Free radical synthesis of benzofused tricyclic β-lactams by intramolecular cyclization of 2-azetidinone-tethered haloarenes

Article abstract of DOI:10.1016/j.tet.2005.01.082

o-Halogenophenyl- and o-halogenobenzyl-4-alkenyl-β-lactams can be prepared both in the racemic form and in optically pure form using the ketene-imine cyclization. These 2-azetidinone-tethered haloarenes were used for the regio- and stereoselective prepara

Full text of DOI:10.1016/j.tet.2005.01.082

Tetrahedron 61 (2005) 2767–2778
Free radical synthesis of benzofused tricyclic b-lactams by
intramolecular cyclization of 2-azetidinone-tethered haloarenes
b
a
a
Benito Alcaide,a, Pedro Almendros, Alberto Rodrıguez-Vicente and M. Pilar Ruiz
*
´
a
´ ´ ´
Departamento de Quımica Organica I, Facultad de Quımica, Universidad Complutense de Madrid, 28040-Madrid, Spain
´ ´
b
Instituto de Quımica Organica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Received 6 December 2004; revised 14 January 2005; accepted 20 January 2005
Abstract—o-Halogenophenyl- and o-halogenobenzyl-4-alkenyl-b-lactams can be prepared both in the racemic form and in optically pure
form using the ketene–imine cyclization. These 2-azetidinone-tethered haloarenes were used for the regio- and stereoselective preparation of
benzofused tricyclic b-lactams including benzocarbapenems and benzocarbacephems via intramolecular aryl radical cyclisation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(racemic and asymmetric) to benzofused tricyclic b-lactams
including benzocarbapenems as well as benzocarbace-
phems, through intramolecular aryl radical cyclization of
2-azetidinone-tethered haloarenes.7
Since the discovery of penicillin, 2-azetidinone-based
heterocycles have been one of the main classes of drugs
used for the treatment of bacterial infections.1 The extensive
use of common b-lactam antibiotics such as penicillins and
cephalosporins in medicine has resulted in an increasing
number of resistant strains of bacteria through mutation and
b-lactamase gene transfer.2 In order to oppose the
destructive action of b-lactamases, one strategy consists of
modifying the structure of the b-lactam antibiotic, aiming to
render it insensitive to the b-lactamase attack. A second
approach uses a reagent, typically a b-lactam derivative,
which incapacitates the b-lactamase, in synergy with the
b-lactam antibiotic. Among others, benzocarbapenems and
benzocarbacephems have been designed as suicide inacti-
vators of b-lactamases. The preparation of benzocarbace-
phems has received more attention,3 while the synthesis of
benzocarbapenems is a less explored area. The first
synthesis of these benzofused b-lactams was reported by
Wakselman by using a copper-promoted intramolecular aryl
substitution of 4-(o-bromophenyl)methyl-2-azetidinones.4
A more recent contribution by Gilchrist described the
preparation of benzocarbapenems by reduction and cycliza-
tion of 2-substituted indoles.5 Both syntheses are racemic.
2. Results and discussion
Starting cyclisation substrates, alkenyl- and alkynyl-b-
lactam-tethered haloarenes 1–8 (Scheme 1), were prepared
both in the racemic form and in optically pure form using
the ketene–imine cycloaddition as the key step.8 2-
Azetidinones 1–4 were obtained from the corresponding
imine9 through Staudinger reaction with the appropriate
acid chloride in the presence of Et3N (Scheme 1, Table 1).
Racemic compounds 1 bearing a N-(o-halophenyl) moiety
were obtained as cis/trans mixtures with low cis-selectivity,10
the cis-isomers being easily separated by fractional
recrystallization of the mixtures. In contrast, racemic
compounds 2 were obtained as single cis-diastereomers.
Enantiomerically pure b-lactams (C)-3a, (C)-3b and (C)-4
were prepared by reaction of the corresponding imines with
¨
the ketene derived from the Evans and Sjogren chiral
oxazolidinone.11 b-Lactams 3 and 4 were obtained exclu-
sively as their cis-diastereoisomers with good to excellent
stereoselectivity.12
In connection with our current research interest in the
preparation and synthetic utility of b-lactams,6 here we
examine the feasibility and efficiency of an approach
Enantiopure b-lactam (C)-9 was obtained as a single cis-
enantiomer from the o-bromobenzyl imine of (R)-2,3-O-
isopropylideneglyceraldehyde, through Staudinger reaction
with phenoxyacetyl chloride in the presence of Et3N.
Sequential acidic acetonide hydrolysis and oxidative
cleavage of the resulting diol, followed by Wittig olefination
Keywords: Lactams; Nitrogen heterocycles; Radical reactions; Polycycles;
Cycloaddition.
* Corresponding author. Tel.: C34 913 944 314; fax: C34 913944103;
e-mail: alcaideb@quim.ucm.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.082

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B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
Scheme 2. Reagents and conditions: (a) PhOCH2COCl, Et3N, dichloro-
methane, rt, 12 h; (b) PTSA, THF/H2O, reflux, 3 h; (c) NaIO4, NaHCO3,
dichloromethane, rt, 2 h; (d) for 5a: Ph3P]CHCO2Me, THF, reflux, 3 h.
For 5b: Ph3(Et)PI, LiBu, THF, rt, 16 h.
Scheme 1. Starting b-lactam-tethered haloarenes 1–8.
of the corresponding 4-oxoazetidine-2-carbaldehyde
afforded the enantiopure alkenes (C)-5a and (C)-5b
(Scheme 2). The preparation of cyclization precursors 6a–
c bearing the haloaryl moiety at C3 is shown in Scheme 3.
Styryl-2-azetidinone 6a was obtained with total cis-
selectivity via direct Staudinger reaction of the E-cinnam-
aldehyde/p-anisidine derived imine and the ketene obtained
from o-bromophenoxy acetic acid. Racemic b-lactam
aldehyde 10 was obtained as a single cis-diastereoisomer,
following our one-pot method from N,N-di-(p-methoxy-
phenyl)glyoxal diimine.13 Alkene 6b was achieved through
Wittig olefination of aldehyde 10, while imine 6c was
prepared by condensation with benzylamine in the presence
of magnesium sulphate.
Scheme 3. Reagents and conditions: (a) PhOP(O)Cl2, Et3N, dichloro-
methane, rt, 16 h; (b) 5% aqueous HCl; (c) Ph3P]CHCO2Me, THF, reflux,
3 h.; (d) BnNH2, MgSO4, dichloromethane, rt, 16 h.
Alkynyl-2-azetidinones 7 and (C)-8 were obtained with
complete stereoselectivity in good yields, through the
ketene–imine cycloaddition of the imine obtained from
o-bromobenzaldehyde and propargylamine on reacting with
the corresponding ketene (Scheme 4).
stereoselective synthesis of complex heterocycles and
carbocycles by radical cyclisation has now been established
as an efficient methodology in organic chemistry.14 This
wide research has been fostered by its operational simplicity
and its tolerance to substrate functionalization. Furthermore,
by a combination of stereoelectronic and molecular orbital
Having obtained the monocyclic precursors, the next stage
was set to carry out the key radical cyclisation step. The
Table 1. Preparation of b-lactams 1–4a
Product
R1
R2
R3
X
n
Yield (%)b
cis/trans ratioc
1a
1b
1c
2a
Me
PhO
BnO
PhO
Me
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Br
Br
I
Br
Br
Br
Br
Br
0
0
0
1
1
0
0
1
40
74
70
40
60
61
69
50
62:38
64:36
100:0
100:0
100:0
90:10
100:0
2b
BnO
(C)-3a
(C)-3b
(C)-4
(S)-Oxd
(S)-Ox
(S)-Ox
a Compounds 1 and 2 are racemic.
b Yield of pure, isolated product (or mixture of isomers, when applicable) with correct analytical and spectral data.
c The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before purification.
d (S)-OxZ (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl.

