A versatile synthesis of β-lactam-fused oxacycles through the palladium-catalyzed chemo-, regio-, and diastereoselective cyclization of allenic diols

Article abstract of DOI:10.1002/chem.201405181

Chemo-, regio- and stereocontrolled palladiumcatalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2-azetidinone-tethered γ,δ-, δ,ε-, and ε,ζ-allendiols. The palladium-catalyzed cyclizative coupling

Full text of DOI:10.1002/chem.201405181

DOI: 10.1002/chem.201405181
Full Paper
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Synthetic Methods
A Versatile Synthesis of b-Lactam-Fused Oxacycles through the
Palladium-Catalyzed Chemo-, Regio-, and Diastereoselective
Cyclization of Allenic Diols
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocꢀo Carrascosa,[a] Luis Casarrubios,[c] and
Elena Soriano[b]
Abstract: Chemo-, regio- and stereocontrolled palladium-
catalyzed preparations of enantiopure morpholines,
oxocines, and dioxonines have been developed starting
from 2-azetidinone-tethered g,d-, d,e-, and e,z-allendiols.
The palladium-catalyzed cyclizative coupling reaction of
g,d-allendiols 2 with allyl bromide or lithium bromide was ef-
fective as 8-endo cyclization by attack of the primary hy-
droxy group to the terminal allene carbon to afford enantio-
pure functionalized oxocines; whereas the palladium-cata-
lyzed cyclizative coupling reaction of 2-azetidinone-tethered
e,z-allendiols 4 furnished dioxonines 16 through a totally
chemo- and regioselective 9-endo oxycyclization. By contrast,
the palladium-catalyzed cyclizative coupling reaction of 2-
azetidinone-tethered d,e-allendiols 3 with aryl and alkenyl
halides exclusively generated six-membered-ring com-
pounds 14a and 15a. These results could be explained
through a 6-exo cyclization by chemo- and regiospecific
attack of the secondary hydroxy group to the internal allene
carbon. Chemo- and regiocontrol issues are mainly
influenced by the length of the tether rather than by the
nature of the metal catalysts and substituents. This reactivity
can be rationalized by means of density functional theory
calculations.
Introduction
On the other hand, cyclic ethers are important structures fre-
quently found in biologically active natural products such as
acetogenins, prostaglandins, polyether antibiotics, and macro-
cyclic natural products, and great interest is focused on the de-
velopment of new and efficient methods for the synthesis of
oxygen heterocycles.[3] Catalytic regioselective OꢀH addition to
the C=C bonds of pendant olefins is a highly desirable, atom-
economical transformation for accessing oxygen-containing
heterocycles. Thus, HO/cyclization across an allene moiety
fulfills green chemical requirements more satisfactorily than
conventional byproduct-producing substitution reactions.
Though this mode of reactivity has previously been reported
for allenols, similar reactions for the corresponding allenic
diols have remained largely unexplored.[4]
The 2-azetidinone motif is used as a template on which to
build cyclic structures fused to the four-membered ring and is
also present in a large number of naturally occurring and me-
dicinally relevant substances.[1] Moreover, the rigid structure
and strain-driven reactivity make 2-azetidinone derivatives at-
tractive as versatile intermediates in organic synthesis.[2] Over
the past decades, vast efforts from chemists have been en-
gaged by this area. Even so, complementary new approaches
with high synthetic efficiency to build b-lactam-based
structures remain highly desirable.
[a] Prof. Dr. B. Alcaide, Dr. R. Carrascosa
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Quꢀmica Orgꢁnica I
Unidad Asociada al CSIC, Facultad de Quꢀmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax: (+34)91-3944103
The discovery of new reactivity and principles for controlling
chemo-, regio- and stereoselectivity is a fundamental task for
organic synthesis. Both the enormous potential of confronta-
tion of two functional groups that are either reactive or inert
(chemoselectivity) and the preferential reaction with one direc-
tion of bond-making (regioselectivity) joined to the possibility
of stereocontrol can all be encountered in the heterocycliza-
tion reaction of allenic diols. Thus, although catalytic intramo-
lecular allene hydroalkoxylation of 1,2-dienes bearing two con-
tiguous nucleophilic centers offers many attractions, efficient
transformations remain elusive due to additional selectivity
problems. Depending on both the regioselectivity (endo-trig
vs. endo-dig versus exo-dig vs. exo-trig cyclization) as well as
the chemoselectivity (distal vs. proximal nucleophile cycliza-
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros, Dr. E. Soriano
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas
IQOG-CSIC, Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
[c] Dr. L. Casarrubios
Departamento de Quꢀmica Orgꢁnica I Facultad de Quꢀmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405181.
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tion), any of the eight possible heterocycles could be the reac-
tion products. Following our interest in heterocyclic and allene
chemistry,[5] we now studied 2-azetidinone-tethered g,d-, d,e-,
and e,z-allendiols with the views to tracing their propensity to
suffer selective palladium-catalyzed CꢀO bond-forming
reactions (Scheme 1).
A number of different oxabicyclic
b-lactam products also emerged in the present study.
Scheme 3. Preparation of enantiopure d,e-allenic diols 3a,b and e,z-allen-
diols 4a,b. Reagents and conditions: i) (CH2O)n, iPr2NH, CuBr, dioxane, reflux,
1 h; ii) 50 mol% BiCl3, MeCN/H2O, RT, 15 h. PMP=4-MeOC6H4.
Our next efforts focused on the application of palladium cat-
alysis to the selective construction of fused oxacycles starting
from allenic diols having a b-lactam moiety. g,d-Allendiol 2a
was chosen as a model substrate for palladium-catalyzed oxy-
cyclization reactions. Attempts to generate a bicyclic structure
from 2a by using Pd0 catalysis in the presence of iodobenzene
Scheme 1. General Scheme defining the processes that can take place.
Results and Discussion
failed, because b-hydride elimination to afford diene
9
To explore the effects of various substrates on palladium-cata-
lyzed oxycyclization reactions, a number of new b-lactam allen-
ic diols were synthesized. Starting materials, allenes 1a–f were
made from the corresponding azetidine-2,3-diones through an
indium-mediated Barbier-type carbonyl–allenylation reaction in
aqueous media using our previously described methodology.[6]
Precursors for the oxacycle formation, enantiopure 2-azetidi-
none-tethered g,d-allendiols 2a–f were smoothly obtained in
quantitative yields by treatment of dioxolanes 1 with bismuth
trichloride (Scheme 2). 2-Azetidinone-tethered d,e-allendiols 3a
competes more effectively. Despite this failure, g,d-allendiols 2
were exposed to allyl bromide or 2,3-dibromoprop-1-ene
under PdII catalysis in DMF. Much to our delight, adducts
10a–g were obtained in good yields in a totally chemo- and
regioselective fashion using the [PdCl2]-catalyzed cyclizative
coupling reaction with allyl halides (Scheme 4), through an 8-
endo cyclization by attack of the primary hydroxy group to
the terminal allene carbon. To the best of our knowledge, no
example of an 8-endo cyclization at the terminal allene carbon
of a d-allenol has been reported. Thus, we present experimen-
tal evidence concerning the 8-endo-trig cyclization pathways in
allene oxycyclization reactions that enriches Baldwin’s rules for
ring closure.
Traditional ring-closure strategies are effective for five- or
six-membered rings, but problematic for medium-sized ring
systems owing to entropic and transannular penalties incurred
Scheme 2. Preparation of enantiopure g,d-allenic diols 2a–f. Reagents and
conditions: 50 mol% BiCl3, MeCN/H2O, RT, 72 h. PMP=4-MeOC6H4.
and 3b and 2-azetidinone-tethered e,z-allendiols 4a and 4b
were obtained in optically pure form from 2-azetidinone-teth-
ered alkynyl dioxolanes 5 and 6, respectively.[7] Terminal
alkynes 5 and 6 were conveniently converted into allendiols 3
and 4 by treatment with paraformaldehyde in the presence of
diisopropylamine and copper(I) bromide (Crabbꢂ reaction),[8]
followed by BiCl3-catalyzed acetonide cleavage (Scheme 3).
