Synthesis of novel 4-(2-oxoethylidene)azetidin-2-ones by a Lewis acid mediated reaction of acyldiazo compounds

Article abstract of DOI:10.1002/ejoc.200210702

We report the synthesis of a class of 4-(2-oxoethylidene)azetidin-2-ones by a novel Lewis acid mediated reaction of acyldiazo compounds with 4-acetoxyazetidin-2-ones. Using this approach, C-3-and C-4-substituted 4-alkylideneazetidin-2ones were obtained de

Full text of DOI:10.1002/ejoc.200210702

FULL PAPER
Synthesis of Novel 4-(2-Oxoethylidene)azetidin-2-ones by a Lewis Acid
Mediated Reaction of Acyldiazo Compounds
Gianfranco Cainelli,[a] Daria Giacomini,*[a] Paola Galletti,*[a] and Arianna Quintavalla[a]
Keywords: Diazo compounds / Lactams / Lewis acids
We report the synthesis of a class of 4-(2-oxoethylidene)azeti- nature of the C-3 side chain, the Lewis acid, and the β-lactam
din-2-ones by a novel Lewis acid mediated reaction of acyldi-
azo compounds with 4-acetoxyazetidin-2-ones. Using this
approach, C-3-and C-4-substituted 4-alkylideneazetidin-2-
ones were obtained depending on the choice of starting azet-
idinone and α-diazocarbonyl compound. The products reveal
excellent Z diastereoselection of the C-4 double bond. Vari-
able amounts of E isomers are obtained depending on the
protection. VT NMR spectroscopic experiments and X-ray
structural analysis of crystalline derivatives demonstrate the
presence of an intramolecular hydrogen bond in Z isomers,
which drives the stereochemical outcome of the reaction. A
possible mechanism for this novel reaction is proposed.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
elimination step. Some years ago we reported the synthesis
of 4-alkylideneazetidin-2-ones starting from an ester-enol-
ate and ketenimine.[11] Many efforts have also been devoted
to accomplishing the synthesis of 3-alkylidene-β-lactams[12]
and, recently, 7-alkylidene-cephalosporin esters[13] and
other β-lactam antibiotics with exo methylene double bonds
have been reported as inhibitors of Human Leukocyte Elas-
tase.[14]
Because of the unique properties of the azetidinone ring,
which is particularly strained and activated towards nucleo-
philic acyl substitution, the β-lactam structure is a funda-
mental and versatile building block in the design and syn-
thesis of several biologically active compounds. It has been
widely used to obtain fundamental antibacterial products
(β-lactam antibiotics),[1] unusual peptide derivatives,[2] and,
recently, enzymatic inhibitors of different serine proteases.[3]
Indeed, in the last ten years several derivatized cephalospor-
ins, penicillins, penems, and non-conventional monocyclic
and bicyclic β-lactam derivatives have proved to be efficient
inhibitors of HLE (Human Leukocyte Elastase),[4] HCMV
(Human Cytomegalovirus Protease),[5] PSA (prostate-
specific antigen),[6] and cholesterol absorption.[7]
Some structural requirements have been recognized in or-
der for monocyclic β-lactam derivatives to gain inhibitory
activity,[8] but the possibility of activating the azetidinone
ring through unsaturated systems directly linked to the β-
lactam ring has been poorly investigated. Notwithstanding
the fact that thousands of different β-lactam compounds
have been synthesized, very few examples of alkylidene-
azetidin-2-ones have been reported in the literature, which
were studied in the 1980s by only a few authors who found
little antibacterial activity.[9] For example, Bachi[10] reported
the synthesis of some 4-alkylidene-β-lactams starting from
4-thioxo-2-azetidinones and disubstituted diazo com-
pounds using rhodium catalysis followed by a reductive
As an extension of our continuing studies in the field of
β-lactams,[15] here we report the synthesis of a class of 4-(2-
oxoethylidene)azetidin-2-ones by a novel Lewis acid me-
diated reaction of acyldiazo compounds with 4-acetoxy-az-
etidin-2-ones.[16] 4-Acetoxy-β-lactam derivatives are import-
ant, frequently used intermediates in the synthesis of peni-
cillins, cephalosporins, and carbapenems,[17] with the pres-
ence of the good leaving group at the C-4 position allowing
different functionalizations.[18] In particular, compound 1 is
the industrial intermediate[19] for the synthesis of thienamy-
cin, imipenem, and derivatives, and some years ago we ac-
complished a simple stereocontrolled synthesis of it starting
from methyl (R)-3-hydroxybutyrate and hexahydrotria-
zine.[20] Diazo compounds, ranging from simple diazoal-
kanes to highly substituted diazocarbonyl compounds, play
an important role in modern organic synthesis.[21] In the
chemistry of β-lactams, diazo compounds have been largely
used as a carbene precursor to perform insertion into the
NϪH bond, of which the most powerful application is rep-
resented by the ring closure step in the Merck synthesis of
carbapenems.[22] The reactions of 4-acetoxyazetidin-2-ones
with diazomalonate in the presence of a catalytic amount
of rhodium() acetate are also reported to furnish poor
yields of N-substituted β-lactams through a carbene NH
insertion.[23] To the best of our knowledge, no reaction is
known between 4-acetoxyazetidin-2-one derivatives and a
diazo-functionalized species involving the C-4 position.
[a]
Dipartimento di Chimica ‘‘G. Ciamician’’
Via Selmi 2, 40126 Bologna, Italy
Fax: (internat.) ϩ 39-051/2099456
E-mail: giacomin@ciam.unibo.it, paolag@ciam.unibo.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2003, 1765Ϫ1774
DOI: 10.1002/ejoc.200200702
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1765

G. Cainelli, D. Giacomini, P. Galletti, A. Quintavalla
FULL PAPER
In our approach to 4-alkylidene-β-lactam derivatives, we we obtained traces of the 4-alkylidene compound 3 only
obtain C-3- and C-4-substituted 4-alkylideneazetidin-2- when using TiCl4. When we investigated the coupling of N-
ones, depending on the choice of starting azetidinone and trimethylsilyl derivative 1b with catalytic TiCl4 and Cu-
α-diazocarbonyl compound. Moreover, the products are (OTf)2 (entries 6 and 7), we obtained moderate yields of
obtained with variable Z/E ratios, depending on the nature two diastereoisomeric products 3-Z and 3-E that were easily
of the C-3 side chain, the Lewis acid, and the β-lactam pro- separated by chromatography (see Exp. Sect.). Treatment of
tection at nitrogen.
the major isomer with HCl in methanol produced a depro-
tected crystalline derivative 22 whose X-ray diffraction
analysis established the Z configuration of the CϭC bond
(Scheme 1 and Figure 2).
