β-Lactam derivatives as enzyme inhibitors: Halogenated β-lactams and related compounds

Article abstract of DOI:10.1007/s00706-007-0837-5

Different modifications of the imine - acyl chloride reaction were used for the synthesis of 3-mono- and 3,3-dihalogenated 1,4-diaryl substituted β-lactams. Furthermore, these β-lactams were modified by halogen substitution either at the aryl at position

Full text of DOI:10.1007/s00706-007-0837-5

Monatsh Chem 139, 835–846 (2008)
DOI 10.1007/s00706-007-0837-5
Printed in The Netherlands
b-Lactam derivatives as enzyme inhibitors: halogenated b-lactams
and related compounds
Ali Elriati, Jutta Loose, Roswitha Mayrhofer, Hans-Joachim Bergmann, Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University, Greifswald, Germany
Received 20 October 2007; Accepted 27 October 2007; Published online 9 June 2008
# Springer-Verlag 2008
Abstract Different modifications of the imine – acyl
chloride reaction were used for the synthesis of 3-
mono- and 3,3-dihalogenated 1,4-diaryl substituted
ꢀ-lactams. Furthermore, these ꢀ-lactams were modi-
fied by halogen substitution either at the aryl at posi-
tion 1 or at the aryl substituent at position 4, or at both
positions. The influence of the halogen atoms on the
reactivity of the ꢀ-lactam ring, visible by the carbonyl
frequence in their IR spectra, was studied. A selection
of compounds was tested as inhibitors of the serin
protease porcine pancreatic elastase. No simple cor-
relation between IR frequence and biological activity
was found. Finally, the base induced rearrangement of
N-benzyl ꢀ-lactams was used for the synthesis of 4,5-
diaryl substituted pyrrolidinones.
clinical use as antibacterials, these compounds serve
as synthons in the synthesis of other biological active
heterocycles [2], and in many examples the bio-
logical activity can be interpreted as an interaction
between the ꢀ-lactam and a serine containing en-
zyme (serine protease) like elastase [3]. Therefore,
the search for clinical useful ꢀ-lactams is a growing
field of interest. We have described a number of ꢀ-
lactam peptides [4] and studied their properties as
elastase inhibitors. In continuation of our research
in this field, we describe herein the synthesis of other
substituted ꢀ-lactams and their biological evaluation.
Some of these compounds showed a weak activity as
inhibitors of elastase, and some showed an activity
against some tumor cell lines [5]. As ꢁ-halo-ꢀ-lac-
tams have attracted attention [6] because of their
interesting biological properties we have extended
our studies in this direction.
Keywords ꢀ-Lactams; Halogenated; 1,4-Diaryl-substituted;
Pyrrolidinone derivatives; Elastase inhibitors.
Introduction
Results and discussion
The ꢀ-lactam structure known from penicillins and
cephalosporins as highly active and clinically useful
ꢀ-lactam antibiotics [1] has motivated synthesis and
evaluation during the last few decades. Apart from
All ꢀ-lactams were synthesized from the appropriate
imines 1, which were obtained by reaction between
aldehyde and aromatic amine according to literature
procedures. The ring formation was done depending
on the substituents by different methods. Using a
Reformatsky-like reaction [7] with 2-bromoalkano-
ates and zinc=iodine in toluene, we obtained the
substituted ꢀ-lactams 2a–2g with a fluoro substituent
as part of the aromatic substituents Ar or Ar0.
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

836
A. Elriati et al.
These compounds were obtained either as race-
resulted in two separated peaks (1:1) from the race-
mates. All IR spectra showed a strong carbonyl band
between ꢃꢀ¼ 1730 and 1760 cmꢀ1, whereby the
highest values were found for 2e and 2f, compounds
bearing in position 4 a p-(trifluoromethyl)phenyl
substituent.
A second charge of ꢀ-lactams, 3-mono, and 3,3-
dichloro derivatives 3a–3g, and the ester derivative
4, was prepared by a modification of the Staudinger
reaction [8]. The imine and Et3N were dissolved in
CH2Cl2, and the acyl chloride was dropwise added.
Using 3-methylbutyryl chloride or methyl (chloro-
carbonyl)acrylate and some imines under similar re-
action conditions (Et3N) we could not isolate any
ꢀ-lactam. Instead, an amidation had occurred form-
mates (2a, 2c, 2e, and 2g) or as racemates of the trans
form (2b, 2d, and 2f), which was deduced from their
1H NMR spectra and their chromatographic properties
(exp. part). The 1H NMR spectra of 2a, 2c, 2e, and 2g
were characterized by AMX spectra of the protons 3-
H, 30-H, and 4-H with coupling constants of JAX
¼
2.5–2.6 Hz, JAM ¼ 15.1–15.2 Hz, and JMX ¼ 5.6–
5.7 Hz. The signals of the protons 3-H and 4-H were
1
found in the H NMR spectra of 2b, 2d, and 2f at
ꢂ ¼ 3.63 and 5.16 (5.13 and 5.20) ppm with J3,4 ¼ 5.8–
5.9 Hz, clearly indicating the trans configuration.
In HPLC experiments using a column with a non-
chiral adsorbent the compounds showed one single
peak, while using a column with a chiral adsorbent

ꢀ-Lactam derivatives as enzyme inhibitors
837
ing the amides 6a, 6b [9], 7a [10], and 7b. Each of
the four compounds was prepared from the acyl
chloride and two different imines (see Experimental)
or may be prepared from the acyl chloride and the
appropriate amine. Additionally, we prepared 8 by
the same way, and the reactive N-chloro ꢀ-lactam
5 was obtained by direct chlorination of 18 at room
temperature with 75% yield.
A third charge of halogenated ꢀ-lactams was pre-
pared by addition of 1 to a solution of the acyl chlo-
ride in toluene, adding of Et3N with heating, and
refluxing the mixture for 3–4 h. This mode was de-
scribed as a two step reaction with a zwitterionic
intermediate [11] which cyclized to the lactam ring.
We isolated the crystalline ꢀ-lactams 9a–12 usually
in high yields. The 3,3-dichloro derivatives 9a–9l
and 12 were obtained as racemates whereas the 3-
monochloro compounds 10a–10g should be isolated
as trans=cis mixtures. As demonstrated by the HPLC
1
and H NMR data, the isolated compounds were
racemates of the favored trans diastereoisomers with
J3H,4H ¼ 1.9–2.6 Hz. Furthermore, the IR spectra of
the dichloro compounds showed the highest carbon-
yl absorption between ꢃꢀ¼ 1770 and 1796 cmꢀ1,
whereas these bands in the spectra of the monochloro
compounds were registered between ꢃꢀ¼ 1759 and
1777 cmꢀ1.
The lowest values of the carbonyl bands, ꢃꢀ¼
1731–1747 cmꢀ1, were found in the spectra of 11a–
11e, derivatives substituted at position 3 by an iso-
propyl group and at position 1 by a p-fluoro phenyl
ring. The coupling constants J3H,4H ¼ 2.0–2.5 Hz
clearly showed the trans orientation of the substitu-
ents at C-3 and C-4.
The ꢀ-lactam derivatives 16c–16b and 17a, 17b
were prepared from diethyl p-toluidinomalonate (13)

838
A. Elriati et al.
by reaction with chloroacetyl chloride yielding 14
[12] which was transformed into the 3-trimethylsilyl
compound 15 by the reaction with LDA and CTMS at
ꢀ78ꢁC. The reaction of 14 with acetone or acetalde-
hyde in the presence of LDA yielded the 3-(ꢁ-hy-
droxy)ethyl derivatives 16a and 16b, whereas using
similar conditions and 4-nitrobenzaldehyde the par-
ent ꢁ-hydroxy compound 16c became assesible. On
the other hand, reactions of 15 with aromatic alde-
hydes resulted in the formation of the ꢁ,ꢀ-unsaturat-
ed lactams 17a and 17b [13].
zyl halogenides in THF in the presence of KOH and
tetrabutylammonium bromide (TBAF). Treatment
of these N-benzyl derivatives with BuLi in THF at
ꢀ78ꢁC resulted in a deprotonation of the benzylic
methylene group followed by a rearrangement end-
ing up with the isolation of the pyrrolidinone deriv-
atives 20a–20f [14]. An analogous reaction was
described for N-benzyl azetidines [15] and aza-ꢀ-
lactams [16], and 20a was first described by Durst
[17] who discussed a diradical mechanism for this
rearrangement.
An interesting observation was made when we
tried to alkylate N-benzyl ꢀ-lactams at position 3.
19b–19f were prepared by reaction of 18 with ben-
The pyrrolidinones 20a and 20f were isolated as
trans isomers, whereas compounds 20b and 20d
were obtained as cis=trans mixtures. No product