B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
2769
standard dilution conditions, and did not require the use of
high dilution techniques. Removal of the organotin halides
by a solution of KF in water is essential for an appropriate
chromatographic purification of compounds 11–15.15 With
the exception of the reaction of (C)-3b, neither cyclisation
products different from 11–15 nor reduction products were
detected in the 1H NMR spectra of the crude reaction
mixtures. The full stereoselectivity of the radical cyclisation
is particularly attractive, being independent of the substi-
tution at C3 or N1 on the b-lactam ring. In addition, 2-
azetidinones bearing styryl or carboxymethyl substituents at
C4 underwent 5(or 6)-exo-trig radical cyclization to
benzocarbapenems and benzocarbacephems 11–15 in a
totally regioselective fashion, as expected when the radical
acceptor has a radical-stabilizing moiety at the b-position.
The radical reaction of the crotonaldehyde-imine derived
b-lactam (C)-3b, lacking a radical-stabilizing moiety,
deserves special mention. Haloalkenyl b-lactam (C)-3b
formed, along with benzocarbapenem (C)-13b (major
product, 30%), benzocarbacephem (C)-16 (minor product,
10%) and 1,4-dihydroquinoline 17 (relative proportions
3:1:2.5, respectively) (Scheme 6). Compounds (C)-13b,
(C)-16, and 17 were obtained as single diastereoisomers,
and thus it is clear that 6-endo cyclisation competes with
5-exo process when an unactivated double bond is used as
the radical acceptor. However, this result is in sharp contrast
with the radical reaction of compound (C)-5b, being
obtained exclusively the 6-exo cyclisation product. In this
case, independently of the substituent at the acceptor double
bond, the 7-endo mode of cyclisation is not competitive.16
Formation of compounds 11, 13, 16, and 17 may be
Scheme 4. Reagents and conditions: (a) PhOCH2COCl, Et3N, dichloro-
methane, rt, 12 h; (b) PhOP(O)Cl2, Et3N, dichloromethane, rt, 16 h.
effects, radical cyclisations occur, in general, with high
degrees of both regio- and stereo-control.
Haloaryl b-lactams 1–5 were reacted with tributyltin
hydride and AIBN in benzene at reflux to give the expected
benzocarbapenems 11 and 13 and benzocarbacephems 12,
14 and 15 in good yields as single diastereomers after
chromatographic purification (Scheme 5, Table 2). These
intramolecular radical reactions were carried out under
Scheme 5. Reagents and conditions: (a) Bu3SnH (1.2 equiv), AIBN
(0.1 equiv), benzene, reflux, 1–2 h. (b) 10% aqueous KF, 30 min.
Scheme 6. Reagents and conditions: (a) Bu3SnH (1.2 equiv), AIBN
(0.1 equiv), benzene, reflux, 1.5 h. (b) 10% aqueous KF, 30 min.
Table 2. Preparation of fused tricyclic b-lactams 11–15
Substratea
R1
R2
R3
X
n
Producta
Yield (%)b
1a
1b
cis-1c
trans-1c
2a
Me
Me
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
CO2Me
Me
Br
Br
I
I
Br
Br
0
0
0
0
1
1
0
0
1
11a
11b
cis-11c
trans-11c
12a
65
66
60
65
50
61
70
30
57
64
47
PhO
BnO
BnO
PhO
BnO
2b
H
12b
(C)-3a
(C)-3b
(C)-4
(C)-5a
(C)-5b
(C)-13a
(C)-13b
(C)-14
(C)-15a
(C)-15b
a Compounds 1, 2, 11 and 12 are racemic.
b Yield of pure, isolated product with correct analytical and spectral data.

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B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
rationalized as shown in Scheme 7. Bromine abstraction by
a stannyl radical followed by either 5-exo- or 6-endo
cyclisation of radical 18 would form radicals 19 and 20,
respectively, depending on which of the two olefinic
carbons is attacked. These radicals would lead to benzo-
carbapenems 11 and 13 or benzocarbacephem 16, respec-
tively, after hydrogen abstraction from tributyltin hydride.
Formation of compound 17 may be explained by an
homolytic C3–C4 bond cleavage in the 2-azetidinone
nucleus of intermediate 20 to form radical intermediate
21. This interesting process, which is an example of a
radical C3–C4 bond breakage in the b-lactam ring,17 is
closely related to the cyclobutylcarbinyl radical cleavage, a
useful methodology for the synthesis of medium size
rings.18 In our case, the driving force of the cleavage may
be the stability of the captodative radical 21 together with
the strain in the b-lactam ring.
Scheme 8. Selected NOE effects and stereochemistry of compounds 11a,
(C)-13b and 12a.
benzocarbapenems 11 and 13 and benzocarbacephems 12,
14 and 15 must be due to the preference of the radical
intermediates for the conformation depicted in Scheme 9 for
these cyclisations.
Scheme 9.
Next, we decided to explore the extension of the above
radical intramolecular cyclisation of N-haloaryl-b-lactams
to 2-azetidinones bearing the proradical center at C3. The
treatment of haloarenes 6a–c under similar conditions for
the preparation of benzocarbapenems and benzocarbace-
phems 11–15 gave the fused tricyclic b-lactams 22a–c
(Scheme 10, Table 3). Compounds 22a and 22b were
obtained as mixtures of diastereomers, which are epimers at
the newly formed C5 stereocenter, while the amino
derivative 22c could be prepared as a single isomer. The
relative stereochemistry of the new chiral center of
compounds 22 at C5 was determined by the value of
coupling constants of H5–H6 protons (JZ0–1.2 Hz for the
major anti-isomers; JZ3.6–4.2 Hz for the minor syn-
isomers).20
Scheme 7.
The relative stereochemistry of the 4-membered ring was
established from the values of J5,6 (benzocarbapenems) or
J
6,7 (benzocarbacephems) vicinal proton couplings and it is
transferred unaltered from the starting 2-azetidinone to the
cyclized products. The stereochemistry of the new stereo-
center at C1 in compounds 11–15 was derived from our
previous results on stannylcarbapenams and stannylcarbace-
phams,19 as well as by qualitative homonuclear NOE
difference spectra on representative compounds. As an
example, irradiation of the H5 hydrogen in compound 11a
resulted in a 5% increment on the proton signal of the
methylene group at lower field (2.67 ppm), and a 5%
increment on the phenyl group, and on the methyl group at
lower field (1.18 ppm). Irradiation of the H5 hydrogen in
compound (C)-13b gave a 3% increment both on the most
shielded proton of the methylene group (1.43 ppm), and on
the methyl group corresponding to the ethyl substituent at
C1. Similar figures were observed on performing NOE
experiments in tricycle 12a (Scheme 8). In this way, anti
stereochemistries H1/H5 (benzocarbapenems) or H1/H6
(benzocarbacephems) were assigned.
Scheme 10. Reagents and conditions: (a) Bu3SnH (1.2 equiv), AIBN
(0.1 equiv), benzene, reflux, 1 h. (b) 10% aqueous KF, 30 min.
The slight variation in the diastereomeric ratio in the
formation of compounds 22a and 22b, could be explained
taking into account the higher bulkiness of the phenyl group
in comparison to the carboxymethyl moiety. However,
steric reasons can not be used to explain the nearly total
stereoselectivity of the azaderivative 22c.
The complete selectivity observed in the formation of
These cyclisations may be understood in terms of the

B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
Table 3. Preparation of fused tricyclic b-lactams 22a
2771
Substrateb
R3
X
drc
Productb
Yield (%)d
6a
6b
6c
Ph
CO2Me
Bn
CH
CH
N
85:15
70:30
O95:5
22a
22b
22c
69
56
60
a PMPZ4-MeOC6H4.
b Compounds 6 and 22 are racemic.
1
c The ratio was determined by integration of well-resolved signals in the H NMR spectra of the crude reaction mixtures before purification.
d Yield of pure product (mixture of isomers).
possible conformations presented in Scheme 11. The
highest overlap between the aryl radical and the p* orbital
of the acceptor double bond is for the conformations giving
rise to the major anti-isomers. For 22c, the possible
electronic repulsion between the unshared electronic pairs
of the nitrogen atoms can be responsible of the destabiliza-
tion of the conformation giving rise to the minor syn-isomer.
benzocarbapenems, benzocarbacephems, as well as other
fused tricyclic b-lactams. A new radical C3–C4 bond
cleavage of the b-lactam ring has been also observed.
Efforts to develop this methodology for the preparation of
more elaborate benzocarbapenems and benzocarbacephems
are currently underway in our research group.
3. Experimental
3.1. General methods
Melting points were taken using a Gallenkamp apparatus
and are uncorrected. IR spectra were recorded on a Perkin–
Elmer 781 spectrophotometer. 1H NMR and 13C NMR
spectra were recorded on a Bruker Avance-300, Varian
VRX-300S or Bruker AC-200. NMR spectra were recorded
in CDCl3 solutions, except otherwise stated. Chemical shifts
are given in ppm relative to TMS (1H, 0.0 ppm), or CDCl3
(13C, 76.9 ppm). Mass spectra were recorded on a Hewlett–
Packard 5989A spectrometer. Microanalyses were per-
formed in the UCM Microanalysis Service (Facultad de
Farmacia, UCM, Madrid). Optical rotations were measured
using a Perkin–Elmer 241 polarimeter. Specific rotation
[a]D is given in deg cm2 gK1 at 25 8C, and the concentration
(c) is expressed in g per 100 mL. All commercially available
compounds were used without further purification. THF was
distilled from Na-benzophenone. Benzene, dichloro-
methane and triethylamine were distilled from CaH2.
Flame-dried glassware and standard Schlenk techniques
were used for moisture sensitive reactions. Flash chromato-
graphy was performed using Merck silica gel 60 (230–400
mesh). Identification of products was made by TLC
(Kiesegel 60F-254). UV light (lZ254 nm), and a vanillin
solution in sulfuric acid and 95% EtOH (1 g vanillin, 5 mL
H2SO4, 150 mL EtOH) was used to develop the plates.
Scheme 11.
2-Azetidinones 7 and (C)-8 were selected as monocyclic
precursors with the aim of using a terminal alkyne as a
proradical center in the synthesis of benzofused tricyclic
b-lactams. Unfortunately, tricycle 23 was isolated in a poor
20% yield from the alkynyl haloarene 7, while the radical
reaction of (C)-8 gave a complex mixture (Scheme 12).
3.2. Materials
The following chemicals were prepared according to
previously reported procedures: N,N-di-(p-methoxy-phenyl)
glyoxaldiimine,21 2,3-O-(isopropylidene)-D-glyceralde-
hyde,22 (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl-acetic
acid,23 (2-bromophenoxy)acetic acid.24
3.3. General procedures for the synthesis of cyclisation
substrates 1–4, 6a, and 7–9
Scheme 12. Reagents and conditions: (a) Bu3SnH (1.2 equiv), AIBN
(0.1 equiv), benzene, reflux. (b) 10% aqueous KF, 30 min.
Method A. A mixture of aldehyde (10 mmol), 2-halogeno-
aniline (10 mmol) and a catalytic amount of ZnCl2/
a-phenylethylamine complex (0.1 mmol) in benzene
(50 mL) was heated at reflux (2–4 h) on a Dean–Stark
apparatus. Then, the mixture was filtered and the solvent
In conclusion, easily available 2-azetidinone-tethered
haloarenes have proved to be appropriate substrates for
the regio- and stereoselective intramolecular aryl radical
cyclisation leading to different enantiopure or racemic

