Indium-mediated selective introduction of a 1,3-butadien-2-yl group at the C4-position in 2-azetidinones and application of 1,3-diene-tethered 2-azetidinones in the diels-alder reaction

Article abstract of DOI:10.1002/chem.200700796

The reaction of 4-acetoxy-2-azetidinones with organoindium reagents generated in situ from indium and 1,4-dibromo-2-butyne in the presence of LiCl in DMF selectively produced 2-azetidinones which contain a 1,3-butadienyl-2-yl group at the C4-position in g

Full text of DOI:10.1002/chem.200700796

FULL PAPER
DOI: 10.1002/chem.200700796
Indium-Mediated Selective Introduction of a 1,3-Butadien-2-yl Group at the
C4-Position in 2-Azetidinones and Application of 1,3-Diene-Tethered
2-Azetidinones in the Diels–Alder Reaction
Kooyeon Lee and Phil Ho Lee*[a]
Abstract: The reaction of 4-acetoxy-2-azetidinones with organoindium reagents
generated in situ from indium and 1,4-dibromo-2-butyne in the presence of LiCl in
DMF selectively produced 2-azetidinones which contain a 1,3-butadienyl-2-yl
group at the C4-position in good yields. The Diels–Alder reaction of 4-[(1-methyl-
ene)prop-2-enyl]-2-azetidinones with a variety of dienophiles provided 2-azetidi-
nones with valuable functional-group-substituted six-membered rings at the C4-po-
sition in good yields.
Keywords: 1,3-butadien-2-ylation
azetidinones catalysis
Diels–Alder reactions · indium
·
·
·
Introduction
effort has been devoted to the selective introduction of
these groups by the reaction of 4-acetoxy-2-azetidinones
with a variety of organometallic nucleophiles.[2b] However,
introduction of a 1,3-butadien-2-yl and 1,3-butadien-1-yl
group on the 2-azetidinone ring has remained a formidable
challenge due to the tremendous further functionalization
through the Diels–Alder reactions. Recently, the selective
indium-mediated 1,3-butadien-2-ylation at the C3-position
of azetidine-2,3-dione was reported by Alcaide et al.[9] Al-
though 1,3-butadien-1-ylation at the C4-position of 2-azeti-
dinone from the reaction of allylsilane with 4-oxoazetidine-
2-carbaldehyde followed by dehydration,[10] [3,3]-Sigmatrop-
ic rearrangements in a-allenic methanesulfonates,[11] and
[2+2] cycloaddition of butadienylketene with various
imines[12] have been found, there is no synthetic method for
the direct introduction of the 1,3-butadien-2-yl group at the
C4-position of 2-azetidinone through substitution reactions
from 4-acetoxy-2-azetidinone.[13] Accordingly, we envisioned
the introduction of the 1,3-butadien-2-yl group at the C4-po-
sition of 2-azetidinone because 2-azetidinone, which has this
group, could be further functionalized through Diels–Alder
reactions to produce 2-azetidinones possessing various six-
membered rings at the C4-position. Described herein is a se-
lective introduction of a 1,3-butadien-2-yl group on the C4-
position of 2-azetidinone with organoindium reagents gener-
ated in situ from 1,4-dibromo-2-butyne (3) and indium as
well as the Diels–Alder reaction of 4-[(1-methylene)prop-2-
b-Lactam antibiotics, which are a large class of antibiotics
characterized by the presence of a 2-azetidinone ring,
proved to be therapeutic agents of unique effectiveness, con-
jugating a broad spectrum of activity with low toxicity.[1]
Therefore, introduction or transformation of functional
groups on the ring of 2-azetidinone, which is the core of the
biological activity, represents one of the most important en-
deavors in b-lactam chemistry.[2] Although introduction of
various heteroatoms, such as oxygen, halide, and nitrogen at
the C4-position of 2-azetidinone have been reported, the se-
lective introduction of carbon nucleophiles such as ethyn-
yl,[3] allyl,[4] vinyl,[4a,b] propargyl,[5] and allenyl[6] groups is a
mostly attractive and fundamental problem in the field of
carbapenem syntheses because further functionalization of
these groups has high possibilities for the construction of
the bicyclic nucleus.[7] Generally, it has been accomplished
as a result of the ability of 4-acetoxy-2-azetidinone to take
part in SN1reactions very easily at the C4-position via acyli-
minium or acylimine intermediates.[8] Therefore, a lot of
[a] Dr. K. Lee, Prof. Dr. P. H. Lee
National Research Laboratory of Catalytic Organic Reaction
Department of Chemistry and Institute for Basic Science
Kangwon National University
Chunchon 200–701(Republic of Korea)
Fax : (+82)33-253-7582
enyl]-2-azetidinones with
(Scheme 1).
a
variety of dienophiles
E-mail: phlee@kangwon.ac.kr
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 8877 – 8883
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8877

Among several reaction condi-
tions that were examined, the
best results were obtained with
the organoindium reagent,
which was generated in situ
from the reaction of 3.0 equiv-
alents
of
indium
with
2.5 equivalents of 3 in the pres-
ence of 3.0 equivalents of LiCl,
Scheme 1. 1,3-Buadien-2-ylation of 4-acetoxy-2-azetidinones and their application to the Diels–Alder reaction.
producing
4 in 77% yield
(DMF, 908C, 3 h, entry 16).
Results and Discussion
The use of indium in less than 3.0 equivalents and 1,4-dibro-
mo-2-butyne in less than 2.5 equivalents resulted in a slug-
gish reaction and gave lower yields as well as a longer reac-
tion time, indicating that the stoichiometry of indium and 3
is critically important for successful reactions. The use of
lithium chloride as an additive is very essential for good re-
sults (entries 9 and 13–17). DMF was the best solvent
among several reaction media (DMF, THF, H2O, H2O/THF,
CH3CN) that were screened.
