Intramolecular substitution reactions involving π-nucleophiles and N-acyliminium cations generated from azetidin-2-ones

Article abstract of DOI:10.1016/j.tet.2010.03.108

The Lewis acid-catalyzed intramolecular substitution reactions of 4-vinyloxy- or 4-acyloxy-azetidin-2-ones with nitrogen-bound allyl-, propargyl- and vinyl-silanes leading to the carbacephams or carbacephems, are reported. The formation of carbapenams was not observed. To illustrate the potential of these reactions to be carried out under solid-phase conditions, a synthesis of diastereomeric 5-vinyl-carbacephams via the cyclization/cleavage methodology was performed.

Full text of DOI:10.1016/j.tet.2010.03.108

Tetrahedron 66 (2010) 3904–3911
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular substitution reactions involving
p
-nucleophiles and
N-acyliminium cations generated from azetidin-2-ones
*
Barbara Grzeszczyk, Barbara Szechner, Bart1omiej Furman, Marek Chmielewski
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The Lewis acid-catalyzed intramolecular substitution reactions of 4-vinyloxy- or 4-acyloxy-azetidin-2-
ones with nitrogen-bound allyl-, propargyl- and vinyl-silanes leading to the carbacephams or carbace-
phems, are reported. The formation of carbapenams was not observed. To illustrate the potential of these
reactions to be carried out under solid-phase conditions, a synthesis of diastereomeric 5-vinyl-carba-
cephams via the cyclization/cleavage methodology was performed.
Received 16 December 2009
Received in revised form 8 March 2010
Accepted 29 March 2010
Available online 2 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
p-Nucleophiles
Acyliminium cations
Azetidin-2-ones
Cyclizations
1. Introduction
atom.4 Subsequently, the vinyloxyl group itself, or formyloxyl (readily
available by ozonolysis), in the presence of a Lewis acid, undergoes
The N-acyliminium ions are important reactive intermediates in
organic synthesis, which can act as electron-deficient C-electrophiles
toward weak, soft nucleophiles providing useful methodologies for
both the inter- and intramolecular carbon–carbon and carbon–het-
eroatom bond formation.1 N-Acyliminium species can be generated
intramolecular displacement leading to the ring closure.5 The acid-
catalyzed nucleophilic substitution at C-4 of the azetidinone ring
proceeds via a flat intermediate 2, which in the presence of a chiral
reagent may allow discrimination of its faces thus providing a con-
figurationally enriched product. The intramolecular diaster-
eoselective process involving chiral N-substituent offers high
asymmetric induction,6 whereas the commonly used intermolecular
reaction proceeds usually with poor stereoselectivity.6b,7
inacidicmedia fromlactams bearinga leavinggroupinthea-position
to the nitrogen atom. Over the last 40 years, the cationic cyclization
involving benzenoid, alkene, or alkyne nucleophiles and N-acylimi-
niumionshasfoundabroadapplicationinthesynthesisofavarietyof
ring systems.2 It should be noted, however, that as a rule, the cyclic
N-acyliminium cations have been generated from five- or six-
membered ring lactams,2 and only a few reported examples have
A search for the enantioselective formation of bicyclic b-lactams
prompted us to investigate the chiral Lewis acid-catalyzed intra-
molecular formation of the 5-oxa-3,4-benzocephams 4 from com-
pounds 3.8 The observed moderate yield, which never exceeded
50%, in parallel with a high asymmetric induction, suggested a ki-
netic asymmetric destruction of the initially formed racemic oxa-
cepham 4. This has been proved independently by the asymmetric
degradation of racemic 4 in the presence of a chiral catalyst.8
referred to 4-substituted
b
-lactams.3 We have shown that the
4-vinyloxyazetidin-2-one (1) is an attractive starting material for
the synthesis of 5-oxacephams since it allows for N-alkylation of the
substrate prior to the nucleophilic substitution at the C-4 carbon
MeO
OMe
O
R
O
R
O
O
*
OMe
N
N
HN
N
N
N
O
O
O
O
O
R1
OH
O
1
1
2
3
4
5
6
R =H, Bn
Recently, we have also shown that the N-acyliminium ions 2
generated from -lactams can be used as electrophilic agents to
* Corresponding author. Tel.: þ4822 631 87 88; fax: þ4822 632 66 81; e-mail
address: chmiel@icho.edu.pl (M. Chmielewski).
b
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.108

B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
3905
substitute nucleophilic arenes in both inter- and intramolecular
processes.9 The former reaction was successfully carried out only
with p-dimethoxybenzene to provide compounds 5 in moderate
yield, whereas the latter can be done with a variety of nucleophilic
arenes affording bicyclic compounds 6 in a good yield. Reactions of
rule.17 The cyclization of compound 28 led to slow decomposition of
the substrate and we were able to isolate only a minute amount of
desilylated product 29. Compounds 22 and 23 with 4-vinyloxy
substituents afforded oxazepane 32 resulting from addition of the
allylsilane fragment to the vinyloxy group. Oxazepane 32 was
formed with a high stereoselectivity providing a single isomer with
both bridgehead protons syn located. This was corroborated by NOE
spin–spin interaction between both protons. The cyclization of
4-acyloxy-azetidinones 27, 30, and 31 did not offer any advantage in
comparison with the corresponding vinyloxy congeners. Slightly
better yields were realized in the former reactions but at the cost of
one additional synthetic step (oxidation).
N-acyliminium cations generated from 1 with simple
p-nucleo-
philes, such as vinylsilanes, allylsilanes, and propargylsilanes are
logical continuation of our investigation. It should be noted that
reactions of allyltrimethylsilane with N-acyliminium cations de-
rived from alkoxylactams have been investigated in the past provide
the corresponding C-allylated product.10 A Similar reaction in-
volving the trimethylsilyl trifluoromethanesulfonate-mediated allyl
transfer from an N-allyldimethylsilylated
b
-lactam to C-4 carbon
Cyclization of vinyl silane 20 led to the carbacephem 33 in 78%
yield, whereas the (Z)-allylsilanes 21 and 27 gave a mixture of
carbacephams 34 and 35 in a ratio of about 1.0:1.3, respectively, as
determined by the HPLC. The relative configuration of both di-
astereomers was assigned using NOE to show a spin–spin in-
teraction between H-5 and H-6 protons in the case of 35.
atom of 4-acetoxyazetidinone fragment has also been reported.11
2. Result and discussion
Theknownvinyl-712, allyl-813,1014,11–12,15 andpropargylsilanes
1313 were transformed into the corresponding p-chlorobenzene-
sulfonates 14–19. Subsequently, the 4-vinyloxyazetidin-2-one (1)
was N-alkylated with chloride 9 and sulfonates 14–19 to afford
azetidinones 20–26, using our general procedure.16 Since we have
previously shown5a–c that in the presence of acid catalysts, vinyloxyl
played the role of a leaving group, compounds 20–26 were directly
subjected to the cyclization. To demonstrate that the 4-acyloxy
congeners provide the similar result of cyclization, compounds 21,
23, and 26 were oxidized to corresponding acetates 27, 28, and
30 using the standard PCC procedure, whereas compound 26 was
also treated with ozone to give formate 31.