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B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
was removed under reduced pressure. To a cooled (0 8C)
solution of the imine in anhydrous dichloromethane
(50 mL), Et3N (4.16 mL, 30 mmol), the corresponding
acid or acid chloride (15 mmol), [and PhOP(O)Cl2, only
when (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl-acetic acid
and 2-(o-bromophenyl)acetic acid are used, 2.25 mL,
15 mmol] were successively added under argon. The
resulting mixture was allowed to warm to room tempera-
ture, and was stirred for 16 h. The crude mixture was diluted
with dichloromethane (100 mL) and washed with saturated
NaHCO3 (2!20 mL) and brine (40 mL). The organic layer
was dried (MgSO4) and concentrated under reduced
pressure.
C23H18NO2Br: C, 65.73; H, 4.32; N, 3.33. Found: C, 65.63;
H, 4.34; N, 3.35.
3.3.3. (G)-3-Benzyloxy-1-(2-iodophenyl)-4-(E)-styryl-
azetidin-2-one (cis- and trans-1c). Method A. From
1.44 g (11.0 mmol) of trans-cinnamaldehyde, 2.39 g
(11.0 mmol) of o-iodooaniline, and 3.04 g (16.5 mmol) of
benzyloxyacetyl chloride, 3.70 g (70%) of compound 1c
was obtained as a mixture of isomers cis/trans (64:36). The
cis isomer was isolated by recrystallization, while the trans
isomer was purified by flash chromatography (hexanes/ethyl
acetate, 2:1).
2-Azetidinone cis-1c. Colourless solid. Mp 139–141 8C
(hexanes/ethyl acetate). H NMR: d 4.68 (AB system, 2H,
1
Method B. A solution of the corresponding aldehyde
(10 mmol), and amine (10 mmol) in dichloromethane
(50 mL) was stirred overnight at room temperature over
MgSO4 (100 mmol). Then, the MgSO4 was filtered off,
washed with an additional 15 mL of dichloromethane, and
the resulting solution cooled at 0 8C under argon. Et3N
(4.16 mL, 30 mmol), the corresponding acid or acid
chloride (15 mmol), [and PhOP(O)Cl2, only when (S)-4-
phenyl-2-oxo-1,3-oxazolidin-3-yl-acetic acid and 2-(o-bro-
mophenyl)-acetic acid are used, 2.25 mL, 15 mmol] were
successively added under argon. The resulting mixture was
allowed to warm to room temperature, and was stirred for
16 h. The crude mixture was diluted with dichloromethane
(100 mL) and washed with saturated NaHCO3 (2!20 mL)
and brine (40 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure.
JZ8.7 Hz), 4.97 (d, 1H, JZ4.5 Hz), 5.13 (dd, 1H, JZ4.5,
9.3 Hz), 6.34 (dd, 1H, JZ9.3, 15.9 Hz), 6.61 (d, 1H, JZ
15.9 Hz), 6.90 (m, 1H), 7.20 (m, 12H), 7.75 (dd, 1H, JZ1.2,
7.8 Hz). 13C NMR: d 165.6, 139.9, 137.3, 137.2, 136.5,
135.8, 129.3, 129.0, 128.6, 128.4, 128.4, 128.3, 128.3,
128.1, 127.8, 122.6, 93.7, 82.9, 73.0, 63.8. IR (CHCl3, cmK1):
n 1750, 1470. MS (EI), m/z: 390 (MCK91, 6), 298 (12), 245
(10), 115 (32), 91 (100%). Anal. Calcd for C24H20NO2I: C,
59.78; H, 4.21; N, 2.93. Found: C, 59.89; H, 4.19; N, 2.91.
2-Azetidinone trans-1c. Colourless oil. 1H NMR: d 4.57 (d,
1H, JZ2.1 Hz), 4.64 (d, 1H, JZ12.0 Hz), 4.85 (dd, 1H, JZ
2.1, 9.0 Hz), 4.88 (d, 1H, JZ12 Hz), 5.96 (dd, 1H, JZ9.0,
16.2 Hz), 6.44 (d, 1H, JZ16.2 Hz), 6.9 (m, 1H), 7.25 (m,
12H), 7.75 (d, 1H). 13C NMR: d 164.7, 140.4, 137.6, 137.0,
135.6, 129.5, 129.1, 128.7, 128.6, 128.5, 127.7, 127.1,
126.8, 124.0, 122.8, 93.7, 87.3, 83.1, 73.2, 65.7. IR (CHCl3,
cmK1): n 1760, 1600. Anal. Calcd for C24H20NO2I: C,
59.99; H, 4.16; N, 2.90. Found: C, 59.89; H, 4.19; N, 2.91.
3.3.1. (G)-1-(2-Bromophenyl)-3,3-dimethyl-4-(E)-styryl-
azetidin-2-one (1a). Method A. From 1.32 g (10 mmol) of
trans-cinnamaldehyde, 1.67 g (10 mmol) of o-bromoaniline,
and 1.59 g (15 mmol) of 2-methylpropanoyl chloride,
840 mg (40%) of compound 1a was obtained as a pale
yellow oil after purification by flash chromatography
3.3.4. (G)-cis-1-(2-Bromobenzyl)-3-phenoxy-4-(E)-
styryl-azetidin-2-one (2a). Method B. From 260 mg
(2.0 mmol) of trans-cinnamaldehyde, 370 mg (2.0 mmol)
of o-bromobenzylamine, and 450 mg (3.0 mmol) of
phenoxyacetyl chloride, 340 mg (40%) of compound 2a
was obtained as a pale yellow oil after purification by flash
1
(hexanes/ethyl acetate, 2:1). H NMR: d 1.30 (s, 3H), 1.52
(s, 3H), 4.79 (d, 1H, JZ8.7 Hz), 6.17 (dd, 1H, JZ8.7,
15.9 Hz), 6.64 (d, 1H, JZ15.9 Hz), 7.30 (m, 9H). 13C NMR:
d 172.2, 135.8, 134.4, 133.7, 128.6, 128.2, 128.1, 128.0,
128.0, 127.4, 126.6, 124.3, 118.2, 68.7, 55.5, 22.6, 17.9. IR
(CHCl3, cmK1): n 1755, 1480. MS (EI), m/z: 357 (MCC2,
7), 355 (MC, 7), 286 (41), 284 (36), 158 (100), 143 (94%).
Anal. Calcd for C19H18NOBr: C, 64.06; H, 5.09; N, 3.93.
Found: C, 64.18; H, 5.06; N, 3.91.
1
chromatography (hexanes/ethyl acetate, 1:1). H NMR: d
4.26 (d, 1H, JZ15 Hz), 4.35 (dd, 1H, JZ4.5, 9.0 Hz), 4.7
(d, 1H, JZ15 Hz), 5.27 (d, 1H, JZ4.5 Hz), 6.05 (dd, 1H,
JZ9.0, 15.6 Hz), 6.48 (d, 1H, JZ15.6 Hz), 7.15 (m, 14H,
Ar). 13C NMR: d 165.3, 157.2, 137.1, 135.9, 134.3, 133.0,
131.1, 129.7, 129.7, 129.4, 129.2, 128.5, 128.2, 127.8,
126.6, 122.1, 115.6, 82.0, 61.0, 44.7. IR (CHCl3, cmK1): n
1760, 1600, 1500. Anal. Calcd for C24H20NO2Br: C, 66.37;
H, 4.64; N, 3.22. Found: C, 66.46; H, 4.66; N, 3.20.
3.3.2. (G)-cis-1-(2-Bromophenyl)-3-phenoxy-4-(E)-
styryl-azetidin-2-one (1b). Method A. From 790 mg
(6.0 mmol) of trans-cinnamaldehyde, 1.0 g (6.0 mmol) of
o-bromoaniline, and 1.53 g (9.0 mmol) of phenoxyacetyl
chloride, 1.87 g (74%) of compound 1b was obtained as a
mixture of isomers cis/trans (62:38). The cis isomer was
isolated by recrystallization as a colourless solid. Mp 130–
3.3.5. (G)-cis-3-Benzyloxy-1-(2-bromobenzyl)-4(E)-
styryl-azetidin-2-one (2b). Method B. From 260 mg
(2.0 mmol) of trans-cinnamaldehyde, 370 mg (2.0 mmol)
of o-bromobenzylamine, and 470 mg (3.0 mmol) of benzyl-
oxyacetyl chloride, 540 mg (60%) of compound 2b was
obtained as a colourless oil after purification by flash
1
132 8C (hexanes/ethyl acetate). H NMR: d 5.50 (dd, 1H,
JZ4.8, 9.0 Hz), 5.59 (d, 1H, JZ4.8 Hz), 6.32 (dd, 1H, JZ
9.0, 15.9 Hz), 6.74 (d, 1H, JZ15.9 Hz), 7.30 (m, 14H). 13C
NMR: d 164.4, 157.2, 137.7, 135.7, 133.7, 129.5, 128.7,
128.7, 128.5, 128.3, 128.1, 127.7, 126.7, 122.3, 121.7,
117.6, 115.6, 81.8, 64.0. IR (CHCl3, cmK1): n 1750, 1480.
MS (EI), m/z: 421 (MCC2, 1), 419 (MC, 1), 328 (15), 286
(36), 246 (45), 222 (23), 128 (100%). Anal. Calcd for
1
chromatography (hexanes/ethyl acetate, 3:1). H NMR: d
4.11 (dd, 1H, JZ4.5, 9.0 Hz), 4.21 (d, 1H, JZ15.0 Hz),
4.56 (AB system, 2H, JZ11.4 Hz), 4.64 (d, 1H, JZ
15.0 Hz), 4.74 (d, 1H, JZ4.5 Hz), 6.09 (dd, 1H, JZ9.0,
15.6 Hz), 6.44 (d, 1H, JZ15.6 Hz), 7.20 (m, 14H). 13C
NMR: d 166.8, 136.7, 136.6, 136.2, 134.7, 133.1, 131.1,

