β-Lactam derivatives as potential anti-cancer compounds

Article abstract of DOI:10.1007/s00706-007-0838-4

A number of 1,4-diaryl-3-methylene substituted β-lactams, the addition products obtained from their reactions with N-, S-, and C-nucleophiles, and diverse related compounds were prepared, and a selection of 43 compounds was screened in preliminary tests a

Full text of DOI:10.1007/s00706-007-0838-4

Monatsh Chem 139, 847–857 (2008)
DOI 10.1007/s00706-007-0838-4
Printed in The Netherlands
b-Lactam derivatives as potential anti-cancer compounds
Sabine Ruf, Gerd Neudert, Susanne Gu¨rtler, Renate Gru¨nert, Patrick J. Bednarski, Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University, Greifswald, Germany
Received 21 October 2007; Accepted 27 October 2007; Published online 9 June 2008
# Springer-Verlag 2008
Abstract A number of 1,4-diaryl-3-methylene substi-
tuted ꢀ-lactams, the addition products obtained from
their reactions with N-, S-, and C-nucleophiles, and
diverse related compounds were prepared, and a se-
lection of 43 compounds was screened in preliminary
tests as anti-tumor compounds by using 4 or 5 human
cancer cell lines of diverse origins. Twelve com-
pounds were highly active against all cell lines, 6
showed low activity, 12 no activity, and 13 exhibited
a selective activity against a human small cell lung
carcinoma cell line.
[4] and studied their properties as elastase inhibitors.
During the last decade a few papers were published
reporting on the cytotoxicity and anticancer activity
of ꢀ-lactams [5]. Extending our research in this field,
we describe herein preliminary results concerning
substituted ꢀ-lactams and some derivatives thereof
and their biological evaluation regarding their activ-
ity against tumor cell lines [6].
Results and discussion
Keywords ꢀ-Lactams; Anti-cancer compounds.
Chemistry
As starting material for most syntheses substituted
(RS)-1,4-diphenylazetidin-2-ones (1) were used.
These were transformed either via the 3-trimethyl-
silyl compounds (2) and their reaction with carbonyl
compounds in the presence of LDA or BuLi or via
the aldols (3, Table 1) obtained by reaction with al-
dehydes followed by dehydration into the substituted
3-methylene derivatives (4, Table 2). These com-
pounds were isolated as mixtures of the E- and Z-
diastereoisomers, and were either separated and the
diastereoisomers or the mixtures were tested.
Compounds 4 allowed nucleophilic additions of
C-, N-, or S-nucleophiles at C-3 of the ꢀ-lactam
ring if at least one of the substituents R0 and R00 is
an electron withdrawing group, yielding compounds
of the general structure 5 and the oxidation products
6 (Table 3). From a few reactions we obtained dif-
ferent products. When 4o and 4s reacted under iden-
Introduction
The ꢀ-lactam ring is known as an important struc-
tural part of the highly active and clinically useful
ꢀ-lactam antibiotics [1]. Apart from clinical use as
antibacterials, ꢀ-lactams serve as synthons in the
synthesis of other biological active heterocycles [2],
and in many examples the biological activity can be
interpreted as an interaction between the ꢀ-lactam
ring and a serine containing enzyme (serine prote-
ase) like elastase [3]. Therefore, the search for clini-
cal useful ꢀ-lactams is a growing field of interest.
We have described a number of ꢀ-lactam derivatives
Correspondence: Hans-Hartwig Otto, Department of Pharma-
ceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany.
E-mail: ottohh@pharmazie.uni-greifswald.de

848
S. Ruf et al.
Table 1 1,4-Diaryl-3-(subst.-ꢂ-hydroxybenzyl)-ꢀ-lactams and
ꢀ
migration of the amine from the quaternary C-atom
to the lactam carbonyl group. 7 was prepared by
cycloaddition of maleinimide [7a], 8 according to
Ref. [7b], 9a and 9b by epoxidation and 10 by car-
ben addition to the exocyclic double bond [7c]. Two
products, 14 and 15, obtained as rearrangement prod-
ucts from the reaction of 3-methylidene ꢀ-lactams
with hydrazines [7c] were included in the biological
testing.
diverse compounds
Cpd. R
R0
Mol. formula
Mol.
weight
Ref.
3a
3b
3c
7
H
Br
Br
CH¼CH–Ph C24H19NO2
353.42 [6d]
453.30 [6d]
4-O2N–Ph
2-O2N–Ph
C22H17BrN2O4
C22H17BrN2O4
C24H22N2O4
C17H18N2O4S
C23H23NO7
453.29
–
402.45 [6a]
346.41 [6b]
425.44 [6c]
455.47 [6c]
423.47 [6c]
8
9a
9b
10
11
12
13a
13b
14
15
H
MeO
C24H25NO8
C24H25NO6
C24H23BrN2O3 467.36
C27H24BrF3N2O2 545.39
C34H39N3O3
C32H35N3O5
C15H17N3O5
C27H25N3O5
Biology
–
–
–
–
With the goal of obtaining information on the poten-
tial antitumor activity of the new compounds, all com-
pounds were tested at a concentration of 20 ꢁM in an
in vitro screening method with the following human
cancer cell lines of diverse origins: 5637 (urinary
bladder carcinoma), RT-4 (urinary bladder carci-
noma), A-427 (lung carcinoma), LCLC-103H (large
cell lung carcinoma), and compounds 4n–4z were
additionally tested against MCF-7 (breast adenocar-
cinoma). The method has been previously described
and validated in [8], and the results are summarized
in Tables 4 and 5. Values are the averages from 2 to
5 independent experiments.
537.70
541.65
319.32 [6c]
471.52 [6c]
ꢀ
Cpds without a ref. see ‘Experimental’ of this paper
tical conditions with morpholine, we isolated the
products 11 and 12 formed by an attack of the nu-
cleophile to the carbonyl group and not to the double
bond. The 2-butene derivatives 13a and 13b were
formed from 5l to 5m by an attack of the amine
to the ester group followed by a ring opening with

ꢀ-Lactam derivatives as potential anti-cancer compounds
849
A first interpretation of the obtained values yield-
ed the following four groups of compounds. No ac-
tivity against all cell lines was found for compounds
3a, 4g, (Z)-4j, 4k, 5q, 6b, 7, 8, 9a, 9b, 9b, 10, 14,
and 15 (Table 4); the data in Table 5 also showed no
activity for compounds (Z)-4o, (Z)-4t, (Z)-4u, (Z)-
4w, and (Z)-4y. We do not intend to continue study-
ing these compounds. A high activity against all cell
lines was exhibited by 3b, 4a, (E)-4n, 5a, 5b, 5c, 5d,
5e, 5y, and 5z (Table 4); a similar result was found in
Table 5 for compounds (Z)-4n, (Z)-4p, (Z)-4q, and,
less clear, (Z)-12. This high activity against all cell
lines might be interpreted as an indication for gener-
al toxicity. The remaining compounds seem to form
the most interesting group, as they exhibited a dif-
ferentiated behavior, i.e., we found growth inhibitory
effects only against one cell line, the small cell lung
cancer line A-427. Compounds (Table 4) (E)-4b,
(Z)-4l, (Z)-4m, 5f, 5m, 5n, 5o, and 5u exhibited a
significant effect only against this cell line. A similar
effect was seen for compounds 4u, 4x, (Z)-4z, and
(Z)-11 in Table 5 in A-427 cells. A fourth group of

850
S. Ruf et al.
ꢀ
Table 2 1,4-Diaryl-3-(subst. methylene)-ꢀ-lactams (4)
Cpd.
R
R0
R00
Mol. formula
Mol. weight
Ref.
(Z)-4a
(E)-4b
4c
4d
4e
4f
4g
4h
4i
MeO
MeO
H
MeO
MeO
MeO
MeO
MeO
MeO
H
MeO
MeO
MeO
MeO
Br
MeO
Br
Br
CHO
H
H
1-propenyl
Ph
Ph
Me
Me
CONHPh
Me
Ph
H
1-pyrrolidinyl
Ph
Me
2-furyl
H
5-O2N-2-furyl
C19H17NO3
C20H19NO2
C24H19NO3
C25H21NO4
C20H19NO4
C25H22N2O3
C30H24N2O3
C25H28N2O3
C31H26N2O3
C18H17NO
C21H22N2O2
C25H21NO4
C20H19NO4
307.35
305.38
369.42
399.45
227.38
398.47
460.54
404.51
474.56
263.34
334.42
399.45
337.38
331.37
380.24
376.36
425.23
396.30
458.27
386.40
435.27
459.13
424.72
435.27
459.16
424.72
[6b]
[6a]
[6e]
[6e]
[6e]
–
–
–
–
[6e]
[6e]
[6e]
[4]
–
–
–
–
–
–
–
–
–
–
–
–
–
CO2CH3
CO2CH3
CO2CH3
CONHPh
Ph
CONHC6H11
CONHBn
Et
(Z)-4j
4k
H
(Z)-4l
(Z)-4m
(E)-4n
(Z)-4o
(E)-4p
(Z)-4q
(Z)-4r
4sꢀꢀ
(Z)-4t
4uꢀꢀ
(E)-4v
(Z)-4w
4x
CO2CH3
CO2CH3
H
2-furyl
H
5-O2N-2-furyl
2-thienyl
H
4-O2N–Ph
H
C21H17NO3
C20H14BrNO2
C21H16N2O5
C20H13BrN2O4
C20H14BrNOS
C23H15BrF3NO
C23H18N2O4
C22H15BrN2O3
C20H13Br2NO2
C22H15BrClNO
C22H15BrN2O3
C22H14BrCl2NO
C22H15BrClNO
H
H
4-F3C–Ph
H
4-O2N–Ph
5-Br-2-furyl
H
H
H
H
Br
MeO
Br
Br
Br
Br
H
4-Cl–Phe
2-O2N–Phe
2,4-di–Cl–Phe
2-Cl–Phe
(Z)-4y
(Z)-4z
Br
Br
ꢀ
ꢀꢀ
Cpds without a ref. see ‘Experimental’ of this paper.
E=Z-mixture
paratus series 7000 Merck Hitachi, LiChrospher 250-4, RP-18,
5 ꢁm, LiChroCART 250-4 (S,S)-Whelk-O1, 5 ꢁm, and DIA-
CEL+ ChiraCel+ OJ–RTM, 5 ꢁm. HPLC experiments were
done using a)MeCN=H2O (7=3) or b)MeCN=H2O (4=1) and
detection by UV if not noted otherwise.
two compounds, (Z)-4o and (Z)-4r, showed a mod-
erate growth inhibitory effect against the cell line
5637. Comparing the values of (E)-4n (Table 4) with
those of (Z)-4n (Table 5) one might suggest, at least
in this example, that the (Z)-isomer is the slightly
more active form. In a following paper (in prepara-
tion) one of us will report on potency studies with
detailed IC50 values and studies about a possible
mechanism of action.
THF was stored with KOH, then refluxed with Na and ben-
zophenone, and distilled prior to use. Other solvents were
dried=purified according to literature procedures. LDA (lithi-
um diisopropylamide) was freshly prepared by mixing of
equivalent amounts of freshly distilled diisopropylamine and
n-BuLi (15% in hexane) at ꢁ78ꢂC.
Abbreviations: AcOEt¼ Ethyl acetate; CTMS Chlorotri-
methylsilane; PE Petroleum ether; ar ¼ Aromatic.
Experimental
The following compounds were prepared according to
literature: (RS)-1,4-diphenylazetidin-2-one (1a) [9], (RS)-
General
1-(4-Methoxyphenyl)-4-phenylazetidin-2-one
(1b)
[10],
Mp Mel-Temp-II Laboratory Devices Inc., USA. IR Spectra:
Perkin-Elmer FTIR 1600; in KBr (cmꢁ1), if not noted other-
wise. NMR Spectra: Bruker WP 80 (80 MHz), DPX 200
(200 MHz), WM 400 (400 MHz) for 1H and DPX 200
(50 MHz) for 13C; ꢃ (ppm) rel. to TMS as internal standard;
values from DPX 200 (200=50 MHz) spectra in CDCl3, if not
noted otherwise. MS: M40 AMD Intectra, EI 70eV. Elemen-
tary analyses: Perkin-Elmer Analyzer 2400 CHN, Pharmazeu-
(RS)-1-(4-Bromophenyl)-4-phenylazetidin-2-one (1c), cis-1,4-
Diphenyl-3-(trimethylsilyl)azetidin-2-one (2a), cis-1-(4-Me-
thoxyphenyl)-4-phenyl-3-(trimethylsilyl)azetidin-2-one (2b)
[7b], cis-1-(4-Bromophenyl)-4-phenyl-3-(trimethylsilyl)azeti-
din-2-one (2c) [7h], (Z=E)-3-(Furan-2-ylmethylene)-1-(4-me-
thoxyphenyl)-4-phenylazetidin-2-one (4n) [7b].
Reaction of 2 with carbonyl compounds. General procedure
At ꢁ78ꢂC, a solution of 2 in THF (1cm3=mmol) was added
drop by drop with stirring to a solution of 2 equivalents LDA
¨
tisches Institut der Universitat Greifswald. All compounds
gave satisfactory elemental analyses. Column chromatography
(CC): Silica gel 60 (Merck 7734). HPLC with LaChrom ap-

