Regioselectivity control in the metal-catalyzed functionalization of γ-allenols, part 2: Theoretical study

Article abstract of DOI:10.1002/chem.200802035

The gold-, palladium- and lanthanum-catalyzed oxycyclization reactions of azetidin-2-one-tethered γ-allenol derivatives to a variety of fused enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines have been developed experimentally (Part 1, a

Full text of DOI:10.1002/chem.200802035

FULL PAPER
DOI: 10.1002/chem.200802035
Regioselectivity Control in the Metal-Catalyzed Functionalization of
g-Allenols, Part 2: Theoretical Study#
Benito Alcaide,*[a] Pedro Almendros,*[b] Teresa Martꢀnez del Campo,[a]
Elena Soriano,*[b] and Josꢁ L. Marco-Contelles[b]
Dedicated to Professor Franco Fernꢀndez on the occasion of his 65th birthday
Abstract: The gold-, palladium- and
lanthanum-catalyzed oxycyclization re-
actions of azetidin-2-one-tethered g-al-
lenol derivatives to a variety of fused
enantiopure tetrahydrofurans, dihydro-
pyrans, and tetrahydrooxepines have
been developed experimentally (Part 1,
accompanying paper). The mechanisms
of these regiocontrolled metal-cata-
lyzed heterocyclization reactions have
now been computationally explored at
the DFT level (Part 2). The energies of
the reaction intermediates and transi-
tion states for different possible path-
ways have been calculated in various
model systems very close to the real
system. Additionally, we selected the
La[NACTHNUGTRNEG(UN SiH3)2]3 complex to simulate the
lanthanide amide precatalyst species.
The agreement of theoretically predict-
ed and experimentally observed selec-
tivities is very good in all cases
Keywords: allenes
density functional calculations
·
cyclization
·
·
gold · palladium
Introduction
structure, not the reagent, is the controlling factor in the se-
lective reaction of one double bond of the allene over the
other. In this context, transition metal-catalyzed-cyclization
of functionalized allenes bearing nucleophilic centers, such
as allenols, has become a useful methodology for the synthe-
sis of heterocycles.[2] In the preceding contribution (Part 1,
accompanying paper),[3] we describe versatile regiocontrol-
led metal-catalyzed heterocyclization reactions of azetidin-2-
one-tethered g-allenol derivatives leading to a variety of
fused enantiopure tetrahydrofurans, dihydropyrans, and tet-
Transition-metal-catalyzed cyclizations of allenes provide
rapid routes to certain molecular skeletons, although the ef-
ficiencies of these reactions can be limited by regioselectivi-
ty issues.[1] It is well known in the chemistry of allenes that
the regioselectivities of the reactions mainly depend upon
the metal catalysts employed. In most cases, the substrate
À
rahydrooxepines. Regioselectivity control in the O C func-
tionalization of g-allenols can be achieved through the
choice of catalyst: AuCl3 exclusively affords tetrahydrofur-
ans, La[NACTHUNGRTNEUNG(SiMe3)2]3 usually favors the formation of dihydro-
[a] Prof. Dr. B. Alcaide, T. Martꢀnez del Campo
Departamento de Quꢀmica Orgꢁnica I
Facultad de Quꢀmica
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax : (+34) 91-3944103
pyrans, whereas PdCl2 entirely gives tetrahydrooxepines. In
addition, it has been observed that for the Au-catalyzed cy-
cloisomerization, a methoxymethyl protecting group not
only masks a hydroxy functionality, but also exerts directing
effects as a controlling unit in a regioselectivity reversal (7-
endo versus 5-exo cyclization). In addition, the regioselectiv-
ity of the La-catalyzed cycloetherification can be tuned (5-
exo versus 7-endo) simply through a subtle variation in the
substitution pattern of the allene component (Ph versus
Me). Thus, for the first time the regiocontrolled heterocycli-
zation of g-allenol derivatives is both catalyst- and sub-
strate-directable.
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros, Dr. E. Soriano, Prof. Dr. J. L. Marco-Contelles
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
esoriano@iqog.csic.es
[#] For Part 1, see ref. [3].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802035.
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1909

The lack of mechanistic information on allenol heterocyc-
lization reactions prompted us to investigate the mechanistic
course of the above processes at a theoretical level. Here we
report the results of a computational study of the regiocon-
trolled metal-catalyzed cycloetherification reactions of azeti-
din-2-one-tethered g-allenols.
and palladium-catalyzed reactions. In order to elucidate gen-
eral mechanistic aspects of the intramolecular lanthanide-
catalyzed hydroalkoxylation/cyclization of g-allenols 4, to
Computational Methods
The density functional theory (DFT) calculations were performed with
the aid of the Gaussian 03 package.[5] The B3LYP hybrid functional of
Becke and of Lee, Yang, and Parr was used.[6] The 6-31G(d) basis set
was used for main-group atoms, while the metal centers Au, Pd, and La
were described with the LANL2DZ basis set,[7] in which the innermost
electrons are replaced by a relativistic effective core potential (ECP) and
the valence electrons are explicitly treated by a double-z basis set. The
optimized geometries were characterized by harmonic analysis, and the
natures of the stationary points were determined according to the
number of negative eigenvalues of the Hessian matrix. The intrinsic reac-
tion coordinate (IRC) pathways from the transition structures were fol-
lowed with a second-order integration method to verify the connections
with the correct local minima.[8] The reported energies, enthalpies, and
free-energies include the vibrational gas-phase zero-point energy term
and thermal corrections, respectively. Solvent effects were allowed for
through single-point calculations on the gas-phase optimized geometries.
The conductor polarizable continuum model (CPCM)[9] as implemented
in the Gaussian 03 package was used, with the parameters chosen by de-
fault. CH2Cl2, DMF, and toluene were selected as model solvents, with
dielectric constants e=8.93, 39.0, and 2.38, respectively. Natural bond or-
bital (NBO) analyses[10] were performed with the module NBO v.3.1 im-
plemented in Gaussian 03 to evaluate the NPA charges at the optimiza-
tion level. To overcome an inherent error in the NBO module as imple-
mented in Gaussian 03 for the La complexes,[11] the LANL2DZ basis set
was applied augmented by addition of an f orbital.
determine factors that govern the observed high regio- and
stereoselectivities, as well as to highlight the roles of sub-
stituents, we have performed a computational study on the
hydroalkoxylation of precursors I, II, and IV (see above) as
theoretical models. Additionally, we also selected the La[N-
AHCTUNGTRENNUNG
in Part 1 (accompanying paper)[3] suggest different activa-
tion modes of the allene moiety on complexation with the
different catalysts. Unfortunately, the computed NPA charg-
es on the reactant complexes I·AuCl3 and I·PdCl2 reveal
similar trends. Complexation on the proximal allenic double
bond (mode a, Figure 1) induces a stronger electrophilic
Results and Discussion
To obtain insights into the factors that govern the regiose-
lectivities of the transition-metal-catalyzed cyclizations and
the roles of substituents, we performed a theoretical study
on different precursors. Taking account both of the experi-
mental observations (Part 1, accompanying paper) and of
the available computational resources, we selected precur-
sors I–III (see below) as theoretical models for the gold-
Figure 1. Optimized structures of the reactant complexes. Mode a relates
to coordination of the proximal allene C=C, and mode b to coordination
of the distal C=C. Hydrogen atoms have been omitted for clarity.
character at C3 (Table 1; see also Figure 2 for orbital topol-
ogy), hence preferentially promoting a 5-exo-trig cyclization.
Because of the hindrance between the catalyst and the TMS
group, the allene moiety coordinates the metal center only
through C2 (Au–C2=2.211 ꢃ), forming a slipped h1-reac-
tant complex, I·AuCl3, whereas the less sterically demanding
PdCl2 forms a h2-complex through coordination of C2 and
C3 (2.057 and 2.279 ꢃ, respectively). The engagement of the
distal allenic double bond (mode b, Figure 1) enhances the
electrophilic character at the central allene carbon C2
(Table 1). The lower steric hindrance induced by the methyl
substituent allows the formation of a more symmetric com-
plex with the gold catalyst (Au–C1 2.283, Au–C2 2.489 ꢃ).
In the case of the complex formed by p-coordination of the
Abstract in Spanish: La reacciꢁn de heterociclaciꢁn de g-ale-
noles catalizada por metales es un proceso regiocontrolado
que da lugar a una amplia variedad de tetrahidrofuranos, te-
trahidropiranos y tetrahidrooxepinas fusionadas enantiopu-
ras, que contienen ademꢀs un anillo b-lactꢀmico, que es la
unidad estructural clave en productos biolꢁgicos relevantes
como antibiꢁticos e inhibidores enzimꢀticos. Se ha llevado a
cabo un estudio teꢁrico para la elucidaciꢁn de los mecanis-
mos de estas ciclaciones catalizadas por oro, paladio y lanta-
no, en estrecha relaciꢁn con el trabajo experimental (Parte 1,
artꢂculo anterior), corroborando los resultados obtenidos en
el laboratorio.
1910
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
Table 1. NPA atomic charges on the reactant complexes. The charge for the uncomplexed precursor is also shown, to illustrate the effect of the catalyst.[a]
Mode[a]
C1
C2
C3
C4
C5
C6
O
M
MCln
–
a
a
b
b
–
À0.495
À0.386
À0.418
À0.473
À0.428
+0.072
À0.188
À0.012
+0.133
+0.057
À0.122
+0.158
+0.050
À0.065
À0.065
+0.091
+0.065
+0.083
+0.108
+0.104
À0.073
À0.075
À0.076
À0.066
À0.064
+0.026
+0.027
+0.028
+0.029
+0.029
À0.738
À0.740
À0.738
À0.764
À0.763
–
–
AuCl3
PdCl2
AuCl3
PdCl2
+0.996
+0.716
+1.011
+0.719
À0.319
À0.339
À0.297
À0.289
[a] Mode a: coordination of the proximal allene C=C. Mode b: coordination of the distal C=C.
Figure 2. Topologies of the acceptor molecular orbital LUMOs on the
complexed structure precursors of I according to the mode of coordina-
tion: mode a (left) and mode b (right).
proximal allenic double bond, the net charge transfer from
the p system to the catalyst is slightly larger than that com-
puted from the distal bond (MCln, Table 1), which produces
a more electrophilic allene moiety (mainly at C3).
On the basis of these electronic data, these binding modes
would preferably promote either 5-exo-trig or 6-exo-dig cyc-
lization through intramolecular nucleophilic addition by al-
ternative paths, to form tetrahydrofuran or dihydropyran
skeletons, respectively. However, the fact that divergent re-
sults are observed suggests that other factors must also
come into play. Firstly, we focused on the AuCl3-catalyzed
cycloisomerization of I. The computed energy values clearly
reveal a kinetic preference for the formation of the fused
tetrahydrofuran scaffold (Table 2). The free energy barrier
to reach the transition structure TSI-5 is thus 5.1 and
8.2 kcalmolÀ1 lower than the corresponding transition struc-
tures for addition to the central (TSI-6) and the terminal
allene carbon (TSI-7), respectively (Figure 3). These results
agree with experimental evidence.
Figure 3. Optimized structures of the transition states and intermediates
for the oxycyclization by alternative pathways.
most stable structure in the gas phase is the tetrahydrofuran
complex, but solvent effects exert a larger effect on the sta-
bilization of the seven-membered ring. The transition struc-
tures and subsequent intermediates show the formation of a
weak hydrogen bond between one of the chloride ligands
From a thermodynamic viewpoint, the formation of the
tetrahydrooxepine intermediate (INI-7) is slightly more exo-
thermic than the formation of the tetrahydrofuran (INI-5)
and dihydropyran (INI-6) intermediates. In this regard, the
and the acidic hydroxy hydrogen (for TS1-5, TS1-6, TS1-7
:
,
2.240, 3.793, 2.242 ꢃ; for IN1-5
IN1-6
1.875 ꢃ).
,
IN1-7
:
1.790,
1.691,
Table 2. Enthalpy and free energy in the gas phase, as well as free energy in solution (kcalmolÀ1) for the cycli-
This
interaction
zation of I by alternative regioisomeric 5-exo-trig, 6-exo-dig, and 7-endo-trig pathways.
slightly stabilizes the structures
relative to non-hydrogen-
bonded structures (when this al-
ternative is possible).
The fact that the cyclization
generates a quaternary center
in an asymmetric manner when
a 5-exo cyclization route is fol-
lowed is due to steric effects in
the transition state. Thus, while
AuCl3
PdCl2
DGgas
DHgas
DGgas
DGsol
DHgas
DGsol
I·MCln
TSI-5
INI-5
TSI-6
INI-6
TSI-7
INI-7
0.0
3.7
0.0
6.1
0.0
1.9
0.0
6.2
0.0
7.5
0.0
4.8
À4.0
À2.7
À5.5
À2.8
15.2
À2.1
15.9
À1.5
À1.2
15.9
À0.8
17.9
0.1
À2.3
8.3
9.6
7.0
9.5
À3.5
14.2
À3.2
À2.6
15.0
À2.5
À5.8
10.1
À10.0
À1.9
11.2
À2.2
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1911