In our initial study, optimum conditions for the introduction
of an indium-mediated 1,3-butadien-2-yl group at the C4-po-
sition of 2-azetidinones were examined by the reaction of
[3R
ACHTREUNG
A
ACHTREUNG
erated in situ from indium and 1,4-dibromo-2-butyne (3)
(Table 1). Reaction of 2 with 1.5 equivalents of 3 and
Encouraged by these results, we next examined the reac-
tion of 4-acetoxy-2-azetidinone (1) with an organoindium re-
agent generated in situ from indium and 3 under the opti-
mum conditions, producing 4-[(1-methylene)prop-2-enyl]-2-
azetidinone (5) in 76% yield (Scheme 2).
Table 1. Reaction optimization.[a]
Entry
In [equiv]
KI
3 [equiv]
Additive
Solvent
Yield [%][b]
[c]
13.0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
.5
1
THF
0
40
43
51
62
29
49
48
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
6.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
4.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
KI
KI
KI
KI
THF[c]
THF[c]
THF[d]
THF
Scheme 2. Reaction of 4-acetoxy-2-azetidinone with organoindium re-
agents.
KI
THF[e]
THF
KI[f]
–
To establish the synthetic potential of 1,3-diene-tethered
2-azetidinones, the Diels–Alder reactions of 4 and 5 with a
variety of dienophiles were examined (Table 2). Treatment
of 5 with 2.0 equivalents of 6e gave the desired adduct 7e in
88% yield (dr=1:1.6) in toluene at 1108C for 48 h (entry 6).
However, 7e was produced in a quantitative yield (dr=
1:1.6) in acetonitrile (25 8C, 24 h) in the presence of 5 mol%
InCl3 (entry 5). Exposure of 5 to maleimide (6d) afforded
7d in 72% yield under these conditions (entry 4).[14] Similar-
ly, the reaction of 5 with a variety of dienophiles, such as
THF
THF
H2O
KI
KI
KI
KI
LiBr
LiI
LiCl
LiCl
KI
68
0[g,h]
0[h]
20
H2O/THF[i]
CH3CN
THF
46
58
73
THF
THF
DMF
DMF
77[g,j]
66[k]
[a] Reactions were performed in the presence of additive (3 equiv) in
THF (2 mL). [b] Isolated yield. [c] THF (5 mL) was used. [d] THF
(3 mL) was used. [e] THF (1.5 mL) was used. [f] KI (2 equiv) was used.
[g] Reaction was heated at 908C. [h] Reaction time was 24 h. [i] H2O/
THF 1:1. [j] Reaction time was 3 h. [k] 1008C for 3 h.
tetra(cyano)ethylene (6a), dimethylacetylene dicarboxylate
G
(DMAD, 6b), and dimethyl fumarate (6c), gave rise to the
desired adducts in the presence of 5 mol% InCl3 in good to
excellent yields (CH3CN, 258C; entries 1–3).
Next, we turned our attention to the Diels–Alder reaction
of 4 with various dienophiles. Reaction of 4 with tetra-
3.0 equivalents of indium did not proceed in the presence of
KI as an additive in THF (entry 1). However, treatment of 2
with 3.0 equivalents of 3, 2.0 equivalents of indium, and
3.0 equivalents of KI selectively gave rise to the desired
product 4 in 62% yield (entry 5). No other isomeric prod-
ucts, especially in regard to the 1,3-butadienyl group, were
obtained in this reaction. Product yields were dependent on
the concentration of the reaction mixture (entries 3–6).
A
83% yields, respectively, in benzene at 838C (entries 7
and 8). Treatment of 4 with 4.0 equivalents of dimethyl fu-
marate (6c) and dimethyl maleate (6 f) furnished the Diels–
Alder adducts 7h (dr=1:1.5) and 7i (dr=1:1.9) in 96 and
95% yields, respectively (entries 9 and 10). Compound 4 re-
acted with maleimide (6d) to afford 7j in a quantitative
8878
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Chem. Eur. J. 2007, 13, 8877 – 8883

Indium Catalysis
FULL PAPER
Table 2. Diels–Alder reaction of 1,3-diene-tethered 2-azetidinones with dienophiles.[a]
Entry
1
Diene
Dienophile
T [8C]
t [h]
Product
Yield [%][b]
25
24
85[c]
2
3
5
5
25
25
48
24
83[c]
72[c,d]
4
5
25
24
72[c]
5
6
5
5
25
110
24
48
98[c,e]
88[e,f]
7
83
5
86[g]
8
4
4
4
83
83
83
48
48
48
83[g]
9
96[d,g,h]
10
95[d,g,i]
11
4
83
24
99[g]
12
13
4
4
25
110
24
48
93[c]
83[e]
14
15
16
4
4
4
110
25
25
48
48
48
89[e]
98[c]
56[j]
Chem. Eur. J. 2007, 13, 8877 – 8883
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8879

P. H. Lee and K. Lee
Table 2. (Continued)
Entry
Diene
Dienophile
T [8C]
t [h]
Product
Yield [%][b]
17
4
83
48
84[g]
[a] Dienophiles (2 equiv) were used. [b] Isolated yield. [c] CH3CH was used as a solvent in the presence of 5 mol% of InCl3. [d] Dienophile (4.0 equiv)
was used. [e] Diastereomeric ratio=1:1.6. [f] Toluene was used as a solvent. [g] Benzene was used as a solvent. [h] Diastereomeric ratio 1:1.5. See refer-
ence [14]. [i] Diastereomeric ratio=1:1.9. [j] DMF was used as a solvent and 5 mol% of InCl3 was used.
yield in benzene (838C, 24 h, entry 11). Reaction of 4 with
N-ethyl maleimide (6g) gave 7k in 83% yield (toluene,
1108C, 48 h, entry 13). However, the use of 5 mol% of InCl3
in acetonitrile accelerated the Diels–Alder reaction, produc-
ing 7k in 93% yield (entry 12). Refluxing 4 and 6e in tolu-
ene (1108C, 48 h) afforded the desired cycloadduct 7l in
89% yield (entry 14). Although compound 4 reacted with
6e to give the desired adduct 7l in 56% yield in the pres-
ence of 5 mol% of InCl3 (DMF, 258C, 48 h, entry 16), the
use of acetonitrile gave 7l in a quantitative yield (entry 15).