ꢀ-Lactam derivatives as potential anti-cancer compounds
851
ꢀ
Table 3 ꢀ-Lactams of structure 5
Cpd.
Structure
Nu
Mol. formula
Mol. weight
Ref.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
A
A
A
A
A
B
B
B
B
C
Bꢀꢀ
B
B
D
C
B
B
B
C
B
B
B
A
A
A
B
C
S
NH–NH–Ph
NH–NH–CO2Me
CH(CO2Me)(CH2)2SMe
S–Ph
C29H31N3O6
C25H29N3O8
C29H36N2O8S
C29H29NO6S
C26H31NO6S
C31H36N2O4
C37H44N2O4
C29H32N2O4
C29H30N2O4
C24H28N2O4
C29H30N2O3
C30H32N2O4
C29H30N2O5
C34H33N3O3
C26H25NO4S
C28H29NO4S
C28H27NO4S
C29H29NO6S
C24H27NO6S
C29H31NO4S
C29H31NO4S
C29H31NO4
C23H26N2O6
C27H32N2O7
C29H29NO8S
C29H29NO8S
C26H25NO6S
C24H27NO8S
517.59
499.53
572.68
519.62
485.60
500.64
580.77
472.59
470.57
408.50
454.57
484.60
486.57
531.66
447.56
475.61
473.60
519.62
457.55
489.64
489.64
457.57
426.47
496.57
551.62
551.62
479.56
489.55
[6f]
[6c]
[6c]
[6c]
[6c]
–
–
–
–
–
–
–
–
–
–
–
–
–
S–CHMe2
N(CHMe2)2
N(C6H11)2
NEt2
pyrrolidino
pyrrolidino
piperidino
piperidino
4-morpholino
pyrrolidino
S-Ph
S–CHMe2
S–CH2–CH¼CH2
S–(CH2)2–CO2Me
S–(CH2)2–CO2Me
S–CMe3
S–Bu
Bu
NH2
4-morpholino
SO2–Ph
SO2–(CH2)2CO2Me
SO2Ph
SO2–(CH2)2–CO2Me
–
–
–
5t
5u
5v
5y
5z
6a
6b
6c
6d
[6e]
[6e]
–
–
–
–
ꢀ
ꢀꢀ
Cpds without a ref. see ‘Experimental’ of this paper.
Ar ¼ Ph
in THF. After 15min, an equivalent amount of the carbonyl
compounds (freshly distilled or a solution in THF) was added
slowly and with stirring. Stirring was continued until the mix-
ture was warmed to room temperature (ca. 1 h); a solution of
NH4Cl was added until pH 7.5–8 was reached. The organic
layer was separated, the aqueous layer was extracted (2–
3ꢃ) with AcOEt, the combined organic layers were dried
(Na2SO4), evaporated in vacuo, and the residue was purified
as noted below.
EtOH); IR:
(CO), 1589, 1522, 1491 (NO2) cmꢁ1; 1H NMR (DMSO-d6):
ꢄꢀ¼ 3334 (OH), 3036, 2934, 2850 (CH), 1717
3
3
ꢃ ¼ 3.47 (ddd, J3;ꢂ ¼ 3.7, J3;4 ¼ 2.6, 5J3;OH ¼ 0.7 Hz, 3-H),
3
3
3
5.46 (d, J4;3 ¼ 2.6 Hz, 4-H), 5.64 (dd, Jꢂ;OH ¼ 4.8, Jꢂ;3
¼
3
3
3.7 Hz, ꢂ-H), 6.35 (dd, JOH;ꢂ ¼ 4.8, JOH;3 ¼ 0.7 Hz, OH),
3
4
7.12–7.31 (m, 7 ar H), 7.50 (dd, J ¼ 6.8, J ¼ 2.1 Hz, 2 ar
H), 7.55 (m, 40-H), 7.84 (ddd, 3J ¼ 7.8, 3J ¼ 7.6, 4J ¼ 1.3 Hz,
50-H), 7.94 (dd, 3J ¼ 8.1, J ¼ 1.3 Hz, 30-H), 8.19 (dd,
4
3J ¼ 7.8, J ¼ 1.3 Hz, 60-H) ppm; 13C NMR (DMSO-d6):
4
ꢃ ¼ 54.86 (C-3), 64.13 (C-4), 65.62 (C–OH), 115.32,
118.54, 124.24, 126.03, 126.98, 127.19, 128.04, 128.75,
128.86, 128.98, 131.92, 132.12, 133.35, 133.62, 136.29,
137.37, 137.66, 146.81 (C–NO2), 164.54 (CO) ppm; HPLC:
RP-18b): t0 ¼ 1.83 min, k0 ¼ 4.18, lmax ¼ 331.4 nm.
1-(4-Bromophenyl)-3-[hydroxy(2-nitrophenyl)methyl]-4-
phenylazetidin-2-one (3c, C22H17BrN2O4)
From 1.9 g (5 mmol) 2c and 7.5 g (50 mmol) 2-nitrobenzal-
dehyde. Yield 1.3 g (58%); yellow crystals; mp 230ꢂC (dec.,

