A simple and direct synthesis of 3-methylene-1, 4-diarylazetidin-2-ones and (E)-3-arylidene-1-phenylazetidin-2-ones using baylis-hillman derivatives

Article abstract of DOI:10.1071/CH13382

Herein we describe a direct method, promoted by potassium tert-butoxide (KOtBu), for the synthesis of highly substituted α-methylene β-lactams and α-arylidene β-lactams from the amino ester intermediates derived from the acetates and bromo derivatives of

Full text of DOI:10.1071/CH13382

CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 295–301
Full Paper
http://dx.doi.org/10.1071/CH13382
A Simple and Direct Synthesis of 3-Methylene-1,
4-diarylazetidin-2-ones and (E)-3-Arylidene-1-
phenylazetidin-2-ones Using Baylis Hillman Derivatives
]
A B C
, ,
B
Manickam Bakthadoss,
Jayakumar Srinivasan,
B
and Raman Selvakumar
A
Department of Chemistry, Pondicherry University, Puducherry 605 014, India.
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai 600 025, India.
B
C
Corresponding author. Email: bhakthadoss@yahoo.com
Herein we describe a direct method, promoted by potassium tert-butoxide (KOtBu), for the synthesis of highly substituted
a-methylene b-lactams and a-arylidene b-lactams from the amino ester intermediates derived from the acetates and
bromo derivatives of the Baylis–Hillman adducts. A variety of b-lactams was synthesized in a single step with good yields.
Manuscript received: 30 July 2013.
Manuscript accepted: 14 October 2013.
Published online: 2 December 2013.
Introduction
without hydrolyzing the ester group. Therefore, we planned to
directly connect the ester moiety and amino group (which is
present in the b-position) in an intramolecular fashion using
KOtBu in a shorter synthetic sequence to obtain a-methylene
b-lactam 4 from the amino ester 3 (Table 1). We also envisage
that the a-arylidene b-lactam 7 can be easily achieved from
the amino ester 6 (Table 2). According to the retro-synthetic
strategy, Baylis–Hillman adducts can be easily converted into
the corresponding substituted amino ester 3 by an SN20 reaction.
The amino ester 3 can be easily converted into the corresponding
a-methylene b-lactam 4 by direct intramolecular cyclization.
Similarly, the amino ester 6 can be easily synthesized from the
bromo derivative of Baylis–Hillman adducts by an SN2 reaction,
and a direct lactamization of an amino group with an ester group
in an intramolecular fashion will lead to the desired a-arylidene
b-lactam 7 core as described in Scheme 1.
The b-lactam moiety is an important integral part of many natural
products and biologically active molecules, the latter being
mostly antibiotics and serine protease inhibitors.[1] Penicillins,
carbapenems, cephalosporins, and monobactams are some of
the b-lactam core-containing antibacterials which have been
used therapeutically to date (Fig. 1). Apart from clinical use,
b-lactams can also serve as good synthons in the synthesis of
many biologically active heterocycles.[2]
In recent years, the Baylis–Hillman reaction has emerged as a
powerful synthetic tool for the synthesis of diverse classes of
multifunctional molecules.[3] Baylis–Hillman adducts can be
used as synthons to obtain a wide variety of natural products and
biologically active molecules.[4] We have been working on the
application of Baylis–Hillman adducts[5] with a view to demon-
strate that Baylis–Hillman chemistry is a powerful tool for the
synthesis of various important and useful structural frameworks.
Due to the multifunctionality present in Baylis–Hillman
adducts, the opportunity for converting them into a new class
of cyclic compounds is high and is very attractive in the field of
organic chemistry. Although Baylis–Hillman adducts have been
utilised for numerous applications,[6] the transformation of
Baylis–Hillman adducts into b-lactam is very limited.[7] All
the literature methods available for the formation of b-lactams
involves lactamization, achieved by the coupling of amino and
ester groups which is a two step process: the ester group is
hydrolyzed to an acid moiety followed by the coupling of
acid and amino groups in an intramolecular fashion to obtain
the b-lactam core moiety.
