–OCH3), 3.83 (s, 3H, Ar–
OCH3), 5.37 (d, J¼1.2 Hz, 1H, C4H), 6.24 (dt, J¼1.2,
7.6 Hz, 1H, ]CH(CH2)6CH3), 6.81 (d, J¼9.1 Hz, 2H, Ar),
6.92 (d, J¼8.7 Hz, 2H, Ar), 7.31 (d, J¼9.1 Hz, 2H, Ar),
7.28 (d, J¼8.7 Hz, 2H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 13.7, 22.2, 27.4, 28.0, 28.5, 31.3, 54.8, 55.0,
62.3, 114, 114.1, 117.8, 127.6, 128.3, 128.5, 131.1, 141.8,
155.5, 159.5, 161; MS (m/z): 394 (M+1).
4.2.10. Z-1,4-Bis-(4-methoxyphenyl)-3-heptylideneazeti-
din-2-one (8e). Yield 29%; 107–108 ꢀC [Found: C, 75.89;
H, 7.76; N, 3.65; C24H29NO3: requires C, 75.96; H, 7.70;
N, 3.69%]; Rf (5% EtOAc/Pet ether) 0.5; nmax (CHCl3)
4.2.6. Z-1,4-Bis-(4-methoxyphenyl)-3-octylideneazetidin-
2-one (8c). Yield 29%; colorless oil [Found: C, 76.35; H,
7.89; N, 3.64; C25H31NO3: requires C, 76.30; H, 7.94; N,
3.56%]; Rf (5% EtOAc/Pet ether) 0.5; nmax (CHCl3)
1740 cmꢂ1
;
1H NMR (200 MHz, CDCl3): d 0.83 (t,
1743 cmꢂ1
;
1H NMR (200 MHz, CDCl3): d 0.88 (t,
J¼6.6 Hz, 3H, ]CH–CH2(CH2)4CH3), 1.19–1.39 (m,
8H, ]CH–CH2(CH2)4CH3), 2.46–2.57 (m, 2H, ]CH–
CH2(CH2)4CH3), 3.70 (s, 3H, Ar–OCH3), 3.76 (s, 3H, Ar–
OCH3), 5.17 (d, J¼1.0 Hz, 1H, C4H), 5.49 (dt, J¼1.0,
8.0 Hz, 1H, ]CH–CH2(CH2)4CH3), 6.72 (d, J¼9.1 Hz,
2H, Ar), 6.85 (d, J¼8.7 Hz, 2H, Ar), 7.34 (d, J¼9.1 Hz,
2H, Ar), 7.39 (d, J¼8.7 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 14, 22.5, 28.2, 28.7, 31.5, 55.2,
55.4, 62.4, 114.3, 114.4, 118.1, 128.1, 129.3, 131.6, 141.7,
155.8, 159.7, 161.5; MS (m/z): 380 (M+1).
J¼6.5 Hz, 3H, ]CH–CH2(CH2)5CH3), 1.14–1.62 (m,
10H, ]CH–CH2(CH2)5CH3), 2.48–2.62 (m, 2H, ]CH–
CH2(CH2)5CH3), 3.75 (s, 3H, Ar–OCH3), 3.80 (s, 3H, Ar–
OCH3), 5.22 (d, J¼1.0 Hz, 1H, C4H), 5.54 (dt, J¼1.0,
7.9 Hz, 1H, ]CH(CH2)6CH3), 6.79 (d, J¼9.1 Hz, 2H, Ar),
6.89 (d, J¼8.7 Hz, 2H, Ar), 7.26 (d, J¼8.7 Hz, 2H, Ar),
7.28 (d, J¼9.0 Hz, 2H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 14.0, 22.5, 28.6, 28.9, 29.1, 31.7, 55.1, 55.3,
62.3, 114.2, 118.1, 127.9, 129.3, 131.5, 141.7, 155.8,
159.7, 161.5; MS (m/z): 394 (M+1).
4.2.11. E-1-(Methoxyphenyl)-3-heptylidene-4-phenyl-
azetidin-2-one (7f). Yield 69%; white solid, mp 74 ꢀC
[Found: C, 79.41; H, 7.99; N, 3.73; C23H27NO2: requires
C, 79.05; H, 7.79; N, 4.01%]; Rf (5% EtOAc/Pet ether)
0.3; nmax (CHCl3) 1731 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 0.78 (t, J¼6.4 Hz, 3H, ]CH–CH2(CH2)4CH3), 1.14–1.65
(m, 8H, ]CH–CH2(CH2)4CH3), 2.34–2.53 (m, 2H, ]CH–
CH2(CH2)4CH3), 3.66 (s, 3H, Ar–OCH3), 5.17 (d, J¼1.2 Hz,
1H, C4H), 6.30 (dt, J¼1.2, 7.3 Hz, 1H, ]CH(CH2)5CH3),
6.70 (d, J¼9.1 Hz, 2H, Ar), 7.16–7.36 (m, 7H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 13.7, 22.3, 28.4, 29.4, 31.3,
55.1, 62.5, 114.1, 117.8, 126.3, 128.2, 128.7, 131.2, 131.6,
141.1, 155.6, 161.1; MS (m/z): 350 (M+1).