ꢀ-Lactam derivatives as enzyme inhibitors
839
idene)(4-fluorophenyl)amine (1o) [19]; ethyl (4-methoxyphe-
nylimino)acetate (1p) [20]; benzyl (4-chlorobenzylideneami-
no)acetate (1q) [21]; diethyl 1-(4-methylphenyl)-2-oxo-
azetidine-4,4-dicarboxylate (14) [22]; trans-3-chloro-4-
(2-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-one (10c);
3,3-dichloro-1-methoxyphenyl-4-phenylazetidin-2-one (3a)
[23]; Ethyl 3-isopropyl-1-(4-methoxyphenyl)-4-oxoazetidin-
2-carboxylate (4) [24] 3-chloro-4-(4-chlorophenyl)-1-(4-
methoxyphenyl)azetidin-2-one (10a) [25]; (RS)-1-benzyl-
4-phenylazetidin-2-one (19a) [26]; (RS)-4-phenylazetidin-
2-one (18) [18].
was isolated from the reaction of 19c, probably be-
cause the nitro group had reacted with BuLi, and
from the reaction of 19e most of the starting material
was reisolated. Furthermore, experiments to rear-
range ꢀ-lactams with one or 2 aliphatic substituents
in position 4 failed completely. No defined products
were obtained.
Testing the biological activity of these compounds
as inhibitors of elastase was done as we described
earlier [18]. Compounds 3b, 3e, 3g, 6b, 7a, 9b, 10b,
and 10f showed activities against PPE reaching
maxima of about 10% of the activity of the standard
inhibitor trifluoroacetyl-L-val-L-tyr-L-val. Therefore,
no further experiments and elastase tests were done
with these compounds.
Synthesis of imines. General procedure
If not otherwise noted, 0.25 mol of the aldehyde, and
0.25 mol of the amine were dissolved with slight warming
in 200 cm3 EtOH. The mixture was stirred at 3–18ꢁC until
the precipitate was completed. The products were crystal-
lized from EtOH.
(2-Chlorobenzylidene)(2-fluorophenyl)amine
(1r, C13H9ClFN)
Experimental
From 11.11 g (0.1mol) 2-fluoroaniline and 14.1g (0.1 mol) 2-
chlorobenzaldehyde in 60 cm3 EtOH. Yield 22.6g (97%); col-
orless needles; mp 44ꢁC; IR: ꢃꢀ¼ 3062 (CH), 1620 (C¼N),
1239 (C–F), 1051 (C–Cl), 762 (ar) cmꢀ1; 1H NMR (60 MHz):
ꢂ ¼ 6.75–7.3 (m, 7 ar H), 7.87–8.3 (m, 1 ar H), 8.76 (s, H–
C¼) ppm.
General
Mp PHMX 80=2778 (Ku¨stner, Dresden) apparatus. IR Spectra:
Perkin-Elmer FTIR 1600; in KBr, if not noted otherwise.
NMR Spectra: Bruker DPX 200 (200 MHz), ARX 300
(300 MHz) for H; ꢂ (ppm) rel. to TMS as internal standard;
1H-values from DPX 200 (200MHz) spectra in CDCl3, if not
noted otherwise. Elementary analyses: Perkin-Elmer Analyzer
1
¨
2400 CHN, Pharmazeutisches Institut der Universitat
(4-Chlorobenzylidene)(2-fluorophenyl)amine
Greifswald. All compounds gave satisfactory elemental anal-
yses. Column chromatography (CC): Silica gel 60 (Merck
7734). HPLC with LaChrom apparatus series 7000 Merck
Hitachi, LiChrospher 250–4, RP-18, 5 ꢄm, and Chiralcel
(1s, C13H9ClFN)
From 8.33 g (0.075 mol) 2-fluoroaniline and 10.6 g (0.075 mol)
4-chlorobenzaldehyde in 60cm3 EtOH. Yield 14.9g (85%);
light yellow needles; mp 47ꢁC; IR: ꢃꢀ¼ 3058 (CH), 1626
(C¼N), 1567 (ar), 1219 (C–F), 1092 (C–Cl), 827, 757 (ar)
OJ–R, Flow ¼ 1 ml=min, lmax ¼ 220 nm, T ¼ 20ꢁC (2a–2g),
3
Flow 1 ¼ 0.8 cm =min, lmax ¼ 220 nm, T ¼ 30ꢁC (5–12),
ꢂ
1
cmꢀ1; H NMR (300 MHz): ꢂ ¼ 7.08 (t, 2 ar H), 7.16–7.22
b
c
d
solvents MeCN=H2O 7=3, or MeCN=H2O 4=6, or MeCN=
H2O 1=1. PPE (Porcine pancreatic elastase, ꢃ 200 U=mg)
was purchased from Serva, Suc-(Ala)3-pNA from Fluka.
THF was stored with CaCl2, refluxed with Na and benzophe-
none, and distilled prior to use. Other solvents were dried=
purified according to literature procedures. LDA (lithium
diisopropylamide) was freshly prepared by mixing of equiva-
lent amounts of freshly distilled HN(CHMe2)2 and n-BuLi
(15% in hexane) at ꢀ78ꢁC. CTMS ¼ Chlorotrimethylsilane;
PE¼ Petroleum ether.
(m, 2 ar H), 7.45 (d, J ¼ 8.5 Hz, 2 ar H), 7.38 (d, J ¼ 8.5 Hz,
2 ar H), 8.40 (s, H–C¼) ppm.
(4-Chlorobenzylidene)(3-fluorophenyl)amine
(1t, C13H9ClFN)
From 8.3g (0.075mol) 3-fluoroaniline and 10.5g (0.075 mol)
4-chlorobenzaldehyde in 60cm3 EtOH. Yield 15.4g (88%);
colorless needles; mp 48ꢁC; IR: ꢃꢀ¼ 1630 (C¼N), 1586 (ar),
1259 (C–F), 1087 (C–Cl), 824, 779 (ar) cmꢀ1 1H NMR
;
(60 MHz): ꢂ ¼ 6.48–7.60 (m, 4 ar H), 7.7 (d, J ¼ 9 Hz, 2 ar
Benzylidene(4-fluorophenyl)amine (1a); benzylidene(tri-
fluoromethylphenyl)amine (1b); 4-fluorobenzylidene(4-meth-
oxyphenyl)amine (1c); 4-fluorobenzylidene(3-nitrophenyl)-
amine (1d); 4-trifluoromethylbenzylidene(4-trifluoromethyl-
phenyl)amine (1e); 4-fluorophenyl(4-trifluoromethylbenzyli-
dene)amine (1f); (4-methoxyphenyl)-4-trifluoromethylbenz-
ylideneamine (1g); 4-fluorophenyl(4-methoxybenzylidene)-
amine (1h); 4-(dimethylamino)benzylidene(4-fluorophenyl)-
amine (1i); isopropylidene(4-methoxyphenyl)amine (1j);
(4-chlorobenzylidene)(4-methoxyphenyl)amine (1k); (4-
chlorobenzylidene)(4-fluorophenyl)amine (1l); (2-chloro-ben-
zylidene)(4-methoxyphenyl)amine (1m); (2-chlorobenz-yli-
H), 7.58 (d, J ¼ 9 Hz, 2 ar H), 8.11 (s, H–C¼) ppm.
(2,4-Difluorobenzylidene)(4-fluorophenyl)amine
(1u, C13H8F3N)
From 4.4g (0.04 mol) 4-fluoroaniline and 5.7 g (0.04 mol) 2,4-
difluorobenzaldehyde in 100cm3 of EtOH. When the reaction
was completed, the solvent was evaporated, the residue was
dissolved in 200 cm3 Et2O, the solution was dried (Na2SO4)
and evaporated in vacuo. Yield 7.5g (80%); brown viscous
liquid; IR: ꢃꢀ¼ 1624 (C¼N), 1589, 1502 (ar), 1238 (C–F),
1
832, 787 (ar) cmꢀ1; H NMR (60 MHz): ꢂ ¼ 6.16–7.26 (m,
dene)(4-fluorophenyl)amine
(1n);
(2,4-dichlorobenzyl-
7 ar H), 8.27 (s, H–C¼) ppm.