R2
H
N
H
N
R
R1
O
CH3
CH3
OH
S
O
R3
N
O
CO2H
O
Penicillins
Carbapenems
R
H
N
H
N
H
N
CH3
R2
S
O
O
N
R1
O
O
SO3H
CO2H
Cephalosporins
Results and Discussion
Monobactams
We envisaged that an amino group and ester moiety could be
directly cyclized using potassium tert-butoxide (KOtBu)
Fig. 1. b-Lactam antibacterials currently in use.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

296
M. Bakthadoss, J. Srinivasan, and R. Selvakumar
Table 1. Synthesis of a-methylene b-lactams 4a j from methyl 2-(aryl (phenylamino)methyl)acrylates 3a j
]
]
Lactamization was performed using KOtBu as a base in single step
R2
R2
1. DABCO
OAc
O
CO2Me
NH
H2N
R2
N
2.
KOtBu
R1
CO2Me
R1
Dry THF
0ЊC,1h
THF/rt/1h
2a–f
R1
4a–j
3a–j
R
1 ϭ H, 4-Me, 4-Et,
4-iPropyl, 4-Cl, 4-F
R2 ϭ H, Me
Entry
Amino ester intermediatesA
YieldC [%]
b-Lactam productsB
YieldC,D [%]
O
N
NH
1
76
66
OCH3
4a
O
3a
O
N
Me
NH
OCH3
2
88
87
78
80
67
70
65
68
Me
O
4b
3b
Et
O
N
NH
OCH3
3
Et
4c
O
3c
Me
Me
O
N
NH
OCH3
4
Me
O
Me
3d
4d
Cl
O
N
NH
OCH3
5
Cl
4e
4f
O
3e
F
O
N
NH
OCH3
6
86
83
69
67
F
O
3f
Me
Me
O
OCH3
O
N
NH
7
3g
3h
4g
4h
Me
Me
Me
O
NH
OCH3
O
N
8
75
68
Me
(continued)

Synthesis of b-lactams
297
Table 1. (Continued)
Entry
Amino ester intermediatesA
YieldC [%]
b-Lactam productsB
YieldC,D [%]
Me
Me
NH
OCH3
O
O
N
Me
Me
9
77
71
Me
3i
Me
4i
Me
Cl
Me
NH
OCH3
O
O
N
10
72
66
3j
Cl
4j
AAll reactions were carried out using 5 mmol of acetates 2a f.
]
BAll the reactions were carried out using 2.5 mmol of amino esters 3a j with 2.5 mmol of potassium tert-butoxide in dry THF (10 mL) for 1 h at 08C.
]
CYields of the pure products 3a j and 4a j obtained after column chromatography.
]
]
DAll the products gave satisfactory IR, 1H and 13C NMR, and mass spectra.
To execute our idea, we first selected methyl 2-(acetoxy
(phenyl)methyl)acrylate (2a), and treated it with 1,4-diazabi-
cyclo[2.2.2]octane (DABCO) in THF at room temperature for
15 min which led to the DABCO salt of Baylis–Hillman acetate.
To this DABCO salt, aniline was added and stirred at room
temperature for 1 h which successfully furnished the required
amino ester precursor, i.e. methyl 2-(phenyl(phenylamino)
methyl)acrylate (3a) in 76 % yield. Further treatment of amino
ester 3a with KOtBu in dry THF at 08C for 1 h successfully led to
the desired b-lactam, i.e. 3-methylene-1,4-diphenylazetidin-
2-one (4a) in 66 % yield (Entry 1, Table 1). Encouraged by this
substituted a-arylidene b-lactams 7b f in 63–72 % yields
(Entries 2–6, Table 2).