Scheme 4. Preparation of diene 9 and oxocines 10. Reagents and condi-
tions: i) 5 mol% [Pd(PPh3)4], PhI, K2CO3, toluene, 808C, 120 h; ii) 5 mol%
[PdCl2], CH2=CH(Z)CH2Br, DMF, RT, 10a: 14 h; 10b: 16 h; 10c: 16 h; 10d:
15 h; 10e: 15 h; 10 f: 16 h; 10g: 19 h. PMP=4-MeOC6H4.
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when bringing the two ends of a reactant together; eight- to
ten-membered rings have shown to be the most challenging
for cyclization strategies. Thus, fused bicycles 10 are remark-
able, because they comprise an oxocine fused to a strained
trans-b-lactam. HMBC experiments of 4-oxa-10-azabicy-
clo[6.2.0]decene derivatives 10 satisfactorily established infor-
mation about the presence of a new eight-membered oxacycle
fused to the b-lactam ring. Chemical evidence was obtained by
oxidation of adduct 10a with Dess–Martin periodinane to
afford ketone 11 (Scheme 5).
diols 3a,b and 4a,b were employed. The palladium-catalyzed
cyclizative coupling reaction of 2-azetidinone-tethered d,e-al-
lendiols 3a and 3b with aryl and alkenyl halides was explored
next. It is worth mentioning that six-membered ring com-
pounds 14a,b and 15a,b can also be exclusively generated
under these conditions (Scheme 7). These results could be ex-
Scheme 7. Preparation of morpholines 14 and 15. Reagents and conditions:
i) 5 mol% [PdCl2], CH2=CH(Z)CH2Br, DMF, RT, 4 h; ii) 5 mol% [Pd(PPh3)4], PhI,
K2CO3, DMF, 808C, 15 h. DMF=N,N-dimethylformamide.
Scheme 5. Preparation of oxocinone 11. PMP=4-MeOC6H4.
plained through a 6-exo cyclization by chemo- and regiospecif-
ic attack of the secondary hydroxy group to the internal allene
carbon with concomitant incorporation of the unsaturated bro-
mide into the central allene carbon. Besides, the reaction is to-
tally diastereoselective so that just one diastereomer is formed
(morpholines 14 and 15 bearing a quaternary stereocenter are
formed as single isomers). Thus, by using a related allendiol
homologue (d,e-allendiols 3 vs. g,d-allendiols 2), both the
chemo- and regioselectivity can be reversed, favoring the 6-
exo cyclization of secondary hydroxy group towards the inter-
nal allene carbon (morpholine adduct) over the 8-endo cycliza-
tion by attack of the primary hydroxy group towards the termi-
nal allene carbon (oxocine adduct).[9] The stereo-
Our interest then turned to the cycloetherification reaction
by way of palladium-induced oxybromination. Thus, g,d-allen-
diols 2 were treated with lithium bromide using a PdꢀCu
bimetallic catalytic system. In the event, only the hydroxy
group in d-position participates in the [Pd(OAc)2]-catalyzed re-
giocontrolled oxybromination reaction of methyl- and ethyl-
g,d-allendiols 2a–c, giving exclusively the eight-membered
fused derivatives 12 (Scheme 6).[10] The use of the above oxy-
bromination reaction conditions on phenyl g,d-allendiol 2e
1
chemical assignments were based on a H NMR eval-
uation, which involves the analysis of the coupling
constants between the different protons of the cyclo-
hexane ring, and in some cases were confirmed by
NOE experiments.
The one-atom longer allenic diols 4 were found to
show a mixed behavior (regioselectivity similar to 2,
whereas chemoselectivity similar to 3). Upon expo-
sure to a catalytic amount of [PdCl2] in the presence
of allyl bromide, e,z-allendiols 4a,b produced the 1,5-
dioxonine derivatives 16a,b in reasonable yields as
single isomers (Scheme 8). The nine-membered oxa-
cycles 16 may arise from a totally chemo- and regio-
Scheme 6. Preparation of oxocines 12 and dibromide 13. Reagents and conditions:
i) 7 mol% [Pd(OAc)2], LiBr, [Cu(OAc)2], K2CO3, MeCN, O2, RT, 12a: 6d; 12b: 7d; 12c: 6d;
ii) 7 mol% [Pd(OAc)2], LiBr, [Cu(OAc)2], K2CO3, MeCN, O2, RT, 8d. PMP=4-MeOC6H4.
changes the reactivity pattern, suppressing the oxy-
cyclization while retaining the same regioselectivity
of the bromination step. Thus, in the case of phenyl-
allendiol 2e we observed exclusive formation of the
monocyclic dibromide 13. The divergence between
alkyl- and arylallendiols 2 may arise from the different
stereoelectronic effect imparted by the phenyl group
in the oxycyclization step, which directs the reaction
toward a new bromide attack to the terminal allene
carbon rather than toward a cycloetherification.
To demonstrate the synthetic utility of this selec-
Scheme 8. Preparation of dioxonines 16 and dibromide 17. Reagents and conditions:
i) 5 mol% [PdCl2], CH2=CH(Z)CH2Br, DMF, RT, 4 h; ii) 7 mol% [Pd(OAc)2], LiBr, [Cu(OAc)2],
tive cycloetherification reaction in the synthesis of
non-oxocine cyclic compounds, four additional allenic K2CO3, MeCN, O2, RT, 2d. PMP=4-MeOC6H4.
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selective 9-endo oxycyclization of the secondary hydroxy
group to the terminal allene carbon with concurrent alkene
functionalization. By contrast, the cyclization of e,z-allenic diol
4b was not as rewarding when it was treated with lithium bro-
mide using a PdꢀCu bimetallic catalytic system. No ring-closing
product could be detected in the reaction mixture, producing
the dibromide 17 (Scheme 8).
As shown in Scheme 9, the oxybromination reaction of alkyl
g,d-allendiols 2a–c proceeds through an external nucleophilic
attack (Brꢀ) on the (p-allene)palladium complex 18 to afford
the (p-allyl)palladium species 19. Subsequent chemoselective
Scheme 10. Mechanistic explanation for the palladium-catalyzed oxycycliza-
tion of d,e-allendiols 3 in presence of iodobenzene.
internal allene carbon on species 20 to give adducts 15, may
be related to an easier attack of the incoming oxygen nucleo-
phile to the allene-metal complex from the less-hindered face.
The palladium-catalyzed heterocyclization reaction of e,z-
allendiols 4 shows the same regioselectivity but different
chemoselectivity as that observed under palladium catalysis
for g,d-allendiols 2, that is, the initial cyclization takes place
preferentially by selective nucleophilic addition of the secon-
dary hydroxylic oxygen to the activated terminal allene
carbon. Scheme 11 outlines a mechanistic proposal[11] for the
achievement of 1,5-dioxonines 16. Initial PdII-coordination to
the 1,2-diene moiety gave an allene palladium complex 21,
which suffers a chemo- and regioselective 9-endo oxycycliza-
tion reaction to give the intermediate palladatetrahydrodioxo-
nine 22. The presence of an allyl halide alternatively promotes
a coupling reaction by trapping of the alkenylꢀPd intermedi-
Scheme 9. Mechanistic explanation for the metal-catalyzed dibromination
and bromoheterocyclization reaction of g,d-allendiols 2 under PdꢀCu bimet-
allic catalysis.
intramolecular attack by the primary hydroxyl group gives oxo-
cines 12. Formation of monocyclic dibromides 13 is the conse-
quence of a second addition of the bromide ion to the allene
side remote from the diol group. Finally, in situ-oxidation of
Pd0 to PdII by [Cu(OAc)2] completes the catalytic cycle. It may
be inferred that different steric effects in the organometallic
species 19 may be responsible for the different reactivity pref-
erence, stabilizing one of the intermediates rather than the
other. Cicloetherification falters in the presence of sterically en-
cumbering phenylallendiols. Probably, oxybromination through
19 is restricted by the steric hindrance of the R1 substituent
(R1 =Ph) when the diol moiety is trying to approach to the
palladacomplex 19.
A mechanistic hypothesis for the achievement of morpho-
lines 15 from d,e-allendiols 3 is outlined in Scheme 10. The
Pd0-catalyzed insertion of iodobenzene generated the corre-
sponding (p-allyl)palladium intermediate 20. Then, an intramo-
lecular chemo-, regio-, and stereoselective 6-exo oxycyclization
reaction on the (p-allyl)palladium complex must account for
the formation of the fused bicycles 15 with concurrent regen-
eration of the Pd0 catalytic species (Scheme 10). The reason for
the total diastereoselectivity for 6-exo cyclization toward the
Scheme 11. Mechanistic explanation for the palladium-catalyzed oxycycliza-
tion of e,z-allendiols 4 in presence of allyl bromide.