The intramolecular nucleophilic substitution at C-4 carbon atom
of the azetidinone residue was performed in the presence of Lewis
acids SnCl2/TMSCl, Yb(OTf)3, SnCl4, and TiF4. Reactions were per-
formed on both 4-vinyloxy-(20–26) and 4-acyloxy-azetidinones
(27,28, 30, and 31). In all feasible cases (22, 23, and 28), the for-
mation of carbapenams (five-membered pyrrolidine ring fused to
the four-membered ring) was unsuccessful. This result may be
explained as a 5-endo process, which is disfavored by the Baldwin
H
H
H
H
H
H
O
N
N
N
N
O
O
O
O
O
O
O
32
33
34
35
H
H
N
H
H
N
Cl
N
N
O
36
37a
37b
3
7c
The cyclization of allylsilanes 24 and 25 proceeded in somewhat
unanticipated manner. In the presence of SnCl2 or SnCl4, the
4-chloro-4-methylcarbacepham 36 was formed. The configuration
at C-3 carbon in 36 was assigned assuming that the addition of
OR
R2
TMS
R2
OR
TES
OR
R1
TMS
OR1
9 R1=Cl,
10 R1=OH,
16
R2=TMS
11 R1=H,
R2=TMS
13 R=H
19
7 R=H
14
8 R=H
R2=Me2PhSi 12 R1=H,
17
R2=Me2PhSi
R=p-C6H4SO2
15
R=p-C6H4SO2
R=p-C6H4SO2
R1=p-C6H4SO2; R2=Me2PhSi
R1=p-C6H4SO2; R2=TMS
R1=p-C6H4SO2; R2=Me2PhSi
18
R1
X
R
R
X
X
O
O
O
N
N
N
O
O
R2
O
TES
TMS
22 X=CH2, R1=H, R2=TMS
20 X=CH2, R=H
21 X=CH2, R=H
27
23 X=CH2, R1=H, R2=M e2PhSi
28
X=O, R=CH3
X=O, R1=CH3, R2=Me2PhSi
R1
X
R
X=O, R1=CH3, R2=H
29
X
O
O
N
N
O
O
TMS
R2
24 X=CH2, R1=H, R2= TMS
25
26 X=CH2, R = H
30 X=O, R=CH3
X=CH2, R1=H, R2= Me2PhSi
31
X=O, R=H

3906
B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
chloride anion to the tertiary carbocation proceeded from the exo
side of the bicyclic cepham skeleton. In the presence of Yb(OTf)3,
both silanes 24 and 25 afforded a mixture of carbacephams 37b and
37a in a ratio of about 1.3:1.0. Both regioisomers were separated by
chromatography. The signals due to a minute amount of the
expected cepham 37c were detected only in the 1H NMR spectrum
of the post reaction mixture. This unexpected pathway of the re-
action is likely a result of a low stability of the initially formed
cepham 37c. One could speculate that in the presence of acids
bearing chlorine atoms the cepham 37c forms 36, whereas other
acids induce migration of the double bond.18
The intermolecular reaction of 4-acetoxy-azetidinone with
propargyl silane to provide 4-allenyl-azetidinone is a known pro-
cess.19 The corresponding intramolecular process involving prop-
argylsilanes 26 and 30 should proceed more readily. Indeed, both
compounds easily underwent the cyclization in an analogous yield,
however, the structure of the final product depended onwhich Lewis
acid was used. In the presence of titanium tetrafluoride allene 38 was
obtained as a sole product in a good yield from both silanes 26 and 30.
In the presence of Yb(OTf)3, compounds 26 and 31 afforded allene 38
(50% yield) accompanied by the TMS-substituted diastereomers 39
(29% yield) in a ratio of about 3:1. The relative configuration of di-
astereomers 39 was not assigned. The cyclization of 26 and 31 in the
presence of SnCl2/TMSCl catalyst gave expected allene 38 (43%) ac-
companied only by the chloro-trimethylsilyl compound 40 (21%).20
The configuration of the double bond in 40 was not assigned.
resin according to the literature method.22 Cyclization involving 43,
under conditions used for the cyclization of its (Z) isomer 27, affor-
ded a mixture of 34, and 35 in the same ratio as cyclization of 27. This
result shows that the endo approach of the double bond (structure
47) to acyliminium cation is slightly preferred over the exo approach
(structure 46) owing to the overlapping of the nucleophilic double
bond with electrophilic acyliminium cation. The configuration of the
double bond, (Z) 27 and (E) 43, does not affect the stereochemical
pathway of the reaction. The cyclization/cleavage performed on solid
support 45, however, led to a mixture of cephams 34 and 35 in
a ratio 1.3:1.0, respectively, being reversed to that observed for re-
actions performed in solution. This indicates that the spatial re-
quirements of the silyl substituent bound to the resin make the exo
approach (structure 46) preferred.
3. Conclusion
It was demonstrated that the vinyloxy group at C-4 of the aze-
tidinone ring is an attractive substituent. It is stable under basic
conditions allowing alkylation of the nitrogen atom, whereas in the
presence of a Lewis acid catalyst it plays a role of a leaving group,
which promotes a nucleophilic substitution. We have shown that
cyclization reactions involving N-acyliminium cations generated
from the azetidinone fragment and
p-nucleophiles, such as vinyl-
silanes, allylsilanes, and propargylsilanes proceeds smoothly only if
a six-membered cepham ring can be formed. The formation of
H
H
TMS
TMS
X
Cl
•
•
O
N
N
O
N
N
O
O
O
41 X=CH2, R=H
42 X=O, R=CH3
39
40
38
O
O
O
O
N
Si
N
O
Si
O
TMS
43
45
44
SiMe2R
SiMe2R
H
H
N
R=Me,
N
O
O
46
47
To demonstrate that cyclizations involving
p
-nucleophiles to
carbapenam skeletons was never observed. Instead, if the substrate
contains 4-vinyloxy group, addition of the nucleophile to vinyl
ether takes place.
N-acyliminium cations can be performed using solid-phase meth-
odology, we chose the intramolecular alkylation of the (E) allylsilane
43. The reaction should proceed via the cyclization/cleavage meth-
odology.21 Starting material, N-(pent-4-enyl)azetidin-2-one 41 was
obtained from 1 by a standard alkylation procedure. In order to
compare the reaction performed in solution and on a solid support,
the vinyloxy group in compound 41 was oxidized to the acetoxy
group to afford compound 42. The latter was coupled with trime-
thylallylsilane in the presence of Grubbs catalyst second generation
to give compound 43. The same cross-metathesis reaction was
performed using the allylsilane resin 44, synthesized from Merrifield
4. Experimental section
4.1. General
1H and 13C NMR spectra were recorded on a Brucker DRX 500
Avance Spectrometer at 500 MHz and 125 MHz, respectively, in
CDCl3 unless otherwise stated. TMS was used as an internal stan-
dard. Chemical shifts are reported as
d values in parts per million

B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
3907
and coupling constants are in hertz. Proton assignment was done
(ESI): calcd for
417.0726.
C
19H23O3NaSiSCl [MþNa]þ: 417.0718; found:
based on COSY experiments. Infrared spectra were recorded on
a FT-IR-1600 Perkin–Elmer spectrophotometer. High-resolution
mass spectra were recorded on ESI-TOF Mariner Spectrometer
(Perspective Biosystem) or AMD 604 mass spectrometer. Thin layer
chromatography was performed on Merck aluminum sheet Silica
Gel 60 F254. Column chromatography was carried out using Merck
silica gel (230–400 mesh) and Florisil (100–200 mesh). All re-
actions were performed under argon in predried glassware. All
solvents were purified by standard techniques. 5-Bromo-1-pentene
was obtain according to literature method.23 Diastereomeric ratios
of cephams obtained were determined by HPLC of crude post re-
action mixtures on Kromasil Si 60 column.
4.2.2. Method B24. To a solution of hydroxy compound (7, 8, 10, 11–
13; 1.0 mmol) in dry dichloromethane (5 mL/mmol) were added
DABCO (0.224 g, 2.0 mmol) and 4-chlorobenzenesulfonyl chloride
(0.317 g, 1.5 mmol). The reaction progress was monitored by TLC.
After 1.5 h, the reaction mixture was diluted with ethyl acetate
(100 mL), washed with water (50 mL), dried (MgSO4), and the
solvent evaporated in vacuo. Pure products were obtained by flash
chromatography (10% ethyl acetate/hexane).
4.2.2.1. (Z)-6-Trimethylsilylhex-4-en-1-yl-4-chlorobenzenesulfo-
nate (15). Yield (0.141 g, 82%) from 8. 1H NMR
d: 7.87–7.82 (m, 2H,
aromatic), 7.55–7.51 (m, 2H, aromatic), 5.47–5.38 (m, 1H, H-5),
5.16–5.10 (m,1H, H-4), 4.08 (t, 2H, J 6.5 Hz, H-1a, H-1b), 2.02 (m, 2H,
H-3a, H-3b),1.74–1.68 (m, 2H, H-2a, H-2b),1.40 (dm, 2H, J 8.7 Hz, H-
4.2. Sulfonylation of compounds 7, 8, 10–13
4.2.1. Method A. To a solution of hydroxy compound (7, 8, 10–13;
1.0 mmol), DMAP (0.024 g, 0.2 mmol), and NEt3 (0.42 mL,
3.0 mmol) in dry dichloromethane (5 mL/mmol) cooled to 0 ꢀC
4-chlorobenzenesulfonyl chloride (0.317 g, 1.5 mmol) was added
and the reaction mixture was allowed to warm to room tempera-
ture. The reaction progress was monitored by TLC. After 1.5 h, the
reaction mixture was diluted with ethyl acetate (100 mL), washed
with water (50 mL), dried (MgSO4), and the solvent evaporated in
vacuo. Pure products were obtained by flash chromatography (10%
ethyl acetate/hexane).
