Vinylic halogenation in 4-alkylidenazetidin-2-ones

Article abstract of DOI:10.1002/ejoc.200601095

The synthesis of a new family of halogenated β-lactams by oxidative substitution of vinylic hydrogen in conjugated double bonds of 4-alkylidenazetidinones is reported. Optimised procedures give good to excellent yields of chloro, bromo, iodo and nitro der

Full text of DOI:10.1002/ejoc.200601095

FULL PAPER
DOI: 10.1002/ejoc.200601095
Vinylic Halogenation in 4-Alkylidenazetidin-2-ones
Gianfranco Cainelli,[a] Paola Galletti,*[a] Daria Giacomini,[a] Sebastiano Licciulli,[a] and
Arianna Quintavalla[a]
Keywords: Halogenation / 4-Alkylidenazetidin-2-ones / Vinylic substitution / Lactams / Azetidinones
The synthesis of a new family of halogenated β-lactams by
oxidative substitution of vinylic hydrogen in conjugated
double bonds of 4-alkylidenazetidinones is reported. Op-
timised procedures give good to excellent yields of chloro,
bromo, iodo and nitro derivatives. A mechanism to explain
the direct vinylic substitution is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
1. Introduction
β-Lactams are an important and extremely large class
of compounds, the synthesis of which has been intensively
investigated because of their effective biological activity[1]
and their usefulness as intermediates in the syntheses of im-
portant compounds like β-amino acids,[2] aminols[3] and
heterocycles of various sizes.[4]
4-Alkylidenazetidin-2-ones in particular represent a new
class of monocyclic β-lactam compounds that show promis-
ing biological activity both as antibiotics[5] and as enzyme
inhibitors.[6] Their biological and chemical reactivity is at-
tributed to the direct connection of the conjugated double
bond to the β-lactam ring: in fact, these compounds have
been found to be highly activated towards ring-opening by
nucleophilic acyl substitution and can act as enzymatic in-
hibitors of serine-dependent enzymes or can be function-
alised and used as chemical synthons.
Scheme 1.
Here we report our results in a further derivatisation of
4-alkylidene-β-lactams designed to produce highly func-
tionalised azetidinones by substitution of vinylic hydrogen
in conjugated double bond to form chloro, bromo, iodo or
nitro derivatives (Scheme 1).
α-Halogenation of simple α,β-unsaturated carbonyl com-
pounds has been little reported in the literature.[7] α-Bromo
enones are generally synthesised by a two-step procedure:
dibromination followed by bromide elimination in the pres-
ence of a base. The few examples of direct vinylic bromina-
tion that exist are mainly restricted to unsaturated ketones.
One-step preparation of α-bromo α,β-unsaturated carbonyl
compounds, for example, has been achieved with the ex-
pensive Dess–Martin periodinane coupled with Et4NBr,[8]
whereas iodination has recently been accomplished with I2
in aqueous THF with DMAP catalysis in a Baylis–Hillman-
type reaction.[9] Direct bromination of more complex sub-
strates such as uracils[10] or β-amino- and β-alkoxy α,β-un-
saturated compounds, has been accomplished more fre-
quently,[11] as in the cases of the bromination of 2-alkyl-
idenetetrahydrofurans and 2-alkylidenepyrrolidines,[12] β-
butoxyvinyl trifluoromethyl ketone[13] and β-aminovinyl
chlorodifluoromethyl ketones.[14] To the best of our knowl-
edge, vinylic substitution on β-amido α,β-unsaturated esters
has never been reported in the literature.
2. Results and Discussion
As previously reported by our group, 4-alkylidene-β-lac-
tams are easily prepared by Lewis acid-promoted addition
of diazocarbonyl compounds to 4-acetoxyazetidin-2-ones
variously functionalised at the C-3 position (see
Scheme 2).[15] Depending on the starting materials and
[a] Department of Chemistry “G. Ciamician”, University of
Bologna,
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: paola.galletti@unibo.it
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Vinylic Halogenation in 4-Alkylidenazetidin-2-ones
FULL PAPER
Lewis acid used, 4-alkylidene-β-lactams can be obtained
Bromination was initially achieved with NBS in chlori-
with Z or E diastereoselectivity. Diastereoisomers are easily nated solvents (see Table 1). In CH2Cl2, the reaction pro-
separated by flash chromatography: Z isomers are configu- ceeded in a few minutes with excellent yield (Entry 4). The
rationally stable whereas E isomers slowly convert into Z presence of TEA was not essential, although it seemed to
isomers, which are more stable because of the formation of accelerate the reaction with 3-substituted β-lactams (En-
an intramolecular hydrogen bond.[15]
tries 7 and 8). In CCl4, bromination appeared to be slower
and less efficient (Entries 1–3).
Good results were also obtained with use either of Br2
in chlorinated solvents or of pyridinium tribromide
(PyHBr3) in CH3CN, in the presence of an equimolecular
amount of TEA. The reaction with bromine was immediate
(Entry 11) and could be monitored through decolouration
of bromine drops added to the reaction vessel. Reactions
with Br2 proceeded with almost quantitative yields with 1a,
and with formation of O-desilylated product when con-
ducted on 1b in absence of the base (Entry 10). Reaction
yields remained high with PyHBr3[16] and TEA (Entries 12–
15), with the major advantage of an easier to handle bromi-
nation reagent.
Bromination with NBS was also carried out with an N-
Bn-protected 4-alkylidene-β-lactam.[17] At room tempera-
ture the reaction proceeded in low yield, whereas the use of
higher temperatures allowed the brominated products to be
obtained in 75% isolated yield, with the formation of equal
amounts of Z and E bromo derivatives.
Scheme 2.