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ate. This process should be favored by the easy HCl release
from the coordination to the metal center. The allyl coupling
with the alkenylꢀPdII intermediate occurs through a three-step
mechanism: 1) Ligand displacement from the metal coordina-
tion sphere, 2) insertion into the allylic halide C=C bond to
give a s-CꢀPd intermediate, and 3) trans b-elimination to
afford the 1,5-dioxonine product. The palladium-coordinated
HCl is easily displaced by the incoming allyl bromide in a fast
ligand-interchange displacement mechanism to yield the h2-
complex 23 upon p-coordination of the CꢀC double bond to
the metal. The coordinated alkene undergoes a 2,1-insertion
into the Pdꢀalkyl bond in a stepwise process that proceeds
through the formation of a h2-Pd-complex 24. A cis/trans iso-
merization of the chloride ligand takes place to reach the tran-
sition state, probably to reduce the back-bonding interaction
and to favor the PdꢀC bond formation. The h2-Pd-complex
then suffers a b-heteroatom elimination to give the coupling
product 16 and the active catalyst [PdCl2]. Probably, the liber-
ated HCl plays a key role in promoting the dehalopalladation
and inhibiting the usual b-H elimination.
complex 27, in which phosphine is trans to the aryl group
(kinetically favored over the cis)[19] through transition state
TS26ꢀ27. This exergonic process (DG=ꢀ4.9 kcalmolꢀ1) proceeds
by surmounting a low barrier of 1.6 kcalmolꢀ1
.
The next step does not have to take place necessarily in the
same ligand arrangement resulting from the oxidative addi-
tion, and an additional isomerization step is possible. In brief,
the plausible processes involves low activation barriers (see
Figures S1 and S2, the Supporting Information); thus, the iso-
merization of 27 to the trans arrangement of iodide and aryl
(27’) takes place through two consecutive isomerizations[19]
(27!27’’ and 27’’!27’, Figure 1) involving low-energy barriers
(6.6 and 3.5 kcalmolꢀ1, respectively), with 27’ being more
stable (by 12.3 kcalmolꢀ1
) than 27 and that 27’’ (trans
arrangement of I and PMe3, by 1.0 kcalmolꢀ1).
Density functional theory (DFT) calculations have been car-
ried out to gain more insight into the reaction mechanisms,
chemo-, and regioselectivity of these processes.
To explore the reactivity of d,e-allendiols 3 to form morpho-
lines 15, we selected allenol 25 as a model substrate. The first
step of the mechanism is an oxidative addition. Normally, theo-
retical calculations[12] have considered a concerted mechanism
using bis(phosphine)palladium(0) ([PdL2]), on the basis of the
early experimental studies of oxidative addition of organoha-
lides to [Pd(PPh3)4].[13] Kinetic studies also showed that in solu-
tion, PdL4 easily dissociates one of the four phosphine ligands
and the resulting [PdL3] is in rapid equilibrium with [PdL2].[14]
However, in the last years it has been suggested that bulky
phosphine ligands promote the oxidative addition through
monophosphine palladium complexes [PdL], which are more
active in the oxidative addition reactions.[15] Theoretical studies
by Norrby and co-workers showed that the barriers calculated
for oxidative addition of R1X to [PdL] are significantly smaller
than those to [PdL2].[16] These results are in agreement with
the observations by Hartwig et al. who found that a highly un-
saturated monophosphine Pd0 complex is the active species.[17]
They also found that the intimate mechanism of oxidative
addition is sensitive to the nature of the halide.[18]
Figure 1. Optimized geometries of tricoordinate palladium complexes po-
tentially involved in the catalytic cycle.
Two different coordination modes of the PdII-complex to the
allenic double bond, that is, distal versus proximal, are possi-
ble. Thus, three potential geometries for the catalyst with re-
spect to the coordinated allene have been taken into account,
namely, with the phosphine group (A,A’), iodide (B,B’) and
phenyl (C,C’, although unproductive for coupling) in a trans
disposition regarding the distal and proximal double bonds of
the coordinated allene. The p-coordination of one of the
double bond of the allene moiety can give rise to six square-
planar h2-allene complexes 28A–28C’ (see Figure S3, the Sup-
porting Information). They are 0.3–11.7 kcalmolꢀ1 more stable
than the isolated PdII-complex and allene (see Table S1, the
Supporting Information), because of the interaction between
the vacant site in the Pd center and the filled p orbital of the
double bond. Due to a stronger back-donation by the phos-
phine ligand, the most stable complexes (by 4.0–10.3 kcal
molꢀ1) bear the phosphine ligand trans to the unsaturated
group.
For PhI, the calculations predicted that the monophosphine
pathway is preferred.[18a] However, the bisphosphine pathway
is very close to that for the monophosphine pathway, so both
pathways might well be competitive and are not mutually ex-
clusive.[19] The accessibility to the monophosphine Pd complex
is thus key to obtain good catalytic activity. Very recently, Ma-
seras and co-workers provided computational evidence for the
formation of [Pd] solvent adducts. The results revealed that the
bare [Pd0(PPh3)] shows a limited lifetime and suggested that
the main pathway leading to formation of the reactant species
[(PhX)Pd(PPh3)] will proceed through the substitution of a PPh3
ligand of [Pd(PPh3)2] by the incoming PhX substrate.[20]
At this point, two different mechanisms can be postulated in
the Pd-catalyzed cyclization of allenes with a nucleophilic func-
tionality (Scheme 12): 1) Intramolecular nucleophilic attack on
On this basis, we have computed the oxidative addition
from the complex [(PhI)Pd0(PMe3)] (26). This step goes to PdII-
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Thus, path B (Scheme 12) in-
volves coordination of the allene
moiety to the metal center and
subsequent insertion of the co-
ordinated allene into the PdꢀC
bond to afford an h3-allyl com-
plex (31). The allene could coor-
dinate to the palladium center in
an h2-mode through the distal
or the proximal double bond, as
was shown above, to form com-
plexes 28. As for path A, we
have evaluated the effect of the
ligands arrangement on the
structure and energy outcomes.
Coordination of the allene trans
to the aryl group was not con-
sidered, as it is unproductive;
only cis coordination is relevant
Scheme 12. Possible reaction pathways for the formation of morpholines of type 15.
for the insertion process.
Since a coordinated allene can
the activated allene, followed by the coupling process (path
A); 2) Carbopalladation of the allene leading to a p-allyl inter-
mediate, which undergoes a subsequent intramolecular nucle-
ophilic attack (path B).[21] Since both paths share a common ini-
tial reactant complex, the most stable complex (28A), will be
taken as reference for the following discussion.
switch the coordinated C=C double bond rapidly, it is reasona-
ble to assume that the four precursor complexes 28A, 28B,
28A’, and 28B’, or at least 28A and 28A’, could participate in
the insertion reaction, following possible reaction pathways.
Figure 2 summarizes the transition structures found for the
plausible coupling routes between the aromatic group and the
central allene carbon. The computed barriers for the structures
bearing the iodide trans to the allene (transition structures
TS28B’ꢀ31 and TS28Bꢀ31’) are higher than for the phosphine trans
For the first pathway (path A), we have considered the
possible heterocyclization routes by nucleophilic attack of the
d- and e-allenol functionalities on the three carbon atoms of
the PdII-activated allene, starting from the six possible reactant
complexes 28A–28C’ (see the Supporting Information).
From a kinetic point of view, our calculations indicated that
the preferred heterocyclization event involves the nucleophilic
attack of the primary e-OH group on the central allene carbon
(through e-TS8ꢀexoꢀdig, with a barrier of 33.0 kcalmolꢀ1), which
drives to the oxocine scaffold e-298ꢀexoꢀdig. This result disagrees
with the observed formation of morpholines 15, which should
proceed through a 6-exo-trig cyclization according to this
mechanism (barrier of 34.8 kcalmolꢀ1). Moreover, these values
for the heterocyclization are too high to take place under the
experimental conditions. Additionally, the calculations on the
following steps revealed that the coupling step also involves
a high activation barrier.[22] Hence, this path can be ruled out
since it is cannot account for the observed reactivity, and
quimio- and regioselectivity.