852
S. Ruf et al.
(Z=E)-1-(4-Bromophenyl)-3-(furan-2-ylmethylene)-4-
Table 4 Cell growth relative to untreated controls=% after
application of 20 ꢁM compounds 3a–15 for 96 h
phenylazetidin-2-one (4o, C20H14BrNO2)
From 6 g (16 mmol) 2c and 15cm3 (160mmol) furfural as 4n.
Ratio of isomers (HPLC) E=Z 1:1. Yield 3.2 g (42%); light
yellow crystals; mp (Z): 206–207ꢂC (MeOH), (E): 178–183ꢂC
(MeOH); IR: ꢄꢀ¼ 3144, 3033 (CH), 1889, 1804, 1724 (CO),
Cell lines
Compounds
5637
RT-4
A-427
LCLC-103H
1
4
1687 (C¼C) cmꢁ1; H NMR (Z): ꢃ ¼ 5.37 (d, J4;ꢂ ¼ 1.0 Hz,
3a
3b
4a
(E)-4b
4g
(Z)-4j
4k
(Z)-4l
(Z)-4m
(E)-4n
5a
5b
5c
5d
5e
5f
5m
5n
5o
5q
5u
5y
5z
6b
7
8
9a
9b
10
14
15
81
0
79
ꢁ5
ꢁ5
79
88
91
93
60
79
7
ꢁ6
ꢁ6
ꢁ6
ꢁ6
ꢁ6
41
31
64
39
50
32
ꢁ8
ꢁ8
74
93
102
94
87
84
98
97
10
ꢁ5
ꢁ3
ꢁ4
56
52
48
ꢁ4
8
46
3
4
5
4-H), 6.24 (dd, Jꢂ;4 ¼ 1.0, Jꢂ;F4 ¼ 0.6 Hz, ꢂ-H), 6.50 (ddd,
3
5
3JF4;F3 ¼ 3.5, JF4;F5 ¼ 1.8, JF4;ꢂ ¼ 0.6Hz, 4-HF), 7.20–7.30
ꢁ3
ꢁ2
74
76
81
65
44
67
9
(m, 3-HF, 1 ar H), 7.47 (dd, 3JF5;F4 ¼ 1.8, 4JF5;F3 ¼ 0.6 Hz, 5-
90
91
4
HF), 7.30–7.44 (m, 8 ar H) ppm; (E): ꢃ ¼ 5.66 (d, J4;ꢂ
¼
3
3
95
80
56
83
1.4 Hz, 4-H), 6.35 (dd, JF4;F3 ¼ 3.4, JF4;F5 ¼ 1.7 Hz, 4-HF),
6.44 (d, 3JF3;F4 ¼ 3.4 Hz, 3-HF), 6.91 (d, 4Jꢂ;4 ¼ 1.4 Hz, ꢂ-H),
3
7.51 (d, JF5;F4 ¼ 1.7 Hz, 5-HF), 7.15–7.58 (m, 9 ar H) ppm;
13C NMR (Z): ꢃ ¼ 62.44 (C-4), 112.68 (C-4F), 114.72 (C-3F),
116.56 (C–Br), 117.06 (C-ꢂ), 118.37, 126.70, 129.02, 129.26,
132.19, 136.45, 136.91, 137.42, 144.13 (C-5F), 150.12 (C-2F),
159.97 (CO) ppm; (E): ꢃ ¼ 64.43 (C-4), 112.24, 112.82
(C-4F), 114.98 (C-3F), 116.43 (C–Br), 117.06 (C-ꢂ), 118.41,
126.71, 127.76, 128.82, 128.91, 132.12, 136.35, 136.81,
137.78, 144.78 (C-5F), 149.64 (C-2F), 161.96 (CO) ppm;
HPLC (Z) RP-18a): t0 ¼ 1.79 min, k0 ¼ 11.73, lmax ¼ 341.1 nm;
RP-18b): t0 ¼ 1.83min, k0 ¼ 3.43; (E) RP-18a): t0 ¼ 1.79 min,
k0 ¼ 7.35, lmax ¼ 333.8nm; RP-18b): t0 ¼ 1.83min, k0 ¼ 2.36.
6
1
ꢁ3
ꢁ3
ꢁ3
ꢁ3
ꢁ3
23
33
54
61
90
ꢁ5
ꢁ5
ꢁ5
ꢁ5
ꢁ5
ꢁ4
ꢁ1
8
ꢁ2
ꢁ2
ꢁ2
ꢁ2
ꢁ2
33
31
42
65
57
44
ꢁ3
ꢁ3
85
65
90
73
74
72
90
91
2
14
3
(Z=E)-1-(4-Bromophenyl)-3-(5-nitrofuran-2-ylmethylene)-4-
phenylazetidin-2-one (4p, C21H16N2O5)
26
ꢁ3
ꢁ3
98
ꢁ5
ꢁ5
64
81
89
81
92
42
112
114
From 1.6 g (5mmol) 2b and 2 g (14 mmol) 5-nitro-2-furfural.
CC (n-hexane=CH2Cl2 1=1). Yield 150mg (8%); orange crys-
tals, >90% (Z); mp 180–183ꢂC (MeOH); IR: ꢄꢀ¼ 3113, 2927,
2836 (CH), 1731 (CO), 1610 (C¼C), 1582, 1573 (NO2), 1510,
97
107
104
107
78
93
96
1
1474, 1380, 1353 (NO2), 1245 (OMe) cmꢁ1; H NMR (Z):
4
ꢃ ¼ 3.76 (s, OMe), 5.45 (d, J4;ꢂ ¼ 1.1 Hz, 4-H), 6.24 (dd,
4Jꢂ;4 ¼ 1.1, Jꢂ;F4 ¼ 0.5 Hz, ꢂ-H), 6.83 (dd, 3J ¼ 6.8, 4J ¼
4
2.3 Hz, 2 ar H), 7.32 (dd, 3J ¼ 6.8, 4J ¼ 2.3 Hz, 2 ar H),
3
5
7.37 (dd, JF4;F3 ¼ 3.9, JF4;ꢂ ¼ 0.5Hz, 4-HF), 7.37–7.43 (m,
5 ar H), 7.83 (d, 3JF3;F4 ¼ 3.9Hz, 3-HF) ppm; (E): ꢃ ¼ 3.75 (s,
4
OMe), 5.80 (d, J4;ꢂ ¼ 1.4 Hz, 4-H), 6.56 (d, J ¼ 3.7 Hz, 3-
3
4
4
HF), 6.80 (dd, J ¼ 6.8, J ¼ 2.3 Hz, 2 ar H), 6.83 (d, Jꢂ;4
¼
Table 5 Cell growth relative to untreated controls=% after appli-
cation of 20 ꢁM compounds 4n–4z, (Z)-11, and (Z)-12 for 96 h
3
1,4 Hz, ꢂ-H), 7.23 (d, JF4;F3 ¼ 3.7 Hz, 4-HF), 7.31 (dd,
3J ¼ 6.8, J ¼ 2.3 Hz, 2 ar H), 7.27–7.40 (m, 5 ar H), 7.63–
4
7.70 (m, 2 ar H) ppm; 13C NMR: (Z): ꢃ ¼ 55.49 (OMe), 62.70
(C-4), 113.79, 114.66, 115.89, 118.60 (C-ꢂ), 126.62, 129.34,
129.39, 130.77, 135.62, 145.92 (C-2F), 152.16 (C-4F), 156.82
(C-5F), 158.26 (CO) ppm; (E): ꢃ ¼ 55.47 (OMe), 64.53 (C-4),
109.12, 113.12, 114.59, 115.42, 118.68 (C-ꢂ), 128.05, 128.92,
129.14 ppm; HPLC (Z) RP-18a): t0 ¼ 1.78min, k0 ¼ 5.45,
lmax ¼ 384.3 nm; (E) RP-18a): t0 ¼ 1.78min, k0 ¼ 3.50.
5637 RT-4 A-427 LCLC-103H MCF-7
(Z)-4n
(Z)-4o
(Z)-4p
(Z)-4q
(Z)-4r
(Z)-4s
(Z)-4t
(Z)-4u
4u
(Z)-4v
(Z)-4w
4x
(Z)-4y
(Z)-4z
(Z)-11
(Z)-12
ꢁ2
10
ꢁ4
ꢁ3
8
64
85
42
55
76
63
94
72
48
54
21
ꢁ11
63
ꢁ9
ꢁ14
85
93
85
85
81
47
79
88
81
85
78
15
ꢁ2
67
ꢁ4
ꢁ4
59
11
30
15
8
ꢁ1
70
2
33
8
0
56
ꢁ3
ꢁ3
68
76
82
61
59
60
83
90
81
72
57
1
ꢁ1
23
8
ꢁ14
74
70
56
54
47
18
82
53
77
64
27
2
(Z)-1-(4-Bromophenyl)-3-(5-nitrofuran-2-ylmethylene)-4-
phenylazetidin-2-one (4q, C20H13BrN2O4)
From 1.87 g (5mmol) 2c and 3.5 g (25 mmol) 5-nitro-2-fural-
dehyde as 4p. CC (n-Hexane=CH2Cl2 2=1). Yield 340 mg
(16%); yellow crystals; mp ca. 250ꢂC (dec., MeOH); IR:
ꢄꢀ¼ 3154, 1724 (CO), 1632 (C¼C), 1586, 1574 (NO2), 1518,
1489, 1354 (NO2) cmꢁ1; 1H NMR: ꢃ ¼ 5.47 (d, 4J4;ꢂ ¼ 1.1 Hz,
4
5
4-H), 6.29 (dd, Jꢂ;4 ¼ 1.1, Jꢂ;F4 ¼ 0.6 Hz, ꢂ-H), 7.20–7.30
6
ꢁ2
3
(m, 5 ar H), 7.34–7.47 (m, 5 ar H, 4-HF), 7.81 (d, JF3;F4
¼
4.0 Hz, 1H, 3-HF) ppm; 13C NMR: ꢃ ¼ 62.76 (C-4), 113.65,