840
A. Elriati et al.
1735 (CO), 1515 (ar), 1453, 1391 (C–N), 1216 (C–F), 836,
1
(2,4-Difluorobenzylidene)(4-methoxyphenyl)amine
(1v, C14H11F2NO)
818 (ar) cmꢀ1; H NMR: ꢂ ¼ 0.86 (d, J ¼ 7.6 Hz, Me), 3.63
(m, J ¼ 7.6, 5.9 Hz, 3-H), 5.16 (d, J ¼ 5.9 Hz, 4-H), 6.90 (t,
J ¼ 8.7, 8.5 Hz, 2 ar H), 7.19–7.38 (m, 7 ar H) ppm; HPLC:
tR ¼ 5.96min, k0 ¼ 2.39, RP-18b; tR ¼ 12.35, 14.05 min, k0 ¼
5.86, 6.80, Chiralcel OJ–Rc.
From 9.2 g (0.075 mol) p-anisidine and 10.7g (0.075 mol) 2,4-
difluorobenzaldehyde in 100 cm3 EtOH as described for 1u.
Yield 13.1g (66%); greenish viscous liquid; IR: ꢃꢀ¼ 1622
(C¼N), 1578, 1504 (ar), 1247 (C–F), 828, 786 (ar) cmꢀ1
;
1H NMR (60 MHz): ꢂ ¼ 3.61 (s, OMe), 6.0–7.4 (m, 7 ar H),
(RS)-4-(4-Fluorophenyl)-1-(4-methoxyphenyl)azetidin-2-one
(2c, C16H14FNO2)
8.44 (s, H–C¼) ppm.
From 1c and ethyl 2-bromoacetate. Yield 7.3g (31%); color-
less crystals; mp 127ꢁC; IR: ꢃꢀ¼ 3063, 2972 (CH), 1740 (CO),
1604, 1508 (ar), 1379 (C–N), 1298 (C–F), 802 (ar) cmꢀ1; 1H
NMR: ꢂ ¼ 2.85–2.94 (dd, JAX ¼ 2.6, JAM ¼ 15.1Hz, 3-H),
3.49–3.59 (dd, JMX ¼ 5.6, JAM ¼ 15.1 Hz, 30-H), 3.74 (s,
OMe), 4.94–4.98 (dd, JAX ¼ 2.5 Hz, JMX ¼ 5.5Hz, 4-H),
6.76–6.80 (d, J ¼ 8.9 Hz, 2 ar H), 7.02–7.10 [t(2d), J ¼
8.6 Hz, J ¼ 8.6 Hz, 2 ar H], 7.18–7.23 (d, J ¼ 9.0 Hz, 2 ar
H), 7.31–7.38 (2 d, J ¼ 8.8 Hz, 2 ar H) ppm; HPLC:
tR ¼ 4.39min, k0 ¼ 1.49, RP-18b; tR ¼ 27.50 min, k0 ¼ 14.28,
Chiralcel OJ–R, MeCN=H2O 1=3.
Ethyl-2-[(2-chlorobenzylidene)amino]-4-methylvaleriate
(1w, C14H18ClNO2)
5 g (0.0344 mol) L-Leu-OMe was added to 4.8 g (0.0344 mol)
2-chlorobenzaldehyde. The mixture was cooled to room tem-
perature, dissolved in 250 cm3 CH2Cl2, dried (Na2SO4), and
evaporated in vacuo. Yield 7.9 g (86%); light yellow viscous
liquid; IR: ꢃꢀ¼ 3067, 2954 (CH), 1738 (CO), 1634 (C¼N),
1592 (ar), 756 (ar) cmꢀ1; 1H NMR (60 MHz): ꢂ ¼ 1.0–1.4 (m,
2Me), 1.7–2.32 (m, CH, CH2), 3.95 (s, OMe), 4.3 (t, J ¼ 6 Hz,
CH), 7.1–8.3 (m, 4 ar H), 8.8 (s, H–C¼) ppm.
Ethyl-(4-fluorophenylimino)acetate (1x, C10H10FNO2)
From 10.2g (0.1mol) ethyl glyoxylate (ꢄ20g, 50% solution
in toluene), 11.1g (0.1mol) 4-fluoroaniline, and 20 g MgSO4
in 200 cm3 toluene as described for 1u. Yield 7.8 g (40%);
orange solid used for the synthesis of 7b without further puri-
fication; IR: ꢃꢀ¼ 3381 (NH), 2993 (CH), 1740 (CO), 1612
trans-4-(4-Fluorophenyl)-1-(4-methoxyphenyl)-3-methyl-
azetidin-2-one (2d, C17H16FNO2)
From 1c and ethyl 2-bromopropionate. Yield 3.7 g (44%);
colorless crystals; mp 125ꢁC; IR: ꢃꢀ¼ 3058, 2973 (CH), 1731
(CO), 1518 (ar), 1389 (C–N), 1160 (C–F), 839, 804 (ar)
cmꢀ1; 1H NMR: ꢂ ¼ 0.85 (d, J ¼ 7.6 Hz, Me), 3.63 (m, 3-H),
3.76 (s, OMe), 5.13 (d, J ¼ 5.8 Hz, 4-H), 6.77–6.82 (d,
J ¼ 9.0 Hz, 2 ar H), 7.05–7.09 (t (2d), J ¼ 8.6 Hz, 2 ar H),
7.17–7.25 (m, 4 ar H) ppm; HPLC: tR ¼ 5.24 min, k0 ¼ 1.98,
RP-18b; tR ¼ 12.93, 14.52 min, k0 ¼ 6.18, 7.07, Chiralcel
OJ–Rc.
(C¼N), 1513 (ar), 1275 (C–F), 820 (ar) cmꢀ1
;
1H NMR
(300 MHz): ꢂ ¼ 1.38 (t, Me), 4.41 (q, CH2) 7.1 (t, 2 ar H),
7.32 (m, 2 ar H), 7.90 (s, H–C¼) ppm.
Synthesis of ꢀ-lactams 2. General procedure
In 50–100 cm3 toluene, equivalent amounts (0.05–0.1) of 1,
Zn (filings), and a crystal of I2 were refluxed, while ethyl
2-bromoalkanoate (0.05–0.1mol) was dropwise added with
stirring. Then, the mixture was refluxed for another 30min,
cooled to room temperature, and washed with conc. ammonia
(50 cm3), water (50 cm3), HCl (10%, 50 cm3), a solution of
NaHSO3 (20%, 50 cm3), and water. The organic layer was
dried (Na2SO4), and evaporated in vacuo. The residue was
crystallized from MeOH.
(RS)-1-(4-Methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]-
azetidin-2-one (2e, C17H14F3NO2)
From 1g and ethyl 2-bromoacetate. Yield 3.8 g (33%);
colorless needles; mp 135ꢁC; IR: ꢃꢀ¼ 3078, 2961 (CH),
1760 (CO), 1621, 1511 (ar), 1376 (C–N), 1298 (C–F),
854, 824, 800 (ar) cmꢀ1
;
1H NMR: ꢂ ¼ 2.88 (dd,
JAX ¼ 2.5, JAM ¼ 15.1 Hz, 3-H), 3.56 (dd, JMX ¼ 5.7,
JAM ¼ 15.1 Hz, 30-H), 3.74 (s, OMe), 5.03 (dd, JAX ¼ 2.5,
JMX ¼ 5.6 Hz, 4-H), 6.77–6.81 (d, J ¼ 9.0 Hz, 2 ar H), 7.17–
7.22 (d, J ¼ 9.2 Hz, 2 ar H), 7.46 (d, J ¼ 8.2 Hz, 2 ar H), 7.61
(d, J ¼ 8.6 Hz, 2 ar H) ppm; HPLC: tR ¼ 5.75 min, k0 ¼ 2.27,
RP-18c; tR ¼ 12.61, 13.50 min, k0 ¼ 6.01, 6.50, Chiralcel
OJ–Rc.
(RS)-1-(4-Fluorophenyl)-4-phenylazetidin-2-one
(2a, C15H12FNO)
From 1a and ethyl 2-bromoacetate. Yield 10 g (30%); color-
less crystals; mp 116ꢁC; IR: ꢃꢀ¼ 3060, 2956 (CH), 1739 (CO),
1511(ar), 1456, 1383, 1361 (N–C), 1210, 1156 (C–F), 837,
1
814, 759, 701 (ar) cmꢀ1; H NMR: ꢂ ¼ 2.91–3.0 (dd, JAX
¼
trans-1-(4-Methoxyphenyl)-3-methyl-4-[4-(trifluoromethyl)-
phenyl]azetidin-2-one (2f, C18H16F3NO2)
2.6, JAM ¼ 15.2Hz, 3-H), 3.51–3.61 (dd, JMX ¼ 5.7,
JAM ¼ 15.2Hz, 30-H), 4.96 (dd, JAX ¼ 2.6, JMX ¼ 5.7 Hz, 4-
H), 6.88–6.97 (t, J ¼ 8.6, J ¼ 8.8 Hz, 2 ar H), 7.22–7.36
(m, 7 ar H) ppm; HPLC: tR ¼ 4.88 min, k0 ¼ 1.77, RP-18b;
tR ¼ 12.17, 13.52 min, k0 ¼ 5.76, 6.51, Chiralcel OJ–Rc.
From 1g and ethyl 2-bromopropionate. Yield 3.3 g (35%);
colorless crystals; mp 107ꢁC; IR: ꢃꢀ¼ 3076, 2961 (CH), 1760
(CO), 1621, 1511 (ar), 1376, 1333, (C–F), 1246 (C–O), 854,
1
824 (ar) cmꢀ1; H NMR: ꢂ ¼ 0.85 (d, J ¼ 7.6 Hz, Me), 3.63
(m, 3-H), 3.76 (s, OMe), 5.20 (d, J ¼ 5.9Hz, 4-H), 6.78–6.83
(d, J ¼ 8.9 Hz, 2 ar H), 7.2–7.24 (d, J ¼ 8.9 Hz, 2 ar H), 7.33–
7.37 (d, J ¼ 8.0 Hz, 2 ar H), 7.61 (d, J ¼ 8.3 Hz, 2 ar H) ppm;
HPLC: tR ¼ 6.93min, k0 ¼ 2.94, RP-18b; tR ¼ 12.66, 14.99 min,
k0 ¼ 6.03, 7.33, Chiralcel OJ–Rc.
trans-1-(4-Fluorophenyl)-3-methyl-4-phenylazetidin-2-one
(2b, C16H14FNO)
From 1a and ethyl 2-bromopropionate. Yield 7.6g (48%);
colorless crystals; mp 123ꢁC; IR: ꢃꢀ¼ 3064, 2978 (CH),