]
Conclusion
In conclusion, we have successfully developed a first general
method for the synthesis of both a-methylene b-lactams and
a-arylidene b-lactams in a single step with good yields using
Baylis–Hillman adducts. Comparatively, this method is very
simple and better than the methods already known in the
literature. Since the core unit of b-lactam is an integral part of
many biologically active molecules, the derivatives which we
have synthesized may also possess similar activity which will
be studied in our laboratory in the future.
result, we prepared a variety of amino esters using anilines 3b f
]
and treated them with KOtBu which successfully led to the
anticipated substituted a-methylene b-lactams 4b f in 65–70 %
]
yields (Entries 2–6, Table 1). To further extend the methodo-
logy, we also employed p-toluidine for the lactamization reac-
tion. Reaction of methyl 2-(acetoxy(aryl)methyl)acrylates 2a,
2b, 2d, and 2e, with DABCO in THF for 15 min led to the
corresponding DABCO salts. To these DABCO salts, p-tolui-
dine was added and the mixture stirred at room temperature for
Experimental
All reagents were purchased from commercial sources and used
without further purification. Solvents were distilled before use.
Column chromatography was performed on silica gel. IR spectra
were recorded on an FTIR-8300 Shimadzu spectrophotometer.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Bruker spectrometer using CDCl3 as solvent and
tetramethylsilane as an internal standard; chemical shifts are
reported in d (ppm). Mass spectra were recorded on a Jeol-
JMS-DX 303 HF mass spectrometer. Elemental analyses were
recorded on a Perkin–Elmer 240C-CHN analyzer. Melting
points are uncorrected. Thin-layer chromatography (TLC) was
performed using glass plates coated with silica gel (ACME,
254F). Spots were visualized using iodine vapour and UV lamp.
1 h which led to the anticipated amino esters 3g j in 72–83 %
]
yields. Further treatment of amino ester precursors 3g j with
]
KOtBu successfully provided the desired products, i.e. 3-meth-
ylene-4-aryl-1-p-tolylazetidin-2-ones 4g j in 66–71 % yields
]
(Entries 7–10, Table 1).
After successfully synthesizing an array of 3-methylene-
1,4-diarylazetidin-2-ones (4a j), we planned to utilise the same
]
protocol for the synthesis of (E)-3-benzylidene-1-phenylazeti-
din-2-one (7a) from (E)-methyl 2-((phenylamino)methyl)-
3-phenylacrylate (6a).
Treatment of (Z)-methyl 2-(bromomethyl)-3-phenylacrylate
(5a) with aniline in the presence of potassium carbonate in
CH3CN for 3 h led to the formation of required amino ester
precursor 6a in 79 % yield. The amino ester 6a was further
treated with KOtBu in dry THF at 08C for 1 h which success-
fully led to the desired (E)-3-benzylidene-1-phenylazetidin-
2-one (7a) in 65 % yield (Entry 1, Table 2). Encouraged by this
Methyl 2-(Phenyl(phenylamino)methyl)acrylate (3a):
Typical Procedure
To a stirred solution of methyl 2-(acetoxy(phenyl)methyl)
acrylate (2a) (1.17 g, 5 mmol) in THF (8 mL), DABCO (0.56 g,
5 mmol) was added and stirred at room temperature for 15 min.
To this solution aniline (0.47 g, 5 mmol) was added and stirred
for 1 h at room temperature. After completion of the reaction, as
monitored by TLC, the reaction mixture was evaporated under
result, we prepared a variety of amino ester precursors 6b f and
]
treated them with KOtBu which smoothly led to the desired

298
M. Bakthadoss, J. Srinivasan, and R. Selvakumar
Table 2. Synthesis of a-arylidene b-lactams 7a f from (E)-methyl 2-((phenylamino)methyl)-3-arylacrylates 6a f
]
]
Lactamization was performed using KOtBu as a base in single step
O
CO2Me
Br
CO2Me
NHPh
KOtBu
Aniline
R
R
R1
N
K2CO3
CH3CN
3h
Dry THF
0ЊC, 1h
7a–f
5a–f
6a–f
R1 ϭ H, 2-Me, 4-Me, 4-Et,
4-iPropyl, 2-OMe
Entry
Amino ester intermediatesA
YieldC [%]
b-Lactam productsB
YieldC,D [%]
CO2Me
O
N
H
N
1
79
65
7a
6a
Me
Me
O
CO2Me
H
N
N
2
74
63
7b
6b
CO2Me
H
O
N
Me
Et
N
Me
3
76
68
68
69
7c
6c
6d
CO2Me
O
H
N
N
Et
4
7d
CO2Me
O
Me
H
N
Me
N
Me
Me
5
6
66
77
64
72
7e
6e
OMe
OMe
O
CO2Me
H
N
N
7f
6f
AAll the reactions were carried out using 5 mmol of bromo derivatives (5a f).
