New aspects of the indium chemistry of carbonyl-β-lactams

Article abstract of DOI:10.1055/s-2003-39388

Reactions of racemic as well as optically pure carbonyl-β-lactams with stabilized organo-indium reagents were investigated in aqueous media. The regio- and stereochemistry of the processes were generally good, offering a convenient asymmetric entry to den

Full text of DOI:10.1055/s-2003-39388

PAPER
1163
New Aspects of the Indium Chemistry of Carbonyl- -lactams
New
Aspects of
t
e
he Indium
n
i
Carbo
t
nyl- -L
o
actam
s
Alcaide,*a Pedro Almendros,*b Cristina Aragoncillo,a Raquel Rodríguez-Acebesa
a
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid, Spain
Fax +34(91)3944103; E-mail: alcaideb@quim.ucm.es
b
Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
Fax +34(91)5644853; E-mail: iqoa392@iqog.csic.es
Received 27 March 2003
bonylic compounds, at the outset of the present studies lit-
tle was known about the reactions of carbonyl- -lactams
with stabilized organometallic reagents. Thus, the infor-
mation available on the use of -lactams as chiral building
blocks on the propargylation–allenylation reactions was
very scarce; only Cho has recently reported the propargyl-
metalation of 6-oxopenicillanates in anhydrous and aque-
ous tetrahydrofuran.7 Bose8 and Paquette9 have indepen-
dently reported the allylindation of azetidine-2,3-diones.
However, the asymmetric version was achieved with poor
diastereoselectivity on azetidine-2,3-diones bearing a
chiral auxiliary at nitrogen.9
Abstract: Reactions of racemic as well as optically pure carbonyl-
-lactams with stabilized organo-indium reagents were investigated
in aqueous media. The regio- and stereochemistry of the processes
were generally good, offering a convenient asymmetric entry to
densely functionalized hydroxy- -lactams.
Key words: addition reactions, asymmetric synthesis, lactams, in-
dium, organometallic reagents
The metallic element indium has a number of useful prop-
erties that suggest it should be useful in organic synthesis.
It is unreactive towards air and water, is non-toxic, and is
readily available in high purity due to the ease with which
it zone refines. However, it is relatively rare, being the
63rd most abundant element in the Earth’s crust, and hence
available at prices similar to other rare elements such as
silver. Generally speaking, indium exhibits a low hetero-
philicity in organic reactions and thus, oxygen- and nitro-
gen-containing functional groups are usually tolerated by
organoindium reagents. Moreover, indium-assisted reac-
tions display a low nucleophilicity thus permiting
chemoselective transformations of groups of similar reac-
tivity.1 Despite its desirable chemical properties, indium
has only recently been exploited in organic synthesis,2
most notably in the generation of synthetically useful al-
lylindium species.3
Removing organic solvents in chemical synthesis is im-
portant in the drive towards benign chemical technolo-
gies. Recently, organometallic reactions in aqueous media
have elicited considerable interest due to their synthetic
advantages as well as its potential as an environmentally
benign chemical process.10 Since indium in aqueous solu-
tion has shown considerable promise in the addition of un-
saturated halides to the carbonyl group, we decide to
explore further the indium-mediated reactions of carbon-
yl- -lactams with stabilized organic halides under Barbi-
er-type conditions in aqueous media.
The carbon–carbon bond formation reactions were initial-
ly investigated through the indium-mediated allylations
between the azetidine-2,3-diones 1 and allyl bromides in
aqueous tetrahydrofuran at room temperature. In the
event, the indium as mediator showed total diastereoselec-
tivity and good yields (70–100%) on product formation
during allylation reactions of azetidine-2,3-diones 1 with
allyl bromide, 2-(bromomethyl)acrylic acid, and prenyl
bromide, in an aqueous environmment (Table 1).11 Since
the main drawbacks of the Barbier-type carbon–carbon
bond formation are long reaction times, we thought that
the allylation reaction could proceed with rate enhance-
ment in the presence of some additives. Indeed, the addi-
tion of ammonium chloride, indium trichloride or hafnium
chloride to the aqueous medium shortened reactions
times, exhibiting the same facial preference (see Table 1).
It is to be presumed that the ionic strength enhancement of
the reaction solvent provided by the ammonium chloride
accelerated the process. Although the role of the indium-
and hafnium-derived additives is not completely under-
stood, it may be explained in terms of Lewis acid, which
activates the carbonyl group and the softness of these or-
ganoindium reagents.
The development of new approaches to the stereocon-
trolled synthesis of -lactam systems is a subject of great
interest in the context of their possible use as biologically
active compounds4 or as versatile chiral building blocks.5
On the other hand, the chiral -amino alcohol moiety is
present in many biologically important molecules such as
dipeptide isosteres, statine and its analogues, and there-
fore its stereocontrolled synthesis remains an intensive re-
search area.6
On the other hand, the development of new carbon–car-
bon bond forming reactions is of particular interest in or-
ganic synthesis. Among the most fundamental and
important reactions for constructing carbon–carbon bonds
are the allylation, the propargylation–allenylation and the
1,3-butadien-2-ylation of aldehydes and ketones (carbon-
yls) with organometallic reagents. Although many efforts
have been made in these fields with various types of car-
Synthesis 2003, No. 8, Print: 05 06 2003.
Art Id.1437-210X,E;2003,0,08,1163,1170,ftx,en;C00903SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

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B. Alcaide et al.