4.2.7. E-1-(Methoxyphenyl)-3-octylidene-4-phenylazeti-
din-2-one (7d). Yield 71%; white solid, mp 74–76 ꢀC
[Found: C, 79.41; H, 7.99; N, 3.72; C24H29NO2: requires
C, 79.30; H, 8.04; N, 3.86%]; Rf (8% EtOAc/Pet ether)
0.3; nmax (CHCl3) 1733 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 0.79 (t, J¼6.8 Hz, 3H, ]CH–CH2(CH2)5CH3),
1.03–1.20 (m, 10H, ]CH–CH2(CH2)5CH3), 1.78–1.92 (m,
2H, ]CH–CH2(CH2)5CH3), 3.67 (s, 3H, Ar–OCH3), 5.31
(d, J¼1.4 Hz, 1H, C4H), 6.16 (dt, J¼1.4, 7.3 Hz, 1H,
]CHCH2(CH2)5CH3), 6.76 (d, J¼8.9 Hz, 2H, Ar), 7.16–
7.36 (m, 7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.7,
22.3, 27.5, 28.1, 28.5, 31.3, 55.1, 62.7, 114, 117.8, 126.7,
127.1, 127.8, 128.3, 128.7, 131.7, 141.6, 155.6, 161.9; MS
(m/z): 364 (M+1).
4.2.12. Z-1-(Methoxyphenyl)-3-heptylidene-4-phenylaze-
tidin-2-one (8f). Yield 31%; white solid, mp 68–70 ꢀC
[Found: C, 79.31; H, 7.83; N, 3.71; C23H27NO2: requires
C, 79.05; H, 7.79; N, 4.01%]; Rf (5% EtOAc/Pet ether)
4.2.8. Z-1-(Methoxyphenyl)-3-octylidene-4-phenylazeti-
din-2-one (8d). Yield 29%; colorless oil [Found: C, 79.41;
H, 8.02; N, 3.82; C24H29NO2: requires C, 79.30; H, 8.04;
N, 3.86%]; Rf (8% EtOAc/Pet ether) 0.5; nmax (CHCl3)
0.5; nmax (CHCl3) 1731 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 0.78 (t, J¼6.4 Hz, 3H, ]CH–CH2(CH2)4CH3),
1.14–1.65 (m, 8H, ]CH–CH2(CH2)4CH3), 2.34–2.53 (m,
2H, ]CH–CH2(CH2)4CH3), 3.66 (s, 3H, Ar–OCH3), 5.17
(d, J¼1.0 Hz, 1H, C4H), 5.46 (dt, J¼1.0, 7.9 Hz, 1H,
]CH(CH2)4CH3), 6.70 (d, J¼9.1 Hz, 2H, Ar), 7.16–7.36
(m, 7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.5, 22.6,
28.7, 29.1, 31.8, 55.2, 62.4, 114.2, 117.8, 126.5, 128.3,
1
1733, 1616 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.77 (t,
J¼6.6 Hz, 3H, ]CH–CH2(CH2)5CH3), 1.17–1.57 (m,
10H, ]CH–CH2(CH2)5CH3), 2.34–2.56 (m, 2H, ]CH–
CH2(CH2)5CH3), 3.66 (s, 3H, Ar–OCH3), 5.17 (d,
J¼1.0 Hz, 1H, C4H), 5.46 (dt, J¼1.0, 7.8 Hz, 1H,
]CH(CH2)6CH3), 6.70 (d, J¼8.9 Hz, 2H, Ar), 7.16–7.36

D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
2531
128.7, 131.4, 131.9, 141.1, 155.6, 161.1; MS (m/z): 350
(M+1).
nmax (CHCl3) 1731 cmꢂ1
;
1H NMR (200 MHz, CDCl3):
a
b
d 1.54 (s, 3H, CH3–C]), 2.11 (s, 3H, CH3–C]), 3.73
(s, 3H, Ar–OCH3), 3.80 (s, 3H, Ar–OCH3), 5.22 (s, 1H,
C4H), 6.76 (d, J¼9.1 Hz, 2H, Ar), 6.89 (d, J¼8.9 Hz, 2H,
Ar), 7.25 (d, J¼9.0 Hz, 2H, Ar), 7.32 (d, J¼8.7 Hz, 2H,
Ar); 13C NMR (50.3 MHz, CDCl3): d 19.8, 20.2, 55.2,
55.4, 62.3, 114.3, 117.8, 128.4, 129.2, 131.8, 136.3, 137,
155.6, 159.6, 162; MS (m/z): 324 (M+1).