Compound 7l as a representative was characterized structur-
ally by using X-ray crystallography (Figure 1).[15] As shown
in entry 17, the Diels–Alder reaction with concomitant aro-
matization proceeded by treating 4 with 1,4-naphthoqui-
none, affording cycloadduct 7m in 84% yield (benzene,
838C, 48 h).
Figure 1. Projection of a molecule of compound 7l as determined by X-
Although the mechanism for the indium-mediated 1,3-bu-
tadien-2-ylation of 4-acetoxy-
2-azetidinones by using 1,4-di-
bromo-2-butyne has not been
established, a possible reaction
pathway is described in
Scheme 3.[16,9b] It may be rea-
sonable to postulate a metallo-
tropic rearrangement between
the propargylindium (8) and
allenylindium (9) reagents gen-
erated in situ from indium and
1,4-dibromo-2-butyne. The re-
actions of 8 and 9 with 4-ace-
toxy-2-azetidinones have trou-
ble with competing reactions.
Thus, both intermediates from
this equilibrium between 8 and
9 can react with the acylimines
11 obtained through the elimi-
ray crystallography.
Scheme 3. Plausible mechanism for the regioselective synthesis of 4-[(1-methylene)prop-2-enyl]-2-azetidinone.
nation of AcOH from 4-ace-
toxy-2-azetidinones 10, pro-
ducing 4-(2,3-butadien-1-yl)-2-
azetidinone 13 or 4-[(1-methylene)prop-2-enyl]-2-azetidi-
none 15. The formation of 2-azetidinones (13 and 15) is con-
sistent with participation of the six-membered cyclic transi-
tion structures 12 (path a) and 14 (path b), respectively. It
seems feasible to suggest that the regiochemical preference
observed for the indium-promoted reactions of 1,4-dibromo-
2-butyne with 4-acetoxy-2-azetidinones must be controlled
by steric effects. The isomerization of propargylindium to al-
lenylindium is presumably prohibited by the steric effect of
both InBrn substituents. Thus, the propargylindium reagent 8
A
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Chem. Eur. J. 2007, 13, 8877 – 8883

Indium Catalysis
FULL PAPER
0.6 (EtOAc/hexane 1:1); 1H NMR (400 MHz, CDCl3, 258C, TMS): d=
6.38 (dd, J=17.74, 11.12 Hz, 1H), 5.84 (s, 1H), 5.46 (d, J=17.72 Hz,
1H), 5.25 (d, J=9.69 Hz, 2H), 5.18 (d, J=11.12 Hz, 1H), 4.48 (d, J=
1.40 Hz, 1H), 4.29–4.23 (m, 1H), 2.95 (t, J=5.31Hz, 1H), 1.22 (d, J=
6.40 Hz, 3H), 0.89 (s, 9H), 0.09 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3, 258C, TMS): d=168.8, 145.2, 135.4, 115.3, 114.5, 66.0, 65.0, 50.3,
undergoes nucleophilic addition to the acylimine 11 to
afford exclusively allenyl compounds 14, which after protio-
deindation provided 4-[(1-methylene)prop-2-enyl]-2-azetidi-
nones 15 through path b (Scheme 3).
The stereochemistry of 1,3-diene-tethered 2-azetidinone
at the C4-position for compounds 4 was assigned by analysis
of the coupling constants in the NMR spectra. The stereose-
lectivity in the addition reaction of an organoindium reagent
generated in situ from indium and 3 with 4-acetoxy-2-azeti-
dinones 2 is believed to be controlled by the bulky 1-(tert-
butyldimethylsilyloxy)ethyl group at the C3-position, in
which one face of the iminyl group is blocked, thus the orga-
noindium reagent is delivered to the less-hindered face.[15b]
25.7, 22.8, 17.9, À4.3, À4.9 ppm; IR (film): n˜ =3176, 2926, 1757, 776 cmÀ1
.
4-[(1-Methylene)prop-2-enyl]azetidin-2-one (5): Compound 5 was pro-
duced by a similar procedure to that described for the preparation of 4.
M.p. 838C; Rf =0.4 (EtOAc/hexane 1:1); 1H NMR (400 MHz, CDCl3,
258C, TMS): d=6.41(dd, J=17.94, 11.07 Hz, 1H), 5.99 (s, 1H), 5.26 (s,
1H), 5.20 (s, 1H), 5.16 (dd, J=17.81, 3.84 Hz, 2H), 4.40 (s, 1H), 3.31
(ddd, J=14.58, 5.43, 2.41 Hz, 1H), 2.71 ppm (dd, J=14.60, 2.63 Hz, 1H);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=167.6, 144.8, 135.8, 114.7,
114.6, 47.5, 45.7 ppm; IR (KBr): n˜ =1752 cmÀ1
5-(4-Oxoazetidin-2-yl)-3a,4,7,7a-tetrahydroisoindole-1,3-dione (7d) : In a
V-vial, solution of (36.9 mg, 0.3 mmol), maleimide (58.2 mg,
.