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Table 1 Indium-Mediated Stereoselective Allylation of Enantiopure Azetidine-2,3-diones 1 in Aqueous Mediaa
O
R2
O
O
R2
R3
H
N
OH
R3
O
O
O
O
R2
Br
THF/H2O
+
N
In/additive
R1
R1
R2
1
2
Product
(+)-2a
(+)-2a
(+)-2a
(+)-2a
(+)-2d
(–)-2b
(–)-2f
R1
R2
H
R3
H
H
H
H
Additive
T (°C)/t (h)
20/18
0/3
Yield (%)b
PMP
PMP
PMP
PMP
PMP
73
73
H
NH4Cl
InCl3
H
20/2
73
H
HfCl4
NH4Cl
20/1.5
0/1.5
20/18
0/1
73
H
COOH
H
83
2-Propenyl
2-Propenyl
3-Butenyl
2-Propynyl
2-Propynyl
H
70
Me
H
H
NH4Cl
NH4Cl
NH4Cl
NH4Cl
80
(–)-2g
(–)-2h
(–)-2h
H
0/1
100
99
H
CO2H
CO2H
0/1.5
0/1.5
H
99
a All reactions were carried out on 1 mmol scale. PMP = 4-MeOC6H4. Only one isomer was detected in the 1H NMR spectra of the crude reaction
mixtures before purification.
b Yield of pure, isolated product with correct analytical and spectral data.
Once we had established the best reaction conditions to product. Surprisingly, the regiochemical preference was
carry out the allylation reaction, our aim was to evaluate reversed on the indium-promoted reaction just by chang-
the feasibility of other related indium-mediated Barbier- ing the solvent system (a saturated aqueous solution of
type reactions in enantiomerically pure azetidine-2,3-di- NH4Cl in THF was used instead of aqueous THF), with
ones, studying the diastereochemistry (syn vs. anti) and the expected alcohols 3 and 4 being obtained as a mixture
the regiochemistry of the connection (e.g., allenylation vs. of regioisomers in a ratio of 3:4, 29:71 (Scheme 1).12
propargylation). The reaction of propargyl bromide with
metals has been proposed to generate an equilibrium be-
O
O
O
tween the allenyl and propargyl organometallics. This
metallotropic rearrangement often results in poor regiose-
lection in the final organic product, because both organo-
metallic species can react with the carbonyl compounds.
The aim of achieving full control of regiochemistry
prompted us to seek an aqueous indium-induced propar-
gylation–allenylation reaction. For this purpose, azeti-
dine-2,3-diones were treated with prop-2-ynyl bromides,
bearing substituents of varying steric demand at C3. Not
unexpectedly, the diastereoselectivity was complete in all
cases. However, while the chemical yield of the addition
was generally good, the regioselectivity of the process
was a function of the nature of the propargyl bromide and
in some cases of the system-solvent as well.
H
N
OH
OH
O
O
O
O
O
Br
+
N
N
In
PMP
O
PMP
O
PMP
(+)-1a
3
4
THF/H2O
58:42 (50%)
THF/NH4Cl (aq satd) 29:71 (67%)
Scheme 1 Indium-mediated propargylation of azetidine-2,3-dione
(+)-1a in aqueous media
Our next aim was to find a carbonyl propargylation–alle-
nylation method that proceeds in a highly regioselective
fashion by the use of 3-substituted prop-2-ynyl bromides
through choice of reaction conditions. Metal-promoted re-
actions of azetidine-2,3-diones 1 with propargyl bromides
bearing aliphatic or aromatic substituents at the terminal
position, afforded the -allenic alcohols 5 as essentially
regio- and diastereoisomerically pure products. This ob-
servation is in sharp contrast to the metal-mediated reac-
tion of propargyl bromide itself. The results are
summarized in Table 2.
The regio- and diastereoselectivity of the addition reac-
tion was initially investigated through the indium-mediat-
ed reaction between the azetidine-2,3-dione (+)-1a and
propargyl bromide in aqueous tetrahydrofuran at room
temperature. In the event, the 3-substituted 3-hydroxy- -
lactam moiety was obtained; however the observed regio-
selectivity was very poor (58:42) in favor of the allenic
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

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New Aspects of the Indium Chemistry of Carbonyl- -lactams
1165
Table 2 Indium-Mediated Regio- and Stereoselective Allenylation of Azetidine-2,3-diones 1 in Aqueous Mediaa
Compound
5a/6a
R1
R2
Additive
NH4Cl
NH4Cl
NH4Cl
5:6 ratiob
100:0
100:0
100:0
100:0
100:0
100:0
Yield (%)c
PMP
Me
Me
Ph
Ph
Ph
Ph
74
63
76
75
62
48
5b/6b
5c/6c
2-Propenyl
PMP
5c/6c
PMP
5d/6d
5e/6e
2-Propenyl
2-Propynyl
NH4Cl
NH4Cl
a All reactions were carried out on 1 mmol scale.
b The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before purification.
c Yield of pure, isolated product with correct analytical and spectral data.
We were interested in studying these addition reactions on 10 could not easily be separated by gravity flow chroma-
other relevant class of non-racemic -lactam carbonyl tography.
compounds. Thus, we evaluated the feasibility of the met-
Next, we needed to find a carbonyl allenylation method
al-mediated Barbier-type carbonyl propargylation–alle-
that proceeds in a highly regio- and diastereoselective
nylation reactions of 4-oxoazetidine-2-carbaldehydes in
fashion. Thus, we used propargyl bromides bearing an al-
iphatic or an aromatic substituent at the terminal position.