6a, H-6b), ꢂ0.02 (s, 9H, TMS); 13C NMR
d: 140.3, 134.8, 129.5, 129.3,
127.4, 124.8, 70.7, 28.9, 22.8, 18.5, ꢂ1.8. IR (CHCl3)
n: 2957, 1366,
1185 cmꢂ1
.
HRMS (ESI): calcd for C15H23O3NaSiSCl [MþNa]þ:
369.0718; found: 369.0700.
4.2.2.2. 6-Trimethylsilylhex-4-yn-1-yl-4-chlorobenzenesulfonate
(19). Yield (0.122 g, 71%) from 13. 1H NMR (400 MHz, CDCl3)
7.88–
d
7.84 (m, 2H, aromatic), 7.55–7.52 (m, 2H, aromatic), 4.17 (t, 2H, J
6.2 Hz, H-1a, H-1b), 2.25–2.20 (m, 2H, H-3a, H-3b), 1.81 (dt, 2H, J
13.0, 6.5 Hz, H-2a, H-2b), 1.34 (t, 2H, J 2.7 Hz, H-6a, H-6b), 0.04 (s,
9H, TMS); 13C NMR
d: 140.4, 134.6, 129.6, 129.3, 79.0, 76.1, 69.7, 28.6,
4.2.1.1. (E)-4-Triethylsilylbut-1-enyl-4-chlorobenzenesulfonate
15.1, 6.8, ꢂ0.02, ꢂ2.1. IR (CH2Cl2)
n: 2952, 1590, 1368, 1186,
(14). Yield (0.141 g, 76%) from 7. 1H NMR
d: 7.85–7.83 (m, 2H, aro-
850 cmꢂ1
.
HRMS (ESI): calcd for C15H21O3NaSiSCl [MþNa]þ:
matic), 7.53–7.51 (m, 2H, aromatic), 5.86 (dt, 1H, J 18.8, 6.2 Hz, H-
3), 5.65 (dt, 1H, J 18.8, 1.4 Hz, H-4), 4.12 (t, 2H, J 6.7 Hz, H-1a, H-1b),
2.48 (dq, 2H, J 6.7, 1.4 Hz, H-2a, H-2b), 0.89 (t, 9H, J 8.0 Hz, 3ꢁCH3),
367.0561; found: 367.0548.
4.3. Alkylation of 4-vinyloxyazetidin-2-one
General method.16 4-Vinyloxyazetidin-2-one
0.52 (q, 6H, J 8.0 Hz, 2ꢁCH2); 13C NMR
d: 140.9, 140.4, 134.8, 131.1,
129.6, 129.3, 69.8, 36.0, 7.3, 3.3. IR (neat)
n: 2941, 1590, 1367,
1
(0.113 g,
1187 cmꢂ1. HRMS (ESI): calcd for C16H25NO3NaSiCl [MþNa]þ:
1.0 mmol) was added to a suspension of Bu4NHSO4 (0.373 g,
1.1 mmol) in dry THF (20 mL) cooled to ꢂ70 ꢀC. Butyllithium (2.5 M
in hexanes, 0.88 mL, 2.2 mmol) was then added dropwise at such
a rate that the temperature did not exceed ꢂ60 ꢀC. Afterward stir-
ring at ꢂ70 ꢀC was continued for 1 h and then alkylating agent (4-
chlorobenzenesulfonate chloride) in THF (2 mL) was added. The
reaction mixture was left overnight for slow warming up. Then it
was diluted with ether (20 mL) and quenched with NH4Cl solution
(10 mL). After separation, the water layer was extracted with ether
(20 mL) and combined organic layers were washed with water until
neutral. Drying (Na2SO4), evaporation of solvents, and flash-
chromatography afforded pure product.
383.0874; found: 383.0860.
4.2.1.2. 2-[(Dimethylphenylsilyl)methyl]prop-2-enyl 4-chloro-
benzenesulfonate (16). Yield (0.138 g, 67%) from 10. 1H NMR
d:
7.77–7.73 (m, 2H, aromatic), 7.50–7.46 (m, 2H, aromatic), 7.45–7.43
(m, 2H, aromatic), 7.38–7.30 (m, 3H aromatic), 4.91 (d, 1H, J 1.0 Hz,
H-3a), 4.73 (s, 1H, H-3b), 4.19 (s, 2H, H-4a, H-4b), 1.69 (s, 2H, H-1a,
H-1b), 0.27 (s, 6H, 2ꢁCH3); 13C NMR
d: 140.3, 138.9, 137.8, 134.8,
133.5, 129.5, 129.3, 127.9, 113.5, 74.1, 22.2, -3.2. IR (neat) n: 2951,
1589, 1369, 1186, 829 cmꢂ1. HRMS (ESI): calcd for C18H21O3NaSiSCl
[MþNa]þ: 403.0561. found: 403.0542.
4.2.1.3. 3-[(Trimethylsilyl)methyl]but-3-enyl-4-chlorobenzenesul-
4.3.1. (E)-1-(400-Triethylsilylbut-300-enyl)-4-vinyloxyazetidin-2-one
fonate (17). yield (0.079 g, 50%) from 11. 1H NMR (C6D6)
d: 7.48–
(20). Yield 0(0.059 g, 21%) from 14. 1H NMR
d: 6.40 (dd, 1H, J 14.3,
7.40 (m, 2H, aromatic), 6.76–6.70 (m, 2H, aromatic), 4.50–4.41 (m,
2H, H-5a, H-5b), 3.90 (t, 2H, J 7.0 Hz, H-1a, H-1b), 2.00 (bt, 2H, J
6.9 Hz, H-2a, H-2b), 1.20 (d, 2H, J 1.0 Hz H-4a, H-4b), ꢂ0.14 (s, 9H,
6.7 Hz, H-1 ), 5.98 (dt, 1H, J 18.7, 6.2 Hz, H-300), 5.69 (dt, 1H, J 18.7,
1.5 Hz, H-400), 5.27 (dd, 1H, J 3.6, 1.1 Hz, H-4), 4.35 (dd, 1H, J 14.3,
2.2 Hz, H-20a), 4.21 (dd, 1H, J 6.7, 2.2 Hz, H-20b), 3.44–3.37 (m, 1H,
H-100a), 3.28–3.21 (m, 1H, H-100b), 3.10 (dd, 1H, J 14.8, 3.6 Hz, H-3a),
2.85 (d, 1H, J 14.8 Hz, H-3b), 2.49–2.36 (m, 2H, H-200a, H-200b), 0.92
TMS); 13C NMR
d: 141.7, 135.2, 129.1, 129.0, 127.8, 127.6, 127.5, 109.7,
68.6, 37.0, 26.5, ꢂ1.9. IR (neat)
n: 2956, 1637, 1478, 1366, 1186,
853 cmꢂ1
.
HRMS (ESI): calcd for C14H21O3NaSiSCl [MþNa]þ:
(s, 9H, TMS), 0.55 (q, 6H, J 7.9 Hz, 3ꢁCH2); 13C NMR
d
: 165.3, 147.7,
355.0561; found: 355.0579.