B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
2773
129.7, 128.7, 128.5, 128.4, 128.3, 128.2, 127.8, 126.8,
123.9, 123.2, 83.5, 72.9, 61.1, 44.5. IR (CHCl3, cmK1): n
1755, 1600. Anal. Calcd for C25H22NO2Br: C, 66.97; H,
4.95; N, 3.12. Found: C, 66.86; H, 4.98; N, 3.10.
130.9, 129.6, 129.5, 129.4, 129.4, 128.6, 128.4, 127.8,
126.8, 123.6, 123.1, 70.8, 62.8, 61.6, 60.1, 45.2. IR (CHCl3,
cmK1): n 1760, 1750. Anal. Calcd for C27H23N2O3Br: C,
64.42; H, 4.61; N, 5.56. Found: C, 64.53; H, 4.63; N, 5.53.
3.3.6. (C)-(3S,4R)-1-(2-Bromophenyl)-3-[(S)-4-phenyl-
2-oxo-1,3-oxazolidin-3-yl]-4-(E)-styryl-azetidin-2-one,
(C)-3a. Method A. From 260 mg (2.0 mmol) of trans-
cinnamaldehyde, 330 mg (2.0 mmol) of o-bromoaniline,
660 mg (3.0 mmol) of (S)-(2-oxo-4-phenyl-oxazolidin-3-
yl)-acetic acid, and 440 mL (3.0 mmol) of phenyl dichloro-
phosphate, 600 mg (61%) of compound (C)-3a was
obtained as a colourless solid after purification by flash
chromatography (hexanes/ethyl acetate, 1:1). Mp 169–
171 8C (hexanes/ethyl acetate). [a]DZC59.0 (c 1.0,
3.3.9. (G)-cis-3-(2-Bromophenoxy)-1-(4-methoxyphenyl)-
4(E)-styryl-azetidin-2-one (6a). Method B. From 130 mg
(1.0 mmol) of trans-cinnamaldehyde, 120 mg (1.0 mmol) of
p-anisidine, 350 mg (1.5 mmol) of (o-bromo)phenoxyacetic
acid, and 220 mL (1.5 mmol) of phenyl dichlorophosphate,
320 mg (71%) of compound 6a was obtained as a colourless
solid after purification by flash chromatography (hexanes/
ethyl acetate, 1:1). Mp 80–82 8C (hexanes/ethyl acetate). 1H
NMR: d 3.76 (s, 3H), 4.99 (dd, 1H, JZ4.8, 8.7 Hz), 5.48 (d,
1H, JZ4.8 Hz), 6.45 (dd, 1H, JZ8.7, 16.2 Hz), 6.86 (m,
4H), 7.30 (m, 10H). 13C NMR: d 162.0, 156.7, 154.1, 137.2,
136.0, 133.6, 131.0, 128.8, 128.7, 128.5, 127.0, 123.6,
123.1, 118.9, 115.7, 114.5, 112.4, 82.1, 60.9, 55.6. IR
(CHCl3, cmK1): n 1750. Anal. Calcd for C24H20NO3Br: C,
64.01; H, 4.48; N, 3.11. Found: C, 64.12; H, 4.45; N, 3.09.
1
CHCl3). H NMR: d 4.15 (dd, 1H, JZ7.5, 8.7 Hz.), 4.61
(t, 1H, JZ8.7 Hz), 4.64 (d, 1H, JZ5.1 Hz), 4.87 (t, 1H, JZ
8.7 Hz), 5.24 (dd, 1H, JZ5.1, 9.3 Hz), 6.12 (dd, 1H, JZ9.3,
15.9 Hz), 6.63 (d, 1H, JZ15.9 Hz), 7.02 (m, 1H), 7.35 (m,
13H). 13C NMR: d 163.0, 158.0, 138.0, 137.0, 135.7, 134.2,
133.5, 129.7, 128.8, 128.8, 128.7, 128.5, 128.3, 127.9,
127.0, 127.0, 122.6, 117.7, 71.1, 64.2, 62.8, 60.5. IR
(CHCl3, cmK1): n 1760, 1740. MS (EI), m/z: 490 (MCC2,
3), 488 (MC, 3), 286 (100), 284 (70%). Anal. Calcd for
C26H21N2O3Br: C, 63.81; H, 4.33; N, 5.72. Found: C, 63.93;
H, 4.31; N, 5.75.
3.3.10. (G)-cis-4-(2-Bromophenyl)-3-phenoxy-1-prop-2-
ynyl-azetidin-2-one (7). Method B. From 370 mg
(2.0 mmol) of o-bromobenzaldehyde, 100 mg (2.0 mmol)
of propargylamine, and 510 mg (3.0 mmol) of phenoxy-
acetyl chloride, 450 mg (61%) of compound 7 was obtained
as a pale orange oil after purification by flash chromato-
graphy (hexanes/ethyl acetate, 1:1). 1H NMR: d 2.28 (t, 1H,
JZ2.5 Hz), 3.77 (dd, 1H, JZ2.5, 17.7 Hz), 4.47 (dd, 1H,
JZ2.7, 17.7 Hz), 5.50 (d, 1H, JZ4.7 Hz), 5.56 (d, 1H, JZ
4.7 Hz), 7.15 (m, 9H). 13C NMR: d 165.6, 156.9, 132.9,
132.4, 130.0, 129.3, 128.9, 127.3, 124.1, 122.4, 115.9, 82.5,
75.6, 73.7, 60.8, 30.3. IR (CHCl3, cmK1): n 3310, 1755.
Anal. Calcd for C18H14NO2Br: C, 60.69; H, 3.96; N, 3.93.
Found: C, 60.60; H, 3.93; N, 3.96.
3.3.7. (C)-(3S,4R)-1-(2-Bromophenyl)-3-[(S)-4-phenyl-
2-oxo-1,3-oxazolidin-3-yl]-4-[(E)-1-propenyl]-azetidin-
2-one, (C)-3b. Method A. From 130 mg (1.95 mmol) of
2-butenal, 326 mg (1.95 mmol) of o-bromoaniline, 630 mg
(2.85 mmol) of (S)-(2-oxo-4-phenyl-oxazolidin-3-yl)-acetic
acid, and 420 mL (2.85 mmol) of phenyl dichlorophosphate,
570 mg (69%) of compound (C)-3b was obtained as a
colourless solid after purification by flash chromatography
(hexanes/ethyl acetate, 1:1). Mp 201–203 8C (hexanes/ethyl
acetate). [a]DZC97.2 (c 0.6, CHCl3). 1H NMR: d 1.65 (dd,
3H, JZ1.8, 6.9 Hz), 4.26 (dd, 1H, JZ7.5, 8.7 Hz), 4.65 (d,
1H, JZ5.4 Hz), 4.73 (t, 1H, JZ8.7 Hz), 4.96 (dd, 1H, JZ
7.5, 8.7 Hz), 5.07 (dd, 1H, JZ5.4, 9.3 Hz), 5.25 (m, 1H),
5.80 (m, 1H), 7.25 (m, 9H). 13C NMR: d 163.0, 137.2,
135.5, 134.2, 133.5, 129.7, 129.6, 128.7, 128.5, 128.2,
128.0, 127.8, 124.3, 117.7, 71.1, 63.8, 62.3, 60.2, 18.3. IR
(CHCl3, cmK1): n 1752, 1748. MS (EI), m/z: 428 (MCC2,
3), 426 (MC, 3), 229 (20), 224 (68), 184 (70), 144 (57%).
Anal. Calcd for C21H19N2O3Br: C, 59.03; H, 4.48; N, 6.56.
Found: C, 58.93; H, 4.51; N, 6.53.
3.3.11. (C)-(3S,4R)-4-(2-Bromophenyl)-3-[(S)-4-phenyl-
2-oxo-1,3-oxazolidin-3-yl]-1-prop-2-ynyl-azetidin-2-one,
(C)-8. Method B. From 180 mg (1.0 mmol) of o-bromo-
benzaldehyde, 60 mg (1.0 mmol) of propargylamine,
330 mg (1.5 mmol) of (S)-(2-oxo-4-phenyl-oxazolidin-3-
yl)-acetic acid, and 220 mL (1.5 mmol) of phenyl dichloro-
phosphate, 360 mg (84%) of compound (C)-8 was obtained
as a colourless oil after purification by flash chromatography
(hexanes/ethyl acetate, 1:1). [a]DZC145 (c 1.0, CHCl3).
1H NMR: d 2.17 (t, 1H, JZ2.7 Hz), 3.77 (dd, 1H, JZ2.7,
17.7 Hz), 3.92 (dd, 1H, JZ7.5, 8.7 Hz), 4.22 (t, 1H, JZ
8.7 Hz), 4.35 (d, 1H, JZ4.8 Hz), 4.53 (dd, 1H, JZ2.7,
17.7 Hz), 4.66 (dd, 1H, JZ7.5, 8.7 Hz), 5.15 (d, 1H, JZ
4.8 Hz), 7.40 (m, 9H). 13C NMR: d 164.0, 156.3, 136.5,
132.6, 132.2, 129.9, 129.7, 129.6, 128.0, 127.4, 127.3,
122.7, 75.9, 73.5, 70.3, 63.1, 61.8, 60.2, 30.9. IR (CHCl3,
cmK1): n 3300, 1750. Anal. Calcd for C21H17N2O3Br: C,
59.31; H, 4.03; N, 6.59. Found: C, 59.24; H, 4.10; N, 6.48.
3.3.8. (C)-(3S,4R)-1-(2-Bromobenzyl)-3-[(S)-4-phenyl-2-
oxo-1,3-oxazolidin-3-yl]-4-(E)-styryl-azetidin-2-one, (C)-4.
Method B. From 260 mg (2.0 mmol) of trans-cinnamalde-
hyde, 370 mg (2.0 mmol) of o-bromobenzylamine, 660 mg
(3.0 mmol) of (S)-(2-oxo-4-phenyl-oxazolidin-3-yl)-acetic
acid, and 440 mL (3.0 mmol) of phenyl dichlorophosphate,
510 mg (50%) of compound (C)-4 was obtained as a
colourless solid after purification by flash chromatography
(hexanes/ethyl acetate, 1:1). Mp 193–195 8C (hexanes/ethyl
acetate). [a]DZC35.9 (c 2.0, CHCl3). 1H NMR: d 4.10 (dd,
1H, JZ7.5, 9.0 Hz), 4.20 (dd, 1H, JZ4.8, 9.0 Hz), 4.28 (d,
1H, JZ15.6 Hz), 4.47 (d, 1H, JZ4.8 Hz), 4.55 (m, 2H),
4.80 (dd, 1H, JZ7.5, 9.0 Hz), 5.84 (dd, 1H, JZ9.0,
16.2 Hz), 6.43 (d, 1H, JZ16.2 Hz), 7.20 (m, 14H). 13C
NMR: d 170.0, 166.8, 152.2, 137.0, 135.7, 134.4, 132.8,
3.3.12. (C)-(3R,4S)-1-(2-Bromobenzyl)-4-(2,2-dimethyl-
[1,3]dioxolan-4-yl)-3-phenoxy-azetidin-2-one, (C)-9.
Method B. From 980 mg (7.6 mmol) of 2,3-O-isopropyliden-
D-glyceraldehyde, 1.42 g (7.6 mmol) of o-bromobenzyl-
amine, and 1.70 g (11.4 mmol) of phenoxyacetyl chloride,
2.0 g (60%) of compound (C)-9 was obtained as a
colourless solid after purification by flash chromatography
(hexanes/ethyl acetate, 3:1). Mp 95–97 8C (hexanes/ethyl