a
4
0.6 mmol), and indium trichloride (2.8 mg, 0.015 mmol) in CH3CN
(0.5 mL) was stirred at room temperature for 24 h. After this time, the
reaction mixture was poured into saturated ammonium chloride solution
(10 mL), extracted with CH2Cl2 (3ꢁ20 mL), and washed with brine
(20 mL). The organic layer was dried over anhydrous MgSO4 and evapo-
rated under reduced pressure. The crude product was purified by silica
gel column chromatography (EtOAc/hexane 1:1) to afford 7d (47.4 mg,
72%). Rf =0.3 (EtOAc/hexane 1:1); 1H NMR (400 MHz, [D6]DMSO,
258C, TMS): d=12.88 (s, 1H), 8.06 (s, 1H), 5.81 (t, J=3.27 Hz, 1H), 3.50
(d, J=1.49 Hz, 1H), 3.17 (d, J=6.73 Hz, 1H), 3.11 (d, J=7.52 Hz, 1H),
2.99 (dd, J=14.58, 5.29 Hz, 1H), 2.43 (d, J=14.01 Hz, 1H), 2.37–2.28 (m,
2H), 2.15 (dd, J=14.90, 7.51 Hz, 1H), 2.06 ppm (dd, J=15.10, 7.04 Hz,
1H); 13C NMR (100 MHz, [D6]DMSO, 258C, TMS): d=181.72, 181.70,
167.1, 139.6, 122.8, 49.6, 42.8, 23.7, 22.6 ppm; IR (film): n˜ =3418, 2249,
Conclusion
We have shown that the reaction of 4-acetoxy-2-azetidi-
nones with organoindium reagents generated in situ from
indium and 1,4-dibromo-2-butyne in the presence of LiCl in
DMF selectively produced 2-azetidinones which contained a
1,3-butadienyl-2-yl group at the C4-position in good yields.
It was also demonstrated that the Diels–Alder reaction of 4-
[(1-methylene)prop-2-enyl]-2-azetidinones with a variety of
dienophiles provided 2-azetidinones possessing valuable
functional-group-substituted six-membered rings at the C4-
position in good yields; in this way, it serves as a new syn-
thetic methodology for b-lactam compounds.
1655, 1025, 1003, 763 cmÀ1
.
4-(4-Oxoazetidin-2-yl)cyclohex-4-ene-1,1,2,2-tetracarbonitrile (7a): Com-
pound 7a was prepared by a similar procedure to that described for 7d.
Rf =0.3 (EtOAc/hexane 1:1); 1H NMR (400 MHz, [D6]DMSO, 258C,
TMS): d=8.22 (s, 1H), 5.88 (s, 1H), 4.14 (s, 1H), 3.49–3.30 (m, 4H), 3.13
(dd, J=14.72, 5.28 Hz, 1H), 2.64 ppm (d, J=14.75, 1H); 13C NMR
(100 MHz, [D6]DMSO, 258C, TMS): d=167.1, 133.7, 117.0, 112.5, 112.4,
112.3, 112.32, 49.4, 44.1, 31.3, 30.3, 21.0, 14.1 ppm; IR (film): n˜ =3388,
Experimental Section
General: Reactions were carried out in oven-dried glassware under a ni-
trogen atmosphere. All commercial reagents were used without purifica-
tion and all solvents were reaction grade. THF was freshly distilled from
sodium/benzophenone under a nitrogen atmosphere. All reaction mix-
tures were monitored by TLC using Merck silica gel 60F254 precoated
glass plates, which were visualized with UV light, and then, developed by
using Fluka silica gel 60 (0.040–0.063 mm, 230–400 mesh). 1H NMR and
13C NMR spectra were recorded on a Brucker DPX FT (400 MHz) spec-
trometer. Deuterated chloroform was used as the solvent, and chemical
shift values (d) are reported in parts per million relative to the residual
signals of this solvent (d=7.24 for 1H and d=77.0 ppm for 13C NMR
spectra). IR spectra were recorded on a JASCO FTIR-460 plus FTIR
spectrometer as either a thin film or as a solid suspended in a potassium
bromide pellet. Indium metal (99.99%, 100 mesh), 4-acetoxy-2-azetidi-
1759, 1165, 736 cmÀ1
.
4-(4-Oxoazetidin-2-yl)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl
ester (7b): Compound 7b was prepared by a similar procedure to that
described for 7d. Rf =0.3 (EtOAc/hexane 1:1); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=6.19 (s, 1H), 5.77 (s, 1H), 4.22 (s, 1H), 3.79 (s,
6H), 3.20–3.08 (m, 5H), 2.78 ppm (dd, J=14.75, 2.04 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=167.8, 167.5, 167.4, 133.2, 132.3,
131.1, 118.7, 52.8, 52.4, 43.6, 28.4, 26.3 ppm; IR (film): n˜ =3365, 1722,
1265 cmÀ1
.
4-(4-Oxoazetidin-2-yl)cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester
(7c): Compound 7c was prepared by a similar procedure to that de-
scribed for 7d. M.p. 1108C; Rf =0.1(EtOAc/hexane :14);
1H NMR
(400 MHz, CDCl3, 258C, TMS): d=5.88 (d, J=10.04, 1H), 5.74 (d, J=
9.60, 1H), 4.09 (m, 1H), 3.71 (m, 6H), 3.20–3.18 (m, 1H), 2.93–2.87 (m,
2H), 2.78–2.74 (m, 1H), 2.44–2.29 (m, 2H), 2.24–2.17 ppm (m, 2H);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=174.82, 174.79, 174.7, 174.6,
167.6, 167.5, 134.5, 134.4, 121.8, 121.1, 52.13, 52.09, 51.3, 51.2, 43.4, 43.5,
41.0, 40.9, 27.4, 27.1, 26.1, 25.8 ppm; IR (KBr): n˜ =3333, 2953, 1735,
none, and [3R(1’R,4R)]-(+)-4-acetoxy-3-[1’-(tert-butyldimethylsilyloxy)-
G
ethyl]-2-azetidinone were purchased from Aldrich. 1,4-Dibromo-2-butyne
was prepared from the reaction of 2-butyne-1,4-diol with PBr3.[17] Com-
mercially available solvents were purified by standard procedures.