Results and Discussion
To obtain 4-(2-oxoethylidene)azetidin-2-ones, we reacted
different 3-substituted 4-acetoxy-β-lactams Ϫ in particular,
3-(1-hydroxy-1-ethyl), 3-chloro, 3-bromo, and 3-H deriva-
tives Ϫ with several diazo compounds: diazo esters, diazo
ketones, and diazomethane derivatives.
The study was initiated by analyzing the reaction of 1
with commercial ethyl diazoacetate (EDA) and different
Lewis acids, for which the results are summarized in
Table 1.
No reaction occurred when 1a was treated with one
equivalent of EDA (2) in CH2Cl2 in the absence of a Lewis
acid (entry 1). By reacting 1a and 2 in the presence of a
Scheme 1
Critical to the success of the reaction was the use of a
catalytic amount of either TiCl4, Rh2(OAc)4, or Cu(OTf)2, stoichiometric amount of TiCl4 and a requirement for tri-
Table 1. Reaction of 1aϪd with 2 (EDA) using different Lewis acids
Entry
Substrate
R1
Equiv. of EDA
Lewis acid (equiv.)
Yields (%)[a]
Z/E (%)
1
2
3
4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1a
1a
1a
1a
1b
1b
1a
1b
1a
1b
1b
1a
1b
1a
1b
1b
1b
1a
1b
1a
1b
1b
1b
1b
1c
1d
H
H
H
H
SiMe3
SiMe3
H
SiMe3
H
SiMe3
SiMe3
H
SiMe3
H
SiMe3
SiMe3
SiMe3
H
SiMe3
H
SiMe3
SiMe3
SiMe3
SiMe3
SiMe2tBu
COCH3
1
1
1
1
1
1
1
1
4
4
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Rh2(OAc)4 (0.01)
Cu(OTf)2 (0.1)
TiCl4 (0.1)
TiCl4 (0.1)
Cu(OTf)2 (0.1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
Me3SiCl (1)
Me3SiCl (2) /TiCl4 (0.1)
Me3SiCl (2) /TiCl4 (0.1)
Cu(OTf)2 (1)
Cu(OTf)2 (1)
TiF4 (1)
InBr3 (1)
SnCl4 (1)
SnCl4 (1)
AlCl3 (1)
traces
38
24
23
60
77
91
Ϫ
49
81
Ϫ
Ϫ
72
Ϫ
58
35
45
73
59
18
16
Ϫ
86:14
25:75
Ͼ 99:1
85:15
Ͼ 99:1
80:20
Ϫ
Ͼ 99:1
60:40
Ϫ
Ϫ
58:42
Ϫ
Ͼ 99:1
Ͼ 99:1
50:50
53:47
50:50
Ͻ 1:99
Ͼ 99:1
Ϫ
AlCl3 (1)
Et2AlCl (1)
BF3·Et2O (1)
ZnCl2 (1)
TiCl4 (1)
TiCl4 (1)
Ϫ
Ϫ
[a]
Isolated yields after flash chromatography.
1766
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Synthesis of Novel 4-(2-Oxoethylidene)azetidin-2-ones
FULL PAPER
Figure 1. Temperature dependence of 1H NMR chemical shifts for the amido protons of 3-Z (ᮀ) and 3-E (᭿) in CDCl3 and [D6]DMSO
The compounds 3-Z and 3-E were evaluated as inhibitors
of Human Leucocyte Elastase (HLE)[24] and compared
with the corresponding product saturated at the C-4 posi-
tion.[25] Preliminary results indicate that, at a concentration
of 100 µ, 3-Z and 3-E inhibited HLE by 57.6 and 66.2%,
respectively, and the saturated compound was inactive. This
result is consistent with the concept that a C-4-unsaturated
system is able to activate monocyclic β-lactams towards ser-
ine proteases, such as HLE.
To extend the scope of this new reaction, we analyzed the
reactivity of 1a/b toward different diazo compounds. The
results are reported in Table 2.
Using one equivalent of tert-butyl diazoacetate 4 and
TiCl4, we obtained β-lactam 9 in 42% yield with complete
Figure 2. A view of the molecular compound 22; the hydrogen
Z diastereoselectivity (Table 2, entry 1). Hydrolysis of the
bonds are shown as dotted lines
tert-butyl ester 9 using TiCl4 in CH2Cl2 at 0 °C produced
the carboxylic acid derivative 23 (Scheme 1) whose single-
crystal X-ray diffraction analysis indicated the structure re-
ported in Figure 3.
methylsilyl protection of the β-lactam nitrogen atom
(Table 1, entry 9). Four equivalents of ethyl diazoacetate,
together with one equivalent of TiCl4, improved the reac-
tion yield from 38 to 91% (Table 1, entry 11).
Even diazo ketones 5 and 6 furnished the corresponding
4-alkylideneazetidin-2-ones 10 and 11 (complete Z dia-
stereoselectivity) with TiCl4 catalysis (Table 2, entries 2 and
4). Diazo compound 7 (ethyl 4-diazoacetoacetate) did not
yield the β-lactam product when using either TiCl4 or AlCl3
(Table 2, entries 5, 6). Diazo compound 8 (2,4-bis(diazo)-
acetoacetate, entry 7) gave the expected product 12 in 20%
yield (Z isomer only).
We found that there was no reaction with diazomethane
derivatives (i.e., diazomethane, trimethylsylildiazomethane,
and diphenyldiazomethane) under TiCl4 catalysis. In ad-
dition, no product was observed, using tert-butyl α-diazo-
acetoacetate.
To obtain 3-substituted 4-alkylidene derivatives, we inves-
tigated the reactivity of diazo compounds 2, 5, and 6 to-
ward several 4-acetoxy-β-lactams. The results are summar-
ized in Table 3.
Phenylacetamido-4-acetoxyazetidin-2-one 13 failed to
give the desired product under a variety of conditions
Among the Lewis acids we tested, ZnCl2 and BF3.OEt2
promoted the reaction with excellent, and complementary,
stereoselectivities, but the yields were not satisfactory
(Table 1, entries 24 and 25). TiF4, AlCl3, and Et2AlCl were
good catalysts for this reaction, furnishing 3 in almost equi-
molar Z/E mixtures (Table 1, entries 17, 22 and 23). SnCl4
effectively catalyzed the addition of EDA to 1a and 1b, with
the formation of 3-Z as the sole isomeric product (Table 1,
entries 19 and 20). Me3SiCl did not promote the reaction
(Table 1, entry 12), but a combination of two equivalents of
TMSCl and 10% of TiCl4 provided a catalytic version of
the reaction (Table 1, entries 13 and 14) with complete
stereoselectivity for 3-Z starting from 1a. Interestingly, at
least when TiCl4 was used as a catalyst, complete stereoch-
emical control in favor of the Z isomer was achieved with
the free-amine starting material 1a, whereas the N-SiMe3
derivative 1b gave Z/E mixtures.