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B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
acetate). [a]DZC56.7 (c 1.0, CHCl3). 1H NMR: d 1.25 (s,
3H), 1.27 (s, 3H), 3.53 (dd, 1H, JZ6.0, 8.7 Hz), 3.61 (dd,
1H, JZ5.1, 8.7 Hz), 4.05 (dd, 1H, JZ5.4 Hz), 4.39 (m, 2H),
4.86 (d, 1H, JZ15.3 Hz), 5.14 (d, 1H, JZ5.4 Hz), 7.20 (m,
9H). 13C NMR: d 165.8, 157.3, 134.3, 133.0, 131.5, 129.6,
129.5, 127.3, 123.7, 122.5, 115.7, 109.7, 79.8, 76.9, 66.8,
59.9, 45.7, 26.5, 25.0. IR (CHCl3, cmK1): n 1770. Anal.
Calcd for C21H22NO4Br: C, 58.34; H, 5.13; N, 3.24. Found:
C, 58.24; H, 5.19; N, 3.26.
temperature. Then, a solution of crude aldehyde (178 mg,
0.5 mmol) in THF (5 mL) was added dropwise, and the
reaction mixture was stirred for 16 h at room temperature.
The crude mixture was diluted with brine and extracted with
ethyl acetate. The organic extract was washed with brine,
dried (MgSO4), and concentrated under reduced pressure.
Compound (C)-5b (143 mg, 77%) was obtained as a
colourless oil after purification by flash chromatography
(hexanes/ethyl acetate, 5:1) as a mixture of isomers E/Z
(75:25). A fraction containing analytically pure E-isomer
could be isolated. [a]DZC45.0 (c 1.0, CHCl3). 1H NMR: d
1.49 (dd, 3H, JZ1.8, 7.0 Hz), 4.24 (d, 1H, JZ17.8 Hz),
4.60 (dd, 1H, JZ4.5, 10.2 Hz), 4.77 (d, 1H, JZ17.8 Hz),
5.28 (d, 1H, JZ4.5 Hz), 5.40 (m, 1H), 5.75 (m, 1H), 7.30
(m, 9H). IR (CHCl3, cmK1): n 1750. Anal. Calcd for
C19H18NO2Br: C, 61.30; H, 4.87; N, 3.76. Found: C, 61.19;
H, 4.84; N, 3.78.
3.4. Synthesis of other cyclisation substrates
3.4.1. (C)-(3R,4S)-1-(2-Bromobenzyl)-4-(E)-(2-methoxy-
carbonylethenyl)-3-phenoxy-azetidin-2-one, (C)-5a. To
a solution of the corresponding acetonide b-lactam (C)-9
(233 mg, 0.54 mmol) in THF/water (1:1, 12 mL) was added
solid p-TsOH$H2O (124 mg, 0.65 mmol) in a single portion.
The resulting clear solution was heated under reflux for 3 h.
The reaction mixture was allowed to cool to room tem-
perature, and then was neutralized with solid NaHCO3. The
mixture was extracted with ethyl acetate, the organic layer
was dried (MgSO4) and the solvent was removed under
reduced pressure. The crude product (colourless oil) was
used for next step without any further purification. Saturated
aqueous sodium hydrogen carbonate (0.05 mL) was added
to a solution of the corresponding diol (196 mg, 0.5 mmol)
in dichloromethane (10 mL), maintaining the temperature
below 25 8C. Solid sodium periodate (214 mg, 1.0 mmol)
was added over a 10 min period with vigorous stirring and
the reaction was allowed to proceed for 2 h, while the
temperature was maintained below 25 8C. The solid was
removed by filtration, the filtrate was dried (MgSO4) and the
solvent was removed under reduced pressure to afford the
crude aldehyde as a colourless oil (178 mg, 0.5 mmol)
which was directly used without further purification. To a
stirred solution of the aldehyde in THF (10 mL) at 0 8C a
solution of methyl (triphenylphosphoranylidene)acetate
(202 mg, 0.6 mmol) in THF (2 mL) was slowly added and
the mixture was heated at reflux under an argon atmosphere
for 3 h, before being concentrated under reduced pressure.
Flash chromatography of the residue eluting with hexanes/
ethyl acetate 3:1 mixture gave compound (C)-5a (185 mg,
82% overall yield from 9) as a colourless solid. Mp 96–
98 8C (hexanes/ethyl acetate). [a]DZC7.4 (c 1.0, CHCl3).
1H NMR: d 3.62 (s, 3H), 4.25 (d, 1H, JZ15.3 Hz), 4.31 (dd,
1H, JZ5.1, 7.8 Hz), 4.72 (d, 1H, JZ15.3 Hz), 5.26 (d, 1H,
JZ5.1 Hz), 5.91 (d, 1H, JZ15.9 Hz), 6.73 (dd, 1H, JZ7.8,
15.9 Hz), 6.88 (m, 3H), 7.20 (m, 5H), 7.50 (m, 1H). 13C
NMR: d 165.4, 165.0, 157.2, 140.5, 134.0, 133.3, 131.5,
130.2, 129.7, 128.1, 126.8, 124.1, 122.6, 115.7, 82.3, 59.1,
51.9, 45.2. IR (CHCl3, cmK1): n 1750, 1710. Anal. Calcd for
C20H18NO4Br: C, 57.71; H, 4.36; N, 3.36. Found: C, 57.81;
H, 4.33; N, 3.38.
3.4.3. (G)-cis-3-(2-Bromophenoxy)-4-[(E)-(2-methoxy-
carbonylethenyl)]-1-(4-methoxyphenyl)-azetidin-2-one
(6b). To a stirred solution of aldehyde 10 (150 mg,
0.40 mmol) in THF (8 mL) at 0 8C a solution of methyl
(triphenylphosphoranylidene)acetate (162 mg, 0.48 mmol)
in THF (2 mL) was slowly added and the mixture was
heated at reflux under an argon atmosphere for 3 h, before
being concentrated under reduced pressure. Flash chromato-
graphy of the residue eluting with hexanes/ethyl acetate 1:1
mixture gave compound 6b (150 mg, 87%) as a colourless
oil. 1H NMR: d 3.66 (s, 3H), 3.72 (s, 3H), 4.91 (dd, 1H, JZ
5.4, 7.5 Hz), 5.40 (d, 1H, JZ5.4 Hz), 6.14 (d, 1H, JZ
16.5 Hz), 6.81 (d, 2H, JZ9.0 Hz), 6.86 (m, 1H), 7.04 (dd,
1H, JZ7.5, 16.5 Hz), 7.22 (m, 4H), 7.45 (d, 1H, JZ7.8 Hz).
13C NMR: d 165.5, 162.0, 157.0, 154.5, 151.6, 140.6, 133.7,
131.3, 128.8, 126.8, 124.1, 118.7, 116.2, 114.7, 82.4, 58.4,
55.6, 52.0. IR (CHCl3, cmK1): n 1760, 1715. Anal. Calcd for
C20H18NO5Br: C, 55.57; H, 4.20; N, 3.24. Found: C, 55.68;
H, 4.24; N, 3.21.
3.4.4. Synthesis of b-lactam imine (G)-6c. A solution of
benzylamine (0.03 mL, 0.27 mmol) in dichloromethane
(1 mL) was added dropwise to a stirred suspension of the
4-oxoazetidine-2-carbaldehyde 10 (100 mg, 0.27 mmol)
and magnesium sulfate (320 mg, 2,7 mmol) in dichloro-
methane (5 mL) at room temperature. After stirring 16 h at
room temperature, the mixture was filtered and the solvent
was removed under reduced pressure to give 120 mg
(100%) of compound 6c which was directly used without
further purification. Colourless oil. 1H NMR: d 3.80 (s, 3H),
4.70 (m, 2H), 4.90 (dd, 1H, JZ5.0, 6.0 Hz), 5.50 (d, 1H, JZ
5.0 Hz), 6.90 (d, 2H, JZ9.0 Hz), 6.95 (m, 1H), 7.25 (m,
6H), 7.40 (d, 2H, JZ9.0 Hz), 7.55 (d, 1H), 8.0 (d, 1H, JZ
4.0 Hz). 13C NMR: d 161.3, 160.8, 156.8, 153.6, 137.7,
133.5, 130.8, 128.7, 128.6, 128.2, 127.3, 123.8, 118.5,
115.4, 114.5, 112.2, 81.6, 65.2, 60.6, 55.5. IR (CHCl3, cmK1):
n 1755, 1670.
3.4.2. (C)-(3R,4S)-1-(2-Bromobenzyl)-3-phenoxy-4-[1-
(E)-propenyl]-azetidin-2-one, (C)-5b. The starting alde-
hyde obtained from b-lactam (C)-9 as described in Section
3.4.1 was directly used without further purification. To a
stirred suspension of ethyltriphenylphosphonium iodide
(292 mg, 0.7 mmol) in THF (5 mL) under an argon
atmosphere, BuLi (1.6 M in hexanes, 0.6 mmol) was
added dropwise. After the addition was finished, the
reaction mixture was stirred for further 30 min at room
3.5. General procedure for the radical cyclization
reaction. Synthesis of tricyclic b-lactams 11, 12, 13a, 14,
15, 23, and 24
A solution of the corresponding o-halogenophenyl-b-lactam
1–7 (1 mmol), Bu3SnH (1.2 mmol), and AIBN (0.1 mmol)
in dry benzene (20 mL) was refluxed under argon