]
BAll the reactions were carried out using 2.5 mmol of amino esters (6a–f) with 2.5 mmol of potassium tert-butoxide in dry THF (10 mL) for 1 h at 08C.
CYields of the pure products 6a f and 7a f obtained after column chromatography.
]
]
DAll the products gave satisfactory IR, 1H and 13C NMR, and mass spectra.
reduced pressure to remove THF. The crude mixture obtained
was diluted with water (10 mL) and extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure
which led to the crude product. The crude product thus obtained
was purified by column chromatography (with 4 % ethyl acetate
in hexanes) to afford the methyl 2-(phenyl(phenylamino)
methyl)acrylate (3a) as a colourless liquid.
129.18, 140.13140.66, 146.70, 166.68. nmax (KBr)/cmꢁ1 3389.35,
1714.64, 1629.58.
3-Methylene-1,4-diphenylazetidin-2-one (4a):
Typical Procedure
To a stirred solution of methyl 2-(phenyl(phenylamino)
methyl)acrylate (3a) (0.67 g, 2.5 mmol) in dry THF (10 mL),
KOtBu (0.37 g, 2.5 mmol) was added at 08C. The reaction
mixture was stirred for one hour at 08C and then THF was
removed under reduced pressure. The crude product thus
obtained was diluted with water (10 mL) and extracted with
ethyl acetate (3 ꢀ 10 mL). The combined organic layers were
washed with brine solution and dried over anhydrous Na2SO4.
Methyl 2-(Phenyl(phenylamino)methyl)acrylate (3a)
Yield: 76 %. Reaction time: 1 h. dH 3.71 (s, 3H), 4.15 (br
s, 1H), 5.42 (s, 1H), 5.97 (s, 1H), 6.39 (s, 1H), 6.56–7.39 (m, 10H).
dC 51.90, 58.99, 113.48, 117.94, 126.18, 127.52, 127.81, 128.77,

Synthesis of b-lactams
299
OAc
OH
CO2Me
Br
CO2Me
CO2Me
Acetylation
Bromination
R1
R1
R1
1
5
2
H2N
R2
H2N
R2
SN2Ј
SN2
R2
CO2Me
O
Direct
lactamization
O
Direct R1
NH
N
R1
lactamization
NH
N
CO2Me
6
R1
R1
3
7
4
Scheme 1. Retro-synthetic strategy for a-methylene b-lactams and a-arylidene b-lactams.
Solvent was evaporated under reduced pressure and the crude
product thus obtained was purified by column chromatography
(with 20 % ethyl acetate in hexanes) which afforded the
3-methylene-1,4-diphenylazetidin-2-one (4a) as a colourless
solid.
4-(4-Chlorophenyl)-3-methylene-1-phenylazetidin-
2-one (4e)
Yield: 68 %. Reaction time:1 h. Mp152–1548C. dH (300 MHz,
CDCl3) 5.27 (s, 1H), 6.01 (s, 1H), 6.58 (s, 1H), 6.86–7.35
(m, 9H). dC (75 MHz, CDCl3) 58.09, 113.61, 118.43, 128.89,
128.99, 129.10, 129.27, 133.78, 138.87, 139.29, 146.27,
170.91. nmax (neat)/cmꢁ1 1684, 1600. m/z 269 (Mþ). Anal. Calc.
for C16H12ClNO: C 71.25, H 4.48, N 5.19. Found: C 71.21,
H 4.43, N 5.23.
