Additions of allenyl/propargyl organometallic reagents to 4-oxoazetidine-2-carbaldehydes: Novel palladium-catalyzed domino reactions in allenynes

Article abstract of DOI:10.1002/1521-3765(20020402)8:7<1719::AID-CHEM1719>3.0.CO;2-U

Metal-mediated carbonyl allenylation and propargylation of 4-oxoazetidine-2-carbaldehydes were investigated in aqueous environment. Different propargyl bromide and metal promoters showed varied regio- and stereoselectivities on product formation. In addit

Full text of DOI:10.1002/1521-3765(20020402)8:7<1719::AID-CHEM1719>3.0.CO;2-U

FULL PAPER
Additions of Allenyl/Propargyl Organometallic Reagents to 4-Oxoazetidine-
2-carbaldehydes: Novel Palladium-Catalyzed Domino Reactions in Allenynes
Benito Alcaide,* Pedro Almendros, and Cristina Aragoncillo[a]
Abstract: Metal-mediated carbonyl al-
lenylation and propargylation of 4-ox-
oazetidine-2-carbaldehydes were inves-
tigated in aqueous environment. Differ-
ent propargyl bromide and metal
promoters showed varied regio- and
stereoselectivities on product formation.
In addition,an unprecedented one-pot
stereoselective synthesis of b-chlorinat-
ed allylic alcohols,which can also be
considered as functionalized allylsilanes,
has been developed,which involves
tin(iv) chloride-mediated reaction of
propargyltrimethylsilane and 4-oxoaze-
tidine-2-carbaldehydes. Some of the re-
sulting coupling products were submit-
ted to transition metal catalyzed reac-
tions,such as the allenic Pauson Khand
and palladium-catalyzed reactions,lead-
ing to novel fused or bridged tricyclic b-
lactams. Remarkably,a novel domino
process,namely the allene cyclization/
intramolecular Heck reaction was
found. A likely mechanism for the
cascade reaction should involve an in-
tramolecular cyclization on a (p-allyl)-
palladium complex and a Heck-type
reaction.
Keywords: allenes
synthesis domino reactions
b-lactams ¥ transition metals
¥
asymmetric
¥
¥
methodology comes from the tendency of such ambident
nucleophiles to produce mixtures of both homopropargylic
and allenic species. Normally,propargyl and allenyl metal
compounds furnish allenyl and propargylic alcohols,respec-
tively,through an addition reaction to carbonyls. In recent
years,pertinent synthetic strategies for the introduction of
propargyl or allenyl groups into carbonyl groups have been
described. In such procedures,the regiochemical selection
was elegantly tuned towards either acetylenic or allenyl
adducts. Thus,the synthesis of homopropargyl alcohols from
propargylpalladium by the umpolung approach,[3] reported by
Tamaru et al.,and the preparation of homopropargyl and
allenyl alcohols from transient allenylindium reagents or
propargylic stannanes,respectively,described by Marshall
et al.,[4] deserve special mention.
Introduction
The efficient formation of carbon carbon bonds with good,
and preferably predictable,stereocontrol is still a synthetic
challenge in organic chemistry. Among the most fundamental
and important reactions for constructing carbon carbon
bonds are the allylation and the propargylation/allenylation
of aldehydes and ketones (carbonyls) with organometallic
reagents. For example,Sakurai,Grignard,and Barbier-type
reactions have been widely used for the allylation of carbon-
yls.[1] Allenes,alkynes,and their derivatives have established a
reputation as increasingly popular intermediates in modern
organic synthesis because of their unique structural character-
istics and reactivities,which include ionic,radical,or con-
certed processes. The reactions of allenyl and propargyl
organometallic reagents with carbonyl compounds provide
useful synthetic intermediates.[2] The major drawback of this
Organometallic reactions in aqueous media have been the
subject of considerable study because of their potential as
environmentally benign chemical processes,and because of
their synthetic advantages,particularly the unique reactivities
[a] Prof. Dr. B. Alcaide,Dr. P. Almendros,C. Aragoncillo
[5]
and selectivities,which are often exhibited in water.
b-
¬
Departamento de QuÌmica Organica I
Facultad de QuÌmica
Lactam antibiotics represent the most widely prescribed drugs
in medicine because of their high antibacterial activities
against many pathogenic bacteria,as well as their exception-
ally low toxicity toward hosts.[6] Additionally, b-lactams show
other interesting biological properties,especially in enzyme
inhibition,and from a synthetic point of view the develop-
ment of new methodologies based on the 2-azetidinone
nucleus has reached considerable importance.[7] As part of a
continuing commitment to the synthesis and synthetic appli-
Universidad Complutense de Madrid,28040 Madrid (Spain)
Fax : (‡34)91-3944103
E-mail: alcaideb@quim.ucm.es
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author. It con-
tains spectroscopic and analytical data for compounds (‡)-3b, (‡)-3c,
(Æ)-3 f, (‡)-4b, (‡)-4c, (Æ)-4 f, (‡)-7a, (‡)-7d, 7 f, g, 13b e, 13j, 13l
n, (‡)-17, (‡)-18b, (À)-20, (‡)-26b,and acetylmandelates of alcohols
(‡)-3a, (‡)-7 f,and ( ‡)-13 f; as well as experimental procedures for
compounds (‡)-17, (À)-20,and acetylmandelates of alcohols ( ‡)-3a,
(‡)-7 f,and ( ‡)-13 f.
[8]
cations of chiral,functionalized 2-azetidinones, we decided
Chem. Eur. J. 2002, 8,No. 7
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1719

B. Alcaide et al.
FULL PAPER
to pursue metal-based approaches for the stereoselective
incorporation of new substituents,which retain versatile and
useful unsaturated groups capable of future transformations,
into the b-lactam ring. We report here a general study of the
additions of allenyl/propargyl organometallic compounds to
4-oxoazetidine-2-carbaldehydes,together with further inter-
esting new synthetic transformations.
H
H
N
CH3O
O
O
(+)-1a
a)
OH
H
OH
H
H
N
H
H
N
CH3O
CH3O
+
H
Results and Discussion
O
O
(+)-syn-2 (42%)
(+)-anti-2 (4%)
One might think that propargyl organometallic compounds
would serve as allenyl reagents,with propargyltrimethylsilane
being a well-documented reagent for regioselective carbonyl
allenylation.[9] In this context,we began this work by
investigating the effect of various Lewis acids,such as tin( iv)
chloride,titanium( iv) chloride,and boron trifluoride diethyl
etherate,on the diastereoselectivity of the allenylation of
4-oxoazetidine-2-carbaldehyde (‡)-1a with propargyltrime-
thylsilane. In the event,the expected allenyl alcohol was
obtained for the boron trifluoride diethyl etherate induced
reaction,whereas the titanium-promoted reaction was messy.
The a-allenic alcohol (‡)-2 was obtained in 46% yield as a
mixture (90:10) of chromatographically separable syn/anti
isomers (Scheme 1).
Scheme 1. Preparation of a-allenic alcohol (‡)-2: a) propargyltrimethyl-
silane,BF 3 ¥ Et2O,dichloromethane, À788C,12 h.
H
H
N
R2
O
O
R1
(+)-1a R1 = 2-Propenyl, R2 = CH3O
(+)-1b R1 = 2-Propenyl, R2 = PhO
(+)-1c R1 = 3-Butenyl, R2 = CH3O
(+)-1d R1 = 3-Butenyl, R2 = PhO
(+)-1e R1 = 4-MeOC6H4, R2 = 2-Propenyloxy
(±)-1f R1 = 4-MeOC6H4, R2 = 2-Propenyl
a)
To our delight,we found that the tin( iv) chloride promoted
reaction between propargyltrimethylsilane and (‡)-1a pro-
duced the isomerically pure functionalized b-chlorinated
allylic alcohol (‡)-3a. Similarly,the tin-catalyzed reaction of
4-oxoazetidine-2-carbaldehydes 1b f,produced 2-azetidi-
none b-chlorovinyl alcohols 3b f as single isomers in
moderate to reasonable yields (42 55%) (Scheme 2).
Compounds 3 can also be considered as multifunctionalized
allylsilanes,exhibiting a valuable manifold reactivity,which
could potentially be used in a broad range of synthetic
applications.[10] Also,adducts 3 are protected b-amino alco
Cl
OH Cl
H
H
N
H
H
N
R2
R2
+
SiMe3
O
R1
O
R1
(+)-4a (14%)
(+)-4b (18%)
(+)-4c (5%)
(+)-4d (15%)
(+)-4e (20%)
(±)-4f (4%)
(+)-3a (34%)
(+)-3b (50%)
(+)-3c (42%)
(+)-3d (55%)
(+)-3e (42%)
(±)-3f (53%)
Scheme 2. Preparation of 2-chloro-3-silapropenyl alcohols 3: a) propar-
gyltrimethylsilane,SnCl 4,dichloromethane, À788C,1 h.
¬
Abstract in Spanish: Se investigaron la alenilacion y propar-
¬
gilacion de 4-oxoazetidin-2-carbaldehidos promovidas por
hols,which constitute an important class of biologically
interesting compounds.[11] In all cases,by-products 4a f were
detected in the 1H NMR spectra of the crude reaction
mixtures,accounting for approximately 7 30% of the
products formed. Compounds 4a f were isolated as pure
compounds by gravity flow chromatography in a similar ratio
(4 20% yield). Modification of the reaction of a propargyl-
silane with an aldehyde so that a diene can be made rather
than an allenyl alcohol would be a useful extension.[12] b-
Chlorovinyl alcohols 3 were transformed into b-lactam-
tethered chlorodienes 4 in one step (SnCl4/CH2Cl2/ À 788C
or CH3SO2Cl/Et3N/CH2Cl2/08C). This reaction confirms that
by-products 4 arise from hydroxy elimination in adducts 3
with concomitant trimethylsilyl cleavage under the reaction
conditions. For synthetic purposes,we chose the slightly higher
yielding methanesulfonyl chloride procedure (Scheme 3).