B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
2775
atmosphere until complete disappearance of the starting
substrate (TLC, 1.5–3 h). The resulting crude reaction
mixture was treated with 10% aqueous solution of KF
(20 mL) for 30 min. The organic layer was separated, dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography of the residue eluting with hexanes/ethyl
acetate mixtures gave analytically pure tricyclic b-lactam.
(0.46 mmol) of compound 2a, 80 mg (50%) of compound
12a was obtained as a pale yellow oil after purification by
flash chromatography (hexanes/ethyl acetate, 1:1). 1H
NMR: d 3.03 (dd, 1H, JZ7.5, 14.7 Hz), 3.12 (dd, 1H, JZ
5.1, 14.7 Hz), 3.68 (m, 1H), 3.82 (dd, 1H, JZ4.5, 8.1 Hz),
4.06 (d, 1H, JZ15.6 Hz), 4.72 (d, 1H, JZ15.6 Hz), 5.28
(dd, 1H, JZ1.5, 4.5 Hz), 7.15 (m, 14H). 13C NMR: d 167.2,
157.6, 139.3, 136.7, 131.8, 129.7, 129.2, 128.7, 128.4,
127.5, 126.9, 126.7, 126.5, 122.4, 115.9, 81.8, 54.7, 40.9,
38.9, 36.3. IR (CHCl3, cmK1): n 1760, 1600. Anal. Calcd for
C24H21NO2: C, 81.10; H, 5.96; N, 3.94. Found: C, 81.22; H,
5.94; N, 3.94.
3.5.1. Tricyclic b-lactam (G)-11a. From 300 mg
(0.84 mmol) of compound 1a, 149 mg (65%) of compound
11a was obtained as a colourless solid after purification by
flash chromatography (hexanes/ethyl acetate, 1:1). Mp 123–
1
125 8C (hexanes/ethyl acetate). H NMR: d 0.79 (s, 3H),
1.18 (s, 3H), 2.72 (dd, 1H, JZ10.8, 13.5 Hz), 3.44 (dd, 1H,
JZ4.8, 13.5 Hz), 3.66 (m, 1H), 3.79 (d, 1H, JZ8.1 Hz),
7.20 (m, 9H). 13C NMR: d 179.6, 141.6, 140.4, 139.1, 128.8,
128.8, 128.8, 126.7, 125.0, 124.5, 116.8, 69.7, 52.8, 45.9,
39.9, 23.1, 18.1. IR (CHCl3, cmK1): n 1760, 1600. MS (EI),
m/z: 277 (MC, 11), 208 (25), 186 (96), 158 (59), 91 (100%).
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05.
Found: C, 82.12; H, 6.72; N, 5.28.
3.5.6. Tricyclic b-lactam (G)-12b. From 220 mg
(0.49 mmol) of compound 2b, 110 mg (61%) of compound
12b was obtained as a colourless oil after purification by
flash chromatography (hexanes/ethyl acetate, 3:1). 1H
NMR: d 3.00 (br s, 2H), 3.56 (br s, 2H), 3.97 (d, 1H, JZ
18.3 Hz), 4.45 (d, 1H, JZ11.7 Hz), 4.64 (d, 1H, JZ
18.3 Hz), 4.64 (br s, 1H), 4.72 (d, 1H, JZ11.7 Hz), 7.15 (m,
14H). 13C NMR: d 168.5, 139.5, 137.1, 136.8, 131.6, 129.1,
128.7, 128.6, 128.5, 127.8, 127.2, 126.7, 126.6, 126.4,
126.2, 82.4, 72.7, 54.7, 40.4, 38.9, 35.9. IR (CHCl3, cmK1):
n 1750, 1640. Anal. Calcd for C25H23NO2: C, 81.27; H,
6.27; N, 3.79. Found: C, 81.40; H, 6.24; N, 3.81.
3.5.2. Tricyclic b-lactam (G)-11b. From 300 mg
(0.71 mmol) of compound 1b, 160 mg (66%) of compound
11b was obtained as a colourless solid after purification
by flash chromatography (hexanes/ethyl acetate, 1:1). Mp
1
O130 8C (decomp.) (hexanes/ethyl acetate). H NMR: d
3.5.7. Tricyclic b-lactam (C)-13a. From 100 mg
(0.20 mmol) of compound (C)-3a, 66 mg (70%) of
compound (C)-13a was obtained as a colourless solid
after purification by flash chromatography (hexanes/ethyl
acetate, 1:1). Mp 168–170 8C (hexanes/ethyl acetate).
2.92 (dd, 1H, JZ8.4, 13.8 Hz), 3.30 (dd, 1H, JZ6.6,
13.8 Hz), 4.14 (m, 1H), 4.38 (dd, 1H, JZ4.5, 7.8 Hz), 5.46
(d, 1H, JZ4.5 Hz), 7.05 (m, 14H). 13C NMR: d 173.2,
157.2, 142.1, 141.1, 138.6, 129.8, 129.2, 128.8, 128.3,
126.8, 126.0, 125.2, 122.5, 117.9, 115.6, 80.7, 64.2, 43.0,
39.8. IR (CHCl3, cmK1): n 1740, 1670. MS (EI), m/z: 341
(MC, 6), 319 (19), 250 (8), 235 (44), 105 (76), 91 (100%).
Anal. Calcd for C23H19NO2: C, 80.92; H, 5.61; N, 4.10.
Found: C, 80.77; H, 5.53; N, 4.05.
1
[a]DZC110.0 (c 0.5, CHCl3). H NMR: d 2.57 (dd, 1H,
JZ11.1, 13.2 Hz), 3.05 (t, 1H, JZ7.8 Hz), 3.45 (dd, 1H,
JZ3.9, 13.2 Hz), 3.86 (dd, 1H, JZ7.8, 8.7 Hz), 4.07 (m,
3H), 4.23 (t, 1H, JZ8.7 Hz), 7.20 (m, 14H). 13C NMR: d
169.6, 157.3, 141.9, 140.8, 140.4, 136.6, 129.6, 129.5,
129.3, 129.2, 128.3, 127.3, 126.8, 125.7, 124.7, 117.4, 70.9,
65.5, 59.7, 59.5, 46.3, 39.5. IR (CHCl3, cmK1): n 1795,
1755, 1600. MS (EI), m/z: 410 (MC, 7), 319 (81), 207 (52),
130 (84), 104 (62), 91 (100%). Anal. Calcd for C26H22N2O3:
C, 76.08; H, 5.40; N, 6.82. Found: C, 76.19; H, 5.43; N,
6.78.
3.5.3. Tricyclic b-lactam cis-(G)-11c. From 400 mg
(0.92 mmol) of compound cis-1c, 170 mg (60%) of
compound cis-11c was obtained as a colourless oil after
purification by flash chromatography (hexanes/ethyl acet-
ate, 1:1). This compound decomposed quickly on standing
1
in solution at room temperature. H NMR: d 2.80 (dd, 1H,
JZ9.9, 13.8 Hz), 3.42 (dd, 1H, JZ4.5, 13.8 Hz), 4.12 (m,
1H), 4.19 (dd, 1H, JZ4.5, 4.8 Hz), 4.25 (AB system, 2H,
JZ12.0 Hz), 4.78 (d, 1H, JZ4.8 Hz), 7.20 (m, 14H). IR
(CHCl3, cmK1): n 1775, 1650.
3.5.8. Tricyclic b-lactam (C)-14. From 250 mg
(0.50 mmol) of compound (C)-4, 120 mg (57%) of
compound (C)-14 was obtained as a colourless solid after
purification by flash chromatography (hexanes/ethyl acet-
ate, 1:1). Mp 178–180 8C (hexanes/ethyl acetate). [a]DZ
1
3.5.4. Tricyclic b-lactam trans-(G)-11c. From 200 mg
(0.46 mmol) of compound trans-1c, 90 mg (62%) of
compound trans-11c was obtained as a white solid after
purification by flash chromatography (hexanes/ethyl acet-
ate, 1:1). Mp 87–89 8C (hexanes/ethyl acetate). 1H NMR: d
2.69 (dd, 1H, JZ10.5, 13.8 Hz), 3.29 (dd, 1H, JZ5.7,
13.8 Hz), 3.63 (m, 1H), 3.99 (m, 3H), 4.35 (d, 1H, JZ
2.4 Hz), 7.0–7.3 (m, 14H). 13C NMR: d 171.9, 141.0, 139.1,
138.8, 136.7, 129.3, 129.1, 128.6, 128.2, 127.9, 127.0,
125.6, 124.7, 116.6, 87.2, 71.9, 67.0, 48.0, 40.1, 25.3. IR
(CHCl3, cmK1): n 1770, 1650, 1600. MS (EI), m/z: 298 (27),
264 (5), 91 (100). Anal. Calcd for C24H21NO2: C, 81.10; H,
5.96; N, 3.94. Found: C, 80.98; H, 6.03; N, 3.86.
C97.4 (c 0.5, CHCl3). H NMR: d 2.65 (dd, 1H, JZ9.3,
13.8 Hz), 3.26 (br s, 1H), 3.41 (dd, 1H, JZ4.5, 13.8 Hz),
3.53 (br s, 1H), 3.65 (dd, 1H, JZ4.5, 8.7 Hz), 3.91 (dd, 1H,
JZ5.7, 8.7 Hz), 4.04 (d, 1H, JZ4.5 Hz), 4.06 (d, 1H, JZ
17.1 Hz), 4.28 (t, 1H, JZ8.7 Hz), 4.70 (d, 1H, JZ17.1 Hz),
7.20 (m, 14H). 13C NMR: d 162.9, 157.5, 140.2, 138.0,
135.6, 131.2, 129.6, 129.5, 129.3, 129.1, 128.3, 127.3,
127.2, 126.9, 126.8, 126.6, 70.9, 62.6, 59.3, 56.8, 41.0, 40.4,
36.2. IR (CHCl3, cmK1): n 1760, 1750. Anal. Calcd for
C27H24N2O3: C, 76.39; H, 5.70; N, 6.60. Found: C, 76.51;
H, 5.68; N, 6.57.
3.5.9. Tricyclic b-lactam (C)-15a. From 70 mg
(0.17 mmol) of compound (C)-5a, 40 mg (64%) of
compound (C)-15a was obtained as a colourless oil after
3.5.5. Tricyclic b-lactam (G)-12a. From 200 mg