3-[1-(tert-Butyldimethylsilanyloxy)
azetidin-2-one (4): Propargyl bromide (264.9 mg, 1.25 mmol) was added
to solution of indium (172.2 mg, 1.5 mmol) and lithium chloride
ethyl]-4-[(1-methylene)prop-2-enyl]-
1196 cmÀ1
.
5-(4-Oxoazetidin-2-yl)-2-phenyl-3a,4,7,7a-tetrahydroisoindole-1,3-dione
(7e): Compound 7e was prepared by a similar procedure to that de-
scribed for 7d. Rf =0.3 (EtOAc); 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=7.48–7.43 (m, 2H), 7.40–7.37 (m, 1H), 7.19 (d, J=8.04 Hz,
2H), 5.97 (dd, J=6.54, 3.26 Hz, 1H), 5.81 (d, J=16.70 Hz, 1H), 4.14 (s,
1H), 3.39–3.28 (m, 2H), 3.20–3.08 (m, 2H), 2.83–2.73 (m, 1H), 2.63–2.58
(m, 1H), 2.38–2.32 (m, 1H), 2.29–2.23 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=178.7, 178.6, 178.5, 167.1, 167.0,
139.2, 138.7, 129.2, 126.2, 123.7, 122.9, 50.8, 50.4, 44.1, 43.1, 39.6, 39.2,
a
(174.0 mg, 1.5 mmol) in DMF (1.5 mL) under a nitrogen atmosphere at
room temperature. After the mixture had been stirred for 40 min, 4-ace-
toxy-2-azetidinone (143.7 mg, 0.5 mmol) in DMF (0.5 mL) was added to
the reaction mixture. After further stirring at 908C for 3 h, the mixture
was poured into saturated ammonium chloride solution (10 mL), extract-
ed with CH2Cl2 (3ꢁ20 mL), and washed with brine (20 mL). The organic
layer was dried over anhydrous MgSO4 and evaporated under reduced
pressure. The crude product was purified by silica gel column chromatog-
raphy (EtOAc/hexane 1:1) to afford 4 (108.0 mg, 77%). M.p. 848C; Rf =
24.5, 22.9 ppm; IR (film): n˜ =3309, 2952, 1713, 1497, 734 cmÀ1
.
Chem. Eur. J. 2007, 13, 8877 – 8883
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8881

P. H. Lee and K. Lee
4-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}cyclohex-
4-ene-1,1,2,2-tetracarbonitrile (7 f): In a V-vial, a reaction mixture of 4
lar procedure to that described for 7g. M.p. 1898C; Rf =0.2 (EtOAc/
hexane 1:3); H NMR (400 MHz, CDCl3, 258C, TMS): isomer A: d=7.85
1
(s, 1H), 5.95–5.91 (m, 1H), 5.80 (s, 1H), 4.25–4.17 (m, 2H), 3.21–3.15 (m,
2H), 2.70–2.65 (m, 2H), 1.14 (d, J=6.24 Hz, 3H), 0.87 (s, 9H), 0.08 ppm
(s, 6H); isomer B d=7.97 (s, 1H), 5.95–5.91 (m, 1H), 5.84 (s, 1H), 4.25–
4.17 (m, 2H), 3.27–3.20 (m, 2H), 2.77–2.72 (m, 2H), 1.23 (d, J=6.21Hz,
3H), 0.87 (s, 9H), 0.08 ppm (s, 6H); (100 MHz, CDCl3, 258C, TMS): iso-
mer A: d=179.3, 179.0, 168.4, 138.9, 123.4, 65.0, 63.8, 53.4, 40.7, 40.3,
25.7, 24.0, 23.3, 22.7, 17.9, À4.2, À4.9 ppm; isomer B: d=179.3, 179.0,
168.3, 139.2, 122.7, 65.0, 64.5, 52.9, 40.39, 40.32, 25.7, 24.0, 23.3, 22.6, 17.9,
(140.7 mg, 0.5 mmol) and tetra(cyano)ethylene (128.1 mg, 1.0 mmol) in
G
benzene (0.8 mL) was refluxed at 838C. After this mixture had been
stirred for 5 h, it was poured into saturated ammonium chloride solution
(10 mL), extracted with CH2Cl2 (3ꢁ20 mL), and washed with brine
(20 mL). The organic layer was dried over anhydrous MgSO4 and evapo-
rated under reduced pressure. The crude product was purified by silica
gel column chromatography (EtOAc/hexane 1:1) to afford 7 f (175.6 mg,
86%). M.p. 1768C; Rf =0.6 (EtOAc/hexane 1:1); 1H NMR (400 MHz,
[D6]DMSO, 258C, TMS): d=8.23 (s, 1H), 5.83 (s, 1H), 4.08 (t, J=
5.41Hz, 1H), 4.00 (s, 1H), 3.51 (s, 1H), 3.45 (s, 1H), 3.34 (d, J=
10.22 Hz, 1H), 3.14 (d, J=18.65 Hz, 1H), 2.83 (dd, J=2.31, 2.31 Hz,
1H), 1.10 (d, J=6.22 Hz, 3H), 0.79 (s, 9H), 0.01ppm (s, 6H); 13C NMR
(100 MHz, [D6]DMSO, 258C, TMS): d=167.1, 132.6, 116.3, 111.7, 111.6,
111.4, 64.9, 64.0, 51.7, 30.7, 30.2, 25.8, 22.2, 17.7, À4.2, À4.8 ppm; IR
À4.2, À4.9 ppm; IR (KBr): n˜ =3241, 2954, 1714, 1161, 778 cmÀ1
.