3-Methylene-1,4-diphenylazetidin-2-one (4a)
Yield:66%. Reactiontime:1 h.Mp121–1238C. dH (300 MHz,
CDCl3) 5.31 (s, 1H), 5.98 (s, 1H), 6.45–7.29 (m, 11H).
dC (75 MHz, CDCl3) 58.65, 113.57, 118.16, 127.59, 127.95,
128.68, 128.84, 129.23, 139.55, 140.35, 146.52, 171.38. nmax
(neat)/cmꢁ1 1685, 1602. m/z 235 (Mþ). Anal. Calc. for
C16H13NO: C 81.68, H 5.57, N 5.95. Found: C 81.61, H 5.49,
N 6.06 %.
4-(4-Fluorophenyl)-3-methylene-1-phenylazetidin-
2-one (4f)
Yield:69%. Reactiontime: 1 h. Mp158–1608C. dH (300 MHz,
CDCl3) 5.29 (s, 1H), 5.98 (s, 1H), 6.46–7.28 (m, 10H). dC
(75 MHz, CDCl3) 58.06, 113.72 (d, J 66), 115.54, 115.85,
116.14, 118.46 (d, J 69), 129.28, 131.90 (d, J 36), 143.96,
146.36, 147.37, 172.47. nmax (neat)/cmꢁ1 1232, 1592, 1627,
1697, 3254. m/z 253 (Mþ). Anal. Cal. for C16H12FNO: C 75.88,
H 4.78, N 5.53. Found: C 75.93, H 4.71, N 5.61 %.
3-Methylene-1-phenyl-4-p-tolylazetidin-2-one (4b)
Yield:67%. Reactiontime:1 h.Mp136–1388C. dH (300 MHz,
CDCl3) 2.33 (s, 3H), 5.34 (s, 1H), 6.04 (s,1H), 6.51–7.25
(m, 10H). dC (75 MHz, CDCl3) 21.14, 58.35, 113.53, 118.06,
127.55, 128.43, 129.23, 129.54, 137.39, 137.72, 139.61,
146.58, 171.67. nmax (neat)/cmꢁ1 1686, 1600. m/z 249 (Mþ).
Anal. Calc. for C17H15NO: C 81.90, H 6.06, N 5.62. Found:
C 81.95, H 6.12, N 5.59 %.
3-Methylene-4-phenyl-1-p-tolylazetidin-2-one (4g)
Yield:67%. Reactiontime: 1 h. Mp126–1288C. dH (300 MHz,
CDCl3) 2.23 (s, 3H), 5.24 (s, 1H), 5.94 (s, 1H), 6.40–7.14
(m, 10H). dC (75 MHz, CDCl3) 20.01, 57.27, 112.45, 116.98,
126.42, 127.31, 128.12, 128.42, 136.30, 136.60, 138.54, 145.48,
170.64. nmax (neat)/cmꢁ1 1237, 1592, 1635, 1717, 3284. m/z 249
(Mþ). Anal. Calc. for C17H15NO: C 81.90, H 6.06, N 5.62.
Found: C 81.86. H 6.09. N 5.68 %.
4-(4-Ethylphenyl)-3-methylene-1-phenylazetidin-
2-one (4c)
Yield:70%. Reactiontime:1 h.Mp140–1428C. dH (300 MHz,
CDCl3) 1.15 (t, 3H, J 7.5), 2.56 (q, 2H, J 7.5), 5.27 (s, 1H), 6.01
(s, 1H), 6.46 (s, 1H), 6.55–7.21 (m, 9H). dC (75 MHz, CDCl3)
15.38, 28.49, 58.67, 113.81, 118.35, 127.60, 128.31,
128.36, 129.21, 137.35, 139.48, 144.05, 146.26, 171.22. nmax
(neat)/cmꢁ1 1686, 1627. m/z 263 (Mþ). Anal. Calc. for
C18H17NO: C 82.10, H 6.51, N 5.32. Found: C 82.06, H 6.55,
N 5.28 %.