Indium-mediated reactions of aldehydes 7 with 3-substi-
eco-friendly media, studying the diastereochemistry (syn
vs. anti) and the regiochemistry of the connection (e.g., al-
lenylation vs. propargylation). Results from the metal-
tuted prop-2-ynyl bromides afforded the corresponding -
promoted reactions between aldehydes 7 and propargyl
allenic alcohols 14 as regioisomerically pure products in
bromide are summarized in Table 3. The indium-promot-
diastereomeric ratios of about 90:10–100:0 (Table 4). The
ed reaction proceeded with total diastereocontrol, but poor
diastereomeric syn- and anti-alcohols were amenable to
separation by bench chromatography.
regiocontrol.13 Unfortunately, the isomeric alcohols 8 and
Table 3 Indium-Mediated Propargylation of 4-Oxoazetidine-2-carbaldehydes 7 in Aqueous Mediaa
OH
OH
H
H
H
N
H
H
H
N
MeO
MeO
H
H
N
O
R
O
R
MeO
8
9
Br
O
In/additive
THF/H2O
OH
OH
O
R
H
N
H
N
MeO
MeO
7
O
R
O
R
10
11
Aldehyde
(+)-1a
(+)-1f
R
Additive
NH4Cl
NH4Cl
NH4Cl
NH4Cl
8:9:10:11 Ratiob
55:0:45:0
Yield 8/10 (%)c
72 (8a/10a)
65 (8b/10b)
66 (8c/10c)
74 (8d/10d)
69 (8d/10d)
2-Propenyl
2-Propynyl
4-Pentynyl
PMP
57:0:43:0
(+)-1h
(+)-1i
55:0:45:0
80:0:20:0
(+)-1i
PMP
65:0:35:0
a All reactions were carried out on 1 mmol scale. PMP = 4-MeOC6H4.
b The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before purification.
c Yield of pure, isolated product with correct analytical and spectral data.
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

1166
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Table 4 Indium-Mediated Regio- and Stereoselective Allenylation of 4-Oxoazetidine-2-carbaldehydes 7 in Aqueous Mediaa
R3
R2
OH
R3
OH
H
H
H
H
H
H
N
R2
O
N
R3
R1
O
R1
H
H
N
R2
O
12
13
Br
O
THF/H2O/NH4Cl
In
R1
OH
OH
H
N
H
N
R3
R3
R2
O
R2
O
7
R1
R1
14
15
Aldehyde
(+)-1a
(+)-1b
(+)-1c
(+)-1d
( )-1e
(+)-1f
(+)-1g
(+)-1i
( )-1j
( )-1k
(+)-1a
(+)-1f
(+)-1i
( )-1j
R1
R2
R3
12:13:14:15 ratiob
0:0:95:5
Yield (%)c
2-Propenyl
3-Butenyl
3-Butenyl
PMP
MeO
MeO
PhO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
75 (14a)
77 (14b)
92 (14c)
80 (14d)
90 (14e)
75 (14f)
69 (14g)
77 (14h)
60 (14i)
90 (14j)
64 (14k)
60 (14l)
84 (14m)
89 (14n)
0:0:97:3
0:0:90:10
0:0:90:10
0:0:90:10
0:0:98:2
2-Propenyloxy
2-Propenyl
MeO
PMP
2-Propynyl
3-Butynyl
PMP
MeO
0:0:93:7
MeO
0:0:91:9
PMP
Ethenyl
2-Propynyl
MeO
0:0:90:10
0:0:90:10
0:0:100:0
0:0:95:5
PMP
2-Propenyl
2-Propynyl
PMP
MeO
Ph
MeO
Ph
0:0:90:10
0:0:90:10
PMP
Ethenyl
Ph
a All reactions were carried out on 1 mmol scale.
b The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before purification.
c Yield of pure, isolated product with correct analytical and spectral data.
It may be inferred that different steric effects in the orga- hydroxy- -lactam (+)-18a in 54% yield as the only regio-
no-indium reagents derived from differently substituted and stereoisomer (Table 5).14 Because water is an eco-
propargyl bromides may be responsible for the different nomical solvent, we decide to increase the amount of wa-
regiochemical preference of the propargyl–allenyl metals ter in the Barbier-type reaction. However, when the
involved in the reaction, stabilizing one of the intermedi- reaction was conducted in a THF–H2O (1:5) mixture the
ates of the metallotropic equilibrium rather than the other. coupling was not as efficient as before (18% yield). A
Probably, the isomerization of propargylindium to alle- higher proportion of THF beyond the 1:1 ratio in the sol-
nylindium is restricted by the steric effect of a substituent vent did not seem to improve the yield further. In addition,
(R1 = Me or Ph) in the bromopropyne (Scheme 2).
the ionic strength enhancement of the reaction solvent
provided by the ammonium chloride was counter-produc-
tive for the indium-mediated 1,3-butadien-2-ylation.