143.8, 129.7, 91.2, 80.2, 44.8, 39.8, 35.3, 7.31, 3.4. IR (neat) n 2953,
1774, 1619, 1195 cmꢂ1
. HRMS (ESI): calcd for C15H27NO2NaSi
4.2.1.4. 3-[(Dimethylphenylsilyl)methyl]but-3-enyl 4-chlorobenz-
[MþNa]þ: 304.1703; found: 304.1698.
enesulfonate (18). Yield (0.200 g, 91%) from 12. 1H NMR
d: 7.82–7.78
(m, 2H, aromatic), 7.54–7.44 (m, 4H, aromatic), 7.38–7.30 (m, 3H,
aromatic,), 4.60 (br s, 1H, H-4a), 4.58–4.55 (m, 1H, H-4b), 4.03–
4.07 (m, 2H, H-2a, H-2b), 2.10–2.04 (m 2H, H-1a, H-1b), 1.66 (d,
4.3.2. (Z)-1-(600-Trimethylsilylhex-400-enyl)-4-vinyloxyazetidin-2-one
(21). Yield (0.139 g, 52%) from 15. 1H NMR
: 6.39 (dd, 1H, J 14.3,
d
6.7 Hz, H-10), 5.46–5.40 (m, 1H, H-400), 5.26 (dd, 1H, J 3.6, 1.1 Hz, H-
4), 5.25–5.19 (m, 1H, H-500), 4.34 (dd, 1H, J 14.3, 2.2 Hz, H-20a), 4.20
(dd, 1H, J 6.7, 2.2 Hz, H-20b), 3.27–3.16 (m, 2H, H-100a, H-100b), 3.12
(dd, 1H, J 14.8, 3.6 Hz, H-3a), 2.85 (d, 1H, J 14.8 Hz, H-3b), 2.22 (dq,
2H, J 0.7 Hz, H-5a, H-5b), 0.28 (s, 6H, 2ꢁCH3); 13C NMR
d: 141.1,
140.4, 133.5, 129.5ꢁ2, 129.3, 129.2, 127.8, 110.7, 69.1, 36.9, 26.1, -0.0,
ꢂ3.2. IR (neat)
n
: cmꢂ1 2958, 1636, 1365, 1186, 832 cmꢂ1. HRMS

3908
B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
2H, J 7.5, 1.3 Hz, H-200a, H-200b), 1.70–1.55 (m, 2H, H-300a, H-300b), 1.45
(ESI): calcd for
288.1391.
C
14H23NO2NaSi [MþNa]þ: 288.1363; found:
(dd, 2H, J 8.6, 1.0 Hz, H-600a, H-600b), ꢂ0.1 (s, 9H, TMS); 13C NMR
d:
165.3, 147.8, 126.7, 125.7, 91.1, 80.2, 44.8, 40.6, 28.1, 24.5, 18.5, ꢂ1.8.
IR (CHCl3)
n
: 2957, 1759, 1642, 1621, 855 cmꢂ1. HRMS (ESI): calcd for
4.4. Oxidation of the vinyloxy group to the acetoxy one.
General procedure
C14H25NO2NaSi [MþNa]þ: 290.1547; found: 290.1550.
4.3.3. 1-[200-(Trimethylsilylmethyl)-prop-200enyl]-4-vinyloxyazetidin-
PCC on silica gel (2.2 g, 3 mmol/g) was added to a solution of 1-
alkyl-4-vinyloxyazetidin-2-one (1.0 mmol) in dry CH2Cl2 (20 mL).
The reaction mixture was refluxed for 3 h and then filtered through
Celite and evaporated to dryness. Flash chromatography (20% ethyl
acetate/hexane) afforded pure products.
2-one (22). Yield (0.072 g, 30%) from 9. 1H NMR
d: 6.38 (dd, 1H, J
14.2, 6.7 Hz, H-10), 5.26 (dd, 1H, J 3,6, 1.0 Hz, H-4), 4.78 (d, 1H, J
1.2 Hz, H-400a), 4.72 (br s, 1H, H-400b), 4.37 (dd, 1H, J 14.2, 2.2 Hz,
H-20a), 4.18 (dd, 1H, J 6.7, 2.2 Hz, H-20b), 3.90 (d, 1H, J 15.8 Hz, H-
100a), 3.52 (d, 1H, J 15.8 Hz, H-100b), 3.18 (dd, 1H, J 14.9, 3.7 Hz, H-
3a), 2.91 (d, 1H, J 14.9 Hz, H-3b), 1.58–1.43 (m, 2H, H-300a, H-300b),
4.4.1. (Z)-4-Acetoxy-1-(600-trimethylsilylhex-400-enyl)-azetidin-2-one
0.05 (s, 9H, TMS); 13C NMR
d
: 165.6, 148.2, 141.1, 110.6, 91.1, 79.9,
(27). Yield (0.175 g, 62%) from 21. 1H NMR
d: 5.98 (dd, 1H, J 3.9,
47.0, 44.8, 24.2, ꢂ1.5. IR (CH2Cl2)
n
: 2955, 1774, 1640, 1621 cmꢂ1
.
1.2 Hz, H-4), 5.46–5.39 (m, 1H, H-500), 5.25–5.18 (m, 1H, H-400), 3.27
(ddd,1H, J 14.2, 8.3, 6.8 Hz, H-100a), 3.21 (dd,1H, J 15.0, 4.0 Hz, H-3a),
3.11 (ddd, 1H, J 14.1, 8.2, 6.1 Hz, H-100b), 2.89 (d, 1H, J 15.0 Hz, H-3b),
2.10 (s, 3H, Ac), 2.03–1.97 (m, 2H, H-300a, H-300b), 1.69–1.54 (m, 2H,
H-200a, H-200b), 1.44 (br d, 2H, J 8.6 Hz, H-600a, H-600b), ꢂ0.01 (s, 9H,
HRMS (ESI): calcd for C12H21NO2NaSi.[MþNa]þ: 262.1234; found:
262.1241.
4.3.4. 1-[(200-Dimethylphenylsilylmethyl)-prop-200enyl]-4-vinyl-
oxyazetidin-2-one (23). Yield (0.238 g, 79%) from 16. 1H NMR
d:
TMS); 13C NMR
d: 170.7,165.3,126.7,125.7, 76.1, 44.6, 41.0, 28.1, 24.4,
7.53–7.49 (m, 2H, aromatic), 7.37–7.34 (m, 3H, aromatic), 6.31 (dd,
1H, J 14.2, 6.7 Hz, H-10), 5.14 (dd, 1H, J 3.6, 1.0 Hz, H-4), 4.75 (d, 1H, J
1.3 Hz, H-100a), 4.70 (br s, 1H, H-100b), 4.32 (dd, 1H, J 14.2, 2.2 Hz, H-
20a), 4.16 (dd, 1H, J 6.6, 2.2 Hz, H-20b), 3.72 (d, 1H, J 15.7 Hz, H-400a),
3.40 (d, 1H, J 15.7 Hz, H-400b), 3.12 (dd, 1H, J 14.8, 3.6 Hz, H-3a), 2.86
(d, 1H, J 14.8, H-3b), 1.72 (ABq, 2H, J 13.9 Hz, H-300a, H-300b), 0.33 (s,
20.9, 18.6, ꢂ1.8. IR (CHCl3)
n
: 1763, 1252, 1038, 856 cmꢂ1. HRMS
(ESI): calcd for C14H25NO3NaSi [MþNa]þ: 306.1496; found:
306.1509.
4.4.2. 4-Acetoxy-1-[(200-dimethylphenylsilyl-methyl)-prop-200-enyl]-
azetidin-2-one (28). Yield (0.237 g, 75%) from 23. 1H NMR
d: 7.54–
6H, 2ꢁCH3); 13C NMR
d
: 165.5, 148.2, 140.6, 138.1,133.6,129.2, 127.9,
: 2957, 1771,
HRMS (ESI): calcd for
7.49 (m, 2H, aromatic), 7.37–7.34 (m, 3H, aromatic), 5.93 (dd, 1H, J
1.3, 4.0 Hz, H-4), 4.75 (q, 1H, J 1.2 Hz, H-400a), 4.66 (q, 1H, J 1.2 Hz, H-
400b), 3.62 (d, 1H, J 16.0 Hz, H-10a), 3.48 (d, 1H, J 16.0, Hz, H-10b), 3.23
(dd,1H, J 15.0, 4.0 Hz, H-3a), 2.91 (d,1H, J 15.0 Hz, H-3b), 2.04 (s, 3H,
CH3), 1.72 (ABq, 2H, J 13.9 Hz, H-300a, H-300b), 0.34 (s, 3H, CH3), 0.33
111.4, 91.0, 79.9, 47.1, 44.8, 23.4, ꢂ3.0, ꢂ3.2. IR (neat)
n
1640, 1621. 1392, 1195, 837 cmꢂ1
.