ꢀ-Lactam derivatives as enzyme inhibitors
841
(CH), 1792 (CO), 1522 (ar), 1386 (C–N), 1187 (C–F), 838,
824, 763, 700 (ar) cmꢀ1; 1H NMR (300MHz): ꢂ ¼ 5.55 (s, 4-
H), 7.32 (m, 2 ar H), 7.45 (m, 5 ar H), 7.56 (d, J ¼ 8.9 Hz, 2
ar H) ppm; HPLC: t0 ¼ 1.77 min, k0 ¼ 7.16, RP-18b; t0 ¼
(RS)-1-(4-Fluorophenyl)-4-[4-(trifluoromethyl)phenyl]-
azetidin-2-one (2g, C16H11F4NO)
From 1f and ethyl 2-bromoacetate. Yield 2.5g (25%); color-
less crystals; mp 176–177ꢁC; IR: ꢃꢀ¼ 3085, 2971 (CH), 1749
(CO), 1513 (ar), 1384 (C–N), 1214, 1113 (C–F), 887, 815 (ar)
ꢂ;d
2.25min, k0 ¼ 9.07, 11.25, Chiralcel OJ–R
.
cmꢀ1
;
1H NMR: ꢂ ¼ 2.90–2.99 (dd, JAX ¼ 2.6, JAM
¼
15.2Hz, 3-H), 3.59 (dd, JMX ¼ 5.7, JAM ¼ 15.2Hz, 30-H),
5.03 (dd, JAX ¼ 2.6, JMX ¼ 5.7 Hz, 4-H), 6.91–7.0 [t(2d),
J ¼ 9.0 , 8.4Hz, 2 ar H], 7.20–7.26 (m, 2 ar H), 7.46 (d,
J ¼ 8.2 Hz, 2 ar H), 7.63 (d, J ¼ 8.2 Hz, 2 ar H) ppm; HPLC:
tR ¼ 6.25min, k0 ¼ 2.53, RP-18b; tR ¼ 22.33, 23.67 min,
k0 ¼ 11.40, 12.15, Chiralcel OJ–Rc.
(RS)-3,3-Dichloro-1,4-bis[4-(trifluoromethyl)phenyl]-
azetidin-2-one (3f, C17H9Cl2F6NO)
From 1e and Cl2CHCOCl. Yield 1.2g (28%); colorless crys-
tals; mp 113ꢁC (AcOEt=n-hexane); IR: ꢃꢀ¼ 1789 (CO), 1615,
1521 (ar), 1381 (C–N), 1327 (C–F), 1068 (C–Cl), 840 (ar)
cmꢀ1
;
1H NMR (300MHz): ꢂ ¼ 5.60 (s, 4-H), 7.37 (d,
J ¼ 8.5 Hz, 2 ar H), 7.45 (d, J ¼ 7.9 Hz, 2 ar H), 7.59 (d,
J ¼ 8.5 Hz, 2 ar H), 7.73 (d, J ¼ 8.2 Hz, 2 ar H) ppm; HPLC:
Synthesis of compounds 3–8. General procedure
t0 ¼ 1.77 min, k0 ¼ 10.23, RP-18b; t0 ¼ 2.25min, k0 ¼ 11.59,
A solution of 1 (0.2–0.5mol), and Et3N (0.2–0.5 mol) in
100 cm3 CH2Cl2 was dropwise added to a solution of the acid
chloride (0.2–0.5 mol) in 50 cm3 CH2Cl2 over 2 h. Then, the
mixture was refluxed for 30 min, cooled to room temperature
and filtered. The filtrate was pored into a mixture (1=1) of
0.1 N HCl and crashed ice, the organic layer was separated,
washed with a satd. solution of NaHCO3, dried (Na2SO4), and
evaporated in vacuo. The residue was crystallized as noted.
ꢂ;d
Chiralcel OJ–R
.
trans-3-Chloro-4-(4-fluorophenyl)-1-(3-nitrophenyl)azetidin-
2-one (3g, C15H10ClFN2O3)
From 1d and ClCH2COCl. Yield 0.6 g (9%); colorless crys-
tals; mp 140ꢁC (AcOEt=n-hexane); IR: ꢃꢀ¼ 3090 (CH), 1775
(CO), 1530, 1512 (ar), 1376 (C–N), 1229 (C–F), 880 (C–Cl),
840, 736 (ar) cmꢀ1
;
1H NMR (300MHz): ꢂ ¼ 4.67 (d,
J ¼ 2.1Hz, 3-H), 5.08 (d, J ¼ 2.1 Hz, 4-H), 7.15 (t, J ¼
8.5 Hz, 2 ar H), 7.39 (m, 2 ar H), 7.48 (t, J ¼ 8.1 Hz, 1 ar
H), 7.68 (dq, J ¼ 8.2 Hz, 1 ar H), 7.95–8.0 (m, 2 ar H) ppm;
HPLC: t0 ¼ 1.82 min, k0 ¼ 1.79, RP-18d; t0 ¼ 2.33min,
trans-3-Chloro-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-
azetidin-2-one (3b, C16H13ClFNO2)
From 1h and ClCH2COCl. Yield 1.3 g (19%); colorless needles;
mp 132ꢁC (Me2CHOH); IR: ꢃꢀ¼ 3067, 2964 (CH), 1759 (CO),
1508 (ar), 1382 (C–N), 1248 (C–F), 1028 (C–Cl), 834, 816 (ar)
k0 ¼ 5.11, Chiralcel OJ–R
.
ꢂ;b
1
cmꢀ1; H NMR (300 MHz): ꢂ ¼ 3.81 (s, OMe), 4.59 (d, J ¼
(RS)-1-Chloro-4-phenylazetidin-2-one (5, C9H8ClNO)
1.6 g (10.8 mmol) of 18 was dissolved in a mixture of Et2O
and H2O (100 cm3, 1=1) and with stirring, chlorine was blown
in for 1 h. Stirring was continued for 12h, the organic layer
was separated, dried (Na2SO4), and evaporated in vacuo. Yield
1.48g (75%); colorless crystals; mp 67ꢁC; IR: ꢃꢀ¼ 3086, 2959
1.9 Hz, 3-H), 4.93 (d, J ¼ 1.9 Hz, 4-H), 6.91–6.98 (m, 4 ar H),
7.23–7.29 (m, 4 ar H) ppm; HPLC: t0 ¼ 1.83 min, k0 ¼ 2.27,
b
RP-18 ; t0 ¼ 1.81 min, k0 ¼ 12.79, 14.67, Chiralcel OJ–R
.
ꢂ;c
(RS)-3,3-Dichloro-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-
azetidin-2-one (3c, C16H12Cl2FNO2)
(CH), 1791, 1772 (CO), 762, 701 (ar) cmꢀ1 1H NMR:
;
From 1h and Cl2CHCOCl. Yield 0.4 g (5%); colorless needles;
mp 140–141ꢁC (AcOEt=n-hexane); IR: ꢃꢀ¼ 3064, 2946 (CH),
1769 (CO), 1511 (ar), 1388 (C–N), 1264 (C–F), 834, 818 (ar)
cmꢀ1; 1H NMR: ꢂ ¼ 3.83 (s, OMe), 5.43 (s, 4-H), 6.93–7.02 (m,
4 ar H), 7.22–7.31 (m, 4 ar H) ppm; HPLC: t0 ¼ 1.77 min, k0 ¼
4.10, RP-18b; t0 ¼ 2.25min, k0 ¼ 8.59, 15.26, Chiralcel OJ–Rd.
ꢂ ¼ 3.05 (dd, JAM ¼ 2.6, JAX ¼ 13.6Hz, 3-H), 3.55 (dd,
JAM ¼ 5.5, JMX ¼ 13.6Hz, 30-H), 4.81 (dd, JAX ¼ 2.6, JMX
¼
5.5 Hz, 4-H), 7.34 (m, 5 ar H) ppm; HPLC: t0 ¼ 1.77min,
k0 ¼ 5.34, RP-18b; t0 ¼ 1.77 min, k0 ¼ 18.01, 19.29, Chiralcel
OJ–Rd.
N-(4-Methoxyphenyl)-3-methylbutyramide (6a, C12H17NO2)
a) From 8.1g isovalerianyl chloride, 9.3 g (12.8cm3) Et3N,
and 10g 1j. b) From 3 g 1k and 1.9 g isovalerianyl chloride.
Yield a) 6.2 g (49%), b) 0.7 g (28%); colorless needles; mp
126ꢁC (MeOH); IR: ꢃꢀ¼ 3293 (NH), 3049, 2954 (CH), 1655,
(RS)-3,3-Dichloro-1-(4-fluorophenyl)-4-phenylazetidin-2-
one (3d, C15H10Cl2FNO)
From 1a and Cl2CHCOCl. Yield 4.2 g (27%); colorless nee-
dles; mp 112ꢁC (MeOH); IR: ꢃꢀ¼ 3065, 2922 (CH), 1782,
1741 (CO), 1509 (ar), 1387 (C–N), 1229 (C–F), 1051 (C–
1
1601 (CO), 1530, 1513 (ar), 1369 (C–N), 823 (ar) cmꢀ1; H
1
Cl), 832, 765, 700 (ar) cmꢀ1; H NMR (300 MHz): ꢂ ¼ 5.49
NMR (300MHz): ꢂ ¼ 1.01 (d, J ¼ 6.5 Hz, 2 Me), 2.17–2.23
(m, CH, CH2), 3.78 (s, OMe), 6.85 (d, J ¼ 9.0 Hz, 2 ar H),
7.06 (s, H–N), 7.41 (d, J ¼ 9.0 Hz, 2 ar H) ppm; HPLC:
t0 ¼ 1.79 min, k0 ¼ 0.74, RP-18b; t0 ¼ 1.94min, k0 ¼ 3.87,
Chiralcel OJ–Rb.
(s, 4-H), 7.0 (t, J1 ¼ 8.4, J2 ¼ 8.8 Hz, 2 ar H), 7.29 (m, 5 ar H),
7.42-7.45 (m, 2 ar H) ppm; HPLC: t0 ¼ 1.83min, k0 ¼ 3.53,
RP-18b; t0 ¼ 1.73min, k0 ¼ 14.08, 21.35, Chiralcel OJ–R,
MeCN=H2O 45=55.
(RS)-3,3-Dichloro-4-phenyl-1-[4-(trifluoromethyl)phenyl]-
azetidin-2-one (3e, C16H10Cl2F3NO)
3-Methyl-N-(4-trifluoromethylphenyl)butyramide
(6b, C12H14F3NO)
From 1b and Cl2CHCOCl. Yield 1.7g (69%); light brown
crystals; mp 73–75ꢁC (MeOH=n-hexane); IR: ꢃꢀ¼ 3093, 2934
a) From 2.5 g 1b or b) from 3.2g 1e, 1.2 g isovalerianyl
chloride, and 1.5 g Et3N. Yield a) 1.3 g (53%); b) 0.6 g