ꢀ-Lactam derivatives as potential anti-cancer compounds
853
114.91, 116.20 (C–Br), 117.64 (C-3F), 118.69 (ꢂ-CH), 126.56,
129.53, 129.57, 132.41, 135.12, 136.21, 145.26 (C-2Furan),
151.75 (C-4F), 159.83 (CO) ppm; HPLC RP-18a): t0 ¼ 1.79 min,
(31%); yellow needles; mp 179ꢂC (MeOH, (Z)); IR: ꢄꢀ¼
3108, 3064, 2934, 2907, 2838 (CH), 1806, 1730 (CO), 1594
1
(C¼C), 1512, 1467, 1382, 1340 (NO2) cmꢁ1; H NMR (Z):
k0 ¼ 10.76, lmax ¼ 377.0 nm; RP-18b): t0 ¼ 1.83 min, k0 ¼ 2.99;
ꢃ ¼ 3.76 (s, OMe), 5.41 (d, J4;ꢂ ¼ 1.0Hz, 4-H), 6.29 (d,
4
a)
3
4
0
0
ChiralCel OJ–R : t0 ¼ 2.01 min, k1 ¼ 4.47, k2 ¼ 4.90.
4Jꢂ;4 ¼ 1.0 Hz, ꢂ-H), 6.83 (dd, J ¼ 7.0, J ¼ 2.2 Hz, 2 ar H),
7.34 (dd, 3J ¼ 7.0, 4J ¼ 2.2 Hz, 2 ar H), 7.37–7.47 (m, 5 ar H),
3
4
3
8.16 (dd, J ¼ 6.8, J ¼ 2.5 Hz, 2 ar H), 8.23 (dd, J ¼ 6.8,
(Z=E)-1-(4-Bromophenyl)-4-phenyl-3-(thien-2-ylmethylene)-
azetidin-2-one (4r, C20H14BrNOS)
4J ¼ 2.5 Hz, 2 ar H) ppm; (E): ꢃ ¼ 3.75 (s, OMe), 5.73 (d,
4J4;ꢂ ¼ 1.4Hz, 4-H), 7.15 (d, Jꢂ;4 ¼ 1.4 Hz, ꢂ-H), 6.75–7.58
4
From 6 g (16 mmol) 2c and 14.5cm3 (160mmol) thiophene-
2-carbaldehyde. First the (Z)-isomer was obtained by crystal-
lization of the residue from propanol, then the filtrate was
evaporated in vacuo, and the residue crystallized from MeOH.
Yield 2.1 g (33%); mp (Z) 248ꢂC (Propanol); light yellow
crystals; mp (E) 224ꢂC (MeOH); light yellow plats; IR:
ꢄꢀ¼ 3082, 3031, 2962 (CH), 1885, 1725 (CO), 1678 (C¼C)
(m, 9 ar H), 8.05 (dd, 3J ¼ 7.0, 4J ¼ 1.9 Hz, 2 ar H), 8.09 (dd,
3J ¼ 7.0, J ¼ 1.9 Hz, 2 ar H) ppm; 13C NMR (Z): ꢃ ¼ 55.49
4
(OMe), 62.59 (C-4), 114.61, 118.59, 123.89, 126.78, 127.27,
127.89, 129.15, 129.34, 130.59, 136.32, 140.11, 145.25,
147.76 (C–NO2), 156.69 (C–OMe), 158.92 (CO) ppm; HPLC
(Z) RP-18a): t0 ¼ 1.79 min, k0 ¼ 8.09, lmax ¼ 363.7 nm; RP-
18b): t0 ¼ 2.40min, k0 ¼ 2.07; (E) RP-18a): t0 ¼ 1.79 min,
k0 ¼ 3.97, lmax ¼ 363.7nm, RP-18b): t0 ¼ 2.40 min, k0 ¼ 1.00.
1
4
cmꢁ1; H NMR (Z): ꢃ ¼ 5.38 (d, J4;ꢂ ¼ 1.2 Hz, 4-H), 6.43
3
3
(dd, ꢂ-H), 7.06 (dd, JT4;T5 ¼ 5.1, JT4;T3 ¼ 3.7 Hz, 4-HT),
7.20–7.44 (m, 9 ar H), 7.43 (dd, 3JT5;T4 ¼ 5.1 Hz, 5-HT), 7.72
(Z=E)-1-(4-Bromophenyl)-3-(4-nitrobenzylidene)-4-
phenylazetidin-2-one (4u, C22H15BrN2O3)
3
4
(ddd, JT3;T4 ¼ 3.7 Hz, 3-HT) ppm; (E): ꢃ ¼ 5.58 (d, J4;ꢂ
¼
3
3
1.6 Hz, 4-H), 6.95 (dd, JT4;T5 ¼ 5.1, JT4;T3 ¼ 3.7 Hz, 4-HT),
7.09 (ddd, 3-HT), 7.20–7.44 (m, 9 ar H), 7.56 (d, 4Jꢂ;4 ¼ 1.6 Hz,
Hz, ꢂ-H), 7.59 (m, 5-HT) ppm; 13C NMR (Z): ꢃ ¼ 62.48 (C-
4), 116.58 (C–Br), 118.39 (C-ꢂ), 122.00, 126.76, 128.09,
129.02, 129.28, 129.66, 131.81, 132.19, 136.52, 136.92,
137.26, 137.72, 160.12 (CO) ppm; (E): ꢃ ¼ 64.28 (C-4),
116.50 (C–Br), 118.32, 118.39 (C-ꢂ), 118.89, 126.76, 127.76,
128.49, 128.53, 129.06, 129.27, 129.43, 129.85, 131.72, 132.12,
132.18, 135.22, 136.63, 136.79, 137.79, 162.12 (CO) ppm;
HPLC (Z) RP-18a): t0 ¼ 1.79 min, k0 ¼ 14.76, lmax ¼ 341.1 nm;
From 3.74g (10 mmol) 2c and 15g (100mmol) 4-nitrobenzal-
dehyde. Ratio of isomers (HPLC) Z=E 2:1. Yield 2.9 g (66%);
yellow crystals; mp 230–233ꢂC (MeOH, (Z)); IR: ꢄꢀ¼ 3105,
3041, 2936, 2852 (CH), 1807, 1715 (CO), 1598 (C¼C), 1520,
1
1488, 1375, 1343 (NO2) cmꢁ1; H NMR (Z): ꢃ ¼ 5.44 (d,
4
4J4;ꢂ ¼ 1.1Hz, 4-H), 6.35 (d, Jꢂ;4 ¼ 1.1 Hz, ꢂ-H), 7.23–7.47
3
4
(m, 9 ar H), 8.15 (dd, J ¼ 6.9, J ¼ 2.3 Hz, 2 ar H), 8.24
(dd, 3J ¼ 6.9, 4J ¼ 2.3 Hz, 2 ar H) ppm; (E): ꢃ ¼ 5.74 (d,
4
4J4;ꢂ ¼ 1.5Hz, 4-H), 7.20 (d, Jꢂ;4 ¼ 1.5 Hz, ꢂ-H), 7.21–7.57
(m, 11 ar H), 8.07 (dd, 3J ¼ 6.9, 4J ¼ 1.9 Hz, 2 ar H) ppm; 13
C
RP-18b): t0 ¼ 1.83 min, k0 ¼ 4.19; ChiralCel OJ–Rb): t0 ¼
a)
0
0
NMR (Z): ꢃ ¼ 62.65 (C-4), 117.46, 118.71, 123.92, 126.72,
128.47, 129.37, 129.46, 129.55, 130.68, 132.35, 135.80,
136.38, 139.72, 144.72, 147.97 (C–NO2), 159.32 (CO) ppm;
(E): ꢃ ¼ 64.74 (C-4), 117.28, 118.57, 123.43, 123.84, 127.83,
129.90, 129.94, 132.29, 134.82, 139.02, 144.39, 147.87 (C–
NO2), 161.16 (CO) ppm; HPLC (Z) RP-18a): t0 ¼ 1.83 min,
k0 ¼ 6.74, lmax ¼ 346.3 nm; RP-18b): t0 ¼ 1.89 min, k0 ¼ 2.88;
(E) RP-18b): t0 ¼ 1.89 min, k0 ¼ 2.37, lmax ¼ 346.3nm.
1.89 min, k1 ¼ 2.72, k2 ¼ 3.39; (E) RP-18 : t0 ¼ 1.79 min,
k0 ¼ 10.70, lmax ¼ 338.6 nm; RP-18b): t0 ¼ 1.83 min, k0 ¼ 2.86.
(Z=E)-1-(4-Bromophenyl)-3-(4-trifluoromethylbenzylidene)-
4-phenylazetidin-2-one (4s, C23H15BrF3NO)
From 1.9 g (5mmol) 2c and 6.7 cm3 (50 mmol) 4-trifluoro-
methylbenzaldehyde. The residue was crystallized from
MeOH. The first fraction was pure (Z)-isomer, the following
fractions contained mixtures of (E)- and (Z)-isomer, ratio ca.
1:3. Yield 1.2g (53%); colorless crystals; mp (Z) 176.5ꢂC
(MeOH); IR: ꢄꢀ¼ 3059 (CH), 1807, 1734, 1720 (CO), 1616
(Z=E)-3-(5-Bromofuran-2-ylmethylene)-1-(4-bromophenyl)-
4-phenylazetidin-2-one (4v, C20H13Br2NO2)
From 430mg (1.15 mmol) 2c and 1 g (5.7mmol) 5-bromfur-
fural. On crystallization from MeOH first the (E)- and then
the (Z)-isomer was obtained. Yield 230mg (44%); yellow
brownish crystals; mp 180ꢂC (dec., (Z)); IR: ꢄꢀ¼ 3146, 2359
1
(C¼C) cmꢁ1; H NMR (Z): ꢃ ¼ 5.41 (d, 4J4;ꢂ ¼ 1.1 Hz, 4-H),
6.32 (m, ꢂ-H), 7.27 (dd, 2 ar H), 7.35–7.47 (m, 7 ar H), 7.63
(d, 3J ¼ 8.2 Hz, 2 ar H), 8.09 (d, 3J ¼ 8.2 Hz, 2 ar H) ppm; (E):
ꢃ ¼ 5.72 (d, 4J4;ꢂ ¼ 1.5 Hz, 4-H), 7.18 (d, 4Jꢂ;4 ¼ 1.5 Hz, ꢂ-H),
7.20–7.57 (m, 13 ar H) ppm; 13C NMR (Z): ꢃ ¼ 62.55 (C-4),
117.16 (C–Br), 118.51, 118.63, 125.51 (CF3), 125.66, 125.73,
126.66, 126.74, 129.22, 129.38, 129.56, 130.13, 130.84,
132.29, 136.15, 136.57, 142.98, 159.69 (CO) ppm; HPLC
(Z) RP-18a): t0 ¼ 1.69 min, k0 ¼ 23.51, lmax ¼ 322.6 nm; RP-
1
(CH), 1786, 1721 (CO), 1681 (C¼C) cmꢁ1; H NMR (Z):
4
4
ꢃ ¼ 5.37 (d, J4;ꢂ ¼ 1.1Hz, 4-H), 6.18 (dd, Jꢂ;4 ¼ 1.1,
5Jꢂ;F4 ¼ 0.6 Hz, ꢂ-H), 6.43 (dd, JF4;F3 ¼ 3.6, JF4;ꢂ ¼ 0.6 Hz,
3
5
4-HF), 7.15–7.43 (m, 9 ar H), 7.46 (d, 3JF3;F4 ¼ 3.6Hz, 3-HF)
4
3
ppm; (E): ꢃ ¼ 5.67 (d, J4;ꢂ ¼ 1.4 Hz, 4-H), 6.28 (d, JF3;F4
¼
3
3.5 Hz, 3-HF), 6.40 (d, JF4;F3 ¼ 3.5 Hz, 4-HF), 6.79 (d,
4Jꢂ;4 ¼ 1.4 Hz, ꢂ-H), 7.15–7.62 (m, 9 ar H); 13C NMR (Z):
ꢃ ¼ 62.38 (C-4), 118.38 (ꢂ-CH), 152.03, 159.71 (CO) ppm;
(E): ꢃ ¼ 64.37 (C-4), 118.45 (ꢂ-CH), 151.38, 161.55 (CO);
(Z=E): ꢃ ¼ 111.53, 114.06, 114.58, 115.99, 116.58, 116.73,
116.81, 116.91, 124.20, 125.56, 126.64, 128.02, 128.88,
128.91, 129.12, 129.30, 132.15, 132.22, 135.85, 136.16,
136.69, 136.76, 137.75, 138.76 ppm; HPLC (Z) (RP-18b): t0 ¼
1.83min, k0 ¼ 7.56, lmax ¼ 346.3nm; (E): (RP-18b): t0 ¼
1.83min, k0 ¼ 4.92, lmax ¼ 343.7 nm.
18b): t0 ¼ 1.83 min, k0 ¼ 7.56; ChiralCel OJ–Ra): t0 ¼ 2.01min,
a)
0
0
k1 ¼ 6.79, k2 ¼ 7.20; (E) RP-18 : t0 ¼ 1.69 min, k0 ¼ 11.61,
a)
0
UVmax ¼ 322.6nm; ChiralCel OJ–R : t0 ¼ 2.01min, k1 ¼
0
2.81, k2 ¼ 3.64.
(Z=E)-1-(4-Methoxyphenyl)-3-(4-nitrobenzylidene)-4-
phenylazetidin-2-one (4t, C23H18N2O4)
From 3.25 g (10 mmol) 2b and 15 g (100 mmol) 4-nitroben-
zaldehyde. Ratio of isomers (HPLC) Z=E 2:1. Yield 1.2 g