4.2.13. E-1,4-Bis-(4-methoxyphenyl)-3-propylideneazeti-
din-2-one (7g). Yield 72%; white solid, mp 88–90 ꢀC
[Found: C, 74.23; H, 6.68; N, 4.29; C20H21NO3: requires
C, 74.28; H, 6.55; N, 4.33%]; Rf (5% EtOAc/Pet ether)
0.3; nmax (CHCl3) 1735 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 0.84 (t, J¼7.5 Hz, 3H, ]CH–CH2CH3), 1.67–
2.05 (m, 2H, ]CH–CH2CH3), 3.74 (s, 3H, Ar–OCH3),
3.81 (s, 3H, Ar–OCH3), 5.36 (d, J¼1.4 Hz, 1H, C4H),
6.22 (dt, J¼1.4, 7.3 Hz, 1H, ]CHCH2CH3), 6.78 (d,
J¼9.1 Hz, 2H, Ar), 6.88 (d, J¼8.7 Hz, 2H, Ar), 7.25 (d,
J¼9.1 Hz, 2H, Ar), 7.38 (d, J¼8.7 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 12.9, 21.3, 55.2, 55.3, 62.5, 114.2,
114.3, 118.1, 128.3, 128.8, 129.l, 131.4, 141.5, 155.8,
159.8, 161.4; MS (m/z): 324 (M+1).
4.2.18. 3-Isopropylidene-1-(4-methoxyphenyl)-4-phenyl-
azetidin-2-one (7j). Yield 92%; white solid, mp 192–
194 ꢀC [Found: C, 77.65; H, 6.65; N, 4.52; C19H19NO2: re-
quires C, 77.79; H, 6.53; N, 4.77%]; Rf (10% EtOAc/Pet
1
ether) 0.5; nmax (CHCl3) 1735 cmꢂ1; H NMR (200 MHz,
a
b
CDCl3): d 1.55 (s, 3H, CH3–C]), 2.12 (s, 3H, CH3–
C]), 3.73 (s, 3H, Ar–OCH3), 5.28 (s, 1H, C4H), 6.78 (d,
J¼9.1 Hz, 2H, Ar), 7.33–7.43 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 16.7, 17.7, 33.2, 55.4, 65.2, 114.3,
118.8, 127.2, 128.6, 129.1, 130.5, 131, 156.3, 162; MS
(m/z): 294 (M+1).
4.2.14. Z-1,4-Bis-(4-methoxyphenyl)-3-propylideneazeti-
din-2-one (8g). Yield 28%; white solid, mp 98–99 ꢀC
[Found: C, 74.23; H, 6.60; N, 4.37; C20H21NO3: requires
C, 74.28; H, 6.55; N, 4.33%]; Rf (5% EtOAc/Pet ether)
4.2.19. E-1,4-Bis-(4-methoxyphenyl)-3-(3-phenylpropyl-
idene)azetidin-2-one (7k). Yield 70%; white solid, mp
91–92 ꢀC [Found: C, 78.02; H, 6.32; N, 3.85; C26H25NO3:
requires C, 78.17; H, 6.31; N, 3.51%]; Rf (10% EtOAc/Pet
0.5; nmax (CHCl3) 1728 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 0.96 (t, J¼7.6 Hz, 3H, ]CH–CH2CH3), 2.40–
2.70 (m, 2H, ]CH–CH2CH3), 3.75 (s, 3H, Ar–OCH3),
3.80 (s, 3H, Ar–OCH3), 5.22 (d, J¼1.0 Hz, 1H, C4H),
5.54 (dt, J¼1.0, 7.7 Hz, 1H, ]CHCH2CH3), 6.79 (d,
J¼9.1 Hz, 2H, Ar), 6.89 (d, J¼8.7 Hz, 2H, Ar), 7.26 (d,
J¼9.1 Hz, 2H, Ar), 7.29 (d, J¼8.7 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 13.8, 22.3, 55.2, 55.4, 62.3, 114.3,
114.4, 118.1, 127.9, 129.3, 131.6, 132.9, 141.2, 155.9,
159.8, 161.4; MS (m/z): 324 (M+1).
1
ether) 0.3; nmax (CHCl3) 1737 cmꢂ1; H NMR (200 MHz,
CDCl3): d 2.16–2.52 (m, 4H, ]CH(CH2)2Ph), 3.79 (s, 3H,
Ar–OCH3), 3.83 (s, 3H, Ar–OCH3), 5.11 (s, 1H, C4H),
6.24 (t, J¼7.5 Hz, 1H, ]CH(CH2)2Ph), 6.79 (d,
J¼9.1 Hz, 2H, Ar), 6.78 (d, J¼9.0 Hz, 2H, Ar), 6.89 (d,
J¼8.7 Hz, 2H, Ar), 6.98–7.33 (m, 7H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 29.8, 34.6, 55.2, 55.4, 67.5, 114.3,
114.4, 118.2, 126.1, 126.3, 128.4, 128.7, 131.4, 140.6,
142.9, 155.9, 159.9, 161.1; MS (m/z): 400 (M+1).