Not unexpectedly,only the trans-olefin was formed in
compounds 4.[13] Our production of chlorodienes closely
resembles a result obtained by Pornet in the titanium(iv)
chloride induced reaction of propargyltrimethylsilane with
metales en medios acuosos. Los diferentes metales produjeron
regio- y estereoselectividades variadas. Ademas, se ha desa-
rrollado una sÌntesis sin precedentes de alcoholes alÌlicos b-
clorados, que pueden considerarse tambien como alilsilanos
funcionalizados, mediante la reaccion de propargiltrimetilsila-
no y 4-oxoazetidin-2-carbaldehidos catalizada por tetracloruro
de estanƒo. En los productos de acoplamiento resultantes se
realizaron transformaciones sinteticas catalizadas por metales
de transicion, como por ejemplo la variante alenica de la
ciclacion de Pauson-Khand y reacciones catalizadas por
Pd(II). De esta forma, se han obtenido diferentes sistemas b-
lactamicos tricÌclicos fusionados o puenteados, con diferentes
conectividades de anillos y estructuralmente muy novedosos.
Hay que resaltar el descubrimiento de un nuevo proceso
¬
¬
¬
¬
¬
¬
¬
¬
¬
¬
¬
domino, que se ha denominado ciclacion de alenos/reaccion
intramolecular de Heck. Un mecanismo razonable para esta
¬
¬
reaccion en cascada deberÌa involucrar la ciclacion intramo-
¬
lecular de un complejo de (p-alil)paladio y una reaccion
intramolecular de tipo Heck.
1720
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Chem. Eur. J. 2002, 8,No. 7

Pd-Catalyzed Domino Reactions in Allenynes
1719 1729
Cl
OSnCl3
OH Cl
H
H
N
H
H
N
H
H
N
H
H
N
R2
R2
R2
R2
SiMe3
SnCl4
a)
O
+
SiMe3
R1
O
R1
O
R1
O
R1
Me3Si
O
1
6
(+)-3a
(+)-3b
(+)-3c
(+)-3d
(+)-3e
(±)-3f
(+)-4a (80%)
(+)-4b (81%)
(+)-4c (80%)
(+)-4d (79%)
(+)-4e (90%)
(±)-4f (88%)
SnCl4
Cl–
–ClSiMe3
SiMe3
–Me3Si+
SnCl3
OSnCl3
R1
O
Cl
H
H
N
R2
H
H
N
R2
Scheme 3. Synthesis of chlorodienes 4: a) CH3SO2Cl,Et 3N,dichloro-
methane,0 8C,30 min.
Me3Si
O
O
R1
ClSiMe3
carbonyls.[14] However,his interpretation of the pathway to
the chlorodienes may be needs amending,because he
postulated that an allenyl carbinol is the intermediate. We
think that this reaction actually goes through an intermediate
such as compounds 3. These are the first examples of the
reaction of propargyltrimethylsilane to give b-chlorinated
allylic alcohols,in either thermal or metal-mediated additions.
The configuration at the carbinolic chiral center of the
product (‡)-3a was established by comparison of the
1H NMR chemical shifts of its acetylmandelates,[15] and was
assumed to be the same for the
H2O
Me
Me
Me
Cl
Si
Cl
O
H
Sn
Cl
Cl
OH Cl
H
H
H
H
N
R2
R2
N
Me3Si
R1
O
R1
O
5
3
Scheme 4. Mechanistic explanation for the formation of 2-chloro-3-
silapropenyl alcohols 3.
There are several reported reactions of propargyltrime-
thylsilane in which the intermediate cation is captured
without loss of the silyl group. They include the intramolec-
ular capture of the cation by oxygen nucleophiles[16] and
carbon nucleophiles,[17] as well as the capture of the cation
after a silyl shift.[18] What makes the present reaction
unprecedented is the capture of the cation by an external
nucleophile. The observed stereochemistry is not in conflict
with this stepwise mechanism,because the chlorine ion must
attack anti to the silyl group,which will almost certainly be
rest of b-lactams 3. The stereo-
OH Cl
H
H
N
chemistry of the double bond in
compounds 3 was assigned by
qualitative homonuclear NOE
difference spectra,as depicted
in Figure 1 for compound (‡)-
3a. Similar values of NOE en-
hancements for compounds
3b f were observed,in agree-
ment with the proposed stereo-
chemistry.
CH3O
H
SiMe3
O
(+)-3a
Figure 1. Selected NOE effects
and stereochemistry of chloro-
silapropenyl alcohol (‡)-3a.
À
placed anti to the incoming electrophile when the C C bond is
being formed. Although it looks as though the chlorine ion
has attacked the more hindered site, syn to the carbinol atom,
it is actually the less hindered side at the time of attack,
because the silyl group is larger. The high preference for the
formation of the 4,1'-syn products 3 in the tandem proccess
must be set up at the carbonyl addition step. The observed syn
stereochemistry could be elucidated as the consequence of a
Felkin addition,as shown in the transition state model
depicted in Figure 2. The large substituent (the amino group
The high selectivity observed in the formation of b-
chlorovinyl alcohols 3 could point to a concerted mechanism.
According to this theory,the whole process from 1 to 3 could
be explained by an initial carbonyl-allenylation,followed by a
chlorotrimethylsilane transfer. The formation of 2-chloro-3-
silapropenyl alcohols 3 could be consistent with participation
of the six-membered,cyclic,chairlike transition structure 5,
which controls both the regio- and the stereochemistry of the
reaction (Scheme 4). To probe the above mechanism we had
to show that the intermediate a-allenic alcohol does give the
corresponding chlorodiene in the presence of tin(iv) chloride
and chlorotrimethylsilane. Treatment of the a-allenic alcohol
(‡)-2 with tin(iv) chloride and chlorotrimethylsilane in
dichloromethane at À788C was informative in that compound
(‡)-2 remained unaltered after several hours at the above
conditions. This experiment leads us to suggest an alternative
explanation,which involves a change in mechanism for the
formation of the b-chlorovinyl alcohols. We believe the
reaction is a stepwise process with the chlorination proceeding
via a silicon-stabilized carbocation. Thus,the propargylsilane
attacks the aldehyde (coordinated to the tin chloride),but
instead of losing the trimethylsilyl group,the intermediate b-
silyl-stabilized cation 6 accepts a nucleophile,the chloride ion
(Scheme 4).
SiMe3
OH Cl
H
H
M
R2
H
H
N
R2
H
O
H
SiMe3
O
R1
N
O
R1
syn isomer
Figure 2. Model to explain the observed 4,1'-syn stereochemistry.
of the four-membered ring) is assumed to be arranged
perpendicular to the carbonyl group,the propargyltrimethyl-
silane group attacks the C O bond in the most favored
ˆ
conformation,explaining the preference for the syn-config-
ured products.
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B. Alcaide et al.
FULL PAPER
In a previous report we described additions to a-keto
lactans of allenyl/propargylzinc,tin,and indium reagents,
prepared in situ through metal-mediated reaction of prop-
argyl bromides in aqueous media.[8e,f] It was found that these
additions proceed with full regioselectivity under certain
conditions. We were particularly interested in probing the
degree of reagent versus substrate regio- and stereocontrol in
such reactions with other relevant classes of nonracemic
carbonyl compounds. We thus evaluated the feasibility of
metal-mediated Barbier-type carbonyl-propargylation/alleny-
lation reactions of 4-oxoazetidine-2-carbaldehydes in eco-
friendly media,studying the diastereochemistry ( syn vs. anti)
and the regiochemistry of the connection (e.g.,allenylation vs.
propargylation). Since alkynes and allenes possess a rich
chemistry,the resulting coupled products are prone to under-
go further transformations,making them versatile synthetic
tools. Since we recently reported that the ionic strength
enhancement of the reaction solvent provided by the addition
of ammonium chloride accelerated the carbonyl additions in
aqueous media,the propargylation/allenylation reactions
were conducted in the presence of a saturated solution of
NH4Cl.[8e] Results from the metal-promoted reactions be-
tween aldehydes 1 and propargyl bromide (Scheme 5) are
summarized in Table 1. The tin- and indium-promoted
reactions proceeded with total diastereocontrol,but poor
regiocontrol. The results in Table 1 show that the zinc-
mediated reaction is the best method for the regio- and
stereoselective addition of propargyl bromide to aldehydes 1,
affording the syn adducts with complete regioselectivity and
85:15 98:2 diastereoselectivity. Fortunately,the diastereo-
meric homopropargylic alcohols 7 and 8 were easily separated
by gravity flow chromatography in all cases.
Next,we needed to find a metal-mediated carbonyl-
allenylation method that proceeds in a highly regio- and
diastereoselective fashion. Thus,we used propargyl bromides
bearing an aliphatic or an aromatic substituent at the terminal
position. Reactions of aldehydes 1 with 3-substituted prop-2-
ynyl bromides afforded the corresponding a-allenic alcohols
13 as regioisomerically pure products in diastereomeric ratios
of about 90:10 100:0 (Scheme 6). The diastereomeric syn-
and anti-alcohols were amenable to separation by bench
Scheme 6. Regioselective preparation of a-allenic alcohols 13 in aqueous
media.
chromatography. This regiochemical preference is in sharp
contrast to the behavior of propargyl bromide itself in metal-
mediated reactions in aqueous media. The results are
summarized in Table 2.
It may be reasonable to postulate a metallotropic rear-
rangement between the propargyl- and allenylmetallic spe-
cies. Both intermediates from this equilibrium can react with
the aldehydes 1. In our case,depending on the structure of the
parent halide and the reaction conditions,either the a-allenic
or homopropargylic alcohols could be synthesized. It may be
inferred that different steric effects in the organometallic
reagents derived from differently substituted propargyl bro-
mides may be responsible for the different regiochemical
preference of the propargyl/allenyl metals involved in the
reaction,by stabilizing one of the intermediates of the
metallotropic equilibrium rather than the other. Probably,
the isomerization of propargylmetal to allenylmetal is re-
stricted by the steric effect of a
OH
OH
H
H
N
H
H
N
R2O
R2O
R1
H
H
N
O
R1
O
R2O
7
8
Br
O
aqueous medium
metal
OH
OH
O
R1
H
H
N
H
H
N
R2O
R2O
1
O
R1
O
R1
9
10
Scheme 5. Regioselective preparation of homopropargylic alcohols 7 in
aqueous media.
substituent (R1 ˆ CH3 or C6H5)
Table 1. Regio- and stereoselective propargylation of 4-oxoazetidine-2-carbaldehydes 1.[a]
in the bromopropyne. Thus,
allenyl alcohols 13 are pro-
duced almost exclusively. Iso-
merization of the initially
formed propargylmetal species
to the corresponding allenyl
organometallic can be induced
by the absence of substituent
(R1 ˆ H) at the propargyl bro-
mide. Then,the allenylmetal
undergoes nucleophilic addi-
tion to afford homopropargylic
alcohols 7 selectively. The for-
mation of alcohols 7 and 13 is
consistent with participation of
Aldehyde
R1
R2
M
System solvent
7:8:9:10 ratio[b]
Yield [%][c]
(‡)-1a
(‡)-1a
(‡)-1c
(‡)-1g
(‡)-1g
(‡)-1h
(‡)-1i
(‡)-1i
(‡)-1j
(‡)-1j
(‡)-1j
(‡)-1j
(‡)-1j
(‡)-1j
(‡)-1k
2-propenyl
2-propenyl
3-butenyl
2-propynyl
2-propynyl
2-propynyl
4-pentynyl
4-pentynyl
PMP
PMP
PMP
PMP
PMP
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Zn
In
Zn
Zn
In
Zn
Zn
In
Zn
Zn
In
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
MeOH/NH4Cl (aq. sat.)