As an alternative mechanism, we have also analyzed the
path B (Scheme 12) involving carbopalladation of the allene
leading to a h3-allyl intermediate (31), followed by an intramo-
lecular nucleophilic attack of the alcohol moiety.[23] Allenes
insert into the PdꢀCaryl bonds to give h3-allyl complexes in
which a new bond forms between the previously metalated
carbon and the central carbon of the allene moiety.[24,25] These
insertion reactions have been widely investigated because
they have been proposed as the key step in the palladium-
catalyzed coupling reactions of 1,2-dienes and aryl halides to
afford carbo- and heterocycles.[26]
Figure 2. Free-energy profiles for the possible insertion steps.
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complexes (TS28Aꢀ31 and TS28A’ꢀ31’). These data are consistent
with the fact that the more p-acceptor the ligand trans to the
PdꢀCallene (PMe3 vs. Iꢀ (indeed, p-donor)), the lower should be
the coupling barrier because it draws electron density away
from the s-Pd orbital, and this orbital is antibonding in the
transition state.[22a] Additionally, these results are consistent
with the common notion that stronger donor ligands, such as
Iꢀ, make the metal center more electron-rich (natural popula-
tion analysis (NPA) charges of ꢀ0.062 and ꢀ0.053e for 28B
and 28B’, respectively, vs. ꢀ0.051 and ꢀ0.047e for 28A and
28A’, respectively) and inhibit the CꢀC coupling.[27] The trans
arrangement of the iodide ligand with respect to the allene
constitutes a push–pull scenario that enhances the metal (d)-
to-allene (p*) back-bonding interactions.[28] The second-order
perturbation energy analysis (natural bond order (NBO) com-
putations) reflects this effect, since this interaction is 27.91 kcal
molꢀ1 for 28B versus 16.59 kcalmolꢀ1 for 28A. It increases the
p-electron density of the two carbons in the coordinated C=C
bond, and, hence, increases the phenyl migration energy
barriers.
Figure 3. Optimized transition structures for the insertion on C1 and C3.
complex. In monosubstituted (h3-allyl)Pd complexes, the regio-
selectivity of the nucleophilic attack is known to be sensitive
to many factors, such as steric and electronic influences from
the substrate substituents,[32] regiochemical memory,[33]
preferred configuration[34] and dynamic exchange in the
(h3-allyl)Pd intermediate,[35] nucleophile,[36] and the nature
of the ligands.[37–39]
In contrast to reactions of (h3-allyl)Pd complexes with other
nucleophiles,[40] and surpassing the regioselectivity for
reactions of amines and phenols[41] or allylic fluorination,[42]
On the other hand, the coordination of the distal bond im-
plies lower barriers to reach the transition structures, probably
also due to steric effects. In this process, the phenyl ring mi-
grates to the central carbon of the coordinated allene, forming
a
a
new bond and, simultaneously, the palladium atom
regioselective oxycyclization involving the substituted allylic
carbon was obtained (Scheme 7).
approached the non-coordinated double bond.
The transition structures evolve into two types of h3-allyl in-
termediates, 31 and 31’, in which the phosphine ligand is trans
and cis, respectively, to C1. These processes are highly exer-
gonic and therefore, probably irreversible. Complex 31’ is
0.4 kcalmolꢀ1 less stable than the h3-allyl complex 31. This
slight difference could be explained by the slightly greater
steric hindrance due to the bulky iodide ligand. Notably, the
possible insertion products of vinyl complexes were not ob-
served in this study. It has been reported that solutions of re-
lated complexes[29] contain only the isomer in which the PR3 is
trans to the more substituted allylic carbon. In other studies,
both trans and cis isomers were observed,[30] such as for
complexes PdI[CH2C(Ph)CHR](PPh3).[28b]
The inherent electronic difference between phosphorus and
halide results in a difference in PdꢀC bond lengths,[43] as illus-
trated with the PdC1 bond length in 31 (2.225 ꢃ), and in 31’
(2.186 ꢃ) trans to phosphorous and iodide, respectively, and
the PdC3 bond length (2.152 and 2.202 ꢃ, respectively in 31
and 31’). Norrby et al. found (for the nucleophilic addition to
the intermediate [Pd(h3-allyl)] complex) a preference for the
terminus trans to phosphine of 11–13 kJmolꢀ1 rather than to
an halide ligand.[44] Analogously, in nucleophilic additions to
monosubstituted (h3-allyl)Pd complexes, it has been assumed
that (due to the relative trans influences of the ligands)[45] the
nucleophile would preferentially attack the allylpalladium
terminus trans to the phosphine ligand.[46]
In most of the catalytic reactions mediated by these phos-
phine complexes, the aryl group is transferred to the central
carbon of allenes. In contrast to the two terminal carbons of
the isolated allene (NPA charges of ꢀ0.465 and ꢀ0.282e for C1
and C3, respectively), the central carbon of the allene (C2) is
electron-deficient (+0.088e). Therefore, the migrating group
(benzenide, NPA charge of ꢀ0.220e) can preferentially attack
the central carbon of allene in 28A.[28] Occasionally, attachment
of aryl to the terminal carbons of allenes has been also observ-
ed.[26m,31] To check this point, we have computed the insertion
processes on the terminal and proximal allene carbon atoms.
The computed activation barriers are 2.1 and 4.6 kcalmolꢀ1
(Figure 3), respectively, higher than the insertion with the
central allene carbon (TS28Aꢀ31), in good agreement with the
regioselectivity found experimentally.
The plausible transition structures involving both the allylic
carbons and both the d- and e-OH functionalities have been
calculated starting from the [Pd(h3-allyl)] complexes 31 and 31’
(Figure 4). The optimized transition structures show an H-
bonding interaction between the attacking nucleophile and
the iodide. Any attempt to locate a transition structure lacking
this interaction, was met with failure. This interaction is not
feasible for the nucleophilic attack on C1 from the intermedi-
ate 31’ or on C3 from 31 without a severe steric distortion or
from a syn conformation.[47] Hence, herein we only show the
reasonable transition structures.
The results reveal a kinetic preference for the internal attack,
through TS31’ꢀ30’’ (11.3 kcalmolꢀ1 below the reactant complex)
and TS31’ꢀ32 (ꢀ9.1 kcalmolꢀ1), rather than for the terminal
attack of the nucleophile, through TS31ꢀ33 (ꢀ5.9 kcalmolꢀ1) and
TS31ꢀ34 (ꢀ4.2 kcalmolꢀ1) since the barriers are 5.8–7.1 kcal
molꢀ1 higher for the later than for the former. Amazingly, the
attack of the secondary alcohol moiety (TS31’ꢀ30’’) is the pre-
The following heterocyclization step takes places by
a chemo- and regioselective nucleophilic attack of the secon-
dary OH moiety on the substituted carbon of the (h3-allyl)Pd
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tively. Similar observations have been reported by Grady, Vice-
nte, and co-workers in the synthesis of N-heterocycles, which
suggested that the reaction takes place with the carbon
bonded to the most electron-releasing substituents of the allyl
group.[50]
These electronic effects due to the trans effect of the phos-
phine ligand, conformation and allylic substitution on the (h3-
allyl) palladium complex strongly point out a preferred nucleo-
philic attack on the substituted allylic carbon C3, in agreement
with the experimental results. Hence, this mechanism
(Figure 5) is energetically more favorable than path A and can
account for the chemo- and regioselectivity.
The synthesis of medium-sized oxacycles,[3a,51] in particular
eight and nine-membered rings,[52] has been and continues to
be a challenging and fascinating endeavor in synthetic organic
chemistry; this is due to unfavorable entropy and enthalpy fac-
tors that prevent the adaptation of traditional methods of ring
formations, and accordingly there are few examples of synthe-
sis of oxocines from allene derivatives. Mukai et al. reported
a reliable and efficient procedure for constructing nine-mem-
bered oxacycles through an endo-mode ring-closing reaction
of allenyl derivatives in a base-catalyzed process.[53] Gagnꢂ
et al. developed a method to generate polyether skeletons
Figure 4. Optimized transition structures for the plausible heterocyclization
step (path B).
ferred heterocyclization pathway,
leading to the morpholine scaf-
fold.