4.2.15. E-1-(Methoxyphenyl)-3-propylidene-4-phenyl-
azetidin-2-one (7h). Yield 69%; white solid, mp 153–
154 ꢀC [Found: C, 77.67; H, 6.49; N, 4.74; C19H19NO2: re-
quires C, 77.79; H, 6.53; N, 4.77%]; Rf (8% EtOAc/Pet
4.2.20. Z-1,4-Bis-(4-methoxyphenyl)-3-(3-phenylpropyl-
idene)azetidin-2-one (8k). Yield 30%; white solid, mp
103–105 ꢀC [Found: C, 78.14; H, 6.15; N, 3.63; C26H25NO3:
requires C, 78.17; H, 6.31; N, 3.51%]; Rf (10% EtOAc/Pet
1
ether) 0.3; nmax (CHCl3) 1733 cmꢂ1; H NMR (200 MHz,
CDCl3): d 0.82 (t, J¼7.4 Hz, 3H, ]CH–CH2CH3), 1.81–
2.06 (m, 2H, ]CH–CH2CH3), 3.74 (s, 3H, Ar–OCH3),
5.39 (d, J¼1.4 Hz, 1H, C4H), 6.21 (dt, J¼1.4, 7.7 Hz, 1H,
]CHCH2CH3), 6.79 (d, J¼9.1 Hz, 2H, Ar), 7.16–7.28 (m,
7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 12.9, 21.3, 55.3,
62.9, 114.3, 118.1, 127, 128.6, 128.9, 129.2, 131.4, 137,
141.4, 155.9, 161.3; MS (m/z): 294 (M+1).
1
ether) 0.5; nmax (CHCl3) 1733 cmꢂ1; H NMR (200 MHz,
CDCl3): d 2.71–2.94 (m, 4H, ]CH(CH2)2Ph), 3.73 (s, 3H,
Ar–OCH3), 3.79 (s, 3H, Ar–OCH3), 5.18 (s, 1H, C4H),
5.51 (t, J¼7.5 Hz, 1H, ]CH(CH2)2Ph), 6.79 (d, J¼9.1 Hz,
2H, Ar), 6.82 (d, J¼8.6 Hz, 2H, Ar), 7.17–7.37 (m, 9H, Ar);
13C NMR (50.3 MHz, CDCl3): d 29.2, 34.4, 55.1, 55.3, 67.8,
114.1, 114.3, 118.2, 126.1, 126.3, 128.4, 128.7, 131.4, 140.6,
142.9, 155.9, 159.9, 161.2; MS (m/z): 400 (M+1).
4.2.16. Z-1-(Methoxyphenyl)-3-propylidene-4-phenyl-
azetidin-2-one (8h). Yield 31%; white solid, mp 125–
126 ꢀC [Found: C, 77.64; H, 6.56; N, 4.71; C19H19NO2: re-
quires C, 77.79; H, 6.53; N, 4.77%]; Rf (8% EtOAc/Pet ether)
4.2.21. E-1-(4-methoxyphenyl)-4-phenyl-3-(3-phenylpro-
pylidene)azetidin-2-one (7l). Yield 70%; white solid, mp
102–103 ꢀC [Found: C, 81.32; H, 6.38; N, 3.58; C25H23NO2:
requires C, 81.27; H, 6.27; N, 3.79%]; Rf (12% EtOAc/Pet
1
0.5; nmax (CHCl3) 1739, 1610 cmꢂ1; H NMR (200 MHz,
CDCl3): d 0.96 (t, J¼7.2 Hz, 3H, ]CH–CH2CH3), 2.33–
2.61 (m, 2H, ]CH–CH2CH3), 3.66 (s, 3H, Ar–OCH3),
5.17 (d, J¼1.1 Hz, 1H, C4H), 5.46 (dt, J¼1.1, 8.1 Hz, 1H,
]CHCH2CH3), 6.72 (d, J¼9.1 Hz, 2H, Ar), 7.16–7.28 (m,
7H, Ar); 13C NMR (50.3 MHz, CDCl3): d 13.8, 22.3, 55.4,
62.7, 114.3, 118.1, 126.5, 128.4, 128.9, 131.5, 133.1,
137.4, 140.9, 155.9, 161.3; MS (m/z): 294 (M+1).
1
ether) 0.4; nmax (CHCl3) 1736 cmꢂ1; H NMR (200 MHz,
CDCl3): d 2.19–2.56 (m, 4H, ]CH(CH2)2Ph), 3.73 (s, 3H,
Ar–OCH3), 5.15 (s, 1H, C4H), 6.25 (t, J¼7.7 Hz, 1H,
]CH(CH2)2Ph), 6.78 (d, J¼9.1 Hz, 2H, Ar), 6.95 (d,
J¼8.0 Hz, 2H, Ar), 7.21–7.38 (m, 10H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 29.8, 34.6, 55.3, 62.8, 114.3, 118.1,
126.1, 126.5, 127.1, 128.4, 128.7, 131.3, 136.8, 140.5,
142.7, 155.9, 161; MS (m/z): 370 (M+1).