3-Methylene-1,4-dip-tolylazetidin-2-one (4h)
Yield:68%. Reactiontime: 1 h. Mp134–1368C. dH (300 MHz,
CDCl3) 2.23 (s, 3H), 2.33 (s, 3H), 5.29 (s, 1H), 6.02 (s, 1H),
6.48–7.25 (m, 9H). dC (75 MHz, CDCl3) 20.38, 21.09, 58.79,
113.78, 127.43, 127.47, 128.33, 129.48, 129.70, 137.49, 137.64,
139.72, 144.24, 171.16. nmax (neat)/cmꢁ1 1234, 1486, 1621,
1700, 3381. m/z 263 (Mþ). Anal. Calc. for C18H17NO: C 82.10,
H 6.51, N 5.32. Found: C 82.14, H 6.48, N 5.27 %.
4-(4-Isopropylphenyl)-3-methylene-1-phenylazetidin-
2-one (4d)
Yield:65%. Reactiontime:1 h.Mp148–1518C. dH (300 MHz,
CDCl3) 1.16 (d, 6H, J 6.9), 2.82 (sep, 1H, J 6.9), 5.26 (s, 1H),
6.01 (s, 1H), 6.52 (s, 1H), 6.70–7.26 (m, 9H). dC (75 MHz,
CDCl3) 23.95, 33.80, 58.32, 113.50, 118.03, 126.91, 127.57,
128.41, 129.22, 137.64, 139.54, 146.57, 148.64, 171.71. nmax
(neat)/cmꢁ1 1683, 1625. m/z 277 (Mþ). Anal. Calc. for
C19H19NO: C 82.28, H 6.90, N 5.05. Found: C 82.32, H 6.95,
N 5.08 %.
4-(4-Isopropylphenyl)-3-methylene-1-p-tolylazetidin-
2-one (4i)
Yield:71%. Reactiontime: 1 h. Mp155–1578C. dH (300 MHz,
CDCl3) 1.24 (d, 6H, J 6.9), 2.23 (s, 3H), 2.89 (sep, 1H, J 6.9),
5.31 (s, 1H), 6.03 (s, 1H), 6.49–7.28 (m, 9H). dC (75 MHz,
CDCl3) 20.37, 23.90, 33.76, 59.00, 113.90, 126.86, 127.45,

300
M. Bakthadoss, J. Srinivasan, and R. Selvakumar
128.30, 129.70, 130.18, 137.98, 139.60, 144.02, 148.43, 170.26.
n
(E)-3-(2-Methylbenzylidene)-1-phenylazetidin-
2-one (7b)
max (neat)/cmꢁ1 1236, 1485, 1594, 1706, 3436. m/z 291 (Mþ).
Anal. Calc. for C20H21NO: C 82.44, H 7.26, N 4.81. Found: C
82.38, H 7.31. N 4.87 %.
Yield: 63 %. Reaction time: 1 h. Mp 122–1248C. dH
(300 MHz, CDCl3) 2.27 (s, 3H), 4.12 (s, 2H), 6.42–7.34 (m,
9H), 8.07 (s, 1H). dC (75 MHz, CDCl3) 19.97, 40.82, 113.95,
118.31, 126.01, 128.98, 129.14, 129.46, 130.34, 133.91, 137.38,
144.09, 147.20, 173.06. nmax (KBr)/cmꢁ1 1234, 1511, 1630,
1711, 3244. m/z 249 (Mþ). Anal. Calc. for C17H15NO: C 81.90,
H 6.06, N 5.62. Found: C 81.92, H 6.09, N 5.58 %.