Previous theoretical studies on
the nucleophilic addition to (h3-
allyl) palladium complexes have
suggested that the reaction is
controlled by the frontier orbi-
tals rather than by the charg-
es.[48] The presence of an elec-
tron-donating group on the allyl-
ic complex induces a polarization
of the allyl orbitals. Thus, the n
and
p
orbitals are polarized
the nonsubstituted
toward
Figure 5. Free-energy profile (in kcalmolꢀ1) for the palladium-catalyzed oxycyclization of d,e-allendiols in presence
of iodobenzene.
carbon (C1) and the p* orbital
toward the substituted carbon
(C3). Due to this polarization of
the n orbital toward the nonsub-
stituted carbon C1, the PdꢀC1 interaction is stronger, whereas
the PdꢀC3 bond is weaker.[38] It has been found that a longer
PdꢀC bond corresponds to a more reactive allyl terminus, with
each 0.01 ꢃ elongation giving approximately a doubling in re-
activity.[49] The lengthening of PdꢀC3 allows the destabilizing
four-electron interaction between the p-orbital and the metal
to be diminished. The in-phase mixing with the p*-orbital that
is polarized toward the substituted carbon yields a larger con-
tribution of this carbon in the LUMO orbital of the complex.
The larger the coefficient in the LUMO on a carbon in the di-
rection of the attack, which itself depends on the electron-do-
nating character of the substituent, the more regioselective
the reaction toward this carbon. Thus, the computed LUMO
coefficients in 31’ for C1 and C3 are 0.432 and 0.987, respec-
from allene-epoxide cascade reactions promoted by AuI.[54] Ma-
jumdar et al. have synthesized several types of heterocycles by
the utilization of various palladium complexes[55] in phosphine-
free intramolecular Heck reactions.[56] In this context, the
chemo- and regioselective 9-endo oxycyclization of the secon-
dary hydroxy group to the terminal allene carbon merits
a mechanistic rationalization.
As a model substrate for DFT calculations, we have selected
compound 35 (Scheme 13). We have located two expected
types of reactant complexes: 1) By p-coordination of the distal
and 2) by p-coordination of the proximal alkene bonds of the
allene to the catalyst, to form the h2-allene structures 36 (Pdꢀ
C1=2.111 and PdꢀC2=2.104 ꢃ) and 37 (PdꢀC2=2.090, and
PdꢀC3=2.121 ꢃ), respectively. Unsurprisingly, the coordination
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pathway very unlikely because of enthalpic penalty
of the longer chain and probably because it lacks the
stabilizing intramolecular H-bond and requires
a higher structural distortion of the allenic group (di-
hedral angle of 20.9 vs. 9.48 for TS9ꢀendoꢀtrig).
The alternative transition structures for the intra-
molecular nucleophilic attack of the alcohol to the
activated allene, which involve the e- or z-allenol
moiety and/or other allenic positions, show higher
activation energy values than TS9ꢀendoꢀtrig (DDG# =
2.0–21.4 kcalmolꢀ1). These energy differences are
high enough to support the kinetic preference for
the chemo- and regioselective formation of the diox-
onine framework, in full agreement with the experi-
mental observations.
The formation of the exo-cyclized products is
slightly exergonic, likely due to the higher flexibility
to form the stabilizing H-bond between the attacking
alcohol and the chloride ligand for the subsequent
HCl displacement step. On the contrary, the forma-
tion of the endo-intermediates is slightly endergonic,
such as for I8ꢀendoꢀdig, in which there is no possibility
to form this H-bond interaction.
The experimental results have shown a different
selectivity as function of the chain length (2 vs. 4).
Thus, upon exposure to a catalytic amount of [PdCl2]
in the presence of allyl bromide, these precursors
yield oxocines 10 (Scheme 4) and oxonines 16
(Scheme 8), respectively, therefore showing the same
regioselectivity but a divergent chemoselectivity. To
get insights into this issue, we have performed fur-
ther calculations with 37 as a model substrate
Scheme 13. Plausible [PdCl2]-catalyzed heterocyclization routes.
of the allenic distal C=C bond to the catalyst gives rise to
(Scheme 14).
a more stable Pd-h2-allene reactant complex (by 2.3 kcalmolꢀ1
)
Amazingly, the computed results (Table 1) indicate that the
lowest-energy transition structure is TS8ꢀendoꢀtrig (13.2 kcalmolꢀ1
above the reactant complex 38), which involves the nucleo-
philic addition of the primary hydroxylic oxygen to the activat-
ed terminal allene carbon. These results confirm the same re-
gioselective endo-trig cyclization mode for these precursors.
However, regarding the chemoselectivity, the substitution
and configuration at the b-lactam carbons, as well as the
shorter tether, involves a higher tension for the nucleophilic
addition of the secondary hydroxylic functionality on the ter-
due to lower steric hindrance effects. Scheme 13 shows the
plausible intermediate structures that can be formed by intra-
molecular heterocyclization through attack of both e- and z-
OH groups from each complex. Thus, the possible processes
imply 9-endo-trig, 8-exo-dig, 10-endo-trig, 9-exo-dig (from 36), 8-
endo-dig, 7-exo-trig, 9-endo-dig, and 8-exo-trig (from 37) intra-
molecular oxycyclizations. Moreover, we have also take into
account the formation of both the isomers cis and trans of the
endocyclic C=C double bond (see Table S3, the Supporting
Information).
The computed results (Figure 6) indicate that the lowest-
energy transition structure is TS9ꢀendoꢀtrig (14.5 kcalmolꢀ1 above
36), which involves the nucleophilic addition of the secondary
hydroxylic oxygen to the activated terminal allene carbon. A
strong H-bond is observed between the endocyclic oxygen
and the attacking OH, which likely enhances the nucleophilici-
ty of the alcohol and stabilizes the transition structure. It has
been reported that metal-catalyzed cyclizations of allenols[57]
and closely related palladium-catalyzed cyclizative coupling re-
actions[11,58] favor an endo-trig cyclization mode. Noteworthy,
the analogous transition structure by attack of the primary OH
(TS10endoꢀtrig), which would also eventually afford products of
type oxecine, is 5.9 kcalmolꢀ1 higher in energy. It makes that
Table 1. Free-energy differences (in solution) of the computed structures.
Structure
Alcohol
DG
[kcalmolꢀ1
]
38
39
0.0
11.4
13.2
21.8
22.3
28.9
38.2
22.7
39.4
42.9
TS8ꢀendoꢀtrig
TS7ꢀexoꢀdig
TS7ꢀendoꢀtrig
TS6ꢀexoꢀdig
TS7ꢀendoꢀdig
TS6ꢀexoꢀtrig
TS5ꢀexoꢀtrig
TS6ꢀendoꢀdig
d
d
g
g
d
d
g
g
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minal allene carbon, as the
computed
barrier
suggests
(TS7ꢀendoꢀtrig 22.3 kcalmolꢀ1). Like-
wise, TS7ꢀexoꢀdig, which implies
the same chemoselectivity and
different
regioselectivity
as
TS8ꢀendoꢀtrig, also involves a mark-
edly higher energy barrier
(21.8 kcalmolꢀ1).
Other alternative transition
structures leading to smaller
heterocycles also show even
higher activation barriers than
TS8ꢀendoꢀtrig (DDG# =9.5–29.7 kcal
molꢀ1) due to the more severe
steric tension to reach the perti-
nent transition states. These
energy differences clearly sup-
port the kinetic preference for
the chemo- and regioselective
formation of the oxocine skele-
ton, in harmony with the experi-
mental observations.
Conclusion
Figure 6. Computed free-energy profile (in kcalmolꢀ1) for the possible Pd-catalyzed heterocyclizations of 35.
The chemo-, regio-, and diaste-
reocontrolled cicloetherification
of 2-azetidinone-tethered g,d-,
d,e- and e,z-allenic diols into morpholines, oxocines, and dioxo-
nines has been realized by using various palladium-catalyzed
cyclizative coupling reactions. Chemo- and regiocontrol issues
are mainly influenced by the length of the tether rather than
by the nature of the metal catalysts and substituents. Besides,
to understand this difference in reactivity, a DFT study has
been performed. We hope that these selective cyclization reac-
tions can be used in the selective preparation of other types of
heterocyclic compounds.