4.2.17. 3-Isopropylidene-1,4-bis-(4-methoxyphenyl)aze-
tidin-2-one (7i). Yield 91%; white solid, mp 146–147 ꢀC
[Found: C, 74.12; H, 6.65; N, 4.02; C20H21NO3: requires
C, 74.28; H, 6.55; N, 4.33%]; Rf (15% EtOAc/Pet ether) 0.5;
4.2.22. Z-1-(4-Methoxyphenyl)-4-phenyl-3-(3-phenyl-
propylidene)azetidin-2-one (8l). Yield 30%; white solid,

2532
D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
mp 107–109 ꢀC [Found: C, 81.37; H, 6.35; N, 3.63;
C25H23NO2: requires C, 81.27; H, 6.27; N, 3.79%]; Rf (8%
3.87; C24H31NO2: requires C, 78.87; H, 8.55; N, 3.83%]; Rf
1
(14% EtOAc/Pet ether) 0.5; nmax (CHCl3) 1739 cmꢂ1. H
1
EtOAc/Pet ether) 0.5; nmax (CHCl3): 1736 cmꢂ1; H NMR
NMR (200 MHz, CDCl3): d 0.78 (t, J¼7.0 Hz, 3H,
CH3(CH2)6CH2), 1.09–1.40 (m, 12H, CH3(CH2)6CH2),
1.29–1.46 (m, 2H, CH3(CH2)6CH2), 3.42–3.56 (m, 1H,
C3H), 3.69 (s, 3H, Ar–OCH3), 5.09 (d, 1H, J¼5.70 Hz,
C4H), 6.73 (d, J¼9.1 Hz, 2H, Ar), 7.14–7.28 (m, 7H,
Ar); 13C NMR (50.3 MHz, CDCl3): d 13.9, 22.4, 25.2,
27.1, 28.7, 29.2, 29.4, 31.5, 54.7, 55.1, 55.3, 57.9, 113.9,
114.1, 118.3, 126.9, 131.3, 155.8, 167.7; MS (m/z): 366
(M+1).
(200 MHz, CDCl3): d 2.78–2.94 (m, 4H, ]CH(CH2)2Ph),
3.78 (s, 3H, Ar–OCH3), 5.25 (s, 1H, C4H), 5.83 (t,
J¼7.5 Hz, 1H, ]CH(CH2)2Ph), 6.83 (d, J¼8.9 Hz, 2H,
Ar), 7.19–7.37 (m, 12H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 29.9, 35.4, 55.4, 62.7, 114.3, 118.1, 126, 126.3,
128.3, 128.5, 130.3, 137.2, 140.6, 142.1, 155.9, 161.1; MS
(m/z): 370 (M+1).
4.2.23. 1,4-Bis-(4-methoxyphenyl)-3-butylazetidin-2-one
(9a). To a mixture of 3-alkylidene-b-lactams 7a and 8a
(0.168 g, 0.5 mmol) in 15 mL of ethyl acetate was added
a catalytic amount of 10% Pt/C (30 mg). Hydrogenation
was carried out under atmospheric pressure for 12 h. The
catalyst was filtered through a pad of Celite and the solvent
was removed under reduced pressure to give compound 9a
(0.155 g, 92%) as a white solid, mp 85–86 ꢀC [Found: C,
74.27; H, 7.36; N, 4.02; C21H25NO3: require C, 74.31; H,
7.42; N, 4.13%]; Rf (14% EtOAc/Pet ether) 0.5; nmax
4.2.27. 3-Heptyl-1,4-bis(4-methoxyphenyl)azetidin-2-one
(9e). Yield 94%; thick oil [Found: C, 75.46; H, 8.34; N,
3.83; C24H31NO3: requires C, 75.56; H, 8.19; N, 3.67%];
Rf (15% EtOAc/Pet ether) 0.5; nmax (CHCl3) 1741 cmꢂ1
;
1H NMR (200 MHz, CDCl3): d 0.84 (t, J¼6.9 Hz, 3H,
CH3(CH2)5CH2), 1.11–1.53 (m, 12H, CH3(CH2)6), 3.44–
3.47 (m, 1H, C3H), 3.75 (s, 3H, Ar–OCH3), 3.81(s,
3H, Ar–OCH3), 5.11 (d, J¼5.6 Hz, 1H, C4H), 6.77 (d,
J¼9.1 Hz, 2H, Ar), 6.85 (d, J¼8.9 Hz, 2H, Ar), 7.19 (d,
J¼8.9 Hz, 2H, Ar), 7.24 (d, J¼9.00 Hz, 2H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 13.9, 22.4, 25.2, 27.1, 29.2,
31.5, 54.7, 55.1, 55.3, 57.9, 113.9, 114.1, 118.3, 126.9,
128.3, 131.3, 155.7, 159.7, 167.7; MS (m/z): 382 (M+1).