B. Alcaide, P. Almendros, E. Soriano et al.
TSI-5 lacks unfavorable steric interactions, the formation of
the epimer proceeds through the transition structure TSI-5’
(Figure 4), exhibiting distortion of the allenic group in order
to alleviate the steric interaction with the protons at the
lactam ring (distance from the terminal allenic proton to the
lactam proton=2.034 ꢃ in TSI-5’, shorter than sum of van
der Waals radii, versus the distance from the methyl proton
to the lactam proton=2.307 ꢃ in TSI-5). This effect results in
a transition structure 5.3 kcalmolÀ1 higher in energy than
TSI-5, which accounts for the observed stereoselectivity.
imposed by the lactam and endocyclic alkene group re-
strains the tether flexibility and the interaction between re-
active centers. It should be noted, however, that a ring-puck-
ering change upon optimization to the intermediate, INI-7, is
observed to relieve steric congestion in the cyclized adduct
(Figure 3).
Protonolysis of the s-carbon-gold bond would yield the
bicycle type 5 with simultaneous regeneration of the AuIII
species. This process could proceed through two conceivable
paths from the vinyl-Au complex INI-5: by a direct 1,3-H
shift (pathway a), or through a stepwise migration assisted
by the catalyst (pathway b) (Scheme 1).
The results, summarized in Table 3, clearly point to the
stepwise mechanism as the most likely route. It should be
noted that the first step is nearly thermoneutral and takes
place with
a
negligible activation barrier (DGsol =
0.3 kcalmolÀ1) to afford an intermediate, INHb, that still ex-
hibits a strong Au–Cl interaction (2.559 ꢃ). This suggests
that the ligand remains partially attached to the metal
throughout the assisted H-shift. The last step could then be
À
the cleavage of the Au C bond by HCl, to liberate the bicy-
À
cloadduct. The formation of the C H bond and regenera-
tion of the catalyst thus proceeds in a highly exothermic
step through the transition structure TS2Hb, which involves a
free energy barrier of 7.0 kcalmolÀ1. The direct transforma-
tion (pathway a), via TSHa, requires a significantly higher
free energy of activation (DGs°ol =19.8 kcalmolÀ1). The step-
wise pathway is therefore predicted to be considerably fa-
Figure 4. Transition structures for the 5-exo-trig cyclization, showing criti-
cal steric interactions that account for the observed stereochemistry.
The higher stability of the transition structure TSI-5, and
hence the kinetic preference for the formation of the five-
membered oxacycle, is mostly
due to the electronic effects de-
scribed above. In addition,
steric hindrance produced by
the TMS protecting group plays
a significant role. As can be
seen in Figure 3, the bulky
TMS group on the tether center
causes compression of the inter-
nal angle (C3-C4-C5 108.28) to
relieve the steric pressure with
the allenic moiety and lactam
ring, so the reactive centers at
the ends of the system are
moved closer together, thus fa-
voring the cyclization and im-
Scheme 1. Possible pathways for the production of the bicycle of type 5 through protonolysis.
proving the reaction rate
(Thorpe–Ingold effect). In con-
trast, the formation of the
larger seven-membered ring
proceeds through a transition
structure TSI-7, in which the
methyl substituent can rest in
the same plane as the TMS
group. This conformation is
reached without angle compres-
sion; in fact, it proceeds with an
Table 3. Free energy differences in solution (kcalmolÀ1) for the 1,3-H shift from the 5-exo and 7-endo cyclized
adducts.[a]
AuCl3
PdCl2
n=5
n=7
n=5
n=7
INI-n
TSHa
TS1Hb
INHb
TS2Hb
product
0.0 (À5.5)
0.0 (À10.0)
0.0 (À2.3)
0.0 (À2.2)
19.8 (14.3)
0.3 (À5.2)
19.2 (9.2)
0.4 (À9.6)
20.8 (18.5)
À0.1 (À2.4)
À0.2 (À2.5)
7.0 (4.7)
21.3 (19.1)
À0.4 (À2.6)
À0.5 (À2.7)
8.8 (6.6)
À0.3 (À5.8)
6.7 (1.2)
À22.3 (À27.8)
À0.9 (À10.6)
8.6 (À2.4)
À19.6 (À29.6)
À19.7 (À22.0)
À16.0 (À18.2)
angle
opening
(C3-C4-C5
119.78) because the ring strain [a] Free energy differences relative to the reactant complex are shown in parenthesis.
1912
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
vored (by 13.1 kcalmolÀ1) over the concerted path, which
can hence be ruled out as operative. Overall, the 1,3-H shift
is a strongly exothermic process (À22.3 kcalmolÀ1), pointing
to a poorly reversible character.
To sum up, the AuIII-catalyzed cyclization of g-allenol I
(Figure 5) takes place regio- and stereoselectively through a
5-exo hydroalkoxylation because of a kinetic preference
governed by electronic and steric factors.
A possible pathway for the production of the bicyclic tet-
rahydrofuran of type 5 from g-allenol I might thus initially
involve the formation of a complex I·AuCl3 through coordi-
nation of the gold trichloride to the proximal allenic double
bond. Next, regioselective 5-exo oxyauration forms zwitter-
ionic species INI-5. Loss of HCl, followed by protonolysis of
the carbon-gold bond of INHb, affords a product of type 5
and regenerates the gold catalyst (Scheme 2).
Scheme 2. Mechanistic explanation for the AuIII-catalyzed heterocycliza-
tion of g-allenol I.
The PdII-catalyzed cyclizative couplings of g-allenols 4
with allyl halides gave the tetrahydrooxepine-b-lactams 7
Whereas the transition struc-
ture for the 5-exo-trig cycliza-
tion appears to be slightly later
for the PdII-catalyzed processes
than for the AuIII-catalyzed ones
(2.429 vs 2.457 ꢃ, respectively),
the alternative 7-endo-trig pro-
cess is earlier (2.055 vs 1.942 ꢃ,
respectively). Likewise, the
transition structures (very weak
for TSI-6) and subsequent inter-
mediates each show the forma-
tion of a hydrogen bond be-
tween the closest halide ligand
and the hydroxy proton (for
TSI-5, TSI-6, TSI-7: 2.177, 2.607,
2.145 ꢃ; for INI-5, INI-6, INI-7:
1.708, 1.707, 1.741 ꢃ), which is
stronger (shorter) than in the
case of the related AuIII-com-
plexed structures. This effect
Figure 5. Free energy profile (kcalmolÀ1) for the transformation of g-allenol I into the tetrahydrofuran of type 5.
makes the first event of the 1,3-
H shift (formation of INHb inter-
mediate, pathway b, Scheme 1)
(Scheme 2 in Part 1, accompanying paper), resulting from 7-
endo oxycyclization. However, the computed results for the
plausible cyclization modes on the allenol model I show the
same trend as seen before for the AuIII-catalyzed process:
namely, a kinetic preference for the 5-exo-trig cyclization, al-
though the 7-endo-trig cyclization proceeds with a barrier
only 6.4 kcalmolÀ1 higher (versus DGs°ol =8.2 kcalmolÀ1 for
AuIII catalysis). This weaker kinetic preference may be due
to a lower polarization of the allene upon p-coordination to
the metal (Table 1). In this context, we have explored every
alternative process to determine the factors that promote
the 7-endo over the 5-exo cyclization and the allyl coupling
over the H-shift.
a barrierless step (Table 3). Although pallada-tetrahydroox-
epine and pallada-furan intermediates show equivalent
structural and energetic properties, we focus here on the
former; discussion of the latter is presented below. The
formed HCl shows a greater elongation of the Pd–Cl dis-
tance (hence, weaker interaction) in relation to the same
state INI-7 for the Au counterpart (DdM–Cl =0.10 vs 0.06 ꢃ,
respectively; for optimized structures and selected geometric
parameters for AuIII and PdII-mediated protonolysis of INI-7
see the Supporting Information), which suggests easier HCl
À
release. The final formation of the C H bond and regenera-
tion of the catalyst requires a low energy barrier of
8.3 kcalmolÀ1 to be overcome.
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1913