Thus, moving from THF–H2O (1:1) to THF–NH4Cl (aq
sat.) (1:1) decreased the yield for the indium-promoted re-
action between 1,4-dibromo-2-butyne and azetidine-2,3-
dione (+)-1a (Table 5). The reaction time was increased
20 fold as the solvent changed from THF–H2O (1:1) to a
MeOH–H2O (1:1) mixed solvent. No reaction was ob-
served in THF–NaHCO3 (aq sat.) (1:1). Next, we explored
1,4-bis(methanesulfonyl)-2-butyne 17 as a Barbier-type
1,3-butadien-2-ylating reagent, rather than 1,4-dibromo-
In contrast to the allylation and propargylation–allenyla-
tion, the analogous reaction involving butadienyl-metals
has been much less investigated. Therefore, we were in-
terested in exploring the indium-mediated 1,3-butadien-2-
ylation of enantiomerically pure azetidine-2,3-diones in
aqueous media using 1,4-dibromo-2-butyne 16 or 1,4-
bis(methanesulfonyl)-2-butyne 17. The indium-mediated
reaction between the azetidine-2,3-dione (+)-1a and 1,4-
dibromo-2-butyne in aqueous tetrahydrofuran (1:1) at
room temperature afforded the 3-(1,3-butadien-2-yl)-3-
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

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New Aspects of the Indium Chemistry of Carbonyl- -lactams
1167
R1
2-butyne 16, because the mesylates are superior to the ha-
lides for ease of preparation and the stability of propargyl-
ic substrates. The bismesylate 17 was then reacted with
azetidine-2,3-diones 1, sodium iodide and indium in dif-
ferent aqueous media to afford the corresponding (buta-
1,3-dien-2-yl)methanol derivatives 18 in moderate yield
(up to 42%). In all cases, the same regioselectively was
observed, but the conversion was enhanced as the solvent
system changed from THF–H2O (1:1) to THF–NH4Cl (aq
sat.) (1:5). These results suggest that the metal-promoted
carbonyl 1,3-butadien-2-ylation in aqueous media may be
quite sensitive to various factors.
Br
In
R1
R1
InBr
InBr
R1
R1
R1 = Me, Ph
2 = 2-azetidinone
R1 = H
2 = 2-azetidinone
BrIn
O
BrIn
R
R
O
H
H
R2
R2
InBr
InBr
R1
From a mechanistic point of view, our results for the indi-
um-mediated 1,3-butadien-2-ylation process of azetidine-
2,3-diones using 1,4-bis(methanesulfonyl)-2-butyne or
1,4-dibromo-2-butyne could be explained as illustrated in
Scheme 3.15 It may be reasonable to postulate a metallo-
tropic rearrangement between the propargylindium and
allenylindium species. Their reactions with electrophiles
suffer from competing reactions. Thus, both intermediates
from this equilibrium are able to react with the azetidine-
2,3-diones 1, leading to the (buta-1,3-dien-2-yl)methanols
18 or homoallenic alcohols 19. The formation of alcohols
18 and 19 is consistent with participation of the six-mem-
bered, cyclic transition structures 20 and 21, respectively.
O
O
H
H
R2
R2
R1
H2O
H2O
R1
OH
H
OH
H
R2
R2
R1
8
14
Scheme 2 Explanation for the regioselectivity in the propargylati-
on–allenylation reaction of carbonyl- -lactams
Table 5 Indium-Mediated Regio- and Stereoselective 1,3-Butadien-2-ylation of Azetidine-2,3-diones 1 in Aqueous Mediaa
O
O
OH
O
O
O
O
In
+
N
N
X
X
solvent
R
O
R
1
18
16 X = Br
17 X = MsO
Compdb
(+)-18a
(+)-18a
(+)-18a
(+)-18a
(+)-18a
(+)-18a
(+)-18a
(–)-18b
(+)-18c
(+)-18d
(–)-18b
(+)-18c
(+)-18d
R
X
System solvent
t (h)
1
Yield (%)c
PMP
Br
THF–H2O (1:1)
54
18
19
26
PMP
Br
THF–H2O (1:5)
1
PMP
Br
THF–NH4Cl (aq sat.) (1:1)
MeOH–H2O (1:1)
4
PMP
Br
20
PMP
Br
THF–NaHCO3 (aq sat.) (1:1)
THF–NH4Cl (aq sat.) (1:5)
THF–H2O (1:1)
PMP
MsO
MsO
Br
4
5
1
1
1
4
4
4
42
32
62
38
45
33
37
34
PMP
2-Propenyl
2-Propynyl
3-Butenyl
2-Propenyl
2-Propynyl
3-Butenyl
THF–H2O (1:1)
Br
THF–H2O (1:1)
Br
THF–H2O (1:1)
MsO
MsO
MsO
THF–NH4Cl (aq sat.) (1:5)
THF–NH4Cl (aq sat.) (1:5)
THF–NH4Cl (aq sat.) (1:5)
a All reactions were carried out on 1 mmol scale.
b Obtained as single regio- and stereoisomers, to judge by the 1H NMR spectra of the crude reaction mixtures before purification.
c Yield of pure, isolated product with correct analytical and spectral data.
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

1168
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It seems reasonable to propose that the regiochemical tially, thus the organoindium species being delivered to
preference observed on the indium-promoted reactions of the less hindered face. Derivatization of the alcohols 8 and
1,4-dibromo-2-butyne and 1,4-bis(methanesulfonyl)-2- 14 with (R)- and (S)-acetylmandelic acids allowed assign-
butyne with azetidine-2,3-diones must be controlled by ment of the configuration at the carbinolic stereocenter.
steric effects. Probably, the isomerization of propargyl- The stereochemical result can be interpreted by the Fel-
metal to allenylmetal is prohibited by the steric effect of kin–Anh model.
both MLn substituents. Thus, the propargylindium reagent
undergoes nucleophilic addition to produce exclusively
allenyl compounds, which after protiodemetalation gave
1,3-butadien-2-yl alcohols 18 (Scheme 3).
As well as the above addition reactions, indium itself was
able to promote the reaction of azetidine-2,3-dione (+)-1a
and water, with concomitant CO extrusion. In this way, a
one-step synthesis of the -amino acid (+)-22 was
achieved (Scheme 4).