854
S. Ruf et al.
were dried (Na2SO4) and evaporated. The residue was crystal-
lized or purified by CC as noted.
(Z=E)-1-(4-Bromophenyl)-3-(4-chlorobenzylidene)-4-
phenylazetidin-2-one (4w, C22H15BrClNO)
From 1.9 g (5mmol) 2c and 7 g (50 mmol) 4-chlorobenzalde-
hyde. Yield 0.6 g (29%); colorless crystals; mp (Z) 234–235ꢂC
(2-Propanol); IR: ꢄꢀ¼ 3061, 2861 (CH), 1720 (CO), 1633
1-(4-Methoxyphenyl)-3-[ꢂ-(phenylcarbamoyl)ethylidene]-4-
phenylazetidin-2-one (4f, C25H22N2O3)
1
(C¼C) cmꢁ1; H NMR (Z): ꢃ ¼ 5.37 (d, 4J4;ꢂ ¼ 1.1 Hz, 4-H),
From (E)-4e (1.0 g, 2.9 mmol), aniline (0.93 g, 10 mmol), and
n-BuLi (6.3cm3, 10mmol). Yield 870 mg (76%); yellow crys-
tals; mp 188ꢂC (MeOH); IR: ꢄꢀ¼ 3255 (NH), 3130, 3060,
3040, 3017, 2990, 2965, 2930, 2840 (CH), 1740, 1640 (CO)
cmꢁ1; 1H NMR: ꢃ ¼ 2.40 (s, Me), 3.70 (s, MeO), 5.60 (s, 4-H),
6.98 (s, NH), 6.59–7.55 (m, 14 ar H).
6.24 (dd, ꢂ-H), 7.21–7.45 (m, 11 ar H), 7.93 (dd, J ¼ 6.7,
1.8 Hz, 2 ar H) ppm; 13C NMR: ꢃ ¼ 62.45 (C-4), 116.92,
118.39, 118.53, 126.74, 128.94, 129.09, 129.32, 130.03,
131.31, 132.24, 132.35, 135.73, 136.39, 140.88, 160.61 (CO)
ppm; HPLC (Z) RP-18b): t0 ¼ 2.40 min, k0 ¼ 7.53, lmax
¼
322.5 nm; (E)RP-18b):t0 ¼ 2.40 min, k0 ¼ 3.81, lmax ¼ 320.5 nm.
1-(4-Methoxyphenyl)-3-[ꢂ-(phenylcarbamoyl)benzylidene]-
4-phenylazetidin-2-one (4g, C30H24N2O3)
(Z)-1-(4-Bromophenyl)-3-(2-nitrobenzylidene)-4-
phenylazetidin-2-one (4x, C22H15BrN2O3)
From (E)-4d (1.0g, 2.51mmol), aniline (0.93 cm3, 10 mmol),
and n-BuLi (6.3cm3, 10mmol). Yield 980 mg (85%); yellow
crystals; mp 133ꢂC (MeOH); IR: ꢄꢀ¼ 3400, 3320 (NH), 3070,
3030, 3000, 2960, 2935, 2840 (CH), 1735, 1660 (CO), 1685
Themother liquor of 3cwas concentrated and thenrefluxed with
10% (m=m) conc. H3PO4 and ca. 1% (m=m) conc. H2SO4 with
˚
3 A mol. sieves for 2 h. After neutralization (Na2CO3) the
mixture was extracted with AcOEt, and the organic layer was
evaporated in vacuo. Mp 177–178ꢂC (MeOH); 1H NMR
(C¼C) cmꢁ1
;
6.61–7.83 (m, 19 ar H, NH).
1H NMR: ꢃ ¼ 3.67 (s, MeO), 5.73 (s, 4-H),
(DMSO-d6): ꢃ ¼ 5.88 (d, 4J4;ꢂ ¼ 1.5 Hz, 4-H), 6.86 (d, 4Jꢂ;4
¼
1.5 Hz, ꢂ-H), 7.20–7.60 (m, 9 ar H), 7.60–7.90 (m, 40-H, 50-
3-[ꢂ-(Cyclohexylcarbamoyl)ethylidene)]-1-(4-methoxy-
phenyl)-4-phenylazetidin-2-one (4h, C25H28N2O3)
3
4
0
0
0
0
0
H), 8.08 (dd, J3 ;4 ¼ 8.0, J3 ;5 ¼ 1.3 Hz, 3 -H), 8.26 (dd,
3
4
From (E)-4e (1.0g, 2.97 mmol), cyclohexylamine (1.18 g,
11.88 mmol), and n-BuLi (7.48 cm3, 11.88mmol). CC
(CHCl3). Yield 150 mg (12%); yellowish crystals; mp 98ꢂC
(MeOH); IR: ꢄꢀ¼ 3250 (NH), 3090, 3060, 3030, 2930, 2850
(CH), 1740, 1620 (CO) cmꢁ1; 1H NMR: ꢃ ¼ 0.73–1.69 (m, 11
cyclohexyl-H), 2.31 (s, Me), 3.70 (s, MeO), 5.25 (s, NH), 5.85
(s, 4-H), 6.68–7.50 (m, 9 ar H).
0
0
0
0
J6 ;5 ¼ 7.8, J6 ;4 ¼ 1.3 Hz) ppm; HPLC: ((S,S)-Whelk 01, n-
hexane=2-propanol 3=1): t0 ¼ 2.24 min, k01 ¼ 3.90, k02 ¼ 4.15,
lmax ¼ 336.1 nm.
(Z=E)-1-(4-Bromophenyl)-3-(2,4-dichlorobenzylidene)-4-
phenylazetidin-2-one (4y, C22H14BrCl2NO)
From 1 g (2.7 mmol) 2c and 3 g (17 mmol) 2,4-dichlorobenzal-
dehyde. Yield 210 mg (17%); colorless crystals; mp (Z) 212–
214ꢂC (2-Propanol); IR: ꢄꢀ¼ 3087, 3064, 3029 (CH), 1810,
3-[ꢂ-(Benzylcarbamoyl)benzylidene]-1-(4-methoxyphenyl)-
4-phenylazetidin-2-one (4i, C31H26N2O3)
1
1715 (CO), 1631 (C¼C) cmꢁ1; H NMR (Z): ꢃ ¼ 5.41 (d,
4J4;ꢂ ¼ 1.1 Hz, 4-H), 6.72 (dd, ꢂ-H), 7.18–7.50 (m, 10 ar H),
From (E)-4d (1.0g, 2.5 mmol), benzylamine (1.07 g,
10mmol), and n-BuLi (6.3cm3, 10mmol). CC (CHCl3). Yield
460 mg (39%); yellow crystals; mp 193ꢂC (MeOH); IR:
ꢄꢀ¼ 3340 (NH), 3080, 3030, 3000, 2860, 2940, 2840 (CH),
7.32 (d, J ¼ 8.5 Hz, 50-H), 8.67 (d, J ¼ 8.5 Hz, 60-H) ppm; (E):
4
ꢃ ¼ 5.65 (d, J4;ꢂ ¼ 1.5 Hz, 4-H), 7.02 (d, J ¼ 1.5 Hz, ꢂ-H),
7.02–7.50 (m, 11 ar H), 7.87 (d, J ¼ 8.5 Hz, 60-H) ppm; HPLC
(Z) RP-18b): t0 ¼ 1.90 min, k0 ¼ 14.94, lmax ¼ 326.9nm; (E)
RP-18b): t0 ¼ 1.90 min, k0 ¼ 7.20, lmax ¼ 322.6 nm.
1
1740, 1655 (CO), 1690 (C¼C) cmꢁ1; H NMR: ꢃ ¼ 3.64 (s,
MeO), 4.20 (d, J ¼ 7 Hz, CH2), 5.64 (t, NH), 5.75 (s, 4-H),
6.60–7.59 (m, 19 ar H).
(Z=E)-1-(4-Bromophenyl)-3-(2-chlorobenzylidene)-4-
phenylazetidin-2-one (4z, C22H15BrClNO)
3-(Diisopropylamino)-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5f, C31H36N2O4)
From 4d (1.0 g, 2.51 mmol), diisopropylamine (1.4 cm3,
10 mmol), and n-BuLi (6.3 cm3, 10 mmol). Yield 900 mg
(72%); colorless crystals; mp 175ꢂC (MeOH); IR: ꢄꢀ¼
3060, 3020, 2950, 2860, 2830 (CH), 1760–1720 (CO)
From 1 g (2.7 mmol) 2c and 3.5 cm3 (31 mmol) 2-chlorobenzal-
dehyde. Yield 220mg (19%); colorless crystals; mp 216ꢂC
(EtOH); IR: ꢄꢀ¼ 3060, 3025 (CH), 1814, 1717 (CO), 1678
(C¼C) cmꢁ1
;
1H NMR (Z): ꢃ ¼ 5.43 (d, J ¼ 1.2 Hz, 4-H),
6.81 (d, J ¼ 1.2 Hz, ꢂ-H), 8.68 (m, 60-H), 7.20–7.48 (m, 12 ar
H) ppm; 13C NMR (Z): ꢃ ¼ 114.14, 121.72, 127.99, 128.06,
128.27, 131.07, 137.61, 144.88ppm; HPLC (Z) RP-18b): t0 ¼
1.90 min, k0 ¼ 8.32, lmax ¼ 322.6 nm; (E) RP-18b): t0 ¼
1.90 min, k0 ¼ 4.38.
cmꢁ1
;
1H NMR (80 MHz): ꢃ ¼ 1.19–1.37 (m, 2CHMe2),
3.54, 3.70 (2s, 2MeO), 4.12 (s, ꢂ-H), 5.22 (s, 4-H), 6.55–
7.30 (m, 14 ar H).
3-(Dicyclohexylamino)-3-[ꢂ-(methoxycarbonyl)benzyl]-1-
(4-methoxyphenyl)-4-phenylazetidin-2-one (5g, C37H44N2O4)
From (Z)-4d (1.0g, 2.51mmol), dicyclohexylamine (1.8cm3,
10mmol), and n-BuLi (6.3cm3, 10 mmol). Yield 1.00 g (68%);
colorless crystals;mp181–182ꢂC (MeOH);IR:ꢄꢀ¼ 3060, 3030,
Reactions with amines. General procedure
Under N2 at ꢁ78ꢂC, n-BuLi was added to a solution of the
amine (freshly distilled) in THF, and after 15 min stirring, a
solution of 4 in THF was added drop by drop. After 30min,
the mixture was hydrolyzed with a solution of NH4Cl (60 g
dmꢁ3). The organic layer was separated, the aqueous layer
was 3ꢃ washed with CHCl3, the combined organic layers
2925, 2850 (CH), 1740 (CO) cmꢁ1 1H NMR (80 MHz):
;
ꢃ ¼ 1.01–2.05 (m, 22 cyclohexyl-H), 3.50, 3.69 (2s, 2MeO),
4.05 (s, ꢂ-H), 5.13 (s, 4-H), 6.63–7.31 (m, 14 ar H).