C17H23NO2NaSi [MþNa]þ: 324.1390; found: 324.1386.
4.3.5. 1-[(300-Trimethylsilylmethyl)-but-300-enyl]-4-vinyloxyazetidin-
(s, 3H, CH3); 13C NMR
110.5, 76.1, 47.6, 44.7, 23.5, 20.7–3.2, ꢂ3.1. IR (neat)
d
: 170.5,165.4, 140.8, 138.2, 133.6, 129.2, 127.8,
: 2957, 1777,
1750, 1391, 1235, 1038, 837 cmꢂ1
. HRMS (ESI): calcd for
2-one (24). Yield (0.076 g, 30%) from 17. 1H NMR
d: 6.40 (dd, 1H, J
n
14.3, 6.7 Hz, H-10), 5.29 (dd, 1H, J 3.6, 1.2 Hz, H-4), 4.65 (q, 1H, J 2.8,
1.4 Hz, H-500a), 4.61 (br s, 1H, H-500b), 4.36 (dd 1H, J 14.3, 2.2 Hz, H-
20a), 4.21 (dd 1H, J 6.7, 2.2 Hz, H-20b), 3.44 (ddd, 1H, J 14.5, 8.1,
6.7 Hz, H-10a), 3.28 (ddd, 1H, J 14.5, 7.3, 0.8 Hz, H-10b), 3.11 (dd, 1H, J
14.8, 3.6 Hz, H-3a), 2.85 (d,1H, J 14.8 Hz, H-3b), 2.31–2.15 (m, 2H, H-
200a, H-200b), 1.58–1.50 (m, 2H, H-400a, H-400b), 0.22 (s, 9H, TMS); 13C
C17H23NO3NaSi [MþNa]þ: 340.1355; found: 340.1355.
4.4.3. 4-Acetoxy-1-(200-methyl-prop-200-enyl)-azetidin-2-one
(29). Yield 0.011 g, 6%. 1H NMR
d: 6.01 (dd, 1H, J 1.3, 4.0 Hz, H-4),
4.90–4.85 (m, 2H, H-100a, H-100b), 3.82–3.69 (m, 2H, H-40a, H-40b),
NMR
d
: 165.2, 147.8, 144.0, 109.2, 91.2, 80.3, 44.8, 39.0, 36.3, 26.5,
3.28 (dd, 1H, J 15.0, 4.0 Hz, H-3a), 2.96 (d, 1H, J 15.0 Hz, H-3b), 2.08
ꢂ1.4. IR (neat)
n
: 2955, 1771, 1194, 850 cmꢂ1. HRMS (ESI): calcd for
(s, 3H, Ac), 1.73 (s, 3H, CH3); 13C NMR
d: 170.7, 165.5, 139.7, 113.2,
C13H23NO2NaSi [MþNa]þ: 276.1390; found: 276.1385.
76.1, 47.3, 44.7, 20.7, 20.2. IR (neat) n: 2922, 1774, 1750, 1393, 1234,
1037, 922 cmꢂ1. HRMS (ESI): calcd for C9H13NO3Na [MþNa]þ:
4.3.6. 1-[(300-Dimethylphenylsilylmethyl)-but-300-enyl]-4-vinyl-
206.0788; found: 206.0778.
oxyazetidin-2-one (25). yield (0.095 g, 30%) from 18. 1H NMR
d:
7.52–7.48 (m, 2H, aromatic), 7.37–7.34 (m, 3H, aromatic), 6.33 (dd,
1H, J 14.3, 6.7 Hz, H-10), 5.16 (dd,1H, J 3.7,1.0 Hz, H-4), 4.66–4.65 (m,
1H, H-500a), 4.61 (br s, 1H, H-500b), 4.33 (dd, 1H, J 14.3, 2.2 Hz, H-20a),
4.19 (dd, 1H, J 6.7, 2.2 Hz, H-20b), 3.36 (dt, 1H, J 14.3, 7.6 Hz, H-100a),
3.17 (dt, 1H, J 14.3, 7.2 Hz, H-100b), 3.07 (dd, 1H, J 14.8, 3.6 Hz, H-3a),
2.81 (br d, 1H, J 14.8, H-3b), 2.11–2.04 (m, 2H, H-200a, H-200b), 1.77
(dd, 2H, J 0.8, 3.2 Hz, H-400a, H-400b), 0.311 (s, 3H, CH3), 0.308 (s, 3H,
4.4.4. 4-Acetoxy-1-(600-trimethylsilylhex-400-ynyl)-azetidin-2-one
(30). Yield (0.210 g, 75%) from 26. 1H NMR
d: 5.99 (dd, 1H, J 3.9,
1.2 Hz, H-4), 3.38–3.31 (m, 1H, H-10a), 3.23 (dd, 1H, J 14.8, 3.7 Hz, H-
3 a), 3.23–3.19 (m, 1H, H-10b), 2.89 (d, 1H, J 14.8 Hz, H-3b), 2.23–2.18
(m, 2H, H-20a, H-20b), 2.12 (s, 3H, Ac), 1.79–1.70 (m, 2H, H-30a, H-
30b), 1.41 (t, 2H, J 2.7 Hz, H-60a, H-60b); 13C NMR
d: 170.6, 165.3, 78.5,
77.0, 76.2. 44.7, 40.6, 27.8, 20.9, 16.6, 6.9, ꢂ2.1. IR (CHCl3)
n: 2959,
CH3); 13C NMR
80.1, 44.7, 38.7, 36.0, 25.7, ꢂ3.0, ꢂ3.1. IR (neat)
d
: 165.2, 147.7, 138.6, 133.6, 129.1, 127.8, 109.9, 91.1,
: 2961, 1760, 1641,
HRMS (ESI): calcd for C18H25NO2NaSi
1764, 1400, 1039, 853 cmꢂ1. HRMS (ESI): calcd for C14H23NO3NaSi
n
[MþNa]þ: 304.1339; found: 304.1325.
1402, 1195, 837 cmꢂ1
.
[MþNa]þ: 338.1547; found: 338.1560.
4.4.5. 4-Formyloxy-1-(600-trimethylsilylhex-400-ynyl)-azetidin-2-one
(31). A solution of 26 (0.280 g, 1.05 mmol) in CH2Cl2 (5 mL) was
placed in a three-necked flask equipped with a thermometer,
bubbling tube, and ozone outlet. The solution was stirred and upon
cooling to ꢂ78 ꢀC ozone was bubbled. After about 15 min TLC
showed the disappearance of substrate, and the solution turned
light blue. The ozone generator was switched off, and oxygen was
passed through the solution for 5 min to remove the excess of
ozone. Dimethyl sulfide (0.5 mL) was added in one portion and
stirring was continued at ꢂ78 ꢀC for 20 min. Subsequently the re-
action mixture was slowly brought to room temperature and the
4.3.7. (600-Trimethylsilyl-hex-400-ynyl)-4-vinyloxyazetidin-2-one
(26). Yield (0.153 g, 58%) from 19. 1H NMR
d: 6.40 (dd, 1H, J 14.3,
6.7 Hz, H-10), 5.27 (dd, 1H, J 3.6, 1.1 Hz, H-4), 4.25 (dd, 1H, J 14.3,
2.2 Hz, H-20a), 4.21 (dd, 1H, J 6.7, 2.2 Hz, H-20b), 3.32 (br d, 2H, J
7.3 Hz, H-100a, H-100b), 3.13 (dd, 1H, J 14.8, 5.6 Hz, H-3a), 2.86 (br d,
1H, J 14.8 Hz, H-3b), 2.25–2.18 (m, 2H, H-200a, H-200b), 1.83–1.69 (m,
2H, H-300a, H-300b), 1.42 (t, 2H, J 2.7 Hz, H-600a, H-600b), 0.09 (s, 9H,
TMS); 13C NMR
16.7, 6.9, ꢂ2.1. IR (neat)
d
: 165.4, 147.8, 91.1, 80.4, 78.6, 77.1, 44.8, 40.2, 27.8,
n
: 2956, 2221, 1770, 1641, 1621 cmꢂ1. HRMS

B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
3909
solvent was evaporated. Purification on silica gel (20% ethyl acetate/
hexane) gave 31 (0.210 g, 77.0%). 1H NMR
: 8.1 (br s, 1H, CHO), 6.3–
36% yield: 1H NMR
d
: 6.04 (dt, 1H, J 16.8,10.2 Hz, H-9), 5.20–5.14 (m,
d
2H, H-10a, H-10b), 3.84–3.78 (m, 1H, H-2a), 3.52 (dt, 1H, J 4.7,
2.0 Hz, H-6), 2.88 (ddd, 1H, J 14.6, 4.7, 1.9 Hz, H-7a), 2.82–2.75 (m,
1H, H-2b), 2.77 (dd, 1H, J 14.6, 1.9 Hz, H-7b), 2.57 (m, 1H, H-5), 1.90–
6.0 (m, 1H, H-4), 3.38 (dt, 1H, J 14.3, 7.3 Hz, H-100a), 3.29 (dd, 1H, J
15.1, 3.9 Hz, H-3a), 3.24 (dt, 1H, J 14.3, 6.9 Hz, H-100b), 2.94 (d, 1H, J
15.1 Hz, H-3b), 2.23–2.19 (m, 2H, H-200a, H-200b), 1.95–1.72 (m, 2H,
H-300a, H-300b), 1.42 (t, 2H, J 2.7 Hz, H-600a, H-600b), 0.09 (9H, s, TMS);
1.68 (m, 3H, H-3a, H-3b, H-4a), 1.51–1.37 (m, 1H, H-4b); 13C NMR
165.5, 134.6, 117.8, 49.3, 41.0, 39.4, 38.3, 28.8, 18.3. IR (CHCl3)
d
:
:
n
13C NMR
d
: 165.0, 160.2, 78.7, 76.9, 76.2, 44.9, 40.7, 27.6, 16.6, 6.9,
2948, 1735, 1409, 1104 cmꢂ1. HRMS (ESI): calcd for C9H13NONa
ꢂ2.08. IR (CH2Cl2)
n
: 2956, 1775, 1730, 1397, 1157 cmꢂ1. HRMS (ESI):
[MþNa]þ: 174.0889; found: 174.0892.