Protecting the β-lactam nitrogen atom with less-labile (Table 3, entry 1). 4-Acetoxyazetidin-2-one 14 furnished
and more-hindered groups, such as SitBuMe2 or acetyl products 17 in good yields and with different diastereoselec-
(Table 1, entries 26 and 27), resulted in no product forma- tivities depending on the substitution of the β-lactam nitro-
tion.
gen atom. 4-Alkylidene-β-lactams 18 and 19 were obtained
Eur. J. Org. Chem. 2003, 1765Ϫ1774
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G. Cainelli, D. Giacomini, P. Galletti, A. Quintavalla
FULL PAPER
Table 2. Reaction of 1a/b with different diazo compounds and Lewis acids
Entry
Substrate
R1
R2
Diazo compound (equiv.)
Lewis acid (equiv.)
Product
Yields (%)[a]
Z/E (%)
1
2
3
4
5
6
7
1b
1b
1a
1b
1b
1b
1b
SiMe3
SiMe3
H
SiMe3
SiMe3
SiMe3
SiMe3
OtBu
Ph
Ph
CHϭCHPh
CH2COOEt
CH2COOEt
C(N2)COOEt
4 (1)
5 (4)
5 (2)
6 (4)
7 (4)
7 (3)
8 (2)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
AlCl3 (1)
TiCl4 (1)
9
10
10
11
Ϫ
Ϫ
12
42
55
20
22
Ϫ
Ϫ
20
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ϫ
Ϫ
Ͼ 99:1
[a]
Isolated yields after flash chromatography.
from diazo ketones 5 and 6 in moderate to poor yields, but
with complete Z diastereoselectivity (entries 4 and 5). Un-
expectedly, 3-chloro- and 3-bromo-4-acetoxyazetidin-2-one
15 and 16 furnished products 20 and 21 in poor yields only
(entries 8Ϫ11).
In each case (Table 1, 2, and 3) when the reaction did not
proceed or the yields were poor, we never isolated β-lactam
intermediates or byproducts containing the β-lactam ring.
All derivatives obtained show a peculiar IR absorption
of the β-lactam carbonyl group at 1820 cmϪ1, indicative of
a strong activation towards nucleophilic acylation. Very
high frequencies have previously been observed in 4-alkylid-
ene derivatives (see refs.[9Ϫ11]). Furthermore, the more-de-
1
shielded NH resonances in the H NMR spectra in CDCl3
Figure 3. A view of the molecular compound 23; for the sake of
clarity, the alkyl substituents of the silicon atom (wider atom) are
omitted; the hydrogen bonds are shown as dotted lines
of the Z isomers, compared to those of the E isomers, are
quite interesting, for they suggest the existence of intramol-
Table 3. Reaction of 4-acetoxyazetidin-2-ones with different diazo compounds and Lewis acids
R1 R2 Diazo compound (4 equiv.) Lewis acid (equiv.) Product Yields (%)[a] Z/E (%)
Entry Substrate
R
1
2
3
4
5
6
7
8
9
13
BnCONH SiMe3 OEt
2
2
2
5
6
2
2
2
2
2
2
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
TiCl4 (1)
AlCl3 (1)
TiCl4 (1)
TiCl4 (1)
Ϫ
Ϫ
Ϫ
14a
14b
14b
14b
15
H
H
H
H
H
OEt
17
17
18
19
20
20
20
20
21
21
54
79
30
10
20
14
26
10
10
10
83:17
33:67
Ͼ 99:1
Ϫ
86:14
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
SiMe3 OEt
SiMe3 Ph
SiMe3 CHϭCHPh
Cl (trans) SiMe3 OEt
15
Cl (cis)
Cl (cis)
Cl (cis)
H
OEt
15
SiMe3 OEt
SiMe3 OEt
15
10
11
16
Br (trans) SiMe3 OEt
Br (cis) SiMe3 OEt
16
[a]
Isolated yields after flash chromatography.
1768
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Eur. J. Org. Chem. 2003, 1765Ϫ1774

Synthesis of Novel 4-(2-Oxoethylidene)azetidin-2-ones
FULL PAPER
ecular hydrogen bonds in the Z isomers. The details of the
hydrogen bonding patterns in 3-Z and 3-E were further sub-
stantiated by variable-temperature 1H NMR experi-
ments.[26] Figure 1 shows the temperature dependence of the
chemical shifts of the amide protons in Z and E isomers.
1
In a [D6]DMSO solution over a range 294Ϫ342 K, the H
NMR chemical shifts of the amide NH resonance in 3-Z
and 3-E show a linear relationship for δ vs. T, with a slight
temperature dependence (4.9 and 3.7 ϫ 10Ϫ3 ppm KϪ1
,
respectively). In a non-competitive solvent, such as CDCl3,
the value of Ϫdδ/dT of the NH unit in the Z isomer is small
(2.4 ϫ 10Ϫ3 ppm KϪ1), whereas that of the E isomer shows
a greater temperature dependence (9.4 ϫ 10Ϫ3 ppm KϪ1).
Such a low value of Ϫdδ/dT (Յ 6 ϫ 10Ϫ3 ppm KϪ1) has
generally been attributed to intramolecularly hydrogen-
bonded amido groups, and indicates that the NH unit is
hydrogen bonded with the COOEt group, and shielded
from the solvent, in the Z isomer.[27]
Because of its intramolecular hydrogen bond, the Z iso-
mer is likely to be the more stable of the two, a suggestion
that was supported experimentally by the observed spon-
taneous slow conversion of the isolated E isomer into its
Z isomer.
The conformations adopted by compounds 22 and 23 in
the crystalline state are depicted in Figure 2 and Figure 3,
respectively.