ꢀ-Lactam derivatives as potential anti-cancer compounds
855
4=1). Rf¼ 0.75. Yield a) 300mg (24%), b) 490 mg (39%); col-
orless crystals; mp 192ꢂC (MeOH); IR: ꢄꢀ¼ 3065, 3030, 2970,
2955, 2850 (CH), 1750, 1730 (CO) cmꢁ1; 1H NMR (80 MHz):
ꢃ ¼ 2.97 (m, 2CH2), 3.59–3.74 (m, 2CH2), 3.61, 3.67 (2s,
2MeO), 3.97 (s, ꢂ-H), 5.20 (s, 4-H), 6.70–7.31 (m, 14 ar H).
3-(Diethylamino)-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5h, C29H32N2O4)
From (Z)-4d (1.0 g, 2.51 mmol), diethylamine (740mg,
10mmol), and n-BuLi (6.3cm3, 10mmol). Yield 800 mg
(68%); colorless crystals; mp 112–114ꢂC (MeOH); IR:
ꢄꢀ¼ 3070, 3030, 2970, 2930, 2840 (CH), 1755–1745, 1720
1
(CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.07 (t, 2 Me), 2.75–
1-(4-Methoxyphenyl)-4-phenyl-3-[ꢂ-(phenylcarbamoyl)-
benzyl]-3-(pyrrolidin-1-yl)azetidin-2-one (5n, C34H33N3O3)
From 4g (500mg, 1.1 mmol), pyrrolidine (0.42 cm3, 5 mmol),
and n-BuLi (3.16 cm3, 5 mmol). Yield 233 mg (40%); color-
less crystals mp 212ꢂC (MeOH); IR: ꢄꢀ¼ 3390, 3260 (NH),
3.05 (m, 2CH2), 3.52, 3.67 (2s, 2MeO), 3.97 (s, ꢂ-H), 5.00
(s, 4-H), 6.66–7.26 (m, 14 ar H).
3-[ꢂ-(Methoxycarbonyl)benzyl]-1-(4-methoxyphenyl)-4-
phenyl-3-(pyrrolidin-1-yl)azetidin-2-one (5i, C29H30N2O4)
From a) (Z)-4d or b) (E)-4d (1.0g, 2.51mmol), pyrrolidine
(720 mg, 10.04 mmol), and n-BuLi (6.3cm3, 10ml). Yield a)
720 mg (61%), b) 550 mg (47%); colorless crystals; mp 166–
167ꢂC (MeOH); IR: ꢄꢀ¼ 3070, 3030, 2950, 2880, 2840, 2820
1
3130, 3060, 3030, 2970, 2830 (CH), 1735 (CO) cmꢁ1; H
NMR (80 MHz): ꢃ ¼ 1.50, 3.17 (2mc, 4CH2), 3.67 (s, MeO),
4.77 (s, ꢂ-H), 6.00 (s, 4-H), 6.55–7.80 (m, NH, 19 ar H).
Addition of S-nucleophiles. General procedure
At ꢁ78ꢂC, an equivalent amount of n-BuLi was added to the
thiol in 10cm3 THF, and after 15min stirring, the ꢀ-lactam 4
in 20cm3THF was added drop by drop. After 10min, the
mixture was hydrolyzed with a solution of NH4Cl (30 cm3,
60g dmꢁ3), the aqueous layer was once washed with CHCl3,
the organic layers were dried (Na2SO4) and evaporated.
1
(CH), 1755, 1735 (CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.85
(m, 2CH2), 2.80 (m, 2CH2), 3.60, 3.72 (2s, 2MeO), 3.99 (s, ꢂ-
H), 5.05 (s, 4-H), 6.67–7.35 (m, 14 ar H).
3-[ꢂ-(Methoxycarbonyl)ethyl]-1-(4-methoxyphenyl)-4-
phenyl-3-(pyrrolidin-1-yl)azetidin-2-one (5j, C24H28N2O4)
From (E=Z)-4e (800 mg, 2.37 mmol), pyrrolidine (0.84 cm3,
10mmol), and n-BuLi (6.32 cm3, 10mmol). Yield 520 mg
(54%); colorless crystals; mp 104ꢂC (MeOH); IR: ꢄꢀ¼ 3060,
3-[1-(Methoxycarbonyl)ethyl]-1-(4-methoxyphenyl)-4-
phenyl-3-(phenylthio)azetidin-2-one (5o, C26H25NO4S)
From thiophenol (1.2cm3, 10mmol), (Z)-4e (700 mg,
2.06mmol), and n-BuLi (3.15 ml, 5 mmol). Yield 600 mg
(65%); colorless crystals; mp 157–158ꢂC (MeOH); IR: ꢄꢀ¼
3055, 3030, 3000, 2950, 2930, 2900, 2830 (CH), 1740, 1725
3030, 3010, 2980, 2950, 2900, 2840 (CH), 1760 (CO) cmꢁ1
;
1H NMR (80 MHz): ꢃ ¼ 1.13 (d, J ¼ 7 Hz, Me), 1.81 (m,
2CH2), 2.94 (m, J ¼ 7 Hz, 2CH2, ꢂ-H), 3.44, 3.77 (2s,
2MeO), 5.17 (s, 4-H), 6.70–7.43 (m, 9 ar H).
1
(CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.33 (d, J ¼ 7 Hz, Me),
3.08 (q, J ¼ 7 Hz, ꢂ-H), 3.73 (s, 2MeO), 5.70 (s, 4-H), 6.70–
7.63 (m, 14 ar H).
3-[ꢂ-(Methoxycarbonyl)benzyl]-1,4-diphenyl-3-
piperidinoazetidin-2-one (5k, C29H30N2O3)
From (E=Z)-4c (1.0g, (2.71 mmol), piperidine (460mg,
5.42mmol), and n-BuLi (3.41 cm3, 5.42mmol), CC (cyclo-
hexane=AcOEt 4=1). Yield 340 mg (28%); colorless crystals;
mp 185ꢂC (dec., MeOH); IR: ꢄꢀ¼ 3050, 3020, 2980, 2920,
3-Isopropylthio-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5p, C28H29NO4S)
From 1-methylethanethiol (0.4cm3, 5 mmol), n-BuLi
(3.16 cm3, 5 mmol), and (Z)-4d (500 mg, 1.25mmol). Yield
346 mg (58%); colorless crystals; mp 127ꢂC (MeOH); IR:
ꢄꢀ¼ 3060, 3030, 2950, 2930, 2910, 2860, 2830 (CH), 1745
2840 (CH), 1750, 1720 (CO) cmꢁ1 1H NMR (80 MHz):
;
ꢃ ¼ 1.25–1.85 (m, 3CH2), 2.93 (s, 2CH2), 3.65 (s, MeO),
4.03 (s, ꢂ-H), 5.18 (s, 4-H), 6.80–7.74 (m, 15 ar H).
(CO) cmꢁ1
;
1H NMR (80 MHz): ꢃ ¼ 1.25 (d, J ¼ 7 Hz, 2
Me), 3.55 (mc, J ¼ 7 Hz, CHMe2), 3.60, 3.71 (2s, 2MeO),
4.55 (s, ꢂ-H), 5.33 (s, 4-H), 6.45–7.55 (m, 14 ar H).
3-[ꢂ-(Methoxycarbonyl)benzyl]-1-(4-methoxyphenyl)-4-
phenyl-3-piperidinoazetidin-2-one (5l, C30H32N2O4)
From a) (E=Z)-4d or b) (Z)-4d (1.0g, 2.51 mmol), piperidine
(1.28 cm3, 10.84 mmol) and n-BuLi (6.82 cm3, 10.84mmol):
a) 900 mg (72%), b) 803 mg (66%), mixture of 5l and 13a.
Separation CC (cyclohexane=AcOEt 4=1). Yield a) 440 mg
(36%), b) 290 mg (24%); colorless crystals; mp 175ꢂC
(MeOH); IR: ꢄꢀ¼ 3060, 3030, 2930, 2860, 2800 (CH), 1745,
3-Allylthio-3-[ꢂ-(methyoxycarbonyl)benzyl]-1-(4-methoxy-
phenyl)-4-phenylazetidin-2-one (5q, C28H27NO4S)
From 2-propenethiol (0.6cm3, 5 mmol), n-BuLi (3.15 cm3,
5 mmol), and (Z)-4d (500mg, 1.25 mmol). Yield 295 mg
(50%); yellowish crystals; mp 93ꢂC (MeOH); IR: ꢄꢀ¼ 3060,
1
3030, 3010, 2950, 2835 (CH), 1735 (CO) cmꢁ1; H NMR
1
1720 (CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.56 (s, 3CH2),
(80 MHz): ꢃ ¼ 3.50–3.74 (m, CH2), 3.63, 3.73 (2s, MeO),
4.63 (s, ꢂ-H), 4.93–5.25 (m, CH2), 5.34 (s, 4-H), 5.50–6.04
(m, –CH¼), 6.48–7.55 (m, 14 ar H).
2.91 (s, 4CH2), 3.62, 3.70 (2s, 2MeO), 4.04 (s, ꢂ-H), 5.14
(s, 4-H), 6.69–7.30 (m, 14 ar H).
3-[ꢂ-(Methoxycarbonyl)benzyl]-1-(4-methoxyphenyl)-3-
(morpholin-4-yl)-4-phenylazetidin-2-one (5m, C29H30N2O5)
From a) (E=Z)-4d or b) (Z)-4d or c) (E)-4d (1.0g, 2.51mmol),
morpholine (0.88cm3, 10.84 mmol) and n-BuLi (6.82 cm3,
10.84 mmol). Yield a) 800 mg (66%), b) 872mg (72%), mixture
of 5m and 13b, c) 260 mg (21%). CC (cyclohexane=AcOEt
3-[ꢂ-(Methoxycarbonyl)benzyl]-3-[2-(methoxycarbonyl)-
ethylthio]-1-(4-methoxyphenyl)-4-phenylazetidin-2-one
(5r, C29H29NO6S)
From methyl 3-mercaptopropionate (2.6cm3, 20mmol), n-
BuLi (12.6 cm3, 20mmol), and (Z)-4d (1.0g, 2.5 mmol). Yield