B. Alcaide, P. Almendros, E. Soriano et al.
Alternatively, the presence of an allyl halide promotes a
coupling reaction by trapping with the intermediate INHb
IN1AL). The formation of this h2-complex is exothermic by
.
À7.5 kcalmolÀ1. The coordinated alkene undergoes a 2,1-in-
[15]
À
This process should be favored by the easy HCl release/
metal decoordination. Furthermore, a close inspection of
the vinyl intermediates INI-n suggests that this reaction
should take place more favorably for the pallada-tetrahy-
drooxepine that for the pallada-furan intermediate because
of lower steric hindrance around the reactive centers. The
allyl coupling with the alkenyl PdII intermediate occurs
through insertion into the allylic halide C=C bond to give a
s-C-Pd intermediate, which then undergoes a trans b-elimi-
nation to afford the oxepane product (Figure 6).[12] The
weakly Pd-coordinated HCl in INHb can be easily displaced
by the incoming allyl bromide in a fast ligand-interchange
displacement mechanism, which yields the h2-complex IN1AL
upon p-coordination to the metal. The alkene in this h2-
complex may adopt four perpendicular conformations[13] rel-
sertion into the Pd alkyl bond in a stepwise process that
proceeds through the formation of a Pd complex IN2AL
.
This intermediate is formed via TS1AL, in which the four
atoms forming new bonds (Pd–C 2.079 and C–C 2.097 ꢃ)
are roughly planar (deviation of 8.28). Intriguingly, a cis/
trans isomerization of the chloride ligand takes place to
reach the transition state, probably in order to reduce the
À
back-bonding interaction and to favor the Pd C bond for-
mation. A moderate activation barrier is found for this ele-
mentary step (11.6 kcalmolÀ1), the formation of the pallada-
cyclobutane complex being favored from a thermodynamic
viewpoint (À9.7 kcalmolÀ1).
The cycloalkene fragment in the Pd-complex IN2AL still
appears to be strongly, though asymmetrically, bound to the
metal (Pd–C2 2.169, Pd–C3 2.232 ꢃ), so the intermediate
shows a distorted square-planar geometry around the metal
ative to the Pd-CACHTUNGTRENNUNG(alkenyl) vector, involving different orien-
tations of the methyl bromide moiety.[14] Here we have only
shown the conformation giving rise to the lowest-energy
with a vacant position trans to the new s-Pd C bond. The
À
intermediate IN2AL may then undergo a b-heteroatom elimi-
nation[16,17] to give the coupling product of type 7, regenerat-
ing the active catalyst PdCl2. Here, the liberated HCl plays a
very important role in promoting the dehalopalladation and
inhibiting the b-H elimination.[16g,18] It has been postulated
that halide ions would assist the b-heteroatom elimination,
À
profile for the insertion, in which the CH2Br rests on the
opposite side of the ring and of the endocyclic oxygen. The
p-coordination gives rise to symmetrical Pd-alkene bonds
À
À
[Pd C(H2) 2.246 and Pd C(H) 2.264 ꢃ], and a lengthened
C=C bond (Dd 0.044 ꢃ from the uncomplexed precursor to
Figure 6. Free energy profile (kcalmolÀ1) for the transformation of g-allenol I into the tetrahydrooxepine of type 7. Formation of the corresponding bicy-
cle from protonolysis of the intermediate INHb is shown for comparison.
1914
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
through an E2-like mechanism promoted by halide ion coor-
dination to Pd.[19] This trans b-elimination step takes place
via TS2AL, in which the lengths of the forming and breaking
À
À
bonds (2.481 ꢃ for the Pd Cl bond, 2.088 ꢃ for the Br C)
on one hand, and enlargement of the Pd-alkene distance
(2.703 and 3.205 ꢃ) and advanced opening of the tetracycle
(C-C-C 113.28) indicate a large asynchronicity. The forma-
tion of the diene product thus proceeds in a final exothermic
step by surmounting a low activation barrier (5.1 kcalmolÀ1).
Figure 7 shows the optimized structures for the olefin inser-
Scheme 3. Mechanistic explanation for the PdII-catalyzed heterocycliza-
tion of g-allenol I.
for
the
olefin
insertion
(Figure 8), which accounts for
the rather high activation barri-
er (25.4 kcalmolÀ1) for this step,
14.8 kcalmolÀ1 higher than that
from the seven-membered ring
intermediate. Therefore, given
that the cyclization and HCl for-
mation are likely reversible pro-
cesses under the reaction condi-
tions, it could be argued that intermediate.
the kinetic preference for the
coupling event from the seven
membered-ring relative to other cyclic adducts and also to
the protonolysis of the metal-carbon bond, along with the
greater stability of the coupling product relative to the H-
shift adduct, should funnel the reaction toward the observed
product.
Figure 7. Optimized structures for the PdII–allyl coupling. Some H atoms
have been omitted for clarity.
Figure 8. Transition structure
for the alternative allyl-cou-
pling with the 5-exo cyclized
tion and b-dehalopalladation processes. Alternatively, a syn
b-dehalopalladation might be envisaged, in analogy with the
b-H-elimination in related PdII-promoted processes.[20] Nev-
ertheless, our computed results indicate that this pathway is
less favored from a kinetic viewpoint because the transition
structure on the pathway to the metalla-cyclobutane inter-
mediate is 5.2 kcalmolÀ1 higher in energy that the equivalent
for the alternative b-dehalopalladation (see the Supporting
Information for details).
Scheme 3 outlines a proposed mechanistic explanation for
the production of compounds of type 7. Initial PdII coordina-
tion to the 1,2-diene moiety would give an allenepalladium
complex I·PdCl2. Species I·PdCl2 would undergo an intramo-
lecular cycloetherification reaction to give the intermediate
palladatetrahydrooxepine INI-7, which would react with allyl
bromide via IN1AL to form intermediate IN2AL. A trans b-
heteroatom elimination would generate a tetrahydrooxe-
pine-b-lactam of type 7 with concomitant regeneration of
the PdII species (Scheme 3).
It is worth noting that the cyclization/coupling process af-
fords cycloadducts 7 from 7-endo-trig cyclizations rather
than from the kinetically preferred 5-exo-trig cyclization in-
termediates. This latter plausible mechanism, however, has
been found to involve a highly congested transition structure
Protection of the a-hydroxy functionality with a MOM
moiety has been shown to induce a different process when
AuCl3 is used as catalyst (Scheme 4 in Part 1, accompanying
paper): g-allenols 4 are transformed into dihydrofurans 10
by a chemoselective 5-endo-trig cyclization involving the
ether protecting group. In view of these experimental find-
ings, we carried out calculations on the g-allenol model II;
the optimized structures are depicted in Figure 9. In this
case, the results suggest that the formation of the gold-dihy-
drofuran intermediate complex INII-5endo is kinetic and ther-
modynamically favored over the competing 5-exo-trig and 7-
endo-trig cyclization (Table 4).
The active participation of the protecting group as a nu-
cleophilic entity is due to stereoelectronic and thermody-
namic effects. The reaction takes place through a planarized
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1915