In both compounds the β-lactam ring and the unsatu-
rated chain in the C-4 position are coplanar. Even the ester
group in compound 22 lies almost within this plane, with
˚
its displacement being only 0.09 A. The voluminous TBS
group in the C-3 position of 23 completely shields one side
of the azetidinone ring (Figure 4). The endocyclic angles at
the C-4 positions appear to be unusual (89° and 91° for the
carboxylic acid and ester, respectively) in that they are wider
than those found in the literature for analogous β-lactams
having sp3 hybridization at that position (86° for the C-4-
saturated carboxylic acid).[28] The main difference between
Figure 4. Two views of the molecular compound 23 showing the
TBS protecting group; in A, the plane of the β-lactam ring is per-
pendicular to the view direction; in B, it is parallel
the structures of the two compounds in the crystalline state philes. This hypothesis is drawn from three pieces of evi-
is in the network of hydrogen bonds (Figure 2 and 3). Car- dence: i) only stabilized α-diazocarbonyl compounds gave
boxylic acid 23 shows an intramolecular hydrogen bond products; ii) Rh2(OAc)4 is not a catalyst for the reaction;
and four intermolecular contacts that extend throughout and iii) no product was derived from carbene insertion. The
the crystal, whereas in the ester 22 only hydrogen-bonded tendency of diazoesters to react as nucleophiles has been
dimers exist.
described both in base-promoted reactions with carbonyl
On the basis of our experimental results and the struc- compounds to form diazoketols[30] and in Lewis acid cata-
tures of the products, a possible mechanism for this novel lyzed addition to give β-dicarbonyls.[31]
reaction is proposed.
That higher yields were obtained for the addition of di-
It has been stated that 4-acetoxy-β-lactams undergo reac- azo compound to the iminium species when 4 equivalents
tions with nucleophiles in the presence of Lewis acids of EDA were used could indicate a slow reaction rate. This
through an iminium ion intermediate.[29] It is possible that rate may even account for the lower yields obtained when
in the case studied here, the main role of the Lewis acid is using 3-chloro- and 3-bromo-azetidinones. In these cases,
to activate the displacement of the acetoxy group to form the corresponding iminium ion intermediates might be too
an intermediate iminium ion of type A (Scheme 2). It is short-lived to undergo the slow addition to the diazocar-
important to note that the preliminary activation of the β- bonyl compound, and so instead they decompose.[32]
lactam is a basic requirement for the reaction, because no
Addition of a diazo compound to an iminium ion inter-
product was isolated with an inverse addition of reagents mediate leads to four possible diazo derivatives (B1, B2, B3,
(i.e., TiCl4 as the last added reagent after EDA).
and B4) obtained by attack on the two faces of the iminium
Under our reaction conditions, it is highly probable that ion.[33] In particular, trans intermediates B2 and B3 would
the diazo compounds do not react as carbenes, but as nucleo- be greatly favored in the case of a bulky R substituent on
Eur. J. Org. Chem. 2003, 1765Ϫ1774
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G. Cainelli, D. Giacomini, P. Galletti, A. Quintavalla
FULL PAPER
Scheme 2
the β-lactam. This preference is supported by the crystal tam has been silylated. Indeed, in this case there is no stabil-
structure of 23, in which the TBS group completely shields ization by an intramolecular hydrogen bond and so all of
one face of the β-lactam ring (Figure 4).
the diazo intermediates B are active and result in the forma-
The elimination of molecular nitrogen and a proton, tion of the Z/E mixtures.
leading to 4-alkylidene products, could, in principle, follow
Our results demonstrate that the nature of the Lewis acid
an E1 or an E2 mechanism. Because of the occurrence of an also governs the Z/E ratio of the products, indicating that
intramolecular rearrangement, E1 elimination (carbocation it plays a further role. The evidence that 4-acetoxyazetidi-
formation) has been proposed by Wang et al.[34] to occur in nones with less-labile N-protecting groups (such as N-Sit-
the reaction of N-tosyl diazoketamines catalyzed by BuMe2 or N-COCH3) did not produce 4-alkylidene deriva-
Rh2(OAc)4 or TsOH. In the present study, however, the lack tives, and that, in the case of N-SiMe3, we failed to find N-
of rearranged products, which should generate more-stable SiMe3-4-alkylidene derivatives in the reaction mixture,
γ-lactams, and the instability of the α-carboxy cation could indicate a possible ligand-exchange process that irrev-
strongly suggest that an E2 elimination occurs. Thus, the ersibly bonds the metal cation of the Lewis acid to the β-
stereochemical outcome of the reaction probably occurs lactam nitrogen atom leading to a N-metallated iminium
through an anti-periplanar elimination from the four diazo species. This process could also account for the requirement
derivatives B1, B2, B3, and B4; in particular, B1 and B2 will of a full equivalent of the Lewis acid being necessary for
lead to Z isomers and B3 and B4 to E isomers.
obtaining good yields of reaction. Then diazo intermediates
VT 1H NMR spectroscopy and X-ray structures have B1 and B2 (R1 ϭ MXnϪ1) should favor the stereochemical
demonstrated that an intramolecular hydrogen bond has a predominance of the Z isomer by means of chelation of the
stabilizing effect in the Z diastereoisomer. It seems quite metal (e.g., from TiCl4 or SnCl4) to the carboxyethyl chain.
reasonable that, whenever the reaction was performed on It follows from this hypothesis that whenever the Lewis acid
the NH-containing β-lactam, a hydrogen bond should al- is not a part of chelation and/or of a ligand exchange (e.g.,
ready be present in the diazo intermediates (Scheme 2). It for TiF4, AlCl3, Cu(OTf)2, and BF3·OEt2), the result is a
follows that only B1 and B2 (R1 ϭ H) present the correct variable Z/E ratio or a predominance of the E isomer.[35]
anti-periplanar arrangement for the E2 elimination, thus
leading to the Z isomer, whereas B3 and B4 must first re-
lease the hydrogen bond and then undergo rotation around
the CϪC bond in order to undergo elimination to furnish
the E isomer. Thus, the preferential formation of the Z iso-
Conclusion
The synthesis of a class of 4-(2-oxoethylidene)azetidin-2-
mers is dictated by the stabilizing effect of the intramolecu- ones was carried out efficiently by novel Lewis acid me-
lar hydrogen bond and by the more-favorable kinetics re- diated reactions of 4-acetoxy-azetidin-2-ones with α-diazo-
sulting from the stereochemical requirements of the elimin- carbonyl compounds. All the starting materials are widely
ation step.
used and readily accessible compounds, which allow for the
This model also accounts for the appearance of a signifi- preparation of several different products. In particular, the
cant amount of the E isomer whenever the starting β-lac- reaction could be performed using differently 3-substituted
1770
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1765Ϫ1774

Synthesis of Novel 4-(2-Oxoethylidene)azetidin-2-ones
FULL PAPER
COCH2CO), 4.18 (q, J ϭ 7.4 Hz, 2 H, CH2CH3), 5.56 (br. s, 1 H,
N2CH) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 14.1, 47.0, 55.9,
61.6, 167.1, 186.0 ppm.