842
A. Elriati et al.
(24%); colorless crystals; mp 123ꢁC (EtOH=n-hexane) (Ref. [9]
115ꢁC); IR: ꢃꢀ¼ 3305 (NH), 3040, 2952 (CH), 1669
(CO), 1526 (ar), 1335 (C–N), 1160 (C–F), 1068 (C–Cl),
(CH), 1767 (CO), 1513 (ar), 1390 (C–N), 1092 (C–Cl),
1
825, 808 (ar) cmꢀ1; H NMR (60 MHz): ꢂ ¼ 3.65 (s, OMe),
5.3 (s, 4-H), 6.63 (d, J ¼ 9.0 Hz, 2 ar H), 6.9–7.42 (m, 6 ar H)
ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 6.60 RP-18, MeCN=H2O
839 (ar) cmꢀ1
;
1H NMR (300 MHz): ꢂ ¼ 1.02 (d, J ¼
ꢂ;d
6.6 Hz, 2 Me), 2.17–2.27 (m, CH, CH2), 7.30 (s, H–N),
7.56 (d, J ¼ 8.7 Hz, 2 ar H), 7.66 (d, J ¼ 8.6 Hz, 2 ar H)
ppm; HPLC: t0 ¼ 1.77 min, k0 ¼ 1.90, RP-18b; t0 ¼ 2.30 min,
7=3); t0 ¼ 2.21min, k0 ¼ 15.17, 16.67, Chiralcel OJ–R
.
(RS)-3,3-Dichloro-4-(4-chlorophenyl)-1-(4-fluorophenyl)-
azetidin-2-one (9b, C15H9Cl3FNO)
ꢂ;c
k0 ¼ 4.00, Chiralcel OJ–R
.
From 3 g 1l and 1.9 g Cl2CHCOCl. Yield 2.8g (63%); color-
less needles; mp 118ꢁC (EtOH); IR: ꢃꢀ¼ 3088 (CH), 1780
(CO), 1509 (ar), 1385 (C–N), 1228 (C–F), 1092 (C–Cl),
(E)-Methyl-3-(4-methoxyphenylcarbamoyl)acrylate
(7a, C12H13NO4) [10]
1
From 5 g 1p, 3.2 g Et3N, and 4.7g methyl 3-(chlorocarbon-
yl)acrylate. Yield 0.7g (12%); yellow needles; mp 169–170ꢁC
(MeOH); IR: ꢃꢀ¼ 3353 (NH), 3072, 2955 (CH), 1715, 1677,
833, 820 (ar) cmꢀ1; H NMR (300MHz): ꢂ ¼ 5.46 (s, 4-H),
6.99 (t, J ¼ 8.4 Hz, 2 ar H), 7.24–7.29 (m, 4 ar H), 7.41 (d,
J ¼ 8.5 Hz, 2 ar H) ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 3.76, RP-
1
b
ꢂ;d
1645 (CO), 1545, 1512 (ar), 1342 (C–N), 830 (ar) cmꢀ1; H
18 ; t0 ¼ 2.26min, k0 ¼ 9.20, 11.48, Chiralcel OJ–R
.
NMR (300MHz): ꢂ ¼ 3.80, 3.82 (2 s, 2 OMe), 6.87 (d,
J ¼ 9 Hz, 2 ar H), 6.92–7.10 (dd, J ¼ 15.3Hz, HC¼CH),
7.51 (d, J ¼ 9.1 Hz, 2 ar H), 7.61 (s, H–N) ppm; HPLC:
t0 ¼ 1.83 min, k0 ¼ 0.57, RP-18b; t0 ¼ 1.87min, k0 ¼ 3.86
(3.85), Chiralcel OJ–Rb.
(RS)-3,3-Dichloro-4-(2-chlorophenyl)-1-(4-methoxyphenyl)-
azetidin-2-one (9c, C16H12Cl3NO2)
From 3 g 1m and 2.6 g Cl2CHCOCl. The residue was dis-
solved in Me2CHOH, and dropwise addition of PE yielded
light yellow crystals. Yield 1.8 g (41%); colorless needles; mp
136.5ꢁC (EtOH); IR: ꢃꢀ¼ 1778 (CO), 1513 (ar), 1388 (C–N),
(E)-Methyl-3-(4-fluorophenylcarbamoyl)acrylate
(7b, C11H10FNO3)
1052 (C–Cl), 838, 754 (ar) cmꢀ1 1H NMR (300 MHz):
;
a) From 8 g 1a, 4.5 g Et3N, and 6.8 g methyl 3-(chlorocarbon-
yl)acrylate. b) From 5 g 1x, 3.37 g Et3N, and 4.95g methyl 3-
(chlorocarbonyl)acrylate. Yield a) 2.4 g (27%); b) 2.3g (40%);
colorless needles; mp 169–170ꢁC (MeOH); IR: ꢃꢀ¼ 3358
(NH), 3066, 2955 (CH), 1710, 1679, 1649 (CO), 1551, 1510
ꢂ ¼ 3.78 (s, OMe), 5.89 (s, 4-H), 6.8–7.6 (m, 8 ar H) ppm;
HPLC: t0 ¼ 1.77 min, k0 ¼ 5.54, RP-18b; t0 ¼ 2.21min, k0 ¼
ꢂ;d
13.65, Chiralcel OJ–R
.
(RS)-3,3-Dichloro-1-(4-fluorophenyl)-4-phenylazetidin-2-
one (9d, C15H10Cl2FNO)
(ar), 1339 (C–N), 1206 (C–F), 847 (ar) cmꢀ1 1H NMR
;
(300 MHz): ꢂ ¼ 3.83 (s, OMe), 6.93–7.11 (dd, J ¼ 15.3 Hz,
HC¼CH), 7.0–7.7 (m, 4 ar H), 7.67 (s, H–N) ppm; HPLC:
t0 ¼ 1.83 min, k0 ¼ 0.62 (0.68), RP-18b; t0 ¼ 1.87min,
k0 ¼ 4.23 (4.17), Chiralcel OJ–Rb.
From 3 g 1a and 2.2g Cl2CHCOCl. Yield 2.5g (53%); color-
less needles; mp 134–136ꢁC (EtOH); IR: ꢃꢀ¼ 1784 (CO),
1510 (ar), 1388 (C–N), 1231 (C–F), 832, 700 (ar) cmꢀ1
;
1H NMR (300MHz): ꢂ ¼ 5.49 (s, 4-H), 7.02 (t, J1 ¼ 9.0,
J2 ¼ 8.3 Hz, 2 ar H), 7.29 (m, 5 ar H), 7.44 (m, 2 ar H)
ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 4.10, RP-18b; t0 ¼ 2.26 min,
2-Chloro-N-(4-methoxyphenyl)acetamide (8, C9H10ClNO2)
From 3 g 1v and 1.4 g ClCH2COCl. Yield 0.4g (17%); color-
less crystals; mp 120–121ꢁC (AcOEt=n-hexane); IR: ꢃꢀ¼ 3294
(NH), 3073, 2957 (CH), 1665, 1630 (CO), 1512 (ar), 1345
ꢂ;d
k0 ¼ 9.65, 14.30, Chiralcel OJ–R
.
(RS)-3,3-Dichloro-4-[4-(dimethylamino)phenyl]-1-(4-fluoro-
phenyl)azetidin-2-one (9e, C17H15Cl2FN2O)
1
(C–N), 1251 (C–F), 1030 (C–Cl), 830 (ar) cmꢀ1; H NMR
(300 MHz): ꢂ ¼ 3.80 (s, OMe), 4.18 (s, CH2), 6.89 (d,
J ¼ 9.0 Hz, 2 ar H), 7.44 (d, J ¼ 9.0 Hz, 2 ar H), 8.14 (s,
N–H) ppm; HPLC: t0 ¼ 1.73 min, k0 ¼ 1.56, RP-18d; t0 ¼
From 3 g 1i and 1.9 g Cl2CHCOCl. Yield 2.3g (52%); color-
less needles; mp 148–150ꢁC (EtOH); IR: ꢃꢀ¼ 1778 (CO),
1510 (ar), 1386 (C–N), 1232 (C–F), 1054 (C–Cl), 834, 816
ꢂ;b
2.29min, k0 ¼ 3.52, Chiralcel OJ–R
.
1
(ar) cmꢀ1; H NMR (300MHz): ꢂ ¼ 2.99 (s, NMe2), 5.38 (s,
4-H), 6.69 (d, J ¼ 8.9 Hz, 2 ar H), 6.97 (t, J1 ¼ 9.0, J2 ¼
8.4 Hz, 2 ar H), 7.15 (d, J ¼ 8.8 Hz, 2 ar H), 7.31 (dd,
J1 ¼ 9.1, J2 ¼ 4.6 Hz, 2 ar H) ppm; HPLC: t0 ¼ 1.77min,
Synthesis of ꢀ-lactams 9–12. General procedure
The acyl chloride was given at once to a solution of 1 in
toluene (80 cm3). Then, Et3N (2.5g, 0.024 mol, 3.4 cm3) dis-
solved in toluene (80 cm3) was dropwise added with heating.
After refluxing for 3–4 h, the solution was cooled to room
temperature, filtered, the filtrate was dried (Na2SO4), and
evaporated in vacuo. The residue was crystallized or purified
by CC.
k0 ¼ 5.72, RP-18b; t0 ¼ 2.26 min, k0 ¼ 19.81, 26.67, Chiralcel
ꢂ;d
OJ–R
.
(RS)-3,3-Dichloro-4-(2-chlorophenyl)-1-(2-fluorophenyl)-
azetidin-2-one (9f, C15H9Cl3FNO)
From 3 g 1r and 1.8g Cl2CHCOCl. Yield 0.6 g (14%); color-
less solid; mp 113–114ꢁC (Me2CHOH); IR: ꢃꢀ¼ 1785 (CO),
1504 (ar), 1372 (C–N), 1238 (C–F), 1053 (C–Cl), 754 (ar)
(RS)-3,3-Dichloro-4-(4-chlorophenyl)-1-(4-methoxyphenyl)-
azetidin-2-one (9a, C16H12Cl3NO2)
cmꢀ1
;
1H NMR (60 MHz): ꢂ ¼ 6.22 (d, J ¼ 3.6 Hz, 4-H),
From 5 g 1k and 3 g Cl2CHCOCl. Yield 1.5 g (17%); colorless
crystals; mp 135ꢁC (AcOEt=n-hexane); IR: ꢃꢀ¼ 3087, 2998
6.99–7.09 (m, 2 ar H), 7.15–7.23 (m, 3 ar H), 7.30–7.36
(dt, 1 ar H), 7.49–7.52 (dd, 1 ar H), 8.02–8.08 (dt, 1 ar H)