B. Alcaide, P. Almendros, E. Soriano et al.
DSI°I-7 =À11.2, and DS°II-5endo =+2.9 calmolÀ1 KÀ1, respective-
ly). This thus leads to a lower free energy of activation to
achieve TSII-5endo than to achieve other transition structures.
Also, it implies that the formation of INI-5endo has a thermo-
dynamic driving force greater than that corresponding to
the transformation into the alkenyl palladium intermediates
INII-5 or INII-7 (Figure 10).
From the results detailed above, the regioselectivities of
AuIII-catalyzed cyclizations of g-allenols 4 mainly depend on
two factors: the electronic properties of the acceptor carbon
atom of the allene induced by the catalyst, and the structur-
al properties of the a-substituent.
In sharp contrast, protection of the g-hydroxy group in-
hibits the 5-exo cyclization, the 7-endo mode now being the
operative pathway, to yield fused tetrahydrooxepines 11
(Scheme 5 in Part 1, accompanying paper). To shed light on
this result, we have explored both cyclization modes for pre-
cursor III. In this case, the calculations provide a clear pic-
ture and indicate that the 5-exo-trig cyclization transition
structure TSIII-5 is 5.1 kcalmolÀ1 less stable than the 7-endo
cyclization intermediate TSIII-7 because of strong steric ef-
fects. The intramolecular attack on the internal allenic
carbon is inhibited by steric hindrance between the methox-
ymethyl group and the catalyst (Figure 11). A comparison
with the preferential 5-exo transition structure of I (TSI-5)
reveals that TSIII-5 not only lacks the stabilizing H-bond in-
teraction between the hydroxy group and the ligand catalyst
found in TSI-5, but also shows a destabilizing steric interac-
tion owing to the protecting group. The O–C3 distance in
TSIII-5 is shorter (2.384 ꢃ) than
Table 4. Enthalpy and free energy differences in gas and in solution for
the competing AuIII-catalyzed cyclization modes of g-allenol II.
DH
DG
DGsol
II·AuCl3
TSII-5
INII-5
TSII-7
INII-7
0.0
0.0
0.0
7.9
0.3
14.1
À0.2
6.9
À12.7
3.5
À3.4
12.5
À1.8
5.1
6.9
À0.4
15.8
1.0
4.2
À3.5
TSII-5endo
INII-5endo
À2.9
five-membered cyclic transition structure, TSII-5endo, as is
highlighted by the dihedral angle values (C1-C2-C3-C4 1.48,
C2-C3-C4-O À12.28, C3-C4-O-C1 13.2, C4-O-C1-C2 11.5,
O-C1-C2-C3 6.18; see Figure 9). The metal lies in the C1-
C2-C3 allene plane (0.88 in TSII-5endo, vs 6.1 and 17.88 in TSII-
and TSII-7, respectively), which enhances the electrophilic
5
activation of C1. The conformation in TSII-5endo, easily at-
tained with small structural distortion from the reactant
complex, allows an effective orbital overlap between the
lone-pair orbital n and the p* orbital and charge transfer-
ence to the electrophilic fragment, which results in a stabili-
zation of the transition state relative to alternative routes. It
should be noted that the bulky a-substituent in g-allenol I
would preclude effective interaction between the activated
allene carbon and the oxygen atom. Additionally, as can be
deduced from Table 4, the formation of the fused bicycle is
associated with a less favored entropy contribution than in
the case of the non-fused dihydrofuran (DSI°I-5 =À7.9,
in TSI-5 (2.457 ꢃ), which further
enhances the steric repulsion,
as indicated by the deviation of
the metal from the p plane (9.7
vs 0.18 in TSI-5) and the torsion
of the C1-C2-C3-C4 angle (41.4
vs À7.18 in TSI-5). The transition
structure is thus achieved with
a
higher structural distortion
from ideal values. The subse-
quent alkenyl gold intermediate
INIII-5 should be formed by
opening of the C1-C2-C3-C4 di-
hedral angle as the O–C3 dis-
tance decreases, but this torsion
would increase the strong steric
congestion between the catalyst
or the alkene fragment. In fact,
the calculations reveal that
TSIII-5 evolves to a highly unsta-
ble uncyclized intermediate (O–
C3 2.367 ꢃ), only 0.01 kcal
molÀ1 more stable than TSIII-5
,
so it must revert to the reactant
Au complex, which funnels the
reaction toward the formation
of the tetrahydrooxepine.
Figure 9. Optimized structures of the AuIII-catalyzed cyclization step of g-allenol II by the competing 5-endo-
trig, 5-exo-trig, and 7-endo-trig modes.
1916
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
MOM-protected g-allenol 3e
(numbering of compounds con-
sistently with Part 1, accompa-
nying paper) in dichlorome-
thane afforded [4-D]-11a in
48% yield, indicating that a
deuterium atom was incorporat-
ed at the alkenyl carbon
(Scheme 5). The fact that the
AuCl3-catalyzed conversion of
allenol 3e into bicycle 11a in
the presence of two equivalents
of D2O afforded [4-D]-11a—as
judged from the disappearance
of the peak at 6.35 ppm in the
1H NMR spectrum, which is the
signal of the 4-H proton in 2-
oxa-8-azabicycloACTHNUGRTNEUNG[5.2.0]non-4-
en-9-one (11a)—suggests that
deuterolysis of the carbon-gold
bond in species type INIII-7 has
occurred. Along with the
clarification of the reaction
Figure 10. Free energy profile (kcalmolÀ1) for the Au-catalyzed oxycyclization of g-allenol II through alterna-
tive pathways.
Figure 11. Comparison between the transition structures TSI-5 and TSIII-5
.
The pathway proposed in Scheme 4 looks valid for the
formation of products of type 11 from MOM-protected g-al-
lenol derivative III. It could be presumed that the initially
formed allenegold complex III·AuCl3 undergoes an intramo-
lecular attack (7-endo versus 5-exo oxyauration) by the me-
thoxymethyl group, giving rise not to species INIII-5 but to
the tetrahydrooxepine intermediate INIII-7. Protonolysis of
the carbon-gold bond associated with an elimination of me-
thoxymethanol would then liberate the bicycle type 11 with
concomitant regeneration of the AuIII species. Probably, the
proton in the last step of the catalytic cycle comes from
trace amounts of water present in the solvent or the catalyst.
In the presence of the MOM group, 5-exo cyclization falters.
As calculations reveal, 5-exo oxyauration via INIII-5 is re-
stricted by the steric hindrance between the methoxymethyl
group and the substituents at the quaternary stereocenter.
With the aim of trapping the organogold intermediate to
confirm the mechanism of this reaction, we performed deu-
terium labeling studies with deuterium oxide. Under other-
wise the same conditions, but with the addition of two
equivalents of D2O, AuCl3-catalyzed heterocyclization of
Scheme 4. Mechanistic explanation for the AuIII-catalyzed heterocycliza-
tion of MOM-protected g-allenol derivatives III.
Scheme 5. AuIII-catalyzed heterocyclization of MOM-protected g-allenol
derivative 3e (numbering of compounds consistently with Part 1, accom-
panying paper). Reagents and conditions: a) AuCl3 (5 mol%), D2O
(2 equiv), CH2Cl2, RT; MOM=MeOCH2, PMP=4-MeOC6H4.
mechanism, we should at the same time point out that, al-
though metal-catalyzed oxycyclization reactions of allenes
are well known in the case of hydroxyallenes, heterocycliza-
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1917