5-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}-2-propyl-
3a,4,7,7a-tetrahydroisoindole-1,3-dione (7k) : In a V-vial, a reaction mix-
ture of 4 (56.3 mg, 0.2 mmol), N-ethylmaleimide (50.0 mg, 0.4 mmol), and
indium trichloride (1.9 mg, 0.01 mmol) in acetonitrile (0.3 mL) was
stirred at 258C. After the reaction mixture had been stirred for 24 h, it
was poured into saturated ammonium chloride solution (10 mL), extract-
ed with CH2Cl2 (3ꢁ20 mL), and washed with brine (20 mL). The organic
layer was dried over anhydrous MgSO4 and evaporated under reduced
pressure. The crude product was purified by silica gel column chromatog-
raphy (EtOAc/hexane 1:3) to afford 7k (75.6 mg, 93%). M.p. 1548C;
Rf =0.4 (EtOAc/hexane 1:3); 1H NMR (400 MHz, CDCl3, 258C, TMS):
d=5.88 (d, J=12.03 Hz, 2H), 4.24–4.15 (m, 1H), 4.11 (s, 1H), 3.49 (dd,
J=7.16, 7.05 Hz, 2H), 3.16–3.07 (m, 3H), 2.24–2.08 (m, 2H), 1.25 (d, J=
6.30, 3H), 1.09 (t, J=3.78, 7.16 Hz, 3H), 0.87 (s, 9H), 0.08 ppm (d, J=
3.84 Hz, 6H); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=179.5, 179.3,
168.2, 139.1, 122.2, 65.0, 64.7, 52.8, 39.4, 39.0, 33.9, 25.7, 24.2, 23.1, 22.6,
(KBr): n˜ =3433, 1686, 707 cmÀ1
.
4-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}cyclohexa-
1,4-diene-1,2-dicarboxylic acid dimethyl ester (7g): In a V-vial, a reaction
mixture of 4 (140.7 mg, 0.5 mmol) and dimethylacetylene dicarboxylate
(98.1mg, 1.0 mmol) in benzene (0.8 mL) was refluxed at 83 8C. After the
mixture had been stirred for 48 h, it was poured into saturated ammoni-
um chloride solution (10 mL), extracted with CH2Cl2 (3ꢁ20 mL), and
washed with brine (20 mL). The organic layer was dried over anhydrous
MgSO4 and evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (EtOAc/hexane 1:3) to
afford 7g (175.7 mg, 83%). M.p. 1998C; Rf =0.1(EtOAc/hexane 1:)1;
1H NMR (400 MHz, CDCl3, 258C, TMS): d=6.00 (s, 1H), 5.76 (s, 1H),
4.20 (t, J=5.78 Hz, 1H), 4.13 (s, 1H), 3.79 (s, 6H), 3.09–3.05 (m, 3H),
2.99–2.94 (m, 1H), 2.89 (dd, J=2.13, 1.98 Hz, 1H), 1.24 (d, J=6.27 Hz,
3H), 0.88 (s, 9H), 0.09 ppm (s, 1H); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=168.3, 168.2, 167.9, 132.8, 132.5, 131.5, 118.0, 65.5, 64.7, 53.9,
52.3, 52.4, 28.3, 27.2, 25.7, 22.7, 17.9, À4.2, À4.7 ppm; IR (KBr): n˜ =3310,
17.9, 13.2, À4.2, À4.9 ppm; IR (KBr): n˜ =3235, 2950, 1754, 778 cmÀ1
.
5-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}-2-phenyl-
3a,4,7,7a-tetrahydroisoindole-1,3-dione (7l) : Compound 7l was prepared
by a similar procedure to that described for 7k. M.p. 1938C; Rf =0.7
(EtOAc); 1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.47 (t, J=
7.62 Hz, 2H), 7.39 (t, J=7.12 Hz, 1H), 7.19 (d, J=7.73 Hz, 2H), 5.97 (t,
J=3.24 Hz, 1H), 5.58 (s, 1H), 4.21 (t, J=8.06 Hz, 2H), 3.38–3.27 (m,
2H), 2.87–2.75 (m, 3H), 2.38–2.25 (m, 2H), 1.24 (d, J=3.12 Hz), 0.88 (s,
9H), 0.73 ppm (s, 6H); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
178.8, 178.6, 168.1, 139.4, 131.1, 129.2, 128.7, 126.2, 122.4, 65.0, 64.7, 52.8,
39.6, 39.1, 25.7, 24.5, 23.2, 22.6, 17.9, À4.2, À4.9 ppm; IR (KBr): n˜ =3280,
2953, 1729, 1263, 1263 cmÀ1
.
4-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}cyclohex-
4-ene-1,2-dicarboxylic acid dimethyl ester (7h): Compound 7h was pre-
pared by a similar procedure to that described for 7g by using 6c
(4 equiv). M.p. 928C; Rf =0.1(EtOAc/hexane 1:3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): isomer A: d=6.07 (s, 1H), 5.73 (d, J=5.16 Hz, 1H),
4.21–4.15 (m, 1H), 3.70 (s, 6H), 2.91–2.84 (m, 2H), 2.49 (t, J=16.46 Hz,
2H), 2.26–2.17 (m, 2H), 1.23 (dd, J=6.24, 6.09 Hz, 3H), 0.88 (s, 9H),
0.08 ppm (s, 6H); isomer B: d=6.10 (s, 2H), 5.73 (d, J=5.16 Hz, 1H),
4.21–4.15 (m, 1H), 3.70 (s, 6H), 2.91–2.84 (m, 2H), 2.49 (t, J=16.46 Hz,
2H), 2.26–2.17 (m, 2H), 1.23 (dd, J=6.24, 6.09 Hz, 3H), 0.88 (s, 9H),
0.08 ppm (s, 6H); 13C NMR (100 MHz, CDCl3, 258C, TMS): isomer A:
d=174.3, 174.1, 168.29, 134.1, 120.0, 65.3, 63.8, 53.8, 53.7, 51.4, 40.56,
40.48, 26.8, 25.1, 22.0, 17.3, 13.5, À5.3, À5.4 ppm; isomer B: d=174.3,
174.2, 168.2, 134.2, 119.5, 64.9, 64.5, 53.8, 53.7, 51.4, 49.4, 40.41, 26.9, 25.1,
22.1, 20.4, 17.3, 13.5, À4.8, À5.3 ppm; IR (KBr): n˜ =3324, 2953, 2249,
2953, 1760, 1444, 777 cmÀ1
.