4-acetoxy-β-lactams with diazoesters and diazo ketones.
The products have been obtained with an excellent Z dia-
stereoselectivity at the C-4 double bond. Variable amounts
of E isomers can be obtained depending on the nature of
the C-3 side chain, the Lewis acid, and the degree of β-
lactam protection. VT NMR spectroscopic experiments
and X-ray structure determination of crystalline derivatives
demonstrate the presence of an intramolecular hydrogen
bond in Z isomers that drives the stereochemical result.
Preliminary biological results provide a basis for the de-
velopment of more-potent 4-alkylidene-β-lactam-based in-
hibitors of serine enzymes.
Ethyl 2,4-Bis(diazo)-3-oxobutyrate (8): Rf ϭ 0.6 (cyclohexane/ethyl
acetate, 7:3). IR (neat): ν˜ ϭ 2137, 2107, 1705, 1599, 1357, 1308
1
cmϪ1. H NMR (CDCl3, 200 MHz): δ ϭ 1.33 (t, J ϭ 7.0 Hz, 3 H,
CH3), 4.29 (q, J ϭ 7.0 Hz, 2 H, CH2CH3), 6.49 (s, 1 H, N2CH)
ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 14.4, 54.6, 61.6, 161.7,
177.3 ppm.
Typical Procedure for the Preparation of 4-(2-Oxoethylidene)azeti-
din-2-ones, Compounds 3, 9, 10, 11, 12, 17, 18, 19, 20, 21, 22: Et3N
(1.3 mmol, 0.172 mL) and Me3SiCl (1.1 mmol, 0.140 mL) were ad-
ded at room temperature to a solution of 4-acetoxy-β-lactam 1 or
13, 14, 15, 16 (1 mmol) in CH2Cl2 (5 mL). After complete conver-
sion of the starting material (GC monitoring), the solution was
brought to 0 °C and a solution of TiCl4 (or of the appropriate
Lewis Acid) (1 , 1 mL, 1 mmol) in CH2Cl2 was added. After
1 min, a solution of the chosen diazo compound (4 equiv.) in
CH2Cl2 (2 mL) was slowly added dropwise (over 30 min) at 0 °C.
The reaction mixture was stirred at room temperature and the con-
version was monitored by TLC or GC. After 3 h the reaction was
quenched in ice-cold water and extracted with CH2Cl2 (3 ϫ
15 mL). The extracts were dried (Na2SO4) and concentrated. The
residue was purified by flash chromatography (eluent: cyclohexane/
ethyl acetate) to afford separated Z and E isomers as products.
Yields and isomer percentages are reported in Tables 1, 2, and 3.
Experimental Section
General: 1H and 13C NMR spectra were recorded using a 5-mm
probe. All chemical shifts are quoted relative to deuterated solvent
signals, δ in ppm, J in Hz. FT-IR spectra were measured as films
between NaCl plates and reported in cmϪ1. GC-MS: HP5980,
capillary column HP-1 or HP-5 connected to HP5970 (70 eV).
HRMS: VG7070E, positive-ion mode. Elemental analysis was per-
formed at the Istituto di Biologia Marina, CNR, Bologna, Italy.
Single-crystal X-ray diffraction data collection was performed at
room temperature on a Bruker SMART2000 (CCD detector, com-
pound 22) and Nonius CAD4 (counter, compound 23) diffractome-
ters equipped with a graphite monochromated Mo-Kα radiation
Ethyl
{(2Z,3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
˚
oxoazetidin-2-ylidene}acetate (compound 3, Z isomer): Rf ϭ 0.8
(λ ϭ 0.71073 A). In both cases the data handling was performed
(cyclohexane/ethyl acetate, 7:3). [α]2D5 ϭ Ϫ40.8 (c ϭ 0.53, CHCl3).
using the SMART software package. 9161 (22) and 2921 (23) inde-
pendent reflections were collected, 3140 (22) and 1212 (23) ob-
served for I Ͼ 2σ(I). Data were corrected for Lorentz-polarization
effects and for absorption using an empirical method (SADABS
program). The structure was solved by direct methods (SHELXTL
program) and refined by full-matrix least-squares calculations. Hy-
drogen atoms were placed in calculated positions and refined iso-
tropically. Anisotropic thermal parameters were used for all the
non-hydrogen atoms. The final R factors obtained are R1 ϭ 0.056
(22) and R1 ϭ 0.054 (23). Both molecules crystallize in the mono-
clinic P21 space group. The unit cell parameters are a ϭ 5.3090(6),
IR (neat): ν˜ ϭ 3250, 1821, 1693, 1652, 1238 cmϪ1 1H NMR
.
(CDCl3, 300 MHz): δ ϭ 0.06 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3),
0.87 (s, 9 H, SitBu), 1.29 (t, J ϭ 7.2 Hz, 3 H, CH3CH2), 1.31 (d,
J ϭ 6.3 Hz, 3 H, CH3CHO), 3.66 (dd, J ϭ 5.4, 0.9 Hz, 1 H,
CHOCH), 4.19 (q, J ϭ 7.2 Hz, 2 H, CH3CH2), 4.23 (m, 1 H,
CHO), 5.21 (d, J ϭ 0.9 Hz, 1 H, CϭCH), 8.61 (br. s, 1 H, NH)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ5.0, Ϫ4.3, 14.3, 17.9,
22.3, 25.6, 60.1, 64.7, 65.1, 90.3, 153.3, 166.7, 167.2 ppm. MS
(70 eV): m/z (%) ϭ 298 (3) [Mϩ Ϫ CH3], 268 (5), 256 (90) [Mϩ
Ϫ
tBu], 210 (100), 184 (14), 143 (44), 75 (32), 73 (29). C15H27NO4Si
(313.46): calcd: C 57.47, H 8.68, N 4.47; found C 57.58, H 8.63,
N 4.41.
˚
b ϭ 9.7675(11), c ϭ 19.872(2) A, β ϭ 91.485(3)° for 22, and a ϭ
˚
7.7935(16), b ϭ 11.744(2), c ϭ 8.9742(18) A, β ϭ 93.18(3)° for 23.
CCDC-163737 for compound 22 and CCDC-163974 for compound
23 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax:
(internat.) ϩ44Ϫ1223/336Ϫ033; E-mail: deposit@ccdc.cam.ac.uk].
Ethyl
{(2E,3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}acetate (compound 3, E isomer): Rf ϭ 0.7
(cyclohexane/ethyl acetate, 7:3) [α]2D5 ϭ ϩ106.5 (c ϭ 1.7, CH2Cl2).