THF/NH4Cl (aq. sat.)
THF/H2O
85:15:0:0
55:0:45:0
90:10:0:0
90:10:0:0
57:0:43:0
98:2:0:0
55 (7a)
72 (7a)
50 (7b)
64 (7c)
65 (7c)
57 (7d)
60 (7e)
66 (7e)
65 (7 f)
28 (7 f)
74 (7 f)
69 (7 f)
65 (7 f)
59 (7 f)
75 (7g)
92:8:0:0
55:0:45:0
90:10:0:0
90:10:0:0
80:0:20:0
65:0:35:0
57:0:43:0
54:0:46:0
90:10:0:0
In
Sn
Sn
Zn
THF/NH4Cl (aq. sat.)
THF/H2O
THF/NH4Cl (aq. sat.)
PMP
PMP
1722
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Chem. Eur. J. 2002, 8,No. 7

Pd-Catalyzed Domino Reactions in Allenynes
1719 1729
Table 2. Regio- and stereoselective allenylation of 4-oxoazetidine-2-carbaldehydes 1.[a]
at the carbinolic stereocenter.
Again,the stereochemical re-
sult can be interpreted by the
Felkin Anh model.
Aldehyde
R1
R2
R3
Metal
11:12:13:14 ratio[b]
Yield [%][c]
(‡)-1a
(‡)-1c
(‡)-1d
(‡)-1e
(Æ)-1 f
(‡)-1g
(‡)-1g
(‡)-1h
(‡)-1j
(‡)-1j
(Æ)-1l
(Æ)-1m
(‡)-1a
(‡)-1g
(‡)-1j
(‡)-1j
(Æ)-1l
2-propenyl
3-butenyl
3-butenyl
PMP
MeO
MeO
PhO
2-propenyloxy
2-propenyl
MeO
MeO
MeO
MeO
MeO
ethenyl
2-propynyl
MeO
MeO
MeO
MeO
ethenyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
In
In
In
In
In
In
Zn
In
In
Zn
In
In
In
In
In
Zn
In
0:0:95:5
0:0:97:3
0:0:90:10
0:0:90:10
0:0:90:10
0:0:98:2
0:0:92:8
0:0:93:7
0:0:91:9
0:0:90:10
0:0:90:10
0:0:90:10
0:0:100:0
0:0:95:5
0:0:90:10
18:2:75:5
0:0:90:10
75 (13a)
77 (13b)
92 (13c)
80 (13d)
90 (13e)
75 (13 f)
40 (13 f)
69 (13g)
77 (13h)
55 (13h)
60 (13i)
90 (13j)
64 (13k)
60 (13l)
84 (13m)
80 (13m)
89 (13n)
The allene moiety represents
a versatile and useful building
block in organic synthesis.[19]
However,selectivity problems
are significant. Intramoleculari-
zation of the reactions,usually
caused by placement of the
group at such a distance that
five- or six-membered rings are
formed,should automatically
solve the positional selectivity
problems,because larger rings
are unfavored. Considering that
the use of allenes in transition
metal catalyzed cyclization re-
actions is of great current inter-
est,[20] we turned our attention
to transition metal catalyzed
PMP
2-propynyl
2-propynyl
3-butynyl
PMP
PMP
PMP
PMP
2-propenyl
2-propynyl
PMP
PMP
PMP
Ph
Ph
Ph
Ph
[a] All reactions were carried out on 1 mmol scale. PMP ˆ 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.
the six-membered,cyclic transition structures 15 and 16. From
a mechanistic point of view,our results could be explained as
illustrated in Scheme 7.
Derivatization of the alcohols 7 and 13 with (R)- and (S)-
acetylmandelic acids allowed assignment of the configuration
reactions in our b-lactam-tethered a-allenic alcohols.[21] Thus,
we tried the less exploited allenic variant of the Pauson
Khand type cycloaddition with the allenynes (‡)-13 f and
(‡)-17.[22] In a previous study in our group on the use of the
Pauson Khand cyclization as an entry to fused tricyclic
2-azetidinones,attempts at generating central ring systems
larger than six proved unsuccessful.[23] This result was
expected because until recently the intramolecular variant
of this reaction was largely restricted to the construction of
bicyclo[3.3.0]octenones and bicyclo[4.3.0]nonenones.[24] Sub-
stitution patterns on allenynes (‡)-13 f and (‡)-17 were
selected in order to direct the
regiochemical outcome of the
cycloaddition to the six-mem-
bered central ring formation.
However,we found that the
[2‡2‡1] cycloaddition pro-
duced tricycles 18 bearing a
central seven-membered ring
as the only isomer. Cycload-
ducts 18 presumably arise from
the isomerization of the initially
formed adducts 19 (Scheme 8).
Conjugation of the dienone
moiety with the lone pair of
the nitrogen atom is believed to
promote the formation of com-
pounds 18.
The tandem or domino reac-
tions are versatile methods for
constructing complex structures
in one step,offering a conven-
ient and economical way to
prepare desired organic mole-
cules.[25] A requirement for suc-
cessful tandem reactions is the
compatibility of all reactions
Scheme 8. Synthesis of fused
tricyclic b-lactams 18 by
a
[2‡2‡1] cyclization of 2-azeti-
dinone-tethered allenynes 13
and CO: a) [Co2(CO)8],Me
NO,dichloromethane,room
temperature.
-
3
Scheme 7. Mechanistic explanation for the regioselective formation of
alcohols 7 and 13.
Chem. Eur. J. 2002, 8,No. 7
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1723

B. Alcaide et al.
FULL PAPER
involved in such processes. Transition metal catalysts are
ideally suited for this,and palladium catalysts have attracted
special interest because of their tolerance of many functional
groups.[26] However,one of the major problems associated
with the combination of two Pd-catalyzed reactions is the
differentiation of the reacting functional groups; thus a fine
adjustment of their reactivity is necessary. In contrast to 1,3-
dienes,the corresponding 12,-dienes (allenes) have found
limited use in palladium(ii)-catalyzed oxidations.[27] We were
interested in exploring the 1,2-functionalization of the allene
moiety in our allenynol derivatives. The carbamate (À)-20
was selected as the starting material for the palladium(ii)-
catalyzed reaction. The above carbamate was prepared from
the a-allenic alcohol (‡)-13 f by treatment with tosyl iso-
cyanate (Scheme 9). Reaction of compound (À)-20 was
Scheme 10. Rationalization for the formation of fused tricyclic b-lactam 21
by domino allene carbamate insertion/intramolecular Heck reaction.
Scheme 9. Synthesis of fused tricyclic b-lactam 21 from a-allenic alcohol
13 f through palladium(ii)-catalyzed domino cyclization reaction of 2-aze-
tidinone-tethered allenyne carbamate 20: a) TsNCO,THF,room temper-
ature; b) [Pd(OAc)2] 10 mol% ,LiBr,[Cu(OAc) 2],K 2CO3, O2,acetoni-
trile,room temperature.
Encouraged by this interesting result,we decided to explore
the reactivity of the allenynol moiety itself under these
cascade conditions. To our delight,treatment of allenynols
(‡)-13 f, (‡)-13g,and 13j under the above palladium-
catalyzed domino reaction conditions afforded the bridged
medium-sized ring tricycles 26a c as single isomers,albeit in
moderate yields (Scheme 11). Although complete conversion
carried out at room temperature in acetonitrile in the
presence of 10 mol% of [Pd(OAc)2],five equivalents of LiBr,
two equivalents of [Cu(OAc)2],and 1.2 equivalents of K 2CO3
under an atmospheric pressure of oxygen. The 1H NMR
spectrum of the crude material displayed no signal corre-
sponding to the allene or alkyne moieties. To our delight,the
resulting product was identified after purification as the
tricycle (‡)-21(Scheme 9). Compound (‡)-21 was isolated in
moderate yield as the only isomer,indicating that both the
regio- and stereoselectivity are extremely high.
The formation of compound 21 could be rationalized in
terms of an unprecedented domino allene amidation/intra-
molecular Heck-type reaction.[28] Compound 22 must be the
nonisolable intermediate (see Scheme 10). A likely mecha-
nism for 22 would involve a (p-allyl)palladium intermediate
as proposed by B‰ckvall and co-workers.[27b] The allenepalla-
dium complex 23 is formed initially and undergoes a
nucleophilic attack by the bromide to produce a s-allylpalla-
dium intermediate,which rapidly equilibrates to the corre-
sponding (p-allyl)palladium intermediate 24. Then,an intra-
molecular amidation reaction on the (p-allyl)palladium com-
plex must account for the formation of intermediate 22.
Compound 22 evolves to tricycle 21 through a Heck-type
coupling reaction. The alkenylpalladium intermediate 25,
generated in the 7-exo-dig cyclization of bromoenyne 22,is
trapped by the bromide anion to yield the fused tricycle 21
(Scheme 10). Thus,the same catalytic system is able to
promote two different but sequential catalytic cycles.