3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-(9,10-dihydroxy-1,4-dihydro-
anthracen-2-yl)azetidin-2-one (7m): Compound 7m was prepared by a
AHCTREUNG
similar procedure to that described for 7g. M.p. 1928C; Rf =0.6 (EtOAc/
hexane 1:1); 1H NMR (400 MHz, CDCl3, 258C, TMS): d=8.12–8.09 (m,
2H), 7.74–7.71(m, 2H), 5.93 (s, 1H), 5.86 (s, 1H), 4.27 (d,
J=5.65 Hz,
2H), 3.32–3.29 (m, 2H), 3.26–3.23 (m, 2H), 2.97 (s, 1H), 1.28 (d, J=
6.13 Hz, 3H), 0.91 (s, 9H), 0.12 ppm (d, J=4.67 Hz, 6H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=166.9, 133.1, 115.8, 110.3, 110.2,
110.1, 110.0, 66.2, 65.5, 53.0, 37.6, 37.4, 32.5, 32.4, 25.7, 17.9, À4.2,
À4.6 ppm; IR (KBr): n˜ =3184, 2926, 1755, 1669, 730 cmÀ1
.
1653, 731 cmÀ1
.
4-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}cyclohex-
4-ene-1,2-dicarboxylic acid dimethyl ester (7i): Compound 7i was pre-
pared by a similar procedure to that described for 7g by using 6 f
Acknowledgements
(4 equiv). Rf =0.1(EtOAc/hexane :13);
1H NMR (400 MHz, CDCl3,
258C, TMS): isomer A: d=5.96 (s, 1H), 5.71 (s, 1H), 4.22–4.19 (m, 1H),
4.11 (d, J=6.03 Hz, 1H), 3.69 (t, J=4.17 Hz, 6H), 3.08 (m, 2H), 2.87 (d,
J=2.97, 1H), 2.58 (m, 2H), 2.34 (m, 2H), 1.25 (m, 3H), 0.88 (s, 9H),
0.08 ppm (s, 6H); isomer B d=5.96 (s, 1H), 5.71 (s, 1H), 4.22–4.19 (m,
1H), 4.11 (d, J=6.03 Hz, 1H), 3.69 (t, J=4.17 Hz, 6H), 3.08 (m, 2H),
2.84 (d, J=2.61, 1H), 2.58 (m, 2H), 2.34 (m, 2H), 1.25 (m, 3H), 0.88 (s,
9H), 0.08 ppm (s, 6H); 13C NMR (100 MHz, CDCl3, 258C, TMS): iso-
mer A: d=173.4, 173.1, 168.6, 134.8, 120.7, 65.5, 64.7, 54.3, 52.0, 39.9,
39.6, 25.7, 25.3, 22.6, 17.9, 14.2, À4.23, À4.84 ppm; isomer B: d=173.2,
173.1, 168.6, 134.9, 120.9, 65.4, 64.6, 54.2, 51.9, 39.7, 34.6, 25.6, 25.4, 22.7,
17.9, 14.2, À4.27, À4.88 ppm; IR (film): n˜ =3324, 2953, 2249, 1653,
This work was supported by the Korea Science and Engineering Founda-
tion (KOSEF, R01–2006–000–11283–0), by the KOSEF through the Na-
tional Research Lab. Program funded by the Ministry of Science and
Technology (grant no. M10600000203–06 J0000–20310), and by the
CMDS at KAIST. The NMR and mass data were obtained from the cen-
tral instrumental facility in Kangwon National University. We thank Pro-
fessor Y. Kang for assistance with X-ray crystallography.
[1] A. J. Wright, Mayo Clin. Proc. 1999, 74, 290–307.
[2] a) M. S. Manhas, D. R. Wagle, J. Chiang, A. K. Bose, Heterocycles
1988, 27, 1755; b) G. I. Georg, The Organic Chemistry of b-Lactams;
Wiley-VCH, New York, 1992; c) I. Ojima, Adv. Asymmetric Synth.
1995, 1, 95; d) I. Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26, 377;
731cm À1
.
5-{3-[1-(tert-Butyldimethylsilanyloxy)ethyl]-4-oxoazetidin-2-yl}-3a,4,7,7a-
tetrahydroisoindole-1,3-dione (7j): Compound 7j was prepared by a simi-
8882
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8877 – 8883

Indium Catalysis
FULL PAPER
e) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Amino Acids
Yang, J. Am. Chem. Soc. 1999, 121, 3228; Y. Yang, J. Am. Chem.
Soc. 1999, 121, 3228, Org. Lett. 2000, 2, 3469.
[10] a) B. Alcaide, P. Almendros, Tetrahedron Lett. 1999, 40, 1015; b) B.
Alcaide, P. Almendros, N. R. Salgado, J. Org. Chem. 2000, 65, 3310;
c) B. Alcaide, P. Almendros, N. R. Salgado, M. P. Martinez-Alcazar,
F. Hernandez-Cano, Eur. J. Org. Chem. 2001, 2001.
[11] B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo, Eur. J.