1
(CHCl3) 3359 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.97
(t, J¼6.8 Hz, 3H, CH3(CH2)3), 1.12–1.50 (m, 6H,
CH3(CH2)3), 3.47–3.57 (m, 1H, C3H), 3.74 (s, 3H, Ar–
OCH3), 3.80 (s, 3H, Ar–OCH3), 5.11 (d, J¼5.6 Hz, 1H,
C4H), 6.79 (d, J¼9.1 Hz, 2H, Ar), 6.82 (d, J¼8.7 Hz, 2H,
Ar), 7.22 (d, J¼8.7 Hz, 2H, Ar), 7.29 (d, J¼8.9 Hz, 2H,
Ar); 13C NMR (50.3 MHz, CDCl3): d 13.9, 22.9, 25.6,
35.1, 54.6, 55.4, 55.8, 59.9, 114.5, 114.8, 118.9, 125.9,
128.7, 130.6, 156.2, 159.9, 168.5; MS (m/z): 340 (M+1).
4.2.28. 3-Heptyl-1-(4-methoxyphenyl)-4-phenylazetidin-
2-one (9f). Yield 95%; white solid, mp 75–76 ꢀC [Found:
C, 78.45; H, 8.13; N, 3.87; C23H29NO2: requires C, 78.60;
H, 8.32; N, 3.99%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
1
(CHCl3) 1739 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.89
Following a similar procedure other 3-alkyl-b-lactams 9b–l
were synthesized.
(t, J¼6.8 Hz, 3H, CH3(CH2)6), 1.03–1.46 (m, 12H,
CH3(CH2)6), 3.40–3.51 (m, 1H, C3H), 3.69 (s, 3H, Ar–
OCH3), 5.14 (d, J¼5.7 Hz, 1H, C4H), 6.81 (d, J¼9.1 Hz,
2H, Ar), 7.27–7.39 (m, 7H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 14, 22.5, 25.3, 27.1, 28.8, 29.2, 31.6, 54.7, 55.4,
58.4, 114.3, 118.4, 127.2, 128.3, 128.6, 131.3, 135.2,
156.5, 168.2; MS (m/z): 352 (M+1).
4.2.24. 3-Butyl-1-(4-methoxyphenyl)-4-phenylazetidin-2-
one (9b). Yield 95%; white solid, mp 89–91 ꢀC [Found: C,
73.98; H, 7.36; N, 3.98; C20H23NO2: requires C, 73.82; H,
7.12; N, 4.30%]; Rf (15% EtOAc/Pet ether) 0.5; nmax
1
(CHCl3) 1737 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.72
(t, J¼6.9 Hz, 3H, CH3(CH2)3), 1.25–1.69 (m, 6H,
CH3(CH2)3), 3.46–3.57 (m, 1H, C3H), 3.76 (s, 3H, Ar–
OCH3), 5.11 (d, J¼5.7 Hz, C4H), 6.73 (d, J¼9.1 Hz, 2H,
Ar), 7.20–7.36 (m, 7H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 13.7, 22.4, 25, 29.4, 54.7, 55.3, 58.4, 114.4,
118.7, 127.2, 128.6, 129.1, 130.6, 134, 156.3, 167.9; MS
(m/z): 310 (M+1).
4.2.29. 3-Propyl-1,4-bis(4-methoxyphenyl)azetidin-2-one
(9g). Yield 97%; white solid, mp 84–85 ꢀC [Found: C,
73.76; H, 7.06; N, 4.25; C20H23NO3: requires C, 73.82;
H, 7.12; N, 4.30%]; Rf (9% EtOAc/Pet ether) 0.4; nmax
1
(CHCl3): 1737 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.77
(t, J¼6.5 Hz, 3H, CH3(CH2)2), 1.14–1.45 (m, 4H,
CH3(CH2)2), 3.47–3.57 (m, 1H, C3H), 3.75 (s, 3H, Ar–
OCH3), 3.82 (s, 3H, Ar–OCH3), 5.11 (d, J¼5.4 Hz, 1H,
C4H), 6.80 (d, J¼9.00 Hz, 2H, Ar), 6.89–7.14 (d, J¼8.9 Hz,
2H, –Ar), 7.22 (d, J¼8.9 Hz, 2H, Ar), 7.29 (d, J¼9.0 Hz, 2H,
Ar); 13C NMR (50.3 MHz, CDCl3): d 13.9, 20.5, 27.5, 54.5,
55.2, 55.4, 58, 113.9, 114.2, 118.3, 126.9, 127.1, 128.3,
131.3, 155.7, 159.4, 167.3; MS (m/z): 326 (M+1).