In addition to evaluation of the biological activity of this
new class of compounds, we were also interested in their
chemical reactivity. The double bond on C-4 proved par-
The double bond configurations of the halogenated com-
ticularly unreactive, especially towards addition reactions, pounds were assigned by comparison with spectral and
but attempted C-3 bromination with NBS (N-bromosuc- HPLC data for the starting materials (see Experimental Sec-
cinimide) resulted in unexpected oxidative substitution of tion, Table 4). Once separated by preparative HPLC, pure Z
double bond vinylic hydrogen, prompting us to take a closer or E isomers were configurationally stable, whereas bases,
look at the reaction (see Table 1).
acids or silica gel were able to promote Z/E interconversion.
Table 1. Bromination of 4-alkylidenazetidin-2-ones 1a–b.
Entry
Starting material
Reagents (equiv.) and conditions
Yield (%)
Z/E Products[a]
1
2
3
4
5
6
7
8
(E)-1a
(Z)-1a
(Z)-1a
(E)-1a
(E)-1a
(Z)-1b
(Z)-1b
(Z)-1b
(E)-1a
(Z)-1b
(Z)-1b
(Z)-1a
(E)-1a
(Z)-1b
(E)-1b
(Z)-1b
NBS (1), CCl4, room temp., 15 h
NBS (1), CCl4, room temp., 15 h
NBS (1), CCl4, 0 °C, 15 h
69[b]
90
30:70
33:67
70:30
59:41
80:20
30:70
17:83
40:60
63:37
–
45:55
80:20
95:5
65:35
63:37
–
71[b]
95
NBS (1), CH2Cl2, room temp., 15 min
NBS (1), TEA (1) CH2Cl2, room temp., 15 min
NBS (1.1), CCl4, AIBN cat, reflux, 9 h
NBS (1), CH2Cl2, room temp., 22 h
NBS (1), TEA (1) CH2Cl2, room temp., 15 min
Br2 (1), CCl4, room temp., 18 h
Br2 (1.5), CH2Cl2, room temp., 15 min
Br2 (1.1), TEA (1.1), CH2Cl2, 0 °C, 15 min
PyHBr3 (1.1), TEA (1.1), CH3CN, 0 °C, 2 h
PyHBr3 (1.1), TEA (1.1), CH3CN, 0 °C, 5.5 h
PyHBr3 (1.1), TEA (1.1), CH3CN, 0 °C, 1.5 h
PyHBr3 (1.1), TEA (1.1), CH3CN, 0 °C, 1.5 h
PyHBr3 (1.1), CH3CN, 0 °C, 2 h
95
21[b]
82
95
9
90
10
11
12
13
14
15
16
90[c]
95
95
90
95
78
90[c]
1
[a] Diastereomeric ratios were evaluated by HPLC or H NMR on crude reaction mixtures. [b] Isolated yields after chromatography; all
1
other yields were evaluated by H NMR on crude reaction mixtures. [c] Complete bromination but concurrent O-desilylation.
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FULL PAPER
With regard to the diastereoselectivity outcome reflected however, the preference was for formation of the Z isomers.
in the data reported in Table 1, stereochemistry was not pre- When the starting materials were C-3 unsubstituted β-lac-
served, since mixtures of diastereoisomers were always ob- tams 1a, Z isomers were preferred in most cases.
tained whether starting from pure (Z)- or (E)-4-alkylidenaz-
In view of the good results obtained with bromination,
etidin-2-ones. Moreover, the results were not easy to inter- we also tested the reactivity of other halogens. The first
pret because of the large number of parameters influencing attempts were made with chlorination (Table 2) with N-
the diastereomeric ratios of products: configurations of chlorosuccinimide (NCS) in various chlorinated solvents,
starting materials, steric hindrance of substituents on C-3, but in all cases only traces of the products were obtained
formation of intramolecular hydrogen bonds in product E (Entries 1–3), even in the presence of TEA and/or AIBN
isomers, reagent type, coordinating ability of reaction sol- (2,2Ј-azobisisobutyronitrile).
vents, reaction times and temperatures. Even the partial
Better results were obtained with a saturated solution of
double bond isomerisations of E starting materials and/or chlorine in CH2Cl2. Once prepared at 0 °C, the yellow chlo-
Z products during the reaction course should be taken into rine solution was added dropwise to the β-lactam solution
consideration, especially in cases in which TEA was used.
and the conversion was monitored by drop-decolouration
As a general trend, when the starting materials were C- and TLC. In this case, addition of TEA did not improve
3-substituted β-lactams 1b, E isomers seemed to be pre- reaction yield or rate, but instead gave rise to side products.
ferred in noncoordinating chlorinated solvents, because of
As in the bromination, C-3-unsubstituted starting mate-
the steric hindrance of the side chain, together with the for- rials 1a preferentially gave (Z)-chlorinated compounds (En-
mation of the intramolecular hydrogen bond. In CH3CN, tries 7 and 8), whereas C-3-substituted ones 1b preferen-
Table 2. Chlorination of 4-alkylidenazetidin-2-ones 1a–b.
Entry
Starting material
Reagents (equiv.) and conditions
Isolated yield (%)
Z/E Products[a]
1
2
3
4
5
6
7
8
(Z)-1b
(E)-1b
(E)-1b
(Z)-1b
(Z)-1b
(E)-1b
(E)-1a
(Z)-1a
NCS (1.5), CH2Cl2, room temp., 8 d
NCS (1.5), CH2Cl2, room temp., 8 d
NCS (2), TEA (1), CH2Cl2, room temp., 2 d
Cl2 (satd. sol.), CH2Cl2, 0 °C, 30 min
Cl2 (satd. sol.), TEA (1.1), CH2Cl2, 0 °C, 2 h
Cl2 (satd. sol.), CH2Cl2, 0 °C, 30 min
Cl2 (satd. sol.), CH2Cl2, 0 °C, 30 min
Cl2 (satd. sol.), CH2Cl2, 0 °C, 30 min
–
traces
traces
67
traces
39
–
–
–
80:20
–
36:64
67:33
83:17
64
60
1
[a] Diastereomeric ratios were evaluated by HPLC or HNMR on crude reaction mixture.
Table 3. Iodination of 4-alkylidenazetidin-2-ones 1a–b.