calcd for C13H21NO3NaSi [MþNa]þ: 290.1183; found: 290.1197.
4.5.4. Cyclization of acetoxy compound 27. Cyclization was per-
formed analogously to the procedure described for 21 to afford
4.5. Cyclization. General procedure
compounds: (5R*,6R*)d34 (0.004 g, 27% yield) and (5S
*
,6R )d35
*
To a stirred solution of
b-lactam (0.1 mmol) in CH2Cl2 (2 mL) at
(0.005 g, 30%).
0 ꢀC or at ꢂ20 ꢀC was added Lewis acid (0.1 mmol). The reaction
mixture was brought to 20 ꢀC and kept at this temperature until
disappearance of substrate (TLC). The reaction was quenched by the
addition of saturated solution of NaHCO3 (2 mL) and stirring was
continued for 10 min. The organic phase was separated, washed
with water, dried (MgSO4), and evaporated. The crude product was
purified on silica gel.
4.5.5. 4-Chloro-4-methylo-1-azabicyclo[4.2.0]octan-8-one
(36). Cyclization of compound 24 or compound 25 was performed
according to the general method. From 24 (0.051 g, 0.2 mmol),
SnCl2/TMSCl catalysed 0.010 g, 30% yield. From 25 (0.063 g,
0.2 mmol) SnCl2/TMSCl catalysedd0.020 g, 57% yield, SnCl4 cata-
lysedd0.020 g, 57% yield. 1H NMR
d: 3.82 (dd, 1H, J 13.7, 5.9 Hz, H-
2a), 3.76–3.70 (m, 1H, H-6), 3.18 (ddd, 1H, J 1.6, 4.6, 14.6 Hz, H-7a),
3.11 (dddd, 1H, J 4.0, 1.5, 11.9, 13.7 Hz, H-2b), 2.60 (dd, 1H, J 1.6,
14.6 Hz, H-7b), 2.33 (ddd, 1H, J 1.5, 4.0, 13.6 Hz, H-5a), 1.91–1.86 (m,
1H, H-3a), 1.67 (s, 3H, CH3), 1.62 (ddd, 1H, J 14.0, 11.8, 5.9 Hz, H-3b),
4.5.1. 5-Methyl-3-methylene-6-oxa-1-azabicyclo[5.2.0]nonan-9-one
(32). Obtained according to the general procedure. SnCl2/TMSCl
catalysedd0.015 g, 88% yield from 22 (0.024 g, 0.1 mmol), 0.008 g,
50% from 23 (0.031 g, 0.1 mmol); Yb(OTf)3 catalysedd0.012 g, 70%
yield from 22 (0.024 g, 0.0 mmol), 0.009 g, 57% from 23 (0.031 g,
1.41 (dd, 1H, J 10.2, 13.6 Hz, H-5b); 13C NMR
d: 166.0, 68.2, 44.8,
44.4, 44.3, 38.9, 35.7, 34.1. IR (neat)
n 2929, 1750, 1390, 1135, 786,
0.1 mmol). 1H NMR
d
: 5.03 (br d, 2H, J 8.5 Hz, H-10), 4.94 (dd, 1H, J
561 cmꢂ1. HRMS (ESI): calcd for C8H12NONaCl [MþNa]þ: 196.0500;
3.8, 0.8 Hz, H-7), 4.09 (br d, 1H, J 13.6 Hz, H-2a), 3.80 (br d, 1H, J
13.6 Hz, H-2b), 3.62–3.51 (m, 1H, H-5), 3.06 (ddd, 1H, J 14.6, 3.8,
2.0 Hz, H-8a), 2.78 (dd, 1H, J 14.6, 1.0 Hz, H-8b), 2.53 (d, 1H, J
13.7 Hz, H-4a), 2.20 (dd, 1H, J 13.6, 9.8 Hz, H-2b), 1.30 (d, 1H, J
found 196.0498.
4.5.6. 1-Azabicyclo[4.2.0]oct-4-en-4-methyl-8-one (37a) and 1-aza-
bicyclo[4.2.0]oct-3-en-4-methyl-8-one (37b). Cyclization of com-
pound 25 (0.063. 0.2 mmol) was performed according to the
general method. Catalysed Yb(OTf)3 afforded less polar product
compound 37a, 0.006 g, 21% yield and more polar product 37b,
0.008 g, 28% yield.
6.3 Hz, H-11); 13C NMR
d: 165.7, 141.0, 118.1, 80.7, 79.1, 49.0, 46.5,
44.0, 22.1. IR (neat) n
2924, 1766, 1385, 1079 cmꢂ1. HRMS (EI): calcd
for C9H13NO2 (Mþ): 167.0946; found: 167.0940.
4.5.2. 1-Azabicyclo[4.2.0]oct-4-en-8-one (33). Cyclization of com-
pound 20 (0.028 g, 0.1 mmol) was performed according to the
general procedure. SnCl2/TMSCl catalysedd0.010 g, 78% yield,
4.5.7. 1-Azabicyclo[4.2.0]oct-4-en-4-methyl-8-one (37a). 1H NMR
d:
5.64 (br s, 1H, H-5), 3.92 (dd, 1H, J 13.8, 7.8 Hz, H-2a), 3.85–3.83 (m,
1H, H-6), 3.14 (ddd, 1H, J 14.6, 5.1, 0.8 Hz, H-7a), 2.84 (dddd, 1H, J
13.8, 10.6, 5.5, 0.7 Hz, H-2b), 2.53 (dd,1H, J 14.6, 2.2 Hz, H-7b), 2.38–
SnCl4 catalysedd0.005 g, 44% yield. 1H NMR
d: 5.94–5.92 (m,1H, H-
5), 5.90–5.87 (m, 1H, H-4), 3.93 (dd, 1H, J 13.8, 7.8 Hz, H-2a), 3.91–
3.88 (m,1H, H-6), 3.19 (ddd,1H, J 14.7, 5.2, 0.9 Hz. H-7a), 2.89 (dddd,
1H, J 13.8, 10.5, 5.5, 0.5 Hz, H-2b), 2.61 (dd, 1H, J 14.7, 2.3 Hz, H-7b),
2.26 (m, 1H, H-3a), 1.89–1.81 (m, 1H, H-3b), 1.72 (br s, 3H, CH3); 13
C
NMR
d
: 169.8, 134.7, 120.9, 45.2, 43.8, 36.6, 28.3. 24.1. IR (CH2Cl2)
n
2.36–2.37 (m, 1H, H-3a), 2.07–2.00 (m, 1H, H-3b); 13C NMR
d
: 176.6,
: 5.40–
2925, 1730, 1025, 996 cmꢂ1. HRMS (EI): calcd for C8H11NO [M]þ:
137.0841; found 137.0843.