IR (CHCl3): ν˜ ϭ 3257, 1819, 1706, 1666, 1268 cmϪ1 1H NMR
.
(CDCl3, 300 MHz): δ ϭ 0.11 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3),
0.91 (s, 9 H, SitBu), 1.22 (d, J ϭ 6.3 Hz, 3 H, CH3CHO), 1.28 (t,
J ϭ 7.2 Hz, 3 H, CH3CH2), 4.10 (m, 1 H, CHOCH), 4.17 (q, J ϭ
7.2 Hz, 2 H, CH3CH2), 4.65 (dq, J ϭ 6.3, 3.9 Hz, 1 H, CHO), 5.31
(d, J ϭ 0.6 Hz, 1 H, CϭCH), 7.9 (br. s, 1 H, NH) ppm. 13C NMR
(CDCl3, 100 MHz): δ ϭ Ϫ5.0, Ϫ4.7, 14.3, 18.0, 19.5, 25.7, 59.9,
64.6, 64.7, 92.5, 153.0, 166.3, 168.0 ppm. MS (70 eV): m/z (%) ϭ
298 (2) [Mϩ Ϫ CH3], 268 (5), 256 (92) [Mϩ Ϫ tBu], 210 (20), 184
(18), 143 (11), 75 (85), 73 (100). C15H27NO4Si (313.46): calcd: C
57.47, H 8.68, N 4.47; found C 57.51, H 8.75, N 4.51.
Starting Materials: Azetidin-2-ones 1 and 14 and ethyl diazoacetate
2 are commercial products, β-lactams 13, 15, and 16 were synthe-
sized by degradation of penicillin G.[36] Diazo compounds 4, 5, and
6 where synthesized according to a known procedure.[37]
Diazo compounds 7 and 8 were known,[38] but were prepared ac-
cording to an improved procedure: 7 was prepared in 72% yield by
reacting commercial ethyl malonyl chloride with diazomethane (5
equiv.) in Et2O and converted into 8 by diazo transfer using p-
acetamidobenzenesulfonyl azide (1 equiv.) and Et3N (1 equiv.) in
CH3CN (88% yield).
tert-Butyl {(2Z,3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}acetate (compound 9, Z isomer): Rf ϭ 0.7
(cyclohexane/ethyl acetate, 7:3). [α]2D5 ϭ Ϫ20.1 (c ϭ 0.6, CHCl3).
Ethyl 4-Diazo-3-oxobutyrate (7): Rf ϭ 0.5 (cyclohexane/ethyl acet-
IR (nujol): ν˜ ϭ 3251, 1819, 1699, 1660, 1235 cmϪ1 1H NMR
.
ate, 1:1). IR (neat): ν˜ ϭ 2109, 1734, 1637 cmϪ1. 1H NMR (CDCl3, (300 MHz, CDCl3): δ ϭ 0.06 (s, 3 H, OSiCH3), 0.07 (s, 3 H,
200 MHz): δ ϭ 1.27 (t, J ϭ 7.4 Hz, 3 H, CH3), 3.35 (br. s, 2 H,
www.eurjoc.org
OSiCH3), 0.87 (s, 9 H, OSitBu), 1.31 (d, J ϭ 6.3 Hz, 3 H,
1771
Eur. J. Org. Chem. 2003, 1765Ϫ1774
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

G. Cainelli, D. Giacomini, P. Galletti, A. Quintavalla
FULL PAPER
CH3CHOSi), 1.49 (s, 9 H, OtBu), 3.63 (d, J ϭ 4.8 Hz, 1 H, Ethyl [(2E)-4-Oxoazetidin-2-ylidene]acetate (compound 17, E iso-
SiOCHCH), 4.23 (dq, J ϭ 4.8, 6.3 Hz, 1 H, CH3CHOSi), 5.13 (s, 1 mer): Rf ϭ 0.4 (cyclohexane/ethyl acetate, 1:1). IR (CH2Cl2): ν˜ ϭ
H, CϭCH), 8.31 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz,
3204, 1812, 1779, 1713, 1646, 1275 cmϪ1 1H NMR (CDCl3,
.
CDCl3): δ ϭ Ϫ5.0, Ϫ4.2, 17.9, 22.3, 25.7, 28.3, 64.6, 65.0, 80.3, 300 MHz): δ ϭ 1.29 (t, J ϭ 7.2 Hz, 3 H, CH3CH2), 3.80 (m, 2 H,
92.4, 151.5, 166.0, 166.1 ppm. MS (70 eV): m/z (%) ϭ 284 (3) [Mϩ
CH2CϭCH), 4.18 (q, 2 H, CH3CH2, J ϭ 7.2 Hz), 5.35 (m, 1 H,
Ϫ tBu], 228 (55), 210 (46), 73 (67), 57 (100), 41 (81). C17H31NO4Si CϭCH), 7.29 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz):
(341.52): calcd. C 59.79, H 9.15, N 4.10; found C 59.65, H 9.12, δ ϭ 14.4, 46.1, 60.1, 92.4, 150.4, 165.7, 166.4 ppm. MS (70 eV): m/
N 4.01.
z (%) ϭ 155 (30) [Mϩ],127 (12), 99 (100), 85 (30), 68 (78), 43 (50).
HRMS: calcd.for C7H9NO3 m/z ϭ 155.0582; found m/z
ϭ
(3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-[(1Z)-2-oxo-2-
phenylethylidene]azetidin-2-one (compound 10, Z isomer): Rf ϭ 0.6
(cyclohexane/ethyl acetate, 7:3). [α]2D5 ϭ ϩ17.3 (c ϭ 1.1, CHCl3).
155.0584. C7H9NO3 (155.2): calcd. C 54.19, H 5.85, N 9.03; found
C 54.12, H 5.70, N 9.00.
IR (CH2Cl2): ν˜ ϭ 3251, 1813, 1660, 1593, 1240 cmϪ1 1H NMR
.