Scheme 11. Synthesis of bridged tricyclic b-lactams 26 from 2-azetidinone-
tethered allenynols 13 through palladium(ii)-catalyzed domino cyclization
reactions: a) [Pd(OAc)2] 10 mol%,LiBr,[Cu(OAc) 2],K 2CO3, O2,aceto-
nitrile,room temperature; b) [Pd(OAc) 2] 10 mol% ,LiBr,[Cu(OAc) 2],
K2CO3, O2,acetonitrile,reflux temperature.
1
was observed by TLC and H NMR analysis of the crude
reaction mixtures,the high polarity of adducts 26 may be
responsible for the modest yields of isolated products.
Compounds 26 are remarkable since they possess an unusual
pyramidalized bridgehead structure.[29] A cascade process
1724
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Chem. Eur. J. 2002, 8,No. 7

Pd-Catalyzed Domino Reactions in Allenynes
1719 1729
analogous to the formation of compound 21 seems to be
taking place in this transformation. However,a dramatic
change in the regioselectivity of the nucleophilic insertion into
the (p-allyl)palladium intermediate 27 was observed when the
bridged dihydrofurans were formed as the exclusive products.
The thermochemically more stable five-membered intermedi-
ate 28 must be involved in the reaction rather than the
corresponding regioisomeric oxirane. Taking into account the
precedent explanation for formation of fused compound 21,
Scheme 12 outlines a mechanistic hypothesis for the achieve-
ment of bridged compounds 26.
Conclusion
In conclusion,we have demonstrated the first direct prepa-
ration of b-chlorovinyl alcohols from aldehydes,together with
a study on the regio- and stereoselective manner in which
enantiopure 4-oxoazetidine-2-carbaldehydes undergo cou-
pling with a variety of propynyl-,and allenylmetal reagents
in aqueous media. Some of the resulting coupling products are
amenable to transition metal catalyzed reactions,such as the
allenic variant of the Pauson Khand type cycloaddition,and
an unprecedented tandem allene cyclization/intramolecular
Heck reaction,with high regio- and stereoselectivity control-
ability,leading to novel fused or bridged tricyclic b-lactams.
These results open up the possibility of future application to
chiral building blocks other than 2-azetidinones. Other
aspects of this chemistry are currently under investigation in
our laboratory.
Experimental Section
General methods: 1H NMR and 13C NMR spectra were recorded on a
Bruker AMX-500,Bruker Avance-300,Varian VRX-300S,or Bruker AC-
200 spectrometer. NMR spectra were recorded in CDCl3 solutions,except
when stated otherwise. Chemical shifts are given in ppm relative to TMS
(d ˆ 0, 1H),or CDCl 3 (d ˆ 76.9, 13C). Low- and high-resolution mass spectra
were recorded on a HP5989A spectrometer using the chemical ionization
mode (CI) unless otherwise stated. Electrospray ionization (ESI) was
performed on a Bruker ESQUIRE LC at 400 eV. Specific rotation [a]D is
given in deg per dm at 208C,and the concentration ( c) is expressed in
g100 mLÀ1. All commercially available compounds were used without
further purification. The starting substrates,4-oxoazetidine-2-carbalde-
hydes 1,were prepared both in racemic and in optically pure forms using
our previously described methodologies. Enantiomerically pure 2-azetidi-
nones 1a e and 1g k were obtained as single cis enantiomers from imines
of (R)-2,3-O-isopropylideneglyceraldehyde,through Staudinger reaction
with the corresponding acid chlorides in the presence of Et3N,followed by
sequential acidic acetonide hydrolysis and oxidative cleavage.[8] Racemic
compounds (Æ)-1 f, (Æ)-1l,and ( Æ)-1m were obtained from N,N-di-(p-
methoxyphenyl)glyoxal diimine in one pot as single cis-diastereoisomers.[30]
Scheme 12. Rationalization for the formation of bridged tricyclic b-
lactams 26 through domino allenynol cyclization/intramolecular Heck
reaction.
Tin(iv) chloride promoted reactions between propargyltrimethylsilane and
4-oxoazetidine-2-carbaldehydes 1; general procedure for the synthesis of
2-chloro-3-silapropenyl alcohols 3: A solution of the appropriate 4-oxo-
azetidine-2-carbaldehyde 1 (0.5 mmol) in dichloromethane (1.0 mL) was
added dropwise to a stirred solution of tin(iv) chloride (0.75 mmol) in
dichloromethane (0.75 mL) at À788C. After 5 min,propargyltrimethylsi-
lane (1.0 mmol) was added and the mixture was stirred for 1 h at À788C.
Saturated aqueous sodium hydrogen carbonate (5 mL) was added and the
mixture was allowed to warm to room temperature before being
partitioned between dichloromethane and water. The organic extract was
washed with brine and dried (MgSO4). The solvent was removed under
reduced pressure and after flash chromatography with ethyl acetate/
hexanes mixtures as eluent,compounds 3 were obtained in analytically
pure form. Variable amounts of the isomerically pure more polar
compounds 4 were isolated in all cases. Spectroscopic and analytical data
for some representative pure forms of 3 follow.[31]
The tricyclic structure (by DEPT,HETCOR,and COSY)
and the stereochemistry (by vicinal proton couplings and
NOE experiments) of compounds 18, 21,and 26 were
established by NMR mono- and two-dimensional techniques.
Selected NOE effects and stereochemistry of some of the
above trycicles are shown in Figure 3.
OH
H
H
N
Me
CH3O
H
O
O
(3R,4S)-4-[(R)-1-Hydroxy-3-chloro-4-trimethylsilyl-2-butenyl]-3-meth-
oxy-1-(2-propenyl)-2-azetidinone ((‡)-3a): Starting with 4-oxoazetidine-2-
carbaldehyde (‡)-1a (96 mg,0.568 mmol),and after chromatography of
the residue with hexanes/ethyl acetate (1:1) as eluent,two fractions were
obtained. The more polar fraction contained the chlorodiene (‡)-4a
(18 mg,14%). The less polar fraction contained the allylic alcohol ( ‡)-3a
(61 mg,34%) as a colorless oil. [ a]D ˆ ‡11.8 (c ˆ 1.2 in CHCl3); 1H NMR
(300 MHz,CDCl 3,25 8C): d ˆ 5.76 (m,1H),5.42 (d, J ˆ 7.6 Hz,1H),5.22
(m,2H),4.82 (dd, J ˆ 7.6,2.9 Hz,1H),4.54 (d, J ˆ 4.9 Hz,1H),4.13 (ddt,
(+)-18a
O
H
O
NTs
Me
Br
H
H
N
O
H
CH3O
H
H
H
H
O
N
H
PMP
(±)-26c
O
Br
(+)-21
Figure 3. Selected NOE experiments of compounds (‡)-18a, (‡)-21,and
(Æ)-26c.
J ˆ 15.9,5.1,1.5 Hz,1H),3.90 (dd,
J ˆ 4.9,2.9 Hz,1H),3.69 (dd, J ˆ 6.8,
1.5 Hz,1H),3.63 (s,3H),2.70 (brs,1H),1.91 (s,2H),0.09 (s,9H);
13C NMR
Chem. Eur. J. 2002, 8,No. 7
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1725

B. Alcaide et al.
FULL PAPER
13C NMR (75 MHz,CDCl 3,25 8C): d ˆ 166.3,137.4,132.9,131.2,128.5,
(75 MHz,CDCl 3,25 8C): d ˆ 167.2,135.8,131.6,121.9,118.4,83.7,68.2,59.9,
59.6,44.0,30.9, À1.4; IR (CHCl3): nÄ ˆ 3422,1751 cm À1; MS (CI): m/z (%):
118.9,117.0,85.5,59.1,58.7,42.8; IR (CHCl
3): nÄ 1749 cmÀ1; MS (CI): m/z
‡
‡
‡
‡
(%): 230 (40) [M ‡ 3] ,228 (100) [ M ‡ H] ; elemental analysis calcd (%)
for C11H14NO2Cl (227.7): C 58.03,H 6.10,N 6.15,Cl 15.57; found: C 58.13,H
6.14,N 6.11,Cl 15.51.
320 (10) [M ‡ 3] ,318 (22) [ M ‡ H] ,57 (100); elemental analysis calcd
(%) for C14H24NO3SiCl (317.9): C 52.90,H 7.61,N 4.41,Cl 11.15; found: C
52.81,H 7.65,N 4.45,Cl 11.10.
(3R,4S)-1-(3-Butenyl)-4-[(1E)-3-chloro-1,3-butadienyl]-3-phenoxy-2-aze-
tidinone ((‡)-4d), method A: Starting with 2-chloro-3-silapropenyl alcohol
(‡)-3d (36 mg,0.108 mmol),and after chromatography of the residue with
hexanes/ethyl acetate (1:1) as eluent,the chlorodiene ( ‡)-4d (11 mg,46%)
was obtained as a colorless oil.
(3R,4S)-1-(3-Butenyl)-4-[(R)-1-hydroxy-3-chloro-4-trimethylsilyl-2-bu-
tenyl]-3-phenoxy-2-azetidinone ((‡)-3d): Starting with 4-oxoazetidine-2-
carbaldehyde (‡)-1d (92 mg,0.376 mmol), and after chromatography of the
residue with hexanes/ethyl acetate (2:1) as eluent,two fractions were
obtained. The more polar fraction contained the chlorodiene (‡)-4d
(17 mg,15%). The less polar fraction contained the allylic alcohol ( ‡)-3d
Method B: Starting with 2-chloro-3-silapropenyl alcohol (‡)-3d (30 mg,
0.075 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (2:1) as eluent,the chlorodiene ( ‡)-4d (18 mg,79%) was obtained
as a colorless oil. [a]D ˆ ‡66.3 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz,
CDCl3,25 8C): d ˆ 6.41 (d, J ˆ 15.0 Hz,1H),6.15 (dd, J ˆ 15.0,8.8 Hz,1H),
5.78 (m,1H),5.41 (m,2H),5.32 (d, J ˆ 4.4 Hz,1H),5.14 (m,2H),4.48 (dd,
J ˆ 8.5,4.4 Hz,1H),3.52 (dt, J ˆ 14.4,7.3 Hz,1H),3.17 (dt, J ˆ 13.9,6.8 Hz,
1H),2.34 (m,2H); IR (CHCl 3): nÄ ˆ 1750 cmÀ1; MS (CI): m/z (%): 306 (42)
1
(81 mg,55%) as a colorless oil. [ a]D ˆ ‡67.7 (c ˆ 1.4 in CHCl3); H NMR
(300 MHz,CDCl 3,25 8C): d ˆ 7.31 (m,2H),7.07 (m,3H),5.79 (m,1H),5.43
(d, J ˆ 7.6 Hz,1H),5.23 (d, J ˆ 4.9 Hz,1H),5.14 (m,2H),4.94 (m,1H),
4.09 (t, J ˆ 4.9 Hz,1H),3.69 (dt, J ˆ 13.9,7.6 Hz,1H),3.21 (dt,
J ˆ 13.9,
7.1 Hz,1H),2.39 (m,3H),1.89 (s,2H),0.10 (s,9H);
13C NMR (75 MHz,
CDCl3,25 8C): d ˆ 165.9,157.3,136.5,134.8,129.6,122.6,121.9,117.2,115.8,
80.3,68.6,60.4,40.9,31.6,30.9,
À1.4; IR (CHCl3): nÄ ˆ 3426,1748 cm À1; MS
‡
‡
‡
‡
(CI): m/z (%): 396 (42) [M ‡ 3] ,394 (100) [ M ‡ H] ; elemental analysis
calcd (%) for C20H28NO3SiCl (393.9): C 60.97,H 7.16,N 3.56,Cl 8.00;
found: C 60.90,H 7.18,N 3.55,Cl 8.02.