Entry
Starting material
Reagents (equiv.) and conditions
Yield (%)
Z/E Products[a]
1
2
3
4
5
6
7
(Z)-1a
(E)-1a
(E)-1a
(Z)-1a
(E)-1a
(Z)-1b
(E)-1b
NIS (1.5), CH2Cl2, room temp., 2 h
NIS (1.3), CH2Cl2, room temp., 3 h
NIS (1),TEA (1), CH2Cl2, room temp., 15 min
I2 (2.5), TEA (2.2), CH2Cl2, room temp., 72 h
I2 (2.0), TEA (1.3), CH2Cl2, room temp., 19 h
I2 (2.5), TEA (1.2), CH2Cl2, room temp., 12 h
I2 (2.5), TEA (1.2), CH2Cl2, room temp., 12 h
90
82[b]
95
75:25
75:25
54:46
73:27
83:17
44:56
49:51
95
84[b]
52[b]
27
1
[a] Diastereomeric ratios were evaluated by HPLC or H NMR on crude reaction mixtures. [b] Isolated yields after chromatography; all
1
other yields are evaluated by H NMR on the crude reaction mixtures.
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Vinylic Halogenation in 4-Alkylidenazetidin-2-ones
FULL PAPER
tially give either Z or E products, depending on the starting of which should be strongly disfavoured by the endocyclic
material configuration (Entries 4 and 6). carbon–carbon double bond. A reaction pathway through
Even iodination gave good yields with use of N-iodosuc- B should even result in racemisation at the C-3 position,
cinimide (NIS) or molecular I2 in the presence of TEA. The but the presence of diastereoisomers was never observed in
results are reported in Table 3.
reactions performed with enantiomerically pure 1b.
With C-3-unsubstituted starting materials 1a, iodination
To exclude a radical mechanism more emphatically, we
always produced good yields with either NIS or I2 in the also carried out the bromination reaction with a deuterium-
presence of TEA (Entries 3 and 4). As in bromination, the labelled 4-alkylidene-β-lactam (Scheme 4). For this, we pre-
base was not essential to formation of the product, though pared the deuteriodiazoacetate 5, which was treated with 4-
it very much raised reaction rates and yields (Entries 2 and acetoxyazetidin-2-one in the presence of TiCl4 to give the
3). Preferential formation of Z isomers was always observed 4-(1-deuterio-alkyliden)azetidin-2-one 6. The bromination
regardless of the double bond configurations in the reac- reaction with 6 proceeded as usual in high yields to furnish
tants. From 1b, iodination still proceeded but with much products 7 with no deuterium incorporated in any position.
lower yields.
Two hypotheses can be advanced for the reaction mecha- NBS is taken to be a source of molecular bromine (analo-
nism (Scheme 3). gously to PyHBr3). It is known that NBS can provide a
(ii) NBS as Source of Molecular Bromine. In this case,
(i) Radical Allylic Bromination. In this case the forma- constant concentration of Br2 through HBr bromide ion
tion of the final vinyl brominated product is considered to attack on NBS.[18] Addition of bromine results in the for-
take place through a radical allylic bromination followed mation of a positively charged bromonium intermediate,
by an allylic rearrangement. Although reported by other further stabilised by the nitrogen lone pair (C, Scheme 3);
authors,[12] this mechanism seemed improbable in our case a contribution of an iminium ion to the stabilisation of a
since the use of AIBN did not improve yields and no traces C-4 cationic intermediate in substitution reactions of
of the 3-bromo derivatives (A, Scheme 3) were detected in 4-acetoxyazetidinones has in fact already been suggested.[19]
crude reaction mixtures. Moreover, the final product should Intermediate C could then undergo bromide addition or β-
derive from an allylic rearrangement of B, the formation hydrogen elimination. Bromide addition would give rise to
Scheme 3.
Scheme 4.
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G. Cainelli, P. Galletti, D. Giacomini, S. Licciulli, A. Quintavalla
FULL PAPER
a 1,2-dibromo adduct (D, Scheme 3), in which a base-medi- the starting material 8 was predominantly E and that the
ated elimination would be needed to provide the final vinyl hydrogen syn addition to the double bond occurred at the
bromide.[20] However, no 1,2-dibromo intermediate D was less hindered face.[22]
ever isolated, even in the presence of an excess of bromide
ion by addition of a soluble bromide salt such as Et4NBr,
3. Conclusion
and moreover we observed that the base was not strictly
necessary for formation of the product (see Table 1, En-
tries 7 and 9). Evolution of the bromonium intermediate
towards the final vinyl bromide by β-hydrogen elimination
therefore appeared to be the most likely mechanism, as-
sisted by the formation of an extended conjugated system.
The role of the base would just be to favour the hydrogen
elimination and to buffer the hydrobromic acid. Further-
more, formation of a long-lived, freely rotatable intermedi-
ate C helps explain the lack of stereocontrol.
The same mechanism (ii) could be advanced for chlorine
and iodine substitution, and was confirmed by the lack of
reactivity with use of NCS, which has a weaker tendency to
generate Cl2 than the tendency of NBS and NIS to behave
as active sources of their molecular halogens.[19]
We have developed the synthesis of a new family of halo-
genated β-lactams by direct vinylic substitution on 4-alkyl-
idenazetidinones. Optimised procedures gave good to excel-
lent yields of chloro, bromo and iodo derivatives. An ex-
tended procedure gave a nitrovinyl compound, which was
stereoselectively hydrogenated to provide the corresponding
α-amino ester.
All new vinyl-substituted 4-alkylidene-β-lactams are cur-
rently under pharmacological screening and further re-
search on the reactivity of the new halogenated-β-lactams
is in progress.