4-[(1Z)-2-Oxo-2-phenylethylidene]azetidin-2-one (compound 18, Z
isomer): Rf ϭ 0.6 (cyclohexane/ethyl acetate, 1:1). IR (nujol): ν˜ ϭ
(200 MHz, CDCl3): δ ϭ 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3),
0.89 (s, 9 H, SitBu), 1.39 (d, J ϭ 6.2 Hz, 3 H, CH3CHOSi), 3.81
(d, J ϭ 5.6 Hz, 1 H, SiOCHCH), 4.30 (dq, J ϭ 5.6, 6.2 Hz, 1 H,
CH3CHOSi), 6.41 (s, 1 H, CϭCH), 7.40Ϫ7.94 (m, 5 H), 9.28 (br.
s, 1 H, NH). 13C NMR (50 MHz, CDCl3): δ ϭ Ϫ4.9, Ϫ4.1, 18.0,
22.6, 25.7, 65.5, 65.8, 94.8, 127.8, 128.5, 132.5, 137.9, 155.3, 167.2,
189.9 ppm. MS (70 eV): m/z (%) ϭ 330 (2) [Mϩ Ϫ CH3], 288 (100)
[Mϩ Ϫ tBu], 244 (43), 105 (39), 77 (28), 73 (33). C19H27NO3Si
(345.51): calcd. C 66.05, H 7.88, N 4.05; found C 65.69, H 7.80,
N 4.03.
1
3225, 1805, 1660, 1600, 1255 cmϪ1. H NMR (300 MHz, CDCl3):
δ ϭ 3.67 (s, 2 H), 6.36 (s, 1 H), 7.5Ϫ7.8 (m, 5 H), 9.71 (br. s, 1 H,
NH) Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 45.9, 94.8, 127.9, 128.6,
132.7, 17.8, 151.9, 165.6, 190.0 ppm. MS (70 eV): m/z (%) ϭ 187
(9) [Mϩ], 159 (42), 105 (27), 77 (100), 51 (48). HRMS: calcd.for
C11H9NO2 m/z ϭ 187.0633; found m/z ϭ 187.0635. C11H9NO2
(187.2): calcd. C 70.58, H 4.85, N 7.48; found C 70.63, H 4.84,
N 7.48.
4-[(1Z,3E)-2-Oxo-4-phenylbut-3-enylidene]azetidin-2-one
(compound 19, Z isomer): IR (nujol): ν˜ ϭ 3198, 1806, 1660, 1630
(3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-[(1Z,3E)-2-
oxo-4-phenylbut-3-enylidene]azetidin-2-one (compound 11, Z iso-
mer): [α]2D5 ϭ ϩ23.1 (c ϭ 1.3, CHCl3). IR (CH2Cl2): ν˜ ϭ 3231,
cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 3.65 (s, 2 H, CH2CO),
.
5.91 (s, 1 H, CϭCϭCH), 6.78 (d, J ϭ 15.9 Hz, 1 H, CHϭCHPh),
7.3Ϫ7.6 (m, 6 H, CHϭCHPh ϩ Ph), 9.28 (br. s, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 45.8, 97.9, 126.8, 128.3, 128.9,
130.4, 134.7, 142.5, 150.8, 165.3, 188.9 ppm. MS (70 eV): m/z (%) ϭ
213 (34) [Mϩ], 156 (21), 115 (28), 77 (100). HRMS: calcd.for
C13H11NO2 m/z ϭ 213.0790; found m/z ϭ 213.0792. C13H11NO2
(213.2) calcd. C 73.23, H 5.20, N 6.57; found C 73.20, H 5.18,
N 6.54.
1
1825, 1680, 1630, 1580, 1254 cmϪ1. H NMR (200 MHz, CDCl3):
δ ϭ 0.09 (s, 6 H, OSiCH3), 0.89 (s, 9 H, OSitBu), 1.37 (d, J ϭ
6.2 Hz, 3 H, CH3CHOSi), 3.76 (d, J ϭ 5.6 Hz, 1 H, SiOCHCH),
4.27 (dq, J ϭ 5.6, 6.2 Hz, 1 H, CH3CHOSi), 5.96 (s, 1 H, CϭCH),
6.77 (d, J ϭ 16.2 Hz, 1 H, CHϭCHPh), 7.40Ϫ7.70 (m, 6 H, CHϭ
CHPh ϩ Ph), 9.09 (br. s, 1 H, NH) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ Ϫ4.9, Ϫ4.1, 18.0, 22.6, 25.7, 65.5, 65.8, 98.1, 126.7,
128.2, 128.8, 130.2, 134.7, 142.3, 154.4, 167.3, 188.7 ppm. MS
(70 eV): m/z (%) ϭ 356 (2) [Mϩ Ϫ CH3], 315 (100) [Mϩ Ϫ tBu],
270 (33), 131 (48), 103 (42), 75 (82), 73 (67). C21H29NO3Si (371.55):
calcd. C 67.89, H 7.87, N 3.77; found C 67.98, H 7.92, N 3.80.
Ethyl [(2Z,3R)-3-Chloro-4-oxoazetidin-2-ylidene]acetate (compound
20, Z isomer): Rf ϭ 0.8 (cyclohexane/ethyl acetate, 1:1). [α]2D5
ϭ
ϩ7.3 (c ϭ 0.84, CHCl3). IR (CH2Cl2): ν˜ ϭ 3260, 1830, 1705, 1660,
1250 cmϪ1. 1H NMR (CDCl3, 200 MHz): δ ϭ 1.32 (t, J ϭ 7.0 Hz,
3 H, CH3CH2), 4.23 (q, 2 H, CH3CH2, J ϭ 7.0 Hz), 5.23 (s, 1 H,
CϭCH), 5.40 (d, J ϭ 0.8 Hz,, 1 H, ClCH), 8.80 (br. s, 1 H, NH)
ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 14.3, 59.8, 60.8, 91.3, 150.9,
161.8, 166.7 ppm. MS (70 eV): m/z (%) ϭ 189 (8) [Mϩ], 161 (31),
143 (46), 68 (100), 52 (58). HRMS: calcd.for C7H8ClNO3 m/z ϭ
189.0193; found m/z ϭ 189.0194. C7H8ClNO3 (189.6) calcd. C
44.34, H 4.25, N 7.39; found C 44.31, H 4.20, N 7.38.
Ethyl 4-{(2Z,3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}-2-diazo-3-oxobutyrate (compound 12, Z iso-
mer): Rf ϭ 0.7 (cyclohexane/ethyl acetate, 7:3). [α]2D5 ϭ Ϫ12.0 (c ϭ
0.7, CHCl3). IR (CH2Cl2): ν˜ ϭ 3290, 2136, 1817, 1717, 1652, 1312
cmϪ1. 1H NMR (CDCl3, 200 MHz): δ ϭ 0.06 (s, 6 H, SiCH3), 0.85
(s, 9 H, SitBu), 1.34 (d, J ϭ 7.0 Hz, 3 H, CH3CHO), 1.34 (t, J ϭ
7.2 Hz, 3 H, CH3CH2), 3.74 (d, J ϭ 4.4 Hz 1 H, OCHCH), 4.25
(m, 1 H, CHO), 4.31 (q, J ϭ 7.2 Hz, 2 H, CH3CH2), 6.69 (s, 1 H,
CϭCH), 9.05 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz):
δ ϭ Ϫ5.0, Ϫ4.3, 14.4, 18.0, 22.2, 25.7, 53.4, 61.4, 64.9, 65.8, 95.6,
153.5, 161.2, 167.2, 181.3 ppm. MS (70 eV): m/z (%) ϭ 366.5 (3)
[Mϩ Ϫ CH3], 324 (48) [Mϩ Ϫ tBu], 223 (38), 143 (33), 73 (100).