127.1, 127.0, 45.0, 43.4, 36.5, 23.5; 1H NMR (500 MHz, C6D6)
d
5.34 (m, 2H, H-4, H-5), 3.65 (dd, 1H, J 13.7, 7.7 Hz, H-2a), 3.23–3.18
(m,1H, H-6), 2.64 (ddd,1H, J 14.5, 5.3, 0.7 Hz., H-7a), 2.29 (dddd,1H,
J 13.6, 10.6, 5.0, 0.7 Hz, H-2b), 2.15 (dd, 1H, J 14.5, 2.3 Hz, H-7b),
4.5.8. 1-Azabicyclo[4.2.0]oct-3-en-4-methyl-8-one (37b). 1H NMR
d:
5.43–5.39 (m, 1H, H-3), 4.09–4.02 (m, 1H, H-2a), 3.49–3.41 (m, 2H,
H-6, H-2b), 3.20 (ddd, 1H, J 14.5, 4.4, 2.0 Hz. H-7a), 2.54 (dd, 1H, J
14.5, 1.5 Hz, H-7b), 2.26 (dd, 1H, J 14.8, 5.1 Hz, H-5a), 2.09–2.01 (m,
2.00–1.91 (m, 1H, H-3a), 1.32–1.25 (m, 1H, H-3b). IR (CH2Cl2) n:
2927, 1756, 1378, 1097 cmꢂ1. HRMS (EI): calcd for C7H9NO [M]þ:
123.0684; found 123.0680.
1H, H-5b), 1.75 (br s, 3H, CH3); 13C NMR
d
: 167.1, 131.3, 116.1, 45.0,
: 2926, 1750, 1389, 866 cmꢂ1
HRMS (EI): calcd for C8H11NO [M]þ: 137.0846; found 137.0846. 1H
NMR (500 MHz, C6D6) : 4.85 (br s, 1H, H-3), 3.95–3.84 (m, 1H, H-
45.4, 38.5, 33.7, 24.2. IR (CH2Cl2)
n
.
*
4.5.3. (5R ,6R
*
)
and (5S
*
,6R )-5-Vinyl-1-azabicyclo[4.2.0]octan-8-
*
one (34 and 35). Cyclization of compound 21 (0.053 g, 0.2 mmol)
d
was performed according to the general procedure. TiF4 catalysed
2a); 3.04–2.96 (m, 1H, H-2b), 2.76–2.71 (m, 1H, H-6); 2.67 (ddd, 1H,
J 14.1, 4.6, 1.9 Hz, H-7a), 2.01 (dd, 1H, J 14.1, 1.4 Hz, H-7b), 1.51–1.45
(m, 1H, H-5a), (s, 3H, CH3), 1.34–1.22 (m, 1H, H-5b).
reaction afforded as less polar product (5R
cyclo[4.2.0]octan-8-one (34) in 0.010 g, 32% yield: 1H NMR
(500 MHz, C6D6) : 5.27 (ddd, 1H, J 17.4, 10.5, 7.0 Hz, H-9), 4.79 (ddd,
*
,6R
*
)-5-vinyl-1-azabi-
d
1H, J 10.4, 1.5, 1.1 Hz, H-10a), 4.71 (ddd, 1H, J 17.4, 1.5, 0.6 Hz, H-10b),
3.58–3.52 (m, 1H, H-2a), 2.65 (ddd, 1H, J 14.3, 4.6, 1.7 Hz, H-7a), 2.45
(ddd, 1H, J 9.6, 4.7, 1.8 Hz, H-6), 2.25 (dd, 1H, J 14.3, 1.8 Hz, H-7b),
2.1–2.0 (m, 1H, H-2b), 1.40–1.33 (m, 1H, H-5), 1.32–1.26 (m, 1H, H-
4.5.9. 4-Methylene-1-azabicyclo[4.2.0]octan-8-one (37c). Selected
signals taken from the spectrum of a crude post-reaction mixture:
1H NMR
d: 4.90–4.88 (m, 2H,]CH2), 3.96 (dd, 1H, J 13.0,.6.6 Hz, H-
2), 3.38 (ddd, 1H, J 10.5, 1.0, 4.5 Hz, H-6), 3.13 (ddd, 1H, J 14.5, 4.5,
1.8 Hz, H-7a), 2.65 (dd, 1H, J 14.5, 1.6 Hz, H-7b).
4a), 1.03–0.91 (m, 2H, H-3), 0.74–0.65 (m, 1H, H-4b); 13C NMR
164.6, 138.9, 115.0, 51.0, 46.5, 44.3, 38.1, 28.7, 24.9. IR (CHCl3)
d
:
:
n
2946,1734, 1411,1396, 1094 cmꢂ1. HRMS (ESI): calcd for C9H13NONa
4.5.10. 5-Vinylidene-1-azabicyclo[4.2.0]octan-8-on (38). Cyclization
of compound 26 (0.053 g, 0.2 mmol) was performed according to
the general method, TiF4 catalysedd0.017 g, 56% yield. From
[MþNa]þ: 174.0889; found: 174.0883. More polar product:
(5S
*
,6R )-5-vinyl-1-azabicyclo[4.2.0]octan-8-one (35) in 0.011 g,
*

3910
B. Grzeszczyk et al. / Tetrahedron 66 (2010) 3904–3911
compound 30 (0.056 g, 0.2 mmol), TiF4 catalysed, 38 was obtained
in 0.018 g, 61% yield. 1H NMR
: 4.86 (dt, 1H, J 10.3, 3.8 Hz, H-10a),
H-100a, H-100b); 13C NMR
30.9, 27.2, 20.9. IR (CH2Cl2)
d: 170.8, 165.4, 137.2, 115.4, 76.1, 44.9, 40.7,
d
n: 2955, 1772, 1749, 1399, 1225,
4.73 (ddt, 1H, J 10.3, 4.3, 0.5 Hz, H-10b), 3.96–3.90 (m, 1H, H-6), 3.83
(dd, 1H, J 13.7, 5.5 Hz, H-2a), 3.12 (ddd, 1H, J 14.6, 4.6, 1.7 Hz, H-7a),
2.87 (dd, 1H, J 14.6, 1.9 Hz, H-7b), 2.76 (dddd, 1H, J 13.7, 12.1, 4.3,
1.7 Hz, H-2b), 2.46–2.24 (m, 1H, H-4a), 2.17–2.09 (m, 1H, H-4b),
1037 cmꢂ1
.
HRMS (ESI): calcd for C10H15NO3Na [MþNa]þ:
220.0944; found: 220.0936.
4.5.15. (E)-4-Acetoxy-1-(600-trimethylsilylhex-400-enyl)azetidin-2-one
(43). Compound 42 (0.035 g, 0.18 mmol) was dissolved in CH2Cl2
(10 mL) and trimethylallylsilane (0.14 mL) and Grubbs catalyst
second generation (5 mg) was added. The reaction mixture was
refluxed for 12 h. Evaporation of solvent and flash chromatography
of the residue afforded product 43 as an oil (0.038 g, 75%). 1H NMR
1.76–1.70 (m, 1H, H-3a), 1.66–1.57 (m, 1H, H-3b); 13C NMR
d
: 202.8,
167.3, 99.4, 77.1, 47.7, 43.7, 39.2, 27.6, 25.9. IR (CH2Cl2)
n: 2952, 2923,
1962, 1748, 1384, 848 cmꢂ1. HRMS (ESI): calcd for C9H11NONa
[MþNa]þ: 172.0733; found: 172.0729.