X
X
X = Br, MsO In
O
O
H
H
O
LnIn
LnIn
O
O
O
O
In/NH4Cl
NHPMP
InLn
InLn
InLn
N
MeOH/H2O
OH
PMP
LnIn
LnIn
(+)-22 (42%)
(+)-1a
LnIn
O
Scheme 4 Indium-mediated synthesis of -amino acid (+)-22 from
-keto lactam (+)-1a
O
O
O
O
O
O
N
N
R
O
R
In conclusion, we have developed a very efficient asym-
metric synthesis of highly substituted monocyclic -lac-
tams and -amino acids using indium chemistry in
aqueous media. Furthermore, additional transformations
of the alkene, alkyne, and allene moieties can be envi-
sioned thus providing an array of useful building blocks.
InLn
O
LnIn
O
O
O
O
O
M
M
Ln
Ln
N
N
O
R
O
R
20
21
All commercially available compounds were used without further
purification. H NMR and 13C NMR spectra were recorded on a
1
InLn
InLn
Bruker AMX-500, Bruker Avance-300, Varian VRX-300S or Bruk-
er AC-200. NMR spectra were recorded in CDCl3 solutions, except
otherwise stated. Chemical shifts are given in ppm relative to TMS
(1H, = 0.0), or CDCl3 (13C, = 76.9). Low and high-resolution
mass spectra were taken on a HP5989A spectrometer using the
chemical ionization modes (CI) unless otherwise stated. Electro-
spray ionization (ESI) was performed on a Bruker ESQUIRE LC at
400 eV. Specific rotation [ ]D is given in deg per dm at 20 °C, and
the concentration (c) is expressed in g per 100 mL.
O
O
R
LnIn
O
O
O
O
N
N
LnIn
O
R
O
O
O
MLn+1
MLn+1
InLn
InLn
O
O
O
O
O
O
N
Indium Promoted Reaction Between Allyl Bromides and Azeti-
dine-2,3-diones 1 in an Aqueous Medium Containing NH4Cl;
General Procedure for the Synthesis of Homoallylic Alcohols 2
The appropriate allyl bromide (363 mg, 3.0 mmol) was added to a
well-stirred suspension of the corresponding -keto lactam (1.0
mmol) and indium powder (688 mg, 6.0 mmol) in THF–NH4Cl (aq
sat.) (1:5, 5 mL) at 0 °C. After disappearance of the starting material
(TLC) the mixture was extracted with EtOAc (3 × 5 mL). The or-
ganic extract was washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
(EtOAc–hexanes mixtures) gave analytically pure compounds.
Spectroscopic and analytical data for some representative pure
forms of 2 follow.
N
R
O
R
H2O
O
H2O
O
OH
OH
O
O
N
N
R
O
R
19
18
Scheme 3 Mechanistic explanation for the regioselective formation
of alcohols 18
(3R,4S)-3-(2-Carboxy-2-propenyl)-4-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-3-hydroxy-1-(p-methoxyphenyl)-2-azetidinone
[(+)-2d]
From azetidine-2,3-dione (+)-1a (53 mg, 0.18 mmol), compound
(+)-2d was obtained.
The stereochemistry at the C3-heterosubstituted quaterna-
ry center for compounds 2, 4, 5 and 18 was assigned by
qualitative homonuclear NOE difference spectra. The ste-
reoselectivity in the addition reaction of these stabilized
organo-indium reagents with azetidine-2,3-diones 1 is be-
lieved to be controlled by the bulky acetonide at C-4, in
which one face of the carbonyl group is blocked preferen-
Yield: 58 mg (83%); colorless oil; [ ]D +47.4 (c 1.0, CHCl3).
IR (CHCl3): 3205, 1708 cm–1.
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
New Aspects of the Indium Chemistry of Carbonyl- -lactams
1169
1H NMR: = 1.28 and 1.47 (s, 3 H each), 2.86 (m, 2 H), 3.65 (m, 1
H), 3.76 (s, 3 H), 3.99 (m, 1 H), 4.27 (m, 2 H), 5.69 (s, 1 H), 6.35 (s,
1 H), 6.81 (d, 2 H, J = 8.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz).
13C NMR: = 171.0, 168.6, 156.7, 130.7, 128.2, 120.1, 119.9,
113.9, 109.4, 83.5, 77.2, 68.8, 66.5, 55.4, 38.3, 26.6, 24.9.
(3R,4S)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-3-(1-
phenyl-1,2-propadienyl)-1-(2-propenyl)-2-azetidinone [(–)-5d]
From azetidine-2,3-dione (–)-1b (58 mg, 0.257 mmol), compound
(–)-5d was obtained.
Yield: 54 mg (62%); colorless oil; [ ]D –75.8 (c 0.7, CHCl3).
MS (CI): m/z = 334 (M+ +1, 100), 333 (M+, 25).
IR (CHCl3): 3334, 2991, 1940, 1745 cm–1.
Anal. Calcd for C19H22NO7: C, 60.63; H, 5.84; N, 3.72. Found: C,
60.70; H, 5.81; N, 3.70.
1H NMR: = 1.34 (s, 3 H), 1.40 (s, 3 H), 3.67 (dd, 1 H, J = 8.8, 5.4
Hz), 3.68 (m, 1 H), 3.80 (d, 1 H, J = 7.1 Hz), 4.17 (dd, 1 H, J = 8.8,
6.8 Hz), 4.22 (ddt, 1 H, J = 15.4, 4.6, 1.7 Hz), 4.44 (dd, 1 H, J = 7.1,
5.6 Hz), 4.47 (s, 1 H), 5.13 (m, 2 H), 5.21 (s, 2 H), 5.61 (m, 1 H),
7.28 (m, 3 H), 7.59 (m, 2 H).