B. Alcaide, P. Almendros, E. Soriano et al.
tion of alkoxyallenes is not an
easy task and still remains a
real challenge.
The regioselectivities ob-
served in organolanthanide-
mediated
hydrofunctionaliza-
tion processes such as hydro-
phosphination, hydrosilylation,
hydroboration, intermolecular
hydroamination, and intramo-
lecular hydroamination/cycliza-
tion differ markedly from those
seen in the cases of most transi-
tion metal catalysts with similar
substrates, which suggests a dif-
ferent activation mode and re-
action mechanism. In this con-
text, Marks et al. have carried
out comprehensive kinetic and
mechanistic studies that have
led to a generally accepted mechanistic scenario for organo-
lanthanide-catalyzed intramolecular hydroamination/cycliza-
tion.[21] It is characterized by the following features common
to the various unsaturated C=C functionalities: 1) smooth
precatalyst activation through protonolysis by the substrate,
2) a large negative activation entropy (DS°), suggesting a
rather organized transition state, and 3) a reaction rate that
is first order in [catalyst] and zeroth order in [substrate].
Similar conclusions have been also drawn for intramolecular
Scheme 6. Various cyclization modes (5-exo, 6-exo, and 7-endo) of g-allenol I on organolanthanide-catalyzed
hydroalkoxylation.
12.3 kcalmolÀ1)
and
is
slightly
exergonic
(by
À2.7 kcalmolÀ1), thereby indicating a favorable transforma-
tion. The catalytically active structure 15 has relatively poor
conformational freedom because of the b-lactam ring, al-
though other conformers, readily interconvertible, may be
envisaged as a function of the allene orientation; neverthe-
less, the h1-allene complex (La–C1=3.103 ꢃ; Figure 12) is
thermodynamically more stable because of the coordinative
saturation of the electrophilic La center by the p system.
The geometry of the model precatalyst is found to be a tet-
rahedral arrangement around the La3+ ion. The allenic C=C
hydroalkoxylation/cyclization when using La[NACHTNUTRGNEG(UN SiMe3)2]3 as
precatalyst. In addition, labeling studies have suggested a
nonprimary isotopic effect, which is consistent with the un-
saturated C=C bond insertion being the turnover-limiting
step.[22] These observations point to a mechanism through a
slow insertion into the unsaturated moiety, followed by
rapid substrate protonolysis. Computational work by To-
bisch, however, has suggested that in the case of amino de-
rivatives the protonolysis step is only slightly kinetically dis-
À
linkage subsequently adds across the La O functionality of
catalyst complex 15 to afford cyclized intermediates. This
addition can occur through 5-exo, 6-exo, or 7-endo cycliza-
tion pathways, giving rise to the regioisomeric five-, six-, and
seven-membered intermediates IN15-5, IN15-6, and IN15-7, re-
spectively (Scheme 6).
The overall energies involved in hydroalkoxylation/cycli-
zation processes on passing from the acyclic substrates to
the final cyclized products reveal that the processes are
more exothermic for the dihydropyran derivative type 6
(DH0 =À30.8 kcalmolÀ1 vs. À17.8 for the tetrahydrofuran of
type 5 and À15.5 kcalmolÀ1 for the tetrahydrooxepine deriv-
ative of type 13). As can be deduced from the calculated
atomic charges (Table 5), the lanthanide complex increases
the charge density on the bonded oxygen, thus enhancing its
nucleophilic character and preferentially promoting the in-
tramolecular nucleophilic attack over the more electrophilic
allene carbon atoms, C2 and C3.
À
favored relative to the intramolecular C N bond formation,
accounting for the origin of the measured large negative
DS°.[23]
As can be deduced from experimental results (Schemes 1
and 6 in Part 1, accompanying paper)[3], the regioselectivi-
ties of the intramolecular hydroalkoxylations/cyclizations of
g-allenols 4 depend very much on the protecting group and
allene substitution pattern. The catalytic cycle for the orga-
nolanthanide-mediated cyclohydroalkoxylation of allenol I
is initiated by the precatalyst La[NACTHUNGTRNEG(UN SiH3)2]3, which is activat-
ed—through protonolysis—by substrate I, generating the
catalytically active La-alkoxy complex species 15 and liber-
ating the amine ligand (Scheme 6). The precatalyst activa-
In analogy with the results computed for the cyclizations
catalyzed by late transition metals (AuIII and PdII; see
above), these electronic data suggest that the reaction
should preferentially proceed through 5-exo or 6-exo cycliza-
tion, so other factors must mediate to account for the ob-
served structure-dependent regiochemistries. The optimized
structures and energies for the alternative pathways are de-
picted in Figure 1. As can be observed, the 5-exo and 6-exo
tion proceeds through the early transition structure TSPRE
,
in which the acidic hydroxylic proton is still close to the
oxygen atom (1.260 ꢃ). The La–N distance with the leaving
ligand is only slightly longer than that with the oxygen
(2.296 vs. 2.248 ꢃ, respectively). This proton transfer takes
place with a moderately low activation barrier (DG° =
1918
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
furan intermediate (IN15-5
) is
endothermic (by 5.2 kcalmolÀ1).
The formation of the tetrahy-
drooxepine adduct (IN15-7
) is
largely endergonic (by 16.7 kcal
molÀ1), which along with the
unfavorable kinetics suggests
that this would be an inopera-
tive route. The 5-exo cyclization
takes place through a syn addi-
tion of the metal and alkoxy
units across the C=C double
bond. Two alternative pathways
can be envisioned, distinguished
by the orientation of the allene-
methyl substituent relative to
the O-protecting group. In anal-
ogy with the results computed
for the cyclization catalyzed by
late transition metals, the 5-exo
cyclization route should stereo-
selectively afford intermediate
IN15-5, because the formation of
its epimer at C3 takes place
through the less stable transi-
tion structure TS15-5’ (5.6 kcal
molÀ1 higher in energy than
TS15-5
) in which the allene
group adopts a cis orientation
relative to the silyl ether
moiety. This last conformation
results in marked steric conges-
tion arising from the protecting
group and catalyst ligands.
Steric effects can thus discrimi-
nate between the two 5-exo cyc-
lization routes both kinetically
and also thermodynamically,
because IN15-5 is 7.4 kcalmolÀ1
lower in energy than IN15-5’.
Figure 12. Optimized structures of the hydroalkoxylation/cyclization step of g-allenol I in the competing 5-exo,
6-exo, and 7-endo modes. For IN15-5, the molecular structure with the van der Waals atomic radii is depicted.
Free energy differences are given in kcalmolÀ1. Hydrogen atoms have been omitted for the sake of clarity.
À
cyclization paths are kinetically more favorable than the 7-
endo route, a trend consistent with the computed atomic
charges. This La-catalyzed cyclization step therefore shows
the same regioselectivity as that computed for the cycliza-
tion step mediated by late transition metals, although with
the obvious differences in activation and mechanism. From
a thermodynamic viewpoint, the formation of the dihydro-
In TS15-5 the La O bond lengthens from the reactant state
À
(Dl=+0.313 ꢃ) to allow the formation of the incipient C O
À
(2.009 ꢃ) and La C2 (2.705 ꢃ) bonds. This four-membered
metallacycle is found to have a 4.98 folding angle. In this
sense, it should be noted that the tension imposed by the b-
lactam ring would favor the more restrained five-membered
ring closing over larger heterocycles. TS15-5 evolves to the
tetrahydrofuran intermediate IN15-5 (C–O 1.492, La–C2
2.606 ꢃ), which notably displays a strong interaction be-
pyran intermediate (IN15-6
) is slightly exothermic (by
À2.7 kcalmolÀ1), whereas the formation of the tetrahydro-
Table 5. NPA atomic charges on the reactant complex 15. The charge for the uncomplexed precursor I is also shown, to illustrate the effect of the cata-
lyst.[a]
C1
C2
C3
C4
C5
C6
O
La
La[N
–
ACHTUNGTRENNUNG(SiH3)2]2
I
15
À0.480
À0.624
+0.065
+0.076
À0.103
À0.067
+0.125
+0.125
À0.020
À0.019
+0.075
+0.097
À0.758
À1.160
+2.764
+2.771
+0.913
[a] Calculated at the B3LYP/LANL2DZ level (see Computational Methods for details).
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1919