Experimental Section
To extend the scope of the vinylic substitution, we also
attempted to perform the reaction with various electro-
philes. Fluorination, acylation and alkylation did not take
place even on experimentation with reaction conditions and
reagents, though we did successfully achieve nitration with
use of trifluoroacetic anhydride/NH4NO3 in CHCl3 (see
Scheme 5).[21] Nitrovinyl derivatives 8 were isolated and
characterised, and a 90:10 diastereoisomerically enriched
mixture was reduced to give the corresponding cis α-amino
ester 9 as prevalent isomer. In this compound, the stereo-
chemistry has been tentatively assigned as shown in
Scheme 5, under the hypothesis that the stereochemistry of
1
General: H and 13C NMR: recorded on a Varian INOVA 300 or
a GEMINI 200 instrument with a 5 mm probe. All chemical shifts
have been quoted relative to deuterated solvent signals, δ in ppm,
J in Hz. Spectra of products 2–4 and 8 were recorded on dia-
stereomerically enriched column fractions. FT-IR: Nicolet 380 FT
measured as films between NaCl plates, wavenumbers reported
in cm–1. Melting points: collected on a Büchi B-540 and uncor-
rected. TLC: Merck 60 F254. Column chromatography: Merck sil-
ica gel 200–300 mesh. HPLC: Agilent Technologies HP1100, col-
umn ZORBAX-Eclipse XDB-C8 Agilent Technologies, mobile
phase: H2O/CH3CN, gradient: from 10% to 100% of CH3CN in
25 min, then 100% of CH3CN, 0.5 mLmin–1. MS: Agilent Technol-
ogies MSD1100 single-quadrupole mass spectrometer, full-scan
mode from m/z 50 to m/z 2600, scan time 0.1 s in positive ion mode,
ESI spray voltage 4500 V, nitrogen gas 35 psi, drying gas flow
11.5 mLmin–1, fragmentor voltage 20 V. HRMS: Thermo Finnigan
mat 95 xp, 70 eV, 10000 resolution (Mass Spectrometry Centre,
Faculty of Industrial Chemistry, University of Bologna). Elemental
analysis: performed at the Istituto di Biologia Marina, CNR,
Bologna, Italy.
Starting Materials: 4-Alkylidene-β-lactams 1a–b were prepared by
the already reported procedure.[15]
Halogenation Procedures
Bromination with NBS: NBS (89 mg, 0.5 mmol) was added to a
solution of 1a (72 mg, 0.5 mmol) or 1b (156 mg, 0.5 mmol) and
TEA (0.07 mL, 0.5 mmol) in CH2Cl2 (10 mL). The reaction was
monitored by TLC. After full conversion, a saturated solution of
NH4Cl (10 mL) was added. The mixture was extracted with
CH2Cl2 (3ϫ10 mL), dried with Na2SO4 and concentrated. If nec-
essary, residues of succinimide were eliminated by trituration with
CCl4.
Bromination with PyHBr3: PyHBr3 (176 mg, 0.55 mmol) was added
to a solution of 1a (72 mg, 0.5 mmol) or 1b (156 mg, 0.5 mmol)
and TEA (0.08 mL, 0.55 mmol) in CH3CN (10 mL). After full con-
version, a saturated solution of NH4Cl (10 mL) was added. The
mixture was extracted with EtOAc (3ϫ10 mL), dried with Na2SO4
and concentrated.
Bromination with Br2: A solution of Br2 (88 mg, 0.55 mmol) in
CH2Cl2 (2 mL) was added dropwise to a solution of 1a (72 mg,
Scheme 5.
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Vinylic Halogenation in 4-Alkylidenazetidin-2-ones
FULL PAPER
H, CH3CH2), 4.04 (dd, JH3,NH = 1.8 Hz, J = 3.9 Hz, 1 H,
CHCHOSi), 4.27 (q, J = 7.2 Hz, 2 H, CH3CH2), 4.58 (dq, J = 3.9,
6.3 Hz, 1 H, CHCHOSi), 7.98 (brs, 1 H, NH) ppm. 13C NMR
4
0.5 mmol) or 1b (156 mg, 0.5 mmol) and TEA (0.08 mL,
0.55 mmol) in CH2Cl2 (10 mL). The reaction was monitored by
drop discoloration and TLC. After full conversion, a saturated
solution of NH4Cl (10 mL) was added. The mixture was extracted (CDCl3, 75 MHz, 22 °C): δ = –5.0, –4.7, 14.3, 17.9, 19.9, 25.6, 61.9,
with CH2Cl2 (3ϫ10 mL), dried with Na2SO4 and concentrated.
64.5, 66.5, 84.8, 150.3, 162.1, 165.0 ppm. HPLC-MS (ESI): Rt =
26.1 min; m/z: 392.0–394.1 [M + H]+.
Chlorination with Cl2: Saturated chlorine solution was prepared by
bubbling gaseous chlorine into dichloromethane at 0 °C until the
solution became yellow. This solution was added dropwise at 0 °C
to a solution of CH2Cl2 (10 mL) containing 1a (72 mg, 0.5 mmol)
or 1b (156 mg, 0.5 mmol). The reaction was monitored by TLC,
and after full conversion the reaction mixture was concentrated.
The products were isolated by flash chromatography.
Ethyl (E,Z)-Chloro-(4-oxoazetidin-2-yliden)acetate (3a): White so-
lid. IR (CH Cl ): ν = 3244, 1825, 1661 cm–1. HRMS (EI) calculated
˜
2
2
for C7H8ClNO3: 189.0193; found: 189.0185. C7H8ClNO3 (189.60)
calculated: C 44.34, H 4.25, N 7.39; found: C 44.41, H 4.21, N
7.46.
Isomer (E)-3a: Rf = 0.68 (cyclohexane/ethyl acetate, 1:1). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 1.35 (t, J = 6.9 Hz, 3 H, CH3CH2),
3.66 (s, 2 H, CH2), 4.29 (q, J = 6.9 Hz, 2 H, CH3CH2), 8.54 (brs,
1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = 14.2, 45.6,
Iodination with NIS: NIS (112 mg, 0.5 mmol) was added to a solu-
tion of 1a (72 mg, 0.5 mmol) or 1b (156 mg, 0.5 mmol) and TEA
(0.07 mL, 0.5 mmol) in CH2Cl2 (10 mL). The reaction was moni-
tored by TLC. After full conversion, a saturated solution of NH4Cl
(10 mL) was added. The mixture was extracted with CH2Cl2
(3ϫ10 mL), dried with Na2SO4 and concentrated. Where neces-
sary, residues of succinimide were eliminated by trituration with
CCl4.