4.2.25. 3-Octyl-1,4-bis(4-methoxyphenyl)azetidin-2-one
(9c). Yield 94%; thick oil [Found: C, 75.57; H, 8.32; N,
3.55; C25H33NO3: requires C, 75.91; H, 8.41; N, 3.54%];
Rf (8% EtOAc/Pet ether) 0.4; nmax (CHCl3) 1742 cmꢂ1; 1H
NMR (200 MHz, CDCl3): d 0.86 (t, J¼6.7 Hz, 3H,
CH3(CH2)7), 1.10–1.53 (m, 14H, CH3(CH2)7), 3.44–3.54
(m, 1H, C4H), 3.75 (s, 3H, Ar–OCH3), 3.81 (s, 3H, Ar–
OCH3), 5.37 (d, J¼5.6 Hz, 1H, C4H), 6.79 (d, J¼9.0 Hz,
2H, Ar), 6.88 (d, J¼8.8 Hz, 2H, Ar), 7.19 (d, J¼8.7 Hz,
2H, Ar), 7.26 (d, J¼9.1 Hz, 2H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 14.1, 22.6, 25.23, 27.2, 29.2, 29.3, 29.4, 31.8,
54.7, 55.2, 55.3, 57.9, 113.9, 114.2, 118.3, 118.4, 126.9,
128.4, 131.3, 155.7, 159.4, 167.7; MS (m/z): 396 (M+1).
4.2.30. 3-Propyl-1-(4-methoxyphenyl)-4-phenylazetidin-
2-one (9h). Yield 94%; white solid, mp 111–112 ꢀC [Found:
C, 77.18; H, 7.06; N, 4.66; C19H21NO2: requires C, 77.26; H,
7.17; N, 4.74%]; Rf (12% EtOAc/Pet ether) 0.4; nmax
1
(CHCl3) 1739 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.75
(t, J¼6.8 Hz, 3H, CH3(CH2)2), 1.08–1.46 (m, 4H,
CH3(CH2)2), 3.51–3.61 (m, 1H, C3H), 3.75 (s, 3H, Ar–
OCH3), 5.16 (d, J¼5.7 Hz, 1H, C4H), 6.81 (d, J¼9.1 Hz,
2H, Ar), 7.14–7.31 (m, 7H, Ar); 13C NMR (50.3 MHz,
CDCl3): d 13.8, 20.4, 27.9, 54.4, 55.3, 58.3, 114.2, 118.1,
4.2.26. 3-Octyl-1-(4-methoxyphenyl)-4-phenylazetidin-2-
one (9d). Yield 94%; thick oil [Found: C, 78.67; H, 8.39; N,

D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
2533
118.3, 127.1, 128.1, 128.5, 131.3, 135.1, 155.4, 167.6; MS
(m/z): 296 (M+1).
requires C, 70.14; H, 5.12; Cl, 9.00; N, 3.56%]; Rf (12%
1
EtOAc/Pet ether) 0.4; nmax (CHCl3) 1757 cmꢂ1; H NMR
(200 MHz, CDCl3): d 3.70 (s, 3H, Ar–OCH3), 3.76 (s, 3H,
Ar–OCH3), 5.50 (s, 1H, C4H), 6.65 (d, J¼8.8 Hz, 2H, Ar),
6.82 (d, J¼8.7 Hz, 2H, Ar), 7.12–7.34 (m, 9H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 55.1, 55.4, 72.7, 113.9, 114.3,
119.3, 124.9, 125.1, 128.1, 128.6, 128.8, 130.2, 132,
156.6, 159.8, 161.7; MS (m/z): 394 (M+1).
4.2.31. 3-Isopropyl-1,4-bis(4-methoxyphenyl)azetidin-2-
one (9i). Yield 92%; white solid, mp 124–126 ꢀC [Found:
C, 73.79; H, 7.07; N, 4.27; C20H23NO3: requires C, 73.82;
H, 7.12; N, 4.30%]; Rf (14% EtOAc/Pet ether) 0.4; nmax
1
(CHCl3) 1731 cmꢂ1; H NMR (200 MHz, CDCl3): d 0.49
a
(d, J¼6.3 Hz, 3H, CH3–CH–bCH3), 1.15 (d, J¼6.5 Hz,
3H, aCH3–CH–bCH3), 1.52–1.79 (m, 1H, aCH3–CH–bCH3),
3.17 (dd, J¼5.5, 11.2 Hz, 1H, C3H), 3.73 (s, 3H, Ar–OCH3),
3.80 (s, 3H, Ar–OCH3), 5.06 (d, J¼5.5 Hz, 1H, C4H), 6.74
(d, J¼9.1 Hz, 2H, Ar), 6.81 (d, J¼8.7 Hz, 2H, Ar), 7.23 (d,
J¼8.6 Hz, 2H, Ar), 7.30 (d, J¼9.2 Hz, 2H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 20.6, 20.9, 25.7, 55.2, 55.4, 58.2,
62, 114, 114.2, 114.5, 127, 127.2, 128.4, 131.3, 155.7,
159.7, 167.2; MS (m/z): 326 (M+1).
Acknowledgements
The authors thank Department of Science and Technology
(DST), New Delhi, for financial support.