4.5.11. 5-Vinylidene-1-azabicyclo[4.2.0]octan-8-on (38) and 5-(2-
trimethylsilylvinylidene)-1-azabicyclo-[4.2.0]octan-8-on
(39). Cyclization of compound 26 (0.053 g, 0.2 mmol) was per-
formed according to the general method. Yb(OTf)3 catalysed pro-
vided 38 in 0.016 g, 50% yield, and 39 in 0.013 g, 29%. From 31
(0.054 g, 0.2 mmol) using Yb(OTf)3 as a catalyst compounds 38
(0.012 g, 38%) and 39 (0.003 g, 7%) were obtained NMR spectrum of
d
: 5.98 (dd, 1H, J 1.2, 3.9 Hz, H-4), 5.44–5.37 (m, 1H, H-40), 5.26–5.17
(m, 1H, H-50), 3.32–3.18 (m, 2H, H-10a, H-3a), 3.15–3.05 (m, 1H, H-
10b), 2.89 (d, 1H, J 15.0 Hz, H-3b), 2.10 (s, 3H, OAc), 2.03–1.96 (m, 2H,
H-30a, H-30b), 1.68–1.54 (m, 2H, H-20a, H-20b), 1.46–1.38 (m, 2H, H-
60a, H-60b), 0.01 (s, 9H, TMS); 13C NMR
d
: 170.7, 165.4, 127.4, 127.0,
76.0, 44.6, 40.7, 30.1, 27.2, 20.9, 18.5, ꢂ2.0. IR (CH2Cl2) : 2955, 1777,
HRMS (ESI): calcd for
n
1751, 1247, 1223, 1036, 854; cmꢂ1
.
two diastereoisomers (39) in the approx. ratio 3:1. 1H NMR
d: 5.12
C14H25NO3NaSi [MþNa]þ: 306.1496; found. 306.1490.
(t, 1H J 4.5 Hz, H-10), 3.99–3.95 (m, 1H, H-6), 3.86 (bdd, 1H, J 13.5,
5.5 Hz, H-2a), 3.12 (ddd, 1H, J 14.6, 4.6, 1.7 Hz, H-7a), 2.85 (dd, 1H, J
14.6, 1.8, H-7b), 2.80–2.73 (m, 1H, H-2b), 2.44–2.38 (m, 1H, H-4a),
2.16–2.10 (m, 1H, H-4b), 1.77–1.69 (m, 1H, H-3a), 1.66–1.56 (m, 1H,
4.6. Cyclization of compound 43
Performed according to the procedure described for 27 afforded
H-3b); 13C NMR
d: 204.2, 93.0, 85.8, 77.2, 47.5, 43.6, 39.3, 27.1, 25.9,
(5R
*
,6R
*
) and (5S
*
,6R )-5-vinyl-1-azabicyclo[4.2.0]octan-8-one (34
*
0.03, 0.02, ꢂ0.9. IR (CH2Cl2)
n
2954, 1946, 1756 cmꢂ1. HRMS (ESI):
and 35) in a ratio of about 1.0:1.3.
calcd for C12H19NONaSi [MþNa]þ: 244.1128; found: 244.1126. Se-
lected 1H NMR data of the less abundant isomer: 5.06 (t, 1H, J
4.8 Hz, H-10), 3.13 (ddd, 1H, J 14.6, 4.6, 1.6 Hz, H-7a).
4.6.1. (E)-4-Acetoxy-1-(600-diethylsilylhex-400-enyl)-azetidin-2-one
bound to the resin (45). Compound 42 (0.17 g; 0.95 mmol) was
dissolved at CH2Cl2 (20 mL) and allylsilane resin 4422 (0.4 g) and
Grubbs catalyst second generation (0.005 g) was added and the
reaction mixture was refluxed overnight. Solvent was evaporated,
and the resin was washed with THF (3ꢁ2 mL), THF/H2O (1:1)
(3ꢁ2 mL), THF (3ꢁ2 mL), and CH2Cl2 (3ꢁ2 mL) and dried under
4.5.12. 5-Vinylidene-1-azabicyclo[4.2.0]octan-8-on (38) and 5-([10-
chloro-20-trimethylsilyl-ethylidene)-1-azabicyclo[4.2.0]octan-8-one
(40). Cyclization of compound 26 (0.032 g, 0.2 mmol) was per-
formed according to the general procedure. Using SnCl2/TMSCl,
compounds 38 (0.012 g, 43%), and 40 (0.010 g, 21%) were obtained.
Cyclization of 31 was performed according to the general method.
Using SnCl2/TMSCl compounds 38 (0.016 g, 53%) and 40 (0.008 g,
reduced pressure. IR (KBr)
n .
: 1777, 1751 cmꢂ1
4.6.2. (5R ,6R ) and (5S , 6R )-5-Vinyl-1-azabicyclo [4.2.0]octan-8-
*
*
*
*
17%) were obtained. 1H NMR
d: 4.21–4.18 (m, 1H, H-6), 3.69 (ddd,
one (34 and 35). A solution of SnCl2 (0.0095 g, 0.05 mmol) in
CH2Cl2 (1.5 mL) was cooled to ꢂ10 ꢀC and added TMSCl (25
1H, J 12.6, 9.0, 6.7 Hz, H-2a), 3.39 (ddd, 1H, J 15.0, 4.7, 1.8 Hz, H-7a),
3.0 (dddd, 1H, J 12.6, 6.3, 4.6, 1.7 Hz, H-2a), 2.81 (dd, 1H, J 15.0,
2.2 Hz, H-7b), 2.32 (ddd, 1H, J 15.3, 6.8, 3.1 Hz, H-4a), 2.18–2.12 (m,
1H, H-4b), 1.99 (br d, 1H, J 14.4 Hz, H-10a), 1.90 (br d, 1H, J 14.4 Hz,
H-10b),1.84–1.77 (m, 1H, H-3a),1.70–1.61 (m, 1H, H-3b), 0.09 (s, 9H,
mL,
0.2 mmol). After 10 min, when solution became clear (E)-1-(6-tri-
methylsilyl)hex-4-enyl-4-acetoxyazetidin-2-one resin (45) was
added. After 2 h the saturated solution of NaHCO3 (1 mL) was added
and stirring was continued for 10 min. The solvent was evaporated
and the resin was washed with H2O (2ꢁ1 mL) and CH2Cl2 (3ꢁ2 mL).
The crude product was purified on silica gel. Elution 30% Et2O in
CH2Cl2 gave mixture of diastereoisomers 34 and 35, 1.3:1.0,
respectively.
TMS); 13C NMR
d: 168.7, 127.9, 128.3, 48.9, 45.9, 38.5, 26.6, 26.3,
22.5, ꢂ1.0. IR (CH2Cl2)
n
: 2917, 1738, 1249, 851 cmꢂ1. HRMS (ESI):
calcd for C12H20NONaSiCl [MþNa]þ: 280.0895; found: 280.0903.
4.5.13. 1-(Pent-40-enyl)-4-vinyloxyazetidin-2-one (41). Compound
41 was obtained according to the general method of alkylation
Acknowledgements
0.129 g, 71% yield from 5-bromo-1-pentene. 1H NMR
d: 6.41 (dd,1H,
J 14.3, 6.7 Hz, H-10), 5.84–5.75 (m, 1H, H-400), 5.28 (dd, 1H, J 3.6,
1.0 Hz, H-4), 5.09–4.98 (m, 2H, H-500a, H-500b), 4.37 (dd, 1H, J 14.3,
2.2 Hz, H-20a), 4.22 (dd,1H, J 6.7, 2.2 Hz, H-20b), 3.30–3,19 (m, 2H, H-
300a, H-300b), 3.14 (dd, 1H, J 14.8, 3.6 Hz, H-3a), 2.88 (d, 1H, J 14.8, H-
3b), 2.14–2.08 (m, 2H, H-100a, H-100b), 1.77–1.66 (m, 2H, H-200a. H-
This work was supported by the Ministry of Education and
Science, grant PBZ-KBN-126/T09/08/2004.
Supplementary data
200b); 13C NMR
27.2. IR (neat)
d: 165.4, 147.7, 137.2, 115.5, 91.1, 80.3, 44.8, 40.3, 31.0,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.03.108.
n
: 2932, 1769, 1641, 1195 cmꢂ1. HRMS (ESI): calcd for
C10H15NO2Na [MþNa]þ: 204.0995; found: 204.1004.
References and notes
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42 was obtained according to the general procedure of oxidation of
the vinyloxy group to the acetoxy one, 0.154 g, 78% yield from 41
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