856
S. Ruf et al.
970 mg (75%); colorless crystals; mp 102ꢂC (MeOH); IR:
MCPBA was destroyed by NaOH solution, the organic layer
was dried (Na2SO4) and evaporated in vacuo.
ꢄꢀ¼ 3070, 3030, 3010, 2950, 2840 (CH), 1740 (CO) cmꢁ1
;
1H NMR (80 MHz): ꢃ ¼ 2.35–3.35 (m, CH2–CH2), 3.63 (s,
2CO2Me), 3.75 (s, MeO), 4.59 (s, ꢂ-H), 5.38 (s, 4-H), 6.49–
7.58 (m, 14 ar H).
Diethyl [1-(4-methoxyphenyl)-2-oxo-4-phenylsulfonyl-
azetidin-3-yl]malonate (6a, C29H29NO8S)
From 5d (500mg, 1 mmol) and MCPBA (492mg, 3 mmol).
Yield 375 mg (68%); light yellow crystals; mp 120ꢂC (MeOH);
IR: ꢄꢀ¼ 3060, 2990, 2970, 2910, 2830 (CH), 1755 (CO), 1330,
3-[1-(Methoxycarbonyl)ethyl]-3-[2-(methoxycarbonyl)-
ethylthio]-1-(4-methoxyphenyl)-4-phenylazetidin-2-one
(5s, C24H27NO6S)
1145 (SO2) cmꢁ1
;
1H NMR (80 MHz): ꢃ ¼ 1.10, 1.40 (2t,
J ¼ 7 Hz, Me), 3.74 (s, MeO), 3.96–4.50 (m, 2OCH2), 4.10
(s, ꢂ-H), 6.23 (s, 4-H), 6.73–8.04 (m, 14 ar H).
From (Z)-4e (560 mg, 1.66mmol), methyl 3-mercaptopro-
pionate (0.65 cm3, 5 mmol), and n-BuLi (3.15 cm3, 5 mmol).
Yield 620 mg (82%); colorless crystals; mp 116ꢂC (MeOH);
IR: ꢄꢀ¼ 3090, 3070, 3040, 2990, 2955, 2850 (CH), 1745, 1700
3-[ꢂ-(Methoxycarbonyl)benzyl]-3-[2-(methoxycarbonyl)-
ethylsulfonyl]-1-(4-methoxyphenyl)-4-phenylazetidin-2-one
(6b, C29H29NO8S)
1
(CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.43 (d, J ¼ 7 Hz, Me),
2.55, 3.05 (mc, 2CH2), 3.38 (q, J ¼ 7 Hz, ꢂ-H), 3.63 (s, MeO),
3.75 (s, 2CO2Me), 5.54 (s, 4-H), 6.70–7.38 (m, 9 ar H).
From 5r (400mg, 0.77mmol) and MCPBA (378mg,
2.31mmol). Yield 364 mg (81%); colorless crystals; mp
137–138ꢂC (MeOH); IR: ꢄꢀ¼ 3060, 3030, 3005, 2950, 2930,
2830 (CH), 1765 (CO Lactam), 1735 (CO Ester), 1310, 1125
3-(t-Butylthio)-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5t, C29H31NO4S)
From t-BuSH (900 mg, 10mmol), n-BuLi (6.3cm3, 10 mmol),
and (Z)-4d (1.0g, 2.5 mmol). Yield 907 mg (74%); colorless
crystals; mp 151–153ꢂC (MeOH); IR: ꢄꢀ¼ 3070, 3040, 3000,
2960 (CH), 1745 (CO) cmꢁ1; 1H NMR (80 MHz): ꢃ ¼ 1.53 (s,
CMe3), 3.61, 3.74 (2s, 2MeO), 4.79 (s, ꢂ-H), 5.35 (s, 4-H),
6.45–7.50 (m, 14 ar H).
1
(SO2) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 2.33–3.44 (m, CH2–
CH2), 3.64 (s, 2CO2Me), 3.79 (s, MeO), 4.88 (s, ꢂ-H), 5.76
(s, 4-H), 6.50–7.71 (m, 14 ar H).
3-[1-(Methoxycarbonyl)ethyl]-1-(4-methoxyphenyl)-4-
phenyl-3-(phenylsulfonyl)azetidin-2-one (6c, C26H25NO6S)
From 5o (350mg, 0.78 mmol) and MCPBA (438 mg,
2.34mmol). Yield 233 mg (62%); colorless crystals; mp
150–152ꢂC (dec, MeOH); IR: ꢄꢀ¼ 3035, 3015, 3000, 2950,
2825 (CH), 1760 (CO Lactam), 1735 (CO Ester), 1325,
3-(n-Butylthio)-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5u, C29H31NO4S)
From n-BuSH (900 mg, 10 mmol), n-BuLi (6.3 cm3, 10 mmol),
and (Z)-4d (1.0g, 2.5mmol). Yield 860 mg (70%); yellowish
crystals; mp 115ꢂC (MeOH); IR: ꢄꢀ¼ 3085, 3040, 2970, 2950,
2880, 2855 (CH), 1750, 1730 (CO) cmꢁ1; 1H NMR (80 MHz):
ꢃ ¼ 0.69–0.94 (m, Me), 1.10–1.60 (m, CH2–CH2), 2.65–3.06
(m, SCH2), 3.65, 3.75 (2s, 2MeO), 4.60 (s, ꢂ-H), 5.38 (s, 4-H),
6.53–7.63 (m, 14 ar H).
1
1140 (SO2) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 1.35 (d, J ¼ 7 Hz,
Me), 3.23 (q, J ¼ 7 Hz, ꢂ-H), 3.76, 3.85 (2s, 2MeO), 6.05 (s, 4-
H), 6.74–8.05 (m, 14 ar H).
3-[1-(Methoxycarbonyl)ethyl]-3-[2-(methoxycarbonyl)-
ethylsulfonyl]-1-(4-methoxyphenyl)-4-phenylazetidin-2-one
(6d, C24H27NO8S)
From 5s (350 mg, 0.76mmol) and MCPBA (375 mg,
2.28mmol). Yield 360 mg (97%); colorless crystals; mp
150ꢂC (MeOH); IR: ꢄꢀ¼ 3070, 3040, 3000, 2960, 2850 (CH),
3-n-Butyl-3-[ꢂ-(methoxycarbonyl)benzyl]-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one (5v, C29H31NO4)
At ꢁ78ꢂC, n-BuLi (6.3 cm3, 10 mmol) was added to (Z)-4d
(1.0 g, 2.51 mmol) in 20 cm3 THF. After 10 min, the mixture
was hydrolyzed with a solution of NH4Cl (30 cm3, 60 g
dmꢁ3), the aqueous layer was once washed with CHCl3,
the combined organic layers were dried (Na2SO4) and evap-
orated. Yield 252 mg (21%); colorless crystals; mp 165ꢂC
(MeOH); IR: ꢄꢀ¼ 3080, 3060, 3025, 2950, 2930, 2875, 2835
1750 (CO), 1330, 1140 (SO2) cmꢁ1 1H NMR (80 MHz):
;
ꢃ ¼ 1.45 (d, J ¼ 7 Hz, Me), 2.48–3.90 (m, CH2–CH2, ꢂ-H),
3.64 (s, MeO), 3.73, 3.80 (2s, 2CO2Me), 5.88 (s, 4-H), 6.69–
8.03 (m, 9 ar H).
2-[(4-Bromophenylamino)(phenyl)methyl)]-3-(furan-2-yl)-1-
(morpholin-4-yl)-prop-2-en-1-one (11, C24H23BrN2O3)
From 0.8 g (2.1mmol) (Z)-4o and 0.87 cm3 (10 mmol) morpho-
line. Yield 710 mg (73%); colorless crystals; mp 208–209ꢂC
(MeOH); IR: ꢄꢀ¼ 3398 (NH), 3060, 3019, 2977, 2926, 2863
(CH), 1613 (CO), 1594 (C¼C) cmꢁ1; 1H NMR Isomer 1: ꢃ ¼
2.3–3.9 (m, 8HM), 5.10 (d, 3JCH;NH ¼ 5.7 Hz, CH–NH), 5.93 (d,
3JNH;CH ¼ 5.7 Hz, NH), 6.62 (s, ꢂ-H), 6.36–6.43 (m, 3-HF, 4-
HF), 6.70 (dd, J ¼ 6.8 Hz, 2 ar H), 7.26 (dd, J ¼ 6.8 Hz, 2 ar H),
7.36 (m, 5-HF), 7.20–7.45 (m, 5 ar H); Isomer 2: ꢃ ¼ 2.3–3.9 (m,
8HM), 4.31 (d, 3JNH;CH ¼ 2.8 Hz, NH), 5.14 (m, 3JCH;NH ¼ 2.8,
1
(CH), 1725 (CO) cmꢁ1; H NMR (80 MHz): ꢃ ¼ 0.73–2.76
(m, CH2–CH2–CH2–Me), 3.05 (s, CO2Me), 3.68 (s, MeO),
3.95 (s, ꢂ-H), 5.03 (s, 4-H), 6.65–7.29 (m, 14 ar H); 13C
NMR: ꢃ ¼ 14.47 (Me), 23.54, 26.83, 28.99 (CH2), 51.92
(CO2Me), 52.35 (C-ꢂ), 55.86 (MeO), 63.15 (C-4), 64.49
(C-3), 114.80, 119.16, 128.08, 130.22 (ar C), 131.04,
134.62, 134.86 (quart. ar C), 156.51 (CO Lactam), 171.81
(CO Ester).
3
4JCH;ꢂ ¼ 1.2 Hz, CH–NH), 6.29 (d, JF3;F4 ¼ 3.3 Hz, 3-HF),
Oxidation with m-chloroperbenzoic acid (MPCBA). General
procedure
6.36–6.43 (m, 4-HF), 6.38 (dd, J ¼ 6.8 Hz, 2 ar H), 6.54 (d,
4Jꢂ;CH ¼ 1.2 Hz, ꢂ-H), 7.14 (dd, J ¼ 6.8 Hz, 2 ar H), 7.36 (m,
5-HF), 7.20–7.45 (m, 5 ar H); 13C NMR Isomer 1: ꢃ ¼ 64.76
A threefold excess of MCPBA was added to a solution of the
sulfide in 20cm3 CH2Cl2. After stirring for 1 h the excess of