B. Alcaide, P. Almendros, E. Soriano et al.
tween the metal and the lactam carbonylic oxygen atom
(2.556 ꢃ), already incipient in TS15-5 (2.692 ꢃ). This structur-
al element, although it most likely stabilizes the transition
state, places the metal center shielded from other reactive
groups in IN15-5 (see molecular structure constructed with
the van der Waals atomic radii, Figure 12), which could in-
hibit the ensuing protonolysis event and explain the lack of
the tetrahydrofuran scaffold from the reaction products, as
we discuss later.
closure through the 6-exo route is sterically demanding as a
result of severe repulsive interactions between the methyl
substituent and the catalyst backbone (Figure 12), thus
making this pathway significantly more expensive kinetically
than the 5-exo path. Remarkably, a ring-puckering change
takes place to afford a boat-like cyclized intermediate, IN15-
6, a conformation that allows the coordination, albeit weak,
of the lanthanide complex to both ether moieties (La–O
2.973 and La–OTMS 2.693 ꢃ). This coordination mode, along
with the h3-allylic coordination (La–C1 2.777, La–C2 2.699,
La–C3 2.928 ꢃ), stabilizes the dihydropyran framework. Al-
ternatively, the ring closure can proceed through the catalyst
approaching trans to the OTMS group. However, this step is
about 2 kcalmolÀ1 less favorable because of the lack of sta-
bilizing interaction between the ether and the metal center.
In summary, the kinetic preference for the formation of
IN15-5 is likely due to electronic effects, whereas the thermo-
dynamic preference for the formation of IN15-6 can be traced
back to steric factors associated with the coordination mode
of the catalyst. The evolution of each heterocyclic inter-
mediate is thus decisive to account for the experimental re-
sults.
The cyclization is followed by a La–C protonolysis pro-
cess, which regenerates the catalyst and releases the hetero-
cyclic product. In this context it is possible to envision two
possible pathways: i) protonolysis by g-allenol I, which leads
to the corresponding cycloadduct and regenerates 15, thus
reinitiating the catalytic cycle, or ii) protonolysis by the li-
berated amine, which ends the process and regenerates the
precatalyst form. As suggested by the results shown in
Figure 12, the thermodynamic population of IN15-7 is likely
negligible, owing to the kinetically precluded, strongly endo-
thermic 7-endo cyclization. As a consequence, the path for
protonolysis to provide the tetrahydrooxepine product
should remain blocked, irrespective of whether or not proto-
nolysis is kinetically feasible. The discussion is therefore pri-
marily focused on the favorable pathways for proton trans-
fer for IN15-5 and IN15-6 intermediates.
Similarly to what was computed for the AuIII- and PdII-
catalyzed processes, the formation of the seven-membered
ring intermediate IN15-7 proceeds with the highest activation
barrier of the regioisomeric paths, the subsequent intermedi-
ate also being the least stable cycloadduct out of the possi-
ble regioisomers. Although electronic factors can account
for the high barrier, the distorted structure of IN15-7 would
explain the low thermodynamic stability. The metal center
bonds both with the oxygen atom and with C2 in IN15-7
,
which obstructs the coplanar arrangement of the olefin sub-
stituents, that is, La and methyl moieties (torsion angle
C
methyl-C3-C2-La 56.88), whereas the ring-puckering changes
(as in the case of INI-7; see above) to relieve steric conges-
tion due to the bulky protecting group in the cyclized
adduct. Additionally, this arrangement enhances the steric
repulsion between the methyl substituent and the protecting
group.
Alternatively, a relaxed conformed IN15-7’ in which the
lack of La–O interaction allows the coplanar rearrangement
of the olefinic substituents has been located (Figure 13).
However, this intermediate is only 1 kcalmolÀ1 more stable
than IN15-7. The conformational rearrangement involves the
relaxation and opening of the C3-C4-C5 bond angle and the
concomitant closure of the angles C3-C4-OTMS and C5-C4-
OTMS, thus giving rise to stronger steric repulsions between
the protecting group and the lactam and C3 substituents
(Figure 13).
A second substrate molecule (simulated here as 3-hy-
droxy-1-methylazetidin-2-one) coordinates to the lanthanum
center to form the complex INP15-n prior to the proton trans-
fer from the hydroxy group to the La species. Under these
conditions, it would be expected that the larger the steric
crowding around the metal center, the harder the transfer.
This proton transfer step affords a La–O complex stabilized
by coordinative interaction with the oxygen lone pair, which
after dissociation regenerates the active catalyst. If the pro-
tonolysis of the five- and six-membered intermediates IN15-5
and IN15-6, respectively, is taken into account, the initial for-
mation of the precursor adducts INP15-5 and INP15-6 is uphill
at the DG surface because the pertinent enthalpic stabiliza-
tion is not counterbalanced by the entropic penalty accom-
panying the bimolecular association. We therefore focus on
the cyclization adduct as reference.
Figure 13. Optimized geometries of 7-endo-oxycyclized conformers.
In the 6-exo cyclization, the late transition structure TS15-6
(reached at the shortest C–O distance: 1.856 ꢃ, vs. 2.009
and 2.067 ꢃ for TS15-5 and TS15-7, respectively) is a nearly
symmetric h2-complex (C1–La 2.855; C2–La 2.810 ꢃ). Ring
For the protonolysis of the external allyl position of IN15-6
,
the hydroxy group of the incoming substrate can freely
accede to the coordination sphere around the metal center.
1920
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
A transition-state structure, TSP15-6, representing simultane-
have a pseudotetrahedral architecture around the La3+ ion,
with alkenyl and carbonyl moieties as ligands (La–C2=
2.606 and La–O=2.556 ꢃ), so an efficient approach by the
alcohol must take place on the opposite side to the La–O in-
teraction and must be accompanied by a conformational re-
arrangement around the metal, which should indeed weaken
the carbonyl interaction. In addition, the methyl substituent
at C3 and the terminal alkene carbon C1 also exert strong
steric hindrance. The activation energy to reach transition
À
À
ous O H bond cleavage and C H bond formation in an
asynchronous mode (1.161 vs. 1.406 ꢃ) is encountered along
the favorable path for the proton transfer. TSP15-6 evolves to
the complexed product P15-6, from which the cyclic skeleton
of type 6 is liberated in a kinetically facile displacement by
the incoming I. The transition state energy for protonolysis
relative to complex IN15-6 is 23.1 kcalmolÀ1 (20.4 kcalmolÀ1
relative to reactants; Figure 14), and the product, P15-6, is
stabilized by 1.4 kcalmolÀ1 with respect to IN15-6 (4.1 kcal
molÀ1 relative to reactants). The accessible activation enthal-
py (DH2°98 =11.8 kcalmolÀ1) in the protonolysis step is con-
sistent with a concerted transition state, with significant
bond formation to compensate for simultaneous bond cleav-
state TSP15-5 is therefore high (25.9 kcalmolÀ1 from IN15-5
,
31.1 kcalmolÀ1 relative to reactants), this structure being
>10 kcalmolÀ1 less stable than TS15-6 for the competing for-
mation of the dihydropyran type 6.
The protonolysis of diastereomeric IN15-5’ was also consid-
ered, but the attack of the alcohol is predictably inhibited
by the bulky protecting group (activation barrier of 30.4 kcal
molÀ1 from IN15-5’) or, alternatively, by the terminal alkene
carbon C1 (activation barrier of 28.2 kcalmolÀ1 from IN15-5’),
depending on the approaching mode. Consequently, these
findings suggest that, whereas a 5-exo mode would be the
preferred cyclization pathway from a kinetic viewpoint, the
ensuing protonolysis step is inhibited by severe steric con-
gestion around the reactive centers on the cyclized inter-
mediate. These results show an overall kinetic preference
for the competing formation of the six-membered ring
adduct type 6, which has a thermodynamic driving force
greater than that corresponding to the transformation of g-
allenol I into bicycle type 5. With regard to the second con-
ceivable protonolysis mode—that is, protonolysis by the li-
age. The large, negative activation entropy (DS°298
=
À28.6 calmolÀ1 KÀ1) is consistent with a highly organized
transition state in which a significant loss of internal degrees
of freedom occurs from a bimolecular association. Release
of the heterocyclic products by complex dissociation is an
exothermic process. The overall transformation from I into
bicycle type 6 is exothermic, driven by a thermodynamic
force of À30.8/À28.9 molÀ1 (DH/DG).
Alternatively, we explored the protonolysis of the 5-exo
cyclization intermediate IN15-5. The regioisomeric pathway
for protonation to afford IN15-6 is predicted to be distinctly
impeded kinetically because the access of the external alco-
hol to the metal center is complicated by the moderately
strong interaction with the carbonyl oxygen of the amide
moiety in IN15-5 (Figure 12). This intermediate is found to
Figure 14. Free energy profile (kcalmolÀ1) of the intramolecular hydroalkoxylation/cyclization of La-alkoxy complex 15 to give the tetrahydrofuran of
type 5 and the tetrahydropyran of type 6.
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1921

B. Alcaide, P. Almendros, E. Soriano et al.
berated amine, thus ending the process and regenerating the
homoleptic lanthanide amide precatalyst—the pertinent
transition structure (N–H=1.213, C–H=1.378 ꢃ) is only
1.2 kcalmolÀ1 less stable than that found for the alternative
mode. Consequently, this path cannot be ruled out as an op-
erative mechanism.
Scheme 7 shows a mechanistic rationale for the La[N-
ACHTUNGTRENNUNG(SiH3)2]3-promoted conversion of methyl g-allenol I into the
fused tetrahydropyran of type 6. Firstly, lanthanum precata-
4b is transformed exclusively into the unprotected tetrahy-
drooxepine 13 in a regioselective 7-endo cyclization under
the lanthanide amide conditions. In view of these experi-
mental findings, we carried out calculations on the La com-
plex 16, formed through protonolysis by g-allenol II. The
computed free energy profiles for the cyclization step by the
possible modes (Scheme 8) show the same trend as seen for
15: that is, the 5-exo cyclization and 6-exo cyclization paths
are kinetically and thermodynamically more favorable than
the 7-endo route (Figure 15), in disagreement with the ex-
perimental evidence. The optimized structures are depicted
in Figure 15. These results led us to suppose that the elimi-
nation of the protecting group might take place before the
cyclization event, thus relaxing the reactant complex struc-
ture and favoring the formation of the larger seven-mem-
bered adduct over alternative pathways. Nevertheless, the
calculations predict that the unprotected complex 17 should
undergo a 7-endo cyclization by surmounting an energy bar-
rier of 23.1 kcalmolÀ1, only 0.5 kcalmolÀ1 lower than that
computed for the parent model 16.
As we have described above, the strained 7-endo cyclized
intermediate can undergo a conformational rearrangement
to a rotamer lacking La–O interaction, allowing the copla-
nar rearrangement of the olefinic substituents. Unlike in the
case of 15, this conformational relaxation to IN16-7’ gives rise
to a stabilization of 7.6 kcalmolÀ1 in relation to IN16-7 be-
cause the protecting group is positioned without steric repul-
sions after the opening of the C3-C4-C5 and the closure of
the C3-C4-OMOM and C5-C4-OMOM bond angles in IN16-7
’
(Figure 16). Moreover, this s–h1 complex shows a suitable,
unhindered, geometry around the reactive points for the
subsequent attack of the alcohol in the protonolysis step. To
address this question conveniently, we computed the ener-
getics of the protonolysis step for the proposed intermedi-
Scheme 7. Mechanistic explanation for the LaIII-catalyzed heterocycliza-
tion of methyl g-allenol I.
ates IN16-5, IN16-6, and IN16-7
.
lyst would form the alkoxide–La compound 15 through pro-
tonolysis at the La-[NACHTUNGTRNEGNU(SiH3)2]3 bond by allenol I. Subse-
The calculations predict that the tetrahydrofuran frame-
work should undergo a protonolysis showing an energy bar-
quently, one p bond of the oxal-
lene-La complex would regio-
À
specifically add across the La
O functionality of 15 to afford
oxacyclic intermediate IN15-6 by
6-exo cyclization to the central
allene carbon. The intervention
of a second molecule of allenol
I would facilitate the proton-
transfer step to afford species
P15-6 via transition state TSP15-6
,
which after dissociation would
deliver the oxacycle of type 6
and regenerate 15, thus reiniti-
ating the catalytic cycle.
A rather different regiochem-
ical outcome is experimentally
found for MOM-protected g-al-
lenols (Scheme 6 in Part 1, ac-
Scheme 8. Various organolanthanide-catalyzed hydroalkoxylation cyclization modes (5-exo, 6-exo, and 7-endo)
companying paper). The allenol of MOM-protected g-allenol II.
1922
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
undergo a slightly less favorable
protonolysis, due to the stron-
ger La–OOMOM interaction in
IN16-6 (2.654 vs. 2.692 ꢃ in IN15-
6), which provides a less electro-
philic metal center for subse-
quent interaction with allenol
II. As would be expected, the
tetrahydrooxepine skeleton fol-
lows the kinetically more acces-
sible protonolysis because of
the decreased repulsive steric
interactions between the incom-
ing allenol and the La-s–h1
complex. The allenol can inter-
À
act with the La C bond
through an unhindered tilted
approach to the p plane of
IN16-7’ (Figure 17).
The steric pressure therefore
raises the protonolysis barrier
and inhibits the formation of 18
and 19 in favor of the less ob-
structed
tetrahydrooxepine
adduct 20. In summary, these
data suggest that the cyclization
event is sensitive to electronic
and steric factors in the alkoxy-
cyclization, but that the proto-
nolysis process is even more de-
pendent on steric effects as a
result of the substituents on
more compact and congested
intermediate structures. This
would account for the different
mechanistic schemes postulated
by Marks,[21] who defended a
À
rate-limiting intramolecular C
Figure 15. Optimized structures in the hydroalkoxylation/cyclization of g-allenol II by competing 5-exo, 6-exo,
and 7-endo modes. Free energy differences are given in kcalmolÀ1. Hydrogen atoms have been omitted for the
sake of clarity.
C insertion into the lanthanide-
heteroatom bond, and To-
bisch,[24] who claimed a turn-
over-limiting protonation of the
cyclized intermediate for related hydroamination/cyclization
processes.
The proposed catalytic cycle for the La[NACHTUNGTRNEG(UN SiH3)2]3-cata-
lyzed conversion of g-allenol II into fused tetrahydrooxepine
20 is depicted in Scheme 9. Initially, lanthanum precatalyst
would form the alkoxide-La compound 16 through protonol-
À
ysis at the La [NACTHNUTRGNEUNG(SiH3)2]3 bond by allenol II. Next, the
distal p bond of the oxallene-La complex would regiospecif-
À
ically add across the La O functionality of 16 to afford tet-
Figure 16. Optimized geometries of 7-endo oxycyclized conformers IN16-7
and IN16-7’.
rahydrooxepine intermediate IN16-7’ by 7-endo cyclization.
The intervention of a second molecule of allenol II would
facilitate the proton-transfer step to afford species P16-7 via
transition state TSP16-7, which after dissociation would deliv-
er oxacycle 20 and regenerate 16, thus reinitiating the cata-
lytic cycle.
rier similar to that seen for the silylated derivative (Fig-
ures 17 and 18), while the dihydropyran h3-complex should
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1923