4-(4-Chlorophenyl)-3-methylene-1-p-tolylazetidin-
2-one (4j)
Yield:66 %. Reactiontime:1 h.Mp160–1628C. dH (300MHz,
CDCl3) 2.23 (s, 3H), 5.32 (s, 1H), 6.02 (s, 1H), 6.47–7.32
(m, 9H). dC (75 MHz, CDCl3) 20.38, 58.46, 113.83, 127.75,
128.88, 128.95, 129.77, 131.06, 133.68, 139.03, 139.44, 143.98,
170.66. nmax (neat)/cmꢁ1 1242, 1590, 1600, 1716, 3434. m/z 283
(Mþ). Anal. Calc. for C17H14ClNO: C 71.96, H 4.97, N 4.94.
Found: C 71.92, H 4.92, N 4.96 %.
(E)-3-(4-Methylbenzylidene)-1-phenylazetidin-
2-one (7c)
Yield: 68 %. Reaction time: 1 h. Mp 112–1148C. dH
(300 MHz, CDCl3) 2.38 (s, 3H), 4.15 (s, 2H), 6.57–7.47 (m,
9H), 8.05 (s, 1H). dC (75 MHz, CDCl3) 21.45, 41.02, 113.71,
118.17, 128.40, 129.55, 129.91, 130.26, 131.69, 140.04, 145.10,
147.67, 172.93. nmax (KBr)/cmꢁ1 1266, 1606, 1631, 1710, 3289.
m/z 249 (Mþ). Anal. Calc. for C17H15NO: C 81.90, H 6.06, N
5.62. Found: C 81.94, H 6.08, N 5.67 %.
(E)-Methyl 2-((Phenylamino)methyl)-3-phenylacrylate
(6a): Typical Procedure
To a stirred solution of aniline (0.47 g, 5 mmol) in dry
CH3CN (15 mL), potassium carbonate (1.04 g, 7.5 mmol) was
added and stirred well at room temperature. To this solution,
(Z)-methyl 2-(bromomethyl)-3-phenylacrylate (5a) (1.27 g,
5 mmol) in dry CH3CN (10 mL) was added drop wise and stirred
at room temperature for 3 h. After completion of the reaction, the
reaction mixture was evaporated under reduced pressure to
remove CH3CN. The crude mixture obtained was diluted with
water (10 mL) and extracted with ethyl acetate (3 ꢀ 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
the solvent was evaporated under reduced pressure which led to
the crude product. The crude product was purified by column
chromatography (4 % ethyl acetate in hexanes) to afford
(E)-methyl 2-((phenylamino)methyl)-3-phenylacrylate (6a) as
a pale yellow liquid.
(E)-3-(4-Ethylbenzylidene)-1-phenylazetidin-2-one (7d)
Yield: 69 %. Reaction time: 1 h. Mp 136–1388C. dH
(300 MHz, CDCl3) 1.25 (t, 3H, J 7.5), 2.68 (q, 2H, J 7.5), 4.17
(s, 2H), 6.58–7.43 (m, 9H), 8.00 (s, 1H). dC (75 MHz, CDCl3)
15.34, 28.81, 41.07, 113.79, 118.20, 127.48, 128.40, 129.26,
130.09, 131.92, 145.33, 146.39, 147.66, 173.40. nmax (KBr)/
cmꢁ1 1237, 1600, 1625, 2217, 3415. m/z 263 (Mþ). Anal. Calc.
for C18H17NO: C 82.10, H 6.51, N 5.32. Found: C 82.15, H 6.55,
N 5.36 %.