ꢀ-Lactam derivatives as potential anti-cancer compounds
857
(NH–CH), 131.79, 132.50, 139.53, 143.64 (C-5F), 145.78 (p–
Ar–C–NH), 149.73 (C-2F), 167.52 (CO); Isomer 2: ꢃ ¼ 62.69
(NH–CH), 131.96, 132.50, 139.53, 143.20 (C-5F), 145.37 (p–
Ar–NH), 150.34 (C-2F), 168.76 (CO); Isomer 1 or 2: ꢃ ¼ 41.30,
41.45, 46.21, 65.40, 65.70, 66.05, 66.32, 108.80, 110.27, 111.34,
111.76, 111.87, 112.14, 113.93, 114.90, 115.55, 117.69, 126.77,
127.59, 128.08, 128.63, 128.84, 129.02, 129.25, 130.84; HPLC
ar H); 13C NMR: ꢃ ¼ 41.33, 41.61, 46.75, 47.35 (morpholine-
C), 55.57 (MeO), 57.52 (CH–N), 66.07, 66.10, 66.58, 66.72
(morpholine-C), 114.69, 114.86, 127.11, 128.39, 128.72,
128.89, 128.92 (ar C), 131.94, 133.46, 133.49 (quart. ar C),
139.32, 139.53 (C¼C), 151.86 (MeO-Car), 166.84, 167.57
(NCO). MS: 541 (34, Mþ), 542 (14, [Mþ 1]þ), 70 (100).
RP-18, MeCN=H2O: 1=1): t0 ¼ 1.79 min, k0 ¼ 17.67, lmax
¼
260.5 nm; ChiralCel OJ–R, MeCN=H2O: 2=3): t0 ¼ 2.40 min,
Acknowledgements
0
0
k1 ¼ 12.86, k2 ¼ 13.59; MS (70 eV): m=z (%) ¼ 468.7 (3.3,
13C=81Br–Mþ), 467.7 (16.1, 81Br–Mþ), 466.7 (3.6, 13C=79Br–
Mþ), 465.7 (16.4, 79Br–Mþ), 176.0 (100%).
We thank E. Merck KGaG, Darmstadt, for extended generous
support with chemicals, with chromatography materials, and
some biological tests, Lonza AG, Basel, for continuous sup-
port with chlorosulfonyl isocyanate, and we thank the ‘‘Fonds
der Chemischen Industrie’’, Frankfurt a. Main, for continuous
financial support.
(Z)-2-[(4-Bromophenylamino)(phenyl)methyl)]-1-
(morpholin-1-yl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-
one (12, C27H24BrF3N2O2)
From 0.9 g (2mmol) (Z)-4s and 0.87cm3 (10 mmol) morpho-
line. Yield 730 mg (67%); colorless crystals; mp 204ꢂC
(MeOH); IR: ꢄꢀ¼ 3398 (NH), 3061, 3020, 2978, 2925, 2864
References
1
1. Helwig H, Otto H-H (2004) Arzneimittel-Handbuch
th
fu¨r Arzte und Apotheker, 10 edn. Wiss, Verlagsges,
(CH), 1613 (CO), 1594 (C¼C) cmꢁ1; H NMR: Isomer 1:
¨
3
ꢃ ¼ 2.3–3.9 (m, 8HM), 5.20 (d, JCH;NH ¼ 5.7Hz, CH–NH),
Stuttgart; b) Georg GI, Ravikumar VT, The Organic
Chemistry of ꢀ-Lactams, VCH Publisher Weinheim
2. a) Ojima I (1995) Acc Chem Res 28:383; b) Suffness M
(1995) Taxol Science and Applications, CRC Press, Boca
Raton
3. a) Finke PE, Shah SK, Fletcher DS, Ashe BM, Brause
KA, Chandler GO, Dellea PS, Hand KM, Maycock AL,
Osinga DG, Underwood DJ, Weston H, Davies P, Doherty
JB (1995) J Med Chem 38:2449; b) Buynak JD, Rao AS,
Fod GP, Carver C, Adam G, Geng B, Bachmann B,
Shobassy S, Lackey S (1997) J Med Chem 40:3423
4. a) Venz C, Otto H-H (2001) Pharmazie 56:686; b)
Schneider M, Otto H-H (2001) Arch Pharm Pharm
Med Chem 334:167; c) Elriati A, Otto H-H (2006)
Monatsh Chem submitted
3
6.01 (d, JNH;CH ¼ 5.7 Hz, NH), 6.89 (s, ꢂ-H), 6.74 (dd,
J ¼ 6.8, J ¼ 2.1 Hz, 2 ar H), 7.20–7.69 (m, 11 ar H); Isomer
2: ꢃ ¼ 2.3–3.9 (m, 8HM), 4.32 (d, 3JNH;CH ¼ 2.8 Hz, NH), 5.25
(m, 3JCH;NH ¼ 2.8, 4JCH;ꢂ ¼ 1.2 Hz, CH–NH), 6.42 (dd, J ¼ 6.8,
4
J ¼ 2.1 Hz, 2 ar H), 6.84 (d, Jꢂ;CH ¼ 1.2 Hz, ꢂ-H), 7.16 (dd,
J ¼ 6.8, J ¼ 2.1 Hz, 2 ar H), 7.20–7.69 (m, 11 ar H); 13C NMR:
ꢃ ¼ 41.17, 41.33, 45.77, 45.84, 62.78, 64.68, 65.34, 65.57,
65.76, 114.85, 115.04, 115.53, 124.11, 125.41, 125.49, 125.54,
125.62, 126.74, 127.10, 127.53, 128.19, 128.24, 128.28,
128.50, 128.81, 128.95, 129.11, 129.17, 129.36, 131.87,
132.03, 136.53, 139.01, 139.09, 145.23 (p–Ar–C–NH),
145.60 (p–Ar–C–NH), 167.30 (CO), 168.23 (CO); HPLC RP-
18b): t0 ¼ 1.79 min, k0 ¼ 8.80, lmax ¼ 258.6 nm; ChiralCel OJ–
0
0
R, MeCN=H2O: 1=1): t0 ¼ 2.01 min, k1 ¼ 12.31, k2 ¼ 13.07.
5. a) Kazi A, Hill R, Long TE, Kuhn DJ, Turos E, Dou QP
(2004) Biochem Pharmacol 67:365; b) Sun L, Vasilevich
NI, Fuselier JA, Hocart SJ, Coy DH (2004) Bioorg Med
Chem Lett 14:2041; c) Banik BK, Becker FF, Banik I
(2004) Bioorg Med Chem 12:2523; d) Veinberg G,
Shestakova I, Vorona M, Kanepe I, Lukevies E (2004)
Bioorg Med Chem Lett 14:147
6. As the author has retired, and his lab was closed, he is
hopeful that anyone else will be stimulated by this paper
in continuing this interesting research
2-[ꢂ-(4-Methoxyanilino)benzyl]-3-phenyl-1,4-dipiperidino-
2-butenedicarboxamide (13a, C34H39N3O3)
As a by-product of the synthesis of 5l. Yield a) 160 mg (21%),
b) 142 mg (12%); colorless crystals, mp 224–225ꢂC (MeOH);
IR: ꢄꢀ¼ 3370 (NH), 3060, 3030, 3000, 2940, 2860 (CH), 1630,
1
1610, (CO) cmꢁ1; H NMR (400MHz): ꢃ ¼ 1.11–1.66 (m,
6CH2), 2.41, 3.05 (mc, J ¼ 13.5, 7.5, 3.3 Hz, 2HPip), 3.17–
3.56 (m, 3CH2), 3.65 (s, MeO), 5.29 (s, benzyl-CH), 5.98 (s,
NH), 6.35–7.66 (m, 14 ar H); 13C NMR: ꢃ ¼ 23.53, 23.93,
24.37, 24.80, 25.11, 25.44 (6ꢃCH2), 41.36, 41.63, 47.18,
47.88 (4ꢃCH2), 55.18 (MeO), 57.26 (C–NHR), 114.23,
114.29, 126.84, 127.01, 127.97, 128.07, 128.12, 128.19 (ar
C), 131.30, 133.25, 134.02 (quart. ar C), 139.37, 139.54
(C¼C), 151.14 (MeO–Car), 166.17, 166.82 (N–COR).
7. a) Ruf S, Otto H-H (1995) Helv Chim Acta 78:629; b)
Gu¨rtler S, Ruf S, Johner M, Otto H-H (1996) Pharmazie
51:811; c) Gu¨rtler S, Johner M, Ruf S, Otto H-H (1993)
Helv Chim Acta 76:2958; d) Otto H-H, Mayrhofer R,
Bergmann H-J (1983) Liebigs Ann Chem:1152; e)
Gu¨rtler S, Otto H-H (1989) Arch Pharm (Weinheim)
322:105; f) Gu¨rtler S, Ruf S, Otto H-H (1989) Arch Pharm
(Weinheim) 322:603; g) Bergmann H-J, Mayrhofer R,
Otto H-H (1986) Arch Pharm (Weinheim) 319:203; h)
Gu
2-[ꢂ-(4-Methoxyanilino)benzyl]-1,4-bis(morpholin-4-yl)-3-
phenyl-2-butenedicarboxamide (13b, C32H35N3O5)
As a by-product of the synthesis of 5m. Rf¼ 0.43. Yield
140 mg (16%); colorless crystals; mp 227ꢂC (MeOH); IR:
ꢄꢀ¼ 3270 (NH), 3070, 3030, 3000, 2980, 2940, 2910, 2860
¨rtler S, Otto H-H (1989) Arch Pharm (Weinheim) 322:3
8. Bracht K, Boubakari, Gru¨nert R, Bednarski PJ (2006)
Anti-Cancer Drugs 17:41
9. Gilman H, Speeter M (1943) J Am Chem Soc 65:2255
1
(CH), 1630 (CO) cmꢁ1; H NMR (250 MHz): ꢃ ¼ 2.23, 2.50
(mc, 2 morpholine-H), 3.19–3.78 (m, 14 morpholine-H), 3.68
(s, MeO), 5.36 (s, benzyl-CH), 5.79 (s, NH), 6.38–7.68 (m, 14
¨
10. Pfleger R, Jager A (1956) Chem Ber 89:2769

¨
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