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B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
purification by flash chromatography (hexanes/ethyl acet-
ate, 4:1). [a]DZC56.0 (c 0.5, CHCl3). 1H NMR: d 2.76 (dd,
1H, JZ6.0, 16.5 Hz), 2.85 (dd, 1H, JZ5.1, 16.5 Hz), 3.57
(s, 3H), 3.62 (m, 1H), 4.04 (dd, 1H, JZ4.2, 9.3 Hz), 4.21
(dd, 1H, JZ1.8, 16.8 Hz), 4.78 (d, 1H, JZ16.8 Hz), 5.43
(dd, 1H, JZ1.8, 4.2 Hz), 7.10 (m, 9H). 13C NMR: d 172.2,
166.8, 157.5, 135.1, 131.1, 129.7, 127.7, 127.1, 127.0,
126.6, 122.5, 115.7, 81.5, 54.0, 52.0, 40.8, 35.2, 33.3. IR
(CHCl3, cmK1): n 1775. Anal. Calcd for C20H19NO4: C,
71.20; H, 5.68; N, 4.15. Found: C, 71.09; H, 5.72; N, 4.12.
(CHCl3, cmK1): n 3200, 1750, 1590. Anal. Calcd for
C24H22N2O3: C, 74.59; H, 5.74; N, 7.25. Found: C, 74.70;
H, 5.70; N, 7.20.
3.5.14. Tricyclic b-lactam (G)-23. From 500 mg
(1.40 mmol) of compound 7, 80 mg (20%) of compound
23 was obtained as a colourless oil after purification by flash
1
chromatography (hexanes/ethyl acetate, 3:1). H NMR: d
3.75 (d, 1H, JZ15.3 Hz), 4.58 (d, 1H, JZ15.3 Hz), 4.91 (d,
1H, JZ4.4 Hz), 5.12 (s, 1H), 5.53 (d, 1H, JZ4.4 Hz), 5.60
(s, 1H), 7.15 (m, 8H), 7.63 (d, 1H, JZ7.7 Hz). 13C NMR: d
168.5, 157.5, 136.3, 133.3, 129.6, 129.5, 129.2, 128.6,
127.9, 125.4, 122.3, 115.7, 112.2, 82.0, 54.2, 43.7. IR
(CHCl3, cmK1): n 1760. Anal. Calcd for C18H15NO2: C,
77.96; H, 5.45; N, 5.05. Found: C, 77.84; H, 5.43; N, 5.08.
3.5.10. Tricyclic b-lactam (C)-15b. From 200 mg
(0.54 mmol) of compound (C)-5b, 80 mg (47%) of
compound (C)-15b was obtained as a colourless oil after
purification by flash chromatography (hexanes/ethyl acet-
ate, 3:1). [a]DZC47.0 (c 1.0, CHCl3). 1H NMR: d 0.89 (t,
3H, JZ7.5 Hz), 1.90 (m, 2H), 3.23 (m, 1H), 3.74 (dd, 1H,
JZ4.2, 8.9 Hz), 4.13 (d, 1H, JZ17.0 Hz), 4.73 (d, 1H, JZ
17.0 Hz), 5.38 (dd, 1H, JZ1.6, 4.2 Hz), 7.25 (m, 9H). 13C
NMR: d 166.8, 157.8, 135.9, 131.5, 129.7, 127.7, 127.4,
126.9, 126.5, 122.4, 115.8, 81.9, 54.1, 40.6, 35.7, 24.0, 10.9.
IR (CHCl3, cmK1): n 1775. Anal. Calcd for C19H19NO2: C,
77.79; H, 6.53; N, 4.77. Found: C, 77.91; H, 6.49; N, 4.75.
3.6. Radical reaction of haloaryl b-lactam (C)-3b.
Preparation of benzocarbapenem (C)-13b,
benzocarbacephem (C)-16, and 1,4-dihydroquinoline 17
According to the general procedure described in Section 3.5.
From 150 mg (0.35 mmol) of b-lactam (C)-3b, and after
column chromatography eluting with hexanes/ethyl acetate
(1:1), 40 mg (30%) of the less polar compound (C)-13b,
13 mg (10%) of compound (C)-16, and 33 mg (25%) of the
more polar compound 17 were obtained.
3.5.11. Tricyclic b-lactam (G)-22a. From 220 mg
(0.49 mmol) of compound 6a, 120 mg (69%) of compound
22a was obtained as a mixture (85:15) of epimers. The
major isomer could be isolated after purification by flash
chromatography (hexanes/ethyl acetate, 1:1). Colourless
1
solid. Mp 155–157 8C (hexanes/ethyl acetate). H NMR: d
3.6.1. Benzocarbapenem (C)-13b. Colourless oil.
1
2.87 (d, 2H, JZ8.1 Hz), 3.43 (t, 1H, JZ8.7 Hz), 3.69 (s,
3H), 4.46 (dd, 1H, JZ1.2, 5.1 Hz), 5.33 (d, 1H, JZ5.1 Hz),
6.95 (m, 13H). 13C NMR: d 162.1, 156.5, 152.2, 138.5,
130.4, 129.7, 129.0, 128.9, 128.6, 126.8, 125.8, 123.5,
118.6, 118.5, 114.5, 79.6, 58.2, 55.4, 40.3, 39.9. IR (CHCl3,
cmK1): n 1755, 1590. Anal. Calcd for C24H21NO3: C, 77.61;
H, 5.70; N, 3.77. Found: C, 77.73; H, 5.67; N, 3.75.
[a]DZC126.0 (c 0.7, CHCl3). H NMR: d 0.98 (t, 3H,
JZ7.5 Hz), 1.43 (m, 1H), 1.95 (m, 1H), 3.0 (m, 1H), 4.01
(dd, 1H, JZ5.4, 8.1 Hz), 4.35 (dd, 1H, JZ6.0, 9.0 Hz), 4.75
(t, 1H, JZ9.0 Hz), 4.96 (d, 1H, JZ5.4 Hz), 5.02 (dd, 1H,
JZ6.6, 9.0 Hz), 7.15 (m, 9H). 13C NMR: d 170.6, 157.7,
141.6, 141.2, 137.9, 129.4, 129.3, 127.7, 127.7, 125.4,
124.7, 116.8, 71.0, 64.4, 61.9, 59.3, 44.3, 26.5, 11.8. IR
(CHCl3, cmK1): n 1760, 1600. Anal. Calcd for C21H20N2O3:
C, 72.40; H, 5.79; N, 8.04. Found: C, 72.28; H, 5.82; N,
8.07.
3.5.12. Tricyclic b-lactam (G)-22b. From 100 mg
(0.23 mmol) of compound 6b, 50 mg (56%) of compound
22b was obtained as a mixture (70:30) of epimers. The
major isomer could be isolated after purification by flash
chromatography (hexanes/ethyl acetate, 3:1). Colourless oil.
1H NMR: d 2.49 (dd, 1H, JZ5.1, 17.1 Hz), 2.70 (dd, 1H,
JZ10.2, 17.1 Hz), 3.68 (s, 3H), 3.71 (s, 3H), 3.78 (dd, 1H,
JZ5.1, 9.9 Hz), 4.59 and 5.30 (d, each 1H, JZ4.5 Hz), 6.81
(d, 2H, JZ9.0 Hz), 6.93 (m, 3H), 7.15 (m, 1H), 7.35 (d, 2H,
JZ9.0 Hz). 13C NMR: d 172.1, 161.8, 156.6, 152.4, 130.0,
129.8, 129.4, 125.1, 124.0, 118.9, 118.6, 114.6, 79.5, 58.5,
55.5, 52.0, 37.1, 34.3. IR (CHCl3, cmK1): n 1760, 1750.
Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96.
Found: C, 67.87; H, 5.45; N, 3.98.
3.6.2. Benzocarbacephem (C)-16. Colourless solid. Mp
O170 8C (decomp.) (hexanes/ethyl acetate). [a]DZC114.6
(c 0.5, CHCl3). 1H NMR: d 1.09 (d, 3H, JZ7.2 Hz), 1.7 (m,
2H), 2.72 (m, 1H), 3.87 (dddd, 1H, JZ1.5, 4.2, 8.1,
12.0 Hz), 4.34 (dd, 1H, JZ5.4, 8.7 Hz), 4.70 (t, 1H, JZ
8.7 Hz), 4.81 (d, 1H, JZ4.2 Hz), 5.01 (dd, 1H, JZ5.4,
8.7 Hz), 7.0–7.4 (m, 9H). 13C NMR: d 161.1, 157.9, 138.6,
132.6, 130.0, 129.4, 129.4, 128.0, 127.0, 126.5, 124.2,
118.5, 70.8, 63.2, 59.1, 54.1, 30.0, 29.3, 19.6. IR (CHCl3,
cmK1): n 1760, 1595. Anal. Calcd for C21H20N2O3: C,
72.40; H, 5.79; N, 8.04. Found: C, 72.54; H, 5.83; N, 8.00.
3.5.13. Tricyclic b-lactam (G)-22c. From 70 mg
(0.14 mmol) of compound 6c, 30 mg (60%) of compound
22c was obtained as a pale yellow oil after purification by
flash chromatography (hexanes/ethyl acetate, 3:1). 1H
NMR: d 3.75 (s, 3H), 3.76 (br s, 2H), 4.13 (d, 1H, JZ
1.2 Hz), 4.73 (dd, 1H, JZ1.2, 5.1 Hz), 5.4 (d, 1H, JZ
5.1 Hz), 6.80 (d, 2H, JZ9.0 Hz), 7.0 (m, 2H), 7.18 (d, 2H,
JZ9.0 Hz), 7.35 (m, 7H). 13C NMR: d 161.9, 156.6, 152.4,
139.4, 130.6, 130.0, 129.8, 128.6, 128.2, 127.3, 124.9,
123.5, 119.2, 118.5, 114.6, 79.5, 59.9, 55.5, 53.6, 51.3. IR
3.6.3. 1,4-Dihydroquinoline 17. Colourless oil. 1H NMR: d
1.19 (d, 3H, JZ7.5 Hz), 3.35 (m, 1H), 3.55 (d, 1H, JZ
17.4 Hz), 4.18 (t, 1H, JZ7.8 Hz), 4.64 (d, 1H, JZ17.4 Hz),
4.75 (t, 1H, JZ9.3 Hz), 5.19 (t, 1H, JZ8.4 Hz), 5.51 (dd,
1H, JZ5.1, 7.2 Hz), 6.56 (d, 1H, JZ7.2 Hz), 7.25 (m, 8H),
7.95 (d, 1H). IR (CHCl3, cmK1): n 1750, 1650. Anal. Calcd
for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C,
72.52; H, 5.75; N, 8.08.