62.1, 96.3, 146.6, 162.6, 163.4 ppm. HPLC-MS (ESI): Rt
=
15.0 min; m/z: 190.1 [M + H]+.
Isomer (Z)-3a: Rf = 0.66 (cyclohexane/ethyl acetate, 1:1). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 1.31 (t, J = 6.9 Hz, 3 H, CH3CH2),
3.81 (s, 2 H, CH2), 4.26 (q, J = 6.9 Hz, 2 H, CH3CH2), 7.95 (brs,
1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = 14.2, 46.1,
Iodination with I2: I2 (318 mg, 1.25 mmol) was added to a solution
of 1a (72 mg, 0.5 mmol) or 1b (156 mg, 0.5 mmol) and TEA 61.9, 96.6, 145.6, 162.5, 163.6 ppm. HPLC-MS (ESI): Rt
=
(0.15 mL, 1.1 mmol) in CH2Cl2 (10 mL). The reaction was moni-
tored by drop discoloration and TLC. After full conversion, a satu-
rated solution of NH4Cl (10 mL) was added. The mixture was ex-
tracted with CH2Cl2 (3ϫ10 mL), dried with Na2SO4 and concen-
trated.
13.6 min; m/z: 190.1 [M + H]+.
Ethyl (E,Z)-{(3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}-chloroacetate (3b): Pale yellow oil. IR
(CH Cl ): ν = 3283, 1823, 1652 cm–1. C H ClNO Si (347.91) cal-
˜
2
2
15 26
4
culated: C 51.78, H 7.53, N 4.03; found: C 51.71, H 7.48, N 4.07.
Ethyl (E,Z)-Bromo-(4-oxoazetidin-2-yliden)acetate (2a): Pale yellow
Isomer (E)-3b: Rf = 0.67 (cyclohexane/ethyl acetate, 7:3). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 0.08 (s, 6 H, SiMe2), 0.87 (s, 9 H,
SitBu), 1.35 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.38 (d, J = 6.6 Hz, 3
H, CH3CH), 3.92 (m, 1 H, CHCHOSi), 4.29 (q, J = 7.0 Hz, 2 H,
CH3CH2), 4.47 (dq, J = 3.4, 6.6 Hz, 1 H, CHCHOSi), 8.39 (brs, 1
H, NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = –5.2, –4.5,
14.2, 18.0, 21.6, 25.7, 62.0, 64.5, 65.9, 95.9, 149.5, 163.7,
164.6 ppm. HPLC-MS (ESI): Rt = 26.8 min; m/z: 348.3–350.3 [M
+ H]+, 370.2–372.1 [M + Na]+.
solid. IR (CH Cl ): ν = 3500, 3250, 1823, 1668 cm–1. HRMS (EI)
˜
2
2
calculated for C7H8BrNO3: 232.9687; found: 232.9683.
C7H8BrNO3 (234.05) calculated: C 35.92, H 3.45, N 5.98; found:
C 35.99, H 3.38, N 5.91.
Isomer (E)-2a: Rf = 0.61 (cyclohexane/ethyl acetate, 6:4). 1H NMR
(300 MHz, CDCl3, 22 °C): δ = 1.36 (t, J = 6.9 Hz, 3 H, CH3CH2),
3.63 (s, 2 H, CH2), 4.28 (q, J = 6.9 Hz, 2 H, CH3CH2), 8.31 (brs,
1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = 14.1, 47.3,
62.2, 83.7, 148.9, 162.2, 163.8 ppm. HPLC-MS (ESI): Rt
=
Isomer (Z)-3b: Rf = 0.65 (cyclohexane/ethyl acetate, 7:3). 1H NMR
(CDCl3, 200 MHz, 22 °C): δ = 0.10 (s, 3 H, SiMe), 0.11 (s, 3 H,
SiMe), 0.91 (s, 9 H, SitBu), 1.33 (d, J = 6.6 Hz, 3 H, CH3CH), 1.34
15.9 min; m/z = 234.0–236.0 [M + H]+, 256.1–258.1 [M + Na]+.
Isomer (Z)-2a: Rf = 0.53 (cyclohexane/ethyl acetate, 6:4). 1H NMR
(300 MHz, CDCl3, 22 °C): δ = 1.32 (t, J = 6.9 Hz, 3 H, CH3CH2),
3.79 (s, 2 H, CH2), 4.26 (q, J = 6.9 Hz, 2 H, CH3CH2), 7.58 (brs,
1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = 14.1, 46.9,
4
(t, J = 7.0 Hz, 3 H, CH3CH2), 4.10 (dd, JH3,NH = 1.8 Hz, J =
4.0 Hz, 1 H, CHCHOSi), 4.31 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.58
(dq, J = 4.0, 6.6 Hz, 1 H, CHCHOSi), 7.56 (brs, 1 H, NH) ppm.
13C NMR (CDCl3, 50 MHz): δ = –5.0, –4.6, 14.3, 18.0, 19.9, 25.6,
61.8, 64.7, 65.9, 96.8, 148.0, 162.1, 164.6 ppm. HPLC-MS (ESI):
62.2, 84.5, 147.8, 162.4, 162.9 ppm. HPLC-MS (ESI): Rt
=
14.3 min; m/z: 234.0–236.0 [M + H]+, 256.1–258.1 [M + Na]+.
Rt
= 26.0 min; m/z: 348.3–350.3 [M +
H]+, 370.2–372.1
Ethyl (E,Z)-Bromo-{(3S)-3-[(1R)-1-(tert-butyldimethylsilanyloxy)-
ethyl]-4-oxoazetidin-2-ylidene}acetate (2b): Pale yellow oil. IR
[M + Na]+.