Org. Chem. 2005, 98.
[12] A. K. Sharma, S. N. Mazumdar, M. P. Mahajan, J. Org. Chem. 1996,
61, 5506.
1999, 16, 321; f) B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30,
226; g) B. Alcaide, P. Almendros, Org. Prep. Proced. Int. 2001, 33,
315; h) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Synlett
2001, 1813; i) B. Alcaide, P. Almendros, Synlett 2002, 381.
[3] S. Mori, H. Iwakura, S. Takechi, Tetrahedron Lett. 1988, 29, 5391.
[4] a) T. Kobayashi, N. Ishida, T. Hiraoka, J. Chem. Soc. Chem.
Commun. 1980, 736; b) D. H. Hua, A. Verma, Tetrahedron Lett.
1985, 26, 547; c) M. Aratani, H. Hirai, K. Sawada, M. Hashimoto,
Heterocycles 1985, 23, 1889; d) H. Fliri, C.-P. Mak, J. Org. Chem.
1985, 50, 3438; e) K. Fujimoto, Y. Iwano, K. Hirai, Bull. Chem. Soc.
Jpn. 1986, 59, 1363; f) L. C. Blaszczak, H. K. Armour, N. G. Hallign,
Tetrahedron Lett. 1990, 31, 5693; g) C. A. Tarling, A. B. Holmes,
R. E. Markwell, N. D. Pearson, J. Chem. Soc. Perkin Trans. 1, 1990,
1695; h) S.-K. Kang, T.-G. Baik, X.-H. Jiao, K.-J. Lee, C. H. Lee,
Synlett 1999, 447.
[5] a) M. Shibasaki, A. Nishida, S. Ikegami, J. Chem. Soc. Chem.
Commun. 1982, 1324; b) J.-I. Haruta, K. Nishi, K. Kikuchi, S. Matsu-
da, Y. Tamura, Y. Kita, Chem. Pharm. Bull. 1989, 37, 2338; c) B. Al-
caide, P. Almendros, J. M. Alonso, J. Org. Chem. 2004, 69, 993.
[6] a) J. S. Prasad, L. S. Liebeskind, Tetrahedron Lett. 1988, 29, 4253;
b) J. S. Prasad, L. S. Liebeskind, Tetrahedron Lett. 1988, 29, 4257;
c) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Eur. J. 2002, 8,
1719; d) B. Alcaide, P. Almendros, C. Aragoncillo, Org. Lett. 2003,
5, 3795; e) P. H. Lee, H. Kim, K. Lee, M. Lee, K. Noh, H. Kim, D.
Seomoon, Angew. Chem. 2005, 117, 1874; Angew. Chem. Int. Ed.
2005, 44, 1840.
[7] a) T. Kobayashi, N. Ishida, T. Hiraoka, J. Chem. Soc. Chem.
Commun. 1980, 736; b) D. H. Hua, A. Verma, Tetrahedron Lett.
1985, 26, 547.
[8] G. I. Georg, The Organic Chemistry of b-Lactams; Wiley-VCH,
New York, 1992, pp. 64–70.
[9] a) B. Alcaide, P. Almendros, R. Rodriguez-Acebes, J. Org. Chem.
2002, 67, 1925; b) B. Alcaide, P. Almendros, C. Aragoncillo, R. Ro-
driguez-Acebes, Synthesis 2003, 1163; for 1,3-butadienyl-2-ylation of
carbonyl compounds see c) W. Lu, J. Ma, Y. Yang, T. H. Chan; Y.
[13] 4-(1,3-Butadien-2-yl)-2-azetidinone was reported as a side product
(9%) in the reaction of alkyl-iodide-tethered 2-azetidinone with
NaBH3CN: Y. Sendo, M. Kii, M. Sakanoue, K. Motokawa, Y.
Kimura, Chem. Pharm. Bull. 1992, 40, 2410.
[14] Although we have tried to separate these diastereomers (7c–e and
7h–l), we failed to separate them. These compounds decomposed
during separation when using preparative HPLC. Therefore, we re-
1
ported H NMR spectroscopic data for the mixture of diastereomers
of 7h–j and 1H and 13C NMR spectroscopic data for the mixture of
diastereomers of 7c–e. Ratios of diastereomers of 7e, 7h, and 7i
were determined on the basis of the integration ratio of separated
peaks. 13C NMR spectra of 7h and 7i were obtained in two sets. Al-
though the 13C NMR spectrum of 7j was obtained in two sets, the
ratio of diastereomers of 7j could not be determined. 1H and
13C NMR spectra of 7k and 7l were obtained in one set, indicating
that a single diastereomer was produced. In addition, X-ray data of
7k and 7l (see the Supporting Information) were obtained.
[15] SHELXTL NT Crystal Structure Analysis Package, Version 5.14,
Bruker AXS, Analytical X-ray System, Madison, WI, 1999.
[16] a) T. H. Chan; Y. Yang, J. Am. Chem. Soc. 1999, 121, 3228; b) K.
Lee, D. Seomoon, P. H. Lee, Angew. Chem. 2002, 114, 4057; Angew.
Chem. Int. Ed. 2002, 41, 3901; c) W. M. Miao, W. Lu, T. K. Chan, J.
Am. Chem. Soc. 2003, 125, 2412; d) W. Miao, L. W. Chung, Y.-D.
Wu, T. H. Chan, J. Am. Chem. Soc. 2004, 126, 13326.
[17] A. W. Johnson, J. Chem. Soc. 1946, 1009.
Received: May 24, 2007
Published online: August 17, 2007
Chem. Eur. J. 2007, 13, 8877 – 8883
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8883