B. Alcaide et al. / Tetrahedron 61 (2005) 2767–2778
2777
reviews on the ketene–imine approach to b-lactams, see:
(b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Curr. Med. Chem. 2004, 11, 1837. (c) Palomo, C.; Aizpurua,
J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999, 3223.
(d) Tidwell, T. T. Ketenes; Wiley: New York, 1995; pp 518–
527. (e) Georg, G. I.; Ravikumar, V. T. In The Organic
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Acknowledgements
Support for this work by the D.G.I.-M.C.Y.T. (Project
BQU2003-07793-C02-01) is gratefully acknowledged.
9. N-(2-Halogenophenyl)imines were prepared by the con-
densation of an o-halogenoaniline with the corresponding
a,b-unsaturated aldehyde in the presence of the ZnCl2/
a-phenylethylamine complex as catalyst, using benzene as
solvent and a Dean–Stark apparatus to remove the water
formed during the reaction. Alternatively, N-alkylimines
required in our work were smoothly prepared by the
condensation of the appropriate aldehyde with the correspond-
ing amine in dichloromethane at room temperature in the
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received much attention, problems associated with the
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ology are widely appreciated. Even the formation of seven-
membered rings in the 7-exo-trig mode is likely to be
unsuccessful in most cases (at 25 8C, k7-exo!7!10K1 sK1).
However, we and others were able to prepare seven-membered
rings by radical cyclization of b-lactam-tethered haloalkenes
or alkynes. See: (a) Alcaide, B.; Almendros, P.; Aragoncillo,
C. J. Org. Chem. 2001, 66, 1612. (b) Penfold, D. J.; Pike, K.;
Genge, A.; Anson, M.; Kitteringham, J.; Kilburn, J. D.
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P.; Aragoncillo, C. Chem. Commun. 1999, 1913. (d) Knight, J.;
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(e) Knight, J.; Parsons, P. J.; Southgate, R. J. Chem. Soc.,
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Rodrıguez-Acebes, R. J. Org. Chem. 2004, 69, 826. (d) Alcaide,
B.; Almendros, P.; Alonso, J. M. Chem. Eur. J. 2003, 9, 5793.
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(a) Alcaide, B.; Moreno, A. M.; Rodrıguez-Vicente, A.; Sierra,
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8. (a) Staudinger, M. Liebigs Ann. Chem. 1907, 356, 51. For

2778
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See: Bertha, F.; Fetter, M.; Kajtar-Peredy, M.; Lempert, K.;
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20. These values are in good agreement with previously reported
data for related compounds obtained by different methods.
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