[M ‡ 3] ,304 (100) [ M ‡ H] ; elemental analysis calcd (%) for
C17H18NO2Cl (303.8): C 67.21,H 5.97,N 4.61,Cl 11.67; found: C 67.29,H
5.95,N 4.60,Cl 11.70.
(3R,4S)-4-[(1E)-3-Chloro-1,3-butadienyl]-1-(p-methoxyphenyl)-3-(2-pro-
penyloxy)-2-azetidinone ((‡)-4e), method A: Starting with 2-chloro-3-
silapropenyl alcohol (‡)-3e (27 mg,0.066 mmol),and after chromatog-
raphy of the residue with hexanes/ethyl acetate (2:1) as eluent,the
chlorodiene (‡)-4e (11 mg,50%) was obtained as a colorless oil.
(3R,4S)-4-[(R)-1-Hydroxy-3-chloro-4-trimethylsilyl-2-butenyl]-1-(p-meth-
oxyphenyl)-3-(2-propenyloxy)-2-azetidinone ((‡)-3e): Starting with 4-oxo-
azetidine-2-carbaldehyde (‡)-1e (94 mg,0.36 mmol), and after chromatog-
raphy of the residue with hexanes/ethyl acetate (2:1) as eluent,two
fractions were obtained. The more polar fraction contained the chlorodiene
(‡)-4e (23 mg,20%). The less polar fraction contained the allylic alcohol
(‡)-3e (62 mg,42%) as a colorless oil. [ a]D ˆ ‡67.7 (c ˆ 1.4 in CHCl3);
1H NMR (300 MHz,CDCl 3,25 8C): d ˆ 7.43 (d, J ˆ 9.1 Hz,2H),6.89 (d, J ˆ
9.1 Hz,2H),5.96 (m,1H),5.47 (d, J ˆ 7.6 Hz,1H),5.35 (m,2H),5.10 (m,
1H),4.82 (d, J ˆ 5.2 Hz,1H),4.49 (ddt, J ˆ 12.6,5.3,1.5 Hz,1H),4.29 (ddt,
J ˆ 12.6,5.0,1.2 Hz,1H),4.28 (dd, J ˆ 5.2,2.9 Hz,1H),3.79 (s,3H),3.00 (d,
Method B: Starting with 2-chloro-3-silapropenyl alcohol (‡)-3e (27 mg,
0.066 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (2:1) as eluent,the chlorodiene ( ‡)-4e (19 mg,90%) was obtained
as a colorless oil. [a]D ˆ ‡66.3 (c ˆ 0.6 in CHCl3); 1H NMR (200 MHz,
CDCl3,25 8C): d ˆ 7.35 (dd, J ˆ 6.8,2.2 Hz,2H),6.86 (dd, J ˆ 6.8,2.2 Hz,
2H),6.52 (d, J ˆ 15.0 Hz,1H),6.28 (dd, J ˆ 15.0,8.0 Hz,1H),5.92 (m,1H),
J ˆ 10.6 Hz,1H),1.93 (s,2H),0.10 (s,9H);
13C NMR (75 MHz,CDCl
,
3
5.46 (brs,1H),5.44 (brs,1H),5.30 (m,2H),4.87 (d,
J ˆ 4.8 Hz,1H),4.72
13C NMR (50 MHz,
258C): d ˆ 164.1,156.6,135.4,132.9,130.2,122.5,119.0,118.8,114.5,81.2,
(dd, J ˆ 7.9,4.8 Hz,1H),4.16 (m,2H),3.79 (s,3H);
72.8,67.2,59.3,55.5,30.7,30.9,
À1.5; IR (CHCl3): nÄ ˆ 3423,1750 cm À1; MS
CDCl3,25 8C): d ˆ 163.4,156.5,137.4,133.3,132.6,130.9,128.8,118.6,118.4,
‡
‡
117.2,114.4,82.9; IR (CHCl 3): nÄ ˆ 1748 cmÀ1; MS (CI): m/z (%): 322 (40)
(CI): m/z (%): 412 (43) [M ‡ 3] ,410 (100) [ M ‡ H] ; elemental analysis
calcd (%) for C20H28NO4SiCl (409.9): C 58.59,H 6.88,N 3.42,Cl 8.65;
found: C 58.66,H 6.86,N 3.43,Cl 8.68.
‡
‡
[M ‡ 3] ,320 (100) [ M ‡ H] ; elemental analysis calcd (%) for
C17H18NO3Cl (319.8): C 63.85,H 5.67,N 4.38,Cl 11.09; found: C 63.92,H
5.65,N 4.39,Cl 11.06.
General methods for the preparation of chlorodienes 4 from 2-chloro-3-
silapropenyl alcohols 3, method A:
A solution of tin(iv) chloride
Zinc-promoted reaction between propargyl bromide and 4-oxoazetidine-2-
carbaldehydes 1; general procedure for the synthesis of homopropargylic
alcohols 7: Propargyl bromide (3.0 mmol) was added to a well stirred
suspension of the corresponding aldehyde (1.0 mmol) and zinc dust
(6.0 mmol) in THF/NH4Cl (aq. sat.) (1:5,5 mL) at 0 8C. After disappear-
ance of the starting material (TLC),the mixture was extracted with ethyl
acetate (3 Â 5 mL). The organic extract was washed with brine,dried
(MgSO4),and concentrated under reduced pressure. Chromatography of
the residue with ethyl acetate/hexanes mixtures gave analytically pure
compounds. Spectroscopic and analytical data for some representative pure
forms of 7 follow.
(0.75 mmol) in dichloromethane (0.75 mL) was added dropwise to a stirred
solution of the corresponding allylic alcohol 3 (0.5 mmol) at À788C in
dichloromethane (1.0 mL),and the mixture was stirred for 2 h at À788C.
Saturated aqueous sodium hydrogen carbonate (5 mL) was added,and the
mixture was allowed to warm to room temperature before being
partitioned between dichloromethane and water. The organic extract was
washed with brine and dried (MgSO4). The solvent was removed under
reduced pressure and after flash chromatography with ethyl acetate/
hexanes mixtures as eluent,chlorodienes 4 were obtained in analytically
pure form.
Method B: Methanesulfonyl chloride (0.60 mmol) and triethylamine
(1.20 mmol) were sequentially added dropwise to a stirred solution of the
corresponding allylic alcohol 3 (0.50 mmol),in dichloromethane (5 mL) at
08C,and the mixture was stirred for 30 minutes at 0 8C. The organic phase
was washed with water (2 Â 2 mL),dried (MgSO 4),and concentrated under
reduced pressure. Chromatography of the residue with ethyl acetate/
hexanes mixtures as eluent,gave analytically pure chlorodienes 4.
(3R,4S)-1-(3-Butenyl)-4-[(R)-1-hydroxy-3-butynyl]-3-methoxy-2-azetidi-
none ((‡)-7b): Starting with aldehyde (‡)-1c (59 mg,0.322 mmol),and
after chromatography of the residue with hexanes/ethyl acetate (1:1) as
eluent,compound ( ‡)-7b (36 mg,50%) was obtained as a colorless oil.
[a]D ˆ ‡57.5 (c ˆ 0.6 in CHCl3); 1H NMR (300 MHz,CDCl 3,25 8C): d ˆ
5.76 (m,1H),5.10 (m,2H),4.46 (d, J ˆ 4.6 Hz,1H),3.99 (m,1H),3.94 (d,
J ˆ 5.0 Hz,1H),3.63 (m,1H),3.59 (s,3H),3.22 (ddd,
J ˆ 13.9,6.8,5.9 Hz,
1H),2.69 (d, J ˆ 3.7 Hz,1H),2.53 (ddd, J ˆ 6.3,2.7,1.2 Hz,1H),2.39 (m,
2H),2.12 (t, J ˆ 2.7 Hz,1H); 13C NMR (75 MHz,CDCl 3,25 8C): d ˆ 167.6,
(3R,4S)-4-[(1E)-3-Chloro-1,3-butadienyl]-3-methoxy-1-(2-propenyl)-2-
azetidinone ((‡)-4a), method A: Starting with 2-chloro-3-silapropenyl
alcohol (‡)-3a (29 mg,0.091 mmol),and after chromatography of the
residue with hexanes/ethyl acetate (2:1) as eluent,the chlorodiene ( ‡)-4a
(9 mg,45%) was obtained as a colorless oil.
134.9,117.1,82.8,79.7,71.6,69.2,59.3,59.0,40.8,31.8,24.1; IR (CHCl
3): nÄ ˆ
‡
‡
3424,1748 cm À1; MS (CI): m/z (%): 224 (100) [M ‡ H] ,223 (18) [ M] ;
elemental analysis calcd (%) for C12H17NO3 (223.3): C 64.55,H 7.67,N 6.27;
found: C 64.61,H 7.64,N 6.25.