C17H27N3O5Si (381.50): calcd. C 53.52, H 7.13, N 11.01; found C
53.30, H 7.10, N 10.90.
Ethyl [(2Z,3R)-3-Bromo-4-oxoazetidin-2-ylidene]acetate (compound
21, Z isomer): Rf ϭ 0.8 (cyclohexane/ethyl acetate, 1:1) [α]2D5 ϭ Ϫ7.0
(c ϭ 0.57, CHCl3). IR (CH2Cl2): ν˜ ϭ 3250, 1830, 1710, 1660, 1250
1
cmϪ1. H NMR (CDCl3, 200 MHz): δ ϭ 1.31 (t, J ϭ 7.4 Hz, 3 H,
CH3CH2), 4.22 (q, 2 H, CH3CH2, J ϭ 7.4 Hz), 5.26 (dd, J ϭ 0.8,
2.2 Hz, 1 H, CϭCH), 5.38 (d, J ϭ 0.8 Hz, 1 H, BrCH), 8.65 (br. s,
1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.3, 45.5, 60.8,
91.4, 151.2, 161.7, 166.8 ppm. C7H8BrNO3 (234.05): calcd. C 35.92,
H 3.45, N 5.98; found C 35.91, H 3.48, N 5.94.
Ethyl [(2Z)-4-Oxoazetidin-2-ylidene]acetate (compound 17, Z iso-
mer): Rf ϭ 0.5 (cyclohexane/ethyl acetate, 1:1). IR (nujol): ν˜ ϭ
1
3230, 1819, 1699, 1646, 1255 cmϪ1. H NMR (CDCl3, 300 MHz): Ethyl [(2Z,3R)-3-(1-Hydroxyethyl)-4-oxoazetidin-2-ylidene]acetate
δ ϭ 1.30 (t, J ϭ 7.2 Hz, 3 H, CH3CH2), 3.56 (s, 2 H, CH2CϭCH), (compound 22, Z isomer): 1  HCl (1 mL) was added to a solution
4.20 (q, H CH3CH2, J ϭ 7.2 Hz), 5.17 (s, 1 H, CϭCH), 8.47 (br.
of β-lactam 3-Z (313 mg, 1 mmol) in CH3OH (8 mL). The reaction
s, 1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.4, 44.9, was monitored by TLC and further portions of 1  HCl (1 mL)
60.2, 90.6, 149.7, 164.6, 167.0 ppm. MS (70 eV): m/z (%) ϭ 155 (11)
were added until total conversion was accomplished. The reaction
was quenched in ice-cold water and extracted with CH2Cl2 (3 ϫ
[Mϩ],127 (37), 99 (100), 85 (35), 67 (29), 43 (52). HRMS: calcd.for
C7H9NO3 m/z ϭ 155.0582; found m/z ϭ 155.0584. C7H9NO3 15 mL). The extracts were dried (Na2SO4) and concentrated, and
(155.2): calcd. C 54.19, H 5.85, N 9.03; found C 54.12, H 5.85,
N 9.02.
then the residue was purified by flash chromatography (cyclohex-
ane/ethyl acetate, 4:6). Yield 72%. [α]2D5 ϭ Ϫ24 (c ϭ 0.61, CHCl3).
1772
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 1765Ϫ1774

Synthesis of Novel 4-(2-Oxoethylidene)azetidin-2-ones
FULL PAPER
[7]
[8]
IR (neat): ν˜ ϭ 3423, 3257, 1805, 1792, 1646 cmϪ1 1H NMR
.
D. A. Burnett, M. A. Caplen, M. S. Domalski, M. E. Browne,
H. R, Davis Jr, J. W. Clader, Bioorg. Med. Chem. Lett. 2002,
12, 311.
C. Beauve, M. Bouchet, R. Touillaux, J. Faszer, J. Marchand-
Brynaert, Tetrahedron 1999, 55, 13301.
(CDCl3, 300 MHz): δ ϭ 1.30 (t, J ϭ 7.2 Hz, 3 H, CH3CH2), 1.39
(d, J ϭ 6.6 Hz, 3 H, CH3CHO), 2.1 (br. s, 1 H, OH), 3.75 (d, J ϭ
5.7 Hz, 1 H, CHOCH), 4.21 (q, H CH3CH2, J ϭ 7.2 Hz), 4.23 (m,
1 H, CHOH), 5.27 (d, J ϭ 0.3 Hz, 1 H, CϭCH), 8.73 (br. s, 1 H,
NH) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 14.3, 21.5, 60.3, 64.0,
64.8, 90.9, 152.2, 166.3, 166.9 ppm. MS (70 eV): m/z (%) ϭ 199 (4)
[Mϩ], 184 (11) [Mϩ Ϫ CH3], 166 (43), 155 (57), 138 (57), 99 (100),
68 (41). HRMS: calcd.for m/z ϭ 199.0845; found m/z ϭ 199.0848.
C9H13NO4 (199.2) calcd. C 54.26, H 6.58, N 7.03; found C 53.68,
H 6.64, N 7.03.
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TiCl4 (3 mmol) in CH2Cl2 (2 mL) was added at 0 °C to a solution
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is controlled by TLC (cyclohexane/ethyl acetate 1:1), the reaction
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.
[15c]
G. Cainelli, M. Panunzio, D. Giacomini, G. Martelli, G.
NMR (200 MHz, CDCl3): δ ϭ 0.07 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.88 (s, 9 H, SitBu), 1.33 (d, J ϭ 6.2 Hz, 3 H, CH3CHOSi),
3.71 (d, J ϭ 4.6 Hz, 1 H, SiOCHCH), 4.24 (m, 1 H, CH3CHOSi),
5.24 (s, 1 H, CϭCH), 8.40 (br. s, 1 H, NH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ Ϫ5.0, Ϫ4.2, 18.0, 22.3, 25.7, 65.0, 65.0,
90.0, 155.4, 166.4, 171.8 ppm. C17H31NO4Si (341.52): calcd. C
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 1765Ϫ1774