ꢀ-Lactam derivatives as enzyme inhibitors
843
ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 6.02, RP-18b; t0 ¼ 2.26min,
(C–Cl), 835, 814, 784 (ar) cmꢀ1
;
1H NMR (60 MHz):
ꢂ;d
k0 ¼ 8.37, 8.60, Chiralcel OJ–R
.
ꢂ ¼ 5.72 (s, 4-H), 6.5–7.6 (m, 7 ar H) ppm; HPLC:
t0 ¼ 1.77 min, k0 ¼ 3.63, RP-18b; t0 ¼ 2.27min, k0 ¼ 6.55,
ꢂ;d
Chiralcel OJ–R
.
(RS)-3,3-Dichloro-4-(4-chlorophenyl)-1-(2-fluorophenyl)-
azetidin-2-one (9g, C15H9Cl3FNO)
trans-3-Chloro-4-(4-chlorophenyl)-1-(4-fluorophenyl)-
azetidin-2-one (10b, C15H10Cl2FNO)
From 3 g 1s and 1.9g Cl2CHCOCl. Yield 2.5 g (57%); color-
less crystals; mp 119–121ꢁC (Me2CHOH=PE); IR: ꢃꢀ¼ 1780
(CO), 1504 (ar), 1374 (C–N), 1240 (C–F), 1093 (C–Cl), 827,
From 3 g 1l and 1.45g ClCH2COCl. Yield 1.2g (30%); color-
less crystals; mp 115ꢁC (Me2CHOH=PE 1=1); IR: ꢃꢀ¼ 1769
(CO), 1509 (ar),1380 (C–N), 1229 (C–F), 1091 (C–Cl), 831,
817 (ar) cmꢀ1; 1H NMR (60 MHz): ꢂ ¼ 4.46 (d, J ¼ 2.4 Hz, 3-
H), 4.82 (d, J ¼ 2.4 Hz, 4-H), 6.63–7.38 (m, 8 ar H) ppm;
817, 763 (ar) cmꢀ1
;
1H NMR (300MHz): ꢂ ¼ 5.7 (d,
J ¼ 3.5 Hz, 4-H), 6.9–8.0 (m, 8 ar H) ppm; HPLC: t0 ¼
1.77min, k0 ¼ 5.96, RP-18b; t0 ¼ 2.05min, k0 ¼ 11.26, 11.43,
ꢂ;d
Chiralcel OJ–R
.
HPLC: t0 ¼ 1.77 min, k0 ¼ 3.77, RP-18b; t0 ¼ 2.26min, k0 ¼
ꢂ;d
9.21, 11.82, Chiralcel OJ–R
.
(RS)-3,3-Dichloro-4-(4-chlorophenyl)-1-(3-fluorophenyl)-
azetidin-2-one (9h, C15H9Cl3FNO)
From 3 g 1t and 1.9 g Cl2CHCOCl. Yield 1.1 g (25%); color-
less plats; mp 97ꢁC (EtOH); IR: ꢃꢀ¼ 1782 (CO), 1611, 1594
(ar), 1387 (C–N), 1256 (C–F), 1092 (C–Cl), 845, 827, 784,
trans-3-Chloro-4-(2-chlorophenyl)-1-(2-fluorophenyl)-
azetidin-2-one (10d, C15H10Cl2FNO)
From 3 g 1r and 1.6 g ClCH2COCl. Yield 1.1 g (35%); col-
orless needles; mp 114–116ꢁC (Me2CHOH); IR: ꢃꢀ¼ 1777,
1758 (CO), 1504 (ar), 1373 (C–N), 1230 (C–F), 1037
1
772 (ar) cmꢀ1; H NMR (300 MHz): ꢂ ¼ 5.47 (s, 4-H), 6.8–
7.5 (m, 8 ar H) ppm; HPLC: t0 ¼ 2.05min, k0 ¼ 7.37, RP-18b;
ꢂ;d
t0 ¼ 2.26 min, k0 ¼ 12.14, 12.58, Chiralcel OJ–R
.
(C–Cl), 754 (ar) cmꢀ1
;
1H NMR (300 MHz): ꢂ ¼ 4.66
(d, J ¼ 2.0 Hz, 3-H), 5.76 (dd, J1 ¼ 2.0 Hz, J2 ¼ 3.4 Hz,
4-H), 6.99–7.30 (m, 6 ar H), 7.45 (d, J ¼ 7.6 Hz, 1 ar H),
7.99 (dt, J1 ¼ 1.9 Hz, J2 ¼ 7.8 Hz, 1 ar H) ppm; HPLC:
t0 ¼ 1.77 min, k0 ¼ 3.72, RP-18b; t0 ¼ 2.49 min, k0 ¼ 14.63,
(RS)-3,3-Dichloro-1-(4-methoxyphenyl)4-[4-(trifluoro-
methyl)phenyl]azetidin-2-one (9i, C17H12Cl2F3NO3)
From 2.5 g 1g and 1.3g Cl2CHCOCl. Yield 1.2 g (34%); col-
orless crystals; mp 110–112ꢁC (Me2CHOH); IR: ꢃꢀ¼ 3010,
2981 (CH), 1781 (CO), 1511 (ar), 1327 (C–N), 1256 (C–F),
;
1065 (C–Cl), 840, 807 (ar) cmꢀ1 1H NMR (300MHz):
ꢂ
Chiralcel OJ–R , MeCN=H2O 4=6.
trans-3-Chloro-4-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-
azetidin-2-one (10e, C15H9Cl3FNO)
ꢂ ¼ 3.78 (s, OMe), 5.75 (s, 4-H), 6.15–7.5 (m, 8 ar H) ppm;
HPLC: t0 ¼ 1.75min, k0 ¼ 11.63, RP-18b; t0 ¼ 2.25min,
From 3 g 1o and 1.3g ClCH2COCl. Yield 0.3g (13%); color-
less solid; mp 83ꢁC (Me2CHOH=PE); IR: ꢃꢀ¼ 1774 (CO),
1509 (ar), 1378 (C–N), 1229 (C–F), 1047 (C–Cl), 832, 818,
743 (ar) cmꢀ1; 1H NMR (60 MHz): ꢂ ¼ 4.40 (d, J ¼ 2.6 Hz, 3-
H), 5.2 (d, J ¼ 2.6 Hz, 4-H), 6.48–7.32 (m, 7 ar H) ppm;
ꢂ;d
k0 ¼ 8.57, Chiralcel OJ–R
.
(RS)-3,3-Dichloro-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-
azetidin-2-one (9j, C16H12Cl2FNO2)
HPLC: t0 ¼ 1.77min, k0 ¼ 6.65, RP-18b; t0 ¼ 2.32min, k0 ¼
From 3 g 1h and 1.9 g Cl2CHCOCl. Yield 3.5 g (79%);
colorless crystals; mp 145–147ꢁC (Me2CHOH=n-hexane);
IR: ꢃꢀ¼ 3064 (CH), 1769 (CO), 1512 (ar), 1388 (C–N),
ꢂ;b
1.93, Chiralcel OJ–R
.
1264 (C–F), 1028 (C–Cl), 834, 818 (ar) cmꢀ1 1H NMR
;
trans-3-Chloro-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-
azetidin-2-one (10f, C16H13ClFNO2)
(300 MHz): ꢂ ¼ 3.83 (s, OMe), 5.43 (s, 4-H), 6.9–7.4 (m, 8
ar H) ppm; HPLC: t0 ¼ 2.05 min, k0 ¼ 4.15, RP-18b; t0 ¼
From 3 g 1h and 1.5 g ClCH2COCl. Yield 1.8g (45%); color-
less crystals; mp 138–139ꢁC (Me2CHOH=n-hexane); IR: ꢃꢀ¼
2965 (CH), 1759 (CO), 1508 (ar), 1382 (C–N), 1248 (C–F),
;
1028 (C–Cl), 834, 816 (ar) cmꢀ1 1H NMR (300 MHz):
ꢂ;d
2.25min, k0 ¼ 8.38, 15.09, Chiralcel OJ–R
.
(RS)-Benzyl 3,3-dichloro-4-(4-chlorophenyl)-2-oxoazetidin-
1-yl]acetate (9k, C18H14Cl3NO3)
ꢂ ¼ 3.78 (s, OMe), 4.60 (d, J ¼ 1.9Hz, 3-H), 4.94 (d, J ¼
1.9 Hz, 4-H), 6.9–7.3 (m, 8 ar H) ppm; HPLC: t0 ¼ 2.05 min,
From 3 g 1q and 1.5 g Cl2CHCOCl. Yield 0.3 g (7%); brown
solid; mp 95ꢁC (Me2CHOH); IR (KBr): ꢃꢀ¼ 3068, 2971 (CH),
1796, 1750 (CO), 1492 (ar), 1386 (C–N), 1089 (C–Cl), 828
k0 ¼ 2.55, RP-18b; t0 ¼ 2.27min, k0 ¼ 4.51, 5.13, Chiralcel
ꢂ;d
OJ–R
.
1
(ar) cmꢀ1; H NMR (60 MHz): ꢂ ¼ 3.5, 4.4 (2 d, J ¼ 18 Hz,
CH2), 5.02 (s, CH2(benzyl)), 5.4 (s, 4-H), 6.9–7.4 (m, 9 ar H)
ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 4.72, RP-18b; t0 ¼ 2.21min,
trans-3-Chloro-4-(2,4-difluorophenyl)-1-(4-fluorophenyl)-
azetidin-2-one (10g, C15H9ClF3NO)
ꢂ
k0 ¼ 6.32, 9.11, Chiralcel OJ–R , MeCN=H2O 6=4.
From 3 g 1u and 1.5 g ClCH2COCl. Yield 1.6g (40%); color-
less crystals; mp 89–93ꢁC (Et2O); IR: ꢃꢀ¼ 1771 (CO), 1510
(ar), 1380 (C–N), 1221 (C–F), 835, 728 (ar) cmꢀ1; 1H NMR
(60 MHz): ꢂ ¼ 5.51 (d, J ¼ 2.4Hz, 3-H), 5.38 (d, J ¼ 2.4 Hz,
4-H), 6.6–7.8 (m, 7 ar H) ppm; HPLC: t0 ¼ 1.77min,
(RS)-3,3-Dichloro-4-(2,4-difluorophenyl)-1-(4-fluorophenyl)-
azetidin-2-one (9l, C15H8Cl2F3NO)
From 3 g 1u and 1.9 g Cl2CHCOCl. Yield 1.3 g (29%); color-
less needles; mp 121–122.5ꢁC (EtOH); IR: ꢃꢀ¼ 3081 (CH),
1737 (CO), 1626, 1593 (ar), 1391 (C–N), 1231 (C–F), 1054
k0 ¼ 2.50, RP-18b; t0 ¼ 2.27min, k0 ¼ 3.70, 4.08, Chiralcel
ꢂ;d
OJ–R
.