References and notes
€
4.2.32. 3-Isopropyl-1-(4-methoxyphenyl)-4-phenylazeti-
din-2-one (9j). Yield 95%; white solid, mp 153–154 ꢀC
[Found: C, 77.21; H, 7.11; N, 4.76; C19H21NO2: requires
C, 77.26; H, 7.17; N, 4.74%]; Rf (16% EtOAc/Pet ether)
1. For reviews on b-lactam antibiotics, see: (a) Durkheimer, W.;
Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180–202; (b) Chemistry and
Biology of b-Lactam Antibiotics; Morin, R. B., Gorman, M.,
Eds.; Academic: New York, NY, 1982; Vols. 1–3; (c)
Coulton, S.; Hunt, E. Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products;
Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621; (d)
Southgate, R. Contemp. Org. Synth. 1994, 1, 417–431.
2. The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
3. For comprehensive general reviews, see: (a) Koppel, G. A.
Small Ring Heterocycles; Hasner, A., Ed.; Wiley: New York,
NY, 1983; Vol. 42, p 219; (b) Backes, J. Houben–Weyl,
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Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.,
Eds.; Pergamon: Oxford, 1996; Vol. 1B, p 507.
0.5; nmax (CHCl3) 1737 cmꢂ1
;
1H NMR (200 MHz,
a
CDCl3): d 0.57 (d, J¼6.6 Hz, 3H, CH3–CH–bCH3), 1.12
(d, J¼6.7 Hz, 3H, aCH3–CH–bCH3), 1.63–1.76 (m, 1H,
aCH3–CH–bCH3), 3.17 (dd, J¼5.7, 11.2 Hz, 1H, C3H),
3.67 (s, 3H, Ar–OCH3), 5.01 (d, J¼5.7 Hz, 1H, C4H),
6.74 (d, J¼9.0 Hz, 2H, Ar), 6.81–7.30 (m, 7H, Ar); 13C
NMR (50.3 MHz, CDCl3): d 20.4, 24.9, 25.4, 55.4, 58.7,
62, 114.2, 114.5, 127.3, 127.6, 128.4, 131.3, 159.7, 167.2;
MS (m/z): 296 (M+1).
4.2.33. 1,4-Bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-
azetidin-2-one (9k). Yield 94%; white solid, mp 90–93 ꢀC
[Found: C, 77.57; H, 6.62; N, 3.49; C26H27NO3: requires
C, 77.78; H, 6.78; N, 3.49%]; Rf (10% EtOAc/Pet ether)
0.3; nmax (CHCl3) 1741 cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 1.18–1.66 (m, 4H, PhCH2(CH2)2), 2.35–2.49
(m, 2H, PhCH2(CH2)2), 3.46–3.57 (m, 1H, C3H), 3.75 (s,
3H, Ar–OCH3), 3.83 (s, 3H, Ar–OCH3), 5.11 (d,
J¼5.7 Hz, 1H, C4H), 6.78 (d, J¼9.1 Hz, 2H, Ar), 6.90 (d,
J¼8.9 Hz, 2H, Ar), 7.00–7.27 (m, 9H, Ar); 13C NMR
(50.3 MHz, CDCl3): d 24.9, 28.8, 35.6, 54.4, 55.2, 55.3,
57.9, 114.0, 114.1, 118.3, 125.6, 126.6, 127.1, 128.2,
131.2, 141.7, 155.7, 159.4, 167.4; MS (m/z): 402 (M+1).
4. (a) Ojima, I. The Chemistry of b-Lactams; Georg, G. I., Ed.;
VCH: New York, NY, 1993; p 197 and references cited therein;
(b) Palomo, C.; Aizpurua, J.; Ganboa, I. Enantioselective
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4.2.34. 1-(4-Methoxyphenyl)-4-phenyl-3-(3-phenylpro-
pyl)azetidin-2-one (9l). Yield 95%; white solid, mp 115–
117 ꢀC [Found: C, 80.58; H, 6.69; N, 3.49; C25H25NO2: re-
quires C, 80.83; H, 6.78; N, 3.77%]; Rf (10% EtOAc/Pet
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1
ether) 0.3; nmax (CHCl3) 1739 cmꢂ1; H NMR (200 MHz,
CDCl3): d 1.21–1.62 (m, 4H, PhCH2(CH2)2), 2.36–2.45
(m, 2H, PhCH2(CH2)2), 3.49–3.60 (m, 1H, C3H), 3.74 (s,
3H, Ar–OCH3), 5.15 (d, J¼5.8 Hz, 1H, C4H), 6.79 (d,
J¼9.1 Hz, 2H, Ar), 6.97 (d, J¼8.9 Hz, 2H, Ar), 7.16–7.35
(m, 10H, Ar); 13C NMR (50.3 MHz, CDCl3): d 24.7, 28.9,
35.7, 54.5, 55.3, 57.9, 114.0, 114.1, 118.3, 125.6, 126.6,
127.1, 128.2, 129.5, 131.2, 141.7, 159.4, 167.4; MS (m/z):
372 (M+1).
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[Found: C, 70.07; H, 5.07; Cl, 8.92; N, 3.46; C23H20ClNO3:

2534
D. K. Tiwari et al. / Tetrahedron 63 (2007) 2524–2534
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€
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