13C NMR: = 207.3, 168.8, 132.8, 131.3, 128.5, 127.6, 118.3,
109.7, 105.8, 84.8, 80.3, 76.0, 66.6, 64.9, 43.4, 26.5, 25.0.
(3R,4S)-3-(1-Methyl-2-propenyl)-4-[(S)-2,2-dimethyl-1,3-diox-
olan-4-yl]-3-hydroxy-1-(2-propenyl)-2-azetidinone [(–)-2f]
From -keto lactam (–)-1b (52 mg, 0.23 mmol), compound (–)-2f
was obtained.
Yield: 54.2 mg (80%); colorless oil; [ ]D –35.9 (c 0.5, CHCl3).
IR (CHCl3): 3332, 1744 cm–1.
MS (CI): m/z = 342 (M+ + 1, 100), 341 (M+, 24).
Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.44; H, 6.82; N, 4.12.
1H NMR: = 1.13 (s, 6 H), 1.34 (s, 3 H), 1.42 (s, 3 H), 3.49 (d, 1 H,
J = 6.8 Hz), 3.65 (dd, 1 H, J = 15.1, 8.3 Hz), 3.71 (dd, 1 H, J = 8.8,
5.9 Hz), 4.01 (br s, 1 H), 4.12 (dd, 1 H, J = 8.8, 6.8 Hz), 4.21 (dd, 1
H, J = 14.6, 4.9 Hz), 4.29 (q, 1 H, J = 6.3 Hz), 5.20 (m, 4 H), 5.72
(m, 1 H).
13C NMR: = 169.7, 142.6, 131.5, 119.2, 114.7, 109.6, 88.9, 76.4,
66.7, 61.5, 43.5, 41.1, 26.6, 25.1, 21.6, 21.2.
(3R,4S)-1-(3-Butenyl)-4-[(R)-1-hydroxy-2-methyl-2,3-butadie-
nyl]-3-methoxy-2-azetidinone [(+)-14b]
Aldehyde (+)-1b (95 mg, 0.52 mmol), after chromatography of the
residue (hexanes–EtOAc, 1:1), gave compound (+)-14b.
Yield: 95 mg (77%); colorless oil; [ ]D +46.1 (c 0.7, CHCl3).
MS (CI): m/z = 296 (M+ + 1, 100), 295 (M+, 24).
IR (CHCl3): 3421, 2992, 1942, 1747 cm–1.
Anal. Calcd for C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found: C,
65.14; H, 8.56; N, 4.70.
1H NMR: = 5.73 (m, 1 H), 5.06 (m, 2 H), 4.81 (q, J = 3.0 Hz, 1 H),
4.42 (d, J = 4.8 Hz, 1 H), 4.23 (m, 1 H), 3.94 (t, J = 4.6 Hz, 1 H),
3.55 (s, 3 H), 3.50 (m, 1 H), 3.20 (ddd, J = 13.6, 7.0, 6.0 Hz, 1 H),
2.67 (br s, 1 H), 2.31 (m, 2 H), 1.79 (t, J = 3.0 Hz, 3 H).
13C NMR: = 205.4, 167.7, 135.0, 116.8, 99.8, 83.3, 77.2, 70.3,
59.5, 59.3, 40.7, 31.9, 16.0.
Indium Promoted Reaction Between 3-Substituted 1-Bromo-2-
propynes and Carbonyl- -lactams 1 or 7 in an Aqueous Medi-
um Containing NH4Cl; General Procedure for the Synthesis of
-Allenic Alcohols 5 and 14
MS (CI): m/z = (%): 238 (M+ + 1, 100), 237 (M+, 19).
The appropriate 1-bromo-3-substituted-2-propyne (3.0 mmol) was
added to a well stirred suspension of the corresponding carbonyl- -
lactam (1.0 mmol) and indium powder (6.0 mmol) in THF–NH4Cl
(aq sat.) (1:5, 5 mL) at 0 °C. After disappearance of the starting ma-
terial (TLC) the mixture was extracted with EtOAc (3 × 5 mL). The
organic extract was washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
(EtOAc–hexanes mixtures) gave analytically pure compounds.
Spectroscopic and analytical data for some representative pure
forms of 5 and 14 follow.
Anal. Calcd for C13H19NO3: C, 65.80; H, 8.0; N, 5.90. Found: C,
65.87; H, 8.09; N, 5.88.
(3R,4S)-4-[(R)-1-Hydroxy-2-phenyl-2,3-butadienyl]-3-meth-
oxy-1-(p-methoxyphenyl)-2-azetidinone [(+)-14m]
Aldehyde (+)-1i (46 mg (0.197 mmol), after chromatography of the
residue (CH2Cl2–EtOAc, 9.5:0.5), gave compound (+)-14m.
Yield: 58 mg (84%); colorless oil; [ ]D +99.8 (c 1.3, CHCl3).
IR (CHCl3): 3419, 2989, 1940, 1746 cm–1.
(3R,4S)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-1-(p-
methoxyphenyl)-3-(1-methyl-1,2-propadienyl)-2-azetidinone
[(+)-5a]
From azetidine-2,3-dione (+)-1a (50.5 mg, 0.173 mmol), compound
(+)-5a was obtained.
1H NMR: = 7.51 (m, 2 H), 7.32 (dd, J = 6.8, 2.2 Hz, 2 H), 6.87 (dd,
J = 6.8, 2.2 Hz, 2 H), 7.31 (m, 3 H), 5.22 (m, 3 H), 4.72 (d, J = 4.9
Hz, 1 H), 4.48 (dd, J = 4.9, 2.7 Hz, 1 H), 3.79 (s, 3 H), 3.69 (s, 3 H).