B. Alcaide, P. Almendros, E. Soriano et al.
erties, such as atomic charges,
for the reactant La-complexes
16 and 21 (Scheme 8) appear
similar for both g-allenols
(Table 6), hence pointing to
parallel electrophilicity of the
allene carbon C3. The differ-
ence in reactivity thus likely
arises from steric effects. Under
these circumstances, the steri-
cally more demanding C-phenyl
group might drive the reaction
through a divergent mechanistic
Figure 17. Optimized transition structures for the protonolysis step.
channel.
In sharp contrast, the lanthanum-catalyzed reaction of the
related phenyl-allene 4e affords the strained tricycle 14 in
high yield, with dihydropyran 6b as a minor product
(Scheme 6 in Part 1, accompanying paper). Thus, through a
subtle variation in the substitution pattern of the allene
component (Ph vs. Me) the preferential formation of the
seven-membered regioisomer can be reversed. To account
for this unexpected result, it might be envisaged that elec-
tronic factors could come into play, because the electron-
withdrawing phenyl substituent could enhance the electro-
philicity of the benzylic carbon relative to the electron-do-
nating methyl group, therefore favoring the 5-exo over the
7-endo cyclization. However, the calculated electronic prop-
The formation of the tricyclic skeleton indicates the initial
formation of the 5-exo cyclized adduct, which, as has been
shown above, is the kinetically preferred cyclization route.
As would be expected, the computed results once again pre-
dict the same trend as seen before for 15 and 16: a kinetical-
ly favored 5-exo cyclization. The activation barriers are
slightly higher than those predicted for the simpler model 16
because of the steric effects arising from the allene substitu-
ent: the transition structures for the 7-endo and 6-exo cycli-
zations—TS21-7 and TS21-6, respectively—show the phenyl
plane moderately deviating from the p plane of the bounded
unsaturated C=C group (27 and 238) to alleviate steric re-
pulsions with the protecting group and catalyst ligands.
Figure 18. Free energy profile (kcalmolÀ1) of the intramolecular hydroalkoxylation/cyclization of La–alkoxy complex 16. Some structures have been
omitted for the sake of clarity.
1924
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
stems from the steric repulsion between the aromatic ring
and the alkoxy oxygen, which induces the opening of the di-
hedral angle C3-C4-C5-C6 (À33.98 for TS21-5’, À0.28 for TS16-5’),
thus allowing a moderate stabilizing La–OOMOM interaction
(2.943 for TS21-5’, 4.772 ꢃ for TS16-5’) (Figure 19). These ob-
servations indicate that the steric effects introduced by the
phenyl group are able to lead to significant changes in the
position of the transition state on the reaction coordinate.
With regard to the protonolysis step, the computed
energy profiles (Figure 20) reveal higher barriers for the six-
and seven-membered heterocycles than for the parent pre-
cursor 16 because of the steric obstruction from the phenyl
substituent to the incoming H-donor. As would be expected,
this effect is stronger for TSP21-7 (energy barrier increased by
14 kcalmolÀ1) than for TSP21-6 (energy barrier increased by
5 kcalmolÀ1), due to the disposition of the aromatic ring
with respect to the metal center and the approaching H-
donor. In contrast, the five-membered ring intermediate un-
dergoes a protonolysis process showing similar energy barri-
ers (cis and trans) to those for 16.
Overall, these results suggest the preferential formation
of the dihydropyran skeleton, which disagrees with the ex-
perimental evidence because that was found as a minor
product. The formation of the tricyclic framework of type 14
might proceed through the paths depicted in Scheme 10. By
the postulated pathway a, a protonolysis step of the inter-
Scheme 9. Mechanistic explanation for the LaIII-catalyzed heterocycliza-
tion of g-allenol II.
These effects are probably responsible for the slightly in-
creased energy barriers.
A better stabilization of the
h3-allyl lanthanide complex
IN21-6, probably as a conse-
quence of a weak La–phenyl in-
teraction, should also be noted.
For 21, on the other hand, the
5-exo cyclization through
a
trans orientation of the allene
moiety relative to the protect-
ing group (through TS21-5) in-
volves an energy barrier about
1 kcalmolÀ1 higher than in 16
because of the steric pressure
caused by the allene substitu-
ent, whereas the cyclization
through
a
cis orientation
(through TS21-5’) is kinetically
more accessible than in the
analogous case for 16. The tran-
sition state is reached earlier
for 21 than for 16, as suggested
by the forming bond lengths
(1.995 for TS21-5’ and 1.970 ꢃ
for TS16-5’). This divergent trend
Figure 19. Optimized geometries of 5-exo oxycyclization.
Table 6. NPA atomic charges on the reactant complexes 16 and 21.[a]
C1
C2
C3
C4
C5
C6
O
La
La[NACHTUNGTRENNUNG(SiH3)2]2
21
16
À0.612
À0.588
+0.077
+0.092
À0.079
À0.106
+0.092
+0.103
À0.021
À0.023
+0.100
+0.101
À1.158
À1.155
+2.768
+2.762
+0.914
+0.911
[a] Calculated at the B3LYP/LANL2DZ level (see Computational Methods for details).
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1925