Computational Details
All the calculations reported in this paper were performed with the
Gaussian 09 suite of programs.[59] All species were optimized with
Truhlar’s dispersion-corrected meta hybrid exchange-correlation
functional M06, which has been recommend for species involving
transition metals,[60] in combination with 6-311g(2d,p) basis sets for
all atoms except Pd and I, which were treated with the LANL2DZ
electron core potential,[61] and associated basis set with the correc-
tion factors proposed by Frenking.[62] The stationary points thus
obtained were characterized by means of harmonic analysis. It was
verified that for all the transition structures, the normal mode relat-
ed to the imaginary frequency corresponds to the nuclear motion
along the reaction coordinates under study. In several significant
cases, intrinsic reaction coordinate (IRC) calculations were per-
formed to unambiguously connect transition structures with reac-
tants and products. Solvents effects were taken into account by
use of the Polarizable Continuum Model (PCM).[63] Single-point cal-
culations on the gas-phase optimized geometries were performed
Scheme 14. Plausible [PdCl2]-catalyzed heterocyclization routes.
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to estimate the changes in the Gibbs energies in the presence of
DMF as solvent. The natural bond orbital analysis (NBO)[64] were
carried on the optimized structures.
6.1 Hz), 1.99 (s, 3H), 1.65 ppm (d, 1H, J=6.6 Hz); 13C NMR (75 MHz,
CDCl3, 258C): d=168.0, 137.1, 136.5, 134.1, 129.4, 128.8, 128.2,
127.7, 116.0, 90.8, 79.8, 76.8, 71.9, 68.6, 53.8, 45.2, 37.4, 17.8 ppm;
; HRMS (ES): m/z calcd for
C20H25NNaO4: 366.1681 [M+Na]+; found: 366.1687.
IR (CHCl3,): n˜ =3435, 1746 cmꢀ1
Oxocine (+)-10d: From g,d-allendiol (ꢀ)-2c (56 mg, 0.18 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-10d (40 mg, 62%) as a col-
orless oil. [a]D = +7.5 (c=0.3, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.23 (m, 5H), 5.64 (m, 1H), 4.98 (m, 1H), 4.93 (dd, 1H,
J=3.1, 1.7 Hz), 4.53 and 4.38 (d, each 1H, J=14.8 Hz), 4.06 (m, 4H),
3.71 (dd, 1H, J=12.7, 2.2 Hz), 3.66 (d, 1H, J=8.5 Hz), 3.41 (s, 3H),
2.70 (m, 2H), 2.41 and 2.15 (m, each 1H), 0.91 ppm (t, 3H, J=
7.4 Hz); 13C NMR (75 MHz, CDCl3, 258C): d=167.5, 136.8, 136.2,
136.0, 134.9, 128.7, 128.5, 127.7, 116.3, 90.7, 80.5, 76.2, 72.9, 69.5,
Experimental Section
General methods
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
AVIII-700 with cryoprobe, Bruker Avance-300, Varian VRX-300S or
Bruker AC-200. NMR spectra were recorded in CDCl3 solutions,
except otherwise stated. Chemical shifts are given in ppm relative
to TMS (1H, d=0.0 ppm), or CDCl3 (13C, d=76.9 ppm). Low- and
high-resolution mass spectra were taken on an AGILENT 6520 Ac-
curate-Mass QTOF LC/MS spectrometer using the electronic impact
(EI) or electrospray modes (ES) unless otherwise stated. Specific ro-
tation [a]D is given in 10ꢀ1 8cm2 gꢀ1 at 208C, and the concentration
(c) is expressed in g per 100 mL. All commercially available com-
pounds were used without further purification.
General procedure for the PdII-catalyzed cyclization of allenic
diols in presence of allyl bromide: Preparation of oxocines 10,
morpholines 14, and dioxonines 16: Palladium(II) chloride
(0.005 mmol) was added to a stirred solution of the corresponding
allenic diol 2–4 (0.10 mmol) and allyl bromide (0.50 mmol) in N,N-
dimethylformamide (0.6 mL). The reaction was stirred under argon
atmosphere until disappearance of the starting material (TLC).
Water (0.5 mL) was added before being extracted with ethyl ace-
tate (3ꢄ4 mL). The organic phase was washed with water (2ꢄ
2 mL), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with hexanes/ethyl acetate
mixtures gave analytically pure adducts 10, 14, or 16.[65]
53.6, 45.1, 37.3, 24.3, 13.9 ppm; IR (CHCl3): n˜ =3429, 1747 cmꢀ1
;
HRMS (ES): m/z calcd for C21H27NNaO4: 380.1838 [M+Na]+; found:
380.1831.
Oxocine (ꢀ)-10e: From g,d-allendiol (ꢀ)-2d (38 mg, 0.089 mmol)
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (ꢀ)-10e (25 mg, 60%) as a col-
orless oil. [a]D =ꢀ1.5 (c=2.5, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.59 and 6.83 (d, each 2H, J=9.0 Hz), 7.10 (m, 5H), 5.74
(m, 1H), 5.06 (m, 2H), 4.44 and 4.40 (d, each 1H, J=5.3 Hz), 4.33
(m, 7H), 3.97 (dd, 1H, J=12.4, 1.9 Hz), 3.80 (s, 3H), 3.55 (s, 3H),
2.89 ppm (dd, 2H, J=5.1, 0.9 Hz); 13C NMR (75 MHz, CDCl3, 258C):
d=165.4, 156.2, 142.3, 137.7, 134.5, 131.4, 130.9, 128.0, 127.7,
127.2, 120.4, 116.8, 113.9, 88.3, 81.1, 76.1, 73.3, 72.8, 70.3, 67.6, 55.4,
53.4, 37.4 ppm; IR (CHCl3,): n˜ =3432, 1746 cmꢀ1; HRMS (ES): m/z
calcd for C27H31NNaO6: 488.2049 [M+Na]+; found: 488.2041.
Oxocine (+)-10 f: From g,d-allendiol (+)-2e (47 mg, 0.125 mmol)
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-10 f (31 mg, 58%) as a col-
orless oil. [a]D = +14.3 (c=0.4, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.59 and 6.82 (d, each 2H, J=9.2 Hz), 7.31 (m, 5H), 5.68
(m, 1H), 5.08 (dd, 1H, J=3.4, 1.7 Hz,), 5.00 (dd, 1H, J=9.5, 1.7 Hz,),
4.68 (d, 1H, J=7.8 Hz,), 4.52 and 4.15 (d, each 1H, J=12.7 Hz), 4.39
(d, 2H, J=2.2 Hz), 4.31 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 2.66 (m,
2H), 2.16 ppm (d, 1H, J=6.1 Hz); 13C NMR (75 MHz, CDCl3, 258C):
d=167.3, 156.4, 140.5, 138.5, 135.1, 131.1, 128.4, 127.5, 120.4,
116.7, 114.0, 81.8, 75.1, 74.1, 71.1, 55.4, 54.0, 39.3 ppm; IR (CHCl3,):
n˜ =3432, 1744 cmꢀ1; MS (ES): m/z: 421 ([M+], 17), 420 ([M+ꢀ1],
100).
Oxocine (+)-10a: From g,d-allendiol (+)-2a (45 mg, 0.14 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-10a (37 mg, 73%) as a col-
orless oil; [a]D = +21.9 (c=0.4, CHCl3); 1H NMR (500 MHz, CDCl3,
258C): d=7.66 and 6.86 (d, each 2H, J=9.2 Hz), 5.10 (dd, 1H, J=
6.3, 1.8 Hz), 5.03 (t, 2H, J=1.5 Hz), 4.35 and 3.88 (d, each 1H, J=
10.5 Hz), 4.30 (m, 4H), 3.78 (s, 3H), 3.53 (s, 3H), 2.80 (d, 2H, J=
4.9 Hz), 2.40 (brs, 1H), 1.97 ppm (s, 3H); 13C NMR (125 MHz, CDCl3,
258C): d=165.4, 156.5, 137.4, 134.1, 131.1, 129.2, 120.4, 116.1,
114.0, 90.0, 80.4, 76.6, 72.8, 69.5, 55.5, 53.5, 37.6, 17.8 ppm; IR
(CHCl3,): n˜ =3430, 1745 cmꢀ1; HRMS (ES): m/z calcd for C20H25NO5:
359.1733 [M]+; found: 359.1740.