13C NMR: = 208.2, 164.4, 156.8, 133.9, 129.6, 128.6, 127.3,
126.8, 119.8, 114.5, 106.0, 84.3, 80.2, 67.1, 60.0, 59.4, 55.5.
Yield: 44 mg (74%); colorless oil; [ ]D +75.4 (c 0.7, CHCl3).
IR (CHCl3): 3340, 2991, 1940, 1742 cm–1.
1H NMR: = 1.36 (s, 3 H), 1.51 (s, 3 H), 1.85 (t, 3 H, J = 3.0 Hz),
3.79 (s, 3 H), 3.80 (dd, 1 H, J = 8.8, 6.4 Hz), 4.14 (br s, 1 H), 4.24
(d, 1 H, J = 7.7 Hz), 4.32 (dd, 1 H, J = 8.8, 6.8 Hz), 4.49 (q, 1 H,
J = 7.0 Hz), 4.98 (dd, 2 H, J = 6.4, 3.0 Hz), 6.86 (dd, 2 H, J = 7.0,
2.5 Hz),
MS (CI): m/z = (%): 352 (M+ + 1, 100), 351 (M+, 34).
Anal. Calcd for C21H21NO4 (289.3): C, 71.78; H, 6.02; N, 3.99.
Found: C, 71.86; H, 6.00; N, 3.97.
Indium Promoted Reaction Between 1,4-Dibromo-2-butyne
and Azetidine-2,3-diones in Aqueous Medium; General Proce-
dure
1,4-Dibromo-2-butyne 16 (2.0 mmol) was added to a well stirred
suspension of the corresponding -keto lactam 1 (1.0 mmol) and in-
dium powder (1.99 mmol) in THF–H2O (1:1, 5 mL) at 0 °C. After
1 h at r.t., sat. aq NH4Cl (2 mL) was added at 0 °C, and the mixture
was allowed to warm to r.t., before being extracted with EtOAc. The
organic extract was washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
(EtOAc–hexane mixtures), gave analytically pure compounds 18.
Spectroscopic and analytical data for some representative forms of
18 follow.
7.63 (dd, 2 H, J = 7.0, 2.5 Hz).
13C NMR: = 205.2, 166.6, 156.7, 130.7, 120.0, 114.0, 109.7, 98.6,
83.5, 79.4, 76.8, 66.8, 66.5, 55.4, 26.6, 25.0, 13.9.
MS (CI): m/z = 346 (M+ + 1, 100), 345 (M+, 20).
Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C,
66.13; H, 6.65; N, 4.00.
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York

1170
B. Alcaide et al.
PAPER
(3R,4S)-3-(1,3-Butadien-2-yl)-4-[(S)-2,2-dimethyl-1,3-dioxolan-
4-yl]-3-hydroxy-1-(2-propynyl)-2-azetidinone [(+)-18c]
From azetidine-2,3-dione (–)-1c (64 mg, 0.287 mmol), compound
(+)-18c was obtained.
References
(1) (a) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
(b) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans.
1 2000, 3015.
(2) Since the landmark review by Cintas in 1995, the organic
chemistry community has witnessed an explosion of interest
in the utility of indium reagents in synthesis, see: Cintas, P.
Synlett 1995, 1087.
Yield: 30 mg (38%); colorless oil; [ ]D +1.7 (c 0.7, CHCl3).
IR (CHCl3): 3344, 1743 cm–1.
1H NMR: = 1.37 (s, 3 H), 1.48 (s, 3 H), 2.28 (t, 1 H, J = 2.6 Hz),
3.90 (m, 4 H), 4.20 (m, 1 H), 4.53 (m, 2 H), 5.22 (d, 1 H, J = 11.0
Hz), 5.37 (s, 1 H), 5.47 (s, 1 H), 5.56 (dd, 1 H, J = 17.6, 1.2 Hz),
6.30 (ddd, 1 H, J = 17.6, 11.0, 0.7 Hz).
(3) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149.
(4) See, for example: (a) Niccolai, D.; Tarsi, L.; Thomas, R. J.
Chem. Commun. 1997, 2333. (b) Southgate, R. Contemp.
Org. Synth. 1994, 1, 417. (c) Southgate, R.; Branch, C.;
Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products,
Vol. 2; Lukacs, G., Ed.; Springer: Berlin, 1993, 621.
(d) The Chemistry of -Lactams; Page, M. I., Ed.; Chapman
and Hall: London, 1992A.
(5) See, for instance: (a) Alcaide, B.; Almendros, P. Synlett
2002, 381. (b) Alcaide, B.; Almendros, P. Chem. Soc. Rev.
2001, 30, 226. (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Oiarbide, M. Synlett 2001, 1813. (d) Palomo, C.; Aizpurua,
J. M.; Ganboa, I.; Oiarbide, M. Amino Acids 1999, 16, 321.
(e) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
(f) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K.
Heterocycles 1988, 27, 1755.
(6) See, for example: (a) Enders, D.; Reinhold, U. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1219. (b) Rich, D. H. In
Peptidase Inhibitors, Comprehensive Medicinal Chemistry,
Vol. 2; Sammes, P. G., Ed.; Pergamon Press: Oxford, 1990,
391. (c) Huff, J. R. J. Med. Chem. 1991, 34, 2305.
(d) Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.;
Han, F.-S. J. Med. Chem. 1987, 30, 976.
(7) Cho, Y. S.; Lee, J. E.; Pae, N. A.; Choi, K. I.; Koh, H. Y.