B. Alcaide, P. Almendros, E. Soriano et al.
the metal center by the exocy-
clic group.[23–25] However, the 5-
endo cyclization under study
could gain from a smaller annu-
lar tension in relation to the 4-
exo route. Indeed, the comput-
ed energy profiles for the two
processes reveal a slight kinetic
preference (by 1.1 kcalmolÀ1)
for the formation of IN521-5’.
These results led us to pro-
pose pathway b, in which a 4-
exo oxyclization directly affords
Figure 20. Free energy profile (kcalmolÀ1) of potential intramolecular hydroalkoxylation/cyclizations of La-
alkoxy complex 21.
tricycle type 14 and the La
complex 23. Ensuing protonoly-
sis, kinetically very accessible,
regenerates the precatalyst
structure and liberates dimethyl
ether as by-product. This path-
way is structurally characterized
in Figure 21. As a result of the
steric repulsions produced by
the phenyl substituent, the ini-
tial oxycyclization to IN21-5
’
places the reactive centers close
enough (2.714 ꢃ) to ensure a
minor geometric rearrangement
to achieve the transition state
TSC21-5
computed
’
(C–O 2.120 ꢃ). The
atomic charges
reveal a higher value for the O
atom (À0.678) and a lower one
for the C2 atom (À0.586) than
observed in the initial complex
21 (Table 6), although the
energy barrier value appears
slightly higher than that for an
alternative path (protonolysis
Scheme 10. Proposed modes of formation of tricycle type 14 by two alternative pathways.
mediate IN21-5’ would yield the coordinated alkene IN221-5’,
which might undergo a subsequent 4-exo oxycyclization to
IN421-5’ through catalyst activation via IN321-5’. Predictably,
the formation of IN221-5’ and IN321-5’ takes place with energy
barriers lower than for the formation of IN21-5’, hence sup-
porting this path as an operative route. Nevertheless, two
disappointing questions now arise. Firstly, IN421-5’ could un-
dergo an easy protonolysis to afford 22, because the reactive
centers are unhindered to the incoming H-donor structure,
whereas the lanthanide-assisted elimination of the olefinic
proton to yield compound type 14 would involve higher
steric pressure.
Secondly, IN321-5’ could evolve through a 5-endo oxycycli-
zation to deliver a less strained five-membered ring inter-
mediate IN521-5’. Theoretical studies have found a preference
for exo cyclization over its endo counterpart (in general to
yield 5- rather than 6-cyclized adducts) for a variety of unsa-
turated precursors and have concluded that endo cyclization
is not seen to benefit from a coordinative stabilization of
of the 6-exo cyclization adduct). This mechanism would be
favored over other conceivable routes (Scheme 10) and it
accounts for the competing formation of the tricyclic frame-
work over other five- and seven-membered ring adducts.
A conceivable catalytic cycle to account for the La[N-
AHCTUNGTRENNUNG
Conclusion
In summary, an efficient metal-controlled regiodivergent
preparation of bicyclic tetrahydrofurans, dihydropyrans, and
tetrahydrooxepines, also bearing b-lactam moieties, from
starting enantiopure g-allenols has been developed. These
are key structural motifs in biologically relevant compounds
such as antibiotics and enzyme inhibitors. Theoretical work
directed towards the elucidation of the mechanisms of the
gold-, palladium-, and lanthanum-catalyzed oxycyclizations
1926
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928

g-Allenols
FULL PAPER
31, 12; g) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737; Angew.
Chem. Int. Ed. 2000, 39, 3590.
[3] For Part 1, see preceding paper: B. Alcaide, P. Almendros, T. Martꢀ-
nez del Campo, E. Soriano, J. L. Marco-Contelles, Chem. Eur. J.
2009, 15, 1909–1928.
[4] For a preliminary communication, see: B. Alcaide, P. Almendros, T.
Martꢀnez del Campo, Angew. Chem. 2007, 119, 6804; Angew. Chem.
Int. Ed. 2007, 46, 6684.
[5] Gaussian 03, Revision B.03, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgo-
mery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2003.
Figure 21. Optimized geometries for the final oxycyclization to the tricy-
clic product.
[6] a) C. Lee, W. Yang, R. Parr, Phys. Rev. B 1988, 37, 785–789; b) A.
Becke, J. Chem. Phys. 1993, 98, 5648.
[7] P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 270.
[8] a) K. Fukui, Acc. Chem. Res. 1981, 14, 363–368; b) C. Gonzalez,
H. B. Schlegel, J. Phys. Chem. 1990, 94, 5523.
[9] V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995.
[10] NBO Version 3.1, E. D. Glendening, A. E. Reed, J. E. Carpenter, F.
Weinhold, for original literature, see: a) A. E. Reed, F. Weinhold, J.
Chem. Phys. 1983, 78, 4066; b) A. E. Reed, L. A. Curtiss, F. Wein-
hold, Chem. Rev. 1988, 88, 899.
[11] NBO is generating an incorrect table for the number of valence or-
bitals of each angular momentum type. It assumes that the last elec-
tron occupies an f orbital but it is actually a d electron and so the
LANL2DZ basis does not include f functions.
Scheme 11. Mechanistic explanation for the LaIII-catalyzed heterocycliza-
tion of g-allenol IV.
[12] a) J. S. Prasad, L. S. Liebeskind, Tetrahedron Lett. 1988, 29, 4257.
For studies on PdII-catalyzed coupling-cyclization of a- or b-amino
allenes with allylic halides, see: b) S. Ma, W. Gao, Tetrahedron Lett.
2000, 41, 8933; c) S. Ma, F. Yu, W. Gao, J. Org. Chem. 2003, 68,
5943; d) S. Ma, F. Yu, J. Li, W. Gao, Chem. Eur. J. 2007, 13, 247.
[13] a) A. Michalak, T. Ziegler, Organometallics 1999, 18, 3998; b) R. J.
Deeth, A. Smith, J. Brown, J. Am. Chem. Soc. 2004, 126, 7144.
[14] In addition to these perpendicular conformations, four parallel
has been pursued in closed relationship with the experimen-
tal study (Part 1, accompanying paper) and has corroborated
the bench results to provide a complete study of the reactiv-
ity of g-allenols.
À
structures with the C=C parallel to the s-Pd C bond could also be
envisioned. However, in these cases the local minima either do not
exist at all or are so shallow that the geometry optimizations eventu-
ally lead to the perpendicular complexes.
Acknowledgement
[15] The regioselectivity found here is quite similar to those found in the
insertion reactions of alkenes with many neutral PdII complexes.
a) A. Michalak, T. Ziegler, Organometallics 2000, 19, 1850; b) W.
Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2. It can readily be ex-
plained by a polarization of the p orbital in alkene toward the CH2
group.
Support for this work by the DGI-MEC (CTQ2006-10292), the Comuni-
dad Autꢄnoma de Madrid (CCG-07-UCM/PPQ-2308), and the Universi-
dad Complutense de Madrid (Grant GR74/07) is gratefully acknowl-
edged. T.M.C. thanks the MEC for a predoctoral grant.
[16] a) P. J. Harrington, L. S. Hegedus, K. F. McDaniel, J. Am. Chem.
Soc. 1987, 109, 4335; b) J. W. Francis, P. M. Henry, Organometallics
1991, 10, 3498; c) M. Kimura, Y. Horino, R. Mukai, S. Tanaka, Y.
Tamaru, J. Am. Chem. Soc. 2001, 123, 10401; d) F. Ozawa, H. Oka-
moto, S. Kawagishi, S. Yamamoto, T. Minami, M. Yoshifuji, J. Am.
Chem. Soc. 2002, 124, 10968; e) K. Manabe, S. Kobayashi, Org. Lett.
2003, 5, 3241; f) G. W. Kabalka, G. Dong, B. Venkataiah, Org. Lett.
2003, 5, 893; g) M. Yoshida, T. Gotou, M. Ihara, Chem. Commun.
2004, 1124; h) G. Liu, X. Lu, Org. Lett. 2001, 3, 3879.
[1] For general and comprehensive reviews, see: a) S. Ma, Chem. Rev.
2005, 105, 2829; b) Modern Allene Chemistry (Eds.: N. Krause,
A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; c) R. Zimmer, C. U.
Dinesh, E. Nandanan, F. A. Khan, Chem. Rev. 2000, 100, 3067.
[2] For selected reviews, see: a) R. A. Widenhoefer, Chem. Eur. J. 2008,
14, 5382–5391; b) N. Bongers, N. Krause, Angew. Chem. 2008, 120,
2208; Angew. Chem. Int. Ed. 2008, 47, 2178; c) R. A. Widenhoefer,
X. Han, Eur. J. Org. Chem. 2006, 4555; d) A. Hoffmann-Rçder, N.
Krause, Org. Biomol. Chem. 2005, 3, 387; e) S. Ma, Acc. Chem. Res.
2003, 36, 701; f) R. W. Bates, V. Satcharoen, Chem. Soc. Rev. 2002,
[17] For the stereoselectivity of b-heteroatom elimination, see: a) C. G.
Frost, J. Howarth, J. M. J. Williams, Tetrahedron: Asymmetry 1990,
Chem. Eur. J. 2009, 15, 1909 – 1928
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1927

B. Alcaide, P. Almendros, E. Soriano et al.
23, 201; b) G. Zhu, X. Lu, Organometallics 1995, 14, 4899; c) B. Al-
caide, P. Almendros, T. Martꢀnez del Campo, Angew. Chem. 2006,
118, 4613; Angew. Chem. Int. Ed. 2006, 45, 4501.
[22] For the sole report on lanthanide-catalyzed hydroalkoxylations of al-
lenols, see: X. Yu, S. Seo, T. J. Marks, J. Am. Chem. Soc. 2007, 129,
7244.
[23] S. Tobisch, Chem. Eur. J. 2007, 13, 9127.
[18] X. Lu, G. Zhu, Z. Wang, Synlett 1998, 115, and references therein.
[19] Z. Zhang, X. Lu, Z. Xu, Q. Zhang, X. Han, Organometallics 2001,
20, 3724.
[20] For a computational study, see: D. Balcells, F. Maseras, B. A. Keay,
T. Ziegler, Organometallics 2004, 23, 2784.
[24] S. Tobisch, J. Am. Chem. Soc. 2005, 127, 11979.
[25] a) S. Tobisch, Chem. Eur. J. 2006, 12, 2520; b) for a computational
mechanistic study of the organolanthanide-mediated intermolecular
hydroamination of 1,3-dienes and primary amines, see: S. Tobisch,
Chem. Eur. J. 2005, 11, 6372.
[21] S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673.
Received: October 2, 2008
Published online: January 8, 2009
1928
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1909 – 1928