Method B: Starting with 2-chloro-3-silapropenyl alcohol (‡)-3a (29 mg,
0.091 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (2:1) as eluent,the chlorodiene ( ‡)-4a (17 mg,80%) was obtained
as a colorless oil. [a]D ˆ ‡56.5 (c ˆ 0.7 in CHCl3); 1H NMR (300 MHz,
CDCl3,25 8C): d ˆ 6.40 (d, J ˆ 15.0 Hz,1H),6.14 (dd, J ˆ 15.0,8.8 Hz,1H),
Preparation of homopropargylic alcohols (‡)-7c and (‡)-8c: Starting with
aldehyde (‡)-1g (68 mg,0.407 mmol),and after chromatography of the
residue with hexanes/ethyl acetate (1:1) as eluent,49 mg (58%) of the less
polar compound (‡)-7c and 5 mg (6%) of the more polar compound (‡)-
8c were obtained.
5.72 (m,1H),5.46 (brs,1H),5.42 (brs,1H),5.23 (q,
J ˆ 1.2 Hz,1H),5.10
(dq, J ˆ 6.6,1.2 Hz,1H),4.61 (d, J ˆ 4.4 Hz,1H),4.27 (dd, J ˆ 8.8,4.4 Hz,
(3R,4S)-4-[(R)-1-Hydroxy-3-butynyl]-3-methoxy-1-(2-propynyl)-2-azetidi-
none ((‡)-7c): Colorless oil. [a]D ˆ ‡1.5 (c ˆ 0.8 in CHCl3); 1H NMR
1H),4.05 (ddt, J ˆ 15.6,5.4,1.5 Hz,1H),3.54 (m,1H),3.45 (s,3H);
1726
¹ WILEY-VCH Verlag GmbH,69451 Weinheim,Germany,2002
0947-6539/02/0807-1726 $ 20.00+.50/0
Chem. Eur. J. 2002, 8,No. 7

Pd-Catalyzed Domino Reactions in Allenynes
1719 1729
(300 MHz,CDCl 3,25 8C): d ˆ 4.50 (d, J ˆ 4.7 Hz,1H),4.34 (dd, J ˆ 17.6,
2.4 Hz,1H),4.02 (d, J ˆ 4.7 Hz,1H),4.01 (s,1H),3.97 (dd, J ˆ 17.6,2.4 Hz,
1H),3.59 (s,3H),2.56 (dt, J ˆ 5.6,2.7 Hz,1H),2.32 (t, J ˆ 2.7 Hz,1H),2.11
(t, J ˆ 2.7 Hz,1H); 13C NMR (75 MHz,CDCl 3,25 8C): d ˆ 166.7,83.1,79.7,
0.756 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (1:1) as eluent,compound ( ‡)-13g (123 mg,69%) was obtained as
a colorless oil. [a]D ˆ ‡40.2 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3,25 8C): d ˆ 4.84 (td, J ˆ 3.2,1.0 Hz,1H),4.48 (d, J ˆ 4.8 Hz,1H),
4.25 (m,1H),4.03 (t, J ˆ 4.8 Hz,1H),3.59 (m,1H),3.58 (s,3H),3.36 (dt,
J ˆ 13.7,6.8 Hz,1H),2.59 (d, J ˆ 4.6 Hz,1H),2.50 (td, J ˆ 7.3,2.7 Hz,1H),
1.99 (t, J ˆ 2.7 Hz,1H),1.81 (t, J ˆ 3.2 Hz,3H); 13C NMR (75 MHz,CDCl 3,
258C): d ˆ 205.4,167.6,99.7,83.5,81.2,77.3,70.4,70.0,59.9,59.6,40.2,17.9,
16.1; IR (CHCl3): nÄ ˆ 3424,2989,1940,1745 cm À1; MS (CI): m/z (%): 236
76.7,72.9,71.4,68.9,59.4,59.1,30.9,24.1; IR (CHCl
3): nÄ ˆ 3422,1747 cm À1
;
‡
‡
MS (CI): m/z (%): 208 (100) [M ‡ H] ,207 (13) [ M] ; elemental analysis
calcd (%) for C11H13NO3 (207.2): C 63.76,H 6.32,N 6.76; found: C 63.59,H
6.31,N 6.77.
(3R,4S)-4-[(S)-1-Hydroxy-3-butynyl]-3-methoxy-1-(2-propynyl)-2-azetidi-
none ((‡)-8c): Colorless oil. [a]D ˆ ‡107.3 (c ˆ 1.4 in CHCl3); 1H NMR
(300 MHz,CDCl 3,25 8C): d ˆ 4.64 (d, J ˆ 4.9 Hz,1H),4.29 (dd, J ˆ 17.8,
2.7 Hz,1H),4.07 (d, J ˆ 4.9 Hz,1H),3.88 (dd, J ˆ 17.8,2.4 Hz,1H),3.64 (s,
‡
‡
(100) [M ‡ H] ,235 (17) [ M] ; elemental analysis calcd (%) for C13H17NO3
(235.3): C 66.36,H 7.28,N 5.95; found: C 66.43,H 7.26,N 5.94.
Preparation of a-allenic alcohols (‡)-13h and (‡)-14h: Starting with
aldehyde (‡)-1j (55 mg,0.234 mmol),and after chromatography of the
residue with dichloromethane/ethyl acetate (9:1) as eluent,47 mg (70%) of
the less polar compound (‡)-13h and 5 mg (7%) of the more polar
compound (‡)-14h were obtained.
3H),2.95 (d, J ˆ 7.8 Hz,1H),2.61 (dt, J ˆ 6.1,2.7 Hz,1H),2.31 (t,
J ˆ
2.7 Hz,1H),2.10 (t, J ˆ 2.7 Hz,1H); 13C NMR (75 MHz,CDCl 3,25 8C):
d ˆ 166.4,84.3,78.5,73.2,70.9,68.4,59.5,58.5,30.0,24.2; IR (CHCl
3): nÄ ˆ
‡
‡
3421,1748 cm À1; MS (CI): m/z (%): 208 (100) [M ‡ H] ,207 (16) [ M] ;
elemental analysis calcd (%) for C11H13NO3 (207.2): C 63.76,H 6.32,N 6.76;
found: C 63.82,H 6.31,N 6.75.
(3R,4S)-4-[(R)-1-hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(p-meth-
oxyphenyl)-2-azetidinone ((‡)-13h): Colorless solid. m.p. 117 1198C;
1
[a]D ˆ ‡213.8 (c ˆ 0.7 in CHCl3); H NMR (300 MHz,CDCl 3,25 8C): d ˆ
(3R,4S)-4-[(R)-1-Hydroxy-3-butynyl]-3-methoxy-1-(4-pentynyl)-2-azetidi-
none ((‡)-7e): Starting with aldehyde (‡)-1i (62 mg,0.315 mmol),and
after chromatography of the residue with hexanes/ethyl acetate (1:1) as
eluent,compound ( ‡)-7e (45 mg,60%) was obtained as a colorless oil.
[a]D ˆ ‡68.6 (c ˆ 0.6 in CHCl3); 1H NMR (200 MHz,CDCl 3,25 8C): d ˆ
4.47 (d, J ˆ 4.7 Hz,1H),4.03 (m,1H),3.89 (d, J ˆ 4.7 Hz,1H),3.60 (s,3H),
3.57 (m,1H),3.32 (ddd, J ˆ 13.9,7.6,6.3 Hz,1H),2.68 (d, J ˆ 3.9 Hz,1H),
2.54 (dd, J ˆ 6.3,2.7 Hz,2H),2.25 (m,2H),2.12 (t, J ˆ 2.7 Hz,1H),1.99 (t,
J ˆ 2.7 Hz,1H),1.88 (m,2H); 13C NMR (50 MHz,CDCl 3,25 8C): d ˆ 167.6,
7.33 (d, J ˆ 9.0 Hz,2H),6.87 (d, J ˆ 9.0 Hz,2H),4.48 (d, J ˆ 4.9 Hz,1H),
4.65 (m,3H),4.40 (dd, J ˆ 4.9,3.4 Hz,1H),3.79(s,3H),3.67 (s,3H),3.07
(d, J ˆ 40.0 Hz,1H),1.83 (t, J ˆ 3.0 Hz,3H); 13C NMR (75 MHz,CDCl
258C): d ˆ 205.5,164.2,156.7,129.9,119.6,114.4,99.1,84.1,81.2,76.3,69.3,
,
3
59.9,59.1,55.5,15.7; IR (CHCl 3): nÄ ˆ 3422,2990,1940,1748 cm À1; MS (CI):
‡
‡
m/z (%): 290 (100) [M ‡ H] ,289 (16) [ M] ; elemental analysis calcd (%)
for C16H19NO4 (289.3): C 66.42,H 6.62,N 4.84; found: C 66.50,H 6.60,N
4.83.
83.0,82.8,79.7,71.6,69.2,69.1,59.4,59.3,41.1,26.4,24.1,16.2; IR (CHCl
3):
(3R,4S)-4-[(S)-1-hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(p-meth-
oxyphenyl)-2-azetidinone ((‡)-14h): Colorless oil. [a]D ˆ ‡753.5 (c ˆ 0.8
in CHCl3); 1H NMR (300 MHz,CDCl 3,25 8C): d ˆ 7.31(d, J ˆ 9.0 Hz,2H),
6.88 (d, J ˆ 9.0 Hz,2H),4.68 (m,2H),4.59 (d, J ˆ 5.0 Hz,1H),4.48 (t, J ˆ
‡
‡
nÄ ˆ 3423,1748 cm À1; MS (CI): m/z (%): 236 (100) [M ‡ H] ,235 (19) [ M] ;
elemental analysis calcd (%) for C13H17NO3 (235.3): C 66.36,H 7.28,N 5.95;
found: C 66.43,H 7.31,N 5.93.
5.0 Hz,1H),4.39 (s,1H),3.79(s,3H),3.64 (s,3H),2.42 (d,
J ˆ 4.6 Hz,1H),
Indium-promoted reaction between 1-bromo-2-butyne and 4-oxoazetidine-
2-carbaldehydes 1; general procedure for the synthesis of a-allenic alcohols
13: 1-Bromo-2-butyne (3.0 mmol) was added to a well stirred suspension of
the corresponding 4-oxoazetidine-2-carbaldehyde 1 (1.0 mmol) and indium
powder (6.0 mmol) in THF/NH4Cl (aq. sat.) (1:5,5 mL) at 0 8C. After
disappearance of the starting material (TLC) the mixture was extracted
with ethyl acetate (3 Â 5 mL). The organic extract was washed with brine,
dried (MgSO4),and concentrated under reduced pressure. Chromatogra-
phy of the residue with ethyl acetate/hexanes or dichloromethane/ethyl
acetate mixtures gave analytically pure compounds. Spectroscopic and
analytical data for some representative pure forms of 13 follow.