(CH Cl ): ν = 3400, 1820, 1650 cm–1. C H BrNO Si (392.36) cal-
Ethyl (E,Z)-Iodo-(4-oxoazetidin-2-yliden)acetate (4a): White solid.
˜
2
2
15 26
4
culated: C 45.92, H 6.68, N 3.57; found: C 45.85, H 6.62, N 3.54.
IR (CH Cl ): ν = 3227, 1823, 1650 cm–1. HRMS (EI) calculated
˜
2
2
for C7H8INO3: 280.9549; found: 280.9552. C7H8INO3 (281.05) cal-
culated: C 29.91, H 2.87, N 4.98; found: C 29.81, H 2.80, N 4.91.
Isomer (E)-2b: Rf = 0.63 (cyclohexane/ethyl acetate, 8:2). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 0.09 (s, 6 H, SiMe2), 0.87 (s, 9 H,
SitBu), 1.20 (d, J = 6.3 Hz, 3 H, CH3CH), 1.24 (t, J = 7.2 Hz, 3 Isomer (E)-4a: Rf = 0.45 (cyclohexane/ethyl acetate, 7:3). 1H NMR
H, CH3CH2), 3.88 (dd, JH3,NH = 1.2 Hz, J = 3.3 Hz, 1 H, (CDCl3, 200 MHz, 22 °C): δ = 1.33 (t, J = 7.0 Hz, 3 H, CH3CH2),
4
CHCHOSi), 4.24 (q, J = 7.2 Hz, 2 H, CH3CH2), 4.53 (dq, J = 3.3,
6.3 Hz, 1 H, CHCHOSi), 8.77 (brs, 1 H, NH) ppm. 13C NMR
(CDCl3, 75 MHz, 22 °C): δ = –5.1, –4.6, 14.2, 17.9, 20.8, 25.6, 62.2,
64.1, 64.6, 82.9, 151.4, 163.4, 164.9 ppm. HPLC-MS (ESI): Rt =
27.0 min; m/z: 392.0–394.1 [M + H]+.
3.56 (s, 2 H, CH2), 4.24 (q, J = 7.0 Hz, 2 H, CH3CH2), 8.53 (brs,
1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz, 22 °C): δ = 14.3, 45.1,
53.2, 62.3, 152.6, 162.7, 163.7 ppm. HPLC-MS (ESI): Rt
16.3 min; m/z: 282.1 [M + H]+.
=
Isomer (Z)-4a: Rf = 0.42 (cyclohexane/ethyl acetate, 7:3). 1H NMR
(CDCl3, 200 MHz, 22 °C): δ = 1.31 (t, J = 7.0 Hz, 3 H, CH3CH2),
3.77 (s, 2 H, CH2), 4.24 (q, J = 7.0 Hz, 2 H, CH3CH2), 7.35 (brs,
Isomer (Z)-2b: Rf = 0.60 (cyclohexane/ethyl acetate, 8:2). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 0.08 (s, 6 H, SiMe2), 0.88 (s, 9 H,
SitBu), 1.33 (d, J = 6.3 Hz, 3 H, CH3CH), 1.33 (t, J = 7.2 Hz, 3 1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz): δ = 14.2, 49.7, 57.2,
Eur. J. Org. Chem. 2007, 2526–2533
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Cainelli, P. Galletti, D. Giacomini, S. Licciulli, A. Quintavalla
FULL PAPER
62.4, 153.4, 162.3, 163.3 ppm. HPLC-MS (ESI): Rt = 14.8 min;
m/z: 282.1 [M + H]+.
Benzyl (E,Z)-Bromo-(4-oxoazetidin-2-yliden)acetate (7): Pale yellow
oil.
Isomer (E)-7: 1H NMR (CDCl3, 300 MHz, 22 °C): δ = 3.64 (s, 2
H, CH2), 5.25 (s, 2 H, CH2Ph), 7.39 (m, 5 H, Ph), 8.2 (brs, 1 H,
NH) ppm.
Ethyl (E,Z)-{(3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}-iodoacetate (4b): Pale yellow oil. IR
(CH Cl ): ν = 3277, 1822, 1634 cm–1. C H INO Si (439.36) calcu-
˜
2
2
15 26
4
lated: C 41.01, H 5.96, N 3.19; found: C 40.95, H 5.88, N 3.11.
Isomer (Z)-7: 1H NMR (CDCl3, 300 MHz, 22 °C): δ = 3.75 (s, 2
H, CH2), 5.23 (s, 2 H, CH2Ph), 7.39 (m, 5 H, Ph), 7.5 (brs, 1 H,
NH) ppm.
Isomer (E)-4b: Rf = 0.67 (cyclohexane/ethyl acetate, 8:2). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 0.11 (s, 6 H, SiMe2), 0.89 (s, 9 H,
SitBu), 1.19 (d, J = 6.3 Hz, 3 H, CH3CH), 1.36 (t, J = 7.0 Hz, 3
Ethyl (E,Z)-{(3S)-3-[(1R)-1-(tert-Butyldimethylsilanyloxy)ethyl]-4-
oxoazetidin-2-ylidene}-nitroacetate (8): Trifluoroacetic anhydride
(0.178 mL, 1.25 mmol) and solid NH4NO3 (40 mg, 0.5 mmol) were
added to a solution of 1b (156 mg, 0.5 mmol) in CHCl3 (10 mL),
and the reaction mixture was heated to reflux with monitoring by
HPLC and then poured into saturated NaCl (10 mL) and extracted
with CH2Cl2 (3ϫ10 mL). The product was obtained as a pale yel-
low oil and could be further purified by flash chromatography, al-
4
H, CH3CH2), 3.82 (dd, JH3,NH = 1.0 Hz, J = 3.6 Hz, 1 H,
CHCHOSi), 4.22 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.63 (m, 1 H,
CHCHOSi), 8.85 (brs, 1 H, NH) ppm. 13C NMR (CDCl3,
75 MHz, 22 °C): δ = –5.0, –4.6, 14.3, 17.9, 19.9, 25.7, 57.0, 62.5,
63.8, 67.5, 155.5, 163.8, 164.5 ppm. HPLC-MS (ESI): Rt
=
27.2 min; m/z: 440.0 [M + H]+, 457.1 [M + H20]+, 462.0 [M +
Na]+.