Oxocine (+)-10g: From g,d-allendiol (ꢀ)-2 f (42 mg, 0.13 mmol)
and after chromatography of the residue using hexanes/ethyl ace-
tate (1:1) as eluent gave compound (+)-10g (30 mg, 57%) as a col-
orless oil. [a]D = +50.0 (c=2.5, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.25 (m, 10H), 5.61 (m, 1H), 5.02 (dd, 1H, J=6.0,
1.7 Hz,), 4.95 (dd, 1H, J=12.7, 1.7 Hz,), 4.61 and 4.18 (d, each 1H,
J=14.8 Hz), 4.30 (s, 2H), 4.13 (m, 4H), 3.69 (s, 3H), 2.58 (m, 2H),
2.82 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=166.3,
139.9, 138.4, 137.0, 136.0, 135.9, 135.1, 128.7, 128.6, 128.2, 127.7,
127.5, 116.7, 90.8, 81.5, 75.0, 73.9, 69.2, 54.1, 44.9, 39.2 ppm; IR
(CHCl3,): n˜ =3434, 1745 cmꢀ1; HRMS (ES): m/z calcd for C25H28NO4:
406.2018 [M+H]+; found: 406.2014.
Oxocine (+)-10b: From g,d-allendiol (+)-2a (40 mg, 0.125 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-10b (33 mg, 60%) as a col-
orless oil. [a]D = +18.8 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.67 and 6.88 (d, each 2H, J=9.3 Hz), 5.68 and 5.51 (m,
each 1H), 5.24 (d, 1H, J=6.1 Hz,), 4.38 (m, 4H), 4.32 and 3.97 (d,
each 1H, J=10.5 Hz), 3.94 (s, 3H), 3.58 (s, 3H), 3.20 (d, 2H, J=
24.0 Hz,), 2.01 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
164.9, 156.6, 139.3, 135.2, 130.9, 130.3, 120.4, 118.1, 114.1, 90.0,
80.9, 75.8, 73.3, 69.5, 55.5, 53.8, 45.3, 18.4 ppm; IR (CHCl3): n˜ =3435,
1746 cmꢀ1; HRMS (ES): m/z calcd for C20H24BrNO5[M]+: 437.0838;
found: 437.0843.
Morpholine (+)-14a: From d,e-allendiol (+)-3a (51 mg,
0.24 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (1:3) as eluent gave compound (+)-14a (30 mg,
50%) as a colorless oil. [a]D = +4.9 (c=1.0, CHCl3); 1H NMR
(500 MHz, CDCl3, 258C): d=5.78 (m, 1H), 5.13 (m, 2H), 5.08 (m,
1H), 5.01 (m, 1H), 4.54 (dd, 1H, J=4.5, 1.2 Hz), 3.92 (dd, 1H, J=
11.1, 3.1 Hz), 3.80 (m, 2H), 3.66 (m, 2H), 3.58 (s, 3H), 3.56 (dd, 1H,
J=9.5, 4.5 Hz), 2.84 (m, 2H), 2.72 ppm (ddd, 1H, J=13.7, 10.7,
Oxocine (+)-10c: From g,d-allendiol (ꢀ)-2b (43 mg, 0.14 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (1:1) as eluent gave compound (+)-10c (27 mg, 56%) as a col-
orless oil; [a]D = +89.0 (c=2.2, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.33 (m, 5H), 5.70 (m, 1H), 5.05 (m, 1H), 4.98 (m, 1H),
4.57 and 4.47 (d, each 1H, J=15.0 Hz), 4.17 (m, 4H), 3.74 (d, 1H,
J=8.5 Hz), 3.64 (d, 1H, J=9.0 Hz), 3.51 (s, 3H), 2.75 (d, 2H, J=
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1.2 Hz); 13C NMR (125 MHz, CDCl3, 258C): d=168.3, 144.5, 135.3,
117.2, 112.9, 83.8, 77.7, 77.4, 63.1, 59.3, 50.5, 42.0, 37.2 ppm; IR
(CHCl3,): n˜ =3435, 1744 cmꢀ1; HRMS (ES): m/z calcd for C13H20NO4:
254.1392 [M+H]+; found: 254.1401.
HRMS (ES): m/z calcd for C17H20BrNO5: 397.0525 [M]+; found:
397.0519.
Oxocine (+)-12b: From g,d-allendiol (ꢀ)-2b (51 mg, 0.16 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-12b (32 mg, 52%) as
a pale-yellow oil; [a]D = +6.8 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.33 (m, 5H), 4.62 and 4.45 (d, each 1H, J=
16.1 Hz), 4.52 (s, 2H), 4.17 (m, 2H), 3.74 (d, 1H, J=8.8 Hz), 3.59 (d,
1H, J=8.1 Hz), 3.55 (s, 3H), 2.20 (t, 3H, J=1.6 Hz), 1.52 ppm (d,
1H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3, 258C): d=166.9, 136.3,
133.5, 129.0, 128.1, 127.9, 126.9, 80.8, 79.7, 71.0, 68.2, 54.3, 45.3,
23.1 ppm; IR (CHCl3,): n˜ =3427, 1743 cmꢀ1; MS (ES): m/z: 382 ([M+
+1], 98), 380 ([M+ꢀ1], 100).
Morpholine (+)-14b: From d,e-allendiol (+)-3b (72 mg,
0.25 mmol) and after chromatography of the residue using hex-
anes/ethyl acetate (2:1) as eluent gave compound (+)-14b (51 mg,
62%) as a colorless oil. [a]D = +5.0 (c=0.8, CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.34 (m, 5H), 5.80 (m, 1H), 5.13 (m,
1H), 5.08 (m, 1H), 5.00 (m, 1H), 4.94 and 4.68 (d, each 1H, J=
11.8 Hz), 4.73 (dd, 1H, J=4.4, 0.9 Hz), 3.94 (dd, 1H, J=10.5, 3.1 Hz),
3.82 (m, 2H), 3.66 (m, 2H), 3.56 (dd, 1H, J=9.5, 4.7 Hz), 2.83 (m,
2H), 2.73 ppm (ddd, 1H, J=13.1, 10.7, 1.2 Hz); 13C NMR (75 MHz,
CDCl3, 258C): d=168.7, 144.8, 136.9, 135.5, 128.5, 128.4, 128.2,
117.4, 113.2, 81.6, 77.6, 77.5, 73.4, 63.3, 50.8, 42.3, 37.4 ppm; IR
(CHCl3,): n˜ =3438, 1746 cmꢀ1; HRMS (ES): m/z calcd for C19H24NO4:
330.1705 [M+H]+; found: 330.1711.
Oxocine (+)-12c: From g,d-allendiol (ꢀ)-2c (67 mg, 0.21 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-12c (37 mg, 44%) as
a pale-yellow oil. [a]D = +7.0 (c=0.5, CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.34 (m, 5H, Ar), 4.60 and 4.47 (d, each 1H, J=
14.7 Hz), 4.57 and 4.48 (d, each 1H, J=15.8 Hz), 4.14 (m, 2H), 3.70
(d, 1H, J=8.6 Hz), 3.68 (dd, 1H, J=12.2, 3.4 Hz), 3.53 (s, 3H, OMe),
2.70 (m, 1H), 2.47 (m, 1H),1.00 ppm (t, 3H, J=7.53 Hz); 13C NMR
(75 MHz, CDCl3, 258C): d=166.5, 139.5, 135.9, 128.8, 128.5, 127.9,
126.5, 89.3, 80.8, 80.0, 71.6, 68.8, 54.1, 45.3, 29.4, 11.8 ppm; IR
(CHCl3,): n˜ =3431, 1745 cmꢀ1; HRMS (ES): m/z calcd for C18H22BrNO4:
395.0732 [M]+; found: 395.0739.