844
A. Elriati et al.
(RS)-Methyl 2-[3,3-dichloro-2-(2-chlorophenyl)-4-
trans-4-(4-Chlorophenyl)-1-(4-fluorophenyl)-3-isopropyl-
azetidin-2-one (11a, C18H17ClNO)
oxoazetidin-1-yl]-4-methylpentanoate (12, C16H18Cl3NO3)
From 2.7 g 1w and 1.5 g Cl2CHCOCl. Yield 0.4g (11%);
lightly colored crystals; mp 85ꢁC (Me2CHOH); IR:
ꢃꢀ¼ 3073, 2958 (CH), 1788, 1778, 1745 (CO), 1331 (C–N),
From 3 g 1l and 1.6 g isovalerianyl chloride as 9c. Yield 0.6 g
(15%); colorless needles; mp 136ꢁC (EtOH); IR: ꢃꢀ¼ 2961
(CH), 1740 (CO), 1510 (ar), 1385 (C–N), 1226 (C–F), 1092
1
1
(C–Cl), 835, 817 (ar) cmꢀ1; H NMR (300MHz): ꢂ ¼ 1.06,
1039 (C–Cl), 760 (ar) cmꢀ1; H NMR (300MHz): ꢂ ¼ 0.85,
1.14 (2 d, each J ¼ 6.7 Hz, Me), 2.20 (m, CH), 2.88 (dd,
0.95 (2d, each J ¼ 6.2 Hz, Me), 1.59–1.78 (m, CH, CH2(Leu)),
3.78 (s, OMe), 4.25 (m, ꢁ-H(Leu)), 5.81 (s, 4-H), 7.2–7.5 (m, 4
ar H) ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 6.13, RP-18b; t0 ¼
J1 ¼ 2.4 Hz, J2 ¼ 8.4 Hz, 3-H), 4.66 (d, J ¼ 2.4Hz, 4-H),
6.9–7.4 (m, 8 ar H) ppm; HPLC: t0 ¼ 1.77min, k0 ¼ 6.47,
b
ꢂ;d
ꢂ;d
RP-18 ; t0 ¼ 2.26 min, k0 ¼ 9.95, 10.55, Chiralcel OJ–R
.
2.25min, k0 ¼ 4.35, 4.83, Chiralcel OJ–R
.
(RS)-Diethyl 1-(4-methylphenyl)-2-oxo-3-(trimethylsilyl)-
azetidine-4,4-dicarboxylate (15, C19H27NO5Si)
trans-4-(2-Chlorophenyl)-1-(4-fluorophenyl)-3-isopropyl-
azetidin-2-one (11b, C18H17ClFNO)
From 0.01mol 14, 0.02 mol LDA, and 0.05 mol CTMS, 1 h,
ꢀ78ꢁC, as described in Ref. [27]. Yield 98%; light yellow
From 3 g 1n and 1.6 g isovalerianyl chloride. Yield 1.0 g
(25%); colorless needles; mp 136–138ꢁC (Me2CHOH); IR:
ꢃꢀ¼ 3069, 2959 (CH), 1747 (CO), 1508 (ar), 1388 (C–N),
1
liquid; IR: ꢃꢀ¼ 2980, 2950, 2920 (CH), 1750 (CO) cmꢀ1; H
1224 (C–F), 1033 (C–Cl), 830, 757 (ar) cmꢀ1 1H NMR
;
NMR (80 MHz): ꢂ ¼ 0.14 (s, 3 Me), 1.24 (2 t, 2 Me), 2.28 (s,
Me), 3.48 (s, 3-H), 4.26 (2 q, 2CH2), 7.2 (q, 4 ar H) ppm.
(60 MHz): ꢂ ¼ 1.11, 1.15 (2d, each J ¼ 6 Hz, Me), 2.3 (m,
CH), 3.0 (dd, J1 ¼ 2.0, J2 ¼ 6.4 Hz, 3-H), 5.15 (d,
J ¼ 2.0 Hz, 4-H), 6.51–7.42 (m, 8 ar H) ppm; HPLC: t0 ¼
Diethyl 3-(ꢁ-hydroxyisopropyl)-1-(4-methylphenyl)-2-
oxoazetidine-4,4-dicarboxylate (16a, C19H25NO6)
1.77min, k0 ¼ 7.11, RP-18b; t0 ¼ 2.26min, k0 ¼ 8.15, 8.45,
ꢂ;d
Chiralcel, OJ–R
.
From 0.005 mol 14, 0.02mol acetone, and 0.01mol LDA as
16c. Yield 0.3 g (8%); colorless crystals; mp 198–200ꢁC
(Acetone); IR: ꢃꢀ¼ 3420 (OH), 2980, 2930 (CH), 1740 (CO)
trans-4-(2,4-Dichlorophenyl)-1-(4-fluorophenyl)-3-isopro-
pylazetidin-2-one (11c, C18H16Cl2FNO)
1
cmꢀ1; H NMR (80 MHz, CDCl3=DMSO-d6: 1=3): ꢂ ¼ 1.24
(t, 2 Me), 1.30 (s, 2 Me), 2.24 (s, Me), 3.38 (s, O–H), 3.49 (s,
4-H), 4.16 (q, 2CH2), 7.26 (q, 4 ar H) ppm.
From 3 g 1o and 1.4g isovalerianyl chloride. Yield 0.1 g
(2.5%); colorless needles; mp 128ꢁC (Me2CHOH); IR:
ꢃꢀ¼ 3063, 2960 (CH) 1740 (CO), 1509 (ar), 1381 (C–N),
1231 (C–F), 1045 (C–Cl), 831, 816, 755 (ar) cmꢀ1 1H
;
Diethyl 3-(ꢁ-hydroxyethyl)-1-(4-methylphenyl)-2-
oxoazetidine-4,4-dicarboxylate (16b, C18H23NO6)
NMR (300MHz): ꢂ ¼ 0.90, 1.00 (2d, each J ¼ 6.0 Hz, Me),
1.63 (m, CH), 2.8 (dd, J1 ¼ 2.0, J2 ¼ 7.0Hz, 3-H), 4.9 (d,
From 0.005 mol 14, 0.05mol acetaldehyde, and 0.01mol
LDA. Yield 0.4 g (12%); colorless crystals; mp 196–198ꢁC
(MeOH=Et2O: 1=1); IR: ꢃꢀ¼ 3430 (OH), 3160, 2980, 2920,
J ¼ 2.0 Hz, 4-H), 6.5-7.4 (m,
7 ar H) ppm; HPLC:
t0 ¼ 1.77 min, k0 ¼ 11.98, 12.11, RP-18b; t0 ¼ 2.49min, k0 ¼
2860 (CH), 1750, 1745 (CO) cmꢀ1 1H NMR (80 MHz,
;
ꢂ;d
11.09, 11.49, 12.50, Chiralcel OJ–R
.
CDCl3=DMSO-d6, 1=1): ꢂ ¼ 1.24 (m, 2 Me), 2,27 (s, Me),
3.36 (s, O–H), 3.3–4.2 (m, 3-H, Me), 4.34 (q, 2CH2), 6.42
(s, ꢁ-H), 7.24 (q, 4 ar H) ppm.
trans-4-[4-(Dimethylamino)phenyl]-1-(4-fluorophenyl)-3-
isopropylazetidin-2-one (11d, C20H23FN2O)
From 3 g 1i and 1.5g isovalerianyl chloride. Yield 1.7 g (42%);
colorless needles; mp 134ꢁC (EtOH); IR: ꢃꢀ¼ 3077, 2961
(CH), 1731 (CO), 1614, 1508 (ar), 1386 (C–N), 1212 (C–
Diethyl 3-(ꢁ-hydroxy-4-nitrobenzyl)-1-(4-methylphenyl)-2-
oxoazetidine-4,4-dicarboxylate (16c, C23H24N2O8)
1
F), 1068 (C–Cl), 834, 810 (ar) cmꢀ1; H NMR (300 MHz):
From 0.005 mol 14 and 0.0075mol 4-nitrobenzaldehyde with
0.01mol LDA as described in Ref. [28] 1 h, ꢀ78ꢁC. Yield
0.9 g (39%); colorless crystals; mp 154ꢁC (dec., EtOH);
IR: ꢃꢀ¼ 3430 (OH), 3080, 3040, 2980, 2920 (CH), 1740
ꢂ ¼ 1.05, 1.75 (2d, each J ¼ 6.7 Hz, Me), 2.15 (m, CH), 2.9
(dd, J1 ¼ 2.3, J2 ¼ 8.4 Hz, 3-H), 2.94 (s, NMe2), 4.61 (d,
J ¼ 2.3 Hz, 4-H), 6.6–7.3 (m, 8 ar H) ppm; HPLC: t0 ¼
2.05min, k0 ¼ 7.20, RP-18b; t0 ¼ 2.26min, k0 ¼ 6.13, 6.71,
1
(CO), 1510, 1340 (NO2) cmꢀ1; H NMR (80 MHz, CDCl3=
ꢂ;d
Chiralcel OJ–R
.
DMSO-d6, 1=1): ꢂ ¼ 1,12 (t, 2 Me), 2.27 (s, Me), 3.24–4.28
(m, 2CH2, 3-H, O–H), 5.42 (s, ꢁ-H), 7.3 (q, 4 ar H), 8.0 (q, 4
ar H) ppm.
trans-1-(4-Fluorophenyl)-3-isopropyl-4-(4-methoxyphenyl)-
azetidin-2-one (11e, C19H20FNO2)
(E)-Diethyl 3-(4-chlorobenzylidene)-1-(4-methylphenyl)-2-
oxoazetidine-4,4-dicarboxylate (17a, C23H22ClNO5)
From 3 g 1h and 1.6 g isovalerianyl chloride. Yield 1.1 g
(27%); colorless crystals; mp 114–115ꢁC (Me2CHOH=n-hex-
ane); IR: ꢃꢀ¼ 3065, 2958 (CH), 1736 (CO), 1510 (ar), 1386
(C–N), 1248 (C–F), 832, 818 (ar) cmꢀ1; 1H NMR (300MHz):
ꢂ ¼ 1.08, 1.14 (2 d, each J ¼ 6.7 Hz, Me), 2.17 (m, CH), 2.89
(dd, J1 ¼ 2.5 Hz, J2 ¼ 8.4Hz, 3-H), 3.80 (s, OMe), 4.65 (d,
J ¼ 2.4, 4-H), 6.8–7.3 (m, 8 ar H) ppm; HPLC: t0 ¼
From 0.0005 mol 15, 0.01mol LDA, and 0.0075 mol p-chlo-
robenzaldehyde, ꢀ78ꢁC, 1 h, as described in Ref. [28]. Yield
1.4 g (56%); colorless crystals; mp 105–106ꢁC (EtOH); IR:
ꢃꢀ¼ 3060, 3040, 2980, 2940, 2890 (CH), 1750, 1730 (CO),
1
1680 (C=C) cmꢀ1; H NMR (80 MHz): ꢂ ¼ 1.24 (t, 2 Me),
2.05min, k0 ¼ 3.96, RP-18b; t0 ¼ 2.27min, k0 ¼ 4.29, 4.56,
2.31 (s, Me), 4.3 (q, 2CH2), 6.66 (s, ꢁ-H), 6.95–8.06 (m, 8 ar
H) ppm.
ꢂ;d
Chiralcel OJ–R
.