Isomer (Z)-4b: Rf = 0.65 (cyclohexane/ethyl acetate, 8:2). 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 0.10 (s, 6 H, SiMe2), 0.91 (s, 9 H,
SitBu), 1.29 (d, J = 6.2 Hz, 3 H, CH3CH), 1.37 (t, J = 7.0 Hz, 3
though the diastereoselectivity ratio changed. IR (CH Cl ): ν =
˜
2
2
1842, 1564, 1515 cm–1. Rf = 0.7 (cyclohexane/ethyl acetate, 7:3).
HPLC-MS (ESI): Rt = 24.9 min; m/z: 359.4 [M + H]+, 381.5 [M +
Na]+, 397.2 [M + K]+. C15H26N2O6Si (358.46) calculated: C 50.26,
H 7.31, N 7.81; found: C 50.14, H 7.42, N 7.75.
4
H, CH3CH2), 4.04 (dd, JH3,NH = 1.8 Hz, J = 6.0 Hz, 1 H,
CHCHOSi), 4.24 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.61 (dq, J = 6.0,
6.2 Hz, 1 H, CHCHOSi), 7.58 (brs, 1 H, NH) ppm. 13C NMR
(CDCl3, 75 MHz, 22 °C): δ = –4.9, –4.6, –14.2, 17.9, 19.9, 25.7,
52.1, 62.2, 63.6, 67.5, 154.8, 163.8, 164.5 ppm. HPLC-MS (ESI):
Rt = 26.4 min; m/z: 440.0 [M + H]+, 462.0 [M + Na]+.
Isomer (Z)-8: 1H NMR (CDCl3, 200 MHz, 22 °C): δ = 0.09 (s, 6
H, SiMe2), 0.88 (s, 9 H, SitBu), 1.23 (d, J = 5.8 Hz, 3 H, CH3CH),
1.33 (t, J = 7.4 Hz, 3 H, CH3CH2), 4.45 (m, 4 H, CH3CH2,
CHCHOSi, CHCHOSi), 8.73 (brs, 1 H, NH) ppm. 13C NMR
(CDCl3, 50 MHz, 22 °C): δ = –5.3, –4.5, 14.0, 17.8, 21.1, 25.5, 62.3,
64.8, 67.3, 106.1, 157.3, 159.9, 163.6 ppm.
Isomer (E)-8: 1H NMR (CDCl3, 200 MHz, 22 °C): δ = 0.09 (s, 6
H, SiMe2), 0.88 (s, 9 H, SitBu), 1.19 (d, J = 5.8 Hz, 3 H, CH3CH),
1.33 (t, J = 7.4 Hz, 3 H, CH3CH2), 4.45 (m, 4 H, CH3CH2,
CHCHOSi, CHCHOSi), 8.95 (brs, 1 H, NH) ppm. 13C NMR
(CDCl3, 50 MHz, 22 °C): δ = –5.4, –4.54, 14.1, 17.8, 21.3, 25.5,
62.5, 64.8, 68.0, 106.0, 159.6, 160.7, 164.0 ppm.
Benzyl 2-Deuterio-diazoacetate (5): Deep yellow liquid. The diazo
ester was prepared as reported in the literature[23] by quenching
1
of the reaction mixture with D2O and NaOD. H NMR (CDCl3,
200 MHz, 22 °C): δ = 5.23 (s, 2 H, CH2Ph), 7.38 (m, 5 H, Ph) ppm.
13C NMR (CDCl3, 75 MHz, 22 °C): δ = 45.4 (t, JC,D = 31.5 Hz),
66.1, 127.7, 127.8, 129.1, 135.8, 166.1 ppm.
Benzyl Deuterio-(4-oxoazetidin-2-yliden)acetate (6): This compound
was prepared from 5 as reported in Ref.[6]. Pale yellow oil. 1H NMR
(CDCl3, 300 MHz, 22 °C): δ = 3.55 (s, 2 H,CH2), 5.19 (s, 2 H,
Ethyl (S)-Amino{(2S,3S)-3-[(1R)-1-(tert-butyldimethylsilanyloxy)-
CH2Ph), 7.35 (m, 5 H, Ph), 8.65 (brs, 1 H, NH) ppm. 13C NMR ethyl]-4-oxoazetidin-2-yl}acetate (9):[22] Compound
8
(35 mg,
0.1 mmol) was dissolved in EtOAc (5 mL), and Pd (10 wt.% on
activated carbon, 3 mg) was added. The reaction mixture was
(CDCl3, 75 MHz, 22 °C): δ = 44.8, 66.0, 90.3 (t, JC,D = 25.2 Hz),
128.1, 128.3, 128.6, 135.9, 150.4, 164.7, 166.8 ppm.
1
Table 4. Selected H NMR and HPLC data for compounds 1–4.
[a] In halogenated compounds (X = Cl, Br, I) a change in the priority order of C=C substituents causes an apparent inversion of
configuration respect to starting materials (X = H).
2532
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2526–2533

Vinylic Halogenation in 4-Alkylidenazetidin-2-ones
FULL PAPER
[5] F. Broccolo, G. Cainelli, G. Caltabiano, C. E. A. Cocuzza,
C. G. Fortuna, P. Galletti, D. Giacomini, G. Musumarra, R.
Musumeci, A. Quintavalla, J. Med. Chem. 2006, 49, 2804–2811.
[6] a) G. Cainelli, P. Galletti, S. Garbisa, D. Giacomini, L. Sartor,
A. Quintavalla, Bioorg. Med. Chem. 2003, 11, 5391–5399; b)
G. Cainelli, P. Galletti, S. Garbisa, D. Giacomini, L. Sartor, A.
Quintavalla, Bioorg. Med. Chem. 2005, 13, 6120–6132.