1.78 (t, J ˆ 3.0 Hz,3H); IR (CHCl ): nÄ ˆ 3420,2993,1940,1747 cm À1; MS
3
‡
‡
(CI): m/z (%): 290 (100) [M ‡ H] ,289 (21) [ M] ; elemental analysis calcd
(%) for C16H19NO4 (289.3): C 66.42,H 6.62,N 4.84; found: C 66.35,H 6.64,
N 4.83.
Preparation of a-allenic alcohols (Æ)-13i and (Æ)-14i: Starting with
aldehyde (Æ)-1l (48 mg,0.208 mmol), and after chromatography of the
residue with hexanes/ethyl acetate (1:1) as eluent,32 mg (54%) of the less
polar compound (Æ)-13i and 4 mg (6%) of the more polar compound (Æ)-
14i were obtained.
(3RS,4SR)-4-[(RS)-1-hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(p-
methoxyphenyl)-2-azetidinone ((Æ)-13i): Colorless oil. 1H NMR
(300 MHz,CDCl 3,25 8C): d ˆ 6.87 (dd, J ˆ 6.8,2.4 Hz,2H),7.31 (dd, J ˆ
(3R,4S)-4-[(R)-1-Hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(2-pro-
penyl)-2-azetidinone ((‡)-13a): Starting with aldehyde (‡)-1a (50 mg,
0.298 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (1:2) as eluent,compound ( ‡)-13a (50 mg,75%) was obtained as a
6.8,2.4 Hz,2H),6.19 (ddd,
1.5 Hz,1H),5.32 (m,1H),4.74 (m,1H),4.62 (m,1H),4.58 (m,1H),4.37
J ˆ 17.3,10.3,7.8 Hz,1H),5.49 (dt,
J ˆ 17.3,
colorless oil. [a]D ˆ ‡99.1 (c ˆ 0.7 in CHCl3); 1H NMR (300 MHz,CDCl 3
,
(dd, J ˆ 5.6,4.2 Hz,1H),4.05 (m,1H),3.79 (s,3H),2.07 (d,
J ˆ 5.4 Hz,
1H),1.76 (t, J ˆ 3.0 Hz,3H); 13C NMR (75 MHz,CDCl 3,25 8C): d ˆ 205.8,
165.6,156.5,130.2,130.1,120.4,119.8,114.3,98.7,77.3,69.3,58.0,55.5,15.5;
IR (CHCl3): nÄ ˆ 3425,2993,1942,1746 cm À1; MS (CI): m/z (%): 286 (100)
258C): d ˆ 5.76 (m,1H),5.18 (m,2H),4.80 (m,2H),4.47 (d,
1H),4.24 (s,1H),4.13 (ddt, J ˆ 15.6,5.1,1.7 Hz,1H),3.95 (t,
1H),3.73 (ddt, J ˆ 15.6,6.8,1.2 Hz,1H),3.57 (s,3H),2.58 (d,
J ˆ 5.0 Hz,
J ˆ 4.9 Hz,
J ˆ 4.4 Hz,
1H),1.78 (td, J ˆ 3.2,0.7 Hz,3H); 13C NMR (75 MHz,CDCl 3,25 8C): d ˆ
205.5,167.4,132.1,118.0,99.7,83.6,77.3,70.3,59.6,59.2,43.9,16.0; IR
‡
‡
[M ‡ H] ,285 (23) [ M] ; elemental analysis calcd (%) for C17H19NO3
(285.3): C 71.56,H 6.71,N 4.91; found: C 71.50,H 6.73,N 4.89.
(CHCl3): nÄ ˆ 3424,2991,1940,1748 cm À1; MS (CI): m/z (%): 224 (100) [M
(3RS,4SR)-4-[(SR)-1-hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(p-
methoxyphenyl)-2-azetidinone ((Æ)-14i): Colorless oil. 1H NMR
(300 MHz,CDCl 3,25 8C): d ˆ 7.32 (dd, J ˆ 6.8,2.4 Hz,2H),6.89 (dd, J ˆ
6.8,2.4 Hz,2H),5.43 (dt, J ˆ 17.3,1.2 Hz,1H),5.32 (dq, J ˆ 10.2,1.0 Hz,
‡
‡
‡ H] ,223 (21) [ M] ; elemental analysis calcd (%) for C12H17NO3 (223.3):
C 64.55,H 7.67,N 6.27; found: C 64.62,H 7.65,N 6.29.
(3R,4S)-4-[(R)-1-Hydroxy-2-methyl-2,3-butadienyl]-3-methoxy-1-(2-prop-
ynyl)-2-azetidinone ((‡)-13 f): Starting with aldehyde (‡)-1g (54 mg,
0.324 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (2:3) as eluent,compound ( ‡)-13 f (54 mg,75%) was obtained as a
1H),4.81 (ddd, J ˆ 10.3,3.2,2.4 Hz,1H),4.63 (ddd,
J ˆ 10.3,3.2,2.4 Hz,
1H),4.44 (dd, J ˆ 7.3,5.9 Hz,1H),3.96 (m,1H),4.17 (m,1H),3.78 (s,3H),
2.08 (d, J ˆ 6.1 Hz,1H),1.79 (t,
J ˆ 3.0 Hz,3H); 13C NMR (75 MHz,
colorless oil. [a]D ˆ ‡58.1 (c ˆ 0.9 in CHCl3); 1H NMR (300 MHz,CDCl 3
258C): d ˆ 4.86 (m,2H),4.49 (d, J ˆ 4.9 Hz,1H),4.36 (dd, J ˆ 17.6,2.4 Hz,
1H),4.26 (m,1H),4.06 (t, J ˆ 4.9 Hz,1H),3.89 (dd, J ˆ 17.6,2.4 Hz,1H),
,
CDCl3,25 8C): d ˆ 205.8,165.9,156.3,131.3,128.9,121.0,120.4,113.9,99.0,
77.6,72.8,58.4,55.4,55.0,15.6; IR (CHCl 3): nÄ ˆ 3424,2991,1941,1745 cm
À1
;
‡
‡
MS (CI): m/z (%): 286 (100) [M ‡ H] ,285 (15) [ M] ; elemental analysis
calcd (%) for C17H19NO3 (285.3): C 71.56,H 6.71,N 4.91; found: C 71.63,H
6.72,N 4.93.
3.57 (s,3H),2.57 (d, J ˆ 4.9 Hz,1H),2.26 (t, J ˆ 2.4 Hz,1H),1.82 (td, J ˆ
3.2,0.5 Hz,3H); 13C NMR (75 MHz,CDCl 3,25 8C): d ˆ 205.4,166.8,99.5,
83.8,77.4,72.3,70.3,59.6,59.1,30.8,15.9; IR (CHCl
3): nÄ ˆ 3425,2990,1941,
(3R,4S)-4-[(R)-1-Hydroxy-2-phenyl-2,3-butadienyl]-3-methoxy-1-(2-pro-
penyl)-2-azetidinone ((‡)-13k): Starting with aldehyde (‡)-1a (56 mg,
0.331 mmol),and after chromatography of the residue with hexanes/ethyl
acetate (2:1) as eluent,compound ( ‡)-13k (60 mg,64%) was obtained as a
1747 cmÀ1; MS (CI): m/z (%): 222 (100) [M ‡ H] ,221 (14) [ M] ;
elemental analysis calcd (%) for C12H15NO3 (221.3): C 65.14,H 6.83,N 6.33;
found: C 65.21,H 6.81,N 6.35.
‡
‡
(3R,4S)-1-(3-Butynyl)-4-[(R)-1-hydroxy-2-methyl-2,3-butadienyl]-3-meth-
oxy-2-azetidinone ((‡)-13g): Starting with aldehyde (‡)-1h (137 mg,
colorless oil. [a]D ˆ ‡70.6 (c ˆ 1.0 in CHCl3); 1H NMR (300 MHz,CDCl 3
258C): d ˆ 7.39 (m,5H),5.78 (m,1H),5.24 (m,3H),4.94 (m,1H),4.47 (d,
,
Chem. Eur. J. 2002, 8,No. 7
¹ WILEY-VCH Verlag GmbH,69451 Weinheim,Germany,2002
0947-6539/02/0807-1727 $ 20.00+.50/0
1727

B. Alcaide et al.
FULL PAPER
J ˆ 4.9 Hz,1H),4.16 (ddt,
J ˆ 15.5,5.3,1.6 Hz,1H),4.04 (dd,
J ˆ 5.6,
Bridged tricyclic azetidinone (À)-26a: Starting with allenynol (‡)-13 f
(67 mg,0.305 mmol),compound ( À)-26a (43 mg,48%) was obtained as a
4.9 Hz,1H),3.82 (ddt, J ˆ 15.5,6.7,1.0 Hz,1H),3.63 (d,
J ˆ 4.9 Hz,1H),
3.53 (s,3H),2.58 (d, J ˆ 5.1 Hz,1H); 13C NMR (75 MHz,CDCl 3,25 8C):
d ˆ 207.7,167.4,133.9,132.0,128.6,127.4,126.7,118.2,107.0,83.6,80.6,68.7,
59.8,59.6,44.1; IR (CHCl 3): nÄ ˆ 3424,2991,1940,1748 cm À1; MS (CI):
colorless oil. [a]D ˆ ‡14.0 (c ˆ 0.9 in CHCl3); 1H NMR (500 MHz,CDCl 3
258C): d ˆ 6.56 (t, J ˆ 1.5 Hz,1H),4.61 (dd, J ˆ 4.6,1.2 Hz,1H),4.56 (d,
J ˆ 4.0 Hz,1H),4.47 (dd, J ˆ 15.0,1.5 Hz,1H),4.32 (d, J ˆ 11.2 Hz,1H),
4.07 (d, J ˆ 11.2 Hz,1H),3.88 (t, J ˆ 4.6 Hz,1H),3.87 (d, J ˆ 15.0 Hz,1H),
,
‡
‡
m/z (%): 286 (100) [M ‡ H] ,285 (31) [ M] ; elemental analysis calcd (%)
for C17H19NO3 (285.3): C 71.56,H 6.71,N 4.91; found: C 71.48,H 6.69,N
4.92.