ꢀ-Lactam derivatives as enzyme inhibitors
845
J ¼ 2.5Hz, 15.0Hz, 3-Htrans), 3.50 (dd, J ¼ 5.0, 15.0Hz,
3-Hcis) 3.98 (d, J ¼ 16.0Hz, 1H, CH2), 4.53 (dd, J ¼ 2.5,
5.0 Hz, 4-H), 4.83 (d, J ¼ 16.0Hz, 1H, CH2), 7.33–7.73 (m,
9 ar H) ppm.
(E)-Diethyl 3-(4-nitrobenzylidene)-1-(4-methylphenyl)-2-
oxoazetidine-4,4-dicarboxylate (17b, C23H22N2O7)
From 0.005 mol 15, 0.01 mol LDA, and 0.0075 mol p-nitro-
benzaldehyde, ꢀ78ꢁC, 45min, as 17a. Yield 1.53 g (70%);
yellow crystals; mp 142–144ꢁC (EtOH); IR: ꢃꢀ¼ 3100, 3060,
1
3040, 2980, 2940, 2850 (CH), 1750, 1730 (CO) cmꢀ1; H
(RS)-1-(3,4,5-Trimethoxybenzyl)-4-phenylazetidin-2-one
NMR (80 MHz): ꢂ ¼ 1.26 (t, 2 Me), 2.34 (s, Me), 4.36 (q,
(19f, C19H21NO4)
From 18 and 3.3g (15 mmol) 3,4,5-trimethoxybenzyl chloride,
2CH2), 6.88 (s, ꢁ-H), 7.34 (q, 4 ar H), 8.22 (m, 4 ar H) ppm.
20
CC (CHCl3). Yield 1.7 g (52%); colorless liquid; nD
1.5086; IR: ꢃꢀ¼ 3080, 3000 (CH), 2940 (OMe), 2840 (CH),
¼
Synthesis of N-benzyl-ꢀ-lactams 19. General procedure
Compund 18 (1.47 g, 10 mmol) was dissolved in 100 cm3
THF. Then 620 mg (11 mmol) KOH (pulv.), 320 mg (1mmol)
TBABr, and 15 mmol of the benzyl halogenide were added.
The mixture was stirred for 8 h at room temperature, filtered,
and the filtrate was evaporated. The residue was dissolved in
CH2Cl2, twice washed with water, dried (Na2SO4), and evap-
orated in vacuo. Work-up as noted.
1745 (CO), 1590, 1500 (ar) cmꢀ1 1H NMR (80 MHz):
;
ꢂ ¼ 2.90 (dd, J ¼ 2.5 Hz, 14.5Hz, 3-Htrans), 3.43 (dd, J ¼
5.0, 14.5Hz, 3-Hcis), 3.82 (s, 2 OMe), 3.82 (d, J ¼
15.0Hz, 1H, CH2), 3.88 (s, OMe), 4.48 (dd, J ¼ 2.5, 5.0Hz,
4-H), 4.73 (d, J ¼ ꢀ15.0Hz, 1H, CH2), 6.42 (s, 2 ar H), 7.20–
7.63 (m, 5 ar H) ppm.
trans-4,5-Diphenylpyrrolidin-2-one (20a, C16H15NO)
A solution of 2.4g (10 mmol) 19a was dropwise added to a
solution of 1.3 g (20 mmol) BuLi in 10 cm3 THF at ꢀ78ꢁC, the
mixture was stirred for 1 h, and then pored into 100 cm3 of a
satd. solution of NaCl. The organic layer was separated, dried
(Na2SO4), and evaporated in vacuo. Yield 2.0 g (85%); color-
less crystals; mp 204–205ꢁC (Me2CHOH); IR: ꢃꢀ¼ 3200,
3080 (NH), 3030, 2920, 2890 (CH), 1685 (CO), 1600, 1490
(RS)-1-(4-Chlorobenzyl)-4-phenylazetidin-2-one
(19b, C16H14ClNO)
From 18 and 4.8 g (15 mmol) 4-chlorobenzyl chloride, CC
(CHCl3). Yield 1.8 g (67%); light yellow viscous liquid;
20
nD ¼ 1.5850; IR: ꢃꢀ¼ 3070, 3040, 2960, 2920 (CH), 1750
1
(CO), 1600, 1490 (ar) cmꢀ1; H NMR (80 MHz): ꢂ ¼ 2.83
(dd, J ¼ 2.8 Hz, 14.5Hz, 3-Htrans), 3.38 (dd, J ¼ 5.0 Hz,
14.5Hz, 3-Hcis) 3.73 (d, J ¼ 15.0Hz, 1H, CH2), 4.35 (dd,
J ¼ 2.8 Hz, 5.0 Hz, 4-H), 4.73 (d, J ¼ 15.0Hz, 1H, CH2),
6.97–7.55 (m, 9 ar H) ppm.
(ar) cmꢀ1
;
1H NMR (DMSO-d6, 80MHz): ꢂ ¼ 2.38 (dd,
J ¼ 10.0, 16.0 Hz, 3-H), 2.64 (dd, J ¼ 8.5, 16.0 Hz, 3-H), 3.29
(ddd, J ¼ 8.5, 10.0, 7.5Hz, 4-H), 4.61 (d, J ¼ 7.5Hz, 5-H),
7.00–7.43 (m, 10 ar H), 8.10 (m, N–H) ppm.
(RS)-1-(4-Nitrobenzyl)-4-phenylazetidin-2-one
(19c, C16H14N2O3)
cis=trans-5-(4-Chlorophenyl)-4-phenylpyrrolidin-2-one
(20b, C16H14ClNO)
From 18 and 3.2g (15 mmol) 4-nitrobenzyl bromide, CC
(CHCl3). Yield 1.9 g (67%); yellowish viscous solid; mp
71–72ꢁC; IR: ꢃꢀ¼ 3070, 3030, 2980, 2920 (CH), 1750 (CO),
From 2.7 g (10 mmol) 19b as described for 20a, CC (CHCl3).
Yield 1.2 g (43%); light yellow waxy solid; mp 124–125ꢁC;
IR: ꢃꢀ¼ 3185, 3080 (NH), 3020, 2870 (CH), 1690 (CO), 1595,
1600 (ar), 1515, 1345 (NO2) cmꢀ1 1H NMR (80 MHz):
;
1495 (ar) cmꢀ1
;
1H NMR (80 MHz) trans: ꢂ ¼ 2.54 (dd,
ꢂ ¼ 2.98 (dd, J ¼ 2.5Hz, 15.0Hz, 3-Htrans), 3.53 (dd, J ¼
5.0 Hz, 15.0Hz, 3-Hcis), 4.02 (d, J ¼ 15.5 Hz, 1H, CH2),
4.55 (dd, J ¼ 2.5 Hz, 5.0 Hz, 4-H), 4.83 (d, J ¼ 15.5 Hz, 1H,
CH2), 7.10–8.22 (m, 9 ar H) ppm.
J ¼ 10.0 Hz, 16.75 Hz, 3-H), 2.84 (dd, J ¼ 8.0 Hz, 16.75 Hz,
3-H), 3.30 (ddd, J ¼ 10.0 Hz, 8.0Hz, 8.0 Hz, 4-H), 4.68 (d,
J ¼ 8.0Hz, 5-H), 6.69–7.45 (m, 9 ar H), 7.56 (m, N–H);
cis: ꢂ ¼ 3.99 (ddd, J ¼ 8.0 Hz, 4-H), 4.99 (d, J ¼ 8.0 Hz, 5-
H) ppm; ratio of isomers trans:cis ¼ 9:1.
(RS)-1-[3-(Trifluoromethyl)benzyl]-4-phenylazetidin-2-one
(19d, C17H14F3NO)
cis=trans-5-[3-(Trifluoromethyl)phenyl]-4-phenylpyrrolidin-
2-one (20d, C17H14F3NO)
From 18 and 2.9g (15 mmol) 3-(trifluoromethyl)benzyl chlo-
ride. CC (CHCl3). Yield 2.5g (83%); colorless liquid;
From 3.1 g (10 mmol) 19d as described for 20a, CC (CHCl3).
Yield 1.5g (50%); yellow waxy solid; mp 104–105ꢁC; IR:
ꢃꢀ¼ 3180, 3080 (NH), 2970, 2890 (CH), 1685 (CO), 1595,
20
nD ¼ 1.5276; IR: ꢃꢀ¼ 3060, 3040, 2960, 2920 (CH), 1750
(CO), 1495 (ar) cmꢀ1
;
1H NMR (80 MHz): ꢂ ¼ 2.97 (dd,
1490 (ar) cmꢀ1
;
1H NMR (80 MHz) trans: ꢂ ¼ 2.60 (dd,
J ¼ 2.5 Hz, 14.5 Hz, 3-Htrans), 3.50 (dd, J ¼ 5.0 Hz, 14.5 Hz,
3-Hcis), 4.02 (d, J ¼ 15.0Hz, 1 H, CH2), 4.53 (dd, J ¼
2.5 Hz, 5.0 Hz, 4-H), 4.88 (d, J ¼ 15Hz, 1H, CH2), 7.20-
7.90 (m, 9 ar H) ppm.
J ¼ 10.0 Hz, 17.0 Hz, 3-H), 2.88 (dd, J ¼ 8.25 Hz, 17.0 Hz,
3-H), 3.36 (ddd, J ¼ 10.0Hz, 8.25 Hz, 7.5Hz, 4-H), 4.80 (d,
J ¼ 7.5Hz, 5-H), 6.71–7.64 (m, 9 ar H), 7.69 (m, N–H); cis:
ꢂ ¼ 4.05 (ddd, J ¼ 7.5 Hz, 4-H), 5.13 (d, J ¼ 7.5 Hz, 5-H) ppm;
ratio of isomers trans:cis ¼ 8:2.
(RS)-1-(4-Cyanobenzyl)-4-phenylazetidin-2-one
(19e, C17H14N2O)
trans-5-(3,4,5-Trimethoxyphenyl)-4-phenylpyrrolidin-2-one
(20f, C19H21NO4)
From 18 and 2.9g (15 mmol) 4-cyanobenzyl bromide, CC
(CHCl3). Yield 1.4 g (55%); colorless crystals; mp 63–65ꢁC;
IR: ꢃꢀ¼ 3060, 3040, 2960, 2920 (CH), 2220 (CN), 1750 (CO),
From 3.3 g (10 mmol) 19f as described for 20a, CC (CHCl3),
then extraction of the column with EtOH, and evaporation of
1610, 1495 (ar) cmꢀ1
;
1H NMR (80 MHz): ꢂ ¼ 2.95 (dd,

846
A. Elriati et al.
EtOH. Yield 1.44 g (44%); colorless crystals; mp 171–172ꢁC;
IR: ꢃꢀ¼ 3320 (NH), 3020, 2930 (CH), 2830 (OMe), 1690
7. Gilman H, Speeter M (1943) J Am Chem Soc 65:2255
8. (a) Staudinger H (1907) Justus Liebigs Ann Chem 356:51;
(b) Cossio FP, Arrieta A, Lecea B, Ugalde JM (1994)
J Am Chem Soc 116:2085
9. Fukui K, Kitano H, Ijiri R, Inamoto Y, Matsufuji T (1958)
Nippon Kagaku Zasshi 79:889; (1960) Chem Abstr
54:4430
1
(CO), 1595, 1505 (ar) cmꢀ1; H NMR (80 MHz): ꢂ ¼ 2.63
(dd, J ¼ 10.0, 17.0Hz, 3-H), 2.90 (dd, J ¼ 8.5, 17.0 Hz, 3-H),
3.38 (ddd, J ¼ 10.0, 8.5, 7.8 Hz, 4-H), 3.74 (s, 2 OMe), 3.80
(s, OMe), 4.63 (d, J ¼ 7.8 Hz, 5-H), 6.36 (s, 2 ar H), 6.90 (m,
N–H), 7.06–7.55 (m, 5 ar H) ppm.
10. (a) Balasubramaniyan V, Bhatia VG, Wagh SBV (1983)
Tetrahedron 39:1475; (b) Patel MV, Balasubramaniyan V
(1981) Indian J Chem Sect B 20:804
11. Arrieta A, Lecea B, Cossio FP (1998) J Org Chem 63:5869
12. Chatterjee BG, Moza PN, Roy SK (1963) J Org Chem
28:1418
13. Mayrhofer R (1980) PhD Thesis University of Freiburg
14. Bergmann H-J (1984) PhD Thesis University of
Freiburg
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Acknowledgements
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.
17. Durst T, van den Elzen R , Lebelle MJ (1972) J Am Chem
Soc 94:9261
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