[7] C. Ye, J. M. Shreeve, J. Org. Chem. 2004, 69, 8561–8563.
[8] G. V. Ramanarayanan, V. G. Shukla, K. G. Akamanchi, Syn-
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[9] M. E. Krafft, J. W. Cran, Synlett 2005, 1263–1266.
[10] a) F. Fernandez, X. Garcia-Mera, C. Lopez, M. Morales, J. E.
Rodriquez-Borges, Synthesis 2005, 3549–3554; b) S.-Y. Wang,
Nature 1957, 180, 91–92.
[11] a) M. E. F. Braibante, H. T. S. Braibante, G. B. Rosso, J. K.
da Roza, Synthesis 2001, 1935–1937; b) N. Amishiro, A. Oka-
moto, M. Okabe, H. Saito, Bioorg. Med. Chem. 2000, 8, 1195–
2001; c) E. N. Koz’minykh, A. O. Belyaev, V. O. Koz’minykh,
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2289.
treated with H2 (1 atm) and stirred at room temperature until full
conversion (1 h). The catalyst was filtered off and the solution was
concentrated to give 9 (33 mg) as a yellow oil. H NMR (CDCl3,
1
300 MHz, 22 °C): δ = 0.17 (s, 6 H, SiMe2), 0.94 (s, 9 H, SitBu),
1.34 (t, J = 7.2 Hz, 3 H, CH3CH2), 1.47 (d, J = 6.3 Hz, 3 H,
4
CH3CH), 2.0–2.3 (brs, 2 H, NH2), 3.37 (ddd, JH3,NH = 1.5 Hz, J
= 5.4, 5.4 Hz, 1 H, CHCHCHOSi), 3.89 (dd, J = 5.4, 8.4 Hz, 1 H,
OCOCHCHNH2), 4.23 (m, 1 H, OCOCHCHNH2), 4.27 (q, J =
7.2 Hz, 2 H, CH3CH2), 4.51 (m, 1 H, CH3CH), 6.20 (brs, 1 H,
NH) ppm. 13C NMR (CDCl3, 75 MHz, 22 °C): δ = –4.3, –4.8, 14.2,
18.1, 22.8, 25.9, 54.7, 54.9, 60.9, 61.7, 65.8, 167.6, 172.8 ppm.
HPLC-MS (ESI): Rt = 22.9 min; m/z: 332 [M + H]+. C15H30N2O4Si
(330.49) calculated: C 54.51, H 9.15, N 8.48; found: C 54.63, H
9.23, N 8.41.
Double Bond Configuration Assignment
Double bond configurations of halogenated products 2–4 were as-
signed by comparison with 1H NMR and HPLC data for their
starting materials[15] (see Table 4).
In particular, diastereoisomers with stronger intramolecular hydro-
gen bonds [E diastereoisomers in products, Z in starting materials
according to IUPAC rules] have longer HPLC retention times and
[14] M. Médebielle, O. Onomura, R. Keirouz, E. Okada, H. Yano,
T. Terauchi, Synthesis 2002, 2601–2608.
[15] a) G. Cainelli, P. Galletti, D. Giacomini, A. Quintavalla, Eur.
J. Org. Chem. 2003, 1765–1774; b) G. Cainelli, P. Galletti, M.
Gazzano, D. Giacomini, A. Quintavalla, Tetrahedron Lett.
2002, 43, 233–235.
1
more powerfully unshielded NH resonances in the H NMR spec-
tra in CDCl3. Proton chemical shifts on C-3 are downfield in E
halogenated-β-lactams and in Z starting materials.
[16] a) C. Djerassi, C. R. Scholz, J. Am. Chem. Soc. 1948, 70, 417–
418; b) L. C. McKenzie, L. M. Huffman, J. E. Hutchison, J.
Chem. Educ. 2005, 82, 306.
In nitro derivatives 8 the double bond configuration has been tenta-
tively assigned on the hypothesis that in chlorinated solvents the
intramolecular hydrogen bond between NH and ester C=O group
is stronger than that between NH and nitro group.[24]
[17] For the synthesis of N-benzyl-4-alkylidene-β-lactams, see ref.[6]
.
[18] a) M. A. Lischwe, M. T. Sung, J. Biol. Chem. 1977, 252, 4976–
4980; b) M. B. Smith, J. March, March’s Advanced Organic
Chemistry; 2001, John Wiley & Sons, New York, chapter 14,
p. 913.
[19] For a discussion on the iminium ion in azetidin-2-ones, see for
example: a) R. P. Attrill, A. G. M. Barrett, P. Quayle, J.
van der Westhuizen, J. Org. Chem. 1984, 49, 1679 ; b) F. Gav-
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[20] I. I. Gerus, L. M. Kacharova, S. I. Vdovenko, Synthesis 2001,
431–436.
Acknowledgments
We would like to thank Mr. Paolo Bedonni for experimental assist-
ance and Mr. Andrea Garelli for technical assistance. We also
acknowledge the Ministero dell’Università e della Ricerca (MIUR)
and the University of Bologna for funding.
[21] J. V. Crivello, J. Org. Chem. 1981, 46, 3056–3060.
[22] The cis stereochemistry in the β-lactam ring has been assigned
by analysis of 1H NMR coupling constants. On starting materi-
als 1, the same hydrogenation procedure stereospecifically af-
fords the cis isomer, thus suggesting a stereospecific syn ad-
dition from the less hindered face, G. Cainelli, P. Galletti, D.
Giacomini, A. Quintavalla, unpublished results.
[23] R. L. Danheiser, R. F. Miller, R. G. Brisbois, S. Z. Park, J. Org.
Chem. 1990, 55, 1959–1964.
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Received: December 18, 2006
Published Online: March 28, 2007
Eur. J. Org. Chem. 2007, 2526–2533
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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