Tetrahedron Lett. 1999, 40, 1725.
(8) Jayaraman, M.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1997, 38, 709.
(9) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.; Rogers, L. M.;
Rogers, R. D. J. Org. Chem. 1998, 63, 5463.
(10) For recent selected reviews on organic reaction in aq media,
see: (a) Lindström, U. M. Chem. Rev. 2002, 102, 2751.
(b) Manabe, K.; Kobayashi, S. Chem.–Eur. J. 2002, 8, 4095.
(c) Paquette, L. A. In Green Chemistry: Frontiers in Benign
Chemical Synthesis and Processing; Anastas, P. T.;
Williamson, T. C., Eds.; Oxford University Press: New
York, 1998. (d) Lubineau, A.; Augé, J. Top. Curr. Chem.
1999, 206, 1.
MS (CI): m/z = 278 (M+ + 1, 100), 277 (M+, 14).
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C,
64.91; H, 6.93; N, 5.04.
(3R,4S)-3-(1,3-Butadien-2-yl)-1-(3-butenyl)-4-[(S)-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-3-hydroxy-2-azetidinone [(+)-18d]
From azetidine-2,3-dione (–)-1d (54 mg, 0.226 mmol), compound
(+)-18d was obtained.
Yield: 22 mg (34%); colorless oil; [ ]D +1.1 (c 0.8, CHCl3).
IR (CHCl3): 3343, 1745 cm–1.
1H NMR: = 1.36 and 1.45 (s, each 3 H), 2.37 (m, 2 H), 3.27 (m, 1
H), 3.57 (d, 1 H, J = 7.3 Hz), 3.67 (m, 2 H), 4.22 (dd, 1 H, J = 8.7,
6.7 Hz), 4.18 (s, 1 H), 4.41 (dt, 1 H, J = 7.0, 5.8 Hz), 5.08 (m, 2 H),
5.19 (dd, 1 H, J = 11.0, 1.5 Hz), 5.33 (s, 1 H), 5.37 (s, 1 H), 5.54 (dd,
1 H, J = 17.6, 1.6 Hz), 5.77 (m, 1 H), 6.25 (ddd, 1 H, J = 17.3, 11.0,
0.9 Hz).
13C NMR: = 169.1, 143.6, 134.8, 133.7, 117.3, 117.1, 114.8,
109.7, 85.8, 76.1, 66.6, 65.6, 40.4, 31.6, 26.6, 25.0.
MS (CI): m/z = 294 (M+ + 1, 100), 293 (M+, 19).
Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C,
65.59; H, 7.88; N, 4.75.
Indium Promoted Reaction Between Azetidine-2,3-dione (+)-1a
and Water; Procedure for the -Amino Acid (+)-22
A suspension of the azetidine-2,3-dione (+)-1a (0.5 mmol), indium
powder (5 mmol), and solid NH4Cl (3 mmol) in aq MeOH (10 mL;
5% of H2O) was stirred at r.t. for 3 days. The solvent was removed
under reduced pressure and, after flash chromatography (hexanes–
EtOAc, 1:1), compound (+)-22 was obtained in analytically pure
form.
Yield: 42%.
(+)-(2S)-2-(4-Methoxyphenylamino)-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]acetic Acid [(+)-22]
Colorless solid; mp 185–186 °C (hexanes–EtOAc); [ ]D +34.8 (c
1.1, CHCl3).
(11) Similar results were obtained using zinc instead of indium,
see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.;
Rodríguez-Acebes, R. J. Org. Chem. 2001, 66, 5208.
(b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett.
2000, 2, 1411.
(12) The zinc-mediated reaction gave rise to the corresponding
homopropargyl alcohol as a single isomer, see reference.11
(13) The zinc-mediated reaction afforded the syn-adducts with
complete regioselectivity and good diastereoselectivity, see:
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.–Eur. J.
2002, 8, 1719.
(14) When the above coupling was promoted by zinc, the yield
fell considerably, see: Alcaide, B.; Almendros, P.;
Rodríguez-Acebes, R. J. Org. Chem. 2002, 67, 1925.
(15) Chan has postulated that an allylindium(I) intermediate is
formed in indium-mediated organometallic reactions in
aqueous media, see: Chan, T. H.; Yang, Y. J. Am. Chem.
Soc. 1999, 121, 3228.
IR (CHCl3): 3345, 3130, 1710 cm–1.
1H NMR: = 6.93 (br s, 1 H), 6.80 (d, J = 8.9 Hz, 2 H), 6.62 (d,
J = 8.9 Hz, 2 H), 5.63 (br s, 1 H), 4.59 (m, 1 H), 4.11 (dd, J = 8.6,
6.6 Hz, 1 H), 3.97 (dd, J = 8.6, 5.6 Hz, 1 H), 3.76 (s, 3 H), 3.64 (d,
J = 4.1 Hz, 1 H), 1.49 (s, 3 H), 1.38 (s, 3 H).
13C NMR: = 174.2, 153.4, 140.9, 115.1, 109.9, 75.5, 66.8, 61.9,
55.8, 26.6, 24.8.
MS (CI): m/z = (%) 282 (M+ + 1, 100), 281 (M+, 14).
Anal. Calcd for C14H19NO5 (281.3): C, 59.78; H, 6.81; N, 4.98.
Found: C, 59.85; H, 6.79; N, 5.00.
Acknowledgment
Support for this work by the DGI-MCYT (Project BQU2000-0645)
is gratefully acknowledged.
Synthesis 2003, No. 8, 1163–1170 ISSN 1234-567-89 © Thieme Stuttgart · New York