(E)-3-(4-Isopropylbenzylidene)-1-phenylazetidin-
2-one (7e)
Yield: 64 %. Reaction time: 1 h. Mp 135–1378C. dH
(300 MHz, CDCl3) 1.26 (d, 6H, J 6.9), 2.93 (sep, 1H, J 6.9),
4.16 (s, 2H), 6.58–7.44 (m, 9H), 8.00 (1H). dC (75 MHz, CDCl3)
23.80, 34.08, 41.03, 113.74, 118.23, 126.98, 129.24, 130.12,
132.00, 145.37, 147.66, 151.01, 172.00. nmax (KBr)/cmꢁ1 1246,
1490, 1590, 2210, 3248. m/z 277 (Mþ). Anal. Calc. for
C19H19NO: C 82.28, H 6.90, N 5.05. Found: C 82.32, H 6.87,
N 5.09 %.
Yield: 79 %. Reaction time: 3 h. dH 3.83 (s, 3H), 4.13 (br
s, 3H), 6.51–7.46 (m, 10H), 7.89 (s, 1H). dC 41.00, 52.20,
113.47, 117.89, 128.73, 129.18, 129.25, 129.32, 129.56,
134.81, 142.88, 147.78, 168.19. nmax (KBr)/cmꢁ1 3393.60,
1717.79, 1629.58.
(E)-3-Benzylidene-1-phenylazetidin-2-one (7a):
Typical Procedure
To a stirred solution of (E)-methyl 2-((phenylamino)meth-
yl)-3-phenylacrylate (6a) (0.67 g, 2.5 mmol) in dry THF
(10 mL), KOtBu was added (0.37 g, 2.5 mmol) at 08C. The
reaction mixture was stirred for 1 h at 08C and then THF was
removed under reduced pressure. The crude mass obtained
was diluted with water (10 mL) and extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic layer was washed with
brine and was dried over anhydrous Na2SO4. Solvent was
evaporated under reduced pressure and the crude product thus
obtained was purified by column chromatography (15 % ethyl
acetate in hexanes) which afforded the (E)-3-benzylidene-
1-phenylazetidin-2-one (7a) as a yellow solid.
(E)-3-(2-Methoxybenzylidene)-1-phenylazetidin-
2-one (7f)
Yield: 72 %. Reaction time: 1 h. Mp 134–1368C. dH
(300 MHz, CDCl3) 3.86 (s, 3H), 4.10 (s, 2H), 6.55–7.41 (m,
9H), 8.16 (s, 1H). dC (75 MHz, CDCl3) 41.39, 55.56, 110.71,
113.84, 118.18, 120.66, 123.66, 128.19, 129.16, 130.34, 131.21,
141.13, 147.66, 157.83, 173.07. nmax (KBr)/cmꢁ1 1239, 1495,
1600, 2210, 3228. m/z 265 (Mþ). Anal. Calc. C17H15NO2: C
76.96, H 5.70, N 5.28. Found: C 76.92. H 5.73, N 5.31 %.
Supplementary Material
1H and 13C NMR spectra for compounds 3a, 4a j, 6a and 7a f
are available on the Journal’s website.
]
]
(E)-3-Benzylidene-1-phenylazetidin-2-one (7a)
Yield:65 %. Reactiontime:1 h.Mp144–1468C. dH (300MHz,
CDCl3) 4.17 (s, 2H), 6.52–7.48 (m, 10H), 8.03 (s, 1H).
dC (75 MHz, CDCl3) 41.05, 113.83, 118.40, 128.33, 128.80,
129.22, 129.63, 129.72, 134.48, 145.00, 147.46, 172.13. nmax
(KBr)/cmꢁ1 1234, 1487, 1599, 1722, 3426. m/z 235 (Mþ). Anal.
Calc. for C16H13NO: C 81.68, H 5.57, N 5.95. Found: C 81.72,
H 5.61. N 5.91 %.
Acknowledgements
The authors thank the Department of Science and Technology-Science and
Engineering Research Board (DST-SERB) New Delhi, India, for financial
support. The authors also thank the Department of Science and Technology-
Fund for Improvement of S&T Infrastructure (DST-FIST) for use of the
NMR facility. J.S. and R.S. thank the Council of Scientific & Industrial
Research (CSIR) for their Senior Research Fellowship.

Synthesis of b-lactams
301
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