3.64 (s,3H),2.00 (s,3H); 13C NMR (125 MHz,CDCl 3,25 8C): d ˆ 167.0,
141.7,139.6,130.0,109.2,84.4,71.8,55.1,45.8,43.4,16.5; IR (CHCl
3): nÄ ˆ
‡
1745 cmÀ1; MS (ESI): m/z (%): 324 (100) [M (81Br) ‡ Na] ,322 (86) [ M
General procedure for the synthesis of tricyclic 2-azetidinones 18: Solid
[Co2(CO)8] (0.21 g,0.6 mmol) was added to a solution of the corresponding
allenyne (0.5 mmol) in anhydrous CH2Cl2 (7 mL) under argon. The dark
solution thus obtained was stirred at room temperature until complete
complex formation by TLC (ca 1 h) The resulting solution of [Co2(CO)6]
alkyne complex was cooled to 08C and solid anhydrous TMANO (0.08 g,
1 mmol) was added. The reaction flask was warmed to room temperature
by immediate removal of the ice bath. After 30 min,the reaction was again
cooled to 08C,solid anhydrous TMANO (0.08 g,1 mmol) was added,and
the solution was warmed again to room temperature by immediate removal
of the ice bath. This sequence was repeated until a total of 3 mmol (0.24 g)
of anhydrous TMANO was added. After that,the solution was stirred for
1 h at room temperature. The crude mixture was diluted with AcOEt
(20 mL),filtereed through a short path of Celite,and the solvent was
removed under reduced pressure. Chromatography of the residue with
hexanes/ethyl acetate mixtures as eluent gave analytically pure tricycles 18.
‡
(79Br) ‡ Na] ; elemental analysis calcd (%) for C12H14NO3Br (300.2): C
48.02,H 4.70,N 4.67; found: C 48.09,H 4.72,N 4.65.
Bridged tricyclic azetidinone (Æ)-26c: Starting with allenynol (Æ)-13j
(42 mg,0.141 mmol),compound ( Æ)-26c (28 mg,52%) was obtained as a
colorless oil. 1H NMR (500 MHz,CDCl 3,25 8C): d ˆ 7.30 and 6.85 (dd, J ˆ
6.8,2.2 Hz,each 2H),5.81 (d, J ˆ 2.4 Hz,1H),4.30 (t, J ˆ 6.0 Hz,1H),3.89
(d, J ˆ 6.0 Hz,1H),3.84 (d, J ˆ 9.5 Hz,1H),3.78 (s,3H),3.65 (ddd,
J ˆ
12.0,6.0,1.5 Hz,1H),3.43 (d,
1H),2.40 (m,1H),1.31 (s,3H);
J ˆ 9.5 Hz,1H),2.92 (dt, J ˆ 15.9,1.2 Hz,
13C NMR (125 MHz,CDCl 3,25 8C): d ˆ
165.3,155.9,146.4,146.0,134.1,132.0,130.2,117.8,114.3,75.4,70.8,55.4,
50.2,45.3,20.4,14.5; IR (CHCl 3): nÄ ˆ 1747 cmÀ1; MS (ESI): m/z (%): 400
‡
‡
(100) [M (81Br) ‡ Na] ,398 (88) [ M (79Br) ‡ Na] ; elemental analysis
calcd (%) for C18H18NO3Br (376.3): C 57.46,H 4.82,N 3.72; found: C 57.53,
H 4.80,N 3.71.
Tricyclic azetidinone (‡)-18a: Starting with allenyne (‡)-13 f (49 mg,
0.222 mmol),and after chromatography of the residue with ethyl acetate as
eluent compound (‡)-18a (22 mg,40%) was obtained as a colorless oil.
[a]D ˆ ‡183.1 (c ˆ 1.0 in CHCl3); 1H NMR (500 MHz,C 6D6,25 8C): d ˆ
6.09 (s,1H),5.89 (s,1H),3.79 (d, J ˆ 5.0 Hz,1H),3.44 (m,1H),3.23 (d, J ˆ
Acknowledgements
Support for this work by the DGI-MCYT (Project BQU2000 0645) is
gratefully acknowledged. C. Aragoncillo thanks the Comunidad Autonoma
de Madrid for a fellowship.
¬
5.0 Hz,1H),3.09 (m,1H),3.03 (s,3H),2.87 (d,
J ˆ 2.0 Hz,1H),2.52 (t, J ˆ
10.1 Hz,1H),0.60 (d, J ˆ 7.7 Hz,3H); 13C NMR (125 MHz,C D6,25 8C):
6
d ˆ 203.4,172.9,162.5,136.1,120.9,116.9,85.9,69.4,59.8,56.9,41.4,40.6,
20.8; IR (CHCl3): nÄ ˆ 3325,1746,1705 cm À1; MS (CI): m/z (%): 250 (100)
‡
‡
[M ‡ H] ,249 (19) [ M] ; elemental analysis calcd (%) for C13H15NO4
[1] For recent reviews of allylmetal additions,see: a) W. R. Roush,C. R.
Chemler in Modern Carbonyl Chemistry (Ed.: J. Otera),Wiley-VCH,
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Stuttgart, 1996,pp. 1357 1602; g) Y. Yamamoto,N. Asao, Chem. Rev.
1993, 93,2207.
(249.3): C 62.64,H 6.07,N 5.62; found: C 62.72,H 6.09,N 5.60.
Procedure for the palladium-catalyzed domino allene amidation/intra-
molecular Heck reaction of compound 20: Palladium(ii) acetate (2.5 mg,
0.011 mmol),lithium bromide (51.2 mg,0.59 mmol),potassium carbonate
(20.2 mg,0.146 mmol),and copper( ii) acetate (46.5 mg,0.256 mmol) were
sequentially added to a stirred solution of the a-allenic tosylcarbamate 20
(51 mg,0.122 mmol) in acetonitrile (5 mL). The resulting suspension was
stirred at room temperature under an oxygen atmosphere for 16 h at room
temperature. The organic phase was diluted with brine (2 mL),extracted
with ethyl acetate (5 Â 5 mL),washed with brine (2 mL),dried (MgSO 4),
and concentrated under reduced pressure. Chromatography of the residue
eluting first with hexanes/ethyl acetate (2:1) and later with ethyl acetate
gave 25 mg (41%) of analytically pure compound 21.
[2] For reviews,see: a) J. A. Marshall, Chem. Rev. 2000, 100,3163; b) H.
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Trost),Pergamon Press,Oxford, 1991,Chapter 1.3; c) J. S. Panek in
Comprehensive Organic Synthesis Vol.
1
(Ed.: S. L. Schreiber),
Tricyclic azetidinone (‡)-21: Colorless oil. [a]D ˆ ‡14.0 (c ˆ 0.9 in CHCl3);
1H NMR (500 MHz,CDCl 3,25 8C): d ˆ 7.95 (d, J ˆ 8.5 Hz,1H),7.35 (d, J ˆ
8.5 Hz,1H),6.56 (dd, J ˆ 1.9,0.7 Hz,1H),5.62 (s,1H),5.42 (s,1H),4.89
(dd, J ˆ 15.1,0.98 Hz,1H),4.60 (dd, J ˆ 4.9,1.5 Hz,1H),4.33 (s,1H),3.94
(d, J ˆ 4.6 Hz,1H),3.58 (dt, J ˆ 15.1,1.7 Hz,1H),3.55 (s,3H),2.46 (s,3H),
1.97 (s,3H); 13C NMR (125 MHz,CDCl 3,25 8C): d ˆ 165.8,150.9,145.8,
144.6,136.0,135.3,129.7,128.7,121.3,111.3,83.4,79.3,69.1,59.3,54.7,45.2,
23.0,21.7; IR (CHCl 3): nÄ ˆ 1746,1740,1348 cm À1; MS (ESI): m/z (%): 521
Pergamon Press,Oxford, 1991,p. 595.
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‡
‡
(100) [M (81Br) ‡ Na] ,519 (88) [ M (79Br) ‡ Na] ; elemental analysis
calcd (%) for C20H21N2SO6Br (497.4): C 48.30,H 4.26,N 5.63; found: C
48.37,H 4.28,N 5.60.
¬
New York, 1997; b) A. Lubineau,J. Auge ,Y. Queneau in Organic
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General procedure for the palladium-catalyzed domino allene cyclization/
intramolecular Heck reaction of allenols 13: Palladium(ii) acetate
(0.009 mmol),lithium bromide (0.49 mmol),potassium carbonate
(0.12 mmol) and copper(ii) acetate (0.21 mmol) were sequentially added
to a stirred solution of the a-allenic alcohols 13 (0.10 mmol) in acetonitrile
(5 mL). The resulting suspension was stirred at room temperature under an
oxygen atmosphere for 16 h at room temperature. Compound 26c needs an
extra hour at reflux temperature. The organic phase was diluted with brine
(2 mL),extracted with ethyl acetate (5 Â 5 mL),washed with brine (2 mL),
dried (MgSO4),and concentrated under reduced pressure. Chromatogra-
phy of the residue eluting first with hexanes/ethyl acetate (1:1) and later
with ethyl acetate gave analytically pure compounds 26.
¬
[6] R. B. Kammer in Chemistry and Biology of b-Lactam Antibiotics;
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1728
¹ WILEY-VCH Verlag GmbH,69451 Weinheim,Germany,2002
0947-6539/02/0807-1728 $ 20.00+.50/0
Chem. Eur. J. 2002, 8,No. 7

Pd-Catalyzed Domino Reactions in Allenynes
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¬
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¬
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[31] Full spectroscopic and analytical data for compounds not included in
the Experimental Section are described in the Supporting Informa-
tion.
[20] For a review on transition metal catalyzed reactions of allenes,see:
a) A. S. K. Hashmi, Angew. Chem. 2000, 112,3737; Angew. Chem. Int.
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Received: October 12,2001 [F3611]
Chem. Eur. J. 2002, 8,No. 7
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0947-6539/02/0807-1729 $ 20.00+.50/0
1729