Dioxonine (+)-16a: From e,z-allendiol (+)-4a (51 mg, 0.17 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (1:2) as eluent gave compound (+)-16a (36 mg, 61%) as a col-
orless oil; [a]D = +2.3 (c=1.3, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.40 and 6.87 (d, each 2H, J=9.1 Hz), 5.80 (m, 2H), 5.13
(m, 2H), 4.77 (d, 1H, J=5.3 Hz), 4.45 (m, 3H), 4.17 (m, 1H), 4.00 (m,
2H), 3.79 (s, 3H), 3.69 (m, 2H), 3.04 ppm (m, 2H); 13C NMR
(75 MHz, CDCl3, 258C): d=164.9, 156.8, 138.8, 134.0, 130.0, 126.0,
120.0, 117.1, 114.3, 80.6, 77.2, 67.8, 67.6, 63.5, 58.0, 55.5, 32.6 ppm;
IR (CHCl3,): n˜ =3440, 1742 cmꢀ1
;
HRMS (ES): m/z calcd for
Procedure for the Pd0-catalyzed cyclization of d,e-allenic diols 3
in the presence of iodobenzene: Preparation of morpholines 15:
[Pd(PPh3)4] (11 mg, 0.0093 mmol) was added to a mixture of the
corresponding d,e-allendiol 3 (0.18 mmol), iodobenzene (22 mL,
0.19 mmol), and silver carbonate (99 mg, 0.36 mmol) in DMF
(1.5 mL) under argon, and the resulting mixture was heated at
808C until disappearance of the starting material (TLC, 15 h). The
reaction was then quenched with brine (1.8 mL) and the mixture
was extracted with ethyl acetate (3ꢄ3 mL). The organic extract
was washed with brine, dried (MgSO4) and concentrated under re-
duced pressure. Chromatography of the residue eluting with hex-
anes/ethyl acetate mixtures gave analytically pure adducts 15.
C19H24NO5: 346.1654 [M+H]+; found: 346.1638.
Dioxonine (+)-16b: From e,z-allendiol (ꢀ)-4b (70 mg, 0.24 mmol),
and after chromatography of the residue using hexanes/ethyl ace-
tate (1:2) as eluent gave compound (+)-16b (46 mg, 58%) as a col-
orless oil. [a]D = +0.9 (c=0.8, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d=7.20 (m, 5H), 5.67 (m, 2H), 5.03 (m, 2H), 4.70 and 4.20
(d, each 1H, J=15.0 Hz), 4.53 (d, 1H, J=5.1 Hz), 4.40 (dd, 1H, J=
12.4, 6.0 Hz), 4.24 (dd, 1H, J=12.6, 7.0 Hz), 3.98 (s, 1H), 3.88 (m,
1H), 3.55 (m, 2H), 2.91 ppm (m, 2H); 13C NMR (75 MHz, CDCl3,
258C): d=167.6, 138.5, 135.6, 134.1, 128.9, 128.3, 127.9, 126.3,
117.0, 81.4, 71.1, 67.4, 67.0, 63.9, 58.1, 45.6, 32.7 ppm; IR (CHCl3,
cmꢀ1): n˜ =3442, 1743; HRMS (ES): m/z calcd for C19H24NO4:
330.1705 [M+H]+; found: 330.1706.
Morpholine (+)-15a: From d,e-allendiol (+)-3a (11 mg,
0.52 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (1:2) as eluent gave compound (+)-15a (78 mg,
61%) as a colorless oil. [a]D = +5.0 (c=0.5, CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.34 (m, 5H), 5.42 (m, 2H), 4.55 (dd,
1H, J=4.7, 1.3 Hz), 4.44 (dd, 1H, J=10.7, 3.1 Hz), 3.94 (m, 2H), 3.77
(m, 3H), 3.60 (s, 3H), 3.59 (m, 1H), 2.67 ppm (ddd, 1H, J=13.4,
10.7, 1.3 Hz); 13C NMR (75 MHz, CDCl3, 258C): d=168.2, 146.0,
138.4, 128.6, 128.1, 126.6, 114.3, 83.7, 77.7, 76.5, 63.1, 59.3, 50.5,
42.6 ppm; IR (CHCl3,): n˜ =3442, 1747 cmꢀ1; HRMS (ES): m/z calcd for
C16H20NO4: 290.1392 [M+H]+; found: 290.1397.
General procedure for the PdII-catalyzed cyclization of g,d-allen-
ic diols 2 in presence of lithium bromide: Preparation of bro-
mooxocines 12: Palladium(II) acetate (0.01 mmol), lithium bromide
(0.74 mmol), potassium carbonate (0.18 mmol), and copper(II) ace-
tate (0.32 mmol) were sequentially added to a stirred solution of
the corresponding g,d-allendiol 2 (0.15 mmol) in acetonitrile (5 mL).
The resulting suspension was stirred at room temperature under
an oxygen atmosphere until disappearance of the starting material
(TLC). The organic phase was diluted with brine (2 mL), extracted
with ethyl acetate (3ꢄ5 mL), washed with brine (2 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue eluting with hexanes/ethyl acetate mixtures
gave analytically pure adducts 12.
Morpholine (+)-15b: From d,e-allendiol (+)-3b (36 mg,
0.12 mmol) and after chromatography of the residue using hex-
anes/ethyl acetate (1:1) as eluent gave compound (+)-15b (24 mg,
55%) as a colorless oil. [a]D = +3.3 (c=0.5, CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.35 (m, 10H), 5.42 (m, 2H), 4.95 and
4.70 (d, each 1H, J=11.7 Hz), 4.74 (dd, 1H, J=4.7, 1.2 Hz), 4.46 (dd,
1H, J=10.7, 3.2 Hz), 4.01 (m, 1H), 3.83 (dd, 1H, J=5.4, 3.4 Hz), 3.79
(m, 1H), 3.71 (dd, 1H, J=11.8, 5.7 Hz), 3.59 (dd, 1H, J=9.6, 4.7 Hz),
2.69 ppm (ddd, 1H, J=13.4, 10.7, 1.3 Hz); 13C NMR (75 MHz, CDCl3,
258C): d=168.3, 146.0, 138.4, 136.6, 128.6, 128.5, 128.2, 128.1,
128.0, 126.6, 114.3, 81.3, 77.8, 77.2, 73.1, 63.1, 50.5, 42.7 ppm; IR
(CHCl3): n˜ =3444, 1746 cmꢀ1; HRMS (ES): m/z calcd for C22H24NO4:
366.1705 [M+H]+; found: 366.1703.
Oxocine (+)-12a: From g,d-allendiol (+)-2a (53 mg, 0.17 mmol)
and after chromatography of the residue using hexanes/ethyl ace-
tate (2:1) as eluent gave compound (+)-12a (34 mg, 50%) as
a pale-yellow oil. [a]D = +25.8 (c=1.0, CHCl3); 1H NMR (300 MHz,
CDCl3, 258C): d=7.63 and 6.88 (d, each 2H, J=9.2 Hz), 4.63 (d, 2H,
J=1.7 Hz), 4.39 (m, 3H), 3.86 (dd, 1H, J=11.0, 2.2 Hz), 3.57 (s, 3H),
2.20 ppm (t, 3H, J=1.5 Hz); 13C NMR (75 MHz, CDCl3, 258C): d=
164.1, 156.7, 133.4, 130.6, 127.0, 120.5, 114.1, 90.0, 88.7, 80.7, 80.2,
72.1, 68.9, 55.5, 54.1, 23.2 ppm; IR (CHCl3,): n˜ =3426, 1742 cmꢀ1
;
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Acknowledgements
Support for this work by the MINECO (Projects CTQ2012–
33664-C02–01, CTQ2012–33664-C02–02, CTQ2010–20714-C02–
01, and Consolider-Ingenio 2010 (CSD2007–00006)) is gratefully
acknowledged. R.C. thanks the MEC for a predoctoral grant.
E.S. thanks CESGA (USC) and CTI-CSIC for supercomputing
time.
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Keywords: allenes
·
cyclization
·
density functional
calculations · palladium · stereoselectivity
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Published online on && &&, 2014
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FULL PAPER
Joy of cyclization: A chemo-, regio-,
and stereoselective methodology for
the preparation of a variety of diversely
functionalized enantiopure morpholines,
oxocines, and dioxonines involves the
controlled palladium-catalyzed cycliza-
tive coupling reaction of 2-azetidinone-
tethered g,d-, d,e- and e,z-allenic diols
(see scheme).
&
Synthetic Methods
B. Alcaide,* P. Almendros,* R. Carrascosa,
L. Casarrubios, E. Soriano
&& – &&
A Versatile Synthesis of b-Lactam-
Fused Oxacycles through the
Palladium-Catalyzed Chemo-, Regio-,
and Diastereoselective Cyclization of
Allenic Diols
Chem. Eur. J. 2014, 20, 1 – 15
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